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Background@#and Purpose Cognitive and behavioral changes are common in amyotrophic lateral sclerosis (ALS), with about 15% of patients presenting with overt frontotemporal dementia and 30%–50% with varying degrees of impairments. We aimed to develop and validate the Korean version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS-K), a brief multidomain assessment tool developed for ALS patients with physical disability. @*Methods@#We developed the ECAS-K according to the translation guidelines, and administered it to 38 patients with ALS and 26 age- and education-level-matched controls. We also administered the Montreal Cognitive Assessment (MoCA) and Frontal Assessment Battery (FAB) to investigate convergent validity, and the Center for Neurologic Study-Liability Scale to assess the association between pseudobulbar affect and cognitive/behavioral changes. @*Results@#Internal consistency among the ECAS-K test items was found to be high, with a Cronbach’s alpha of 0.87. Significant differences were found between patients with ALS and the controls in language, fluency, and memory functions (p<0.05). Abnormal performance based on the ECAS total score was noted in 39.4% of patients, and 66.6% presented behavioral changes in at least one domain. Significant correlations were observed between the scores of the ECAS-K and those of other cognitive screening tools (MoCA and FAB, with correlation coefficients of 0.69 and 0.55, respectively; p<0.01). @*Conclusions@#We developed and validated the ECAS-K which could be used as an effective tool to screen the cognitive and behavioral impairments in Korean patients with ALS.
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Background@#Muscle cramp is possibly related to peripheral nerve hyperexcitability (PNH), and one of the most debilitating symptoms frequently encountered in patients with liver cirrhosis. We investigated whether pregabalin, a gamma-aminobutyric acid analogue, can suppress neuronal excitability and reduce muscle cramps in cirrhotic patients. @*Methods@#We conducted a randomized, double-blind, placebo-controlled trial in which study participants with cirrhosis from a single tertiary center were enrolled. Primary endpoint was the relative change in cramp frequency from the run-in to standard dose treatment phase (4 weeks per each). Secondary endpoints included the responder rate, and the changes in cramp frequency during sleep, pain intensity, health-related quality of life (Liver Disease Quality of Life Instrument, Short Form-36) and electrophysiological measures of PNH. @*Results@#This study was terminated early because of insufficient accrual. 80% (n = 56) of the target number of participants (n = 70) were randomized to pregabalin (n = 29) or placebo (n = 27). Median baseline frequency of muscle cramps (interquartile range) was 5.8 (3.5–10) per week in the pregabalin group and 6.5 (4.0–10) in the placebo group (P = 0.970). The primary analysis showed a significant reduction in cramp frequency with pregabalin compared to placebo (−36% vs. 4.5% for the percentage change, P = 0.010). Secondary outcomes did not differ significantly between the two groups. Adverse effects with pregabalin were mainly dizziness and lethargy. @*Conclusion@#With multiple problems emerging from premature termination in mind, the results suggested an acceptable safety profile and favorable effect of pregabalin in reducing muscle cramps compared to placebo in cirrhotic patients.
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Limb-Girdle Muscular Dystrophy 2B (LGMD2B) presents with proximal and/or distal muscle weakness and markedly high creatine kinase level. It is caused by the loss of dysferlin due to mutations in the DYSF gene. Due to its similar clinical features as inflammatory myopathy, it is often difficult to distinguish between the two. We present a case of a 48-year-old male who developed progressive proximal muscle weakness, papulosquamous lesions on the knuckles, elevated levels of muscle enzymes, and electromyogram abnormalities. Based on the clinical presentation, the initial impression was dermatomyositis, yet it was refractory to immunosuppressive therapy. Subsequently, dysferlin immunostaining and genetic analysis led to the final diagnosis of LGMD2B. This case shows that LGMD2B can present with extramuscular symptoms mimicking inflammatory myopathy in later stages of life. Dysferlin immunostaining and/or genetic analysis of the DYSF gene are essential for its diagnosis.
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Background@#Myasthenia gravis (MG) is a rare classic autoimmune disease where immunosuppressant therapies have been successful to reduce MG attributable mortality fairly well. However, patients with refractory MG (rMG) among the actively treated MG (aMG) are nonresponsive to conventional therapy and display high disease severity, which calls for further research. We aimed to determine survival, prognosis, and clinical feature of patients with rMG compared to non-rMG. @*Methods@#Retrospective nationwide cohort study using Korea's healthcare database between 2002 and 2017 was conducted. Patients with rMG (n = 47) and non-rMG (n = 4,251) who were aged > 18 years, followed-up for ≥ 1 year, and prescribed immunosuppressants within 2 years after incident MG diagnosis were included. Patients with rMG were defined as administered plasma exchange or intravenous immunoglobulin at least 3 times per year after receiving ≥ 2 immunosuppressants. All-cause mortality, myasthenic crisis, hospitalization, pneumonia/ sepsis, and emergency department (ED) visits were measured using Cox proportional hazard models and pharmacotherapy patterns for rMG were assessed. @*Results@#The rMG cohort included a preponderance of younger patients and women. The adjusted hazard ratio was 2.49 (95% confidence interval, 1.26–4.94) for mortality, 3.14 (2.25–4.38) for myasthenic crisis, 1.54 (1.15–2.06) for hospitalization, 2.69 (1.74–4.15) for pneumonia/sepsis, and 1.81 (1.28–2.56) for ED visits for rMG versus non-rMG. The immunosuppressant prescriptions were more prevalent in patients with rMG, while the difference was more remarkable before rMG onset rather than after rMG onset. @*Conclusion@#Despite the severe prognosis of rMG, the strategies for pharmacotherapeutic regimens were similar in those two groups, suggesting that intensive monitoring and introduction of timely treatment options in the early phase of MG are required.
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Background@#Myasthenia gravis (MG) is a rare classic autoimmune disease where immunosuppressant therapies have been successful to reduce MG attributable mortality fairly well. However, patients with refractory MG (rMG) among the actively treated MG (aMG) are nonresponsive to conventional therapy and display high disease severity, which calls for further research. We aimed to determine survival, prognosis, and clinical feature of patients with rMG compared to non-rMG. @*Methods@#Retrospective nationwide cohort study using Korea's healthcare database between 2002 and 2017 was conducted. Patients with rMG (n = 47) and non-rMG (n = 4,251) who were aged > 18 years, followed-up for ≥ 1 year, and prescribed immunosuppressants within 2 years after incident MG diagnosis were included. Patients with rMG were defined as administered plasma exchange or intravenous immunoglobulin at least 3 times per year after receiving ≥ 2 immunosuppressants. All-cause mortality, myasthenic crisis, hospitalization, pneumonia/ sepsis, and emergency department (ED) visits were measured using Cox proportional hazard models and pharmacotherapy patterns for rMG were assessed. @*Results@#The rMG cohort included a preponderance of younger patients and women. The adjusted hazard ratio was 2.49 (95% confidence interval, 1.26–4.94) for mortality, 3.14 (2.25–4.38) for myasthenic crisis, 1.54 (1.15–2.06) for hospitalization, 2.69 (1.74–4.15) for pneumonia/sepsis, and 1.81 (1.28–2.56) for ED visits for rMG versus non-rMG. The immunosuppressant prescriptions were more prevalent in patients with rMG, while the difference was more remarkable before rMG onset rather than after rMG onset. @*Conclusion@#Despite the severe prognosis of rMG, the strategies for pharmacotherapeutic regimens were similar in those two groups, suggesting that intensive monitoring and introduction of timely treatment options in the early phase of MG are required.
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Background@#Although neuromyelitis optica spectrum disorder (NMOSD) is known to be a rare disease, its prevalence and incidence have not yet been studied in Korea. We performed a population-based study to examine the prevalence and incidence of NMOSD in Korea using data from the Korean National Health Insurance (NHI) claims database. @*Methods@#Data from 2013 to 2017 were obtained, with a washout period set as 2013 and 2014. The prevalence and incidence of NMOSD in 2016 and 2017 were calculated using population census data. Subjects were divided into 5 groups at 15-year intervals, depending on the age at which the diagnostic code was entered. The relative risk (RR) for each age group was compared with the oldest (≥ 60 years) age group. @*Results@#The overall prevalence was estimated to be 3.36 and 3.56 per 100,000 individuals, with an incidence of 0.41 and 0.65 per 100,000 individuals-year in 2016 and 2017, respectively. The mean age was 43.08 (standard deviation, 14.56) years, and the ratio of male to females was 1:4.7. The incidence was higher in female individuals aged between 30 and 59 years (RR, 2.8–3.05; P < 0.05). @*Conclusion@#Nationwide prevalence of NMOSD in Korea was 3.36 and 3.56/100,000 and its incidence was 0.41 and 0.65/100,000-year in 2016 and 2017 respectively.
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Myasthenia gravis (MG) is an autoimmune neuromuscular junction disorders mediated by various autoantibodies. Although most patients with MG require chronic immunosuppressive treatment to control disease activity, appropriate surveillance biomarkers that monitor disease activity or potential toxicity of immunosuppressants are yet to be developed. Herein, we investigated quantitative distribution of peripheral blood B cell subsets and transcriptional profiles of memory B cells (CD19+ CD27+) in several subgroups of MG patients classified according to the Myasthenia Gravis Foundation of America (MGFA) Clinical Classification. This study suggests potential immunologic B-cell markers that may guide treatment decision in future clinical settings.
Subject(s)
Humans , Americas , Autoantibodies , B-Lymphocyte Subsets , B-Lymphocytes , Biomarkers , Classification , Flow Cytometry , Immunophenotyping , Immunosuppressive Agents , Memory , Myasthenia Gravis , Neuromuscular Junction Diseases , TranscriptomeABSTRACT
BACKGROUND AND PURPOSE: There have been a few national population-based epidemiological studies of myasthenia gravis (MG) with wide variation of incidence and prevalence rates worldwide. Herein we report the first nationwide population-based epidemiological study of MG in Korea. METHODS: We attempted to estimate the incidence and prevalence rates of MG using the Korean National Health Insurance claims database for 2010 to 2013. Cases with MG were defined as those having claim records with a principal diagnosis of MG and the prescription of acetylcholinesterase inhibitors or immunosuppressive agents including corticosteroids and azathioprine within 2 years after the diagnosis. The year 2010 was set as a washout period, such that patients were defined as incident cases if their first records of MG were observed in 2011. RESULTS: In 2011 there were 1,236 incident cases, and the standardized incidence rate was 2.44 per 100,000 person-years. The standardized prevalence rates were 9.67 and 10.66 per 100,000 persons in 2010 and 2011, respectively. The incidence and prevalence rates peaked in the elderly population aged 60 to 69 years for both sexes. CONCLUSIONS: This is one of the largest national population-based epidemiological studies of MG, and it has confirmed the high incidence and prevalence rates of MG in the elderly population of South Korea.
Subject(s)
Aged , Humans , Adrenal Cortex Hormones , Azathioprine , Cholinesterase Inhibitors , Diagnosis , Epidemiologic Studies , Epidemiology , Immunosuppressive Agents , Incidence , Korea , Myasthenia Gravis , National Health Programs , Prescriptions , PrevalenceABSTRACT
Myasthenia gravis (MG) is an antibody-mediated autoimmune disease characterized by exertional weakness. There is no biomarker to reflect disease activity and guide treatment decision. Here, we reported a pilot blood transcriptome study using RNA sequencing (RNA-seq) that identified differences of 5 samples in active status and 5 in remission from 8 different patients and 2 patients provided samples for both active and remission phase. We found a total of 28 differentially expressed genes (DEGs) possibly related to disease activity (23 up-regulated and 5 down-regulated). The DEGs were enriched for the cell motion and cell migration processes in which included were ICAM1, CCL3, S100P and GAB2. The apoptosis and cell death pathway was also significantly enriched, which includes NFKBIA, ZC3H12A, TNFAIP3, and PPP1R15A. Our result suggests that transcript abundance profiles of the genes involved in cell trafficking and apoptosis may be a molecular signature of the disease activity in MG patients.
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Humans , Apoptosis , Autoimmune Diseases , Cell Death , Cell Movement , Gene Expression Profiling , Myasthenia Gravis , Sequence Analysis, RNA , TranscriptomeABSTRACT
Most amyotrophic lateral sclerosis (ALS) patients show focal onset of upper and lower motor neuron signs and spread of symptoms to other regions or the other side clinically. Progression patterns of sporadic ALS are unclear. The aim of this study was to evaluate the pattern of respiratory deterioration in sporadic ALS according to the onset site by using respiratory function tests. Study participants included 63 (42 cervical-onset [C-ALS] and 21 lumbosacral-onset [L-ALS]) ALS patients and 31 healthy controls. We compared respiratory function test parameters among the 3 groups. Age was 57.4+/-9.6 (mean+/-SD), 60.8+/-9, and 60.5+/-7 years, and there were 28, 15, and 20 male participants, in the C-ALS, L-ALS, and control groups, respectively. Disease duration did not differ between C-ALS and L-ALS patients. Sniff nasal inspiratory pressure (SNIP) was significantly low in C-ALS patients compared with controls. Maximal expiratory pressure (MEP) and forced vital capacity percent predicted (FVC% predicted) were significantly low in C-ALS and L-ALS patients compared with controls. Maximal inspiratory pressure to maximal expiratory pressure (MIP:MEP) ratio did not differ among the 3 groups. Eighteen C-ALS and 5 L-ALS patients were followed up. DeltaMIP, DeltaMEP, DeltaSNIP, DeltaPEF, and DeltaFVC% predicted were higher in C-ALS than L-ALS patients without statistical significance. Fourteen C-ALS (77.8%) and 3 L-ALS (60%) patients showed a constant MIP:MEP ratio above or below 1 from the first to the last evaluation. Our results suggest that vulnerability of motor neurons in sporadic ALS might follow a topographic gradient.
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Humans , Male , Amyotrophic Lateral Sclerosis , Motor Neurons , Respiratory Function Tests , Vital CapacityABSTRACT
No abstract available.
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Brachial Plexus Neuropathies , Lipomatosis, Multiple SymmetricalABSTRACT
BACKGROUND AND PURPOSE: Involvement of the corpus callosum (CC) is reported to be a consistent feature of amyotrophic lateral sclerosis (ALS). We examined the CC pathology using diffusion tensor tractography analysis to identify precisely which fiber bundles are involved in ALS. METHODS: Diffusion tensor imaging was performed in 14 sporadic ALS patients and 16 age-matched healthy controls. Whole brain tractography was performed using the multiple-region of interest (ROI) approach, and CC fiber bundles were extracted in two ways based on functional and structural relevance: (i) cortical ROI selection based on Brodmann areas (BAs), and (ii) the sulcal-gyral pattern of cortical gray matter using FreeSurfer software, respectively. RESULTS: The mean fractional anisotropy (FA) values of the CC fibers interconnecting the primary motor (BA4), supplementary motor (BA6), and dorsolateral prefrontal cortex (BA9/46) were significantly lower in ALS patients than in controls, whereas those of the primary sensory cortex (BA1, BA2, BA3), Broca's area (BA44/45), and the orbitofrontal cortex (BA11/47) did not differ significantly between the two groups. The FreeSurfer ROI approach revealed a very similar pattern of abnormalities. In addition, a significant correlation was found between the mean FA value of the CC fibers interconnecting the primary motor area and disease severity, as assessed using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale, and the clinical extent of upper motor neuron signs. CONCLUSIONS: Our findings suggest that there is some degree of selectivity or a gradient in the CC pathology in ALS. The CC fibers interconnecting the primary motor and dorsolateral prefrontal cortices may be preferentially involved in ALS.
Subject(s)
Humans , Amyotrophic Lateral Sclerosis , Anisotropy , Brain , Corpus Callosum , Diffusion Tensor Imaging , Diffusion , Motor Neuron Disease , Motor Neurons , Pathology , Prefrontal CortexABSTRACT
BACKGROUND AND PURPOSE: The receptor for advanced glycation end products (RAGE) may contribute to the development of diabetic neuropathy. To assess its relevance in humans, this study examined the expression of RAGE in the skin biopsy samples of patients with diabetes mellitus, and investigated its correlation with intraepidermal nerve-fiber density (IENFD) and clinical measures of neuropathy severity. METHODS: Forty-four patients who either had type 2 diabetes or were prediabetes underwent clinical evaluation and a 3-mm skin punch biopsy. The clinical severity of their neuropathy was assessed using the Michigan Diabetic Neuropathy Score. IENFD was measured along with immunohistochemical staining for RAGE in 29 skin biopsy samples. The expression of RAGE was also quantified by real-time reverse-transcription PCR in the remaining 15 patients. RESULTS: RAGE was localized mostly in the dermal and subcutaneous vascular endothelia. The staining was more intense in patients with a lower IENFD (p=0.004). The quantity of RAGE mRNA was significantly higher in patients with severe neuropathy than in those with no or mild neuropathy (p=0.003). The up-regulation of RAGE was related to dyslipidemia and diabetic nephropathy. There was a trend toward decreased sural nerve action-potential amplitude and slowed peroneal motor-nerve conduction with increasing RAGE expression. CONCLUSIONS: The findings of this study demonstrate up-regulation of RAGE in skin biopsy samples from patients with diabetic neuropathy, supporting a pathogenic role of RAGE in the development of diabetic neuropathy.
Subject(s)
Humans , Biopsy , Diabetes Mellitus , Diabetic Nephropathies , Diabetic Neuropathies , Dyslipidemias , Michigan , Polymerase Chain Reaction , Prediabetic State , Rage , RNA, Messenger , Skin , Sural Nerve , Up-Regulation , Receptor for Advanced Glycation End ProductsABSTRACT
BACKGROUND: Acquired neuromyotonia (NMT) forms part of the spectrum of acquired peripheral nerve hyperexcitability syndrome, and is thought to be caused by antibodies to voltage-gated potassium channels (VGKC). Exertional weakness is unusual unless autoimmune myasthenia gravis (MG) is superimposed. CASE REPORT: A case of acquired NMT accompanied by exertional weakness without coexistence of seropositive MG is reported herein. CONCLUSIONS: Clinical and electrophysiological observations suggest that the cholinergic overactivity in NMT can compromise the safety factor sufficiently to cause a defect in neuromuscular junction transmission.
Subject(s)
Antibodies , Isaacs Syndrome , Myasthenia Gravis , Neuromuscular Junction , Peripheral Nerves , Potassium Channels, Voltage-GatedABSTRACT
BACKGROUND: The autophagy is the major route for lysosomal degradation of misfolded protein aggregates and oxidative cell components. We hypothesized that rapamycin (autophagy enhancer) would prolong the survival of motor neuron and suppress the disease progression in amyotrophic lateral sclerosis (ALS). METHODS: A total of 24 transgenic mice harboring the human G93A mutated SOD1 gene were used. The clinical status involving rotarod test and survival, and biochemical study of ALS mice model were evaluated. RESULTS: The onset of symptoms was significantly delayed in the rapamycin administration group compared with the control group. However, after the clinical symptom developed, the rapamycin exacerbated the disease progression and shortened the survival of ALS mice model, and apoptosis signals were up-regulated compared with control group. CONCLUSIONS: Even though further detailed studies on the relevancy between autophagy and ALS will be needed, our results revealed that the rapamycin administration was not effective for being novel promising therapeutic strategy in ALS transgenic mice and exacerbated the apoptosis.
Subject(s)
Animals , Humans , Mice , Amyotrophic Lateral Sclerosis , Apoptosis , Autophagy , Cellular Structures , Disease Progression , Mice, Transgenic , Motor Neurons , Neuroprotective Agents , Rotarod Performance Test , SirolimusABSTRACT
To evaluate the efficacy and safety of ursodeoxycholic acid (UDCA) with oral solubilized formula in amyotrophic lateral sclerosis (ALS) patients, patients with probable or definite ALS were randomized to receive oral solubilized UDCA (3.5 g/140 mL/day) or placebo for 3 months after a run-in period of 1 month and switched to receive the other treatment for 3 months after a wash-out period of 1 month. The primary outcome was the rate of progression, assessed by the Appel ALS rating scale (AALSRS), and the secondary outcomes were the revised ALS functional rating scale (ALSFRS-R) and forced vital capacity (FVC). Fifty-three patients completed either the first or second period of study with only 16 of 63 enrolled patients given both treatments sequentially. The slope of AALSRS was 1.17 points/month lower while the patients were treated with UDCA than with placebo (95% CI for difference 0.08-2.26, P = 0.037), whereas the slopes of ALSFRS-R and FVC did not show significant differences between treatments. Gastrointestinal adverse events were more common with UDCA (P < 0.05). Oral solubilized UDCA seems to be tolerable in ALS patients, but we could not make firm conclusion regarding its efficacy, particularly due to the high attrition rate in this cross-over trial.
Subject(s)
Female , Humans , Male , Middle Aged , Administration, Oral , Amyotrophic Lateral Sclerosis/drug therapy , Cholagogues and Choleretics/pharmacology , Cross-Over Studies , Double-Blind Method , Placebo Effect , Severity of Illness Index , Ursodeoxycholic Acid/pharmacology , Vital Capacity/drug effectsABSTRACT
BACKGROUND AND PURPOSE: Recently published, evidence-based guidelines should alter the management of amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). However, the newest recommendations for ALS/MND therapy are not reflected in actual clinical practice. We sought to evaluate the current status of the diagnosis and management of ALS in Korea. METHODS: The Korean ALS/MND research group was organized in 2010, involving more than 50 neurologists from neuromuscular centers in Korea. Participating centers collected data from April to September 2010 on the diagnosis and management of patients with ALS. Data forms from the ALS patient care database, which is a component of the ALS clinical assessment, research, and education program (http://www.outcomes-umassmed.org/ALS/), were modified and used for data collection. RESULTS: In total, 373 sporadic ALS cases from 35 centers were enrolled. The demographic features and clinical findings were similar to those in previous reports from other countries. The mean age at onset was 50-60 years, and a slight male predominance was observed. The enrolled patients predominantly showed focal onset of cervical or lumbosacral symptoms. Only about one-half of the indicated patients (31.4%) received a physician's recommendation for a parenteral gastrostomy, and 18.1% underwent the procedure. Noninvasive ventilation was recommended in 23% of patients, but applied in only 9.5% of them. Tracheostomy was performed in 12.7% of patients. CONCLUSIONS: The demographic and clinical features of the diagnosis and management of ALS in Korea are similar to those reported in other countries; however, supportive management, as recommended in evidence-based guidelines, are not yet widely recommended or performed for patients with ALS in Korea.