Epilepsy&

Epilepsy & Behavior 5 (2004) 67–71

Behavior

www.elsevier.com/locate/yebeh

Pharmacological outcomes in people with mental retardationand epilepsy

Kevin Kelly, Linda J. Stephen, and Martin J. Brodie*

Epilepsy Unit, Division of Cardiovascular and Medical Sciences, Western Infirmary, Glasgow G11 6NT, Scotland, UK

Received 1 August 2003; revised 22 October 2003; accepted 22 October 2003

Abstract

The aim of this study was to examine prospective outcomes in mentally retarded people with epilepsy seen for the first time

during 1998 until the end of 2001. Two hundred and fourteen patients (120 men, 94 women, aged 11–70 years [median 34 years])

were referred over this 4-year period. Median duration of follow-up was 18 months (range, 13–36 months). Seventeen (8%) had

nonepileptic attacks only, 10 of whom were being treated with antiepileptic drugs (AEDs). The remaining 197 (92%) patients had

epilepsy, the majority (n ¼ 151, 77%) presenting with focal seizures. A total of 22 patients were started on AED treatment, with

seizure freedom for at least a year being achieved in 10 (45%). AED manipulation was undertaken in a further 136 patients, resulting

in 59 (43%) becoming seizure-free. No relationship was found between extent of mental retardation and seizure control. There was

no deterioration in mean caregiver scores rating sleep, appetite, alertness, and behavior. These findings suggest that AED therapy

can result in seizure freedom in more than 40% of mentally retarded people with epilepsy without producing unacceptable toxicity.

� 2003 Elsevier Inc. All rights reserved.

Keywords: Epilepsy; Mental retardation; Antiepileptic drugs; Side effects; Death

1. Introduction

Epilepsy is common in people with mental retarda-

tion. More than 30% develop seizures [1], with the

prevalence rising to 50% for institutionalized patients[2]. Obtaining an accurate history can be problematic as

difficulties with communication are common and these

individuals often present with multiple seizure types [3].

Intolerance of investigations, comorbidities, behavioral

factors, psychiatric disorders, concomitant medication,

and difficulties with antiepileptic drug (AED) adherence

and formulations can complicate diagnosis and man-

agement. Uncontrolled seizures and resultant injuriescan impair quality of life [4] and outcomes are com-

monly perceived to be poor [5].

There are few randomized double-blind, placebo-

controlled AED studies in people with mental retarda-

tion and epilepsy [6,7]. Clinicians, therefore, have to

refer to evidence derived from other populations when

* Corresponding author. Fax: +44-141-334-9329.

E-mail address: Martin.J.Brodie@clinmed.gla.ac.uk (M.J. Brodie).

1525-5050/$ - see front matter � 2003 Elsevier Inc. All rights reserved.

doi:10.1016/j.yebeh.2003.10.016

prescribing for these patients. Although modern treat-

ment strategies strive for monotherapy, at least 40% of

mentally retarded patients with epilepsy take more than

one AED [8,9]. In recent years, the scope to provide

better pharmacotherapy has widened with the intro-duction of seven new AEDs in the United Kingdom.

With this in mind, we undertook a prospective outcome

study in all patients with mental retardation and

epilepsy referred to the Epilepsy Unit at the Western

Infirmary in Glasgow, Scotland, over a 4-year period.

2. Methods

All mentally retarded patients referred to our epilepsy

clinics between 1st January 1998 and 31st December

2001 took part in the study. Each had been diagnosed as

mentally retarded and the retardation graded as mild

(IQ 50–70), moderate (IQ 35–49), severe (IQ 20–34), or

profound (IQ <20) by a consultant psychiatrist with a

specialist interest in that discipline [10]. Criteria for re-ferral were a definite or possible first seizure or a known

or possible diagnosis of epilepsy. Patients were reviewed

68 K. Kelly et al. / Epilepsy & Behavior 5 (2004) 67–71

at the clinic within 4 weeks of referral and were asked tobring a family member or caregiver who was familiar

with them and their seizures. A questionnaire was in-

cluded with the clinic appointment requesting demo-

graphic and social details, past medical and drug

history, and information regarding risk factors (e.g.,

birth trauma, febrile convulsions, family history). The

patient�s companion had also been asked by letter to

provide a description of the seizures and to supply awritten record of their frequency over the previous 3

months. The first clinic visit consisted of a consultation

with a doctor and epilepsy nurse specialist. All clinical

information was entered into a computerized database

and a customized case sheet containing copies of all

correspondence and investigations was developed for

each individual.

If the diagnosis was unclear, the patient was revieweduntil a decision was made as to whether or not he or she

had epilepsy. Seizure types and epilepsy syndromes were

classified according to the guidelines of the International

League Against Epilepsy [11]. Electroencephalography

was performed, when clinically appropriate, to aid

classification. Brain imaging was undertaken, when

possible, in patients thought to have localization-related

epilepsy. Patients thought not to have epilepsy werereferred for videotelemetry and psychological or psy-

chiatric assessment when necessary.

All patients and their caregivers were provided with

standard seizure description and frequency charts. Each

family received a telephone contact card, facilitating

support between clinic appointments and enabling rapid

review by the epilepsy nurse specialist if seizure control

deteriorated. The initiation of treatment was consideredfor any patient who had had two or more witnessed sei-

zures. Choice of AED depended on the seizure type and/

or epilepsy syndrome and side-effect and interaction

profiles [12]. Prior to starting treatment, the implications

and prophylactic nature of drug therapy and the common

side effects were discussed. Female patients were given

advice, when appropriate, about teratogenesis and preg-

nancy issues. Written information on these topics wasalso provided, as were leaflets on support organizations.

Adherence to drug regimens was emphasized and

compliance monitored by measuring serum concentra-

tions of AEDs during clinic visits. Doses were titrated

according to efficacy and tolerability. When the first

AED was not well tolerated or ineffective, a second was

substituted. If a poor response was again obtained,

duotherapy was tried [13]. Patients were categorized ashaving refractory epilepsy if they continued to report

seizures despite treatment with three or more AED

schedules [14]. A pharmacological strategy was tailored

for each patient taking AEDs at referral.

Following discussion about possible outcomes, real-

istic goals were set with respect to seizure control and

quality of life issues by the epilepsy nurse specialist.

Between visits, patients and/or caregivers were advisedto keep a record of their seizure description and fre-

quency and caregivers were asked to chart the patient�ssleep, appetite, alertness, and behavior as poor (1),

reasonable (2), or good (3). Clinic visits continued until

it was considered unanimously by patient, family, nurse

specialist, and doctor that an optimal response to

treatment had been obtained. Once seizure freedom or

an acceptable seizure frequency was reached, patientswere followed up for at least 1 year. After this time, they

were discharged to the care of their general practitioner.

The v2 test was used for comparisons of categorical

data. All statistical tests were two-tailed.

3. Results

Two hundred and fourteen consecutive patients (120

men, 94 women; aged 11–70 years [median 34 years])

were included in the outcome study. The majority (90%)

were referred by their general practitioner, with 10%

coming via accident and emergency departments, psy-

chiatrists, and pediatricians. Mild mental retardation

had been diagnosed in 86 (40%), with 47 (22%) being

classified as moderate, 55 (26%) as severe, and 26 (12%)as profound. Most (n ¼ 158, 74%) were referred because

of poor seizure control. Of the remaining 56 (26%), 40

(19%) were referred because of diagnostic issues, 10 of

whom had had a first seizure. Other reasons for review

included possible drug toxicity (n ¼ 6, 2.5%), the need

for counseling and education (n ¼ 5, 2.5%), potential for

AED withdrawal (n ¼ 4, 1.5%), and advice on preg-

nancy (n ¼ 1, 0.5%). Ten (5%) patients were seizure-freeat referral. The median (range) age of initial seizure

onset was 4 (<1–67) years.

Seventeen (8%) patients had nonepileptic attacks

only, 10 of whom were being treated with AEDs.

The remaining 197 (92%) had epilepsy (151 [77%]

partial� secondary generalized seizures, 46 [23%] pri-

mary generalized epilepsy [32 tonic–clonic, 7 myoclonic,

and 2 akinetic seizures], 3 Lennox–Gastaut syndrome, 1Landau–Kleffner syndrome, 1 infantile spasms). At re-

ferral, 170 (86%) patients were receiving AED treat-

ment, 24 (12%) had never been treated, and 3 (2%) had

previously taken AEDs. Median (range) monthly seizure

frequency was 6 (1–140), excluding myoclonic jerks.

A total of 22 patients (14 male, 8 female; aged 14–61

years [median 32 years]) were started on AED treatment

at the clinic. Seven patients had never taken AEDs be-fore. Patients were followed up for a median time of 18

months (range 13–36 months). Seizure freedom for at

least a year was achieved in 10 patients (45%), all with

AED monotherapy. Ten others had P50% reduction in

their seizure frequency at presentation and 2 had <50%

seizure reduction. Pharmacological manipulation was

undertaken in 136 (83%) treated patients. This resulted

Fig. 1. Mean caregiver scores at initial and final visits in all patients

undergoing antiepileptic drug manipulation (A, n ¼ 136) and in those

seizure-free for at least a year (B, n ¼ 69).

Fig. 2. Mean caregiver scores at initial and final visits in all patients

starting antiepileptic drug treatment (A, n ¼ 22) and in those seizure-

free for at least a year (B, n ¼ 10).

K. Kelly et al. / Epilepsy & Behavior 5 (2004) 67–71 69

in 59 (43%) becoming seizure-free for a year or more, 54

(40%) having P50% reduction in seizure frequency, 16(12%) having <50% seizure reduction, and 7 (5%) re-

porting no improvement in seizure control. No rela-

tionship was found between seizure control and extent

of learning disability, neurological deficit, or behavioral

comorbidity.

At presentation, 53 (39%) of the 136 patients who

underwent AED manipulation had been taking one

AED, with 55 (40%) receiving two, 24 (18%) on three,and 4 (3%) on four. At discharge, 24 (18%) were re-

ceiving one AED, 63 (46%) were on two, 41 (30%) were

on three, and 8 (6%) on four. The total number of AEDs

taken by these patients prior to referral was 251, which

had increased at discharge to 305. There was an overall

small nonsignificant improvement in mean caregiver

scores for sleep, appetite, alertness, and behavior at the

end of follow-up compared with scores at the initial visit(Fig. 1). Similarly, no deterioration was observed in

these scores in patients started on AED therapy (Fig. 2).

Brain imaging was undertaken in 104 (53%) patients.

Twenty-eight underwent magnetic resonance imaging

(MRI), 89 computed tomography (CT), and 13 both.

Significant pathology was reported in 49 (47%) patients,

including 8 with cortical dysplasia (8%) and 5 (5%) with

mesial temporal sclerosis. Patients with mild mental re-tardation were just as likely to have abnormal results as

those with more severe deficits (Table 1).

During the study period, 9 (5%) patients died. Five

succumbed to sudden unexpected death in epilepsy

(SUDEP), the diagnosis being supported by autopsy and

toxicology. All but one of the 5 had been seizure-free for

more than 6 months. The other 4 patients died of post-

ictal aspiration pneumonia, cerebral hemorrhage, bron-chopneumonia, and esophageal carcinoma, respectively.

4. Discussion

The majority of our patients had localization-related

epilepsy. Other studies have tended to report a higher

prevalence of idiopathic generalized epilepsies [15–18],although populations are difficult to compare as they

vary in setting and ages of participants, from adults in

institutions to children in the community. Seventeen of

our patients had nonepileptic attacks, 10 of whom were

being treated with AEDs. Psychiatric and behavioral

problems are recognized to complicate the management

of epilepsy in patients with mental retardation [5]. AED

treatment has been linked to these effects in some indi-viduals [19,20].

Although the aims of treatment were to achieve sei-

zure freedom and optimal physical and mental func-

tioning, this is not always possible in patients with

mental retardation [21]. Most treated patients showed

an improvement in seizure control, with 45% becoming

seizure-free and 55% having fewer seizures. Indeed, the

percentage of seizure-free patients was only a little lowerthan that reported in our general epilepsy population,

56% of whom became seizure-free following AED

manipulation [14,22,23]. These results are difficult to

Table 1

Brain imaging in patients with different degrees of mental retardationa

Mild

n ¼ 54 (63%)bModerate

n ¼ 20 (43%)bSevere

n ¼ 22 (40%)bProfound

n ¼ 8 (31%)b

Normal (%) 27 (50) 11 (55) 14 (64) 3 (37.5)

Atrophy (%) 10 (19) 5 (25) 5 (23) 1 (12.5)

Gliosis (%) 6 (11) 0 (0) 0 (0) 1 (12.5)

Mesial temporal sclerosis (%) 3 (5) 0 (0) 1 (4) 1 (12.5)

Hydrocephalus (%) 2 (4) 2 (10) 2 (9) 0 (0)

Infarct (%) 2 (4) 0 (0) 0 (0) 0 (0)

Cortical dysplasia (%) 4 (7) 2 (10) 0 (0) 2 (25)

a There was no statistical significance between presence of neuroimaging abnormalities and degree of mental retardation.b Percentage of patients imaged within this classification of mental retardation.

70 K. Kelly et al. / Epilepsy & Behavior 5 (2004) 67–71

compare with others, as a range of studies have been

performed in patients of varying ages and in different

settings. Brodtkorb found that 23% of institutionalized

mentally retarded adults had been seizure-free for morethan 3 years and were able to have their AED treatment

discontinued [17]. Brorson and Wranne followed up 74

patients with mental retardation over 12 years and ob-

served that 39% were seizure-free [24]. Delgado and

colleagues reported only a 13% two-year remission rate

in 531 children with cerebral palsy [25]. In our clinic

some mentally retarded patients with refractory epilepsy

have responded well to the addition of newer AEDs,such as topiramate [26] and levetiracetam [27].

The importance of quality-of-life assessment as part

of the management of epilepsy in mentally retarded

patients has been emphasized [5,28]. Mean caregiver

scores for sleep, appetite, alertness, and behavior

showed a small nonsignificant improvement at the end

of follow-up compared with at referral. This may reflect

changes made to AED regimens. Similar findings havebeen reported by Mirza and colleagues whose patients

became more sociable and had more positive behavior

with reduction in number of drugs [29]. However, our

population had an increase in number of AEDs, sug-

gesting that the improved scores were the result of better

seizure control. Our results imply that our patients

benefitted from the addition of AEDs to their regimens.

Although polytherapy has generally been regarded asundesirable, it has been shown that there is no conclu-

sive evidence favoring monotherapy over polytherapy

for patients failing initial monotherapy [30].

Brain imaging was performed in more than half the

patients, with 49 having significant pathology. This may

be an underestimate, as most individuals underwent CT

scanning only, which is recognized to be a less sensitive

tool than MRI for detecting brain lesions in people withepilepsy. For patients with neuropathology, imaging

findings helped to define the cause of seizure activity for

the patient, their caregiver, and the clinician. Although

none of our patients in this series underwent assessment

for epilepsy surgery, these results have allowed us to

consider possible surgical management for future pa-

tients with mental retardation.

Nine patients died during the follow-up period, giving

a ratio of 1 death for every 22 patients. Five patients (1

in every 39) succumbed to SUDEP. As uncontrolled

seizures are a risk factor for sudden death [31], thishighlights the importance of achieving good seizure

control. Interestingly, however, 4 of our patients were

reported as having been seizure-free for at least 6

months at the time of their demise. Mortality is recog-

nized to be higher in people with epilepsy compared with

the general population and mental retardation further

increases that risk [32]. Nashef and colleagues found

that the incidence of SUDEP was more than three timesgreater in young people with epilepsy and mental re-

tardation than in people with epilepsy alone [33].

There has been a transformation in the lives of

mentally retarded people in the United Kingdom with

the closure of long-stay institutions and the placing of

clients in the community. For the many with epilepsy,

the burden of care has shifted from an inpatient setting

to general practice surgeries and outpatient clinics. Theintroduction of epilepsy nurse specialists has helped to

bridge the gap between community and hospital settings

[34]. These health care professionals can assess epilepsy

control, quality of life, and medication at home, pro-

viding information, education, and support for patients

and their caregivers [35,36]. It may be that the close

support of the epilepsy nurse specialist in this study had

a positive influence on his patients� quality of life.

5. Conclusions

AED introduction and manipulation resulted in sei-

zure freedom for more than 40% of patients with mental

retardation. Brain imaging was found to be a useful tool

to detect underlying pathology. There is a high risk ofseizure-related death in this population.

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