Multi-actor system dynamics in access to disease-modifying treatments for multiple sclerosis in Southeast Asia: A regional survey and suggestions for improvement.

BACKGROUND: Despite the global availability of multiple sclerosis (MS) treatments, accessing and financing them in Southeast Asia (SEA) remains a challenge. This descriptive survey-based study aimed to describe the current state of MS treatment access and local access dynamics within this region. METHODS: The survey questionnaire, comprising of 15 closed-ended and five open-ended questions, was developed by three neurologists with expertise in MS and routine MS patient management, or had training in neuroimmunology. Questionnaire development was guided by the recent Atlas of MS and in alignment with the Access to Treatment framework, focusing on MS diagnosis and treatment issues in SEA. Fifteen neurologists experienced in managing MS across the region were identified as key informants for this study. RESULTS: All fifteen neurologists participated in the survey via email and videoconferencing between January 2020 and February 2023, which included the following countries: Brunei, Cambodia, Indonesia, Malaysia, Myanmar, Lao PDR, Philippines, Singapore, Thailand, Timor-Leste, and Vietnam. All had at least five years of experience in managing MS patients and six had previously completed a neuroimmunology fellowship programme. SEA countries showed disparities in healthcare financing, availability of neurologists, MS treatments, and investigative tools. Access to MS disease-modifying treatments (DMTs) is hindered by high cost, lack of MS specialists, and weak advocacy efforts. On-label DMTs are not listed as essential medicines regionally except for interferon beta1a and teriflunomide in Malaysia. On-label monoclonals are available only in Malaysia, Singapore, and Thailand. Generic on-label DMTs are unavailable due to lack of distributorship and expertise in using them. Off-label DMTs (azathioprine, methotrexate, and rituximab) predominate in most SEA countries. Other challenges include limited access to investigations, education, and knowledge about DMTs among general neurologists, and absence of registries and MS societies. Patient champions, communities, and MS organisations have limited influence on local governments and pharmaceutical companies. Despite its increasing prevalence, there is a lack of concerted priority setting due to MS being perceived as a rare, non-communicable disease. CONCLUSION: This study highlights the distinct dynamics, challenges, and research gaps within this region, and provides suggestions to improve MS diagnosis, education, and medicine access.

Facilities, selection, outcome measurement, and limitations of therapeutic plasma exchange for neuroimmunological disorders: The South East Asian survey study.

INTRODUCTION: Therapeutic plasma exchange (TPE) for neuroimmunological disorders has played an important role in the Southeast Asian region. This study investigates the challenges of performing TPE within the region. METHOD: A questionnaire-based survey was conducted and launched to 15 South East Asian Therapeutic Plasma Exchange Consortium (SEATPEC) members from seven countries in January 2021. It included demographics, TPE techniques, indications, challenges, timing, outcome measurement, and access to laboratory testing in each local center. RESULTS: A total of 15 neurologists from 12 participating centers were included. They usually perform five sessions of TPE (100.0%), with 1 to 1.5 plasma volume (93.3%), and exchanges via the central catheter (100.0%). Acute relapses of neuromyelitis optica spectrum disorder and myasthenia gravis are the most common indications. They used a combination of normal saline and 5% albumin (60.0%) as replacement fluid. Most (66.7%) used TPE as an add-on treatment in steroid-refractory cases or as first-line treatment for severe attacks. They suggested assessing the TPE efficacy of TPE by the interval to the next attack, post-TPE relapse rates, and TPE-related complications. The major challenges within our region are expense, reimbursibility, and access to TPE. CONCLUSION: Although countrywise differences exist, all share similarities regarding methods, indications, timing, obstacles, and challenges of TPE for neuroimmunological conditions. Regional collaboration will be essential to identify strategies to reduce these barriers to access to TPE in the future.

Repurposing povidone-iodine to reduce the risk of SARS-CoV-2 infection and transmission: a narrative review.

BACKGROUND: Accumulating data suggest antiviral effects of povidone-iodine against the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. This narrative review aims to examine the antiviral mechanisms of povidone-iodine, efficacy of povidone-iodine against the SARS-CoV-2 virus, and safety of povidone-iodine to human epithelial cells and thyroid function. METHODS: We searched the electronic databases PubMed, Embase, Cochrane Library, ClinicalTrials.gov and World Health Organization's International Clinical Trials Registry Platform for articles containing the keywords "povidone-iodine", "SARS-CoV-2" and "COVID-19" from database inception till 3 June 2021. RESULTS: Despite in vitro data supporting the anti-SARS-CoV-2 effects of povidone-iodine, findings from clinical studies revealed differences in treatment response depending on study settings (healthy vs. hospitalized individuals), treatment target (nasal vs. oral vs. pharynx), method of administration (oral rinse vs. gargle vs. throat spray) and choice of samples used to measure study endpoints (nasopharyngeal vs. saliva). One large-scale clinical trial demonstrated reduction in the incidence of SARS-CoV-2 infection among participants who administered povidone-iodine 3 times daily during an active outbreak. Povidone-iodine is also used to disinfect the oro-pharyngeal space prior to dental or otolaryngology procedures. Although existing data suggest minimal impact of povidone-iodine on thyroid function, high-quality safety data are presently lacking. CONCLUSIONS: Povidone-iodine application to the oropharyngeal space could complement existing non-pharmacological interventions to reduce SARS-CoV-2 infection especially in high exposure settings.Key messagesAccumulating data suggest antiviral effects of povidone-iodine against the SARS-CoV-2 virus.Findings from clinical studies reveal differences in treatment response depending on study settings, treatment target, method of administration and choice of samples used to measure study endpoints. One large-scale clinical trial observed reduction in the incidence of SARS-CoV-2 infection among participants who administered povidone-iodine 3 times daily during an active outbreak.Povidone-iodine application to the oropharyngeal space could complement existing non-pharmacological interventions to reduce SARS-CoV-2 infection especially in high exposure settings.

Mitigating SARS-CoV-2 Transmission in Hospitals: A Systematic Literature Review.

Objectives: Hospital outbreaks of SARS-CoV-2 infection are dreaded but preventable catastrophes. We review the literature to examine the pattern of SARS-CoV-2 transmission in hospitals and identify potential vulnerabilities to mitigate the risk of infection. Methods: Three electronic databases (PubMed, Embase and Scopus) were searched from inception to July 27, 2021 for publications reporting SARS-CoV-2 outbreaks in hospital. Relevant articles and grey literature reports were hand-searched. Results: Twenty-seven articles that described 35 SARS-CoV-2 outbreaks were included. Despite epidemiological investigations, the primary case could not be identified in 37% of outbreaks. Healthcare workers accounted for 40% of primary cases (doctors 17%, followed by ancillary staff 11%). Mortality among infected patients was approximately 15%. By contrast, none of the infected HCWs died. Several concerning patterns were identified, including infections involving ancillary staff and healthcare worker infections from the community and household contacts. Conclusion: Continuous efforts to train-retrain and enforce correct personal protective equipment use and regular routine screening tests (especially among ancillary staff) are necessary to stem future hospital outbreaks of SARS-CoV-2.

Impact of Covid-19 on the therapeutic plasma exchange service within the South East Asian region: Consensus recommendations and global perspectives.

INTRODUCTION: Therapeutic plasma exchange (TPE) for neuroimmunological disorders has played an increasingly important role within the Southeast Asian (SEA) region. The South East Asian Therapeutic Plasma exchange Consortium (SEATPEC) was formed in 2018 to promote education and research on TPE within the region. The advent of the Covid-19 pandemic has produced challenges for the development and expansion of this service. METHODOLOGY: A qualitative and semi-quantitative questionnaire-based survey was conducted by SEATPEC member countries from January to June 2020 (Phase 1) and then from July 2020 to January 2021 in (Phase 2) to assess the impact of Covid-19 on regional TPE. OBJECTIVES: The study's main objectives were to explore the challenges experienced and adaptations/adjustments taken by SEATPEC countries in order to continue safe and efficient TPE during the Covid-19 pandemic. RESULTS: The pandemic was found to disrupt the delivery of TPE services in all SEATPEC countries. Contributing factors were multifactorial due to overstretched medical services, staff shortages, quarantines and redeployments, fear of acquiring Covid-19, movement restriction orders, and patient's psychological fear of attending hospitals/testing for Covid-19. All SEATPEC countries practiced careful stratification of cases for TPE (electives vs emergencies, Covid-19 vs non-Covid-19 cases). SEATPEC countries had to modify TPE treatment protocols to include careful preprocedure screening of patient's for Covid-19, use of personal protective equipment (PPE) and post-TPE sanitization of machines and TPE suites. CONCLUSION: Based on the responses of the survey, SEATPEC countries produced a consensus statement with five recommendations for safe and effective TPE within the region.

Blood biomarkers to detect new-onset atrial fibrillation and cardioembolism in ischemic stroke patients.

BACKGROUND: Accumulating data suggest blood biomarkers could inform stroke etiology. OBJECTIVE: The purpose of this study was to investigate the performance of multiple blood biomarkers in elucidating stroke etiology with a focus on new-onset atrial fibrillation (AF) and cardioembolism. METHODS: Between January and December 2017, information on clinical and laboratory parameters and stroke characteristics was prospectively collected from ischemic stroke patients recruited from the National University Hospital, Singapore. Multiple blood biomarkers (N-terminal pro-brain natriuretic peptide [NT-proBNP], d-dimer, S100ß, neuron-specific enolase, vitamin D, cortisol, interleukin-6, insulin, uric acid, and albumin) were measured in plasma. These variables were compared with stroke etiology and the risk of new-onset AF and cardioembolism using multivariable regression methods. RESULTS: Of the 515 ischemic stroke patients (mean age 61 years; 71% men), 44 (8.5%) were diagnosed with new-onset AF, and 75 (14.5%) had cardioembolism. The combination of 2 laboratory parameters (total cholesterol ≤169 mg/dL; triglycerides ≤44.5 mg/dL) and 3 biomarkers (NT-proBNP ≥294 pg/mL; S100ß ≥64 pg/mL; cortisol ≥471 nmol/l) identified patients with new-onset AF (negative predictive value [NPV] 90%; positive predictive value [PPV] 73%; area under curve [AUC] 85%). The combination of 2 laboratory parameters (total cholesterol ≤169 mg/dL; triglycerides ≤44.5 mg/dL) and 2 biomarkers (NT-proBNP ≥507 pg/mL; S100ß ≥65 pg/mL) identified those with cardioembolism (NPV 86%; PPV 78%; AUC 87%). Adding clinical predictors did not improve the performance of these models. CONCLUSION: Blood biomarkers could identify patients with increased likelihood of cardioembolism and direct the search for occult AF.

Autoimmune Epilepsy: The Evolving Science of Neural Autoimmunity and Its Impact on Epilepsy Management.

Autoimmune epilepsy is increasingly recognized as a distinct clinical entity, driven in large part by the recent discovery of neural autoantibodies in patients with isolated or predominant epilepsy presentations. Detection of neural autoantibodies in high-risk epilepsy patients supports an immune-mediated cause of seizures and, if applicable, directs the search for an underlying cancer when the paraneoplastic association of the associated antibody is compelling. Early diagnosis of autoimmune epilepsy is crucial, as prompt initiation of immunosuppressive treatment increases the likelihood of achieving either seizure freedom or a substantial reduction in seizure frequency. A practical clinical approach that incorporates risk scores to guide patient selection on the basis of clinical features, neural autoantibodies, and a treatment trial of immunotherapy is suggested. Elucidating an immunological basis of epilepsy provides neurologists with wider treatment options (incorporating immune-suppressive treatment), in addition to standard antiepileptic drugs, which often improves patient outcomes.

Chronic Manganese Toxicity Associated with Voltage-Gated Potassium Channel Complex Antibodies in a Relapsing Neuropsychiatric Disorder.

Heavy metal poisoning is a rare but important cause of encephalopathy. Manganese (Mn) toxicity is especially rare in the modern world, and clinicians’ lack of recognition of its neuropsychiatric manifestations can lead to misdiagnosis and mismanagement. We describe the case of a man who presented with recurrent episodes of confusion, psychosis, dystonic limb movement and cognitive impairment and was initially diagnosed with anti-voltage-gated potassium channel (VGKC) complex limbic encephalitis in view of previous positive autoantibodies. His failure to respond to immunotherapy prompted testing for heavy metal poisoning, which was positive for Mn. This is the first report to examine an association between Mn and VGKC antibodies and the effects of Mn on functional brain activity using functional near-infrared spectroscopy (fNIRS).

Stroke biomarkers in clinical practice: A critical appraisal.

Biomarkers provide critical mechanistic insights to key biologic processes that occur during cerebral ischemia which, when carefully applied, can improve clinical decision-making in acute stroke management. The translation of a blood-based biomarker in ischemic stroke to clinical practice is challenging, in part, due to the complexity of ischemic stroke pathogenesis and the presence of a blood-brain barrier that restricts the release of brain-specific markers into the circulation. The pathologic and clinical aspects of ischemic stroke are described in this review, where a non-exhaustive list of biomarkers that interrogate different aspects of ischemic stroke such as oxidative damage, inflammation, thrombus formation, cardiac function and brain injury are described. The potential roles of these biomarkers are further examined under different clinical scenarios aimed at (1) averting the risk of hemorrhagic transformation, (2) identifying individuals at risk of early neurologic deterioration and malignant infarction, (3) aiding in the diagnosis of ischemic stroke and its differentiation from other stroke mimics, (4) guiding the search for stroke etiology, and (5) assessing stroke risk within the community. Researchers should explore the roles of stroke biomarkers to enhance clinical decision-making that is presently largely based on intuition and subjective reasoning.

Intravenous immunoglobulin may reduce relapse frequency in neuromyelitis optica.

OBJECTIVES: To evaluate the use of intravenous immunoglobulin (IVIG) in preventing relapses in patients with neuromyelitis optica (NMO) and its spectrum disorders (NMOSDs). METHODS: Six NMO/NMOSD patients who were treated with IVIG induction dose followed by 2- to 3- monthly infusions were retrospectively identified. Annualized relapse rates (ARR) and Expanded Disability Status Scale (EDSS) pre- and post-IVIG were recorded. RESULTS: Median number of relapses and median ARR significantly reduced from 8.0 to 1.0 and 0.75 to 0.15 (p<0.05) respectively. Median EDSS of 6.5 remained the same. Median duration of treatment was 4.0 years. CONCLUSION: IVIG may be used to reduce the relapse frequency in patients with NMO/NMOSD.

Does influenza A infection increase oxidative damage?

Considerable data implicate oxidative damage in influenza pathogenesis. We examined temporal changes in oxidative damage using accurate biomarkers in an adult cohort with acute influenza infection and their relationships with clinical parameters. Clinical information and blood samples were collected during their acute illness and 3 months later. A fatigue questionnaire was administered 3 months following influenza infection. Thirty-five patients (mean age, 34 years) with polymerase chain reaction-confirmed influenza A infection were included; all patients returned for follow-up assessments. Adjusted levels of plasma F2-isoprostanes, total hydroxyeicosatetraenoic products (HETEs), 7ß-hydroxycholesterol and 7-ketocholesterol, serum gamma-glutamyltransferase, and high-sensitivity C-reactive protein (hsCRP) were increased during the acute illness compared with age-matched controls. Despite clinical recovery, levels of these biomarkers remained higher at month 3 compared with controls. A proportion of patients had persistent symptoms such as fatigue (23%), myalgia (14%), and arthralgia (11%) at month 3. Patients with significant fatigue had higher baseline levels of plasma F2-isoprostanes, F4-neuroprostanes, and total HETEs compared to those without fatigue. By contrast, patients with persistent arthralgia and myalgia had higher baseline levels of serum hsCRP compared to those without these symptoms. Our observations lead to the hypothesis that oxidative damage participates in the pathogenesis of influenza infection and postinfectious fatigue.

Does high-dose coenzyme Q10 improve oxidative damage and clinical outcomes in Parkinson's disease?

Evidence on the efficacy of high-dose coenzyme Q10 (CoQ10) in Parkinson's disease (PD) is conflicting. An open-label dose-escalation study was performed to examine the effects of CoQ10 on biomarkers of oxidative damage and clinical outcomes in 16 subjects with early idiopathic PD. Each dose (400, 800, 1200, and 2400 mg/day) was consumed daily for 2 weeks. High-dose CoQ10 was well tolerated and improvements in the total Unified Parkinson's Disease Rating Scale (median, 37 vs. 27; p=0.048) were observed following study completion. Plasma F2-isoprostanes (adjusted for arachidonate) were significantly reduced in the 400-1200 mg/day dose range, but increased at 2400 mg/day dosage. A similar pattern of change was observed with serum phospholipase A2 activities. Levels of plasma all trans-retinol, plasma total tocopherol, serum uric acid, and serum total cholesterol were unchanged despite an increase in the CoQ10 dosage. Subjects with symptomatic benefits from CoQ10 (decrease in total UPDRS >10 points) had lower baseline plasma ubiquinol (p=0.07, Mann-Whitney U test) and decreased F2-isoprostanes per unit arachidonate (p=0.04, Wilcoxon Signed-Ranks test). These results lead to the hypothesis that the therapeutic response to CoQ10 depends on baseline levels of ubiquinol and whether the dosage of CoQ10 used can ameliorate the burden of oxidative damage.

Cyclooxygenase-1 mediated platelet reactivity in young male smokers.

BACKGROUND: The purpose of this study is to investigate the acute and chronic effects of cigarette smoking on cyclooxygenase- 1(COX-1)-mediated platelet reactivity among cigarette smokers. METHODS: The levels of collagen-induced platelet aggregation, platelet COX-1 activity, and expressions were compared between smokers and age-matched nonsmokers. In smokers, the acute effects of cigarette smoking were assessed by repeating these measurements an hour after smoking. RESULTS: Twenty-five smokers and age-matched nonsmokers (all men; mean age, 29 years) were studied. Collagen-induced platelet aggregation and plasma/urinary thromboxane B2 (TXB2) and 11-dehydroxythromboxane B2 levels were higher in cigarette smokers compared to nonsmokers. Greater expression of platelet COX-1 was observed in smokers than in nonsmokers. Among smokers, collagen-induced platelet aggregation correlated positively with platelet volume and circulating nicotine and cotinine concentrations. The levels of plasma/urinary TXB2 were significantly increased an hour after cigarette smoking. CONCLUSION: Cigarette smoking aggravates COX-1-mediated platelet reactivity in young, otherwise healthy, smoking men.

Aquaporin 4 IgG serostatus and outcome in recurrent longitudinally extensive transverse myelitis.

IMPORTANCE: Studies focused on recurrent longitudinally extensive transverse myelitis (rLETM) are lacking. OBJECTIVES: To determine the aquaporin 4 (AQP4) IgG detection rate using recombinant human APQ4-based assays in sequential serum specimens collected from patients with rLETM categorized as negative by first-generation tissue-based indirect immunofluorescence (IIF) assay and to define the clinical characteristics and motor disability outcomes in AQP4-IgG-positive rLETM. DESIGN, SETTING, AND PARTICIPANTS: A search of the Mayo Clinic computerized central diagnostic index (October 1, 2005, through November 30, 2011), cross-linked with the Neuroimmunology Laboratory database, identified 48 patients with rLETM, of whom 36 (75%) were positive and 12 (25%) negative for neuromyelitis optica (NMO) IgG (per IIF of serial serum specimens). Stored serum specimens from "seronegative" patients were retested with recombinant human AQP4-based assays, including enzyme-linked immunosorbent, transfected cell-based, and fluorescence-activated cell-sorting assays. Control patients included 140 AQP4-IgG-positive patients with NMO, of whom a subgroup of 20 initially presented with 2 attacks of transverse myelitis (rLETM-onset NMO). MAIN OUTCOMES AND MEASURES: AQP4-IgG serostatus, clinical characteristics, and Expanded Disability Status Scale score. RESULTS: Six patients with negative IIF results were reclassified as AQP4-IgG positive, yielding an overall AQP4-IgG seropositivity rate of 89%. Fluorescence-activated cell-sorting, cell-based, and enzyme-linked immunosorbent assays improved the detection rate to 89%, 85%, and 81%, respectively. The female to male ratio was 2:3 for AQP4-IgG-negative rLETM and 5:1 for AQP4-IgG-positive patients. The AQP4-IgG-positive patients with rLETM or rLETM-onset NMO were similar in age at onset, sex ratio, attack severity, relapse rate, and motor disability. From Kaplan-Meier analyses, 36% of AQP4-IgG-positive patients with rLETM are anticipated to need a cane to walk within 5 years after onset. For patients with rLETM-onset NMO, the median time from onset to first optic neuritis attack (54 months) was similar to the median disease duration for AQP4-IgG-positive patients with rLETM (59 months). The median number of attacks was 3 for AQP4-IgG-positive patients with rLETM (range, 2-22), and the first optic neuritis attack for those with rLETM-onset NMO followed a median of 3 myelitis attacks (range, 2-19). Immunosuppressant therapy reduced the relapse rate in both AQP4-IgG-positive and AQP4-IgG-negative patients with rLETM. CONCLUSIONS AND RELEVANCE: Recombinant antigen-based assays significantly increase AQP4-IgG detection in patients with rLETM, and AQP4-IgG-negative adults with rLETM are rare. Evolution to NMO can be anticipated in AQP4-IgG-positive patients. Early initiation of immunotherapy may result in a more favorable motor outcome.

Augmentation of 5-lipoxygenase activity and expression during dengue serotype-2 infection.

BACKGROUND: Leukotriene B4, a 5-lipoxygenase product of arachidonic acid with potent chemotactic effects on neutrophils, has not been assessed in dengue patients. In this study, plasma leukotriene B4 and serum high-sensitivity C-reactive protein levels were determined in adult patients during the febrile, convalescent and defervescent stages of dengue serotype-2 (DENV-2) infection, and compared with those of age-matched healthy and non-dengue febrile subjects. In vitro studies were performed to examine the effects of live and heat-inactivated DENV-2 on the activities and expression of 5-lipoxygenase in human neutrophils. RESULTS: Plasma leukotriene B4 was elevated during the febrile stages of dengue infection compared to levels during convalescence and in study controls. Plasma leukotriene B4 also correlated with serum high-sensitivity C-reactive protein in dengue patients (febrile, r = 0.91, p < 0.001; defervescence, r = 0.87, p < 0.001; convalescence, r = 0.87, p < 0.001). Exposure of human neutrophils to DENV-2 resulted in a significant rise in leukotriene B4; the extent of increase, however, did not differ between exposure to live and heat-inactivated DENV-2. Pre-incubation of either live or heat-inactivated DENV-2 resulted in reduced leukotriene B4 release by neutrophils, indicating that contact with dengue antigens (and not replication) triggers the neutrophil response. Production of leukotriene B4 was associated with an increase in 5-lipoxygenase expression in human neutrophils; addition of MK886 (a 5-lipoxygenase activating protein inhibitor) attenuated further increase in leukotriene B4 production. CONCLUSION: These findings provide important clinical and mechanistic data on the involvement of 5-lipoxygenase and its metabolites in dengue infection. Further studies are needed to elucidate the therapeutic implications of these findings.

Updated estimate of AQP4-IgG serostatus and disability outcome in neuromyelitis optica.

OBJECTIVE: To 1) determine, using contemporary recombinant antigen-based assays, the aquaporin-4 (AQP4)-immunoglobulin G (IgG) detection rate in sequential sera of patients assigned a clinical diagnosis of neuromyelitis optica (NMO) but initially scored negative by tissue-based indirect immunofluorescence (IIF) assay; and 2) evaluate the impact of serostatus on phenotype and outcome. METHODS: From Mayo Clinic records (2005-2011), we identified 163 patients with NMO; 110 (67%) were seropositive by IIF and 53 (33%) were scored seronegative. Available stored sera from 49 "seronegative" patients were tested by ELISA, AQP4-transfected cell-based assay, and in-house fluorescence-activated cell sorting assay. Clinical characteristics were compared based on final serostatus. RESULTS: Thirty of the 49 IIF-negative patients (61%) were reclassified as seropositive, yielding an overall AQP4-IgG seropositivity rate of 88% (i.e., 12% seronegative). The fluorescence-activated cell sorting assay improved the detection rate to 87%, cell-based assay to 84%, and ELISA to 79%. The sex ratio (female to male) was 1:1 for seronegatives and 9:1 for seropositives (p < 0.0001). Simultaneous optic neuritis and transverse myelitis as onset attack type (i.e., within 30 days of each other) occurred in 32% of seronegatives and in 3.6% of seropositives (p < 0.0001). Relapse rate, disability outcome, and other clinical characteristics did not differ significantly. CONCLUSIONS: Serological tests using recombinant AQP4 antigen are significantly more sensitive than tissue-based IIF for detecting AQP4-IgG. Testing should precede immunotherapy; if negative, later-drawn specimens should be tested. AQP4-IgG-seronegative NMO is less frequent than previously reported and is clinically similar to AQP4-IgG-seropositive NMO.

Biomarkers of oxidative damage are elevated among individuals with high cardiovascular risk: refining subject selection strategies for antioxidant trials.

The purpose of this study was to evaluate the use of Framingham risk scores (FRRs) to identify high-risk individuals with biochemical evidence of increased oxidative damage, who may benefit from antioxidant therapies. A bimodal change in plasma F2-isoprostane levels was observed with cardiovascular risk categories, while plasma neuroprostanes, 7α-hydroxycholesterol, and serum γ-glutamyltransferase levels were higher among individuals at high risk of cardiovascular events (Framingham score, > 36). Total plasma hydroxyeicosatetraenoic acid products (HETEs) and serum high-sensitivity CRP (hsCRP) levels were consistently higher across Framingham risk categories. Multivariable analysis identified plasma 7α-hydroxycholesterol (odds ratio (OR), 1.06; 95% confidence interval (CI), 1.03-1.10) and γ-glutamyltransferase (OR, 1.02; 95% CI, 1.01-1.03) as significant predictors of high cardiovascular risk (Framingham score, > 36), accounting for approximately 21% of its variation. Cardiovascular risk scores are useful to identify individuals with high burden of oxidative damage who may benefit from antioxidant therapy.

Acute effects of cigarette smoking on insulin resistance and arterial stiffness in young adults.

BACKGROUND: It is unclear whether changes in insulin sensitivity or arterial stiffness in cigarette smokers could explain the link between cigarette smoking and diabetes mellitus. The purpose of the study was to evaluate the acute effects of cigarette smoking on insulin resistance and arterial stiffness in a cohort of young healthy adults. METHODS: Metabolic risk components, hemodynamic parameters, plasma nitrite/nitrate and high-sensitivity C-reactive protein (hsCRP) levels, were compared between smokers and age- and gender-matched controls (non-smokers). In smokers, these levels were determined 8-h following cigarette abstinence and an hour after smoking. RESULTS: One hundred nineteen smokers and age-matched non-smokers (mean age, 32 years; 83% men) were included in this study. Compared with non-smokers, smokers had a significantly higher number of abnormal metabolic risk components, HOMA-IR index and total nitrite/nitrate levels. There were no differences in brachial/central blood pressure, augmentation index and hsCRP between smokers and non-smokers. An hour after smoking, smokers had significantly higher levels of HOMA-IR, total nitrite/nitrate, hsCRP and heart rate compared with baseline levels. By contrast, brachial/central blood pressure and augmentation index were unchanged after cigarette smoking. Baseline vascular and insulin resistance status predicted the extent of rise in the HOMA-IR and augmentation indices acutely after cigarette smoking (adjusted R(2) 0.358 and 0.124, p < 0.001 respectively). CONCLUSIONS: Individuals with more advanced vascular damage and insulin resistance are vulnerable to the acute effects of cigarette smoking.

Effects of age and sex on aquaporin-4 autoimmunity.

OBJECTIVE: To determine the sex and age distribution of aquaporin-4 (AQP4) autoimmunity using data derived from clinical service laboratory testing of 56,464 patient samples. DESIGN: Observational analysis. SETTING: Mayo Clinic Neuroimmunology Laboratory. PATIENTS: Between October 1, 2005, and January 4, 2011, 56,464 patients were tested for AQP4-IgG; 2960 (5.2%) patients were seropositive. MAIN OUTCOME MEASURE: Seropositivity for AQP4-IgG. RESULTS: Patients seropositive for AQP4-IgG were older than seronegative patients (mean [SD] age, 46 [16] vs 42 [15] years, respectively; P < .001). More females than males were tested (37,662 vs 16,810, respectively; P < .001). Among 2743 seropositive patients, 146 (5.3%) were pediatric (aged ≤18 years) and 333 (12.1%) were elderly (aged ≥65 years). The sex distribution of seropositive patients was 2465 females and 306 males (absolute female:male ratio, 8.1:1; P < .001). After adjusting for the number of females tested, an excess of females persisted (adjusted female:male ratio, 3.6:1). Female predominance for AQP4-IgG was more striking in adults (absolute female:male ratio, 8.4:1; adjusted female:male ratio, 3.5:1) than in pediatric patients (absolute female:male ratio, 4.3:1; adjusted female:male ratio, 2.9:1) (P < .001). Elderly women were more likely to be seropositive than individuals in other age categories (13.1% vs 6.0%, respectively; P < .001). The proportion of AQP4-IgG-seropositive individuals (detection rate), defined by decade of age, increased exponentially in women after age 50 years. CONCLUSIONS: Seropositivity for AQP4-IgG occurs predominantly in females, particularly in individuals older than 18 years. Among seropositive patients, 1 in 6 is in the extremes of age. The detection rate of AQP4-IgG increased in women after age 50 years.

Autoimmune epilepsy: clinical characteristics and response to immunotherapy.

OBJECTIVE: To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy. DESIGN: Observational, retrospective case series. SETTING: Mayo Clinic Health System. PATIENTS: Thirty-two patients with an exclusive (n=11) or predominant (n=21) seizure presentation in whom an autoimmune etiology was suspected (on the basis of neural autoantibody [91%], inflammatory cerebrospinal fluid [31%], or magnetic resonance imaging suggesting inflammation [63%]) were studied. All had partial seizures: 81% had failed treatment with 2 or more antiepileptic drugs and had daily seizures and 38% had seizure semiologies that were multifocal or changed with time. Head magnetic resonance imaging was normal in 15 (47%) at onset. Electroencephalogram abnormalities included interictal epileptiform discharges in 20; electrographic seizures in 15; and focal slowing in 13. Neural autoantibodies included voltage-gated potassium channel complex in 56% (leucine-rich, glioma-inactivated 1 specific, 14; contactin-associated proteinlike 2 specific, 1); glutamic acid decarboxylase 65 in 22%; collapsin response- mediator protein 5 in 6%; and Ma2, N-methyl-D-aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each. INTERVENTION: Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclophosphamide. MAIN OUTCOME MEASURE: Seizure frequency. RESULTS: After a median interval of 17 months (range, 3-72 months), 22 of 27 (81%) reported improvement postimmunotherapy; 18 were seizure free. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P<.05). All voltage-gated potassium channel complex antibody-positive patients reported initial or lasting benefit (P<.05). One voltage-gated potassium channel complex antibody-positive patient was seizure free after thyroid cancer resection; another responded to antiepileptic drug change alone. CONCLUSION: When clinical and serological clues suggest an autoimmune basis for medically intractable epilepsy, early-initiated immunotherapy may improve seizure outcome.