Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis.

OBJECTIVE: This nationwide cohort study evaluates seizure responses to immunotherapy and antiepileptic drugs (AEDs) in patients with anti-leucine-rich glioma-inactivated 1 (LGI1), anti-NMDA receptor (NMDAR), and anti-gamma-aminobutyric-acid B receptor (GABABR) encephalitis. METHODS: Anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis patients with new-onset seizures were included. Medical information about disease course, AEDs and immunotherapies used, effects, and side effects were collected. Outcome measures were (1) seizure freedom while using AEDs or immunotherapy, (2) days to seizure freedom from start of AEDs or immunotherapy, and (3) side effects. RESULTS: Of 153 patients with autoimmune encephalitis (AIE) (53 LGI1, 75 NMDAR, 25 GABABR), 72% (n = 110) had epileptic seizures, and 89% reached seizure freedom. At least 53% achieved seizure freedom shortly after immunotherapy, and 14% achieved seizure freedom while using only AEDs (p < 0.0001). This effect was similar in all types (p = 0.0001; p = 0.0005; p = 0.013, respectively). Median time to seizure freedom from AEDs start was 59 days (interquartile range [IQR] 27-160), and 28 days from start of immunotherapy (IQR 9-71, p < 0.0001). Side effects were psychotic behavior and suicidal thoughts by the use of levetiracetam, and rash by the use of carbamazepine. Carbamazepine was more effective than levetiracetam in reducing seizures in anti-LGI1 encephalitis (p = 0.031). Only 1 patient, of 86 surviving patients, developed epilepsy after resolved encephalitis. CONCLUSION: Epilepsy after resolved encephalitis was rare in our cohort of patients with AIE treated with immunotherapy. In addition, seizure freedom is achieved faster and more frequently after immunotherapy. Therefore, AEDs should be considered as add-on treatment, and similar to treatment of other encephalitis symptoms, immunotherapy is crucial.

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.

Epilepsy surgery can help many more adult patients with intractable seizures.

PURPOSE: To quantify underreferral for epilepsy surgery in The Netherlands, and reveal its causes. METHODS: Cross-sectional sample of medical files of epilepsy patients from eight general hospitals and two tertiary care epilepsy centers. We selected patients, not seizure free despite 3 or more anti-epileptic drugs. Medical records were judged by an expert panel whether referral should have been done according to published Dutch guidelines. The treating neurologists were confronted with the panel's judgement. KEY FINDINGS: In a sample of 1424 patients, 69 had been referred; another 265 were intractable and not referred; 139 of these 265 patients should have been according to the panel. In 89 of 139 patients, the neurologist gave additional arguments for not referring, mainly the physician's estimate of (low) seizure burden or the patient's psychological condition. In 66 of 89 cases, this could not convince the panel. Attitudes were similar in secondary and tertiary treatment centers. Multivariable data analysis showed independent predictors of incorrectly, versus correctly, not referred patients. SIGNIFICANCE: Substantial underreferral exists in The Netherlands, withholding refractory patients seizure freedom. Adherence to existing guidelines, better prioritizing of surgical work-up, and unprejudiced discussion of surgical treatment with the patient, could lead to 2-2.5 times more referrals.

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.

[Epilepsy from seizure to care]. / Epilepsie van aanval tot zorg.

Epilepsy is very common. The prevalence in the Netherlands is 5:1000 inhabitants. The diagnosis is mostly made on clinical grounds and often incorrectly. If there are doubts about the diagnosis, the patient can be referred to a specialised centre for a seizure registration with an EEG and video recording. The disorder generally responds well to treatment with anti-epileptics. Some 60-70% of patients treated with these remain free of seizures. If medicinal treatment fails then a surgical intervention can be considered. For patients with temporal epilepsy in particular, there is quite a high chance that a surgical intervention will resolve the symptoms. Where it proves difficult to satisfactorily adjust the medication of a patient, stimulation of the left vagus nerve can be considered. Paying more attention to the side effects of the medication and the limitations imposed on the patients can reduce the negative influence of epilepsy on the quality of life.

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.

How confident are we of the diagnosis of epilepsy?

The diagnosis of a first seizure or epilepsy may be subject to interobserver variation and inaccuracy with possibly far-reaching consequences for the patients involved. We reviewed the current literature. Studies on the interobserver variation of the diagnosis of a first seizure show that such a diagnosis is subject to considerable interobserver disagreement. Interpretation of the electroencephalogram (EEG) findings is also subject to interobserver disagreement and is influenced by the threshold of the reader to classify EEG findings as epileptiform. The accuracy of the diagnosis of epilepsy varies from a misdiagnosis rate of 5% in a prospective childhood epilepsy study in which the diagnosis was made by a panel of three experienced pediatric neurologists to at least 23% in a British population-based study, and may be even higher in everyday practice. The level of experience of the treating physician plays an important role. The EEG may be helpful but one should be reluctant to make a diagnosis of epilepsy mainly on the EEG findings without a reasonable clinical suspicion based on the history. Being aware of the possible interobserver variation and inaccuracy, adopting a systematic approach to the diagnostic process, and timely referral to specialized care may be helpful to prevent the misdiagnosis of epilepsy.

Validation of two prognostic models predicting outcome at two years after diagnosis in a new cohort of children with epilepsy: the Dutch Study of Epilepsy in Childhood.

PURPOSE: To validate two prognostic models for childhood-onset epilepsy designed to predict a terminal remission of <6 months at 2 years after diagnosis in children referred to the hospital. METHODS: A hospital-based cohort of children with newly diagnosed epilepsy was recruited and followed up for 2 years to validate previously developed models. One model was based on variables collected at intake, and the other was based on intake variables plus variables collected during the first 6 months of follow-up. The accuracy of both models was estimated by measuring the area under the receiver-operant-characteristic curves (ROC area). RESULTS: The ROC area of the model developed with intake variables was 0.69 [95% confidence interval (CI), 0.64-0.74] for the original cohort and 0.62 (95% CI, 0.55-0.69) for the validation cohort. The best combination of sensitivity and specificity for the original cohort was 61.6% and 69.1%, whereas it was 60.0% and 61.4% for the validation cohort. For the model with intake and 6-month variables combined, the ROC area was 0.78 (95% CI, 0.73-0.82) for the original cohort and 0.71 (95% CI, 0.64-0.78) for the validation cohort. The sensitivity and specificity were 72.6% and 73.1%, respectively, for the original cohort and 67.4% and 60.2%, respectively, for the validation cohort. CONCLUSIONS: Although both models predict outcome better than chance, they are insufficiently accurate to be of practical value. Both models performed marginally less well with the validation cohort than with the original cohort, but in both instances, the model based on intake and 6-month variables was more accurate.

Interobserver reliability of visual interpretation of electroencephalograms in children with newly diagnosed seizures.

The reliability of visual interpretation of electroencephalograms (EEG) is of great importance in assessing the value of this diagnostic tool. We prospectively obtained 50 standard EEGs and 61 EEGs after partial sleep deprivation from 93 children (56 males, 37 females) with a mean age of 6 years 10 months (SE 5 mo; range 4 mo-15 y 7 mo) with one or more newly diagnosed, unprovoked seizures. Two clinical neurophysiologists independently classified the background pattern and the presence of epileptiform discharges or focal non-epileptiform abnormalities of each EEG. The agreement was substantial for the interpretation of the EEG as normal or abnormal (kappa 0.66), almost perfect for the presence of epileptiform discharges (kappa 0.83), substantial for the occurrence of an abnormal background pattern (kappa 0.73), and moderate for the presence of focal non-epileptiform discharges (kappa 0.54). In conclusion, the reliability of the visual interpretation of EEGs in children is almost perfect as regards the presence of epileptiform abnormalities, and moderate to substantial for the presence of other abnormalities.

Increased occurrence of left-handedness after severe childhood bacterial meningitis: support for the pathological left-handedness hypothesis.

The hypothesis that brain damage during infancy causes pathological left-handedness was tested by assessing handedness in 182 survivors of childhood non-Hemophilus influenza type b bacterial meningitis in the Netherlands (mean age of 9.7 years). These children were selected randomly after clustering them into those with or without parental report on academic and behavioural problems. Medical records were obtained from the hospitals, while handedness and neurodevelopmental outcome were assessed at school age. Logistic regression analysis was used to study the relationship between a severity score of bacterial meningitis and handedness. Fifteen percent were left-handed. Severity of childhood bacterial meningitis was related to left-handedness (Odds ratio (OR) 6.2, 95% confidence interval (CI) 2.0-18.6 for those with a total severity score above the median as compared to those below). Compared to non-left-handed children, left-handed children had lower IQ (mean difference -6.6, 95% CI -12 to -1.2), tended to have lower vocabulary scores on WISC-r (-1.0, -2.1 to 0), and lower Beery scores on visual-motor integration (-4.9, -10.1 to 0.4). Left-handed children also tended to have more combined academic and behavioural limitations (OR 2.7, 95% CI 0.9-8.6), lower manual speed of the dominant hand (mean difference -9 taps, p < 0.05) and better manual steadiness in the non-dominant hand (mean difference of contact's time -2.7 s, p < 0.05). Left-handed post-meningitic children generally have worse neurodevelopmental outcome than non-left-handed survivors. Our results support the role of early life brain damage in left-handedness.

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.

Propofol in status epilepticus: little evidence, many dangers?

INTRODUCTION: Several guidelines recommend the use of propofol for the treatment of refractory status epilepticus. An increased mortality rate in high dose, long-term treatment with propofol in adult patients was published recently. This prompted us to assess the literature on the scientific evidence for the efficacy and safety of propofol in the treatment of refractory status epilepticus. METHODS: Medline was searched and the three authors independently reviewed all Medline abstracts for selection of papers. RESULTS: We included 22 articles with original data on the use of propofol in refractory status epilepticus. Randomised clinical trials were lacking. Two non-randomised studies compared propofol with barbiturates and midazolam respectively. Both studies reported a higher risk of mortality for propofol. In addition, case reports and case series on the use of propofol as anaesthetic or sedative in children and adults reported several lethal cases. CONCLUSIONS: Serious doubts may be raised on the safety of propofol in the treatment of refractory status epilepticus. The two non-randomised studies and several case reports show an increased risk of mortality. Guidelines should not recommend the use of propofol as a routine treatment in refractory status epilepticus before a proper randomised trial has been performed.

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.