Ictal and interictal electric source imaging in pre-surgical evaluation: a prospective study.

BACKGROUND AND PURPOSE: Accurate localization of the epileptic focus is essential for surgical treatment of patients with drug-resistant epilepsy. Electric source imaging (ESI) is increasingly used in pre-surgical evaluation. However, most previous studies have analysed interictal (II) discharges. Prospective studies comparing the feasibility and accuracy of II and ictal (IC) ESI are lacking. METHODS: We prospectively analysed long-term video-electroencephalography recordings (LTM) of patients admitted for pre-surgical evaluation. We performed ESI of II and IC signals using two methods, i.e. equivalent current dipole (ECD) and a distributed source model (DSM). LTM recordings employed the standard 25-electrode array (including inferior temporal electrodes). An age-matched template head model was used for source analysis. Results were compared with intracranial recordings, conventional neuroimaging methods [magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT)] and outcome at 1 year after surgery. RESULTS: A total of 87 consecutive patients were analysed. ECD gave a significantly higher proportion of patients with localized focal abnormalities (94%) compared with MRI (70%), PET (66%) and SPECT (64%). Agreement between the ESI methods and intracranial recording was moderate to substantial (k = 0.56-0.79). A total of 54 patients were operated (47 patients more than 1 year ago) and 62% of them became seizure-free. The localization accuracy of II-ESI was 51% for DSM and 57% for ECD, and that for IC-ESI was 51% for DSM and 62% for ECD. The differences between the ESI methods were not significant. Differences in localization accuracy between ESI and MRI (55%), PET (33%) and SPECT (40%) were not significant. CONCLUSIONS: The II-ESI and IC-ESI of LTM data have high feasibility and their localization accuracy is similar to that of conventional neuroimaging methods.

Risk of impaired cognition after prenatal exposure to psychotropic drugs.

OBJECTIVE: Prenatal exposure to psychotropic drugs may affect the trajectories of brain development. In a register study, we investigated whether such exposure is associated with long-term impaired cognitive abilities. METHOD: Individuals born in Denmark in 1995-2008 were included. As proxies for cognitive impairment, requiring special needs education, attending special needs school, diagnoses of neurological/mental disorder, missed final examinations, and low school grade average were used. We accounted for maternal confounders. RESULTS: We identified 868 159 individuals of whom 13 983 (1.6%) were prenatally exposed. The adjusted odds ratio (OR) was 0.97[0.92-1.02] for requiring special needs education, 1.28[1.14-1.43] for attending special needs school, 1.32[1.20-1.46] for a neurological/mental disorder diagnosis, 1.37[1.22-1.54] for missing the final examinations, and 1.13[0.82-1.55] for obtaining a low school grade average. Exposure to psycholeptics (primarily antipsychotics and sedatives) was correlated with significantly increased risk for four outcomes. The highest was the risk of missing the primary school examinations (OR: 1.51[1.29-1.76]). The overall highest risk concerned the presence of a neurological/mental disorder after prenatal exposure to psychoanaleptics (primarily antidepressants) (OR: 1.86[1.24-2.78). CONCLUSION: Prenatal exposure to psychotropic drugs affects proxy outcomes of cognitive disabilities at school age. Exposure to psycholeptics carries the largest risk. The role of psychoanaleptics is currently unclear.

Multiplicity and early gestational age contribute to an increased risk of cerebral palsy from assisted conception: a population-based cohort study.

BACKGROUND: This paper assesses the risk of cerebral palsy (CP) in children born after assisted conception compared with children born after natural conception (NC). METHODS: This population based follow-up study included all 588,967 children born in Denmark from 1995 to 2003. Assisted conception was defined as IVF, with or without ICSI, and ovulation induction (OI), with or without subsequent insemination. RESULTS: There were 33 139 (5.6%) children born in Denmark from 1995 to 2003 as a result of assisted conception and through to June 2009, 1146 (0.19%) children received a CP diagnosis. Children born after assisted conception had an increased risk of a CP diagnosis, crude hazard rate ratio (HRR) 1.90 (95% CI: 1.57-2.31) compared with NC children. Divided into IVF and OI children compared with NC children, the risk was HRR 2.34 (95% CI: 1.81-3.01) and HRR 1.55 (95% CI: 1.17-2.06), respectively. When we included the intermediate factors multiplicity and gestational age in multivariate models, the risk of CP in assisted conception disappeared. In general, children with CP born after assisted conception had similar CP subtypes and co-morbidities as children with CP born after NC. CONCLUSION: The risk of CP is increased after both IVF and OI. The increased risk of CP in children born after assisted conception, and in particular IVF, is strongly associated with the high proportion of multiplicity and preterm delivery in these pregnancies. A more widespread use of single embryo transfer warrants consideration to enhance the long-term health of children born after IVF.

Intraoperative hyperventilation vs remifentanil during electrocorticography for epilepsy surgery - a case report.

BACKGROUND: Traditionally, intraoperative intracranial electroen-cephalography-recordings are limited to the detection of the irritative zone defined by interictal spikes. However, seizure patterns revealing the seizure onset zone are thought to give better localizing information, but are impractical due to the waiting time for spontaneous seizures. Therefore, provocation by seizure precipitants may be used with the precaution that spontaneous and provoked seizures may not be identical. OBJECTIVE: We present evidence that hyperventilation induced and drug induced focal seizures may arise from different brain regions in the same patient. METHODS: Hyperventilation and ultra short acting opioid remifentanil were used separately as intraoperative precipitatants of seizure patterns, while recording from subdural and intraventricular electrodes in a patient with temporal lobe epilepsy. Two different ictal onset zones appeared in response to hyperventilation and remifentanil. Both zones were resected and the patient has remained essentially seizure free for 1 year. Furthermore, this is the first description of hyperventilation used as an intraoperative seizure precipitant in human focal epilepsy.

Asphyxia-related risk factors and their timing in spastic cerebral palsy.

OBJECTIVE: To investigate the association of asphyxia-related conditions (reducing blood flow or blood oxygen levels in the fetus) with spastic cerebral palsy (CP) considering different gestational age groups and the timing of risk. DESIGN: Population-based case-control study. SETTING: Danish Cerebral Palsy Register in eastern Denmark and Danish Medical Birth Register. POPULATION OR SAMPLE: 271 singletons with spastic CP and 217 singleton controls, frequency matched by gestational age group, born 1982-1990 in eastern Denmark. METHODS: Data were abstracted from medical records, and a priori asphyxia-related conditions and other risk factors were selected for analysis. Each factor was classified according to the time at which it was likely to first be present. MAIN OUTCOME MEASURES: Spastic CP. RESULTS: Placental and cord complications accounted for the majority of asphyxia conditions. In multivariate analysis, placental infarction was significantly associated with a four-fold increased risk for spastic quadriplegia and cord around the neck was significantly associated with a three-fold increased risk for spastic CP overall. The combination of placental infarction and being small for gestational age (SGA) afforded an especially high risk for spastic quadriplegia. Placental and cord complications were present in 21% of cases and 12% of controls. CONCLUSIONS: The risk for spastic quadriplegia from placental infarction may be linked in some cases with abnormal fetal growth (17% of all children with spastic quadriplegia and 3% of control children both had an infarction and were SGA) -- suggesting an aetiologic pathway that encompasses both factors. The risk for spastic CP from cord around the neck is not accounted for by other prepartum or intrapartum factors we examined. Considering the relative timing of risk factors provides a useful framework for studies of CP aetiology.

The misdiagnosis of epilepsy in children admitted to a tertiary epilepsy centre with paroxysmal events.

AIMS: To determine the proportion of children admitted with difficult to treat paroxysmal events to a tertiary epilepsy centre who did not have epilepsy. METHODS: In an observational retrospective study, all case notes of 223 children admitted in 1997 were examined. The referral was made from the local paediatric department in 51% of cases, other departments in 27%, and from general or specialist practitioners in 22%. Doubt regarding the diagnosis of epilepsy was expressed in the referral note in 17%. On admission, 86% were on antiepileptic drug treatment. During admission all children were subjected to a comprehensive intensive observation and 62% had EEG monitoring. RESULTS: In total, 39% (87/223) were found not to have epilepsy. In 30% of children (55/184) referred without any doubts about the epilepsy diagnosis, the diagnosis was disproved. Of the 159 children admitted for the first time, 75 (47%) were discharged with a diagnosis of non-epileptic seizures. Of 125 children admitted for the first time with no doubts about the diagnosis of epilepsy, 44 (35%) did not have epilepsy. Staring episodes were the most frequently encountered non-epileptic paroxysmal event. Psychogenic non-epileptic seizures were found in 12 children. A total of 34 (15%) had their medication tapered off; a further 22 (10%) had tapered off medication before admission. CONCLUSION: The present study supports the view that misdiagnosis of epilepsy is common. The treating physician should be cautious in diagnosis, especially of staring episodes. A diagnostic re-evaluation should be undertaken in difficult cases with continuing paroxysmal events in order to avoid unnecessary drug treatment and restrictions on the child's lifestyle.

Perinatal risk factors of adverse outcome in very preterm children: a role of initial treatment of respiratory insufficiency?

AIM: To investigate risk factors of adverse outcome in a cohort of very preterm children treated mainly with nasal continuous positive airway pressure (CPAP) during the neonatal course. METHODS: In Denmark, preterm children are treated with nasal CPAP as a first approach to respiratory support. A national prospective study of all infants with a birthweight below 1000 g or a gestational age below 28 wk born in 1994-1995 was initiated to evaluate this approach. Of the 269 surviving children 164 (61%) were not treated with mechanical ventilation in the neonatal period. A follow-up of the children at 5 y of age was conducted. Data from the neonatal period and the 5-y follow-up were analysed. RESULTS: In multivariate analyses including 250 children, a severely abnormal neonatal brain ultrasound scan was predictive of cerebral palsy (OR = 19.9, CI 95%: 6.1-64.8) and intellectual disability (OR = 6.2, CI 95%: 2.3-16.5). A high Clinical Risk Index for Babies (CRIB) score (OR = 2.4, CI 95%: 1.1-5.5) and chronic lung disease (OR = 2.8, CI 95%: 1.2-6.9) were predictive of intellectual disability. In univariate analyses mechanical ventilation was associated with cerebral palsy (OR=4.3, CI 95%: 1.7-10.8) and intellectual disability (OR = 2.2, CI 95%: 1.2-4.2), but the associations became insignificant in multivariate analyses including chronic lung disease and a severely abnormal ultrasound scan. CONCLUSION: The associations between neonatal risk factors and adverse outcome in our cohort were very similar to those found in other cohorts with another initial treatment of respiratory insufficiency. We found no significant adverse effects of mechanical ventilation beyond what could be explained by associations with chronic lung disease and IVH 3-4/PVL.

Lamotrigine plasma levels reduced by oral contraceptives.

Although it is known that the use of oral contraceptives (OC's) can induce glucuronide conjugating enzymes, currently no data exists as to the potential that the elimination of the glucuronidated drug lamotrigine (LTG) is increased by OC's. We present seven cases in whom the plasma levels of LTG were significantly decreased by OC's (mean 49%, range 41-64%). The interaction was of clinical relevance in most of the patients who either experienced increased seizure frequency/recurrence of seizures after OC's had been added, or adverse effects following withdrawal of OC's.

The Danish Cerebral Palsy Registry. A registry on a specific impairment.

Cerebral palsy (CP) is the commonest disabling impairment in childhood, with a prevalence of 2-3 per 1000 live births. The Danish Cerebral Palsy Registry is a research registry that contains cases of CP from birth year 1925 and has estimated the birth prevalence since 1950. Data on children with CP are collected from paediatric departments and one special institution for disabled children. The children are included by a child neurologist and an obstetrician, and information on pregnancy, birth, neonatal period, impairments and demographic data on the child and mother are registered in a standard form. The uptake area is eastern Denmark, covering about 50% of the population, but the rest of Denmark is planned to be included from 2001. The Registry is large, well established and validated, and the definitions and collection procedures have not changed through several decades. It therefore has great research potential. Birth prevalence is estimated continuously, and changes over time are analysed and correlated with pre- and perinatal conditions. A correlation between increased survival of preterm babies and an increased prevalence was found previously, and a decreased prevalence in very preterm infants was later associated with less use of mechanical ventilation. A study correlating CP and maternal infection is ongoing. Collaboration between 14 European CP registries allows the true differences in prevalence between different countries to be studied. Linkage to other individually based registries in Denmark will allow the social consequences of CP to be described.

Cerebral palsy births in eastern Denmark, 1987--90: implications for neonatal care.

The Cerebral Palsy Register in eastern Denmark has collected cases using a uniform data sampling procedure since birth year 1979. We have investigated changes in the rate of cerebral palsy, related to gestational age, mortality and perinatal risk factors in children born 1983--90. The total cerebral palsy birth prevalence decreased from 3.0 in the birth year period 1983--86 to 2.4 per 1000 live births (P < 0.01) in 1987--90, owing to a decrease among all preterm infants (29--19 per 1000, P < 0.001). The perinatal and early neonatal mortality in preterm infants was unchanged from 1983--86 to 1987--90. The rate of cerebral palsy in term infants was 1.5 per 1000 in all birth-year periods from 1979--90. Among the cerebral palsy infants, the proportion of very preterm babies treated with mechanical ventilation in the neonatal period decreased from 95% in 1983--86 to 61% in 1987--90 (P < 0.001), while the group treated with CPAP among the moderately preterm babies increased from 61% to 78% (P < 0.05). The significant decline in cerebral palsy rate in preterm infants born 1987--90 may be due to a change in treatment at the neonatal intensive care units using less mechanical ventilation, a hypothesis which needs further investigation.

Tiagabine adjunctive therapy in children with refractory epilepsy: a single-blind dose escalating study.

Tiagabine, a specific gamma-aminobutyric acid-uptake inhibitor, has been shown to be reasonably well tolerated and efficacious as adjunctive treatment for partial seizures in adults and is now being investigated in children. This 4-month, single-blind study evaluated the tolerability, safety and preliminary efficacy of ascending doses (0.25-1.5 mg/kg/day) of tiagabine add-on therapy in 52 children over the age of 2 years with different syndromes of refractory epilepsy. Adverse events, mostly mild to moderate, were reported by 39% of children during the single-blind placebo period and by 83% of children during tiagabine treatment. The events predominantly affected the nervous system with asthenia (19%), nervousness (19%), dizziness (17%) and somnolence (17%) being the most common. Only three children (6%) withdrew because of adverse events. Tiagabine appeared to reduce seizures more in localisation-related epilepsy syndromes than in generalised epilepsy syndromes. Twenty-three patients with localisation-related epilepsy syndromes were included and 17 of these patients entered the fourth dosing period. The 17 patients had a median reduction of seizure rate in the fourth month of treatment of 33% compared with baseline. In comparison, 13 of 22 children with seven different generalised epilepsy syndromes entered the fourth dosing period with a median change of seizure rate of 0%. Two patients experienced single episodes of status epilepticus during treatment; both cases resolved. Tiagabine showed efficacy mainly in localisation-related syndromes and was well tolerated by most children in a group of very refractory patients and warrants further study in children with epilepsy.

Provocation of non-convulsive status epilepticus by tiagabine in three adolescent patients.

Three girls, two aged 12 years and one aged 17 years with refractory localization-related epilepsy were treated on an add-on basis with tiagabine. At dosages 22.5-30 mg/day (0.45-0.57 mg/kg/day) longstanding non-convulsive status epilepticus was noted in all three patients. The events of non-convulsive status epilepticus subsided following reduction in tiagabine dosages. In two cases, tiagabine was withdrawn, whereas it was continued at a lower dosage in one case. This is the first report of non-convulsive status epilepticus provoked by tiagabine in adolescent patients.

Landau-Kleffner syndrome with onset at 18 months and an initial diagnosis of pervasive developmental disorder.

We report one of the youngest and most intensively studied cases of Landau-Kleffner syndrome, with a follow-up of 5 years. The boy developed normally until the age of 18 months when he had two attacks, possibly epileptic. Electroencephalogram (EEG) was normal. Over the next 5 months he lost his six to ten words, did not engage with other children and became mute. When he was 34 months old a child-psychiatrist suggested a diagnosis of pervasive developmental disorder or developmental dysphasia. An EEG 3 months later showed abnormalities typical of Landau-Kleffner syndrome. His non-verbal abilities were normal as well as his neurological examination and brain magnetic resonance imaging (MRI). A trial of clobazam and vigabatrin was unsuccessful. When he was 4 years and 9 months old he was treated with corticosteroids and within 3 months his vocabulary increased from the standard for 1 1/2 years of age to that for 2 1/2 years of age. His language abilities continued to improve slowly until a stagnation period at the age of 6 years and 9 months. A second course of corticosteroids improved his comprehension and vocabulary to an almost normal level, and his EEG normalized. A total of 11 EEGs were obtained; all included sleep, but continuous spike and wave during slow sleep was never documented. This report illustrates that Landau-Kleffner syndrome should be considered as an alternative diagnosis in children diagnosed with developmental dysphasia. An EEG including sleep should be considered, and in the presence of abnormalities a trial of anti-epileptic drugs or corticosteroids should be undertaken.

Clinical experiences with topiramate in children with intractable epilepsy.

At a tertial referral epilepsy centre 39 children were consecutively enrolled in an open add-on study with topiramate (TPM). All children had intractable epilepsy; the mean seizure frequency was 36 per month, and 31 children were treated with polypharmacy. All but five children were mentally retarded. The initial dose of TPM was 0.5-1 mg/kg daily, slowly titrated with 1-3 mg/kg daily every second week with an estimated target dose of 10 mg/kg daily. At latest follow-up 19 children continued on TPM, three (8%) were seizure-free, eight (21%) had a seizure reduction of more than 50% and eight (21%) improved their general condition. Mean follow-up was 13 months (range 9-36 months). Seizure reduction was seen in focal as well as generalized epilepsies. Adverse effects were reported in 21 cases (54%), weight loss and sedation being most frequent. The mean steady state dose in the children continuing on TPM was at latest follow-up: 14 mg/kg daily (< 5 years), 10 mg/kg daily (5-7 years), 5.8 mg/kg daily (8-17 years). The corresponding plasma level varied from 3 to 45 mumol/litre, and a significant correlation between the daily dose in mg/kg and the plasma level was found. Two patients with progressive myoclonus epilepsy are described separately; one had a dramatic general improvement. It is concluded that TPM seems to be a promising new broad-spectrum anti-epileptic drug, which is efficacious even in epilepsy syndromes, intractable to other new anti-epileptic drugs such as vigabatrin and lamotrigine.

Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder.

The late-infantile form of neuronal ceroid lipofuscinosis (LINCL) is a progressive and ultimately fatal neurodegenerative disease of childhood. The defective gene in this hereditary disorder, CLN2, encodes a recently identified lysosomal pepstatin-insensitive acid protease. To better understand the molecular pathology of LINCL, we conducted a genetic survey of CLN2 in 74 LINCL families. In 14 patients, CLN2 protease activities were normal and no mutations were identified, suggesting other forms of NCL. Both pathogenic alleles were identified in 57 of the other 60 LINCL families studied. In total, 24 mutations were associated with LINCL, comprising six splice-junction mutations, 11 missense mutations, 3 nonsense mutations, 3 small deletions, and 1 single-nucleotide insertion. Two mutations were particularly common: an intronic G-->C transversion in the invariant AG of a 3' splice junction, found in 38 of 115 alleles, and a C-->T transition in 32 of 115 alleles, which prematurely terminates translation at amino acid 208 of 563. An Arg-->His substitution was identified, which was associated with a late age at onset and protracted clinical phenotype, in a number of other patients originally diagnosed with juvenile NCL.