Neuronal antibodies in pediatric epilepsy: Clinical features and long-term outcomes of a historical cohort not treated with immunotherapy.

OBJECTIVE: In autoimmune encephalitis the etiologic role of neuronal cell-surface antibodies is clear; patients diagnosed and treated early have better outcomes. Neuronal antibodies have also been described in patients with pediatric epilepsy without encephalitis. The aim was to assess whether antibody presence had any effect on long-term outcomes in these patients. METHODS: Patients (n = 178) were recruited between 1988 and 1992 as part of the prospective Dutch Study of Epilepsy in Childhood; none received immunotherapy. Healthy age-matched bone-marrow donors served as controls (n = 112). All sera were tested for serum N-methyl-d-aspartate receptor (NMDAR), alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, leucine rich glioma inactivated 1, contactin associated protein like 2 (CASPR2), contactin-2, glutamic acid decarboxylase, and voltage gated potassium channel (VGKC)-complex antibodies by standard techniques. No cerebrospinal fluid (CSF) samples were available. Results were correlated with clinical data collected over 15 years. RESULTS: Seventeen patients (9.5%) were positive for VGKC complex (n = 3), NMDAR (n = 7), CASPR2 (n = 4), and contactin-2 (n = 3), compared to three (3/112; 2.6%) healthy controls (VGKC complex [n = 1], NMDAR [n = 2]; p = 0.03; Fisher's exact test). Titers were relatively low (≤1:100 for cell-surface antibodies), but 8 (47%) of the 17 positive samples bound to the surface of live hippocampal neurons consistent with a potential pathogenic antibody. Preexisting cognitive impairment was more frequent in antibody-positive patients (9/17 vs. 33/161; p = 0.01). Fourteen antibody-positive patients were treated with standard antiepileptic drugs (AEDs); three (17%) became intractable but this was not different from the 16 (10%) of 161 antibody-negative patients. In 96 patients with available follow-up samples at 6 and/or 12 months, 6 of 7 positive antibodies had disappeared and, conversely, antibodies had appeared for the first time in a further 7 patients. SIGNIFICANCE: Neuronal antibodies were found at low levels in 9.5% of patients with new-onset pediatric epilepsy but did not necessarily persist over time, and the development of antibodies de novo in later samples suggests they could be due to a secondary response to neuronal damage or inflammation. Moreover, as the response to standard AEDs and the long-term outcome did not differ from those of antibody-negative pediatric patients, these findings suggest that routine neuronal antibody testing is unlikely to be helpful in pediatric epilepsy. However, the higher incidence of preexisting cognitive problems in the antibody-positive group, the CASPR2 and contactin-2 antibodies in 7 of 17 patients, and the binding of 8 of 17 of serum samples to live hippocampal neurons suggest that neuronal antibodies, even if secondary, could contribute to the comorbidities of pediatric epilepsy.

Progressive cerebellar atrophy and polyneuropathy: expanding the spectrum of PNKP mutations.

We present a neurodegenerative disorder starting in early childhood of two brothers consisting of severe progressive polyneuropathy, severe progressive cerebellar atrophy, microcephaly, mild epilepsy, and intellectual disability. The cause of this rare syndrome was found to be a homozygous mutation (c.1250_1266dup, resulting in a frameshift p.Thr424GlyfsX48) in PNKP, identified by applying homozygosity mapping and whole-genome sequencing. Mutations in PNKP have previously been associated with a syndrome of microcephaly, seizures and developmental delay (MIM 613402), but not with a neurodegenerative disorder. PNKP is a dual-function enzyme with a key role in different pathways of DNA damage repair. DNA repair disorders can result in accelerated cell death, leading to underdevelopment and neurodegeneration. In skin fibroblasts from both affected individuals, we show increased susceptibility to apoptosis under stress conditions and reduced PNKP expression. PNKP is known to interact with DNA repair proteins involved in the onset of polyneuropathy and cerebellar degeneration; therefore, our findings explain this novel phenotype.

Onset of intractability and its course over time: the Dutch study of epilepsy in childhood.

PURPOSE: Intractability in epilepsy is difficult to define, and little is known about its onset, course, and duration. We investigated these aspects (as well as the occurrence of intractability) during long-term follow-up in patients with epilepsy, focusing on possible explanations for the variation in time of onset and duration of intractability. METHODS: After diagnosis, 453 patients with childhood-onset epilepsy had a 5-year follow-up with regular visits and data collection. Ten years later they received a questionnaire with items concerning epilepsy, which was completed by 413 patients resulting in a mean follow-up of 15 years. Intractability during the first 5 years was compared with that in the last year of follow-up. Intractability was defined as having no 3-month remission during a 1-year period despite adequate medical treatment. KEY FINDINGS: At least 12.1% of the cohort had a period of intractability during the 15-year follow-up, and 8.5% were intractable in the final year. Of the patients with idiopathic etiology 4.3% had a period of intractability versus 17.0% for those with cryptogenic, and 22.6% for those with remote symptomatic etiology (p < 0.001). Other risk factors at baseline were younger age at first seizure, generalized cryptogenic/symptomatic or localization-related symptomatic epilepsy, mental retardation, and febrile convulsions before enrollment. The cumulative risk of a period of intractability was 6.1% (95% confidence interval [CI] 3.7-8.5) at 2 years follow-up and 8.2% (95% CI 5.4-11.0) at 5 years. The mean time to onset of intractability during the first 5 years of follow-up was 1.6 (95% CI 1.3-2.0; median 1.0) years and the mean duration of intractability during these 5 years was 3.3 (95% CI 2.8-3.8; median 3.6) years. Fifteen patients were intractable only during the first 5 years of follow-up (group A), and 19 subjects were intractable both during the first 5 years and the last year of follow-up (group B). Compared with group A, group B had shorter remission and a longer time to intractability during the first 5 years and more were intractable in the fifth year of follow-up. Sixteen other patients had a late onset of intractability after 5 years of follow-up, sometimes after long periods of remission (group C). No significant differences in baseline characteristics were found among groups A, B, and C, but slightly more children in groups B and C became mentally retarded during the follow-up. In all groups, antiepileptic drugs were of little use in preventing and ending intractability. SIGNIFICANCE: There is a large unpredictable variation in time of onset, course, and duration of intractability, with a higher chance of final intractability after a poor course during the first 5 years of follow-up. The natural course of epilepsy probably best explains the variable course of intractability. The effect of medication seems to be minor.

Atypical timing and presentation of periventricular haemorrhagic infarction in preterm infants: the role of thrombophilia.

AIM: Periventricular haemorrhagic infarction (PVHI) is a complication of preterm birth associated with cardiorespiratory instability. To date, the role of thrombophilia as a possible additional risk factor in infants with atypical timing and presentation of PVHI has not been investigated. METHOD: This was a retrospective cohort study of preterm infants who developed PVHI with an atypical timing and presentation either of antenatal onset or late in the postnatal course in the absence of a preceding sudden deterioration of their clinical condition. In infants with atypical PVHI mutation analysis of the factor V Leiden (G1691A), prothrombin (G20210A) gene, and C677T and A1298C polymorphisms in the MTHFR gene was performed, and plasma lipoprotein(a) and homocysteine levels were measured. RESULTS: Sixty-two preterm infants who presented with a PVHI were studied. Seventeen had an atypical presentation (seven males, 10 females; median birthweight 1170g [range 580-1990g]; median gestational age 30.6wks [range 28.7-33.7wks]). The typical PVHI group comprised 28 males and 17 females (median birthweight 1200g [range 670-2210g]; median gestational age 29.6wks [range 25.3-33.6wks]). Among the 17 infants with atypical presentation, the factor V Leiden mutation was found in seven infants (41%) as well as in the mothers of six of these seven infants; in one infant this was concomitant with a prothrombin gene mutation. A polymorphism in the MTHFR gene was also present in these infants. In two infants with an atypical presentation who were tested for this, a mutation in the COL4A1 gene was found (reported previously). All but two of the infants with an atypical presentation developed spastic unilateral cerebral palsy. INTERPRETATION: An atypical presentation of PVHI in preterm infants tends to occur more often in the presence of thrombophilia. Testing of thrombophilia, especially factor V Leiden and prothrombin gene mutation, is recommended in these infants.

Nav 1.1 dysfunction in genetic epilepsy with febrile seizures-plus or Dravet syndrome.

Relatively few SCN1A mutations associated with genetic epilepsy with febrile seizures-plus (GEFS+) and Dravet syndrome (DS) have been functionally characterized. In contrast to GEFS+, many mutations detected in DS patients are predicted to have complete loss of function. However, functional consequences are not immediately apparent for DS missense mutations. Therefore, we performed a biophysical analysis of three SCN1A missense mutations (R865G, R946C and R946H) we detected in six patients with DS. Furthermore, we compared the functionality of the R865G DS mutation with that of a R859H mutation detected in a GEFS+ patient; the two mutations reside in the same voltage sensor domain of Na(v) 1.1. The four mutations were co-expressed with ß1 and ß2 subunits in tsA201 cells, and characterized using the whole-cell patch clamp technique. The two DS mutations, R946C and R946H, were nonfunctional. However, the novel voltage sensor mutants R859H (GEFS+) and R865G (DS) produced sodium current densities similar to those in wild-type channels. Both mutants had negative shifts in the voltage dependence of activation, slower recovery from inactivation, and increased persistent current. Only the GEFS+ mutant exhibited a loss of function in voltage-dependent channel availability. Our results suggest that the R859H mutation causes GEFS+ by a mixture of biophysical defects in Na(v) 1.1 gating. Interestingly, while loss of Na(v) 1.1 function is common in DS, the R865G mutation may cause DS by overall gain-of-function defects.

Health perception and socioeconomic status following childhood-onset epilepsy: the Dutch study of epilepsy in childhood.

PURPOSE: Epilepsy may have far-reaching consequences for patients, other than having seizures and medication. At 15 years after diagnosis, this study investigates health perception, restrictions due to epilepsy, living arrangements (including marital status and offspring), and the educational and occupational attainment of patients with childhood-onset epilepsy. METHODS: A total of 453 patients with epilepsy had a 5-year follow-up since diagnosis with regular visits and data collection. Ten years later, a questionnaire addressing epilepsy was completed by 413 patients, resulting in a mean follow-up of 15 years. Subjects were compared with age peers of the Dutch population for each etiologic group separately, and also for subjects with/without a 5-year terminal remission regardless of treatment. Age-adjusted standardized incidence rates were calculated for each variable. KEY FINDINGS: Subjects with normal intelligence had a health perception comparable with that of the general population, but significantly more subjects without remission had a worse health perception, especially those still using medication. Restrictions and symptoms due to epilepsy were reported by 14% of the subjects, mainly by those without remission or with ongoing medication. The living arrangement of subjects with idiopathic or cryptogenic etiology was similar to that of Dutch persons of the same age (age peers). Subjects with remote symptomatic etiology less often lived independently or with a partner, and more frequently resided in an institution or living group for the disabled. Those with and without remission were more often part of another household, mainly due (in both groups) to having a remote symptomatic etiology. Rates of having a partner and offspring were significantly reduced only for subjects with remote symptomatic etiology. Fewer students with idiopathic/remote symptomatic etiology and students in remission followed higher vocational or scientific education. In these latter groups, the highest attained education of employees was lower than expected. The employment status of subjects with idiopathic or cryptogenic etiology was comparable with that of their Dutch age peers, but fewer subjects with remote symptomatic etiology were employed and more of them were part of the dependent population. However, for those in the labor force (employed/unemployed) all employment rates were ≥90%, even for those with remote symptomatic etiology. Nevertheless, fewer employees than expected had a higher vocational or scientific level of occupation, even those with idiopathic etiology and those in remission. SIGNIFICANCE: Health perception, living arrangement, and socioeconomic status were influenced by epilepsy, comorbidities, or treatment, particularly for subjects with remote symptomatic etiology or no remission. The group in remission fared less well than expected, mainly due to the numbers of subjects with remote symptomatic etiology in this group. In line with others, we conclude that childhood-onset epilepsy is associated with lower educational attainment, even for subjects with idiopathic etiology and subjects in remission; probably related to this, their occupational level was also lower than expected.

Course and outcome of childhood epilepsy: a 15-year follow-up of the Dutch Study of Epilepsy in Childhood.

PURPOSE: To study the course and outcome of childhood-onset epilepsy during 15-year follow-up (FU). METHODS: We extended FU in 413 of 494 children with new-onset epilepsy recruited in a previously described prospective hospital-based study by questionnaire. RESULTS: Mean FU was 14.8 years (range 11.6-17.5 years). Five-year terminal remission (TR) was reached by 71% of the cohort. Course during FU was favorable in 50%, improving in 29%, and poor or deteriorating in 16%. Mean duration of seizure activity was 6.0 years (range 0-21.5 years), strongly depending on etiology and epilepsy type. Duration was <1 year in 25% of the cohort and exceeded 12 years in another 25%. Antiepileptic drugs (AEDs) were used by 86% during a mean of 7.4 years: one-third had their last seizure within 1 year of treatment, and one-third continued treatment at the end, although some had a 5-year TR. At last contact, 9% of the cohort was intractable. In multivariate analysis, predictors were nonidiopathic etiology, febrile seizures, no 3-month remission, and early intractability. Eighteen patients died; 17 had remote symptomatic etiology. Standardized mortality ratio for remote symptomatic etiology was 31.6 [95% confidence interval (CI) 18.4-50.6], versus 0.8 [95% CI 0.02-4.2] for idiopathic/cryptogenic etiology. DISCUSSION: In most children with newly diagnosed epilepsy, the long-term prognosis of epilepsy is favorable, and in particular, patients with idiopathic etiology will eventually reach remission. In contrast, epilepsy remains active in approximately 30% and becomes intractable in approximately 10%. AEDs probably do not influence epilepsy course; they merely suppress seizures. Mortality is significantly higher only in those with remote symptomatic etiology.

A network approach to investigate the bi-hemispheric synchrony in absence epilepsy.

OBJECTIVE: Our objective was to unravel the dynamics underlying spike-and-wave discharges (SWDs) characteristic for childhood absence epilepsy. METHODS: SWDs were recorded for a cohort of 28 children using magnetoencephalography. Non-linear association analyses and a graph theoretical metric of local connectedness (LoC) were utilized in a sliding window starting one s before till four s after ictal onset. RESULTS: A focal pattern of bilateral frontal and parietal areas with high LoC during the spikes alternated by generalized patterns during the waves was found for all children studied during generalization of the SWDs. In the interval preceding the generalization a focal parietal region was most often (16/28) encountered and less often an occipital (4/28), temporal (5/28) or frontal (3/28) region. 55% of the children with a parietal/occipital focal onset became seizure free after the administration of two anti-epileptic drugs, and only 12.5% with a temporal/frontal focal onset. CONCLUSIONS: The transition from the interictal to the ictal state is for some of the children characterized by dominant LoC at either the parietal/occipital and for others at the frontal/temporal region. SIGNIFICANCE: The focal onset of the SWDs varies in location among the children with a clinical similar profile, who, however, seemingly are differing with regard to seizure control.

Childhood epilepsy with a small number of seizures may be left untreated: an international prospective study.

It is unknown whether treatment with antiepileptic drugs in children with epilepsy with a presumed good prognosis is always necessary. We aimed to study the course of newly diagnosed epilepsy in children with a presumed good prognosis who are managed without AED treatment. A total of 151 children (one month to 12 years of age) with two to five lifetime unprovoked seizures (excluding febrile convulsions), were followed for three years. Treatment was initially withheld. Children with symptomatic epilepsy, or absence or myoclonic epilepsy, were excluded. AED treatment was started after >10 lifetime seizures or an episode of status epilepticus during follow-up, or if the parents or treating physician deemed it otherwise necessary. During follow-up, 113 children continued to meet our criteria for refraining from treatment with antiepileptic drugs, yet 30 started treatment at the request of the parents. Thirty-eight children at some time met the criteria to start treatment, but the parents of 16 declined treatment. In all, 99 (66%) children maintained the no-treatment regime. Ninety-eight children (65% of 151) reached terminal remission for at least one year, including 83 who did not receive antiepileptic drug treatment (84% of the untreated 99). Mean terminal remission was significantly longer in the group with a total of <10 seizures compared to those with >10 seizures. Treatment did not increase the length of terminal remission. Adverse events, including traumatic injury, occurred equally in the treated and untreated children. Measures of quality of life suggested a better outcome in those without treatment. Children with newly diagnosed epilepsy with a presumed good prognosis may not need immediate AED treatment. Postponing treatment does not alter the chance of remission or the risk of accidents and adverse events and appears to be associated with a good quality of life.

Add-on levetiracetam in children and adolescents with refractory epilepsy: results of an open-label multi-centre study.

PURPOSE: To study the efficacy and tolerability of add-on levetiracetam in children and adolescents with refractory epilepsy. METHODS: In this prospective multi-centre, open-label, add-on study, 33 children aged 4-16 years (median 8.5 years) with epilepsy refractory to at least two antiepileptic drugs were treated with levetiracetam in addition to their present treatment regimen with a follow-up of 26 weeks. The starting dose of 10 mg/kg/day was increased with 2-week steps of 10 mg/kg/day, if necessary, up to a maximum dose of 60 mg/kg/day. RESULTS: Retention rate was 69.7% after 26 weeks on a median levetiracetam dosage of 22 mg/kg/day. Four children dropped-out because levetiracetam was ineffective, four because seizure frequency increased and/or seizures became more severe, and two because they developed aggressive behaviour. Compared to their baseline seizure frequency, 13 children (39.4%) had a >50% seizure reduction 12 weeks after initiation of levetiracetam, and 17 children (51.5%) at 26 weeks. At 26 weeks, nine children (27.3%) had been seizure-free for at least the last 4 weeks, terminal remission ranged from 0 to 187 days (mean 46 days). Levetiracetam was effective in both partial and primary generalized seizures, but had most effect in partial seizures. Most reported side effects were hyperactivity (48.5%), somnolence (36.4%), irritability (33.3%) and aggressive behaviour (27.3%). Severity of most side effects was mild. Five children had a serious adverse event, which all concerned hospital admissions that were not related to levetiracetam use. CONCLUSION: Levetiracetam proved to be an effective and well-tolerated add-on treatment in this group of children with refractory epilepsy.

Is colour modulation an independent factor in human visual photosensitivity?

Considering that the role of colour in photosensitive epilepsy (PSE) remains unclear, we designed a study to determine the potential of different colours, colour combinations and white light to trigger photoparoxysmal responses (PPRs) under stringent controlled conditions. After assessing their photosensitivity to stroboscopic white light and black and white patterns, we studied 43 consecutive PSE patients (mean age 19 years, 34 women), using a specially designed colour stimulator. Stimuli included: pulse trains between 10 and 30 Hz of white light and of all primary colours, and also isoluminant alternating time-sequences of colours. Illuminance was kept constant at 100 lux. A progressive stepwise increase of the modulation-depth (MD) of the stimuli was used to determine PPRs threshold. Whereas all the 43 patients were found to be sensitive during the stroboscopic and pattern protocol, only 25 showed PPRs (Waltz's score >2) at least in one session when studied with the colour stimulator. Coloured stimuli elicited PPRs in all these patients, whereas white light did so only in 17 patients. Of the primary colours, red elicited more PPRs (54 in 22 patients) and at a lower MD (max Z-score 0.93 at 10 Hz). Of the alternating sequences, the red-blue was the most provocative stimulus, especially below 30 Hz (100% of patients, max Z-score: 1.65 at 15 Hz). Blue-green was the least provocative stimulus, since it elicited only seven PPRs in seven (28%) patients (max Z-score 0.44 at 10 Hz). Sensitivity to alternating colours was not correlated to sensitivity to individual colours. We conclude that colour sensitivity follows two different mechanisms: one, dependent on colour modulation, plays a role at lower frequencies (<30 Hz). Another, dependent on single-colour light intensity modulation correlates to white light sensitivity and is activated at higher frequencies. Our results suggest that the prescription of spectacles with coloured lenses, tailored to the patient, can be an effective preventative measure against visually induced seizures.

Pancreatitis, complicated by a pancreatic pseudocyst associated with the use of valproic acid.

A 12-year-old boy developed pancreatitis, complicated by a pancreatic pseudocyst, as an adverse reaction to valproic acid (VPA) treatment for epilepsy. Pancreatitis subsided within three weeks after discontinuation of VPA. The pancreatic pseudocyst was managed without surgery and resolved spontaneously in four weeks. Valproic acid was concluded to be the most probable cause, since no other explanation was found. According to the literature VPA is a rare but known cause of pancreatitis. A computer-assisted literature search revealed seven previously reported cases of VPA-induced pancreatitis complicated by a pancreatic pseudocyst. Six of these patients were under 20 years of age. Four patients were treated conservatively; three needed cystostomy or external drainage. All patients recovered. Patients using VPA, especially children, presenting with acute abdominal pain should be suspected of valproic acid-induced pancreatitis. If VPA induced pancreatitis is complicated by a pseudocyst, conservative treatment should be the first line of treatment.

Course and prognosis of childhood epilepsy: 5-year follow-up of the Dutch study of epilepsy in childhood.

Knowing the prognosis of epilepsy will undoubtedly influence the treatment strategy. This study aimed to define the prospects of newly diagnosed childhood epilepsy, assess the dynamics of its course, identify relevant variables and develop models to assess the individual prognosis. Four hundred and fifty-three children with newly diagnosed epilepsy were followed for 5 years. Terminal remission at 5 years (TR5) was compared with terminal remission at 2 years (TR2) and with the longest remission during follow-up. Variables defined at intake and at 6 months of follow-up were analysed for their prognostic relevance. In multivariate analyses, combinations of variables were tested to develop reliable models for the calculation of the individual prognosis. Data on treatment, course during follow-up and epilepsy syndromes were also studied. Three hundred and forty-five children (76%) had a TR5 >1 year, 290 (64%) >2 years and 65 (14%) had not had any seizure during the entire follow-up. Out of 108 children (24%) with TR5 <1 year, 27 were actually intractable at 5 years. Medication was started in 388 children (86%). In 227 of these (59%), anti-epileptic drugs (AEDs) could be withdrawn. A TR5 >1 year was attained by 46% on one AED, on the second AED by 19%, and by 9% on all additional AED regimes. Almost 60% of the children treated with a second or additional AED regime had a TR5 >1 year. Variables predicting the outcome at intake were aetiology, history of febrile seizures and age. For intake and 6-month variables combined, sex, aetiology, postictal signs, history of febrile seizures and TR at 6 months were significant. The model derived from intake variables only predicted TR5 <1 year correctly in 36% and TR5 >1 year in 85% (sensitivity 0.65, specificity 0.64). The corresponding values for the model derived from intake and 6-month variables were 43 and 88% (sensitivity 0.69, specificity 0.71). The course of the epilepsy was constantly favourable in 51%, steadily poor in 17%, improving in 25% and deteriorating in 6%. Intractability was in part only a temporary phenomenon. The outcome at 5 years in this cohort of children with newly diagnosed epilepsy was favourable in 76%; 64% were off medication at that time. Almost a third of the children had a fluctuating course; improvement was clearly more common than deterioration. After failure of the first AED, treatment can still be successful. Models predicting the outcome have fewer misclassifications when predicting a long terminal remission than when predicting continuing seizures.

Effect of vaccinations on seizure risk and disease course in Dravet syndrome.

OBJECTIVE: To study the effect of vaccination-associated seizure onset on disease course and estimate the risk of subsequent seizures after infant pertussis combination and measles, mumps, and rubella (MMR) vaccinations in Dravet syndrome (DS). METHODS: We retrospectively analyzed data from hospital medical files, child health clinics, and the vaccination register for children with DS and pathogenic SCN1A mutations. Seizures within 24 hours after infant whole-cell, acellular, or nonpertussis combination vaccination or within 5 to 12 days after MMR vaccination were defined as "vaccination-associated." Risks of vaccination-associated seizures for the different vaccines were analyzed in univariable and in multivariable logistic regression for pertussis combination vaccines and by a self-controlled case series analysis using parental seizure registries for MMR vaccines. Disease courses of children with and without vaccination-associated seizure onset were compared. RESULTS: Children who had DS (n = 77) with and without vaccination-associated seizure onset (21% and 79%, respectively) differed in age at first seizure (median 3.7 vs 6.1 months, p < 0.001) but not in age at first nonvaccination-associated seizure, age at first report of developmental delay, or cognitive outcome. The risk of subsequent vaccination-associated seizures was significantly lower for acellular pertussis (9%; odds ratio 0.18, 95% confidence interval [CI] 0.05-0.71) and nonpertussis (8%; odds ratio 0.11, 95% CI 0.02-0.59) than whole-cell pertussis (37%; reference) vaccines. Self-controlled case series analysis showed an increased incidence rate ratio of seizures of 2.3 (95% CI 1.5-3.4) within the risk period of 5 to 12 days following MMR vaccination. CONCLUSIONS: Our results suggest that vaccination-associated earlier seizure onset does not alter disease course in DS, while the risk of subsequent vaccination-associated seizures is probably vaccine-specific.

Encephalopathy associated with influenza A.

We report a 3-year-old boy with influenza A virus-associated encephalopathy. The diagnosis was based on clinical findings, magnetic resonance imaging, repeated isolation of influenza A virus from nasopharyngeal aspirate and seroconversion between acute and convalescent sera. The clinical picture was characterized by fever and aphasia followed by seizures and a rapid deterioriation of consciousness 2 days later. This patient illustrates that influenza A-associated encephalopathy with severe neurological deficit can occur with atypical distribution of brain lesions during the course of the illness, while initial brain MRI and laboratory findings of cerebrospinal fluid are normal, including reverse transcription polymerase chain reaction.

Parent-reported subjective complaints in children using antiepileptic drugs: what do they mean?

We used a parent-completed 20-item "side effect scale" quantifying complaints that parents perceive to be caused by antiepileptic drugs (AEDs) in 108 children with active epilepsy. We studied the associations between parent-reported complaints, severity of seizures, and restrictions due to epilepsy, and clinical data including number and AED load. In 85% of the children at least one complaint was reported, in less than 20% complaints were perceived as a substantial problem. In a multivariate analysis, there was no significant relationship between the "side effect scale" score and AED load, or the number of AEDs. However, complaints were associated with parent-reported frequency and severity of seizures. We conclude that the adverse effects of seizures or parental concern about the severity and intractability of seizures in their children may have influenced the reported complaints.

Long term outcome of benign childhood epilepsy with centrotemporal spikes: Dutch Study of Epilepsy in Childhood.

PURPOSE: To determine long-term outcome in a cohort of children with newly diagnosed benign childhood epilepsy with centrotemporal spikes (BECTS). METHODS: 29 children with BECTS were included in the Dutch Study of Epilepsy in Childhood. Each child was followed for 5 years, and subsequently contacted 12-17 years after enrolment to complete a structured questionnaire. Twenty children had typical BECTS, nine had atypical BECTS (age at onset <4 years, developmental delay or learning difficulties at inclusion, other seizure types, atypical EEG abnormalities). RESULTS: Mean age at onset of epilepsy was 8.0 years with slight male preponderance. Most common seizure-types before enrolment were generalized tonic-clonic seizures (GTCS) and simple partial seizures; in 86% of the children seizures occurred during sleep. After 12-17 years, 96% had a terminal remission (TR(F)) of more than 5 years and 89% of more than 10 years. Mean duration of epilepsy was 2.7 years; mean age at reaching TR(F) was 10.6 years. Many children (63%) had experienced one or more (secondary) GTCS. Antiepileptic drugs were used by 79% of the children with a mean duration of 3.0 years. None of the children seemed to have developed learning problems or an arrest of cognitive development during follow-up. No significant differences were observed in patient characteristics or outcome between children with typical BECTS and children with atypical BECTS. CONCLUSIONS: All children in our cohort, both those with typical and atypical BECTS, had a very good prognosis with high remission rates after 12-17 years. None of the predictive factors for disease course and outcome observed in earlier studies (other seizure types, age at onset, multiple seizures at onset) were prognostic in our cohort.

Fatigue and depression in children with multiple sclerosis and monophasic variants.

BACKGROUND: Fatigue is an important symptom in adult multiple sclerosis (MS) and it is likely to occur in children with MS. It is currently unknown whether children who experienced a monophasic inflammatory demyelinating event of the central nervous system in the past also suffer from fatigue. METHODS: We studied the presence and severity of fatigue in 32 children (18 boys, 14 girls) between 11-17 years old (mean: 14 years, 10 months) with a monophasic inflammatory demyelinating disease (n=22) or definite MS (n=10). This was measured with the Checklist Individual Strength. A score of >or=40 on the severity of fatigue subscale indicated the presence of severe fatigue. We also examined the relation between fatigue and depression (assessed by the Child Depression Inventory). Additionally we measured the health-related quality of life (HRQoL), using the TNO-AZL Child Quality of Life child form. We compared the scores of the MS and monophasic patients with the scores of healthy Dutch children. RESULTS: The highest scores on the fatigue scales subjective fatigue and physical activity were found in the children with MS. Only 1 of the monophasic patients suffered from severe fatigue in contrast to 4 of the MS patients. In the MS group fatigue and depression were correlated. MS patients experienced a lower HRQoL on the scales locomotor functioning, cognitive functioning and interaction with peers. CONCLUSION: The occurrence of fatigue is very rare after a monophasic inflammatory demyelinating event in the past. As expected, fatigue occurs more frequent in paediatric MS patients.

Long-term outcome of childhood absence epilepsy: Dutch Study of Epilepsy in Childhood.

SUMMARY: We determined long-term outcome and the predictive value of baseline and EEG characteristics on seizure activity evolution in 47 children with newly diagnosed childhood absence epilepsy (CAE) included in the Dutch Study of Epilepsy in Childhood. All children were followed for 12-17 years. The children were subdivided in three groups for the analyses: those becoming seizure-free (I) within 1 month after enrolment; (II) 1-6 months after enrolment; and (III) more than 6 months after enrolment or having seizures continuing during follow-up. No significant differences were observed between groups in sex, age at onset, occurrence of febrile seizures, and positive first-degree family history for epilepsy. All groups had high remission rates after 12-17 years. Significantly more relapses occurred in group III than in group I. Total duration of epilepsy and mean age at final remission were 3.9 and 9.5 years, respectively, being significantly longer and higher in group III than in groups I and II. In all groups only a small number of children (total 13%) developed generalized tonic-clonic seizures. In conclusion, our children with CAE had an overall good prognosis with few children (7%) still having seizures after 12-17 years. Remission rate in children with CAE cannot be predicted on the basis of baseline and EEG characteristics. The early clinical course (i.e. the first 6 months) has some predictive value with respect to the total duration of absence epilepsy.

Status epilepticus in children with epilepsy: Dutch study of epilepsy in childhood.

PURPOSE: To study course and outcome of epilepsy in children having had a status epilepticus (SE) as the presenting sign or after the diagnosis. METHODS: A total of 494 children with newly diagnosed epilepsy, aged 1 month through 15 years, were followed prospectively for 5 years. RESULTS: A total of 47 Children had SE. Forty-one of them had SE when epilepsy was diagnosed. For 32 (78%), SE was the first seizure. SE recurred in 13 out of 41 (32%). Terminal remission at 5 years (TR5) was not significantly worse for these 41 children: 31.7% had a TR5 <1 year versus 21.2% of 447 children without SE. They were not more often intractable. Five out of six children with first SE after diagnosis had a TR5 <1 year. Mortality was not significantly increased for children with SE. Independent factors associated with SE at presentation were remote symptomatic and cryptogenic etiology, and a history of febrile convulsions. Children with first SE after inclusion more often had symptomatic etiology. CONCLUSIONS: Although we find a trend for shorter TR5 in children with SE at presentation, outcome and mortality are not significantly worse. Etiology is an important factor for prognosis. Children with SE during the course of their epilepsy have a worse prognosis and a high recurrence rate of SE. This outcome is not due to the SE itself, but related to the etiology and type of epilepsy. The occurrence of SE is just an indicator of the severity of the disease.