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The clinical features, underlying immunology, and treatment of autoantibody‐mediated movement disorders - Damato - 2018 - Movement Disorders - Wiley Online Library

ABSTRACT An increasing number of movement disorders are associated with autoantibodies. Many of these autoantibodies target the extracellular domain of neuronal surface proteins and associate with highly specific phenotypes, suggesting they have pathogenic potential. Below, we describe the phenotypes associated with some of these commoner autoantibody‐mediated movement disorders, and outline increasingly well‐established mechanisms of autoantibody pathogenicity which include antigen downregulation and complement fixation. Despite these advances, and the increasingly robust evidence for improved clinical outcomes with early escalation of immunotherapies, the underlying cellular immunology of these conditions has received little attention. Therefore, here, we outline the likely roles of T cells and B cells in the generation of autoantibodies, and reflect on how these may guide both current immunotherapy regimes and our future understanding of precision medicine in the field. In addition, we summarise potential mechanisms by which these peripherally‐driven immune responses may reach the central nervous system. We integrate this with the immunologically‐relevant clinical observations of preceding infections, tumours and human leucocyte antigen‐associations to provide an overview of the therapeutically‐relevant underlying adaptive immunology in the autoantibody‐mediated movement disorders. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. The spectrum of autoantibody‐mediated movement disorders includes a broad and clinically heterogeneous group of conditions. The movement disorders occur either in isolation or, more commonly, as prominent and often distinctive manifestations of autoimmune encephalitides. Patients typically present with a subacute onset and multifocal neurological features involving the cortex, basal ganglia, brain stem, and/or spinal cord (Table 1). Although formal epidemiological data are still emerging, it is clear that both sexes and patients of all ages can be affected by this spectrum of disorders. The detection of neuronal autoantibodies in serum and the CSF can help to guide the diagnostic process, prognosis, and the treatment of these disorders. In addition, the autoantibody specificity may predict an underlying tumour association (Table 1). Perhaps most important, many of these conditions respond to immunotherapies, making them one of the earliest therapeutic considerations in the correct clinical context.1-5 Antigen Movement disorders Additional features Tumour association Extracellular antigens NMDA receptor Orobuccolingual dyskinesia, catatonia, limb dystonia, stereotypies, chorea Amnesia, psychiatric features, seizures, dysautonomia, coma Ovarian teratoma (especially if > 18 years old) LGI1 Faciobrachial dystonic seizures, myoclonus, chorea, parkinsonism LE, hyponatremia Thymoma, SCLC CASPR2 Chorea, ataxia LE, Morvan's syndrome, neuromyotonia, neuropathic pain Thymoma GABAB receptor Ataxia, OMS, chorea LE SCLC GABAA receptor OMS, SPS, chorea Status epilepticus, LE Thymoma, SCLC mGluR1 Ataxia Seizures, cognitive impairment Hodgkin Lymphoma, renal cancer VGCC Ataxia Lambert‐Eaton syndrome SCLC DPPX PERM, OMS, tremor, ataxia Behaviour changes, cognitive decline, seizures, dysautonomia, diarrhoea, weight loss B cell neoplasms IgLON5 Chorea, parkinsonism, ataxia, limb stiffness, dystonia Non‐REM and REM‐sleep disorder, stridor, bulbar symptoms, cognitive impairment, eye movement abnormalities Not reported Glycine receptor SPSD Seizures, encephalopathy Thymoma, lymphoma, SCLC, breast cancer Dopamine 2 receptor Chorea, dystonia, parkinsonism, tics Psychiatric disturbances Not reported Neurexin‐3α Orofacial dyskinesias Confusion, seizures, decrease level of consciousness Not reported Intracellular antigens Amphiphysin SPSD SCLC, breast cancer GAD65 SPSD, ataxia LE, epilepsy Rare: thymoma, lymphoma, breast cancer, other CRMP5 Chorea, ataxia, OMS LE, encephalomyelitis, neuropathies SCLC, thymoma Ma2 OMS, parkinsonism LE, brain stem encephalopathy Testicular cancer Ri Jaw dystonia, ataxia, OMS, parkinsonism Brain stem encephalopathy SCLC, breast cancer Yo Ataxia Ovarian cancer, breast cancer Hu Ataxia LE, polyneuropathy, brainstem encephalopathy, pseudoathetosis SCLC Tr/DNER Ataxia Hodgkin Lymphoma GFAP Tremor, ataxia Encephalopathy, meningitis, myelopathy, seizures, dysautonomia, psychiatric Ovarian teratoma, prostate adenocarcinoma NMDA, N‐methyl‐d‐aspartate; LGI1, leucine‐rich glioma‐inactivated 1; CASPR2, contactin‐associated protein‐like 2; GABAA/B, gamma‐aminobutyric acid A/B; mGluR1, metabotropic glutamate receptor type 1; VGCC, voltage gated calcium channel; DPPX, dipeptidyl‐peptidase‐like protein‐6; GAD, glutamic acid decarboxylase; CRMP5, collapsin‐response mediated protein 5; GFAP, glial fibrillary acidic protein; SCLC, small cell lung cancer; LE, limbic encephalitis; SPS, stiff person syndrome; SPSD, stiff‐person syndrome spectrum disorder; PERM, progressive encephalomyelitis with rigidity and myoclonus; OMS, opsoclonus myoclonus syndrome; REM, rapid eye movement. The practical importance of both the antigenic specificity and the effects of immunotherapies make our understanding of the underlying immunopathology critical to managing patients with these conditions.4, 6-10 Therefore, in this review, we focus on the immunological mechanisms that are likely to initiate and propagate the diseases and outline roles for the autoantibody‐producing plasma cells, their precursor B cells, and Tcells. We also discuss the relevance of antigen‐drainage, tumors, the blood‐brain barrier and theprinciple pathogenic mechanisms by which the autoantibodies may induce disease at a molecular level(Figs. 1 and 2).1, 4, 6 This permits us to consider methods to tailor immunotherapies toward the underlying immunology. However, to ensure the accurate administration of immunotherapies, we describe these alongside the key clinical features that permit early recognition of immunotherapy‐responsive autoantibody‐mediated movement disorders.3, 5, 7 Throughout, we focus on the most common likely pathogenic autoantibodies and review those autoantibodies which potentially challenge the paradigm that targetting of surface epitopes implies causation. Inside or Outside the Plasma Membrane? Location Matters The major factor that governs the likely pathogenicity of an autoantibody response is whether it targets the intracellular versus extracellular domain of the autoantigen (Table 1 and Fig. 1). Autoantibodies directed against the extracellular domains of surface proteins (NSAbs; often termed neuroglial surface autoantibodies) are able to exert an effect on their target antigen in vivo and are therefore considered to have pathogenic potential. In contrast, autoantibodies that target intracellular antigens may never have the opportunity to bind their target.8-10 Many such autoantibodies (including Hu, Yo, Ri, CRMP5, and Ma2) are considered bystanders of an immunological process that is often mediated by pathogenic CD8 (cluster of differentiation) T cells.11, 12 These autoantibodies are frequently associated with tumors and are summarized in Table 1 and previous reviews.3, 13 Indeed, unlike NSAb‐related disorders,14 the passive transfer of intracellular‐directed autoantibodies to experimental animals has failed to reproduce features of the disease.15 Furthermore, it may be predicted that if driven by a dominant CD8 T cell response, the human disease should benefit from drugs directed to inhibit T cell function and, indeed, sirolimus has been shown to somewhat improve functional outcomes in these disorders that typically have a very poor prognosis.16 In addition, a hinterland category exists of antigens that may transiently reach the cell surface, such as those directed at the synaptic vescicle protein glutamic acid decarboxylase (GAD, Fig. 3). Here, exposure to the extracellular compartment may occur during vescicle fusion and potentially account for an effect on the intracellular antigenic target.8 Alternatively, they may represent an immune epiphenomenon that is sometimes detectable alongside, currently largely unidentified, coexistent NSAbs.17 In addition, antibodies to the voltage‐gated potassium channel complex that do not target leucine‐rich glioma‐inactivated‐1 (LGI1) or contactin‐associated protein‐like 2 (CASPR2) are directed against intracelluar epitopes and, associate with a broad, diverse, and seemingly unrelated set of neurological conditions.18 Therefore, these clinically‐irrelevant ‘double‐negative’ voltage gated potassium channel complex antibodies will not be discussed further herein. Treatment Principles Unlike most of those with solely intracellular‐directed autoantibodies, patients with NSAbs often show a good response to first‐line therapies such as corticosteroids, intravenous immunoglobulins, and plasma exchange.19-21 Patients with GAD antibodies can also show a response to many of these treatments, but overall this cohort is more refractory to available agents. However, in all patients, the upscaling of immunotherapies to second‐line treatments—such as cyclophosphamide and rituximab—should be instigated in those refractory to the first‐line therapies. This up‐titration should be quicker in patients whose disease is more severe, often within 2 weeks in N‐methyl‐d‐aspartate receptor (NMDAR)‐antibody encephalitis. Also, there are increasingly strong data to support the generic notion that early treatments improve clinical outcomes19, 21-25; hence, therapies should be ideally instigated on the basis of a clinical diagnosis while awaiting confirmatory serology. Therefore, in this review, we emphasize highly distinctive clinical features within the autoantibody‐associated movement disorders and use the aforementioned framework to reflect on the underlying mechanistic neuroimmunology as a basis to guide current and future immunotherapy options. The NSAb‐Mediated Syndromes and Their Related Immunology NMDAR Antibodies Clinical Features The discovery of autoantibodies against the GluN1 (NR1) subunit of the NMDAR identified a diffuse encephalitis with early psychiatric and cognitive features.19, 24-26 The associated characteristic hyperkinetic movement disorder is typically recognized after about 1 to 2 weeks, commonly involves the face, limbs, and trunk and has been variably described as dyskinetic orchoreoathetoid.24, 25, 27, 28 However, a recent study has suggested a more complex, combinatorial nomenclature may be most appropriate with expert raters noting the highly‐distinctive combination of dystonia, chorea and stereotypies with a paucity of tremor or myoclonus in many patients (Fig. 3C).29 Accompanying agitation may alternate with periods of catalepsy and catatonia and sometimes a hypokinetic phenotype can predominate, resembling endophenotypes of encephalitis lethargica.30 Treatment In NMDAR‐antibody encephalitis, around 50% of patients respond to first‐line medications, usually with a good recovery over several weeks to months.19, 24 However, in this condition, their use may be limited by agitation and behavioral difficulties. This is especially true of plasma exchange, which requires significant patient compliance. Hence, it is sometimes necessary to sedate patients to permit administration of these first‐line therapies. For patients who are refractory to these drugs, rituximab and/or cyclophosphamide are recommended second‐line options, and there are data to suggest that their administration is associated with improved outcomes.19, 22, 24, 25 Throughout, early removal of the ovarian teratoma should be a therapeutic goal. As recent laboratory observations may explain some of these clinical findings,31-33 we next discuss the immunology in the context of the therapeutic data. Immunology NMDAR‐antibody encephalitis is associated with 2 known immunological triggers: an ovarian teratoma and preceding herpes simplex virus encephalitis (HSVE). Although in patients with intracellular directed autoantibodies tumors are often malignant, the ovarian teratoma in patients with NMDAR antibodies is typically benign. The teratoma, seen in about 20% of adults and few children,24, 25, 30 is likely to be a site of immunization as it contains dense infiltrations of T cells and B cells31 and its removal can hasten recovery.19, 24 Indeed, a recent paper showed that lymphocytes—both B cells and plasma cells—within the teratoma have the capacity to produce NR1‐directed autoantibodies, and the cystic teratoma fluid contains higher levels of NMDAR‐antibodies than serum.31 By contrast, the mechanism of NMDAR‐antibody encephalitis post‐HSVE is less clear.34-36 Typically, this disorder begins around 4 to 8 weeks after onset of HSVE at a time where patients, mainly children, are improving from the HSVE. Children often present with prominent choreoathetosis, abnormal behavior, and cognitive impairment: this syndrome appears identical to a primary NMDAR‐antibody encephalitis and distinctive from a relapse of HSVE.37 In adults, a similar pathophysiological phenomenon is observed but is not associated with a clear clinical relapse, rather a prolonged cognitive syndrome associated with a lower rate of abnormal movements.38, 39 Mechanistically, the necrotic disease process of HSVE may release a variety of neuronal antigens, including neuronal surface proteins. This may be more prominent after HSVE and other viruses, by comparison to traumatic brain injury, stroke, or neurodegeneration40 due to the more inflammatory environment or direct effects of viruses on lymphocytes.41 Subsequently, released antigen may be soluble or taken up by antigen‐presenting cells that migrate to cervical lymph nodes, the secondary lymphoid organs known to drain CNS lymphatics.42 Presentation of this antigen to T cells can lead to consequent B cell activation and antibody production in lymph node germinal centres (Figure 2). Consistent with this interaction, interruption of germinal center reactions with ongoing T cell and B cell interactions may explain the benefits of early and rapidly escalated immunotherapies including corticosteroids, cyclophosphamide, and rituximab.19, 24, 25, 43 Indeed, circulating B cells from patients with NMDAR antibody encephalitis can produce NMDAR antibodies in vitro, especially under conditions that mimic T cell help.31 Methods to determine the degree and nature of T and B cell involvement may in future help predict the value of cell specific therapies: for example, the autoantibodies can be transiently removed with plasma exchange, B cells deleted with rituximab, and the T cells inhibited with drugs such as cyclophosphamide. In terms of autoantibody generation mechanisms, molecular mimicry between HSV‐associated antigens and the NMDAR seems unlikely as other CNS viruses, such as varicella zoster, have been shown to trigger NMDAR‐antibody encephalitis.44 By analogy, we have also observed NMDAR‐antibody encephalitis after other viral and idiopathic neurological inflammatory illnesses (Irani and Leite, 92). In addition, there is often the concomitant presence of other antigen‐specific NSAbs, such as those against the dopamine 2 receptor, gamma‐aminobutyric acid type A receptor (GABAAR) and other unknown targets, after HSVE.35, 45 Finally, no viral epitope has been reported with sequence homology to the NMDAR. Rather, this array of autoantibody specificities post‐HSVE is likely to reflect the concept of epitope spread, where, in an inflammatory milleu, there is a polyclonal immune response against a range of antigens exposed after a single inciting event. However, given that most patients have neither preceding HSVE nor a teratoma and this idiopathic group have the highest relapse rate,19, 24 the most common immunological triggers of this condition have clinical importance and await discovery. One such trigger may be genetic, perhaps a HLA predisposition, particularly given the known nonwhite racial bias of this condition.24, 46 By contrast to emerging data about the cellular immunology, the autoantibodies themselves have been relatively well characterized. Their principle mechanism of action appears to be the downregulation of surface NMDARs. This leads to a direct reduction infunctional NMDARs and, in addition, may have consequences for the stability and function of other neighboring synaptic and extrasynaptic proteins.25, 47 Furthermore, although the NMDAR antibodies are of the complement‐fixing IgG1 subclass, the available brain pathology does not show complement deposition.24, 48 Complement induction often causes tissue necrosis. Hence the absence of complement deposition, alongside established functional effects of the autoantibodies, may explain the substantial reversibility and limited atrophy observed in this condition after immunotherapy.19, 24, 25 LGI1 Antibodies Clinical Features Faciobrachial dystonic seizures (FBDS) are stereotyped, frequent, and brief dystonic movements consistently associated with LGI1 antbodies (see Supporting Information Video). They predominantly involve the arm and the ipsilateral face, and less commonly the leg or the trunk.20, 21, 49 As the attacks are rarely associated with disturbance of consciousness or ictal EEG changes, they may be considered to lie in a borderland between movement disorders and seizures.50 However, and consistent with seizures, FBDS can be preceded by sensory auras and automatisms, and both agitation and speech arrest are described during or after the episodes.20, 49 Nevertheless, the semiology of FBDS is very different to that of more typical frontal and temporal lobe epilepsies. The attacks show a limited response to antiepileptic drugs, and multimodal radiological involvement of the basal ganglia is frequently observed in patients with FBDS (Fig. 3A).20, 49, 51, 52 Therefore, the origin of FBDS, and their preferred classification as a movement disorder or an epilepsy, is still debated, but pragmatically FBDS certainly continue to present to movement disorder neurologists, amongst others. Importantly, although FBDS were originally observed in the context of marked cognitive impairment (as part of an “encephalitis”), several patients present with FBDS alone. Furthermore, the relatively dramatic response of FBDS to immunotherapies, and their onset preceding the development of cognitive impairment, led to the hypothesis that their effective cessation may prevent the occurrence of cognitive impairment associated with limbic encephalitis.20, 49 Indeed, in a recent cohort of 103 patients with FBDS, this appeared to be the case, with cognitive impairment appearing frequently, and almost exclusively, in patients with ongoing FBDS.21 This may also be true of other seizure semiologies in patients with LGI1‐antibodies, which are well‐recognised and also very frequent.53-55 Moreover, as generalized chorea can sometimes precede the onset of LGI1‐antibody encephalitis, perhaps a similar paradigm also operates in this clinical scenario.56, 57 Treatment Therefore, after a clinical diagnosis is made, and by analogy to NMDAR antibodies, early immunotherapy appears to be key to outcome optimization.21 Timing is especially critical in this condition as there has been a demonstrable reduction in the probability of seizure cessation with each day of delay to immunotherapy, and because the effective treatment of FBDS may prevent cognitive impairment. In this condition, there are surprisingly limited data to suggest a benefit of rituximab.58 However, to date, early treatment with rituximab has not been systematically reported, nor have studies using medications including cyclophosphamide or bortezomib. Immunology The highly consistent association between a distinctive clinical phenotype and the presence of LGI1 antibodies strongly suggests that they have a pathogenic role. This has been strengthened by in vitro data that implicate alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)‐receptors and potassium channels in the downstream mechanisms of LGI1‐modulation induced neuronal dysfunction.10, 59, 60 Other functional effects of the LGI1 autoantibodies include the downregulation of the LGI1 complex, which includes LGI1's natural binding partners a disintegrin and metalloproteinase domain‐containing protein 22 and 23 (ADAM22/23).21 In addition, and by contrast to the NMDAR‐directed antibodies, LGI1 antibodies are mainly of the IgG4 subclass.21, 61 However, the LGI1‐IgG1 antibodies appear to correlate with disease severity, perhaps as they have the potential to deposit complement in the brain, as observed from some postmortem tissues.21, 62 Although tumors and prodromal infections have not been consistently observed in patients with LGI1 antibodies, the recent description of an almost universal HLA‐DRB1*07:01 allele strongly implicates a role for T cells in disease pathogenesis.63, 64 These LGI1‐specific T cells are likely to interact with B cells in peripheral germinal centers. CASPR2 Antibodies Clinical Features Antibodies against the juxtaparanodal protein CASPR2 are associated with a variety of movement disorders including neuromyotonia, chorea, ataxia, and a syndrome of orthostatic myoclonus.3, 65 Many of these typically occur in the context of an encephalopathy that is similar to that associated with LGI1 antibodies. Indeed, although neuromyotonia is often thought to occur as an isolated phenomenon, it is intriguing that many patients have additional autonomic and CNS features, suggesting a frequently more diffuse neuronal disease process.66 Treatment The management of CASPR2‐antibody conditions has received little attention to date.67-69 Our experience suggests that the ataxia and encephalopathy are usually responsive to similar therapeutic approaches as for patients with LGI1‐antibody encephalitis (Irani, Jacob, & Leite, 2017). Immunology As with LGI1 antibodies, one plausible mechanism of CASPR2‐antibody‐induced hyperexcitability is interference with the tightly CASPR2‐complexed juxtaparanodal potassium channels.10 This mechanism has been suggested by human models of CASPR2 mutations and was recently confirmed in animals receiving CASPR2‐IgG.70 In terms of autoantibody generation, CASPR2 antibodies are often associated with a thymoma, particularly in patients with neuromyotonia and Morvan's syndrome,61 and this frequent clinical observation may implicate defective central tolerance checkpoints that permit autoreactive T cells to escape into the periphery and facilitate antigen‐specific autoimmunity. In addition, 50% of patients with CASPR2‐antibodies have a recently described HLA (human leucocyte antigen)‐DRB1*11:01 association, which contrasts to the HLA‐DRB1*07:01 allele observed in patients with LGI1‐antibodies.64 Aquaporin‐4 (AQP4) and Myelin Oligodendrocyte Glycoprotein (MOG) Antibodies Clinical Features Another distinctive paroxysmal phenomenon is the tonic spasms observed in neuromyelitis optica spectrum disorders (NMOSD). Tonic spasms occur more frequently in NMOSD than multiple sclerosis71 and consist of recurrent, painful, asymmetrical dystonic posturing, typically in one or more limbs, that usually last a few seconds to minutes and occur at high frequency.72 Occasionally, they can be preceded by a sensory aura and frequently they are triggered by hyperventilation, tactile stimuli, or voluntary movements. Typically, patients have a favorable course with a rapid response to anticonvulsant drugs. Patients with the more recently described MOG antibodies typically associate with phenotypes of optic neuritis, longitudinally extensive myelitis, and acute disseminated encephalomyelitis.73 Although the latter often shows basal ganglia and thalamic imaging changes, there are only rare descriptions of movement disorders in patients with MOG antibodies in addition to the few with ataxia.74 Treatment AQP4‐antibody‐mediated NMOSD is a chronic, naturally relapsing condition. Although immunotherapy efficacy has not been explored alongside a placebo arm, to date it appears that rituximab, azathioprine, and mycophenolate mofetil all reduce relapse rates by around 60% to 70%.75, 76 Furthermore, the avoidance of several agents with proven efficacy in multiple sclerosis is important in NMOSD as they can promote NMOSD relapses.77 The longer term treatment of MOG‐antibody‐mediated diseases has only recently been investigated, and it was revealed that a corticosteroid duration of less than 6 months is associated with a higher rate of relapses.73 Immunology The astrocytopathy associated with NMOSD is characterized by autoantibodies directed against AQP4, a water channel expressed on the astrocyte end‐foot processes. These autoantibodies can induce complement deposition, AQP4 internalization, and cointernalization of the glutamate transporter excitatory amino acid transporter‐2 (EAAT2).78 The deposition of complement is marked in tissue from patients with NMOSD and is a likely explanation as to why the relapses can produce severe disability. Indeed, a recent study using the monoclonal antibody eculizumab, which neutralizes the C5 complement component, has shown striking efficacy.79 By contrast to AQP4 antibodies, the initial pathology induced by MOG antibodies occurs on oligodendrocytes, and the downstream mechanisms are currently under active investigation. IgLON5‐Antibody Associated Neurodegeneration Clinical Features Patients with Iglon5‐autoantibodies mostly present with a chronic history of a rapid eye movement sleep behavior disorder with a distinctive non–rapid eye movement parasomnia plus bulbar involvement, dysautonomia, stridor, and hypoventilation.4 The main movement disorder described is chorea, but a few cases with postural instability and a supranuclear vertical gaze palsy had a phenotype resembling progressive supranucelar palsy (PSP), and the clinical spectrum continues to expand with the recent inclusion of myoclonus, myorhythmia, and dystonia.80, 81 Immunology IgLON family member 5 (IgLON5) antibodies are found in the serum and CSF of patients with postmortem evidence of a tauopathy. This finding highlights a novel relationship between autoimmune and degenerative disorders.81 IgLON5 antibodies bind the extracellular domain of their target neuronal protein and avidly label live neurons in culture. Furthermore, these patients have a consistent HLA‐DQB1*0501 and HLA‐DRB1*1001 genotype association. However, the phenotype and histology are highly suggestive of a neurodegenerative process. Brain pathology shows neuronal loss and extensive deposits of hyperphosphorylated tau protein predominantly in the hypothalamus and the brain stem tegmentum, with a different distribution from other tauopathies. Treatment Although initial reports described a universally poor outcome after immunotherapy, with death a common outcome,81, 82 more recent work reports a relatively frequent response to immunotherapies.80 It may be that earlier recognition of this condition portends a promising outcome with immunotherapies. In summary, this distinctive tauopathy is associated with NSAbs and a clear HLA association and may be a paradigm for the future study of the immune system leading to neurodegeneration. If so, it may yet be that all known NSAbs are pathogenic. Indeed, in the other NSAb‐associated diseases discussed previously, the autoantibodies are also very likely to be causative. Hence, knowledge of the location and subsets of B cells that produce these autoantibodies has biological and therapeutic relevance.31, 83 Therefore, next we use conventional immunological paradigms to help describe and model mechanisms of antigen‐specific autoantibody generation in these conditions and link these to current and future immunotherapies. The Therapeutically Relevant Immunology Identifying the autoantibody‐producing cells has important potential implications for considering future individualized therapies because, as shown in Figure 2, through the B cell lineage there are different sets of expressed surface markers. These markers alter as originally naïve B cells encounter T cell help and antigen, and differentiate into class‐switched IgG‐positive memory B cells.84, 85 Spatial requirements for these interactions are met in germinal centers, and this interaction involves a number of T and B cell molecules—both inhibitory and stimulatory—that regulate the intensity of this reaction.86 In humans, this balance is well exemplified by the appearance of autoantibody‐mediated neurology after administration of T cell–directed checkpoint inhibitors.87, 88 Therefore, even in the most well‐established NSAb‐mediated diseases, an isolated contribution of B cells is unlikely, and there should be more consideration given to therapies targeting both T cells and B cells. Successfully activated B cells will typically undergo successive rounds of interactions with antigen and T cells until they acquire high‐affinity antibodies. Subsequently, these activated B cells may differentiate into antibody secreting cells in circulation (plasmablasts), where importantly they downregulate CD20, the target of rituximab.89 The plasmablasts which reach bone marrow niches have also often downregulated CD19 and expressed CD138.90 One important question is the degree to which these now long‐lived bone marrow resident plasma cells produce the autoantibodies.85 If they are major producers of autoantibodies, patients should be sensitive to drugs such as bortezomib, which target the proteasome—an organelle that is highly active in plasma cells. Indeed, early observational studies suggest a possible, albeit limited, response to bortezomib.91 Conversely, rituximab should have little impact as these cells are CD20 negative. Yet there is evidence that several such syndromes can respond to CD20‐targeted medications.19, 76, 58 Therefore, further careful clinic‐immunological studies are required to highlight the relative roles of these therapies and their effect on B cell subsets and autoantibody levels: these will better inform our understanding of disease immunobiology.31-33, 83 It may be that combinations of plasma cell depleting agents plus removal of precursor B cells are required to effectively remove autoreactive capacities from the B cell lineage. However, it is not solely the lymphocyte surface markers that provide therapeutically tractable drug targets. There are increasing examples where pharmacological manipulation of the cytokine and chemokine signalling pathways produce therapeutic efficacy. For example, B cells and antibody‐secreting cells are known to show dependence on Interleukin 6 (IL‐6) for survival. Indeed, inhibition of the IL‐6 receptor with tociluzimab has some proven benefit in both NMOSD and NMDAR‐antibody encephalitis.93, 94 Perhaps this line of inquiry will generate further targets to which there are already available modulators. As causative autoantibodies are consistently, albeit not universally, found in the CSF, one possibility is disease initiation and propagation by a primary intrathecal response: a hypothesis that does not involve peripheral lymph nodes. This is strongly mitigated by the consistent observation of serum autoantibodies in all of these conditions, including NMDAR‐antibody encephalitis post‐HSVE, typically at concentrations far in excess of the CSF autoantibodies.1, 10, 24, 34, 95, 96 In addition, the universal observation of peripheral, likely immunizing, systemic tumors also mitigates this possibility. More plausible is the notion of an initiating peripheral immunization. Perhaps in a manner akin to HSVE, many CNS‐restricted antigens reach the periphery via CNS lymphatics and draining cervical lymph nodes (Fig. 2).42 The constitutive versus active nature of this drainage requires further investigation as it may determine the probability of a CNS lesion initiating a peripheral immunization. Subsequent to the immunization, at least some of the peripheral response must transfer to the CNS to mediate a brain disease. One outstanding question is whether this is principally mediated by migration of the B cells or the soluble antibodies across the blood‐brain or blood‐CSF barrier. This distinction may alter clinical management strategies; for example, natalizumab will block lymphocyte trafficking across the blood‐brain barrier. Several clues exist to help us understand the nature of the brain‐based immune response. Animal studies lend support to the intuitive notion that the brain‐expressed antigens can act as a “sink” for CNS‐transferred serum autoantibodies resulting in undetectable CSF autoantibody levels.97 Indeed, although CSF LGI1 antibodies are present in most patients, they are undetectable in some cases,96, 98 and this balance may represent a saturation point of the “sink.” By contrast, in patients with NMDAR‐antibody encephalitis, the presence of autoantibodies in CSF is a requirement for definitive diagnosis.99 However, serial measurements of CSF or serum autoantibody levels in all of these conditions only broadly correlate with clinical outcomes,19, 20, 100 and perhaps other, many as yet undetermined, factors including cytokines, complement and even other autoantibody reactivities,33 together contribute to the overall clinical status. In addition to diffusion alone, there is often marked intrathecal synthesis of the NMDAR antibodies and, indeed, NMDAR‐autoantibody secreting cells within the CNS have recently been isolated by single‐cell cloning techniques.33 Therefore, the intrathecal retention of antigen‐specific cells appears necessary for generation of NMDAR‐antibody encephalitis and may be mediated by the high CSF levels of the B cell and plasma cell chemokine (C‐X‐C motif) ligand 13 (CXCL13).32 These observations, coupled with the highly heterogeneous phenotypes of patients with NMDAR antibodies in serum but not CSF,40, 101, 102 may suggest that the predicted natural diffusion of NMDAR‐IgG into the CNS is insufficient to generate this encephalitis phenotype. Yet, maybe the soluble autoantibodies do play a role in ongoing disease as plasma immunoabsorption of IgG leads to a fall in CSF autoantibodies and correlates with improvements in clinical status.103 The relative contributions of serum autoantibody transfer into the CNS and the degree of immune cell infiltration may vary across diseases but also within diseases, and could determine the likelihood of amelioration with plasma exchange or predict the need for future intrathecal‐directed therapies. Autoantibodies Against Glutamic Acid Decarboxylase 65 (GAD65), an Intracellular Synaptic Protein: Syndromes, Immunology, and Treatments In contrast to the NSAb‐mediated disorders, those associated with autoantibodies directed against intracellular targets are generally considered nonpathogenic. Indeed, as discussed previously, passive transfer and active immunization experiments have proven that some of these autoantibodies do not cause neurological diseases.104 However, the spectrum of disorders associated with autoantibodies against GAD65 and amphiphysin may challenge this notion from clinical and laboratory perspectives.105, 106 Here, we discuss the GAD‐antibody syndromes, with prominent movement disorders, in greater detail. Clinical Features Antibodies against the intracellular enzyme GAD65 are very frequently detected in stiff person syndrome and related disorders (stiff person spectrum disorders [SPSD]). This group of disorders share the hallmark features of fluctuating muscle stiffness with superimposed spasms and hyperekplexia (an excessive startle response to acoustic or tactile stimuli).107 Classic stiff person syndrome involves stiffness of the lower back and proximal leg muscles with characteristic hyperlordotic posturing. In focal forms of SPSD, stiffness may be restricted to 1 limb (stiff limb syndrome).108 Other variants of SPSD are defined by the presence of additional neurological signs such as cerebellar ataxia. Progressive encephalomyelitis with rigidity and myoclonus typically designates the severe end of the spectrum, characterized by prominent hyperekplexia and myoclonus, generalized stiffness, brain stem signs, and dysautonomia.109 Immunology Including Coexistent NSAbs High concentrations of GAD65 antibodies associate with a limited set of clinically distinctive phenotypes, namely: SPSD, cerebellar ataxia, epilepsy and limbic encephalitis (Fig. 3B), suggesting some syndrome specificity.107, 110, 111 In addition, several patients with GAD65 antibodies do respond to immunotherapy. Also, by comparison to patients with Hu‐ or Ma2‐antibody‐associated encephalitis, patients with GAD65‐antibody encephalitis showed lower CD8/CD3 ratios, indicating an appropriate designation of GAD65 antibodies between other intracellular autoantibodies and NSAbs.62 These collective observations lead to the intriguing notion that GAD65 antibodies may have some causative potential. Indeed, the closely related amphiphysin antibodies, typically associated with paraneoplastic stiff person syndrome, have been shown to both reproduce disease upon transfer to experimental animals, and they may gain access to their intracellular antigenic target.8, 106, 112 Alternatively, maybe the GAD65 antibodies coexist with NSAbs that target the extracellular domains of antigens at GABAergic and glycinergic inhibitory synapses, such as the alpha 1 subunit of the glycine receptor (GlyRα1), and GABAAR.3, 105-107 Furthermore, another NSAb found in some SPSD patients is directedagainst dipeptidyl‐peptidase‐like protein‐6 (DPPX),113, 114 a regulatory subunit of Kv4.2 potassium channels. Perhaps these coexistent autoantibodies, often with antigens expressed in the same neurons, implicate epitope spread as a mechanism to diversify the polyclonal immune responses after a triggering event that exposes several antigens to the immune system. Indeed, it appears that these coexistent NSAbs confer even more disease specificity: for example, Glycine Receptor (GlyR) antibodies frequently associate with progressive encephalomyelitis with rigidity and myoclonus and DPPX antibodies with a distinct phenotype of truncal stiffness, prominent hyperekplexia, and cerebellar ataxia.113 Both GlyR and DPPX are surface expressed, and the respective NSAbs are likely to be pathogenic, with in vitro evidence they induce antigen internalization.109, 114 Treatment Consistent with the aforementioned paradigm of intracellular antibodies versus NSAbs, from patients with SPSD the treatment responses appear better in patients with GlyR antibodies than GAD65 antibodies alone.115 The treatment with the only proven randomized clinical data within the conditions discussed in this review is intravenous immunoglobulins in SPSD.116 Patients often show a moderate benefit from this drug, but longer term alternatives are yet to be satisfactorily explored. Future Directions Given that our understanding of the immunology underlying NSAb‐mediated diseases remains in its infancy, this appears to be an important avenue for future study. Available data have led researchers to consider drugs that appear biologically intuitive, but it is yet to be seen if we can achieve disease specificity. There are some potential reasons to maintain optimism in the potential for precision medicine. First, the generation of patient‐derived monoclonal antibodies in some of these conditions offers a method to directly out‐compete the endogenous patient antibodies.117 Of course, this comes with a series of potential immunological hazards, but it would form an elegant method to test the hypothesis of whether the antibodies are the major disease perpetrators. Other options in the pipeline include the use of selective cytokine and chemokine blockade. For example, in NMDAR‐antibody encephalitis, raised CSF levels of CXCL13 have been proposed as an intrathecal lymphocyte chemoattractant. Their neutralization may inhibit lymphocyte crossing. However, if this were effective, it may yet require a parallel peripheral depletion of B cells to adequately extinguish the disease. Indeed, this combinatorial approach may be a future theme in these increasingly complex diseases that require collaborations of at least T cells and B cells. One such vision may by combinatorial assessment of the autoantibody production from patient lymphocytes under a large number of cytokine conditions31, 83 and then block the dominant culprit pathways with targeted monoclonal therapies. Such an approach would be patient specific, especially if complemented by evaluation of endogenous cytokine levels, but if generic stimuli expanded these B cells, this approach may be intrinsically limited. Given recent advances in the clinical immunology,31, 83, 93 future studies should be able to answer these possibilities rapidly. Conclusions The increasing numbers of identified neuronal autoantibodies are associated with a broadening clinical spectrum of autoantibody‐mediated movement disorders. This contemporary expansion makes the field increasingly important for the movement disorder specialist and for the general neurologist. This is particularly the case given the recognition that early immunotherapy is likely to improve prognosis and prevent the ongoing pathogenic effects of the autoantibodies. However, to understand the root causes of these illnesses, the field requires an improved future understanding of the varied roles of immune components—including T cells, B cells, plasma cells—and their associated surface markers. Indeed, many of the conventional immunological paradigms as outlined require confirmation with the direct study of these diseases. In addition to biological insights, this may offer a method to specifically target causative cell types in these diseases. The relative roles of these different immune components may vary in conditions with intracellular versus surface autoantibodies and depend on the inciting factor in the autoantibody‐mediated conditions. Furthermore, the degree to which reduction in T cell function or autoantibody level is required to achieve clinical improvement should be considered as many of these autoantibodies can persist for years despite good clinical remission.20, 24, 118 Therefore, to move toward precision medicine in these conditions, there is an urgency to better appreciate the immunological mechanisms that underlie the generation and perpetuation of the autoantibodies, and this may lead to novel therapeutic strategies that could be addressed in clinical trials. Author Roles 1) Research project: A. Conception, B. Organization, C. Execution; 2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3) Manuscript: A. Writing of the first draft, B. Review and Critique. V.D.: 1A, 1B, 1C, 3A, 3B B.B.: 1A, 1B, 1C, 3A, 3B A.K.K.: 1B, 1C, 3B S.R.I.: 1A, 1B, 1C, 3A, 3B Full financial disclosure for the previous 12 months SRI is a coapplicant and receives royalties on patent application WO/2010/046716 (U.K. patent no., PCT/GB2009/051441) entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed to Euroimmun AG for the development of assays for LGI1 and other VGKC‐complex antibodies. Supporting Information References
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Call for Abstracts and Society Prize Submissions for the Anti-NMDA Receptor Encephalitis Foundation Prize 2022.

Call for Abstracts and Society Prize Submissions for the Anti-NMDA Receptor Encephalitis Foundation Prize 2022. | AntiNMDA | Scoop.it
Once again, the Canadian Neurological Sciences Federation (CNSF) is calling for submissions of Abstracts and Society prize submissions by or before 31 January 2022. The ...Read More...
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A video-based discussion of movement disorders in paediatric anti NMDAR encephalitis: A case series from Eastern India

A video-based discussion of movement disorders in paediatric anti NMDAR encephalitis: A case series from Eastern India | AntiNMDA | Scoop.it
MDs are a core feature of anti NMDAR encephalitis, particularly in the paediatric age group, understanding and characterization of which, is the key to early diagnosis and effective therapy.
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Autoimmune Encephalitis and Autoantibodies: A Review of Clinical Implications | The Journal of Applied Laboratory Medicine | Oxford Academic

Autoimmune Encephalitis and Autoantibodies: A Review of Clinical Implications | The Journal of Applied Laboratory Medicine | Oxford Academic | AntiNMDA | Scoop.it
AbstractBackground. Autoimmune encephalitis (AE) is a common cause of encephalitis.We review the most recent evidence on this neuroimmune condition and autoant...
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Clinical Sensitivity, Specificity, and Predictive Value of Neural Antibody Testing for Autoimmune Encephalitis | The Journal of Applied Laboratory Medicine | Oxford Academic

Clinical Sensitivity, Specificity, and Predictive Value of Neural Antibody Testing for Autoimmune Encephalitis | The Journal of Applied Laboratory Medicine | Oxford Academic | AntiNMDA | Scoop.it
A plethora of antibodies against neural antigens have emerged as biomarkers of autoimmune encephalitis.This has led to a rise in neural antibody testing among...
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The Spectrum of Movement Disorders in Anti-N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis Both in Children and Adults: An Experience From a Single Tertiary Care Center

The Spectrum of Movement Disorders in Anti-N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis Both in Children and Adults: An Experience From a Single Tertiary Care Center | AntiNMDA | Scoop.it
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a form of autoimmune encephalitis. The characteristic clinical features include seizure, psychosis-like symptoms, abnormal movements, and autonomic disturbances.
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Anti-NMDA Receptor Encephalitis Associated With an Ovarian T... : Journal of Psychiatric Practice®

Anti-NMDA Receptor Encephalitis Associated With an Ovarian T... : Journal of Psychiatric Practice® | AntiNMDA | Scoop.it
We report an unusual case of a 27-year-old previously healthy female who presented with a 15-day his...
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Anti-NMDA Receptor Encephalitis: A Challenge in Psychiatric... : Journal of Psychiatric Practice®

Anti-NMDA Receptor Encephalitis: A Challenge in Psychiatric... : Journal of Psychiatric Practice® | AntiNMDA | Scoop.it
Anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis is a condition that was only identified...
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Olfactory impairment in autoimmune encephalitis: another piece of the puzzle

Olfactory impairment in autoimmune encephalitis: another piece of the puzzle | AntiNMDA | Scoop.it
Background Despite being long neglected, olfaction has recently become a focus of intense research in neuroscience, as smell impairment has been consistently documented in both neurodegenerative and neuroinflammatory diseases.
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Residual symptoms and long-term outcomes after all-cause autoimmune encephalitis in adults - ScienceDirect

Residual symptoms and long-term outcomes after all-cause autoimmune encephalitis in adults - ScienceDirect | AntiNMDA | Scoop.it
To evaluate residual symptoms after all-cause autoimmune encephalitis in a real-life outpatient setting and compare long-term outcome measures. A seco…
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Anti-NMDAR Encephalitis in the Netherlands, Focusing on Late-Onset Patients and Antibody Test Accuracy | Neurology Neuroimmunology & Neuroinflammation

Anti-NMDAR Encephalitis in the Netherlands, Focusing on Late-Onset Patients and Antibody Test Accuracy | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
Except for the high frequency of patients in the age ≥45 years, our cohort showed no discrepancies compared with other NMDAR cohorts.2,4 A fifth of our patients would be considered late-onset anti-NMDAR encephalitis compared with only 5% in earlier reports.4 As the differential diagnosis in...
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Frontiers | Autoimmune Encephalitis in Long-Standing Schizophrenia: A Case Report | Neurology

Frontiers | Autoimmune Encephalitis in Long-Standing Schizophrenia: A Case Report | Neurology | AntiNMDA | Scoop.it
Anti-NMDA Antibody (Ab) mediated encephalitis is an autoimmune disorder involving the production of antibodies against NMDA receptors (NMDAR; N-Methyl-D-aspartate receptors) in the central nervous system (CNS) that leads to neurological or psychiatric dysfunction.
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Brain on fire: an imaging-based review of autoimmune encephalitis

Brain on fire: an imaging-based review of autoimmune encephalitis | AntiNMDA | Scoop.it
Autoimmune encephalitis represents an increasingly recognized group of immune-mediated
disorders the affect the central nervous system. The purpose of this article is to highlight the characteristic MR imaging findings associated with autoimmune encephalitis, describe the pathophysiology, review...
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Overlapping NMDA-R and GFAP Antibody Autoimmune Encephalitis After Nivolumab Therapy | Neurology Clinical Practice

Overlapping NMDA-R and GFAP Antibody Autoimmune Encephalitis After Nivolumab Therapy | Neurology Clinical Practice | AntiNMDA | Scoop.it
The differential diagnosis associated with acute encephalopathy is broad; however, given the increasing frequency with which immunotherapy is being used in the treatment of cancer, consider checkpoint inhibitor-induced autoimmune encephalitis in the appropriate clinical context.
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Frontiers | Case Report: Anti-LGI1 Encephalitis Following COVID-19 Vaccination | Immunology

Frontiers | Case Report: Anti-LGI1 Encephalitis Following COVID-19 Vaccination | Immunology | AntiNMDA | Scoop.it
Anti-leucine rich glioma inactivated 1 (LGI1) autoimmune encephalitis (AE) is characterized by cognitive impairment or rapid progressive dementia, psychiatric disorders, faciobrachial dystonic seizures (FBDS) and refractory hyponatremia.
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Clinical manifestations and immunomodulatory treatment experiences in psychiatric patients with suspected autoimmune encephalitis: a case series of 91 patients from Germany | Molecular Psychiatry

Clinical manifestations and immunomodulatory treatment experiences in psychiatric patients with suspected autoimmune encephalitis: a case series of 91 patients from Germany | Molecular Psychiatry | AntiNMDA | Scoop.it
Autoimmune encephalitis (AE) can rarely manifest as a predominantly psychiatric syndrome without overt neurological symptoms. This study’s aim was to characterize psychiatric patients with AE; therefore, anonymized data on patients with suspected AE with predominantly or isolated psychiatric...
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Clinical Significance of Delirium With Catatonic Signs in Patients With Neurological Disorders

Clinical Significance of Delirium With Catatonic Signs in Patients With Neurological Disorders | AntiNMDA | Scoop.it
Delirium is a common complication of neurological diseases, and it can coexist with catatonia. The recognition of catatonic delirium has clinical significance in terms of etiology, as it was significantly associated with viral and anti-NMDAR encephalitis.
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Pediatric anti-NMDA receptor encephalitis associated with COVID-19

Pediatric anti-NMDA receptor encephalitis associated with COVID-19 | AntiNMDA | Scoop.it
Anti-N-methyl-D-aspartate receptor encephalitis is a clinical condition characterized by acute behavioral and mood changes, abnormal movements, autonomic instability, seizures, and encephalopathy.We describe a 7-year-old boy diagnosed with autoimmune encephalitis due to NMDAR antibody in associatio...
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Herpes simplex virus–1 encephalitis can trigger anti-NMDA receptor encephalitis: Case report - PMC

Herpes simplex virus–1 encephalitis can trigger anti-NMDA receptor encephalitis: Case report - PMC | AntiNMDA | Scoop.it
Relapsing symptoms post herpes simplex virus 1 (HSV) encephalitis (HSVE) usually occur a few weeks after viral therapy and represent either 1) a true viral relapse of HSVE (CSF PCR positive for HSV, new necrotic lesions on brain MRI, and response to acyclovir ...
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Anti-NMDA Receptor Encephalitis Masquerades as Psychosis: A... : Journal of Psychiatric Practice®

Anti-NMDA Receptor Encephalitis Masquerades as Psychosis: A... : Journal of Psychiatric Practice® | AntiNMDA | Scoop.it
A 28-year-old male patient with an unclear history of psychosis was admitted to the inpatient psychi...
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Neuroleptic Malignant Syndrome in a Patient With Anti-N-Methyl-D-Aspartate Receptor Encephalitis: Case Report and Review of Related Literature

Neuroleptic Malignant Syndrome in a Patient With Anti-N-Methyl-D-Aspartate Receptor Encephalitis: Case Report and Review of Related Literature | AntiNMDA | Scoop.it
Anti- NMDAR encephalitis patients are at risk for NMS due to antipsychotic intolerance and other interrelated pathophysiological mechanisms. The overlap between the signs and symptoms of anti-NMDAR encephalitis and NMS poses a diagnostic dilemma and warrants a careful investigation and management.
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Acute Psychosis Due to Anti-N-Methyl D-Aspartate Receptor Encephalitis Following COVID-19 Vaccination: A Case Report

Acute Psychosis Due to Anti-N-Methyl D-Aspartate Receptor Encephalitis Following COVID-19 Vaccination: A Case Report | AntiNMDA | Scoop.it
Anti-N-methyl D-aspartate (NMDA) receptor (anti-NMDAR) encephalitis has been reported after SARS-CoV-2 infection, but not after SARS-CoV-2 vaccination.We report the first known case of anti-NMDAR encephalitis after SARS-CoV-2 immunization in a young female presenting with acute psychosis, highlight...
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Immunomodulation in the acute phase of autoimmune encephalitis - ScienceDirect

Immunomodulation in the acute phase of autoimmune encephalitis - ScienceDirect | AntiNMDA | Scoop.it
Autoimmune encephalitides constitute an emerging group of diseases for which the diagnosis and management may be challenging, and are usually associat…
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Sleep disturbances in patients with autoimmune encephalitis

Sleep disturbances in patients with autoimmune encephalitis | AntiNMDA | Scoop.it
To review sleep complaints reported in patients with autoimmune encephalitis, explore the relationship between sleep disturbances and subtypes of autoimmune encephalitis, and leverage knowledge concerning antibody-antigen specificity to inform the receptors, ...
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Frontiers | Clinical Characteristics and Follow-Up of Seizures in Children With Anti-NMDAR Encephalitis | Neurology

Frontiers | Clinical Characteristics and Follow-Up of Seizures in Children With Anti-NMDAR Encephalitis | Neurology | AntiNMDA | Scoop.it
Objective: To analyze the seizure characteristics of children with anti-NMDAR encephalitis.Methods: This was a retrospective analysis of 50 children with anti-NMDAR encephalitis between July 1, 2013, and July 1, 2019.Results: Fifty children with anti-NMDAR encephalitis were included in this study,...
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Evaluating cognitive outcomes in adult patients with acute encephalitis syndrome: a prospective study from a tertiary care center in Nepal

Introduction Acute encephalitis syndrome (AES) is clinically defined as acute onset of fever and change in mental status with or without new-onset seizures. The term AES was coined in 2008 by the World Health Organization to streamline the surveillance and research of AES in India. AES results from an inflammation of the brain parenchyma and can be caused by a broad range of etiologies, including infections, autoimmune conditions, and chemicals/toxins [1]. Most cases of AES are secondary to a viral infection, with herpes simplex virus (HSV) encephalitis being the leading cause internationally [2]. Though not common globally, Japanese encephalitis (JE) is the leading cause of AES in Asia [3]. Additional infectious etiologies include bacterial meningoencephalitis, tuberculous (TB) meningoencephalitis, enterovirus, adenovirus, scrub typhus, fungus, leptospirosis, neurobrucellosis, and toxoplasmosis [1,2,4]. The causative agents of AES vary with season, geographical location, immune status, and vaccination. A wide range of differential diagnoses in the face of rapid neurologic decline requires physicians to act quickly in AES cases. Shortening the time between diagnosis and treatment is crucial because delayed management can result in neurological sequelae, including long-term cognitive impairment, personality changes, hearing or vision defects, speech impairment, convulsions, motor-sensory deficits, and movement disorders [5-7]. Although cognitive impairment is a known complication of AES, few studies have evaluated cognitive outcomes in patients with encephalitis [8]. Our primary objective in this study was to assess the cognitive profiles of patients diagnosed with AES, with the goal of improving rehabilitation strategies and prognostic measures. Methods Participants This study was approved by the Institutional Review Committee at Tribhuvan University Institute of Medicine (458(6-11-E) 2/074/075) and conformed to the principles of the Declaration of Helsinki. Written informed consent was obtained from the patients, if possible, or their legal surrogates before enrollment. All subjects diagnosed with AES who fulfilled the inclusion criteria and were admitted to the neurology ward of Tribhuvan University Teaching Hospital (TUTH), Kathmandu, from June 20, 2018 to March 20, 2019 were enrolled. The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. Inclusion and criteria Adult patients with stable neurological and general health status with a clinical diagnosis of AES with or without comorbidities were included. AES was defined as acute onset fever with a change in mental status with or without new-onset seizures [1]. The following patients were excluded from our study: age less than 16 years or more than 75 years; patients with a neurological or psychiatric illness known to influence cognitive function; AES secondary to sepsis, cerebral malaria, typhoid toxemia, scrub typhus, leptospirosis, poisoning, malignancy, or electrolyte imbalance; and death during follow-up. Objectives The primary objective of this study was to evaluate the cognitive profiles of patients diagnosed with AES. Cognitive function in each patient was tracked using the Montreal Cognitive Assessment (MoCA) at admission, discharge, and 3-month follow-up [9]. If MoCA at admission could not be assessed due to core symptoms of AES (decreased level of consciousness, seizures, etc.), MoCA was administered after the patient’s general neurological status was improved and the patient was alert. MoCA is a rapid screening instrument for mild cognitive dysfunction. It assesses attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculation, and orientation. The time needed to administer the MoCA is approximately 10 minutes. The total possible score is 30 points; a score of 26 or above is considered normal [9]. Data collection All patients admitted to TUTH’s neurology department with a history of fever and altered sensorium or seizure were evaluated for this study. Final enrollment was done according to the inclusion and exclusion criteria. The initial investigations were complete blood count, random blood sugar, electrocardiogram, chest X-ray, renal function test, liver function test, erythrocyte sedimentation rate (ESR), C-reactive protein, hematocrit, and computed tomography or magnetic resonance imaging (MRI). Lumbar puncture was performed in all patients, and the opening pressure was measured using a manometer. A routine cerebrospinal fluid (CSF) investigation (total cell count, white blood cell differential, glucose, adenosine deaminase [ADA], and protein) was completed at the hospital-affiliated laboratory. Additional samples were preserved for specific work-up, such as CSF gram stain, culture, molecular testing by polymerase chain reaction (PCR), protein or antigen testing, venereal disease research laboratory (VDRL) testing, antibody or autoimmune panel tests, and electroencephalograms (EEGs), as deemed necessary. Patients were treated and admitted to the neurology ward or intensive care unit, depending on disease severity. Diagnostic criteria Five etiologies for AES were identified in our study; mycobacterium TB, HSV, bacterial infection, JE, and autoimmunity. Diagnoses were based on clinical features, CSF analyses, imaging results, and laboratory tests. The criteria for each etiology found in our study are as follows. Tuberculous meningoencephalitis TB meningoencephalitis was suspected when the clinical features of fever, night sweats, chronic cough, weight loss, altered sensorium, and past medical history of TB infection were present. Elevated lymphocytic-predominant pleocytosis, elevated protein and ADA levels, and low glucose levels in the CSF analysis were supportive of TB infection. In those cases, CSF was subjected to PCR to find TB, but TB treatment was still administered if the PCR test was negative but the other findings were highly suggestive of TB meningoencephalitis. Brain MRI, ESR, and the Mantoux test were also done to rule out contending diagnoses. Herpes simplex virus encephalitis This entity was confirmed when MRI findings showed limbic system hyperintensities and the CSF analysis revealed a viral picture. Additionally, PCR testing of the CSF was done to find HSV. EEG results that showed diffuse slowing, focal temporal changes, periodic complexes, and periodic lateralizing epileptiform discharges were considered supportive features. If a patient responded to an empiric trial of acyclovir, the diagnosis of HSV encephalitis was made. Bacterial meningoencephalitis This diagnosis was made via the CSF analysis, blood cultures, and the elimination of competing diagnoses with imaging and laboratory tests. The CSF opening pressure and chemistry analysis can vary depending on the infectious agent. Still, in general, an increased pressure, neutrophilic pleocytosis, and low glucose level were considered supportive of a nonviral infection. When deemed appropriate, CSF gram stain, bacterial, and fungal cultures, India ink stain, cryptococcal antigen testing, and VDRL testing were conducted. Positive results were considered diagnostic. Japanese encephalitis AES patients with lymphocytic pleocytosis, elevated protein, or a normal ratio of CSF to plasma glucose in their CSF analyses had their serum tested for JE virus immunoglobulin M antibodies. A positive serum JE antibody test was considered diagnostic. Theta and delta coma, burst suppression, and epileptiform activity on EEG were deemed to be supportive features. MRI findings of bilateral hyperintensities in the thalamus and substantia nigra aided in the diagnosis. Autoimmune encephalitis Results supporting a potential inflammatory origin for the disease were confirmed with specific CSF tests for autoimmune antibodies against the N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, gamma-aminobutyric acid receptor A and B, contactin-associated protein-like 2 protein, or leucine-rich glioma-inactivated 1 protein. Positive neuronal surface or synaptic protein autoantibodies were considered diagnostic for this etiology. Treatment TB meningoencephalitis was treated according to the National TB Management Guideline of Nepal [10]. Patients were given 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol followed by 7 to 10 months of isoniazid, rifampin, and ethambutol. Adjuvant dexamethasone was administered for up to 12 weeks. HSV encephalitis was treated with intravenous acyclovir at a dose of 10 mg/kg every 8 hours for 14 to 21 days. Bacterial meningoencephalitis was treated empirically using intravenous ceftriaxone and vancomycin. JE has no specific treatment; patients were hospitalized and provided with supportive care and close observation. All cases of autoimmune encephalitis were treated first with intravenous methylprednisolone. If the response was poor, patients were further treated with intravenous immunoglobulin or plasma exchange. Tumor surveillance was also done in all cases of autoimmune encephalitis. Statistical analysis We used IBM SPSS version 23.0 (IBM Corp, Armonk, NY, USA) to analyze the study data. Statistical analyses included the calculation of means, standard deviations, ranges, frequencies, and percentages. Independent sample t-testing was used to compare mean MoCA scores between male and female patients and between the 16-50 years age group and the 51-74 years age group. A one-way analysis of variance (ANOVA) test with the Bonferroni post hoc analysis was used to compare mean MoCA scores among the different etiologies. A comparison of mean MoCA scores at different times was made using a paired t-test. To identify a variable to predict the MoCA score at the 3-month follow-up, we used a linear regression analysis. The prerequisite for the linear regression model was a linear relationship, normality, minimal multicollinearity, and no autocorrelation or homoscedasticity. A two-tailed p-value of <0.05 was considered statistically significant. Results Demographics We enrolled 36 patients in our study (Figure 1). Fourteen patients (38.9%) were female, and 22 patients (61.1%) were male. Among the patients, 8.3% were aged 16 to 20 years, 61.1% were 21 to 50 years, and 30.6% were 51 to 74 years. The mean age of the participants in our study was 43 ± 18 years. Thirty-five patients (97.2%) were married. Thirty-one patients were Hindu (86.1%), two (5.6%) were Buddhist, two (5.6%) were Muslim, and one (2.8%) was Christian. Three patients (8.3%) were from province no. 1, 11 (30.6%) were from province no. 2, nine (25.0%) were from Baghmati province, three (8.3%) were from Gandaki province, six (16.7%) were from Lumbini province, one (2.8%) was from Karnali province, two (5.6%) were from Sudur Paschim province, and one (2.8%) was from Bihar, India. Background characteristics of included patients The background laboratory characteristics of our patients are provided in Table 1. CSF total cell count, protein level, ADA, ESR level, and Mantoux diameter were all highest in TB meningoencephalitis patients. CSF neutrophil counts and CSF sugar levels were highest in bacterial meningoencephalitis patients. CSF lymphocyte counts were highest in TB meningoencephalitis and HSV encephalitis patients. The various comorbidities present in our study population are listed in Table 2. Diagnoses Of our 36 patients with AES, TB meningoencephalitis was diagnosed in 14 cases (38.9%), HSV encephalitis in 14 (38.9%), bacterial meningoencephalitis in four (11.1%), autoimmune encephalitis in two (5.6%), and JE in two (5.6%) (Figure 1). Notably, the PCR results were positive in eight (57.1 %) of the 14 TB meningoencephalitis cases and 10 (71.4%) of the 14 HSV encephalitis cases. No specific organism could be cultured from two patients (50.0%) with bacterial meningoencephalitis, but the other two cases (50.0%) yielded Streptococcus pneumoniae. Both cases of autoimmune encephalitis were positive for NMDAR antibodies. The JE antibody test was positive in all cases of JE. Clinical features In our study, nine clinical features were charted for comparison among the etiologies; fever, headache, vomiting, convulsions, neck rigidity, Kernig’s and Brudzinski’s sign, photophobia, rash, and dystonia. The frequency of these features in each etiology is documented in Table 3. Fever and headache were seen in all 36 patients. Our study had only two cases of JE, and fever and headache were the only clinical features documented in those patients. Of the remaining clinical features, neck rigidity was seen in 14 patients with TB encephalitis (100%), 12 patients with HSV encephalitis (85.7%), and four patients with bacterial encephalitis (100%). Kernig’s and Brudzinski’s sign was most commonly seen in TB meningoencephalitis (10, 71.4%), although it was also present in patients with bacterial (2, 50.0%) and HSV (4, 29.0%) encephalitis. Photophobia was reported in half of TB (7, 50.0%), bacterial (2, 50.0%), and HSV (7, 50.0%) encephalitis cases. Neck rigidity, Kernig’s and Brudzinski’s sign, and photophobia were not reported by patients with autoimmune encephalitis. Vomiting was experienced by eight patients with HSV encephalitis (57.1%), seven with TB encephalitis (50.0%), two with bacterial encephalitis (50.0%), and one with autoimmune encephalitis (50.0%). Convulsions were also seen in patients with encephalitis of HSV (2, 14.3%), TB (1, 7.1%), and autoimmune (1, 50.0%) etiologies, but they were most common in cases of bacterial meningoencephalitis (4, 100%). JE was the only cause that presented without vomiting or convulsions. Rash was present in one patient with bacterial meningoencephalitis (25.0%), and dystonia was seen in one patient with autoimmune encephalitis (50.0%). Cognitive assessment The mean ± standard deviation values of the MoCA scores for various etiologies at different times are given in Table 4. MoCA at admission was highest in patients with bacterial meningoencephalitis. At discharge and follow-up, the MoCA scores were highest in HSV encephalitis and TB meningoencephalitis patients. We found statistically significant differences among the various etiologies in MoCA scores at admission, as determined by one-way ANOVA (F [4, 31] = 2.98, p = 0.034). To distinguish which etiological groups differed significantly from one another, a post hoc test was conducted. The Bonferroni post hoc test revealed that the MoCA score at admission was significantly lower in HSV encephalitis patients than in bacterial meningoencephalitis patients (mean difference, -6; standard error, 1.74; p = 0.017). One-way ANOVA showed no statistically significant differences among the etiologies in MoCA scores at discharge (F [4, 31] = 1.76, p = 0.16). Similarly, one-way ANOVA showed no differences among the etiologies in MoCA scores at the 3-month follow-up (F [4, 31] = 0.87, p = 0.493). We compared MoCA scores between the sexes and age groups. We found no difference in cognitive profile between the sexes (Table 5). MoCA at discharge and 3-month follow-up were significantly higher in the 16 to 50 years age group than in the 51 to 74 years age group (Table 5). Evolution of cognitive impairment For each AES etiology, we used paired t-testing to evaluate increases in the mean MoCA scores between admission and discharge and between admission and the 3-month follow-up (Table 6). Among TB and HSV encephalitis patients, MoCA scores increased significantly at discharge and 3-month follow-up, compared with admission. In bacterial encephalitis, autoimmune encephalitis, and JE, the scores did not increase substantially from admission to discharge or 3-month follow-up. Predictor of MoCA score at the 3-month follow-up A linear regression analysis was performed to find a predictor of the 3-month follow-up MoCA scores. We found that, holding all other variables constant, every unit increase in the MoCA score at discharge predicted a 0.96 unit increase in the MoCA score at the 3-month follow-up (p < 0.0001). The R2 value was 97.8%, indicating the excellent quality of this predictor (Table 7). Discussion Disorders that affect the brain, activate the immune system and cause brain inflammation lead to the clinical presentation of AES. AES is a common neurological disorder with an estimated incidence of 1.5 to 7 cases/100,000 inhabitants/year, excluding epidemics [11]. Though encephalitis is a broad diagnosis with a vast range of known pathologies, roughly half of cases arise from an unknown etiology [11]. HSV encephalitis is the most common cause of AES worldwide and is responsible for 14% of the 20,258 AES patients admitted annually to hospitals in the United States [12]. We found that HSV encephalitis and TB encephalitis were equally common in Nepal, which contrasts with studies from other nations. Because Nepal is a low-income country, many Nepalis live with unsuitable housing, overcrowding, and inadequate sanitation, which foster the transmission of agents such as TB. Additionally, the problem of drug-resistant TB is magnified by inappropriate antibiotic use, non-adherence to TB regimens, and poor diagnostic facilities [13,14]. After TB and HSV, bacterial encephalitis was the third most common etiology in our study. We also had two cases of autoimmune encephalitis and two cases of JE in our study population. JE is a significant public health problem in Asia, accounting for 50,000 cases and 15,000 deaths annually in the region [3]. Although Nepal lies in an area with endemic JE, its prevalence was low in our study. It is principally considered a disease of children; therefore, our rate might have been low because we excluded patients younger than 16 years [3]. Furthermore, JE outbreaks occur most commonly in the monsoon season, especially in the Terai belt of Nepal, and most cases are managed in local districts or provincial hospitals [15]. The Kathmandu Valley lies in the hill belt of Nepal, with minimal mosquito transmission and thus low disease activity. Only complicated cases from the Terai belt are referred to Kathmandu Valley, and our low proportion of JE cases likely reflects those facts. Our study population contained 14 female and 22 male patients, which is in accordance with the proportions reported in other studies [7-10] and suggests that AES is more common in males. Increased outdoor activity, contact exposure, and stress are potential explanations for this discrepancy. Another reason might be social stigma or low health-seeking behavior among women, leading to a falsely reduced presentation rate in this population. The current literature has reported age, sex, and level of education to be the factors most predictive of a patient’s MoCA score [16,17]. Higher levels of education and female sex have been associated with higher scores, and older age is associated with lower scores [16]. Although the cognitive profiles of male and female patients in our study did not differ significantly from each other, we found that MoCA scores at discharge and the 3-month follow-up were significantly higher in patients aged 16 to 50 years than in those aged 51 to 74 years. Several variables could be responsible for that finding. MoCA examinations were not conducted before AES onset, so we cannot establish how well the follow-up scores reflect each age group's baseline function. Cognitive impairment is more common among older people and could therefore be a contributing factor to the lower scores in the group of 51- to 74-year-old patients. Additionally, the MoCA assessment has been validated for the detection of cognitive impairment only in individuals aged 55 to 85 years, which could have resulted in less accurate analysis of our younger patients’ cognition [9]. Although no difference was seen between male and female patients in our study, normative data from a large population-based cohort found the effect sizes of age and education on MoCA scores to be twice that of sex [9]. Because women are less likely than men to receive formal education in Nepal, the educational difference might have contributed to the lack of significance we found between the sexes. We observed that among TB and HSV patients, the MoCA score increased significantly at discharge and the 3-month follow-up compared with admission. Specific treatments available for TB meningoencephalitis and HSV encephalitis could be related to that improvement [1,18]. Among bacterial encephalitis patients, the MoCA score at admission did not increase significantly at discharge or 3-month follow-up. Bacterial meningoencephalitis is associated with a fulminant course, contributing to poor cognitive function among its patients. Additionally, the growth of bacteria from CSF cultures is often difficult, making empiric treatment, which might not always be effective, common in these cases [19]. In patients with autoimmune encephalitis, MoCA scores at admission did not increase significantly at discharge or 3-month follow-up. In low-income countries where infectious etiologies are common, work-up and treatment for autoimmune encephalopathies occur later in the clinical timeline. Significant diagnostic delay is therefore expected in cases of autoimmune encephalitis. Autoimmune encephalitis is treated with nonspecific modalities, including corticosteroid regimens, that are not always adequate to prevent relapse and neurological sequelae. Intravenous immunoglobulin, plasma exchange, and second-line drugs such as rituximab are not readily available or affordable in low-income countries [20]. JE patients face a similar situation of nonspecific treatment guided mainly by symptom management. A minimal, nonsignificant increase in MoCA scores at discharge and 3-month follow-up was seen in these two populations [5,7]. The research on cognitive impairment in encephalitis is scant. Hébert et al. [21] observed that 52% of 21 individuals with autoimmune encephalitis showed persistent cognitive impairment at their last follow-up (median of 20 months). Visuospatial and executive abilities, language, attention, and delayed recall were predominantly affected. They also discovered that shorter treatment delays and no status epilepticus at onset were linked to greater MoCA scores more than a year later, possibly predicting better long-term cognitive results. A study by Hang et al. [22] reported that 90.48% of 21 autoimmune encephalitis patients experienced short-term memory loss. After therapy, it dropped to 14.29%. A MoCA-B score 6.19 points higher than the onset score was observed at the 1-year follow-up (p < 0.001). Three studies have considered the cognitive outcomes of TB meningitis patients. Ganaraja et al. [23] found that TB meningitis patients had impaired results in auditory verbal learning (88.3%), complex figure (50%), spatial span (50%), clock drawing (48.3%), digit span (35%), color trail 1 and 2 (30% and 33.3%, respectively), and animal naming (28.3%) tests. Treatment improved the animal naming, clock drawing, color trail 2, spatial span, and digit span test results. Verbal learning showed no change. Overall, neuropsychological testing revealed improved attention, working memory, and category fluency but minimal language learning recovery [23]. In two other cohort studies from India (n = 30 and 65, respectively), patients were evaluated using the 30-point Mini-Mental State Exam 6 months [24] and 1 year [25] after their TB meningitis diagnoses. Using cutoff scores of 22 to 29, depending on education level, more than half of the patients tested (54% and 55%, respectively) sustained cognitive impairments. Our study has several limitations. First, the sample size was small. Second, individual cognitive domains in the MoCA tool were not evaluated or analyzed. Third, some patients were illiterate, which rendered cognitive testing with the MoCA difficult. The MoCA test was modified to suit our study’s Nepalese context, which could have resulted in bias. Fourth, we acknowledge that 3 months is too short a period to fully evaluate cognitive outcomes after AES. Fifth, our sample contained only a few JE patients, even though JE is one of the commonest causes of AES in this part of the world. In conclusion, we found that AES patients with low cognitive function can improve with active treatment. At discharge and follow-up, AES patients with treatable causes such as TB meningoencephalitis and HSV encephalitis saw statistically significant improvements in their cognitive functioning. Although infectious etiologies are most common in low-income countries such as Nepal, autoimmune etiologies should not be overlooked. Early testing for autoantibodies could reduce cognitive sequelae by offering timely diagnosis and treatment. Continued research is warranted to improve the early diagnosis of AES and understanding of the cognitive sequelae that can follow.
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