Is Refractory Epilepsy Preventable?

$Page 1: Is Refractory Epilepsy Preventable?$
Is Refractory Epilepsy Preventable?

*Santiago Arroyo, †Martin J. Brodie, ‡Giuliano Avanzini, §Christoph Baumgartner,\¶Catherine Chiron, ¶Olivier Dulac, **Jacqueline A. French, and ††José M. Serratosa

*Epilepsy Unit, Hospital Clinic i Provincial, Barcelona, Spain; †Epilepsy Unit, University Department of Medicine andTherapeutics, Western Infirmary, Glasgow, Scotland; ‡Instituto Nazionale Neurologico C. Besta, Department of Experimental

Neurophysiology and Epileptology, Milano, Italy; §Klinische Abteilung fur Klinische Neurologie, Universitatsklinik furNeurologie, University of Vienna, Austria;\INSERM Unit 29, Marseille, France; ¶Neuropediatric Department, Hospital Saint

Vincent de Paul, Paris, France; **Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A; and††Epilepsy Unit, Neurology Service, Fundación Jiménez Díaz, Madrid, Spain

Summary: About a third of the patients diagnosed with epi-lepsy will not be fully controlled with antiepileptic drugs(AEDs), and many of them will have frequent and disablingseizures. These patients will undergo multiple drug trials, mostoften without complete seizure remission. Moreover, refractoryepilepsy is associated with increased morbidity (from seizuresand medications), social isolation, unemployment, and overallreduced quality of life. There is evidence that refractory epi-lepsy can be a progressive disorder, which, if controlled early,might never develop into a full syndrome with all of its asso-ciated sequelae. The difficulty lies in identifying at an earlystage patients who are likely to progress to intractability. No

currently known markers enable clinicians to make this iden-tification with confidence. Advances in pharmacogenomics andour understanding of pharmacologic responsiveness in epilepsymay change this situation. Even now, we are able to identifymany patients with a poor prognosis earlier than before, par-ticularly in the pediatric population, in which syndromic clas-sification may provide an approach to predict intractability. Theearly initiation of aggressive therapy may improve outcomeand overall quality of life.Key Words: Epileptogenesis—Seizures—Epilepsy surgery—Anticonvulsants—Refractoryepilepsy.

Approximately 5% of the general population will ex-perience at least one seizure during the course of theirlifetimes (excluding febrile seizures), and as many as20% of these will have recurrent seizures throughouttheir lives (1,2). In the majority (60–70%), seizures arecontrolled with a single antiepileptic drug (AED) whoseselection is dictated by the type of seizure disorder (1,3).The remainder of patients with frequent recurrent sei-zures are commonly referred to as having “refractoryepilepsy,” although there is some disagreement as to thebest way to define the term. Some identifying character-istics that have been suggested include failure of two tothree AEDs or lack of control within a defined timeperiod after diagnosis (e.g., 1–2 years). Of course, thesevariables may be misleading. For example, two drugs

may fail because of inappropriate drug selection as aresult of misclassification of seizure or epilepsy types, orbecause two drugs with similar mechanisms of actionwere tried. Every physician who treats epilepsy knows ofmany patients with “refractory” epilepsy, who do notrespond to a number of therapeutic trials but then remitwhen a new specific drug is tried. Perhaps it is moreappropriate to separate patients into “easily controlled”and “difficult to control.” Most patients with easily con-trolled epilepsy will respond to the first appropriate AED(4), whereas patients with difficult-to-control epilepsywill not (5,6). Thus a fundamental question lies at thecore of our understanding of refractory epilepsy and howbest to manage it: Is refractory epilepsy simply a failureto achieve “seizure control,” or is it a distinct conditionthat may be characterized by progressive neuronal, cog-nitive, and psychosocial deterioration (7)?

Some basic research favors the notion that refractoryepilepsy could be a distinct condition. In the kindlingmodel of epilepsy in rats, different responses to phenyt-oin (PHT) are observed (responders and nonresponders)despite the similarity in all other variables (seizures and

Revision accepted January 15, 2002.Address correspondence and reprint requests to Dr. S. Arroyo at

Froedtert Hospital, Medical College of Wisconsin, Dept. of Neurology,9200 West Wisconsin Avenue, Milwaukee, WI 53226.

This article is the result of a workshop on “Prevention of RefractoryEpilepsy” sponsored by European Concerted Action and Research inEpilepsy (EUCARE) and held October 2000 in Barcelona, Spain.

Epilepsia,43(4):437–444, 2002Blackwell Publishing, Inc.© International League Against Epilepsy

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testing conditions) (8,9). In this model, topiramate(TPM), gabapentin (GBP), or levetiracetam were moreeffective in responders than in nonresponders, indicatingthat there could be two different populations with diverseresponses to AEDs, and that response could be geneti-cally determined.

Identifying refractory epilepsy as early as possiblecould allow more aggressive therapy and the avoidanceof sequelae. A number of “markers” have been advancedas indicators of refractory epilepsy, including age at on-set (younger than 1 year) (10), type of epilepsy (e.g.,partial epilepsies or catastrophic epilepsies of childhood)(5,11,12), failure of the first AED (5,6), use of more thantwo drugs (5), and duration of treatment without achiev-ing control (11). The presence of certain brain lesionsalso is an important marker for refractory epilepsy(11,13). In a cohort of 2,200 adults with epilepsy, intrac-table seizures were much more frequent in patients withbrain abnormalities on magnetic resonance imaging(MRI) than in those without such findings (11). In par-ticular, hippocampal sclerosis and cortical dysgenesiswere important indicators of a poor prognosis, whereasseizures in patients who had strokes, vascular malforma-tions, or tumors were more likely to be controlled. How-ever, other studies have found a better outcome forpatients with medial temporal lobe epilepsy (MTLE),indicating an heterogeneous clinical presentation for pa-tients with MR-detected mesial temporal sclerosis(14,15). Thus none of these markers is especially sensi-tive or specific for refractory epilepsy. Consequently, theliterature is highly contradictory when it comes to iden-tifying the best indicators of refractory epilepsy. Severalrisk factors considered together may be more predictiveof a poorer prognosis on a case-by-case basis (12,16). Inchildren, syndromic classification provides a good ap-proach to delineate refractory epilepsy syndromes (17).

Disagreement in the literature may stem from the factthat there is no universally accepted definition of refrac-tory epilepsy. Published definitions vary depending onthe patient population, study objectives, and perspectiveof the investigators. For example, large epidemiologicstudies may simply categorize patients by etiologies (i.e.,mesial temporal sclerosis) that have a high probability ofmedical intractability, rather than quantify seizure activ-ity. Others may examine groups of patients according totreatment modalities associated with refractory epilepsy,such as multiple AEDs and early surgical intervention.Interventional studies may choose to focus on the sequel-ae of refractory epilepsy and define improvement bychanges in neuropsychological or neurodevelopmentalstate. We define refractory epilepsy as a condition inwhich at least two AEDs have failed to control seizures(because of lack of efficacy but not because of adverseevents) (5).

IS REFRACTORY EPILEPSY PROGRESSIVE?

One of the major unsettled questions is whether pa-tients are predetermined to become refractory at the timeof their first seizure, or whether they progress to a re-fractory state over time. The clinical implications areimportant; if refractoriness is not predetermined, it mightbe possible to intervene therapeutically at an early stageand prevent disease progression.

Certain “benign” epilepsies clearly do not progress toa medically refractory state. Idiopathic generalized epi-lepsies (infantile absence, juvenile myoclonic epilepsy)are usually easily controlled with AEDs (18). Similarly,certain focal epilepsies also are mostly benign and oftendo not need to be treated (i.e., benign rolandic epilepsy)(19,20).

There are, however, epileptic syndromes that do ap-pear to be progressive, and if allowed to progress, pose ahigh risk of becoming refractory. MTLE is perhaps themost frequent and more widely studied of these syn-dromes in adults. MTLE commonly starts during the firstdecade of life, when it is often amenable to control withAEDs. However, by adolescence or early adulthood, itfrequently becomes refractory (21,22). Most of the pa-tients with MTLE have histopathologic and MRI evi-dence of neuropathologic damage (23,24).

Basic researchAn important body of basic and human research sup-

ports the possible progression of hippocampal atrophyand dysfunction in MTLE. Histologically, the hippocam-pus of patients with MTLE shows neuronal cell loss inCA1 and CA4 somewhat selectively, with dense fibril-lary astrogliosis in all segments (23). Of interest is therecent observation that both bcl-2 and caspase familyproteins are elevated in brain tissue specimens from pa-tients undergoing surgery for intractable epilepsy (25).This suggests that seizure activity may induce both pro-and antiapoptotic activities within the temporal lobe andmight account for some of the selectivity in neuronal cellloss.

How do these changes contribute to the establishmentof refractory epilepsy? Numerous studies have demon-strated that the mossy fibers of the dentate granule cells,which normally project to hippocampal neurons in CA4and CA3, form aberrant synaptic connections within thedentate gyrus in patients with hippocampal sclerosis andrefractory epilepsy (25,26). This abnormal sprouting ap-pears to be the result of vacated connections secondary toneuronal loss in the affected regions. Similar changesassociated with neuronal loss have been observed in kin-dling models of epilepsy, where repeated low-intensityelectrical stimulation induces a permanent susceptibilityto seizures (27,28). Changes to neurotransmitter systemsalso have been reported to be associated with intractableseizures on a molecular and cellular level. For example,

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alterations in hippocampalg-aminobutyric acid (GABA)and glutamate transporter expression have been de-scribed in TLE patients (29). Other studies have demon-strated changes in GABA and glutamate receptor subunitcomposition (23). These findings suggest that develop-ment of abnormalities in the neurotransmitter systemsmay underlie changes in excitatory and inhibitory syn-aptic transmission, resulting in a lowered seizure thresh-old and facilitating the progression of the epileptogenicprocess (30).

Clinical dataClinical studies have also suggested that MTLE might

be progressive. In one study, patients with a unilateralseizure focus in the hippocampus and chronic drug-resistant seizures had significantly smaller hippocampalvolume on the side of the focus than did normal controlsor patients with newly diagnosed or well-controlled tem-poral lobe seizures (24). The greater the number of sei-zures reported, the greater the loss of volume in thehippocampus, suggesting that the loss might be inducedby seizure activity (24). MRI spectroscopy studies andother MRI-based measurements of hippocampal volumein patients with refractory TLE have shown that there isa negative correlation between ipsilateral and contralat-eral N-acetylaspartate to creatine values (indicative ofneuronal dysfunction) and the duration of epilepsy (31).Again, a negative correlation was seen between durationand ipsilateral hippocampal volume shrinkage but notcontralateral volume. Patients with frequent generalizedtonic–clonic seizures had smaller hippocampal volumesand lowerN-acetylaspartate-to-creatine values than didpatients with infrequent generalized seizures. Similarconclusions were drawn in two other studies of patientswith uncontrolled complex partial seizures, whichshowed that hippocampal volume shrinkage was associ-ated with both a history of complex or prolonged febrileseizures and epilepsy duration (32,33). These results sug-gest that the original hippocampal injury may be earlyand fixed, but that frequent seizures cause progressiveneuronal dysfunction or loss (31). Despite these data,progression in humans has not been confirmed by pro-spective longitudinal population studies, so the questionof progression remains unanswered. In any case, even ifseizures do not cause greater brain damage, functionaldisturbances affecting various locations far from the epi-leptogenic focus could occur (34). Such functional/structural damage could be responsible for theneuropsychological and psychiatric dysfunction that isfrequently observed in patients with refractory epilepsy(35).

The phenomenon of secondary epileptogenesis mayrepresent an example of progression of focal epilepsy,although it has been demonstrated convincingly only inanimal models. Secondary epileptogenesis involves the

establishment of a second epileptic focus on the contra-lateral side of the brain in a homotopic location withrespect to the primary focus (36,37). Secondary sitesbegin as epileptiform events that occur only in conjunc-tion with similar activity at the primary focus. Aftermany seizures, the secondary focus becomes indepen-dent as a source of seizure activity on a permanent basis(36,37). Secondary epileptic foci are more likely to begenerated if the primary focus is in an area with denseinterhemispheric connections, emphasizing the potentialimportance of excitatory synaptic connections for epilep-togenesis. In addition to decreasing seizure threshold,some have speculated that aberrant synaptic connectionsalso may contribute to the cognitive and psychologicalabnormalities associated with chronic epilepsy, espe-cially in the developing nervous system (38). However,secondary epileptogenesis has not been directly demon-strated in humans. Information on the mirror focuscomes from a retrospective assessment of patients, and itis possible that patients with mirror focus could havebilateral seizures from the outset. There is evidence thatthe outcome of surgery is similar regardless of durationof epilepsy or number of seizures, suggesting that sec-ondary epileptogenesis might not be relevant in humans(39).

Epidemiologic dataKnowledge of the natural progression of epilepsy

without treatment is limited, because most seizure disor-ders are treated aggressively with AEDs or surgery. Nev-ertheless, some studies have examined this issue. Britishinvestigators evaluated, retrospectively, 183 patientswith untreated epilepsy who were first seen after two tofive seizures. The majority experienced a progressivedecrease in the interval between seizures, suggesting pro-gression (40). This study looked only at generalized sei-zures, however, and excluded a large percentage ofpatients who could not remember the time intervals be-tween seizures. A more recent study examined the effectof one to 20 untreated seizures on the course of epilepsyin 479 children (41). Delaying treatment until a childexperienced#10 seizures appeared to have no adverseeffect on gaining seizure control or subsequent remis-sion, leading the authors to conclude that there may be noharm in delaying treatment. Again, the retrospective na-ture of this study and the inclusion of different types ofepilepsy syndromes make it difficult to draw firm con-clusions.

Progressive epilepsy in childrenHighly refractory epilepsies of childhood such as West

syndrome, severe myoclonic epilepsy in infancy, Len-nox–Gastaut syndrome, and Rasmussen encephalitis(often called “catastrophic epilepsies”) constitute a num-ber of progressive epilepsy syndromes (38). Landau–Kleffner syndrome and continuous spikes-and-waves

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during slow sleep (CSWS) syndrome are associated withsevere epileptic activity and age-dependent disturbancesof brain function (42). However, epileptic seizures ofthese two syndromes often resolve over time, leavingbehind cognitive deficits of varying severity. The newproposal for classifying epileptic seizures includes thenew concept of epileptic encephalopathy to describe syn-dromes in which the epileptiform activity is believed tocontribute to the progressive disturbance of brain func-tion (43).

Accumulating data from animal models of epilepsysuggest that early seizures can provoke structural andphysiologic changes in developing neural circuits thatresult in permanent alterations in the balance betweenneuronal excitation and inhibition, deficits in cognitivefunction, and increased susceptibility to further seizures(44). In kainate-induced seizures in rats, even a singleseizure early in life can make the brain more susceptibleto seizure-induced injury later in life (45). Seizure-related disruption of normal neuronal activity can affectmultiple developmental processes, resulting in long-lasting changes (46). For example, most children withWest syndrome will deteriorate during the first weeks ofspasms. However, a small subset (often with idiopathicWest syndrome) will respond to therapy, and spasms andhypsarrythmia will disappear and will not lead to devel-opmental and cognitive deterioration (47). Moreover,children with symptomatic or cryptogenic spasms whorespond to vigabatrin (VGB) or to surgery have a betterseizure and cognitive outcome (48–51). Reversibility ofthe epilepsy could account for the arrest of progression.Thus animal experimentation data and some evidence inchildren with highly refractory epilepsies suggest thatearly intervention may prevent some of these long-termneurologic deficits.

EARLY IDENTIFICATION OFREFRACTORY EPILEPSY

It is well known that more than half of the patientswith recent-onset epilepsy will enter terminal remission.However, it is not possible to identify with certaintythose patients who are likely to have multiple seizures orbecome refractory to medication at the outset, except inwell-defined epilepsy syndromes in children. Early iden-tification would ideally be performed before epilepsystarts (even before the first seizure), so that close follow-up and more “aggressive” or antiepileptogenic treatmentcould be provided.

Several ways of predicting refractory epilepsy earlymay be possible by using epidemiologic data, geneticanalysis, neuroimaging techniques, and syndromic clas-sification. A group of Dutch investigators monitored 466children for 2 years. Combining several variables (thenumber of seizures, seizure type, etiology, failure to at-

tain a 3-month remission during a 6-month period, andthe EEG at 6 months), they correctly predicted a pooroutcome in 66% of patients and a “not poor” outcomein 79% of patients (12). Similar variables have beenused by others seeking to identify risk factors for medi-cation resistance (52–55). Finally, using the syndromicclassification provides a better approach to predict in-tractability in childhood epilepsy, particularly in highlyrefractory epilepsies (see pediatric section, later). Unfor-tunately, this approach is not so useful in other partialepilepsies and in adults.

To improve this situation, investigators have begun toexamine the genetics associated with drug resistance. Itis now recognized that genetic variations in enzymesresponsible for drug metabolism and disposition, andsubtle differences in drug targets (cell receptors), mayhelp determine who becomes refractory (56). Ebert andLöscher (57) attempted to breed PHT responder and non-responder rats by selecting individuals who clearly werein one category or the other from a population ofamygdala-kindled Wistar rats. They found a small in-crease in the proportion of similarly responsive rats inthe next generation, but it was clear that the trait did notfollow simple mendelian inheritance, suggesting thatmultiple genes might be involved. In humans, a varietyof genes have been identified that influence responsive-ness to many agents. One of these, the multiple drugresistance gene (MDR1), encodes a glycoprotein that ex-ports planar hydrophobic molecules (including manyAEDs) from cells (58). In this way, the AED could beexported back through the endothelial cells to the vascu-lar space, reducing its concentration in the central ner-vous system (CNS). MDR1 is overexpressed >10-fold inthe capillary endothelium of brain tissue from many re-fractory epilepsy patients undergoing surgery (58). Thissuggests that these patients may be AED resistant be-cause they cannot concentrate the drug in brain paren-chyma despite “therapeutic” blood levels. Thus increasedexpression of multidrug resistant genes could contributein at least some cases to pharmacoresistant epilepsy.

With recent advances in defining the molecularmechanisms of drug metabolism and the pharmacologiceffects of AEDs, it may soon be possible to identifyprospectively individuals with a high probability of be-ing drug responders or nonresponders. Each of the genesinvolved in these processes exists, with minor variations(single nucleotide polymorphisms), in different individu-als. With the completion of the human genome project,and advances in functional genomic screening, it maysoon be possible to screen individuals for polymorphicallelic variants and to use that information to assess ac-curately their likely response (56,59).

Finally, advances in neuroimaging tools might in thenear future provide information about potential refracto-riness of patients with new-onset epilepsy. For example,

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changes inN-acetyl-aspartate/creatine quotient might bepresent in or around the epileptogenic region before thepatient is considered refractory, and could serve as amarker of refractoriness (33). Sensitivity of MRI spec-troscopy could be increased with novel techniques suchas chemical shift spectroscopy, which allows a largerneurochemical sampling of the brain (60).

CAN “PROGRESSIVE EPILEPSY” BE HALTED?

There is ample experimental evidence that someAEDs have antiepileptogenic properties, in addition tothe mere suppression of seizures. In one study of the ratkindling model of epilepsy, sodium valproate (VPA) andphenobarbital (PB) were shown to have antiepilepto-genic activity, although this was more pronounced withVPA (61). No antiepileptogenic effects were detectedwith carbamazepine (CBZ). In a similar study, in whichseizure severity and duration were induced by repeatedamygdala stimulation, levetiracetam suppressed the in-crease, and the effect persisted after the drug was dis-continued, even though amygdala stimulations werecontinued (62). Similar findings in antiepileptogenicproperties have been observed with lamotrigine (LTG) orTPM (63,64).

Unfortunately, there is no good evidence that currentAEDs are antiepileptogenic in humans. For example, inlarge trials of prophylactic therapy for posttraumatic sei-zures, there has been no indication that AEDs could re-duce the risk of epilepsy (65–67). Moreover, prompttreatment (after the first seizure) with current AEDs doesnot appear to improve the overall outcome of the epi-lepsy (68). Thus therapeutic strategies should focus onmodifying the underlying epileptogenic neuronal dys-function giving rise to seizures rather than on merelysuppressing seizures. In this way, antiepileptogenicagents could modify the natural history of refractory epi-lepsy. However, demonstrating an antiepileptogenic ef-fect in humans will require well-designed clinical trials.

Although there is little clinical evidence that medicaltherapy today can halt the epileptogenic process, there isgreater evidence that surgery can do so (69). Remissionrates vary considerably from study to study, but manypatients with medication-refractory partial epilepsy whoundergo surgery become seizure free or experience asignificant reduction in seizure frequency (22,69–72).Moreover, pediatric patients may have a more normalneurologic development, whereas adolescents and adultsmay have improved psychosocial outcomes (71,73). In arecent long-term study of temporal lobectomy (meanfollow-up, 14 years), patients who were seizure free for2 years after surgery were unlikely to become refractory,and none of the patients who had seizures recurring morethan 1 year after surgery became refractory, suggestingthat the underlying disease process was arrested (74). A

direct measure of the improvement seen with surgerywas demonstrated in a study in which MR spectroscopicimaging of the ipsilateral temporal lobe normalized post-operatively in patients with TLE (75). It should be noted,however, that the best surgical outcome is in patientswith specific, surgically amenable conditions. Patientswithout surgically remedial lesions, for example, cryp-togenic partial epilepsy with negative imaging studies,have a <50% chance of becoming seizure free postop-eratively (22).

An additional benefit from surgery rests in reducingthe mortality associated with uncontrolled partial epi-lepsy (76). However, it is less clear that surgery couldimprove the neuropsychological or psychiatric morbidityassociated with refractory epilepsy (77,78). For example,adults are at risk of verbal memory impairment afterremoval of the dominant temporal lobe (78,79). Never-theless, general cognitive abilities and material-specificmemory function of the temporal lobe contralateral to ananterior temporal lobectomy improve after surgery (80).Surgery performed during childhood could potentiallyreduce the risk for postsurgical cognitive morbidity: asuperior cognitive outcome was found in school-agechildren with TLE, probably because of differences inplasticity and ongoing maturation (73).

Given the fact that many patients with medically in-tractable partial epilepsy improve with surgery, and thatmany of the developmental, psychological, and socio-economic consequences of intractable epilepsy can beavoided if surgery is performed early, it would seem thatsurgery should be performed as soon as possible. Advo-cates for very early surgery point out that there is rela-tively low surgical morbidity, that outcome is betterwhen the surgery is done as early as possible, and thatdevastating consequences of some refractory epilepsysyndromes in children may be avoided with early surgery(21,22,73,81–83). However, the inherent risks associatedwith surgery mandate that medical therapy be tried firstfor a period of time. The difficulty is of course in iden-tifying appropriate patients at a very early time point. Asreviewed earlier, many factors may be associated with ahigh risk for refractory epilepsy. Much clearly dependson establishing a precise diagnosis, characterizing theunderlying syndrome, and determining whether it fits theprofile (based on its likely clinical course and imagingcharacteristics) of a seizure disorder that is likely to re-spond to surgery.

Assuming all this supports a decision to proceed withsurgery, the next question is: how soon do you give up onmedical therapy? Most of the published data suggest thattrying more than two rationally chosen AEDs might becounterproductive. In a study of 470 adults with idio-pathic, symptomatic, or cryptogenic epilepsy who hadnever been treated with an AED, 47% were controlledwith the first drug tried (5). Although 13% became sei-



zure free with a second drug, only 1% responded to thethird monotherapy choice. Three percent became seizurefree with duotherapy. In this study, there were no differ-ences in seizure control between established AEDs andthe new generation of drugs. These findings suggest it isreasonable to try two rationally chosen AEDs in adultsbefore proceeding with surgery, because a sizable per-centage of patients might respond to the second drug. Tocontinue trying additional AEDs in a patient who is oth-erwise eligible for high-success surgery (for example,surgery of MTLE or lesional temporal lobe seizures)may be harmful to that patient’s long-term outcome.However, it is reasonable to continue to explore phar-macologic options longer if the success of surgery is notpredictably high or there are higher risks involved (forexample, nonlesional frontal lobe seizures).

PEDIATRIC ISSUES

Intractability is more difficult to define in childrenthan in adults. In one population-based study of 417 chil-dren with newly diagnosed epilepsy, in only 4% of pa-tients who had a promising response with the first AEDdid refractory epilepsy develop, compared with 29% whofailed to respond to the first AED (84). In another study,613 children with newly diagnosed epilepsy were pro-spectively assessed (85). Ten percent of the childrenwere considered intractable within the first 2 years ofdiagnosis (failure of two or more drugs and one or moreseizure per month over 18 months). Nonidiopathic gen-eralized epilepsy, high initial seizure frequency, and fo-cal slowing on EEG were the best predictors ofintractability. However, 14% of the children with intrac-table epilepsy went into remission during follow-up,whereas other children who were easily controlled be-came refractory during adolescence or adulthood (i.e.,mesial temporal sclerosis patients). A recently publishedretrospective cohort study, of 120 children aged 1–18years with temporal lobe seizures who were assessed ina tertiary care facility, showed that failure of the firstAED accurately predicts refractoriness 2 years after theonset of epilepsy (6). Refractoriness was defined as sei-zures with impaired consciousness between 18 and 24months of the onset of epilepsy and despite at least twomaximally tolerated AED trials. In this study, after thefirst AED failed, additional AEDs resulted in completeseizure control in only 11% of the children, similar to theresults observed in adult populations (5). Despite itsmethodologic shortcomings, this study indicates that inwell-defined pediatric subpopulations (e.g., TLE), amore distinct outcome can be predicted.

Although these studies do not provide enough infor-mation to indicate early “aggressive” treatments in chil-dren, they at least offer useful indications of whichchildren are at risk and should be closely followed. Thus

the definition of intractability proposed for adults (theabsence of a satisfactory response to the second AED) isnot so pertinent for childhood epilepsy.

On the other hand, intractability is highly predictablein some well-defined epilepsy syndromes. Early predic-tors of intractability identified on case–controlled studiesin childhood epilepsy include onset at younger than 1year and symptomatic etiology, infantile spasms, highseizure frequency, history of status epilepticus, and dif-fuse slowing and focal spike-and-wave activity on EEG(10,53). However, rather than using a model based onthese variables, syndromic classification is an accurateway to predict intractability by identifying early the vari-ous severe epilepsy syndromes. Accurate classificationof children with newly diagnosed epilepsy into epilepsysyndromes has repeatedly proved to be feasible in >90%of cases (18,86–88). Syndromes that carry the highestrisk of refractoriness and are recognizable early includeOhtahara syndrome in neonates (89), West syndromeand severe myoclonic epilepsy in infants (90,91), myo-clonic–astatic epilepsy (92), Lennox–Gastaut syndrome(93), Rasmussen encephalitis (94), and partial epilepsiesdue to malformations of cortical development whateverthe age (95).

Predicting intractability as soon as the first seizuresappear is extremely important in children, because earlycontrol is likely to improve cognitive outcome (49).Some of the newer drugs can be used as first-line treat-ment in specific syndromes [e.g., VGB for infantilespasms (48,51) or LTG and TPM for Lennox–Gastautsyndrome (96,97)]. Epilepsy surgery may be offered atprogressively younger ages, permitting the control ofsome epilepsies previously considered to be highly re-fractory (48,70).

CONCLUSIONS

There is evidence to suggest that in some cases, epi-lepsy is refractory from the outset, even if it appearsinitially to be benign. Unfortunately, there is as yet nosingle factor that enables us to predict confidently wheth-er a newly diagnosed patient will become refractory. Thehope for the future is that improved understanding of themechanisms underlying refractoriness, and advancedtechnology in identifying individual genetic variations,might improve our ability to identify patients at risk. Atthis time, early identification and prompt (and adequate)therapeutic intervention might improve the overall out-come of the disease and maximize quality of life. How-ever, with the current AEDs, we are far from being ableto prevent refractoriness. We hope that new classes ofAEDs with antiepileptogenic properties will change thisprospect.

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REFERENCES

1. Brodie MJ, Dichter MA. Antiepileptic drugs.N Engl J Med1996;334:168–75.

2. Brodie MJ, Shorvon SD, Canger R, et al. Commission on EuropeanAffairs: appropriate standards of epilepsy care across Europe:ILEA. Epilepsia1997;38:1245–50.

3. Brodie MJ, French JA. Management of epilepsy in adolescents andadults.Lancet2000;356:323–9.

4. Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug.Epi-lepsia2001;42:1255–60.

5. Kwan P, Brodie MJ. Early identification of refractory epilepsy.NEngl J Med2000;342:314–9.

6. Douglos DJ, Sammel MD, Strom BL, et al. Response to first drugtrial predicts outcome in childhood temporal lobe epilepsy.Neu-rology 2002;57:2259–64.

7. Kwan P, Brodie MJ. Refractory epilepsy: a progressive, intractablebut preventable condition?Seizure(in press).

8. Reissmuller E, Ebert U, Loscher W. Anticonvulsant efficacy oftopiramate in phenytoin-resistant kindled rats.Epilepsia2000;41:372–9.

9. Loscher W, Reissmuller E, Ebert U. Anticonvulsant efficacy ofgabapentin and levetiracetam in phenytoin-resistant kindled rats.Epilepsy Res2000;40:63–77.

10. Casetta I, Granieri E, Monetti VC, et al. Early predictors of in-tractability in childhood epilepsy: a community-based case-controlstudy in Copparo, Italy.Acta Neurol Scand1999;99:329–33.

11. Semah F, Picot MC, Adam C, et al. Is the underlying cause ofepilepsy a major prognostic factor for recurrence?Neurology1998;51:1256–62.

12. Arts WF, Geerts AT, Brouwer OF, et al. The early prognosis ofepilepsy in childhood: the prediction of a poor outcome: the Dutchstudy of epilepsy in childhood.Epilepsia1999;40:726–34.

13. Stephen LJ, Kwan P, Brodie MJ. Does the cause of localisation-related epilepsy influence the response to antiepileptic drug treat-ment?Epilepsia2001;42:357–62.

14. Kobayashi E, Lopes-Cendes I, Guerreiro CA, et al. Seizure out-come and hippocampal atrophy in familial mesial temporal lobeepilepsy.Neurology2001;56:166–72.

15. Kim WJ, Park SC, Lee SJ, et al. The prognosis for control ofseizures with medications in patients with MRI evidence for mesialtemporal sclerosis.Epilepsia1999;40:290–3.

16. Regesta G, Tanganelli P. Clinical aspects and biological bases ofdrug-resistant epilepsies.Epilepsy Res1999;34:109–22.

17. Commission on Classification and Terminology of the Interna-tional League Against Epilepsy. Proposal for revised classificationof epilepsies and epileptic syndromes.Epilepsia1989;30:389–99.

18. Eriksson KJ, Koivikko MJ. Prevalence, classification, and severityof epilepsy and epileptic syndromes in children.Epilepsia1997;38:1275–82.

19. Berg AT, Shinnar S. Do seizures beget seizures? An assessment ofthe clinical evidence in humans.J Clin Neurophysiol1997;14:102–10.

20. Bouma PAD, Bovenkerk AC, Westendorp RGJ, et al. The courseof benign partial epilepsy of childhood with centrotemporal spikes:a meta-analysis.Neurology1997;48:430–7.

21. Engel J Jr. The timing of surgical intervention for mesial temporallobe epilepsy: a plan for a randomized clinical trial.Arch Neurol1999;56:1338–41.

22. Engel J Jr. Surgery for seizures.N Engl J Med1996;334:647–52.23. Blumcke I, Beck H, Lie AA, et al. Molecular neuropathology of

human mesial temporal lobe epilepsy.Epilepsy Res1999;36:205–23.

24. Kalviainen R, Salmenpera T, Partanen K, et al. Recurrent seizuresmay cause hippocampal damage in temporal lobe epilepsy.Neu-rology 1998;50:1377–82.

25. Henshall DC, Clark RS, Adelson PD, et al. Alterations in bcl-2 andcaspase gene family protein expression in human temporal lobeepilepsy.Neurology2000;55:250–7.

26. Sutula T, Cascino G, Cavazos J, et al. Mossy fiber synaptic reor-ganization in the epileptic human temporal lobe.Ann Neurol1989;26:321–30.

27. Cavazos JE, Das I, Sutula TP. Neuronal loss induced in limbic

pathways by kindling: evidence for induction of hippocampal scle-rosis by repeated brief seizures.J Neurosci1994;14:3106–21.

28. Cavazos JE, Sutula TP. Progressive neuronal loss induced by kin-dling: a possible mechanism for mossy fiber synaptic reorganiza-tion and hippocampal sclerosis.Brain Res1990;527:1–6.

29. Mathern GW, Mendoza D, Lozada A, et al. Hippocampal GABAand glutamate transporter immunoreactivity in patients with tem-poral lobe epilepsy.Neurology1999;52:453–72.

30. Sutula TP, Hermann B. Progression in mesial temporal lobe epi-lepsy.Ann Neurol1999;45:553–6.

31. Tasch E, Cendes F, Li LM, et al. Neuroimaging evidence of pro-gressive neuronal loss and dysfunction in temporal lobe epilepsy.Ann Neurol1999;45:568–76.

32. Fuerst D, Shah J, Kupsky WJ, et al. Volumetric MRI, pathological,and neuropsychological progression in hippocampal sclerosis.Neurology2001;57:184–8.

33. Theodore WH, Bhatia S, Hatta J, et al. Hippocampal atrophy,epilepsy duration, and febrile seizures in patients with partial sei-zures.Neurology1999;52:132–6.

34. Miller SP, Li LM, Cendes F, et al. Medial temporal lobe neuronaldamage in temporal and extratemporal lesional epilepsy.Neurol-ogy 2000;54:1465–70.

35. Aldenkamp AP, Overweg-Plandsoen WC, Arends J. An open, non-randomized clinical comparative study evaluating the effect ofepilepsy on learning.J Child Neurol1999;14:795–800.

36. Morrell F. The role of secondary epileptogenesis in human epi-lepsy.Arch Neurol1991;48:1221–4.

37. Morrell F. Varieties of human secondary epileptogenesis.J ClinNeurophysiol1989;6:227–75.

38. Shields WD. Catastrophic epilepsy in childhood.Epilepsia2000;41(suppl 2):S2–6.

39. Kilpatrick C, Cook M, Matkovic Z, et al. Seizure frequency andduration of epilepsy are not risk factors for postoperative seizureoutcome in patients with hippocampal sclerosis.Epilepsia1999;40:899–903.

40. Elwes RD, Johnson AL, Reynolds EH. The course of untreatedepilepsy.BMJ 1988;297:948–50.

41. Camfield C, Camfield P, Gordon K, et al. Does the number ofseizures before treatment influence ease of control or remission ofchildhood epilepsy? Not if the number is 10 or less.Neurology1996;46:41–4.

42. Beaumanoir A. The Landau-Kleffner syndrome. In: Roger J, Bu-reau M, Dreifuss FE, et al., eds.Epileptic syndromes in infancy,childhood and adolescence.London: John Libbey, 1992:231–43.

43. Engel J. A proposed diagnostic scheme for people with epilepticseizures and with epilepsy: report of the ILAE task force on clas-sification and terminology.Epilepsia2001;42:796–803.

44. Koh S, Storey TW, Santos TC, et al. Early-life seizures in ratsincrease susceptibility to seizure-induced brain injury in adulthood.Neurology1999;53:915–21.

45. Hu RQ, Koh S, Torgerson T, et al. Neuronal stress and injury inC57/BL mice after systemic kainic acid administration.Brain Res1998;810:229–40.

46. Holmes GL. Epilepsy in the developing brain: lessons from thelaboratory and clinic.Epilepsia1997;38:12–30.

47. Wyllie E. Surgery for catastrophic localization-related epilepsy ininfants.Epilepsia1996;37(suppl 1):S22–5.

48. Chiron C, Dumas C, Jambaque I, et al. Randomized trial compar-ing vigabatrin and hydrocortisone in infantile spasms due to tuber-ous sclerosis.Epilepsy Res1997;26:389–95.

49. Jambaque I, Chiron C, Dumas C, et al. Mental and behaviouraloutcome of infantile epilepsy treated by vigabatrin in tuberoussclerosis patients.Epilepsy Res2000;38:151–60.

50. Caplan R, Guthrie D, Komo S, et al. Infantile spasms: the devel-opment of nonverbal communication after epilepsy surgery.DevNeurosci1999;21:165–73.

51. Fejerman N, Cersosimo R, Caraballo R, et al. Vigabatrin as afirst-choice drug in the treatment of West syndrome.J Child Neu-rol 2000;15:161–5.

52. Shinnar S, Berg AT, O’Dell C, et al. Predictors of multiple seizuresin a cohort of children prospectively followed from the time oftheir first unprovoked seizure.Ann Neurol2000;48:140–7.



53. Ko TS, Holmes GL. EEG and clinical predictors of medicallyintractable childhood epilepsy.Clin Neurophysiol1999;110:1245–51.

54. Guldvog B, Loyning Y, Hauglie-Hanssen E, et al. Predictive fac-tors for success in surgical treatment for partial epilepsy: a multi-variate analysis.Epilepsia1994;35:566–78.

55. MacDonald BK, Johnson AL, Goodridge DM, et al. Factors pre-dicting prognosis of epilepsy after presentation with seizures.AnnNeurol 2000;48:833–41.

56. Evans WE, Relling MV. Pharmacogenomics: translating func-tional genomics into rational therapeutics.Science1999;286:487–91.

57. Ebert U, Loscher W. Characterization of phenytoin-resistantkindled rats, a new model of drug-resistant partial epilepsy: influ-ence of genetic factors.Epilepsy Res1999;33:217–26.

58. Tishler DM, Weinberg KI, Hinton DR, et al. MDR1 gene expres-sion in brain of patients with medically intractable epilepsy.Epi-lepsia1995;36:1–6.

59. Patsalos PN. Antiepileptic drug pharmacogenetics.Ther DrugMonit 2000;22:127–30.

60. Pauli E, Eberhardt KW, Schafer I, et al. Chemical shift imagingspectroscopy and memory function in temporal lobe epilepsy.Epi-lepsia2000;41:282–9.

61. Silver JM, Shin C, McNamara JO. Antiepileptogenic effects ofconventional anticonvulsants in the kindling model of epilepsy.Ann Neurol1991;29:356–63.

62. Loscher W, Honack D, Rundfeldt C. Antiepileptogenic effects ofthe novel anticonvulsant levetiracetam (UCB L059) in the kindlingmodel of temporal lobe epilepsy.J Pharmacol Exp Ther1998;284:474–9.

63. Wiard RP, Dickerson MC, Beek O, et al. Neuroprotective proper-ties of the novel antiepileptic lamotrigine in a gerbil model ofglobal cerebral ischemia.Stroke1995;26:466–72.

64. Yang Y, Shuaib A, Li Q, et al. Neuroprotection by delayed ad-ministration of topiramate in a rat model of middle cerebral arteryembolization.Brain Res1998;804:169–76.

65. Temkin NR. Antiepileptogenesis and seizure prevention trials withantiepileptic drugs: meta-analysis of controlled trials.Epilepsia2001;42:515–24.

66. Temkin NR, Dikmen SS, Anderson GD, et al. Valproate therapyfor prevention of posttraumatic seizures: a randomized trial.J Neu-rosurg 1999;91:593–600.

67. Temkin NR, Dikmen SS, Wilensky AJ, et al. A randomized,double-blind study of phenytoin for the prevention of post-traumatic seizures.N Engl J Med1990;323:497–502.

68. Musicco M, Beghi E, Solari A, et al. Treatment of first tonic-clonicseizure does not improve the prognosis of epilepsy: First SeizureTrial Group (FIRST Group).Neurology1997;49:991–8.

69. Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlledtrial of surgery for temporal-lobe epilepsy.N Engl J Med2001;345:311–8.

70. Duchowny M, Jayakar P, Resnick T, et al. Epilepsy surgery in thefirst three years of life.Epilepsia1998;39:737–43.

71. Holmes GL. Intractable epilepsy in children.Epilepsia 1996;37(suppl 3):14–27.

72. Zentner J, Hufnagel A, Wolf HK, et al. Surgical treatment oftemporal lobe epilepsy: clinical, radiological, and histopathologi-cal findings in 178 patients.J Neurol Neurosurg Psychiatry1995;58:666–73.

73. Lendt M, Helmstaedter C, Elger CE. Pre- and postoperative neuro-psychological profiles in children and adolescents with temporallobe epilepsy.Epilepsia1999;40:1543–50.

74. Foldvary N, Nashold B, Mascha E, et al. Seizure outcome aftertemporal lobectomy for temporal lobe epilepsy: a Kaplan-Meiersurvival analysis.Neurology2000;54:630–4.

75. Cendes F, Andermann F, Dubeau F, et al. Normalization of neu-ronal metabolic dysfunction after surgery for temporal lobe epi-lepsy: evidence from proton MR spectroscopic imaging.Neurology1997;49:1525–33.

76. Sperling MR, Feldman H, Kinman J, et al. Seizure control andmortality in epilepsy.Ann Neurol1999;46:45–50.

77. Jokeit H, Ebner A. Long-term effects of refractory temporal lobeepilepsy on cognitive abilities: a cross sectional study.J NeurolNeurosurg Psychiatry1999;67:44–50.

78. Dodrill CB. Epilepsy surgery: non-invasive versus invasive focuslocalization: what is needed from a neuropsychological point ofview. Acta Neurol Scand Suppl1994;152:198–203.

79. Helmstaedter C, Elger CE. Cognitive consequences of two-thirdsanterior temporal lobectomy on verbal memory in 144 patients: athree-month follow-up study.Epilepsia1996;37:171–80.

80. Hermann BP, Wyler AR, Bush AJ, et al. Differential effects of leftand right anterior temporal lobectomy on verbal learning andmemory performance.Epilepsia1992;33:289–97.

81. Lendt M, Helmstaedter C, Elger CE. Pre- and postoperative so-cioeconomic development of 151 patients with focal epilepsies.Epilepsia1997;38:1330–7.

82. Behrens E, Schramm J, Zentner J, et al. Surgical and neurologicalcomplications in a series of 708 epilepsy surgery procedures.Neu-rosurgery1997;41:1–9.

83. Mathern GW, Giza CC, Yudovin S, et al. Postoperative seizurecontrol and antiepileptic drug use in pediatric epilepsy surgerypatients: the UCLA experience, 1986-1997.Epilepsia 1999;40:1740–9.

84. Camfield PR, Camfield CS, Gordon K, et al. If a first antiepilepticdrug fails to control a child’s epilepsy, what are the chances ofsuccess with the next drug?J Pediatr1997;131:821–4.

85. Berg AT, Shinnar S, Levy SR, et al. Early development of intrac-table epilepsy in children: a prospective study.Neurology2001;56:1445–52.

86. Berg AT, Levy SR, Testa FM, et al. Classification of childhoodepilepsy syndromes in newly diagnosed epilepsy: interrater agree-ment and reasons for disagreement.Epilepsia1999;40:439–44.

87. Berg AT, Shinnar S, Levy SR, et al. Newly diagnosed epilepsy inchildren: presentation at diagnosis.Epilepsia1999;40:445–52.

88. Sillanpaa M, Jalava M, Shinnar S. Epilepsy syndromes in patientswith childhood-onset seizures in Finland.Pediatr Neurol1999;21:533–7.

89. Ohtahara S, Ohtsuka Y, Yamatogi Y, et al. Early infantile epilepticencephalopathy with suppression-bursts. In: Roger J, Bureau M,Dreifuss FE, et al., eds.Epileptic syndromes in infancy, childhoodand adolescence.London: John Libbey, 1992:25–34.

90. Dravet C, Bureau M, Guerrini R, et al. Severe myoclonic epilepsyin infants. In: Roger J, Bureau M, Dreifuss FE, et al., eds.Epilepticsyndromes in infancy, childhood and adolescence.London: JohnLibbey, 1992:75–88.

91. Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myo-clonic epilepsy in infancy: a randomised placebo-controlledsyndrome-dedicated trial: STICLO study group.Lancet2000;356:1638–42.

92. Kaminska A, Ickowicz A, Plouin P, et al. Delineation of crypto-genic Lennox-Gastaut syndrome and myoclonic astatic epilepsyusing multiple correspondence analysis.Epilepsy Res1999;36:15–29.

93. Schmidt D, Bourgeois B. A risk-benefit assessment of therapies forLennox-Gastaut syndrome.Drug Saf2000;22:467–77.

94. Dulac O. Rasmussen’s syndrome.Curr Opin Neurol1996;9:75–7.95. Lequin MH, Barkovich AJ. Current concepts of cerebral malfor-

mation syndromes.Curr Opin Pediatr1999;11:492–6.96. Motte J, Trevathan E, Arvidsson JF, et al. Lamotrigine for gener-

alized seizures associated with the Lennox-Gastaut syndrome:Lamictal Lennox-Gastaut Study Group [published erratum appearsin N Engl J Med 1998;339:851–2].N Engl J Med1997;337:1807–12.

97. Sachdeo RC, Glauser TA, Ritter F, et al. A double-blind, random-ized trial of topiramate in Lennox-Gastaut syndrome: TopiramateYL Study Group.Neurology1999;52:1882–7.

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