Clinical Neurology and Neurosurgery xxx (2005) xxx–xxx

Efficacy and tolerability of antiepileptic drugs in anOmani epileptic population

Yolande Hanssensa,∗, Abdullah Al Asmib, Intisar Al Busaidic, Dirk Deleud

a Department of Pharmacy (Clinical Pharmacy Services), Hamad Medical Corporation, P.O. Box 3050, Doha, Qatarb Department of Medicine (Neurology), Sultan Qaboos University Hospital, P.O. Box 38, Al Khod, PC 123, Oman

c Department of Pharmacy, Sultan Qaboos University Hospital, P.O. Box 38, Al Khod, PC 123, Omand Department of Neurology, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar

Received 12 March 2005; received in revised form 9 August 2005; accepted 15 August 2005

Abstract

Objective: The aim of this hospital-based study is to get an insight into the efficacy and tolerability of antiepileptic drugs (AED) in Omaniepileptic patients.Patients and methods:All Omani patients (aged 14 years and above) suffering from epileptic seizures for at least 2 years and followed-upb first visit atS ffect profileswR ommonlyo controlledw follow-upp m valproate( eriod was5 ) and PHT(C ective int©

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y board-certified neurologists in Sultan Qaboos University Hospital (SQUH) were evaluated. The treatment retention rate sinceQUH and over the last 2 years was used as primary efficacy measure of AED therapy. Change in seizure-frequency and side eere also assessed.esults:In this population of 203 confirmed epileptic patients, generalized tonic-clonic (40%) and partial seizures (39%) were most cbserved, idiopathic/cryptogenic origin (81%) being the most frequent encountered origin. Sixty one percent of the patients wereith an AED in monotherapy and overall 34% of patients could be successfully maintained on monotherapy during the wholeeriod at SQUH (median 6 years). The treatment retention rates for carbamazepine (CBZ) at a daily dose of 400–600 mg, sodiuVPA) at a daily dose of 500–1000 mg, and phenytoin (PHT) at a daily dose of 300 mg, in monotherapy over the total follow-up p1, 50, and 21%, respectively. In contrast, over the last 2 years these rates were highest for VPA (91%) followed by CBZ (83%73%). Adverse drug reactions were recorded in 67% of patients, and were most commonly encountered with VPA.onclusions:Despite a higher adverse effect profile for VPA, long-term treatment with CBZ and VPA appeared to be equally eff

erms of treatment retention rates and seizure control.2005 Elsevier B.V. All rights reserved.

eywords:Epilepsy; Efficacy; Tolerability; Antiepileptic drugs; Seizures; Oman

. Introduction

Epilepsy is a chronic disorder characterized by the occur-ence of unprovoked, recurrent seizures, which are theanifestation of abnormal paroxysmal hypersynchronousischarges of cortical neurons. Epidemiological studies

ndicate that 40–70 individuals per 100,000 will developpilepsy each year[1,2]. The incidence rate of epilepsy

s higher in developing countries where it easily exceeds

∗ Corresponding author. Tel.: +974 439 21 86; fax: +974 439 22 53.E-mail address:yhanssens@hmc.org.qa (Y. Hanssens).

65/100,000 compared to its incidence in industrialized ctries (43.4/100,000).

The aim of antiepileptic drug (AED) therapy shouldthe restoration of a normal life through complete seizcontrol, with minimal or no adverse drug reactions (AD[3]. In the majority of these patients, seizures can betrolled on monotherapy usually with the first or second Achosen[4]. However, in up to 30% of patients, seizuare refractory to treatment with a single AED despite omal AED therapy, and others have unacceptable side e[4,5]. Accurate diagnosis of the type of seizure is essebecause antiepileptic drugs (AEDs) are selective. Howclinical studies have shown that some patients pres

303-8467/$ – see front matter © 2005 Elsevier B.V. All rights reserved.oi:10.1016/j.clineuro.2005.08.007

CLINEU-1452; No. of Pages

2 Y. Hanssens et al. / Clinical Neurology and Neurosurgery xxx (2005) xxx–xxx

tailored response to an AED—established AEDs such ascarbamazepine (CBZ), phenytoin (PHT), sodium valproate(VPA), phenobarbital (PB), primidone (PRM), and clon-azepam (CLO) remain the mainstay of treatment. However,treatment with these AEDs is often complicated by sideeffects, the need for plasma drug concentration monitor-ing, interactions with a number of drugs and by failure toadequately control seizures. This may prompt some clini-cians to use newer AEDs such as gabapentin (GBP), lam-otrigine (LTG), levetiracetam (LEV), oxcarbazapine (OXC),tiagabine (TGB), topiramate (TPM), and zonisamide (ZNS).

Situated at the southeastern part of the Arabian Peninsula,the Sultanate of Oman has currently an ethnic population ofabout 2.2 million[6]. Free health care service is provided toall its citizens. In the Sultanate of Oman, the large majority ofneurological patients are treated at the tertiary referral cen-ter, Sultan Qaboos University Hospital (SQUH). All AEDs,established and new generation ones, are available free ofcharge in this institution which is functional since 1989. Thecatchment area for SQUH is estimated approach 300,000 peo-ple [7].

In our pharmacoepidemiological[8] and pharmacoeco-nomic [9] studies, data from 488 adult patients on epilepsyprovided an insight on the disease and AED profile inthis institution. In this rather young epileptic population(median age 24 years), generalized tonic-clonic seizuresw n ani ofp eingt byC

p-t n orJ ment ll asd lationsa n-d Ds.T effi-c ntsf er ap lp inp ula-t

2

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lep-t eanso ndf rol-o uary2 ents

under the care of other specialties were excluded because oflack of or incomplete data on the nature and etiology of theepileptic seizures.

This study was approved by the Medical and Ethics Com-mittee of the College of Medicine and Health Sciences, SultanQaboos University, and included strict confidentiality for allcollected information.

2.2. Data collection

The following data were collected from the patient’s medi-cal record: demographics (age and gender), type and etiologyof epileptic seizures, type of epilepsy, age of onset of seizures,duration of disease and therapy, duration of follow-up atSQUH, seizure frequency at the initial evaluation at SQUHand at the end of the follow-up period. The type of epilepticseizure was grouped according to the revised classificationof the International League Against Epilepsy[12,13]: com-plex partial, simple partial, tonic-clonic, absence, myoclonic,clonic, tonic, atonic, and status. The following etiologieswere considered: brain tumor, degenerative, drug-induced,encephalitis, febrile seizures, idiopathic/cryptogenic, menin-gitis, metabolic/toxic, perinatal event, stroke, systemic dis-ease, and trauma.

2.3. Antiepileptic drug use profile data

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ere most frequently encountered (51%) and this odiopathic/cryptogenic background (83%). The majorityatients (78%) were managed with monotherapy, VPA b

he most commonly prescribed AED (49%), followedBZ (44%), PHT (12%), and LTG (11%).Data on efficacy and tolerability of AEDs in epile

ic patients are almost exclusively based on Westerapanese populations. Based on genetic and environal factors, pharmacokinetic, pharmacodynamic as weisease-related processes differ amongst these popund ours[10,11], possibly leading to distinct populatioependent efficacy and tolerability profiles of these AEherefore, the aim of this study was to evaluate theacy and tolerability of AEDs in Omani epileptic patieollowed-up by board-certified neurologists at SQUH overiod of at least 2 years. Ultimately, these data may heredicting the response for individual AEDs in this pop

ion.

. Materials and methods

.1. Patient population

We reviewed the medical records of all Omani epiic patients (aged 14 years and above) diagnosed by mf EEG and neuroimaging (CT scan or MRI brain) a

ollowed-up for at least 2 years by board-certified neugists at our institution. The data were reviewed in Jan003, and is referred to as ‘end of follow-up period’. Pati

-

The following data were collected: AED regimen at fiisit and at the end of the follow-up period, AED data (dame(s), dose range, and regimen) as well as the nuf AEDs prescribed per patient. In addition, the intervenelated to the adverse drug reaction (ADR) was recorde

.4. Efficacy

The antiepileptic efficacy was measured by treatmetention rate (the percentage of patients which were mained on the same AED therapy since the time fromrst visit at SQUH (referral patients) or start of therapyQUH (de novo patients) and the number of patients sei

ree on a particular AED regimen at the end of the followeriod (ranging between minimum 2 years to a maximf 13 years). To avoid bias and allow standardized com

son of the AED therapy (availability of newer AEDs, sauration of evaluation, same clinical setting), the treatmetention rate for these patients was also assessed ovast 2 years of therapy.

.5. Tolerability

Tolerability was assessed through monitoring of ADecorded in the patients’ files. Special attention was alsoo any significant weight changes. In patients aged 18 ynd above at their first visit at SQUH, a minimal 5% incre

n bodyweight during their follow-up period was consideo be relevant.

Y. Hanssens et al. / Clinical Neurology and Neurosurgery xxx (2005) xxx–xxx 3

2.6. Statistical analysis

Where appropriate, data are given as mean or median(range). Descriptive statistical analysis was carried out usingSPSS.

3. Results

3.1. Patient characteristics

Two hundred and three patients – referred to as the indexpopulation – fulfilled the criteria for inclusion in this study.The patients not included in this study were either notfollowed-up by board-certified neurologists or did not com-plete 2 years of AED therapy. The index population consistedof two subpopulation of patients: those who were diagnosedand treated on their first visit at SQUH (‘de novo patients’),14 (7%) and those already on AED therapy when referred toSQUH (‘referral patients’), 189 (93%). With respect to thedata analysis, no distinction was made.

The demographic characteristics of the index populationat the end of the follow-up period are given inTable 1. Themean age was 30.3 (range 17–78) years with 66% of patientsbeing younger than 30 years of age. Patients were diagnoseda 41)y ears.T as6 rapy( 34)y

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Table 2Seizure and epilepsy characteristics (n= 203)

n (%)

Classification of epileptic seizuresTonic-clonic 81 39.9PSSG 79 38.9Myoclonic 14 6.9PSC 13 6.4Myoclonic + tonic-clonic 11 5.4Clonic 3 1.5Unclassified 2 0.9

Classification of epilepsyCryptogenic focal 103 50.8Juvenile myoclonic 26 12.8Symptomatica 26 12.8Other generalized idiopathic epilepsies 24 11.8Inborn errors 7 3.4Undetermined as to whether focal or generalized 5 2.5Generalized with grand mal 5 2.5Other 7 3.4

EtiologyIdiopathic/cryptogenic 164 80.7Encephalopathy 9 4.4Trauma 7 3.4Stroke 5 2.5Febrile seizures 5 2.5Cerebral malformation 3 1.5Meningitis 3 1.5Perinatal event 3 1.5Brain tumor 2 1.0Degenerative 2 1.0

PSSG, partial seizures progressing to secondary generalized seizures; PSC,partial seizures with complex manifestations.

a Charachterized by seizures with specific modes of presentation.

tic seizures, very closely followed by partial seizures withsecondary generalization (39%). Cryptogenic focal epilep-sies were the most frequent form of epilepsy (51%) followedby juvenile myoclonic epilepsy and symptomatic epilepsy(each 13%). Idiopathic/cryptogenic epilepsy was the mostcommon etiology of epileptic seizures (81%) followed byencephalopathy (4%), trauma and stroke, each less than 3.5%.Four patients with mesial temporal sclerosis were identifiedand classified in the group of febrile convulsions since allof them had a history of febrile convulsions. The group ofcerebral malformations included focal cortical dysplasia (twopatients) and heterotopia (one patient).

3.3. Pharmacoepidemiologic data

3.3.1. Antiepileptic drug utilization patternAt the end of the follow-up period, the number of AEDs

prescribed totaled 287, corresponding to an average of 1.4AEDs per patient. This corresponded with an increase by 11%compared to the average of these patients at their first visit atSQUH. In addition, the number of patients on monotherapyand dual AED therapy, at end of the follow-up period, was115 (61%) and 52 (28%), respectively. Polytherapy (i.e. >3AEDs) was used in only 20 patients (11%), a combination of:

s suffering from epilepsy for a median of 9.5 (range 2–ears and with a median age of onset of 16 (range 0–72) yhe median follow-up of the index population at SQUH w(range 2–13) years and number of years on AED the

including while followed up at SQUH) was 5.5 (range 2–ears.

From the referral population, 148 patients (73%) weronotherapy and 62 patients (33%) were seizure-free a

rst visit at SQUH. The patients lost to follow-up were nigible and equaled less than 5%.

.2. Classification and etiology of epileptic seizures

The types of epileptic seizure, epilepsy type as well atiology are summarized inTable 2. Generalized tonic-cloneizures accounted for almost 40% of all types of ep

able 1emographics of the study population (n= 203).

n (%)

exMale 105 52Female 98 48

ge (years)14–20 28 13.821–30 105 51.31–40 37 18.241–50 19 9.451–60 8 3.961–70 3 1.5>70 3 1.5

4 Y. Hanssens et al. / Clinical Neurology and Neurosurgery xxx (2005) xxx–xxx

Fig. 1. Proportion of patients maintained on initial antiepileptic therapythroughout the follow-up period (median 6 years).

three AEDs in 15 patients (8%), four AEDs in four patients(2%), and six AEDs in 1 patient.

Independent of the AED-use profile (either monotherapyor combination therapy), VPA (34%) was the most frequentlyprescribed AED, followed by CBZ (25%), LTG (12%), PHT(8%), CLO (6%), PRM (3%), and PB (2%) while other AEDsuch as ethosuxemide, GBP, LEV, TPM, vigabatrin, and ZNSwere contributing for 5% to the total AED usage. From 115patients on monotherapy, VPA (41%) and CBZ (39%) werethe most commonly prescribed AEDs in monotherapy, fol-lowed by LTG (10%), PHT (8%), and PB (2%). The mostfrequent prescribed combination therapy of AEDs consistedof VPA/CBZ and VPA/LTG each accounting for 7%, fol-lowed by VPA/CLO (5%).

The commonest doses and or ranges were 400–600 mgfor CBZ, 500–1000 mg for VPA, 300 mg for PHT, and100–200 mg for LTG.

3.4. Efficacy of antiepileptic drug regimens

3.4.1. Evaluation over the entire follow-up periodDuring the follow-up period at SQUH, AED therapy

could be successfully withdrawn in 16 patients (12%), all on

monotherapy. Consequently, these patients were not includedin the AED therapy efficacy analysis.

Independent of the seizure type, 78 patients (48%) stayedon the same AED treatment throughout their follow-up atSQUH (Fig. 1) while 75 patients (37%) required one or moreAED additions. Fifty patients (25%) had one or more AEDdeleted from their regimen.

Table 3shows the treatment retention rates of the differ-ent AEDs and their combination over the whole follow-upperiod and over the last 2 years. These data show that fromall patients evaluated, 34% could be successfully maintainedon monotherapy for several years. Irrespective of the ther-apy and type of seizures, 148 patients (73%) who had beentreated in monotherapy or polytherapy were seizure-free atthe end of the follow-up period. From the 115 patients receiv-ing monotherapy, 96% were seizure-free: CBZ and VPA eachachieved a seizure-free status in 96% of patients, while 100and 91% of patients were seizure-free with PHT and LTG,respectively. Other AEDs were prescribed in less than ninepatients and therefore did not allow meaningful analysis.Fifty percent of patients in whom the AED therapy couldbe withdrawn were on VPA.

3.4.2. Evaluation over the last 2 years of therapyIrrespective of the seizure type, the treatment retention

rates over the last 2 years for the AEDs in monotherapy variedb wedb nr cy oft izure-f

3

ntedw ofAp ntingw 1%f Rsn ts onP

TE

A etentio% (num

ars)]

C 83 (44V 91 (39/P 73 (8/1P 67 (2/3L 88 (7/8C 100 (10V 100 (8/V 00 (11

C obarbi

able 3fficacy data for different AED regimens

ED regimen Retention rate during total follow-upperiod [% (number of patients)]

R[

BZ 51 (37/72)PA 50 (21/42)HT 21 (5/24)B 20 (1/5)TG 67 (2/3)BZ + VPA 11 (1/9)PA + CLO 25 (2/8)PA + LTG NA 1

BZ, carbamazepine; CLO, clonazepam; LTG, lamotrigine; PB, phen

etween 67 and 91% and were highest for VPA, folloy LTG and CBZ (Table 3). Each one of the combinatioegimens had a treatment retention rate of 100%. Efficahe AEDs measured as the number of patients being seree over this last 2-year period, is provided inTable 3.

.5. Tolerability

From the index population, 135 patients (67%) preseith an ADR while being on AED therapy. The distributionDRs according to the AED regimen is given inTable 4. Theercentage of patients on AED in monotherapy preseith non-body weight-related ADR was: 33% for PHT, 2

or VPA, 14% for CBZ, and 9% for LTG. Overall, these ADecessitated change in AED therapy in: 29% of patienHT, 13% on VPA, 11% on CBZ, and 9% on LTG.

n rate over last 2 yearsber of patients)]

Seizure-free at the end of last 2 yeof treatment [% (number of patients

/53) 95 (42/44)43) 95 (37/39)1) 100 (8/8)) 100 (2/2)) 86 (6/7)/10) 80 (8/10)8) 88 (7/8)/11) 82 (9/11)

tal; PHT, phenytoin; VPA, valproate. NA, not applicable.

Y. Hanssens et al. / Clinical Neurology and Neurosurgery xxx (2005) xxx–xxx 5

Table 4Summary of adverse drug reactions (ADR) in relation to AED in monotherapy

ADR AED (n)

VPA (52) CBZ (72) PHT (24) LTG (11) PRI CLO TPM PB (5) Total

Blood – 3 (2 plain and 1 m/r) 1 – – – – – 4BW 41 (9 EC and 32 m/r) 28 (25 plain and 3 m/r) 9 3 1 – – 1 83CNS 9 (4 EC and 5 m/r) 4 (all plain) 4 1 2 2 2 – 24Eye – – 1 – – – – – 1GI 2 (2 m/r) 1 (1 plain) 2 – 1 – – – 6Liver – 2 (2 plain) – – – – – – 2

Total ADR per AED 52 (13 EC and 39 m/r) 38 (34 plain and 4 m/r) 17 4 4 2 2 1 120

BW, body weight; CBZ, carbamazepine; CNS, central nervous system; CLO, clonazepam; GI, gastrointestinal; LTG, lamotrigine; PB, phenobarbital; PHT,phenytoin, PRI, primidone; TPM, topiramate; EC, enteric coated; m/r, modified release; –, none reported;n, number of patients exposed to particular AED asmonotherapy during the course of their treatment.

In 156 patients (77%) aged 18 years and above at theirinitial visit, complete data (at first visit and at end of follow-up) on body weight could be retrieved from the patients’medical records. A significant increase in body weight wasrecorded in 91 patients (58%), which necessitated change inAED therapy in 15% of them. One patient on a combinationVPA/CBZ/PHT had a significant reduction in body weightover the entire follow-up period, while 60 patients (39%)observed no change in body weight.

From the patients receiving monotherapy, 79% takingVPA had significant weight gain while these figures forCBZ, PHT, and LTG were 39, 38, and 27%, respectively.Overall, because of weight gain the treatment was changedin 34 cases (22%) while the dose was reduced in 9 othercases.

4. Discussion

In accordance with our pharmacoepidemiological study[8] and consistent with the Omani population in general[6],the index population was characterized by its young age(over two-thirds of patients were younger than 30 years).The distribution of epileptic seizures in our index popu-lation was quite unique with generalized seizures beingslightly more frequent than partial seizures. Similar find-i therda bor-i h)[ pre-d only2 ro-l yp-t s one ablye tion[

onice frac-

tory seizures versus monotherapy; duration of the trial), orparameters of antiepileptic efficacy are different, it is diffi-cult to compare studies on epileptic patients with one another.Depending on the duration and type of clinical study, sev-eral parameters have been used as measure of antiepilepticefficacy, e.g. (a) time to the achievement of a period of pro-longed remission, 1 year or more; (b) time to first seizure;(c) change in seizure counts and 50% reduction in seizurefrequency; (d) time to withdrawal of the AED due to lack ofefficacy (poor seizure control) or intolerable side-effects, orthe addition of other AEDs whichever is the earliest. The lat-ter parameter being a composite endpoint is well-establishedand also known as the retention time on treatment[17]. Sinceall patients had different follow-up periods in our study, treat-ment retention rate was preferred as a practical measure ofclinical efficacy and utility of the AED therapy. Parameters(a) and (b) have less clinical relevance and cannot be appliedin this study setting. Although parameter (c) adds little to thequality of life of patients, it is a pragmatic measure of eval-uating antiepileptic efficacy and was therefore included assecondary parameter. Other parameters included, e.g. num-ber of additions or deletions of AEDs.

About 75% of patients took one AED at their initial visit atSQUH, which at the end of the follow-up period was substan-tially reduced by almost 20%. The increase in dual therapyand polytherapy was probably explained by the fact that mostp olledo onp epi-d onp yt ntsa d-upb mio-l andi road-s ibedV ngec etics

ngs were reported in epidemiological surveys from oeveloping countries in the geographical region[14] as wells in a large hospital-based study performed in neigh

ng Saudi Arabia (King Khalid University Hospital, Riyad15]. The causes of symptomatic epilepsies revealed aominance of cryptogenic and inherited factors and0% of the index population had an identifiable neu

ogic or systemic disorder. In our study, the rate of crogenic and inherited forms was higher than in studiepileptic patients originating from the West, and is probxplained by a higher rate of consanguinity in our popula16].

Since each patient population (newly versus chrpileptic patients), study design (add-on therapy for re

atients were referral patients, presenting with uncontrr refractory seizures. VPA was by far the most commrescribed AED. However, in contrast to our pharmacoemiological study, CBZ and VPA were equally commrescribed AED in monotherapy[8]. This is explained b

he fact that this study did not include all epileptic patiet SQUH but only those classified, treated and followey board-certified neurologists. In our pharmacoepide

ogical study, epileptic patients seen by psychiatristsnternists were also included but were – because of the bpectrum antiepileptic properties – predominantly prescrPA. With respect to the dose of CBZ and PHT, the raonfirmed the findings from our population pharmacokintudy[10,11].

6 Y. Hanssens et al. / Clinical Neurology and Neurosurgery xxx (2005) xxx–xxx

In published clinical trials – exclusively originating fromCaucasian or Japanese populations – treatment retention ratesof 30% at a median of 2.5 years are considered to be relevant[18]. Our population of epileptic patients had treatment reten-tion rates which were much higher and this over a mediantreatment period of 5.5 years. This is likely to be based on abetter clinical response and tolerability to AEDs of our pop-ulation. Not surprisingly, the treatment retention rates werehigher over the 2-year period compared with the total follow-up period. Considering the patients on AED in monotherapyin our population, VPA appeared to be more effective at short-term than CBZ and equally effective as CBZ at long-term.The results of our study correlate with findings from West-ern populations in which these AEDs in monotherapy controlseizures in 50–70% of patients[19–21].

Compared to CBZ and VPA, the numbers of patientson PHT and PB were much smaller and at the end of thefollow-up period very few patients remained on PHT or PB inmonotherapy. This can be explained by the unfavorable sideeffect profile of these AEDs. The number of patients takingCBZ, PHT, and PB reduced markedly during the follow-upat SQUH, this to the advantage of VPA and LTG. Probablythe broad antiepileptic properties of VPA and more favorablyside effect profile of LTG in this population explains this shift.

Over 70% of patients on an AED in monotherapy or poly-therapy became seizure-free while in another 8% the AEDt icatet ed-io ddi-t am,c ringf butd eso zeds xpe-r ames count[ 6%[ nd isl .

idee Ta ersee , then reg-i nd1 DRr liket apy[ . Ina VPAh ce ofwd ind-i s,

which are known to be involved in pancreatic�-cell regu-lation and insulin secretion[31]. Also in this population ofpatients weight gain was significant and occurred in almost60% of patients treated with AEDs (particularly VPA, CBZ,and PHT). The monotherapy data indicated that VPA wasassociated with 40% higher rate in weight gain compared tothe other AEDs. These findings correspond with those froma Canadian study where significant weight gain was foundin 71 and 43% of patients with VPA and CBZ, respectively[32]. Unlike in the Canadian study, weight gain was mostlyaccepted by our patients and necessitated change in therapyin only one-fifth of them.

The limitations of this study include its retrospectivenature based on review of medical records. However, thestudy forms a ‘reality check’ away from the artificial con-ditions of clinical studies. Under these circumstances, andaway from the rigid framework of clinical trials, no limita-tions are imposed on neurologist and patient, and treatmentscan be adjusted, changed or withdrawn whenever judged nec-essary. Admittedly, certain biases have to be considered, e.g.availability of newer drugs leaving the option to the treat-ing neurologist to shift to more convenient AED regimens.However, overall relatively few new AED were introduced inour patients’ regimen over the follow-up period. The omis-sion of patients not followed-up by board-certified neurol-ogists forms a large bias in terms of number of patients noti dataf revi-o werew se ac , ourp ch oft

5

apst nsea etics piteb ng-t ianp ials.T entsw allp d ont to bee itsh herr weds on-p lation[ -a tablee

herapy was successfully withdrawn. Literature data indhat in over 60% of patients who remain seizure-free, the mcation can eventually be withdrawn successfully[22,23]. Inur population, the withdrawal rate was lower, which in a

ion to a more cautious approach from the neurology teould be explained by the high numbers of patients sufferom cryptogenic epilepsies which are easy to control,ifficult to withdraw from AED therapy. Long-term studif VPA in monotherapy in epileptic patients with generalieizures inadequately controlled with other AEDs or eiencing ADRs, revealed that 70–83% of patients beceizure-free or had at least a 50% reduction in seizure24,25]. Similar studies for CBZ show values of up to 726]. These values are much higher in our population aikely to be an example of pharmacogenetic differences

Up to 60% of patients with seizures report having sffects with AEDs[27]. In this study, patients taking PHnd VPA had a higher incidence of mild to moderate advvents than those treated with CBZ or LTG. Despite thisumber of patients necessitating a change in their drug

men while taking VPA or CBZ was comparable (arou2%). Although commonly reported, there were no Aeports of skin rash while on CBZ therapy and no ADRshrombocytopenia, hair loss or tremor while on VPA ther28,29]. Many AEDs are known to increase body weightddition to increases in serum leptin levels, the use ofas traditionally been associated with a greater incideneight gain than that of other AEDs[30]. VPA, a fatty aciderivative, competes with free fatty acids for albumin b

ng, and acts as a�-aminobutyric acid agonist, mechanism

ncluded in the evaluation. However, when reviewing therom these excluded patients, and confirmed by our pus study, it appears that over 90% of these patientsell-controlled on monotherapy and hence, did not pohallenge for the neurology team. In the current studyatients required a more intricate therapeutical approa

heir epileptic seizures.

. Conclusions

Genetic variability is one of the contributing and perhhe major underlying cause of differences in AED respond resistance[33]. Hence the relevance of pharmacogentudies of epileptic patients in different populations. Deseing a retrospective study we provided for the first time lo

erm efficacy data of AEDs in a population of the Arabeninsula, usually deprived from early stage clinical trhe data indicate that two thirds of the epileptic patiere controlled with an AED in monotherapy, and fromatients evaluated 34% could be successfully maintaine

his therapy for several years. CBZ and VPA appearedqually effective in terms of seizure reduction. Despiteigher adverse effect profile, VPA proved to have a higetention rate than CBZ over 2 years of treatment but shoimilar treatment retention rate as CBZ at long-term. Nharmacological strategies such as vagus nerve stimu

34] and direct deep brain stimulation[35] are now availble, and serve as useful alternatives in medically intracpileptic seizures.

Y. Hanssens et al. / Clinical Neurology and Neurosurgery xxx (2005) xxx–xxx 7

Acknowledgements

We would like to thank Mr. Kassim Al-Riyami, chiefpharmacist at SQUH for his support and the staff of Medi-cal Records at Sultan Qaboos University Hospital for theirunlimited help in providing access to the patients’ medi-cal files. This study was supported by the research grant:IG/MED/DEAN/03/01, Sultan Qaboos University.

References

[1] Kotsopoulos IA, van Merode T, Kessels FG, de Krom MC, Knot-tnerus JA. Systematic review and meta-analysis of incidence studiesof epilepsy and unprovoked seizures. Epilepsia 2002;43:1402–9.

[2] Sander JW, Shorvon SD. Epidemiology of the epilepsies. J NeurolNeurosurg Psychiatry 1996;61:433–43.

[3] Brodie MJ, Kwan P. Staged approach to epilepsy management. Neu-rology 2002;58(Suppl. 5):2–8.

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

[5] Beghi E, Di Mascio R, Tognoni G. Drug treatment of epilepsy:outlines, criticism and perspectives. Drugs 1986;31:249–65.

[6] http://www.nationbynation.com [accessed 24 July 2004].[7] Hanssens Y, Deleu D, Taqi A. Etiologic and demographic charac-

teristics of poisoning: a prospective hospital-based study in Oman.J Toxicol Clin Toxicol 2001;39:371–80.

[8] Hanssens Y, Deleu D, Al Balushi K, Al Hashar A, Al-Zakwani I.Drug utilization pattern of anti-epileptic drugs: a pharmacoepidemi-

Al-tors

[ ofClin

[ a-ents.:186.

[ nalelec-epsia

[ onaln of.

[ mi-udies

[ ,con-

[[ ovo.

[18] Chadwick D. Monotherapy clinical trials of new antiepileptic drugs:design, indications, and controversies. Epilepsia 1997;38(Suppl.9):16–20.

[19] Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-EscuetaAV, Browne TR, et al. Comparison of carbamazepine, phenobarbi-tal, phenytoin, and primidone in partial and secondarily generalizedtonic-clonic seizures. N Engl J Med 1985;313:145–51.

[20] Sander JW. Some aspects of prognosis in the epilepsies: a review.Epilepsia 1993;34:1007–16.

[21] Mattson RH, Cramer JA, Collins JF. Prognosis for total control ofcomplex partial and secondarily generalized tonic clonic seizuresDepartment of Veterans Affairs Epilepsy Cooperative Studies No.118 and No. 264 Group. Neurology 1996;47:68–76.

[22] Dean JC, Penry JK. Discontinuation of antiepileptic drugs. In:Levy RH, Dreifuss FE, Mattson RH, Meldrum BS, Penry JK, edi-tors. Antiepileptic drugs. 3rd ed. New York: Raven Press; 1999.p. 133–42.

[23] Medical Research Council Antiepileptic Drug Withdrawal StudyGroup. Randomised study of antiepileptic drug withdrawal in remis-sion. Lancet 1991;337:1175–80.

[24] Bourgeois B, Beaumanoir A, Blajev B, de la Cruz N, Despland PA,Egli M, et al. Monotherapy with valproate in primary generalizedepilepsies. Epilepsia 1987;28(Suppl. 2):S8–11.

[25] Hassan MN, Laljee HC, Parsonage MJ. Sodium valproate in thetreatment of resistant epilepsy. Acta Neurol Scand 1976;54:209–18.

[26] Andersen EB, Philbert A, Klee JG. Carbamazepine monotherapy inepileptic out-patients. Acta Neurol Scand Suppl 1983;94:29–34.

[27] Curry WJ, Kulling DL. Newer antiepileptic drugs: gabapentin, lam-otrigine, felbamate, topiramate and fosphenytoin. Am Fam Physician1998;57:513–20.

[28] Collaborative Group for Epidemiology of Epilepsy. Adverse reac-ith

.[ ntre

adulteu-

[ S.ther-

[ I,ls in;51:

[ ptictudy.

[ dlede of

[ N,fectspsy.

[ timu-n of

ologic study in Oman. J Clin Pharm Ther 2002;27:357–64.[9] Al-Zakwani I, Hanssens Y, Deleu D, Cohen A, McGhan W,

Balushi K, et al. Annual direct medical cost and contributing facto total cost of epilepsy in Oman. Seizure 2003;12:555–60.

10] Deleu D, Aarons L, Ahmed IA. Population pharmacokineticsfree-carbamazepine in adult Omani epileptic patients. Eur JPharmacol 2001;57:243–8.

11] Deleu D, Aarons L, Ahmed IA. Estimation of population pharmcokinetic parameters of free-phenytoin in adult epileptic patiArch Med Res 2005;36:49–53. Erratum: Arch Med Res 2005;36

12] Commission on Classification Terminology of the InternatioLeague Against Epilepsy. Proposal for revised clinical andtroencephalographic classification of epileptic seizures. Epil1981;22:489–501.

13] Commission on Classification and Terminology of the InternatiLeague Against Epilepsy. Proposal for revised classificatioepilepsies and epileptic syndromes. Epilepsia 1989;30:389–99

14] Aziz H, Guvener A, Akhtar SW, Hasan KZ. Comparative epideology of epilepsy in Pakistan and Turkey: population-based stusing identical protocols. Epilepsia 1997;38:716–22.

15] Abduljabbar M, Ogunniyi A, Daif AK, Al-Tahan A, Al-Bunyan MAl-Rajeh S. Epilepsy classification and factors associated withtrol in Saudi adult patients. Seizure 1998;7:501–4.

16] Chadwick DW. Diagnosis of epilepsy. Lancet 1990;336:291–5.17] Kalviainen R. Monotherapy trial design: conversion versus de n

Epilepsy Res 2001;45:75–8.

tions to antiepileptic drugs: a follow-up study of 355 patients wchronic antiepileptic drug treatment. Epilepsia 1988;29:787–93

29] Richens A, Davidson DL, Cartlidge NE, Easter DJ. A multicecomparative trial of sodium valproate and carbamazepine inonset epilepsy Adult EPITEG Collaborative Group. J Neurol Nrosurg Psychiatry 1994;57:682–7.

30] Biton V, Mirza W, Montouris G, Vuong A, Hammer AE, Barrett PWeight change associated with valproate and lamotrigine monoapy in patients with epilepsy. Neurology 2001;56:172–7.

31] Luef G, Abraham I, Hoppichler F, Trinka E, UnterbergerBauer G, et al. Increase in postprandial serum insulin leveepileptic patients with valproic acid therapy. Metabolism 20021274–8.

32] Corman CL, Leung NM, Guberman AH. Weight gain in epilepatients during treatment with valproic acid: a retrospective sCan J Neurol Sci 1997;24:240–4.

33] Ebert U, Loscher W. Characterization of phenytoin-resistant kinrats, a new model of drug-resistant partial epilepsy: influencgenetic factors. Epilepsy Res 1999;33:217–26.

34] Chkhenkeli SA, Sramka M, Lortkipanidze GS, Rakviashvili TBregvadze ESh, Magalashvili GE, et al. Electrophysiological efand clinical results of direct brain stimulation for intractable epileClin Neurol Neurosurg 2004;106:318–29.

35] Tanganelli P, Ferrero S, Colotto P, Regesta G. Vagus nerve slation for treatment of medically intractable seizures Evaluatiolong-term outcome. Clin Neurol Neurosurg 2002;105:9–13.