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  • Updated 08.28.2020
  • Released 08.23.2019
  • Expires For CME 08.28.2023

Nonparaneoplastic autoimmune cerebellar ataxias



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 (93; 66; 63). 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. (12). 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 (10). 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 (27), 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 (21). At present, there is general agreement that autoimmunity triggeredd by the neoplasm results in the development of cerebellar ataxias (21). The association of cerebellar ataxias with autoantibodies targeting the cerebellum was reported in patients with non-paraneoplastic ataxia (28; 39; 72; 71; 75; 76; 40; In press-a). Two main clinical entities have been established based on specific clinical features and type of associated autoantibodies: gluten ataxia (35) and anti-glutamic acid decarboxylase 65 antibodies (GAD 65 antibodies)-associated cerebellar ataxia (anti-GAD ataxia) (47).

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