Four-year outcome after early withdrawal of antiepileptic drugs in childhood epilepsy.

Four-year follow-up of children with epilepsy included in a randomized trial of early withdrawal of antiepileptic drugs showed that 51% achieved a terminal remission of at least 2 years without medication and 21% with medication; 15% had seizures during the fourth year. Early medication withdrawal is not recommended as standard practice in children with a rapid response to medication. The authors developed a model to predict outcome if withdrawal is considered.

Interrater agreement of the diagnosis and classification of a first seizure in childhood. The Dutch Study of Epilepsy in Childhood.

OBJECTIVE: To assess the interrater agreement of the diagnosis and the classification of a first paroxysmal event in childhood. METHODS: The descriptions of 100 first paroxysmal events were submitted to two panels each consisting of three experienced paediatric neurologists. Each observer independently made a diagnosis based on clinical judgment and thereafter a diagnosis based on predefined descriptive criteria. Then, the observers discussed all patients within their panel. The agreement between the six individual observers was assessed before discussion within each panel and after that, between the two panels. RESULTS: Using their clinical judgement, the individual observers reached only fair to moderate agreement on the diagnosis of a first seizure (mean (SE) kappa 0.41 (0.03)). With use of defined descriptive criteria the mean (SE) kappa was 0.45 (0.03). The kappa for agreement between both panels after intra-panel discussion increased to 0.60 (0.06). The mean (SE) kappa for the seizure classification by individual observers was 0.46 (0.02) for clinical judgment and 0.57 (0.03) with use of criteria. After discussion within each panel the kappa between the panels was 0.69 (0.06). In 24 out of 51 children considered to have had a seizure, agreement was reached between the panels on a syndrome diagnosis. However, the epileptic syndromes were in most cases only broadly defined. CONCLUSIONS: The interrater agreement on the diagnosis of a first seizure in childhood is just moderate. This phenomenon hampers the interpretation of studies on first seizures in which the diagnosis is only made by one observer. The use of a panel increased the interrater agreement considerably. This approach is recommended at least for research purposes. Classification into clinically relevant syndromes is possible only in a very small minority of children with a single seizure.

Immunoglobulins in children with epilepsy: the Dutch Study of Epilepsy in Childhood.

In an unselected cohort of 282 children, serum immunoglobulin (Ig) concentrations were determined shortly after the first presentation with one or more unprovoked epileptic seizures and before the start of treatment with anti-epileptic drugs (AEDs), and after 9-18 months of AEDs use. At intake, IgA, IgG1, IgG2 and IgG4 concentrations were significantly higher than published reference values in healthy age-matched controls. In a subset of 127 children, Ig levels at intake were compared with those after AEDs use for 9-18 months. IgA and IgG4 levels had decreased significantly to normal concentrations, but IgG1 and IgG3 levels increased significantly. To determine the influence of AEDs, Ig levels in children who used carbamazepine or valproic acid monotherapy were analysed separately. The use of carbamazepine was associated with a significant decrease of IgA and IgG4 levels, and the use of valproic acid with a significant decrease of IgA and increase of IgG1 levels. In conclusion, humoral immunity is already altered in children shortly after the first presentation with epileptic seizures. Whether this is the consequence of an exogenous event, and to what extent this is related to an interaction of the central nervous system and the immune system, remains to be evaluated. Treatment with AEDs, such as carbamazepine and valproic acid, is associated with significant changes of Ig (sub)class concentrations.

The accuracy of the diagnosis of paroxysmal events in children.

OBJECTIVE: To assess the accuracy of the diagnosis of epileptic seizures in children. METHODS: The Dutch Study of Epilepsy in Childhood is a prospective hospital-based study of 881 children referred because of possible seizures. The diagnosis was based on predefined descriptive criteria, as applied by a panel of three pediatric neurologists. Children with a definite other diagnosis were excluded. All children with unclear events were followed up for 1 year and children with seizures were followed up for 2 years to assess the accuracy of the diagnosis. RESULTS: In 170 of 224 children seen after a single event, the incident was classified initially as epileptic, in 54 as unclear. In none of the 170 children did the diagnosis prove to be wrong. In four of the 54 children, recurrent episodes enabled a definite diagnosis of epilepsy. In 412 of the 536 children seen with multiple events, an initial diagnosis of epilepsy was made. After follow-up, this initial diagnosis was probably incorrect in 19. In contrast, seven of 124 children with multiple unclear episodes at intake later received the diagnosis epilepsy. CONCLUSIONS: A false-positive diagnosis of epilepsy was made in 4.6%, whereas a definite diagnosis of epilepsy or seizure was delayed in 5.6% of children with multiple unclear events and in 7.4% of children with one unclear event.

Nonsymptomatic generalized epilepsy in children younger than six years: excellent prognosis, but classification should be reconsidered after follow-up: the Dutch Study of Epilepsy in Childhood.

PURPOSE: To assess the prognosis and the accuracy of the epilepsy classification in young children with nonsymptomatic generalized epilepsy. METHODS: Of the cohort of the Dutch Study of Epilepsy in Childhood (n = 466), all children younger than 6 years with a diagnosis of idiopathic (IGE) or cryptogenic (CGE) generalized epilepsy either at intake (n = 108) and/or after 2 years of follow-up (n = 102) were included. The number of reclassifications after 2 years was determined, and the reasons for reclassification were analyzed. All children receiving a diagnosis of IGE or CGE at 2 years were followed up for 5 years to study their outcome in terms of terminal remission (TR). Data on their level of intellectual functioning were collected at the start of this analysis. RESULTS: The epilepsy syndrome was reclassified in 17 children. In 14 of them, the seizure type also was reclassified, and in three, the course of the epilepsy determined the new epilepsy type. Two other children had a reclassification of their seizure types without a change of the epilepsy type. Many children were categorized as having IGE not otherwise specified. In all probability, this is a heterogeneous group, containing patients with various epilepsy syndromes, with generalized tonic-clonic seizures as a common hallmark. Of the 102 children with IGE or CGE at 2 years of follow-up, 75% had a TR of >6 months after 2 years, and 85% a TR of >or=1 year after 5 years. CONCLUSIONS: In a fair proportion of children with nonsymptomatic generalized epilepsy in this age group, it is not possible to classify firmly the epilepsy and/or the seizures immediately after the intake. Instead, they are reclassified during the course of the disease. This and the apparent heterogeneity of the category IGE not otherwise specified point to inherent drawbacks of the current International League Against Epilepsy (ILAE) classification of epilepsy and epileptic syndromes. The prognosis of IGE at this young age is generally excellent.

Mortality risk in children with epilepsy: the Dutch study of epilepsy in childhood.

OBJECTIVE: Long-term follow-up studies of patients with epilepsy have revealed an increased mortality risk compared with the general population. Mortality of children who have epilepsy in modern times is as yet unknown. Therefore, the objective of this study was to determine mortality of children who have epilepsy in comparison with the general population. METHODS: Between August 1988 and August 1992, 472 children, aged 1 month to 16 years, who presented in 1 of the participating hospitals with 2 or more newly diagnosed unprovoked seizures or at least 1 status epilepticus were enrolled in the study. All children were followed for 5 years or until death. The number of deaths observed during follow-up was compared with the expected number of deaths in the same age group in the general population in the Netherlands. RESULTS: Nine children died during follow-up, amounting to a mortality rate of 3.8/1000 person-years, which is sevenfold higher than expected (95% confidence interval = 2.4-11.5). No deaths were observed among the 328 children who had epilepsy of nonsymptomatic cause. All deceased children had epilepsy that was caused by a static or progressive neurologic disorder (mortality risk = 22.9; 95% confidence interval = 7.9-37.9). None of them died from sudden unexpected and unexplained death of epilepsy. CONCLUSIONS: In our cohort, we found no indication that children who have nonsymptomatic epilepsy have an increased mortality risk compared with the general population, whereas children who have symptomatic epilepsy have a 20-fold increased mortality risk. These data provide guidance for counseling parents of children who have epilepsy.

The early prognosis of epilepsy in childhood: the prediction of a poor outcome. The Dutch study of epilepsy in childhood.

PURPOSE: To examine which variables available early in the course of childhood epilepsy are associated with a poor short-term outcome and to develop models to predict such an outcome. METHODS: We prospectively followed up 466 children with newly diagnosed epilepsy for 2 years. Variables were collected at intake and after 6 months. Outcome was defined as the duration of the terminal remission (TR): poor (<6 months) and not poor (> or =6 months). RESULTS: Of the subjects, 31% had a poor outcome. Multivariate analysis based on the intake variables identified number of seizures, seizure type, and etiology as risk factors for a poor outcome. With the intake and 6-month variables combined, seizure type, etiology, the number of seizures, and not attaining a 3-month remission during these 6 months, and the EEG at 6 months were predictive variables. A predictive model based on the multivariate logistic-regression analysis with the intake variables was correct in 56% of the children in whom it predicted a poor outcome and in 73% of the children in whom it predicted a not-poor outcome. With the intake and 6-month variables together, these percentages were 66 and 79%, respectively. The sensitivity of these models was low (29 and 47%, respectively); the specificity was good (90 and 89%). CONCLUSIONS: The 2-year outcome of childhood epilepsy is closely related to its early course. The prognosis is poor in approximately 30% of patients. By using our data, the prediction of a poor outcome is correct in almost two thirds of the patients; however, the models produce many false-negative predictions.

Epilepsy in childhood: an audit of clinical practice.

BACKGROUND: It is not known how many children with epilepsy may not need treatment with antiepileptic drugs (AEDs), how many respond unsatisfactorily to subsequent treatment regimens, and how many achieve "acceptable control" despite lack of remission. METHODS: In a prospective multicenter hospital-based study, 494 children with a broad range of seizure types and types of epilepsy were followed up for at least 2 years. There was no standard treatment protocol. We describe the treatment strategies applied to these children by the neurologists in charge and outcome with respect to remission from seizures. RESULTS: Treatment was initially withheld in 29% of the children, and after 2 years 17% still had not received any AEDs. There were no serious complications caused by withholding treatment. Of the children treated with AEDs, 60% were still using the first AED after 2 years; 80% received monotherapy and 20%, polytherapy. Children with severe symptomatic epilepsies, such as the West or Lennox-Gastaut syndrome, received polytherapy early on in the course of treatment. When 3 regimens had failed, the chance of achieving a remission of more than 1 year with subsequent regimens was 10%. Nevertheless, 15 of 50 children receiving AEDs in whom the "longest remission ever" was less than 6 months did achieve acceptable seizure control according to the neurologist in charge of treatment. Hence, of 494 children, only 35 (7%) developed an intractable form of epilepsy, defined as failure to bring seizures under acceptable control. CONCLUSIONS: A substantial percentage of children with new-onset epilepsy did not need treatment with AEDs. Chances of achieving a good outcome declined with subsequent treatment regimens. Not all children with recurrent seizures were suffering from intractable epilepsy; some had achieved acceptable control of seizures.

Familial occurrence of epilepsy in children with newly diagnosed multiple seizures: Dutch Study of Epilepsy in Childhood.

PURPOSE: To study the familial occurrence of epilepsy in children with newly diagnosed multiple unprovoked seizures. METHODS: Between August 1988 and September 1992, 462 children with two or more unprovoked seizures were included in the prospective Dutch Study of Epilepsy in Childhood. Seizures and epilepsy syndromes of probands were classified according to the International Classifications. Probands with at least 1 first-degree relative with epilepsy were selected. Seizures and syndromes of their relatives were classified using medical files and telephone interviews. RESULTS: In 42% of the probands, the epilepsy was classified as localization-related, in 57% as generalized, and in 1% as undetermined whether focal or generalized. The 47 (10.2%) children with at least 1 first-degree relative with epilepsy less frequently had localization-related epilepsy (23%) and more often had generalized epilepsy (77%) as compared with the total group of probands. Fifty-eight first-degree and 21 other relatives had epilepsy. Thirty-three of the 40 (83%) first-degree relatives with idiopathic or cryptogenic epilepsy had the same seizure type as the proband, but detailed information about their seizures was sometimes difficult to obtain. Of the 12 first-degree relatives with epilepsy syndromes classifiable according to the International League Against Epilepsy (ILAE) 7 (58%) had the same syndrome as the proband. CONCLUSIONS: In 10% of children with newly diagnosed epilepsy, the condition is familial. Relatively more often, these children have generalized epilepsy syndromes as compared with children with a negative family history. Most of the relatives with idiopathic or cryptogenic epilepsy had the same seizure type as the proband. These findings confirm the role of genetic factors in the pathogenesis of epilepsy.

The first unprovoked, untreated seizure in childhood: a hospital based study of the accuracy of the diagnosis, rate of recurrence, and long term outcome after recurrence. Dutch study of epilepsy in childhood.

OBJECTIVE: To assess the accuracy of the diagnosis of a first unprovoked seizure in childhood, the recurrence rate within two years, the risk factors for recurrence, and the long term outcome two years after recurrence. METHODS: One hundred and fifty six children aged 1 month to 16 years after a first seizure, and 51 children with a single disputable event were followed up. The diagnosis of a seizure was confirmed by a panel of three child neurologists on the basis of predescribed diagnostic criteria. None of the children was treated after the first episode. RESULTS: Five children with a disputable event developed epileptic seizures during follow up. The diagnosis did not have to be revised in any of the 156 children with a first seizure. The overall recurrence rate after two years was 54%. Significant risk factors were an epileptiform EEG (recurrence rate 71%) and remote symptomatic aetiology and/or mental retardation (recurrence rate 74%). For the 85 children with one or more recurrences, terminal remission irrespective of treatment two years after the first recurrence was >12 months in 50 (59%),

Randomized prospective study of early discontinuation of antiepileptic drugs in children with epilepsy.

We studied recurrence rate, risk factors for recurrence, and outcome after recurrence in children after early withdrawal of antiepileptic drugs (AEDs). One hundred sixty-one children with newly diagnosed epilepsy who had become seizure free within 2 months after starting treatment and remained so for 6 months were randomly assigned to immediate withdrawal of AEDs (n = 78) or continuation of treatment for another 6 months followed by withdrawal (n = 83). The probability of remaining seizure free at 24 months after randomization was 51% (95% CI, 40 to 62) in Group A and 52% (41 to 63) in Group B. Significant predictive factors for relapse were partial epilepsy, seizure onset at 12 years or older, defined etiology, and epileptiform EEG before randomization. At the end of follow-up (median, 41.9 months), 129 children (80.6%) had a terminal remission of at least 1 year, 88 without AEDs and 41 with AEDs. No significant difference in outcome was found between Groups A and B. In children with epilepsy and an early response to therapy, AED withdrawal after 6 or 12 months of treatment leads to seizure recurrence in approximately half of all patients regardless of the duration of therapy. More than 60% of those with one or more recurrences reach a terminal remission of at least 1 year after long-term follow-up with or without AEDs.

The diagnostic yield of a second EEG after partial sleep deprivation: a prospective study in children with newly diagnosed seizures.

PURPOSE: To assess the diagnostic yield of a repeated EEG (REPEEG) after partial sleep deprivation (SD) in children and adolescents with one or more seizures who previously had had a standard EEG (STDEEG) without epileptiform abnormalities (EAs). In the literature, 32-75% of such REPEEGs after SD were reported to show EA. METHODS: In a prospective, multicentred study, we selected children aged 1 month to 16 years with one or more idiopathic or remote symptomatic newly diagnosed seizures. A REPEEG was recorded in children without EAs in their STDEEG. RESULTS: Of 552 children and adolescents who entered the study, 243 (44%) had a STDEEG without EAs. In 177 (73% of eligible children), REPEEGs were recorded after SD. We found EAs in 61 (34.5%) REPEEGs and new nonepileptiform abnormalities in five (1%). In 552 children in the total cohort, the REPEEG thus added 11% with EAs to the 56% with EAs in the STDEEG. Of REPEEGs, 81% included sleep compared with 20% of STDEEGs. In about half the REPEEGs, EAs occurred during sleep only. One child had tonic-clonic seizures probably related to the SD. CONCLUSIONS: One third of REPEEGs yielded new diagnostic information. Partial, age-dependent SD was highly effective in inducing sleep, which is important because in many cases EAs were found only during EEG recording in sleep. The procedure was safe and convenient.

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

OBJECTIVE: To assess decleration and acceleration in the disease process in the initial phase of epilepsy in children with new onset tonic-clonic seizures. STUDY DESIGN: Hospital based follow up study. SETTING: Two university hospitals, a general hospital, and a children's hospital in the Netherlands. PATIENTS: 204 children aged 1 month to 16 years with idiopathic or remote symptomatic, newly diagnosed, tonic-clonic seizures, of whom 123 were enrolled at time of their first ever seizure; all children were followed until the start of drug treatment (78 children), the occurrence of the fourth untreated seizure (41 children), or the end of the follow up period of two years (85 untreated children). MAIN OUTCOME MEASURES: Analysis of disease pattern from first ever seizure. The pattern was categorised as decelerating if the child became free of seizures despite treatment being withheld. In cases with four seizures, the pattern was categorised as decelerating if successive intervals increased or as accelerating if intervals decreased. Patterns in the remaining children were classified as uncertain. RESULTS: A decelerating pattern was found in 83 of 85 children who became free of seizures without treatment. Three of the 41 children with four or more untreated seizures showed a decelerating pattern and eight an accelerating pattern. In 110 children the disease process could not be classified, mostly because drug treatment was started after the first, second, or third seizure. The proportion of children with a decelerating pattern (42%, 95% confidence interval 35% to 49%) may be a minimum estimate because of the large number of patients with an uncertain disease pattern. CONCLUSIONS: Though untreated epilepsy is commonly considered to be a progressive disorder with decreasing intervals between seizures, a large proportion of children with newly diagnosed, unprovoked tonic-clonic seizures have a decelerating disease process. The fear that tonic-clonic seizures commonly evolve into a progressive disease should not be used as an argument in favour of early drug treatment in children with epilepsy.

Value of the electroencephalogram in adult patients with untreated idiopathic first seizures.

We prospectively studied the reliability and accuracy of the electroencephalogram as a predictor of the risk of recurrence within 2 years in 157 patients with untreated idiopathic first seizures. In all patients, a standard electroencephalogram and, if necessary, an electroencephalogram after partial sleep deprivation were obtained. All electroencephalograms were scored by one observer according to a fixed protocol. The finding of epileptic discharges was associated with a risk of recurrence of 83% (95% confidence interval, 69% to 97%) vs 41% (95% confidence interval, 29% to 53%) in patients with nonepileptic abnormalities and 12% (95% confidence interval, 3% to 21%) in patients in whom both electroencephalograms were normal. The sensitivity proved to be 48%. Interobserver agreement among four neurologists, who independently read 50 electroencephalograms, was found to be moderate. Predictive value for each observer, however, was good. We conclude that electroencephalogram findings may play a role in the decision to initiate or delay treatment after an idiopathic first seizure.

Idiopathic first seizure in adult life: who should be treated?

OBJECTIVE: To assess the accuracy of the diagnosis, recurrence rate, and fate after the first recurrence in adult patients with an untreated idiopathic first seizure. DESIGN: Hospital based follow up study. SETTING: One university hospital and three general hospitals in The Netherlands. PATIENTS: 165 patients aged 15 years or more with a clinically presumed idiopathic seizure; diagnosis was based on a description of the episode according to prespecified diagnostic criteria. MAIN OUTCOME MEASURES: Results of additional investigations and follow up regarding the accuracy of the diagnosis; first recurrence; and response to treatment after the first recurrence. RESULTS: Computed tomography showed major abnormalities in 5.5% of the patients and follow up led to doubts about the initial clinical diagnosis in another 6%. Cumulative risk of recurrence was 40% at two years. The cumulative risk of recurrence at two years was 81% (95% confidence interval 66% to 97%) in patients with epileptic discharges on a standard or partial sleep deprivation electroencephalogram, 39% (27% to 51%) in patients with other electroencephalographic abnormalities, and 12% (3% to 21%) in patients with normal electroencephalograms. Treatment was initiated in most patients who had one or more recurrences; 40 (70%) patients were completely controlled, eight (14%) had sporadic seizures, and nine (16%) did not become free of seizures within one year despite treatment. CONCLUSIONS: The decision to initiate or delay treatment should be based on electroencephalographic findings.

A model for breast cancer screening.

A model for breast cancer screening has been developed. When the appropriate screening policy is specified, the model reproduces the detection rates and the incidence of interval cancers as observed in the recent screening projects in Utrecht and Nijmegen, the Netherlands. The model-predicted mortality rate reduction is in accordance with the results of the Kopparberg/Ostergötland randomized trial in Sweden. Key parameters of the model are the duration of the preclinical stages and the sensitivity of mammography. The average duration is approximately 2 years at age 40 and increases to approximately 5 years at age 70. The sensitivity is high (approximately 95%) for tumors larger than 1 cm. The model is used in the prospective evaluation of effects and costs of various screening policies.

Usefulness of an aura for classification of a first generalized seizure.

In 67 of 149 patients with a generalized first seizure, the occurrence of some kind of sensation immediately preceding the loss of consciousness was the only clue that possibly indicated focal onset of the seizure. We studied the interobserver agreement between six neurologists regarding the interpretation of these preceding feelings as either a nonspecific symptom or an aura implicating a focal onset of the seizure. The observers also classified the seizures as generalized from onset, undetermined, or partial secondarily generalized. To assess the accuracy of the classification, we obtained a standard EEG, an EEG after partial sleep deprivation, a computed tomography (CT) scan, and a follow-up report after 1 year. The subclassification on clinical grounds of a generalized first seizure is too unreliable and probably too invalid as well to be useful in clinical practice or in epidemiologic research.

The cost-effectiveness of breast cancer screening.

The costs and effects of different invitation schedules of breast cancer screening are compared. The effect estimates are based on trials from the USA, Sweden and the Netherlands. The cost estimates use registration data, file studies and organization charts. The calculations were performed with the MISCAN computer simulation package, which is developed especially for the evaluation of mass screening programmes. Screening women of 50-70 years at 2-yearly intervals is a relatively cost-effective schedule. In a real population, it will reduce breast cancer mortality by 12%. Screening of women under 50 is probably far less cost-effective. Screening induces a considerable shift towards breast-conserving therapy. Although a 12% mortality reduction may seem low, in absolute numbers this represents more than the total mortality from, e.g., cervical cancer. Moreover, cost per death prevented or per life-year saved is much lower than for most other medical interventions for which cost-effectiveness ratios are known, screening for cervical cancer included.

Reliability of the diagnosis of a first seizure.

We studied the interrater variability among three neurologists of the diagnosis of a seizure in 100 patients evaluated for a possible "first seizure." We found that use of simple descriptive diagnostic criteria and discussion among the neurologists themselves improved the diagnostic agreement.