Effectiveness and Safety of High-Dose Oral Phenobarbital in Children With Recurrent and Treatment-Refractory Seizures

Abstract

In this study, we applied high-dose oral phenobarbital (PB) to children with recurrent and treatment-refractory seizures or recurrent status epilepticus and evaluated the effectiveness and safety of this treatment. We retrospectively reviewed patients’ medical records who received oral high-dose PB treatment between January 2019 and July 2024. In this study, recurrent and treatment-refractory seizures was defined as the persistence of daily epileptic seizures or recurrent attacks of status epilepticus despite treatment with oral antiepileptic drugs or continuous intravenous midazolam therapy. High-dose oral PB therapy was performed on 11 patients (7 females and 4 males). The median age at the onset of epilepsy was 2 months (range: 0.06-132 months). The underlying disorders or comorbidity were genetic disorders (1q14 del, compound heterozygous for the PNKP gene, Wolf-Hirschhorn syndrome, ring chromosome 14 syndrome) in 4 patients, cerebral palsy in 2 patients, metabolic disorders (Zellweger syndrome, pyridoxine-dependent epilepsy) in 2 patients, traumatic brain injury and hypoxia, hemimegalencephaly, and ataxia and intellectual disability in 1 patient. The median age at initiation of high-dose PB therapy was 11 months (range: 2-203 months). The maximal dose of PB ranged from 6 to 14.7 mg/kg/d (median: 10 mg/kg/day). The maximal serum PB levels ranged from 33 to 56 µg/mL (median: 44 µg/mL). We evaluated the effectiveness of this treatment as follows: “effective” represented more than 50% seizure reduction, “ineffective” represented less than 50% seizure reduction, and “exacerbation” represented an increase in seizure frequency. In 7 of the 11 patients (63.6%), oral high-dose PB therapy was effective and was transiently effective in the other 4 patients. Adverse effects were noted in 6 patients (54.5%) during high-dose oral PB therapy: drowsiness in 5 patients and mild elevations in transaminases in 2 patients.

Introduction

Phenobarbital (PB), one of the oldest antiepileptics, is used in the long-term treatment of generalized and focal motor seizures. ¹ Phenobarbital is a highly effective drug with GABA-ergic and anti-glutamatergic activity. ² After more than 100 years of continuous use, PB remains one of the most widely prescribed antiepileptic drugs in the developing world. However, its use is decreasing in developed countries due to perceived significant tolerability problems, especially in children and adults. ¹ Phenobarbital is associated with several dose-dependent and idiosyncratic drug reactions. Sedation and listlessness, irritability and hyperactivity, exacerbation of aggression, depression, and memory and concentration disorders are among the potential adverse effects on mental functions. Learning difficulties and other undesirable effects on cognition, attention, and mood have been described, especially in children. ³ Phenobarbital is used in both acid and sodium salt forms and can be administered orally, intravenously, intramuscularly, or rectally. ¹

Despite its extended use in clinical practice, there are remarkably few randomized clinical trials of PB in status epilepticus. ² High-dose PB treatment, usually given intravenously, is effective for refractory status epilepticus.^4-6 Moreover, several reports have claimed that non-intravenous high-dose PB therapy is effective as an adjunctive treatment for childhood intractable epilepsy.^7-10 It is generally well tolerated and has several clinical advantages, including rapid and long-lasting action and a favorable safety profile, even at high doses. ²

There is limited information in the literature regarding the efficacy and safety of high-dose oral PB in children with recurrent and treatment-refractory seizures. In this study, we applied high-dose oral PB to children with recurrent and treatment-refractory seizures and evaluated the effectiveness and safety of this treatment.

Material and Methods

We retrospectively reviewed patients’ medical records who received oral high-dose PB treatment at Bursa Uludağ University Child Neurology Clinic between January 2019 and July 2024. In this study, recurrent and treatment-refractory seizures was defined as the persistence of daily epileptic seizures or recurrent attacks of status epilepticus despite treatment with oral antiepileptic drugs or continuous intravenous midazolam therapy. All patients were hospitalized and treated in our institution. Medical records were reviewed as follows: gender, age, age at epilepsy onset, age at high-dose PB treatment, underlying disorders or comorbidity, developmental delay and level, if any, seizure type, frequency of seizures and antiepileptics drugs used before high-dose PB treatment, PB maximum dosage, PB maximum serum level (samples for PB level were taken before the next dose), seizure frequency after treatment, interictal electroencephalogram (EEG) findings, brain magnetic resonance imaging (MRI) findings, and side effects during the treatment period. As there is no IV form of PB in our country, all patients received PB tablet treatment orally, nasogastric, orogastric, or via percutaneous endoscopic gastrostomy (PEG), depending on the patient’s conditions. Patients were initially given an oral dose of 20 mg/kg PB, which was then reduced to a maintenance dose of 5 to 10 mg/kg/day. Phenobarbital serum level was evaluated after 7 to 10 days. We planned the target PB level as 35 to 45 µg/mL for high-dose PB levels (reference range of PB concentration: 20-40 µg/mL). We evaluated the effectiveness of this treatment as follows: “effective” represented more than 50% seizure reduction, “ineffective” represented less than 50% seizure reduction, and “exacerbation” represented an increase in seizure frequency.

The study was approved by the local ethics committee (2024-12/7). The data were analyzed using IBM-SPSS statistics (version 28), and median, maximum, and minimum values were used in descriptive statistics.

Results

Table 1 summarizes patients receiving high-dose oral PB therapy’s clinical features, outcomes, and adverse effects. High-dose oral PB therapy was performed on 11 patients (7 females and 4 males). The median age at the onset of epilepsy was 2 months (range: 0.06-132 months). The underlying disorders or comorbidity were genetic disorders (1q14 del, compound heterozygous for the PNKP gene, Wolf-Hirschhorn syndrome, ring chromosome 14 syndrome) in 4 patients, cerebral palsy in 2 patients, metabolic disorders (Zellweger syndrome, pyridoxine-dependent epilepsy) in 2 patients, traumatic brain injury and hypoxia, hemimegalencephaly, and ataxia and intellectual disability in 1 patient. The patient with hemimegalencephaly was diagnosed with tuberous sclerosis in the later period. All patients exhibited delayed psychomotor development, which was severe in 9 patients and mild in 2 patients.

Table 1.

Clinical Characteristics, Outcomes, and Side Effects of Patients.

Case	Sex	Age (M)	Underlying disorders/comorbidity	Age at epilepsy onset (M)	Seizure type	Developmental delay	AEDs before high-dose PB	Age at high-dose PB	Maximal dose of PB (mg/kg)	Seizure frequency before high-dose PB	Seizure frequency after titration of PB	Maximal serum PB level (µg/mL)	Seizure outcome	AEDs at last follow-up	Adverse effects
1	M	178	Cerebral palsy	2	Deviations of the eyes to the right, blinking, tonic posture of the arms and legs	Severe	CBZ, VPA, TPM, DZM	176	7	10-15/day	1-3/month	42	Effective	PB, VPA, CLN	Drowsiness
2	M	216	Ataxia, intellectual disability	132	Rolling up of the eyes, Clonic movements of the arms	Mild	CBZ, CLN, LEV, VPA	203	7.5	3-4/day	Seizure free for 4 months then monthly	40	Effective	PB, CBZ, LEV, CLN	None
3	F	10	Zellweger syndrome	0.66	Tonic posturing of the legs, myoclonus of the arms	Severe	PB, LEV	4	14.7	40-50/day	1-2/day for 2 months then previous situation	55	Transiently effective	PB, LEV, LRZ	Drowsiness, mild elevation of transaminases
4	F	22	1q14 del, microcephaly	14	Deviations of the eyes to the right, tonic posturing of the arms	Severe	VPA, TPM, LEV	16	12.5	15-20/day	4-5/day	34	Effective	PB, VPA, TPM	Drowsiness
5	M	58	Compound heterozygous for the PNKP gene, microcephaly	0.73	Oral automatism, blinking eyes, clonic movements of the right arm	Severe	PB, CLN	11	10	4-5/month	1-2/year	45	Effective	PB, CLB	Mild elevation of transaminases
6	F	35	Wolf-Hirschhorn syndrome	6	Rolling up of the eyes, clonic movements of the arms	Severe	None	6	10	First attack status epilepticus	3-4/year	35	Effective	PB	None
7	M	24	Pyridoxine-dependent epilepsy	0.1	Clonic movements of the arms and legs	Mild	VPA, CLB	2	6	4-5/day	Seizure free for 1 month then previous situation	44	Transiently effective	Pyridoxine	None
8	F	47	Ring chromosome 14 syndrome	1.13	Head rotation to the right, deviations of the eyes to the right, tonic posturing of the arms	Severe	PHT, LEV	7	7	7-8/day	3-4/year	49	Effective	PB, CLN	Drowsiness
9	F	29	Traumatic brain injury and hypoxia	27	Rolling up of the eyes, apnea, clonic movements of the arms	Severe	LEV, PHT, VPA, MDL infusion	27	10	First attack status epilepticus	Seizure free	56	Effective	PB, LEV	None
10	F	66	Cerebral palsy, pyruvate kinase deficiency	25	Clonic movements of the right arms and legs	Severe	PHT, LRZ	27	10	3-4/day	Seizure free for 1 month then previous situation	54	Transiently effective	PB, VPA, CLB	Drowsiness
11	F	28	Hemimegalencephaly	0.06	Rolling up of the eyes, tonic posturing of the right arm	Severe	PB, LEV	4	10	10-15/day	3-4/month for 2 months then previous situation	33	Transiently effective	VGB, CBZ, Everolimus	None

Abbreviations: M, male; F, female; M, month; AEDs, antiepileptic drugs; PB, phenobarbital; CBZ, carbamazepine; VPA, valproic acid, TPM, topiramate; DZM, diazepam; CLN, clonazepam; LEV, levetiracetam, CLB, clobazam; PHT, phenytoin; MDZ, midazolam; LRZ, lorazepam; VGB, vigabatrin.

Regarding interictal EEG findings, all patients frequently had focal, multifocal, and generalized electric abnormalities, such as spikes, polyspikes, spike-wave complexes, and high-amplitude slow waves. Regarding brain MRI findings, MRI of 2 cases (cases 2, 10) was normal. Abnormal MRI findings were multicystic encephalomalacia (case 1), perisylvian polymicrogyria, germinolytic cysts, diffuse white matter abnormality (case 3), diffuse cerebral and cerebellar atrophy (case 4), severe microcephaly, gyral simplification, corpus callosum dysgenesis (case 5), corpus callosum dysgenesis (case 6), periventricular leukomalacia (case 7), cerebral cortical atrophy, corpus callosum agenesis (case 8), traumatic subarachnoid hemorrhage and brain edema (case 9), and hemimegalencephaly (case 11), respectively.

The median age at initiation of high-dose PB therapy was 11 months (range: 2-203 months). Two patients presenting with status epilepticus (cases 6 and 9) received oral high-dose PB therapy from the beginning of this treatment. Eight of the 11 patients were suffering multiple daily seizures when high-dose PB was commenced. Different seizure types are observed in patients, as summarized in Table 1. Antiepileptic drugs used before high-dose PB are shown in Table 1. Levetiracetam was used for 6 patients; valproic acid for 5 patients; phenytoin for 3 patients; PB for 3 patients; topiramate for 2 patients; clonazepam for 2 patients; and clobazam, lorazepam, diazepam, and midazolam infusion for 1 patient. The maximal dose of PB ranged from 6 to 14.7 mg/kg/day (median: 10 mg/kg/day). The maximal serum PB levels ranged from 33 to 56 µg/mL (median: 44 µg/mL). In 7 of the 11 patients (63.6%), oral high-dose PB therapy was effective and was transiently effective in the other 4 patients. In these 4 patients (cases 3, 7, 10, 11), seizure frequency decreased for 1 to 2 months and then seizures returned to their previous levels.

Adverse effects were noted in 6 patients (54.5%) during high-dose oral PB therapy: drowsiness in 5 patients and mild elevations in transaminases in 2 patients. No patient’s medication was discontinued due to adverse effects. Drowsiness and elevations in transaminases disappeared as the PB serum level decreased. Drug interactions were seen in 2 patients who received high doses of phenobarbital. Both of these patients were using valproic acid, and a decrease in valproic acid levels due to phenobarbital use was observed in the patients, and the dose of valproic acid had to be increased to ensure appropriate plasma concentrations.

Discussion

This study demonstrated that oral high-dose PB therapy is effective for recurrent and treatment-refractory seizures in childhood. Oral high-dose PB treatment was effective in all 11 children with recurrent and treatment-refractory seizures, but these effects returned within 1 to 2 months in 4 patients. Adverse effects were noted in 6 patients (54.5%) during high-dose PB therapy: drowsiness in 5 patients and mild elevations in transaminases in 2 patients. These side effects were reversible with drug dose adjustments, and no patient’s medication was discontinued due to side effects.

Phenobarbital is a highly effective drug with GABA-ergic and anti-glutamatergic activity. It is frequently used in early, established, refractory status epilepticus. It has a long clinical history and is still one of the most effective drugs in status epilepticus. It is one of the few drugs for status epilepticus in young children and neonates. However, there are relatively few randomized clinical trials involving PB. ² ,^4-6 In the literature, the use of high-dose enteral PB to manage refractory status in children is described as effective and uncomplicated for centers with limited resources and lacking parenteral PB.^11,12 Moreover, several reports have claimed that non-intravenous high-dose PB therapy is effective as an adjunctive treatment for childhood treatment-refractory seizures.^7-10 In this study, oral high-dose PB treatment was effective in all 11 children with recurrent and treatment-resistant seizures (Table 1). Phenobarbital is an antiepileptic drug widely used orally in the treatment of epilepsy and intravenously in status epilepticus. Especially in countries with limited resources and no access to IV phenobarbital treatment, such as ours, oral phenobarbital treatment should be considered as an option for refractory and recurrent seizures. Oral administration is as effective as IV administration, especially when high doses are reached. The disadvantage of oral administration compared with IV administration may be the time it takes to reach stable serum levels. We believe that it would be appropriate to follow these patients with closer serum levels. Before high-dose PB was started, 2 patients had status epilepticus, 8 patients had multiple daily seizures, and 1 patient had 4 to 5 seizures per month. When the seizure frequencies of the patients were examined at the last follow-up after high-dose PB treatment, one of the 2 patients who presented with status epilepticus was seizure-free. In contrast, the other patient had 3 to 4 seizures per year. Four of the 8 patients with multiple daily seizures had a 50% or more significant decrease in seizures, and 4 patients had temporary improvement. In the patient who had 4 to 5 seizures per month, the seizure frequency decreased to 1 to 2 seizures per year at the last follow-up.

All patients exhibited delayed psychomotor development, which was severe in 9 patients and mild in 2 patients. All patients frequently had focal, multifocal, and generalized electric abnormalities in interictal EEG. Brain MRIs were abnormal in all other patients except 2 patients. When high-dose PB was started, 8 of the 11 patients had multiple seizures per day, and 2 patients presented with their first episode of status epilepticus. The maximal dose of PB ranged from 6 to 14.7 mg/kg/day. Consistent with the literature, this study also showed that oral high-dose PB treatment is effective for recurrent and treatment-refractory seizures in childhood.

The primary concern with the use of PB is the dose-related central nervous system depressant effect common to all barbiturates. Serum levels above 70 µg/mL almost always impair consciousness, which may contribute to postictal coma. Of more concern appear to be respiratory depression, hypotension, and, at high doses, a negative inotropic effect on the myocardium. ² Studies suggest that adjusting the dose to maintain PB serum concentration between 50 and 60 µg/mL may be necessary in controlling seizures without triggering harmful side effects.^9,10 In our study, the effective PB maximum levels ranged from 33 to 56 µg/mL, consistent with the levels recommended in the literature.

Phenobarbital therapy is associated with several dose-related and idiosyncratic drug reactions. Phenobarbital has sedative, behavioral, and mood effects, particularly in children. ¹³ Adverse effects of PB therapy have been reported to include cognitive decline, learning, and mental performance. ⁹ High-dose PB therapy was very well tolerated in our study. In our study, 54.5% of patients experienced transient side effects during high-dose oral PB therapy. These were drowsiness in 5 patients and mild elevations in transaminases in 2 patients, which resolved with dose adjustment. No patient’s medication was discontinued due to side effects.

Phenobarbital is metabolized in the liver and potent inducer of the cytochrome P450 system. When used mainly with drugs metabolized by the cytochrome P450 system, the effectiveness of these drugs is reduced by decreasing their plasma levels. ¹⁴ Our study observed drug interactions between phenobarbital and valproic acid in 2 patients. Both of these patients were using valproic acid in addition to phenobarbital treatment. A decrease in valproic acid levels was observed in the patients due to phenobarbital use, and the valproic acid dose had to be increased to provide appropriate plasma concentrations. For this reason, we think that serum levels of drugs used together with enzyme-inducing drugs such as phenobarbital should be monitored more closely in terms of their efficacy and side effects.

The limitations of this study were that it was conducted on a small number of patients and was retrospective. We also did not compare the efficacy and tolerance of oral high-dose PB treatment with other antiepileptic drugs. As almost all of our patients had severe developmental delays, we could not investigate changes in cognitive functions before and after high-dose PB. Therefore, our results should be interpreted with caution.

Conclusions

This study showed that high-dose oral PB treatment is effective and safe in children with recurrent and treatment-refractory seizures. This condition is especially true in developing countries with limited resources or no access to intravenous PB therapy, such as our country. High-dose oral PB therapy should be individualized, taking into account the severity of epilepsy, the level of development delay, and the presence of side effects.

Author Contributions

MB: Contributed to conception and design, contributed to analysis, drafted the manuscript, critically revised the manuscript, gave final approval, agrees to be accountable for all aspects of work ensuring integrity and accuracy.

RTT: Contributed to conception and design, drafted the manuscript, gave final approval, agrees to be accountable for all aspects of work ensuring integrity and accuracy