Mental retardation subsequent to refractory partial seizures in infancy

Brain & Development 22 (2000) 31±34

Original article

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Mental retardation subsequent to refractory partial seizures in infancy Uri Kramer*, Aviva Fattal, Yoram Nevo, Yael Leitner, Shaul Harel Pediatric Neurology Unit and Child Development Center, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Received 28 June 1999; received in revised form 1 September 1999; accepted 2 September 1999

Abstract Whether seizures are the direct cause of cognitive deterioration in epileptic children is undetermined. This retrospective study aimed to delineate a subgroup of pediatric patients with cognitive deterioration and refractory seizures in the absence of recognized causes for mental retardation. Of the 80 children identi®ed as having mental retardation and refractory seizure disorder, seven (8.7%) had normal cognitive development until at least 1 year of age. Their metabolic status was normal. Five of them suffered repeated frequent partial seizures with onset in the ®rst year of life and two had repeated episodes of status epilepticus. All seven had similar characteristics of early onset partial seizures, six of them had partial seizures secondarily generalized and one had complex partial seizures. The time of peak cognitive deterioration correlated with increases in seizure frequency during that period. Evaluation revealed a well-de®ned epileptic focus in the absence of neuroimaging abnormality except for hippocampal atrophy in the two children with complex partial seizures and a small vascular malformation in one child. Uncontrolled partial seizures in the ®rst months of life may result in cognitive deterioration. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Partial; Seizures; Infancy; Mental; Retardation

1. Introduction The risk for epilepsy in children with mental retardation is higher than that among normal children [1,2]. The risk for mental retardation is associated with earlier seizure onset [3] and with associated additional handicaps [4]. Documentation that seizures are the direct cause of cognitive deterioration is lacking [5]. For the most part, both mental retardation and epilepsy are caused by the same etiologies [6]. These include a variety of insults to the developing brain, such as structural brain lesion, infection of the central nervous system, pre/perinatal insult as well as epileptic encephalopathies such as West syndrome [7], Lennox± Gastaut syndrome [8], severe myoclonic epilepsy of infancy [9], electrical status epilepticus in sleep (ESES) [10], and malignant migrating partial seizures in infancy [11]. The neurologist who works with epileptic children often encounters patients with mental retardation whose reason can usually be traced. At other times, however, the etiology is elusive: some of these patients may have had con®rmed episodes of prolonged status epilepticus (SE) while others may have shown some cognitive improvement following the discontinuation of some of the many medications they * Corresponding author. Child Development Center, Beit Habriut Strauss, 14 Balfour Street, Tel Aviv 65211, Israel. Tel.: 1972-3-6974839; fax: 1972-3-620-3177.

take. There remains a small subgroup of patients for whom there is no apparent cause for their cognitive decline other than seizures per se, raising the question that, for them, the cognitive decline might be a consequence of the refractory repetitive seizure disorder. The neurologist is often asked about the associated cognitive outcome of pediatric patients with new onset epilepsy. In the absence of a well-de®ned syndrome or etiology, the common answer is that a cognitive deterioration is unlikely. However, since experienced clinicians know only too well that patients may later manifest cognitive deterioration without displaying any of the foreboding predicting factors, a delineation of this small subgroup needs to be established. The purpose of this retrospective study is to identify the subgroup of patients who are cognitively normal at the onset of an epileptic disease characterized by repetitive seizures but whose cognitive level deteriorates with time for no apparent reason. 2. Patients and methods As of 1995, all patients with epilepsy in our pediatric neurology out-patient clinic are prospectively registered into a computerized database. This database includes all the epileptic children who were seen in this clinic since 1975, and our information was retrieved by means of a

0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0387-760 4(99)00109-6

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U. Kramer et al. / Brain & Development 22 (2000) 31±34

retrospective review of all clinic ®les. In addition, as of 1996, we have been examining refractory seizure patients as part of an evaluation process for epilepsy surgery in a tertiary epilepsy center. For the purpose of the current study, the database was screened for all patients who had both refractory seizures and mental retardation. We de®ned patients as having refractory seizures when they suffered more than one seizure episode per year after unsuccessfully trying four or more different anti-epileptic drugs. Patients with mental retardation were de®ned as such when they scored 70 points or less in a formal IQ test (Stanford Binet Intelligence Scale or Wechsler Preschool and Primary Scale of Intelligence) given by a developmental psychologist. The tests were carried out either in the Child Developmental Center (CDC) of the Tel Aviv Medical Center or in other CDCs in Israel. The patients underwent developmental evaluation while being treated with antiepileptic drugs. Developmental status at the onset of seizures was assessed clinically by a pediatric neurologist during screening for major milestones. The ®les of all the patients who had both refractory seizures and mental retardation were reviewed. It was possible to de®ne the underlying pathological etiology for most patients. Children who had had West syndrome or Lennox± Gastaut syndrome with no known etiology for these encephalopathies were grouped according to the syndromes, otherwise they were grouped according to the de®nitive pathology. In order to select only those patients who could be suspected of having mental retardation due to refractory seizures with or without episodes of SE, we excluded children who had one of the following conditions:

seizure disorder and mental retardation. Among them was a subgroup of seven patients for whom no underlying mechanism for their mental retardation could be determined except for either repeated episodes of status epilepticus (n ˆ 2) or frequent repetitive seizures (n ˆ 5) (the `repeated SE' and the `repetitive seizures' groups, respectively, Table 1). These seven children had either partial seizures secondarily generalized (PSSG, n ˆ 6) or complex partial seizures (CPS, n ˆ 1). All seven patients presented with seizures at the age of 4±7 months (Table 2). Four of them had their ®rst seizures associated with a febrile disease. There were three patients with mild mental retardation and four patients with moderate retardation. The two patients with SE showed cognitive deterioration following episodes of SE while, in the other ®ve, most of the cognitive decline occurred during a period of less than 1 year, correlating with very frequent seizures, at times a few seizures per day. All the members of this subgroup had normal neurological examinations except for motor clumsiness. They all had an epileptic focus responsible for their seizure, with the foci located outside the temporal lobe in six of them. Five of these six patients with an extra-temporal focus had normal MRI studies, while the sixth one had a small single vascular malformation non-congruent with the epileptic focus. The patient with temporal lobe seizures showed unilateral hippocampal atrophy indicative of temporal mesial sclerosis. One patient had recently undergone anterior temporal lobectomy, another underwent anterior callosotomy and, one had insertion of a vagal stimulator.

1. epileptic encephalopathies such as West syndrome, Lennox±Gastaut syndrome, ESES, and severe myoclonic epilepsy of infancy, 2. a history of CNS infection, 3. a suspected neurodegenerative disorder, 4. mental retardation preceding or accompanying the onset of seizures, 5. neurocutaneous disorders, 6. a history of perinatal insult, 7. diffuse or large abnormality in neuroimaging.

4. Discussion

All the patients that were included in the `repetitive seizure' or `status epilepticus' subgroups underwent intensive investigations that included medical history and neurological examination, MRI, blood tests for lactic acid, pyruvic acid, ammonia, amino acids, very long chain fatty acids, and urinalysis for organic acids. All had repeated routine EEGs and all except one also underwent VideoEEG evaluation. 3. Results We identi®ed 80 patients who had both a refractory

The seven patients in the refractory seizures and SE groups presented with seizures prior to the age of 7 months. An onset of seizures in the ®rst year of life is found in 28± Table 1 Etiologies for refractory seizures and mental retardation a Etiology

Number of patients (total n ˆ 80)

Perinatal insult Neurocutaneous syndrome S/P West syndrome S/P CNS infection S/P Lennox±Gastaut Repeated SE Repetitive seizures Genetic syndromes Structural lesions ESES Neurodegenerative Immunization Others

12 12 11 11 10 2 5 4 5 3 2 1 2

a

S/P, status post; SE, status epilepticus; ESES, electrical status epilepticus in sleep.

U. Kramer et al. / Brain & Development 22 (2000) 31±34

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Table 2 Characteristics of patients with mental retardation and no de®ned etiologies a No.

Current age (years)

Age at onset (months)

SE

FC

Type

Focus

Maximum frequency

Peak det (year)

1 2 3 4 5 6 7

4 14 14 8 7 7 8

7 5 6 4 5 4 5

No No No No No Yes Yes

Yes Yes Yes Yes Yes No No

PSSG PSSG CPS PSSG PSSG PSSG PSSG

LC LF LT LF F LP RF

Few/day 10/day Clusters 12/day 30/day ± ±

2 8 2.5 6 5 1 1

a

SE, status epilepticus; FC, febrile convulsions; det., deterioration; CPS, complex partial seizures; PSSG, partial seizures secondarily generalized; L, left, R, right, F, frontal, T, temporal, P, partial; Hem, hemisphere; Meds, medications.

53% of children with combined mental retardation and refractory seizure disorder [6,12]. Two studies showed that an onset of seizures in the ®rst half of the ®rst year carries worse prognosis in terms of seizures persistence and cognitive status at follow-up than seizures with an onset in the second half of the ®rst year [13,14]. All seven of our study patients had partial seizures (PS). PS in the ®rst year of life have worse prognosis than generalized seizures [15±17]. Cognitive outcome in patients with seizures is largely determined by the underlying cause for the seizures and not by the seizures per se [18,19]. There are, however, certain diseases such as Sturge±Weber syndrome or tuberous sclerosis where seizures are known to aggravate cognitive outcome [20,21]. Status epilepticus (SE) may also be the reason for cognitive deterioration [22]. While most authors believe that repetitive brief seizures do not contribute to mental deterioration [22], others showed cognitive decline in a small subgroup of patients with frequent seizures [23,24]. The data presented in the current study suggest that in a small subgroup of patients, i.e. patients with PS presenting in the ®rst months of life, repeated uncontrolled seizures may be the only apparent cause for a cognitive decline. As can be seen from our data, this group is particularly prone to SE. There are established epileptic syndromes such as West syndrome, Lennox±Gastaut syndrome, and ESES that are associated with poor cognitive outcome even in the absence of a well-de®ned etiology. The reason for the additional insult in these syndromes may be the continuous non-convulsive electrical epileptic activity. The reason for the mental retardation in the case of frequent repetitive brief seizures is not clear. Two of our seven study children had a discrete lesion on MRI: one had mesial temporal atrophy and one had small vascular anomaly. In our opinion, such focal pathology would not explain a cognitive regression. The natural history presented by this group of patients suggests that early onset refractory seizure disorder may in itself be responsible for a cognitive decline.

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