Evolution and course of early life developmental encephalopathic epilepsies: Focus on Lennox-Gastaut syndrome.

OBJECTIVES: Developmental encephalopathic epilepsies (DEEs) are characterized by refractory seizures, disability, and early death. Opportunities to improve care and outcomes focus on West syndrome/infantile spasms (WS/IS). Lennox-Gastaut syndrome (LGS) is almost as common but receives little attention. We examined initial presentations of DEEs and their evolution over time to identify risk and indicators of developing LGS. METHODS: Data are from the Connecticut Study of Epilepsy, a prospective, longitudinal study of 613 children with newly diagnosed epilepsy recruited in 1993-1997. Central review of medical records permitted classification of epilepsy syndromes at diagnosis and at reclassification 2, 5, and 9 years later. DEEs were compared to other epilepsies for seizure and cognitive outcomes and mortality. Analyses examined the evolution of DEE syndromes after initial presentation, with specific comparisons made between WS/IS and LGS. Statistical analyses were performed with t tests and chi-square tests. RESULTS: Fifty-eight children (9.4%) had DEEs, median onset age = 1.1 years (interquartile range ([IQR] 0.3-1.3) in DEEs and 6.0 years (IQR 3.0-9.0) in other epilepsies (P < 0.001). DEEs vs other epilepsies had more pharmacoresistance (71% vs 18%), intellectual disability (84% vs 11%), and mortality (21% vs <1%; all P < 0.001). During follow-up, the form of epilepsy evolved in 33 children. WS/IS was the most common initial diagnosis (N = 23) and in 5 children WS/IS evolved later. LGS was diagnosed initially in 4 children (1 later revised) and in 22 by the end of follow-up, including 7 evolving from WS/IS and 12 from nonsyndromic generalized, focal, or undetermined epilepsies. Evolution to LGS took a median of 1.9 years. LGS developed in 13% of infants, including 9% of those who did not present initially with WS/IS. SIGNIFICANCE: DEEs account for disproportionate amounts of pharmacoresistance, disability, and early mortality. LGS often has a window between initial presentation and full expression. LGS should become targeted for early detection and prevention.

Surgical outcome in adolescents with mesial temporal sclerosis: Is it different?

There are extensive studies evaluating mesial temporal sclerosis (MTS) in adults and limited studies in children, with adolescents being included within both patient populations. Our aim was to evaluate predictors of surgical outcome solely in adolescent patients with MRI- and pathology -proven MTS. The Yale Epilepsy Surgery Database was reviewed from 1987 to 2012 for adolescent patients with confirmed MTS on MRI and pathology who underwent temporal lobectomy and had greater than two-year postsurgical follow-up. Clinical and electrographic data were reviewed. Eighteen patients were identified. Eleven patients (61%) were seizure-free. All seven patients (39%) who were not seizure-free free were found to have lateralized ictal onset within one hemisphere involving two or more lobes on scalp EEG (p<0.001). Of the 7 patients who were not seizure-free, 4 had a history of status epilepticus (compared to 1/11 seizure-free patients; p=0.047), and 4 had lateralized hypometabolism involving two or more lobes within a hemisphere seen on PET (compared to 0/8 seizure-free patients; p=0.002). A novel finding in our study was that lateralized (rather than localized) ictal onset on scalp EEG, lateralized hypometabolism on PET, and history of status epilepticus were risk factors for not attaining seizure freedom in adolescents with MTS who underwent temporal lobectomy.

Determinants of Social Outcomes in Adults With Childhood-onset Epilepsy.

BACKGROUND: Adults with childhood-onset epilepsy experience poorer adult social outcomes than their peers. The relative roles of seizures over time versus learning and psychiatric problems are unclear. METHODS: We examined independent influences of psychiatric and learning disorders and of seizure course in 241 young adults (22-35 years old) with uncomplicated epilepsy in a longitudinal community-based cohort study. Social outcomes were ascertained throughout the study. A history of psychiatric and learning problems was ascertained ∼9 years after study entry. Seizure course was: "Excellent," no seizures after the first year, in complete remission at last contact (N = 95, 39%); "Good," seizures occurred 1 to 5 years after diagnosis, in complete remission at last contact (N = 56, 23%); "Fluctuating," more complicated trajectories, but never pharmacoresistant (N = 70, 29%); "Pharmacoresistant," long-term pharmacoresistant (N = 20, 8%). Multiple logistic regression was used to identify contributors to each social outcome. RESULTS: Better seizure course predicted college completion, being either employed or pursuing a degree, and driving, but was not substantially associated with other social outcomes. Poorer seizure course was associated with a greater likelihood of having offspring, particularly in women without partners. Learning problems, psychiatric disorders, or both negatively influenced all but 2 of the social outcomes. CONCLUSIONS: In young adults with uncomplicated epilepsy, the course of seizures contributed primarily to education, employment, and driving. A history of learning problems and psychiatric disorders adversely influenced most adult outcomes. These findings identify potential reasons for vocational and social difficulties encountered by young adults with childhood epilepsy and areas to target for counseling and transition planning.

Complete remission of childhood-onset epilepsy: stability and prediction over two decades.

The ultimate seizure outcome of childhood epilepsy is complete resolution of all seizures without further treatment. How often this happens and how well it can be predicted early in the course of epilepsy could be valuable in helping families understand the nature of childhood epilepsy and what to expect over time. In the Connecticut study of epilepsy, a prospective cohort of 613 children with newly-diagnosed epilepsy (onset age 0-15 years), complete remission, ≥5 years both seizure-free and medication-free, was examined as a proxy of complete seizure resolution. Predictors at initial diagnosis were tested. Information about seizure outcomes within 2 years and from 2-5 years after diagnosis was sequentially added in a proportional hazards model. The predictive value of the models was determined with logistic regression. Five hundred and sixteen subjects were followed ≥10 years. Three hundred and twenty-eight (63%) achieved complete remission; 23 relapsed. The relapse rate was 8.2 per 1000 person-years and decreased over time: 10.7, 6.7, and 0 during first 5 years, the next 5 years, and then >10 years after complete remission (P=0.06 for trend). Six participants regained complete remission; 311 (60%) were in complete remission at last contact. Baseline factors predicting against complete remission at last contact included onset age≥10 years (hazard ratio=0.55, P=0.0009) and early school or developmental problems (hazard ratio=0.74, P=0.01). Factors predicting for complete remission were uncomplicated epilepsy presentation (hazard ratio=2.23, P<0.0001), focal self-limited epilepsy syndrome (hazard ratio=2.13, P<0.0001), and uncharacterized epilepsy (hazard ratio=1.61, P=0.04). Remission (hazard ratio=1.95, P<0.0001) and pharmaco-resistance (hazard ratio=0.33, P<0.0001) by 2 years respectfully predicted in favour and against complete remission. From 2 to 5 years after diagnosis, relapse (hazard ratio=0.21, P<0.0001) and late pharmaco-resistance (hazard ratio=0.21, P=0.008) decreased and late remission (hazard ratio=2.40, P<0.0001) increased chances of entering complete remission. The overall accuracy of the models increased from 72% (baseline information only), to 77% and 85% with addition of 2-year and 5-year outcomes. Relapses after complete remission are rare making this an acceptable proxy for complete seizure resolution. Complete remission after nearly 20 years is reasonably well predicted within 5 years of initial diagnosis.

Long-term seizure remission in childhood absence epilepsy: might initial treatment matter?

OBJECTIVE: Examine the possible association between long-term seizure outcome in childhood absence epilepsy (CAE) and the initial treatment choice. METHODS: Children with CAE were prospectively recruited at initial diagnosis and followed in a community-based cohort study. Children presenting with convulsive seizures, significant imaging abnormalities, or who were followed <5 years were excluded. Early outcomes included success of initial medication, early remission, and pharmacoresistance. The primary long-term outcome was complete remission: ≥5 years both seizure free and medication free. Survival methods were used for analyses. RESULTS: The first medication was ethosuximde (ESM) in 41 (69%) and valproic acid (VPA) in 18 (31%). Initial success rates were 59% (ESM) and 56% (VPA). Early remission and pharmacoresistance were similar in each group. Apart from atypical electroencephalography (EEG) features (61% [VPA], 17% [ESM]), no clinical features varied substantially between the treatment groups. Complete remission occurred in 31 children (76%) treated with ESM and 7 (39%) who received VPA (p = 0.007). Children with versus without atypical EEG features were less likely to enter complete remission (50% vs. 71%, p = 0.03). In a Cox regression, ESM was associated with a higher rate of complete remission than VPA (hazards ratio [HR] 2.5, 95% confidence interval [CI] 1.1-6.0; p = 0.03). Atypical EEG features did not independently predict outcome (p = 0.15). Five-year and 10-year remission, regardless of continued treatment, occurred more often in children initially treated with ESM versus VPA. SIGNIFICANCE: These findings are congruent with results of studies in genetic absence models in rats and provide preliminary evidence motivating a hypothesis regarding potential disease-modifying effects of ESM in CAE. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Age at onset of epilepsy, pharmacoresistance, and cognitive outcomes: a prospective cohort study.

OBJECTIVES: Increasing evidence suggests that uncontrolled seizures have deleterious effects on cognition and behavior, particularly in the developing brain. METHODS: In a community-based cohort, 198 children, aged <8 years with new-onset epilepsy were followed prospectively and reassessed with the Wechsler Intelligence Scales for Children, Third Edition (WISC-III) 8-9 years later. Linear regression analyses with interactions between age at onset (age) and pharmacoresistance (PR) were used to test whether earlier onset conveyed greater vulnerability to the effects of uncontrolled seizures. Full-scale IQ (FSIQ) and the 4 subdomain scores were examined. Adjustment for adaptive behavior scores in a subset was performed. A dichotomous indicator for IQ <80 or ≥80 was used to permit inclusion of children who were not tested, particularly those who were untestable. RESULTS: FSIQ was not correlated with age. PR was associated with an 11.4 point lower FSIQ (p = 0.002) and similar decrements in each WISC-III domain. There were substantial age-PR interactions for FSIQ (p = 0.003) and 3 domain scores, indicating a lessening impact of PR with increasing age. The dichotomous IQ indicator was strongly correlated with age at onset in the pharmacoresistant group (p < 0.0001) and not in the non-pharmacoresistant group (p = 0.61). Adjustment for adaptive behavior measured near onset did not alter the conclusions. CONCLUSIONS: Uncontrolled seizures impair cognitive function with effects being most severe in infancy and lessening with increasing age at onset. These findings further emphasize the need for early aggressive treatment and seizure control in infants and young children.

Complete remission in nonsyndromic childhood-onset epilepsy.

OBJECTIVE: Determine the probability of attaining complete remission in children with nonsyndromic epilepsy (NSE) over the course of ≥10 years from initial diagnosis; identify early predictors of complete remission; and assess the risk of relapse after achieving complete remission. METHODS: In a prospective community-based cohort, complete remission was defined as 5 years seizure-free and medication-free. Any subsequent seizure for any reason was a relapse. Univariate and bivariate analyses were conducted with standard methods including the Kaplan-Meier approach. Proportional hazards modeling was used for multivariable analysis. RESULTS: Of 613 cohort members, 347 had NSEs, of whom 294 (85%) were followed ≥10 years (maximum = 17.9). A total of 170 in 294 (58%) achieved complete remission, 10 of whom (6%) relapsed. Seizure outcome at 2 years (remission, pharmacoresistant, unclear) (p < 0.0001) and underlying cause (p < 0.0001) distinguished groups with complete remission ranging from ~20% to ~75%. Older age at onset was independently associated with a poorer chance of complete remission. Relapses occurred up to 7.5 years after attaining complete remission and were marginally associated with underlying cause (p = 0.06). INTERPRETATION: Complete remission occurs in over one-half of young people with NSE and generally persists. Meaningful but imperfect predication is possible based on underlying cause and early seizure control. The finding of age effects may play a role in meaningful identification of phenotypes, which could become fruitful targets for genetic and imaging investigations in these otherwise poorly differentiated epilepsies.

Parental report of behavioral and cognitive diagnoses in childhood-onset epilepsy: A case-sibling-controlled analysis.

Evidence from multiple sources has highlighted the increased burden of cognitive, behavioral, and psychiatric disorders in childhood-onset epilepsy. Some of this increased morbidity, however, is attributable to underlying structural and metabolic insults. We assessed whether cognitive/behavioral/psychiatric disorders are associated with epilepsy of unknown or presumed genetic cause in young people with epilepsy (cases) compared with sibling controls. Our analyses included 217 cases who were enrolled in the Connecticut Study of Epilepsy between 1993 and 1997 and 217 sibling controls. Information was collected from a parent interview conducted 8-9years after the case was diagnosed with epilepsy. Relative to controls, parents were more likely to report that their case children were slow learners (OR=4.6, P<0.001), had a language disorder (OR=5.8, P<0.001), and had engaged in self-injurious behaviors other than suicide attempts (OR=5.5, P=0.013). Future research should examine whether these conditions first present during childhood influence prognosis into adulthood.

Frequency, prognosis and surgical treatment of structural abnormalities seen with magnetic resonance imaging in childhood epilepsy.

The epidemiology of lesions identified by magnetic resonance imaging (MRI), along with the use of pre-surgical evaluations and surgery in childhood-onset epilepsy patients has not previously been described. In a prospectively identified community-based cohort of children enrolled from 1993 to 1997, we examined (i) the frequency of lesions identified by MRI; (ii) clinical factors associated with 'positive' MRI scans; and (iii) the utilization of comprehensive epilepsy evaluations and neurosurgery. Of the original cohort of 613 children, 518 (85%) had usable MRI scans. Eighty-two (16%) had MRI abnormalities potentially relevant to epilepsy ('positive' scans). Idiopathic epilepsy syndromes were identified in 162 (31%) of whom 3% had positive scans. The remainder had non-idiopathic epilepsy syndromes of which 22% had positive MRI findings. Multiple logistic regression analysis identified non-idiopathic epilepsy and abnormal motor-sensory (neurological) examinations as predictors of a positive MRI scan. Of the non-idiopathic patients with normal neurological exams and who were not pharmacoresistant, 10% had positive MRI scans, including four patients with gliomas. Evaluations at comprehensive epilepsy centres occurred in 54 pharmacoresistant cases. To date 5% of the imaged cohort or 8% of non-idiopathic epilepsy patients have undergone surgical procedures (including vagal nerve stimulator implantation) to treat their epilepsy (n = 22) or for tumours (n = 6) without being drug resistant. Applying our findings to the general population of children in the USA, we estimate that there will be 127/1 000 000 new cases per year of pharmacoresistant epilepsy, and 52/1 000 000 childhood-onset epilepsy patients undergoing epilepsy evaluations. In addition, approximately 27/1 000 000 will have an epilepsy-related surgical procedure. These findings support recommendations for the use of MRI in evaluating newly diagnosed paediatric epilepsy patients, especially with non-idiopathic syndromes, and provide estimates on the utilization of comprehensive evaluations and surgery.

Remission of epilepsy after two drug failures in children: a prospective study.

OBJECTIVE: Determine the probability of a more than 1-year remission after failure of a second drug in children prospectively followed from initial diagnosis of epilepsy and then from time of second drug failure. Identify prognostic factors for remission after second drug failure. METHODS: Of 613 children, 128 did not respond favorably to 2 drugs, had a trial of at least a third drug (median, 3), and were followed for more than 1 year (median, 10.1 years) since second drug failure. Product limit and proportional hazards techniques were used to analyze predictors of any 1-year remission (Rem1) and 1- and 3-year remission at last contact (Rem1/3-LC). RESULTS: Seventy-three patients (57%) had a remission. Repeated remissions and relapses were common. Only 48 (37.5%) achieved Rem1-LC and 28 (23%) Rem3-LC. Idiopathic epilepsy (Rem1: rate ratio [RR], 3.64, p < 0.0001; Rem1-LC: RR, 2.57, p = 0.008) and seizure frequency (Rem1: RR, 0.76, p = 0.003; Rem1-LC: RR, 0.82, p = 0.04 per increase in category) were the most robust predictors. Symptomatic cause was the only correlate of Rem3-LC. Remission before second drug failure did not predict remission after second drug failure. INTERPRETATION: Remission after second drug failure is common but often temporary. Children who have not responded to two appropriate drugs should be carefully evaluated to maximize therapy and possibly considered for more aggressive treatments.

Residual cognitive effects of uncomplicated idiopathic and cryptogenic epilepsy.

We assessed residual cognitive deficits in young people with idiopathic and cryptogenic epilepsy. In the setting of an ongoing prospective study, we invited participants initially diagnosed and enrolled in the cohort 8-9 years earlier to undergo standardized neuropsychological assessment. Sibling controls were invited when available. We analyzed 143 pairs in which cases had idiopathic or cryptogenic epilepsy and both case and control had normal intelligence. Compared with that for siblings, the Full Scale IQ for cases was 3.3 points lower (P=0.01) mainly due to slower processing speed, which was 5.6 points lower (P=0.0004). Word reading (P=0.04) and spelling (P=0.01), but not other scores, were also lower in cases. Remission status and drug use did not influence findings. In young people of normal intelligence with idiopathic or cryptogenic childhood-onset epilepsy, substantial residual effects of epilepsy appear to be confined largely to slower processing speed.

Global cognitive function in children with epilepsy: a community-based study.

PURPOSE: To determine the frequency and determinants of subnormal global cognitive function in a representative, community-based sample of children prospectively identified at the time of initial diagnosis of epilepsy. METHODS: In children enrolled with newly diagnosed epilepsy and followed a median of 10.5 years, level of cognitive function (within normal, borderline, mild, moderate to severe mental retardation (MR), neurologically devastated, and impaired but not further classified (NFC)) was determined based upon neurologists' and school records, repeated parental interviews, and, in over half the participants, standardized neuropsychological testing. For multivariable analyses, subnormal cognitive function was designated as consistent with a full scale IQ < 80. RESULTS: Global cognitive function was considered within normal, N = 451 (73.6%), borderline, N = 31 (5.1%), mild MR, N = 21 (3.4%), more severe MR, N = 45 (7.3%), devastated, N = 29 (4.7%), and impaired-NFC, N = 36 (5.9%). Age at onset <5 years, symptomatic etiology, epileptic encephalopathy, remission status and current AED treatment were each strongly associated with level of cognitive function (all p-values <0.0001). In a multivariable logistic regression model, all variables except remission status independently contributed to subnormal global cognitive function. DISCUSSION: Evidence of subnormal global cognitive function is apparent in approximately one of four children with epilepsy. Young age at onset, symptomatic cause, epileptic encephalopathy, and continued treatment, despite their strong intercorrelations, are independently associated with this outcome.

Behavior and social competency in idiopathic and cryptogenic childhood epilepsy.

Behavioral and related disorders are frequently reported in association with childhood epilepsy but the reasons for this are unclear. In a long-term prospective, community-based study of newly-diagnosed childhood epilepsy, behavioral assessments (Child Behavior Checklist) were performed in children 8 to 9 years after the initial diagnosis of epilepsy to determine the impact of remission and medication status on behavioral problems. Children with epilepsy were also compared with sibling controls. A total of 226 children (108 females, 118 males; mean age 13y 1mo [SD 2y 8mo], range 8-17y) with idiopathic or cryptogenic epilepsy were included in the analyses. One hundred and twenty-eight matched pairs were included in analyses of case-sibling differences. Lack of remission and current medication use were associated with worse behavioral problem and competency scores. Lack of remission generally had a greater effect than medication use, except for attention problems; medication status had the more deleterious effect (p<0.001). Children with epilepsy had significantly worse behavioral problems and competency scores relative to sibling controls. Even in paris in which the patient was seizure-free and off medication, significant case-sibling differences persisted for most scales (p=0.05 to p=0.001). Lack of remission and continued use of antiepileptic drugs have a negative influence on behavioral problems in children with epilepsy but do not fully explain the worse scores relative to siblings. This suggests an independent effect associated with the epilepsy itself.

How long does it take for epilepsy to become intractable? A prospective investigation.

OBJECTIVE: To determine prospectively when in the course of epilepsy intractability becomes apparent. METHODS: Data are from a prospective cohort of 613 children followed for a median of 9.7 years. Epilepsy syndromes were grouped: focal, idiopathic, catastrophic, and other. Intractability was defined in two ways: (1) 2 drugs failed, 1 seizure/month, on average, for 18 months (stringent), and (2) failure of 2 drugs. Delayed intractability was defined as 3 or more years after epilepsy diagnosis. RESULTS: Eighty-three children (13.8%) met the stringent and 142 (23.2%) met the two-drug definition. Intractability depended on syndrome (p < 0.0001): 26 (31.3%) children meeting stringent and 39 (27.5%) meeting the 2-drug definition had delayed intractability. Intractability was delayed more often in focal than catastrophic epilepsy (stringent: 46.2 vs 14.3%, p = 0.003; two-drug: 40.3 vs 2.2%, p

Special education needs of children with newly diagnosed epilepsy.

Children with epilepsy often experience poor social and educational outcomes. This study aimed to determine the timing of services with respect to the onset of seizures. It also aimed to identify the aspects of childhood epilepsy (type of epilepsy, etiology, seizure control, and treatment) that are associated with the use of special education services. As part of a prospective community-based study, 613 children were recruited when first diagnosed with epilepsy. Mean age at first seizure was 5 years 11 months (SD 4, range 1mo to 15y 8mo). Parents were interviewed 5 years after children were first diagnosed with epilepsy (n=542; 276 [51%] males). Children's mean age at time of interview was 11 years 10 months (SD 4y 1mo, range 5y 8mo to 21y 8mo). Etiology was classified as idiopathic (n=181, 33.4%), cryptogenic (n=261, 48.2%), and remote symptomatic (n=100, 18.5%). Service use was reported in 315 (58%) children. Compared with neurologically intact children (i.e. cryptogenic and idiopathic etiology; n=415, 77%), children with a remote symptomatic etiology and/or an epileptic encephalopathy (n=127, 23%) received services more frequently (88% vs 49%, p<0.001). In the former group, services were initiated for 66 (15%) children before their first seizure; according to age at onset, services were initiated before the first seizures in 12/164 (7.3%) if <5 years, 34/171 (19.9%) if 5-9 years, and 20/80 (25%) if >10 years. A large proportion of children with epilepsy, even if neurologically otherwise normal, receive special education services. Initiation of services often precedes onset of seizures even in neurologically intact children. This suggests that behavioral and cognitive abnormalities may predate the onset of epilepsy and are not necessarily the direct consequences of epilepsy.

Mortality in childhood-onset epilepsy.

OBJECTIVES: To evaluate mortality in children with newly diagnosed epilepsy, to determine the risk of death, and to identify predictors of death from the point of diagnosis. DESIGN: Prospective community-based cohort of 613 children with newly diagnosed epilepsy. The outcome measure was death. Chi2 Tests were used for bivariate analyses and the Cox proportional hazards model for multivariable analyses. Standardized mortality ratios were used to quantify the excess mortality in the cohort relative to the population. RESULTS: Thirteen deaths occurred during 4733 person-years of follow-up, for a crude death rate of 2.7 per 1000 person-years (0.52 per 1000 person-years in those with nonsymptomatic epilepsy and 12.6 per 1000 person-years in those with symptomatic epilepsy). Ten deaths were associated with the underlying cause of the seizures, 2 were associated with the occurrence or probable occurrence of seizures, and 1 was unrelated to seizures or the underlying disorder. On multivariable analysis, symptomatic etiology (rate ratio, 10.2; 95% confidence interval [CI], 2.1-49.6) and epileptic encephalopathy (rate ratio, 13.3; 95% CI, 3.4-51.7) were independently associated with mortality. The overall standardized mortality ratio for the cohort was 7.54 (95% CI, 4.38-12.99). In children with symptomatic epilepsy, the standardized mortality ratio was 33.46 (95% CI, 18.53-60.43), and in those with nonsymptomatic epilepsy, it was 1.43 (95% CI, 0.36-5.73). CONCLUSIONS: Children with epilepsy have an increased risk of death. Most deaths occur in children with severe underlying conditions and are not directly related to the occurrence of seizures.

Longitudinal assessment of adaptive behavior in infants and young children with newly diagnosed epilepsy: influences of etiology, syndrome, and seizure control.

OBJECTIVES: The outcomes of childhood-onset epilepsy are highly varied and have several potential determinants. We examined the independent effects of syndrome type, seizure control, and etiology over time on adaptive behavior as measured by the Vineland Scales of Adaptive Behavior. METHODS: As part of a prospective community-based study of newly diagnosed epilepsy, parents of children who were younger than 3 years at the time of initial onset of epilepsy completed the Vineland Adaptive Behavior Scales screener version at entry into the study and once a year thereafter for up to 3 years. Longitudinal analyses were performed on the composite score as the primary outcome and on the 4 domain scores (communication, socialization, motor, and daily living) as confirmatory/secondary outcomes to determine the effects of syndrome (epileptic encephalopathy or other), seizure control (intractable or not), and etiology (symptomatic or not) on adaptive behavior at the time of initial diagnosis and over time. RESULTS: A total of 613 children were enrolled in the study, and 191 (31%) of these children met the age criterion for this analysis. Of these, 172 (90%) had adequate follow-up and had completed baseline and at least 1 subsequent Vineland assessment. Overall, Vineland scores (composite and individual domains) were somewhat below average at baseline (initial diagnosis). All declined significantly over time. All of the effects at baseline, however, were limited to children with epileptic encephalopathies and symptomatic etiology. Substantial declines over time occurred in these children, and there was an independent effect of intractable seizures as well. In children with none of these factors ( approximately 75% of the study group), baseline scores were consistent with average performance for the test norms and there was no evidence of any decline over time. CONCLUSIONS: Children with an underlying symptomatic etiology or a syndrome that can be characterized as 1 of the epileptic encephalopathies demonstrate impaired adaptive behavior at the time of initial diagnosis and experience additional declines in assessments of age-adjusted performance over time. Our results suggest that future seizure outcome is not strongly reflected in adaptive behavior at initial diagnosis but that it takes its toll on the child over time. Understanding how each of these factors affects development and how they interact with each other is the next step in designing effective interventions for lessening the impact of these disorders on the child. In the majority of children with onset of epilepsy during infancy or early childhood, adaptive behavior is within the normal range and does not show any evidence of declining over time. Although this is encouraging, it does not contradict other studies that have demonstrated behavioral and relatively subtle cognitive difficulties in school-aged children with epilepsy. Long-term follow-up in this cohort will permit us to examine the predictive value of the Vineland for later behavioral and cognitive difficulties in this group that, so far, seems to be doing well.

Modeling remission and relapse in pediatric epilepsy: application of a Markov process.

Seizure outcome is frequently described in terms of patients ever attaining remission or being in terminal remission. Outcomes are more complicated and, over many years, repeated remission and relapses may occur. These are difficult to quantify with standard survival techniques used in analysis of remission and relapse. The Markov process, which allows one to track a patient's state (remission or not) over time, provides a suitable approach for studying repeated remission and relapse. In a prospective community-based study of children followed from the point of the initial diagnosis of epilepsy, we examined the probability of repeated remission and relapse over up to three different remission episodes (minimum 1 year each) per patient. The role of epilepsy syndrome was the main determinant of remission-relapse patterns considered in the analysis. Two different Markov models were used, one involving three states and the other seven states. Of 613 children initially recruited into the study, 602 were followed at least 1 year and thus eligible for the analysis. Almost 90% of the cohort experienced a remission; however, almost half then relapsed. Second remissions occurred in 81% of those who relapsed of whom 38% relapsed again. A third remission occurred in 82% of those after a second relapse of whom 58% relapsed yet again. After the first 2 years, approximately 70% of the cohort was in remission, 20% was no longer in remission having relapsed, and 10% had never been in remission. Significant differences were seen by underlying epilepsy syndrome. Children with one of the epileptic encephalopathies were least likely of all syndrome groups ever to remit. Those with symptomatic partial epilepsies were less likely to remit than children with any of the other syndromes, idiopathic partial or generalized, cryptogenic partial, and unclassified. Differences between these last groups became apparent when considering their subsequent remission and relapse histories. These differences were best seen in the seven-state model. For example, idiopathic partial epilepsies were most likely to enter remission and never relapse. By contrast, idiopathic generalized and cryptogenic partial epilepsies were more likely to remit and relapse repeatedly. The Markov approach provides an alternative to standard survival techniques for understanding remission and relapse outcomes in epilepsy. Its advantage is that it allows one to track the individuals' outcome over time even as the condition fluctuates. The technique would also be applicable in virtually any remitting-relapsing disorder.

Hypothalamic hamartomas: seven cases and review of the literature.

Hypothalamic hamartomas constitute rare developmental lesions associated with gelastic epilepsy and/or precocious puberty (PP). We elected to review cases encountered at our center (7 patients) and the existing literature (277 patients) to obtain a better understanding of the clinical aspects, pathogenesis, and treatment of this entity. Evidence suggests that gelastic seizures are due to intrinsic epileptogenicity. The cause of the subsequent development of other seizure types, cognitive decline, and diffuse spike-and-wave pattern remains unresolved and is addressed. Anticonvulsants often fail to control seizures and different surgical options are available. Available evidence suggests that a resection through a subtemporal approach is best for lesions that are pedunculated or with a significant prepontine component, while a transcallosal approach is more appropriate for sessile lesions with an intraventricular component. Gamma knife surgery may be especially useful for small sessile lesions, failed partial resections, or patients not appropriate or refusing open surgery.