Cognitive Training With Head-Mounted Display Virtual Reality in Neurorehabilitation: Pilot Randomized Controlled Trial.

BACKGROUND: Neurological rehabilitation is technologically evolving rapidly, resulting in new treatments for patients. Stroke, one of the most prevalent conditions in neurorehabilitation, has been a particular focus in recent years. However, patients often need help with physical and cognitive constraints, whereby the cognitive domain in neurorehabilitation does not technologically exploit existing potential. Usually, cognitive rehabilitation is performed with pen and paper or on a computer, which leads to limitations in preparation for activities of daily living. Technologies such as virtual reality (VR) can bridge this gap. OBJECTIVE: This pilot study investigated the use of immersive VR in cognitive rehabilitation for patients undergoing inpatient neurorehabilitation. The goal was to determine the difference in rehabilitation effectiveness between a VR serious game that combines everyday activities with cognitive paradigms and conventional computerized cognitive training. We hypothesized the superiority of the VR serious game regarding cognitive abilities and patient-reported outcomes as well as transfer to daily life. METHODS: We recruited 42 patients with acute brain affection from a German neurorehabilitation clinic in inpatient care with a Mini Mental Status Test score >20 to participate in this randomized controlled trial. Participants were randomly assigned to 2 groups, with 1 receiving the experimental VR treatment (n=21). VR training consisted of daily life scenarios, for example, in a kitchen, focusing on treating executive functions such as planning and problem-solving. The control group (n=21) received conventional computerized cognitive training. Each participant received a minimum of 18 treatment sessions in their respective group. Patients were tested for cognitive status, subjective health, and quality of life before and after the intervention (Alters-Konzentrations-Test, Wechsler Memory Scale-Revised, Trail Making Test A and B, Tower of London-German version, Short Form 36, European Quality of Life 5 Dimensions visual analog scale, and Fragebogen zur Erfassung der Performance in VR). RESULTS: Repeated-measures ANOVA revealed several significant main effects in the cognitive tests: Tower of London-German version (P=.046), Trail Making Test A (P=.01), and Wechsler Memory Scale-Revised (P=.006). However, post hoc tests revealed that the VR group showed significant improvement in the planning, executive control, and problem-solving domains (P=.046, Bonferroni P=.02). In contrast, no significant improvement in the control group between t0 and t1 was detected (all P>.05). Furthermore, a nonsignificant trend was observed in visual speed in the VR group (P=.09, Bonferroni P=.02). CONCLUSIONS: The results of this pilot randomized controlled trial showed that immersive VR training in cognitive rehabilitation had greater effectiveness than the standard of care in treating patients experiencing stroke in some cognitive domains . These findings support the further use and study of VR training incorporating activities of daily living in other neurological disorders involving cognitive dysfunction. TRIAL REGISTRATION: Federal Registry of Clinical Trials of Germany (DRKS) DRKS00023605; https://drks.de/search/de/trial/DRKS00023605.

Reactive Exercises with Interactive Objects: Interim Analysis of a Randomized Trial on Task-Driven NMES Grasp Rehabilitation for Subacute and Early Chronic Stroke Patients.

Enriched environments and tools are believed to promote grasp rehabilitation after stroke. We designed S2, an interactive grasp rehabilitation system consisting of smart objects, custom orthoses for selective grasp constraining, and an electrode array system for forearm NMES. Motor improvements and perceived usability of a new enriched upper limb training system for sub-acute stroke patients was assessed in this interim analysis. INCLUSION CRITERIA: sub-acute stroke patients with MMSE>20, ipsilesional MI>80%, and contralesional MI<80%. Effects of 30-min therapy supplements, conventional vs. S2 prototype, are compared through a parallel two-arms dose-matched open-label trial, lasting 27 sessions. Clinical centres: Asklepios Neurologische Klinik Falkenstein, Königstein im Taunus, Germany, and Clinica Villa Beretta, Costa Masnaga, Italy. Assessment scales: ARAT, System Usability, and Technology Acceptance. METHODOLOGY: 26 participants were block randomized, allocated to the study (control N=12, experimental N=14) and underwent the training protocol. Among them, 11 participants with ARAT score at inclusion below 35, n = 6 in the experimental group, and n = 5 in the control group were analysed. RESULTS: participants in the enriched treatment group displayed a larger improvement in the ARAT scale (+14.9 pts, pval=0.0494). Perceived usability differed between clinics. No adverse effect was observed in relation to the treatments. Trial status: closed. CONCLUSIONS: The S2 system, developed according to shared clinical directives, was tested in a clinical proof of concept. Variations of ARAT scores confirm the feasibility of clinical investigation for hand rehabilitation after stroke.

A Robotic System with EMG-Triggered Functional Eletrical Stimulation for Restoring Arm Functions in Stroke Survivors.

BACKGROUND: Robotic systems combined with Functional Electrical Stimulation (FES) showed promising results on upper-limb motor recovery after stroke, but adequately-sized randomized controlled trials (RCTs) are still missing. OBJECTIVE: To evaluate whether arm training supported by RETRAINER, a passive exoskeleton integrated with electromyograph-triggered functional electrical stimulation, is superior to advanced conventional therapy (ACT) of equal intensity in the recovery of arm functions, dexterity, strength, activities of daily living, and quality of life after stroke. METHODS: A single-blind RCT recruiting 72 patients was conducted. Patients, randomly allocated to 2 groups, were trained for 9 weeks, 3 times per week: the experimental group performed task-oriented exercises assisted by RETRAINER for 30 minutes plus ACT (60 minutes), whereas the control group performed only ACT (90 minutes). Patients were assessed before, soon after, and 1 month after the end of the intervention. Outcome measures were as follows: Action Research Arm Test (ARAT), Motricity Index, Motor Activity Log, Box and Blocks Test (BBT), Stroke Specific Quality of Life Scale (SSQoL), and Muscle Research Council. RESULTS: All outcomes but SSQoL significantly improved over time in both groups (P < .001); a significant interaction effect in favor of the experimental group was found for ARAT and BBT. ARAT showed a between-group change of 11.5 points (P = .010) at the end of the intervention, which increased to 13.6 points 1 month after. Patients considered RETRAINER moderately usable (System Usability Score of 61.5 ± 22.8). CONCLUSIONS: Hybrid robotic systems, allowing to perform personalized, intensive, and task-oriented training, with an enriched sensory feedback, was superior to ACT in improving arm functions and dexterity after stroke.

National Institutes of Health Stroke Scale (NIHSS) on admission predicts acute symptomatic seizure risk in ischemic stroke: a population-based study involving 135,117 cases.

The National Institutes of Health Stroke Scale (NIHSS) score is the most frequently used score worldwide for assessing the clinical severity of a stroke. Prior research suggested an association between acute symptomatic seizures after stroke and poorer outcome. We determined the frequency of acute seizures after ischemic stroke in a large population-based registry in a central European region between 2004 and 2016 and identified risk factors for acute seizures in univariate and multivariate analyses. Additionally, we determined the influence of seizures on morbidity and mortality in a matched case-control design. Our analysis of 135,117 cases demonstrated a seizure frequency of 1.3%. Seizure risk was 0.6% with an NIHSS score at admission <3 points and increased up to 7.0% with >31 score points. Seizure risk was significantly higher in the presence of acute non-neurological infections (odds ratio: 3.4; 95% confidence interval: 2.8-4.1). A lower premorbid functional level also significantly increased seizure risk (OR: 1.7; 95%CI: 1.4-2.0). Mortality in patients with acute symptomatic seizures was almost doubled when compared to controls matched for age, gender, and stroke severity. Acute symptomatic seizures increase morbidity and mortality in ischemic stroke. Their odds increase with a higher NIHSS score at admission.

Could the 2017 ILAE and the four-dimensional epilepsy classifications be merged to a new "Integrated Epilepsy Classification"?

Over the last few decades the ILAE classifications for seizures and epilepsies (ILAE-EC) have been updated repeatedly to reflect the substantial progress that has been made in diagnosis and understanding of the etiology of epilepsies and seizures and to correct some of the shortcomings of the terminology used by the original taxonomy from the 1980s. However, these proposals have not been universally accepted or used in routine clinical practice. During the same period, a separate classification known as the "Four-dimensional epilepsy classification" (4D-EC) was developed which includes a seizure classification based exclusively on ictal symptomatology, which has been tested and adapted over the years. The extensive arguments for and against these two classification systems made in the past have mainly focused on the shortcomings of each system, presuming that they are incompatible. As a further more detailed discussion of the differences seemed relatively unproductive, we here review and assess the concordance between these two approaches that has evolved over time, to consider whether a classification incorporating the best aspects of the two approaches is feasible. To facilitate further discussion in this direction we outline a concrete proposal showing how such a compromise could be accomplished, the "Integrated Epilepsy Classification". This consists of five categories derived to different degrees from both of the classification systems: 1) a "Headline" summarizing localization and etiology for the less specialized users, 2) "Seizure type(s)", 3) "Epilepsy type" (focal, generalized or unknown allowing to add the epilepsy syndrome if available), 4) "Etiology", and 5) "Comorbidities & patient preferences".

Acute symptomatic seizures in intracerebral and subarachnoid hemorrhage: A population study of 19,331 patients.

BACKGROUND: Risk factors for acute symptomatic seizures after stroke demonstrated in retrospective analyses should be confirmed in large population studies. While seizures following ischemic stroke have been studied intensively, less is known about seizure predictors in hemorrhagic stroke. This study sought to identify risk factors of acute symptomatic seizures and to elucidate associated short-term (in-hospital) morbidity and mortality rates in primary intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). METHODS: We determined the frequency of all acute symptomatic seizures perceived by clinical staff after hemorrhagic stroke in a large population-based registry in a central European region between 2004 and 2016. Further, we analyzed risk factors for seizure occurrence, morbidity, and mortality in univariate and multivariate analyses. RESULTS: Of 297,120 stroke patients, 19,331 experienced a hemorrhagic stroke. Frequency of acute seizures (without semiological differentiation) in this subpopulation was 4% (4.0% in ICH and 3.6% in SAH). The risk for acute symptomatic seizures was significantly increased in both stroke types in the presence of an acute non-neurological infection (odds ratio: 2.0 for ICH and 4.2 for SAH). A lower premorbid functional level also significantly increased the seizure risk (odds ratio: 2.0 for ICH and 3.1 for SAH). The odds of in-hospital mortality in the presence of acute seizures were significantly reduced in ICH patients (odds ratio: 0.7) but not in SAH patients. CONCLUSION: Acute symptomatic seizures are equally common in ICH and SAH patients in this registry. Seizure risk is invariably increased in the presence of acute non-neurological infection. Mortality is reduced in ICH patients with seizures, but the exact reason for this relationship is not clear and might represent a biased finding.

Effects of a robot intervention on visuospatial hemineglect in postacute stroke patients: a randomized controlled trial.

OBJECTIVE: To evaluate the effects of an intervention using the robot device PARO on visuospatial hemineglect and activities of daily living, and its acceptance during stroke rehabilitation. PARO is an interactive robotic toy with the appearance of a baby seal, which can move, produce sounds, and react to speech and touch. DESIGN: A randomized controlled trial. SETTING: Hospital for neurorehabilitation. SUBJECTS: Patients above 60 years old who have suffered their first stroke within the previous three months with left hemineglect (n = 39). INTERVENTIONS: The PARO group (n = 21) was exposed to PARO over a period of two weeks, three times per week. The participants of the control group (n = 18) were read to aloud. OUTCOME MEASURE: Visuospatial hemineglect was measured by a cancellation test and a Line Bisection Test, and independence in the activities of daily living was assessed by Scores of Independence Index for Neurological and Geriatric Rehabilitation (SINGER) test. The acceptance of PARO was also evaluated. Data were collected blinded at three times: baseline (T0), after two weeks of interventions (T1), and after additional two weeks as follow-up (T2). RESULTS: Improvement of hemineglect at T1 and T2 was significantly higher in the PARO group (T1: mean (SD) = 6.23 (3.81); T2: mean (SD) = 7.85 (3.68)) compared to the control group (T1: mean (SD) = 2.66 (4.19); T2: mean (SD) = 3.33 (4.16)) (T1: P < 0.05; T2: P < 0.05). CONCLUSION: The study showed that the use of the PARO is well accepted and can help to improve neglect symptoms in patients with subacute stroke.

A Hybrid Robotic System for Arm Training of Stroke Survivors: Concept and First Evaluation.

OBJECTIVE: To develop and evaluate a hybrid robotic system for arm recovery after stroke, combining ElectroMyoGraphic (EMG)-triggered functional electrical stimulation (FES) with a passive exoskeleton for upper limb suspension. METHODS: The system was used in a structured exercise program resembling activities of daily life. Exercises execution was continuously controlled using angle sensor data and radio-frequency identification technology. The training program consisted of 27 sessions lasting 30 min each. Seven post-acute stroke patients were recruited from two clinical sites. The efficacy of the system was evaluated in terms of action research arm test, motricity index, motor activity log, and box & blocks tests. Furthermore, kinematics-based and EMG-based outcome measures were derived directly from data collected during training sessions. RESULTS: All patients showed an improvement of motor functions at the end of the training program. After training, the exercises were in most cases executed faster, smoother, and with an increased range of motion. Subjects were able to trigger FES, but in some cases, they did not maintain the voluntary effort during task execution. All subjects but one considered the system usable. CONCLUSION: The preliminary results showed that the system can be used in a clinical environment with positive effects on arm functional recovery. However, only the final results of the currently ongoing clinical trial will unveil the system's full potential. SIGNIFICANCE: The presented hybrid robotic system is highly customizable, allows to monitor the daily performance, requires low supervision of the therapist, and might have the potential to enhance arm recovery after stroke.

Synergy effects of combined multichannel EMG-triggered electrical stimulation and mirror therapy in subacute stroke patients with severe or very severe arm/hand paresis.

BACKGROUND: Neurorehabilitation requires the development of severity-dependent and successful therapies for arm/hand rehabilitation in stroke patients. OBJECTIVE: To evaluate the effectiveness of adding mirror therapy to bilateral EMG-triggered multi-channel electrostimulation for the treatment of severe arm/hand paresis in stroke patients. METHODS: The subjects of this randomized, controlled, multicentre study were stroke patients who had suffered their first insult between 1 and 6 months before study start and had severe or very severe arm/hand paresis, as classified by Fugl-Meyer-Assessment. Subjects were randomly allocated to an intervention group (n = 16) or control group (n = 17). Both groups were treated for 3 weeks (5x week, 30 minutes) with bilateral EMG-triggered multi-channel electrostimulation. The intervention group additionally received mirror feedback of the unaffected limb. The primary outcome measure was motor recovery of the upper extremities, as measured by the Fugl-Meyer Assessment. RESULTS: The Intervention Group with very severe paresis had significantly better motor recovery in total Fugl-Meyer Assessment (p = 0.017) at a medium effect size (Cohen) of d = 0.7, due to a significant recovery of shoulder and elbow function (p = 0.003) in the Fugl-Meyer Assessment Part A subtest. For subjects with severe paresis, additional mirror therapy did not significantly influence outcome. CONCLUSION: Additional mirror therapy in combination with EMG-triggered multi-channel electrostimulation is therapeutically beneficial for post-acute stroke patients with very severe arm/hand paresis.

Effects of training with the ReWalk exoskeleton on quality of life in incomplete spinal cord injury: a single case study.

It is a single case study. An investigation to what extent the quality of life (QoL) of patients with spinal cord injury can be influenced by the training with an exoskeleton. The study was carried out at a Hospital for neurological rehabilitation, Germany. One patient (male, 22 years), initially unable to walk independently after traumatic spinal cord injury with neurological level Th11 (ASIA Impairment Scale C) was recruited for this study 1 year after injury. The progress of the first 6 months of ReWalk training was documented and as primary outcome measure the QoL was measured with SF-36 questionnaire. Secondary outcome measures were ASIA scale, Berg-Balance-Scale and Dynamic Gait Index. At the end of the studyperiod the patient was able to walk independently supervised by one person. QoL, mobility, risk of falling, motor skills and control of bladder and bowel functions were improved. A positive effect of robot-assisted gait training on various areas of the QoL was shown. Subsequent studies should aim to verify this effect through a higher number of patients and to different injury levels.

Effects of an aquatic therapy approach (Halliwick-Therapy) on functional mobility in subacute stroke patients: a randomized controlled trial.

OBJECTIVE: To evaluate the effects of an aquatic physiotherapy method (Halliwick-Therapy) upon mobility in the post-acute phase of stroke rehabilitation. DESIGN: Randomized controlled trial. SETTING: Hospital for neurological rehabilitation. PARTICIPANTS: Adult patients after first-ever stroke in post-acute inpatient rehabilitation at least two weeks after the onset of stroke (n = 30). INTERVENTIONS: In the Halliwick-Therapy group (n = 14) the treatment over a period of two weeks included 45 minutes of aquatic therapy three times per week and a conventional physiotherapeutic treatment twice a week. Subjects in the control group (n = 16) received conventional physiotherapeutic treatment over a period of two weeks five times per week. OUTCOME MEASURES: The primary outcome variable was postural stability (Berg Balance Scale). Secondary outcome variables were functional reach, functional gait ability and basic functional mobility. RESULTS: Compared to the control group, significantly more subjects in the Halliwick-Therapy group (83.3% versus 46.7%) attained significant improvement of the Berg Balance Scale (P < 0.05). Improvement of the functional gait ability was significantly higher in the Halliwick-Therapy group (mean (SD) 1.25(0.86)) than in the control group (mean (SD) 0.73 (0.70)) (P < 0.1). The mean differences of improvements in functional reach and basic functional mobility were not statistically significant between groups. CONCLUSIONS: This study indicates that Halliwick-Therapy is safe and well tolerated in stroke patients in post-acute rehabilitation and has positive effects upon some aspects of mobility.

Predictors of acute poststroke seizures.

BACKGROUND: In this study, we tried to identify predictors of acute poststroke seizures (aPSS) in stroke patients. METHODS: We analyzed a large prospective hospital-based stroke registry in Germany. 58,874 patients with the diagnosis of transient ischemic attack (TIA), ischemic stroke (IS) or intracerebral hemorrhage (ICH) were admitted within 24 h after symptom onset. Predictors for aPSS were identified using multivariate regression analysis adjusted for age, gender, stroke severity, vascular risk factors, acute nonneurologic infection, history of TIA and length of hospital stay. RESULTS: aPSS occurred in 0.7% of patients with TIA (mean duration of hospitalization 8 days), in 2.2% of patients with IS (12 days) and in 5.1% of patients with ICH (13 days). A lower age, a higher stroke severity, acute nonneurologic infection, a history of diabetes mellitus and a history of preceding TIA were identified to be independent predictors of aPSS in IS, whereas younger age, acute infection and a history of TIA were found predictive for aPSS in ICH. CONCLUSIONS: This study characterized so far unknown predictors of aPSS and may help to improve the identification of patients with a high risk of aPSS.

Effects of antiepileptic drugs on associative LTP-like plasticity in human motor cortex.

Antiepileptic drugs (AEDs) are used extensively in clinical practice but relatively little is known on their specific effects at the systems level of human cortex. Here we tested, using a double-blind randomized placebo-controlled crossover design in healthy subjects, the effects of a single therapeutic oral dose of seven AEDs with different modes of action (tiagabine, diazepam, gabapentin, lamotrigine, topiramate, levetiracetam and piracetam) on long-term potentiation (LTP)-like motor cortical plasticity induced by paired associative transcranial magnetic stimulation (PAS). PAS-induced LTP-like plasticity was assessed from the increase in motor evoked potential amplitude in a hand muscle contralateral to the stimulated motor cortex. Levetiracetam significantly reduced LTP-like plasticity when compared to the placebo condition. Tiagabine, diazepam, lamotrigine and piracetam resulted in nonsignificant trends towards reduction of LTP-like plasticity while gabapentin and topiramate had no effect. The particularly depressant effect of levetiracetam is probably explained by its unique mode of action through binding at the vesicle membrane protein SV2A. Enhancement of gamma-amino butyric acid-dependent cortical inhibition by tiagabine, diazepam and possibly levetiracetam, and blockage of voltage-gated sodium channels by lamotrigine, may also depress PAS-induced LTP-like plasticity but these mechanisms appear to be less relevant. Findings may inform about AED-related adverse effects on important LTP-dependent central nervous systems processes such as learning or memory formation. The particular depressant effect of levetiracetam on LTP-like plasticity may also relate to the unique properties of this drug to inhibit epileptogenesis, a potentially LTP-associated process.

Arousal thresholds during human tonic and phasic REM sleep.

The goal of the present study was to investigate arousal thresholds (ATs) in tonic and phasic episodes of rapid eye movement (REM) sleep, and to compare the frequency spectrum of these sub-states of REM to non-REM (NREM) stages of sleep. We found the two REM stages to differ with regard to behavioural responses to external acoustic stimuli. The AT in tonic REM was indifferent from that in sleep stage 2, and ATs in phasic REM were similar to those in slow-wave sleep (stage 4). NREM and REM stages of similar behavioural thresholds were distinctly different with regard to their frequency pattern. These data provide further evidence that REM sleep should not be regarded a uniform state. Regarding electroencephalogram frequency spectra, we found that the two REM stages were more similar to each other than to NREM stages with similar responsivity. Ocular activity such as ponto-geniculo-occipital-like waves and microsaccades are discussed as likely modulators of behavioural responsiveness and cortical processing of auditory information in the two REM sub-states.

Imaging epileptic activity using functional MRI.

This review concentrates on functional MRI (fMRI) methods to identify the epileptic focus, i.e. ictal and interictal fMRI. First, established clinical applications of fMRI in the field of epilepsy are briefly introduced: fMRI of sensorimotor, language and memory function can already be considered as clinically relevant tools to identify the eloquent cortex and to predict postoperative functional deficits in patients considered for epilepsy surgery. fMRI offers a valid alternative to invasive methods like the Wada test for establishing language dominance, and it is likely that it will also replace the Wada test for assessing presurgical memory function in the nearer future. Ictal fMRI (fMRI studies of epileptic seizures) will remain confined to exceptional cases due to practical limitations. The generators of interictal epileptiform discharges (IED) can be studied with EEG-correlated fMRI. Despite its technical challenges, it has proved useful to provide insights into the generation of IED in patients with focal and generalized epilepsy. In selected patients with focal IED, EEG-correlated fMRI has the potential to reproducibly identify cortical areas involved in generating IED, i.e. the irritative zone. In patients with generalizes IED, suspension of functional networks due to the IED can be demonstrated. The utility of EEG-correlated fMRI in clinical epileptology cannot be definitely determined yet.

Intraoperative ultrasound to define focal cortical dysplasia in epilepsy surgery.

Focal cortical dyplasia (FCD) is a frequent cause of medication-resistant focal epilepsy. Patients with FCD may benefit from epilepsy surgery. However, it is difficult to intraoperatively define lesion boundaries. In this case report we present a novel tool to identify FCD intraoperatively. A patient with frontal lobe epilepsy underwent resection of a left frontomesial FCD. Image guidance was achieved by intraoperative ultrasound, which depicted the lesion with a higher resolution than preoperative MRI. Postoperatively the patient remained seizure free. Intraoperative ultrasound may be helpful in identifying and targeting subtle epileptogenic lesions, which are difficult to visualize.

fMRI correlates of interictal epileptic activity in patients with idiopathic benign focal epilepsy of childhood. A simultaneous EEG-functional MRI study.

EEG-correlated fMRI (EEG/fMRI) can identify alterations of brain function associated with interictal epileptiform discharges (IED). fMRI activation can localize the irritative zone and indicate functional disturbance distant from the spike focus. This might be of particular interest in paediatric epilepsy syndromes with frequent IED. Using simultaneous EEG/fMRI in a 3T MR scanner we studied blood oxygen level-dependent (BOLD) signal changes related to spontaneous IED in 10 children with typical and atypical benign focal epilepsy of childhood (BFE) or benign epileptic activity of childhood (BEAC). EEG artefacts were subtracted offline and IED were used as regressors for event-related fMRI analysis in SPM2. In four of the seven children with IED during EEG/fMRI we found IED related positive and negative signal changes (p<0.001, uncorrected). In three children we found only significant negative signal changes. At a more liberal threshold (p<0.05, uncorrected) these three children had positive signal changes congruent with the four children with significant positive signal changes. In summary, we found positive or negative signal changes in perisylvian, central, premotor and prefrontal regions. One child showed additional bilateral occipital fMRI activation. In addition to former reports our results indicated that frontal brain areas are functionally disturbed during IED corresponding to general neuropsychological findings in BFE and BEAC. We conclude that using EEG/fMRI it might be possible to localize generators of IED and functionally disturbed brain regions in children with BFE. Further studies are required to differentiate between BFE subtypes and to identify fMRI signatures of specific syndromes or corresponding neuropsychological deficits.

Sleep improvement in an insomniac patient with global pituitary insufficiency after change from triple to quadruple cortisol replacement therapy.

Although cortisol has a distinct circadian rhythm, patients with adrenal insufficiency usually receive diurnal hydrocortisone replacement therapy (HRT), disregarding possible consequences for sleep quality. The case reported here concerns the resolution of severe insomnia in a patient with global hypopituitary insufficiency upon adjustment of triple HRT to quadruple HRT. The data show a strong influence of cortisol on total sleep time and slow wave sleep (SWS) as well as rapid eye movement (REM) sleep. Clinically, the data are suggestive of the need to assimilate HRT to the natural circadian cortisol rhythm and not restrict it to the active part of the day.

Levetiracetam intravenous infusion as an alternative to oral dosing in patients with partial-onset seizures.

PURPOSE: This multicenter, open-label study evaluated the short-term tolerability of intravenously (IV)-infused levetiracetam (LEV; 500-1,500 mg/100 ml, 15 min, b.i.d.) as a substitute for the same oral dose. METHODS: The study consisted of screening, 4-day IV LEV and 1-7 days of follow-up, and was conducted in 25 adults with partial-onset seizures receiving adjunctive oral LEV. RESULTS: During the 4-day IV LEV, 11 (44%) subjects experienced at least one treatment-emergent adverse event (TEAE), with headache and fatigue being the most frequently reported. Five (20%) subjects experienced TEAEs considered to be related to the study drug. The tolerability profile was consistent with that of oral LEV, with all events judged mild or moderate in severity, no discontinuations, and no serious AEs or deaths reported. No AE related to seizure worsening was reported during IV LEV or brief follow-up. CONCLUSIONS: LEV IV appears to be a well-tolerated, practical alternative in patients with partial-onset seizures temporarily unable to take the drug orally.