Stiff person syndrome - Quantification, specificity, and intrathecal synthesis of GAD(65) antibodies

Objective: To characterize the specificity of anti-GAD(65) antibodies in pa tients with stiff person syndrome (SPS), quantify antibody titers, and exam ine antibody production within the CNS. Methods: The authors studied 18 pat ients with SPS and positive serum immunoreactivity to gamma-aminobutyric ac id (GABA)-ergic neurons. The reactivity of serum and CSF to purified GAD an tigen was examined by Western blots, and the anti-GAD(65) antibody titers i n serum and CSF were quantified by ELISA and compared with 70 disease contr ols (49 with other autoimmune disorders and 11 with insulin-dependent diabe tes mellitus). The intrathecal synthesis of anti-GAD(65) IgG was calculated , and the functional significance of the antibodies was examined by measuri ng the GABA levels in the CSF. Results: The serum and CSF of all selected p atients with SPS had high anti-GAD(65) titers (from 7.0 to 215 mug/mL in se rum and from 92 to 2500 ng/mL in CSF) and immunoreacted strongly with recom binant GAD(65) on Western blots and with GABA-ergic neurons on rat cerebell um. Among controls, only the serum of eight patients with insulin-dependent diabetes mellitus had low anti-GAD(65) antibody titers (from 200 to 1760 n g/mL) but no reactivity to recombinant GAD(65). The CSF showed oligoclonal IgG bands in 10 (67%) of 15 patients and an increased anti-GAD(65)-specific IgG index in 11 (85%) of 13. The mean level of GABA in the CSF was lower i n patients with SPS than in controls. Conclusions: In patients with SPS, th ere is marked intrathecal antibody response against neuronal GAD(65) epitop es, indicating a clonal B cell activation in the CNS. Anti-GAD(65) antibodi es at high titers, when confirmed with immunoblots, are highly specific for SPS and appear to impair GABA synthesis.