Glutamic acid decarboxylase autoantibodies in controlled and uncontrolled epilepsy: a pilot study
Introduction
Gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in mammalian brain, is formed exclusively from l-glutamic acid via an irreversible reaction catalysed by glutamic acid decarboxylase (GAD) (Fariello et al., 1991). Apart from GABA-ergic neurons in the central and peripheral nervous systems, GAD is present in pancreatic β-cells, epithelial cells of the fallopian tube, and within the spermatozoa of the testes (Folli, 1998, Erdo and Wolff, 1990). GAD is a dominant autoantigen in insulin dependent diabetes mellitus (IDDM) and stiff man syndrome (SMS), a rare neurological disorder characterised by progressive and fluctuating muscle rigidity and painful spasms (Ellis and Atkinson, 1996, Atkinson, 2000). In IDDM, immune response to GAD and other islet-cell antigens is thought to be involved in the destruction of insulin-secreting cells (Lohmann et al., 2000) while GAD autoantibodies have been suggested to inhibit GABA synthesis in SMS (Dinkel et al., 1998).
More than one third of patients with epilepsy continue to have seizures despite antiepileptic drug (AED) treatment (Kwan and Brodie, 2000). The cause of this inadequate response is largely unknown. There have been recent case reports of elevated GAD autoantibodies in patients with refractory partial seizures (Martinelli et al., 1978, Solimena et al., 1988 Saiz et al., 1996; Nemni et al., 1994 Giometto et al., 1998). Impairment of GABA function is recognised to provoke seizures while glutamate is a pro-convulsant (Meldrum, 1995). Many AEDs exert their anticonvulsant effect by facilitating GABA-ergic activities (Macdonald and Kelly, 1995). Based on such theoretical consideration and anecdotal case reports a causal relationship between GAD autoantibodies and refractory epilepsy has been postulated and immunotherapy has been advocated as treatment (Giometto et al., 1998). Whether GAD autoantibodies are associated with seizure disorders in general or with specific epilepsy syndromes, and perhaps more importantly, with refractoriness, have not been studied.
To explore the hypothesis that raised GAD autoantibodies may be associated with pharmacoresistance, we conducted a pilot study to compare titres between patients with controlled and uncontrolled epilepsy. To maximise the applicability of our results to everyday clinical practice, common epilepsy types and aetiologies of both idiopathic and symptomatic nature were chosen.
Section snippets
Methods
We enrolled 105 patients (44% male) with a diagnosis of juvenile myoclonic epilepsy, or with partial-onset seizures as a result of mesial temporal sclerosis, cortical dysplasia, or cortical gliosis. Thirty one patients had been seizure-free for at least one year while the epilepsy had been refractory to AED treatment in the remaining 74 patients (Table 1). All were attending the Epilepsy Unit in Glasgow, Scotland. Median age was 37 years (range, 17–71 years) and median duration of epilepsy was
Results
There was no significant difference in serum GAD autoantibody titres between patients who were seizure-free and those with uncontrolled epilepsy, either analysing the syndromes in combination (Fig. 1) or individually (Table 1). There was no significant association between the titre of GAD autoantibody and duration of epilepsy or seizure frequency. However, four female patients with uncontrolled epilepsy had GAD autoantibody levels at least three times above the highest titre measured in the
Discussion
A causal relationship between GAD autoantibodies and epilepsy has been postulated based on anecdotal case reports, and immunotherapy, such as corticosteroids and intravenous immunoglobulins, has been advocated as treatment (Giometto et al., 1998). However, in these patients, additional features were present such as SMS (Solimena et al., 1988), diabetes mellitus (Saiz et al., 1997), impaired glucose tolerance (Nemni et al., 1994), or acute encephalitis (Giometto et al., 1998), all of which might
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