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.

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.

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.

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.

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.

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.

A local group differences test for subject-level multivariate density neuroimaging outcomes.

A great deal of neuroimaging research focuses on voxel-wise analysis or segmentation of damaged tissue, yet many diseases are characterized by diffuse or non-regional neuropathology. In simple cases, these processes can be quantified using summary statistics of voxel intensities. However, the manifestation of a disease process in imaging data is often unknown, or appears as a complex and nonlinear relationship between the voxel intensities on various modalities. When the relevant pattern is unknown, summary statistics are often unable to capture differences between disease groups, and their use may encourage post hoc searches for the optimal summary measure. In this study, we introduce the multi-modal density testing (MMDT) framework for the naive discovery of group differences in voxel intensity profiles. MMDT operationalizes multi-modal magnetic resonance imaging (MRI) data as multivariate subject-level densities of voxel intensities and utilizes kernel density estimation to develop a local two-sample test for individual points within the density space. Through simulations, we show that this method controls type I error and recovers relevant differences when applied to a specified point. Additionally, we demonstrate the ability to maintain power while controlling the family-wise error rate and false discovery rate when applying the test over a grid of points within the density space. Finally, we apply this method to a study of subjects with either multiple sclerosis (MS) or conditions that tend to mimic MS on MRI, and find significant differences between the two groups in their voxel intensity profiles within the thalamus.

The frequency and characteristics of multiple sclerosis misdiagnosis in Latin America: A referral center study in Buenos Aires, Argentina.

OBJECTIVE: Most contemporary data concerning the frequency and causes of multiple sclerosis (MS) misdiagnosis are from North America and Europe with different healthcare system structure and resources than countries in Latin America. We sought to determine the frequency, and potential contributors to MS misdiagnosis in patients evaluated at an MS referral center in Argentina. METHODS: The study was a retrospective medical record review. We included patients evaluated at the MS Clinic at Fleni between April 2013 and March 2021. Diagnoses prior to consultation, final diagnoses after consultation, demographic, clinical and paraclinical data, and treatment were extracted and classified. RESULTS: Seven hundred thirty-six patients were identified. Five hundred seventy-two presented with an established diagnosis of MS and after evaluation, misdiagnosis was identified in 89 (16%). Women were at 83% greater risk of misdiagnosis (p = 0.034). The most frequent alternative diagnoses were cerebrovascular disease, radiological isolated syndrome (RIS), and headache. Seventy-four (83%) of misdiagnosed patients presented with a syndrome atypical for demyelination, 62 (70%) had an atypical brain magnetic resonance imaging (MRI), and 54 (61%) were prescribed disease-modifying therapy. CONCLUSION: Sixteen percent of patients with established MS were subsequently found to have been misdiagnosed. Women were at higher risk for misdiagnosis. Expert application of the McDonald criteria may prevent misdiagnosis and its associated morbidity and healthcare system cost.

Multiple sclerosis diagnosis: Knowledge gaps and opportunities for educational intervention in neurologists in the United States.

BACKGROUND: Few studies have addressed the results of educational efforts concerning proper use of McDonald criteria (MC) revisions outside multiple sclerosis (MS) subspecialty centers. Neurology residents and MS subspecialist neurologists demonstrated knowledge gaps for core elements of the MC in a recent prior study. OBJECTIVE: To assess comprehension and application of MC core elements by non-MS specialist neurologists in the United States who routinely diagnose MS. METHODS: Through a cross-sectional study design, a previously developed survey instrument was distributed online. RESULTS: A total of 222 neurologists completed the study survey. Syndromes atypical for MS were frequently incorrectly considered "typical" MS presentations. Fourteen percent correctly identified definitions of both "periventricular" and "juxtacortical" lesions and 2% correctly applied these terms to 9/9 images. Twenty-four percent correctly identified all four central nervous system (CNS) regions for satisfaction of magnetic resonance imaging (MRI) dissemination in space. In two presented cases, 61% and 71% correctly identified dissemination in time (DIT) was not fulfilled, and 85% and 86% subsequently accepted nonspecific historical symptoms without objective evidence for DIT fulfillment. CONCLUSION: The high rate of knowledge deficiencies and application errors of core elements of the MC demonstrated by participants in this study raise pressing questions concerning adequacy of dissemination and educational efforts upon publication of revisions to MC.

An Update on Diagnostic Laboratory Biomarkers for Multiple Sclerosis.

PURPOSE: For many patients, the multiple sclerosis (MS) diagnostic process can be lengthy, costly, and fraught with error. Recent research aims to address the unmet need for an accurate and simple diagnostic process through discovery of novel diagnostic biomarkers. This review summarizes recent studies on MS diagnostic fluid biomarkers, with a focus on blood biomarkers, and includes discussion of technical limitations and practical applicability. RECENT FINDINGS: This line of research is in its early days. Accurate and easily obtainable biomarkers for MS have not yet been identified and validated, but several approaches to uncover them are underway. Continue efforts to define laboratory diagnostic biomarkers are likely to play an increasingly important role in defining MS at the earliest stages, leading to better long-term clinical outcomes.

How Much Data Is Enough? A Reliable Methodology to Examine Long-Term Wearable Data Acquisition in Gait and Postural Sway.

Wearable sensors facilitate the evaluation of gait and balance impairment in the free-living environment, often with observation periods spanning weeks, months, and even years. Data supporting the minimal duration of sensor wear, which is necessary to capture representative variability in impairment measures, are needed to balance patient burden, data quality, and study cost. Prior investigations have examined the duration required for resolving a variety of movement variables (e.g., gait speed, sit-to-stand tests), but these studies use differing methodologies and have only examined a small subset of potential measures of gait and balance impairment. Notably, postural sway measures have not yet been considered in these analyses. Here, we propose a three-level framework for examining this problem. Difference testing and intra-class correlations (ICC) are used to examine the agreement in features computed from potential wear durations (levels one and two). The association between features and established patient reported outcomes at each wear duration is also considered (level three) for determining the necessary wear duration. Utilizing wearable accelerometer data continuously collected from 22 persons with multiple sclerosis (PwMS) for 6 weeks, this framework suggests that 2 to 3 days of monitoring may be sufficient to capture most of the variability in gait and sway; however, longer periods (e.g., 3 to 6 days) may be needed to establish strong correlations to patient-reported clinical measures. Regression analysis indicates that the required wear duration depends on both the observation frequency and variability of the measure being considered. This approach provides a framework for evaluating wear duration as one aspect of the comprehensive assessment, which is necessary to ensure that wearable sensor-based methods for capturing gait and balance impairment in the free-living environment are fit for purpose.

Lipoic acid supplementation associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy.

Lipoic acid (alpha lipoic acid, thioctic acid) is a popular over-the-counter antioxidant and insulin-mimetic supplement under investigation in a variety of conditions including multiple sclerosis, diabetes, and schizophrenia. Unfortunately, high-grade proteinuria was an unexpected adverse event specific to the treatment arm of our clinical trial investigating lipoic acid supplementation in patients with multiple sclerosis. This observation led to detection of similar patients in our nephrology practice. Here, we describe four biopsy-proven cases of neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy following lipoic acid supplementation and a fifth suspected case. Discontinuation of lipoic acid and supportive therapy resulted in remission.

Challenges in multiple sclerosis diagnosis: Misunderstanding and misapplication of the McDonald criteria.

OBJECTIVE: To assess comprehension and application of the McDonald criteria. BACKGROUND: Studies suggest that knowledge gaps for specific core elements of the McDonald criteria may contribute to multiple sclerosis (MS) misdiagnosis. METHODS: Neurology residents (NR) and multiple sclerosis specialists (MSS) in North America completed a web-based survey. RESULTS: A total of 160 participants were included: 72 NR and 88 MSS. Syndromes incorrectly identified as typical of MS included: complete transverse myelopathy (35% NR and 15% MSS), intractable vomiting/nausea/hiccoughs (20% NR and 5% MSS), and bilateral optic neuritis/unilateral optic neuritis with poor visual recovery (17% NR and 10% MSS). Periventricular magnetic resonance imaging (MRI) lesions were correctly identified by 39% NR and 52% MSS, and juxtacortical lesions were correctly identified by 28% NR and 53% MSS. The correct definition of "periventricular" was chosen by 38% NR and 61% MSS, and that of "juxtacortical" was chosen by 19% NR and 54% MSS. Regions incorrectly identified for MRI dissemination in space fulfillment included the optic nerve (31% NR and 26% MSS) and the subcortical white matter (11% NR and 18% MSS). The majority of participants assessed previous non-specific neurological symptoms without objective evidence of a central nervous system (CNS) lesion as sufficient for clinical dissemination in time. CONCLUSION: The McDonald criteria are often misunderstood and misapplied. Concerted educational efforts may prevent MS misdiagnosis.

Prospective growth and developmental outcomes in infants born to mothers with multiple sclerosis.

BACKGROUND: The importance of supporting pregnancy-related decisions in multiple sclerosis (MS) patients has increasingly been recognized and hence the need for prospective data on pregnancy and pediatric outcomes in this patient population. OBJECTIVE: To assess prospective growth and developmental outcomes of infants born to mothers with multiple sclerosis (IMS). METHODS: PREG-MS is a prospective multicenter cohort study in New England, United States. We followed 65 women with MS and their infants with up to 12 months consistent pediatric follow-up. Pediatric, neurologic, and demographic information was obtained via structured telephone interviews and validated with medical records. RESULTS: No differences in infant weights and lengths with World Health Organization (WHO) 50th percentile standards were observed (p > 0.05). However, larger head circumference (HC) measurements than WHO standards were reported in cohort infants (p < 0.05). There was no association between HC and markers of maternal MS activity, demographic, or social factors. No irreversible pediatric developmental abnormalities were observed. CONCLUSION: This first prospective study on pediatric anthropometry in IMS suggests a possible increase in HC compared to WHO standards without an increase in irreversible developmental abnormalities. The observations are exploratory and require confirmation with larger prospective studies in diverse groups of MS patients.

Diagnostic performance of central vein sign for multiple sclerosis with a simplified three-lesion algorithm.

BACKGROUND: Detection of a "central vein sign" (CVS) on FLAIR* magnetic resonance imaging (MRI) is highly specific and sensitive for multiple sclerosis (MS). We evaluated the specificity and sensitivity of simplified CVS algorithms for MS diagnosis. METHODS: MRIs from 10 participants with MS without additional comorbidities for MRI white matter abnormalities; 10 with MS and additional comorbidities for white matter abnormalities; 10 with migraine, white matter abnormalities, and no additional comorbidities; and 10 who had previously been erroneously diagnosed with MS were evaluated. 3T MRI T2-FLAIR and T2*-weighted sequences were acquired to create FLAIR* images. Three MS physician reviewers, blinded to diagnosis, evaluated two different algorithms: (1) three lesions pre-selected on FLAIR were subsequently evaluated for CVS on FLAIR*( select3). (2) FLAIR* was evaluated for up to three lesions with CVS ( select3*). RESULTS: For select3, average specificity across reviewers for MS was 0.98 and sensitivity 0.52 and a correct prediction of diagnosis demonstrated kappa = 0.29. For select3*, specificity was 0.81, sensitivity was 0.83, and kappa was 0.31. CONCLUSION: A simplified determination of CVS in three white matter lesions on 3T FLAIR* MRI demonstrated good specificity and sensitivity and fair inter-rater reliability for a diagnosis of MS and with further study, may be a candidate for clinical application.

Patient perspectives on physician conflict of interest in industry-sponsored clinical trials for multiple sclerosis therapeutics.

BACKGROUND: Pharmaceutical industry financial support of physicians, physician practices, and academic departments involved in multicenter industry-sponsored clinical trials of novel therapeutic agents is a relatively new and infrequently acknowledged source of potential physician conflict of interest. Detailed disclosure of these relationships to study participants is not uniformly a part of informed consent and documentation practices. OBJECTIVE: To understand attitudes of patients with multiple sclerosis concerning disclosure of potential physician-industry conflicts of interest created by clinical trials and how such disclosures may influence study participation METHODS: An anonymous online instrument was developed. RESULTS: 597 people with multiple sclerosis participated in the study. The study found that detailed disclosure of conflicts of interest is important to potential participants in industry-sponsored clinical trials for multiple sclerosis therapies and that the presence of these conflicts of interest may influence patients' decisions to participate in these studies. CONCLUSIONS: Findings from this study support a call for uniform guidelines regarding disclosure of physician-industry relationships to prospective research participants for industry-sponsored clinical trials.

A Clinical Approach to the Differential Diagnosis of Multiple Sclerosis.

The diagnostic criteria for multiple sclerosis (MS) rely on clinical, paraclinical, and radiographic findings of limited specificity. Many disorders mimic MS, and the decision of when to investigate an alternative diagnosis can be challenging. Reliance on extensive ancillary testing to exclude potential mimics, however, is unnecessary in most cases. Rather, recognition and rigorous interpretation of "classic" clinical and radiographic features of MS are often sufficient to establish the diagnosis. Misinterpretation of the clinical and radiographic diagnostic criteria for MS in the setting of more common diseases and syndromes and a lack of vigilance for "red flags" are important contributors to misdiagnosis. A clinical framework for the differential diagnosis of MS that emphasizes phenotypes atypical for MS and suggests diseases or syndromes in which they more commonly occur may be an important diagnostic guide for clinicians in contemporary practice.