Acetazolamide and Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

To the Editor: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an inherited seizure syndrome characterized by childhood or adolescence onset of stereotyped clusters of motor seizures from sleep. Intelligence, neurologic examination, and structural neuroimaging are normal (1, 2). Interictal EEG is usually normal. Ictal EEG may show bilateral frontal spike and wave or no abnormality (3). Seizures usually respond to carbamazepine (CBZ) (1-3). Mutations in genes encoding the neuronal nicotinic acetylcholine receptor ion channel have been described in some families, suggesting the condition to be a channelopathy (4-6). We report a female patient with ADNFLE, who, with other family members, responded to acetazolamide (ACZ). The family were included in the original article describing ADNFLE as a distinctive clinical disorder (2). Although linkage studies in this family localize to chromosome 15, mutational analysis for the known cholinergic receptor genes is negative. Seizures began at age 7 years and were characterized by arousal from sleep, clearing of her throat, aphasia, arm movements, and retained awareness. CBZ was initiated with response. Seizure frequency increased from age 12 years, with clusters of >20 seizures per night. Nocturnal waking resulted in daytime somnolence and inability to attend school. Neurologic examination, interictal EEG, and brain magnetic resonance imaging (MRI) were normal. Video-telemetry showed brief stereotyped attacks of frontal lobe semiology, after abrupt electrographic arousal from non–rapid eye movement (REM) sleep. Ictal EEG was unremarkable. ACZ, 500 mg at night, was added to CBZ. She became seizure free and was able to return to school full-time. When last reviewed at age 17 years, she remained taking ACZ and CBZ, occasionally waking at night with a cough, but satisfied with her seizure control. Other members of this family also responded to ACZ. The proband's father had failed to achieve seizure control with primidone (PRM), lorazepam (LZP), CBZ, phenytoin (PHT), topiramate, gabapentin, valproate (VPA), and phenobarbitone. The addition of ACZ to CBZ, VPA, and PRM led to a decrease in seizure frequency. The proband's brother failed to achieve seizure control with diazepam, LZP, CBZ, PRM, and PHT. The addition of ACZ to CBZ, PHT, and PRM led to seizure freedom and successful weaning of PHT and PRM. Attempts to decrease the dose of ACZ after the development of renal calculi led to seizure return. He has elected to continue ACZ. ACZ has been used as an antiepileptic drug (AED) since the 1950s, particularly in catamenial and partial epilepsies (7, 8). Its use as adjunctive treatment to CBZ has been reported in refractory partial, generalized tonic–clonic, and complex partial seizures (9, 10). Pharmacokinetic interaction, leading to increased CBZ levels, has been debated but not proven as a mechanism of action (9, 10). To our knowledge, no reports mentioned of the use of ACZ specifically in ADNFLE. In addition to antiepileptic properties, ACZ is effective in nonepileptic channelopathies, and evidence from in vivo animal studies suggests it may be acting directly on ion channels (11). The response reported here, of three members of a kindred with ADNFLE to ACZ with CBZ, is interesting. As ADNFLE is suspected to be a channelopathy, ACZ may be exerting its therapeutic effect through this action, rather than by potentiating CBZ. We recommend consideration of ACZ in ADNFLE resistant to CBZ. Acknowledgment: This work was undertaken by Great Ormond Street Hospital for Children NHS Trust, which receives a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and are not necessarily those of the NHS Executive.