juvenile myoclonic epilepsy: more trials are needed to guide therapy

7/30/2019 JUVENILE MYOCLONIC EPILEPSY: MORE TRIALS ARE NEEDED TO GUIDE THERAPY

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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.Neurology2008;70:607616. BACKGROUND: Currently, there are no published randomized controlled trials evaluating the efficacyand safety of adjunctive antiepileptic therapy in idiopathic generalized epilepsy with myoclonic seizures. METHODS: This random-

ized, double-blind, placebo-controlled multicenter trial assessed the efficacy and tolerability of adjunctive treatment with levetiracetam

3,000 mg/day in adolescents (12 years) and adults (65 years) withidiopathic 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

Juvenile myoclonic epilepsy is the most common idiopathic

generalized epileptic syndrome, accounting for about 10%

of all patients with epilepsy. The diagnosis requires the pres-

ence of generalized myoclonic seizures, thus 100% of patients

have these seizures. About 90% of patients also have general-

ized tonicclonic seizures and approximately 30% have gener-

alized absence seizures. Approximately 15 years ago, valproate

emerged as the antiepileptic drug of choice for juvenile my-

oclonic 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, ran-domized study (the Standard and New Antiepileptic Drugs,

or SANAD, trial) that compared valproate, lamotrigine, and

topiramate for idiopathic generalized epilepsy showed that val-

proate was more effective than lamotrigine and better toler-

ated than topiramate (4). These data highlight the need for

alternative or adjunctive therapeutic options for patients with

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 col-

leagues 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

definition, even though 8 patients in the study were given

the diagnosis of juvenile absence epilepsy by the local inves-

tigator. The most commonly used baseline antiepileptic drugs

in the active arm of the trial were valproate (60.7% of pa-

tients) and lamotrigine (24.6% of patients). Levetiracetam add-

on 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 ju-

venile 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

Epilepsy Currents, Vol. 9, No. 1 ( January/February) 2009 pp. 1011

Wiley Periodicals, Inc.C American Epilepsy Society


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Current Literature in Clinical Science 11

seizures. However, there are no solid data regarding the efficacy

of adjunctive levetiracetam for juvenile myoclonic epilepsy pa-

tients who have refractory absence seizures. In fact, one ret-

rospective study showed that absence seizures, compared with

myoclonic or tonicclonic generalized seizures types, are the

least likely to benefit from levetiracetam for patients with re-

fractory idiopathic generalized epilepsy (6).The syndrome of juvenile myoclonic epilepsy is hetero-

geneous, both genetically and clinically. One large study of

257 patients suggested four subgroups (7). The largest sub-

group, accounting for 72% of patients, was represented by

classic juvenile myoclonic epilepsy with adolescent onset my-

oclonic or generalized tonicclonic seizures, and infrequent ab-

sence 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 pa-

tients. These patients were easily distinguished from classic ju-

venile myoclonic epilepsy because their first seizure type was

absence seizures,which began in thefirstdecade of life, with my-

oclonic and tonicclonic seizures following in adolescence. This

group was refractory to treatment, with only 7% of patients be-

coming 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 ju-

venile 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). Consideringthat 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 efficacy of

levetiracetam by juvenile myoclonic epilepsy subgroup (for ex-

ample, 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 specifically 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

classified only 26% of the patients with juvenile myoclonic

epilepsy (4). Thus, there is also a need for a comparative trial ofinitial therapies for patients with juvenile myoclonic epilepsy.

Sucha trialcould stratify patients by juvenile myoclonicepilepsy

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 epilepsyof Janz. Neurology1984;34:285294.

2. Panayiotopoulos CP, Obeid T, Tahan AR. Juvenile myoclonic

epilepsy: A 5-year prospective study. Epilepsia1994;35:285296.3. Prasad A, Kuzniecky RI, Knowlton RC, Welty TE, MartinRC, Mendez M, Faught RE. Evolving antiepileptic drug treat-ment in juvenile myoclonic epilepsy. Arch Neurol 2003;60:11001105.

4. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA,

Chadwick DW, Cramp C, Cockerell OC, Cooper PN, DoughtyJ, Eaton B, Gamble C, Goulding PJ, Howell SJ, Hughes A, Jack-son 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 unclassi-fiable epilepsy: An unblinded randomised controlled trial. Lancet2007;369:10161026.

5. Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U.Placebo-controlled study of levetiracetam in idiopathic generalized

epilepsy. Neurology2007;69:17511760.6. Krauss GL, Betts T, Abou-Khalil B, Gergey G, Yarrow H, Miller A.

Levetiracetam treatment of idiopathic generalised epilepsy. Seizure2003;12:617620.

7. Martinez-Juarez IE, Alonso ME, Medina MT, Duron RM, BaileyJN, Lopez-Ruiz M, Ramos-Ramirez R, Leon L, Pineda G, Castro-viejo IP, Silva R, Mija L, Perez-Gosiengfiao K, Machado-Salas J,Delgado-Escueta AV. Juvenile myoclonic epilepsy subsyndromes:Family studies and long-term follow-up. Brain 2006;129:12691280.

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 Psychiatry2001;70:240243.


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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.

Sillanpaa 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 first seizures; and in 12 patients, clusters

occurred during treatment. In these 12 patients, first 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 significantly 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

M ore than a century ago, Gowers recognized seizure clus-tering as a pattern exhibited by many people withepilepsy (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 influence 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 pat-

tern 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,

Sillanpaa and Schmidt providepreliminary evidence that seizure

clusters occurring during anticonvulsant treatment are also as-

sociated 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 defined 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-

tering, such as Lennox-Gastaut syndrome, infantile spasms, and

absence or myoclonic seizures. Patients were considered drug-

resistant 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 chil-

dren with epilepsy be referred to Dr. Sillanpaa. In contrast to

studies arising from tertiary epilepsy programs that treat onlymedically 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 in-

dependent. 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 at-

tributable to poorer overall seizure control in patients who

have seizure clustersrather than seizures occurring in suc-

cession. 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).

Thecurrentstudyislimitedbythesmallnumberofpatients

who exhibited a clustering pattern. Given the limited power of

the study, the finding that seizure clustering is not associated

with an increased risk for status epilepticus will need to be

confirmed by a larger study, especially since 5 of the 12 patients

with seizure clusters during treatment had episodes of status




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epilepticus. An additional consequence of the limited number

of clustering patients in this study is a large confidence interval

for the risk ratiosfor mortality andintractability, suggesting that

it is premature to use these specific 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 Sillanpaa and Schmidt report is

that they did not use a statistical model to ensure that patients

who were designated as clusterers actually deserved that desig-

nation. Other investigators have found that using their clinical

criterion of three seizures in 24 hours is too broad, as it allows

inclusionof patients who meet this definitionby 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 identification 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 pa-

tients. Furthermore, a clinical definition offers clinicians prac-

tical guidance in identifying patients for purposes of counseling

and modifying treatment.

Patients who have seizure clusters have been identified as

ideal candidates for using rescue medications, such as rectal di-

azepam (3) and buccal midazolam (4). Though the association

is uncertain, it is interesting to note that the incidence of gener-

alized 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 mortal-ity, however. Since the cause of death for patients with seizure

clusters was not attributed to status epilepticus in the Sillanpaa

and Schmidt study, it seems clear that rescue medications will

not completely eliminate the mortality associated with a clus-

tering seizure pattern.

In summary, Sillanpaa and Schmidt have raised awareness

of seizure clustering as a risk for poor seizure control andmortal-

ity. While the practical implications are not clear, the findings

may indicate a need for more aggressive management in pa-

tients exhibiting this pattern. Studies powered to confirm and

extend the outcomes would be desirable and are necessary be-

fore the findings can be used to counsel patients about specificrisks.

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 Neurol2002;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 efficacy of buccal midazolam versus rectal diazepam foremergency treatment of seizures in children: A randomised con-trolled trial. Lancet 2005;366:205210.

5. Mitchell WG. Status epilepticus and acute repetitive seizures inchildren, adolescents, and young adults: Etiology, outcome, andtreatment. Epilepsia1996;37(suppl 1):S7480.

6. Sperling MR, Harris A, Nei M, Liporace JD, OConnor MJ.Mortality after epilepsy surgery. Epilepsia2005;46(suppl 11):4953.

7. Tomson T, Walczak T, Sillanpaa M, Sander JW. Sudden unex-pected death in epilepsy: A review of incidence and risk factors.

Epilepsia2005;46(suppl 11):5461.8. Haut SR, Lipton RB, LeValley AJ, Hall CB, Shinnar S. Identifying

seizure clusters in patients with epilepsy. Neurology2005;65:13131315.

9. Wu YW,Shek DW,Garcia PA, Zhao S, Johnston SC.Incidence and

mortality of generalized convulsive status epilepticus in California.Neurology2002;58:10701076.


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CHILDREN WITH EPILEPSY: WHY CANT THEY PAY ATTENTION?

The Frequency, Complications and Aetiology of ADHD in New Onset Paediatric Epilepsy. Hermann B, JonesJ, Dabbs K, Allen CA, Sheth R, Fine J, McMillan A, Seidenberg M. Brain 2007;130(Pt 12):31353148. Recent studiessuggest that Attention Deficit Hyperactivity Disorder (ADHD) is a common comorbid condition in childhood epilepsy, but little is known

regarding the nature, frequency and timingof 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. Seventy-

five children (age 818) with new/recent onset idiopathic epilepsy and 62 healthy controls underwent structured interview (K-SADS) to

identify thepresence andtype of DSM-IVdefined ADHD,neuropsychologicalassessment, 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 significantly more prevalent in new onset epilepsy than healthy controls (31% vs 6%),

characterized predominantly by theinattentive variant, withonset antedating the diagnosis of epilepsy in themajority of children.ADHD

in childhoodepilepsyis associated with significantlyincreased ratesof school basedremedialservices 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 signi ficantly increased gray matter in

distributed regions of thefrontal lobe andsignificantly smallerbrainstemvolume. Overall, ADHD is a prevalent comorbidity of newonset

idiopathic epilepsy associated with a diversity of salient educational, cognitive, behavioural and social complications that antedateepilepsy onset in a significant proportion of cases, and appear related to neurodevelopmental abnormalities in brain structure.

COMMENTARY

P erhaps, the fact that the paper by Hermann et al. includesalmost no references dated before 1995 is due to the con-straints 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,

virtuallyall issuesof epilepsy journals will include studies of psy-

chiatric, cognitive, and social disorders that are overrepresented

in populations with various types of epileptic disorders. Of-

ten 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 mal-

adies. In other words, a still unnamed disease or diseases may

be manifested by a variety of symptoms and signs, including

depression, attention deficit hyperactivity disorder (ADHD), a

range of cognitive deficits, as well as seizures.Hermann et al. have made a significant contribution to

this field in their study of ADHD in children with recent on-

set 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, superficially ap-

peared to be completely healthy: normal neurological exam,

normal MRI scan, no developmental disability, and no other

neurological disorder. The control group consisted of age- and

gender-matched first cousins.

Using careful parental interviewing, a broad range of neu-

ropsychological testing, and quantitative MR volumetrics, in-

vestigators found that the apparently healthy children with id-

iopathic 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 chil-

dren with ADHD (82%) had been symptomatic prior to their

first seizure, ruling out medication or psychosocial stressors as

etiological factors. In this study, the symptom profile of the

epilepsy-associated ADHD seemed distinct from that seen in

the general population, with the inattentive subtype predomi-

nating 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. Neu-

ropsychological testing as well as parental reports performed

confirmed the high prevalence of symptoms and signs at-

tributable to frontal lobe dysfunction in many of the children

with epilepsy, but especially in those with ADHD. Neuropsy-

chological test results included impairments in motor and psy-

chomotor 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 initi-

ation of problem solving for those children with both epilepsy

and ADHD. Finally, while MR volumetrics demonstrated that




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the epilepsy/ADHD group had significantly 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 significance of these findings 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 ser-

vices that frequently were begun beforethe first seizure occurred.

Only 15% of the children with seizures but without ADHD

needed such help.

The findings 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) classification proposal cited by the authors de-

fines idiopathic epilepsy syndrome as one that is only epilepsy,

with no underlying structural brain lesion or other neurological

signs or symptoms (1). This definition is a moving target, since

the same paper mentions other classification schemes for idio-

pathic epilepsy that would include idiopathic focal epilepsies

of infancy and childhooda definition that would embrace

benign childhood epilepsy with centrotemporal spikes, for ex-

ample. This syndrome has been shown to be accompanied by

subtle attention and language deficits (2,3). Other idiopathic

epilepsies such as childhood absence epilepsy and juvenile my-

oclonic 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 neu-rological signs or symptoms seems to be dissolving under in-

creasingly sophisticated scrutiny of these patients. Hermann

et al. enrolled study patients with both focal and generalized

syndromes but gave no further specific diagnoses of subtypes.

The patient population studied by Hermann et al. presents

further interpretive problems. The study group was defined as

children with epilepsy with no signs or symptoms indicative

of neurological abnormality. Yet, many in the subgroup dis-

covered 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, allsubjects were re-

cruited from pediatric neurology clinics. Could they have been

referred to pediatric neurologists because their physicians orparents 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 findings?

This remains a valuable study, adding to a growing litera-

ture of similar findings. As the number of known and defined

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 withepileptic seizures and with epilepsy: Report of the ILAE TaskForce on Classification and Terminology. Epilepsia2001;42:796803.

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 deficits in child-

hood epilepsy syndromes. [Review] [160 refs] [Journal Article Re-view]. 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 patientswith idiopathic generalized epilepsies. Neuroimage 2006;32:498502.


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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. Epilepsia2008;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 wasfound that pregnancy had little influence 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 50 70%

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

The current article is a report from the Australian Preg-

nancy Registry (APR), and the main points of interestare found in the abstract. The prospective APR is one of several

similar trials currently ongoing throughout the world. In addi-

tion to the APR, the most significant 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 Preg-

nancy 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 off-

spring. These registries aredesigned to provide the best evidence

possible on unresolved questions regarding the course of preg-

nancy for women with epilepsy who are exposed to antiepilep-

tic drugs, including what effects lactation may have on the in-

fant 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) whetherseizuresoccur less

or more frequently during pregnancy and 2) what the effects on

theoffspring arewhen seizures do occur. Thefirststudytoreportto 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

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

thepreviouslevelafterdelivery. Another variable that needs to be

addressedis whether patientsare compliantand 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 perti-nent information by their doctor. Therefore, the patient had to

take the initiative to make the first phone call, causing a selec-

tion 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 reg-

istry, however, was (and still is) instigated by the physician

who asks the patient if she wants to participate. After ac-

ceptance, the patient is then followed throughout her entire

pregnancy. In contrast, once enrolled in the Australian study,

patients are first 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 seizure-

free during pregnancy is being seizure-free the year before

pregnancy and that, in accordance with the EURAP registry,

pregnancy itself does not influence seizure frequency rates

in most patients. However, patients who had seizures before




8/8


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 dur-

ing pregnancy. This conclusion is based on a comparison

of events during 9 months of pregnancy with events during12 months before pregnancy. The same interpretation may not

have applied if accurate counts of seizure numbers had been

available.

Similarly, the outcome findingsfortheoffspringintheAPR

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 findings, 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.

Sowhatcanwelearnfromthesetwostudiesthatcanhelpto

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 havingnew seizures duringpregnancy and

deliveryalthough there is still a chance it could occur. Learn-

ing from the EURAP study, patients will benefit from doctors

who work diligently to find 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 levelsare 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 preg-nancy:Observations fromthe EURAPEpilepsy PregnancyRegistry.Neurology2006;66:354360.

2. De Haan GJ, Edelbroek P, Segers J, Engeksman M, Lindhout D,Devile-Notschaele M, Augustijn P. Gestation-induced changes inlamotrigine pharmacokinetics: A monotherapy study. Neurology2004;63:571573.

3. Pennell PB, Newport DJ, Stowe ZN, Helmers SL, MontgomeryJQ, Henry TR. The impact of pregnancy and childbirth on the

metabolism of lamotrigine. Neurology2004;62:292295.4. Christensen J, Sabers A, Sidenius P. Oxcarbazepine concentrations

during pregnancy: A retrospective study in patients with epilepsy.Neurology2006;67:14971499.

juvenile myoclonic epilepsy: more trials are needed to guide therapy

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