Evolving Diagnostic Criteria in Amyotrophic Lateral Sclerosis and Its Differential Diagnosis / 대한신경근육질환학회지

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of upper motor neurons in the brainstem and spinal cord and lower motor neurons. ALS was first described by Jean-Martin Charcot in 1874 based on clinical features and postmortem examinations. In 1990, the first diagnostic criteria for ALS were developed based on clinical features. Subsequently, three additional diagnostic criteria were published. In this article, we introduce the clinical features, diagnostic criteria, and diseases that need to be differentiated in ALS.

Differences in Dysphagia between Patients with Stroke or Amyotrophic Lateral Sclerosis / 대한연하장애학회지

Objective@#Dysphagia is a common symptom of stroke and affects 23–50% of such patients. In addition, bulbar involvement, which causes dysphagia, is the primary initial symptom in approximately 25–30% of amyotrophic lateral sclerosis (ALS) patients. The purpose of this study was to compare patterns of swallowing difficulties in stroke and ALS patients. @*Methods@#We retrospectively recruited 84 ALS patients with dysphagia and 294 stroke patients with dysphagia between January 2017 and December 2019. Swallowing processes were reviewed by videofluoroscopic swallowing studies (VFSSs). The presence of oral residues and oral transit times (OTTs) were measured in the oral phase, and the presence of penetration and aspiration and residues in valleculae or pyriform sinuses were evaluated. Statistical analysis was performed using SPSS 25.0 and comparisons using the Chi-square test. @*Results@#ALS patients more frequently had delayed OTTs and oral residues than stroke patients, and stroke patients more frequently experienced aspiration and had delayed thin liquid pharyngeal transit times (PTTs). However, no significant intergroup difference was observed for the presence of penetration, residues in valleculae or pyriform sinuses, or thick liquid PTTs. @*Conclusion@#The study shows that ALS patients exhibit slower food processing in the oral cavity and more significant bulbar muscle weakness than stroke patients. On the other hand, stroke patients had greater thin liquid aspiration rates than ALS patients. These findings should be considered when choosing treatments for ALS and stroke.

Clinical Characteristics of Korean Juvenile Amyotrophic Lateral Sclerosis / 대한신경근육질환학회지

Background@#Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron degeneration with phenotypic heterogeneity, including age at onset. Juvenile ALS (JALS) includes ALS patients aged less than 25 years who typically show slow progression. This study aimed to identify the characteristics of juvenile ALS from Korean ALS cohorts. @*Methods@#We retrospectively investigated the clinical characteristics of JALS patients, who met the revised El Escorial-Airlie House criteria, in the Korean motor neuron disease cohort om January 2002 to November 2018. To evaluate the genetic background ofin JALS, we screened the SOD1 mutation in all JALS patients using PCR. @*Results@#Among the seven JALS patients, the mean age was 22.1 years (± 2.19 years) and 4 patients were male. Most patients were diagnosed within less than 12 months, but in one patient, it took 96 months to make the initial diagnosis. On assessing the cognitive function, none of the patients had dementia. The progression rate of JALS during follow-up was usually low (median [IQR], 0.31 [0.11-0.52]), except in patients with SOD1 mutation (3.40) and CLEC4C mutation (1.12). One patient revealed a family history of ALS with SOD1 mutation, but we also detected the SOD1 mutation among sporadic JALS patients. @*Conclusions@#Although JALS patients with genetic mutations (SOD1-p.Asn87Ser and CLEC4C-p.Lys210*) showed faster progression than other JALS patients, one patient with SOD1 mutation (p.Gly17Ala) showed slow progression. Familial ALS was rare; however, it might be caused by low or incomplete penetrance of the genes or by small number of JALS patients. To investigate the other genetic causes of JALS without the SOD1 mutation, a further study including detailed genetic analysis is needed.

Post-Traumatic Guillain-Barre Syndrome / 대한신경근육질환학회지

Guillain-Barre syndrome (GBS) is acute inflammatory demyelinating polyradiculoneuropathy, which is often related to post-infectious etiology. However, GBS has also been reported to be caused by non-infectious factors such as trauma. This report describes a rare case of post-traumatic GBS with dramatic response to immunoglobulin therapy. And here, we also discussed about the importance of differential diagnosis with critical illness polyneuropathy.

Clinical Characteristics of Korean Juvenile Amyotrophic Lateral Sclerosis / 대한신경근육질환학회지

Background@#Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron degeneration with phenotypic heterogeneity, including age at onset. Juvenile ALS (JALS) includes ALS patients aged less than 25 years who typically show slow progression. This study aimed to identify the characteristics of juvenile ALS from Korean ALS cohorts. @*Methods@#We retrospectively investigated the clinical characteristics of JALS patients, who met the revised El Escorial-Airlie House criteria, in the Korean motor neuron disease cohort om January 2002 to November 2018. To evaluate the genetic background ofin JALS, we screened the SOD1 mutation in all JALS patients using PCR. @*Results@#Among the seven JALS patients, the mean age was 22.1 years (± 2.19 years) and 4 patients were male. Most patients were diagnosed within less than 12 months, but in one patient, it took 96 months to make the initial diagnosis. On assessing the cognitive function, none of the patients had dementia. The progression rate of JALS during follow-up was usually low (median [IQR], 0.31 [0.11-0.52]), except in patients with SOD1 mutation (3.40) and CLEC4C mutation (1.12). One patient revealed a family history of ALS with SOD1 mutation, but we also detected the SOD1 mutation among sporadic JALS patients. @*Conclusions@#Although JALS patients with genetic mutations (SOD1-p.Asn87Ser and CLEC4C-p.Lys210*) showed faster progression than other JALS patients, one patient with SOD1 mutation (p.Gly17Ala) showed slow progression. Familial ALS was rare; however, it might be caused by low or incomplete penetrance of the genes or by small number of JALS patients. To investigate the other genetic causes of JALS without the SOD1 mutation, a further study including detailed genetic analysis is needed.

A Therapeutic Strategy for Alzheimer's Disease Focused on Immune-inflammatory Modulation

Alzheimer's disease (AD), the most common form of dementia, has emerged as a major global public health challenge. However, the complexity of AD in its biological, genetic, and clinical aspects has hindered the development of effective therapeutic agents. Research plans that integrate new drug discoveries are urgently needed, including those based on novel and reliable biomarkers that reflect not only clinical phenotype, but also genetic and neuroimaging information. Therapeutic strategies such as stratification (i.e., subgrouping of patients having similar clinical characteristics or genetic background) and personalized medicine could be set as new directions for developing effective drugs for AD. In this review, we describe a therapeutic strategy that is based on immune-inflammation modulation for a subgroup of AD and related dementias, arguing that the use of stratification and personalized medicine is a promising way to achieve targeted medicine. The Korean AD Research Platform Initiative based on Immune-Inflammatory biomarkers (K-ARPI) has recently launched a strategy to develop novel biomarkers to identify a subpopulation of patients with AD and to develop new drug candidates for delaying the progression of AD by modulating toxic immune inflammatory response. Sphingosine kinase 1 (SphK1) and its metabolites, triggering receptor expressed on myeloid cells-2 (TREM2) related signals, and actin motility related proteins including Nck-associated protein 1 (Nap1) were selected as promising targets to modulate neuroinflammation. Their roles in stratification and personalized medicine will be discussed.

Subacute Combined Degeneration and Pulmonary Thromboembolism due to Nitrous Oxide Inhalation for Recreational Use

No abstract available.

A De Novo RAPGEF2 Variant Identified in a Sporadic Amyotrophic Lateral Sclerosis Patient Impairs Microtubule Stability and Axonal Mitochondria Distribution

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is frequently linked to microtubule abnormalities and mitochondrial trafficking defects. Whole exome sequencing (WES) of patient-parent trios has proven to be an efficient strategy for identifying rare de novo genetic variants responsible for sporadic ALS (sALS). Using a trio-WES approach, we identified a de novo RAPGEF2 variant (c.4069G>A, p.E1357K) in a patient with early-onset sALS. To assess the pathogenic effects of this variant, we have used patient-derived skin fibroblasts and motor neuron-specific overexpression of the RAPGEF2-E1357K mutant protein in Drosophila. Patient fibroblasts display reduced microtubule stability and defective microtubule network morphology. The intracellular distribution, ultrastructure, and function of mitochondria are also impaired in patient cells. Overexpression of the RAPGEF2 mutant in Drosophila motor neurons reduces the stability of axonal microtubules and disrupts the distribution of mitochondria to distal axons and neuromuscular junction (NMJ) synapses. We also show that the recruitment of the pro-apoptotic protein BCL2-associated X (BAX) to mitochondria is significantly increased in patient fibroblasts compared with control cells. Finally, increasing microtubule stability through pharmacological inhibition of histone deacetylase 6 (HDAC6) rescues defects in the intracellular distribution of mitochondria and BAX. Overall, our data suggest that the RAPGEF2 variant identified in this study can drive ALS-related pathogenic effects through microtubule dysregulation.

Impaired Perception of Emotional Expression in Amyotrophic Lateral Sclerosis

BACKGROUND AND PURPOSE: The increasing recognition that deficits in social emotions occur in amyotrophic lateral sclerosis (ALS) is helping to explain the spectrum of neuropsychological dysfunctions, thus supporting the view of ALS as a multisystem disorder involving neuropsychological deficits as well as motor deficits. The aim of this study was to characterize the emotion perception abilities of Korean patients with ALS based on the recognition of facial expressions. METHODS: Twenty-four patients with ALS and 24 age- and sex-matched healthy controls completed neuropsychological tests and facial emotion recognition tasks [ChaeLee Korean Facial Expressions of Emotions (ChaeLee-E)]. The ChaeLee-E test includes facial expressions for seven emotions: happiness, sadness, anger, disgust, fear, surprise, and neutral. RESULTS: The ability to perceive facial emotions was significantly worse among ALS patients performed than among healthy controls [65.2±18.0% vs. 77.1±6.6% (mean±SD), p=0.009]. Eight of the 24 patients (33%) scored below the 5th percentile score of controls for recognizing facial emotions. CONCLUSIONS: Emotion perception deficits occur in Korean ALS patients, particularly regarding facial expressions of emotion. These findings expand the spectrum of cognitive and behavioral dysfunction associated with ALS into emotion processing dysfunction.

Impaired Perception of Emotional Expression in Amyotrophic Lateral Sclerosis

BACKGROUND AND PURPOSE: The increasing recognition that deficits in social emotions occur in amyotrophic lateral sclerosis (ALS) is helping to explain the spectrum of neuropsychological dysfunctions, thus supporting the view of ALS as a multisystem disorder involving neuropsychological deficits as well as motor deficits. The aim of this study was to characterize the emotion perception abilities of Korean patients with ALS based on the recognition of facial expressions. METHODS: Twenty-four patients with ALS and 24 age- and sex-matched healthy controls completed neuropsychological tests and facial emotion recognition tasks [ChaeLee Korean Facial Expressions of Emotions (ChaeLee-E)]. The ChaeLee-E test includes facial expressions for seven emotions: happiness, sadness, anger, disgust, fear, surprise, and neutral. RESULTS: The ability to perceive facial emotions was significantly worse among ALS patients performed than among healthy controls [65.2±18.0% vs. 77.1±6.6% (mean±SD), p=0.009]. Eight of the 24 patients (33%) scored below the 5th percentile score of controls for recognizing facial emotions. CONCLUSIONS: Emotion perception deficits occur in Korean ALS patients, particularly regarding facial expressions of emotion. These findings expand the spectrum of cognitive and behavioral dysfunction associated with ALS into emotion processing dysfunction.

Prognostic Role of Serum Levels of Uric Acid in Amyotrophic Lateral Sclerosis

BACKGROUND AND PURPOSE: It has been suggested that oxidative stress is one of the pathomechanisms underlying amyotrophic lateral sclerosis (ALS), and thus antioxidants such as uric acid (UA) that could reduce oxidative stress might be beneficial in the prevention or treatment of this disease. The objective of this study was to prospectively investigate serum UA levels in Korean ALS patients and to relate them to disease progression. METHODS: ALS patients and healthy controls who were individually well-matched for sex, age, and body mass index (BMI) underwent blood testing for serum UA levels, and analyzed whether UA levels were correlated with the disease status of the patients, as defined by the ALS Functional Rating Scale-Revised (ALSFRS-R). RESULTS: The study included 136 ALS patients and 136 matched controls. The UA level was lower in the ALS patients (4.50+/-1.17 mg/dL, mean+/-SD) than in the controls (5.51+/-1.22 mg/dL; p<0.001). Among the ALS patients, the level of UA acid was inversely correlated with the rate of disease progression (decrease in ALSFRS-R score). Kaplan-Meier analysis revealed that a better survival rate was more strongly correlated with top-tertile levels of serum UA than with bottom-tertile levels (log-rank test: p=0.035). CONCLUSIONS: ALS patients had lower serum UA levels than did healthy individuals. UA levels in ALS were negatively correlated with the rate of disease progression and positively associated with survival, suggesting that UA levels contribute to the progression of ALS. UA levels could be considered a biomarker of disease progression in the early phase in ALS patients.

A Novel F45S SOD1 Mutation in Amyotrophic Lateral Sclerosis Coexisting with Bullous Pemphigoid

BACKGROUND: The coexistence of an autoimmune disease and amyotrophic lateral sclerosis (ALS) has led to the hypothesis that immune-mediated pathological mechanisms are overlapping in the two diseases. We report herein a rare coexistence of bullous pemphigoid (BP) in a novel mutation (F45S) of the gene encoding Cu/Zn superoxide dismutase (SOD1) in an ALS patient, and discuss a role for the SOD1 mutation in this unusual overlap. CASE REPORT: A 57-year-old male with familial ALS, including vesicles and tense bullae on erythematous bases, was diagnosed with BP. Direct immunofluorescence revealed deposits of C3 and immunoglobulin G in the basement membrane zone. Direct sequencing of SOD1 in the patient revealed a novel mutation (c.137T>C; F45S). CONCLUSIONS: We report a novel SOD1 mutation in ALS, which was combined with BP. This novel SOD1 mutation could affect the phenotype of a combined autoimmune disease and matrix metalloproteinase-9. There may therefore be common factors linking BP and ALS with the SOD1 mutation.

Depression and Caregiving Burden in Families of Patients with Amyotrophic Lateral Sclerosis

PURPOSE: The purpose of this study was to describe depression, caregiving burden and the correlation of the two variables in the families of patients with amyotrophic lateral sclerosis (ALS) and to clarify factors predicting caregiving burden. METHODS: A descriptive and cross-sectional study was conducted with 139 family members who provided care to patients with ALS. The characteristics of patients and families, Korean-Beck Depression Inventory (K-BDI), Korean version of Zarit Burden Interview (K-ZBI) and Korean-Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (K-ALSFRS-R) were used as study measures. RESULTS: The mean score for K-BDI was 19.39 out of 63 suggesting sub-clinical depression and 38.2% of the family members exhibited depression. The mean score for K-ZBI was 66.03 out of 88. The predictors for K-ZBI were K-BDI, age of family member, length of time spent per day in caring, relationship to patient and K-ALSFRS-R. CONCLUSION: The results of this study suggest that levels of depression and caregiving burden are high among family members caring for patients with ALS. As depression is associated with caregiving burden, screening and emotional supports should be provided to reduce the burden of care for these family. Support programs to alleviate the care burden are also needed, considering family demographics, time per day in caring giving and K-ALSFRS-R.

Stem Cell Therapy for Neurodegenerative Diseases / 한양의대학술지

Neurodegenerative diseases are the hereditary and sporadic conditions which are characterized by progressive neuronal degeneration. Neurodegenerative diseases are emerging as the leading cause of death, disabilities, and a socioeconomic burden due to an increase in life expectancy. There are many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis, but we have no effective treatments or cures to halt the progression of any of these diseases. Stem cell-based therapy has become the alternative option to treat neurodegenerative diseases. There are several types of stem cells utilized; embryonic stem cells, induced pluripotent stem cells, and adult stem cell (mesenchymal stem cells and neural progenitor cells). In this review, we summarize recent advances in the treatments and the limitations of various stem cell technologies. Especially, we focus on clinical trials of stem cell therapies for major neurodegenerative diseases.

Clinical Features and Prognostic Effects of Behavioral and Psychological Symptoms in Patients with Amyotrophic Lateral Sclerosis

BACKGROUND: The evaluation of behavioral and psychological symptoms (BPS) in ALS is important because its existence may serve as a prognostic factor and suggest a shared pathology with frontotemporal dementia (FTD) in ALS. In this study, we sought to identify the prevalence of the BPS of ALS patients and evaluate its relationship with the clinical profiles and survival of ALS patients. METHODS: One hundred sixty-six patients were enrolled in a cross-sectional cohort analysis from September 2008 to February 2012. All patients had sporadic ALS without a genetic mutation and were collected clinical profiles. The t-test and chi-square test were used to assess differences in the clinical characteristics and caregiver-administered neuropsychiatric inventory (CGA-NPI) scores. The Kaplan-Meier method and Cox proportional hazard model were used for the survival analysis. RESULTS: Forty-two patients had clinically significant BPS (42/166, 25.3%). ALS patients with BPS had worse clinical dementia rating (CDR), ALS Functional Rating Scale-Revised (ALSFRS-R) score, and progression rate of disease than those without BPS. Among CGA-NPI subscales, depression, irritability, apathy, and agitation were higher prevalent than the others. There was a trend for ALS patients with BPS having short survival time than those without BPS in the Kaplan-Meier analysis (p=0.006). However, in the Cox proportional hazard model, BPS in ALS patients were not associated with poor survival. CONCLUSION: These results support the presence of an overlapping spectrum between ALS and FTD and emphasize the importance of neuropsychiatric evaluations in ALS. Although the association between BPS and prognosis are not explained clearly, these results could be used to stratify ALS patients according to neuropsychiatric symptoms and help investigators to evaluate the BPS in ALS patients.

Recombinant Human Erythropoietin in Amyotrophic Lateral Sclerosis: A Pilot Study of Safety and Feasibility

BACKGROUND AND PURPOSE: It has been shown that erythropoietin is neuroprotective in animal models of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The aim of this study was to determine the safety and feasibility of repetitive high-dose recombinant human erythropoietin (rhEPO) therapy in ALS patients. METHODS: Two consecutive studies were conducted. We first recruited 26 subjects for an initial single-arm safety study. After a lead-in period of 3 months to assess the disease progression, rhEPO was infused intravenously (35,000 IU) once per month for 3 months, and the subjects were followed for an additional 3 months. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used for clinical assessment. After confirming the safety of rhEPO, 60 subjects were recruited for the second controlled study (rhEPO and control groups), which involved a total of 6 infusions at a rate of 1/month. RESULTS: There were no serious adverse events in the first study. The mean rate of decline in the ALSFRS-R score was lower during the treatment period than during the lead-in period (mean+/-SD: 2.6+/-1.8 and 3.7+/-2.6, respectively; p=0.02). However, the rate of decline during the subsequent 3 months returned to that observed in the lead-in period. In the second study, the mean rate of decline in ALSFRS-R score was significantly lower in the rhEPO group than in the control group (during months 0-3, 1.8+/-1.7 vs. 3.1+/-2.3, p=0.03; during months 4-6, 2.1+/-2.2 vs. 3.5+/-2.3, p=0.02). CONCLUSIONS: Intravenous high-dose rhEPO is both safe and feasible for the treatment of ALS. Further investigation using different intervals and doses should be considered.

Superior Mesenteric Artery Syndrome in Patient with Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that causes progressive muscular weakness, severe weight loss, and ultimately death. Gastrostomy or nasogastric tube is beneficial for ALS patients with severe weight loss and dysphagia. However, the development of superior mesenteric artery (SMA) syndrome in ALS patients when the enteral feeding time is delayed is rarely reported. We report herein the first case of SMA syndrome in a Korean ALS patient who showed improvement after percutaneous endoscopic gastrojejunostomy(PEGJ).

A Case of Transient Isolated Splenial Lesion of the Corpus Callosum After New Onset Seizure / 대한간질학회지

Reversible lesion in the splenium of the corpus callosum can be caused by various conditions. There is no report about the case with first seizure attack. We report a 25-year-old man shown transient isolated splenial lesion of the corpus callosum associated with new onset seizure. Lesion was shown in the splenium of the corpus callosum on MRI. Theses findings were resolved on follow up MRI without specific treatment. This case suggests that the first attack seizure could make a reversible splenial lesion.

A case of Crohn's Disease with Optic Neuritis and Wernicke's Encephalopathy

Neurological complications associated with Crohn's disease are infrequent and optic neuritis is extremely rare. We report a 20-year-old man showing optic neuritis and Wernicke's encephalopathy as complications of Crohn's disease. We suggest that nutritional deficiency caused Wernicke's encephalopathy and the immunologic abnormality of Crohn's disease induced the complication of optic neuritis. This patient is the first reported case showing optic neuritis and Wernicke's encephalopathy simultaneously as neurological complications of Crohn's disease in Korea.

Relapsing Herpes Simplex Encephalitis

Herpes simplex encephalitis (HSE) is the most common type of viral encephalitis and a fourteen day administration of acyclovir is well-known as the treatment of choice for HSE. Occasionally HSE relapses, but rarely with acyclovir treatment. We report a case of relapsing HSE after treatment with acyclovir for 14 days. Our case suggests that patients with progressive high signal intensities in diffusion-weighted brain MRIs might need longer antiviral therapy over 14 days for preventing the relapse of herpes simplex encephalitis.