Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias

Abstract

In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ataxia associated with anti-GAD antibodies, the cerebellar type of Hashimoto's encephalopathy, primary autoimmune cerebellar ataxia, gluten ataxia, Miller Fisher syndrome, ataxia associated with systemic lupus erythematosus, and paraneoplastic cerebellar degeneration. Humoral mechanisms, cell-mediated immunity, inflammation, and vascular injuries contribute to the cerebellar deficits in immune-mediated cerebellar ataxias.

Keywords: Anti-GAD antibodies; Cerebellar ataxias; Gluten ataxia; Hashimoto’s encephalopathy; Miller Fisher syndrome; Paraneoplastic cerebellar degeneration; Primary autoimmune cerebellar ataxia; Systemic lupus erythematosus.

Fig. 1

An example of the staining seen using sera (dilution of 1 in 600) from a patient with primary autoimmune cerebellar ataxia on rat cerebellum. There is clear staining of Purkinje cells as well as cells within the granular layer. Such staining is not seen when using sera from healthy controls or patients with genetic ataxia. The serum was negative for all known Purkinje cell antibodies

Fig. 2

MR spectroscopy of the vermis from a patient with gluten ataxia. There is significant reduction of NAA/Cr ratio (0.56, normally should be above 1). This is a typical finding in patients with gluten ataxia even in the absence of significant atrophy. Primarily involvement of the vermis is also seen in a number of other immune-mediated ataxias in contrast to degenerative and genetic ataxias where there is global involvement of the cerebellum

Fig. 3

Relationship between the B/K ratio of predictive motor command and tracking score. Circles represent the normal control subjects. Red symbols represent the patients with degenerative CAs. Blue symbols represent the patients with immune-mediated CAs. MSA multiple systemic atrophy, SCA6 spinocerebellar ataxia type 6, anti-GAD anti-glutamic acid decarboxylase (GAD) antibody associated cerebellar ataxia, gluten gluten ataxia, HE cerebellar type of Hashimoto’s encephalopathy

Fig. 4

In immune-mediated cerebellar ataxias (CAs), cerebellar feed-forward control is still present, although its property is not exact, whereas in spinocerebellar degeneration (SCD), cerebellar feed-forward control is abolished and, instead, feed-back control is compensatively operational. The survival of cerebellar feed-forward controls could be a physiological evidence for reversibility in immune-mediated CAs. Motor Cx Motor cortex