CSF-restricted Oligoclonal Bands Research Articles

Kappa index in the diagnostic work-up of autoimmune encephalitis

BackgroundThe presence of inflammatory changes in the cerebrospinal fluid (CSF), including immunoglobulin intrathecal synthesis (IS), can support the diagnosis of autoimmune encephalitis (AE) and allow prompt treatment. The main aim of our study was to calculate the Kappa index as a marker of IS, in patients with AE. MethodsCharts of patients undergoing a diagnostic work-up for suspected AE between 2009 and 2023 were reviewed and the Graus criteria applied. CSF and serum kappa free light chains were determined using the Freelite assay (The Binding Site Group) and the turbidimetric Optilite analyzer. ResultsWe identified 34 patients with “definite” AE (9 anti-NMDAR AE and 25 limbic AE) and nine patients with “possible” AE. Five patients (15%) with definite AE had pleocytosis and twelve (34%) showed CSF-restricted oligoclonal bands (OCB) at isoelectric focusing. The Kappa index was >6 in 29.4% and > 3 in 50% of the definite AE patients. It was elevated (>3) in 36.4% of patients with definite AE who resulted negative to OCB testing and was the only altered parameter suggestive of an ongoing inflammatory process in the CNS in three definite AE patients with otherwise normal CSF findings (i.e. normal cell count and protein levels, no OCBs). In the possible AE group, one patient had a Kappa index >3 in the absence of OCB. ConclusionsThe Kappa index could be useful, as a more sensitive marker of IS and as a supportive marker of neuroinflammation, in the diagnostic work-up of suspected AE.

Clinical and radiological characteristics and outcomes of patients with recurrent or relapsing tumefactive demyelination

BackgroundRelapsing or recurrent tumefactive demyelination is rare and has not been studied beyond individual case reports. ObjectiveWe examined the clinical course, neuroimaging, cerebrospinal fluid (CSF), treatment and outcomes of patients with recurrent tumefactive demyelinating lesions (TDLs). MethodsWe used PubMed to identify reports of recurrent TDLs and included the details of an additional, unpublished patient. ResultsWe identified 18 cases (11F, 7 M). The median age at onset of the index TDL was 37 years (range 12–72) and most were solitary lesions 72 % (13/18). CSF-restricted oligoclonal bands (OCBs) were detected in 25 % (4/16). Only one of those tested (n = 13) was positive for AQP4-IgG. A moderate-to-marked treatment response (high dose corticosteroid with or without additional plasmapheresis, IVIg or disease modifying therapies) was evident in 89 % of treated patients. Median EDSS at the median follow-up of 36 months (range 6–144) was 2 (range 1–10). Most remained ambulatory (EDSS < 4 in 13/18), but 1 patient died. ConclusionThe median age of patients with relapsing TDLs is similar to that of typical MS, but differences include a lower female:male sex ratio, larger lesions, and a comparative lack of CSF-restricted OCBs. Outcomes vary among this group of patients ranging from minimal disability through to death.

Cerebrospinal fluid findings in patients with neurological manifestations in post-COVID-19 syndrome

BackgroundInformation on cerebrospinal fluid (CSF) findings in patients with neurological manifestations in post-COVID-19 syndrome is scarce.MethodsRetrospective evaluation of 84 CSF samples in patients fulfilling post-COVID-19 criteria in two neurological post-COVID-19 outpatient clinics.ResultsIn 68% of samples, all CSF parameters were normal. The most frequent pathological CSF finding was elevation of total protein (median total protein 33.3 mg/dl [total range 18.5–116.2]) in 20 of 83 (24%) samples. The second most prevalent pathological finding was a blood–CSF barrier dysfunction as measured by elevation of QAlb (median QAlb 4.65 [2.4–13.2]) in 11/84 (13%). Pleocytosis was found in only 5/84 (6%) samples and was mild in all of them. CSF-restricted oligoclonal bands were found in 5/83 (6%) samples. Anti-neuronal autoantibodies in CSF were negative in most cases, whilst 12/68 (18%) samples were positive for anti-myelin autoantibodies in serum. PCR for herpesviridae (HSV-1/-2, VZV, EBV, CMV, HHV6) showed, if at all, only weakly positive results in CSF or EDTA whole blood/plasma.ConclusionsThe majority of samples did not show any pathologies. The most frequent findings were elevation of total protein and blood–CSF barrier dysfunction with no signs of intrathecal inflammation. CSF analysis still keeps its value for exclusion of differential diagnoses.

Basic CSF parameters and MRZ reaction help in differentiating MOG antibody-associated autoimmune disease versus multiple sclerosis.

Myelin oligodendrocyte glycoprotein antibody-associated autoimmune disease (MOGAD) is a rare monophasic or relapsing inflammatory demyelinating disease of the central nervous system (CNS) and can mimic multiple sclerosis (MS). The variable availability of live cell-based MOG-antibody assays and difficulties in interpreting low-positive antibody titers can complicate diagnosis. Literature on cerebrospinal fluid (CSF) profiles in MOGAD versus MS, one of the most common differential diagnoses, is scarce. We here analyzed the value of basic CSF parameters to i) distinguish different clinical MOGAD manifestations and ii) differentiate MOGAD from MS. This is retrospective, single-center analysis of clinical and laboratory data of 30 adult MOGAD patients and 189 adult patients with relapsing-remitting multiple sclerosis. Basic CSF parameters included CSF white cell count (WCC) and differentiation, CSF/serum albumin ratio (QAlb), intrathecal production of immunoglobulins, CSF-restricted oligoclonal bands (OCB) and MRZ reaction, defined as intrathecal production of IgG reactive against at least 2 of the 3 viruses measles (M), rubella (R) and varicella zoster virus (Z). MOGAD patients with myelitis were more likely to have a pleocytosis, a QAlb elevation and a higher WCC than those with optic neuritis, and, after review and combined analysis of our and published cases, they also showed a higher frequency of intrathecal IgM synthesis. Compared to MS, MOGAD patients had significantly more frequently neutrophils in CSF and WCC>30/µl, QAlb>10×10-3, as well as higher mean QAlb values, but significantly less frequently CSF plasma cells and CSF-restricted OCB. A positive MRZ reaction was present in 35.4% of MS patients but absent in all MOGAD patients. Despite these associations, the only CSF parameters with relevant positive likelihood ratios (PLR) indicating MOGAD were QAlb>10×10-3 (PLR 12.60) and absence of CSF-restricted OCB (PLR 14.32), whereas the only relevant negative likelihood ratio (NLR) was absence of positive MRZ reaction (NLR 0.00). Basic CSF parameters vary considerably in different clinical phenotypes of MOGAD, but QAlb>10×10-3 and absence of CSF-restricted OCB are highly useful to differentiate MOGAD from MS. A positive MRZ reaction is confirmed as the strongest CSF rule-out parameter in MOGAD and could be useful to complement the recently proposed diagnostic criteria.

Acute optic neuritis: What are the clues to the aetiological diagnosis in real life?

Previous cross-sectional studies have reported distinct clinical and radiological features among the different acute optic neuritis (ON) aetiologies. Nevertheless, these reports often included the same number of patients in each group, not taking into account the disparity in frequencies of ON aetiologies in a real-life setting and thus, it remains unclear what are the truly useful features for distinguishing the different ON causes. To determine whether clinical evaluation, ophthalmological assessment including the optical coherence tomography (OCT), CSF analysis, and MRI imaging may help to discriminate the different causes of acute ON in a real-life cohort. In this prospective monocentric study, adult patients with recent acute ON (<1 month) underwent evaluation at baseline and 1 and 12 months, including, high- and low-contrast visual acuity, visual field assessment and OCT measurements, baseline CSF analysis and MRI. Among 108 patients, 71 (65.7%) had multiple sclerosis (MS), 19 (17.6%) had idiopathic ON, 13 (12.0%) and 5 (4.6%) had myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies, at last follow up respectively.At baseline, the distribution of bilateral ON, CSF-restricted oligoclonal bands, optic perineuritis, optic nerve length lesions and positive dissemination in space and dissemination in time criteria on MRI were significantly different between the four groups (p <0.001). No significant difference in visual acuity nor inner retinal layer thickness was found between the different ON aetiologies. In this large prospective study, bilateral visual involvement, CSF and MRI results are the most useful clues in distinguishing the different aetiologies of acute ON, whereas ophthalmological assessments including OCT measurements revealed no significant difference between the aetiologies.

Refractory anti-NMDA Receptor Encephalitis During Pregnancy: Treatment and Neonatal Outcome with Review of Literature (P5-5.001)

<h3>Objective:</h3> To report a case of refractory anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis with multiple relapses during pregnancy and peripartum with successful use of rituximab during pregnancy and resultant healthy neonatal outcome. <h3>Background:</h3> Anti-NMDAR encephalitis is a severe but treatable autoimmune encephalitis which often affects women of childbearing age. The clinical presentation in pregnancy is usually characterized by progressive neuropsychiatric manifestations, seizures and dysautonomia posing a danger to the fetus and a challenge to the treating neurologist. Refractory presentations often need escalation to second-line immunotherapies which have limited safety data in pregnancy. <h3>Design/Methods:</h3> Case report and literature review. <h3>Results:</h3> A 25-year-old primiparous Caucasian woman, 24 weeks pregnant presented with a 3-week history of worsening behavioral/personality changes, confusion, dysarthria, emotional lability and a single generalized tonic-clonic seizure. Brain MRI showed T2/FLAIR hyperintensity in the right frontal lobe suggestive of remote cortical infarct vs cortical dysplasia. CSF showed pleocytosis (WBC 19; 75% lymphocytes) with &gt;10 CSF-restricted oligoclonal bands. Due to high clinical suspicion for an immune-mediated process, she was started on IV methylprednisolone and IVIG. Subsequently, NMDAR antibody returned positive in serum (1:10) and CSF (1:128). Abdominal/pelvic ultrasound and MRI showed no ovarian teratoma. She clinically improved and was discharged, but subsequently relapsed 10 days later at 27 weeks needing treatment with plasma exchange and rituximab, and her symptoms improved. She delivered a healthy baby at 37 weeks but had another relapse immediately post-partum necessitating further immunotherapy. Since then, she has remained stable on maintenance rituximab with no further relapses. At one-year follow up, the baby remains healthy. <h3>Conclusions:</h3> This case illustrates the successful use of rituximab during pregnancy for anti-NMDAR encephalitis. Our literature review showed only a handful of such patients treated with rituximab and one patient with cyclophosphamide. Further studies are needed to assess the safety and long-term outcomes of using rituximab for anti-NMDAR encephalitis during pregnancy. <b>Disclosure:</b> The institution of Mr. Lew has received research support from NIH. Dr. Shirani has nothing to disclose. Dr. Arcot Jayagopal has nothing to disclose.

The radiologically isolated syndrome: revised diagnostic criteria.

The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within individuals lacking symptoms typical of multiple sclerosis (MS). 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, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two 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. Seven hundred and forty-seven 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 one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 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 MS. At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 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 5 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 Groups 1 and 2 with at least two 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.

Cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis: A consensus statement

Cerebrospinal fluid (CSF) analysis is of utmost importance for diagnosis and differential diagnosis of patients with suspected multiple sclerosis (MS). Evidence of intrathecal immunoglobulin G (IgG) synthesis proves the inflammatory nature of the disease, increases diagnostic certainty and substitutes for dissemination in time according to current diagnostic criteria. The gold standard to determine intrathecal IgG synthesis is the detection of CSF-restricted oligoclonal bands (OCBs). However, advances in laboratory methods brought up κ-free light chains (FLCs) as a new biomarker, which are produced in excess over intact immunoglobulins and accumulate in CSF in the case of central nervous system-derived inflammation. Overwhelming evidence showed a high diagnostic accuracy of intrathecal κ-FLC synthesis in MS with sensitivity and specificity of approximately 90% similar to OCB. κ-FLCs have advantages as its detection is fast, easy, cost-effective, reliable, rater-independent and returning quantitative results which might also improve the value of predicting MS disease activity. An international panel of experts in MS and CSF diagnostics developed a consensus of all participants. Six recommendations are given for establishing standard CSF evaluation in patients suspected of having MS. The panel recommended to include intrathecal κ-FLC synthesis in the next revision of MS diagnostic criteria as an additional tool to measure intrathecal immunoglobulin synthesis.

Re-examining the characteristics of pediatric multiple sclerosis in the era of antibody-associated demyelinating syndromes.

The discovery of anti-myelin oligodendrocyte glycoprotein (MOG)-IgG and anti-aquaporin 4 (AQP4)-IgG and the observation on certain patients previously diagnosed with multiple sclerosis (MS) actually have an antibody-mediated disease mandated re-evaluation of pediatric MS series. To describe the characteristics of recent pediatric MS cases by age groups and compare with the cohort established before 2015. Data of pediatric MS patients diagnosed between 2015 and 2021 were collected from 44 pediatric neurology centers across Türkiye. Clinical and paraclinical features were compared between patients with disease onset before 12 years (earlier onset) and ≥12 years (later onset) as well as between our current (2015-2021) and previous (<2015) cohorts. A total of 634 children (456 girls) were enrolled, 89 (14%) were of earlier onset. The earlier-onset group had lower female/male ratio, more frequent initial diagnosis of acute disseminated encephalomyelitis (ADEM), more frequent brainstem symptoms, longer interval between the first two attacks, less frequent spinal cord involvement on magnetic resonance imaging (MRI), and lower prevalence of cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCBs). The earlier-onset group was less likely to respond to initial disease-modifying treatments. Compared to our previous cohort, the current series had fewer patients with onset <12 years, initial presentation with ADEM-like features, brainstem or cerebellar symptoms, seizures, and spinal lesions on MRI. The female/male ratio, the frequency of sensorial symptoms, and CSF-restricted OCBs were higher than reported in our previous cohort. Pediatric MS starting before 12 years was less common than reported previously, likely due to exclusion of patients with antibody-mediated diseases. The results underline the importance of antibody testing and indicate pediatric MS may be a more homogeneous disorder and more similar to adult-onset MS than previously thought.

Genomic analysis, immunomodulation and deep phenotyping of patients with nodding syndrome.

The aetiology of nodding syndrome remains unclear, and comprehensive genotyping and phenotyping data from patients remain sparse. Our objectives were to characterize the phenotype of patients with nodding syndrome, investigate potential contributors to disease aetiology, and evaluate response to immunotherapy. This cohort study investigated members of a single-family unit from Lamwo District, Uganda. The participants for this study were selected by the Ugandan Ministry of Health as representative for nodding syndrome and with a conducive family structure for genomic analyses. Of the eight family members who participated in the study at the National Institutes of Health (NIH) Clinical Center, three had nodding syndrome. The three affected patients were extensively evaluated with metagenomic sequencing for infectious pathogens, exome sequencing, spinal fluid immune analyses, neurometabolic and toxicology testing, continuous electroencephalography and neuroimaging. Five unaffected family members underwent a subset of testing for comparison. A distinctive interictal pattern of sleep-activated bursts of generalized and multifocal epileptiform discharges and slowing was observed in two patients. Brain imaging showed two patients had mild generalized cerebral atrophy, and both patients and unaffected family members had excessive metal deposition in the basal ganglia. Trace metal biochemical evaluation was normal. CSF was non-inflammatory and one patient had CSF-restricted oligoclonal bands. Onchocerca volvulus-specific antibodies were present in all patients and skin snips were negative for active onchocerciasis. Metagenomic sequencing of serum and CSF revealed hepatitis B virus in the serum of one patient. Vitamin B6 metabolites were borderline low in all family members and CSF pyridoxine metabolites were normal. Mitochondrial DNA testing was normal. Exome sequencing did not identify potentially causal candidate gene variants. Nodding syndrome is characterized by a distinctive pattern of sleep-activated epileptiform activity. The associated growth stunting may be due to hypothalamic dysfunction. Extensive testing years after disease onset did not clarify a causal aetiology. A trial of immunomodulation (plasmapheresis in two patients and intravenous immunoglobulin in one patient) was given without short-term effect, but longer-term follow-up was not possible to fully assess any benefit of this intervention.

Leptomeningeal Gadolinium Enhancement in Autoimmune GFAP Astrocytopathy.

A 46-year-old woman presented with urinary retention, headache, tremor, ataxia, mental slowness, and tetra-hyperreflexia following urinary infection. MRI showed signs of encephalomyelitis with diffuse postcontrast 3D fluid-attenuated inversion recovery leptomeningeal enhancement, a common finding in several neuroinflammatory conditions1 (Figures 1 and 2). An extensive diagnostic workup (serum and CSF neurotropic viruses, Borrelia burgdorferi , Treponema pallidum , serum anti–myelin oligodendrocyte glycoprotein and anti–aquaporin-4 antibodies, antinuclear antibodies, extractable nuclear antigen , antineutrophil cytoplasmic antibodies, angiotensin-converting enzyme and α-chitotriosidase levels, quantiferon, total body CT scan) was unrevealing. CSF analysis disclosed lymphocytic pleocytosis (204 leukocytes/μL), high protein levels (123 mg/dL), CSF-restricted oligoclonal bands, and anti–glial fibrillary acidic protein (GFAP) antibodies (cell-based assay), leading to the diagnosis of autoimmune GFAP astrocytopathy.2 After receiving IV methylprednisolone, the patient improved substantially.

Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients

BackgroundComprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far.ObjectiveTo analyze systematically the CSF profile in COVID-19.MethodsRetrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centersResultsThe most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72–50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3–240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF l-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2–4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease.ConclusionsThe CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and ‘long COVID’. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19.

Natalizumab Induces Changes of Cerebrospinal Fluid Measures in Multiple Sclerosis.

Background: There is a lack of knowledge about the evolution of cerebrospinal fluid (CSF) markers in multiple sclerosis (MS) patients undergoing natalizumab treatment. Aim: We aimed to evaluate the effect of natalizumab on basic inflammatory CSF and MRI measures. Methods: Together, 411 patients were screened for eligibility and 93 subjects with ≥2 CSF examinations ≤6 months before and ≥12 months after natalizumab initiation were recruited. The effect of natalizumab on CSF as well as clinical and paraclinical measures was analyzed using adjusted mixed models. Results: Natalizumab induced a decrease in CSF leukocytes (p < 1 × 10−15), CSF protein (p = 0.00007), the albumin quotient (p = 0.007), the IgG quotient (p = 6 × 10−15), the IgM quotient (p = 0.0002), the IgG index (p = 0.0004), the IgM index (p = 0.003) and the number of CSF-restricted oligoclonal bands (OCBs) (p = 0.0005). CSF-restricted OCBs positivity dropped from 94.6% to 86% but 26 patients (28%) had an increased number of OCBs at the follow-up. The baseline to follow-up EDSS and T2-LV were stable; a decrease in the relapse rate was consistent with a decrease in the CSF inflammatory markers and previous knowledge about the effectiveness of natalizumab. The average annualized brain volume loss during the follow-up was −0.50% (IQR = −0.96, −0.16) and was predicted by the baseline IgM index (B = −0.37; p = 0.003). Conclusions: Natalizumab is associated with a reduction of basic CSF inflammatory measures supporting its strong anti-inflammatory properties. The IgM index at the baseline predicted future brain volume loss during the course of natalizumab treatment.

"Antibody of Unknown Significance" (AUS): The Issue of Interpreting Antibody Test Results.

"Antibody of Unknown Significance" (AUS): The Issue of Interpreting Antibody Test Results.

Early factors associated with later conversion to multiple sclerosis in patients presenting with isolated myelitis

ObjectiveTo 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...

Clinical and laboratory features distinguishing MOG antibody disease from multiple sclerosis and AQP4 antibody-positive neuromyelitis optica

BackgroundAntibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with a CNS inflammatory disorder distinct from multiple sclerosis (MS) and aquaporin-4 antibody-positive neuromyelitis optica (NMO). Knowledge of the clinical spectrum of MOG antibody disease (MOGAD) remains incomplete, particularly in comparison to two related inflammatory demyelinating diseases, MS and NMO. ObjectiveCompare demographics, clinical characteristics, estimated disability, laboratory results, and treatment responses of a U.S. MOGAD cohort with age- and sex-matched MS and NMO patients. Design, setting, and participantsThis observational, case-control, single-center study identified each group via ICD-10 diagnosis code searches through the electronic medical records of adult patients seen at the John L. Trotter MS Center between January 1, 2019 and January 1, 2020. MOGAD and NMO patients were confirmed to have at least one positive antibody test; those in the MS group had a confirmed diagnosis by a physician with MS subspecialty training. Data were collected after IRB approval. ResultsTwenty-six patients were included in each group. MOGAD patients were predominantly Caucasian (88.5%) with mean onset age of 43.9 years. MOGAD patients had no comorbid other autoimmune diseases and comparatively lower rates of family members with autoimmune disease (20.0%) than either MS (40.0%) or NMO (34.6%) matched cohorts. 91% of MOGAD attacks were monofocal, and over 70% presented with optic neuritis. Severity of MOGAD attacks was similar to that of seropositive NMO, but the robust degree of recovery was more similar to MS. Four MOGAD patients converted to negative antibody status, with no attacks occurring after conversion. Serum ANA and ENA were less frequently elevated in MOGAD (21.7%, 5.0%) than in seropositive NMO patients (66.7%, 42.9%). Elevated IgG synthesis rate and positive CSF-restricted oligoclonal bands were not seen in our MOGAD cohort, and only one MOGAD patient had an elevated IgG index. Despite anti-CD20 therapy, 28.6% of MOGAD patients continued to suffer relapses. ConclusionsMOGAD was characterized by a predominantly monofocal presentation (typically optic neuritis) and severe attacks with better recovery than seen with seropositive NMO attacks. Lack of CSF-restricted oligoclonal bands distinguished MOGAD from MS.

Diagnostic features of initial demyelinating events associated with serum MOG-IgG

BackgroundMyelin oligodendrocyte glycoprotein (MOG)-IgG associated disorders are increasingly recognized as a distinct disease entity. However, diagnostic sensitivity and specificity of serum MOG-IgG as well as recommendations for testing are still debated. Materials and methodsBetween October 2015 and July 2017 we tested serum MOG-IgG in 91 adult patients (49 females) with a demyelinating event (DE) not fulfilling 2010 McDonald criteria for MS at sampling, negative for neuromyelitis optica (NMO)-IgG and followed-up for at least 12 months. We assessed the sensitivity and specificity of a live-cell MOG-IgG assay for each final diagnosis at last follow-up, for the 2018 international recommendations for MOG-IgG testing, and for other combinations of clinical and laboratory characteristics. ResultsClinical presentations included acute myelitis (n = 48), optic neuritis (n = 36), multifocal encephalomyelitis (n = 4), and brainstem syndrome (n = 3). Twenty-four patients were MOG-IgG positive. Sensitivity and specificity of MOG-IgG test applied to the 2018 international recommendations were 28.4% and 86.7%, while they were 42.1% and 88.6% when applied to DE of unclear aetiology as defined above with two or more among: 1_no periventricular and juxtacortical MS-like lesions on brain MRI; 2_longitudinally extensive MRI optic nerve lesion; 3_no CSF-restricted oligoclonal bands; 4_CSF protein > 50 mg/dl. ConclusionsSimplified requirements compared to those currently proposed for MOG-IgG testing could facilitate the applicability of the assay in the diagnosis of adults with DEs of unclear aetiology.

Clinical and MRI phenotypes of sarcoidosis-associated myelopathy.

ObjectiveTo determine the characteristic clinical and spinal MRI phenotypes of sarcoidosis-associated myelopathy (SAM), we analyzed a large cohort of patients with this disorder.MethodsPatients diagnosed with SAM at a single center between 2000 and 2018 who met the established criteria for definite and probable neurosarcoidosis were included in a retrospective analysis to identify clinical profiles, CSF characteristics, and MRI lesion morphology.ResultsOf 62 included patients, 33 (53%) were male, and 30 (48%) were African American. SAM was the first clinical presentation of sarcoidosis in 49 patients (79%). Temporal profile of symptom evolution was chronic in 81%, with sensory symptoms most frequently reported (87%). CSF studies showed pleocytosis in 79% and CSF-restricted oligoclonal bands in 23% of samples tested. Four discrete patterns of lesion morphology were identified on spine MRI: longitudinally extensive myelitis (n = 28, 45%), short tumefactive myelitis (n = 14, 23%), spinal meningitis/meningoradiculitis (n = 14, 23%), and anterior myelitis associated with areas of disc degeneration (n = 6, 10%). Postgadolinium enhancement was seen in all but 1 patient during the acute phase. The most frequent enhancement pattern was dorsal subpial enhancement (n = 40), followed by meningeal/radicular enhancement (n = 23) and ventral subpial enhancement (n = 12). In 26 cases (42%), enhancement occurred at locations with coexisting structural changes (e.g., spondylosis).ConclusionsRecognition of the clinical features (chronically evolving myelopathy) and distinct MRI phenotypes (with enhancement in a subpial and/or meningeal pattern) seen in SAM can aid diagnosis of this disorder. Enhancement patterns suggest that SAM may have a predilection for areas of the spinal cord susceptible to mechanical stress.

Bal\xf3\u2019s concentric sclerosis is immunologically distinct from multiple sclerosis: results from retrospective analysis of almost 150 lumbar punctures

BackgroundBaló’s concentric sclerosis (BCS) is a rare inflammatory demyelinating disorder of the central nervous system characterised by concentric layers of demyelination. It is unclear whether BCS is a variant of multiple sclerosis (MS) or a disease entity in its own right.ObjectiveTo compare the cerebrospinal fluid (CSF) features of BCS to those of MS.MethodsRetrospective analysis of the CSF profile of all patients with BCS reported in the medical literature between 1980 and 2017.ResultsIn total, the results of 146 lumbar punctures (LP) in 132 patients were analysed. The most striking finding was a lack of CSF-restricted oligoclonal bands (OCB) in 66% (56/85) of all LP in the total BCS group, in 74% (14/19) in the subgroup of patients with both MRI and histological evidence for BCS, and in 82% (18/22) in the subgroup of patients with highest radiological confidence (high MRI quality, ≥ 3 layers of demyelination). OCB disappeared in 1/2 initially OCB-positive patients. These findings are in stark contrast to MS, in which OCB are present in ≥ 95% of patients and are thought to remain stably detectable over the entire course of disease (p < 0.000001). OCB frequency was low both in ‘historic’ patients (1980–2009; 37%) and in more recent patients (2010–2017; 31%). OCB-positive and OCB-negative patients did not differ significantly with regard to age, sex, disease duration, number of Baló-like lesions on MRI, number of relapses, treatment or final outcome. In accordance with the high rate of OCB negativity, Link’s IgG index was negative in 63% of all tested samples (p < 0.000001 vs. MS). CSF pleocytosis was present in 28% (27/96; p < 0.000001 vs. MS) and elevated CSF total protein levels in 41% (31/76) of samples.ConclusionOCB and IgG index frequencies in BCS are much more similar to those reported in neuromyelitis optica or myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis than to those in MS. Our findings suggest that in most cases BCS-like lesions denote the presence of a disease entity immunologically distinct from MS. In addition, we provide data on the demographics, clinical course and radiological features of BCS based on the largest cohort analysed to date.

Cerebrospinal fluid parameters of B cell-related activity in patients with active disease during natalizumab therapy

Recently, the disappearance of oligoclonal bands (OCBs) from the cerebrospinal fluid (CSF) of a few natalizumab-treated patients with multiple sclerosis (MS) has been reported. This is interesting since CSF-restricted OCB are believed to persist in MS. We pooled CSF data from 14 MS centers to obtain an adequate sample size for investigating the suspected changes in central nervous system (CNS)-restricted humoral immune activities in the context of natalizumab therapy. In a retrospective chart analysis, CSF parameters of blood–CSF barrier integrity and intrathecal IgG production from 73 natalizumab-treated MS patients requiring a diagnostic puncture for exclusion of progressive multifocal leukoencephalopathy were compared with CSF data obtained earlier in the course of disease before natalizumab therapy. At the time of repeat lumbar puncture, local IgG production (according to Reibergram) was significantly reduced (p < 0.0001) and OCB had disappeared in 16% of the patients. We therefore conclude that natalizumab therapy interferes with intrathecal antibody production at least in a significant number of patients.