Vol. XXII Issue 10
Epilepsy is a major public health concern, with prevalence estimated to be slightly less than 1% (Annegers, 1996). Each year, 25,000 to 40,000 children in the United States alone experience their first unprovoked seizure (Hirtz et al., 2003). Depending on the type of seizure (e.g., generalized versus focal) or specific epilepsy syndrome (e.g., juvenile myoclonic epilepsy, benign rolandic epilepsy), there are several recommended medications with demonstrated clinical efficacy from which to choose (Hirtz et al., 2003). Selection of a specific medication, however, is often based upon clinical experience due to the absence of adequate antiepileptic drug (AED) pediatric clinical trials.
Antiepileptic drugs decrease membrane excitability, increase postsynaptic inhibition or alter synchronization of neural networks to decrease excessive neuronal excitability associated with seizure development. Common side effects of decreasing neuronal excitability, however, are slowed motor and psychomotor speed, poorer attention and mild memory impairment (Meador, 2005). Unlike adults, cognitive side effects in children occur against the backdrop of normal cognitive and psychosocial development, and treatment decisions made in childhood may have lifelong implications. Adults who developed epilepsy during their childhood tend to have less education, decreased rates of employment and employment at lower job levels, lower rates of marriage, poorer physical health, and increased incidence of psychiatric disorders (Jalava and Sillanpaa 1997a, 1997b; Jalava et al., 1997; Sillanpaa et al., 1998). Importantly, these long-term effects are also present in adults who are no longer taking medications. The persistence of these effects after discontinuation of AED treatment suggests a role of either seizure etiology, cumulative effects of repeated seizures or AED treatment permanently altering the course of development. Because significant brain impairment and more frequent seizures are associated with more difficult-to-treat epilepsy, these patients are unlikely to stop their seizure medications. Studies in rats have shown significant AED effects in the developing brain including apoptotic neurodegeneration (Bittigau et al., 2003; Olney et al., 2002). Thus, long-term AED side effects should be considered when selecting an AED for pediatric use.
Cognitive AED side effects in children, unfortunately, have been inadequately studied (Loring and Meador, 2004). Although several patterns of AED treatment in young adults continue to be described, the lack of data needed to generate evidence-based AED guidelines in children has been highlighted by the American Academy of Neurology (AAN), Child Neurology Society (CNS) and American Academy of Pediatrics (AAP) (AAP Committee on Drugs, 1995; Hirtz et al., 2003). A recent AAN/CNS practice guideline stated, "Behavioral and cognitive side effects need to be better evaluated, especially for new AED[s], and individual risks as well as group differences assessed on tests of cognition" (Hirtz et al., 2003). The AAP Committee on Drugs (1995) concluded, "Few studies have been comprehensive, and for most drugs, neuropsychological effects have been incompletely described." Thus, major organizations representing both pediatrics and neurology emphasized the need to establish the neuropsychological profiles of newer AEDs in children and to determine the behavioral and cognitive consequences of long-term AED treatment on academic achievement and neuropsychological function to maximize treatment effectiveness.
Phenobarbital (Luminal, Solfoton) and traditional benzodiazepines are associated with the greatest risk of cognitive side effects. The effects of phenobarbital are well established since it was used for many years for seizure prophylaxis after a febrile seizure. Although no longer a first-line therapy, its effects on IQ illustrate a pattern for concern that requires careful examination in all AEDs with demonstrated cognitive side effects. In studies, children on phenobarbital displayed IQ declines (Farwell et al., 1990; Wolf et al., 1981), and although IQ improved following discontinuation of phenobarbital (Farwell et al., 1990; Sulzbacher et al., 1999), there continued to be long-term achievement effects when these children were tested three to five years later (Sulzbacher et al., 1999). The inability of children to fully catch up and compensate for "lost time" is important because it suggests a more complex interaction of AED therapy and developmental maturation than simply interfering with new learning efficiency. Because IQ declines are thought to reflect slowed mental growth rather than a loss of previously acquired cognitive function or cognitive regression, concern exists that any AED with cognitive side effects may result in significant impairment based upon cumulative effects if used over extended periods.
The cognitive side effects of carbamazepine (Equetro, Tegretol), phenytoin (Dilantin) and valproate sodium (Depacon) are comparable and associated with modest psychomotor slowing accompanied by decreased attention and memory (Meador, 2005). Neuropsychological side effects generally emerge according to a dose-dependent relationship (Meador, 2005); however, both quality of life (Gilliam, 2002) and memory may be affected, even when serum blood concentrations are within standard therapeutic ranges. In children, AED effects are seen in decreased performance on the Continuous Performance Test (CPT) (Mandelbaum et al., 2003) or memory. In addition, some children are at heightened risk for developing disproportionate cognitive side effects with carbamazepine (Seidel and Mitchell, 1999). Treatment with carbamazepine has also been associated with electroencephalogram slowing in the alpha range (Frost et al., 1995). How these short-term effects translate into academic achievement has not been adequately established (Bailet and Turk, 2000). However, there appears to be some relationship between the magnitude of EEG slowing and subsequent decline on selected Wechsler Intelligence Scale for Children-Revised (WISC-R) subtests tested after one year of therapy (Frost et al., 1995).
Dr. Loring is professor in the departments of neurology and clinical health psychology at the University of Florida.
AAP Committee on Drugs (1995), Behavioral and cognitive effects of anticonvulsant therapy. Pediatrics 96(3 pt 1):538-540.
Akaho R (1996), The effects of antiepileptic drugs on cognition in normal volunteers. Psychiatry Clin Neurosci 50(2):61-69.
Annegers JF (1996), The epidemiology of epilepsy. In: The Treatment of Epilepsy: Principles and Practice, Wyllie E, ed. Baltimore: Williams & Wilkins.
Bailet LL, Turk WR (2000), The impact of childhood epilepsy on neurocognitive and behavioral performance: a prospective longitudinal study. Epilepsia 41(4):426-431.
Berent S, Sackellares JC, Giordani B et al. (1987), Zonisamide (CI-912) and cognition: results from preliminary study. Epilepsia 28(1):61-67.
Bittigau P, Sifringer M, Ikonomidou C (2003), Antiepileptic drugs and apoptosis in the developing brain. Ann N Y Acad Sci 993:103-114 [see discussion pp123-124].
Dodrill CB, Arnett JL, Shu V et al. (1998), Effects of tiagabine monotherapy on abilities, adjustment, and mood. Epilepsia 39(1):33-42.
Dooley JM, Camfield PR, Smith E et al. (1999), Topiramate in intractable childhood onset epilepsy-a cautionary note. Can J Neurol Sci 26(4):271-273.
Farwell JR, Lee YJ, Hirtz DG et al. (1990), Phenobarbital for febrile seizures-effects on intelligence and on seizure recurrence. [Published erratum N Engl J Med 1992;326(2):144.] N Engl J Med 322(6):364-369 [see comment].
Franz DN, Tudor C, Leonard J et al. (2001), Lamotrigine therapy of epilepsy in tuberous sclerosis. Epilepsia 42(7):935-940.
Fritz N, Glogau S, Hoffmann J et al. (2005), Efficacy and cognitive side effects of tiagabine and topiramate in patients with epilepsy. Epilepsy Behav 6(3):373-381.
Frost JD Jr, Hrachovy RA, Glaze DG, Rettig GM (1995), Alpha rhythm slowing during initiation of carbamazepine therapy: implications for future cognitive performance. J Clin Neurophysiol 12(1):57-63.
Gilliam F (2002), Optimizing health outcomes in active epilepsy. Neurology 58(8 suppl 5):S9-S20.
Hirtz D, Berg A, Bettis D et al. (2003), Practice parameter: treatment of the child with a first unprovoked seizure: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 60(2):166-175.
Jalava M, Sillanpaa M (1997a), Physical activity, health-related fitness, and health experience in adults with childhood-onset epilepsy: a controlled study. Epilepsia 38(4):424-429.
Jalava M, Sillanpaa M (1997b), Reproductive activity and offspring health of young adults with childhood-onset epilepsy: a controlled study. Epilepsia 38(5):532-540.
Jalava M, Sillanpaa M, Camfield C, Camfield P (1997), Social adjustment and competence 35 years after onset of childhood epilepsy: a prospective controlled study. Epilepsia 38(6):708-715.
Khan A, Ginsberg LD, Asnis GM et al. (2004), Effect of lamotrigine on cognitive complaints in patients with bipolar I disorder. J Clin Psychiatry 65(11):1483-1490.
Kockelmann E, Elger CE, Helmstaedter C (2003), Significant improvement in frontal lobe associated neuropsychological functions after withdrawal of topiramate in epilepsy patients. Epilepsy Res 54(2-3):171-178.
Leach JP, Girvan J, Paul A, Brodie MJ (1997), Gabapentin and cognition: a double blind, dose ranging, placebo controlled study in refractory epilepsy. J Neurol Neurosurg Psychiatry 62(4):372-376.
Lezak MD, Loring DW, Howieson DB et al. (2004), Neuropsychological Assessment. New York: Oxford University Press.
Loring DW, Meador KJ (2004), Cognitive side effects of antiepileptic drugs in children. Neurology 62(6):872-877.
Mandelbaum DE, Burack G, Bhise V (2003), Effects of anticonvulsant therapy on cognition and attention in children with new-onset, idiopathic epilepsy: prospective study. Abstract E-07. Ann Neurology 56(suppl 8):S113.
Martin R, Kuzniecky R, Ho S et al. (1999), Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology 52(2):321-327 [see comments].
Meador KJ (2005), Cognitive effects of epilepsy and of antiepileptic medications. In: The Treatment of Epilepsy, Wyllie E, ed. Baltimore: Williams & Wilkins.
Meador KJ, Loring DW, Hulihan JF et al. (2003), Differential cognitive and behavioral effects of topiramate and valproate. Neurology 60(9):1483-1488.
Meador KJ, Loring DW, Ray PG et al. (1999), Differential cognitive effects of carbamazepine and gabapentin. Epilepsia 40(9):1279-1285.
Meador KJ, Loring DW, Ray PG et al. (2001), Differential cognitive and behavioral effects of carbamazepine and lamotrigine. Neurology 56(9):1177-1182.
Meador KJ, Loring DW, Vahle VJ et al. (2005), Cognitive and behavioral effects of lamotrigine and topiramate in healthy volunteers. Neurology 64(12):2108-2114.
Mecarelli O, Vicenzini E, Pulitano P et al. (2004), Clinical, cognitive, and neurophysiologic correlates of short-term treatment with carbamazepine, oxcarbazepine, and levetiracetam in healthy volunteers. Ann Pharmacother 38(11):1816-1822.
Olney JW, Wozniak DF, Jevtovic-Todorovic V et al. (2002), Drug-induced apoptotic neurodegeneration in the developing brain. Brain Pathol 12(4):488-498.
Provinciali L, Bartolini M, Mari F et al. (1996), Influence of vigabatrin on cognitive performances and behaviour in patients with drug-resistant epilepsy. Acta Neurol Scand 94(1):12-18.
Rugino TA, Samsock TC (2002), Levetiracetam in autistic children: an open-label study. J Dev Behav Pediatr 23(4):225-230.
Salinsky MC, Binder LM, Oken BS et al. (2002), Effects of gabapentin and carbamazepine on the EEG and cognition in healthy volunteers. Epilepsia 43(5):482-490.
Salinsky MC, Spencer DC, Oken BS, Storzbach D (2004), Effects of oxcarbazepine and phenytoin on the EEG and cognition in healthy volunteers. Epilepsy Behav 5(6):894-902.
Salinsky MC, Storzbach D, Spencer DC et al. (2005), Effects of topiramate and gabapentin on cognitive abilities in healthy volunteers. Neurology 64(5):792-798.
Seidel WT, Mitchell WG (1999), Cognitive and behavioral effects of carbamazepine in children: data from benign rolandic epilepsy. J Child Neurol 14(11):716-723.
Sillanpaa M, Jalava M, Kaleva O, Shinnar S (1998), Long-term prognosis of seizures with onset in childhood. N Engl J Med 338(24):1715-1722 [see comment].
Sulzbacher S, Farwell JR, Temkin N et al. (1999), Late cognitive effects of early treatment with phenobarbital. Clin Pediatr (Phila) 38(7):387-394.
Thompson PJ, Baxendale SA, Duncan JS, Sander JW (2000), Effects of topiramate on cognitive function. J Neurol Neurosurg Psychiatry 69(5):636-641 [see comment].
Uvebrant P, Bauziene R (1994), Intractable epilepsy in children. The efficacy of lamotrigine treatment, including non-seizure-related benefits. Neuropediatrics 25(6):284-289.
Wolf SM, Forsythe A, Stunden AA et al. (1981), Long-term effect of phenobarbital on cognitive function in children with febrile convulsions. Pediatrics 68(6):820-823.