Refractory generalized seizures and cerebellar ataxia associated with anti‐GAD antibodies responsive to immunosuppressive treatment

Abstract

Anti-glutamic acid decarboxylase antibodies (anti-GAD-Ab) may play a pathogenic role in Stiff-man syndrome [1], cerebellar ataxia withmulti-endocrine auto-immune disease [2] and drug-resistant epilepsy [3]. We described a 42-year-old woman who developed type-1 diabetes, Hashimoto s thyroiditis, vitamin B12 deficiency, horizontal and upbeat nystagmus, cerebellar ataxia and pharmacoresistant generalized seizureswith thepresenceof anti-GAD-Ab. The patient was affected by psoriasis and vitiligo. In March 2004, she developed dizziness and diplopia. She was found to have hyperglycaemia and impaired insulin secretion. She was positive for antithyroglobulin and anti-thyroid peroxidase antibodies, and her TSH levels were elevated. A brain magnetic resonance imaging (MRI) showed mild cerebellar vermis atrophy. Type-1 diabetes and subclinical hypothyroidism because of Hashimoto s thyroiditis were diagnosed. In April 2004, the patient experienced tonic clonic generalized seizures. Neurological examination showed evidence of bilateral eyelid ptosis prevailingon left side, horizontal and upbeat nystagmus, and gait ataxia. Deep sensory function and deep tendon reflexes were normal. A new brain MRI confirmed the cerebellar vermis atrophy (Fig. 1).Cerebrospinal fluid showedan increased IgG index (> 1.7). She was found to have a deficit of vitamin B12. She was positive for anti-ANA (1:40) and antigastric parietal cell antibodies (70 U/ml). Molecular analysis for expanded CAG repeats in the gene for SCA 1-3, 6, 7, 12 and 17 was negative. The patient was well substituted for vitamin B12; however, there was no improvement of neurological symptoms after substitution. Additional therapy was started, initially consisting of oxcarmazepine (900 mg/day); then levetiracetam (3000 mg/day) and finally phenobarbital (150 mg/day) were added without benefit on seizures. In October 2004, the frequency of seizures increased (5–10 episodes/month), and she developed cerebellar ataxia. Serum anti-GAD-Ab level was 67.4 U/ml (n.v. < 1 U/ml). Therapy with prednisone 50 mg/die and azathioprine 100 mg/die resulted in a marked improvement of cerebellar ataxia and epilepsy (3–4 episodes/year). Immunosuppressive therapy was progressively tapered down to suspension in December 2006. At present, the number of seizure episodes is 3–4/year, and the patient is treated with levetiracetam (3000 mg/day) and pregabalin (450 mg/day). Neurological examination shows evidence of only nystagmus and left eyelid ptosis. Anti-GAD-Ab is negative. Cerebellar ataxia [2] as well as nystagmus [4,5] associated with anti-GAD-Ab have been previously described. High titres of anti-GAD-Ab have also been associated with some cases of epilepsy [3,6]. Immunosuppressive treatment has been performed in some of these patients, with somewhat varying success [4,6,7]. In our patient, prednisolone and azathioprine treatment markedly improved the cerebellar ataxia and reduced the frequency of seizures. These data support the autoimmune pathogenesis of our patient s complex clinical syndrome. In our opinion, it is important to search for anti-GAD-Ab in presence of neurological symptoms such as cerebellar ataxia, nystagmus and pharmacoresistant epilepsy in which a combination of immunosuppressive drugs may be very effective.