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Smell loss may be a biomarker of Alzheimer’s disease risk
, according to new research findings.
Olfactory dysfunction is common in late life and well documented among people with Alzheimer’s disease. However, it was unknown whether faster olfactory decline predicts either onset of Alzheimer’s disease or structural brain changes associated with Alzheimer’s disease.
In a study published online in Alzheimer’s and Dementia, Jayant M. Pinto, MD, and his colleagues at the University of Chicago Medical Center reported that among older adults with normal cognition at baseline, people who experienced rapid loss of sense of smell were more likely to be subsequently diagnosed with mild cognitive impairment (MCI) or dementia, compared with those who did not.
Participants were recruited from Rush University’s Memory and Aging Project, a longitudinal cohort of older adults who undergo yearly cognitive and sensory exams, including a scratch test of 12 common smells to identify. The Rush study “was ahead of the curve in looking at smell,” Dr. Pinto said in an interview. “It gave us a very valuable resource with which to attack these questions.”
Dr. Pinto has long investigated links between smell and accelerated aging; in 2014 his group published the finding that olfactory dysfunction could predict death within 5 years in older adults, and in 2018 they reported that olfactory dysfunction could predict dementia.
Smell and cognition over time
For the current study, Dr. Pinto said, “we were able to look at the question not just using a single point in time, but a more granular trajectory of smell loss. Measuring change year by year showed that the faster people’s sense of smell declined, the more likely they were to be diagnosed with MCI or Alzheimer’s disease.”
Dr. Pinto and his colleagues evaluated results from 515 adults (mean age 76.6, 78% female, 94% White) with no cognitive impairment and at least 3 years of normal results on smell tests at baseline. The subjects were followed for a mean 8 years. One hundred subjects (19%) were diagnosed with MCI or dementia by the end of the study period. A subset of the cohort (n = 121) underwent structural magnetic resonance imaging (MRI) between their final smell tests and the study’s end. Of these, most still had normal cognition; 17 individuals had MCI.
Patients’ individual trajectories of smell loss were mapped as slopes. After adjusting for expected differences in age and sex, the investigators found steeper decline associated with greater risk of incident MCI or dementia (odds ratio, 1.89; 95% confidence interval, 1.26-2.90; P < .01). The risk was comparable to that of carrying an apo E ε4 allele, the key risk variant for late-onset Alzheimer’s disease, but was independent of apo E status. The association was strongest among subjects younger than 76 years.
Olfactory decline and brain volume
Dr. Pinto and his colleagues, including lead author Rachel R. Pacyna, a 4th-year medical student at the University of Chicago, also sought to identify brain volume changes corresponding with olfactory decline and Alzheimer’s disease. The researchers hypothesized that certain brain regions not seen affected in Alzheimer’s disease would remain unchanged regardless of olfactory status, but that regions associated with smell and Alzheimer’s disease would see smaller volumes linked with olfactory decline.
Faster olfactory decline did predict lower gray matter volume in olfactory regions, even after controlling for apo E status and other known risk factors. Conversely, cognitively unimpaired patients undergoing MRI saw more gray matter volume in primary olfactory and temporal brain regions, compared with those with cognitive symptoms.
Taken together, the findings suggest that “change in sense of smell is better than looking at sense of smell at one time point,” Dr. Pinto commented. “There are other reasons people have impaired sense of smell: car accidents, COVID, other viruses and infections. But if you identify on a time course those who are starting to lose it faster, these are the people on whom we need to focus.”
Not yet diagnostic
More work needs to be done to establish thresholds for smell loss that could be useful in clinical or investigative settings as a marker of dementia risk, Dr. Pinto acknowledged. “Everyone gets their hearing tested; everyone gets their vision tested. It’s not as easy to get your sense of smell tested. But this study is telling people that if we were to start measuring it routinely, we could actually use it.”
Smell testing “could become a component of a diagnostic battery that includes things like genotyping and cerebrospinal fluid markers, but adds a little more information. It could be useful in clinical prevention trials to identify people at the highest risk, as smell loss presents quite a few years before MCI or Alzheimer’s disease.”
The investigators acknowledged that their findings need to be replicated in more diverse cohorts that better represent the Alzheimer’s population in the United States. Another limitation of their study, they said, was that the method used to calculate the rate of olfactory decline “was based on slope of measured time points assuming linearity, which may oversimplify the complexity of olfactory changes in normal aging and during the preclinical Alzheimer’s disease period.” The study was funded by the National Institutes of Health. Dr. Pinto disclosed receiving consulting fees from Sanofi/Regeneron, Optinose, and Genentech not related to this work.
, according to new research findings.
Olfactory dysfunction is common in late life and well documented among people with Alzheimer’s disease. However, it was unknown whether faster olfactory decline predicts either onset of Alzheimer’s disease or structural brain changes associated with Alzheimer’s disease.
In a study published online in Alzheimer’s and Dementia, Jayant M. Pinto, MD, and his colleagues at the University of Chicago Medical Center reported that among older adults with normal cognition at baseline, people who experienced rapid loss of sense of smell were more likely to be subsequently diagnosed with mild cognitive impairment (MCI) or dementia, compared with those who did not.
Participants were recruited from Rush University’s Memory and Aging Project, a longitudinal cohort of older adults who undergo yearly cognitive and sensory exams, including a scratch test of 12 common smells to identify. The Rush study “was ahead of the curve in looking at smell,” Dr. Pinto said in an interview. “It gave us a very valuable resource with which to attack these questions.”
Dr. Pinto has long investigated links between smell and accelerated aging; in 2014 his group published the finding that olfactory dysfunction could predict death within 5 years in older adults, and in 2018 they reported that olfactory dysfunction could predict dementia.
Smell and cognition over time
For the current study, Dr. Pinto said, “we were able to look at the question not just using a single point in time, but a more granular trajectory of smell loss. Measuring change year by year showed that the faster people’s sense of smell declined, the more likely they were to be diagnosed with MCI or Alzheimer’s disease.”
Dr. Pinto and his colleagues evaluated results from 515 adults (mean age 76.6, 78% female, 94% White) with no cognitive impairment and at least 3 years of normal results on smell tests at baseline. The subjects were followed for a mean 8 years. One hundred subjects (19%) were diagnosed with MCI or dementia by the end of the study period. A subset of the cohort (n = 121) underwent structural magnetic resonance imaging (MRI) between their final smell tests and the study’s end. Of these, most still had normal cognition; 17 individuals had MCI.
Patients’ individual trajectories of smell loss were mapped as slopes. After adjusting for expected differences in age and sex, the investigators found steeper decline associated with greater risk of incident MCI or dementia (odds ratio, 1.89; 95% confidence interval, 1.26-2.90; P < .01). The risk was comparable to that of carrying an apo E ε4 allele, the key risk variant for late-onset Alzheimer’s disease, but was independent of apo E status. The association was strongest among subjects younger than 76 years.
Olfactory decline and brain volume
Dr. Pinto and his colleagues, including lead author Rachel R. Pacyna, a 4th-year medical student at the University of Chicago, also sought to identify brain volume changes corresponding with olfactory decline and Alzheimer’s disease. The researchers hypothesized that certain brain regions not seen affected in Alzheimer’s disease would remain unchanged regardless of olfactory status, but that regions associated with smell and Alzheimer’s disease would see smaller volumes linked with olfactory decline.
Faster olfactory decline did predict lower gray matter volume in olfactory regions, even after controlling for apo E status and other known risk factors. Conversely, cognitively unimpaired patients undergoing MRI saw more gray matter volume in primary olfactory and temporal brain regions, compared with those with cognitive symptoms.
Taken together, the findings suggest that “change in sense of smell is better than looking at sense of smell at one time point,” Dr. Pinto commented. “There are other reasons people have impaired sense of smell: car accidents, COVID, other viruses and infections. But if you identify on a time course those who are starting to lose it faster, these are the people on whom we need to focus.”
Not yet diagnostic
More work needs to be done to establish thresholds for smell loss that could be useful in clinical or investigative settings as a marker of dementia risk, Dr. Pinto acknowledged. “Everyone gets their hearing tested; everyone gets their vision tested. It’s not as easy to get your sense of smell tested. But this study is telling people that if we were to start measuring it routinely, we could actually use it.”
Smell testing “could become a component of a diagnostic battery that includes things like genotyping and cerebrospinal fluid markers, but adds a little more information. It could be useful in clinical prevention trials to identify people at the highest risk, as smell loss presents quite a few years before MCI or Alzheimer’s disease.”
The investigators acknowledged that their findings need to be replicated in more diverse cohorts that better represent the Alzheimer’s population in the United States. Another limitation of their study, they said, was that the method used to calculate the rate of olfactory decline “was based on slope of measured time points assuming linearity, which may oversimplify the complexity of olfactory changes in normal aging and during the preclinical Alzheimer’s disease period.” The study was funded by the National Institutes of Health. Dr. Pinto disclosed receiving consulting fees from Sanofi/Regeneron, Optinose, and Genentech not related to this work.
, according to new research findings.
Olfactory dysfunction is common in late life and well documented among people with Alzheimer’s disease. However, it was unknown whether faster olfactory decline predicts either onset of Alzheimer’s disease or structural brain changes associated with Alzheimer’s disease.
In a study published online in Alzheimer’s and Dementia, Jayant M. Pinto, MD, and his colleagues at the University of Chicago Medical Center reported that among older adults with normal cognition at baseline, people who experienced rapid loss of sense of smell were more likely to be subsequently diagnosed with mild cognitive impairment (MCI) or dementia, compared with those who did not.
Participants were recruited from Rush University’s Memory and Aging Project, a longitudinal cohort of older adults who undergo yearly cognitive and sensory exams, including a scratch test of 12 common smells to identify. The Rush study “was ahead of the curve in looking at smell,” Dr. Pinto said in an interview. “It gave us a very valuable resource with which to attack these questions.”
Dr. Pinto has long investigated links between smell and accelerated aging; in 2014 his group published the finding that olfactory dysfunction could predict death within 5 years in older adults, and in 2018 they reported that olfactory dysfunction could predict dementia.
Smell and cognition over time
For the current study, Dr. Pinto said, “we were able to look at the question not just using a single point in time, but a more granular trajectory of smell loss. Measuring change year by year showed that the faster people’s sense of smell declined, the more likely they were to be diagnosed with MCI or Alzheimer’s disease.”
Dr. Pinto and his colleagues evaluated results from 515 adults (mean age 76.6, 78% female, 94% White) with no cognitive impairment and at least 3 years of normal results on smell tests at baseline. The subjects were followed for a mean 8 years. One hundred subjects (19%) were diagnosed with MCI or dementia by the end of the study period. A subset of the cohort (n = 121) underwent structural magnetic resonance imaging (MRI) between their final smell tests and the study’s end. Of these, most still had normal cognition; 17 individuals had MCI.
Patients’ individual trajectories of smell loss were mapped as slopes. After adjusting for expected differences in age and sex, the investigators found steeper decline associated with greater risk of incident MCI or dementia (odds ratio, 1.89; 95% confidence interval, 1.26-2.90; P < .01). The risk was comparable to that of carrying an apo E ε4 allele, the key risk variant for late-onset Alzheimer’s disease, but was independent of apo E status. The association was strongest among subjects younger than 76 years.
Olfactory decline and brain volume
Dr. Pinto and his colleagues, including lead author Rachel R. Pacyna, a 4th-year medical student at the University of Chicago, also sought to identify brain volume changes corresponding with olfactory decline and Alzheimer’s disease. The researchers hypothesized that certain brain regions not seen affected in Alzheimer’s disease would remain unchanged regardless of olfactory status, but that regions associated with smell and Alzheimer’s disease would see smaller volumes linked with olfactory decline.
Faster olfactory decline did predict lower gray matter volume in olfactory regions, even after controlling for apo E status and other known risk factors. Conversely, cognitively unimpaired patients undergoing MRI saw more gray matter volume in primary olfactory and temporal brain regions, compared with those with cognitive symptoms.
Taken together, the findings suggest that “change in sense of smell is better than looking at sense of smell at one time point,” Dr. Pinto commented. “There are other reasons people have impaired sense of smell: car accidents, COVID, other viruses and infections. But if you identify on a time course those who are starting to lose it faster, these are the people on whom we need to focus.”
Not yet diagnostic
More work needs to be done to establish thresholds for smell loss that could be useful in clinical or investigative settings as a marker of dementia risk, Dr. Pinto acknowledged. “Everyone gets their hearing tested; everyone gets their vision tested. It’s not as easy to get your sense of smell tested. But this study is telling people that if we were to start measuring it routinely, we could actually use it.”
Smell testing “could become a component of a diagnostic battery that includes things like genotyping and cerebrospinal fluid markers, but adds a little more information. It could be useful in clinical prevention trials to identify people at the highest risk, as smell loss presents quite a few years before MCI or Alzheimer’s disease.”
The investigators acknowledged that their findings need to be replicated in more diverse cohorts that better represent the Alzheimer’s population in the United States. Another limitation of their study, they said, was that the method used to calculate the rate of olfactory decline “was based on slope of measured time points assuming linearity, which may oversimplify the complexity of olfactory changes in normal aging and during the preclinical Alzheimer’s disease period.” The study was funded by the National Institutes of Health. Dr. Pinto disclosed receiving consulting fees from Sanofi/Regeneron, Optinose, and Genentech not related to this work.
FROM ALZHEIMER’S & DEMENTIA
Geriatric-Centered Interdisciplinary Care Pathway Reduces Delirium in Hospitalized Older Adults With Traumatic Injury
Study 1 Overview (Park et al)
Objective: To examine whether implementation of a geriatric trauma clinical pathway is associated with reduced rates of delirium in older adults with traumatic injury.
Design: Retrospective case-control study of electronic health records.
Setting and participants: Eligible patients were persons aged 65 years or older who were admitted to the trauma service and did not undergo an operation. A Geriatric Trauma Care Pathway was developed by a multidisciplinary Stanford Quality Pathways team and formally launched on November 1, 2018. The clinical pathway was designed to incorporate geriatric best practices, which included order sets (eg, age-appropriate nonpharmacological interventions and pharmacological dosages), guidelines (eg, Institute for Healthcare Improvement Age-Friendly Health systems 4M framework), automated consultations (comprehensive geriatric assessment), and escalation pathways executed by a multidisciplinary team (eg, pain, bowel, and sleep regulation). The clinical pathway began with admission to the emergency department (ED) (ie, automatic trigger of geriatric trauma care admission order set), daily multidisciplinary team meetings during acute hospitalization, and a transitional care team consultation for postdischarge follow-up or home visit.
Main outcome measures: The primary outcome was delirium as determined by a positive Confusion Assessment Method (CAM) score or a diagnosis of delirium by the clinical team. The secondary outcome was hospital length of stay (LOS). Process measures for pathway compliance (eg, achieving adequate pain control, early mobilization, advance care planning) were assessed. Outcome measures were compared between patients who underwent the Geriatric Trauma Care Pathway intervention (postimplementation group) vs patients who were treated prior to pathway implementation (baseline pre-implementation group).
Main results: Of the 859 eligible patients, 712 were included in the analysis (442 [62.1%] in the baseline pre-implementation group and 270 [37.9%] in the postimplementation group); mean (SD) age was 81.4 (9.1) years, and 394 (55.3%) were women. The injury mechanism was similar between groups, with falls being the most common cause of injury (247 [55.9%] in the baseline group vs 162 [60.0%] in the postimplementation group; P = .43). Injuries as measured by Injury Severity Score (ISS) were minor or moderate in both groups (261 [59.0%] in baseline group vs 168 [62.2%] in postimplementation group; P = .87). The adjusted odds ratio (OR) for delirium in the postimplementation group was lower compared to the baseline pre-implementation group (OR, 0.54; 95% CI, 0.37-0.80; P < .001). Measures of advance care planning in the postimplementation group improved, including more frequent goals-of-care documentation (53.7% in postimplementation group vs 16.7% in baseline group; P < .001) and a shortened time to first goals-of-care discussion upon presenting to the ED (36 hours in postimplementation group vs 50 hours in baseline group; P = .03).
Conclusion: Implementation of a multidisciplinary geriatric trauma clinical pathway for older adults with traumatic injury at a single level I trauma center was associated with reduced rates of delirium.
Study 2 Overview (Bryant et al)
Objective: To determine whether an interdisciplinary care pathway for frail trauma patients can improve in-hospital mortality, complications, and 30-day readmissions.
Design: Retrospective cohort study of frail patients.
Setting and participants: Eligible patients were persons aged 65 years or older who were admitted to the trauma service and survived more than 24 hours; admitted to and discharged from the trauma unit; and determined to be pre-frail or frail by a geriatrician’s assessment. A Frailty Identification and Care Pathway designed to reduce delirium and complications in frail older trauma patients was developed by a multidisciplinary team and implemented in 2016. The standardized evidence-based interdisciplinary care pathway included utilization of order sets and interventions for delirium prevention, early ambulation, bowel and pain regimens, nutrition and physical therapy consults, medication management, care-goal setting, and geriatric assessments.
Main outcome measures: The main outcomes were delirium as determined by a positive CAM score, major complications as defined by the Trauma Quality Improvement Project, in-hospital mortality, and 30-day hospital readmission. Outcome measures were compared between patients who underwent Frailty Identification and Care Pathway intervention (postintervention group) vs patients who were treated prior to pathway implementation (pre-intervention group).
Main results: A total of 269 frail patients were included in the analysis (125 in pre-intervention group vs 144 in postintervention group). Patient demographic and admission characteristics were similar between the 2 groups: mean age was 83.5 (7.1) years, 60.6% were women, and median ISS was 10 (interquartile range [IQR], 9-14). The injury mechanism was similar between groups, with falls accounting for 92.8% and 86.1% of injuries in the pre-intervention and postintervention groups, respectively (P = .07). In univariate analysis, the Frailty Identification and Care Pathway intervention was associated with a significant reduction in delirium (12.5% vs 21.6%, P = .04) and 30-day hospital readmission (2.7% vs 9.6%, P = .01) compared to patients in the pre-intervention group. However, rates of major complications (28.5% vs 28.0%, P = 0.93) and in-hospital mortality (4.2% vs 7.2%, P = .28) were similar between the pre-intervention and postintervention groups. In multivariate logistic regression models adjusted for patient characteristics (age, sex, race, ISS), patients in the postintervention group had lower delirium (OR, 0.44; 95% CI, 0.22-0.88; P = .02) and 30-day hospital readmission (OR, 0.25; 95% CI, 0.07-0.84; P = .02) rates compared to those in the pre-intervention group.
Conclusion: Implementation of an interdisciplinary care protocol for frail geriatric trauma patients significantly decreased their risks for in-hospital delirium and 30-day hospital readmission.
Commentary
Traumatic injuries in older adults are associated with higher morbidity and mortality compared to younger patients, with falls and motor vehicle accidents accounting for a majority of these injuries. Astoundingly, up to one-third of this vulnerable population presenting to hospitals with an ISS greater than 15 may die during hospitalization.1 As a result, a large number of studies and clinical trials have focused on interventions that are designed to reduce fall risks, and hence reduce adverse consequences of traumatic injuries that may arise after falls.2 However, this emphasis on falls prevention has overshadowed a need to develop effective geriatric-centered clinical interventions that aim to improve outcomes in older adults who present to hospitals with traumatic injuries. Furthermore, frailty—a geriatric syndrome indicative of an increased state of vulnerability and predictive of adverse outcomes such as delirium—is highly prevalent in older patients with traumatic injury.3 Thus, there is an urgent need to develop novel, hospital-based, traumatic injury–targeting strategies that incorporate a thoughtful redesign of the care framework that includes evidence-based interventions for geriatric syndromes such as delirium and frailty.
The study reported by Park et al (Study 1) represents the latest effort to evaluate inpatient management strategies designed to improve outcomes in hospitalized older adults who have sustained traumatic injury. Through the implementation of a novel multidisciplinary Geriatric Trauma Care Pathway that incorporates geriatric best practices, this intervention was found to be associated with a 46% lower risk of in-hospital delirium. Because of the inclusion of all age-eligible patients across all strata of traumatic injuries, rather than preselecting for those at the highest risk for poor clinical outcomes, the benefits of this intervention extend to those with minor or moderate injury severity. Furthermore, the improvement in delirium (ie, the primary outcome) is particularly meaningful given that delirium is one of the most common hospital-associated complications that increase hospital LOS, discharge to an institution, and mortality in older adults. Finally, the study’s observed reduced time to a first goals-of-care discussion and increased frequency of goals-of-care documentation after intervention should not be overlooked. The improvements in these 2 process measures are highly significant given that advanced care planning, an intervention that helps to align patients’ values, goals, and treatments, is completed at substantially lower rates in older adults in the acute hospital setting.4
Similarly, in an earlier published study, Bryant and colleagues (Study 2) also show that a geriatric-focused interdisciplinary trauma care pathway is associated with delirium risk reduction in hospitalized older trauma patients. Much like Study 1, the Frailty Identification and Care Pathway utilized in Study 2 is an evidence-based interdisciplinary care pathway that includes the use of geriatric assessments, order sets, and geriatric best practices. Moreover, its exclusive inclusion of pre-frail and frail older patients (ie, those at higher risk for poor outcomes) with moderate injury severity (median ISS of 10 [IQR, 9-14]) suggests that this type of care pathway benefits hospitalized older trauma patients, who are particularly vulnerable to adverse complications such as delirium. Moreover, the successful utilization of the FRAIL questionnaire, a validated frailty screening tool, by surgical residents in the ED to initiate this care pathway demonstrates the feasibility of its use in expediting frailty screening in older patients in trauma care.
Application for Clinical Practice and System Implementation
Findings from the 2 studies discussed in this review indicate that implementation of interdisciplinary clinical care pathways predicated on evidence-based geriatric principles and best practices is a promising approach to reduce delirium in hospitalized older trauma patients. These studies have helped to lay the groundwork in outlining the roadmaps (eg, processes and infrastructures) needed to create such clinical pathways. These key elements include: (1) integration of a multidisciplinary committee (eg, representation from trauma, emergency, and geriatric medicine, nursing, physical and occupational therapy, pharmacy, social work) in pathway design and implementation; (2) adaption of evidence-based geriatric best practices (eg, the Institute for Healthcare Improvement Age-Friendly Health System 4M framework [medication, mentation, mobility, what matters]) to prioritize interventions and to design a pathway that incorporates these features; (3) incorporation of comprehensive geriatric assessment by interdisciplinary providers; (4) utilization of validated clinical instruments to assess physical and cognitive functions, frailty, delirium, and social determinants of health; (5) modification of electronic health record systems to encompass order sets that incorporate evidence-based, nonpharmacological and pharmacological interventions to manage symptoms (eg, delirium, pain, bowel movement, sleep, immobility, polypharmacy) essential to quality geriatric care; and (6) integration of patient and caregiver preferences via goals-of-care discussions and corresponding documentation and communication of these goals.
Additionally, these 2 studies imparted some strategies that may facilitate the implementation of interdisciplinary clinical care pathways in trauma care. Examples of such facilitators include: (1) collaboration with champions within each specialty to reinforce education and buy-in; (2) creation of automatically triggered order sets upon patient presentation to the ED that unites distinct features of clinical pathways; (3) adaption and reorganization of existing hospital infrastructures and resources to meet the needs of clinical pathways implementation (eg, utilizing information technology resources to develop electronic health record order sets; using quality department to develop clinical pathway guidelines and electronic outcome dashboards); and (4) development of individualized patient and caregiver education materials based on care needs (eg, principles of delirium prevention and preservation of mobility during hospitalization) to prepare and engage these stakeholders in patient care and recovery.
Practice Points
- A geriatric interdisciplinary care model can be effectively applied to the management of acute trauma in older patients.
- Interdisciplinary clinical pathways should incorporate geriatric best practices and guidelines and age-appropriate order sets to prioritize and integrate care.
—Fred Ko, MD, MS
1. Hashmi A, Ibrahim-Zada I, Rhee P, et al. Predictors of mortality in geriatric trauma patients: a systematic review and meta-analysis. J Trauma Acute Care Surg. 2014;76(3):894-901. doi:10.1097/TA.0b013e3182ab0763
2. Hopewell S, Adedire O, Copsey BJ, et al. Multifactorial and multiple component interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev. 2018;7(7):CD012221. doi:10.1002/14651858.CD012221.pub2
3. Joseph B, Pandit V, Zangbar B, et al. Superiority of frailty over age in predicting outcomes among geriatric trauma patients: a prospective analysis. JAMA Surg. 2014;149(8):766-772. doi:10.1001/jamasurg.2014.296
4. Hopkins SA, Bentley A, Phillips V, Barclay S. Advance care plans and hospitalized frail older adults: a systematic review. BMJ Support Palliat Care. 2020;10(2):164-174. doi:10.1136/bmjspcare-2019-002093
Study 1 Overview (Park et al)
Objective: To examine whether implementation of a geriatric trauma clinical pathway is associated with reduced rates of delirium in older adults with traumatic injury.
Design: Retrospective case-control study of electronic health records.
Setting and participants: Eligible patients were persons aged 65 years or older who were admitted to the trauma service and did not undergo an operation. A Geriatric Trauma Care Pathway was developed by a multidisciplinary Stanford Quality Pathways team and formally launched on November 1, 2018. The clinical pathway was designed to incorporate geriatric best practices, which included order sets (eg, age-appropriate nonpharmacological interventions and pharmacological dosages), guidelines (eg, Institute for Healthcare Improvement Age-Friendly Health systems 4M framework), automated consultations (comprehensive geriatric assessment), and escalation pathways executed by a multidisciplinary team (eg, pain, bowel, and sleep regulation). The clinical pathway began with admission to the emergency department (ED) (ie, automatic trigger of geriatric trauma care admission order set), daily multidisciplinary team meetings during acute hospitalization, and a transitional care team consultation for postdischarge follow-up or home visit.
Main outcome measures: The primary outcome was delirium as determined by a positive Confusion Assessment Method (CAM) score or a diagnosis of delirium by the clinical team. The secondary outcome was hospital length of stay (LOS). Process measures for pathway compliance (eg, achieving adequate pain control, early mobilization, advance care planning) were assessed. Outcome measures were compared between patients who underwent the Geriatric Trauma Care Pathway intervention (postimplementation group) vs patients who were treated prior to pathway implementation (baseline pre-implementation group).
Main results: Of the 859 eligible patients, 712 were included in the analysis (442 [62.1%] in the baseline pre-implementation group and 270 [37.9%] in the postimplementation group); mean (SD) age was 81.4 (9.1) years, and 394 (55.3%) were women. The injury mechanism was similar between groups, with falls being the most common cause of injury (247 [55.9%] in the baseline group vs 162 [60.0%] in the postimplementation group; P = .43). Injuries as measured by Injury Severity Score (ISS) were minor or moderate in both groups (261 [59.0%] in baseline group vs 168 [62.2%] in postimplementation group; P = .87). The adjusted odds ratio (OR) for delirium in the postimplementation group was lower compared to the baseline pre-implementation group (OR, 0.54; 95% CI, 0.37-0.80; P < .001). Measures of advance care planning in the postimplementation group improved, including more frequent goals-of-care documentation (53.7% in postimplementation group vs 16.7% in baseline group; P < .001) and a shortened time to first goals-of-care discussion upon presenting to the ED (36 hours in postimplementation group vs 50 hours in baseline group; P = .03).
Conclusion: Implementation of a multidisciplinary geriatric trauma clinical pathway for older adults with traumatic injury at a single level I trauma center was associated with reduced rates of delirium.
Study 2 Overview (Bryant et al)
Objective: To determine whether an interdisciplinary care pathway for frail trauma patients can improve in-hospital mortality, complications, and 30-day readmissions.
Design: Retrospective cohort study of frail patients.
Setting and participants: Eligible patients were persons aged 65 years or older who were admitted to the trauma service and survived more than 24 hours; admitted to and discharged from the trauma unit; and determined to be pre-frail or frail by a geriatrician’s assessment. A Frailty Identification and Care Pathway designed to reduce delirium and complications in frail older trauma patients was developed by a multidisciplinary team and implemented in 2016. The standardized evidence-based interdisciplinary care pathway included utilization of order sets and interventions for delirium prevention, early ambulation, bowel and pain regimens, nutrition and physical therapy consults, medication management, care-goal setting, and geriatric assessments.
Main outcome measures: The main outcomes were delirium as determined by a positive CAM score, major complications as defined by the Trauma Quality Improvement Project, in-hospital mortality, and 30-day hospital readmission. Outcome measures were compared between patients who underwent Frailty Identification and Care Pathway intervention (postintervention group) vs patients who were treated prior to pathway implementation (pre-intervention group).
Main results: A total of 269 frail patients were included in the analysis (125 in pre-intervention group vs 144 in postintervention group). Patient demographic and admission characteristics were similar between the 2 groups: mean age was 83.5 (7.1) years, 60.6% were women, and median ISS was 10 (interquartile range [IQR], 9-14). The injury mechanism was similar between groups, with falls accounting for 92.8% and 86.1% of injuries in the pre-intervention and postintervention groups, respectively (P = .07). In univariate analysis, the Frailty Identification and Care Pathway intervention was associated with a significant reduction in delirium (12.5% vs 21.6%, P = .04) and 30-day hospital readmission (2.7% vs 9.6%, P = .01) compared to patients in the pre-intervention group. However, rates of major complications (28.5% vs 28.0%, P = 0.93) and in-hospital mortality (4.2% vs 7.2%, P = .28) were similar between the pre-intervention and postintervention groups. In multivariate logistic regression models adjusted for patient characteristics (age, sex, race, ISS), patients in the postintervention group had lower delirium (OR, 0.44; 95% CI, 0.22-0.88; P = .02) and 30-day hospital readmission (OR, 0.25; 95% CI, 0.07-0.84; P = .02) rates compared to those in the pre-intervention group.
Conclusion: Implementation of an interdisciplinary care protocol for frail geriatric trauma patients significantly decreased their risks for in-hospital delirium and 30-day hospital readmission.
Commentary
Traumatic injuries in older adults are associated with higher morbidity and mortality compared to younger patients, with falls and motor vehicle accidents accounting for a majority of these injuries. Astoundingly, up to one-third of this vulnerable population presenting to hospitals with an ISS greater than 15 may die during hospitalization.1 As a result, a large number of studies and clinical trials have focused on interventions that are designed to reduce fall risks, and hence reduce adverse consequences of traumatic injuries that may arise after falls.2 However, this emphasis on falls prevention has overshadowed a need to develop effective geriatric-centered clinical interventions that aim to improve outcomes in older adults who present to hospitals with traumatic injuries. Furthermore, frailty—a geriatric syndrome indicative of an increased state of vulnerability and predictive of adverse outcomes such as delirium—is highly prevalent in older patients with traumatic injury.3 Thus, there is an urgent need to develop novel, hospital-based, traumatic injury–targeting strategies that incorporate a thoughtful redesign of the care framework that includes evidence-based interventions for geriatric syndromes such as delirium and frailty.
The study reported by Park et al (Study 1) represents the latest effort to evaluate inpatient management strategies designed to improve outcomes in hospitalized older adults who have sustained traumatic injury. Through the implementation of a novel multidisciplinary Geriatric Trauma Care Pathway that incorporates geriatric best practices, this intervention was found to be associated with a 46% lower risk of in-hospital delirium. Because of the inclusion of all age-eligible patients across all strata of traumatic injuries, rather than preselecting for those at the highest risk for poor clinical outcomes, the benefits of this intervention extend to those with minor or moderate injury severity. Furthermore, the improvement in delirium (ie, the primary outcome) is particularly meaningful given that delirium is one of the most common hospital-associated complications that increase hospital LOS, discharge to an institution, and mortality in older adults. Finally, the study’s observed reduced time to a first goals-of-care discussion and increased frequency of goals-of-care documentation after intervention should not be overlooked. The improvements in these 2 process measures are highly significant given that advanced care planning, an intervention that helps to align patients’ values, goals, and treatments, is completed at substantially lower rates in older adults in the acute hospital setting.4
Similarly, in an earlier published study, Bryant and colleagues (Study 2) also show that a geriatric-focused interdisciplinary trauma care pathway is associated with delirium risk reduction in hospitalized older trauma patients. Much like Study 1, the Frailty Identification and Care Pathway utilized in Study 2 is an evidence-based interdisciplinary care pathway that includes the use of geriatric assessments, order sets, and geriatric best practices. Moreover, its exclusive inclusion of pre-frail and frail older patients (ie, those at higher risk for poor outcomes) with moderate injury severity (median ISS of 10 [IQR, 9-14]) suggests that this type of care pathway benefits hospitalized older trauma patients, who are particularly vulnerable to adverse complications such as delirium. Moreover, the successful utilization of the FRAIL questionnaire, a validated frailty screening tool, by surgical residents in the ED to initiate this care pathway demonstrates the feasibility of its use in expediting frailty screening in older patients in trauma care.
Application for Clinical Practice and System Implementation
Findings from the 2 studies discussed in this review indicate that implementation of interdisciplinary clinical care pathways predicated on evidence-based geriatric principles and best practices is a promising approach to reduce delirium in hospitalized older trauma patients. These studies have helped to lay the groundwork in outlining the roadmaps (eg, processes and infrastructures) needed to create such clinical pathways. These key elements include: (1) integration of a multidisciplinary committee (eg, representation from trauma, emergency, and geriatric medicine, nursing, physical and occupational therapy, pharmacy, social work) in pathway design and implementation; (2) adaption of evidence-based geriatric best practices (eg, the Institute for Healthcare Improvement Age-Friendly Health System 4M framework [medication, mentation, mobility, what matters]) to prioritize interventions and to design a pathway that incorporates these features; (3) incorporation of comprehensive geriatric assessment by interdisciplinary providers; (4) utilization of validated clinical instruments to assess physical and cognitive functions, frailty, delirium, and social determinants of health; (5) modification of electronic health record systems to encompass order sets that incorporate evidence-based, nonpharmacological and pharmacological interventions to manage symptoms (eg, delirium, pain, bowel movement, sleep, immobility, polypharmacy) essential to quality geriatric care; and (6) integration of patient and caregiver preferences via goals-of-care discussions and corresponding documentation and communication of these goals.
Additionally, these 2 studies imparted some strategies that may facilitate the implementation of interdisciplinary clinical care pathways in trauma care. Examples of such facilitators include: (1) collaboration with champions within each specialty to reinforce education and buy-in; (2) creation of automatically triggered order sets upon patient presentation to the ED that unites distinct features of clinical pathways; (3) adaption and reorganization of existing hospital infrastructures and resources to meet the needs of clinical pathways implementation (eg, utilizing information technology resources to develop electronic health record order sets; using quality department to develop clinical pathway guidelines and electronic outcome dashboards); and (4) development of individualized patient and caregiver education materials based on care needs (eg, principles of delirium prevention and preservation of mobility during hospitalization) to prepare and engage these stakeholders in patient care and recovery.
Practice Points
- A geriatric interdisciplinary care model can be effectively applied to the management of acute trauma in older patients.
- Interdisciplinary clinical pathways should incorporate geriatric best practices and guidelines and age-appropriate order sets to prioritize and integrate care.
—Fred Ko, MD, MS
Study 1 Overview (Park et al)
Objective: To examine whether implementation of a geriatric trauma clinical pathway is associated with reduced rates of delirium in older adults with traumatic injury.
Design: Retrospective case-control study of electronic health records.
Setting and participants: Eligible patients were persons aged 65 years or older who were admitted to the trauma service and did not undergo an operation. A Geriatric Trauma Care Pathway was developed by a multidisciplinary Stanford Quality Pathways team and formally launched on November 1, 2018. The clinical pathway was designed to incorporate geriatric best practices, which included order sets (eg, age-appropriate nonpharmacological interventions and pharmacological dosages), guidelines (eg, Institute for Healthcare Improvement Age-Friendly Health systems 4M framework), automated consultations (comprehensive geriatric assessment), and escalation pathways executed by a multidisciplinary team (eg, pain, bowel, and sleep regulation). The clinical pathway began with admission to the emergency department (ED) (ie, automatic trigger of geriatric trauma care admission order set), daily multidisciplinary team meetings during acute hospitalization, and a transitional care team consultation for postdischarge follow-up or home visit.
Main outcome measures: The primary outcome was delirium as determined by a positive Confusion Assessment Method (CAM) score or a diagnosis of delirium by the clinical team. The secondary outcome was hospital length of stay (LOS). Process measures for pathway compliance (eg, achieving adequate pain control, early mobilization, advance care planning) were assessed. Outcome measures were compared between patients who underwent the Geriatric Trauma Care Pathway intervention (postimplementation group) vs patients who were treated prior to pathway implementation (baseline pre-implementation group).
Main results: Of the 859 eligible patients, 712 were included in the analysis (442 [62.1%] in the baseline pre-implementation group and 270 [37.9%] in the postimplementation group); mean (SD) age was 81.4 (9.1) years, and 394 (55.3%) were women. The injury mechanism was similar between groups, with falls being the most common cause of injury (247 [55.9%] in the baseline group vs 162 [60.0%] in the postimplementation group; P = .43). Injuries as measured by Injury Severity Score (ISS) were minor or moderate in both groups (261 [59.0%] in baseline group vs 168 [62.2%] in postimplementation group; P = .87). The adjusted odds ratio (OR) for delirium in the postimplementation group was lower compared to the baseline pre-implementation group (OR, 0.54; 95% CI, 0.37-0.80; P < .001). Measures of advance care planning in the postimplementation group improved, including more frequent goals-of-care documentation (53.7% in postimplementation group vs 16.7% in baseline group; P < .001) and a shortened time to first goals-of-care discussion upon presenting to the ED (36 hours in postimplementation group vs 50 hours in baseline group; P = .03).
Conclusion: Implementation of a multidisciplinary geriatric trauma clinical pathway for older adults with traumatic injury at a single level I trauma center was associated with reduced rates of delirium.
Study 2 Overview (Bryant et al)
Objective: To determine whether an interdisciplinary care pathway for frail trauma patients can improve in-hospital mortality, complications, and 30-day readmissions.
Design: Retrospective cohort study of frail patients.
Setting and participants: Eligible patients were persons aged 65 years or older who were admitted to the trauma service and survived more than 24 hours; admitted to and discharged from the trauma unit; and determined to be pre-frail or frail by a geriatrician’s assessment. A Frailty Identification and Care Pathway designed to reduce delirium and complications in frail older trauma patients was developed by a multidisciplinary team and implemented in 2016. The standardized evidence-based interdisciplinary care pathway included utilization of order sets and interventions for delirium prevention, early ambulation, bowel and pain regimens, nutrition and physical therapy consults, medication management, care-goal setting, and geriatric assessments.
Main outcome measures: The main outcomes were delirium as determined by a positive CAM score, major complications as defined by the Trauma Quality Improvement Project, in-hospital mortality, and 30-day hospital readmission. Outcome measures were compared between patients who underwent Frailty Identification and Care Pathway intervention (postintervention group) vs patients who were treated prior to pathway implementation (pre-intervention group).
Main results: A total of 269 frail patients were included in the analysis (125 in pre-intervention group vs 144 in postintervention group). Patient demographic and admission characteristics were similar between the 2 groups: mean age was 83.5 (7.1) years, 60.6% were women, and median ISS was 10 (interquartile range [IQR], 9-14). The injury mechanism was similar between groups, with falls accounting for 92.8% and 86.1% of injuries in the pre-intervention and postintervention groups, respectively (P = .07). In univariate analysis, the Frailty Identification and Care Pathway intervention was associated with a significant reduction in delirium (12.5% vs 21.6%, P = .04) and 30-day hospital readmission (2.7% vs 9.6%, P = .01) compared to patients in the pre-intervention group. However, rates of major complications (28.5% vs 28.0%, P = 0.93) and in-hospital mortality (4.2% vs 7.2%, P = .28) were similar between the pre-intervention and postintervention groups. In multivariate logistic regression models adjusted for patient characteristics (age, sex, race, ISS), patients in the postintervention group had lower delirium (OR, 0.44; 95% CI, 0.22-0.88; P = .02) and 30-day hospital readmission (OR, 0.25; 95% CI, 0.07-0.84; P = .02) rates compared to those in the pre-intervention group.
Conclusion: Implementation of an interdisciplinary care protocol for frail geriatric trauma patients significantly decreased their risks for in-hospital delirium and 30-day hospital readmission.
Commentary
Traumatic injuries in older adults are associated with higher morbidity and mortality compared to younger patients, with falls and motor vehicle accidents accounting for a majority of these injuries. Astoundingly, up to one-third of this vulnerable population presenting to hospitals with an ISS greater than 15 may die during hospitalization.1 As a result, a large number of studies and clinical trials have focused on interventions that are designed to reduce fall risks, and hence reduce adverse consequences of traumatic injuries that may arise after falls.2 However, this emphasis on falls prevention has overshadowed a need to develop effective geriatric-centered clinical interventions that aim to improve outcomes in older adults who present to hospitals with traumatic injuries. Furthermore, frailty—a geriatric syndrome indicative of an increased state of vulnerability and predictive of adverse outcomes such as delirium—is highly prevalent in older patients with traumatic injury.3 Thus, there is an urgent need to develop novel, hospital-based, traumatic injury–targeting strategies that incorporate a thoughtful redesign of the care framework that includes evidence-based interventions for geriatric syndromes such as delirium and frailty.
The study reported by Park et al (Study 1) represents the latest effort to evaluate inpatient management strategies designed to improve outcomes in hospitalized older adults who have sustained traumatic injury. Through the implementation of a novel multidisciplinary Geriatric Trauma Care Pathway that incorporates geriatric best practices, this intervention was found to be associated with a 46% lower risk of in-hospital delirium. Because of the inclusion of all age-eligible patients across all strata of traumatic injuries, rather than preselecting for those at the highest risk for poor clinical outcomes, the benefits of this intervention extend to those with minor or moderate injury severity. Furthermore, the improvement in delirium (ie, the primary outcome) is particularly meaningful given that delirium is one of the most common hospital-associated complications that increase hospital LOS, discharge to an institution, and mortality in older adults. Finally, the study’s observed reduced time to a first goals-of-care discussion and increased frequency of goals-of-care documentation after intervention should not be overlooked. The improvements in these 2 process measures are highly significant given that advanced care planning, an intervention that helps to align patients’ values, goals, and treatments, is completed at substantially lower rates in older adults in the acute hospital setting.4
Similarly, in an earlier published study, Bryant and colleagues (Study 2) also show that a geriatric-focused interdisciplinary trauma care pathway is associated with delirium risk reduction in hospitalized older trauma patients. Much like Study 1, the Frailty Identification and Care Pathway utilized in Study 2 is an evidence-based interdisciplinary care pathway that includes the use of geriatric assessments, order sets, and geriatric best practices. Moreover, its exclusive inclusion of pre-frail and frail older patients (ie, those at higher risk for poor outcomes) with moderate injury severity (median ISS of 10 [IQR, 9-14]) suggests that this type of care pathway benefits hospitalized older trauma patients, who are particularly vulnerable to adverse complications such as delirium. Moreover, the successful utilization of the FRAIL questionnaire, a validated frailty screening tool, by surgical residents in the ED to initiate this care pathway demonstrates the feasibility of its use in expediting frailty screening in older patients in trauma care.
Application for Clinical Practice and System Implementation
Findings from the 2 studies discussed in this review indicate that implementation of interdisciplinary clinical care pathways predicated on evidence-based geriatric principles and best practices is a promising approach to reduce delirium in hospitalized older trauma patients. These studies have helped to lay the groundwork in outlining the roadmaps (eg, processes and infrastructures) needed to create such clinical pathways. These key elements include: (1) integration of a multidisciplinary committee (eg, representation from trauma, emergency, and geriatric medicine, nursing, physical and occupational therapy, pharmacy, social work) in pathway design and implementation; (2) adaption of evidence-based geriatric best practices (eg, the Institute for Healthcare Improvement Age-Friendly Health System 4M framework [medication, mentation, mobility, what matters]) to prioritize interventions and to design a pathway that incorporates these features; (3) incorporation of comprehensive geriatric assessment by interdisciplinary providers; (4) utilization of validated clinical instruments to assess physical and cognitive functions, frailty, delirium, and social determinants of health; (5) modification of electronic health record systems to encompass order sets that incorporate evidence-based, nonpharmacological and pharmacological interventions to manage symptoms (eg, delirium, pain, bowel movement, sleep, immobility, polypharmacy) essential to quality geriatric care; and (6) integration of patient and caregiver preferences via goals-of-care discussions and corresponding documentation and communication of these goals.
Additionally, these 2 studies imparted some strategies that may facilitate the implementation of interdisciplinary clinical care pathways in trauma care. Examples of such facilitators include: (1) collaboration with champions within each specialty to reinforce education and buy-in; (2) creation of automatically triggered order sets upon patient presentation to the ED that unites distinct features of clinical pathways; (3) adaption and reorganization of existing hospital infrastructures and resources to meet the needs of clinical pathways implementation (eg, utilizing information technology resources to develop electronic health record order sets; using quality department to develop clinical pathway guidelines and electronic outcome dashboards); and (4) development of individualized patient and caregiver education materials based on care needs (eg, principles of delirium prevention and preservation of mobility during hospitalization) to prepare and engage these stakeholders in patient care and recovery.
Practice Points
- A geriatric interdisciplinary care model can be effectively applied to the management of acute trauma in older patients.
- Interdisciplinary clinical pathways should incorporate geriatric best practices and guidelines and age-appropriate order sets to prioritize and integrate care.
—Fred Ko, MD, MS
1. Hashmi A, Ibrahim-Zada I, Rhee P, et al. Predictors of mortality in geriatric trauma patients: a systematic review and meta-analysis. J Trauma Acute Care Surg. 2014;76(3):894-901. doi:10.1097/TA.0b013e3182ab0763
2. Hopewell S, Adedire O, Copsey BJ, et al. Multifactorial and multiple component interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev. 2018;7(7):CD012221. doi:10.1002/14651858.CD012221.pub2
3. Joseph B, Pandit V, Zangbar B, et al. Superiority of frailty over age in predicting outcomes among geriatric trauma patients: a prospective analysis. JAMA Surg. 2014;149(8):766-772. doi:10.1001/jamasurg.2014.296
4. Hopkins SA, Bentley A, Phillips V, Barclay S. Advance care plans and hospitalized frail older adults: a systematic review. BMJ Support Palliat Care. 2020;10(2):164-174. doi:10.1136/bmjspcare-2019-002093
1. Hashmi A, Ibrahim-Zada I, Rhee P, et al. Predictors of mortality in geriatric trauma patients: a systematic review and meta-analysis. J Trauma Acute Care Surg. 2014;76(3):894-901. doi:10.1097/TA.0b013e3182ab0763
2. Hopewell S, Adedire O, Copsey BJ, et al. Multifactorial and multiple component interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev. 2018;7(7):CD012221. doi:10.1002/14651858.CD012221.pub2
3. Joseph B, Pandit V, Zangbar B, et al. Superiority of frailty over age in predicting outcomes among geriatric trauma patients: a prospective analysis. JAMA Surg. 2014;149(8):766-772. doi:10.1001/jamasurg.2014.296
4. Hopkins SA, Bentley A, Phillips V, Barclay S. Advance care plans and hospitalized frail older adults: a systematic review. BMJ Support Palliat Care. 2020;10(2):164-174. doi:10.1136/bmjspcare-2019-002093
Novel guidance informs plasma biomarker use for Alzheimer’s disease
SAN DIEGO – The organization has previously published recommendations for use of amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease.
The recommendations were the subject of a presentation at the 2022 Alzheimer’s Association International Conference and were published online in Alzheimer’s & Dementia.
During his presentation, Oskar Hansson, MD, PhD, stressed that the document describes recommendations, not criteria, for use of blood-based biomarkers. He suggested that the recommendations will need to be updated within 9-12 months, and that criteria for blood-based biomarkers use could come within 2 years.
The new recommendations reflect the recent acceleration of progress in the field, according to Wiesje M. van der Flier, PhD, who moderated the session. “It’s just growing so quickly. I think within 5 years the whole field will have transformed. By starting to use them in specialized memory clinics first, but then also local memory clinics, and then finally, I think that they may also transform primary care,” said Dr. van der Flier, who is a professor of neurology at Amsterdam University Medical Center.
Guidance for clinical trials and memory clinics
The guidelines were created in part because blood-based biomarkers for Alzheimer’s disease have become increasingly available, and there has been a call from the community for guidance, according to Dr. Hansson. There is also a hazard that widespread adoption could interfere with the field itself, especially if physicians don’t understand how to interpret the results. That’s a particularly acute problem since Alzheimer’s disease pathology can precede symptoms. “It’s important to have some guidance about regulating their use so we don’t get the problem that they are misused and get a bad reputation,” said Dr. Hansson in an interview.
The current recommendations are for use in clinical trials to identify patients likely to have Alzheimer’s disease, as well as in memory clinics, though “we’re still a bit cautious. We still need to confirm it with other biomarkers. The reason for that is we still don’t know how these will perform in the clinical reality. So it’s a bit trying it out. You can start using these blood biomarkers to some degree,” said Dr. Hansson.
However, he offered the caveat that plasma-based biomarkers should only be used while confirming that the blood-based biomarkers agree with CSF tests, ideally more than 90% of the time. “If suddenly only 60% of the plasma biomarkers agree with CSF, you have a problem and you need to stop,” said Dr. Hansson.
The authors recommend that blood-based biomarkers be used in clinical trials to help select patients and identify healthy controls. Dr. Hansson said that there is not enough evidence that blood-based biomarkers have sufficient positive predictive value to be used as the sole criteria for clinical trial admission. However, they could also be used to inform decision-making in adaptive clinical trials.
Specifically, plasma Abeta42/Abeta40 and P-tau assays using established thresholds can be used in clinical studies first-screening step for clinical trials, though they should be confirmed by PET or CSF in those with abnormal blood biomarker levels. The biomarkers could also be used in non–Alzheimer’s disease clinical trials to exclude patients with probable Alzheimer’s disease copathology.
In memory clinics, the authors recommend that BBMs be used only in patients who are symptomatic and, when possible, should be confirmed by PET or CSF.
More work to be done
Dr. Hansson noted that 50%-70% of patients with Alzheimer’s disease are misdiagnosed in primary care, showing a clear need for biomarkers that could improve diagnosis. However, he stressed that blood-based biomarkers are not yet ready for use in that setting.
Still, they could eventually become a boon. “The majority of patients now do not get any biomarker support to diagnosis. They do not have access to amyloid PET or [CSF] biomarkers, but when the blood-based biomarkers are good enough, that means that biomarker support for an Alzheimer’s diagnosis [will be] available to many patients … across the globe,” said Dr. van der Flier.
There are numerous research efforts underway to validate blood-based biomarkers in more diverse groups of patients. That’s because the retrospective studies typically used to identify and validate biomarkers tend to recruit carefully selected patients, with clearly defined cases and good CSF characterization, according to Charlotte Teunissen, PhD, who is also a coauthor of the guidelines and professor of neuropsychiatry at Amsterdam University Medical Center. “Now we want to go one step further to go real-life practice, and there are several initiatives,” she said.
Dr. Hansson, Dr. Tenuissen, and Dr. van der Flier have no relevant financial disclosures.
SAN DIEGO – The organization has previously published recommendations for use of amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease.
The recommendations were the subject of a presentation at the 2022 Alzheimer’s Association International Conference and were published online in Alzheimer’s & Dementia.
During his presentation, Oskar Hansson, MD, PhD, stressed that the document describes recommendations, not criteria, for use of blood-based biomarkers. He suggested that the recommendations will need to be updated within 9-12 months, and that criteria for blood-based biomarkers use could come within 2 years.
The new recommendations reflect the recent acceleration of progress in the field, according to Wiesje M. van der Flier, PhD, who moderated the session. “It’s just growing so quickly. I think within 5 years the whole field will have transformed. By starting to use them in specialized memory clinics first, but then also local memory clinics, and then finally, I think that they may also transform primary care,” said Dr. van der Flier, who is a professor of neurology at Amsterdam University Medical Center.
Guidance for clinical trials and memory clinics
The guidelines were created in part because blood-based biomarkers for Alzheimer’s disease have become increasingly available, and there has been a call from the community for guidance, according to Dr. Hansson. There is also a hazard that widespread adoption could interfere with the field itself, especially if physicians don’t understand how to interpret the results. That’s a particularly acute problem since Alzheimer’s disease pathology can precede symptoms. “It’s important to have some guidance about regulating their use so we don’t get the problem that they are misused and get a bad reputation,” said Dr. Hansson in an interview.
The current recommendations are for use in clinical trials to identify patients likely to have Alzheimer’s disease, as well as in memory clinics, though “we’re still a bit cautious. We still need to confirm it with other biomarkers. The reason for that is we still don’t know how these will perform in the clinical reality. So it’s a bit trying it out. You can start using these blood biomarkers to some degree,” said Dr. Hansson.
However, he offered the caveat that plasma-based biomarkers should only be used while confirming that the blood-based biomarkers agree with CSF tests, ideally more than 90% of the time. “If suddenly only 60% of the plasma biomarkers agree with CSF, you have a problem and you need to stop,” said Dr. Hansson.
The authors recommend that blood-based biomarkers be used in clinical trials to help select patients and identify healthy controls. Dr. Hansson said that there is not enough evidence that blood-based biomarkers have sufficient positive predictive value to be used as the sole criteria for clinical trial admission. However, they could also be used to inform decision-making in adaptive clinical trials.
Specifically, plasma Abeta42/Abeta40 and P-tau assays using established thresholds can be used in clinical studies first-screening step for clinical trials, though they should be confirmed by PET or CSF in those with abnormal blood biomarker levels. The biomarkers could also be used in non–Alzheimer’s disease clinical trials to exclude patients with probable Alzheimer’s disease copathology.
In memory clinics, the authors recommend that BBMs be used only in patients who are symptomatic and, when possible, should be confirmed by PET or CSF.
More work to be done
Dr. Hansson noted that 50%-70% of patients with Alzheimer’s disease are misdiagnosed in primary care, showing a clear need for biomarkers that could improve diagnosis. However, he stressed that blood-based biomarkers are not yet ready for use in that setting.
Still, they could eventually become a boon. “The majority of patients now do not get any biomarker support to diagnosis. They do not have access to amyloid PET or [CSF] biomarkers, but when the blood-based biomarkers are good enough, that means that biomarker support for an Alzheimer’s diagnosis [will be] available to many patients … across the globe,” said Dr. van der Flier.
There are numerous research efforts underway to validate blood-based biomarkers in more diverse groups of patients. That’s because the retrospective studies typically used to identify and validate biomarkers tend to recruit carefully selected patients, with clearly defined cases and good CSF characterization, according to Charlotte Teunissen, PhD, who is also a coauthor of the guidelines and professor of neuropsychiatry at Amsterdam University Medical Center. “Now we want to go one step further to go real-life practice, and there are several initiatives,” she said.
Dr. Hansson, Dr. Tenuissen, and Dr. van der Flier have no relevant financial disclosures.
SAN DIEGO – The organization has previously published recommendations for use of amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease.
The recommendations were the subject of a presentation at the 2022 Alzheimer’s Association International Conference and were published online in Alzheimer’s & Dementia.
During his presentation, Oskar Hansson, MD, PhD, stressed that the document describes recommendations, not criteria, for use of blood-based biomarkers. He suggested that the recommendations will need to be updated within 9-12 months, and that criteria for blood-based biomarkers use could come within 2 years.
The new recommendations reflect the recent acceleration of progress in the field, according to Wiesje M. van der Flier, PhD, who moderated the session. “It’s just growing so quickly. I think within 5 years the whole field will have transformed. By starting to use them in specialized memory clinics first, but then also local memory clinics, and then finally, I think that they may also transform primary care,” said Dr. van der Flier, who is a professor of neurology at Amsterdam University Medical Center.
Guidance for clinical trials and memory clinics
The guidelines were created in part because blood-based biomarkers for Alzheimer’s disease have become increasingly available, and there has been a call from the community for guidance, according to Dr. Hansson. There is also a hazard that widespread adoption could interfere with the field itself, especially if physicians don’t understand how to interpret the results. That’s a particularly acute problem since Alzheimer’s disease pathology can precede symptoms. “It’s important to have some guidance about regulating their use so we don’t get the problem that they are misused and get a bad reputation,” said Dr. Hansson in an interview.
The current recommendations are for use in clinical trials to identify patients likely to have Alzheimer’s disease, as well as in memory clinics, though “we’re still a bit cautious. We still need to confirm it with other biomarkers. The reason for that is we still don’t know how these will perform in the clinical reality. So it’s a bit trying it out. You can start using these blood biomarkers to some degree,” said Dr. Hansson.
However, he offered the caveat that plasma-based biomarkers should only be used while confirming that the blood-based biomarkers agree with CSF tests, ideally more than 90% of the time. “If suddenly only 60% of the plasma biomarkers agree with CSF, you have a problem and you need to stop,” said Dr. Hansson.
The authors recommend that blood-based biomarkers be used in clinical trials to help select patients and identify healthy controls. Dr. Hansson said that there is not enough evidence that blood-based biomarkers have sufficient positive predictive value to be used as the sole criteria for clinical trial admission. However, they could also be used to inform decision-making in adaptive clinical trials.
Specifically, plasma Abeta42/Abeta40 and P-tau assays using established thresholds can be used in clinical studies first-screening step for clinical trials, though they should be confirmed by PET or CSF in those with abnormal blood biomarker levels. The biomarkers could also be used in non–Alzheimer’s disease clinical trials to exclude patients with probable Alzheimer’s disease copathology.
In memory clinics, the authors recommend that BBMs be used only in patients who are symptomatic and, when possible, should be confirmed by PET or CSF.
More work to be done
Dr. Hansson noted that 50%-70% of patients with Alzheimer’s disease are misdiagnosed in primary care, showing a clear need for biomarkers that could improve diagnosis. However, he stressed that blood-based biomarkers are not yet ready for use in that setting.
Still, they could eventually become a boon. “The majority of patients now do not get any biomarker support to diagnosis. They do not have access to amyloid PET or [CSF] biomarkers, but when the blood-based biomarkers are good enough, that means that biomarker support for an Alzheimer’s diagnosis [will be] available to many patients … across the globe,” said Dr. van der Flier.
There are numerous research efforts underway to validate blood-based biomarkers in more diverse groups of patients. That’s because the retrospective studies typically used to identify and validate biomarkers tend to recruit carefully selected patients, with clearly defined cases and good CSF characterization, according to Charlotte Teunissen, PhD, who is also a coauthor of the guidelines and professor of neuropsychiatry at Amsterdam University Medical Center. “Now we want to go one step further to go real-life practice, and there are several initiatives,” she said.
Dr. Hansson, Dr. Tenuissen, and Dr. van der Flier have no relevant financial disclosures.
FROM AAIC 2022
ICU stays linked to a doubling of dementia risk
compared with older adults who have never stayed in the ICU, new research suggests.
“ICU hospitalization may be an underrecognized risk factor for dementia in older adults,” Bryan D. James, PhD, epidemiologist with Rush Alzheimer’s Disease Center, Chicago, said in an interview.
“Health care providers caring for older patients who have experienced a hospitalization for critical illness should be prepared to assess and monitor their patients’ cognitive status as part of their long-term care plan,” Dr. James added.
The findings were presented at the Alzheimer’s Association International Conference.
Hidden risk factor?
ICU hospitalization as a result of critical illness has been linked to subsequent cognitive impairment in older patients. However, how ICU hospitalization relates to the long-term risk of developing Alzheimer’s and other age-related dementias is unknown.
“Given the high rate of ICU hospitalization in older persons, especially during the COVID-19 pandemic, it is critical to explore this relationship, Dr. James said.
The Rush team assessed the impact of an ICU stay on dementia risk in 3,822 older adults (mean age, 77 years) without known dementia at baseline participating in five diverse epidemiologic cohorts.
Participants were checked annually for development of Alzheimer’s and all-type dementia using standardized cognitive assessments.
Over an average of 7.8 years, 1,991 (52%) adults had at least one ICU stay; 1,031 (27%) had an ICU stay before study enrollment; and 961 (25%) had an ICU stay during the study period.
In models adjusted for age, sex, education, and race, ICU hospitalization was associated with 63% higher risk of Alzheimer’s dementia (hazard ratio, 1.63; 95% confidence interval, 1.41-1.88) and 71% higher risk of all-type dementia (HR, 1.71; 95% CI, 1.48-1.97).
In models further adjusted for other health factors such as vascular risk factors and disease, other chronic medical conditions and functional disabilities, the association was even stronger: ICU hospitalization was associated with roughly double the risk of Alzheimer’s dementia (HR 2.10; 95% CI, 1.66-2.65) and all-type dementia (HR, 2.20; 95% CI, 1.75-2.77).
Dr. James said in an interview that it remains unclear why an ICU stay may raise the dementia risk.
“This study was not designed to assess the causes of the higher risk of dementia in persons who had ICU hospitalizations. However, researchers have looked into a number of factors that could account for this increased risk,” he explained.
One is critical illness itself that leads to hospitalization, which could result in damage to the brain; for example, severe COVID-19 has been shown to directly harm the brain, Dr. James said.
He also noted that specific events experienced during ICU stay have been shown to increase risk for cognitive impairment, including infection and severe sepsis, acute dialysis, neurologic dysfunction and delirium, and sedation.
Important work
Commenting on the study, Heather Snyder, PhD, vice president of medical & scientific relations at the Alzheimer’s Association, said what’s interesting about the study is that it looks at individuals in the ICU, regardless of the cause.
“The study shows that having some type of health issue that results in some type of ICU stay is associated with an increased risk of declining cognition,” Dr. Snyder said.
“That’s really important,” she said, “especially given the increase in individuals, particularly those 60 and older, who did experience an ICU stay over the last couple of years and understanding how that might impact their long-term risk related to Alzheimer’s and other changes in memory.”
“If an individual has been in the ICU, that should be part of the conversation with their physician or health care provider,” Dr. Snyder advised.
The study was funded by the National Institute on Aging. Dr. James and Dr. Snyder disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
compared with older adults who have never stayed in the ICU, new research suggests.
“ICU hospitalization may be an underrecognized risk factor for dementia in older adults,” Bryan D. James, PhD, epidemiologist with Rush Alzheimer’s Disease Center, Chicago, said in an interview.
“Health care providers caring for older patients who have experienced a hospitalization for critical illness should be prepared to assess and monitor their patients’ cognitive status as part of their long-term care plan,” Dr. James added.
The findings were presented at the Alzheimer’s Association International Conference.
Hidden risk factor?
ICU hospitalization as a result of critical illness has been linked to subsequent cognitive impairment in older patients. However, how ICU hospitalization relates to the long-term risk of developing Alzheimer’s and other age-related dementias is unknown.
“Given the high rate of ICU hospitalization in older persons, especially during the COVID-19 pandemic, it is critical to explore this relationship, Dr. James said.
The Rush team assessed the impact of an ICU stay on dementia risk in 3,822 older adults (mean age, 77 years) without known dementia at baseline participating in five diverse epidemiologic cohorts.
Participants were checked annually for development of Alzheimer’s and all-type dementia using standardized cognitive assessments.
Over an average of 7.8 years, 1,991 (52%) adults had at least one ICU stay; 1,031 (27%) had an ICU stay before study enrollment; and 961 (25%) had an ICU stay during the study period.
In models adjusted for age, sex, education, and race, ICU hospitalization was associated with 63% higher risk of Alzheimer’s dementia (hazard ratio, 1.63; 95% confidence interval, 1.41-1.88) and 71% higher risk of all-type dementia (HR, 1.71; 95% CI, 1.48-1.97).
In models further adjusted for other health factors such as vascular risk factors and disease, other chronic medical conditions and functional disabilities, the association was even stronger: ICU hospitalization was associated with roughly double the risk of Alzheimer’s dementia (HR 2.10; 95% CI, 1.66-2.65) and all-type dementia (HR, 2.20; 95% CI, 1.75-2.77).
Dr. James said in an interview that it remains unclear why an ICU stay may raise the dementia risk.
“This study was not designed to assess the causes of the higher risk of dementia in persons who had ICU hospitalizations. However, researchers have looked into a number of factors that could account for this increased risk,” he explained.
One is critical illness itself that leads to hospitalization, which could result in damage to the brain; for example, severe COVID-19 has been shown to directly harm the brain, Dr. James said.
He also noted that specific events experienced during ICU stay have been shown to increase risk for cognitive impairment, including infection and severe sepsis, acute dialysis, neurologic dysfunction and delirium, and sedation.
Important work
Commenting on the study, Heather Snyder, PhD, vice president of medical & scientific relations at the Alzheimer’s Association, said what’s interesting about the study is that it looks at individuals in the ICU, regardless of the cause.
“The study shows that having some type of health issue that results in some type of ICU stay is associated with an increased risk of declining cognition,” Dr. Snyder said.
“That’s really important,” she said, “especially given the increase in individuals, particularly those 60 and older, who did experience an ICU stay over the last couple of years and understanding how that might impact their long-term risk related to Alzheimer’s and other changes in memory.”
“If an individual has been in the ICU, that should be part of the conversation with their physician or health care provider,” Dr. Snyder advised.
The study was funded by the National Institute on Aging. Dr. James and Dr. Snyder disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
compared with older adults who have never stayed in the ICU, new research suggests.
“ICU hospitalization may be an underrecognized risk factor for dementia in older adults,” Bryan D. James, PhD, epidemiologist with Rush Alzheimer’s Disease Center, Chicago, said in an interview.
“Health care providers caring for older patients who have experienced a hospitalization for critical illness should be prepared to assess and monitor their patients’ cognitive status as part of their long-term care plan,” Dr. James added.
The findings were presented at the Alzheimer’s Association International Conference.
Hidden risk factor?
ICU hospitalization as a result of critical illness has been linked to subsequent cognitive impairment in older patients. However, how ICU hospitalization relates to the long-term risk of developing Alzheimer’s and other age-related dementias is unknown.
“Given the high rate of ICU hospitalization in older persons, especially during the COVID-19 pandemic, it is critical to explore this relationship, Dr. James said.
The Rush team assessed the impact of an ICU stay on dementia risk in 3,822 older adults (mean age, 77 years) without known dementia at baseline participating in five diverse epidemiologic cohorts.
Participants were checked annually for development of Alzheimer’s and all-type dementia using standardized cognitive assessments.
Over an average of 7.8 years, 1,991 (52%) adults had at least one ICU stay; 1,031 (27%) had an ICU stay before study enrollment; and 961 (25%) had an ICU stay during the study period.
In models adjusted for age, sex, education, and race, ICU hospitalization was associated with 63% higher risk of Alzheimer’s dementia (hazard ratio, 1.63; 95% confidence interval, 1.41-1.88) and 71% higher risk of all-type dementia (HR, 1.71; 95% CI, 1.48-1.97).
In models further adjusted for other health factors such as vascular risk factors and disease, other chronic medical conditions and functional disabilities, the association was even stronger: ICU hospitalization was associated with roughly double the risk of Alzheimer’s dementia (HR 2.10; 95% CI, 1.66-2.65) and all-type dementia (HR, 2.20; 95% CI, 1.75-2.77).
Dr. James said in an interview that it remains unclear why an ICU stay may raise the dementia risk.
“This study was not designed to assess the causes of the higher risk of dementia in persons who had ICU hospitalizations. However, researchers have looked into a number of factors that could account for this increased risk,” he explained.
One is critical illness itself that leads to hospitalization, which could result in damage to the brain; for example, severe COVID-19 has been shown to directly harm the brain, Dr. James said.
He also noted that specific events experienced during ICU stay have been shown to increase risk for cognitive impairment, including infection and severe sepsis, acute dialysis, neurologic dysfunction and delirium, and sedation.
Important work
Commenting on the study, Heather Snyder, PhD, vice president of medical & scientific relations at the Alzheimer’s Association, said what’s interesting about the study is that it looks at individuals in the ICU, regardless of the cause.
“The study shows that having some type of health issue that results in some type of ICU stay is associated with an increased risk of declining cognition,” Dr. Snyder said.
“That’s really important,” she said, “especially given the increase in individuals, particularly those 60 and older, who did experience an ICU stay over the last couple of years and understanding how that might impact their long-term risk related to Alzheimer’s and other changes in memory.”
“If an individual has been in the ICU, that should be part of the conversation with their physician or health care provider,” Dr. Snyder advised.
The study was funded by the National Institute on Aging. Dr. James and Dr. Snyder disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AAIC 2022
Is it psychosis, or an autoimmune encephalitis?
Hidden within routine presentations of first-episode psychosis is a rare subpopulation whose symptoms are mediated by an autoimmune process for which proper treatment differs significantly from standard care for typical psychotic illness. In this article, we present a hypothetical case and describe how to assess if a patient has an elevated probability of autoimmune encephalitis, determine what diagnostics or medication-induced effects to consider, and identify unresolved questions about best practices.
CASE REPORT
Bizarre behavior and isolation
Ms. L, age 21, is brought to the emergency department (ED) by her college roommate after exhibiting out-of-character behavior and gradual self-isolation over the last 2 months. Her roommate noticed that she had been spending more time isolated in her dorm room and remaining in bed into the early afternoon, though she does not appear to be asleep. Ms. L’s mother is concerned about her daughter’s uncharacteristic refusal to travel home for a family event. Ms. L expresses concern about the intentions of her research preceptor, and recalls messages from the association of colleges telling her to “change her future.” Ms. L hears voices telling her who she can and cannot trust. In the ED, she says she has a headache, experiences mild dizziness while standing, and reports having a brief upper respiratory illness at the end of last semester. Otherwise, a medical review of systems is negative.
Although the etiology of first-episode psychosis can be numerous or unknown, many psychiatrists feel comfortable with the initial diagnostic for this type of clinical presentation. However, for some clinicians, it may be challenging to feel confident in making a diagnosis of autoimmune encephalitis.
Autoimmune encephalitis is a family of syndromes caused by autoantibodies targeting either intracellular or extracellular neuronal antigens. Anti-N-methyl-
In this article, we focus on anti-NMDA receptor encephalitis and use the term interchangeably with autoimmune encephalitis for 2 reasons. First, anti-NMDA receptor encephalitis can present with psychotic symptoms as the only symptoms (prior to cognitive or neurologic manifestations) or can present with psychotic symptoms as the main indicator (with other symptoms that are more subtle and possibly missed). Second, anti-NMDA receptor encephalitis often occurs in young adults, which is when it is common to see the onset of a primary psychotic illness. These 2 factors make it likely that these cases will come into the evaluative sphere of psychiatrists. We give special attention to features of cases of anti-NMDA receptor encephalitis confirmed with antineuronal antibodies in the CSF, as it has emerged that antibodies in the serum can be nonspecific and nonpathogenic.2,3
What does anti-NMDA receptor encephalitis look like?
Symptoms of anti-NMDA receptor encephalitis resemble those of a primary psychotic disorder, which can make it challenging to differentiate between the 2 conditions, and might cause the correct diagnosis to be missed. Pollak et al4 proposed that psychiatrically confusing presentations that don’t clearly match an identifiable psychotic disorder should raise a red flag for an autoimmune etiology. However, studies often fail to describe the specific psychiatric features of anti-NMDA receptor encephalitis, and thus provide little practical evidence to guide diagnosis. In some of the largest studies of patients with anti-NMDA receptor encephalitis, psychiatric clinical findings are often combined into nonspecific headings such as “abnormal behavior” or “behavioral and cognitive” symptoms.5 Such groupings make this the most common clinical finding (95%)5 but make it difficult to discern particular clinical characteristics. Where available, specific symptoms identified across studies include agitation, aggression, changes in mood and/or irritability, insomnia, delusions, hallucinations, and occasionally catatonic features.6,7 Attempts to identify specific psychiatric phenotypes distinct from primary psychotic illnesses have fallen short due to contradictory findings and lack of clinical practicality.8 One exception is the presence of catatonic features, which have been found in CSF-confirmed studies.2 In contrast to the typical teaching that the hallucination modality (eg, visual or tactile) can be helpful in estimating the likelihood of a secondary psychosis (ie, drug-induced, neurodegenerative, or autoimmune), there does not appear to be a difference in hallucination modality between encephalitis and primary psychotic disorders.9
History and review of systems
Another red flag to consider is the rapidity of symptom presentation. Symptoms that progress within 3 months increase the likelihood that the patient has autoimmune encephalitis.10 Cases where collateral information indicates the psychotic episode was preceded by a long, subtle decline in school performance, social withdrawal, and attenuated psychotic symptoms typical of a schizophrenia prodrome are less likely to be an autoimmune psychosis.11 A more delayed presentation does not entirely exclude autoimmune encephalitis; however, a viral-like prodrome before the onset of psychosis increases the likelihood of autoimmune encephalitis. Such a prodrome may include fever, headache, nausea, vomiting, and diarrhea.7
Continue to: Another indication is the presence...
Another indication is the presence of new seizures within 1 year of presenting with psychotic symptoms.10 The possibility of undiagnosed seizures should be considered in a patient with psychosis who has episodes of unresponsiveness, dissociative episodes, or seizure-like activity that is thought to be psychogenic but has not been fully evaluated. Seizures in autoimmune encephalitis involve deep structures in the brain and can be present without overt epileptiform activity on EEG, but rather causing only bilateral slowing that is often described as nonspecific.12
In a young patient presenting with first-episode psychosis, a recent diagnosis of cancer or abnormal finding in the ovaries increases the likelihood of autoimmune encephalitis.4 Historically, however, this type of medical history has been irrelevant to psychosis. Although rare, any person presenting with first-episode psychosis and a history of herpes simplex virus (HSV) encephalitis should be evaluated for autoimmune encephalitis because anti-NMDA receptor antibodies have been reported to be present in approximately one-third of these patients.13 Finally, the report of focal neurologic symptoms, including neck stiffness or neck pain, should raise concern, although sensory, working memory, and cognitive deficits may be difficult to fully distinguish from common somatic and cognitive symptoms in a primary psychiatric presentation.
Table 1 lists 4 questions to ask patients who present with first-episode psychosis that may not usually be part of a typical evaluation.
CASE CONTINUED
Uncooperative with examination
In the ED, Ms. L’s heart rate is 101 beats per minute and her blood pressure is 102/72 mm Hg. Her body mass index (BMI) is 22, which suggests an approximate 8-pound weight loss since her BMI was last assessed. Ms. L responds to questions with 1- to 6-word sentences, without clear verbigeration. Though her speech is not pressured, it is of increased rate. Her gaze scans the room, occasionally becoming fixed for 5 to 10 seconds but is aborted by the interviewer’s comment on this behavior. Ms. L efficiently and accurately spells WORLD backwards, then asks “Why?” and refuses to engage in further cognitive testing, stating “Not doing that.” When the interviewer asks “Why not?” she responds “Not doing that.” Her cranial nerves are intact, and she refuses cerebellar testing or requests to assess tone. There are no observed stereotypies, posturing, or echopraxia.
While not necessary for a diagnosis of autoimmune encephalitis, short-term memory loss is a common cognitive finding across studies.5-7 A common clinical finding from a mental status exam is speech disorders, including (but not limited to) increased rates of speech or decreased verbal output.7 Autonomic instability—including tachycardia, markedly labile blood pressures, and orthostasis—all increase the likelihood of autoimmune encephalitis.14 Interpreting a patient’s vital sign changes can be confounded if they are agitated or anxious, or if they are taking an antipsychotic that produces adverse anticholinergic effects. However, vital sign abnormalities that precede medication administration or do not correlate with fluctuations in mental status increase suspicion for an autoimmune encephalitis.
Continue to: In the absence of the adverse effect...
In the absence of the adverse effect of a medication, orthostasis is uncommon in a well-hydrated young person. Some guidelines4 suggest that symptoms of catatonia should be considered a red flag for autoimmune encephalitis. According to the Bush-Francis Catatonia Rating Scale, commonly identified features include immobility, staring, mutism, posturing, withdrawal, rigidity, and gegenhalten.15 Catatonia is common among patients with anti-NDMA receptor encephalitis, though it may not be initially present and could emerge later.2 However, there are documented cases of autoimmune encephalitis where the patient had only isolated features of catatonia, such as echolalia or mutism.2
CASE CONTINUED
History helps narrow the diagnosis
Ms. L’s parents say their daughter has not had prior contact with a therapist or psychiatrist, previous psychiatric diagnoses, hospitalizations, suicide attempts, self-injury, or binging or purging behaviors. Ms. L’s paternal grandfather was diagnosed with schizophrenia, but he is currently employed, lives alone, and has not taken medication for many years. Her mother has hypothyroidism. Ms. L was born at full term via vaginal delivery without cardiac defects or a neonatal intensive care unit stay. Her mother said she did not have postpartum depression or anxiety, a complicated pregnancy, or exposure to tobacco, alcohol, or illicit drug use. Ms. L has no history of childhood seizures or head injury with loss of consciousness. She is an only child, born and raised in a house in a metropolitan area, walked at 13 months, did not require early intervention or speech therapy, and met normal language milestones.
She attended kindergarten at age 6 and progressed throughout public school without regressions in reading, writing, or behavioral manifestations, and did not require a 504 Plan or individualized education program. Ms. L graduated high school in the top 30% of her class, was socially active, and attended a local college. In college, she achieved honor roll, enrolled in a sorority, and was a part of a research lab. Her only medication is oral contraception. She consumes alcohol socially, and reports no cannabis, cigarette, or vaping use. Ms. L says she does not use hallucinogens, stimulants, opiates, or cocaine, and her roommate and family confirm this. She denies recent travel and is sexually active. Ms. L’s urinary and serum toxicology are unremarkable, human chorionic gonadotropin is undetectable, and her sodium level is 133 mEq/L. A measure of serum neutrophils is 6.8 x 109/L and serum lymphocytes is 1.7 x 109/L. Her parents adamantly request a Neurology consultation and further workup, including a lumbar puncture (LP), EEG, and brain imaging (MRI).
This information is useful in ruling out other potential causes of psychosis, such as substance-induced psychosis and neurodevelopmental disorders that can present with psychosis. Additionally, neurodevelopmental abnormalities and psychiatric prodromal symptoms are known precedents in individuals who develop a primary psychotic disorder such as schizophrenia.16 A family history that includes a psychotic illness may increase the likelihood of a primary psychotic disorder in offspring; however, clinicians must also consider the accuracy of diagnosis in the family, as this can often be inaccurate or influenced by historical cultural bias. We recommend further elucidating the likelihood of a genetic predisposition to a primary psychotic disorder by clarifying familial medication history and functionality.
For example, the fact that Ms. L’s grandfather has not taken medication for many years and has a high degree of functioning and/or absence of cognitive deficits would lower our suspicion for an accurate diagnosis of schizophrenia (given the typical cognitive decline with untreated illness). Another piece of family history relevant to autoimmune encephalitis includes the propensity for autoimmune disorders, but expert opinion on this matter is mixed.17 Ms. L’s mother has hypothyroidism, which is commonly caused by a prior episode of Hashimoto’s autoimmune thyroiditis. Some physicians advocate for measuring antithyroid antibodies and erythrocyte sedimentation rate or C-reactive protein to gauge the level of autoimmunity, but the usefulness of these measures for detecting autoimmune encephalitis is unclear. These serum markers can be useful in detecting additional important etiologies such as systemic infection or systemic inflammation, and there are conditions such as steroid-responsive encephalopathy with associated thyroiditis, which, as the name suggests, responds to steroids rather than other psychotropic medications. Other risk factors for autoimmune encephalitis include being female, being young, having viral infections (eg, HSV), prior tumor burden, and being in the postpartum period.18 Some experts also suggest the presence of neurologic symptoms 4 weeks after the first psychiatric or cognitive symptom presentation increases the likelihood of anti-NMDA receptor encephalitis, and a lack of neurologic symptoms would make this diagnosis less likely.6,19
Continue to: Another item of interest...
Another item of interest in Ms. L’s case is her parents’ request for a Neurology consultation and further workup, as there is an association between caregiver request for workup and eventual diagnosis.6 While the etiology of this phenomenon is unclear, the literature suggests individuals with autoimmune encephalitis who initially present to Psychiatry experience longer delays to the appropriate treatment with immunomodulatory therapy than those who first present to Neurology.20
Laboratory and diagnostic testing
Guasp et al2 recommend EEG, MRI, and serum autoimmune antibodies (ie, screening for anti-NMDA receptor antibodies) for patients who present with first-episode psychosis, even in the absence of some of the red flags previously discussed. A recent economic analysis suggested screening all patients with first-episode psychosis for serum antibodies may be cost-effective.21
For patients whose presentations include features concerning for anti-NMDA receptor encephalitis, an EEG and MRI are reasonable. In a review of EEG abnormalities in anti-NMDA receptor encephalitis, Gillinder et al23 noted that while 30% did not have initial findings, 83.6% of those with confirmed anti-NMDA receptor encephalitis demonstrated EEG abnormalities; the most common were generalized slowing, delta slowing, and focal abnormalities. Discovering an extreme delta-brush activity on EEG is specific for anti-NMDA receptor encephalitis, but its absence is not fully informative. Practically, slowing can be a nonspecific manifestation of encephalopathy or a medication effect, and many people who present with first-episode psychosis will have recently received antipsychotics, which alter EEG frequency. In a study of EEG changes with antipsychotics, Centorrino et al24 found that generalized background slowing into the theta range across all antipsychotics was not significantly different from control participants, while theta to delta range slowing occurred in 8.2% of those receiving antipsychotics vs 3.3% of controls. Clozapine and olanzapine may be associated with greater EEG abnormalities, while haloperidol and quetiapine contribute a lower risk.25 For young patients with first-episode psychosis without a clear alternative explanation, we advocate for further autoimmune encephalitis workup among all individuals with generalized theta or delta wave slowing.
Because these medication effects are most likely to decrease specificity but not sensitivity of EEG for autoimmune encephalitis, a normal EEG without slowing can be reassuring.26 Moreover, for patients who receive neuroimaging, an MRI may detect inflammation that is not visible on CT. The concerning findings for anti-NMDA receptor encephalitis are temporal or multifocal T2 hyperintensities, though the MRI is normal in most cases and thus should not be reassuring if other concerning features are present.27
The role of lumbar puncture
Another area of active debate surrounds the usefulness and timing of LP. Guasp et al2 proposed that all individuals with first-episode psychosis and focal neurologic findings should receive LP and CSF antineuronal antibody testing. They recommend that patients with first-episode psychosis without focal neurologic findings also should receive LP and CSF testing if ≥1 of the following is present:
- slowing on EEG
- temporal or multifocal T2 hyperintensities on MRI
- positive anti-NMDA receptor antibody in the serum.2
Continue to: Evidence suggests that basic CSF parameters...
Evidence suggests that basic CSF parameters, such as elevated protein and white blood cell counts, are some of the most sensitive and specific tests for autoimmune encephalitis.2 Thus, if the patient is amenable and logistical factors are in place, it may be reasonable to pursue LP earlier in some cases without waiting for serum antibody assays to return (these results can take several weeks). CSF inflammatory changes without neuronal antibodies should lead to other diagnostic considerations (eg, systemic inflammatory disease, psychosis attributed to systemic lupus erythematosus).7 While nonspecific, serum laboratory values that may increase suspicion of anti-NMDA receptor encephalitis include hyponatremia6 and an elevated neutrophil-to-lymphocyte ratio (NLR).28 An NLR >4 in conjunction with CSF albumin-to- serum albumin ratio >7 is associated with impaired blood brain barrier integrity and a worse prognosis for those with anti-NMDA receptor encephalitis.28
Additional clinical features that may sway decisions in favor of obtaining LP despite negative findings on EEG, MRI, and serum antibodies include increased adverse reactions to antipsychotics (eg, neuroleptic malignant syndrome), prodromal infectious symptoms, known tumor, or new-onset neurologic symptoms after initial evaluation.2,8
Table 2 summarizes key features of laboratory and diagnostic findings in anti-NMDA receptor encephalitis.
When should you pursue a more extensive workup?
There are some practical tools and rating scales to help clinicians conceptualize risk for autoimmune encephalitis. For psychiatric purposes, however, many of these scales assume that LP, MRI, and EEG have already been completed, and thus it is challenging to incorporate them into psychiatric practice. One such tool is the Antibody Prevalence in Epilepsy and Encephalopathy scale; a score ≥4 is 98% sensitive and 78% to 84% specific for predicting antineural autoantibody positivity.10 Table 3 describes warning signs that may be useful in helping clinicians decide how urgently to pursue a more extensive workup in the possibility of autoimmune encephalitis.
The importance of catching anti-NMDA receptor encephalitis is underscored by the fact that appropriate treatment is very different than for primary psychosis, and outcomes worsen with delay to appropriate treatment.20 Without treatment, severe cases may progress to autonomic instability, altered consciousness, and respiratory compromise warranting admission to an intensive care unit. While the details are beyond the scope of this review, the recommended treatment for confirmed cases of anti-NMDA receptor encephalitis includes tumor removal (if indicated), reducing inflammation (steroids), removing antibodies via IV immunoglobulins, or plasma exchange.8,29 Progression of the disease may warrant consideration of rituximab or cyclophosphamide. In nonresponsive cases, third-line treatments include proteasome inhibitors or interleukin-6 receptor antagonists.8 For patients with severe catatonia, some studies have investigated the utility of electroconvulsive therapy.30 Conceptually, clinicians may consider the utility of antipsychotics as similar to recommendations for hyperactive delirium for the management of psychotic symptoms, agitation, or insomnia. However, given the risk for antipsychotic intolerance, using the lowest effective dose and vigilant screening for the emergence of extrapyramidal symptoms, fever, and autonomic instability is recommended.
CASE CONTINUED
Finally, something objective
Ms. L receives haloperidol 2 mg and undergoes an MRI without contrast. Findings are unremarkable. A spot EEG notes diffuse background slowing in the theta range, prompting lumbar puncture. Findings note 0.40 g/L, 0.2 g/L, and 3.5 for the total protein, albumin, and albumin/CSF-serum quotient (QAlb), respectively; all values are within normal limits. A mild lymphocytic pleocytosis is present as evidenced by a cell count of 35 cells/µL. The CSF is sent for qualitative examination of immunoglobulin G and electrophoresis of proteins in the CSF and serum, of which an increased concentration of restricted bands (oligoclonal bands) in the CSF but not the serum would indicate findings of oligoclonal bands. CSF is sent for detection of anti-NMDA receptor antibodies by indirect immunofluorescence, with a plan to involve an interdisciplinary team for treatment if the antibodies return positive and to manage the case symptomatically in the interim.
Bottom Line
A small subpopulation of patients who present with apparent first-episode psychosis will have symptoms caused by autoimmune encephalitis (specifically, anti-NMDA receptor encephalitis). We provide 4 screening questions to determine when to pursue a workup for an autoimmune encephalitis, and describe relevant clinical symptoms and warning signs to help differentiate the 2 conditions.
Related Resources
- Askandaryan AS, Naqvi A, Varughese A, et al. Anti-N-methyl-D-aspartate receptor encephalitis: neuropsychiatric and multidisciplinary approach to a patient not responding to first-line treatment. Cureus. 2022;14(6):e25751.
- Kayser MS, Titulaer MJ, Gresa-Arribas N, et al. Frequency and characteristics of isolated psychiatric episodes in anti-NMDA receptor encephalitis. JAMA Neurol. 2013;70(9):1133-1139.
Drug Brand Names
Clozapine • Clozaril
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Rituximab • Rituxan
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2. Guasp M, Giné-Servén E, Maudes E, et al. Clinical, neuroimmunologic, and CSF investigations in first episode psychosis. Neurology. 2021;97(1):e61-e75.
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13. Armangue T, Spatola M, Vlagea A, et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol. 2018;17(9):760-772.
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15. Espinola-Nadurille M, Flores-Rivera J, Rivas-Alonso V, et al. Catatonia in patients with anti-NMDA receptor encephalitis. Psychiatry Clin Neurosci. 2019;73(9):574-580.
16. Keshavan M, Montrose DM, Rajarethinam R, et al. Psychopathology among offspring of parents with schizophrenia: relationship to premorbid impairments. Schizophr Res. 2008;103(1-3):114-120.
17. Jeppesen R, Benros ME. Autoimmune diseases and psychotic disorders. Front Psychiatry. 2019;10:131.
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25. Raymond N, Lizano P, Kelly S, et al. What can clozapine’s effect on neural oscillations tell us about its therapeutic effects? A scoping review and synthesis. Biomarkers in Neuropsychiatry. 2022;6:100048.
26. Kaufman DM, Geyer H, Milstein MJ. Kaufman’s Clinical Neurology for Psychiatrists. 8th ed. Elsevier Inc; 2016.
27. Kelley BP, Patel SC, Marin HL, et al. Autoimmune encephalitis: pathophysiology and imaging review of an overlooked diagnosis. AJNR Am J Neuroradiol. 2017;38(6):1070-1078.
28. Yu Y, Wu Y, Cao X, et al. The clinical features and prognosis of anti-NMDAR encephalitis depends on blood brain barrier integrity. Mult Scler Relat Disord. 2021;47:102604.
29. Dalmau J, Graus F. Antibody-mediated neuropsychiatric disorders. J Allergy Clin Immunol. 2022;149(1):37-40.
30. Warren N, Grote V, O’Gorman C, et al. Electroconvulsive therapy for anti-N-methyl-daspartate (NMDA) receptor encephalitis: a systematic review of cases. Brain Stimul. 2019;12(2):329-334.
Hidden within routine presentations of first-episode psychosis is a rare subpopulation whose symptoms are mediated by an autoimmune process for which proper treatment differs significantly from standard care for typical psychotic illness. In this article, we present a hypothetical case and describe how to assess if a patient has an elevated probability of autoimmune encephalitis, determine what diagnostics or medication-induced effects to consider, and identify unresolved questions about best practices.
CASE REPORT
Bizarre behavior and isolation
Ms. L, age 21, is brought to the emergency department (ED) by her college roommate after exhibiting out-of-character behavior and gradual self-isolation over the last 2 months. Her roommate noticed that she had been spending more time isolated in her dorm room and remaining in bed into the early afternoon, though she does not appear to be asleep. Ms. L’s mother is concerned about her daughter’s uncharacteristic refusal to travel home for a family event. Ms. L expresses concern about the intentions of her research preceptor, and recalls messages from the association of colleges telling her to “change her future.” Ms. L hears voices telling her who she can and cannot trust. In the ED, she says she has a headache, experiences mild dizziness while standing, and reports having a brief upper respiratory illness at the end of last semester. Otherwise, a medical review of systems is negative.
Although the etiology of first-episode psychosis can be numerous or unknown, many psychiatrists feel comfortable with the initial diagnostic for this type of clinical presentation. However, for some clinicians, it may be challenging to feel confident in making a diagnosis of autoimmune encephalitis.
Autoimmune encephalitis is a family of syndromes caused by autoantibodies targeting either intracellular or extracellular neuronal antigens. Anti-N-methyl-
In this article, we focus on anti-NMDA receptor encephalitis and use the term interchangeably with autoimmune encephalitis for 2 reasons. First, anti-NMDA receptor encephalitis can present with psychotic symptoms as the only symptoms (prior to cognitive or neurologic manifestations) or can present with psychotic symptoms as the main indicator (with other symptoms that are more subtle and possibly missed). Second, anti-NMDA receptor encephalitis often occurs in young adults, which is when it is common to see the onset of a primary psychotic illness. These 2 factors make it likely that these cases will come into the evaluative sphere of psychiatrists. We give special attention to features of cases of anti-NMDA receptor encephalitis confirmed with antineuronal antibodies in the CSF, as it has emerged that antibodies in the serum can be nonspecific and nonpathogenic.2,3
What does anti-NMDA receptor encephalitis look like?
Symptoms of anti-NMDA receptor encephalitis resemble those of a primary psychotic disorder, which can make it challenging to differentiate between the 2 conditions, and might cause the correct diagnosis to be missed. Pollak et al4 proposed that psychiatrically confusing presentations that don’t clearly match an identifiable psychotic disorder should raise a red flag for an autoimmune etiology. However, studies often fail to describe the specific psychiatric features of anti-NMDA receptor encephalitis, and thus provide little practical evidence to guide diagnosis. In some of the largest studies of patients with anti-NMDA receptor encephalitis, psychiatric clinical findings are often combined into nonspecific headings such as “abnormal behavior” or “behavioral and cognitive” symptoms.5 Such groupings make this the most common clinical finding (95%)5 but make it difficult to discern particular clinical characteristics. Where available, specific symptoms identified across studies include agitation, aggression, changes in mood and/or irritability, insomnia, delusions, hallucinations, and occasionally catatonic features.6,7 Attempts to identify specific psychiatric phenotypes distinct from primary psychotic illnesses have fallen short due to contradictory findings and lack of clinical practicality.8 One exception is the presence of catatonic features, which have been found in CSF-confirmed studies.2 In contrast to the typical teaching that the hallucination modality (eg, visual or tactile) can be helpful in estimating the likelihood of a secondary psychosis (ie, drug-induced, neurodegenerative, or autoimmune), there does not appear to be a difference in hallucination modality between encephalitis and primary psychotic disorders.9
History and review of systems
Another red flag to consider is the rapidity of symptom presentation. Symptoms that progress within 3 months increase the likelihood that the patient has autoimmune encephalitis.10 Cases where collateral information indicates the psychotic episode was preceded by a long, subtle decline in school performance, social withdrawal, and attenuated psychotic symptoms typical of a schizophrenia prodrome are less likely to be an autoimmune psychosis.11 A more delayed presentation does not entirely exclude autoimmune encephalitis; however, a viral-like prodrome before the onset of psychosis increases the likelihood of autoimmune encephalitis. Such a prodrome may include fever, headache, nausea, vomiting, and diarrhea.7
Continue to: Another indication is the presence...
Another indication is the presence of new seizures within 1 year of presenting with psychotic symptoms.10 The possibility of undiagnosed seizures should be considered in a patient with psychosis who has episodes of unresponsiveness, dissociative episodes, or seizure-like activity that is thought to be psychogenic but has not been fully evaluated. Seizures in autoimmune encephalitis involve deep structures in the brain and can be present without overt epileptiform activity on EEG, but rather causing only bilateral slowing that is often described as nonspecific.12
In a young patient presenting with first-episode psychosis, a recent diagnosis of cancer or abnormal finding in the ovaries increases the likelihood of autoimmune encephalitis.4 Historically, however, this type of medical history has been irrelevant to psychosis. Although rare, any person presenting with first-episode psychosis and a history of herpes simplex virus (HSV) encephalitis should be evaluated for autoimmune encephalitis because anti-NMDA receptor antibodies have been reported to be present in approximately one-third of these patients.13 Finally, the report of focal neurologic symptoms, including neck stiffness or neck pain, should raise concern, although sensory, working memory, and cognitive deficits may be difficult to fully distinguish from common somatic and cognitive symptoms in a primary psychiatric presentation.
Table 1 lists 4 questions to ask patients who present with first-episode psychosis that may not usually be part of a typical evaluation.
CASE CONTINUED
Uncooperative with examination
In the ED, Ms. L’s heart rate is 101 beats per minute and her blood pressure is 102/72 mm Hg. Her body mass index (BMI) is 22, which suggests an approximate 8-pound weight loss since her BMI was last assessed. Ms. L responds to questions with 1- to 6-word sentences, without clear verbigeration. Though her speech is not pressured, it is of increased rate. Her gaze scans the room, occasionally becoming fixed for 5 to 10 seconds but is aborted by the interviewer’s comment on this behavior. Ms. L efficiently and accurately spells WORLD backwards, then asks “Why?” and refuses to engage in further cognitive testing, stating “Not doing that.” When the interviewer asks “Why not?” she responds “Not doing that.” Her cranial nerves are intact, and she refuses cerebellar testing or requests to assess tone. There are no observed stereotypies, posturing, or echopraxia.
While not necessary for a diagnosis of autoimmune encephalitis, short-term memory loss is a common cognitive finding across studies.5-7 A common clinical finding from a mental status exam is speech disorders, including (but not limited to) increased rates of speech or decreased verbal output.7 Autonomic instability—including tachycardia, markedly labile blood pressures, and orthostasis—all increase the likelihood of autoimmune encephalitis.14 Interpreting a patient’s vital sign changes can be confounded if they are agitated or anxious, or if they are taking an antipsychotic that produces adverse anticholinergic effects. However, vital sign abnormalities that precede medication administration or do not correlate with fluctuations in mental status increase suspicion for an autoimmune encephalitis.
Continue to: In the absence of the adverse effect...
In the absence of the adverse effect of a medication, orthostasis is uncommon in a well-hydrated young person. Some guidelines4 suggest that symptoms of catatonia should be considered a red flag for autoimmune encephalitis. According to the Bush-Francis Catatonia Rating Scale, commonly identified features include immobility, staring, mutism, posturing, withdrawal, rigidity, and gegenhalten.15 Catatonia is common among patients with anti-NDMA receptor encephalitis, though it may not be initially present and could emerge later.2 However, there are documented cases of autoimmune encephalitis where the patient had only isolated features of catatonia, such as echolalia or mutism.2
CASE CONTINUED
History helps narrow the diagnosis
Ms. L’s parents say their daughter has not had prior contact with a therapist or psychiatrist, previous psychiatric diagnoses, hospitalizations, suicide attempts, self-injury, or binging or purging behaviors. Ms. L’s paternal grandfather was diagnosed with schizophrenia, but he is currently employed, lives alone, and has not taken medication for many years. Her mother has hypothyroidism. Ms. L was born at full term via vaginal delivery without cardiac defects or a neonatal intensive care unit stay. Her mother said she did not have postpartum depression or anxiety, a complicated pregnancy, or exposure to tobacco, alcohol, or illicit drug use. Ms. L has no history of childhood seizures or head injury with loss of consciousness. She is an only child, born and raised in a house in a metropolitan area, walked at 13 months, did not require early intervention or speech therapy, and met normal language milestones.
She attended kindergarten at age 6 and progressed throughout public school without regressions in reading, writing, or behavioral manifestations, and did not require a 504 Plan or individualized education program. Ms. L graduated high school in the top 30% of her class, was socially active, and attended a local college. In college, she achieved honor roll, enrolled in a sorority, and was a part of a research lab. Her only medication is oral contraception. She consumes alcohol socially, and reports no cannabis, cigarette, or vaping use. Ms. L says she does not use hallucinogens, stimulants, opiates, or cocaine, and her roommate and family confirm this. She denies recent travel and is sexually active. Ms. L’s urinary and serum toxicology are unremarkable, human chorionic gonadotropin is undetectable, and her sodium level is 133 mEq/L. A measure of serum neutrophils is 6.8 x 109/L and serum lymphocytes is 1.7 x 109/L. Her parents adamantly request a Neurology consultation and further workup, including a lumbar puncture (LP), EEG, and brain imaging (MRI).
This information is useful in ruling out other potential causes of psychosis, such as substance-induced psychosis and neurodevelopmental disorders that can present with psychosis. Additionally, neurodevelopmental abnormalities and psychiatric prodromal symptoms are known precedents in individuals who develop a primary psychotic disorder such as schizophrenia.16 A family history that includes a psychotic illness may increase the likelihood of a primary psychotic disorder in offspring; however, clinicians must also consider the accuracy of diagnosis in the family, as this can often be inaccurate or influenced by historical cultural bias. We recommend further elucidating the likelihood of a genetic predisposition to a primary psychotic disorder by clarifying familial medication history and functionality.
For example, the fact that Ms. L’s grandfather has not taken medication for many years and has a high degree of functioning and/or absence of cognitive deficits would lower our suspicion for an accurate diagnosis of schizophrenia (given the typical cognitive decline with untreated illness). Another piece of family history relevant to autoimmune encephalitis includes the propensity for autoimmune disorders, but expert opinion on this matter is mixed.17 Ms. L’s mother has hypothyroidism, which is commonly caused by a prior episode of Hashimoto’s autoimmune thyroiditis. Some physicians advocate for measuring antithyroid antibodies and erythrocyte sedimentation rate or C-reactive protein to gauge the level of autoimmunity, but the usefulness of these measures for detecting autoimmune encephalitis is unclear. These serum markers can be useful in detecting additional important etiologies such as systemic infection or systemic inflammation, and there are conditions such as steroid-responsive encephalopathy with associated thyroiditis, which, as the name suggests, responds to steroids rather than other psychotropic medications. Other risk factors for autoimmune encephalitis include being female, being young, having viral infections (eg, HSV), prior tumor burden, and being in the postpartum period.18 Some experts also suggest the presence of neurologic symptoms 4 weeks after the first psychiatric or cognitive symptom presentation increases the likelihood of anti-NMDA receptor encephalitis, and a lack of neurologic symptoms would make this diagnosis less likely.6,19
Continue to: Another item of interest...
Another item of interest in Ms. L’s case is her parents’ request for a Neurology consultation and further workup, as there is an association between caregiver request for workup and eventual diagnosis.6 While the etiology of this phenomenon is unclear, the literature suggests individuals with autoimmune encephalitis who initially present to Psychiatry experience longer delays to the appropriate treatment with immunomodulatory therapy than those who first present to Neurology.20
Laboratory and diagnostic testing
Guasp et al2 recommend EEG, MRI, and serum autoimmune antibodies (ie, screening for anti-NMDA receptor antibodies) for patients who present with first-episode psychosis, even in the absence of some of the red flags previously discussed. A recent economic analysis suggested screening all patients with first-episode psychosis for serum antibodies may be cost-effective.21
For patients whose presentations include features concerning for anti-NMDA receptor encephalitis, an EEG and MRI are reasonable. In a review of EEG abnormalities in anti-NMDA receptor encephalitis, Gillinder et al23 noted that while 30% did not have initial findings, 83.6% of those with confirmed anti-NMDA receptor encephalitis demonstrated EEG abnormalities; the most common were generalized slowing, delta slowing, and focal abnormalities. Discovering an extreme delta-brush activity on EEG is specific for anti-NMDA receptor encephalitis, but its absence is not fully informative. Practically, slowing can be a nonspecific manifestation of encephalopathy or a medication effect, and many people who present with first-episode psychosis will have recently received antipsychotics, which alter EEG frequency. In a study of EEG changes with antipsychotics, Centorrino et al24 found that generalized background slowing into the theta range across all antipsychotics was not significantly different from control participants, while theta to delta range slowing occurred in 8.2% of those receiving antipsychotics vs 3.3% of controls. Clozapine and olanzapine may be associated with greater EEG abnormalities, while haloperidol and quetiapine contribute a lower risk.25 For young patients with first-episode psychosis without a clear alternative explanation, we advocate for further autoimmune encephalitis workup among all individuals with generalized theta or delta wave slowing.
Because these medication effects are most likely to decrease specificity but not sensitivity of EEG for autoimmune encephalitis, a normal EEG without slowing can be reassuring.26 Moreover, for patients who receive neuroimaging, an MRI may detect inflammation that is not visible on CT. The concerning findings for anti-NMDA receptor encephalitis are temporal or multifocal T2 hyperintensities, though the MRI is normal in most cases and thus should not be reassuring if other concerning features are present.27
The role of lumbar puncture
Another area of active debate surrounds the usefulness and timing of LP. Guasp et al2 proposed that all individuals with first-episode psychosis and focal neurologic findings should receive LP and CSF antineuronal antibody testing. They recommend that patients with first-episode psychosis without focal neurologic findings also should receive LP and CSF testing if ≥1 of the following is present:
- slowing on EEG
- temporal or multifocal T2 hyperintensities on MRI
- positive anti-NMDA receptor antibody in the serum.2
Continue to: Evidence suggests that basic CSF parameters...
Evidence suggests that basic CSF parameters, such as elevated protein and white blood cell counts, are some of the most sensitive and specific tests for autoimmune encephalitis.2 Thus, if the patient is amenable and logistical factors are in place, it may be reasonable to pursue LP earlier in some cases without waiting for serum antibody assays to return (these results can take several weeks). CSF inflammatory changes without neuronal antibodies should lead to other diagnostic considerations (eg, systemic inflammatory disease, psychosis attributed to systemic lupus erythematosus).7 While nonspecific, serum laboratory values that may increase suspicion of anti-NMDA receptor encephalitis include hyponatremia6 and an elevated neutrophil-to-lymphocyte ratio (NLR).28 An NLR >4 in conjunction with CSF albumin-to- serum albumin ratio >7 is associated with impaired blood brain barrier integrity and a worse prognosis for those with anti-NMDA receptor encephalitis.28
Additional clinical features that may sway decisions in favor of obtaining LP despite negative findings on EEG, MRI, and serum antibodies include increased adverse reactions to antipsychotics (eg, neuroleptic malignant syndrome), prodromal infectious symptoms, known tumor, or new-onset neurologic symptoms after initial evaluation.2,8
Table 2 summarizes key features of laboratory and diagnostic findings in anti-NMDA receptor encephalitis.
When should you pursue a more extensive workup?
There are some practical tools and rating scales to help clinicians conceptualize risk for autoimmune encephalitis. For psychiatric purposes, however, many of these scales assume that LP, MRI, and EEG have already been completed, and thus it is challenging to incorporate them into psychiatric practice. One such tool is the Antibody Prevalence in Epilepsy and Encephalopathy scale; a score ≥4 is 98% sensitive and 78% to 84% specific for predicting antineural autoantibody positivity.10 Table 3 describes warning signs that may be useful in helping clinicians decide how urgently to pursue a more extensive workup in the possibility of autoimmune encephalitis.
The importance of catching anti-NMDA receptor encephalitis is underscored by the fact that appropriate treatment is very different than for primary psychosis, and outcomes worsen with delay to appropriate treatment.20 Without treatment, severe cases may progress to autonomic instability, altered consciousness, and respiratory compromise warranting admission to an intensive care unit. While the details are beyond the scope of this review, the recommended treatment for confirmed cases of anti-NMDA receptor encephalitis includes tumor removal (if indicated), reducing inflammation (steroids), removing antibodies via IV immunoglobulins, or plasma exchange.8,29 Progression of the disease may warrant consideration of rituximab or cyclophosphamide. In nonresponsive cases, third-line treatments include proteasome inhibitors or interleukin-6 receptor antagonists.8 For patients with severe catatonia, some studies have investigated the utility of electroconvulsive therapy.30 Conceptually, clinicians may consider the utility of antipsychotics as similar to recommendations for hyperactive delirium for the management of psychotic symptoms, agitation, or insomnia. However, given the risk for antipsychotic intolerance, using the lowest effective dose and vigilant screening for the emergence of extrapyramidal symptoms, fever, and autonomic instability is recommended.
CASE CONTINUED
Finally, something objective
Ms. L receives haloperidol 2 mg and undergoes an MRI without contrast. Findings are unremarkable. A spot EEG notes diffuse background slowing in the theta range, prompting lumbar puncture. Findings note 0.40 g/L, 0.2 g/L, and 3.5 for the total protein, albumin, and albumin/CSF-serum quotient (QAlb), respectively; all values are within normal limits. A mild lymphocytic pleocytosis is present as evidenced by a cell count of 35 cells/µL. The CSF is sent for qualitative examination of immunoglobulin G and electrophoresis of proteins in the CSF and serum, of which an increased concentration of restricted bands (oligoclonal bands) in the CSF but not the serum would indicate findings of oligoclonal bands. CSF is sent for detection of anti-NMDA receptor antibodies by indirect immunofluorescence, with a plan to involve an interdisciplinary team for treatment if the antibodies return positive and to manage the case symptomatically in the interim.
Bottom Line
A small subpopulation of patients who present with apparent first-episode psychosis will have symptoms caused by autoimmune encephalitis (specifically, anti-NMDA receptor encephalitis). We provide 4 screening questions to determine when to pursue a workup for an autoimmune encephalitis, and describe relevant clinical symptoms and warning signs to help differentiate the 2 conditions.
Related Resources
- Askandaryan AS, Naqvi A, Varughese A, et al. Anti-N-methyl-D-aspartate receptor encephalitis: neuropsychiatric and multidisciplinary approach to a patient not responding to first-line treatment. Cureus. 2022;14(6):e25751.
- Kayser MS, Titulaer MJ, Gresa-Arribas N, et al. Frequency and characteristics of isolated psychiatric episodes in anti-NMDA receptor encephalitis. JAMA Neurol. 2013;70(9):1133-1139.
Drug Brand Names
Clozapine • Clozaril
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Rituximab • Rituxan
Hidden within routine presentations of first-episode psychosis is a rare subpopulation whose symptoms are mediated by an autoimmune process for which proper treatment differs significantly from standard care for typical psychotic illness. In this article, we present a hypothetical case and describe how to assess if a patient has an elevated probability of autoimmune encephalitis, determine what diagnostics or medication-induced effects to consider, and identify unresolved questions about best practices.
CASE REPORT
Bizarre behavior and isolation
Ms. L, age 21, is brought to the emergency department (ED) by her college roommate after exhibiting out-of-character behavior and gradual self-isolation over the last 2 months. Her roommate noticed that she had been spending more time isolated in her dorm room and remaining in bed into the early afternoon, though she does not appear to be asleep. Ms. L’s mother is concerned about her daughter’s uncharacteristic refusal to travel home for a family event. Ms. L expresses concern about the intentions of her research preceptor, and recalls messages from the association of colleges telling her to “change her future.” Ms. L hears voices telling her who she can and cannot trust. In the ED, she says she has a headache, experiences mild dizziness while standing, and reports having a brief upper respiratory illness at the end of last semester. Otherwise, a medical review of systems is negative.
Although the etiology of first-episode psychosis can be numerous or unknown, many psychiatrists feel comfortable with the initial diagnostic for this type of clinical presentation. However, for some clinicians, it may be challenging to feel confident in making a diagnosis of autoimmune encephalitis.
Autoimmune encephalitis is a family of syndromes caused by autoantibodies targeting either intracellular or extracellular neuronal antigens. Anti-N-methyl-
In this article, we focus on anti-NMDA receptor encephalitis and use the term interchangeably with autoimmune encephalitis for 2 reasons. First, anti-NMDA receptor encephalitis can present with psychotic symptoms as the only symptoms (prior to cognitive or neurologic manifestations) or can present with psychotic symptoms as the main indicator (with other symptoms that are more subtle and possibly missed). Second, anti-NMDA receptor encephalitis often occurs in young adults, which is when it is common to see the onset of a primary psychotic illness. These 2 factors make it likely that these cases will come into the evaluative sphere of psychiatrists. We give special attention to features of cases of anti-NMDA receptor encephalitis confirmed with antineuronal antibodies in the CSF, as it has emerged that antibodies in the serum can be nonspecific and nonpathogenic.2,3
What does anti-NMDA receptor encephalitis look like?
Symptoms of anti-NMDA receptor encephalitis resemble those of a primary psychotic disorder, which can make it challenging to differentiate between the 2 conditions, and might cause the correct diagnosis to be missed. Pollak et al4 proposed that psychiatrically confusing presentations that don’t clearly match an identifiable psychotic disorder should raise a red flag for an autoimmune etiology. However, studies often fail to describe the specific psychiatric features of anti-NMDA receptor encephalitis, and thus provide little practical evidence to guide diagnosis. In some of the largest studies of patients with anti-NMDA receptor encephalitis, psychiatric clinical findings are often combined into nonspecific headings such as “abnormal behavior” or “behavioral and cognitive” symptoms.5 Such groupings make this the most common clinical finding (95%)5 but make it difficult to discern particular clinical characteristics. Where available, specific symptoms identified across studies include agitation, aggression, changes in mood and/or irritability, insomnia, delusions, hallucinations, and occasionally catatonic features.6,7 Attempts to identify specific psychiatric phenotypes distinct from primary psychotic illnesses have fallen short due to contradictory findings and lack of clinical practicality.8 One exception is the presence of catatonic features, which have been found in CSF-confirmed studies.2 In contrast to the typical teaching that the hallucination modality (eg, visual or tactile) can be helpful in estimating the likelihood of a secondary psychosis (ie, drug-induced, neurodegenerative, or autoimmune), there does not appear to be a difference in hallucination modality between encephalitis and primary psychotic disorders.9
History and review of systems
Another red flag to consider is the rapidity of symptom presentation. Symptoms that progress within 3 months increase the likelihood that the patient has autoimmune encephalitis.10 Cases where collateral information indicates the psychotic episode was preceded by a long, subtle decline in school performance, social withdrawal, and attenuated psychotic symptoms typical of a schizophrenia prodrome are less likely to be an autoimmune psychosis.11 A more delayed presentation does not entirely exclude autoimmune encephalitis; however, a viral-like prodrome before the onset of psychosis increases the likelihood of autoimmune encephalitis. Such a prodrome may include fever, headache, nausea, vomiting, and diarrhea.7
Continue to: Another indication is the presence...
Another indication is the presence of new seizures within 1 year of presenting with psychotic symptoms.10 The possibility of undiagnosed seizures should be considered in a patient with psychosis who has episodes of unresponsiveness, dissociative episodes, or seizure-like activity that is thought to be psychogenic but has not been fully evaluated. Seizures in autoimmune encephalitis involve deep structures in the brain and can be present without overt epileptiform activity on EEG, but rather causing only bilateral slowing that is often described as nonspecific.12
In a young patient presenting with first-episode psychosis, a recent diagnosis of cancer or abnormal finding in the ovaries increases the likelihood of autoimmune encephalitis.4 Historically, however, this type of medical history has been irrelevant to psychosis. Although rare, any person presenting with first-episode psychosis and a history of herpes simplex virus (HSV) encephalitis should be evaluated for autoimmune encephalitis because anti-NMDA receptor antibodies have been reported to be present in approximately one-third of these patients.13 Finally, the report of focal neurologic symptoms, including neck stiffness or neck pain, should raise concern, although sensory, working memory, and cognitive deficits may be difficult to fully distinguish from common somatic and cognitive symptoms in a primary psychiatric presentation.
Table 1 lists 4 questions to ask patients who present with first-episode psychosis that may not usually be part of a typical evaluation.
CASE CONTINUED
Uncooperative with examination
In the ED, Ms. L’s heart rate is 101 beats per minute and her blood pressure is 102/72 mm Hg. Her body mass index (BMI) is 22, which suggests an approximate 8-pound weight loss since her BMI was last assessed. Ms. L responds to questions with 1- to 6-word sentences, without clear verbigeration. Though her speech is not pressured, it is of increased rate. Her gaze scans the room, occasionally becoming fixed for 5 to 10 seconds but is aborted by the interviewer’s comment on this behavior. Ms. L efficiently and accurately spells WORLD backwards, then asks “Why?” and refuses to engage in further cognitive testing, stating “Not doing that.” When the interviewer asks “Why not?” she responds “Not doing that.” Her cranial nerves are intact, and she refuses cerebellar testing or requests to assess tone. There are no observed stereotypies, posturing, or echopraxia.
While not necessary for a diagnosis of autoimmune encephalitis, short-term memory loss is a common cognitive finding across studies.5-7 A common clinical finding from a mental status exam is speech disorders, including (but not limited to) increased rates of speech or decreased verbal output.7 Autonomic instability—including tachycardia, markedly labile blood pressures, and orthostasis—all increase the likelihood of autoimmune encephalitis.14 Interpreting a patient’s vital sign changes can be confounded if they are agitated or anxious, or if they are taking an antipsychotic that produces adverse anticholinergic effects. However, vital sign abnormalities that precede medication administration or do not correlate with fluctuations in mental status increase suspicion for an autoimmune encephalitis.
Continue to: In the absence of the adverse effect...
In the absence of the adverse effect of a medication, orthostasis is uncommon in a well-hydrated young person. Some guidelines4 suggest that symptoms of catatonia should be considered a red flag for autoimmune encephalitis. According to the Bush-Francis Catatonia Rating Scale, commonly identified features include immobility, staring, mutism, posturing, withdrawal, rigidity, and gegenhalten.15 Catatonia is common among patients with anti-NDMA receptor encephalitis, though it may not be initially present and could emerge later.2 However, there are documented cases of autoimmune encephalitis where the patient had only isolated features of catatonia, such as echolalia or mutism.2
CASE CONTINUED
History helps narrow the diagnosis
Ms. L’s parents say their daughter has not had prior contact with a therapist or psychiatrist, previous psychiatric diagnoses, hospitalizations, suicide attempts, self-injury, or binging or purging behaviors. Ms. L’s paternal grandfather was diagnosed with schizophrenia, but he is currently employed, lives alone, and has not taken medication for many years. Her mother has hypothyroidism. Ms. L was born at full term via vaginal delivery without cardiac defects or a neonatal intensive care unit stay. Her mother said she did not have postpartum depression or anxiety, a complicated pregnancy, or exposure to tobacco, alcohol, or illicit drug use. Ms. L has no history of childhood seizures or head injury with loss of consciousness. She is an only child, born and raised in a house in a metropolitan area, walked at 13 months, did not require early intervention or speech therapy, and met normal language milestones.
She attended kindergarten at age 6 and progressed throughout public school without regressions in reading, writing, or behavioral manifestations, and did not require a 504 Plan or individualized education program. Ms. L graduated high school in the top 30% of her class, was socially active, and attended a local college. In college, she achieved honor roll, enrolled in a sorority, and was a part of a research lab. Her only medication is oral contraception. She consumes alcohol socially, and reports no cannabis, cigarette, or vaping use. Ms. L says she does not use hallucinogens, stimulants, opiates, or cocaine, and her roommate and family confirm this. She denies recent travel and is sexually active. Ms. L’s urinary and serum toxicology are unremarkable, human chorionic gonadotropin is undetectable, and her sodium level is 133 mEq/L. A measure of serum neutrophils is 6.8 x 109/L and serum lymphocytes is 1.7 x 109/L. Her parents adamantly request a Neurology consultation and further workup, including a lumbar puncture (LP), EEG, and brain imaging (MRI).
This information is useful in ruling out other potential causes of psychosis, such as substance-induced psychosis and neurodevelopmental disorders that can present with psychosis. Additionally, neurodevelopmental abnormalities and psychiatric prodromal symptoms are known precedents in individuals who develop a primary psychotic disorder such as schizophrenia.16 A family history that includes a psychotic illness may increase the likelihood of a primary psychotic disorder in offspring; however, clinicians must also consider the accuracy of diagnosis in the family, as this can often be inaccurate or influenced by historical cultural bias. We recommend further elucidating the likelihood of a genetic predisposition to a primary psychotic disorder by clarifying familial medication history and functionality.
For example, the fact that Ms. L’s grandfather has not taken medication for many years and has a high degree of functioning and/or absence of cognitive deficits would lower our suspicion for an accurate diagnosis of schizophrenia (given the typical cognitive decline with untreated illness). Another piece of family history relevant to autoimmune encephalitis includes the propensity for autoimmune disorders, but expert opinion on this matter is mixed.17 Ms. L’s mother has hypothyroidism, which is commonly caused by a prior episode of Hashimoto’s autoimmune thyroiditis. Some physicians advocate for measuring antithyroid antibodies and erythrocyte sedimentation rate or C-reactive protein to gauge the level of autoimmunity, but the usefulness of these measures for detecting autoimmune encephalitis is unclear. These serum markers can be useful in detecting additional important etiologies such as systemic infection or systemic inflammation, and there are conditions such as steroid-responsive encephalopathy with associated thyroiditis, which, as the name suggests, responds to steroids rather than other psychotropic medications. Other risk factors for autoimmune encephalitis include being female, being young, having viral infections (eg, HSV), prior tumor burden, and being in the postpartum period.18 Some experts also suggest the presence of neurologic symptoms 4 weeks after the first psychiatric or cognitive symptom presentation increases the likelihood of anti-NMDA receptor encephalitis, and a lack of neurologic symptoms would make this diagnosis less likely.6,19
Continue to: Another item of interest...
Another item of interest in Ms. L’s case is her parents’ request for a Neurology consultation and further workup, as there is an association between caregiver request for workup and eventual diagnosis.6 While the etiology of this phenomenon is unclear, the literature suggests individuals with autoimmune encephalitis who initially present to Psychiatry experience longer delays to the appropriate treatment with immunomodulatory therapy than those who first present to Neurology.20
Laboratory and diagnostic testing
Guasp et al2 recommend EEG, MRI, and serum autoimmune antibodies (ie, screening for anti-NMDA receptor antibodies) for patients who present with first-episode psychosis, even in the absence of some of the red flags previously discussed. A recent economic analysis suggested screening all patients with first-episode psychosis for serum antibodies may be cost-effective.21
For patients whose presentations include features concerning for anti-NMDA receptor encephalitis, an EEG and MRI are reasonable. In a review of EEG abnormalities in anti-NMDA receptor encephalitis, Gillinder et al23 noted that while 30% did not have initial findings, 83.6% of those with confirmed anti-NMDA receptor encephalitis demonstrated EEG abnormalities; the most common were generalized slowing, delta slowing, and focal abnormalities. Discovering an extreme delta-brush activity on EEG is specific for anti-NMDA receptor encephalitis, but its absence is not fully informative. Practically, slowing can be a nonspecific manifestation of encephalopathy or a medication effect, and many people who present with first-episode psychosis will have recently received antipsychotics, which alter EEG frequency. In a study of EEG changes with antipsychotics, Centorrino et al24 found that generalized background slowing into the theta range across all antipsychotics was not significantly different from control participants, while theta to delta range slowing occurred in 8.2% of those receiving antipsychotics vs 3.3% of controls. Clozapine and olanzapine may be associated with greater EEG abnormalities, while haloperidol and quetiapine contribute a lower risk.25 For young patients with first-episode psychosis without a clear alternative explanation, we advocate for further autoimmune encephalitis workup among all individuals with generalized theta or delta wave slowing.
Because these medication effects are most likely to decrease specificity but not sensitivity of EEG for autoimmune encephalitis, a normal EEG without slowing can be reassuring.26 Moreover, for patients who receive neuroimaging, an MRI may detect inflammation that is not visible on CT. The concerning findings for anti-NMDA receptor encephalitis are temporal or multifocal T2 hyperintensities, though the MRI is normal in most cases and thus should not be reassuring if other concerning features are present.27
The role of lumbar puncture
Another area of active debate surrounds the usefulness and timing of LP. Guasp et al2 proposed that all individuals with first-episode psychosis and focal neurologic findings should receive LP and CSF antineuronal antibody testing. They recommend that patients with first-episode psychosis without focal neurologic findings also should receive LP and CSF testing if ≥1 of the following is present:
- slowing on EEG
- temporal or multifocal T2 hyperintensities on MRI
- positive anti-NMDA receptor antibody in the serum.2
Continue to: Evidence suggests that basic CSF parameters...
Evidence suggests that basic CSF parameters, such as elevated protein and white blood cell counts, are some of the most sensitive and specific tests for autoimmune encephalitis.2 Thus, if the patient is amenable and logistical factors are in place, it may be reasonable to pursue LP earlier in some cases without waiting for serum antibody assays to return (these results can take several weeks). CSF inflammatory changes without neuronal antibodies should lead to other diagnostic considerations (eg, systemic inflammatory disease, psychosis attributed to systemic lupus erythematosus).7 While nonspecific, serum laboratory values that may increase suspicion of anti-NMDA receptor encephalitis include hyponatremia6 and an elevated neutrophil-to-lymphocyte ratio (NLR).28 An NLR >4 in conjunction with CSF albumin-to- serum albumin ratio >7 is associated with impaired blood brain barrier integrity and a worse prognosis for those with anti-NMDA receptor encephalitis.28
Additional clinical features that may sway decisions in favor of obtaining LP despite negative findings on EEG, MRI, and serum antibodies include increased adverse reactions to antipsychotics (eg, neuroleptic malignant syndrome), prodromal infectious symptoms, known tumor, or new-onset neurologic symptoms after initial evaluation.2,8
Table 2 summarizes key features of laboratory and diagnostic findings in anti-NMDA receptor encephalitis.
When should you pursue a more extensive workup?
There are some practical tools and rating scales to help clinicians conceptualize risk for autoimmune encephalitis. For psychiatric purposes, however, many of these scales assume that LP, MRI, and EEG have already been completed, and thus it is challenging to incorporate them into psychiatric practice. One such tool is the Antibody Prevalence in Epilepsy and Encephalopathy scale; a score ≥4 is 98% sensitive and 78% to 84% specific for predicting antineural autoantibody positivity.10 Table 3 describes warning signs that may be useful in helping clinicians decide how urgently to pursue a more extensive workup in the possibility of autoimmune encephalitis.
The importance of catching anti-NMDA receptor encephalitis is underscored by the fact that appropriate treatment is very different than for primary psychosis, and outcomes worsen with delay to appropriate treatment.20 Without treatment, severe cases may progress to autonomic instability, altered consciousness, and respiratory compromise warranting admission to an intensive care unit. While the details are beyond the scope of this review, the recommended treatment for confirmed cases of anti-NMDA receptor encephalitis includes tumor removal (if indicated), reducing inflammation (steroids), removing antibodies via IV immunoglobulins, or plasma exchange.8,29 Progression of the disease may warrant consideration of rituximab or cyclophosphamide. In nonresponsive cases, third-line treatments include proteasome inhibitors or interleukin-6 receptor antagonists.8 For patients with severe catatonia, some studies have investigated the utility of electroconvulsive therapy.30 Conceptually, clinicians may consider the utility of antipsychotics as similar to recommendations for hyperactive delirium for the management of psychotic symptoms, agitation, or insomnia. However, given the risk for antipsychotic intolerance, using the lowest effective dose and vigilant screening for the emergence of extrapyramidal symptoms, fever, and autonomic instability is recommended.
CASE CONTINUED
Finally, something objective
Ms. L receives haloperidol 2 mg and undergoes an MRI without contrast. Findings are unremarkable. A spot EEG notes diffuse background slowing in the theta range, prompting lumbar puncture. Findings note 0.40 g/L, 0.2 g/L, and 3.5 for the total protein, albumin, and albumin/CSF-serum quotient (QAlb), respectively; all values are within normal limits. A mild lymphocytic pleocytosis is present as evidenced by a cell count of 35 cells/µL. The CSF is sent for qualitative examination of immunoglobulin G and electrophoresis of proteins in the CSF and serum, of which an increased concentration of restricted bands (oligoclonal bands) in the CSF but not the serum would indicate findings of oligoclonal bands. CSF is sent for detection of anti-NMDA receptor antibodies by indirect immunofluorescence, with a plan to involve an interdisciplinary team for treatment if the antibodies return positive and to manage the case symptomatically in the interim.
Bottom Line
A small subpopulation of patients who present with apparent first-episode psychosis will have symptoms caused by autoimmune encephalitis (specifically, anti-NMDA receptor encephalitis). We provide 4 screening questions to determine when to pursue a workup for an autoimmune encephalitis, and describe relevant clinical symptoms and warning signs to help differentiate the 2 conditions.
Related Resources
- Askandaryan AS, Naqvi A, Varughese A, et al. Anti-N-methyl-D-aspartate receptor encephalitis: neuropsychiatric and multidisciplinary approach to a patient not responding to first-line treatment. Cureus. 2022;14(6):e25751.
- Kayser MS, Titulaer MJ, Gresa-Arribas N, et al. Frequency and characteristics of isolated psychiatric episodes in anti-NMDA receptor encephalitis. JAMA Neurol. 2013;70(9):1133-1139.
Drug Brand Names
Clozapine • Clozaril
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Rituximab • Rituxan
1. Granerod J, Ambrose HE, Davies NW, et al; UK Health Protection Agency (HPA) Aetiology of Encephalitis Study Group. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis. 2010;10(12):835-44. doi:10.1016/S1473-3099(10)70222-X
2. Guasp M, Giné-Servén E, Maudes E, et al. Clinical, neuroimmunologic, and CSF investigations in first episode psychosis. Neurology. 2021;97(1):e61-e75.
3. From the American Association of Neurological Surgeons (AANS), American Society of Neuroradiology (ASNR), Cardiovascular and Interventional Radiology Society of Europe (CIRSE), Canadian Interventional Radiology Association (CIRA), Congress of Neurological Surgeons (CNS), European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), European Stroke Organization (ESO), Society for Cardiovascular Angiography and Interventions (SCAI), Society of Interventional Radiology (SIR), Society of NeuroInterventional Surgery (SNIS), and World Stroke Organization (WSO), Sacks D, Baxter B, Campbell BCV, et al. Multisociety consensus quality improvement revised consensus statement for endovascular therapy of acute ischemic stroke. Int J Stroke. 2018;13(6):612-632. doi:10.1177/1747493018778713
4. Pollak TA, Lennox BR, Muller S, et al. Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin. Lancet Psychiatry. 2020;7(1):93-108.
5. Guasp M, Módena Y, Armangue T, et al. Clinical features of seronegative, but CSF antibody-positive, anti-NMDA receptor encephalitis. Neurol Neuroimmunol Neuroinflamm. 2020;7(2):e659.
6. Herken J, Prüss H. Red flags: clinical signs for identifying autoimmune encephalitis in psychiatric patients. Front Psychiatry. 2017;8:25. doi:10.3389/fpsyt.2017.00025
7. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
8. Dalmau J, Armangue T, Planaguma J, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol. 2019;18(11):1045-1057.
9. Rattay TW, Martin P, Vittore D, et al. Cerebrospinal fluid findings in patients with psychotic symptoms—a retrospective analysis. Sci Rep. 2021;11(1):7169.
10. Dubey D, Pittock SJ, McKeon A. Antibody prevalence in epilepsy and encephalopathy score: increased specificity and applicability. Epilepsia. 2019;60(2):367-369.
11. Maj M, van Os J, De Hert M, et al. The clinical characterization of the patient with primary psychosis aimed at personalization of management. World Psychiatry. 2021;20(1):4-33. doi:10.1002/wps.20809
12. Caplan JP, Binius T, Lennon VA, et al. Pseudopseudoseizures: conditions that may mimic psychogenic non-epileptic seizures. Psychosomatics. 2011;52(6):501-506.
13. Armangue T, Spatola M, Vlagea A, et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol. 2018;17(9):760-772.
14. Takamatsu K, Nakane S. Autonomic manifestations in autoimmune encephalitis. Neurol Clin Neurosci. 2022;10:130-136. doi:10.1111/ncn3.12557
15. Espinola-Nadurille M, Flores-Rivera J, Rivas-Alonso V, et al. Catatonia in patients with anti-NMDA receptor encephalitis. Psychiatry Clin Neurosci. 2019;73(9):574-580.
16. Keshavan M, Montrose DM, Rajarethinam R, et al. Psychopathology among offspring of parents with schizophrenia: relationship to premorbid impairments. Schizophr Res. 2008;103(1-3):114-120.
17. Jeppesen R, Benros ME. Autoimmune diseases and psychotic disorders. Front Psychiatry. 2019;10:131.
18. Bergink V, Armangue T, Titulaer MJ, et al. Autoimmune encephalitis in postpartum psychosis. Am J Psychiatry. 2015;172(9):901-908.
19. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091-8. doi: 10.1016/S1474-4422(08)70224-2
20. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-165.
21. Ross EL, Becker JE, Linnoila JJ, et al. Cost-effectiveness of routine screening for autoimmune encephalitis in patients with first-episode psychosis in the United States. J Clin Psychiatry. 2020;82(1):19m13168.
22. Sonderen AV, Arends S, Tavy DLJ, et al. Predictive value of electroencephalography in anti-NMDA receptor encephalitis. J Neurol Neurosurg Psychiatry. 2018;89(10):1101-1106.
23. Gillinder L, Warren N, Hartel G, et al. EEG findings in NMDA encephalitis--a systematic review. Seizure. 2019;65:20-24.
24. Centorrino F, Price BH, Tuttle M, et al. EEG abnormalities during treatment with typical and atypical antipsychotics. Am J Psychiatry. 2002;159(1):109-115.
25. Raymond N, Lizano P, Kelly S, et al. What can clozapine’s effect on neural oscillations tell us about its therapeutic effects? A scoping review and synthesis. Biomarkers in Neuropsychiatry. 2022;6:100048.
26. Kaufman DM, Geyer H, Milstein MJ. Kaufman’s Clinical Neurology for Psychiatrists. 8th ed. Elsevier Inc; 2016.
27. Kelley BP, Patel SC, Marin HL, et al. Autoimmune encephalitis: pathophysiology and imaging review of an overlooked diagnosis. AJNR Am J Neuroradiol. 2017;38(6):1070-1078.
28. Yu Y, Wu Y, Cao X, et al. The clinical features and prognosis of anti-NMDAR encephalitis depends on blood brain barrier integrity. Mult Scler Relat Disord. 2021;47:102604.
29. Dalmau J, Graus F. Antibody-mediated neuropsychiatric disorders. J Allergy Clin Immunol. 2022;149(1):37-40.
30. Warren N, Grote V, O’Gorman C, et al. Electroconvulsive therapy for anti-N-methyl-daspartate (NMDA) receptor encephalitis: a systematic review of cases. Brain Stimul. 2019;12(2):329-334.
1. Granerod J, Ambrose HE, Davies NW, et al; UK Health Protection Agency (HPA) Aetiology of Encephalitis Study Group. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis. 2010;10(12):835-44. doi:10.1016/S1473-3099(10)70222-X
2. Guasp M, Giné-Servén E, Maudes E, et al. Clinical, neuroimmunologic, and CSF investigations in first episode psychosis. Neurology. 2021;97(1):e61-e75.
3. From the American Association of Neurological Surgeons (AANS), American Society of Neuroradiology (ASNR), Cardiovascular and Interventional Radiology Society of Europe (CIRSE), Canadian Interventional Radiology Association (CIRA), Congress of Neurological Surgeons (CNS), European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), European Stroke Organization (ESO), Society for Cardiovascular Angiography and Interventions (SCAI), Society of Interventional Radiology (SIR), Society of NeuroInterventional Surgery (SNIS), and World Stroke Organization (WSO), Sacks D, Baxter B, Campbell BCV, et al. Multisociety consensus quality improvement revised consensus statement for endovascular therapy of acute ischemic stroke. Int J Stroke. 2018;13(6):612-632. doi:10.1177/1747493018778713
4. Pollak TA, Lennox BR, Muller S, et al. Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin. Lancet Psychiatry. 2020;7(1):93-108.
5. Guasp M, Módena Y, Armangue T, et al. Clinical features of seronegative, but CSF antibody-positive, anti-NMDA receptor encephalitis. Neurol Neuroimmunol Neuroinflamm. 2020;7(2):e659.
6. Herken J, Prüss H. Red flags: clinical signs for identifying autoimmune encephalitis in psychiatric patients. Front Psychiatry. 2017;8:25. doi:10.3389/fpsyt.2017.00025
7. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
8. Dalmau J, Armangue T, Planaguma J, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol. 2019;18(11):1045-1057.
9. Rattay TW, Martin P, Vittore D, et al. Cerebrospinal fluid findings in patients with psychotic symptoms—a retrospective analysis. Sci Rep. 2021;11(1):7169.
10. Dubey D, Pittock SJ, McKeon A. Antibody prevalence in epilepsy and encephalopathy score: increased specificity and applicability. Epilepsia. 2019;60(2):367-369.
11. Maj M, van Os J, De Hert M, et al. The clinical characterization of the patient with primary psychosis aimed at personalization of management. World Psychiatry. 2021;20(1):4-33. doi:10.1002/wps.20809
12. Caplan JP, Binius T, Lennon VA, et al. Pseudopseudoseizures: conditions that may mimic psychogenic non-epileptic seizures. Psychosomatics. 2011;52(6):501-506.
13. Armangue T, Spatola M, Vlagea A, et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol. 2018;17(9):760-772.
14. Takamatsu K, Nakane S. Autonomic manifestations in autoimmune encephalitis. Neurol Clin Neurosci. 2022;10:130-136. doi:10.1111/ncn3.12557
15. Espinola-Nadurille M, Flores-Rivera J, Rivas-Alonso V, et al. Catatonia in patients with anti-NMDA receptor encephalitis. Psychiatry Clin Neurosci. 2019;73(9):574-580.
16. Keshavan M, Montrose DM, Rajarethinam R, et al. Psychopathology among offspring of parents with schizophrenia: relationship to premorbid impairments. Schizophr Res. 2008;103(1-3):114-120.
17. Jeppesen R, Benros ME. Autoimmune diseases and psychotic disorders. Front Psychiatry. 2019;10:131.
18. Bergink V, Armangue T, Titulaer MJ, et al. Autoimmune encephalitis in postpartum psychosis. Am J Psychiatry. 2015;172(9):901-908.
19. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091-8. doi: 10.1016/S1474-4422(08)70224-2
20. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-165.
21. Ross EL, Becker JE, Linnoila JJ, et al. Cost-effectiveness of routine screening for autoimmune encephalitis in patients with first-episode psychosis in the United States. J Clin Psychiatry. 2020;82(1):19m13168.
22. Sonderen AV, Arends S, Tavy DLJ, et al. Predictive value of electroencephalography in anti-NMDA receptor encephalitis. J Neurol Neurosurg Psychiatry. 2018;89(10):1101-1106.
23. Gillinder L, Warren N, Hartel G, et al. EEG findings in NMDA encephalitis--a systematic review. Seizure. 2019;65:20-24.
24. Centorrino F, Price BH, Tuttle M, et al. EEG abnormalities during treatment with typical and atypical antipsychotics. Am J Psychiatry. 2002;159(1):109-115.
25. Raymond N, Lizano P, Kelly S, et al. What can clozapine’s effect on neural oscillations tell us about its therapeutic effects? A scoping review and synthesis. Biomarkers in Neuropsychiatry. 2022;6:100048.
26. Kaufman DM, Geyer H, Milstein MJ. Kaufman’s Clinical Neurology for Psychiatrists. 8th ed. Elsevier Inc; 2016.
27. Kelley BP, Patel SC, Marin HL, et al. Autoimmune encephalitis: pathophysiology and imaging review of an overlooked diagnosis. AJNR Am J Neuroradiol. 2017;38(6):1070-1078.
28. Yu Y, Wu Y, Cao X, et al. The clinical features and prognosis of anti-NMDAR encephalitis depends on blood brain barrier integrity. Mult Scler Relat Disord. 2021;47:102604.
29. Dalmau J, Graus F. Antibody-mediated neuropsychiatric disorders. J Allergy Clin Immunol. 2022;149(1):37-40.
30. Warren N, Grote V, O’Gorman C, et al. Electroconvulsive therapy for anti-N-methyl-daspartate (NMDA) receptor encephalitis: a systematic review of cases. Brain Stimul. 2019;12(2):329-334.
Genetic link adds to gut-brain axis theory in Alzheimer’s disease
The same genes that send people to the bathroom with an irritable bowel syndrome flare-up may be involved in future brain health, according to a new study. Researchers have found a genetic correlation between individuals with gastrointestinal tract (GIT) disorders and Alzheimer’s disease (AD).
Analyzing years of genetic data from AD studies and similar data from six GIT disorders, the scientists at the Center for Precision Health at Edith Cowan University in Australia found that many disease-specific genes shared the same loci, or chromosomal location, in each group.
The researchers say it is the first comprehensive look at the genetic relationship between these disorders. Prior to this, it was widely believed that there was a link between gastrointestinal disorders and AD. A 2020 longitudinal study noted that people with irritable bowel disease were six times more likely to suffer from AD. But the gut-brain axis had not yet been examined on a genetic basis.
“The study provides a novel insight into the genetics behind the observed co-occurrence of AD and gut disorders,” Emmanuel Adewuyi, PhD, MPH, said in an interview with EurekaAlert. Dr. Adewuyi, a postdoctoral research fellow at the Center for Precision Health at Edith Cowan University, led the study.
The authors say that understanding the underlying genetics of AD can provide clues about how the disease works, which is largely a mystery. Treatment of the disease is increasingly urgent in a world with growing life expectancy and incidence of AD. By 2030, over 82 million people will likely suffer from AD, according to the 2015 World Alzheimer’s Report.
The Australian study relied upon previously performed genome-wide association studies. They searched data for patients with AD, gastroesophageal reflux disease, peptic ulcer disease, gastritis-duodenitis, irritable bowel syndrome, diverticulosis, and irritable bowel disorder.
The final cohort represented over 450,000 people. Of those analyzed, they found that all the GIT disorders except irritable bowel disorder were correlated with AD.
One of the biological factors that underscored this relationship was the amount of abnormal cholesterol in both sets studied. From the study, It appears that altered cholesterol was a risk factor for both AD and gut disorders. Therefore, the authors suggest that next steps should investigate the use of statins, such as atorvastatin or lovastatin, which lower cholesterol to see whether they help protect the gut and, in turn, the brain.
Although these results point toward a correlation, the researchers caution that a causal relationship cannot be established between these two sets of disorders. The data advance the idea of the gut-brain axis but don’t show that GI problems cause AD or vice versa. Nor do the findings mean that someone with AD will always have gut problems or that a person with gut problems will develop AD.
The authors suggest the role of diet in health maintenance. They specifically highlight the Mediterranean diet, which is rich in natural fats and vegetables.
The study was independently supported. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The same genes that send people to the bathroom with an irritable bowel syndrome flare-up may be involved in future brain health, according to a new study. Researchers have found a genetic correlation between individuals with gastrointestinal tract (GIT) disorders and Alzheimer’s disease (AD).
Analyzing years of genetic data from AD studies and similar data from six GIT disorders, the scientists at the Center for Precision Health at Edith Cowan University in Australia found that many disease-specific genes shared the same loci, or chromosomal location, in each group.
The researchers say it is the first comprehensive look at the genetic relationship between these disorders. Prior to this, it was widely believed that there was a link between gastrointestinal disorders and AD. A 2020 longitudinal study noted that people with irritable bowel disease were six times more likely to suffer from AD. But the gut-brain axis had not yet been examined on a genetic basis.
“The study provides a novel insight into the genetics behind the observed co-occurrence of AD and gut disorders,” Emmanuel Adewuyi, PhD, MPH, said in an interview with EurekaAlert. Dr. Adewuyi, a postdoctoral research fellow at the Center for Precision Health at Edith Cowan University, led the study.
The authors say that understanding the underlying genetics of AD can provide clues about how the disease works, which is largely a mystery. Treatment of the disease is increasingly urgent in a world with growing life expectancy and incidence of AD. By 2030, over 82 million people will likely suffer from AD, according to the 2015 World Alzheimer’s Report.
The Australian study relied upon previously performed genome-wide association studies. They searched data for patients with AD, gastroesophageal reflux disease, peptic ulcer disease, gastritis-duodenitis, irritable bowel syndrome, diverticulosis, and irritable bowel disorder.
The final cohort represented over 450,000 people. Of those analyzed, they found that all the GIT disorders except irritable bowel disorder were correlated with AD.
One of the biological factors that underscored this relationship was the amount of abnormal cholesterol in both sets studied. From the study, It appears that altered cholesterol was a risk factor for both AD and gut disorders. Therefore, the authors suggest that next steps should investigate the use of statins, such as atorvastatin or lovastatin, which lower cholesterol to see whether they help protect the gut and, in turn, the brain.
Although these results point toward a correlation, the researchers caution that a causal relationship cannot be established between these two sets of disorders. The data advance the idea of the gut-brain axis but don’t show that GI problems cause AD or vice versa. Nor do the findings mean that someone with AD will always have gut problems or that a person with gut problems will develop AD.
The authors suggest the role of diet in health maintenance. They specifically highlight the Mediterranean diet, which is rich in natural fats and vegetables.
The study was independently supported. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The same genes that send people to the bathroom with an irritable bowel syndrome flare-up may be involved in future brain health, according to a new study. Researchers have found a genetic correlation between individuals with gastrointestinal tract (GIT) disorders and Alzheimer’s disease (AD).
Analyzing years of genetic data from AD studies and similar data from six GIT disorders, the scientists at the Center for Precision Health at Edith Cowan University in Australia found that many disease-specific genes shared the same loci, or chromosomal location, in each group.
The researchers say it is the first comprehensive look at the genetic relationship between these disorders. Prior to this, it was widely believed that there was a link between gastrointestinal disorders and AD. A 2020 longitudinal study noted that people with irritable bowel disease were six times more likely to suffer from AD. But the gut-brain axis had not yet been examined on a genetic basis.
“The study provides a novel insight into the genetics behind the observed co-occurrence of AD and gut disorders,” Emmanuel Adewuyi, PhD, MPH, said in an interview with EurekaAlert. Dr. Adewuyi, a postdoctoral research fellow at the Center for Precision Health at Edith Cowan University, led the study.
The authors say that understanding the underlying genetics of AD can provide clues about how the disease works, which is largely a mystery. Treatment of the disease is increasingly urgent in a world with growing life expectancy and incidence of AD. By 2030, over 82 million people will likely suffer from AD, according to the 2015 World Alzheimer’s Report.
The Australian study relied upon previously performed genome-wide association studies. They searched data for patients with AD, gastroesophageal reflux disease, peptic ulcer disease, gastritis-duodenitis, irritable bowel syndrome, diverticulosis, and irritable bowel disorder.
The final cohort represented over 450,000 people. Of those analyzed, they found that all the GIT disorders except irritable bowel disorder were correlated with AD.
One of the biological factors that underscored this relationship was the amount of abnormal cholesterol in both sets studied. From the study, It appears that altered cholesterol was a risk factor for both AD and gut disorders. Therefore, the authors suggest that next steps should investigate the use of statins, such as atorvastatin or lovastatin, which lower cholesterol to see whether they help protect the gut and, in turn, the brain.
Although these results point toward a correlation, the researchers caution that a causal relationship cannot be established between these two sets of disorders. The data advance the idea of the gut-brain axis but don’t show that GI problems cause AD or vice versa. Nor do the findings mean that someone with AD will always have gut problems or that a person with gut problems will develop AD.
The authors suggest the role of diet in health maintenance. They specifically highlight the Mediterranean diet, which is rich in natural fats and vegetables.
The study was independently supported. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Hospital programs tackle mental health effects of long COVID
There’s little doubt that long COVID is real. Even as doctors and federal agencies struggle to define the syndrome, hospitals and health care systems are opening long COVID specialty treatment programs. As of July 25, there’s at least one long COVID center in almost every state – 48 out of 50, according to the patient advocacy group Survivor Corps.
Among the biggest challenges will be treating the mental health effects of long COVID. 
Specialized centers will be tackling these problems even as the United States struggles to deal with mental health needs.
One study of COVID patients found more than one-third of them had symptoms of depression, anxiety, or PTSD 3-6 months after their initial infection. Another analysis of 30 previous studies of long COVID patients found roughly one in eight of them had severe depression – and that the risk was similar regardless of whether people were hospitalized for COVID-19.
“Many of these symptoms can emerge months into the course of long COVID illness,” said Jordan Anderson, DO, a neuropsychiatrist who sees patients at the Long COVID-19 Program at Oregon Health & Science University, Portland. Psychological symptoms are often made worse by physical setbacks like extreme fatigue and by challenges of working, caring for children, and keeping up with daily routines, he said.
“This impact is not only severe, but also chronic for many,” he said.
Like dozens of hospitals around the country, Oregon Health & Science opened its center for long COVID as it became clear that more patients would need help for ongoing physical and mental health symptoms. Today, there’s at least one long COVID center – sometimes called post-COVID care centers or clinics – in every state but Kansas and South Dakota, Survivor Corps said.
Many long COVID care centers aim to tackle both physical and mental health symptoms, said Tracy Vannorsdall, PhD, a neuropsychologist with the Johns Hopkins Post-Acute COVID-19 Team program. One goal at Hopkins is to identify patients with psychological issues that might otherwise get overlooked.
A sizable minority of patients at the Johns Hopkins center – up to about 35% – report mental health problems that they didn’t have until after they got COVID-19, Dr. Vannorsdall says. The most common mental health issues providers see are depression, anxiety, and trauma-related distress.
“Routine assessment is key,” Dr. Vannorsdall said. “If patients are not asked about their mental health symptoms, they may not spontaneously report them to their provider due to fear of stigma or simply not appreciating that there are effective treatments available for these issues.”
Fear that doctors won’t take symptoms seriously is common, says Heather Murray MD, a senior instructor in psychiatry at the University of Colorado at Denver, Aurora.
“Many patients worry their physicians, loved ones, and society will not believe them or will minimize their symptoms and suffering,” said Dr. Murray, who treats patients at the UCHealth Post-COVID Clinic.
Diagnostic tests in long COVID patients often don’t have conclusive results, which can lead doctors and patients themselves to question whether symptoms are truly “physical versus psychosomatic,” she said. “It is important that providers believe their patients and treat their symptoms, even when diagnostic tests are unrevealing.”
Growing mental health crisis
Patients often find their way to academic treatment centers after surviving severe COVID-19 infections. But a growing number of long COVID patients show up at these centers after milder cases. These patients were never hospitalized for COVID-19 but still have persistent symptoms like fatigue, thinking problems, and mood disorders.
Among the major challenges is a shortage of mental health care providers to meet the surging need for care since the start of the pandemic. Around the world, anxiety and depression surged 25% during the first year of the pandemic, according to the World Health Organization.
In the United States, 40% of adults report feelings of anxiety and depression, and one in three high school students have feelings of sadness and hopelessness, according to a March 2022 statement from the White House.
Despite this surging need for care, almost half of Americans live in areas with a severe shortage of mental health care providers, according to the Health Resources and Services Administration. As of 2019, the United States had a shortage of about 6,790 mental health providers. Since then, the shortage has worsened; it’s now about 7,500 providers.
“One of the biggest challenges for hospitals and clinics in treating mental health disorders in long COVID is the limited resources and long wait times to get in for evaluations and treatment,” said Nyaz Didehbani, PhD, a neuropsychologist who treats long COVID patients at the COVID Recover program at the University of Texas Southwestern Medical Center, Dallas.
These delays can lead to worse outcomes, Dr. Didehbani said. “Additionally, patients do not feel that they are being heard, as many providers are not aware of the mental health impact and relationship with physical and cognitive symptoms.” .
Even when doctors recognize that psychological challenges are common with long COVID, they still have to think creatively to come up with treatments that meet the unique needs of these patients, said Thida Thant, MD, an assistant professor of psychiatry at the University of Colorado who treats patients at the UCHealth Post-COVID Clinic.
“There are at least two major factors that make treating psychological issues in long COVID more complex: The fact that the pandemic is still ongoing and still so divisive throughout society, and the fact that we don’t know a single best way to treat all symptoms of long COVID,” she said.
Some common treatments for anxiety and depression, like psychotherapy and medication, can be used for long COVID patients with these conditions. But another intervention that can work wonders for many people with mood disorders – exercise – doesn’t always work for long COVID patients. That’s because many of them struggle with physical challenges like chronic fatigue and what’s known as postexertional malaise, or a worsening of symptoms after even limited physical effort.
“While we normally encourage patients to be active, have a daily routine, and to engage in physical activity as part of their mental health treatment, some long COVID patients find that their symptoms worsen after increased activity,” Dr. Vannorsdall said.
Patients who are able to reach long COVID care centers are much more apt to get mental health problems diagnosed and treated, doctors at many programs around the country agree. But many patients hardest hit by the pandemic – the poor and racial and ethnic minorities – are also less likely to have ready access to hospitals that offer these programs, said Dr. Anderson.
“Affluent, predominantly White populations are showing up in these clinics, while we know that non-White populations have disproportionally high rates of acute infection, hospitalization, and death related to the virus,” he said.
Clinics are also concentrated in academic medical centers and in urban areas, limiting options for people in rural communities who may have to drive for hours to access care, Dr. Anderson said.
“Even before long COVID, we already knew that many people live in areas where there simply aren’t enough mental health services available,” said John Zulueta, MD, an assistant professor of clinical psychiatry at the University of Illinois at Chicago who provides mental health evaluations at the UI Health Post-COVID Clinic.
“As more patients develop mental health issues associated with long COVID, it’s going to put more stress on an already stressed system,” he said.
A version of this article first appeared on WebMD.com.
There’s little doubt that long COVID is real. Even as doctors and federal agencies struggle to define the syndrome, hospitals and health care systems are opening long COVID specialty treatment programs. As of July 25, there’s at least one long COVID center in almost every state – 48 out of 50, according to the patient advocacy group Survivor Corps.
Among the biggest challenges will be treating the mental health effects of long COVID.
Specialized centers will be tackling these problems even as the United States struggles to deal with mental health needs.
One study of COVID patients found more than one-third of them had symptoms of depression, anxiety, or PTSD 3-6 months after their initial infection. Another analysis of 30 previous studies of long COVID patients found roughly one in eight of them had severe depression – and that the risk was similar regardless of whether people were hospitalized for COVID-19.
“Many of these symptoms can emerge months into the course of long COVID illness,” said Jordan Anderson, DO, a neuropsychiatrist who sees patients at the Long COVID-19 Program at Oregon Health & Science University, Portland. Psychological symptoms are often made worse by physical setbacks like extreme fatigue and by challenges of working, caring for children, and keeping up with daily routines, he said.
“This impact is not only severe, but also chronic for many,” he said.
Like dozens of hospitals around the country, Oregon Health & Science opened its center for long COVID as it became clear that more patients would need help for ongoing physical and mental health symptoms. Today, there’s at least one long COVID center – sometimes called post-COVID care centers or clinics – in every state but Kansas and South Dakota, Survivor Corps said.
Many long COVID care centers aim to tackle both physical and mental health symptoms, said Tracy Vannorsdall, PhD, a neuropsychologist with the Johns Hopkins Post-Acute COVID-19 Team program. One goal at Hopkins is to identify patients with psychological issues that might otherwise get overlooked.
A sizable minority of patients at the Johns Hopkins center – up to about 35% – report mental health problems that they didn’t have until after they got COVID-19, Dr. Vannorsdall says. The most common mental health issues providers see are depression, anxiety, and trauma-related distress.
“Routine assessment is key,” Dr. Vannorsdall said. “If patients are not asked about their mental health symptoms, they may not spontaneously report them to their provider due to fear of stigma or simply not appreciating that there are effective treatments available for these issues.”
Fear that doctors won’t take symptoms seriously is common, says Heather Murray MD, a senior instructor in psychiatry at the University of Colorado at Denver, Aurora.
“Many patients worry their physicians, loved ones, and society will not believe them or will minimize their symptoms and suffering,” said Dr. Murray, who treats patients at the UCHealth Post-COVID Clinic.
Diagnostic tests in long COVID patients often don’t have conclusive results, which can lead doctors and patients themselves to question whether symptoms are truly “physical versus psychosomatic,” she said. “It is important that providers believe their patients and treat their symptoms, even when diagnostic tests are unrevealing.”
Growing mental health crisis
Patients often find their way to academic treatment centers after surviving severe COVID-19 infections. But a growing number of long COVID patients show up at these centers after milder cases. These patients were never hospitalized for COVID-19 but still have persistent symptoms like fatigue, thinking problems, and mood disorders.
Among the major challenges is a shortage of mental health care providers to meet the surging need for care since the start of the pandemic. Around the world, anxiety and depression surged 25% during the first year of the pandemic, according to the World Health Organization.
In the United States, 40% of adults report feelings of anxiety and depression, and one in three high school students have feelings of sadness and hopelessness, according to a March 2022 statement from the White House.
Despite this surging need for care, almost half of Americans live in areas with a severe shortage of mental health care providers, according to the Health Resources and Services Administration. As of 2019, the United States had a shortage of about 6,790 mental health providers. Since then, the shortage has worsened; it’s now about 7,500 providers.
“One of the biggest challenges for hospitals and clinics in treating mental health disorders in long COVID is the limited resources and long wait times to get in for evaluations and treatment,” said Nyaz Didehbani, PhD, a neuropsychologist who treats long COVID patients at the COVID Recover program at the University of Texas Southwestern Medical Center, Dallas.
These delays can lead to worse outcomes, Dr. Didehbani said. “Additionally, patients do not feel that they are being heard, as many providers are not aware of the mental health impact and relationship with physical and cognitive symptoms.” .
Even when doctors recognize that psychological challenges are common with long COVID, they still have to think creatively to come up with treatments that meet the unique needs of these patients, said Thida Thant, MD, an assistant professor of psychiatry at the University of Colorado who treats patients at the UCHealth Post-COVID Clinic.
“There are at least two major factors that make treating psychological issues in long COVID more complex: The fact that the pandemic is still ongoing and still so divisive throughout society, and the fact that we don’t know a single best way to treat all symptoms of long COVID,” she said.
Some common treatments for anxiety and depression, like psychotherapy and medication, can be used for long COVID patients with these conditions. But another intervention that can work wonders for many people with mood disorders – exercise – doesn’t always work for long COVID patients. That’s because many of them struggle with physical challenges like chronic fatigue and what’s known as postexertional malaise, or a worsening of symptoms after even limited physical effort.
“While we normally encourage patients to be active, have a daily routine, and to engage in physical activity as part of their mental health treatment, some long COVID patients find that their symptoms worsen after increased activity,” Dr. Vannorsdall said.
Patients who are able to reach long COVID care centers are much more apt to get mental health problems diagnosed and treated, doctors at many programs around the country agree. But many patients hardest hit by the pandemic – the poor and racial and ethnic minorities – are also less likely to have ready access to hospitals that offer these programs, said Dr. Anderson.
“Affluent, predominantly White populations are showing up in these clinics, while we know that non-White populations have disproportionally high rates of acute infection, hospitalization, and death related to the virus,” he said.
Clinics are also concentrated in academic medical centers and in urban areas, limiting options for people in rural communities who may have to drive for hours to access care, Dr. Anderson said.
“Even before long COVID, we already knew that many people live in areas where there simply aren’t enough mental health services available,” said John Zulueta, MD, an assistant professor of clinical psychiatry at the University of Illinois at Chicago who provides mental health evaluations at the UI Health Post-COVID Clinic.
“As more patients develop mental health issues associated with long COVID, it’s going to put more stress on an already stressed system,” he said.
A version of this article first appeared on WebMD.com.
There’s little doubt that long COVID is real. Even as doctors and federal agencies struggle to define the syndrome, hospitals and health care systems are opening long COVID specialty treatment programs. As of July 25, there’s at least one long COVID center in almost every state – 48 out of 50, according to the patient advocacy group Survivor Corps.
Among the biggest challenges will be treating the mental health effects of long COVID.
Specialized centers will be tackling these problems even as the United States struggles to deal with mental health needs.
One study of COVID patients found more than one-third of them had symptoms of depression, anxiety, or PTSD 3-6 months after their initial infection. Another analysis of 30 previous studies of long COVID patients found roughly one in eight of them had severe depression – and that the risk was similar regardless of whether people were hospitalized for COVID-19.
“Many of these symptoms can emerge months into the course of long COVID illness,” said Jordan Anderson, DO, a neuropsychiatrist who sees patients at the Long COVID-19 Program at Oregon Health & Science University, Portland. Psychological symptoms are often made worse by physical setbacks like extreme fatigue and by challenges of working, caring for children, and keeping up with daily routines, he said.
“This impact is not only severe, but also chronic for many,” he said.
Like dozens of hospitals around the country, Oregon Health & Science opened its center for long COVID as it became clear that more patients would need help for ongoing physical and mental health symptoms. Today, there’s at least one long COVID center – sometimes called post-COVID care centers or clinics – in every state but Kansas and South Dakota, Survivor Corps said.
Many long COVID care centers aim to tackle both physical and mental health symptoms, said Tracy Vannorsdall, PhD, a neuropsychologist with the Johns Hopkins Post-Acute COVID-19 Team program. One goal at Hopkins is to identify patients with psychological issues that might otherwise get overlooked.
A sizable minority of patients at the Johns Hopkins center – up to about 35% – report mental health problems that they didn’t have until after they got COVID-19, Dr. Vannorsdall says. The most common mental health issues providers see are depression, anxiety, and trauma-related distress.
“Routine assessment is key,” Dr. Vannorsdall said. “If patients are not asked about their mental health symptoms, they may not spontaneously report them to their provider due to fear of stigma or simply not appreciating that there are effective treatments available for these issues.”
Fear that doctors won’t take symptoms seriously is common, says Heather Murray MD, a senior instructor in psychiatry at the University of Colorado at Denver, Aurora.
“Many patients worry their physicians, loved ones, and society will not believe them or will minimize their symptoms and suffering,” said Dr. Murray, who treats patients at the UCHealth Post-COVID Clinic.
Diagnostic tests in long COVID patients often don’t have conclusive results, which can lead doctors and patients themselves to question whether symptoms are truly “physical versus psychosomatic,” she said. “It is important that providers believe their patients and treat their symptoms, even when diagnostic tests are unrevealing.”
Growing mental health crisis
Patients often find their way to academic treatment centers after surviving severe COVID-19 infections. But a growing number of long COVID patients show up at these centers after milder cases. These patients were never hospitalized for COVID-19 but still have persistent symptoms like fatigue, thinking problems, and mood disorders.
Among the major challenges is a shortage of mental health care providers to meet the surging need for care since the start of the pandemic. Around the world, anxiety and depression surged 25% during the first year of the pandemic, according to the World Health Organization.
In the United States, 40% of adults report feelings of anxiety and depression, and one in three high school students have feelings of sadness and hopelessness, according to a March 2022 statement from the White House.
Despite this surging need for care, almost half of Americans live in areas with a severe shortage of mental health care providers, according to the Health Resources and Services Administration. As of 2019, the United States had a shortage of about 6,790 mental health providers. Since then, the shortage has worsened; it’s now about 7,500 providers.
“One of the biggest challenges for hospitals and clinics in treating mental health disorders in long COVID is the limited resources and long wait times to get in for evaluations and treatment,” said Nyaz Didehbani, PhD, a neuropsychologist who treats long COVID patients at the COVID Recover program at the University of Texas Southwestern Medical Center, Dallas.
These delays can lead to worse outcomes, Dr. Didehbani said. “Additionally, patients do not feel that they are being heard, as many providers are not aware of the mental health impact and relationship with physical and cognitive symptoms.” .
Even when doctors recognize that psychological challenges are common with long COVID, they still have to think creatively to come up with treatments that meet the unique needs of these patients, said Thida Thant, MD, an assistant professor of psychiatry at the University of Colorado who treats patients at the UCHealth Post-COVID Clinic.
“There are at least two major factors that make treating psychological issues in long COVID more complex: The fact that the pandemic is still ongoing and still so divisive throughout society, and the fact that we don’t know a single best way to treat all symptoms of long COVID,” she said.
Some common treatments for anxiety and depression, like psychotherapy and medication, can be used for long COVID patients with these conditions. But another intervention that can work wonders for many people with mood disorders – exercise – doesn’t always work for long COVID patients. That’s because many of them struggle with physical challenges like chronic fatigue and what’s known as postexertional malaise, or a worsening of symptoms after even limited physical effort.
“While we normally encourage patients to be active, have a daily routine, and to engage in physical activity as part of their mental health treatment, some long COVID patients find that their symptoms worsen after increased activity,” Dr. Vannorsdall said.
Patients who are able to reach long COVID care centers are much more apt to get mental health problems diagnosed and treated, doctors at many programs around the country agree. But many patients hardest hit by the pandemic – the poor and racial and ethnic minorities – are also less likely to have ready access to hospitals that offer these programs, said Dr. Anderson.
“Affluent, predominantly White populations are showing up in these clinics, while we know that non-White populations have disproportionally high rates of acute infection, hospitalization, and death related to the virus,” he said.
Clinics are also concentrated in academic medical centers and in urban areas, limiting options for people in rural communities who may have to drive for hours to access care, Dr. Anderson said.
“Even before long COVID, we already knew that many people live in areas where there simply aren’t enough mental health services available,” said John Zulueta, MD, an assistant professor of clinical psychiatry at the University of Illinois at Chicago who provides mental health evaluations at the UI Health Post-COVID Clinic.
“As more patients develop mental health issues associated with long COVID, it’s going to put more stress on an already stressed system,” he said.
A version of this article first appeared on WebMD.com.
Metabolic syndrome raises dementia risk in under-60s
The more components of metabolic syndrome a person has in midlife seems to raise their risk of dementia, although that relationship seems to go away after age 70, a post hoc analysis of data from a major European cohort study has found.
A team of European researchers reported online in the journal Diabetes Care that the follow-up of the Whitehall II cohort study, a study of more than 10,000 civil servants in London that was established in the late 1980s, also found that cardiovascular disease (CVD) may only partially contribute to the risk of dementia in study participants.
They found that each additional metabolic syndrome component before age 60 years was linked to a 13% rise in the risk of dementia (hazard ratio, 1.13; 95% confidence interval [CI], 1.05-1.23) and, from age 60 to 70, the risk rose 8% (HR, 1.08; 95% CI, 1.00-1.16). However, in people aged 70 years and older, the relationship wasn’t statistically significant (HR, 1.04; 95% CI, 0.96-1.13]).
The study used “the latest harmonized definition” of metabolic syndrome; that is, participants were classified as having metabolic syndrome if they had three or more of the five components. As lead author Marcos D. Machado-Fragua, PhD, noted in an email interview, those components are abdominal obesity, high triglycerides, low HDL cholesterol levels, high blood pressure, and high fasting glucose.
“Our research question was on the association between metabolic syndrome and late-life dementia. We found that the presence of one metabolic syndrome component and the presence of metabolic risk before age 60, but not after, is associated with higher risk of dementia,” said Dr. Machado-Fragua, a post-doctoral researcher at the French Institute for Health and Medical Research in Paris.
The study cohort consisted of 10,308 London-based civil servants aged 35-55 years. Every 4-5 years after enrollment, from 1991 through 2016, they completed a questionnaire and had a clinical examination. The U.K. National Health Service electronic health record system tracked outcomes for all but 10 participants through March 2019.
The study identified the individual metabolic syndrome components that posed the highest risk for dementia in these three age groups:
- Age < 60 years: elevated waist circumference (HR 1.39 [95% CI 1.07, 1.81]), low HDL-C, (HR 1.30 [95% CI 1.02, 1.66]), and elevated blood pressure (HR 1.34 [95% CI 1.09, 1.63]).
- Age 60-70 years: low HDL-C (HR 1.26 [95% CI 1.02, 1.57]) and elevated fasting glucose (HR 1.40 [95% CI 1.12, 1.74]).
- Age >70 years: elevated fasting glucose (HR 1.38 [95% CI 1.07, 1.79]).
The study found that the dementia risk was significantly high in study participants under age 60 who had at least one (HR 1.99 [95% CI 1.08, 3.66]) or two (HR 1.69 [95% CI 1.12, 2.56]) metabolic syndrome components even when they didn’t have CVD.
“The present study adds to the understanding of the association between metabolic syndrome and dementia due to three novel features,” Dr. Machado-Fragua said. “First, we tested alternative thresholds to define ‘high metabolic risk,’ and findings show increased risk of dementia to start with the presence of one metabolic syndrome component. Second, assessment of metabolic syndrome components in midlife and later life allowed the examination of the role of age at prevalence of metabolic risk for incident dementia at older ages. Third, our findings showed high dementia risk in those free of cardiovascular disease during follow-up, suggesting that the association between high metabolic risk and incident dementia is not fully explained by cardiovascular disease.”
Dr. Machado-Fragua added, “For now, a cure for dementia remains elusive, making it important to think of prevention strategies. Our findings support targeting the components of the metabolic syndrome in midlife, even in those who have fewer than three of the metabolic syndrome components.”
Applicability ‘confusing’
In an interview, Yehuda Handelsman, MD, questioned the applicability of the study findings in the clinic. “Metabolic syndrome is a clinical manifestation of insulin resistance,” he said. “The more metabolic syndrome criteria a person has, the more insulin resistant that person will be. There is literature that is [suggesting] that insulin resistance is an important cause of dementia.”
The finding of a higher dementia risk before age 70, compared to afterward, makes the applicability “even more confusing,” he said. The results are even more muddled for U.S. physicians, who have moved away from the term metabolic syndrome in favor of cardiometabolic syndrome, said Dr. Handelsman, medical director and principal investigator at the Metabolic Institute of America and president of the Diabetes CardioRenal & Metabolism Institute, both in Tarzana, Calif.
Confusion also surrounds one of the components of metabolic syndrome: Waist circumference, per the harmonized definition the study used, and body mass index, which the more traditional definition uses.
Nonetheless, metabolic syndrome can be used as “kind of a risk calculator” for CVD, diabetes, and dementia, he said. One strength of the study, Dr. Handelsman said, is its size and scope, following 28 years of data. But a weakness was its observational design. “It doesn’t evaluate any true intervention to modify risk,” he said.
Dr. Machado-Fragua and coauthors have no disclosures.
The more components of metabolic syndrome a person has in midlife seems to raise their risk of dementia, although that relationship seems to go away after age 70, a post hoc analysis of data from a major European cohort study has found.
A team of European researchers reported online in the journal Diabetes Care that the follow-up of the Whitehall II cohort study, a study of more than 10,000 civil servants in London that was established in the late 1980s, also found that cardiovascular disease (CVD) may only partially contribute to the risk of dementia in study participants.
They found that each additional metabolic syndrome component before age 60 years was linked to a 13% rise in the risk of dementia (hazard ratio, 1.13; 95% confidence interval [CI], 1.05-1.23) and, from age 60 to 70, the risk rose 8% (HR, 1.08; 95% CI, 1.00-1.16). However, in people aged 70 years and older, the relationship wasn’t statistically significant (HR, 1.04; 95% CI, 0.96-1.13]).
The study used “the latest harmonized definition” of metabolic syndrome; that is, participants were classified as having metabolic syndrome if they had three or more of the five components. As lead author Marcos D. Machado-Fragua, PhD, noted in an email interview, those components are abdominal obesity, high triglycerides, low HDL cholesterol levels, high blood pressure, and high fasting glucose.
“Our research question was on the association between metabolic syndrome and late-life dementia. We found that the presence of one metabolic syndrome component and the presence of metabolic risk before age 60, but not after, is associated with higher risk of dementia,” said Dr. Machado-Fragua, a post-doctoral researcher at the French Institute for Health and Medical Research in Paris.
The study cohort consisted of 10,308 London-based civil servants aged 35-55 years. Every 4-5 years after enrollment, from 1991 through 2016, they completed a questionnaire and had a clinical examination. The U.K. National Health Service electronic health record system tracked outcomes for all but 10 participants through March 2019.
The study identified the individual metabolic syndrome components that posed the highest risk for dementia in these three age groups:
- Age < 60 years: elevated waist circumference (HR 1.39 [95% CI 1.07, 1.81]), low HDL-C, (HR 1.30 [95% CI 1.02, 1.66]), and elevated blood pressure (HR 1.34 [95% CI 1.09, 1.63]).
- Age 60-70 years: low HDL-C (HR 1.26 [95% CI 1.02, 1.57]) and elevated fasting glucose (HR 1.40 [95% CI 1.12, 1.74]).
- Age >70 years: elevated fasting glucose (HR 1.38 [95% CI 1.07, 1.79]).
The study found that the dementia risk was significantly high in study participants under age 60 who had at least one (HR 1.99 [95% CI 1.08, 3.66]) or two (HR 1.69 [95% CI 1.12, 2.56]) metabolic syndrome components even when they didn’t have CVD.
“The present study adds to the understanding of the association between metabolic syndrome and dementia due to three novel features,” Dr. Machado-Fragua said. “First, we tested alternative thresholds to define ‘high metabolic risk,’ and findings show increased risk of dementia to start with the presence of one metabolic syndrome component. Second, assessment of metabolic syndrome components in midlife and later life allowed the examination of the role of age at prevalence of metabolic risk for incident dementia at older ages. Third, our findings showed high dementia risk in those free of cardiovascular disease during follow-up, suggesting that the association between high metabolic risk and incident dementia is not fully explained by cardiovascular disease.”
Dr. Machado-Fragua added, “For now, a cure for dementia remains elusive, making it important to think of prevention strategies. Our findings support targeting the components of the metabolic syndrome in midlife, even in those who have fewer than three of the metabolic syndrome components.”
Applicability ‘confusing’
In an interview, Yehuda Handelsman, MD, questioned the applicability of the study findings in the clinic. “Metabolic syndrome is a clinical manifestation of insulin resistance,” he said. “The more metabolic syndrome criteria a person has, the more insulin resistant that person will be. There is literature that is [suggesting] that insulin resistance is an important cause of dementia.”
The finding of a higher dementia risk before age 70, compared to afterward, makes the applicability “even more confusing,” he said. The results are even more muddled for U.S. physicians, who have moved away from the term metabolic syndrome in favor of cardiometabolic syndrome, said Dr. Handelsman, medical director and principal investigator at the Metabolic Institute of America and president of the Diabetes CardioRenal & Metabolism Institute, both in Tarzana, Calif.
Confusion also surrounds one of the components of metabolic syndrome: Waist circumference, per the harmonized definition the study used, and body mass index, which the more traditional definition uses.
Nonetheless, metabolic syndrome can be used as “kind of a risk calculator” for CVD, diabetes, and dementia, he said. One strength of the study, Dr. Handelsman said, is its size and scope, following 28 years of data. But a weakness was its observational design. “It doesn’t evaluate any true intervention to modify risk,” he said.
Dr. Machado-Fragua and coauthors have no disclosures.
The more components of metabolic syndrome a person has in midlife seems to raise their risk of dementia, although that relationship seems to go away after age 70, a post hoc analysis of data from a major European cohort study has found.
A team of European researchers reported online in the journal Diabetes Care that the follow-up of the Whitehall II cohort study, a study of more than 10,000 civil servants in London that was established in the late 1980s, also found that cardiovascular disease (CVD) may only partially contribute to the risk of dementia in study participants.
They found that each additional metabolic syndrome component before age 60 years was linked to a 13% rise in the risk of dementia (hazard ratio, 1.13; 95% confidence interval [CI], 1.05-1.23) and, from age 60 to 70, the risk rose 8% (HR, 1.08; 95% CI, 1.00-1.16). However, in people aged 70 years and older, the relationship wasn’t statistically significant (HR, 1.04; 95% CI, 0.96-1.13]).
The study used “the latest harmonized definition” of metabolic syndrome; that is, participants were classified as having metabolic syndrome if they had three or more of the five components. As lead author Marcos D. Machado-Fragua, PhD, noted in an email interview, those components are abdominal obesity, high triglycerides, low HDL cholesterol levels, high blood pressure, and high fasting glucose.
“Our research question was on the association between metabolic syndrome and late-life dementia. We found that the presence of one metabolic syndrome component and the presence of metabolic risk before age 60, but not after, is associated with higher risk of dementia,” said Dr. Machado-Fragua, a post-doctoral researcher at the French Institute for Health and Medical Research in Paris.
The study cohort consisted of 10,308 London-based civil servants aged 35-55 years. Every 4-5 years after enrollment, from 1991 through 2016, they completed a questionnaire and had a clinical examination. The U.K. National Health Service electronic health record system tracked outcomes for all but 10 participants through March 2019.
The study identified the individual metabolic syndrome components that posed the highest risk for dementia in these three age groups:
- Age < 60 years: elevated waist circumference (HR 1.39 [95% CI 1.07, 1.81]), low HDL-C, (HR 1.30 [95% CI 1.02, 1.66]), and elevated blood pressure (HR 1.34 [95% CI 1.09, 1.63]).
- Age 60-70 years: low HDL-C (HR 1.26 [95% CI 1.02, 1.57]) and elevated fasting glucose (HR 1.40 [95% CI 1.12, 1.74]).
- Age >70 years: elevated fasting glucose (HR 1.38 [95% CI 1.07, 1.79]).
The study found that the dementia risk was significantly high in study participants under age 60 who had at least one (HR 1.99 [95% CI 1.08, 3.66]) or two (HR 1.69 [95% CI 1.12, 2.56]) metabolic syndrome components even when they didn’t have CVD.
“The present study adds to the understanding of the association between metabolic syndrome and dementia due to three novel features,” Dr. Machado-Fragua said. “First, we tested alternative thresholds to define ‘high metabolic risk,’ and findings show increased risk of dementia to start with the presence of one metabolic syndrome component. Second, assessment of metabolic syndrome components in midlife and later life allowed the examination of the role of age at prevalence of metabolic risk for incident dementia at older ages. Third, our findings showed high dementia risk in those free of cardiovascular disease during follow-up, suggesting that the association between high metabolic risk and incident dementia is not fully explained by cardiovascular disease.”
Dr. Machado-Fragua added, “For now, a cure for dementia remains elusive, making it important to think of prevention strategies. Our findings support targeting the components of the metabolic syndrome in midlife, even in those who have fewer than three of the metabolic syndrome components.”
Applicability ‘confusing’
In an interview, Yehuda Handelsman, MD, questioned the applicability of the study findings in the clinic. “Metabolic syndrome is a clinical manifestation of insulin resistance,” he said. “The more metabolic syndrome criteria a person has, the more insulin resistant that person will be. There is literature that is [suggesting] that insulin resistance is an important cause of dementia.”
The finding of a higher dementia risk before age 70, compared to afterward, makes the applicability “even more confusing,” he said. The results are even more muddled for U.S. physicians, who have moved away from the term metabolic syndrome in favor of cardiometabolic syndrome, said Dr. Handelsman, medical director and principal investigator at the Metabolic Institute of America and president of the Diabetes CardioRenal & Metabolism Institute, both in Tarzana, Calif.
Confusion also surrounds one of the components of metabolic syndrome: Waist circumference, per the harmonized definition the study used, and body mass index, which the more traditional definition uses.
Nonetheless, metabolic syndrome can be used as “kind of a risk calculator” for CVD, diabetes, and dementia, he said. One strength of the study, Dr. Handelsman said, is its size and scope, following 28 years of data. But a weakness was its observational design. “It doesn’t evaluate any true intervention to modify risk,” he said.
Dr. Machado-Fragua and coauthors have no disclosures.
FROM DIABETES CARE
Understanding the neuroscience of narcissism
Editor’s Note: The study covered in this summary was published on ResearchSquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
The cognitive features and phenotypic diversity of narcissism subtypes are partially unknown.
This study integrates both grandiose and vulnerable narcissism into a common framework with cognitive components connected to these traits.
Study design
This study enrolled 478 participants (397 female and 4 did not reveal their gender).
The average age of participants was 35 years (standard deviation, 14.97), with a range of 18-76 years.
A 25-item version of the Narcissistic Personality Inventory (NPI), a 40-item self-report measure of narcissism traits, was used to assess the level of authority, grandiose exhibitionism, and entitlement/exploitativeness characteristics of study participants.
The Maladaptive Covert Narcissism Scale, an expanded version of the 23-item self-report Hypersensitive Narcissism Scale, was used to assess the level of hypersensitivity, vulnerability, and entitlement of study participants.
The Rosenberg Self-Esteem Scale, a 10-item self-report scale, was used to assess the level of self-esteem of study participants.
The Young Schema Questionnaire is a 244-item measure of 19 different maladaptive schemas and was used to observe Emotional Deprivation, Vulnerability to Harm and Illness, and Entitlement schemas of study participants.
The Empathizing Quotient is a self-report measure and was used to assess the emotional intelligence of study participants.
Key results
Moderate correlation between grandiose and vulnerable narcissism and the Entitlement schema was observed.
A moderate/strong connection was observed between vulnerable narcissism and the Vulnerability to Harm and Illness schema and a moderate connection with the Emotional Deprivation schema.
No significant correlation was observed between grandiose narcissism and the Emotional Deprivation schema.
A moderate, negative correlation between vulnerable narcissism and emotional skills was observed.
A positive, weak connection between grandiose narcissism and self-esteem; and a negative, moderate connection between vulnerable narcissism and self-esteem were observed.
Gender and age were associated with empathic skills, and age was weakly/moderately connected with self-esteem and vulnerable narcissism.
Limitations
This was a cross-sectional analysis investigating a temporally specific state of personality and cognitive functioning.
The gender ratio was shifted toward women in this study.
Conclusions drawn from connections between observed components are interchangeable and cause/effect connections cannot be discerned.
Disclosures
The study was supported by the National Research, Development, and Innovation Office (Grant No. NRDI–138040) and by the Human Resource Development Operational Program – Comprehensive developments at the University of Pécs for the implementation of intelligent specialization (EFOP-3.6.1-16-2016-00004). First author Dorian Vida’s work was supported by the Collegium Talentum Programme of Hungary. None of the authors disclosed any competing interests.
This is a summary of a preprint research study, “In the mind of Narcissus: the mediating role of emotional regulation in the emergence of distorted cognitions,” written by Dorian Vida from the University of Pécs, Hungary and colleagues on ResearchSquare.com. This study has not yet been peer reviewed. The full text of the study can be found on ResearchSquare.com.
A version of this article first appeared on Medscape.com
Editor’s Note: The study covered in this summary was published on ResearchSquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
The cognitive features and phenotypic diversity of narcissism subtypes are partially unknown.
This study integrates both grandiose and vulnerable narcissism into a common framework with cognitive components connected to these traits.
Study design
This study enrolled 478 participants (397 female and 4 did not reveal their gender).
The average age of participants was 35 years (standard deviation, 14.97), with a range of 18-76 years.
A 25-item version of the Narcissistic Personality Inventory (NPI), a 40-item self-report measure of narcissism traits, was used to assess the level of authority, grandiose exhibitionism, and entitlement/exploitativeness characteristics of study participants.
The Maladaptive Covert Narcissism Scale, an expanded version of the 23-item self-report Hypersensitive Narcissism Scale, was used to assess the level of hypersensitivity, vulnerability, and entitlement of study participants.
The Rosenberg Self-Esteem Scale, a 10-item self-report scale, was used to assess the level of self-esteem of study participants.
The Young Schema Questionnaire is a 244-item measure of 19 different maladaptive schemas and was used to observe Emotional Deprivation, Vulnerability to Harm and Illness, and Entitlement schemas of study participants.
The Empathizing Quotient is a self-report measure and was used to assess the emotional intelligence of study participants.
Key results
Moderate correlation between grandiose and vulnerable narcissism and the Entitlement schema was observed.
A moderate/strong connection was observed between vulnerable narcissism and the Vulnerability to Harm and Illness schema and a moderate connection with the Emotional Deprivation schema.
No significant correlation was observed between grandiose narcissism and the Emotional Deprivation schema.
A moderate, negative correlation between vulnerable narcissism and emotional skills was observed.
A positive, weak connection between grandiose narcissism and self-esteem; and a negative, moderate connection between vulnerable narcissism and self-esteem were observed.
Gender and age were associated with empathic skills, and age was weakly/moderately connected with self-esteem and vulnerable narcissism.
Limitations
This was a cross-sectional analysis investigating a temporally specific state of personality and cognitive functioning.
The gender ratio was shifted toward women in this study.
Conclusions drawn from connections between observed components are interchangeable and cause/effect connections cannot be discerned.
Disclosures
The study was supported by the National Research, Development, and Innovation Office (Grant No. NRDI–138040) and by the Human Resource Development Operational Program – Comprehensive developments at the University of Pécs for the implementation of intelligent specialization (EFOP-3.6.1-16-2016-00004). First author Dorian Vida’s work was supported by the Collegium Talentum Programme of Hungary. None of the authors disclosed any competing interests.
This is a summary of a preprint research study, “In the mind of Narcissus: the mediating role of emotional regulation in the emergence of distorted cognitions,” written by Dorian Vida from the University of Pécs, Hungary and colleagues on ResearchSquare.com. This study has not yet been peer reviewed. The full text of the study can be found on ResearchSquare.com.
A version of this article first appeared on Medscape.com
Editor’s Note: The study covered in this summary was published on ResearchSquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
The cognitive features and phenotypic diversity of narcissism subtypes are partially unknown.
This study integrates both grandiose and vulnerable narcissism into a common framework with cognitive components connected to these traits.
Study design
This study enrolled 478 participants (397 female and 4 did not reveal their gender).
The average age of participants was 35 years (standard deviation, 14.97), with a range of 18-76 years.
A 25-item version of the Narcissistic Personality Inventory (NPI), a 40-item self-report measure of narcissism traits, was used to assess the level of authority, grandiose exhibitionism, and entitlement/exploitativeness characteristics of study participants.
The Maladaptive Covert Narcissism Scale, an expanded version of the 23-item self-report Hypersensitive Narcissism Scale, was used to assess the level of hypersensitivity, vulnerability, and entitlement of study participants.
The Rosenberg Self-Esteem Scale, a 10-item self-report scale, was used to assess the level of self-esteem of study participants.
The Young Schema Questionnaire is a 244-item measure of 19 different maladaptive schemas and was used to observe Emotional Deprivation, Vulnerability to Harm and Illness, and Entitlement schemas of study participants.
The Empathizing Quotient is a self-report measure and was used to assess the emotional intelligence of study participants.
Key results
Moderate correlation between grandiose and vulnerable narcissism and the Entitlement schema was observed.
A moderate/strong connection was observed between vulnerable narcissism and the Vulnerability to Harm and Illness schema and a moderate connection with the Emotional Deprivation schema.
No significant correlation was observed between grandiose narcissism and the Emotional Deprivation schema.
A moderate, negative correlation between vulnerable narcissism and emotional skills was observed.
A positive, weak connection between grandiose narcissism and self-esteem; and a negative, moderate connection between vulnerable narcissism and self-esteem were observed.
Gender and age were associated with empathic skills, and age was weakly/moderately connected with self-esteem and vulnerable narcissism.
Limitations
This was a cross-sectional analysis investigating a temporally specific state of personality and cognitive functioning.
The gender ratio was shifted toward women in this study.
Conclusions drawn from connections between observed components are interchangeable and cause/effect connections cannot be discerned.
Disclosures
The study was supported by the National Research, Development, and Innovation Office (Grant No. NRDI–138040) and by the Human Resource Development Operational Program – Comprehensive developments at the University of Pécs for the implementation of intelligent specialization (EFOP-3.6.1-16-2016-00004). First author Dorian Vida’s work was supported by the Collegium Talentum Programme of Hungary. None of the authors disclosed any competing interests.
This is a summary of a preprint research study, “In the mind of Narcissus: the mediating role of emotional regulation in the emergence of distorted cognitions,” written by Dorian Vida from the University of Pécs, Hungary and colleagues on ResearchSquare.com. This study has not yet been peer reviewed. The full text of the study can be found on ResearchSquare.com.
A version of this article first appeared on Medscape.com
‘Case closed’: Bridging thrombolysis remains ‘gold standard’ in stroke thrombectomy
Two new noninferiority trials address the controversial question of whether thrombolytic therapy can be omitted for acute ischemic stroke in patients undergoing endovascular thrombectomy for large-vessel occlusion.
Both trials show better outcomes when standard bridging thrombolytic therapy is used before thrombectomy, with comparable safety.
The results of SWIFT-DIRECT and DIRECT-SAFE were published online June 22 in The Lancet.
“The case appears closed. Bypass intravenous thrombolysis is highly unlikely to be noninferior to standard care by a clinically acceptable margin for most patients,” writes Pooja Khatri, MD, MSc, department of neurology, University of Cincinnati, in a linked comment.
SWIFT-DIRECT
SWIFT-DIRECT enrolled 408 patients (median age 72; 51% women) with acute stroke due to large vessel occlusion admitted to stroke centers in Europe and Canada. Half were randomly allocated to thrombectomy alone and half to intravenous alteplase and thrombectomy.
Successful reperfusion was less common in patients who had thrombectomy alone (91% vs. 96%; risk difference −5.1%; 95% confidence interval, −10.2 to 0.0, P = .047).
With combination therapy, more patients achieved functional independence with a modified Rankin scale score of 0-2 at 90 days (65% vs. 57%; adjusted risk difference −7.3%; 95% CI, −16·6 to 2·1, lower limit of one-sided 95% CI, −15·1%, crossing the noninferiority margin of −12%).
“Despite a very liberal noninferiority margin and strict inclusion and exclusion criteria aimed at studying a population most likely to benefit from thrombectomy alone, point estimates directionally favored intravenous thrombolysis plus thrombectomy,” Urs Fischer, MD, cochair of the Stroke Center, University Hospital Basel, Switzerland, told this news organization.
“Furthermore, we could demonstrate that overall reperfusion rates were extremely high and yet significantly better in patients receiving intravenous thrombolysis plus thrombectomy than in patients treated with thrombectomy alone, a finding which has not been shown before,” Dr. Fischer said.
There was no significant difference in the risk of symptomatic intracranial bleeding (3% with combination therapy and 2% with thrombectomy alone).
Based on the results, in patients suitable for thrombolysis, skipping it before thrombectomy “is not justified,” the study team concludes.
DIRECT-SAFE
DIRECT-SAFE enrolled 295 patients (median age 69; 43% women) with stroke and large vessel occlusion from Australia, New Zealand, China, and Vietnam, with half undergoing direct thrombectomy and half bridging therapy first.
Functional independence (modified Rankin Scale 0-2 or return to baseline at 90 days) was more common in the bridging group (61% vs. 55%).
Safety outcomes were similar between groups. Symptomatic intracerebral hemorrhage occurred in 2 (1%) patients in the direct group and 1 (1%) patient in the bridging group. There were 22 (15%) deaths in the direct group and 24 in the bridging group.
“There has been concern across the world regarding cost of treatment, together with fears of increasing bleeding risk or clot migration with intravenous thrombolytic,” lead investigator Peter Mitchell, MBBS, director, NeuroIntervention Service, The Royal Melbourne Hospital, Parkville, Victoria, Australia, told this news organization.
“We showed that patients in the bridging treatment arm had better outcomes across the entire study, especially in Asian region patients” and therefore remains “the gold standard,” Dr. Mitchell said.
To date, six published trials have addressed this question of endovascular therapy alone or with thrombolysis – SKIP, DIRECT-MT, MR CLEAN NO IV, SWIFT-DIRECT, and DIRECT-SAFE.
Dr. Fischer said the SWIFT-DIRECT study group plans to perform an individual participant data meta-analysis known as Improving Reperfusion Strategies in Ischemic Stroke (IRIS) of all six trials to see whether there are subgroups of patients in whom thrombectomy alone is as effective as thrombolysis plus thrombectomy.
Subgroups of interest, he said, include patients with early ischemic signs on imaging, those at increased risk for hemorrhagic complications, and patients with a high clot burden.
SWIFT-DIRECT was funding by Medtronic and University Hospital Bern. DIRECT-SAFE was funded by Australian National Health and Medical Research Council and Stryker USA. A complete list of author disclosures is available with the original articles.
A version of this article first appeared on Medscape.com.
Two new noninferiority trials address the controversial question of whether thrombolytic therapy can be omitted for acute ischemic stroke in patients undergoing endovascular thrombectomy for large-vessel occlusion.
Both trials show better outcomes when standard bridging thrombolytic therapy is used before thrombectomy, with comparable safety.
The results of SWIFT-DIRECT and DIRECT-SAFE were published online June 22 in The Lancet.
“The case appears closed. Bypass intravenous thrombolysis is highly unlikely to be noninferior to standard care by a clinically acceptable margin for most patients,” writes Pooja Khatri, MD, MSc, department of neurology, University of Cincinnati, in a linked comment.
SWIFT-DIRECT
SWIFT-DIRECT enrolled 408 patients (median age 72; 51% women) with acute stroke due to large vessel occlusion admitted to stroke centers in Europe and Canada. Half were randomly allocated to thrombectomy alone and half to intravenous alteplase and thrombectomy.
Successful reperfusion was less common in patients who had thrombectomy alone (91% vs. 96%; risk difference −5.1%; 95% confidence interval, −10.2 to 0.0, P = .047).
With combination therapy, more patients achieved functional independence with a modified Rankin scale score of 0-2 at 90 days (65% vs. 57%; adjusted risk difference −7.3%; 95% CI, −16·6 to 2·1, lower limit of one-sided 95% CI, −15·1%, crossing the noninferiority margin of −12%).
“Despite a very liberal noninferiority margin and strict inclusion and exclusion criteria aimed at studying a population most likely to benefit from thrombectomy alone, point estimates directionally favored intravenous thrombolysis plus thrombectomy,” Urs Fischer, MD, cochair of the Stroke Center, University Hospital Basel, Switzerland, told this news organization.
“Furthermore, we could demonstrate that overall reperfusion rates were extremely high and yet significantly better in patients receiving intravenous thrombolysis plus thrombectomy than in patients treated with thrombectomy alone, a finding which has not been shown before,” Dr. Fischer said.
There was no significant difference in the risk of symptomatic intracranial bleeding (3% with combination therapy and 2% with thrombectomy alone).
Based on the results, in patients suitable for thrombolysis, skipping it before thrombectomy “is not justified,” the study team concludes.
DIRECT-SAFE
DIRECT-SAFE enrolled 295 patients (median age 69; 43% women) with stroke and large vessel occlusion from Australia, New Zealand, China, and Vietnam, with half undergoing direct thrombectomy and half bridging therapy first.
Functional independence (modified Rankin Scale 0-2 or return to baseline at 90 days) was more common in the bridging group (61% vs. 55%).
Safety outcomes were similar between groups. Symptomatic intracerebral hemorrhage occurred in 2 (1%) patients in the direct group and 1 (1%) patient in the bridging group. There were 22 (15%) deaths in the direct group and 24 in the bridging group.
“There has been concern across the world regarding cost of treatment, together with fears of increasing bleeding risk or clot migration with intravenous thrombolytic,” lead investigator Peter Mitchell, MBBS, director, NeuroIntervention Service, The Royal Melbourne Hospital, Parkville, Victoria, Australia, told this news organization.
“We showed that patients in the bridging treatment arm had better outcomes across the entire study, especially in Asian region patients” and therefore remains “the gold standard,” Dr. Mitchell said.
To date, six published trials have addressed this question of endovascular therapy alone or with thrombolysis – SKIP, DIRECT-MT, MR CLEAN NO IV, SWIFT-DIRECT, and DIRECT-SAFE.
Dr. Fischer said the SWIFT-DIRECT study group plans to perform an individual participant data meta-analysis known as Improving Reperfusion Strategies in Ischemic Stroke (IRIS) of all six trials to see whether there are subgroups of patients in whom thrombectomy alone is as effective as thrombolysis plus thrombectomy.
Subgroups of interest, he said, include patients with early ischemic signs on imaging, those at increased risk for hemorrhagic complications, and patients with a high clot burden.
SWIFT-DIRECT was funding by Medtronic and University Hospital Bern. DIRECT-SAFE was funded by Australian National Health and Medical Research Council and Stryker USA. A complete list of author disclosures is available with the original articles.
A version of this article first appeared on Medscape.com.
Two new noninferiority trials address the controversial question of whether thrombolytic therapy can be omitted for acute ischemic stroke in patients undergoing endovascular thrombectomy for large-vessel occlusion.
Both trials show better outcomes when standard bridging thrombolytic therapy is used before thrombectomy, with comparable safety.
The results of SWIFT-DIRECT and DIRECT-SAFE were published online June 22 in The Lancet.
“The case appears closed. Bypass intravenous thrombolysis is highly unlikely to be noninferior to standard care by a clinically acceptable margin for most patients,” writes Pooja Khatri, MD, MSc, department of neurology, University of Cincinnati, in a linked comment.
SWIFT-DIRECT
SWIFT-DIRECT enrolled 408 patients (median age 72; 51% women) with acute stroke due to large vessel occlusion admitted to stroke centers in Europe and Canada. Half were randomly allocated to thrombectomy alone and half to intravenous alteplase and thrombectomy.
Successful reperfusion was less common in patients who had thrombectomy alone (91% vs. 96%; risk difference −5.1%; 95% confidence interval, −10.2 to 0.0, P = .047).
With combination therapy, more patients achieved functional independence with a modified Rankin scale score of 0-2 at 90 days (65% vs. 57%; adjusted risk difference −7.3%; 95% CI, −16·6 to 2·1, lower limit of one-sided 95% CI, −15·1%, crossing the noninferiority margin of −12%).
“Despite a very liberal noninferiority margin and strict inclusion and exclusion criteria aimed at studying a population most likely to benefit from thrombectomy alone, point estimates directionally favored intravenous thrombolysis plus thrombectomy,” Urs Fischer, MD, cochair of the Stroke Center, University Hospital Basel, Switzerland, told this news organization.
“Furthermore, we could demonstrate that overall reperfusion rates were extremely high and yet significantly better in patients receiving intravenous thrombolysis plus thrombectomy than in patients treated with thrombectomy alone, a finding which has not been shown before,” Dr. Fischer said.
There was no significant difference in the risk of symptomatic intracranial bleeding (3% with combination therapy and 2% with thrombectomy alone).
Based on the results, in patients suitable for thrombolysis, skipping it before thrombectomy “is not justified,” the study team concludes.
DIRECT-SAFE
DIRECT-SAFE enrolled 295 patients (median age 69; 43% women) with stroke and large vessel occlusion from Australia, New Zealand, China, and Vietnam, with half undergoing direct thrombectomy and half bridging therapy first.
Functional independence (modified Rankin Scale 0-2 or return to baseline at 90 days) was more common in the bridging group (61% vs. 55%).
Safety outcomes were similar between groups. Symptomatic intracerebral hemorrhage occurred in 2 (1%) patients in the direct group and 1 (1%) patient in the bridging group. There were 22 (15%) deaths in the direct group and 24 in the bridging group.
“There has been concern across the world regarding cost of treatment, together with fears of increasing bleeding risk or clot migration with intravenous thrombolytic,” lead investigator Peter Mitchell, MBBS, director, NeuroIntervention Service, The Royal Melbourne Hospital, Parkville, Victoria, Australia, told this news organization.
“We showed that patients in the bridging treatment arm had better outcomes across the entire study, especially in Asian region patients” and therefore remains “the gold standard,” Dr. Mitchell said.
To date, six published trials have addressed this question of endovascular therapy alone or with thrombolysis – SKIP, DIRECT-MT, MR CLEAN NO IV, SWIFT-DIRECT, and DIRECT-SAFE.
Dr. Fischer said the SWIFT-DIRECT study group plans to perform an individual participant data meta-analysis known as Improving Reperfusion Strategies in Ischemic Stroke (IRIS) of all six trials to see whether there are subgroups of patients in whom thrombectomy alone is as effective as thrombolysis plus thrombectomy.
Subgroups of interest, he said, include patients with early ischemic signs on imaging, those at increased risk for hemorrhagic complications, and patients with a high clot burden.
SWIFT-DIRECT was funding by Medtronic and University Hospital Bern. DIRECT-SAFE was funded by Australian National Health and Medical Research Council and Stryker USA. A complete list of author disclosures is available with the original articles.
A version of this article first appeared on Medscape.com.
FROM THE LANCET