We report six children who were treated with topiramate for neonatal seizures that were refractory to standard doses of phenobarbital and/or phenytoin. In five of the children, topiramate was administered as an enteric loading dose of 10mg/kg, and in one child, maintenance therapy was initiated at 3mg/kg/day. In four of five children who received a loading dose of topiramate, there was apparent reduction or absence of further seizures, whereas one child who received only a maintenance dose continued to have seizures without evident change in frequency. None of the children experienced side effects that resulted in discontinuation of the drug, either during the hospital admission or after discharge home, although three with neurological impairment had weight at or below the 5th percentile at follow-up.
Animal model data suggest that topiramate is effective as both an anti-seizure and a neuroprotective agent, and, unlike phenobarbital and phenytoin, does not enhance apoptosis [18
]. Human data from open label studies suggest that topiramate may be a safe and effective anti-seizure therapy for infants greater than one month. Topiramate has been used for refractory status epilepticus with reported effect in at least two infants ([27
]), as well as for many more infants as initial monotherapy or for refractory epilepsy ([29
]), and for infantile spasms ([33
]). However, a recent randomized controlled trial suggested that topiramate in doses up to 25mg/kg/day may not be an efficacious add-on agent for infants aged one month to two years with refractory epilepsy [38
Though this is a novel series of newborns treated with topiramate for refractory neonatal seizures, our case series is not without limitations. We report a small series of patients who were evaluated retrospectively. Like many centers, the Montreal Children’s Hospital does not have the capacity for long term video-EEG monitoring, and so seizures were identified based on clinical diagnosis and intermittent EEG evaluations. Neonatal seizures are best evaluated with continuous video-EEG monitoring: clinical diagnosis is uncertain and there is a high rate of electroclinical dissociation in newborns (with ongoing electrographic seizures following resolution of clinical seizures) [39
]. For this reason, there is consensus among experts that video-EEG is the “gold standard” for confirmation of neonatal seizures, and we agree that future studies must evaluate the immediate effect of topiramate on electrographic seizures [41
]. Neonatal seizures are often self-limited over 48–72 hours, making any add-on agent appear more effective than the initial therapy. Fourth, clinical testing for serum topiramate levels was not possible, so it is uncertain how much of the drug was absorbed via the enteric route, especially in the setting of hypoxic-ischemic encephalopathy. This is especially important considering that hypoxic-ischemic encephalopathy was the most common diagnosis, and ischemia to the gut may have limited absorption. Evaluation of the side effects of topiramate was limited by documentation by the treating physician. Due to this limitation, as well as small sample size, we cannot exclude medication side effects from topiramate. Finally, the small size of the cohort and lack of pharmacokinetic evaluation makes any speculation about optimal doses, timing and treatment population impossible.