Nonparaneoplastic autoimmune cerebellar ataxias

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.

Marios Hadjivassiliou MD (

Dr. Hadjivassiliou of Royal Hallamshire Hospital has no relevant financial relationships to disclose.

Francesc Graus MD PhD, editor. (

Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.

Originally released August 23, 2019; last updated August 28, 2020; expires August 28, 2023


Immune-mediated cerebellar ataxias are divided in paraneoplastic and nonparaneoplastic diseases. The latter include gluten ataxia, postinfectious cerebellitis, opsoclonus myoclonus ataxia 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 stabilize any clinical deficits. Immunotherapy should be introduced as soon as possible, during the period of existing 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, frequent autoimmune disease history in the patient or relatives, and predominant gait ataxia, usually associated with autoantibodies.


• Immunotherapy should be considered when the underlying trigger is not identified or cannot be removed.


• Immunotherapies should be introduced during the period of the presence 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 in 1919, which described the association of cerebellar ataxias with ovarian tumor and was the first report of paraneoplastic cerebellar degeneration (Brouwer 1919). Two further breakthroughs occurred in the 1980s. First, an autoantibody against the Purkinje cells, later called anti-Yo, was described in a patient with ovarian tumor-associated 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 triggeredd by the neoplasm results in the development of cerebellar ataxias (Ducray et al 2014). The association of cerebellar ataxias with autoantibodies targeting the cerebellum was reported in patients with non-paraneoplastic ataxia (Hadjivassiliou 2012; Hadjivassiliou 2017a; Mitoma et al 2015; Mitoma et al 2016; Mitoma et al 2017a; Mitoma et al 2019; Hadjivassiliou et al 2019a; In press-a). 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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