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Source: Honnorat J, et al. Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies. Arch Neurol. 2001;58:225-230.
Insidious cerebellar ataxia is usually an ominous clinical presentation. The differential diagnosis of a slowly progressive cerebellar disorder beginning in adulthood is not broad. Sporadic olivopontocerebellar degeneration (better known as OPCA), Jacob-Creutzfeldt disease, autosomal dominant spinocerebellar degeneration (SCA-1, 2, 3, 6, 8), paraneoplastic disease (mediated by anti-Yo antibody), and celiac disease are the most common causes of this clinical picture. There is currently no therapy that alters the natural history of OPCA, prion disease or the inherited spinocerebellar degenerations. While celiac and paraneoplastic cerebellar disorders may partially respond to treatment, improvements are usually modest at best.
There have been scattered case reports of cerebellar degeneration occurring in patients with antibodies to glutamic acid decarboxylase (GAD). Anti-GAD antibodies are present in a variety of immune-mediated disorders, including insulin-dependent diabetes mellitus, polyendocrine autoimmunity, and in the stiff-person syndrome, a neurologic disorder characterized by progressive muscle rigidity and painful muscle spasms. Stiff-person syndrome is a relentlessly progressive neurologic disorder that can respond dramatically to treatment with immuno-modulatory therapy. This paper is the first to link cerebellar ataxia and anti-GAD antibodies in a series of patients, implying a new and potentially treatable form of cerebellar dysfunction in adults.
Honnorat and colleagues describe 14 patients with anti-GAD antibodies and adult-onset cerebellar degeneration. The patients were identified by analyzing 9000 patient serum samples sent from 4 different European laboratories during screening for paraneoplastic antibodies. Thirteen of 14 patients were women, and their average age at the onset of cerebellar symptoms was 51 years. Ten patients had coincident insulin-dependent diabetes mellitus, and 6 had a family history of autoimmune disease. Autoimmune illnesses were common among this group of 14 patients, including thyroiditis (8 patients), pernicious anemia (2 patients), myasthenia gravis (1 patient), and psoriasis (1 patient). In virtually every case, cerebellar symptoms were slow and insidious. The predominant symptom was gait ataxia (10 patients), which could be severe. Limb ataxia was highly prevalent but mild. Twelve patients had nystagmus, 8 had dysarthria, and 2 had leg rigidity suggestive of a peripheral form of stiff-person syndrome.
Imaging of the brain was abnormal in 7 patients, demonstrating pure cerebellar atrophy. Cerebrospinal fluid examination was abnormal in 10 patients, with oligoclonal IgG bands present in the CSF. Radioimmunoassay and Western blot confirmed the presence of anti-GAD antibodies in all 14 patients, at levels that were similar to those seen in stiff-person syndrome.
This paper is important for several reasons. It suggests that neurologists who encounter patients with slowly progressive cerebellar symptoms should be aware of the possibility that anti-GAD antibodies are responsible for the condition. The neurologic features of these patients are identical to patients with sporadic OPCA, making it difficult to recognize them. Clues that may help the neurologist identify these patients include female gender, a history of insulin-dependent diabetes mellitus or other autoimmune disorders, and a family history of autoimmune disorders.
It is unknown how an antibody in the serum or CSF is able to access GAD, an intracytoplasmic antigen. Once present inside the cell however, anti-GAD antibodies have been demonstrated to reduce GAD enzyme activity, and GABA synthesis from glutamate. Glutamate is a known excitotoxin, and increased glutamate and decreased GABA may perhaps explain the loss of cerebellar neurons.
This paper does not comment about possible treatments for patients with cerebellar ataxia and anti-GAD antibodies. However, IVIG and plasmapheresis have both been reported to benefit selected patients with stiff-person syndrome, and presumably one of these approaches should be tried in autoimmune-mediated cerebellar disease. The importance of early recognition of this potentially treatable cause of cerebellar degeneration cannot be over-emphasized. —Steven Frucht