Phenytoin toxicity in children – A tertiary center experience

INTRODUCTION

Phenytoin, a voltage-gated sodium channel blocker, is a widely used anti-seizure medication (ASM) in children for generalized tonic-clonic and partial seizures.^[1] Phenytoin has a narrow therapeutic index, and the peak plasma concentration is reached in 4–8 h. About 90% of phenytoin is bound to plasma proteins (mainly albumin), and the unbound phenytoin is the pharmacologically active form.^[1] Higher fractions of unbound phenytoin are seen in neonates, pregnant patients, and hypoalbuminemia conditions, including liver failure, chronic kidney disease, and malnutrition.^[1] It has targeted action on neurons with high-frequency activity and a selective inhibitory effect on the motor cortex.^[1-3] It binds to inactivate sodium channels, prolongs the neuronal refractory period, and increases the levels of the inhibitory neurotransmitters, including serotonin and g-aminobutyric acid. This inhibits abnormal neuronal discharges, prevents the transmission of abnormal impulses, and reduces withdrawal symptoms.^[3] The nature of phenytoin toxicity mainly depends on the dose, administration route, and exposure duration.^[1] The dose-dependent manifestations of phenytoin toxicity (plasma concentration) include tremor at 20 μg/mL, ataxia at 30 μg/mL, and coma at ≥40 μg/mL.^[3] Phenytoin is a commonly available ASM in the primary and community level hospitals, and awareness regarding the proper dosage and dilution for usage in children is limited. Hence, we studied the characteristics of phenytoin toxicity in children who were referred from peripheral/rural hospitals to a tertiary care pediatric center.

METHODS

This study is a retrospective case series of children presenting with phenytoin toxicity to a tertiary care pediatric hospital over 18 months (May 2022–October 2023). Inclusion criteria are as follows: Children aged from 1 to 18 years presenting with phenytoin toxicity. Exclusion criteria are as follows: Children with documented poly-ASM usage for termination of seizures before referral. A total of 15 children were included, and the basic demographic data, clinical profile, treatment, and outcomes were recorded in a pre-structured proforma. Descriptive statistics were used. Statistical Package for the Social Sciences version 28 (IBM, Chicago, IL, USA) was used for data analysis.

RESULTS

In our study, of the 15 children included, 60% were male and 40% were female. The mean age was 7.5 ± 5.3 years. The clinical presentations were cerebellar ataxia (15/15), gaze-evoked nystagmus (14/15), intentional tremor (14/15), acute encephalopathy (12/15), behavioral abnormalities including confusion, restlessness, agitation (11/15), seizures (5/15), dystonia (4/15), and deep encephalopathy requiring mechanical ventilation (2/15). Among them, 6/15 received appropriate doses, 5/15 received doses higher than the ceiling dose (1500 mg/dose), and in 4/15 of children, dose documentation was unavailable. On reviewing the available documents, 3/15 of children had improper methods of administration, including rapid intravenous push, inadequate dilution, and inadequate infusion time. About 3/15 of children did not have proper documentation regarding the dose and administration methods. The mean time of resolution of toxicity symptoms was 8.3 ± 3.9 days. The results and clinical details are summarized in Table 1.

DISCUSSION

Phenytoin has an increased risk of toxicity due to the narrow therapeutic window and varied inter-individual elimination of the drug.^[4] Phenytoin is bound to albumin and is mainly metabolized by the cytochrome-p450 enzyme. Hence, the drugs that displace phenytoin from albumin and inhibit cytochrome-p450 will indirectly result in phenytoin toxicity. Phenytoin metabolism follows first-order kinetics at the therapeutic range and zero-order kinetics at higher doses.^[3] The therapeutic range for phenytoin is defined as between 10 and 20 mg/L. However, it exhibits inter-individual variation.^[5] The short-term toxic effects of phenytoin are reversible but can also be life-threatening.^[1]

Acute toxicity can cause ataxia, tremors, nystagmus, diplopia, chorea, dyskinesia, dystonia, and dysrhythmias.^[1,6] Chronic toxicity causes gingival hypertrophy, cerebellar atrophy, nocturnal enuresis, alopecia, altered Vitamin D and thyroid hormone homeostasis, peripheral neuropathy, drug reaction with eosinophilia and systemic symptoms syndrome, Stevens-Johnson syndrome, and purple glove syndrome.^[1,5-7] The other rarely reported symptoms of phenytoin toxicity are complex visual hallucinations and status dystonicus.^[8,9] In the index study, the common clinical signs of toxicity at presentation were cerebellar ataxia, nystagmus, intentional tremors, encephalopathy, and dystonias, as reported in the literature.^[1,6]

Liver cirrhosis, chronic kidney disease, malnutrition, and malignancy can cause changes in the phenytoin plasma concentration due to altered physiology in patients on chronic therapy without dose modifications.^[2] Bansal et al. studied the adverse effects of common ASMs in a pediatric outpatient setting and reported that phenytoin was the most common causative agent of adverse drug reactions.^[10] In children with suspected phenytoin toxicity, complete hemogram, metabolic profile including liver function test and serum albumin levels, serum phenytoin levels, and electrocardiogram should be done. If seizures occur, benzodiazepines are the preferred first line of medications.^[1] The management is supportive care, as there is no specific antidote for phenytoin toxicity. Knecht et al. reported a successful utilization of extracorporeal membrane oxygenation support in a 3-dayold infant with severe phenytoin toxicity.^[4]

The key to phenytoin toxicity is prevention, as there is no specific antidote. The ancillary treatments for phenytoin toxicity are intravenous albumin, lipid infusion, phenobarbital, and folic acid supplementation.^[1] We emphasize the need for awareness regarding the proper dosage, dilution, and narrow therapeutic profile of phenytoin among general practitioners, especially at the primary and community healthcare levels.

CONCLUSION

The clinical presentation can mimic an array of neurological symptoms and can sometimes mislead clinicians toward unnecessary investigations and treatment strategies. This study opens a research opportunity at the grassroots level for quality improvement studies and educating the primary health care workers about the drugs, their dosages, route of administration, rate of administration, and most importantly, the knowledge about the ceiling dosages of various ASMs.