Nonparaneoplastic autoimmune cerebellar diseases

Hiroshi Mitoma MD PhD (

Dr. Mitoma of Tokyo Medical University has no relevant financial relationships to disclose.

Mario Manto MD PhD (

Dr. Manto of University of Mons, Belgium, has no relevant financial relationships to disclose.

George M Hadjigeorgiou MD ()
Francesc Graus MD PhD, editor. (Dr. Graus of the University of Barcelona has no relevant financial relationships to disclose.)
Originally released August 23, 2019; expires August 23, 2022

This article includes discussion of nonparaneoplastic autoimmune cerebellar diseases, non-paraneoplastic autoimmune cerebellar ataxias, and nonparaneoplastic immune-mediated cerebellar ataxias. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


Immune-mediated cerebellar ataxias include paraneoplastic and nonparaneoplastic diseases. The latter include gluten ataxia, postinfectious cerebellitis, opsoclonus myoclonus syndrome, anti-GAD ataxia, and primary autoimmune cerebellar ataxia. When autoimmunity is triggered by another condition (eg, gluten sensitivity in gluten ataxia and infection in postinfectious cerebellitis), treatment priority should be given to the removal of the trigger. If this is not possible or when autoimmunity is not triggered by another condition (eg, anti-GAD ataxia or primary autoimmune cerebellar ataxia), various combinations of immunotherapies can be used to prevent the progression of the ataxia or revert the clinical deficits. Immunotherapy should be introduced as soon as possible, during the period of cerebellar reserve, defined as the capacity for compensation and restoration of neural function. Assuming immunotherapies arrest the progression, the reversibility of the ataxia depends on functional remodeling in the cerebellar circuitry, which is characterized by a high degree of plasticity. Good prognosis is characteristic of nonparaneoplastic immune-mediated cerebellar ataxias, in contrast to the poor prognosis seen in paraneoplastic cerebellar degeneration. For successful intervention, a diagnosis of nonparaneoplastic immune-mediated cerebellar ataxias is necessary at the early stages of the disease.

Key points


• Nonparaneoplastic immune-mediated cerebellar ataxias include diverse etiologies.


• Nonparaneoplastic immune-mediated cerebellar ataxias are characterized by subacute onset, autoimmune disease history, predominant gait ataxia, associated autoantibodies, and good response to immunotherapies.


• Immunotherapies should be introduced during the period of cerebellar reserve, defined as the capacity for compensation and restoration of cerebellar function.

Historical note and terminology

Various pathologies result in cerebellar insult, leading to the development of cerebellar ataxias and resulting in motor and cognitive incoordination (Schmahmann et al 2006; Manto 2010; Manto et al 2012). Examples include vascular diseases, tumors, and metabolic, degenerative, and immune-mediated cerebellar ataxias. The documentation of immune-mediated cerebellar ataxias originates from a classical work by Charcot J.M. (Charcot 1868). At a well-known lecture on multiple sclerosis in 1868, he described the development of cerebellar ataxias in patients with multiple sclerosis and the appearance of intention tremor, scanning speech, and nystagmus (Charcot's triad) in addition to optic neuritis and paralysis. Another historical milestone was the report by Brouwer B. in 1919, which described the association of cerebellar ataxias with ovarian tumor (Brouwer 1919), the first report of primary autoimmune cerebellar ataxia. Two further breakthroughs occurred in the 1980s. First, an autoantibody, anti-Yo, was described in a patient with ovarian tumor-associated primary autoimmune cerebellar ataxia (Greenlee and Brashear 1983), which was followed by the identification other specific autoantibodies, including anti-Hu, anti-Tr, anti-CV2, anti-Ri, anti-Ma2, and anti-VGCC antibodies associated with specific types of neoplasms, especially breast, uterine, and ovarian cancers as well as small-cell lung carcinoma and Hodgkin lymphoma (Ducray et al 2014). At present, there is general agreement that autoimmunity trigged by the neoplasm results in the development of cerebellar ataxias (Ducray et al 2014). Second, the association of cerebellar ataxias with autoantibodies targeting the cerebellum was reported in patients with nonparaneoplastic conditions, and these cerebellar ataxias responded well to various immunotherapies (Hadjivassiliou 2012; Mitoma et al 2015; Mitoma et al 2016; Mitoma et al 2017a; Mitoma et al 2019; Hadjivassiliou 2017; Hadjivassiliou et al 2019; in press). Two main clinical entities have been established based on specific clinical features and type of associated autoantibodies: gluten ataxia (Hadjivassiliou et al 1998) and anti-glutamic acid decarboxylase 65 antibodies (GAD 65 antibodies)-associated cerebellar ataxia (anti-GAD ataxia) (Honnorat et al 2001).

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