Management of cortical dysplasia in epilepsy.

Focal cortical dysplasias (FCD) are increasingly diagnosed as a cause of symptomatic focal epilepsy in paediatric and adult patients. Nowadays, focal cortical dysplasias are identified as the underlying pathology in up to 25% of patients with focal epilepsies. The histological appearance can vary from mild architectural disturbances to severe malformation containing atypical cellular elements like dysmorphic neurons and Balloon cells. Clinical presentation depends on the age at onset of epilepsy, the location and size of the lesion. In most patients seizures begin in early childhood and the course of epilepsy is often severe and pharmaco-resistant. For the majority of patients, epilepsy surgery is the only treatment option in order to become seizure free.In this review an overview on the literature of the last ten years is provided, focussing on histological appearance and classification, pathogenetic mechanisms and clinical presentation of cortical dysplasias. Recent developments in the presurgical diagnostic and outcome after operative treatment as well as prognostic factors are summarized. Finally, an outlook is given on the development of future novel treatment options that might be minimally invasive and help especially the patient group who is inoperable or has failed epilepsy surgery.

Randomized controlled trial of 2.5-cm versus 3.5-cm mesial temporal resection--Part 2: volumetric resection extent and subgroup analyses.

BACKGROUND: This paper is addressing outcome differences in interesting subgroups from a previous randomized controlled trial of the extent of mesial temporal lobe resection (TLR) for drug-resistant epilepsy, by looking at effects of randomization, intended resection group, center, and true resection extent on seizure outcome. METHODS: One hundred and seventy-nine cases with volumetrically assessed resection extent were used. Analyses of the extent of resection and subgroups and within subgroups for the two treatment arms will be performed, looking for confounding factors and using statistical methods (chi-square test, logistic regression analysis, and two-factorial ANOVA). RESULTS: True resection extent varied considerably. Outcome comparison for right versus left resections, subgroups with mesial temporal sclerosis (MTS), or largest and smallest resections revealed no remarkable difference, compared to overall class I outcome. The intent-to-treat analyses within these subgroups revealed differences for class I outcome, albeit lacking in significance, except for better TLR outcome. Small true resection volume differences or randomization into the two resection groups could not explain the outcome differences between the selective amygdalohippocampectomy (SAH) and TLR subgroups. Logistic regression analysis showed an interaction between intended resection length and surgery type, confirming the impression of different impacts of the intended resection length under the two surgery types. The outcome difference between SAH and TLR was more likely explained by a center effect. In a two-factorial ANOVA for resected hippocampal volume, Engel outcome class I, and resection type, the outcome was not found to be correlated with true resection volume. A multifactorial logistic regression showed a mild interaction between the resection type with center on the Engel outcome class, extent of resection, and surgery type interacted, as did the extent of resection and center. CONCLUSION: Patients with quite similar extent of resection can be seizure free or non-seizure free. In this cohort, seizure freedom rates fell again when the extent of mesial resection was maximized. Differences in class I outcome for SAH and TLR were not due to erroneous randomization, true resection extent, or presence of MTS, but were influenced by a center effect. Subgroup analyses did not help to provide arguments to favor one surgery type over the other.

Randomized controlled trial of 2.5-cm versus 3.5-cm mesial temporal resection in temporal lobe epilepsy--Part 1: intent-to-treat analysis.

BACKGROUND: Only one prospective randomized study on the extent of mesial resection in surgery for temporal lobe epilepsy (TLE) exists. This randomized controlled trial (RCT) examines whether 3.5-cm mesial resection is leading to a better seizure outcome than a 2.5-cm resection. METHODS: Three epilepsy surgery centers using similar MRI protocols, neuropsychological tests, and resection types for TLE surgery included 207 patients in a RCT with pre- and postoperative volumetrics. One hundred and four patients were randomized into a 2.5-cm resection group and 103 patients into a 3.5-cm resection group, i.e., an intended minimum resection length of 25 versus 35 mm for the hippocampus and parahippocampus. Primary outcome measure was seizure freedom Engel class I throughout the first year. The study was powered to detect a 20% difference in class I outcome. Seizure outcome was available for 207 patients, complete volumetric results for 179 patients. Outcome analysis was restricted to control of successful randomization and an intent-to-treat analysis of seizure outcome. RESULTS: The mean true resection volumes were significantly different for the 2.5-cm and 3.5-cm resection groups; thus, the randomization was successful. Median resection volume in the 2.5-cm group was 72.86% of initial volume and 83.44% in the 3.5-cm group. At 1 year, seizure outcome Engel class I was 74% in the 2.5-cm and 72.8% in the 3.5-cm resection group. CONCLUSIONS: The primary intent-to-treat analysis did not show a different seizure freedom rate for the more posteriorly reaching 3.5-cm resection group. It appears possible that not maximal volume resection but adequate volume resection leads to good seizure freedom.

Alterations of intracerebral connectivity in epilepsy patients with secondary bilateral synchrony.

INTRODUCTION: The aim of our study was to evaluate intracerebral network changes in epilepsy patients demonstrating secondary bilateral synchrony (SBS) in EEG by applying a new Diffusion Tensor Imaging (DTI) method using an energy-based global tracking algorithm. MATERIALS AND METHODS: 10 MRI negative epilepsy patients demonstrating SBS in 10-20 surface EEG were included. EEG findings were analyzed for irritative zones characterized by focal interictal epileptiform discharges (IEDs) triggering SBS. In addition, DTI including an energy-based global tracking algorithm was applied to analyze fiber tract alterations in irritative zones. To measure the deviation of a certain cortical connection in comparison to healthy controls, normalized differences of fiber tract streamline counts (SC) and their p-values were evaluated in comparison to corresponding fibers of the control group. RESULTS: In 6 patients the irritative zone initiating SBS was located in the frontal lobe, in 3 patients in the temporal lobe and in 1 patient in the region surrounding the right central sulcus. All patients demonstrated significantly altered SC in brain lobes where the irritative zone triggering SBS was located (p ≤ 0.05). Seven out of 10 patients demonstrated SC alterations in tracts connecting brain lobes between the ipsilateral and the contralateral hemisphere (p ≤ 0.05). CONCLUSION: Our data demonstrate that alterations in fiber tracts in irritative zones triggering SBS are not necessarily associated with intracerebral lesions visible in high resolution MRI. Our study gives evidence that diffusion tensor imaging is a promising non-invasive additive tool for intracerebral network analyses even in MRI-negative epilepsy patients.

The impact of extratemporal epilepsy surgery on quality of life.

Quality of life (QOL) with respect to seizure outcome, cognitive performance, and depressive symptoms was analyzed in 21 adult patients undergoing extratemporal epilepsy surgery (EXTLE). The Subjective Handicap of Epilepsy questionnaire was administered before and 1 year after surgery. Additionally, cognitive performance, depressive symptoms (Beck Depression Inventory), and seizure frequency were assessed. After surgery, seizure frequency decreased and various aspects of QOL significantly improved. Improvements in the domain of Work and Activities correlated with a reduction in complex partial seizure frequency. Alterations in the subscale change correlated with a decrease in simple partial seizure frequency. The present results provide detailed evidence that patients with extratemporal epilepsy benefit from epilepsy surgery.

Preoperative depressive symptoms predict postoperative seizure outcome in temporal and frontal lobe epilepsy.

OBJECTIVE: Recent research has pointed to the possibility of a bidirectional relationship between seizure frequency in epilepsy and depressive symptoms. The study described here investigated the relationship between preoperative depressive symptomatology and postoperative seizure outcome in a sample of patients with temporal (TLE) and frontal (FLE) lobe epilepsy. METHODS: A retrospective analysis was conducted on the data from 115 eligible patients with TLE (N=97) and FLE (N=18) and resections limited to one cortical lobe who were evaluated preoperatively and 1year after epilepsy surgery with respect to depressive symptoms (Beck Depression Inventory, BDI) and seizure outcome. The latter was assessed in terms of actual total seizure frequency as well as a dichotomous variable (seizure free vs. not seizure free) for the 1-year outcome. Repeated-measures analyses of variance and regression analyses were applied. RESULTS: Seizure-free patients had significantly lower BDI scores preoperatively as well as postoperatively than patients who were not seizure free. In the regression analyses, the preoperative BDI score was a significant predictor of postoperative seizure frequency as well as seizure freedom. When only patients with TLE were analyzed, the results for the association between preoperative BDI and postoperative seizure frequency and seizure freedom remained consistent. CONCLUSION: The present results provide evidence for a statistical bidirectionality of the relationship between depressive symptoms and postoperative seizure status in a mixed sample of patients with TLE and FLE. Possible reasons for this bidirectional association include an underlying common pathology in both depression and epilepsy, for example, structural changes or functional alterations in neurotransmitter systems.

Epilepsy surgery in patients with multiple cerebral cavernous malformations.

PURPOSE: Cerebral cavernous malformations (CCMs) are frequently associated with intractable epilepsy. Whereas surgery indication in single CCMs is clear, data regarding the efficacy of epilepsy surgery in patients with multiple CCMs are scarce. We sought to clarify diagnostic requirements and postoperative outcome in patients with multiple CCMs and refractory epilepsy. METHODS: Retrospective analysis of clinical records of hospitalized patients who underwent comprehensive diagnostic work-up including long-term video-EEG monitoring. RESULTS: From a total of 63 consecutive patients with CCMs and medically refractory epilepsy, 11 (17%) had multiple CCMs and underwent epilepsy surgery. There were three females and eight males. Mean age at epilepsy onset was 28.3 years (S.D. 12.3), and at epilepsy surgery, 40.7 years (S.D. 10.3). On average, each patient had 3.7 (S.D. 2.2) supratentorial CCMs. In all cases we identified only one epileptogenic zone. The epileptogenicity was higher for the CCMs located within the temporal lobe. At 2 years follow-up, the outcome according to the Engel classification was Ia (seizure-free) in nine patients (81.8%) and IIb (rare seizures) and IVc (worsening) in two patients, respectively. In one patient, a dual pathology was present and, in another case, de novo appearance of CCMs was demonstrated. CONCLUSIONS: Our results show that postoperative outcome in patients with multiple CCMs can be as good as in those with single malformations if proper presurgical identification of the epileptogenic CCMs is done. The possibility of the novo appearance of CCMs or dual pathology may occur and may affect long-term outcome negatively.

[Quality of life following extratemporal epilepsy surgery]. / Lebensqualität nach extratemporaler Epilepsiechirurgie.

Extratemporal epileptic foci are increasingly treated successfully with surgery. This study assesses the effect of extratemporal epilepsy surgery on the subjective handicaps of epilepsy patients. Twenty-one adults with pharmacoresistant focal epilepsy undergoing extratemporal surgical interventions were analyzed compared to an age-, gender-, and IQ-matched patient group with temporal lobe epilepsy. A questionnaire on subjective handicaps was given prior to surgery and after 1 year of follow-up. There were significant postoperative improvements in the domains of work and activities, self perception, and judgement of changes in handicap. These changes were similar to those in patients undergoing temporal lobe surgery and not restricted to those achieving complete seizure remission. Epilepsy surgery thus improves not only seizure control but also quality of life in patients with extratemporal focus localization.

Factors influencing surgical outcome in patients with focal cortical dysplasia.

A total of 120 patients with histologically proven focal cortical dysplasias (FCD) were retrospectively analysed for prognostic factors for successful epilepsy surgery. Multivariate data analyses showed that older age at epilepsy surgery, occurrence of secondarily generalised seizures and a multilobar extent of the dysplasia were significant negative predictors. In univariate analyses, longer duration of epilepsy, need for intracranial EEG recordings and incomplete resection of the FCD were factors which significantly reduced the chance of becoming seizure free. Histological subtype of the FCD and age at epilepsy onset had no significant predictive value. These findings strongly suggest early consideration of epilepsy surgery in FCD patients.

Comparison of two different measurement techniques of hippocampal resection length in temporal lobe epilepsy: results of a prospective study.

BACKGROUND: Magnetic resonance imaging (MRI) volumetry has evolved to a highly sensitive method for presurgical detection of hippocampal sclerosis in temporal lobe epilepsy (TLE). Seizure resolution and neuropsychological sequelae are believed to correlate with extent of resection. Therefore an easy volumetric method to determine extent of resection is desirable. The purpose of this work is to evaluate and compare two different measurement techniques for hippocampal resection length. METHODS: Sixty-one patients with a mean seizure history of 25.1 years and medically intractable TLE were included. They underwent MRI with sagittal acquired 3D T1-weighted spoiled gradient recalled echo sequence in 1 mm(3) isotropic voxel. Hippocampal resection length was calculated with two different methods. In the slice counting method (SCM) the number of consecutive 1-mm-thick slices containing resected hippocampus formation was counted. In the vector method (VM) the sum of the oblique and thus longer distances between the centre points of segmented hippocampal areas on each MRI slice were calculated. RESULTS: Since the hippocampus is a curved body, the resection lengths measured with VM were always larger than measured with SCM. The comparison of resection length expressed in "percent of total length" showed good agreement between the two methods, because unlike the absolute values of resection length, the percentage values are unaffected by the three-dimensional shape of the hippocampus. CONCLUSION: The easier and quicker method of "slice counting" may be used to determine resection length expressed in "percent of total length", giving reliable values for resection length but causing less volumetric work.

A realistic multimodal modeling approach for the evaluation of distributed source analysis: application to sLORETA.

OBJECTIVE: Electrical source localization (ESL) deriving from scalp EEG and, in recent years, from intracranial EEG (iEEG), is an established method in epilepsy surgery workup. We aimed to validate the distributed ESL derived from scalp EEG and iEEG, particularly regarding the spatial extent of the source, using a realistic epileptic spike activity simulator. APPROACH: ESL was applied to the averaged scalp EEG and iEEG spikes of two patients with drug-resistant structural epilepsy. The ESL results for both patients were used to outline the location and extent of epileptic cortical patches, which served as the basis for designing a spatiotemporal source model. EEG signals for both modalities were then generated for different anatomic locations and spatial extents. ESL was subsequently performed on simulated signals with sLORETA, a commonly used distributed algorithm. ESL accuracy was quantitatively assessed for iEEG and scalp EEG. MAIN RESULTS: The source volume was overestimated by sLORETA at both EEG scales, with the error increasing with source size, particularly for iEEG. For larger sources, ESL accuracy drastically decreased, and reconstruction volumes shifted to the center of the head for iEEG, while remaining stable for scalp EEG. Overall, the mislocalization of the reconstructed source was more pronounced for iEEG. SIGNIFICANCE: We present a novel multiscale framework for the evaluation of distributed ESL, based on realistic multiscale EEG simulations. Our findings support that reconstruction results for scalp EEG are often more accurate than for iEEG, owing to the superior 3D coverage of the head. Particularly the iEEG-derived reconstruction results for larger, widespread generators should be treated with caution.

The role of presurgical EEG parameters and of reoperation for seizure outcome in temporal lobe epilepsy.

PURPOSE: After surgery for intractable mesiotemporal lobe epilepsy (mTLE) seizures recur in 30-40%. One predictor for seizure recurrence is the distribution of seizure onset and interictal epileptiform discharges (IED). Our study focused on lateralization and extent of epileptiform activity regarding postoperative seizure persistence and the effect of reoperation. METHODS: This study comprises 426 consecutive patients operated for intractable mTLE. Impact of preoperative seizure onset and IED on the persistence of seizures and results of reoperation were analyzed. RESULTS: One year after surgery, 27% of patients with mTLE experienced persistent seizures (Engel II-IV). Preoperative bilateral seizure onset in EEG was predictive for postoperative seizure recurrence (Engel II-IV: 64%). Seizure foci and IED exceeding the temporal lobe in the ipsilateral hemisphere were not found to be associated with worse seizure outcome (Engel I: 72% and 75%) compared to patients with seizure foci confined to the ipsilateral temporal lobe (Engel I: 75% and 76%). Moreover, IED exceeding the affected temporal lobe in the ipsilateral hemisphere or even bilateral IED did not negatively affect seizure freedom if seizure onset was strictly limited to the affected temporal lobe (Engel I: 85% and 65%, respectively). 60% of patients reoperated in the ipsilateral temporal lobe for persistent seizures became seizure free. CONCLUSIONS: Preoperative bilateral ictal foci are a negative predictor for seizure outcome. Contrarily, IED exceeding the affected temporal lobe in the ipsilateral hemisphere or even bilateral IED had favorable seizure outcome if seizure onset is strictly limited to the affected temporal lobe. Reoperation for seizure persistence constitutes a promising therapeutic option.

Long-term outcome characteristics in mesial temporal lobe epilepsy with and without associated cortical dysplasia.

OBJECT: The intention of our study was to identify predictive characteristics for long-term seizure control and running down phenomenon after surgical treatment of pharmacoresistant mesiotemporal lobe epilepsy (mTLE) with and without associated cortical dysplasia. MATERIALS AND METHODS: Our study comprises a consecutive series of 458 patients who underwent surgical treatment for intractable mTLE at the Epilepsy Center Freiburg. Data evaluated included semiology, duration and frequency of seizures, results of presurgical diagnostics including video-EEG monitoring, MRI, PET and SPECT as well as postoperative seizure outcome. Results were evaluated forming two groups: Group A consisted of isolated mesiotemporal lesions. Group B comprised patients with mTLE and additional focal cortical dysplasia (FCD). Statistical evaluation was based on the Kaplan Meier survival analysis, using log-rank-tests and a multivariate regression model. Postoperative running down phenomenon was defined as seizure freedom after a period of gradual reduction of postoperative seizure frequency. This was compared to patients with ongoing epilepsy. RESULTS: Complete seizure freedom was achieved in 65.0% of investigated patients at 1year and in 56.5% at long-term follow-up of ≥5 years after surgery. Corresponding results were 64.2% and 56.8% at 1 and ≥5 years, respectively in group A and 66.4% and 56.0%, respectively in group B. Predictive for favorable postoperative outcome in the total group were younger age at surgery, shorter duration of epilepsy, absence of secondarily generalized tonic-clonic seizures (SGTCS), presence of strictly ipsilateral temporal interictal epileptiform discharges (IEDs), complete resection of the lesion as well as absence of postoperative epileptiform activity and of early postoperative seizures. In subgroup analyses, patients of group A demonstrated longer postoperative seizure-free intervals with adolescent age at surgery, short duration of epilepsy before surgery and absence of SGTCS, whereas in patients of group B ipsilateral temporal seizure onset and strictly unilateral IEDs in EEG as well as complete resection were predictors for favorable seizure outcome. Furthermore, absence of early postoperative seizures and of spikes in EEG were predictive factors for long-term seizure-freedom in both subgroups. The running down phenomenon was found in 33 (7.2%) patients. None of the parameters evaluated demonstrated significant predictive power. Only late seizure onset and neoplastic lesions showed a trend for postoperative gradual seizure reduction in multivariate analyses. CONCLUSION: Depending on the presence or absence of focal cortical dysplasia in addition to mesiotemporal structural alterations, predictors of long-term seizure control differed regarding the relevant clinical and electrophysiological features. This is important for specific patient counseling in respective groups.

Surgical pathology of temporal lobe epilepsy. Experience with 216 cases.

The surgical treatment of chronic epilepsies is increasing rapidly. Here we report the histopathologic findings in 216 consecutive surgical specimens of patients with chronic pharmacoresistant temporal lobe epilepsy. In 75 cases (34.7%) there were tumors, all but two of which were of low histopathological grade (WHO grade I or II). The most common tumors were gangliogliomas (34 cases), pilocytic astrocytomas (17 cases), oligodendrogliomas (9 cases), fibrillary astrocytomas (6 cases), and dysembryoplastic neuroepithelial tumors (6 cases). There were 51 cases with non-neoplastic focal lesions and an additional 13 cases with tumors and non-neoplastic focal lesions within the same specimen. The most frequent non-neoplastic focal lesions were microscopic glioneuronal hamartias (32 cases), glioneuronal hamartomas (7 cases), and vascular malformations (13 cases). The hippocampal formation was structurally well preserved in 71 specimens. In 51 of these (71.8%) there was Ammon's horn sclerosis. Presurgical placement of depth electrodes was invariably associated with circumscribed defects of the brain parenchyma. The implantation of subdural electrodes was sometimes followed by chronic inflammatory changes of the leptomeninges. Our findings indicate that in the majority of patients with medically intractable temporal lobe epilepsy there are significant histopathologic findings, many of which are only rarely encountered otherwise.

Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy.

The present study investigated the effect of frontal lobe surgery on "cognitive functions", which have previously been shown to be discriminative in the evaluation of non-resected patients with frontal lobe epilepsy (FLE). The cognitive outcome was evaluated with particular consideration of the side (left/right), the site (lateral, orbital, mesial, premotor/SMA), the type of surgery (resections vs. resections plus multiple subpial transections; MST), and seizure outcome. The evaluation is based on 33 patients with left (n = 17) or right (n = 16) frontal surgery. Forty-five patients who underwent successful left (n = 21) or right (n = 24) temporal lobectomy served as controls. The neuropsychological examination covered speed/attention, motor sequencing/coordination, response maintenance/inhibition, short-term memory, and language. With the exception of short-term memory, the chosen tests were discriminative in determining preoperative frontal lobe dysfunctions but they did not differentiate patients with a different lateralization or localization of the frontal focus. At the 3 month follow-up examination, patients with temporal lobectomy had improved frontal functions, whereas patients with frontal lobe surgery showed a mild deterioration. Within the frontally resected group, completely seizure-free patients had significantly improved short-term memory. Further consideration of the side, site and the type of the frontal resection indicated that patients with premotor/SMA surgery and patients with precentral/central MST had additional impairment after surgery. Premotor/SMA resections led to a deterioration in response maintenance/inhibition and if performed left sided also to deteriorated language functions. The latter impairment could be clearly related to transient aphasia directly after surgery. Irrespective of pareses observed immediately after surgery, patients with MSTs of the precentral/central areas displayed additional problems in motor coordination at the follow-up examination. In this group the seizure outcome was also less favourable. In summing up, frontal lobe surgery does not cause any considerable additional impairment in the short-term follow-up. However, caution is recommended when surgery or MST affect functional relevant cortex (here the prefrontal/SMA and precentral/central area). Finally, a release of functions associated with frontal areas not affected by surgery is suggested, when seizures are successfully controlled by surgery.

Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy.

The present study investigated the effect of frontal lobe surgery on "cognitive functions", which have previously been shown to be discriminative in the evaluation of non-resected patients with frontal lobe epilepsy (FLE). The cognitive outcome was evaluated with particular consideration of the side (left/right), the site (lateral, orbital, mesial, premotor/SMA), the type of surgery (resections vs resections plus Multiple Subpial Transections), and seizure outcome. The evaluation is based on 33 patients with left (n = 17) or right (n = 16) frontal surgery. Forty-five patients who underwent successful left (n = 21) or right (n = 24) temporal lobectomy served as controls. The neuropsychological examination covered speed/attention, motor sequencing/coordination, response maintenance/inhibition, short-term memory, and language. With the exception of short term memory, the chosen tests were discriminative in determining preoperative frontal lobe dysfunctions but they did not differentiate patients with a different lateralization or localization of the frontal focus. At the three month follow-up examination, patients with temporal lobectomy had improved frontal functions, while patients with frontal lobe surgery showed a mild deterioration. Within the frontally resected group, completely seizure free patients had significantly improved short-term memory. Further consideration of the side, site and the type of the frontal resection indicated that patients with premotor/SMA surgery and patients with precentral/central MST had additional impairment after surgery. Premotor/SMA resections led to a deterioration in response maintenance/inhibition and if performed left sided also to deteriorated language functions. The latter impairment could be clearly related to transient aphasia directly after surgery. Irrespective of pareses observed immediately after surgery, patients with MST's of precentral/central areas displayed additional problems in motor coordination at the follow-up examination. In this group the seizure outcome was also less favorable. In summing up, frontal lobe surgery does not cause any considerable additional impairment in the short term follow-up. However, caution is recommended when surgery or MST affect functional relevant cortex (here the prefrontal/SMA and precentral/central area). Finally, a release of functions associated to frontal areas not affected by surgery is suggested, when seizures are successfully controlled by surgery.

Modulation of electrically evoked acetylcholine release through cannabinoid CB1 receptors: evidence for an endocannabinoid tone in the human neocortex.

Cannabinoids are known to inhibit neurotransmitter release in the CNS through CB1 receptors. The present study compares the effects of synthetic cannabinoids on acetylcholine (ACh) release in human and mice neocortex. We further investigated a possible endocannabinoid tone on CB1 receptors in human neocortex caused by endogenous agonists like anandamide or 2-arachidonylglycerol. Brain slices, incubated with [3H]-choline, were superfused and stimulated electrically under autoinhibition-free conditions to evoke tritium overflow assumed to represent ACh release. The first series of experiments was performed with 26 pulses, 60 mA, at 0.1 Hz. In mice neocortical slices, the cannabinoid receptor agonist WIN55212-2 decreased ACh release (pIC50=6.68, I(max)=67%). In the human neocortex the concentration-response curve of WIN55212-2 was bell-shaped and flat (I(max observed) approximately 30%). The estimated maximum possible inhibition, however, was much larger: I(max derived)=79%. Lec, the negative logarithm (lg) of the biophase concentration of endocannabinoids in 'WIN55212-2 units,' was -6.52, the pKd of WIN55212-2 was 7.47. The CB1 receptor antagonist/inverse agonist SR141716 enhanced ACh release in the human neocortex (by 38%) and prevented the inhibitory effect of WIN55212-2. The concentration-response curve of WIN55212-2 was changed in its shape including a shift to the right due to the presence of SR141716. A pA2 of this antagonist between 11.60 and 11.18 was obtained. SR141716 alone had no effect in mice neocortical slices. A partial agonist without inverse agonistic activity, O-1184, enhanced ACh release in the human neocortex. The endocannabinoid uptake-inhibitor AM404 decreased ACh release in human, but not in mice, neocortical slices. Change of the stimulation parameters (eight trains of pseudo-one-pulse bursts (4 pulses, 76 mA, 100 Hz), spaced by 45 s intervals) led to a stronger inhibitory effect of WIN55212-2, and abolished the disinhibitory effect of SR141716 and O-1184. The results show that activation of CB1 cannabinoid receptors leads to inhibition of ACh release in the human and mouse neocortex. The endocannabinoid tone is high in the human, but not in the mouse neocortex and is dependent on neuronal activity. SR141716 acts as a competitive CB1 receptor antagonist.

Cannabinoid CB1 receptor-mediated modulation of evoked dopamine release and of adenylyl cyclase activity in the human neocortex.

1. The present study investigated the binding characteristics of various ligands to cannabinoid CB(1) receptors in human neocortex and amygdala. In addition, the functionality of CB(1) receptors in the human neocortex was assessed by examining the effects of CB(1) receptor ligands on evoked [(3)H]-dopamine (DA) release in superfused brain slices and on synaptosomal cAMP accumulation. 2. Saturation-binding assays in human neocortical and amygdala synaptosomes using a radiolabelled cannabinoid receptor agonist ([(3)H]-CP55.940) revealed pK(d) values of 8.96 and 8.63, respectively. The numbers of binding sites (B(max)) were 3.99 and 2.67 pmol (mg protein)(-1), respectively. 3. Various cannabinoid receptor ligands inhibited [(3)H]-CP55.940 binding with rank order potencies corresponding to those of previous studies in animal tissues. 4. Electrically evoked [(3)H]-DA release from human neocortical slices was inhibited by CP55.940 (IC(50) 6.76 nm, I(max) 65%) and strongly enhanced by the cannabinoid receptor antagonist AM251. However, [(3)H]-DA release was not influenced in rat neocortex. In human tissue, the estimated endocannabinoid concentration in the biophase of the release-modulating CB(1) receptors was 1.07 nm, expressed in CP55.940 units. 5. K(+)-evoked [(3)H]-DA release in the presence of tetrodotoxin (TTX) was strongly inhibited by CP55.940 in humans, but not in rats. 6. In human tissue, CP55.940 inhibited forskolin-stimulated cAMP accumulation (IC(50) 20.89 nm, I(max) 35%). AM251 blocked this effect and per se increased forskolin-stimulated cAMP accumulation by approximately 20%. 7. In conclusion, cannabinoids modulate [(3)H]-DA release and adenylyl cyclase activity in the human neocortex. CB(1) receptors are located on dopaminergic nerve terminals and seem to be tonically activated by endocannabinoids.

Shutting down operating theater ventilation when the theater is not in use: infection control and environmental aspects.

OBJECTIVE: In hospital operating rooms (ORs), specially conditioned air is supplied to protect patients from airborne agents that may cause infections. This study investigated whether it is hygienically safe to shut down the air supply at night if measures are taken to ensure a timely restart before surgery is performed. DESIGN: Experimental study. SETTING: Neurosurgical OR of a German university hospital. METHODS: The ventilation system was switched off and restarted after 10 hours. Particles suspended in the air near the operating table were counted, OR temperature was measured, and settle plates were exposed and incubated. RESULTS: In 13 investigations, a median of 1.3 x 10(4) particles 0.5 microm/m3 or greater (range, 5.8 x 10(3) to 1.1 x 10(5)) were documented immediately after restart in the morning. After 10 minutes and subsequently, no test showed a particle count exceeding the threshold limit of 1.0 x 10(4) particles 0.5 microm/m3 or greater recommended by the German Society of Hygiene and Microbiology. Only a few colony-forming units (CFU) were detected per settle plate (median, 0 CFU/60 cm2; range, 0 to 8) and OR temperatures quickly reached normal levels. CONCLUSIONS: Shutting down OR ventilation during off-duty periods does not appear to result in an unacceptably high particle count or microbial contamination of the OR air shortly after the system is restarted. Because substantial energy and cost savings are likely, this should be considered in hygienically safe heating, ventilation, and air conditioning systems. However, normal ventilation should be established at least 30 minutes before surgical activity.