Adult-Onset Idiopathic Generalized Epilepsy: Clinical andBehavioral Features

Shawna Cutting, Aaron Lauchheimer, William Barr, and Orrin Devinsky

Department of Neurology, New York University School of Medicine, New York, New York, U.S.A.

Summary: Purpose:To identify and define clinical and be-havioral features of patients with adult-onset idiopathic gener-alized epilepsy (IGE).

Methods:We reviewed the charts of 313 IGE patients at theNYU Comprehensive Epilepsy Center over the past 5 years toidentify patients with adult onset (18 years old or older). Weexcluded patients with childhood or adolescent symptoms thatsuggested absence, myoclonic, or tonic–clonic seizures, as wellas those with a history of significant head injury or other knowncauses of localization-related epilepsy.

Results:Forty-two (13.4%) patients had a clear onset of IGEin adulthood; average age of onset was early 20s (mean, 23.8years; range, 18–55 years). Twenty-one patients had adult myo-

clonic epilepsy (AME, 50%), and three had generalized tonic–clonic seizures on awakening (GTCS-A, 7%). More than twothirds (n 4 30) are well controlled with current antiepilepticdrugs (AEDs), and almost 90% are currently employed (n437). One third were diagnosed and treated for mental disorders,including depression (n4 12), anxiety (n4 7), obsessive–compulsive personality disorder (n4 2), and postictal psycho-sis (n4 1).

Conclusions:Adult-onset IGE is associated with a goodprognosis. An association may exist between psychological dis-orders, psychotropic medication, and level of seizure control inadults with IGE.Key Words: Epilepsy/EEG—Neuro-psychology—Behavior—Psychotropic medication.

Idiopathic generalized epilepsy (IGE) typically ap-pears within the first two decades of life. Types of sei-zures, distinct EEG patterns, age at onset, and circadianrhythmicity of seizures are used to classify specific syn-dromes. These patients usually are considered to have anexcellent prognosis. Most are well controlled on one an-tiepileptic drug (AED), cognitive function is normal, andthe frequency of depression and anxiety is lower thanthat in patients with localization-related epilepsy (1,2).However, some long-term follow-up studies suggesthigher rates of persistent seizures despite AED therapy,failure to outgrow epilepsy, and an increased frequencyof problems in academic, social, and behavioral func-tioning (3,4).

The diagnosis of IGE becomes more problematicwhen symptoms appear in adulthood. Some investigatorsquestion whether IGE syndromes with adult onset exist(5). The definitive appearance of generalized seizuresduring adolescence or adulthood may lead momentarylapses of attention in childhood, considered normal day-dreaming spells, to be reclassified as absence seizures.

Apparent adult onset of IGE may be a localization-related epilepsy related to traumatic brain injuries sus-tained in the recent past or may reflect a failure torecognize IGE symptoms present since childhood or ado-lescence. However, evidence is growing in support ofadult-onset IGE. Gilliam et al. (6) recently describedadult myoclonic epilepsy as a distinct syndrome that oc-curs with no previous childhood or adolescent seizures.

We studied a consecutive group of patients with onsetof IGE in adulthood to define further the prognosis, clini-cal features, and behavioral features of this population.We sought information on provocative factors for firstseizures within the adult IGE population and comparedthese factors with those of other patients with new-onsetseizures (7–9). We examined rate of psychological com-plaints, level of cognitive performance, use of psycho-tropic medications, and seizure control to determinewhether a relation exists.

METHODS

We reviewed the outpatient charts of 646 epilepsypatients evaluated at the NYU Comprehensive EpilepsyCenter between 1995 and 2000. Patients came from avariety of sources, including patients being seen for newonset of epilepsy and referrals with medically refractory

Revision accepted August 30, 2001.Address correspondence and reprint requests to Dr. O. Devinsky at

Neurology Department, NYU-Mt Sinai Comprehensive Epilepsy Cen-ter, 560 1st Avenue, Rivergate Building, 4th Floor, New York, NY10016, U.S.A. E-mail: od4@is4.nyu.edu

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epilepsy. Patients whose clinical history supported alocalization-related epilepsy, who had never had an ab-normal EEG, whose EEG showed focal slowing or focalepileptiform activity, who were developmentally de-layed, who had a potentially epileptogenic brain lesion,or who had resective brain surgery were excluded fromthis study, leaving 313 cases. Patients younger than 18years at the time of their first diagnosed seizure wereexcluded, leaving 42 cases. Each EEG report (video, rou-tine, and ambulatory) was reviewed, and the presence ofinterictal generalized spike and slow-wave activity andits frequency was recorded. Patients whose generalizedspike and slow-wave discharges were never$3 Hz wereexcluded.

We reviewed the history of seizures and clinical diag-nosis of each patient. The diagnosis of adult myoclonicepilepsy (AME) was made if the patient experiencedmyoclonic jerks (not limited to sleep or transition intosleep) and at least one other seizure type. Generalizedtonic–clonic seizures on awakening (GTCS-A) was di-agnosed if the majority of seizures occurred within 90min of waking. The gender, age at onset, and familyhistory of each patient was recorded. Time of day andtype of initial seizure were recorded. Loss of conscious-ness associated with head trauma was recorded, andthose patients who had a loss of consciousness 30 swithin 4 years of seizure onset were excluded.

We categorized current seizure activity as grade I (fullcontrol), grade II (fair control), or grade III (poor con-trol). These were arbitrary categories assigned to esti-mate the potential impact of a patient’s seizure activityon daily living. “Current” was defined as the past 12months. Grade I was defined as experiencing no seizuresor only infrequent (fewer than one per month) absence ormyoclonic seizures. Grade II was defined as a moderatedecrease (>75%) in the number of seizures from priorbaseline, with no more than one TCS per year and nomore than one absence or myoclonic seizure per day.Grade III was used when patients had$75% reduction inseizure frequency compared with baseline, with morethan one TCS per year or an average of more than onemyoclonic or absence seizure per day. Current and pastAED treatment history was recorded.

Precipitating factors before the initial seizure, such assleep deprivation, increased stress, and consumption oftwo or more alcoholic beverages or an illegal substancewere recorded. A final category of “other” was listed,which consisted of atypical factors that might have con-tributed to the initial seizure (such as an overdose ofover-the-counter medicine).

Patient charts also were reviewed for current and pastpsychiatric history. Psychiatric diagnosis, individualtherapy sessions attended, and psychotropic treatment ofpatient complaints (past and present) were recorded. Psy-chiatric diagnoses based on uncertain criteria or originat-

ing from an unclear or nonpsychological source wereexcluded. Psychotropic medication was categorized aseffective, somewhat effective, or ineffective in treatingpsychic complaints as per patient report and physicianinterview of patient and family members; in many casesthese findings were supplemented with standardized in-ventories.

Marital status, level of education, number of children,and current employment status were noted. Patients cur-rently attending college or presently caring for childrenwere considered employed. Neuropsychological test re-sults also were examined, where available.

RESULTS

Among 313 patients with IGE, 42 (13.4%) patientshad onset in adulthood. Table 1 summarizes the demo-graphics of these patients. The average age of the patientat seizure onset was 23.8 years (range, 18–55 years);median age at onset was 20 years. Twenty-three patientswere female (55%) and nineteen were male (45%). Gen-eralized spike and slow-wave activity$3 Hz was seen inall patients. Twenty-one (50%) patients have AME, three(7%) have GTCS-A, and the remaining eighteen (43%)have an IGE that does not fit either category. Eleven(26%) patients have a family history of epilepsy; in six ofthese 11 patients, the family history was consistent witha generalized epilepsy. Ambiguous periods of blankingout or “daydreaming” were reported in three of our 42patients; however, none was typical of absence seizures,as patients were fully responsive during these spells.

Twenty-two (52%) patients are single, 17 (40%) pa-tients are currently married, and one (2%) patient is wid-owed. Divorce occurred in three (7%) patients, one ofwhom remarried. Thirty-seven (88%) patients are cur-rently employed, including six (14%) college studentsand two (5%) homemakers. Four (10%) patients are notemployed, and one (2%) patient is retired. Twenty-eight(67%) patients have attended at least one semester ofcollege; five (12%) of these have a bachelor’s degree,and three (7%) have a master’s or doctoral degree. For 11patients, educational status is not known.

Nine (21%) patients have had a neuropsychologicalevaluation, including a standard measure of cognitivefunction. Of those patients, seven have an average full-scale IQ score (between 90 and 110), one has a low-average full-scale IQ score (between 80 and 90), and onehas a borderline full-scale IQ score (between 70 and 80).

Twenty (48%) patients are well controlled (grade I)with no AEDs (n4 1) or monotherapy (n4 19); 10additional patients (n4 30 total, 71%) are well con-trolled. Valproic acid (VPA) is the most frequentlyprescribed medication; more than two thirds of mono-therapy patients and 26 patients in total are using thisAED. Further information regarding AEDs used formonotherapy is summarized in Table 2.

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Factors that may have precipitated the first seizureinclude sleep deprivation (n4 14; 33%), patient reportof increased stress (n4 8; 19%), and consumption oftwo or more alcoholic beverages within the 24 h preced-ing the seizure (n4 8, 19%). Frequently, combinationsof these factors led to seizure onset. Sixteen (38%) pa-tients reported no precipitating factors. The first seizurewas a GTC in 79% of patients (n4 33), myoclonic jerksor myoclonic jerks followed by a GTC in 12% of patients(n 4 5), and was unclear or unknown in 10% of thepatients (n4 4). More than one fourth of patients (n411) experienced their first seizure within 90 min ofawakening. Patients diagnosed with AME were no moresensitive to sleep deprivation than were those who hadother diagnoses (p4 0.54).

Diagnosis and treatment of mental disorders occurredin more than one third of the population. Five (12%)patients have been to a therapist at least twice for indi-vidual counseling sessions. Fifteen (36%) patients havetaken psychotropic medications at some point. Ten(24%) patients have taken medication to treat depression

or depressive symptoms, seven (17%) to treat anxiety,one (2%) to control obsessive–compulsive symptoms,and one (2%) for psychotic symptoms.

Ten (24%) patients are currently taking psychotropicmedication. Six take one psychotropic, and the remain-ing four take two. Half use selective serotonin reuptakeinhibitors (SSRIs) to treat psychological complaints.More than two thirds (n4 7) reported current psycho-tropic treatment to be effective, and one third (n4 3)reported current psychotropic treatment to be ineffective.

Among the 10 patients taking psychotropics, five havegrade I seizure control, two have grade II, and three havegrade III. Patients taking psychotropic medication wereno more likely to have grade II or III seizure control thanwas the population as a whole (p4 0.26). However,patients taking two psychotropics seem to have less sei-zure control (three of four or 75% have grade II or IIIcontrol) than do patients taking a single psychotropic(two of six or 33.3% have grade II or III control). Ad-ditionally, those patients who are not treated effectivelywith psychotropics seem to have poor seizure control aswell (two of the three reporting ineffective psychotropictreatment had grade II or III seizure control).

DISCUSSION

Adult onset occurred in 13% of our patients with IGE;this supports the existence of a clinically distinct syn-drome, which is consistent with reports of other investi-gators (6,10). These patients have a good prognosis, withmost experiencing good to excellent seizure control with

TABLE 2. AEDs prescribed to patients with adult-onset IGE

Medications for monotherapyValproic acid (Depakote) 18Topirimate (Topamax) 3Phenytoin (Dilantin) 2Lamotrigine (Lamictal) 1Acetazolamide (Diamox) 1Clonazepam (Klonopin) 1

AED, antiepileptic drug; IGE, idiopathic generalized epilepsy.

TABLE 1. Characteristics of adult IGE population and selected subpopulations

Adult-onsetIGE

Familyhistory

AMEdiagnosis

Current use ofpsychotropics

Number of patients 42 10 21 10Percentage of IGE adult-onset population 100% 23.8% 50.0% 23.8%Average age at onset 23.8 24.8 23.7 24.5Seizure control

Grade I 30 6 13 5Grade II 6 2 5 2Grade III 6 2 3 3

Clinical presentationTonic–clonic seizures 41 10 20 9Myoclonic seizures 21 6 21 6Absence seizures 16 5 7 5

Drug therapy regimenNo AEDs 1 — — —One AED (monotherapy) 26 6 14 3Two AEDs 10 2 4 5Three AEDs 5 2 3 2

Precipitants of first seizureNo factor 16 4 5 4Sleep deprivation 6 1 5 3Sleep deprivation and alcohol intake 5 1 2 —Sleep deprivation and increased stress 3 2 2 —Increased stress 4 2 3 2Alcohol intake/illegal drug use 3 — 2 —Other 5 — 2 1

Patients may be included in multiple subpopulations.IGE, idiopathic generalized epilepsy; AED, antiepileptic drug.

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a single AED and being able to support themselves. Psy-chiatric disorders such as depression and anxiety areepidemiologically similar to the general epilepsy popu-lation; symptoms typically are well treated by a singlepsychotropic medication.

Clinical, behavioral, and EEG findings were similaramong patients with a family history of seizures, thosewith AME, and the adult-onset IGE population as awhole. Demographic and social features, use and re-sponse to AEDs (∼65% in all three groups are taking noor one AED; 65% have grade I control) and age at sei-zure onset (low 20s) were comparable. Precipitating fac-tors for the first seizure were reported by 61.9% of ourgroup, with sleep deprivation being the most commonfactor. This is consistent with current theories regardingthe sensitivity of generalized epilepsies to changes insleep patterns (8). Contrary to recent studies, patientswith AME were no more sensitive to sleep deprivation asa contributing factor for their first seizure than were oth-ers (p4 0.54)

Depression and anxiety were the most common psy-chological disorders diagnosed, consistent with otherepilepsy syndromes. Because most adult IGE patientswere seizure free and self-supported, depression andanxiety may be primarily related to primary brain dys-function or medication effects rather than ongoing sei-zures or disability. According to several communitybased studies, between 10 and 22% of epilepsy patientsexperience some level of depression, and between 10 and25% experience significant anxiety (11–13). Theseranges are lower than figures suggested for hospital-based samples, which typically include more severe, in-tractable epilepsy cases. Most of our patients weretreated successfully for their psychic and seizure needsand thus are more similar to a community sample. Theprevalence of adult-onset IGE patients treated for depres-sion (23.8%) and anxiety (16.6%) in our study is similarto the ranges of the community-based studies.

Patients taking psychotropics had seizure control andcombination AED therapy rates similar to the adult IGEpopulation, suggesting that psychotropic medication canbe effectively used to treat psychological symptomswithout fear of affecting seizure control. Our study wasconsistent with several other studies stating that psycho-tropic medications do not directly adversely affect sei-zure control (14,15). The trend toward poor seizurecontrol with the use of multiple psychotropics raises analternate explanation. All of our patients currently takingmultiple psychotropics also were taking multiple AEDs.Patients taking multiple AEDs may have more difficult-to-control epilepsy than those effectively treated withmonotherapy; poor seizure control could then lead toincreased cognitive and behavioral dysfunction. The use

of multiple AEDs is linked with self-reported decreasedlife satisfaction and poorer health (16). Disruption ofsleep, circadian rhythm, and wakefulness, which can re-sult from AEDs or frequent seizures, also could influencequality of life and psychological complaints (17).

Further research is needed to confirm our observationon the relationship of seizure frequency and psychiccomplaints to use of multiple psychotropics and AEDs inpatients with IGE. Our sample size did not allow the useof more sensitive statistical analysis. If supported, theassociation between multiple AEDs, poor seizure con-trol, and increased behavioral and cognitive disturbancescould be attributed to a more refractory condition, psy-chological stress, drug interactions, or changes in seizurethreshold induced by psychotropic agents.

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