Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association

Abstract

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 > or =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.

Intrathecal injection of P/Q type voltage-gated calcium channel antibodies from paraneoplastic cerebellar degeneration cause ataxia in mice

“…A similar situation occurs in patients with glutamic acid decarboxylase (GAD)-ab. Patients with high titers of GAD-ab may develop stiff-man syndrome or cerebellar ataxia and postmortem studies show neuronal loss only in those with cerebellar ataxia (Ishida et al, 2007;Saiz et al, 2008). Taken together, these data suggest that when antibodies target cerebellar antigens, the functional impairment of the synaptic activity may lead to irreversible neuronal loss, a feature that is uncommon in other antibody-mediated neurological syndromes probably also mediated by antibodies targeting brain areas different from the cerebellum.…”

Non‐paraneoplastic limbic encephalitis and immune deficiency

“…To prove a causal link between GAD autoimmunity and the neurological syndrome, determination of the level of GAD-antibodies in cerebrospinal fluid (CSF) is necessary to confirm intrathecal synthesis. 2 In the patient reported by Akman et al, GAD-antibody levels were about 200-fold the upper limit of normal values in serum and CSF, which to the authors suggested a causal relationship between these antibodies and the neurological symptoms. As the CSF ⁄ serum antibody-index is not mentioned in their report, intrathecal antibody synthesis cannot be shown in this patient.…”

“…Recently four patients with non-paraneoplastic limbic encephalitis associated with anti-GAD antibodies were reported. 2,3 Differentiation between autoimmune limbic encephalitis and paraneoplastic limbic encephalitis is important because the former is less frequently associated with cancer and often responds well to immunotherapy.…”

The role of humoral autoimmunity in gastrointestinal neuromuscular diseases

“…A low positive result would suggest that these individuals are predisposed to or have Type I diabetes mellitus. However, these titres are not considered high enough to have a neurological impact (Saiz et al 2008;Liimatainen et al 2010). None of the GINMD or UK healthy control sera were positive UK.HC = UK healthy controls, SID = severe intestinal dysmotility B.HC = Brazilian healthy controls.…”

“…Data regarding stage of disease at diagnosis in the study of Kraichely et al are not provided. It should be mentioned that none of the positive anti-GAD sera, which were detected using an indirect immunofluorescence assay, were confirmed using the radioimmunoprecipitation assay to confirm specificity (Saiz et al 2008). …”