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Abstract The association of anosmia/ageusia with a positive severe respiratory syndrome coronavirus 2 (SARS-CoV-2) test is well-established, suggesting these symptoms are reliable indicators of coronavirus disease 2019 (COVID-19) infection. This study investigates the clinical characteristics and systemic inflammatory markers in hospitalized COVID-19 patients in Taiwan, focusing on those with anosmia/ageusia. We conducted a retrospective observational study on 231 hospitalized COVID-19 patients (alpha variant) from April to July 2021. Clinical symptoms, dyspnea grading, and laboratory investigations, including neutrophil-lymphocyte ratios (NLRs), platelet-lymphocyte ratios (PLRs), and ANDC scores (an early warning score), were analyzed. Cough (64.1%), fever (58.9%), and dyspnea (56.3%) were the most common symptoms, while anosmia/ageusia affected 9% of patients. Those with anosmia/ageusia were younger, had lower BMI, lower systemic inflammatory markers, and better ANDC scores than those without these symptoms. Female patients exhibited lower NLR values and ANDC scores compared to male patients (all p

Introduction: For patients with acute intermittent porphyria (AIP), a true attack could be difficult to distinguish from chronic abdominal pain. This study focused on treatment responses from two patients with confirmed elevated biochemical data (delta-aminolevulinic acid (ALA), porphobilinogen (PBG)) and clinical evidence for acute attacks before starting givosiran. Methods: Data from patients who participated in the phase III givosiran trial in Taiwan between May 2018 and May 2021 were reviewed. The pre-trial and post-trial biochemical data (urinary ALA/PBG), annualized attack rate (AAR), for two participants were obtained from our hospital record. Results: Two patients had detailed records of biochemical evidence of acute attacks pre-trial (ALA:11.66–79.8 mg/24-h urine collection, PBG:75.45–160.11 mg/24-h). Patient Pb/Gn#1 with a disease duration of 1.6-years, had zero AAR during givosiran treatment. Patient Pb/Gn#2 had received prior hemin prophylaxis, had AIP for 6.7-years, had an AAR of 17.0 before givosiran, and an AAR of 12 at the post-trial compassionate-use period. The change in SF-12 PCS score from baseline was marginally clinical-meaningful (2.8 for Patient Pb/Gn#1 and 2.0 for Patient Pb/Gn#2). Conclusion: Our data from 2 AIP patients with biochemical and clinical evidence of acute attacks suggested that patient with a shorter disease duration may respond better in terms of AAR. Further studies are necessary to understand the association between disease characteristics, treatment history, and optimal treatment response for patients with recurrent AIP in terms of both attack frequency and quality of life.

Abstract Background Approximately 10% to 20% of myasthenia gravis (MG) patients have experienced a myasthenic crisis (MC), which contributes to morbidity and mortality. MC triggered by infection is associated with poor outcomes. However, there is a lack of prognostic factors that clinicians can utilize to target interventions for preventing recurrent infection-triggered MC. This study aimed to characterize clinical manifestations, comorbidities, and biochemical profiles associated with recurrent infection-triggered MC in MG patients. Methods This retrospective study included 272 MG patients hospitalized with an infection requiring at least 3 days of antibiotics from January 2001 to December 2019. Patients were further stratified into non-recurrent or recurrent infection groups. Clinical features such as gender, age, concomitant diseases, acetylcholine receptor antibodies and biochemical data (including electrolytes and coagulants), muscle strength of pelvic and shoulder girdle, bulbar and respiratory function, management with an endotracheal tube, Foley catheter, or plasmapheresis, duration of hospitalization, and culture pathogens were recorded. Results The recurrent infection group was significantly older than the non-recurrent group (median age, 58.5 versus 52.0 years). Pneumonia was the most common infection and Klebsiella pneumoniae was the most common pathogen. The presence of concomitant diabetes mellitus, activated partial thromboplastin time prolongation, the duration of hospitalization, and hypomagnesaemia were independently associated with recurrent infection. The presence of deep vein thrombosis, thymic cancer, and electrolyte imbalances i.e., hypokalemia, and hypoalbuminemia were significantly associated with a risk for infection. The influence of endotracheal intubation, anemia, and plasmapheresis during hospitalization were inconsistent. Conclusions The independent risk factors for recurrent infections in MG patients identified in this study include the presence of concomitant diabetes mellitus, hypomagnesaemia, activated partial thromboplastin time prolongation, and longer duration of hospitalization, highlighting the need for targeted interventions to prevent recurrent infections in this population. Further research and prospective studies are warranted to validate these findings and refine interventions for optimizing patient care.

Cancer-associated thrombosis (CAT) and atrial fibrillation (AF)-related stroke are two subtypes of acute embolic stroke with distinct lesion patterns on diffusion weighted imaging (DWI). This pilot study aimed to evaluate the feasibility and performance of DWI-based machine learning models for differentiating between CAT and AF-related stroke. Patients with CAT and AF-related stroke were enrolled. In this pilot study with a small sample size, DWI images were augmented by flipping and/or contrast shifting to build convolutional neural network (CNN) predicative models. DWI images from 29 patients, including 9 patients with CAT and 20 with AF-related stroke, were analyzed. Training and testing accuracies of the DWI-based CNN model were 87.1% and 78.6%, respectively. Training and testing accuracies were 95.2% and 85.7%, respectively, for the second CNN model that combined DWI images with demographic/clinical characteristics. There were no significant differences in sensitivity, specificity, accuracy, and AUC between two CNN models (all P = n.s.). The DWI-based CNN model using data augmentation may be useful for differentiating CAT from AF-related stroke.

Background: Walking entails orchestration of the sensory, motor, balance, and coordination systems, and walking disability is a critical concern after stroke. How and to what extent these systems influence walking disability after stroke and recovery have not been comprehensively studied. Methods: We retrospectively analyzed patients with stroke in the Post-acute care-Cerebrovascular Diseases (PAC-CVD) program. We compared the characteristics of patient groups stratified by their ability to complete the 5-m walk test across various time points of rehabilitation. We then used stepwise linear regression to examine the degree to which each stroke characteristic and functional ability could predict patient gait performance. Results: Five hundred seventy-three patients were recruited, and their recovery of walking ability was defined by the timing of recovery in a 5-m walk test. The proportion of patients who could complete the 5-m walk test at admission, at 3 weeks of rehabilitation, at 6 weeks of rehabilitation, between 7 and 12 weeks of rehabilitation, and who could not complete the 5-m walk test after rehabilitation was 52.2%, 21.8%, 8.7%, 8.7%, and 8.6%, respectively. At postacute care discharge, patients who regained walking ability earlier had a higher chance of achieving higher levels of walking activity. Stepwise linear regression showed that Berg Balance Scale (BBS) (β: 0.011, p

Various vaccines have been developed in response to the SARS-CoV-2 pandemic, and the safety of vaccines has become an important issue. COVID-19 vaccine-related central nervous system inflammatory demyelinating diseases (CNS IDDs) have been reported recently. We present one case of AstraZeneca vaccine-related myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease and a literature review of another 78 patients published from January 2020 to October 2022. Patients were divided into three vaccine types (viral vector, mRNA, and inactivated vaccines) for further analyses. Among 79 patients with COVID-19 vaccine-related CNS IDDs, 49 (62%) cases received viral vector vaccines, 20 (25.3%) received mRNA vaccines, and 10 (12.7%) received inactivated vaccines. Twenty-seven cases (34.2%) were confirmed with autoantibodies, including fifteen patients (19%) with anti-MOG, eleven (13.9%) with anti-aquaporin 4 (AQP4), and one (1.3%) with both antibodies. Significantly, more males developed CNS IDDs post viral vector vaccines compared to mRNA and inactivated vaccines. Patients receiving mRNA vaccines were older than those receiving other types. Furthermore, mRNA and inactivated vaccines correlated more with anti-AQP4 antibodies, while viral vector vaccines showed higher MOG positivity. This research suggests potential associations between COVID-19 vaccine-related CNS IDDs and gender, age, and autoantibodies, contingent on vaccine types. Protein sequence analysis implies similarities between the S protein and AQP4/MOG. Further studies may elucidate the mechanisms of CNS IDDs, aiding vaccine selection for specific types.

Background: The relationships among small fiber neuropathy, age, sex and pain intensity in the context of Fabry's disease remain unclear. We aim to study the correlations of small fiber neuropathy, age, sex and pain intensity in Fabry patients. Methods: We evaluated C-fiber function by recording the withdrawal latencies to painful heat stimulus (WLPHS) when each subject's right hand was immersed in a 50 °C hot water bath and correlated this parameter with the patient's perceived pain intensity and quality of life assessed by the short-form McGill Pain Questionnaire (SF-MPQ) in a large Taiwanese Fabry family and normal controls. Results: Male Fabry patients showed a significantly increased WLPHS compared to that of normal controls. Furthermore, male Fabry patients showed a positive correlation of increased WLPHS with patient age. The SF-MPQ of male Fabry patients showed a bell distribution with age, and maximal pain scores were detected between the ages of the early 20s and late 40s. In contrast, the female Fabry patients had variable associations of WLPHS and SF-MPQ with age. Conclusions: We proposed a probable mechanism by which globotriaosylceramide (Gb3) or globotriaosylsphingosine (lyso-Gb3) is gradually deposited into the small nerve bundles with increasing age, which induces continuous damage and produces injury discharges to sustain neuropathic pain in young male Fabry patients. However, once the small fibers are reduced to a certain degree, they no longer produce enough noxious discharges to sustain neuropathic pains in older male Fabry patients, which leads these patients to have lower SF-MPQ scores. In contrast, female Fabry patients had less and variable small fiber damage, pain intensity and clinical signs/symptoms.

IntroductionAxial muscles are involved earlier and to a greater extent in late-onset Pompe disease (LOPD) than in myotonic muscular dystrophy type 1 (DM1). We aimed to evaluate abdominal muscles in LOPD compared in DM1 using muscle ultrasonography.MethodsPatients with LOPD (n = 3), DM1 (n = 10), and age- and gender-matched healthy subjects (n = 34) were enrolled for muscle ultrasonography. Patients with LOPD and DM1 were 20 to 59 years of age with a disease duration ranging between 7 and 30 years. A multifrequency linear transducer was used to evaluate quality and thickness in the abdominal muscles and extremities.ResultsThe quantitative muscle echo score revealed a higher Z score in abdominal muscles in Patients with LOPD (scores were relatively normal for the biceps and flexor digitorum groups). Patients with LOPD had significantly lower abdominal muscle thickness than patients with DM1. Abdominal muscle strength was significantly correlated with the muscle echogenicity, trunk impairment scale, and trunk control test. The extremities' sum score was correlated with the total Medical Research Council score.DiscussionThe increased quantitative muscle score in abdominal muscles, sparing the biceps and flexor digitorum groups, may offer differential diagnosis between LOPD and DM1. Ultrasound can easily access abdominal muscles and investigate muscle echogenicity and thickness. A quantitative approach using muscle echogenicity rather than muscle thickness may provide a greater correlation with trunk muscle function.

Abstract Background Neuromyelitis optica spectrum disorder (NMOSD) is a rare neuroinflammatory disorder of the central nervous system that typically involves the optic nerve, the spinal cord and other specific brain regions. In relapse of the disease, factors associated with clinical features and lesion severity are important for clinicians to predict disease-related disability. Methods We retrospectively analyzed 22 female patients with NMOSD who had spinal cord lesions. Detailed clinical features, onset symptoms, motor disability, relapse episodes, serum aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) autoantibodies and MRI characteristics were documented to correlate their associations with the nadir and three-month Expanded Disability Status Scale (EDSS) scores. Patients with three-month EDSS scores below four ( 4) were categorized as the poor outcome group. Results In patients with NMOSD, the mean age was 44.5 ± 12.8 years, and the mean three-month EDSS score was 4.3 ± 1.9. A significantly higher all-limb muscle power score was found in the good EDSS group than in the poor EDSS group (p = 0.01). A tendency toward longer follow-up periods and lower anti-AQP4 antibody levels was found in the good outcome group. Serum anti-AQP4 antibodies were present in 86% of patients with NMOSD, and MOG autoantibodies were found in one anti-AQP4 antibody-negative patient (33.3%). In patients with NMOSD, more than 40% of spinal cord lesions were distributed at the middle cervical and upper thoracic levels. Conclusions Our findings suggest that EDSS scores and MRC scores at the nadir had significant associations with three-month EDSS scores. The topographic distributions of the spinal cord lesions might relate to different serum anti-AQP4 antibody status. However, further studies will be needed to corroborate this finding.

Abstract “Real-world” data on the nationwide epidemiology and treatment patterns of multiple sclerosis (MS) is very scarce in Asia. This study is aim to evaluate the 10-years trends in epidemiology and treatment patterns of MS with Taiwan’s National Health Insurance Database (NHIRD). Patients aged 20 years or older and were newly diagnosed with MS between 2007 and 2016 were identified. The crude incidences of MS were presented annually and stratified by sex and age. Baseline characteristics and treatment patterns, particularly disease-modifying drugs (DMDs), were also analyzed. This study included 555 MS patients (mean age was 36.9 and 74.4% were female). The crude incidence rate of MS decreased slightly from 0.43 per 100,000 persons in 2007 to 0.24 per 100,000 persons in 2015. The female to male ratios remained mainly between 2 to 3. Approximately 80% of MS patients received initial DMDs, with interferon β-1a as the dominant one. Furthermore, 37.5% of MS patients received subsequent DMDs, with fingolimod being the most frequently used. The median times from diagnosis to initial and to subsequent DMDs were 77 and 1239 days, respectively. This nationwide study provides up-to-date and sophisticated estimates of MS epidemiology and treatment pattern in “real-world” setting in Taiwan.

Abstract Our study aimed to investigate the incidence, risk factors and time to occurrence of malignancy in patients with dermatomyositis (DM) and polymyositis (PM). The electronic medical records of 1100 patients with DM and 1164 patients with PM were studied between January 2001 and May 2019. Malignancies after myositis were diagnosed in 61 (5.55%) patients with DM and 38 (3.26%) patients with PM. The cumulative incidence of malignancies in patients with DM were significantly higher than patients with PM (hazard ratio = 1.78, log-rank p = 0.004). Patients with DM had a greater risk of developing malignancy than those with PM at 40–59 years old (p = 0.01). Most malignancies occurred within 1 year after the initial diagnosis of DM (n = 35; 57.38%). Nasopharyngeal cancer (NPC) was the most common type of malignancy in patients with DM (22.95%), followed by lung, and breast cancers. In patients with PM, colorectal, lung and hepatic malignancies were the top three types of malignancy. The risk factors for malignancy included old age (≥ 45 years old) and low serum levels of creatine phosphokinase (CPK) for patients with DM and male sex and low serum levels of CPK for patients with PM. Low serum levels of CPK in patients with myositis with malignancy represented a low degree of muscle destruction/inflammation, which might be attributed to activation of the PD-L1 pathway by tumor cells, thus inducing T-cell dysfunction mediating immune responses in myofibers. A treatment and follow-up algorithm should explore the occurrence of malignancy in different tissues and organs and suggested annual follow-ups for at least 5.5 years to cover the 80% cumulative incidence of malignancy in patients with DM and PM.

Background/Purpose: Multiple sclerosis is classified as a rare disease in Taiwan. This study evaluated the safety and effectiveness of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) from routine clinical practice in Taiwan. Methods: In this retrospective, multicentre, observational study, we collected clinical data of patients treated with fingolimod 0.5 mg/day in routine clinical practice between September 2012 and December 2015. Primary outcome was the overall safety of fingolimod; secondary outcome was the annualized relapse rate (ARR). Results: Overall, 62/69 (86.1%) patients were on fingolimod by the end of data collection period. Mean age (±standard deviation [SD]) at inclusion was 37.7 ± 10.10 years; mean duration of MS was 5.4 ± 4.52 years and mean duration of fingolimod exposure was 135.8 patient-years. The most common adverse events (AEs) were bradycardia (21.7%; first-dose related), upper respiratory tract infection, dizziness, and hypoaesthesia (numbness) (11.6% each), followed by urinary tract infection and back pain (7.2% each). Seven patients had liver enzyme-related AEs. Eight patients had absolute lymphocyte counts

Abstract Objectives Blood–brain barrier (BBB) disruption is a critical pathological process involved in neuromyelitis optica spectrum disorder (NMOSD). Here, we characterized the profile of five cell adhesion molecules in patients with NMOSD. Methods We measured levels of cell adhesion molecules, including ICAM‐1, ICAM‐2, VCAM‐1, PECAM‐1, and NCAM‐1, in the serum of 28 patients with NMOSD, 24 patients with multiple sclerosis (MS), and 25 healthy controls (HCs). Results ICAM‐2 levels (median: 394.8 ng/mL) were increased in patients with NMOSD compared with MS (267.1 ng/mL, P = 0.005) and HCs (257.4 ng/mL, P = 0.007), and VCAM‐1 and ICAM‐1 levels were higher in patients with NMOSD (641.9 ng/mL and 212.7 ng/mL, respectively) compared with HCs (465 ng/mL [P = 0.013] and 141.8 ng/mL [P = 0.002], respectively). However, serum PECAM‐1 levels were lower in patients with NMOSD (89.62 ng/mL) compared with MS (106.9 ng/mL, P = 0.015) and HCs (107.2 ng/mL, P = 0.007). Receiver operating characteristic curve analysis revealed that PECAM‐1 (area under the curve (AUC): 0.729) and ICAM‐2 (AUC: 0.747) had adequate abilities to distinguish NMOSD from MS, and VCAM‐1 (AUC: 0.719), PECAM‐1 (area under the curve: 0.743), ICAM‐1 (AUC: 0.778), and ICAM‐2 (AUC: 0.749) exhibited potential to differentiate NMOSD and HCs. Serum levels of PECAM‐1 also demonstrated a negative correlation with Kurtzke Expanded Disability Status Scale scores in patients with NMOSD. Interpretation Our results reveal possible BBB breakdown signals specifically observed in NMOSD and highlight the potential role of cell adhesion molecules as biomarkers of this disease.

Background: The overlapping clinical presentations of limb-girdle muscular dystrophy (LGMD) and idiopathic inflammatory myopathy (IIM) make clinical diagnosis challenging. This study provides a comprehensive evaluation of the distributions and characteristics of muscle fat substitution and edema and aims to differentiate those two diseases.Methods: This retrospective study reviewed magnetic resonance imaging (MRI) of seventeen patients with pathologically proved diagnosis, comprising 11 with LGMD and 6 with IIM. The fat-only and water-only images from a Dixon sequence were used to evaluate muscle fat substitution and edema, respectively. The degrees of muscle fat substitution and edema were graded and compared using the appropriate statistical methods.Results: In LGMD, more than 50% of patients had high-grade fat substitution in the majority of muscle groups in the thigh and calf. However,

Background: Neuromuscular ultrasound is a complementary technology that aids in the diagnosis of peripheral neuropathy. The interpretation of neuromuscular ultrasound results requires the use of accurate normative cross-sectional area (CSA) reference values. This study aims to provide CSA reference values specific to Taiwanese adults for Sonography of peripheral nerves in the upper and lower extremities.Methods: The study cohort included 66 healthy subjects (36 women; 30 men). A linear probe was used to measure the CSA of the median, ulnar, radial, tibial, sural, and peroneal nerves at multiple sites. These data were analyzed to determine standard ranges for the CSA at each site (reference range = mean ± 2 × SD) and identify correlations between the CSA and patient characteristics.Results: Normative CSA ranges were determined for all the assessed nerve sites, revealing that the nerve sizes in this Taiwanese population were smaller than Caucasian populations but comparable to those reported for other Asian cohorts. Men tended to have larger nerves than women, even after adjusting for height and weight. The size of ulnar nerve in the cubital tunnel and the peroneal nerve in the popliteal fossa correlated negatively with increasing age. The nerve size correlated positively with increasing weight and BMI at several sites, correlation of median nerve in the forearm with weight and BMI was significant after multiple testing. Significant correlation was also found between size of ulnar nerve in cubital tunnel and decreasing height.Conclusion: We provide reference ranges for neuromuscular ultrasound CSA values for the upper and lower extremities that are specific to the Taiwanese population. These reference values may be useful for evaluating peripheral neuropathy in Taiwanese subjects.

Abstract Background This study aims to investigate the etiology and prognosis of spinal cord infarction (SCI). Methods Over a period of 16 years, we retrospectively analyzed 31 patients with SCI. Demographic features and symptom presentations were carefully documented. Etiology‐specific MRI features, such as the length and distribution of the lesions and owl’s eyes sign, were recorded and analyzed to determine their associations with the clinical signs/symptoms. Results In total, seven patients had aortic or vertebral artery dissections. We divided the patients with SCI into two groups: those with or without vessel dissection. Among SCI patients, the onset age was younger, and the proportion of patients with long‐segment lesions and posterior pattern involvement on axial view was higher in the group with dissection than in the group without dissection (all P

Background: Acute necrotizing encephalopathy (ANE), a fulminant encephalopathy, is often found in childhood. It is still uncertain whether adult patients with ANE display clinical features different from patients with typical pediatric onset. Furthermore, alterations in neuroinflammatory factors in patients with ANE have not been well-characterized. Here, we present an adult patient with ANE, and review all reported adult ANE cases in the literature. Methods: Serum levels of five cytokines were checked in an adult patient with ANE and compared with gender/age-matched controls. Literature search was performed with PubMed, using the term as “acute necrotizing encephalopathy” with the filter of adult 19 + years. Results: A total of 13 adult patients were reviewed. Compared with pediatric patients, adult ANE patients had similar clinical symptoms, biochemical data, and neuroimage findings, whereas adult ANE were more female-biased (female:male, 9:4) with a worse prognosis. Elevated cytokine levels in the serum and/or CSF is found in both adult-onset and pediatric-onset ANE. We found significantly elevated serum levels of IL-6 (17.17 pg/mL; healthy control: 1.43 ± 1.22 pg/mL) and VCAM-1 (3033.92 ng/mL; healthy control: 589.71 ± 133.13 ng/mL), and decreased serum TGF-β1 level (14.78 ng/mL, healthy controls: 25.81 ± 6.97 ng/mL) in our patient. Conclusions: Our findings clearly delineate the clinical features and further indicate the potential change in cytokine levels in adult patients with ANE, advancing our understanding of this rare disease. Keywords: Acute necrotizing encephalopathy, Adult, Cytokine, VCAM-1

Background: Postpartum spinal cord infarction is a very rare disease. Only two cases have been reported in the English literature. Methods: We reported a 26 year old female who received second doses of the mRNA-1273 vaccine 52 days before delivery. She presented as sudden onset of paraplegia, sensory level, and sphincter incontinence at postpartum period. No history of heparin exposure was noted. Imaging findings confirmed the T10-11 level infarction and her anti–human heparin platelet factor 4 (anti-PF4) antibody was positive. After 7 days of dexamethasone therapy, her paraplegia and urinary incontinence gradually improved. Results: The CT angiography (CTA) of the artery of Adamkiewicz (Aka) showed tandem narrowing, most conspicuous at the T10-11 level, which was presumably due to partial occlusion of the arteriolar lumen. The thoracolumbar spine magnetic resonance imaging with contrast medium showed owl’s eyes sign at the T10 and T11 levels. We compared our case with two other case reports from the literature. Conclusions: Post-partum spinal cord infarction with positive anti-PF4 antibody and relatively thrombocytopenia are the characteristics of our case.

Abstract Background Family genetic testing of patients newly diagnosed with a rare genetic disease can improve early diagnosis of family members, allowing patients to receive disease‐specific therapies when available. Fabry disease, an X‐linked lysosomal storage disorder caused by pathogenic variants in GLA, can lead to end‐stage renal disease, cardiac arrhythmias, and stroke. Diagnostic delays are common due to the rarity of the disease and non‐specificity of early symptoms. Newborn screening and screening of at‐risk populations, (e.g., patients with hypertrophic cardiomyopathy or undiagnosed nephropathies) can identify individuals with Fabry disease. Subsequent cascade genotyping of family members may disclose a greater number of affected individuals, often at younger age than they would have been diagnosed otherwise. Methods We conducted a literature search to identify all published data on family genetic testing for Fabry disease, and discussed these data, experts’ own experiences with family genetic testing, and the barriers to this type of screening that are present in their respective countries. Results There are potential barriers that make implementation of family genetic testing challenging in some countries. These include associated costs and low awareness of its importance, and cultural and societal issues. Regionally, there are barriers associated with population educational levels, national geography and infrastructures, and a lack of medical geneticists. Conclusion In this review, the worldwide experience of an international group of experts of Fabry disease highlights the issues faced in the family genetic testing of patients affected with rare genetic diseases.

Currently, there is no objective biomarker to indicate disease progression and monitor therapeutic effects for amyotrophic lateral sclerosis (ALS). This study aimed to identify plasma biomarkers for ALS using a targeted metabolomics approach. Plasma levels of 185 metabolites in 36 ALS patients and 36 age- and sex-matched normal controls (NCs) were quantified using an assay combining liquid chromatography with tandem mass spectrometry and direct flow injection. Identified candidates were correlated with the scores of the revised ALS Functional Rating Scale (ALSFRS-r). Support vector machine (SVM) learning applied to selected metabolites was used to differentiate ALS and NC subjects. Forty-four metabolites differed significantly between ALS and NC subjects. Significant correlations with ALSFRS-r score were seen in 23 metabolites. Six of them showing potential to distinguish ALS from NC—asymmetric dimethylarginine (area under the curve (AUC): 0.829), creatinine (AUC: 0.803), methionine (AUC: 0.767), PC-acyl-alkyl C34:2 (AUC: 0.808), C34:2 (AUC: 0.763), and PC-acyl-acyl C42:2 (AUC: 0.751)—were selected for machine learning. The SVM algorithm using selected metabolites achieved good performance, with an AUC of 0.945. In conclusion, our findings indicate that a panel of metabolites were correlated with disease severity of ALS, which could be potential biomarkers for monitoring ALS progression and therapeutic effects.

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity among the global youth and commonly results in long-lasting sequelae, including paralysis, epilepsy, and a host of mental disorders such as major depressive disorder. Previous studies were mainly focused on severe TBI as it occurs in adults. This study explored the long-term adverse effect of mild TBI in juvenile animals (mTBI-J). Male Sprague Dawley rats received mTBI-J or sham treatment at six weeks old, then underwent behavioral, biochemical, and histological experiments three weeks later (at nine weeks old). TTC staining, H&E staining, and brain edema measurement were applied to evaluate the mTBI-J induced cerebral damage. The forced swimming test (FST) and sucrose preference test (SPT) were applied for measuring depression-like behavior. The locomotor activity test (LAT) was performed to examine mTBI-J treatment effects on motor function. After the behavioral experiments, the dorsal hippocampus (dHip) and ventral hippocampus (vHip) were dissected out for western blotting to examine the expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB). Finally, a TrkB agonist 7,8-DHF was injected intraperitoneally to evaluate its therapeutic effect on the mTBI-J induced behavioral abnormalities at the early adult age. Results showed that a mild brain edema occurred, but no significant neural damage was found in the mTBI-J treated animals. In addition, a significant increase of depression-like behaviors was observed in the mTBI-J treated animals; the FST revealed an increase in immobility, and a decrease in sucrose consumption was found in the mTBI-J treated animals. There were no differences observed in the total distance traveled of the LAT and the fall latency of the rotarod test. The hippocampal BDNF expression, but not the TrkB, were significantly reduced in mTBI-J, and the mTBI-J treatment-induced depression-like behavior was lessened after four weeks of 7,8-DHF administration. Collectively, these results indicate that even a mild juvenile TBI treatment that did not produce motor deficits or significant histological damage could have a long-term adverse effect that could be sustained to adulthood, which raises the depression-like behavior in the adult age. In addition, chronic administration of 7,8-DHF lessens the mTBI-J treatment-induced depression-like behaviors in adult rats. We suggest the potential usage of 7,8-DHF as a therapeutic agent for preventing the long-term adverse effect of mTBI-J.

Abstract Background The disease course and early signs specific to ATTR Ala97Ser, the most common endemic mutation in Taiwan, have not been well described. Since new medications can slow down the rate of disease progression, the early diagnosis of this heterogeneous and fatal disease becomes critical. Methods We retrospectively reviewed the characteristics of genetically confirmed ATTR Ala97Ser patients at a tertiary referral medical center. Results Eight patients from 7 different families were enrolled (61.7 ± 5.5 years). Gastrointestinal symptoms, dyspnea or chest tightness, rather than sensory symptoms, were the initial symptoms in two patients (2/7 = 29%). Body weight loss (3/7 = 43%), muscle wasting (4/7 = 57%), or dysphagia (3/7 = 43%) were the consecutive symptoms. Orthostatic symptoms including orthostatic hypotension (7/7 = 100%), dizziness (6/7 = 86%) and syncope (5/7 = 71%) tended to develop in the late phase of the disease. Autonomic dysfunction was conspicuous. Cardiographic findings included a combination of ventricular wall thickening and pericardial effusion (7/7 = 100%), a granular sparkling appearance of the ventricular myocardium (4/7 = 57%), or conduction abnormalities (5/7 = 71%). Conclusions This study broadens the recognition of the initial signs and symptoms, including cardiographic findings and longitudinal manifestations in Taiwanese individuals with ATTR Ala97Ser mutation. These manifestations should prompt doctors to perform further studies and make an early diagnosis.

Abstract Guillain-Barre Syndrome (GBS) is an inflammatory disease of the peripheral nervous system. Given that plasma metabolic profiles in GBS patients have never been explored, plasma samples of 38 GBS patients, 22 multiple sclerosis (MS) patients, and 40 healthy controls were analyzed by using untargeted and targeted metabolomics analysis. The untargeted analysis showed that levels of a set of plasma lipid metabolites were significantly decreased in GBS patients compared to the controls. Furthermore, the targeted analysis demonstrated that levels of 41 metabolites in GBS patients were significantly changed compared to either the controls or MS patients. A further metabolic analysis showed that 12 of 41 metabolites were significantly lower in classical GBS patients compared to Miller-Fisher syndrome. Among them, each of PCae C34:0, PCae C42:2, PCae C42:3, and SM C24:0 was inversely correlated with Hughes functional grading scale of GBS patients at both nadir and discharge. Receiver operating characteristic curve analysis of combination of three metabolites (PCaa C42:2, PCae C36:0 and SM C24:0) showed a good discrimination between the GBS and the controls (area under curve = 0.86). This study has demonstrated disruption of lipid metabolites in GBS may be potential biomarkers to indicate disease severity and prognosis of GBS.

This cross-sectional study is aimed at determining the prevalence of distal symmetrical polyneuropathy (DSPN) and diabetic peripheral neuropathic pain (DPNP) in participants with type 2 diabetes mellitus (T2DM); finding the risk factors for DSPN and DPNP via biochemical tests; and correlating DSPN and DPNP with the results of electrophysiologic studies, quantitative sensory tests, and neurologic examination. The 145 participants with T2DM enrolled were divided into the DSPN (abnormal nerve conduction studies (NCS) with signs of polyneuropathy), subclinical DSPN (abnormal NCS without signs of polyneuropathy), minimal DSPN (normal NCS with signs of polyneuropathy), and no DSPN groups. The biochemical risk factors of diabetic peripheral neuropathy were investigated. Neurologic examinations, laboratory tests, NCS, vibration threshold tests, and thermal threshold tests were conducted. The modified Michigan Neuropathy Screening Instrument (mMNSI) and Douleur Neuropathique 4 were used to evaluate the severity of DSPN and DPNP, respectively. In all, 30% of participants had DSPN and 11% had DPNP. DSPN correlated strongly with male gender and higher glycohaemoglobin levels; NCS abnormality correlated with higher glycohaemoglobin levels; DSPN severity correlated with NCS of each stimulating nerve. DPNP commonly occurred with clinical and electrophysiologic evidence of DSPN. Symptomatic diabetic polyneuropathy significantly correlated with longer disease duration, higher glycohaemoglobin levels, and abnormal vibration tests. The thermal threshold test combined with nerve conduction tests could detect most of the patients with DSPN, subclinical DSPN, and minimal DSPN. Poor diabetic control was independently associated with the development of DSPN. DPNP was associated with DSPN. The combination of thermal threshold tests with NCS can potentially provide the diagnosis of DSPN.

Our previous studies have shown that early systemic granulocyte colony-stimulating factor (G-CSF) treatment can attenuate neuropathic pain in rats with chronic constriction injury (CCI) by modulating expression of different proinflammatory cytokines, microRNAs, and proteins. Besides the modulation of inflammatory mediators’ expression, previous studies have also reported that G-CSF can modulate autophagic and apoptotic activity. Furthermore, both autophagy and apoptosis play important roles in chronic pain modulation. In this study, we evaluated the temporal interactions of autophagy, and apoptosis in the dorsal root ganglion (DRG) and injured sciatic nerve after G-CSF treatment in CCI rats. We studied the behaviors of CCI rats with or without G-CSF treatment and the various levels of autophagic, proinflammatory, and apoptotic proteins in injured sciatic nerves and DRG neurons at different time points using Western blot analysis and immunohistochemical methods. The results showed that G-CSF treatment upregulated autophagic protein expression in the early phase and suppressed apoptotic protein expression in the late phase after nerve injury. Thus, medication such as G-CSF can modulate autophagy, apoptosis, and different proinflammatory proteins in the injured sciatic nerve and DRG neurons, which have the potential to treat neuropathic pain. However, autophagy-mediated regulation of neuropathic pain is a time-dependent process. An increase in autophagic activity in the early phase before proinflammatory cytokines reach the threshold level to induce neuropathic pain can effectively alleviate further neuropathic pain development.

Our previous animal studies and several human clinical trials have shown that granulocyte-colony stimulating factor (GCSF) can attenuate neuropathic pain through various mechanisms. GCSF itself is also a multipotent cytokine that can modulate microribonucleic acid (microRNA) expression profiles in vitro. In this study, we used the NanoString nCounter analysis system to screen the expression of different rodent microRNAs at early stage after nerve injury and studied the expression of related cytokines/chemokines in the dorsal root ganglia (DRGs) of rats that underwent chronic constriction injury (CCI) to explore the underlying mechanisms of the analgesic effects of GCSF. We found that microRNA-122 expression was downregulated by CCI; in contrast, GCSF treatment significantly upregulated microRNA-122 expression in the DRGs of CCI rats on the 1st day after nerve injury. We further studied the expression of different cytokines/chemokines (IL-1β, IL-6, and monocyte chemoattractant protein-1 (MCP-1)) that were modulated by microRNA-122. MCP-1 has been reported to participate in neuropathic pain development, and its expression on the DRGs of vehicle-treated CCI rats was significantly higher than that on the DRGs of sham-operated rats; in contrast, GCSF-treated rats exhibited significantly lower MCP-1 expression in the DRG than vehicle-treated rats on the 7th day after nerve injury. An early GCSF treatment can suppress MCP-1 expressions, through upregulating microRNA-122 expressions in the DRGs of CCI rats at an earlier stage, thus indirectly attenuating neuropathic pain development.

ImportanceCIS to MS conversion rates vary depending on population cohorts, initial manifestations, and durations of follow-up.ObjectiveTo investigate conversion rate of patients from CIS to MS and the prognostic significance of demographic and clinical variables in Taiwanese population.DesignNationwide, prospective, multi-centric, observational study from November 2008 to November 2014 with 4 years follow-up.SettingMulti-centre setting at 5 institutions in Taiwan.Participants152 patients having single clinical event potentially suggestive of MS in last 2 years were enrolled as consecutive sample. 33 patients were lost to follow-up and 16 patients did not complete the study.103 patients completed the study.Intervention(s) (for clinical trials) or exposure(s) (for observational studies)Natural progression from first episode of CIS to MS or NMO was observed.Main outcome(s) and measure(s)Variables analysed were 'proportion of patients converting to MS or NMO after first episode of CIS', 'duration between first episode of neurological event and diagnosis of MS', 'status of anti-AQP4 IgG' and 'length of longest contiguous spinal cord lesion in MS patients'. Association between baseline characteristics and progression to MS from CIS was analyzed using multiple logistic regression. Multivariate time dependent effect of baseline characteristics on progression to MS was plotted.Results14.5% patients with CIS converted to MS after 1.1 ± 1.0 years with greater predisposition (18.8%) in those having syndromes referable to the cerebral hemispheres. Conversion rate from ON to MS was 9.7%. 90.9% patients had mild disease course. 46.7% patients had abnormal MRIs at baseline, with 0.6±0.5 contrast enhanced lesions. 'Below normal BMI' and 'MRI lesion load (≥ 4 lesions)' were identified as risk indicators for the development of MS. Amongst the patients who developed NMO as diagnosed by modern criteria, 80% were positive for anti-AQP4 IgG antibody.Conclusions and relevance'Below normal BMI' and 'number of demyelinating lesions (≥4)' are significant predictors of conversion from CIS to MS. A low conversion rate to MS in Taiwanese CIS patients and majority of them having a mild course and minimal disability suggest the roles of geographic, genetic and ethnic factors.Trial registrationNon-trial observational study.

We investigated whether the intensity of cancer pain differs for malignant tumors that have spread to anterior or anterolateral/lateral portions of the vertebral body. We hypothesize that tumor spread to the anterolateral/lateral vertebral body elicits more serious pain due to increased irritation of the spinal nerve. The selection criteria were as follows: (1) advanced or metastatic solid tumor; (2) radicular pain without extremity weakness; (3) malignant lesions anteriorly, anterolaterally, or laterally located at the vertebral body either spread locoregionally or over a greater distance via metastasis based on CT scan diagnosis; and (4) patient needs to use opioids for pain relief. Severe spinal pain intensity was defined as spinal pain for which patients required either strong opioids or spinal irradiation for relief. Eighty-six patients were enrolled in the study. Bone lesions were mainly osteolytic. Thirty-nine tumors spread to the vertebral body in the anterior direction, and 47 in the anterolateral/lateral direction. Severe pain intensity related to vertebral body lesions was due to anterolateral/lateral spread, primary sites of nonurothelial carcinoma, metastatic vertebral lesions, multiple lesions within a vertebrum, and location within the cervical-thoracic spine. In conclusion, patients with tumor spread to the anterolateral/lateral portion of vertebrae bodies based on CT scan diagnosis experienced severe cancer pain. These patients needed strong opioids or palliative spinal irradiation for pain relief.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, is a rare neurodegenerative disorder presenting with insidious onset of weakness in bulbar and limb muscles. Information regarding long-term clinical and functional progression has been limited, especially for the Taiwanese population. The purpose of the study aimed to investigate early diagnosis and long-term prognosis of SBMA. Methods: We retrospectively analyzed 21 genetically confirmed SBMA patients who visited our hospital between 1993 and 2010, focusing on clinical symptoms, nerve conduction studies, and functional disability. We also analyzed the relationship between length of cytosine-adenine-guanine (CAG) repeats and age of disease onset. Results: Weakness developed at a mean age of 39 ± 7 years (mean ± standard deviation). The length of CAG repeats and age at onset of weakness showed inverse (but nonsignificant) correlation. The most common symptoms at initial presentation were hand tremor (86%), limb weakness (86%), and perioral fasciculation (76%). Creatine kinase (CK) was elevated in 17 out of 18 patients. Initial nerve conduction studies showed statistical difference from normal controls, especially decreased amplitudes of compound motor action potential (CMAP) and sensory nerve action potential (SNAP). Functional disability showed very slow progression, with only three patients becoming wheelchair-dependent during follow-up at a median age of 72 years. Conclusion: Patients with SBMA may present with a myriad of symptoms, including limbs weakness, tremor, muscle atrophy, and perioral fasciculations. Elevated serum CK and decreased CMAP and SNAP amplitudes were supportive laboratory findings of SBMA. Disease progression was gradual, and most patients remained functionally independent many years after the onset of weakness.

To investigate the clinical characteristics of patients with uncommon distal symmetric painful small-fiber neuropathy (DSPSFN).From September 2012 to September 2014, participants between 18-70 years of age that had DSPSFN defined by clinical signs/symptoms and ID pain > 2 or DN4 > 4 on questionnaires for more than 1 month were included. Participants who had previous historical or laboratory evidence of common etiologies of DSPSFN were excluded. Enzyme activity and genetic studies for Fabry diseaseand familial amyloid polyneuropathy were performed after participants fulfilled the inclusion and exclusion criteria. The cryoglobulin test, autoantibodies studies and electrophysiological studies were performed in these participants.In total, 100 cases were enrolled in the current study. Three cases of subclinical diabetes mellitus and two cases of fibromyalgia were found. Fabry disease (1%) and familial amyloid polyneuropathy (3%) with Ala97Ser transthyretin (TTR) mutations were also detected. The cryoglobulin test was positive in 30% of participants, and these participants had higher DN4 scores than the negative group. In the autoantibodies studies, 59% of the participants had abnormal anti-Ro/SSA and/or anti-La/SSB antibodies.Cryoglobulinemia is not a rare etiology of uncommon DSPSFN. The long-term prognosis is quite good in these participants. From our structuralized protocol, Fabry disease and familial amyloid polyneuropathy could be easily detected in these cases of uncommon DSPSFN.

The clinical analyses and prognoses of mitochondrial diseases with A3243G mutation are rarely documented in Taiwan. Our study investigated the clinical phenotypes and the outcomes of patients with mitochondrial disease and the A3243G mutation of mtDNA in a Taiwanese population, and compared these with previous reports. Methods: We retrospectively studied 22 consecutive patients with mitochondrial disease and the A3243G mutation of mtDNA in Chang Gung Memorial Hospital between 1988 and 2009. All patients underwent a detailed demographic registration, neurological examinations, a muscle biopsy, and mitochondrial DNA analysis. Modified Rankin scale, the presence of recurrent strokes or seizures, critical medical complications, and death were monitored during the follow-up period. Results: Of the 22 patients, seizures and stroke-like episodes were found in 12 (55%). Visceral involvement, including cardiomyopathy, nephropathy, and pulmonary hypertension, were noted in five patients (23%). Patients with seizures had a high frequency of status epilepticus (92%) and a younger age of onset (21.3±7.2 years). Both the Kaplan–Meier survival analysis and the Cox-regression model showed a marked deterioration in patients with seizures after 7 years of follow-up. Conclusion: Our study found that seizures and status epilepticus are the most important predictive values for a poor outcome in patients with the mtA3243G mutation of mtDNA. Age of onset and visceral organ involvement had no prominent influence on the prognosis. Some medical complications could be well controlled or even reversed after management.

Despite effective vaccine programs, tetanus is occasionally observed in adults. We reviewed clinical presentation data for adult patients with tetanus in the post-vaccine era in Taiwan. Methods: We retrospectively reviewed the medical records of all adult patients (age >18 years) discharged from Chang-Gung Memorial Hospital at Lin-Ko (CGMHLK) after treatment for tetanus between January 1996 and July 2005. Data regarding demographic characteristics, clinical manifestation, treatment, and outcome were collected. To assess the features for different age groups, patients were divided into those aged ≥65 years and those aged

About 5-10% of patients with myasthenia gravis concomitantly have other autoimmune diseases. However, the coexistence of myasthenia gravis and pernicious anemia is rare. Here, we report a 73-year-old Taiwanese woman who developed myasthenia gravis 5 months after the onset of pernicious anemia. Her myasthenic and pernicious anemia symptoms markedly improved after pyridostigmine, prednisolone and hydroxo-cobalamine treatment. It is important to recognize concurrence of myasthenia gravis and pernicious anemia in the same patient because the therapeutic results for both diseases are rewarding.

BACKGROUND: Motor and somatosensory evoked potentials (MEPs and SSEPs) are sensitive tools for detecting subclinical lesions, assessing disease severity, and determining the prognosis for outcomes of patients with inflammatory neurological diseases such as multiple sclerosis. However, their roles in neuromyelitis optica (NMO), a severe inflammatory neurological disease that predominantly involves optic nerves and spinal cord, have not yet been clarified. METHODS AND FINDINGS: Clinical symptoms and examination findings at relapses of 30 NMO patients were retrospectively reviewed. Abnormal MEPs were observed in 69.2% of patients. Patients with abnormal motor central conduction time (CCT) of the lower limbs had higher Kurtzke Expanded Disability Status Scale (EDSS) scores than those with normal responses (P = 0.027). Abnormal SSEPs were found in 69.0% of patients. Patients with abnormal lower limb sensory CCT had higher EDSS scores than those with normal responses (P = 0.019). In 28 patients followed up more than 6 months, only one of 11 patients (9.1%) with normal SSEPs of the lower limbs had new relapses within 6 months, whereas 8 of 17 patients (47.1%, P = 0.049) with abnormal SSEPs of the lower limbs had new relapses. CONCLUSIONS: These results indicate MEPs and SSEPs of the lower limbs are good indicators for the disability status at relapses of NMO. Lower limb SSEPs may be a good tool for reflecting the frequency of relapses of NMO.

Essential tremor (ET), which is one of the most common movement disorders, may lead to severe interference in quality of life. The first genome-wide association study (GWAS) has identified an association of the LINGO1 variant (rs9652490) with ET in Americans and Europeans. Recently, a second GWAS that was performed in a European population has discovered a new variant (rs3794087) of the main glial glutamate transporter (SLC1A2) that increases the risk of ET with an odds ratio of about 1.4. SLC1A2 encodes for the major glial high-affinity glutamate reuptake transporter in the brain and is a potential ET susceptibility gene. Because replication in a different ethnic population is important for validating a finding, we conducted a case-control study to investigate the SLC1A2 variant in an Asian cohort with ET in Taiwan. A total of 542 subjects (273 ET patients and 269 controls) were included. The results showed that rs3794087 was associated with ET among the Taiwanese. The odds ratio was 1.37. Our results were similar to those of the second GWAS of ET in Europeans, and this confirms that SLC1A2 may be a good functional candidate gene for ET. A replication study in another independent population is of importance to validate this association.