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Differential diagnosis of suspected multiple sclerosis: an updated consensus approach
Abstract
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.
... However, the criteria´s specificity when applied to patients with noninflammatory optic neuropathies, ON-T2-hyperintensity and acute/subacute vision loss is unknown. Although the new optic neuritis diagnostic criteria consider clinical features along with paraclinical tests to make a diagnosis of optic neuritis, other causes of optic neuropathies, especially nonarteritic anterior ischemic optic neuropathy (NAION) and Leber hereditary optic neuropathy (LHON), may have overlapping clinical presentations that mimic optic neuritis [16][17][18][19][20][21]. ...
... This is consistent with prior studies that showed NAION as one of the most frequent causes of optic neuritis misdiagnosis, representing about 12% of all misdiagnosed cases [17,18], and 75% of misdiagnosed optic neuropathies [17]. Indeed, a recently published expert opinion consensus about the differential diagnosis of multiple sclerosis [19] raised concerns about optic neuritis misdiagnosis specifically in patients with NAION because of ON-T2-hyperintensity and ONH-CE in these patients [22][23][24]. ...
Introduction
Recent diagnostic criteria for optic neuritis include T2-hyperintensity of the optic nerve (ON), even without associated contrast enhancement. However, isolated ON-T2-hyperintensity is a nonspecific finding found in any optic neuropathy or severe retinopathy. We applied the 2022 optic neuritis diagnostic criteria to a cohort of patients with noninflammatory optic neuropathy and ON-T2-hyperintensity in at least one eye, to assess the rate of optic neuritis misdiagnosis using these criteria.
Methods
Retrospective study of consecutive patients who underwent brain/orbit MRI with/without contrast between 07/01/2019 and 06/30/2022. Patients with ON-T2-hyperintensity in at least one eye were included. The 2022 optic neuritis diagnostic criteria were applied to patients with noninflammatory optic neuropathies who had an ophthalmologic examination available for review.
Results
Of 150 patients included, 85/150 had compressive optic neuropathy; 32/150 had glaucoma; 12/150 had papilledema; 8/150 had hereditary (3), radiation-induced (3), nutritional (1), traumatic (1) optic neuropathies (none fulfilled the criteria); 13/150 had ischemic optic neuropathy and 4 fulfilled the criteria as definite optic neuritis due to contrast enhancement of the ON head. Seven additional patients would have satisfied the diagnostic criteria if red flags for alternative diagnoses had been overlooked.
Discussion
The application of the 2022 optic neuritis diagnostic criteria in patients with noninflammatory optic neuropathy and ON-T2-hyperintensity in at least one ON resulted in misdiagnosis of optic neuritis in only 4 patients because of ON head enhancement, all with nonarteritic anterior ischemic optic neuropathy. Neuro-ophthalmologic evaluation and exclusion of the ON head as a location in the MRI criteria would have prevented optic neuritis misdiagnosis in our study.
... Nevertheless, it should be considered that the field of both MS and epilepsy has been affected by the evolution of their understanding and by diagnostical errors due to a SciBase Neurology lack of specific diagnostic tests for them. Several diseases mimic MS [48]. In some cases, they were mistakenly diagnosed with MS, especially before the MRI era (i.e., before the 1980s [49]). ...
Objectives: Most patients with Multiple Sclerosis (MS) never have a seizure, although they are at risk for seizures since the onset of MS. This paradox leads us to suppose that MS plays a minor role in seizure generation and epileptogenesis. Methods: Qualitative study using data triangulation and inductive content analysis. A comprehensive literature search was carried out in four electronic databases (MEDLINE, Embase, Web of Science, and Google Scholar). Results: In MS patients, unprovoked seizures occur rarely (in about 3 percent of cases). Pediatric MS involves seizures more common than adult or late-onset MS. In general, children with seizures do not have poorer MS prognoses than children without seizures. Contrary to the general population, seizures do not peak in older MS patients. Since the use of disease-modifying therapies in the treatment of MS (i.e., since 1993), the frequency of seizures in MS patients has not changed considerably. Epilepsy syndrome cannot be recognized in MS patients with seizures. As a rule, seizures in MS are not difficult to treat. A sudden unexpected death in MS patients with seizures has not been observed more commonly than in the general epilepsy population. A disruption of the blood–brain barrier is the most obvious proconvulsive factor of MS. However, neither MS relapses nor a high rate of MS relapses is normally accompanied by seizures. Structural brain abnormalities usually accumulate over the course of MS. However, a high brain magnetic resonance imaging lesion load does not have a substantial impact on seizure occurrence in MS. Conclusion: MS does not have a major role in seizure generation and epileptogenesis. In most cases, the seizure-promoting effects of MS can be successfully counteracted by the brain´s protective mechanisms.
... 32 In addition, countervailing factors, including misclassifying MRI lesions as having an origin related to CNS demyelination, are palpable risks. 34 Despite all best efforts, individuals will be improperly treated. ...
The radiologically isolated syndrome (RIS) currently represents the earliest detectable preclinical phase of multiple sclerosis (MS). Remarkable advancements have been recently made, including the identification of risk factors for disease evolution, revisions to the existing 2009 RIS criteria, and our understanding of the impact of early disease-modifying therapy use in the prevention/delay of symptomatic MS from two randomized clinical trials. Here, we discuss RIS in the context of the spectrum of MS, implications in the clinical management of individuals, and provide insights into future opportunities and challenges given the anticipated inclusion of asymptomatic MS in the formal definition of MS.
... 5 In clinical practice, detection of enhancing lesions aids the differentiation of DIS-fulfilling common MS mimics-such as migraine or small vessel ischemic disease-from RIS or MS. 6,7 More broadly, the concept of DIT in MS diagnostic criteria has delivered improved specificity by providing not just evidence of ongoing disease but also supportive evidence of neuroinflammation. Accordingly, potential substitutes for clinical or MRI DIT have maintained this diagnostic role. ...
... L'expertise repose essentiellement sur une lecture approfondie de la forme, de la localisation, et du nombre des hypersignaux de la substance blanche, encéphalique ou médullaire [19]. Les critères diagnostiques de 2009 et 2023 du RIS insiste sur l'absence de symptômes cliniques ou d'antécédents de signes évocateurs de maladie démyélinisante, mais aussi l'absence d'arguments pour une autre pathologie qui pourrait expliquer les hypersignaux de la substance blanche [20]. La présence de bandes oligoclonales, même si l'analyse du LCR n'est pas obligatoire, viendra renforcer de façon importante la suspicion diagnostique de maladie chronique démyélinisante asymptomatique. ...
... Demyelinating disorders of the central nervous system (CNS) that affect the brain and spine have a variety of etiologies and can be separated into primary such as multiple sclerosis (MS) and other inflammatory-demyelinating diseases such as neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein-related antibody disease (MOGAD) as well as secondary (e.g., infectious, ischemic, metabolic, or toxic) diseases. MRI is the imaging modality of choice to assess demyelinating disorders of the brain and the cord and, together with the clinical and laboratory findings, can accurately classify them in most cases [1][2][3]. This review will highlight the important imaging manifestations of some acquired demyelinating diseases that allow more specific diagnosis. ...
Multiple sclerosis (MS) is the most important inflammatory demyelinating disorder that affects both the brain and spine. Dissemination in space and time on MRI is not limited to MS and can occur in neuromyelitis optica spectrum disorder (NMOSD) with aquaporin 4 antibodies, myelin oligodendrocyte glycoprotein-related antibody disease (MOGAD), and a series of other (inflammatory) demyelinating disorders. Spinal cord imaging is an important element of MS (differential) diagnosis and especially relevant in case of possible age-related vasculo-ischemic brain white matter lesions; a negative scan will help to rule out MS. Increasingly, MRI is used to monitor treatment and their complications such as progressive multifocal leukoencephalopathy (PML).
Neuromyelitis optica spectrum disorders (NMOSD) include a rare group of autoimmune conditions that primarily affect the central nervous system. They are characterized by inflammation and damage to the optic nerves, brain and spinal cord, leading to severe vision impairment, locomotor disability and sphynteric disturbances. In the majority of cases, NMOSD arises due to specific serum immunoglobulin G (IgG) autoantibodies targeting aquaporin 4 (AQP4-IgG), which is the most prevalent water-channel protein of the central nervous system. Early diagnosis and treatment are crucial to manage symptoms and prevent long-term disability in NMOSD patients. NMOSD were previously associated with a poor prognosis. However, recently, a number of randomized controlled trials have demonstrated that biological therapies acting on key elements of NMOSD pathogenesis, such as B cells, interleukin-6 (IL-6) pathway, and complement, have impressive efficacy in preventing the occurrence of clinical relapses. The approval of the initial drugs marks a revolutionary advancement in the treatment of NMOSD patients, significantly transforming therapeutic options and positively impacting their prognosis. In this review, we will provide an updated overview of the key immunopathological, clinical, laboratory, and neuroimaging aspects of NMOSD. Additionally, we will critically examine the latest advancements in NMOSD treatment approaches. Lastly, we will discuss key aspects regarding optimization of treatment strategies and their monitoring.
Aims
Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease. Microglia are reportedly involved in the pathogenesis of MS. However, the key molecules that control the inflammatory activity of microglia in MS have not been identified.
Methods
Experimental autoimmune encephalomyelitis (EAE) mice were randomized into CD22 blockade and control groups. The expression levels of microglial CD22 were measured by flow cytometry, qRT–PCR, and immunofluorescence. The effects of CD22 blockade were examined via in vitro and in vivo studies.
Results
We detected increased expression of microglial CD22 in EAE mice. In addition, an in vitro study revealed that lipopolysaccharide upregulated the expression of CD22 in microglia and that CD22 blockade modulated microglial polarization. Moreover, an in vivo study demonstrated that CD22 blockade aggravated EAE in mice and promoted microglial M1 polarization.
Conclusion
Collectively, our study indicates that CD22 may be protective against EAE and may play a critical role in the maintenance of immune homeostasis in EAE mice.
The diagnosis of MS relies on a combination of imaging, clinical examinations, and biological analyses, including blood and cerebrospinal fluid (CSF) assessments. G-Oligoclonal bands (OCBs) are considered a “gold standard” for MS diagnosis due to their high sensitivity and specificity. Recent advancements have involved the introduced of kappa free light chain (k-FLC) assay into cerebrospinal fluid (CSF) and serum (S), along with the albumin quotient, leading to the development of a novel biomarker known as the “K-index” or “k-FLC index”. The use of the K-index has been recommended to decrease costs, increase laboratory efficiency, and to skip potential subjective operator-dependent risk that could happen during the identification of OCBs profiles. This review aims to provide a comprehensive overview and analysis of recent scientific articles, focusing on updated methods for MS diagnosis with an emphasis on the utility of the K-index. Numerous studies indicate that the K-index demonstrates high sensitivity and specificity, often comparable to or surpassing the diagnostic accuracy of OCBs evaluation. The integration of the measure of the K-index with OCBs assessment emerges as a more precise method for MS diagnosis. This combined approach not only enhances diagnostic accuracy, but also offers a more efficient and cost-effective alternative.
Background
Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease that involves attacks of inflammatory demyelination and axonal damage, with variable but continuous disability accumulation. Transcranial magnetic stimulation (TMS) is a noninvasive method to characterize conduction loss and axonal damage in the corticospinal tract. TMS as a technique provides indices of corticospinal tract function that may serve as putative MS biomarkers. To date, no reviews have directly addressed the diagnostic performance of TMS in MS. The authors aimed to conduct a critical narrative review on the diagnostic performance of TMS in MS.
Methods
The authors searched the Embase, PubMed, Scopus, and Web of Science databases for studies that reported the sensitivity and/or specificity of any reported TMS technique compared to established clinical MS diagnostic criteria. Studies were summarized and critically appraised for their quality and validity.
Results
Seventeen of 1,073 records were included for data extraction and critical appraisal. Markers of demyelination and axonal damage—most notably, central motor conduction time (CMCT)—were specific, but not sensitive, for MS. Thirteen (76%), two (12%), and two (12%) studies exhibited high, unclear, and low risk of bias, respectively. No study demonstrated validity for TMS techniques as diagnostic biomarkers in MS.
Conclusions
CMCT has the potential to: (1) enhance the specificity of clinical MS diagnostic criteria by “ruling in” true-positives, or (2) revise a diagnosis from relapsing to progressive forms of MS. However, there is presently insufficient high-quality evidence to recommend any TMS technique in the diagnostic algorithm for MS.
The widespread use of magnetic resonance imaging (MRI) has led to increased detection of individuals exhibiting asymptomatic brain and spinal cord lesions suggestive of multiple sclerosis (MS), defined as “radiologically isolated syndrome” (RIS). Specific criteria have been proposed and updated over time to identify individuals with RIS. Moreover, a younger age, the presence of infratentorial, spinal cord or gadolinium-enhancing lesions, as well as of cerebrospinal fluid-specific oligoclonal bands have been recognized as relevant risk factors for the occurrence of a first clinical event. Recent randomized controlled trials conducted in individuals with RIS have shown that dimethyl fumarate and teriflunomide significantly reduce the occurrence of clinical events in this population. These findings support the notion that early treatment initiation may positively influence the prognosis of these patients. However, several aspects should be taken into account before treating individuals with RIS in the real-world clinical setting, including an accurate identification of individuals with RIS to avoid misdiagnosis, a precise stratification of their risk of experiencing a first clinical event and further data supporting favorable balance between benefits and risks, even in the long term. This commentary provides an overview of the latest updates in RIS diagnosis, prognosis, and emerging treatment evidence.
A 42-year-old woman and active cocaine user complained of subacutely worsening blurred vision and imbalance. Examination of the brain MRI showed rapidly expanding white matter lesions. Brain biopsy was consistent with inflammatory demyelination. Given an unusual presentation and a history of cocaine use, a broad differential diagnosis was considered including neurologic toxidromes.
Early diagnosis of multiple sclerosis (MS) relies on clinical evaluation, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis. Reliable biomarkers are needed to differentiate MS from other neurological conditions and to define the underlying pathogenesis. This study aimed to comprehensively profile immune activation biomarkers in the CSF of individuals with MS and explore distinct signatures between MS with and without oligoclonal bands (OCB). A total of 118 subjects, including relapsing–remitting MS with OCB (MS OCB+) (n = 58), without OCB (MS OCB−) (n = 24), and controls with other neurological diseases (OND) (n = 36), were included. CSF samples were analyzed by means of proximity extension assay (PEA) for quantifying 92 immune-related proteins. Neurofilament light chain (NfL), a marker of axonal damage, was also measured. Machine learning techniques were employed to identify biomarker panels differentiating MS with and without OCB from controls. Analyses were performed by splitting the cohort into a training and a validation set. CSF CD5 and IL-12B exhibited the highest discriminatory power in differentiating MS from controls. CSF MIP-1-alpha, CD5, CXCL10, CCL23 and CXCL9 were positively correlated with NfL. Multivariate models were developed to distinguish MS OCB+ and MS OCB− from controls. The model for MS OCB+ included IL-12B, CD5, CX3CL1, FGF-19, CST5, MCP-1 (91% sensitivity and 94% specificity in the training set, 81% sensitivity, and 94% specificity in the validation set). The model for MS OCB− included CX3CL1, CD5, NfL, CCL4 and OPG (87% sensitivity and 80% specificity in the training set, 56% sensitivity and 48% specificity in the validation set). Comprehensive immune profiling of CSF biomarkers in MS revealed distinct pathophysiological signatures associated with OCB status. The identified biomarker panels, enriched in T cell activation markers and immune mediators, hold promise for improved diagnostic accuracy and insights into MS pathogenesis.
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.
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.
Background:
Intrathecal immunoglobulin-G synthesis is a hallmark of multiple sclerosis (MS), which can be detected by oligoclonal IgG bands (OCB) or by κ-free light chains (κ-FLC) in cerebrospinal fluid.
Objective:
To perform a systematic review and meta-analysis to evaluate whether κ-FLC index has similar diagnostic value to identify patients with clinically isolated syndrome (CIS) or MS compared to OCB, and to determine κ-FLC index cut-off.
Methods:
PubMed was searched for studies that assessed diagnostic sensitivity and specificity of κ-FLC index and OCB to discriminate CIS/MS patients from control subjects. Two reviewers following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines performed study eligibility assessment and data extraction. Findings from studies were analyzed with bivariate mixed models.
Results:
A total of 32 studies were included in the meta-analysis to evaluate diagnostic value of κ-FLC index. Sensitivity and specificity ranged from 52% to 100% (weighted average: 88%) and 69% to 100% (89%) for κ-FLC index and from 37% to 100% (85%) and 74% to 100% (92%) for OCB. Mean difference of sensitivity and specificity between κ-FLC index and OCB was 2 and -4 percentage points. Diagnostic accuracy determined by mixed models revealed no significant difference between κ-FLC index and OCB. A discriminatory cut-off for κ-FLC index was determined at 6.1.
Conclusion:
The findings indicate that κ-FLC index has similar diagnostic accuracy in MS as OCB.
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.
Summary
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.
The current diagnostic criteria for multiple sclerosis (MS) lack specificity, and this may lead to misdiagnosis, which remains an issue in present-day clinical practice. In addition, conventional biomarkers only moderately correlate with MS disease progression. Recently, some MS lesional imaging biomarkers such as cortical lesions (CL), the central vein sign (CVS), and paramagnetic rim lesions (PRL), visible in specialized magnetic resonance imaging (MRI) sequences, have shown higher specificity in differential diagnosis. Moreover, studies have shown that CL and PRL are potential prognostic biomarkers, the former correlating with cognitive impairments and the latter with early disability progression. As machine learning-based methods have achieved extraordinary performance in the assessment of conventional imaging biomarkers, such as white matter lesion segmentation, several automated or semi-automated methods have been proposed as well for CL, PRL, and CVS. In the present review, we first introduce these MS biomarkers and their imaging methods. Subsequently, we describe the corresponding machine learning-based methods that were proposed to tackle these clinical questions, putting them into context with respect to the challenges they are facing, including non-standardized MRI protocols, limited datasets, and moderate inter-rater variability. We conclude by presenting the current limitations that prevent their broader deployment and suggesting future research directions.
Background
White matter lesions (WMLs) on brain magnetic resonance imaging (MRI) in multiple sclerosis (MS) may contribute to misdiagnosis. In chronic active lesions, peripheral iron-laden macrophages appear as paramagnetic rim lesions (PRLs).
Objective
To evaluate the sensitivity and specificity of PRLs in differentiating MS from mimics using clinical 3T MRI scanners.
Method
This retrospective international study reviewed MRI scans of patients with MS ( n = 254), MS mimics ( n = 91) and older healthy controls ( n = 217). WMLs, detected using fluid-attenuated inversion recovery MRI, were analysed with phase-sensitive imaging. Sensitivity and specificity were assessed for PRLs.
Results
At least one PRL was found in 22.9% of MS and 26.1% of clinically isolated syndrome (CIS) patients. Only one PRL was found elsewhere. The identification of ⩾1 PRL was the optimal cut-off and had high specificity (99.7%, confidence interval (CI) = 98.20%–99.99%) when distinguishing MS and CIS from mimics and healthy controls, but lower sensitivity (24.0%, CI = 18.9%–36.6%). All patients with a PRL showing a central vein sign (CVS) in the same lesion ( n = 54) had MS or CIS, giving a specificity of 100% (CI = 98.8%–100.0%) but equally low sensitivity (21.3%, CI = 16.4%–26.81%)
Conclusion
PRLs may reduce diagnostic uncertainty in MS by being a highly specific imaging diagnostic biomarker, especially when used in conjunction with the CVS.
Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is the most recently defined inflammatory demyelinating disease of the central nervous system (CNS). Over the last decade, several studies have helped delineate the characteristic clinical-MRI phenotypes of the disease, allowing distinction from aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) and multiple sclerosis (MS). The clinical manifestations of MOGAD are heterogeneous, ranging from isolated optic neuritis or myelitis to multifocal CNS demyelination often in the form of acute disseminated encephalomyelitis (ADEM), or cortical encephalitis. A relapsing course is observed in approximately 50% of patients. Characteristic MRI features have been described that increase the diagnostic suspicion (e.g., perineural optic nerve enhancement, spinal cord H-sign, T2-lesion resolution over time) and help discriminate from MS and AQP4+NMOSD, despite some overlap. The detection of MOG-IgG in the serum (and sometimes CSF) confirms the diagnosis in patients with compatible clinical-MRI phenotypes, but false positive results are occasionally encountered, especially with indiscriminate testing of large unselected populations. The type of cell-based assay used to evaluate for MOG-IgG (fixed vs. live) and antibody end-titer (low vs. high) can influence the likelihood of MOGAD diagnosis. International consensus diagnostic criteria for MOGAD are currently being compiled and will assist in clinical diagnosis and be useful for enrolment in clinical trials. Although randomized controlled trials are lacking, MOGAD acute attacks appear to be very responsive to high dose steroids and plasma exchange may be considered in refractory cases. Attack-prevention treatments also lack class-I data and empiric maintenance treatment is generally reserved for relapsing cases or patients with severe residual disability after the presenting attack. A variety of empiric steroid-sparing immunosuppressants can be considered and may be efficacious based on retrospective or prospective observational studies but prospective randomized placebo-controlled trials are needed to better guide treatment. In summary, this article will review our rapidly evolving understanding of MOGAD diagnosis and management.
Machine learning (ML) and its subset, deep learning (DL), are branches of artificial intelligence (AI) showing promising findings in the medical field, especially when applied to imaging data. Given the substantial role of MRI in the diagnosis and management of patients with multiple sclerosis (MS), this disease is an ideal candidate for the application of AI techniques. In this narrative review, we are going to discuss the potential applications of AI for MS clinical practice, together with their limitations. Among their several advantages, ML algorithms are able to automate repetitive tasks, to analyze more data in less time and to achieve higher accuracy and reproducibility than the human counterpart. To date, these algorithms have been applied to MS diagnosis, prognosis, disease and treatment monitoring. Other fields of application have been improvement of MRI protocols as well as automated lesion and tissue segmentation. However, several challenges remain, including a better understanding of the information selected by AI algorithms, appropriate multicenter and longitudinal validations of results and practical aspects regarding hardware and software integration. Finally, one cannot overemphasize the paramount importance of human supervision, in order to optimize the use and take full advantage of the potential of AI approaches.
Background
Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is now recognized as distinct from multiple sclerosis (MS).
Objective
To evaluate the importance of considering myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin-G (IgG) serology when applying MS diagnostic criteria in children.
Methods
Within a prospective cohort of children meeting MS criteria (median follow-up = 6 years, interquartile range (IQR) = 4–9), we measured MOG-IgG in serial archived serum obtained from presentation, and compared imaging and clinical features between seropositive and seronegative participants.
Results
Of 65 children meeting MS criteria (median age = 14.0 years, IQR = 10.9–15.1), 12 (18%) had MOG-IgG at disease onset. Seropositive participants were younger, had brain magnetic resonance imaging (MRI) features atypical for MS, rarely had cerebrospinal fluid (CSF) oligoclonal bands (2/8, 25%), and accumulated fewer T2 lesions over time. On serial samples, 5/12 (42%) were persistently seropositive, 5/12 (42%) became seronegative, and 2/12 (17%) had fluctuating results. All 12 children experienced a disease course different from typical MS.
Conclusion
While children with MOG-IgG can have clinical, CSF, and MRI features conforming to MS criteria, the presence of MOG-IgG is associated with atypical features and predicts a non-MS disease course. Given MOG-IgG seropositivity can wane over time, testing at first attack is of considerable importance for the diagnosis of MOGAD.
Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.
Objective
Determine the utility of aquaporin 4 IgG (AQP4-IgG) testing (live cell-based assay) for Neuromyelitis Optica Spectrum Disorders (NMOSD).
Methods
We included Mayo Clinic patients (1/1/2018-12/31/2019) tested for serum AQP4-IgG by live cell-based flow-cytometric assay. Medical records were reviewed to assess if patients fulfilled 2015 NMOSD criteria.
Results
Of 1371 patients tested, 41 were positive (3%) and all fulfilled NMOSD criteria with AQP4-IgG (specificity = 100%). Only 10/1330 testing negative met NMOSD criteria without AQP4-IgG (sensitivity = 80%) and seven of these 10 were MOG-IgG positive.
Conclusions
AQP4-IgG by live cell-based assay was highly specific and without false positives in a high throughput setting.
Although often regarded as a protean illness with myriad clinical and imaging manifestations, neurosarcoidosis typically presents as recognizable syndromes that can be approached in a rational, systematic fashion. Understanding of neurosarcoidosis has progressed significantly in recent years, including updated diagnostic criteria and advances in treatment. The diagnosis of neurosarcoidosis is established by the clinical syndrome, imaging and histopathological findings, and exclusion of other causes. Mounting evidence supports the use of tumor necrosis factor inhibitors as an important addition to the therapeutic armamentarium, along with glucocorticoids and steroid-sparing cytotoxic immunosuppressants. In this narrative review, we summarize recent advances in the diagnosis and treatment of neurosarcoidosis.
The specificity and implementation of current MRI-based diagnostic criteria for multiple sclerosis (MS) are imperfect. Approximately 1 in 5 of individuals diagnosed with MS are eventually determined not to have the disease, with overreliance on MRI findings a major cause of MS misdiagnosis. The central vein sign (CVS), a proposed MRI biomarker for MS lesions, has been extensively studied in numerous cross sectional studies and may increase diagnostic specificity for MS. CVS has desirable analytical, measurement, and scalability properties. “Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS)” is an NIH-supported, 2-year, prospective, international, multicenter study conducted by the North American Imaging in MS Cooperative (NAIMS) to evaluate CVS as a diagnostic biomarker for immediate translation into clinical care. Study objectives include determining the concordance of CVS and McDonald Criteria to diagnose MS, the sensitivity of CVS to detect MS in those with typical presentations, and the specificity of CVS among those with atypical presentations. The study will recruit a total of 400 participants (200 with typical and 200 with atypical presentations) across 11 sites. T2*-weighted, high-isotropic-resolution, segmented echo-planar MRI will be acquired at baseline and 24 months on 3-tesla scanners, and FLAIR* images (combination of FLAIR and T2*) will be generated for evaluating CVS. Data will be processed on a cloud-based platform that contains clinical and CVS rating modules. Imaging quality control will be conducted by automated methods and neuroradiologist review. CVS will be determined by Select6* and Select3* lesion methods following published criteria at each site and by central readers, including neurologists and neuroradiologists. Automated CVS detection and algorithms for incorporation of CVS into McDonald Criteria will be tested. Diagnosis will be adjudicated by three neurologists who served on the 2017 International Panel on the Diagnosis of MS. The CAVS-MS study aims to definitively establish CVS as a diagnostic biomarker that can be applied broadly to individuals presenting for evaluation of the diagnosis of MS.
Background
Myelin oligodendrocyte glycoprotein (MOG)-IgG is increasingly detected in children with CNS demyelinating diseases. Due to the clinical overlap in children with CNS demyelination with and without MOG-IgG positivity, identifying distinct characteristics would help early diagnosis.
Objective
To compare the specific features that may help differentiate MOG-IgG positive from negative children with CNS demyelinating diseases. To compare characteristics of patients with high and low MOG-IgG titers.
Methods
Children with CNS demyelinating disorders with onset before 18 years of age who were tested for MOG-IgG at the University of California San Francisco were included. This retrospective study collected the following by chart review: demographic, clinical, MRI, CSF, and treatment data. Serum was tested for MOG-IgG at Mayo Clinic by live cell-based fluorescent activated cell sorting assay with titer ≥1:20 confirming positivity.
Results
We assessed 65 Mog-IgG positive and 65 MOG-IgG negative patients. Median (IQR) age of onset was 7.6 (6.6) years for MOG-IgG positive and 13.8 (5.8) years for MOG-IgG negative (p<0.001). The female to male ratio was approximately 1:1 for the MOG-IgG positive group and 3:1 for the negative group (p=0.042). The most common initial diagnosis was demyelinating disease not otherwise specified (52.3%) in the positive group, compared to relapsing-remitting multiple sclerosis (41.5%) in the negative group (p<0.01). Optic nerve involvement (52.3%) was the most common clinical localization at onset for the MOG-IgG positive group, while brainstem/cerebellar (49.2%) localization predominated in the MOG-IgG negative group. The positive group also presented more often with a severe event at disease onset than the negative group (81.5% vs 60.3%; p< 0.002). MOG-IgG positive children had a lower frequency of oligoclonal bands (15.8% vs 57.4%; p<0.001). The frequency of baseline brain and spinal cord MRI abnormalities were similar in both groups; however, MOG-IgG positive patients more often had T2 hyperintense lesions in the optic nerves (26/43 vs 10/41; p<0.001). Disease-modifying medications were used in 64.6% of MOG-IgG positive patients versus 80% of negative children. Of the 32 positive patients with follow-up titers, seven reverted to negative while two who tested negative initially converted to positive. Positive titers greater than 1:160 were only observed within four months of a clinical event (disease onset or relapse). Patients with high and low MOG-IgG titers were comparable in demographic and clinical characteristics.
Conclusion
Despite some clinical overlap, we report notable demographic, MRI and CSF differences between MOG-IgG positive and negative children with CNS demyelinating disorders at disease onset. High MOG-IgG titers were only observed close to a clinical event.
Background and objective:
There are few studies that compare lesion evolution across different CNS demyelinating diseases, yet knowledge of this may be important for diagnosis and understanding differences in disease pathogenesis. We sought to compare MRI T2-lesion evolution in myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG-NMOSD), and multiple sclerosis (MS).
Methods:
In this descriptive study, we retrospectively identified Mayo Clinic patients with MOGAD, AQP4-IgG-NMOSD, or MS and: 1) brain or myelitis attack; 2) available attack MRI within 6 weeks; and 3) follow-up MRI beyond 6 months without interval relapses in that region. Two neurologists identified the symptomatic or largest T2-lesion for each patient (index lesion). MRIs were then independently reviewed by two neuroradiologists blinded to diagnosis to determine resolution of T2-lesions by consensus. The index T2-lesion area was manually outlined acutely and at follow-up to assess variation in size.
Results:
We included 156 patients (MOGAD, 38; AQP4-IgG-NMOSD, 51; MS, 67) with 172 attacks (brain, 81; myelitis, 91). The age (median [range]) differed between MOGAD (25 [2-74]), AQP4-IgG-NMOSD (53 [10-78]) and MS (37 [16-61]) (p<0.01) and female sex predominated in the AQP4-IgG-NMOSD (41/51 [80%]) and MS (51/67 [76%]) groups but not among those with MOGAD (17/38 [45%]). Complete resolution of the index T2-lesion was more frequent in MOGAD (brain, 13/18[72%]; spine, 22/28[79%]) than AQP4-IgG-NMOSD (brain, 3/21[14%]; spine, 0/34[0%]) and MS (brain, 7/42[17%]; spine, 0/29[0%]), p<0.001. Resolution of all T2-Lesions occurred most often in MOGAD (brain, 7/18[39%]; spine, 22/28[79%]) than AQP4-IgG-NMOSD (brain, 2/21[10%]; spine, 0/34[0%]), and MS (brain, 2/42[5%]; spine, 0/29[0%]), p< 0.01. There was a larger median (range) reduction in T2-lesion area in mm2 on follow-up axial brain MRI with MOGAD (213[55-873]) than AQP4-IgG-NMOSD (104[0.7-597]) (p=0.02) and MS, 36[0-506]) (p< 0.001) and the reductions in size on sagittal spine MRI follow-up in MOGAD (262[0-888]) and AQP4-IgG-NMOSD (309[0-1885]) were similar (p=0.4) and greater than MS (23[0-152]) (p<0.001).
Conclusions:
The MRI T2-lesions in MOGAD resolve completely more often than AQP4-IgG-NMOSD and MS. This has implications for diagnosis, monitoring disease activity, and clinical trial design, while also providing insight into pathogenesis of central nervous system demyelinating diseases.
Background:
Identifying magnetic resonance imaging (MRI) markers in myelin-oligodendrocytes-glycoprotein antibody-associated disease (MOGAD), neuromyelitis optica spectrum disorder-aquaporin-4 positive (NMOSD-AQP4) and multiple sclerosis (MS) is essential for establishing objective outcome measures.
Objectives:
To quantify imaging patterns of central nervous system (CNS) damage in MOGAD during the remission stage, and to compare it with NMOSD-AQP4 and MS.
Methods:
20 MOGAD, 19 NMOSD-AQP4, 18 MS in remission with brain or spinal cord involvement and 18 healthy controls (HC) were recruited. Volumetrics, lesions and cortical lesions, diffusion-imaging measures, were analysed.
Results:
Deep grey matter volumes were lower in MOGAD (p = 0.02) and MS (p = 0.0001), compared to HC and were strongly correlated with current lesion volume (MOGAD R = -0.93, p < 0.001, MS R = -0.65, p = 0.0034). Cortical/juxtacortical lesions were seen in a minority of MOGAD, in a majority of MS and in none of NMOSD-AQP4. Non-lesional tissue fractional anisotropy (FA) was only reduced in MS (p = 0.01), although focal reductions were noted in NMOSD-AQP4, reflecting mainly optic nerve and corticospinal tract pathways.
Conclusion:
MOGAD patients are left with grey matter damage, and this may be related to persistent white matter lesions. NMOSD-AQP4 patients showed a relative sparing of deep grey matter volumes, but reduced non-lesional tissue FA. Observations from our study can be used to identify new markers of damage for future multicentre studies.
Importance:
Myelin oligodendrocyte glycoprotein-IgG1-associated disorder (MOGAD) is a distinct central nervous system-demyelinating disease. Positive results on MOG-IgG1 testing by live cell-based assays can confirm a MOGAD diagnosis, but false-positive results may occur.
Objective:
To determine the positive predictive value (PPV) of MOG-IgG1 testing in a tertiary referral center.
Design, setting, and participants:
This diagnostic study was conducted over 2 years, from January 1, 2018, through December 31, 2019. Patients in the Mayo Clinic who were consecutively tested for MOG-IgG1 by live cell-based flow cytometry during their diagnostic workup were included. Patients without research authorization were excluded.
Main outcomes and measures:
Medical records of patients who were tested were initially reviewed by 2 investigators blinded to MOG-IgG1 serostatus, and pretest probability was classified as high or low (suggestive of MOGAD or not). Testing of MOG-IgG1 used a live-cell fluorescence-activated cell-sorting assay; an IgG binding index value of 2.5 or more with an end titer of 1:20 or more was considered positive. Cases positive for MOG-IgG1 were independently designated by 2 neurologists as true-positive or false-positive results at last follow-up, based on current international recommendations on diagnosis or identification of alternative diagnoses; consensus was reached for cases in which disagreement existed.
Results:
A total of 1617 patients were tested, and 357 were excluded. Among 1260 included patients tested over 2 years, the median (range) age at testing was 46 (0-98) years, and 792 patients were female (62.9%). A total of 92 of 1260 (7.3%) were positive for MOG-IgG1. Twenty-six results (28%) were designated as false positive by the 2 raters, with an overall agreement on 91 of 92 cases (99%) for true and false positivity. Alternative diagnoses included multiple sclerosis (n = 11), infarction (n = 3), B12 deficiency (n = 2), neoplasia (n = 2), genetically confirmed adrenomyeloneuropathy (n = 1), and other conditions (n = 7). The overall PPV (number of true-positive results/total positive results) was 72% (95% CI, 62%-80%) and titer dependent (PPVs: 1:1000, 100%; 1:100, 82%; 1:20-40, 51%). The median titer was higher with true-positive results (1:100 [range, 1:20-1:10000]) than false-positive results (1:40 [range, 1:20-1:100]; P < .001). The PPV was higher for children (94% [95% CI, 72%-99%]) vs adults (67% [95% CI, 56%-77%]) and patients with high pretest probability (85% [95% CI, 76%-92%]) vs low pretest probability (12% [95% CI, 3%-34%]). The specificity of MOG-IgG1 testing was 97.8%.
Conclusions and relevance:
This study confirms MOG-IgG1 as a highly specific biomarker for MOGAD, but when using a cutoff of 1:20, it has a low PPV of 72%. Caution is advised in the interpretation of low titers among patients with atypical phenotypes, because ordering MOG-IgG1 in low pretest probability situations will increase the proportion of false-positive results.
Multiple sclerosis (MS) and functional neurological disorder (FND) are both diagnostically challenging conditions which can present with similar symptoms. We systematically reviewed the literature to identify patients with MS who were misdiagnosed with FND, patients with FND who were misdiagnosed with MS, and reports of patients with both conditions. In addition to FND, we included studies of patients with other functional and psychiatric disorders where these caused symptoms leading to investigation for or a diagnosis of MS, which in a different context would likely have been labeled as FND. Our review suggests that MS is one of the most common causes of misdiagnosis of FND and vice versa. We discuss the clinical errors that appear to result in misdiagnoses, such as over-reliance on psychiatric comorbidity when making a diagnosis of FND or over-reliance on neuroimaging for the diagnosis of MS, and practical ways to avoid them. Comorbidity between these two conditions is also likely common, has been poorly studied, and adds complexity to diagnosis and treatment in patients with both MS and FND. Misdiagnosis and comorbidity in a landscape of emerging evidence-based treatments for both MS and FND are issues not only of clinical importance to the care of these patients, but also to treatment trials, especially of MS, where FND could be a hidden confounder.
Objective
To determine if MRI gadolinium enhancement patterns in myelopathies with longitudinally-extensive T2-lesions can be reliably distinguished and assist in diagnosis.
Methods
We retrospectively identified 74 Mayo Clinic patients (1/1/1996–12/31/2019) fulfilling the following criteria: 1) Clinical myelopathy; 2) MRI spine available; 3) Longitudinally-extensive T2-hyperintensity (≥3 vertebral segments); and 4) Characteristic gadolinium enhancement pattern associated with a specific myelopathy etiology. Thirty-nine cases with alternative myelopathy etiologies, without previously described enhancement patterns, were included as controls. Two independent readers, educated on enhancement patterns, reviewed T2-weighted and post-gadolinium T1-weighted images and selected the diagnosis based on this knowledge. These were compared to the true diagnoses and agreement was measured with Kappa coefficient.
Results
Among all cases and controls (n=113), there was excellent agreement for diagnosis using post-gadolinium images (Kappa, 0.76) but poor agreement with T2-weighted characteristics alone (Kappa, 0.25). A correct diagnosis was more likely when assessing post-gadolinium image characteristics than with T2-weighted images alone (Rater 1: 100/113 [88%] vs 61/113 [54%] correct, p<0.0001; Rater 2: 95/113 [84%] vs 68/113 [60%] correct, p<0.0001). Of the 74 with characteristic enhancement patterns, 55 (74%) were assigned an alternative incorrect or non-specific diagnosis when originally evaluated in clinical practice, 12 (16%) received immunotherapy for non-inflammatory myelopathies, and 2 (3%) underwent unnecessary spinal cord biopsy.
Conclusions
Misdiagnosis of myelopathies is common. The gadolinium enhancement patterns characteristic of specific diagnoses can be identified with excellent agreement between raters educated on this topic. This study highlights the potential diagnostic utility of enhancement patterns in myelopathies with longitudinally-extensive T2-lesions.
Background:
New-generation cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD).
Objective:
To describe systematically the CSF profile in MOG-EM.
Material and methods:
Cytological and biochemical findings (including white cell counts and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgA/IgM fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster (MRZ) reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF L-lactate) from 163 lumbar punctures in 100 adult patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively.
Results:
Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in almost 90% of samples (N = 151), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 62). If present, intrathecal IgG (and, more rarely, IgM) synthesis was low, often transient and mostly restricted to acute attacks. CSF WCC was elevated in > 50% of samples (median 31 cells/μl; mostly lymphocytes and monocytes; > 100/μl in 12%). Neutrophils were present in > 40% of samples; activated lymphocytes were found less frequently and eosinophils and/or plasma cells only very rarely (< 4%). Blood-CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 48% of all samples and at least once in 55% of all patients (N = 88) tested. The frequency and degree of CSF alterations were significantly higher in patients with acute myelitis than in patients with acute ON and varied strongly depending on attack severity. CSF L-lactate levels correlated significantly with the spinal cord lesion load in patients with acute myelitis (p < 0.0001). Like pleocytosis, blood-CSF barrier dysfunction was present also during remission in a substantial number of patients.
Conclusion:
MOG-IgG-positive EM is characterized by CSF features that are distinct from those in MS. Our findings are important for the differential diagnosis of MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.
Background
Differentiating multiple sclerosis (MS) from vascular risk factor (VRF)-small vessel disease (SVD) can be challenging.
Objective and Methods
In order to determine whether or not pontine lesion location is a useful discriminator of MS and VRF-SVD, we classified pontine lesions on brain magnetic resonance imaging (MRI) as central or peripheral in 93 MS cases without VRF, 108 MS patients with VRF and 43 non-MS cases with VRF.
Results
MS without VRF were more likely to have peripheral pons lesions (31.2%, 29/93) than non-MS with VRF (0%, 0/43) (Exp( B) = 29.8; 95% confidence interval (CI) = (1.98, 448.3); p = 0.014) but there were no significant differences regarding central pons lesions between MS without VRF (5.4%, 5/93) and non-MS with VRF patients (16.3%, 7/43) (Exp( B) = 0.89; 95% CI = (0.2, 3.94); p = 0.87). The presence of peripheral pons lesions discriminated between MS and VRF-SVD with 100% (95% CI = (91.8, 100)) specificity. The proportion of peripheral pons lesions in MS with VRF (30.5%, 33/108) was similar to that seen in MS without VRF (31.2%, 29/93, p = 0.99). Central lesions occurred in similar frequency in MS with VRF (8.3%, 9/108) and non-MS with VRF (16.3%, 7/43, p = 0.15).
Conclusion
Peripheral pons lesion location is a good discriminator of MS from vascular lesions.
The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the central nervous system within individuals lacking symptoms typical of multiple sclerosis. The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown.
2009-RIS subjects, by definition, fulfill 3-4 of 4 criteria for 2005 dissemination in space [DIS] and subjects fulfilling only 1 or 2 lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated.
747 subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled 1 or 2 2017 DIS criteria (designated as Group 1 and Group 2, respectively), and 496 (66.4%) fulfilled 3 or 4 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS Group and were more likely to develop new T2 lesions over time (p < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to multiple sclerosis.
At five years, the cumulative probability for a clinical event was 29.0% for Groups 1-2 compared to 38.7% for 2009-RIS (p = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1-2 increased the risk of symptomatic MS evolution at five years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (p < 0.001). The 2009-RIS subjects or Group 1-2 with at least 2 of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied.
This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria.
Serum antibodies directed against myelin oligodendrocyte glycoprotein (MOG) are found in patients with acquired CNS demyelinating syndromes that are distinct from multiple sclerosis and aquaporin-4-seropositive neuromyelitis optica spectrum disorder. Based on an extensive literature review and a structured consensus process, we propose diagnostic criteria for MOG antibody-associated disease (MOGAD) in which the presence of MOG-IgG is a core criterion. According to our proposed criteria, MOGAD is typically associated with acute disseminated encephalomyelitis, optic neuritis, or transverse myelitis, and is less commonly associated with cerebral cortical encephalitis, brainstem presentations, or cerebellar presentations. MOGAD can present as either a monophasic or relapsing disease course, and MOG-IgG cell-based assays are important for diagnostic accuracy. Diagnoses such as multiple sclerosis need to be excluded, but not all patients with multiple sclerosis should undergo screening for MOG-IgG. These proposed diagnostic criteria require validation but have the potential to improve identification of individuals with MOGAD, which is essential to define long-term clinical outcomes, refine inclusion criteria for clinical trials, and identify predictors of a relapsing versus a monophasic disease course.
Background and Objectives
Studies on tumefactive brain lesions in myelin-oligodendrocyte-glycoprotein-IgG-associated disease (MOGAD) are lacking. We sought to characterize the frequency, clinical, laboratory, and MRI features of these lesions in MOGAD and compare them to multiple sclerosis (MS) and aquaporin-4-IgG-positive-neuromyelitis-optica-spectrum-disorder (AQP4+NMOSD).
Methods
We retrospectively searched 194 MOGAD and 359 AQP4+NMOSD patients with clinical/MRI details available from the Mayo Clinic databases and included those with ≥1 tumefactive brain lesion (maximum transverse diameter ≥2 cm) on MRI. Tumefactive MS patients were identified using the Mayo Clinic medical-record-linkage-system. Binary multivariable stepwise logistic regression identified independent predictors of MOGAD diagnosis; Cox proportional regression models were used to assess the risk of relapsing disease and gait aid in tumefactive vs . non-tumefactive MOGAD patients.
Results
We included 108 patients with tumefactive demyelination (MOGAD=43; AQP4+NMOSD=16; MS=49). Tumefactive lesions were more frequent among MOGAD (43/194[22%]) than AQP4+NMOSD (16/359[5%]) (p<0.001). Risk of relapse and need for gait aid were similar in tumefactive and non-tumefactive MOGAD. Clinical features more frequent in MOGAD than MS included headache (18/43[42%] vs. 10/49[20%]; p=0.03) and somnolence (12/43[28%] vs. 2/49[4%]; p=0.003), the latter also more frequent than AQP4+NMOSD (0/16[0%]; p=0.02). The presence of: peripheral T2-hypointense rim, T1-hypointensity, diffusion restriction (particularly an arc pattern), ring enhancement, Balo’-like or cystic appearance favored MS over MOGAD (p < 0.001). MRI features were broadly similar in MOGAD and AQP4+NMOSD, except for more frequent diffusion restriction in AQP4+NMOSD (10/15[67%]) than MOGAD (11/42[26%], p=0.005). Cerebrospinal fluid analysis revealed less frequent positive oligoclonal bands in MOGAD (2/37[5%]) than MS (30/43[70%]) (p<0.001) and higher median white cell count in MOGAD than MS (33 vs. 6 cells/µl, p<0.001). At baseline, independent predictors of MOGAD diagnosis were presence of somnolence/headache, absence of T2-hypointense rim, lack of T1-hypointensity, and no diffusion restriction (Nagelkerke R Squared=0.67). Tumefactive lesion resolution was more common in MOGAD than MS or AQP4+NMOSD and improved model performance.
Discussion
Tumefactive lesions are frequent in MOGAD but are not associated with a worse prognosis. The clinical, MRI, and CSF attributes of tumefactive MOGAD differ from tumefactive MS, and are more similar to tumefactive AQP4+NMOSD with the exception of lesion resolution, which favors MOGAD.
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 of 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.
Optic neuritis is an inflammatory optic neuropathy that is commonly indicative of autoimmune neurological disorders including multiple sclerosis, myelin-oligodendrocyte glycoprotein antibody-associated disease, and neuromyelitis optica spectrum disorder. Early clinical recognition of optic neuritis is important in determining the potential aetiology, which has bearing on prognosis and treatment. Regaining high-contrast visual acuity is common in people with idiopathic optic neuritis and multiple sclerosis-associated optic neuritis; however, residual deficits in contrast sensitivity, binocular vision, and motion perception might impair vision-specific quality-of-life metrics. In contrast, recovery of visual acuity can be poorer and optic nerve atrophy more severe in individuals who are seropositive for antibodies to myelin oligodendrocyte glycoprotein, AQP4, and CRMP5 than in individuals with typical optic neuritis from idiopathic or multiple-sclerosis associated optic neuritis. Key clinical, imaging, and laboratory findings differentiate these disorders, allowing clinicians to focus their diagnostic studies and optimise acute and preventive treatments. Guided by early and accurate diagnosis of optic neuritis subtypes, the timely use of high-dose corticosteroids and, in some instances, plasmapheresis could prevent loss of high-contrast vision, improve contrast sensitivity, and preserve colour vision and visual fields. Advancements in our knowledge, diagnosis, and treatment of optic neuritis will ultimately improve our understanding of autoimmune neurological disorders, improve clinical trial design, and spearhead therapeutic innovation.
Importance
Adult-onset genetic disorders may present with clinical and magnetic resonance imaging (MRI) features suggestive of acquired inflammatory diseases. An ever-growing number of potentially treatable adult-onset genetic neuroinflammatory disorders have been described in the past few years that need to be rapidly identified.
Observations
Adult-onset acquired neuroinflammatory disorders encompass a large group of central nervous system (CNS) diseases with varying presentation, MRI characteristics, and course, among which the most common is multiple sclerosis. Despite recent progress, including the discovery of specific autoantibodies, a significant number of adult-onset neuroinflammatory disorders with progressive or relapsing course still remain without a definite diagnosis. In addition, some patients with genetic disorders such as leukodystrophies, hemophagocytic lymphohistiocytosis, or genetic vasculopathies can mimic acquired neuroinflammatory disorders. These genetic disorders, initially described in pediatric populations, are increasingly detected in adulthood thanks to recent progress in molecular genetics and the larger availability of high-throughput sequencing technologies.
Conclusions and Relevance
Genetic adult-onset neuroinflammatory diseases are at the border between primary CNS inflammatory diseases and systemic disorders with multiorgan involvement and predominantly neurologic manifestations. Neurologists must be aware of the main clues and red flags so they can confirm a diagnosis early, when some of these genetic disorders can be successfully treated.
Intrathecal production of kappa free light chains (KFLC) occurs in multiple sclerosis and can be measured using the KFLC index. KFLC index values can be determined more easily than oligoclonal bands (OB) detection and seem more sensitive than the immunoglobulin (Ig)G index to diagnose multiple sclerosis. We assessed the value of OB, KFLC index cut-offs 5.9, 6.6, and 10.61, and IgG index to diagnose multiple sclerosis with prospectively acquired data from a clinically isolated syndrome (CIS) inception cohort.
We selected patients with sufficient data to determine OB positivity, MRI dissemination in space (DIS) and time (DIT), IgG index, and sufficient quantities of paired CSF and blood samples to determine KFLC indexes (n = 214). We used Kendall´s Tau coefficient to estimate concordance; calculated the number of additional diagnoses when adding each positive index to DIS and positive OB; performed survival analyses for OB and each index with the outcomes second attack and 2017 MRI DIS and DIT; and estimated the diagnostic properties of OB and the different indexes for the abovementioned outcomes at five years.
OB were positive in 138 patients (64.5%), KFLC-5.9 in 136 (63.6%), KFLC-6.6 in 135 (63.1%), KFLC-10.61 in 126 (58.9%) and IgG index in 101 (47.2%). The highest concordance was between OB and KFLC-6.6 (τ=0.727) followed by OB and KFLC-5.9 (τ=0.716). Combining DIS plus OB or KFLC-5.9 increased the number of diagnosed patients by 11 (5.1%), with KFLC-6.6 by 10 (4.7%), with KFLC-10.61 by 9 (4.2%), and with IgG index by 3 (1.4%). Patients with positive OB or indexes reached second attack and MRI DIS and DIT faster than patients with negative results (P < 0.0001 except IgG index in second attack: P = 0.016). In multivariable Cox models [aHR (95% CI)], the risk for second attack was very similar between KFLC-5.9 [2.0 (0.9-4.3), P = 0.068] and KFLC-6.6 [2.1 (1.1-4.2), P = 0.035]. The highest risk for MRI DIS and DIT was demonstrated with KFLC-5.9 [4.9 (2.5-9.6), P < 0.0001], followed by KFLC-6.6 [3.4 (1.9-6.3), P < 0.0001]. KFLC-5.9 and KFLC-6.6 had a slightly higher diagnostic accuracy than OB for second attack (70.5, 71.1, and 67.8) and MRI DIS and DIT (85.7, 85.1, and 81.0).
KFLC indexes 5.9 and 6.6 performed slightly better than OB to assess multiple sclerosis risk and in terms of diagnostic accuracy. Given the concordance between OB and these indexes, we suggest using DIS plus positive OB or positive KFLC index as a modified criterion to diagnose multiple sclerosis.
The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future.
Introduction
As an immune-mediated disease of the central nervous system, multifaceted aspects of a humoral immune response are widely described during multiple sclerosis (MS). However, the prevalence of different auto-antibodies, such as antinuclear antibodies (ANA), during MS is very variable and their clinical relevance remains controversial. Our aim was to evaluate the prevalence and clinical correlations of ANA positivity in South Tunisian MS patients.
Material and methods
We performed ANA screening using indirect immunofluorescence (IIF) on HEp-2 cells (Biosystems®) in 82 MS patients. For ANA positive samples (titer ≥1/160), anti-ds-DNA detection (IIF on Crithidia luciliae (Biosystems®)) and extractable nuclear antigen typing (immunodot (Euroimmun®)) were performed.
Results
ANA were positive in 35/82 MS patients (42.7%). The titer was ≥ 1/320 in 16/35 patients. The antigenic specificity of ANA was identified in 7/35 patients. None of the patients had extra-neurological manifestations. No correlation was found between ANA and age, gender, MS course, disease duration, disability, annual relapse rate nor IgG index. ANA positivity was more frequent in patients with IgG oligoclonal bands (OCB) (47.1%) than in patients without IgG OCB (16,6%) (p = 0.049). Regarding disease activity, ANA positivity was significantly more frequent in patients with relapse (52.6%) than in patients in remission (25.9%) (p = 0.031).
Conclusion
Our results showed that ANA positivity in MS disease is not rare. This positivity was not associated with clinical expression of any connective tissue disease. ANA occurrence in MS was associated with IgG OCB+ profile and relapsing status, probably reflecting an ongoing immune dysregulation.
Objective:
To determine whether the prevalence of multiple sclerosis (MS) varies by race and ethnicity.
Methods:
We conducted a retrospective cohort study of more than 2.6 million adults from the multiethnic, community-dwelling members of Kaiser Permanente Southern California. The complete electronic health record of individuals with at least one ICD9 code for MS between January 1, 2008 to December 31, 2010 were reviewed. MS prevalence and 95% confidence intervals (CI) stratified by age-, sex- and race and ethnicity among 2010 members were estimated using binomial regression. Age- and sex-standardized prevalence was estimated according to the 2010 US Census population.
Results:
We identified 3863 patients with MS. The average age of prevalent MS patients was 51.7 years (standard deviation, 13.1) and 76.8% were women. The female preponderance was more pronounced among Black (81.2%) and Asian (83.6%) than White (76.3%) or Hispanic (74.5%) individuals with MS. Age- and sex-standardized MS prevalence per 100,000 was similarly high among Black (225.8, 95%CI=207.1-244.5) and White (237.7, 95%CI=228.2-247.2) and significantly lower among Hispanic (69.9, 95%CI=64.4-75.5) and Asian persons (22.6, 95%CI=17.1-28.1). MS prevalence was highest between the ages of 35 and 64 years and declined after 65, across all racial and ethnic groups. Among adults ages 18-24, crude MS prevalence was low, but was highest among Black and Hispanic young adults, lower in White and lowest in Asian/PI individuals (48.5, 25.0, 18.0 and 7.1/100,000, respectively).
Conclusions:
MS prevalence varies by race and ethnicity, being similarly high in White and Black and significantly lower in Hispanic and Asian persons in Southern California. Taken together with previous studies, these findings indicate that the burden of MS in the US Black community has long been under-recognized. More studies are needed to determine whether MS is an emerging disease among US Hispanic adults and whether MS susceptibility and prevalence vary among Hispanic or Asian individuals from different cultures and/or ancestral backgrounds.
Background
Internuclear ophthalmoparesis (INO) occurs in 15-52% of individuals with multiple sclerosis (MS) and is reliably detected by infrared oculography. Methods for diagnosing INO with infrared oculography and the association between INO and MS characteristics need confirmation. We aimed to describe INO prevalence and the clinical characteristics of individuals with MS and INO in a population-based cohort of individuals with MS born in the year 1966 (Project Y).
Methods
Previously described thresholds for the versional dysconjugacy index (VDI), assessed with standardized infrared oculography, were used to detect INO in participants of project Y. Clinical characteristics, visual functioning and complaints were compared between individuals with MS with INO and individuals with MS without INO.
Results
Two-hundred-twenty individuals with MS and 110 healthy controls were included. VDI values exceeding the threshold for INO presented in 53 (24%) individuals with MS and 19 controls (13%). INO was associated with male sex, greater disability, worse cognition and worse arm function in individuals with MS. There was no association with disease duration, visual functioning or complaints.
Conclusions
INO is prevalent among individuals with MS aged fifty-three and related to clinical characteristics of MS. INO was more frequently detected in healthy controls than previous studies, implying that oculography based diagnosis of INO requires further refinement.
Some pathogenic variants in mtDNA and nuclear DNA, affecting mitochondrial function, are associated with hearing loss. Behavioral and electrophysiological auditory performance are obtained from 62 patients, clinically diagnosed with different mitochondrial diseases (MD) using tone/speech audiometry and Auditory Brainstem Responses (ABR). Audiological variables (hearing loss type, pure tone average (PTA), interaural asymmetry, speech perception and brainstem neural conductivity) were analyzed and related to Newcastle Mitochondrial Disease Scale for Adults (NMDAS). In 35% of MDs, a mild to severe symmetrical sensorineural hearing loss (SNHL) was found. Patients with Maternally Inherited Diabetes and Deafness (MIDD) show significantly higher PTAs compared to other MDs. For all MDs, speech recognition scores were in accordance with their individual age- and gender-corrected tone audiometry, but ABR peak latencies were prolonged in patients with MIDD, Mitochondrial Encephalopathy Lactate acidosis and Stroke-like episodes (MELAS), Chronic Progressive External Ophthalmoplegia (CPEO) and Subacute necrotizing encephalopathy (Leigh). Correlations between NMDAS and audiological variables were low.
A 63-year-old Caucasian woman with a history of hypertension and type 2 diabetes presented for care for a previously established diagnosis of MS.
The patient reported receiving care from numerous neurologists over the previous 25 years for a diagnosis of MS, including recent care from a MS subspecialist neurologist. However, records were unavailable with exception of the prior two years. Symptoms started with an episode of severe myelitis with lower extremity numbness and weakness at age 36 that resulted in irreversible paraplegia, followed by vision loss in her left eye at age 40 resulting in a severe residual visual deficit of no light perception in that eye. The patient was subsequently diagnosed with MS. She reports an episode of bilateral arm weakness at age 46 that completely resolved after treatment with corticosteroids. At age 55, upon establishing care with a new neurologist, she was prescribed weekly intramuscular interferon beta-1a as MS disease modifying therapy (DMT).
Background
Optic neuritis (ON) is the most common manifestation of myelin oligodendrocyte glycoprotein antibody associated disorder (MOGAD) and multiple sclerosis (MS). Acute ON in MOGAD is thought to be associated with more severe optic disc edema than in other demyelinating diseases, but this has not been quantitatively confirmed. The goal of this study was to determine whether optical coherence tomography (OCT) can distinguish acute optic neuritis (ON) in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) from multiple sclerosis (MS), and establish the sensitivity of OCT as a confirmatory biomarker of ON in these entities.
Methods
This was a multicenter cross-sectional study of MOGAD and MS patients with peripapillary retinal nerve fiber layer (pRNFL) thickness measured with OCT within two weeks of acute ON symptom. Cirrus HD-OCT (Carl Zeiss Meditec, Inc. Dublin, CA, USA) was used to measure the pRNFL during acute ON. Eyes with prior optic neuritis or disc pallor were excluded. A receiver operating characteristic (ROC) curve analysis was performed to assess the ability of pRNFL thickness to distinguish MOGAD from MS.
Results
Sixty-four MOGAD and 50 MS patients met study inclusion criteria. Median age was 46.5 years (interquartile range [IQR]: 34.3-57.0) for the MOGAD group and 30.4 years (IQR: 25.7-38.4) for the MS group (p<0.001). Thirty-nine (61%) of MOGAD patients were female compared to 42 (84%) for MS (p=0.007). The median pRNFL thickness was 164µm (IQR: 116-212) in 96 acute MOGAD ON eyes compared to 103µm (IQR: 93-113) in 51 acute MS ON eyes (p<0.001). The ROC area under the curve for pRNFL thickness was 0.81 (95% confidence interval 0.74–0.88) to discriminate MOGAD from MS. The pRNFL cutoff that maximized Youden's index was 118µm, which provided a sensitivity of 74% and specificity of 82% for MOGAD. Among 31 MOGAD and 48 MS eyes with an unaffected contralateral eye or a prior baseline, the symptomatic eye had a median estimated pRNFL thickening of 45µm (IQR: 17-105) and 7.5µm (IQR: 1-18), respectively (p<0.001). All MOGAD affected eyes had a ≥5µm pRNFL thickening, whereas 26 (54%) MS affected eyes had a ≥5µm thickening.
Conclusion
OCT-derived pRNFL thickness in acute ON can help differentiate MOGAD from MS. This can aid with early diagnosis and guide disease-specific therapy in the acute setting before antibody testing returns, and help differentiate borderline cases. In addition, pRNFL thickening is a sensitive biomarker for confirming acute ON in MOGAD, which is clinically helpful and could be used for adjudication of attacks in future MOGAD clinical trials.
Patients with a historical diagnosis of multiple sclerosis (MS) — a patient presenting with a diagnosis of MS made previously and by a different clinician — present specific diagnostic and therapeutic challenges in clinical practice. Application of the McDonald criteria is most straightforward when applied contemporaneously with a syndrome typical of an MS attack or relapse; however, retrospective application of the criteria in some patients with a historical diagnosis of MS can be problematic. Limited patient recollection of symptoms and evolution of neurological examination and MRI findings complicate confirmation of an earlier MS diagnosis and assessment of subsequent disease activity or clinical progression. Adequate records for review of prior clinical examinations, laboratory results, and/or MRI scans obtained at the time of diagnosis or during ensuing care may be inadequate or unavailable. This paper provides recommendations for a clinical approach to the evaluation of patients with a historical diagnosis of MS to aid diagnostic confirmation, avoid misdiagnosis, and inform therapeutic decision-making.
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.
The prevalence of cerebrospinal fluid–specific oligoclonal bands (CSF-OCBs) was reported to be low in Asian people with multiple sclerosis (pwMS) compared to that in Western pwMS. It is yet to be determined whether it is a genuine feature of Asian pwMS or a misapprehension owing to past mis-classification of MS-mimicking diseases as MS. We aimed to reappraise the prevalence of CSF-OCBs in Korean pwMS after carefully excluding other central nervous system-inflammatory demyelinating diseases since 2017. Among 88 subjects, 78 (88.6%) were positive for CSF-OCBs, which suggests the prevalence of CSF-OCBs is not different between Korean and Western pwMS.
Purpose:
To compare the visual evoked potentials (VEPs) of optic neuritis (ON) patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and controls. To evaluate correlations between VEP and optical coherence tomography (OCT), contrast sensitivity (CS), and automated perimetry.
Methods:
Fifty-five eyes with ON from 29 patients (MS = 14 and NMOSD = 15) and 57 eyes from 29 controls were evaluated using VEP, automated perimetry, CS, and optical coherence tomography. Three groups were analyzed: 1) MS eyes with history of ON (ON-MS), 2) NMOSD eyes with ON (ON-NMOSD), and 3) healthy controls. Groups were compared and associations between the parameters were tested.
Results:
Compared to controls, ON-MS eyes showed significantly delayed N75 and P100 latencies when using a medium-sized stimulus (30'), and delayed P100 latency when using a large stimulus (1.5°), but similar amplitudes. Compared to controls, ON-NMOSD eyes showed significantly lower N75/P100 amplitudes (both stimulus sizes) and P100/N135 amplitudes (with the 30' stimulus), but latencies did not differ, except for a delayed P100 latency with the 30' stimulus. When comparing the 2 ON groups using the 1.5° stimulus, there was significant delay in P100 latency in ON-MS eyes and a reduction in N75/P100 amplitude in ON-NMOSD eyes. Peripapillary retinal nerve fiber layer, macular inner retinal layers, and CS measurements were significantly smaller in ON patients than in controls. A strong correlation was found between VEP parameters and inner retinal layer thickness in ON-NMOSD eyes.
Conclusions:
ON-MS eyes had normal amplitude and delayed VEP latency, whereas ON-NMOSD eyes displayed reduced amplitude and preserved latency when elicited by checkerboard stimulus with large 1.5° checks. Under such conditions, VEP may help distinguish resolved MS-related ON from resolved NMOSD-related ON.
Background
: Differentiation of the demyelinating disorders of the CNS seems challenging in practice. Conus medullaris, the cone-shaped end of the spinal cord, is more involved in anti-MOG patients based on preliminary studies, a possibly helpful detail in its differentiation. Nevertheless, the evidence is still limited and the underlying cause is unclear and undiscussed in previous studies.
Objective
: To contribute to preliminary studies by comparing conus involvement among patients with MS, anti-AQP4, and anti-MOG diseases using larger sample size.
Methods
: More than a thousand MS, anti-AQP4, and anti-MOG patients were followed up for a maximum of five years, scanned for conus medullaris involvement. Data regarding each cohort were then analyzed and compared using statistical methods.
Results
: The rate of conus medullaris involvement was significantly higher in anti-MOG patietns (OR = 27.109, P < 0.001), followed by anti-AQP4 (OR = 4.944, P = 0.004), and MS patients (OR = reference). Survival analysis showed higher pace and cumulative incidence of conus attacks in anti-MOG patients. Conus-involved patients, showed no significant difference regarding age, sex, concurrent brain lesions, and their partial recovery. Predictive values show that the probability of being diagnosed with anti-MOG is roughly 13 times higher in conus-involved patients (25.93% vs. 1.97%), although this probability was still higher for MS, as it has a much higher incidence.
Conclusion
: Despite minor differences, the results were in line with previous studies, confirming the higher rate of conus medullaris involvement among anti-MOG patients. Potential underlying causes are proposed and remain to be investigated in future studies.
Background:
Limited studies have described long-term outcomes in pathology confirmed multiple sclerosis (MS).
Objectives:
To describe long-term clinical-radiographic-cognitive outcomes in a prospectively followed cohort of patients with pathologically confirmed CNS demyelinating disease, consistent with MS.
Methods:
Subjects underwent clinical assessment, standardized 3T-MRI brain, and cognitive battery.
Results:
Seventy-five patients were included. Biopsied lesion size was ⩾ 2 cm in 62/75. At follow-up, median duration since biopsy was 11 years. Median EDSS was 3 and lesion burden was large (median 10 cm3). At follow-up, 57/75 met MS criteria, 17/75 had clinically isolated syndrome, and 1 radiographic changes only. Disability scores were comparable to a prevalence cohort in Olmsted County (p < 0.001, n = 218). Cognitive outcomes below age-normed standards included psychomotor, attention, working memory, and executive function domains. Total lesion volume and index lesion-related severity correlated with EDSS and cognitive performance. Volumetric cortical/subcortical GM correlated less than lesion metrics to cognitive outcomes.
Conclusion:
Despite early aggressive course in pathologically confirmed MS, its long-term course was comparable to typical MS in our study. Cognitive impairment in this group seemed to correlate strongest to index lesion severity and total lesion volume. It remains to be established how the aggressive nature of the lesion, biopsy, and treatment affect clinical/cognitive outcomes.
A prodrome is an early set of signs, symptoms or other findings that occur before the onset of typical symptoms of a disease. Prodromal phases are well recognized in several neurological and inflammatory diseases, but the possibility of a prodrome in multiple sclerosis (MS) has received relatively little attention until the past few years. In this Perspective, we summarize what is currently known about the MS prodrome, including its possible duration, clinical features and potential biomarkers. We also consider what insights and lessons can be learned from knowledge of and research into the prodromal phases of other diseases. A better understanding of the MS prodrome could have profound clinical implications as it could enable earlier recognition of MS and earlier initiation of treatments that reduce relapse rates and long-term disability. Knowledge of the MS prodrome could also affect research into the causes of MS, and putative risk factors must be re-evaluated in light of the MS prodrome. We conclude by outlining the major knowledge gaps and propose future initiatives. In this Perspective, Makhani and Tremlett provide an overview of the evidence for a prodromal phase in multiple sclerosis, discuss possible characteristics and markers of this prodrome, and consider its profound clinical and research implications.
The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future.
Objective
To identify early clinical and paraclinical factors that may help predict later conversion to multiple sclerosis (MS) in patients presenting with isolated myelitis (ie, ‘transverse myelitis’ without clinical or radiological evidence of inflammation/demyelination elsewhere in the central nervous system).
Methods
In this retrospective cohort study, we included patients with isolated myelitis who were followed clinically and radiologically at our specialised myelopathy clinic. We excluded patients with MS at the onset, aquaporin-4-IgG seropositivity, myelin oligodendrocyte glycoprotein-IgG seropositivity or other identified aetiology. Logistic regression was used to identify factors predictive of conversion to MS (defined by the 2017 McDonald criteria).
Results
We included 100 patients, followed for a median of 4.3 years. Conversion to MS occurred in 25 of 77 patients (32%) with short-segment myelitis (longest lesion spanning <3 vertebral segments on MRI) as compared with 0 of 23 patients (0%) with longitudinally extensive myelitis (p=0.002). Among patients with short-segment myelitis, factors identified as highly predictive of conversion to MS using multivariate logistic regression included cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCB) (OR (OR) 9.2, 95% CI 2.1 to 41.0, p=0.004), younger age (OR 1.1 for each year younger, 95% CI 1.0 to 1.1, p=0.04) and longer follow-up (OR 1.3 for each year longer, 95% CI 1.0 to 1.6, p=0.04). Conversion to MS occurred at a median of 2.8 years after myelitis onset.
Conclusions
Short-segment MRI cord lesion(s), CSF-restricted OCB, younger age and longer follow-up are all factors predictive of conversion to MS in patients presenting with isolated myelitis.
Prevalence of anemia in India is almost 40% with no significant change since 1998–99, whereas globally this prevalence has been reduced to < 15%. This could be because our national nutritional programs (mainly National Nutritional Anemia Control Program-NNACP) focus on supplementation with iron and folate but not with vitamin B12. Some Indian studies, including our study (2012), indicated high prevalence of B12 deficiency in North Indian urban population. Hence, we conducted a retrospective analysis of 3 years’ data (2012–2014 including 48,317 subjects) and compared it with last year’s retrospective data (April 2019–March 2020 including 4775 subjects) to ascertain prevalence of deficiencies of these micronutrient with special reference to patients of anemia, and improvement therein over the subsequent 5-year period. Our results indicate that amongst our subjects with anemia, iron deficiency has reduced from 66.73% (2012–2014) to 56.86% (2019), but prevalence of vitamin B12 deficiency is still the same (36.54% in 2012–2014; 37.04% in 2019). Folate deficiency was similar in both sets of data (2.95% in 2012–2014 and 2.55% in 2019). Thus, NNACP has reduced prevalence of iron deficiency by ~ 10%points and folate deficiency marginally; B12 deficiency has not been addressed. It would, therefore, follow that we need to add to our current national programs to effectively deal with these deficiencies. Food fortification (with iron, folate and B12) seems the most likely means to add value to the existing programs. In addition, food diversification needs to be included in regular school curriculum to bring about community awareness and change in food habits.
Background:
Multiple sclerosis (MS) misdiagnosis may cause physical and emotional damage to patients.
Objectives:
The objective of this study is to determine the frequency and characteristics of MS misdiagnosis in patients referred to the Multiple Sclerosis Centre of Catalonia.
Methods:
We designed a prospective study including all new consecutive patients referred to our centre between July 2017 and June 2018. Instances of misdiagnosis were identified, and referral diagnosis and final diagnosis were compared after 1 year of follow-up. Association of misdiagnosis with magnetic resonance imaging (MRI) findings, presence of comorbidities and family history of autoimmunity were assessed.
Results:
A total of 354 patients were referred to our centre within the study period, 112 (31.8%) with 'established MS'. Misdiagnosis was identified in eight out of 112 cases (7.1%). MRI identified multifocal white matter lesions, deemed non-specific or not suggestive of MS in all misdiagnosed cases. Patients with MS misdiagnosis had more comorbidities in general than patients with MS (p = 0.026) as well as a personal history of autoimmunity (p < 0.001).
Conclusion:
A low frequency of MS misdiagnosis was found in our clinical setting. Multifocal non-specific white matter lesions in referral MRI examinations and the presence of comorbidities, including a personal history of autoimmunity, seem to be contributing factors to misdiagnosis.
Purpose of review:
This article reviews the neuroimaging of disorders of the spinal cord and cauda equina, with a focus on MRI. An anatomic approach is used; diseases of the extradural, intradural-extramedullary, and intramedullary (parenchymal) compartments are considered, and both neoplastic and non-neoplastic conditions are covered. Differentiating imaging features are highlighted.
Recent findings:
Although T2-hyperintense signal abnormality of the spinal cord can have myriad etiologies, neuroimaging can provide specific diagnoses or considerably narrow the differential diagnosis in many cases. Intradural-extramedullary lesions compressing the spinal cord have a limited differential diagnosis and are usually benign; meningiomas and schwannomas are most common. Extradural lesions can often be specifically diagnosed. Disk herniations are the most commonly encountered mass of the epidural space. Cervical spondylotic myelopathy can cause a characteristic pattern of enhancement, which may be mistaken for an intrinsic myelopathy. A do-not-miss diagnosis of the extradural compartment is idiopathic spinal cord herniation, the appearance of which can overlap with arachnoid cysts and webs. Regarding intrinsic causes of myelopathy, the lesions of multiple sclerosis are characteristically short segment but can be confluent when multiple. Postcontrast MRI can be particularly helpful, including when attempting to differentiate the long-segment myelopathy of neurosarcoidosis and aquaporin-4 (AQP4)-IgG-seropositive neuromyelitis optica spectrum disorder (NMOSD) and when characterizing spinal cord tumors such as primary neoplasms and metastases. Spinal dural arteriovenous fistula is another do-not-miss diagnosis, with characteristic MRI features both precontrast and postcontrast. Tract-specific white matter involvement can be a clue for diseases such as subacute combined degeneration, paraneoplastic myelopathy, and radiation myelitis, whereas gray matter-specific involvement can suggest conditions such as cord infarct, viral myelitis, or myelin oligodendrocyte glycoprotein (MOG)-IgG associated disorder.
Summary:
Knowledge of the neuroimaging findings of the many causes of spinal cord and cauda equina dysfunction is critical for both neurologists and neuroradiologists. A structured approach to lesion compartmental location and imaging feature characterization is recommended.
Purpose of review:
This article provides an update on the clinical diagnosis and management of immune-mediated myelopathies, including the relevance of imaging, ancillary testing with an emphasis on autoantibody biomarkers, recognition of myelitis mimics, and therapeutic approach.
Recent findings:
The imaging characterization of immune-mediated myelopathies and the discovery of neural autoantibodies have been crucial in improving our ability to accurately diagnose myelitis. The identification of autoantibodies directed against specific central nervous system targets has led to major improvements in our understanding of the mechanisms underlying inflammation in myelitis. It has also allowed distinction of these myelopathy etiologies from noninflammatory etiologies of myelopathy and from multiple sclerosis and provided insight into their risk of recurrence, treatment response, and long-term clinical outcomes. Prompt recognition and appropriate testing in the setting of acute and subacute myelopathies is critical as timely administration of immunotherapy can help improve symptoms and prevent permanent neurologic disability. A patient should not be classified as having "idiopathic transverse myelitis" without a comprehensive evaluation for a more specific etiology. Achieving the correct diagnosis and learning to recognize noninflammatory myelitis mimics is crucial as they have therapeutic and prognostic implications.
Summary:
Identifying the clinical and radiographic features of immune-mediated myelitis and recognizing mimics and pitfalls will help clinicians treat confirmed autoimmune myelitis appropriately.
Acute isolated optic neuritis can be the initial presentation of demyelinating inflammatory central nervous system disease related to multiple sclerosis (MS), neuromyelitis optica (NMO) or myelin oligodendrocyte glycoprotein antibody disease (MOG-AD). In addition to the well-characterized brain and spinal cord imaging features, important and characteristic differences in the radiologic appearance of the optic nerves in these disorders are being described, and magnetic resonance imaging (MRI) of the optic nerves is becoming an essential tool in the differential diagnosis of optic neuritis. Whereas typical demyelinating optic neuritis is a relatively mild and self-limited disease, atypical optic neuritis in NMO and MOG-AD is potentially much more vision-threatening and merits a different treatment approach. Thus, differentiation based on MRI features may be particularly important during the first attack of optic neuritis, when antibody status is not yet known. This review discusses the optic nerve imaging in the major demyelinating disorders with an emphasis on clinically relevant differences that can help clinicians assess and manage these important neuro-ophthalmic disorders. It also reviews the utility of optic nerve MRI as a prognostic indicator in acute optic neuritis.
Objective
To determine the frequency and characteristics of brainstem or cerebellar involvement in myelin-oligodendrocyte-glycoprotein-antibody-associated-disorder (MOGAD) versus aquaporin-4-IgG-seropositive-neuromyelitis optica spectrum disorder (AQP4-IgG-NMOSD) and multiple sclerosis (MS).
Methods
In this observational study, we retrospectively identified 185 Mayo Clinic MOGAD patients with: (1) characteristic MOGAD phenotype, (2) MOG-IgG seropositivity by live cell-based assay and (3) MRI lesion(s) of brainstem, cerebellum or both. We compared the symptomatic attacks to AQP4-IgG-NMOSD (n=30) and MS (n=30).
Results
Brainstem or cerebellar involvement occurred in 62/185 (34%) MOGAD patients of which 39/62 (63%) were symptomatic. Ataxia (45%) and diplopia (26%) were common manifestations. The median age in years (range) in MOGAD of 24 (2–65) was younger than MS at 36 (16–65; p=0.046) and AQP4-IgG-NMOSD at 45 (6–72; p=0.006). Isolated attacks involving the brainstem, cerebellum or both were less frequent in MOGAD (9/39 (23%)) than MS (22/30 (73%); p<0.001) but not significantly different from AQP4-IgG-NMOSD (14/30 (47%); p=0.07). Diffuse middle cerebellar peduncle MRI-lesions favoured MOGAD (17/37 (46%)) over MS (3/30 (10%); p=0.001) and AQP4-IgG-NMOSD (3/30 (10%); p=0.001). Diffuse medulla, pons or midbrain MRI lesions occasionally occurred in MOGAD and AQP4-IgG-NMOSD but never in MS. Cerebrospinal fluid (CSF) oligoclonal bands were rare in MOGAD (5/30 (17%)) and AQP4-IgG-NMOSD (2/22 (9%); p=0.68) but common in MS (18/22 (82%); p<0.001). Disability at nadir or recovery did not differ between the groups.
Conclusion
Involvement of the brainstem, cerebellum or both is common in MOGAD but usually occurs as a component of a multifocal central nervous system attack rather than in isolation. We identified clinical, CSF and MRI attributes that can help discriminate MOGAD from AQP4-IgG-NMOSD and MS.
on behalf of the AFM working group* Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.
Data on long-term outcomes of patients with myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG)–associated disorder (MOGAD) are scarce.¹,2 We report outcomes in a single-institution cohort with long-term follow-up.