Disease-modifying treatments for neuromyelitis optica spectrum disorder in the context of a new generation of biotherapies.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare but debilitating autoimmune disease of the central nervous system (CNS) for which several biotherapies have recently been approved on the market. Historically, NMOSD disease-modifying treatments relied on wide-spectrum off-label immunosuppressants, such as azathioprine, mycophenolate mofetil, and cyclophosphamide. Since 2015, evidence has accumulated to support off-label biotherapies (rituximab and tocilizumab) and to approve satralizumab, inebilizumab, eculizumab, and ravulizumab. This next generation of drugs provides several targeted disease-modifying treatment options for NMOSD. Here, we review this modern panel. We first review the mechanistic rationales associated with their specific targets. We then review the pivotal evidence supporting their use in practice and their respective regimens. Lastly, we discuss the positioning of each therapeutic class. The current therapeutic options in NMOSD comprise three targeted mechanisms at different stages of a unique tissue-injury cascade: B-cell depleting, anti-cytokine, and anti-complement therapies. One drug has been approved on the market in each class. The current consensus proposes positioning the approved drugs as first-line treatments for newly-diagnosed patients and as alternative therapies in case of failure of historical treatment. Yet, there has been limited acceptance in practice due to high drug prices.

Impact of disease-modifying treatments on humoral response after COVID-19 vaccination: A mirror of the response after SARS-CoV-2 infection.

OBJECTIVE: To analyze the humoral response after COVID-19 vaccination in patients with multiple sclerosis (MS) according to disease-modifying treatments (DMTs) and in comparison with the humoral response after SARS-CoV-2 infection. METHODS: We included 28 MS patients with serological results after COVID-19 vaccination (Pfizer-BioNTech or Moderna ARNm) and 61 MS patients with serological results after COVID-19 (COVID-19 group) among patients followed up at the MS Center of Strasbourg, France, between January and April 2021. The primary endpoint was the IgG index according to DMTs (anti-CD20 mAb, sphingosine 1-phosphate receptor [S1PR] modulator and other treatments) and COVID-19 vaccine or COVID-19 groups. RESULTS: In the vaccinated MS patients, the median IgG index was lower in patients treated with anti-CD20 mAb and in patients treated with S1PR modulator compared to patients receiving other or no DMTs (4.80 [1.58-28.6], 16.5 [16.3-48.5], 1116 [434-1747] and 1272 [658-1886], respectively, P<0.001). Similar results were found for MS patients after COVID-19. CONCLUSIONS: Patients with MS and treated with S1PR modulators or anti-CD20 mAb had a reduced humoral response after COVID-19 vaccine.

Atypical myelitis in patients with multiple sclerosis: Characterization and comparison with typical multiple sclerosis and neuromyelitis optica spectrum disorders.

BACKGROUND: Atypical myelitis in multiple sclerosis (MS) is characterized by extensive myelitis in the longitudinal (longitudinally extensive transverse myelitis) or axial plane (transverse myelitis). OBJECTIVE: To characterize a cohort of MS patients with atypical myelitis. METHODS: Atypical myelitis was extracted from the French and Luxembourg MS databases and compared to two cohorts of MS patients with typical myelitis and neuromyelitis optica spectrum disorders (NMOSDs) patients with myelitis. RESULTS: We enrolled 28 MS patients with atypical myelitis, 68 MS patients with typical myelitis and 119 NMOSD patients with a first episode of myelitis. MS patients with atypical myelitis were characterized by a mean age of 34.0 (±10.7) years and 64.3% were women. In 82.1% of the patients, atypical myelitis was the first episode of MS. Mean Expanded Disability Status Scale (EDSS) scores at nadir and 3-6 months after onset were 4.1 ± 2.1 and 3.3 ± 2, respectively. Differences between groups revealed a predominance of cervicothoracic myelitis and a higher level of disability in NMOSD patients. Disability in MS patients with atypical myelitis was more severe than in the MS patients with typical myelitis; 28% had already converted to progressive MS within our mean follow-up of 39.6 (±30.4) months. CONCLUSION: Atypical myelitis may be the first presentation of MS and is associated with poorer prognosis.

Cytokine release syndrome-associated encephalopathy in patients with COVID-19.

BACKGROUND AND PURPOSE: Neurological manifestations in coronavirus disease (COVID)-2019 may adversely affect clinical outcomes. Severe COVID-19 and uremia are risk factors for neurological complications. However, the lack of insight into their pathogenesis, particularly with respect to the role of the cytokine release syndrome (CRS), is currently hampering effective therapeutic interventions. The aims of this study were to describe the neurological manifestations of patients with COVID-19 and to gain pathophysiological insights with respect to CRS. METHODS: In this longitudinal study, we performed extensive clinical, laboratory and imaging phenotyping in five patients admitted to our renal unit. RESULTS: Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Notably, neurological disturbances were accompanied by laboratory evidence of CRS. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was undetectable in the cerebrospinal fluid (CSF). Hyperalbuminorrachia and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain magnetic resonance imaging findings comprised evidence of acute leukoencephalitis (n = 3, one of whom had a hemorrhagic form), cytotoxic edema mimicking ischaemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted, resulting in rapid recovery from neurological disturbances in two cases. SARS-CoV2 was undetectable in 88 of the 90 patients with COVID-19 who underwent Reverse Transcription-PCR testing of CSF. CONCLUSIONS: Patients with COVID-19 can develop neurological manifestations that share clinical, laboratory and imaging similarities with those of chimeric antigen receptor T-cell-related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.

MRI characteristics of MOG-Ab associated disease in adults: An update.

Our knowledge of the radiological spectrum of myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) is growing rapidly. An update on the radiological features of the disease, and its evolution is thus necessary. Magnetic resonance imaging (MRI) has an increasingly important role in the differential diagnosis of MOGAD particularly from aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), and multiple sclerosis (MS). Differentiating these conditions is of prime importance because the management is different between the three inflammatory diseases, and thus could prevent further attack-related disability. Therefore, identifying the MRI features suggestive of MOGAD has diagnostic and prognostic implications. We herein review optic nerve, spinal cord and the brain MRI findings from MOGAD adult patients, and compare them to AQP4-NMOSD and MS.

Identification and measurement of cervical spinal cord atrophy in neuromyelitis optica spectrum disorders (NMOSD) and correlation with clinical characteristics and cervical spinal cord MRI data.

INTRODUCTION: The spinal cord is one of the two main targets of neuromyelitis optica (NMO). The aim of this study was to highlight cervical spinal cord atrophy in NMO patients as compared to controls and to assess correlations between atrophy and clinical characteristics and cervical spinal cord MRI data. METHODS: This prospective study investigated 15 patients with a diagnosis of NMOSD and 15 healthy controls. The whole cervical spinal cord was explored by MRI. The cross-sectional area (CSA) was estimate at every level of cup. This measurement was then averaged on the whole cervical spinal cord, providing a single measurement for every subject, denoted as mean CSA. RESULTS: Mean CSA was 68.5 mm2 in the population of NMO patients and 72.8 mm2 in the population of healthy subjects. NMO patients had significantly smaller cervical spinal cord area than healthy controls (T test=0.009). Cervical spinal cord atrophy was associated with clinical signs of medullary involvement (T test=0.0006). There was a tendency toward a relation between cervical spinal cord atrophy and the Expanded Disability Status Scale (EDSS) (T test=0.07). This correlation seems statistically significant (T test<0.05) at the level of the upper cervical spinal cord (C2-C3) CONCLUSION: This study provides the first evidence of cervical spinal cord atrophy in NMOSD by studying the entire cervical spinal cord. Upper cervical spinal cord atrophy was substantially correlated to clinical disability and seems more involved in the development of clinical disability in NMOSD patients in comparison to the lower cervical spinal cord.

[Clinical and epidemiological features in Neuromyelitis Optica Spectrum Disorder]. / Comparaison clinico-épidémiologique des pathologies du spectre des neuromyélites optiques.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMO-SD) has been recognized for the past decade. Biomarkers such as anti-Aquaporin 4 antibodies (AQP4) and anti-Myelin Oligodendrocyte Glycoprotein (MOG) have been able to classify NMO-SD into several groups. METHODS: A retrospective study was performed in the Strasbourg University Medical Center among patients with AQP4+, MOG+ and double-seronegative NMO to compare their clinical, epidemiological and paraclinical features. RESULTS: Thirty-two patients with NMO were included. The AQP4+ NMO patients had a median of age of 45 years, with associated myelitis in 62.5% of cases and other autoantibodies in 37.5% of cases. The mean number of relapses by clinical history was 3. The mean initial visual acuity during an exacerbation was 0.3 LogMAR, and the visual acuity after an exacerbation was 0.1 LogMAR. MOG+NMO patients had a median age of 23 years, with severely impaired initial visual acuity (0.6 LogMAR) but better recovery (0 LogMAR); optic disc edema was present in 80% of cases; the mean number of relapses on clinical history was 1. AQP4-/MOG- NMO's were more common in women (70%) and were bilateral in 40% of cases. CONCLUSION: The diagnostic characteristics of NMO-SD are becoming increasingly differentiated, with a positive impact on functional prognosis and long-term progression. Other biomarkers have yet to be identified to improve the diagnosis and treatment of these disorders.

A comparative evaluation of different neuromyelitis optica spectrum disorder sets of criteria.

BACKGROUND AND PURPOSE: Three different sets of criteria have been proposed for the diagnosis of neuromyelitis optica spectrum disorder (NMOSD). The objective was to compare the specificity, sensitivity and diagnostic accuracy of the three different sets of NMOSD criteria in patients presenting with inflammatory disorders of the central nervous system suggestive of NMOSD. METHODS: For 236 suspected NMOSD patients referred for serum aquaporin-4 immunoglobulin G antibody (AQP4-IgG) testing between 2012 and 2014, the three sets of NMOSD criteria [1999, 2006 NMO criteria and 2015 International Panel for NMO Diagnosis (IPND) criteria] were applied and compared to the final diagnosis. RESULTS: Seventy-six patients fulfilled at least one set of criteria and 28 patients fulfilled all NMOSD sets of criteria. The final diagnosis was NMOSD in 66 cases, multiple sclerosis according to the MacDonald 2010 criteria in 85 cases and another diagnosis in 85 cases. The 2006 NMO criteria have the highest specificity (99%) and the 2015 IPND NMOSD criteria the highest sensitivity (97%). For the 1999, 2006 and 2015 IPND NMOSD criteria, the accuracy was respectively 82%, 87% and 97%. CONCLUSIONS: Our study highlights the limitations of the first set of criteria that include the optico-spinal form of multiple sclerosis. The accuracy of NMOSD diagnostic criteria improved from 1999 to 2015. It confirms the increased performance of the last set of criteria which covers a larger spectrum of clinical presentation. This study raises some concerns for classifying patients with seronegative transverse myelitis or optic neuritis, and myelin oligodendrocyte glycoprotein (MOG) antibody- associated disease.

Recommendations for the use of Rituximab in neuromyelitis optica spectrum disorders

There is growing evidence of a preventive effect of Rituximab (RTX) in neuromyelitis optica spectrum disorders (NMO-SD). This monoclonal antibody against CD20 is becoming the most widely used preventive therapy in NMO-SD, as a first-line therapy or as a rescue therapy. Nevertheless, considerable heterogeneity still exists concerning the pre-treatment work-up, the vaccinations required before and under treatment, the number and dosage of infusions, prevention of the risk of infusion-related reactions, prevention of infections under treatment, and frequency of therapeutic cycles. Thanks to a collaborative work among NMO-SD experts belonging to the NOMADMUS project, we provide here recommendations for all these topics concerning RTX use in NMO-SD.

Neuromyelitis optica spectrum disorders: Features of aquaporin-4, myelin oligodendrocyte glycoprotein and double-seronegative-mediated subtypes.

The new diagnostic classification of neuromyelitis optica spectrum disorder (NMOSD) in 2015 highlights the central role of biomarkers, such as antibodies against aquaporin-4 (AQP4-Ab), in diagnosis. Also, in approximately 20-25% of patients without AQP4-Ab (NMOSDAQP4-) the presence of an antibody directed against myelin oligodendrocyte glycoprotein (MOG) characterizes a specific population of NMOSD patients (NMOSDMOG+), according to their demographic and clinical data and prognoses. While double-seronegative cases (NMOSDNEG) have not been fully described, they may correspond to the very first patients with opticospinal demyelination reported by Devic and Gault in 1894. The present report reviews the current knowledge of the pathophysiology and clinical features of NMOSDAQP4+, NMOSDMOG+ and NMOSDNEG patients, and also discusses the relationship between the extended spectrum of MOG disease and NMOSDMOG+. Finally, the current treatments for acute relapses and relapse prevention are described, with a focus on serological-based therapeutic responses and the promising new therapeutic targets.

Neuromyelitis optica spectrum disorder (NMOSD): A new concept.

The relationship between neuromyelitis optica (NMO) and multiple sclerosis (MS) has long been controversial. NMO was previously considered a form of MS involving predominantly the spinal cord and optic nerve. However, since the discovery of NMO-IgG/aquaporin-4 (AQP4) antibody, an NMO-specific autoantibody to AQP4, some unique clinical features, and magnetic resonance imaging (MRI) and other laboratory findings in NMO, have been further clarified. AQP4 antibody is now the most important laboratory finding for the diagnosis of NMO. Besides typical NMO, some patients with recurrent optic neuritis or recurrent longitudinally extensive transverse myelitis alone are also often positive for AQP4 antibody. Moreover, studies of AQP4 antibody-positive patients have revealed that brain and brainstem lesions are not uncommon in NMO, and some patterns appear to be unique to NMO. All these findings have expanded the NMO concept into 'NMO spectrum disorder' (NMOSD), and new criteria have recently been published. A new antigenic target, myelin oligodendrocyte glycoprotein (MOG), has also been discovered recently. This new antibody seems to correspond to around 20% of seronegative patients, but its specificity needs to be evaluated more precisely, especially in pediatric populations. These recent findings may also have therapeutic impact, as it has been demonstrated that many MS drugs can exacerbate NMO. This report provides an overview of the clinical and neuroimaging features of NMOSD, followed by its treatment.

Efficacy of rituximab in refractory neuromyelitis optica.

BACKGROUND: Despite a growing use of rituximab (RTX) in neuromyelitis optica (NMO), data are lacking in patients with refractory NMO (RNMO), defined as cases with at least one relapse during immunosuppressive therapy. OBJECTIVE: The purpose of this study was to assess RTX as a maintenance therapy in RNMO. METHODS: Out of a total of 305 NMO cases from a population-based cohort, 21 RNMO patients received RTX during a mean follow-up period of 31 months. RESULTS: After RTX, 11 patients (52.3%) were relapse free, meaning that 47.7% were refractory to RTX. The mean annualized relapse rate decreased from 1.3 to 0.4 (p<0.001) and median EDSS from 5 to 3 (p=0.02). Body mass index (BMI) was predictive of EDSS worsening. CONCLUSIONS: RTX is an effective and well-tolerated treatment in RNMO. BMI could be a predictive factor for efficacy.

Tear analysis as a tool to detect oligoclonal bands in radiologically isolated syndrome.

BACKGROUND: Although radiologically isolated syndrome (RIS) is a newly defined entity, incidental findings of T2 hypersignals on brain MRI can lead to misdiagnosis or useless investigations. The detection of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) is a major indicator that helps in diagnosis of subclinical inflammatory disease of the central nervous system, but lumbar puncture still remains an invasive option. METHODS: We have prospectively included patients with RIS, have compared the results of CSF and tear OCB detection by isoelectric focusing (IEF) and assessed concordance between OCB detection in tears and in CSF. Tears were collected using a Schirmer strip. RESULTS: In 45 recruited RIS patients, OCBs were detected in CSF for 55% (25/45) and in tears for 50% (21/42) of samples. CONCLUSIONS: We suggest that tear OCB detection may replace CSF OCB detection as a diagnostic tool in patients with RIS and be useful in follow-up.

[Cerebrotendinous xanthomatosis: a multicentric retrospective study of 15 adults, clinical and paraclinical typical and atypical aspects]. / Étude rétrospective multicentrique de 15 cas adultes de xanthomatose cérébrotendineuse : aspects cliniques et paracliniques typiques et atypiques.

INTRODUCTION: Cerebrotendinous xanthomatosis, a metabolic leukodystrophy with an autosomal recessive inheritance, is secondary to deficiency of sterol 27-hydroxylase, an enzyme involved in cholesterol catabolism. Classical symptoms include clinical or infraclinical xanthomas affecting the skin and tendons, early cataracts, neurological signs and diarrhea. Brain imaging reveals involvement of the dentate nuclei and periventricular white matter hyperintensities. The diagnosis is based on an increased cholestanol level in serum, confirmed by the presence of a mutation in the CYP27A1 gene. Treatment is based on chenodeoxycholic acid. METHOD: We report a retrospective multicentric study of 15 cases of cerebrotendinous xanthomatosis diagnosed in French adults. Clinical, molecular and MRI findings were recorded in all patients. RESULTS: The average age at diagnosis was 39years (range 27-65). Disease onset occurred in childhood in 73% of patients and in adulthood in 27%. All patients with a pediatric onset were diagnosed during adulthood (age range 28-65years). Clinical symptoms variably associated cerebellar syndrome, pyramidal syndrome, cognitive decline, epilepsy, neuropathy (sought in 10 of our patients, present in forms in 8), psychiatric disorders, cataract and xanthomas. One patient had an atypical presentation: monoparesis associated with xanthomas. Brain MRI was abnormal in all: findings consisted in T2-weighted hyperintensity of the dentate nuclei (47%), periventricular leuoencephalopathy (73%) which preferentially involved the posterior cerebral part (60%), leucoencephalopathy with a vascular pattern (7%), hyperintensity of the cortico-spinal tracts (53%), globi pallidi, corpus callosum and cerebral atrophy (33%). Serum cholestanol was elevated in 93% of patients. The most frequent mutation was 1183C>T (n=5/15). Under treatment with chenodeoxycholic acid, eight patients improved initially, followed by stabilization in five of them, and worsening in the others. Four patients died. CONCLUSION: Patients with the xanthoma-neurological disorder association should be tested for cerebrotendinous xanthomatosis. The disease often begins in childhood with a diagnostic delay but also in adulthood. Involvement of the dentate nuclei is specific but not sensitive and the supratentorial leucoencephalopathy is not specific but with an antero-posterior gradient. A vascular distribution and involvement of the corpus callosum are possible. Serum cholestanol assay is very reliable: an elevated level provides the diagnosis, which must nevertheless be confirmed by molecular biology.

Isolated anti-ß2-glycoprotein I antibodies in neurology: a frontier syndrome between multiple sclerosis and antiphospholipid syndrome?

BACKGROUND AND PURPOSE: Anti-ß2-glycoprotein I (anti-ß2-GPI) antibodies are part of the heterogeneous family of antiphospholipid antibodies and seem to be present in various neurological manifestations in addition to antiphospholipid syndrome (APS). Our objective was to analyse the clinical, radiological and therapeutic characteristics of neurological patients with positive anti-ß2-GPI antibodies and without the Sapporo criteria for APS. METHODS: The medical records were retrospectively reviewed of 28 consecutive patients hospitalized in the Neurology Department of Strasbourg University Hospital, France, in whom anti-ß2-GPI antibodies (immunoglobulin G and/or immunoglobulin M) were positive and other antiphospholipid antibodies negative, from November 2005 to July 2011. Clinical, radiological, biological and therapeutic data and clinical course were studied. RESULTS: Positive anti-ß2-GPI antibodies were present in 28 patients. The predominant physiopathological process was mainly inflammatory (25% with myelitis, 14.3% with optic neuritis) or vascular (14.3% with cerebral ischaemia, 7.1% with cerebral vasculitis). Brain magnetic resonance imaging was performed in 89.3% of patients: atypical lesions were observed in 44% and typical inflammatory and vascular lesions in 16% and 12%, respectively. CONCLUSION: The anti-ß2-GPI antibody seems to be involved in two types of neurological disease: vascular or inflammatory 'multiple sclerosis-like' disease. These two types of patients frequently develop an autoimmune disease (multiple sclerosis, systemic lupus erythematosus, APS). However, a large proportion of the patients had an undefined profile with aspecific cerebral lesions and required monitoring. This study raises questions about a separate entity at the border between APS and multiple sclerosis which remains to be better defined in a larger cohort.

Brainstem manifestations in neuromyelitis optica: a multicenter study of 258 patients.

BACKGROUND: Neuromyelitis optica (NMO) is a severe autoimmune disease of the central nervous system characterized by spinal cord and optic nerve involvement. Brainstem manifestations have recently been described. OBJECTIVE: To evaluate the time of occurrence, the frequency and the characteristics of brainstem symptoms in a cohort of patients with NMO according to the ethnic background and the serologic status for anti-aquaporin-4 antibodies (AQP4-abs). METHODS: We performed a multicenter study of 258 patients with NMO according to the 2006 Wingerchuk criteria and we evaluated prospectively the frequency, the date of onset and the duration of various brainstem signs in this population. RESULTS: Brainstem signs were observed in 81 patients (31.4%). The most frequently observed signs were vomiting (33.1%), hiccups (22.3%), oculomotor dysfunction (19.8%), pruritus (12.4%), followed by hearing loss (2.5%), facial palsy (2.5%), vertigo or vestibular ataxia (1.7%), trigeminal neuralgia (2.5%) and other cranial nerve signs (3.3%). They were inaugural in 44 patients (54.3%). The prevalence was higher in the non-Caucasian population (36.6%) than in the Caucasian population (26%) (p<0.05) and was higher in AQP4-ab-seropositive patients (32.7%) than in seronegative patients (26%) (not significant). CONCLUSIONS: This study confirms the high frequency of brainstem symptoms in NMO with a majority of vomiting and hiccups. The prevalence of these manifestations was higher in the non Caucasian population.