Treatment of Cerebellar Ataxia in the Context of Systemic Diseases

Abstract

Purpose of review The purpose of this review is to assess the evidence behind treatment regimens for cerebellar ataxias occurring in the context of systemic disease. We will address systemic conditions which are associated with specific involvement of the cerebellum (rather than widespread nervous system involvement) and those conditions for which some degree of evidence of treatment response exists. Recent findings We have divided systemic disorders affecting the cerebellum into systemic immunological disorders, endocrine and metabolic disorders and paraneoplastic. Recent studies have increased understanding of the range of cerebellar disorders associated with a systemic immunological condition. The identification of newer pathogenic antibodies has improved diagnosis in conditions which would have previously been labelled as idiopathic. However, their rarity and phenotypic variability makes defining optimal immunomodulatory treatment regimens challenging. There is some evidence for beneficial effects of immunomodulation, particularly in anti-GAD ataxia and Hashimoto’s encephalopathy, although, at this time, specific treatment regimens cannot be defined. Immune-mediated paraneoplastic cerebellar disorders show response to therapy dependent, to some extent, on the underlying pathogenic antibody. Much is still to be understood concerning treatment regimens for the ataxic manifestations of metabolic disorders, notably alcohol-induced cerebellar injury, which are common and which are associated with significant disability. Summary Despite their rarity, cerebellar ataxias occurring in the context of systemic disease cause significant morbidity and better therapies are required to improve outcomes associated with these conditions.

Clinical Reasoning: A 67-Year-Old Woman With Progressive Diplopia, Vertigo, and Ataxia

“…11 However, steroids, IVIg, plasmapheresis, and a variety of immunotherapies have been used with varying degrees of success. 11 The Yo antigen is an intracellular onconeuronal antigen rather than a cell surface antigen, thus unlikely to be reached without a cytotoxic immunotherapy, such as cyclophosphamide. 12 No specific immunotherapy has been consistently shown to improve outcomes.…”

Anti-glutamate Dehydrogenase Antibody Positive Cerebellar Ataxia and Stiff Person Syndrome Responding to Dual Treatment with Steroids and Intravenous Immunoglobulin: A Case Presentation and Literature Review

“…GAD catalyzes the conversion of glutamate to GABA, and antibodies to this enzyme can lead to a multitude of neurologic syndromes including, but not limited to, limbic encephalitis, stiff person syndrome, refractory epilepsy, and cerebellar ataxia [8-9]. Anti-GAD antibody syndrome (aGAS) can present with thyroiditis, pernicious anemia, vitiligo, and type one diabetes [10-12]. In addition to hypothyroidism, our patient was diagnosed with type 2 diabetes mellitus, shortly before the diagnosis of aGAS.…”

“…Antibodies to gliadin and transglutaminase need to be checked as there is an overlap between gluten ataxia and aGAS ataxia. A strict gluten diet may improve the ataxia in this subgroup regardless of detectable enteropathy [10]. Brain imaging can be helpful to differentiate subacute vs. chronic disease as the latter one can present with cerebellar atrophy on an MRI brain scan.…”

Impact of Alcohol Abuse on Susceptibility to Rare Neurodegenerative Diseases

“…Alcohol withdrawal also increases the permeability of mitochondria to Ca+2 influx and increases the opening of the nonspecific permeability transition pore, which causes efflux of mitochondrial signals that induce neuron death ( Rewal et al, 2005 ). At the same time, alcohol reduces the expression of inhibitory GABAA receptors, glutamic acid decarboxylase, which catalyzes the metabolism of glutamate to GABA ( Proudfoot and Wilkins, 2017 ), and the protein that promotes GABA uptake into synaptic vesicles ( Gruol et al, 2020 ), further pushing the signaling balance toward a hyperexcitatory state. Interestingly, the actions of alcohol that evoke glutamate excitotoxicity differentiate alcohol-induced cerebellar ataxia from many other forms, which have been shown to depend on glutamate excitotoxicity through a deficiency in the expression of glutamic acid decarboxylase, which catalyzes the metabolism of glutamate to GABA ( Proudfoot and Wilkins, 2017 ).…”