Autoimmune Movement Disorders.

OBJECTIVE: This article reviews the clinical and antibody spectrum of autoimmune cerebellar ataxia and other autoimmune movement disorders. It highlights characteristic phenotypes and red flags to the diagnosis and how these rare, but treatable, disorders are integrated into a differential diagnosis. LATEST DEVELOPMENTS: An increasing number of neuronal antibodies have been identified in patients with cerebellar ataxia, for example, against Kelch-like protein 11 (KLHL11), seizure-related 6 homolog-like 2, septin-3 and septin-5, or tripartite motif containing protein 9 (TRIM9), TRIM46, and TRIM67. Ig-like cell adhesion molecule 5 (IgLON5) antibody-associated syndromes have emerged as an important alternative diagnostic consideration to various neurodegenerative diseases such as Huntington disease or atypical parkinsonism. Opsoclonus-myoclonus syndrome emerged as the most relevant parainfectious movement disorder related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ESSENTIAL POINTS: Autoimmune cerebellar ataxia and other autoimmune movement disorders encompass a broad spectrum of different clinical syndromes, antibodies, and immunopathophysiologic mechanisms. Clinical acumen is key to identifying the cases that should undergo testing for neuronal antibodies. Given the overlap between phenotypes and antibodies, panel testing in serum and CSF is recommended.

Clinical spectrum and diagnostic pitfalls of neurologic syndromes with Ri antibodies.

OBJECTIVE: To describe the main syndrome and clinical course in a large cohort of patients with anti-Ri-associated paraneoplastic neurologic syndrome (Ri-PNS). METHODS: Twenty-year retrospective nationwide study and systematic review of the literature. RESULTS: Thirty-six patients with complete clinical information were identified (median age 66 years, range: 47-87 years). In this French cohort, the majority were women (78%). At onset, 4 main patterns were observed: cerebellar syndrome (39%), isolated tremor (24%), oculomotor disturbances (17%), and other symptoms (19%). Course was multistep for 78% of cases. At the time the disease reached the plateau phase (median 12 weeks, range: 1-64 weeks; 28% >3 months), 24 (67%) showed an overt cerebellar syndrome, which was isolated in 3 patients, and was most frequently (21/24 cases) part of a multisystem neurologic disease. Patients manifested a variety of movement disorders, including myoclonus (33%), dystonia (17%), either cervical or oromandibular, and parkinsonism (17%). Most patients had cancer (92%), mainly breast cancer (n = 22). Misdiagnoses concerned 22% of patients (n = 8) and included atypical parkinsonism (n = 2), MS (n = 2), Bickerstaff encephalitis (n = 1), hyperekplexia (n = 1), vestibular neuritis (n = 1), and functional neurologic disorder (n = 1). Survival at 12 months was 73% (95% CI [0.54-0.85]), at 24 months 62% (95% CI [0.41-0.78]), and at 36 months 47% (95% CI [0.25-0.65]). There was no major clinical difference between cases retrieved from the systematic review of the literature (n = 55) and the French cohort. CONCLUSIONS: Ri-PNS is a multisystem neurologic syndrome with prominent cerebellum/brainstem involvement. Opsoclonus-myoclonus is less common than expected, and the disorder can mimic neurodegenerative diseases.

Phosphodiesterase 10A IgG: A novel biomarker of paraneoplastic neurologic autoimmunity.

OBJECTIVE: To describe a novel antibody biomarker of neurologic paraneoplastic autoimmunity specific for phosphodiesterase 10A (PDE10A), a striatum-enriched phosphodiesterase, and to characterize the clinical phenotype of patients with PDE10A immunoglobulin G (IgG). METHODS: We describe 7 patients with autoantibodies specific for PDE10A identified in the Mayo Clinic Neuroimmunology Laboratory. Patient specimens (sera, 7; CSF, 4) produced identical basal ganglia-predominant synaptic staining of murine brain tissue by indirect immunofluorescence. The autoantigen was identified by immunoprecipitation and mass spectrometry as PDE10A, and confirmed by antigen-specific recombinant Western blot and cell-based assays, and immune absorption experiments. RESULTS: The median patient age was 70 years (range 66-76); 4 were men. Four patients with clinical information available had movement disorders (hyperkinetic in 3 [chorea, ballismus, dystonia] and parkinsonism in 1). All patients but one had cancer (lung [adenocarcinoma 1, squamous cell carcinoma 1, poorly differentiated mesenchymal carcinoma 1], renal adenocarcinoma 2, and pancreatic adenocarcinoma 1). Two of the 7 patients developed hyperkinetic movement disorders during treatment with immune checkpoint inhibitors (nivolumab and pembrolizumab), though none of 26 cancer control patients treated with immune checkpoint inhibitors harbored PDE10A IgG in their serum. MRIs from those 2 patients with hyperkinetic movement disorders demonstrated fluid-attenuated inversion recovery/T2 basal ganglia hyperintensities, and their CSF harbored unique oligoclonal bands. One of those 2 patients had substantial improvement after corticosteroids. One patient's renal adenocarcinoma expressed PDE10A by immunohistochemistry. CONCLUSIONS: PDE10A IgG defines a novel rare neurologic autoimmune syndrome and expands the spectrum of diagnosable paraneoplastic CNS disorders. The intracellular location of PDE10A suggests a T-cell-mediated pathology targeting cells displaying MHC1-bound PDE10A peptides.

Clinical characteristics of autoimmune GFAP astrocytopathy.

The clinical features of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy remain to be elucidated. We describe here the clinical features of 14 patients with GFAP astrocytopathy confirmed by detection of GFAP-IgG in cerebrospinal fluid (CSF). The novel findings of this study are as follows. First, over half of the patients presented with movement disorders (tremor, myoclonus, and ataxia), autonomic dysfunction (mainly urinary dysfunction), and hyponatremia. Second, most patients showed transient elevation of adenosine deaminase activity levels in CSF. Finally, some patients showed bilateral hyperintensities in the posterior part of the thalamus on brain magnetic resonance imaging.

The clinical features, underlying immunology, and treatment of autoantibody-mediated movement disorders.

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.

Autoimmune Movement Disorders.

Autoimmune movement disorders are rare but potentially treatable entities. They can present with an excess or paucity of movement and may have other associated neurological symptoms. These disorders were originally recognized by their classic clinical presentations and the cancers associated with them. Recent emphasis has been targeted on associated, and sometimes causative, antibodies. Although some disorders have stereotypical presentations, the spectrum of abnormalities reported in association with antibodies is widening. Determining whether antibodies are incidental or pathogenic and, hence, foregoing or commencing immunotherapy treatment can be challenging for practicing neurologists. Physicians often have to make the decision to empirically treat patients while awaiting test results. Due to the lack of randomized controlled trials, the ideal immunotherapy treatments and regimens are unknown. Patients with intracellularly targeted antibodies tend to fare less well, while those with extracellularly targeted antibody disorders often respond to treatments reducing antibody production. This review aims to summarize reported adult-onset autoimmune movement disorders to date, and to provide a template for the workup and treatment of suspected disorders. Rarer antibodies that are not yet fully characterized, or reported in a few cases only, will not be covered in detail as these are not likely to be readily commercially available. Childhood disorders will be only be mentioned briefly in the discussion, as there is a separate article in this issue on autoimmune neurologic diseases in children.

Paraneoplastic movement disorders.

Paraneoplastic movement disorders are rare, autoimmune-mediated, nonmetastatic complications of malignant neoplasms. Common paraneoplastic movement disorders include paraneoplastic chorea, dystonia, cerebellar degeneration, different types of encephalitis, opsoclonus-myoclonus syndrome, stiff person syndrome, and neuromyotonia. Syndromes usually develop before tumor diagnosis, have subacute onset, and are associated with serum or cerebrospinal fluid antibodies. Two types of antibodies can be distinguished: antibodies against nuclear and cytoplasmic neuronal antigens (anti-Hu, anti-Ri, anti-Yo, anti-Ma, anti-CV2/CRMP5, anti-Gephrin, and anti-GABATRAP) and antibodies recently identified against cell surface and synaptic proteins (anti-NMDAR, anti-LGI1, and anti-Caspr2). These two types differ from each other in a few important aspects. Antibodies against cell surface and synaptic protein disrupt cell-surface antigens. Clinical symptoms are related to the disruption of antigens and potentially can be reversed by immunotherapy. The association between these antibodies and malignancy is much less consistent. On the other hand, antibodies against nuclear and cytoplasmic neuronal antigens seem to be not pathogenic; however, they most likely indicate a T-cell-mediated immune response against neurons. Due to T-cell-mediated neuronal loss, response to immunotherapy is generally disappointing. Early recognition of all these diseases is crucial because it may lead to the disclosure of occult cancer. This review is focused on paraneoplastic movement disorders with emphasis on clinical presentations, investigational findings, and therapeutic results.

Principles and approaches to the treatment of immune-mediated movement disorders.

Immune mediated movement disorders include movement disorders in the context of autoimmune encephalitis such as anti-NMDAR encephalitis, post-infectious autoimmune movement disorders such as Sydenham chorea, paraneoplastic autoimmune movement disorders such as opsoclonus myoclonus ataxia syndrome, and infection triggered conditions such as paediatric acute neuropsychiatric syndrome. This review focuses on the approach to treatment of immune mediated movement disorders, which requires an understanding of the immunopathogenesis, whether the disease is destructive or 'altering', and the natural history of disease. Factors that can influence outcome include the severity of disease, the delay before starting therapy, use of multimodal therapy and whether the course is monophasic or relapsing. Although the four main conditions listed above have different pathophysiological processes, there are general themes that broadly apply including: early diagnosis and treatment is better, minimise the severity of disease, escalate treatment if the patient is not responding to initial treatments, and minimise relapse.

Clinical and immunological characteristics of the spectrum of GFAP autoimmunity: a case series of 22 patients.

OBJECTIVE: To report the clinical and immunological characteristics of 22 new patients with glial fibrillar acidic protein (GFAP) autoantibodies. METHODS: From January 2012 to March 2017, we recruited 451 patients with suspected neurological autoimmune disease at the Catholic University of Rome. Patients' serum and cerebrospinal fluid (CSF) samples were tested for neural autoantibodies by immunohistochemistry on mouse and rat brain sections, by cell-based assays (CBA) and immunoblot. GFAP autoantibodies were detected by immunohistochemistry and their specificity confirmed by CBA using cells expressing human GFAPα and GFAPδ proteins, by immunoblot and immunohistochemistry on GFAP-/- mouse brain sections. RESULTS: Serum and/or CSF IgG of 22/451 (5%) patients bound to human GFAP, of which 22/22 bound to GFAPα, 14/22 to both GFAPα and GFAPδ and none to the GFAPδ isoform only. The neurological presentation was: meningoencephalomyelitis or encephalitis in 10, movement disorder (choreoathetosis or myoclonus) in 3, anti-epileptic drugs (AED)-resistant epilepsy in 3, cerebellar ataxia in 3, myelitis in 2, optic neuritis in 1 patient. Coexisting neural autoantibodies were detected in five patients. Six patients had other autoimmune diseases. Tumours were found in 3/22 patients (breast carcinoma, 1; ovarian carcinoma, 1; thymoma, 1). Nineteen patients were treated with immunotherapy and 16 patients (84%) improved. Histopathology analysis of the leptomeningeal biopsy specimen from one patient revealed a mononuclear infiltrate with macrophages and CD8+ T cells. CONCLUSIONS: GFAP autoimmunity is not rare. The clinical spectrum encompasses meningoencephalitis, myelitis, movement disorders, epilepsy and cerebellar ataxia. Coexisting neurological and systemic autoimmunity are relatively common. Immunotherapy is beneficial in most cases.

Autoimmune Movement Disorders: a Clinical and Laboratory Approach.

Autoimmune movement disorders are caused by an aberrant immune response to neural self-antigens. These disorders may be paraneoplastic, parainfectious, or (most commonly) idiopathic. The neurological presentations are diverse, and sometimes multifocal. Movement disorders can occur as part of the spectrum with phenotypes including chorea, myoclonus, ataxia, CNS hyperexcitability (including stiff-person syndrome), dystonia, and parkinsonism. Symptoms are subacute in onset and may have a fluctuating course. The best characterized disorders are unified by neural autoantibodies identified in serum or cerebrospinal fluid. The antibody specificity may predict the association with cancer and the response to immunotherapy. In this article, we review autoimmune-mediated movement disorders, associated cancers, diagnosis, and treatment.

Autoimmune movement disorders.

Autoimmune movement disorders encapsulate a large and diverse group of neurologic disorders occurring either in isolation or accompanying more diffuse autoimmune encephalitic illnesses. The full range of movement phenomena has been described and, as they often occur in adults, many of the presentations can mimic neurodegenerative disorders, such as Huntington disease. Disorders may be ataxic, hypokinetic (parkinsonism), or hyperkinetic (myoclonus, chorea, tics, and other dyskinetic disorders). The autoantibody targets are diverse and include neuronal surface proteins such as leucine-rich, glioma-inactivated 1 (LGI1) and glycine receptors, as well as antibodies (such as intracellular antigens) that are markers of a central nervous system process mediated by CD8+ cytotoxic T cells. However, there are two conditions, stiff-person syndrome (also known as stiff-man syndrome) and progressive encephalomyelitis with rigidity and myoclonus (PERM), that are always autoimmune movement disorders. In some instances (such as Purkinje cell cytoplasmic antibody-1 (PCA-1) autoimmunity), antibodies detected in serum and cerebrospinal fluid can be indicative of a paraneoplastic cause, and may direct the cancer search. In other instances (such as 65kDa isoform of glutamic acid decarboxylase (GAD65) autoimmunity), a paraneoplastic cause is very unlikely, and early treatment with immunotherapy may promote improvement or recovery. Here we describe the different types of movement disorder and the clinical features and antibodies associated with them, and discuss treatment.

Reduced serum TNF alpha level in chronic schizophrenia patients with or without tardive dyskinesia.

BACKGROUND: Mounting evidences have demonstrated the association of altered immune factors with neurodevelopmental and pathological progression of schizophrenia. However, whether immune factors play any role in the pathogenesis of tardive dyskinesia (TD) has been underexplored. To our best knowledge, ours is among the piloting studies examining the association of TNF alpha with extrapyramidal symptoms of schizophrenic patients so far. OBJECTIVE: The aim of this study was to assess the clinical significance of serum TNF alpha level in chronic schizophrenia, especially its potential association with TD. METHODS: Serum TNF alpha level was measured in a sandwich enzyme-linked immunosorbent assay (ELISA) from 46 medicated chronic schizophrenia patients with TD, 43 chronic schizophrenia patients without TD, and 43 healthy control subjects. The symptoms of schizophrenia were assessed by the positive and negative syndrome scale (PANSS). RESULTS: Chronic patients both with TD and without TD had significantly lower serum level of TNF alpha than controls (TD=9.5±2.1pg/ml, non-TD=10.7±1.8pg/ml, control=37.8±3.4pg/ml, p<0.001). Compared to patients without TD, TD patients showed marginally significant reduction in the serum TNF alpha level (p=0.05). The reduced TNF alpha level was not significantly affected by daily dose or duration of antipsychotic drugs (p>0.05). Serum TNF alpha level was negatively correlated with the PANSS total score in the whole schizophrenia patients (p<0.01), but no significant association with TD severity was observed. CONCLUSIONS: Our results suggested that at chronic stage, serum TNF activity is associated with psychopathology of schizophrenia patients, but whether it can be a biomarker for TD needs further clarification in the future.

CCR2+ Ly6C(hi) inflammatory monocyte recruitment exacerbates acute disability following intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a devastating type of stroke that lacks a specific treatment. An intense immune response develops after ICH, which contributes to neuronal injury, disability, and death. However, the specific mediators of inflammation-induced injury remain unclear. The objective of the present study was to determine whether blood-derived CCR2+ Ly6C(hi) inflammatory monocytes contribute to disability. ICH was induced in mice and the resulting inflammatory response was quantified using flow cytometry, confocal microscopy, and neurobehavioral testing. Importantly, blood-derived monocytes were distinguished from resident microglia by differential CD45 staining and by using bone marrow chimeras with fluorescent leukocytes. After ICH, blood-derived CCR2+ Ly6C(hi) inflammatory monocytes trafficked into the brain, outnumbered other leukocytes, and produced tumor necrosis factor. Ccr2(-/-) mice, which have few circulating inflammatory monocytes, exhibited better motor function following ICH than control mice. Chimeric mice with wild-type CNS cells and Ccr2(-/-) hematopoietic cells also exhibited early improvement in motor function, as did wild-type mice after inflammatory monocyte depletion. These findings suggest that blood-derived inflammatory monocytes contribute to acute neurological disability. To determine the translational relevance of our experimental findings, we examined CCL2, the principle ligand for the CCR2 receptor, in ICH patients. Serum samples from 85 patients were collected prospectively at two hospitals. In patients, higher CCL2 levels at 24 h were independently associated with poor functional outcome at day 7 after adjusting for potential confounding variables. Together, these findings suggest that inflammatory monocytes worsen early disability after murine ICH and may represent a therapeutic target for patients.

Movement disorders in paraneoplastic and autoimmune disease.

PURPOSE OF REVIEW: The most relevant advances in immune-mediated movement disorders are described, with emphasis on the clinical--immunological associations, novel antigens, and treatment. RECENT FINDINGS: Many movement disorders previously considered idiopathic or degenerative are now recognized as immune-mediated. Some disorders are paraneoplastic, such as anti-CRMP5-associated chorea, anti-Ma2 hypokinesis and rigidity, anti-Yo cerebellar ataxia and tremor, and anti-Hu ataxia and pesudoathetosis. Other disorders such as Sydenham's chorea, or chorea related to systemic lupus erythematosus and antiphospholipid syndrome occur in association with multiple antibodies, are not paraneoplastic, and are triggered by molecular mimicry or unknown mechanisms. Recent studies have revealed a new category of disorders that can be paraneoplastic or not, and associate with antibodies against cell-surface or synaptic proteins. They include anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, which may cause dyskinesias, chorea, ballismus or dystonia (NMDAR antibodies), the spectrum of Stiff-person syndrome/muscle rigidity (glutamic acid decarboxylase, amphiphysin, GABA(A)-receptor-associated protein, or glycine receptor antibodies), neuromyotonia (Caspr2 antibodies), and opsoclonus--myoclonus--ataxia (unknown antigens). SUMMARY: Neurologists should be aware that many movement disorders are immune-mediated. Recognition of these disorders is important because it may lead to the diagnosis of an occult cancer, and a substantial number of patients, mainly those with antibodies to cell-surface or synaptic proteins, respond to immunotherapy.

Nigral neurodegeneration triggered by striatal AdIL-1 administration can be exacerbated by systemic IL-1 expression.

Neuroinflammation has been proposed as an important component of Parkinson's Disease (PD) aetiology and/or progression. However, the inflammatory components and the mechanisms underlying their effects are only partially known. By injecting an adenovirus expressing IL-1 in the striatum, we provoked progressive neurodegeneration of dopaminergic cells in the substantia nigra, motor symptoms and microglial activation. All these effects were attenuated by an anti-inflammatory treatment. Interestingly, peripheral inflammatory stimuli exacerbated IL-1beta induced neurodegeneration and the central inflammatory reaction. These data provide evidence that central, chronic IL-1beta expression can trigger and systemic IL-1beta exacerbate nigral neurodegeneration and highlight the functional relevance of this cytokine in PD.

Neuroprotective and anti-inflammatory activities of ketogenic diet on MPTP-induced neurotoxicity.

Ketogenic diet (KD) is a high-fat, low-protein and low-carbohydrate diet. It is reported that KD can provide the neuroprotection for the neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD) and amyotrophic lateral sclerosis. The main clinical symptom of PD is motor dysfunction derived from the loss of dopaminergic neurons in the substantia nigra (SN) and dopamine content in the striatum subsequently. It is well known that treatments with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice produce motor dysfunction, biochemical, and neurochemical changes remarkably similar to idiopathic PD patients. In this study, we investigated the neuroprotective and anti-inflammatory effects of KD in MPTP-treated mice. The data showed that pretreatment with KD alleviated the motor dysfunction induced by MPTP. The decrease of Nissl-staining and tyrosine hydroxylase (TH)-positive neurons induced by MPTP was inhibited in the SN. The change of dopamine was very similar to dopaminergic neurons in the SN. KD inhibited the activation of microglia induced by MPTP in the SN. The levels of proinflammatory cytokines (interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha) in the SN were also decreased and induced by MPTP. So, we concluded that KD was neuroprotective and anti-inflammatory against MPTP-neurotoxicity.

Skin denervation and cutaneous vasculitis in eosinophilia-associated neuropathy.

BACKGROUND: Eosinophilia is frequently associated with peripheral neuropathy, and neuropathic pain is a major presentation. Little is known about the involvement of sensory nerve terminals and the vasculature in the skin of patients with eosinophilia. OBJECTIVES: To investigate the skin innervation and the pathological abnormalities of the cutaneous vasculature and their clinical significance in eosinophilia-associated neuropathy. DESIGN: Case series. SETTING: National Taiwan University Hospital, Taipei, Taiwan. Patients Twelve patients with neuropathy and concomitant eosinophilia (with an eosinophilic ratio of white blood cell classification > 10% or absolute eosinophil count of > 1000/microL). INTERVENTIONS: Clinical assessments of neurological deficits, laboratory tests, nerve conduction studies, and a skin biopsy specimen 3 mm in diameter taken from the distal leg without active skin lesions. MAIN OUTCOME MEASURES: Quantitation of epidermal innervation, immunopathological findings of the cutaneous vasculature, and motor disability grade. RESULTS: Six patients fulfilled the criteria of Churg-Strauss syndrome, and the other 6 patients were categorized as having primary eosinophilia. All of the 12 patients had mononeuropathy multiplex or polyneuropathy with sensory symptoms as the initial manifestation. Intraepidermal nerve fiber densities were reduced in 10 patients (83.3%), being significantly lower than in the controls (mean +/- SD, 2.12 +/- 2.30 vs 10.56 +/- 3.69 fibers/mm, respectively; P < .001) and negatively correlated with the disability grade (P = .003). Nine patients (75.0%), including all of the 6 patients with Churg-Strauss syndrome, had cutaneous vasculitis, and two-thirds of the 9 patients had perivascular infiltration of eosinophils. CONCLUSION: Skin denervation with cutaneous vasculitis is a major manifestation of eosinophilia-associated neuropathy.