Anticonvulsants in the Treatment of Behavioral and Psychological Symptoms in Dementia: A Systematic Review.

OBJECTIVES: Behavioral and psychological symptoms of dementia (BPSD) are common and impart a significant burden to patients, caregivers, and the health system. However, there are few pharmacological options for treating BPSD. We conducted a systematic review of clinical trials examining the efficacy of anticonvulsants in BPSD. METHODS: We searched five electronic databases through January 2023, for randomized controlled trials and systematic reviews evaluating the efficacy of non-benzodiazepine anticonvulsants for the treatment of BPSD. We used the Cochrane risk of bias tool to ascertain the risk of bias in included trials. Because statistical pooling of results using meta-analysis was not feasible, we synthesized findings using the Cochrane Synthesis Without Meta-analysis reporting guidelines. RESULTS: We identified 12 studies, including randomized controlled trials (RCTs) and 1 systematic review. Five RCTs evaluating valproic acid were synthesized by a recent Cochrane review which concluded that this drug is likely ineffective for BPSD. We extracted data from 6 trials involving 248 individuals comparing non-benzodiazepine anticonvulsants to either placebo or risperidone. Four trials (n = 97 participants) evaluated carbamazepine, only one of which demonstrated an improvement in the Brief Psychiatric Rating Scale measuring agitation, hostility, psychosis, and withdrawal/depression (effect size: 1.13; 95% confidence interval [CI]: 0.54-1.73) relative to placebo. Adverse effects were more common in patients receiving carbamazepine (20/27; 74%) relative to placebo (5/24; 21%). There is low quality evidence that oxcarbazepine is likely ineffective and that topiramate may be comparable to risperidone. CONCLUSION: Anticonvulsants are unlikely to be effective in BPSD, although the quality of existing evidence is low.

Outcomes of a Medication Optimization Virtual Interdisciplinary Geriatric Specialist (MOVING) Program: A Feasibility Study.

BACKGROUND: Adverse drug events among older adults result in significant mortality, morbidity and cost. This harm may be mitigated with appropriate prescribing and deprescribing. We sought to understand the prescribing outcomes of an interdisciplinary geriatric virtual consultation service. METHODS: We conducted a retrospective, before-and-after feasibility study to measure prescribing outcomes for a medication optimization virtual interdisciplinary geriatric specialist (MOVING) programme comprised of expertise from geriatric clinical pharmacology, pharmacy and psychiatry for older adults (aged ≥ 65 years) between June and December 2018, Ontario, Canada. The primary outcome was the number of distinct prescriptions and the presence of polypharmacy (defined as ≥ 4 medications) before and after the service. Secondary outcomes included the number of as needed and regularly administered prescriptions, number of potentially inappropriate prescriptions as defined by the Beers and STOPP criteria, and number of prescriptions for psychotropics, long-acting opioids and diabetic medications. RESULTS: We studied 40 patients with a mean age of 80.6 [standard deviation (SD) 8.8] years who received a MOVING consult. We found no significant change in the mean total number of prescriptions per patient before (12.02, SD 5.83) and after the intervention (11.58, SD 5.28), with a mean difference of -0.45 [95% confidence interval (CI) -0.94 to 0.04; p = 0.07]. We found statistically significant decreases in as needed prescriptions (mean difference - 0.30, 95% CI - 0.45 to - 0.15; p<0.001), and potentially harmful medications as identified by the Beers (mean difference -1.25, 95% CI -2.00 to -0.50; p = 0.002) and STOPP (mean difference -1.65, 95% CI -2.33 to -0.97; p < 0.001) scores. Without including the cost savings from hospital diversion by a MOVING consult, the costs of a MOVING consult were $545.80-$629.80 per person, compared with the costs associated with traditional in-person consults involving similar specialist clinical services ($904.89-$1270.69 per person). CONCLUSION: A MOVING model of care is associated with decreases in prescriptions for potentially inappropriate medications in older adults. These findings support further evaluation to ascertain health system impacts.

Canadian Guidelines on Alcohol Use Disorder Among Older Adults.

BACKGROUND: Alcohol use disorder (AUD) is an increasingly common, under-recognized, and under-treated health concern in older adults. Its prevalence is expected to reach unprecedented levels as the Canadian population ages. In response, Health Canada commissioned the Canadian Coalition of Seniors' Mental Health to create guidelines for the prevention, screening, assessment, and treatment of AUD in older adults. METHODS: A systematic review of English language literature from 2008-2018 regarding AUD in adults was conducted. Previously published guidelines were evaluated using AGREE II, and key guidelines updated using ADAPTE method by drawing on current literature. Recommendations were created and assessed using the GRADE method. RESULTS: Twenty-two recommendations were created. Prevention recommendations: Best advice for older adults who choose to drink is to limit intake to well below the national Low-Risk Alcohol Drinking Guidelines. Screening recommendations: Alcohol consumption should be reviewed and discussed on an annual basis by primary care providers. This type of discussion needs to be normalized and approached in a simple, neutral, straight-forward manner. Assessment recommendations: Positive screens for AUD should be followed by a comprehensive assessment. Once more details are obtained an individualized treatment plan can be recommended, negotiated, and implemented. Treatment recommendations: AUD falls on a spectrum of mild, moderate, and severe. It can also be complicated by concurrent mental health, physical, or social issues, especially in older adults. Naltrexone and Acamprosate pharmacotherapies can be used for the treatment of AUD in older adults, as individually indicated. Psychosocial treatment and support should be offered as part of a comprehensive treatment plan. CONCLUSION: These guidelines provide practical and timely clinical recommendations on the prevention, assessment, and treatment of AUD in older adults within the Canadian context.

Anticonvulsants for behavioral and psychological symptoms in dementia: protocol for a systematic review.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are present in a majority of patients with dementia contributing to increased morbidity, health care costs, and caregiver burden. While there are no United States Food and Drug Administration (FDA)-approved medications for these symptoms, off-label use of medications such as antipsychotics have been shown to have significant adverse effects including increased mortality. The goal of this review is to examine the efficacy and safety of anticonvulsants in the treatment of BPSD. METHODS: We will systematically search for randomized trials of anticonvulsants compared to placebo or other treatments such as antidepressants and antipsychotics from the following sources: The Cochrane Library, MEDLINE (OVID SP) in Process and Other Non-Indexed Citations (latest version), EMBASE, clinicalTrials.gov , and the WHO Clinical Trials Registry. The studies will be limited to those published in English but the study location can be worldwide. We will include studies pertaining to individuals with dementia and symptoms of BPSD. The primary outcomes will be behavioral change as measured by validated scales and secondary outcomes will include caregiver burden, quality of life, placement in long term care facility, serious adverse effects, and treatment discontinuation due to adverse effects. Two sets of reviewers will independently screen select and extract data. We will narratively describe the major findings and conclusions from individual studies. Patients who are prescribed antiepileptic drugs (AEDs) for other indications, including seizures, will be excluded. Outcomes of interest will include a change in a validated scale that measures BPSD, serious adverse events, and caregiver quality of life outcomes. If the data are found to be appropriate for a meta-analysis, we will use a random effects model to compute summary estimates of treatment effects. DISCUSSION: This is a protocol for a systematic review addressing the anticonvulsant group of medications as a whole, and as such, our results will inform current clinical practice in the use of anticonvulsants for BPSD. It will also help clinicians and policy makers compare the efficacy of anticonvulsants compared to antidepressants and antipsychotics as well as identify areas which will need further study. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017079826.

Clinical Performance of the DentalVibe® Injection System on Pain Perception During Local Anesthesia in Children.

Purpose: The purpose of this study was to clinically compare injection pain experience in children using three methods.Methods: This was a randomized clinical trial conducted among 150 children (81 girls, 69 boys), from seven to 14 years of age, who required operative dental treatment. Fifty patients were randomized into one of three groups: DentalVibe®, manual stimulation, or no stimulation (control). During the injection, the pulse rate and perceived pain, using the Wong Baker FACES Pain Rating Scale were recorded. Generalized linear models were used to analyze the data.Results: We found a statistically significant decrease in the FACES score in the DentalVibe® group compared to the control group and the manual stimulation group (P<0.001). Injection type (mandibular inferior alveolar block/long buccal injections versus maxillary infiltration injections) did not differ statistically in pain perception. The heart rate in the DentalVibe® group showed no significant difference compared to the other groups at all time points. Conclusion: The DentalVibe® may reduce pain for pediatric patients receiving dental injections.

GeriMedRisk, a telemedicine geriatric pharmacology consultation service to address adverse drug events in long-term care: a stepped-wedge cluster randomized feasibility trial protocol (ISRCTN17219647).

BACKGROUND: Multimorbidity, polypharmacy, and older age predispose seniors to adverse drug events (ADE). Seniors with an ADE experience greater morbidity, mortality, and health care utilization compared to their younger counterparts. To mitigate and manage ADEs among this vulnerable population, we designed a geriatric pharmacology consultation service connecting clinicians with specialist physicians and pharmacists and will investigate the feasibility and acceptability of this complex intervention in the long-term care setting, prior to conducting a larger efficacy trial. METHODS/DESIGN: We will conduct a cluster randomized feasibility trial and qualitative analysis of GeriMedRisk among four long-term care homes in the Waterloo-Wellington region from May 1 to December 31, 2017. The primary outcome is the feasibility and acceptability of GeriMedRisk and the stepped-wedge cluster randomized controlled trial design. We hypothesize that GeriMedRisk is a feasible intervention and its potential to decrease falls and drug-related hospital visits can be evaluated with a stepped-wedge cluster randomized controlled trial design. DISCUSSION: This mixed methods study will inform a larger efficacy trial of GeriMedRisk's ability to decrease adverse drug events among seniors in the long-term care setting. ETHICS AND DISSEMINATION: The Hamilton Integrated Research Ethics Board granted the approval for this study protocol 2812. We plan to disseminate the results of this study in peer-reviewed journals and also to our partners and stakeholders. TRIAL REGISTRATION: ISRCTN clinical trials registry, ISRCTN17219647 (March 27, 2017).

Extracorporeal membrane oxygenation for cardiac arrest during moyamoya cerebral revascularization surgery: case report.

The authors describe the case of a 51-year-old man with bilateral moyamoya disease and prior strokes who developed an asystolic cardiac arrest while undergoing revascularization surgery under mild hypothermia. The patient was successfully treated with venoarterial (VA) extracorporeal membrane oxygenation (ECMO) after manual cardiopulmonary resuscitation (CPR) was unsuccessful for 45 minutes. ECMO is a cardiopulmonary support system that is indicated for respiratory failure in pediatric and adult patients. It is increasingly being used as an extension to mechanical CPR for patients who have suffered cardiac arrest if the underlying cause of cardiac arrest is thought to be reversible. Identifying which patients should be placed on emergency ECMO after cardiac arrest is controversial given its high morbidity and mortality. ECMO in neurosurgical settings has associated risks of intracranial hemorrhage and neurological compromise, while resource utilization is paramount given the high costs of this treatment. This paper is significant because it describes the use of ECMO in an unindicated setting. Limited data are available for ECMO usage after cardiac arrest with baseline cerebral ischemia. Furthermore, this paper raises important considerations for extracorporeal CPR use in a patient who had recently undergone craniotomy. The patient in this report remained on ECMO for 48 hours, after which he was successfully weaned. He developed a pericardial effusion and compartment syndrome from the ECMO but made a complete neurological recovery. Use of ECMO emergently in an appropriately chosen neurosurgical patient is safe, even in the setting of baseline cerebral ischemia and recent craniotomy.

Rates of ischemic stroke during warfarin treatment for atrial fibrillation.

BACKGROUND AND PURPOSE: Recent evidence suggests that there may be an increased risk of ischemic stroke immediately after warfarin initiation. We examined the rate of ischemic stroke among patients with atrial fibrillation newly started on warfarin therapy. METHODS: We conducted a population-based cohort study among Ontario residents aged ≥66 years with atrial fibrillation who received warfarin between April 1, 1997, and March 31, 2010. Each patient was followed up for ≤5 years in 30-day intervals. For each interval, we determined the rate of ischemic stroke. RESULTS: After 5 years, the cumulative incidence of ischemic stroke among new users of warfarin (n=148,446) was 4.0% (n=6006). The risk was highest during the first 30 days after initiation (6.0% per person-year; 95% confidence interval, 5.5%-6.4%) compared with the remainder of follow-up (1.6% per person-year; 95% confidence interval, 1.5%-1.6%), and increased with higher baseline CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke) scores. Less frequent monitoring may have contributed. CONCLUSIONS: In a large cohort of older patients with atrial fibrillation, we observed the highest rate of ischemic stroke in the first 30 days after warfarin initiation. Although causation cannot be established given the observational nature of this study, our findings highlight the need for future research in this population.

Sequential bilateral lung isolation with a single bronchial blocker.

Sequential bilateral lung separation and selective lung collapse can be accomplished with either a double-lumen tube, a single bronchial blocker (BB) that must be repositioned during the operation, or by using 2 BBs, 1 placed in each main bronchus. We provided sequential bilateral lung collapse using a single BB without the need to reposition during surgery.

Tips, stalks, tubes: notch-mediated cell fate determination and mechanisms of tubulogenesis during angiogenesis.

Angiogenesis is the process of developing vascular sprouts from existing blood vessels. Luminal endothelial cells convert into "tip" cells that contribute to the development of a multicellular stalk, which then undergoes lumen formation. In this review, we consider a variety of cellular and molecular pathways that mediate these transitions. We focus first on Notch signaling in cell fate determination as a mechanism to define tip and stalk cells. We next discuss the current models of lumen formation and describe new players in this process, such as chloride intracellular channel proteins. Finally, we consider the possible medical therapeutic benefits of understanding these processes and acknowledge potential obstacles in drug development.

Chloride intracellular channel 1 functions in endothelial cell growth and migration.

BACKGROUND: Little is known about the role of CLIC1 in endothelium. These studies investigate CLIC1 as a regulator of angiogenesis by in vitro techniques that mimic individual steps in the angiogenic process. METHODS: Using shRNA against clic1, we determined the role of CLIC1 in primary human endothelial cell behavior. RESULTS: Here, we report that reduced CLIC1 expression caused a reduction in endothelial migration, cell growth, branching morphogenesis, capillary-like network formation, and capillary-like sprouting. FACS analysis showed that CLIC1 plays a role in regulating the cell surface expression of various integrins that function in angiogenesis including ß1 and α3 subunits, as well as αVß3 and αVß5. CONCLUSIONS: Together, these results indicate that CLIC1 is required for multiple steps of in vitro angiogenesis and plays a role in regulating integrin cell surface expression.

A randomized clinical trial of immunization with combined hepatitis A and B versus hepatitis B alone for hepatitis B seroprotection in hemodialysis patients.

BACKGROUND: The Centers for Disease Control and Prevention recommend immunizing susceptible high-risk groups, such as hemodialysis patients, against hepatitis B virus. However, hemodialysis patients may not develop seroprotective antibodies despite receiving high doses of the vaccine. Recent reports indicate that combined vaccination against hepatitis B and hepatitis A viruses may improve the immunogenicity of hepatitis B vaccine in healthy individuals, but the effectiveness of this strategy in hemodialysis patients is unknown. STUDY DESIGN: Prospective randomized controlled trial. SETTING & PARTICIPANTS: Hepatitis B virus-seronegative hemodialysis patients with undetectable antibody levels at baseline. INTERVENTION: Intramuscular administration of Twinrix (inactivated hepatitis A virus [720 ELISA units] and purified hepatitis B virus surface antigen [20 µg]; GlaxoSmithKline) and Engerix-B (purified hepatitis B virus surface antigen [20 µg]) at 0, 1, and 6 months plus Engerix-B, 40 µg, at month 2 (intervention arm) or Engerix-B, 40 µg, at 0, 1, 2, and 6 months (control arm). Both groups received a total dose of 160 µg of hepatitis B antigen. OUTCOMES: The primary outcome was the difference in seroprotection rates at 7 months, defined by antibody titers >10 mIU/mL. The secondary outcome was frequency of adverse events. MEASUREMENTS: Antibody response at months 3 and 7. RESULTS: 96 patients were enrolled, and 73 completed the investigation. At 3 months, there was no difference in the groups' seroprotection rates (25% vs 27%; P = 0.4). At the completion of the vaccination series, using per-protocol analysis, 27 of 40 (68%) and 16 of 33 (49%) had antibody titers >10 mIU/mL in the treatment and control groups, respectively (P = 0.05; RR, 1.4; absolute abatement, 19%). Intention-to-treat analysis showed 58% and 38% seroprotection rates in the treatment and control groups, respectively (P = 0.02; RR, 1.5; absolute abatement, 20%). There was no difference in adverse events. LIMITATIONS: Lack of evidence of long-term protection. CONCLUSION: Vaccination of hemodialysis patients with a combined hepatitis A and hepatitis B regimen resulted in a statistically significant and clinically important improvement in seroprotection against hepatitis B virus compared with hepatitis B monovalent vaccine.

Prevention of Clostridium difficile infection with Saccharomyces boulardii: a systematic review.

BACKGROUND: Clostridium difficile is a major cause of antibiotic-associated diarrhea within the hospital setting. The yeast Saccharomyces boulardii has been found to have some effect in reducing the risk of C difficile infection (CDI); however, its role in preventive therapy has yet to be firmly established. OBJECTIVE: To review the effectiveness of S boulardii in the prevention of primary and recurrent CDI. Benefit was defined as a reduction of diarrhea associated with C difficile. Risk was defined as any adverse effects of S boulardii. METHODS: A literature search in MEDLINE, EMBASE, CINAHL and the Cochrane Library was performed. Included studies were English language, randomized, double-blind placebo controlled trials evaluating S boulardii in CDI prevention. RESULTS: Four studies were reviewed. Two studies investigated the prevention of recurrence in populations that were experiencing CDI at baseline. One trial showed a reduction of relapses in patients experiencing recurrent CDI (RR=0.53; P<0.05). The other demonstrated a trend toward reduction of CDI relapse in the recurrent treatment group of patients receiving high-dose vancomycin (RR=0.33; P=0.05). Two other studies examined primary prevention of CDI in populations that had been recently prescribed antibiotics. These studies lacked the power to detect statistically significant differences. Patients on treatment experienced increased risk for thirst and constipation. CONCLUSION: S boulardii seems to be well tolerated and may be effective for secondary prevention in some specific patient populations with particular concurrent antibiotic treatment. Its role in primary prevention is poorly defined and more research is required before changes in practice are recommended.

Patterned rhodopsin expression in R7 photoreceptors of mosquito retina: Implications for species-specific behavior.

Visual perception of the environment plays an important role in many mosquito behaviors. Characterization of the cellular and molecular components of mosquito vision will provide a basis for understanding these behaviors. A unique feature of the R7 photoreceptors in Aedes aegypti and Anopheles gambiae is the extreme apical projection of their rhabdomeric membrane. We show here that the compound eye of both mosquitoes is divided into specific regions based on nonoverlapping expression of specific rhodopsins in these R7 cells. The R7 cells of the upper dorsal region of both mosquitoes express a long wavelength op2 rhodopsin family member. The lower dorsal hemisphere and upper ventral hemisphere of both mosquitoes express the UV-sensitive op8 rhodopsin. At the lower boundary of this second region, the R7 cells again express the op2 family rhodopsin. In Ae. aegypti, this third region is a horizontal stripe of one to three rows of ommatidia, and op8 is expressed in a fourth region in the lower ventral hemisphere. However, in An. gambiae the op2 family member expression is expanded throughout the lower region in the ventral hemisphere. The overall conserved ommatidial organization and R7 retinal patterning show these two species retain similar visual capabilities. However, the differences within the ventral domain may facilitate species-specific visual behaviors.

Chloride intracellular channel 4 is involved in endothelial proliferation and morphogenesis in vitro.

New capillaries are formed through angiogenesis and an integral step in this process is endothelial tubulogenesis. The molecular mechanisms driving tube formation during angiogenesis are not yet delineated. Recently, the chloride intracellular channel 4 (CLIC4)-orthologue EXC-4 was found to be necessary for proper development and maintenance of the Caenorhabditis elegans excretory canal, implicating CLIC4 as a regulator of tubulogenesis. Here, we studied the role of CLIC4 in angiogenesis and endothelial tubulogenesis. We report the effects of inhibiting or inducing CLIC4 expression on distinct aspects of endothelial cell behavior in vitro. Our experiments utilized RNA interference to establish cultured human endothelial cell lines with significant reduction of CLIC4 expression, and a CLIC4-expressing lentiviral plasmid was used to establish CLIC4 overexpression in endothelial cells. We observed no effect on cell migration and a modest effect on cell survival. Reduced CLIC4 expression decreased cell proliferation, capillary network formation, capillary-like sprouting, and lumen formation. This suggests that normal endogenous CLIC4 expression is required for angiogenesis and tubulogenesis. Accordingly, increased CLIC4 expression promoted proliferation, network formation, capillary-like sprouting, and lumen formation. We conclude that CLIC4 functions to promote endothelial cell proliferation and to regulate endothelial morphogenesis, and is thus involved in multiple steps of in vitro angiogenesis.

Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway.

Cerebral cavernous malformations (CCMs) are human vascular malformations caused by mutations in three genes of unknown function: KRIT1, CCM2 and PDCD10. Here we show that the heart of glass (HEG1) receptor, which in zebrafish has been linked to ccm gene function, is selectively expressed in endothelial cells. Heg1(-/-) mice showed defective integrity of the heart, blood vessels and lymphatic vessels. Heg1(-/-); Ccm2(lacZ/+) and Ccm2(lacZ/lacZ) mice had more severe cardiovascular defects and died early in development owing to a failure of nascent endothelial cells to associate into patent vessels. This endothelial cell phenotype was shared by zebrafish embryos deficient in heg, krit1 or ccm2 and reproduced in CCM2-deficient human endothelial cells in vitro. Defects in the hearts of zebrafish lacking heg or ccm2, in the aortas of early mouse embryos lacking CCM2 and in the lymphatic vessels of neonatal mice lacking HEG1 were associated with abnormal endothelial cell junctions like those observed in human CCMs. Biochemical and cellular imaging analyses identified a cell-autonomous pathway in which the HEG1 receptor couples to KRIT1 at these cell junctions. This study identifies HEG1-CCM protein signaling as a crucial regulator of heart and vessel formation and integrity.