Clinical pitfalls and serological diagnostics of MuSK myasthenia gravis.

BACKGROUND: We aimed to evaluate the diagnostic accuracy of enzyme-linked immunosorbent assay (ELISA) for anti-muscle specific tyrosine kinase (MuSK) antibody (Ab) in a large cohort of anti-acetylcholine receptor (AChR) Ab-negative generalized myasthenia gravis (MG), and also to investigate clinical contexts for the diagnosis of MuSK MG. METHODS: A retrospective study of 160 patients with a clinical suspicion of AChR Ab-negative generalized MG was performed. The serum samples were tested for anti-clustered AChR Ab by cell-based assay (CBA), anti-MuSK Ab by ELISA, CBA and/or radioimmunoprecipitation assay (RIPA). Clinical data were compared between anti-MuSK Ab-positive MG and double seronegative (AChR and MuSK) MG groups. RESULTS: After excluding non-MG and clustered AChR Ab-positive patients, we identified 89 patients as a cohort of AChR Ab-negative generalized MG. Anti-MuSK Ab was positive by ELISA in 22 (24.7%) patients. While CBA identified five additional anti-MuSK Ab-positive patients, the results of ELISA were mostly consistent with CBA and RIPA with Cohen's kappa of 0.80 and 0.90, respectively (p < 0.001). The most frequent differential diagnosis was motor neuron disease particularly of bulbar onset which showed remarkably overlapping clinical and electrophysiological features with MuSK MG at presentation. CONCLUSION: While confirming the highest sensitivity of CBA for detecting anti-MuSK Ab, our results highlight the clinical pitfalls in making a diagnosis of MuSK MG and may support a diagnostic utility of MuSK-ELISA in clinical practice.

Genotype and Phenotype Differences in CADASIL from an Asian Perspective.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small-vessel disease caused by mutations in the NOTCH3 gene. Classical pathogenic mechanisms are associated with cysteine gain or loss, but recent studies suggest that cysteine-sparing mutations might have a potential role as a pathogen. In comparison with CADASIL patients in Western countries, there are several differences in Asian patients: (1) prevalent locus of NOTCH3 mutations (exons 2-6 [particularly exon 4] vs. exon 11), (2) age at symptom onset, (3) prevalence of cerebral microbleeds and hemorrhagic stroke, (4) clinical symptoms, and (5) severity of white matter hyperintensities and typical involvement of the anterior temporal pole in magnetic resonance imaging. Both ethnicity and founder effects contribute to these differences in the clinical NOTCH3 spectrum in different cohorts. More functional investigations from diverse races are needed to clarify unknown but novel variants of NOTCH3 mutations. This review may broaden the spectrum of NOTCH3 variants from an Asian perspective and draw attention to the hidden pathogenic roles of NOTCH3 variants.

Bidirectional association between migraine and rheumatoid arthritis: two longitudinal follow-up studies with a national sample cohort.

OBJECTIVE: To investigate the bidirectional association between migraine and rheumatoid arthritis (RA). DESIGN: Two longitudinal follow-up studies. SETTING: Data collected from a national cohort between 2002 and 2013 by the Korean National Health Insurance Service-Health Screening Cohort. PARTICIPANTS: In cohort 1, matching resulted in the inclusion of 31 589 migraine patients and 126 356 control I participants. In cohort 2, matching resulted in the inclusion of 9287 RA patients and 37 148 control II participants. PRIMARY AND SECONDARY OUTCOME MEASURES: The HRs for RA in patients with migraine (cohort 1) and migraine in patients with RA (cohort 2) were analysed using stratified Cox proportional hazard models after adjusting for autoimmune disease, Charlson Comorbidity Index scores without rheumatoid diseases, obesity (body mass index), smoking and history of alcohol intake. Subgroup analyses stratified by age, sex, income and region of residence were also performed. RESULTS: The incidence of RA in the migraine group (2.0% (640/31 589)) was higher than that in the control I group (1.4% (1709/126 356), p<0.001). The adjusted HR for RA in the migraine without aura group was 1.48 (95% CIs=1.34 to 1.63, p<0.001).The incidence of migraine in the RA group (6.4% (590/9287)) was higher than that in the control II group (4.6% (1721/37 148), p<0.001). The adjusted HR for migraine without aura in the RA group was 1.35 (95% CI=1.23 to 1.49, p<0.001). CONCLUSION: Migraine increases the risk of RA, and RA is also associated with an increased risk of migraine.

Validity and Reliability of the Fibromyalgia Rapid Screening Tool Among Individuals with Chronic Daily Headache: A Clinic-Based Study.

BACKGROUND: Fibromyalgia is a common chronic pain disorder typically associated with headache disorders, particularly chronic daily headache. However, fibromyalgia is typically underdiagnosed and undertreated. The Fibromyalgia Rapid Screening Tool questionnaire is a brief, self-administered questionnaire composed of six "yes/no" questions for detecting fibromyalgia. The Fibromyalgia Rapid Screening Tool questionnaire has demonstrated high sensitivity and specificity among patients with chronic diffuse pain conditions. This study assessed the validity and reliability of the aforementioned questionnaire for detecting fibromyalgia among patients with chronic daily headache. METHODS: Consecutive first-visit headache patients with primary chronic daily headache (≥15 days/month for three or more months) at the outpatient clinics of four university hospitals were enrolled in this study from April 2015 to October 2015, and the validity and reliability of the Fibromyalgia Rapid Screening Tool questionnaire for determining fibromyalgia were evaluated. Fibromyalgia was diagnosed according to the American College of Rheumatology criteria of 2010. RESULTS: A total of 171 patients with primary chronic daily headache were recruited, and 100 (58.4%) were determined to have fibromyalgia. Receiver operating characteristic curve analysis revealed that a cutoff score of 5 (corresponding to the number of positive items) provided the highest rate of correct identification of patients (77.2%), with a sensitivity of 70.0% and specificity of 87.3%. The positive and negative predictive values were 88.6% and 67.4%, respectively. The Cronbach's alpha coefficient was 0.684. CONCLUSIONS: The Fibromyalgia Rapid Screening Tool is a valid and reliable instrument for identifying fibromyalgia among patients with chronic daily headache.

Myasthenia gravis seronegative for acetylcholine receptor antibodies in South Korea: Autoantibody profiles and clinical features.

Acquired myasthenia gravis (MG) is a prototype autoimmune disease of the neuromuscular junction, caused in most patients by autoantibodies to the muscle nicotinic acetylcholine receptor (AChR). There seem to be ethnic and regional differences in the frequency and clinical features of MG seronegative for the AChR antibody. This study aimed to describe the autoantibody profiles and clinical features of Korean patients with generalized MG seronegative for the AChR antibody. A total of 62 patients with a high index of clinical suspicion of seronegative generalized MG were identified from 18 centers, and we examined their sera for antibodies to clustered AChR, muscle-specific tyrosine kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (LRP4) by cell-based assays (CBA) and to MuSK by radioimmunoprecipitation assay (RIPA). We also included 8 patients with ocular MG, 3 with Lambert-Eaton myasthenic syndrome, 5 with motor neuron disease, and 9 with other diagnoses as comparators for the serological testing. Antibodies were identified in 25/62 (40.3%) patients: 7 had antibodies to clustered AChR, 17 to MuSK, and 2 to LRP4. Three patients were double seropositive: 1 for MuSK and LRP4, and 2 for MuSK and clustered AChR. The patients with MuSK antibodies were mostly female (88.2%) and characterized by predominantly bulbar involvement (70%) and frequent myasthenic crises (58.3%). The patients with antibodies to clustered AChR, including 2 with ocular MG, tended to have a mild phenotype and good prognosis.

Fibromyalgia Among Patients With Chronic Migraine and Chronic Tension-Type Headache: A Multicenter Prospective Cross-Sectional Study.

OBJECTIVES: To investigate the frequency and impact of fibromyalgia among patients with chronic migraine (CM) and chronic tension-type headache (CTTH). BACKGROUND: Fibromyalgia (FM) is a common comorbidity in patients with chronic headaches. CM and CTTH are the two common types of chronic headaches. METHODS: We conducted a cross-sectional study in neurology outpatient clinics of four university hospitals and selected first-visit 136 patients with CM and 35 patients with CTTH. FM was assessed based on the 2010 American College of Rheumatology diagnostic criteria. RESULTS: The frequency of FM was significantly higher among patients with CM when compared to those with CTTH (91/136 [66.9%] vs 9/35 [25.7%], P < .001). Logistic regression analyses revealed an increased odds ratio (OR) for FM for patients with CM when compared to those with CTTH after adjustment for age, sex, anxiety, depression, and insomnia (OR = 3.6, 95% confidence interval = 1.1-11.4). Furthermore, CM patients with FM had higher scores in FM Impact Questionnaire compared to CTTH patients with FM (51.5 ± 16.3 vs 43.7 ± 18.7, P = .015). Comorbidity of FM was associated with increased frequency of photophobia, phonophobia, anxiety, depression, and insomnia among patients with CM. Such association was not noted among patients with CTTH. CONCLUSION: FM based on 2010 American College of Rheumatology diagnostic criteria was more prevalent among patients with CM than those with CTTH. Some clinical features and comorbidities of CM varied with the presence of FM.

Top 100 cited articles on epilepsy and status epilepticus: A bibliometric analysis.

The purpose of this study is to identify the top 100-cited articles dedicated to epilepsy and status epilepticus published in journals from January, 1950 through February, 2016 that have made key contributions in the field. We performed a search of journals and selected the top 100-cited articles on epilepsy and status epilepticus, respectively, by utilizing the Institute for Scientific Information database available under the banner of the Web of Science. The top-cited articles on epilepsy and status epilepticus were all published in 24 journals, respectively. In both fields of epilepsy and status epilepticus, the most frequently cited journal was Epilepsia (26 articles on epilepsy and 19 articles on status epilepticus). The 100 most-cited articles in the field of both epilepsy and status epilepticus mainly originated from institutions in the United States of America. The articles on epilepsy included 25 laboratory studies, 15 pharmacotherapy studies, 13 general review studies, 12 surgery studies, 11 neuroimaging studies, eight epidemiology studies, eight neuropsychiatry studies, six genetic studies, and two electrophysiology studies, whereas 41 laboratory studies, 21 epidemiology studies, 16 pharmacotherapy studies, nine electrophysiology studies, nine general review studies, and four neuroimaging studies were included in the field of status epilepticus. We demonstrate that neuroimaging, genetics, and surgery are emerging topics in the field of epilepsy over the past decades. Moreover, we found that the majority of top-cited articles on epilepsy and status epilepticus originated from institutions in the United States of America and most were published in Epilepsia.

Comparison of new adenosine diphosphate receptor antagonists with clopidogrel in patients with coronary artery disease: a meta-analysis.

Recent data suggest the superiority of new adenosine diphosphate (ADP) receptor antagonists compared with clopidogrel in acute coronary syndrome patients. We aimed to assess the risks and benefits of new ADP receptor antagonists in patients with coronary artery disease (CAD). Relevant studies published through February 28, 2014 were searched and identified in the MEDLINE, EMBASE, and Cochrane databases. Summary estimates were obtained using a random-effects model. All nine published randomized controlled studies comparing new ADP receptor antagonists with clopidogrel in CAD were included. The database consisted of 66,900 patients; 33,782 on novel agents, and 33,118 on clopidogrel. New ADP receptor antagonists reduced the composite incidence of all-cause mortality, myocardial infarction or stroke (odds ratio [OR] 0.89, 95 % confidence interval [CI] 0.81-0.97, p = 0.01) but increased the incidence of non-coronary artery bypass grafting-related major bleeding (OR 1.24, 95 % CI 1.08-1.42, p = 0.003). The composite end point of the net rate of adverse clinical events, which was the combination of the primary efficacy end point and the primary safety end point, was significantly lower in the new agent group compared to the clopidogrel group (9.7 versus 10.6 %, OR 0.92, 95 % CI 0.85-1.00). Use of recently introduced new ADP receptor antagonists results in a reduction in adverse clinical outcomes but a substantial increase in bleeding. New agents revealed an improved combined efficacy and safety outcome compared to that of clopidogrel in patients with CAD.

CPAP therapy reverses weakness of myasthenia gravis: role of obstructive sleep apnea in paradoxical weakness of myasthenia gravis.

Fatigability after exercise and restoration of strength by rest are clinical hallmarks of myasthenia gravis (MG). These unique features are originated from a reduced safety factor, which is related to a defect of acetylcholine receptor, and post-exercise exhaustion of neuromuscular junction transmission. Therefore, most patients with MG feel recharged muscle strength and show normal muscle power after nocturnal sleep. As such, worsening of MG symptoms during nighttime is usual. However, in very rare cases, some patients with MG complain fatigability and weakness in the morning, so called "paradoxical weakness (PW)." We report two MG patients with typical PW, diagnosed with OSA by polysomnography. CPAP therapy successfully improved their morning symptoms and quality of life. So far, the detailed mechanism of PW in MG is unknown; however, our report highlights the possible role of sleep disorders in developing a PW in MG and the therapeutic target for life quality of MG.

Clinical predictors of steroid-induced exacerbation in myasthenia gravis.

Although oral corticosteroids are effective for the treatment of myasthenia gravis (MG), the possibility of steroid-induced exacerbation of symptoms, especially during the initial course of steroid therapy, has limited their use patients with severe MG. However, the factors influencing or predicting in exacerbation are not well understood. The purpose of this study was to identify the clinical factors that predict the initial paradoxical exacerbation of MG in response to steroid therapy. Fifty-five consecutive patients who were administered for the first time high doses of prednisone (40-80 mg) in a tertiary medical centre in Seoul, were included. Prednisone-induced exacerbation was defined as a significant reduction in a patient's Myasthenia Gravis Severity Scale (MSS) score within 4 weeks of prednisone administration. We divided the patients into two groups on the basis of whether or not they experienced prednisone-induced exacerbation, and investigated the differences between the two groups with respect to clinical, laboratory and electrophysiological features. Twenty-three patients (42%) experienced definite exacerbation after prednisone therapy. Older age, predominantly severe bulbar symptoms, and low MSS score were found to be significant clinical predictors of exacerbation by multivariate logistic regression analysis. A high daily dosage of prednisone relative to body weight was found to be neither a predictor of exacerbation nor a predictor of early improvement in bivariate correlation analysis. Steroid-induced exacerbation in MG is a frequently encountered and challenging problem. Clinicians should be aware of the possibility of exacerbation of MG when prescribing prednisone, especially when treating elderly, bulbar dominant, or severely myasthenic patients.

[Grading of histology, expression of apoptosis and cell proliferation in gastric mucosa adjacent to gastric adenoma or adenocarcinoma].

BACKGROUND/AIMS: Helicobacter pylori (H. pylori) infection can lead to gastric adenoma and carcinoma through atrophic gastritis and intestinal metaplasia. Imbalance between apoptosis and proliferation may play a role in gastric carcinogenesis. We tried to investigate H. pylori infection rate, grade of gastritis, environmental risk factors, expression rate of apoptosis and cell proliferation in mucosa adjacent to tumor, and we also tried to find significant factors associated with gastric carcinogenesis. METHODS: Endoscopically diagnosed twenty cases of intestinal type gastric carcinoma, 20 cases of gastric adenoma, and 40 cases of control (normal or gastritis) were enrolled. H. pylori infection rate, histologic grading, apoptosis and immunohistochemical stain (Ki-67 and p53) to check mucosal proliferation were done in endoscopically biopsied tissues at antrum and body at least 2 cm apart from adenoma or carcinoma. RESULTS: In three groups, H. pylori infection rates were not significantly different. In the multivariate analysis, only atrophy of gland was a significant risk factor for adenoma compared to control group (OR 3.7). Intestinal metaplasia in antrum and alcohol drinking were significant risk factors for carcinoma compared to control group (OR 4.4 and 4.9 respectively). Expressions of apoptosis, Ki-67 and p53 were not significantly different in three groups. CONCLUSIONS: Intestinal metaplasia in antrum and alcohol drinking are significant risk factors for gastric carcinoma. Degree of mucosal proliferation and apoptosis in gastric mucosa adjacent to tumor are not significantly different in three groups.

Percutaneous transhepatic cholangioscopic treatment of patients with benign bilio-enteric anastomotic strictures.

BACKGROUND: Percutaneous transhepatic cholangioscopy is a nonoperative method for accessing bilio-enteric anastomotic strictures that cannot be reached via the transpapillary route. This study evaluated the immediate and long-term results of treatment via percutaneous transhepatic cholangioscopy of patients with benign bilio-enteric anastomotic strictures. METHODS: A retrospective analysis was conducted of 21 patients who, between October 1994 and March 2001, had undergone percutaneous transhepatic cholangioscopy for bilio-enteric anastomotic strictures. Follow-up ranged from 12 to 79 months (mean 33.3 months). RESULTS: The initial technical success rate was 100%, and the short-term morbidity and mortality rates were, respectively, 14.3% and 0%. However, strictures recurred in 8 patients (38.1%) at a mean of 17.1 months (range 2-38 months). The success rate exclusive of patients with recurrent strictures was 61.9%, and the overall success rate was 81.0% when the procedures were repeated. The long-term morbidity rate was 38.1%, but most complications resolved with conservative treatment. In 17 patients (81.0%), strictures were complicated by biliary stones, and these were successfully treated via percutaneous transhepatic cholangioscopy (stone removal rate 94.1%, recurrence rate 37.5%). CONCLUSIONS: Percutaneous transhepatic cholangioscopy-based treatment of patients with benign bilio-enteric anastomotic strictures is safe and effective. This minimally invasive method frequently can be used as a substitute for surgery.

[Clinical characteristics and malignant predictive factors in patients with nonfunctioning islet cell tumors of the pancreas].

BACKGROUND/AIMS: It is difficult to determine preoperatively whether nonfunctioning islet cell tumors (NFICTs) are malignant or benign. The purposes of this study were to evaluate clinical characteristics and to differentiate benign from malignant behavior of NFICTs. METHODS: We retrospectively analyzed 21 patients with NFICTs between 1990 and 2002. RESULTS: Mean age was 51.4+/-13.2 years and female was predominant. Tumor size ranged from 0.5 to 13 cm (average 3.3+/-1.8 cm). Thirteen patients had variable symptoms. Histologically, 14 tumors were malignant and 7 were benign. In 9 out of 13 patients, pancreatogram showed narrowing of the main pancreatic duct, which was more frequently detected in patients with malignant NFICTs than in patients with benign ones (p<0.01). Surgical resection was performed in 20 patients. All patients with benign NFICTs are still alive after surgery, while 3 out of 14 patients with malignant NFICTs died 11, 22, 30 months after operation or diagnosis, respectively. The follow up time ranged from 1 to 111 months (mean 32.6 months) CONCLUSIONS: The presenting symptoms of patients with NFICTs were non-specific. The malignancy rate of NFICTs was high. Narrowing of the main pancreatic duct on pancreatogram suggested the malignancy.

Ectopic opening of the common bile duct in the duodenal bulb: clinical implications.

BACKGROUND: An ectopic opening of the common bile duct in the duodenal bulb is extremely rare, and the clinical significance of this anomaly has not been clarified. This study analyzed the clinical implications and cholangiographic findings of this anomaly. METHODS: A total of 18 patients (15 men, 3 women; median age, 51 years) with an ectopic opening of the common bile duct in the duodenal bulb were studied. Medical records, endoscopic findings, and cholangiographic and other radiographic findings were reviewed. RESULTS: All 18 patients had biliary pain; 7 had fever and chills. Fifteen (83%) had diffuse dilatation of the extrahepatic bile ducts with or without intrahepatic bile duct dilation. Associated bile duct stones were found in 10 (56%) patients. The papilla in the bulb had an orifice stained with bile at endoscopy, which was associated with duodenal ulcer disease found in 13 (72%) patients. The distal end of the common bile duct was tapered and narrowed and had a hook shape in all patients. CONCLUSION: An ectopic opening of the common bile duct in the duodenal bulb may be associated with clinical entities such as recurrent or intractable duodenal ulcer, choledocholithiasis, or acute cholangitis. Although these openings are rare, knowledge of the endoscopic and radiographic findings of an ectopic opening of the common bile duct in the duodenal bulb may help to clarify the cause of chronic recurrent duodenal ulcer disease in some patients and prevent damage to the bile duct during surgery.