Haemarthrosis model in mice: BSS - Bleeding Severity Score assessment system.

INTRODUCTION: The prophylactic administration of clotting factor concentrate is currently the most effective strategy for the prevention of joint bleeding. As new agents with different mechanisms of action and administration schedules are developed, it will be important to study them in relevant preclinical models. AIM: The aim of this study was the standardization of a mouse haemarthrosis model in a haemophilia mouse and the development and validation of a comprehensive bleeding assessment system, the Bleeding Severity Score (BSS). METHODS AND RESULTS: Four outcome measurements were assessed, two of which, the extra-articular bleeding score and intra-articular bleeding score, were determined to be the most reliable and were summarized into a BSS which was validated using a mouse haemarthrosis variability model. CONCLUSION: Using this model, the haemostatic effect of prospective drugs can be assessed in a clinically relevant joint bleeding model and will significantly increase the value of preclinical studies.

A comparison of parallel and diverging screw angles in the stability of locked plate constructs.

We investigated the static and cyclical strength of parallel and angulated locking plate screws using rigid polyurethane foam (0.32 g/cm(3)) and bovine cancellous bone blocks. Custom-made stainless steel plates with two conically threaded screw holes with different angulations (parallel, 10° and 20° divergent) and 5 mm self-tapping locking screws underwent pull-out and cyclical pull and bending tests. The bovine cancellous blocks were only subjected to static pull-out testing. We also performed finite element analysis for the static pull-out test of the parallel and 20° configurations. In both the foam model and the bovine cancellous bone we found the significantly highest pull-out force for the parallel constructs. In the finite element analysis there was a 47% more damage in the 20° divergent constructs than in the parallel configuration. Under cyclical loading, the mean number of cycles to failure was significantly higher for the parallel group, followed by the 10° and 20° divergent configurations. In our laboratory setting we clearly showed the biomechanical disadvantage of a diverging locking screw angle under static and cyclical loading.

Spectroscopy of heliumlike argon resonance and satellite lines for plasma temperature diagnostics.

The n=2-1 spectral emission pattern of heliumlike argon, together with the associated satellite emission originating from lithiumlike argon have been measured with high-resolution x-ray spectroscopy at the Berlin electron-beam ion trap. The observed line intensity across a wide range of excitation energies was weighted by an electron-energy distribution to analyze as a function of plasma temperature the line ratios between KLL dielectronic recombination satellites, in particular the j+z, j, and k satellites, and the w-resonance line. A good agreement between various theoretical models is found, supporting the method of line-ratio measurement as a temperature diagnostic for plasmas. A value for the so-called R-line ratio is determined and calculations with the HULLAC suite of codes predict it to be electron density independent over a wide range.

Lateralized seizure termination: relationship to outcome following anterior temporal lobectomy.

Determination of side of seizure onset is critical for a successful outcome following epilepsy surgery. Little is known about the significance of lateralized seizure termination. Sustained seizure activity contralateral to side of seizure onset, following termination of ictal activity ipsilateral to side of onset, may suggest the presence of an independent focus. Such activity, if present, should predict a poor outcome. We studied side of seizure termination in 13 patients undergoing monitoring with bitemporal depth electrodes and correlated this to outcome following anterior temporal lobectomy (ATL). Side of seizure onset was determined for all seizures during that evaluation. Based on side of final cessation of ictal activity, patients were classified as having ipsilateral final termination or simultaneous termination (Group 1; N=6) or contra-lateral or mixed final termination (Group 2; N=7). The Duke outcome classification system was used. At the end of 2 years follow-up, 6/6 patients in Group 1 and 3/7 patients in Group 2 were seizure free. We conclude that lateralized seizure termination during evaluation with depth electrodes may be useful in predicting outcome following ATL. Continued seizure activity contralateral to side of seizure onset (following termination of ictal activity ipsilateral to side of onset) predicts a poor outcome. This may indicate the presence of an independent seizure focus opposite to the side of surgery.

Pharmacokinetics of levetiracetam.

Major considerations in the acceptance and impact of new antiepileptic drugs include their pharmacokinetics and their potential for interaction with other drugs. The pharmacokinetics of levetiracetam, a newly approved add-on antiepileptic agent for partial-onset seizures in adults, has been evaluated in 27 phase I and II studies. Consistent findings in these studies include rapid and complete oral absorption, linear dose kinetics, a minimal degree of protein binding, and predominantly renal excretion. Because of the lack of hepatic metabolism and low protein binding, the risk of interaction with other drugs is considered low.

Does cognitive-behavioral insomnia therapy alter dysfunctional beliefs about sleep?

STUDY OBJECTIVES: This study was conducted to exam the degree to which cognitive-behavioral insomnia therapy (CBT) reduces dysfunctional beliefs about sleep and to determine if such cognitive changes correlate with sleep improvements. DESIGN: The study used a double-blind, placebo-controlled design in which participants were randomized to CBT, progressive muscle relaxation training or a sham behavioral intervention. Each treatment was provided in 6 weekly, 30-60-minute individual therapy sessions. SETTING: The sleep disorders center of a large university medical center. PARTICIPANTS: Seventy-five individuals (ages 40 to 80 years of age) who met strict criteria for persistent primary sleep-maintenance insomnia were enrolled in this trial. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Participants completed the Dysfunctional Beliefs and Attitudes About Sleep (DBAS) Scale, as well as other assessment procedures before treatment, shortly after treatment, and at a six-month follow-up. Items composing a factor-analytically derived DBAS short form (DBAS-SF) were then used to compare treatment groups across time points. Results showed CBT produced larger changes on the DBAS-SF than did the other treatments, and these changes endured through the follow-up period. Moreover, these cognitive changes were correlated with improvements noted on both objective and subjective measures of insomnia symptoms, particularly within the CBT group. CONCLUSIONS: CBT is effective for reducing dysfunctional beliefs about sleep and such changes are associated with other positive outcomes in insomnia treatment.

Interactions between sleep and epilepsy.

Sleep is one of the best-documented factors influencing the expression of seizures and interictal discharges. Janz studied the relation between seizures and the sleep/wake cycle and divided the epilepsies into three categories: nocturnal, awakening, and diffuse. Since then, the effect of sleep on the ictal and interictal manifestations of epilepsy has been studied extensively. Many seizures are activated by sleep or arousal from sleep. Interictal discharges are also seen more commonly during sleep, with the greatest activation seen during nonrapid eye movement sleep. Sleep not only increases the frequency of epileptiform abnormalities, but also may alter their morphology and distribution. Sleep deprivation also facilitates both epileptiform abnormalities and seizures. Seizures, on the other hand, also impact sleep. Epileptic patients demonstrate multiple sleep abnormalities, including an increased sleep latency, fragmented sleep, increased awakenings and stage shifts, and an increase in stages 1 and 2 of nonrapid eye movement sleep. These disturbances may in turn be modulated by antiepileptic treatment. This review summarizes the interactions between sleep and epilepsy, including the timing of seizures during the sleep/wake cycle, the influence of sleep on various seizure disorders, the effects of sleep deprivation, and the changes in sleep patterns caused by seizures and their treatment.

Phasic and tonic coupling between EEG and EMG demonstrated with independent component analysis.

The authors describe a method for demonstrating the tonic and phasic couplings between suitably time-aligned surface eletromyographs (sEMGs) and the simultaneously recorded EEGs. The method, based on independent component analysis, was applied to data recorded from two normal subjects performing sustained submaximal contractions or continual repetitive movements of the arm. Augmented datasets, consisting of the EEG and either the sEMG from a single muscle (subject 1) or a combination of sEMGs from several muscles (subject 2), were analyzed with independent component analysis to determine the EEG/sEMG coupling. Each derived coupling consisted of a spatial distribution on the scalp and a waveform representing an EEG channel combination coactivating with the sEMG. The combinations of sEMGs, derived by applying independent component analysis to the simultaneous sEMG recordings from several muscles to create sEMG independent components (ICs), were either tonic or phasic with differing periods of activation. The topographic distributions on the scalp of the couplings between the EEG and sEMG ICs were different for each sEMG IC. The spatial distributions of the couplings between tonic sEMG ICs or single-muscle sEMGs and the EEG followed topographic patterns in sensorimotor regions. Phasic couplings were bifrontal, lateral, and bioccipital. Calculation of coherence between the sEMG ICs and calculated EEG combinations agreed well with the frequency spectra of the independent component analysis-derived coupling waveforms. These preliminary results demonstrate that detection of both the tonic and phasic coupling between the sEMG and the EEG is possible when monitoring unpaced proximal arm movement. This may thus be a practical means of exploring the dynamic cortical/muscle relationships in subjects unable to perform fine finger movements, such as patients recovering from stroke.

Cognitive behavioral therapy for treatment of chronic primary insomnia: a randomized controlled trial.

CONTEXT: Use of nonpharmacological behavioral therapy has been suggested for treatment of chronic primary insomnia, but well-blinded, placebo-controlled trials demonstrating effective behavioral therapy for sleep-maintenance insomnia are lacking. OBJECTIVE: To test the efficacy of a hybrid cognitive behavioral therapy (CBT) compared with both a first-generation behavioral treatment and a placebo therapy for treating primary sleep-maintenance insomnia. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled clinical trial conducted at a single academic medical center, with recruitment from January 1995 to July 1997. PATIENTS: Seventy-five adults (n = 35 women; mean age, 55.3 years) with chronic primary sleep-maintenance insomnia (mean duration of symptoms, 13.6 years). INTERVENTIONS: Patients were randomly assigned to receive CBT (sleep education, stimulus control, and time-in-bed restrictions; n = 25), progressive muscle relaxation training (RT; n = 25), or a quasi-desensitization (placebo) treatment (n = 25). Outpatient treatment lasted 6 weeks, with follow-up conducted at 6 months. MAIN OUTCOME MEASURES: Objective (polysomnography) and subjective (sleep log) measures of total sleep time, middle and terminal wake time after sleep onset (WASO), and sleep efficiency; questionnaire measures of global insomnia symptoms, sleep-related self-efficacy, and mood. RESULTS: Cognitive behavioral therapy produced larger improvements across the majority of outcome measures than did RT or placebo treatment. For example, sleep logs showed that CBT-treated patients achieved an average 54% reduction in their WASO whereas RT-treated and placebo-treated patients, respectively, achieved only 16% and 12% reductions in this measure. Recipients of CBT also showed a greater normalization of sleep and subjective symptoms than did the other groups with an average sleep time of more than 6 hours, middle WASO of 26.6 minutes, and sleep efficiency of 85.1%. In contrast, RT-treated patients continued to report a middle WASO of 43.3 minutes and sleep efficiency of 78.8%. CONCLUSIONS: Our results suggest that CBT represents a viable intervention for primary sleep-maintenance insomnia. This treatment leads to clinically significant sleep improvements within 6 weeks and these improvements appear to endure through 6 months of follow-up.

Slow wave sleep rebound and REM rebound following the first night of treatment with CPAP for sleep apnea: correlation with subjective improvement in sleep quality.

Objective: The purpose of this study was to correlate changes in PSG parameters between the diagnostic polysomnogram (dPSG) and the first night of treatment with continuous positive airway pressure (CPAP) (cpapPSG) to subjective improvement in sleep quality.Background: In patients with obstructive sleep apnea syndrome (OSAS), therapy with CPAP results in reduction of sleep latency, stage 1 sleep, arousal index (Al) and respiratory disturbance index (RDI), and increase in stage 2 sleep, REM sleep and REM density. No data exists on the differences in polysomnographic (PSG) parameters in patients who have subjective improvement in sleep quality and those who do not.Methods: We retrospectively reviewed PSG studies of 44 patients with OSAS who presented to the Sleep Disorders Center at Duke University Medical Center. Patient's qualitative assessment of sleep was noted using a Likert-type scale administered the morning after the dPSG and cpapPSG. PSG indices of patients noting subjective improvement were compared to those with no improvement.Results: Patients noting a subjective improvement in sleep quality showed a decrease in the percentages of stage 1 sleep (P<0.001) and an increase in percentages of stages 3 and 4 sleep (slow wave sleep rebound; P<0.007) and stage REM sleep (REM rebound; P<0.008).

Periventricular nodular heterotopia in patients with filamin-1 gene mutations: neuroimaging findings.

BACKGROUND: The filamin-1 (FLN-1) gene is responsible for periventricular nodular heterotopia (PNH), which is an X-linked dominant neuronal migration disorder. OBJECTIVE: To review the clinical and imaging findings in a series of patients with documented filamin-1 mutations. MATERIALS AND METHODS: A retrospective review of the medical records and MR studies of a series of patients with PNH and confirmed FLN-1 mutations was done. There were 16 female patients (age range: .67-71 years; mean = 28.6) with filamin-1 gene mutations. RESULTS: In six of the patients the same mutation was inherited in four generations in one pedigree. In a second pedigree, a distinct mutation was found in two patients in two generations. In a third pedigree, a third mutation was found in four patients in two generations. The remaining four patients had sporadic de novo mutations that were not present in the parents. Ten patients had seizures, and all patients had normal intelligence. In all 16 patients MR demonstrated bilateral near-continuous PNH. There were no consistent radiographic or clinical differences between patients carrying different mutations. CONCLUSION: Patients with confirmed FLN-1 gene mutations are usually female and have a distinctive MR pattern of PNH. Other female patients with this same MR pattern probably harbor FLN-1 mutations and risk transmission to their progeny. This information is important for genetic counseling.

Measurement of the radiative cooling rates for high-ionization species of krypton using an electron beam ion trap

We describe a measurement of the radiative cooling rate for krypton made at the Berlin electron beam ion trap (EBIT). The EBIT was tuned to a charge-state distribution approaching the ionization balance of a plasma at a temperature of about 5 keV. To determine the cooling rate, we made use of EBIT's capabilities to sample a wide range of electron-beam energies and distinguish between different radiation channels. We have measured the x-ray emission from bremsstrahlung, radiative recombination, dielectronic recombination, and line radiation following electron-impact excitation. The dominant contribution to the cooling rate is made by the n=3-2, n=4-2, ellipsis x rays of the L-shell spectra of krypton, which produce more than 75% of the total radiation loss. A difference with theoretical calculations is noted for the measured total cooling rate. The predicted values are lower by a factor of 1.5-2, depending on the theoretical model. For our measurement of the cooling rate, we estimate an uncertainty interval of 22-30 %.

Characteristics of valproic acid resistant juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is often exquisitely responsive to treatment with valproic acid (VPA). However, a subset of patients does not respond to this medication and often has intractable seizures. We wanted to identify differences between these two subsets of JME patients. Charts of all JME patients followed at the Duke Epilepsy Center were reviewed. Clinical parameters, electroencephalogram (EEG) findings and magnetic resonance imaging (MRI) data were reviewed. These features were compared between patients with VPA sensitive and VPA resistant JME. Thirty-three patients with JME were identified: 23 (70%) were VPA sensitive (13 females, 10 males; mean age of onset 15.9 years) and 10 (30%) were VPA resistant (5 females, 5 males; mean age of onset 14.1 years). The VPA resistant group had a higher frequency of EEG asymmetries (40% vs. 10%); atypical seizure characteristics including auras and post-ictal confusion (30% vs. 4%); and intellectual deficiency (20% vs. 0%). Clinical characteristics combined with EEG data may help in predicting which JME patients will respond favorably to VPA. This study also raises the issue whether VPA resistant JME is in fact a localization-related epilepsy.

Inhibitory simple partial (non-convulsive) status epilepticus after intracranial surgery.

OBJECTIVES: To report on five patients who developed, 2 to 4 days after an intracranial neurosurgical procedure, new, persistent, focal neurological deficits which were due to inhibitory simple partial (non-convulsive) status epilepticus, and resolved with anticonvulsant treatment. METHODS: The age range of the five patients was 15-74 years. The operations were: aneurysm clipping (three patients) and resections of an oligodendroglioma and a cavernous haemangioma (one patient each). The new focal deficits were: right hemiparesis and aphasia (two patients), aphasia alone (two patients), and left hemiparesis (one patient). The deficits were not explained by CT (obtained in all patients) or cerebral angiography (performed in two). RESULTS: Electroencephalography showed, in all patients, continuous or intermittent focal seizures arising from cortex regionally relevant to the clinical dysfunction. Subtle positive epileptic phenomena (jerking) occurred intermittently in three patients as a late concommitant. Administration of anticonvulsant drugs resulted in significant improvement within 24 hours in four patients, with parallel resolution of ictal EEG activity. The fifth patient improved more slowly. Two patients relapsed when anticonvulsant concentrations fell, and improved again when they were raised. CONCLUSIONS: It is suggested that inhibitory simple partial (non-convulsive) status epilepticus be considered in the differential diagnosis when a new unexplained neurological deficit develops after an intracranial neurosurgical procedure. An EEG may help to diagnose this condition, leading to definitive treatment.

Improved sexual function in three men taking lamotrigine for epilepsy.

Little information exists about the effects of newer antiepileptic drugs (AEDs) on sexual function in men with epilepsy. We report a series of three male veterans whose sexual disorders improved with lamotrigine. All three had partial seizures. One patient was taking phenobarbital and gabapentin and complained of decreased potency and anorgasmia. After lamotrigine was added for better seizure control and the dosage of gabapentin was tapered, anorgasmia improved. The second patient complained of impotence after a rash while taking phenytoin and carbamazepine. Impotence persisted with phenobarbital, valproate, and gabapentin. Eight months after gabapentin was replaced with lamotrigine, impotence improved. The third patient complained of long-standing impotence. Treatment with five AEDs had no effect on the dysfunction. Lamotrigine was added to the carbamazepine regimen; impotence improved with decrease in carbamazepine and increase in lamotrigine. The favorable effect of lamotrigine on sexual disorders in these three patients suggests this drug should be considered under appropriate circumstances for men who have sexual dysfunction while taking other antiepileptic agents.

Seizure outcome after temporal lobectomy for temporal lobe epilepsy: a Kaplan-Meier survival analysis.

OBJECTIVE: To determine seizure outcome and its predictors in patients with medically refractory temporal lobe epilepsy (TLE) after temporal lobectomy (TL). BACKGROUND: TL is the most common surgical procedure performed in adolescents and adults for the treatment of medically refractory TLE. Seizure outcome has been reported extensively during the first few postoperative years, but little is known beyond that time. METHODS: The authors analyzed seizure outcome in 79 patients who underwent TL for epilepsy at the Duke University Medical Center from 1962 through 1984. Patients with less than 2 years of follow-up and degenerative disorders were excluded. Predictors of seizure outcome were analyzed using Kaplan-Meier survival analyses. RESULTS: The mean follow-up was 14 years (range, 2.1 to 33.6 years). Using Engel's classification, 65% of patients were class I, 15% were class II, 11% were class III, and 9% were class IV. At least one postoperative seizure occurred in 55% of subjects. The majority of recurrences (86%) took place within 2 years of surgery. Later recurrences tended not to lead to medical intractability. Higher monthly preoperative seizure frequency was associated with poor seizure outcome. A seizure-free state at 2 years was found to be a better predictor of long-term outcome than the 6-, 12-, and 18-month landmarks. CONCLUSIONS: TL provides sustained, long-term benefit in patients with medically refractory TLE. Seizure-free status at 2 years from the time of surgery is predictive of long-term remission.

A case of sustained massive gabapentin overdose without serious side effects.

Gabapentin is an antiepileptic agent that is indicated for use as adjunctive therapy for partial seizures. It has a relatively benign side effect profile, but little data exists on massive overdoses with this agent. The authors present a case of a patient who received a massive overdose of this agent but suffered no clinically significant toxicity.

Lamotrigine-induced blepharospasm.

Movement disorders such as tremor and ataxia occur commonly during therapy with antiepileptic drugs (AEDs). Dystonias, however, are rare. Blepharospasm, although reported with neuroleptic agents, has never been reported with AEDs. Our patient developed blepharospasm during therapy with lamotrigine.

Succinylcholine induced hyperkalemia and cardiac arrest death related to an EEG study.

Changes in EEGs during cardiac arrest have been described in detail by many authors; however, mortality because of an EEG has never been reported. The authors report the case of a patient who developed cardiac arrest causally related to administration of succinylcholine for reduction of excessive amounts of myogenic artifact during an EEG. This case indicates the need for caution when doing an EEG study in an intensive care unit setting.