Brain Sciences

Editorial

6 pages, 236 KiB

Open AccessEditorial

Recent Advances in Immune-Mediated Cerebellar Ataxias: Pathogenesis, Diagnostic Approaches, Therapies, and Future Challenges—Editorial

by Mario Manto and Hiroshi Mitoma

Brain Sci. 2023, 13(12), 1626; https://doi.org/10.3390/brainsci13121626 - 24 Nov 2023

Cited by 1 | Viewed by 1108

Abstract

The clinical category of immune-mediated cerebellar ataxias (IMCAs) has been established after 3 decades of clinical and experimental research. The cerebellum is particularly enriched in antigens (ion channels and related proteins, synaptic adhesion/organizing proteins, transmitter receptors, glial cells) and is vulnerable to immune [...] Read more.

The clinical category of immune-mediated cerebellar ataxias (IMCAs) has been established after 3 decades of clinical and experimental research. The cerebellum is particularly enriched in antigens (ion channels and related proteins, synaptic adhesion/organizing proteins, transmitter receptors, glial cells) and is vulnerable to immune attacks. IMCAs include various disorders, including gluten ataxia (GA), post-infectious cerebellitis (PIC), Miller Fisher syndrome (MFS), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), and anti-GAD ataxia. Other disorders such as multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), Behçet disease, and collagen vascular disorders may also present with cerebellar symptoms when lesions are localized to cerebellar pathways. The triggers of autoimmunity are established in GA (gluten sensitivity), PIC and MFS (infections), PCD (malignancy), and OMS (infections or malignant tumors). Patients whose clinical profiles do not match those of classic types of IMCAs are now included in the spectrum of primary autoimmune cerebellar ataxia (PACA). Recent remarkable progress has clarified various characteristics of these etiologies and therapeutic strategies in terms of immunotherapies. However, it still remains to be elucidated as to how immune tolerance is broken, leading to autoimmune insults of the cerebellum, and the consecutive sequence of events occurring during cerebellar damage caused by antibody- or cell-mediated mechanisms. Antibodies may specifically target the cerebellar circuitry and impair synaptic mechanisms (synaptopathies). The present Special Issue aims to illuminate what is solved and what is unsolved in clinical practice and the pathophysiology of IMCAs. Immune ataxias now represent a genuine category of immune insults to the central nervous system (CNS). Full article

(This article belongs to the Special Issue Recent Advances in Immune-Mediated Cerebellar Ataxias: Pathogenesis, Diagnostic Approaches, Therapies, and Future Challenges)

Research

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11 pages, 1463 KiB

Open AccessArticle

Characteristics of Movement Disorders in Patients with Autoimmune GFAP Astrocytopathy

by Akio Kimura, Akira Takekoshi and Takayoshi Shimohata

Brain Sci. 2022, 12(4), 462; https://doi.org/10.3390/brainsci12040462 - 29 Mar 2022

Cited by 11 | Viewed by 3542

Abstract

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A) is a type of autoimmune corticosteroid-responsive meningoencephalitis that occurs with or without myelitis. Movement disorders have been reported in GFAP-A patients but have not been characterized. In this study, we examined the characteristics of movement [...] Read more.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A) is a type of autoimmune corticosteroid-responsive meningoencephalitis that occurs with or without myelitis. Movement disorders have been reported in GFAP-A patients but have not been characterized. In this study, we examined the characteristics of movement disorders in GFAP-A patients. We retrospectively reviewed clinical data from 87 consecutive patients with GFAP-A attending Gifu University Hospital in Japan. We compared the demographics, clinical features, cerebrospinal fluid characteristics, and neuroimaging findings from patients with and without movement disorders. Seventy-four patients (85%) had movement disorders, including ataxia (49%), tremor (45%), myoclonus (37%), dyskinesia (2%), opsoclonus (2%), rigidity (2%), myokymia (1%), and choreoathetosis (1%). GFAP-A patients with movement disorders were significantly older than those without. Movement disorders are therefore common in GFAP-A patients, and the main types of movement disorders observed in this population were ataxia, tremor, and myoclonus. These abnormal movements can serve as clinical features that facilitate the early diagnosis of GFAP-A. Elderly GFAP-A patients are more likely to have movement disorder complications than younger patients. Full article

(This article belongs to the Special Issue Recent Advances in Immune-Mediated Cerebellar Ataxias: Pathogenesis, Diagnostic Approaches, Therapies, and Future Challenges)

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Review

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17 pages, 930 KiB

Open AccessFeature PaperReview

Rare Etiologies in Immune-Mediated Cerebellar Ataxias: Diagnostic Challenges

by Marios Hadjivassiliou, Mario Manto and Hiroshi Mitoma

Brain Sci. 2022, 12(9), 1165; https://doi.org/10.3390/brainsci12091165 - 30 Aug 2022

Cited by 6 | Viewed by 2779

Abstract

The cerebellum is particularly enriched in antigens and represents a vulnerable target to immune attacks. Immune-mediated cerebellar ataxias (IMCAs) have diverse etiologies, such as gluten ataxia (GA), post-infectious cerebellitis (PIC), Miller Fisher syndrome (MFS), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), and [...] Read more.

The cerebellum is particularly enriched in antigens and represents a vulnerable target to immune attacks. Immune-mediated cerebellar ataxias (IMCAs) have diverse etiologies, such as gluten ataxia (GA), post-infectious cerebellitis (PIC), Miller Fisher syndrome (MFS), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), and anti-GAD ataxia. Apart from these well-established entities, cerebellar ataxia (CA) occurs also in association with autoimmunity against ion channels and related proteins, synaptic adhesion/organizing proteins, transmitter receptors, glial cells, as well as the brainstem antigens. Most of these conditions manifest diverse neurological clinical features, with CAs being one of the main clinical phenotypes. The term primary autoimmune cerebellar ataxia (PACA) refers to ataxic conditions suspected to be autoimmune even in the absence of specific well-characterized pathogenic antibody markers. We review advances in the field of IMCAs and propose a clinical approach for the understanding and diagnosis of IMCAs, focusing on rare etiologies which are likely underdiagnosed. The frontiers of PACA are discussed. The identification of rare immune ataxias is of importance since they are potentially treatable and may lead to a severe clinical syndrome in absence of early therapy. Full article

(This article belongs to the Special Issue Recent Advances in Immune-Mediated Cerebellar Ataxias: Pathogenesis, Diagnostic Approaches, Therapies, and Future Challenges)

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24 pages, 8707 KiB

Open AccessReview

Acute Cerebellar Inflammation and Related Ataxia: Mechanisms and Pathophysiology

by Md. Sorwer Alam Parvez and Gen Ohtsuki

Brain Sci. 2022, 12(3), 367; https://doi.org/10.3390/brainsci12030367 - 10 Mar 2022

Cited by 11 | Viewed by 8219

Abstract

The cerebellum governs motor coordination and motor learning. Infection with external microorganisms, such as viruses, bacteria, and fungi, induces the release and production of inflammatory mediators, which drive acute cerebellar inflammation. The clinical observation of acute cerebellitis is associated with the emergence of [...] Read more.

The cerebellum governs motor coordination and motor learning. Infection with external microorganisms, such as viruses, bacteria, and fungi, induces the release and production of inflammatory mediators, which drive acute cerebellar inflammation. The clinical observation of acute cerebellitis is associated with the emergence of cerebellar ataxia. In our animal model of the acute inflammation of the cerebellar cortex, animals did not show any ataxia but hyperexcitability in the cerebellar cortex and depression-like behaviors. In contrast, animal models with neurodegeneration of the cerebellar Purkinje cells and hypoexcitability of the neurons show cerebellar ataxia. The suppression of the Ca²⁺-activated K⁺ channels in vivo is associated with a type of ataxia. Therefore, there is a gap in our interpretation between the very early phase of cerebellar inflammation and the emergence of cerebellar ataxia. In this review, we discuss the hypothesized scenario concerning the emergence of cerebellar ataxia. First, compared with genetically induced cerebellar ataxias, we introduce infection and inflammation in the cerebellum via aberrant immunity and glial responses. Especially, we focus on infections with cytomegalovirus, influenza virus, dengue virus, and SARS-CoV-2, potential relevance to mitochondrial DNA, and autoimmunity in infection. Second, we review neurophysiological modulation (intrinsic excitability, excitatory, and inhibitory synaptic transmission) by inflammatory mediators and aberrant immunity. Next, we discuss the cerebellar circuit dysfunction (presumably, via maintaining the homeostatic property). Lastly, we propose the mechanism of the cerebellar ataxia and possible treatments for the ataxia in the cerebellar inflammation. Full article

(This article belongs to the Special Issue Recent Advances in Immune-Mediated Cerebellar Ataxias: Pathogenesis, Diagnostic Approaches, Therapies, and Future Challenges)

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19 pages, 1281 KiB

Open AccessReview

A Breakdown of Immune Tolerance in the Cerebellum

by Christiane S. Hampe and Hiroshi Mitoma

Brain Sci. 2022, 12(3), 328; https://doi.org/10.3390/brainsci12030328 - 28 Feb 2022

Cited by 5 | Viewed by 3060

Abstract

Cerebellar dysfunction can be associated with ataxia, dysarthria, dysmetria, nystagmus and cognitive deficits. While cerebellar dysfunction can be caused by vascular, traumatic, metabolic, genetic, inflammatory, infectious, and neoplastic events, the cerebellum is also a frequent target of autoimmune attacks. The underlying cause for [...] Read more.

Cerebellar dysfunction can be associated with ataxia, dysarthria, dysmetria, nystagmus and cognitive deficits. While cerebellar dysfunction can be caused by vascular, traumatic, metabolic, genetic, inflammatory, infectious, and neoplastic events, the cerebellum is also a frequent target of autoimmune attacks. The underlying cause for this vulnerability is unclear, but it may be a result of region-specific differences in blood–brain barrier permeability, the high concentration of neurons in the cerebellum and the presence of autoantigens on Purkinje cells. An autoimmune response targeting the cerebellum—or any structure in the CNS—is typically accompanied by an influx of peripheral immune cells to the brain. Under healthy conditions, the brain is protected from the periphery by the blood–brain barrier, blood–CSF barrier, and blood–leptomeningeal barrier. Entry of immune cells to the brain for immune surveillance occurs only at the blood-CSF barrier and is strictly controlled. A breakdown in the barrier permeability allows peripheral immune cells uncontrolled access to the CNS. Often—particularly in infectious diseases—the autoimmune response develops because of molecular mimicry between the trigger and a host protein. In this review, we discuss the immune surveillance of the CNS in health and disease and also discuss specific examples of autoimmunity affecting the cerebellum. Full article

(This article belongs to the Special Issue Recent Advances in Immune-Mediated Cerebellar Ataxias: Pathogenesis, Diagnostic Approaches, Therapies, and Future Challenges)

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15 pages, 267 KiB

Open AccessReview

The Neuropathology of Autoimmune Ataxias

by H. Brent Clark

Brain Sci. 2022, 12(2), 257; https://doi.org/10.3390/brainsci12020257 - 12 Feb 2022

Cited by 7 | Viewed by 2841

Abstract

Autoimmune-mediated ataxia has been associated with paraneoplastic disease, gluten enteropathy, Hashimoto thyroiditis as well as autoimmune disorders without a known associated disease. There have been relatively few reports describing the neuropathology of these conditions. This review is an attempt to consolidate those reports [...] Read more.

Autoimmune-mediated ataxia has been associated with paraneoplastic disease, gluten enteropathy, Hashimoto thyroiditis as well as autoimmune disorders without a known associated disease. There have been relatively few reports describing the neuropathology of these conditions. This review is an attempt to consolidate those reports and determine the ways in which autoimmune ataxias can be neuropathologically differentiated from hereditary or other sporadic ataxias. In most instances, particularly in paraneoplastic forms, the presence of inflammatory infiltrates is a strong indicator of autoimmune disease, but it was not a consistent finding in all reported cases. Therefore, clinical and laboratory findings are important for assessing an autoimmune mechanism. Such factors as rapid rate of clinical progression, presence of known autoantibodies or the presence of a malignant neoplasm or other autoimmune disease processes need to be considered, particularly in cases where inflammatory changes are minimal or absent and the pathology is largely confined to the cerebellum and its connections, where the disease can mimic hereditary or other sporadic ataxias. Full article

(This article belongs to the Special Issue Recent Advances in Immune-Mediated Cerebellar Ataxias: Pathogenesis, Diagnostic Approaches, Therapies, and Future Challenges)

19 pages, 592 KiB

Open AccessReview

Update on Paraneoplastic Cerebellar Degeneration

by Philipp Alexander Loehrer, Lara Zieger and Ole J. Simon

Brain Sci. 2021, 11(11), 1414; https://doi.org/10.3390/brainsci11111414 - 26 Oct 2021

Cited by 19 | Viewed by 3708

Abstract

Purpose of review: To provide an update on paraneoplastic cerebellar degeneration (PCD), the involved antibodies and tumors, as well as management strategies. Recent findings: PCD represents the second most common presentation of the recently established class of immune mediated cerebellar ataxias (IMCAs). Although [...] Read more.

Purpose of review: To provide an update on paraneoplastic cerebellar degeneration (PCD), the involved antibodies and tumors, as well as management strategies. Recent findings: PCD represents the second most common presentation of the recently established class of immune mediated cerebellar ataxias (IMCAs). Although rare in general, PCD is one of the most frequent paraneoplastic presentations and characterized clinically by a rapidly progressive cerebellar syndrome. In recent years, several antibodies have been described in association with the clinical syndrome related to PCD; their clinical significance, however, has yet to be determined. The 2021 updated diagnostic criteria for paraneoplastic neurologic symptoms help to establish the diagnosis of PCD, direct cancer screening, and to evaluate the presence of these newly identified antibodies. Recognition of the clinical syndrome and prompt identification of a specific antibody are essential for early detection of an underlying malignancy and initiation of an appropriate treatment, which represents the best opportunity to modulate the course of the disease. As clinical symptoms can precede tumor diagnosis by years, co-occurrence of specific symptoms and antibodies should prompt continuous surveillance of the patient. Summary: We provide an in-depth overview on PCD, summarize recent findings related to PCD, and highlight the transformed diagnostic approach. Full article

(This article belongs to the Special Issue Recent Advances in Immune-Mediated Cerebellar Ataxias: Pathogenesis, Diagnostic Approaches, Therapies, and Future Challenges)

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Other

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8 pages, 857 KiB

Open AccessOpinion

The Clinical Concept of LTDpathy: Is Dysregulated LTD Responsible for Prodromal Cerebellar Symptoms?

by Hiroshi Mitoma, Kazuhiko Yamaguchi, Jerome Honnorat and Mario Manto

Brain Sci. 2022, 12(3), 303; https://doi.org/10.3390/brainsci12030303 - 24 Feb 2022

Cited by 2 | Viewed by 1542

Abstract

Long-term depression at parallel fibers-Purkinje cells (PF-PC LTD) is essential for cerebellar motor learning and motor control. Recent progress in ataxiology has identified dysregulation of PF-PC LTD in the pathophysiology of certain types of immune-mediated cerebellar ataxias (IMCAs). Auto-antibodies towards voltage-gated Ca channel [...] Read more.

Long-term depression at parallel fibers-Purkinje cells (PF-PC LTD) is essential for cerebellar motor learning and motor control. Recent progress in ataxiology has identified dysregulation of PF-PC LTD in the pathophysiology of certain types of immune-mediated cerebellar ataxias (IMCAs). Auto-antibodies towards voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta) induce dysfunction of PF-PC LTD, resulting in the development of cerebellar ataxias (CAs). These disorders show a good response to immunotherapies in non-paraneoplastic conditions but are sometimes followed by cell death in paraneoplastic conditions. On the other hand, in some types of spinocerebellar ataxia (SCA), dysfunction in PF-PC LTD, and impairments of PF-PC LTD-related adaptive behaviors (including vestibulo-ocular reflex (VOR) and prism adaptation) appear during the prodromal stage, well before the manifestations of obvious CAs and cerebellar atrophy. Based on these findings and taking into account the findings of animal studies, we re-assessed the clinical concept of LTDpathy. LTDpathy can be defined as a clinical spectrum comprising etiologies associated with a functional disturbance of PF-PC LTD with concomitant impairment of related adaptative behaviors, including VOR, blink reflex, and prism adaptation. In IMCAs or degenerative CAs characterized by persistent impairment of a wide range of molecular mechanisms, these disorders are initially functional and are followed subsequently by degenerative cell processes. In such cases, adaptive disorders associated with PF-PC LTD manifest clinically with subtle symptoms and can be prodromal. Our hypothesis underlines for the first time a potential role of LTD dysfunction in the pathogenesis of the prodromal symptoms of CAs. This hypothesis opens perspectives to block the course of CAs at a very early stage. Full article

(This article belongs to the Special Issue Recent Advances in Immune-Mediated Cerebellar Ataxias: Pathogenesis, Diagnostic Approaches, Therapies, and Future Challenges)

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5 pages, 1364 KiB

Open AccessCase Report

Stiff-Eye Syndrome—Anti-GAD Ataxia Presenting with Isolated Ophthalmoplegia: A Case Report

by Abel Dantas Belém, Thaís de Maria Frota Vasconcelos, Rafael César dos Anjos de Paula, Francisco Bruno Santana da Costa, Pedro Gustavo Barros Rodrigues, Isabelle de Sousa Pereira, Paulo Roberto de Arruda Tavares, Gabriela Studart Galdino, Daniel Aguiar Dias, Carolina de Figueiredo Santos, Manoel Alves Sobreira-Neto, Pedro Braga-Neto and Paulo Ribeiro Nobrega

Brain Sci. 2021, 11(7), 932; https://doi.org/10.3390/brainsci11070932 - 14 Jul 2021

Cited by 1 | Viewed by 2163

Abstract

Anti-GAD ataxia is one of the most common forms of immune-mediated cerebellar ataxias. Many neurological syndromes have been reported in association with anti-GAD. Ophthalmoparesis has been described in stiff person syndrome. We report a case of anti-GAD ataxia presenting initially with isolated ophthalmoplegia [...] Read more.

Anti-GAD ataxia is one of the most common forms of immune-mediated cerebellar ataxias. Many neurological syndromes have been reported in association with anti-GAD. Ophthalmoparesis has been described in stiff person syndrome. We report a case of anti-GAD ataxia presenting initially with isolated ophthalmoplegia and showing complete resolution after immunotherapy. A 26-year-old male patient presented with ophthalmoparesis characterized by tonic upwards deviation of the right eye. In the following month, he developed progressive ataxia with anti-GAD titers of 1972 UI/mL. After treatment with methylprednisolone and immunoglobulin, there was complete resolution of symptoms and anti-GAD titers decreased. This is the first report of isolated ophthalmoparesis due to tonic eye deviation associated with anti-GAD antibodies without stiff-person syndrome. Tonic eye deviation has been reported in SPS, possibly secondary to continuous discharge in gaze holding neurons in the brainstem (similar to what occurs in spinal motor neurons). With growing evidence for ocular abnormalitites in SPS, anti-GAD associated neurological syndromes should be included in the differential diagnosis of isolated ophthalmoplegia. Full article

(This article belongs to the Special Issue Recent Advances in Immune-Mediated Cerebellar Ataxias: Pathogenesis, Diagnostic Approaches, Therapies, and Future Challenges)

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