Brain Advance Access originally published online on August 7, 2008
Brain 2008 131(10):2553-2563; doi:10.1093/brain/awn183
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Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association
1Service of Neurology and 2Laboratory of Hormonal, Hospital Clinic and Institut d’ Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, 3Service of Neurology, Hospital La Fe, Valencia and 4Service of Neurology, Hospital Trueta, Girona, Spain
Correspondence to: Francesc Graus, MD, Servei de Neurologia, Hospital Clinic, Villarroel 170, Barcelona 08036, Spain E-mail: fgraus{at}clinic.ub.es
The association of high levels of autoantibodies to glutamic acid decarboxylase (GAD-ab) and stiff-person syndrome (SPS) is well known. However, the full spectrum of neurological syndromes associated with GAD-ab is not well established. In addition, these patients usually present type 1 diabetes mellitus (DM1) that could justify the presence of high GAD-ab levels. To clarify these issues, we reviewed the clinical and immunological features of patients in whom high GAD-ab levels were detected in a reference centre for DM1 and for the detection of antineuronal antibodies in suspected paraneoplastic neurological syndromes (PNS). High GAD-ab levels were defined as values 
2000 U/ml by radioimmunoassay. Intrathecal synthesis (IS) of GAD-ab was calculated in paired serum/CSF samples. Values higher than the IgG index were considered indicators for positive GAD-ab-specific IS. High GAD-ab levels were identified in 61 patients, 22 (36%) had SPS, 17 (28%) cerebellar ataxia, 11 (18%) other neurological disorders (epilepsy—four, PNS—four; idiopathic limbic encephalitis—two; myasthenia gravis—one), and 11 (18%) isolated DM1. Patients with SPS and cerebellar ataxia had the same frequency of female gender (86% vs 94%), DM1 (59% vs 53%), CSF oligoclonal bands (35% vs 69%). Three of the four PNS patients, with paraneoplastic encephalomyelitis, a predominant gait cerebellar ataxia, and limbic encephalitis, had neuroendocrine carcinomas. GAD expression was confirmed in the two tumours in which the study was done. The fourth patient presented with paraneoplastic cerebellar degeneration antedating a lung adenocarcinoma. The frequency of increased IS of GAD-ab was 85% in SPS, 100% in cerebellar ataxia, and 86% in other neurological disorders. In conclusion, our study emphasizes that high GAD-ab levels associate with other neurological disorders besides SPS. Cerebellar ataxia, the second most common syndrome associated with high GAD-ab levels, shares with SPS the same demographic, clinical and immunological features. The demonstration of an increased IS of GAD-ab is important to confirm that the GAD autoimmunity is related to the neurological syndrome particularly when there is a concomitant DM1 that could justify the presence of high GAD-ab levels. Lastly, in patients who develop neurological syndromes that suggest a PNS, the finding of GAD-ab does not rule out this possibility and appropriate studies should be done to confirm an underlying cancer.
Key Words: glutamic acid decarboxylase; stiff-person syndrome; cerebellar ataxia; paraneoplastic neurological syndromes; diabetes mellitus
Abbreviations: DM1, Type 1 diabetes mellitus; ELISA, enzyme-linked immunosorbent assay; GAD, Glutamic acid decarboxylase; GAD-ab, Autoantibodies to GAD; IS, Intrathecal synthesis; IVIg, Intravenous immunoglobulins; LE, Limbic encephalitis; PNS, Paraneoplastic neurological syndromes; RIA, Radioimmunoassay; SCLC, Small cell lung cancer; SPS, Stiff person syndrome
Received May 26, 2008. Revised July 11, 2008. Accepted July 11, 2008.
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