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Focal onset epilepsy carries a higher risk of intractability than generalized onset epilepsy. Knowledge of the risk factors of intractability will help guide the treatment of children with focal epilepsy. In addition to risk factors present at initial diagnosis, the evolution of clinical and electroencephalographic features may also play a role in predicting intractability.A prospective cohort study was done on children aged one month to three years with newly diagnosed focal epilepsy. Initial treatment of carbamazepine was given according to a standard protocol after assessment of clinical manifestations, neurologic and developmental status, EEG, and brain MRI. Depending on response to therapy, subjects may also receive valproic acid or phenobarbitone following the protocol. Follow-up was done in the second week and every month thereafter. At the end of the study period, seizure type was re-assessed and a repeat neurological and developmental examination and EEG was obtained to evaluate the role of clinical and EEG evolution in predicting intractability.Out of 71 subjects, 21 (29.6%) had intractable epilepsy at the end of the study period. Age of onset (p = 0.216) and neurological status (p = 0.052) were not associated with intractable epilepsy. On logistic regression analysis, evolution of seizure type (p 0.001; RR 56.45; 95%CI 6.56 to 485.85) and evolution of background EEG rhythm (p 0.001; RR 56.51; 95%CI 2.77 to 1152.16) were significantly associated with intractable epilepsy.Changes in seizure type and baseline EEG rhythm may predict intractability in children one month to three years of age with focal epilepsy.

To investigate whether theory of mind (ToM), an important requirement for adaptive social functioning, is different between children with pharmacologically refractory epilepsy who undergo epilepsy surgery and healthy control children, whether ToM is affected by epilepsy surgery in these children, and whether ToM is associated with demographic or epilepsy variables. The "ToM storybooks", a psychometrically sound ToM instrument designed for children, was administered shortly before and 0.5, one and two years after surgery as part of a neuropsychological assessment. Fifteen patients (mean age: 7.1 years) completed the ToM storybooks before and at least twice after surgery. Two sex- and age-matched healthy control children were included per patient. Linear mixed models were used to analyse differences between patients and controls. The association between ToM and demographic, epilepsy and surgical variables was explored. Patients had lower ToM scores than healthy control children, even when corrected for verbal intelligence quotient (VIQ). Epilepsy surgery had neither a harmful nor a favourable effect on ToM. Later epilepsy onset and temporal origin of epilepsy were associated with higher (better) ToM scores relative to earlier epilepsy onset and extra-temporal epilepsy (including hemispherotomy in one case). Children in whom the amygdala was resected had worse ToM scores. Children with refractory epilepsy have a ToM deficit that may not be accounted for by lower VIQ. Epilepsy surgery does not affect ToM functioning. Younger age at epilepsy onset is associated with poorer ToM, and temporal epilepsy with better ToM. Finally, the amygdala is implicated in ToM deficit. Patients and their parents should be educated about the possible consequences of epilepsy with regards to the development of social cognition and should be guided in order to help improve ToM.

The purpose of this study was to determine whether children with epilepsy surgery in their history are able to recognize emotions expressed by faces and whether this recognition is associated with demographic variables [age, sex, and verbal intelligence (VIQ)] and/or epilepsy variables (epilepsy duration, side of the surgery, surgery area, resection of the amygdala, etiology, antiepileptic drug use, and seizure freedom).Two years after epilepsy surgery, the Facial Expression of Emotion: Stimuli and Tests (FEEST) was administered to 41 patients (age: 4-20years, mean: 13.5years, 24 girls) and 82 age- and sex-matched healthy controls. Data obtained longitudinally (before surgery and 6, 12, and 24months after surgery) in a small subset (11 patients and 22 matched controls) were explored to obtain clues about the course of REEF from before surgery.Corrected for VIQ, REEF scored significantly lower in the 41 surgically treated patients than in matched control children. No significant relationship was found between REEF and any epilepsy variable. Only age at assessment predicted REEF score in both patients and controls. The longitudinal data revealed a 'dip' in emotion recognition at the first postsurgical assessment in the six younger patients (age:12.1years). The older patients (age: 13-17years) showed a continuous increase in REEF scores that was similar to that in controls. Two years after surgery, REEF of the younger patients recovered to, but did not exceed, the presurgical level.Neither poor REEF present two years after childhood epilepsy surgery, nor the aberrant course of REEF in younger patients (age:12.1years) was explained by epilepsy variables or poor verbal intelligence. Disentangling the mechanism of the abnormality is urgently needed, as recognizing emotional expressions is a key component in the development of more complex social perception skills.

Item does not contain fulltext Objective: To know whether change in the intelligence quotient (IQ) of children who undergo epilepsy surgery is associated with the educational level of their parents. Methods: Retrospective analysis of data obtained from a cohort of children who underwent epilepsy surgery between January 1996 and September 2010. We performed simple and multiple regression analyses to identify predictors associated with IQ change after surgery. In addition to parental education, six variables previously demonstrated to be associated with IQ change after surgery were included as predictors: age at surgery, duration of epilepsy, etiology, presurgical IQ, reduction of antiepileptic drugs, and seizure freedom. We used delta IQ (IQ 2 years after surgery minus IQ shortly before surgery) as the primary outcome variable, but also performed analyses with pre- and postsurgical IQ as outcome variables to support our findings. To validate the results we performed simple regression analysis with parental education as the predictor in specific subgroups. Results: The sample for regression analysis included 118 children (60 male; median age at surgery 9.73 years). Parental education was significantly associated with delta IQ in simple regression analysis (p = 0.004), and also contributed significantly to postsurgical IQ in multiple regression analysis (p = 0.008). Additional analyses demonstrated that parental education made a unique contribution to prediction of delta IQ, that is, it could not be replaced by the illness-related variables. Subgroup analyses confirmed the association of parental education with IQ change after surgery for most groups. Significance: Children whose parents had higher education demonstrate on average a greater increase in IQ after surgery and a higher postsurgical - but not presurgical - IQ than children whose parents completed at most lower secondary education. Parental education - and perhaps other environmental variables - should be considered in the prognosis of cognitive function after childhood epilepsy surgery. 9 p.

article i nfo Purpose: This study aimed to investigate parenting stress expressed by parents before and two years after their children's epilepsy surgery. Methods: Subjects: Parents of 31 consecutively included surgery patients with epilepsy and parents of 31 healthy sex- and age-matched control children were the subjects of this study. Materials and procedure: The question- naire 'Parenting Stress Index', which distinguishes a Parent domain (stress leading parents to feel themselves inadequate) from a Child domain (child features felt by parent to cause stress) was completed before surgery of the patients and two years thereafter. At both time points, intelligence examination of the child was part of a comprehensive neuropsychological assessment, as were evaluations of recent stress-enhancing life events and epilepsy severity. Results: Prior to surgery, total parenting stress was significantly higher in parents of patients than in parents of con- trols. Two years after surgery, total parenting stress had decreased significantly in parents of patients. The scores on parent-related subscales Role Restriction and Spouse and on the child-related subscale Distractibility/Hyperactivity, all relatively high before surgery, decreased significantly. Still, parents of patients experienced significantly more stress compared with parents of controls mainly because of persistently higher stress scores in par- ents of patients on the subscale Role Restriction (Parent domain) and on five of six subscales in the Child domain. Intelligence of the child was associated with parenting stress: the lower the child's intelligence, the higher the stress score on the subscale Distractibility/Hyperactivity and the lower the stress score on the subscale Mood. Stress decreased more in parents of patients who became seizure-free after surgery than in parents of patients with recurrent seizures. Conclusions: Parenting stress decreases but does not normalize in the first two years after epilepsy surgery. Parents should be offered counseling on epilepsy-related intricacies contributing to parenting stress, immediately after diagnosis as well as after epilepsy surgery, notwithstanding the resulting seizure status of the child.

This literature review on social functioning of children after epilepsy surgery is based on 24 papers addressing two categories of social functioning: social cognition (n = 4) and general social functioning (n = 20). Overall, studies that compared with healthy peers revealed children who had undergone epilepsy surgery to have more problems in both social cognition and general social functioning. Half of the studies found some improvement in social functioning in the first year(s) after epilepsy surgery, but this pertained to general social functioning, not to social cognition. The persistence of the problems in social cognition after surgery may be related to the critical period of brain maturation, lacking improvement of impairments in related cognitive domains or to a defective underlying brain condition — rather than to the epilepsy. Problems in general social functioning may be explained by the adjustments the children and their families had to make because of the child's drug-resistant epilepsy and difficulties to adjust to the new situation after surgery. The neurological and behavioral explanations are likely to be interrelated in light of the multifaceted and complex nature of social functioning. Epilepsy surgery does not appear to solve the problems in social functioning associated with having had drug-resistant epilepsy. As social functioning is an important aspect of healthy development, it should be assessed comprehensively in order to obtain a knowledge base that allows 1) proper treatment of children with epilepsy (CwE) and 2) counseling patients and families prior to and after epilepsy surgery.

AIM: The aim of the study was to assess cognitive outcome in children with periventricular haemorrhagic infarction (PVHI) or perinatal arterial ischaemic stroke (PAIS) and relate these findings to early developmental outcome and neonatal magnetic resonance imaging findings. METHOD: A neuropsychological assessment was performed in 50 children (26 males, 24 females) with unilateral PVHI (n=21) or PAIS (n=29) at a median age of 11 years 9 months (range 6-20y). This included tests for intelligence, verbal memory, visual-motor integration, word comprehension, attention, reaction times, and executive function. The Griffiths Mental Development Scale was used for early developmental assessment at 24 months (range 18-32mo). RESULTS: In children with PVHI, both the early Griffiths scores (mean 87; 95% CI 83-92) and the Full-scale IQ (FSIQ) scores at school age (mean 86; 95% CI 78-94) were below the test mean of 100. In the PAIS group, early Griffiths scores were within the normal range (mean 98; 95% CI 93-104), but at school age FSIQ scores were below average (mean 87; 95% CI 80-94). In children with PVHI, FSIQ scores correlated with the level of maternal education and were lower after ventricular dilatation, whereas both involvement of the basal ganglia and thalami and development of postneonatal epilepsy were associated with lower cognitive outcome in children who had experienced PAIS. INTERPRETATION: Cognitive outcome after PVHI or PAIS is below average, but still within 1SD for most children. Prediction of cognitive outcome remains challenging, but some early predictors can be recognized. Language: en

Item does not contain fulltext Prediction of functional motor outcome after hemispherectomy is difficult due to the heterogeneity of motor outcomes observed. We hypothesize that this might be related to differences in plasticity during the onset of the underlying epileptogenic disorder or lesion and try to identify predictors of motor outcome after hemispherectomy. Thirty-five children with different etiologies (developmental, stable acquired or progressive) underwent functional hemispherectomy and motor function assessment before hemispherectomy and 24 months after hemispherectomy. Preoperatively, children with developmental etiologies performed better in terms of distal arm strength and hand function, but not on gross motor function tests. Postoperatively, the three etiology groups performed equally poor in muscle strength and hand function, but gross motor function improved in those with acquired and progressive etiologies. Loss of voluntary hand function and distal arm strength after surgery was associated with etiology, intact insular cortex and intact structural integrity of the ipsilesional corticospinal tract on presurgical MRI scans. In conclusion, postoperative motor function can be predicted more precisely based on etiology and on preoperative MRI. Children with developmental etiology more often lose distal arm strength and hand function and show less improvement in gross motor function, compared to those with acquired pathology.

Childhood status epilepticus (SE) initiates an epileptogenic process that leads to spontaneous seizures and hippocampal pathology characterized by neuronal loss, gliosis and an imbalance between excitatory and inhibitory neurotransmission. It remains unclear whether these changes are a cause or consequence of chronic epilepsy. In this study, in vivo MRS was used in a post-SE juvenile rat model of temporal lobe epilepsy (TLE) to establish the temporal evolution of hippocampal injury and neurotransmitter imbalance. SE was induced in P21 rats by injection of lithium and pilocarpine. Four and eight weeks after SE, in vivo (1) H and γ-aminobutyric acid (GABA)-edited MRS of the hippocampus was performed in combination with dedicated ex vivo immunohistochemistry for the interpretation and validation of MRS findings. MRS showed a 12% decrease (p

In this case report we describe the presence of a unilateral watershed infarction in a preterm born infant. Structural imaging in the neonatal period and in adolescence confirmed a typical lesion pattern compatible with watershed infarction in term born infants. Though the resulting parasagittal cleft transected the primary motor cortex, motor function of the affected hand was relatively spared. Functional MRI and transcranial magnetic stimulation revealed an important role for the unaffected hemisphere in motor control of the affected hand, showing once again that early cortical reorganization may lead to a near normal hand function.

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 β1 and β2 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.

Summary Although epilepsy is historically considered a disease of gray matter, recent diffusion tensor imaging (DTI) studies have shown white matter abnormalities in patients with epilepsy. The histopathologic correlate of these findings, and whether they are a cause or consequence of epilepsy, remains unclear. To characterize these changes and their underlying histopathology, DTI was performed in juvenile rats, 4 and 8 weeks after pilocarpine-induced status epilepticus (SE). In the medial corpus callosum (CC), mean diffusivity and axial diffusivity (MD and λ1) as well as a myelin staining were significantly reduced at 4 weeks. Only the λ1 decrease persisted at 8 weeks. In the fornix fimbriae (FF), λ1 and myelin staining were decreased at both time points, whereas fractional anisotropy (FA) and MD were significantly reduced at 8 weeks only. We conclude that SE induces both transient and chronic white matter changes in the medial CC and FF that are to some degree related to myelin pathology.

Objectives The objective of this study was to explore whether parents experience problems in their own psychological wellbeing and their family functioning two to four years after their child's epilepsy surgery and whether these problems are associated with epilepsy variables, demographic and cognitive variables, and parent-observed behavior problems of the child. Methods Of the 65 approached families, parents of 31 children participated by completing the Brief Symptom Inventory (BSI), the Family Questionnaire, and the Child Behavior Checklist (CBCL). High scores indicating clinically relevant problems were reported and called ‘problem scores’. Correlations between results of questionnaires and demographic and illness variables (abstracted from medical files) were computed for fathers and mothers separately. By comparing the group with at least one problem score with the group without problem scores, risk factors for parent-perceived problems in their own psychological functioning and in family functioning were explored. Results Thirty percent of the mothers had problem scores on hostility and on communication within their family. Only a few fathers obtained problem scores, most of these pertaining to their family's organization. Not one parent had a problem score regarding their partner relationship. Many parents had problem scores on behavior problems in their child. Brain area of surgery was the only epilepsy variable related to parents' wellbeing and family functioning, with lowest problem scores for the hemispherotomy group. Scores on behavior problems in the child were also lowest for children after hemispherotomy and for those who had achieved freedom of seizures and antiepileptic drugs (AEDs). Fathers of older children experienced more problems than those of young children. Conclusions Parent's wellbeing and family functioning cannot be understood from epilepsy or epilepsy surgery variables only but are related to the child's age and behavior. Having epilepsy is associated with emotional and behavior problems and limits children in developing age-appropriate self-dependence. These problems are not resolved after achieving seizure freedom and have great influence on the family. Professionals should set realistic expectations of epilepsy surgery and should assess, acknowledge, and follow up problems of parental psychological wellbeing and family functioning, regardless of the outcome.

Mutations in the gene encoding of the catalytic subunit of mtDNA polymerase gamma (POLG1) can cause typical Alpers' syndrome. Recently, a new POLG1 mutation phenotype was described, the so-called juvenile-onset Alpers' syndrome. This POLG1 mutation phenotype is characterized by refractory epilepsy with recurrent status epilepticus and episodes of epilepsia partialis continua, which often necessitate admission to the intensive care unit (ICU) and pose an important mortality risk. We describe two previously healthy unrelated teenage girls, who both were admitted with generalized tonic-clonic seizures and visual symptoms leading to a DNA-supported diagnosis of juvenile-onset Alpers' syndrome. Despite combined treatment with anti-epileptic drugs, both patients developed status epilepticus requiring admission to the ICU. Intravenous magnesium as anti-convulsant therapy was initiated, resulting in clinical and neurophysiological improvement and rapid extubation of both patients. Treating status epilepticus in juvenile-onset Alpers' syndrome with magnesium has not been described previously. Given the difficulties encountered while treating epilepsy in patients with this syndrome, magnesium therapy might be considered.

The postsurgical medication policy was reviewed for 109 children (age at surgery, 0-16 years) who had epilepsy surgery between 1991 and 2005. Intervals between surgery and both start (n = 84) and completion (n = 68) of withdrawal of antiepileptic drugs (AEDs) were calculated and analyzed in relation to demographic and epilepsy variables and to recurrent seizures. Postoperative seizure freedom was associated with completeness of surgical resection, defined as complete removal of the cortical region exhibiting ictal or interictal abnormalities on intracranial electroencephalography and lesion on magnetic resonance imaging (P = 0.008). Etiology seemed to be related, but numbers were too small for statistical analysis. In 24 children (22%), seizures recurred postoperatively, and in 19 of these 24 children the AEDs were never withdrawn. Two of the five children in whom seizures recurred after medication withdrawal regained seizure freedom. Mean interval from surgery to start of drug withdrawal was 1.71 years (n = 84), and 2.86 years (n = 68) from surgery to complete withdrawal. Seizure recurrence seemed not associated with withdrawal decisions. Timing of seizure relapse was identical in children still on AEDs and in those who stopped. Eight children with early discontinuation (0.6 years from surgery to start of withdrawal and 0.8 years to complete withdrawal) had no seizure recurrence. Long-term continuation of AEDs is probably not indicated in children with complete resection of the epileptogenic zone. The optimal timing needs to be further explored.

This study reports on the findings of longitudinal follow-up of visual function in a 12-year-old girl affected by congenital right hemihydranencephaly. This extremely rare unilateral brain malformation allowed the authors to gather new information on neuronal plasticity and functional compensations of the visual system across a period of 10 years. An extension of the preserved right visual hemifields above the middle line and strategical eye or head positions developed to increase visual functions are discussed. In addition, ophthalmological and orthoptical findings, as well as the development of monocular grating and linear acuity, are described.

Item does not contain fulltext Objective: Poor performance on confrontation naming tasks by children and adolescents with pharmacologically intractable epilepsy has been interpreted as indicating impairments of lexicon, that is, the store of words in long-term memory. However, confrontation naming performance crucially depends not only on word knowledge but also on other functions such as fluency. We applied an alternative method to assess lexicon with the aim of tracing deficits in lexicon before and after surgery in adolescents with pharmacologically intractable epilepsy. Method: Sixteen patients and 32 age- and sex-matched controls completed the Dutch version of the controlled oral word production task. Responses were used to calculate indices of lexical fluency (retrieval efficiency), lexical breadth (vocabulary size), and lexical depth (knowledge of word properties), as well as use of search strategies. Results: Adolescents with pharmacologically intractable epilepsy had lower lexical fluency scores than healthy peers, but did not differ from them on the dimensions of lexical breadth and lexical depth. Patients demonstrated reduced use of search strategies. In fact, the difference in lexical fluency between patients and controls disappeared after controlling for Full Scale IQ (obtained using the Dutch version of the 3rd edition of the Wechsler Intelligence Scale for Children (WISC–IIINL; Kort et al., 2005; Wechsler, 2002) or—for older children—the Dutch version of the first edition of the Kaufman Adult and Adolescent Intelligence Test (KAIT; Kaufman & Kaufman, 1993; Mulder, Dekker, & Dekker, 2004) and use of search strategies. In patients, changes in the use of the antiepileptic drug carbamazepine were associated with lexical fluency. Conclusion: Adolescents with pharmacologically intractable epilepsy differ from their healthy peers mainly in lexical fluency, rather than word knowledge per se. 9 p.

The authors undertook this study to identify predictors of persistent postoperative seizures in their group of 28 Dutch pediatric and adolescent patients with medically intractable epilepsy who underwent functional hemispherectomy.The records of 28 pediatric and adolescent patients who underwent a functional hemispherectomy in the University Medical Center Utrecht were retrospectively analyzed. The authors performed a Cox regression analysis, using the first postoperative seizure as the event. Pathology, age at surgery, age at seizure onset, duration of epilepsy, type of surgery, surgeon, possible incomplete disconnection on MR images, and presence of residual insular cortex were analyzed as potential associated variables during the follow-up period.The patients' mean age at surgery was 69.9 months (range 3.0-294.2 months) and mean duration of follow-up was 39.0 months (range 6.0-132.0 months). Six patients had postoperative seizures (21%). One patient had persistent bilateral status epilepticus and died 4 months after surgery. The Cox regression analysis showed presence of insular cortex to be the only variable statistically associated with postoperative seizures (p = 0.021) in this group of 28 patients.In this group of Dutch pediatric and adolescent patients, residual insular cortex was positively correlated with persistent postoperative seizures. Given the small sample size in this study, however, caution should be used in drawing conclusions about the role of the insular cortex.

Summary: Purpose: Tuberous sclerosis complex (TSC) is often associated with intractable epilepsy. Although epilepsy surgery has gained interest in recent years uncertainties exist about which patients are good surgical candidates. A systematic review of the available literature has been undertaken to assess the overall outcome of epilepsy surgery and identify risk factors of seizure recurrence. Methods: We searched MEDLINE, Embase, and bibliographies of reviews and book chapters to identify articles published in English since 1960. Twenty-five articles, describing postoperative seizure outcome and type of surgery in 177 TSC patients, were included in this study. Seizure outcome was analyzed both as seizure freedom and good outcome, including patients with >90% seizure reduction. Results: Seizure freedom was achieved in 101 patients (57%). Seizure frequency was improved by > 90% in 32 patients (18%). Moderate or severe intellectual disability (IQ < 70) (RR 1.8; 95% CI 1.2–2.8) and the presence of tonic seizures (RR 1.7; 95 % CI 1.2–2.4) were related to seizure recurrence. Conclusions: A relation between multiple seizures types with early onset, multiple cortical tubers and multifocal epileptogenicity, and poor outcome is not supported by this systematic analysis. Although there is considerable variation among studies reviewed here, the literature suggests that resective surgery may offer benefit in a selected population of TSC patients with drug-resistant epilepsy.

PURPOSE To assess motor and mental development before and after strabismus surgery in children with infantile esotropia. PATIENTS AND METHODS Mental and motor development indexes of 20 children with infantile esotropia without neurologic abnormalities and 17 age-matched healthy control subjects were prospectively tested at regular intervals before and after strabismus surgery with the Dutch version of the Bayley and ordinal scales of infant development. RESULTS The mean age for surgery in the study group was 13.5 months. Before strabismus surgery, the Bayley scales of infant development showed a significant delay in both mental (P < .045) and motor (P < .008) development for children with infantile esotropia compared with the control group. Three weeks after surgery, the delay in mental development had disappeared. The delay in motor development persisted for months. Two of the 7 ordinal scales—object permanence (P < .01) and means–end (P < .036)—showed a statistically significant delay for children with infantile esotropia. Three weeks after strabismus surgery, there was no difference between the study group and the control group. CONCLUSIONS Children with infantile esotropia had delayed motor and mental development compared with healthy children. After strabismus surgery, patients recovered mentally, but their motor delays persisted for months when tested with the Bayley scales of infant development. J Pediatr Ophthalmol Strabismus 2007;44:350-355. AUTHORS Drs. Tukkers-van Aalst, Rensen, de Graaf, and Wittebol-Post are from the Department of Ophthalmology, and Dr. van Nieuwenhuizen is from the Department of Neurology, University Medical Center of Utrecht, The Netherlands. Dr. Tukkers-van Aalst is also from the Department of Ophthalmology, St. Elisabeth Hospital, Tilburg, The Netherlands. Originally submitted December 21, 2005. Accepted for publication March 22, 2006. Address correspondence to Floor S. Tukkers-van Aalst, MD, St. Elisabeth Hospital, Department of Ophthalmology, Hilvarenbeekseweg 60, 5000 LC Tilburg, The Netherlands. Supported by Dr. F. P. Fischer Stichting. Drs. Tukkers-van Aalst, Rensen, de Graaf, van Nieuwenhuizen, and Wittebol-Post have disclosed no relevant financial relationships. The audience is advised that this continuing medical education activity may contain references to unlabeled uses of FDA-approved products or to products not approved by the FDA for use in the United States. The faculty members have been made aware of their obligation to disclose such usage. The material presented at or in any Vindico Medical Education continuing medical education activity does not necessarily reflect the views and opinions of Vindico Medical Education or SLACK Incorporated. Neither Vindico Medical Education or SLACK Incorporated, nor the faculty endorse or recommend any techniques, commercial products, or manufacturers. The faculty/author may discuss the use of materials and/or products that have not yet been approved by the U.S. Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or utilizing any product.

Febrile seizures are the most prevalent type of seizures among children up to 5 years of age (2-4% of Western-European children). Complex febrile seizures are associated with an increased risk to develop temporal lobe epilepsy. To investigate short- and long-term effects of experimental febrile seizures (eFS), we induced eFS in highly febrile convulsion-susceptible C57BL/6J mice at post-natal day 10 by exposure to hyperthermia (HT) and compared them to normotherm-exposed (NT) mice. We detected structural re-organization in the hippocampus 14 days after eFS. To identify molecular candidates, which entrain this structural re-organization, we investigated temporal changes in mRNA expression profiles eFS 1 hour to 56 days after eFS. We identified 931 regulated genes and profiled several candidates using in situ hybridization and histology at 3 and 14 days after eFS. This is the first study to report genome-wide transcriptome analysis after eFS in mice. We identify temporal regulation of multiple processes, such as stress-, immune- and inflammatory responses, glia activation, glutamate-glutamine cycle and myelination. Identification of the short- and long-term changes after eFS is important to elucidate the mechanisms contributing to epileptogenesis.

Summary: Purpose: We compared epileptiform activity recorded with EEG and magnetoencephalography (MEG) in 19 patients with tuberous sclerosis complex (TSC) and epilepsy. Methods: High-resolution (HR) EEG, HR-MEG, and 1.5-T MRI scans were performed. Epileptiform spikes were identified in EEG and MEG recordings offline by three observers. Spikes for which the interobserver agreement (spike consensus) was >0.40 were used for source localization with CURRYV 3.0 software. MUSIC analysis was performed. The distance between the source determined from EEG and MEG recordings and the border of the closest tuber was calculated and compared. Results: Consensus spikes (kappa >0.4) were identified in 12 patients in the EEG recording and in 14 patients in the MEG recording. MEG sources were closer to tubers in all but one patient. Three patients underwent epilepsy surgery, two of whom are seizure free after complete resection of the tuber. Conclusions: In patients with TSC, epileptogenic sources identified on MEG are closer to the presumed epileptogenic tuber than are similar sources identified on EEG. Moreover, spike consensus is greater with MEG. Clear identification of the epileptogenic zone may offer opportunities for surgery in patients with TSC with intractable epilepsy.

Purpose To evaluate cerebral abnormalities in childhood idiopathic anatomic megalencephaly (MC) by means of different magnetic resonance (MR) modalities. Materials and Methods MRI, volumetry, spectroscopy, and cerebropetal blood flowmetry were performed in six children with idiopathic anatomic MC, and seven volunteers. Results MRI revealed an increased ventricular system in five of six patients. A thalamic hamartoma was found in one patient and a Chiari I malformation was found in two. Volumetric analysis showed a disproportional increase of ventricular volume but normal subarachnoid cerebrospinal fluid (CSF) volume. Supratentorial volume was disproportionally increased compared to cerebellar volume. Intracranial volume correlated significantly with skull circumference. MR spectroscopy (MRS) N-acetyl aspartate/choline (NAA/Cho) peak ratios in WM were significantly higher in patients than in controls. Choline/creatine (Cho/Cr) peak ratios in WM were significantly lower in patients. Cortical gray matter (GM) MRS ratios were unaltered. Cerebropetal flow was increased in MC, possibly related to increased brain volume. Conclusion This study reveals associated developmental anomalies for idiopathic anatomic MC. A relative ventriculomegaly was found, which should not be misinterpreted as true hydrocephalus. In contrast to metabolic MC, MRS showed no severe disturbances. Total intracranial volume is correlated to skull circumference and cerebropetal blood flow. J. Magn. Reson. Imaging 2006. © 2006 Wiley-Liss, Inc.

Summary: Purpose: To measure outcome of epilepsy surgery in terms of health-related quality of life (HrQoL) and self-perceived competence of children and adolescents. Methods: Prospective longitudinal follow-up study of 21 patients (aged 6.2 to 16.8 years). Frequency and severity of seizures and epilepsy-related restrictions, HrQoL, and self-perceived competence were rated before and 6, 12, and 24 months after epilepsy surgery. Data were analysed nonparametrically and using analysis of variance for repeated measures. Results: Group-wise, seizure parameters had almost normalized 6 months after surgery (p < 0.001) and remained so. Two years after surgery, 15 (72%) patients were free of seizures. At the first postsurgical assessment, parents and children evaluated the frequency of activities as improved and that of seizures as diminished (p < 0.05). Parents evaluated their children as having positive emotions more frequently (p < 0.05). Children started to feel better about seizure variables in the second year after surgery. Two years after surgery, children perceived themselves as being socially more competent and having greater self-worth (p = 0.05). In the adolescent group, several aspects of self-perceived competence improved shortly after surgery (p < 0.05), whereas 2 years after surgery, athletic competence and romance had improved (p < 0.05). Conclusions: In children and adolescents, epilepsy surgery sets the stage for improvement in HrQoL and in competence to participate in social and societal domains. Most improvement occurs in the first 6 months after surgery.

Temporal lobe epilepsy (TLE) is associated with febrile convulsions and childhood status epilepticus (SE). Since the initial precipitating injury, triggering epileptogenesis, occurs during this SE, we aimed to examine the metabolic and morphological cerebral changes during the acute phase of experimental SE noninvasively. In the rat lithium–pilocarpine model of SE, we performed quantified T2- and isotropic-diffusion-weighted (DW) magnetic resonance imaging (MRI) at 3 and 5 h of SE and acquired single-voxel 1H MR spectra at 2, 4 and 6 h of SE. T2 was globally decreased, most pronounced in the amygdala (Am) and piriformic cortex (Pi), in which also a significant decrease in apparent diffusion coefficient (ADC) was found. In contrast, ADC values increased transiently in the hippocampus (HC) and thalamus (Th). MR spectra showed a decrease in N-acetylaspartate (NAA) and choline (Cho) and an increase of lactate in a hippocampal voxel. Discussion: The T2 decrease, attributed to raised deoxyhemoglobin, and the presence of lactate both indicate a mismatch between oxygen demand and delivery. The ADC decrease, indicative of excitotoxicity, confirms that the amygdala and piriformic cortex are particularly vulnerable to lithium–pilocarpine-induced seizures. The transient ADC increase in the thalamus may reflect the breakdown of the blood–brain barrier (BBB), which is shown to occur in this region at these time points. Neuronal damage and failure of energy-dependent formation of NAA are likely causes of an observed decrease in NAA, while the decrease in Cho is possibly due to depletion of the cholinergic system. This study illustrates that relative hypoxia, excitotoxicity and concomitant neuronal damage associated with SE can be probed noninvasively with MR. These pathological phenomena are the first to contribute to the pathophysiology of spontaneous recurrent seizures in a later stage in this animal model.

Using high resolution EEG and MEG and a realistic volume conductor model, the authors investigated spatio-temporal aspects of the sources of spikes in children with benign rolandic epilepsy. A 64-channel EEG and simultaneous 151-channel MEG of interictal spike activity in five children all having general and/or focal seizures were recorded. A spatio-temporal multiple signal classification (MUSIC) analysis was performed on the spike data. Sources having a complex spatio-temporal configuration as well as single stationary sources were found. Results for the EEG and MEG were different. In this group of five patients, both high resolution EEG and MEG revealed that in some cases sources well separated in space and time exist, whereas in other cases only single source activity can be resolved. For multiple sources, differences for EEG and MEG in timing and localization of activity suggest that sources are spatio-temporally distributed. Sources can propagate from initial activity in the finger/hand area around the central sulcus down to the mouth/tongue area.

The purpose of this study was to identify early predictors of seizure remission in occipital lobe epilepsy irrespective of syndrome classification i.e. idiopathic or symptomatic occipital lobe epilepsy. Forty-three children with occipital lobe epilepsy had taken part in an earlier study of seizure semiology, neurological deficits, psychomotor/cognitive status, electroencephalography (EEG) and neuroimaging. On the basis of the results of a questionnaire on the state of their epilepsy in 2000, two groups were composed. One group (n=17) consisted of the children with a complete seizure remission of 5 years or more, and the other (n=26) comprised children whose last seizure occurred less than 5 years ago. Our findings indicate that neurological deficit and EEG characteristics can predict 5 year outcome of occipital lobe epilepsy. Neuroradiological abnormality, psychomotor/cognitive status and seizure semiology appear to be of more limited value.

Localization of vital components of neurological functioning has to be performed before epilepsy surgery can be considered in children with intractable epilepsy. This study reports the experience with the Wada procedure in very young children and/or developmentally delayed children with an a priori considerable chance of failing the procedure. The aim of this study was to indicate the applicability of this procedure in this patient group. The Wada procedure is described in 16 children under 10 years of age and/or have intelligence quotient scores below 50 and/or are critically ill and/or are behaviourally disturbed. Information on motor, language and memory functioning is obtained in respectively 13/15, 9/13, and 5/11 children. Nine children underwent epilepsy surgery without postoperative impairment of neurological functioning. In five children epilepsy surgery was not performed because of the results of the Wada procedure or the lack of information during the Wada procedure. One child became seizure-free before surgery. Even in very young, developmentally delayed or behaviourally disturbed children, the Wada test can provide important information with respect to the decision pro or contra epilepsy surgery.

We studied how children with epilepsy (CWE) who are candidates for epilepsy surgery, perceive themselves with respect to overarching personality traits and whether the traits change after surgery. We explored influences of demographic and illness variables. A total of 23 CWE [mean age at inclusion 12.8 (sd 2.3); 12 girls] participated. Using the Dutch Personality Questionnaire Juniors (DPQ-J), we assessed 20 of the CWE shortly before epilepsy surgery and compared the results to those of 39 age- and gender-matched healthy controls. Furthermore, we obtained follow-up scores 6, 12 and 24 months after epilepsy surgery from the clinical group. CWE who were candidates for epilepsy surgery scored above average in inadequacy, perseverance, social inadequacy and recalcitrance, whereas healthy peers scored average. Over the two years' period after epilepsy surgery we found no changes, apart from a decrease of social inadequacy. Sporadic illness and demographic variables were related to some personality traits. However, neither post-surgical seizure freedom nor cessation of AEDs did noticeably change the self-evaluations of CWE. Asking CWE to evaluate their personality themselves may offer a shared basis for individually tailored behavior intervention in order to help them adapting to their ameliorated circumstances after surgery.

Background: Cerebral lesions causing hemiplegia can affect the retrochiasmatical visual pathways. Objective: The aim of this study was to investigate visual function in children suffering from congenital hemiplegia. Methods: Twenty children (mean age: 5 yrs, 5 mo; SD: 2 yrs, 11 mo) underwent orthoptic and ophthalmological examinations. Visual acuity was assessed using the Acuity Card Procedure and standard optotypes. In addition, visual fields were assessed using conventional perimetry (Goldmann’s perimeter or Peritest) or behavioral test (BEFIE test). Results: A remarkable finding was that 75% of the subjects showed a visual field defect, mainly homolateral to the hemiplegic side and contralateral to the (most extensive) cerebral lesions. Conclusion: Visual functions of children suffering from congenital hemiplegia should be routinely assessed, with particular attention to the visual field.

Several studies have described impairment of visual function in children with hydrocephalus. Decreased visual acuity in hydrocephalic children can be due to either ophthalmological defects or defective function of the cerebral part of the visual pathways. In the latter case, the term cerebral visual impairment (CVI) is used. The aims of the present study were (1) to assess the prevalence of decreased visual acuity in children with hydrocephalus, (2) to determine the contribution of CVI to the prevalence of decreased visual acuity in these children, (3) to determine the relation between ventricular dilatation and decreased visual acuity, and (4) to seek a correlation between the number of shunt dysfunctions experienced and visual impairment. The study was carried out in a group of 72 children with hydrocephalus. Binocular visual acuity was assessed using Teller Acuity Cards and found to be below the 10th centile of normal in 37 of the 72 children (51%). Ophthalmological data, available for 33 of these chil...

Background: In order to obtain a method to assess the peripheral visual field of neurologically impaired children in a clinical setting, the arc perimeter was modified into a simple behavioral visual field test. This new test is based on a graded semicircular black metal arc with a white ball at the end. The arc is rotated by an examiner around the head of the subject in such a way that the white ball moves from the periphery towards the center of the visual field. Objective: Here we describe the device, the procedure, and its validation by testing healthy subjects. Methods: Sixty subjects (infants, children, and adults) were tested. Results: The success rate of the test ranged from 63% in infants to 100% in younger children. Normative and reference values for clinical application were derived from the data obtained. The extension of the monocular peripheral visual field increased progressively along each meridian with increasing age (p values for trend 0.0062, 0.0069, 0.0077 and 0.0058, respectively). Co...

A 13-year-old female is described with presumed viral encephalitis, who developed progressive catatonia, agitation, and autonomic dysfunction. The diagnosis of malignant catatonia was made, and the patient improved with electroconvulsive treatment. This article discusses features, causes, differential diagnosis, and treatment of malignant catatonia. In children with this syndrome, electroconvulsive treatment should be considered.

Visual memory is vulnerable to epilepsy surgery in adults, but studies in children suggest no change or small improvements. We investigated visual memory after epilepsy surgery, both group-wise and in individual children, using two techniques to assess change: 1) repeated measures analysis of variance (ANOVA) and 2) an empirically based technique for detecting cognitive change [standardized regression-based (SRB) analysis]. A prospective cohort consisting of 21 children completed comprehensive assessments of memory both before surgery (T0) and 6 (T1), 12 (T2), and 24 months (T3) after surgery. For each patient, two age- and gender-matched controls were assessed with the same tests at the same intervals. Repeated measures ANOVA replicated the results of previous studies reporting no change or minor improvements after surgery. However, group analysis of SRB results eliminated virtually all improvements, indicating that the ANOVA results were confounded by practice effects. Standardized regression-based group results showed that in fact patients scored lower after surgery than would be predicted based on their presurgical performance. Analysis of individual SRB results showed that per visual memory measure, an average of 18% of patients obtained a significantly negative SRB score, whereas, on average, only 2% obtained a significantly positive SRB score. At T3, the number of significantly negative SRB scores outweighed the number of significantly positive SRB scores in 62% of patients. There were no clear associations of clinical variables (including side and site of surgery and postsurgical seizure freedom) with memory outcome. The present analysis revealed that given their individual presurgical functioning, many children obtained disappointing results on some visual memory tests after epilepsy surgery. Comparison of the SRB analysis with ANOVA results emphasizes the importance of empirically based techniques for detecting cognitive effects of epilepsy surgery in childhood.

Aim Unilateral perinatal brain injury may result in recruitment of ipsilateral projections originating in the unaffected hemisphere and development of unilateral spastic cerebral palsy (USCP). The aim of this study was to assess the predictive value of neonatal neuroimaging following perinatal brain injury for recruitment of ipsilateral corticospinal tracts. Method Neonatal magnetic resonance imaging (MRI) and cranial ultrasound scans of 37 children (20 males, 17 females; median [range] gestational age 36 wks+4 [26+6–42wks+5] and birthweight 2312 g ([770–5230g]) with unilateral perinatal arterial ischaemic stroke (n=23) or periventricular haemorrhagic infarction (n=14) were reviewed and scored for involvement of the corticospinal trajectory. Hand function was assessed using the Assisting Hand Assessment (AHA) and transcranial magnetic stimulation (TMS) was performed (age range 7y 4mo–18y and 7mo) to determine the type of cortical motor organization (normal, mixed or ipsilateral). Neuroimaging scores were used to predict TMS patterns. Results Eighteen children developed USCP with ipsilateral corticospinal tract projections in 13 children (eight mixed, five ipsilateral). AHA scores decreased with increased ipsilateral projections. Asymmetry of the corticospinal tracts seen on neonatal MRI was predictive of development of USCP and recruitment of ipsilateral tracts (positive and negative predictive value of 73% and 91%). Interpretation Neonatal neuroimaging can predict recruitment of ipsilateral corticospinal tracts. Early knowledge of the expected pattern of cortical motor organization will allow early identification of children eligible for early therapy.

Summary Purpose To investigate verbal memory after epilepsy surgery both group-wise and at the level of individual children, and to assess associations with side of surgery and removal of the temporal lobe. Methods A prospective controlled study in a consecutive sample of 21 children undergoing epilepsy surgery, with comprehensive assessments of verbal memory before surgery and six, 12 and 24 months after surgery. For each patient, two age- and gender-matched controls were tested at similar intervals. Standardized regression-based (SRB) analysis was applied to compare post-surgical change in individual patients with change in controls. Results Group-wise, average normed scores on verbal memory tests were higher after epilepsy surgery than before, corroborating earlier reports. By dint of empirically based SRB analysis, however, considerable individual differences in post-surgical change were revealed. Children with resections that included the left temporal lobe functioned significantly poorer than predicted on the basis of their pre-surgical performance. In contrast, verbal memory performance after surgery was consistent with pre-surgical baseline in the majority of children with resections that spared the left temporal lobe. Conclusions Despite cessation of epileptic seizures, verbal memory remains vulnerable in children who required surgery including the left temporal lobe. In most – but not all – children with other types of surgery, post-surgical verbal memory is consistent with their individual pre-surgical base level.

A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.

Purpose To evaluate cognition, behavior, daily functioning and health-related quality of life (HrQoL) five years to more than a decade after hemispherectomy (HE) in childhood. Methods This countrywide Dutch cohort study of 31 patients, who underwent HE between 1994 and 2009, included a semi-structured interview with parents, an assessment of cognition, and screening of behavioral problems and HrQoL. Results Twenty-two school-age children and young adults [median age 13.8 years (0.5 at epilepsy onset, 5.3 at HE)] were assessed with age-appropriate cognitive tests. IQ ranged from 45 to 82 (median 61). Despite performing below mean norm scores, these participants could learn and remember, sustain attention, inhibit irrelevant responses, read and write. Nine more children [median age 9.7 years (0.25 at epilepsy onset, 1.4 at HE)] were so mentally retarded that age-appropriate testing was impossible. This group was almost totally dependent on others in daily activities, had the highest proportion of pre-existing contralateral MRI-abnormalities and after HE the highest rates of seizure recurrence and behavioral problems. Parents in both groups rated HrQoL surprisingly positively (mean VAS-score 72.5), with a scarce low rating (40). All parents reported problems with respect to their children's self-care, daily activities and mobility. Conclusion At least five years after HE, cognitive, behavioral and daily functioning encompasses a broad spectrum that varies from profound retardation and almost total dependence to low normal cognition and a reasonably independent existence. Pre-existing contralateral MRI abnormalities reflect a more generally affected brain with a limited ability to mediate development after HE.

Mesial temporal lobe epilepsy (mTLE) is a chronic and often treatment-refractory brain disorder characterized by recurrent seizures originating from the hippocampus. The pathogenic mechanisms underlying mTLE remain largely unknown. Recent clinical and experimental evidence supports a role of various inflammatory mediators in mTLE. Here, we performed protein expression profiling of 40 inflammatory mediators in surgical resection material from mTLE patients with and without hippocampal sclerosis, and autopsy controls using a multiplex bead-based immunoassay. In mTLE patients we identified 21 upregulated inflammatory mediators, including 10 cytokines and 7 chemokines. Many of these upregulated mediators have not previously been implicated in mTLE (for example, CCL22, IL-7 and IL-25). Comparing the three patient groups, two main hippocampal expression patterns could be distinguished, pattern I (for example, IL-10 and IL-25) showing increased expression in mTLE + HS patients compared to mTLE-HS and controls, and pattern II (for example, CCL4 and IL-7) showing increased expression in both mTLE groups compared to controls. Upregulation of a subset of inflammatory mediators (for example, IL-25 and IL-7) could not only be detected in the hippocampus of mTLE patients, but also in the neocortex. Principle component analysis was used to cluster the inflammatory mediators into several components. Follow-up analyses of the identified components revealed that the three patient groups could be discriminated based on their unique expression profiles. Immunocytochemistry showed that IL-25 IR (pattern I) and CCL4 IR (pattern II) were localized in astrocytes and microglia, whereas IL-25 IR was also detected in neurons. Our data shows co-activation of multiple inflammatory mediators in hippocampus and neocortex of mTLE patients, indicating activation of multiple pro- and anti-epileptogenic immune pathways in this disease.

Background and Purpose— Unilateral intracranial focal nonprogressive arteriopathy is often found in children with arterial ischemic stroke. We aimed to investigate the course of unilateral intracranial arteriopathy in young adults. Methods— We searched the Utrecht Stroke Database for patients between 16 and 50 years of age diagnosed with anterior circulation arterial ischemic stroke and a nonatherosclerotic, unilateral intracranial large-artery arteriopathy between 1991 and 2005. We assessed clinical features, potential causes, risk factors, extent of infarction and arteriopathy at presentation, long-term angiographic course, and clinical outcome. Results— Of 356 patients with anterior circulation arterial ischemic stroke, 17 (5%) had a documented unilateral intracranial arteriopathy, of whom 14 could be included for follow-up investigations (median age, 34 years; range, 27–49 years). Median duration of follow-up was 8.8 years (range, 1.7–12.8 years). In 11 patients, onset of symptoms was not abrupt. The arteriopathy normalized completely in 5 and improved in 3 patients; in none of the patients did the arteriopathy worsen. Two of 14 patients had recurrent symptoms. Ten patients (71%) had a good outcome (modified Rankin Scale score ≤2). Conclusions— In young adults, arterial ischemic stroke is rarely caused by a unilateral intracranial arteriopathy. Similar to children, onset of symptoms in young adults is often not abrupt and the arteriopathy may improve over time. Late recurrences were rare. Possibly, a monophasic inflammatory process, as has been suggested for childhood intracranial focal nonprogressive arteriopathies, also occurs in young adults.

Background How adolescents and their caregivers look back on epilepsy surgery performed in early life, and whether epilepsy-related restrictions are still in force years after the operation, are insufficiently known. Aims To obtain retrospective evaluations of the decision for epilepsy surgery at an early age, and to inventory current epilepsy-related restrictions. Methods Of 177 children who underwent epilepsy surgery between 1992 and 2009, 129 could be approached. They and their parents received a rating list inventorying whether, in retrospect, they would opt again for epilepsy surgery, which were motives for their answer, how successful they felt surgery had been and which, if any, epilepsy-related restrictions were still in force. Results Forty-one of 44 seizure-free adolescents and 9 of 10 adolescents with current seizures were inclined to (re-)opt for surgery. Parents also would in majority re-opt for surgery. Age at surgery, post-surgical interval, nor type of surgery was statistically significantly related with re-opting for surgery. Seizure-freedom was the paramount motive of seizure-free respondents; respondents with current seizures in majority mentioned amelioration of seizures and/or medication. For parents of children with current seizures, a better developmental perspective was another important motive. Rare hesitation/refusal was related to uncertainties in weighing advantages and disadvantages. Current seizures were no reason to consider surgery as a failure. Among children who were free of both seizures and anti-epileptic drugs, 42% lived with restrictions. Conclusions Epilepsy surgery that does not result in seizure freedom is nevertheless felt to be beneficial. Proper advice should prevent meaningless continuation of restrictions.

Childhood status epilepticus (SE) initiates an epileptogenic process that leads to spontaneous seizures and hippocampal pathology characterized by neuronal loss, gliosis and an imbalance between excitatory and inhibitory neurotransmission. It remains unclear whether these changes are a cause or consequence of chronic epilepsy. In this study, in vivo MRS was used in a post-SE juvenile rat model of temporal lobe epilepsy (TLE) to establish the temporal evolution of hippocampal injury and neurotransmitter imbalance. SE was induced in P21 rats by injection of lithium and pilocarpine. Four and eight weeks after SE, in vivo (1) H and γ-aminobutyric acid (GABA)-edited MRS of the hippocampus was performed in combination with dedicated ex vivo immunohistochemistry for the interpretation and validation of MRS findings. MRS showed a 12% decrease (p0.0001) in N-acetylaspartate and a 15% increase (p=0.0226) in choline-containing compound concentrations, indicating neuronal death and gliosis, respectively. These results were confirmed by FluoroJade and vimentin staining. Furthermore, severe and progressive decreases in GABA (-41%, p0.001) and glutamate (Glu) (-17%, p0.001) were found. The specific severity of GABAergic cell death was confirmed by parvalbumin immunoreactivity (-68%, p0.001). Unexpectedly, we found changes in glutamine (Gln), the metabolic precursor of both GABA and Glu. Gln increased at 4 weeks (+36%, p0.001), but returned to control levels at 8 weeks. This decrease was consistent with the simultaneous decrease in glutamine synthase immunoreactivity (-32%, p=0.037). In vivo MRS showed gliosis and (predominantly GABAergic) neuronal loss. In addition, an increase in Gln was detected, accompanied by a decrease in glutamine synthase immunoreactivity. This may reflect glutamine synthase downregulation in order to normalize Gln levels. These changes occurred before spontaneous recurrent seizures were present but, by creating a pre-epileptic state, may play a role in epileptogenesis. MRS can be applied in a clinical setting and may be used as a noninvasive tool to monitor the development of TLE.

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 β1 and β2 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.

Item does not contain fulltext We describe two patients with severe developmental delay, hypotonia and breathing abnormalities initially diagnosed with the autosomal recessive Joubert syndrome (JBS) who at a later stage appeared to carry chromosomal abnormalities. One case was due to a 4.8 Mb terminal 1q44 deletion, and the other due to a 15.5 Mb duplication of Xq27.2-qter containing the MECP2 gene. Critical evaluation of the clinical data showed that, retrospectively, the cases did not fulfil the diagnostic criteria for JBS, and that the diagnosis of JBS was incorrectly made. We discuss the diagnostic pitfalls and recommend adhering strictly to the JBS diagnostic criteria in the case of a negative molecular diagnosis. Critical assessment of the MRI findings by a specialized neuroradiologist is imperative. As chromosomal abnormalities may give rise to symptoms resembling JBS, we recommend array-based screening for segmental aneuploidies as an initial genetic test in all cases with a JBS-like phenotype.

Although epilepsy is historically considered a disease of gray matter, recent diffusion tensor imaging (DTI) studies have shown white matter abnormalities in patients with epilepsy. The histopathologic correlate of these findings, and whether they are a cause or consequence of epilepsy, remains unclear. To characterize these changes and their underlying histopathology, DTI was performed in juvenile rats, 4 and 8 weeks after pilocarpine-induced status epilepticus (SE). In the medial corpus callosum (CC), mean diffusivity and axial diffusivity (MD and λ₁) as well as a myelin staining were significantly reduced at 4 weeks. Only the λ₁ decrease persisted at 8 weeks. In the fornix fimbriae (FF), λ₁ and myelin staining were decreased at both time points, whereas fractional anisotropy (FA) and MD were significantly reduced at 8 weeks only. We conclude that SE induces both transient and chronic white matter changes in the medial CC and FF that are to some degree related to myelin pathology.