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.

'Sirim' (Cold) Pain as a Common Symptom in Korean Patients with Clinically Suspected Small-Fiber Neuropathy.

BACKGROUND AND PURPOSE: Diagnosing small-fiber neuropathy (SFN) is challenging because there is no gold-standard test and few diagnostic tests. This study investigated the clinical symptom profile and its associations with the results of quantitative sensory testing (QST) and the quantitative sudomotor axon reflex test (QSART) as well as the quality of life (QOL) in patients with clinically suspected SFN. METHODS: This study involved 63 patients with clinically suspected length-dependent SFN. Assessments were performed using QST, QSART, SFN Symptoms Inventory Questionnaire, Neuropathic Pain Symptom Inventory, 'Sirim' frequency and 'Sirim' (cold) pain severity, and 36-item Short-Form Health Survey. Multiple logistic and linear regression analyses were performed to predict risk factors for QST or QSART abnormalities and QOL, respectively. RESULTS: 'Sirim' and 'Sirim' pain was the most-common (84%) and the most-severe complaint (mean score of 6.3 on a numerical rating scale ranging from 0 to 10) in patients with clinically suspected SFN. The findings of QST [cold detection threshold (CDT)] and QSART were abnormal in 71% (n=45/57) and 62% (n=39/56) of the patients, respectively. An abnormal CDT was correlated with more-severe stabbing pain (odds ratio=2.23, 95% CI=1.02-4.87, p=0.045). Restless-leg symptoms (ß=-7.077) and pressure-evoked pain (ß=-5.034) were independent predictors of the physical aspects of QOL. CONCLUSIONS: 'Sirim' pain, similar to cold pain, should be considered a major neuropathic pain in SFN. Among pain characteristics, stabbing pain of a spontaneous paroxysmal nature may be more pronounced in the setting of dysfunctional Aδ fibers with functional autonomic C fibers.

Changes in Serum Electrolytes, ECG, and Baroreflex Sensitivity during Combined Pituitary Stimulation Test.

The mechanisms by which hypoglycemia increases cardiovascular mortality remain unclear. The aim of the study is to investigate changes in serum electrolytes, norepinephrine concentrations, electrocardiography, and baroreflex sensitivity (BRS) and associations between corrected QT (QTc) intervals and the changes in serum electrolytes during combined pituitary stimulation test (CPST). We recruited the subjects who were admitted to the Gyeongsang National University Hospital to undergo CPST between September 2013 and December 2014. Participants were 12 patients suspected of having hypopituitarism. Among 12 patients, cardiac arrhythmia in two patients occurred during hypoglycemia. There were significant differences in serum levels of potassium (P < 0.001), sodium (P = 0.003), chloride (P = 0.002), and calcium (P = 0.017) at baseline, hypoglycemia, and 30 and 120 minutes after hypoglycemia. Also, there was a significant increase in heart rate (P = 0.004), corrected QT (QTc) interval (P = 0.008), QRS duration (P = 0.021), and BRS (P = 0.005) at hypoglycemia, compared to other time points during CPST. There was a positive association between QTc intervals and serum sodium levels (P < 0.001) in 10 patients who did not develop arrhythmia during CPST. This study showed that there were significant changes in serum levels of potassium, sodium, chloride, and calcium, as well as heart rate, QTc interval, QRSd, and BRS during CPST. It was revealed that QTc intervals had a significant association with concentrations of sodium.

Atorvastatin pretreatment attenuates kainic acid-induced hippocampal neuronal death via regulation of lipocalin-2-associated neuroinflammation.

Statins mediate vascular protection and reduce the prevalence of cardiovascular diseases. Recent work indicates that statins have anticonvulsive effects in the brain; however, little is known about the precise mechanism for its protective effect in kainic acid (KA)-induced seizures. Here, we investigated the protective effects of atorvastatin pretreatment on KA-induced neuroinflammation and hippocampal cell death. Mice were treated via intragastric administration of atorvastatin for 7 days, injected with KA, and then sacrificed after 24 h. We observed that atorvastatin pretreatment reduced KA-induced seizure activity, hippocampal cell death, and neuroinflammation. Atorvastatin pretreatment also inhibited KA-induced lipocalin-2 expression in the hippocampus and attenuated KA-induced hippocampal cyclooxygenase-2 expression and glial activation. Moreover, AKT phosphorylation in KA-treated hippocampus was inhibited by atorvastatin pretreatment. These findings suggest that atorvastatin pretreatment may protect hippocampal neurons during seizures by controlling lipocalin-2-associated neuroinflammation.

Erratum to: The KMDS-NATION Study: Korean Movement Disorders Society Multicenter Assessment of Non-Motor Symptoms and Quality of Life in Parkinson's Disease NATION Study Group.

This corrects the article on p. 393 in vol. 12, PMID: 27819413.

NUDT15 p.R139C variant is common and strongly associated with azathioprine-induced early leukopenia and severe alopecia in Korean patients with various neurological diseases.

Azathioprine (AZA)-induced leukopenia is a relatively common complication in Korean patients. In addition to variation in TPMT (thiopurine S-methyltransferase), the NUDT15 p.R139C variant was recently identified to have a strong association with AZA-induced leukopenia. We investigated these associations in Korean patients undergoing AZA treatment with various neurological diseases. Among 84 enrolled patients, 20 (23.8%; 7 early, 13 late) exhibited leukopenia. The NUDT15 p.R139C variant was associated with leukopenia (OR: 11.844, 95% CI 3.984-36.024, p=1.327 × 10-5). The allelic frequency of NUDT15 p.R139C was as high as 10.7% and the frequency of the C/C, C/T, and T/T genotypes was 84.5, 10.7, and 5.9%, respectively. All T/T homozygous patients (5/5) developed early severe-grade leukopenia (white blood cells <1000mm-3) and severe alopecia. NUDT15 p.R139C was strongly associated with early leukopenia and severe alopecia (OR for early leukopenia: 107.624, 95% CI 18.857-614.250, p=1.403 × 10-7, OR for severe alopecia: 77.152, 95% CI 17.378-342.526, p=1.101 × 10-8). The sensitivity and specificity for predicting AZA-induced early leukopenia were 85.7% and 92.2%, respectively. Therefore, the NUDT15 p.R139C variant is common and strongly associated with AZA-induced early leukopenia and severe alopecia in Korean patients with various neurological diseases.

Hemianopic line bisection error in a patient with Alzheimer's disease.

Visual symptoms are frequently observed in posterior cortical atrophy compared to typical amnestic Alzheimer's disease (AD). We report the case of a patient with amnestic AD with long-lasting homonymous hemianopia. A 62-year-old woman, who was diagnosed in amnestic AD, complained of visual disturbance. She had left homonymous hemianopia in the perimetry test and left tactile extinction. Regardless of posture, retinotopically leftward error was observed on 21 cm line bisection test. Brain single photon emission computerized tomography (SPECT) showed bilateral temporoparietal hypoperfusion, which was more severe to the right than left side. This case suggested that long-lasting hemianopia could occur in the patient with amnestic AD and that hemianopic line bisection error might be compensatory mechanism.

The KMDS-NATION Study: Korean Movement Disorders Society Multicenter Assessment of Non-Motor Symptoms and Quality of Life in Parkinson's Disease NATION Study Group.

BACKGROUND AND PURPOSE: Nonmotor symptoms (NMS) in Parkinson's disease (PD) have multisystem origins with heterogeneous manifestations that develop throughout the course of PD. NMS are increasingly recognized as having a significant impact on the health-related quality of life (HrQoL). We aimed to determine the NMS presentation according to PD status, and the associations of NMS with other clinical variables and the HrQoL of Korean PD patients. METHODS: We surveyed patients in 37 movement-disorders clinics throughout Korea. In total, 323 PD patients were recruited for assessment of disease severity and duration, NMS, HrQoL, and other clinical variables including demographics, cognition, sleep scale, fatigability, and symptoms. RESULTS: In total, 98.1% of enrolled PD subjects suffered from various kinds of NMS. The prevalence of NMS and scores in each NMS domain were significantly higher in the PD group, and the NMS worsened as the disease progressed. Among clinical variables, disease duration and depressive mood showed significant correlations with all NMS domains (p<0.001). NMS status impacted HrQoL in PD (rS=0.329, p<0.01), and the association patterns differed with the disease stage. CONCLUSIONS: The results of our survey suggest that NMS in PD are not simply isolated symptoms of degenerative disease, but rather exert significant influences throughout the disease course. A novel clinical approach focused on NMS to develop tailored management strategies is warranted to improve the HrQoL in PD patients.

Weight Change Is a Characteristic Non-Motor Symptom in Drug-Naïve Parkinson's Disease Patients with Non-Tremor Dominant Subtype: A Nation-Wide Observational Study.

Despite the clinical impact of non-motor symptoms (NMS) in Parkinson's disease (PD), the characteristic NMS in relation to the motor subtypes of PD is not well elucidated. In this study, we enrolled drug-naïve PD patients and compared NMS between PD subtypes. We enrolled 136 drug-naïve, early PD patients and 50 normal controls. All the enrolled PD patients were divided into tremor dominant (TD) and non-tremor dominant (NTD) subtypes. The Non-Motor Symptom Scale and scales for each NMS were completed. We compared NMS and the relationship of NMS with quality of life between normal controls and PD patients, and between the PD subtypes. Comparing with normal controls, PD patients complained of more NMS, especially mood/cognitive symptoms, gastrointestinal symptoms, unexplained pain, weight change, and change in taste or smell. Between the PD subtypes, the NTD subtype showed higher total NMS scale score and sub-score about weight change. Weight change was the characteristic NMS related to NTD subtype even after controlled other variables with logistic regression analysis. Even from the early stage, PD patients suffer from various NMS regardless of dopaminergic medication. Among the various NMS, weight change is the characteristic NMS associated with NTD subtype in PD patients.

Toxocara canis-Associated Myelitis with Eosinophilic Pneumonia.

The existence of Toxocara canis-specific antibodies has recently been reported in patients with atopic myelitis. Here, we report the case of a 35-year-old male patient admitted with a chief complaint of right lower limb hypoesthesia lasting for a month. The patient was diagnosed with eosinophilic pneumonia 3 months ago, and a spine MRI revealed the presence of myelitis in the cervicothoracic cord. After confirming the presence of hyper-IgE-emia and Toxocara canis antibodies, the patient was treated with steroids and albendazole treatment, which improved his symptoms. To our knowledge, this is the first case of Toxocara canis-associated myelitis with eosinophilic pneumonia.

Location of Irritative Zone in Epileptic Brains of Schizencephalic Patients.

Although many schizencephaly patients suffer from epilepsy, the relationship between schizencephalic lesions and epileptic foci remains unclear. Previous studies have shown that schizencephalic lesions may be associated with, rather than contain, epileptogenic zones. Thus, the purpose of this study was to investigate the current source distribution (CSD) of epileptiform discharges in schizencephalic patients and to correlate this activity with existing structural lesions. A consecutive series of 30 schizencephalic patients who were diagnosed using brain magnetic resonance imaging (MRI) were selected retrospectively and prospectively. Of the original 30 subjects selected, 13 had epilepsy, and 6 of these patients exhibited schizencephaly, epilepsy, and interictal spikes on electroencephalograms (EEG) and were enrolled in the present study investigating the current source analysis of interictal spikes. The CSDs of the initial rising phases and the peak points of the interictal spikes were obtained using standardized low-resolution brain electromagnetic tomography (LORETA). Five patients exhibited a single focus of interictal spikes, while 1 patient showed 2 foci. Relative to the structural brain lesions, 5 patients displayed extrinsically localized CSDs, while 1 patient showed a partially intrinsically localized CSD. The present findings demonstrate that the CSDs of interictal spikes in schizencephalic patients are in general anatomically distinct from the cerebral schizencephalic lesions and that these lesions may display an extrinsic epileptogenicity.

Comparison of Solitaire thrombectomy and Penumbra suction thrombectomy in patients with acute ischemic stroke caused by basilar artery occlusion.

BACKGROUND AND PURPOSE: Acute ischemic stroke (AIS) caused by basilar artery occlusion (BAO) is a very severe neurological disease with a high mortality rate and poor clinical outcomes. In this study, we compared our experience of mechanical thrombectomy using the Solitaire stent (Solitaire thrombectomy) and manual aspiration thrombectomy using the Penumbra reperfusion catheter (Penumbra suction thrombectomy) in patients with AIS caused by BAO. MATERIALS AND METHODS: Between March 2011 and December 2011, 13 patients received Solitaire thrombectomy. In January 2012, the Korean Food and Drug Administration banned the use of the Solitaire stent as a thrombectomy device, and a further 18 patients received Penumbra suction thrombectomy until December 2013. We compared parameters between patients treated with each device. RESULTS: Successful recanalization rates (Thrombolysis in Cerebral Infarction (TICI) score ≥2b: 84.6% vs 100%, p=0.168) and clinical outcomes (judged by the modified Rankin Scale scores recorded at 3 months: 3.6±2.6 vs 3.2±2.6, p=0.726) were not significantly different between the two groups. However, complete recanalization rates (TICI score of 3: 23.1% vs 72.2%, p=0.015) and total procedure times (101.9±41.4 vs 62.3±34.8 min, p=0.044) were significantly higher, and shorter, respectively, in patients treated by Penumbra suction thrombectomy. CONCLUSIONS: The two thrombectomy devices were associated with similar recanalization rates and clinical outcomes in patients with AIS caused by BAO. However, Penumbra suction thrombectomy seemed to allow more rapid and complete recanalization than Solitaire thrombectomy.

Initial factors affecting the clinical outcome after successful recanalization via MR-based mechanical thrombectomy in patients with acute ischemic stroke due to basilar artery occlusion.

BACKGROUND AND PURPOSE: To determine the initial factors, including patient characteristics, stroke etiology and severity, time factors, and imaging findings, that could affect the clinical outcome of patients with acute ischemic stroke (AIS) caused by basilar artery occlusion (BAO) where successful recanalization was achieved via mechanical thrombectomy. METHODS: Between March 2011 and December 2014, 35 patients with AIS caused by BAO received MRI/MR angiography-based mechanical thrombectomies, and recanalization was achieved with a Thrombolysis In Cerebral Infarction score of >2b. The patients were divided into a good outcome group (n=19), defined as those with a modified Rankin Scale (mRS) score of 0-2 at 3 months after stroke onset, and a poor outcome group (n=16), defined as a mRS score of 3-6. The differences between the groups were analyzed. RESULTS: Initial National Institutes of Health Stroke Scale (NIHSS) score (good vs poor: 17.9±8.9 vs 27.6±8.5, p=0.003), posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) based on initial diffusion-weighted images (DWI) (good vs poor: 7.8±1.6 vs 5.4±1.8, p=0.001), pc-ASPECTS based on contrast staining on the post-thrombectomy control CT (good vs poor: 9.2±1.5 vs 6.3±2.2, p<0.001), and presence of contrast staining in the brainstem on that CT (good vs poor: 15.8% vs 81.6%, p<0.001) were significantly different between the groups. CONCLUSIONS: Patients with AIS caused by BAO with a lower initial NIHSS score, fewer lesions on initial DWI, and less contrast staining on the post-thrombectomy control CT have higher probabilities of a good clinical outcome after successful recanalization via a mechanical thrombectomy.

Emergency carotid artery stenting in patients with acute ischemic stroke due to occlusion or stenosis of the proximal internal carotid artery: a single-center experience.

BACKGROUND: The feasibility, safety and effectiveness of emergency carotid artery stenting (eCAS) in patients with acute ischemic stroke (AIS) due to proximal internal carotid artery (ICA) stenosis or occlusion are still controversial. In this study we analyzed our experience with eCAS in patients with AIS. METHODS: Twenty-two eCAS procedures for proximal ICA stenosis or occlusion were performed in 22 patients at our institution between January 2011 and November 2013. The mean time from stroke symptom onset to presentation was 204 min (range 50-630 min) and the mean initial score on the National Institutes of Health Stroke Scale (NIHSS) was 12.55 (range 5-23). Ten patients had total occlusion of the proximal ICA and the remaining 12 patients had near total occlusion or severe stenosis (mean degree 90.7%, range 80-100%). Eleven patients also had tandem occlusion on the more distal intracranial arteries. RESULTS: Successful stent insertion was achieved in all patients and additional thrombectomy using a Solitaire stent or Penumbra aspiration catheter achieved a Thrombolysis In Cerebral Infarction grade of more than 2a in all patients with distal tandem occlusion. Procedure-related complications occurred in one patient (cerebral hyperperfusion syndrome) who recovered successfully. The mean NIHSS score at discharge was 3.55 (range 0-18). The mean modified Rankin Scale score at 3 months was 1 ± 1.67 (range 0-6). CONCLUSIONS: eCAS in patients with AIS due to proximal ICA stenosis or occlusion appears to be a technically feasible and effective method for achieving good clinical outcomes.

Utility of corrected QT interval in orthostatic intolerance.

We performed this study to determine whether electrocardiographic corrected QT (QTc) interval predicts alterations in sympathovagal balance during orthostatic intolerance (OI). We reviewed 1,368 patients presenting with symptoms suggestive of OI who underwent electrocardiography and composite autonomic function tests (AFTs). Patients with a positive response to the head-up tilt test were classified into orthostatic hypotension (OH), neurocardiogenic syncope (NCS), or postural orthostatic tachycardia syndrome (POTS) groups. A total of 275 patients (159 OH, 54 NCS, and 62 POTS) were included in the final analysis. Between-group comparisons of OI symptom grade, QTc interval, QTc dispersion, and each AFT measure were performed. QTc interval and dispersion were correlated with AFT measures. OH Patients had the most severe OI symptom grade and NCS patients the mildest. Patients with OH showed the longest QTc interval (448.8±33.6 msec), QTc dispersion (59.5±30.3 msec) and the lowest values in heart rate response to deep breathing (HRDB) (10.3±6.0 beats/min) and Valsalva ratio (1.3±0.2). Patients with POTS showed the shortest QTc interval (421.7±28.6 msec), the highest HRDB values (24.5±9.2 beats/min), Valsalva ratio (1.8±0.3), and proximal and distal leg sweat volumes in the quantitative sudomotor axon reflex test. QTc interval correlated negatively with HRDB (r = -0.443, p<0.001) and Valsalva ratio (r = -0.425, p<0.001). We found negative correlations between QTc interval and AFT values representing cardiovagal function in patients with OI. Our findings suggest that prolonged QTc interval may be considered to be a biomarker for detecting alterations in sympathovagal balance, especially cardiovagal dysfunction in OH.

Prevalence of anti-ganglioside antibodies and their clinical correlates with guillain-barré syndrome in Korea: a nationwide multicenter study.

BACKGROUND AND PURPOSE: No previous studies have investigated the relationship between various anti-ganglioside antibodies and the clinical characteristics of Guillain-Barré syndrome (GBS) in Korea. The aim of this study was to determine the prevalence and types of anti-ganglioside antibodies in Korean GBS patients, and to identify their clinical significance. METHODS: Serum was collected from patients during the acute phase of GBS at 20 university-based hospitals in Korea. The clinical and laboratory findings were reviewed and compared with the detected types of anti-ganglioside antibody. RESULTS: Among 119 patients, 60 were positive for immunoglobulin G (IgG) or immunoglobulin M antibodies against any type of ganglioside (50%). The most frequent type was IgG anti-GM1 antibody (47%), followed by IgG anti-GT1a (38%), IgG anti-GD1a (25%), and IgG anti-GQ1b (8%) antibodies. Anti-GM1-antibody positivity was strongly correlated with the presence of preceding gastrointestinal infection, absence of sensory symptoms or signs, and absence of cranial nerve involvement. Patients with anti-GD1a antibody were younger, predominantly male, and had more facial nerve involvement than the antibody-negative group. Anti-GT1a-antibody positivity was more frequently associated with bulbar weakness and was highly associated with ophthalmoplegia when coupled with the coexisting anti-GQ1b antibody. Despite the presence of clinical features of acute motor axonal neuropathy (AMAN), 68% of anti-GM1- or anti-GD1a-antibody-positive cases of GBS were diagnosed with acute inflammatory demyelinating polyradiculoneuropathy (AIDP) by a single electrophysiological study. CONCLUSIONS: Anti-ganglioside antibodies were frequently found in the serum of Korean GBS patients, and each antibody was correlated strongly with the various clinical manifestations. Nevertheless, without an anti-ganglioside antibody assay, in Korea AMAN is frequently misdiagnosed as AIDP by single electrophysiological studies.

Timely event-related synchronization fading and phase de-locking and their defects in migraine.

OBJECTIVE: To investigate the characteristics of event-related synchronization (ERS) fading and phase de-locking of alpha waves during passive auditory stimulation (PAS) in the migraine patients. METHODS: The subjects were 16 adult women with migraine and 16 normal controls. Electroencephalographic (EEG) data obtained during PAS with standard (SS) and deviant stimuli (DS) were used. Alpha ERS fading, the phase locking index (PLI) and de-locking index (DLI) were evaluated from the 10 Hz complex Morlet wavelet components at 100 ms (t100) and 300 ms (t300) after PAS. RESULTS: At t100, significant ERS was found with SS and DS in the migraineurs and controls (P=0.000). At t300 in the controls, ERS faded to zero for DS while in the migraineurs there was no fading for DS. In both groups the PLI for SS and DS was significantly reduced, i.e. de-locked, at t300 compared to t100 (P=0.000). In the migraineurs, the DLI for DS was significantly lower than in the controls (P=0.003). CONCLUSION: The alpha ERS fading and phase de-locking are defective in migraineurs during passive auditory cognitive processing. SIGNIFICANCE: The defects in timely alpha ERS fading and in de-locking may play a role in the different attention processing in migraine patients.