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Epilepsy and mental retardation limited to females (EFMR), caused by PCDH19 mutations, has a variable clinical expression that needs further exploration. Onset of epilepsy may be provoked by fever and can resemble Dravet syndrome. Furthermore, transmitting males have no seizures, but are reported to have rigid personalities suggesting possible autism spectrum disorders (ASD). Therefore, this study aimed to determine the phenotypic spectrum associated with PCDH19 mutations in Dravet-like and EFMR female patients and in males with ASD. We screened 120 females suffering from Dravet-like epilepsy, 136 females with EFMR features and 20 males with ASD. Phenotypes and genotypes of the PCDH19 mutation carriers were compared with those of 125 females with EFMR reported in the literature. We report 15 additional patients with a PCDH19 mutation. Review of clinical data of all reported patients showed that the clinical picture of EFMR is heterogeneous, but epilepsy onset in infancy, fever sensitivity and occurrence of seizures in clusters are key features. Seizures remit in the majority of patients during teenage years. Intellectual disability and behavioural disturbances are common. Fifty percent of all mutations are missense mutations, located in the extracellular domains only. Truncating mutations have been identified in all protein domains. One ASD proband carried one missense mutation predicted to have a deleterious effect, suggesting that ASD in males can be associated with PCDH19 mutations.

Purpose: Two large prospective cohort studies of childhood epilepsy (Nova Scotia and the Netherlands) each developed a statistical model to predict long-term outcome. We sought to evaluate the accuracy of a prognostic model based on the two studies combined., Methods: Analyses with classification tree models and stepwise logistic regression produced predictive models for the combined dataset and the two separate cohorts. The resulting models were then externally validated on the opposite cohort. Remission was defined as no longer receiving daily medication for any length of time at the end of follow-up., Results: The combined cohorts yielded 1,055 evaluable patients. At the end of follow-up (>or=5 years in >96%), 622 (59%) were in remission. By using the combined data, the classification tree model and the logistic regression model predicted the outcome correctly in approximately 70%. The classification tree model split the data on epilepsy type and age at first seizure. Predictors in the logistic regression model were: seizure number before treatment, age at first seizure, absence seizures, epilepsy types of symptomatic generalized and symptomatic partial, preexisting neurologic signs, intelligence, and the combination of febrile seizures and cryptogenic partial epilepsy. When the prediction models from each cohort were cross-validated on the opposite cohort, the outcome was predicted slightly less accurately than did the model from the combined data., Conclusions: Based on currently available clinical and EEG variables, predicting the outcome of childhood epilepsy may be difficult and appears to be incorrect in about one of every three patients.

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.

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.

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.

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.

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.

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.

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.

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%),

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.

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.

Parents and doctors impose restrictions on children with epilepsy to avoid seizure-related injuries. We intended to quantify disability due to such restrictions by using a newly developed parent-completed 10-item scale (The Hague Restrictions in Childhood Epilepsy Scale, HARCES). Parents reported disability on at least one item of the HARCES in 83% of 122 children with epilepsy and a remission from seizures for less than 1 year. Psychometric analysis of the scale's reliability demonstrated good internal consistency and retest stability. Its validity was supported by the association between HARCES scores and the physicians' advice imposing restrictions. We found no substantial association with such variables as seizure type, short-term remission, or seizure activity. These findings suggest that in children with recurrent seizures, restrictions were probably not optimally adapted to seizure-related risks. A repeat test after 1 year showed that a seizure remission of more than 1 year substantially reduced restrictions, which is probably associated with an improvement in quality of life.

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.

Purpose: We wished to compare a parent-completed scale quantifying seizure severity (SS) in children with various seizure types with the clinicians' impression of SS and other clinical data., Methods: The parents of 117 children with recurrent seizures completed a 13-item, subjective scale (The Hague Seizure Severity Scale, HASS). Eight treating neurologists quantified SS on a 10-point Visual Analog Scale (VAS) and supplied other clinical data., Results: Both the HASS and the VAS assessments of SS showed considerable variation within one seizure type. Significant differences were noted between groups with (a) absences and simple partial seizures (SPS), (b) complex partial seizures (CPS), and (c) generalized tonic-clonic seizures (GTCS). The correlation coefficient between the neurologists' and the parents' scores was 0.45 but did not exceed 0.26 after stratification for seizure type. The parents' score was not substantially influenced by various other clinical variables. The neurologists' score was correlated with resistance to treatment and presence of mental retardation., Conclusions: The SS ratings of the parents and the neurologists were not substantially correlated. The consideration that parents, as eyewitnesses to the seizures, are probably better judges of SS than clinicians may favor the use of a parent-completed scale to quantify SS. The HASS is a valid and reliable measure of parent-perceived SS that can be useful as an outcome measure in childhood epilepsy.

During the past decade, several scales have been developed to improve the assessment of outcome in epilepsy. These scales were developed for adults and their reliability, validity and usefulness have been established. However, there is also a need for alternative measures of outcome in childhood epilepsy, especially a measure of seizure severity (SS) and measures pertaining to quality of life (QoL). Four of these adult scales are reviewed and compared to examine their applicability in childhood epilepsy. Two important methodological differences between them are discussed: (a) patient self-report vs. physician-based scales and (b) generic vs. disease-specific instruments. QoL in epilepsy is briefly reviewed. Severity of seizures and severity of side-effects are relatively neglected areas of importance to QoL in epilepsy. The existing instruments for adults are not appropriate for children in their present form. Some specific methodological issues, which are relevant for the development of scales for children with epilepsy, are subsequently discussed. New scales pertaining to physical and psychosocial aspects of QoL in childhood epilepsy are being developed. In the near future, data on their reliability, validity and usefulness will become available. A combination of scales focusing on specific aspects of QoL, including SS and severity of adverse effects, and more traditional clinical data may provide a more complete assessment of outcome in childhood epilepsy.

We have developed two outcome measures for childhood epilepsy: a seizure severity (SS) scale and a side-effects (SE) scale. Both scales have been designed for completion by parents. The scales were tested in two pilot phases and the results of this stepwise analysis are described here. The final scales' psychometric properties were assessed in a group of 80 children with active epilepsy, representative of the population at whom the scales were aimed: children with chronic epilepsy, aged 4-16 years, including all seizure types and epilepsies, as well as children with neurological comorbidity. The SS scale and SE scale showed good internal consistency and test-retest stability. Although there was a significant positive correlation between the SS scale and the SE scale, this was low, indicating that the scales measure a different clinical trait. The SE scale consisted of two subscales: a Toxic subscale, measuring the severity of dose-related side-effects, and a Chronic subscale, measuring the severity of long-term behavioural and cognitive side-effects. These subscales for side-effects showed a high correlation and can be used as a joint scale. These scales have the potential to improve outcome assessment in childhood epilepsy and they can be used to assess important aspects of quality of life in this population.

The relapse rate after discontinuation of antiepileptic drug treatment was investigated in 146 children with epilepsy, in whom medication was withdrawn according to a predesigned protocol, after a seizure-free period of at least 2 years and normalization of the EEG. The cumulative probability of remaining seizure-free in this series was 74.5%. Three-quarters of the relapses occurred during the withdrawal period and in the 2 years thereafter. From multivariate analysis, the factors indicating a significantly higher relapse risk were seizures with a known cause and female sex. In primary generalized epilepsy, no factor significantly increased the likelihood of a recurrence. In partial epilepsy, significant factors predictive of recurrence were the presence of a neurological deficit (focal neurological signs and/or mental retardation), female sex, a positive family history for epilepsy, and the number of drugs necessary for control of the seizures. The present results are compared with the available literature data. It is argued that using multivariate analysis after elimination of EEG variables uncovers significant clinical predictive factors that in other studies may have remained hidden. Finally, it is argued that statistical analysis may be used to enable the clinician to predict the likelihood of recurrence in individual children with a given set of relevant predictive factors.

Epilepsy and mental retardation limited to females (EFMR), caused by PCDH19 mutations, has a variable clinical expression that needs further exploration. Onset of epilepsy may be provoked by fever and can resemble Dravet syndrome. Furthermore, transmitting males have no seizures, but are reported to have rigid personalities suggesting possible autism spectrum disorders (ASD). Therefore, this study aimed to determine the phenotypic spectrum associated with PCDH19 mutations in Dravet-like and EFMR female patients and in males with ASD. We screened 120 females suffering from Dravet-like epilepsy, 136 females with EFMR features and 20 males with ASD. Phenotypes and genotypes of the PCDH19 mutation carriers were compared with those of 125 females with EFMR reported in the literature. We report 15 additional patients with a PCDH19 mutation. Review of clinical data of all reported patients showed that the clinical picture of EFMR is heterogeneous, but epilepsy onset in infancy, fever sensitivity and occurrence of seizures in clusters are key features. Seizures remit in the majority of patients during teenage years. Intellectual disability and behavioural disturbances are common. Fifty percent of all mutations are missense mutations, located in the extracellular domains only. Truncating mutations have been identified in all protein domains. One ASD proband carried one missense mutation predicted to have a deleterious effect, suggesting that ASD in males can be associated with PCDH19 mutations. [ABSTRACT FROM AUTHOR]

Summary: 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 ≥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... [ABSTRACT FROM AUTHOR]