| Note | Stiff-person syndrome is a rare neurological disorder characterized by stiffness of skeletal muscles with superimposed spasms. The syndrome is a putative autoimmune disease occurring as an idiopathic or paraneoplastic condition. It is often associated with antibodies to glutamic acid decarboxylase (GAD) or, less commonly, to the 128 kD synaptic protein later amphiphysin (AMPH) and few other autoantigens. |
| Phenotype and clinics | Diagnosis of GAD-antibody associated stiff-person syndrome is made according to the following criteria: Prodrome of stiffness and rigidity in axial muscles
Progression to include stiffness of limbs, making walking difficult
Increased lumbar lordosis
Presence of superimposed painful spasm, often precipitated by external stimuli (auditory stimulation like hand clapping)
Normal sensation, no paresis
An EMG finding of continuous motor unit activity (CMUA) at rest
Response to benzodiazepines including clinical response and reduction on CMUA
High levels of GAD antibodies
Other features: Less frequently, stiff-person syndrome is associated with antibodies to the 128 kDa synaptic protein amphiphysin. It is then a paraneoplastic condition, most often occurring with breast cancer. The pathogenic role of the antibodies directed against the 128 kDa synaptic protein amphiphysin has been shown by transmission of disease symptoms by passive transfer to rats. One case of stiff-person syndrome associated with antibodies to the synaptic protein gephyrin has been described. |
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| Neoplastic risk | GAD-antibody positive stiff-person syndrome has not been described as a paraneoplastic condition. Most cases of amphiphysin antibody associated stiff-person syndrome are paraneoplastic. Cancers described are breast cancer, small-cell lung, and ovarian carcinoma. The one case with anti-gephyrin antibodies was associated with an undifferentiated carcinoma of the mediastinum. |
| Treatment | Patients may respond to symptomatic treatment with benzodiazepines, and to a certain extent baclofen, valproic acid, tiagabine, and other drugs enhancing GABAergic transmission. Given the autoimmune pathogenesis immunosuppression, plasmapheresis, and high dose intravenous immunoglobulins (IVIG) seem to be treatments of choice. The only randomized controlled trial in this disorder showed that IVIG was an efficient treatment in GAD-antibody positive stiff-person syndrome. In the paraneoplastic forms, removal of the cancer is essential. Anti-amphiphysin associated stiff-person syndrome has been successfully treated with plasmapheresis. |
| Evolution | GAD-antibody positive stiff-person syndrome is usually slowly progressive, but can make patients bed-bound in the end. The paraneoplastic types are usually rapidly progressive and may be associated with encephalitis and other paraneoplastic syndromes. The prognosis of the neurological disorder depends on tumor treatment. |
| Antiamphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors. |
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