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BackgroundWe sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid exposure.MethodsIn a retrospective multicentre cohort study, Cox proportional hazards models examined the relationship between corticosteroid course as a time-varying covariate and time to first relapse. Simon-Makuch and Kaplan-Meier plots identified an optimal dosing strategy.ResultsWe evaluated 109 patients (62 female, 57%; 41 paediatric, 38%; median age at onset 26 years, (IQR 8–38); median follow-up 6.2 years (IQR 2.6–9.6)). 76/109 (70%) experienced a relapse (median time to first relapse 13.7 months; 95% CI 8.2 to 37.9). In a multivariable model, higher doses of oral prednisone delayed time to first relapse with an effect estimate of 3.7% (95% CI 0.8% to 6.6%; p=0.014) reduced hazard of relapse for every 1 mg/day dose increment. There was evidence of reduced hazard of relapse for patients dosed ≥12.5 mg/day (HR 0.21, 95% CI 0.07 to 0.6; p=0.0036), corresponding to a 79% reduction in relapse risk. There was evidence of reduced hazard of relapse for those dosed ≥12.5 mg/day for at least 3 months (HR 0.12, 95% CI 0.03 to 0.44; p=0.0012), corresponding to an 88% reduction in relapse risk compared with those never treated in this range. No patient with this recommended dosing at onset experienced a Common Terminology Criteria for Adverse Events grade >3 adverse effect.ConclusionsThe optimal dose of 12.5 mg of prednisone daily in adults (0.16 mg/kg/day for children) for a minimum of 3 months at the onset of MOGAD delays time to first relapse.

BackgroundMyelin oligodendrocyte glycoprotein (MOG) IgG seropositivity is a prerequisite for MOG antibody-associated disease (MOGAD) diagnosis. While a significant proportion of patients experience a relapsing disease, there is currently no biomarker predictive of disease course. We aim to determine whether MOG-IgG epitopes can predict a relapsing course in MOGAD patients.MethodsMOG-IgG-seropositive confirmed adult MOGAD patients were included (n=202). Serum MOG-IgG and epitope binding were determined by validated flow cytometry live cell-based assays. Associations between epitopes, disease course, clinical phenotype, Expanded Disability Status Scale and Visual Functional System Score at onset and last review were evaluated.ResultsOf 202 MOGAD patients, 150 (74%) patients had MOG-IgG that recognised the immunodominant proline42 (P42) epitope and 115 (57%) recognised histidine103/serine104 (H103/S104). Fifty-two (26%) patients had non-P42 MOG-IgG and showed an increased risk of a relapsing course (HR 1.7; 95% CI 1.15 to 2.60, p=0.009). Relapse-freedom was shorter in patients with non-P42 MOG-IgG (p=0.0079). Non-P42 MOG-IgG epitope status remained unchanged from onset throughout the disease course and was a strong predictor of a relapsing course in patients with unilateral optic neuritis (HR 2.7, 95% CI 1.06 to 6.98, p=0.038), with high specificity (95%, 95% CI 77% to 100%) and positive predictive value (85%, 95% CI 45% to 98%).ConclusionsNon-P42 MOG-IgG predicts a relapsing course in a significant subgroup of MOGAD patients. Patients with unilateral optic neuritis, the most frequent MOGAD phenotype, can reliably be tested at onset, regardless of age and sex. Early detection and specialised management in these patients could minimise disability and improve long-term outcomes.

ObjectiveTo investigate potential neuroprotective and pro-remyelinating effects of alemtuzumab in multiple sclerosis (MS), using the visual pathway as a model.MethodsWe monitored clinical, multifocal visual evoked potential (mfVEP) and MRI outcomes in 30 patients commencing alemtuzumab for relapsing MS, and a reference group of 20 healthy controls (HCs), over 24 months. Change in mfVEP latency was the primary endpoint; change in optic radiation (OR) lesion diffusion metrics and Mars letter contrast sensitivity over the course of the study were secondary endpoints.ResultsIn patients, we observed a mean shortening of mfVEP latency of 1.21 ms over the course of the study (95% CI 0.21 to 2.21, p=0.013), not altered by correction for age, gender, disease duration or change in OR T2 lesion volume. Mean mfVEP latency in the HC group increased over the course of the study by 0.72 ms (not significant). Analysis of chronic OR T2 lesions (patients) showed an increase in normalised fractional anisotropy and axial diffusivity between baseline and 24 months (both p<0.01). Mean Mars letter contrast sensitivity was improved at 24 months vs baseline (p<0.001), and driven by an early improvement, in both patients and HC.ConclusionWe found evidence of partial lesion remyelination after alemtuzumab therapy, indicating either natural restoration in the context of a ‘permissive’ local milieu; or potentially an independent, pro-reparative mechanism of action. The visual system presents a unique opportunity to study function-structure specific effects of therapy and inform the design of future phase 2 MS remyelination trials.

The coronavirus disease 2019 (COVID-19) pandemic is concerning for patients with neuroimmunological diseases who are receiving immunotherapy. Uncertainty remains about whether immunotherapies increase the risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or increase the risk of severe disease and death upon infection. National and international societies have developed guidelines and statements, but consensus does not exist in several areas. In this Review, we attempt to clarify where consensus exists and where uncertainty remains to inform management approaches based on the first principles of neuroimmunology. We identified key questions that have been addressed in the literature and collated the recommendations to generate a consensus calculation in a Delphi-like approach to summarize the information. We summarize the international recommendations, discuss them in light of the first available data from patients with COVID-19 receiving immunotherapy and provide an overview of management approaches in the COVID-19 era. We stress the principles of medicine in general and neuroimmunology in particular because, although the risk of viral infection has become more relevant, most of the considerations apply to the general management of neurological immunotherapy. We also give special consideration to immunosuppressive treatment and cell-depleting therapies that might increase susceptibility to SARS-CoV-2 infection but reduce the risk of severe COVID-19.

•The median age of patients with relapsing TDLs is similar to that of typical MS.•Differences from MS include a lower female: male ratio and relative lack of OCBs.•More than half of those with relapsing TDL underwent a brain biopsy.•Screening for systemic malignancy in those with relapsing TDLs is recommended.•Outcomes in those with relapsing TDLs vary from minimal disability to death.

•Tumefactive demyelination (TD) can occur in patients with multiple sclerosis (MS).•TD lesions are often a diagnostic challenge as they can mimic neoplasm or infection.•More investigations are required than in typical MS, including brain biopsy in 20%.•The cost of investigating TD lesions is more than 7.5 times that of MS.•There were more adverse effects in TD due to the more extensive diagnostic process.

A 34-year-old woman presented with a 3-month history of right-sided headaches associated with photophobia and pulsatile tinnitus. Investigations including lumbar puncture revealed elevated opening CSF pressure, increased protein, and presence of monocytosis consistent with an inflammatory/infective process. Brain MRI showed an area of thickened enhancing dura around the venous sinus posteriorly. 67Ga scintigraphy demonstrated focal intracranial uptake in the posterior occipital region, and biopsy confirmed a chronic inflammatory infiltrate with no granulomas.

The triad of central nervous system symptoms, visual disturbance and hearing impairment is an oft-encountered clinical scenario. A number of immune-mediated diseases should be considered among the differential diagnoses including: Susac syndrome, Cogan syndrome or Vogt-Koyanagi-Harada disease; demyelinating conditions such as multiple sclerosis or neuromyelitis optica spectrum disorder; systemic diseases such as systemic lupus erythematosus, Sjo¨gren syndrome or Behcet disease and granulomatous diseases such as sarcoidosis. In this article, we coin the term ‘BEE syndromes’ to draw attention to the various immune-mediated diseases that affect the brain, eye and ear. We present common disease manifestations and identify key clinical and investigation features.

ObjectiveWe characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination.MethodsWe evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients.ResultsThe most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10 mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of ≥2 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077).ConclusionRelapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation.

Background:The L25 mouse line was generated by random genomic insertion of a lens-specific transgene. Inbreeding of L25 hemizygotes revealed an unanticipated spastic phenotype in the hind limbs. Objective:The goals were to characterize the motor phenotype in the L25 mice and to map the transgene insert site within the mouse genome. Methods:Six pairs of L25+/–mice were repeatedly mated. Beginning at weaning, all progeny were inspected for body weight and motor signs twice weekly until they displayed predefined ethical criteria for termination. The transgene insert site was determined by whole genome sequencing. Western blotting was used to compare the expression levels of beta-IV spectrin protein in the brain. Results:Matings of hemizygous L25+/–× L25+/–mice yielded 20% (29/148) affected weanlings, identified by an abnormal retraction of the hind limbs when lifted by the tail, and a fine tremor. Affected mice were less mobile and grew more slowly than wild-type littermates. All affected mice required termination due to >15% loss of body weight (50% survival age 92 days). At the endpoint, mice showed varying degrees of spastic paresis or spastic paralysis localised to the hind limbs. Motor endplates remained fully innervated. Genome sequencing confirmed that the transgene was inserted in the locus of βIV spectrin of L25 mice. Western blotting indicated that this random insertion had greatly reduced the expression of βIV spectrin protein in the affected L25 mice. Conclusions:The results confirm the importance of βIV spectrin for maintaining central motor pathway control of the hind limbs, and provide a developmental time course for the phenotype.

ObjectivesWe have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry.BackgroundNMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established.MethodsCentres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture–recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases.ResultsNMOSD was confirmed in 81/170 (48%) cases referred. Capture–recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD.ConclusionsNMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.

IMPORTANCE: To our knowledge, the efficacy of transferring next-generation sequencing from a research setting to neuromuscular clinics has never been evaluated. OBJECTIVE: To translate whole-exome sequencing (WES) to clinical practice for the genetic diagnosis of a large cohort of patients with limb-girdle muscular dystrophy (LGMD) for whom protein-based analyses and targeted Sanger sequencing failed to identify the genetic cause of their disorder. DESIGN, SETTING, AND PARTICIPANTS: We performed WES on 60 families with LGMDs (100 exomes). Data analysis was performed between January 6 and December 19, 2014, using the xBrowse bioinformatics interface (Broad Institute). Patients with LGMD were ascertained retrospectively through the Institute for Neuroscience and Muscle Research Biospecimen Bank between 2006 and 2014. Enrolled patients had been extensively investigated via protein studies and candidate gene sequencing and remained undiagnosed. Patients presented with more than 2 years of muscle weakness and with dystrophic or myopathic changes present in muscle biopsy specimens. MAIN OUTCOMES AND MEASURES: The diagnostic rate of LGMD in Australia and the relative frequencies of the different LGMD subtypes. Our central goals were to improve the genetic diagnosis of LGMD, investigate whether the WES platform provides adequate coverage of known LGMD-related genes, and identify new LGMD-related genes. RESULTS: With WES, we identified likely pathogenic mutations in known myopathy genes for 27 of 60 families. Twelve families had mutations in known LGMD-related genes. However, 15 families had variants in disease-related genes not typically associated with LGMD, highlighting the clinical overlap between LGMD and other myopathies. Common causes of phenotypic overlap were due to mutations in congenital muscular dystrophy–related genes (4 families) and collagen myopathy–related genes (4 families). Less common myopathies included metabolic myopathy (2 families), congenital myasthenic syndrome (DOK7), congenital myopathy (ACTA1), tubular aggregate myopathy (STIM1), myofibrillar myopathy (FLNC), and mutation of CHD7, usually associated with the CHARGE syndrome. Inclusion of family members increased the diagnostic efficacy of WES, with a diagnostic rate of 60% for “trios” (an affected proband with both parents) vs 40% for single probands. A follow-up screening of patients whose conditions were undiagnosed on a targeted neuromuscular disease–related gene panel did not improve our diagnostic yield. CONCLUSIONS AND RELEVANCE: With WES, we achieved a diagnostic success rate of 45.0% in our difficult-to-diagnose cohort of patients with LGMD. We expand the clinical phenotypes associated with known myopathy genes, and we stress the importance of accurate clinical examination and histopathological results for interpretation of WES, with many diagnoses requiring follow-up review and ancillary investigations of biopsy specimens or serum samples.

We describe a patient with hyperekplexia as the initial presenting symptom in sporadic Creutzfeldt-Jakob disease (CJD). We also demonstrate the utility of the sensitive and highly specific new prion protein amplification assay, real-time quaking-induced conversion (RT-QUIC), which amplifies and detects misfolded β-sheet–rich conformers of the prion protein (PrPsc), in expediting a confident clinical diagnosis of CJD in an atypical case.

Alemtuzumab, a humanized anti-CD52 monoclonal antibody that results in profound depletion and repopulation of mature lymphocytes, is a highly efficacious therapy for active, relapsing-remitting multiple sclerosis (RRMS). In 2 phase 3 clinical trials of alemtuzumab, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I and II, 14% and 23% of patients treated with alemtuzumab had a clinical relapse within the first 12 months, respectively.1,2

Antibodies to muscle-specific tyrosine kinase (MuSK) characterize up to 5 of myasthenia gravis patients. This review focuses on the differences to clinical antiacetylcholine receptor-myasthenia gravis, and on the physiology and animal studies that elucidate the role of MuSK and help explain the clinical disease.

New immunomodulating approaches to neuroinflammatory diseases present new challenges in clinical risk management. We review recent data on immunosuppression in diverse settings to guide the assessment and prevention of adverse effects from these therapies with the aim of improving the benefit to risk equation.

A population of metachromatic cells with mast cell (MC) and basophil features was identified recently in the peripheral blood of patients with several allergic disorders. This study now shows that these metachromatic cells express on their surface the high-affinity IgE receptor (FcεRI), CD4, and the chemokine receptors CCR3, CCR5, and CXCR4, but not the T-cell surface protein CD3 and the monocyte/macrophage surface protein CD68. This population of MCs/basophils can be maintained ex vivo for at least 2 weeks, and a comparable population of cells can be generated in vitro from nongranulated hematopoietic CD3−/CD4+/CD117− progenitors. Both populations of MCs/basophils are susceptible to an M-tropic strain of human immunodeficiency virus 1 (HIV-1). Finally, many patients with acquired immunodeficiency syndrome have HIV-1–infected MCs/basophils in their peripheral blood. Although it is well known that HIV-1 can infect CD4+ T cells and monocytes, this finding is the first example of a human MC or basophil shown to be susceptible to the retrovirus.

A population of metachromatic cells with mast cell (MC) and basophil features was identified recently in the peripheral blood of patients with several allergic disorders. This study now shows that these metachromatic cells express on their surface the high-affinity IgE receptor (FcεRI), CD4, and the chemokine receptors CCR3, CCR5, and CXCR4, but not the T-cell surface protein CD3 and the monocyte/macrophage surface protein CD68. This population of MCs/basophils can be maintained ex vivo for at least 2 weeks, and a comparable population of cells can be generated in vitro from nongranulated hematopoietic CD3−/CD4+/CD117−progenitors. Both populations of MCs/basophils are susceptible to an M-tropic strain of human immunodeficiency virus 1 (HIV-1). Finally, many patients with acquired immunodeficiency syndrome have HIV-1–infected MCs/basophils in their peripheral blood. Although it is well known that HIV-1 can infect CD4+T cells and monocytes, this finding is the first example of a human MC or basophil shown to be susceptible to the retrovirus.

This paper examines the methodology of anti-β2-glycoprotein I (β2-GPI) epitope determination and provides further epitope studies using human sera containing anti-β2-GPI autoantibodies. Studies in this field may be misleading as the antigen coating density using mutant forms of β2-GPI may be below the threshold required for monogamous divalent binding by low affinity anti-β2-GPI autoantibodies, while being easily detected by high affinity anti-β2-GPI from immunized animals. The antigen density threshold effect is found in anti-β2-GPI autoantibodies from humans and from monoclonal anti-β2-GPI derived from mice with models of autoimmune disease. Anti-β2-GPI from an autoimmune mouse and from 18/21 human sera did not bind above background levels to a domain-I-deleted mutant. In addition, single point mutations in domain I result in dramatic changes in the binding of many human sera containing anti-β2-GPI. These findings support a conclusion that domain I of β2-GPI contains significant epitopes for the anti-β2-GPI antibodies found in the antiphospholipid syndrome.

IntroductionNecrotizing autoimmune myositis (NAM) is an increasingly recognised myositis.1While diagnosis is primarily from muscle pathology, antibodies to signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR) are also associated.CaseA 67 year old woman presented with proximal weakness and elevated creatine kinase (CK) levels following a complicated AMI, CABG and commencement of atorvastatin. Muscle biopsy confirmed necrotizing myositis and SRP (not HMGCoAR) antibodies were positive. Recovery and rehabilitation was slow and her CK did not normalise for 12 months. She was treated with immunotherapy including intravenous immunoglobulin, oral and intravenous corticosteroids, azathioprine, and mycophenolate.Residual hip, abdominal and truncal weakness remained, affecting her gait and posture. CK levels during this period remained normal. MRI demonstrated extensive paravertebral muscle loss with fatty replacement without oedema. Small myopathic units without active features were present on EMG.ConclusionThis case illustrates several important aspects of NAM, which remains a rare disorder. Recovery can be incomplete in up to 40%, especially if control is delayed.2In our opinion, normalisation of CK is an important target and may be necessary for full recovery, and rising CK may predict relapse.3We suggest MRI and EMG of weak muscles may assist in distinguishing persisting myositis from ‘burnt-out’ disease, clarifying whether immunotherapy should be increased or not. However relapse on weaning immunosuppression remains frequent. While SRP antibodies in patients who had also taken statins has been previously reported, the quick sequential onset in this case suggests possible causality.ReferencesMammen AL. Autoimmune Myopathies. Contin Lifelong Learn Neurol. 2016;22(6):1852–1870.Watanabe Y, Uruha A, Suzuki S, et al. Clinical features and prognosis in anti-SRP and anti-HMGCR necrotising myopathy. J Neurol Neurosurg Psychiatry2016;87(10):1038–1044.Ramanathan S, Langguth D, Hardy TA, et al. Clinical course and treatment of anti-HMGCR antibody–associated necrotizing autoimmune myopathy. Neurol Neuroimmunol Neuroinflammation2015;2:e96.

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We present serial neuropsychological, magnetic resonance (MR) imaging and EEG changes in a case of widespread CNS myelinopathy due to intravenous heroin overdose complicated by a period of prolonged unconsciousness. Following recovery from the acute ove rdose, the subject had the delayed onset of akinetic mutism with urinary incontinence. Sequential formal neuro-psychological assessments over 9 months showed evolution from severe global cerebral dysfunction to moderate disturbance of frontal lobe functi on. Almost complete resolution of diffuse white matter signal changes, accompanied by the development of a degree of volume loss, was evident on serial MR imaging overthe same period, and generalized arrhythmic delta-range slowingon the EEG evolved int o a near normal pattern.