The apoE-mimetic peptide, COG1410, improves functional recovery in a murine model of intracerebral hemorrhage.

BACKGROUND: Apolipoprotein E has previously been demonstrated to modulate acute brain injury responses, and administration of COG1410, an apoE-mimetic peptide derived from the receptor-binding region of apoE, improves outcome in preclinical models of acute neurological injury. In the current study, we sought to establish the optimal dose and timing of peptide administration associated with improved functional outcome in a murine model of intracerebral hemorrhage (ICH). METHODS: Ten to twelve-week-old C57/BL6 male mice were injured by collagenase-induced ICH and randomly selected to receive either vehicle or one of four doses of COG1410 (0.5, 1, 2, or 4 mg/kg) via tail vein injection at 30 min after injury and then daily for 5 days. The injured mice were euthanized at various time points to assess inflammatory mediators, cerebral edema, and hematoma volume. Over the first 5 days following injury, vestibulomotor function was tested via Rotorod (RR) latency. After an optimal dose was demonstrated, a final cohort of animals was injured with ICH and randomly assigned to receive the first dose of COG1410 or vehicle at increasingly longer treatment initiation times after injury. The mice were then assessed for functional deficit via RR testing over the first 5 days following injury. RESULTS: The mice receiving 2 mg/kg of COG1410 after injury demonstrated reduced functional deficit, decreased brain concentrations of inflammatory proteins, and less cerebral edema, although hematoma volume did not vary. The improved RR performance was maintained when peptide administration was delayed for up to 2 h after ICH. CONCLUSIONS: COG1410 administered at a dose of 2 mg/kg within 2 h after injury improves functional recovery in a murine model of ICH.

Clinical Features and Evolution of Blepharospasm: A Multicenter International Cohort and Systematic Literature Review.

Objective: Blepharospasm is a type of dystonia where the diagnosis is often delayed because its varied clinical manifestations are not well recognized. The purpose of this study was to provide a comprehensive picture of its clinical features including presenting features, motor features, and non-motor features. Methods: This was a two-part study. The first part involved a systematic literature review that summarized clinical features for 10,324 cases taken from 41 prior reports. The second part involved a summary of clinical features for 884 cases enrolled in a large multicenter cohort collected by the Dystonia Coalition investigators, along with an analysis of the factors that contribute to the spread of dystonia beyond the periocular region. Results: For cases in the literature and the Dystonia Coalition, blepharospasm emerged in the 50s and was more frequent in women. Many presented with non-specific motor symptoms such as increased blinking (51.9%) or non-motor sensory features such as eye soreness or pain (38.7%), photophobia (35.5%), or dry eyes (10.7%). Non-motor psychiatric features were also common including anxiety disorders (34-40%) and depression (21-24%). Among cases presenting with blepharospasm in the Dystonia Coalition cohort, 61% experienced spread of dystonia to other regions, most commonly the oromandibular region and neck. Features associated with spread included severity of blepharospasm, family history of dystonia, depression, and anxiety. Conclusions: This study provides a comprehensive summary of motor and non-motor features of blepharospasm, along with novel insights into factors that may be responsible for its poor diagnostic recognition and natural history.

Phenotypic Features of Isolated Essential Tremor, Essential Tremor Plus, and Essential Tremor-Parkinson's Disease in a Movement Disorders Clinic.

Background: Patients with essential tremor were initially considered to have isolated tremor, but additional motor and non-motor features have been increasingly recognized. The term "essential tremor plus" was adopted by the Task Force on Tremor of the International Parkinson and Movement Disorder Society to describe essential tremor patients with additional neurologic signs. Objectives: To characterize essential tremor patients and their phenotypes in a movement disorders clinic population in the context of the new tremor classification. Methods: Demographic, clinical, historical, treatment, and diagnostic data were retrospectively collected on 300 patients diagnosed by movement disorder experts with essential tremor. Patients were classified as having essential tremor, essential tremor plus, or essential tremor-Parkinson's disease combination, and features between these groups were compared. Results: Of the 300 patients, 20.7% were classified as isolated essential tremor, 53.3% as essential tremor plus, and 26.0% as essential tremor-Parkinson's disease. There was no significant difference in the duration of tremor symptoms. Essential tremor plus patients were more likely to have dystonia, tandem gait abnormalities, head tremor and greater tremor severity. Essential tremor-Parkinson's disease patients were more likely to have RBD symptoms. There was no significant difference in cognitive impairment between essential tremor plus and essential tremor-Parkinson's disease patients. Conclusions: Additional motor and non-motor features, including parkinsonism, are common in patients with essential tremor. Further studies are needed to clarify essential tremor phenotypes and to provide insights into possible subtypes. Highlights: 300 patients with essential tremor from a movement disorders clinic were re-classified based on the Movement Disorder Society Consensus Statement on the Classification of Tremors. Additional motor and non-motor features, including parkinsonism, were common, and only 20.7% of patients remained classified as isolated essential tremor.

Survey of anesthesiologists practicing in American neurointensive care units as neurointensivists.

BACKGROUND: A group of anesthesiologists practice as intensivists in neurointensive care units (NeuroICU). The current nature and implications of the role of anesthesiology-based neurointensivist remain unclear. The purpose of this survey was to assess today's practice environment of anesthesiology-based neurointensivists as a framework for future study. METHODS: During the period between January 2011 and March 2011, we identified anesthesiologists who provide patient care in specialized NeuroICUs in the United States. We used an online, 15-question survey to gauge the environment and their role in the delivery of care to critically ill patients admitted to NeuroICUs. RESULTS: Of the 104 NeuroICUs in the United States, 22 institutions include anesthesiology-based neurointensivists (n=41). With a response from 33 of 41 requested surveys, anesthesiology-based neurointensivists reported that background training and roles for providing patient care in the NeuroICU setting varied widely between institutions. In contrast, these practices were similar in providing 24-hour coverage (76%), working with neurosurgical (88%) and anesthesiology residents (85%), and having critical-care fellowship training (97%). Almost all surveyed individuals practice both neurocritical care and anesthesia in the operating room, and 76% reported satisfaction with their working environment in the NeuroICU relative to other responsibilities. CONCLUSIONS: Anesthesiology-based neurointensivists currently represent a small subgroup within the rapidly growing neurointensivist workforce in the United States and consider neurocritical care a valuable aspect of their career. Promoting subspecialty training in neurocritical care among anesthesiologists may provide an opportunity for new patient-care frontiers and address the increasing need for NeuroICU physicians.

Interrater reliability of the bedside shivering assessment scale.

BACKGROUND: Since its early development, the Bedside Shivering Assessment Scale (BSAS) has had only initial psychometric testing. Before this instrument is incorporated into routine practice, its interrater reliability should be explored in a diverse group of practitioners. METHODS: This prospective nonrandomized study used a panel of 5 observers who completed 100 paired assessments. Observers independently scored patients for shivering by using the BSAS. Kappa statistics were determined by using SAS version 9.4 with BSAS scores treated as ordinal data. RESULTS: A weighted kappa value of 0.48 from 100 paired observations of 22 patients indicates moderate agreement of the BSAS scores. Most of the BSAS scores were 0 or 1; dichotomizing shivering as little or no shivering versus significant shivering resulted in a kappa of 0.66 (substantial agreement). No relationship was found between timing of assessment or the role of the practitioner and the likelihood of both observers assigning the same BSAS score. CONCLUSION: The BSAS has adequate interrater reliability to be considered for use among a diverse group of practitioners.

Interaction between sex and apolipoprotein e genetic background in a murine model of intracerebral hemorrhage.

Emerging evidence suggests sex and apolipoprotein E (APOE) genotype separately modify outcomes after intracerebral hemorrhage (ICH). We test the hypothesis that an interaction exists between sex and APOE polymorphism in modifying outcomes after ICH and is altered by administration of exogenous apoE-mimetic peptide. To define the effects of sex and APOE polymorphism in ICH, we created collagenase-induced ICH in male and female APOETR mice (targeted replacement mice homozygous for APOE3 or APOE4 alleles; n=12/group) and assessed performance on Rotarod (RR) and Morris water maze (MWM). To evaluate hematoma formation, we used hematoxylin and eosin staining at 24 h after injury (n=8/group). Using separate cohorts (n=12/group), apoE-mimetic peptide (COG1410 at 2 mg/kg) was administered after ICH, and mice were assessed by RR and MWM. Female mice outperformed male mice via RR and MWM by over 190% improvement through 7 days (RR) and 32 days (MWM) of testing after ICH (p<0.01). Female APOE3TR mice demonstrated improved function compared with all other groups (p<0.05) without any difference in hematoma volume at 24 h after injury in any group. Administration of a therapeutic apoE-mimetic peptide improved RR latencies through 7 days after ICH in male and female APOE4TR mice and MWM latencies over days 28-32 after ICH in male APOE4TR mice (p<0.05). Sex and APOE polymorphism influence functional outcomes in our murine model of ICH. Moreover, administration of exogenous apoE-mimetic peptide after injury differentially modifies the interaction between sex and APOE polymorphism.