Clinical course of untreated tonic-clonic seizures in childhood: prospective, hospital based study

Introduction

Untreated epilepsy may be thought of as a progressive disorder. Such a view has emerged from the observation by Elwes et al that untreated epilepsy shows an accelerating pattern.1 They found that intervals between successive untreated seizures decreased in many patients. In addition, a larger number of seizures before starting treatment seemed to be associated with a poorer control of seizures.2 If these observations are correct, an aggressive approach may be appropriate, as has been advocated by Reynolds et al, who advised starting treatment as soon as possible, preferably after the first seizure, to prevent the development of intractable epilepsy.3 4 5 Early treatment for all patients with newly diagnosed seizures has considerable consequences, however, as all antiepileptic drugs have side effects. A randomised trial comparing early and delayed treatment, the multicentre study of epilepsy and single seizures, is being conducted by D Chadwick.

Intervals between seizures may vary. Patients with accelerating patterns–shortening intervals between seizures–may be more likely to be referred and treated. The retrospective study by Elwes et al 1 was confined to patients for whom the decision to start treatment had already been made. Patients with accelerating seizure patterns may have been overrepresented, and it is doubtful that these findings could be applied to newly diagnosed patients.

The uncertainty about the clinical course of epilepsy and the possible clinical consequences of early treatment of all patients prompted us to study the pattern of seizures in a cohort of children with newly diagnosed, unprovoked tonic-clonic seizures.

Methods

This study is part of the prospective, multicentre Dutch study of epilepsy in childhood, which started in 1988. We enrolled all children aged 1 month to 16 years with newly diagnosed single seizures or epilepsy who had been referred to two university hospitals, a general hospital, and a children's hospital in the Netherlands up to August 1992. The main aims were to study the prognosis of single seizures, the prognosis of newly diagnosed epilepsy, and the consequences of early withdrawal of antiepileptic drugs in children who responded well to treatment. The study was approved by the medical ethical committees of the participating hospitals. Most children were referred directly by their general practitioners; some were seen in casualty departments, and some were referred by paediatricians.

A committee of three child neurologists judged whether the description of the ictal events fulfilled the predefined descriptive diagnostic criteria adapted from van Donselaar et al.6 Children with neonatal, febrile or other acute symptomatic seizures were excluded, as were children who were referred from other hospitals. The panel assessed the diagnosis of epilepsy, classified the seizures according to the revised classification of the International League Against Epilepsy,7 and categorised the epilepsies according to the criteria proposed by Gastaut.8 Etiology was classified as remote symptomatic or idiopathic.9 Children with single seizures were not treated with antiepileptic drugs, but the attending child neurologists were free to start or to delay treatment in children presenting with a status epilepticus or in children who had suffered two seizures or more.

Of the 563 children who were enrolled between 1 August 1988 and 1 August 1992, 261 children had seizures of only the tonic-clonic type, including seizures with partial onset. We excluded 57 of these patients because no accurate data on numbers and dates of all seizures could be obtained. The remaining 204 children formed our study group; table 1 presents their main characteristics. Children enrolled in this study were seen at an early stage of their disease. The mean interval between the first ever seizure and time of recruitment was 4.5 months for all 563 patients, 1.4 months for the study population, and 9.2 months for the 57 children excluded because accurate data were lacking. All children were followed until the occurrence of the fourth untreated seizure, the start of drug treatment, or the end of the follow up period of two years, whichever came first.

Multiple seizures within 24 hours were considered as separate events and a status epilepticus as a single event. Disease pattern was categorised as uncertain if the child was given drug treatment after the first, second, or third seizure. We classified the pattern as decelerating if the child became free of seizures without drugs. In cases with four seizures or more the pattern was classified as decelerating if the time intervals from the first ever seizure successively increased and as accelerating if the time intervals successively decreased. The patterns in all remaining children were classified as uncertain.

Results

We enrolled 123 children after their first seizure, 41 after two seizures, 19 after three seizures, and 21 after four or more seizures. Drug treatment was started in 10, 19, 9, and 20 patients, respectively, at time of intake. Table 2 presents the number of seizures before intake and during follow up.

Table 3 shows seizure patterns as from the first ever seizure. We classified the disease pattern as decelerating in 83 patients because they became free of seizures without medication: 60 had only one seizure, 15 had only two, and eight had only three. In two additional untreated children, whose last seizure occurred too close to the end of the follow up period to assess the disease pattern, we classified the disease pattern as uncertain. The pattern could not be assessed in an additional 78 children who were treated after their first seizure (10 children presenting with a status epilepticus) or their second (46 children) or third seizure (22 children). Of the 22 children treated after their third seizure, the intervals had decreased in 14 and increased in eight. Of the 41 patients with four or more untreated seizures, three showed a decelerating pattern, 30 an erratic pattern (classified as uncertain), and eight an accelerating pattern. In summary, the pattern was decelerating in 86 children (42%, 95% confidence interval 35-49%), uncertain in 110 (54%), and accelerating in eight (4%).

Discussion

The possibility that untreated epilepsy is a progressive disorder is of major importance in balancing the pros and cons of early treatment with antiepileptic drugs. Our study shows that in a large proportion of children with newly diagnosed, untreated tonic-clonic seizures the intervals between successive seizures become longer. This proportion may be a low estimate because we could not classify the pattern in the substantial number of patients who were given drug treatment after the first or subsequent seizures.

Ideally, the clinical course of epilepsy would be studied in an unselected, untreated group of children enrolled at the onset of the disease and followed for a long time without treatment, but such a study design is ethically not acceptable at this time. Our study reflects clinical practice. We enrolled the patients at an early stage of their disease and were rather reluctant to start treatment with antiepileptic drugs. On the basis of the catchment area of the participating hospitals and the incidence figures from epidemiological studies we estimate that we have enrolled about 75% of the children with new onset epilepsy.