Je-Young Shin

Neuroprotective effects of JGK-263 in transgenic SOD1-G93A mice of amyotrophic lateral sclerosis

BACKGROUND Glycogen synthase kinase-3β (GSK-3β) activity plays a central role in motor neuron degeneration. GSK-3β inhibitors have been shown to prolong motor neuron survival and suppress disease progression in amyotrophic lateral sclerosis (ALS). In this study, we evaluated the therapeutic effects of a new GSK-3b inhibitor, JGK-263, on ALS in G93A SOD1 transgenic mice. METHODS Previously, biochemical efficacy of JGK-263 was observed in normal and mutant (G93A) hSOD1-transfected motor neuronal cell lines (NSC34). Based on these previous results, we administered JGK-263 orally to 93 transgenic mice with the human G93A-mutated SOD1 gene. The mice were divided into three groups: a group administered 20mg/kg JGK-263, a group administered 50mg/kg JGK-263, and a control group not administered with JGK-263. Clinical status, rotarod test, and survival rates of transgenic mice with ALS were evaluated. Sixteen mice from each group were selected for further biochemical study that involved examination of motor neuron count, apoptosis, and cell survival signals. RESULTS JGK-263 administration remarkably improved motor function and prolonged the time until symptom onset, rotarod failure, and death in transgenic mice with ALS compared to control mice. In JGK-263 groups, choline acetyltransferase (ChAT) staining in the ventral horn of the lower lumbar spinal cord showed a large number of motor neurons, suggesting normal morphology. The neuroprotective effects of JGK-263 in ALS mice were also suggested by western blot analysis of spinal cord tissues in transgenic mice. CONCLUSION These results suggest that JGK-263, an oral GSK-3β inhibitor, is promising as a novel therapeutic agent for ALS. Still, further biochemical studies on the underlying mechanisms and safety of JGK-263 are necessary.

Motor unit number index (MUNIX) in the orbicularis oculi muscle of healthy subjects

Introduction: The motor unit number index (MUNIX) refers to an electrophysiological method that measures the number of motor units in the surface electromyographic interference pattern (SIP) recorded during graded muscle contractions. MUNIX studies of limb muscles have been conducted, but MUNIX studies of bulbo‐facial muscles have not been reported. Methods: We assessed bilateral orbicularis oculi muscles using MUNIX, and the reference values and reproducibility of MUNIX and motor unit size index (MUSIX) were investigated in healthy subjects. Results: In this study, MUNIX was applied successfully to the orbicularis oculi muscles and showed good reproducibility. The correlation coefficients for MUNIX and MUSIX were 0.803 and 0.592, respectively, and the coefficients of variation were 20.9% and 8.5%, respectively. Conclusions: The MUNIX procedure for the orbicularis oculi muscle would be a useful tool for evaluating bulbar symptoms, especially in amyotrophic lateral sclerosis. Muscle Nerve 51: 197–200, 2015

Split-hand phenomenon in amyotrophic lateral sclerosis: A motor unit number index study

Introduction: The split‐hand phenomenon refers to preferential wasting of the thenar muscles with relative sparing of the hypothenar muscles in amyotrophic lateral sclerosis (ALS). Methods: We compared the split‐hand index (SI) calculated from the compound muscle action potential (CMAP; SICMAP) with that calculated from the motor unit number index (MUNIX; SIMUNIX). We performed MUNIX on the abductor policis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) muscles of 39 ALS patients and 40 age‐matched, healthy controls. SI is derived by multiplying the CMAP (or MUNIX) recorded over the APB and FDI and dividing by the CMAP (or MUNIX) recorded over the ADM. Results: Receiver‐operating characteristic curve analysis revealed good diagnostic accuracy for both indices, but better performance of SIMUNIX than SICMAP. Conclusion: SIMUNIX and SICMAP were useful in differentiating ALS patients from healthy controls. SIMUNIX appears to be a better electrophysiological marker than SICMAP for the split‐hand sign of ALS. Muscle Nerve 53: 885–888, 2016

A Case of Thyrotoxic Myopathy with Extreme Type 2 Fiber Predominance

In hyperthyroidism, many patients had neuromuscular symptoms and clinical weakness correlated with free thyroxine (T4) concentrations. The common clinical symptoms of chronic thyrotoxic myopathy were characterized by progressive weakness in proximal muscles and atrophy. A 55-year old woman was visited our hospital with two years of progressive weakness of both legs. Physical examination showed diffuse enlargement of the thyroid gland, muscle atrophy and tachycardia. Motor examination showed proximal weakness in both legs. Serum creatine phosphokinase was normal and electromyography showed a myopathic pattern. Serum thyroxine (T4) was greatly increased and serum thyroid stimulating hormone was very low. Muscle biopsy showed mild atrophic change and type 2 fiber predominance. The patients symptoms were improved during treatment with methimazole. Herein we report a case of thyrotoxic myopathy with extreme type 2 fiber predominance histologically.

Spontaneous Carotid Cavernous Fistula in a Case with Protein S Deficiency that Newly Developed Ophthalmoplegia after Embolization

Background Carotid cavernous fistula (CCF) is an abnormal communication between the carotid artery and the cavernous sinus. The pathogenesis of spontaneous CCF remains unclear, although sinus thrombosis is known to be a predisposing factor for dural arteriovenous fistula. Because spontaneous CCFs are mainly of the dural type, we considered that thrombogenic conditions, such as, protein S deficiency might be associated with CCF. Case Report A 42-year-old woman complained of conjunctival injection and retro-orbital pain that first appeared 1-month before visiting our hospital. She had no history of head trauma or intracranial surgery. Exophthalmos and chemosis were observed in her left eye, which also had lower visual acuity and higher intraocular pressure than the right eye. Magnetic resonance images and cerebral angiography revealed a left dural CCF. Her protein S was low, at 41% (normal range: 70-140%), but other hematologic values related to coagulation were normal. Her symptoms were relieved after initial transvenous coil embolization. However, a newly developed sixth-nerve palsy was detected 4 days after initial embolization. Follow-up angiography revealed a minimal shunt, and thus transvenous coil embolization was repeated. Two days later, the ophthalmoplegia started reducing, and 1-month later it had almost disappeared. Conclusions To the best of our knowledge, this is the first report of spontaneous dural CCF in a Korean patient with concurrent protein S deficiency. Interestingly, transient sixth-nerve palsy developed after transvenous coil embolization in this patient. This additional symptom caused by the residual fistula was relieved after additional transarterial embolization.

Takotsubo cardiomyopathy in amyotrophic lateral sclerosis

OBJECTIVE To investigate the frequency, features, and prognosis of takotsubo cardiomyopathy (TTC) in patients with amyotrophic lateral sclerosis (ALS). METHODS We reviewed detailed clinical, laboratory, and cardiovascular data from 64 ALS patients (38 men and 26 women) who underwent echocardiographic evaluation for various reasons at a single referral center between January 2011 and December 2015. RESULTS TTC was diagnosed in 9 ALS patients (4 men and 5 women). Mean age was 61.3years (range 55-71years), and median disease duration was 51.5months (range 18-134months). All patients were bulbar or cervical onset, and were at advanced stages of ALS when TTC was diagnosed. Acute exacerbation of dyspnea was an invariable presentation, and chest discomfort mimicking acute coronary syndrome was present in 2 patients. Six patients had significant hypotension requiring intravenous fluid challenge and inotropic support. Three patients showed altered mentality, and 2 of them suffered cardiopulmonary arrest. CONCLUSIONS TTC should be suspected in ALS patients presenting with acute exacerbation of dyspnea and chest discomfort, particularly at advanced stages of the disease. This study highlights the need for proper evaluation and management of cardiac dysfunction in ALS.

Pathological Modification of TDP-43 in Amyotrophic Lateral Sclerosis with SOD1 Mutations

Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, progressive neurodegenerative disorder with no known cure. Cu/Zn-superoxide dismutase (SOD1) was the first identified protein associated with familial ALS (fALS). Recently, TAR DNA-binding protein 43 (TDP-43) has been found to be a principal component of ubiquitinated cytoplasmic inclusions in neurons and glia in ALS. However, it remains unclear whether these ALS-linked proteins partly have a shared pathogenesis. Here, we determine the association between mutant SOD1 and the modification of TDP-43 and the relationship of pathologic TDP-43 to neuronal cytotoxicity in SOD1 ALS. In this work, using animal model, human tissue, and cell models, we provide the evidence that the association between the TDP-43 modification and the pathogenesis of SOD1 fALS. We demonstrated an age-dependent increase in TDP-43 C-terminal fragments and phosphorylation in motor neurons and glia of SOD1 mice and SOD1G85S ALS patient. Cytoplasmic TDP-43 was also observed in iPSC-derived motor neurons from SOD1G17S ALS patient. Moreover, we observed that mutant SOD1 interacts with TDP-43 in co-immunoprecipitation assays with G93A hSOD1-transfected cell lines. Mutant SOD1 overexpression led to an increase in TDP-43 modification in the detergent-insoluble fraction in the spinal cord of SOD1 mice and fALS patient. Additionally, we showed cellular apoptosis in response to the interaction of mutant SOD1 and fragment forms of TDP-43. These findings suggest that mutant SOD1 could affect the solubility/insolubility of TDP-43 through physical interactions and the resulting pathological modifications of TDP-43 may be involved in motor neuron death in SOD1 fALS.

Spinobulbar muscular atrophy combined with atypical hereditary neuropathy with liability to pressure palsy

Spinobulbar muscular atrophy (SBMA) is an X-linked recessive disease, presenting motor weakness and wasting of facial, bulbar and limb muscles. Hereditary neuropathy with liability to pressure palsy (HNPP) is autosomal dominant disorder characterized by recurrent neuropathies at common entrapment sites. We report a case of co-existence of SBMA and atypical HNPP with genetic confirmation of CAG expansion in the androgen receptor (AR) gene and deletion of the peripheral myelin protein 22 (PMP22) gene. A 62-year-old man presented with progressive muscle weakness, fasciculations in upper and lower limbs and dysesthesia predominantly in the distal regions. No family members, including his children, experienced similar symptoms. The electrodiagnostic examination was compatible with demyelinating sensorimotor polyneuropathy. Simultaneous hereditary polyneuropathy and motor neuron disease were suspected and relevant genetic testing was confirmed HNPP and SBMA. This case presented with 2 rare genetic neuromuscular disorders and the atypical HNPP phenotype. This case highlight the importance of detailed patient histories, as well as neurological and electrophysiological examinations for diagnosis of atypical and combination of rare genetic disorders.

T91. Factors predicting the successful generation of baseline motor evoked potentials in patients undergoing spine surgery

Introduction The purpose of this study was to search for clinical factors predicting the successful generation of baseline muscle motor evoked potentials (mMEPs) in patients undergoing spine surgery and to determine the relationship with postoperative functional outcome. Methods From July 2014 to June 2015, a total of 345 patients underwent spine surgery with intraoperative mMEPs monitoring and were consecutively included in this study. Their demographic features, clinical parameters, and mMEPs recording results were reviewed retrospectively. Results Two hundred and fifty-three (73%) patients showed the successful generation of baseline mMEPs at all recording muscles, and 92 (27%) patients failed to record baseline mMEPs at one or more limb muscles. When we compared the preoperative clinical parameters of the two groups, the latter group (“Failure group”) significantly had a higher male ratio, lower MRC grades, higher Nurick grades, more often cervical/cervicothoracic segment involvement, higher proportion of the presence of spine surgery history, motor deficits, sensory symptoms, bladder/bowel dysfunction, T2-weighted high signal intensity (HSI) of cord at spine MRI compared to the former group (“Success group”) and were older. Among these factors, male sex, cervical/cervicothoracic lesion location the presence of T2-weighted HSI of cord, preoperative Nurick grade, and MRC grade showed a significant contribution for predicting the successful generation of mMEPs. When analyzing predictors for postoperative poor functional outcomes, the success rate of mMEPs recording and lesion etiology were significantly related factors for the aggravation of the Nurick grades before and after surgery. Conclusion Various clinical parameters including lesion location, abnormal cord signal on MRI, preoperative motor power, and functional status were revealed to have a significant relationship with the successful generation of baseline mMEPs. Additionally, the successful generation of mMEPs was one of the indicators for predicting the long-term functional outcome.

Platform Session – Evoked potentials & NIOM: Prognostic value of intra- and extra-operative lateral spread responses in microvascular decompression surgeries of hemifacial spasm

Introduction Lateral spread response is observed in patients with hemifacial spasm (HFS) by eletrically stimulating one branch of the facial nerve activates facial muscles innervated by other branches of the facial nerve by electromyography. Nowadays, LSR has been used to confirm adequacy of microvascular decompression (MVD). The aim of this study was to evaluate the prognostic value of intra- and extra-operative lateral spread response (LSR) in microvascular decompression (MVD) surgeries of hemifacial spasm (HFS). Methods A retrospective review was made of consecutive 25 patients who underwent continuous intraoperative monitoring during MVD. LSR and continuous electromyography were monitored in the frontalis, orbicularis oculi, and mentalis muscles. Extra-operative LSRs were done pre- and postoperatively. The neurological status of each patient was evaluated before and immediately after surgery, on discharge, and at 3 months after surgery. Results Intraoperative neurophysiologic monitorings were successful in all patients. On admission and discharge, extra-operative LSR recordings were done in 23 patients. Twenty-one patients completed a follow- up evaluation. In 17, the intraoperative LSRs disappeared during surgery. In 5, the intraoperative LSRs were absent before incision and remained the same until the end of surgery. In one, the intraoperative LSR were present before incision and persisted despite MVD. For extra-operative LSRs, they disappeared after surgery in 10. LSRs were absent before and after surgery in 7. In 6, LSRs were present before surgery and persisted after MVD. For 5, intraoperative LSRs disappeared during surgery but extra-operative LSRs were persisted despite adequate MVD. In one, intraoperative LSRs were absent before incision and remained during the surgery. But extra-operative LSRs were present before surgery and disappeared after adequate MVD. Statistically, the extra-operative disappearance of LSR was correlated with the HFS relief in 4 days after surgery and the 3-month follow up period. ( P = 0.049 and 0.044 ). However, the intaroperative disapearance of LSR was not. Conclusion In our study, extra-operative LSR monitoring may be more predictive of the surgical outcome compared with intraoperative LSR during the 3-month follow up.