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EPILEPSY

COMORBIDITIESSean Hwang, Alan Ettinger, and Elson L. So

ABSTRACT

Psychiatric and cognitive disorders in persons with epilepsy (PWE) are often over-looked or undertreated. Studies have shown that they occur in all types of epilepsy,but they are especially prominent when epilepsy is severe and multiple antiepilepticdrugs are used. In particular, the clinician should be vigilant about the coexistence ofdepression with epilepsy. The depression must be properly treated to improve qualityof life and also to prevent the mood disorder from interfering with epilepsy treatment.

Mortality in PWE is overall twice that in the general population, but most of theincreased mortality is due to major conditions with which the epilepsy is associated.The clinician should be aware that some PWE have increased risk for suicide. Thephenomenon of sudden unexplained death in epilepsy occurs at the highest rate inpersons with uncontrolled seizures, especially generalized convulsive seizures. Fornow, optimizing seizure control appears to be the best way to reduce the risk for thisstill mysterious and catastrophic event.

Continuum Lifelong Learning Neurol 2010;16(3):86–104.

PSYCHIATRIC COMORBIDITIESIN EPILEPSY

Depressive Disorders

Depressive symptoms are highly preva-lent among persons with epilepsy (PWE),

with rates ranging up to 20% to 55% inpersons with uncontrolled seizures. De-spite variations in methodology andpatient selection, depression has beenconsistently shown to occur threefold to

10-fold more often in persons with re-fractory epilepsy than in the generalpopulation.1 Although the coexistenceof ‘‘melancholy’’ and epilepsy has been

recognized since the time of Hippoc-rates, depression in PWE is still fre-quently underdiagnosed and untreated.

Whereas PWE do present with major

depression meeting Diagnostic and Statistical Manual of Mental Disorders

(Fourth Edition) ( DSM-IV ) criteria, dif-ferences in the nature of depressivesymptoms in the setting of epilepsy ascompared to those in primary mooddisorders have been observed. PWE

may present with a more pleomorphic, waxing and waning, chronic state of de-pressive symptoms that has been de-scribed by Blumer as the ‘‘interictal

86

Relationship Disclosure: Dr Hwang has received research support from GlaxoSmithKline for a research projecton bipolar disorder in epilepsy. Dr Ettinger has received personal compensation for serving on scientificadvisory boards for epidemiologic studies unrelated to any specific product from GlaxoSmithKline, Johnson & Johnson Services, Inc., and Ortho-McNeil-Janssen Pharmaceuticals, Inc. Dr Ettinger has received license feepayments or royalty payments from GlaxoSmithKline for research activities conducted at an institution with which he was formerly associated (Long Island Jewish Medical Center). Dr Ettinger has received researchsupport from GlaxoSmithKline for a study of rates of bipolar disorder in epilepsy patients. Dr Ettinger’scompensation and/or research work has been funded, entirely or in part, by a grant to his university from apharmaceutical or device company. Dr So has nothing to disclose.Unlabeled Use of Products/Investigational Use Disclosure: Drs Hwang, Ettinger, and So have nothing to disclose.

Copyright # 2010, American Academy of Neurology. All rights reserved.

KEY POINT

A Persons with

epilepsy may

present with

a morepleomorphic,

waxing and

waning, chronic

state of depressive

symptoms

that has been

described as

the ‘‘interictal

dysphoric

disorder’’ or the

‘‘dysthymic-like

disorder of

epilepsy.’’

Note: Text referenced in the Quintessentials Preferred Responses, which appear

later in this issue, is indicated in yellow shading throughout this chapter.

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Continuum Lifelong Learning Neurol 2010;16(3)

dysphoric disorder’’ or by Kanner as the‘‘dysthymic like disorder of epilepsy.’’2

In addition to the variable presenta-

tion of interictal depression in epilepsy,acute peri-ictal mood symptoms may oc-cur, as well as iatrogenic mood fluc-tuations secondary to antiepileptic drug(AED) use or after epilepsy surgery. Dys-phoric symptoms have been describedas a prodrome for up to 3 days prior toseizure onset, and the symptoms may last up to several days after the seizurehas occurred.

AEDs such as phenobarbital, primi-done, tiagabine, vigabatrin, and the ben-

zodiazepines can exacerbate depression.

Felbamate, levetiracetam, topiramate,and zonisamide have also been associ-ated with depression. AEDs commonly

recognized for their mood-stabilizingproperties, such as carbamazepine, la-motrigine, and valproic acid, may lessfrequently also cause depressive symp-toms. Underlying depression could attimes emerge after withdrawal of mood-stabilizing AEDs ( Table 4-1 ).3

Irrespective of the manner in whichdepressive disorders may present in epi-lepsy, it is paramount to appreciate their considerable adverse impact upon qual-ity of life (QOL). Mood has been shown

in several series to be a critical factor

87

TABLE 4-1 Potential Psychotropic Effects of Antiepileptic Drugs

AntiepilepticDrug Beneficial Effects Harmful Effects

Barbiturates Anxiety, mood stabilizing, sleep Aggression, impaired cognition and attention,depression, irritability, sexual function and desire

Carbamazepine Aggression, mania, mood

stabilizingaIrritability, impaired attention

Ethosuximide . . . Aggression, confusion, depression, insomnia

Gabapentin Anxiety, insomnia, socialphobia,a mood stabilizing

Irritability/agitation (usually in children withdisabilities)

Lamotrigine Depression,a moodstabilization,a maniaa

Insomnia, irritability (usually in children withdisabilities)

Levetiracetam Data not available Anxiety, depression, irritability (all appearmore common in children)

Phenytoin Mania Depression, impaired attention

Tiagabine Mania, mood stabilization Depression, irritability

Topiramate Binge eating, mania, mood

stabilization

Depression, impaired cognition (word finding,

memory) and attention, irritability

Valproate Agitation, aggression, irritability,mania,a mood stabilizationa

Depression

Zonisamide Mania Aggression, emotional lability, irritability

a Signifies the existence of good, affirmative data from well-planned studies to support a beneficial effect.

Reprinted with permission from Nadkarni S, Devinsky O. Psychotropic effects of antiepileptic drugs. Epilepsy Curr 2005;5(5):179.

KEY POINT

A Failing to

identify and

treat depressive

disordersappropriately may

result in negative

impacts on

patient quality

of life, excessive

health care use,

and increased risk

of suicidality.

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associated with perceived health statusin PWE, consistently more so than evenseizure frequency or severity among

patients with persistent seizures.

4

Co-morbid depression in PWE has also beenlinked to increased utilization of medi-cal services and health care cost.5 Lastly,suicide is an important cause of mortal-ity in PWE ( Figure 4-1 ).

Of particular interest is mountingevidence of a bidirectional relationshipbetweendepressionandepilepsy. Emer-gent data suggest that depression may alsoadverselyaffectseizure control. Peo-ple with new-onset epilepsy who have a

history of psychiatric illness, when com-pared to those without, were reportedto be more than twice as likely to be-come refractory to AEDs.6 After tem-poral lobectomy, significantly worseseizure outcomes occurred for people

with a psychiatric history compared withthose without, and a history of depres-sion was predictive of persistent dis-abling seizures.4,5 Data from three largepopulation-based studies indicate a 1.7-fold to seven-fold risk of developingepilepsy in patients with a history of depression. A history of suicide attemptmay increase the risk of developingseizures by more than fivefold.7

The notion that depression in epilepsy simply occurs as a reaction to a chronicmedical illness fails to recognize the com-plex biological relationships between thetwo disorders and reduces the motiva-tion of the clinician to appropriately iden-tify and address depression. Psychosocial

factors, which include personal attribu-tional style, discrimination, social isola-tion, loss of independence, and limited

vocational opportunities, certainly do con-tribute to the pathogenesis of depression.However, recent research further eluci-dates some of the common biologicalmechanisms underlying both depression

and epilepsy.Potential biological mechanisms

of depression in epilepsy. Consid-erable data support the hypothesis of


88

FIGURE 4-1 Scatterplot of the correlation of health-relatedquality of life with adverse antiepileptic drugeffects, depression symptoms, and averagemonthly seizure rate.

QOLIE = Quality of Life in Epilepsy.

Reprinted with permission from Gilliam F. Optimizing health outcomes in activeepilepsy.Neurology 2002;58(8 suppl 5):S17. Copyright#2002, AAN Enterprises, Inc.All rights reserved.

"EPILEPSY COMORBIDITIES

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monoamine neurotransmitter abnor-malities in depression and their influ-ence on the seizure threshold of specific

brain regions. In addition to beinglinked to depression, decreased sero-tonin (5-HT) and norepinephrine (NE)activity has been demonstrated to facili-tate kindling andlower seizure thresholdin several animal models of epilepsy.8

Pathologic and MRI studies of primary depression anddepression comorbidwithepilepsyhaverevealed common structuralandhistologicchangeswithseveralmech-anisms implicated, including: elevatedglucocorticoid levels, stress-induced re-

ductions in neurotrophic factors, im-paired neurogenesis, and glial loss.9,10

Functional neuroimaging studies withproton MR spectroscopy ( 1H-MRS),fluorine-18 2-fluoro-2-deoxy-D-glucose(FDG)-PET, and PET utilizing serotoninreceptor antagonistsas radioligands sug-gest that depression in epilepsy is cor-related with changes in temporal lobemetabolism and impaired limbic sero-tonergictransmission ( Figure4-2 ).11–13

The treatment of depression in persons with epilepsy. A recent ex-pert consensus statement was gener-ated by the Mood Disorders Initiativesponsored by the Epilepsy Foundation.1

The crucial first step in initiating ap-propriate therapeutic intervention for depression in epilepsy is its recogni-tion by both the patient and clinician.Most neurologists report that they donot routinely screen for depression. Thesimplest approach may be to ask about

symptoms of anhedonia. Alternatively,self-report measures may be an efficientmeans of screening for depression. Thesix-item Neurological Disorders Depres-sion Inventory for Epilepsy has been

validated to identify major depression inPWE. The Inventory was specifically de-signed to minimize the confounders of

adverse medication effects or comorbidcognitive issues. The Beck DepressionInventory and Center for EpidemiologicStudies Depression Scale have also been

validated as self-rating screening instru-ments for depression.

When depression is suspected, more

in-depth evaluation should be under-taken to ascertain the appropriate di-agnosis and severity of illness. Theclinician should assess the risk for sui-cidality, which may be increased withcomorbid anxiety and bipolar illness,because of the potential for unleashingmanic symptoms with antidepressantadministration in vulnerable individuals.

A current or past mood or anxiety dis-order, family history of mood disorders,and prior suicide attempts are impor-

tant risk factors for suicidality. Patients with a major depression prior to age 15,a family history of bipolar disorder, or ahistory of manic symptoms with prior exposure to antidepressants may be at a40% to 60% probability of developingbipolar disorder. The clinical history

89

FIGURE 4-2 Correlation of severity of depressionsymptoms with spatial extent ofhippocampal dysfunction defined by

proton magnetic resonance spectroscopy (1H-MRS)creatine/ N -acetylaspartate ratio maps (n = 31).

POMS = Profile of Mood States; MR = magneticresonance.

Reprinted with permission from Gilliam FG, Maton BM, Martin RC,et al. Hippocampal 1H-MRSI correlates with severity of depressionsymptoms in temporal lobe epilepsy. Neurology 2007;68(5):366.Copyright # 2007, AAN Enterprises, Inc. All rights reserved.

KEY POINT

A Functional

neuroimaging

studies with1

H-MRS,FDG-PET, and PET

utilizing serotonin

receptor

antagonists as

radioligands

suggest that

depression in

epilepsy is

correlated with

changes in

temporal lobe

metabolism and

impaired limbic

serotonergic

transmission.

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should also be reviewed to make thedistinction between ictal, peri-ictal, andinterictal mood disorder.

Once a diagnosis of interictal depres-sion has been established, initial effortsshould be made to exclude iatrogeniccauses, such as the titration of an AED

with known adverse psychotropic prop-erties or the withdrawal of a mood sta-bilizing AED. An AED with the potentialfor exacerbating mood dysfunction may need to be decreased or replaced with analternative AED with characteristically favorable effects on mood. The use of la-motrigine in particular has been associ-

ated with improvements in depressivesymptoms in PWE and has been usedoff-label for the adjunctive treatmentof unipolar depression.14 If depressivesymptoms persist or are severe, the ini-tiation of psychotherapy and the useof antidepressants should be strongly considered. Interpersonal psychother-apy and cognitive behavioral therapy may be effective. Family, group, cou-ples, and supportive therapy may alsobe beneficial. In the study of patients

with primary depression, the combina-tion of psychotherapy and antidepres-sant medication may be more effectivethan either treatment alone, and may also reduce the risk for relapse.1

Open-label uncontrolled prospectiveand retrospective studies of antidepres-sant drug therapy in series of depressedPWE have shown improvements in de-pressive symptoms without exacerbationof seizures. The studies had involved

serotonin reuptake inhibitors (SSRIs)such as citalopram, sertraline, paroxetine,and fluoxetine; serotonin-norepinephrinereuptake inhibitors (SNRIs) such as ven-lafaxine; tricyclic antidepressants (TCAs)such as doxepin; and novel drugs suchas mirtazapine and reboxetine.

Many clinicians are concerned about

the risk of lowering the seizure thresh-old with the use of antidepressants, but,fortunately, the actual risk of causing

worsening seizures in PWE appears to

be small. In fact, some antidepressantshave exhibited anticonvulsant effects inboth experimental models of epilepsy

and humans. Reports of TCA-inducedseizures typically have occurred in thesetting of supratherapeutic serum AEDconcentrations. In a prospective study by Kanner and colleagues of 100 PWEtreated with sertraline, only one per-son had definite worsening of sei-zures, with five others believed to haveprobable worsening of seizures thatdid not require discontinuation of thedrug.2 Resolution of depressive symp-toms was achieved in more than half

of the patients. Antidepressants bestavoided in epilepsy include amoxapine,clomipramine, maprotiline, and bupro-pion, particularly at higher doses.

Whether the neurologist should bethe treating physician for depressionremains controversial. However, thereality is that in many regions andpractice settings, prompt and adequateoutpatient psychiatric consultation isoften not readily available. To minimizethe potential of seizure exacerbation, itis advisable to initiate SSRIs at a low dose, and then make small dose incre-ments at 2-week intervals until thedesired clinical effect is obtained.1

Because of concerns for interaction withhepatically metabolized AEDs, first-linepharmacologic therapy using SSRIs withminimal effects on CYP450 isoenzymes,such as citalopram, escitalopram, andsertraline, may be preferred. Alterna-tively, use of an SNRI may be consid-

ered, particularly in the setting of comorbid pain syndromes. Contact withthe patient at 2, 4, 6, 8, and 12 weeks isrecommended for monitoring for sideeffects, clinical deterioration, suicidalideation, and appropriate dose changes.The rate of relapse of depression is high,and at least 8 weeks or more of

symptom freedom is required to deter-mine remission. Maintenance therapy isrecommended for 4 to 9 months toprevent relapse ( Case 4-1 ).


90

A Inadequateresponse to an

initial trial of

antidepressant,

manic symptoms,

suicidality,

homicidal

ideation, or

substance abuse

issues generally

require more

urgent psychiatric

consultation.

KEY POINTS

A Many clinicians

are concerned

about the risk of

lowering theseizure threshold

with the use of

antidepressants,

but, fortunately,

the actual risk of

causing

worsening

seizures in

patients with

epilepsy appears

to be small.


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Additional treatments for refractory depression may include a change to analternative agent, such as an SNRI, mir-tazapine, or a monoamine oxidase in-hibitor. Augmentation strategies includetreatment with atypical antipsychoticagents, stimulants, thyroid hormone, or electroconvulsive therapy (ECT). A sug-gested treatment algorithm for thetreatment of depression in PWE is pro-

posed in Figure 4-3. The vagal nervestimulator may also be an option to con-sider in the setting of intractable epi-lepsy, given its antiepileptic effect andbenefit as an adjunctive therapy in re-fractory depression.

ECT has been used safely in PWE andshould be considered in the setting of

medically refractory depression, increas-ing suicidality, or psychotic symptoms.Seizures can be adequately induced by ECT without the need to reduce AED

dose. Marked improvements in psychi-atric symptoms have been observed af-ter ECT.

Bipolar Disorder

Surprisingly little is known about therates of bipolar disorder symptoms inepilepsy. In one community-based sam-ple using the Mood Disorders Ques-tionnaire, up to 12% of PWE reported

bipolar symptoms in contrast to 2% of healthy controls. The 12% rate is nearly twice that of what was observed in other chronic medical conditions. The authorsposited that the bipolar symptoms may not necessarily constitute formal bipolar disorder, but they may be mood insta-bility symptoms observed in the ‘‘inter-ictal dysphoric disorder of epilepsy.’’15

Fortunately, many of the commonly used AEDs also have potential mood-stabilizing properties. Valproic acid,

91

Case 4-1A 33-year-old man was referred for a diagnosis of temporal lobe epilepsy(TLE). He continued to have seizures monthly despite a regimen of

topiramate, levetiracetam, phenytoin, and phenobarbital. He reporteddifficulty concentrating, failing ability to remember lists, weightfluctuation, and poor sleep quality. He was easily frustrated, irritable, andtook little pleasure in the things he used to enjoy. He had excessive worry,concerns about his ability to have a relationship, and ongoing vocationalissues. He had a history of poor academic performance and had beenrecently fired from his job. His mood was generally worse after a cluster ofseizures; however, he felt depressed on most days irrespective of havinga recent seizure.

Comment. The patient has symptoms of anhedonia, depressedmood, and anxiety, in addition to several cognitive concerns. Postictalsymptoms of depression are notable; however, he appears to have

chronic interictal dysphoria as well. He should be screened for depression,and the severity of the condition and the risk for suicidality should beascertained. He is on several AEDs with the potential for mood andcognitive exacerbation, and his regimen should be reassessed becauseof concerns for side effects and efficacy. Should changes to his medicationsnot improve his circumstances, and in the absence of the concern forbipolar disorder, the initiation of a low-dose SSRI or SNRI should beconsidered with close follow-up. Referral for psychotherapy, psychiatricevaluation, and formal neuropsychological assessment should beconsidered. The patient could also benefit from relationship counseling,social work evaluation, and vocational training. Appropriate evaluationfor epilepsy surgery should also be performed.

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carbamazepine, and lamotrigine have

proven efficacy for the treatment andprevention of manic symptoms. In thepresence of frank bipolar disorder, theatypical antipsychotics(risperidone,olan-zapine, quetiapine, ziprasidone, and ari-piprazole) are also effective in treatingmania. As dopamine antagonists, thesemedications do carry a small risk of

lowering the seizure threshold. The useof lithium for bipolar disorder is wellsupported in the literature, and it hasbeen reported to be safe and effective in

PWE.1 Of concern, lithium does have

proconvulsant properties, and its use iscautiously advised.

Anxiety Disorders

Population-based study shows that PWEare 2.4 times more likely than healthy controls to report a lifetime history of

anxiety disorder.16 Similar to the find-ings observed with depression, anxiety is independently correlated with QOLmeasures in epilepsy. The coexistence


92

KEY POINT

A Antiepileptic

drugs (AEDs)

that are helpful

in bipolardisorder include

valproic acid,

carbamazepine,

and lamotrigine.

FIGURE 4-3 Proposed algorithm: stages of medical therapy.

SSRI = selective serotonin reuptake inhibitor; CBT = cognitive behavioral therapy;TCA = tricyclic antidepressant; MAOI = monoamine oxidase inhibitor.

Reprinted with permission from Barry JJ, Ettinger AB, Friel P, et al. Consensus statement: the evaluation and treatmentof people with epilepsy and affective disorders. Epilepsy Behav 2008;13(suppl 1):S22. Copyright# 2008, Elsevier.


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of an anxiety disorder in persons suf-fering from epilepsy and depression hasbeen cited to be as high as 73%, and the

coexistence may worsen QOL further than what is observed with either co-morbidity alone.4 Anxiety may addition-ally compound the risk for suicidality.17

Currently, no self-rating instrument hasbeen validated for anxiety in PWE. How-ever, the Patient’s Health Question-naire Generalized Anxiety Disorder-7may assist in detection of the condition.

Anxiety as a direct result of seizureactivity is the most common ictal psychi-atric symptom and is classically asso-

ciated with mesial TLE.3

Autonomicsymptoms, similar to those experiencedin panic attacks, have also been de-scribed to occur during cingulate sei-zures. Characteristically, ictal anxiety isof short duration, stereotypic, and oc-curs out of emotional context. Notably,interictal panic attacks, which are typi-cally longer and more severe in intensi-ty, have a high prevalence in up to 25%of PWE.18 Postictal anxiety has beenreported in up to 45% of persons withpharmacoresistant epilepsy, with symp-toms lasting a median of 24 hours.

Approaches to treating anxiety disor-ders are similar to those for depression.SSRIs and SNRIs may be considered for initial therapy, although controlled stud-ies have not evaluated their specific usein PWE. Paroxetine, escitalopram, and

venlafaxine have shown some efficacy against generalized anxiety; while paro-

xetine, sertraline, fluoxetine, escitalo-

pram, and venlafaxine may be useful inthe treatment of panic disorder.4 Benzo-diazepines have been traditionally usedin anxiety disorders; however, long-termuse is associated with sedation, tachy-phylaxis, and the potential for abuse.

Psychotic Disorders

Despite variability in ascertainment, clas-sification, and patient selection, overallprevalence rates for psychotic disor-

ders have been reported in 5% to 10%of PWE.3 Interictal psychosis similar to

what is observed in patients with schi-

zophrenia has also been reported to be6 to 12 times more common in PWEthan in the general population.19 Simi-lar to what has been described in de-pression, interictal psychosis has beenpurported to sometimes present in aunique manner in PWE. Symptoms may be less severe, with less disintegration of the person’s personality, more respon-sive to therapy, and frequently withoutnegative psychotic symptoms. How-ever, limited data suggest that psy-

chotic symptoms may increase the riskof suicide, again underscoring the im-portance of prompt recognition andtreatment of the condition.17

The prevalence of psychosis occur-ring as a postictal manifestation is es-timated to be between 2% and 10%.Findings common in postictal psycho-sis include a delay between the seizureoccurrence and onset of psychiatricsymptoms, relatively shorter durationof symptoms, affect-laden symptomol-ogy, delusional thinking, preceding clus-ter of generalized convulsions, epilepsy history of more than 10 years, and re-sponse to low-dose neuroleptics or ben-zodiazepines.3 Insomnia may be an initialpresenting symptom in many cases. If recognized early, treatment typically in-

volves a low dose of an atypical antipsy-chotic medication, such as risperidoneor quetiapine, administered for a shortcourse of 2 to 5 days.

Although rare in occurrence, iatro-genic psychosis has been described withthe use of some AEDs, including topir-amate, levetiracetam, and zonisamide,and may also potentially occur whendiscontinuing an AED, particularly one

with mood-stabilizing properties.14 Sim-ilarly, acute benzodiazepine withdrawal

may provoke an acute psychotic epi-sode. De novo psychosis after temporallobectomy for intractable epilepsy isgenerally rare, but it has been reported

93

KEY POINT

A Findings common

in postictal

psychosis include

a delay betweenthe seizure

occurrence

and onset of

psychiatric

symptoms,

relatively shorter

duration of

symptoms,

affect-laden

symptomology,

delusional

thinking,

preceding cluster

of generalized

convulsions,

epilepsy history

of more than

10 years, and

response to

low-dose

neuroleptics or

benzodiazepines.

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to occur in 3% to 28% of patients insome centers.19

Atypical antipsychotic drugs have a

more favorable side effect profile andare less likely to cause extrapyrami-dal symptoms, hyperprolactinemia, or emotional blunting. They may haveadditional mood-stabilizing propertiesas well. The risk for precipitating sei-zures with the antipsychotics is rela-tively low, with rates of seizures in non-epileptic patients ranging from 0.5% to1.2%. Paroxysmal epileptiform abnor-malities have been described to occur innonepileptic individuals taking antipsy-

chotic medications. The risk for seizuresis increased with rapid titration, highdoses, or with clozapine, chlorproma-zine, or loxapine.3

Barriers to the treatment of psychiat-ric issues in PWE are as follows:

o Failure to screen

o Failure to recognize the potentialimpact on QOL

o Failure to initiate treatment

o Concerns regarding medication

interactionso Concerns of exacerbating seizures

o The lack of expertise in treatingdifficult cases

o The absence of appropriateresources

Personality Disorders

The controversial notion of an ‘‘epi-leptic personality’’ has been promotedfor centuries; nevertheless, systematic

study with sound methodology is fre-quently lacking. Certain characteriza-tions of PWE in the past have had theadverse consequence of propagatingsocial stigma. Personality characteris-tics such as heightened emotionality,circumstantiality, hyperreligiosity, andalterations in sexual behavior were sug-

gested specifically in persons with TLE,of which Geschwind was a strong initialproponent in the 1970s. However, theassociation between these personality

characteristics and others, such as in-creased dependency, hyperviscosity, im-pulsivity, humorlessness, hypergraphia,

and any specific type of epilepsy syn-drome or region of cerebral localization,remains uncertain.20

The prevalence of Axis II disordersin PWE may be slightly higher in com-parison to the general population; yetthis may represent the elevated riskassociated with chronic medical dis-orders in general, and not specifically

with epilepsy. Based on limited data,rates of Axis II disorders in PWE haveranged from 4% to 38%.21 As in the gen-

eral population, avoidant, dependent,and obsessive-compulsive personality disorders are most prevalent in PWE.The optimal treatment for personality disorder remains elusive. Psychother-apy is most commonly employed.

Psychogenic NonepilepticAttacks

Beyond the scope of this review is thepoorly understood and immense prob-lem of people suffering from psycho-genic nonepileptic attacks, which may constitute 5% to 20% of patients car-rying a diagnosis of epilepsy. Makingeffective diagnosis and treatment is fur-ther complicated by observations that10% to 30% of persons with psycho-genic nonepileptic spells also haveepilepsy. Despite depictions of the typi-cal clinical features and associated riskfactors for psychogenic nonepilepticattacks, the criterion standard for diag-

nosis remains video-EEG monitoring.Because of the paucity of studies onthe formal treatment of psychogenicnonepileptic spells, the most effectivemeans of treatment and outcome datahave not been established. General con-sensus regarding the principles of treat-ing psychogenic nonepileptic attacksinvolve transparency in regard to thediagnosis, appropriate referral for psy-chotherapy, psychopharmacologic treat-ment of comorbid psychiatric disease,


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prevention of iatrogenic harm, and con-tinuity of care.3

COGNITIVE COMORBIDITIESIN EPILEPSY

Introduction

Cognitive comorbidities in epilepsy havetraditionally been attributed to under-lying cerebral structural abnormalities,adverse effects of recurrent seizures, AED-related side effects, or medical comor-bidities. More recent evidence suggestscontributions from early neurodevel-opmental changes, functional and ana-

tomic alterations in neuronal networksthat may be relatively remote from theseizure focus, and acceleration of phys-iologic age-related decline in cognitivefunction. Morphologic and functionalfactors influencing cognition in chronicepilepsy are illustrated in Figure 4-4.

Review of the available data indicatespresence of baseline cognitive abnor-malities in PWE, with mild longitudinaldecline over time.22,23 Earlier age of on-

set of seizures appears to correlate witha higher degree of cognitive dysfunc-tion. In quantitative MRI studies of pa-

tients with early-onset compared withadult-onset epilepsy, reduced brain vol-ume and thinning of the corpus cal-losum were observed. In comparisonto control groups, prospective study of people with childhood-onset epilepsy has revealed lower levels of educationalachievement and persistent problems

with socialization, independence, andemployment, even when adulthood hasbeen reached in well-controlled epi-lepsy or benign epilepsy syndromes.

Intelligence scores in children with epi-lepsy have been shown to be below age-adjusted means across epilepsy syn-dromes, regardless of seizure frequency,age of epilepsy onset, or number of med-ications in use.23 After the first seizureever, cognitive deficits were detected in27% of children who were intellectually normal prior to the seizure.24

The risk of developing dementia inolder PWE is elevated when compared

95

FIGURE 4-4 Morphologic and functional factors influencing cognition in the chronic epilepsysyndromes.

HS = hippocampal sclerosis; FCD = focal cortical dysplasia.

Reprinted with permission from Elger CE, Helmstaedter C, Kurthen M. Chronic epilepsy and cognition. Lancet Neurol2004;3(11):667. Copyright # 2004, Elsevier.

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with healthy age-matched control sub-jects. Elderly PWE on AED polytherapy seem to suffer the most severe cognitive

disability.

23,25

Either global or region-specific cognitive dysfunction, or both,can occur in some older PWE. Whereasregion-specific dysfunction is expected tobe the type encountered in localization-related epilepsy, it has also been ob-served in some patients with gener-alized epilepsy syndromes. Likewise,region-specific cognitive dysfunction canoccur in either symptomatic or idio-pathic epilepsies.

Cognitive Dysfunction inLocalization-Related Epilepsy

Temporal lobe epilepsy. Cognitiveissues in TLE have been studied themost extensively, given the preponder-ance of this syndrome. Material-specificmemory concerns are most common,

which is not surprising because hippo-campal sclerosis commonly underliesTLE. Verbal episodic memory that in-

volvesthe dominant hemisphere is mostaffected in TLE, with less consistentfindings of impaired visuospatial mem-ory seen in association with TLE involv-ing the nondominant hemisphere.26

Impairments in overall intelligence andin specific domains such as confronta-tional naming, executive functioning,

visuospatial skills, and motor dexterity have also been observed, suggestingmore widespread or multifocal cerebralinvolvement.27 Mounting evidence sup-

ports the effect of localization-relatedepilepsy on networks involving multipleanatomic regions.

Cross-sectional studies have shownincreasing cognitive morbidity in asso-ciation with longer duration of TLE,independent of AED polytherapy or his-tory of status epilepticus. This may be

indicative of factors such as cumulativeseizure burden, additive neuronal dam-age, a longer exposure to AEDs, earlier cerebral insult or lesion, higher risk for

injuries, and protracted psychiatric is-sues. The effect appears to be mitigatedin people with a higher level of edu-

cation, possibly due to the role of cere-bral reserve.27

Whereas episodic memory and con-frontational naming deficits are associated

with hippocampal atrophy, diminishedcognitive processing speed has beencorrelated with total cerebral white mat-ter volume and abnormal proceduralmemory with cerebellar atrophy. Onthe other hand, hypometabolism of the frontal lobes is associated with ex-ecutive dysfunction, while thalamic hy-

pometabolism may further contribute tomemory impairments.23

After unilateral surgical resection of the mesial temporal structures, generalintellectual function typically remainsstable in adults. No demonstrable post-operative changes in memory functionoccur in most patients, and up to 25% of patients may exhibit an improvement.Overall, the literature shows the risk of ameasurable decline in verbal memory in approximately one-third of patientsundergoing unilateral temporal loberesection. On the other hand, a disso-nance between subjective memory com-plaints and objective changes on memory testing is not uncommonly observed after temporal lobectomy. The real-life impactof statistically significant changes on thepostoperative memory test is unknown.Few patients report worsening of QOL.

Verbal memory deficits occur morefrequently with dominant temporal lobe

resections, and disturbances of langu-age function, such as word-finding dif-ficulties, can also occur. A consistentpredictor of a higher risk for postoper-ative memory deficit is the presence of normal or close to normal preoperativememory function. Other factors includenormal hippocampal size, older ageat time of surgery, male gender, andhigher IQ. However, persistent seizures,medication side effects, and psychiatriccomorbidity may also have profound


96

KEY POINT

A A consistent

predictor of a

higher risk for

memory deficitafter temporal

lobectomy is

the presence

of normal

preoperative

memory function.

Other factors

include normal

hippocampal

size, older age

at time of surgery,

male gender,

and higher IQ.


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effects on objective and subjective mea-sures of postsurgical cognitive functionand QOL.28

Frontal lobe epilepsy. Patterns of cognitive impairment in frontal lobeepilepsy are less well characterized thanthose in TLE, given the diversity of func-tions that are observed in the differentsubsections of the frontal lobe. Themore general term executive dysfunc-tion likely encompasses a variety of deficits, including those in attention,planning, goal selection, initiation, an-ticipation of outcome, set shifting, andself-monitoring. On the whole, patients

with frontal lobe epilepsy have beenreported to have abnormalities in at-tention, response inhibition, workingmemory,planning, motor skills, andpsy-chomotor speed when compared withpersons with other types of epilepsy or

without epilepsy.26

Patients undergoing frontal lobe re-section on the dominant hemispherehave a greater likelihood of developingdeficits in verbal fluency, while patientsundergoing resection of the nondomi-nant hemisphere have a trend towardgreater impairments in nonverbal or design fluency. Decreases in the abil-ity to adapt to one’s environment andincreased perseveration have been de-scribed in association with nondomi-nant frontopolar and precentral gyrusresections.29

Cognitive Dysfunction inIdiopathic Epilepsy Syndromes

Whereas benign childhood epilepsy with centrotemporal spikes has a goodprognosis in regard to remission andgeneral cognition, evidence supportsimpairments in language, memory andlearning of auditory material, executivefunction, attention, and academic skills,especially during the active phase of the

disease.22 Similarly, idiopathic occipitallobe epilepsy has been associated withlower scores on measures of intellectualfunctioning, memory, and attention.26

Cognitive impairment has been vari-ously reported in idiopathic generalizedepilepsy, with mildly decreased mea-

sures of intelligence, executive function,and psychomotor speed in compari-son to control subjects. For example,juvenile myoclonic epilepsy has beenassociated with subtle structural ab-normalities in the mesial frontal lobes,

with evidence of frontal lobe dysfunc-tion demonstrated by PET and 1H-MRS.Corresponding impairments in such do-mains as abstract reasoning, planning,and mental flexibility are disclosed by neuropsychological testing.23,26

Cognitive Dysfunction inCryptogenic and SymptomaticEpilepsy Syndromes

The many types of cryptogenic andsymptomatic epilepsy syndromes vary in etiology and in the brain regions in-

volved by EEG and MRI abnormalities. West syndrome characteristically hasensuing cognitive deterioration, asso-ciated behavioral regression, and di-minished social interaction. Twenty per cent to 50% of patients with West Syn-drome may go on to develop Lennox-Gastaut syndrome. Long-term cognitiveoutcome of these patients is generally but not uniformly unfavorable. Theoutcome is worse with early age atseizure onset. Progressive intellectualdecline, behavioral problems, autistictraits, motor speed impairment, apraxia,hyperkinesia, spatial disorientation, andperseveration have been described.

Neuropsychological batteries are unat-tainable in many patients because of limitations in general intelligence.26 Prog-nosis of the cognitive regression withauditory agnosia and progressive apha-sia in Landau-Kleffner syndrome is alsofrequently worse with earlier age of onset. Poor prognosis has been linked

to sleep EEG showing a continuousslow spike pattern that is maximal at theposterior temporal regions. Other symp-toms associated with electrical status

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epilepticus in sleep include substantialglobal cognitive deterioration and re-gression in attention, speech, commu-

nication, and behavior.

Attention Deficit Disorder

Pediatric PWE are at a higher risk for behavioral and attention problems. Theprevalence of attention deficit hyper-activity disorder (ADHD) in PWE hasbeen reported to be 10% to 40%, whichis higher than in the general pediatricpopulation.3 A large proportion may continue to manifest into adulthoodsymptoms of distractibility, irritability,

impulsive behavior, and poor frustra-tion tolerance. The contributing factorsare complex and may involve the un-derlying pathogenic lesion responsiblefor the epilepsy, the effects of AEDs,seizure-related variables, and perhapsthe chronic effect of EEG epileptiformabnormalities. Limited studies show that stimulant therapy with methylphe-nidate is generally safe and effective inthe treatment of ADHD in children withepilepsy, although anecdotal reportsof seizure exacerbation exist. Cogni-tive and psychiatric issues may occur inchildren prior to the onset of seizures.In a population-based study, a history of ADHD was 2.5-fold more commonamong children with newly diagnosedseizures than among control subjects,implying a common antecedentfor bothconditions.30

MORTALITY IN PERSONSWITH EPILEPSY

The standard mortality ratio of PWE ingeneral is about 2.0, which means thatthe risk of death is about 2 times thatin the general population. Although a2-times higher risk of death sounds

worrisome, the higher risk is mostly dueto serious illnesses and disabilities as-

sociated with epilepsy, such as malig-nant brain tumors, severe strokes, major head trauma, or profound developmen-tal disabilities. The higher standard mor-

tality ratio of 7.5 in children is due tomore cases of profound mental andphysical disabilities as in cerebral palsy,

and severe medical or genetic disorders.Therefore, remote symptomatic epi-lepsy in both children and adults hasa higher mortality rate than idiopathicand cryptogenic epilepsies. In any case,increased mortality risk in children andadults diminishes as time passes after the diagnosis of epilepsy is made.6

For people with well-controlled epi-lepsy and without serious illnesses, therisk of death is no higher than that in thegeneral population, and their life expec-

tancy is comparable with the generalpopulation. This is also true for mostpeople whose seizures are not com-pletely controlled. However, medically intractable epilepsy itself is associated

with slightly higher risk in mortality,including the phenomenon of suddenunexplained death in epilepsy (SUDEP).

Seizure-Related Deaths

For most PWE, the potential for seizuresto cause death is very small. An impor-tant cause of seizure-related death isstatus epilepticus (SE), specifically con-

vulsive SE and nonconvulsive SE (NCSE).The mortality of convulsive SE rangesfrom 10% to 50% if the SE is associated

with acute brain injury, such as severetraumatic injury, anoxic-ischemic en-cephalopathy, or major strokes. How-ever, the mortality of convulsive SE ismuch less, at about 1%, when the SEoccurs in the absence of acute brain

injury and in the setting of chronicepilepsy exacerbated by missed doses of AED. It should be noted that the low mortality in this situation is still predi-cated on prompt treatment of the SE.

NCSE is characterized by frequentor continuous EEG seizures occurring

when clinical signs or symptoms areeither absent or subtle. NCSE typically occurs in obtunded patients with acuteglobal brain injury or dysfunction, suchas anoxic-hypoxemic encephalopathy


98

KEY POINT

A For people with

well-controlled

epilepsy and

without seriousillnesses, the risk

of death is no

higher than that

in the general

population, and

their life

expectancy is

comparable with

the general

population.


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after cardiac arrest, subarachnoid hem-orrhage, or severe metabolic encepha-lopathy. Some of the subtle clinical signs

of NCSE are nystagmoid eye move-ments, muscle twitches, pupillary activ-ity, episodic blood pressure changes,and fluctuating mental status. About14% of convulsive SE is followed by NCSE. Therefore, when a patient’smental status has not recovered despitesuccessful control of convulsive SE, EEGmonitoring is advisable for detection of NCSE. The mortality of NCSE is very dependent on the seriousness of theunderlying acute brain dysfunction. Ob-

servational data suggest that NCSE it-self is probably associated with higher mortality, but the effectiveness of NCSEcontrol in improving survival remainsuncertain. Moreover, observational datashow that overly aggressive treatmentof NCSE increases mortality.

Accidents account for an average10% of all deaths in PWE. In the UnitedStates, the risk of accidental death inPWE is about 21 / 2 times that in thegeneral population. About 40% of ac-cidental deaths are directly related toseizures. The remaining non–seizure-related causes are varied. Conditionsassociated with epilepsy, such as phys-ical or mental disabilities and medicationside effects, have been suspected, butnot proven, to contribute importantly to these non–seizure-related accidents.Poor seizure control appears to be themajor risk factor for accidental deaths,

whether or not the deaths directly re-

sult from seizure episodes. Major typesof accidental deaths in PWE are falls,drowning, burns, motor vehicular crashinjuries, and, rarely, choking on vomit.31

Drowning occurs more commonly inteenagers and young adults with epi-lepsy than in any other age groups.

Younger children may be at less risk of

drowning because they are more closely supervised than are teenagers and

young adults. On the other hand, older adults may not engage in water sports

and recreation as often as teenagers and young adults. Drowning has also oc-curred in the bathtub in all age groups

of PWE. People with uncontrolled epi-lepsy should be particularly aware of this risk.

The following are potential factorsthat contribute to the risk of nonfataland fatal injuries due to seizures:

o Type of seizure

o Seizures that cause loss of consciousness or falls: generalizedconvulsive seizures (generalizedtonic-clonic seizures or ‘‘grand mal,’’

generalized tonic seizures),atonic seizures, and complex partial seizures

o Seizures that do not have aura

o High frequency of seizures

o Insufficient AED treatment,often because of failure to takemedications as prescribed

o Lack of supervision, especially for risk of drowning in children

o Side effects of medications

o Presence of physical or mental handicaps

The risk factors listed above werederived from several studies consistingmainly of patients with poorly controlledepilepsy. In our study of Rochester,Minnesota, residents with epilepsy, themost important risk factor for seizure-related injury is the degree of seizurecontrol.32

The adjustments that PWE have tomake to prevent injuries from seizures

depend on their degree of seizure con-trol and the type of seizure they have.Persons whose seizures are not con-trolled need to follow more precau-tions than persons with well-controlledepilepsy.

General Advice for All PersonsWith Epilepsy

o Practice general rules for safety when engaged in

99

A It is important to

find a balance

between seizure

precaution and

the freedom

to enjoy life.

Unnecessaryrestrictions of

activity can

adversely affect

quality of life,

often to a more

serious extent

than what seizure

attacks can do.

KEY POINTS

A Poor seizure

control appears to

be the major risk

factor foraccidental deaths,

whether or not

the deaths are

directly related to

seizure episodes.

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outdoor activities, such as wearing seat belts, life jackets,or helmets

o

Take medications regularly asprescribed by the doctor

o Report medication side effects tothe doctor

o Avoid situations that can enhanceseizure recurrence, such aslack of sleep, undue stressand fatigue, excessive alcoholconsumption, and use of recreational drugs

o Try to stay physically fit andconditioned

o Have appropriate companion or supervision for activities, such asswimming, that may pose highrisk of serious injuries if a seizureshould occur

Advice for Persons WithUncontrolled Seizures

o Follow doctors’ advice onrestriction of activities andprivileges such as driving andcertain recreational andoccupational activities

o Modify the home and workenvironment, such as paddingfloors and fixtures; minimizingbarriers, steps, obstacles, andunprotected heights; useshatterproof glass and mirrors

o Eliminate sources of extremeheat, such as open hearth, stove,heaters, and hot running water

(consider microwave cooking asan alternative)

o Install antiscalding plumbingdevice and reduce water heater settings

o Avoid baths and Jacuzzis;instead take showers in a sittingposition (consider supervision

of activity, or installation of water level–sensing device)

o Leave bathroom door unlocked for emergency access

o Minimize use of breakable dishesor utensils

o Use bed rails and chairs with arms

o

Stop smokingo Wear helmet when out of bed

or chair

o Strive for the best control of seizures, by considering alltreatment options, includingepilepsy surgery

School authorities and work person-nel should understand that the risk of injuries from seizures is very small inpersons whose epilepsy is well con-trolled. The overall risk for injuries in

persons with well-controlled epilepsy iscomparable to or lower than the risk inmany persons without epilepsy.

Suicide Risk

The overall lifetime prevalence rate of suicidal ideation in PWE is about 25%

with the rate of suicide as the cause of

mortality in patients with refractory epilepsy as high as 12%.17 Notably, therates reported in the individual studiesthat contribute to this estimate vary

widely. A study of PWE residing inRochester, Minnesota, shows that their risk for suicide is about the same asin the nonepilepsy population. Other studies, however, have shown that therisk for suicidal attempts in PWE is ashigh as 5 to 10 times that in the generalpopulation, with depression being amajor risk factor.16,33 These findings arecompatible with the fact that PWE have

approximately a 6-times greater risk for major depression than persons who donot have epilepsy.

The US Food and Drug Administra-tion has advised that AED use is asso-ciated with very slight risk of suicidalthoughts or attempts (less than 1%).This can also occur when the AED is

used to treat nonepilepsy conditionssuch as pain disorder. Therefore, peopledeveloping depressed mood, especially after starting AED treatment, should


100

KEY POINT

A People

developing

depressed mood,

especially afterstarting AED

treatment, should

promptly let

their family

and doctor

know about the

development.


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promptly let their family and doctor know about the development.

Sudden Unexplained Deathin Epilepsy

The diagnosis of SUDEP is made if thefollowing situations occur: (1) personhad epilepsy; (2) death occurred sud-denly; (3) death occurred unexpectedly

while the person was in a reasonablestate of health; (4) death occurred dur-ing normal activity, often while sleeping;(5) there was no determinable cause of death after autopsy; and (6) death was

not due to SE nor accidental injury, suchas falls or asphyxiation from aspiration.

The cause of SUDEP is still a mys-tery.34 SUDEP usually occurs unob-served. A case-control study shows thatSUDEP patients are more likely to havehad a seizure near the time of death,and death occurring while in bed ismore common with SUDEP than withnon-SUDEP deaths.35 Poor seizure con-trol is associated with high risk for SUDEP. Whereas the risk of SUDEP ingeneral is about one in 2800 person-

years, the risk is markedly higher at onein 150 person-years when the epilepsy ismedically intractable.36

Evidence thus far indicates that, of alltypes of seizures, uncontrolled general-ized convulsive seizures pose the high-est SUDEP risk. In contrast, the risk of SUDEP in patients with absence seizuresis nil. A case-control study showed thatthe risk for SUDEP is 14 times higher

when at least one generalized convul-sive seizure had occurred in the mostrecent 3 months than when no seizurehad occurred in the same period.37

Higher frequency of convulsive seizuresis also associated with greater SUDEPrisk. Independent of seizure frequency,the number of AEDs used has also been

associated with increased SUDEP risk.Poor compliance with medication

intake and low serum AED concentra-tions have long been suspected to in-

crease SUDEP risk. More recent studieshave not consistently shown these twofactors to increase SUDEP risk, but med-

ication compliance is difficult to verify on a retrospective basis after death, anddetermination of AED in postmortemblood sample is known to be poten-tially inaccurate. Nonetheless, noncom-pliance with AED intake should bestrongly discouraged because it often

worsens seizure frequency and intensity, which could increase morbidity andmortality, including SUDEP.

Very little is known about the termi-nal events that lead to SUDEP, even in

the few patients who had been ob-served to have a seizure immediately before death.38 Pulmonary edema, cen-tral apnea, and seizure-induced asystole(ictal asystole) have each been rarely observed during video-EEG monitoringto precede SUDEP or near-SUDEP. Cir-cumstantial evidence abounds for eachof these potential terminal mechanismsin SUDEP. Autopsy shows increasedlung weight or pulmonary congestionin some cases.39 These findings, howev-er, are usually not to a degree sufficientto cause sudden death. Also, congestivepulmonary failure would be expected toresult in observable respiratory distressprior to death, rather than suddenly precipitating death.

Circumstantial evidence for seizure-induced arrhythmia as a SUDEP etiol-ogy arises from the rare occurrence of seizure-induced bradycardia or asystole(ictal bradycardia/asystole).40 Ictal bra-

dycardia/asystole is uncommon, evenamong patients with intractable epilepsy.It is reported to occur in only 0.4% of patients undergoing video-EEG moni-toring. Moreover, most seizures in thesusceptible patient do not induce bra-dycardia or asystole. Outpatient record-ing with implantable loop recorders

over 2 years and 220,000 patient-hoursrevealed that 21% of the patients withintractable epilepsy studied had at leastone bradycardic seizure, but only 2% of

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the 377 recorded seizures were associ-ated with bradycardia.

Although the mechanism underlying

SUDEP is still unknown, current knowl-edge about SUDEP does allow us toadvise patients about practicable andreasonable measures to lower SUDEPrisk.41The measures given earlier forpre-

venting seizure-related injuries shouldalso contribute toward SUDEP risk re-

duction. Additionally, every effort shouldbe made to optimize seizure control aspromptly as possible and with the least

number of AEDs possible. Epilepsy sur-gery evaluation should be considered assoon as two AEDs have been ineffectiveand seizures are adversely impactingQOL. Generalized convulsive seizuresdeserve special attention as one strivesfor the best seizure control possible.

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KEY POINT

A Higher frequency

of convulsive

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associated withgreater SUDEP

risk. Independent

of seizure

frequency, the

number of AEDs

used has also

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with increased

SUDEP risk. Every

effort should be

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promptly as

possible and with

the least number

of AEDs possible.


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