Multiple sclerosis presenting with paroxysmal symptoms: Patients at the limitations of current diagnostic criteria.

Paroxysmal neurological symptoms in patients with multiple sclerosis (MS) have long been acknowledged. However, consideration of whether such symptoms are a clinical attack and sufficient for fulfillment of MS diagnostic criteria has varied as criteria have evolved over time. Previous studies and anecdotal reports indicate that some patients with MS first present with syndromes such as trigeminal neuralgia, Lhermitte's phenomenon, tonic spasm, and seizure years before an attack typical of MS such as optic neuritis or myelitis. We discuss four patients with presumed MS who initially presented with these syndromes with evidence of a corresponding central nervous system (CNS) lesion who, were these symptoms considered an attack, could have been diagnosed with relapsing remitting MS or clinically isolated syndrome. This case series aims to highlight the unmet need for data for such patient presentations and for clinical guidance from future MS diagnostic criteria to optimize care.

Diagnosis concealment behaviors and disclosure beliefs are associated with health and quality of life in people with multiple sclerosis.

BACKGROUND: People with multiple sclerosis (pwMS) struggle with whether, how, and how much to disclose their diagnosis. They often expend resources to conceal their diagnosis, and hold beliefs that it may negatively affect their personal relationships and/or professional opportunities. To better understand these effects, we developed a measure to quantify concealment behaviors and disclosure beliefs. Our main objective is to evaluate relationships of DISCO-MS responses to health and quality of life in a multinational cohort. METHODS: Survey responses were obtained for DISCO-MS and PROMIS-MS scales: global health, communication, social roles participation, anxiety, depression, emotional / behavioral dyscontrol, fatigue, lower extremity function, positive affect / well-being, social roles satisfaction, sleep, stigma, upper extremity function, cognitive function, bladder control, bowel control, visual function. Simple linear regression assessed associations. RESULTS: 263 pwMS were include. Higher concealment was associated with higher anxiety (beta= 0.15 [0.07, 0.23]), depression (beta = 0.13 [0.05, 0.21]), emotional dyscontrol (beta = 0.12 [0.04, 0.20]), lower affect / well-being (beta = -0.13 [-0.21, - 0.05]). Higher anticipation of negative consequences of disclosure was associated with lower self-reported physical (beta = -0.15) and mental health (beta = -0.14), lower positive affect / well-being, social roles satisfaction, higher anxiety, depression, emotional dyscontrol, sleep disturbance, and higher perceived stigma. DISCUSSION: These results reveal potential consequences of diagnosis concealment for physical and mental health and quality of life. Raising awareness and implementing interventions may mitigate negative repercussions of concealment.

Choroid plexus volume differentiates MS from its mimics.

This study aimed to determine whether choroid plexus volume (CPV) could differentiate multiple sclerosis (MS) from its mimics. A secondary analysis of two previously enrolled studies, 50 participants with MS and 64 with alternative diagnoses were included. CPV was automatically segmented from 3T magnetic resonance imaging (MRI), followed by manual review to remove misclassified tissue. Mean normalized choroid plexus volume (nCPV) to intracranial volume demonstrated relatively high specificity for MS participants in each cohort (0.80 and 0.76) with an area under the receiver-operator characteristic curve of 0.71 (95% confidence interval (CI) = 0.55-0.87) and 0.65 (95% CI = 0.52-0.77). In this preliminary study, nCPV differentiated MS from its mimics.

Assessing Free-Living Postural Sway in Persons With Multiple Sclerosis.

Postural instability is associated with disease status and fall risk in Persons with Multiple Sclerosis (PwMS). However, assessments of postural instability, known as postural sway, leverage force platforms or wearable accelerometers, and are most often conducted in laboratory environments and are thus not broadly accessible. Remote measures of postural sway captured during daily life may provide a more accessible alterative, but their ability to capture disease status and fall risk has not yet been established. We explored the utility of remote measures of postural sway in a sample of 33 PwMS. Remote measures of sway differed significantly from lab-based measures, but still demonstrated moderately strong associations with patient-reported measures of balance and mobility impairment. Machine learning models for predicting fall risk trained on lab data provided an Area Under Curve (AUC) of 0.79, while remote data only achieved an AUC of 0.51. Remote model performance improved to an AUC of 0.74 after a new, subject-specific k-means clustering approach was applied for identifying the remote data most appropriate for modelling. This cluster-based approach for analyzing remote data also strengthened associations with patient-reported measures, increasing their strength above those observed in the lab. This work introduces a new framework for analyzing data from remote patient monitoring technologies and demonstrates the promise of remote postural sway assessment for assessing fall risk and characterizing balance impairment in PwMS.

A multicenter pilot study evaluating simplified central vein assessment for the diagnosis of multiple sclerosis.

BACKGROUND: The central vein sign (CVS) is a proposed magnetic resonance imaging (MRI) biomarker for multiple sclerosis (MS); the optimal method for abbreviated CVS scoring is not yet established. OBJECTIVE: The aim of this study was to evaluate the performance of a simplified approach to CVS assessment in a multicenter study of patients being evaluated for suspected MS. METHODS: Adults referred for possible MS to 10 sites were recruited. A post-Gd 3D T2*-weighted MRI sequence (FLAIR*) was obtained in each subject. Trained raters at each site identified up to six CVS-positive lesions per FLAIR* scan. Diagnostic performance of CVS was evaluated for a diagnosis of MS which had been confirmed using the 2017 McDonald criteria at thresholds including three positive lesions (Select-3*) and six positive lesions (Select-6*). Inter-rater reliability assessments were performed. RESULTS: Overall, 78 participants were analyzed; 37 (47%) were diagnosed with MS, and 41 (53%) were not. The mean age of participants was 45 (range: 19-64) years, and most were female (n = 55, 71%). The area under the receiver operating characteristic curve (AUROC) for the simplified counting method was 0.83 (95% CI: 0.73-0.93). Select-3* and Select-6* had sensitivity of 81% and 65% and specificity of 68% and 98%, respectively. Inter-rater agreement was 78% for Select-3* and 83% for Select-6*. CONCLUSION: A simplified method for CVS assessment in patients referred for suspected MS demonstrated good diagnostic performance and inter-rater agreement.

Implementing Shared Decision-Making for Multiple Sclerosis: The MS-SUPPORT Tool.

BACKGROUND: Disease modifying therapies (DMTs) offer opportunities to improve the course of multiple sclerosis (MS), but decisions about treatment are difficult. People with multiple sclerosis (pwMS) want more involvement in decisions about DMTs, but new approaches are needed to support shared decision-making (SDM) because of the number of treatment options and the range of outcomes affected by treatment. We designed a patient-centered tool, MS-SUPPORT, to facilitate SDM for pwMS. We sought to evaluate the feasibility and impact of MS-SUPPORT on decisions about disease modifying treatments (DMTs), SDM processes, and quality-of-life. METHODS: This multisite randomized controlled trial compared the SDM intervention (MS-SUPPORT) to control (usual care) over a 12-month period. English-speaking adults with relapsing MS were eligible if they had an upcoming MS appointment and an email address. To evaluate clinician perspectives, participants' MS clinicians were invited to participate. Patients were referred between November 11, 2019 and October 23, 2020 by their MS clinician or a patient advocacy organization (the Multiple Sclerosis Association of America). MS-SUPPORT is an online, interactive, evidence-based decision aid that was co-created with pwMS. It clarifies patient treatment goals and values and provides tailored information about MS, DMTs, and adherence. Viewed by patients before their clinic appointment, MS-SUPPORT generates a personalized summary of the patient's treatment goals and preferences, adherence, DMT use, and clinical situation to share with their MS clinician. Outcomes (DMT utilization, adherence, quality-of-life, and SDM) were assessed at enrollment, post-MS-SUPPORT, post-appointment, and quarterly for 1 year. RESULTS: Participants included 501 adults with MS from across the USA (84.6% female, 83% white) and 34 of their MS clinicians (47% neurologists, 41% Nurse Practitioners, 12% Physician Assistants). Among the 203 patients who completed MS-SUPPORT, most (88.2%) reported they would recommend it to others and that it helped them talk to their doctor (85.2%), understand their options (82.3%) and the importance of taking DMTs as prescribed (82.3%). Among non-users of DMTs at baseline, the probability ratio of current DMT use consistently trended higher over one-year follow-up in the MS-SUPPORT group (1.30 [0.86-1.96]), as did the cumulative probability of starting a DMT within 6-months, with shorter time-to-start (46 vs 90 days, p=0.24). Among the 222 responses from 34 participating clinicians, more clinicians in the MS-SUPPORT group (vs control) trended towards recommending their patient start a DMT (9 of 108 (8%) vs 5 of 109 (5%), respectively, p=0.26). Adherence (no missed doses) to daily-dosed DMTs was higher in the MS-SUPPORT group (81.25% vs 56.41%, p=.026). Fewer patients forgot their doses (p=.046). The MS-SUPPORT group (vs control) reported 1.7 fewer days/month of poor mental health (p=0.02). CONCLUSIONS: MS-SUPPORT was strongly endorsed by patients and is feasible to use in clinical settings. MS-SUPPORT increased the short-term probability of taking and adhering to a DMT, and improved long-term mental health. Study limitations include selection bias, response bias, social desirability bias, and recall bias. Exploring approaches to reinforcement and monitoring its implementation in real-world settings should provide further insights into the value and utility of this new SDM tool.

Laboratory evaluation for the differential diagnosis of possible multiple sclerosis in the United States: A physician survey.

BACKGROUND: There is limited evidence and lack of guidelines for diagnostic laboratory evaluation of patients with possible multiple sclerosis (MS). OBJECTIVE: To survey neurologists on their practice of laboratory testing in patients with possible MS. METHODS: An online survey was developed to query the frequency of serum and cerebrospinal fluid (CSF) studies ordered in the routine evaluation of patients with possible MS, and in three hypothetical clinical cases. Non-MS specialist neurologists who evaluate patients for MS in their practice were invited to participate by MedSurvey (a medical market research company). RESULTS: The survey was completed by 190 neurologists. A mean of 17.2 (SD: 17.0) tests in serum and CSF were reported "always" ordered in the evaluation of patients with possible MS. CSF oligoclonal bands was the most frequently selected ("always" among 73.7% of participants). Antinuclear antibody (43.2%), erythrocyte sedimentation rate (34.2%), and thyroid stimulating hormone (31.6%) were also among the most frequently ordered. DISCUSSION: Extensive laboratory evaluations are often completed in the evaluation of possible MS. However, many of these tests have poor specificity and false positive results could yield unnecessary increased costs, diagnostic delay, and potentially misdiagnosis. Further research is needed to identify optimal laboratory approaches for possible MS.

Clinical and radiologic characteristics associated with multiple sclerosis misdiagnosis at a tertiary referral center in the United States.

BACKGROUND: Misdiagnosis of multiple sclerosis (MS) is common and can have harmful effects on patients and healthcare systems. Identification of factors associated with misdiagnosis may aid development of prevention strategies. OBJECTIVE: To identify clinical and radiological predictors of MS misdiagnosis. METHODS: We retrospectively reviewed medical records of all patients who were referred to Johns Hopkins MS Center from January 2018 to June 2019. Patients who carried a diagnosis of MS were classified as correctly diagnosed or misdiagnosed with MS by the Johns Hopkins clinician. Demographics, clinical, laboratory, and radiologic data were collected. Differences between the two groups were evaluated, and a regression model was constructed to identify predictors of misdiagnosis. RESULTS: Out of 338 patients who were previously diagnosed with MS, 41 (12%) had been misdiagnosed. An alternative diagnosis was confirmed in 28 (68%) of the misdiagnosed patients; cerebrovascular disease was the most common alternate diagnosis. Characteristics associated with misdiagnosis were female sex (odds ratio (OR): 5.81 (95% confidence interval (CI): 1.60, 21.05)) and non-specific brain magnetic resonance imaging (MRI) lesions (OR: 7.66 (3.42, 17.16)). CONCLUSION: Misdiagnosis is a frequent problem in MS care. Non-specific brain lesions were the most significant predictor of misdiagnosis. Interventions aimed to reduce over-reliance on imaging findings and misapplication of the McDonald criteria may prevent MS misdiagnosis.

Differential diagnosis of suspected multiple sclerosis: an updated consensus approach.

Accurate diagnosis of multiple sclerosis requires careful attention to its differential diagnosis-many disorders can mimic the clinical manifestations and paraclinical findings of this disease. A collaborative effort, organised by The International Advisory Committee on Clinical Trials in Multiple Sclerosis in 2008, provided diagnostic approaches to multiple sclerosis and identified clinical and paraclinical findings (so-called red flags) suggestive of alternative diagnoses. Since then, knowledge of disorders in the differential diagnosis of multiple sclerosis has expanded substantially. For example, CNS inflammatory disorders that present with syndromes overlapping with multiple sclerosis can increasingly be distinguished from multiple sclerosis with the aid of specific clinical, MRI, and laboratory findings; studies of people misdiagnosed with multiple sclerosis have also provided insights into clinical presentations for which extra caution is warranted. Considering these data, an update to the recommended diagnostic approaches to common clinical presentations and key clinical and paraclinical red flags is warranted to inform the contemporary clinical evaluation of patients with suspected multiple sclerosis.

Global Barriers to the Diagnosis of Multiple Sclerosis: Data From the Multiple Sclerosis International Federation Atlas of MS, Third Edition.

BACKGROUND AND OBJECTIVES: Recent data suggest increasing global prevalence of multiple sclerosis (MS). Early diagnosis of MS reduces the burden of disability-adjusted life years and associated health care costs. Yet diagnostic delays persist in MS care and even within national health care systems with robust resources, comprehensive registries, and MS subspecialist referral networks. The global prevalence and characteristics of barriers to expedited MS diagnosis, particularly in resource-restricted regions, have not been extensively studied. Recent revisions to MS diagnostic criteria demonstrate potential to facilitate earlier diagnosis, but global implementation remains largely unknown. METHODS: The Multiple Sclerosis International Federation third edition of the Atlas of MS was a survey that assessed the current global state of diagnosis including adoption of MS diagnostic criteria; barriers to diagnosis with respect to the patient, health care provider, and health system; and existence of national guidelines or national standards for speed of MS diagnosis. RESULTS: Coordinators from 107 countries (representing approximately 82% of the world population), participated. Eighty-three percent reported at least 1 "major barrier" to early MS diagnosis. The most frequently reported barriers included the following: "lack of awareness of MS symptoms among general public" (68%), "lack of awareness of MS symptoms among health care professionals" (59%), and "lack of availability of health care professionals with knowledge to diagnose MS" (44%). One-third reported lack of "specialist medical equipment or diagnostic tests." Thirty-four percent reported the use of only 2017 McDonald criteria (McD-C) for diagnosis, and 79% reported 2017 McD-C as the "most commonly used criteria." Sixty-six percent reported at least 1 barrier to the adoption of 2017 McD-C, including "neurologists lack awareness or training" by 45%. There was no significant association between national guidelines pertaining to MS diagnosis or practice standards addressing the speed of diagnosis and presence of barriers to early MS diagnosis and implementation of 2017 McD-C. DISCUSSION: This study finds pervasive consistent global barriers to early diagnosis of MS. While these barriers reflected a lack of resources in many countries, data also suggest that interventions designed to develop and implement accessible education and training can provide cost-effective opportunities to improve access to early MS diagnosis.

Processing speed and memory test performance are associated with different brain region volumes in Veterans and others with progressive multiple sclerosis.

Background: Cognitive dysfunction and brain atrophy are both common in progressive multiple sclerosis (MS) but are seldom examined comprehensively in clinical trials. Antioxidant treatment may affect the neurodegeneration characteristic of progressive MS and slow its symptomatic and radiographic correlates. Objectives: This study aims to evaluate cross-sectional associations between cognitive battery components of the Brief International Cognitive Assessment for Multiple Sclerosis with whole and segmented brain volumes and to determine if associations differ between secondary progressive (SPMS) and primary progressive (PPMS) MS subtypes. Design: The study was based on a baseline analysis from a multi-site randomized controlled trial of the antioxidant lipoic acid in veterans and other people with progressive MS (NCT03161028). Methods: Cognitive batteries were conducted by trained research personnel. MRIs were processed at a central processing site for maximum harmonization. Semi-partial Pearson's adjustments evaluated associations between cognitive tests and MRI volumes. Regression analyses evaluated differences in association patterns between SPMS and PPMS cohorts. Results: Of the 114 participants, 70% had SPMS. Veterans with MS made up 26% (n = 30) of the total sample and 73% had SPMS. Participants had a mean age of 59.2 and sd 8.5 years, and 54% of them were women, had a disease duration of 22.4 (sd 11.3) years, and had a median Expanded Disability Status Scale of 6.0 (with an interquartile range of 4.0-6.0, moderate disability). The Symbol Digit Modalities Test (processing speed) correlated with whole brain volume (R = 0.29, p = 0.01) and total white matter volume (R = 0.33, p < 0.01). Both the California Verbal Learning Test (verbal memory) and Brief Visuospatial Memory Test-Revised (visual memory) correlated with mean cortical thickness (R = 0.27, p = 0.02 and R = 0.35, p < 0.01, respectively). Correlation patterns were similar in subgroup analyses. Conclusion: Brain volumes showed differing patterns of correlation across cognitive tasks in progressive MS. Similar results between SPMS and PPMS cohorts suggest combining progressive MS subtypes in studies involving cognition and brain atrophy in these populations. Longitudinal assessment will determine the therapeutic effects of lipoic acid on cognitive tasks, brain atrophy, and their associations.

Chest-Based Wearables and Individualized Distributions for Assessing Postural Sway in Persons With Multiple Sclerosis.

Typical assessments of balance impairment are subjective or require data from cumbersome and expensive force platforms. Researchers have utilized lower back (sacrum) accelerometers to enable more accessible, objective measurement of postural sway for use in balance assessment. However, new sensor patches are broadly being deployed on the chest for cardiac monitoring, opening a need to determine if measurements from these devices can similarly inform balance assessment. Our aim in this work is to validate postural sway measurements from a chest accelerometer. To establish concurrent validity, we considered data from 16 persons with multiple sclerosis (PwMS) asked to stand on a force platform while also wearing sensor patches on the sacrum and chest. We found five of 15 postural sway features derived from the chest and sacrum were significantly correlated with force platform-derived features, which is in line with prior sacrum-derived findings. Clinical significance was established using a sample of 39 PwMS who performed eyes-open, eyes-closed, and tandem standing tasks. This cohort was stratified by fall status and completed several patient-reported measures (PRM) of balance and mobility impairment. We also compared sway features derived from a single 30-second period to those derived from a one-minute period with a sliding window to create individualized distributions of each postural sway feature (ID method). We find traditional computation of sway features from the chest is sensitive to changes in PRMs and task differences. Distribution characteristics from the ID method establish additional relationships with PRMs, detect differences in more tasks, and distinguish between fall status groups. Overall, the chest was found to be a valid location to monitor postural sway and we recommend utilizing the ID method over single-observation analyses.

Top Ten Tips Palliative Care Clinicians Should Know about Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic, immune-mediated, neurodegenerative condition of the central nervous system, with distinct challenges due to its heterogeneous presentation, prognostic uncertainty, and variable clinical course of neurological and non-neurological symptoms and disability. Although there have been significant advances in management of MS, many patients experience disability progression. Despite MS being a frequent cause of neurological disability, particularly in young persons, involvement of palliative care physicians in the care of patients with MS has been limited. This article provides ten tips for palliative clinicians for caring for patients with MS and their care partners.

Digital Phenotypes of Instability and Fatigue Derived From Daily Standing Transitions in Persons With Multiple Sclerosis.

Impairment in persons with multiple sclerosis (PwMS) can often be attributed to symptoms of motor instability and fatigue. Symptom monitoring and queued interventions often target these symptoms. Clinical metrics are currently limited to objective physician assessments or subjective patient reported measures. Recent research has turned to wearables for improving the objectivity and temporal resolution of assessment. Our group has previously observed wearable assessment of supervised and unsupervised standing transitions to be predictive of fall-risk in PwMS. Here we extend the application of standing transition quantification to longitudinal home monitoring of symptoms. Subjects (N=23) with varying degrees of MS impairment were recruited and monitored with accelerometry for a total of  âˆ¼  6 weeks each. These data were processed using a preexisting framework, applying a deep learning activity classifier to isolate periods of standing transition from which descriptive features were extracted for analysis. Participants completed daily and biweekly assessments describing their symptoms. From these data, Canonical Correlation Analysis was used to derive digital phenotypes of MS instability and fatigue. We find these phenotypes capable of distinguishing fallers from non-fallers, and further that they demonstrate a capacity to characterize symptoms at both daily and sub-daily resolutions. These results represent promising support for future applications of wearables, which may soon augment or replace current metrics in longitudinal monitoring of PwMS.

T1 /T2 ratio from 3T MRI improves multiple sclerosis cortical lesion contrast.

BACKGROUND AND PURPOSE: Cortical demyelinated lesions are prevalent in multiple sclerosis (MS), associated with disability, and have recently been incorporated into MS diagnostic criteria. Presently, advanced and ultrahigh-field MRIs-not routinely available in clinical practice-are the most sensitive methods for detection of cortical lesions. Approaches utilizing MRI sequences obtainable in routine clinical practice remain an unmet need. We plan to assess the sensitivity of the ratio of T1 -weighted and T2 -weighted (T1 /T2 ) signal intensity for focal cortical lesions in comparison to other high-field imaging methods. METHODS: 3-Tesla and 7-Tesla MRI collected from 10 adults with MS were included in the study. T1 /T2 images were calculated by dividing 3T T1 -weighted (T1 w) images by 3T T2 -weighted (T2 w) fluid-attenuated inversion recovery images for each participant. A total of 614 cortical lesions were identified using 7T T2 *w and T1 w images and corresponding voxels were assessed on registered 3T images. Signal intensities were compared across 3T imaging sequences, including T1 /T2 , T1 w, T2 w, and inversion recovery susceptibility-weighted imaging with enhanced T2 weighting (IR-SWIET) images. RESULTS: T1 /T2 images demonstrated a larger contrast between median lesional and nonlesional cortical signal intensity (median ratio = 1.29, range: 1.19-1.38) when compared to T1 w (1.01, 0.97-1.10, p < .002), T2 w (1.17, 1.07-1.26, p < .002), and IR-SWIET (1.21, 1.01-1.29, p < .03). CONCLUSION: T1 /T2 images are sensitive to cortical lesions. Approaches incorporating T1 /T2 could improve the accessibility of cortical lesion detection in research settings and clinical practice.

Should trigeminal neuralgia be considered a clinically isolated syndrome?

The association between trigeminal neuralgia (TN) and multiple sclerosis (MS) is well established. Many MS patients with TN have magnetic resonance imaging (MRI) evidence of a symptomatic demyelinating lesion. Although infratentorial presentations are included in the diagnostic criteria for MS, there remains confusion in clinical practice as to whether TN should be considered a clinically isolated syndrome for the application of McDonald criteria. In this case series, we discuss this diagnostic quandary in patients presenting with TN and additional MRI findings suggestive of MS and highlight the unmet need for data in such patients to optimally guide their care.

Limited diagnostic utility of serologic testing for neurologic manifestations of systemic disease in the evaluation of suspected multiple sclerosis: A single-center observational study.

BACKGROUND: The clinical evaluation of a new diagnosis of MS typically includes serologic testing to evaluate for its many mimics, yet there is little data to guide approaches to such testing. OBJECTIVE: To evaluate for the frequency and clinical significance of serologic testing for MS diagnostic evaluations. METHODS: In a single MS subspeciality center retrospective study, new patient evaluations for MS over the course of a year were identified, and the results of serologic testing and diagnostic evaluation extracted. Retrospective longitudinal diagnostic assessment was performed to confirm the accuracy of initial serological testing assessments. RESULTS: 150 patients had 823 serologic tests. 40 (5%) tests were positive, and resulted in 117 additional serologic tests, 10 radiographs, and 2 biopsies. 77 (51%) patients were diagnosed with a non-demyelinating disorder. Serologic testing results did not change any diagnosis, yet in some patients, it resulted in unnecessary additional testing and diagnostic delay. CONCLUSIONS: Serologic testing in the clinical assessment for routine MS resulted in unnecessary diagnostic delay, additional testing, and considerable healthcare cost.

Autoimmune Encephalitis Misdiagnosis in Adults.

Importance: Autoimmune encephalitis misdiagnosis can lead to harm. Objective: To determine the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis. Design, Setting, and Participants: This retrospective multicenter study took place from January 1, 2014, to December 31, 2020, at autoimmune encephalitis subspecialty outpatient clinics including Mayo Clinic (n = 44), University of Oxford (n = 18), University of Texas Southwestern (n = 18), University of California, San Francisco (n = 17), University of Washington in St Louis (n = 6), and University of Utah (n = 4). Inclusion criteria were adults (age ≥18 years) with a prior autoimmune encephalitis diagnosis at a participating center or other medical facility and a subsequent alternative diagnosis at a participating center. A total of 393 patients were referred with an autoimmune encephalitis diagnosis, and of those, 286 patients with true autoimmune encephalitis were excluded. Main Outcomes and Measures: Data were collected on clinical features, investigations, fulfillment of autoimmune encephalitis criteria, alternative diagnoses, potential contributors to misdiagnosis, and immunotherapy adverse reactions. Results: A total of 107 patients were misdiagnosed with autoimmune encephalitis, and 77 (72%) did not fulfill diagnostic criteria for autoimmune encephalitis. The median (IQR) age was 48 (35.5-60.5) years and 65 (61%) were female. Correct diagnoses included functional neurologic disorder (27 [25%]), neurodegenerative disease (22 [20.5%]), primary psychiatric disease (19 [18%]), cognitive deficits from comorbidities (11 [10%]), cerebral neoplasm (10 [9.5%]), and other (18 [17%]). Onset was acute/subacute in 56 (52%) or insidious (>3 months) in 51 (48%). Magnetic resonance imaging of the brain was suggestive of encephalitis in 19 of 104 patients (18%) and cerebrospinal fluid (CSF) pleocytosis occurred in 16 of 84 patients (19%). Thyroid peroxidase antibodies were elevated in 24 of 62 patients (39%). Positive neural autoantibodies were more frequent in serum than CSF (48 of 105 [46%] vs 7 of 91 [8%]) and included 1 or more of GAD65 (n = 14), voltage-gated potassium channel complex (LGI1 and CASPR2 negative) (n = 10), N-methyl-d-aspartate receptor by cell-based assay only (n = 10; 6 negative in CSF), and other (n = 18). Adverse reactions from immunotherapies occurred in 17 of 84 patients (20%). Potential contributors to misdiagnosis included overinterpretation of positive serum antibodies (53 [50%]), misinterpretation of functional/psychiatric, or nonspecific cognitive dysfunction as encephalopathy (41 [38%]). Conclusions and Relevance: When evaluating for autoimmune encephalitis, a broad differential diagnosis should be considered and misdiagnosis occurs in many settings including at specialized centers. In this study, red flags suggesting alternative diagnoses included an insidious onset, positive nonspecific serum antibody, and failure to fulfill autoimmune encephalitis diagnostic criteria. Autoimmune encephalitis misdiagnosis leads to morbidity from unnecessary immunotherapies and delayed treatment of the correct diagnosis.

Effect of GBCA Use on Detection and Diagnostic Performance of the Central Vein Sign: Evaluation Using a 3-T FLAIR* Sequence in Patients With Suspected Multiple Sclerosis.

BACKGROUND. The central vein sign (CVS) is a proposed MRI biomarker of multiple sclerosis (MS). The impact of gadolinium-based contrast agent (GBCA) administration on CVS evaluation remains poorly investigated. OBJECTIVE. The purpose of this study was to assess the effect of GBCA use on CVS detection and on the diagnostic performance of the CVS for MS using a 3-T FLAIR* sequence. METHODS. This study was a secondary analysis of data from the pilot study for the prospective multicenter Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), which recruited adults with suspected MS from April 2018 to February 2020. Participants underwent 3-T brain MRI including FLAIR and precontrast and post-contrast echo-planar imaging T2*-weighted acquisitions. Postprocessing was used to generate combined FLAIR and T2*-weighted images (hereafter, FLAIR*). MS diagnoses were established using the 2017 McDonald criteria. Thirty participants (23 women, seven men; mean age, 45 years) were randomly selected from the CAVS-MS pilot study cohort. White matter lesions (WMLs) were marked using FLAIR* images. A single observer, blinded to clinical data and GBCA use, reviewed marked WMLs on FLAIR* images for the presence of the CVS. RESULTS. Thirteen of 30 participants had MS. Across participants, on precontrast FLAIR* imaging, 218 CVS-positive and 517 CVS-negative WMLs were identified; on post-contrast FLAIR* imaging, 269 CVS-positive and 459 CVS-negative WMLs were identified. The fraction of WMLs that were CVS-positive on precontrast and postcontrast images was 48% and 58% in participants with MS and 7% and 10% in participants without MS, respectively. The median patient-level CVS-positivity rate on precontrast and postcontrast images was 43% and 67% for participants with MS and 4% and 8% for participants without MS, respectively. In a binomial model adjusting for MS diagnoses, GBCA use was associated with an increased likelihood of at least one CVS-positive WML (odds ratio, 1.6; p < .001). At a 40% CVS-positivity threshold, the sensitivity of the CVS for MS increased from 62% on precontrast images to 92% on postcontrast images (p = .046). Specificity was not significantly different between precontrast (88%) and postcontrast (82%) images (p = .32). CONCLUSION. GBCA use increased CVS detection on FLAIR* images, thereby increasing the sensitivity of the CVS for MS diagnoses. CLINICAL IMPACT. The postcontrast FLAIR* sequence should be considered for CVS evaluation in future investigational trials and clinical practice.