Topiramate for the Treatment of Neonatal Seizures

Abstract

Current therapeutic options for treatment of neonatal seizures, such as phenobarbital and phenytoin lack efficacy, and are potentially harmful to the developing brain. Topiramate appears to be effective as both an anti-seizure and neuroprotective agent in animal models of newborn brain injury. Though topiramate is commonly used as an add-on agent in newborns, its use in this population has not yet been reported. We performed a retrospective cohort study of clinical topiramate use in newborns with acute symptomatic seizures that were refractory to standard agents. In four of six identified newborns, there was apparent reduction or no further seizures, and none of the children experienced side effects that resulted in discontinuation of the drug, either during the hospital admission or after discharge home. Prospective studies evaluating the safety and efficacy of topiramate for both seizures and neuroprotection will be important to determine whether this medication deserves widespread use in clinical practice.

Introduction

Neonatal seizures occur in approximately 1–3.5 per 1,000 live births [1–7], and are the most common acute sign of serious underlying newborn brain injury [8]. Treatment for neonatal seizures has gained increasing attention in light of accumulating evidence that seizures, in and of themselves, may harm the developing brain [9–11]. However, anti-seizure therapy for newborns has remained largely unchanged for decades, with phenobarbital as the preferred first line agent in both the North America and abroad [12–14]. This is despite good evidence demonstrating that phenobarbital and phenytoin (a commonly-used second line agent) are effective in less than 50% of newborns with seizures [15]. Furthermore, there is increasing evidence from animal models that these agents have intrinsic potentially neurotoxic effects, though their effect on human newborns with seizures is not known [16,17].

Topiramate is approved by the US Food and Drug Administration for children older than age two. In animal models of newborn brain injury, topiramate appears to be an effective anti-seizure medication with evident neuroprotective properties [18–22]. Furthermore, animal models show no evidence of harmful effects of topiramate on the developing brain [23].

In spite of survey results suggesting that topiramate is commonly used as an add-on agent for neonatal seizures [24], its use has not yet been reported. We examined medical records to identify and report six children who were treated with topiramate for neonatal seizures.

Study Design and Methods

This is a retrospective cohort study of clinical use of topiramate in newborns treated for seizures at the Montreal Children’s Hospital, after January 1, 2009. The Montreal Children’s Hospital neonatal intensive care unit is an outborn Level III nursery serving newborns delivered in hospitals in Montreal and the province of Québec. We identified newborns treated with topiramate for acute symptomatic seizures that were refractory to initial medications, and who were followed in the Neonatal Neurology clinic at the Montreal Children’s Hospital. Seizure therapy (including drug dosing), measurement of phenobarbital levels, timing and duration of electroencephalogram (EEG) monitoring, and imaging were at the discretion of the attending neonatologist and neurologist. Topiramate drug levels were not clinically available and were not performed.

The hospital charts were systematically reviewed for clinical features of interest, including perinatal history, clinical course, seizure etiology, neurophysiology, imaging, and follow-up data. Clinical seizures were diagnosed when the medical records indicated events that were considered to be and treated as seizures. Semiology was classified according to Mizrahi et al [25]. Electrographic seizures were diagnosed based on the clinical neurophysiology reports. Seizure control was considered when there was no further mention of clinical seizures, or electrographic seizures when EEG was available. Potential side effects of topiramate (including anorexia, weight loss, vomiting, diarrhea, acidosis leading to discontinuation of medication, glaucoma and renal calculi) were noted by reviewing the medical records. The children were evaluated in the Neonatal Neurology follow-up clinic by a neurologist who is familiar with the use of topiramate in children (MS or CP). Routine blood work was not performed as part of the follow-up evaluation. The Director of Professional Services at the Montreal Children’s Hospital approved the chart review as per standard local protocol.

Results

We identified six term newborns treated with topiramate for acute symptomatic seizures that were refractory to phenobarbital (30–60mg/kg, level 34–42μg/mL), and who were followed in the Neonatal Neurology clinic at the Montreal Children’s Hospital. In all cases, the topiramate was administered as a suspension of the crushed tablet via a nasogastric tube. The dose used was 10mg/kg in five subjects and 3mg/kg in one subject. No seizures were detected on follow-up EEG in three subjects and frequency was reduced in one subject. No side effects of topiramate therapy were noted during the admission or at follow-up, though three subjects had a weight <5^th percentile. The case histories are summarized in Table 1.

Table 1.

Use of topiramate in six newborns with seizures.

	Clinical History	Seizure Etiology	Clinical Seizure Semiology	EEG Confirmation of Seizure	Medications	Response to Topiramate	Follow-up	Side Effects
1	41 2/7 week Male	Perinatal asphyxia with HIE and hemorrhagic infarct	Generalized tonic	Yes	Pb 45mg/kg TPM 10mg/kg	No further clinical or EEG seizures	11.5 months Seizure-free on TPM monotherapy Evolving spastic quadriparesis NG dependent for 50% of intake	Weight 10–25th %ile
2	39 6/7 week Female	Temporal lobe hemorrhage	Apnea	Yes	Pb 30mg/kg TPM 3mg/kg	Ongoing EEG seizures	8 months Seizure-free on TPM monotherapy Normal exam	Nil
3	38 6/7 week Male	Presumed prenatal HI injury	Focal clonic	Yes	Pb 40mg/kg TPM 10mg/kg	No further clinical or EEG seizures	11 months Seizure-free on TPM monotherapy Normal exam	Nil
4	37 1/7 week Female	Perinatal asphyxia with HIE	Focal clonic or tonic* and motor automatisms	No	Pb 40mg/kg TPM 10mg/kg	No further clinical or EEG seizures	8.5 months Seizure-free on TPM monotherapy Evolving spastic quadriparesis	Weight <5th %ile
5	Term Female	Presumed prenatal HI injury	Focal clonic and motor automatisms	Yes	Pb 60mg/kg PHT 30mg/kg TPM 10mg/kg	Reduced frequency of EEG seizures	5 months Infantile spasms while on Pb and TPM Evolving spastic quadriparesis	Weight <5th %ile
6	40 2/7 week Female	Perinatal asphyxia with HIE	Unavailable	Yes	Pb 30mg/kg TPM 10mg/kg	Ongoing clinical seizures	6 months Seizure-free on TPM Mild increased tone	Weight <5th %ile

HIE hypoxic-ischemic encephalopathy; Pb Phenobarbital; TPM topiramate; EEG electroencephalogram

^*Clonic vs tonic semiology cannot be determined based on available documentation

Discussion

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 [18–23,26]. 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 ([27,28]), as well as for many more infants as initial monotherapy or for refractory epilepsy ([29–32]), and for infantile spasms ([33–37]). 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) [39,40]. 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.

Conclusions

There is an urgent need for well-designed clinical trials to test newer seizure treatments for newborns. Topiramate is an attractive candidate, since it is neuroprotective in animal models of hypoxic-ischemic injury, the most common etiology of seizures in the newborn and a common cause of developmental disability. Furthermore, a stable intravenous formulation has been tested in adults with epilepsy and healthy volunteers, and the results show that IV and oral bioavailability are equivalent, and that the IV formulation is well tolerated [42].

Prospective studies evaluating topiramate safety and efficacy for both seizures and neuroprotection will be important to determine whether this medication deserves widespread use in clinical practice.