A novel variant in the tropomyosin 3 gene presenting as an adult-onset distal myopathy - a case report.

BACKGROUND: We report a patient with a novel c.737 C > T variant (p.Ser246Leu) of the TPM3 gene presenting with adult-onset distal myopathy. CASE PRESENTATION: A 35-year-old Chinese male patient presented with a history of progressive finger weakness. Physical examination revealed differential finger extension weakness, together with predominant finger abduction, elbow flexion, ankle dorsiflexion and toe extension weakness. Muscle MRI showed disproportionate fatty infiltration of the glutei, sartorius and extensor digitorum longus muscles without significant wasting. Muscle biopsy and ultrastructural examination showed a non-specific myopathic pattern without nemaline or cap inclusions. Genetic sequencing revealed a novel heterozygous p.Ser246Leu variant (c.737C>T) of the TPM3 gene which is predicted to be pathogenic. This variant is located in the area of the TPM3 gene where the protein product interacts with actin at position Asp25 of actin. Mutations of TPM3 in these loci have been shown to alter the sensitivity of thin filaments to the influx of calcium ions. CONCLUSION: This report further expands the phenotypic spectrum of myopathies associated with TPM3 mutations, as mutations in TPM3 had not previously been reported with adult-onset distal myopathy. We also discuss the interpretation of variants of unknown significance in patients with TPM3 mutations and summarise the typical muscle MRI findings of patients with TPM3 mutations.

Unique Clinical, Radiological and Histopathological Characteristics of a Southeast Asian Cohort of Patients with Limb-Girdle Muscular Dystrophy 2G/LGMD-R7-Telethonin-Related.

AIM: We describe a cohort of five patients with limb-girdle muscular dystrophy (LGMD) 2G/LGMD-R7 in a South-east Asian cohort. BACKGROUND: LGMD2G/LGMD-R7-telethonin-related is caused by mutations in the TCAP gene that encodes for telethonin. METHODS: We identified consecutive patients with LGMD2G/LGMD-R7-telethonin-related, diagnosed at the National Neuroscience Institute (NNI) and National University Hospital (NUH) between January 2000 and June 2021. RESULTS: At onset, three patients presented with proximal lower limb weakness, one patient presented with Achilles tendon contractures, and one patient presented with delayed gross motor milestones. At last follow up, three patients had a limb girdle pattern of muscle weakness and two had a facioscapular humeral pattern of weakness. Whole body muscle MRI performed for one patient with a facioscapular-humeral pattern of weakness showed a pattern of muscle atrophy similar to facioscapular-humeral dystrophy. One patient had histological features consistent with myofibrillar myopathy; electron microscopy confirmed the disruption of myofibrillar architecture. One patients also had reduced staining to telethonin antibody on immunohistochemistry. CONCLUSION: We report the unique clinical and histological features of a Southeast Asian cohort of five patients with LGMD2G/LGMD-R7-telethonin-related muscular dystrophy and further expand its clinical and histopathological spectrum.

Acute to Subacute Atraumatic Entrapment Neuropathies in Patients With CMT1A: A Report of a Distinct Phenotypic Variant of CMT1A.

Charcot-Marie-Tooth type 1A (CMT1A) is typically characterised as a childhood-onset, symmetrical, length-dependent polyneuropathy with a gradual progressive clinical course. Acute to subacute neurological deterioration in CMT1A is rare, and has been reported secondary to overlap pathologies including inflammatory neuropathy. We identified two patients with CMT1A who presented with acute to subacute, atraumatic, entrapment neuropathies as an initial symptom. A superimposed inflammatory neuropathy was excluded. Both patients had a diffuse demyelinating polyneuropathy, with markedly low motor nerve conduction velocities (<20 m/s). In both patients, we demonstrated symptomatic and asymptomatic partial conduction blocks at multiple entrapment sites. Nerve ultrasound findings in our patients demonstrated marked diffuse nerve enlargement, more pronounced at non-entrapment sites compared to entrapment sites. We discuss ways to distinguish this condition from its other differentials. We propose pathophysiological mechanisms underlying this condition. We propose that CMT1A with acute to subacute, atraumatic, entrapment neuropathies to be a distinct phenotypic variant of CMT1A.

Hospital-based observational study of neurological disorders in patients recently vaccinated with COVID-19 mRNA vaccines.

PURPOSE: We describe the spectrum of acute neurological disorders among hospitalized patients who recently had COVID-19 mRNA vaccination. METHOD: We performed a prospective study at 7 acute hospitals in Singapore. Hospitalized patients who were referred for neurological complaints and had COVID-19 mRNA vaccines, BNT162b2 and mRNA-1273, in the last 6 weeks were classified into central nervous system (CNS) syndromes, cerebrovascular disorders, peripheral nervous system (PNS) disorders, autonomic nervous system (ANS) disorders and immunization stress-related responses (ISRR). RESULTS: From 30 December 2020 to 20 April 2021, 1,398,074 persons (median age 59 years, 54.5% males) received COVID-19 mRNA vaccine (86.7% BNT162b2, 13.3% mRNA-1273); 915,344(65.5%) completed 2 doses. Four hundred and fifty-seven(0.03%) patients were referred for neurological complaints [median age 67(20-97) years, 281(61.5%) males; 95.8% received BNT162b2 and 4.2% mRNA-1273], classified into 73(16.0%) CNS syndromes, 286(62.6%) cerebrovascular disorders, 59(12.9%) PNS disorders, 0 ANS disorders and 39(8.5%) ISRRs. Eleven of 27 patients with cranial mononeuropathy had Bell's palsy. Of 33 patients with seizures, only 4 were unprovoked and occurred within 2 weeks of vaccination. All strokes occurred among individuals with pre-existing cardiovascular risk factors. We recorded 2 cases of cerebral venous thrombosis; none were vaccine-induced thrombotic thrombocytopenia. Five had mild flares of immune-mediated diseases. CONCLUSION: Our observational study does not establish causality of the described disorders to vaccines. Though limited by the lack of baseline incidence data of several conditions, we observed no obvious signal of serious neurological morbidity associated with mRNA vaccination. The benefits of COVID-19 vaccination outweigh concerns over neurological adverse events.

Hereditary Transthyretin Amyloidosis- Clinical and Genetic Characteristics of a Multiracial South-East Asian Cohort in Singapore.

BACKGROUND AND AIMS: Studies of hereditary transthyretin amyloidosis (ATTRv amyloidosis) in South-East Asia are underrepresented in the literature. We report the unique phenotypic and genetic characteristics of this disorder in a multiracial South-East Asian cohort. METHODS: Patients with genetically proven ATTRv amyloidosis were identified over a 13-year period (2007-2020) at the National Neuroscience Institute, Singapore. Clinical, laboratory, genotypic and electrophysiological features were retrospectively reviewed. RESULTS: 29 patients comprising Chinese, Malay, Burmese, Vietnamese and Indonesians with ATTRv amyloidosis were identified. Somatic neuropathy was the most common initial presentation, followed by carpal tunnel syndrome, autonomic dysfunction and cardiac dysfunction. ATTR-A97S (p.Ala117Ser) was the most common variant found in 14 patients, constituting 66.7%of ethnic Chinese patients and 48.3%of the entire cohort. Five patients had early-onset disease (age < 50 years) with the following variants: ATTR-V30M (p.Val50Met), ATTR-G47A (p.Gly67Ala), ATTR-S50I (p.Ser70Ile) and ATTR-A97S (p.Ala117Ser); one patient with ATTR-A97S (p.Ala117Ser) had isolated unilateral carpal tunnel syndrome with amyloid deposits identified on histological examination of the transverse carpal ligament. All early-onset patients had a positive parental history; two patients, with ATTR-S50I (p.Ser70Ile) and ATTR-Ala97Ser (p.Ala117Ser) respectively, demonstrated anticipation with mother-to-daughter inheritance. Amongst the 24 patients with late-onset disease (age≥50 years), two patients had novel variants, ATTR-G66D (p.Glu86Asp) and ATTR-A81V (p.Ala101Val) that were confirmed to be pathogenic based on the histological identification of transthyretin amyloid. Other identified variants included ATTR-V30M (p.Val50Met), ATTR-R34T (p.Arg54Thr), ATTR-S50I (p.Ser70Ile), ATTR-H88R (p.His108Arg) and ATTR-A97S (p.Ala117Ser). CONCLUSION: Our study further expands the genotypic and phenotypic knowledge regarding ATTRv amyloidosis.

Use of Twitter in Neurology: Boon or Bane?

Twitter is a free, open access social media platform that is widely used in medicine by physicians, scientists, and patients. It provides an opportunity for advocacy, education, and collaboration. However, it is likely not utilized to its full advantage by many disciplines in medicine, and pitfalls exist in its use. In particular, there has not been a review of Twitter use and its applications in the field of neurology. This review seeks to provide an understanding of the current use of Twitter in the field of neurology to assist neurologists in engaging with this potentially powerful application to support their work.

Transient global amnesia and focal diffusion weighted imaging lesions in mesiotemporal region: A ten-year experience.

OBJECTIVE: To determine prevalence and characteristics of mesiotemporal diffusion weighted imaging (DWI) lesions in transient global amnesia (TGA), and to determine prevalence of "missed" DWI lesions on routine radiological reporting. METHODS: This is a retrospective study of patients with TGA admitted to a tertiary care hospital over ten years. Patients with TGA, who underwent magnetic resonance imaging (MRI) of the brain within one week of index event, were included in this study. MRI's were reviewed by two independent raters. Clinical data and other investigations were collated. RESULTS: Of the 55 patients of TGA, 19 (35 %) had hyperintense DWI lesions with concordant apparent diffusion coefficient (ADC) hypointensity in the mesiotemporal region. Fifteen out of 19 (79 %) had unilateral lesions (6 left, 9 right). Twelve out of 19 DWI lesions were reported at the time of index scan. The false negative reporting rate was 36.8 %. DWI slice thickness (5 mm versus 3 mm), MRI machine strength (1.5 versus 3 T) and time interval from symptom onset to MRI brain (>24 h versus ≤ 24 h) were not significantly different between patients with or without DWI lesions and as well between patients with DWI lesions missed and initially reported at the time of index scan. CONCLUSION: Punctuate DWI mesiotemporal lesions in TGA are prone to under-reporting. These lesions need to be categorically searched for at the time of reporting MRI Brain.

Syphilitic Spinal Disease: An Old Nemesis Revisited. A Case Series and Review of Literature.

ABSTRACT: Syphilitic spinal disease is a rare condition caused by the spirochete Treponema pallidum, either from direct spirochete involvement of the cord or as a consequence of indirect spirochete involvement of the meninges, blood vessels, or the vertebral column. After the introduction of penicillin therapy in the 1940s, it has become an increasingly rare condition. We report 3 challenging cases of syphilitic spinal disease presenting as myelopathy-1 with an extra-axial gumma of tertiary syphilis causing cord compression and 2 with tabes dorsalis complicated by tabetic spinal neuroarthropathy-each presenting a diagnostic dilemma to their treating physicians. We also review the literature for updates on modern investigative modalities and discuss pitfalls physicians need to avoid to arrive at the diagnosis.

Facial Nerve Involvement Accompanying Optic Neuritis Secondary to Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disorder.

ABSTRACT: We present the first reported case of facial nerve involvement accompanying an optic neuritis in myelin oligodendrocyte glycoprotein antibody-associated disorder.

Neurology of COVID-19 in Singapore.

PURPOSE: To describe the spectrum of COVID-19 neurology in Singapore. METHOD: We prospectively studied all microbiologically-confirmed COVID-19 patients in Singapore, who were referred for any neurological complaint within three months of COVID-19 onset. Neurological diagnoses and relationship to COVID-19 was made by consensus guided by contemporaneous literature, refined using recent case definitions. RESULTS: 47,572 patients (median age 34 years, 98% males) were diagnosed with COVID-19 in Singapore between 19 March to 19 July 2020. We identified 90 patients (median age 38, 98.9% males) with neurological disorders; 39 with varying certainty of relationship to COVID-19 categorised as: i) Central nervous system syndromes-4 acute disseminated encephalomyelitis (ADEM) and encephalitis, ii) Cerebrovascular disorders-19 acute ischaemic stroke and transient ischaemic attack (AIS/TIA), 4 cerebral venous thrombosis (CVT), 2 intracerebral haemorrhage, iii) Peripheral nervous system-7 mono/polyneuropathies, and a novel group, iv) Autonomic nervous system-4 limited dysautonomic syndromes. Fifty-one other patients had pre/co-existent neurological conditions unrelated to COVID-19. Encephalitis/ADEM is delayed, occurring in critical COVID-19, while CVT and dysautonomia occurred relatively early, and largely in mild infections. AIS/TIA was variable in onset, occurring in patients with differing COVID-19 severity; remarkably 63.2% were asymptomatic. CVT was more frequent than expected and occurred in mild/asymptomatic patients. There were no neurological complications in all 81 paediatric COVID-19 cases. CONCLUSION: COVID-19 neurology has a wide spectrum of dysimmune-thrombotic disorders. We encountered relatively few neurological complications, probably because our outbreak involved largely young men with mild/asymptomatic COVID-19. It is also widely perceived that the pandemic did not unduly affect the Singapore healthcare system.

How can the World Stroke Organization (WSO) optimize education in stroke medicine around the world? Report of the 2018 WSO Global Stroke Stakeholder Workshop.

BACKGROUND: Education in stroke is relevant to stroke survivors, clinicians, care providers, and healthcare system administrators and is of special importance in resource-limited settings. The World Stroke Organization Education Committee undertook a program of work, culminating in a focused workshop, to establish the key educational priorities, and work toward maximizing the WSOs impact on the global burden of stroke. METHODS: A facilitated workshop took place during the World Stroke Congress in Montreal, Canada in October 2018. The workshop was developed using opinions on priority topics for World Stroke Organization educational activities obtained from web-based surveys of World Stroke Organization Members, supplemented by interviews with international stroke support organizations. The workshop included over 50 international participants, selected to represent a balance of age, gender, geographical region, and different levels of health resources. Participants also included members of the World Stroke Organization Education Committee, the World Stroke Academy, stroke support organizations, and the International Journal of Stroke editorial board. The workshop focused on understanding more about educational needs (at all levels), with emphasis on resource-limited settings. Three broad questions were posed: (1) What are the key educational needs: (a) in your region, (b) from your perspective (e.g. stroke support organization)? (2) Do the current educational activities offered by World Stroke Organization and WSA meet your needs? (3) What could World Stroke Organization/World Stroke Academy offer in your region that would meet your needs? The facilitated discussions were recorded, and the results transcribed and summarized by members of the World Stroke Organization Education Committee. RESULTS: Five key needs were identified: 1. Collaborative interdisciplinary, training in both stroke care and how to advocate for stroke. 2. Educational materials provided in a wider range of formats that could be adapted to local circumstances and clinical practices. 3. Educational activities for healthcare providers and stroke support organizations organized regionally, with the World Stroke Organization providing organizational support, and a pool of experts, therapists, nurses, etc. to deliver locally relevant materials. 4. Clear and authoritative online resources, where it is easy to find key policy and protocol guidance. 5. A range of online interactive education and training resources to help build knowledge and competence in stroke care. CONCLUSION: The results of the workshop have been presented to the World Stroke Organization Board and will be used to help to guide the educational initiatives of the World Stroke Organization and World Stroke Academy going forward.

Increased blood pressure variability after acute ischemic stroke increases the risk of death: A secondary analysis of the Virtual International Stroke Trial Archive.

BACKGROUND: Despite promising epidemiological data, it remains unclear if increased blood pressure variability is associated with death after acute ischemic stroke. Our objective was to examine this association in a large cohort of acute ischemic stroke patients. METHODS: We conducted a retrospective analysis of anonymized, pooled, participant data from the Virtual International Stroke Trial Archive. We included patients with a 90-day modified Rankin Scale and blood pressure readings in the 24 h after study enrollment. The exposure was blood pressure variability during the day after study enrollment, calculated for the systolic and diastolic blood pressure using six statistical methodologies. The primary outcome was death within 90 days of stroke onset. RESULTS: Our cohort comprised 1891 patients of whom 277 (14.7%) died within 90 days. All indices of blood pressure variability were higher in patients who died, but the difference was more pronounced for systolic than diastolic blood pressure variability (systolic standard deviation for alive versus dead patients = 13.4 versus 15.9 mmHg, p < 0.001). Similar results were found in logistic regression models fit to the outcome of death, but only systolic blood pressure variability remained significant in adjusted models (Odds Ratio for death when comparing highest to lowest tercile of systolic blood pressure variability = 1.41-1.89, p < 0.03 for all).Conclusions and relevance: These results reinforce prior studies that found increased blood pressure variability is associated with worse neurologic outcome after stroke. These data should help guide research on blood pressure variability after stroke and advocate for the inclusion of death as a clinical outcome in future studies that therapeutically reduce blood pressure variability.

Top 10 global educational topics in stroke: A survey by the World Stroke Organization.

AIM: As part of a program of work to develop an educational strategy and implementation plan for the World Stroke Organization, we conducted a survey of World Stroke Organization members (health professionals, laypersons (Stroke Support Organizations)) to identify their potential educational needs. METHODS: We developed a questionnaire to identify priority educational needs in consultation with the World Stroke Organization Education Committee. The World Stroke Organization invited all individual members and associated Stroke Support Organizations to complete the questionnaire via a web-based survey. Survey responses were supplemented by questionnaires emailed directly to key persons in Stroke Support Organizations and information from semi-structured telephone interviews, where necessary. The questionnaire asked respondents to prioritize topics in diagnosis, management of acute stroke, stroke care services, stroke rehabilitation, and stroke prevention. Free-text responses were assessed with word cloud. RESULTS: The online survey was completed by 264 respondents from 60 countries; 19.1% were from low- and middle-income countries, 59% were stroke specialist physicians, 28% allied health professionals or nurses, 9% Stroke Support Organizations, 4% general physicians. Fifteen Stroke Support Organizations from 11 countries responded to the emailed survey. Seven Stroke Support Organizations' members were interviewed by telephone; one was interviewed in-person. We highlight the two highest priority topics in each of the five questionnaire domains. CONCLUSION: The 10 priority topics were all applicable in a low- or middle-income setting: setting up and delivering stroke diagnosis, treatment, rehabilitation and prevention services, and emphasized the most basic elements of care. The survey participants have identified a number of key topics that merit inclusion in stroke teaching materials and courses, especially those aimed at practitioners working in resource-limited settings.

Acute flaccid paralysis: Do not forget beriberi neuropathy.

We aimed to elucidate characteristics of beriberi neuropathy (BB) in a general hospital (GH) setting. Nerve conduction studies (NCS), cross-referenced with clinical records of patients admitted to a GH (May 2011-July 2017), were reviewed for diagnosis of BB. Thirteen patients (age range 23-64 years; five women) were diagnosed with BB. Eleven were incarcerated (2-24 months) at time of index event. Eleven reported prior, severe anorexia (2-6 months); five reported significant weight loss, three had recurrent vomiting, and three reported alcohol misuse. Commonest presentation was weakness (12/13); nine had symptom evolution over ≥3 weeks. At nadir, 11/13 could not walk independently. Other features included numbness/paraesthesiae (10/13), dysautonomia (6/13), vocal cord dysfunction/dysphagia (4/13), nystagmus (3/13). Pain was not prominent. Cerebrospinal fluid, tested in five patients, was acellular; one showed mildly increased protein. NCS showed predominantly sensorimotor, axonal polyneuropathy, rarely asymmetric. Only one patient had sural-sparing pattern. All received high dose thiamine. Two of the thirteen received intravenous immunoglobulin for suspicion of Guillain-Barré syndrome (GBS). Eleven improved to independent ambulation. One patient died from pulmonary embolism; one was lost to follow-up. Two of the thirteen had residual neurocognitive effects; both misused alcohol. Besides GBS, BB is an important cause of acute to subacute flaccid paralysis, especially in incarcerated patients and those with significant dietary deprivation. Features favoring BB over GBS are ≥3 weeks of symptoms, nystagmus, confusion, vocal cord dysfunction, volume overload, normal spinal fluid, elevated lactate, and absence of sural-sparing pattern in NCS.

Stroke doctors: Who are we? A World Stroke Organization survey.

Background Specialist training provides skilled workforce for service delivery. Stroke medicine has evolved rapidly in the past years. No prior information exists on background or training of stroke doctors globally. Aims To describe the specialties that represent stroke doctors, their training requirements, and the scientific organizations ensuring continuous medical education. Methods The World Stroke Organization conducted an expert survey between June and November 2014 using e-mailed questionnaires. All Organization for Economic Co-operation and Development countries with >1 million population and other countries with >50 million population were included ( n = 49, total 5.6 billion inhabitants, 85% of global strokes). Two stroke experts from each selected country were surveyed, discrepancies resolved, and further information on identified stroke-specific curricula sought. Results We received responses from 48 (98%) countries. Of ischemic stroke patients, 64% were reportedly treated by neurologists, ranging from 5% in Ireland to 95% in the Netherlands. Per thousand annual strokes there were average six neurologists, ranging from 0.3 in Ethiopia to 33 in Israel. Of intracerebral hemorrhage patients, 29% were reportedly treated by neurosurgeons, ranging from 5% in Sweden to 79% in Japan, with three neurosurgeons per thousand strokes, ranging from 0.1 in Ethiopia to 24 in South Korea. Most countries had a stroke society (86%) while only 10 (21%) had a degree or subspecialty for stroke medicine. Conclusions Stroke doctor numbers, background specialties, and opportunities to specialize in stroke vary across the globe. Most countries have a scientific society to pursue advancement of stroke medicine, but few have stroke curricula.

Prevalence and Risk Factors of Acute Incidental Infarcts.

BACKGROUND AND PURPOSE: The study of silent stroke has been limited to imaging of chronic infarcts; acute incidental infarcts (AII) detected on brain magnetic resonance imaging have been less investigated. This study aims to describe prevalence and risk factors of AII in a community and a clinic-based population. METHODS: Subjects were drawn from 2 ongoing studies: Epidemiology of Dementia in Singapore study, which is a subsample from a population-based study, and a clinic-based case-control study. Subjects from both studies underwent similar clinical and neuropsychological assessments and brain magnetic resonance imaging. Prevalence of AII from these studies was determined. Subsequently, risk factors of AII were examined using multivariable logistic regression models. RESULTS: AII were seen in 7 of 623 (1.2%) subjects in Epidemiology of Dementia in Singapore (mean age, 70.9±6.8 years; 45% men) and in 12 of 389 (3.2%) subjects (mean age, 72.1±8.3 years; 46% men) in the clinic-based study. AII were present in 0.8% of subjects with no cognitive impairment, 1.9% of those with cognitive impairment not dementia, and 4.2% of subjects with dementia. Significant association of AII was found with cerebral microbleeds (≥5) in the Epidemiology of Dementia in Singapore (odds ratio, 6.76; 95% confidence interval, 1.28-35.65; P=0.02) and in the clinic-based cohort (odds ratio, 4.65; 95% confidence interval, 1.39-15.53; P=0.01). There was no association of AII with hypertension, diabetes mellitus, or hyperlipidemia. CONCLUSIONS: AII are more likely to be present in those with cognitive impairment. Although a cause-effect relationship between the presence of AII and cognitive impairment is plausible, the association may be because of under-reporting of symptoms by individuals with cognitive impairment. The association between AII and cerebral microbleeds may indicate cerebral vasculopathy, independent of traditional vascular risk factors.