Cerebrospinal Fluid Pleocytosis Not Attributable to Status Epilepticus in First 24 Hours.

BACKGROUND: Status epilepticus (SE) has traditionally been thought to cause cerebrospinal fluid (CSF) pleocytosis. However, attributing CSF pleocytosis solely to SE without addressing the underlying etiology may lead to poor outcomes. Leukocyte recruitment to CSF has been shown to peak around 24 hours after prolonged seizures in animal studies, suggesting that CSF pleocytosis within the first 24 hours of SE onset may be due to underlying causes. The goal of this study is to assess if SE is associated with CSF pleocytosis, independent of other causes within the first 24 hours of onset. METHODS: We completed a historical cohort study of adult patients with SE admitted to the intensive care unit of Vancouver General Hospital between March 2010 and May 2019. RESULTS: Of the 441 patients admitted with SE during the study period, 107 met our inclusion criteria leading to 111 lumbar punctures (LPs), with 4 patients receiving two LPs. CSF pleocytosis was seen in 12 of 72 patients who underwent an LP within the first 24 hours of SE onset. In all 12 patients, a secondary etiology for the pleocytosis was observed aside from SE. Of the six CSF samples collected after 24 hours of onset that demonstrated pleocytosis, four had no cause for pleocytosis other than SE. CONCLUSIONS: In all 12 patients with CSF pleocytosis in the first 24 hours of onset of SE, an underlying etiology was identified. Therefore, any pleocytosis noticed within the first 24 hours of onset of refractory SE should not be attributed solely to SE.

Plasma PrPC and ADAM-10 as novel biomarkers for traumatic brain injury and concussion: a pilot study.

BACKGROUND: Cellular prion protein (PrPC) is a lipid raft protein abundant within CNS. It is regulated by a disintegrin and metalloproteinase domain containing protein 10 (ADAM10). PrPC has previously been implicated as a biomarker for TBI. ADAM10 has not been investigated as a TBI biomarker. OBJECTIVE: We evaluated PrPC and ADAM10 as candidate biomarkers for TBI. METHODS: We performed ELISA for ADAM10 and PrPC on plasma samples of patients with TBI admitted to Brigham and Women's Hospital. Plasma samples from 20 patients admitted for isolated TBI were acquired from a biobank with clinical information. Control plasma (37 samples) was acquired from a commercial source. GraphPad was used to conduct statistical analysis. RESULTS: 37 controls and 20 TBI samples were collected. Of the patients with TBI, eight were mild, three were moderate, and nine were severe. Both PrPC and ADAM10 were elevated in patients with TBI compared with control (p < .001). ADAM10 exhibited greater expression in patients with worse clinical grade. There was no significant association of either PrPC or ADAM10 with time after injury. CONCLUSIONS: Our results indicate that PrPC and ADAM10 appear to be useful potential tools for screening of TBI. ADAM10 is closely associated with clinical grade.

Update on Minimal Standards for Electroencephalography in Canada: A Review by the Canadian Society of Clinical Neurophysiologists.

Surface electroencephalogram (EEG) recording remains the gold standard for noninvasive assessment of electrical brain activity. It is the most efficient way to diagnose and classify epilepsy syndromes as well as define the localization of the epileptogenic zone. The EEG is useful for management decisions and for establishing prognosis in some types of epilepsy. Electroencephalography is an evolving field in which new methods are being introduced. The Canadian Society of Clinical Neurophysiologists convened an expert panel to develop new national minimal guidelines. A comprehensive evidence review was conducted. This document is organized into 10 sections, including indications, recommendations for trained personnel, EEG yield, paediatric and neonatal EEGs, laboratory minimal standards, requisitions, reports, storage, safety measures, and quality assurance.

StatNet Electroencephalogram: A Fast and Reliable Option to Diagnose Nonconvulsive Status Epilepticus in Emergency Setting.

BACKGROUND: The StatNet electrode set is a system that can be applied by a non-electroencephalogram (EEG) technologist after minimal training. The primary objectives of this study are to assess the quality and reliability of the StatNet recordings in comparison to the conventional EEG. METHODS: Over 10 months, 19 patients with suspected nonconvulsive status epilepticus were included from university hospital emergency settings. Each patient received a StatNet EEG by a trained epilepsy fellow and a conventional EEG by registered technologists. We compared the studies in a blinded fashion, for the timeframe from EEG order to the setup time, start of acquisition, amount of artifact, and detection of abnormalities. The nonparametric Mann-Whitney two-sample t test was used for comparisons. The kappa score was used to assess reliability. RESULTS: Mean age of patients was 61±16.3 (25-93) years. The inter-observer agreement for detection of abnormal findings was 0.83 for StatNet and 0.75 for conventional EEG. Nonconvulsive status epilepticus was detected in 10% (2/19) in both studies. The delay from the time of EEG requisition to acquisition was shorter in the StatNet (22.4±2.5 minutes) than the conventional EEG (217.7±44.6 minutes; p<0.0001). The setup time was also shorter in the StatNet (9.9±0.8 minutes) compared with the conventional EEG (17.8±0.8 minutes; p<0.0001). There was no difference in the percentage of artifact duration between the two studies (p=0.89). CONCLUSION: This study demonstrates that StatNet EEG is a practical and reliable tool in the emergency setting, which reduces the delay of testing compared with conventional EEG, without significant compromise of study quality.

Discontinuation of antiepileptic drugs after successful surgery: who and when?

Surgery is a highly effective treatment for some specific types of refractory epilepsy and once seizure freedom is achieved many patients and clinicians have to ponder whether to taper or discontinue antiepileptic drugs (AEDs). However, there is no standard practice or guidelines and practices vary widely. The few studies that have addressed this question are retrospective and lack randomised, controlled comparisons, making it difficult to draw any solid inferences. This review examines this topic by analysing key data based on the following: controlled studies which compare outcomes in patients with either withdrawn or unmodified AEDs after epilepsy surgery, non-controlled studies, information from meta-analyses and systematic reviews, surveys of clinical practice, and other relevant reviews. Between 12 and 32% of patients had seizure relapse following tapering or discontinuation of AEDs, which was not significantly different from 7 to 45% in patients without AED modification. In the event of seizure relapse upon tapering of AEDs, 45-92.3% restarted AED treatment and regained seizure freedom. The most consistent risk factors for seizure relapse were: age older than 30 years at the time of surgery, persistent auras, early drug tapering, seizure recurrence before a reduction of drugs, normal MRI, a longer period with epilepsy, absence of hippocampal sclerosis, and the presence of interictal discharges on EEG after surgery.

Ambulatory EEG: a cost-effective alternative to inpatient video-EEG in adult patients.

INTRODUCTION: Ambulatory electroencephalography (AEEG) is a monitoring technique that allows the recording of continuous EEG activity when patients are at home, without the necessity of admission to the hospital for prolonged video-EEG monitoring. METHODS: This is a prospective cohort study performed in a Canadian academic centre in order to assess the yield and tolerability of AEEG in the adult population. Over a period of three years, 101 patients were included. The yield of AEEG was assessed by taking into account the questions asked by the clinician before and after the investigation. RESULTS: One hundred and one patients undergoing AEEG were prospectively recruited during a three-year-period. Our population consisted of 45 males (44.6%) and 56 females (55.4%). The mean age of the group was 36.6 ± 16.1 years. Most of the patients had at least one previous routine EEG (93%). The primary reasons for the AEEGs were subdivided into four categories: a) to differentiate between seizures and non-epileptic events; b) to determine the frequency of seizures and epileptiform discharges; c) to characterize seizure type or localization; and d) to potentially diagnose epilepsy. The mean duration of AEEG recording was 32 ± 17 hours (15-96 hours). For 73 (72%) patients, the AEEG provided information that was useful for the management. For 28 (28%) patients, the AEEG did not provide information on diagnosis because no events or epileptiform activity occurred. In only 1 patient was the AEEG inconclusive due to non-physiological artefacts. Three patients were referred for epilepsy surgery without the necessity of video-EEG telemetry. CONCLUSION: In this study, we found that AEEG has a high diagnostic yield (72%) and believe that careful selection of patients is the most important factor for a high diagnostic yield. The main use of AEEG is the characterization of patients with non-epileptic events, in patients with a diagnosis of epilepsy that is not clear, and quantification of spikes and seizures to improve the medical management. Ambulatory EEG is a cost-effective solution for increasing demands for in-hospital video-EEG monitoring of adult patients.

Enhanced Interplay of Neuronal Coherence and Coupling in the Dying Human Brain.

The neurophysiological footprint of brain activity after cardiac arrest and during near-death experience (NDE) is not well understood. Although a hypoactive state of brain activity has been assumed, experimental animal studies have shown increased activity after cardiac arrest, particularly in the gamma-band, resulting from hypercapnia prior to and cessation of cerebral blood flow after cardiac arrest. No study has yet investigated this matter in humans. Here, we present continuous electroencephalography (EEG) recording from a dying human brain, obtained from an 87-year-old patient undergoing cardiac arrest after traumatic subdural hematoma. An increase of absolute power in gamma activity in the narrow and broad bands and a decrease in theta power is seen after suppression of bilateral hemispheric responses. After cardiac arrest, delta, beta, alpha and gamma power were decreased but a higher percentage of relative gamma power was observed when compared to the interictal interval. Cross-frequency coupling revealed modulation of left-hemispheric gamma activity by alpha and theta rhythms across all windows, even after cessation of cerebral blood flow. The strongest coupling is observed for narrow- and broad-band gamma activity by the alpha waves during left-sided suppression and after cardiac arrest. Albeit the influence of neuronal injury and swelling, our data provide the first evidence from the dying human brain in a non-experimental, real-life acute care clinical setting and advocate that the human brain may possess the capability to generate coordinated activity during the near-death period.

The Concept of an Epilepsy Brain Bank.

Epilepsy comprises more than 40 clinical syndromes affecting millions of patients and families worldwide. To decode the molecular and pathological framework of epilepsy researchers, need reliable human epilepsy and control brain samples. Brain bank organizations collecting and supplying well-documented clinically and pathophysiologically tissue specimens are important for high-quality neurophysiology and neuropharmacology studies for epilepsy and other neurological diseases. New development in molecular mechanism and new treatment methods for neurological disorders have evoked increased demands for human brain tissue. An epilepsy brain bank is a storage source for both the frozen samples as well as the formaldehyde fixed paraffin embedded (FFPE) tissue from epilepsy surgery resections. In 2014, the University of Saskatchewan have started collecting human epilepsy brain tissues for the first time in Canada. This review highlights the necessity and importance of Epilepsy Brain bank that provides unique access for research to valuable source of brain tissue and blood samples from epilepsy patients.

Safety and yield of early cessation of AEDs in video-EEG telemetry and outcomes.

BACKGROUND: Video-electroencephalography (VEEG) telemetry is the simultaneous recording of ictal and interictal EEG pattern and paroxysmal behavior to investigate the nature of paroxysmal events. METHODS: This is a prospective study performed to asses the safety and yield of early discontinuation of antiepileptic drugs (AEDs) in the telemetry unit. Over a 2.5-year period, 50 patients that met the indications for VEEG monitoring were admitted by an epileptologist to neuro-observation units with continuous monitoring, nursing coverage and EEG technicians support during working hours and on-call thereafter. In most cases AEDs (except Phenobarbital) were discontinued in 24h. We prospectively assessed the yield and safety of the telemetry investigation as well as epilepsy surgery outcomes. RESULTS: Our monitoring answered the study question in 88% of the patients. The question was not answered in 12% of cases due to the lack of recorded events. Our results changed the management in 74% of cases and potentially improved quality of life by decreasing the AEDs consumption and number of seizures per month. Over all, 22% received epilepsy surgery and became either seizure free or their seizures became non-disabling. Our method significantly decreased the duration of hospital admission for monitoring and minimal complications occurred only in 8% of patients. CONCLUSIONS: In conclusion, our method for short VEEG monitoring has a high yield for diagnosis, minimal complications and is cost effective. These qualities, together with good surgery results validate our method for the investigation and treatment of refractory seizure cases.

Occipital seizures induced by hyperglycemia: a case report and review of literature.

An 83-year-old right-handed male presented with a 2-day history of episodic jerking and "spasms" in the left arm, each lasting approximately 1min, followed by weakness. He also described episodes of flashing colorful lights (green and blue) in his left visual field, not always accompanied by arm jerking, associated with intermittent confusion. His past medical history was significant for type-2 diabetes mellitus. Neurological exam showed an intermittent visual deficit in both eyes, in the inferior fields, mild left upper extremity weakness with brisk reflexes. Several brief episodes of focal motor (clonic) seizure activity involving the left upper limb were observed. Blood glucose was 639mg/dL, with serum osmolarity of 316mosmol/L. Ketoacidosis was absent. Two electrographic seizures from the left occipital region maximum at O1 associated with visual symptoms were recorded. CT head performed on the day of admission was normal. MRI was not done because of a pacemaker. Patient was treated with hydration and insulin and all the neurological symptoms including the seizures disappeared after 24h. We report a patient with clinical and electrographic seizures from the occipital region associated with hyperglycemia. This is a unique complication of hyperglycemia and anecdotal reports of patients with this clinical presentation have been published over the years. Sporadic EEG descriptions have been reported before.

Perampanel but Not Amantadine Prevents Behavioral Alterations and Epileptogenesis in Pilocarpine Rat Model of Status Epilepticus.

Pilocarpine-induced status epilepticus (SE), which results in the development of spontaneous recurrent seizures (SRSs) activates glutamatergic receptors that contribute to seizure sustenance and neuronal cell death. In the current study, we evaluate whether the exposure to perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker, or amantadine, a N-methyl-D-aspartic acid (NMDA) receptor blocker would reduce the SE-induced long-term consequences. SE was induced in adult male Sprague Dawley rats with pilocarpine. Perampanel or amantadine was injected 10 or 60 min after SE onset. The efficacy of either, in overcoming pilocarpine-induced SE was assessed using electroencephalogram (EEG) recordings. In addition, alterations in cognitive function, development of spontaneous recurrent seizures (SRSs), and hippocampal damage that are generally encountered after SE were also assessed at 72 h and 5 weeks after the induction of SE. Our results indicate that both early and late treatment with perampanel but not amantadine significantly reduced seizure activity. Furthermore, perampanel but not amantadine, reversed the memory deficits in Y-maze and novel object recognition (NOR) tests and retarded the appearance of SRSs. Moreover, perampanel treatment led to reduced SE-induced caspase-3 activation in the hippocampal lysates. Taken together, the data obtained from the study reveals that blocking AMPA receptors by perampanel can modify SE-induced long-term consequences. Our results may provide a proof of principle for the potential therapeutic application of perampanel in clinical use for status epilepticus in future.

Sulfaphenazole treatment restores endothelium-dependent vasodilation in diabetic mice.

Vascular dysfunction is linked with increased free radical generation and is a major contributor to the high mortality rates observed in diabetes. Several probable sources of free radical generation have been suggested in diabetes, including cytochrome P450 (CYP) monooxygenase-dependent pathways. CYP-mediated superoxide production reduces nitric oxide (NO) bioavailability. In this study, we focus on the contribution of monooxygenase enzyme-generated reactive oxygen species in vascular dysfunction in an experimental model of diabetes mellitus type II. Diabetic male mice (db/db strain) and their age-matched controls received daily intraperitoneal injections of either the CYP 2C inhibitor sulfaphenazole (5.13 mg/kg) or saline (vehicle control) for 8 weeks. Although sulfaphenazole did not change endothelium-dependent vasodilation in control mice, it restored endothelium-mediated relaxation in db/db mice. We report for the first time that CYP 2C inhibition reduces oxidative stress (measured as plasma levels of 8-isoprostane), increases NO bioavailability (measured as NO(2)(-)) and restores endothelial function in db/db mice without affecting plasma glucose levels. Based on our findings, we speculate that inhibition of free radical generating CYP 450 monooxygenase enzymes restores endothelium-dependent vasodilation to acetylcholine. In addition, it reduces oxidative stress and increases NO bioavailability.

Increased vascular contractility in isolated vessels from cigarette smoking rats is mediated by basal endothelin release.

The effect of chronic cigarette smoking on endothelin modulation of vascular contraction, and CYP enzyme levels was studied in 20 male Sprague-Dawley rats. The animals were divided equally into smoking and non-smoking groups. The smoking group was exposed to 6 research cigarettes per rat per day 5 days a week for 16 weeks. The control group was sham smoked. Functional contractile studies were performed in aortas and carotid arteries to determine the regulation of vascular tone by basal release of endothelin. Liver samples were analyzed for CYP1A1 and CYP1A2 gene expression by RT-PCR. Plasma samples were assessed for endothelin-1 (ET-1) level by enzyme immuno assay (EIA). Treatment of aortas and carotid arteries with bosentan, the dual endothelin receptor antagonist, caused a significant reduction in constrictor responses of smoking rats, indicating, increase greater regulation of tone by endothelin in smoker rats compared to controls. There was a greater expression of the cytochrome P450-liver enzymes (CYP1A1 and CYP1A2) in smoker rats. Body weight gain was also significantly decreased in smoker rats. We conclude that increased endothelin release in smoker rats significantly contributes to increased arterial tone and so contribute to the cardiovascular pathophysiology associated with cigarette smoking, such as increased vascular muscularization, increased contraction, decreased dilation and possibly vasospasm.

Evaluating the single seizure clinic model: Findings from a Canadian Center.

INTRODUCTION: The effect of the single seizure clinic (SSC) model on patient diagnose, work-up, wait-times, and clinical care is poorly characterized and its efficacy unclear. The present study assesses patient characteristics and evaluates the impact of a single seizure clinic (SSC) model on wait-times and access to care. MATERIAL AND METHODS: A prospective study of all patients (n=200) referred to our SSC for first seizure evaluation. Demographic, clinical, and paraclinicial variables were systematically collected and analyzed against a historical cohort. Binary logistic regression analysis was performed to predict impact of dichotomized variables on diagnosis of epilepsy. Diagnostic concordance between SSC nurses and epileptologists was also assessed. RESULTS: Predominant referral sources were emergency department physicians and general practitioners. Mean wait-time for first assessment was significantly reduced by 70.5% employing the SSC model versus historical usual care. A diagnosis was established at first-contact in 80.5% of cases while 16.0% of patients required a second visit. Eighty-two patients (41.0%) were diagnosed with epilepsy. An abnormal EEG was found in 93.9% of patients diagnosed with epilepsy. Sixty-three patients were started on anti-epileptic drugs (63.5% lamotrigine, 7.0% levetiracetam, 5.0% phenytoin, and 5.0% topiramate). In 18% of cases driving restrictions were initiated by the SSC. The most common non-seizure diagnosis was syncope (24.0%). DISCUSSION: The SSC reduced wait-times for assessment and investigations, clarified diagnoses, affected management decisions with respect to further workup, pharmacotherapy, and driving. There was moderate correlation between SSC nurses and physicians (kappa=0.54; p<0.001) as physicians were significantly more likely to diagnose epilepsy. Key factors identified as predictors of epilepsy were: presence of abnormalities on electroencephalography and imaging studies, patients stratified as high or medium-risk for seizure recurrence, semiological characteristics such as amnesia and limb stiffening, and presence of tongue trauma, or incontinence. CONCLUSIONS: The SSC model reduces wait-times, streamlines assessments, and impacts clinical care decisions.

How many adults with temporal epilepsy have a mild course and do not require epilepsy surgery?

Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy in adults and commonly requires surgical treatment. While an overwhelming preponderance of literature supports the notion that a large percentage of patients with TLE benefit from surgery, there is a paucity of outcome data on patients who demonstrate a sustained response to pharmacological treatment. In this study, we present an adult cohort of patients with TLE, with the purpose of identifying the proportion of patients with a mild course of the disease, as well as potential risk factors. A prospective cohort study of all patients with TLE assessed and followed by the Saskatchewan Epilepsy Program, from 1 March 2007 to Jan 29(th) 2014. Patients were dichotomized as having a mild (seizure freedom without surgical intervention) or severe (surgical intervention required and/or failure to achieve seizure remission) course. Descriptive statistics, odds ratios and confidence intervals were calculated to identify predictors of seizure freedom. The cohort consisted of 159 patients. Mean patient age at last follow-up visit was 46±14.4 (range: 19-88) years. Mean follow-up period was 43.4±22.6 (6 to 84) months. Forty-six patients (29%) demonstrated mild-course TLE while 113 (71%) had a severe course of TLE. Patients with a mild course of TLE were more likely to be older (p = 0.002), have late-onset epilepsy (p < 0.001) with shorter evolution (p < 0.001). A good response to the first antiepileptic drug (OR: 6.8; 95% CI: 2.5-19; p < 0.001) was associated with a mild course of TLE. Although a majority of patients with TLE eventually require surgery, operative treatment is not necessary for all patients. This study identifies prognostic factors that may help patients and clinicians characterize long-term outcome.

Immunosuppression and transplant vascular disease: benefits and adverse effects.

Cardiac allograft vasculopathy (CAV) occurs within 5 years of transplantation surgery and represents the main cause of death in long-term heart transplant survivors. The detailed pathogenesis of CAV is unknown, but there are strong indications that immunologic mechanisms, which are regulated by nonimmunologic factors, are the major cause of this phenomenon. Cyclosporine A (CsA) is a frequently used immunosuppressive agent in transplant medicine to prevent rejection. The mechanism of action of CsA involves initial binding to cyclophilin to form a complex that then inhibits calcineurin (CN), leading to reduced interleukin (IL)-2 production as part of the signal transduction pathway for the activation of B-lymphocytes and T-lymphocytes. Based on this proposed mechanism, it was expected that CsA should be an effective strategy in attenuating the host immune response against transplanted allograft tissue; however, CsA has not changed the outcome of CAV. Several mechanisms have been suggested for the ineffectiveness of CsA in long-term prevention of CAV. For example, routine therapeutic doses of CsA may block CN incompletely (50%), whereas complete blockade requires doses that are not clinically tolerable. Another explanation is the possible activation of T-cell receptors directly (CN independent) by the immune response, which induces protein kinase C theta (PKCtheta) and leads to IL-2 production and immune rejection. Moreover, there may be a role for nonimmunologic mechanisms, such as complement, which cannot be controlled by CsA, or CsA may cause hypercholesterolemia or induce overexpression of transforming growth factor-beta (TGF-beta). This review also compares the effect of CsA with other immunosuppressants in allograft artery preservation and their clinical efficacy.

Cyclosporine treatment preserves coronary resistance artery function in rat cardiac allografts.

BACKGROUND: A marked decline in vascular myogenic response occurs during the course of rat cardiac allograft rejection. Two important contributory features are an inducible nitrous oxide synthase (iNOS)-catalyzed, NO-mediated vasodilation and a loss of smooth muscle function. In this study, we examine the effect of cyclosporine immunosuppressive therapy on the alleviation of arterial dysfunction of coronary resistance arteries in allografts using pressure myography. METHODS: Rats receiving heterotopic abdominal cardiac transplantation were treated with cyclosporine (5 mg/kg), Cremophore or distilled water. Coronary septal arteries (internal diameter 200 microm) were dissected from isograft (Lewis to Lewis) and allograft (Fisher to Lewis) rat hearts at Day 21 post-transplantation and mounted on a pressure myograph. Pressure-induced vasoconstriction was measured before and after iNOS inhibition with aminoguanidine (AG; 100 micromol/liter). Both endothelium-based (ACh-induced) and endothelium-independent (sodium nitroprusside-induced) vasorelaxation were also recorded in each group. RESULTS: Pressure-induced myogenic contraction was reduced in allograft coronary arteries at Day 21 post-transplantation compared with matched isografts (p < 0.05). AG potentiated myogenic tone in allograft arteries, but had no effect on untreated Day 21 isograft vessels, indicating the presence of iNOS-based relaxation only in allograft vessels. Depolarization-induced vasoconstriction was lower in allograft compared with isograft arteries (p < 0.05). Cyclosporine therapy also improved depolarization-induced constriction in allograft vessels compared with untreated groups (p < 0.05). Furthermore, cyclosporine therapy preserved endothelium-based and endothelium-independent vasorelaxation in allograft arteries at Day 21 post-transplantation. CONCLUSIONS: Cyclosporine immunosuppressive therapy has a significant effect on the alleviation of early endothelial and smooth muscle dysfunction in coronary allograft arteries.