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A fourfold increase in type 1 diabetes (T1D) among idiopathic generalized epilepsies (IGEs) was recently reported,1 and anti–glutamic acid decarboxylase antibodies (GAD-Ab) may be the biological basis of the association.2, 3

We retrospectively identified 2 patients with T1D (requiring insulin within 1 year of presentation) among our IGE population aged 15 years or older (n = 199) and measured the plasmatic levels of GAD-Ab in these patients.

Patient 1 is a 51-year-old man with T1D requiring insulin from early childhood. From age 12 years he suffered from tonic-clonic seizures. More than 5 episodes/yr occurred at the onset; electroencephalograms showed 3 to 3.5c/sec generalized spike waves and photosensitivity. Patient 2 is a 15-year-old boy with insulin-dependent T1D from age 8 years and childhood absence epilepsy diagnosed when he was 9. Both patients had unremarkable family history for IGE or T1D, normal neurological examination and neuroimaging, and no other autoimmune disorders. In both patients, epilepsy is controlled by valproate and glycemic levels, with normal fasting blood glucose and glycosylated hemoglobin (HbA1c).

GAD-Abs were investigated by immunoradiometric assay CentAK anti-GAD65 (Berlin Medipan, Selchow, Germany). GAD-Ab levels greater than 0.9U/ml were positive. Approval by the local ethical committee and signed informed consent were obtained.

GAD-Ab titers were 7.12U/ml in Patient 1 and 6.53 U/ml in Patient 2. Serum titers of anti–islet cell–specific, anti-insulin, anti-protein tyrosine phosphatase-like protein anti-cardiolipin, anti-nuclear, anti–thyroid peroxidase, anti-gliadin, and anti-GM1 antibodies were normal. Normal GAD-Ab levels were detected in 40 IGE patients older than 15 years and in 40 healthy volunteers (aged 10–50 years).

Autoimmunity has been previously involved in epilepsy.4 In particular, GAD-Abs are implicated in T1D and in several neurological conditions, including drug-resistant focal epilepsy.5

The present observation highlights the role of autoimmunity in IGE-T1D and expands the spectrum of GAD-Ab–associated neurological diseases. The absence of GAD-Ab in isolated IGE confirms previous reports.5, 6

According to McCorry and colleagues,1 our cases manifested T1D before IGE and there was no positive family history for these conditions suggestive of a genetic association.

The pathogenetic role of GAD-Ab in IGE remains speculative. GAD inhibition may decrease the GABA synthesis and, hence, reduce the (GABA-mediated) inhibitory activity of interneurons leading to hyperexcitability. Interestingly, genetic inactivation of GABA receptors causes IGE7; therefore, autoimmune mechanisms affecting the GABA pathway may be potentially pathogenetic. Moreover, GAD65 knock-out mice display cortical hyperexcitability with spontaneous seizures.8

Further studies will be required to assess the prevalence of GAD-Abs among IGE and to explore GAD autoimmunity in epilepsy in other GAD-Ab–associated disorders.

References

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Pasquale Striano MD* †, Giuseppe Perruolo MSc‡, Luca Errichiello MSc*, Pietro Formisano MD‡, Francesco Beguinot MD‡, Federico Zara PhD†, Salvatore Striano MD*, * Epilepsy Center, Department of Neurological Sciences, “Federico II” University, Napoli, † Unit of Muscular and Neurodegenerative Diseases, Istituto “G. Gaslini,” Genova, ‡ Department of Molecular Cell Biology and Pathology, “Federico II” University, Napoli, Italy