Risk factors predicting intractability in focal epilepsy in children under 3 years of age: A cohort study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Changes in seizure type and baseline EEG rhythm may predict intractability in children one month to three years of age with focal epilepsy.

Social functioning of children after epilepsy surgery: A literature review.

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.

Parents experience problems in psychological and family functioning two to four years after their child's epilepsy surgery.

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.

Parental education predicts change in intelligence quotient after childhood epilepsy surgery.

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.

Two years after epilepsy surgery in children: Recognition of emotions expressed by faces.

OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Parenting stress does not normalize after child's epilepsy surgery.

PURPOSE: This study aimed to investigate parenting stress expressed by parents before and two years after their children's epilepsy surgery. 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 questionnaire '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 controls. 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 parents 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.

Visual memory after epilepsy surgery in children: a standardized regression-based analysis of group and individual outcomes.

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.

In vivo MRS and histochemistry of status epilepticus-induced hippocampal pathology in a juvenile model of temporal lobe epilepsy.

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<0.0001) 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%, p<0.001) and glutamate (Glu) (-17%, p<0.001) were found. The specific severity of GABAergic cell death was confirmed by parvalbumin immunoreactivity (-68%, p<0.001). Unexpectedly, we found changes in glutamine (Gln), the metabolic precursor of both GABA and Glu. Gln increased at 4 weeks (+36%, p<0.001), 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.

Neonatal neuroimaging predicts recruitment of contralesional corticospinal tracts following perinatal brain injury.

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.

Cognitive outcome in childhood after unilateral perinatal brain injury.

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.

The course of unilateral intracranial arteriopathy in young adults with arterial ischemic stroke.

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.

Protein expression profiling of inflammatory mediators in human temporal lobe epilepsy reveals co-activation of multiple chemokines and cytokines.

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.

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

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

In vivo diffusion tensor imaging and ex vivo histologic characterization of white matter pathology in a post-status epilepticus model of temporal lobe epilepsy.

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.

Hemispherectomy: a basis for mental development in children with epilepsy.

To detect change in mental development or intelligence over two years following hemispherectomy in children with pharmacologically intractable epilepsy. Seventeen infants and preschoolers (median age at epilepsy onset of 0.0 years and at hemispherectomy 1.5 years; epilepsy duration of 0.2-2.6 years) and 12 older children (median age at onset of 1.0 year and at hemispherectomy 8.3 years; epilepsy duration of 1.1-11.7 years) with pharmacologically intractable seizures due to developmental, acquired or progressive pathology. Prospective study with consecutive inclusion of children, fixed assessment intervals (shortly before and 6, 12 and 24 months after hemispherectomy) and assessment using developmental scales and intelligence scales. Dependent variables included mental developmental index (MDI), mental age (MA) and mental developmental delay (MDD) in younger children and intelligence quotient (IQ) in older children. Mental development had arrested or deteriorated prior to hemispherectomy in 14 children (82%) assessed with developmental scales. In 14 children, it was not possible to more precisely determine MDI than "below the lowest MDI that the test manual provided" either before or after hemispherectomy. MA, however, increased in 16 children. Overall, IQ changed negligibly over two years after hemispherectomy, although an individual approach revealed variability. Children with Rasmussen encephalitis did not recover from the significant presurgical deterioration of intelligence. Removal of the affected hemisphere enables epileptic children, even those with severe mental delay, to further develop mentally.

Language development before and after temporal surgery in children with intractable epilepsy.

PURPOSE: To obtain systematic knowledge of language development before and after epilepsy surgery in regions that, if damaged, are known to entail language impairment in adults. METHODS: Twenty-four children (mean age 11 years; range 5.8-15.7 years) with pharmacologically intractable epilepsy participated prior to (the majority) anterior temporal lobectomy and 6, 12, and 24 months thereafter. Reception and production of lexicon (vocabulary) and syntax (sentence structure including grammar) were examined using developmental language tests that provide normative data. RESULTS: Prior to surgery the mean language delay varied from 1.7 years (productive syntax) to 3.5 years (productive lexicon). For lexicon, language delay was larger, the older the children; for syntax it was smaller in children with mothers with higher education. Over the 2 years following surgery, the children developed in all four language components. Development was, however, slower than normal, that is, language delay increased, in three of the four components: in productive lexicon it continued to increase, and in receptive lexicon and productive syntax it appeared to stabilize during the second year. Receptive syntax developed at a normal pace. The development of productive lexicon was remarkably slow when surgery and language mediation were both in the left hemisphere. DISCUSSION: Pharmacologically intractable epilepsy of the temporal lobe, or the underlying condition, is a significant risk factor for delayed language development. Temporal epilepsy surgery does not result in acceleration of language development. If language is still mediated in the operated left hemisphere, development of particular language components may slow down after surgery.

Epilepsy surgery in children: no further threat to theory of mind.

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.

DNA analysis of AHI1, NPHP1 and CYCLIN D1 in Joubert syndrome patients from the Netherlands.

Joubert syndrome (JBS) is a clinically variable and genetically heterogeneous developmental brain disorder with autosomal recessive inheritance. Five genes, AHI1, NPHP1, CEP290, MKS3, and RPGRIP1L, and two additional loci on chromosome 9 and 11 have been identified so far. The relative contributions of AHI1 mutations and NPHP1 deletions have not yet been determined in a population-based JBS patient cohort. We therefore undertook a nationwide survey of JBS in the Netherlands and performed DNA analysis of the AHI1 and NPHP1 genes, as well as a new candidate gene CYCLIN D1. We obtained clinical data and DNA samples of 25 Dutch JBS patients. DNA analysis of AHI1 revealed pathogenic homozygous or compound heterozygous AHI1 mutations in four patients (16%). Based on the birth prevalence of about 1 in 100,000 for JBS in the Netherlands, we estimated a carrier frequency of AHI1 mutations of approximately 1 in 400. In another two patients, the AHI1 mutation Arg830Trp was identified (homozygously and heterozygously), a possible low penetrance allele. No deletions of NPHP1 or CYCLIN D1 mutations were detected in these 25 patients. In the four patients with AHI1 mutations, retinal disease (Leber congenital amaurosis or retinal dystrophy) was present in two, whereas none had renal disease. Pooling our data and data from the literature, retinal disease seems to occur in 75% of AHI1-associated JBS patients. Renal disease is present in 10% at most. We conclude that AHI1 mutations are an important cause of JBS in Dutch patients, and should always be looked for in patients suspected of JBS, especially when retinal dystrophy is present. Patients with AHI1 mutations should be regularly checked for retinal and renal disease up until adolescence.

Stesolid emergency treatment: cave social fear!

PURPOSE: To explore psychosocial effects of rectiole emergency treatment. METHODS: Children who had at some time been treated with Stesolid rectiole for seizure relief were questioned about feelings of shame in relation to this treatment and their expectation of bullying by peers who might be aware of it. In addition to parental shame, parental worries concerning their children's epilepsy were explored. Data from 39 patients (18 girls) aged 5-19 years were analysed. RESULTS: Of the children aged over seven, most girls (9/12), but not boys (1/6) reported to feeling a sense of shame. Children's shame was not related to parental shame, parental worries or seizure severity. A higher frequency of rectiole applications was related to a stronger expectation of being bullied. DISCUSSION AND CONCLUSION: Rectal emergency medication may elicit social fear, particularly in girls and if recurring it may (not solely in girls) elicit increased expectations of bullying.

Seizure freedom after functional hemispherectomy and a possible role for the insular cortex: the Dutch experience.

OBJECT: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.