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BACKGROUND AND OBJECTIVES: Recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears exponential, leaving a tail of patients reporting various long COVID symptoms including unexplained fatigue/exertional intolerance and dysautonomic and sensory concerns. Indirect evidence links long COVID to incident polyneuropathy affecting the small-fiber (sensory/autonomic) axons. METHODS: We analyzed cross-sectional and longitudinal data from patients with World Health Organization (WHO)-defined long COVID without prior neuropathy history or risks who were referred for peripheral neuropathy evaluations. We captured standardized symptoms, examinations, objective neurodiagnostic test results, and outcomes, tracking participants for 1.4 years on average. RESULTS: Among 17 patients (mean age 43.3 years, 69% female, 94% Caucasian, and 19% Latino), 59% had ≥1 test interpretation confirming neuropathy. These included 63% (10/16) of skin biopsies, 17% (2/12) of electrodiagnostic tests and 50% (4/8) of autonomic function tests. One patient was diagnosed with critical illness axonal neuropathy and another with multifocal demyelinating neuropathy 3 weeks after mild COVID, and ≥10 received small-fiber neuropathy diagnoses. Longitudinal improvement averaged 52%, although none reported complete resolution. For treatment, 65% (11/17) received immunotherapies (corticosteroids and/or IV immunoglobulins). DISCUSSION: Among evaluated patients with long COVID, prolonged, often disabling, small-fiber neuropathy after mild SARS-CoV-2 was most common, beginning within 1 month of COVID-19 onset. Various evidence suggested infection-triggered immune dysregulation as a common mechanism. Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

B cells have an ever-increasing role in the etiopathology of a number of autoimmune neurological disorders, acting as antigen-presenting cells facilitating antibody production but also as sensors, coordinators, and regulators of the immune response. In particular, B cells can regulate the T cell activation process through their participation in antigen presentation, production of proinflammatory cytokines (bystander activation or suppression), and contribution to ectopic lymphoid aggregates. Such an important interplay between B and T cells makes therapeutic depletion of B cells an attractive treatment strategy. The last decade, anti-B cell therapies using monoclonal antibodies against B cell surface molecules have evolved into a rational approach for successfully treating autoimmune neurological disorders, even when T cells seem to be the main effector cells. The paper summarizes basic aspects of B cell biology, discusses the roles of B cells in neurological autoimmunities, and highlights how the currently available or under development anti-B cell therapeutics exert their action in the wide spectrum and immunologically diverse neurological disorders. The efficacy of the various anti-B cell therapies and practical issues on induction and maintenance therapy is specifically detailed for the treatment of patients with multiple sclerosis, neuromyelitis-spectrum disorders, autoimmune encephalitis and hyperexcitability CNS disorders, autoimmune neuropathies, myasthenia gravis, and inflammatory myopathies. The success of anti-B cell therapies in inducing long-term remission in IgG4 neuroautoimmunities is also highlighted pointing out potential biomarkers for follow-up infusions. © 2022, The Author(s).

Introduction: The inflammatory myopathies (IM) have now evolved into distinct subsets requiring clarification about their immunopathogenesis to guide applications of targeted therapies Areas covered: Immunohistopathologic criteria of IM with a focus on complement, anti-complement therapeutics, and other biologic immunotherapies. The COVID19-triggered muscle autoimmunity along with the correct interpretation of muscle amyloid deposits is discussed. Expert opinion: The IM, unjustifiably referred as idiopathic, comprise Dermatomyositis (DM), Necrotizing Autoimmune Myositis (NAM), Anti-synthetase syndrome-overlap myositis (Anti-SS-OM), and Inclusion-Body-Myositis (IBM). In DM, complement activation with MAC-mediated endomysial microvascular destruction and perifascicular atrophy is the fundamental process, while innate immunity activation factors, INF1 and MxA, sense and secondarily enhance inflammation. Complement participates in muscle fiber necrosis from any cause and may facilitate muscle-fiber necrosis in NAM but seems unlikely that myositis-associated antibodies participate in complement-fixing. Accordingly, anti-complement therapeutics should be prioritized for DM. SARS-CoV-2 can potentially trigger muscle autoimmunity, but systematic studies are needed as the reported autopsy findings are not clinically relevant. In IBM, tiny amyloid deposits within muscle fibers are enhanced by inflammatory mediators contributing to myodegeneration; in contrast, spotty amyloid deposits in the endomysial connective tissue do not represent ‘amyloid myopathy’ but only have diagnostic value for amyloidosis due to any cause. © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common, heterogeneous, immune-mediated neuropathy, characterized by predominant demyelination of motor and sensory nerves. CIDP follows a relapsing–remitting or a progressive course and causes substantial disability. The pathogenesis of CIDP involves a complex interplay of multiple aberrant immune responses, creating a pro-inflammatory environment, subsequently inflicting damage on the myelin sheath. Though the exact triggers are unclear, diverse immune mechanisms encompassing cellular and humoral pathways are implicated. The complement system appears to play a role in promoting macrophage-mediated demyelination. Complement deposition in sural nerve biopsies, as well as signs of increased complement activation in serum and CSF of patients with CIDP, suggest complement involvement in CIDP pathogenesis. Here, we present a comprehensive overview of the preclinical and clinical evidence supporting the potential role of the complement system in CIDP. This understanding furnishes a strong rationale for targeting the complement system to develop new therapies that could serve the unmet needs of patients affected by CIDP, particularly in those refractory to standard therapies. © 2022, The Author(s).

Introduction: Cross-reactivity to SARS-CoV-2 antigenic peptides has been detected on T-cells from pre-pandemic donors due to recognition of conserved protein fragments within members of the coronavirus's family. Further, preexisting antibodies recognizing SARS-CoV-2 with conserved epitopes in the spike region have been now seen in uninfected individuals. High-dose Intravenous Immunoglobulin (IVIg), derived from thousands of healthy donors, contains natural IgG antibodies against various antigens which can be detected both within the IVIg preparations and in the serum of IVIg-receiving patients. Whether IVIg preparations from pre-pandemic donors also contain antibodies against pre-pandemic coronaviruses or autoreactive antibodies that cross-react with SARS-CoV-2 antigenic epitopes, is unknown. Methods: 13 samples from 5 commercial IVIg preparations from pre-pandemic donors (HyQvia (Baxalta Innovations GmbH); Privigen (CSL Behring); Intratect (Biotest AG); IgVena (Kedrion S.p.A); and Flebogamma (Grifols S.A.) were blindly screened using a semi-quantitative FDA-approved and validated enzyme-linked immunosorbent assay (ELISA) (Euroimmun, Lubeck, Germany). Results: Nine of thirteen preparations (69.2%), all from two different manufactures, were antibody-positive based on the defined cut-off positivity (index of sample OD to calibrator OD > 1.1). From one manufacturer, 7/7 lots (100%) and from another 2/3 lots (67%), tested positive for cross-reacting antibodies. 7/9 of the positive preparations (77%) had titers as seen in asymptomatically infected individuals or recent COVID19-recovered patients, while 2/9 (23%) had higher titers, comparable to those seen in patients with active symptomatic COVID-19 infection (index > 2.2). Conclusion: Pre-pandemic IVIg donors have either natural autoantibodies or pre-pandemic cross-reactive antibodies against antigenic protein fragments conserved among the “common cold” - related coronaviruses. The findings are important in: (a) assessing true anti-SARS-CoV-2-IgG seroprevalence avoiding false positivity in IVIg-receiving patients; (b) exploring potential protective benefits in patients with immune-mediated conditions and immunodeficiencies receiving acute or chronic maintenance IVIg therapy, and (c) validating data from a recent controlled study that showed significantly lower in-hospital mortality in the IVIg- treated group. © Copyright © 2021 Dalakas, Bitzogli and Alexopoulos.

In the last 25 years, intravenous immunoglobulin (IVIg) has had a major impact in the successful treatment of previously untreatable or poorly controlled autoimmune neurological disorders. Derived from thousands of healthy donors, IVIg contains IgG1 isotypes of idiotypic antibodies that have the potential to bind pathogenic autoantibodies or cross-react with various antigenic peptides, including proteins conserved among the “common cold”-pre-pandemic coronaviruses; as a result, after IVIg infusions, some of the patients’ sera may transiently become positive for various neuronal antibodies, even for anti-SARS-CoV-2, necessitating caution in separating antibodies derived from the infused IVIg or acquired humoral immunity. IVIg exerts multiple effects on the immunoregulatory network by variably affecting autoantibodies, complement activation, FcRn saturation, FcγRIIb receptors, cytokines, and inflammatory mediators. Based on randomized controlled trials, IVIg is approved for the treatment of GBS, CIDP, MMN and dermatomyositis; has been effective in, myasthenia gravis exacerbations, and stiff-person syndrome; and exhibits convincing efficacy in autoimmune epilepsy, neuromyelitis, and autoimmune encephalitis. Recent evidence suggests that polymorphisms in the genes encoding FcRn and FcγRIIB may influence the catabolism of infused IgG or its anti-inflammatory effects, impacting on individualized dosing or efficacy. For chronic maintenance therapy, IVIg and subcutaneous IgG are effective in controlled studies only in CIDP and MMN preventing relapses and axonal loss up to 48 weeks; in practice, however, IVIg is continuously used for years in all the aforementioned neurological conditions, like is a “forever necessary therapy” for maintaining stability, generating challenges on when and how to stop it. Because about 35-40% of patients on chronic therapy do not exhibit objective neurological signs of worsening after stopping IVIg but express subjective symptoms of fatigue, pains, spasms, or a feeling of generalized weakness, a conditioning effect combined with fear that discontinuing chronic therapy may destabilize a multi-year stability status is likely. The dilemmas of continuing chronic therapy, the importance of adjusting dosing and scheduling or periodically stopping IVIg to objectively assess necessity, and concerns in accurately interpreting IVIg-dependency are discussed. Finally, the merit of subcutaneous IgG, the ineffectiveness of IVIg in IgG4-neurological autoimmunities, and genetic factors affecting IVIg dosing and efficacy are addressed. © 2021, The Author(s).

Autoimmune neurogenic dysphagia refers to manifestation of dysphagia due to autoimmune diseases affecting muscle, neuromuscular junction, nerves, roots, brainstem, or cortex. Dysphagia is either part of the evolving clinical symptomatology of an underlying neurological autoimmunity or occurs as a sole manifestation, acutely or insidiously. This opinion article reviews the autoimmune neurological causes of dysphagia, highlights clinical clues and laboratory testing that facilitate early diagnosis, especially when dysphagia is the presenting symptom, and outlines the most effective immunotherapeutic approaches. Dysphagia is common in inflammatory myopathies, most prominently in inclusion body myositis, and is frequent in myasthenia gravis, occurring early in bulbar-onset disease or during the course of progressive, generalized disease. Acute-onset dysphagia is often seen in Guillain–Barre syndrome variants and slowly progressive dysphagia in paraneoplastic neuropathies highlighted by the presence of specific autoantibodies. The most common causes of CNS autoimmune dysphagia are demyelinating and inflammatory lesions in the brainstem, occurring in patients with multiple sclerosis and neuromyelitis optica spectrum disorders. Less common, but often overlooked, is dysphagia in stiff-person syndrome especially in conjunction with cerebellar ataxia and high anti-GAD autoantibodies, and in gastrointestinal dysmotility syndromes associated with autoantibodies against the ganglionic acetyl-choline receptor. In the setting of many neurological autoimmunities, acute-onset or progressive dysphagia is a potentially treatable condition, requiring increased awareness for prompt diagnosis and early immunotherapy initiation. © 2021, The Author(s).

Antibodies against glutamic acid decarboxylase (GAD), originally linked to stiff person syndrome (SPS), now denote the “GAD antibody-spectrum disorders” (GAD-SD) that also include autoimmune epilepsy, limbic encephalitis, cerebellar ataxia and nystagmus with overlapping symptomatology highlighting autoimmune neuronal excitability disorders. The reasons for the clinical heterogeneity among GAD-antibody associated syndromes remain still unsettled, implicating variable susceptibility of GABAergic neurons to anti-GAD or other still unidentified autoantibodies. Although anti-GAD antibody titers do not correlate with clinical severity, very high serum titers, often associated with intrathecal synthesis of anti-GAD-specific IgG, point to in-situ effects of GAD or related autoantibodies within the central nervous system. It remains, however, uncertain what drives these antibodies, why they persist and whether they are disease markers or have pathogenic potential. The review, focused on these concerns, describes the widened clinical manifestations and overlapping features of all GAD-SD; addresses the importance of GAD antibody titers and potential significance of GAD epitopes; summarizes the biologic basis of autoimmune hyperexcitability; highlights the electrophysiological basis of reciprocal inhibition in muscle stiffness; and provides practical guidelines on symptomatic therapies with gamma-aminobutyric acid-enhancing drugs or various immunotherapies. © The Author(s), 2021.

Our study objective was testing for anti-neuronal autoantibodies within commercially available intravenous immunoglobulin (IVIg) preparations. Sixteen samples from 5 different commercially available IVIg preparations were tested with cell-based assays (CBA) and enzyme-linked immunosorbent assay (ELISA) to detect and characterize common neuronal autoantibodies, and with immunohistochemistry on teased fibers from mouse sciatic nerve and on mouse brain sections to screen for nodal and not yet identified neuronal antigens. In 15/16 IVIg preparations, anti-GAD antibodies were detected in titers ranging from 40 to 1507 IU/mL, as typically seen in type 1 diabetes, but not in the range (> 2000 IU/mL) seen in GAD-positive neurological patients. None of the preparations was however positive with anti-GAD CBA. Antibodies to AQP4 were also detected by ELISA in 15/16 IVIg preparations with titers comparable to those seen in AQP4-seropositive NMO patients; with CBA, however, all IVIg samples were AQP4-negative. IVIg preparations contained IgG-anti-MAG antibodies by ELISA at statistically significant higher titers compared to controls. Two of the 16 IVIg samples were positive for human 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. All IVIg preparations were negative for antibodies to MOG, NMDAR, anti-nodal, and other neuronal-specific proteins. IVIg preparations contain antibodies against GAD and AQP4 in titers comparable to those seen in autoimmune patients when tested by ELISA, but not by CBA or tissue immunohistochemistry, suggesting that the autoantibodies within the IVIg are against linear rather than structural epitopes, as part of the natural antibody immune repertoire. The information is clinically important for diagnosis when testing patients’ sera after they have received therapy with IVIg to avoid false interpretation. © 2019, The American Society for Experimental NeuroTherapeutics, Inc.

OBJECTIVE: To present the COVID-19-associated GBS, the prototypic viral-triggered autoimmune disease, in the context of other emerging COVID-19-triggered autoimmunities, and discuss potential concerns with ongoing neuroimmunotherapies. METHODS: Eleven GBS cases in four key COVID-19 hotspots are discussed regarding presenting symptoms, response to therapies and cross-reactivity of COVID spike proteins with nerve glycolipids. Emerging cases of COVID-19-triggered autoimmune necrotizing myositis (NAM) and encephalopathies are also reviewed in the context of viral invasion, autoimmunity and ongoing immunotherapies. RESULTS: Collective data indicate that in this pandemic any patient presenting with an acute paralytic disease-like GBS, encephalomyelitis or myositis-even without systemic symptoms, may represent the first manifestation of COVID-19. Anosmia, ageusia, other cranial neuropathies and lymphocytopenia are red flags enhancing early diagnostic suspicion. In Miller-Fisher Syndrome, ganglioside antibodies against GD1b, instead of QG1b, were found; because the COVID-19 spike protein also binds to sialic acid-containing glycoproteins for cell-entry and anti-GD1b antibodies typically cause ataxic neuropathy, cross-reactivity between COVID-19-bearing gangliosides and peripheral nerve glycolipids was addressed. Elevated Creatine Kinase (>10,000) is reported in 10% of COVID-19-infected patients; two such patients presented with painful muscle weakness responding to IVIg indicating that COVID-19-triggered NAM is an overlooked entity. Cases of acute necrotizing brainstem encephalitis, cranial neuropathies with leptomeningeal enhancement, and tumefactive postgadolinium-enhanced demyelinating lesions are now emerging with the need to explore neuroinvasion and autoimmunity. Concerns for modifications-if any-of chronic immunotherapies with steroids, mycophenolate, azathioprine, IVIg, and anti-B-cell agents were addressed; the role of complement in innate immunity to viral responses and anti-complement therapeutics (i.e. eculizumab) were reviewed. CONCLUSIONS: Emerging data indicate that COVID-19 can trigger not only GBS but other autoimmune neurological diseases necessitating vigilance for early diagnosis and therapy initiation. Although COVID-19 infection, like most other viruses, can potentially worsen patients with pre-existing autoimmunity, there is no evidence that patients with autoimmune neurological diseases stable on common immunotherapies are facing increased risks of infection. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

The inflammatory myopathies constitute a heterogeneous group of acquired myopathies that have in common the presence of endomysial inflammation. Based on steadily evolved clinical, histological and immunopathological features and some autoantibody associations, these disorders can now be classified in five characteristic subsets: Dermatomyositis (DM) Polymyositis (PM), Necrotizing Autoimmune Myositis (NAM), Anti-synthetase syndrome-overlap myositis (Anti-SS-OM), and Inclusion-Body-Myositis (IBM). Each inflammatory myopathy subset has distinct immunopathogenesis, prognosis and response to immunotherapies, necessitating the need to correctly identify each subtype from the outset to avoid disease mimics and proceed to early therapy initiation. The review presents the main clinicopathologic characteristics of each subset highlighting the importance of combining expertise in clinical neurological examination with muscle morphology and immunopathology to avoid erroneous diagnoses and therapeutic schemes. The main autoimmune markers related to autoreactive T cells, B cells, autoantibodies and cytokines are presented and the concomitant myodegenerative features seen in IBM muscles are pointed out. Most importantly, unsettled issues related to a role of autoantibodies and controversies with reference to possible triggering factors related to statins are clarified. The emerging effect SARS-CoV-2 as the cause of hyperCKemia and potentially NAM is addressed and practical guidelines on the best therapeutic approaches and concerns regarding immunotherapies during COVID-19 pandemic are summarized. © Gaetano Conte Academy - Mediterranean Society of Myology.

OBJECTIVE: To investigate the pathophysiologic mechanism of encephalopathy and prolonged comatose or stuporous state in severally ill patients with coronavirus disease 2019 (COVID-19). METHODS: Eight COVID-19 patients with signs of encephalopathy were tested for antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the serum and CSF using a Food and Drug Administration-approved and independently validated ELISA. Blood-brain barrier (BBB) integrity and immunoglobulin G (IgG) intrathecal synthesis were further tested using albumin and IgG indices. The CSF was also tested for autoimmune encephalitis antibodies and 14-3-3, a marker of ongoing neurodegeneration. RESULTS: All patients had anti-SARS-CoV-2 antibodies in their CSF, and 4 of 8 patients had high titers, comparable to high serum values. One patient had anti-SARS-CoV-2 IgG intrathecal synthesis, and 3 others had disruption of the blood-brain barrier. The CSF in 4 patients was positive for 14-3-3-protein suggesting ongoing neurodegeneration. In all patients, the CSF was negative for autoimmune encephalitis antibodies and SARS-CoV-2 by PCR. None of the patients, apart from persistent encephalopathic signs, had any focal neurologic signs or history or specific neurologic disease. CONCLUSIONS: High-titer anti-SARS-CoV-2 antibodies were detected in the CSF of comatose or encephalopathic patients demonstrating intrathecal IgG synthesis or BBB disruption. A disrupted BBB may facilitate the entry of cytokines and inflammatory mediators into the CNS enhancing neuroinflammation and neurodegeneration. The observations highlight the need for prospective CSF studies to determine the pathogenic role of anti-SARS-CoV-2 antibodies and identify early therapeutic interventions. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

The complement system consists of a network of plasma and membrane proteins that modulate tissue homeostasis and contribute to immune surveillance by interacting with the innate and adaptive immune systems. Dysregulation, impairment or inadvertent activation of complement components contribute to the pathogenesis of some autoimmune neurological disorders and could even contribute to neurodegenerative diseases. In this Review, we summarize current knowledge about the main functions of the complement pathways and the involvement of complement in neurological disorders. We describe the complex network of complement proteins that target muscle, the neuromuscular junction, peripheral nerves, the spinal cord or the brain and discuss the autoimmune mechanisms of complement-mediated myopathies, myasthenia, peripheral neuropathies, neuromyelitis and other CNS disorders. We also consider the emerging role of complement in some neurodegenerative diseases, such as Alzheimer disease, amyotrophic lateral sclerosis and even schizophrenia. Finally, we provide an overview of the latest complement-targeted immunotherapies including monoclonal antibodies, fusion proteins and peptidomimetics that have been approved, that are undergoing phase I–III clinical trials or that show promise for the treatment of neurological conditions that respond poorly to existing immunotherapies. © 2020, Springer Nature Limited.

ObjectiveTo assess whether canakinumab, a monoclonal antibody against IL-1β approved for autoinflammatory diseases, is effective as target-specific therapy in patients with sporadic inclusion body myositis (sIBM).MethodsBecause in sIBM IL-1β colocalizes with amyloid precursor protein and upregulates amyloid aggregates enhancing degeneration, targeting IL-1β with canakinumab may arrest disease progression. On this basis, 5 ambulatory patients with sIBM participated in an institutional review board-approved open-labeled study with 150 mg canakinumab [4 bimonthly, then monthly subcutaneous injections] for a mean period of 15.8 months. Patients were assessed bimonthly with a manual dynamometer in 12 proximal and distal muscles and with grip force (GF) in both hands. Total muscle strength (TMS) was expressed in kilograms. Efficacy was defined as >15% increased strength after 12 months.ResultsPatient 1 stopped at month 5 because of 23% loss in TMS and 32.35% in GF; patient 2 showed 37.1% increase in TMS and 13% in GF by month 9; patient 3 exhibited 26.7% reduction in TMS and 10% in GF at month 33; patient 4 showed 6.5% reduction in TMS and 1.6% in GF after 15 months, denoting relative stability; and patient 5 showed 30.4% loss in TMS and 20.8% in GF after 18 months. In patients 2 and 4, in whom 3-year longitudinal data were available, no effect on disease progression was noted.ConclusionsIn this long-term, open-label study, canakinumab showed small, but not clinically appreciable, stabilizing benefits in 2 of 5 patients with sIBM over 1 year, was ineffective in 2 others, and might have worsened one. No patient improved.Classification of evidenceThis study provides Class IV evidence that canakinumab was ineffective for patients with sIBM. © 2019 American Academy of Neurology.

Patients with acute and chronic inflammatory demyelinating neuropathies exhibit elevated serum and cerebrospinal fluid (CSF) levels of terminal complement activation products and therapeutic inhibition of complement activation is currently tested for its safety and efficacy in patients with Guillain-Barré syndrome (GBS). Here, we determined serum levels of the complement activation products C3a, C5a and the soluble terminal complement complex (sTCC) in 39 individuals with chronic inflammatory demyelinating polyneuropathy (CIDP) who participated in one of the largest ever conducted clinical trial in patients with CIDP (ICE trial) and received Intravenous Immunoglobulin (IVIG) or placebo (albumin) in 3 week intervals for up to 24 weeks. In placebo-treated patients with spontaneous disease remission, serum sTCC levels moderately decreased over time. Levels of complement activation products were, however, not modulated by IVIG and remained unchanged in patients with a beneficial response to IVIG therapy as compared to those with steady or worsened disease. These results suggest that the therapeutic efficacy of IVIG in CIDP is based on immunomodulatory mechanisms different from complement inhibition. Terminal complement activation merits further investigation as a surrogate marker for disease progression and therapeutic target in patients with CIDP. © 2019 Elsevier B.V.

Background: Stiff Person Syndrome (SPS) is an under-diagnosed disorder that affects mobility and the quality of life of affected patients. The aim of the study is to describe the natural history of SPS, the extent of accumulated disability and the associated clinical and immunological features in patients followed for up to 8 years in a single center. Methods: Our collective cohort included 57 SPS patients. Additionally, 32 of these patients were examined every 6 months for a two-year period in a longitudinal study protocol, to assess disease progression using quantitative measures of stiffness and heightened sensitivity. Results: The most frequent initial symptom was leg stiffness, followed by paraspinal muscle rigidity and painful spasms in 95% of the patients. Although none of the patients required assistance for ambulation during the first 2 years of disease onset, 46 patients (80%) lost the ability to walk independently during our follow-up, despite symptomatic medications. In the longitudinal cohort, the number of stiff areas increased (p < 0.0001), consistent with worsening functional status and quality of life. High-titer anti-GAD antibodies were present in serum and CSF with elevated intrathecal GAD-specific IgG synthesis, but they did not correlate with clinical severity or progression. Conclusions: This large study on SPS patients, combining an eight-year follow-up at a single center by the same leading neurologist and his team, is the first to provide longitudinal data in a large patient subgroup using objective clinical measures. One of the main findings is that SPS is a progressive disease leading to physical disability over time. © 2019 The Author(s).

Autoimmune encephalitides, with an estimated incidence of 1.5 per million population per year, although described only 15 years ago, have already had a remarkable impact in neurology and paved the field to autoimmune neuropsychiatry. Many patients traditionally presented with aberrant behavior, especially of acute or subacute onset, and treated with anti-psychotic therapies, turn out to have a CNS autoimmune disease with pathogenic autoantibodies against synaptic antigens responding to immunotherapies. The review describes the clinical spectrum of these disorders, and the pathogenetic role of key autoantibodies directed against: a) cell surface synaptic antigens and receptors, including NMDAR, GABAa, GABAb, AMPA and glycine receptors; b) channels such as AQP4 water-permeable channel or voltage-gated potassium channels; c) proteins that stabilize voltage-gated potassium channel complex into the membrane, like the LGI1 and CASPR2; and d) enzymes that catalyze the formation of neurotransmitters such as Glutamic Acid Decarboxylase (GAD). These antibodies, effectively target excitatory or inhibitory synapses in the limbic system, basal ganglia or brainstem altering synaptic function and resulting in uncontrolled neurological excitability disorder clinically manifested with psychosis, agitation, behavioral alterations, depression, sleep disturbances, seizure-like phenomena, movement disorders such as ataxia, chorea and dystonia, memory changes or coma. Some of the identified triggering factors include: viruses, especially herpes simplex, accounting for the majority of relapses occurring after viral encephalitis, which respond to immunotherapy rather than antiviral agents; tumors especially teratoma, SCLC and thymomas; and biological cancer therapies (immune-check-point inhibitors). As anti-synaptic antibodies persist after viral infections or tumor removal, augmentation of autoreactive B cells which release autoantigens to draining lymph nodes, molecular mimicry and infection-induced bystander immune activation products play a role in autoimmunization process or perpetuating autoimmune neuroinflammation. The review stresses the importance of early detection, clinical recognition, proper antibody testing and early therapy initiation as these disorders, regardless of a known or not trigger, are potentially treatable responding to systemic immunotherapy with intravenous steroids, IVIg, rituximab or even bortezomid © 2019 Elsevier Ltd

No consensus has been reached on the ideal therapeutic algorithm for myasthenia gravis (MG). Most patients with MG require induction therapy with high doses of corticosteroids and maintenance with an immunosuppressant. Severe cases and acute worsening require intravenous immunoglobulin or plasmapheresis before oral immunosuppressants start having an effect. However, biologics are emerging as important therapeutic tools that promise to provide better corticosteroid sparing effects than standard treatments and can even induce remission. In particular, eculizumab, a monoclonal antibody against complement C5, has been approved by the FDA for refractory MG on the basis of a phase III trial. Rituximab, an anti-CD20 monoclonal antibody that depletes peripheral B cells, has also been effective in many large uncontrolled series, although was not in a small phase III trial. Whether the newer anti-CD20 agents ocrelizumab, ofatumumab, obinutuzumab, ublituximab or inebilizumab will be more effective remains unclear. Belimumab, an antibody against the B cell trophic factor BAFF, was ineffective in phase III trials, and efgartigimod, which depletes antibodies, was effective in a phase II study. Some anti-cytokine agents relevant to MG immunopathogenesis also seem promising. Checkpoint inhibitors can trigger MG in some patients, necessitating early intervention. Increased availability of new biologics provides targeted immunotherapies and the opportunities to develop more specific therapies. © 2018, Springer Nature Limited.

Stiff-person syndrome (SPS) is characterized by (1) stiffness of truncal and limb muscles due to continuous co-contracture of agonist and antagonist muscles resulting in hyperlordosis, difficulty bending or turning, and slow, wide-based gait, (2) sudden spasms precipitated by unexpected noises and tactile or visual stimuli, and (3) overt anxiety with task-specific phobias. The symptoms vary in severity and can be fluctuating or fixed leading to disability in up to 65% of patients. SPS is an autoimmune disease with antibodies against (a) GAD-65, the enzyme responsible for synthesis of GABA, the brain’s main inhibitory neurotransmitter, (b) anti-glycine receptor, and (c) amphiphysin when paraneoplastic. The treatment begins with GABA-enhancing drugs such as diazepam, baclofen, and gabapentin, followed by immunotherapy. IVIg, proven effective in a controlled trial, is the first-in-line immunotherapy followed by rituximab and plasmapheresis. © 2019, Springer Nature Switzerland AG.

Background: Fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis and was effective in experimental autoimmune neuritis in rats, a possible model for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to evaluate the efficacy of fingolimod in delaying disability progression in patients with CIDP who withdrew from currently effective treatments (intravenous immunoglobulin [IVIg] or corticosteroids). Methods: This double-blind, multicentre, randomised, placebo-controlled, parallel-group, event-driven study was done at 48 neurology centres in Australia, Canada, Israel, Japan, the USA, and nine countries in Europe. Participants with CIDP who were receiving IVIg or corticosteroids were randomly assigned (1:1) to once-daily oral fingolimod 0·5 mg or placebo. Owing to the event-driven design, treatment duration was flexible and could be up to 4·5 years. Randomisation was done with an automated interactive voice response-web response system and was stratified by Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale scores. Previous IVIg treatment was discontinued after one final course ending the day before the first dose of fingolimod or placebo was given, whereas corticosteroids were tapered off over 8 weeks after randomisation. The primary endpoint was time to first confirmed worsening (≥1 point increase on the adjusted INCAT disability scale score versus baseline) and was assessed in the full analysis set, which consisted of all patients who underwent randomisation and had at least one efficacy assessment for the primary analysis. The survival distribution functions of time to first worsening were estimated within each treatment group according to the Kaplan-Meier survival distribution function and compared with a stratified log-rank test. The trial is registered with ClinicalTrials.gov, number NCT01625182. Findings: Of 106 participants randomly assigned between Jan 24, 2013, and March 10, 2016, 54 received fingolimod (41 who had been receiving IVIg and 13 who had been receiving corticosteroids) and 52 received placebo (41 who had been receiving IVIg and 11 who had been receiving corticosteroids). The trial ended for futility as recommended by an independent data monitoring committee after an interim analysis when 44 confirmed worsening events had occurred. At the end of the study, the survival estimate of the proportion of participants free from confirmed worsening was not significantly different between the fingolimod group (42%, 95% CI 23–60) and the placebo group (43%, 28–59; p=0·91). Adverse events occurred in 41 (76%) participants receiving fingolimod and 44 (85%) on placebo, and serious adverse events occurred in nine (17%) and four (8%) patients, respectively. The most common adverse events with fingolimod were headache (12 [22%] patients), hypertension (ten [19%]), and extremity pain (seven [13%]). Adverse events leading to study discontinuation occurred in seven (13%) participants on fingolimod and none on placebo. Interpretation: Fingolimod 0·5 mg once-daily was not better than placebo for the treatment of CIDP. Future trial designs should take account of the possibility that if IVIg is stopped abruptly, some patients might relapse soon afterwards whereas others might remain in remission. Funding: Novartis Pharma. © 2018 Elsevier Ltd

Patients with advanced malignancies treated with immune checkpoint inhibitors are at increased risk for developing immune-related neurological complications. It is a phenomenon of immunological twist when immunotherapy against co-stimulatory molecules activates previously normal T cells to kill tumor cells but, in so doing, the T cells become unrestrained, triggering other autoimmune diseases for which conventional immunotherapy is needed. The most common autoimmune neurological diseases, usually occurring within 2–12 weeks after immune checkpoint inhibitor initiation, include: inflammatory myopathies, myasthenia gravis, acute and chronic demyelinating polyradiculoneuropathies, vasculitic neuropathies, isolated cranial neuropathies, aseptic meningitis, autoimmune encephalitis, multiple sclerosis and hypophysitis. The neurological events can evolve rapidly, necessitating the need for vigilance at all stages of treatment, even after completion, because early immunotherapeutic interventions are effective. The review addresses these complications and the applied therapies, discusses immune pathomechanisms including triggering preexisting autoimmunity, highlights the distinction between paraneoplastic and autoimmune etiologies, and identifies uncertainties regarding risk factors, use of immune checkpoint inhibitors in patients with known immune diseases or restarting therapy after a neurological event. Although the autoimmune neurological complications are not very common, their incidence will likely increase as the use of immune checkpoint inhibitors in metastatic cancer is growing rapidly. © The Author(s), 2018.

Background: Recent evidence suggests that patients with herpes simplex virus (HSV) encephalitis may relapse because of autoimmunity against the N-methyl-D-aspartate receptor (NMDAR). We present a case series of post-HSV relapsing encephalopathy associated with antibodies to central nervous system (CNS) synaptic antigens. Patient/Methods: Sera and cerebrospinal fluid (CSF) from five patients with HSV encephalitis who relapsed after antiviral therapy were tested for anti-NMDAR, gamma-aminobutyric acid b receptor (GABAbR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), Leucine-rich, glioma inactivated 1 (LGI1), anti -contactin-associated protein-like 2 (CASPR2) and dipeptidyl-peptidase-like protein-6 (DDPX) antibodies using cell-based assays. Results: Five patients (two infants, one child and two adults) developed post-HSV autoimmune encephalitis. The infants, aged 9 months and 10 months, after prompt and seemingly successful anti-HSV therapy, were readmitted with typical signs of NMDAR-encephalitis evolving within days, with NMDAR antibodies detected in both serum and CSF. Although they were promptly treated with intravenous immunoglobulin (IVIg) and with IVIg followed by rituximab, respectively, they were both left with psychomotor deficits. A 14-year-old girl with seizures due to HSV encephalitis improved with anti-HSV therapy. Later, she manifested intractable seizures and she was found positive for anti-NMDAR antibodies which persist. The two adults were women, aged 58 and 33 years. The first recovered after anti-HSV therapy and remained asymptomatic for 6 months, until she developed generalized seizures with persisting CSF anti-NMDAR antibodies; the second, who continued to be encephalopathic after 2 weeks of anti-HSV therapy, tested positive for anti-NMDAR antibodies in the serum and anti-GABAbR antibodies in the serum and CSF. She recovered fully following IVIg therapy but her serum anti-GABAbR antibodies persist 34 months later. Discussion: Infection of the CNS with HSV can trigger CNS autoimmunity associated not only with anti-NMDAR but also with anti-GABAbR antibodies. These antibodies can persist in the serum, even without associated symptoms, but their presence in the CSF is firmly associated with disease development. In contrast to children and adults who responded well to therapies, the infants had an incomplete recovery with severe psychomotor deficits probably due to the interference of anti-NMDAR antibodies with neuro-developmental processes. © The Author(s), 2018.

Anti-MAG demyelinating neuropathy is difficult to treat. All immunotherapies have failed except for rituximab, a chimeric B-cell-depleting monoclonal antibody against CD20, that helps up to 40% of patients based on 2 controlled and several uncontrolled series.1-3 Because the majority of these patients are left disabled, stronger anti-B-cell agents might be promising. © American Academy of Neurology.

Objective: In stiff person syndrome (SPS), an antibody-mediated impaired γ-aminobutyric acidergic (GABAergic) neurotransmission is believed to cause muscle stiffness and spasms. Most patients improve with GABA-enhancing drugs and intravenous immunoglobulin, but some respond poorly and remain disabled. The need for more effective therapy prompted a trial with the anti-CD20 monoclonal antibody rituximab. Methods: This was a placebo-controlled randomized trial of rituximab (2 biweekly infusions of 1g each). The primary outcome was a change in stiffness scores at 6 months. Secondary outcomes were changes in heightened-sensitivity and quality of life scores. Enrolling 24 patients was calculated to detect 50% change in stiffness scores. Results: Randomization was balanced for age, sex, disease duration, and glutamic acid decarboxylase autoantibody titers. No significant changes were noted at 6 months after treatment in all outcomes. Specifically, no differences were noted in the stiffness index, the primary outcome, or sensitivity scores, the secondary outcome, at 3 or 6 months. Quality of life scores improved significantly (p < 0.01) at 3 months in both groups, but not at 6 months, denoting an early placebo effect. Blinded self-assessment rating of the overall stiffness for individual patients revealed improvement in 4 patients in each group. At 6 months, improvement persisted in 1 patient in the placebo group versus 3 of 4 in the rituximab group, where these meaningful improvements were also captured by video recordings. Interpretation: This is the largest controlled trial conducted in SPS patients and demonstrates no statistically significant difference in the efficacy measures between rituximab and placebo. Rituximab's lack of efficacy could be due to a considerable placebo effect; insensitivity of scales to quantify stiffness, especially in the less severely affected patients; or drug effectiveness in only a small patient subset. Ann Neurol 2017;82:271–277. © 2017 American Neurological Association

Objective: To describe newly identified autoantibodies associated with cerebellar disorders. Design/Methods: We first screened the sera of 15 patients with cerebellar ataxia, without any known associated autoantibodies, with immunocytochemistry on mouse brain. After characterization and validation of a newly identified antibody, 85 additional patients with suspected autoimmune cerebellar disease were screened using a cell-based assay. Results: Immunoglobulin G from one of the first 15 patients demonstrated a distinct staining pattern on Purkinje neurons. This autoantibody, as characterized further by immunoprecipitation and mass spectrometry, was binding inositol 1,4,5-triphosphate receptor 1 (IP3R1), an intracellular channel that mediates the release of Ca2+ from intracellular stores. Anti-IP3R1 specificity was then validated with a cell-based assay. On this basis, screening of 85 other patients with cerebellar disease revealed 2 additional IP3R1-positive patients. All 3 patients presented with cerebellar ataxia; the first was eventually diagnosed with primary progressive multiple sclerosis, the second had a homozygous CAG insertion at the gene TBP, and the third was thought to have a neurodegenerative disease. Conclusions: We independently identified an autoantibody against IP3R1, a protein highly expressed in Purkinje neurons, confirming an earlier report. Because a mouse knockout model for IP3R1 exhibits ataxia and epilepsy, this autoantibody may have a functional role. The heterogeneity of the antibody-positive patients suggests that this antibody may either have a direct involvement in disease pathogenesis or it is a surrogate marker secondary to cerebellar injury. Anti-IP3R1 antibodies should be further explored in various ataxic and epileptic syndromes as they may denote a marker of response to immunotherapies. Copyright © 2016 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common and gratifying chronic autoimmune neuropathy because it is treatable in the majority of cases. 1 The demyelination is multifocal, accounting for the variable distribution of symptoms and signs, clinically expressed as CIDP variants. Although histologically the demyelination is associated with macrophages, complement-fixing immunoglobulin G (IgG) antibodies have been implicated for more than 30 years 2 but never clearly identified, probably because we had focused on compact myelin molecules as antigenic targets. © 2016 American Academy of Neurology.

Neurological involvement is relatively common in the majority of systemic autoimmune diseases and may lead to severe morbidity and mortality, if not promptly treated. Treatment options vary greatly, depending on the underlying systemic pathophysiology and the associated neurological symptoms. Selecting the appropriate therapeutic scheme is further complicated by the lack of definite therapeutic guidelines, the necessity to differentiate primary neurological syndromes from those related to the underlying systemic disease, and to sort out adverse neurological manifestations caused by immunosuppressants or the biological agents used to treat the primary disease. Immunotherapy is a sine qua non for treating most, if not all, neurological conditions presenting in the context of systemic autoimmunity. Specific agents include classical immune modulators such as corticosteroids, cyclophosphamide, intravenous immunoglobulin, and plasma exchange, as well as numerous biological therapies, for example anti-tumor necrosis factor agents and monoclonal antibodies that target various immune pathways such as B cells, cytokines, and co-stimulatory molecules. However, experience regarding the use of these agents in neurological complications of systemic diseases is mainly empirical or based on small uncontrolled studies and case series. The aim of this review is to present the state-of-the-art therapies applied in various neurological manifestations encountered in the context of systemic autoimmune diseases; evaluate all treatment options on the basis of existing guidelines; and compliment these data with our personal experience derived from a large number of patients. © 2015, The American Society for Experimental NeuroTherapeutics, Inc.