Clinical and Pathological Features of Korean Patients with DNM2-Related Centronuclear Myopathy

Background and Purpose

Centronuclear myopathy (CNM) is characterized by the presence of central nuclei within a large number of muscle fibers. Mutations of the dynamin 2 gene (DNM2) are common causes of autosomal dominant or sporadic CNM. The aim of this study was to characterize the clinical and pathological features of CNM relative to the presence of DNM2 mutations.

Methods

Six patients with clinical and pathological features of CNM were recruited. Detailed clinical and pathological findings were analyzed according to the presence of DNM2 mutations.

Results

We detected DNM2 mutations in four of the six sporadic CNM patients, and identified the following distinct clinical and pathological features in those patients with DNM2 mutations: preferential involvement of the distal lower limbs, typical nuclear centralization, and radially distributed sarcoplasmic strands in muscle pathology. In contrast, those without DNM2 mutations exhibited rather diffuse muscular involvement, and nuclear internalization and myofibrillar disorganization were more pronounced features of their muscle pathology.

Conclusions

These findings suggest the presence of specific features in Korean CNM patients. A detailed clinical and pathological examination of CNM patients would be helpful for molecular genetic analyses of this condition.     

Naltrexone is neuroprotective against traumatic brain injury in mu opioid receptor knockout mice

AimsNaltrexone is a mu opioid receptor (MOR) antagonist used to treat drug dependence in patients. Previous reports indicated that MOR antagonists reduced neurodegeneration and inflammation after brain injury. The purpose of this study was to evaluate the neuroprotective effect of naltrexone in cell culture and a mouse model of traumatic brain injury (TBI).MethodsThe neuroprotective effect of naltrexone was examined in primary cortical neurons co‐cultured with BV2 microglia. Controlled cortical impact (CCI) was delivered to the left cerebral cortex of adult male MOR wild‐type (WT) and knockout (KO) mice. Naltrexone was given daily for 4 days, starting from day 2 after lesioning. Locomotor activity was evaluated on day 5 after the CCI. Brain tissues were collected for immunostaining, Western, and qPCR analysis.ResultsGlutamate reduced MAP2 immunoreactivity (‐ir), while increased IBA1‐ir in neuron/BV2 co‐culture; both responses were antagonized by naltrexone. TBI significantly reduced locomotor activity and increased the expression of IBA1, iNOS, and CD4 in the lesioned cortex. Naltrexone significantly and equally antagonized the motor deficits and expression of IBA1 and iNOS in WT and KO mice. TBI‐mediated CD4 protein production was attenuated by naltrexone in WT mice, but not in KO mice.ConclusionNaltrexone reduced TBI‐mediated neurodegeneration and inflammation in MOR WT and KO mice. The protective effect of naltrexone involves non‐MOR and MOR mechanisms.     

Which treatment modality is more injurious to the brain in patients with subarachnoid hemorrhage? Degree of brain damage assessed by serum s100 protein after aneurysm clipping or coiling

Background: Serum S100 protein has been known to reflect the severity of brain damage. The purpose of this study was to compare the degree of brain damage based on the serum S100 protein level between aneurysm clipping and coiling groups and to evaluate the prognostic value of S100 protein in patients with subarachnoid hemorrhage (SAH). Methods: Serum S100 protein was measured by Elecsys S100 immunoassay at admission, and at 6 and 24 h, and days 3 and 5 postoperatively for 100 consecutive SAH patients (clipping group: 56, coiling group: 44) and for 74 healthy controls. Hunt-Hess grade (HHG), Fisher grade (FG), the presence of intraventricular (IVH) or intracerebral hemorrhage (ICH), and outcome at discharge were evaluated. The time course of serum S100 was compared between the groups. The prognostic value of S100 protein was evaluated by logistic regression analysis. Results: The median S100 level in SAH patients on admission was significantly higher than in healthy controls (0.081 vs. 0.05 μg/l, p < 0.0001) and it was also higher as HHG and FG increased (p < 0.0001). Logistic regression analysis revealed that only the S100 value at admission was an independent prognostic factor for poor outcomes after adjusting for age, sex, HHG, presence of IVH or ICH, and treatment modality (OR: 100.5, 95% CI: 1.65-6,053.61). The baseline S100 value of 0.168 predicted poor outcomes with a sensitivity of 75% and a specificity of 83%. The time course of the median S100 level peaked at 6 h and then decreased serially in both clipping and coiling groups. However, the degree of S100 elevation was marked in the clipping group, especially at 6 h postoperatively (0.177 vs. 0.116 μg/l, p = 0.022), suggesting more severe brain damage in the clipping group. In the coiling group, the S100 value was significantly higher in patients who showed high signal intensity lesions in diffusion-weighted images, suggesting ischemic brain damage. Furthermore, even in patients who were categorized as good clinical grade at admission and as good outcome at discharge, the median S100 values at 6 and 24 h postoperatively were significantly higher in the clipping group than in the coiling group (p < 0.05). Conclusion: The initial S100 protein value is an independent prognostic factor for poor outcomes in SAH patients. Based on the S100 protein level, aneurysm clipping seems to provoke more brain damage than aneurysm coiling. Endovascular coiling should be considered the first therapeutic option for aneurysmal SAH patients.     

DSM-IV psychiatric comorbidity according to symptoms of insomnia: a nationwide sample of Korean adults

Purpose

The diagnosis of insomnia is based on the presence of four different symptoms: difficulty in initiating sleep (DIS), difficulty in maintaining sleep (DMS), early morning awakening (EMA), and non-restorative sleep (NRS). This study investigated the differences in sociodemographic correlates and psychiatric comorbidity between the four symptoms of insomnia in the general population of South Korea.

Methods

A sample of the population aged 18–64 (N?=?6,510) was questioned using a face-to-face interview. Insomnia was defined as having at least one of the four following symptoms three or more times per week: DIS, DMS, EMA, and NRS. Psychiatric disorders were evaluated using the Korean version of Composite International Diagnostic Interview. Logistic regression analysis was used to test each of the sleep outcomes (DIS, DMS, EMA, or NRS) for an association with sociodemographic and clinical variables.

Results

The prevalence of DIS, DMS, EMA, and NRS were 7.9?% (95?% CI 6.6–9.5?%), 7.9?% (95?% CI 6.5–9.6?%), 4.9?% (95?% CI 3.9–6.0?%), and 14.8?% (95?% CI 12.6–17.4?%), respectively. The overall prevalence of insomnia was 19.0?% (95?% CI 16.1–22.2?%). Being separated, divorced, or widowed, being single, having a part-time job, having a psychiatric illness, and having a physical illness were all significantly related to insomnia. Older age also increased the risk of DMS and EMA, and younger age was a risk factor for NRS. The presence of most psychiatric disorders was significantly related to insomnia. However, the relationship between the psychiatric illness and each insomnia symptom varied and was dependent on the insomnia symptom.

Conclusions

Most psychiatric disorders were significantly associated with each insomnia symptom in different ways. Differences in sociodemographic and clinical correlates between the four insomnia symptoms implied the heterogeneous characteristics of insomnia as defined by the current diagnostic criteria.     

Dissociation of Structural and Functional Integrities of the Motor System in Amyotrophic Lateral Sclerosis and Behavioral-Variant Frontotemporal Dementia

MethodsStructural changes were examined using a region-of-interest approach, applying voxel-based morphometry for gray-matter changes and diffusion tensor imaging for white-matter changes. Functional changes in the motor system were elucidated using threshold-tracking transcranial magnetic stimulation (TMS) measurements of upper motor-neuron excitability.ResultsThe structural analyses showed that in ALS there were more white-matter changes in the corticospinal and motor-cortex regions and more gray-matter changes in the cerebellum in comparison to controls. bvFTD showed substantial gray- and white-matter changes across virtually all motor-system regions compared to controls, although the brainstem was affected less than the other regions. Direct comparisons across patient groups showed that the gray- and white-matter motor-system changes inclusive of the motor cortex were greater in bvFTD than in ALS. By contrast, the functional integrity of the motor system was more adversely affected in ALS than in bvFTD, with both patient groups showing increased excitability of upper motor neurons compared to controls.ConclusionsCross-correlation of structural and functional data further revealed a neural dissociation of different motor-system regions and tracts covarying with the TMS excitability across both patient groups. The structural and functional motor-system integrities appear to be dissociated between ALS and bvFTD, which represents useful information for the diagnosis of motor-system changes in these two disorders.     

Combined Intravenous and Intraarterial Revascularization Therapy Using MRI Perfusion/Diffusion Mismatch Selection for Acute Ischemic Stroke at 3–6 h After Symptom Onset

Background and Purpose  Intravenous (IV) thrombolysis with recombinant tissue plasminogen activator (rt-PA) has demonstrated favorable clinical outcomes in a 3–6 h window in patients selected with perfusion/diffusion mismatch. However, the advantages of combined IV and intraarterial (IA) thrombolysis after 3 h of stroke onset are unexplored. Methods  Acute ischemic stroke patients with persistent occlusion of intracranial large arteries were screened prospectively for thrombolysis by evaluating perfusion/diffusion mismatch on MRI. The IV rt-PA was initiated within 3–6 h, and additional urokinase (UK) was then administered via the IA route after angiography. Results  Four patients had middle cerebral artery occlusion and one patient had an internal carotid artery occlusion. The median time from the symptom onset to the initiation of IV therapy and to the initiation of IA treatment was 215 ± 30 min and 292 ± 41 min, respectively. The median National Institutes of Health Stroke Scale (NIHSS) scores were as follows: initial, 13; immediately after IA treatment, 8; at 24 h, 5; and at 7 days, 3. The Thrombolysis in Myocardial Infarction (TIMI) score after the completion of thrombolysis was 2–3. Four patients without intracerebral hemorrhage recovered completely or exhibited mild disability and one patient with hemorrhage also demonstrated a favorable outcome. Conclusion  This preliminary result suggests that if a significant perfusion/diffusion mismatch on MRI is identified, a sequential combination thrombolysis of IV rt-PA and IA UK is potentially beneficial in moderate to severe acute ischemic stroke patients who are treated within 3–6 h after symptom onset.     

The Relationship between Alexithymia and General Symptoms of Patients with Depressive Disorders

Objective

Depression has been associated with alexithymic features. However, few studies have investigated the differences in the general symptoms of patients with depressive disorders according to the presence of alexithymia. Thus, the aim of this study was to evaluate the relationship between alexithymia and symptoms experienced by patients with clinically diagnosed depressive disorders.

Methods

A chart review of patients who were evaluated using the Korean version of the 20-item Toronto Alexithymia Scale (TAS-20) and Symptom Checklist 90-Revised (SCL-90-R) at the same time between the years 2003 and 2007 was conducted. A total of 104 patients with depressive disorders were included and divided into two groups: alexithymia (n=52) and non-alexithymia (n=52). A direct comparison between the two groups was carried out. Regression analysis was also carried out for the TAS-20 total and subset scores in order to model the relationship between alexithymia and symptoms.

Results

The presence of alexithymia was confirmed in 50% of the patients with depressive disorders, and the symptoms of depressive patients with alexithymia were more severe than those of their non-alexithymic counterparts on all 9 symptom domains of the SCL-90-R. Furthermore, regression analysis revealed that the presence of alexithymia was positively associated with depression, phobic anxiety, and psychoticism but inversely associated with anxiety.

Conclusion

These results suggest that the clinical features of depression are partially dependent on the presence of alexithymia. Alexithymic patients with depressive disorders are likely to show more severe depressive, psychotic, and phobic symptoms. In other words, clinicians should suspect the presence of alexithymic tendencies if these symptoms coexist in patients with depressive disorders and address their difficulties in effective communication.     

Comparison of 90-day case-fatality after ischemic stroke between two different stroke outcome registries using propensity score matching analysis

Yu K‐H, Hong K‐S, Lee B‐C, Oh M‐S, Cho Y‐J, Koo J‐S, Park J‐M, Bae H‐J, Han M‐K, Ju Y‐S, Kang D‐W, Appelros P, Norrving B, Terent A. Comparison of 90‐day case‐fatality after ischemic stroke between two different stroke outcome registries using propensity score matching analysis.
Acta Neurol Scand: 2011: 123: 325–331.
© 2010 John Wiley & Sons A/S. Background – It has not been clarified whether the disparity in ischemic stroke outcome between populations is caused by ethnic and geographic differences or by variations in case mix. Propensity score matching (PSM) analysis can overcome some analytical problems but is rarely used in stroke outcome research. This study was to compare the ischemic stroke case‐fatality between two PSM cohorts of Sweden and Korea. Methods – Prognostic variables related to baseline characteristics and stroke care were included in our PSM model. Then, we selected 7675 Swedish and 1220 Korean patients with ischemic stroke from each stroke registers and performed one‐to‐one matching based on propensity scores of each patient. Results – After PSM, all measured variables were well balanced in 1163 matched subjects, and the 90‐day case‐fatality was identical 6.2% (HR 0.997, 95%CI 0.905–1.099) in Sweden and Korea. Conclusions – No difference is found in the 90‐day case‐fatality in propensity score‐matched Swedish and Korean patients with ischemic stroke.     

Inhibition of hexokinase leads to neuroprotection against excitotoxicity in organotypic hippocampal slice culture

During seizures, glucose concentrations are high in the hippocampus. Mitochondrial hexokinase (HK) catalyzes the first essential step of glucose metabolism and directly couples extramitochondrial glycolysis to intramitochondrial oxidative phosphorylation. The neuroprotective effects of an HK inhibitor, 3-bromopyruvate (3-BrPA), on kainic acid (KA)-induced excitotoxic injury were investigated. Hippocampal slices were prepared from hippocampi of 6-8-day-old rats using a tissue chopper and placed on a membrane insert. After a treatment with KA (5 μM) for 15 hr, neuronal death was quantified by propidium iodide (PI), cresol violet, and TUNEL staining. KA-induced cell death was significantly prevented by 30 μM 3-BrPA treatment. According to Western blots, the expression level of phospho-Akt increased after 3-BrPA treatment. The induction of long-term potentiation (LTP) at 48 hr after 3-BrPA treatment tended to increase in the CA1 area compared with the KA-only group, but the difference was not significant. Blocking the PI3 kinase/Akt pathway using LY294002 reversed the neuroprotective effect of 3-BrPA. These results suggest that inhibition of HK may play a protective role against neuronal death in KA-induced excitotoxic injury.     

Clinical Practice Guidelines for the Medical and Surgical Management of Primary Intracerebral Hemorrhage in Korea

The purpose of this clinical practice guideline (CPG) is to provide current and comprehensive recommendations for the medical and surgical management of primary intracerebral hemorrhage (ICH). Since the release of the first Korean CPGs for stroke, evidence has been accumulated in the management of ICH, such as intracranial pressure control and minimally invasive surgery, and it needs to be reflected in the updated version. The Quality Control Committee at the Korean Society of cerebrovascular Surgeons and the Writing Group at the Clinical Research Center for Stroke (CRCS) systematically reviewed relevant literature and major published guidelines between June 2007 and June 2013. Based on the published evidence, recommendations were synthesized, and the level of evidence and the grade of the recommendation were determined using the methods adapted from CRCS. A draft guideline was scrutinized by expert peer reviewers and also discussed at an expert consensus meeting until final agreement was achieved. CPGs based on scientific evidence are presented for the medical and surgical management of patients presenting with primary ICH. This CPG describes the current pertinent recommendations and suggests Korean recommendations for the medical and surgical management of a patient with primary ICH.