Adverse Effects of Antiepileptic Medications in Children: A Case Report and Review

On physical examination, the patient appeared well, except for the obvious diffuse rash. Erythematous macules, papules, and patches covered his extremities, face, trunk, palms, and soles. His conjunctivae, mucous membranes, and joints were normal, as were the results of cardiac, pulmonary, abdominal, and neurologic examinations. Several anterior and posterior cervical lymph nodes (0.5 to 1 cm) were present bilaterally.

An extensive laboratory investigation, including throat, blood, and urine cultures; complete blood cell count; Epstein-Barr virus antibody titers; and urinalysis, was unremarkable. Liver transaminase levels were mildly elevated. Phenytoin hypersensitivity reaction was diagnosed, and the phenytoin was immediately discontinued. The patient was closely monitored. The rash improved within 48 hours and completely resolved, along with the lymphadenopathy, within the next 3 weeks.

Reactions to phenytoin can range in severity from the minor (simple exanthem) to the life-threatening (Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]).¹ Exanthems may occur in 5% to 54% of patients and are more likely to occur in children.² SJS and TEN are rare, potentially fatal, and debilitating conditions that have been reported in patients who have been exposed to other older antiepileptic drugs (AEDs), such as carbamazepine and phenobarbital.¹

Phenytoin hypersensitivity reaction is characterized by fever, rash, lymphadenopathy, and hepatitis. It can cause great distress for both the child and his or her family. A child with any phenytoin reaction needs to be monitored closely for signs of a life-threatening condition. The exact mechanisms of each potential phenytoin reaction are not fully understood, but the metabolites of phenytoin probably cause cell damage themselves or serve as haptens that stimulate a destructive immunologic response.³

Despite the approval of several AEDs since 1993, clinicians are still more likely to initially prescribe a more traditional AED for a child with seizures,⁴ even though some evidence shows that the newer agents are better tolerated than the older ones.⁵ Attractive features of the newer agents are their minimal effects on the hepatic enzyme system and their limited effects on the metabolism of other drugs. Also, the need for less laboratory monitoring is an advantage, especially when treating children.

However, the newer medications are not risk-free. For instance, lamotrigine (Lamictal, GlaxoSmithKline) is associated with the development of SJS and TEN within the first 8 weeks of treatment initiation,¹ and oxcarbazepine (Trileptal, Novartis) cross-reacts with other aromatic anticonvulsants (phenytoin and carbamazepine).³

Oxcarbazepine, along with the older liver-inducing AEDs, has been associated with a very limited increased risk of bone fractures.⁶ All the AEDs have the potential to cause adverse CNS and GI side effects, and the long-term cognitive effects of the newer AEDs, in particular, are unknown because data from the controlled trials on the neuropsychological effects of these agents are lacking.⁷ A more complete review of the potential adverse reactions of some of the older and newer AEDs in children is provided in the Table, with emphasis on the particular problems associated with each agent.

OLDER AEDs

Carbamazepine A boxed warning emphasizes that aplastic anemia and agranulocytosis are associated with the use of carbamazepine.⁸ Because of this, baseline and periodic complete blood cell counts need to be obtained throughout the treatment course. Liver function test results also should be monitored because carbamazepine therapy has been associated with liver damage. CNS side effects such as dizziness, drowsiness, and unsteadiness, along with GI symptoms such as nausea and vomiting, occur occasionally. SJS, cardiotoxicity, and bone fractures are some of the other uncommon complications associated with carbamazepine use. Since carbamazepine is a hepatic enzyme inducer, interactions with other drugs are a concern.

Phenobarbital The CNS side effects of phenobarbital limit its usefulness in children. Behavioral problems and cognitive deficits are particularly worrisome. A lowered IQ may result, and decreased academic achievement may persist for years.⁷ Phenobarbital also may increase the risk of fractures and, as a potent hepatic enzyme inducer, it is capable of modifying the serum levels of many other drugs.

Phenytoin The development of local or generalized lymphadenopathy, as well as lymphoma or pseudolymphoma, in association with the administration of phenytoin is an interesting phenomenon. A case of childhood lymphoma after prenatal exposure to phenytoin also has been reported.⁹ Lymphadenopathy is typically part of the hypersensitivity reaction, as in the case presented here. A child with this diagnosis should be reexamined frequently and monitored in the long term to ensure that the lymph nodes have returned to baseline size. SJS, TEN, and hypertrichosis are potential dermatologic complications. Disruption of bone mineralization and connective tissue abnormalities, such as coarsening of facial features and gingival hyperplasia, can result from long-term use of phenytoin. Drug-drug interactions also can occur with phenytoin.

Valproic acid A boxed warning about the use of valproic acid emphasizes that hepatic failure may result, and children younger than 2 years are at particular risk, especially if they are taking multiple AEDs and suffering from a metabolic disorder or organic brain disease.⁸ Life-threatening pancreati-tis in children also has been described.¹⁰ Although GI symptoms (nausea, vomiting, abdominal pain) are common complaints when starting any new drug, the clinician must be vigilant to rule out pancreatitis in the patient who is taking valproic acid. Thrombocytopenia and a slightly increased risk of bone fractures are other potential side effects. Because of possible hematologic and liver complications, blood cell counts and liver function tests should be performed routinely. Interactions with other AEDs are common; for instance, the dosing of lamotrigine has to be modified if the patient is simultaneously taking valproate.

Newer AEDs

Felbamate Felbamate is approved for use in children in very limited circumstances; a warning box emphasizes that acute liver failure and aplastic anemia are associated with its administration.⁸ Pediatric patients accounted for half the reported cases of liver failure and 1 case of aplastic anemia. Although some children in the first several years of life experienced liver failure, no child younger than 13 years suffered from aplastic anemia.¹¹ CNS and GI disturbances can be experienced by children taking felbamate, and drowsiness is the most common treatment-emergent side effect.⁷

Gabapentin Generally well tolerated, gabapentin (Neurontin, Pfizer) primarily causes CNS symptoms in children, including somnolence, headache, dizziness, and hostility.^5,12,13 Aggressive behavioral changes are particularly worrisome, and mentally retarded children may be more likely to display these changes.⁷ Fatigue and weight gain also may occur.¹³

Lamotrigine As previously mentioned, SJS and TEN have been reported to occur with use of lamotrigine.¹ A higher proportion of rashes have been observed in pediatric patients when lamotrigine is administered with valproate.¹⁴ Beginning with a low initial dose of lamotrigine, then titrating it up slowly, may decrease the risk of this complication.¹⁴ SJS and TEN are exceedingly rare; Bialer and colleagues¹² suggest that concern about these possible complications should not be a major factor when deciding whether to use this agent. Children also may experience CNS (headache, dizziness, ataxia, tremor) and GI disturbances (abdominal pain, nausea) while being treated with lamotrigine.^5,13 Although some children may become irritable and aggressive, many experience behavioral improvement during treatment with lamotrigine.⁷

Levetiracetam The CNS is the main system to be adversely affected by levetiracetam (Keppra, UCB Pharma). In a report on its use in children with Lennox-Gastaut syndrome, the most significant side effect was irritability.¹⁵ Somnolence, ataxia, headache, and psychiatric complaints, as well as anorexia, are other possible untoward effects. A significant increase in aggressive behavior has been observed in children receiving this medication who had recently discontinued risperidone (Risperdal, Janssen).⁷

Oxcarbazepine As previously mentioned, oxcarbazepine can cross-react with other aromatic AEDs. However, adolescent and adult patients may tolerate it better than phenytoin and carbamazepine.⁵ Oxcarbazepine is included in the list of agents that are associated with a slightly increased risk of bone fractures.⁶ Rash and SJS can occur, along with CNS side effects such as somnolence, intolerable headache, and dizziness.^13,16 Unusual complications include leukopenia and hyponatremia.¹⁶ Hyponatremia rarely is clinically significant and may result from oxcarbazepine's direct effect on the renal collecting tubules.¹²

Topiramate Hyperchloremic nonanion gap metabolic acidosis is associated with administration of topiramate (Topamax, Ortho-McNeil). The clinicial significance of this metabolic side effect has not been fully elucidated. Nevertheless, the clinician should be on the lookout for presenting features of metabolic acidosis, such as hyperventilation, fatigue, anorexia, cardiac arrhythmias, and stupor.¹⁷ In children, chronic metabolic acidosis can result in growth retarda-tion and, in general, it can lead to nephrolithiasis.

Emotional lability, difficulty in concentrating, memory deficits, weight loss, and hypohidrosis are reported side effects of topiramate.⁵ Acute myopia and angle-closure glaucoma are possible ophthalmologic consequences of topiramate treatment in children and adults.^18,19

SUMMARY

Familiarity and lower prices make traditional AEDs the attractive first choice. However, the seemingly improved tolerance profiles of the newer medications and the decreased need for expensive hematologic monitoring are also important factors to consider when selecting an AED. The long-term effects of the newer AEDs on the developing body systems need to be further elucidated. When selecting appropriate treatment, weighing the risks of the tried-and-true AEDs against those of the novel AEDs is a step that clinicians need to take with the parents of children who have seizure disorders. *

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