Search

Small fiber neuropathy (SFN) is a relatively common, but largely understudied neurological syndrome which has affected the lives of many globally. The common symptoms of SFN include pain, dysesthesia, and autonomic dysfunction, which are caused by damage to small nerve fibers. Due to its heterogeneous nature, SFN causes a multitude of symptoms which makes the disease and its subtypes difficult to diagnose. Furthermore, as the pathophysiology of SFN remains largely enigmatic, no cause is found in around 50% of the cases and these are classified as idiopathic SFN (iSFN). The difficult task of diagnosing SFN, and the even more elusive feat of hunting for the underlying etiology, demands accurate, precise, preferably noninvasive, and affordable tools, or a combination of them. Accordingly, appropriate biomarkers for SFN are needed to stratify patients and develop cause-centered treatments in addition to symptomatic treatments. As peripheral axons grow and repair, identifying underlying causes of SFN and intervening early may spur axonal regeneration in young patients, which can greatly improve their symptoms and improve quality of life. This narrative review aims to objectively highlight functional, histological, and molecular biomarkers to aid clinicians in discerning the diagnostic tests they should use to diagnose, confirm and determine the etiology of SFN. The strengths and limitations of each potential biomarker will be discussed. Clearer diagnostic criteria, guidelines, and work-up for SFN are required for clinicians to better identify the disease in patients presenting with non-specific symptoms.

OBJECTIVE Small fiber neuropathy (SFN) is clinically and etiologically heterogeneous. Although autoimmunity has been postulated to be pathophysiologically important in SFN, few autoantibodies have been described. We aimed to identify autoantibodies associated with idiopathic SFN (iSFN) by a novel high-throughput protein microarray platform that captures autoantibodies expressed in the native conformational state. METHODS Sera from 58 SFN patients and 20 age- and gender-matched healthy controls (HCs) were screened against >1,600 immune-related antigens. Fluorescent unit readout and postassay imaging were performed, followed by composite data normalization and protein fold change (pFC) analysis. Analysis of an independent validation cohort of 33 SFN patients against the same 20 HCs was conducted to identify reproducible proteins in both cohorts. RESULTS Nine autoantibodies were screened with statistical significance and pFC criteria in both cohorts, with at least 50% change in serum levels. Three proteins showed consistently high fold changes in main and validation cohorts: MX1 (FC��=���2.99 and 3.07, respectively, p��=���0.003, q��=���0.076), DBNL (FC��=��2.11 and 2.16, respectively, p��=���0.009, q��

Small-fiber neuropathy (SFN) is a disorder that exclusively affects the small nerve fibers, sparing the large nerve fibers. Thinly myelinated Aδ-fibers and unmyelinated C-fibers are damaged, leading to development of neuropathic pain, thermal dysfunction, sensory symptoms, and autonomic disturbances. Although many SFNs are secondary and due to immunological causes or metabolic disturbances, the etiology is unknown in up to half of the patients. Over the years, this proportion of "idiopathic SFN" has decreased, as familial and genetic causes have been discovered, thus shifting a proportion of once "idiopathic" cases to the genetic category. After the discovery of SCN9A-gene variants in 2012, SCN10A and SCN11A variants have been found to be pathogenic in SFN. With improved accessibility of SFN diagnostic tools and genetic tests, many non-SCN variants and genetically inherited systemic diseases involving the small nerve fibers have also been described, but only scattered throughout the literature. There are 80 SCN variants described as causing SFN, 8 genes causing hereditary sensory autonomic neuropathies (HSAN) described with pure SFN, and at least 7 genes involved in genetically inherited systemic diseases associated with SFN. This systematic review aims to consolidate and provide an updated overview on the genetic variants of SFN to date---SCN genes and beyond. Awareness of these genetic causes of SFN is imperative for providing treatment directions, prognostication, and management of expectations for patients and their health-care providers.

IntroductionWhite matter hyperintensities (WMHs) have been observed with greater frequency in patients with migraine and are thought to be associated with impaired cognition and function. The relationship between WMHs and right-to-left shunt (RLS) in migraine patients is unknown. We performed a systematic review to determine if there is an association between RLS and WMHs in patients with migraine.MethodsA systematic search of the literature was performed in PubMed and Embase using a suitable keyword search strategy from inception up to 16th June 2021. All studies that included patients with migraine and studied RLS and WMHs were included.ResultsA total of 8 non-randomized observational studies comprising 1125 patients with migraine were included; 576 had an RLS, compared to 549 patients with no RLS. The mean age of the study populations ranged from 28.4 to 43 years, while the average duration from migraine diagnosis ranged from 5.1 to 19 years. The proportion of female to male patients was consistently higher in all studies (60.0–94.4%). Amongst migraine patients with RLS, 338 patients (58.7%) had WMHs. In contrast, 256 (46.6%) of migraine patients without RLS had WMHs. RLS was significantly associated with the presence of WMHs in migraine patients (OR: 1.56, 95% CI: 1.05–2.34, p = 0.03).ConclusionIn migraine patients, RLS was significantly associated with the presence of WMHs. Longitudinal studies are warranted to establish RLS as a risk factor for WMHs in patients with migraine, and to establish the significance of these changes.

An increasing number of studies have shown an association between migraine and cardiovascular disease, in particular cardio- and cerebro-vascular events.Three electronic databases (PubMed, Embase and Scopus) were searched from inception to May 22, 2021 for prospective cohort studies evaluating the risk of myocardial infarction, stroke and cardiovascular mortality in migraine patients. A random effects meta-analysis model was used to summarize the included studies.A total of 18 prospective cohort studies were included consisting of 370,050 migraine patients and 1,387,539 controls. Migraine was associated with myocardial infarction (hazard ratio, 1.36; 95% CI, 1.23-1.51; p = 0.001), unspecified stroke (hazard ratio, 1.30; 95% CI, 1.07-1.60; p = 0.01), ischemic stroke (hazard ratio, 1.35; 95% CI, 1.03-1.78; p = 0.03) and hemorrhagic stroke (hazard ratio, 1.43; 95% CI, 1.07-1.92; p = 0.02). Subgroup analysis of migraine with aura found a further increase in risk of myocardial infarction and both ischemic and hemorrhagic stroke, as well as improved substantial statistical heterogeneity. Migraine with aura was also associated with an increased risk of cardiovascular mortality (hazard ratio, 1.27; 95% CI, 1.14-1.42; p = 0.001).Migraine, especially migraine with aura, is associated with myocardial infarction and stroke. Migraine with aura increases the risk of overall cardiovascular mortality.

Purpose of Review Personal protection equipment (PPE)–associated headache is an unusual secondary headache disorder that predominantly occurs in healthcare workers as a consequence of the donning of protective respirators, face masks and/or eyewear. The appreciation of this entity is important given the significant ramifications upon the occupational health of healthcare workers and could additionally have an impact on persons living with pre-existing headache disorder(s). Recent Findings There has been a renewed interest and recognition of PPE-associated headaches amongst healthcare professionals, largely brought about by the ongoing COVID-19 pandemic which has besieged healthcare systems worldwide. De novo PPE-associated headaches may present with migrainous or tension-type features and can be viewed as a subtype of external compression headache. The prognosis of the disorder is generally favourable, given that most headaches are short-lived without long-term sequalae. Several aetiologies have been postulated to account for the development of these headaches. Notably, these headaches can affect the occupational health and work performance of healthcare workers. Summary In this review, we discuss the epidemiology, clinical characteristics, probable etiopathogenesis, management and prognosis of PPE-associated headaches in the context of the COVID-19 pandemic. Future directions for research and PPE development are proposed.

Background and purpose COVID-19 pandemic led to wide-spread use of face-masks, respirators and other personal protective equipment (PPE) by healthcare workers. Various symptoms attributed to the use of PPE are believed to be, at least in part, due to elevated carbon-dioxide (CO2) levels. We evaluated concentrations of CO2 under various PPE. Methods In a prospective observational study on healthy volunteers, CO2 levels were measured during regular breathing while donning 1) no mask, 2) JustAir® powered air purifying respirator (PAPR), 3) KN95 respirator, and 4) valved-respirator. Serial CO2 measurements were taken with a nasal canula at a frequency of 1-Hz for 15-min for each PPE configuration to evaluate whether National Institute for Occupational Safety and Health (NIOSH) limits were breached. Results The study included 11 healthy volunteers, median age 32 years (range 16–54) and 6 (55%) men. Percent mean (SD) changes in CO2 values for no mask, JustAir® PAPR, KN95 respirator and valve respirator were 0.26 (0.12), 0.59 (0.097), 2.6 (0.14) and 2.4 (0.59), respectively. Use of face masks (KN95 and valved-respirator) resulted in significant increases in CO2 concentrations, which exceeded the 8-h NIOSH exposure threshold limit value-weighted average (TLV-TWA). However, the increases in CO2 concentrations did not breach short-term (15-min) limits. Importantly, these levels were considerably lower than the long-term (8-h) NIOSH limits during donning JustAir® PAPR. There was a statistically significant difference between all pairs (p p = 0.25). However, whether increase in CO2 levels are clinically significant remains debatable. Conclusion Although, significant increase in CO2 concentrations are noted with routinely used face-masks, the levels still remain within the NIOSH limits for short-term use. Therefore, there should not be a concern in their regular day-to-day use for healthcare providers. The clinical implications of elevated CO2 levels with long-term use of face masks needs further studies. Use of PAPR prevents relative hypercapnoea. However, whether PAPR should be advocated for healthcare workers requiring PPE for extended hours needs to evaluated in further studies.

Background: Despite vaccination against SARS-CoV-2 (Covid-19), individuals may still develop acute COVID-19 illness. We examined the clinical profile and outcomes of healthcare workers (HCW) in India who developed Covid-19 infection despite being vaccinated. Methods: HCWs in India who developed acute Covid-19 infection despite receiving at least 1 dose of the vaccination were invited to complete an online questionnaire. Out of contacted 2160 HCWs, 316 (14.6%) developed acute Covid-19 infection post- vaccination. We compared their clinical profile based on whether they had received the first or second dose of vaccine, presence or absence of pneumonia and fever at presentation. Results: Of the 316 participants, 50 (15.8%) had developed Covid-19 after receiving only the first dose of the vaccine. Participants who completed both doses of vaccine (n=266) were more likely to be asymptomatic (13.9% vs 2.0%, p=0.016), but clinical outcomes such as hospitalization, need for mechanical ventilation and supplemental oxygen were similar. Participants with pneumonia (n=105, 33.2%) had elevated C-reactive protein (CRP, 25.4±21.2 vs 6.8±8.8 mg/L, p

Migraine is one of top 5 medical conditions that contribute to Years Lived with Disability and affects approximately 1 billion people from around the world. To date, preventive treatment and acute therapies for migraine are limited, have undesirable side effects and are poorly tolerated in patients. In the last few decades, considerable advances in our understanding of migraine and its pathophysiology have paved the way for the development of targeted treatment options. Calcitonin gene-related peptide (CGRP) plays an integral role in the neurobiology of migraine, and new classes of drugs that target the CGRP pathway have included gepants and CGRP pathway monoclonal antibodies. Serotonin 5-HT

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease of pandemic proportions. Healthcare workers in Singapore working in high-risk areas were mandated to wear personal protective equipment (PPE) such as N95 face mask and protective eyewear while attending to patients.We sought to determine the risk factors associated with the development of de novo PPE-associated headaches as well as the perceived impact of these headaches on their personal health and work performance. The impact of COVID-19 on pre-existing headache disorders was also investigated.This is a cross-sectional study among healthcare workers at our tertiary institution who were working in high-risk hospital areas during COVID-19. All respondents completed a self-administered questionnaire.A total of 158 healthcare workers participated in the study. Majority [126/158 (77.8%)] were aged 21-35 years. Participants included nurses [102/158 (64.6%)], doctors [51/158 (32.3%)], and paramedical staff [5/158 (3.2%)]. Pre-existing primary headache diagnosis was present in about a third [46/158 (29.1%)] of respondents. Those based at the emergency department had higher average daily duration of combined PPE exposure compared to those working in isolation wards [7.0 (SD 2.2) vs 5.2 (SD 2.4) hours, P .0001] or medical ICU [7.0 (SD 2.2) vs 2.2 (SD 0.41) hours, P .0001]. Out of 158 respondents, 128 (81.0%) respondents developed de novo PPE-associated headaches. A pre-existing primary headache diagnosis (OR = 4.20, 95% CI 1.48-15.40; P = .030) and combined PPE usage for4 hours per day (OR 3.91, 95% CI 1.35-11.31; P = .012) were independently associated with de novo PPE-associated headaches. Since COVID-19 outbreak, 42/46 (91.3%) of respondents with pre-existing headache diagnosis either "agreed" or "strongly agreed" that the increased PPE usage had affected the control of their background headaches, which affected their level of work performance.Most healthcare workers develop de novo PPE-associated headaches or exacerbation of their pre-existing headache disorders.

BACKGROUND: Recanalization of occluded intracranial arteries remains the aim of intravenous (IV) tissue plasminogen activator (tPA) therapy in acute ischemic stroke (AIS). OBJECTIVE: To examine the timing and impact of recanalization on functional outcomes in AIS. DESIGN: A longitudinal cohort of consecutive IV tPA–treated patients with AIS from January 2007 through December 2010. Data were collected for demography, risk factors, stroke subtypes, blood pressure, and National Institutes of Health Stroke Scale scores. Early recanalization (ER) was identified by transcranial Doppler monitoring during the first 2 hours of treatment. Recanalization was reevaluated at 24 hours by computed tomographic angiography (CTA). Patients with ER and patent index artery at 24 hours on CTA were labeled as having persistent recanalization (PR). Recanalization at 24 hours on CTA regardless of transcranial Doppler status was labeled as CTR. Favorable outcome was defined as a modified Rankin Scale score of 0 to 1 at 3 months. SETTING: University hospital stroke center. PATIENTS: A total of 240 patients with AIS who underwent IV tPA treatment. RESULTS: Of 2238 patients with AIS, 240 (11%) received IV tPA. The median age was 65 years (range, 19-92 years) and 44% of the study group was male. The median National Institutes of Health Stroke Scale score was 17 (range, 3-35) and the median onset-to-treatment time was 149 minutes (range, 46-270 minutes). Of the 240 patients, 122 (50.8%) achieved favorable outcomes at 3 months. Data for ER, PR, and CTR were analyzed for 160 patients. Early recanalization was seen in 82 patients (51.3%); 67 cases (81.7%) had PR and 84 cases (52.5%) had CTR. National Institutes of Health Stroke Scale score at onset (odds ratio per 1-point increase, 0.938; 95% CI, 0.888-0.991), ER (odds ratio, 3.048; 95% CI, 1.537-6.046), PR (odds ratio, 5.449; 95% CI, 2.382-12.464), and CTR (odds ratio, 4.329; 95% CI, 2.131-8.794) were independent predictors of favorable outcomes. CONCLUSIONS: Intravenous tPA–induced arterial recanalization within the first 24 hours in AIS is a strong predictor of favorable outcomes at 3 months.

Evaluation of: Cui R, Iso H, Yamagishi K et al.; JPHC Study Group. High serum total cholesterol levels is a risk factor of ischemic stroke for general Japanese population: the JPHC study. Atherosclerosis 221(2), 565–569 (2012). An elevated cholesterol level is one of the established modifiable risk factors for secondary prevention of stroke. However, the stroke–cholesterol relationship remains a relatively weak relationship. Furthermore, the controversy regarding the optimal cholesterol level still persists. While elevated cholesterol levels are associated with higher risk for cerebral ischemic events, lower levels might increase the risk for hemorrhagic events. This study by Cui and colleagues presents robust large-scale epidemiological data regarding the association of elevated total cholesterol with the stroke risk among the Asian cohort. One of the important findings of this study is the relationship between elevated cholesterol and large artery atherosclerotic stroke. This is especially relevant in the Asian context, where large artery atherosclerosis constitutes more than half of all ischemic stroke subtypes. This paper reviews the study by Cui and colleagues regarding the role of high serum total cholesterol as a risk factor for ischemic stroke in Japanese men.

A 51-year-old woman experienced intermittent left hand numbness and weakness over 2 years, with a claw-hand deformity and weakness of finger abduction, adduction, and distal interphalangeal joint flexion of the medial 2 fingers. Wrist flexion produced hand radial deviation. Palmar and dorsal aspects of digits IV (medially) and V, including medial forearm, had decreased pinprick sensation. Nerve conduction studies showed conduction block 14 cm above the medial epicondyle (figure 1), where Tinel sign was positive. Sonography (figure 2) revealed a hyperechogenic structure distorting the ulnar nerve. The patient had a surgically implanted subdermal contraceptive 10 years prior, causing a rare occurrence of neuropathy.1,2

Objective: To determine the usefulness of Eutectic Mixture of Local Anesthetic (EMLA)-induced stimulated skin wrinkling (SSW) to detect diabetic sensorimotor polyneuropathy (DSPN). Research Design and Methods: Two hundred and ten diabetics were prospectively recruited (mean age 58.5 ± 12.7 years) from a large tertiary center from 2009 to 2011. EMLA was applied to the tips of digits 2, 3, and 4 and the degree of wrinkling graded. Diabetic Neuropathy Symptom (DNS) score, nerve conduction studies (NCS), Semmes–Weinstein monofilament (SWMF) tests, and vibratory perception thresholds (VPTs) testing were chosen as comparative clinical standards to diagnose length-dependent DSPN. Results: Inter-rater agreement for two examiners of SSW was high, with Cohen’s weighted κ of 0.912 for the right hand, and 0.823 for the left. K measure of agreement of SSW with the NCS, DNS scores, SWMF testing, and VPT testing was 0.486, 0.243, 0.289, and 0.395 respectively. SSW was able to distinguish between normal and abnormal NCS and DNS results, with median scores of 3.333 vs. 1.667 (p