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Evaluating automated rules for rapid response system alarm triggers in medical and surgical patients
Patients typically show signs and symptoms of deterioration hours to days prior to cardiorespiratory arrest.1,2 The rate of inhospital cardiorespiratory arrest (CRA) requiring cardiopulmonary resuscitation is estimated to be 0.174 per bed per year in the United States.3 After CRA, survival to discharge is estimated to be as low as 18%.3,4 Efforts to predict and prevent arrest could prove beneficial.1,2
Rapid response systems (RRS) have been proposed as a means of identifying clinical deterioration and facilitating a timely response. These systems were designed to bring clinicians with critical care expertise to the bedside to prevent unnecessary deaths. They typically include an afferent limb (detects deteriorating patients), an efferent limb (responds to calls and acts to avoid further deterioration), and administrative and data analysis limbs.5,6 Automatic provision of recommendations and computer-based systems are desirable components of the afferent limb of the detection system.6 Both are independent predictors of improved clinical practices for clinical decision support systems.7 However, the existing early warning scores (EWS) may not be ready for automation due to low positive predictive values (PPV) and sensitivities.8
It is possible that the low discriminatory accuracy of the published EWS may be secondary to the use of aggregate patient populations for derivation of scores. We hypothesized that these EWS perform differently in medical and in surgical subpopulations. Also, the EWS need to be tested in a time-dependent manner to serve as a realistic clinical support tool for hospitalized patients.
STUDY AIM
The aim of this study was to evaluate the differential performance of widely used EWS in medical vs surgical patients.
METHODS
Site
The study was conducted in an academic center with 2 hospitals in Southeastern Minnesota totaling approximately 1500 general care nonintensive care unit (ICU) beds. The Mayo Clinic Institutional Review Board approved the research proposal.
Subjects
Our retrospective cohort was comprised of all adult inpatients discharged from 2 academic hospitals between January 1, 2011 and December 31, 2011 who spent any time in a general care (non-ICU) unit. We excluded patients younger than 18 years, psychiatric or rehabilitation inpatients, those without research authorization, and patients admitted for research purposes.
Study patients were divided into medical and surgical cohorts. Hospitalizations were considered surgical if patients had surgery at any time during their hospital stay according to billing data. A trigger was an instance in which a patient met the conditions of a specific rule (score/vital sign exceeded the published/defined threshold).
A resuscitation call was defined as a call for cardiopulmonary resuscitation when a patient has a CRA.
An event was an occurrence of 1 of the following in a general care setting: unplanned transfer to the ICU, resuscitation call, or RRS activation.
The RRS activation criteria consisted of an “acute and persistent change” in any 1 or more of the following: oxygen saturations less than 90%, heart rate less than 40 or greater than 130 beats/minute, systolic blood pressure less than 90 mm Hg, or respiratory rate less than 10 or greater than 28 breaths/minute. The RRS activation requires health provider action; they are not electronically generated. Nurses and physicians may also activate the RRS if they are concerned about a patient, even if calling criteria are not met. This is in contrast to the EWS analyzed, which are aggregate composites of multiple parameters. However, whether or not a derangement in vital signs is considered an “acute and persistent change” still involves clinical judgment. Any movement from a general care bed to an ICU bed, or from a general care bed to a procedure area, and from there to an ICU, was considered unplanned. Transfers to the ICU directly from the emergency department or operating room (OR) were not considered as an unplanned transfer and were not included in the analyses.
Coverage time was the period observed for events after a rule was triggered. In this analysis, a coverage time of 24 hours was considered, with a 1-hour look-back. A trigger was counted as a true positive if an event occurred during the following 24 hours. The 1-hour look-back was included to take into account the nursing clinical process of prioritizing a call to the RRS followed by documentation of the altered vital signs that prompted the call.
An episode was the continuous time on the general care floor within a hospitalization, excluding times when a patient was in the OR or ICU. For example, if a patient was admitted to a general bed on a surgery floor, subsequently went to the OR, and then returned to the surgery floor, the 2 episodes were considered separate: the time on the floor before surgery, and the time on the floor after surgery.
Assessment of implementation of RRS in our hospitals showed a significant drop in the failure-to-rescue rate (issues considered related to delay or failure to identify or intervene appropriately when a patient was deteriorating, as identified through mortality review) and a decrease in non-ICU mortality.9,10 This suggests that our current process captures many of the relevant episodes of acute deterioration when a rapid response team is needed and supports using RRS activation as outcomes.
Data Sources
We developed a time-stamped longitudinal database of patient data from the electronic health record, including vital signs, laboratory test results, demographics (age, sex), administrative data (including length of stay), comorbidities, resuscitation code status, location in hospital, and at the minute level throughout each patient’s hospital stay. Physiologically impossible values (eg, blood pressures of 1200 mm Hg) were considered entered in error and eliminated from the database. Time spent in the OR or ICU was excluded because RRS activation would not be applied in these already highly monitored areas. SAS Statistical software (SAS Institute Inc. Cary, North Carolina) was used for database creation.
We applied the current RRS calling criteria in our institution and calculated the Kirkland score,11 along with some of the most widely used early warning scores:12 Modified Early Warning System (MEWS),13 Standardized Early Warning Scoring System (SEWS),14 Global Modified Early Warning Score (GMEWS),15 Worthing physiologic scoring system,16 National Early Warning Score (NEWS),17 and VitaPAC Early Warning Score (ViEWS).18 Published thresholds for these scores were used to create rule triggers in the data. Once a trigger was created to calculate the number of false positives and true positives, all subsequent triggers were ignored until the end of the episode or until 24 hours elapsed. We calculated triggers in a rolling fashion throughout the episodes of care. The EWS score was updated every time a new parameter was entered into the analytical electronic health record, and the most recent value for each was used to calculate the score. SAS statistical software was used for calculation of scores and identification of outcomes.
For our analysis, events were treated as dependent variables, and triggers were independent variables. We calculated the score for each EWS to the minute level throughout our retrospective database. If the score for a specific EWS was higher than the published/recommended threshold for that EWS, an alert was considered to have been issued, and the patient was followed for 24 hours. If the patient had an event in the subsequent 24 hours, or 1 hour before (1-hour look-back), the alert was considered a true positive; if not, a false positive. Events that were not preceded by an alert were false negatives, and 24-hour intervals without either an alert or an event were considered true negatives. This simulation exercise was performed for each EWS in both subcohorts (medical and surgical). Clusters of RRS calls followed by transfers to the ICU within 3 hours were considered as a single adverse event (RRS calls, as it was the first event to occur) to avoid double counting. We have described how well this simulation methodology,8 correlates with results from prospective studies.19
Statistical Analysis
To calculate whether results were statistically significant for subgroups, a jackknife method of calculating variance20 was used. The jackknife method calculates variance by repeating the calculations of the statistic leaving out 1 sample at a time. In our case, we repeated the calculation of sensitivity and PPV leaving out 1 patient at a time. Once the simulation method had been run and the false/true positives/negatives had been assigned, calculation of each metric (PPV and sensitivity) was repeated for n subsamples, each leaving out 1 patient. The variance was calculated and 2 Student t tests were performed for each EWS: 1 for PPV and another for sensitivity. SAS statistical software v 9.3 was used for the simulation analysis; R statistical software v 3.0.2 (The R Foundation, Vienna, Austria) was used for the calculation of the statistical significance of results. A univariable analysis was also performed to assess the sensitivity and PPVs for the published thresholds of the most common variables in each EWS: respiratory rate, systolic blood pressure, heart rate, temperature, and mental status as measured by the modified Richmond Agitation Sedation Score.21
RESULTS
The initial cohort included 60,020 hospitalizations, of which the following were excluded: 2751 because of a lack of appropriate research authorization; 6433 because the patients were younger than 18 years; 2129 as psychiatric admissions; 284 as rehabilitation admissions; 872 as research purposes-only admissions; and 1185 because the patient was never in a general care bed (eg, they were either admitted directly to the ICU, or they were admitted for an outpatient surgical procedure and spent time in the postanesthesia care unit).
Table 1 summarizes patient and trigger characteristics, overall and by subgroup. The final cohort included 75,240 total episodes in 46,366 hospitalizations, from 34,898 unique patients, of which 48.7% were male. There were 23,831 medical and 22,535 surgical hospitalizations. Median length of episode was 2 days both for medical and surgical patients. Median length of stay was 3 days, both for medical and for surgical patients.
There were 3332 events in total, of which 1709 were RRS calls, 185 were resuscitation calls, and 1438 were unscheduled transfers to the ICU. The rate of events was 4.67 events per 100 episodes in the aggregate adult population. There were 3.93 events per 100 episodes for surgical hospitalizations, and 5.86 events per 100 episodes for medical hospitalizations (P < .001). The number of CRAs in our cohort was 0.27 per 100 episodes, 0.128 per hospital bed per year, or 4.37 per 1000 hospital admissions, similar to other reported numbers in the literature.3, 22,23
The total number of EWS triggers varied greatly between EWS rules, with the volume ranging during the study year from 1363 triggers with the GMEWS rule to 77,711 triggers with the ViEWS score.
All scores had PPVs less than 25%. As seen in Table 2 and shown graphically in the Figure, all scores performed better on medical patients (blue) than on surgical patients (yellow). The P value was < .0001 for both PPV and sensitivity. The Worthing score had the highest sensitivity (0.78 for medical and 0.68 for surgical) but a very low PPV (0.04 for medical and 0.03 for surgical), while GMEWS was the opposite: low sensitivity (0.10 and 0.07) but the highest PPV (0.22 and 0.18).
The results of the univariable analysis can be seen in Table 3. Most of the criteria performed better (higher sensitivity and PPV) as predictors in the medical hospitalizations than in the surgical hospitalizations.
DISCUSSION
We hypothesized that EWS may perform differently when applied to medical rather than surgical patients. Studies had not analyzed this in a time-dependent manner,24-26 which limited the applicability of the results.8
All analyzed scores performed better in medical patients than in surgical patients (Figure). This could reflect a behavioral difference by the teams on surgical and medical floors in the decision to activate the RRS, or a bias of the clinicians who designed the scores (mostly nonsurgeons). The difference could also mean that physiological deteriorations are intrinsically different in patients who have undergone anesthesia and surgery. For example, in surgical patients, a bleeding episode is more likely to be the cause of their physiological deterioration, or the lingering effects of anesthesia could mask underlying deterioration. Such patients would benefit from scores where variables such as heart rate, blood pressure, or hemoglobin had more influence.
When comparing the different scores, it was much easier for a patient to meet the alerting score with the Worthing score than with GMEWS. In the Worthing score, a respiratory rate greater than 22 breaths per minute, or a systolic blood pressure less than 100 mm Hg, already meet alerting criteria. Similar vital signs result in 0 and 1 points (respectively) in GMEWS, far from its alerting score of 5. This reflects the intrinsic tradeoff of EWS: as the threshold for considering a patient “at risk” drops, not only does the number of true positives (and the sensitivity) increase, but also the number of false positives, thus lowering the PPV.
However, none of the scores analyzed were considered to perform well based on their PPV and sensitivity, particularly in the surgical subpopulation. Focusing on another metric, the area under the receiver operator curve can give misleadingly optimistic results.24,27 However, the extremely low prevalence of acute physiological deterioration can produce low PPVs even when specificity seems acceptable, which is why it is important to evaluate PPV directly.28
To use EWS effectively to activate RRS, they need to be combined with clinical judgment to avoid high levels of false alerts, particularly in surgical patients. It has been reported that RRS is activated only 30% of the time a patient meets RRS calling criteria.29 While there may be cultural characteristics inhibiting the decision to call,30 our study hints at another explanation: if RRS was activated every time a patient met calling criteria based on the scores analyzed, the number of RRS calls would be very high and difficult to manage. So health providers may be doing the right thing when “filtering” RRS calls and not applying the criteria strictly, but in conjunction with clinical judgment.
A limitation of any study like this is how to define “acute physiological deterioration.” We defined an event as recognized episodes of acute physiological deterioration that are signaled by escalations of care (eg, RRS, resuscitation calls, or transfers to an ICU) or unexpected death. By definition, our calculated PPV is affected by clinicians’ recognition of clinical deteriorations. This definition, common in the literature, has the limitation of potentially underestimating EWS’ performance by missing some events that are resolved by the primary care team without an escalation of care. However, we believe our interpretation is not unreasonable since the purpose of EWS is to trigger escalations of care in a timely fashion. Prospective studies could define an event in a way that is less affected by the clinicians’ judgment.
Regarding patient demographics, age was similar between the 2 groups (average, 58.2 years for medical vs 58.9 years for surgical), and there was only a small difference in gender ratios (45.1% male in the medical vs 51.4% in the surgical group). These differences are unlikely to have affected the results significantly, but unknown differences in demographics or other patient characteristics between groups may account for differences in score performance between surgical and medical patients.
Several of the EWS analyzed had overlapping trigger criteria with our own RRS activation criteria (although as single-parameter triggers and not as aggregate). To test how these potential biases could affect our results, we performed a post hoc sensitivity analysis eliminating calls to the RRS as an outcome (so using the alternative outcome of unexpected transfers to the ICU and resuscitation calls). The results are similar to those of our main analysis, with all analyzed scores having lower sensitivity and PPV in surgical hospitalizations when compared to medical hospitalizations.
Our study suggests that, to optimize detection of physiological deterioration events, EWS should try to take into account different patient types, with the most basic distinction being surgical vs medical. This tailoring will make EWS more complex, and less suited for paper-based calculation, but new electronic health records are increasingly able to incorporate decision support, and some EWS have been developed for electronic calculation only. Of particular interest in this regard is the score developed by Escobar et al,31 which groups patients into categories according to the reason for admission, and calculates a different subscore based on that category. While the score by Escobar et al. does not split patients based on medical or surgical status, a more general interpretation of our results suggests that a score may be more accurate if it classifies patients into subgroups with different subscores. This seems to be confirmed by the fact that the score by Escobar et al performs better than MEWS.28 Unfortunately, the paper describing it does not provide enough detail to use it in our database.
A recent systematic review showed increasing evidence that RRS may be effective in reducing CRAs occurring in a non-ICU setting and, more important, overall inhospital mortality.32 While differing implementation strategies (eg, different length of the educational effort, changes in the frequency of vital signs monitoring) can impact the success of such an initiative, it has been speculated that the afferent limb (which often includes an EWS) might be the most critical part of the system.33 Our results show that the most widely used EWS perform significantly worse on surgical patients, and suggest that a way to improve the accuracy of EWS would be to tailor the risk calculation to different patient subgroups (eg, medical and surgical patients). Plausible next steps would be to demonstrate that tailoring risk calculation to medical and surgical patients separately can improve risk predictions and accuracy of EWS.
Disclosure
The authors report no financial conflicts of interest.
1. Buist MD, Jarmolowski E, Burton PR, Bernard SA, Waxman BP, Anderson J. Recognising clinical instability in hospital patients before cardiac arrest or unplanned admission to intensive care. A pilot study in a tertiary-care hospital. Med J Aust. 1999; 171(1):22-25. PubMed
2. Schein RM, Hazday N, Pena M, Ruben BH, Sprung CL. Clinical antecedents to in-hospital cardiopulmonary arrest. Chest. 1990;98(6):1388-1392. PubMed
3. Peberdy MA, Kaye W, Ornato JP, Larkin GL, Nadkarni V, Mancini ME, et al. Cardiopulmonary resuscitation of adults in the hospital: a report of 14720 cardiac arrests from the National Registry of Cardiopulmonary Resuscitation. Resuscitation. 2003; 58(3):297-308. PubMed
4. Nadkarni VM, Larkin GL, Peberdy MA, Carey SM, Kaye W, Mancini ME, et al. First documented rhythm and clinical outcome from in-hospital cardiac arrest among children and adults. JAMA. 2006;295(1):50-57. PubMed
5. Devita MA, Bellomo R, Hillman K, Kellum J, Rotondi A, Teres D, et al. Findings of the first consensus conference on medical emergency teams. Crit Care Med. 2006;34(9):2463-2478. PubMed
6. DeVita MA, Smith GB, Adam SK, Adams-Pizarro I, Buist M, Bellomo R, et al. “Identifying the hospitalised patient in crisis”--a consensus conference on the afferent limb of rapid response systems. Resuscitation. 2010;81(4):375-382. PubMed
7. Kawamoto K, Houlihan CA, Balas EA, Lobach DF. Improving clinical practice using clinical decision support systems: a systematic review of trials to identify features critical to success. BMJ. 2005;330(7494):765. PubMed
8. Romero-Brufau S, Huddleston JM, Naessens JM, Johnson MG, Hickman J, Morlan BW, et al. Widely used track and trigger scores: are they ready for automation in practice? Resuscitation. 2014;85(4):549-552. PubMed
9. Huddleston JM, Diedrich DA, Kinsey GC, Enzler MJ, Manning DM. Learning from every death. J Patient Saf. 2014;10(1):6-12. PubMed
10. Moriarty JP, Schiebel NE, Johnson MG, Jensen JB, Caples SM, Morlan BW, et al. Evaluating implementation of a rapid response team: considering alternative outcome measures. Int J Qual Health Care. 2014;26(1):49-57. PubMed
11. Kirkland LL, Malinchoc M, O’Byrne M, Benson JT, Kashiwagi DT, Burton MC, et al. A clinical deterioration prediction tool for internal medicine patients. Am J Med Qual. 2013;28(2):135-142. PubMed
12. Griffiths JR, Kidney EM. Current use of early warning scores in UK emergency departments. Emerg Med J. 2012;29(1):65-66. PubMed
13. Subbe CP, Kruger M, Rutherford P, Gemmel L. Validation of a modified Early Warning Score in medical admissions. QJM. 2001;94(10):521-526. PubMed
14. Paterson R, MacLeod DC, Thetford D, Beattie A, Graham C, Lam S, et al.. Prediction of in-hospital mortality and length of stay using an early warning scoring system: clinical audit. Clin Med (Lond). 2006;6(3):281-284. PubMed
15. Harrison GA, Jacques T, McLaws ML, Kilborn G. Combinations of early signs of critical illness predict in-hospital death–the SOCCER study (signs of critical conditions and emergency responses). Resuscitation. 2006;71(3):327-334. PubMed
16. Duckitt RW, Buxton-Thomas R, Walker J, Cheek E, Bewick V, Venn R, et al. Worthing physiological scoring system: derivation and validation of a physiological early-warning system for medical admissions. An observational, population-based single-centre study. Br J Anaesth. 2007; 98(6):769-774. PubMed
17. Smith GB, Prytherch DR, Meredith P, Schmidt PE, Featherstone PI. The ability of the National Early Warning Score (NEWS) to discriminate patients at risk of early cardiac arrest, unanticipated intensive care unit admission, and death. Resuscitation. 2013;84(4):465-470. PubMed
18. Prytherch DR, Smith GB, Schmidt PE, Featherstone PI. ViEWS--Towards a national early warning score for detecting adult inpatient deterioration. Resuscitation. 2010;81(8):932-937. PubMed
19. Romero-Brufau S, Huddleston JM. Reply to letter: widely used track and trigger scores: are they ready for automation in practice? Resuscitation. 2014;85(10):e159. PubMed
20. Efron B, Stein C. The jackknife estimate of variance. Annals of Statistics. 1981;586-596.
21. Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O’Neal PV, Keane KA, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166(10):1338-1344. PubMed
22. DeVita MA, Braithwaite RS, Mahidhara R, Stuart S, Foraida M, Simmons RL. Medical Emergency Response Improvement Team (MERIT). Use of medical emergency team responses to reduce hospital cardiopulmonary arrests. Qual Saf Health Care. 2004;13(4):251-254. PubMed
23. Goncales PD, Polessi JA, Bass LM, Santos Gde P, Yokota PK, Laselva CR, et al. Reduced frequency of cardiopulmonary arrests by rapid response teams. Einstein (Sao Paulo). 2012;10(4):442-448. PubMed
24. Cuthbertson BH, Boroujerdi M, McKie L, Aucott L, Prescott G. Can physiological variables and early warning scoring systems allow early recognition of the deteriorating surgical patient? Crit Care Med. 2007;35(2):402-409. PubMed
25. Gardner-Thorpe J, Love N, Wrightson J, Walsh S, Keeling N. The value of Modified Early Warning Score (MEWS) in surgical in-patients: a prospective observational study. Ann R Coll Surg Engl. 2006;88(6):571-575. PubMed
26. Stenhouse C, Coates S, Tivey M, Allsop P, Parker T. Prospective evaluation of a modified Early Warning Score to aid earlier detection of patients developing critical illness on a general surgical ward. British Journal of Anaesthesia. 2000;84(5):663-663.
27. Smith GB, Prytherch DR, Schmidt PE, Featherstone PI. Review and performance evaluation of aggregate weighted ‘track and trigger’ systems. Resuscitation. 2008;77(2):170-179. PubMed
28. Romero-Brufau S, Huddleston JM, Escobar GJ, Liebow M. Why the C-statistic is not informative to evaluate early warning scores and what metrics to use. Crit Care. 2015; 19:285. PubMed
29. Hillman K, Chen J, Cretikos M, Bellomo R, Brown D, Doig G, et al. Introduction of the medical emergency team (MET) system: a cluster-randomised controlled trial. Lancet. 2005;365(9477):2091-2097. PubMed
30. Shearer B, Marshall S, Buist MD, Finnigan M, Kitto S, Hore T, et al. What stops hospital clinical staff from following protocols? An analysis of the incidence and factors behind the failure of bedside clinical staff to activate the rapid response system in a multi-campus Australian metropolitan healthcare service. BMJ Qual Saf. 2012;21(7):569-575. PubMed
31. Escobar GJ, LaGuardia JC, Turk BJ, Ragins A, Kipnis P, Draper D. Early detection of impending physiologic deterioration among patients who are not in intensive care: development of predictive models using data from an automated electronic medical record. J Hosp Med. 2012;7(5):388-395. PubMed
32. Winters BD, Weaver SJ, Pfoh ER, Yang T, Pham JC, Dy SM. Rapid-response systems as a patient safety strategy: a systematic review. Ann Intern Med. 2013;158(5 pt 2):417-425. PubMed
33. Jones DA, DeVita MA, Bellomo R. Rapid-response teams. N Engl J Med. 2011;365(2):139-146. PubMed
Patients typically show signs and symptoms of deterioration hours to days prior to cardiorespiratory arrest.1,2 The rate of inhospital cardiorespiratory arrest (CRA) requiring cardiopulmonary resuscitation is estimated to be 0.174 per bed per year in the United States.3 After CRA, survival to discharge is estimated to be as low as 18%.3,4 Efforts to predict and prevent arrest could prove beneficial.1,2
Rapid response systems (RRS) have been proposed as a means of identifying clinical deterioration and facilitating a timely response. These systems were designed to bring clinicians with critical care expertise to the bedside to prevent unnecessary deaths. They typically include an afferent limb (detects deteriorating patients), an efferent limb (responds to calls and acts to avoid further deterioration), and administrative and data analysis limbs.5,6 Automatic provision of recommendations and computer-based systems are desirable components of the afferent limb of the detection system.6 Both are independent predictors of improved clinical practices for clinical decision support systems.7 However, the existing early warning scores (EWS) may not be ready for automation due to low positive predictive values (PPV) and sensitivities.8
It is possible that the low discriminatory accuracy of the published EWS may be secondary to the use of aggregate patient populations for derivation of scores. We hypothesized that these EWS perform differently in medical and in surgical subpopulations. Also, the EWS need to be tested in a time-dependent manner to serve as a realistic clinical support tool for hospitalized patients.
STUDY AIM
The aim of this study was to evaluate the differential performance of widely used EWS in medical vs surgical patients.
METHODS
Site
The study was conducted in an academic center with 2 hospitals in Southeastern Minnesota totaling approximately 1500 general care nonintensive care unit (ICU) beds. The Mayo Clinic Institutional Review Board approved the research proposal.
Subjects
Our retrospective cohort was comprised of all adult inpatients discharged from 2 academic hospitals between January 1, 2011 and December 31, 2011 who spent any time in a general care (non-ICU) unit. We excluded patients younger than 18 years, psychiatric or rehabilitation inpatients, those without research authorization, and patients admitted for research purposes.
Study patients were divided into medical and surgical cohorts. Hospitalizations were considered surgical if patients had surgery at any time during their hospital stay according to billing data. A trigger was an instance in which a patient met the conditions of a specific rule (score/vital sign exceeded the published/defined threshold).
A resuscitation call was defined as a call for cardiopulmonary resuscitation when a patient has a CRA.
An event was an occurrence of 1 of the following in a general care setting: unplanned transfer to the ICU, resuscitation call, or RRS activation.
The RRS activation criteria consisted of an “acute and persistent change” in any 1 or more of the following: oxygen saturations less than 90%, heart rate less than 40 or greater than 130 beats/minute, systolic blood pressure less than 90 mm Hg, or respiratory rate less than 10 or greater than 28 breaths/minute. The RRS activation requires health provider action; they are not electronically generated. Nurses and physicians may also activate the RRS if they are concerned about a patient, even if calling criteria are not met. This is in contrast to the EWS analyzed, which are aggregate composites of multiple parameters. However, whether or not a derangement in vital signs is considered an “acute and persistent change” still involves clinical judgment. Any movement from a general care bed to an ICU bed, or from a general care bed to a procedure area, and from there to an ICU, was considered unplanned. Transfers to the ICU directly from the emergency department or operating room (OR) were not considered as an unplanned transfer and were not included in the analyses.
Coverage time was the period observed for events after a rule was triggered. In this analysis, a coverage time of 24 hours was considered, with a 1-hour look-back. A trigger was counted as a true positive if an event occurred during the following 24 hours. The 1-hour look-back was included to take into account the nursing clinical process of prioritizing a call to the RRS followed by documentation of the altered vital signs that prompted the call.
An episode was the continuous time on the general care floor within a hospitalization, excluding times when a patient was in the OR or ICU. For example, if a patient was admitted to a general bed on a surgery floor, subsequently went to the OR, and then returned to the surgery floor, the 2 episodes were considered separate: the time on the floor before surgery, and the time on the floor after surgery.
Assessment of implementation of RRS in our hospitals showed a significant drop in the failure-to-rescue rate (issues considered related to delay or failure to identify or intervene appropriately when a patient was deteriorating, as identified through mortality review) and a decrease in non-ICU mortality.9,10 This suggests that our current process captures many of the relevant episodes of acute deterioration when a rapid response team is needed and supports using RRS activation as outcomes.
Data Sources
We developed a time-stamped longitudinal database of patient data from the electronic health record, including vital signs, laboratory test results, demographics (age, sex), administrative data (including length of stay), comorbidities, resuscitation code status, location in hospital, and at the minute level throughout each patient’s hospital stay. Physiologically impossible values (eg, blood pressures of 1200 mm Hg) were considered entered in error and eliminated from the database. Time spent in the OR or ICU was excluded because RRS activation would not be applied in these already highly monitored areas. SAS Statistical software (SAS Institute Inc. Cary, North Carolina) was used for database creation.
We applied the current RRS calling criteria in our institution and calculated the Kirkland score,11 along with some of the most widely used early warning scores:12 Modified Early Warning System (MEWS),13 Standardized Early Warning Scoring System (SEWS),14 Global Modified Early Warning Score (GMEWS),15 Worthing physiologic scoring system,16 National Early Warning Score (NEWS),17 and VitaPAC Early Warning Score (ViEWS).18 Published thresholds for these scores were used to create rule triggers in the data. Once a trigger was created to calculate the number of false positives and true positives, all subsequent triggers were ignored until the end of the episode or until 24 hours elapsed. We calculated triggers in a rolling fashion throughout the episodes of care. The EWS score was updated every time a new parameter was entered into the analytical electronic health record, and the most recent value for each was used to calculate the score. SAS statistical software was used for calculation of scores and identification of outcomes.
For our analysis, events were treated as dependent variables, and triggers were independent variables. We calculated the score for each EWS to the minute level throughout our retrospective database. If the score for a specific EWS was higher than the published/recommended threshold for that EWS, an alert was considered to have been issued, and the patient was followed for 24 hours. If the patient had an event in the subsequent 24 hours, or 1 hour before (1-hour look-back), the alert was considered a true positive; if not, a false positive. Events that were not preceded by an alert were false negatives, and 24-hour intervals without either an alert or an event were considered true negatives. This simulation exercise was performed for each EWS in both subcohorts (medical and surgical). Clusters of RRS calls followed by transfers to the ICU within 3 hours were considered as a single adverse event (RRS calls, as it was the first event to occur) to avoid double counting. We have described how well this simulation methodology,8 correlates with results from prospective studies.19
Statistical Analysis
To calculate whether results were statistically significant for subgroups, a jackknife method of calculating variance20 was used. The jackknife method calculates variance by repeating the calculations of the statistic leaving out 1 sample at a time. In our case, we repeated the calculation of sensitivity and PPV leaving out 1 patient at a time. Once the simulation method had been run and the false/true positives/negatives had been assigned, calculation of each metric (PPV and sensitivity) was repeated for n subsamples, each leaving out 1 patient. The variance was calculated and 2 Student t tests were performed for each EWS: 1 for PPV and another for sensitivity. SAS statistical software v 9.3 was used for the simulation analysis; R statistical software v 3.0.2 (The R Foundation, Vienna, Austria) was used for the calculation of the statistical significance of results. A univariable analysis was also performed to assess the sensitivity and PPVs for the published thresholds of the most common variables in each EWS: respiratory rate, systolic blood pressure, heart rate, temperature, and mental status as measured by the modified Richmond Agitation Sedation Score.21
RESULTS
The initial cohort included 60,020 hospitalizations, of which the following were excluded: 2751 because of a lack of appropriate research authorization; 6433 because the patients were younger than 18 years; 2129 as psychiatric admissions; 284 as rehabilitation admissions; 872 as research purposes-only admissions; and 1185 because the patient was never in a general care bed (eg, they were either admitted directly to the ICU, or they were admitted for an outpatient surgical procedure and spent time in the postanesthesia care unit).
Table 1 summarizes patient and trigger characteristics, overall and by subgroup. The final cohort included 75,240 total episodes in 46,366 hospitalizations, from 34,898 unique patients, of which 48.7% were male. There were 23,831 medical and 22,535 surgical hospitalizations. Median length of episode was 2 days both for medical and surgical patients. Median length of stay was 3 days, both for medical and for surgical patients.
There were 3332 events in total, of which 1709 were RRS calls, 185 were resuscitation calls, and 1438 were unscheduled transfers to the ICU. The rate of events was 4.67 events per 100 episodes in the aggregate adult population. There were 3.93 events per 100 episodes for surgical hospitalizations, and 5.86 events per 100 episodes for medical hospitalizations (P < .001). The number of CRAs in our cohort was 0.27 per 100 episodes, 0.128 per hospital bed per year, or 4.37 per 1000 hospital admissions, similar to other reported numbers in the literature.3, 22,23
The total number of EWS triggers varied greatly between EWS rules, with the volume ranging during the study year from 1363 triggers with the GMEWS rule to 77,711 triggers with the ViEWS score.
All scores had PPVs less than 25%. As seen in Table 2 and shown graphically in the Figure, all scores performed better on medical patients (blue) than on surgical patients (yellow). The P value was < .0001 for both PPV and sensitivity. The Worthing score had the highest sensitivity (0.78 for medical and 0.68 for surgical) but a very low PPV (0.04 for medical and 0.03 for surgical), while GMEWS was the opposite: low sensitivity (0.10 and 0.07) but the highest PPV (0.22 and 0.18).
The results of the univariable analysis can be seen in Table 3. Most of the criteria performed better (higher sensitivity and PPV) as predictors in the medical hospitalizations than in the surgical hospitalizations.
DISCUSSION
We hypothesized that EWS may perform differently when applied to medical rather than surgical patients. Studies had not analyzed this in a time-dependent manner,24-26 which limited the applicability of the results.8
All analyzed scores performed better in medical patients than in surgical patients (Figure). This could reflect a behavioral difference by the teams on surgical and medical floors in the decision to activate the RRS, or a bias of the clinicians who designed the scores (mostly nonsurgeons). The difference could also mean that physiological deteriorations are intrinsically different in patients who have undergone anesthesia and surgery. For example, in surgical patients, a bleeding episode is more likely to be the cause of their physiological deterioration, or the lingering effects of anesthesia could mask underlying deterioration. Such patients would benefit from scores where variables such as heart rate, blood pressure, or hemoglobin had more influence.
When comparing the different scores, it was much easier for a patient to meet the alerting score with the Worthing score than with GMEWS. In the Worthing score, a respiratory rate greater than 22 breaths per minute, or a systolic blood pressure less than 100 mm Hg, already meet alerting criteria. Similar vital signs result in 0 and 1 points (respectively) in GMEWS, far from its alerting score of 5. This reflects the intrinsic tradeoff of EWS: as the threshold for considering a patient “at risk” drops, not only does the number of true positives (and the sensitivity) increase, but also the number of false positives, thus lowering the PPV.
However, none of the scores analyzed were considered to perform well based on their PPV and sensitivity, particularly in the surgical subpopulation. Focusing on another metric, the area under the receiver operator curve can give misleadingly optimistic results.24,27 However, the extremely low prevalence of acute physiological deterioration can produce low PPVs even when specificity seems acceptable, which is why it is important to evaluate PPV directly.28
To use EWS effectively to activate RRS, they need to be combined with clinical judgment to avoid high levels of false alerts, particularly in surgical patients. It has been reported that RRS is activated only 30% of the time a patient meets RRS calling criteria.29 While there may be cultural characteristics inhibiting the decision to call,30 our study hints at another explanation: if RRS was activated every time a patient met calling criteria based on the scores analyzed, the number of RRS calls would be very high and difficult to manage. So health providers may be doing the right thing when “filtering” RRS calls and not applying the criteria strictly, but in conjunction with clinical judgment.
A limitation of any study like this is how to define “acute physiological deterioration.” We defined an event as recognized episodes of acute physiological deterioration that are signaled by escalations of care (eg, RRS, resuscitation calls, or transfers to an ICU) or unexpected death. By definition, our calculated PPV is affected by clinicians’ recognition of clinical deteriorations. This definition, common in the literature, has the limitation of potentially underestimating EWS’ performance by missing some events that are resolved by the primary care team without an escalation of care. However, we believe our interpretation is not unreasonable since the purpose of EWS is to trigger escalations of care in a timely fashion. Prospective studies could define an event in a way that is less affected by the clinicians’ judgment.
Regarding patient demographics, age was similar between the 2 groups (average, 58.2 years for medical vs 58.9 years for surgical), and there was only a small difference in gender ratios (45.1% male in the medical vs 51.4% in the surgical group). These differences are unlikely to have affected the results significantly, but unknown differences in demographics or other patient characteristics between groups may account for differences in score performance between surgical and medical patients.
Several of the EWS analyzed had overlapping trigger criteria with our own RRS activation criteria (although as single-parameter triggers and not as aggregate). To test how these potential biases could affect our results, we performed a post hoc sensitivity analysis eliminating calls to the RRS as an outcome (so using the alternative outcome of unexpected transfers to the ICU and resuscitation calls). The results are similar to those of our main analysis, with all analyzed scores having lower sensitivity and PPV in surgical hospitalizations when compared to medical hospitalizations.
Our study suggests that, to optimize detection of physiological deterioration events, EWS should try to take into account different patient types, with the most basic distinction being surgical vs medical. This tailoring will make EWS more complex, and less suited for paper-based calculation, but new electronic health records are increasingly able to incorporate decision support, and some EWS have been developed for electronic calculation only. Of particular interest in this regard is the score developed by Escobar et al,31 which groups patients into categories according to the reason for admission, and calculates a different subscore based on that category. While the score by Escobar et al. does not split patients based on medical or surgical status, a more general interpretation of our results suggests that a score may be more accurate if it classifies patients into subgroups with different subscores. This seems to be confirmed by the fact that the score by Escobar et al performs better than MEWS.28 Unfortunately, the paper describing it does not provide enough detail to use it in our database.
A recent systematic review showed increasing evidence that RRS may be effective in reducing CRAs occurring in a non-ICU setting and, more important, overall inhospital mortality.32 While differing implementation strategies (eg, different length of the educational effort, changes in the frequency of vital signs monitoring) can impact the success of such an initiative, it has been speculated that the afferent limb (which often includes an EWS) might be the most critical part of the system.33 Our results show that the most widely used EWS perform significantly worse on surgical patients, and suggest that a way to improve the accuracy of EWS would be to tailor the risk calculation to different patient subgroups (eg, medical and surgical patients). Plausible next steps would be to demonstrate that tailoring risk calculation to medical and surgical patients separately can improve risk predictions and accuracy of EWS.
Disclosure
The authors report no financial conflicts of interest.
Patients typically show signs and symptoms of deterioration hours to days prior to cardiorespiratory arrest.1,2 The rate of inhospital cardiorespiratory arrest (CRA) requiring cardiopulmonary resuscitation is estimated to be 0.174 per bed per year in the United States.3 After CRA, survival to discharge is estimated to be as low as 18%.3,4 Efforts to predict and prevent arrest could prove beneficial.1,2
Rapid response systems (RRS) have been proposed as a means of identifying clinical deterioration and facilitating a timely response. These systems were designed to bring clinicians with critical care expertise to the bedside to prevent unnecessary deaths. They typically include an afferent limb (detects deteriorating patients), an efferent limb (responds to calls and acts to avoid further deterioration), and administrative and data analysis limbs.5,6 Automatic provision of recommendations and computer-based systems are desirable components of the afferent limb of the detection system.6 Both are independent predictors of improved clinical practices for clinical decision support systems.7 However, the existing early warning scores (EWS) may not be ready for automation due to low positive predictive values (PPV) and sensitivities.8
It is possible that the low discriminatory accuracy of the published EWS may be secondary to the use of aggregate patient populations for derivation of scores. We hypothesized that these EWS perform differently in medical and in surgical subpopulations. Also, the EWS need to be tested in a time-dependent manner to serve as a realistic clinical support tool for hospitalized patients.
STUDY AIM
The aim of this study was to evaluate the differential performance of widely used EWS in medical vs surgical patients.
METHODS
Site
The study was conducted in an academic center with 2 hospitals in Southeastern Minnesota totaling approximately 1500 general care nonintensive care unit (ICU) beds. The Mayo Clinic Institutional Review Board approved the research proposal.
Subjects
Our retrospective cohort was comprised of all adult inpatients discharged from 2 academic hospitals between January 1, 2011 and December 31, 2011 who spent any time in a general care (non-ICU) unit. We excluded patients younger than 18 years, psychiatric or rehabilitation inpatients, those without research authorization, and patients admitted for research purposes.
Study patients were divided into medical and surgical cohorts. Hospitalizations were considered surgical if patients had surgery at any time during their hospital stay according to billing data. A trigger was an instance in which a patient met the conditions of a specific rule (score/vital sign exceeded the published/defined threshold).
A resuscitation call was defined as a call for cardiopulmonary resuscitation when a patient has a CRA.
An event was an occurrence of 1 of the following in a general care setting: unplanned transfer to the ICU, resuscitation call, or RRS activation.
The RRS activation criteria consisted of an “acute and persistent change” in any 1 or more of the following: oxygen saturations less than 90%, heart rate less than 40 or greater than 130 beats/minute, systolic blood pressure less than 90 mm Hg, or respiratory rate less than 10 or greater than 28 breaths/minute. The RRS activation requires health provider action; they are not electronically generated. Nurses and physicians may also activate the RRS if they are concerned about a patient, even if calling criteria are not met. This is in contrast to the EWS analyzed, which are aggregate composites of multiple parameters. However, whether or not a derangement in vital signs is considered an “acute and persistent change” still involves clinical judgment. Any movement from a general care bed to an ICU bed, or from a general care bed to a procedure area, and from there to an ICU, was considered unplanned. Transfers to the ICU directly from the emergency department or operating room (OR) were not considered as an unplanned transfer and were not included in the analyses.
Coverage time was the period observed for events after a rule was triggered. In this analysis, a coverage time of 24 hours was considered, with a 1-hour look-back. A trigger was counted as a true positive if an event occurred during the following 24 hours. The 1-hour look-back was included to take into account the nursing clinical process of prioritizing a call to the RRS followed by documentation of the altered vital signs that prompted the call.
An episode was the continuous time on the general care floor within a hospitalization, excluding times when a patient was in the OR or ICU. For example, if a patient was admitted to a general bed on a surgery floor, subsequently went to the OR, and then returned to the surgery floor, the 2 episodes were considered separate: the time on the floor before surgery, and the time on the floor after surgery.
Assessment of implementation of RRS in our hospitals showed a significant drop in the failure-to-rescue rate (issues considered related to delay or failure to identify or intervene appropriately when a patient was deteriorating, as identified through mortality review) and a decrease in non-ICU mortality.9,10 This suggests that our current process captures many of the relevant episodes of acute deterioration when a rapid response team is needed and supports using RRS activation as outcomes.
Data Sources
We developed a time-stamped longitudinal database of patient data from the electronic health record, including vital signs, laboratory test results, demographics (age, sex), administrative data (including length of stay), comorbidities, resuscitation code status, location in hospital, and at the minute level throughout each patient’s hospital stay. Physiologically impossible values (eg, blood pressures of 1200 mm Hg) were considered entered in error and eliminated from the database. Time spent in the OR or ICU was excluded because RRS activation would not be applied in these already highly monitored areas. SAS Statistical software (SAS Institute Inc. Cary, North Carolina) was used for database creation.
We applied the current RRS calling criteria in our institution and calculated the Kirkland score,11 along with some of the most widely used early warning scores:12 Modified Early Warning System (MEWS),13 Standardized Early Warning Scoring System (SEWS),14 Global Modified Early Warning Score (GMEWS),15 Worthing physiologic scoring system,16 National Early Warning Score (NEWS),17 and VitaPAC Early Warning Score (ViEWS).18 Published thresholds for these scores were used to create rule triggers in the data. Once a trigger was created to calculate the number of false positives and true positives, all subsequent triggers were ignored until the end of the episode or until 24 hours elapsed. We calculated triggers in a rolling fashion throughout the episodes of care. The EWS score was updated every time a new parameter was entered into the analytical electronic health record, and the most recent value for each was used to calculate the score. SAS statistical software was used for calculation of scores and identification of outcomes.
For our analysis, events were treated as dependent variables, and triggers were independent variables. We calculated the score for each EWS to the minute level throughout our retrospective database. If the score for a specific EWS was higher than the published/recommended threshold for that EWS, an alert was considered to have been issued, and the patient was followed for 24 hours. If the patient had an event in the subsequent 24 hours, or 1 hour before (1-hour look-back), the alert was considered a true positive; if not, a false positive. Events that were not preceded by an alert were false negatives, and 24-hour intervals without either an alert or an event were considered true negatives. This simulation exercise was performed for each EWS in both subcohorts (medical and surgical). Clusters of RRS calls followed by transfers to the ICU within 3 hours were considered as a single adverse event (RRS calls, as it was the first event to occur) to avoid double counting. We have described how well this simulation methodology,8 correlates with results from prospective studies.19
Statistical Analysis
To calculate whether results were statistically significant for subgroups, a jackknife method of calculating variance20 was used. The jackknife method calculates variance by repeating the calculations of the statistic leaving out 1 sample at a time. In our case, we repeated the calculation of sensitivity and PPV leaving out 1 patient at a time. Once the simulation method had been run and the false/true positives/negatives had been assigned, calculation of each metric (PPV and sensitivity) was repeated for n subsamples, each leaving out 1 patient. The variance was calculated and 2 Student t tests were performed for each EWS: 1 for PPV and another for sensitivity. SAS statistical software v 9.3 was used for the simulation analysis; R statistical software v 3.0.2 (The R Foundation, Vienna, Austria) was used for the calculation of the statistical significance of results. A univariable analysis was also performed to assess the sensitivity and PPVs for the published thresholds of the most common variables in each EWS: respiratory rate, systolic blood pressure, heart rate, temperature, and mental status as measured by the modified Richmond Agitation Sedation Score.21
RESULTS
The initial cohort included 60,020 hospitalizations, of which the following were excluded: 2751 because of a lack of appropriate research authorization; 6433 because the patients were younger than 18 years; 2129 as psychiatric admissions; 284 as rehabilitation admissions; 872 as research purposes-only admissions; and 1185 because the patient was never in a general care bed (eg, they were either admitted directly to the ICU, or they were admitted for an outpatient surgical procedure and spent time in the postanesthesia care unit).
Table 1 summarizes patient and trigger characteristics, overall and by subgroup. The final cohort included 75,240 total episodes in 46,366 hospitalizations, from 34,898 unique patients, of which 48.7% were male. There were 23,831 medical and 22,535 surgical hospitalizations. Median length of episode was 2 days both for medical and surgical patients. Median length of stay was 3 days, both for medical and for surgical patients.
There were 3332 events in total, of which 1709 were RRS calls, 185 were resuscitation calls, and 1438 were unscheduled transfers to the ICU. The rate of events was 4.67 events per 100 episodes in the aggregate adult population. There were 3.93 events per 100 episodes for surgical hospitalizations, and 5.86 events per 100 episodes for medical hospitalizations (P < .001). The number of CRAs in our cohort was 0.27 per 100 episodes, 0.128 per hospital bed per year, or 4.37 per 1000 hospital admissions, similar to other reported numbers in the literature.3, 22,23
The total number of EWS triggers varied greatly between EWS rules, with the volume ranging during the study year from 1363 triggers with the GMEWS rule to 77,711 triggers with the ViEWS score.
All scores had PPVs less than 25%. As seen in Table 2 and shown graphically in the Figure, all scores performed better on medical patients (blue) than on surgical patients (yellow). The P value was < .0001 for both PPV and sensitivity. The Worthing score had the highest sensitivity (0.78 for medical and 0.68 for surgical) but a very low PPV (0.04 for medical and 0.03 for surgical), while GMEWS was the opposite: low sensitivity (0.10 and 0.07) but the highest PPV (0.22 and 0.18).
The results of the univariable analysis can be seen in Table 3. Most of the criteria performed better (higher sensitivity and PPV) as predictors in the medical hospitalizations than in the surgical hospitalizations.
DISCUSSION
We hypothesized that EWS may perform differently when applied to medical rather than surgical patients. Studies had not analyzed this in a time-dependent manner,24-26 which limited the applicability of the results.8
All analyzed scores performed better in medical patients than in surgical patients (Figure). This could reflect a behavioral difference by the teams on surgical and medical floors in the decision to activate the RRS, or a bias of the clinicians who designed the scores (mostly nonsurgeons). The difference could also mean that physiological deteriorations are intrinsically different in patients who have undergone anesthesia and surgery. For example, in surgical patients, a bleeding episode is more likely to be the cause of their physiological deterioration, or the lingering effects of anesthesia could mask underlying deterioration. Such patients would benefit from scores where variables such as heart rate, blood pressure, or hemoglobin had more influence.
When comparing the different scores, it was much easier for a patient to meet the alerting score with the Worthing score than with GMEWS. In the Worthing score, a respiratory rate greater than 22 breaths per minute, or a systolic blood pressure less than 100 mm Hg, already meet alerting criteria. Similar vital signs result in 0 and 1 points (respectively) in GMEWS, far from its alerting score of 5. This reflects the intrinsic tradeoff of EWS: as the threshold for considering a patient “at risk” drops, not only does the number of true positives (and the sensitivity) increase, but also the number of false positives, thus lowering the PPV.
However, none of the scores analyzed were considered to perform well based on their PPV and sensitivity, particularly in the surgical subpopulation. Focusing on another metric, the area under the receiver operator curve can give misleadingly optimistic results.24,27 However, the extremely low prevalence of acute physiological deterioration can produce low PPVs even when specificity seems acceptable, which is why it is important to evaluate PPV directly.28
To use EWS effectively to activate RRS, they need to be combined with clinical judgment to avoid high levels of false alerts, particularly in surgical patients. It has been reported that RRS is activated only 30% of the time a patient meets RRS calling criteria.29 While there may be cultural characteristics inhibiting the decision to call,30 our study hints at another explanation: if RRS was activated every time a patient met calling criteria based on the scores analyzed, the number of RRS calls would be very high and difficult to manage. So health providers may be doing the right thing when “filtering” RRS calls and not applying the criteria strictly, but in conjunction with clinical judgment.
A limitation of any study like this is how to define “acute physiological deterioration.” We defined an event as recognized episodes of acute physiological deterioration that are signaled by escalations of care (eg, RRS, resuscitation calls, or transfers to an ICU) or unexpected death. By definition, our calculated PPV is affected by clinicians’ recognition of clinical deteriorations. This definition, common in the literature, has the limitation of potentially underestimating EWS’ performance by missing some events that are resolved by the primary care team without an escalation of care. However, we believe our interpretation is not unreasonable since the purpose of EWS is to trigger escalations of care in a timely fashion. Prospective studies could define an event in a way that is less affected by the clinicians’ judgment.
Regarding patient demographics, age was similar between the 2 groups (average, 58.2 years for medical vs 58.9 years for surgical), and there was only a small difference in gender ratios (45.1% male in the medical vs 51.4% in the surgical group). These differences are unlikely to have affected the results significantly, but unknown differences in demographics or other patient characteristics between groups may account for differences in score performance between surgical and medical patients.
Several of the EWS analyzed had overlapping trigger criteria with our own RRS activation criteria (although as single-parameter triggers and not as aggregate). To test how these potential biases could affect our results, we performed a post hoc sensitivity analysis eliminating calls to the RRS as an outcome (so using the alternative outcome of unexpected transfers to the ICU and resuscitation calls). The results are similar to those of our main analysis, with all analyzed scores having lower sensitivity and PPV in surgical hospitalizations when compared to medical hospitalizations.
Our study suggests that, to optimize detection of physiological deterioration events, EWS should try to take into account different patient types, with the most basic distinction being surgical vs medical. This tailoring will make EWS more complex, and less suited for paper-based calculation, but new electronic health records are increasingly able to incorporate decision support, and some EWS have been developed for electronic calculation only. Of particular interest in this regard is the score developed by Escobar et al,31 which groups patients into categories according to the reason for admission, and calculates a different subscore based on that category. While the score by Escobar et al. does not split patients based on medical or surgical status, a more general interpretation of our results suggests that a score may be more accurate if it classifies patients into subgroups with different subscores. This seems to be confirmed by the fact that the score by Escobar et al performs better than MEWS.28 Unfortunately, the paper describing it does not provide enough detail to use it in our database.
A recent systematic review showed increasing evidence that RRS may be effective in reducing CRAs occurring in a non-ICU setting and, more important, overall inhospital mortality.32 While differing implementation strategies (eg, different length of the educational effort, changes in the frequency of vital signs monitoring) can impact the success of such an initiative, it has been speculated that the afferent limb (which often includes an EWS) might be the most critical part of the system.33 Our results show that the most widely used EWS perform significantly worse on surgical patients, and suggest that a way to improve the accuracy of EWS would be to tailor the risk calculation to different patient subgroups (eg, medical and surgical patients). Plausible next steps would be to demonstrate that tailoring risk calculation to medical and surgical patients separately can improve risk predictions and accuracy of EWS.
Disclosure
The authors report no financial conflicts of interest.
1. Buist MD, Jarmolowski E, Burton PR, Bernard SA, Waxman BP, Anderson J. Recognising clinical instability in hospital patients before cardiac arrest or unplanned admission to intensive care. A pilot study in a tertiary-care hospital. Med J Aust. 1999; 171(1):22-25. PubMed
2. Schein RM, Hazday N, Pena M, Ruben BH, Sprung CL. Clinical antecedents to in-hospital cardiopulmonary arrest. Chest. 1990;98(6):1388-1392. PubMed
3. Peberdy MA, Kaye W, Ornato JP, Larkin GL, Nadkarni V, Mancini ME, et al. Cardiopulmonary resuscitation of adults in the hospital: a report of 14720 cardiac arrests from the National Registry of Cardiopulmonary Resuscitation. Resuscitation. 2003; 58(3):297-308. PubMed
4. Nadkarni VM, Larkin GL, Peberdy MA, Carey SM, Kaye W, Mancini ME, et al. First documented rhythm and clinical outcome from in-hospital cardiac arrest among children and adults. JAMA. 2006;295(1):50-57. PubMed
5. Devita MA, Bellomo R, Hillman K, Kellum J, Rotondi A, Teres D, et al. Findings of the first consensus conference on medical emergency teams. Crit Care Med. 2006;34(9):2463-2478. PubMed
6. DeVita MA, Smith GB, Adam SK, Adams-Pizarro I, Buist M, Bellomo R, et al. “Identifying the hospitalised patient in crisis”--a consensus conference on the afferent limb of rapid response systems. Resuscitation. 2010;81(4):375-382. PubMed
7. Kawamoto K, Houlihan CA, Balas EA, Lobach DF. Improving clinical practice using clinical decision support systems: a systematic review of trials to identify features critical to success. BMJ. 2005;330(7494):765. PubMed
8. Romero-Brufau S, Huddleston JM, Naessens JM, Johnson MG, Hickman J, Morlan BW, et al. Widely used track and trigger scores: are they ready for automation in practice? Resuscitation. 2014;85(4):549-552. PubMed
9. Huddleston JM, Diedrich DA, Kinsey GC, Enzler MJ, Manning DM. Learning from every death. J Patient Saf. 2014;10(1):6-12. PubMed
10. Moriarty JP, Schiebel NE, Johnson MG, Jensen JB, Caples SM, Morlan BW, et al. Evaluating implementation of a rapid response team: considering alternative outcome measures. Int J Qual Health Care. 2014;26(1):49-57. PubMed
11. Kirkland LL, Malinchoc M, O’Byrne M, Benson JT, Kashiwagi DT, Burton MC, et al. A clinical deterioration prediction tool for internal medicine patients. Am J Med Qual. 2013;28(2):135-142. PubMed
12. Griffiths JR, Kidney EM. Current use of early warning scores in UK emergency departments. Emerg Med J. 2012;29(1):65-66. PubMed
13. Subbe CP, Kruger M, Rutherford P, Gemmel L. Validation of a modified Early Warning Score in medical admissions. QJM. 2001;94(10):521-526. PubMed
14. Paterson R, MacLeod DC, Thetford D, Beattie A, Graham C, Lam S, et al.. Prediction of in-hospital mortality and length of stay using an early warning scoring system: clinical audit. Clin Med (Lond). 2006;6(3):281-284. PubMed
15. Harrison GA, Jacques T, McLaws ML, Kilborn G. Combinations of early signs of critical illness predict in-hospital death–the SOCCER study (signs of critical conditions and emergency responses). Resuscitation. 2006;71(3):327-334. PubMed
16. Duckitt RW, Buxton-Thomas R, Walker J, Cheek E, Bewick V, Venn R, et al. Worthing physiological scoring system: derivation and validation of a physiological early-warning system for medical admissions. An observational, population-based single-centre study. Br J Anaesth. 2007; 98(6):769-774. PubMed
17. Smith GB, Prytherch DR, Meredith P, Schmidt PE, Featherstone PI. The ability of the National Early Warning Score (NEWS) to discriminate patients at risk of early cardiac arrest, unanticipated intensive care unit admission, and death. Resuscitation. 2013;84(4):465-470. PubMed
18. Prytherch DR, Smith GB, Schmidt PE, Featherstone PI. ViEWS--Towards a national early warning score for detecting adult inpatient deterioration. Resuscitation. 2010;81(8):932-937. PubMed
19. Romero-Brufau S, Huddleston JM. Reply to letter: widely used track and trigger scores: are they ready for automation in practice? Resuscitation. 2014;85(10):e159. PubMed
20. Efron B, Stein C. The jackknife estimate of variance. Annals of Statistics. 1981;586-596.
21. Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O’Neal PV, Keane KA, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166(10):1338-1344. PubMed
22. DeVita MA, Braithwaite RS, Mahidhara R, Stuart S, Foraida M, Simmons RL. Medical Emergency Response Improvement Team (MERIT). Use of medical emergency team responses to reduce hospital cardiopulmonary arrests. Qual Saf Health Care. 2004;13(4):251-254. PubMed
23. Goncales PD, Polessi JA, Bass LM, Santos Gde P, Yokota PK, Laselva CR, et al. Reduced frequency of cardiopulmonary arrests by rapid response teams. Einstein (Sao Paulo). 2012;10(4):442-448. PubMed
24. Cuthbertson BH, Boroujerdi M, McKie L, Aucott L, Prescott G. Can physiological variables and early warning scoring systems allow early recognition of the deteriorating surgical patient? Crit Care Med. 2007;35(2):402-409. PubMed
25. Gardner-Thorpe J, Love N, Wrightson J, Walsh S, Keeling N. The value of Modified Early Warning Score (MEWS) in surgical in-patients: a prospective observational study. Ann R Coll Surg Engl. 2006;88(6):571-575. PubMed
26. Stenhouse C, Coates S, Tivey M, Allsop P, Parker T. Prospective evaluation of a modified Early Warning Score to aid earlier detection of patients developing critical illness on a general surgical ward. British Journal of Anaesthesia. 2000;84(5):663-663.
27. Smith GB, Prytherch DR, Schmidt PE, Featherstone PI. Review and performance evaluation of aggregate weighted ‘track and trigger’ systems. Resuscitation. 2008;77(2):170-179. PubMed
28. Romero-Brufau S, Huddleston JM, Escobar GJ, Liebow M. Why the C-statistic is not informative to evaluate early warning scores and what metrics to use. Crit Care. 2015; 19:285. PubMed
29. Hillman K, Chen J, Cretikos M, Bellomo R, Brown D, Doig G, et al. Introduction of the medical emergency team (MET) system: a cluster-randomised controlled trial. Lancet. 2005;365(9477):2091-2097. PubMed
30. Shearer B, Marshall S, Buist MD, Finnigan M, Kitto S, Hore T, et al. What stops hospital clinical staff from following protocols? An analysis of the incidence and factors behind the failure of bedside clinical staff to activate the rapid response system in a multi-campus Australian metropolitan healthcare service. BMJ Qual Saf. 2012;21(7):569-575. PubMed
31. Escobar GJ, LaGuardia JC, Turk BJ, Ragins A, Kipnis P, Draper D. Early detection of impending physiologic deterioration among patients who are not in intensive care: development of predictive models using data from an automated electronic medical record. J Hosp Med. 2012;7(5):388-395. PubMed
32. Winters BD, Weaver SJ, Pfoh ER, Yang T, Pham JC, Dy SM. Rapid-response systems as a patient safety strategy: a systematic review. Ann Intern Med. 2013;158(5 pt 2):417-425. PubMed
33. Jones DA, DeVita MA, Bellomo R. Rapid-response teams. N Engl J Med. 2011;365(2):139-146. PubMed
1. Buist MD, Jarmolowski E, Burton PR, Bernard SA, Waxman BP, Anderson J. Recognising clinical instability in hospital patients before cardiac arrest or unplanned admission to intensive care. A pilot study in a tertiary-care hospital. Med J Aust. 1999; 171(1):22-25. PubMed
2. Schein RM, Hazday N, Pena M, Ruben BH, Sprung CL. Clinical antecedents to in-hospital cardiopulmonary arrest. Chest. 1990;98(6):1388-1392. PubMed
3. Peberdy MA, Kaye W, Ornato JP, Larkin GL, Nadkarni V, Mancini ME, et al. Cardiopulmonary resuscitation of adults in the hospital: a report of 14720 cardiac arrests from the National Registry of Cardiopulmonary Resuscitation. Resuscitation. 2003; 58(3):297-308. PubMed
4. Nadkarni VM, Larkin GL, Peberdy MA, Carey SM, Kaye W, Mancini ME, et al. First documented rhythm and clinical outcome from in-hospital cardiac arrest among children and adults. JAMA. 2006;295(1):50-57. PubMed
5. Devita MA, Bellomo R, Hillman K, Kellum J, Rotondi A, Teres D, et al. Findings of the first consensus conference on medical emergency teams. Crit Care Med. 2006;34(9):2463-2478. PubMed
6. DeVita MA, Smith GB, Adam SK, Adams-Pizarro I, Buist M, Bellomo R, et al. “Identifying the hospitalised patient in crisis”--a consensus conference on the afferent limb of rapid response systems. Resuscitation. 2010;81(4):375-382. PubMed
7. Kawamoto K, Houlihan CA, Balas EA, Lobach DF. Improving clinical practice using clinical decision support systems: a systematic review of trials to identify features critical to success. BMJ. 2005;330(7494):765. PubMed
8. Romero-Brufau S, Huddleston JM, Naessens JM, Johnson MG, Hickman J, Morlan BW, et al. Widely used track and trigger scores: are they ready for automation in practice? Resuscitation. 2014;85(4):549-552. PubMed
9. Huddleston JM, Diedrich DA, Kinsey GC, Enzler MJ, Manning DM. Learning from every death. J Patient Saf. 2014;10(1):6-12. PubMed
10. Moriarty JP, Schiebel NE, Johnson MG, Jensen JB, Caples SM, Morlan BW, et al. Evaluating implementation of a rapid response team: considering alternative outcome measures. Int J Qual Health Care. 2014;26(1):49-57. PubMed
11. Kirkland LL, Malinchoc M, O’Byrne M, Benson JT, Kashiwagi DT, Burton MC, et al. A clinical deterioration prediction tool for internal medicine patients. Am J Med Qual. 2013;28(2):135-142. PubMed
12. Griffiths JR, Kidney EM. Current use of early warning scores in UK emergency departments. Emerg Med J. 2012;29(1):65-66. PubMed
13. Subbe CP, Kruger M, Rutherford P, Gemmel L. Validation of a modified Early Warning Score in medical admissions. QJM. 2001;94(10):521-526. PubMed
14. Paterson R, MacLeod DC, Thetford D, Beattie A, Graham C, Lam S, et al.. Prediction of in-hospital mortality and length of stay using an early warning scoring system: clinical audit. Clin Med (Lond). 2006;6(3):281-284. PubMed
15. Harrison GA, Jacques T, McLaws ML, Kilborn G. Combinations of early signs of critical illness predict in-hospital death–the SOCCER study (signs of critical conditions and emergency responses). Resuscitation. 2006;71(3):327-334. PubMed
16. Duckitt RW, Buxton-Thomas R, Walker J, Cheek E, Bewick V, Venn R, et al. Worthing physiological scoring system: derivation and validation of a physiological early-warning system for medical admissions. An observational, population-based single-centre study. Br J Anaesth. 2007; 98(6):769-774. PubMed
17. Smith GB, Prytherch DR, Meredith P, Schmidt PE, Featherstone PI. The ability of the National Early Warning Score (NEWS) to discriminate patients at risk of early cardiac arrest, unanticipated intensive care unit admission, and death. Resuscitation. 2013;84(4):465-470. PubMed
18. Prytherch DR, Smith GB, Schmidt PE, Featherstone PI. ViEWS--Towards a national early warning score for detecting adult inpatient deterioration. Resuscitation. 2010;81(8):932-937. PubMed
19. Romero-Brufau S, Huddleston JM. Reply to letter: widely used track and trigger scores: are they ready for automation in practice? Resuscitation. 2014;85(10):e159. PubMed
20. Efron B, Stein C. The jackknife estimate of variance. Annals of Statistics. 1981;586-596.
21. Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O’Neal PV, Keane KA, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166(10):1338-1344. PubMed
22. DeVita MA, Braithwaite RS, Mahidhara R, Stuart S, Foraida M, Simmons RL. Medical Emergency Response Improvement Team (MERIT). Use of medical emergency team responses to reduce hospital cardiopulmonary arrests. Qual Saf Health Care. 2004;13(4):251-254. PubMed
23. Goncales PD, Polessi JA, Bass LM, Santos Gde P, Yokota PK, Laselva CR, et al. Reduced frequency of cardiopulmonary arrests by rapid response teams. Einstein (Sao Paulo). 2012;10(4):442-448. PubMed
24. Cuthbertson BH, Boroujerdi M, McKie L, Aucott L, Prescott G. Can physiological variables and early warning scoring systems allow early recognition of the deteriorating surgical patient? Crit Care Med. 2007;35(2):402-409. PubMed
25. Gardner-Thorpe J, Love N, Wrightson J, Walsh S, Keeling N. The value of Modified Early Warning Score (MEWS) in surgical in-patients: a prospective observational study. Ann R Coll Surg Engl. 2006;88(6):571-575. PubMed
26. Stenhouse C, Coates S, Tivey M, Allsop P, Parker T. Prospective evaluation of a modified Early Warning Score to aid earlier detection of patients developing critical illness on a general surgical ward. British Journal of Anaesthesia. 2000;84(5):663-663.
27. Smith GB, Prytherch DR, Schmidt PE, Featherstone PI. Review and performance evaluation of aggregate weighted ‘track and trigger’ systems. Resuscitation. 2008;77(2):170-179. PubMed
28. Romero-Brufau S, Huddleston JM, Escobar GJ, Liebow M. Why the C-statistic is not informative to evaluate early warning scores and what metrics to use. Crit Care. 2015; 19:285. PubMed
29. Hillman K, Chen J, Cretikos M, Bellomo R, Brown D, Doig G, et al. Introduction of the medical emergency team (MET) system: a cluster-randomised controlled trial. Lancet. 2005;365(9477):2091-2097. PubMed
30. Shearer B, Marshall S, Buist MD, Finnigan M, Kitto S, Hore T, et al. What stops hospital clinical staff from following protocols? An analysis of the incidence and factors behind the failure of bedside clinical staff to activate the rapid response system in a multi-campus Australian metropolitan healthcare service. BMJ Qual Saf. 2012;21(7):569-575. PubMed
31. Escobar GJ, LaGuardia JC, Turk BJ, Ragins A, Kipnis P, Draper D. Early detection of impending physiologic deterioration among patients who are not in intensive care: development of predictive models using data from an automated electronic medical record. J Hosp Med. 2012;7(5):388-395. PubMed
32. Winters BD, Weaver SJ, Pfoh ER, Yang T, Pham JC, Dy SM. Rapid-response systems as a patient safety strategy: a systematic review. Ann Intern Med. 2013;158(5 pt 2):417-425. PubMed
33. Jones DA, DeVita MA, Bellomo R. Rapid-response teams. N Engl J Med. 2011;365(2):139-146. PubMed
© 2017 Society of Hospital Medicine
Effect of Plate in Close Proximity to Empty External-Fixation Pin Site on Long-Bone Torsional Strength
Take-Home Points
- The location of a bicortical defect in proximity to a tibia plate does not appear to affect the torsional stiffness or torsional failure strength of the bone.
- External fixator pin placement should be based on considerations other than the potential for creating a distal stress riser after definitive fracture management.
A stress riser in cortical bone may be considered any abrupt change in the contour or consistency of the hollow structure, such as a surface defect, that not only weakens the bone but concentrates stresses at that transition point.1 A cortical defect that is 20% of the bone diameter is associated with a 34% decrease in torsional strength, thus representing a “stress riser.”2 High-energy and complex tibia fractures are often provisionally stabilized with external fixation that gives the soft tissues time to recover before definitive fracture fixation. Pin diameter for a medium-size tibia external fixator typically is 5.0 mm, resulting in a 10-mm defect in bicortical placement. Therefore, any tibia with a diameter of <50 mm is at risk for a stress riser fracture.
Although it had been established that sizable cortical defects can decrease the torsional strength of long bone,2 the effect of a plate in close proximity to a defect secondary to an empty external-fixator pin site on torsional strength has not been determined. We conducted a study to evaluate this effect. The null hypothesis was there would be no difference in tibia torsional strength attributable to varying the proximity of a tibia midshaft plate to a 5.0-mm bicortical defect.
Methods
Forty fourth-generation, medium-size left composite tibias (Pacific Research Laboratories) were divided into 8 groups of 5 bones (Figure 1). 
Torsion testing to failure was performed for all specimens in a manner similar to that described by Gardner and colleagues.3 Impression molds for the composite tibia constructed from polymethylmethacrylate encased the superior and distal ends, leaving 25.5 cm of exposed midshaft. This allowed the composites to be rigidly clamped into a materials testing system (858 Mini-Bionix; MTS) equipped with a 100.0-Nm torsional load cell (Figure 2).
Results
Graphical results for torsional stiffness are presented in Figure 3. R2 for all stiffness calculations was >0.99. 
Discussion
Many tibia fractures require provisional stabilization with an external fixator that spans the knee, because of the high-energy nature of the injury or other, higher-priority polytrauma concerns. When the patient or injury is suitable for definitive fixation, the external fixator typically is removed in favor of internal fixation with a plate and screws. Depending on the nature and location of the fracture and the subsequent plate, the empty cortical pin-site defects, often lying at varying distances from the distal end of the plate, can potentially serve as stress risers for fracture.4
Other studies have evaluated long-bone cortical defects biomechanically1,2,4 and clinically,5-7 and multiple studies have been conducted on the effects of plates on long-bone strength for fracture stabilization.8-13 The present study evaluated the torsional strength of long bones in the presence of a bicortical defect and the proximity of the defect to a plate. There were no differences in stiffness or failure load between any of the groups of plated and unplated fourth-generation composite tibias tested to failure in torsion with varying distal bicortical defects. Hypothetically, one would expect the torsional stiffness of these specimens to increase with the mere addition of a metallic diaphyseal plate. However, this study demonstrated that the addition of a plate did not affect the torsional stiffness or strength of the tibias. Clinically, it is common practice to place external fixator pins as far as possible outside the planned incision site for definitive fracture fixation. Thus, we also hypothesized that the presence of a bicortical pin-site defect and its proximity to the plate would alter the torsional strength of the tibia specimens, and that the distal pin-site defect’s location farthest from the plate would exhibit greater strength, but this did not occur. Although other studies have shown that the presence of bicortical defects decreases the strength of long bones, we were unable to quantify this decrease because the 2 intact groups of composites, plated and unplated, survived failure testing.
This study had several limitations, first being the use of composite tibias as opposed to human cadaver bone. Although fourth-generation composite bone models have been validated as a suitable and accurate biomechanical substitute for cadaver specimens,14 anatomical variations in cadaver tibias may transfer forces differently through plates, screws, and distal pin sites. In order to test plated specimens against the unplated controls, we did not simulate a mid-shaft fracture in any of the tibias. The pin-site defects were intended to reflect the mechanical effects of bicortical defects immediately after pin removal and in the absence of any degree of bone healing. Finally, this study focused on pin-site defects that were distal to a midshaft plate and that may not represent the effects of bicortical pin-site defects proximal to the plate.
Given the results of this biomechanical study in composite tibias, varying the proximity of a bicortical defect to a plate does not affect the torsional stiffness or torsional failure strength of the bone. Placement of an intended bicortical defect should be based on considerations other than the potential for creating a distal stress riser after definitive fracture management.
Am J Orthop. 2017;46(2):E108-E111. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
1. Brooks DB, Burstein AH, Frankel VH. The biomechanics of torsional fractures. The stress concentration effect of a drill hole. J Bone Joint Surg Am. 1970;52(3):507-514.
2. Edgerton BC, An KN, Morrey BF. Torsional strength reduction due to cortical defects in bone. J Orthop Res. 1990;8(6):851-855.
3. Gardner MP, Chong AC, Pollock AG, Wooley PH. Mechanical evaluation of large-size fourth-generation composite femur and tibia models. Ann Biomed Eng. 2010;38(3):613-620.
4. Wysocki RW, Sheinkop MB, Virkus WW, Della Valle CJ. Femoral fracture through a previous pin site after computer-assisted total knee arthroplasty. J Arthroplasty. 2008;23(3):462-465.
5. Burstein AH, Currey J, Frankel VH, Heiple KG, Lunseth P, Vessely JC. Bone strength. The effect of screw holes. J Bone Joint Surg Am. 1972;54(6):1143-1156.
6. Clark CR, Morgan C, Sonstegard DA, Matthews LS. The effect of biopsy-hole shape and size on bone strength. J Bone Joint Surg Am. 1977;59(2):213-217.
7. Evans PE, Thomas WG. Tibial fracture through a traction-pin site. A report of two cases. J Bone Joint Surg Am. 1984;66(9):1475-1476.
8. Stoffel K, Dieter U, Stachowiak G, Gächter A, Kuster MS. Biomechanical testing of the LCP—how can stability in locked internal fixators be controlled? Injury. 2003;34(suppl 2):B11-B19.
9. Klaue K, Fengels I, Perren SM. Long-term effects of plate osteosynthesis: comparison of four different plates. Injury. 2000;31(suppl 2):B51-B62.
10. Uhthoff HK, Poitras P, Backman DS. Internal plate fixation of fractures: short history and recent developments. J Orthop Sci. 2006;11(2):118-126.
11. Takemoto RC, Sugi MT, Kummer F, Koval KJ, Egol KA. The effects of locked and unlocked neutralization plates on load bearing of fractures fixed with a lag screw. J Orthop Trauma. 2012;26(9):519-522.
12. Wagner M. General principles for the clinical use of the LCP. Injury. 2003;34(suppl 2):B31-B42.
13. Strauss EJ, Schwarzkopf R, Kummer F, Egol KA. The current status of locked plating: the good, the bad, and the ugly. J Orthop Trauma. 2008;22(7):479-486.
14. Elfar J, Menorca RM, Reed JD, Stanbury S. Composite bone models in orthopaedic surgery research and education. J Am Acad Orthop Surg. 2014;22(2):111-120.
Take-Home Points
- The location of a bicortical defect in proximity to a tibia plate does not appear to affect the torsional stiffness or torsional failure strength of the bone.
- External fixator pin placement should be based on considerations other than the potential for creating a distal stress riser after definitive fracture management.
A stress riser in cortical bone may be considered any abrupt change in the contour or consistency of the hollow structure, such as a surface defect, that not only weakens the bone but concentrates stresses at that transition point.1 A cortical defect that is 20% of the bone diameter is associated with a 34% decrease in torsional strength, thus representing a “stress riser.”2 High-energy and complex tibia fractures are often provisionally stabilized with external fixation that gives the soft tissues time to recover before definitive fracture fixation. Pin diameter for a medium-size tibia external fixator typically is 5.0 mm, resulting in a 10-mm defect in bicortical placement. Therefore, any tibia with a diameter of <50 mm is at risk for a stress riser fracture.
Although it had been established that sizable cortical defects can decrease the torsional strength of long bone,2 the effect of a plate in close proximity to a defect secondary to an empty external-fixator pin site on torsional strength has not been determined. We conducted a study to evaluate this effect. The null hypothesis was there would be no difference in tibia torsional strength attributable to varying the proximity of a tibia midshaft plate to a 5.0-mm bicortical defect.
Methods
Forty fourth-generation, medium-size left composite tibias (Pacific Research Laboratories) were divided into 8 groups of 5 bones (Figure 1).
Torsion testing to failure was performed for all specimens in a manner similar to that described by Gardner and colleagues.3 Impression molds for the composite tibia constructed from polymethylmethacrylate encased the superior and distal ends, leaving 25.5 cm of exposed midshaft. This allowed the composites to be rigidly clamped into a materials testing system (858 Mini-Bionix; MTS) equipped with a 100.0-Nm torsional load cell (Figure 2).
Results
Graphical results for torsional stiffness are presented in Figure 3. R2 for all stiffness calculations was >0.99.
Discussion
Many tibia fractures require provisional stabilization with an external fixator that spans the knee, because of the high-energy nature of the injury or other, higher-priority polytrauma concerns. When the patient or injury is suitable for definitive fixation, the external fixator typically is removed in favor of internal fixation with a plate and screws. Depending on the nature and location of the fracture and the subsequent plate, the empty cortical pin-site defects, often lying at varying distances from the distal end of the plate, can potentially serve as stress risers for fracture.4
Other studies have evaluated long-bone cortical defects biomechanically1,2,4 and clinically,5-7 and multiple studies have been conducted on the effects of plates on long-bone strength for fracture stabilization.8-13 The present study evaluated the torsional strength of long bones in the presence of a bicortical defect and the proximity of the defect to a plate. There were no differences in stiffness or failure load between any of the groups of plated and unplated fourth-generation composite tibias tested to failure in torsion with varying distal bicortical defects. Hypothetically, one would expect the torsional stiffness of these specimens to increase with the mere addition of a metallic diaphyseal plate. However, this study demonstrated that the addition of a plate did not affect the torsional stiffness or strength of the tibias. Clinically, it is common practice to place external fixator pins as far as possible outside the planned incision site for definitive fracture fixation. Thus, we also hypothesized that the presence of a bicortical pin-site defect and its proximity to the plate would alter the torsional strength of the tibia specimens, and that the distal pin-site defect’s location farthest from the plate would exhibit greater strength, but this did not occur. Although other studies have shown that the presence of bicortical defects decreases the strength of long bones, we were unable to quantify this decrease because the 2 intact groups of composites, plated and unplated, survived failure testing.
This study had several limitations, first being the use of composite tibias as opposed to human cadaver bone. Although fourth-generation composite bone models have been validated as a suitable and accurate biomechanical substitute for cadaver specimens,14 anatomical variations in cadaver tibias may transfer forces differently through plates, screws, and distal pin sites. In order to test plated specimens against the unplated controls, we did not simulate a mid-shaft fracture in any of the tibias. The pin-site defects were intended to reflect the mechanical effects of bicortical defects immediately after pin removal and in the absence of any degree of bone healing. Finally, this study focused on pin-site defects that were distal to a midshaft plate and that may not represent the effects of bicortical pin-site defects proximal to the plate.
Given the results of this biomechanical study in composite tibias, varying the proximity of a bicortical defect to a plate does not affect the torsional stiffness or torsional failure strength of the bone. Placement of an intended bicortical defect should be based on considerations other than the potential for creating a distal stress riser after definitive fracture management.
Am J Orthop. 2017;46(2):E108-E111. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
Take-Home Points
- The location of a bicortical defect in proximity to a tibia plate does not appear to affect the torsional stiffness or torsional failure strength of the bone.
- External fixator pin placement should be based on considerations other than the potential for creating a distal stress riser after definitive fracture management.
A stress riser in cortical bone may be considered any abrupt change in the contour or consistency of the hollow structure, such as a surface defect, that not only weakens the bone but concentrates stresses at that transition point.1 A cortical defect that is 20% of the bone diameter is associated with a 34% decrease in torsional strength, thus representing a “stress riser.”2 High-energy and complex tibia fractures are often provisionally stabilized with external fixation that gives the soft tissues time to recover before definitive fracture fixation. Pin diameter for a medium-size tibia external fixator typically is 5.0 mm, resulting in a 10-mm defect in bicortical placement. Therefore, any tibia with a diameter of <50 mm is at risk for a stress riser fracture.
Although it had been established that sizable cortical defects can decrease the torsional strength of long bone,2 the effect of a plate in close proximity to a defect secondary to an empty external-fixator pin site on torsional strength has not been determined. We conducted a study to evaluate this effect. The null hypothesis was there would be no difference in tibia torsional strength attributable to varying the proximity of a tibia midshaft plate to a 5.0-mm bicortical defect.
Methods
Forty fourth-generation, medium-size left composite tibias (Pacific Research Laboratories) were divided into 8 groups of 5 bones (Figure 1).
Torsion testing to failure was performed for all specimens in a manner similar to that described by Gardner and colleagues.3 Impression molds for the composite tibia constructed from polymethylmethacrylate encased the superior and distal ends, leaving 25.5 cm of exposed midshaft. This allowed the composites to be rigidly clamped into a materials testing system (858 Mini-Bionix; MTS) equipped with a 100.0-Nm torsional load cell (Figure 2).
Results
Graphical results for torsional stiffness are presented in Figure 3. R2 for all stiffness calculations was >0.99.
Discussion
Many tibia fractures require provisional stabilization with an external fixator that spans the knee, because of the high-energy nature of the injury or other, higher-priority polytrauma concerns. When the patient or injury is suitable for definitive fixation, the external fixator typically is removed in favor of internal fixation with a plate and screws. Depending on the nature and location of the fracture and the subsequent plate, the empty cortical pin-site defects, often lying at varying distances from the distal end of the plate, can potentially serve as stress risers for fracture.4
Other studies have evaluated long-bone cortical defects biomechanically1,2,4 and clinically,5-7 and multiple studies have been conducted on the effects of plates on long-bone strength for fracture stabilization.8-13 The present study evaluated the torsional strength of long bones in the presence of a bicortical defect and the proximity of the defect to a plate. There were no differences in stiffness or failure load between any of the groups of plated and unplated fourth-generation composite tibias tested to failure in torsion with varying distal bicortical defects. Hypothetically, one would expect the torsional stiffness of these specimens to increase with the mere addition of a metallic diaphyseal plate. However, this study demonstrated that the addition of a plate did not affect the torsional stiffness or strength of the tibias. Clinically, it is common practice to place external fixator pins as far as possible outside the planned incision site for definitive fracture fixation. Thus, we also hypothesized that the presence of a bicortical pin-site defect and its proximity to the plate would alter the torsional strength of the tibia specimens, and that the distal pin-site defect’s location farthest from the plate would exhibit greater strength, but this did not occur. Although other studies have shown that the presence of bicortical defects decreases the strength of long bones, we were unable to quantify this decrease because the 2 intact groups of composites, plated and unplated, survived failure testing.
This study had several limitations, first being the use of composite tibias as opposed to human cadaver bone. Although fourth-generation composite bone models have been validated as a suitable and accurate biomechanical substitute for cadaver specimens,14 anatomical variations in cadaver tibias may transfer forces differently through plates, screws, and distal pin sites. In order to test plated specimens against the unplated controls, we did not simulate a mid-shaft fracture in any of the tibias. The pin-site defects were intended to reflect the mechanical effects of bicortical defects immediately after pin removal and in the absence of any degree of bone healing. Finally, this study focused on pin-site defects that were distal to a midshaft plate and that may not represent the effects of bicortical pin-site defects proximal to the plate.
Given the results of this biomechanical study in composite tibias, varying the proximity of a bicortical defect to a plate does not affect the torsional stiffness or torsional failure strength of the bone. Placement of an intended bicortical defect should be based on considerations other than the potential for creating a distal stress riser after definitive fracture management.
Am J Orthop. 2017;46(2):E108-E111. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
1. Brooks DB, Burstein AH, Frankel VH. The biomechanics of torsional fractures. The stress concentration effect of a drill hole. J Bone Joint Surg Am. 1970;52(3):507-514.
2. Edgerton BC, An KN, Morrey BF. Torsional strength reduction due to cortical defects in bone. J Orthop Res. 1990;8(6):851-855.
3. Gardner MP, Chong AC, Pollock AG, Wooley PH. Mechanical evaluation of large-size fourth-generation composite femur and tibia models. Ann Biomed Eng. 2010;38(3):613-620.
4. Wysocki RW, Sheinkop MB, Virkus WW, Della Valle CJ. Femoral fracture through a previous pin site after computer-assisted total knee arthroplasty. J Arthroplasty. 2008;23(3):462-465.
5. Burstein AH, Currey J, Frankel VH, Heiple KG, Lunseth P, Vessely JC. Bone strength. The effect of screw holes. J Bone Joint Surg Am. 1972;54(6):1143-1156.
6. Clark CR, Morgan C, Sonstegard DA, Matthews LS. The effect of biopsy-hole shape and size on bone strength. J Bone Joint Surg Am. 1977;59(2):213-217.
7. Evans PE, Thomas WG. Tibial fracture through a traction-pin site. A report of two cases. J Bone Joint Surg Am. 1984;66(9):1475-1476.
8. Stoffel K, Dieter U, Stachowiak G, Gächter A, Kuster MS. Biomechanical testing of the LCP—how can stability in locked internal fixators be controlled? Injury. 2003;34(suppl 2):B11-B19.
9. Klaue K, Fengels I, Perren SM. Long-term effects of plate osteosynthesis: comparison of four different plates. Injury. 2000;31(suppl 2):B51-B62.
10. Uhthoff HK, Poitras P, Backman DS. Internal plate fixation of fractures: short history and recent developments. J Orthop Sci. 2006;11(2):118-126.
11. Takemoto RC, Sugi MT, Kummer F, Koval KJ, Egol KA. The effects of locked and unlocked neutralization plates on load bearing of fractures fixed with a lag screw. J Orthop Trauma. 2012;26(9):519-522.
12. Wagner M. General principles for the clinical use of the LCP. Injury. 2003;34(suppl 2):B31-B42.
13. Strauss EJ, Schwarzkopf R, Kummer F, Egol KA. The current status of locked plating: the good, the bad, and the ugly. J Orthop Trauma. 2008;22(7):479-486.
14. Elfar J, Menorca RM, Reed JD, Stanbury S. Composite bone models in orthopaedic surgery research and education. J Am Acad Orthop Surg. 2014;22(2):111-120.
1. Brooks DB, Burstein AH, Frankel VH. The biomechanics of torsional fractures. The stress concentration effect of a drill hole. J Bone Joint Surg Am. 1970;52(3):507-514.
2. Edgerton BC, An KN, Morrey BF. Torsional strength reduction due to cortical defects in bone. J Orthop Res. 1990;8(6):851-855.
3. Gardner MP, Chong AC, Pollock AG, Wooley PH. Mechanical evaluation of large-size fourth-generation composite femur and tibia models. Ann Biomed Eng. 2010;38(3):613-620.
4. Wysocki RW, Sheinkop MB, Virkus WW, Della Valle CJ. Femoral fracture through a previous pin site after computer-assisted total knee arthroplasty. J Arthroplasty. 2008;23(3):462-465.
5. Burstein AH, Currey J, Frankel VH, Heiple KG, Lunseth P, Vessely JC. Bone strength. The effect of screw holes. J Bone Joint Surg Am. 1972;54(6):1143-1156.
6. Clark CR, Morgan C, Sonstegard DA, Matthews LS. The effect of biopsy-hole shape and size on bone strength. J Bone Joint Surg Am. 1977;59(2):213-217.
7. Evans PE, Thomas WG. Tibial fracture through a traction-pin site. A report of two cases. J Bone Joint Surg Am. 1984;66(9):1475-1476.
8. Stoffel K, Dieter U, Stachowiak G, Gächter A, Kuster MS. Biomechanical testing of the LCP—how can stability in locked internal fixators be controlled? Injury. 2003;34(suppl 2):B11-B19.
9. Klaue K, Fengels I, Perren SM. Long-term effects of plate osteosynthesis: comparison of four different plates. Injury. 2000;31(suppl 2):B51-B62.
10. Uhthoff HK, Poitras P, Backman DS. Internal plate fixation of fractures: short history and recent developments. J Orthop Sci. 2006;11(2):118-126.
11. Takemoto RC, Sugi MT, Kummer F, Koval KJ, Egol KA. The effects of locked and unlocked neutralization plates on load bearing of fractures fixed with a lag screw. J Orthop Trauma. 2012;26(9):519-522.
12. Wagner M. General principles for the clinical use of the LCP. Injury. 2003;34(suppl 2):B31-B42.
13. Strauss EJ, Schwarzkopf R, Kummer F, Egol KA. The current status of locked plating: the good, the bad, and the ugly. J Orthop Trauma. 2008;22(7):479-486.
14. Elfar J, Menorca RM, Reed JD, Stanbury S. Composite bone models in orthopaedic surgery research and education. J Am Acad Orthop Surg. 2014;22(2):111-120.
A Review of Psychostimulants for Adults With Depression
Depression is a common condition that significantly impairs social and occupational functioning. Many patients do not respond to first-line pharmacotherapies and are considered to have treatment-resistant depression (TRD). These patients may benefit from augmentation of their antidepressant to reduce depression. Multiple medications have demonstrated various degrees of efficacy for augmentation, including psychostimulants. This article reviews studies of psychostimulants as augmentation agents for TRD and discusses risks, offers advice, and makes recommendations for clinicians who prescribe stimulants.
Background
Major depressive disorder (MDD) is a common psychiatric condition that significantly impairs quality of life.1 It is a recurrent illness, averaging 2 relapses per decade. The probability of recurrence increases with the number of depressive episodes.2,3 A patient who experiences major depressive episodes alternating with euthymia has unipolar depression; whereas one who experiences major depressive episodes alternating with episodes of mania or hypomania has bipolar depression.4
Despite adequate dose and duration of pharmacotherapy, many individuals with unipolar or bipolar depression do not achieve and sustain remission.5 Remission rates decrease and relapse rates increase with subsequent failed antidepressant trials.6 It is difficult to identify factors that predict treatment resistance, but one review of antidepressant studies found that patients who did not demonstrate a response within 3 weeks of medication initiation were less likely to respond after a longer duration.7
Treatment-resistant depression is commonly, but not universally, defined as lack of response after trials of 2 or more antidepressants with different mechanisms of action for sufficient duration.5 This definition will be used here as well. Other definitions have proposed stages of TRD, but these require further study to evaluate their reliability and predictive utility.8 Due to lack of consensus regarding the definition of TRD, it is not possible to determine the exact prevalence of TRD.
Patients with TRD may benefit from augmentation of their medication regimen. Augmentation with lithium has yielded conflicting results, and its efficacy with newer antidepressants is not well studied.9-12 Triiodothyronine, buspirone, and pindolol have demonstrated some efficacy when added to serotonin reuptake inhibitors (SRIs).10,12,13 Second-generation antipsychotic drugs, antidepressant drug combinations, omega-3 fatty acids, S-adenosyl methionine (SAMe), and L-methylfolate have demonstrated some efficacy in some studies as well.12,14-23 In patients with depression who have not responded to these strategies, psychostimulant augmentation may be appropriate.
Methods
A literature search was conducted following an algorithmic approach in the MEDLINE/PubMed database for studies in English from January 1985 to August 2014 of stimulants as augmenting agents for depression, using the Medical Subject Headings stimulant, depression, and augmentation, combined with an AND operator. The search was limited to adult humans and excluded case reports and letters, to identify studies with stronger evidence. Also excluded were studies using caffeine (to augment electroconvulsive therapy for depression) and pemoline as the sole augmenting stimulant as well as studies of patients with comorbid mental health diagnoses and studies that initiated stimulants and antidepressants simultaneously to assess antidepressant response.
This review organized results by stimulant rather than by depression type, even though some studies used > 1 stimulant or recruited patients with different types of depression. Although prevalence, prognosis, and monotherapy differ for unipolar and bipolar depression, psychostimulants target similar symptoms, despite augmenting different monotherapies in unipolar and bipolar depression. Therefore, no distinction is made between assessing studies of stimulants for unipolar and bipolar depression.
Results
A total of 70 articles were identified, and 31 studies met inclusion criteria (Figure). Of the studies included, 12 were double-blind, placebo-controlled (DBPC) trials and 19 were retrospective chart reviews or open studies. Most studies evaluated depression, using validated scales, such as the Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale, Clinical Global Impressions of Severity, Inventory of Depressive Symptoms, Carroll Depression Rating Scale, Global Assessment of Functioning, Quick Inventory of Depressive Symptomatology, or the Psychiatric Symptom Assessment Scale. Study details are provided in Tables 1 to 4.
Dextroamphetamine and Methylphenidate
Dextroamphetamine and methylphenidate are indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) and exert their effects by inhibiting uptake of norepinephrine and dopamine.24 In one chart review, patients received dextroamphetamine or methylphenidate augmentation of monoamine oxidase inhibitors (MAOIs) alone or with concurrent tricyclic antidepressants; the majority reported decreased depression.25 In an openlabel trial, dextroamphetamine was titrated to efficacy in patients who were receiving an MAOI with or without pemoline.26 Nearly 80% of patients reported long-lasting improvement in depression. In an open-label trial, all patients reported decreased depression when methylphenidate was added to SRIs; however, no scales were used.27
In a case series, patients with both major depression and persistent depressive disorder (dysthymia) experienced a substantial, quick, and sustained response to dextroamphetamine or methylphenidate augmentation.28 Addition of lisdexamfetamine significantly reduced depressive symptoms in individuals with inadequate response to escitalopram.29 Patients with full or partial remission of depression noted improved executive function and residual depressive symptoms after lisdexamfetamine was added to SRI monotherapy.30 In a trial in which patients received dexamphetamine or methylphenidate as monotherapy or augmentation, 30% to 34% of patients reported mood improvement, but 36% reported no improvement.31 In an extension study, low-dose psychostimulants quickly diminished melancholia.32
Methylphenidate was safe and effective in patients with bipolar depression receiving treatment for 1 to 5 years; 44% evidenced significant improvement.33 When offered to patients with bipolar depression, patients receiving methylphenidate or dextroamphetamine reported less depression or sedation and did not develop tolerance, mania, or misuse.34 A case series concluded that methylphenidate addition to mood stabilizers was generally effective and safe.35
However, not all preparations of methylphenidate have demonstrated efficacy. In one study, osmotic controlledrelease oral system (OROS) methylphenidate improved apathy and fatigue but not overall depression.36 Although OROS methylphenidate similarly failed to demonstrate statistically significant efficacy in another study, more responders were documented in the treatment group.37
Although this review focuses on stimulants as augmenting agents in patients with depression, it is worth noting the limited number of studies evaluating stimulants’ effect on depression in patients with traumatic brain injury. This observation is of concern, as these conditions are frequently comorbid in returning veterans. One study noted that methylphenidate was an effective monotherapy for depression; whereas another study found that methylphenidate monotherapy reduced depression as well as sertraline, was better tolerated, and improved fatigue and cognition.38,39
Modafinil and Armodafinil
Modafinil and armodafinil (the R-enantiomer of modafinil) are indicated for improving wakefulness in individuals with narcolepsy, obstructive sleep apnea, and shift work sleep disorder by modulating glutamate, gamma amino-butyric acid, and histamine.40,41 Although they increase extracellular dopamine concentrations, they do not cause an increase in dopamine release and may have less misuse potential than that of dextroamphetamine and methylphenidate.40,41 In a study of 7 patients with unipolar or bipolar depression, all patients achieved full or partial remission with minimal adverse effects (AEs).42 In a prospective study, 41% of patients reported only mild depression or full remission with modafinil augmentation.43
Multiple trials and a pooled analysis noted decreased depression and fatigue and improved cognition in patients receiving modafinil augmentation compared with mood stabilizers or antidepressants.44-49 Modafinil is a useful adjunct for partial responders to SRIs, resulting in rapid mood improvement and decreased fatigue.50-54 However, in one study, modafinil did not demonstrate efficacy compared with placebo. This result was attributed to premature study termination after 2 modafinil-treated patients developed suicidal ideation.55 A post hoc analysis found no difference in frequency of suicidal ideation between groups.
Two DBPC studies evaluated armodafinil in patients with bipolar depression. In both studies it was added to a mood-stabilizing agent (lithium, valproate, aripiprazole, olanzapine, lamotrigine, risperidone, or ziprasidone), and patients receiving armodafinil reported significant reductions
in depression.56,57
Atomoxetine
Atomoxetine is a norepinephrine reuptake inhibitor indicated for the treatment of ADHD and is considered to have no misuse potential due to lack of dopamine modulation.58 In one study, 15 patients received atomoxetine added to their antidepressant, and 60% experienced significant symptom reduction.59 A chart review noted decreases in fatigue and depression when atomoxetine was added to an SRI, mirtazapine, or amitriptyline.60 However, in a DBPC trial, atomoxetine did not lead to significant changes in depression.61
Discussion
There is a limited amount of high-quality evidence to support psychostimulant augmentation, as noted by the relatively few DBPC trials, most of short duration. The evidence supports their efficacy primarily for unipolar depression, as 14 studies evaluated patients with unipolar depression, whereas only 7 studies evaluated patients with bipolar depression. The remaining studies recruited patients with both depression types. Collectively, modafinil and armodafinil have the most evidence in DBPC trials.
There are relatively few DBPC trials with high power and sufficient duration for dextroamphetamine and methylphenidate preparations. This discovery is surprising, considering the duration that these medications have been available. However, several chart reviews and open-label trials provided some evidence to support their use in patients without a history of substance misuse or cardiac conditions.62 Osmotic controlled- release oral system methylphenidate seems to be ineffective, and the efficacy of atomoxetine for augmentation
is uncertain.
Precautions
Prescribing physicians who offer stimulants should consider potential AEs, such as psychosis, anorexia, anxiety, insomnia, mood changes (eg, anger), misuse, addiction, mania, and cardiovascular problems. Psychostimulants have been implicated in precipitating psychosis.63,64 However, in a 12-month study of 250 adults with ADHD, 73 reported AEs, and only 31 discontinued the stimulant. Adverse effects leading to discontinuation included mood instability (n = 7), agitation (n = 6), irritability (n = 4), or decreased appetite (n = 4).65
Although associated with the risks of anorexia and insomnia in patients with ADHD, methylphenidate rapidly improved daytime sleepiness and mood, and—paradoxically—appetite and nighttime sleep in medically ill elderly patients with depression.66 Misuse or abuse of methylphenidate and dextroamphetamine were noted in 23% of patients referred for substance misuse.67 Nonetheless, little evidence exists that these drugs possess significant misuse potential in patients taking them as prescribed. As a prodrug, lisdexamfetamine is hypothesized to have less abuse potential compared with dextroamphetamine and methylphenidate, but it carries the same prescribing and monitoring precautions.68 Risks related to stimulant usage extend to manic symptoms.69 Patients with bipolar disorder should not receive stimulants if they have a history of stimulant-induced mania, rapid cycling, or psychosis.70
Long-term cardiovascular safety data exist for dextroamphetamine and methylphenidate but are limited or unavailable for modafinil, armodafinil, and atomoxetine. A retrospective cohort study found no significant increase in the number of cardiac events in patients receiving dextroamphetamine,
methylphenidate, or atomoxetine for an average of 1 year compared with controls.71 Another cohort study of > 44,000 patients found that initiation of
methylphenidate was associated with increased risk of sudden death or arrhythmia, but the risk was attributed to an unmeasured confounding factor, as the authors found a negative correlation between methylphenidate dose and all cardiovascular events.72
Recent practice guidelines recommend that before prescribing stimulants, clinicians should perform a physical examination (including heart and lung auscultation), obtain vital signs and height and weight, and request an electrocardiogram in case of abnormal findings on a cardiovascular examination or in case of a personal or family history of heart disease. Before offering atomoxetine, clinicians should evaluate the patient for a history of liver disease (and check liver function studies in case of a positive history). Clinicians should also assess risk of self-harm prior to initiating psychostimulant therapy.73 Throughout treatment, clinicians should evaluate the patient for changes in blood pressure, pulse, weight or mood, as well as the development of dependence or misuse. Urine toxicology testing is recommended for dextroamphetamine and methylphenidate to screen for adherence and diversion.
Limitations
Using only PubMed and MEDLINE databases limited the search to articles published in English after 1985, excluding letters and case reports to identify studies with higher evidence (the studies were not weighted based on study design). In addition, the studies had certain limitations. These include a limited number of DBPC trials, most were of short duration. It is also difficult to compare studies due to various rating scales used and concurrent
medication regimens of study subjects. These limitations raise questions surrounding the long-term efficacy of stimulants, and there is no consensus for how long a stimulant should be continued if beneficial. Longer, higherpowered, DBPC trials are warranted to determine longterm efficacy and safety of stimulant augmentation.62
Conclusion
For patients with depression who have not responded to other augmentation strategies, psychostimulants may be offered to improve mood, energy, and concentration. For clinicians considering stimulant augmentation, modafinil and armodafinil are reasonable choices given their efficacy in double-blind, placebo-controlled trials and lower risk of misuse. Dextroamphetamine (particularly lisdexamphetamine) and methylphenidate may be appropriate for patients who have not benefited from or tolerated modafinil or armodafinil, provided these patients do not have a medical history of cardiac disease or current substance use.
Osmotic controlled-release oral system methylphenidate seems to be ineffective as an augmenting agent. The efficacy of atomoxetine for augmentation is questionable, but atomoxetine could be offered if other stimulants were contraindicated, ineffective, or poorly tolerated. Both OROS methylphenidate and atomoxetine should be evaluated in additional trials before they can be recommended as augmentation therapies. Certain psychostimulants may be appropriate and reasonable adjunctive pharmacotherapies for patients with unipolar or bipolar depression who have failed other augmentation strategies, for patients who have significant fatigue or cognitive complaints, or for elderly patients with melancholic or somatic features of depression.
Acknowledgements
The authors thank Maureen Humphrey-Shelton and Kathy Thomas for their help in obtaining references.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
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Depression is a common condition that significantly impairs social and occupational functioning. Many patients do not respond to first-line pharmacotherapies and are considered to have treatment-resistant depression (TRD). These patients may benefit from augmentation of their antidepressant to reduce depression. Multiple medications have demonstrated various degrees of efficacy for augmentation, including psychostimulants. This article reviews studies of psychostimulants as augmentation agents for TRD and discusses risks, offers advice, and makes recommendations for clinicians who prescribe stimulants.
Background
Major depressive disorder (MDD) is a common psychiatric condition that significantly impairs quality of life.1 It is a recurrent illness, averaging 2 relapses per decade. The probability of recurrence increases with the number of depressive episodes.2,3 A patient who experiences major depressive episodes alternating with euthymia has unipolar depression; whereas one who experiences major depressive episodes alternating with episodes of mania or hypomania has bipolar depression.4
Despite adequate dose and duration of pharmacotherapy, many individuals with unipolar or bipolar depression do not achieve and sustain remission.5 Remission rates decrease and relapse rates increase with subsequent failed antidepressant trials.6 It is difficult to identify factors that predict treatment resistance, but one review of antidepressant studies found that patients who did not demonstrate a response within 3 weeks of medication initiation were less likely to respond after a longer duration.7
Treatment-resistant depression is commonly, but not universally, defined as lack of response after trials of 2 or more antidepressants with different mechanisms of action for sufficient duration.5 This definition will be used here as well. Other definitions have proposed stages of TRD, but these require further study to evaluate their reliability and predictive utility.8 Due to lack of consensus regarding the definition of TRD, it is not possible to determine the exact prevalence of TRD.
Patients with TRD may benefit from augmentation of their medication regimen. Augmentation with lithium has yielded conflicting results, and its efficacy with newer antidepressants is not well studied.9-12 Triiodothyronine, buspirone, and pindolol have demonstrated some efficacy when added to serotonin reuptake inhibitors (SRIs).10,12,13 Second-generation antipsychotic drugs, antidepressant drug combinations, omega-3 fatty acids, S-adenosyl methionine (SAMe), and L-methylfolate have demonstrated some efficacy in some studies as well.12,14-23 In patients with depression who have not responded to these strategies, psychostimulant augmentation may be appropriate.
Methods
A literature search was conducted following an algorithmic approach in the MEDLINE/PubMed database for studies in English from January 1985 to August 2014 of stimulants as augmenting agents for depression, using the Medical Subject Headings stimulant, depression, and augmentation, combined with an AND operator. The search was limited to adult humans and excluded case reports and letters, to identify studies with stronger evidence. Also excluded were studies using caffeine (to augment electroconvulsive therapy for depression) and pemoline as the sole augmenting stimulant as well as studies of patients with comorbid mental health diagnoses and studies that initiated stimulants and antidepressants simultaneously to assess antidepressant response.
This review organized results by stimulant rather than by depression type, even though some studies used > 1 stimulant or recruited patients with different types of depression. Although prevalence, prognosis, and monotherapy differ for unipolar and bipolar depression, psychostimulants target similar symptoms, despite augmenting different monotherapies in unipolar and bipolar depression. Therefore, no distinction is made between assessing studies of stimulants for unipolar and bipolar depression.
Results
A total of 70 articles were identified, and 31 studies met inclusion criteria (Figure). Of the studies included, 12 were double-blind, placebo-controlled (DBPC) trials and 19 were retrospective chart reviews or open studies. Most studies evaluated depression, using validated scales, such as the Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale, Clinical Global Impressions of Severity, Inventory of Depressive Symptoms, Carroll Depression Rating Scale, Global Assessment of Functioning, Quick Inventory of Depressive Symptomatology, or the Psychiatric Symptom Assessment Scale. Study details are provided in Tables 1 to 4.
Dextroamphetamine and Methylphenidate
Dextroamphetamine and methylphenidate are indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) and exert their effects by inhibiting uptake of norepinephrine and dopamine.24 In one chart review, patients received dextroamphetamine or methylphenidate augmentation of monoamine oxidase inhibitors (MAOIs) alone or with concurrent tricyclic antidepressants; the majority reported decreased depression.25 In an openlabel trial, dextroamphetamine was titrated to efficacy in patients who were receiving an MAOI with or without pemoline.26 Nearly 80% of patients reported long-lasting improvement in depression. In an open-label trial, all patients reported decreased depression when methylphenidate was added to SRIs; however, no scales were used.27
In a case series, patients with both major depression and persistent depressive disorder (dysthymia) experienced a substantial, quick, and sustained response to dextroamphetamine or methylphenidate augmentation.28 Addition of lisdexamfetamine significantly reduced depressive symptoms in individuals with inadequate response to escitalopram.29 Patients with full or partial remission of depression noted improved executive function and residual depressive symptoms after lisdexamfetamine was added to SRI monotherapy.30 In a trial in which patients received dexamphetamine or methylphenidate as monotherapy or augmentation, 30% to 34% of patients reported mood improvement, but 36% reported no improvement.31 In an extension study, low-dose psychostimulants quickly diminished melancholia.32
Methylphenidate was safe and effective in patients with bipolar depression receiving treatment for 1 to 5 years; 44% evidenced significant improvement.33 When offered to patients with bipolar depression, patients receiving methylphenidate or dextroamphetamine reported less depression or sedation and did not develop tolerance, mania, or misuse.34 A case series concluded that methylphenidate addition to mood stabilizers was generally effective and safe.35
However, not all preparations of methylphenidate have demonstrated efficacy. In one study, osmotic controlledrelease oral system (OROS) methylphenidate improved apathy and fatigue but not overall depression.36 Although OROS methylphenidate similarly failed to demonstrate statistically significant efficacy in another study, more responders were documented in the treatment group.37
Although this review focuses on stimulants as augmenting agents in patients with depression, it is worth noting the limited number of studies evaluating stimulants’ effect on depression in patients with traumatic brain injury. This observation is of concern, as these conditions are frequently comorbid in returning veterans. One study noted that methylphenidate was an effective monotherapy for depression; whereas another study found that methylphenidate monotherapy reduced depression as well as sertraline, was better tolerated, and improved fatigue and cognition.38,39
Modafinil and Armodafinil
Modafinil and armodafinil (the R-enantiomer of modafinil) are indicated for improving wakefulness in individuals with narcolepsy, obstructive sleep apnea, and shift work sleep disorder by modulating glutamate, gamma amino-butyric acid, and histamine.40,41 Although they increase extracellular dopamine concentrations, they do not cause an increase in dopamine release and may have less misuse potential than that of dextroamphetamine and methylphenidate.40,41 In a study of 7 patients with unipolar or bipolar depression, all patients achieved full or partial remission with minimal adverse effects (AEs).42 In a prospective study, 41% of patients reported only mild depression or full remission with modafinil augmentation.43
Multiple trials and a pooled analysis noted decreased depression and fatigue and improved cognition in patients receiving modafinil augmentation compared with mood stabilizers or antidepressants.44-49 Modafinil is a useful adjunct for partial responders to SRIs, resulting in rapid mood improvement and decreased fatigue.50-54 However, in one study, modafinil did not demonstrate efficacy compared with placebo. This result was attributed to premature study termination after 2 modafinil-treated patients developed suicidal ideation.55 A post hoc analysis found no difference in frequency of suicidal ideation between groups.
Two DBPC studies evaluated armodafinil in patients with bipolar depression. In both studies it was added to a mood-stabilizing agent (lithium, valproate, aripiprazole, olanzapine, lamotrigine, risperidone, or ziprasidone), and patients receiving armodafinil reported significant reductions
in depression.56,57
Atomoxetine
Atomoxetine is a norepinephrine reuptake inhibitor indicated for the treatment of ADHD and is considered to have no misuse potential due to lack of dopamine modulation.58 In one study, 15 patients received atomoxetine added to their antidepressant, and 60% experienced significant symptom reduction.59 A chart review noted decreases in fatigue and depression when atomoxetine was added to an SRI, mirtazapine, or amitriptyline.60 However, in a DBPC trial, atomoxetine did not lead to significant changes in depression.61
Discussion
There is a limited amount of high-quality evidence to support psychostimulant augmentation, as noted by the relatively few DBPC trials, most of short duration. The evidence supports their efficacy primarily for unipolar depression, as 14 studies evaluated patients with unipolar depression, whereas only 7 studies evaluated patients with bipolar depression. The remaining studies recruited patients with both depression types. Collectively, modafinil and armodafinil have the most evidence in DBPC trials.
There are relatively few DBPC trials with high power and sufficient duration for dextroamphetamine and methylphenidate preparations. This discovery is surprising, considering the duration that these medications have been available. However, several chart reviews and open-label trials provided some evidence to support their use in patients without a history of substance misuse or cardiac conditions.62 Osmotic controlled- release oral system methylphenidate seems to be ineffective, and the efficacy of atomoxetine for augmentation
is uncertain.
Precautions
Prescribing physicians who offer stimulants should consider potential AEs, such as psychosis, anorexia, anxiety, insomnia, mood changes (eg, anger), misuse, addiction, mania, and cardiovascular problems. Psychostimulants have been implicated in precipitating psychosis.63,64 However, in a 12-month study of 250 adults with ADHD, 73 reported AEs, and only 31 discontinued the stimulant. Adverse effects leading to discontinuation included mood instability (n = 7), agitation (n = 6), irritability (n = 4), or decreased appetite (n = 4).65
Although associated with the risks of anorexia and insomnia in patients with ADHD, methylphenidate rapidly improved daytime sleepiness and mood, and—paradoxically—appetite and nighttime sleep in medically ill elderly patients with depression.66 Misuse or abuse of methylphenidate and dextroamphetamine were noted in 23% of patients referred for substance misuse.67 Nonetheless, little evidence exists that these drugs possess significant misuse potential in patients taking them as prescribed. As a prodrug, lisdexamfetamine is hypothesized to have less abuse potential compared with dextroamphetamine and methylphenidate, but it carries the same prescribing and monitoring precautions.68 Risks related to stimulant usage extend to manic symptoms.69 Patients with bipolar disorder should not receive stimulants if they have a history of stimulant-induced mania, rapid cycling, or psychosis.70
Long-term cardiovascular safety data exist for dextroamphetamine and methylphenidate but are limited or unavailable for modafinil, armodafinil, and atomoxetine. A retrospective cohort study found no significant increase in the number of cardiac events in patients receiving dextroamphetamine,
methylphenidate, or atomoxetine for an average of 1 year compared with controls.71 Another cohort study of > 44,000 patients found that initiation of
methylphenidate was associated with increased risk of sudden death or arrhythmia, but the risk was attributed to an unmeasured confounding factor, as the authors found a negative correlation between methylphenidate dose and all cardiovascular events.72
Recent practice guidelines recommend that before prescribing stimulants, clinicians should perform a physical examination (including heart and lung auscultation), obtain vital signs and height and weight, and request an electrocardiogram in case of abnormal findings on a cardiovascular examination or in case of a personal or family history of heart disease. Before offering atomoxetine, clinicians should evaluate the patient for a history of liver disease (and check liver function studies in case of a positive history). Clinicians should also assess risk of self-harm prior to initiating psychostimulant therapy.73 Throughout treatment, clinicians should evaluate the patient for changes in blood pressure, pulse, weight or mood, as well as the development of dependence or misuse. Urine toxicology testing is recommended for dextroamphetamine and methylphenidate to screen for adherence and diversion.
Limitations
Using only PubMed and MEDLINE databases limited the search to articles published in English after 1985, excluding letters and case reports to identify studies with higher evidence (the studies were not weighted based on study design). In addition, the studies had certain limitations. These include a limited number of DBPC trials, most were of short duration. It is also difficult to compare studies due to various rating scales used and concurrent
medication regimens of study subjects. These limitations raise questions surrounding the long-term efficacy of stimulants, and there is no consensus for how long a stimulant should be continued if beneficial. Longer, higherpowered, DBPC trials are warranted to determine longterm efficacy and safety of stimulant augmentation.62
Conclusion
For patients with depression who have not responded to other augmentation strategies, psychostimulants may be offered to improve mood, energy, and concentration. For clinicians considering stimulant augmentation, modafinil and armodafinil are reasonable choices given their efficacy in double-blind, placebo-controlled trials and lower risk of misuse. Dextroamphetamine (particularly lisdexamphetamine) and methylphenidate may be appropriate for patients who have not benefited from or tolerated modafinil or armodafinil, provided these patients do not have a medical history of cardiac disease or current substance use.
Osmotic controlled-release oral system methylphenidate seems to be ineffective as an augmenting agent. The efficacy of atomoxetine for augmentation is questionable, but atomoxetine could be offered if other stimulants were contraindicated, ineffective, or poorly tolerated. Both OROS methylphenidate and atomoxetine should be evaluated in additional trials before they can be recommended as augmentation therapies. Certain psychostimulants may be appropriate and reasonable adjunctive pharmacotherapies for patients with unipolar or bipolar depression who have failed other augmentation strategies, for patients who have significant fatigue or cognitive complaints, or for elderly patients with melancholic or somatic features of depression.
Acknowledgements
The authors thank Maureen Humphrey-Shelton and Kathy Thomas for their help in obtaining references.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Depression is a common condition that significantly impairs social and occupational functioning. Many patients do not respond to first-line pharmacotherapies and are considered to have treatment-resistant depression (TRD). These patients may benefit from augmentation of their antidepressant to reduce depression. Multiple medications have demonstrated various degrees of efficacy for augmentation, including psychostimulants. This article reviews studies of psychostimulants as augmentation agents for TRD and discusses risks, offers advice, and makes recommendations for clinicians who prescribe stimulants.
Background
Major depressive disorder (MDD) is a common psychiatric condition that significantly impairs quality of life.1 It is a recurrent illness, averaging 2 relapses per decade. The probability of recurrence increases with the number of depressive episodes.2,3 A patient who experiences major depressive episodes alternating with euthymia has unipolar depression; whereas one who experiences major depressive episodes alternating with episodes of mania or hypomania has bipolar depression.4
Despite adequate dose and duration of pharmacotherapy, many individuals with unipolar or bipolar depression do not achieve and sustain remission.5 Remission rates decrease and relapse rates increase with subsequent failed antidepressant trials.6 It is difficult to identify factors that predict treatment resistance, but one review of antidepressant studies found that patients who did not demonstrate a response within 3 weeks of medication initiation were less likely to respond after a longer duration.7
Treatment-resistant depression is commonly, but not universally, defined as lack of response after trials of 2 or more antidepressants with different mechanisms of action for sufficient duration.5 This definition will be used here as well. Other definitions have proposed stages of TRD, but these require further study to evaluate their reliability and predictive utility.8 Due to lack of consensus regarding the definition of TRD, it is not possible to determine the exact prevalence of TRD.
Patients with TRD may benefit from augmentation of their medication regimen. Augmentation with lithium has yielded conflicting results, and its efficacy with newer antidepressants is not well studied.9-12 Triiodothyronine, buspirone, and pindolol have demonstrated some efficacy when added to serotonin reuptake inhibitors (SRIs).10,12,13 Second-generation antipsychotic drugs, antidepressant drug combinations, omega-3 fatty acids, S-adenosyl methionine (SAMe), and L-methylfolate have demonstrated some efficacy in some studies as well.12,14-23 In patients with depression who have not responded to these strategies, psychostimulant augmentation may be appropriate.
Methods
A literature search was conducted following an algorithmic approach in the MEDLINE/PubMed database for studies in English from January 1985 to August 2014 of stimulants as augmenting agents for depression, using the Medical Subject Headings stimulant, depression, and augmentation, combined with an AND operator. The search was limited to adult humans and excluded case reports and letters, to identify studies with stronger evidence. Also excluded were studies using caffeine (to augment electroconvulsive therapy for depression) and pemoline as the sole augmenting stimulant as well as studies of patients with comorbid mental health diagnoses and studies that initiated stimulants and antidepressants simultaneously to assess antidepressant response.
This review organized results by stimulant rather than by depression type, even though some studies used > 1 stimulant or recruited patients with different types of depression. Although prevalence, prognosis, and monotherapy differ for unipolar and bipolar depression, psychostimulants target similar symptoms, despite augmenting different monotherapies in unipolar and bipolar depression. Therefore, no distinction is made between assessing studies of stimulants for unipolar and bipolar depression.
Results
A total of 70 articles were identified, and 31 studies met inclusion criteria (Figure). Of the studies included, 12 were double-blind, placebo-controlled (DBPC) trials and 19 were retrospective chart reviews or open studies. Most studies evaluated depression, using validated scales, such as the Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale, Clinical Global Impressions of Severity, Inventory of Depressive Symptoms, Carroll Depression Rating Scale, Global Assessment of Functioning, Quick Inventory of Depressive Symptomatology, or the Psychiatric Symptom Assessment Scale. Study details are provided in Tables 1 to 4.
Dextroamphetamine and Methylphenidate
Dextroamphetamine and methylphenidate are indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) and exert their effects by inhibiting uptake of norepinephrine and dopamine.24 In one chart review, patients received dextroamphetamine or methylphenidate augmentation of monoamine oxidase inhibitors (MAOIs) alone or with concurrent tricyclic antidepressants; the majority reported decreased depression.25 In an openlabel trial, dextroamphetamine was titrated to efficacy in patients who were receiving an MAOI with or without pemoline.26 Nearly 80% of patients reported long-lasting improvement in depression. In an open-label trial, all patients reported decreased depression when methylphenidate was added to SRIs; however, no scales were used.27
In a case series, patients with both major depression and persistent depressive disorder (dysthymia) experienced a substantial, quick, and sustained response to dextroamphetamine or methylphenidate augmentation.28 Addition of lisdexamfetamine significantly reduced depressive symptoms in individuals with inadequate response to escitalopram.29 Patients with full or partial remission of depression noted improved executive function and residual depressive symptoms after lisdexamfetamine was added to SRI monotherapy.30 In a trial in which patients received dexamphetamine or methylphenidate as monotherapy or augmentation, 30% to 34% of patients reported mood improvement, but 36% reported no improvement.31 In an extension study, low-dose psychostimulants quickly diminished melancholia.32
Methylphenidate was safe and effective in patients with bipolar depression receiving treatment for 1 to 5 years; 44% evidenced significant improvement.33 When offered to patients with bipolar depression, patients receiving methylphenidate or dextroamphetamine reported less depression or sedation and did not develop tolerance, mania, or misuse.34 A case series concluded that methylphenidate addition to mood stabilizers was generally effective and safe.35
However, not all preparations of methylphenidate have demonstrated efficacy. In one study, osmotic controlledrelease oral system (OROS) methylphenidate improved apathy and fatigue but not overall depression.36 Although OROS methylphenidate similarly failed to demonstrate statistically significant efficacy in another study, more responders were documented in the treatment group.37
Although this review focuses on stimulants as augmenting agents in patients with depression, it is worth noting the limited number of studies evaluating stimulants’ effect on depression in patients with traumatic brain injury. This observation is of concern, as these conditions are frequently comorbid in returning veterans. One study noted that methylphenidate was an effective monotherapy for depression; whereas another study found that methylphenidate monotherapy reduced depression as well as sertraline, was better tolerated, and improved fatigue and cognition.38,39
Modafinil and Armodafinil
Modafinil and armodafinil (the R-enantiomer of modafinil) are indicated for improving wakefulness in individuals with narcolepsy, obstructive sleep apnea, and shift work sleep disorder by modulating glutamate, gamma amino-butyric acid, and histamine.40,41 Although they increase extracellular dopamine concentrations, they do not cause an increase in dopamine release and may have less misuse potential than that of dextroamphetamine and methylphenidate.40,41 In a study of 7 patients with unipolar or bipolar depression, all patients achieved full or partial remission with minimal adverse effects (AEs).42 In a prospective study, 41% of patients reported only mild depression or full remission with modafinil augmentation.43
Multiple trials and a pooled analysis noted decreased depression and fatigue and improved cognition in patients receiving modafinil augmentation compared with mood stabilizers or antidepressants.44-49 Modafinil is a useful adjunct for partial responders to SRIs, resulting in rapid mood improvement and decreased fatigue.50-54 However, in one study, modafinil did not demonstrate efficacy compared with placebo. This result was attributed to premature study termination after 2 modafinil-treated patients developed suicidal ideation.55 A post hoc analysis found no difference in frequency of suicidal ideation between groups.
Two DBPC studies evaluated armodafinil in patients with bipolar depression. In both studies it was added to a mood-stabilizing agent (lithium, valproate, aripiprazole, olanzapine, lamotrigine, risperidone, or ziprasidone), and patients receiving armodafinil reported significant reductions
in depression.56,57
Atomoxetine
Atomoxetine is a norepinephrine reuptake inhibitor indicated for the treatment of ADHD and is considered to have no misuse potential due to lack of dopamine modulation.58 In one study, 15 patients received atomoxetine added to their antidepressant, and 60% experienced significant symptom reduction.59 A chart review noted decreases in fatigue and depression when atomoxetine was added to an SRI, mirtazapine, or amitriptyline.60 However, in a DBPC trial, atomoxetine did not lead to significant changes in depression.61
Discussion
There is a limited amount of high-quality evidence to support psychostimulant augmentation, as noted by the relatively few DBPC trials, most of short duration. The evidence supports their efficacy primarily for unipolar depression, as 14 studies evaluated patients with unipolar depression, whereas only 7 studies evaluated patients with bipolar depression. The remaining studies recruited patients with both depression types. Collectively, modafinil and armodafinil have the most evidence in DBPC trials.
There are relatively few DBPC trials with high power and sufficient duration for dextroamphetamine and methylphenidate preparations. This discovery is surprising, considering the duration that these medications have been available. However, several chart reviews and open-label trials provided some evidence to support their use in patients without a history of substance misuse or cardiac conditions.62 Osmotic controlled- release oral system methylphenidate seems to be ineffective, and the efficacy of atomoxetine for augmentation
is uncertain.
Precautions
Prescribing physicians who offer stimulants should consider potential AEs, such as psychosis, anorexia, anxiety, insomnia, mood changes (eg, anger), misuse, addiction, mania, and cardiovascular problems. Psychostimulants have been implicated in precipitating psychosis.63,64 However, in a 12-month study of 250 adults with ADHD, 73 reported AEs, and only 31 discontinued the stimulant. Adverse effects leading to discontinuation included mood instability (n = 7), agitation (n = 6), irritability (n = 4), or decreased appetite (n = 4).65
Although associated with the risks of anorexia and insomnia in patients with ADHD, methylphenidate rapidly improved daytime sleepiness and mood, and—paradoxically—appetite and nighttime sleep in medically ill elderly patients with depression.66 Misuse or abuse of methylphenidate and dextroamphetamine were noted in 23% of patients referred for substance misuse.67 Nonetheless, little evidence exists that these drugs possess significant misuse potential in patients taking them as prescribed. As a prodrug, lisdexamfetamine is hypothesized to have less abuse potential compared with dextroamphetamine and methylphenidate, but it carries the same prescribing and monitoring precautions.68 Risks related to stimulant usage extend to manic symptoms.69 Patients with bipolar disorder should not receive stimulants if they have a history of stimulant-induced mania, rapid cycling, or psychosis.70
Long-term cardiovascular safety data exist for dextroamphetamine and methylphenidate but are limited or unavailable for modafinil, armodafinil, and atomoxetine. A retrospective cohort study found no significant increase in the number of cardiac events in patients receiving dextroamphetamine,
methylphenidate, or atomoxetine for an average of 1 year compared with controls.71 Another cohort study of > 44,000 patients found that initiation of
methylphenidate was associated with increased risk of sudden death or arrhythmia, but the risk was attributed to an unmeasured confounding factor, as the authors found a negative correlation between methylphenidate dose and all cardiovascular events.72
Recent practice guidelines recommend that before prescribing stimulants, clinicians should perform a physical examination (including heart and lung auscultation), obtain vital signs and height and weight, and request an electrocardiogram in case of abnormal findings on a cardiovascular examination or in case of a personal or family history of heart disease. Before offering atomoxetine, clinicians should evaluate the patient for a history of liver disease (and check liver function studies in case of a positive history). Clinicians should also assess risk of self-harm prior to initiating psychostimulant therapy.73 Throughout treatment, clinicians should evaluate the patient for changes in blood pressure, pulse, weight or mood, as well as the development of dependence or misuse. Urine toxicology testing is recommended for dextroamphetamine and methylphenidate to screen for adherence and diversion.
Limitations
Using only PubMed and MEDLINE databases limited the search to articles published in English after 1985, excluding letters and case reports to identify studies with higher evidence (the studies were not weighted based on study design). In addition, the studies had certain limitations. These include a limited number of DBPC trials, most were of short duration. It is also difficult to compare studies due to various rating scales used and concurrent
medication regimens of study subjects. These limitations raise questions surrounding the long-term efficacy of stimulants, and there is no consensus for how long a stimulant should be continued if beneficial. Longer, higherpowered, DBPC trials are warranted to determine longterm efficacy and safety of stimulant augmentation.62
Conclusion
For patients with depression who have not responded to other augmentation strategies, psychostimulants may be offered to improve mood, energy, and concentration. For clinicians considering stimulant augmentation, modafinil and armodafinil are reasonable choices given their efficacy in double-blind, placebo-controlled trials and lower risk of misuse. Dextroamphetamine (particularly lisdexamphetamine) and methylphenidate may be appropriate for patients who have not benefited from or tolerated modafinil or armodafinil, provided these patients do not have a medical history of cardiac disease or current substance use.
Osmotic controlled-release oral system methylphenidate seems to be ineffective as an augmenting agent. The efficacy of atomoxetine for augmentation is questionable, but atomoxetine could be offered if other stimulants were contraindicated, ineffective, or poorly tolerated. Both OROS methylphenidate and atomoxetine should be evaluated in additional trials before they can be recommended as augmentation therapies. Certain psychostimulants may be appropriate and reasonable adjunctive pharmacotherapies for patients with unipolar or bipolar depression who have failed other augmentation strategies, for patients who have significant fatigue or cognitive complaints, or for elderly patients with melancholic or somatic features of depression.
Acknowledgements
The authors thank Maureen Humphrey-Shelton and Kathy Thomas for their help in obtaining references.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
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2. Solomon DA, Keller MB, Leon AC, et al. Multiple recurrences of major depressive disorder. Am J Psychiatry. 2000;157(2):229-233.
3. Katon WJ, Fan MY, Lin EH, Unützer J. Depressive symptom deterioration in a large
primary care-based elderly cohort. Am J Geriatr Psychiatry. 2006;14(3):246-254.
4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
5. McIntyre RS, Filteau M-J, Martin L, et al. Treatment-resistant depression: Definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014;156:1-7.
6. Gaynes BN, Warden D, Trivedi MH, Wisniewski SR, Fava M, Rush AJ. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Focus. 2012;10(4):510-517.
7. Kudlow PA, Cha DS, McIntyre RS. Predicting treatment response in major depressive disorder: The impact of early symptomatic improvement. Can J Psychiatry. 2012;57(12):782-788.
8. Ruhé HG, van Rooijen G, Spijker J, Peeters FP, Schene AH. Staging methods for treatment resistant depression. A systematic review. J Affect Disord. 2012;137(1-3):35-45.
9. Bauer M, Dopfmer S. Lithium augmentation treatment-resistant depression: Metaanalysis of placebo-controlled studies. J Clin Psychopharmacol. 1999;19(5):427-434.
10. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: A STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530.
11. Nierenberg AA, Papakostas GI, Petersen T, et al. Lithium augmentation of nortriptyline
for subjects resistant to multiple antidepressants. J Clin Psychopharmacol. 2003;23(1):92-95.
12. Connolly KR, Thase ME. If at first you don’t succeed: A review of the evidence for antidepressant augmentation, combination, and switching strategies. Drugs. 2011;71(1):43-64.
13. Trivedi MH, Fava M, Wisniewski SR, et al; STAR*D Study Team. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252.
14. Papakostas GI, Shelton RC, Smith J, Fava M. Augmentation of antidepressants with atypical antipsychotic medications for treatment resistant major depressive disorder: A meta-analysis. J Clin Psychiatry. 2007;68(6):826-831.
15. Mahmoud RA, Pandina GJ, Turkoz I, et al. Risperidone for treatment-refractory major depressive disorder: A randomized trial. Ann Intern Med. 2007;147(9):593-602.
16. Barbee JG, Conrad EJ, Jamhour NJ. The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment resistant depressive disorder. J Clin Psychiatry. 2004;65(7):975-981.
17. Fatemi SH, Emamian ES, Kist DA. Venlafaxine and bupropion combination therapy in a case of treatment-resistant depression. Ann Pharmacother.1999;33(6):701-703.
18. Carpenter LL, Yasman S, Price LH. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry. 2002;51(2):183-188.
19. Hannan N, Hamzah Z, Akinpeloye HO, Meagher D. Venlafaxine-mirtazapine combination therapy in the treatment of persistent depressive illness. J Psychopharmacol. 2007;21(2):161-164.
20. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: A STAR*D report. Am J Psychiatry. 2006;163(9):1531-1541.
21. Blier P, Ward HE, Tremblay P, Laberge L, Hébert C, Bergeron R. Combination of antidepressant medications from treatment initiation for major depressive disorder: A double-blind randomized study. Am J Psychiatry. 2010;167(3):281-288.
22. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: A double blind randomized clinical trial. Am J Psychiatry. 2010;167(8):942-948.
23. Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy
for SSRI-resistant major depression: Results of two randomized, double-blind,
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27. Stoll AL, Pillay SS, Diamond L, Workum SB, Cole JO. Methylphenidate augmentation of serotonin selective reuptake inhibitors: A case series. J Clin Psychiatry. 1996;57(2):72-76.
28. Masand PS, Anand VS, Tanquary JF. Psychostimulant augmentation of second generation antidepressants: A case series. Depress Anxiety. 1998;7(2):89-91.
29. Trivedi MH, Cutler AJ, Richards C, et al. A randomized control trial of the efficacy and safety of lisdesxamfetamine dimesylate as augmentation therapy in adults with residual symptoms of major depressive disorder after treatment with escitalopram. J Clin Psychiatry. 2013;74(8):802-809.
30. Madhoo M, Keefe RS, Roth RM, et al. Lisdexamfetamine dimesylate augmentation in adults with persistent executive dysfunction after partial or full remission of major depressive disorder. Neuropsychopharmacology. 2014;39(6):1388-1398.
31. Parker G, Brotchie H. Do the old psychostimulant drugs have a role in managing treatment-resistant depression. Acta Psychiatr Scand. 2010;121(4):308-314.
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33. Lydon E, El-Mallakh RS. Naturalistic long-term use of methylphenidate in bipolar disorder. J Clin Psychopharmacol. 2006;26(5):516-518.
34. Carlson PJ, Merlock MC, Suppes T. Adjunctive stimulant use in patients with bipolar disorder: Treatment of residual depression and sedation. Bipolar Disord. 2004;6(5):416-420.
35. El-Mallakh RS. An open study of methylphenidate in bipolar depression. Bipolar Disord. 2000;2(1):56-59.
36. Ravindran AV, Kennedy SH, O’Donovan MC, Fallu A, Camacho F, Binder CE. Osmotic-release oral system methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: Results of a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2008;69(1):87-94.
37. Patkar AA, Masand PS, Pae CU, et al. A randomized, double-blind, placebocontrolled
trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. J Clin Psychopharmacol. 2006;26(6):653-656.
38. Lee H, Kim SW, Kim JM, Shin IS, Yang SJ, Yoon JS Comparing effects of methylphenidate, sertraline, and placebo on neuropsychiatric sequelae in patients with
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39. Gualtieri CT, Evans RW. Stimulant treatment for the neurobehavioural sequelae of traumatic brain injury. Brain Inj. 1988;2(4):273-290.
40. Provigil [package insert]. North Wales, PA: Cephalon Inc; 2015.
41. Nuvigil [package insert]. Frazer, PA: Cephalon, Inc; 2013.
42. Menza MA, Kaufman KR, Castellanos A. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry. 2000;61(5):378-381.
43. Markovitz PJ, Wagner S. An open-label trial of modafinil augmentation in patients with partial response to antidepressant therapy. J Clin Psychopharmacol. 2003;23(2):207-209.
44. Fernandes PP, Petty F. Modafinil for remitted bipolar depression with hypersomnia. Ann Pharmacother. 2003;37(12):1807-1809.
45. Nasr S. Modafinil as adjunctive therapy in depressed outpatients. Ann Clin Psychiatry. 2004;16(3):133-138.
46. DeBattista C, Lembke A, Solvason HB, Ghebremichael R, Poirier J. A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacol. 2004;24(1):87-90.
47. Nasr S, Wendt B, Steiner K. Absence of mood switch with and tolerance to modafinil: A replication study from a large private practice. J Affect Disord. 2006;95(1-3):111-114.
48. DeBattista C, Doghramji K, Menza MA, Rosenthal MH, Fieve RR; Modafinil in Depression Study Group. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: A preliminary doubleblind, placebo-controlled study. J Clin Psychiatry. 2003;64(9):1057-1064.
49. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007;164(8):1242-1249.
50. Fava M, Thase ME, DeBattista C, Doghramji K, Arora S, Hughes RJ. Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness. Ann Clin Psychiatry. 2007;19(3):153-159.
51. Thase ME, Fava M, DeBattista C, Arora S, Hughes RJ. Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: A 12-week, open-label, extension study. CNS Spectr. 2006;11(2):93-102.
52. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005;66(1):85-93.
53. Abolfazli R, Hosseini M, Ghanizadeh A, et al. Double-blind randomized parallelgroup clinical trial of efficacy of the combination fluoxetine plus modafinil versus fluoxetine plus placebo in the treatment of major depression. Depress Anxiety. 2011;28(4):297-302.
54. Rasmussen NA, Schrøder P, Olsen LR, Brødsgaard M, Undén M, Bech P. Modafinil augmentation in depressed patients with partial response to antidepressants: A pilot study on self-reported symptoms covered by the Major Depression Inventory (MDI) and the Symptom Checklist (SCL-92). Nord J Psychiatry. 2005;59(3):173-178.
55. Dunlop BW, Crits-Christoph P, Evans DL, et al. Coadministration of modafinil and a selective serotonin reuptake inhibitor from the initiation of treatment of major depressive disorder with fatigue and sleepiness: A double-blind, placebocontrolled study. J Clin Psychopharmacol. 2007;27(6):614-619.
56. Calabrese JR, Ketter TA, Youakim JM, Tiller JM, Yang R, Frye MA. Adjunctive armodafinil
for major depressive episodes associated with bipolar I disorder: A randomized multicenter, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry. 2010;71(10):1363-1370.
57. Calabrese JR, Frye MA, Yang R, Ketter TA; Armodafinil Treatment Trial Study Network. Efficacy and safety of adjunctive armodafinil in adults with major depressive episodes associated with bipolar I disorder: A randomized, double-blind, placebo-controlled, multicenter trial. J Clin Psychiatry. 2014;75(10):1054-1061.
58. Strattera [package insert]. Indianapolis, IN. Lilly; 2015.
59. Carpenter LL, Milosavljevic N, Schecter JM, Tyrka AR, Price LH. Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants. J Clin Psychiatry. 2005;66(10):1234-1238.
60. Papakostas GI, Petersen TJ, Burns AM, Fava M. Adjunctive atomoxetine for residual
fatigue in major depressive disorder. J Psychiatr Res. 2006;40(4):370-373.
61. Michelson D, Adler LA, Amsterdam JD, et al. Addition of atomoxetine for depression
incompletely responsive to sertraline: A randomized, double-blind, placebocontrolled study. J Clin Psychiatry. 2007;68(4):582-587.
62. Corp SA, Gitlin MJ, Altshuler LL. A review of the use of stimulants and stimulant alternatives in treating bipolar depression and major depressive disorder. J Clin Psychiatry. 2014;75(9):1010-1018.
63. Kraemer M, Uekermann J, Wiltfang J, Kis B. Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: Report of 3 new cases and review of the literature. Clin Neuropharmacol. 2010;33(4):204-206.
64. Berman SM, Kuczenski R, McCracken JT, London ED. Potential adverse effects of amphetamine treatment on brain and behavior: A review. Mol Psychiatry. 2009;14(2):123-142.
65. Fredriksen M, Dahl AA, Martinsen EW, Klungsøyr O, Haavik J, Peleikis DE. Effectiveness of one-year pharmacological treatment of adult attention-deficit/hyperactivity disorder (ADHD): An open-label prospective study of time in treatment, dose, side-effects and comorbidity. Eur Neuropsychopharmacol. 2014;24(12):1873-1874.
66. Hardy SE. Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults. Am J Geriatr Pharmacother. 2009;7(1):34-59.
67. Williams RJ, Goodale LA, Shay-Fiddler MA, Gloster SP, Chang SY. Methylphenidate and dextroamphetamine abuse in substance-abusing adolescents. Am J Addict. 2004;13(4):381-389.
68. Madaan V, Kolli V, Bestha DP, Shah MJ. Update on optimal use of lisdexamfetamine in the treatment of ADHD. Neuropsychiatr Dis Treat. 2013;9:977-983.
69. Ross RG. Psychotic and manic-like symptoms during stimulant treatment of attention deficit hyperactivity disorder. Am J Psychiatry. 2006;163(7):1149-1152.
70. Dell’Osso B, Ketter TA. Use of adjunctive stimulants in adult bipolar depression. Int J Neuropsychopharmacol. 2013;16(1):55-68.
71. Habel LA, Cooper WO, Sox CM, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306(24):2673-2683.
72. Schelleman H, Bilker WB, Kimmel SE, et al. Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry. 2012;169(2):178-185.
73. Bolea-Alamañac B, Nutt DJ, Adamou M, et al; British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: Update on recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28(3):179-203.
74. Moher D, Liberati A, Tetzlaff J, Altman DG; The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6(6):e1000097.
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6. Gaynes BN, Warden D, Trivedi MH, Wisniewski SR, Fava M, Rush AJ. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Focus. 2012;10(4):510-517.
7. Kudlow PA, Cha DS, McIntyre RS. Predicting treatment response in major depressive disorder: The impact of early symptomatic improvement. Can J Psychiatry. 2012;57(12):782-788.
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9. Bauer M, Dopfmer S. Lithium augmentation treatment-resistant depression: Metaanalysis of placebo-controlled studies. J Clin Psychopharmacol. 1999;19(5):427-434.
10. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: A STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530.
11. Nierenberg AA, Papakostas GI, Petersen T, et al. Lithium augmentation of nortriptyline
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12. Connolly KR, Thase ME. If at first you don’t succeed: A review of the evidence for antidepressant augmentation, combination, and switching strategies. Drugs. 2011;71(1):43-64.
13. Trivedi MH, Fava M, Wisniewski SR, et al; STAR*D Study Team. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252.
14. Papakostas GI, Shelton RC, Smith J, Fava M. Augmentation of antidepressants with atypical antipsychotic medications for treatment resistant major depressive disorder: A meta-analysis. J Clin Psychiatry. 2007;68(6):826-831.
15. Mahmoud RA, Pandina GJ, Turkoz I, et al. Risperidone for treatment-refractory major depressive disorder: A randomized trial. Ann Intern Med. 2007;147(9):593-602.
16. Barbee JG, Conrad EJ, Jamhour NJ. The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment resistant depressive disorder. J Clin Psychiatry. 2004;65(7):975-981.
17. Fatemi SH, Emamian ES, Kist DA. Venlafaxine and bupropion combination therapy in a case of treatment-resistant depression. Ann Pharmacother.1999;33(6):701-703.
18. Carpenter LL, Yasman S, Price LH. A double-blind, placebo-controlled study of antidepressant augmentation with mirtazapine. Biol Psychiatry. 2002;51(2):183-188.
19. Hannan N, Hamzah Z, Akinpeloye HO, Meagher D. Venlafaxine-mirtazapine combination therapy in the treatment of persistent depressive illness. J Psychopharmacol. 2007;21(2):161-164.
20. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: A STAR*D report. Am J Psychiatry. 2006;163(9):1531-1541.
21. Blier P, Ward HE, Tremblay P, Laberge L, Hébert C, Bergeron R. Combination of antidepressant medications from treatment initiation for major depressive disorder: A double-blind randomized study. Am J Psychiatry. 2010;167(3):281-288.
22. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: A double blind randomized clinical trial. Am J Psychiatry. 2010;167(8):942-948.
23. Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy
for SSRI-resistant major depression: Results of two randomized, double-blind,
parallel-sequential trials. Am J Psychiatry. 2012;169(12):1267-1274.
24. Korston TR. Drugs of abuse. In: Katzung BG, ed. Basic and Clinical Pharmacology. 9th ed. New York, NY: McGraw-Hill; 2004:521-523.
25. Feighner JP, Herbstein J, Damlouji N. Combined MAOI, TCA, and direct stimulant therapy of treatment-resistant depression. J Clin Psychiatry. 1985;46(6):206-209.
26. Fawcett J, Kravitz HM, Zajecka JM, Schaff MR. CNS stimulant potentiation of monoamine oxidase inhibitors in treatment-refractory depression. J Clin Psychopharmacol. 1991;11(2):127-132.
27. Stoll AL, Pillay SS, Diamond L, Workum SB, Cole JO. Methylphenidate augmentation of serotonin selective reuptake inhibitors: A case series. J Clin Psychiatry. 1996;57(2):72-76.
28. Masand PS, Anand VS, Tanquary JF. Psychostimulant augmentation of second generation antidepressants: A case series. Depress Anxiety. 1998;7(2):89-91.
29. Trivedi MH, Cutler AJ, Richards C, et al. A randomized control trial of the efficacy and safety of lisdesxamfetamine dimesylate as augmentation therapy in adults with residual symptoms of major depressive disorder after treatment with escitalopram. J Clin Psychiatry. 2013;74(8):802-809.
30. Madhoo M, Keefe RS, Roth RM, et al. Lisdexamfetamine dimesylate augmentation in adults with persistent executive dysfunction after partial or full remission of major depressive disorder. Neuropsychopharmacology. 2014;39(6):1388-1398.
31. Parker G, Brotchie H. Do the old psychostimulant drugs have a role in managing treatment-resistant depression. Acta Psychiatr Scand. 2010;121(4):308-314.
32. Parker G, Brotchie H, McClure G, Fletcher K. Psychostimulants for managing unipolar and bipolar treatment-resistant melancholic depression: A medium term evaluation of cost benefits. J Affect Disord. 2013;151(1):360-364.
33. Lydon E, El-Mallakh RS. Naturalistic long-term use of methylphenidate in bipolar disorder. J Clin Psychopharmacol. 2006;26(5):516-518.
34. Carlson PJ, Merlock MC, Suppes T. Adjunctive stimulant use in patients with bipolar disorder: Treatment of residual depression and sedation. Bipolar Disord. 2004;6(5):416-420.
35. El-Mallakh RS. An open study of methylphenidate in bipolar depression. Bipolar Disord. 2000;2(1):56-59.
36. Ravindran AV, Kennedy SH, O’Donovan MC, Fallu A, Camacho F, Binder CE. Osmotic-release oral system methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: Results of a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2008;69(1):87-94.
37. Patkar AA, Masand PS, Pae CU, et al. A randomized, double-blind, placebocontrolled
trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. J Clin Psychopharmacol. 2006;26(6):653-656.
38. Lee H, Kim SW, Kim JM, Shin IS, Yang SJ, Yoon JS Comparing effects of methylphenidate, sertraline, and placebo on neuropsychiatric sequelae in patients with
traumatic brain injury. Hum Psychopharmacol. 2005;20(2):97-104.
39. Gualtieri CT, Evans RW. Stimulant treatment for the neurobehavioural sequelae of traumatic brain injury. Brain Inj. 1988;2(4):273-290.
40. Provigil [package insert]. North Wales, PA: Cephalon Inc; 2015.
41. Nuvigil [package insert]. Frazer, PA: Cephalon, Inc; 2013.
42. Menza MA, Kaufman KR, Castellanos A. Modafinil augmentation of antidepressant treatment in depression. J Clin Psychiatry. 2000;61(5):378-381.
43. Markovitz PJ, Wagner S. An open-label trial of modafinil augmentation in patients with partial response to antidepressant therapy. J Clin Psychopharmacol. 2003;23(2):207-209.
44. Fernandes PP, Petty F. Modafinil for remitted bipolar depression with hypersomnia. Ann Pharmacother. 2003;37(12):1807-1809.
45. Nasr S. Modafinil as adjunctive therapy in depressed outpatients. Ann Clin Psychiatry. 2004;16(3):133-138.
46. DeBattista C, Lembke A, Solvason HB, Ghebremichael R, Poirier J. A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacol. 2004;24(1):87-90.
47. Nasr S, Wendt B, Steiner K. Absence of mood switch with and tolerance to modafinil: A replication study from a large private practice. J Affect Disord. 2006;95(1-3):111-114.
48. DeBattista C, Doghramji K, Menza MA, Rosenthal MH, Fieve RR; Modafinil in Depression Study Group. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: A preliminary doubleblind, placebo-controlled study. J Clin Psychiatry. 2003;64(9):1057-1064.
49. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007;164(8):1242-1249.
50. Fava M, Thase ME, DeBattista C, Doghramji K, Arora S, Hughes RJ. Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness. Ann Clin Psychiatry. 2007;19(3):153-159.
51. Thase ME, Fava M, DeBattista C, Arora S, Hughes RJ. Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: A 12-week, open-label, extension study. CNS Spectr. 2006;11(2):93-102.
52. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005;66(1):85-93.
53. Abolfazli R, Hosseini M, Ghanizadeh A, et al. Double-blind randomized parallelgroup clinical trial of efficacy of the combination fluoxetine plus modafinil versus fluoxetine plus placebo in the treatment of major depression. Depress Anxiety. 2011;28(4):297-302.
54. Rasmussen NA, Schrøder P, Olsen LR, Brødsgaard M, Undén M, Bech P. Modafinil augmentation in depressed patients with partial response to antidepressants: A pilot study on self-reported symptoms covered by the Major Depression Inventory (MDI) and the Symptom Checklist (SCL-92). Nord J Psychiatry. 2005;59(3):173-178.
55. Dunlop BW, Crits-Christoph P, Evans DL, et al. Coadministration of modafinil and a selective serotonin reuptake inhibitor from the initiation of treatment of major depressive disorder with fatigue and sleepiness: A double-blind, placebocontrolled study. J Clin Psychopharmacol. 2007;27(6):614-619.
56. Calabrese JR, Ketter TA, Youakim JM, Tiller JM, Yang R, Frye MA. Adjunctive armodafinil
for major depressive episodes associated with bipolar I disorder: A randomized multicenter, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry. 2010;71(10):1363-1370.
57. Calabrese JR, Frye MA, Yang R, Ketter TA; Armodafinil Treatment Trial Study Network. Efficacy and safety of adjunctive armodafinil in adults with major depressive episodes associated with bipolar I disorder: A randomized, double-blind, placebo-controlled, multicenter trial. J Clin Psychiatry. 2014;75(10):1054-1061.
58. Strattera [package insert]. Indianapolis, IN. Lilly; 2015.
59. Carpenter LL, Milosavljevic N, Schecter JM, Tyrka AR, Price LH. Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants. J Clin Psychiatry. 2005;66(10):1234-1238.
60. Papakostas GI, Petersen TJ, Burns AM, Fava M. Adjunctive atomoxetine for residual
fatigue in major depressive disorder. J Psychiatr Res. 2006;40(4):370-373.
61. Michelson D, Adler LA, Amsterdam JD, et al. Addition of atomoxetine for depression
incompletely responsive to sertraline: A randomized, double-blind, placebocontrolled study. J Clin Psychiatry. 2007;68(4):582-587.
62. Corp SA, Gitlin MJ, Altshuler LL. A review of the use of stimulants and stimulant alternatives in treating bipolar depression and major depressive disorder. J Clin Psychiatry. 2014;75(9):1010-1018.
63. Kraemer M, Uekermann J, Wiltfang J, Kis B. Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: Report of 3 new cases and review of the literature. Clin Neuropharmacol. 2010;33(4):204-206.
64. Berman SM, Kuczenski R, McCracken JT, London ED. Potential adverse effects of amphetamine treatment on brain and behavior: A review. Mol Psychiatry. 2009;14(2):123-142.
65. Fredriksen M, Dahl AA, Martinsen EW, Klungsøyr O, Haavik J, Peleikis DE. Effectiveness of one-year pharmacological treatment of adult attention-deficit/hyperactivity disorder (ADHD): An open-label prospective study of time in treatment, dose, side-effects and comorbidity. Eur Neuropsychopharmacol. 2014;24(12):1873-1874.
66. Hardy SE. Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults. Am J Geriatr Pharmacother. 2009;7(1):34-59.
67. Williams RJ, Goodale LA, Shay-Fiddler MA, Gloster SP, Chang SY. Methylphenidate and dextroamphetamine abuse in substance-abusing adolescents. Am J Addict. 2004;13(4):381-389.
68. Madaan V, Kolli V, Bestha DP, Shah MJ. Update on optimal use of lisdexamfetamine in the treatment of ADHD. Neuropsychiatr Dis Treat. 2013;9:977-983.
69. Ross RG. Psychotic and manic-like symptoms during stimulant treatment of attention deficit hyperactivity disorder. Am J Psychiatry. 2006;163(7):1149-1152.
70. Dell’Osso B, Ketter TA. Use of adjunctive stimulants in adult bipolar depression. Int J Neuropsychopharmacol. 2013;16(1):55-68.
71. Habel LA, Cooper WO, Sox CM, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306(24):2673-2683.
72. Schelleman H, Bilker WB, Kimmel SE, et al. Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry. 2012;169(2):178-185.
73. Bolea-Alamañac B, Nutt DJ, Adamou M, et al; British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: Update on recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28(3):179-203.
74. Moher D, Liberati A, Tetzlaff J, Altman DG; The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6(6):e1000097.
Multidisciplinary Management of a Patient With Multiple Sclerosis:Part 3. Psychologists’ Perspective
Multiple sclerosis (MS) poses a host of cognitive and psychosocial challenges that may contribute to functioning and quality of life (QOL). Although each patient’s experience with MS is different, some challenges are more common than are others, including cognitive changes, depression, and maintaining positive health behaviors. William’s case study illustrates some of these challenges as well as the resources and strategies of the psychologists at the MS
Centers of Excellence (MSCoE) to help patients with MS adapt and thrive.
Cognition
Difficulties with cognitive functioning are common in patients with MS. About half of patients with MS will develop cognitive impairments in one or more areas during their lifetime.1 Although cognitive difficulties tend to worsen over the course of the disease, they can appear at any point in the illness, differ greatly from patient to patient, and are only modestly correlated with physical symptoms.1 Impairments are most common in the areas of information processing speed and memory, as well as in complex attention and mental flexibility. These impairments can impact activities of daily living, sustained employment, driving, and social relationships.
Early in the disease, William, who admitted to difficulties with cognition and the impact of cognitive impairment on his life, benefited from neuropsychological testing. Typically, an MSCoE will use a battery of tests tailored to patients with MS. For patients, the results of these tests can be used to clarify areas of relative strength and weakness and inform team decisions related to treatment and future life activities, such as whether the patient will need accommodations at work. Test results may also be used to guide how the MS treatment team interacts with the patient.
An initial clinic screening from neurology indicated William had below average cognitive processing speed, and he agreed to neurocognitive testing. The psycholopsychologist asked William about his functioning at home. William noted poor attention and memory made it difficult to advocate for himself. He recounted an episode of taking his car to be repaired and only later realizing that he had been charged twice for the same part. He also disclosed that he had gotten lost while driving through familiar places. On several occasions while cooking, he had become distracted and started another task only to find he had burned his food.
Cognitive rehabilitation has shown considerable promise in helping patients work through difficulties with memory, attention, and problem solving by developing compensatory strategies.2 Skill training is available in individual and group formats. There is also promising but very preliminary evidence that some psychosocial interventions might improve memory performance for patients with MS.3
William’s neuropsychological testing confirmed impairments in information processing speed, attention, and memory, and William was diagnosed with cognitive disorder not otherwise specified. His cognitive impairment correlated with his magnetic resonance imaging (MRI) findings, which included lesions on the corpus callosum and in multiple subcortical areas.
During a feedback session, William was encouraged to use compensatory strategies, including memory aids, visual cueing, and self-pacing. He was given a referral to speech and language pathology to develop and practice these strategies. The psychologist also reminded William’s health care team to speak slowly and repeat important information to him, write down important instructions, and cue him when asking questions in the clinic. William was provided with a kitchen timer and instructed to set it whenever he began cooking, so that even if he got distracted, the alarm would remind him to return to his cooking. William was asked whether he would like to participate in the MSCoE cognitive compensatory training program.4 The program, offered through a research protocol, involved a series of classes that taught strategies to manage cognitive symptoms and improve patients’ ability to function independently. William agreed to participate and reported feeling hopeful that his situation could improve.
Depression
Multiple sclerosis brings many variable and unpredictable challenges and can be a source of distress. Often these challenges occur with the onset of new disease milestones, such as the diagnosis or an increased disability. Given the physical, cognitive, and social stresses, it is not surprising that depression is extremely common, appearing in about half of patients with MS over their lifetime.5 During the course of ordinary MS care, the majority of patients with depression can be identified by a brief screening and referred for additional assessment and treatment.
Fortunately, there are many available treatment options. Antidepressant medications have shown some efficacy.6 Cognitive behavioral therapy (CBT), a counseling strategy that helps individuals become more active, connects them with rewarding activities, and challenges maladaptive thought patterns, has been shown to be effective in individual and group counseling settings via in-person or telephone-based delivery.7,8 Anxiety is also common experience among patients with MS and is treated with many of the same types of psychotherapy intervention.9
Focusing on the psychological and social needs of patients with MS has obvious implications for holistic care and QOL, but in some instances, MS may also contribute to safety concerns. Nearly one-third of veterans with MS admit to suicidal ideation, and the ultimate risk of suicide is about twice that of similar individuals without MS.10,11 For this reason, screening for risk of self-harm should be routinely incorporated into MS care.
A quick look at William’s Computerized Patient Record System (CPRS) record revealed that he had called the VA suicide prevention hotline. During the conversation he had noted that although he originally thought he would be able to deal with MS on his own, he realized he couldn’t. When the psychologist asked William about life at home, he disclosed that some days he never left his bed except to go to the bathroom. He stated he had given up on dating, and asked “who would want me?” He reported little appetite or interest in sex.
William was anxious about the problems he faced from day to day and grieving about the future that he no longer believed was possible. His distress was generally related to the MS diagnosis, and he spent a significant amount of time minimizing his disability, avoiding his family for this reason.
The psychologist diagnosed William with adjustment disorder with mixed anxiety and depressed mood and initiated individual CBT. The psychologist suggested that William attend the MS social work support group and the MS education group to get to know other veterans with MS and learn about managing symptoms. William agreed to attend the groups and admitted it would be good to have a reason to leave the house.
Health Behavior
Recognizing that MS is a chronic illness that requires coordinated efforts, the MS team helped William manage his disease and maintain his health. The psychological and social components of this process were considerable. For most newly diagnosed patients with MS, diseasemodifying therapies (DMTs) are important tools to decrease relapses and short-term disability. Although the benefits of these medications are well known, many patients are nonadherent. Contributing to poor adherence are adverse effects, cognitive challenges, anxiety, depression, and lack of belief in their efficacy.12,13 Brief
counseling, problem solving, and clinical monitoring have all been shown to reduce missed doses and improve DMT use.13 Both the MS Assessment Tool and the pharmacy database within CPRS are helpful for tracking patient adherence over time.
Other health behaviors may contribute not only to overall health, but also to the disease course. Patients who smoke have accelerated progression of their MS disease process and greater mortality than that of nonsmokers.14 Likewise, patients who engage in regular physical activity experience not only greater strength and endurance, but also less fatigue, depression, and better QOL.15 As part of his chronic illness care, the MS team provided William with information about the potential impact of health behaviors on MS progression.
William’s emotional and cognitive symptoms of MS presented important challenges to the management of his MS care. Initially, he ignored his diagnosis, delayed care, and refused to take a DMT. Once he agreed to taking a DMT, he often forgot to take it. He frequently missed medical appointments, because he did not remember them. Depression, fatigue, and stress decreased his motivation to follow through with recommendations from his health care providers.
Given William’s multiple psychosocial needs and transportation challenges, VA psychologists initiated telehealth visits with William in addition to clinic visits to provide many services, including psychotherapy and health behavior counseling. This continued support, along with the coordination of the rest of his health care team has been vital to maintaining William’s adherence to his treatment plan and QOL.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
1. Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology. 1991;41(5):685-691.
2. Cicerone KD, Langenbahn DM, Braden C, et al. Evidence-based cognitive rehabilitation: Updated review of the literature from 2003 through 2008. Arch Phys Med Rehabil. 2011;92(4):519-530.
3. Chiaravalloti ND, Moore NB, Nikelshpur OM, DeLuca J. An RCT to treat learning impairment in multiple sclerosis: The MEMREHAB trial. Neurology. 2013;81(24):2066-2072.
4. Huckans M, Pavawalla S, Demadura T, et al. A pilot study examining effects of group-based Cognitive Strategy Training treatment on self-reported cognitive problems, psychiatric symptoms, functioning, and compensatory strategy use in OIF/OEF combat veterans with persistent mild cognitive disorder and history of traumatic brain injury. J Rehabil Res Dev. 2010;47(1):43-60.
5. Sadovnick AD, Remick RA, Allen J, et al. Depression and multiple sclerosis. Neurology. 1996;46(3):628-632.
6. Wallin MT, Wilken JA, Turner AP, Williams RM, Kane R. Depression and multiple
sclerosis: Review of a lethal combination. J Rehabil Res Dev. 2006;43(1):45-62.
7. Mohr DC, Boudewyn AC, Goodkin DE, Bostrom A, Epstein L. Comparative outcomes for individual cognitive-behavior therapy, supportive-expressive group psychotherapy, and sertraline for the treatment of depression in multiple sclerosis. J Consult Clin Psychol. 2001;69(6):942-949.
8. Mohr DC, Hart SL, Julian L, et al. Telephone-administered psychotherapy for depression. Arch Gen Psychiatry. 2005;62(9):1007-1014.
9. Korostil M, Feinstein A. Anxiety disorders and their clinical correlates in multiple sclerosis patients. Mult Scler. 2007;13(1):67-72.
10. Turner AP, Williams RM, Bowen JD, Kivlahan DR, Haselkorn JK. Suicidal ideation in multiple sclerosis. Arch Phys Med Rehabil. 2006;87(8):1073-1078.
11. Stenager EN, Stenager E. Suicide and patients with neurologic diseases. Methodologic problems. Arch Neurol. 1992;49(12):1296-1303.
12. Bruce JM, Hancock LM, Arnett P, Lynch S. Treatment adherence in multiple sclerosis:
Association with emotional status, personality, and cognition. J Behav Med. 2010;33(3):219-227.
13. Turner AP, Kivlahan DR, Sloan AP, Haselkorn JK. Predicting ongoing adherence to disease modifying therapies in multiple sclerosis: Utility of the health beliefs model. Mult Scler. 2007;13(9):1146-1152.
14. Overs S, Hughes CM, Haselkorn JK, Turner AP. Modifiable comorbidities and disability in multiple sclerosis. Curr Neurol Neurosci Rep. 2012;12(5):610-617.
15. Motl RW, Pilutti LA. The benefits of exercise training in multiple sclerosis. Nat Rev Neurol. 2012;8(9):487-497.
Multiple sclerosis (MS) poses a host of cognitive and psychosocial challenges that may contribute to functioning and quality of life (QOL). Although each patient’s experience with MS is different, some challenges are more common than are others, including cognitive changes, depression, and maintaining positive health behaviors. William’s case study illustrates some of these challenges as well as the resources and strategies of the psychologists at the MS
Centers of Excellence (MSCoE) to help patients with MS adapt and thrive.
Cognition
Difficulties with cognitive functioning are common in patients with MS. About half of patients with MS will develop cognitive impairments in one or more areas during their lifetime.1 Although cognitive difficulties tend to worsen over the course of the disease, they can appear at any point in the illness, differ greatly from patient to patient, and are only modestly correlated with physical symptoms.1 Impairments are most common in the areas of information processing speed and memory, as well as in complex attention and mental flexibility. These impairments can impact activities of daily living, sustained employment, driving, and social relationships.
Early in the disease, William, who admitted to difficulties with cognition and the impact of cognitive impairment on his life, benefited from neuropsychological testing. Typically, an MSCoE will use a battery of tests tailored to patients with MS. For patients, the results of these tests can be used to clarify areas of relative strength and weakness and inform team decisions related to treatment and future life activities, such as whether the patient will need accommodations at work. Test results may also be used to guide how the MS treatment team interacts with the patient.
An initial clinic screening from neurology indicated William had below average cognitive processing speed, and he agreed to neurocognitive testing. The psycholopsychologist asked William about his functioning at home. William noted poor attention and memory made it difficult to advocate for himself. He recounted an episode of taking his car to be repaired and only later realizing that he had been charged twice for the same part. He also disclosed that he had gotten lost while driving through familiar places. On several occasions while cooking, he had become distracted and started another task only to find he had burned his food.
Cognitive rehabilitation has shown considerable promise in helping patients work through difficulties with memory, attention, and problem solving by developing compensatory strategies.2 Skill training is available in individual and group formats. There is also promising but very preliminary evidence that some psychosocial interventions might improve memory performance for patients with MS.3
William’s neuropsychological testing confirmed impairments in information processing speed, attention, and memory, and William was diagnosed with cognitive disorder not otherwise specified. His cognitive impairment correlated with his magnetic resonance imaging (MRI) findings, which included lesions on the corpus callosum and in multiple subcortical areas.
During a feedback session, William was encouraged to use compensatory strategies, including memory aids, visual cueing, and self-pacing. He was given a referral to speech and language pathology to develop and practice these strategies. The psychologist also reminded William’s health care team to speak slowly and repeat important information to him, write down important instructions, and cue him when asking questions in the clinic. William was provided with a kitchen timer and instructed to set it whenever he began cooking, so that even if he got distracted, the alarm would remind him to return to his cooking. William was asked whether he would like to participate in the MSCoE cognitive compensatory training program.4 The program, offered through a research protocol, involved a series of classes that taught strategies to manage cognitive symptoms and improve patients’ ability to function independently. William agreed to participate and reported feeling hopeful that his situation could improve.
Depression
Multiple sclerosis brings many variable and unpredictable challenges and can be a source of distress. Often these challenges occur with the onset of new disease milestones, such as the diagnosis or an increased disability. Given the physical, cognitive, and social stresses, it is not surprising that depression is extremely common, appearing in about half of patients with MS over their lifetime.5 During the course of ordinary MS care, the majority of patients with depression can be identified by a brief screening and referred for additional assessment and treatment.
Fortunately, there are many available treatment options. Antidepressant medications have shown some efficacy.6 Cognitive behavioral therapy (CBT), a counseling strategy that helps individuals become more active, connects them with rewarding activities, and challenges maladaptive thought patterns, has been shown to be effective in individual and group counseling settings via in-person or telephone-based delivery.7,8 Anxiety is also common experience among patients with MS and is treated with many of the same types of psychotherapy intervention.9
Focusing on the psychological and social needs of patients with MS has obvious implications for holistic care and QOL, but in some instances, MS may also contribute to safety concerns. Nearly one-third of veterans with MS admit to suicidal ideation, and the ultimate risk of suicide is about twice that of similar individuals without MS.10,11 For this reason, screening for risk of self-harm should be routinely incorporated into MS care.
A quick look at William’s Computerized Patient Record System (CPRS) record revealed that he had called the VA suicide prevention hotline. During the conversation he had noted that although he originally thought he would be able to deal with MS on his own, he realized he couldn’t. When the psychologist asked William about life at home, he disclosed that some days he never left his bed except to go to the bathroom. He stated he had given up on dating, and asked “who would want me?” He reported little appetite or interest in sex.
William was anxious about the problems he faced from day to day and grieving about the future that he no longer believed was possible. His distress was generally related to the MS diagnosis, and he spent a significant amount of time minimizing his disability, avoiding his family for this reason.
The psychologist diagnosed William with adjustment disorder with mixed anxiety and depressed mood and initiated individual CBT. The psychologist suggested that William attend the MS social work support group and the MS education group to get to know other veterans with MS and learn about managing symptoms. William agreed to attend the groups and admitted it would be good to have a reason to leave the house.
Health Behavior
Recognizing that MS is a chronic illness that requires coordinated efforts, the MS team helped William manage his disease and maintain his health. The psychological and social components of this process were considerable. For most newly diagnosed patients with MS, diseasemodifying therapies (DMTs) are important tools to decrease relapses and short-term disability. Although the benefits of these medications are well known, many patients are nonadherent. Contributing to poor adherence are adverse effects, cognitive challenges, anxiety, depression, and lack of belief in their efficacy.12,13 Brief
counseling, problem solving, and clinical monitoring have all been shown to reduce missed doses and improve DMT use.13 Both the MS Assessment Tool and the pharmacy database within CPRS are helpful for tracking patient adherence over time.
Other health behaviors may contribute not only to overall health, but also to the disease course. Patients who smoke have accelerated progression of their MS disease process and greater mortality than that of nonsmokers.14 Likewise, patients who engage in regular physical activity experience not only greater strength and endurance, but also less fatigue, depression, and better QOL.15 As part of his chronic illness care, the MS team provided William with information about the potential impact of health behaviors on MS progression.
William’s emotional and cognitive symptoms of MS presented important challenges to the management of his MS care. Initially, he ignored his diagnosis, delayed care, and refused to take a DMT. Once he agreed to taking a DMT, he often forgot to take it. He frequently missed medical appointments, because he did not remember them. Depression, fatigue, and stress decreased his motivation to follow through with recommendations from his health care providers.
Given William’s multiple psychosocial needs and transportation challenges, VA psychologists initiated telehealth visits with William in addition to clinic visits to provide many services, including psychotherapy and health behavior counseling. This continued support, along with the coordination of the rest of his health care team has been vital to maintaining William’s adherence to his treatment plan and QOL.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Multiple sclerosis (MS) poses a host of cognitive and psychosocial challenges that may contribute to functioning and quality of life (QOL). Although each patient’s experience with MS is different, some challenges are more common than are others, including cognitive changes, depression, and maintaining positive health behaviors. William’s case study illustrates some of these challenges as well as the resources and strategies of the psychologists at the MS
Centers of Excellence (MSCoE) to help patients with MS adapt and thrive.
Cognition
Difficulties with cognitive functioning are common in patients with MS. About half of patients with MS will develop cognitive impairments in one or more areas during their lifetime.1 Although cognitive difficulties tend to worsen over the course of the disease, they can appear at any point in the illness, differ greatly from patient to patient, and are only modestly correlated with physical symptoms.1 Impairments are most common in the areas of information processing speed and memory, as well as in complex attention and mental flexibility. These impairments can impact activities of daily living, sustained employment, driving, and social relationships.
Early in the disease, William, who admitted to difficulties with cognition and the impact of cognitive impairment on his life, benefited from neuropsychological testing. Typically, an MSCoE will use a battery of tests tailored to patients with MS. For patients, the results of these tests can be used to clarify areas of relative strength and weakness and inform team decisions related to treatment and future life activities, such as whether the patient will need accommodations at work. Test results may also be used to guide how the MS treatment team interacts with the patient.
An initial clinic screening from neurology indicated William had below average cognitive processing speed, and he agreed to neurocognitive testing. The psycholopsychologist asked William about his functioning at home. William noted poor attention and memory made it difficult to advocate for himself. He recounted an episode of taking his car to be repaired and only later realizing that he had been charged twice for the same part. He also disclosed that he had gotten lost while driving through familiar places. On several occasions while cooking, he had become distracted and started another task only to find he had burned his food.
Cognitive rehabilitation has shown considerable promise in helping patients work through difficulties with memory, attention, and problem solving by developing compensatory strategies.2 Skill training is available in individual and group formats. There is also promising but very preliminary evidence that some psychosocial interventions might improve memory performance for patients with MS.3
William’s neuropsychological testing confirmed impairments in information processing speed, attention, and memory, and William was diagnosed with cognitive disorder not otherwise specified. His cognitive impairment correlated with his magnetic resonance imaging (MRI) findings, which included lesions on the corpus callosum and in multiple subcortical areas.
During a feedback session, William was encouraged to use compensatory strategies, including memory aids, visual cueing, and self-pacing. He was given a referral to speech and language pathology to develop and practice these strategies. The psychologist also reminded William’s health care team to speak slowly and repeat important information to him, write down important instructions, and cue him when asking questions in the clinic. William was provided with a kitchen timer and instructed to set it whenever he began cooking, so that even if he got distracted, the alarm would remind him to return to his cooking. William was asked whether he would like to participate in the MSCoE cognitive compensatory training program.4 The program, offered through a research protocol, involved a series of classes that taught strategies to manage cognitive symptoms and improve patients’ ability to function independently. William agreed to participate and reported feeling hopeful that his situation could improve.
Depression
Multiple sclerosis brings many variable and unpredictable challenges and can be a source of distress. Often these challenges occur with the onset of new disease milestones, such as the diagnosis or an increased disability. Given the physical, cognitive, and social stresses, it is not surprising that depression is extremely common, appearing in about half of patients with MS over their lifetime.5 During the course of ordinary MS care, the majority of patients with depression can be identified by a brief screening and referred for additional assessment and treatment.
Fortunately, there are many available treatment options. Antidepressant medications have shown some efficacy.6 Cognitive behavioral therapy (CBT), a counseling strategy that helps individuals become more active, connects them with rewarding activities, and challenges maladaptive thought patterns, has been shown to be effective in individual and group counseling settings via in-person or telephone-based delivery.7,8 Anxiety is also common experience among patients with MS and is treated with many of the same types of psychotherapy intervention.9
Focusing on the psychological and social needs of patients with MS has obvious implications for holistic care and QOL, but in some instances, MS may also contribute to safety concerns. Nearly one-third of veterans with MS admit to suicidal ideation, and the ultimate risk of suicide is about twice that of similar individuals without MS.10,11 For this reason, screening for risk of self-harm should be routinely incorporated into MS care.
A quick look at William’s Computerized Patient Record System (CPRS) record revealed that he had called the VA suicide prevention hotline. During the conversation he had noted that although he originally thought he would be able to deal with MS on his own, he realized he couldn’t. When the psychologist asked William about life at home, he disclosed that some days he never left his bed except to go to the bathroom. He stated he had given up on dating, and asked “who would want me?” He reported little appetite or interest in sex.
William was anxious about the problems he faced from day to day and grieving about the future that he no longer believed was possible. His distress was generally related to the MS diagnosis, and he spent a significant amount of time minimizing his disability, avoiding his family for this reason.
The psychologist diagnosed William with adjustment disorder with mixed anxiety and depressed mood and initiated individual CBT. The psychologist suggested that William attend the MS social work support group and the MS education group to get to know other veterans with MS and learn about managing symptoms. William agreed to attend the groups and admitted it would be good to have a reason to leave the house.
Health Behavior
Recognizing that MS is a chronic illness that requires coordinated efforts, the MS team helped William manage his disease and maintain his health. The psychological and social components of this process were considerable. For most newly diagnosed patients with MS, diseasemodifying therapies (DMTs) are important tools to decrease relapses and short-term disability. Although the benefits of these medications are well known, many patients are nonadherent. Contributing to poor adherence are adverse effects, cognitive challenges, anxiety, depression, and lack of belief in their efficacy.12,13 Brief
counseling, problem solving, and clinical monitoring have all been shown to reduce missed doses and improve DMT use.13 Both the MS Assessment Tool and the pharmacy database within CPRS are helpful for tracking patient adherence over time.
Other health behaviors may contribute not only to overall health, but also to the disease course. Patients who smoke have accelerated progression of their MS disease process and greater mortality than that of nonsmokers.14 Likewise, patients who engage in regular physical activity experience not only greater strength and endurance, but also less fatigue, depression, and better QOL.15 As part of his chronic illness care, the MS team provided William with information about the potential impact of health behaviors on MS progression.
William’s emotional and cognitive symptoms of MS presented important challenges to the management of his MS care. Initially, he ignored his diagnosis, delayed care, and refused to take a DMT. Once he agreed to taking a DMT, he often forgot to take it. He frequently missed medical appointments, because he did not remember them. Depression, fatigue, and stress decreased his motivation to follow through with recommendations from his health care providers.
Given William’s multiple psychosocial needs and transportation challenges, VA psychologists initiated telehealth visits with William in addition to clinic visits to provide many services, including psychotherapy and health behavior counseling. This continued support, along with the coordination of the rest of his health care team has been vital to maintaining William’s adherence to his treatment plan and QOL.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
1. Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology. 1991;41(5):685-691.
2. Cicerone KD, Langenbahn DM, Braden C, et al. Evidence-based cognitive rehabilitation: Updated review of the literature from 2003 through 2008. Arch Phys Med Rehabil. 2011;92(4):519-530.
3. Chiaravalloti ND, Moore NB, Nikelshpur OM, DeLuca J. An RCT to treat learning impairment in multiple sclerosis: The MEMREHAB trial. Neurology. 2013;81(24):2066-2072.
4. Huckans M, Pavawalla S, Demadura T, et al. A pilot study examining effects of group-based Cognitive Strategy Training treatment on self-reported cognitive problems, psychiatric symptoms, functioning, and compensatory strategy use in OIF/OEF combat veterans with persistent mild cognitive disorder and history of traumatic brain injury. J Rehabil Res Dev. 2010;47(1):43-60.
5. Sadovnick AD, Remick RA, Allen J, et al. Depression and multiple sclerosis. Neurology. 1996;46(3):628-632.
6. Wallin MT, Wilken JA, Turner AP, Williams RM, Kane R. Depression and multiple
sclerosis: Review of a lethal combination. J Rehabil Res Dev. 2006;43(1):45-62.
7. Mohr DC, Boudewyn AC, Goodkin DE, Bostrom A, Epstein L. Comparative outcomes for individual cognitive-behavior therapy, supportive-expressive group psychotherapy, and sertraline for the treatment of depression in multiple sclerosis. J Consult Clin Psychol. 2001;69(6):942-949.
8. Mohr DC, Hart SL, Julian L, et al. Telephone-administered psychotherapy for depression. Arch Gen Psychiatry. 2005;62(9):1007-1014.
9. Korostil M, Feinstein A. Anxiety disorders and their clinical correlates in multiple sclerosis patients. Mult Scler. 2007;13(1):67-72.
10. Turner AP, Williams RM, Bowen JD, Kivlahan DR, Haselkorn JK. Suicidal ideation in multiple sclerosis. Arch Phys Med Rehabil. 2006;87(8):1073-1078.
11. Stenager EN, Stenager E. Suicide and patients with neurologic diseases. Methodologic problems. Arch Neurol. 1992;49(12):1296-1303.
12. Bruce JM, Hancock LM, Arnett P, Lynch S. Treatment adherence in multiple sclerosis:
Association with emotional status, personality, and cognition. J Behav Med. 2010;33(3):219-227.
13. Turner AP, Kivlahan DR, Sloan AP, Haselkorn JK. Predicting ongoing adherence to disease modifying therapies in multiple sclerosis: Utility of the health beliefs model. Mult Scler. 2007;13(9):1146-1152.
14. Overs S, Hughes CM, Haselkorn JK, Turner AP. Modifiable comorbidities and disability in multiple sclerosis. Curr Neurol Neurosci Rep. 2012;12(5):610-617.
15. Motl RW, Pilutti LA. The benefits of exercise training in multiple sclerosis. Nat Rev Neurol. 2012;8(9):487-497.
1. Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology. 1991;41(5):685-691.
2. Cicerone KD, Langenbahn DM, Braden C, et al. Evidence-based cognitive rehabilitation: Updated review of the literature from 2003 through 2008. Arch Phys Med Rehabil. 2011;92(4):519-530.
3. Chiaravalloti ND, Moore NB, Nikelshpur OM, DeLuca J. An RCT to treat learning impairment in multiple sclerosis: The MEMREHAB trial. Neurology. 2013;81(24):2066-2072.
4. Huckans M, Pavawalla S, Demadura T, et al. A pilot study examining effects of group-based Cognitive Strategy Training treatment on self-reported cognitive problems, psychiatric symptoms, functioning, and compensatory strategy use in OIF/OEF combat veterans with persistent mild cognitive disorder and history of traumatic brain injury. J Rehabil Res Dev. 2010;47(1):43-60.
5. Sadovnick AD, Remick RA, Allen J, et al. Depression and multiple sclerosis. Neurology. 1996;46(3):628-632.
6. Wallin MT, Wilken JA, Turner AP, Williams RM, Kane R. Depression and multiple
sclerosis: Review of a lethal combination. J Rehabil Res Dev. 2006;43(1):45-62.
7. Mohr DC, Boudewyn AC, Goodkin DE, Bostrom A, Epstein L. Comparative outcomes for individual cognitive-behavior therapy, supportive-expressive group psychotherapy, and sertraline for the treatment of depression in multiple sclerosis. J Consult Clin Psychol. 2001;69(6):942-949.
8. Mohr DC, Hart SL, Julian L, et al. Telephone-administered psychotherapy for depression. Arch Gen Psychiatry. 2005;62(9):1007-1014.
9. Korostil M, Feinstein A. Anxiety disorders and their clinical correlates in multiple sclerosis patients. Mult Scler. 2007;13(1):67-72.
10. Turner AP, Williams RM, Bowen JD, Kivlahan DR, Haselkorn JK. Suicidal ideation in multiple sclerosis. Arch Phys Med Rehabil. 2006;87(8):1073-1078.
11. Stenager EN, Stenager E. Suicide and patients with neurologic diseases. Methodologic problems. Arch Neurol. 1992;49(12):1296-1303.
12. Bruce JM, Hancock LM, Arnett P, Lynch S. Treatment adherence in multiple sclerosis:
Association with emotional status, personality, and cognition. J Behav Med. 2010;33(3):219-227.
13. Turner AP, Kivlahan DR, Sloan AP, Haselkorn JK. Predicting ongoing adherence to disease modifying therapies in multiple sclerosis: Utility of the health beliefs model. Mult Scler. 2007;13(9):1146-1152.
14. Overs S, Hughes CM, Haselkorn JK, Turner AP. Modifiable comorbidities and disability in multiple sclerosis. Curr Neurol Neurosci Rep. 2012;12(5):610-617.
15. Motl RW, Pilutti LA. The benefits of exercise training in multiple sclerosis. Nat Rev Neurol. 2012;8(9):487-497.
Cultural Competency and Treatment of Veteran and Military Patients With Mental Health Disorders
About 2.5 million U.S. service members have served in conflicts since September 11, 2001. Estimates of the numbers of service members who have deployed to Iraq and Afghanistan and have posttraumatic stress disorder (PTSD) range from 15% to 25%.1-3
This special issue contains several excellent articles about PTSD and comorbidities, including insomnia and depression. Although there are service members who have pure PTSD, in the experience of most clinicians, that is the exception rather than the rule.2 For example, insomnia may lead to patients’ excessive drinking to try to sleep. Numbing and avoidance from the excessive drinking leads to relationship problems and often divorce. Relationship problems are subsequently a key driver of suicide.4,5
Also included in this issue is a series of articles examining the case study of William, who has multiple sclerosis (MS), a disease usually in the domain of neurologists, rather than psychiatrists. However, given the physical, cognitive, and social stresses of MS, it is not surprising that comorbid depression is extremely common, appearing in about half of patients with MS over their lifetime.6 The multidisciplinary approach to care described in this series is critical for successful treatment.
There are well-established guidelines for the treatment of PTSD, developed by the American Psychiatric Association, DoD, and VA, often referred to as evidence-based treatments. However, there are many patients who are either unwilling or unable to adhere or who do not respond to the evidence-based treatments. Although these patients are often called treatment-resistant or refractory, it is also likely that the treatments are not engineered toward service members. That may be due to (1) unacceptable adverse effects from medication; (2) difficulties attending frequent appointments, especially for cognitivebehavioral treatments; (3) the reluctance of many service members to relive their trauma and/or talk about it; or
(4) the stigma of seeking treatment.2,7
The physical stresses of military service, including wounds and injuries, involve corresponding pain and disability. Alcohol, depression, PTSD, and traumatic brain injury have long been associated with one another, but sometimes musculoskeletal injuries are left out of the discussion. The musculoskeletal issues have led to service members being treated with opiates, which can cause dependence and addiction.4,5 In both military and civilian populations, many patients switch from legal opiates to illegal heroin. Many service members, especially after discharge from the military, thus start a slide into substance dependence, unemployment, and homelessness. Unfortunately, death by heroin overdose is increasingly common.8
Suicide rates among U.S. Army personnel have been increasing since 2004, surpassing comparable civilian suicide rates in 2008. The other service branches have not seen such a dramatic rise, but suicide is still a troubling problem. Suicide rates peaked in army active-duty troops over the past few years but are still rising in reservists. Suicides are most prevalent among young white males but have been increasing in older ages and females
as well.4,5
Risk factors for suicide among active-duty members are well known, because data are systemically collected. These include relationship difficulties, financial and occupational problems, pain and physical disability, and access to weapons.4,5
Cultural Compentency
The concept of moral injury is related to but different from PTSD, which is a medical diagnosis. In general, most authors conceptualize moral injury as an insult caused either by shame of killing or the guilt induced when fellow service members die while one has survived. Although not well studied by the medical community, most agree that it is a corrosive condition, which contributes to relationship difficulties and suicide.
A theme throughout military medicine is one of cultural competency: If you are not in the military, how can you understand the military culture? As a start, one of the easy ways is for a provider to ask patients about their military occupational specialty, basic and advanced training, and where they have been stationed. Ask when and where they have been deployed. Learn what their military rank is/was, and ask how they want to be addressed. Some will prefer to be addressed by rank, others by their first name. An important piece of advice for providers: Combat veterans do not want to be seen as victims. Treat them as battle-hardened or maybe battle-scarred, and respect their service.
At present, 15% of active-duty military, 17% of National Guard/Reserves, and 20% of new recruits are women. The recent wars in Iraq and Afghanistan have engendered a growing population of female veterans seeking health care through VA. Thus, women are among the fastest growing segments of new users of VA health care: As many as 40% of women returning from Iraq and Afghanistan may elect to use the VA, for a variety of medical and mental health reasons. In the civilian world, women experience PTSD at twice the rate than do men. In the military, available statistics suggest that the rate is about the same.
There are certain occupations that may lead to an increased rate of PTSD. Medical staff are exposed to horrifically wounded service members and local populations. They and others may have been involved with detainee medical issues. In addition, many service members, including individual augmentees and other reservists, were assigned to detainee missions, such as at Guantanamo Bay and Abu Ghraib. In general, reservists may not have the support of a cohesive unit.
Administrative Issues
Service members need to be physically and mentally fit for duty, according to various regulations.9 If service members have a severe mental illness, they usually will receive a medical evaluation to assess whether or not they are fit for duty. Service members may be medically discharged if found not fit for duty. They may also be medically retired, depending on the severity of their condition, which carries significant disability benefits. The Medical and Physical Evaluation Boards, now called the Integrated Disability Evaluation System, is a complex process.10
The diagnosis of PTSD does not necessarily lead to a medical discharge. If service members respond to treatment, they may be found fit for duty. Alternatively, with actual practice varying according to the service branch, unfortunately they may be administratively discharged without benefits.
Service members may or may not want to be assessed by a Medical Evaluation Board, which offers both benefits and potential shame. Those who want to stay in the military, in general, do not want to see a mental health care provider, because they fear for their jobs. However, those who are nearing the end of their enlistment or planning to retire have many pressures to endorse PTSD symptoms. These include the financial benefits of medical retirement (often at 50% of their base pay), including free medical care and other benefits.
Military, VA, and other providers need to know how to diagnose and treat these psychologic and neurologic brain injuries and disorders. They also need to know when and how to refer elsewhere for further evaluation and treatment. Finally, because PTSD is very much in the public discourse, providers should be prepared to engage in a dialogue with the public.
1. Tanielian T, Jaycox LH, eds. Invisible Wounds of War: Psychological and Cognitive Injuries, Their Consequences, and Services to Assist Recovery. Santa Monica, CA: Rand Corporation; 2008.
2. Treatment of posttraumatic stress disorder in military and veteran populations. Institute of Medicine Website. http://www.iom.edu/Reports/2014/Treatment-for-Posttraumatic-Stress-Disorder-in-Military-and-Veteran-Populations-Final-Assessment.aspx. Published June 20, 2014. Accessed March 9, 2015.
3. Joint mental health advisory team VII (J-MHAT 7) report. U.S. Army Website. http://armylive.dodlive.mil/index.php/2011/05/joint-mental-health-advisory-team-vii-j-mhat-7-report. Published May 24, 2011. Accessed March 9, 2015.
4. Ritchie EC. Suicides and the United States army: Perspectives from the former psychiatry consultant to the army surgeon general. Cerebrum. 2012(2012):1.
5. Black SA, Gallaway MS, Bell MR, Ritchie EC. Prevalence and risk factors associated with suicides of Army soldiers. Milit Psychol. 2011;23(4):433-451.
6. Wallin MT, Wilken JA, Turner AP, Williams RM, Kane R. Depression and multiple sclerosis: Review of a lethal combination. J Rehabil Res Dev. 2006;43(1):45-62.
7. Hoge C. DSM-5 PTSD screening may miss previously diagnosed soldiers. Healio Website. http://www.healio.com/psychiatry/ptsd/news/online/%7B4e137bbf-4bc0-4c31-b6b2-77e83e9b09d9%7D/dsm-5-ptsd-screening-may-miss-previously-diagnosed-soldiers. Published August 25, 2014. Accessed March 10, 2015.
8. Rudd RA, Paulozzi LJ, Burleson RW, et al; Centers for Disease Control (CDC). Increases in heroin overdose deaths—28 states, 2010 to 2012. MMWR Morb Mortal Wkly Rep. 2014;63(39):849-854.
9. U.S. Army. Standards of Medical Fitness, 2011. Army Regulation 40-501. U.S. Army Website. http://www.apd.army.mil/pdffiles/r40_501.pdf. Published August 4, 2011. Accessed March 10, 2015.
10. Army Physical Disability Evaluation System. The army integrated disability evaluation system. U.S. Army Website. http://usarmy.vo.llnwd.net/e2/rv5_downloads/features/readyandresilient/ARMY_IDES.pdf. Accessed March 10, 2015.
About 2.5 million U.S. service members have served in conflicts since September 11, 2001. Estimates of the numbers of service members who have deployed to Iraq and Afghanistan and have posttraumatic stress disorder (PTSD) range from 15% to 25%.1-3
This special issue contains several excellent articles about PTSD and comorbidities, including insomnia and depression. Although there are service members who have pure PTSD, in the experience of most clinicians, that is the exception rather than the rule.2 For example, insomnia may lead to patients’ excessive drinking to try to sleep. Numbing and avoidance from the excessive drinking leads to relationship problems and often divorce. Relationship problems are subsequently a key driver of suicide.4,5
Also included in this issue is a series of articles examining the case study of William, who has multiple sclerosis (MS), a disease usually in the domain of neurologists, rather than psychiatrists. However, given the physical, cognitive, and social stresses of MS, it is not surprising that comorbid depression is extremely common, appearing in about half of patients with MS over their lifetime.6 The multidisciplinary approach to care described in this series is critical for successful treatment.
There are well-established guidelines for the treatment of PTSD, developed by the American Psychiatric Association, DoD, and VA, often referred to as evidence-based treatments. However, there are many patients who are either unwilling or unable to adhere or who do not respond to the evidence-based treatments. Although these patients are often called treatment-resistant or refractory, it is also likely that the treatments are not engineered toward service members. That may be due to (1) unacceptable adverse effects from medication; (2) difficulties attending frequent appointments, especially for cognitivebehavioral treatments; (3) the reluctance of many service members to relive their trauma and/or talk about it; or
(4) the stigma of seeking treatment.2,7
The physical stresses of military service, including wounds and injuries, involve corresponding pain and disability. Alcohol, depression, PTSD, and traumatic brain injury have long been associated with one another, but sometimes musculoskeletal injuries are left out of the discussion. The musculoskeletal issues have led to service members being treated with opiates, which can cause dependence and addiction.4,5 In both military and civilian populations, many patients switch from legal opiates to illegal heroin. Many service members, especially after discharge from the military, thus start a slide into substance dependence, unemployment, and homelessness. Unfortunately, death by heroin overdose is increasingly common.8
Suicide rates among U.S. Army personnel have been increasing since 2004, surpassing comparable civilian suicide rates in 2008. The other service branches have not seen such a dramatic rise, but suicide is still a troubling problem. Suicide rates peaked in army active-duty troops over the past few years but are still rising in reservists. Suicides are most prevalent among young white males but have been increasing in older ages and females
as well.4,5
Risk factors for suicide among active-duty members are well known, because data are systemically collected. These include relationship difficulties, financial and occupational problems, pain and physical disability, and access to weapons.4,5
Cultural Compentency
The concept of moral injury is related to but different from PTSD, which is a medical diagnosis. In general, most authors conceptualize moral injury as an insult caused either by shame of killing or the guilt induced when fellow service members die while one has survived. Although not well studied by the medical community, most agree that it is a corrosive condition, which contributes to relationship difficulties and suicide.
A theme throughout military medicine is one of cultural competency: If you are not in the military, how can you understand the military culture? As a start, one of the easy ways is for a provider to ask patients about their military occupational specialty, basic and advanced training, and where they have been stationed. Ask when and where they have been deployed. Learn what their military rank is/was, and ask how they want to be addressed. Some will prefer to be addressed by rank, others by their first name. An important piece of advice for providers: Combat veterans do not want to be seen as victims. Treat them as battle-hardened or maybe battle-scarred, and respect their service.
At present, 15% of active-duty military, 17% of National Guard/Reserves, and 20% of new recruits are women. The recent wars in Iraq and Afghanistan have engendered a growing population of female veterans seeking health care through VA. Thus, women are among the fastest growing segments of new users of VA health care: As many as 40% of women returning from Iraq and Afghanistan may elect to use the VA, for a variety of medical and mental health reasons. In the civilian world, women experience PTSD at twice the rate than do men. In the military, available statistics suggest that the rate is about the same.
There are certain occupations that may lead to an increased rate of PTSD. Medical staff are exposed to horrifically wounded service members and local populations. They and others may have been involved with detainee medical issues. In addition, many service members, including individual augmentees and other reservists, were assigned to detainee missions, such as at Guantanamo Bay and Abu Ghraib. In general, reservists may not have the support of a cohesive unit.
Administrative Issues
Service members need to be physically and mentally fit for duty, according to various regulations.9 If service members have a severe mental illness, they usually will receive a medical evaluation to assess whether or not they are fit for duty. Service members may be medically discharged if found not fit for duty. They may also be medically retired, depending on the severity of their condition, which carries significant disability benefits. The Medical and Physical Evaluation Boards, now called the Integrated Disability Evaluation System, is a complex process.10
The diagnosis of PTSD does not necessarily lead to a medical discharge. If service members respond to treatment, they may be found fit for duty. Alternatively, with actual practice varying according to the service branch, unfortunately they may be administratively discharged without benefits.
Service members may or may not want to be assessed by a Medical Evaluation Board, which offers both benefits and potential shame. Those who want to stay in the military, in general, do not want to see a mental health care provider, because they fear for their jobs. However, those who are nearing the end of their enlistment or planning to retire have many pressures to endorse PTSD symptoms. These include the financial benefits of medical retirement (often at 50% of their base pay), including free medical care and other benefits.
Military, VA, and other providers need to know how to diagnose and treat these psychologic and neurologic brain injuries and disorders. They also need to know when and how to refer elsewhere for further evaluation and treatment. Finally, because PTSD is very much in the public discourse, providers should be prepared to engage in a dialogue with the public.
About 2.5 million U.S. service members have served in conflicts since September 11, 2001. Estimates of the numbers of service members who have deployed to Iraq and Afghanistan and have posttraumatic stress disorder (PTSD) range from 15% to 25%.1-3
This special issue contains several excellent articles about PTSD and comorbidities, including insomnia and depression. Although there are service members who have pure PTSD, in the experience of most clinicians, that is the exception rather than the rule.2 For example, insomnia may lead to patients’ excessive drinking to try to sleep. Numbing and avoidance from the excessive drinking leads to relationship problems and often divorce. Relationship problems are subsequently a key driver of suicide.4,5
Also included in this issue is a series of articles examining the case study of William, who has multiple sclerosis (MS), a disease usually in the domain of neurologists, rather than psychiatrists. However, given the physical, cognitive, and social stresses of MS, it is not surprising that comorbid depression is extremely common, appearing in about half of patients with MS over their lifetime.6 The multidisciplinary approach to care described in this series is critical for successful treatment.
There are well-established guidelines for the treatment of PTSD, developed by the American Psychiatric Association, DoD, and VA, often referred to as evidence-based treatments. However, there are many patients who are either unwilling or unable to adhere or who do not respond to the evidence-based treatments. Although these patients are often called treatment-resistant or refractory, it is also likely that the treatments are not engineered toward service members. That may be due to (1) unacceptable adverse effects from medication; (2) difficulties attending frequent appointments, especially for cognitivebehavioral treatments; (3) the reluctance of many service members to relive their trauma and/or talk about it; or
(4) the stigma of seeking treatment.2,7
The physical stresses of military service, including wounds and injuries, involve corresponding pain and disability. Alcohol, depression, PTSD, and traumatic brain injury have long been associated with one another, but sometimes musculoskeletal injuries are left out of the discussion. The musculoskeletal issues have led to service members being treated with opiates, which can cause dependence and addiction.4,5 In both military and civilian populations, many patients switch from legal opiates to illegal heroin. Many service members, especially after discharge from the military, thus start a slide into substance dependence, unemployment, and homelessness. Unfortunately, death by heroin overdose is increasingly common.8
Suicide rates among U.S. Army personnel have been increasing since 2004, surpassing comparable civilian suicide rates in 2008. The other service branches have not seen such a dramatic rise, but suicide is still a troubling problem. Suicide rates peaked in army active-duty troops over the past few years but are still rising in reservists. Suicides are most prevalent among young white males but have been increasing in older ages and females
as well.4,5
Risk factors for suicide among active-duty members are well known, because data are systemically collected. These include relationship difficulties, financial and occupational problems, pain and physical disability, and access to weapons.4,5
Cultural Compentency
The concept of moral injury is related to but different from PTSD, which is a medical diagnosis. In general, most authors conceptualize moral injury as an insult caused either by shame of killing or the guilt induced when fellow service members die while one has survived. Although not well studied by the medical community, most agree that it is a corrosive condition, which contributes to relationship difficulties and suicide.
A theme throughout military medicine is one of cultural competency: If you are not in the military, how can you understand the military culture? As a start, one of the easy ways is for a provider to ask patients about their military occupational specialty, basic and advanced training, and where they have been stationed. Ask when and where they have been deployed. Learn what their military rank is/was, and ask how they want to be addressed. Some will prefer to be addressed by rank, others by their first name. An important piece of advice for providers: Combat veterans do not want to be seen as victims. Treat them as battle-hardened or maybe battle-scarred, and respect their service.
At present, 15% of active-duty military, 17% of National Guard/Reserves, and 20% of new recruits are women. The recent wars in Iraq and Afghanistan have engendered a growing population of female veterans seeking health care through VA. Thus, women are among the fastest growing segments of new users of VA health care: As many as 40% of women returning from Iraq and Afghanistan may elect to use the VA, for a variety of medical and mental health reasons. In the civilian world, women experience PTSD at twice the rate than do men. In the military, available statistics suggest that the rate is about the same.
There are certain occupations that may lead to an increased rate of PTSD. Medical staff are exposed to horrifically wounded service members and local populations. They and others may have been involved with detainee medical issues. In addition, many service members, including individual augmentees and other reservists, were assigned to detainee missions, such as at Guantanamo Bay and Abu Ghraib. In general, reservists may not have the support of a cohesive unit.
Administrative Issues
Service members need to be physically and mentally fit for duty, according to various regulations.9 If service members have a severe mental illness, they usually will receive a medical evaluation to assess whether or not they are fit for duty. Service members may be medically discharged if found not fit for duty. They may also be medically retired, depending on the severity of their condition, which carries significant disability benefits. The Medical and Physical Evaluation Boards, now called the Integrated Disability Evaluation System, is a complex process.10
The diagnosis of PTSD does not necessarily lead to a medical discharge. If service members respond to treatment, they may be found fit for duty. Alternatively, with actual practice varying according to the service branch, unfortunately they may be administratively discharged without benefits.
Service members may or may not want to be assessed by a Medical Evaluation Board, which offers both benefits and potential shame. Those who want to stay in the military, in general, do not want to see a mental health care provider, because they fear for their jobs. However, those who are nearing the end of their enlistment or planning to retire have many pressures to endorse PTSD symptoms. These include the financial benefits of medical retirement (often at 50% of their base pay), including free medical care and other benefits.
Military, VA, and other providers need to know how to diagnose and treat these psychologic and neurologic brain injuries and disorders. They also need to know when and how to refer elsewhere for further evaluation and treatment. Finally, because PTSD is very much in the public discourse, providers should be prepared to engage in a dialogue with the public.
1. Tanielian T, Jaycox LH, eds. Invisible Wounds of War: Psychological and Cognitive Injuries, Their Consequences, and Services to Assist Recovery. Santa Monica, CA: Rand Corporation; 2008.
2. Treatment of posttraumatic stress disorder in military and veteran populations. Institute of Medicine Website. http://www.iom.edu/Reports/2014/Treatment-for-Posttraumatic-Stress-Disorder-in-Military-and-Veteran-Populations-Final-Assessment.aspx. Published June 20, 2014. Accessed March 9, 2015.
3. Joint mental health advisory team VII (J-MHAT 7) report. U.S. Army Website. http://armylive.dodlive.mil/index.php/2011/05/joint-mental-health-advisory-team-vii-j-mhat-7-report. Published May 24, 2011. Accessed March 9, 2015.
4. Ritchie EC. Suicides and the United States army: Perspectives from the former psychiatry consultant to the army surgeon general. Cerebrum. 2012(2012):1.
5. Black SA, Gallaway MS, Bell MR, Ritchie EC. Prevalence and risk factors associated with suicides of Army soldiers. Milit Psychol. 2011;23(4):433-451.
6. Wallin MT, Wilken JA, Turner AP, Williams RM, Kane R. Depression and multiple sclerosis: Review of a lethal combination. J Rehabil Res Dev. 2006;43(1):45-62.
7. Hoge C. DSM-5 PTSD screening may miss previously diagnosed soldiers. Healio Website. http://www.healio.com/psychiatry/ptsd/news/online/%7B4e137bbf-4bc0-4c31-b6b2-77e83e9b09d9%7D/dsm-5-ptsd-screening-may-miss-previously-diagnosed-soldiers. Published August 25, 2014. Accessed March 10, 2015.
8. Rudd RA, Paulozzi LJ, Burleson RW, et al; Centers for Disease Control (CDC). Increases in heroin overdose deaths—28 states, 2010 to 2012. MMWR Morb Mortal Wkly Rep. 2014;63(39):849-854.
9. U.S. Army. Standards of Medical Fitness, 2011. Army Regulation 40-501. U.S. Army Website. http://www.apd.army.mil/pdffiles/r40_501.pdf. Published August 4, 2011. Accessed March 10, 2015.
10. Army Physical Disability Evaluation System. The army integrated disability evaluation system. U.S. Army Website. http://usarmy.vo.llnwd.net/e2/rv5_downloads/features/readyandresilient/ARMY_IDES.pdf. Accessed March 10, 2015.
1. Tanielian T, Jaycox LH, eds. Invisible Wounds of War: Psychological and Cognitive Injuries, Their Consequences, and Services to Assist Recovery. Santa Monica, CA: Rand Corporation; 2008.
2. Treatment of posttraumatic stress disorder in military and veteran populations. Institute of Medicine Website. http://www.iom.edu/Reports/2014/Treatment-for-Posttraumatic-Stress-Disorder-in-Military-and-Veteran-Populations-Final-Assessment.aspx. Published June 20, 2014. Accessed March 9, 2015.
3. Joint mental health advisory team VII (J-MHAT 7) report. U.S. Army Website. http://armylive.dodlive.mil/index.php/2011/05/joint-mental-health-advisory-team-vii-j-mhat-7-report. Published May 24, 2011. Accessed March 9, 2015.
4. Ritchie EC. Suicides and the United States army: Perspectives from the former psychiatry consultant to the army surgeon general. Cerebrum. 2012(2012):1.
5. Black SA, Gallaway MS, Bell MR, Ritchie EC. Prevalence and risk factors associated with suicides of Army soldiers. Milit Psychol. 2011;23(4):433-451.
6. Wallin MT, Wilken JA, Turner AP, Williams RM, Kane R. Depression and multiple sclerosis: Review of a lethal combination. J Rehabil Res Dev. 2006;43(1):45-62.
7. Hoge C. DSM-5 PTSD screening may miss previously diagnosed soldiers. Healio Website. http://www.healio.com/psychiatry/ptsd/news/online/%7B4e137bbf-4bc0-4c31-b6b2-77e83e9b09d9%7D/dsm-5-ptsd-screening-may-miss-previously-diagnosed-soldiers. Published August 25, 2014. Accessed March 10, 2015.
8. Rudd RA, Paulozzi LJ, Burleson RW, et al; Centers for Disease Control (CDC). Increases in heroin overdose deaths—28 states, 2010 to 2012. MMWR Morb Mortal Wkly Rep. 2014;63(39):849-854.
9. U.S. Army. Standards of Medical Fitness, 2011. Army Regulation 40-501. U.S. Army Website. http://www.apd.army.mil/pdffiles/r40_501.pdf. Published August 4, 2011. Accessed March 10, 2015.
10. Army Physical Disability Evaluation System. The army integrated disability evaluation system. U.S. Army Website. http://usarmy.vo.llnwd.net/e2/rv5_downloads/features/readyandresilient/ARMY_IDES.pdf. Accessed March 10, 2015.
New Treatments for Hepatitis C
Hepatitis C virus (HCV) infection remains a significant problem in the VA system, with over 174,000 current actively infected patients.1 Despite the availability of antiviral treatment since the early 1990’s, only approximately 26% of patients have ever been treated. These treatments required the use of pegylated interferon alfa (PEG) and ribavirin (RBV), which are associated with significant adverse events (AEs) that prevented many from receiving the treatment. Of those treated, only a minority achieved a sustained virologic response (SVR), due to the limited efficacy of the treatments (Figure 1).2 With the advent of new direct-acting antiviral (DAA) treatments in 2011, treatment efficacy improved. 
The first DAAs in use were the viral nonstructural protein 3/4A (NS3/4A) serine protease inhibitors (PIs) boceprevir and telaprevir, which were used with PEG and RBV for patients with HCV genotype 1 infection. This combination therapy improved SVR rates from about 26% to 50% in patients with HCV genotype 1 in the VA.3,4 However, due to the significant AEs with these combinations, relatively few patients were treated.
In late 2013, the FDA approved other DAAs, which allowed patients to be treated effectively without PEG. These included the nucleotide nonstructural protein 5B (NS5B) polymerase inhibitor sofosbuvir and a secondgeneration NS3/4A PI simeprevir.5-7 The first nucleotide analog NS5B polymerase inhibitor, sofosbuvir and the nonstructural protein 5A (NS5A) replication complex inhibitor, ledipasvir, was approved in October 2014.8-10 The recent developments in noninterferon treatments have been accompanied by revised treatment guidelines or recommendations by major professional societies. Current treatment recommendations will be reviewed here, but the recommendations will continue to evolve as new DAAs come to market.
DAA Sites of Action
The HCV genome is a positive-stranded RNA molecule of about 9,500 nucleotides, which encodes a polyprotein of approximately 3,000 amino acids that form 10 individual viral proteins. These are composed of both structural and nonstructural (NS) proteins that are responsible for replication of the genome and formation of new viral particles. Understanding of the HCV-encoded proteins and their functions has permitted the development of different DAA therapies. In general, targeting a single protein is not effective, and combination therapy targeting 2 proteins is required for viral eradication (Figure 2).11 The 3 drug targets that are currently available include NS3/4A serine PIs (eg, simeprevir, boceprevir, telaprevir), NS5A replication complex inhibitors (eg, ledipasvir, daclatasvir), and NS5B RNA-dependent RNA polymerase inhibitors (eg, sofosbuvir). 
Other DAA’s are in development that have targets in host rather than viral cells. These include cycolphilin A inhibitors and the micro-RNA (miR-122) antagonist miravirsen.12,13
The RNA-dependent RNA polymerase, encoded by the HCV NS5B is targeted by 2 classes of inhibitors: nucleoside or nucleotide analog inhibitors (NIs), and non-nucleoside inhibitors (NNIs).11 The only NI of the NS5B protein approved by the FDA is sofosbuvir. The resistance profiles of NIs and NNIs differ, because they bind to distinct sites on the NS5B protein. NIs are analogs of natural substrates and bind to the active site of the RNA polymerase, whereas NNIs are allosteric site inhibitors. NIs have activity in vitro against all HCV genotypes and have high barrier to resistance as the active site of NS5B polymerase is less tolerant of different amino acid substitutions.
In vitro studies have demonstrated that NIs are less likely to select for mutations compared with NNIs and PIs. The NNIs have limited genotypic coverage and have a lower barrier to resistance. Strategies for targeting HCV proteins include using a NI NS5B protein inhibitor as the backbone with a high barrier to resistance in combination with 1 or 2 other DAAs with lower barriers to resistance, or the combination of 3 DAAs with lower barriers to resistance.11 Ribavirin has broad-spectrum antiviral activity, one of which is anti-HCV activity. The mode of action of RBV against HCV is not well understood, but several mechanisms have been proposed, one of which is via inhibition of viral-dependent RNA polymerase.
Current HCV Treatment Recommendations
Current treatment recommendations are available from the American Association for the Study of the Liver Disease (AASLD) and the Infectious Diseases Society of America (IDSA) (http://www.hcvguidelines.org); the VA National Hepatitis C Resource Center Program and Office of Public Health (http://www.hepatitis.va.gov/pdf/2014hcv.pdf); and the European Association for the Study of the Liver (EASL) (http://www.easl.eu/_newsroom/latest-news/easl-recommendations-on-treatment-of-hepatitis-c-2014). These recommendations are updated frequently as new drugs enter the marketplace (Table 1).14-16
Since most patients are unable or unwilling to tolerate interferon, the majority of patients in treatment are currently receiving interferon-free combinations. Treatment of genotype 1 is currently dominated by the offlabel use of sofosbuvir in combination with simeprevir. Data have been published from a single phase II trial in patients with and without cirrhosis.7 Of note are emerging data from observational studies confirming the efficacy of over 80% SVR in patients with cirrhosis and genotype 1a with or without prior treatment.17 Treatment of patients with genotype 2 infection is dominated by the use of sofosbuvir and RBV combination. However, patients with cirrhosis do not respond as well as patients without cirrhosis, and it remains to be seen whether extending therapy is of any benefit.
One exception for the use of PEG is the recommendation for patients with HCV genotype 3 and cirrhosis to consider the combination of PEG, RBV, and sofosbuvir for 12 weeks.18 This has the advantage of being more effective, less costly, and shorter treatment duration compared with the sofosbuvir and RBV association but is only appropriate for patients who can tolerate interferon. Common AEs and potential contraindications to treatment are listed in Table 2.5-10,19 
New Treatment Options for HCV in 2015
Figure 3 details DAA combinations currently in phase III trials that are expected to receive approval in 2015. This will expand the repertoire of drug combinations available and enable fine-tuning of regimens according to patient and viral characteristics and cost requirements. 
Cost and Effectiveness
Cost-effectiveness issues are of immediate importance for health care systems and payors. The first generation PIs, boceprevir and telaprevir, were used in combination with PEG and RBV and entailed pharmacy costs on par with current noninterferon regimens.20,21 Studies generally demonstrated that these treatments are cost-effective, especially in patients with advanced fibrosis. Ollendorf and colleagues recently published an analysis of the costs of using interferon-free regimens for treatment of 540,000 patients with chronic HCV in California.22 Assuming that 50% of patients would present for treatment, the cost of the new DAAs would be immense and result in an increase in costs from $12 billion to $34 billion in the first year and net costs of $6 billion by the 20th year. If treatment were limited to patients with advanced cirrhosis, the first year costs would be increased by $7 billion, but at 20 years there would be approximately $1 billion in net cost savings.
For current treatments, a 12-week course of simeprevir/sofosbuvir has been shown to be more costeffective than 24 weeks of sofosbuvir/RBV for treatment
of genotype 1.23 Similarly, patients with genotype 1, no cirrhosis, and low viral load can be treated with 8 weeks of sofosbuvir/ledipasvir rather than other 12-week regimens, thereby reducing drug costs. The resources needed for upfront treatment of patients is of obvious concern, and various systems are struggling to determine how to provide access to these pharmaceuticals. Prioritizing patients according to risk for advanced fibrosis using noninvasive scoring systems should be used if there is limited access or resources.
Conclusion
Since the VA has a large population of patients with HCV infection, the advancement in HCV treatment is of paramount importance. The advent of new DAAs in 2011 improved treatment efficacy for patients with HCV, but few patients could be treated due to AEs related to PEG. In 2013, new DAAs were introduced that did not require conjunctive therapy with PEG, providing a treatment option for patients who could not tolerate PEG. New DAA combinations are currently in trials and, upon approval, will provide more options for patients with HCV infection.
Author disclosures
Dr. Ho has received research and grant support from Genentech, Inc. and Gilead; he is on the speakers’ bureau for Prime Education, Inc. The other authors report no actual or potential conflicts of interest with regard to this article.
Grant Support
Funding provided by VA HSR&D grant IIR-13-052-2, VA HIV/HCV QUERI program, and the Research Service of the Department of Veterans Affairs.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
1. Backus LI, Belperio PS, Loomis TP, Yip GH, Mole LA. Hepatitis C virus screening and prevalence among US veterans in Department of Veterans Affairs care. JAMA Intern Med. 2013;173(16):1549-1552.
2. Backus LI, Boothroyd DB, Phillips BR, Mole LA. Predictors of response of US veterans to treatment for the hepatitis C virus. Hepatology. 2007;46(1):37-47.
3. Backus LI, Belperio PS, Shahoumian TA, Cheung R, Mole LA. Comparative effectiveness of the hepatitis C virus protease inhibitors boceprevir and telaprevir in a large U.S. cohort. Aliment Pharmacol Ther. 2014;39(1):93-103.
4. Ioannou GN, Beste LA, Green PK. Similar effectiveness of boceprevir and telaprevir treatment regimens for hepatitis C virus infection on the basis of a nationwide study of veterans. Clin Gastroenterol Hepatol. 2014;12(8):1371-1380.
5. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-1887.
6. Jacobson IM, Gordon SC, Kowdley KV, et al; POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877.
7. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet. 2014;384(9956):1756-1765.
8. Afdhal N, Reddy KR, Nelson DR, et al; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(16):1483-1493.
9. Afdhal N, Zeuzem S, Kwo P, et al; ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889-1898
10. Kowdley KV, Gordon SC, Reddy KR, et al; ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-1888.
11. Pawlotsky JM. New hepatitis C virus (HCV) drugs and the hope for a cure: Concepts in anti-HCV drug development. Semin Liver Dis. 2014;34(1):22-29.
12. Membreno FE, Espinales JC, Lawitz EJ. Cyclophilin inhibitors for hepatitis C therapy. Clin Liver Dis. 2013;17(1):129-139.
13. Janssen HL, Reesink HW, Lawitz EJ, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368(18):1685-1694.
14. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed November 25, 2014.
15. Department of Veterans Affairs. Chronic Hepatitis C Virus (HCV) Infection: Treatment considerations from the Department of Veterans Affairs National Hepatitis C Resource Center Program at the Office of Public Health. http://www.hepatitis.va.gov/pdf/2014hcv.pdf. Revised May 13, 2014. Accessed November 25, 2014.
16. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C in 2014. http://www.easl.eu/_newsroom/latest-news/easl-recommendations-on-treatment-of-hepatitis-c-2014. Accessed November 25, 2014.
17. Dieterich D, Bacon BR, Flamm SL, et al. Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network: academic and community treatment of a real-world, heterogeneous population. Hepatology. 2014;60(suppl S1):220A. Abstract 46.
18. Lawitz EJ, Poordad F, Brainard D, et al. Sofosbuvir with peginterferon-ribavirin for 12 weeks in previously treated patients with hepatitis C genotype 2 or 3 and cirrhosis [published online ahead of print October 16, 2014]. Hepatology. 2014; doi:10.1002/hep.27567.
19. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370(3):211-221.
20. Liu S, Cipriano LE, Holodniy M, Owens DK, Goldhaber-Fiebert JD. New protease inhibitors for the treatment of chronic hepatitis C: a cost-effectiveness analysis. Ann Intern Med. 2012;156(4):279-290.
21. Chan K, Lai MN, Groessl EJ, et al. Cost effectiveness of direct-acting antiviral
therapy for treatment-naive patients with chronic HCV genotype 1 infection in the veterans health administration. Clin Gastroenterol Hepatol. 2013;11(11):1503-1510.
22. Ollendorf DA, Tice JA, Pearson SD. The comparative clinical effectiveness and value of simeprevir and sofosbuvir for chronic hepatitis C virus infection. JAMA Intern Med. 2014;174(7):1170-1171.
23. Hagan LM, Sulkowski MS, Schinazi RF. Cost analysis of sofosbuvir/ribavirin versus sofosbuvir/simeprevir for genotype 1 hepatitis C virus in interferon-ineligible/intolerant individuals. Hepatology. 2014;60(1):37-45.
Hepatitis C virus (HCV) infection remains a significant problem in the VA system, with over 174,000 current actively infected patients.1 Despite the availability of antiviral treatment since the early 1990’s, only approximately 26% of patients have ever been treated. These treatments required the use of pegylated interferon alfa (PEG) and ribavirin (RBV), which are associated with significant adverse events (AEs) that prevented many from receiving the treatment. Of those treated, only a minority achieved a sustained virologic response (SVR), due to the limited efficacy of the treatments (Figure 1).2 With the advent of new direct-acting antiviral (DAA) treatments in 2011, treatment efficacy improved.
The first DAAs in use were the viral nonstructural protein 3/4A (NS3/4A) serine protease inhibitors (PIs) boceprevir and telaprevir, which were used with PEG and RBV for patients with HCV genotype 1 infection. This combination therapy improved SVR rates from about 26% to 50% in patients with HCV genotype 1 in the VA.3,4 However, due to the significant AEs with these combinations, relatively few patients were treated.
In late 2013, the FDA approved other DAAs, which allowed patients to be treated effectively without PEG. These included the nucleotide nonstructural protein 5B (NS5B) polymerase inhibitor sofosbuvir and a secondgeneration NS3/4A PI simeprevir.5-7 The first nucleotide analog NS5B polymerase inhibitor, sofosbuvir and the nonstructural protein 5A (NS5A) replication complex inhibitor, ledipasvir, was approved in October 2014.8-10 The recent developments in noninterferon treatments have been accompanied by revised treatment guidelines or recommendations by major professional societies. Current treatment recommendations will be reviewed here, but the recommendations will continue to evolve as new DAAs come to market.
DAA Sites of Action
The HCV genome is a positive-stranded RNA molecule of about 9,500 nucleotides, which encodes a polyprotein of approximately 3,000 amino acids that form 10 individual viral proteins. These are composed of both structural and nonstructural (NS) proteins that are responsible for replication of the genome and formation of new viral particles. Understanding of the HCV-encoded proteins and their functions has permitted the development of different DAA therapies. In general, targeting a single protein is not effective, and combination therapy targeting 2 proteins is required for viral eradication (Figure 2).11 The 3 drug targets that are currently available include NS3/4A serine PIs (eg, simeprevir, boceprevir, telaprevir), NS5A replication complex inhibitors (eg, ledipasvir, daclatasvir), and NS5B RNA-dependent RNA polymerase inhibitors (eg, sofosbuvir).
Other DAA’s are in development that have targets in host rather than viral cells. These include cycolphilin A inhibitors and the micro-RNA (miR-122) antagonist miravirsen.12,13
The RNA-dependent RNA polymerase, encoded by the HCV NS5B is targeted by 2 classes of inhibitors: nucleoside or nucleotide analog inhibitors (NIs), and non-nucleoside inhibitors (NNIs).11 The only NI of the NS5B protein approved by the FDA is sofosbuvir. The resistance profiles of NIs and NNIs differ, because they bind to distinct sites on the NS5B protein. NIs are analogs of natural substrates and bind to the active site of the RNA polymerase, whereas NNIs are allosteric site inhibitors. NIs have activity in vitro against all HCV genotypes and have high barrier to resistance as the active site of NS5B polymerase is less tolerant of different amino acid substitutions.
In vitro studies have demonstrated that NIs are less likely to select for mutations compared with NNIs and PIs. The NNIs have limited genotypic coverage and have a lower barrier to resistance. Strategies for targeting HCV proteins include using a NI NS5B protein inhibitor as the backbone with a high barrier to resistance in combination with 1 or 2 other DAAs with lower barriers to resistance, or the combination of 3 DAAs with lower barriers to resistance.11 Ribavirin has broad-spectrum antiviral activity, one of which is anti-HCV activity. The mode of action of RBV against HCV is not well understood, but several mechanisms have been proposed, one of which is via inhibition of viral-dependent RNA polymerase.
Current HCV Treatment Recommendations
Current treatment recommendations are available from the American Association for the Study of the Liver Disease (AASLD) and the Infectious Diseases Society of America (IDSA) (http://www.hcvguidelines.org); the VA National Hepatitis C Resource Center Program and Office of Public Health (http://www.hepatitis.va.gov/pdf/2014hcv.pdf); and the European Association for the Study of the Liver (EASL) (http://www.easl.eu/_newsroom/latest-news/easl-recommendations-on-treatment-of-hepatitis-c-2014). These recommendations are updated frequently as new drugs enter the marketplace (Table 1).14-16
Since most patients are unable or unwilling to tolerate interferon, the majority of patients in treatment are currently receiving interferon-free combinations. Treatment of genotype 1 is currently dominated by the offlabel use of sofosbuvir in combination with simeprevir. Data have been published from a single phase II trial in patients with and without cirrhosis.7 Of note are emerging data from observational studies confirming the efficacy of over 80% SVR in patients with cirrhosis and genotype 1a with or without prior treatment.17 Treatment of patients with genotype 2 infection is dominated by the use of sofosbuvir and RBV combination. However, patients with cirrhosis do not respond as well as patients without cirrhosis, and it remains to be seen whether extending therapy is of any benefit.
One exception for the use of PEG is the recommendation for patients with HCV genotype 3 and cirrhosis to consider the combination of PEG, RBV, and sofosbuvir for 12 weeks.18 This has the advantage of being more effective, less costly, and shorter treatment duration compared with the sofosbuvir and RBV association but is only appropriate for patients who can tolerate interferon. Common AEs and potential contraindications to treatment are listed in Table 2.5-10,19
New Treatment Options for HCV in 2015
Figure 3 details DAA combinations currently in phase III trials that are expected to receive approval in 2015. This will expand the repertoire of drug combinations available and enable fine-tuning of regimens according to patient and viral characteristics and cost requirements.
Cost and Effectiveness
Cost-effectiveness issues are of immediate importance for health care systems and payors. The first generation PIs, boceprevir and telaprevir, were used in combination with PEG and RBV and entailed pharmacy costs on par with current noninterferon regimens.20,21 Studies generally demonstrated that these treatments are cost-effective, especially in patients with advanced fibrosis. Ollendorf and colleagues recently published an analysis of the costs of using interferon-free regimens for treatment of 540,000 patients with chronic HCV in California.22 Assuming that 50% of patients would present for treatment, the cost of the new DAAs would be immense and result in an increase in costs from $12 billion to $34 billion in the first year and net costs of $6 billion by the 20th year. If treatment were limited to patients with advanced cirrhosis, the first year costs would be increased by $7 billion, but at 20 years there would be approximately $1 billion in net cost savings.
For current treatments, a 12-week course of simeprevir/sofosbuvir has been shown to be more costeffective than 24 weeks of sofosbuvir/RBV for treatment
of genotype 1.23 Similarly, patients with genotype 1, no cirrhosis, and low viral load can be treated with 8 weeks of sofosbuvir/ledipasvir rather than other 12-week regimens, thereby reducing drug costs. The resources needed for upfront treatment of patients is of obvious concern, and various systems are struggling to determine how to provide access to these pharmaceuticals. Prioritizing patients according to risk for advanced fibrosis using noninvasive scoring systems should be used if there is limited access or resources.
Conclusion
Since the VA has a large population of patients with HCV infection, the advancement in HCV treatment is of paramount importance. The advent of new DAAs in 2011 improved treatment efficacy for patients with HCV, but few patients could be treated due to AEs related to PEG. In 2013, new DAAs were introduced that did not require conjunctive therapy with PEG, providing a treatment option for patients who could not tolerate PEG. New DAA combinations are currently in trials and, upon approval, will provide more options for patients with HCV infection.
Author disclosures
Dr. Ho has received research and grant support from Genentech, Inc. and Gilead; he is on the speakers’ bureau for Prime Education, Inc. The other authors report no actual or potential conflicts of interest with regard to this article.
Grant Support
Funding provided by VA HSR&D grant IIR-13-052-2, VA HIV/HCV QUERI program, and the Research Service of the Department of Veterans Affairs.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Hepatitis C virus (HCV) infection remains a significant problem in the VA system, with over 174,000 current actively infected patients.1 Despite the availability of antiviral treatment since the early 1990’s, only approximately 26% of patients have ever been treated. These treatments required the use of pegylated interferon alfa (PEG) and ribavirin (RBV), which are associated with significant adverse events (AEs) that prevented many from receiving the treatment. Of those treated, only a minority achieved a sustained virologic response (SVR), due to the limited efficacy of the treatments (Figure 1).2 With the advent of new direct-acting antiviral (DAA) treatments in 2011, treatment efficacy improved.
The first DAAs in use were the viral nonstructural protein 3/4A (NS3/4A) serine protease inhibitors (PIs) boceprevir and telaprevir, which were used with PEG and RBV for patients with HCV genotype 1 infection. This combination therapy improved SVR rates from about 26% to 50% in patients with HCV genotype 1 in the VA.3,4 However, due to the significant AEs with these combinations, relatively few patients were treated.
In late 2013, the FDA approved other DAAs, which allowed patients to be treated effectively without PEG. These included the nucleotide nonstructural protein 5B (NS5B) polymerase inhibitor sofosbuvir and a secondgeneration NS3/4A PI simeprevir.5-7 The first nucleotide analog NS5B polymerase inhibitor, sofosbuvir and the nonstructural protein 5A (NS5A) replication complex inhibitor, ledipasvir, was approved in October 2014.8-10 The recent developments in noninterferon treatments have been accompanied by revised treatment guidelines or recommendations by major professional societies. Current treatment recommendations will be reviewed here, but the recommendations will continue to evolve as new DAAs come to market.
DAA Sites of Action
The HCV genome is a positive-stranded RNA molecule of about 9,500 nucleotides, which encodes a polyprotein of approximately 3,000 amino acids that form 10 individual viral proteins. These are composed of both structural and nonstructural (NS) proteins that are responsible for replication of the genome and formation of new viral particles. Understanding of the HCV-encoded proteins and their functions has permitted the development of different DAA therapies. In general, targeting a single protein is not effective, and combination therapy targeting 2 proteins is required for viral eradication (Figure 2).11 The 3 drug targets that are currently available include NS3/4A serine PIs (eg, simeprevir, boceprevir, telaprevir), NS5A replication complex inhibitors (eg, ledipasvir, daclatasvir), and NS5B RNA-dependent RNA polymerase inhibitors (eg, sofosbuvir).
Other DAA’s are in development that have targets in host rather than viral cells. These include cycolphilin A inhibitors and the micro-RNA (miR-122) antagonist miravirsen.12,13
The RNA-dependent RNA polymerase, encoded by the HCV NS5B is targeted by 2 classes of inhibitors: nucleoside or nucleotide analog inhibitors (NIs), and non-nucleoside inhibitors (NNIs).11 The only NI of the NS5B protein approved by the FDA is sofosbuvir. The resistance profiles of NIs and NNIs differ, because they bind to distinct sites on the NS5B protein. NIs are analogs of natural substrates and bind to the active site of the RNA polymerase, whereas NNIs are allosteric site inhibitors. NIs have activity in vitro against all HCV genotypes and have high barrier to resistance as the active site of NS5B polymerase is less tolerant of different amino acid substitutions.
In vitro studies have demonstrated that NIs are less likely to select for mutations compared with NNIs and PIs. The NNIs have limited genotypic coverage and have a lower barrier to resistance. Strategies for targeting HCV proteins include using a NI NS5B protein inhibitor as the backbone with a high barrier to resistance in combination with 1 or 2 other DAAs with lower barriers to resistance, or the combination of 3 DAAs with lower barriers to resistance.11 Ribavirin has broad-spectrum antiviral activity, one of which is anti-HCV activity. The mode of action of RBV against HCV is not well understood, but several mechanisms have been proposed, one of which is via inhibition of viral-dependent RNA polymerase.
Current HCV Treatment Recommendations
Current treatment recommendations are available from the American Association for the Study of the Liver Disease (AASLD) and the Infectious Diseases Society of America (IDSA) (http://www.hcvguidelines.org); the VA National Hepatitis C Resource Center Program and Office of Public Health (http://www.hepatitis.va.gov/pdf/2014hcv.pdf); and the European Association for the Study of the Liver (EASL) (http://www.easl.eu/_newsroom/latest-news/easl-recommendations-on-treatment-of-hepatitis-c-2014). These recommendations are updated frequently as new drugs enter the marketplace (Table 1).14-16
Since most patients are unable or unwilling to tolerate interferon, the majority of patients in treatment are currently receiving interferon-free combinations. Treatment of genotype 1 is currently dominated by the offlabel use of sofosbuvir in combination with simeprevir. Data have been published from a single phase II trial in patients with and without cirrhosis.7 Of note are emerging data from observational studies confirming the efficacy of over 80% SVR in patients with cirrhosis and genotype 1a with or without prior treatment.17 Treatment of patients with genotype 2 infection is dominated by the use of sofosbuvir and RBV combination. However, patients with cirrhosis do not respond as well as patients without cirrhosis, and it remains to be seen whether extending therapy is of any benefit.
One exception for the use of PEG is the recommendation for patients with HCV genotype 3 and cirrhosis to consider the combination of PEG, RBV, and sofosbuvir for 12 weeks.18 This has the advantage of being more effective, less costly, and shorter treatment duration compared with the sofosbuvir and RBV association but is only appropriate for patients who can tolerate interferon. Common AEs and potential contraindications to treatment are listed in Table 2.5-10,19
New Treatment Options for HCV in 2015
Figure 3 details DAA combinations currently in phase III trials that are expected to receive approval in 2015. This will expand the repertoire of drug combinations available and enable fine-tuning of regimens according to patient and viral characteristics and cost requirements.
Cost and Effectiveness
Cost-effectiveness issues are of immediate importance for health care systems and payors. The first generation PIs, boceprevir and telaprevir, were used in combination with PEG and RBV and entailed pharmacy costs on par with current noninterferon regimens.20,21 Studies generally demonstrated that these treatments are cost-effective, especially in patients with advanced fibrosis. Ollendorf and colleagues recently published an analysis of the costs of using interferon-free regimens for treatment of 540,000 patients with chronic HCV in California.22 Assuming that 50% of patients would present for treatment, the cost of the new DAAs would be immense and result in an increase in costs from $12 billion to $34 billion in the first year and net costs of $6 billion by the 20th year. If treatment were limited to patients with advanced cirrhosis, the first year costs would be increased by $7 billion, but at 20 years there would be approximately $1 billion in net cost savings.
For current treatments, a 12-week course of simeprevir/sofosbuvir has been shown to be more costeffective than 24 weeks of sofosbuvir/RBV for treatment
of genotype 1.23 Similarly, patients with genotype 1, no cirrhosis, and low viral load can be treated with 8 weeks of sofosbuvir/ledipasvir rather than other 12-week regimens, thereby reducing drug costs. The resources needed for upfront treatment of patients is of obvious concern, and various systems are struggling to determine how to provide access to these pharmaceuticals. Prioritizing patients according to risk for advanced fibrosis using noninvasive scoring systems should be used if there is limited access or resources.
Conclusion
Since the VA has a large population of patients with HCV infection, the advancement in HCV treatment is of paramount importance. The advent of new DAAs in 2011 improved treatment efficacy for patients with HCV, but few patients could be treated due to AEs related to PEG. In 2013, new DAAs were introduced that did not require conjunctive therapy with PEG, providing a treatment option for patients who could not tolerate PEG. New DAA combinations are currently in trials and, upon approval, will provide more options for patients with HCV infection.
Author disclosures
Dr. Ho has received research and grant support from Genentech, Inc. and Gilead; he is on the speakers’ bureau for Prime Education, Inc. The other authors report no actual or potential conflicts of interest with regard to this article.
Grant Support
Funding provided by VA HSR&D grant IIR-13-052-2, VA HIV/HCV QUERI program, and the Research Service of the Department of Veterans Affairs.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
1. Backus LI, Belperio PS, Loomis TP, Yip GH, Mole LA. Hepatitis C virus screening and prevalence among US veterans in Department of Veterans Affairs care. JAMA Intern Med. 2013;173(16):1549-1552.
2. Backus LI, Boothroyd DB, Phillips BR, Mole LA. Predictors of response of US veterans to treatment for the hepatitis C virus. Hepatology. 2007;46(1):37-47.
3. Backus LI, Belperio PS, Shahoumian TA, Cheung R, Mole LA. Comparative effectiveness of the hepatitis C virus protease inhibitors boceprevir and telaprevir in a large U.S. cohort. Aliment Pharmacol Ther. 2014;39(1):93-103.
4. Ioannou GN, Beste LA, Green PK. Similar effectiveness of boceprevir and telaprevir treatment regimens for hepatitis C virus infection on the basis of a nationwide study of veterans. Clin Gastroenterol Hepatol. 2014;12(8):1371-1380.
5. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-1887.
6. Jacobson IM, Gordon SC, Kowdley KV, et al; POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877.
7. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet. 2014;384(9956):1756-1765.
8. Afdhal N, Reddy KR, Nelson DR, et al; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(16):1483-1493.
9. Afdhal N, Zeuzem S, Kwo P, et al; ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889-1898
10. Kowdley KV, Gordon SC, Reddy KR, et al; ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-1888.
11. Pawlotsky JM. New hepatitis C virus (HCV) drugs and the hope for a cure: Concepts in anti-HCV drug development. Semin Liver Dis. 2014;34(1):22-29.
12. Membreno FE, Espinales JC, Lawitz EJ. Cyclophilin inhibitors for hepatitis C therapy. Clin Liver Dis. 2013;17(1):129-139.
13. Janssen HL, Reesink HW, Lawitz EJ, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368(18):1685-1694.
14. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed November 25, 2014.
15. Department of Veterans Affairs. Chronic Hepatitis C Virus (HCV) Infection: Treatment considerations from the Department of Veterans Affairs National Hepatitis C Resource Center Program at the Office of Public Health. http://www.hepatitis.va.gov/pdf/2014hcv.pdf. Revised May 13, 2014. Accessed November 25, 2014.
16. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C in 2014. http://www.easl.eu/_newsroom/latest-news/easl-recommendations-on-treatment-of-hepatitis-c-2014. Accessed November 25, 2014.
17. Dieterich D, Bacon BR, Flamm SL, et al. Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network: academic and community treatment of a real-world, heterogeneous population. Hepatology. 2014;60(suppl S1):220A. Abstract 46.
18. Lawitz EJ, Poordad F, Brainard D, et al. Sofosbuvir with peginterferon-ribavirin for 12 weeks in previously treated patients with hepatitis C genotype 2 or 3 and cirrhosis [published online ahead of print October 16, 2014]. Hepatology. 2014; doi:10.1002/hep.27567.
19. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370(3):211-221.
20. Liu S, Cipriano LE, Holodniy M, Owens DK, Goldhaber-Fiebert JD. New protease inhibitors for the treatment of chronic hepatitis C: a cost-effectiveness analysis. Ann Intern Med. 2012;156(4):279-290.
21. Chan K, Lai MN, Groessl EJ, et al. Cost effectiveness of direct-acting antiviral
therapy for treatment-naive patients with chronic HCV genotype 1 infection in the veterans health administration. Clin Gastroenterol Hepatol. 2013;11(11):1503-1510.
22. Ollendorf DA, Tice JA, Pearson SD. The comparative clinical effectiveness and value of simeprevir and sofosbuvir for chronic hepatitis C virus infection. JAMA Intern Med. 2014;174(7):1170-1171.
23. Hagan LM, Sulkowski MS, Schinazi RF. Cost analysis of sofosbuvir/ribavirin versus sofosbuvir/simeprevir for genotype 1 hepatitis C virus in interferon-ineligible/intolerant individuals. Hepatology. 2014;60(1):37-45.
1. Backus LI, Belperio PS, Loomis TP, Yip GH, Mole LA. Hepatitis C virus screening and prevalence among US veterans in Department of Veterans Affairs care. JAMA Intern Med. 2013;173(16):1549-1552.
2. Backus LI, Boothroyd DB, Phillips BR, Mole LA. Predictors of response of US veterans to treatment for the hepatitis C virus. Hepatology. 2007;46(1):37-47.
3. Backus LI, Belperio PS, Shahoumian TA, Cheung R, Mole LA. Comparative effectiveness of the hepatitis C virus protease inhibitors boceprevir and telaprevir in a large U.S. cohort. Aliment Pharmacol Ther. 2014;39(1):93-103.
4. Ioannou GN, Beste LA, Green PK. Similar effectiveness of boceprevir and telaprevir treatment regimens for hepatitis C virus infection on the basis of a nationwide study of veterans. Clin Gastroenterol Hepatol. 2014;12(8):1371-1380.
5. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-1887.
6. Jacobson IM, Gordon SC, Kowdley KV, et al; POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867-1877.
7. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet. 2014;384(9956):1756-1765.
8. Afdhal N, Reddy KR, Nelson DR, et al; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(16):1483-1493.
9. Afdhal N, Zeuzem S, Kwo P, et al; ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889-1898
10. Kowdley KV, Gordon SC, Reddy KR, et al; ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-1888.
11. Pawlotsky JM. New hepatitis C virus (HCV) drugs and the hope for a cure: Concepts in anti-HCV drug development. Semin Liver Dis. 2014;34(1):22-29.
12. Membreno FE, Espinales JC, Lawitz EJ. Cyclophilin inhibitors for hepatitis C therapy. Clin Liver Dis. 2013;17(1):129-139.
13. Janssen HL, Reesink HW, Lawitz EJ, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368(18):1685-1694.
14. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed November 25, 2014.
15. Department of Veterans Affairs. Chronic Hepatitis C Virus (HCV) Infection: Treatment considerations from the Department of Veterans Affairs National Hepatitis C Resource Center Program at the Office of Public Health. http://www.hepatitis.va.gov/pdf/2014hcv.pdf. Revised May 13, 2014. Accessed November 25, 2014.
16. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C in 2014. http://www.easl.eu/_newsroom/latest-news/easl-recommendations-on-treatment-of-hepatitis-c-2014. Accessed November 25, 2014.
17. Dieterich D, Bacon BR, Flamm SL, et al. Evaluation of sofosbuvir and simeprevir-based regimens in the TRIO network: academic and community treatment of a real-world, heterogeneous population. Hepatology. 2014;60(suppl S1):220A. Abstract 46.
18. Lawitz EJ, Poordad F, Brainard D, et al. Sofosbuvir with peginterferon-ribavirin for 12 weeks in previously treated patients with hepatitis C genotype 2 or 3 and cirrhosis [published online ahead of print October 16, 2014]. Hepatology. 2014; doi:10.1002/hep.27567.
19. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370(3):211-221.
20. Liu S, Cipriano LE, Holodniy M, Owens DK, Goldhaber-Fiebert JD. New protease inhibitors for the treatment of chronic hepatitis C: a cost-effectiveness analysis. Ann Intern Med. 2012;156(4):279-290.
21. Chan K, Lai MN, Groessl EJ, et al. Cost effectiveness of direct-acting antiviral
therapy for treatment-naive patients with chronic HCV genotype 1 infection in the veterans health administration. Clin Gastroenterol Hepatol. 2013;11(11):1503-1510.
22. Ollendorf DA, Tice JA, Pearson SD. The comparative clinical effectiveness and value of simeprevir and sofosbuvir for chronic hepatitis C virus infection. JAMA Intern Med. 2014;174(7):1170-1171.
23. Hagan LM, Sulkowski MS, Schinazi RF. Cost analysis of sofosbuvir/ribavirin versus sofosbuvir/simeprevir for genotype 1 hepatitis C virus in interferon-ineligible/intolerant individuals. Hepatology. 2014;60(1):37-45.
The State of Hepatitis C Care in the VA
As the largest single provider of hepatitis C virus infection (HCV) care in the U.S., the VA provided care to > 174,000 veterans with chronic HCV in 2013. Identifying veterans most likely to be infected with HCV, particularly those in the highrisk birth cohort born between 1945 and 1965, is a priority given recent CDC and U.S. Preventive Services Task Force (USPSTF) recommendations.1,2 The availability of new, all-oral HCV antiviral regimens with shorter treatment durations and improved tolerability are expected to greatly increase the number of veterans with HCV who could be treated successfully. In order to effectively reach those who are undiagnosed and to ensure that those diagnosed with HCV are evaluated and offered treatment, expanded reliance on primary care providers (PCPs) is essential. This article provides a population view of the current state of VA care for this large HCV-infected population and the important role PCPs share in disease identification and management.
Data Source
Data regarding the state of HCV care in the VA comes from the VA National Clinical Case Registry (CCR) for HCV.3 The VA HCV CCR is an extract of the VA electronic medical record that contains laboratory results, pharmacy information, provider information, and ICD-9 diagnosis codes from inpatient hospitalizations, outpatient visits, and problem lists of veterans with HCV seen at all VAMCs.
Screening and Prevalence of HCV
It is estimated that 2.3 to 2.7 million Americans are living with HCV, with 45% to 85% of those unaware of their infection.4,5 Nearly 75% of those infected are expected to have been born between 1945 and 1965; thus, the CDC and USPSTF now recommend onetime HCV screening for this birth cohort.1,2 Among nearly 5.6 million veterans with a VA outpatient visit in 2013, 56% have been screened for HCV. The HCV screening rate was 42% for those born prior to 1945, 65% for those born during 1945-1965, and 59% for those born after 1965. HCV infection prevalence overall in the VA was 5.8% but differed markedly among the birth cohorts: 1.6% for those born prior to 1945, 9.5% for those born during 1945-1965, and 1.2% for those born after 1965. The prevalence rate of veterans born in the 1945-1965 birth cohort (9.5%) is almost 3 times higher than that of the general U.S. population in this birth cohort (2.4%). The high prevalence serves as a reminder of the greater HCV disease burden in veterans and largely represents Vietman era veterans. Although HCV screening rates in VA have increased over 25% since 2002, the high prevalence among veterans in this birth cohort underscores the importance of continued screening efforts.
Veterans with Chronic HCV Infection
The VA Office of Public Health/Population Health generates national HCV reports annually from the HCV CCR describing the population of veterans with chronic HCV infection receiving VA care. These reports are intended to inform about patient care activities, clinician and patient education, prevention activities, and research directed at continuous improvement of veteran care. The first step in providing responsive care is understanding the affected population, and summarized herein is a description of the veterans with chronic HCV who received VA care in 2013.
In 2013, 174,302 veterans had laboratory evidence of HCV viremia and could be characterized as having chronic HCV. HCV treatment regimens and response depend on the viral genotype. Among veterans with genotype testing, 107,144 (80%) have genotype 1; 15,486 (12%) genotype 2; 9,745 (7%) genotype 3; 1333 (1%) genotype 4; and 63 (< 1%) genotype 5 or 6.
In terms of demographics, most veterans with chronic HCV in VA care in 2013 were men (97%); however, > 5,000 women veterans with chronic HCV received care from the VA. Over half (54%) of veterans with chronic HCV are white, and about one-third (34%) are black. The proportion of blacks within the HCV-infected veteran population is substantially greater than the proportion of blacks in the overall veteran population in VA care (15%) and highlights the disproportionately large burden of HCV that black veterans bear. A smaller proportion of the VA HCV population is Hispanic (6%), and the remaining veterans are other races, multiple races, or unknown.
The HCV-infected veteran population is aging. The mean age of veterans with chronic HCV in 2013 was 59.7 years and for the first time, more veterans with HCV were aged 60 years (Figure 1). 
Among the comorbidities that may have historically prevented veterans from receiving HCV antiviral therapy, 2 of the most pervasive are mental health conditions and alcohol use. The rates of mental illness among veterans overall is high, but mental illness is particularly high in veterans with HCV. Depression has affected 60%; of this population anxiety, 37%; posttraumatic stress disorder, 28%; and schizophrenia, 10%. Alcohol use disorders are also common among veterans with HCV in care. Active mental health conditions and substance use may affect medication adherence or follow-up visit adherence thereby limiting treatment candidacy. Integrating care of these individuals with mental health providers and substance-use treatment specialists is an important aspect of HCV care and is a priority in VA.
Three-quarters (76%) of the HCV-infected veteran population has been screened for HIV and HIV-HCV co-infection is present in 5733 (3%) of veterans with HCV. HIV-HCV co-infection is associated with an increased progression of liver disease and may have implications for the selection of HCV antiviral agents because of drug interactions. Hepatitis B virus (HBV)-HCV co-infection rates are higher at 7%. HBV vaccination or documentation of HBV immunity in those without HBV infection is 78%.
With regard to specific liver complications, 5% to 20% of those infected with chronic HCV will develop cirrhosis over a period of 20 to 30 years, and 1% to 5% will die of hepatocellular carcinoma (HCC) or cirrhosis.6 Given the natural history of chronic HCV and the aging HCV veteran cohort, increasing numbers of conditions related to progression of liver disease are expected over time. This is most evident in the number of veterans with a diagnosis of cirrhosis, which has increased from approximately 10,000 veterans (8%) in care in 2001 to nearly 30,000 veterans (17%) in care in 2013 (Figure 2). 
Antiviral Therapy for Chronic HCV
Prior to mid-2011, the standard of care for HCV treatment was the combination of pegylated interferon and ribavirin. From 2011 through 2013, direct-acting antiviral (DAA) regimens containing boceprevir and telaprevir in combination with pegylated interferon and ribavirin became standard of care for genotype 1 while
the standard of care remained pegylated interferon and ribavirin for genotypes other than genotype 1. Recent advances in HCV antiviral therapy offer higher cure rates and fewer adverse events (AEs) compared with peginterferon-containing treatment. The expected ease and tolerability of these all-oral combination regimens is anticipated to greatly increase the number of veterans with HCV who could be treated successfully.
Because of the poor tolerability, prolonged treatment durations, serious AEs, and relative or absolute contraindications to peginterferon-based therapy, many veterans were not previously candidates for treatment. Of the 174,302 veterans with chronic HCV in care in 2013, 39,388 (23%) had received at least 1 course of HCV antiviral treatment. This largely reflects the time when peginterferon-based therapy was the standard of care. Since the approval of boceprevir and telaprevir 5,732 veterans (5.8%) in care in 2013 had ever received boceprevir or telaprevir-based regimens.
While recognizing that all veterans should be considered for HCV treatment, the urgency for treatment may be greater in those with advanced liver disease, because these patients are at the highest risk of developing decompensated cirrhosis or dying of liver-related disease. In 2013, there were 28,945 veterans in care that had advanced liver disease who might be considered potential HCV treatment candidates with an urgency to treat.
Duration of treatment and anticipated rates of treatment success with the all-oral regimens depend in part on a patient’s prior treatment status in addition to whether the patient has a diagnosis of advanced liver disease/cirrhosis. Regardless of HCV genotype, among all veterans approximately 85% are treatment-naïve and 15% are treatment-experienced. Advanced liver disease is present in 24% of treatment-naïve and 31% of treatment-experienced veterans with HCV genotype 1; 23% and 24% of veterans with HCV genotype 2, respectively; and 34% and 43% of veterans with HCV genotype 3, respectively.
Further understanding the population of veterans with HCV, including prior treatment status and stage of liver disease, is useful in identifying the target population for treatment. The VA uses these data to project treatment costs and assess capacity across the system in preparation for expected uptake of new regimens.
Sustained Virologic Response After HCV Antiviral Treatment
The goal of HCV antiviral therapy is to eradicate HCV and reduce the progression of liver disease and death from HCV infection. Successful antiviral treatment of HCV is determined by achieving a sustained virologic response (SVR) defined as an undetectable HCV viral load 12 weeks after the end of treatment. Of the 39,388 veterans in VA care in 2013 who have ever received antiviral therapy, SVR could be assessed in 32,815 veterans, and the overall SVR rate in this population was 42%. This SVR rate is similar to that observed in phase III trials of pegylated interferon-based regimens, where 42% to 46% of those infected with HCV genotype 1 achieved SVR.7,8 Although most veterans with genotype 1 infection received boceprevir or telaprevir-based regimens in 2013 and achieved higher SVRs of 50% to 52%, the overwhelming majority of veterans in care in 2013 received prior treatment with only peginterferon and ribavirin.9 Although SVR rates are expected to increase with newer all-oral HCV regimens, differences between clinical efficacy and real-world effectiveness will continue to be apparent,
and patient and provider expectations should be tempered accordingly.
The Role of Primary Care in HCV
Primary care providers have held the responsibility for multiple roles in HCV care since the discovery of the virus—particularly for HCV risk factor assessment, screening, and diagnosis. HCV antiviral treatment, however, was largely placed in the hands of specialists, given the complexities of patient selection, frequent reliance on a liver biopsy for determining need for treatment, and the toxicities of peginterferon and ribavirin therapy.
There are discussions both inside and outside the VA about potentially expanding the role of PCPs in HCV care. First, primary care is the major setting where the CDC and USPSTF recommendations for birth cohort screening are being implemented, and thus PCPs will be identifying veterans previously undiagnosed with HCV.1,2 Second, the ease and tolerability of the new all-oral combination regimens is causing a shift in the paradigm for HCV treatment, from a highly individualized approach, toward a more uniform approach.
Expanding the role of primary care would have multiple benefits to patients and the health care system as a whole. Only approximately 9% of HCV-infected veterans in VA care have been successfully treated at this time, largely due to low eligibility rates and the poor response rates, but other barriers have also contributed to the low success rate, one of which has been limited access to specialists. Furthermore, veterans who are referred to specialists are often noncompliant with the referral.10 If seeing an HCV specialist is required for treatment, the time to treat the HCV population will be much greater, more costly, and less efficient. Therefore, if the prospect of delivering HCV treatment to the majority of HCV patients is to be accomplished, it is necessary to consider providing treatment in the primary care setting as well as the specialist setting.
Treatment provided by nonspecialists has been evaluated in patients receiving peginterferon and ribavirin regimens and has shown that with adequate education and support, SVR rates were equivalent in the specialist and nonspecialist setting.11 To develop programs to provide primary care with such support, the VA has implemented the Specialty Care Access Network-Extension of Community Healthcare Outcomes program initiative, with casebased learning along with real-time consultation.
Currently, the majority of HCV-infected patients have never seen an HCV specialist, thus PCPs are already providing the majority of HCV care beyond HCV antiviral
treatment.12 Primary care providers are, therefore, key to addressing multiple important aspects of HCV care, including (1) counseling patients on transmission, prevention, lifestyle, and the role of substance use; (2) providing hepatitis A and B vaccination as well as appropriate general vaccinations for any patient with chronic liver disease; (3) modifying comorbidities that could accelerate fibrosis progression, such as diabetes mellitus, obesity and hyperlipidemia; (4) reducing risk from ongoing alcohol, drug, and tobacco use; (5) monitoring patients for fibrosis progression and identifying the presence of cirrhosis; and (6) providing general care for patients with cirrhosis, including HCC screening. These are critical aspects of HCV care, and many PCPs may still need additional education for these roles. The VA provides education and support for PCPs in their current role and is enhancing efforts to expand delivery of HCV treatment to the primary care setting as well.
Conclusions
In 2013, the typical veteran with chronic HCV was white, aged 60 years, and male, with a history of comorbidities, including hypertension, depression, and current or prior alcohol abuse. The proportion of veterans with advanced liver disease including cirrhosis (17%) and HCC (3%), has grown significantly over the past 10 years. By the end of 2013, almost 40,000 veterans had received antiviral therapy for HCV, more than 5,700 of whom had received DAAs. Overall SVR rates have been about 42% among those who were treated. Of veterans who are still potential treatment candidates, 85% are treatment-naive and about one-quarter have advanced liver disease.
Although HCV screening rates in veterans are higher than reported in other health care settings, particularly among those in the critical 1945-1965 birth cohort (65% screening rate), substantial numbers of veterans still require testing. The burden of disease, the lack of specialists, the ease and tolerability of new HCV antiviral medications, and the interplay of HCV with other traditional primary care efforts underly an increased role for PCPs in the care of veterans with HCV. Together, this information helps to construct a view of historical, current, and future HCV care in veterans.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patient.
1. Smith BD, Morgan RL, Beckett GA, et al; Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965 [published correction appears in MMWR Recomm Rep. 2012;61(43):886]. MMWR Recomm Rep. 2012;61(RR-4):1-32.
2. Moyer VA; U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159(5):349-357.
3. Backus LI, Gavrilov S, Loomis TP, et al. Clinical Case Registries: Simultaneous local and national disease registries for population quality management. J Am Med Inform Assoc. 2009;16(6):775-783.
4. Kabiri M, Jazwinski AB, Roberts MS, Schaefer AJ, Chhatwal J. The changing burden of hepatitis C virus infection in the United States: Model-based predictions. Ann Intern Med. 2014;161(3):170-180
5. Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med. 2014;160(5):293-300
6. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: A population-based study. Gastroenterology. 2004;127(5):1372-1380.
7. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Lancet. 2001;358(9286):958-965.
8. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347(13):975-982.
9. Backus LI, Belperio PS, Shahoumian TA, Cheung R, Mole LA. Comparative effectiveness of the hepatitis C virus protease inhibitors boceprevir and telaprevir in a large U.S. cohort. Aliment Pharmacol Ther. 2014;39(1):93-103.
10. Brady CW, Coffman CJ, Provenzale D. Compliance with referral for hepatitis C evaluation among veterans. J Clin Gastroenterol. 2007;41(10):927-931.
11. Arora S, Thornton K, Murata G, et al. Outcomes of treatment for hepatitis C infection by primary care providers. N Engl J Med. 2011;364(23):2199-2207.
12. Holmberg SD, Spradling PR, Moorman AC, Denniston MM. Hepatitis C in the United States. N Engl J Med. 2013;368(20):1859-1861.
As the largest single provider of hepatitis C virus infection (HCV) care in the U.S., the VA provided care to > 174,000 veterans with chronic HCV in 2013. Identifying veterans most likely to be infected with HCV, particularly those in the highrisk birth cohort born between 1945 and 1965, is a priority given recent CDC and U.S. Preventive Services Task Force (USPSTF) recommendations.1,2 The availability of new, all-oral HCV antiviral regimens with shorter treatment durations and improved tolerability are expected to greatly increase the number of veterans with HCV who could be treated successfully. In order to effectively reach those who are undiagnosed and to ensure that those diagnosed with HCV are evaluated and offered treatment, expanded reliance on primary care providers (PCPs) is essential. This article provides a population view of the current state of VA care for this large HCV-infected population and the important role PCPs share in disease identification and management.
Data Source
Data regarding the state of HCV care in the VA comes from the VA National Clinical Case Registry (CCR) for HCV.3 The VA HCV CCR is an extract of the VA electronic medical record that contains laboratory results, pharmacy information, provider information, and ICD-9 diagnosis codes from inpatient hospitalizations, outpatient visits, and problem lists of veterans with HCV seen at all VAMCs.
Screening and Prevalence of HCV
It is estimated that 2.3 to 2.7 million Americans are living with HCV, with 45% to 85% of those unaware of their infection.4,5 Nearly 75% of those infected are expected to have been born between 1945 and 1965; thus, the CDC and USPSTF now recommend onetime HCV screening for this birth cohort.1,2 Among nearly 5.6 million veterans with a VA outpatient visit in 2013, 56% have been screened for HCV. The HCV screening rate was 42% for those born prior to 1945, 65% for those born during 1945-1965, and 59% for those born after 1965. HCV infection prevalence overall in the VA was 5.8% but differed markedly among the birth cohorts: 1.6% for those born prior to 1945, 9.5% for those born during 1945-1965, and 1.2% for those born after 1965. The prevalence rate of veterans born in the 1945-1965 birth cohort (9.5%) is almost 3 times higher than that of the general U.S. population in this birth cohort (2.4%). The high prevalence serves as a reminder of the greater HCV disease burden in veterans and largely represents Vietman era veterans. Although HCV screening rates in VA have increased over 25% since 2002, the high prevalence among veterans in this birth cohort underscores the importance of continued screening efforts.
Veterans with Chronic HCV Infection
The VA Office of Public Health/Population Health generates national HCV reports annually from the HCV CCR describing the population of veterans with chronic HCV infection receiving VA care. These reports are intended to inform about patient care activities, clinician and patient education, prevention activities, and research directed at continuous improvement of veteran care. The first step in providing responsive care is understanding the affected population, and summarized herein is a description of the veterans with chronic HCV who received VA care in 2013.
In 2013, 174,302 veterans had laboratory evidence of HCV viremia and could be characterized as having chronic HCV. HCV treatment regimens and response depend on the viral genotype. Among veterans with genotype testing, 107,144 (80%) have genotype 1; 15,486 (12%) genotype 2; 9,745 (7%) genotype 3; 1333 (1%) genotype 4; and 63 (< 1%) genotype 5 or 6.
In terms of demographics, most veterans with chronic HCV in VA care in 2013 were men (97%); however, > 5,000 women veterans with chronic HCV received care from the VA. Over half (54%) of veterans with chronic HCV are white, and about one-third (34%) are black. The proportion of blacks within the HCV-infected veteran population is substantially greater than the proportion of blacks in the overall veteran population in VA care (15%) and highlights the disproportionately large burden of HCV that black veterans bear. A smaller proportion of the VA HCV population is Hispanic (6%), and the remaining veterans are other races, multiple races, or unknown.
The HCV-infected veteran population is aging. The mean age of veterans with chronic HCV in 2013 was 59.7 years and for the first time, more veterans with HCV were aged 60 years (Figure 1).
Among the comorbidities that may have historically prevented veterans from receiving HCV antiviral therapy, 2 of the most pervasive are mental health conditions and alcohol use. The rates of mental illness among veterans overall is high, but mental illness is particularly high in veterans with HCV. Depression has affected 60%; of this population anxiety, 37%; posttraumatic stress disorder, 28%; and schizophrenia, 10%. Alcohol use disorders are also common among veterans with HCV in care. Active mental health conditions and substance use may affect medication adherence or follow-up visit adherence thereby limiting treatment candidacy. Integrating care of these individuals with mental health providers and substance-use treatment specialists is an important aspect of HCV care and is a priority in VA.
Three-quarters (76%) of the HCV-infected veteran population has been screened for HIV and HIV-HCV co-infection is present in 5733 (3%) of veterans with HCV. HIV-HCV co-infection is associated with an increased progression of liver disease and may have implications for the selection of HCV antiviral agents because of drug interactions. Hepatitis B virus (HBV)-HCV co-infection rates are higher at 7%. HBV vaccination or documentation of HBV immunity in those without HBV infection is 78%.
With regard to specific liver complications, 5% to 20% of those infected with chronic HCV will develop cirrhosis over a period of 20 to 30 years, and 1% to 5% will die of hepatocellular carcinoma (HCC) or cirrhosis.6 Given the natural history of chronic HCV and the aging HCV veteran cohort, increasing numbers of conditions related to progression of liver disease are expected over time. This is most evident in the number of veterans with a diagnosis of cirrhosis, which has increased from approximately 10,000 veterans (8%) in care in 2001 to nearly 30,000 veterans (17%) in care in 2013 (Figure 2).
Antiviral Therapy for Chronic HCV
Prior to mid-2011, the standard of care for HCV treatment was the combination of pegylated interferon and ribavirin. From 2011 through 2013, direct-acting antiviral (DAA) regimens containing boceprevir and telaprevir in combination with pegylated interferon and ribavirin became standard of care for genotype 1 while
the standard of care remained pegylated interferon and ribavirin for genotypes other than genotype 1. Recent advances in HCV antiviral therapy offer higher cure rates and fewer adverse events (AEs) compared with peginterferon-containing treatment. The expected ease and tolerability of these all-oral combination regimens is anticipated to greatly increase the number of veterans with HCV who could be treated successfully.
Because of the poor tolerability, prolonged treatment durations, serious AEs, and relative or absolute contraindications to peginterferon-based therapy, many veterans were not previously candidates for treatment. Of the 174,302 veterans with chronic HCV in care in 2013, 39,388 (23%) had received at least 1 course of HCV antiviral treatment. This largely reflects the time when peginterferon-based therapy was the standard of care. Since the approval of boceprevir and telaprevir 5,732 veterans (5.8%) in care in 2013 had ever received boceprevir or telaprevir-based regimens.
While recognizing that all veterans should be considered for HCV treatment, the urgency for treatment may be greater in those with advanced liver disease, because these patients are at the highest risk of developing decompensated cirrhosis or dying of liver-related disease. In 2013, there were 28,945 veterans in care that had advanced liver disease who might be considered potential HCV treatment candidates with an urgency to treat.
Duration of treatment and anticipated rates of treatment success with the all-oral regimens depend in part on a patient’s prior treatment status in addition to whether the patient has a diagnosis of advanced liver disease/cirrhosis. Regardless of HCV genotype, among all veterans approximately 85% are treatment-naïve and 15% are treatment-experienced. Advanced liver disease is present in 24% of treatment-naïve and 31% of treatment-experienced veterans with HCV genotype 1; 23% and 24% of veterans with HCV genotype 2, respectively; and 34% and 43% of veterans with HCV genotype 3, respectively.
Further understanding the population of veterans with HCV, including prior treatment status and stage of liver disease, is useful in identifying the target population for treatment. The VA uses these data to project treatment costs and assess capacity across the system in preparation for expected uptake of new regimens.
Sustained Virologic Response After HCV Antiviral Treatment
The goal of HCV antiviral therapy is to eradicate HCV and reduce the progression of liver disease and death from HCV infection. Successful antiviral treatment of HCV is determined by achieving a sustained virologic response (SVR) defined as an undetectable HCV viral load 12 weeks after the end of treatment. Of the 39,388 veterans in VA care in 2013 who have ever received antiviral therapy, SVR could be assessed in 32,815 veterans, and the overall SVR rate in this population was 42%. This SVR rate is similar to that observed in phase III trials of pegylated interferon-based regimens, where 42% to 46% of those infected with HCV genotype 1 achieved SVR.7,8 Although most veterans with genotype 1 infection received boceprevir or telaprevir-based regimens in 2013 and achieved higher SVRs of 50% to 52%, the overwhelming majority of veterans in care in 2013 received prior treatment with only peginterferon and ribavirin.9 Although SVR rates are expected to increase with newer all-oral HCV regimens, differences between clinical efficacy and real-world effectiveness will continue to be apparent,
and patient and provider expectations should be tempered accordingly.
The Role of Primary Care in HCV
Primary care providers have held the responsibility for multiple roles in HCV care since the discovery of the virus—particularly for HCV risk factor assessment, screening, and diagnosis. HCV antiviral treatment, however, was largely placed in the hands of specialists, given the complexities of patient selection, frequent reliance on a liver biopsy for determining need for treatment, and the toxicities of peginterferon and ribavirin therapy.
There are discussions both inside and outside the VA about potentially expanding the role of PCPs in HCV care. First, primary care is the major setting where the CDC and USPSTF recommendations for birth cohort screening are being implemented, and thus PCPs will be identifying veterans previously undiagnosed with HCV.1,2 Second, the ease and tolerability of the new all-oral combination regimens is causing a shift in the paradigm for HCV treatment, from a highly individualized approach, toward a more uniform approach.
Expanding the role of primary care would have multiple benefits to patients and the health care system as a whole. Only approximately 9% of HCV-infected veterans in VA care have been successfully treated at this time, largely due to low eligibility rates and the poor response rates, but other barriers have also contributed to the low success rate, one of which has been limited access to specialists. Furthermore, veterans who are referred to specialists are often noncompliant with the referral.10 If seeing an HCV specialist is required for treatment, the time to treat the HCV population will be much greater, more costly, and less efficient. Therefore, if the prospect of delivering HCV treatment to the majority of HCV patients is to be accomplished, it is necessary to consider providing treatment in the primary care setting as well as the specialist setting.
Treatment provided by nonspecialists has been evaluated in patients receiving peginterferon and ribavirin regimens and has shown that with adequate education and support, SVR rates were equivalent in the specialist and nonspecialist setting.11 To develop programs to provide primary care with such support, the VA has implemented the Specialty Care Access Network-Extension of Community Healthcare Outcomes program initiative, with casebased learning along with real-time consultation.
Currently, the majority of HCV-infected patients have never seen an HCV specialist, thus PCPs are already providing the majority of HCV care beyond HCV antiviral
treatment.12 Primary care providers are, therefore, key to addressing multiple important aspects of HCV care, including (1) counseling patients on transmission, prevention, lifestyle, and the role of substance use; (2) providing hepatitis A and B vaccination as well as appropriate general vaccinations for any patient with chronic liver disease; (3) modifying comorbidities that could accelerate fibrosis progression, such as diabetes mellitus, obesity and hyperlipidemia; (4) reducing risk from ongoing alcohol, drug, and tobacco use; (5) monitoring patients for fibrosis progression and identifying the presence of cirrhosis; and (6) providing general care for patients with cirrhosis, including HCC screening. These are critical aspects of HCV care, and many PCPs may still need additional education for these roles. The VA provides education and support for PCPs in their current role and is enhancing efforts to expand delivery of HCV treatment to the primary care setting as well.
Conclusions
In 2013, the typical veteran with chronic HCV was white, aged 60 years, and male, with a history of comorbidities, including hypertension, depression, and current or prior alcohol abuse. The proportion of veterans with advanced liver disease including cirrhosis (17%) and HCC (3%), has grown significantly over the past 10 years. By the end of 2013, almost 40,000 veterans had received antiviral therapy for HCV, more than 5,700 of whom had received DAAs. Overall SVR rates have been about 42% among those who were treated. Of veterans who are still potential treatment candidates, 85% are treatment-naive and about one-quarter have advanced liver disease.
Although HCV screening rates in veterans are higher than reported in other health care settings, particularly among those in the critical 1945-1965 birth cohort (65% screening rate), substantial numbers of veterans still require testing. The burden of disease, the lack of specialists, the ease and tolerability of new HCV antiviral medications, and the interplay of HCV with other traditional primary care efforts underly an increased role for PCPs in the care of veterans with HCV. Together, this information helps to construct a view of historical, current, and future HCV care in veterans.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patient.
As the largest single provider of hepatitis C virus infection (HCV) care in the U.S., the VA provided care to > 174,000 veterans with chronic HCV in 2013. Identifying veterans most likely to be infected with HCV, particularly those in the highrisk birth cohort born between 1945 and 1965, is a priority given recent CDC and U.S. Preventive Services Task Force (USPSTF) recommendations.1,2 The availability of new, all-oral HCV antiviral regimens with shorter treatment durations and improved tolerability are expected to greatly increase the number of veterans with HCV who could be treated successfully. In order to effectively reach those who are undiagnosed and to ensure that those diagnosed with HCV are evaluated and offered treatment, expanded reliance on primary care providers (PCPs) is essential. This article provides a population view of the current state of VA care for this large HCV-infected population and the important role PCPs share in disease identification and management.
Data Source
Data regarding the state of HCV care in the VA comes from the VA National Clinical Case Registry (CCR) for HCV.3 The VA HCV CCR is an extract of the VA electronic medical record that contains laboratory results, pharmacy information, provider information, and ICD-9 diagnosis codes from inpatient hospitalizations, outpatient visits, and problem lists of veterans with HCV seen at all VAMCs.
Screening and Prevalence of HCV
It is estimated that 2.3 to 2.7 million Americans are living with HCV, with 45% to 85% of those unaware of their infection.4,5 Nearly 75% of those infected are expected to have been born between 1945 and 1965; thus, the CDC and USPSTF now recommend onetime HCV screening for this birth cohort.1,2 Among nearly 5.6 million veterans with a VA outpatient visit in 2013, 56% have been screened for HCV. The HCV screening rate was 42% for those born prior to 1945, 65% for those born during 1945-1965, and 59% for those born after 1965. HCV infection prevalence overall in the VA was 5.8% but differed markedly among the birth cohorts: 1.6% for those born prior to 1945, 9.5% for those born during 1945-1965, and 1.2% for those born after 1965. The prevalence rate of veterans born in the 1945-1965 birth cohort (9.5%) is almost 3 times higher than that of the general U.S. population in this birth cohort (2.4%). The high prevalence serves as a reminder of the greater HCV disease burden in veterans and largely represents Vietman era veterans. Although HCV screening rates in VA have increased over 25% since 2002, the high prevalence among veterans in this birth cohort underscores the importance of continued screening efforts.
Veterans with Chronic HCV Infection
The VA Office of Public Health/Population Health generates national HCV reports annually from the HCV CCR describing the population of veterans with chronic HCV infection receiving VA care. These reports are intended to inform about patient care activities, clinician and patient education, prevention activities, and research directed at continuous improvement of veteran care. The first step in providing responsive care is understanding the affected population, and summarized herein is a description of the veterans with chronic HCV who received VA care in 2013.
In 2013, 174,302 veterans had laboratory evidence of HCV viremia and could be characterized as having chronic HCV. HCV treatment regimens and response depend on the viral genotype. Among veterans with genotype testing, 107,144 (80%) have genotype 1; 15,486 (12%) genotype 2; 9,745 (7%) genotype 3; 1333 (1%) genotype 4; and 63 (< 1%) genotype 5 or 6.
In terms of demographics, most veterans with chronic HCV in VA care in 2013 were men (97%); however, > 5,000 women veterans with chronic HCV received care from the VA. Over half (54%) of veterans with chronic HCV are white, and about one-third (34%) are black. The proportion of blacks within the HCV-infected veteran population is substantially greater than the proportion of blacks in the overall veteran population in VA care (15%) and highlights the disproportionately large burden of HCV that black veterans bear. A smaller proportion of the VA HCV population is Hispanic (6%), and the remaining veterans are other races, multiple races, or unknown.
The HCV-infected veteran population is aging. The mean age of veterans with chronic HCV in 2013 was 59.7 years and for the first time, more veterans with HCV were aged 60 years (Figure 1).
Among the comorbidities that may have historically prevented veterans from receiving HCV antiviral therapy, 2 of the most pervasive are mental health conditions and alcohol use. The rates of mental illness among veterans overall is high, but mental illness is particularly high in veterans with HCV. Depression has affected 60%; of this population anxiety, 37%; posttraumatic stress disorder, 28%; and schizophrenia, 10%. Alcohol use disorders are also common among veterans with HCV in care. Active mental health conditions and substance use may affect medication adherence or follow-up visit adherence thereby limiting treatment candidacy. Integrating care of these individuals with mental health providers and substance-use treatment specialists is an important aspect of HCV care and is a priority in VA.
Three-quarters (76%) of the HCV-infected veteran population has been screened for HIV and HIV-HCV co-infection is present in 5733 (3%) of veterans with HCV. HIV-HCV co-infection is associated with an increased progression of liver disease and may have implications for the selection of HCV antiviral agents because of drug interactions. Hepatitis B virus (HBV)-HCV co-infection rates are higher at 7%. HBV vaccination or documentation of HBV immunity in those without HBV infection is 78%.
With regard to specific liver complications, 5% to 20% of those infected with chronic HCV will develop cirrhosis over a period of 20 to 30 years, and 1% to 5% will die of hepatocellular carcinoma (HCC) or cirrhosis.6 Given the natural history of chronic HCV and the aging HCV veteran cohort, increasing numbers of conditions related to progression of liver disease are expected over time. This is most evident in the number of veterans with a diagnosis of cirrhosis, which has increased from approximately 10,000 veterans (8%) in care in 2001 to nearly 30,000 veterans (17%) in care in 2013 (Figure 2).
Antiviral Therapy for Chronic HCV
Prior to mid-2011, the standard of care for HCV treatment was the combination of pegylated interferon and ribavirin. From 2011 through 2013, direct-acting antiviral (DAA) regimens containing boceprevir and telaprevir in combination with pegylated interferon and ribavirin became standard of care for genotype 1 while
the standard of care remained pegylated interferon and ribavirin for genotypes other than genotype 1. Recent advances in HCV antiviral therapy offer higher cure rates and fewer adverse events (AEs) compared with peginterferon-containing treatment. The expected ease and tolerability of these all-oral combination regimens is anticipated to greatly increase the number of veterans with HCV who could be treated successfully.
Because of the poor tolerability, prolonged treatment durations, serious AEs, and relative or absolute contraindications to peginterferon-based therapy, many veterans were not previously candidates for treatment. Of the 174,302 veterans with chronic HCV in care in 2013, 39,388 (23%) had received at least 1 course of HCV antiviral treatment. This largely reflects the time when peginterferon-based therapy was the standard of care. Since the approval of boceprevir and telaprevir 5,732 veterans (5.8%) in care in 2013 had ever received boceprevir or telaprevir-based regimens.
While recognizing that all veterans should be considered for HCV treatment, the urgency for treatment may be greater in those with advanced liver disease, because these patients are at the highest risk of developing decompensated cirrhosis or dying of liver-related disease. In 2013, there were 28,945 veterans in care that had advanced liver disease who might be considered potential HCV treatment candidates with an urgency to treat.
Duration of treatment and anticipated rates of treatment success with the all-oral regimens depend in part on a patient’s prior treatment status in addition to whether the patient has a diagnosis of advanced liver disease/cirrhosis. Regardless of HCV genotype, among all veterans approximately 85% are treatment-naïve and 15% are treatment-experienced. Advanced liver disease is present in 24% of treatment-naïve and 31% of treatment-experienced veterans with HCV genotype 1; 23% and 24% of veterans with HCV genotype 2, respectively; and 34% and 43% of veterans with HCV genotype 3, respectively.
Further understanding the population of veterans with HCV, including prior treatment status and stage of liver disease, is useful in identifying the target population for treatment. The VA uses these data to project treatment costs and assess capacity across the system in preparation for expected uptake of new regimens.
Sustained Virologic Response After HCV Antiviral Treatment
The goal of HCV antiviral therapy is to eradicate HCV and reduce the progression of liver disease and death from HCV infection. Successful antiviral treatment of HCV is determined by achieving a sustained virologic response (SVR) defined as an undetectable HCV viral load 12 weeks after the end of treatment. Of the 39,388 veterans in VA care in 2013 who have ever received antiviral therapy, SVR could be assessed in 32,815 veterans, and the overall SVR rate in this population was 42%. This SVR rate is similar to that observed in phase III trials of pegylated interferon-based regimens, where 42% to 46% of those infected with HCV genotype 1 achieved SVR.7,8 Although most veterans with genotype 1 infection received boceprevir or telaprevir-based regimens in 2013 and achieved higher SVRs of 50% to 52%, the overwhelming majority of veterans in care in 2013 received prior treatment with only peginterferon and ribavirin.9 Although SVR rates are expected to increase with newer all-oral HCV regimens, differences between clinical efficacy and real-world effectiveness will continue to be apparent,
and patient and provider expectations should be tempered accordingly.
The Role of Primary Care in HCV
Primary care providers have held the responsibility for multiple roles in HCV care since the discovery of the virus—particularly for HCV risk factor assessment, screening, and diagnosis. HCV antiviral treatment, however, was largely placed in the hands of specialists, given the complexities of patient selection, frequent reliance on a liver biopsy for determining need for treatment, and the toxicities of peginterferon and ribavirin therapy.
There are discussions both inside and outside the VA about potentially expanding the role of PCPs in HCV care. First, primary care is the major setting where the CDC and USPSTF recommendations for birth cohort screening are being implemented, and thus PCPs will be identifying veterans previously undiagnosed with HCV.1,2 Second, the ease and tolerability of the new all-oral combination regimens is causing a shift in the paradigm for HCV treatment, from a highly individualized approach, toward a more uniform approach.
Expanding the role of primary care would have multiple benefits to patients and the health care system as a whole. Only approximately 9% of HCV-infected veterans in VA care have been successfully treated at this time, largely due to low eligibility rates and the poor response rates, but other barriers have also contributed to the low success rate, one of which has been limited access to specialists. Furthermore, veterans who are referred to specialists are often noncompliant with the referral.10 If seeing an HCV specialist is required for treatment, the time to treat the HCV population will be much greater, more costly, and less efficient. Therefore, if the prospect of delivering HCV treatment to the majority of HCV patients is to be accomplished, it is necessary to consider providing treatment in the primary care setting as well as the specialist setting.
Treatment provided by nonspecialists has been evaluated in patients receiving peginterferon and ribavirin regimens and has shown that with adequate education and support, SVR rates were equivalent in the specialist and nonspecialist setting.11 To develop programs to provide primary care with such support, the VA has implemented the Specialty Care Access Network-Extension of Community Healthcare Outcomes program initiative, with casebased learning along with real-time consultation.
Currently, the majority of HCV-infected patients have never seen an HCV specialist, thus PCPs are already providing the majority of HCV care beyond HCV antiviral
treatment.12 Primary care providers are, therefore, key to addressing multiple important aspects of HCV care, including (1) counseling patients on transmission, prevention, lifestyle, and the role of substance use; (2) providing hepatitis A and B vaccination as well as appropriate general vaccinations for any patient with chronic liver disease; (3) modifying comorbidities that could accelerate fibrosis progression, such as diabetes mellitus, obesity and hyperlipidemia; (4) reducing risk from ongoing alcohol, drug, and tobacco use; (5) monitoring patients for fibrosis progression and identifying the presence of cirrhosis; and (6) providing general care for patients with cirrhosis, including HCC screening. These are critical aspects of HCV care, and many PCPs may still need additional education for these roles. The VA provides education and support for PCPs in their current role and is enhancing efforts to expand delivery of HCV treatment to the primary care setting as well.
Conclusions
In 2013, the typical veteran with chronic HCV was white, aged 60 years, and male, with a history of comorbidities, including hypertension, depression, and current or prior alcohol abuse. The proportion of veterans with advanced liver disease including cirrhosis (17%) and HCC (3%), has grown significantly over the past 10 years. By the end of 2013, almost 40,000 veterans had received antiviral therapy for HCV, more than 5,700 of whom had received DAAs. Overall SVR rates have been about 42% among those who were treated. Of veterans who are still potential treatment candidates, 85% are treatment-naive and about one-quarter have advanced liver disease.
Although HCV screening rates in veterans are higher than reported in other health care settings, particularly among those in the critical 1945-1965 birth cohort (65% screening rate), substantial numbers of veterans still require testing. The burden of disease, the lack of specialists, the ease and tolerability of new HCV antiviral medications, and the interplay of HCV with other traditional primary care efforts underly an increased role for PCPs in the care of veterans with HCV. Together, this information helps to construct a view of historical, current, and future HCV care in veterans.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patient.
1. Smith BD, Morgan RL, Beckett GA, et al; Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965 [published correction appears in MMWR Recomm Rep. 2012;61(43):886]. MMWR Recomm Rep. 2012;61(RR-4):1-32.
2. Moyer VA; U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159(5):349-357.
3. Backus LI, Gavrilov S, Loomis TP, et al. Clinical Case Registries: Simultaneous local and national disease registries for population quality management. J Am Med Inform Assoc. 2009;16(6):775-783.
4. Kabiri M, Jazwinski AB, Roberts MS, Schaefer AJ, Chhatwal J. The changing burden of hepatitis C virus infection in the United States: Model-based predictions. Ann Intern Med. 2014;161(3):170-180
5. Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med. 2014;160(5):293-300
6. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: A population-based study. Gastroenterology. 2004;127(5):1372-1380.
7. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Lancet. 2001;358(9286):958-965.
8. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347(13):975-982.
9. Backus LI, Belperio PS, Shahoumian TA, Cheung R, Mole LA. Comparative effectiveness of the hepatitis C virus protease inhibitors boceprevir and telaprevir in a large U.S. cohort. Aliment Pharmacol Ther. 2014;39(1):93-103.
10. Brady CW, Coffman CJ, Provenzale D. Compliance with referral for hepatitis C evaluation among veterans. J Clin Gastroenterol. 2007;41(10):927-931.
11. Arora S, Thornton K, Murata G, et al. Outcomes of treatment for hepatitis C infection by primary care providers. N Engl J Med. 2011;364(23):2199-2207.
12. Holmberg SD, Spradling PR, Moorman AC, Denniston MM. Hepatitis C in the United States. N Engl J Med. 2013;368(20):1859-1861.
1. Smith BD, Morgan RL, Beckett GA, et al; Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965 [published correction appears in MMWR Recomm Rep. 2012;61(43):886]. MMWR Recomm Rep. 2012;61(RR-4):1-32.
2. Moyer VA; U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159(5):349-357.
3. Backus LI, Gavrilov S, Loomis TP, et al. Clinical Case Registries: Simultaneous local and national disease registries for population quality management. J Am Med Inform Assoc. 2009;16(6):775-783.
4. Kabiri M, Jazwinski AB, Roberts MS, Schaefer AJ, Chhatwal J. The changing burden of hepatitis C virus infection in the United States: Model-based predictions. Ann Intern Med. 2014;161(3):170-180
5. Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med. 2014;160(5):293-300
6. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: A population-based study. Gastroenterology. 2004;127(5):1372-1380.
7. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Lancet. 2001;358(9286):958-965.
8. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347(13):975-982.
9. Backus LI, Belperio PS, Shahoumian TA, Cheung R, Mole LA. Comparative effectiveness of the hepatitis C virus protease inhibitors boceprevir and telaprevir in a large U.S. cohort. Aliment Pharmacol Ther. 2014;39(1):93-103.
10. Brady CW, Coffman CJ, Provenzale D. Compliance with referral for hepatitis C evaluation among veterans. J Clin Gastroenterol. 2007;41(10):927-931.
11. Arora S, Thornton K, Murata G, et al. Outcomes of treatment for hepatitis C infection by primary care providers. N Engl J Med. 2011;364(23):2199-2207.
12. Holmberg SD, Spradling PR, Moorman AC, Denniston MM. Hepatitis C in the United States. N Engl J Med. 2013;368(20):1859-1861.
One Hundred Case Series of Vocal Cord Dysfunction in a Military Treatment Facility
Vocal cord dysfunction (VCD), also known as paradoxical vocal cord movement, is described as paroxysms of glottis obstruction due to true vocal cord adduction.1 Since VCD presents as a constellation of symptoms associated with dyspnea, it often is misdiagnosed as asthma.2 Vocal cord dysfunction often manifests as episodic dyspnea and wheezing, may occur with exercise, and may be minimally responsive to initial therapies. Flattened inspiratory curves may be noted on pulmonary function tests (PFTs), but direct laryngoscopy is the gold standard for diagnosis.3 A cohort of proven patients with VCD with a plateau in the inspiratory curve of PFTs also had a plateau on expiratory phase in 81% of cases.4
The differential diagnosis of patients presenting with upper airway symptoms is broad. It must include VCD, asthma, angioedema, laryngomalacia, vocal cord polyps, vocal cord tumors, and neurologic conditions such as brain stem compression or movement disorders. Essentially, all movement disorders of vocal cords must be considered, and organic causes of this movement disorder can be evaluated by visualization of the vocal cords. Triggers for VCD include exercise, airborne irritants, gastroesophageal reflux disease (GERD), allergic rhinitis, medications, and psychological conditions.5 Additionally, VCD can coexist with asthma, further complicating accurate diagnoses.6
Therapies are reported in case studies, but no large randomized controlled trials exist to evaluate current therapy options. Primary treatments of asthma therapy were largely ineffective, and ideal therapy includes a multidisciplinary approach, including speech therapy to optimize laryngeal control and treatment of all identified laryngeal irritants.6
The prevalence of VCD is unknown, with no prospective cohort studies completed to date and conflicting diagnostic criteria used in many case studies.7 A prevalence of 2.8% was noted in one particular cohort of 1,028 patients admitted to a rehabilitation center in a calendar year with the primary pulmonary diagnosis on admission.6 Females seemed to be affected at a higher ratio than were males, 2 to 3 females per 1 male diagnosis.7
In the military population, certain risk factors were noted in returning deployed members, including anxiety/high stress, exercise, and acute respiratory illnesses.8 In that particular cohort, 72% positive predictive value was noted for VCD if flattened inspiratory flow loops with negative methacholine challenge were present.
Diagnostic criteria are challenging, as symptoms such as dyspnea may be present acutely, last < 2 minutes, be self-limiting, and completely resolve outside of acute events. Stridor may be noted, primarily above the vocal cords, and less audible on chest auscultation.6 A goal of therapy, in addition to dedicated speech pathologist input, is optimizing comedical conditions, including GERD, allergic rhinitis, concomitant asthma, and any psychological diagnoses.9
Athletes are a particular subset of patients with VCD who are crucial to appropriately diagnose, including a detailed history and physical, PFTs, and proceeding to direct laryngoscopy to confirm diagnoses.10 Behavioral management includes rescue breathing techniques, and speech therapy programs focus on relaxation of the larynx and diaphragmatic breathing techniques, with the goal of establishing sense of control during acute events.10 Military service members are expected to operate at a high-intensity level similar to that of athletes, and treatments considered for athletes are applicable to military service members as well. Military strength and cardiovascular standards are measured by a combination of push-ups, sit-ups, and a run test, in addition to waist measurements. Some of the cohort were identified during physical fitness standard failures, usually in the run test, and ultimately received a pulmonology referral for wheezing or dyspnea with exertion. The objective of this retrospective cohort study was to evaluate 100 consecutively diagnosed cases of VCD in a military treatment facility.
Methods
The authors conducted a retrospective chart review of DoD military medical records of outpatient diagnoses in 100 consecutive diagnoses of VCD from January 2011 to February 2014. Institutional review board approval was obtained under Project RSM20130001E by the Exempt Determination Official at Eglin Air Force Base (AFB), Florida.
All cases were identified at time of VCD visualization and were diagnosed with video stroboscopy by speech therapy or by visual laryngoscopy by the otolaryngology or pulmonology departments via direct visualization.
Cases were collected chronologically, and all diagnosed cases at Eglin AFB hospital were included. Follow-up was scheduled with all patients diagnosed in Speech Therapy, and most patients were concurrently treated by Pulmonology or Allergy/Immunology. Pulmonary function tests were obtained in 98 of the 100 diagnosed cases. Patients eligible for care at Eglin AFB included active-duty and Reserve military members plus dependents and retirees.
The majority of patients diagnosed in this cohort were seen and diagnosed by Speech Therapy. Video stroboscopy is based on the principle that a movement of an object higher than a certain flicker rate appears to stand still to direct visualization, but with a rate of light exposure and imaging above the flicker rate by video, the true movement of the object can be identified.¹¹ Video stroboscopy is considered highly sensitive for organic disorders of vocal cords, but it is not specific for either organic or dysfunctional disorders.¹¹ It is still the gold standard above direct visualization, as it can detect abnormal movement of vocal cords above the critical rate that the human eye would perceive as not moving due to the frequency of movement (Figures 1 & 2).¹¹
In an older study, laryngoscopy was able to diagnose 100% of patients with symptomatic paradoxical vocal cord movement and additional 60% asymptomatic patients with a constellation of symptoms consistent with paradoxical vocal cord movement.¹²
Speech Therapy; Ear, Nose, and Throat (ENT); and Pulmonology may not perform direct visualization in these patients at initial presentation due to other suspected diagnoses. A more common test is the PFT, especially if asthma or other airway tract diseases are suspected (Figure 3).
Patient Descriptions
Study patients were referred for a variety of reasons, often from primary care clinics for concerns for asthma, episodic dyspnea, wheezing, or decreased exercise tolerance thought to be related to pulmonary or allergy causes. Pulmonology worked closely with Speech Therapy and referred VCD cases for speech evaluation, including video stroboscopy. Notably, of the patients in this cohort, although some were suspected to have asthma, those patients were ruled out during part of the pulmonology evaluation, both with PFT testing and methacholine challenges. An asthma diagnosis is important in a military treatment facility, as asthma is often grounds for discharge.
Patients ranged in age from 13 to 68 years, with a median age at 31 years diagnosis. Thirty-nine females and 61 males comprised the total case series. Speech Therapy diagnosed 97 patients, 96 were diagnosed at Eglin AFB hospital via stroboscopy. One patient was diagnosed off-base by Speech Therapy via direct visualization, 1 patient was diagnosed by Pulmonology on-base via direct visualization, and 2 patients were diagnosed by ENT on-base via direct visualization. These patients had direct laryngoscopy completed, often to rule out other organic causes for upper airway disease processes, and were found to have visual paradoxical vocal cord movement. Ninety-eight patients completed PFTs. Several patients were lost to follow-up, as can be common in a military population with frequent moves or members leaving service.
On record review, patient symptoms were present in the range of 2 months to 20 years, with a median duration of symptomatic reports lasting 2 years prior to diagnosis. Common diagnoses prior to visual VCD diagnosis included asthma, exercise-induced asthma, anxiety, and episodic wheezing. Risk factors that were evaluated in this case series included age, sex, body mass index (BMI), GERD, allergic rhinitis, postnasal drip, active smoker, previous smoker, and mental health diagnoses (Figure 4).
Pulmonary function test results were analyzed on 98 patients, including forced expiratory volume in 1 second (FEV1); forced vital capacity (FVC), FEV1/FVC ratio; peak inspiratory flow (PIF) and peak expiratory flow (PEF)—available in 97 studies; forced expiratory flow (FEF) at 25% to 75% of FVC (FEF 25%-75%)—available in 96 studies; and maximum voluntary ventilation (MVV) and MVV/FEV1 ratio—available in 60 of 98 PFTs.
Interventions
All patients diagnosed by Speech Therapy on-base were provided with laryngeal relaxation techniques, diaphragmatic breathing techniques, and controlled inhale/exhale techniques at time of diagnosis, with frequent follow-up scheduled with Speech Therapy and Pulmonology. All diagnoses potentially contributing to laryngeal irritation were treated, including GERD, allergic rhinitis, smoking cessation, weight loss, and exercise recommendations as needed.
Patients reported improvement on follow-up appointments with Speech Therapy in overall control of symptoms, subjectively categorized as poor improvement, partial improvement, and complete improvement. This was a subjective measurement of improvement and fully dependent on follow-up care and patient reporting for improvement. No predefined number of follow-ups was determined; patients were followed monthly until they declined further care, fully improved, moved out of the military treatment system, or were lost to follow-up.
Treatment included structured Speech Therapy sessions. Response to treatment was subjectively qualified by patient report. Fifteen patients reported complete resolution of symptoms, 57 reported partial improvement, 24 reported poor improvement, and 4 patients were lost to follow-up.
Results
Risk factors for the diagnosis of VCD included possible associations with GERD, allergic rhinitis, smoking, prior smoking, BMI, and mental health diagnoses. Body mass index ranged from 17 to 36 in the case series, with median BMI of 27. Mental health diagnoses were present in 35 patients and included diagnoses of anxiety, depression, and adjustment disorders. Gastroesophageal reflux disease diagnosis was present in 59 of the case series patients, 80 had the diagnosis of allergic rhinitis, 63 were diagnosed with postnasal drip. Sixteen case series patients were current smokers. An additional 26 were previous smokers (at least 100 cigarettes in lifetime) for a total of 42 patients that were current or prior smokers.
The chart review was completed to evaluate for the presence of these diagnoses, which included previous treatments; for example, proton pump inhibitors for GERD, antidepressants for depression, or intranasal steroids for allergic rhinitis. The diagnosis was counted as present if the patient was currently being treated for the particular diagnosis in question.
PFT Data
Data from PFTs were available for 98 of 100 cases diagnosed. Review of data across all 98 patients is noted for median FEV1 of 3.6, a median FVC of 4.5, with ratio of 0.80. 
Since PFT values vary according to age, sex, and ethnicity, PFTs were analyzed for percent predicted values based on age, gender, and race. Notably, median values for FEV1, FVC, and PEF were all close to 100% of the predicted value. The MVV percent predicted was available in 60 cases and was 93% of predicted values. The most significant difference from expected values was FEF 25% to 75%, at 84% of expected results.
Flow-volume loop evaluations on the 97 PFTs available were completed, and 58 of the 97 were noted for variable extrathoracic airway obstruction consistent with inspiratory inhibition in the patient population. This is 60% of the available PFTs in this cohort study.
Discussion
This retrospective chart review of 100 consecutive VCD diagnoses in a military treatment facility reinforces many of the findings currently available in the literature. As illustrated in a Chest review article, the diagnosis of VCD on history, physical examination, or PFTs remains ellusive.1 The PFT evaluation contains some subjectivity regarding the flattening of inspiratory flow-volume loops and is not routinely reported in PFT results. In patients diagnosed with VCD, a clear consensus of treatment modalities remains lacking. Modification of risk factors (allergic rhinitis, GERD, smoking cessation, weight loss) assisted in self-reported patient improvement, as did focused speech therapy.
The median age of 31 years, likely reflected the younger military population served at Eglin AFB. Seventy-five of these patients were currently on active duty, 6 were retired from active duty (veterans), and 19 were dependents. The median time of symptoms to diagnosis was 2 years. Prior misdiagnosis with other diseases such as asthma was common. Also, referral to Pulmonology and Speech Therapy was usually completed after failed outpatient primary care management for the alternative diagnoses.
Improvement with therapy was mixed, and during the time of documented follow-up, 72 patients reported complete or partial improvement. Most active-duty patients in the partial improvement category based this subjective reporting on their ability to meet military physical fitness standards.
Previous data suggested a female predominance, but this study population was 61% male. Military populations are about 80% to 85% male, so an increase in male diagnosis is expected.
Many patients in the patient cohort arrived as a result of Pulmonology referrals with a presumptive diagnoses of asthma but were determined not to have asthma through PFT results inconsistent with asthma, no improvement with β-agonist therapies, and negative methacholine challenges (if performed). These results prompted evaluations for other conditions and eventually a VCD diagnosis. As noted, exclusion of asthma is of particular importance in a military population, as medical discharges often are pursued in service members with asthma whether controlled or uncontrolled. Lag time to referral also is possible in failures of military physical, which prompted medical evaluation once several failures had occurred over a 1- to 2-year time frame.
The PFT data evaluation was inconclusive for statistically significant changes when compared with age-matched normal PFT values. This also was noted in previous studies of VCD cases. Most notable was percent predicted values of FEF 25% to 75%, with 84% of expected values. The FEV1, FVC, and PEF all fell within predicted values of normal, despite wide ranges in age, sex, and ethnicity among the subjects. Inspiratory flattening consistent with extrathoracic obstruction was present in 58 of the 97 PFTs available for review at Eglin AFB.
Limitations
Limitations to this retrospective case series are illustrated here. Cases were found only when VCD was diagnosed and coded; and it is the authors’ suspicion that many have been misdiagnosed or improperly treated for asthma or other pulmonary/oropharynx conditions. If providers are not familiar with VCD or if PFT readings do not comment on inspiratory findings, diagnosis is less likely. Some of the authors’ colleagues already have determined that postdeployment prevalence of VCD seems to be elevated.8
This cohort was completed on all patients in a military treatment facility, with 75 active-duty personnel, 6 veterans, and 19 dependents of varying ages. This case series is retrospective and tabulates suspected risk factors; stronger and more informative studies could certainly be completed in prospective studies (although likely difficult with low prevalence) or in treatment comparison studies at the time of diagnosis.
Since the cohort had varied and lengthy time to diagnosis from onset of related symptoms, the treatment patients received prior to diagnosis differed extensively. Diagnosis was completed by numerous primary care managers or other subspecialties prior to arrival to Pulmonology and Speech Therapy at Eglin AFB. Once diagnosed in Speech Therapy, consistent treatment options were provided to patients in accordance with standard of care.
It is the authors’ suspicion that VCD may have a higher prevalence than previously reported in the literature. Military service members are tested annually or biannually on physical fitness standards and are evaluated for medical reasons for recurrent fitness standard failures. This selection of patients is more likely to have a VCD evaluation as part of a comprehensive evaluation than is a healthy adult in a civilian population. A prospective study in military service members would be more fruitful and possibly yield a higher prevalence postdeployment.
Conclusion
Vocal cord dysfunction remains a difficult diagnosis to treat, because multiple comorbidities likely contribute to the diagnosis. This retrospective case series attempted to compile common themes and noted that most of the patients had 2 or more risk factors of smoking, allergic rhinitis, GERD, or mental health diagnoses. A prospective trial would be ideal to evaluate VCD further. A focused trial in the particular communities of athletes or of military service members may be of increased benefit to better define VCD. It is notable that 100 cases were found in a relatively short period for a community hospital, and prevalence may be higher than previously reported.
1. Morris MJ, Christopher KL. Diagnostic criteria for the classification of vocal cord dysfunction. Chest. 2010;138(5):1213-1223.
2. National Heart, Lung, and Blood Institute. Expert panel report 3: guidelines for the diagnoses and management of asthma. Full report 2007. https://www.nhlbi.nih.gov/files/docs/guidelines/asthgdln .pdf. Published 2007.Accessed February 1, 2017.
3. Newman KB, Mason UG III, Schmaling KB. Clinical features of vocal cord dysfunction. Am J Respir Crit Care Med. 1995;152(4, pt 1):1382-1386.
4. Sanz Santiago V, López Neyra A, Almería Gil E, Villa Asensi JR. Spirometry patterns in vocal cord dysfunction [in Spanish]. An Pediatr (Barc). 2013;78(3):173-177.
5. Deckert J, Deckert L. Vocal cord dysfunction. Am Fam Physician. 2010;81(2):156-159.
6. Benninger C, Parsons JP, Mastronarde JG. Vocal cord dysfunction and asthma. Curr Opin Pulm Med. 2011;17(1):45-49.
7. Campainha S, Ribeiro C, Guimar M, Lima R. Vocal cord dysfunction: a frequently forgotten entity. Case Rep Pulmonol. 2012;2012:525493.
8. Morris MJ, Oleszewski RT, Sterner JB, Allan PF. Vocal cord dysfunction related to combat deployment. Mil Med. 2013;178(11):1208-1212.
9. Al-Alwan A, Kaminsky D. Vocal cord dysfunction in athletes: clinical presentation and review of the literature. Phys Sportsmed. 2012;40(2):22-27.
10. Kenn K, Schmitz M. Prevalence of vocal cord dysfunction in patients with dyspnea. First prospective clinical study. Am J Respir Crit Care Med. 1997;155:A965.
11. Wendler, J, Nawka, T, Verges, D. Instructional course: videolaryngo-stroboscopy and phonetography—basic tools for diagnostics and documentation in the voice clinic. Poster presented at: 15th European Congress of Oto-Rhino-Laryngology, Head and Neck Surgery; September 11-16, 2004; Rodos-Kos, Greece.
12. Ibrahim WH, Gheriani HA, Almohamed AA, Raza T. Paradoxical vocal cord motion disorder: past, present and future. Postgrad Med J. 2007;83(977):164-172.
Vocal cord dysfunction (VCD), also known as paradoxical vocal cord movement, is described as paroxysms of glottis obstruction due to true vocal cord adduction.1 Since VCD presents as a constellation of symptoms associated with dyspnea, it often is misdiagnosed as asthma.2 Vocal cord dysfunction often manifests as episodic dyspnea and wheezing, may occur with exercise, and may be minimally responsive to initial therapies. Flattened inspiratory curves may be noted on pulmonary function tests (PFTs), but direct laryngoscopy is the gold standard for diagnosis.3 A cohort of proven patients with VCD with a plateau in the inspiratory curve of PFTs also had a plateau on expiratory phase in 81% of cases.4
The differential diagnosis of patients presenting with upper airway symptoms is broad. It must include VCD, asthma, angioedema, laryngomalacia, vocal cord polyps, vocal cord tumors, and neurologic conditions such as brain stem compression or movement disorders. Essentially, all movement disorders of vocal cords must be considered, and organic causes of this movement disorder can be evaluated by visualization of the vocal cords. Triggers for VCD include exercise, airborne irritants, gastroesophageal reflux disease (GERD), allergic rhinitis, medications, and psychological conditions.5 Additionally, VCD can coexist with asthma, further complicating accurate diagnoses.6
Therapies are reported in case studies, but no large randomized controlled trials exist to evaluate current therapy options. Primary treatments of asthma therapy were largely ineffective, and ideal therapy includes a multidisciplinary approach, including speech therapy to optimize laryngeal control and treatment of all identified laryngeal irritants.6
The prevalence of VCD is unknown, with no prospective cohort studies completed to date and conflicting diagnostic criteria used in many case studies.7 A prevalence of 2.8% was noted in one particular cohort of 1,028 patients admitted to a rehabilitation center in a calendar year with the primary pulmonary diagnosis on admission.6 Females seemed to be affected at a higher ratio than were males, 2 to 3 females per 1 male diagnosis.7
In the military population, certain risk factors were noted in returning deployed members, including anxiety/high stress, exercise, and acute respiratory illnesses.8 In that particular cohort, 72% positive predictive value was noted for VCD if flattened inspiratory flow loops with negative methacholine challenge were present.
Diagnostic criteria are challenging, as symptoms such as dyspnea may be present acutely, last < 2 minutes, be self-limiting, and completely resolve outside of acute events. Stridor may be noted, primarily above the vocal cords, and less audible on chest auscultation.6 A goal of therapy, in addition to dedicated speech pathologist input, is optimizing comedical conditions, including GERD, allergic rhinitis, concomitant asthma, and any psychological diagnoses.9
Athletes are a particular subset of patients with VCD who are crucial to appropriately diagnose, including a detailed history and physical, PFTs, and proceeding to direct laryngoscopy to confirm diagnoses.10 Behavioral management includes rescue breathing techniques, and speech therapy programs focus on relaxation of the larynx and diaphragmatic breathing techniques, with the goal of establishing sense of control during acute events.10 Military service members are expected to operate at a high-intensity level similar to that of athletes, and treatments considered for athletes are applicable to military service members as well. Military strength and cardiovascular standards are measured by a combination of push-ups, sit-ups, and a run test, in addition to waist measurements. Some of the cohort were identified during physical fitness standard failures, usually in the run test, and ultimately received a pulmonology referral for wheezing or dyspnea with exertion. The objective of this retrospective cohort study was to evaluate 100 consecutively diagnosed cases of VCD in a military treatment facility.
Methods
The authors conducted a retrospective chart review of DoD military medical records of outpatient diagnoses in 100 consecutive diagnoses of VCD from January 2011 to February 2014. Institutional review board approval was obtained under Project RSM20130001E by the Exempt Determination Official at Eglin Air Force Base (AFB), Florida.
All cases were identified at time of VCD visualization and were diagnosed with video stroboscopy by speech therapy or by visual laryngoscopy by the otolaryngology or pulmonology departments via direct visualization.
Cases were collected chronologically, and all diagnosed cases at Eglin AFB hospital were included. Follow-up was scheduled with all patients diagnosed in Speech Therapy, and most patients were concurrently treated by Pulmonology or Allergy/Immunology. Pulmonary function tests were obtained in 98 of the 100 diagnosed cases. Patients eligible for care at Eglin AFB included active-duty and Reserve military members plus dependents and retirees.
The majority of patients diagnosed in this cohort were seen and diagnosed by Speech Therapy. Video stroboscopy is based on the principle that a movement of an object higher than a certain flicker rate appears to stand still to direct visualization, but with a rate of light exposure and imaging above the flicker rate by video, the true movement of the object can be identified.¹¹ Video stroboscopy is considered highly sensitive for organic disorders of vocal cords, but it is not specific for either organic or dysfunctional disorders.¹¹ It is still the gold standard above direct visualization, as it can detect abnormal movement of vocal cords above the critical rate that the human eye would perceive as not moving due to the frequency of movement (Figures 1 & 2).¹¹
In an older study, laryngoscopy was able to diagnose 100% of patients with symptomatic paradoxical vocal cord movement and additional 60% asymptomatic patients with a constellation of symptoms consistent with paradoxical vocal cord movement.¹²
Speech Therapy; Ear, Nose, and Throat (ENT); and Pulmonology may not perform direct visualization in these patients at initial presentation due to other suspected diagnoses. A more common test is the PFT, especially if asthma or other airway tract diseases are suspected (Figure 3).
Patient Descriptions
Study patients were referred for a variety of reasons, often from primary care clinics for concerns for asthma, episodic dyspnea, wheezing, or decreased exercise tolerance thought to be related to pulmonary or allergy causes. Pulmonology worked closely with Speech Therapy and referred VCD cases for speech evaluation, including video stroboscopy. Notably, of the patients in this cohort, although some were suspected to have asthma, those patients were ruled out during part of the pulmonology evaluation, both with PFT testing and methacholine challenges. An asthma diagnosis is important in a military treatment facility, as asthma is often grounds for discharge.
Patients ranged in age from 13 to 68 years, with a median age at 31 years diagnosis. Thirty-nine females and 61 males comprised the total case series. Speech Therapy diagnosed 97 patients, 96 were diagnosed at Eglin AFB hospital via stroboscopy. One patient was diagnosed off-base by Speech Therapy via direct visualization, 1 patient was diagnosed by Pulmonology on-base via direct visualization, and 2 patients were diagnosed by ENT on-base via direct visualization. These patients had direct laryngoscopy completed, often to rule out other organic causes for upper airway disease processes, and were found to have visual paradoxical vocal cord movement. Ninety-eight patients completed PFTs. Several patients were lost to follow-up, as can be common in a military population with frequent moves or members leaving service.
On record review, patient symptoms were present in the range of 2 months to 20 years, with a median duration of symptomatic reports lasting 2 years prior to diagnosis. Common diagnoses prior to visual VCD diagnosis included asthma, exercise-induced asthma, anxiety, and episodic wheezing. Risk factors that were evaluated in this case series included age, sex, body mass index (BMI), GERD, allergic rhinitis, postnasal drip, active smoker, previous smoker, and mental health diagnoses (Figure 4).
Pulmonary function test results were analyzed on 98 patients, including forced expiratory volume in 1 second (FEV1); forced vital capacity (FVC), FEV1/FVC ratio; peak inspiratory flow (PIF) and peak expiratory flow (PEF)—available in 97 studies; forced expiratory flow (FEF) at 25% to 75% of FVC (FEF 25%-75%)—available in 96 studies; and maximum voluntary ventilation (MVV) and MVV/FEV1 ratio—available in 60 of 98 PFTs.
Interventions
All patients diagnosed by Speech Therapy on-base were provided with laryngeal relaxation techniques, diaphragmatic breathing techniques, and controlled inhale/exhale techniques at time of diagnosis, with frequent follow-up scheduled with Speech Therapy and Pulmonology. All diagnoses potentially contributing to laryngeal irritation were treated, including GERD, allergic rhinitis, smoking cessation, weight loss, and exercise recommendations as needed.
Patients reported improvement on follow-up appointments with Speech Therapy in overall control of symptoms, subjectively categorized as poor improvement, partial improvement, and complete improvement. This was a subjective measurement of improvement and fully dependent on follow-up care and patient reporting for improvement. No predefined number of follow-ups was determined; patients were followed monthly until they declined further care, fully improved, moved out of the military treatment system, or were lost to follow-up.
Treatment included structured Speech Therapy sessions. Response to treatment was subjectively qualified by patient report. Fifteen patients reported complete resolution of symptoms, 57 reported partial improvement, 24 reported poor improvement, and 4 patients were lost to follow-up.
Results
Risk factors for the diagnosis of VCD included possible associations with GERD, allergic rhinitis, smoking, prior smoking, BMI, and mental health diagnoses. Body mass index ranged from 17 to 36 in the case series, with median BMI of 27. Mental health diagnoses were present in 35 patients and included diagnoses of anxiety, depression, and adjustment disorders. Gastroesophageal reflux disease diagnosis was present in 59 of the case series patients, 80 had the diagnosis of allergic rhinitis, 63 were diagnosed with postnasal drip. Sixteen case series patients were current smokers. An additional 26 were previous smokers (at least 100 cigarettes in lifetime) for a total of 42 patients that were current or prior smokers.
The chart review was completed to evaluate for the presence of these diagnoses, which included previous treatments; for example, proton pump inhibitors for GERD, antidepressants for depression, or intranasal steroids for allergic rhinitis. The diagnosis was counted as present if the patient was currently being treated for the particular diagnosis in question.
PFT Data
Data from PFTs were available for 98 of 100 cases diagnosed. Review of data across all 98 patients is noted for median FEV1 of 3.6, a median FVC of 4.5, with ratio of 0.80.
Since PFT values vary according to age, sex, and ethnicity, PFTs were analyzed for percent predicted values based on age, gender, and race. Notably, median values for FEV1, FVC, and PEF were all close to 100% of the predicted value. The MVV percent predicted was available in 60 cases and was 93% of predicted values. The most significant difference from expected values was FEF 25% to 75%, at 84% of expected results.
Flow-volume loop evaluations on the 97 PFTs available were completed, and 58 of the 97 were noted for variable extrathoracic airway obstruction consistent with inspiratory inhibition in the patient population. This is 60% of the available PFTs in this cohort study.
Discussion
This retrospective chart review of 100 consecutive VCD diagnoses in a military treatment facility reinforces many of the findings currently available in the literature. As illustrated in a Chest review article, the diagnosis of VCD on history, physical examination, or PFTs remains ellusive.1 The PFT evaluation contains some subjectivity regarding the flattening of inspiratory flow-volume loops and is not routinely reported in PFT results. In patients diagnosed with VCD, a clear consensus of treatment modalities remains lacking. Modification of risk factors (allergic rhinitis, GERD, smoking cessation, weight loss) assisted in self-reported patient improvement, as did focused speech therapy.
The median age of 31 years, likely reflected the younger military population served at Eglin AFB. Seventy-five of these patients were currently on active duty, 6 were retired from active duty (veterans), and 19 were dependents. The median time of symptoms to diagnosis was 2 years. Prior misdiagnosis with other diseases such as asthma was common. Also, referral to Pulmonology and Speech Therapy was usually completed after failed outpatient primary care management for the alternative diagnoses.
Improvement with therapy was mixed, and during the time of documented follow-up, 72 patients reported complete or partial improvement. Most active-duty patients in the partial improvement category based this subjective reporting on their ability to meet military physical fitness standards.
Previous data suggested a female predominance, but this study population was 61% male. Military populations are about 80% to 85% male, so an increase in male diagnosis is expected.
Many patients in the patient cohort arrived as a result of Pulmonology referrals with a presumptive diagnoses of asthma but were determined not to have asthma through PFT results inconsistent with asthma, no improvement with β-agonist therapies, and negative methacholine challenges (if performed). These results prompted evaluations for other conditions and eventually a VCD diagnosis. As noted, exclusion of asthma is of particular importance in a military population, as medical discharges often are pursued in service members with asthma whether controlled or uncontrolled. Lag time to referral also is possible in failures of military physical, which prompted medical evaluation once several failures had occurred over a 1- to 2-year time frame.
The PFT data evaluation was inconclusive for statistically significant changes when compared with age-matched normal PFT values. This also was noted in previous studies of VCD cases. Most notable was percent predicted values of FEF 25% to 75%, with 84% of expected values. The FEV1, FVC, and PEF all fell within predicted values of normal, despite wide ranges in age, sex, and ethnicity among the subjects. Inspiratory flattening consistent with extrathoracic obstruction was present in 58 of the 97 PFTs available for review at Eglin AFB.
Limitations
Limitations to this retrospective case series are illustrated here. Cases were found only when VCD was diagnosed and coded; and it is the authors’ suspicion that many have been misdiagnosed or improperly treated for asthma or other pulmonary/oropharynx conditions. If providers are not familiar with VCD or if PFT readings do not comment on inspiratory findings, diagnosis is less likely. Some of the authors’ colleagues already have determined that postdeployment prevalence of VCD seems to be elevated.8
This cohort was completed on all patients in a military treatment facility, with 75 active-duty personnel, 6 veterans, and 19 dependents of varying ages. This case series is retrospective and tabulates suspected risk factors; stronger and more informative studies could certainly be completed in prospective studies (although likely difficult with low prevalence) or in treatment comparison studies at the time of diagnosis.
Since the cohort had varied and lengthy time to diagnosis from onset of related symptoms, the treatment patients received prior to diagnosis differed extensively. Diagnosis was completed by numerous primary care managers or other subspecialties prior to arrival to Pulmonology and Speech Therapy at Eglin AFB. Once diagnosed in Speech Therapy, consistent treatment options were provided to patients in accordance with standard of care.
It is the authors’ suspicion that VCD may have a higher prevalence than previously reported in the literature. Military service members are tested annually or biannually on physical fitness standards and are evaluated for medical reasons for recurrent fitness standard failures. This selection of patients is more likely to have a VCD evaluation as part of a comprehensive evaluation than is a healthy adult in a civilian population. A prospective study in military service members would be more fruitful and possibly yield a higher prevalence postdeployment.
Conclusion
Vocal cord dysfunction remains a difficult diagnosis to treat, because multiple comorbidities likely contribute to the diagnosis. This retrospective case series attempted to compile common themes and noted that most of the patients had 2 or more risk factors of smoking, allergic rhinitis, GERD, or mental health diagnoses. A prospective trial would be ideal to evaluate VCD further. A focused trial in the particular communities of athletes or of military service members may be of increased benefit to better define VCD. It is notable that 100 cases were found in a relatively short period for a community hospital, and prevalence may be higher than previously reported.
Vocal cord dysfunction (VCD), also known as paradoxical vocal cord movement, is described as paroxysms of glottis obstruction due to true vocal cord adduction.1 Since VCD presents as a constellation of symptoms associated with dyspnea, it often is misdiagnosed as asthma.2 Vocal cord dysfunction often manifests as episodic dyspnea and wheezing, may occur with exercise, and may be minimally responsive to initial therapies. Flattened inspiratory curves may be noted on pulmonary function tests (PFTs), but direct laryngoscopy is the gold standard for diagnosis.3 A cohort of proven patients with VCD with a plateau in the inspiratory curve of PFTs also had a plateau on expiratory phase in 81% of cases.4
The differential diagnosis of patients presenting with upper airway symptoms is broad. It must include VCD, asthma, angioedema, laryngomalacia, vocal cord polyps, vocal cord tumors, and neurologic conditions such as brain stem compression or movement disorders. Essentially, all movement disorders of vocal cords must be considered, and organic causes of this movement disorder can be evaluated by visualization of the vocal cords. Triggers for VCD include exercise, airborne irritants, gastroesophageal reflux disease (GERD), allergic rhinitis, medications, and psychological conditions.5 Additionally, VCD can coexist with asthma, further complicating accurate diagnoses.6
Therapies are reported in case studies, but no large randomized controlled trials exist to evaluate current therapy options. Primary treatments of asthma therapy were largely ineffective, and ideal therapy includes a multidisciplinary approach, including speech therapy to optimize laryngeal control and treatment of all identified laryngeal irritants.6
The prevalence of VCD is unknown, with no prospective cohort studies completed to date and conflicting diagnostic criteria used in many case studies.7 A prevalence of 2.8% was noted in one particular cohort of 1,028 patients admitted to a rehabilitation center in a calendar year with the primary pulmonary diagnosis on admission.6 Females seemed to be affected at a higher ratio than were males, 2 to 3 females per 1 male diagnosis.7
In the military population, certain risk factors were noted in returning deployed members, including anxiety/high stress, exercise, and acute respiratory illnesses.8 In that particular cohort, 72% positive predictive value was noted for VCD if flattened inspiratory flow loops with negative methacholine challenge were present.
Diagnostic criteria are challenging, as symptoms such as dyspnea may be present acutely, last < 2 minutes, be self-limiting, and completely resolve outside of acute events. Stridor may be noted, primarily above the vocal cords, and less audible on chest auscultation.6 A goal of therapy, in addition to dedicated speech pathologist input, is optimizing comedical conditions, including GERD, allergic rhinitis, concomitant asthma, and any psychological diagnoses.9
Athletes are a particular subset of patients with VCD who are crucial to appropriately diagnose, including a detailed history and physical, PFTs, and proceeding to direct laryngoscopy to confirm diagnoses.10 Behavioral management includes rescue breathing techniques, and speech therapy programs focus on relaxation of the larynx and diaphragmatic breathing techniques, with the goal of establishing sense of control during acute events.10 Military service members are expected to operate at a high-intensity level similar to that of athletes, and treatments considered for athletes are applicable to military service members as well. Military strength and cardiovascular standards are measured by a combination of push-ups, sit-ups, and a run test, in addition to waist measurements. Some of the cohort were identified during physical fitness standard failures, usually in the run test, and ultimately received a pulmonology referral for wheezing or dyspnea with exertion. The objective of this retrospective cohort study was to evaluate 100 consecutively diagnosed cases of VCD in a military treatment facility.
Methods
The authors conducted a retrospective chart review of DoD military medical records of outpatient diagnoses in 100 consecutive diagnoses of VCD from January 2011 to February 2014. Institutional review board approval was obtained under Project RSM20130001E by the Exempt Determination Official at Eglin Air Force Base (AFB), Florida.
All cases were identified at time of VCD visualization and were diagnosed with video stroboscopy by speech therapy or by visual laryngoscopy by the otolaryngology or pulmonology departments via direct visualization.
Cases were collected chronologically, and all diagnosed cases at Eglin AFB hospital were included. Follow-up was scheduled with all patients diagnosed in Speech Therapy, and most patients were concurrently treated by Pulmonology or Allergy/Immunology. Pulmonary function tests were obtained in 98 of the 100 diagnosed cases. Patients eligible for care at Eglin AFB included active-duty and Reserve military members plus dependents and retirees.
The majority of patients diagnosed in this cohort were seen and diagnosed by Speech Therapy. Video stroboscopy is based on the principle that a movement of an object higher than a certain flicker rate appears to stand still to direct visualization, but with a rate of light exposure and imaging above the flicker rate by video, the true movement of the object can be identified.¹¹ Video stroboscopy is considered highly sensitive for organic disorders of vocal cords, but it is not specific for either organic or dysfunctional disorders.¹¹ It is still the gold standard above direct visualization, as it can detect abnormal movement of vocal cords above the critical rate that the human eye would perceive as not moving due to the frequency of movement (Figures 1 & 2).¹¹
In an older study, laryngoscopy was able to diagnose 100% of patients with symptomatic paradoxical vocal cord movement and additional 60% asymptomatic patients with a constellation of symptoms consistent with paradoxical vocal cord movement.¹²
Speech Therapy; Ear, Nose, and Throat (ENT); and Pulmonology may not perform direct visualization in these patients at initial presentation due to other suspected diagnoses. A more common test is the PFT, especially if asthma or other airway tract diseases are suspected (Figure 3).
Patient Descriptions
Study patients were referred for a variety of reasons, often from primary care clinics for concerns for asthma, episodic dyspnea, wheezing, or decreased exercise tolerance thought to be related to pulmonary or allergy causes. Pulmonology worked closely with Speech Therapy and referred VCD cases for speech evaluation, including video stroboscopy. Notably, of the patients in this cohort, although some were suspected to have asthma, those patients were ruled out during part of the pulmonology evaluation, both with PFT testing and methacholine challenges. An asthma diagnosis is important in a military treatment facility, as asthma is often grounds for discharge.
Patients ranged in age from 13 to 68 years, with a median age at 31 years diagnosis. Thirty-nine females and 61 males comprised the total case series. Speech Therapy diagnosed 97 patients, 96 were diagnosed at Eglin AFB hospital via stroboscopy. One patient was diagnosed off-base by Speech Therapy via direct visualization, 1 patient was diagnosed by Pulmonology on-base via direct visualization, and 2 patients were diagnosed by ENT on-base via direct visualization. These patients had direct laryngoscopy completed, often to rule out other organic causes for upper airway disease processes, and were found to have visual paradoxical vocal cord movement. Ninety-eight patients completed PFTs. Several patients were lost to follow-up, as can be common in a military population with frequent moves or members leaving service.
On record review, patient symptoms were present in the range of 2 months to 20 years, with a median duration of symptomatic reports lasting 2 years prior to diagnosis. Common diagnoses prior to visual VCD diagnosis included asthma, exercise-induced asthma, anxiety, and episodic wheezing. Risk factors that were evaluated in this case series included age, sex, body mass index (BMI), GERD, allergic rhinitis, postnasal drip, active smoker, previous smoker, and mental health diagnoses (Figure 4).
Pulmonary function test results were analyzed on 98 patients, including forced expiratory volume in 1 second (FEV1); forced vital capacity (FVC), FEV1/FVC ratio; peak inspiratory flow (PIF) and peak expiratory flow (PEF)—available in 97 studies; forced expiratory flow (FEF) at 25% to 75% of FVC (FEF 25%-75%)—available in 96 studies; and maximum voluntary ventilation (MVV) and MVV/FEV1 ratio—available in 60 of 98 PFTs.
Interventions
All patients diagnosed by Speech Therapy on-base were provided with laryngeal relaxation techniques, diaphragmatic breathing techniques, and controlled inhale/exhale techniques at time of diagnosis, with frequent follow-up scheduled with Speech Therapy and Pulmonology. All diagnoses potentially contributing to laryngeal irritation were treated, including GERD, allergic rhinitis, smoking cessation, weight loss, and exercise recommendations as needed.
Patients reported improvement on follow-up appointments with Speech Therapy in overall control of symptoms, subjectively categorized as poor improvement, partial improvement, and complete improvement. This was a subjective measurement of improvement and fully dependent on follow-up care and patient reporting for improvement. No predefined number of follow-ups was determined; patients were followed monthly until they declined further care, fully improved, moved out of the military treatment system, or were lost to follow-up.
Treatment included structured Speech Therapy sessions. Response to treatment was subjectively qualified by patient report. Fifteen patients reported complete resolution of symptoms, 57 reported partial improvement, 24 reported poor improvement, and 4 patients were lost to follow-up.
Results
Risk factors for the diagnosis of VCD included possible associations with GERD, allergic rhinitis, smoking, prior smoking, BMI, and mental health diagnoses. Body mass index ranged from 17 to 36 in the case series, with median BMI of 27. Mental health diagnoses were present in 35 patients and included diagnoses of anxiety, depression, and adjustment disorders. Gastroesophageal reflux disease diagnosis was present in 59 of the case series patients, 80 had the diagnosis of allergic rhinitis, 63 were diagnosed with postnasal drip. Sixteen case series patients were current smokers. An additional 26 were previous smokers (at least 100 cigarettes in lifetime) for a total of 42 patients that were current or prior smokers.
The chart review was completed to evaluate for the presence of these diagnoses, which included previous treatments; for example, proton pump inhibitors for GERD, antidepressants for depression, or intranasal steroids for allergic rhinitis. The diagnosis was counted as present if the patient was currently being treated for the particular diagnosis in question.
PFT Data
Data from PFTs were available for 98 of 100 cases diagnosed. Review of data across all 98 patients is noted for median FEV1 of 3.6, a median FVC of 4.5, with ratio of 0.80.
Since PFT values vary according to age, sex, and ethnicity, PFTs were analyzed for percent predicted values based on age, gender, and race. Notably, median values for FEV1, FVC, and PEF were all close to 100% of the predicted value. The MVV percent predicted was available in 60 cases and was 93% of predicted values. The most significant difference from expected values was FEF 25% to 75%, at 84% of expected results.
Flow-volume loop evaluations on the 97 PFTs available were completed, and 58 of the 97 were noted for variable extrathoracic airway obstruction consistent with inspiratory inhibition in the patient population. This is 60% of the available PFTs in this cohort study.
Discussion
This retrospective chart review of 100 consecutive VCD diagnoses in a military treatment facility reinforces many of the findings currently available in the literature. As illustrated in a Chest review article, the diagnosis of VCD on history, physical examination, or PFTs remains ellusive.1 The PFT evaluation contains some subjectivity regarding the flattening of inspiratory flow-volume loops and is not routinely reported in PFT results. In patients diagnosed with VCD, a clear consensus of treatment modalities remains lacking. Modification of risk factors (allergic rhinitis, GERD, smoking cessation, weight loss) assisted in self-reported patient improvement, as did focused speech therapy.
The median age of 31 years, likely reflected the younger military population served at Eglin AFB. Seventy-five of these patients were currently on active duty, 6 were retired from active duty (veterans), and 19 were dependents. The median time of symptoms to diagnosis was 2 years. Prior misdiagnosis with other diseases such as asthma was common. Also, referral to Pulmonology and Speech Therapy was usually completed after failed outpatient primary care management for the alternative diagnoses.
Improvement with therapy was mixed, and during the time of documented follow-up, 72 patients reported complete or partial improvement. Most active-duty patients in the partial improvement category based this subjective reporting on their ability to meet military physical fitness standards.
Previous data suggested a female predominance, but this study population was 61% male. Military populations are about 80% to 85% male, so an increase in male diagnosis is expected.
Many patients in the patient cohort arrived as a result of Pulmonology referrals with a presumptive diagnoses of asthma but were determined not to have asthma through PFT results inconsistent with asthma, no improvement with β-agonist therapies, and negative methacholine challenges (if performed). These results prompted evaluations for other conditions and eventually a VCD diagnosis. As noted, exclusion of asthma is of particular importance in a military population, as medical discharges often are pursued in service members with asthma whether controlled or uncontrolled. Lag time to referral also is possible in failures of military physical, which prompted medical evaluation once several failures had occurred over a 1- to 2-year time frame.
The PFT data evaluation was inconclusive for statistically significant changes when compared with age-matched normal PFT values. This also was noted in previous studies of VCD cases. Most notable was percent predicted values of FEF 25% to 75%, with 84% of expected values. The FEV1, FVC, and PEF all fell within predicted values of normal, despite wide ranges in age, sex, and ethnicity among the subjects. Inspiratory flattening consistent with extrathoracic obstruction was present in 58 of the 97 PFTs available for review at Eglin AFB.
Limitations
Limitations to this retrospective case series are illustrated here. Cases were found only when VCD was diagnosed and coded; and it is the authors’ suspicion that many have been misdiagnosed or improperly treated for asthma or other pulmonary/oropharynx conditions. If providers are not familiar with VCD or if PFT readings do not comment on inspiratory findings, diagnosis is less likely. Some of the authors’ colleagues already have determined that postdeployment prevalence of VCD seems to be elevated.8
This cohort was completed on all patients in a military treatment facility, with 75 active-duty personnel, 6 veterans, and 19 dependents of varying ages. This case series is retrospective and tabulates suspected risk factors; stronger and more informative studies could certainly be completed in prospective studies (although likely difficult with low prevalence) or in treatment comparison studies at the time of diagnosis.
Since the cohort had varied and lengthy time to diagnosis from onset of related symptoms, the treatment patients received prior to diagnosis differed extensively. Diagnosis was completed by numerous primary care managers or other subspecialties prior to arrival to Pulmonology and Speech Therapy at Eglin AFB. Once diagnosed in Speech Therapy, consistent treatment options were provided to patients in accordance with standard of care.
It is the authors’ suspicion that VCD may have a higher prevalence than previously reported in the literature. Military service members are tested annually or biannually on physical fitness standards and are evaluated for medical reasons for recurrent fitness standard failures. This selection of patients is more likely to have a VCD evaluation as part of a comprehensive evaluation than is a healthy adult in a civilian population. A prospective study in military service members would be more fruitful and possibly yield a higher prevalence postdeployment.
Conclusion
Vocal cord dysfunction remains a difficult diagnosis to treat, because multiple comorbidities likely contribute to the diagnosis. This retrospective case series attempted to compile common themes and noted that most of the patients had 2 or more risk factors of smoking, allergic rhinitis, GERD, or mental health diagnoses. A prospective trial would be ideal to evaluate VCD further. A focused trial in the particular communities of athletes or of military service members may be of increased benefit to better define VCD. It is notable that 100 cases were found in a relatively short period for a community hospital, and prevalence may be higher than previously reported.
1. Morris MJ, Christopher KL. Diagnostic criteria for the classification of vocal cord dysfunction. Chest. 2010;138(5):1213-1223.
2. National Heart, Lung, and Blood Institute. Expert panel report 3: guidelines for the diagnoses and management of asthma. Full report 2007. https://www.nhlbi.nih.gov/files/docs/guidelines/asthgdln .pdf. Published 2007.Accessed February 1, 2017.
3. Newman KB, Mason UG III, Schmaling KB. Clinical features of vocal cord dysfunction. Am J Respir Crit Care Med. 1995;152(4, pt 1):1382-1386.
4. Sanz Santiago V, López Neyra A, Almería Gil E, Villa Asensi JR. Spirometry patterns in vocal cord dysfunction [in Spanish]. An Pediatr (Barc). 2013;78(3):173-177.
5. Deckert J, Deckert L. Vocal cord dysfunction. Am Fam Physician. 2010;81(2):156-159.
6. Benninger C, Parsons JP, Mastronarde JG. Vocal cord dysfunction and asthma. Curr Opin Pulm Med. 2011;17(1):45-49.
7. Campainha S, Ribeiro C, Guimar M, Lima R. Vocal cord dysfunction: a frequently forgotten entity. Case Rep Pulmonol. 2012;2012:525493.
8. Morris MJ, Oleszewski RT, Sterner JB, Allan PF. Vocal cord dysfunction related to combat deployment. Mil Med. 2013;178(11):1208-1212.
9. Al-Alwan A, Kaminsky D. Vocal cord dysfunction in athletes: clinical presentation and review of the literature. Phys Sportsmed. 2012;40(2):22-27.
10. Kenn K, Schmitz M. Prevalence of vocal cord dysfunction in patients with dyspnea. First prospective clinical study. Am J Respir Crit Care Med. 1997;155:A965.
11. Wendler, J, Nawka, T, Verges, D. Instructional course: videolaryngo-stroboscopy and phonetography—basic tools for diagnostics and documentation in the voice clinic. Poster presented at: 15th European Congress of Oto-Rhino-Laryngology, Head and Neck Surgery; September 11-16, 2004; Rodos-Kos, Greece.
12. Ibrahim WH, Gheriani HA, Almohamed AA, Raza T. Paradoxical vocal cord motion disorder: past, present and future. Postgrad Med J. 2007;83(977):164-172.
1. Morris MJ, Christopher KL. Diagnostic criteria for the classification of vocal cord dysfunction. Chest. 2010;138(5):1213-1223.
2. National Heart, Lung, and Blood Institute. Expert panel report 3: guidelines for the diagnoses and management of asthma. Full report 2007. https://www.nhlbi.nih.gov/files/docs/guidelines/asthgdln .pdf. Published 2007.Accessed February 1, 2017.
3. Newman KB, Mason UG III, Schmaling KB. Clinical features of vocal cord dysfunction. Am J Respir Crit Care Med. 1995;152(4, pt 1):1382-1386.
4. Sanz Santiago V, López Neyra A, Almería Gil E, Villa Asensi JR. Spirometry patterns in vocal cord dysfunction [in Spanish]. An Pediatr (Barc). 2013;78(3):173-177.
5. Deckert J, Deckert L. Vocal cord dysfunction. Am Fam Physician. 2010;81(2):156-159.
6. Benninger C, Parsons JP, Mastronarde JG. Vocal cord dysfunction and asthma. Curr Opin Pulm Med. 2011;17(1):45-49.
7. Campainha S, Ribeiro C, Guimar M, Lima R. Vocal cord dysfunction: a frequently forgotten entity. Case Rep Pulmonol. 2012;2012:525493.
8. Morris MJ, Oleszewski RT, Sterner JB, Allan PF. Vocal cord dysfunction related to combat deployment. Mil Med. 2013;178(11):1208-1212.
9. Al-Alwan A, Kaminsky D. Vocal cord dysfunction in athletes: clinical presentation and review of the literature. Phys Sportsmed. 2012;40(2):22-27.
10. Kenn K, Schmitz M. Prevalence of vocal cord dysfunction in patients with dyspnea. First prospective clinical study. Am J Respir Crit Care Med. 1997;155:A965.
11. Wendler, J, Nawka, T, Verges, D. Instructional course: videolaryngo-stroboscopy and phonetography—basic tools for diagnostics and documentation in the voice clinic. Poster presented at: 15th European Congress of Oto-Rhino-Laryngology, Head and Neck Surgery; September 11-16, 2004; Rodos-Kos, Greece.
12. Ibrahim WH, Gheriani HA, Almohamed AA, Raza T. Paradoxical vocal cord motion disorder: past, present and future. Postgrad Med J. 2007;83(977):164-172.
Combined Anterior-Posterior Decompression and Fusion for Cervical Spondylotic Myelopathy
Take-Home Points
- Surgical intervention for cervical spondylosis and radiculopathy classically involves either an anterior or posterior approach for adequate decompression of the spinal cord and associated nerve roots.
- Combined anterior-posterior surgery for cervical spondylotic myelopathy is a relatively new technique that has previously been used for disorders of the thoracolumbar spine.
- Combined anterior-posterior cervical decompression and fusion for the treatment of cervical spondylotic myelopathy is associated with minor complications and excellent neurologic outcomes.
- Combined surgery can either be performed in a single day or in a staged manner, with current literature showing that same-day surgery is superior with respect to estimated blood loss and length of stay.
Cervical spondylotic myelopathy (CSM) is a degenerative disease characterized by progressive compression of the spinal cord. CSM has been found to be the most common cause of spinal impairment as well as the most frequently acquired cause of spinal dysfunction in people over 55 years of age.1,2 If left untreated, this condition can reduce manual dexterity and cause gait disturbances, dysesthesias, and weakness in the extremities. When conservative treatments fail, surgical intervention often becomes the preferred course of action for CSM and/or myeloradiculopathy.
The surgical approach for CSM and other advanced cervical spine (CS) deformities varies and is often a source of debate. Being a relatively safe and effective procedure, anterior decompression with fusion is optimal in treating discogenic lesions causing myelopathy but is less effective in multilevel disease.3,4 When pseudarthrosis, adjacent segment degeneration (ASD), and hardware failure are of concern, posterior decompressive laminectomy with instrumentation is a promising option.5 However, this method is less effective in restoring lordosis and can increase the risk for later clinical deterioration.6 There is a select subset of patients for whom a combined anterior-posterior approach is ideal.7-9In cases in which a combined anterior-posterior approach is identified as the best treatment option, whether to perform the operation in a sequential or staged manner must be decided, and this question is another source of debate. Single-day surgery is sometimes anecdotally criticized as posing a greater risk to the patient. On the other hand, some comparative studies have shown no statistically significant difference in major complication rates between the 2 options.10,11 More descriptive studies of combined anterior-posterior decompression and fusion (CAPDF) are needed to explore the efficacy of the procedure. In this article, we describe a study we conducted to characterize the operative data, perioperative complications, and short-term outcomes associated with CAPDF for the treatment of CSM in a select group of patients.
Methods
After receiving Institutional Review Board approval for this study (formal consent was not required), we retrospectively reviewed the charts of 21 patients who underwent CAPDF for CSM at our institution. All patients underwent surgery between February 2010 and March 2015. Criteria for inclusion in the study included same-day CAPDF for CSM. Staged procedures were excluded, as were combined procedures for the treatment of other diseases (eg, malignancies). All patients were operated on by the same primary surgeon (Dr. Davis) and co-surgeon (Dr. Labiak). The 1 patient who was lost to follow-up was excluded from the postoperative outcome analysis.
We reviewed the patients’ medical records for surgical consultations, operative reports, intraoperative reports, progress notes, and postoperative office visit reports. Demographic information included age, sex, body mass index, and preoperative risk factors, such as diabetes and tobacco use. All patients had been diagnosed with myelopathy. Clinical data included previous history of CS surgery, levels fused (and number of levels fused) anteriorly and posteriorly, operative time, estimated blood loss (EBL), length of stay (LOS), and perioperative complications. Short-term (3-month follow-up) neurologic improvement was determined both objectively, with the Nurick grading system,12 and subjectively, with determination of patient quality of life before and after surgery and with neurologic examination.
Operative Technique: Anterior Approach
All operations were performed with continuous somatosensory evoked potential monitoring of both upper and lower extremities. Each patient, positioned supine with the head in a neutral position, underwent standard endotracheal intubation. Intubation was followed by a transverse incision and dissection down to the deep cervical fascia with maintenance of the carotid sheath laterally and tracheoesophageal complex medially. Interspaces were identified and later were confirmed with lateral radiographs. Discectomy, osteophytectomy, and removal of hypertrophied or calcified ligament were then performed until decompression was satisfactory. Corpectomies were not performed. Polyetheretherketone interbody spacers (Stryker) were used with autograft harvested from vertebral body resection. Low-profile screw-plate systems were placed. After completion of the anterior procedure, the patient was placed prone, with the head fixed in a Mayfield clamping device in neutral position and with all pressure points carefully padded.
Operative Technique: Posterior Approach
A midline incision was made through the skin and subcutaneous tissue to the level of the deep cervical fascia. Then, dissection was performed to the tips of the lateral masses. Instrumentation and fusion preceded spinal decompression. This order, chosen to preserve bony landmarks for guidance during instrumentation, did not interfere with subsequent decompression. Segmental spinal instrumentation was placed using lateral mass screw-rod fixation. After the laminae and ligamenta flava were bilaterally mobilized, the entire bony ligamentous complex spanning the area of fusion was removed en masse (most commonly C3–C7) in order to decrease the number of instrument passes near the spinal cord. Next, a modest foraminotomy was performed to extend the opening laterally and ensure adequate decompression of the nerve roots. Autograft harvested from the spinous processes and laminae was used. The posterior portion of the operation contributed significantly to blood loss and postoperative pain during the perioperative period. We recommend performing a very meticulous dissection to minimize these consequences. No patient in this study required a halo orthosis.
Results
Twenty-one patients with CSM were treated with CAPDF between February 2010 and March 2015 (Table 1). 
Table 2 summarizes the operative data. Mean number of levels fused was 2 (range, 1-3) anteriorly and 3 (range, 1-4) posteriorly. 
Of the 21 patients, 9 (42.3%) had at least 1 complication during the perioperative period. Table 3 summarizes all encountered complications. Neither neurologic instability nor mortality was observed after surgery. 
Patient 7 was lost to follow-up. For the other 20 patients, mean time to “3-month follow-up” was 96 days (range, 51-149 days). The most commonly noted improvements in quality of life included resolution of numbness, improvement in gait, and return to previous activities, such as walking and even exercising. 
Representative Case
Patient 15, a 53-year-old man, presented with complaints of dysesthesias of the hands. Focused neurologic evaluation at the time revealed limited CS range of motion on extension. The patient (Figures 2A-2D) was diffusely hyperreflexic and had pathologic spread in the upper extremities. 
Discussion
Cervical myelopathy is a common yet frequently underdiagnosed disease, owing to the fact that many patients remain asymptomatic even after experiencing degenerative changes in the spinal column.14-16 The additive effects of spondylosis, osteophyte formation, ligamentous hypertrophy, and listhesis lead to progressive canal and intervertebral foraminal compromise, ultimately producing the clinical syndromes of myelopathy and radiculopathy.17 The characteristic symptoms of CSM are known to have an insidious onset. In the early stages, patients note a subtle gait disturbance and later experience manual dexterity reductions and upper extremity dysesthesias.18 As the condition progresses and conservative management fails, surgical intervention is sought.
Nevertheless, the pursuit of surgical treatment for CSM remains somewhat controversial. Some authors have found no statistically significant difference between conservative and surgical management of mild to moderate CSM,19 whereas others have found that surgically treated patients had much better outcomes than their medically treated counterparts.20 In 2010, Scardino and colleagues21 reported that CSM patients who were bedridden and/or wheelchair-bound with seemingly irreversible myelopathy were capable of neurologic improvement after surgical intervention. At the very least, what remains clear is that untreated CSM is known to follow an unpredictable course, with the condition deteriorating faster for some patients than others.22Traditional anterior or posterior approaches, which can be used in the majority of cases of cervical spondylosis and/or radiculopathy, have been compared extensively.23,24 The inverse relationship concerning the integrity of an anterior construct and the number of levels fused is a well-established clinical finding.3,4,8,25-28 Laminectomy with fusion is not without its disadvantages: Cervical instability secondary to mechanical loss of posterior cervical support, and subsequent post-laminectomy kyphosis, is a common complication.23 In cases in which more stability is required, the combined anterior-posterior approach is more promising than either approach alone. This technique has its roots in the treatment of several thoracolumbar spine disorders, including infections, scoliosis, trauma, and tumors.29-31 More recently, the technique has been applied to CS disorders.
In 2008, Gok and colleagues32 retrospectively compared the results of anterior-only fusion and CAPDF for CSM. Forty-six patients underwent anterior surgery only, and 21 underwent CAPDF. The groups’ complication rates were similar: 28.6% (anterior only) and 24% (CAPDF); the incidence of ASD was lower in the combined group. Song and colleagues33 conducted a similar study in 2010. They compared anterior fusion alone and CAPDF in treating degenerative cervical kyphosis. Results were strongly in favor of the combined technique, as it led to “greater correction of sagittal alignment, a better maintenance of correction angle, a higher rate of fusion, a lower rate of subsidence and lower complications.” Both studies established that, in a select group of patients, the benefits of CAPDF outweighed the risks. These findings, combined with our study’s findings of no major complications and the transience of minor complications, suggest CAPDF should not be considered too invasive or risky.
The results of our study also mirror those of 3 other studies on the use of CAPDF for CS disorders. In 1995, McAfee and colleagues34 reported on a group of 100 patients with follow-up of 2 years or more. In most cases, the surgical indication was trauma, but neoplasm, infection, rheumatoid arthritis, and CSM were found as well. Outcomes were very favorable: improvement in a previous neurologic deficit (57/75 patients), ability to walk again (21/35 patients), no new neurologic deficits, and no hardware failures. In 2000, Schultz and colleagues35 retrospectively reviewed the cases of 72 patients who underwent CAPDF for a variety of complex CS disorders. Two of the 72 experienced transient neurologic deficits, and, though the immediate complication rate was relatively high (32%), the long-term complication rate was down to 5%. In 2009, Konya and colleagues36 retrospectively reviewed the cases of 40 patients who underwent CAPDF, primarily for CSM. Within 1 week after surgery, neurologic deficits were reduced in 36 patients; by 1 year after surgery, neurologic deficits were reduced in all 40 patients, and fusion was achieved in 39. These 3 studies34-36 helped establish CAPDF of the CS as a viable and effective procedure that can be performed within a single day.
Although many physicians have achieved favorable results with single-day surgery, the decision to operate in a sequential or staged manner remains controversial. Some anecdotally claim CAPDF poses a greater operative risk to the patient. In 1991, the continuous procedure was found to involve less blood loss and shorter LOS while providing for better correction of severe spinal deformity in patients with scoliosis and rigid kyphosis.37 Three more recent comparative studies examining the same issue in the treatment of CS diseases found staging did not reduce the complication rate and may in fact have been associated with higher complication rates, more blood loss, and longer total operative time and LOS.10,11,38 Our study’s lower blood loss, shorter LOS, and lower major complication rate relative to the combined groups in all 3 of those studies are most likely attributable to our operating on a lower mean number of spinal levels and our restricting the surgical indication to CSM. The positive short-term outcomes and low rate of long-term complications in our study, combined with the data from these 3 comparative studies, suggest that same-day surgery is superior to staged surgery. A staged operation should be considered only if the patient cannot tolerate long periods under general anesthesia.
Many have advocated extending fusion down to T1 to prevent ASD at the C7–T1 disk space.35,39,40 We decided against this approach for 2 reasons. First, at C7, lateral mass screws were always chosen over pedicle screws. When possible, shorter lateral mass screws were used at this level, making C7 much less rigid. Second, the C7–T1 facet capsule was maintained to preserve joint integrity. We suggest extending fusion down to T1 only if there is prior evidence of spinal disease and/or listhesis at C7–T1. Although long-term (many-year) follow-up is often desired, we specifically assessed short-term (3-month) outcomes. We have anecdotally found that degree of improvement often follows a predictable course after 3-month follow-up. If myelopathy resolves even to a small extent during the first 3 postoperative months, later improvement will likely follow an upward course. Conversely, if myelopathy does not improve during the first 3 months, further improvement is much less likely.
This trend in neurologic improvement likely is directly related to degree of myelopathy before surgery. Patients with CSM generally experience symptoms over an extended period and try conservative management before any surgical consultation. Although spinal ischemia is often resolved by decompression, permanent ischemic damage to the cord is not uncommon. In this setting, postoperative neurologic improvement is minimal or even nonexistent, and decompression is preventive rather than curative. In our study, 1 patient had no subjective improvement after surgery. At 3-month follow-up, magnetic resonance imaging showed notable myelomalacia without residual spinal cord compression. We attribute the failure of the ischemic changes to resolve to long-standing preoperative damage to the cord. Nevertheless, surgery stabilized the myelopathy and prevented further ischemic damage and clinical deterioration.
As is the case with any operation, patients must be carefully selected for CAPDF. Indications for CAPDF, as described by Kim and Alexander,7 include acute spinal trauma, post-laminectomy kyphosis, kyphotic deformity with intact posterior tension band, multilevel spondylosis and OPLL, and preexisting risk factors for pseudarthrosis. Clearly, the severity of each varies, and the pathologies are not mutually exclusive. We emphasize that these indications provide only a guideline for performing CAPDF, and patients must be selected on a case-by-case basis. All the patients in our study were symptomatic and exhibited significant compression of the spinal cord anteriorly and posteriorly at multiple levels. Several presented with concomitant pathologies, such as cervical kyphotic deformity, congenital spinal stenosis, and OPLL. In each case, the indication for surgical intervention was undoubted. We sought both to improve the patient’s baseline symptoms and to prevent further damage to the spinal cord.
This study had its limitations. First, its retrospective design predisposed it to a higher degree of bias. Second, because CAPDF is not commonly performed, the sample size was relatively small. Third, although it provided a descriptive analysis of CAPDF for CSM, the study did not use a direct comparison group to establish whether treatment within a single day or staged treatment was more beneficial for our cohort in particular. On the basis of prior experience and observation, we think performing the operation within a single day is much more beneficial for the patient. Our discussion of studies that have compared same-day and staged surgery supports this observation. Therefore, staged treatment was not recommended to our patients.
Conclusion
Few descriptive studies have explored CAPDF for CSM. Our study’s results showed the procedure was associated with minor complications and provided symptomatic relief for a majority of patients as early as 3 months after surgery. In addition, CAPDF can be successfully performed sequentially within a single day. As such, it represents an excellent option for treating multilevel symptomatic CSM cases that require more extensive spinal decompression and more stability.
Am J Orthop. 2017;46(2):E97-E104. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
1. Baptiste DC, Fehlings MG. Pathophysiology of cervical myelopathy. Spine J. 2006;6(6 suppl):190S-197S.
2. Kalsi-Ryan S, Karadimas SK, Fehlings MG. Cervical spondylotic myelopathy: the clinical phenomenon and the current pathobiology of an increasingly prevalent and devastating disorder. Neuroscientist. 2013;19(4):409-421.
3. Sasso RC, Ruggiero RA Jr, Reilly TM, Hall PV. Early reconstruction failures after multilevel cervical corpectomy. Spine. 2003;28(2):140-142.
4. Zdeblick TA, Hughes SS, Riew KD, Bohlman HH. Failed anterior cervical discectomy and arthrodesis. Analysis and treatment of thirty-five patients. J Bone Joint Surg Am. 1997;79(4):523-532.
5. Zhu B, Xu Y, Liu X, Liu Z, Dang G. Anterior approach versus posterior approach for the treatment of multilevel cervical spondylotic myelopathy: a systemic review and meta-analysis. Eur Spine J. 2013;22(7):1583-1593.
6. Cabraja M, Abbushi A, Koeppen D, Kroppenstedt S, Woiciechowsky C. Comparison between anterior and posterior decompression with instrumentation for cervical spondylotic myelopathy: sagittal alignment and clinical outcome. Neurosurg Focus. 2010;28(3):E15.
7. Kim PK, Alexander JT. Indications for circumferential surgery for cervical spondylotic myelopathy. Spine J. 2006;6(6 suppl):299S-307S.
8. König SA, Ranguis S, Spetzger U. Management of complex cervical instability. J Neurol Surg A Cent Eur Neurosurg. 2015;76(2):119-125.
9. König SA, Spetzger U. Surgical management of cervical spondylotic myelopathy—indications for anterior, posterior or combined procedures for decompression and stabilisation. Acta Neurochir. 2014;156(2):253-258.
10. Harel R, Hwang R, Fakhar M, et al. Circumferential cervical surgery: to stage or not to stage? J Spinal Disord Tech. 2013;26(4):183-188.
11. Siemionow K, Tyrakowski M, Patel K, Neckrysh S. Comparison of perioperative complications following staged versus one-day anterior and posterior cervical decompression and fusion crossing the cervico-thoracic junction. Neurol Neurochir Pol. 2014;48(6):403-409.
12. Nurick S. The pathogenesis of the spinal cord disorder associated with cervical spondylosis. Brain. 1972;95(1):87-100.
13. Chen CJ, Saulle D, Fu KM, Smith JS, Shaffrey CI. Dysphagia following combined anterior-posterior cervical spine surgeries. J Neurosurg Spine. 2013;19(3):279-287.
14. Boden SD, McCowin PR, Davis DO, Dina TS, Mark AS, Wiesel S. Abnormal magnetic-resonance scans of the cervical spine in asymptomatic subjects. A prospective investigation. J Bone Joint Surg Am. 1990;72(8):1178-1184.
15. Gore DR, Sepic SB, Gardner GM. Roentgenographic findings of the cervical spine in asymptomatic people. Spine. 1986;11(6):521-524.
16. Law MD Jr, Bernhardt M, White AA 3rd. Cervical spondylotic myelopathy: a review of surgical indications and decision making. Yale J Biol Med. 1993;66(3):165-177.
17. Kelly JC, Groarke PJ, Butler JS, Poynton AR, O’Byrne JM. The natural history and clinical syndromes of degenerative cervical spondylosis. Adv Orthop. 2012;(2012):393642.
18. Baron EM, Young WF. Cervical spondylotic myelopathy: a brief review of its pathophysiology, clinical course, and diagnosis. Neurosurgery. 2007;60(1 suppl 1):S35-S41.
19. Kadanka Z, Mares M, Bednarik J, et al. Approaches to spondylotic cervical myelopathy: conservative versus surgical results in a 3-year follow-up study. Spine. 2002;27(20):2205-2210.
20. Sampath P, Bendebba M, Davis JD, Ducker TB. Outcome of patients treated for cervical myelopathy. A prospective, multicenter study with independent clinical review. Spine. 2000;25(6):670-676.
21. Scardino FB, Rocha LP, Barcelos AC, Rotta JM, Botelho RV. Is there a benefit to operating on patients (bedridden or in wheelchairs) with advanced stage cervical spondylotic myelopathy? Eur Spine J. 2010;19(5):699-705.
22. Edwards CC 2nd, Riew KD, Anderson PA, Hilibrand AS, Vaccaro AF. Cervical myelopathy. Current diagnostic and treatment strategies. Spine J. 2003;3(1):68-81.
23. Herkowitz HN. A comparison of anterior cervical fusion, cervical laminectomy, and cervical laminoplasty for the surgical management of multiple level spondylotic radiculopathy. Spine. 1988;13(7):774-780.
24. Hukuda S, Mochizuki T, Ogata M, Shichikawa K, Shimomura Y. Operations for cervical spondylotic myelopathy. A comparison of the results of anterior and posterior procedures. J Bone Joint Surg Br. 1985;67(4):609-615.
25. Fernyhough JC, White JI, LaRocca H. Fusion rates in multilevel cervical spondylosis comparing allograft fibula with autograft fibula in 126 patients. Spine. 1991;16(10 suppl):S561-S564.
26. Macdonald RL, Fehlings MG, Tator CH, et al. Multilevel anterior cervical corpectomy and fibular allograft fusion for cervical myelopathy. J Neurosurg. 1997;86(6):990-997.
27. Mayr MT, Subach BR, Comey CH, Rodts GE, Haid RW Jr. Cervical spinal stenosis: outcome after anterior corpectomy, allograft reconstruction, and instrumentation. J Neurosurg. 2002;96(1 suppl):10-16.
28. Swank ML, Lowery GL, Bhat AL, McDonough RF. Anterior cervical allograft arthrodesis and instrumentation: multilevel interbody grafting or strut graft reconstruction. Eur Spine J. 1997;6(2):138-143.
29. Böhm H, Harms J, Donk R, Zielke K. Correction and stabilization of angular kyphosis. Clin Orthop Relat Res. 1990;(258):56-61.
30. Spencer DL, DeWald RL. Simultaneous anterior and posterior surgical approach to the thoracic and lumbar spine. Spine. 1979;4(1):29-36.
31. Whitesides TE Jr, Shah SGA. On the management of unstable fractures of the thoracolumbar spine: rationale for use of anterior decompression and fusion and posterior stabilization. Spine. 1976;1(2):99-107.
32. Gok B, Sciubba DM, McLoughlin GS, et al. Surgical treatment of cervical spondylotic myelopathy with anterior compression: a review of 67 cases. J Neurosurg Spine. 2008;9(2):152-157.
33. Song KJ, Johnson JS, Choi BR, Wang JC, Lee KB. Anterior fusion alone compared with combined anterior and posterior fusion for the treatment of degenerative cervical kyphosis. J Bone Joint Surg Br. 2010;92(11):1548-1552.
34. McAfee PC, Bohlman HH, Ducker TB, Zeidman SM, Goldstein JA. One-stage anterior cervical decompression and posterior stabilization. A study of one hundred patients with a minimum of two years of follow-up. J Bone Joint Surg Am. 1995;77(12):1791-1800.
35. Schultz KD Jr, McLaughlin MR, Haid RW Jr, Comey CH, Rodts GE Jr, Alexander J. Single-stage anterior-posterior decompression and stabilization for complex cervical spine disorders. J Neurosurg. 2000;93(2 suppl):214-221.
36. Konya D, Ozgen S, Gercek A, Pamir MN. Outcomes for combined anterior and posterior surgical approaches for patients with multisegmental cervical spondylotic myelopathy. J Clin Neurosci. 2009;16(3):404-409.
37. Shufflebarger HL, Grimm JO, Bui V, Thomson JD. Anterior and posterior spinal fusion. Staged versus same-day surgery. Spine. 1991;16(8):930-933.
38. Ozturk C, Aydinli U, Vural R, Sehirlioglu A, Mutlu M. Simultaneous versus sequential one-stage combined anterior and posterior spinal surgery for spinal infections (outcomes and complications). Int Orthop. 2007;31(3):363-366.
39. Aryan HE, Sanchez-Mejia RO, Ben-Haim S, Ames CP. Successful treatment of cervical myelopathy with minimal morbidity by circumferential decompression and fusion. Eur Spine J. 2007;16(9):1401-1409.
40. Steinmetz MP, Miller J, Warbel A, Krishnaney AA, Bingaman W, Benzel EC. Regional instability following cervicothoracic junction surgery. J Neurosurg Spine. 2006;4(4):278-284.
Take-Home Points
- Surgical intervention for cervical spondylosis and radiculopathy classically involves either an anterior or posterior approach for adequate decompression of the spinal cord and associated nerve roots.
- Combined anterior-posterior surgery for cervical spondylotic myelopathy is a relatively new technique that has previously been used for disorders of the thoracolumbar spine.
- Combined anterior-posterior cervical decompression and fusion for the treatment of cervical spondylotic myelopathy is associated with minor complications and excellent neurologic outcomes.
- Combined surgery can either be performed in a single day or in a staged manner, with current literature showing that same-day surgery is superior with respect to estimated blood loss and length of stay.
Cervical spondylotic myelopathy (CSM) is a degenerative disease characterized by progressive compression of the spinal cord. CSM has been found to be the most common cause of spinal impairment as well as the most frequently acquired cause of spinal dysfunction in people over 55 years of age.1,2 If left untreated, this condition can reduce manual dexterity and cause gait disturbances, dysesthesias, and weakness in the extremities. When conservative treatments fail, surgical intervention often becomes the preferred course of action for CSM and/or myeloradiculopathy.
The surgical approach for CSM and other advanced cervical spine (CS) deformities varies and is often a source of debate. Being a relatively safe and effective procedure, anterior decompression with fusion is optimal in treating discogenic lesions causing myelopathy but is less effective in multilevel disease.3,4 When pseudarthrosis, adjacent segment degeneration (ASD), and hardware failure are of concern, posterior decompressive laminectomy with instrumentation is a promising option.5 However, this method is less effective in restoring lordosis and can increase the risk for later clinical deterioration.6 There is a select subset of patients for whom a combined anterior-posterior approach is ideal.7-9In cases in which a combined anterior-posterior approach is identified as the best treatment option, whether to perform the operation in a sequential or staged manner must be decided, and this question is another source of debate. Single-day surgery is sometimes anecdotally criticized as posing a greater risk to the patient. On the other hand, some comparative studies have shown no statistically significant difference in major complication rates between the 2 options.10,11 More descriptive studies of combined anterior-posterior decompression and fusion (CAPDF) are needed to explore the efficacy of the procedure. In this article, we describe a study we conducted to characterize the operative data, perioperative complications, and short-term outcomes associated with CAPDF for the treatment of CSM in a select group of patients.
Methods
After receiving Institutional Review Board approval for this study (formal consent was not required), we retrospectively reviewed the charts of 21 patients who underwent CAPDF for CSM at our institution. All patients underwent surgery between February 2010 and March 2015. Criteria for inclusion in the study included same-day CAPDF for CSM. Staged procedures were excluded, as were combined procedures for the treatment of other diseases (eg, malignancies). All patients were operated on by the same primary surgeon (Dr. Davis) and co-surgeon (Dr. Labiak). The 1 patient who was lost to follow-up was excluded from the postoperative outcome analysis.
We reviewed the patients’ medical records for surgical consultations, operative reports, intraoperative reports, progress notes, and postoperative office visit reports. Demographic information included age, sex, body mass index, and preoperative risk factors, such as diabetes and tobacco use. All patients had been diagnosed with myelopathy. Clinical data included previous history of CS surgery, levels fused (and number of levels fused) anteriorly and posteriorly, operative time, estimated blood loss (EBL), length of stay (LOS), and perioperative complications. Short-term (3-month follow-up) neurologic improvement was determined both objectively, with the Nurick grading system,12 and subjectively, with determination of patient quality of life before and after surgery and with neurologic examination.
Operative Technique: Anterior Approach
All operations were performed with continuous somatosensory evoked potential monitoring of both upper and lower extremities. Each patient, positioned supine with the head in a neutral position, underwent standard endotracheal intubation. Intubation was followed by a transverse incision and dissection down to the deep cervical fascia with maintenance of the carotid sheath laterally and tracheoesophageal complex medially. Interspaces were identified and later were confirmed with lateral radiographs. Discectomy, osteophytectomy, and removal of hypertrophied or calcified ligament were then performed until decompression was satisfactory. Corpectomies were not performed. Polyetheretherketone interbody spacers (Stryker) were used with autograft harvested from vertebral body resection. Low-profile screw-plate systems were placed. After completion of the anterior procedure, the patient was placed prone, with the head fixed in a Mayfield clamping device in neutral position and with all pressure points carefully padded.
Operative Technique: Posterior Approach
A midline incision was made through the skin and subcutaneous tissue to the level of the deep cervical fascia. Then, dissection was performed to the tips of the lateral masses. Instrumentation and fusion preceded spinal decompression. This order, chosen to preserve bony landmarks for guidance during instrumentation, did not interfere with subsequent decompression. Segmental spinal instrumentation was placed using lateral mass screw-rod fixation. After the laminae and ligamenta flava were bilaterally mobilized, the entire bony ligamentous complex spanning the area of fusion was removed en masse (most commonly C3–C7) in order to decrease the number of instrument passes near the spinal cord. Next, a modest foraminotomy was performed to extend the opening laterally and ensure adequate decompression of the nerve roots. Autograft harvested from the spinous processes and laminae was used. The posterior portion of the operation contributed significantly to blood loss and postoperative pain during the perioperative period. We recommend performing a very meticulous dissection to minimize these consequences. No patient in this study required a halo orthosis.
Results
Twenty-one patients with CSM were treated with CAPDF between February 2010 and March 2015 (Table 1).
Table 2 summarizes the operative data. Mean number of levels fused was 2 (range, 1-3) anteriorly and 3 (range, 1-4) posteriorly.
Of the 21 patients, 9 (42.3%) had at least 1 complication during the perioperative period. Table 3 summarizes all encountered complications. Neither neurologic instability nor mortality was observed after surgery.
Patient 7 was lost to follow-up. For the other 20 patients, mean time to “3-month follow-up” was 96 days (range, 51-149 days). The most commonly noted improvements in quality of life included resolution of numbness, improvement in gait, and return to previous activities, such as walking and even exercising.
Representative Case
Patient 15, a 53-year-old man, presented with complaints of dysesthesias of the hands. Focused neurologic evaluation at the time revealed limited CS range of motion on extension. The patient (Figures 2A-2D) was diffusely hyperreflexic and had pathologic spread in the upper extremities.
Discussion
Cervical myelopathy is a common yet frequently underdiagnosed disease, owing to the fact that many patients remain asymptomatic even after experiencing degenerative changes in the spinal column.14-16 The additive effects of spondylosis, osteophyte formation, ligamentous hypertrophy, and listhesis lead to progressive canal and intervertebral foraminal compromise, ultimately producing the clinical syndromes of myelopathy and radiculopathy.17 The characteristic symptoms of CSM are known to have an insidious onset. In the early stages, patients note a subtle gait disturbance and later experience manual dexterity reductions and upper extremity dysesthesias.18 As the condition progresses and conservative management fails, surgical intervention is sought.
Nevertheless, the pursuit of surgical treatment for CSM remains somewhat controversial. Some authors have found no statistically significant difference between conservative and surgical management of mild to moderate CSM,19 whereas others have found that surgically treated patients had much better outcomes than their medically treated counterparts.20 In 2010, Scardino and colleagues21 reported that CSM patients who were bedridden and/or wheelchair-bound with seemingly irreversible myelopathy were capable of neurologic improvement after surgical intervention. At the very least, what remains clear is that untreated CSM is known to follow an unpredictable course, with the condition deteriorating faster for some patients than others.22Traditional anterior or posterior approaches, which can be used in the majority of cases of cervical spondylosis and/or radiculopathy, have been compared extensively.23,24 The inverse relationship concerning the integrity of an anterior construct and the number of levels fused is a well-established clinical finding.3,4,8,25-28 Laminectomy with fusion is not without its disadvantages: Cervical instability secondary to mechanical loss of posterior cervical support, and subsequent post-laminectomy kyphosis, is a common complication.23 In cases in which more stability is required, the combined anterior-posterior approach is more promising than either approach alone. This technique has its roots in the treatment of several thoracolumbar spine disorders, including infections, scoliosis, trauma, and tumors.29-31 More recently, the technique has been applied to CS disorders.
In 2008, Gok and colleagues32 retrospectively compared the results of anterior-only fusion and CAPDF for CSM. Forty-six patients underwent anterior surgery only, and 21 underwent CAPDF. The groups’ complication rates were similar: 28.6% (anterior only) and 24% (CAPDF); the incidence of ASD was lower in the combined group. Song and colleagues33 conducted a similar study in 2010. They compared anterior fusion alone and CAPDF in treating degenerative cervical kyphosis. Results were strongly in favor of the combined technique, as it led to “greater correction of sagittal alignment, a better maintenance of correction angle, a higher rate of fusion, a lower rate of subsidence and lower complications.” Both studies established that, in a select group of patients, the benefits of CAPDF outweighed the risks. These findings, combined with our study’s findings of no major complications and the transience of minor complications, suggest CAPDF should not be considered too invasive or risky.
The results of our study also mirror those of 3 other studies on the use of CAPDF for CS disorders. In 1995, McAfee and colleagues34 reported on a group of 100 patients with follow-up of 2 years or more. In most cases, the surgical indication was trauma, but neoplasm, infection, rheumatoid arthritis, and CSM were found as well. Outcomes were very favorable: improvement in a previous neurologic deficit (57/75 patients), ability to walk again (21/35 patients), no new neurologic deficits, and no hardware failures. In 2000, Schultz and colleagues35 retrospectively reviewed the cases of 72 patients who underwent CAPDF for a variety of complex CS disorders. Two of the 72 experienced transient neurologic deficits, and, though the immediate complication rate was relatively high (32%), the long-term complication rate was down to 5%. In 2009, Konya and colleagues36 retrospectively reviewed the cases of 40 patients who underwent CAPDF, primarily for CSM. Within 1 week after surgery, neurologic deficits were reduced in 36 patients; by 1 year after surgery, neurologic deficits were reduced in all 40 patients, and fusion was achieved in 39. These 3 studies34-36 helped establish CAPDF of the CS as a viable and effective procedure that can be performed within a single day.
Although many physicians have achieved favorable results with single-day surgery, the decision to operate in a sequential or staged manner remains controversial. Some anecdotally claim CAPDF poses a greater operative risk to the patient. In 1991, the continuous procedure was found to involve less blood loss and shorter LOS while providing for better correction of severe spinal deformity in patients with scoliosis and rigid kyphosis.37 Three more recent comparative studies examining the same issue in the treatment of CS diseases found staging did not reduce the complication rate and may in fact have been associated with higher complication rates, more blood loss, and longer total operative time and LOS.10,11,38 Our study’s lower blood loss, shorter LOS, and lower major complication rate relative to the combined groups in all 3 of those studies are most likely attributable to our operating on a lower mean number of spinal levels and our restricting the surgical indication to CSM. The positive short-term outcomes and low rate of long-term complications in our study, combined with the data from these 3 comparative studies, suggest that same-day surgery is superior to staged surgery. A staged operation should be considered only if the patient cannot tolerate long periods under general anesthesia.
Many have advocated extending fusion down to T1 to prevent ASD at the C7–T1 disk space.35,39,40 We decided against this approach for 2 reasons. First, at C7, lateral mass screws were always chosen over pedicle screws. When possible, shorter lateral mass screws were used at this level, making C7 much less rigid. Second, the C7–T1 facet capsule was maintained to preserve joint integrity. We suggest extending fusion down to T1 only if there is prior evidence of spinal disease and/or listhesis at C7–T1. Although long-term (many-year) follow-up is often desired, we specifically assessed short-term (3-month) outcomes. We have anecdotally found that degree of improvement often follows a predictable course after 3-month follow-up. If myelopathy resolves even to a small extent during the first 3 postoperative months, later improvement will likely follow an upward course. Conversely, if myelopathy does not improve during the first 3 months, further improvement is much less likely.
This trend in neurologic improvement likely is directly related to degree of myelopathy before surgery. Patients with CSM generally experience symptoms over an extended period and try conservative management before any surgical consultation. Although spinal ischemia is often resolved by decompression, permanent ischemic damage to the cord is not uncommon. In this setting, postoperative neurologic improvement is minimal or even nonexistent, and decompression is preventive rather than curative. In our study, 1 patient had no subjective improvement after surgery. At 3-month follow-up, magnetic resonance imaging showed notable myelomalacia without residual spinal cord compression. We attribute the failure of the ischemic changes to resolve to long-standing preoperative damage to the cord. Nevertheless, surgery stabilized the myelopathy and prevented further ischemic damage and clinical deterioration.
As is the case with any operation, patients must be carefully selected for CAPDF. Indications for CAPDF, as described by Kim and Alexander,7 include acute spinal trauma, post-laminectomy kyphosis, kyphotic deformity with intact posterior tension band, multilevel spondylosis and OPLL, and preexisting risk factors for pseudarthrosis. Clearly, the severity of each varies, and the pathologies are not mutually exclusive. We emphasize that these indications provide only a guideline for performing CAPDF, and patients must be selected on a case-by-case basis. All the patients in our study were symptomatic and exhibited significant compression of the spinal cord anteriorly and posteriorly at multiple levels. Several presented with concomitant pathologies, such as cervical kyphotic deformity, congenital spinal stenosis, and OPLL. In each case, the indication for surgical intervention was undoubted. We sought both to improve the patient’s baseline symptoms and to prevent further damage to the spinal cord.
This study had its limitations. First, its retrospective design predisposed it to a higher degree of bias. Second, because CAPDF is not commonly performed, the sample size was relatively small. Third, although it provided a descriptive analysis of CAPDF for CSM, the study did not use a direct comparison group to establish whether treatment within a single day or staged treatment was more beneficial for our cohort in particular. On the basis of prior experience and observation, we think performing the operation within a single day is much more beneficial for the patient. Our discussion of studies that have compared same-day and staged surgery supports this observation. Therefore, staged treatment was not recommended to our patients.
Conclusion
Few descriptive studies have explored CAPDF for CSM. Our study’s results showed the procedure was associated with minor complications and provided symptomatic relief for a majority of patients as early as 3 months after surgery. In addition, CAPDF can be successfully performed sequentially within a single day. As such, it represents an excellent option for treating multilevel symptomatic CSM cases that require more extensive spinal decompression and more stability.
Am J Orthop. 2017;46(2):E97-E104. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
Take-Home Points
- Surgical intervention for cervical spondylosis and radiculopathy classically involves either an anterior or posterior approach for adequate decompression of the spinal cord and associated nerve roots.
- Combined anterior-posterior surgery for cervical spondylotic myelopathy is a relatively new technique that has previously been used for disorders of the thoracolumbar spine.
- Combined anterior-posterior cervical decompression and fusion for the treatment of cervical spondylotic myelopathy is associated with minor complications and excellent neurologic outcomes.
- Combined surgery can either be performed in a single day or in a staged manner, with current literature showing that same-day surgery is superior with respect to estimated blood loss and length of stay.
Cervical spondylotic myelopathy (CSM) is a degenerative disease characterized by progressive compression of the spinal cord. CSM has been found to be the most common cause of spinal impairment as well as the most frequently acquired cause of spinal dysfunction in people over 55 years of age.1,2 If left untreated, this condition can reduce manual dexterity and cause gait disturbances, dysesthesias, and weakness in the extremities. When conservative treatments fail, surgical intervention often becomes the preferred course of action for CSM and/or myeloradiculopathy.
The surgical approach for CSM and other advanced cervical spine (CS) deformities varies and is often a source of debate. Being a relatively safe and effective procedure, anterior decompression with fusion is optimal in treating discogenic lesions causing myelopathy but is less effective in multilevel disease.3,4 When pseudarthrosis, adjacent segment degeneration (ASD), and hardware failure are of concern, posterior decompressive laminectomy with instrumentation is a promising option.5 However, this method is less effective in restoring lordosis and can increase the risk for later clinical deterioration.6 There is a select subset of patients for whom a combined anterior-posterior approach is ideal.7-9In cases in which a combined anterior-posterior approach is identified as the best treatment option, whether to perform the operation in a sequential or staged manner must be decided, and this question is another source of debate. Single-day surgery is sometimes anecdotally criticized as posing a greater risk to the patient. On the other hand, some comparative studies have shown no statistically significant difference in major complication rates between the 2 options.10,11 More descriptive studies of combined anterior-posterior decompression and fusion (CAPDF) are needed to explore the efficacy of the procedure. In this article, we describe a study we conducted to characterize the operative data, perioperative complications, and short-term outcomes associated with CAPDF for the treatment of CSM in a select group of patients.
Methods
After receiving Institutional Review Board approval for this study (formal consent was not required), we retrospectively reviewed the charts of 21 patients who underwent CAPDF for CSM at our institution. All patients underwent surgery between February 2010 and March 2015. Criteria for inclusion in the study included same-day CAPDF for CSM. Staged procedures were excluded, as were combined procedures for the treatment of other diseases (eg, malignancies). All patients were operated on by the same primary surgeon (Dr. Davis) and co-surgeon (Dr. Labiak). The 1 patient who was lost to follow-up was excluded from the postoperative outcome analysis.
We reviewed the patients’ medical records for surgical consultations, operative reports, intraoperative reports, progress notes, and postoperative office visit reports. Demographic information included age, sex, body mass index, and preoperative risk factors, such as diabetes and tobacco use. All patients had been diagnosed with myelopathy. Clinical data included previous history of CS surgery, levels fused (and number of levels fused) anteriorly and posteriorly, operative time, estimated blood loss (EBL), length of stay (LOS), and perioperative complications. Short-term (3-month follow-up) neurologic improvement was determined both objectively, with the Nurick grading system,12 and subjectively, with determination of patient quality of life before and after surgery and with neurologic examination.
Operative Technique: Anterior Approach
All operations were performed with continuous somatosensory evoked potential monitoring of both upper and lower extremities. Each patient, positioned supine with the head in a neutral position, underwent standard endotracheal intubation. Intubation was followed by a transverse incision and dissection down to the deep cervical fascia with maintenance of the carotid sheath laterally and tracheoesophageal complex medially. Interspaces were identified and later were confirmed with lateral radiographs. Discectomy, osteophytectomy, and removal of hypertrophied or calcified ligament were then performed until decompression was satisfactory. Corpectomies were not performed. Polyetheretherketone interbody spacers (Stryker) were used with autograft harvested from vertebral body resection. Low-profile screw-plate systems were placed. After completion of the anterior procedure, the patient was placed prone, with the head fixed in a Mayfield clamping device in neutral position and with all pressure points carefully padded.
Operative Technique: Posterior Approach
A midline incision was made through the skin and subcutaneous tissue to the level of the deep cervical fascia. Then, dissection was performed to the tips of the lateral masses. Instrumentation and fusion preceded spinal decompression. This order, chosen to preserve bony landmarks for guidance during instrumentation, did not interfere with subsequent decompression. Segmental spinal instrumentation was placed using lateral mass screw-rod fixation. After the laminae and ligamenta flava were bilaterally mobilized, the entire bony ligamentous complex spanning the area of fusion was removed en masse (most commonly C3–C7) in order to decrease the number of instrument passes near the spinal cord. Next, a modest foraminotomy was performed to extend the opening laterally and ensure adequate decompression of the nerve roots. Autograft harvested from the spinous processes and laminae was used. The posterior portion of the operation contributed significantly to blood loss and postoperative pain during the perioperative period. We recommend performing a very meticulous dissection to minimize these consequences. No patient in this study required a halo orthosis.
Results
Twenty-one patients with CSM were treated with CAPDF between February 2010 and March 2015 (Table 1).
Table 2 summarizes the operative data. Mean number of levels fused was 2 (range, 1-3) anteriorly and 3 (range, 1-4) posteriorly.
Of the 21 patients, 9 (42.3%) had at least 1 complication during the perioperative period. Table 3 summarizes all encountered complications. Neither neurologic instability nor mortality was observed after surgery.
Patient 7 was lost to follow-up. For the other 20 patients, mean time to “3-month follow-up” was 96 days (range, 51-149 days). The most commonly noted improvements in quality of life included resolution of numbness, improvement in gait, and return to previous activities, such as walking and even exercising.
Representative Case
Patient 15, a 53-year-old man, presented with complaints of dysesthesias of the hands. Focused neurologic evaluation at the time revealed limited CS range of motion on extension. The patient (Figures 2A-2D) was diffusely hyperreflexic and had pathologic spread in the upper extremities.
Discussion
Cervical myelopathy is a common yet frequently underdiagnosed disease, owing to the fact that many patients remain asymptomatic even after experiencing degenerative changes in the spinal column.14-16 The additive effects of spondylosis, osteophyte formation, ligamentous hypertrophy, and listhesis lead to progressive canal and intervertebral foraminal compromise, ultimately producing the clinical syndromes of myelopathy and radiculopathy.17 The characteristic symptoms of CSM are known to have an insidious onset. In the early stages, patients note a subtle gait disturbance and later experience manual dexterity reductions and upper extremity dysesthesias.18 As the condition progresses and conservative management fails, surgical intervention is sought.
Nevertheless, the pursuit of surgical treatment for CSM remains somewhat controversial. Some authors have found no statistically significant difference between conservative and surgical management of mild to moderate CSM,19 whereas others have found that surgically treated patients had much better outcomes than their medically treated counterparts.20 In 2010, Scardino and colleagues21 reported that CSM patients who were bedridden and/or wheelchair-bound with seemingly irreversible myelopathy were capable of neurologic improvement after surgical intervention. At the very least, what remains clear is that untreated CSM is known to follow an unpredictable course, with the condition deteriorating faster for some patients than others.22Traditional anterior or posterior approaches, which can be used in the majority of cases of cervical spondylosis and/or radiculopathy, have been compared extensively.23,24 The inverse relationship concerning the integrity of an anterior construct and the number of levels fused is a well-established clinical finding.3,4,8,25-28 Laminectomy with fusion is not without its disadvantages: Cervical instability secondary to mechanical loss of posterior cervical support, and subsequent post-laminectomy kyphosis, is a common complication.23 In cases in which more stability is required, the combined anterior-posterior approach is more promising than either approach alone. This technique has its roots in the treatment of several thoracolumbar spine disorders, including infections, scoliosis, trauma, and tumors.29-31 More recently, the technique has been applied to CS disorders.
In 2008, Gok and colleagues32 retrospectively compared the results of anterior-only fusion and CAPDF for CSM. Forty-six patients underwent anterior surgery only, and 21 underwent CAPDF. The groups’ complication rates were similar: 28.6% (anterior only) and 24% (CAPDF); the incidence of ASD was lower in the combined group. Song and colleagues33 conducted a similar study in 2010. They compared anterior fusion alone and CAPDF in treating degenerative cervical kyphosis. Results were strongly in favor of the combined technique, as it led to “greater correction of sagittal alignment, a better maintenance of correction angle, a higher rate of fusion, a lower rate of subsidence and lower complications.” Both studies established that, in a select group of patients, the benefits of CAPDF outweighed the risks. These findings, combined with our study’s findings of no major complications and the transience of minor complications, suggest CAPDF should not be considered too invasive or risky.
The results of our study also mirror those of 3 other studies on the use of CAPDF for CS disorders. In 1995, McAfee and colleagues34 reported on a group of 100 patients with follow-up of 2 years or more. In most cases, the surgical indication was trauma, but neoplasm, infection, rheumatoid arthritis, and CSM were found as well. Outcomes were very favorable: improvement in a previous neurologic deficit (57/75 patients), ability to walk again (21/35 patients), no new neurologic deficits, and no hardware failures. In 2000, Schultz and colleagues35 retrospectively reviewed the cases of 72 patients who underwent CAPDF for a variety of complex CS disorders. Two of the 72 experienced transient neurologic deficits, and, though the immediate complication rate was relatively high (32%), the long-term complication rate was down to 5%. In 2009, Konya and colleagues36 retrospectively reviewed the cases of 40 patients who underwent CAPDF, primarily for CSM. Within 1 week after surgery, neurologic deficits were reduced in 36 patients; by 1 year after surgery, neurologic deficits were reduced in all 40 patients, and fusion was achieved in 39. These 3 studies34-36 helped establish CAPDF of the CS as a viable and effective procedure that can be performed within a single day.
Although many physicians have achieved favorable results with single-day surgery, the decision to operate in a sequential or staged manner remains controversial. Some anecdotally claim CAPDF poses a greater operative risk to the patient. In 1991, the continuous procedure was found to involve less blood loss and shorter LOS while providing for better correction of severe spinal deformity in patients with scoliosis and rigid kyphosis.37 Three more recent comparative studies examining the same issue in the treatment of CS diseases found staging did not reduce the complication rate and may in fact have been associated with higher complication rates, more blood loss, and longer total operative time and LOS.10,11,38 Our study’s lower blood loss, shorter LOS, and lower major complication rate relative to the combined groups in all 3 of those studies are most likely attributable to our operating on a lower mean number of spinal levels and our restricting the surgical indication to CSM. The positive short-term outcomes and low rate of long-term complications in our study, combined with the data from these 3 comparative studies, suggest that same-day surgery is superior to staged surgery. A staged operation should be considered only if the patient cannot tolerate long periods under general anesthesia.
Many have advocated extending fusion down to T1 to prevent ASD at the C7–T1 disk space.35,39,40 We decided against this approach for 2 reasons. First, at C7, lateral mass screws were always chosen over pedicle screws. When possible, shorter lateral mass screws were used at this level, making C7 much less rigid. Second, the C7–T1 facet capsule was maintained to preserve joint integrity. We suggest extending fusion down to T1 only if there is prior evidence of spinal disease and/or listhesis at C7–T1. Although long-term (many-year) follow-up is often desired, we specifically assessed short-term (3-month) outcomes. We have anecdotally found that degree of improvement often follows a predictable course after 3-month follow-up. If myelopathy resolves even to a small extent during the first 3 postoperative months, later improvement will likely follow an upward course. Conversely, if myelopathy does not improve during the first 3 months, further improvement is much less likely.
This trend in neurologic improvement likely is directly related to degree of myelopathy before surgery. Patients with CSM generally experience symptoms over an extended period and try conservative management before any surgical consultation. Although spinal ischemia is often resolved by decompression, permanent ischemic damage to the cord is not uncommon. In this setting, postoperative neurologic improvement is minimal or even nonexistent, and decompression is preventive rather than curative. In our study, 1 patient had no subjective improvement after surgery. At 3-month follow-up, magnetic resonance imaging showed notable myelomalacia without residual spinal cord compression. We attribute the failure of the ischemic changes to resolve to long-standing preoperative damage to the cord. Nevertheless, surgery stabilized the myelopathy and prevented further ischemic damage and clinical deterioration.
As is the case with any operation, patients must be carefully selected for CAPDF. Indications for CAPDF, as described by Kim and Alexander,7 include acute spinal trauma, post-laminectomy kyphosis, kyphotic deformity with intact posterior tension band, multilevel spondylosis and OPLL, and preexisting risk factors for pseudarthrosis. Clearly, the severity of each varies, and the pathologies are not mutually exclusive. We emphasize that these indications provide only a guideline for performing CAPDF, and patients must be selected on a case-by-case basis. All the patients in our study were symptomatic and exhibited significant compression of the spinal cord anteriorly and posteriorly at multiple levels. Several presented with concomitant pathologies, such as cervical kyphotic deformity, congenital spinal stenosis, and OPLL. In each case, the indication for surgical intervention was undoubted. We sought both to improve the patient’s baseline symptoms and to prevent further damage to the spinal cord.
This study had its limitations. First, its retrospective design predisposed it to a higher degree of bias. Second, because CAPDF is not commonly performed, the sample size was relatively small. Third, although it provided a descriptive analysis of CAPDF for CSM, the study did not use a direct comparison group to establish whether treatment within a single day or staged treatment was more beneficial for our cohort in particular. On the basis of prior experience and observation, we think performing the operation within a single day is much more beneficial for the patient. Our discussion of studies that have compared same-day and staged surgery supports this observation. Therefore, staged treatment was not recommended to our patients.
Conclusion
Few descriptive studies have explored CAPDF for CSM. Our study’s results showed the procedure was associated with minor complications and provided symptomatic relief for a majority of patients as early as 3 months after surgery. In addition, CAPDF can be successfully performed sequentially within a single day. As such, it represents an excellent option for treating multilevel symptomatic CSM cases that require more extensive spinal decompression and more stability.
Am J Orthop. 2017;46(2):E97-E104. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.
1. Baptiste DC, Fehlings MG. Pathophysiology of cervical myelopathy. Spine J. 2006;6(6 suppl):190S-197S.
2. Kalsi-Ryan S, Karadimas SK, Fehlings MG. Cervical spondylotic myelopathy: the clinical phenomenon and the current pathobiology of an increasingly prevalent and devastating disorder. Neuroscientist. 2013;19(4):409-421.
3. Sasso RC, Ruggiero RA Jr, Reilly TM, Hall PV. Early reconstruction failures after multilevel cervical corpectomy. Spine. 2003;28(2):140-142.
4. Zdeblick TA, Hughes SS, Riew KD, Bohlman HH. Failed anterior cervical discectomy and arthrodesis. Analysis and treatment of thirty-five patients. J Bone Joint Surg Am. 1997;79(4):523-532.
5. Zhu B, Xu Y, Liu X, Liu Z, Dang G. Anterior approach versus posterior approach for the treatment of multilevel cervical spondylotic myelopathy: a systemic review and meta-analysis. Eur Spine J. 2013;22(7):1583-1593.
6. Cabraja M, Abbushi A, Koeppen D, Kroppenstedt S, Woiciechowsky C. Comparison between anterior and posterior decompression with instrumentation for cervical spondylotic myelopathy: sagittal alignment and clinical outcome. Neurosurg Focus. 2010;28(3):E15.
7. Kim PK, Alexander JT. Indications for circumferential surgery for cervical spondylotic myelopathy. Spine J. 2006;6(6 suppl):299S-307S.
8. König SA, Ranguis S, Spetzger U. Management of complex cervical instability. J Neurol Surg A Cent Eur Neurosurg. 2015;76(2):119-125.
9. König SA, Spetzger U. Surgical management of cervical spondylotic myelopathy—indications for anterior, posterior or combined procedures for decompression and stabilisation. Acta Neurochir. 2014;156(2):253-258.
10. Harel R, Hwang R, Fakhar M, et al. Circumferential cervical surgery: to stage or not to stage? J Spinal Disord Tech. 2013;26(4):183-188.
11. Siemionow K, Tyrakowski M, Patel K, Neckrysh S. Comparison of perioperative complications following staged versus one-day anterior and posterior cervical decompression and fusion crossing the cervico-thoracic junction. Neurol Neurochir Pol. 2014;48(6):403-409.
12. Nurick S. The pathogenesis of the spinal cord disorder associated with cervical spondylosis. Brain. 1972;95(1):87-100.
13. Chen CJ, Saulle D, Fu KM, Smith JS, Shaffrey CI. Dysphagia following combined anterior-posterior cervical spine surgeries. J Neurosurg Spine. 2013;19(3):279-287.
14. Boden SD, McCowin PR, Davis DO, Dina TS, Mark AS, Wiesel S. Abnormal magnetic-resonance scans of the cervical spine in asymptomatic subjects. A prospective investigation. J Bone Joint Surg Am. 1990;72(8):1178-1184.
15. Gore DR, Sepic SB, Gardner GM. Roentgenographic findings of the cervical spine in asymptomatic people. Spine. 1986;11(6):521-524.
16. Law MD Jr, Bernhardt M, White AA 3rd. Cervical spondylotic myelopathy: a review of surgical indications and decision making. Yale J Biol Med. 1993;66(3):165-177.
17. Kelly JC, Groarke PJ, Butler JS, Poynton AR, O’Byrne JM. The natural history and clinical syndromes of degenerative cervical spondylosis. Adv Orthop. 2012;(2012):393642.
18. Baron EM, Young WF. Cervical spondylotic myelopathy: a brief review of its pathophysiology, clinical course, and diagnosis. Neurosurgery. 2007;60(1 suppl 1):S35-S41.
19. Kadanka Z, Mares M, Bednarik J, et al. Approaches to spondylotic cervical myelopathy: conservative versus surgical results in a 3-year follow-up study. Spine. 2002;27(20):2205-2210.
20. Sampath P, Bendebba M, Davis JD, Ducker TB. Outcome of patients treated for cervical myelopathy. A prospective, multicenter study with independent clinical review. Spine. 2000;25(6):670-676.
21. Scardino FB, Rocha LP, Barcelos AC, Rotta JM, Botelho RV. Is there a benefit to operating on patients (bedridden or in wheelchairs) with advanced stage cervical spondylotic myelopathy? Eur Spine J. 2010;19(5):699-705.
22. Edwards CC 2nd, Riew KD, Anderson PA, Hilibrand AS, Vaccaro AF. Cervical myelopathy. Current diagnostic and treatment strategies. Spine J. 2003;3(1):68-81.
23. Herkowitz HN. A comparison of anterior cervical fusion, cervical laminectomy, and cervical laminoplasty for the surgical management of multiple level spondylotic radiculopathy. Spine. 1988;13(7):774-780.
24. Hukuda S, Mochizuki T, Ogata M, Shichikawa K, Shimomura Y. Operations for cervical spondylotic myelopathy. A comparison of the results of anterior and posterior procedures. J Bone Joint Surg Br. 1985;67(4):609-615.
25. Fernyhough JC, White JI, LaRocca H. Fusion rates in multilevel cervical spondylosis comparing allograft fibula with autograft fibula in 126 patients. Spine. 1991;16(10 suppl):S561-S564.
26. Macdonald RL, Fehlings MG, Tator CH, et al. Multilevel anterior cervical corpectomy and fibular allograft fusion for cervical myelopathy. J Neurosurg. 1997;86(6):990-997.
27. Mayr MT, Subach BR, Comey CH, Rodts GE, Haid RW Jr. Cervical spinal stenosis: outcome after anterior corpectomy, allograft reconstruction, and instrumentation. J Neurosurg. 2002;96(1 suppl):10-16.
28. Swank ML, Lowery GL, Bhat AL, McDonough RF. Anterior cervical allograft arthrodesis and instrumentation: multilevel interbody grafting or strut graft reconstruction. Eur Spine J. 1997;6(2):138-143.
29. Böhm H, Harms J, Donk R, Zielke K. Correction and stabilization of angular kyphosis. Clin Orthop Relat Res. 1990;(258):56-61.
30. Spencer DL, DeWald RL. Simultaneous anterior and posterior surgical approach to the thoracic and lumbar spine. Spine. 1979;4(1):29-36.
31. Whitesides TE Jr, Shah SGA. On the management of unstable fractures of the thoracolumbar spine: rationale for use of anterior decompression and fusion and posterior stabilization. Spine. 1976;1(2):99-107.
32. Gok B, Sciubba DM, McLoughlin GS, et al. Surgical treatment of cervical spondylotic myelopathy with anterior compression: a review of 67 cases. J Neurosurg Spine. 2008;9(2):152-157.
33. Song KJ, Johnson JS, Choi BR, Wang JC, Lee KB. Anterior fusion alone compared with combined anterior and posterior fusion for the treatment of degenerative cervical kyphosis. J Bone Joint Surg Br. 2010;92(11):1548-1552.
34. McAfee PC, Bohlman HH, Ducker TB, Zeidman SM, Goldstein JA. One-stage anterior cervical decompression and posterior stabilization. A study of one hundred patients with a minimum of two years of follow-up. J Bone Joint Surg Am. 1995;77(12):1791-1800.
35. Schultz KD Jr, McLaughlin MR, Haid RW Jr, Comey CH, Rodts GE Jr, Alexander J. Single-stage anterior-posterior decompression and stabilization for complex cervical spine disorders. J Neurosurg. 2000;93(2 suppl):214-221.
36. Konya D, Ozgen S, Gercek A, Pamir MN. Outcomes for combined anterior and posterior surgical approaches for patients with multisegmental cervical spondylotic myelopathy. J Clin Neurosci. 2009;16(3):404-409.
37. Shufflebarger HL, Grimm JO, Bui V, Thomson JD. Anterior and posterior spinal fusion. Staged versus same-day surgery. Spine. 1991;16(8):930-933.
38. Ozturk C, Aydinli U, Vural R, Sehirlioglu A, Mutlu M. Simultaneous versus sequential one-stage combined anterior and posterior spinal surgery for spinal infections (outcomes and complications). Int Orthop. 2007;31(3):363-366.
39. Aryan HE, Sanchez-Mejia RO, Ben-Haim S, Ames CP. Successful treatment of cervical myelopathy with minimal morbidity by circumferential decompression and fusion. Eur Spine J. 2007;16(9):1401-1409.
40. Steinmetz MP, Miller J, Warbel A, Krishnaney AA, Bingaman W, Benzel EC. Regional instability following cervicothoracic junction surgery. J Neurosurg Spine. 2006;4(4):278-284.
1. Baptiste DC, Fehlings MG. Pathophysiology of cervical myelopathy. Spine J. 2006;6(6 suppl):190S-197S.
2. Kalsi-Ryan S, Karadimas SK, Fehlings MG. Cervical spondylotic myelopathy: the clinical phenomenon and the current pathobiology of an increasingly prevalent and devastating disorder. Neuroscientist. 2013;19(4):409-421.
3. Sasso RC, Ruggiero RA Jr, Reilly TM, Hall PV. Early reconstruction failures after multilevel cervical corpectomy. Spine. 2003;28(2):140-142.
4. Zdeblick TA, Hughes SS, Riew KD, Bohlman HH. Failed anterior cervical discectomy and arthrodesis. Analysis and treatment of thirty-five patients. J Bone Joint Surg Am. 1997;79(4):523-532.
5. Zhu B, Xu Y, Liu X, Liu Z, Dang G. Anterior approach versus posterior approach for the treatment of multilevel cervical spondylotic myelopathy: a systemic review and meta-analysis. Eur Spine J. 2013;22(7):1583-1593.
6. Cabraja M, Abbushi A, Koeppen D, Kroppenstedt S, Woiciechowsky C. Comparison between anterior and posterior decompression with instrumentation for cervical spondylotic myelopathy: sagittal alignment and clinical outcome. Neurosurg Focus. 2010;28(3):E15.
7. Kim PK, Alexander JT. Indications for circumferential surgery for cervical spondylotic myelopathy. Spine J. 2006;6(6 suppl):299S-307S.
8. König SA, Ranguis S, Spetzger U. Management of complex cervical instability. J Neurol Surg A Cent Eur Neurosurg. 2015;76(2):119-125.
9. König SA, Spetzger U. Surgical management of cervical spondylotic myelopathy—indications for anterior, posterior or combined procedures for decompression and stabilisation. Acta Neurochir. 2014;156(2):253-258.
10. Harel R, Hwang R, Fakhar M, et al. Circumferential cervical surgery: to stage or not to stage? J Spinal Disord Tech. 2013;26(4):183-188.
11. Siemionow K, Tyrakowski M, Patel K, Neckrysh S. Comparison of perioperative complications following staged versus one-day anterior and posterior cervical decompression and fusion crossing the cervico-thoracic junction. Neurol Neurochir Pol. 2014;48(6):403-409.
12. Nurick S. The pathogenesis of the spinal cord disorder associated with cervical spondylosis. Brain. 1972;95(1):87-100.
13. Chen CJ, Saulle D, Fu KM, Smith JS, Shaffrey CI. Dysphagia following combined anterior-posterior cervical spine surgeries. J Neurosurg Spine. 2013;19(3):279-287.
14. Boden SD, McCowin PR, Davis DO, Dina TS, Mark AS, Wiesel S. Abnormal magnetic-resonance scans of the cervical spine in asymptomatic subjects. A prospective investigation. J Bone Joint Surg Am. 1990;72(8):1178-1184.
15. Gore DR, Sepic SB, Gardner GM. Roentgenographic findings of the cervical spine in asymptomatic people. Spine. 1986;11(6):521-524.
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