Scholarly article on topic 'Early predictors of outcome in newly diagnosed epilepsy'

Early predictors of outcome in newly diagnosed epilepsy Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Rajiv Mohanraj, Martin J. Brodie

Abstract Longitudinal studies of newly diagnosed epilepsy in children and adults have identified prognostic factors that allow early identification 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, specific 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 findings 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.

Academic research paper on topic "Early predictors of outcome in newly diagnosed epilepsy"

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Seizure

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

Review

Early predictors of outcome in newly diagnosed epilepsy

Rajiv Mohanraja, Martin J. Brodieb *

a Salford Royal Hospital, England, UK b Epilepsy Unit, Western Infirmary, Glasgow, Scotland, UK

ARTICLE INFO

ABSTRACT

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 identified prognostic factors that allow early identification 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, specific 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 findings 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 difficult to treat could benefit from non-pharmacological strategies, especially epilepsy surgery, which still remains one of the most underutilised effective treatment modalities worldwide.7,8 Early identification 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

* Corresponding author at: Epilepsy Unit, Western Infirmary, 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).

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 identified 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 conflicting. 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-defined epilepsy (electroclinical) syndromes separately can provide better prognostic information, but accurate classification 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 defined population over a fixed 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

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

List of studies of outcomes in adult epilepsy. Studies from the same population have been grouped together. Studies marked with * (asterix) also inlcuded children.

Recruitment Inclusion period criteria

Exclusion criteria

Type of study Setting

Epilepsy

Follow up

Method of follow-up

n with outcome

Outcomes

Prognostic factors identified

Annegers et al.13

1935-74

Elwes et al.15

Collaborative group18

Cockerell et al.*23

Cockerell et al.*

MacDonald*

Stephen et al.33

1984-97

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

Single seizures

Retrospective Community 618

5-20 years

Chart review

Not stated

Previously untreated epilepsy

Previously untreated afebrile seizures

1984-87 Definite

epilepsy as judged by panel

None stated

Prospective

Clinic

6-106 month

Clinical review

AEDs started >3 Prospective

months

before

enrolment

Polytherapy as

initial

treatment

Prophylactic use of AEDs

Provoked seizures

Expert panel disagree with diagnosis of epilepsy

Clinic

(median)

6 monthly review

Prospective

Community 1091

Newly diagnosed localisation related peilepsy

None stated Retrospective Clinic

564 definite epilepsy

228 - probable epilepsy

Localisation

reltated

epilepsy

6 years

9 years 12 years

Median 5(2-15)

Contact primary care physician

Chart review

Perinatal insult causing physical and intellectual handicap worst outcomes (46% remission)

Post natal acquired epilepsy and idiopathi epilepsy 74% remission

76% by 20 years

82% 2 year sf Poor prognosis periods by 8 years associated with of fu

5 year remission

65% by 10 years

35% immediate responders 28% SF throughout

1-year remission 62% at 1 year, 81% by 2

Years, 92% by 3 years, and 98% by 5 years

3-year remission 92% 5 year remission 78% 22.1% not SF on monotherapy

5 year remission

Partial seizures

High frequency of tonic-clonic seizures before treatment

A neurologic, social, or psychiatric handicap A family history of epilepsy

Remission less likely with multiple seizure types, higher number of seizures before treatment

Number of seizures in the first year of AED treatment correlated with risk of refractory epilepsy

Age and seizure type no effect on outcomes

Idiopathic seizures 69%

Remote symptomatic epilepsy 61%

No difference between cryptogenic and symptomatic LRE

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

MTS worse than other causes of LRE

But 30% were already on treatement

Kwan & 1984-1997 Newly None Prospective Clinic 629

Brodie80 diagnosed

epilepsy

Hitiris 1981-2001 New diagnosis None Retrospective Clinic 890

et al.66 of epilepsy

Mohanraj & Brodie67

Del Felice 1989-99 Newly

et al.*88 diagnosed

epilepsy

None stated Retrospective Clinic 352

5 years (range 2-16)

Chart review

79 months median

Chart review

Upto 10 years Chart review

Seizure free rates worse for MTS 42%

AVM 78% Infarction 63% Primary brain tumour 57% Cortical Gliosis 57%

Cerebral atrophy 55%

Cortical dysplasia 54%

Refractory epilepsy more likely in Symptomatic / cryptogenic (40%) than idiopathic (26%) More than 20 pretreatment seizures (51% v/s 29%) 47% seizure free on first AED 14% on second or 3rd AED

3% seizure free on

combination

therapy

59.2% seizure free Uncontrolled epilepsy

Poor prognosis associated with

Higher number of seizures and poor response to initial monotherapy

for at least 12 months

23.0% achieved early remission (immediate seizure control after start of AED)

associated with

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 deficit and mental retardation.

Late remission associated with

Recruitment Inclusion period criteria

Exclusion criteria

Type of study Setting

Epilepsy type

Follow up

Method of follow-up

n with outcome

Outcomes

Prognostic factors identified

Lindsten et al.45

1985-87

Diagnosis of epilepsy

Provoked seizures

Retrospective Clinic

1-12 years (range)

Chart review

Schiller and Najjar82

1999-2004 Commencing AED therapy

None stated Prospective

Clinic

1.5 to 7.5

Clinical review 478

10.8% achieved late remission (remission after >24 months after start of AED)

1 year remission 68%

3 year remission 64%

5 year remission 58%

Seizure free rates dropped with sequential failure of AED

41.7%, after one AED

16.6%, after 2-5 AED

0% after 6-7 AED

Increased number of partial seizures

Odds ratio (OR) of late remission

2.7 for patients with 25 partial seizures 6.7 in patients with >5 partial seizures Age, aetiology, EEG, neurologic/psychiatric abnormality, disease duration, seizure types not associated with outcomes

Seizures in the first

year after starting AED

predictive of never

achieving 1 year

remission

Not predictive of

remission:

Age at diagnosis,

Seizure type,

Etiology

Response to past AEDs

Type of epilepsy

Duration of epilepsy

Number of seizures in the 3 months prior to AED initiation

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 defined 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 findings 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 significant effect of seizure types on prognosis. In the population based study in Rochester, Minnesota, Annegers and colleagues found that patients with generalised tonic-clonic 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 tonic-clonic seizures.14 These low numbers can be, in part, explained by the inclusion of patients who had already failed their first treatment schedule. Smaller clinic-based studies, however, have also supported this finding.15,16

Patients experiencing multiple seizure types also appear to have worse outcomes in adults17-19 and children.20-22 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.23-25 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.16,27-31 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 identification of well defined electro-clinical syndromes can allow more accurate assessment of prognosis. This is more pertinent to paediatric cases, where epilepsy syndromes are generally better defined. 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 significant heterogeneity existed between various cohorts in inclusion criteria and definition of remission.37 As a result the reported remission rates ranged from 21% to 89%. Development of tonic-clonic 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 identified 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 first 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 reflection of the epilepsy syndromes that are prevalent among the various age groups. Mixed cohorts of various epilepsy syndromes cannot reflect 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

List of studies of outcomes in paediatric epilepsy. Studies from the same population have been grouped together.

Study Recruitment Inclusion Exclusion criteria: Type of study Setting n Epilepsy

period criteria: type

Arts et al.69 1 988-92 Newly None stated Prospective Clinic 494 Mixed

diagnosed epilepsy

Arts et al.91

1988-92

Diagnosis of epilepsy made in the study period

Panel judged not epilepsy

Prospective

Clinic

494 Mixed

Geerts et al.2:

1988-92

As above

As above

Prospective

Clinic

415 Mixed

Camfield et al.64

1977-85

Children with 2 or more unprovoked seizures in the recruitment period Follow up available 2-12 years

Myloclonic, absence, tonic seizures

Progressive brain disease

Unknown pre treatment seizure number

Prospective Community 479 Mixed

Follow up Method of n with Outcomes Prognostic

follow-up outcome factors

2 years

Structured review

5 years

14.8 years mean

Active follow up at 6 months and 2 years

Postal

questionnaire

2-12 years (median not stated)

Structured review for 5 years

Postal

questionnaires at year 10 and 15

Chart review

Contact with primary care physician

31% poor outcome

(Did not achieve 6 m remission by 2 years)

345 (76%) in terminal

remission >1 year at 5 yrs FU 290(64%)> 2years

65 (14%) no seizures since start of follow up 108 (24%) with TR < 1 year at 5 years, 27 intractable

Five-year terminal remission (TR) was reached by 71% of the cohort. Course during

Intake variables associated with poor outcome

Number of seizures

Seizure types Aetiology

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

70% seizure free and attempted drug withdrawal

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

Associations with failure to achieve terminal remission

Non-idiopathic etiology

Febrile seizures No 3 month remission Early intractability

No effect of number of pretreatment seizures on prognosis for seizure control, up to 10 pre treatment seizures

Camfield et al."

1977-85

Children with 2 or more unprovoked seizures in the recruitment period Follow up available 2-12 years

Myloclonic, absence, tonic

Progressive brain disease

Prospective Community 417 Mixed

Unknown pre treatment seizure number

Ma et al.100 2000-2004 Children None stated Retrospective Clinic 520 Mixed

diagnosed with epilepsy in the study period

Ollivier 2000-2008 CAE treated Brain disorders Retrospective Clinic 235 CAE treated

et al.101 with Valproate apart from with

developmental valproate delay and ADHD

Berg et al.3

Berg et al."

1993-97

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

92 =/- 26 months

Chart review

Contact with primary care physician

months

(range)

Chart review 520 (89%)

No difference between patients suffering up to 10 pretreatment seizures and those suffering fewer

61% seizure free on first drug and withdrew medication

Only 41% of those failing first AED became seizure free with second AED

29% of those failing first AED developed refractory epilepsy

344 seizure free with first drug

Presence of neurological deficits and complex partial seizures associated with failure of first AED

Patients with symptomatic epilepsy (60.3%)

Not stated

Chart review

58.3% achieved seizure freedom

Cryptogenic epilepsy (61.5%)

Less likely to become seizure free Idiopathic epilepsy (73.8%)

Generalised tonic clonic seizures

High frequency of seizures (>10/day) at diagnosis Younger age at diagnosis - associated with failure to respond to VPA

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

34.6% with cryptogenic I symptomatic generalised

Initial seizure frequency

Recruitment period

Inclusion criteria:

Exclusion criteria: Type of study Setting

Epilepsy

Follow up

Method of follow-up

n with outcome

Outcomes

Prognostic factors

Berg et al.1

Oskoui et al.21

1991-2000

Sillanpaa & Schmidt90

1965-2008

Communication and geographical factors limiting follow up

Recurrent unprovoked seizure Age 2-17

Single seizures

Seizures starting out with age range

Retrospective Clinic

240 Mixed

55 months (mean)

Chart review

Minimum 2 years follow up

Age 15 or less

2 or more seizures Living in defined geographical

Prospective

Community 150 Mixed based

11-42 years, median 40 years

Structured review

2.7% of idiopathic Focal EEG slowing

10.7% with other loc rel

8.2% oc

unclassified

epilepsy

52.6% were in remission

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

67% terminal remission

Acute symptomatic / neonatal status epileticus bad Age of onset 5-9 years good

Total number of seizures, / febrile status no increased risk

Factors predictive of intractability

Multiple seizure types (hazard ratio 6.5)

Mental retardation at onset (hazard ratio 7.2)

Seizure recurrence in the first 6 to 12 months of treatment (hazard ratio 70)

Weekly seizure frequency in the first year on treatment

Repeated seizures have been shown to produce neuronal loss and mossy fibre sprouting in the hippocampus, which in turn can reinforce their production forming excitatory recurrent cir-cuits.51,52 Cross-sectional magnetic resonance imaging (MRI) studies have demonstrated smaller hippocampal volumes ipsilat-eral 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 first unprovoked seizure has been shown not to affect the long-term outcome, in spite of preventing seizures in the short term.58-61 Several groups have shown a relationship of high initial seizure frequency with poor outcome.18,27,49,62-66 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 pharma-coresistant, and supports the view that the prognosis of each epilepsy syndrome may be a characteristic of that specific disorder.68

6. Concomitant morbidity

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 deficit, 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 significant effect of neurological or intellectual deficits 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 co-morbidity was significantly 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

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 deficit, and those with a family history of epilepsy in a first 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. Electroencephalographs findings

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 first drug

Several studies have found the response to the first AED to be the strongest predictor of long-term outlook in adults and children.27,64,80-82 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 efficacy 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 first 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 first, 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 definition of drug-resistant epilepsy recommends that failure to gain seizure control for at least one year with the first

2 tolerated, appropriately chosen and used AED schedules (whether as monotherapy or in combination) should prompt referral for specialist review for confirmation of the diagnosis for seizure and/or syndrome classification 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 definition 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 efficacy and duration of epilepsy for more than 5 years before entering remission were identified 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 first 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 final 24.8% being refractory de novo.12

11. Genetics of drug resistance

Pharmacogenetics is the study of genetic influences on the pharmacokinetics and pharmacodynamics of medications. This field 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 efficacy 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 influences.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 identification 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 identified several factors that correlate with a poor prognosis in children and adults, although some of this data is conflicting. More long-term studies are required to assess the prognosis of each epilepsy syndrome. Pharmacogenomic studies employing more sophisticated geno-typing and bioinformatics technologies promise greater predictability of response to individual AEDs. Other possibilities include the identification 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 long-term outlook of newly diagnosed epilepsy. Patients who do not achieve complete seizure control with the first two appropriate regimens of AEDs in the first 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 efficacy/tolerability profiles 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. MartinJ. Brodie has served on scientific advisory boards for Pfizer Inc., UCB Pharma, Eisai, GlaxoSmithKline, Novartis, Valeant Pharmaceuticals, Sanofi 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.

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