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.

Respiratory symptoms are common in stiff person syndrome spectrum disorders and are associated with number of body regions involved.

BACKGROUND AND PURPOSE: Stiff person syndrome (SPS) spectrum disorders (SPSSD) cause spasms and rigidity throughout different body regions and can be associated with apnea and acute respiratory failure. There are limited data on the prevalence and predictors of respiratory symptoms with spasms (RSwS) in SPSSD. We sought to characterize the spirometry patterns and the frequency and predictors of RSwS in a large SPSSD cohort. METHODS: Participants were recruited from the Johns Hopkins SPS Center between 1997 and 2021, as part of an ongoing, longitudinal observational study. Medical records were reviewed to assess demographics and clinical characteristics. Data were analyzed using descriptive statistics and multivariable logistic regression models. RESULTS: One-hundred ninety-nine participants (mean age = 53.4 ± 13.6 years, median time to diagnosis = 36 [IQR 66] months, 74.9% women, 69.8% White, 62.8% classic SPS phenotype) were included in final analyses; 35.2% of participants reported RSwS, of whom 24.3% underwent spirometry as part of routine clinical care. Obstructive (23.5%) and restrictive (23.5%) patterns were most commonly observed in those with SPSSD. An increasing number of body regions involved predicted the presence of RSwS (odds ratio [OR] = 1.95, 95% confidence interval [CI] = 1.50-2.53); those with ≥5 body regions involved (vs. ≤4) had higher odds (OR = 6.19, 95% CI = 2.81-13.62) of experiencing RSwS in adjusted models. Two patients died from SPSSD-associated respiratory compromise. CONCLUSIONS: RSwS are common in SPSSD and may be predicted by an increasing number of body regions involved by SPSSD. Close clinical monitoring and having a low threshold to obtain spirometry should be considered in people with SPSSD.

Relevance of antinuclear antibody in diagnosis and characteristics of multiple sclerosis.

BACKGROUND: Criteria for multiple sclerosis (MS) diagnosis rely upon clinical and paraclinical data that are supportive of MS in the absence of a better explanation. Patients referred for consideration of a MS diagnosis often undergo an extensive serologic workup including antinuclear antibody (ANA) testing, even when an individual already meets diagnostic criteria for MS. It is unclear whether ANA serostatus is associated with clinical outcomes in MS. The present study aims to determine if ANA seropositivity in those referred with concern for MS differs in those who meet 2017 revised McDonald criteria compared to those who did not receive a diagnosis of MS. Associations between ANA seropositivity and clinical or radiological phenotype of MS patients are also explored. METHODS: The cohort included people at least 18 years old, referred to our tertiary care MS center with concern for MS (regardless of prior diagnosis) who had an ANA test with known titer completed within one year of first evaluation. Electronic health record (EHR) charts were manually reviewed, and MRIs underwent blinded review by a radiologist with training in neuroradiology. Diagnosis of MS was determined by a neuroimmunologist and was based on 2017 revised McDonald Criteria. Results are reported as odds ratios from multivariable logistic regression analyses adjusted for age, sex at birth, race, smoking history, personal history of comorbid autoimmune conditions, and family history of autoimmunity. Within the MS cohort, similar analytical models were performed to assess association between ANA and clinical and radiological characteristics. RESULTS: A final cohort of 258 patients was analyzed (out of 542 referrals): 106 nonMS and 152 with MS. There was no association between MS (vs. nonMS) diagnosis and ANA status (ANA positive n = 74) in the multivariable models (OR 1.5, 95 % CI 0.82, 2.72, p = 0.20). Among those with MS, there was no association of ANA seropositivity with the odds of atypical brain MRI features, number of cardinal MRI areas involved, location of MRI lesions, or of having an atypical presentation of first demyelinating event. Black race (OR 2.8, 95 % CI 1.27, 6.26, p = 0.01) and family history of autoimmunity (OR 2.1, 95 % CI 1.09, 3.98, p = 0.03) were independently associated with increased odds of ANA positivity. Within the MS cohort analysis, progressive MS (PMS; vs relapsing-remitting MS), a covariate in the model, appeared to be at higher odds of being ANA positive (OR 3.6, 95 % CI 1.03, 13.05, p = 0.046) but only when assessing mean area of cardinal MS locations. CONCLUSIONS: While ANA testing does not appear to be useful in distinguishing MS from non-MS, it remains less clear as to whether it may be associated with differences in the clinical course of MS (relapsing-remitting vs progressive). Future studies should aim to systematically evaluate whether those who are ANA positive are more likely, in well-designed and representative prospective cohorts, to be diagnosed with or develop progressive MS. Whether a positive ANA early in MS is associated with increased risk over time of developing or diagnosing another systemic autoimmune disease would also be of interest.

Expanding clinical profiles and prognostic markers in stiff person syndrome spectrum disorders.

OBJECTIVE: To describe the clinical features of a cohort of individuals with stiff person syndrome spectrum disorders (SPSD) and identify potential early predictors of future disability. BACKGROUND: There is a need to better understand the full spectrum of clinical and paraclinical features and long-term impact of SPSD. DESIGN/METHODS: Observational study from 1997 to 2022 at Johns Hopkins. Clinical phenotypes included classic SPS, partial SPS (limb or trunk limited), SPS-plus (classic features plus cerebellar/brainstem involvement), and progressive encephalomyelitis with rigidity and myoclonus (PERM). Outcome measures were modified Rankin scale (mRS) and use of assistive device for ambulation. Multivariate logistic regression was used to assess significant predictors of outcomes. RESULTS: Cohort included 227 individuals with SPSD with mean follow-up of 10 years; 154 classic, 48 SPS-plus, 16 PERM, and 9 partial. Mean age at symptom onset was 42.9 ± 14.1 years, majority were white (69.2%) and female (75.8%). Median time to diagnosis was 36.2 months (longest for SPS-plus and PERM) and 61.2% were initially misdiagnosed. Most had systemic co-morbidities and required assistive devices for ambulation. Female sex (OR 2.08; CI 1.06-4.11) and initial brainstem/cerebellar involvement (OR 4.41; CI 1.63-14.33) predicted worse outcome by mRS. Older age at symptom onset (OR 1.04; CI 1.01-1.06), female sex (OR 1.99; CI 1.01-4.01), Black race (OR 4.14; CI 1.79-10.63), and initial brainstem/cerebellar involvement (OR 2.44; CI 1.04-7.19) predicted worse outcome by use of assistive device. Early implementation of immunotherapy was associated with better outcomes by either mRS (OR 0.45; CI 0.22-0.92) or use of assistive device (OR 0.79; CI 0.66-0.94). CONCLUSIONS: We present the expanding phenotypic variability of this rare spectrum of disorders and highlight potential predictors of future disability.

The many faces of gastrointestinal dysfunction in stiff person syndrome spectrum disorders.

Introduction: The effect of stiff person syndrome spectrum disorders (SPSD) on the gastrointestinal tract (GIT) is unknown. This case series aims to characterize the prevalence and types of GI dysfunction in individuals with SPSD. Methods: A retrospective chart review included individuals diagnosed with SPSD with descriptors of GI symptoms in their medical records. SPSD phenotypes, type of motility test performed, and dysmotility pattern (upper, lower, or diffuse) were assessed. Descriptive statistics and univariate chi-square analyses were utilized. Results: Of 240 individuals with SPSD, 32% reported GI symptoms, most were female (83.1%), and white (74%), with a median age at time of GI symptom onset of 50 ± 13 years. Most common symptoms reported were dysphagia (45%), constipation (40%), and nausea/vomiting (23%). Most individuals had classic SPS (47%) followed by SPS-plus (29%) and 82.9% were positive for serum antiGAD65 antibodies. Of 36 patients that underwent at least one GI motility test, 26 had evidence of upper, lower, or diffuse GI dysmotility (44.4%, 17%, and 4%, respectively). The group who did not undergo testing had a higher proportion of patients with DM. Discussion: There is a high prevalence of GI symptoms and transit abnormalities in patients with SPSD. Future prospective, longitudinal studies are warranted to further assess GI symptoms in the context of SPSD and to determine if individuals with GI symptoms differ in prognosis or treatment response from those without GI symptoms. In the meantime, there should be a low threshold for motility testing in patients with SPSD.

LAMA2-related muscular dystrophy mimicking multiple sclerosis.

Laminin-alpha2-related muscular dystrophy (LAMA2-MD) is a genetic condition due to reduced LAMA2, a protein found throughout the nervous system. Late-onset LAMA2-MD may present with proximal muscle weakness, joint contractures, neuropathy, epilepsy and/or cardiorespiratory issues, and is less common than the neonatal form. We describe a novel phenotype of LAMA2-MD with progressive myelopathy and spinal cord abnormalities.A woman was referred for evaluation of multiple sclerosis (MS) with progressive gait difficulty and abnormal neuroimaging showing white matter abnormalities in the brain and spinal cord. Ancillary testing was not consistent with primary neuroinflammatory disorders, systemic autoimmunity or infection. Metabolic workup revealed low cyanocobalamin. Genetic testing identified two LAMA2-MD variants.Genetic disorders can mimic treatable neurological conditions. Chronic progressive course, involvement of the peripheral and central nervous systems, and confluent white matter abnormalities should be investigated with molecular testing that includes LAMA2 sequencing to ensure proper diagnosis and management.