The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.

/pdf/diagnosis-of-multiple-sclerosis-2017-revisions-of-the-55ct02l5o1.pdf

Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria

A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes Retrospective multicenter study The sex ratio was 1:28 (m:f) Median age at onset was 31 years (range 6-70) The disease followed a multiphasic course in 80% (median time-to-first-relapse 5 months; annualized relapse rate 092) and resulted in significant disability in 40% (mean follow-up 75 ± 465 months), with severe visual impairment or functional blindness (36%) and markedly impaired ambulation due to paresis or ataxia (25%) as the most common long-term sequelae Functional blindness in one or both eyes was noted during at least one ON attack in around 70% Perioptic enhancement was present in several patients Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70%) Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44% Fourty-one percent had a history of simultaneous ON and myelitis Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one) CSF pleocytosis (partly neutrophilic) was present in 70%, oligoclonal bands in only 13%, and blood-CSF-barrier dysfunction in 32% Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal Full recovery was achieved by plasma exchange in some cases, including after IVMP failure Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids Methotrexate was effective in 5/6 patients Interferon-beta was associated with ongoing or increasing disease activity Rituximab and ofatumumab were effective in some patients However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion Coexisting autoimmunity was rare (9%) Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28%, 32%, 15%, 33%, respectively; MS had been suspected in 36% Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis

/pdf/mog-igg-in-nmo-and-related-disorders-a-multicenter-study-of-3lmh0pnmry.pdf

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome

Over the past few years, new-generation cell-based assays have demonstrated a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations. Most experts now consider MOG-IgG-associated encephalomyelitis (MOG-EM) a disease entity in its own right, immunopathogenetically distinct from both classic multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorders (NMOSD). Owing to a substantial overlap in clinicoradiological presentation, MOG-EM was often unwittingly misdiagnosed as MS in the past. Accordingly, increasing numbers of patients with suspected or established MS are currently being tested for MOG-IgG. However, screening of large unselected cohorts for rare biomarkers can significantly reduce the positive predictive value of a test. To lessen the hazard of overdiagnosing MOG-EM, which may lead to inappropriate treatment, more selective criteria for MOG-IgG testing are urgently needed. In this paper, we propose indications for MOG-IgG testing based on expert consensus. In addition, we give a list of conditions atypical for MOG-EM (“red flags”) that should prompt physicians to challenge a positive MOG-IgG test result. Finally, we provide recommendations regarding assay methodology, specimen sampling and data interpretation.

/pdf/mog-encephalomyelitis-international-recommendations-on-315po7nrta.pdf

MOG encephalomyelitis: International recommendations on diagnosis and antibody testing

See de Seze (doi:10.1093/brain/awx292) for a scientific commentary on this article. A condition associated with an autoantibody against MOG has been recently recognized as a new inflammatory disease of the central nervous system, but the disease course and disability outcomes are largely unknown. In this study we investigated clinical characteristics of MOG-antibody disease on a large cohort of patients from the UK. We obtained demographic and clinical data on 252 UK patients positive for serum immunoglobulin G1 MOG antibodies as tested by the Autoimmune Neurology Group in Oxford. Disability outcomes and disease course were analysed in more detail in a cohort followed in the Neuromyelitis Optica Oxford Service (n = 75), and this included an incident cohort who were diagnosed at disease onset (n = 44). MOG-antibody disease affects females (57%) slightly more often than males, shows no ethnic bias and typically presents with isolated optic neuritis (55%, bilateral in almost half), transverse myelitis (18%) or acute disseminated encephalomyelitis-like presentations (18%). In the total Oxford cohort after a median disease duration of 28 months, 47% of patients were left with permanent disability in at least one of the following: 16% patients had visual acuity ≤6/36 in at least one eye, mobility was limited in 7% (i.e. Expanded Disability Status Scale ≥ 4.0), 5% had Expanded Disability Status Scale ≥ 6.0, 28% had permanent bladder issues, 20% had bowel dysfunction, and 21% of males had erectile dysfunction. Transverse myelitis at onset was a significant predictor of long-term disability. In the incident cohort 36% relapsed after median disease duration of 16 months. The annualized relapse rate was 0.2. Immunosuppression longer than 3 months following the onset attack was associated with a lower risk of a second relapse. MOG-antibody disease has a moderate relapse risk, which might be mitigated by medium term immunosuppression at onset. Permanent disability occurs in about half of patients and more often involves sphincter and erectile functions than vision or mobility.

/pdf/clinical-presentation-and-prognosis-in-mog-antibody-disease-gqvr40s7r0.pdf

Clinical presentation and prognosis in MOG-antibody disease: a UK study.

Over the past few years, new-generation cell-based assays have demonstrated a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations. Most experts now consider MOG-IgG-associated encephalomyelitis (MOG-EM) a disease entity in its own right, immunopathogenetically distinct from both classic multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorders (NMOSD). Owing to a substantial overlap in clinicoradiological presentation, MOG-EM was often unwittingly misdiagnosed as MS in the past. Accordingly, increasing numbers of patients with suspected or established MS are currently being tested for MOG-IgG. However, screening of large unselected cohorts for rare biomarkers can significantly reduce the positive predictive value of a test. To lessen the hazard of overdiagnosing MOG-EM, which may lead to inappropriate treatment, more selective criteria for MOG-IgG testing are urgently needed. In this paper, we propose indications for MOG-IgG testing based on expert consensus. In addition, we give a list of conditions atypical for MOG-EM ('red flags') that should prompt physicians to challenge a positive MOG-IgG test result. Finally, we provide recommendations regarding assay methodology, specimen sampling and data interpretation, and propose for the first time diagnostic criteria for MOG-EM.

MOG-Enzephalomyelitis: Internationale Empfehlungen zu Diagnose und Antikörpertestung [MOG encephalomyelitis: international recommendations on diagnosis and antibody testing]

Objective: To optimize sensitivity and disease specificity of a myelin oligodendrocyte glycoprotein (MOG) antibody assay. Methods: Consecutive sera (n 5 1,109) sent for aquaporin-4 (AQP4) antibody testing were screened for MOG antibodies (Abs) by cell-based assays using either full-length human MOG (FL-MOG) or the short-length form (SL-MOG). The Abs were initially detected by Alexa Fluor goat anti-human IgG (H 1 L) and subsequently by Alexa Fluor mouse antibodies to human IgG1. Results: When tested at 1:20 dilution, 40/1,109 sera were positive for AQP4-Abs, 21 for SLMOG, and 180 for FL-MOG. Only one of the 40 AQP4-Ab–positive sera was positive for SLMOG-Abs, but 10 (25%) were positive for FL-MOG-Abs (p 5 0.0069). Of equal concern, 48% (42/88) of sera from controls (patients with epilepsy) were positive by FL-MOG assay. However, using an IgG1-specific secondary antibody, only 65/1,109 (5.8%) sera were positive on FL-MOG, and AQP4-Ab– positive and control sera were negative. IgM reactivity accounted for the remaining anti-human IgG (H 1 L) positivity toward FL-MOG. The clinical diagnoses were obtained in 33 FL-MOG–positive patients, blinded to the antibody data. IgG1-Abs to FL-MOG were associated with optic neuritis (n 5 11), AQP4-seronegative neuromyelitis optica spectrum disorder (n 5 4), and acute disseminated encephalomyelitis (n 5 1). All 7 patients with probable multiple sclerosis (MS) were MOG-IgG1 negative. Conclusions: The limited disease specificity of FL-MOG-Abs identified using Alexa Fluor goat antihuman IgG (H 1 L) is due in part to detection of IgM-Abs. Use of the FL-MOG and restricting to IgG1-Abs substantially improves specificity for non-MS demyelinating diseases. Classification of evidence: This study provides Class II evidence that the presence of serum IgG1- MOG-Abs in AQP4-Ab–negative patients distinguishes non-MS CNS demyelinating disorders from MS (sensitivity 24%, 95% confidence interval [CI] 9%–45%; specificity 100%, 95% CI 88%–100%). Neurol Neuroimmunol Neuroinflamm 2015;2:e89; doi: 10.1212/ NXI.0000000000000089

https://nn.neurology.org/content/nnn/2/3/e89.full.pdf

M Woodhall

Papers

MOG cell-based assay detects non-MS patients with inflammatory neurologic disease