Genetic Susceptibility Variants of Vascular Dementia among Asians: A Systematic Review and Meta-Analysis.

INTRODUCTION: Vascular dementia (VaD), a neurocognitive impairment directly related to vascular injury, is the second most common cause of age-related dementia. Although numerous studies have investigated candidate genetic polymorphisms associated with VaD in Asia, the genetics of VaD remains unclear. METHODS: This review provides an updated meta-analysis of genetic polymorphisms associated with VaD in Asians, using the PRISMA guidelines. Published literature up to May 2021 was extracted from the PubMed, Scopus, Ovid, and EBSCO host databases. Meta-analysis was conducted using the Open Meta analyst, Review Manager, and MedCalc® Statistical Software. Trial sequential analysis (TSA) was performed using TSA viewer software. RESULTS: A total of 46 eligible studies, comprising 23 genes and 35 SNPs, were retrieved. The meta-analysis was conducted on the following genetic polymorphisms, APOE ε2/3/4, MTHFR rs1801131, ACE rs4340 (I/D) gene polymorphism, and a PSEN1 intron 8 variant. The pooled ORs revealed a significant increase in the risk of VaD in the Apolipoprotein E (APOE) ε4 allelic model: OR, 1.79, p<0.001), and the methylenetetrahydrofolate reductase (MTHFR) rs1801133 polymorphism T allele in the allelic model (OR, 1.23, p=0.013). CONCLUSION: Our findings provide evidence that genetic polymorphisms of the APOE ε4 allele and MTHFR rs1801133 T allele increase the risk of developing VaD in Asians. However, future large-scale investigations examining particularly on South-Eastern and West-Asian populations are highly recommended.

Prevalence and Trajectories of Post-COVID-19 Neurological Manifestations: A Systematic Review and Meta-Analysis.

INTRODUCTION: The aim of this systematic review and meta-analysis was to evaluate the prevalence of thirteen neurological manifestations in people affected by COVID-19 during the acute phase and at 3, 6, 9 and 12-month follow-up time points. METHODS: The study protocol was registered with PROSPERO (CRD42022325505). MEDLINE (PubMed), Embase, and the Cochrane Library were used as information sources. Eligible studies included original articles of cohort studies, case-control studies, cross-sectional studies, and case series with ≥5 subjects that reported the prevalence and type of neurological manifestations, with a minimum follow-up of 3 months after the acute phase of COVID-19 disease. Two independent reviewers screened studies from January 1, 2020, to June 16, 2022. The following manifestations were assessed: neuromuscular disorders, encephalopathy/altered mental status/delirium, movement disorders, dysautonomia, cerebrovascular disorders, cognitive impairment/dementia, sleep disorders, seizures, syncope/transient loss of consciousness, fatigue, gait disturbances, anosmia/hyposmia, and headache. The pooled prevalence and their 95% confidence intervals were calculated at the six pre-specified times. RESULTS: 126 of 6,565 screened studies fulfilled the eligibility criteria, accounting for 1,542,300 subjects with COVID-19 disease. Of these, four studies only reported data on neurological conditions other than the 13 selected. The neurological disorders with the highest pooled prevalence estimates (per 100 subjects) during the acute phase of COVID-19 were anosmia/hyposmia, fatigue, headache, encephalopathy, cognitive impairment, and cerebrovascular disease. At 3-month follow-up, the pooled prevalence of fatigue, cognitive impairment, and sleep disorders was still 20% and higher. At six- and 9-month follow-up, there was a tendency for fatigue, cognitive impairment, sleep disorders, anosmia/hyposmia, and headache to further increase in prevalence. At 12-month follow-up, prevalence estimates decreased but remained high for some disorders, such as fatigue and anosmia/hyposmia. Other neurological disorders had a more fluctuating occurrence. DISCUSSION: Neurological manifestations were prevalent during the acute phase of COVID-19 and over the 1-year follow-up period, with the highest overall prevalence estimates for fatigue, cognitive impairment, sleep disorders, anosmia/hyposmia, and headache. There was a downward trend over time, suggesting that neurological manifestations in the early post-COVID-19 phase may be long-lasting but not permanent. However, especially for the 12-month follow-up time point, more robust data are needed to confirm this trend.

Immune-mediated necrotizing myopathy (NAM) related to SARS-Cov-2 infection: a case report.

BACKGROUND: There is a growing body of evidence that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or COVID-19 infection is associated with the development of autoimmune diseases. A recent systematic review reported that the new-onset autoimmune disorders during or after COVID-19 infection included inflammatory myopathies such as immune-mediated necrotizing myopathies. CASE PRESENTATION: We described a 60-year-old man diagnosed with COVID-19 infection and later presented with a two-week history of myalgia, progressive limb weakness, and dysphagia. He had a Creatinine Kinase (CK) level of more than 10,000 U/L, was strongly positive for anti-signal recognition particle (SRP) and anti-Ro52 antibody, and a muscle biopsy revealed a paucity-inflammation necrotizing myopathy with randomly distributed necrotic fibers, which was consistent with necrotizing autoimmune myositis (NAM). He responded well clinically and biochemically to intravenous immunoglobulin, steroids and immunosuppressant and he was able to resume to his baseline. CONCLUSION: SARS-CoV-2 may be associated with late-onset necrotizing myositis, mimicking autoimmune inflammatory myositis.

Establishing a hyperacute stroke service during the COVID-19 pandemic: our institution's one year experience.

BACKGROUND AND AIMS: The corononavirus 2019 (COVID-19) pandemic resulted in modifications in the workflow and redistribution of human resources, causing challenges in setting up of an acute stroke service. We would like to share our preliminary outcome amid this pandemic, to determine if the implementation of COVID-19 standard operating procedures (SOPs) affected the delivery of our hyperacute stroke service. METHODS: We retrospectively analyzed one-year data from our stroke registry that began with the establishment of our hyperacute stroke service at Universiti Putra Malaysia Teaching Hospital from April 2020 until May 2021. RESULTS: Setting up acute stroke services during the pandemic with constrained manpower and implementation of COVID-19 SOPs, was challenging. There was a significant dip of stroke admission from April to June 2020 due to the Movement Control Order (MCO) implemented by the government to curb the spread of COVID-19. However, the numbers of stroke admission steadily rose approaching 2021, after the implementation of recovery MCO. We managed to treat 75 patients with hyperacute stroke interventions i.e. intravenous thrombolysis (IVT), mechanical thrombectomy (MT) or both. Despite implementing COVID-19 SOPs and using magnetic resonance imaging (MRI) as our first line acute stroke imaging modality, clinical outcomes in our cohort were encouraging; almost 40% of patients who underwent hyperacute stroke treatment had early neurological recovery (ENR), and only 33% of patients had early neurological stability (ENS). In addition, we were able to maintain our door-to-imaging (DTI) and door-to-needle (DTN) time in line with international recommendations. CONCLUSIONS: Our data reflects that COVID-19 SOPs did not deter successful delivery of hyperacute stroke services in our center. However, bigger and multi center studies are required to support our findings.

Spontaneous Bilateral Basal Ganglia Haemorrhage Secondary to Methanol Poisoning.

Methanol toxicity remains as major problem in the medical field.[1],[2],[3] With its active metabolite, formic acid often leads to severe metabolic acidosis and to some extend brain damaged.[4],[5],[6] We are reporting a case of brain hemorrhage at the right external capsule and left basal ganglia with mass effect and obstructive hydrocephalus in a methanol poisoning patient. A confused 29-year-old gentleman was brought into hospital. Initial investigation showed severe metabolic acidosis with raised anion gap. Initial brain CT scan was normal. Subsequently, serum methanol was reported to be high (112 mg/dL). Intravenous (IV) ethanol 10% was given without any delayed. As there was no improvement in his consciousness level, a repeat brain CT was performed and it showed multiple cerebral hemorrhage with obstructive hydrocephalus. Hence, clinicians should have high index of suspicion for cerebral hemorrhage in a patient with methanol toxicity, who presented with altered mental status and severe metabolic acidosis.

A Case of Cobra Bite Complicated with Basilar Artery Occlusion.

Snakebite is one of the most common complaints related to wilderness medicine. Venomous snakebite manifestation is divided into local and systemic envenomation. For the Elapidae group, the most feared complication is respiratory muscle paralysis due to neurotransmitter malfunction at the neuromuscular junction level which leads to respiratory insufficiency. However, there is a lack of evidence or case report incidence to suggest that it can potentially associate with the development of stroke disorder. We present a rare case of massive posterior circulation infarct in a middle-aged gentleman following a cobra bite. He was brought to our center few hours later following the bite and antivenom was administered. He improved shortly after receiving it. However, he had an abrupt drop in his conscious level several hours later. Noncontrast-enhanced computed tomography (NCCT) brain was performed immediately, but stroke disorder was excluded prematurely. Repeated NCCT imaging which was done 12 h apart showed massive posterior circulation infarction with hydrocephalus. He succumbed to death 3 days later. Given its rarity, the evolution of his clinical condition warrants clinician's early suspicion of potential stroke-related complications that can occur following a cobra bite.

Repetitive transcranial magnetic stimulation of the primary motor cortex in stroke survivors-more than motor rehabilitation: A mini-review.

Stroke is a leading cause of morbidity and mortality among elderly populations worldwide. During the early phase of stroke, restoring blood circulation is of utmost importance to protect neurons from further injury. Once the initial condition is stabilized, various rehabilitation techniques can be applied to help stroke survivors gradually regain their affected functions. Among these techniques, transcranial magnetic stimulation (TMS) has emerged as a novel method to assess and modulate cortical excitability non-invasively and aid stroke survivors in the rehabilitation process. Different cortical regions have been targeted using TMS based on the underlying pathology and distorted function. Despite the lack of a standard operational procedure, repetitive TMS (rTMS) of the primary motor cortex (M1) is considered a promising intervention for post-stroke motor rehabilitation. However, apart from the motor response, mounting evidence suggests that M1 stimulation can be employed to treat other symptoms such as dysphagia, speech impairments, central post-stroke pain, depression, and cognitive dysfunction. In this mini-review, we summarize the therapeutic uses of rTMS stimulation over M1 in stroke survivors and discuss the potential mechanistic rationale behind it.

Vessel wall imaging in COVID-19 associated carotid atherothrombosis and stroke: a case report and literature review.

COVID-19 associated neurological syndromes, including acute ischemic stroke, pose a challenge to treating physicians. The role of MRI in aiding diagnosis and further management is indispensable. The advent of new MRI sequences such as vessel wall imaging (VWI) allows an avenue in which these patients could be better investigated and treated. We describe our experience in managing a patient with COVID-19 associated atherothrombosis and stroke, focusing on the VWI imaging findings.

Repetitive Transcranial Magnetic Stimulation of the Primary Motor Cortex beyond Motor Rehabilitation: A Review of the Current Evidence.

Transcranial magnetic stimulation (TMS) has emerged as a novel technique to stimulate the human brain through the scalp. Over the years, identifying the optimal brain region and stimulation parameters has been a subject of debate in the literature on therapeutic uses of repetitive TMS (rTMS). Nevertheless, the primary motor cortex (M1) has been a conventional target for rTMS to treat motor symptoms, such as hemiplegia and spasticity, as it controls the voluntary movement of the body. However, with an expanding knowledge base of the M1 cortical and subcortical connections, M1-rTMS has shown a therapeutic efficacy that goes beyond the conventional motor rehabilitation to involve pain, headache, fatigue, dysphagia, speech and voice impairments, sleep disorders, cognitive dysfunction, disorders of consciousness, anxiety, depression, and bladder dysfunction. In this review, we summarize the latest evidence on using M1-rTMS to treat non-motor symptoms of diverse etiologies and discuss the potential mechanistic rationale behind the management of each of these symptoms.

Stiff Person-Like Syndrome: An Unusual Presentation of Pituitary Macroadenoma with Panhypopituitarism.

Pituitary adenoma can manifest as pituitary hypofunction, which can cause symptoms of panhypopituitarism. Commonly, symptoms of hormonal deficiencies such as lethargy, weight change, cold intolerance, and sexual dysfunction are reported. Optic chiasmal compression leads to visual field changes and the discovery of the pituitary lesion. However, limb stiffness is a rare presentation of hypopituitarism, especially hypocortisolism. We report a 68-year-old man who presented with progressive lower limb stiffness associated with truncal instability mimicking a stiff person syndrome (SPS). Hypoglycaemia and hyponatraemia prompted the discovery of pituitary macroadenoma with panhypopituitarism. Investigation showed pituitary macroadenoma on magnetic resonance imaging with hypocortisolism, hypothyroidism, and hypogonadotropic hypogonadism. After initiating hydrocortisone replacement, the patient had complete resolution of lower limb stiffness with no permanent neurological sequelae. It is postulated that hypocortisolism and hyponatraemia disrupt the metabolic function of muscle leading to stiffness. As a result, lower limb rigidity, flexion deformities, and pain are more common. Differentiating adrenal insufficiency associated with rigidity and SPS is important as the response to treatment for both conditions differs. Prompt treatment leads to fast resolution and prevents contractures in adrenal insufficiency-associated rigidity. Thus, recognizing limb rigidity as the first presentation of hypopituitarism is important to avoid long-term complications.

High-frequency repetitive transcranial magnetic stimulation at dorsolateral prefrontal cortex for migraine prevention: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy of high-frequency repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex as a migraine prevention by conducting a systematic review and meta-analysis. BACKGROUND: The efficacy of high-frequency repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex as preventive migraine treatment remains debatable. METHODS: PubMed, Scopus, CINAHL, CENTRAL, and BioMed Central databases were searched from their inception until December 2020. Randomised trials comparing high-frequency repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex with sham for migraine prevention were included. The risk of bias was assessed using the Cochrane guidelines. Headache days, pain intensity, acute medication intake, and disability were extracted as study outcomes and the mean difference with a random-effects model was used to determine the effect size. RESULTS: Meta-analysis revealed that high-frequency repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex significantly reduced acute medication intake (Mean Difference = 9.78, p = 0.02, 95%CI: 1.60, 17.96, p = 0.02) and functional disability (Mean Difference = 8.00, p < 0.05, 95%CI: 4.21, 11.79). However, no differences were found in headache days and pain intensity reduction, although there was a slight trend favouring high-frequency repetitive transcranial magnetic stimulation. CONCLUSION: High-frequency repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex may be effective in reducing acute medication intake and disability. However, more studies are needed to strengthen this preliminary evidence.

Knowledge of acute stroke management and the predictors among Malaysian healthcare professionals.

Background: Despite rapid advances in acute ischaemic stroke (AIS) management, many healthcare professionals (HCPs) might not be aware of the latest recommended management of AIS patients. Therefore, we aimed to determine the level and factors associated with AIS management knowledge among Malaysian HCPs. Methods: This cross-sectional online questionnaire study was conducted nationwide among 627 HCPs in Malaysia using the Acute Stroke Management Questionnaire (ASMaQ). Multiple logistic regression was used to predict the relationship between the independent variables (age, gender, years of service, profession, work setting, work sector, seeing stroke patients in daily practice, and working with specialists) and the outcome variable (good vs poor knowledge). Results: Approximately 76% (95% CI [73-79%]) of HCPs had good overall knowledge of stroke. The highest proportion of HCPs with good knowledge was noted for General Stroke Knowledge (GSK) [88.5% (95% CI [86-91%])], followed by Advanced Stroke Management (ASM) [61.2% (95% CI [57-65%])] and Hyperacute Stroke Management (HSM) [58.1% (95% CI [54-62%])]. The odds of having poor knowledge of stroke were significantly higher among non-doctor HCPs [adjusted OR = 3.46 (95% CI [1.49-8.03]), P = 0.004]; among those not seeing stroke patients in daily practice [adjusted OR = 2.67 (95% CI [1.73-4.10]), P < 0.001]; and among those working without specialists [adjusted OR = 2.41 (95% CI [1.38-4.18]), P = 0.002]. Conclusions: Stroke education should be prioritised for HCPs with limited experience and guidance. All HCPs need to be up-to-date on the latest AIS management and be able to make a prompt referral to an appropriate facility. Therefore, more stroke patients will benefit from advanced stroke care.

Neurological Events Reported after COVID-19 Vaccines: An Analysis of VAERS.

OBJECTIVE: To identify the rates of neurological events following administration of mRNA (Pfizer, Moderna) or adenovirus vector (Janssen) vaccines in the U.S.. METHODS: We utilized publicly available data from the U.S. Vaccine Adverse Event Reporting System (VAERS) collected between January 1, 2021-June 14, 2021. All free text symptoms that were reported within 42 days of vaccine administration were manually reviewed and grouped into 36 individual neurological diagnostic categories. Post-vaccination neurological event rates were compared between vaccine types and to age-matched baseline incidence rates in the U.S. and rates of neurological events following COVID. RESULTS: Of 306,907,697 COVID vaccine doses administered during the study timeframe, 314,610 (0.1%) people reported any adverse event and 105,214 (0.03%) reported neurological adverse events in a median of 1 day (IQR0-3) from inoculation. Guillain-Barre Syndrome (GBS), and cerebral venous thrombosis (CVT) occurred in fewer than 1 per 1,000,000 doses. Significantly more neurological adverse events were reported following Janssen (Ad26.COV2.S) vaccination compared to either Pfizer-BioNtech (BNT162b2) or Moderna (mRNA-1273; 0.15% versus 0.03% versus 0.03% of doses, respectively,P<0.0001). The observed-to-expected ratios for GBS, CVT and seizure following Janssen vaccination were ≥1.5-fold higher than background rates. However, the rate of neurological events after acute SARS-CoV-2 infection was up to 617-fold higher than after COVID vaccination. INTERPRETATION: Reports of serious neurological events following COVID vaccination are rare. GBS, CVT and seizure may occur at higher than background rates following Janssen vaccination. Despite this, rates of neurological complications following acute SARS-CoV-2 infection are up to 617-fold higher than after COVID vaccination. This article is protected by copyright. All rights reserved.

Case report: Incomplete penetrance of autosomal dominant myotonia congenita caused by a rare CLCN1 variant c.1667T>A (p.I556N) in a Malaysian family.

Myotonia congenita (MC) is a rare neuromuscular disease caused by mutations within the CLCN1 gene encoding skeletal muscle chloride channels. MC is characterized by delayed muscle relaxation during contraction, resulting in muscle stiffness. There is a lack of MC case reports and data on the prevalence among Malaysians. We report a clinical case of a 50-year-old woman presents with muscle stiffness and cramp episodes that started in early childhood. She had difficulty initiating muscle movement and presented with transient muscle weakness after rest, which usually improved after repeated contraction (warm-up phenomenon). She was diagnosed with MC after myotonic discharge on electromyography (EMG). Her brother had similar symptoms; however, no additional family members showed MC symptoms. Serum creatine kinase levels were elevated in both the proband and her brother with 447 U/L and 228 U/L recorded, respectively. Genetic analysis by whole-exome sequencing (WES) revealed a previously reported pathogenic CLCN1 gene variant c.1667T>A (p.I556N). Genetic screening of all family members revealed that the same variant was observed in the children of both the proband and her brother; however, the children did not present with either clinical or electrophysiological MC symptoms. The multiplex ligation-dependent probe amplification (MLPA) analysis conducted identified neither exon deletion nor duplication in CLCN1. In conclusion, this report describes the first case of MC in Malaysia in which incomplete penetrance observed in this family is caused by a known pathogenic CLCN1 variant.

Longitudinal extensive transverse myelitis following ChAdOx1 nCOV-19 vaccine: a case report.

BACKGROUND: Transverse myelitis (TM) is a relatively uncommon condition, and vaccine-associated myelitis is even rarer. Concern regarding neurological complications following vaccination escalated following the report of TM during the safety and efficacy trials of the COVID-19 vaccine. CASE PRESENTATION: We report the first case of Longitudinal Extensive Transverse Myelitis (LETM) in Malaysia following administration of the chimpanzee adenovirus-vectored (ChAdOx1 nCoV-19) vaccine. A 25-year-old female presented with bilateral lower limb weakness and inability to walk with a sensory level up to T8 with absent visual symptoms. Urgent gadolinium-enhanced magnetic resonance imaging (MRI) of the spine showed long segment TM over the thoracic region. Cerebrospinal fluid autoantibodies for anti-aquaporin-4 and anti-myelin-oligodendrocyte were negative. A diagnosis of LETM following vaccination was made, and the patient was started on a high dose of intravenous methylprednisolone. The patient eventually made a recovery following treatment. CONCLUSION: LETM is a rare but serious adverse reaction following vaccination. Previously reported cases showed an onset of symptoms between 10 to 14 days post-vaccination, suggesting a delayed immunogenic reaction. However, the incidence of myelitis in COVID-19 is much more common, far greater than the risk associated with vaccination.

Transcranial direct current stimulation with multiple oral re-reading therapy for pure alexia without agraphia: a case report.

Pure alexia without agraphia is characterized by impaired reading due to damage to the occipitotemporal cortex with preserved writing skills. In this case report, we investigate the effect of multiple oral re-reading (MOR) therapy adjunct with transcranial direct current stimulation (tDCS) in improving reading recovery of a 64-year-old patient with pure alexia without agraphia following a stroke. His MRI revealed an area of infarct with microhemorrhages at the left occipitotemporal region. The patient was blinded to each therapy and underwent seven consecutive sessions of sham tDCS followed by seven consecutive sessions of real tDCS, coupled with 1-hour MOR therapy during each session. Western Aphasia Battery (WAB) was performed at baseline, before sham and real-tDCS, and 6 weeks after completing tDCS therapy. The patient showed improvement using both sham and real-tDCS with better reading comprehension, average reading time, and word per minute after real-tDCS. This study suggests that MOR, coupled with tDCS therapy may accelerate the reading recovery in patients with pure alexia.

Prevalence of glycemic variability and factors associated with the glycemic arrays among end-stage kidney disease patients on chronic hemodialysis.

ABSTRACT: Glycemic variability (GV) confers a significantly higher risk of diabetic-related complications, especially cardiovascular. Despite extensive research in this area, data on end-stage kidney disease (ESKD) patients on chronic hemodialysis are scarce. This study aims to determine the magnitude of GV among ESKD (diabetic vs nondiabetic) patients and its associated factors on hemodialysis days (HDD) and non-hemodialysis days (NHDD) where postulation of a higher GV observed among diabetic on HDD.We recruited 150 patients on hemodialysis, 93 patients with type 2 diabetic (DM-ESKD), and 57 with nondiabetic (NDM-ESKD). The GV indices (standard deviation [SD] and percentage coefficient variant [%CV]) were obtained from 11-point and 7-point self-monitoring blood glucose (fasting to post-meal) (SMBG) profiles on HDD and NHDD. The GV indices and its associated factors of both DM-ESKD and NDM-ESKD were analyzed to compare HDD vs NHDD.Mean blood glucose on HDD was 9.33 [SD 2.7, %CV 30.6%] mmol/L in DM-ESKD compared with 6.07 [SD 0.85, %CV 21.3%] mmol/L in NDM-ESKD (P = <.01). The DM-ESKD group experienced significantly above target GV indices compared to NDM-ESKD on both HDD and NHDD, particularly in the subgroup with HbA1c 8-10% (P = <.01). Presence of diabetes, older age, hyperlipidemia, HbA1c, ferritin levels, and albumin were identified as factors associated with GV.DM-ESKD patients have above-target GV indices, especially on HDD, therefore increasing their risk of developing future complications. We identified high HbA1c, older age group, presence of hyperlipidemia, ferritin levels, and albumin as factors associated with GV indices that may be used as surrogate markers for GV. Since these groups of patients are vulnerable to CVD mortality, urgent attention is needed to rectify it.

Study protocol to develop a core outcome set for thyroid dysfunction to bridge the unmet needs of patient-centred care.

INTRODUCTION: Thyroid dysfunctions (TD) are common medical conditions affecting all global populations. Improved healthcare leading to increasing survival rates and delayed diagnosis rendered significant burden of the disease in the increasing number of patients with TD with comorbid illnesses. Therefore, reducing the burden of TD and improving the quality of care are crucial. Existing poor-quality data that guide evidence-based decisions only provide a fragmented picture of clinical care. The different outcomes across studies assessing the effectiveness of treatments impede our ability to synthesise results for determining the most efficient treatments. This project aims to produce a core outcome set (COS), which embeds the multiple complex dimensions of routine clinical care for the effectiveness studies and clinical care of adult patients with TD. METHODS AND ANALYSIS: This mixed-method project has two phases. In phase 1, we will identify a list of patient-reported and clinical outcomes through qualitative research and systematic reviews. In phase 2, we will categorise the identified outcomes using the Core Outcome Measures in Effectiveness Trials taxonomy of core domains and the International Classification of Functioning, Disability and Health. We will develop questionnaires from the list of outcomes identified from each domain for the two-round online Delphi exercise, aiming to reach a consensus on the COS. The Delphi process will include patients, carers, researchers and healthcare participants. We will hold an online consensus meeting involving representatives of all key stakeholders to establish the final COS. ETHICS AND DISSEMINATION: The study has been reviewed and approved by the Ethics Committee for Research Involving Human Subjects, Universiti Putra Malaysia and the Research Ethics Committee, National University of Malaysia. This proposed COS in TD will improve the value of data, facilitate high-quality evidence synthesis and evidence-based decision-making. Furthermore, we will present the results to participants, in peer-reviewed academic journals and conferences. REGISTRATION DETAILS: Core Outcome Measures in Effectiveness Trials (COMET) Initiative database registration: http://www.comet-initiative.org/studies/details/1371.

High-frequency repetitive transcranial magnetic stimulation at dorsolateral prefrontal cortex for migraine prevention: A protocol for a systematic review of controlled trials.

BACKGROUND: Migraine may lead to a negative impact on the patients' quality of life with a subsequent substantial burden to society. Therapy options for treatment and prevention of migraine have progressed over the years and repetitive transcranial magnetic stimulation (rTMS) is one of the promising non-pharmacological options. It induces and alters electric current in the brain via repetitive non-invasive brain stimulation in high frequency. In migraine patients, two common stimulation sites are the M1 cortex and dorsolateral prefrontal cortex (DLPFC). The mechanism on how rTMS exerts therapeutic effects on migraine is not fully established, but the main postulation is that the neuromodulation via high-frequency rTMS (hf-rTMS) might inhibit pain perception. However, evidence from studies has been conflicting, thus the usefulness of hf-rTMS as migraine preventive treatment is still uncertain at this moment. METHODS: This is a systematic review protocol describing essential reporting items based on the PRISMA for systematic review protocols (PRISMA-P) (Registration number: CRD42020220636). We aim to review the effectiveness, tolerability, and safety of hf-rTMS at DLPFC in randomised controlled trials (RCTs) as migraine prophylactic treatment. We will search Scopus, Cumulative Index to Nursing and Allied Health Literature Plus, PubMed, Cochrane Central Register of Controlled Trials and Biomed Central for relevant articles from randomised controlled clinical trials that used hf-rTMS applied at DLPFC for the treatment of migraine. The risk of bias will be assessed using the version 2 "Risk of bias" tool from Cochrane Handbook for Systematic Reviews of Interventions Version 6.1. We will investigate the evidence on efficacy, tolerability and safety and we will compare the outcomes between the hf-rTMS intervention and sham groups. DISCUSSION: This systematic review will further determine the efficacy, safety, and tolerability of hf-rTMS applied at DLPFC for migraine prophylaxis. It will provide additional data for health practitioners and policymakers about the usefulness of hf-rTMS for migraine preventive treatment.

Effectiveness and tolerability of repetitive transcranial magnetic stimulation for preventive treatment of episodic migraine: a single-centre, randomised, double-blind, sham-controlled phase 2 trial (Magnet-EM).

BACKGROUND: This is a phase II randomised, double-blind, sham-controlled trial to evaluate the effectiveness and tolerability of repetitive transcranial magnetic stimulation for preventive treatment of episodic migraine amongst migraine subjects. METHODS: Subjects age 18 to 60 years will undergo a baseline evaluation to establish the diagnosis of migraine based on the International Classification of Headache Disorder 3rd Edition (ICHD-3). Those who fulfil the ICHD-3 criteria for episodic migraine and compliant to the headache diary during a month run-in period will be enrolled. A total of 76 subjects will be randomised to receive either transcranial magnetic stimulation or sham stimulation for 5 sessions within 2 weeks duration. Follow-up sessions will be conducted monthly for three consecutive months. Prior to treatment, subjects will be required to fill up questionnaires and undergo few procedures such as electroencephalography, transcranial Doppler ultrasound and biochemical analysis for serum serotonin, serum calcitonin gene-related peptide and serum beta-endorphin. These procedures will be repeated at month 3 after receiving the last treatment. The primary outcome measure of this study is the difference in mean monthly migraine days at baseline and at months 1, 2 and 3 after treatment sessions. DISCUSSION: Following evidence from previous studies showing restoration of dorsolateral prefrontal cortex (DLPFC) activation to almost normal level, the rTMS intervention will target left DLPFC in this study. An intermediate duration of treatment sessions is selected for this study. It is set to five treatment sessions given within 2 weeks duration. TRIAL REGISTRATION: ClinicalTrials.gov NCT03556722 . Registered on 14 June 2018.