Abstracts

Rationale: Benzodiazepines (BZDs) are potent anti-status epilepticus (SE) drugs by enhancing GABA receptors. GABA receptor initially poses excitatory function, and its function changes excitatory to inhibitory at around 3 years of age in humans, adopted from rodent experiments. This suggests that the efficacy of BZDs for SE might change with age. Is it true in humans as well? Methods: Medical records were retrospectively reviewed for children with epilepsy < 6 years of age who were visited or admitted to our hospital between 1997 and 2016 because of convulsive SE (CSE) and were initially administered enough dose of IV BZPs: diazepam (DZP), 0.3-0.5mg/kg and/or midazolam (MDL), 0.2-0.4mg/kg. Among non-responders to initial IV BZPs, late responders whose recurrent CSE responded to IV BZPs in older age were analyzed. Results: A total of 83 patients were identified: responders 58, non-responders 26. Non-responders included 14 cases of late responders, 2 cases with single CSE episode, and 9 cases with multiple CSE but treated with IV anti-SE agents other than BZPs. At the initial IV BZPs, age distribution among responders (2-68 months, mean 2 years 4 months), non-responders including late responders (2-71m, mean 2y6m) and late responders (4-67m, mean 2y8m) was not different. Late responders included frontal lobe epilepsy, 7 cases, focal cortical dysplasia, 2, and congenital hydrocephalus with polymicrogyria, occipital lobe epilepsy, Dravet syndrome, PEHO syndrome, and chromosomal abnormality, one each. They presented with tonic +tonic-clonic SE in 13 cases, generalized clonic SE in one case. They did not respond to IV DZP and/or MDL until 7m-5y6 m (mean 2y10m) but well responded to them or DZP suppository at 2y4m-7y3m or later (mean 3y11m). The seizure symptoms were nearly same when CSE did not respond or did respond to IV BZPs in a particular patient. Duration from the onset of CSE to IV BZPs was not so different between non-responding and responding to IV BZPs in individual patient. Outside the present study, there were two patients with FLE whose seizures exaggerated with IV DZP and MDL even at 10 and 12 years of age. Since there are nearly no difference between responders and late responders in age distribution, seizure symptoms in CSE and time from onset of CSE to IV BZPs, change of the efficacy of IV BZPs to CSE seemed to be caused by developmental change of GABA receptors function from excitatory to inhibitory in humans. This change may occur slightly older in humans than in rodent experiments. Conclusions: BZDs do not always suppress SE in younger children but may become effective later because of developmental changes of GABA receptor function. The present result suggests that other anti-SE drugs should be applied instead of repeat BZDs in younger age when the first IV of BZDs fails to stop SE, but that BZDs can be tried for SE in older age even if the response was unfavorable in younger age. However, there are some patients who do not respond to IV BZDs even in older age. Funding: None