Preexisting illness, fetal malformation, and seizure control rates in pregnant women with epilepsy.

Data from 2182 pregnancies in the Australian Register of antiepileptic drugs in pregnancy that were followed to term, with 1965 followed for another year, were analyzed to ascertain whether preexisting illness influenced i. the hazard of fetal malformations, and ii. seizure control during pregnancy. Fetal malformation occurred in 74 of the 842 pregnancies associated with preexisting illness (8.8%) and in 84 of the 1340 comparator pregnancies (6.27%), Relative Risk (R.R.) = 1.402 (95% Confidence Interval (C.I.) = 1.038, 1.893). Logistic regression showed statistically significant effects of preexisting maternal drug-treated psychiatric illness, untreated psychiatric illness, and use of citalopram, carbamazepine, valproate, and topiramate in increasing hazard of fetal malformation. Preexisting nonpsychiatric illness and other antiepileptic drugs and drugs prescribed for psychiatric illness, mainly antidepressants, had no such effect. Seizures occurred during 405 of the 842 pregnancies associated with preexisting illness, and during 593 of 1340 comparison pregnancies (48.1% v 44.3%; R.R. = 1.087; 95% C.I. = 0.991, 1.192). There were no statistically significant relationships between preexisting nonpsychiatric and psychiatric illnesses separately and seizure control during pregnancy. Thus, apart from consequences of antiepileptic drug exposure, preexisting maternal psychiatric illness, in its own right, or when treated with citalopram, appears to be associated with increased hazards of fetal malformation.

IDH1 and IDH2 mutations in postoperative diffuse glioma-associated epilepsy.

OBJECTIVE: Isocitrate dehydrogenase 1 and 2 mutations (IDH1/2) have an established association with preoperative seizures in patients with grades II-IV diffuse gliomas. Here, we examined if IDH1/2 mutations are a biomarker of postoperative seizure frequency. METHODS: This was a retrospective study. Patients with grades II-IV supratentorial diffuse glioma, immunohistochemistry results of IDH1-R132H, and antiepileptic drug (AED) prescribed postoperatively were included. The primary outcome was seizure frequency over the first 12 postoperative months: Group A - postoperative seizure freedom; Group B - 1-11 seizures over 12months (less than one seizure per month); and Group C - greater than one seizure per month. Rates of IDH1-R132H mutation were compared between the three outcome groups in univariate and multivariate analyses. Subgroup analysis was performed in 64 patients with IDH1/2 pyrosequencing data. RESULTS: One hundred cases were included in the analysis: 30.0% grade II, 20.0% grade III, and 50.0% grade IV gliomas. Group B patients averaged 1 seizure over 12months, compared with 2 seizures per month in Group C. Isocitrate dehydrogense 1-R132H mutation was present in 29.3% (17/58) of Group A, 18.2% (14/22) of Group B, and 70.0% (14/20) of Group C patients (p=0.001). On multivariate analysis, after controlling for preoperative seizure, grade, and temporal tumor location, IDH1-R132H was associated with Group C when compared with both Group A (RR 4.75, p=0.032) and Group B (RR 9.70, p=0.012). In the subgroup with IDH1/2 molecular data, an IDH1/2 mutation was present in 64.7% (22/34) of Group A, 28.6% (4/14) of Group C, and 87.5% (14/16) of Group C patients (p=0.004). SIGNIFICANCE: In patients with supratentorial diffuse gliomas, IDH1-R132H mutations are associated with a more severe phenotype of postoperative epilepsy. These findings support further research into IDH mutations, and the potential for an antiepileptic therapeutic effect of their inhibitors, in patients with glioma-associated epilepsy.

Cesarean section in Australian women with epilepsy.

The literature suggests that cesarean delivery or birth is carried out more often in pregnant women with epilepsy (WWE) than in pregnant women in the general population. Data were utilized from the Australian Pregnancy Register (APR) for Women on Antiepileptic Medication to investigate this issue in Australia. Over almost two decades, the mean CS rate in 1900 APR women was 39.2%, but was only 29.9% in women in the general population (relative risk (R.R.) = 1.31, 95% confidence interval (C.I.) 1.24, 1.39). Rates for forceps and suction-assisted delivery were similar in the two datasets. The 9.3% excess CS rate was almost entirely accounted for by operations carried out prior to the onset of labor. The rates for CS during labor were very similar. Only 11.0% of the WWE knew the indication for their prelabor CS, whereas 69.8% knew why theirs had been carried out during labor (odds ratio (O.R.) = 0.054; 99% C.I. 0.032, 0.089). Slightly older mothers and increased proportions of primipara probably made small contributions to the increased prelabor CS rate in the Australian WWE, but most of the excess could not be accounted for in the Register data. Australian obstetricians may have tended to regard prelabor CS as a preferable course of action in managing delivery in WWE, even in the absence of other indications.

Postoperative seizure control in patients with tumor-associated epilepsy.

OBJECTIVE: The patterns of postoperative seizure control and response to antiepileptic drugs (AEDs) in tumor-associated epilepsy (TAE) are poorly understood. We aim to document these characteristics in patients with supratentorial gliomas. METHODS: This was a retrospective analysis of 186 patients with supratentorial gliomas. Seizure patterns were classified into four groups: A, no postoperative seizure; B, early postoperative seizure control within 6 months; C, fluctuating seizure control; and D, never seizure-free. Rates and duration of seizure freedom, subsequent seizure relapse, and response to AED were analyzed. RESULTS: Among patients included, 49 (26.3%) had grade II, 28 (15.1%) had grade III, and 109 (58.6%) had grade IV glioma. Outcome pattern A was observed in 95 (51.1%), B in 22 (11.8%), C in 45 (24.2%), and D in 24 (12.9%). One hundred nineteen patients had at least one seizure and were classified as having TAE. Compared to pattern A, pattern B was predicted by histologic progression; pattern C by tumor grade, preoperative seizure, and histologic progression, and pattern D by preoperative seizure and gross total resection. Among patients with TAE, 57.5% of grade II, 68.2% of grade III, and 26.3% of grade IV experienced a period of 12-month seizure freedom. After first 12-month seizure remission, 39.1%, 60.0%, and 13.3% of grade II, III, and IV gliomas, respectively, experienced subsequent seizure; 22.6% of those with TAE reached terminal seizure freedom of at least 12 months on their first postoperative AED regimen, 6.5% on their second regimen, and 5.4% on subsequent regimens. SIGNIFICANCE: Distinct patterns of postoperative seizure control exist in gliomas; they have specific risk factor profiles, and we hypothesize these correspond to unique pathogenic mechanisms. Twelve-month seizure freedom with subsequent relapse is frequent in grade II-III gliomas. Response to AEDs is markedly poorer than with non-TAE, highlighting the complex epileptogenicity of gliomas.

Bone Mineral Changes in Epilepsy Patients During Initial Years of Antiepileptic Drug Therapy.

Antiepileptic drug (AED) therapy is associated with decreased bone mineral density; however, the time course for this development is unclear. The aim of this study was to evaluate bone mineral changes during the initial years of AED therapy in AED-naive, newly diagnosed epilepsy patients compared with non-AED users. In 49 epilepsy patients newly started on AEDs and in 53 non-AED users of both genders, bone mineral density (BMD) and bone mineral content were measured using dual-energy X-ray absorptiometry at baseline (within the first year of therapy) and at least 1 yr later. Bone changes between the 2 assessments, adjusted for age, height, and weight, were calculated as the annual rate of change. The median duration of AED therapy was 3.5 mo at baseline and 27.6 mo at follow-up. No overall difference was found in mean BMD and bone mineral content measures between user and nonuser cohorts in both cross-sectional baseline and the annual rate of change (p > 0.05). However, users on carbamazepine monotherapy (n = 11) had an increased annual rate of total hip (-2.1% vs -0.8%, p = 0.020) and femoral neck BMD loss (-2.1% vs -0.6%, p = 0.032) compared to nonusers. They also had a marginally higher rate of femoral neck BMD loss (-2.1%, p = 0.049) compared with valproate (-0.1%, n = 13) and levetiracetam users (+0.6%, n = 13). During the initial years of AED treatment for epilepsy, no difference was found in bone measures between AED users as a group and nonuser cohorts. However, the data suggested that carbamazepine monotherapy was associated with increased bone loss at the hip regions, compared to users of levetiracetam or valproate and nonusers. Larger studies of longer duration are warranted to better delineate the bone effects of specific AEDs, with further consideration of the role of early dual-energy X-ray absorptiometry scanning and careful AED selection in potentially minimizing the impact on bone health in these patients.

Seizure Outcome After Surgery for MRI-Diagnosed Focal Cortical Dysplasia: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: Focal cortical dysplasia (FCD) has been associated with poorer postsurgical seizure outcomes compared to other pathologies. FCD surgical series have been assembled on the basis of a histologic diagnosis, including patients with abnormal and normal preoperative MRI. However, in clinical workflow, patient selection for surgery is based on preoperative findings, including MRI. We performed a systematic review and meta-analysis of the literature to determine the rate and predictors of favorable seizure outcome after surgery for MRI-detected FCD. METHODS: We devised our study protocol in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and registered the protocol with PROSPERO. We searched MEDLINE, EMBASE, and Web of Science for studies of patients followed up for ≥12 months after resective surgery for drug-resistant epilepsy with MRI-detected FCD. Random-effects meta-analysis was used to calculate the proportion of patients attaining a favorable outcome, defined as Engel class I, International League Against Epilepsy class 1 to 2, or seizure-free status. Meta-regression was performed to investigate sources of heterogeneity. RESULTS: Our search identified 3,745 references. Of these, 35 studies (total of 1,353 patients) were included. Most studies (89%) followed up patients for ≥24 months after surgery. The overall postsurgical favorable outcome rate was 70% (95% confidence interval [CI] 64-75). There was high interstudy heterogeneity. Favorable outcome was associated with complete resection of the FCD lesion (risk ratio [RR] 2.42 [95% confidence interval (CI) 1.55-3.76], p < 0.001) and location of the FCD lesion in the temporal lobe (RR 1.38 [95% CI 1.07-1.79], p = 0.013) but not lesion extent, intracranial EEG use, or FCD histologic type. The number of FCD histologic types included in the same study accounted for 7.6% of the observed heterogeneity. DISCUSSION: Seventy percent of patients with drug-resistant epilepsy and MRI features of FCD attain a favorable seizure outcome after resective surgery. Our findings can be incorporated into routine preoperative counseling and reinforce the importance of completely resecting the MRI-detected FCD when safe and feasible.

An ovine model of cerebral catheter venography for implantation of an endovascular neural interface.

OBJECTIVE Neural interface technology may enable the development of novel therapies to treat neurological conditions, including motor prostheses for spinal cord injury. Intracranial neural interfaces currently require a craniotomy to achieve implantation and may result in chronic tissue inflammation. Novel approaches are required that achieve less invasive implantation methods while maintaining high spatial resolution. An endovascular stent electrode array avoids direct brain trauma and is able to record electrocorticography in local cortical tissue from within the venous vasculature. The motor area in sheep runs in a parasagittal plane immediately adjacent to the superior sagittal sinus (SSS). The authors aimed to develop a sheep model of cerebral venography that would enable validation of an endovascular neural interface. METHODS Cerebral catheter venography was performed in 39 consecutive sheep. Contrast-enhanced MRI of the brain was performed on 13 animals. Multiple telescoping coaxial catheter systems were assessed to determine the largest wide-bore delivery catheter that could be delivered into the anterior SSS. Measurements of SSS diameter and distance from the motor area were taken. The location of the motor area was determined in relation to lateral and superior projections of digital subtraction venography images and confirmed on MRI. RESULTS The venous pathway from the common jugular vein (7.4 mm) to the anterior SSS (1.2 mm) was technically challenging to selectively catheterize. The SSS coursed immediately adjacent to the motor cortex (< 1 mm) for a length of 40 mm, or the anterior half of the SSS. Attempted access with 5-Fr and 6-Fr delivery catheters was associated with longer procedure times and higher complication rates. A 4-Fr catheter (internal lumen diameter 1.1 mm) was successful in accessing the SSS in 100% of cases with no associated complications. Complications included procedure-related venous dissection in two major areas: the torcular herophili, and the anterior formation of the SSS. The bifurcation of the cruciate sulcal veins with the SSS was a reliable predictor of the commencement of the motor area. CONCLUSIONS The ovine model for cerebral catheter venography has generalizability to the human cerebral venous system in relation to motor cortex location. This novel model may facilitate the development of the novel field of endovascular neural interfaces that may include preclinical investigations for cortical recording applications such as paralysis and epilepsy, as well as other potential applications in neuromodulation.

Development and Implementation of a Corriedale Ovine Brain Atlas for Use in Atlas-Based Segmentation.

Segmentation is the process of partitioning an image into subdivisions and can be applied to medical images to isolate anatomical or pathological areas for further analysis. This process can be done manually or automated by the use of image processing computer packages. Atlas-based segmentation automates this process by the use of a pre-labelled template and a registration algorithm. We developed an ovine brain atlas that can be used as a model for neurological conditions such as Parkinson's disease and focal epilepsy. 17 female Corriedale ovine brains were imaged in-vivo in a 1.5T (low-resolution) MRI scanner. 13 of the low-resolution images were combined using a template construction algorithm to form a low-resolution template. The template was labelled to form an atlas and tested by comparing manual with atlas-based segmentations against the remaining four low-resolution images. The comparisons were in the form of similarity metrics used in previous segmentation research. Dice Similarity Coefficients were utilised to determine the degree of overlap between eight independent, manual and atlas-based segmentations, with values ranging from 0 (no overlap) to 1 (complete overlap). For 7 of these 8 segmented areas, we achieved a Dice Similarity Coefficient of 0.5-0.8. The amygdala was difficult to segment due to its variable location and similar intensity to surrounding tissues resulting in Dice Coefficients of 0.0-0.2. We developed a low resolution ovine brain atlas with eight clinically relevant areas labelled. This brain atlas performed comparably to prior human atlases described in the literature and to intra-observer error providing an atlas that can be used to guide further research using ovine brains as a model and is hosted online for public access.

Falls and fractures in patients chronically treated with antiepileptic drugs.

OBJECTIVE: To evaluate fractures and falls in epilepsy patients taking antiepileptic drugs (AED) and to assess their awareness of AED-related bone health, falls, and fracture risk. METHODS: A cross-sectional study was conducted in epilepsy patients taking AEDs and in nonepileptic non-AED users. Information on falls and fracture history was collected. RESULTS: A total of 150 AED users were compared with 506 non-AED users. Users had greater odds of fracture at spine (odds ratio [OR] 3.92; confidence interval [CI] 1.08-14.16; p = 0.037), clavicle (OR 3.75; CI 1.24-11.34; p = 0.019), and ankle sites (OR 2.34; CI 1.01-5.42; p = 0.048), increased odds for osteoporosis (OR 4.62; CI 1.40-15.30; p = 0.012), and fracture occasions (OR 2.64; CI 1.29-5.43; p = 0.008). We estimate that with every year of AED use the odds of fractures increase by 4%-6%, or 40% per decade for any fracture (OR 1.40; CI 1.02-1.91) and 60% for seizure-related fractures (OR 1.63; CI 1.10-2.37). Non-seizure-related fractures (69% of cumulative fractures) occurred more than seizure-related fractures during therapy. Female users, compared to female nonusers, had more non-seizure falls (31% vs 17%, p = 0.027) and multiple falls (18% vs 5%, p = 0.028) in the preceding year. Fewer than 30% of epilepsy patients knew of the association of AED use with increased risk for fractures, decreased bone mineral density, or falls. CONCLUSIONS: Epilepsy patients taking AEDs had a higher risk of fractures, which was highest in those with longer-term AED exposure. Female AED users had a higher prevalence of falls than matched nonusers. Awareness among epilepsy patients regarding risks of falling and fractures was low.

Acoustic hypersensitivity in adult rats after neonatal ventral hippocampus lesions.

Rats with a bilateral neonatal ventral hippocampus lesion (NVHL) are used as models of neurobiological aspects of schizophrenia. In view of their decreased number of GABAergic interneurons, we hypothesized that they would show increased reactivity to acoustic stimuli. We systematically characterized the acoustic reactivity of NVHL rats and sham operated controls. They were behaviourally observed during a loud white noise. A first cohort of 7 months' old rats was studied. Then the observations were reproduced in a second cohort of the same age after characterizing the reactivity of the same rats to dopaminergic drugs. A third cohort of rats was studied at 2, 3, 4, 5 and 6 months. In subsets of lesioned and control rats, inferior colliculus auditory evoked potentials were recorded. A significant proportion of rats (50-62%) showed aberrant audiogenic responses with explosive wild running resembling the initial phase of audiogenic seizures. This was not correlated with their well-known enhanced reactivity to dopaminergic drugs. The proportion of rats showing this strong reaction increased with rats' age. After the cessation of the noise, NVHL rats showed a long freezing period that did neither depend on the size of the lesion nor on the rats' age. The initial negative deflection of the auditory evoked potential was enhanced in the inferior colliculus of only NVHL rats that displayed wild running. Complementary anatomical investigations using X-ray scans in the living animal, and alizarin red staining of brain slices, revealed a thin layer of calcium deposit close to the medial geniculate nuclei in post-NVHL rats, raising the possibility that this may contribute to the hyper-reactivity to sounds seen in these animals. The findings of this study provide complementary information with potential relevance for the hyper-reactivity noted in patients with schizophrenia, and therefore a tool to investigate the underlying biology of this endophenotype.

A novel system allowing long-term simultaneous video-electroencephalography recording, drug infusion and blood sampling in rats.

INTRODUCTION: Electroencephalography (EEG) recording and drug administration is commonly used for neurological experiments in rats, but is typically cumbersome due the use of multiple lines. We have developed a unique system, which allows long-term simultaneous video-electroencephalography recording, drug infusion and blood sampling in rats. METHODS: The vEEG/drug infusion system was designed and tested on two contrasting animal models of epilepsy. Animals were implanted with EEG-electrodes and a jugular vein cannula fixed in a head cap, avoiding an additional cable for tethering. In an acute infusion study (n=16), repeated blood samples were taken after i.v. bolus injection of valproate. In a subset of these rats (n=10), paired blood samples were removed from the jugular vein and the heart after valproate administration. In a chronic infusion study (n=38), heparinised (4IU/h) saline or valproate (42mg/kg/h) was infused continuously for up to 17 days. RESULTS: In the acute study, repeated blood samples showed a decrease in plasma valproate levels over time following bolus injection. In the chronic study, high quality continuous EEG was achieved and 79% of animals were successfully infused throughout the planned infusion period (13-17 days), with 66% of projected blood samples able to be taken during the infusion. There was a high correlation between the jugular vein and cardiac plasma levels of valproate (Spearman test, r=0.69; p<0.05). CONCLUSION: This system is ideal for pharmacokinetic/dynamic studies and long-term drug infusion where simultaneous EEG and/or frequent blood sampling are desired.