Centella asiatica promotes antioxidant gene expression and mitochondrial oxidative respiration in experimental autoimmune encephalomyelitis.

Centella asiatica (Centella) is a traditional botanical medicine that shows promise in treating dementia based on behavioral alterations seen in animal models of aging and cognitive dysfunction. In order to determine if Centella could similarly improve cognitive function and reduce disease burden in multiple sclerosis (MS), we tested its effects in the neuroinflammatory experimental autoimmune encephalomyelitis (EAE) model of MS. In two independent experiments, C57BL/6J mice were treated following induction of EAE with either a standardized water extract of Centella (CAW) or placebo for 2 weeks. At the dosing schedule and concentrations tested, CAW did not improve behavioral performance, EAE motor disability, or degrees of demyelination. However, CAW-treated mice demonstrated increases in nuclear factor (erythroid-derived 2)-like 2 and other antioxidant response element genes, and increases in mitochondrial respiratory activity. Caw also decreased spinal cord inflammation. Our findings indicate that CAW can increase antioxidant gene expression and mitochondrial respiratory activity in mice with EAE, supporting investigation of the clinical effects of CAW in people with MS.

Processing speed and memory test performance are associated with different brain region volumes in Veterans and others with progressive multiple sclerosis.

Background: Cognitive dysfunction and brain atrophy are both common in progressive multiple sclerosis (MS) but are seldom examined comprehensively in clinical trials. Antioxidant treatment may affect the neurodegeneration characteristic of progressive MS and slow its symptomatic and radiographic correlates. Objectives: This study aims to evaluate cross-sectional associations between cognitive battery components of the Brief International Cognitive Assessment for Multiple Sclerosis with whole and segmented brain volumes and to determine if associations differ between secondary progressive (SPMS) and primary progressive (PPMS) MS subtypes. Design: The study was based on a baseline analysis from a multi-site randomized controlled trial of the antioxidant lipoic acid in veterans and other people with progressive MS (NCT03161028). Methods: Cognitive batteries were conducted by trained research personnel. MRIs were processed at a central processing site for maximum harmonization. Semi-partial Pearson's adjustments evaluated associations between cognitive tests and MRI volumes. Regression analyses evaluated differences in association patterns between SPMS and PPMS cohorts. Results: Of the 114 participants, 70% had SPMS. Veterans with MS made up 26% (n = 30) of the total sample and 73% had SPMS. Participants had a mean age of 59.2 and sd 8.5 years, and 54% of them were women, had a disease duration of 22.4 (sd 11.3) years, and had a median Expanded Disability Status Scale of 6.0 (with an interquartile range of 4.0-6.0, moderate disability). The Symbol Digit Modalities Test (processing speed) correlated with whole brain volume (R = 0.29, p = 0.01) and total white matter volume (R = 0.33, p < 0.01). Both the California Verbal Learning Test (verbal memory) and Brief Visuospatial Memory Test-Revised (visual memory) correlated with mean cortical thickness (R = 0.27, p = 0.02 and R = 0.35, p < 0.01, respectively). Correlation patterns were similar in subgroup analyses. Conclusion: Brain volumes showed differing patterns of correlation across cognitive tasks in progressive MS. Similar results between SPMS and PPMS cohorts suggest combining progressive MS subtypes in studies involving cognition and brain atrophy in these populations. Longitudinal assessment will determine the therapeutic effects of lipoic acid on cognitive tasks, brain atrophy, and their associations.

Long-Term Outcomes of Bariatric Surgery in Idiopathic Intracranial Hypertension Patients.

BACKGROUND: Idiopathic intracranial hypertension (IIH), a rare neurological disorder, has limited effective long-term treatments. Bariatric surgery has shown short-term promise as a management strategy, but long-term efficacy has not been evaluated. We investigated IIH-related outcomes 4 to 16 years postsurgery. MATERIALS AND METHODS: This cross-sectional retrospective cohort study included Intracranial Hypertension Registry (IHR) participants with existing medical records that completed a bariatric surgery questionnaire at least 4 years postsurgery. Two physicians independently evaluated the IIH disease course at bariatric surgery and at the time of the questionnaire using detailed medical records. Determinations of improvements were based on within-participant comparisons between the 2 time points. IIH-related outcomes were then combined with bariatric surgery information and outcomes to assess the relationship between weight loss and alterations in IIH. RESULTS: Among participants that underwent bariatric surgery and met study criteria (n=30) the median body mass index (BMI) at the time of surgery was 45.0 [interquartile range (IQR): 39.8-47.0], dropped to a postsurgical nadir of 27.3 (IQR: 22.8-33.1), and rose to 33.4 (IQR: 29.9-41.7) at the time of the questionnaire. Improvements in the IIH disease course at time of the questionnaire occurred in 37% of participants. However, there was a notable association between durable weight loss and IIH improvement as 90% (9 of 10) of participants that attained and maintained a BMI of 30 or below displayed improvement. CONCLUSIONS: Attaining and maintaining a BMI of 30 or below was associated with long-term improvement in the IIH disease course, including improved disease management and amelioration of signs and symptoms of participants of the IHR.

Lipoic acid supplementation associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy.

Lipoic acid (alpha lipoic acid, thioctic acid) is a popular over-the-counter antioxidant and insulin-mimetic supplement under investigation in a variety of conditions including multiple sclerosis, diabetes, and schizophrenia. Unfortunately, high-grade proteinuria was an unexpected adverse event specific to the treatment arm of our clinical trial investigating lipoic acid supplementation in patients with multiple sclerosis. This observation led to detection of similar patients in our nephrology practice. Here, we describe four biopsy-proven cases of neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy following lipoic acid supplementation and a fifth suspected case. Discontinuation of lipoic acid and supportive therapy resulted in remission.

Cannabis for medical purposes: A cross-sectional analysis of health care professionals' knowledge.

BACKGROUND: Legalization of cannabis use and the evidence base supporting both risks and benefits of cannabinoids are expanding, but our understanding of health care professionals' (HCPs) knowledge about cannabis for medical purposes is limited. Understanding of the knowledge base and knowledge gaps about medical cannabis use is critical to advanced practice registered nurses (APRNs) because they are increasingly called on to manage patients taking multiple drugs, including prescribed and unprescribed cannabis and prescription cannabinoids. PURPOSE: The purpose of this study was to examine HCPs' knowledge of clinical cannabis, including laws and regulations; risks and harms; pharmacology; and effects on pain, multiple sclerosis spasticity, and seizures as assessed with written tests before an in-person, continuing medical education program. METHODS: Total scores and differences among professions and topics were compared. RESULTS: A total of 178 of the 226 program attendees completed the test (79%) (107 [47%] physicians, 30 [13%] APRNs, and 18 [8%] registered nurses). The mean test score was 63.2% (SD = 12.7%) without significant differences among professions (F(3, 174) = 1.53; p = .21) but with significant differences among topics (χ2(7, 1068) = 201.13; p < .001). The score was lowest for effects on seizures (43.8%) and with scores below 70% for all other areas except laws and regulations (85.7%). IMPLICATIONS FOR PRACTICE: There are substantial gaps in HCPs' knowledge about the clinical effects of cannabis, especially about risks and harms, pharmacology, and the effects on pain, multiple sclerosis spasticity, and seizures. Further education may help HCPs to understand the risks and benefits of cannabis and cannabinoids across conditions.

Mortality among patients with idiopathic intracranial hypertension enrolled in the IH Registry.

OBJECTIVE: To determine (1) if mortality among patients with idiopathic intracranial hypertension (IIH) enrolled in the Intracranial Hypertension Registry (IHR) is different from that of the general population of the United States and (2) what the leading underlying causes of death are among this cohort. METHODS: Mortality and underlying causes of death were ascertained from the National Death Index. Indirect standardization using age- and sex-specific nationwide all-cause and cause-specific mortality data extracted from the Centers for Disease Control and Prevention Wonder Online Database allowed for calculation of standardized mortality ratios (SMR). RESULTS: There were 47 deaths (96% female) among 1437 IHR participants that met inclusion criteria. The average age at death was 46 years (range, 20-95 years). Participants of the IHR experienced higher all-cause mortality than the general population (SMR, 1.5; 95% confidence interval [CI], 1.2-2.1). Suicide, accidents, and deaths from medical/surgical complications were the most common underlying causes, accounting for 43% of all deaths. When compared to the general population, the risk of suicide was over 6 times greater (SMR, 6.1; 95% CI, 2.9-12.7) and the risk of death from accidental overdose was over 3 times greater (SMR, 3.5; 95% CI, 1.6-7.7). The risk of suicide by overdose was over 15 times greater among the IHR cohort than in the general population (SMR, 15.3; 95% CI, 6.4-36.7). CONCLUSIONS: Patients with IIH in the IHR possess significantly increased risks of death from suicide and accidental overdose compared to the general population. Complications of medical/surgical treatments were also major contributors to mortality. Depression and disability were common among decedents. These findings should be interpreted with caution as the IHR database is likely subject to selection bias.

Cross-sectional survey of complementary and alternative medicine used in Oregon and Southwest Washington to treat multiple sclerosis: A 17-Year update.

BACKGROUND: In 2001, we conducted a survey on use of complementary and alternative medicine (CAM) in people with multiple sclerosis (pwMS) in Oregon and Southwest Washington to treat their disease. OBJECTIVES, METHODS: In 2018, we administered a revised survey in the same region to describe updated patterns of CAM use in pwMS and to compare changes in use, perceived benefit, and patterns of communication between participants and providers regarding CAM over the past 17 years. RESULTS: 81% of respondents in 2018 (n = 1014) used a CAM supplement (vitamins, minerals, herbs), 39% used mind-body therapies (mindfulness, massage), 41% used specific diet, and 81% used exercise to treat their multiple sclerosis. Since 2001, use of supplements, exercise, and mind-body therapies have increased (65% to 81%, 67 to 81%, and 14% to 39%). Participants were also nine times more likely to speak to their neurologists about CAM use (6.7% to 55.4%). In 2018, factors associated with CAM use included female sex, progressive disease, and longer time since multiple sclerosis diagnosis. CONCLUSION: These findings highlight the high and increasing prevalence of CAM use in pwMS and factors associated with CAM use, and underscore the importance of research to investigate safety and efficacy of these therapies.

Lipoic Acid and Other Antioxidants as Therapies for Multiple Sclerosis.

Oxidative stress (OS), when oxidative forces outweigh endogenous and nutritional antioxidant defenses, contributes to the pathophysiology of multiple sclerosis (MS). Evidence of OS is found during acute relapses, in active inflammatory lesions, and in chronic, longstanding plaques. OS results in both ongoing inflammation and neurodegeneration. Antioxidant therapies are a rational strategy for people with MS with all phenotypes and disease durations. PURPOSE OF REVIEW: To understand the function of OS in health and disease, to examine the contributions of OS to MS pathophysiology, and to review current evidence for the effects of selected antioxidant therapies in people with MS (PwMS) with a focus on lipoic acid (LA). RECENT FINDINGS: Studies of antioxidant interventions in both animal and in vivo models result in reductions in serum markers of OS and increases in levels and activity of antioxidant enzymes. Antioxidant trials in PwMS, while generally underpowered, detect short-term improvements in markers of OS and antioxidant defenses, and to a lesser extent, in clinical symptoms (fatigue, depression). The best evidence to date is a 2-year trial of LA in secondary progressive MS which demonstrated a significant reduction of whole-brain atrophy and trend toward improvement in walking speed. Antioxidant therapy is a promising approach to treat MS across the spectrum and duration of disease. Rigorous and well-powered trials are needed to determine their therapeutic benefits.

Emergency department utilization among individuals with idiopathic intracranial hypertension.

PURPOSE: Idiopathic intracranial hypertension (IIH) can be a debilitating disorder that is difficult to identify and treat. Failure to adequately manage IIH symptoms may force patients to present at emergency departments (EDs) seeking symptom relief. The purpose of this paper is to empirically characterize ED use by previously diagnosed IIH patients. DESIGN/METHODOLOGY/APPROACH: Patients diagnosed with IIH, and who registered with the Intracranial Hypertension Registry by 2014, were solicited for study inclusion. A survey was designed to elicit ED use during the period 2010-2012. Information on demographic and socioeconomic characteristics, IIH signs and symptoms, time since diagnosis, perspectives of ED use and quality of life was collected. Quality of life was assessed using an adaptation of the Migraine-Specific Quality of Life Questionnaire. Data were analyzed using descriptive statistics and nonparametric hypothesis tests. FINDINGS: In total, 39 percent of IIH patients used emergency services over the study period; those that did used the services intensely. These patients were more likely to be non-white, live in households making less than $25,000 annually, have public insurance and have received a diversional shunt procedure. Patients who used the ED were less likely to live in households making $100,000, or more, annually and have private insurance. Participants who used the ED had significantly lower quality-of-life scores, were younger and had been diagnosed with IIH for less time. ORIGINALITY/VALUE: ED staff and outside physicians can utilize the information contained in this study to more effectively recognize the unique circumstances of IIH patients who present at EDs.

Manifestations of Pediatric Intracranial Hypertension From the Intracranial Hypertension Registry.

OBJECTIVE: The purpose of this study was to examine the presenting symptoms, demographics, and interventions in pediatric patients enrolled in the Intracranial Hypertension Registry. METHODS: We analyzed confirmed intracranial hypertension patients ≤18 years at the time of initial diagnosis who were enrolled in the registry. RESULTS: A total of 203 patients met the criteria for inclusion; 142 (70%) were considered primary intracranial hypertension. Females made up 72.5% (103 of 142) and 75.8% (47 of 61) in the primary intracranial hypertension and secondary intracranial hypertension groups, respectively. There were no clinically significant differences in age, body mass index, or opening pressure between the primary intracranial hypertension and secondary intracranial hypertension groups. Symptoms most often reported were headache and blurred vision. Bilateral optic disc edema occurred in 89.3% of primary intracranial hypertension and 78.7% of secondary intracranial hypertension patients. When divided into pre- and postpubertal status, 32.5% of patients were classified prepubertal; 77.3% of these had primary intracranial hypertension. This resulted in a female to male ratio of 1:1.04 for prepubertal and 6:1 for postpubertal primary intracranial hypertension patients. The body mass index was significantly higher in the postpubertal primary intracranial hypertension group (P = 0.0014). There was no significant difference in opening pressure. CONCLUSIONS: The common symptoms of intracranial hypertension, including headache, optic disc edema, and vision changes, occurred with similar frequencies in our cohort to those reported in the literature. In separate subanalyses, we found significantly higher rates of obesity in postpubertal females with primary intracranial hypertension. The female-to-male ratios in the postpubertal primary intracranial hypertension and secondary intracranial hypertension groups were higher than reported in the literature.

Acetazolamide-Induced Nephrolithiasis in Idiopathic Intracranial Hypertension Patients.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a neurological disorder characterized by elevated intracranial pressure of unknown cause. Acetazolamide is widely used as the initial treatment option; however, previously published evidence suggests that this drug may also increase the risk of nephrolithiasis. The purpose of this study was to examine daily acetazolamide use and its relationship to nephrolithiasis and compare clinical presentation of IIH between those with and without nephrolithiasis. METHODS: We conducted a case-control study using patient data collected by the Intracranial Hypertension Registry. A total of 670 patients were identified as potential study participants, 19 meeting the case definition of developing a stone during acetazolamide treatment for IIH. From the remaining pool of eligible participants, 40 controls were randomly selected. Two-sampled t tests, Fisher exact testing, and exact logistic regression were used to examine differences between cases and controls and to ascertain associations with IIH clinical features and mean daily acetazolamide dosage. RESULTS: Among all eligible patients, 19 (2.8%) developed a stone during acetazolamide treatment for IIH. Among these patients, 17 (89.5%) developed a stone within 1.5 years of initial acetazolamide treatment. Daily acetazolamide use was not significantly related to stone development (odds ratio = 0.95; 95% confidence intervals: 0.86-1.05). Additionally, the relationship between the clinical presentation of IIH at the time of diagnosis (signs and symptoms) and stone development did not reach statistical significance (P > 0.05). CONCLUSIONS: Our results demonstrate that: 1) stone formation during acetazolamide treatment is a relatively infrequent occurrence within the IIH population; 2) among patients who develop a stone, formation is likely to occur within the first year and half; 3) there is no evidence to support the association between acetazolamide daily dosage and stone development; and 4) no unique IIH disease features at the time of diagnosis are associated with stone development. Treatment with acetazolamide should be administered to IIH patients with caution and closely monitored for stone development especially within the first year and a half of treatment.