Jangsup Moon

VGKC-complex/LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy.

Leucine-rich glioma inactivated 1 (LGI1) was recently identified as a target protein in autoimmune synaptic encephalitis, a rare condition associated with autoantibodies against structures in the neuronal synapse. Studies dealing with LGI1 are small in number and the various outcomes of different therapeutic regimens are not well studied. Here, we analyzed clinical characteristics of 14 patients with LGI1 antibodies, and outcomes according to therapeutic strategies. Most patients exhibited abnormal brain positron emission tomography and that patients treated with steroids alone were more likely to relapse and had less favorable outcomes than those treated with steroids and intravenous immunoglobulins.

Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study

A considerable portion of autoimmune encephalitis (AE) does not respond to conventional immunotherapies and subsequently has poor outcomes. We aimed to determine the efficacy of tocilizumab, an anti-interleukin-6 antibody, in rituximab-refractory AE compared with other treatment options. From an institutional cohort of AE, 91 patients with inadequate clinical response to first-line immunotherapy and following rituximab were retrospectively reviewed. Patients were grouped according to their further immunotherapy strategies. Thirty (33.0xa0%) patients were included in the tocilizumab group, 31 (34.0xa0%) in the additional rituximab group, and 30 (33.0xa0%) in the observation group. Outcomes were defined as the favorable modified Rankin Scale scores (≤2) at 1 and 2xa0months from the initiation of each treatment strategy and at the last follow-up. Favorable clinical response (improvement of the modified Rankin Scale scores byu2009≥u20092 points or achievement of the mRS scoresu2009≤u20092) at the last follow-up was also analyzed. The tocilizumab group showed more frequent favorable mRS scores at 2xa0months from treatment initiation and at the last follow-up compared with those at the relevant time points of the remaining groups. The majority (89.5xa0%) of the patients with clinical improvement at 1xa0month from tocilizumab treatment maintained a long-term favorable clinical response. No serious adverse effects of rituximab or tocilizumab were reported. Therefore, we suggest that tocilizumab might be a good treatment strategy for treating AE refractory to conventional immunotherapies and rituximab. The tocilizumab-mediated clinical improvement manifests as early at 1xa0month after treatment initiation.

Clinical manifestations and outcomes of the treatment of patients with GABAB encephalitis

Encephalitis associated with anti-γ-aminobutyric acid-B (GABAB) receptor antibodies has been identified recently. However, only a few cases have been reported to date and its clinical manifestations and prognosis have not been investigated systematically. We identified five cases of GABAB encephalitis in Korea. Here we present the clinical features, treatment responses, and brain positron emission tomography findings of the cases. The patients had a clinical triad of memory changes, seizure, and association with small-cell lung cancer. Early diagnosis and comprehensive immune modulation may provide a good outcome.

Distinct Expression of Long Non-Coding RNAs in an Alzheimer's Disease Model

With the recent advancement in transcriptome-wide profiling approach, numerous non-coding transcripts previously unknown have been identified. Among the non-coding transcripts, long non-coding RNAs (lncRNAs) have received increasing attention for their capacity to modulate transcriptional regulation. Although alterations in the expressions of non-coding RNAs have been studied in Alzheimers disease (AD), most research focused on the involvement of microRNAs, and comprehensive expression profiling of lncRNAs in AD has been lacking. In this study, microarray analysis was performed to procure the expression profile of lncRNAs dysregulated in a triple transgenic model of AD (3xTg-AD). A total of 4,622 lncRNAs were analyzed: 205 lncRNAs were significantly dysregulated in 3xTg-AD compared with control mice, and 230 lncRNAs were significantly dysregulated within 3xTg-AD in an age-dependent manner (≥2.0-fold, p < 0.05). Among these, 27 and 15 lncRNAs, respectively, had adjacent protein-coding genes whose expressions were also significantly dysregulated. A majority of these lncRNAs and their adjacent genes shared the same direction of dysregulation. For these pairs of lncRNAs and adjacent genes, significant Gene Ontology terms were DNA-dependent regulation of transcription, transcription regulator activity, and embryonic organ morphogenesis. One of the most highly upregulated lncRNAs had a 395 bp core sequence that overlapped with multiple chromosomal regions. This is the first study that comprehensively identified dysregulated lncRNAs in 3xTg-AD mice and will likely facilitate the development of therapeutics targeting lncRNAs in AD.

Atherosclerosis-Related Circulating MicroRNAs as a Predictor of Stroke Recurrence.

MicroRNAs (miRNAs) are short sequenced non-coding RNAs that posttranscriptionally regulate gene expression. We investigated circulating miRNA expression levels in acute stroke patients and its relationship with future vascular event. We included acute ischemic stroke patients who admitted to a university hospital between May 1, 2011, and July 31, 2012, and the patients with vascular risk factors but not incident stroke as controls. We collected 5xa0ml of venous blood, and circulating miRNA levels were evaluated by quantitative real-time polymerase chain reaction. Five miRNAs (miR-17, miR-21, miR-106a, miR-126, and miR-200b), which had been reported to be related to atherosclerosis, were measured. The levels of miRNAs were compared with the presence of acute stroke, vascular risk factors, stroke subtypes, and stroke recurrence after index stroke. A total of 120 patients were included in the study, with 83 acute stroke patients. The levels of miR-17 were significantly increased in acute stroke patients, and the levels of miR-126 had positive correlation with cerebral atherosclerosis (ru2009=u20090.254, pu2009=u20090.021). Among the 83 stroke patients, eight experienced stroke recurrence during follow-up and higher level of miR-17 was associated with shorter event-free survival (pu2009=u20090.047). This study shows that the miR-17 level was elevated in acute ischemic stroke and associated with future stroke recurrence.

High-resolution MR technique can distinguish moyamoya disease from atherosclerotic occlusion

Moyamoya disease (MMD) is an idiopathic progressive narrowing of distal internal carotid arteries and secondary development of small collaterals.1 The distinction between MMD and intracranial atherosclerosis is not easy when a patient has concomitant vascular risk factors. We attempted to differentiate the 2 disease conditions by applying high-resolution plaque MRI in the occluded segment.2 High-resolution MRI of MMD disclosed blunted obliteration of the vessel lumen without eccentric plaque, and black-blood image delineated the occlusion site with homogeneous material and multiple spring-like vascular structures (figure, A). Intracranial atherosclerosis showed eccentric plaque with heterogeneous signals and enhancement (figure, B).

The HLA-A*2402/Cw*0102 haplotype is associated with lamotrigine-induced maculopapular eruption in the Korean population.

The use of lamotrigine (LTG) can be limited by the occurrence of cutaneous adverse drug reactions (cADRs) that range from maculopapular eruption (MPE) to the more severe Stevens‐Johnson syndrome and toxic epidermal necrolysis. A few human leukocyte antigen (HLA)–related genetic risk factors for carbamazepine‐induced cADR have been identified. However, the HLA‐related genetic risk factors associated with LTG‐induced cADR are not yet well known. We performed HLA genotyping in 50 Korean patients with epilepsy, including 21 patients presenting LTG‐induced MPE and 29 LTG‐tolerant patients. A significant association between the HLA‐A*2402 allele and LTG‐induced MPE was identified, in comparison with the LTG‐tolerant group (odds ratio [OR] 4.09, p = 0.025) and the general Korean population (OR 3.949, p = 0.005). The frequencies of the Cw*0102 or Cw*0702 alleles were significantly higher in the LTG‐MPE group than in the Korean population, whereas the frequency of the A*3303 allele was lower. The coexistence of the A*2402 and Cw*0102 alleles was significantly associated with the LTG‐MPE group when compared to the LTG‐tolerant group (OR 7.88, p = 0.007). In addition, the Cw*0701 allele was more frequent in the LTG‐tolerant group than in the Korean population. These findings suggest the presence of HLA‐related genetic risk factors for LTG‐induced MPE in the Korean population.

Inhibition of miR-203 Reduces Spontaneous Recurrent Seizures in Mice

Inhibitory synaptic receptors are dysfunctional in epileptic brains, and agents that selectively target these receptors may be effective for the treatment of epilepsy. MicroRNAs interfere with the translation of target genes, including various synaptic proteins. Here, we show that miR-203 regulates glycine receptor-β (Glrb) in epilepsy models. miR-203 is upregulated in the hippocampus of epileptic mice and human epileptic brains and is predicted to target inhibitory synaptic receptors, including Glrb. In vitro transfection, target gene luciferase assays, and analysis of human samples confirmed the direct inhibition of GLRB by miR-203, and AM203, an antagomir targeting miR-203, reversed the effect of miR-203. When intranasal AM203 was administered, AM203 reached the brain and restored hippocampal GLRB levels in epileptic mice. Finally, intranasal AM203 reduced the epileptic seizure frequency of mice. Overall, this study suggests that GLRB expression in the epileptic brain is controlled by miR-203, and intranasal delivery of AM203 showed therapeutic effects in chronic epilepsy mice.

Non-stiff anti-amphiphysin syndrome: Clinical manifestations and outcome after immunotherapy

Amphiphysin antibody causes paraneoplastic stiff-person syndrome and can also result in a variety of neurological manifestations. Here, we investigated the clinical spectrum of 20 patients with non-stiff anti-amphiphysin syndrome and their responses to immunotherapy. The most common neurological manifestation was limbic encephalitis (n=10), followed by dysautonomia (n=9), and cerebellar dysfunction (n=6). Cancer was detected in only seven patients. Intravenous immunoglobulin or steroid treatment was effective in most patients, but three improved only after rituximab treatment. Our study suggests that anti-amphiphysin syndrome can manifest as non-stiff encephalomyelitis and is only partially associated with cancer. Active immunotherapy, including rituximab, would be beneficial.

Orthostatic intolerance symptoms are associated with depression and diminished quality of life in patients with postural tachycardia syndrome

BackgroundPatients with postural tachycardia syndrome often appear depressive and report diminished quality of life (QOL). In the current study, we first evaluated if the maximal heart rate (HR) increment after standing is associated with the clinical symptoms in patients with excessive orthostatic tachycardia (OT). Next, we investigated the correlations among the symptoms of orthostatic intolerance (OI), depression, and health-related QOL in these patients. Finally we assessed if patients with minimal OI symptoms suffer from depression or diminished QOL.MethodsWe performed a comprehensive questionnaire-based assessment of symptoms in 107 patients with excessive OT with au2009≥u200930 beats/min heart rate increment (oru2009≥u200940 beats/min in individuals aged between 12 and 19) within 10 min after standing up. An existing orthostatic intolerance questionnaire (OIQ), the Beck depression inventory-II (BDI-II), and the 36 Item Short-Form Health Survey were completed prior to any treatment. Correlation analyses among the items of the questionnaires and other parameters were performed. Additionally, patients with minimal OI symptoms were analysed separately.ResultsThe maximal orthostatic HR increment was not associated with the clinical symptoms. The OI symptoms were significantly correlated with depression and diminished QOL. The BDI-II score demonstrated a positive linear relationship with total OIQ score (ru2009=u20090.516), and both physical and mental component summary scales of SF-36 showed a negative linear relationship with total OIQ score (ru2009=u2009-0.542 and ru2009=u2009-0.440, respectively; all p <0.001). Some OI symptoms were more strongly associated with depression, and others were more strongly related to QOL. Chest discomfort and concentration difficulties were the most influential OI symptoms for depression, while nausea and concentration difficulties were the most influential symptoms for physical and mental QOL, respectively. Dizziness and headache were the two most common complaints in patients with mild to moderate OI symptoms. In addition, subjects with minimal OI symptoms also had considerable deterioration in QOL.ConclusionThe OI symptoms, but not the maximal HR increment, are significantly correlated with depression and diminished QOL in patients with excessive OT. Therefore, pervasive history taking is important when encountering patients with excessive OT.