Prenatal exposure to antiepileptic drugs and early processing of emotionally relevant sounds.

INTRODUCTION: Prenatal exposure to antiepileptic drugs (AEDs) is associated with developmental compromises in verbal intelligence and social skills in childhood. Our aim was to evaluate whether a multifeature Mismatch Negativity (MMN) paradigm assessing semantic and emotional components of linguistic and emotional processing would be useful to detect possible alterations in early auditory processing of newborns with prenatal AED exposure. MATERIAL AND METHODS: Data on AED exposure, pregnancy outcome, neuropsychological evaluation of the mothers, information on maternal epilepsy type, and a structured neurological examination of the newborn were collected prospectively. Blinded to AED exposure, we compared a cohort of 36 AED-exposed with 46 control newborns at the age of two weeks by measuring MMN with a multifeature paradigm with six linguistically relevant deviant sounds and three emotionally uttered sounds. RESULTS: Frontal responses for the emotionally uttered stimulus Happy differed significantly in the exposed newborns compared with the control newborns. In addition, responses to sounds with or without emotional component differed in newborns exposed to multiple AEDs compared with control newborns or to newborns exposed to only one AED. CONCLUSIONS: These preliminary findings suggest that prenatal AED exposure may alter early processing of emotionally and linguistically relevant sound information.

Effects of prenatal antiepileptic drug exposure on newborn brain activity.

OBJECTIVE: Prenatal exposure to antiepileptic drugs (AEDs) is associated with an increased risk of cognitive dysfunction at early school age. Our aim was to investigate whether signs of adverse drug effects on brain function could be detected already during the first 2 weeks of life. METHODS: We studied prospectively 56 full-term newborns with prenatal exposure to AEDs and 67 unexposed newborns for the following characteristics: Background information, AED exposure data, pregnancy outcome, neuropsychological evaluation of the mothers, clinical neurologic status with Hammersmith Neonatal Neurological Examination and early cortical activity using electroencephalography (EEG). For EEG assessment, we developed and provide automated quantitation algorithms of several earlier described features: oscillatory bouts at theta and alpha frequencies, frequency spectra, interhemispheric synchrony, and interburst intervals (IBIs). RESULTS: The AED-exposed newborns had lower limb and axial tone and were less irritable than the unexposed newborns. EEG assessment disclosed significant differences in alpha bouts, in the frequency spectra, as well as in the spatial distributions of interhemispheric synchrony and IBIs. SIGNIFICANCE: The results indicate that fetal AED exposure may affect early neonatal neurologic status and several features of early cortical activity. The findings suggest that interference of activity-dependent network development may be a possible mechanism to explain the link from fetal AED exposure to later neurocognitive sequelae.

Evidence for spared attention to faces in 7-month-old infants after prenatal exposure to antiepileptic drugs.

INTRODUCTION: Prenatal antiepileptic drug (AED) exposure is associated with an increased risk of cognitive impairment and autism spectrum disorders detected mainly at the age of two to six years. We examined whether the developmental aberrations associated with prenatal AED exposure could be detected already in infancy and whether effects on visual attention can be observed at this early age. MATERIAL AND METHODS: We compared a prospective cohort of infants with in utero exposure to AED (n=56) with infants without drug exposures (n=62). The assessments performed at the age of seven months included standardized neurodevelopmental scores (Griffiths Mental Developmental Scale and Hammersmith Infant Neurological Examination) as well as a novel eye-tracking-based test for visual attention and orienting to faces. Background information included prospective collection of AED exposure data, pregnancy outcome, neuropsychological evaluation of the mothers, and information on maternal epilepsy type. RESULTS: Carbamazepine, oxcarbazepine, and valproate, but not lamotrigine or levetiracetam, were associated with impaired early language abilities at the age of seven months. The general speed of visuospatial orienting or attentional bias for faces measured by eye-tracker-based tests did not differ between AED-exposed and control infants. DISCUSSION: Our findings support the idea that prenatal AED exposure may impair verbal abilities, and this effect may be detected already in infancy. In contrast, the early development of attention to faces was spared after in utero AED exposure.

The CAVE score for predicting late seizures after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Seizures are a common complication of intracerebral hemorrhage (ICH). We developed a novel tool to quantify this risk in individual patients. METHODS: Retrospective analysis of the observational Helsinki ICH Study (n=993; median follow-up, 2.7 years) and the Lille Prognosis of InTra-Cerebral Hemorrhage (n=325; 2.2 years) cohorts of consecutive ICH patients admitted between 2004 and 2010. Helsinki ICH Study patients' province-wide electronic records were evaluated for early seizures occurring within 7 days of ICH and among 7-day survivors (n=764) for late seizures (LSs) occurring >7 days from ICH. A Cox regression model estimating risk of LSs was used to derive a prognostic score, validated in the Prognosis of InTra-Cerebral Hemorrhage cohort. RESULTS: Of the Helsinki ICH Study patients, 109 (11.0%) had early seizures within 7 days of ICH. Among the 7-day survivors, 70 (9.2%) patients developed LSs. The cumulative risk of LSs was 7.1%, 10.0%, 10.2%, 11.0%, and 11.8% at 1 to 5 years after ICH, respectively. We created the CAVE score (0-4 points) to estimate the risk of LSs, with 1 point for each of cortical involvement, age<65 years, volume>10 mL, and early seizures within 7 days of ICH. The risk of LSs was 0.6%, 3.6%, 9.8%, 34.8%, and 46.2% for CAVE scores 0 to 4, respectively. The c-statistic was 0.81 (0.76-0.86) and 0.69 (0.59-0.78) in the validation cohort. CONCLUSIONS: One in 10 patients will develop seizures after ICH. The risk of this adverse outcome can be estimated by a simple score based on baseline variables.

Seizure control in Unverricht-Lundborg disease: a single-centre study.

New antiepileptic drug (AED) options for generalised seizure types have been adopted for use as treatment for Unverricht-Lundborg disease. Whether this has led to improved seizure control or functional outcome in ULD patients remains obscure. We retrospectively identified all patients seen at Helsinki University Hospital due to Unverricht-Lundborg disease during 2003-2008 in order to determine which AED treatments had been retained for long-term use. The majority of the patients had severe functional disabilities. In the year preceding the last hospital visit, all patients (n=20) were receiving polytherapy and 14 patients had been free of tonic-clonic seizures. During follow-up, improvement in myoclonia had been recorded for the majority of patients with either add-on piracetam, topiramate, or levetiracetam, but valproate was still in use by all patients. Treatment with lamotrigine had been started and retained less often relative to other AEDs. Add-on AED treatment was often associated with significant adverse effects. Unverricht-Lundborg disease patients may benefit from add-on treatment with levetiracetam or topiramate for seizure control. Treatment of eventual comorbidities with other than AEDs is also discussed.

Glioma features and seizure control during long-term follow-up.

Background: An epileptic seizure is a common presenting symptom of glioma, or epilepsy may develop later during the disease. Epileptic seizures affect the quality of life in patients with glioma. Good seizure control during 6-12 months follow-up has been associated with gross total resection, radiation therapy and chemotherapy of gliomas. Little is known about seizure control during long-term follow-up and about factors which may affect the prognosis of epilepsy in glioma patients. Methods: We identified retrospectively all adult patients with diffuse glioma (grade 2-4) associated epilepsy (n = 123) living in Helsinki, who received treatment at Helsinki University Hospital neuro-oncology center during 2013-2015. We excluded patients with histopathological diagnosis prior to 2005. Data was collected from medical records for five years after diagnosis of glioma, or until death. Results: In this patient cohort 49 (39.8 %) had grade 2 glioma, 19 (15.4 %) had grade 3 glioma and 55 (44.7 %) had grade 4 glioma. 29 (23.6 %) of tumors were astrocytomas, 24 (19.5 %) were oligoastrocytomas, 15 (12.2 %) were oligodendrogliomas and 55 (44.7 %) were glioblastomas. A seizure was the presenting symptom in 87 (70.7 %) of the patients. The majority, 68 (57.6 %) patients were seizure-free for at least 12 months at some point during follow-up and 47 (39.8 %) patients were seizure-free during the last year of follow-up. Survival for five years from glioma diagnosis (p < 0.001), lower grade of tumor (p < 0.001), IDH mutation (p < 0.001), epilepsy as first symptom (p < 0.001), younger age (p < 0.001) and lack of progression (p = 0.021) correlated with seizure freedom at the end of follow-up. When the results were analyzed separately in survivors and deceased patients, only progression correlated negatively with seizure freedom at the end of follow-up in surviving patients (p = 0.008). In 5-year survivors, longer seizure-free periods were achieved by patients without progression of glioma (p = 0.040) vs patients with progression, or without focal aware (p 0.003) or focal impaired awareness seizures (p = 0.002) vs patients with only focal to bilateral tonic-clonic seizures. In deceased patients, progression (p < 0.001) and lower grade of glioma (p = 0.003) correlated positively and focal aware seizures negatively (p = 0.021) with a longer seizure-free period. In all patients, freedom of seizures at the end of follow-up was less likely for patients who had focal aware (p = 0.015) than for patients without focal aware seizures. Conclusion: There are differences in seizure-free times in patients with grade 2-4 glioma and epilepsy. The results suggest that the prognosis of glioma may be the most important factor influencing the prognosis of epilepsy.

Sensitivity and specificity of seizure-onset zone estimation by ictal magnetoencephalography.

PURPOSE: Ictal video-electroencephalography (EEG) is commonly used to establish ictal onset-zone location. Recently software development has enabled systematic studies of ictal magnetoencephalography (MEG). In this article, we evaluate the ability of ictal MEG signals to localize the seizure-onset zone. METHODS: Twenty-six patients underwent ictal MEG and epilepsy surgery. Prediction of seizure-onset zone by ictal and interictal MEG was retrospectively compared with ictal-onset area found by intracranial EEG in 12 patients. The specificity and sensitivity of the prediction were calculated at hemisphere-lobe (HL) and at hemisphere-lobe-surface (HLS) levels. KEY FINDINGS: The sensitivity of ictal MEG source localization was 0.958 on HL and 0.706 on HLS levels, and its specificity was 0.900 on HL and 0.731 on HLS levels. The interictal MEG dipole cluster, defined as >10 dipoles on one lobar surface, had sensitivity of 0.400 and specificity of 0.769. Ictal MEG was equally sensitive and specific on dorsolateral and nondorsolateral neocortical surfaces up to a depth of 4 cm from the scalp. SIGNIFICANCE: Sources of ictal-onset MEG signals and interictal dipole clusters are essentially equally specific in estimation of the ictal-onset zone on lobar surface resolution, but ictal MEG is more sensitive. On the lobe resolution, ictal MEG estimates ictal-onset zone with high sensitivity and specificity.

Feasibility of video/audio monitoring in the analysis of motion and treatment effects on night-time seizures - Interventional study.

THE AIM OF THE STUDY: This pilot study assessed the ability of a video/audio-based seizure monitoring system to evaluate (I) baseline frequency and severity of nocturnal seizures with motor features in patients with drug-resistant epilepsy (DRE) and (II) the individual effect of brivaracetam (BRV) treatment on number, duration and movement intensity of these seizure types. Algorithmic feature analysis was developed for assessment of qualitative changes in movement intensity measurements within seizure types before and after BRV intervention. MATERIALS AND METHODS: Night-time motor seizures of recruited patients were recorded in two separate four-week monitoring periods. The first period defined a prescreening phase (n = 13 patients) to establish a baseline, and the second period defined the intervention phase (n = 9 patients), with BRV initiated during the second week of the second monitoring period. All recorded nights were analyzed by an expert video reviewer, and all unequivocal seizures were classified by an epileptologist. Seizure frequencies using both seizure diaries and video monitoring were compared. The effect of BRV on both seizure duration and movement intensity was assessed by numerical comparison of visual features calculated from motion characteristics of the video, as well as spectral features from the recorded audio. The statistical significance of changes in seizure duration and intensity before and after the intervention were investigated by Wilcoxon rank-sum test and visual inspection of Kernel density estimation. RESULTS: 8 patients marked seizures in their seizure diaries during the prescreening phase. During the three-week follow-up, three patients achieved > 50% seizure decrease, four patients did not respond to treatment, and two patients experienced worsening of seizures. Five patients were able to document 40-70% of their seizures compared to the video/audio monitoring system. According to the signal feature analysis the intervention decreased movement intensity with clear clinical significance in three patients, whereas statistically significant differences in features appeared in 8 out of 9 patients. CONCLUSIONS: The novel video/audio monitoring system improved the evaluation of treatment effect compared to the seizure diaries and succeeded in providing a comparative intra-patient assessment of the movement intensity and duration of the recorded seizures.

Microsurgical treatment of temporal lobe cavernomas.

BACKGROUND: Cavernomas of the temporal lobe occur in 10-20% of patients with cerebral cavernomas. They frequently cause epileptic seizures, some of which tend to become refractory to medical therapy. Surgical removal of safely achievable symptomatic lesions has been frequently consistent with good long-term outcome. In the present study, a postoperative outcome is assessed. METHODS: Of our 360 consecutive patients with cerebral cavernomas, 53 (15%) had a single cavernoma in the temporal lobe. Forty-nine patients were treated surgically and were included in the study. All data were analyzed retrospectively. The cavernomas were allocated into three groups based on the temporal lobe site: medial, anterolateral, and posterolateral. To collect follow-up data, all available patients were interviewed by phone. Seizure outcome was assessed using the Engel classification and general outcome using the Glasgow Outcome Scale (GOS). RESULTS: Patients' median age at presentation was 37 (range, 7-64) years, with a female/male ratio of 2.5:1. Epileptic seizures occurred in 40 patients (82%). Median duration of seizures preoperatively was 3 (range, 0.1-23) years. In addition, four patients (10%) had memory disorder. Three patients without history of seizures (6%) complained of headache and two (4%) had memory problems. Three patients (6%) had an incidental cavernoma. Hemorrhage occurred in nine patients (18%) preoperatively. Median postoperative follow-up time was 6 (range, 0.2-26) years. Favorable seizure outcome (Engel class I and II) was registered in 35 patients (90%). Ten patients (25%) who had only a single seizure before surgery were seizure free during postoperative follow-up. Good general outcome (GOS, 4.5) was detected in 46 patients (96%). Two patients (4%) developed a new mild memory deficit after surgery, and in two patients existing memory deficits worsened. CONCLUSIONS: Microsurgical removal of temporal lobe cavernomas is a safe and effective method to improve seizure outcome in patients with medically intractable epilepsy and to prevent deterioration caused by hemorrhage.

EEG in fitness to drive evaluations in people with epilepsy - Considerable variations across Europe.

PURPOSE: Epilepsy patients consider driving issues to be one of their most serious concerns. Ideally, decisions regarding fitness to drive should be based upon thorough evaluations by specialists in epilepsy care. In 2009, an EU directive was published aiming to harmonize evaluation practices within European countries, but, despite these recommendations, whether all epileptologists use the same criteria is unclear. We therefore conducted this study to investigate routine practices on how epileptologists at European epilepsy centers evaluate fitness to drive. METHODS: A questionnaire was sent to 63 contact persons identified through the European Epi-Care and the E-pilepsy network. The questionnaire addressed how fitness-to-drive evaluations were conducted, the involvement of different professionals, the use and interpretation of EEG, and opinions on existing regulations and guidelines. RESULTS: The questionnaire was completed by 35 participants (56 % response rate). Results showed considerable variation regarding test routines and the emphasis placed on the occurrence and extent of epileptiform discharges revealed by EEG. 82 % of the responders agreed that there was a need for more research on how to better evaluate fitness-to-drive in people with epilepsy, and 89 % agreed that regulations on fitness to drive evaluations should be internationally coordinated. CONCLUSION: Our survey showed considerable variations among European epileptologists regarding use of EEG and how findings of EEG pathology should be assessed in fitness-to-drive evaluations. There is a clear need for more research on this issue and international guidelines on how such evaluations should be carried out would be of value.

Development of epilepsy after ischaemic stroke.

For about 30% of patients with epilepsy the cause is unknown. Even in patients with a known risk factor for epilepsy, such as ischaemic stroke, only a subpopulation of patients develops epilepsy. Factors that contribute to the risk for epileptogenesis in a given individual generally remain unknown. Studies in the past decade on epilepsy in patients with ischaemic stroke suggest that, in addition to the primary ischaemic injury, existing difficult-to-detect microscale changes in blood vessels and white matter present as epileptogenic pathologies. Injury severity, location and type of pathological changes, genetic factors, and pre-injury and post-injury exposure to non-genetic factors (ie, the exposome) can divide patients with ischaemic stroke into different endophenotypes with a variable risk for epileptogenesis. These data provide guidance for animal modelling of post-stroke epilepsy, and for laboratory experiments to explore with increased specificity the molecular 'mechanisms, biomarkers, and treatment targets of post-stroke epilepsy in different circumstances, with the aim of modifying epileptogenesis after ischaemic stroke in individual patients without compromising recovery.

Regulation of restitution after superficial injury in isolated guinea pig gastric mucosa.

The immediate response of the gastrointestinal epithelium to superficial (i.e. microscopic) injury is primarily directed towards restoring the disturbed epithelial continuity. Both structural (i.e. cytoskeleton) and humoral (i.e. growth factors and cytokines) involvement in the process has recently been documented. Yet it is unclear whether humoral signaling regulating mucosal recovery after superficial injury is associated with tyrosine phosphorylation, and whether there are other signs of downstream activation of the signaling pathway. To evaluate the effects of exogenous genistein and phorbol-myristate acetate in the assessment of the role of tyrosine receptor-mediated signaling in the immediate repair of gastric mucosa after superficial injury. Guinea pig gastric mucosa was mounted in a Ussing chamber, injured with 1.25 M NaCl, and perfused for 4 h. Simultaneously, potential difference and tissue resistance were recorded. In some sets of experiments the tissue was exposed bilaterally either to genistein in order to inhibit tyrosine receptor-mediated signaling or to 4-phorbol-myristate 13-acetate (PMA) in order to enhance PKC signaling during the 4 h recovery. Phosphotyrosine (PTYR) and protein kinase C (PKC) immunoreactivity were assessed by immunoblotting and by immunohistochemistry. Proliferative activity was determined morphometrically after staining of the tissue for Ki-67 nuclear antigen and expressed as proliferative index (PI). The inhibition of tyrosine kinases with exogenous genistein resulted in a significant decrease of the PTYR and the stimulation of PKC with PMA increased the PTYR. Nevertheless, no change in the PTYR was observed by immunoblotting after superficial injury alone. Several PKC isoenzymes were found in the guinea pig gastric mucosa, including PKC-alpha, -epsilon, -zeta and -iota. They were unaffected either by the injury or the PMA treatment. The mean PI of tissues subjected to NaCl-injury was higher than that of uninjured control tissues (p<0.05) (n=7). Exposure of tissue to genistein during recovery decreased the PI, while stimulation with PMA increased it (p<0.05 for both) (n=6). Both electrophysiologic and morphologic restitution were sensitive to genistein, but not to PMA. Superficial injury alone does not influence tyrosine phosphorylation to a degree which could be assessed by immunoblotting. Nevertheless, exogenous modulation of tyrosine receptor-mediated signaling results in downstream signaling effects. The injury-associated induction of proliferation is sensitive to modulation of tyrosine phosphorylation and PKC, suggesting that superficial epithelial injury results in endogenous activation of the epithelium, presumably after paracrine stimulation of the neighboring cells.

TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk.

OBJECTIVE: To determine the proportion of children with herpes simplex encephalitis (HSE) displaying TLR3 deficiency, the extent of TLR3 allelic heterogeneity, and the specific clinical features of TLR3 deficiency. METHODS: We determined the sequence of all exons of TLR3 in 110 of the 120 patients with HSE enrolled in our study who do not carry any of the previously described HSE-predisposing mutations of TLR3 pathway genes (TLR3, UNC93B1, TRIF, TRAF3, and TBK1). All the new mutant TLR3 alleles detected were characterized experimentally in-depth to establish the causal relationship between the genotype and phenotype. RESULTS: In addition to the 3 previously reported TLR3-deficient patients from the same cohort, 6 other children or young adults with HSE carry 1 of 5 unique or extremely rare (minor allele frequency <0.001) missense TLR3 alleles. Two alleles (M374T, D592N) heterozygous in 3 patients are not deleterious in vitro. The other 3 are deleterious via different mechanisms: G743D+R811I and L360P heterozygous in 2 patients are loss-of-function due to low levels of expression and lack of cleavage, respectively, and R867Q homozygous in 1 patient is hypomorphic. The 3 patients' fibroblasts display impaired TLR3 responses and enhanced herpes simplex virus 1 susceptibility. Overall, TLR3 deficiency is therefore found in 6 (5%) of the 120 patients studied. There is high allelic heterogeneity, with 3 forms of autosomal dominant partial defect by negative dominance or haploinsufficiency, and 2 forms of autosomal recessive defect with complete or partial deficiency. Finally, 4 (66%) of the 6 TLR3-deficient patients had at least 1 late relapse of HSE, whereas relapse occurred in only 12 (10%) of the total cohort of 120 patients. CONCLUSIONS: Childhood-onset HSE is due to TLR3 deficiency in a traceable fraction of patients, in particular the ones with HSE recurrence. Mutations in TLR3 and TLR3 pathway genes should be searched and experimentally studied in children with HSE, and patients with proven TLR3 deficiency should be followed carefully.