Reactive oxygen species in status epilepticus.

There has been growing evidence for a critical role of oxidative stress in neurodegenerative disease, providing novel targets for disease modifying treatments. Although antioxidants have been suggested and tried in the treatment of epilepsy, it is only recently that the pivotal role of oxidative stress in the pathophysiology of status epilepticus has been recognized. Although conventionally thought to be generated by mitochondria, reactive oxygen species during status epilepticus and prolonged seizure are generated mainly by NADPH (nicotinamide adenine dinucleotide phosphate) oxidase (stimulated by NMDA receptor activation). Excessive production of reactive oxygen species results in lipid peroxidation, DNA damage, enzyme inhibition, and mitochondrial damage, culminating in neuronal death. Antioxidant therapy has been hampered by poor CNS penetration and rapid consumption by oxidants. However, alternative approaches such as inhibiting NADPH oxidase or increasing endogenous antioxidant defenses through activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) could avoid these problems. Small molecules that increase Nrf2 activation have proven to be not only effective neuroprotectants following status epilepticus, but also potently antiepileptogenic. There are "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

[Update on anti-N-methyl-D-aspartate receptor encephalitis]. / Update Anti-N-Methyl-D-Aspartat-Rezeptor-Enzephalitis.

Autoimmune encephalitis is a group of autoimmune inflammatory disorders affecting both grey and white matter of the central nervous system. Encephalitis with autoantibodies against the N­methyl-D-aspartate receptor (NMDA-R) is the most frequent autoimmune encephalitis syndrome presenting with a characteristic sequence of psychiatric and neurological symptoms. Treatment necessitates a close interdisciplinary cooperation. This article provides an update on the current knowledge on diagnostic standards, pathogenesis, and treatment strategies for anti-NMDA-R encephalitis from psychiatric and neurological perspectives.

Status epilepticus results in persistent overproduction of reactive oxygen species, inhibition of which is neuroprotective.

Epilepsy and seizure activity result in the generation of reactive oxygen species (ROS), which contribute to seizure-induced neuronal damage. Recent in vitro evidence indicates that NADPH oxidase contributes significantly to seizure-induced ROS. We further tested this in rat glio-neuronal cultures and in ex vivo chronic epileptic rat brain tissue using live cell-imaging techniques. Here, we show that ROS are upregulated in chronic epilepsy and that ROS production contributes to cell death, which is seen after status epilepticus (SE) and chronic seizures. Inhibition of ROS production by AEBSF, a NADPH oxidase inhibitor, markedly reduced seizure-induced cell death in the perforant path model of epilepsy. These findings demonstrate a critical role for ROS, generated by NADPH oxidase, contributing to seizure-induced cell death. These findings point to NADPH oxidase inhibition as a novel treatment strategy to prevent brain injury in SE and chronic epilepsy.

Seizure activity results in calcium- and mitochondria-independent ROS production via NADPH and xanthine oxidase activation.

Seizure activity has been proposed to result in the generation of reactive oxygen species (ROS), which then contribute to seizure-induced neuronal damage and eventually cell death. Although the mechanisms of seizure-induced ROS generation are unclear, mitochondria and cellular calcium overload have been proposed to have a crucial role. We aim to determine the sources of seizure-induced ROS and their contribution to seizure-induced cell death. Using live cell imaging techniques in glioneuronal cultures, we show that prolonged seizure-like activity increases ROS production in an NMDA receptor-dependent manner. Unexpectedly, however, mitochondria did not contribute to ROS production during seizure-like activity. ROS were generated primarily by NADPH oxidase and later by xanthine oxidase (XO) activity in a calcium-independent manner. This calcium-independent neuronal ROS production was accompanied by an increase in intracellular [Na(+)] through NMDA receptor activation. Inhibition of NADPH or XO markedly reduced seizure-like activity-induced neuronal apoptosis. These findings demonstrate a critical role for ROS in seizure-induced neuronal cell death and identify novel therapeutic targets.

Route of hysterectomy: an evidence-based approach.

The number of hysterectomies performed has long been a concern; now the appropriateness of the surgical method is under more careful scrutiny. What is the clinically appropriate route and method for hysterectomy in a given patient? To ensure that each patient receives the best possible care at reasonable costs, physicians must closely examine recent data comparing surgical approaches to hysterectomy. So, what is the most evidence-based approach for hysterectomy?

Dopamine protects neurons against glutamate-induced excitotoxicity.

Glutamate excitotoxicity is responsible for neuronal death in acute neurological disorders including stroke, trauma and neurodegenerative disease. Loss of calcium homeostasis is a key mediator of glutamate-induced cell death. The neurotransmitter dopamine (DA) is known to modulate calcium signalling, and here we show that it can do so in response to physiological concentrations of glutamate. Furthermore, DA is able to protect neurons from glutamate-induced cell death at pathological concentrations of glutamate. We demonstrate that DA has a novel role in preventing delayed calcium deregulation in cortical, hippocampal and midbrain neurons. The effect of DA in abolishing glutamate excitotoxicity can be induced by DA receptor agonists, and is abolished by DA receptor antagonists. Our data indicate that the modulation of glutamate excitotoxicity by DA is receptor-mediated. We postulate that DA has a major physiological function as a safety catch to restrict the glutamate-induced calcium signal, and thereby prevent glutamate-induced cell death in the brain.

Impact of fumonisin B1 on glutamate toxicity and low magnesium-induced seizure activity in neuronal primary culture.

Fumonisin B(1) (FB(1)) is a mycotoxin produced by Fusarium spp. mould that contaminates maize world-wide. Although its neurodegenerative potential is well established, mechanisms and acute effects of FB(1) on neurons are still not completely understood. Our previous study on astrocytes and neuroblastoma cells demonstrated that acute FB(1) exposure inhibits mitochondrial complex I and leads to mitochondrial membrane potential depolarization and calcium deregulation. To further explore the mechanisms of FB(1) neurotoxicity, we here investigated the effects of acute FB(1) co-exposure with glutamate and in the low magnesium model of epilepsy on neuronal calcium level, mitochondrial membrane potential, and cell death in glio-neuronal cultures. FB(1) increased the glutamate-induced calcium signal in neurons and changed neuronal calcium signals to more sustained intracellular calcium rises in the low magnesium model of epilepsy that coincided with mitochondrial membrane potential depolarization. FB(1) co-exposure increased the percentage of dead neurons in low magnesium conditions dose dependently when compared with low magnesium exposure only, whereas in FB(1) and glutamate co-exposure neuronal death remained unchanged when compared with glutamate treatment only. Our results show that FB(1) makes neurons more vulnerable to glutamate-induced toxicity and epileptiform conditions, indicating that FB(1) can enhance the detrimental effect of these conditions on neurons.

Visual naming performance after ATL resection: impact of atypical language dominance.

PURPOSE: To characterize the interaction between language dominance and lateralization of the epileptic focus for pre- and postoperative Boston Naming Test (BNT) performance in patients undergoing anterior temporal lobectomy (ATL). METHODS: Analysis of pre- and postoperative BNT scores depending on lateralization of language as measured by the intracarotid amobarbital procedure (IAP) versus lateralization of the temporal lobe epileptic focus. RESULTS: Changes between pre- and postoperative BNT performance depended on epilepsy lateralization (effect size=0.189) with significant decrease in patients undergoing left ATL. Subgroup analysis in these showed that postoperative decline in BNT scores was significant in patients with atypical (n=14; p<0.05), but did not reach statistical significance in patients with left language dominance (n=36; p=0.09). Chi-square test revealed a trend of higher proportions of patients experiencing significant postsurgical deterioration in naming performance in atypical (57.1%) as compared to left language dominance (30.6%; p=0.082). Surgical failure was also associated with greater decline of BNT scores and was more common in atypical than in left language dominant patients (chi(2) (1, n=98)=4.62, p=0.032). Age of onset, duration of epilepsy, and seizure frequency had no impact on changes in BNT performance. CONCLUSION: Atypical language dominance is a predictor of change in visual naming performance after left ATL and may also impact postsurgical seizure control. This should be considered when counseling surgical candidates.

Patterns of neurotransmitter receptor distributions following cortical spreading depression.

Spreading depression (SD), a self-propagating depolarization of neurons and glia, is believed to play a role in different neurological disorders including migraine aura and acute brain ischaemia. Initiation and propagation of SD modulate excitability of neuronal network. A brief period of excitation heralds SD which is immediately followed first by prolonged nerve cell depression and later by an excitatory phase. The aim of the present study was to characterize local and remote transmitter receptor changes after propagation of cortical SD. Quantitative receptor autoradiography was used to asses 16 transmitter receptor types in combined striatum-hippocampus-cortex slices of the rat 1 h after induction of cortical SD. In neocortical tissues, local increases of glutamate NMDA, AMPA, and kainate receptor binding sites were observed. In addition to up-regulation of ionotropic glutamate receptors, receptor binding sites of GABA(A), muscarinic M1 and M2, adrenergic alpha(1) and alpha(2), and serotonergic 5-HT(2) receptors were increased in the hippocampus. Cortical SD also upregulated NMDA, AMPA, kainate, GABA(A), serotonergic 5-HT(2), adrenergic alpha(2) and dopaminergic D1 receptor binding sites in the striatum. These findings indicate selective changes in several receptors binding sites both in cortical and subcortical regions by SD which may explain delayed excitatory phase after SD. Mapping of receptor changes by cortical SD increases our understanding of the mechanism of SD action in associated neurological disorders.

Memory performance is related to language dominance as determined by the intracarotid amobarbital procedure.

OBJECTIVE: The goal of this study was to explore the relationship between language and memory lateralization in patients with epilepsy undergoing the intracarotid amobarbital procedure. METHODS: In 386 patients, language lateralization and memory lateralization as determined by laterality index (LI) were correlated with each other. RESULTS: Language lateralization and memory lateralization were positively correlated (r=0.34, P<0.01). Correlations differed depending on the presence and type of lesion (chi(2)=7.98, P<0.05). LIs correlated significantly higher (z=2.82, P<0.05) in patients with cortical dysplasia (n=41, r=0.61, P<0.01) compared with the group without lesions (n=90, r=0.16, P>0.05), with patients with hippocampal sclerosis falling between these two groups. Both memory (P<0.01) and language (P<0.01) LIs were higher in right- compared with left-sided lesions. CONCLUSION: Correlation of language and memory is more pronounced in patients with structural lesions as compared with patients without lesions on MRI.

Intravenous levetiracetam: a new treatment alternative for refractory status epilepticus.

The purpose of this study was to investigate the safety and efficacy of intravenous levetiracetam (LEV-iv) in refractory status epilepticus (SE). A retrospective chart review was performed on patients who received LEV-iv for treatment of SE (n = 36) and had failed at least one other antiepileptic drug. LEV-iv (median 3000 mg/day; range 1000-9000) was administered as a bolus loading (500-2000 mg per 30-60 min, n = 30) or as a continuous pump infusion (n = 6). SE was terminated in 69% ("responders"); 31% ("non-responders") remained in SE. Factors associated with failure were: dose escalation over 3000 mg/day, lack of bolus loading, treatment latency over 48 h, age over 80 years, non-convulsive SE with coma ("subtle SE"), periodic lateralised epileptiform discharges (PLEDs) on EEG, acute cerebral lesion and intubation narcosis. SE was terminated in all eight patients without brain lesion (p = 0.033), and in all seven patients with complex partial SE (p = 0.051). Outcome was favourable (ambulatory patients) in 48% (responders) compared with 0% (non-responders), and "adverse" (death or continuing coma/stupor) in 24% (responders) compared with 100% (non-responders). Mortality was 17% (responders 4%, non-responders 45%). No patient had cardiocirculatory side effects or worsening of SE. Two patients experienced nausea and vomiting during LEV-iv loading, leading to aspiration pneumonia in one. This study suggests that LEV-iv may be a safe and efficacious treatment of SE. Prospective and controlled trials are imperative to confirm these preliminary findings.

Different regional neuroinhibitory effects of adenosine on stimulus-induced patterns of bioelectric activity of rat hippocampal and neocortical tissues.

Adenosine is an inhibitory modulator of brain activity with neuroprotective and anticonvulsant properties. To investigate the distribution of bioelectric activities under application of adenosine, rat hippocampal and neocortical slices were incubated with the voltage-sensitive dye RH795 and neuronal activity was monitored using a fast-imaging photodiode array combined with standard field potential recordings. The effects of adenosine (1-50 micromol/l) on the spatial distribution of stimulus-induced activities were studied in non-epileptiform as well as epileptiform conditions. Epileptiform activity was induced by omission of Mg(2+) from the bath medium. The adenosine's inhibitory effects on the amplitude and spatial extent of stimulus-induced bioelectric activity in the hippocampus were most prominent in strata radiatum and pyramidale in both control and epileptic mediums. Adenosine's inhibitory actions were different on various layers of neocortical tissues in non-epileptiform and epileptiform conditions. Layers II and III showed the most inhibition by application of adenosine in control slices. In epileptiform medium, however, adenosine exerts significant suppressive effects only in layer I of neocortical slices. The data demonstrate a region-specific modulatory potential of adenosine on neuronal network excitability in the hippocampus and neocortex. This may be important in local adenosine therapy in epilepsy.

Frequency of seizures and epilepsy in neurological HIV-infected patients.

BACKGROUND: Infection with the human immunodeficiency virus (HIV) is associated both with infections of the central nervous system and with neurological deficits due to direct effects of the neurotropic virus. Seizures and epilepsy are not rare among HIV-infected patients. We investigated the frequency of acute seizures and epilepsy of patients in different stages of HIV infection. In addition, we compared the characteristics of patients who experienced provoked seizures only with those of patients who developed epilepsy. METHODS: The database of the Department of Neurology, University of Münster, was searched for patients with HIV infection admitted between 1992 and 2004. Their charts were reviewed regarding all available sociodemographic, clinical, neurophysiological, imaging and laboratory data, therapy and outcome. Stage of infection according to the CDC classification and the epileptogenic zone were determined. RESULTS: Of 831 HIV-infected patients treated in our department, 51 (6.1%) had seizures or epilepsy. Three of the 51 patients (6%) were diagnosed with epilepsy before the onset of the HIV infection. Fourteen patients (27%) only had single or few provoked seizures in the setting of acute cerebral disorders (eight patients), drug withdrawal or sleep withdrawal (two patients), or of unknown cause (four patients). Thirty-four patients (67%) developed epilepsy in the course of their HIV infection. Toxoplasmosis (seven patients), progressive multifocal leukencephalopathy (seven patients) and other acute or subacute cerebral infections (five patients) were the most frequent causes of seizures. EEG data of 38 patients were available. EEG showed generalized and diffuse slowing only in 9 patients, regional slowing in 14 patients and regional slowing and epileptiform discharges in 1 patient. Only 14 of the patients had normal EEG. At the last contact, the majority of the patients (46 patients=90%) were on highly active antiretroviral therapy (HAART). Twenty-seven patients (53%) were on anticonvulsant therapy (gabapentin: 14 patients, carbamazepine: 9 patients, valproate: 2 patients, phenytoin: 1 patient, lamotrigine: 1 patient). Patients with only provoked seizures had no epilepsy risk factors except HIV infection, and were less likely to be infected via intravenous drug abuse. CONCLUSIONS: Seizures are a relevant neurological symptom during the course of HIV infection. Although in some patients seizures only occur provoked by acute disease processes, the majority of patients with new onset seizures eventually develops epilepsy and require anticonvulsant therapy. Intravenous drug abuse and the presence of non-HIV-associated risk factors for epilepsy seem to be associated with the development of chronic seizures in this patient group.

Long-term survival of a cemented titanium-aluminium-vanadium alloy straight-stem femoral component.

We present a retrospective series of 170 cemented titanium straight-stem femoral components combined with two types of femoral head: cobalt-chromium (CoCr) alloy (114 heads) and alumina ceramic (50 heads). Of the study group, 55 patients (55 stems) had died and six (six stems) were lost to follow-up. At a mean of 13.1 years (3 to 15.3) 26 stems had been revised for aseptic loosening. The mean follow-up time for stable stems was 15.1 years (12.1 to 16.6). Survival of the stem at 15 years was 75.4% (95% confidence interval (CI) 67.3 to 83.5) with aseptic failure (including radiological failure) as the end-point, irrespective of the nature of the head and the quality of the cement mantle. Survival of the stem at 15 years was 79.1% (95% CI 69.8 to 88.4) and 67.1% (95% CI 51.3 to 82.9) with the CoCr alloy and ceramic heads, respectively. The quality of the cement mantle was graded as a function of stem coverage: stems with complete tip coverage (type 1) had an 84.9% (95% CI 77.6 to 92.2) survival at 15 years, compared with those with a poor tip coverage (type 2) which had a survival of only 22.4% (95% CI 2.4 to 42.4). The poor quality of the cement mantle and the implantation of an alumina head substantially lowered the survival of the stem. In our opinion, further use of the cemented titanium alloy straight-stem femoral components used in our series is undesirable.

Clinical opinion: guidelines for hysterectomy.

OBJECTIVE: Abdominal hysterectomy remains the predominant method of uterine removal in the United States, despite evidence that vaginal hysterectomy offers advantages in regard to operative time, complication rates, return to normal activities, and overall cost of treatment. STUDY DESIGN: The predominance of the abdominal approach may be based on factors other than clinical considerations that include resident training, use of obsolete or limited guidelines, a perception rather than a confirmation that pathologic conditions exist that may suggest contraindications to the vaginal approach, misconceptions regarding the cost and safety of vaginal hysterectomy, and increased third-party reimbursement for the abdominal procedure. RESULTS: Evidence-based practice guidelines that were developed by the Society of Pelvic Reconstructive Surgeons and were adopted by the National Guidelines Clearinghouse have demonstrated that, in a number of studies that span several years, a dramatic shift toward the vaginal approach occurred when the guidelines were applied prospectively. CONCLUSION: The guidelines demonstrate that transvaginal hysterectomy is both feasible and optimal for many patients who long have been considered inappropriate candidates for vaginal hysterectomy. This clinical opinion attempts to address the reasons for the predominant use of the abdominal approach.

Transvaginal hysterectomy: rationale and surgical approach.

Abdominal hysterectomy is performed in the United States at a 3:1 ratio over vaginal hysterectomy, despite evidence that vaginal hysterectomy offers advantages over abdominal hysterectomy with regard to operative time, complication rates, recovery, return to daily activities, and overall costs of treatment. In fact, the predominance of the abdominal approach may be based on factors other than clinical considerations, including resident training, use of limited or obsolete guidelines, greater third-party compensation for abdominal procedures, a presumption rather than a confirmation that pathology exists that contraindicates a vaginal approach, and misconceptions about the safety and cost of vaginal hysterectomy. A number of studies spanning several years demonstrate that the use of more systematic guidelines for selecting the route of hysterectomy results in a major shift toward the vaginal approach. Evidence also shows that transvaginal hysterectomy is both feasible and optimum for types of patients who have long been considered inappropriate candidates for the vaginal route. New instrumentation facilitates the vaginal approach and contributes to improved hemostasis and decreased operative time. Included here is a step-by-step approach to determining appropriate candidates for the vaginal approach via assessment of access, uterus size, and extent of pathology.

Divergent roles for ferric ions in the biological activity of amidated and non-amidated gastrins.

Amidated forms of the peptide hormone gastrin act via the cholecystokinin-2 receptor to stimulate gastric acid secretion, whereas non-amidated forms stimulate colonic mucosal proliferation via a novel, as yet uncharacterised, receptor. Nuclear magnetic resonance (NMR) and fluorescence spectroscopic studies have revealed that glycine-extended gastrin17 bound two ferric ions, and that ferric ion binding was essential for biological activity. We have therefore investigated the role of ferric ions in the biological activity of amidated gastrin17. As with glycine-extended gastrin17, fluorescence quenching experiments indicated that Glu7 Ala and Glu8,9 Ala mutants of amidated gastrin17 each bound only one ferric ion. The affinity of the mutant peptides for the cholecystokinin-2 receptor on transfected COS-7 cells or on Tlymphoblastoid Jurkat cells, and their potency in stimulation of proliferation in Jurkat cells and inositol phosphate production in transfected COS-7 cells, were similar to the values obtained for amidated gastrin17. In addition, the iron chelator desferrioxamine did not significantly inhibit either binding of amidated gastrin17 to the cholecystokinin-2 receptor, or stimulation of inositol phosphate production by amidated gastrin17 in transfected COS-7 cells. We conclude that, in contrast to glycine-extended gastrin17, binding of ferric ions is not essential for the biological activity of amidated gastrin17. Our results support the concept of distinct modes of action for amidated and non-amidated gastrins, and raise the possibility of developing selective antagonists of the actions of non-amidated and amidated gastrins.

Guidelines for the selection of the route of hysterectomy: application in a resident clinic population.

OBJECTIVE: The purpose of this study was to evaluate the effectiveness of the Society of Pelvic Reconstructive Surgeons guidelines for the determination of the route of hysterectomy in a resident clinic population. STUDY DESIGN: A total of 407 consecutive women from the resident clinic population at Wright State University between October 1, 1994, and December 31, 1999, were assigned prospectively to abdominal or vaginal hysterectomy groups according to Society of Pelvic Reconstructive Surgeons guidelines. The women's age, race, and preoperative and postoperative uterine weights, length of stay, laparoscopic scores, operative time, and complications were compared. RESULTS: Vaginal hysterectomy was completed successfully in 91.8% of the women. As expected, vaginal hysterectomy required the shortest operative time and length of stay and was associated with fewer complications than the abdominal approach (P <.01). Laparoscopic assistance was necessary in 25.8% of patients to assess extrauterine disease. CONCLUSION: Resident physicians who followed the practice guidelines reduced the ratio of abdominal-to-vaginal hysterectomy from 3:1 to 1:11. The application of practice guidelines for the selection of the route of hysterectomy can increase the ratio of vaginal hysterectomies that are performed in residency programs and can help eradicate inconsistencies in health care delivery that exist currently.