Dramatic benzodiazepine receptor downregulation observed in holoprosencephaly with drug-resistant epilepsy

Holoprosencephaly (HPE), a central nervous system malformation caused by a defect in the separation of cerebral hemispheres during development, is associated with drug-resistant epilepsy. Animal studies on HPE have suggested its association with dysplasia of the inhibitory interneurons in the cerebral cortex; however, this association has not been reported in patients with HPE. In this study, we presented cases of three children with HPE who were examined for the distribution of benzodiazepine receptors, which are receptors of the inhibitory system, using 123I-iomazenil single-photon emission computed tomography (SPECT). All three children had drug-resistant epilepsy with frequent daily seizures. 99mTc ethyl cysteinate dimer (ECD) SPECT and 123I-iomazenil SPECT were performed to evaluate the epileptogenicity. 99mTc ECD SPECT showed generalized only cerebral hypoperfusion, and 123I-iomazenil SPECT showed widespread benzodiazepine receptor depression in the cerebrum, thalamus, and brainstem. Although, benzodiazepines, including clonazepam, clobazam, and lorazepam have limited effects on epileptic seizures, the addition of levetiracetam led to the reduction in seizure frequency in all three patients. The SPECT findings in children with HPE suggested a defect in the development of GABAergic-benzodiazepinergic inhibitory neurons, especially in the thalamus and brainstem. Therefore, it is inferred that conventional antiepileptic drugs that potentiate the mechanisms of inhibitory neurons are less effective. Agents, with alternative mechanisms of action may be useful for the treatment of refractory epilepsy.