So-Young Huh

Brain Abnormalities in Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica (NMO) is an idiopathic inflammatory syndrome of the central nervous system that is characterized by severe attacks of optic neuritis (ON) and myelitis. Until recently, NMO was considered a disease without brain involvement. However, since the discovery of NMO-IgG/antiaqaporin-4 antibody, the concept of NMO was broadened to NMO spectrum disorder (NMOSD), and brain lesions are commonly recognized. Furthermore, some patients present with brain symptoms as their first manifestation and develop recurrent brain symptoms without ON or myelitis. Brain lesions with characteristic locations and configurations can be helpful in the diagnosis of NMOSD. Due to the growing recognition of brain abnormalities in NMOSD, these have been included in the NMO and NMOSD diagnostic criteria or guidelines. Recent technical developments such as diffusion tensor imaging, MR spectroscopy, and voxel-based morphometry reveal new findings related to brain abnormalities in NMOSD that were not identified using conventional MRI. This paper focuses on the incidence and characteristics of the brain lesions found in NMOSD and the symptoms that they cause. Recent studies using advanced imaging techniques are also introduced.

Clinical Efficacy of Plasmapheresis in Patients with Neuromyelitis Optica Spectrum Disorder and Effects on Circulating Anti-Aquaporin-4 Antibody Levels

Background and Purpose Although plasmapheresis is becoming standard practice as a rescue therapy for neuromyelitis optica (NMO), evidence for the therapeutic efficacy of plasmapheresis is limited, and the effect of plasmapheresis on anti-aquaporin-4 (AQP4) levels in patients with NMO has not been reported. Here, our objective was to evaluate the clinical efficacy of therapeutic plasmapheresis and its effect on anti-AQP4 antibody levels in patients with NMO spectrum disorder (NMOSD). Methods We retrospectively reviewed the medical records of 15 patients with NMOSD who had 18 acute attacks and received plasmapheresis because they did not respond to high-dose intravenous methylprednisolone (IVMP) therapy. Anti-AQP4 antibodies were measured before and after plasmapheresis. The primary outcomes were functional improvements immediately and 6 months after plasmapheresis, and the secondary outcome was the change in anti-AQP4 antibody serum levels following plasmapheresis. Results Plasmapheresis following IVMP therapy led to significant improvement in 50% of the 18 attacks in 15 patients immediately after the procedure was completed, and in 78% (14 attacks) after 6 months. Plasmapheresis was generally well tolerated in all patients. Anti-AQP4 antibody serum levels declined significantly following plasmapheresis, to a mean of 15% of the preplasmapheresis levels. Lower scores on the visual outcome scale recorded before an attack were associated with significant immediate improvement upon the completion of plasmapheresis (p=0.03). Conclusions Plasmapheresis following IVMP therapy effectively removed anti-AQP4 antibodies and was accompanied by a substantial improvement in the neurological disability of patients with NMOSD. Lower levels of pre-existing neurological damage may be associated with an improved acute response to plasmapheresis.

A Longitudinal Brain Magnetic Resonance Imaging Study of Neuromyelitis Optica Spectrum Disorder

Brain involvement is commonly seen in patients with neuromyelitis optica spectrum disorder (NMOSD). However, little is known about the chronic changes of acute brain lesions on MRI over time. Here, our objective was to evaluate how acute brain MRI lesions in NMOSD changed on follow-up MRI. We reviewed the MRIs of 63 patients with NMOSD who had acute brain lesions and follow-up MRI over an interval of at least 3 months. Of the 211 acute brain lesions, 24% of lesions disappeared completely on T2-weighed images (WI) and a decrease in size ≥50% on T2-WI was observed in 58% of lesions on follow-up MRI. However, 47% of lesions revealed focal T1-hypointensity and, in particular, 18% showed focal cystic changes. Cystic changes were observed most commonly in corticospinal tract and corpus callosal lesions whereas the vast majority of lesions in the cerebellum, basal ganglia and temporal white matter resolved completely. MRI remission on T2-WI occurred in 82% of lesions, while approximately half of the lesions presented foci of T1-hypointensity, which may be considered a severe tissue injury over time. The extent of brain injury following an acute brain lesion in NMOSD may depend on the location of the lesion.

Idiopathic aquaporin-4 antibody negative longitudinally extensive transverse myelitis

Background: Longitudinally extensive transverse myelitis (LETM) is a characteristic manifestation of neuromyelitis optica (NMO). However, not all patients with LETM are positive for aquaporin-4 (AQP4) antibodies. We evaluated the characteristics of idiopathic isolated LETM negative for AQP4 antibodies. Methods: From the National Cancer Center registry of inflammatory diseases of the central nervous system, patients with LETM as an initial manifestation and follow-up for at least two years were enrolled. Their medical records and MRIs were reviewed retrospectively. AQP4 antibody was confirmed by three different validated methods at least three times. Cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) levels were measured to investigate astrocyte damage. Results: Among 108 patients with first-ever LETM, 55 were positive for AQP4 antibodies (P-LETM) and 53 were consistently negative. Of them, seven were later diagnosed with seronegative NMO, and four were positive for MOG antibodies. The remaining 42 patients (N-LETM) showed several features distinct from P-LETM: male predominance, older age of onset, milder clinical presentation, spinal cord confinement and absence of combined autoimmunity. CSF GFAP levels were not increased in N-LETM but were markedly elevated in P-LETM. Conclusions: Idiopathic isolated N-LETM is not that rare among first-ever LETM, and has many features distinct from P-LETM where astrocytic damage is evident.

Steroid-Resistant Relapsing IgG4-Related Pachymeningitis Treated With Methotrexate

IMPORTANCE IgG4-related disease, which is newly recognized, is characterized by lymphoplasmacytic infiltration with increased IgG4-secreting plasma cells. Although a favorable response to steroids has previously been reported, the durations of follow-up to confirm the long-term benefits and clinical courses were limited. We describe long-term favorable response of oral methotrexate in a patient with IgG4-related pachymeningitis who was resistant to steroid therapy. OBSERVATIONS A patient in his mid-60s with pathologically proven IgG4-related pachymeningitis who was resistant to steroid therapy and experienced an exacerbation of symptoms 4 times is described. Low-dose oral methotrexate induced significant clinical and radiological improvement, with sustained remission of the disease over 2 years without complications. CONCLUSIONS AND RELEVANCE The long-term favorable response to oral methotrexate in the current patient suggests that methotrexate is a useful alternative treatment option in patients with IgG4-related pachymeningitis who are resistant to steroid therapy or who experience adverse effects from steroids.

Short segment myelitis as a first manifestation of neuromyelitis optica spectrum disorders

Background: Some patients with neuromyelitis optica spectrum disorders (NMOSD) present with spinal cord lesions extending fewer than three vertebral segments (short transverse myelitis, STM), hindering an early diagnosis. Objective: We investigated the frequency and imaging characteristics of STM lesions in patients presenting with myelitis as an initial manifestation of NMOSD. Methods: Patients seen at three referral hospitals in Korea between June 2005 and March 2015 who met the following inclusion criteria were recruited for review: seropositivity for aquaporin-4 antibody, initial presentation with myelitis and spinal cord magnetic resonance imaging (MRI) performed within 1 month of initial myelitis onset. Results: Of the 76 enrolled patients, 65 (85.5%) collectively had 69 longitudinally extensive transverse myelitis lesions, while the remaining 11 (14.5%) had a total of 15 STM lesions. Of the 15 STM lesions, 5 spanned 2.5 vertebral segments, 6 were continuous over two segments, 3 showed a length of 1.5 segments and 1 was confined to a single segment. On axial imaging, all of the STM lesions involved the central grey matter. Conclusion: These MRI findings suggested that STM does not preclude the possibility of an NMOSD diagnosis.

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.

Utility of the rio score and modified rio score in korean patients with multiple sclerosis.

Objectives Early identification of suboptimal responders to multiple sclerosis (MS) treatment is critical for optimizing therapeutic decisions. The Rio score (RS) and modified Rio score (MRS) were developed to discriminate the responses to interferon-beta (IFNB) treatment in MS patients. This study was performed to evaluate the utility of RS and MRS in daily clinical practice in Korea. Methods This was a real-world setting, multicenter, retrospective study of MS patients treated with IFNB from 10 hospitals in Korea. We investigated whether the RS and MRS at the early stage of IFNB therapy could predict treatment responses over 3 years. Suboptimal treatment responses at 3 years were defined as the presence of clinical relapse and/or EDSS progression and/or patients who had been treated with INFB for at least for 1 year and therapy was switched due to perceived treatment failure during the 2 years of follow-up. Results Seventy patients (50 females and 20 males) were enrolled; 92% (12/13) of patients with high RS and 86% (12/14) of patients with high MRS (score 2 or 3) were suboptimal responders, whereas 93% (53/57) of patients with low RS and 93% (52/56) patients with low MRS (score 0 or 1) showed optimal responses. New active lesions on MRI with clinical relapse in high RS and MRS were the most common combination in suboptimal responders. Conclusions We confirmed that RS and MRS at 6–15 months of IFNB therapy were useful for predicting poor responders over 3 years.

Acute bulbar palsy as a variant of Guillain-Barré syndrome

Objective: To categorize a syndrome manifesting as prominent acute bulbar palsy (ABP) without limb motor weakness as a variant form of Guillain-Barré syndrome (GBS) and differentiate it from Miller Fisher syndrome (MFS) and pharyngeal-cervical-brachial (PCB) variants. Methods: We analyzed cases of ABP without limb motor weakness based on a dataset containing clinical information and the results of antiganglioside antibodies assays for acute immune-mediated neuropathies. Results: Eleven cases with an age at onset ranging from 18 to 65 years (mean 33.8 years) were identified as ABP-plus syndrome. All of the enrolled cases manifested with ABP as the predominant symptom, and with no limb weakness. The following features accompanied ABP in order of decreasing frequency: ophthalmoplegia (n = 9, 82%), ataxia (n = 9, 82%), and facial palsy (n = 6, 55%). An enzyme-linked immunosorbent assay study disclosed that immunoglobulin G (IgG) anti-GT1a antibodies were the most frequent (n = 11), followed by IgG anti-GQ1b antibodies (n = 6). Conclusions: We propose that ABP-plus syndrome without neck or limb weakness is a variant of GBS that is distinct from the MFS and PCB variants. The presence of IgG anti-GT1a antibodies can explain the relationships between the distinct clinical characteristics and the underlying pathomechanisms.

Emergence of Myasthenia Gravis with Myositis in a Patient Treated with Pembrolizumab for Thymic Cancer

Dear Editor, A 34-year-old woman presented with a 4-week history of diplopia, dysphagia, and dyspnea. She had no previous history of a neuromuscular disorder. However, she had been diagnosed with thymic cancer (squamous cell carcinoma) 2 years previously, with metastasis to the pericardium, pleura, and lung, which had not been successfully treated with conventional chemotherapy (cyclophosphamide, vincristine, doxorubicin, and cisplatin). She had been treated with four cycles of 100-mg pembrolizumab every 2 weeks, which reduced the size of the tumor. A physical examination revealed bilateral ptosis, ophthalmoplegia, dysarthria, facial diplegia, hypophonia, and weakness of the palatal and neck flexor muscles. Her deep tendon reflexes were symmetrically decreased. Laboratory studies showed a markedly elevated serum creatine kinase (CK) level of 2,125 U/L and seropositivity for acetylcholine-receptor antibodies (0.86 nmol/L). The findings of nerve conduction studies, repetitive nerve stimulation, and brain MRI were normal. Electromyography findings were suggestive of active myopathy. Based on the clinical and laboratory findings, we made a clinical diagnosis of myasthenia gravis (MG) with myositis associated with pembrolizumab. Pembrolizumab was discontinued and the patient underwent a 5-day course of intravenous immunoglobulin (IVIg). She was then subsequently treated with a 3-day course of 1-g intravenous methylprednisolone (IVMP), followed by prednisolone (1 mg/kg). The CK level normalized (230 U/L) and her neck weakness improved after IVMP treatment. However, five cycles of plasmapheresis were applied due to aggravation of dyspnea. The dysphagia and ptosis had improved at the 6-month follow-up, but ophthalmoplegia and mild dyspnea persisted even though she was on continuous prednisolone treatment. Additionally, the thymic cancer remained the same even without additional chemotherapy. Pembrolizumab is a monoclonal antibody targeting the programmed cell death 1 (PD-1) that is clinically beneficial in the treatment of malignancies such as metastatic melanoma and other advanced solid tumors, for which conventional therapies are only weakly effective.1 Pembrolizumab binds to PD-1, which is an inhibitory signaling receptor expressed on the surface of activated T cells, resulting in pembrolizumab preventing the binding of PD-1 to other ligands, thereby increasing the effectiveness of the T-cell-mediated immune response against tumor cells. However, enhanced immune activation by a PD-1 inhibitor may induce adverse side effects. It is particularly notable that autoimmune events in the neuromuscular system have also been reported in patients with metastatic melanoma who were treated with pembrolizumab (Table 1).2-9 Unlike the previously published cases in which metastatic melanoma was the underlying cancer, our patient had a thymic carcinoma. It is well known that thymic abnormalities and So-Young Huh Seong-Hoon Shin Meyung Kug Kim So-Young Lee Ki Hun Son Ha Young Shin