You are on page 1of 8

CURRENT LITERATURE IN CLINICAL SCIENCE

JUVENILE MYOCLONIC EPILEPSY: MORE TRIALS ARE NEEDED TO GUIDE THERAPY


Levetiracetam for the Treatment of Idiopathic Generalized Epilepsy with Myoclonic Seizures. Noachtar S, Andermann E, Meyvisch P, Andermann F, Gough WB, Schiemann-Delgado J, For the N166 Levetiracetam Study Group. Neurology 2008;70:607616. BACKGROUND: Currently, there are no published randomized controlled trials evaluating the efcacy
and safety of adjunctive antiepileptic therapy in idiopathic generalized epilepsy with myoclonic seizures. METHODS: This randomized, double-blind, placebo-controlled multicenter trial assessed the efcacy and tolerability of adjunctive treatment with levetiracetam 3,000 mg/day in adolescents (12 years) and adults (65 years) with idiopathic generalized epilepsy, who experienced myoclonic seizures on 8 days during a prospective 8-week baseline period, despite antiepileptic monotherapy. The 8-week baseline period was followed by 4-week up-titration, 12-week evaluation, and 6-week down-titration/conversion periods. RESULTS: Of 122 patients randomized, 120 (levetiracetam, n = 60; placebo, n = 60) were evaluable. Diagnoses were either juvenile myoclonic epilepsy (93.4%) or juvenile absence epilepsy (6.6%). A reduction of 50% in the number of days/week with myoclonic seizures was seen in 58.3% of patients in the levetiracetam group and in 23.3% of patients in the placebo group (p < 0.001) during the treatment period. Levetiracetam-treated patients were more likely to respond to treatment than patients receiving placebo (OR = 4.77; 95% CI, 2.12 to 10.77; p < 0.001). Levetiracetam-treated patients had higher freedom from myoclonic seizures (25.0% vs 5.0%; p = 0.004) and all seizure types (21.7% vs 1.7%; p < 0.001) during the evaluation period. The only adverse events more frequent with levetiracetam were somnolence and neck pain. CONCLUSION: These results suggest that levetiracetam is an effective and well-tolerated adjunctive treatment for patients with previously uncontrolled idiopathic generalized epilepsy with myoclonic seizures.

COMMENTARY
uvenile myoclonic epilepsy is the most common idiopathic generalized epileptic syndrome, accounting for about 10% of all patients with epilepsy. The diagnosis requires the presence of generalized myoclonic seizures, thus 100% of patients have these seizures. About 90% of patients also have generalized tonicclonic seizures and approximately 30% have generalized absence seizures. Approximately 15 years ago, valproate emerged as the antiepileptic drug of choice for juvenile myoclonic epilepsy, with reported seizure-free rates of about 80% (1,2). Nevertheless, some patients are resistant to valproate and others do not tolerate it well. Lamotrigine, topiramate, and zonisamide have been suggested as possible alternatives for these patients (3). However, one large, prospective, randomized study (the Standard and New Antiepileptic Drugs, or SANAD, trial) that compared valproate, lamotrigine, and topiramate for idiopathic generalized epilepsy showed that valproate was more effective than lamotrigine and better tolerated than topiramate (4). These data highlight the need for alternative or adjunctive therapeutic options for patients with
Epilepsy Currents, Vol. 9, No. 1 ( January/February) 2009 pp. 1011 Wiley Periodicals, Inc. C American Epilepsy Society

juvenile myoclonic epilepsy who do not become seizure-free with valproate, cannot tolerate it, or are concerned about its risks. The international, multicenter study by Noachtar and colleagues evaluated adjunctive levetiracetam for patients with idiopathic generalized epilepsy and myoclonic seizures. Most epileptologists would consider idiopathic generalized epilepsy with myoclonic seizures to be juvenile myoclonic epilepsy, by denition, even though 8 patients in the study were given the diagnosis of juvenile absence epilepsy by the local investigator. The most commonly used baseline antiepileptic drugs in the active arm of the trial were valproate (60.7% of patients) and lamotrigine (24.6% of patients). Levetiracetam addon treatment rendered 21.7% of this refractory patient group completely seizure-free and therefore, should be considered an adjunctive treatment option for similar patients with juvenile myoclonic epilepsy and persistent myoclonic seizures. Another recent study supported adjunctive levetiracetam use for patients with idiopathic generalized epilepsy and refractory generalized tonicclonic seizures (5). Approximately one-third of the patients in that study carried the diagnosis of juvenile myoclonic epilepsy. These two studies combined support the use of adjunctive levetiracetam for juvenile myoclonic epilepsy, with either refractory generalized myoclonic or tonicclonic

Current Literature in Clinical Science

11

seizures. However, there are no solid data regarding the efcacy of adjunctive levetiracetam for juvenile myoclonic epilepsy patients who have refractory absence seizures. In fact, one retrospective study showed that absence seizures, compared with myoclonic or tonicclonic generalized seizures types, are the least likely to benet from levetiracetam for patients with refractory idiopathic generalized epilepsy (6). The syndrome of juvenile myoclonic epilepsy is heterogeneous, both genetically and clinically. One large study of 257 patients suggested four subgroups (7). The largest subgroup, accounting for 72% of patients, was represented by classic juvenile myoclonic epilepsy with adolescent onset myoclonic or generalized tonicclonic seizures, and infrequent absence seizures following in one-third of patients. The second largest subgroup was childhood absence epilepsy evolving to juvenile myoclonic epilepsy; it included 18% of the total patients. These patients were easily distinguished from classic juvenile myoclonic epilepsy because their rst seizure type was absence seizures, which began in the rst decade of life, with myoclonic and tonicclonic seizures following in adolescence. This group was refractory to treatment, with only 7% of patients becoming seizure-free. The remaining two small groups, juvenile myoclonic epilepsy with adolescent absence (7%) and juvenile myoclonic epilepsy with astatic seizures (3%), had seizure-free rates (5662%) that were fairly similar to those seen in the classic juvenile myoclonic epilepsy subgroup. A study exploring factors in drug resistance found that juvenile myoclonic epilepsy patients with a combination of all three seizure types (myoclonic, absence, and tonicclonic) were much more likely to be resistant to therapy (8). Considering that all patients in the study by Noachtar and colleagues were refractory to treatment, it is likely that the investigators had an over-representation of patients with childhood absence epilepsy that evolved to juvenile myoclonic epilepsy and of patients with all three seizure types. Noachtar et al. did not identify juvenile myoclonic epilepsy subgroups. An analysis of the efcacy of levetiracetam by juvenile myoclonic epilepsy subgroup (for example, by initial seizure type and its age at onset) could be very instructive in discriminating which subgroup is most likely to respond to levetiracetam. There are no class I studies to guide the initial therapy of juvenile myoclonic epilepsy, and no drug is specically ap-

proved by the Federal Drug Administration for this indication. Class IV studies suggest that in addition to valproate, the new antiepileptic drugs lamotrigine, topiramate, levetiracetam, and zonisamide can be considered; however, more rigorous trials are needed. The SANAD trial for idiopathic generalized epilepsy classied only 26% of the patients with juvenile myoclonic epilepsy (4). Thus, there is also a need for a comparative trial of initial therapies for patients with juvenile myoclonic epilepsy. Such a trial could stratify patients by juvenile myoclonic epilepsy subgroups and analyze the response of all seizure types within this syndrome. by Bassel W. Abou-Khalil, MD

References
1. Delgado-Escueta AV, Enrile-Bacsal F. Juvenile myoclonic epilepsy of Janz. Neurology 1984;34:285294. 2. Panayiotopoulos CP, Obeid T, Tahan AR. Juvenile myoclonic epilepsy: A 5-year prospective study. Epilepsia 1994;35:285296. 3. Prasad A, Kuzniecky RI, Knowlton RC, Welty TE, Martin RC, Mendez M, Faught RE. Evolving antiepileptic drug treatment in juvenile myoclonic epilepsy. Arch Neurol 2003;60:1100 1105. 4. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, Cramp C, Cockerell OC, Cooper PN, Doughty J, Eaton B, Gamble C, Goulding PJ, Howell SJ, Hughes A, Jackson M, Jacoby A, Kellett M, Lawson GR, Leach JP, Nicolaides P, Roberts R, Shackley P, Shen J, Smith DF, Smith PE, Smith CT, Vanoli A, Williamson PR. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassiable epilepsy: An unblinded randomised controlled trial. Lancet 2007;369:10161026. 5. Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology 2007;69:17511760. 6. Krauss GL, Betts T, Abou-Khalil B, Gergey G, Yarrow H, Miller A. Levetiracetam treatment of idiopathic generalised epilepsy. Seizure 2003;12:617620. 7. Martinez-Juarez IE, Alonso ME, Medina MT, Duron RM, Bailey JN, Lopez-Ruiz M, Ramos-Ramirez R, Leon L, Pineda G, Castroviejo IP, Silva R, Mija L, Perez-Gosiengao K, Machado-Salas J, Delgado-Escueta AV. Juvenile myoclonic epilepsy subsyndromes: Family studies and long-term follow-up. Brain 2006;129:1269 1280. 8. Gelisse P, Genton P, Thomas P, Rey M, Samuelian JC, Dravet C. Clinical factors of drug resistance in juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry 2001;70:240243.

12

Current Literature in Clinical Science

PATIENTS WITH SEIZURE CLUSTERSIDENTIFICATION OF A HIGH-RISK GROUP


Seizure Clustering During Drug Treatment Affects Seizure Outcome and Mortality of Childhood-Onset Epilepsy. Sillanpa a M, Schmidt D. Brain 2008;131(Pt 4):938944. To provide evidence of whether seizure clustering is associated with
drug resistance and increased mortality in childhood-onset epilepsy, a prospective, long-term population-based study was performed. One hundred and twenty patients who had been followed since disease onset (average age 37.0 years, SD 7.1, median 40.0, range 1142; incident cases) were included. At the end of the follow-up period, 26 (11 boys) of these patients (22%) had recorded clusters of seizures. Fourteen recorded pre-treatment clusters, including 10 patients with clusters as rst seizures; and in 12 patients, clusters occurred during treatment. In these 12 patients, rst clustering began after 16 (range 035; median 15) years of treatment. Compared with the patients without clusters, those with clusters more often had at least one seizure per week at the initial stage (63% versus 32%, P = 0.0178) and during the follow-up period (P-value varied from 0.0464 to 0.0064). Patients having seizure clusters during drug therapy were more likely to have drug resistant epilepsy compared to those not experiencing seizure clusters (42% versus 13%; P = 0.0102) and had a lower rate of entering 5-year terminal remission (P = 0.0039) and 5-year remission (P = 0.0230). In addition, the risk of death was signicantly increased among patients with seizure clusters during drug therapy compared with those who had not experienced any clustering (42% versus 14%; P = 0.0299 two-sided Fishers exact test). The risk ratio for patients with clusters was 3.49 (95%CI 1.259.78). In contrast, patients with seizure clustering prior to, but not during, treatment versus those with no clustering showed no difference in seizure outcome or mortality risk. In conclusion, clustering of seizures during treatment, but not prior to treatment, is associated with a poorer long-term seizure and mortality outcome.

COMMENTARY

ore than a century ago, Gowers recognized seizure clustering as a pattern exhibited by many people with epilepsy (1). Seizure clustering patterns imply a nonrandom occurrence of seizures such that a subsequent seizure depends, at least in part, on whether a person has had a recent seizure. Clustering of seizures provided early evidence that hormones and the time of day inuence seizure susceptibility (2). More importantly, recognition of clustering has resulted in successful treatment strategies aimed at reducing the risk of subsequent seizures (3,4). Although seizures occurring in rapid succession might seem ominous, the extent of the risk posed by this pattern has not been studied extensively. Observations suggest that seizure clusters often result in emergency room visits (2) and that they may lead to status epilepticus (5). In the current study, Sillanpa a and Schmidt provide preliminary evidence that seizure clusters occurring during anticonvulsant treatment are also associated with increased mortality and portend a poor prognosis for long-term seizure control. The authors used National Health Service records from Finland to identify all children (aged 15 and younger) who had developed epilepsy by the end of 1964. Seizure clustering was dened clinically to be three or more seizures, during any 24-hour period, on at least one occasion. Patients were excluded from analysis if they had conditions with expected seizure clus-

Epilepsy Currents, Vol. 9, No. 1 ( January/February) 2009 pp. 1213 Wiley Periodicals, Inc. C American Epilepsy Society

tering, such as Lennox-Gastaut syndrome, infantile spasms, and absence or myoclonic seizures. Patients were considered drugresistant if they had not entered a 5-year remission during the 10 or more years of follow-up. The authors emphasize that their cohort represents a true population-based sample since standard practice in Finland in the 1960s dictated that all children with epilepsy be referred to Dr. Sillanpa a . In contrast to studies arising from tertiary epilepsy programs that treat only medically refractory patients, this study is likely to be relevant to the practice of most community-based neurologists. Statistical comparisons were not designed to determine whether the mortality and seizure control outcomes were independent. As the authors note, medication-refractory epilepsy is known to be associated with increased mortality (6). It is certainly possible that the increased risk of death is attributable to poorer overall seizure control in patients who have seizure clustersrather than seizures occurring in succession. Supporting this possibility is the fact that patients with seizure clusters did not die from status epilepticus, a mechanism potentially associated with clustering (5), but instead from sudden unexpected death in epilepsy, or SUDEP, which is known to be associated with drug-resistant epilepsy (7). The current study is limited by the small number of patients who exhibited a clustering pattern. Given the limited power of the study, the nding that seizure clustering is not associated with an increased risk for status epilepticus will need to be conrmed by a larger study, especially since 5 of the 12 patients with seizure clusters during treatment had episodes of status

Current Literature in Clinical Science

13

epilepticus. An additional consequence of the limited number of clustering patients in this study is a large condence interval for the risk ratios for mortality and intractability, suggesting that it is premature to use these specic values to counsel patients with this seizure pattern. Nevertheless, it seems reasonable to counsel patients that a clustering pattern probably confers at least some risk for these outcomes. Another limitation of the Sillanpa a and Schmidt report is that they did not use a statistical model to ensure that patients who were designated as clusterers actually deserved that designation. Other investigators have found that using their clinical criterion of three seizures in 24 hours is too broad, as it allows inclusion of patients who meet this denition by chance (8). Use of a statistical model that demonstrates a seizures dependency on prior seizures can ensure that the observed seizure-clustering pattern represents a physiological phenomenon. While limiting the identication of clustering to patients with such statistical clustering might have been informative, it would have been unfeasible in this study because of the small number of patients. Furthermore, a clinical denition offers clinicians practical guidance in identifying patients for purposes of counseling and modifying treatment. Patients who have seizure clusters have been identied as ideal candidates for using rescue medications, such as rectal diazepam (3) and buccal midazolam (4). Though the association is uncertain, it is interesting to note that the incidence of generalized convulsive status epilepticus has decreased in California over the past decade, as use of rescue medications for seizure clusters has increased (9). It is unclear whether use of rescue medications for this population will have an impact on mortality, however. Since the cause of death for patients with seizure clusters was not attributed to status epilepticus in the Sillanpa a and Schmidt study, it seems clear that rescue medications will not completely eliminate the mortality associated with a clustering seizure pattern.

In summary, Sillanpa a and Schmidt have raised awareness of seizure clustering as a risk for poor seizure control and mortality. While the practical implications are not clear, the ndings may indicate a need for more aggressive management in patients exhibiting this pattern. Studies powered to conrm and extend the outcomes would be desirable and are necessary before the ndings can be used to counsel patients about specic risks. by Paul Garcia, MD

References
1. Gowers W. Epilepsy and Other Convulsive Diseases . Philadelphia: Blackiston, 1901. 2. Haut SR. Seizure clustering. Epilepsy Behav 2006;8:5055. 3. Cereghino JJ, Cloyd JC, Kuzniecky RI. Rectal diazepam gel for treatment of acute repetitive seizures in adults. Arch Neurol 2002;59:19151920. 4. McIntyre J, Robertson S, Norris E, Appleton R, Whitehouse WP, Phillips B, Martland T, Berry K, Collier J, Smith S, Choonara I. Safety and efcacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: A randomised controlled trial. Lancet 2005;366:205210. 5. Mitchell WG. Status epilepticus and acute repetitive seizures in children, adolescents, and young adults: Etiology, outcome, and treatment. Epilepsia 1996;37(suppl 1):S7480. 6. Sperling MR, Harris A, Nei M, Liporace JD, OConnor MJ. Mortality after epilepsy surgery. Epilepsia 2005;46(suppl 11):49 53. 7. Tomson T, Walczak T, Sillanpa a M, Sander JW. Sudden unexpected death in epilepsy: A review of incidence and risk factors. Epilepsia 2005;46(suppl 11):5461. 8. Haut SR, Lipton RB, LeValley AJ, Hall CB, Shinnar S. Identifying seizure clusters in patients with epilepsy. Neurology 2005;65:1313 1315. 9. Wu YW, Shek DW, Garcia PA, Zhao S, Johnston SC. Incidence and mortality of generalized convulsive status epilepticus in California. Neurology 2002;58:10701076.

14

Current Literature in Clinical Science

CHILDREN WITH EPILEPSY: WHY CANT THEY PAY ATTENTION?


The Frequency, Complications and Aetiology of ADHD in New Onset Paediatric Epilepsy. Hermann B, Jones J, Dabbs K, Allen CA, Sheth R, Fine J, McMillan A, Seidenberg M. Brain 2007;130(Pt 12):31353148. Recent studies
suggest that Attention Decit Hyperactivity Disorder (ADHD) is a common comorbid condition in childhood epilepsy, but little is known regarding the nature, frequency and timing of associated neurobehavioural/cognitive complications or the underlying aetiology of ADHD in epilepsy. This investigation examined: (i) the prevalence of ADHD and its subtypes; (ii) the association of ADHD with abnormalities in academic, neuropsychological, behavioural and psychiatric status and (iii) the aetiology of ADHD in paediatric epilepsy. Seventyve children (age 818) with new/recent onset idiopathic epilepsy and 62 healthy controls underwent structured interview (K-SADS) to identify the presence and type of DSM-IV dened ADHD, neuropsychological assessment, quantitative MR volumetrics, characterization of parent observed executive function, review of academic/educational progress and assessment of risk factors during gestation and delivery. The results indicate that ADHD is signicantly more prevalent in new onset epilepsy than healthy controls (31% vs 6%), characterized predominantly by the inattentive variant, with onset antedating the diagnosis of epilepsy in the majority of children. ADHD in childhood epilepsy is associated with signicantly increased rates of school based remedial services for academic underachievement, neuropsychological consequences with prominent differences in executive function, and parent-reported dysexecutive behaviours. ADHD in paediatric epilepsy is neither associated with demographic or clinical epilepsy characteristics nor potential risk factors during gestation and birth. Quantitative MRI demonstrates that ADHD in epilepsy is associated with signicantly increased gray matter in distributed regions of the frontal lobe and signicantly smaller brainstem volume. Overall, ADHD is a prevalent comorbidity of new onset idiopathic epilepsy associated with a diversity of salient educational, cognitive, behavioural and social complications that antedate epilepsy onset in a signicant proportion of cases, and appear related to neurodevelopmental abnormalities in brain structure.

COMMENTARY

erhaps, the fact that the paper by Hermann et al. includes almost no references dated before 1995 is due to the constraints of a literature search by computer; however, the more likely cause is that serious attention paid to the psychosocial accompaniments of epilepsy began at about that time. Today, virtually all issues of epilepsy journals will include studies of psychiatric, cognitive, and social disorders that are overrepresented in populations with various types of epileptic disorders. Often these problems are described as complications of chronic epilepsy. Yet, there is a growing body of observations suggesting that these other brain and behavioral disorders may not spring from the stresses and pathology related to chronic seizures but rather may be other symptoms of a common malady or maladies. In other words, a still unnamed disease or diseases may be manifested by a variety of symptoms and signs, including depression, attention decit hyperactivity disorder (ADHD), a range of cognitive decits, as well as seizures. Hermann et al. have made a signicant contribution to this eld in their study of ADHD in children with recent onset of idiopathic epilepsy. The 75 children in this population were diagnosed with epilepsy within 12 months of entry into the study. These children, aged 8 to 18 years, supercially appeared to be completely healthy: normal neurological exam,

Epilepsy Currents, Vol. 9, No. 1 ( January/February) 2009 pp. 1415 Wiley Periodicals, Inc. C American Epilepsy Society

normal MRI scan, no developmental disability, and no other neurological disorder. The control group consisted of age- and gender-matched rst cousins. Using careful parental interviewing, a broad range of neuropsychological testing, and quantitative MR volumetrics, investigators found that the apparently healthy children with idiopathic epilepsy had astonishingly high rates of abnormalities. Over 31% of them met DSM-IV diagnostic criteria for ADHD, compared with only 6.4% of the control group. Most of the children with ADHD (82%) had been symptomatic prior to their rst seizure, ruling out medication or psychosocial stressors as etiological factors. In this study, the symptom prole of the epilepsy-associated ADHD seemed distinct from that seen in the general population, with the inattentive subtype predominating over the hyperactive or combined type. Virtually all of the techniques used in the Hermann et al. study to characterize the children with epilepsy and ADHD point to the frontal lobe as the primary site of pathology. Neuropsychological testing as well as parental reports performed conrmed the high prevalence of symptoms and signs attributable to frontal lobe dysfunction in many of the children with epilepsy, but especially in those with ADHD. Neuropsychological test results included impairments in motor and psychomotor speed and in executive function. A parent-reported rating scale (Behavior Rating Inventory of Executive Function or BRIEF) revealed more abnormal scores in impulse control, attentional shifts, planning skills, executive function, and initiation of problem solving for those children with both epilepsy and ADHD. Finally, while MR volumetrics demonstrated that

Current Literature in Clinical Science

15

the epilepsy/ADHD group had signicantly larger frontal lobes and smaller brainstem volumes, other brain areas showed no group differences, and interestingly, those children without ADHD showed no differences from the control group. The educational histories of the children highlighted the clinical signicance of these ndings and showed them to be of more than theoretical interest. Of the children with epilepsy, over half of those with ADHD had already required a formal individual education plan (IEP) or other academic support services that frequently were begun before the rst seizure occurred. Only 15% of the children with seizures but without ADHD needed such help. The ndings of Hermann et al. are important to the care of children without obvious features of symptomatic epilepsy, but with idiopathic epilepsy. How are such observations to be interpreted? After all, the 2001 International League Against Epilepsy (ILAE) classication proposal cited by the authors denes idiopathic epilepsy syndrome as one that is only epilepsy, with no underlying structural brain lesion or other neurological signs or symptoms (1). This denition is a moving target, since the same paper mentions other classication schemes for idiopathic epilepsy that would include idiopathic focal epilepsies of infancy and childhooda denition that would embrace benign childhood epilepsy with centrotemporal spikes, for example. This syndrome has been shown to be accompanied by subtle attention and language decits (2,3). Other idiopathic epilepsies such as childhood absence epilepsy and juvenile myoclonic epilepsy also have been associated with abnormal frontal lobe gray matter volumes (4). The designation of idiopathic as meaning no underlying structural brain lesion or other neurological signs or symptoms seems to be dissolving under increasingly sophisticated scrutiny of these patients. Hermann et al. enrolled study patients with both focal and generalized syndromes but gave no further specic diagnoses of subtypes. The patient population studied by Hermann et al. presents further interpretive problems. The study group was dened as

children with epilepsy with no signs or symptoms indicative of neurological abnormality. Yet, many in the subgroup discovered to have ADHD already were dysfunctional enough to have earned IEPs at school and had symptoms of ADHD that preceded the onset of seizures. Furthermore, all subjects were recruited from pediatric neurology clinics. Could they have been referred to pediatric neurologists because their physicians or parents already suspected or recognized behavioral or cognitive problems? The proportion of children with epilepsy cared for by primary care doctors versus neurological specialists in their area are unknown or at least not provided. How generalizable are these ndings? This remains a valuable study, adding to a growing literature of similar ndings. As the number of known and dened genetic epilepsies increases, the number of so-called idiopathic epilepsies appears to be shrinking, adding to the increasing suspicion that there are no true idiopathic epilepsies at all simply epilepsy syndromes whose causes and other clinical and anatomic correlates are yet to be discovered. by Donna C. Bergen, MD

References
1. Engel J Jr. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: Report of the ILAE Task Force on Classication and Terminology. Epilepsia 2001;42:796 803. 2. Staden U, Isaacs E, Boyd SG, Brandl U, Nevelle BG. Language dysfunction in children with rolandic epilepsy. Neuropediatrics 1998;29:242248. 3. MacAllister WS, Schaffer SG. Neuropsychological decits in childhood epilepsy syndromes. [Review] [160 refs] [Journal Article Review]. Neuropsychol Rev 17:427444, 2007 Dec. 4. Betting LE, Mory SB, Li LM, Lopes-Cendes I, Guerreiro MM, Guerreiro CA, Cendes F. Voxel-based mrophometry in patients with idiopathic generalized epilepsies. Neuroimage 2006;32:498 502.

16

Current Literature in Clinical Science

SOME LONG AWAITED ANSWERS REGARDING SEIZURES DURING PREGNANCY


Seizure Control in Antiepileptic Drug-Treated Pregnancy. Vajda FJ, Hitchcock A, Graham J, OBrien T, Lander C, Eadie M. Epilepsia 2008;49(1):172176. This brief report covers an analysis of 7 years outcome data from the Australian Register
of Antiepileptic Drugs in Pregnancy. In studying the control of antiepileptic drug-treated epileptic seizures during pregnancy, it was found that pregnancy had little inuence on antiepileptic drug-treated epileptic seizure disorders. Seizures during pregnancy occurred in 49.7% of 841 antiepileptic drug (AED) treated pregnancies in women with epilepsy. Epilepsies that were active in the year before pregnancy tended to increase the risk of intrapartum and postpartum seizures. The risk of seizures during pregnancy was 5070% less if the prepregnancy year was seizure-free, and decreased relatively little more with longer periods of prepregnancy seizure control. Once there had been 1 years freedom from seizures there seemed relatively little further advantage in deferring pregnancy to avoid seizures returning while pregnant.

COMMENTARY
he current article is a report from the Australian Pregnancy Registry (APR), and the main points of interest are found in the abstract. The prospective APR is one of several similar trials currently ongoing throughout the world. In addition to the APR, the most signicant of these pregnancy registry trials are the European Pregnancy Registry (EURAP), which collects information from 30 different countries, the British Pregnancy Registry, gathering information solely from patients in the UK, and the North American Antiepileptic Drug Pregnancy Registry, which includes patients from the entire USA. There are also pharmaceutical company-sponsored registries both in the Unites States and in the United Kingdom. The purpose of these registries is to prospectively follow women with epilepsy who become pregnant and then assess the course of their pregnancy and the effects of the condition on the offspring. These registries are designed to provide the best evidence possible on unresolved questions regarding the course of pregnancy for women with epilepsy who are exposed to antiepileptic drugs, including what effects lactation may have on the infant and whether developmental parameters of the offspring are impacted. The Australian report is the second published registry trial to try to answer two key questions: 1) whether seizures occur less or more frequently during pregnancy and 2) what the effects on the offspring are when seizures do occur. The rst study to report to address these issues was the EURAP in 2006 (1); therefore, it is interesting to compare the results of the Australian registry with the European one. In that regard, a variable that needs to be assessed in such an inquiry is whether the serum concentration of the AED is kept stable or variesdoes it remain the same during pregnancy as it was before the pregnancy? There are

Epilepsy Currents, Vol. 9, No. 1 ( January/February) 2009 pp. 1617 Wiley Periodicals, Inc. C American Epilepsy Society

many examples in the literature, especially with lamotrigine (2,3) and oxcarbazepine (4), that indicate the concentration of the drug drops to about half during pregnancy to then return to the previous level after delivery. Another variable that needs to be addressed is whether patients are compliant and actually take the drugs as directed. Noncompliance is thought to be high during pregnancy, because the mother may think that less of the AED is better for her baby. The EURAP study did indeed discuss both these variables to some extent with the patients (serial serum levels of AEDs were not assessed, however) but not so in the current Australian publication, which is a major limitation of this study. In fact, the APR protocol did not systematically provide for evaluation of AEDs. The method of recruitment in the APR was for women to call in and register themselves, after being given the pertinent information by their doctor. Therefore, the patient had to take the initiative to make the rst phone call, causing a selection bias of patients who were really interested in the project. This recruitment procedure is similar to that of the current North American registry. Recruitment for the EURAP registry, however, was (and still is) instigated by the physician who asks the patient if she wants to participate. After acceptance, the patient is then followed throughout her entire pregnancy. In contrast, once enrolled in the Australian study, patients are rst interviewed at the time of recruitment, and then followed up at 4-weeks, 28-weeks, and 1-year postpartum; all interviews were conducted by telephone. Nevertheless, the long follow-up period and the large number of patients who participated in the APR have provided valuable results that can be viewed with optimism. It is now possible to inform patientsin spite of the AED taken or how well regulated the drug levels arethat a powerful predictor of being seizurefree during pregnancy is being seizure-free the year before pregnancy and that, in accordance with the EURAP registry, pregnancy itself does not inuence seizure frequency rates in most patients. However, patients who had seizures before

Current Literature in Clinical Science

17

pregnancy continued to have them during pregnancy, labor, and postpartum but did not appear to have an increase in seizures frequency. In the discussion, the authors state that: In terms of the measures studied, the epileptic process seemed to become better no less often than it became worse during pregnancy. This conclusion is based on a comparison of events during 9 months of pregnancy with events during 12 months before pregnancy. The same interpretation may not have applied if accurate counts of seizure numbers had been available. Similarly, the outcome ndings for the offspring in the APR offer some optimism, as the risks in this study for stillbirth or malformations were no higher whether or not the mother had seizures during pregnancy irrespective of seizure type. In the EURAP study, among 1956 pregnancies, there were 36 cases of status epilepticus but only one stillbirth or spontaneous abortion that occurred in close proximity to a seizure. With both registries agreeing on these ndings, there seems to be a high probability that having seizures during pregnancy does not affect the offspring, except in rare cases, probably in connection to prolonged seizures. So what can we learn from these two studies that can help to inform and treat women with epilepsy who become pregnant? As the authors of the ARP point out, patients who have been seizure-free the year before becoming pregnant can be reassured that the risk is low for having new seizures during pregnancy and

deliveryalthough there is still a chance it could occur. Learning from the EURAP study, patients will benet from doctors who work diligently to nd and maintain the optimal AED intake level before conception and avoid adjustments during pregnancy, unless the serum concentration of the AED declines and needs to be readjusted. Special care is warranted for patients treated with oxcarbazepine and lamotrigine to insure that levels are maintained during pregnancy, thus avoiding exacerbation of seizures. Regardless, all pregnant women with epilepsy need to be closely followed by their neurologist and obstetrician to ensure a successful outcome. by Elinor Ben-Menachem, MD, PhD

References
1. The EURAP Study Group. Seizure control and treatment in pregnancy: Observations from the EURAP Epilepsy Pregnancy Registry. Neurology 2006;66:354360. 2. De Haan GJ, Edelbroek P, Segers J, Engeksman M, Lindhout D, De vile -Notschaele M, Augustijn P. Gestation-induced changes in lamotrigine pharmacokinetics: A monotherapy study. Neurology 2004;63:571573. 3. Pennell PB, Newport DJ, Stowe ZN, Helmers SL, Montgomery JQ, Henry TR. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology 2004;62:292295. 4. Christensen J, Sabers A, Sidenius P. Oxcarbazepine concentrations during pregnancy: A retrospective study in patients with epilepsy. Neurology 2006;67:14971499.

You might also like