Seizure 22 (2013) 333344

Contents lists available at SciVerse ScienceDirect

Seizure
journal homepage: www.elsevier.com/locate/yseiz

Review

Early predictors of outcome in newly diagnosed epilepsy

Rajiv Mohanraj a, Martin J. Brodie b,*
a b

Salford Royal Hospital, England, UK Epilepsy Unit, Western Inrmary, Glasgow, Scotland, UK

A R T I C L E I N F O

A B S T R A C T

Article history: Received 27 November 2012 Received in revised form 5 February 2013 Accepted 5 February 2013 Keywords: Epilepsy Prognosis Drug response Outcomes Risk factors

Longitudinal studies of newly diagnosed epilepsy in children and adults have identied prognostic factors that allow early identication of patients whose seizures are likely to remain uncontrolled with antiepileptic medication. Results from outcome studies may be subject to bias, depending on the setting (community versus clinic), design (retrospective versus prospective) and characteristics of the patient cohort studied (age, types of epilepsy, specic comorbidities). Nevertheless, factors such as early response to medication, underlying aetiology, and number of seizures prior to initiation of treatment have consistently been found to be predictive of seizure outcomes. Other variables such as age, electroencephalographic ndings and the presence or absence of psychiatric co-morbidities have been correlated with outcomes in some analyses. This review has examined studies of seizure outcomes in adults and children with newly diagnosed epilepsy identifying the risk factors that are associated with subsequent refractory epilepsy. 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction Epilepsy, the tendency to have recurrent unprovoked seizures, is the most common serious neurological disorder. Its prevalence ranges from 0.5 to 1% of the population in developed countries, and is probably higher in developing countries.1 This condition is, however, merely a symptom of a wide variety of neurological disorders, ranging from self-limiting and benign to devastating and fatal. Regardless of the aetiology, the tendency to suffer recurrent seizures exposes persons with epilepsy to a variety of physical, psychological and social morbidities.2 Complete control of seizures can negate these consequences to a large extent.3 The majority of patients diagnosed with epilepsy can expect to achieve good control of seizures with antiepileptic drug (AED) therapy,4,5 but a substantial minority will continue to experience seizures in spite of a range of AEDs used in adequate doses either singly or in combination.6 Some patients whose seizures prove difcult to treat could benet from non-pharmacological strategies, especially epilepsy surgery, which still remains one of the most underutilised effective treatment modalities worldwide.7,8 Early identication of patients whose seizures are likely to be pharmacoresistant would permit them to be offered referral for epilepsy surgery at the most appropriate juncture.9

2. Methodology This short review will attempt to summarise data from relevant studies of outcomes in newly diagnosed epilepsy in paediatric and adult populations. These were identied from Pubmed using the search terms newly diagnosed epilepsy and outcomes and newly diagnosed epilepsy and prognosis. Search results were reviewed manually to identify relevant publications. All studies with a minimum of 100 patients, who were followed up for at least 2 years, were included in this review (see Tables 1 and 2). Results from studies of prognosis of epilepsy are often conicting. Some of the variability can be explained on the basis of differences in populations and methodologies. As the underlying cause of epilepsy can be widely varied, data from studies that lump together all epilepsy types will be skewed in favour of those most frequent in the population. Studying well-dened epilepsy (electroclinical) syndromes separately can provide better prognostic information, but accurate classication is not always achievable even in patients attending specialist services. Studies based in specialist clinics can be expected to have better characterised patient groups, but may be biased towards the more severe epilepsies. Retrospective studies, especially those from specialist clinics, may not include patients with milder forms of epilepsy. Studies that identify all persons with new onset epilepsy in a dened population over a xed period of time and follow them up prospectively will have the least recruitment bias. However, identifying all cases can be challenging and the diagnosis may be

* Corresponding author at: Epilepsy Unit, Western Inrmary, Glasgow G11 6NT, Scotland, UK. Tel.: +44 141 211 2534; fax: +44 141 211 2072. E-mail address: mjb2k@clinmed.gla.ac.uk (M.J. Brodie).

1059-1311/$ see front matter 2013 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.seizure.2013.02.002

334

Table 1 List of studies of outcomes in adult epilepsy. Studies from the same population have been grouped together. Studies marked with * (asterix) also inlcuded children. Study Annegers et al.13 Recruitment Inclusion period criteria 193574 Exclusion criteria Type of study Retrospective Setting n Epilepsy type Mixed Follow up 520 years Method of follow-up Chart review n with outcome 457 Outcomes 5 year remission Prognostic factors identied Perinatal insult causing physical and intellectual handicap worst outcomes (46% remission) Post natal acquired epilepsy and idiopathi epilepsy 74% remission

> 2 seizures not Febrile and provoked by an other provoked seizures acute cause followed for minimum of 5 years Single seizures

Community 618

65% by 10 years

76% by 20 years Elwes et al.15 Not stated Previously untreated epilepsy None stated Prospective Clinic 106 Mixed 6106 month Clinical review 106 82% 2 year sf periods by 8 years of fu 35% immediate responders 28% SF throughout Poor prognosis associated with Partial seizures R. Mohanraj, M.J. Brodie / Seizure 22 (2013) 333344 High frequency of tonic-clonic seizures before treatment A neurologic, social, or psychiatric handicap A family history of epilepsy

Collaborative group18

1982

Previously untreated afebrile seizures

AEDs started >3 Prospective months before enrolment Polytherapy as initial treatment

Clinic

280

Mixed

48 (median)

6 monthly review

228

Prophylactic use of AEDs Provoked seizures Cockerell et al.*23 198487 Denite epilepsy as judged by panel Expert panel disagree with diagnosis of epilepsy Prospective Community 1091 Mixed 6 years Contact primary care physician

1year remission Remission less likely 62% at 1 year, 81% with multiple seizure types, higher number by 2 of seizures before treatment Number of seizures in Years, 92% by 3 years, and 98% by the rst year of AED treatment correlated 5 years with risk of refractory epilepsy 3year remission 92% 5 year remission 78% 22.1% not SF on monotherapy 5 year remission Age and seizure type no effect on outcomes

Cockerell et al.*24

564 denite epilepsy 228 - probable epilepsy

9 years

Idiopathic seizures 69% Remote symptomatic epilepsy 61% Chart review 550

MacDonald*25

12 years

Children lower remission rates than adults Partial seizures worse than generalised ones

Stephen et al.33

198497

None stated Newly diagnosed localisation related peilepsy

Retrospective

Clinic

550

Localisation reltated epilepsy

Median 5 (215)

MTS worse than other No difference causes of LRE between cryptogenic and symptomatic LRE

But 30% were already on treatement

Seizure free rates worse for MTS 42% AVM 78% Infarction 63% Primary brain tumour 57% Cortical Gliosis 57% Cerebral atrophy 55% Cortical dysplasia 54% None Prospective Clinic 629 Mixed 5 years (range 216) Chart review 525 Refractory epilepsy more likely in Symptomatic / cryptogenic (40%) than idiopathic (26%) More than 20 pretreatment seizures (51% v/s 29%) 47% seizure free on rst AED 14% on second or 3rd AED 3% seizure free on combination therapy Poor prognosis associated with Higher number of seizures and poor response to initial monotherapy R. Mohanraj, M.J. Brodie / Seizure 22 (2013) 333344

Kwan & Brodie80

19841997

Newly diagnosed epilepsy

Hitiris et al.66 Mohanraj & Brodie67

19812001

New diagnosis of epilepsy

None

Retrospective

Clinic

890

Mixed

79 months median

Chart review

780

59.2% seizure free Uncontrolled epilepsy associated with for at least 12 months More than 10 seizures prior to starting treatment Family history of epilepsy History of febrile seizures Post-traumatic epilepsy Recreational drug use Prior or current psychiatric comorbidity Factors not predicting poorer outcome included gender, neurological decit and mental retardation. Late remission 23.0% achieved associated with early remission (immediate seizure control after start of AED)

Del Felice et al.*88

198999

Newly diagnosed epilepsy

None stated

Retrospective

Clinic

352

Mixed

Upto 10 years

Chart review

352

335

336

Table 1 (Continued ) Study Recruitment Inclusion period criteria Exclusion criteria Type of study Setting n Epilepsy type Follow up Method of follow-up n with outcome Outcomes Prognostic factors identied

Increased number of 10.8% achieved partial seizures late remission (remission after >24 months after start of AED) Odds ratio (OR) of late remission 2.7 for patients with 2 5 partial seizures 6.7 in patients with >5 partial seizures Age, aetiology, EEG, neurologic/psychiatric abnormality, disease duration, seizure types not associated with outcomes R. Mohanraj, M.J. Brodie / Seizure 22 (2013) 333344 Lindsten et al.45 198587 Diagnosis of epilepsy Provoked seizures Retrospective Clinic 107 Mixed 112 years (range) Chart review 107 1 year remission 68% Seizures in the rst year after starting AED predictive of never achieving 1 year remission Not predictive of remission: Age at diagnosis, Seizure type, Etiology EEG Schiller and Najjar82 19992004 Commencing AED therapy None stated Prospective Clinic 478 Mixed 1.5 to 7.5 Clinical review 478 Seizure free rates dropped with sequential failure of AED 41.7%, after one AED 16.6%, after 25 AED 0% after 67 AED Response to past AEDs

3 year remission 64% 5 year remission 58%

Type of epilepsy Duration of epilepsy Number of seizures in the 3 months prior to AED initiation

R. Mohanraj, M.J. Brodie / Seizure 22 (2013) 333344

337

less secure in the non-specialist setting.10 Such studies are also resource intensive and very few have been conducted. Alternatively those run by epilepsy specialists are open to the criticism that they are unlikely to be population-based. Studies of prognosis in newly diagnosed epilepsy examine the likelihood of seizure remission with AED therapy, or the likelihood of developing refractory epilepsy, usually dened in terms of the number of AEDs unsuccessfully tried.11,12 While failure to achieve remission with AED therapy does not always equate to refractory epilepsy, we feel that both outcome measures represented poor outcomes and have included studies of remission and of refractory epilepsy in this analysis. Seizure types, aetiology, age of onset, duration of epilepsy and number of seizures before starting AED treatment, history of febrile convulsions, presence of neurological, intellectual or psychiatric co-morbidity family history of epilepsy, electro-encephalographic ndings and early response to AED treatment are some of the variables that have been examined by a number of authors. Their conclusions regarding each variable are summarised below. 3. Seizure types Some studies have suggested a signicant effect of seizure types on prognosis. In the population based study in Rochester, Minnesota, Annegers and colleagues found that patients with generalised tonicclonic and absence seizures had 80 and 85% probability respectively of achieving remission, compared to only 65% for patients with complex partial seizures.13 Analysis of data from two Veterans Affairs randomised control studies of AED treatment also showed that patients with complex partial seizures fared worst, with remission rates of 23 and 26% in the two studies compared to 55 and 48% for patients with generalised tonicclonic seizures.14 These low numbers can be, in part, explained by the inclusion of patients who had already failed their rst treatment schedule. Smaller clinic-based studies, however, have also supported this nding.15,16 Patients experiencing multiple seizure types also appear to have worse outcomes in adults1719 and children.2022 However, another large community based study, the UK National General Practice Survey of Epilepsy (NGPSE), found only a modest effect of seizure type on prognosis.2325 Recent evidence implicates seizure clusters as being associated with poorer prognosis.26 Analysis of these data overall, however, suggests that the effect of seizure types is less important than other factors including early response to treatment in determining eventual outcome. 4. Aetiology Epilepsies relating to structural brain abnormalities are less likely to enter remission compared that occurring in patients with structurally normal brains. This is manifest as a lower remission rate for symptomatic epilepsies (both partial and generalised) compared to idiopathic epilepsy syndromes in children.16,2731 The nature and location of the underlying structural abnormality can also affect the likelihood of response to treatment. Semah and colleagues found that in 2200 treated patients referred to a specialist epilepsy service in France, those with temporal lobe epilepsy were over represented compared to other types of localisation related epilepsy.32 Analysis of 550 patients with localisation related epilepsy in Glasgow also reported worse remission rates in patient with hippocampal sclerosis than in focal epilepsies due to other causes.33 However, many patients included in these analyses did not have newly diagnosed epilepsy, and so could be expected to have a substantially worse prognosis than found in similar studies in newly diagnosed populations.34 Many patients with substrates for epilepsy often regarded as invariably

being associated with drug resistance, such as hippocampal sclerosis, can have a good outcome and so may never be reviewed at a specialist service.35,36 The identication of well dened electro-clinical syndromes can allow more accurate assessment of prognosis. This is more pertinent to paediatric cases, where epilepsy syndromes are generally better dened. A detailed analysis of all published predictive factors in each epilepsy syndrome is beyond the scope of this article, only a few prominent examples will be touched upon. In their meta-analysis of studies on childhood absence epilepsy, Bouma and colleagues found that signicant heterogeneity existed between various cohorts in inclusion criteria and denition of remission.37 As a result the reported remission rates ranged from 21% to 89%. Development of tonicclonic seizures was associated with a reduced chance of remission (35%), compared to absence seizures only (78%), however, prognosis could not be predicted early on. Other studies have identied myoclonic jerks, eyelid or perioral myoclonia and presence of atypical EEG patterns as predictive of a poor prognosis in childhood absence epilepsy and subsequent evolution into juvenile myoclonic epilepsy (JME).38,39 Analysis of JME cohorts suggest that endophenotypes are important in determining prognosis, with good control of seizures with AED treatment but high rate of recurrence on withdrawal of medication.40,41 4.1. Age at onset Some studies in children suggest that onset of epilepsy before the age of 12 months is a poor prognostic factor.28,30,42 Berg and colleagues found that prognosis improved with increasing age, and that this effect was not restricted to the rst year of life.43 However, studies that included patients of all ages did not demonstrate a consistent effect of age at onset on prognosis.13,25 Multivariate analyses of prognostic factors in children44 and in adults15,45 have found no independent correlation of age at onset with prognosis. It is likely that any differences are a reection of the epilepsy syndromes that are prevalent among the various age groups. Mixed cohorts of various epilepsy syndromes cannot reect the effect of individual syndromes on prognosis. In developed countries, the highest incidence of epilepsy is in older patients.46 These present with epilepsy as a consequence of a variety of acquired brain disorders, including cerebrovascular disease and neurodegeneration. Analysis of the Glasgow cohort of newly diagnosed epilepsy suggested that outcomes were generally better in patients aged over 65 years at the onset of epilepsy.47 Possible explanations include lack the neuronal plasticity needed for the development of pharmacoresistance and reduced likelihood of genetic factors adversely affecting prognosis.

5. Duration of epilepsy and number of pre-treatment seizures Many studies have examined the impact of the number of seizures and the time from onset of epilepsy to starting AED treatment on prognosis. An important question for physicians is whether treating patients early, thereby minimising the number of subsequent seizures, will lead to improved outcomes. This is intricately linked to the question of whether drug resistance develops as a result of repeated seizures. The concept that seizures beget seizures was introduced by Gowers in the 19th century48 and reinforced by the writings of Rodin in the 1960s.49 A long history and high numbers of pre-treatment seizures were thought to correlate with a poor outcome. This view was supported by Reynolds and colleagues in the early 1980s and early treatment of seizures was considered key to preventing the emergence of drug-resistant epilepsy.50

338

Table 2 List of studies of outcomes in paediatric epilepsy. Studies from the same population have been grouped together. Study Arts et al.69 Recruitment period 198892 Inclusion criteria: Newly diagnosed epilepsy Exclusion criteria: None stated Type of study Prospective Setting Clinic n 494 Epilepsy type Mixed Follow up 2 years Method of follow-up Structured review n with outcome 466 Outcomes 31% poor outcome (Did not achieve 6 m remission by 2 years) Prognostic factors Intake variables associated with poor outcome Number of seizures

Seizure types Aetiology Arts et al.98 198892 Diagnosis of epilepsy made in the study period Panel judged not epilepsy Prospective Clinic 494 Mixed 5 years Active follow up at 6 months and 2 years Postal questionnaire 466 345 (76%) in terminal remission >1 year at 5 yrs FU 290 (64%) > 2years Aetiology, history of febrile seizures and age (at study entry) Sex, aetiology, post ictal signs, history of febrile seizures, and remission at 6 months At 6 months

R. Mohanraj, M.J. Brodie / Seizure 22 (2013) 333344

65 (14%) no seizures since start of follow up 108 (24%) with TR < 1 year at 5 years, 27 intractable Geerts et al.22 198892 As above As above Prospective Clinic 415 Mixed 14.8 years mean Structured review for 5 years 413 Five-year terminal remission (TR) was reached by 71% of the cohort. Course during

Associations with failure to achieve terminal remission

Postal questionnaires at year 10 and 15

Non-idiopathic etiology

Febrile seizures No 3 month remission Early intractability Cameld et al.64 197785 Children with 2 or more unprovoked seizures in the recruitment period Follow up available 212 years Myloclonic, absence, tonic seizures Prospective Community 479 Mixed 212 years (median not stated) Chart review 479 70% seizure free and attempted drug withdrawal No effect of number of pretreatment seizures on prognosis for seizure control, up to 10 pre treatment seizures

Progressive brain disease Unknown pretreatment seizure number

Contact with primary care physician

70% seizure free after drug withdrawal More patients suffering >10 pre treatment seizures likely to have complex partial seizures

No difference between patients suffering up to 10 pretreatment seizures and those suffering fewer Cameld et al.99 197785 Children with 2 or more unprovoked seizures in the recruitment period Follow up available 212 years Myloclonic, absence, tonic seizures Prospective Community 417 Mixed 92 =/ 26 months Chart review 417 61% seizure free on rst drug and withdrew medication Presence of neurological decits and complex partial seizures associated with failure of rst AED

Progressive brain disease

Contact with primary care physician

Unknown pretreatment seizure number

Only 41% of those failing rst AED became seizure free with second AED 29% of those failing rst AED developed refractory epilepsy 520 (89%) 344 seizure free with rst drug Patients with symptomatic epilepsy (60.3%) Cryptogenic epilepsy (61.5%) Less likely to become seizure free Idiopathic epilepsy (73.8%)

R. Mohanraj, M.J. Brodie / Seizure 22 (2013) 333344

Ma et al.100

20002004

Children diagnosed with epilepsy in the study period

None stated

Retrospective

Clinic

520

Mixed

1275 months (range)

Chart review

Ollivier et al.101

20002008

CAE treated with Valproate

Brain disorders apart from developmental delay and ADHD

Retrospective

Clinic

235

CAE treated with valproate

Not stated

Chart review

180

58.3% achieved seizure freedom

Generalised tonic clonic seizures

High frequency of seizures (>10/day) at diagnosis Younger age at diagnosis - associated with failure to respond to VPA Berg et al.31 199397 Diagnosis of epilepsy in the recruitment period Diagnosis of epilepsy made prior to study period by non participating physician Panel of neurologists felt diagnosis of epilepsy unlikely Prospective Community 885 Mixed 5 years median Active follow up 613 60 (10%) intractable (failure of 2 AEDs, >1 sz per month) Symptomatic/ cryptogenic generalised syndromes most likely to develop IE Initial seizure frequency

Berg et al.44

34.6% with cryptogenic / symptomatic generalised

339

340

Table 2 (Continued ) Study Berg et al.102 Recruitment period Inclusion criteria: Exclusion criteria: Communication and geographical factors limiting follow up Type of study Setting n Epilepsy type Follow up Method of follow-up n with outcome Outcomes 2.7% of idiopathic Prognostic factors Focal EEG slowing

10.7% with other loc rel 8.2% oc unclassied epilepsy

Acute symptomatic / neonatal status epileticus bad Age of onset 59 years good Total number of seizures, / febrile status no increased risk

Oskoui et al.21

19912000

Recurrent unprovoked seizure Age 217

Single seizures

Retrospective

Clinic

240

Mixed

55 months (mean)

Chart review

197

52.6% were in remission 12.8% had a poor outcome (recurrent seizures on therapeutic antiepileptic drug levels within 6 months prior to the nal assessment) 6.9% were intractable (more than one seizure/ month over 1 year with failure of three or more anticonvulsants)

Factors predictive of intractability R. Mohanraj, M.J. Brodie / Seizure 22 (2013) 333344 Multiple seizure types (hazard ratio 6.5)

Seizures starting out with age range

Minimum 2 years follow up

Mental retardation at onset (hazard ratio 7.2)

Seizure recurrence in the rst 6 to 12 months of treatment (hazard ratio 70) Sillanpaa & Schmidt90 19652008 Age 15 or less 2 or more seizures Living in dened geographical area None Prospective Community based 150 Mixed 1142 years, median 40 years Structured review 144 67% terminal remission Weekly seizure frequency in the rst year on treatment

R. Mohanraj, M.J. Brodie / Seizure 22 (2013) 333344

341

Repeated seizures have been shown to produce neuronal loss and mossy bre sprouting in the hippocampus, which in turn can reinforce their production forming excitatory recurrent circuits.51,52 Cross-sectional magnetic resonance imaging (MRI) studies have demonstrated smaller hippocampal volumes ipsilateral to the seizure focus in patients with temporal lobe epilepsy and uncontrolled seizures.53,54 The degree of hippocampal volume loss was related to the duration of epilepsy. Longitudinal studies employing repeat MRI scans have demonstrated progressive hippocampal and temporal neocortical volume loss and have suggested that neuronal loss can be correlated to number of seizures.55,56 Prevention of repeated seizures in this setting by effective drug treatment could theoretically prevent neuronal apoptosis and synaptic reorganisation, which may be responsible for further seizures and thereby the emergence of drug resistance. On the other hand, studies in patients who have suffered seizures for several years, sustaining 100 or more generalised seizures before coming to medical attention have shown that a similar proportion go into remission as patients treated early after only a few seizures.57 Moreover, treatment with AEDs after the rst unprovoked seizure has been shown not to affect the long-term outcome, in spite of preventing seizures in the short term.5861 Several groups have shown a relationship of high initial seizure frequency with poor outcome.18,27,49,6266 However, detailed analyses of data from observational studies have suggested that this is true only for patients suffering complex partial seizures.67 This would imply that the epileptogenic process responsible for the high frequency of complex partial seizures is inherently pharmacoresistant, and supports the view that the prognosis of each epilepsy syndrome may be a characteristic of that specic disorder.68 6. Concomitant morbidity

verbal memory impairment74 and that impaired memory performance at the outset was predictive of poor outcome.16 It is possible, therefore that the presence of a psychiatric co-morbidity early in the course of the epilepsy points to a greater underlying cerebral dysfunction and is, therefore, predictive of a poorer outcome. 7. Family history of epilepsy Studies in children31 and adults15,66 have reported an association between family history of epilepsy and poorer prognosis. In generalised syndromes, this could be related to the underlying genetic mechanisms underpinning the epilepsy, which might also be responsible for determining drug response.75 The role of genetic factors in focal epilepsies is less clear. Genetically determined malformations of cortical development may play a role76 as may pharmacogenetic traits that run in families.77 8. Febrile seizures Febrile seizures have an almost uniformly benign prognosis. However, approximately 3% of affected infants will develop epilepsy in later life.78 Complex febrile seizures, i.e. those that are prolonged, focal or recur within the same day, those occurring in children with pre-existing neurological decit, and those with a family history of epilepsy in a rst degree relative, all confer a higher risk of developing epilepsy. There is, of course, a well known association between febrile seizures in infancy and the development of hippocampal sclerosis in later life.78 Hitiris and colleagues66 found that the febrile convulsions in infancy predicated a poorer outcome to treatment in newly diagnosed epilepsy as did Geerts and co-workers from the Netherlands.22 9. Electroencephalographic ndings

In their landmark population based study of patients with epilepsy in Rochester Minnesota, Annegers and colleagues found that patients who had epilepsy as a result of presumed perinatal cerebral insult, manifesting as physical and intellectual disability had only 46% probability of achieving seizure control, compared to 74% for patients with idiopathic epilepsy and those with epilepsy due to postnatally acquired lesions.13 Early clinic based studies also supported this notion in adults.15 Subsequent studies, especially in children, have demonstrated that the presence of neurological decit, especially associated with intellectual impairment, is indicative of a poorer prognosis.20,29,44,69 However, studies that include all age groups and predominantly adult patients have not supported such an association. The NGPSE and Glasgow cohorts showed no signicant effect of neurological or intellectual decits on prognosis25,66 Psychiatric problems are more frequent in patients with epilepsy. There is evidence to support a close relationship in the pathogenesis of epilepsy and depression.70 Association of psychiatric co-morbidity with refractory epilepsy has previously been reported in adult patients.15 In the Glasgow cohort of 780 patients with newly diagnosed epilepsy, Hitiris and colleagues noted that the presence of prior or current psychiatric comorbidity was signicantly associated with failure to achieve remission.66 Similar observations have been made following temporal lobectomy in patients with refractory epilepsy reporting a psychiatric history.71,72 More recently, Petrovski and colleagues demonstrated that the presence of neuropsychological symptomatology was associated with a worse response to treatment in patients with newly diagnosed epilepsy.73 Other neuropsychological factors may also be important in determining prognosis. One small clinic based study found that patients with newly diagnosed epilepsy had

Some studies, mainly in children, have found a correlation of background slowing and focal spike and wave activity with a poor outcome.16,28,44 An electroencephalogram (EEG) performed soon after a seizure is more likely to detect such abnormalities, and is likely to have greater prognostic value.79 Studies in adults have not found EEG to be independently predictive of outcome after adjusting for other factors.15,45 Thus, in adults, the prognostic value of routine interictal EEG examination has not been established. 10. Response to rst drug Several studies have found the response to the rst AED to be the strongest predictor of long-term outlook in adults and children.27,64,8082 Patients whose seizures continue despite adequate doses of an appropriate AED have a lower chance of subsequent seizure remission, compared to those who are unable to do tolerate the initial AED, and are tried on an alternative agent. Kwan and Brodie reported that only 11% of patient who failed initial monotherapy due to lack of efcacy subsequently became seizure free, compared to 41% of those who failed due to intolerable adverse effects and 55% of those who experienced an idiosyncratic adverse effects.80 If the rst AED is unsuccessful, subsequent AED regimes have a declining likelihood of success. In an analysis of 780 patients diagnosed and treated for epilepsy in Scotland, the authors found that the response rate to the rst, second and third AED was 50.4, 10.7 and 2.7%, respectively.65 More recently responses have been demonstrated in a few patients up to the seventh regimen.12,82 The recently published International League against Epilepsy denition of drug-resistant epilepsy recommends that failure to gain seizure control for at least one year with the rst

342

R. Mohanraj, M.J. Brodie / Seizure 22 (2013) 333344

2 tolerated, appropriately chosen and used AED schedules (whether as monotherapy or in combination) should prompt referral for specialist review for conrmation of the diagnosis for seizure and/or syndrome classication and, if appropriate, for consideration of epilepsy surgery.83 Some authors have suggested that this view might be unduly pessimistic and that further drug trials may still result in worthwhile improvements in seizure control for a proportion of patients. Callaghan and colleagues studied 246 patients who met the above denition of drug resistant epilepsy prospectively for 3 years, and reported a 14% 6-month remission rate (approximately 5% per year) with further drug therapy alone.84 Luciano and Shorvon found that in a population of patients with refractory epilepsy, addition of a new AED resulted in seizure freedom in 16%.85 Many of these patients however, will subsequently relapse.11,12,86,87 Good early response to AED treatment is not always sustained in the long term. Analysis of the Glasgow cohort found that 10.4% of patients entering remission had relapse of seizures, and 5% went on to develop drug resistant epilepsy.65 Other hospital based series have reported the phenomenon of seizure relapse following an initial period of good response to AEDs and eventual development of drug resistant epilepsy. Following up a clinic population of 256 patients who had been seizure free for a minimum of 12 months, Schiller reported that 40% of patients had suffered seizure relapse by 5 years and 23% met the criteria for drug resistant epilepsy.11 The number of AEDs failed due to lack of efcacy and duration of epilepsy for more than 5 years before entering remission were identied as risk factors for relapse and subsequent development of refractory epilepsy. While most patients who respond to AED treatment will do so early, failure to do so does not indicate a uniformly poor prognosis. In the Glasgow series, of 780 newly diagnosed epilepsy patients, 245 (31.4%) became seizure free immediately after starting AEDs, achieving 12 months seizure freedom by one year of treatment, a further 217 patients also achieved the same outcome over the rest of the follow up.65 A retrospective survey of 352 newly diagnosed patients from 2 epilepsy clinics in Italy reported that 56.2% entered 2 year remission immediately on starting treatment, but a further proportion achieved remission with each successive year of follow up, rising to a cumulative 2 year remission rate of 79% by 10 years of follow up.88 In a long term prospective study of childhood onset epilepsy, Sillanpaa and Schmidt reported that patients who experienced ongoing weekly seizures during the rst year on AED treatment were less likely to enter remission.89 However, 50% of patients entered remission late, with a mean delay of 9 years from starting treatment.90 The most recent analyses from the 1098 patients with newly diagnosed epilepsy included in the Glasgow database divided the patient outcomes into 4 distinct groups with 37.2% demonstrating longterm seizure freedom within 6 months of initiating treatment, 22.4% having a delayed response but an excellent outcome, 15.7% with a relapsing-remitting pattern and the nal 24.8% being refractory de novo.12 11. Genetics of drug resistance Pharmacogenetics is the study of genetic inuences on the pharmacokinetics and pharmacodynamics of medications. This eld has expanded enormously in parallel to the strides made in genetics technology.91 A large number of genetic markers have been studied in patients with epilepsy to identify predictors of efcacy and adverse effects.92 Single nucleotide polymorphisms represent the most frequently studied genetic marker to date, but genome wide association studies are underway.77 Many studies have focussed on genes encoding the multidrug resistance protein

MDR1 (ABCB1). This, and other similar proteins are thought to play a role in drug resistant epilepsy by extruding AEDs from the seizure focus. C3435T polymorphism in the ABCB1 gene has been found associated with refractory epilepsy in some studies, but a similar number failed to replicate this association.93 It seems unlikely that a complex outcome such as responsiveness to AED treatment can be fully explained by variability of a single genetic factor. It is more likely that responsiveness to AED treatment depends on a complex interplay of genetic and environmental inuences.94 12. Conclusions Approximately one in three of patients diagnosed with epilepsy will fail to achieve lasting remission of seizures with AEDs treatment despite the global introduction of more than 12 new AEDs over the past 20 years.68 These patients continue to suffer the physical, psychological and social consequences of intractable seizures and adverse effects from an escalating drug burden. They also place a strain on health care resources the world over.95 While there is a clear need for new AEDs with novel mechanisms of action, there is also a need to target available treatments, especially epilepsy surgery, more effectively. Early identication and prediction of patients likely to be unresponsive to initial drug therapy will allow earlier specialist intervention. Advances in cerebral imaging and molecular biological techniques have allowed a greater insight into the mechanisms underlying seizure generation and propagation. However, this knowledge is far from complete. The basic mechanisms of drug resistance in epilepsy also remain largely unclear. Epidemiological data over the years have identied several factors that correlate with a poor prognosis in children and adults, although some of this data is conicting. More long-term studies are required to assess the prognosis of each epilepsy syndrome. Pharmacogenomic studies employing more sophisticated genotyping and bioinformatics technologies promise greater predictability of response to individual AEDs. Other possibilities include the identication of biomarkers for drug-resistance, such as transcranial magnetic stimulation.96 Studies to date show that the early response to treatment is a powerful predictor of the longterm outlook of newly diagnosed epilepsy. Patients who do not achieve complete seizure control with the rst two appropriate regimens of AEDs in the rst one to two years after starting treatment, have a relatively small chance of achieving seizure freedom with further pharmacotherapy and may be considered to have drug-resistant epilepsy.12 There is, therefore, an urgent unmet need for new symptomatic treatments with improved efcacy/tolerability proles and, arguably more importantly, disease-modifying approaches that will prevent or ameliorate the processes underpinning epileptogensis.97 Disclosures Rajiv Mohanraj has served on advisory boards for UCB Pharma and Eisai; has received speaker fees from UCB Pharma, Eisai and GlaxoSmithKline; has accepted conference hospitality from UCB Pharma and Eisai. Martin J. Brodie has served on scientic advisory boards for Pzer Inc., UCB Pharma, Eisai, GlaxoSmithKline, Novartis, Valeant Pharmaceuticals, Sano Aventis, and Lundbeck Inc.; has received funding for travel from UCB Pharma and GlaxoSmithKline; serves as a consultant for Eisai; serves on speakers bureaus for UCB Pharma, GlaxoSmithKline, and Eisai; and has received research support from Eisai and GlaxoSmithKline. References
1. Banerjee PN, Filippi D, Hauser WA. The descriptive epidemiology of epilepsy. A review. Epilepsy Research 2009;85:3145.

R. Mohanraj, M.J. Brodie / Seizure 22 (2013) 333344 2. Devinsky O. Patients with refractory seizures. New England Journal of Medicine 1999;340:156570. 3. McCagh J, Fisk E, Baker GA. Epilepsy, psychosocial and cognitive functioning. Epilepsy Research 2009;86:114. 4. Kwan P, Sander JW. The natural history of epilepsy: an epidemiological view. Journal of Neurology Neurosurgery and Psychiatry 2004;75:137681. 5. Brodie MJ. Antiepileptic drug therapy: the story so far. Seizure 2010;19: 6505. 6. Brodie MJ, Sills GJ. Combining antiepileptic drugs rational polytherapy? Seizure 2011;20:36975. 7. Lhatoo SD, Solomon JK, McEvoy AW, Kitchen ND, Shorvon SD, Sander JW. A prospective study of the requirement for and the provision of epilepsy surgery in the United Kingdom. Epilepsia 2003;44:6736. 8. Engel J, Wiebe S, French J, Gummitt R, Zahn C, Westbrook E, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy. Neurology 2003;60:53847. 9. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Hauser WA, Mathern G, et al. Denition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51:106977. 10. Leach JP, Lauder R, Nicolson A, Smith DF. Epilepsy in the UK: misdiagnosis, mistreatment, and undertreatment? The Wrexham area epilepsy project. Seizure 2005;14:51420. 11. Schiller Y. Seizure relapse and development of drug resistance following longterm seizure remission. Archives of Neurology 2009;66:12339. 12. Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Brodie MJ. Patterns of treatment response in newly diagnosed epilepsy. Neurology 2012;78:154854. 13. Annegers JF, Hauser WA, Elveback LR. Remission of seizures and relapse in patients with epilepsy. Epilepsia 1979;20:72937. 14. Mattson RH, Cramer JA, Collins JF. Prognosis for total control of complex partial and secondarily generalized tonicclonic seizures. Neurology 1996;47:6876. 15. Elwes RD, Johnson AL, Shorvon SD, Reynolds EH. The prognosis for seizure control in newly diagnosed epilepsy. New England Journal of Medicine 1984;311:9447. 16. Aikia M, Kalviainen R, Mervaala E, Riekkinen Sr PJ. Predictors of seizure outcome in newly diagnosed partial epilepsy: memory performance as a prognostic factor. Epilepsy Research 1999;37:15967. 17. Goodridge DM, Shorvon SD. Epileptic seizures in a population of 6000. II: Treatment and prognosis. British Medical Journal 1983;287:6457. 18. Beghi E, Tognoni G. Prognosis of epilepsy in newly referred patients: a multicenter prospective study. Collaborative Group for the Study of Epilepsy. Epilepsia 1988;29:23643. 19. Prognosis of epilepsy in newly referred patients: a multicenter prospective study of the effects of monotherapy on the long-term cause of epilepsy. Collaborative Group for the Study of Epilepsy. Epilepsia 1992;33:4551. 20. Brorson LO, Wranne L. Long-term prognosis in childhood epilepsy: survival and seizure prognosis. Epilepsia 1987;28:32430. 21. Oskoui M, Webster RI, Zhang X, Shevell MI. Factors predictive of outcome in childhood epilepsy. Journal of Child Neurology 2005;20:898904. 22. Geerts A, Arts WF, Stroink H, Peeters E, Brouwer O, Peters B, et al. Course and outcome of childhood epilepsy: a 15-year follow-up of the Dutch Study of Epilepsy in Childhood. Epilepsia 2010;51:118997. 23. Cockerell OC, Johnson AL, Sander JW, Hart YM, Shorvon SD. Remission of epilepsy: results from the National General Practice Study of Epilepsy. Lancet 1995;346:1404. 24. Cockerell OC, Johnson AL, Sander JW, Shorvon SD. Prognosis of epilepsy: a review and further analysis of the rst nine years of the British National General Practice Study of Epilepsy, a prospective population-based study. Epilepsia 1997;38:3146. 25. MacDonald BK, Johnson AL, Goodridge DM, Cockerell OC, Sander JW, Shorvon SD. Factors predicting prognosis of epilepsy after presentation with seizures. Annals of Neurology 2000;48:83341. a M, Schmidt D. Seizure clustering during drug treatment affects 26. Sillanpa seizure outcome and mortality of childhood-onset epilepsy. Brain 2008; 131:93844. a M. Remission of seizures and predictors of intractability in long-term 27. Sillanpa follow-up. Epilepsia 1993;34:9306. 28. Ko TS, Holmes GL. EEG and clinical predictors of medically intractable childhood epilepsy. Clinical Neurophysiology 1999;110:124551. 29. Hauser E, Freilinger M, Seidl R, Groh C. Prognosis of childhood epilepsy in newly referred patients. Journal of Child Neurology 1996;11:2014. 30. Casetta I, Granieri E, Monetti VC, Gilli G, Tola MR, Paolini E, et al. Early predictors of intractability in childhood epilepsy: a community-based casecontrol study in Copparo, Italy. Acta Neurologica Scandinavica 1999;99: 32933. 31. Berg AT, Shinnar S, Levy SR, Testa FM, Smith-Rapaport S, Beckerman B, et al. Two year remission and subsequent relapse in children with newly diagnosed epilepsy. Epilepsia 2001;42:125362. 32. Semah F, Picot M-C, Adam C, Broglin D, Arzimanoglou A, Balin B, et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 1998;51:125662. 33. Stephen LJ, Kwan P, Brodie MJ. Does the cause of localisation-related epilepsy inuence the response to antiepileptic drug treatment? Epilepsia 2001;42:35762. 34. Mohanraj R, Brodie MJ. Outcomes in newly diagnosed localization-related epilepsies. Seizure 2005;14:31823.

343

35. Andrade-Valenca LP, Valenca MM, Ribeiro LT, Matos ALM, Sales LV, Velasco TR, et al. Clinical and neuroimaging features of good and poor seizure control with mesial temporal lobe epilepsy and hippocampal atrophy. Epilepsia 2003;44:80714. 36. Kobayashi E, DAgostino MD, Lopes-Cendes I, Berkovic SF, Andermann E, Andermann F, et al. Hippocampal atrophy and T2-weighted signal changes in familial mesial temporal lobe epilepsy. Neurology 2003;60:4059. 37. Bouma PAD, Westendorp RGJ, Van Dijk JG, Peters ACB, Brouwer OF. The outcome of absence epilepsy. A meta-analysis. Neurology 1996;47:8026. 38. Grosso S, Galimberti D, Vezzosi P, Farnetani M, Di Bartolo RM, Bazzotti S, et al. Childhood absence epilepsy: evolution and prognostic factors. Epilepsia 2005;46:1796801. 39. Wirrell EC, Cameld CS, Cameld PR, Gordon KE, Dooley JM. Long-term prognosis of typical childhood absence epilepsy: remission or progression to juvenile myoclonic epilepsy. Neurology 1996;47:9128. nez-Jua rez IE, Alonso ME, Medina MT, Du Ron RM, Bailey JN, Lopez-Riz M, 40. Mart et al. Juvenile myoclonic epilepsy subsyndromes: family studies and longterm follow-up. Brain 2006;129:126980. 41. Guaranha MS, Filho GM, Lin K, Guilhoto LM, Caboclo LO, Yacubian EM. Prognosis of juvenile myoclonic epilepsy is related to endophenotypes. Seizure 2011;20:428. 42. Cameld C, Cameld P, Gordon K, Smith B, Dooley J. Outcome of childhood epilepsy: a population-based study with a simple predictive scoring system for those treated with medication. Journal of Pediatrics 1993;122:8618. 43. Berg AT, Levy SR, Novotny EJ, Shinnar S. Predictors of intractable epilepsy in childhood: a casecontrol study. Epilepsia 1996;37:2430. 44. Berg AT, Shinnar S, Levy SR, Testa FM, Smith-Rapeport S, Beckerman L. Early development of intractable epilepsy in children: a prospective study. Neurology 2001;56:144552. 45. Lindsten H, Stenlund H, Forsgren L. Remission of seizures in a populationbased adult cohort with a newly diagnosed unprovoked epileptic seizure. Epilepsia 2001;42:102530. 46. Brodie MJ, Elder AT, Kwan P. Epilepsy in later life. Lancet Neurology 2009;8:101930. 47. Stephen LJ, Kelly K, Mohanraj R, Brodie MJ. Pharmacological outcomes in older people with newly diagnosed epilepsy. Epilepsy & Behavior 2006;8:4347. 48. Gowers WR. Epilepsy and other convulsive disorders. London: Churchill; 1881. 49. Rodin EA. The prognosis of patients with epilepsy. Illinois: Thomas Springeld; 1968. 50. Reynolds EH, Elwes RD, Shorvon SD. Why does epilepsy become intractable? Prevention of chronic epilepsy. Lancet 1983;2:9524. 51. Dalby NO, Mody I. The process of epileptogenesis: a pathophysiological approach. Current Opinion in Neurology 2001;14:18792. 52. Sperk G, Drexel M, Pirker S. Neuronal plasticity in animal models and the epileptic human hippocampus. Epilepsia 2009;50(Suppl. 12):2931. 53. Theodore WH, Bhatia S, Hatta J, Falilat S, De Carli C, Bookheimer SY, et al. Hippocampal atrophy, epilepsy duration, and febrile seizures in patients with partial seizures. Neurology 1999;52:1326. 54. Kalviainen R, Salmenpera T. Do recurrent seizures cause neuronal damage? A series of studies with MRI volumetry in adults with partial epilepsy. Progress in Brain Research 2002;135:27995. 55. Briellmann RS, Berkovic SF, Syngeniotis A, King MA, Jackson GD. Seizureassociated hippocampal volume loss: a longitudinal magnetic resonance study of temporal lobe epilepsy. Annals of Neurology 2002;51:6414. 56. Fuerst D, Shah J, Shah A, Watson C. Hippocampal sclerosis is a progressive disorder: a longitudinal volumetric MRI study. Annals of Neurology 2003; 53:4136. 57. Feksi AT, Kaamugisha J, Sander JW, Gatiti S, Shorvon SD. Comprehensive primary health care antiepileptic drug treatment programme in rural and semi-urban Kenya. Lancet 1991;337:4069. 58. Hauser WA, Rich SS, Annegers JF, Anderson VE. Seizure recurrence after a rst unprovoked seizure: an extended follow-up. Neurology 1990;40:116370. 59. Musicco M, Beghi E, Solari A, Viani F. Treatment of rst tonicclonic seizure does not improve the prognosis of epilepsy. Neurology 1997;49:9918. 60. Cameld P, Cameld C, Smith S, Dooley J, Smith E. Long-term outcome is unchanged by antiepileptic drug treatment after a rst seizure: a 15-year follow-up from a randomized trial in childhood. Epilepsia 2002;43:6623. 61. Marson A, Jacoby A, Johnson A, Kim L, Gamble C, Chadwick D, et al. Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomised controlled trial. Lancet 2005;365:200713. 62. Juul-Jensen P. Epilepsy. A clinical and social analysis of 1020 adult patients with epileptic seizures. Acta Neurologica Scandinavica 1964;40(Suppl. 5): 1148. 63. Reynolds EH. Early treatment and prognosis of epilepsy. Epilepsia 1987;28: 97106. 64. Cameld C, Cameld P, Gordon K, Dooley J. Does the number of seizures before treatment inuence ease of control or remission of childhood epilepsy? Not if the number is 10 or less. Neurology 1996;46:414. 65. Mohanraj R, Brodie MJ. Diagnosing refractory epilepsy: response to sequential treatment schedules. European Journal of Neurology 2006;13:27782. 66. Hitiris N, Mohanraj R, Norrie J, Sills GJ, Brodie MJ. Predictors of pharmacoresistant epilepsy. Epilepsy Research 2007;75:1926. 67. Shinnar S, Berg AT. Does antiepileptic drug therapy prevent the development of chronic epilepsy? Epilepsia 1996;37:7018. 68. Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. New England Journal of Medicine 2011;369:91926.

344

R. Mohanraj, M.J. Brodie / Seizure 22 (2013) 333344 86. Berg AT, Levy SR, Testa FM, DSouza R. Remission of epilepsy after two drug failures in children: a prospective study. Annals of Neurology 2009;65:5109. 87. Callaghan B, Schlesinger M, Rodemer W, Pollard J, Hesdorffer D, Hauser WA, et al. Remission and relapse in a drug-resistant epilepsy population followed prospectively. Epilepsia 2011;52:61926. 88. Del Felice A, Beghi E, Boero G, La Neve A, Bogliun G, De Palo A, et al. Early versus late remission in a cohort of patients with newly diagnosed epilepsy. Epilepsia 2010;51:3742. a M, Schmidt D. Early seizure frequency and aetiology predict long89. Sillanpa term medical outcome in childhood-onset epilepsy. Brain 2009;132:98998. a M, Schmidt D. Natural history of treated childhood-onset epilepsy: 90. Sillanpa prospective, long-term population-based study. Brain 2006;129:61724. 91. Reid CA, Berkovic SF, Petrov S. Mechanisms of human inherited epilepsies. Progress in Neurobiology 2009;87:4157. scher W, Klotz U, Zimprich F, Schmidt D. The clinical impact of pharmaco92. Lo genetics on the treatment of epilepsy. Epilepsia 2009;50:123. 93. Cascorbi I. ABC transporters in drug-refractory epilepsy: limited clinical signicance of pharmacogenetics? Clinical Pharmacology and Therapeutics 2010;87:158. 94. Johnson MR, Tan NCK, Kwan P, Brodie MJ. Newly diagnosed epilepsy and pharmacogenomics research: a step in the right direction? Epilepsy & Behavior 2011;22:38. nen A. Research priorities in epilepsy for the next decade a 95. Baulac M, Pitka representative view of the European scientic community. Epilepsia 2009; 50:57183. 96. Badawy RAB, Jackson GD, Berkovic SF, Macdonell RAL. Cortical excitability and refractory epilepsy: a three-year longitudinal transcranial magnetic stimulation study. International Journal of Neural Systems 2003;23:1250030. S, Perucca E, Engel JRJ, et al. 97. Galanopoulou AS, Buckmaster PS, Staley KJ, Moshe Identication of new epilepsy treatments: issues in preclinical methodology. Epilepsia 2012;53:57182. 98. Arts WF, Brouwer OF, Peters AC, Stroink H, Peeters EA, Schmitz PI, et al. Course and prognosis of childhood epilepsy: 5-year follow-up of the Dutch study of epilepsy in childhood. Brain 2004;127:177484. 99. Cameld PR, Cameld CS, Gordon K, Dooley JM. If a rst antiepileptic drug fails to control a childs epilepsy, what are the chances of success with the next drug? Journal of Pediatrics 1997;131:8214. 100. Ma MS, Ding YX, Ying W, Fang F, Ding CH, Zou LP. Effectiveness of the rst antiepileptic drug in the treatment of pediatric epilepsy. Pediatric Neurology 2009;41:226. 101. Ollivier ML, Dubois MF, Krajinovic M, Cossette P, Carmant L. Risk factors for valproic acid resistance in childhood absence epilepsy. Seizure 2009;18: 6904. 102. Berg AT, Shinnar S, Levy SR, Testa FM, Smith-Rapaport S, Beckerman B, et al. Dening early seizure outcomes in pediatric epilepsy: the good, the bad and the in-between. Epilepsy Research 2001;43:7584.

69. Arts WF, Geerts AT, Brouwer OF, Boudewyn Peters AC, Stroink H, van Donselaar CA. The early prognosis of epilepsy in childhood: the prediction of a poor outcome. The Dutch study of epilepsy in childhood. Epilepsia 1999;40: 72634. 70. Kanner AM. Depression and epilepsy: a bidirectional relation? Epilepsia 2011;52(Suppl. l1):217. 71. Kanner AM, Byrne R, Chicharro A, Wuu J, Frey M. A lifetime psychiatric history predicts a worse seizure outcome following temporal lobectomy. Neurology 2009;72:7939. 72. Cleary RA, Thompson PJ, Fox Z, Foong J. Predictors of psychiatric and seizure outcome following temporal lobe epilepsy surgery. Epilepsia 2012;53: 170512. 73. Petrovski S, Szoeke CEI, Jones NC, Salzberg MR, Shefeld LJ, Huggins RM, et al. Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients. Neurology 2010;75:101521. M, Ka lvia inen R, Riekkinen PJ. Verbal learning and memory in newly 74. Aikia diagnosed partial epilepsy. Epilepsy Research 1995;22:15764. 75. Reid CA, Jackson GD, Berkovic SF, Petrov S. New therapeutic opportunities in epilepsy: a genetic perspective. Pharmacology & Therapeutics 2010;128: 27480. 76. Spalice A, Parisi P, Nicita F, Pizzardi G, Del Balzo F, Iannetti P. Neuronal migration disorders: clinical, neuroradiologic and genetics aspects. Acta Paediatrica 2009;98:42133. 77. Sisodiya SM, Marini C. Genetics of antiepileptic drug resistance. Current Opinion in Neurology 2009;22:1506. 78. Lux AL. Treatment of febrile seizures: historical perspective, current opinions, and potential future directions. Brain and Development 2010;32:4250. 79. King MA, Newton MR, Jackson GD, Fitt GJ, Mitchell A, Silvapulle MJ, et al. Epileptology of the rst seizure presentation: a clinical electroencephalographic and magnetic resonance imaging study of consecutive patients. Lancet 1998;352:100711. 80. Kwan P, Brodie MJ. Early identication of refractory epilepsy. New England Journal of Medicine 2000;342:3149. 81. Dlugos DJ, Sammel MD, Stomb BL, Farrar JT. Response to rst drug trial predicts outcome in childhood temporal lobe epilepsy. Neurology 2001;57: 225964. 82. Schiller Y, Najjar Y. Quantifying response to antiepileptic drugs: effect of past treatment history. Neurology 2008;70:5465. 83. Kwan P, Brodie MJ. Denition of refractory epilepsy: dening the indenable? Lancet Neurology 2010;9:279. 84. Callaghan BC, Anand K, Hesdorffer D, Hauser WA, French JA. Likelihood of seizure remission in an adult population with refractory epilepsy. Annals of Neurology 2007;62:3829. 85. Luciano AL, Shorvon SD. Results of treatment changes in patients with apparently drug-resistant chronic epilepsy. Annals of Neurology 2007;62: 37581.