Influence of comorbidity on mortality in patients with epilepsy and psychogenic nonepileptic seizures.

OBJECTIVE: This study aims to determine the contribution of comorbidities to excess psychogenic nonepileptic seizures (PNES) mortality. METHODS: A retrospective cohort study was conducted of tertiary epilepsy outpatients from St. Vincent's Hospital Melbourne, Australia with an 8:1 comparison cohort, matched by age, sex, and socioeconomic status (SES) to national administrative databases between 2007 and 2017. Privacy-preserving data linkage was undertaken with the national prescription, National Death Index, and National Coronial Information System. Forty-five comorbid disease classes were derived by applying the Australian validated RxRisk-V to all dispensed prescriptions. We fitted Cox proportional hazard models controlling for age, sex, SES, comorbidity, disease duration, and number of concomitant antiseizure medications, as a marker of disease severity. We also performed a parallel forward-selection change in estimate strategy to explore which specific comorbidities contributed to the largest changes in the hazard ratio. RESULTS: A total of 13 488 participants were followed for a median 3.2 years (interquartile range = 2.4-4.0 years), including 1628 tertiary epilepsy outpatients, 1384 patients with epilepsy, 176 with PNES, and 59 with both. Eighty-two percent of epileptic seizures and 92% of typical PNES events were captured in an epilepsy monitoring unit. The age-/sex-/SES-adjusted hazard ratio was elevated for epilepsy (4.74, 95% confidence interval [CI] = 3.36-6.68) and PNES (3.46, 95% CI = 1.38-8.68) and remained elevated for epilepsy (3.21, 95% CI = 2.22-4.63) but not PNES (2.15, 95% CI = .77-6.04) after comorbidity adjustment. PNES had more pre-existing comorbidities (p = .0007), with a three times greater median weighted Rx-RiskV score. Psychotic illness, opioid analgesia, malignancies, and nonopioid analgesia had the greatest influence on PNES comorbid risk. SIGNIFICANCE: Higher comorbidity appears to explain the excess PNES mortality and may represent either a wider underrecognized somatoform disorder or a psychological response to physical illness. Better understanding and management of the bidirectional relationship of these wider somatic treatments in PNES could potentially reduce the risk of death.

Dynamical Network Models From EEG and MEG for Epilepsy Surgery-A Quantitative Approach.

There is an urgent need for more informative quantitative techniques that non-invasively and objectively assess strategies for epilepsy surgery. Invasive intracranial electroencephalography (iEEG) remains the clinical gold standard to investigate the nature of the epileptogenic zone (EZ) before surgical resection. However, there are major limitations of iEEG, such as the limited spatial sampling and the degree of subjectivity inherent in the analysis and clinical interpretation of iEEG data. Recent advances in network analysis and dynamical network modeling provide a novel aspect toward a more objective assessment of the EZ. The advantage of such approaches is that they are data-driven and require less or no human input. Multiple studies have demonstrated success using these approaches when applied to iEEG data in characterizing the EZ and predicting surgical outcomes. However, the limitations of iEEG recordings equally apply to these studies-limited spatial sampling and the implicit assumption that iEEG electrodes, whether strip, grid, depth or stereo EEG (sEEG) arrays, are placed in the correct location. Therefore, it is of interest to clinicians and scientists to see whether the same analysis and modeling techniques can be applied to whole-brain, non-invasive neuroimaging data (from MRI-based techniques) and neurophysiological data (from MEG and scalp EEG recordings), thus removing the limitation of spatial sampling, while safely and objectively characterizing the EZ. This review aims to summarize current state of the art non-invasive methods that inform epilepsy surgery using network analysis and dynamical network models. We also present perspectives on future directions and clinical applications of these promising approaches.

Virtual intracranial EEG signals reconstructed from MEG with potential for epilepsy surgery.

Modelling the interactions that arise from neural dynamics in seizure genesis is challenging but important in the effort to improve the success of epilepsy surgery. Dynamical network models developed from physiological evidence offer insights into rapidly evolving brain networks in the epileptic seizure. A limitation of previous studies in this field is the dependence on invasive cortical recordings with constrained spatial sampling of brain regions that might be involved in seizure dynamics. Here, we propose virtual intracranial electroencephalography (ViEEG), which combines non-invasive ictal magnetoencephalographic imaging (MEG), dynamical network models and a virtual resection technique. In this proof-of-concept study, we show that ViEEG signals reconstructed from MEG alone preserve critical temporospatial characteristics for dynamical approaches to identify brain areas involved in seizure generation. We show the non-invasive ViEEG approach may have some advantage over intracranial electroencephalography (iEEG). Future work may be designed to test the potential of the virtual iEEG approach for use in surgical management of epilepsy.

Association Between Psychiatric Comorbidities and Mortality in Epilepsy.

OBJECTIVE: To explore the impact of psychiatric comorbidities on all-cause mortality in adults with epilepsy from a cohort of patients admitted for video-EEG monitoring (VEM) over 2 decades. METHODS: A retrospective medical record audit was conducted on 2,709 adults admitted for VEM and diagnosed with epilepsy at 3 Victorian comprehensive epilepsy programs from 1995 to 2015. A total of 1,805 patients were identified in whom the record of a clinical evaluation by a neuropsychiatrist was available, excluding 27 patients who died of a malignant brain tumor known at the time of VEM admission. Epilepsy and lifetime psychiatric diagnoses were determined from consensus opinion of epileptologists and neuropsychiatrists involved in the care of each patient. Mortality and cause of death were determined by linkage to the Australian National Death Index and National Coronial Information System. RESULTS: Compared with the general population, mortality was higher in people with epilepsy (PWE) with a psychiatric illness (standardized mortality ratio [SMR] 3.6) and without a psychiatric illness (SMR 2.5). PWE with a psychiatric illness had greater mortality compared with PWE without (hazard ratio 1.41, 95% confidence interval 1.02-1.97) after adjusting for age and sex. No single psychiatric disorder by itself conferred increased mortality in PWE. The distribution of causes of death remained similar between PWE with psychiatric comorbidities and those without. CONCLUSION: The presence of comorbid psychiatric disorders in adults with epilepsy is associated with increased mortality, highlighting the importance of identifying and treating psychiatric comorbidities in these patients.

Interictal spike localization for epilepsy surgery using magnetoencephalography beamforming.

OBJECTIVE: Magnetoencephalography (MEG) kurtosis beamforming is an automated localization method for focal epilepsy. Visual examination of virtual sensors, which are source activities reconstructed by beamforming, can improve performance but can be time-consuming for neurophysiologists. We propose a framework to automate the method and evaluate its effectiveness against surgical resections and outcomes. METHODS: We retrospectively analyzed MEG recordings of 13 epilepsy surgery patients who had one-year minimum post-operative follow-up. Kurtosis beamforming was applied and manual inspection was confined to morphological clusters. The region with the Maximum Interictal Spike Frequency (MISF) was validated against prospectively modelled sLORETA solutions and surgical resections linked to outcome. RESULTS: Our approach localized spikes in 12 out of 13 patients. In eight patients with Engel I surgical outcomes, beamforming MISF regions were concordant with surgical resection at overlap level for five patients and at lobar level for three patients. The MISF regions localized to spike onset and propagation modelled by sLORETA in two and six patients, respectively. CONCLUSIONS: Automated beamforming using MEG can predict postoperative seizure freedom at the lobar level but tends to localize propagated MEG spikes. SIGNIFICANCE: MEG beamforming may contribute to non-invasive procedures to predict surgical outcome for patients with drug-refractory focal epilepsy.

Interictal and ictal source localization for epilepsy surgery using high-density EEG with MEG: a prospective long-term study.

Drug-resistant focal epilepsy is a major clinical problem and surgery is under-used. Better non-invasive techniques for epileptogenic zone localization are needed when MRI shows no lesion or an extensive lesion. The problem is interictal and ictal localization before propagation from the epileptogenic zone. High-density EEG (HDEEG) and magnetoencephalography (MEG) offer millisecond-order temporal resolution to address this but co-acquisition is challenging, ictal MEG studies are rare, long-term prospective studies are lacking, and fundamental questions remain. Should HDEEG-MEG discharges be assessed independently [electroencephalographic source localization (ESL), magnetoencephalographic source localization (MSL)] or combined (EMSL) for source localization? Which phase of the discharge best characterizes the epileptogenic zone (defined by intracranial EEG and surgical resection relative to outcome)? Does this differ for interictal and ictal discharges? Does MEG detect mesial temporal lobe discharges? Thirteen patients (10 non-lesional, three extensive-lesional) underwent synchronized HDEEG-MEG (72-94 channel EEG, 306-sensor MEG). Source localization (standardized low-resolution tomographic analysis with MRI patient-individualized boundary-element method) was applied to averaged interictal epileptiform discharges (IED) and ictal discharges at three phases: 'early-phase' (first latency 90% explained variance), 'mid-phase' (first of 50% rising-phase, 50% mean global field power), 'late-phase' (negative peak). 'Earliest-solution' was the first of the three early-phase solutions (ESL, MSL, EMSL). Prospective follow-up was 3-21 (median 12) months before surgery, 14-39 (median 21) months after surgery. IEDs (n = 1474) were recorded, seen in: HDEEG only, 626 (42%); MEG only, 232 (16%); and both 616 (42%). Thirty-three seizures were captured, seen in: HDEEG only, seven (21%); MEG only, one (3%); and both 25 (76%). Intracranial EEG was done in nine patients. Engel scores were I (9/13, 69%), II (2/13,15%), and III (2/13). MEG detected baso-mesial temporal lobe epileptogenic zone sources. Epileptogenic zone OR [odds ratio(s)] were significantly higher for earliest-solution versus early-phase IED-surgical resection and earliest-solution versus all mid-phase and late-phase solutions. ESL outperformed EMSL for ictal-surgical resection [OR 3.54, 95% confidence interval (CI) 1.09-11.55, P = 0.036]. MSL outperformed EMSL for IED-intracranial EEG (OR 4.67, 95% CI 1.19-18.34, P = 0.027). ESL outperformed MSL for ictal-surgical resection (OR 3.73, 95% CI 1.16-12.03, P = 0.028) but was outperformed by MSL for IED-intracranial EEG (OR 0.18, 95% CI 0.05-0.73, P = 0.017). Thus, (i) HDEEG and MEG source solutions more accurately localize the epileptogenic zone at the earliest resolvable phase of interictal and ictal discharges, not mid-phase (as is common practice) or late peak-phase (when signal-to-noise ratios are maximal); (ii) from empirical observation of the differential timing of HDEEG and MEG discharges and based on the superiority of ESL plus MSL over either modality alone and over EMSL, concurrent HDEEG-MEG signals should be assessed independently, not combined; (iii) baso-mesial temporal lobe sources are detectable by MEG; and (iv) MEG is not 'more accurate' than HDEEG-emphasis is best placed on the earliest signal (whether HDEEG or MEG) amenable to source localization. Our findings challenge current practice and our reliance on invasive monitoring in these patients. 10.1093/brain/awz015_video1 awz015media1 6018582479001.

Amyloid Precursor Protein Mediates Neuronal Protection from Rotenone Toxicity.

Mitochondrial complex I dysfunction is the most common respiratory chain defect in human disorders and a hotspot for neurodegenerative diseases. Amyloid precursor protein (APP) and its non-amyloidogenic processing products, in particular soluble APP α (sAPPα), have been shown to provide neuroprotection in models of neuronal injury; however, APP-mediated protection from acute mitochondrial injury has not been previously reported. Here, we use the plant-derived pesticide rotenone, a potent complex I-specific mitochondrial inhibitor, to discover neuroprotective effects of APP and sAPPα in vitro, in neuronal cell lines over-expressing APP, and in vivo, in a retinal neuronal rotenone toxicity mouse model. Our results show that APP over-expression is protective against rotenone toxicity in neurons via sAPPα through an autocrine/paracrine mechanism that involves the Pi3K/Akt pro-survival pathway. APP-/- mice exhibit greater susceptibility to retinal rotenone toxicity, while intravitreal delivery of sAPPα reduces inner retinal neuronal death in wild-type mice following rotenone challenge. We also show a significant decrease in human retinal expression of APP with age. These findings provide insights into the therapeutic potential of non-amyloidogenic processing of APP in complex I-related neurodegeneration.

Evaluation of the Biocompatibility of Polypyrrole Implanted Subdurally in GAERS.

This blinded controlled prospective randomized study investigates the biocompatibility of polypyrrole (PPy) polymer that will be used for intracranial triggered release of anti-epileptic drugs (AEDs). Three by three millimeters PPy are implanted subdurally in six adult female genetic absence epilepsy rats from Strasbourg. Each rat has a polymer implanted on one side of the cortex and a sham craniotomy performed on the other side. After a period of seven weeks, rats are euthanized and parallel series of coronal sections are cut throughout the implant site. Four series of 15 sections are histological (hematoxylin and eosin) and immunohistochemically (neuron-specific nuclear protein, glial fibrillary acidic protein, and anti-CD68 antibody) stained and evaluated by three investigators. The results show that implanted PPy mats do not induce obvious inflammation, trauma, gliosis, and neuronal toxicity. Therefore the authors conclude the PPy used offer good histocompatibility with central nervous system cells and that PPy sheets can be used as intracranial, AED delivery implant.

Managing drug-resistant epilepsy: challenges and solutions.

Despite the development of new antiepileptic drugs (AEDs), ~20%-30% of people with epilepsy remain refractory to treatment and are said to have drug-resistant epilepsy (DRE). This multifaceted condition comprises intractable seizures, neurobiochemical changes, cognitive decline, and psychosocial dysfunction. An ongoing challenge to both researchers and clinicians alike, DRE management is complicated by the heterogeneity among this patient group. The underlying mechanism of DRE is not completely understood. Many hypotheses exist, and relate to both the intrinsic characteristics of the particular epilepsy (associated syndrome/lesion, initial response to AED, and the number and type of seizures prior to diagnosis) and other pharmacological mechanisms of resistance. The four current hypotheses behind pharmacological resistance are the "transporter", "target", "network", and "intrinsic severity" hypotheses, and these are reviewed in this paper. Of equal challenge is managing patients with DRE, and this requires a multidisciplinary approach, involving physicians, surgeons, psychiatrists, neuropsychologists, pharmacists, dietitians, and specialist nurses. Attention to comorbid psychiatric and other diseases is paramount, given the higher prevalence in this cohort and associated poorer health outcomes. Treatment options need to consider the economic burden to the patient and the likelihood of AED compliance and tolerability. Most importantly, higher mortality rates, due to comorbidities, suicide, and sudden death, emphasize the importance of seizure control in reducing this risk. Overall, resective surgery offers the best rates of seizure control. It is not an option for all patients, and there is often a significant delay in referring to epilepsy surgery centers. Optimization of AEDs, identification and treatment of comorbidities, patient education to promote adherence to treatment, and avoidance of triggers should be periodically performed until further insights regarding causative pathology can guide better therapies.

Isolated amygdala enlargement in temporal lobe epilepsy: A systematic review.

OBJECTIVE: The objective of this study was to compare the seizure characteristics and treatment outcomes in patient groups with temporal lobe epilepsy (TLE) identified with isolated amygdala enlargement (AE) on magnetic resonance imaging studies. METHODS: PubMed, Embase, and the Cochrane Library were searched for relevant studies using the keywords 'amygdala enlargement', 'epilepsy', and 'seizures' in April 2015. Human studies, written in English, that investigated cohorts of patients with TLE and AE were included. RESULTS: Of 204 abstracts initially identified using the search strategy, 14 studies met the inclusion criteria (11 epilepsy studies and 3 psychiatry studies). Ultimately, 8 full studies on AE and TLE involving 107 unique patients were analyzed. Gender distribution consisted of 50 males and 57 females. Right amygdala enlargement was seen in 39 patients, left enlargement in 58 patients, and bilateral enlargement in 7 patients. Surgical resection was performed in 28 patients, with the most common finding being dysplasia/hamartoma or focal cortical dysplasia. Most studies involved small samples of less than 12 patients. There was a wide discrepancy in the methods used to measure amygdala volume, in both patients and controls, hindering comparisons. Most TLE with AE studies observed a later age of seizure onset (mean: 32.2years) compared with studies involving TLE with HS (mean of mid- to late childhood). A higher frequency of complex partial seizures compared with that of convulsive seizures is seen in patients with AE (67-100% vs. 26-47%), and they have an excellent response to antiepileptic drugs (81.8%-100% of seizure-free patients). All studies that included controls also found a significant difference in frequency of seizure types between their cases and controls. CONCLUSIONS: Reliable assessment of amygdala volume remains a critical issue hindering better understanding of the clinical management and research of this focal epilepsy syndrome. Within these limitations, the literature suggests characteristics of an older age of epilepsy onset, a greater tendency to nonconvulsive seizures, and a good response to antiepileptic drugs in this interesting group of epilepsies.

Skull Defects in Finite Element Head Models for Source Reconstruction from Magnetoencephalography Signals.

Magnetoencephalography (MEG) signals are influenced by skull defects. However, there is a lack of evidence of this influence during source reconstruction. Our objectives are to characterize errors in source reconstruction from MEG signals due to ignoring skull defects and to assess the ability of an exact finite element head model to eliminate such errors. A detailed finite element model of the head of a rabbit used in a physical experiment was constructed from magnetic resonance and co-registered computer tomography imaging that differentiated nine tissue types. Sources of the MEG measurements above intact skull and above skull defects respectively were reconstructed using a finite element model with the intact skull and one incorporating the skull defects. The forward simulation of the MEG signals reproduced the experimentally observed characteristic magnitude and topography changes due to skull defects. Sources reconstructed from measured MEG signals above intact skull matched the known physical locations and orientations. Ignoring skull defects in the head model during reconstruction displaced sources under a skull defect away from that defect. Sources next to a defect were reoriented. When skull defects, with their physical conductivity, were incorporated in the head model, the location and orientation errors were mostly eliminated. The conductivity of the skull defect material non-uniformly modulated the influence on MEG signals. We propose concrete guidelines for taking into account conducting skull defects during MEG coil placement and modeling. Exact finite element head models can improve localization of brain function, specifically after surgery.

A simple and versatile method for microencapsulation of anti-epileptic drugs for focal therapy of epilepsy.

Nearly 30% of epilepsy cases cannot be adequately controlled with current medical treatments. The reasons for this are still not well understood, but there is a significant body of evidence pointing to the blood-brain barrier. Resective surgery can provide an alternative method of epilepsy control; however this treatment option is not suitable for most epilepsy sufferers. Local drug delivery through micro-injection to or implantation into the brain provides an innovative approach to bypass the blood-brain barrier for epilepsy treatment. In order to develop effective local delivery systems for anti-epilepsy drug (AED), we have prepared a variety of core-shell microcapsules via electrojetting, where a more hydrophobic polymer shell acts as a physical barrier to control the rate of drug release from the drug-loaded polymeric core. The resulting microcapsules demonstrate highly drug encapsulation efficiency, narrow size distribution and uniform morphology. Moreover, the release rate of AED can be modulated by controlling the morphologies of the core-shell microcapsules.

Capture of somatic mtDNA point mutations with severe effects on oxidative phosphorylation in synaptosome cybrid clones from human brain.

Mitochondrial DNA (mtDNA) is replicated throughout life in postmitotic cells, resulting in higher levels of somatic mutation than in nuclear genes. However, controversy remains as to the importance of low-level mtDNA somatic mutants in cancerous and normal human tissues. To capture somatic mtDNA mutations for functional analysis, we generated synaptosome cybrids from synaptic endings isolated from fresh hippocampus and cortex brain biopsies. We analyzed the whole mtDNA genome from 120 cybrid clones derived from four individual donors by chemical cleavage of mismatch and Sanger sequencing, scanning around two million base pairs. Seventeen different somatic point mutations were identified, including eight coding region mutations, four of which result in frameshifts. Examination of one cybrid clone with a novel m.2949_2953delCTATT mutation in MT-RNR2 (which encodes mitochondrial 16S rRNA) revealed a severe disruption of mtDNA-encoded protein translation. We also performed functional studies on a homoplasmic nonsense mutation in MT-ND1, previously reported in oncocytomas, and show that both ATP generation and the stability of oxidative phosphorylation complex I are disrupted. As the mtDNA remains locked against direct genetic manipulation, we demonstrate that the synaptosome cybrid approach can capture biologically relevant mtDNA mutants in vitro to study effects on mitochondrial respiratory chain function.

The cortical excitability profile of temporal lobe epilepsy.

PURPOSE: Transcranial magnetic stimulation (TMS) was used to characterize measurable changes of cortical excitability in patients who were undergoing medical and surgical management of temporal lobe epilepsy (TLE) to investigate whether these alterations depended on timing of achieving seizure control throughout the course of illness and method of management. METHODS: Eighty-five patients with TLE divided into (1) drug naive-new onset, (2) early medically refractor, and (3) late medically refractory, (4) early seizure-free on antiepileptic drugs, and (5) late seizure-free on antiepileptic drugs, (6) postoperative refractory, and (7) postoperative seizure-free groups were studied. Motor threshold (MT) and paired-pulse TMS at short (2, 5, 10, and 15 msec) and long (100-300 msec) interstimulus intervals (ISIs) were measured. Results were compared to those of 20 controls. KEY FINDINGS: A significant interhemispheric difference was observed early at onset prior to starting medication, with higher cortical excitability in the hemisphere ipsilateral to the seizure focus, whereas the unaffected hemisphere was normal. After that, cortical excitability was higher in both hemispheres in the refractory groups (medical and postoperative) compared to the seizure-free and drug-naive groups (p < 0.05). This effect was most prominent at the long ISIs. SIGNIFICANCE: Changes in cortical excitability seen in patients with TLE are influenced by the course of the disease. The alterations that occur due to epilepsy are closely related to course of illness and degree/timing of seizure control. Successful management leads to resolution of this cortical hyperexcitability in a similar fashion regardless of method: medication (intact generator, but modulated by drugs) or surgery (generator removed).

Familial mesial temporal lobe epilepsy: a benign epilepsy syndrome showing complex inheritance.

Temporal lobe epilepsy is the commonest partial epilepsy of adulthood. Although generally perceived as an acquired disorder, several forms of familial temporal lobe epilepsy, with mesial or lateral seizure semiology, have been described. Descriptions of familial mesial temporal lobe epilepsy have varied widely from a benign epilepsy syndrome with prominent déjà vu and without antecedent febrile seizures or magnetic resonance imaging abnormalities, to heterogeneous, but generally more refractory epilepsies, often with a history of febrile seizures and with frequent hippocampal atrophy and high T2 signal on magnetic resonance imaging. Compelling evidence of a genetic aetiology (rather than chance aggregation) in familial mesial temporal lobe epilepsy has come from twin studies. Dominant inheritance has been reported in two large families, though the usual mode of inheritance is not known. Here, we describe clinical and neurophysiological features of 20 new mesial temporal lobe epilepsy families including 51 affected individuals. The epilepsies in these families were generally benign, and febrile seizure history was infrequent (9.8%). No evidence of hippocampal sclerosis or dysplasia was present on brain imaging. A single individual underwent anterior temporal lobectomy, with subsequent seizure freedom and histopathological evidence of hippocampal sclerosis was not found. Inheritance patterns in probands' relatives were analysed in these families, together with 19 other temporal lobe epilepsy families previously reported by us. Observed frequencies of epilepsies in relatives were lower than predicted by dominant Mendelian models, while only a minority (8/39) of families could be compatible with recessive inheritance. These findings strongly suggest that complex inheritance, similar to that widely accepted in the idiopathic generalized epilepsies, is the usual mode of inheritance in familial mesial temporal lobe epilepsy. This disorder, which appears to be relatively common, and not typically associated with hippocampal sclerosis, is an appropriate target for contemporary approaches to complex disorders such as genome-wide association studies for common genetic variants or deep sequencing for rare variants.

Surgery for temporal lobe epilepsy associated with mesial temporal sclerosis in the older patient: a long-term follow-up.

PURPOSE: To assess the outcomes from temporal lobectomy for hippocampal sclerosis in patients 50 years or older. Controversy exists as to the suitability of older patients for epilepsy surgery, with most of the previous studies demonstrating a correlation between increasing age and poor outcome. However, the inclusion of temporal lobe epilepsy of multiple etiologies has confounded many previous studies of this age group. METHODS: Twenty-one patients aged 50 years or older (mean 54.9 years) at the time of surgery were included in the study group. All patients had a pathologic diagnosis of hippocampal sclerosis. A retrospective analysis was performed comparing seizure outcomes following a standardized anterior temporal lobectomy with those from 103 patients younger than 50 (mean age 34.7 years) operated upon over the same time period. The mean follow-up period for the study was 9.57 years. RESULTS: Twenty of the 21 patients in the older group (95.2%) had a satisfactory seizure outcome (Engel classes I and II) compared with 90.3% of the younger patients. There was no statistically significant difference in the outcomes between the two groups (p = 0.719). Across both groups of patients combined, there was no significant difference between the mean age in the patients with a satisfactory seizure outcome compared to those with an unsatisfactory outcome (38.3 vs. 34.7 years, p = 0.213). DISCUSSION: Patients 50 years or older with intractable seizures from hippocampal sclerosis have seizure outcomes following temporal lobectomy that are comparable to young patients over the long term. Older patients should not be denied treatment on the basis of age.

Seizure severity and duration in the cortical stimulation model of experimental epilepsy in rats: a longitudinal study.

The aim of this study was to determine the current intensities necessary to elicit three levels of varying EEG and behavioural phenomena with electrical stimulation, and also to determine the consistency of the EEG and behavioural components of the triggered seizures over time. Electrical stimulation of the primary motor/somatosensory cortex was performed in 16 adult rats with multichannel microwire electrode arrays. Stimulation was delivered at a frequency of 60 Hz (1 ms pulse width), for 2 s duration, as biphasic rectangular pulses over four of the eight available electrode pairs. Current intensity thresholds for interruption of normal behaviour, epileptiform afterdischarge (EAD) longer than 5 s and motor seizures with Racine severity greater than 3 were not correlated to time post-surgery. The Racine threshold was shown to be negatively correlated to the EAD duration and Racine severity of seizures elicited in the following sessions. Seizures were reliably generated in rats through cortical stimulation with microwire electrode arrays and these seizures were not shown to be subject to any kindling type effects up to 53 days post-implantation. Both the electrographic duration and behavioural severity of stimulated seizures remained, on average, constant during this experimental period. Approximately one-third of stimulations did not cause observable motor seizures and of those that did result in seizures, forelimb clonus was the most common manifestation and the mean EAD duration was 18.5 s. No damage beyond that caused by surgical implantation of electrodes was observed in the histological analyses of stimulated and non-stimulated tissue. The consistency, duration and severity of seizures within this timeframe make this cortical stimulation model suitable for investigations into novel therapeutic interventions for epilepsy that require a known seizure focus.

"A twist in the tale" of a surgeon and his patient: an Australian first in seizure localization.

In 1894 at St. Vincent's Hospital Melbourne, George Adlington Syme removed a meningioma from a patient with symptomatic focal epilepsy. The operation stands as the first surgery based on seizure localization in Australia. It is also the country's first documented successful resection of an intracranial meningioma. It followed William Macewen's landmark cerebral localization case on the boy John McKinley by 18 years and Victor Horsley's first epilepsy case on Hughlings Jackson's patient James B. by a mere 8 years. Syme's patient, Constable John G., survived the operation by some 23 years, dying from a gunshot wound to the head in 1917. Newly discovered inquest papers reveal that the coroner's judgment that the death was accidental completely fails to address the more credible scenario of suicide. The story makes for a fascinating epilogue to an important landmark in Australia's neurosurgical history.

Evaluation of Sca-1 and c-Kit as selective markers for muscle remodelling by nonhemopoietic bone marrow cells.

Bone marrow (BM)-derived cells (BMCs) have demonstrated a myogenic tissue remodeling capacity. However, because the myoremodeling is limited to approximately 1%-3% of recipient muscle fibers in vivo, there is disagreement regarding the clinical relevance of BM for therapeutic application in myodegenerative conditions. This study sought to determine whether rare selectable cell surface markers (in particular, c-Kit) could be used to identify a BMC population with enhanced myoremodeling capacity. Dystrophic mdx muscle remodeling has been achieved using BMCs sorted by expression of stem cell antigen-1 (Sca-1). The inference that Sca-1 is also a selectable marker associated with myoremodeling capacity by muscle-derived cells prompted this study of relative myoremodeling contributions from BMCs (compared with muscle cells) on the basis of expression or absence of Sca-1. We show that myoremodeling activity does not differ in cells sorted solely on the basis of Sca-1 from either muscle or BM. In addition, further fractionation of BM to a more mesenchymal-like cell population with lineage markers and CD45 subsequently revealed a stronger selectability of myoremodeling capacity with c-Kit/Sca-1 (p < .005) than with Sca-1 alone. These results suggest that c-Kit may provide a useful selectable marker that facilitates selection of cells with an augmented myoremodeling capacity derived from BM and possibly from other nonmuscle tissues. In turn, this may provide a new methodology for rapid isolation of myoremodeling capacities from muscle and nonmuscle tissues. Disclosure of potential conflicts of interest is found at the end of this article.