Can we predict efficacy of the ketogenic diet in children with refractory epilepsy?

BACKGROUND: The ketogenic diet (KD) can be effective in reducing seizures in children. Predictors of success have not been identified yet. AIMS: To evaluate efficacy of KD treatment and to search for child- or diet-related factors that can predict its efficacy at 12 months follow-up. In addition we wish to determine the usefulness of a 3-month KD trial period. METHODS: Single center retrospective study in a university paediatric hospital of children with refractory epilepsy in which the KD had been initiated. Patient and diet characteristics as well as seizure reduction data were obtained from medical records and parental review. Efficacy of the KD was defined as ≥ 50% seizure reduction. Variables were evaluated in their relation to a successful treatment at three and 12 months after diet initiation. RESULTS: During a 9.5-year period, the KD was initiated in 59 children with refractory epilepsy. Twenty-four children were still on the KD after 12 months, and 21 experienced ≥50% seizure reduction. Success of the KD at three months was significantly related to a successful response to KD treatment at 12 months (p < 0.001). CONCLUSIONS: The KD can be an effective treatment in reducing seizures in children with refractory epilepsy. No significant relationships between variables and efficacy at 12 months were revealed. Children with a successful response at 3 months were significantly more likely to achieve success at 12 months of KD treatment.

Long-term outcome in children with low grade tectal tumours and obstructive hydrocephalus.

BACKGROUND: Neuropsychological deficits after treatment of paediatric brain tumour are well known, but not the role of hydrocephalus in these deficits. AIMS: To study long-term neurological, cognitive, and behavioural deficits in children with a low grade tectal tumour and acquired obstructive hydrocephalus. METHODS: In a consecutive series of 12 children with low-grade tectal tumour diagnosed in our hospital between 1994 and 2008, neurologic, neuropsychological, and radiologic data were prospectively collected. Intelligence, memory, attention, language, visual-spatial, and executive functions were assessed. Median follow-up was 2 years and 9 months. RESULTS: At follow-up, most frequent neurologic disability was fatigue in children with a low-grade tectal tumour. They scored lower on sustained attention, long-term memory and had more behavioural problems. Factor influencing cognition was persisting severe hydrocephalus at time of assessment. The cognitive problems resulted in 60% of children needing assistances of special services at school. CONCLUSIONS: At long-term, children with a low-grade tectal tumour display invalidating neuropsychological impairments resulting in educational problems. Adequate treatment of hydrocephalus may result in better cognitive functioning. Our findings suggest that part of the symptoms of the cerebellar cognitive affective syndrome may not have resulted from a cerebellar lesion itself but rather from a cerebral dysfunction or compression of supratentorial structures in the cerebello-cortical circuitry due to the obstructive hydrocephalus.

Paroxysmal disorders in infancy and their risk factors in a population-based cohort: the Generation R Study.

AIM: To examine the incidence of paroxysmal epileptic and non-epileptic disorders and the associated prenatal and perinatal factors that might predict them in the first year of life in a population-based cohort. METHOD: This study was embedded in the Generation R Study, a population-based prospective cohort study from early fetal life onwards. Information about the occurrence of paroxysmal events, defined as suddenly occurring episodes with an altered consciousness, altered behaviour, involuntary movements, altered muscle tone, and/or a changed breathing pattern, was collected by questionnaires at the ages of 2, 6, and 12 months. Information on possible prenatal and perinatal determinants was obtained by measurements and questionnaires during pregnancy and after birth. RESULTS: Information about paroxysmal events in the first year of life was available in 2860 participants (1410 males, 1450 females). We found an incidence of paroxysmal disorders of 8.9% (n=255) in the first year of life. Of these participants, 17 were diagnosed with febrile seizures and two with epilepsy. Non-epileptic events included physiological events, apnoeic spells, loss of consciousness by causes other than epileptic seizures or apnoeic spells, parasomnias, and other events. Preterm birth (p<0.001) and low Apgar score at 1 minute (p<0.05) were significantly associated with paroxysmal disorders in the first year of life. Continued maternal smoking during pregnancy and preterm birth were significantly associated with febrile seizures in the first year of life (p<0.05). INTERPRETATION: Paroxysmal disorders are frequent in infancy. They are associated with preterm birth and a low Apgar score. Epileptic seizures only form a minority of the paroxysmal events in infancy. In this study, children whose mothers continued smoking during pregnancy had a higher reported incidence of febrile seizures in the first year of life. These findings may generate various hypotheses for further investigations.

Landau-Kleffner syndrome and CSWS syndrome: treatment with intravenous immunoglobulins.

This study reports results of therapy with immunoglobulin in children with Landau-Kleffner syndrome (LKS) or the syndrome of continuous spikes and waves during sleep (CSWS syndrome). In a prospective study, children diagnosed between 2002 and 2006 with either LKS or CSWS syndrome were treated soon after diagnosis with intravenous courses of immunoglobulin (IVIg). We compared the results with those reported in the literature and with data from a retrospective survey of our earlier patients. Six children (two girls), aged 4-9 years, were included. Three had LKS, and three had CSWS syndrome. One child-with typical LKS-had been treated with prednisone before (without response). No patient had seizures during IVIg treatment and follow-up. Their electroencephalography (EEG) findings did not improve. Neuropsychological improvement occurred in one child with CSWS syndrome. Three children did not show any beneficial effect; they were subsequently treated with steroids, one with a clearly positive result. We conclude that successful treatment of LKS and CSWS syndrome with IVIg occurs occasionally. However, the improvement cannot always be clearly attributed to this. It might also reflect the natural course of the disease. Although the temporal relation between IVIg treatment and clinical improvement cannot be denied in individual patients, its real value remains to be determined.

When to start drug treatment for childhood epilepsy: the clinical-epidemiological evidence.

INTRODUCTION: Many data on the course and prognosis after provoked and unprovoked single and multiple seizures in childhood have been collected in the past decennia by prospective, large-scale, long-term observational cohort studies. These data may serve to guide treatment decisions and help to design controlled trials investigating treatment strategies in childhood epilepsy. METHODS: The results of the Dutch study of epilepsy in childhood will be compared with those of other studies. We will also discuss the potential consequences of these results for the "why" and "when" of the decision to start treatment. RESULTS: Recurrence after a solitary unprovoked seizure in childhood is about 50%. Those with a recurrence have a similar outcome of their epilepsy compared to children presenting with multiple seizures, regardless whether they were treated after the first seizure or not. This argues in favour of postponing anti-epileptic drug (AED) treatment until at least a second seizure has occurred. After an unprovoked status epilepticus (SE), later outcome is not worse than after presentation with a short seizure. Therefore, long-term AED treatment after a single unprovoked SE may not be necessary either. The same holds true for children presenting with a short (less than one week) burst of unprovoked seizures. One quarter of them do not have recurrences and the final prognosis of children with recurrences does again not differ from the prognosis of the entire cohort. Findings in new-onset epilepsy further indicate that AED treatment can be safely omitted or at least postponed in about 15%, especially those with only a small number of seizures before presentation, those with benign partial epilepsy and those with sporadic generalised tonic-clonic seizures. On the reverse side, three considerations might lead to the decision to start early and aggressive treatment: the dangers of the seizures, the chance of intractability and the possibility of intellectual decline caused by recurrent seizures or epileptic activity. In idiopathic generalised absence epilepsy, the risks of accidents and learning problems indeed prompt early AED treatment. A self-propagating mechanism of seizures promoting the occurrence of more seizures, in the end causing intractable epilepsy (Gowers), occurs only rarely. Real intractability is seen in only 5-15% of the children with new-onset epilepsy. The chance of intractability is increased by variables like symptomatic aetiology, localisation-related epilepsy, and an early unfavourable course. Landau-Kleffner or continuous spikes and waves during sleep (CSWS) syndrome cause cognitive decline and syndromes like West, Lennox-Gastaut or Dravet's induce both psychomotor regression and intractability. In such cases, early aggressive treatment is indicated, including early consideration of the ketogenic diet, immunotherapy, vagus nerve stimulation and, if possible, referral for epilepsy surgery. CONCLUSIONS: Omitting or postponing treatment after a solitary seizure, an unprovoked SE, a single burst of seizures or multiple infrequent seizures usually does not worsen the prognosis. A poor prognosis and the consequent indication for early and aggressive treatment are dependent mainly upon the presence of variables like symptomatic aetiology, certain epilepsy types and syndromes, and the early evolution of the epilepsy in that particular child. Intellectual decline caused by seizures or epilepsy is rare and may be confined to certain specific and readily recognizable syndromes.

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.

Status epilepticus: clinical analysis of a treatment protocol based on midazolam and phenytoin.

The efficacy of a combination of midazolam and phenytoin in treating generalized convulsive status epilepticus in children was studied retrospectively. The patient group comprised all patients admitted for generalized convulsive status epilepticus to the pediatric intensive care unit over 7 years. Patients treated according to the protocol were included (N = 122). These patients were treated with the following regimen; each subsequent step was taken if clinical evidence of epileptic activity persisted: midazolam 0.5 mg/kg rectally or 0.1 mg/kg intravenously. After 10 minutes: midazolam 0.1 mg/kg intravenously. After 10 minutes: phenytoin 20 mg/kg intravenously in 20 minutes. After phenytoin load: midazolam 0.2 mg/kg intravenously followed by midazolam 0.1 mg/kg/hour continuously, increased by 0.1 mg/kg/hour every 10 minutes to maximum 1 mg/kg/hour. Phenobarbital 20 mg/kg intravenously or pentobarbital 2 to 5 mg/kg intravenous load, 1 to 2 mg/kg/hour continuously intravenously. Patients who received initial rectal diazepam were included. Patients were categorized according to the cause of generalized convulsive status epilepticus. These categories were then related to the level of antiepileptic therapy needed. Patients' ages ranged from 0.5 to 197.4 months. The cause of generalized convulsive status epilepticus was idiopathic or febrile convulsions in two thirds of cases. Most (89%) patients were managed on midazolam and phenytoin. Generalized convulsive status epilepticus was terminated with midazolam alone in 58 patients, with the addition of phenytoin in 19 patients and with continuous midazolam in 32 patients. Thirteen patients needed additional barbiturates. The relationship between the level of antiepileptic therapy and etiology was not significant. Fifty-two patients needed artificial ventilation. Seven patients died; no deaths were directly attributable to generalized convulsive status epilepticus itself. With the use of the proposed protocol, combining midazolam and phenytoin, 89% of the cases of generalized convulsive status epilepticus could be successfully managed.

Early onset neuropathy in a compound form of Charcot-Marie-Tooth disease.

A 2-year-old boy presented with early-onset Charcot-Marie-Tooth disease (CMT). His parents had not been diagnosed previously with CMT, but on careful examination they showed clinical signs of CMT and reduced nerve conduction velocities. Genetic analysis identified the boy as a heterozygote for both a peripheral myelin protein 22 (PMP22) duplication and a mutation in the lipopolysaccharide-induced-tumour-necrosis-factor-alpha-factor (LITAF) gene, whereas each parent only had one mutated CMT gene. This suggests that LITAF mutations can severely affect the CMT phenotype caused by a PMP22 duplication.

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.

Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk.

OBJECTIVE: Recent reports warn that the worldwide cell culture capacity is insufficient to fulfill the increasing demand for human protein drugs. Production in milk of transgenic animals is an attractive alternative. Kilogram quantities of product per year can be obtained at relatively low costs, even in small animals such as rabbits. We tested the long-term safety and efficacy of recombinant human -glucosidase (rhAGLU) from rabbit milk for the treatment of the lysosomal storage disorder Pompe disease. The disease occurs with an estimated frequency of 1 in 40,000 and is designated as orphan disease. The classic infantile form leads to death at a median age of 6 to 8 months and is diagnosed by absence of alpha-glucosidase activity and presence of fully deleterious mutations in the alpha-glucosidase gene. Cardiac hypertrophy is characteristically present. Loss of muscle strength prevents infants from achieving developmental milestones such as sitting, standing, and walking. Milder forms of the disease are associated with less severe mutations and partial deficiency of alpha-glucosidase. METHODS: In the beginning of 1999, 4 critically ill patients with infantile Pompe disease (2.5-8 months of age) were enrolled in a single-center open-label study and treated intravenously with rhAGLU in a dose of 15 to 40 mg/kg/week. RESULTS: Genotypes of patients were consistent with the most severe form of Pompe disease. Additional molecular analysis failed to detect processed forms of alpha-glucosidase (95, 76, and 70 kDa) in 3 of the 4 patients and revealed only a trace amount of the 95-kDa biosynthetic intermediate form in the fourth (patient 1). With the more sensitive detection method, 35S-methionine incorporation, we could detect low-level synthesis of -glucosidase in 3 of the 4 patients (patients 1, 2, and 4) with some posttranslation modification from 110 kDa to 95 kDa in 1 of them (patient 1). One patient (patient 3) remained totally deficient with both detection methods (negative for cross-reactive immunologic material [CRIM negative]). The alpha-glucosidase activity in skeletal muscle and fibroblasts of all 4 patients was below the lower limit of detection (<2% of normal). The rhAGLU was tolerated well by the patients during >3 years of treatment. Anti-rhAGLU immunoglobulin G titers initially increased during the first 20 to 48 weeks of therapy but declined thereafter. There was no consistent difference in antibody formation comparing CRIM-negative with CRIM-positive patients. Muscle alpha-glucosidase activity increased from <2% to 10% to 20% of normal in all patients during the first 12 weeks of treatment with 15 to 20 mg/kg/week. For optimizing the effect, the dose was increased to 40 mg/kg/week. This resulted, 12 weeks later, in normal alpha-glucosidase activity levels, which were maintained until the last measurement in week 72. Importantly, all 4 patients, including the patient without any endogenous alpha-glucosidase (CRIM negative), revealed mature 76- and 70-kDa forms of -glucosidase on Western blot. Conversion of the 110-kDa precursor from milk to mature 76/70-kDa alpha-glucosidase provides evidence that the enzyme is targeted to lysosomes, where this proteolytic processing occurs. At baseline, patients had severe glycogen storage in the quadriceps muscle as revealed by strong periodic acid-Schiff--positive staining and lacework patterns in hematoxylin and eosin--stained tissue sections. The muscle pathology correlated at each time point with severity of signs. Periodic acid-Schiff intensity diminished and number of vacuoles increased during the first 12 weeks of treatment. Twelve weeks after dose elevation, we observed signs of muscle regeneration in 3 of the 4 patients. Obvious improvement of muscular architecture was seen only in the patient who learned to walk. Clinical effects were significant. All patients survived beyond the age of 4 years, whereas untreated patients succumb at a median age of 6 to 8 months. The characteristic cardiac hypertrophy present at start of treatment diminished significantly. The left ventricular mass index decreased from 171 to 599 g/m2 (upper limit of normal 86.6 g/m2 for infants from 0 to 1 year) to 70 to 160 g/m2 during 84 weeks of treatment. In addition, we found a significant change of slope for the diastolic thickness of the left ventricular posterior wall against time at t = 0 for each separate patient. Remarkably, the younger patients (patients 1 and 3) showed no significant respiratory problems during the first 2 years of life. One of the younger patients recovered from a life-threatening bronchiolitis at the age of 1 year without sequelae, despite borderline oxygen saturations at inclusion. At the age of 2, however, she became ventilator dependent after surgical removal of an infected Port-A-Cath. She died at the age of 4 years and 3 months suddenly after a short period of intractable fever of >42 degrees C, unstable blood pressure, and coma. The respiratory course of patient 1 remained uneventful. The 2 older patients, who both were hypercapnic (partial pressure of carbon dioxide: 10.6 and 9.8 kPa; normal range: 4.5-6.8 kPa) at start of treatment, became ventilator dependent before the first infusion (patient 2) and after 10 weeks of therapy (patient 4). Patient 4 was gradually weaned from the ventilator after 1 year of high-dose treatment and was eventually completely ventilator-free for 5 days, but this situation could not be maintained. Currently, both patients are completely ventilator dependent. The most remarkable progress in motor function was seen in the younger patients (patients 1 and 3). They achieved motor milestones that are unmet in infantile Pompe disease. Patient 1 learned to crawl (12 months), walk (16 months), squat (18 months), and climb stairs (22 months), and patient 3 learned to sit unsupported. The Alberta Infant Motor Scale score for patients 2, 3, and 4 remained far below p5. Patient 1 followed the p5 of normal. CONCLUSION: Our study shows that a safe and effective medicine can be produced in the milk of mammals and encourages additional development of enzyme replacement therapy for the several forms of Pompe disease. Restoration of skeletal muscle function and prevention of pulmonary insufficiency require dosing in the range of 20 to 40 mg/kg/week. The effect depends on residual muscle function at the start of treatment. Early start of treatment is required.

Enzyme replacement therapy in late-onset Pompe's disease: a three-year follow-up.

Pompe's disease is an autosomal recessive myopathy. The characteristic lysosomal storage of glycogen is caused by acid alpha-glucosidase deficiency. Patients with late-onset Pompe's disease present with progressive muscle weakness also affecting pulmonary function. In search of a treatment, we investigated the feasibility of enzyme replacement therapy with recombinant human alpha-glucosidase from rabbit milk. Three patients (aged 11, 16, and 32 years) were enrolled in the study. They were all wheelchair-bound and two of them were ventilator dependent with a history of deteriorating pulmonary function. After 3 years of treatment with weekly infusions of alpha-glucosidase, the patients had stabilized pulmonary function and reported less fatigue. The youngest and least affected patient showed an impressive improvement of skeletal muscle strength and function. After 72 weeks of treatment, he could walk without support and finally abandoned his wheelchair. Our findings demonstrate that recombinant human alpha-glucosidase from rabbit milk has a therapeutic effect in late-onset Pompe's disease. There is good reason to continue the development of enzyme replacement therapy for Pompe's disease and to explore further the production of human therapeutic proteins in the milk of mammals.

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.