Neurology

SAN FRANCISCO – Assessing the impact of tardive dyskinesia on the lives of patients requires more than just visual observation, Stanley N. Caroff, MD, said at the annual meeting of the American Psychiatric Association.

“You really need to ask the patient a lot of questions – and the family and the caregivers – about how much tardive dyskinesia affects their lives,” he said.

Those were some of the early results of RE-KINECT, an ongoing study of patients with schizophrenia and schizoaffective disorder who were being treated with antipsychotic agents.

TD occurs in more than 25% of patients in outpatient practices who are exposed to dopamine receptor blockers. Symptoms can include involuntary movements of the tongue, hands, and feet; facial distortions; rapid eye blinking; and difficulty speaking. In some cases, the side effects resolve after patients stop taking the medications.

In this video, Dr. Caroff discussed the studies’ findings and their implications for everyday clinical practice. He also presented some of the early RE-KINECT findings in a poster at the meeting.

Dr. Caroff is professor of psychiatry at the University of Pennsylvania, Philadelphia. He also is affiliated with the Michael J. Crescenz VA Medical Center in Philadelphia. He disclosed working as a consultant for and receiving research funding from Neurocrine Biosciences. He also is a consultant for DisperSol Technologies, Osmotica Pharmaceuticals, Teva Pharmaceutical.

[email protected]

SAN FRANCISCO – Assessing the impact of tardive dyskinesia on the lives of patients requires more than just visual observation, Stanley N. Caroff, MD, said at the annual meeting of the American Psychiatric Association.

“You really need to ask the patient a lot of questions – and the family and the caregivers – about how much tardive dyskinesia affects their lives,” he said.

Those were some of the early results of RE-KINECT, an ongoing study of patients with schizophrenia and schizoaffective disorder who were being treated with antipsychotic agents.

TD occurs in more than 25% of patients in outpatient practices who are exposed to dopamine receptor blockers. Symptoms can include involuntary movements of the tongue, hands, and feet; facial distortions; rapid eye blinking; and difficulty speaking. In some cases, the side effects resolve after patients stop taking the medications.

In this video, Dr. Caroff discussed the studies’ findings and their implications for everyday clinical practice. He also presented some of the early RE-KINECT findings in a poster at the meeting.

Dr. Caroff is professor of psychiatry at the University of Pennsylvania, Philadelphia. He also is affiliated with the Michael J. Crescenz VA Medical Center in Philadelphia. He disclosed working as a consultant for and receiving research funding from Neurocrine Biosciences. He also is a consultant for DisperSol Technologies, Osmotica Pharmaceuticals, Teva Pharmaceutical.

[email protected]

SAN FRANCISCO – Assessing the impact of tardive dyskinesia on the lives of patients requires more than just visual observation, Stanley N. Caroff, MD, said at the annual meeting of the American Psychiatric Association.

“You really need to ask the patient a lot of questions – and the family and the caregivers – about how much tardive dyskinesia affects their lives,” he said.

Those were some of the early results of RE-KINECT, an ongoing study of patients with schizophrenia and schizoaffective disorder who were being treated with antipsychotic agents.

TD occurs in more than 25% of patients in outpatient practices who are exposed to dopamine receptor blockers. Symptoms can include involuntary movements of the tongue, hands, and feet; facial distortions; rapid eye blinking; and difficulty speaking. In some cases, the side effects resolve after patients stop taking the medications.

In this video, Dr. Caroff discussed the studies’ findings and their implications for everyday clinical practice. He also presented some of the early RE-KINECT findings in a poster at the meeting.

Dr. Caroff is professor of psychiatry at the University of Pennsylvania, Philadelphia. He also is affiliated with the Michael J. Crescenz VA Medical Center in Philadelphia. He disclosed working as a consultant for and receiving research funding from Neurocrine Biosciences. He also is a consultant for DisperSol Technologies, Osmotica Pharmaceuticals, Teva Pharmaceutical.

[email protected]

SAN DIEGO – There is no significant increased risk of dementia among patients who use proton pump inhibitors, compared with those who don’t, results from a systematic meta-analysis suggest.

Doug Brunk/MDedge News

The finding runs counter to recent studies, including a large pharmacoepidemiological claims data analysis from Germany, that propose an association between proton pump inhibitor (PPI) use and the development of dementia (JAMA Neurol. 2016;73[4]:410-6). “The issue with these studies is that they’re based on retrospective claims data and pharmacoepidemiological studies and insurance databases that don’t really give you a good causality basis,” lead study author Saad Alrajhi, MD, said in an interview at the annual Digestive Disease Week.

In an effort to better characterize the association between PPI exposure and dementia, Dr. Alrajhi, a gastroenterology fellow at McGill University, Montreal, and colleagues conducted a meta-analysis of all fully published randomized clinical trials or observational studies comparing use of PPIs and occurrence of dementia. The researchers queried Embase, MEDLINE, and ISI Web of Knowledge for relevant studies that were published from 1995 through September 2018. Next, they assessed the quality of the studies by using the Cochrane risk assessment tool for RCTs or the Newcastle-Ottawa Scale for observational studies.

As the primary outcome, the researchers compared dementia incidence after PPI exposure (experimental group) versus no PPI exposure (control group). Development of Alzheimer’s dementia was a secondary outcome. Sensitivity analyses consisted of excluding one study at a time, and assessing results among studies of highest qualities. Subgroup analyses included stratifying patients by age. To report odds ratios, Dr. Alrajhi and colleagues used fixed or random effects models based on the absence or presence of heterogeneity.


Of 549 studies assessed, 5 met the criteria for inclusion in the final analysis: 3 case-control studies and 2 cohort studies, with a total of 472,933 patients. All of the studies scored 8 or 9 on the Newcastle-Ottawa scale, indicating high quality. Significant heterogeneity was noted for all analyses. The researchers found that the incidence of dementia was not significantly increased among patients in the PPI-exposed group (odd ratio, 1.08 (95% confidence interval, 0.97-1.20; P = .18). Sensitivity analyses confirmed the robustness of the results. Subgroup analysis showed no between-group differences among studies that included a minimum age above 65 years (three studies) or less than age 65 (two studies). PPI exposure was not associated with the development of Alzheimer’s dementia (two studies) (OR, 1.32 (95% CI, 0.80-2.17; P = .27).

“In the absence of randomized trial evidence, a PPI prescribing approach based on appropriate utilization of guideline-based prescription should be done without the extra fear of the association of dementia,” Dr. Alrajhi said.

The researchers reported having no financial disclosures.

[email protected]

SAN DIEGO – There is no significant increased risk of dementia among patients who use proton pump inhibitors, compared with those who don’t, results from a systematic meta-analysis suggest.

Doug Brunk/MDedge News

The finding runs counter to recent studies, including a large pharmacoepidemiological claims data analysis from Germany, that propose an association between proton pump inhibitor (PPI) use and the development of dementia (JAMA Neurol. 2016;73[4]:410-6). “The issue with these studies is that they’re based on retrospective claims data and pharmacoepidemiological studies and insurance databases that don’t really give you a good causality basis,” lead study author Saad Alrajhi, MD, said in an interview at the annual Digestive Disease Week.

In an effort to better characterize the association between PPI exposure and dementia, Dr. Alrajhi, a gastroenterology fellow at McGill University, Montreal, and colleagues conducted a meta-analysis of all fully published randomized clinical trials or observational studies comparing use of PPIs and occurrence of dementia. The researchers queried Embase, MEDLINE, and ISI Web of Knowledge for relevant studies that were published from 1995 through September 2018. Next, they assessed the quality of the studies by using the Cochrane risk assessment tool for RCTs or the Newcastle-Ottawa Scale for observational studies.

As the primary outcome, the researchers compared dementia incidence after PPI exposure (experimental group) versus no PPI exposure (control group). Development of Alzheimer’s dementia was a secondary outcome. Sensitivity analyses consisted of excluding one study at a time, and assessing results among studies of highest qualities. Subgroup analyses included stratifying patients by age. To report odds ratios, Dr. Alrajhi and colleagues used fixed or random effects models based on the absence or presence of heterogeneity.


Of 549 studies assessed, 5 met the criteria for inclusion in the final analysis: 3 case-control studies and 2 cohort studies, with a total of 472,933 patients. All of the studies scored 8 or 9 on the Newcastle-Ottawa scale, indicating high quality. Significant heterogeneity was noted for all analyses. The researchers found that the incidence of dementia was not significantly increased among patients in the PPI-exposed group (odd ratio, 1.08 (95% confidence interval, 0.97-1.20; P = .18). Sensitivity analyses confirmed the robustness of the results. Subgroup analysis showed no between-group differences among studies that included a minimum age above 65 years (three studies) or less than age 65 (two studies). PPI exposure was not associated with the development of Alzheimer’s dementia (two studies) (OR, 1.32 (95% CI, 0.80-2.17; P = .27).

“In the absence of randomized trial evidence, a PPI prescribing approach based on appropriate utilization of guideline-based prescription should be done without the extra fear of the association of dementia,” Dr. Alrajhi said.

The researchers reported having no financial disclosures.

[email protected]

SAN DIEGO – There is no significant increased risk of dementia among patients who use proton pump inhibitors, compared with those who don’t, results from a systematic meta-analysis suggest.

Doug Brunk/MDedge News

The finding runs counter to recent studies, including a large pharmacoepidemiological claims data analysis from Germany, that propose an association between proton pump inhibitor (PPI) use and the development of dementia (JAMA Neurol. 2016;73[4]:410-6). “The issue with these studies is that they’re based on retrospective claims data and pharmacoepidemiological studies and insurance databases that don’t really give you a good causality basis,” lead study author Saad Alrajhi, MD, said in an interview at the annual Digestive Disease Week.

In an effort to better characterize the association between PPI exposure and dementia, Dr. Alrajhi, a gastroenterology fellow at McGill University, Montreal, and colleagues conducted a meta-analysis of all fully published randomized clinical trials or observational studies comparing use of PPIs and occurrence of dementia. The researchers queried Embase, MEDLINE, and ISI Web of Knowledge for relevant studies that were published from 1995 through September 2018. Next, they assessed the quality of the studies by using the Cochrane risk assessment tool for RCTs or the Newcastle-Ottawa Scale for observational studies.

As the primary outcome, the researchers compared dementia incidence after PPI exposure (experimental group) versus no PPI exposure (control group). Development of Alzheimer’s dementia was a secondary outcome. Sensitivity analyses consisted of excluding one study at a time, and assessing results among studies of highest qualities. Subgroup analyses included stratifying patients by age. To report odds ratios, Dr. Alrajhi and colleagues used fixed or random effects models based on the absence or presence of heterogeneity.


Of 549 studies assessed, 5 met the criteria for inclusion in the final analysis: 3 case-control studies and 2 cohort studies, with a total of 472,933 patients. All of the studies scored 8 or 9 on the Newcastle-Ottawa scale, indicating high quality. Significant heterogeneity was noted for all analyses. The researchers found that the incidence of dementia was not significantly increased among patients in the PPI-exposed group (odd ratio, 1.08 (95% confidence interval, 0.97-1.20; P = .18). Sensitivity analyses confirmed the robustness of the results. Subgroup analysis showed no between-group differences among studies that included a minimum age above 65 years (three studies) or less than age 65 (two studies). PPI exposure was not associated with the development of Alzheimer’s dementia (two studies) (OR, 1.32 (95% CI, 0.80-2.17; P = .27).

“In the absence of randomized trial evidence, a PPI prescribing approach based on appropriate utilization of guideline-based prescription should be done without the extra fear of the association of dementia,” Dr. Alrajhi said.

The researchers reported having no financial disclosures.

[email protected]

Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke and may also, infrequently, be a consequence of stroke. It is significantly underdiagnosed in the general population and is highly prevalent in patients who have had a stroke. Many patients likely had their stroke because of this chronic untreated condition.

This review focuses on OSA and its prevalence, consequences, and treatment in patients after a stroke.

DEFINING AND QUANTIFYING OSA

OSA is the most common type of sleep-disordered breathing.^1,2 It involves repeated narrowing or complete collapse of the upper airway despite ongoing respiratory effort.^3,4 Apneic episodes are terminated by arousals from hypoxemia or efforts to breathe.⁵ In contrast, central sleep apnea is characterized by a patent airway but lack of airflow due to absent respiratory effort.⁵

In OSA, the number of episodes of apnea (absent airflow) and hypopnea (reduced airflow) are added together and divided by hours of sleep to calculate the apnea-hypopnea index (AHI). OSA is diagnosed by either of the following^3,4:

• AHI of 5 or higher, with clinical symptoms related to OSA (described below)
• AHI of 15 or higher, regardless of symptoms.

The AHI also defines OSA severity, as follows³:

• Mild: AHI 5 to 15
• Moderate: AHI 15 to 30
• Severe: AHI greater than 30.

Diagnostic criteria (eg, definition of hypopnea, testing methods, and AHI thresholds) have varied over time, an important consideration when reviewing the literature.

OSA IS MORE COMMON THAN EXPECTED AFTER STROKE

In the most methodologically sound and generalizable study of this topic to date, the Wisconsin Sleep Cohort Study⁶ reported in 2013 that about 14% of men and 5% of women ages 30 to 70 have an AHI greater than 5 (using 4% desaturation to score hypopneic episodes) with daytime sleepiness. Other studies suggest that 80% to 90% of people with OSA are undiagnosed and untreated.^1,7

The prevalence of OSA in patients who have had a stroke is much higher, ranging from 30% to 96% depending on the study methods and population.^1,8–12 A 2010 meta-analysis¹¹ of 29 studies reported that 72% of patients who had a stroke had an AHI greater than 5, and 29% had severe OSA. In this analysis, 7% of those with sleep-disordered breathing had central sleep apnea; still, these data indicate that the prevalence of OSA in these patients is about 5 times higher than in the general population.

RISK FACTORS MAY DIFFER IN STROKE POPULATION

Several risk factors for OSA have been identified.

Obesity is one of the strongest risk factors, with increasing body mass index (BMI) associated with increased OSA prevalence.^4,6,13 However, obesity appears to be a less significant risk factor in patients who have had a stroke than in the general population. In the 2010 meta-analysis¹¹ of OSA after stroke, the average BMI was only 26.4 kg/m² (with obesity defined as a BMI > 30.0 kg/m²), and increasing BMI was not associated with increasing AHI.

Male sex and advanced age are also OSA risk factors.^4,5 They remain significant in patients after a stroke; about 65% of poststroke patients who have OSA are men, and the older the patient, the more likely the AHI is greater than 10.¹¹

Ethnicity and genetics may also play important roles in OSA risk, with roughly 25% of OSA prevalence estimated to have a genetic basis.^14,15 Some risk factors for OSA such as craniofacial shape, upper airway anatomy, upper airway muscle dysfunction, increased respiratory chemosensitivity, and poor arousal threshold during sleep are likely determined by genetics and ethnicity.^14,15 Compared with people of European origin, Asians have a similar prevalence of OSA, but at a much lower average BMI, suggesting that other factors are significant.¹⁴ Possible genetically determined anatomic risk factors have not been specifically studied in the poststroke population, but it can be assumed they remain relevant.

Several studies have tried to find an association between OSA and type, location, etiology, or pattern of stroke.^{10,11,16–19} Although some suggest links between cardioembolic stroke and OSA,^16,20 or thrombolysis and OSA,¹⁰ most have found no association between OSA and stroke features.^11,12,21,22

HOW DOES OSA INCREASE STROKE RISK?

Untreated severe OSA is associated with increased cardiovascular mortality,^21,22 and OSA is an independent risk factor for incident stroke.²³ A number of mechanisms may explain these relationships.

Intermittent hypoxemia and recurrent sympathetic arousals resulting from OSA are thought to lead to many of the comorbid conditions with which it is associated: hypertension, coronary artery disease, heart failure, arrhythmias, pulmonary hypertension, and stroke. Repetitive decreases in ventilation lead to oxygen desaturations that result in cycles of increased sympathetic outflow and eventual sustained nocturnal hypertension and daytime chronic hypertension.^1,5,9,13 Also implicated are various changes in vasodilator and vasoconstrictor substances due to endothelial dysfunction and inflammation, which are thought to play a role in the atherogenic and prothrombotic states induced by OSA.^1,5,13

Cerebral circulation is altered primarily by the changes in partial pressure of carbon dioxide (Pco₂). During apnea, the Pco₂ rises, causing vasodilation and increased blood flow. After the apnea resolves, there is hyperpnea with resultant decreased Pco₂, and vasoconstriction. In a patient who already has vascular disease, the enhanced vasoconstriction could lead to ischemia.^1,5

Changes in intrathoracic pressure result in distortion of cardiac architecture. When the patient tries to breathe against an occluded airway, the intrathoracic pressure becomes more and more negative, increasing preload and afterload. When this happens repeatedly every night for years, it leads to remodeling of the heart such as left and right ventricular hypertrophy, with reduced stroke volume, myocardial ischemia, and increased risk of arrhythmia.^1,5,13

Untreated OSA is believed to predispose patients to develop atrial fibrillation through sympathetic overactivity, vascular inflammation, heart rate variability, and cardiac remodeling.²⁴ As atrial fibrillation is a major risk factor for stroke, particularly cardioembolic stroke, it may be another pathway of increased stroke risk in OSA.^16,20,25

OSA typically causes both daytime symptoms (excessive sleepiness, poor concentration, morning headache, depressive symptoms) and nighttime signs and symptoms (snoring, choking, gasping, night sweats, insomnia, nocturia, witnessed episodes of apnea).^3,4,26 Unfortunately, because these are nonspecific, OSA is often underdiagnosed.^4,26

Identifying OSA after a stroke may be a particular challenge, as patients often do not report classic symptoms, and the typical picture of OSA may have less predictive validity in these patients.^1,27,28 Within the first 24 hours after a stroke, hypersomnia, snoring history, and age are not predictive of OSA.¹ Patients found to have OSA after a stroke frequently do not have the traditional symptoms (sleepiness, snoring) seen in usual OSA patients. And they have higher rates of OSA at a younger age than the usual OSA patients, so age is not a predictive risk factor. In addition, daytime sleepiness and obesity are often absent or less prominent.^1,9,27,28  Finally, typical OSA signs and symptoms may be attributed to the stroke itself or to comorbidities affecting the patient, lowering suspicion for OSA.

OSA MAY HINDER STROKE RECOVERY, WORSEN OUTCOMES

OSA, particularly when moderate to severe, is linked to pathophysiologic changes that can hinder recovery from a stroke.

Intermittent hypoxemia during sleep can worsen vascular damage of at-risk tissue: nocturnal hypoxemia correlates with white matter hyperintensities on magnetic resonance imaging, a marker of ischemic demyelination.²⁹ Oxidative stress and release of inflammatory mediators associated with intermittent hypoxemia may impair vascular blood flow to brain tissue attempting to repair itself.³⁰ In addition, sympathetic overactivity and Pco₂ fluctuations associated with OSA may impede cerebral circulation.

Taken together, such ongoing nocturnal insults can lead to clinical consequences during this vulnerable period.

A 1996 study³¹ of patients recovering from a stroke found that an oxygen desaturation index (number of times that the blood oxygen level drops below a certain threshold, as measured by overnight oximetry) of more than 10 per hour was associated with worse functional recovery at discharge and at 3 and 12 months after discharge. This study also noted an association between time spent with oxygen saturations below 90% and the rate of death at 1 year.

A 2003 study³² reported that patients with an AHI greater than 10 by polysomnography spent an average of 13 days longer on the rehabilitation service and had worse functional and cognitive status on discharge, even after controlling for multiple confounders. Several subsequent studies have confirmed these and similar findings.^8,33,34

OSA has also been linked to depression,³⁵ which is common after stroke and may worsen outcomes.³⁶ The interaction between OSA, depression, and poststroke outcomes warrants further study.

In the general population, OSA has been independently associated with increased risk of stroke or death from any cause.^21,22,37 These associations have also been reported in the poststroke population: a 2014 meta-analysis found that OSA increased the risk of a repeat stroke (relative risk [RR] 1.8, 95% confidence interval [CI] 1.2–2.6) and all-cause mortality (RR 1.69, 95% CI 1.4–2.1).³⁸

TESTING FOR OSA AFTER STROKE

Because of the high prevalence of OSA in patients who have had a stroke and the potential for worse outcomes associated with untreated OSA, there should be a low threshold for evaluating for OSA soon after stroke. Objective testing is required to qualify for therapy,  and the gold standard for diagnosis of OSA is formal polysomnography conducted in a sleep laboratory.^2–4 Unfortunately, polysomnography may be unacceptable to some patients, is costly, and is resource-intensive, particularly in an inpatient or rehabilitation setting.²⁸ Ideally, to optimize testing efficiency, patients should be screened for the likelihood of OSA before polysomnography is ordered.

Questionnaires can help determine the need for further testing

Questionnaires developed to assess OSA risk³⁹ include the following:

The Berlin questionnaire, developed in 1999, has 10 questions assessing daytime and nighttime signs and symptoms and presence of hypertension.

The STOP questionnaire, developed in 2008, assesses snoring, tiredness, observed apneic episodes, and elevated blood pressure.

The STOP-BANG questionnaire, published in 2010, includes the STOP questions plus BMI over 35 kg/m², age over 50, neck circumference over 41 cm, and male gender.

A 2017 meta-analysis³⁹ of 108 studies with nearly 50,000 people found that the STOP-BANG questionnaire performed best with regard to sensitivity and diagnostic odds ratio, but with poor specificity.

These screening tools and modified versions of them have also been evaluated in patients who have had a stroke.

In 2015, Boulos et al²⁸ found that the STOP-BAG (a version of STOP-BANG that excludes neck circumference) and the 4-variable (4V) questionnaire (sex, BMI, blood pressure, snoring) had moderate predictive value for OSA within 6 months after sroke.

In 2016, Katzan et al⁴⁰ found that the STOP-BAG2 (STOP-BAG criteria plus continuous variables for BMI and age) had a high sensitivity for polysomnographically diagnosed OSA within the first year after a stroke. The specificity was significantly better than the STOP-BANG or the STOP-BAG questionnaire, although it remained suboptimal at 60.5%.

In 2017, Sico et al⁴¹ developed and assessed the SLEEP Inventory (sex, left heart failure, Epworth Sleepiness Scale, enlarged neck, weight in pounds, insulin resistance or diabetes, and National Institutes of Health Stroke Scale) and found that it outperformed the Berlin and STOP-BANG questionnaires in the poststroke setting. The SLEEP Inventory had the best specificity and negative predictive value, and a slightly better ability to correctly classify patients as having OSA or not, classifying 80% of patients correctly.

These newer screening tools (eg, STOP-BAG, STOP-BAG2, SLEEP) can be used to identify with reasonable accuracy which patients need definitive testing after stroke.

Pulse oximetry is another possible screening tool          

Overnight pulse oximetry may also help screen for sleep apnea and stratify risk after a stroke. A 2012 study⁴² of overnight oximetry to screen patients before surgery found that the oxygen desaturation index was significantly associated with the AHI measured by polysomnography. However, oximetry testing cannot distinguish between OSA and central sleep apnea, so it is insufficient to diagnose OSA or qualify patients for therapy. Further study is needed to examine the ability of overnight pulse oximetry to screen or to stratify risk for OSA after stroke.

Polysomnography vs home testing

Polysomnography is the gold standard for diagnosing OSA. Benefits include technical support and trouble-shooting, determining relationships between OSA, body position, and sleep stage, and the ability to intervene with treatment.² However, polysomnography can be cumbersome, costly, and resource-intensive.

A home sleep apnea test, ie, an unattended, limited-channel sleep study, may be an acceptable alternative.^2–4,43,44 Home testing does not require a sleep technologist to be present during testing, uses fewer sensors, and is less expensive than overnight polysomnography, but its utility can be limited: it fails to accurately discriminate between episodes of OSA and central sleep apnea, there is potential for false-negative results, and it can underestimate sleep apnea burden because it does not measure sleep.²

Institutional resources and logistics may influence the choice of diagnostic modality. No data exist on outcomes from different diagnostic testing methods in poststroke patients. Further research is needed.

The first-line treatment for OSA is positive airway pressure (PAP).³ For most patients, this is continuous PAP (CPAP) or autoadjusting PAP (APAP). In some instances, particularly for those who cannot tolerate CPAP or who have comorbid hypoventilation, bilevel PAP (BPAP) may be indicated. More advanced PAP therapies are unlikely to be used after stroke.

PAP therapy is associated with reduced daytime sleepiness, improved mood, normalization of sleep architecture, improved systemic and pulmonary artery blood pressure, reduced rates of atrial fibrillation after ablation, and improved insulin sensitivity.^45–49 Whether it reduces the risk of cardiovascular events, including stroke, remains controversial; most data suggest that it does not.^50,51 However, when adherence to PAP therapy is considered rather than intention to treat, treatment has been found to lead to improved cardiovascular outcomes.⁵²

Mixed evidence of benefits after stroke

Observational studies provide evidence that CPAP may help patients with OSA after stroke, although results are mixed.^53–58 The studies ranged in size from 14 to 105 patients, enrolled patients with mostly moderate to severe OSA, and followed patients from 10 days to 7 years. Adherence to therapy was generally good in the short term (50%–70%), but only  15% to 30% of patients remained adherent at 5 to 7 years. Variable outcomes were reported, with some studies finding improved symptoms in the near term and mixed evidence of cardiovascular benefit in the longer ones. However, as these studies lacked randomization, drawing definitive conclusions on CPAP efficacy is difficult.

Patients were enrolled in the index admission or when starting a rehabilitation service—generally 2 to 3 weeks after their stroke. No clear association was found between the timing of initiating PAP therapy and outcomes. All patients had ischemic strokes, but few details were provided regarding stroke location, size, and severity. Exclusion criteria included severe underlying cardiopulmonary disease, confusion, severe stroke with marked impairment, and inability to cooperate. Almost all patients had moderate to severe OSA, and patients with central sleep apnea were excluded.

The major outcomes examined were drop-out rates, PAP adherence, and neurologic improvement based on neurologic functional scales (National Institutes of Health Stroke Scale and Canadian Neurologic Scale). As expected, dropout rates were higher in patients randomized to CPAP (OR 1.83, 95% CI 1.05–3.21, P = .03), although overall adherence was better than anticipated, with mean CPAP use across trials of 4.5 hours per night (95% CI 3.97–5.08) and with about 50% to 60% of patients adhering to therapy for at least 4 hours nightly.

Improvement in neurologic outcomes favored CPAP (standard mean difference 0.54, 95% CI 0.026–1.05), although considerable heterogeneity was seen. Improved sleepiness outcomes were inconsistent. Major cardiovascular outcomes were reported in only 2 studies (using the same data set) and showed delayed time to the next cardiovascular event for those treated with CPAP but no difference in cardiovascular event-free survival.

PAP poses more challenges after stroke

The primary limitation to PAP therapy is poor acceptance and adherence to therapy.⁵⁹ High rates of refusal of therapy and difficulty complying with treatment have been noted in the poststroke population, although recent studies have reported better adherence rates. How rates of adherence play out in real-world settings, outside of the controlled environment of a research study, has yet to be determined.

In general, CPAP adherence is affected by claustrophobia, difficulty tolerating a mask, problems with pressure intolerance, irritating air leaks, nasal congestion, and naso-oral dryness. Many such barriers can be overcome with use of a properly fitted mask, an appropriate pressure setting, heated humidification, nasal sprays (eg, saline, inhaled steroids), and education, encouragement, and reassurance.

After a stroke, additional obstacles may impede the ability to use PAP therapy.⁶⁸ Facial paresis (hemi- or bifacial) may make fitting of the mask problematic. Paralysis or weakness of the extremities may limit the ability to adjust or remove a mask. Aphasia can impair communication and understanding of the need to use PAP therapy, and upper-airway problems related to stroke, including dysphagia, may lead to pressure intolerance or risk of aspiration. Finally, a lack of perceived benefit, particularly if the patient does not have daytime sleepiness, may limit motivation.

Consider alternatives

For patients unlikely to succeed with PAP therapy, there are alternatives. Surgery and oral appliances are not usually realistic options in the setting of recent stroke, but positional therapy, including the use of body positioners to prevent supine sleep, as well as elevating the head of the bed, may be of some benefit.^69,70 A nasopharyngeal airway stenting device (nasal trumpet) may also be tolerated by some patients.

A proposed algorithm for screening, diagnosing, and treating OSA in patients after stroke is presented in Figure 1.

Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke and may also, infrequently, be a consequence of stroke. It is significantly underdiagnosed in the general population and is highly prevalent in patients who have had a stroke. Many patients likely had their stroke because of this chronic untreated condition.

This review focuses on OSA and its prevalence, consequences, and treatment in patients after a stroke.

DEFINING AND QUANTIFYING OSA

OSA is the most common type of sleep-disordered breathing.^1,2 It involves repeated narrowing or complete collapse of the upper airway despite ongoing respiratory effort.^3,4 Apneic episodes are terminated by arousals from hypoxemia or efforts to breathe.⁵ In contrast, central sleep apnea is characterized by a patent airway but lack of airflow due to absent respiratory effort.⁵

In OSA, the number of episodes of apnea (absent airflow) and hypopnea (reduced airflow) are added together and divided by hours of sleep to calculate the apnea-hypopnea index (AHI). OSA is diagnosed by either of the following^3,4:

• AHI of 5 or higher, with clinical symptoms related to OSA (described below)
• AHI of 15 or higher, regardless of symptoms.

The AHI also defines OSA severity, as follows³:

• Mild: AHI 5 to 15
• Moderate: AHI 15 to 30
• Severe: AHI greater than 30.

Diagnostic criteria (eg, definition of hypopnea, testing methods, and AHI thresholds) have varied over time, an important consideration when reviewing the literature.

OSA IS MORE COMMON THAN EXPECTED AFTER STROKE

In the most methodologically sound and generalizable study of this topic to date, the Wisconsin Sleep Cohort Study⁶ reported in 2013 that about 14% of men and 5% of women ages 30 to 70 have an AHI greater than 5 (using 4% desaturation to score hypopneic episodes) with daytime sleepiness. Other studies suggest that 80% to 90% of people with OSA are undiagnosed and untreated.^1,7

The prevalence of OSA in patients who have had a stroke is much higher, ranging from 30% to 96% depending on the study methods and population.^1,8–12 A 2010 meta-analysis¹¹ of 29 studies reported that 72% of patients who had a stroke had an AHI greater than 5, and 29% had severe OSA. In this analysis, 7% of those with sleep-disordered breathing had central sleep apnea; still, these data indicate that the prevalence of OSA in these patients is about 5 times higher than in the general population.

RISK FACTORS MAY DIFFER IN STROKE POPULATION

Several risk factors for OSA have been identified.

Obesity is one of the strongest risk factors, with increasing body mass index (BMI) associated with increased OSA prevalence.^4,6,13 However, obesity appears to be a less significant risk factor in patients who have had a stroke than in the general population. In the 2010 meta-analysis¹¹ of OSA after stroke, the average BMI was only 26.4 kg/m² (with obesity defined as a BMI > 30.0 kg/m²), and increasing BMI was not associated with increasing AHI.

Male sex and advanced age are also OSA risk factors.^4,5 They remain significant in patients after a stroke; about 65% of poststroke patients who have OSA are men, and the older the patient, the more likely the AHI is greater than 10.¹¹

Ethnicity and genetics may also play important roles in OSA risk, with roughly 25% of OSA prevalence estimated to have a genetic basis.^14,15 Some risk factors for OSA such as craniofacial shape, upper airway anatomy, upper airway muscle dysfunction, increased respiratory chemosensitivity, and poor arousal threshold during sleep are likely determined by genetics and ethnicity.^14,15 Compared with people of European origin, Asians have a similar prevalence of OSA, but at a much lower average BMI, suggesting that other factors are significant.¹⁴ Possible genetically determined anatomic risk factors have not been specifically studied in the poststroke population, but it can be assumed they remain relevant.

Several studies have tried to find an association between OSA and type, location, etiology, or pattern of stroke.^{10,11,16–19} Although some suggest links between cardioembolic stroke and OSA,^16,20 or thrombolysis and OSA,¹⁰ most have found no association between OSA and stroke features.^11,12,21,22

HOW DOES OSA INCREASE STROKE RISK?

Untreated severe OSA is associated with increased cardiovascular mortality,^21,22 and OSA is an independent risk factor for incident stroke.²³ A number of mechanisms may explain these relationships.

Intermittent hypoxemia and recurrent sympathetic arousals resulting from OSA are thought to lead to many of the comorbid conditions with which it is associated: hypertension, coronary artery disease, heart failure, arrhythmias, pulmonary hypertension, and stroke. Repetitive decreases in ventilation lead to oxygen desaturations that result in cycles of increased sympathetic outflow and eventual sustained nocturnal hypertension and daytime chronic hypertension.^1,5,9,13 Also implicated are various changes in vasodilator and vasoconstrictor substances due to endothelial dysfunction and inflammation, which are thought to play a role in the atherogenic and prothrombotic states induced by OSA.^1,5,13

Cerebral circulation is altered primarily by the changes in partial pressure of carbon dioxide (Pco₂). During apnea, the Pco₂ rises, causing vasodilation and increased blood flow. After the apnea resolves, there is hyperpnea with resultant decreased Pco₂, and vasoconstriction. In a patient who already has vascular disease, the enhanced vasoconstriction could lead to ischemia.^1,5

Changes in intrathoracic pressure result in distortion of cardiac architecture. When the patient tries to breathe against an occluded airway, the intrathoracic pressure becomes more and more negative, increasing preload and afterload. When this happens repeatedly every night for years, it leads to remodeling of the heart such as left and right ventricular hypertrophy, with reduced stroke volume, myocardial ischemia, and increased risk of arrhythmia.^1,5,13

Untreated OSA is believed to predispose patients to develop atrial fibrillation through sympathetic overactivity, vascular inflammation, heart rate variability, and cardiac remodeling.²⁴ As atrial fibrillation is a major risk factor for stroke, particularly cardioembolic stroke, it may be another pathway of increased stroke risk in OSA.^16,20,25

OSA typically causes both daytime symptoms (excessive sleepiness, poor concentration, morning headache, depressive symptoms) and nighttime signs and symptoms (snoring, choking, gasping, night sweats, insomnia, nocturia, witnessed episodes of apnea).^3,4,26 Unfortunately, because these are nonspecific, OSA is often underdiagnosed.^4,26

Identifying OSA after a stroke may be a particular challenge, as patients often do not report classic symptoms, and the typical picture of OSA may have less predictive validity in these patients.^1,27,28 Within the first 24 hours after a stroke, hypersomnia, snoring history, and age are not predictive of OSA.¹ Patients found to have OSA after a stroke frequently do not have the traditional symptoms (sleepiness, snoring) seen in usual OSA patients. And they have higher rates of OSA at a younger age than the usual OSA patients, so age is not a predictive risk factor. In addition, daytime sleepiness and obesity are often absent or less prominent.^1,9,27,28  Finally, typical OSA signs and symptoms may be attributed to the stroke itself or to comorbidities affecting the patient, lowering suspicion for OSA.

OSA MAY HINDER STROKE RECOVERY, WORSEN OUTCOMES

OSA, particularly when moderate to severe, is linked to pathophysiologic changes that can hinder recovery from a stroke.

Intermittent hypoxemia during sleep can worsen vascular damage of at-risk tissue: nocturnal hypoxemia correlates with white matter hyperintensities on magnetic resonance imaging, a marker of ischemic demyelination.²⁹ Oxidative stress and release of inflammatory mediators associated with intermittent hypoxemia may impair vascular blood flow to brain tissue attempting to repair itself.³⁰ In addition, sympathetic overactivity and Pco₂ fluctuations associated with OSA may impede cerebral circulation.

Taken together, such ongoing nocturnal insults can lead to clinical consequences during this vulnerable period.

A 1996 study³¹ of patients recovering from a stroke found that an oxygen desaturation index (number of times that the blood oxygen level drops below a certain threshold, as measured by overnight oximetry) of more than 10 per hour was associated with worse functional recovery at discharge and at 3 and 12 months after discharge. This study also noted an association between time spent with oxygen saturations below 90% and the rate of death at 1 year.

A 2003 study³² reported that patients with an AHI greater than 10 by polysomnography spent an average of 13 days longer on the rehabilitation service and had worse functional and cognitive status on discharge, even after controlling for multiple confounders. Several subsequent studies have confirmed these and similar findings.^8,33,34

OSA has also been linked to depression,³⁵ which is common after stroke and may worsen outcomes.³⁶ The interaction between OSA, depression, and poststroke outcomes warrants further study.

In the general population, OSA has been independently associated with increased risk of stroke or death from any cause.^21,22,37 These associations have also been reported in the poststroke population: a 2014 meta-analysis found that OSA increased the risk of a repeat stroke (relative risk [RR] 1.8, 95% confidence interval [CI] 1.2–2.6) and all-cause mortality (RR 1.69, 95% CI 1.4–2.1).³⁸

TESTING FOR OSA AFTER STROKE

Because of the high prevalence of OSA in patients who have had a stroke and the potential for worse outcomes associated with untreated OSA, there should be a low threshold for evaluating for OSA soon after stroke. Objective testing is required to qualify for therapy,  and the gold standard for diagnosis of OSA is formal polysomnography conducted in a sleep laboratory.^2–4 Unfortunately, polysomnography may be unacceptable to some patients, is costly, and is resource-intensive, particularly in an inpatient or rehabilitation setting.²⁸ Ideally, to optimize testing efficiency, patients should be screened for the likelihood of OSA before polysomnography is ordered.

Questionnaires can help determine the need for further testing

Questionnaires developed to assess OSA risk³⁹ include the following:

The Berlin questionnaire, developed in 1999, has 10 questions assessing daytime and nighttime signs and symptoms and presence of hypertension.

The STOP questionnaire, developed in 2008, assesses snoring, tiredness, observed apneic episodes, and elevated blood pressure.

The STOP-BANG questionnaire, published in 2010, includes the STOP questions plus BMI over 35 kg/m², age over 50, neck circumference over 41 cm, and male gender.

A 2017 meta-analysis³⁹ of 108 studies with nearly 50,000 people found that the STOP-BANG questionnaire performed best with regard to sensitivity and diagnostic odds ratio, but with poor specificity.

These screening tools and modified versions of them have also been evaluated in patients who have had a stroke.

In 2015, Boulos et al²⁸ found that the STOP-BAG (a version of STOP-BANG that excludes neck circumference) and the 4-variable (4V) questionnaire (sex, BMI, blood pressure, snoring) had moderate predictive value for OSA within 6 months after sroke.

In 2016, Katzan et al⁴⁰ found that the STOP-BAG2 (STOP-BAG criteria plus continuous variables for BMI and age) had a high sensitivity for polysomnographically diagnosed OSA within the first year after a stroke. The specificity was significantly better than the STOP-BANG or the STOP-BAG questionnaire, although it remained suboptimal at 60.5%.

In 2017, Sico et al⁴¹ developed and assessed the SLEEP Inventory (sex, left heart failure, Epworth Sleepiness Scale, enlarged neck, weight in pounds, insulin resistance or diabetes, and National Institutes of Health Stroke Scale) and found that it outperformed the Berlin and STOP-BANG questionnaires in the poststroke setting. The SLEEP Inventory had the best specificity and negative predictive value, and a slightly better ability to correctly classify patients as having OSA or not, classifying 80% of patients correctly.

These newer screening tools (eg, STOP-BAG, STOP-BAG2, SLEEP) can be used to identify with reasonable accuracy which patients need definitive testing after stroke.

Pulse oximetry is another possible screening tool          

Overnight pulse oximetry may also help screen for sleep apnea and stratify risk after a stroke. A 2012 study⁴² of overnight oximetry to screen patients before surgery found that the oxygen desaturation index was significantly associated with the AHI measured by polysomnography. However, oximetry testing cannot distinguish between OSA and central sleep apnea, so it is insufficient to diagnose OSA or qualify patients for therapy. Further study is needed to examine the ability of overnight pulse oximetry to screen or to stratify risk for OSA after stroke.

Polysomnography vs home testing

Polysomnography is the gold standard for diagnosing OSA. Benefits include technical support and trouble-shooting, determining relationships between OSA, body position, and sleep stage, and the ability to intervene with treatment.² However, polysomnography can be cumbersome, costly, and resource-intensive.

A home sleep apnea test, ie, an unattended, limited-channel sleep study, may be an acceptable alternative.^2–4,43,44 Home testing does not require a sleep technologist to be present during testing, uses fewer sensors, and is less expensive than overnight polysomnography, but its utility can be limited: it fails to accurately discriminate between episodes of OSA and central sleep apnea, there is potential for false-negative results, and it can underestimate sleep apnea burden because it does not measure sleep.²

Institutional resources and logistics may influence the choice of diagnostic modality. No data exist on outcomes from different diagnostic testing methods in poststroke patients. Further research is needed.

The first-line treatment for OSA is positive airway pressure (PAP).³ For most patients, this is continuous PAP (CPAP) or autoadjusting PAP (APAP). In some instances, particularly for those who cannot tolerate CPAP or who have comorbid hypoventilation, bilevel PAP (BPAP) may be indicated. More advanced PAP therapies are unlikely to be used after stroke.

PAP therapy is associated with reduced daytime sleepiness, improved mood, normalization of sleep architecture, improved systemic and pulmonary artery blood pressure, reduced rates of atrial fibrillation after ablation, and improved insulin sensitivity.^45–49 Whether it reduces the risk of cardiovascular events, including stroke, remains controversial; most data suggest that it does not.^50,51 However, when adherence to PAP therapy is considered rather than intention to treat, treatment has been found to lead to improved cardiovascular outcomes.⁵²

Mixed evidence of benefits after stroke

Observational studies provide evidence that CPAP may help patients with OSA after stroke, although results are mixed.^53–58 The studies ranged in size from 14 to 105 patients, enrolled patients with mostly moderate to severe OSA, and followed patients from 10 days to 7 years. Adherence to therapy was generally good in the short term (50%–70%), but only  15% to 30% of patients remained adherent at 5 to 7 years. Variable outcomes were reported, with some studies finding improved symptoms in the near term and mixed evidence of cardiovascular benefit in the longer ones. However, as these studies lacked randomization, drawing definitive conclusions on CPAP efficacy is difficult.

Patients were enrolled in the index admission or when starting a rehabilitation service—generally 2 to 3 weeks after their stroke. No clear association was found between the timing of initiating PAP therapy and outcomes. All patients had ischemic strokes, but few details were provided regarding stroke location, size, and severity. Exclusion criteria included severe underlying cardiopulmonary disease, confusion, severe stroke with marked impairment, and inability to cooperate. Almost all patients had moderate to severe OSA, and patients with central sleep apnea were excluded.

The major outcomes examined were drop-out rates, PAP adherence, and neurologic improvement based on neurologic functional scales (National Institutes of Health Stroke Scale and Canadian Neurologic Scale). As expected, dropout rates were higher in patients randomized to CPAP (OR 1.83, 95% CI 1.05–3.21, P = .03), although overall adherence was better than anticipated, with mean CPAP use across trials of 4.5 hours per night (95% CI 3.97–5.08) and with about 50% to 60% of patients adhering to therapy for at least 4 hours nightly.

Improvement in neurologic outcomes favored CPAP (standard mean difference 0.54, 95% CI 0.026–1.05), although considerable heterogeneity was seen. Improved sleepiness outcomes were inconsistent. Major cardiovascular outcomes were reported in only 2 studies (using the same data set) and showed delayed time to the next cardiovascular event for those treated with CPAP but no difference in cardiovascular event-free survival.

PAP poses more challenges after stroke

The primary limitation to PAP therapy is poor acceptance and adherence to therapy.⁵⁹ High rates of refusal of therapy and difficulty complying with treatment have been noted in the poststroke population, although recent studies have reported better adherence rates. How rates of adherence play out in real-world settings, outside of the controlled environment of a research study, has yet to be determined.

In general, CPAP adherence is affected by claustrophobia, difficulty tolerating a mask, problems with pressure intolerance, irritating air leaks, nasal congestion, and naso-oral dryness. Many such barriers can be overcome with use of a properly fitted mask, an appropriate pressure setting, heated humidification, nasal sprays (eg, saline, inhaled steroids), and education, encouragement, and reassurance.

After a stroke, additional obstacles may impede the ability to use PAP therapy.⁶⁸ Facial paresis (hemi- or bifacial) may make fitting of the mask problematic. Paralysis or weakness of the extremities may limit the ability to adjust or remove a mask. Aphasia can impair communication and understanding of the need to use PAP therapy, and upper-airway problems related to stroke, including dysphagia, may lead to pressure intolerance or risk of aspiration. Finally, a lack of perceived benefit, particularly if the patient does not have daytime sleepiness, may limit motivation.

Consider alternatives

For patients unlikely to succeed with PAP therapy, there are alternatives. Surgery and oral appliances are not usually realistic options in the setting of recent stroke, but positional therapy, including the use of body positioners to prevent supine sleep, as well as elevating the head of the bed, may be of some benefit.^69,70 A nasopharyngeal airway stenting device (nasal trumpet) may also be tolerated by some patients.

A proposed algorithm for screening, diagnosing, and treating OSA in patients after stroke is presented in Figure 1.

Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke and may also, infrequently, be a consequence of stroke. It is significantly underdiagnosed in the general population and is highly prevalent in patients who have had a stroke. Many patients likely had their stroke because of this chronic untreated condition.

This review focuses on OSA and its prevalence, consequences, and treatment in patients after a stroke.

DEFINING AND QUANTIFYING OSA

OSA is the most common type of sleep-disordered breathing.^1,2 It involves repeated narrowing or complete collapse of the upper airway despite ongoing respiratory effort.^3,4 Apneic episodes are terminated by arousals from hypoxemia or efforts to breathe.⁵ In contrast, central sleep apnea is characterized by a patent airway but lack of airflow due to absent respiratory effort.⁵

In OSA, the number of episodes of apnea (absent airflow) and hypopnea (reduced airflow) are added together and divided by hours of sleep to calculate the apnea-hypopnea index (AHI). OSA is diagnosed by either of the following^3,4:

• AHI of 5 or higher, with clinical symptoms related to OSA (described below)
• AHI of 15 or higher, regardless of symptoms.

The AHI also defines OSA severity, as follows³:

• Mild: AHI 5 to 15
• Moderate: AHI 15 to 30
• Severe: AHI greater than 30.

Diagnostic criteria (eg, definition of hypopnea, testing methods, and AHI thresholds) have varied over time, an important consideration when reviewing the literature.

OSA IS MORE COMMON THAN EXPECTED AFTER STROKE

In the most methodologically sound and generalizable study of this topic to date, the Wisconsin Sleep Cohort Study⁶ reported in 2013 that about 14% of men and 5% of women ages 30 to 70 have an AHI greater than 5 (using 4% desaturation to score hypopneic episodes) with daytime sleepiness. Other studies suggest that 80% to 90% of people with OSA are undiagnosed and untreated.^1,7

The prevalence of OSA in patients who have had a stroke is much higher, ranging from 30% to 96% depending on the study methods and population.^1,8–12 A 2010 meta-analysis¹¹ of 29 studies reported that 72% of patients who had a stroke had an AHI greater than 5, and 29% had severe OSA. In this analysis, 7% of those with sleep-disordered breathing had central sleep apnea; still, these data indicate that the prevalence of OSA in these patients is about 5 times higher than in the general population.

RISK FACTORS MAY DIFFER IN STROKE POPULATION

Several risk factors for OSA have been identified.

Obesity is one of the strongest risk factors, with increasing body mass index (BMI) associated with increased OSA prevalence.^4,6,13 However, obesity appears to be a less significant risk factor in patients who have had a stroke than in the general population. In the 2010 meta-analysis¹¹ of OSA after stroke, the average BMI was only 26.4 kg/m² (with obesity defined as a BMI > 30.0 kg/m²), and increasing BMI was not associated with increasing AHI.

Male sex and advanced age are also OSA risk factors.^4,5 They remain significant in patients after a stroke; about 65% of poststroke patients who have OSA are men, and the older the patient, the more likely the AHI is greater than 10.¹¹

Ethnicity and genetics may also play important roles in OSA risk, with roughly 25% of OSA prevalence estimated to have a genetic basis.^14,15 Some risk factors for OSA such as craniofacial shape, upper airway anatomy, upper airway muscle dysfunction, increased respiratory chemosensitivity, and poor arousal threshold during sleep are likely determined by genetics and ethnicity.^14,15 Compared with people of European origin, Asians have a similar prevalence of OSA, but at a much lower average BMI, suggesting that other factors are significant.¹⁴ Possible genetically determined anatomic risk factors have not been specifically studied in the poststroke population, but it can be assumed they remain relevant.

Several studies have tried to find an association between OSA and type, location, etiology, or pattern of stroke.^{10,11,16–19} Although some suggest links between cardioembolic stroke and OSA,^16,20 or thrombolysis and OSA,¹⁰ most have found no association between OSA and stroke features.^11,12,21,22

HOW DOES OSA INCREASE STROKE RISK?

Untreated severe OSA is associated with increased cardiovascular mortality,^21,22 and OSA is an independent risk factor for incident stroke.²³ A number of mechanisms may explain these relationships.

Intermittent hypoxemia and recurrent sympathetic arousals resulting from OSA are thought to lead to many of the comorbid conditions with which it is associated: hypertension, coronary artery disease, heart failure, arrhythmias, pulmonary hypertension, and stroke. Repetitive decreases in ventilation lead to oxygen desaturations that result in cycles of increased sympathetic outflow and eventual sustained nocturnal hypertension and daytime chronic hypertension.^1,5,9,13 Also implicated are various changes in vasodilator and vasoconstrictor substances due to endothelial dysfunction and inflammation, which are thought to play a role in the atherogenic and prothrombotic states induced by OSA.^1,5,13

Cerebral circulation is altered primarily by the changes in partial pressure of carbon dioxide (Pco₂). During apnea, the Pco₂ rises, causing vasodilation and increased blood flow. After the apnea resolves, there is hyperpnea with resultant decreased Pco₂, and vasoconstriction. In a patient who already has vascular disease, the enhanced vasoconstriction could lead to ischemia.^1,5

Changes in intrathoracic pressure result in distortion of cardiac architecture. When the patient tries to breathe against an occluded airway, the intrathoracic pressure becomes more and more negative, increasing preload and afterload. When this happens repeatedly every night for years, it leads to remodeling of the heart such as left and right ventricular hypertrophy, with reduced stroke volume, myocardial ischemia, and increased risk of arrhythmia.^1,5,13

Untreated OSA is believed to predispose patients to develop atrial fibrillation through sympathetic overactivity, vascular inflammation, heart rate variability, and cardiac remodeling.²⁴ As atrial fibrillation is a major risk factor for stroke, particularly cardioembolic stroke, it may be another pathway of increased stroke risk in OSA.^16,20,25

OSA typically causes both daytime symptoms (excessive sleepiness, poor concentration, morning headache, depressive symptoms) and nighttime signs and symptoms (snoring, choking, gasping, night sweats, insomnia, nocturia, witnessed episodes of apnea).^3,4,26 Unfortunately, because these are nonspecific, OSA is often underdiagnosed.^4,26

Identifying OSA after a stroke may be a particular challenge, as patients often do not report classic symptoms, and the typical picture of OSA may have less predictive validity in these patients.^1,27,28 Within the first 24 hours after a stroke, hypersomnia, snoring history, and age are not predictive of OSA.¹ Patients found to have OSA after a stroke frequently do not have the traditional symptoms (sleepiness, snoring) seen in usual OSA patients. And they have higher rates of OSA at a younger age than the usual OSA patients, so age is not a predictive risk factor. In addition, daytime sleepiness and obesity are often absent or less prominent.^1,9,27,28  Finally, typical OSA signs and symptoms may be attributed to the stroke itself or to comorbidities affecting the patient, lowering suspicion for OSA.

OSA MAY HINDER STROKE RECOVERY, WORSEN OUTCOMES

OSA, particularly when moderate to severe, is linked to pathophysiologic changes that can hinder recovery from a stroke.

Intermittent hypoxemia during sleep can worsen vascular damage of at-risk tissue: nocturnal hypoxemia correlates with white matter hyperintensities on magnetic resonance imaging, a marker of ischemic demyelination.²⁹ Oxidative stress and release of inflammatory mediators associated with intermittent hypoxemia may impair vascular blood flow to brain tissue attempting to repair itself.³⁰ In addition, sympathetic overactivity and Pco₂ fluctuations associated with OSA may impede cerebral circulation.

Taken together, such ongoing nocturnal insults can lead to clinical consequences during this vulnerable period.

A 1996 study³¹ of patients recovering from a stroke found that an oxygen desaturation index (number of times that the blood oxygen level drops below a certain threshold, as measured by overnight oximetry) of more than 10 per hour was associated with worse functional recovery at discharge and at 3 and 12 months after discharge. This study also noted an association between time spent with oxygen saturations below 90% and the rate of death at 1 year.

A 2003 study³² reported that patients with an AHI greater than 10 by polysomnography spent an average of 13 days longer on the rehabilitation service and had worse functional and cognitive status on discharge, even after controlling for multiple confounders. Several subsequent studies have confirmed these and similar findings.^8,33,34

OSA has also been linked to depression,³⁵ which is common after stroke and may worsen outcomes.³⁶ The interaction between OSA, depression, and poststroke outcomes warrants further study.

In the general population, OSA has been independently associated with increased risk of stroke or death from any cause.^21,22,37 These associations have also been reported in the poststroke population: a 2014 meta-analysis found that OSA increased the risk of a repeat stroke (relative risk [RR] 1.8, 95% confidence interval [CI] 1.2–2.6) and all-cause mortality (RR 1.69, 95% CI 1.4–2.1).³⁸

TESTING FOR OSA AFTER STROKE

Because of the high prevalence of OSA in patients who have had a stroke and the potential for worse outcomes associated with untreated OSA, there should be a low threshold for evaluating for OSA soon after stroke. Objective testing is required to qualify for therapy,  and the gold standard for diagnosis of OSA is formal polysomnography conducted in a sleep laboratory.^2–4 Unfortunately, polysomnography may be unacceptable to some patients, is costly, and is resource-intensive, particularly in an inpatient or rehabilitation setting.²⁸ Ideally, to optimize testing efficiency, patients should be screened for the likelihood of OSA before polysomnography is ordered.

Questionnaires can help determine the need for further testing

Questionnaires developed to assess OSA risk³⁹ include the following:

The Berlin questionnaire, developed in 1999, has 10 questions assessing daytime and nighttime signs and symptoms and presence of hypertension.

The STOP questionnaire, developed in 2008, assesses snoring, tiredness, observed apneic episodes, and elevated blood pressure.

The STOP-BANG questionnaire, published in 2010, includes the STOP questions plus BMI over 35 kg/m², age over 50, neck circumference over 41 cm, and male gender.

A 2017 meta-analysis³⁹ of 108 studies with nearly 50,000 people found that the STOP-BANG questionnaire performed best with regard to sensitivity and diagnostic odds ratio, but with poor specificity.

These screening tools and modified versions of them have also been evaluated in patients who have had a stroke.

In 2015, Boulos et al²⁸ found that the STOP-BAG (a version of STOP-BANG that excludes neck circumference) and the 4-variable (4V) questionnaire (sex, BMI, blood pressure, snoring) had moderate predictive value for OSA within 6 months after sroke.

In 2016, Katzan et al⁴⁰ found that the STOP-BAG2 (STOP-BAG criteria plus continuous variables for BMI and age) had a high sensitivity for polysomnographically diagnosed OSA within the first year after a stroke. The specificity was significantly better than the STOP-BANG or the STOP-BAG questionnaire, although it remained suboptimal at 60.5%.

In 2017, Sico et al⁴¹ developed and assessed the SLEEP Inventory (sex, left heart failure, Epworth Sleepiness Scale, enlarged neck, weight in pounds, insulin resistance or diabetes, and National Institutes of Health Stroke Scale) and found that it outperformed the Berlin and STOP-BANG questionnaires in the poststroke setting. The SLEEP Inventory had the best specificity and negative predictive value, and a slightly better ability to correctly classify patients as having OSA or not, classifying 80% of patients correctly.

These newer screening tools (eg, STOP-BAG, STOP-BAG2, SLEEP) can be used to identify with reasonable accuracy which patients need definitive testing after stroke.

Pulse oximetry is another possible screening tool          

Overnight pulse oximetry may also help screen for sleep apnea and stratify risk after a stroke. A 2012 study⁴² of overnight oximetry to screen patients before surgery found that the oxygen desaturation index was significantly associated with the AHI measured by polysomnography. However, oximetry testing cannot distinguish between OSA and central sleep apnea, so it is insufficient to diagnose OSA or qualify patients for therapy. Further study is needed to examine the ability of overnight pulse oximetry to screen or to stratify risk for OSA after stroke.

Polysomnography vs home testing

Polysomnography is the gold standard for diagnosing OSA. Benefits include technical support and trouble-shooting, determining relationships between OSA, body position, and sleep stage, and the ability to intervene with treatment.² However, polysomnography can be cumbersome, costly, and resource-intensive.

A home sleep apnea test, ie, an unattended, limited-channel sleep study, may be an acceptable alternative.^2–4,43,44 Home testing does not require a sleep technologist to be present during testing, uses fewer sensors, and is less expensive than overnight polysomnography, but its utility can be limited: it fails to accurately discriminate between episodes of OSA and central sleep apnea, there is potential for false-negative results, and it can underestimate sleep apnea burden because it does not measure sleep.²

Institutional resources and logistics may influence the choice of diagnostic modality. No data exist on outcomes from different diagnostic testing methods in poststroke patients. Further research is needed.

The first-line treatment for OSA is positive airway pressure (PAP).³ For most patients, this is continuous PAP (CPAP) or autoadjusting PAP (APAP). In some instances, particularly for those who cannot tolerate CPAP or who have comorbid hypoventilation, bilevel PAP (BPAP) may be indicated. More advanced PAP therapies are unlikely to be used after stroke.

PAP therapy is associated with reduced daytime sleepiness, improved mood, normalization of sleep architecture, improved systemic and pulmonary artery blood pressure, reduced rates of atrial fibrillation after ablation, and improved insulin sensitivity.^45–49 Whether it reduces the risk of cardiovascular events, including stroke, remains controversial; most data suggest that it does not.^50,51 However, when adherence to PAP therapy is considered rather than intention to treat, treatment has been found to lead to improved cardiovascular outcomes.⁵²

Mixed evidence of benefits after stroke

Observational studies provide evidence that CPAP may help patients with OSA after stroke, although results are mixed.^53–58 The studies ranged in size from 14 to 105 patients, enrolled patients with mostly moderate to severe OSA, and followed patients from 10 days to 7 years. Adherence to therapy was generally good in the short term (50%–70%), but only  15% to 30% of patients remained adherent at 5 to 7 years. Variable outcomes were reported, with some studies finding improved symptoms in the near term and mixed evidence of cardiovascular benefit in the longer ones. However, as these studies lacked randomization, drawing definitive conclusions on CPAP efficacy is difficult.

Patients were enrolled in the index admission or when starting a rehabilitation service—generally 2 to 3 weeks after their stroke. No clear association was found between the timing of initiating PAP therapy and outcomes. All patients had ischemic strokes, but few details were provided regarding stroke location, size, and severity. Exclusion criteria included severe underlying cardiopulmonary disease, confusion, severe stroke with marked impairment, and inability to cooperate. Almost all patients had moderate to severe OSA, and patients with central sleep apnea were excluded.

The major outcomes examined were drop-out rates, PAP adherence, and neurologic improvement based on neurologic functional scales (National Institutes of Health Stroke Scale and Canadian Neurologic Scale). As expected, dropout rates were higher in patients randomized to CPAP (OR 1.83, 95% CI 1.05–3.21, P = .03), although overall adherence was better than anticipated, with mean CPAP use across trials of 4.5 hours per night (95% CI 3.97–5.08) and with about 50% to 60% of patients adhering to therapy for at least 4 hours nightly.

Improvement in neurologic outcomes favored CPAP (standard mean difference 0.54, 95% CI 0.026–1.05), although considerable heterogeneity was seen. Improved sleepiness outcomes were inconsistent. Major cardiovascular outcomes were reported in only 2 studies (using the same data set) and showed delayed time to the next cardiovascular event for those treated with CPAP but no difference in cardiovascular event-free survival.

PAP poses more challenges after stroke

The primary limitation to PAP therapy is poor acceptance and adherence to therapy.⁵⁹ High rates of refusal of therapy and difficulty complying with treatment have been noted in the poststroke population, although recent studies have reported better adherence rates. How rates of adherence play out in real-world settings, outside of the controlled environment of a research study, has yet to be determined.

In general, CPAP adherence is affected by claustrophobia, difficulty tolerating a mask, problems with pressure intolerance, irritating air leaks, nasal congestion, and naso-oral dryness. Many such barriers can be overcome with use of a properly fitted mask, an appropriate pressure setting, heated humidification, nasal sprays (eg, saline, inhaled steroids), and education, encouragement, and reassurance.

After a stroke, additional obstacles may impede the ability to use PAP therapy.⁶⁸ Facial paresis (hemi- or bifacial) may make fitting of the mask problematic. Paralysis or weakness of the extremities may limit the ability to adjust or remove a mask. Aphasia can impair communication and understanding of the need to use PAP therapy, and upper-airway problems related to stroke, including dysphagia, may lead to pressure intolerance or risk of aspiration. Finally, a lack of perceived benefit, particularly if the patient does not have daytime sleepiness, may limit motivation.

Consider alternatives

For patients unlikely to succeed with PAP therapy, there are alternatives. Surgery and oral appliances are not usually realistic options in the setting of recent stroke, but positional therapy, including the use of body positioners to prevent supine sleep, as well as elevating the head of the bed, may be of some benefit.^69,70 A nasopharyngeal airway stenting device (nasal trumpet) may also be tolerated by some patients.

A proposed algorithm for screening, diagnosing, and treating OSA in patients after stroke is presented in Figure 1.

A 69-year-old woman was admitted to the hospital with double vision, weakness in the lower extremities, sensory loss, pain, and falls. Her symptoms started with sudden onset of horizontal diplopia 6 weeks before, followed by gradually worsening lower-extremity weakness, as well as ataxia and patchy and bilateral radicular burning leg pain more pronounced on the right. Her medical history included narcolepsy, obstructive sleep apnea, hypertension, hyperlipidemia, and bilateral knee replacements for osteoarthritis.

Neurologic examination showed inability to abduct the right eye, bilateral hip flexion weakness, decreased pinprick response, decreased proprioception, and diminished muscle stretch reflexes in the lower extremities. Magnetic resonance imaging (MRI) of the brain without contrast and magnetic resonance angiography of the brain and carotid arteries showed no evidence of acute stroke. No abnormalities were noted on electrocardiography and echocardiography.

A diagnosis of idiopathic peripheral neuropathy was made, and outpatient physical therapy was recommended. Over the subsequent 2 weeks, her condition declined to the point where she needed a walker. She continued to have worsening leg weakness with falls, prompting hospital readmission.

INITIAL EVALUATION

In addition to her diplopia and weakness, she said she had lost 15 pounds since the onset of symptoms and had experienced symptoms suggesting urinary retention.

Physical examination

Her temperature was 37°C (98.6°F), heart rate 79 beats per minute, blood pressure 117/86 mm Hg, respiratory rate 14 breaths per minute, and oxygen saturation 98% on room air. Examination of the head, neck, heart, lung, abdomen, lymph nodes, and extremities yielded nothing remarkable except for chronic venous changes in the lower extremities.

The neurologic examination showed incomplete lateral gaze bilaterally (cranial nerve VI dysfunction). Strength in the upper extremities was normal. In the legs, the Medical Research Council scale score for proximal muscle strength was 2 to 3 out of 5, and for distal muscles 3 to 4 out of 5, with the right side worse than the left and flexors and extensors affected equally. Muscle stretch reflexes were absent in both lower extremities and the left upper extremity, but intact in the right upper extremity. No abnormal corticospinal tract reflexes were elicited.

Sensory testing revealed diminished pin-prick perception in a length-dependent fashion in the lower extremities, reduced 50% compared with the hands. Gait could not be assessed due to weakness.

Initial laboratory testing

Results of initial laboratory tests—complete blood cell count, complete metabolic panel, erythrocyte sedimentation rate, C-reactive protein, thyroid-stimulating hormone, and hemoglobin A_1c—were unremarkable.

1. Which of the following is the most likely diagnosis at this point?

• Cerebral infarction
• Guillain-Barré syndrome
• Progressive polyneuropathy
• Transverse myelitis
• Polyradiculopathy

In the absence of definitive diagnostic tests, all of the above options were considered in the differential diagnosis for this patient.

Cerebral infarction

Although acute-onset diplopia can be explained by brainstem stroke involving cranial nerve nuclei or their projections, the onset of diplopia with progressive bilateral lower-extremity weakness makes stroke unlikely. Flaccid paralysis, areflexia of the lower extremities, and sensory involvement can also be caused by acute anterior spinal artery occlusion leading to spinal cord infarction; however, the deficits are usually maximal at onset.

Guillain-Barré syndrome

The combination of acute-subacute progressive ascending weakness, sensory involvement, and diminished or absent reflexes is typical of Guillain-Barré syndrome. Cranial nerve involvement can overlap with the more typical features of the syndrome. However, most patients reach the nadir of their disease by 4 weeks after initial symptom onset, even without treatment.¹ This patient’s condition continued to worsen over 8 weeks. In addition, the asymmetric lower-extremity weakness and sparing of the arms are atypical for Guillain-Barré syndrome.

Given the progression of symptoms, chronic inflammatory demyelinating polyneuropathy is also a consideration, typically presenting as a relapsing or progressive neuropathy in proximal and distal muscles and worsening over at least an 8-week period.²

The initial workup for Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy includes lumbar puncture to assess for albuminocytologic dissociation (elevated protein with normal white blood cell count) in cerebrospinal fluid (CSF), and electromyography (EMG) to assess for neuro­physiologic evidence of peripheral nerve demyelination. In Miller-Fisher syndrome, a rare variant of Guillain-Barré syndrome characterized by ataxia, ophthalmoparesis, and areflexia, serum ganglioside antibodies to GQ1b are found in over 90% of patients.^3,4 Although MRI of the spine is not necessary to diagnose Guillain-Barré syndrome, it is often done to exclude other causes of lower-extremity weakness such as spinal cord or cauda equina compression that would require urgent neurosurgical consultation. MRI can support the diagnosis of Guillain-Barré syndrome when it reveals enhancement of the spinal nerve roots or cauda equina.

Other polyneuropathies

Polyneuropathy is caused by a variety of diseases that affect the function of peripheral motor, sensory, or autonomic nerves. The differential diagnosis is broad and involves inflammatory diseases (including autoimmune and paraneoplastic causes), hereditary disorders, infection, toxicity, and ischemic and nutritional deficiencies.⁵ Polyneuropathy can present in a distal-predominant, generalized, or asymmetric pattern involving individual nerve trunks termed “mononeuropathy multiplex,” as in our patient’s presentation. The initial workup includes EMG and a battery of serologic tests. In cases of severe and progressive polyneuropathy, nerve biopsy can assess for the presence of vasculitis, amyloidosis, and paraprotein deposition.

Transverse myelitis

Transverse myelitis is an inflammatory myelopathy that usually presents with acute or subacute weakness of the upper extremities or lower extremities, or both, corresponding to the level of the lesion, hyperreflexia, bladder and bowel dysfunction, spinal level of sensory loss, and autonomic involvement.⁶ The differential diagnosis of acute myelopathy includes:

• Infection (eg, herpes simplex virus, West Nile virus, Lyme disease, Mycoplasma pneumoniae, human immunodeficiency virus)
• Systemic inflammatory disease (systemic lupus erythematosus, sarcoidosis, Sjögren syndrome, scleroderma, paraneoplastic syndrome)
• Central nervous system demyelinating disease (acute disseminated encephalomyelitis, multiple sclerosis, neuromyelitis optica)
• Vascular malformation (dural arteriovenous fistula)
• Compression due to tumor, bleeding, disc herniation, infection, or abscess.

The workup involves laboratory tests to exclude systemic inflammatory and infectious causes, as well as MRI of the spine with and without contrast to identify a causative lesion. Lumbar puncture and CSF analysis may show pleocytosis, elevated protein concentration, and increased intrathecal immunoglobulin G (IgG) index.⁷

Although our patient’s presentation with subacute lower-extremity weakness, sensory changes, and bladder dysfunction were consistent with transverse myelitis, her cranial nerve abnormalities would be atypical for it.

Polyradiculopathy


Polyradiculopathy has many possible causes. In the United States, the most common causes are lumbar spondylosis, lumbar canal stenosis, and diabetic polyradiculoneuropathy.

When multiple spinal segments are affected, leptomeningeal disease involving the arachnoid and pia mater should be considered. Causes include malignant invasion, inflammatory cell accumulation, and protein deposition, leading to patchy but widespread dysfunction of spinal nerve roots and cranial nerves. Specific causes are myriad and include carcinomatous meningitis,⁸ syphilis, tuberculosis, sarcoidosis, and paraproteinemias. CSF and MRI changes are often nonspecific, leading to the need for meningeal biopsy for diagnosis.

During her hospitalization, our patient developed acute right upper and lower facial weakness consistent with peripheral facial mononeuropathy. Bilateral lower-extremity weakness progressed to disabling paraparesis.

She underwent lumbar puncture and CSF analysis (Table 1). The most notable findings were significant pleocytosis (72% lymphocytic predominance), protein elevation, and elevated IgG index (indicative of elevated intrathecal immunoglobulin synthesis in the central nervous system). Viral, bacterial, and fungal studies were negative. Guillain-Barré syndrome, other polyneuropathies, and spinal cord infarction would not be expected with these CSF features.

Surface EMG demonstrated normal sensory responses, and needle EMG showed chronic and active motor axon loss in the L3 and S1 root distributions, suggesting polyradiculopathy without polyneuropathy. These findings would not be expected in typical acute transverse myelitis but could be seen with spinal cord infarction.

MRI of the entire spine with and without contrast showed cauda equina nerve root thickening and enhancement, especially involving the L5 and S1 roots (Figure 1). The spinal cord appeared normal. These findings further supported polyradiculopathy and a leptomeningeal process.

Further evaluation included chest radiography, erythrocyte sedimentation rate, C-reactive protein, hemoglobin A_1c, human immunodeficiency virus testing, antinuclear antibody, antineutrophil cytoplasmic antibody, extractable nuclear antibody, GQ1b antibody, serum and CSF paraneoplastic panels, levels of vitamin B₁, B₁₂, and B₆, copper, and ceruloplasmin, and a screen for heavy metals. All results were within normal ranges.

ESTABLISHING THE DIAGNOSIS

Serum monoclonal protein analysis with immunofixation revealed IgM kappa monoclonal gammopathy with an IgM level of 1,570 (reference range 53–334 mg/dL) and M-spike 0.75 (0.00 mg/dL), serum free kappa light chains 61.1 (3.30–19.40 mg/L), lambda 9.3 (5.7–26.3 mg/L), and kappa-lambda ratio 6.57 (0.26–1.65).

2. Which is the best next step in this patient’s neurologic evaluation?

• Test CSF angiotensin-converting enzyme level
• CSF cytology
• Meningeal biopsy
• Peripheral nerve biopsy

Given the high suspicion for malignancy, CSF cytology was performed and showed increased numbers of mononuclear chronic inflammatory cells, including a mixture of lymphocytes and monocytes, favoring a reactive lymphoid pleocytosis. Flow cytometry indicated the presence of a monoclonal, CD5- and CD10- negative, B-cell lymphoproliferative disorder. The immunophenotypic findings were not specific for a single diagnosis. The differential diagnosis included marginal zone lymphoma and lymphoplasmacytic lymphoma.

3. Given the presence of serum IgM monoclonal gammopathy in this patient, which is the most likely diagnosis?

• Neurosarcoidosis
• Multiple myeloma
• Waldenström macroglobulinemia
• Carcinomatous meningitis

Study of bone marrow biopsy demonstrated limited bone marrow involvement (1%) by a lymphoproliferative disorder with plasmacytoid features, and DNA testing detected an MYD88 L265P mutation, reported to be present in 90% of patients with Waldenström macroglobulinemia.⁹ This finding confirmed the diagnosis of Waldenström macroglobulinemia with central nervous system involvement. Our patient began therapy with rituximab and methotrexate, which resulted in some improvement in strength, gait, and vision.

Waldenström macroglobulinemia is a lympho­plasmacytic lymphoma associated with a monoclonal IgM protein.¹⁰ It is considered a paraproteinemic disorder, similar to multiple myeloma. The presenting symptoms and complications are related to direct tumor infiltration, hyperviscosity syndrome, and deposition of IgM in various tissues.^11,12

Waldenström macroglobulinemia is usually indolent, and treatment is reserved for patients with symptoms.^13,14 It includes rituximab, usually in combination with chemotherapy or other targeted agents.^15,16

Paraneoplastic antibody-mediated polyneuropathy may occur in these patients. However, the pattern is usually symmetrical clinically, with demyelination on EMG, and is not associated with cranial nerve or meningeal involvement. Management with plasmapheresis, corticosteroids, and intravenous immunoglobulin has not been shown to be effective.¹⁷

Involvement of the central nervous system as a complication of Waldenström macroglobulinemia has been described as Bing-Neel syndrome. It can present as diffuse malignant cell infiltration of the leptomeningeal space, white matter, or spinal cord, or in a tumoral form presenting as intraparenchymal masses or nodular lesions. The distinction between the tumoral and diffuse forms is based primarily on imaging findings.¹⁸

In a report of 44 patients with Bing-Neel syndrome, 36% presented with the disorder as the initial manifestation of Waldenström macroglobulinemia.¹⁸ The primary presenting symptoms were imbalance and gait difficulty (48%) and cranial nerve involvement (36%), which presented as predominantly facial or oculomotor nerve palsy. Cauda equina syndrome with motor involvement (seen in our patient) occurred in 14% of patients. Other presenting symptoms included cognitive impairment, sensory deficits, headache, dysarthria, aphasia, and seizures.

LEARNING POINTS

The differential diagnosis for patients presenting with multifocal neurologic symptoms can be broad, and a systematic approach to the diagnosis is necessary. Localizing the lesion is important in determining the diagnosis for patients presenting with neurologic symptoms. The process of localization begins with taking the history, is further refined during the examination, and is confirmed with diagnostic studies. Atypical presentations of relatively common neurologic diseases such as Guillain-Barré syndrome, transverse myelitis, and peripheral polyneuropathy do occur, but uncommon diagnoses need to be considered when support for the initial diagnosis is lacking.

A 69-year-old woman was admitted to the hospital with double vision, weakness in the lower extremities, sensory loss, pain, and falls. Her symptoms started with sudden onset of horizontal diplopia 6 weeks before, followed by gradually worsening lower-extremity weakness, as well as ataxia and patchy and bilateral radicular burning leg pain more pronounced on the right. Her medical history included narcolepsy, obstructive sleep apnea, hypertension, hyperlipidemia, and bilateral knee replacements for osteoarthritis.

Neurologic examination showed inability to abduct the right eye, bilateral hip flexion weakness, decreased pinprick response, decreased proprioception, and diminished muscle stretch reflexes in the lower extremities. Magnetic resonance imaging (MRI) of the brain without contrast and magnetic resonance angiography of the brain and carotid arteries showed no evidence of acute stroke. No abnormalities were noted on electrocardiography and echocardiography.

A diagnosis of idiopathic peripheral neuropathy was made, and outpatient physical therapy was recommended. Over the subsequent 2 weeks, her condition declined to the point where she needed a walker. She continued to have worsening leg weakness with falls, prompting hospital readmission.

INITIAL EVALUATION

In addition to her diplopia and weakness, she said she had lost 15 pounds since the onset of symptoms and had experienced symptoms suggesting urinary retention.

Physical examination

Her temperature was 37°C (98.6°F), heart rate 79 beats per minute, blood pressure 117/86 mm Hg, respiratory rate 14 breaths per minute, and oxygen saturation 98% on room air. Examination of the head, neck, heart, lung, abdomen, lymph nodes, and extremities yielded nothing remarkable except for chronic venous changes in the lower extremities.

The neurologic examination showed incomplete lateral gaze bilaterally (cranial nerve VI dysfunction). Strength in the upper extremities was normal. In the legs, the Medical Research Council scale score for proximal muscle strength was 2 to 3 out of 5, and for distal muscles 3 to 4 out of 5, with the right side worse than the left and flexors and extensors affected equally. Muscle stretch reflexes were absent in both lower extremities and the left upper extremity, but intact in the right upper extremity. No abnormal corticospinal tract reflexes were elicited.

Sensory testing revealed diminished pin-prick perception in a length-dependent fashion in the lower extremities, reduced 50% compared with the hands. Gait could not be assessed due to weakness.

Initial laboratory testing

Results of initial laboratory tests—complete blood cell count, complete metabolic panel, erythrocyte sedimentation rate, C-reactive protein, thyroid-stimulating hormone, and hemoglobin A_1c—were unremarkable.

1. Which of the following is the most likely diagnosis at this point?

• Cerebral infarction
• Guillain-Barré syndrome
• Progressive polyneuropathy
• Transverse myelitis
• Polyradiculopathy

In the absence of definitive diagnostic tests, all of the above options were considered in the differential diagnosis for this patient.

Cerebral infarction

Although acute-onset diplopia can be explained by brainstem stroke involving cranial nerve nuclei or their projections, the onset of diplopia with progressive bilateral lower-extremity weakness makes stroke unlikely. Flaccid paralysis, areflexia of the lower extremities, and sensory involvement can also be caused by acute anterior spinal artery occlusion leading to spinal cord infarction; however, the deficits are usually maximal at onset.

Guillain-Barré syndrome

The combination of acute-subacute progressive ascending weakness, sensory involvement, and diminished or absent reflexes is typical of Guillain-Barré syndrome. Cranial nerve involvement can overlap with the more typical features of the syndrome. However, most patients reach the nadir of their disease by 4 weeks after initial symptom onset, even without treatment.¹ This patient’s condition continued to worsen over 8 weeks. In addition, the asymmetric lower-extremity weakness and sparing of the arms are atypical for Guillain-Barré syndrome.

Given the progression of symptoms, chronic inflammatory demyelinating polyneuropathy is also a consideration, typically presenting as a relapsing or progressive neuropathy in proximal and distal muscles and worsening over at least an 8-week period.²

The initial workup for Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy includes lumbar puncture to assess for albuminocytologic dissociation (elevated protein with normal white blood cell count) in cerebrospinal fluid (CSF), and electromyography (EMG) to assess for neuro­physiologic evidence of peripheral nerve demyelination. In Miller-Fisher syndrome, a rare variant of Guillain-Barré syndrome characterized by ataxia, ophthalmoparesis, and areflexia, serum ganglioside antibodies to GQ1b are found in over 90% of patients.^3,4 Although MRI of the spine is not necessary to diagnose Guillain-Barré syndrome, it is often done to exclude other causes of lower-extremity weakness such as spinal cord or cauda equina compression that would require urgent neurosurgical consultation. MRI can support the diagnosis of Guillain-Barré syndrome when it reveals enhancement of the spinal nerve roots or cauda equina.

Other polyneuropathies

Polyneuropathy is caused by a variety of diseases that affect the function of peripheral motor, sensory, or autonomic nerves. The differential diagnosis is broad and involves inflammatory diseases (including autoimmune and paraneoplastic causes), hereditary disorders, infection, toxicity, and ischemic and nutritional deficiencies.⁵ Polyneuropathy can present in a distal-predominant, generalized, or asymmetric pattern involving individual nerve trunks termed “mononeuropathy multiplex,” as in our patient’s presentation. The initial workup includes EMG and a battery of serologic tests. In cases of severe and progressive polyneuropathy, nerve biopsy can assess for the presence of vasculitis, amyloidosis, and paraprotein deposition.

Transverse myelitis

Transverse myelitis is an inflammatory myelopathy that usually presents with acute or subacute weakness of the upper extremities or lower extremities, or both, corresponding to the level of the lesion, hyperreflexia, bladder and bowel dysfunction, spinal level of sensory loss, and autonomic involvement.⁶ The differential diagnosis of acute myelopathy includes:

• Infection (eg, herpes simplex virus, West Nile virus, Lyme disease, Mycoplasma pneumoniae, human immunodeficiency virus)
• Systemic inflammatory disease (systemic lupus erythematosus, sarcoidosis, Sjögren syndrome, scleroderma, paraneoplastic syndrome)
• Central nervous system demyelinating disease (acute disseminated encephalomyelitis, multiple sclerosis, neuromyelitis optica)
• Vascular malformation (dural arteriovenous fistula)
• Compression due to tumor, bleeding, disc herniation, infection, or abscess.

The workup involves laboratory tests to exclude systemic inflammatory and infectious causes, as well as MRI of the spine with and without contrast to identify a causative lesion. Lumbar puncture and CSF analysis may show pleocytosis, elevated protein concentration, and increased intrathecal immunoglobulin G (IgG) index.⁷

Although our patient’s presentation with subacute lower-extremity weakness, sensory changes, and bladder dysfunction were consistent with transverse myelitis, her cranial nerve abnormalities would be atypical for it.

Polyradiculopathy


Polyradiculopathy has many possible causes. In the United States, the most common causes are lumbar spondylosis, lumbar canal stenosis, and diabetic polyradiculoneuropathy.

When multiple spinal segments are affected, leptomeningeal disease involving the arachnoid and pia mater should be considered. Causes include malignant invasion, inflammatory cell accumulation, and protein deposition, leading to patchy but widespread dysfunction of spinal nerve roots and cranial nerves. Specific causes are myriad and include carcinomatous meningitis,⁸ syphilis, tuberculosis, sarcoidosis, and paraproteinemias. CSF and MRI changes are often nonspecific, leading to the need for meningeal biopsy for diagnosis.

During her hospitalization, our patient developed acute right upper and lower facial weakness consistent with peripheral facial mononeuropathy. Bilateral lower-extremity weakness progressed to disabling paraparesis.

She underwent lumbar puncture and CSF analysis (Table 1). The most notable findings were significant pleocytosis (72% lymphocytic predominance), protein elevation, and elevated IgG index (indicative of elevated intrathecal immunoglobulin synthesis in the central nervous system). Viral, bacterial, and fungal studies were negative. Guillain-Barré syndrome, other polyneuropathies, and spinal cord infarction would not be expected with these CSF features.

Surface EMG demonstrated normal sensory responses, and needle EMG showed chronic and active motor axon loss in the L3 and S1 root distributions, suggesting polyradiculopathy without polyneuropathy. These findings would not be expected in typical acute transverse myelitis but could be seen with spinal cord infarction.

MRI of the entire spine with and without contrast showed cauda equina nerve root thickening and enhancement, especially involving the L5 and S1 roots (Figure 1). The spinal cord appeared normal. These findings further supported polyradiculopathy and a leptomeningeal process.

Further evaluation included chest radiography, erythrocyte sedimentation rate, C-reactive protein, hemoglobin A_1c, human immunodeficiency virus testing, antinuclear antibody, antineutrophil cytoplasmic antibody, extractable nuclear antibody, GQ1b antibody, serum and CSF paraneoplastic panels, levels of vitamin B₁, B₁₂, and B₆, copper, and ceruloplasmin, and a screen for heavy metals. All results were within normal ranges.

ESTABLISHING THE DIAGNOSIS

Serum monoclonal protein analysis with immunofixation revealed IgM kappa monoclonal gammopathy with an IgM level of 1,570 (reference range 53–334 mg/dL) and M-spike 0.75 (0.00 mg/dL), serum free kappa light chains 61.1 (3.30–19.40 mg/L), lambda 9.3 (5.7–26.3 mg/L), and kappa-lambda ratio 6.57 (0.26–1.65).

2. Which is the best next step in this patient’s neurologic evaluation?

• Test CSF angiotensin-converting enzyme level
• CSF cytology
• Meningeal biopsy
• Peripheral nerve biopsy

Given the high suspicion for malignancy, CSF cytology was performed and showed increased numbers of mononuclear chronic inflammatory cells, including a mixture of lymphocytes and monocytes, favoring a reactive lymphoid pleocytosis. Flow cytometry indicated the presence of a monoclonal, CD5- and CD10- negative, B-cell lymphoproliferative disorder. The immunophenotypic findings were not specific for a single diagnosis. The differential diagnosis included marginal zone lymphoma and lymphoplasmacytic lymphoma.

3. Given the presence of serum IgM monoclonal gammopathy in this patient, which is the most likely diagnosis?

• Neurosarcoidosis
• Multiple myeloma
• Waldenström macroglobulinemia
• Carcinomatous meningitis

Study of bone marrow biopsy demonstrated limited bone marrow involvement (1%) by a lymphoproliferative disorder with plasmacytoid features, and DNA testing detected an MYD88 L265P mutation, reported to be present in 90% of patients with Waldenström macroglobulinemia.⁹ This finding confirmed the diagnosis of Waldenström macroglobulinemia with central nervous system involvement. Our patient began therapy with rituximab and methotrexate, which resulted in some improvement in strength, gait, and vision.

Waldenström macroglobulinemia is a lympho­plasmacytic lymphoma associated with a monoclonal IgM protein.¹⁰ It is considered a paraproteinemic disorder, similar to multiple myeloma. The presenting symptoms and complications are related to direct tumor infiltration, hyperviscosity syndrome, and deposition of IgM in various tissues.^11,12

Waldenström macroglobulinemia is usually indolent, and treatment is reserved for patients with symptoms.^13,14 It includes rituximab, usually in combination with chemotherapy or other targeted agents.^15,16

Paraneoplastic antibody-mediated polyneuropathy may occur in these patients. However, the pattern is usually symmetrical clinically, with demyelination on EMG, and is not associated with cranial nerve or meningeal involvement. Management with plasmapheresis, corticosteroids, and intravenous immunoglobulin has not been shown to be effective.¹⁷

Involvement of the central nervous system as a complication of Waldenström macroglobulinemia has been described as Bing-Neel syndrome. It can present as diffuse malignant cell infiltration of the leptomeningeal space, white matter, or spinal cord, or in a tumoral form presenting as intraparenchymal masses or nodular lesions. The distinction between the tumoral and diffuse forms is based primarily on imaging findings.¹⁸

In a report of 44 patients with Bing-Neel syndrome, 36% presented with the disorder as the initial manifestation of Waldenström macroglobulinemia.¹⁸ The primary presenting symptoms were imbalance and gait difficulty (48%) and cranial nerve involvement (36%), which presented as predominantly facial or oculomotor nerve palsy. Cauda equina syndrome with motor involvement (seen in our patient) occurred in 14% of patients. Other presenting symptoms included cognitive impairment, sensory deficits, headache, dysarthria, aphasia, and seizures.

LEARNING POINTS

The differential diagnosis for patients presenting with multifocal neurologic symptoms can be broad, and a systematic approach to the diagnosis is necessary. Localizing the lesion is important in determining the diagnosis for patients presenting with neurologic symptoms. The process of localization begins with taking the history, is further refined during the examination, and is confirmed with diagnostic studies. Atypical presentations of relatively common neurologic diseases such as Guillain-Barré syndrome, transverse myelitis, and peripheral polyneuropathy do occur, but uncommon diagnoses need to be considered when support for the initial diagnosis is lacking.

A 69-year-old woman was admitted to the hospital with double vision, weakness in the lower extremities, sensory loss, pain, and falls. Her symptoms started with sudden onset of horizontal diplopia 6 weeks before, followed by gradually worsening lower-extremity weakness, as well as ataxia and patchy and bilateral radicular burning leg pain more pronounced on the right. Her medical history included narcolepsy, obstructive sleep apnea, hypertension, hyperlipidemia, and bilateral knee replacements for osteoarthritis.

Neurologic examination showed inability to abduct the right eye, bilateral hip flexion weakness, decreased pinprick response, decreased proprioception, and diminished muscle stretch reflexes in the lower extremities. Magnetic resonance imaging (MRI) of the brain without contrast and magnetic resonance angiography of the brain and carotid arteries showed no evidence of acute stroke. No abnormalities were noted on electrocardiography and echocardiography.

A diagnosis of idiopathic peripheral neuropathy was made, and outpatient physical therapy was recommended. Over the subsequent 2 weeks, her condition declined to the point where she needed a walker. She continued to have worsening leg weakness with falls, prompting hospital readmission.

INITIAL EVALUATION

In addition to her diplopia and weakness, she said she had lost 15 pounds since the onset of symptoms and had experienced symptoms suggesting urinary retention.

Physical examination

Her temperature was 37°C (98.6°F), heart rate 79 beats per minute, blood pressure 117/86 mm Hg, respiratory rate 14 breaths per minute, and oxygen saturation 98% on room air. Examination of the head, neck, heart, lung, abdomen, lymph nodes, and extremities yielded nothing remarkable except for chronic venous changes in the lower extremities.

The neurologic examination showed incomplete lateral gaze bilaterally (cranial nerve VI dysfunction). Strength in the upper extremities was normal. In the legs, the Medical Research Council scale score for proximal muscle strength was 2 to 3 out of 5, and for distal muscles 3 to 4 out of 5, with the right side worse than the left and flexors and extensors affected equally. Muscle stretch reflexes were absent in both lower extremities and the left upper extremity, but intact in the right upper extremity. No abnormal corticospinal tract reflexes were elicited.

Sensory testing revealed diminished pin-prick perception in a length-dependent fashion in the lower extremities, reduced 50% compared with the hands. Gait could not be assessed due to weakness.

Initial laboratory testing

Results of initial laboratory tests—complete blood cell count, complete metabolic panel, erythrocyte sedimentation rate, C-reactive protein, thyroid-stimulating hormone, and hemoglobin A_1c—were unremarkable.

1. Which of the following is the most likely diagnosis at this point?

• Cerebral infarction
• Guillain-Barré syndrome
• Progressive polyneuropathy
• Transverse myelitis
• Polyradiculopathy

In the absence of definitive diagnostic tests, all of the above options were considered in the differential diagnosis for this patient.

Cerebral infarction

Although acute-onset diplopia can be explained by brainstem stroke involving cranial nerve nuclei or their projections, the onset of diplopia with progressive bilateral lower-extremity weakness makes stroke unlikely. Flaccid paralysis, areflexia of the lower extremities, and sensory involvement can also be caused by acute anterior spinal artery occlusion leading to spinal cord infarction; however, the deficits are usually maximal at onset.

Guillain-Barré syndrome

The combination of acute-subacute progressive ascending weakness, sensory involvement, and diminished or absent reflexes is typical of Guillain-Barré syndrome. Cranial nerve involvement can overlap with the more typical features of the syndrome. However, most patients reach the nadir of their disease by 4 weeks after initial symptom onset, even without treatment.¹ This patient’s condition continued to worsen over 8 weeks. In addition, the asymmetric lower-extremity weakness and sparing of the arms are atypical for Guillain-Barré syndrome.

Given the progression of symptoms, chronic inflammatory demyelinating polyneuropathy is also a consideration, typically presenting as a relapsing or progressive neuropathy in proximal and distal muscles and worsening over at least an 8-week period.²

The initial workup for Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy includes lumbar puncture to assess for albuminocytologic dissociation (elevated protein with normal white blood cell count) in cerebrospinal fluid (CSF), and electromyography (EMG) to assess for neuro­physiologic evidence of peripheral nerve demyelination. In Miller-Fisher syndrome, a rare variant of Guillain-Barré syndrome characterized by ataxia, ophthalmoparesis, and areflexia, serum ganglioside antibodies to GQ1b are found in over 90% of patients.^3,4 Although MRI of the spine is not necessary to diagnose Guillain-Barré syndrome, it is often done to exclude other causes of lower-extremity weakness such as spinal cord or cauda equina compression that would require urgent neurosurgical consultation. MRI can support the diagnosis of Guillain-Barré syndrome when it reveals enhancement of the spinal nerve roots or cauda equina.

Other polyneuropathies

Polyneuropathy is caused by a variety of diseases that affect the function of peripheral motor, sensory, or autonomic nerves. The differential diagnosis is broad and involves inflammatory diseases (including autoimmune and paraneoplastic causes), hereditary disorders, infection, toxicity, and ischemic and nutritional deficiencies.⁵ Polyneuropathy can present in a distal-predominant, generalized, or asymmetric pattern involving individual nerve trunks termed “mononeuropathy multiplex,” as in our patient’s presentation. The initial workup includes EMG and a battery of serologic tests. In cases of severe and progressive polyneuropathy, nerve biopsy can assess for the presence of vasculitis, amyloidosis, and paraprotein deposition.

Transverse myelitis

Transverse myelitis is an inflammatory myelopathy that usually presents with acute or subacute weakness of the upper extremities or lower extremities, or both, corresponding to the level of the lesion, hyperreflexia, bladder and bowel dysfunction, spinal level of sensory loss, and autonomic involvement.⁶ The differential diagnosis of acute myelopathy includes:

• Infection (eg, herpes simplex virus, West Nile virus, Lyme disease, Mycoplasma pneumoniae, human immunodeficiency virus)
• Systemic inflammatory disease (systemic lupus erythematosus, sarcoidosis, Sjögren syndrome, scleroderma, paraneoplastic syndrome)
• Central nervous system demyelinating disease (acute disseminated encephalomyelitis, multiple sclerosis, neuromyelitis optica)
• Vascular malformation (dural arteriovenous fistula)
• Compression due to tumor, bleeding, disc herniation, infection, or abscess.

The workup involves laboratory tests to exclude systemic inflammatory and infectious causes, as well as MRI of the spine with and without contrast to identify a causative lesion. Lumbar puncture and CSF analysis may show pleocytosis, elevated protein concentration, and increased intrathecal immunoglobulin G (IgG) index.⁷

Although our patient’s presentation with subacute lower-extremity weakness, sensory changes, and bladder dysfunction were consistent with transverse myelitis, her cranial nerve abnormalities would be atypical for it.

Polyradiculopathy


Polyradiculopathy has many possible causes. In the United States, the most common causes are lumbar spondylosis, lumbar canal stenosis, and diabetic polyradiculoneuropathy.

When multiple spinal segments are affected, leptomeningeal disease involving the arachnoid and pia mater should be considered. Causes include malignant invasion, inflammatory cell accumulation, and protein deposition, leading to patchy but widespread dysfunction of spinal nerve roots and cranial nerves. Specific causes are myriad and include carcinomatous meningitis,⁸ syphilis, tuberculosis, sarcoidosis, and paraproteinemias. CSF and MRI changes are often nonspecific, leading to the need for meningeal biopsy for diagnosis.

During her hospitalization, our patient developed acute right upper and lower facial weakness consistent with peripheral facial mononeuropathy. Bilateral lower-extremity weakness progressed to disabling paraparesis.

She underwent lumbar puncture and CSF analysis (Table 1). The most notable findings were significant pleocytosis (72% lymphocytic predominance), protein elevation, and elevated IgG index (indicative of elevated intrathecal immunoglobulin synthesis in the central nervous system). Viral, bacterial, and fungal studies were negative. Guillain-Barré syndrome, other polyneuropathies, and spinal cord infarction would not be expected with these CSF features.

Surface EMG demonstrated normal sensory responses, and needle EMG showed chronic and active motor axon loss in the L3 and S1 root distributions, suggesting polyradiculopathy without polyneuropathy. These findings would not be expected in typical acute transverse myelitis but could be seen with spinal cord infarction.

MRI of the entire spine with and without contrast showed cauda equina nerve root thickening and enhancement, especially involving the L5 and S1 roots (Figure 1). The spinal cord appeared normal. These findings further supported polyradiculopathy and a leptomeningeal process.

Further evaluation included chest radiography, erythrocyte sedimentation rate, C-reactive protein, hemoglobin A_1c, human immunodeficiency virus testing, antinuclear antibody, antineutrophil cytoplasmic antibody, extractable nuclear antibody, GQ1b antibody, serum and CSF paraneoplastic panels, levels of vitamin B₁, B₁₂, and B₆, copper, and ceruloplasmin, and a screen for heavy metals. All results were within normal ranges.

ESTABLISHING THE DIAGNOSIS

Serum monoclonal protein analysis with immunofixation revealed IgM kappa monoclonal gammopathy with an IgM level of 1,570 (reference range 53–334 mg/dL) and M-spike 0.75 (0.00 mg/dL), serum free kappa light chains 61.1 (3.30–19.40 mg/L), lambda 9.3 (5.7–26.3 mg/L), and kappa-lambda ratio 6.57 (0.26–1.65).

2. Which is the best next step in this patient’s neurologic evaluation?

• Test CSF angiotensin-converting enzyme level
• CSF cytology
• Meningeal biopsy
• Peripheral nerve biopsy

Given the high suspicion for malignancy, CSF cytology was performed and showed increased numbers of mononuclear chronic inflammatory cells, including a mixture of lymphocytes and monocytes, favoring a reactive lymphoid pleocytosis. Flow cytometry indicated the presence of a monoclonal, CD5- and CD10- negative, B-cell lymphoproliferative disorder. The immunophenotypic findings were not specific for a single diagnosis. The differential diagnosis included marginal zone lymphoma and lymphoplasmacytic lymphoma.

3. Given the presence of serum IgM monoclonal gammopathy in this patient, which is the most likely diagnosis?

• Neurosarcoidosis
• Multiple myeloma
• Waldenström macroglobulinemia
• Carcinomatous meningitis

Study of bone marrow biopsy demonstrated limited bone marrow involvement (1%) by a lymphoproliferative disorder with plasmacytoid features, and DNA testing detected an MYD88 L265P mutation, reported to be present in 90% of patients with Waldenström macroglobulinemia.⁹ This finding confirmed the diagnosis of Waldenström macroglobulinemia with central nervous system involvement. Our patient began therapy with rituximab and methotrexate, which resulted in some improvement in strength, gait, and vision.

Waldenström macroglobulinemia is a lympho­plasmacytic lymphoma associated with a monoclonal IgM protein.¹⁰ It is considered a paraproteinemic disorder, similar to multiple myeloma. The presenting symptoms and complications are related to direct tumor infiltration, hyperviscosity syndrome, and deposition of IgM in various tissues.^11,12

Waldenström macroglobulinemia is usually indolent, and treatment is reserved for patients with symptoms.^13,14 It includes rituximab, usually in combination with chemotherapy or other targeted agents.^15,16

Paraneoplastic antibody-mediated polyneuropathy may occur in these patients. However, the pattern is usually symmetrical clinically, with demyelination on EMG, and is not associated with cranial nerve or meningeal involvement. Management with plasmapheresis, corticosteroids, and intravenous immunoglobulin has not been shown to be effective.¹⁷

Involvement of the central nervous system as a complication of Waldenström macroglobulinemia has been described as Bing-Neel syndrome. It can present as diffuse malignant cell infiltration of the leptomeningeal space, white matter, or spinal cord, or in a tumoral form presenting as intraparenchymal masses or nodular lesions. The distinction between the tumoral and diffuse forms is based primarily on imaging findings.¹⁸

In a report of 44 patients with Bing-Neel syndrome, 36% presented with the disorder as the initial manifestation of Waldenström macroglobulinemia.¹⁸ The primary presenting symptoms were imbalance and gait difficulty (48%) and cranial nerve involvement (36%), which presented as predominantly facial or oculomotor nerve palsy. Cauda equina syndrome with motor involvement (seen in our patient) occurred in 14% of patients. Other presenting symptoms included cognitive impairment, sensory deficits, headache, dysarthria, aphasia, and seizures.

LEARNING POINTS

The differential diagnosis for patients presenting with multifocal neurologic symptoms can be broad, and a systematic approach to the diagnosis is necessary. Localizing the lesion is important in determining the diagnosis for patients presenting with neurologic symptoms. The process of localization begins with taking the history, is further refined during the examination, and is confirmed with diagnostic studies. Atypical presentations of relatively common neurologic diseases such as Guillain-Barré syndrome, transverse myelitis, and peripheral polyneuropathy do occur, but uncommon diagnoses need to be considered when support for the initial diagnosis is lacking.

Here are 5 articles from the June issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Expert: There’s no single treatment for fibromyalgia

To take the posttest, go to: https://bit.ly/2EAI5v1
Expires February 3, 2020

2. Mood and behavior are different targets for irritability in children

To take the posttest, go to: https://bit.ly/2wpLS9X
Expires February 6, 2020

3. Biomarkers predict VTE risk with menopausal oral hormone therapy

To take the posttest, go to: https://bit.ly/2JKEQFC
Expires February 6, 2020

4. Mild aerobic exercise speeds sports concussion recovery

To take the posttest, go to: https://bit.ly/30RuYiE
Expires February 4, 2020

5. For CABG, multiple and single arterial grafts show no survival difference

To take the posttest, go to: https://bit.ly/2wtiCiF
Expires January 31, 2020

Here are 5 articles from the June issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Expert: There’s no single treatment for fibromyalgia

To take the posttest, go to: https://bit.ly/2EAI5v1
Expires February 3, 2020

2. Mood and behavior are different targets for irritability in children

To take the posttest, go to: https://bit.ly/2wpLS9X
Expires February 6, 2020

3. Biomarkers predict VTE risk with menopausal oral hormone therapy

To take the posttest, go to: https://bit.ly/2JKEQFC
Expires February 6, 2020

4. Mild aerobic exercise speeds sports concussion recovery

To take the posttest, go to: https://bit.ly/30RuYiE
Expires February 4, 2020

5. For CABG, multiple and single arterial grafts show no survival difference

To take the posttest, go to: https://bit.ly/2wtiCiF
Expires January 31, 2020

Here are 5 articles from the June issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Expert: There’s no single treatment for fibromyalgia

To take the posttest, go to: https://bit.ly/2EAI5v1
Expires February 3, 2020

2. Mood and behavior are different targets for irritability in children

To take the posttest, go to: https://bit.ly/2wpLS9X
Expires February 6, 2020

3. Biomarkers predict VTE risk with menopausal oral hormone therapy

To take the posttest, go to: https://bit.ly/2JKEQFC
Expires February 6, 2020

4. Mild aerobic exercise speeds sports concussion recovery

To take the posttest, go to: https://bit.ly/30RuYiE
Expires February 4, 2020

5. For CABG, multiple and single arterial grafts show no survival difference

To take the posttest, go to: https://bit.ly/2wtiCiF
Expires January 31, 2020

Dr. Nasrallah’s “Psychiatry and neurology: Sister neuroscience specialties with different approaches to the brain” (From the Editor, Current Psychiatry, March 2019, p. 4-5, 8), which explored the distinctions and commonalities between neurology and psychiatry, was important and timely. It was particularly worthwhile to discuss with my medical students the accompanying Table, to better answer the question, “What is the difference between these fields?” However, I believe a critical component of this discussion wasn’t mentioned: the transcendent nature of psychiatry, addressing the full complexity of the human experience beyond the clinical milieu.

In mathematics, chaos theory deals with the impossible complexity of simplicity. From primitive initial states, self-interacting systems give rise to short-term predictability, but an unpredictable long-term. Classically, this is illustrated as a hurricane born from the flapping of a butterfly’s wings. Neurology has found great clinical utility in understanding butterfly wings. However, psychiatry forsakes simplicity for complexity: it dives into the emergent systems that arise from self-interacting neurons, asking us to stand within the eye of the hurricane and understand it in its entirety. Psychiatry asks us to transcend the traditional medical focus of discrete physiological mechanisms, and ask—from the standpoint of biologic, social, and spiritual well-being—how can we calm the hurricane?

Psychiatry once had a widely-encompassing understanding of its remit: to appreciate the multifaceted experience of the human life and grant succor to the fractured or anguished soul. In such times, psychiatry was a popular destination for seniors graduating in the United States. Annually, 7% to 10% of US graduates chose psychiatry as a career, and continued to do so until the late 1970s.¹ In the 1970s, the reductive understanding of the mind increased in prominence, and the role of psychiatry transitioned to one similar to that of other medical specialties: putting patients in boxes, and chronically titrating their medications. The interest of graduating seniors waned alongside the scope of our interest: in 1977, only 4.4% of US graduates pursued psychiatry.² In 2019, 4.06% of graduating senior applications were to the field of psychiatry.³ (This is not meant to undervalue the quality of international medical graduates, but to focus on local trends in cultural values.)

Psychiatry offers diagnostic and therapeutic avenues that are traditionally undervalued in other fields of medicine. Nephrosis may not care if a patient feels that his or her life is spiritually satisfying and their actions meaningful. However, a patient’s anguish at his reduced functional status does not care for whether his albumin level is normalized—he requires that his suffering be recognized, and that we make an earnest effort to cloak “the shameful nakedness of pain.”⁴

Psychiatry also makes unique demands of, and offers benefits to, the practitioner. Neurologists complete their residencies feeling that their clinical acumen has increased: “I can formulate a thorough differential now.” Psychiatry asks us not only to cultivate technical proficiency, but also wisdom. The prolonged reflection on the quality and nature of human experience, and the need to guide such patients in a manner far wider and more meaningful in scope than their serotonin pathways, offers the opportunity to emerge from residency a more mindful and grateful human being.

Ultimately, the loss of this sense of scope has not been a failure of medical education. It has been a surrender of the current generation of psychiatry attendings. We have ceded responsibility for the social and spiritual care of our patients to other fields, or to no one at all. If we give up on understanding the hurricane, how can we be surprised that students prefer to chase butterflies?

James Steinberg, MPH, OMS-IV
New York Institute of Technology
College of Osteopathic Medicine
Old Westbury, New York

Robert Barris, MD
Director
Inpatient Psychiatric Services
Nassau University Medical Center
East Meadow, New York

References
1. Sierles FS, Taylor MA. Decline of U.S. medical student career choice of psychiatry and what to do about it. Am J Psychiatry. 1995;152(10):1416-1426.
2. Results and data: main residency match. NRMP data. The National Resident Matching Program. https://mk0nrmpcikgb8jxyd19h.kinstacdn.com/wp-content/uploads/2013/08/resultsanddata1984.pdf. Published May 1984. Accessed May 8, 2019.
3. Advanced Data Tables. The Match 2019. The National Resident Matching Program. https://mk0nrmpcikgb8jxyd19h.kinstacdn.com/wp-content/uploads/2019/03/Advance-Data-Tables-2019_WWW.pdf. Published March 2019. Accessed May 8, 2019.
4. Kipling R. Doctors. In: Kipling: poems (Everyman’s Library Pocket Poets Series). New York, NY: Random House. 2007:234.

Dr. Nasrallah responds

Thank you, Mr. Steinberg and Dr. Barris, for your comments about my editorial. I genuinely enjoyed the eloquence of your letter. In computers, which we all own and use, hardware is indispensable because it enables us to exploit the software, but the richness of the software is far more interesting than the hardware for the creative productivity of humans. So what you say is correct: The brain is the tangible hardware, and the transcendent mind is the splendid software that encompasses all that makes us human, such as thought, affect, cognition, and behavior. I certainly hope that the psychiatry training programs never reduce the practice of psychiatry to prescribing pills to suppress symptoms. Our patients with psychiatric illness deserve much more than that, and you obviously understand that. But just as neurology should not be mindless, psychiatry should not be brainless. Both specialties are 2 sides of the glorious discipline of neuroscience. By the way, I am pleased and proud to tell you that 13% of the graduating medical school seniors at our university have chosen psychiatry as a career.

Henry A. Nasrallah, MD
Editor-in-Chief
The Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

Continue to: Perspectives on motherhood and psychiatry

I very much enjoyed Drs. Helen M. Farrell’s and Katherine A. Kosman’s recent article “Motherhood and the working psychiatrist” (Psychiatry 2.0, Current Psychiatry, March 2019, p. 40-43). I would love to see a series of similar articles and opinion pieces highlighting different perspectives from other practicing psychiatrists who are also parents—in particular, mothers. I completely relate to the dilemma you pose about the multiple duties one has as both a mother and physician, as well as feeling the pull towards honoring our understanding of attachment in the face of conflicting responsibilities. I imagine it’s an experience to which many can relate. 

Christina Ford, MD
Private psychiatric practice
Los Angeles, California

I doubt that anyone—male or female—would argue against the points made by Drs. Farrell and Kosman’s “Motherhood and the working psychiatrist,” which emphasized the need for breaking down the barriers that continue to exist for female physicians who choose to balance their careers with motherhood. As a female psychiatrist who has known since high school that I would choose to remain child-free, I would like to add a different perspective to this discussion and possibly help represent the 20% of women, age 40 to 44, with an MD or PhD who are also child-free.¹

While Drs. Farrell and Kosman referenced many assumptions made about working physician mothers, I have not been able to move through medical school, residency, and my career without battling certain assumptions as well. Although every mother is a woman, logic dictates that the converse—every woman is a mother—is certainly not true. However, when interviewing for residency, I was paired specifically with a female attending who had children, and I was told that I could ask her questions about how to balance work-life and raising a family, despite the fact that I did not say or indicate that I had any interest in having such a conversation. There is also the assumption (sometimes more explicit than others) that those of us without children are missing out on something—that we are not included in the “having it all” category. However, in my mind, “having it all” means having the choice to remain child-free, to focus more intensely on my career, to travel when I want, and to own a white couch—without feeling the social obligation to fulfill a role in which I really have no interest.

Cherishing that ability to focus more on my career, however, does not imply that I am boundlessly able and willing to take extra calls, work holidays, or cover for all my colleagues with children (which is also a common assumption). And while I may not be a caregiver to children, that should not detract from the devotion and time I want to spend helping my parents, relatives, and friends.

The article also made the case that facilities, medical schools, and residency programs need to implement policies and procedures that guide the development of accommodations, such as flexible scheduling and lactation rooms, to meet the needs of trainees and physicians without having to jump through hoops or rely on colleagues for coverage and other assistance. Having been in situations where such policies and procedures were not in place, I can affirm that the absence of such guidelines leads not only parents but also child-free physicians to feeling unnecessarily stressed. There was no clear coverage in place when fellow classmates in my residency program went on maternity leave. Essentially, everyone else was expected to step up and take on the additional caseloads, leading the pregnant classmates to try to time things around rotations where there were lighter demands or more residents assigned—not a simple task by any means.

Post-residency, there have been continued challenges. At one point, I was working in a clinic with 2 other female psychiatrists, one of whom was making plans to take maternity leave. During a meeting with our supervisors, the other physician and I were told that we were taking on the third doctor’s patients (without any extension of our own hours or reimbursement) while she was on leave. In addition to disgruntlement over the extra work being sprung on us, I pointed out that this would, in effect, make the third physician’s role obsolete. If 2 of us were able to do the work of 3, what would be the point in keeping her position when she returned? I was assured that this wouldn’t be the case. We dealt with the weeks of covering additional patients, and when she returned from leave, she was asked to shift some of her hours to a different (and, in my opinion, less desirable) clinic.

So, yes, it is incumbent upon facilities and training programs to take responsibility and to remove the barriers that make the jobs of female physicians with children even more challenging than they need to be. This can benefit not only those physicians and their children, but also their colleagues and, ultimately, the patients, who often bear the brunt of stressed, burnt-out physicians and disorganized programs. While I am not going to take a stance on whether it truly takes a village to raise a child, I certainly do not think that it should take a village to organize maternity leave and lactation rooms.

Jessica L. Langenhan, MD, MBA, CHCQM
Medical DirectorBeacon Health Options
Cypress, California

Reference
1. Livingston G. Childlessness. Pew Research Center. https://www.pewsocialtrends.org/2015/05/07/childlessness/. Published May 7, 2015. Accessed May 9, 2019.

Dr. Nasrallah’s “Psychiatry and neurology: Sister neuroscience specialties with different approaches to the brain” (From the Editor, Current Psychiatry, March 2019, p. 4-5, 8), which explored the distinctions and commonalities between neurology and psychiatry, was important and timely. It was particularly worthwhile to discuss with my medical students the accompanying Table, to better answer the question, “What is the difference between these fields?” However, I believe a critical component of this discussion wasn’t mentioned: the transcendent nature of psychiatry, addressing the full complexity of the human experience beyond the clinical milieu.

In mathematics, chaos theory deals with the impossible complexity of simplicity. From primitive initial states, self-interacting systems give rise to short-term predictability, but an unpredictable long-term. Classically, this is illustrated as a hurricane born from the flapping of a butterfly’s wings. Neurology has found great clinical utility in understanding butterfly wings. However, psychiatry forsakes simplicity for complexity: it dives into the emergent systems that arise from self-interacting neurons, asking us to stand within the eye of the hurricane and understand it in its entirety. Psychiatry asks us to transcend the traditional medical focus of discrete physiological mechanisms, and ask—from the standpoint of biologic, social, and spiritual well-being—how can we calm the hurricane?

Psychiatry once had a widely-encompassing understanding of its remit: to appreciate the multifaceted experience of the human life and grant succor to the fractured or anguished soul. In such times, psychiatry was a popular destination for seniors graduating in the United States. Annually, 7% to 10% of US graduates chose psychiatry as a career, and continued to do so until the late 1970s.¹ In the 1970s, the reductive understanding of the mind increased in prominence, and the role of psychiatry transitioned to one similar to that of other medical specialties: putting patients in boxes, and chronically titrating their medications. The interest of graduating seniors waned alongside the scope of our interest: in 1977, only 4.4% of US graduates pursued psychiatry.² In 2019, 4.06% of graduating senior applications were to the field of psychiatry.³ (This is not meant to undervalue the quality of international medical graduates, but to focus on local trends in cultural values.)

Psychiatry offers diagnostic and therapeutic avenues that are traditionally undervalued in other fields of medicine. Nephrosis may not care if a patient feels that his or her life is spiritually satisfying and their actions meaningful. However, a patient’s anguish at his reduced functional status does not care for whether his albumin level is normalized—he requires that his suffering be recognized, and that we make an earnest effort to cloak “the shameful nakedness of pain.”⁴

Psychiatry also makes unique demands of, and offers benefits to, the practitioner. Neurologists complete their residencies feeling that their clinical acumen has increased: “I can formulate a thorough differential now.” Psychiatry asks us not only to cultivate technical proficiency, but also wisdom. The prolonged reflection on the quality and nature of human experience, and the need to guide such patients in a manner far wider and more meaningful in scope than their serotonin pathways, offers the opportunity to emerge from residency a more mindful and grateful human being.

Ultimately, the loss of this sense of scope has not been a failure of medical education. It has been a surrender of the current generation of psychiatry attendings. We have ceded responsibility for the social and spiritual care of our patients to other fields, or to no one at all. If we give up on understanding the hurricane, how can we be surprised that students prefer to chase butterflies?

James Steinberg, MPH, OMS-IV
New York Institute of Technology
College of Osteopathic Medicine
Old Westbury, New York

Robert Barris, MD
Director
Inpatient Psychiatric Services
Nassau University Medical Center
East Meadow, New York

References
1. Sierles FS, Taylor MA. Decline of U.S. medical student career choice of psychiatry and what to do about it. Am J Psychiatry. 1995;152(10):1416-1426.
2. Results and data: main residency match. NRMP data. The National Resident Matching Program. https://mk0nrmpcikgb8jxyd19h.kinstacdn.com/wp-content/uploads/2013/08/resultsanddata1984.pdf. Published May 1984. Accessed May 8, 2019.
3. Advanced Data Tables. The Match 2019. The National Resident Matching Program. https://mk0nrmpcikgb8jxyd19h.kinstacdn.com/wp-content/uploads/2019/03/Advance-Data-Tables-2019_WWW.pdf. Published March 2019. Accessed May 8, 2019.
4. Kipling R. Doctors. In: Kipling: poems (Everyman’s Library Pocket Poets Series). New York, NY: Random House. 2007:234.

Dr. Nasrallah responds

Thank you, Mr. Steinberg and Dr. Barris, for your comments about my editorial. I genuinely enjoyed the eloquence of your letter. In computers, which we all own and use, hardware is indispensable because it enables us to exploit the software, but the richness of the software is far more interesting than the hardware for the creative productivity of humans. So what you say is correct: The brain is the tangible hardware, and the transcendent mind is the splendid software that encompasses all that makes us human, such as thought, affect, cognition, and behavior. I certainly hope that the psychiatry training programs never reduce the practice of psychiatry to prescribing pills to suppress symptoms. Our patients with psychiatric illness deserve much more than that, and you obviously understand that. But just as neurology should not be mindless, psychiatry should not be brainless. Both specialties are 2 sides of the glorious discipline of neuroscience. By the way, I am pleased and proud to tell you that 13% of the graduating medical school seniors at our university have chosen psychiatry as a career.

Henry A. Nasrallah, MD
Editor-in-Chief
The Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

Continue to: Perspectives on motherhood and psychiatry

I very much enjoyed Drs. Helen M. Farrell’s and Katherine A. Kosman’s recent article “Motherhood and the working psychiatrist” (Psychiatry 2.0, Current Psychiatry, March 2019, p. 40-43). I would love to see a series of similar articles and opinion pieces highlighting different perspectives from other practicing psychiatrists who are also parents—in particular, mothers. I completely relate to the dilemma you pose about the multiple duties one has as both a mother and physician, as well as feeling the pull towards honoring our understanding of attachment in the face of conflicting responsibilities. I imagine it’s an experience to which many can relate. 

Christina Ford, MD
Private psychiatric practice
Los Angeles, California

I doubt that anyone—male or female—would argue against the points made by Drs. Farrell and Kosman’s “Motherhood and the working psychiatrist,” which emphasized the need for breaking down the barriers that continue to exist for female physicians who choose to balance their careers with motherhood. As a female psychiatrist who has known since high school that I would choose to remain child-free, I would like to add a different perspective to this discussion and possibly help represent the 20% of women, age 40 to 44, with an MD or PhD who are also child-free.¹

While Drs. Farrell and Kosman referenced many assumptions made about working physician mothers, I have not been able to move through medical school, residency, and my career without battling certain assumptions as well. Although every mother is a woman, logic dictates that the converse—every woman is a mother—is certainly not true. However, when interviewing for residency, I was paired specifically with a female attending who had children, and I was told that I could ask her questions about how to balance work-life and raising a family, despite the fact that I did not say or indicate that I had any interest in having such a conversation. There is also the assumption (sometimes more explicit than others) that those of us without children are missing out on something—that we are not included in the “having it all” category. However, in my mind, “having it all” means having the choice to remain child-free, to focus more intensely on my career, to travel when I want, and to own a white couch—without feeling the social obligation to fulfill a role in which I really have no interest.

Cherishing that ability to focus more on my career, however, does not imply that I am boundlessly able and willing to take extra calls, work holidays, or cover for all my colleagues with children (which is also a common assumption). And while I may not be a caregiver to children, that should not detract from the devotion and time I want to spend helping my parents, relatives, and friends.

The article also made the case that facilities, medical schools, and residency programs need to implement policies and procedures that guide the development of accommodations, such as flexible scheduling and lactation rooms, to meet the needs of trainees and physicians without having to jump through hoops or rely on colleagues for coverage and other assistance. Having been in situations where such policies and procedures were not in place, I can affirm that the absence of such guidelines leads not only parents but also child-free physicians to feeling unnecessarily stressed. There was no clear coverage in place when fellow classmates in my residency program went on maternity leave. Essentially, everyone else was expected to step up and take on the additional caseloads, leading the pregnant classmates to try to time things around rotations where there were lighter demands or more residents assigned—not a simple task by any means.

Post-residency, there have been continued challenges. At one point, I was working in a clinic with 2 other female psychiatrists, one of whom was making plans to take maternity leave. During a meeting with our supervisors, the other physician and I were told that we were taking on the third doctor’s patients (without any extension of our own hours or reimbursement) while she was on leave. In addition to disgruntlement over the extra work being sprung on us, I pointed out that this would, in effect, make the third physician’s role obsolete. If 2 of us were able to do the work of 3, what would be the point in keeping her position when she returned? I was assured that this wouldn’t be the case. We dealt with the weeks of covering additional patients, and when she returned from leave, she was asked to shift some of her hours to a different (and, in my opinion, less desirable) clinic.

So, yes, it is incumbent upon facilities and training programs to take responsibility and to remove the barriers that make the jobs of female physicians with children even more challenging than they need to be. This can benefit not only those physicians and their children, but also their colleagues and, ultimately, the patients, who often bear the brunt of stressed, burnt-out physicians and disorganized programs. While I am not going to take a stance on whether it truly takes a village to raise a child, I certainly do not think that it should take a village to organize maternity leave and lactation rooms.

Jessica L. Langenhan, MD, MBA, CHCQM
Medical DirectorBeacon Health Options
Cypress, California

Reference
1. Livingston G. Childlessness. Pew Research Center. https://www.pewsocialtrends.org/2015/05/07/childlessness/. Published May 7, 2015. Accessed May 9, 2019.

Dr. Nasrallah’s “Psychiatry and neurology: Sister neuroscience specialties with different approaches to the brain” (From the Editor, Current Psychiatry, March 2019, p. 4-5, 8), which explored the distinctions and commonalities between neurology and psychiatry, was important and timely. It was particularly worthwhile to discuss with my medical students the accompanying Table, to better answer the question, “What is the difference between these fields?” However, I believe a critical component of this discussion wasn’t mentioned: the transcendent nature of psychiatry, addressing the full complexity of the human experience beyond the clinical milieu.

In mathematics, chaos theory deals with the impossible complexity of simplicity. From primitive initial states, self-interacting systems give rise to short-term predictability, but an unpredictable long-term. Classically, this is illustrated as a hurricane born from the flapping of a butterfly’s wings. Neurology has found great clinical utility in understanding butterfly wings. However, psychiatry forsakes simplicity for complexity: it dives into the emergent systems that arise from self-interacting neurons, asking us to stand within the eye of the hurricane and understand it in its entirety. Psychiatry asks us to transcend the traditional medical focus of discrete physiological mechanisms, and ask—from the standpoint of biologic, social, and spiritual well-being—how can we calm the hurricane?

Psychiatry once had a widely-encompassing understanding of its remit: to appreciate the multifaceted experience of the human life and grant succor to the fractured or anguished soul. In such times, psychiatry was a popular destination for seniors graduating in the United States. Annually, 7% to 10% of US graduates chose psychiatry as a career, and continued to do so until the late 1970s.¹ In the 1970s, the reductive understanding of the mind increased in prominence, and the role of psychiatry transitioned to one similar to that of other medical specialties: putting patients in boxes, and chronically titrating their medications. The interest of graduating seniors waned alongside the scope of our interest: in 1977, only 4.4% of US graduates pursued psychiatry.² In 2019, 4.06% of graduating senior applications were to the field of psychiatry.³ (This is not meant to undervalue the quality of international medical graduates, but to focus on local trends in cultural values.)

Psychiatry offers diagnostic and therapeutic avenues that are traditionally undervalued in other fields of medicine. Nephrosis may not care if a patient feels that his or her life is spiritually satisfying and their actions meaningful. However, a patient’s anguish at his reduced functional status does not care for whether his albumin level is normalized—he requires that his suffering be recognized, and that we make an earnest effort to cloak “the shameful nakedness of pain.”⁴

Psychiatry also makes unique demands of, and offers benefits to, the practitioner. Neurologists complete their residencies feeling that their clinical acumen has increased: “I can formulate a thorough differential now.” Psychiatry asks us not only to cultivate technical proficiency, but also wisdom. The prolonged reflection on the quality and nature of human experience, and the need to guide such patients in a manner far wider and more meaningful in scope than their serotonin pathways, offers the opportunity to emerge from residency a more mindful and grateful human being.

Ultimately, the loss of this sense of scope has not been a failure of medical education. It has been a surrender of the current generation of psychiatry attendings. We have ceded responsibility for the social and spiritual care of our patients to other fields, or to no one at all. If we give up on understanding the hurricane, how can we be surprised that students prefer to chase butterflies?

James Steinberg, MPH, OMS-IV
New York Institute of Technology
College of Osteopathic Medicine
Old Westbury, New York

Robert Barris, MD
Director
Inpatient Psychiatric Services
Nassau University Medical Center
East Meadow, New York

References
1. Sierles FS, Taylor MA. Decline of U.S. medical student career choice of psychiatry and what to do about it. Am J Psychiatry. 1995;152(10):1416-1426.
2. Results and data: main residency match. NRMP data. The National Resident Matching Program. https://mk0nrmpcikgb8jxyd19h.kinstacdn.com/wp-content/uploads/2013/08/resultsanddata1984.pdf. Published May 1984. Accessed May 8, 2019.
3. Advanced Data Tables. The Match 2019. The National Resident Matching Program. https://mk0nrmpcikgb8jxyd19h.kinstacdn.com/wp-content/uploads/2019/03/Advance-Data-Tables-2019_WWW.pdf. Published March 2019. Accessed May 8, 2019.
4. Kipling R. Doctors. In: Kipling: poems (Everyman’s Library Pocket Poets Series). New York, NY: Random House. 2007:234.

Dr. Nasrallah responds

Thank you, Mr. Steinberg and Dr. Barris, for your comments about my editorial. I genuinely enjoyed the eloquence of your letter. In computers, which we all own and use, hardware is indispensable because it enables us to exploit the software, but the richness of the software is far more interesting than the hardware for the creative productivity of humans. So what you say is correct: The brain is the tangible hardware, and the transcendent mind is the splendid software that encompasses all that makes us human, such as thought, affect, cognition, and behavior. I certainly hope that the psychiatry training programs never reduce the practice of psychiatry to prescribing pills to suppress symptoms. Our patients with psychiatric illness deserve much more than that, and you obviously understand that. But just as neurology should not be mindless, psychiatry should not be brainless. Both specialties are 2 sides of the glorious discipline of neuroscience. By the way, I am pleased and proud to tell you that 13% of the graduating medical school seniors at our university have chosen psychiatry as a career.

Henry A. Nasrallah, MD
Editor-in-Chief
The Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

Continue to: Perspectives on motherhood and psychiatry

I very much enjoyed Drs. Helen M. Farrell’s and Katherine A. Kosman’s recent article “Motherhood and the working psychiatrist” (Psychiatry 2.0, Current Psychiatry, March 2019, p. 40-43). I would love to see a series of similar articles and opinion pieces highlighting different perspectives from other practicing psychiatrists who are also parents—in particular, mothers. I completely relate to the dilemma you pose about the multiple duties one has as both a mother and physician, as well as feeling the pull towards honoring our understanding of attachment in the face of conflicting responsibilities. I imagine it’s an experience to which many can relate. 

Christina Ford, MD
Private psychiatric practice
Los Angeles, California

I doubt that anyone—male or female—would argue against the points made by Drs. Farrell and Kosman’s “Motherhood and the working psychiatrist,” which emphasized the need for breaking down the barriers that continue to exist for female physicians who choose to balance their careers with motherhood. As a female psychiatrist who has known since high school that I would choose to remain child-free, I would like to add a different perspective to this discussion and possibly help represent the 20% of women, age 40 to 44, with an MD or PhD who are also child-free.¹

While Drs. Farrell and Kosman referenced many assumptions made about working physician mothers, I have not been able to move through medical school, residency, and my career without battling certain assumptions as well. Although every mother is a woman, logic dictates that the converse—every woman is a mother—is certainly not true. However, when interviewing for residency, I was paired specifically with a female attending who had children, and I was told that I could ask her questions about how to balance work-life and raising a family, despite the fact that I did not say or indicate that I had any interest in having such a conversation. There is also the assumption (sometimes more explicit than others) that those of us without children are missing out on something—that we are not included in the “having it all” category. However, in my mind, “having it all” means having the choice to remain child-free, to focus more intensely on my career, to travel when I want, and to own a white couch—without feeling the social obligation to fulfill a role in which I really have no interest.

Cherishing that ability to focus more on my career, however, does not imply that I am boundlessly able and willing to take extra calls, work holidays, or cover for all my colleagues with children (which is also a common assumption). And while I may not be a caregiver to children, that should not detract from the devotion and time I want to spend helping my parents, relatives, and friends.

The article also made the case that facilities, medical schools, and residency programs need to implement policies and procedures that guide the development of accommodations, such as flexible scheduling and lactation rooms, to meet the needs of trainees and physicians without having to jump through hoops or rely on colleagues for coverage and other assistance. Having been in situations where such policies and procedures were not in place, I can affirm that the absence of such guidelines leads not only parents but also child-free physicians to feeling unnecessarily stressed. There was no clear coverage in place when fellow classmates in my residency program went on maternity leave. Essentially, everyone else was expected to step up and take on the additional caseloads, leading the pregnant classmates to try to time things around rotations where there were lighter demands or more residents assigned—not a simple task by any means.

Post-residency, there have been continued challenges. At one point, I was working in a clinic with 2 other female psychiatrists, one of whom was making plans to take maternity leave. During a meeting with our supervisors, the other physician and I were told that we were taking on the third doctor’s patients (without any extension of our own hours or reimbursement) while she was on leave. In addition to disgruntlement over the extra work being sprung on us, I pointed out that this would, in effect, make the third physician’s role obsolete. If 2 of us were able to do the work of 3, what would be the point in keeping her position when she returned? I was assured that this wouldn’t be the case. We dealt with the weeks of covering additional patients, and when she returned from leave, she was asked to shift some of her hours to a different (and, in my opinion, less desirable) clinic.

So, yes, it is incumbent upon facilities and training programs to take responsibility and to remove the barriers that make the jobs of female physicians with children even more challenging than they need to be. This can benefit not only those physicians and their children, but also their colleagues and, ultimately, the patients, who often bear the brunt of stressed, burnt-out physicians and disorganized programs. While I am not going to take a stance on whether it truly takes a village to raise a child, I certainly do not think that it should take a village to organize maternity leave and lactation rooms.

Jessica L. Langenhan, MD, MBA, CHCQM
Medical DirectorBeacon Health Options
Cypress, California

Reference
1. Livingston G. Childlessness. Pew Research Center. https://www.pewsocialtrends.org/2015/05/07/childlessness/. Published May 7, 2015. Accessed May 9, 2019.

SEATTLE – Patients with multiple sclerosis (MS) who stopped taking their disease-modifying therapy (DMT) for more than 60 days had significantly higher rates of relapse, hospitalization, emergency department visits and outpatient visits, a new study finds. Their nonmedication health care costs were higher, too.

“This information will help to inform patients about downstream economic risks of being off therapy. This may also help to inform payers of the importance of making DMTs easily and quickly available to patients with MS to prevent greater costs of health care resource utilization down the road,” study lead author Jacqueline A. Nicholas, MD, MPH, a clinical neuroimmunologist at OhioHealth Multiple Sclerosis Center, said in an interview. She spoke prior to the presentation of the findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Dr. Nicholas and her colleagues launched their study to better understand the economic and medical impacts of lapses in oral DMT.

The researchers used a claims database to track 8,779 patients with MS during 2011-2015 who had at least one claim for an oral DMT drug. The subjects were aged 18-63; 15% had a drug lapse of more than 60 days. After propensity matching, the subjects in both groups – 60-day lapse or not – had a mean age of 44 years.

An analysis found that “lapses in oral DMT use led to increased relapses, increased health care utilization, and higher costs incurred by individuals with MS,” Dr. Nicholas said.

Over an 18-month follow-up period, those with drug lapses of more than 60 days had 28% more relapses than did the other subjects (mean 1.2 vs. 0.8; P less than .0001).

Those with lapses greater than 60 days also had 40% more hospitalizations (0.2 vs. 0.1; P = .0003), 25% more emergency department visits (0.6 vs. 0.5; P = .0098), and 22% more outpatient visits (6.2 vs. 4.8; P less than .0001).

Nonmedication costs were 25% higher among patients with a greater than 60-day lapse ($16,012 vs. $12,092; P = .0006).

Moving forward, the researchers wrote, “more research is needed to better understand the reasons for lapses in therapy and the impact of lapse timing and lapse duration on outcomes in patients with MS receiving once- or twice-daily oral [disease-modifying drugs].”

The researchers noted that they don’t have information about the reasons why patients lapsed. They added that the information comes mainly from commercial insurers.

EMD Serono, a division of Merck KGaA, provided funding for the study. Dr. Nicholas disclosed grant support from EMD Serono, and two other study authors are employees of the company. Another two authors worked for a consulting firm that received funding from EMD Serono to conduct the study.

SEATTLE – Patients with multiple sclerosis (MS) who stopped taking their disease-modifying therapy (DMT) for more than 60 days had significantly higher rates of relapse, hospitalization, emergency department visits and outpatient visits, a new study finds. Their nonmedication health care costs were higher, too.

“This information will help to inform patients about downstream economic risks of being off therapy. This may also help to inform payers of the importance of making DMTs easily and quickly available to patients with MS to prevent greater costs of health care resource utilization down the road,” study lead author Jacqueline A. Nicholas, MD, MPH, a clinical neuroimmunologist at OhioHealth Multiple Sclerosis Center, said in an interview. She spoke prior to the presentation of the findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Dr. Nicholas and her colleagues launched their study to better understand the economic and medical impacts of lapses in oral DMT.

The researchers used a claims database to track 8,779 patients with MS during 2011-2015 who had at least one claim for an oral DMT drug. The subjects were aged 18-63; 15% had a drug lapse of more than 60 days. After propensity matching, the subjects in both groups – 60-day lapse or not – had a mean age of 44 years.

An analysis found that “lapses in oral DMT use led to increased relapses, increased health care utilization, and higher costs incurred by individuals with MS,” Dr. Nicholas said.

Over an 18-month follow-up period, those with drug lapses of more than 60 days had 28% more relapses than did the other subjects (mean 1.2 vs. 0.8; P less than .0001).

Those with lapses greater than 60 days also had 40% more hospitalizations (0.2 vs. 0.1; P = .0003), 25% more emergency department visits (0.6 vs. 0.5; P = .0098), and 22% more outpatient visits (6.2 vs. 4.8; P less than .0001).

Nonmedication costs were 25% higher among patients with a greater than 60-day lapse ($16,012 vs. $12,092; P = .0006).

Moving forward, the researchers wrote, “more research is needed to better understand the reasons for lapses in therapy and the impact of lapse timing and lapse duration on outcomes in patients with MS receiving once- or twice-daily oral [disease-modifying drugs].”

The researchers noted that they don’t have information about the reasons why patients lapsed. They added that the information comes mainly from commercial insurers.

EMD Serono, a division of Merck KGaA, provided funding for the study. Dr. Nicholas disclosed grant support from EMD Serono, and two other study authors are employees of the company. Another two authors worked for a consulting firm that received funding from EMD Serono to conduct the study.

SEATTLE – Patients with multiple sclerosis (MS) who stopped taking their disease-modifying therapy (DMT) for more than 60 days had significantly higher rates of relapse, hospitalization, emergency department visits and outpatient visits, a new study finds. Their nonmedication health care costs were higher, too.

“This information will help to inform patients about downstream economic risks of being off therapy. This may also help to inform payers of the importance of making DMTs easily and quickly available to patients with MS to prevent greater costs of health care resource utilization down the road,” study lead author Jacqueline A. Nicholas, MD, MPH, a clinical neuroimmunologist at OhioHealth Multiple Sclerosis Center, said in an interview. She spoke prior to the presentation of the findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Dr. Nicholas and her colleagues launched their study to better understand the economic and medical impacts of lapses in oral DMT.

The researchers used a claims database to track 8,779 patients with MS during 2011-2015 who had at least one claim for an oral DMT drug. The subjects were aged 18-63; 15% had a drug lapse of more than 60 days. After propensity matching, the subjects in both groups – 60-day lapse or not – had a mean age of 44 years.

An analysis found that “lapses in oral DMT use led to increased relapses, increased health care utilization, and higher costs incurred by individuals with MS,” Dr. Nicholas said.

Over an 18-month follow-up period, those with drug lapses of more than 60 days had 28% more relapses than did the other subjects (mean 1.2 vs. 0.8; P less than .0001).

Those with lapses greater than 60 days also had 40% more hospitalizations (0.2 vs. 0.1; P = .0003), 25% more emergency department visits (0.6 vs. 0.5; P = .0098), and 22% more outpatient visits (6.2 vs. 4.8; P less than .0001).

Nonmedication costs were 25% higher among patients with a greater than 60-day lapse ($16,012 vs. $12,092; P = .0006).

Moving forward, the researchers wrote, “more research is needed to better understand the reasons for lapses in therapy and the impact of lapse timing and lapse duration on outcomes in patients with MS receiving once- or twice-daily oral [disease-modifying drugs].”

The researchers noted that they don’t have information about the reasons why patients lapsed. They added that the information comes mainly from commercial insurers.

EMD Serono, a division of Merck KGaA, provided funding for the study. Dr. Nicholas disclosed grant support from EMD Serono, and two other study authors are employees of the company. Another two authors worked for a consulting firm that received funding from EMD Serono to conduct the study.

SEATTLE – Multiple sclerosis (MS) adds a layer of complexity to psychiatric illnesses such as depression, and the usual rules of treatment do not necessarily apply, a neuropsychiatrist cautioned colleagues who treat MS.

Randy Dotinga/MDedge News

For example, depression may strike a patient as a primary condition, just as it could in anyone. But it may also be a manifestation of MS itself, or a side effect of an MS medication, or spurred by the fatigue and pain caused by MS, said Laura T. Safar, MD, a psychiatrist affiliated with Brigham and Women's Hospital, Boston*. As a result, popular psychiatric treatments such as SSRIs might not necessarily be the best approach, said Dr. Safar, who spoke in an interview and during a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“You need to follow the why,” she said in the interview, adding that it is crucial to view neurologic and mental health as one and the same in MS. “More integration,” she said, “continues to be the way to go.”

Here are some pearls and tips from Dr. Safar’s presentation on treating psychiatric conditions in patients with MS:

Mental illness incidence

Depression is estimated to affect 25%-45% of people with MS over their lifetimes, while bipolar disorder is thought to affect 6% of patients and a quarter are estimated to have anxiety.

Researchers also believe as many as 10% of patients are affected by pathological laughing and crying during their lives.
 

Psychiatric side effects

Interferon drugs are notoriously linked to depression and psychosis. Glatiramer acetate (Copaxone) and natalizumab (Tysabri) are also thought to cause psychiatric side effects in some cases – anxiety and depression, respectively. But drug-modifying therapies can also provide relief on the psychiatric front, Dr. Safar said.

Meanwhile, dozens of other drugs used to treat aspects of MS such as spasticity, pain, and fatigue have possible psychiatric side effects.
 

Alternatives to SSRIs

SSRIs are often a first option in psychiatric patients, but those with MS may need another option because so many – an estimated 80% – also have fatigue, Dr. Safar said.

Alternatives for patients with MS include serotonin and norepinephrine reuptake inhibitors (SNRIs), which may have an advantage over SSRIs, she said. Specifically, SNRIs and bupropion (Wellbutrin) may be better for patients with fatigue and cognitive problems, she said, while vortioxetine (Trintellix) may benefit cognition.
 

Treating anxiety

There are no data regarding the best drug treatment for anxiety in patients with MS, she said, and SSRIs are typically the starting point. Consider SNRIs and duloxetine, respectively, when patients also have significant fatigue and cognitive symptoms. Use benzodiazepines only in occasional cases (such as anxiety regarding an MRI) and severe cases, she said.

MS-specific side effects

Beware of MS-specific side effects, Dr. Safar said. Some common psychiatric drugs, especially citalopram (Celexa) and escitalopram (Lexapro), may increase the QTc interval and shouldn’t be used in combination with the MS drug fingolimod (Gilenya).

And, she said, bupropion is “a very helpful agent” but poses a rare risk of seizures. Dr. Safar said she has seen this side effect a couple times over 10 years, but both were in patients with “other factors involved.” Still, “it’s something to keep in mind.”

Also understand that serotonergic agents can worsen restless legs syndrome, which is more common in patients with MS. Dr. Safar advises monitoring for the condition.
 

Pathological laughing, crying

Episodes of so-called pathological laughing, crying, or both tend to be brief, frequent, and intense. They may be sparked by nothing at all, and more often feature crying.

Certain SSRIs have proved helpful for the condition in MS, Dr. Safar said. Research also supports a combination of dextromethorphan (cough suppressant) and quinidine (a drug used to treat arrhythmias and malaria). The combination is sold together as Nuedexta.

Other agents such as venlafaxine (Effexor) and duloxetine (Cymbalta) have very limited data and shouldn’t be first-line treatment, she said.

Dr. Safar reports no relevant disclosures.

Correction, 5/31/19: An earlier version of this article misstated Dr. Safar's hospital affiliation.

SEATTLE – Multiple sclerosis (MS) adds a layer of complexity to psychiatric illnesses such as depression, and the usual rules of treatment do not necessarily apply, a neuropsychiatrist cautioned colleagues who treat MS.

Randy Dotinga/MDedge News

For example, depression may strike a patient as a primary condition, just as it could in anyone. But it may also be a manifestation of MS itself, or a side effect of an MS medication, or spurred by the fatigue and pain caused by MS, said Laura T. Safar, MD, a psychiatrist affiliated with Brigham and Women's Hospital, Boston*. As a result, popular psychiatric treatments such as SSRIs might not necessarily be the best approach, said Dr. Safar, who spoke in an interview and during a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“You need to follow the why,” she said in the interview, adding that it is crucial to view neurologic and mental health as one and the same in MS. “More integration,” she said, “continues to be the way to go.”

Here are some pearls and tips from Dr. Safar’s presentation on treating psychiatric conditions in patients with MS:

Mental illness incidence

Depression is estimated to affect 25%-45% of people with MS over their lifetimes, while bipolar disorder is thought to affect 6% of patients and a quarter are estimated to have anxiety.

Researchers also believe as many as 10% of patients are affected by pathological laughing and crying during their lives.
 

Psychiatric side effects

Interferon drugs are notoriously linked to depression and psychosis. Glatiramer acetate (Copaxone) and natalizumab (Tysabri) are also thought to cause psychiatric side effects in some cases – anxiety and depression, respectively. But drug-modifying therapies can also provide relief on the psychiatric front, Dr. Safar said.

Meanwhile, dozens of other drugs used to treat aspects of MS such as spasticity, pain, and fatigue have possible psychiatric side effects.
 

Alternatives to SSRIs

SSRIs are often a first option in psychiatric patients, but those with MS may need another option because so many – an estimated 80% – also have fatigue, Dr. Safar said.

Alternatives for patients with MS include serotonin and norepinephrine reuptake inhibitors (SNRIs), which may have an advantage over SSRIs, she said. Specifically, SNRIs and bupropion (Wellbutrin) may be better for patients with fatigue and cognitive problems, she said, while vortioxetine (Trintellix) may benefit cognition.
 

Treating anxiety

There are no data regarding the best drug treatment for anxiety in patients with MS, she said, and SSRIs are typically the starting point. Consider SNRIs and duloxetine, respectively, when patients also have significant fatigue and cognitive symptoms. Use benzodiazepines only in occasional cases (such as anxiety regarding an MRI) and severe cases, she said.

MS-specific side effects

Beware of MS-specific side effects, Dr. Safar said. Some common psychiatric drugs, especially citalopram (Celexa) and escitalopram (Lexapro), may increase the QTc interval and shouldn’t be used in combination with the MS drug fingolimod (Gilenya).

And, she said, bupropion is “a very helpful agent” but poses a rare risk of seizures. Dr. Safar said she has seen this side effect a couple times over 10 years, but both were in patients with “other factors involved.” Still, “it’s something to keep in mind.”

Also understand that serotonergic agents can worsen restless legs syndrome, which is more common in patients with MS. Dr. Safar advises monitoring for the condition.
 

Pathological laughing, crying

Episodes of so-called pathological laughing, crying, or both tend to be brief, frequent, and intense. They may be sparked by nothing at all, and more often feature crying.

Certain SSRIs have proved helpful for the condition in MS, Dr. Safar said. Research also supports a combination of dextromethorphan (cough suppressant) and quinidine (a drug used to treat arrhythmias and malaria). The combination is sold together as Nuedexta.

Other agents such as venlafaxine (Effexor) and duloxetine (Cymbalta) have very limited data and shouldn’t be first-line treatment, she said.

Dr. Safar reports no relevant disclosures.

Correction, 5/31/19: An earlier version of this article misstated Dr. Safar's hospital affiliation.

SEATTLE – Multiple sclerosis (MS) adds a layer of complexity to psychiatric illnesses such as depression, and the usual rules of treatment do not necessarily apply, a neuropsychiatrist cautioned colleagues who treat MS.

Randy Dotinga/MDedge News

For example, depression may strike a patient as a primary condition, just as it could in anyone. But it may also be a manifestation of MS itself, or a side effect of an MS medication, or spurred by the fatigue and pain caused by MS, said Laura T. Safar, MD, a psychiatrist affiliated with Brigham and Women's Hospital, Boston*. As a result, popular psychiatric treatments such as SSRIs might not necessarily be the best approach, said Dr. Safar, who spoke in an interview and during a presentation at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“You need to follow the why,” she said in the interview, adding that it is crucial to view neurologic and mental health as one and the same in MS. “More integration,” she said, “continues to be the way to go.”

Here are some pearls and tips from Dr. Safar’s presentation on treating psychiatric conditions in patients with MS:

Mental illness incidence

Depression is estimated to affect 25%-45% of people with MS over their lifetimes, while bipolar disorder is thought to affect 6% of patients and a quarter are estimated to have anxiety.

Researchers also believe as many as 10% of patients are affected by pathological laughing and crying during their lives.
 

Psychiatric side effects

Interferon drugs are notoriously linked to depression and psychosis. Glatiramer acetate (Copaxone) and natalizumab (Tysabri) are also thought to cause psychiatric side effects in some cases – anxiety and depression, respectively. But drug-modifying therapies can also provide relief on the psychiatric front, Dr. Safar said.

Meanwhile, dozens of other drugs used to treat aspects of MS such as spasticity, pain, and fatigue have possible psychiatric side effects.
 

Alternatives to SSRIs

SSRIs are often a first option in psychiatric patients, but those with MS may need another option because so many – an estimated 80% – also have fatigue, Dr. Safar said.

Alternatives for patients with MS include serotonin and norepinephrine reuptake inhibitors (SNRIs), which may have an advantage over SSRIs, she said. Specifically, SNRIs and bupropion (Wellbutrin) may be better for patients with fatigue and cognitive problems, she said, while vortioxetine (Trintellix) may benefit cognition.
 

Treating anxiety

There are no data regarding the best drug treatment for anxiety in patients with MS, she said, and SSRIs are typically the starting point. Consider SNRIs and duloxetine, respectively, when patients also have significant fatigue and cognitive symptoms. Use benzodiazepines only in occasional cases (such as anxiety regarding an MRI) and severe cases, she said.

MS-specific side effects

Beware of MS-specific side effects, Dr. Safar said. Some common psychiatric drugs, especially citalopram (Celexa) and escitalopram (Lexapro), may increase the QTc interval and shouldn’t be used in combination with the MS drug fingolimod (Gilenya).

And, she said, bupropion is “a very helpful agent” but poses a rare risk of seizures. Dr. Safar said she has seen this side effect a couple times over 10 years, but both were in patients with “other factors involved.” Still, “it’s something to keep in mind.”

Also understand that serotonergic agents can worsen restless legs syndrome, which is more common in patients with MS. Dr. Safar advises monitoring for the condition.
 

Pathological laughing, crying

Episodes of so-called pathological laughing, crying, or both tend to be brief, frequent, and intense. They may be sparked by nothing at all, and more often feature crying.

Certain SSRIs have proved helpful for the condition in MS, Dr. Safar said. Research also supports a combination of dextromethorphan (cough suppressant) and quinidine (a drug used to treat arrhythmias and malaria). The combination is sold together as Nuedexta.

Other agents such as venlafaxine (Effexor) and duloxetine (Cymbalta) have very limited data and shouldn’t be first-line treatment, she said.

Dr. Safar reports no relevant disclosures.

Correction, 5/31/19: An earlier version of this article misstated Dr. Safar's hospital affiliation.

SEATTLE – Among patients with multiple sclerosis who initiate treatment with fingolimod, a low baseline heart rate may not increase the risk of first-dose cardiac events, according to data presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. In addition, the data “provide further evidence that first-dose cardiac events with fingolimod are rare,” regardless of whether the first dose is given in a clinic or a patient’s home, the study researchers said.

Transient heart rate decreases are an anticipated effect of starting fingolimod, and the U.S. prescribing information for the drug requires first-dose observation of heart rate and blood pressure for at least 6 hours. Heart rate and blood pressure may be monitored in a clinic or at home via the Gilenya@Home program.

To examine whether low baseline heart rate is associated with the likelihood of certain cardiac events during the first-dose observation period, John Osborne, MD, of State of the Heart Cardiology in Grapevine, Tex., and colleagues analyzed retrospective, first-dose observation data from Gilenya@Home between October 2014 and July 2017 and from Gilenya Assessment Network clinics between July 2010 and December 2016.

The investigators sought to determine whether baseline heart rate predicts the risk of documented bradycardia, new-onset second-degree atrioventricular block, or ED transfer for additional monitoring. In addition, they examined whether patients with heart rates above a certain threshold may be at risk of first-dose cardiac events.

Dr. Osborne and colleagues reviewed data from 5,572 in-home and 15,025 in-clinic first-dose observation procedures. They classified patients as having marked bradycardia (under 50 beats per minute), mild bradycardia (50-59 bpm), or a normal heart rate (at least 60 bpm) at baseline. During the 20,001 procedures with available data, 182 cardiac events occurred, including 28 instances of documented bradycardia, 13 instances of second-degree atrioventricular block, and 141 instances of ED transfer for extended monitoring; 40 events occurred during at-home monitoring, and 142 events occurred in clinic.

About 87.0% of the cardiac events occurred in patients with a normal baseline heart rate, 11.5% occurred in patients with mild bradycardia, and 1.1% occurred in patients with marked bradycardia. The two cardiac events in patients with marked bradycardia at baseline were ED transfers of patients whose first-dose observations occurred in clinics. “The threshold heart rate above which patients did not experience a cardiac event was 80 bpm, well within the normal range of 60-100 bpm,” the authors said.

“These data suggest that patients with a low baseline heart rate may be at no more risk of cardiac events than patients with a heart rate in the normal range, nor is there a baseline heart rate threshold below which a patient is at greater risk of cardiac events,” Dr. Osborne and colleagues concluded.

Dr. Osborne reporting receiving a consulting fee from Novartis, which markets Gilenya (fingolimod), and his coauthors are employees of Novartis.
 

[email protected]

SEATTLE – Among patients with multiple sclerosis who initiate treatment with fingolimod, a low baseline heart rate may not increase the risk of first-dose cardiac events, according to data presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. In addition, the data “provide further evidence that first-dose cardiac events with fingolimod are rare,” regardless of whether the first dose is given in a clinic or a patient’s home, the study researchers said.

Transient heart rate decreases are an anticipated effect of starting fingolimod, and the U.S. prescribing information for the drug requires first-dose observation of heart rate and blood pressure for at least 6 hours. Heart rate and blood pressure may be monitored in a clinic or at home via the Gilenya@Home program.

To examine whether low baseline heart rate is associated with the likelihood of certain cardiac events during the first-dose observation period, John Osborne, MD, of State of the Heart Cardiology in Grapevine, Tex., and colleagues analyzed retrospective, first-dose observation data from Gilenya@Home between October 2014 and July 2017 and from Gilenya Assessment Network clinics between July 2010 and December 2016.

The investigators sought to determine whether baseline heart rate predicts the risk of documented bradycardia, new-onset second-degree atrioventricular block, or ED transfer for additional monitoring. In addition, they examined whether patients with heart rates above a certain threshold may be at risk of first-dose cardiac events.

Dr. Osborne and colleagues reviewed data from 5,572 in-home and 15,025 in-clinic first-dose observation procedures. They classified patients as having marked bradycardia (under 50 beats per minute), mild bradycardia (50-59 bpm), or a normal heart rate (at least 60 bpm) at baseline. During the 20,001 procedures with available data, 182 cardiac events occurred, including 28 instances of documented bradycardia, 13 instances of second-degree atrioventricular block, and 141 instances of ED transfer for extended monitoring; 40 events occurred during at-home monitoring, and 142 events occurred in clinic.

About 87.0% of the cardiac events occurred in patients with a normal baseline heart rate, 11.5% occurred in patients with mild bradycardia, and 1.1% occurred in patients with marked bradycardia. The two cardiac events in patients with marked bradycardia at baseline were ED transfers of patients whose first-dose observations occurred in clinics. “The threshold heart rate above which patients did not experience a cardiac event was 80 bpm, well within the normal range of 60-100 bpm,” the authors said.

“These data suggest that patients with a low baseline heart rate may be at no more risk of cardiac events than patients with a heart rate in the normal range, nor is there a baseline heart rate threshold below which a patient is at greater risk of cardiac events,” Dr. Osborne and colleagues concluded.

Dr. Osborne reporting receiving a consulting fee from Novartis, which markets Gilenya (fingolimod), and his coauthors are employees of Novartis.
 

[email protected]

SEATTLE – Among patients with multiple sclerosis who initiate treatment with fingolimod, a low baseline heart rate may not increase the risk of first-dose cardiac events, according to data presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. In addition, the data “provide further evidence that first-dose cardiac events with fingolimod are rare,” regardless of whether the first dose is given in a clinic or a patient’s home, the study researchers said.

Transient heart rate decreases are an anticipated effect of starting fingolimod, and the U.S. prescribing information for the drug requires first-dose observation of heart rate and blood pressure for at least 6 hours. Heart rate and blood pressure may be monitored in a clinic or at home via the Gilenya@Home program.

To examine whether low baseline heart rate is associated with the likelihood of certain cardiac events during the first-dose observation period, John Osborne, MD, of State of the Heart Cardiology in Grapevine, Tex., and colleagues analyzed retrospective, first-dose observation data from Gilenya@Home between October 2014 and July 2017 and from Gilenya Assessment Network clinics between July 2010 and December 2016.

The investigators sought to determine whether baseline heart rate predicts the risk of documented bradycardia, new-onset second-degree atrioventricular block, or ED transfer for additional monitoring. In addition, they examined whether patients with heart rates above a certain threshold may be at risk of first-dose cardiac events.

Dr. Osborne and colleagues reviewed data from 5,572 in-home and 15,025 in-clinic first-dose observation procedures. They classified patients as having marked bradycardia (under 50 beats per minute), mild bradycardia (50-59 bpm), or a normal heart rate (at least 60 bpm) at baseline. During the 20,001 procedures with available data, 182 cardiac events occurred, including 28 instances of documented bradycardia, 13 instances of second-degree atrioventricular block, and 141 instances of ED transfer for extended monitoring; 40 events occurred during at-home monitoring, and 142 events occurred in clinic.

About 87.0% of the cardiac events occurred in patients with a normal baseline heart rate, 11.5% occurred in patients with mild bradycardia, and 1.1% occurred in patients with marked bradycardia. The two cardiac events in patients with marked bradycardia at baseline were ED transfers of patients whose first-dose observations occurred in clinics. “The threshold heart rate above which patients did not experience a cardiac event was 80 bpm, well within the normal range of 60-100 bpm,” the authors said.

“These data suggest that patients with a low baseline heart rate may be at no more risk of cardiac events than patients with a heart rate in the normal range, nor is there a baseline heart rate threshold below which a patient is at greater risk of cardiac events,” Dr. Osborne and colleagues concluded.

Dr. Osborne reporting receiving a consulting fee from Novartis, which markets Gilenya (fingolimod), and his coauthors are employees of Novartis.
 

[email protected]

SAN FRANCISCO – Medical marijuana skipped the usual phased testing of pharmaceuticals, so questions abound about how to counsel patients as legalization rolls out across the country, speakers said at the American Psychiatric Association annual meeting.

M. Alexander Otto/MDedge News

Drug interactions are an issue but remain under the radar. Tetrahydrocannabinol (THC) and cannabidiol (CBD) are inhibitors of cytochrome P450, specifically the CYP2C enzyme and CYP3A liver enzymes, which means possible interactions with drug classes such as antidepressants and antipsychotics might come into play.

Concomitant use could affect, or be affected by, fluoxetine, clozapine, duloxetine, and olanzapine, among other medications. One case study suggested that warfarin doses should be reduced by 30% in a patient who had started with a liquid formulation of CBD for managing epilepsy (Basic Clin Pharmacol Toxicol. 2019 Jan;124[1]:28-31).

At this point, it’s “not clear what the clinic implications are,” but “it’s not unreasonable to consider that your patients’ response to their psychiatric medications might change based on the introduction of cannabinoids,” said Arthur Williams, MD, assistant professor of clinical psychiatry at Columbia University, New York, and one of many researchers playing catch-up as marijuana and its derivatives enter the clinic.

Another question is what, exactly, is a standard dose?

Dosing mostly has been a question of THC, the psychoactive component of marijuana. Washington state and Colorado opted for 10-mg THC when those jurisdictions legalized recreational use; Oregon chose 5 mg. Both are in line with Food and Drug Administration formulations already on the market, including dronabinol (Marinol), a synthetic THC approved in 2.5-mg, 5-mg, and 10-mg doses for AIDS wasting, and chemotherapy nausea and vomiting.

A typical .7-g joint of 8% THC delivers about 5 mg or so, but newer strains range up to 20% THC, and could deliver over 13 mg per joint; occasional users, meanwhile, feel high from just 2-3 mg.

The ratio of THC to CBD matters, as well. Generally, “whole plant marijuana on the black market is much higher in THC and much lower in CBD,” Dr. Williams said. CBD is thought to deliver most of the medical benefits of marijuana.

It’s best to ask people what they’re using, and to counsel new users – especially the elderly – to start low and go slow. But keep in mind that many medical users have years of recreational use and have built up tolerance, he said.

Vaping is not a bad idea for those interested. It heats the plant material to high enough temperatures to release cannabinoids but without combusting. It’s a much more efficient THC delivery system than smoking, and there’s no smoke in the lungs. Vape patients often feel they can titrate their dose exactly.

Edibles are another matter. It can take hours for them to hit. Although THC levels do not spike with edibles as they do when the substance is inhaled, the effects last longer. A lot depends on how much food is in the gut.

The risk with edibles is that people may keep popping gummy bears and brownies because they don’t feel anything but end up overdosing. Children might be tempted by the treats, too, and for those under 4 years old, overdose can lead to fatal encephalopathic comas, “something we never really saw until edibles came around,” Dr. Williams said.

With edibles, “you have no idea what’s actually in the product.” Labels can be “inaccurate by an order of magnitude. Patients should be cautioned about that,” he said.

Pregnant and breastfeeding women, especially, should be warned away from marijuana. Some of the literature suggests a link between exposure to marijuana and preterm birth – in addition to early psychosis in vulnerable children.

Dr. Williams had no relevant disclosures.

[email protected]

SAN FRANCISCO – Medical marijuana skipped the usual phased testing of pharmaceuticals, so questions abound about how to counsel patients as legalization rolls out across the country, speakers said at the American Psychiatric Association annual meeting.

M. Alexander Otto/MDedge News

Drug interactions are an issue but remain under the radar. Tetrahydrocannabinol (THC) and cannabidiol (CBD) are inhibitors of cytochrome P450, specifically the CYP2C enzyme and CYP3A liver enzymes, which means possible interactions with drug classes such as antidepressants and antipsychotics might come into play.

Concomitant use could affect, or be affected by, fluoxetine, clozapine, duloxetine, and olanzapine, among other medications. One case study suggested that warfarin doses should be reduced by 30% in a patient who had started with a liquid formulation of CBD for managing epilepsy (Basic Clin Pharmacol Toxicol. 2019 Jan;124[1]:28-31).

At this point, it’s “not clear what the clinic implications are,” but “it’s not unreasonable to consider that your patients’ response to their psychiatric medications might change based on the introduction of cannabinoids,” said Arthur Williams, MD, assistant professor of clinical psychiatry at Columbia University, New York, and one of many researchers playing catch-up as marijuana and its derivatives enter the clinic.

Another question is what, exactly, is a standard dose?

Dosing mostly has been a question of THC, the psychoactive component of marijuana. Washington state and Colorado opted for 10-mg THC when those jurisdictions legalized recreational use; Oregon chose 5 mg. Both are in line with Food and Drug Administration formulations already on the market, including dronabinol (Marinol), a synthetic THC approved in 2.5-mg, 5-mg, and 10-mg doses for AIDS wasting, and chemotherapy nausea and vomiting.

A typical .7-g joint of 8% THC delivers about 5 mg or so, but newer strains range up to 20% THC, and could deliver over 13 mg per joint; occasional users, meanwhile, feel high from just 2-3 mg.

The ratio of THC to CBD matters, as well. Generally, “whole plant marijuana on the black market is much higher in THC and much lower in CBD,” Dr. Williams said. CBD is thought to deliver most of the medical benefits of marijuana.

It’s best to ask people what they’re using, and to counsel new users – especially the elderly – to start low and go slow. But keep in mind that many medical users have years of recreational use and have built up tolerance, he said.

Vaping is not a bad idea for those interested. It heats the plant material to high enough temperatures to release cannabinoids but without combusting. It’s a much more efficient THC delivery system than smoking, and there’s no smoke in the lungs. Vape patients often feel they can titrate their dose exactly.

Edibles are another matter. It can take hours for them to hit. Although THC levels do not spike with edibles as they do when the substance is inhaled, the effects last longer. A lot depends on how much food is in the gut.

The risk with edibles is that people may keep popping gummy bears and brownies because they don’t feel anything but end up overdosing. Children might be tempted by the treats, too, and for those under 4 years old, overdose can lead to fatal encephalopathic comas, “something we never really saw until edibles came around,” Dr. Williams said.

With edibles, “you have no idea what’s actually in the product.” Labels can be “inaccurate by an order of magnitude. Patients should be cautioned about that,” he said.

Pregnant and breastfeeding women, especially, should be warned away from marijuana. Some of the literature suggests a link between exposure to marijuana and preterm birth – in addition to early psychosis in vulnerable children.

Dr. Williams had no relevant disclosures.

[email protected]

SAN FRANCISCO – Medical marijuana skipped the usual phased testing of pharmaceuticals, so questions abound about how to counsel patients as legalization rolls out across the country, speakers said at the American Psychiatric Association annual meeting.

M. Alexander Otto/MDedge News

Drug interactions are an issue but remain under the radar. Tetrahydrocannabinol (THC) and cannabidiol (CBD) are inhibitors of cytochrome P450, specifically the CYP2C enzyme and CYP3A liver enzymes, which means possible interactions with drug classes such as antidepressants and antipsychotics might come into play.

Concomitant use could affect, or be affected by, fluoxetine, clozapine, duloxetine, and olanzapine, among other medications. One case study suggested that warfarin doses should be reduced by 30% in a patient who had started with a liquid formulation of CBD for managing epilepsy (Basic Clin Pharmacol Toxicol. 2019 Jan;124[1]:28-31).

At this point, it’s “not clear what the clinic implications are,” but “it’s not unreasonable to consider that your patients’ response to their psychiatric medications might change based on the introduction of cannabinoids,” said Arthur Williams, MD, assistant professor of clinical psychiatry at Columbia University, New York, and one of many researchers playing catch-up as marijuana and its derivatives enter the clinic.

Another question is what, exactly, is a standard dose?

Dosing mostly has been a question of THC, the psychoactive component of marijuana. Washington state and Colorado opted for 10-mg THC when those jurisdictions legalized recreational use; Oregon chose 5 mg. Both are in line with Food and Drug Administration formulations already on the market, including dronabinol (Marinol), a synthetic THC approved in 2.5-mg, 5-mg, and 10-mg doses for AIDS wasting, and chemotherapy nausea and vomiting.

A typical .7-g joint of 8% THC delivers about 5 mg or so, but newer strains range up to 20% THC, and could deliver over 13 mg per joint; occasional users, meanwhile, feel high from just 2-3 mg.

The ratio of THC to CBD matters, as well. Generally, “whole plant marijuana on the black market is much higher in THC and much lower in CBD,” Dr. Williams said. CBD is thought to deliver most of the medical benefits of marijuana.

It’s best to ask people what they’re using, and to counsel new users – especially the elderly – to start low and go slow. But keep in mind that many medical users have years of recreational use and have built up tolerance, he said.

Vaping is not a bad idea for those interested. It heats the plant material to high enough temperatures to release cannabinoids but without combusting. It’s a much more efficient THC delivery system than smoking, and there’s no smoke in the lungs. Vape patients often feel they can titrate their dose exactly.

Edibles are another matter. It can take hours for them to hit. Although THC levels do not spike with edibles as they do when the substance is inhaled, the effects last longer. A lot depends on how much food is in the gut.

The risk with edibles is that people may keep popping gummy bears and brownies because they don’t feel anything but end up overdosing. Children might be tempted by the treats, too, and for those under 4 years old, overdose can lead to fatal encephalopathic comas, “something we never really saw until edibles came around,” Dr. Williams said.

With edibles, “you have no idea what’s actually in the product.” Labels can be “inaccurate by an order of magnitude. Patients should be cautioned about that,” he said.

Pregnant and breastfeeding women, especially, should be warned away from marijuana. Some of the literature suggests a link between exposure to marijuana and preterm birth – in addition to early psychosis in vulnerable children.

Dr. Williams had no relevant disclosures.

[email protected]