Clinical and Radiological Features of Korean Patients With Anti-HMGCR Myopathy

Background@#and Purpose To understand the characteristics of Korean patients with anti-3-hydroxy-3-methylglutaryl-coenxyme A reductase (HMGCR) myopathy, we measured antiHMGCR antibodies and analyzed the clinical, radiological, and pathological features of patients with anti-HMGCR myopathy. @*Methods@#We measured titers of anti-HMGCR antibodies in the sera of 99 patients with inflammatory myopathy, 36 patients with genetic myopathy, and 63 healthy subjects using an enzyme-linked immunosorbent assay. We tested 16 myositis-specific autoantibodies (MSAs) in all patients with anti-HMGCR myopathy. @*Results@#Positivity for the anti-HMGCR antibody was observed in 17 (4 males and 13 females) of 99 patients with inflammatory myopathy. The median age at symptom onset was 60 years.Ten (59%) of the patients with anti-HMGCR positivity had taken statins. The titer of antiHMGCR antibodies was significantly higher in the statin-naïve group (median=230 U/mL, interquartile range=170–443 U/mL) than in the statin-exposed group (median=178 U/mL, interquartile range=105–210 U/mL, p=0.045). The most common symptom was proximal muscle weakness in 15 patients (88%), followed by myalgia in 9 (53%), neck weakness in 4 (24%), dysphagia in 3 (18%), and skin lesions in 2 (12%). The median titer of anti-HMGCR antibody was 202 U/mL. We found eight different MSAs in nine (53%) patients. The median disease duration from symptom onset to diagnosis was significantly shorter in the MSA-positive group than in the MSA-negative group (p=0.027). @*Conclusions@#Our study was the first to measure anti-HMGCR antibodies in inflammatory myopathy. It has provided new findings, including the suggestion of the coexistence of other MSAs in Korean patients.

A Practical Review of Paraproteinemic Neuropathy / 대한신경근육질환학회지

Paraproteinemic neuropathy is a heterogeneous set of neuropathies characterized by the presence of homogeneous immunoglobulin in the serum. Most cases are associated with monoclonal gammopathy of undetermined significance. It might also occur in hematologic malignant and nonmalignant conditions. The association between neuropathy and monoclonal gammopathy requires appropriate neurological and hematological investigations. Treatment is mostly based on underlying hematologic disorders. In this review, we provide a clinically practical approach to clinical, laboratory, electrophysiological features and management of patients with paraproteinemic neuropathy.

Statin-Naïve Paraneoplastic Anti-HMGCR Myopathy / 대한신경근육질환학회지

Anti-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (anti-HMGCR) myopathy is a subtype of immune-mediated necrotizing myopathy regardless of exposure to statins. Necrotizing myopathy is distinguished by necrotic muscle fibers with a relative lack of inflammation. It is frequently associated with a high risk of permanent muscle damage and disability. Recent studies have suggested a slightly increased risk of cancer in patients with anti-HMGCR myopathy. This report describes a case of statin-naïve paraneoplastic anti-HMGCR myopathy, with rapidly progressive muscle weakness leading to respiratory failure.

Statin-Naïve Paraneoplastic Anti-HMGCR Myopathy / 대한신경근육질환학회지

Anti-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (anti-HMGCR) myopathy is a subtype of immune-mediated necrotizing myopathy regardless of exposure to statins. Necrotizing myopathy is distinguished by necrotic muscle fibers with a relative lack of inflammation. It is frequently associated with a high risk of permanent muscle damage and disability. Recent studies have suggested a slightly increased risk of cancer in patients with anti-HMGCR myopathy. This report describes a case of statin-naïve paraneoplastic anti-HMGCR myopathy, with rapidly progressive muscle weakness leading to respiratory failure.

Relapse of Neuromyelitis Optica Spectrum Disorder Presented with Suspected Bacterial Meningomyelitis

Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory demyelinating disease. Anti-aquaporin-4 antibodies serve as a specific biomarker, while other factors including antecedent infection may also play a role in the development of NMOSD. Abnormal cerebrospinal fluid (CSF) findings such as leukocytosis with concentration >50/mm3 are one of the characteristics of NMOSD, but these were not specific for identifying other infective neurological diseases. Here we describe a rare case of NMOSD with CSF findings suggestive of bacterial meningomyelitis.

Clinical Heterogeneity of Anti-GM2-Ganglioside-Antibody Syndrome

BACKGROUND AND PURPOSE: Antiganglioside antibodies are known to play a pathogenic role in Guillain-Barré syndrome (GBS). Either an immunoglobulin (Ig)G- or IgM-type anti-GM2 antibody is detected in rare cases in GBS patients. However, the specific pathogenic role of these antibodies in GBS has not been reported previously. This study aimed to define and characterize the clinical spectrum of GBS with anti-GM2 positivity. METHODS: We reviewed the database of the Dong-A University Neuroimmunology Team, which has collected sera of GBS and its variants from more than 40 general and university-based hospitals in Korea. Detailed information about the involved patients was often obtained and then corrected by the charge doctor applying additional questionnaires. RESULTS: Four patients with acute monophasic peripheral neuropathy or cranial neuropathy with isolated IgM-type anti-GM2-antibody positivity were recruited. In addition, IgG-type anti-GM2 antibody was solely detected in the sera of another four patients. The IgM-positive group comprised heterogeneous syndromes: two cases of acute motor axonal neuropathy, one of acute inflammatory demyelinating polyneuropathy, and one of isolated facial diplegia. In contrast, all of the cases enrolled in the IgG-positive group manifested with dizziness with or without oculomotor palsy due to cranial neuropathy syndrome. CONCLUSIONS: This study has identified that anti-GM2 antibody can be found in various subtypes of GBS and its variants in rare cases. Compared to the clinical heterogeneity of the IgM-positive group, the IgG-positive group can be characterized by cranial-dominant GBS variants presenting mainly with oculomotor and vestibular dysfunctions.

Optical Coherence Tomography versus Visual Evoked Potentials for Detecting Visual Pathway Abnormalities in Patients with Neuromyelitis Optica Spectrum Disorder

BACKGROUND AND PURPOSE: Optical coherence tomography (OCT) and visual evoked potentials (VEPs) can be used to detect optic neuritis (ON). However, the comparative sensitivities of OCT and VEPs for detecting ON in neuromyelitis optica spectrum disorder (NMOSD) are unclear, and so we assessed these sensitivities. METHODS: This cross-sectional study included 73 patients with aquaporin-4 antibody-seropositive NMOSD, and 101 eyes with ON. The clinical characteristics, visual acuity (VA), Expanded Disability Status Scale (EDSS) scores, OCT peripapillary retinal nerve fiber layer (RNFL) thickness, and VEPs of the patients were evaluated. RESULTS: OCT and VEPs were abnormal in 68% and 73% of eyes with a history of ON, respectively, and in 2% and 9% of eyes without ON. Test sensitivities were influenced by the number of ON episodes: the OCT RNFL thickness and VEPs were abnormal in 50% and 67% of the eyes with first-ever ON episode, respectively (p=0.041), with the combination of both tests detecting abnormalities in up to 75% of the eyes. The sensitivities of the OCT RNFL thickness and VEPs increased to 95% and 83%, respectively, after the second or subsequent ON episode (p=0.06), with the combination of both tests detecting abnormalities in 95% of cases. The OCT RNFL thickness and VEP latency/amplitude were correlated with EDSS scores and VA. CONCLUSIONS: VEPs were superior for detecting subclinical or first-ever ON, while OCT was better for detecting eyes with multiple ON episodes. The correlations of OCT and VEPs with clinical disability measures indicate that these tests are potential markers of the disease burden in NMOSD.

Clevudine Induced Mitochondrial Myopathy

Clevudine was approved as an antiviral agent for hepatitis B virus, which showed marked, rapid inhibition of virus replication without significant toxicity. However, several studies have reported myopathy associated with clevudine therapy. Also, we experienced seven patients who suffered from myopathy during clevudine therapy. To characterize clevudine-induced myopathy, we collected previously reported cases of clevudine myopathy and analyzed all the cases including our cases. We searched electronic databases that were published in English or Korean using PubMed and KoreaMed. Ninety-five cases with clevudine myopathy, including our seven cases, were selected and analyzed for the demographic data, clinical features, and pathologic findings. The 95 patients with clevudine-induced myopathy comprised 52 women and 43 men aged 48.9 years (27–76 years). The patients received clevudine therapy for about 14.2 months (5–24 months) before the development of symptoms. Weakness mainly involved proximal extremities, especially in the lower extremities, and bulbar and neck weakness were observed in some cases (13.7%). Creatine kinase was elevated in the majority of patients (97.9%). Myopathic patterns on electromyography were observed in most patients examined (98.1%). Muscle biopsy presented patterns compatible with mitochondrial myopathy in the majority (90.2%). The weakness usually improved within about 3 months after the discontinuation of clevudine. Though clevudine has been known to be safe in a 6-month clinical trial, longer clevudine therapy for about 14 months may cause reversible mitochondrial myopathy. Careful clinical attention should be paid to patients with long-term clevudine therapy.

A Case of Cerebral Salt Wasting Syndrome in Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica spectrum disorder (NMOSD) may present with area postrema syndrome, which is characterized by intractable vomiting and hiccups. Hyponatremia is common in NMOSD and is mostly associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In contrast to SIADH, cerebral salt wasting syndrome (CSWS) causes hyponatremia, which is associated with severe natriuresis and extracellular volume depletion in patients with cerebral disease. To our knowledge, hyponatremia associated with CSWS has not been reported in a patient with NMOSD. Here, we describe a NMOSD presenting with hyponatremia, which may be caused by CSWS following area postrema syndrome.

Cerebral Cortex Involvement in Neuromyelitis Optica Spectrum Disorder

BACKGROUND AND PURPOSE: Brain lesions involving the cerebral cortex are rarely described in patients with neuromyelitis optica spectrum disorder (NMOSD), in contrast to multiple sclerosis. We investigated cerebral cortex involvement using conventional brain magnetic resonance imaging (MRI) in anti-aquaporin-4 (AQP4)-antibody-positive NMOSD patients. METHODS: The study enrolled 215 NMOSD patients who were seropositive for the anti-AQP4 antibody from 5 referral hospitals, and retrospectively analyzed their demographic, clinical, and MRI findings. Abnormal cerebral cortex lesions on brain MRI were identified by a neuroradiologist and two neurologists using consensus. RESULTS: Most of the 215 enrolled patients (87%) were female. The median age at onset was 22.5 years (range: 15-36 years) and the mean follow-up duration was 123 months. Brain lesions were found in 143 of 194 patients (74%) in whom MRI was performed during follow-up. Brain lesions involving the cerebral cortex were identified in 6 of these 194 patients (3.1%). Five of the patients were female, and the six patients together had a median age of 29 years (range: 15-36 years) at the time of lesion presentation. Three of them showed leptomeningeal enhancement in the lesions. At presentation of the cortex-involving lesions, five of these patients were not being treated at the time of presentation, while the sixth was being treated with interferon-beta. CONCLUSIONS: Although rare, cortical involvement occurs in NMOSD and is commonly combined with leptomeningeal enhancement. We speculate that this occurs only in patients who are not treated appropriately with immunosuppressant drugs.

Fatal Rhino-Orbital-Cerebral Mucormycosis Complicated with Thrombosis and Rupture of Mycotic Aneurysm in Distal Internal Carotid Artery

Mucormycosis is a rare opportunistic infection caused by fungi of the order Mucorales that typically occurs in patients with diabetes or immunocompromised state. Rhino-orbital-cerebral mucormycosis is the most common type, often has a life-threatening outcome. Mucormycosis has specific vascular tropism complicating mucorthrombosis or mycotic aneurysm. We report a diabetic patient presenting with ophthalmoplegia, orbital necrosis, and contralateral hemiparesis, who suddenly progressed to coma and died of subarachnoid hemorrhage due to the rupture of mycotic aneurysm in distal internal carotid artery.

Fatal Rhino-Orbital-Cerebral Mucormycosis Complicated with Thrombosis and Rupture of Mycotic Aneurysm in Distal Internal Carotid Artery

Mucormycosis is a rare opportunistic infection caused by fungi of the order Mucorales that typically occurs in patients with diabetes or immunocompromised state. Rhino-orbital-cerebral mucormycosis is the most common type, often has a life-threatening outcome. Mucormycosis has specific vascular tropism complicating mucorthrombosis or mycotic aneurysm. We report a diabetic patient presenting with ophthalmoplegia, orbital necrosis, and contralateral hemiparesis, who suddenly progressed to coma and died of subarachnoid hemorrhage due to the rupture of mycotic aneurysm in distal internal carotid artery.

Weekend Admission in Patients with Acute Ischemic Stroke Is Not Associated with Poor Functional Outcome than Weekday Admission

BACKGROUND AND PURPOSE: Stroke requires consistent care, but there is concern over the "weekend effect", whereby a weekend admission results in a poor outcome. Our aim was to determine the impact of weekend admission on clinical outcomes in patients with acute ischemic stroke in Korea. METHODS: The outcomes of patients admitted on weekdays and weekends were compared by analyzing data from a prospective outcome registry enrolling 1247 consecutive patients with acute ischemic stroke admitted to four neurology training hospitals in South Korea between September 2004 and August 2005. The primary outcome was a poor functional outcome at 3 months, defined as modified Rankin Scale (mRS) of 3-6. Secondary outcomes were 3-month mortality, use of thrombolysis, complication rate, and length of hospitalization. Shift analysis was also performed to compare overall mRS distributions. RESULTS: On weekends, 334 (26.8%) patients were admitted. Baseline characteristics were comparable between the weekday and weekend groups except for more history of heart disease and shorter admission time in weekend group. Univariate analysis revealed poor functional outcome at 3 months, 3-month mortality, complication rate, and length of hospitalization did not differ between the two groups. In addition, overall mRS distributions were comparable (p=0.865). After adjusting for baseline factors and stroke severity, weekend admission was not associated with poor functional outcome at 3 months (adjusted odds ratio, 1.05; 95% CI, 0.74-1.50). Furthermore, none of secondary endpoints differed between the two groups in multivariate analysis. CONCLUSIONS: Weekend admission was not associated with poor functional outcome than weekday admission in patients with acute ischemic stroke in this study. The putative weekend effect should be explored further by considering a wider range of hospital settings and hemorrhagic stroke.

Current Status of the Diagnosis and Management of Amyotrophic Lateral Sclerosis in Korea: A Multi-Center Cross-Sectional Study

BACKGROUND AND PURPOSE: Recently published, evidence-based guidelines should alter the management of amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). However, the newest recommendations for ALS/MND therapy are not reflected in actual clinical practice. We sought to evaluate the current status of the diagnosis and management of ALS in Korea. METHODS: The Korean ALS/MND research group was organized in 2010, involving more than 50 neurologists from neuromuscular centers in Korea. Participating centers collected data from April to September 2010 on the diagnosis and management of patients with ALS. Data forms from the ALS patient care database, which is a component of the ALS clinical assessment, research, and education program (http://www.outcomes-umassmed.org/ALS/), were modified and used for data collection. RESULTS: In total, 373 sporadic ALS cases from 35 centers were enrolled. The demographic features and clinical findings were similar to those in previous reports from other countries. The mean age at onset was 50-60 years, and a slight male predominance was observed. The enrolled patients predominantly showed focal onset of cervical or lumbosacral symptoms. Only about one-half of the indicated patients (31.4%) received a physician's recommendation for a parenteral gastrostomy, and 18.1% underwent the procedure. Noninvasive ventilation was recommended in 23% of patients, but applied in only 9.5% of them. Tracheostomy was performed in 12.7% of patients. CONCLUSIONS: The demographic and clinical features of the diagnosis and management of ALS in Korea are similar to those reported in other countries; however, supportive management, as recommended in evidence-based guidelines, are not yet widely recommended or performed for patients with ALS in Korea.

Burden of Ischemic Stroke in Korea: Analysis of Disability-Adjusted Life Years Lost

BACKGROUND AND PURPOSE: Disability-adjusted life years (DALY), incorporating both disability and mortality, has been widely employed to measure regional and global burdens of stroke. Thus far, the DALY lost to stroke in a population has been estimated using only the crude population-level data; no previous study has incorporated refined data from stroke registries. The aim of this study was to integrate the stroke registry data and the population-level incidence data to project the nationwide DALY lost to ischemic stroke. METHODS: From the data of two large ischemic stroke registries, we derived an average DALY lost due to ischemic stroke for each of the following age groups: or =85 years. The nationwide ischemic stroke incidence for each age group was extracted from a cardiovascular and cerebrovascular surveillance study that analyzed the 2004 Korean Health Insurance database. RESULTS: The average DALY lost due to ischemic stroke for the age groups or =85 years was 5.07, 4.63, 4.35, 3.88, 2.88, and 1.73, respectively. By multiplying the incidence and the average DALY lost, the nationwide DALY lost was determined to be 9,952 for those or =85 years, respectively. The projected nationwide DALY lost due to 64,688 ischemic strokes in 2004 was 234,399 (121,482 for men and 113,244 for women), and the DALY lost per 100,000 person-years was 483 (500 for men and 469 for women). CONCLUSIONS: Incidence data from a population study and DALY values derived from stroke registries can be integrated to provide a more refined projection of the nationwide burden of ischemic stroke. In Korea, more than 230,000 years of healthy life are being lost annually due to ischemic stroke, and hence prompt action is imperative.

Progression of Acute Ischemic Infarction after a Hemostatic Therapy for Thrombolysis-Related Intracerebral Hemorrhage / 대한뇌졸중학회지

As thrombolysis for acute ischemic stroke is a double-edged sword, so could be the hemostatic treatment for thrombolysis-induced intracerebral hemorrhage. An 88-year-old woman with acute ischemic stroke presented with severe dysarthria and right hemiparesis. Her neurological symptoms rapidly improved after intravenous tissue plasminogen activator (t-PA) treatment. However, she became drowsy one hour after the intravenous t-PA treatment. Brain CT revealed a small right thalamic hemorrhage which was contralateral to the initial ischemic lesion. To prevent expansion of the hematoma, vitamine K was infused intravenously. Three hours after the infusion, conjugate eyeball deviation to the left side and right hemiplegia developed, which were likely to be resulted from reocclusion. Hemostatic therapy, such as vitamine K infusion, might be related to the worsening of cerebral ischemia after recanalization with t-PA.

Intravenous Recombinant Tissue Plasminogen Activator Thrombolysis in a Patient with Acute Ischemic Stroke Secondary to Aortic Dissection

BACKGROUND: Acute ischemic stroke secondary to aortic dissection (AoD) is challenging in the era of thrombolysis owing to the diagnostic difficulty within a narrow time window and the high risk of complications. CASE REPORT: A 64-year-old woman with middle cerebral artery occlusion syndrome admitted to the emergency room within intravenous recombinant tissue plasminogen activator (rt-PA) time window. Her neurological symptoms improved during thrombolysis, but chest and abdominal pain developed. Repeated history-taking, physical examination, and imaging studies led to the timely diagnosis and surgical treatment of AoD, which produced a successful outcome. CONCLUSIONS: Clinical suspicion is invaluable for the diagnosis of this rare cause of stroke. Considering the stroke mechanism and complications, the risks of thrombolysis might outweigh its benefits.

Acute Subdural Hematoma Following Spinal Cerebrospinal Fluid Drainage in a Patient with Freezing of Gait

BACKGROUND: Headache is a common complication of lumbar puncture (LP). Although in most cases post-LP headaches are not severe and have a benign course, they can also be a manifestation of a potentially life-threatening complication such as subdural hematoma (SDH). CASE REPORT: We describe a patient in whom a massive SDH developed after LP and cerebrospinal fluid (CSF) drainage, which were performed during the diagnostic evaluation of freezing of gait. CONCLUSIONS: SDH should not be excluded from the differential diagnosis of headache following LP, especially when there is a loss of CSF.

Immunopathogenic Mechanism Based Treatment of Multiple Sclerosis / 한양의대학술지

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination, focal infiltration of inflammatory cells and axonal injury, which leads to loss of neurological function. The exact cause of the disease remains unclear, but an autoimmune response directed against CNS antigens is suspected. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, have provided important insights into mechanisms of T cell-mediated CNS autoimmune disease. It appears likely that when a genetically susceptible host encounters a common environmental antigen (such as an infectious organism), a process called 'molecular mimicry' results in the peripheral activation of cross-reactive T cells that can migrate to the CNS and mount pro-inflammatory responses to myelin epitopes. This review describes the current understanding on the immunopathogenesis of MS and the mechanisms of action of currently available disease-modifying therapies in the context of the underlying immunopathogenic processes they are thought to affect.

A Case of Ischemic Stroke Associated with Phendimetrazine as an Appetite Suppressant

The published case series have suggested that appetite suppressants had some association with the development of stroke. Phendimetrazine is an appetite suppressant with sympathomimetic activity and it has a similar chemical structure with amphetamines. We report that a 22-year-old woman who had taken phendimetrazine for one month developed sudden right homonymous hemianopsia. MRI showed acute infarction in the territory of left posterior cerebral artery (PCA). Phendimetrazine should be considered as a cause of ischemic stroke.