Functional seizures are associated with cerebrovascular disease and functional stroke is more common in patients with functional seizures than epileptic seizures.

PURPOSE: To characterize the relationship between functional seizures (FSe), cerebrovascular disease (CVD), and functional stroke. METHOD: A retrospective case-control study of 189 patients at a single large tertiary medical center. We performed a manual chart review of medical records of patients with FSe or epileptic seizures (ES), who also had ICD code evidence of CVD. The clinical characteristics of FSe, ES, CVD, and functional stroke were recorded. Logistic regression and Welch's t-tests were used to evaluate the differences between the FSe and ES groups. RESULTS: Cerebrovascular disease was confirmed in 58.7% and 87.6% of patients with FSe or ES through manual chart review. Stroke was significantly more common in patients with ES (76.29%) than FSe (43.48%) (p = 4.07 × 10-6). However, compared to nonepileptic controls FSe was associated with both CVD (p < 0.0019) and stroke (p < 6.62 × 10-10). Functional stroke was significantly more common in patients with FSe (39.13%) than patients with ES (4.12%) (p = 4.47 × 10-9). Compared to patients with ES, patients with FSe were younger (p = 0.00022), more likely to be female (p = 0.00040), and more likely to have comorbid mental health needs including anxiety (p = 1.06 × 10-6), PTSD or history of trauma (e.g., sexual abuse) (p = 1.06 × 10-13), and bipolar disorder (p = 0.0011). CONCLUSION: Our results confirm the initial observation of increased CVD in patients with FSe and further suggest that patients with FSe may be predisposed to developing another functional neurological disorder (FND) (i.e., functional stroke). We speculate that this may be due to shared risk factors and pathophysiological processes that are common to various manifestations of FND.

Enhanced rates of detection and treatment of depression and anxiety disorders among adult patients with epilepsy using automated EMR-based screening.

OBJECTIVE: Depression and anxiety disorders are common among patients with epilepsy (PWE). These comorbidities have been shown to influence prognosis and may have a greater impact on quality of life than seizure control. Despite guideline recommendations and expert consensus to regularly screen for and treat both conditions, there is evidence that they are underdiagnosed and undertreated. Our goal was to test a novel screening method to determine if it would increase the rate of detecting and treating depression and anxiety disorders among PWE. METHOD: The Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and the Brief Epilepsy Anxiety Survey Instrument (brEASI) were selected as validated screening instruments for depression and anxiety disorders, respectively. They were sent via an electronic medical record-linked patient portal to all patients of four epileptologists 48 h prior to their clinic appointment. We evaluated whether this increased the rate of detecting and treating depression and anxiety disorders relative to a historical control group. RESULTS: A total of 563 patients were included of whom 351 were sent the screening instruments. 62.7% of patients completed the screening instruments of whom 47.7% screened positive for either depression only (16.4%), anxiety disorders only (5.5%) or both (25.9%); a statistically significant increase relative to the control group. There was also a significantly increased proportion of patients for whom treatment was initiated for depression (p < 0.01), anxiety disorders (p < 0.01), or both (p < 0.01). CONCLUSIONS: We identified an easily applicable and efficient means of enhancing detection and treatment rates for depression and anxiety disorders among PWE in a busy clinic setting.

Experience From 211 Transcortical Selective Amygdalohippocampectomy Procedures: Relevant Surgical Anatomy and Review of the Literature.

BACKGROUND: Selective amygdalohippocampectomy (SelAH) is designed to treat medically refractory mesial temporal lobe epilepsy with reduced morbidity compared to standard anterior temporal lobectomy. At our institution, we perform SelAH via a transcortical approach via small corticectomy in the middle temporal gyrus. OBJECTIVE: To discuss the surgical anatomy and nuances of SelAH, share our institutional experience, and perform a review of literature. METHODS: Institutional experience was recorded by collecting demographic and outcome data from 1999 to 2017 under an Institutional Review Board protocol in a prospective manner using a REDCap database. RESULTS: A total of 211 SelAH procedures were performed at our institution between 1999 and 2017. Of these patients, 54% (113/211) were females. The average age at surgery was 39.4 yr. Two-year Engel outcome data were available for 168 patients, of which 73% (123/168) had Engel I outcomes. Engel II outcomes were reported in 16.6% (28/168), III in 4.7% (8/168), and IV in 5.3% (9/168). Our review of literature showed that this is comparable to the seizure freedom rates reported by other groups. We then reviewed our surgical methodology based on operative reports and created illustrations of the surgical anatomy of temporal lobe approach. These illustrations were compared with postoperative magnetic resonance imaging to provide a better 3D understanding of the complex architecture of mesial temporal structures. CONCLUSION: SelAH is a minimally invasive, safe, and effective approach for the treatment of medically refractory epilepsy with good surgical outcomes and low morbidity. We feel that mastering the complex anatomy of this approach helps achieve successful outcomes.

Role of the Nucleus Basalis as a Key Network Node in Temporal Lobe Epilepsy.

OBJECTIVE: To determine whether the nucleus basalis of Meynert (NBM) may be a key network structure of altered functional connectivity in temporal lobe epilepsy (TLE), we examined fMRI with network-based analyses. METHODS: We acquired resting-state fMRI in 40 adults with TLE and 40 matched healthy control participants. We calculated functional connectivity of NBM and used multiple complementary network-based analyses to explore the importance of NBM in TLE networks without biasing our results by our approach. We compared patients to controls and examined associations of network properties with disease metrics and neurocognitive testing. RESULTS: We observed marked decreases in connectivity between NBM and the rest of the brain in patients with TLE (0.91 ± 0.88, mean ± SD) vs controls (1.96 ± 1.13, p < 0.001, t test). Larger decreases in connectivity between NBM and fronto-parietal-insular regions were associated with higher frequency of consciousness-impairing seizures (r = -0.41, p = 0.008, Pearson). A core network of altered nodes in TLE included NBM ipsilateral to the epileptogenic side and bilateral limbic structures. Furthermore, normal community affiliation of ipsilateral NBM was lost in patients, and this structure displayed the most altered clustering coefficient of any node examined (3.46 ± 1.17 in controls vs 2.23 ± 0.93 in patients). Abnormal connectivity between NBM and subcortical arousal community was associated with modest neurocognitive deficits. Finally, a logistic regression model incorporating connectivity properties of ipsilateral NBM successfully distinguished patients from control datasets with moderately high accuracy (78%). CONCLUSIONS: These results suggest that while NBM is rarely studied in epilepsy, it may be one of the most perturbed network nodes in TLE, contributing to widespread neural effects in this disabling disorder.

People with mesial temporal lobe epilepsy have altered thalamo-occipital brain networks.

While temporal lobe epilepsy (TLE) is a focal epilepsy, previous work demonstrates that TLE causes widespread brain-network disruptions. Impaired visuospatial attention and learning in TLE may be related to thalamic arousal nuclei connectivity. Our prior preliminary work in a smaller patient cohort suggests that patients with TLE demonstrate abnormal functional connectivity between central lateral (CL) thalamic nucleus and medial occipital lobe. Others have shown pulvinar connectivity disturbances in TLE, but it is incompletely understood how TLE affects pulvinar subnuclei. Also, the effects of epilepsy surgery on thalamic functional connectivity remains poorly understood. In this study, we examine the effects of TLE on functional connectivity of two key thalamic arousal-nuclei: lateral pulvinar (PuL) and CL. We evaluate resting-state functional connectivity of the PuL and CL in 40 patients with TLE and 40 controls using fMRI. In 25 patients, postoperative images (>1 year) were also compared with preoperative images. Compared to controls, patients with TLE exhibit loss of normal positive connectivity between PuL and lateral occipital lobe (p < 0.05), and a loss of normal negative connectivity between CL and medial occipital lobe (p < 0.01, paired t-tests). FMRI amplitude of low-frequency fluctuation (ALFF) in TLE trended higher in ipsilateral PuL (p = 0.06), but was lower in the lateral occipital (p < 0.01) and medial occipital lobe in patients versus controls (p < 0.05, paired t-tests). More abnormal ALFF in the ipsilateral lateral occipital lobe is associated with worse preoperative performance on Rey Complex Figure Test Immediate (p < 0.05, r = 0.381) and Delayed scores (p < 0.05, r = 0.413, Pearson's Correlations). After surgery, connectivity between PuL and lateral occipital lobe remains abnormal in patients (p < 0.01), but connectivity between CL and medial occipital lobe improves and is no longer different from control values (p > 0.05, ANOVA, post hoc Fischer's LSD). In conclusion, thalamic arousal nuclei exhibit abnormal connectivity with occipital lobe in TLE, and some connections may improve after surgery. Studying thalamic arousal centers may help explain distal network disturbances in TLE.

Epidemiology of Functional Seizures Among Adults Treated at a University Hospital.

Importance: Functional seizures (formerly psychogenic nonepileptic seizures), paroxysmal episodes that are often similar to epileptic seizures in their clinical presentation and display no aberrant brain electrical patterns, are understudied. Patients experience a long diagnostic delay, few treatment modalities, a high rate of comorbidities, and significant stigma due to the lack of knowledge about functional seizures. Objective: To characterize the clinical epidemiology of a population of patients with functional seizures observed at Vanderbilt University Medical Center (VUMC). Design, Setting, and Participants: This case-control study included patients with functional seizures identified in the VUMC electronic health record (VUMC-EHR) system from October 1989 to October 2018. Patients with epilepsy were excluded from the study and all remaining patients in the VUMC medical center system were used as controls. In total, the study included 1431 patients diagnosed with functional seizures, 2251 with epilepsy and functional seizures, 4715 with epilepsy without functional seizures, and 502 200 control patients who received treatment at VUMC for a minimum of a 3 years. Data were analyzed from November 2018 to March 2020. Exposure: Diagnosis of functional seizures, as identified from the VUMC-EHR system by an automated phenotyping algorithm that incorporated International Classification of Diseases, Ninth Revision (ICD-9) codes, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes, Current Procedural Terminology codes, and natural language processing. Main Outcomes and Measures: Associations of functional seizures with comorbidities and risk factors, measured in odds ratios (ORs). Results: Of 2 346 808 total patients in the VUMC-EHR aged 18 years or older, 3341 patients with functional seizures were identified (period prevalence, 0.14%), 1062 (74.2%) of whom were women and for which the median (interquartile range) age was 49.3 (39.4-59.9) years. This assessment replicated previously reported associations with psychiatric disorders including posttraumatic stress disorder (PTSD) (OR, 1.22; 95% CI, 1.21-1.24; P < 3.02 × 10-5), anxiety (OR, 1.14; 95% CI, 1.13-1.15; P < 3.02 × 10-5), and depression (OR, 1.14; 95% CI, 1.13-1.15; P < 3.02 × 10-5), and identified novel associations with cerebrovascular disease (OR, 1.08; 95% CI, 1.06-1.09; P < 3.02 × 10-5). An association was found between functional seizures and the known risk factor sexual assault trauma (OR, 10.26; 95% CI, 10.09-10.44; P < 3.02 × 10-5), and sexual assault trauma was found to mediate nearly a quarter of the association between female sex and functional seizures in the VUMC-EHR. Conclusions and Relevance: This case-control study found evidence to support previously reported associations, discovered new associations between functional seizures and PTSD, anxiety, and depression. An association between cerebrovascular disease and functional seizures was also found. Results suggested that sexual trauma may be a mediating factor in the association between female sex and functional seizures.

Brainstem Functional Connectivity Disturbances in Epilepsy may Recover After Successful Surgery.

BACKGROUND: Focal seizures in temporal lobe epilepsy (TLE) are associated with widespread brain network perturbations and neurocognitive problems. OBJECTIVE: To determine whether brainstem connectivity disturbances improve with successful epilepsy surgery, as recent work has demonstrated decreased brainstem connectivity in TLE that is related to disease severity and neurocognitive profile. METHODS: We evaluated 15 adult TLE patients before and after (>1 yr; mean, 3.4 yr) surgery, and 15 matched control subjects using magnetic resonance imaging to measure functional and structural connectivity of ascending reticular activating system (ARAS) structures, including cuneiform/subcuneiform nuclei (CSC), pedunculopontine nucleus (PPN), and ventral tegmental area (VTA). RESULTS: TLE patients who achieved long-term postoperative seizure freedom (10 of 15) demonstrated increases in functional connectivity between ARAS structures and fronto-parietal-insular neocortex compared to preoperative baseline (P = .01, Kruskal-Wallis), with postoperative connectivity patterns resembling controls' connectivity. No functional connectivity changes were detected in 5 patients with persistent seizures after surgery (P = .9, Kruskal-Wallis). Among seizure-free postoperative patients, larger increases in CSC, PPN, and VTA functional connectivity were observed in individuals with more frequent seizures before surgery (P < .05 for each, Spearman's rho). Larger postoperative increases in PPN functional connectivity were seen in patients with lower baseline verbal IQ (P = .03, Spearman's rho) or verbal memory (P = .04, Mann-Whitney U). No changes in ARAS structural connectivity were detected after successful surgery. CONCLUSION: ARAS functional connectivity disturbances are present in TLE but may recover after successful epilepsy surgery. Larger increases in postoperative connectivity may be seen in individuals with more severe disease at baseline.

Lacosamide efficacy and tolerability in clinical practice - Post marketing analysis from a single dedicated epilepsy center.

OBJECTIVES: Post marketing analysis of anti-epileptic drug (AED) efficacy and tolerability is of great value to the clinician since it is more representative of clinical practice than clinical trial data. We analyzed our experience with lacosamide (LCM) in patients treated after marketing. PATIENTS AND METHODS: We identified all patients who were treated with LCM during the four year period after marketing, excluding patients who were in clinical trials. We recorded demographic data and analyzed efficacy and tolerability in patients who had at least one follow up visit or telephone call 3 months after the initiation of LCM. RESULTS: A total of 165 patients met our inclusion criteria. The mean age was 41 years. The majority of the cohort had focal epilepsy (146 patients) (88.4%). The mean duration of treatment was 31.2 months. Eighty one patients (49.1%) were continuing LCM at last follow up. Adverse effects (AEs) and discontinuation were significantly more common when LCM was added to one or more Na-channel blocking agents (NCB) (p = 0.0003 and 0.17). The 50% responder rate was 26% at 3 months and increased to 49% at 36 months. Patients were more likely to continue the drug and less likely to have AEs with slower titration over >4 weeks (p = 0.02 for each). Four or more previously failed AEDs predicted poorer response rate compared to three or less AEDs (p = 0.001). CONCLUSION: LCM use in clinical practice was associated with greater rate of seizure freedom than in clinical trials. Discontinuation and occurrence of AEs were significantly more likely with faster titration and adding LCM to NCB agents.

A randomized controlled trial of levodopa in patients with Angelman syndrome.

Treatment for Angelman syndrome (AS) is currently limited to symptomatic interventions. A mouse model of AS has reduced calcium/calmodulin-dependent kinase II activity due to excessive phosphorylation of specific threonine residues, leading to diminished long-term potentiation. In a rat model of Parkinson disease, levodopa reduced phosphorylation of various proteins, including calcium/calmodulin-dependent kinase II. Further studies demonstrated that AS mice treated with levodopa performed better on rotarod testing than untreated AS mice. We conducted a multi-center double-blind randomized placebo-controlled 1-year trial of levodopa / carbidopa with either 10 or 15 mg/kg/day of levodopa in children with AS. The outcome of this intervention was assessed using either the Bayley Scales of Infant Development or the Mullen Scales of Early Learning, as well as the Vineland Adaptive Behavior Scales, and the Aberrant Behavior Checklist. Of the 78 participants enrolled, 67 participants received study medication (33 on levodopa, 34 on placebo), and 55 participants (29 on levodopa, 26 on placebo) completed the 1-year study. There were no clinically or statistically significant changes in any of the outcome measures over a 1-year period comparing the levodopa and placebo groups. The number of adverse events reported, including the more serious adverse events, was similar in both groups, but none were related to treatment with levodopa. Our data demonstrate that levodopa is well-tolerated by children with AS. However, in the doses used in this study, it failed to improve their neurodevelopment or behavioral outcome.

Video-EEG results and clinical characteristics in patients with psychogenic nonepileptic spells: The effect of a coexistent epilepsy.

RATIONALE: Epilepsy and psychogenic nonepileptic spells (PNES) can coexist, often posing diagnostic and therapeutic challenges. We sought to identify clinical and historical characteristics of two groups of patients, those with coexisting epilepsy and PNES and those with PNES alone, and determine the prevalence of coexisting epilepsy/PNES with strict diagnostic criteria in a large group of epilepsy monitoring unit (EMU) patients. METHODS: We reviewed the medical records of all consecutive patients admitted to the Vanderbilt University Medical Center Adult EMU between July 1, 2007 and June 30, 2012. We identified patients with recorded PNES and classified them as having coexisting epilepsy/PNES or PNES alone and then systematically compared the clinical characteristics of these two groups. RESULTS: A total of 1567 patient medical records were reviewed. The prevalence rate of coexisting epilepsy/PNES was 5.2% among all EMU admissions (12.3% of all patients with epilepsy and 14.8% of all patients with PNES). These rates were lower when patients with interictal epileptiform activity (IEA) alone and no recorded ictal discharges were not included in the group with epilepsy (2.6%, 6.2%, and 7.4%, respectively). The accuracy of pre-EMU clinical suspicion was significantly higher in the group with PNES-only. Patients with epilepsy/PNES were significantly more likely to require more than one EMU admission for definitive diagnosis. The first PNES event preceded an epileptic seizure (ES) in 94.4% of patients with epilepsy/PNES. The group with PNES-only had significantly higher suggestibility, and the group with epilepsy/PNES had a significantly higher presence of epilepsy risk factors. Abnormal neurological examination and abnormal brain MRI were also significantly more common in the group with epilepsy/PNES. CONCLUSIONS: Our study defined the prevalence of coexisting epilepsy/PNES in a large cohort with strict diagnostic criteria and outlined specific clinical and historical characteristics differentiating the two groups of patients with coexisting epilepsy/PNES and PNES-only. These findings should help guide clinicians to reach the correct diagnosis faster and provide appropriate treatment earlier.

Development and Feasibility Testing of a Critical Care EEG Monitoring Database for Standardized Clinical Reporting and Multicenter Collaborative Research.

PURPOSE: The rapid expansion of the use of continuous critical care electroencephalogram (cEEG) monitoring and resulting multicenter research studies through the Critical Care EEG Monitoring Research Consortium has created the need for a collaborative data sharing mechanism and repository. The authors describe the development of a research database incorporating the American Clinical Neurophysiology Society standardized terminology for critical care EEG monitoring. The database includes flexible report generation tools that allow for daily clinical use. METHODS: Key clinical and research variables were incorporated into a Microsoft Access database. To assess its utility for multicenter research data collection, the authors performed a 21-center feasibility study in which each center entered data from 12 consecutive intensive care unit monitoring patients. To assess its utility as a clinical report generating tool, three large volume centers used it to generate daily clinical critical care EEG reports. RESULTS: A total of 280 subjects were enrolled in the multicenter feasibility study. The duration of recording (median, 25.5 hours) varied significantly between the centers. The incidence of seizure (17.6%), periodic/rhythmic discharges (35.7%), and interictal epileptiform discharges (11.8%) was similar to previous studies. The database was used as a clinical reporting tool by 3 centers that entered a total of 3,144 unique patients covering 6,665 recording days. CONCLUSIONS: The Critical Care EEG Monitoring Research Consortium database has been successfully developed and implemented with a dual role as a collaborative research platform and a clinical reporting tool. It is now available for public download to be used as a clinical data repository and report generating tool.

New-onset refractory status epilepticus: Etiology, clinical features, and outcome.

OBJECTIVES: The aims of this study were to determine the etiology, clinical features, and predictors of outcome of new-onset refractory status epilepticus. METHODS: Retrospective review of patients with refractory status epilepticus without etiology identified within 48 hours of admission between January 1, 2008, and December 31, 2013, in 13 academic medical centers. The primary outcome measure was poor functional outcome at discharge (defined as a score >3 on the modified Rankin Scale). RESULTS: Of 130 cases, 67 (52%) remained cryptogenic. The most common identified etiologies were autoimmune (19%) and paraneoplastic (18%) encephalitis. Full data were available in 125 cases (62 cryptogenic). Poor outcome occurred in 77 of 125 cases (62%), and 28 (22%) died. Predictors of poor outcome included duration of status epilepticus, use of anesthetics, and medical complications. Among the 63 patients with available follow-up data (median 9 months), functional status improved in 36 (57%); 79% had good or fair outcome at last follow-up, but epilepsy developed in 37% with most survivors (92%) remaining on antiseizure medications. Immune therapies were used less frequently in cryptogenic cases, despite a comparable prevalence of inflammatory CSF changes. CONCLUSIONS: Autoimmune encephalitis is the most commonly identified cause of new-onset refractory status epilepticus, but half remain cryptogenic. Outcome at discharge is poor but improves during follow-up. Epilepsy develops in most cases. The role of anesthetics and immune therapies warrants further investigation.

Non-convulsive status epilepticus and non-convulsive seizures in neurological ICU patients.

BACKGROUND: Non-convulsive seizures (NCS) or non-convulsive status epilepticus (NCSE) has been reported in 8-20 % of critically ill patient populations, and delayed diagnosis and treatment of NCSE may lead to increased mortality. This study seeks to better understand the risk factors, characteristics, and outcome of NCS/NCSE in the neurological ICU. METHODS: This is a prospective observational study, recruiting consecutive patients admitted to the adult neurological ICU with altered mental status. Patients with anoxic brain injury were excluded from the study. Data were collected and analyzed for prevalence of NCSE/NCS, EEG patterns, associated risk factors, treatment response, and final outcome. RESULTS: NCSE/NCS was detected in 21 % of 170 subjects. Clinical seizures preceded EEG diagnosis of NCSE/NCS in 25 % of cases. Significant risk factors for NCSE/NCS were a past medical history of intracranial tumor, epilepsy, or meningitis/encephalitis, or MRI evidence of encephalomalacia. Subtle clinical findings such as twitching of oral or ocular muscles and eye deviations were found on exam in 50 % of the NCSE/NCS group. Mortality was increased in NCSE cases as 31 % of NCSE/NCS patients died compared to 14 % in non-NCSE/NCS group. CONCLUSIONS: Specific clinical features along with history and imaging findings may be used to identify patients at high risk of NCSE/NCS in the neurological ICU.

Dosing feasibility and tolerability of intranasal diazepam in adults with epilepsy.

OBJECTIVE: To determine the feasibility of administering a diazepam nasal spray formulation (diazepam-NS) to adults with epilepsy during a generalized tonic-clonic seizure or in the postictal period following a tonic-clonic or other seizure type, to assess pharmacokinetics and to assess tolerability. METHODS: An open-label study was conducted in patients admitted to the epilepsy monitoring unit. Eligible patients received a single dose of diazepam-NS approximating 0.2 mg/kg. Plasma diazepam concentrations were measured serially up to 12 h postdose, and maximum observed plasma concentration (Cmax ); time to maximum concentration (Tmax ); and the area under the plasma concentration-time curve for time zero to last sampling time (AUC0-12 ) were estimated and dose-normalized. Pharmacodynamic assessments included Kaplan-Meier analysis to determine the time-to-next seizure. Safety and tolerability were assessed. RESULTS: Of the 78 patients who consented, 30 had treatment and pharmacokinetic data. Ten patients were treated during a convulsive tonic-clonic seizure, seven within 5 min following the last clonic jerk, and 13 in the postictal period ≥ 5 min after a tonic-clonic or following other seizure-types. Diazepam median Tmax was 45 min. Dose-normalized mean Cmax and AUC0-12 values of diazepam were comparable among patients regardless of the timing of diazepam-NS administration in relation to seizure. Of those treated, 65% were seizure-free during the 12-h observation period and 35% had post-dose seizures. Treatment was well tolerated, with no unexpected safety findings: 74% had mild and 25% had moderate adverse events. Nasopharyngeal signs were resolved by 12 h postdose. SIGNIFICANCE: Diazepam can be delivered in effective therapeutic concentrations by a nasal spray device during the convulsive phase of tonic-clonic seizures or in the postictal periods following tonic-clonic or other seizure types.

Cough syncope in a 43-year-old woman with glomus jugulare tumor.

We present an unusual case of recurrent cough syncope in a 43-year-old woman, which was initially thought to be seizures. Syncopal episodes were triggered by paroxysms of cough and were characterized by unresponsiveness and myoclonic jerks in her extremities. She had a left-sided glomus jugulare tumor that extended into the posterior cranial fossa with evidence of worsening communicating hydrocephalus on brain imaging. We postulate that bouts of cough produced increased intracranial pressure both by raising intrathoracic and intraabdominal pressures as well as by transient obstruction to cerebrospinal fluid flow secondary to intermittent tonsillar herniation during cough. This resulted in diffuse decrease in cerebral blood flow causing syncope. The patient's syncopal episodes decreased in frequency once an external ventricular drain was placed followed by a ventriculoperitoneal shunt. Search for factors that can increase intracranial pressure seems warranted in patients with recurrent cough syncope.

Tissue-specific variation of Ube3a protein expression in rodents and in a mouse model of Angelman syndrome.

Angelman syndrome (AS) is a neurogenetic disorder caused by loss of maternal UBE3A expression or mutation-induced dysfunction of its protein product, the E3 ubiquitin-protein ligase, UBE3A. In humans and rodents, UBE3A/Ube3a transcript is maternally imprinted in several brain regions, but the distribution of native UBE3A/Ube3a(1) protein expression has not been comprehensively examined. To address this, we systematically evaluated Ube3a expression in the brain and peripheral tissues of wild-type (WT) and Ube3a maternal knockout mice (AS mice). Immunoblot and immunohistochemical analyses revealed a marked loss of Ube3a protein in hippocampus, hypothalamus, olfactory bulb, cerebral cortex, striatum, thalamus, midbrain, and cerebellum in AS mice relative to WT littermates. Also, Ube3a expression in heart and liver of AS mice showed greater than the predicted 50% reduction relative to WT mice. Co-localization studies showed Ube3a expression to be primarily neuronal in all brain regions and present in GABAergic interneurons as well as principal neurons. These findings suggest that neuronal function throughout the brain is compromised in AS.

Roles of ubiquitination at the synapse.

The ubiquitin proteasome system (UPS) was first described as a mechanism for protein degradation more than three decades ago, but the critical roles of the UPS in regulating neuronal synapses have only recently begun to be revealed. Targeted ubiquitination of synaptic proteins affects multiple facets of the synapse throughout its life cycle; from synaptogenesis and synapse elimination to activity-dependent synaptic plasticity and remodeling. The recent identification of specific UPS molecular pathways that act locally at the synapse illustrates the exquisite specificity of ubiquitination in regulating synaptic protein trafficking and degradation events. Synaptic activity has also been shown to determine the subcellular distribution and composition of the proteasome, providing additional mechanisms for locally regulating synaptic protein degradation. Together these advances reveal that tight control of protein turnover plays a conserved, central role in establishing and modulating synapses in neural circuits.

Microscopic kinetic determinants of macroscopic currents: insights from coupling and uncoupling of GABAA receptor desensitization and deactivation.

The time course of inhibitory postsynaptic currents (IPSCs) reflects GABA(A) receptor deactivation, the process of current relaxation following transient activation. Fast desensitization has been demonstrated to prolong deactivation, and these processes have been described as being 'coupled'. However, the relationship between desensitization and deactivation remains poorly understood. We investigated the 'uncoupling' of GABA(A) receptor macroscopic desensitization and deactivation using experimental conditions that affected these two processes differently. Changing agonist affinity preferentially altered deactivation, changing agonist concentration preferentially altered macroscopic desensitization, and a pore domain mutation prolonged deactivation despite blocking fast desensitization. To gain insight into the mechanistic basis for coupling and uncoupling, simulations were used to systematically evaluate the interplay between agonist affinity, gating efficacy, and desensitized state stability in shaping macroscopic desensitization and deactivation. We found that the influence of individual kinetic transitions on macroscopic currents depended not only on model connectivity, but also on the relationship among transitions within a given model. In addition, changing single rate constants differentially affected macroscopic desensitization and deactivation, thus providing parsimonious kinetic explanations for experimentally observed uncoupling. Finally, these findings permitted development of an algorithmic framework for kinetic interpretation of experimental manipulations that alter macroscopic current properties.

Proteasome function is required to maintain muscle cellular architecture.

BACKGROUND INFORMATION: Protein degradation via the UPS (ubiquitin-proteasome system) plays critical roles in muscle metabolism and signalling pathways. The present study investigates temporal requirements of the UPS in muscle using conditional expression of mutant proteasome beta subunits to cause targeted inhibition of proteasome function. RESULTS AND CONCLUSIONS: The Drosophila GeneSwitch system was used, with analyses of the well-characterized larval somatic body wall muscles. This method acutely disrupts proteasome function and causes rapid accumulation of polyubiquitinated proteins, specifically within the muscle. Within 12 h of transgenic proteasome inhibition, there was a gross disorganization of muscle architecture and prominent muscle atrophy, progressing to the arrest of all co-ordinated movement by 24 h. Progressive muscle architecture changes include rapid loss of sarcomere organization, loss of nuclei spacing/patterning, vacuole formation and the accumulation of nuclear and cytoplasmic aggregates at the ultrastructural level. At the neuromuscular junction, the highly specialized muscle membrane folds of the subsynaptic reticulum were rapidly lost. Within 24 h after transgenic proteasome inhibition, muscles contained numerous autophagosomes and displayed highly elevated expression of the endoplasmic reticulum chaperone GRP78 (glucose-regulated protein of 78 kDa), indicating that the loss of muscle maintenance correlates with induction of the unfolded protein response. Taken together, these results demonstrate that the UPS is acutely required for maintenance of muscle and neuromuscular junction architecture, and provides a Drosophila genetic model to mechanistically evaluate this requirement.

The ubiquitin-proteasome system postsynaptically regulates glutamatergic synaptic function.

The ubiquitin-proteasome system (UPS) actively controls protein dynamics and local abundance via regulated protein degradation. This study investigates UPS' roles in the regulation of postsynaptic function and molecular composition in the Drosophila neuromuscular junction (NMJ) genetic system. To specifically impair UPS function postsynaptically, the UAS/GAL4 transgenic method was employed to drive postsynaptic expression of proteasome beta2 and beta6 subunit mutant proteins, which operate through a dominant negative mechanism to block proteasome function. When proteasome mutant subunits were constitutively expressed, excitatory junctional current (EJC) amplitudes were increased, demonstrating that postsynaptic proteasome function limits neurotransmission strength. Interestingly, the alteration in synaptic strength was calcium-dependent and miniature EJCs had significantly smaller mean amplitudes and more rapid mean decay rates. Postsynaptic levels of the Drosophila PSD-95/SAP97 homologue, discs large (DLG), and the GluRIIB-containing glutamate receptor were increased, but GluRIIA-containing receptors were unaltered. With acute postsynaptic proteasome inhibition using an inducible transgenic system, neurotransmission was similarly elevated with the same specific increase in postsynaptic GluRIIB abundance. These findings demonstrate postsynaptic proteasome regulation of glutamatergic synaptic function that is mediated through specific regulation of GluRIIB-containing glutamate receptors.