Metha Apiwattanakul

Intractable vomiting as the initial presentation of neuromyelitis optica

We report 12 aquaporin‐4 antibody‐positive patients (12% of seropositive Mayo Clinic patients identified since 2005) whose initial presenting symptom of neuromyelitis optica was intractable vomiting. The initial evaluation in 75% was gastroenterologic. Vomiting lasted a median of 4 weeks (range, 2 days–80 weeks). Optic neuritis or transverse myelitis developed after vomiting onset in 11 patients (median interval, 11 weeks; range, 1–156). At last evaluation (median, 48 months after vomiting onset), 7 patients fulfilled neuromyelitis optica diagnostic criteria. Our clinical, pathologic and neuroimaging observations suggest the aquaporin‐4–rich area postrema may be a first point of attack in neuromyelitis optica. Ann Neurol 2010;68:757–761

Demographic and clinical features of neuromyelitis optica: A review:

The comparative clinical and demographic features of neuromyelitis optica (NMO) are not well known. In this review we analyzed peer-reviewed publications for incidence and prevalence, clinical phenotypes, and demographic features of NMO. Population-based studies from Europe, South East and Southern Asia, the Caribbean, and Cuba suggest that the incidence and prevalence of NMO ranges from 0.05–0.4 and 0.52–4.4 per 100,000, respectively. Mean age at onset (32.6–45.7) and median time to first relapse (8–12 months) was similar. Most studies reported an excess of disease in women and a relapsing course, particularly in anti-aquaporin 4 antibody (anti AQP4-IgG)-positive patients. Ethnicity may have a bearing on disease phenotype and clinical outcome. Despite limitations inherent to the review process, themes noted in clinical and demographic features of NMO among different populations promote a more global understanding of NMO and strategies to address it.

Prediction of Neuromyelitis Optica Attack Severity by Quantitation of Complement-Mediated Injury to Aquaporin-4–Expressing Cells

BACKGROUND Recent reports support a pathogenic role in neuromyelitis optica (NMO) for the aquaporin-4 (AQP4)-specific autoantibody (NMO-IgG). Neuromyelitis optica is an inflammatory demyelinating central nervous system disease, usually relapsing, that causes variable degrees of attack-related disability. The NMO-IgG binds in vitro to the extracellular domain of AQP4, activates complement, and causes astrocyte lesioning. OBJECTIVE To compare the prognostic utility of NMO-IgG titer and quantitative measures of complement-mediated injury to AQP4-expressing cells in NMO attacks. DESIGN, SETTING, AND PARTICIPANTS A retrospective clinical-serological correlative study at Mayo Clinics Neuroimmunology Laboratory was undertaken. Over an 18-month period, we identified NMO-IgG-seropositive patients in whom sufficient serum and adequate clinical information pertaining to NMO attacks (6 severe, 6 mild) were available to analyze clinical-serological correlations. Sera from 9 patients with multiple sclerosis and 9 healthy subjects (all NMO-IgG seronegative) served as controls. Complement activation was measured by quantifying the number of green fluorescent protein-AQP4-transfected HEK 293 cells permeable to the viability dye propidium iodide after exposure to patient serum and active complement. MAIN OUTCOME MEASURES Attack severity (mild or severe), percentage of AQP4-transfected cells lesioned, and NMO-IgG titer. RESULTS The median percentage of AQP4-transfected cells lesioned by complement in the presence of serum from patients with NMO was 14% for patients with mild attacks and 54% for patients with severe attacks (P = .005). Median complement activation values for sera from healthy subjects and patients with multiple sclerosis were 8% and 12%, respectively. Patients with mild NMO attacks and patients with severe NMO attacks did not differ significantly with respect to NMO-IgG titer (P = .089). CONCLUSIONS A laboratory measure of complement-mediated cell injury may serve as a prognostic biomarker in NMO. Larger prospective studies are required to validate this observation.

Diagnosis of Neuromyelitis Spectrum Disorders: Comparative Sensitivities and Specificities of Immunohistochemical and Immunoprecipitation Assays

OBJECTIVE To compare the sensitivity and specificity of immunofluorescence (IF) and immunoprecipitation (IP) assays using green fluorescent protein-tagged aquaporin-4 (AQP4) in 6335 patients for whom serological evaluation was requested on a service basis. DESIGN Case-control study. SETTING Mayo Clinic Neuroimmunology Laboratory (Rochester, Minnesota) and Departments of Neurology (Rochester, Minnesota; Scottsdale, Arizona; and Jacksonville, Florida). Patients Group 1, 835 Mayo Clinic patients, 100 with a neuromyelitis optica (NMO) spectrum disorder diagnosis and 735 without NMO spectrum disorder; group 2, 5500 non-Mayo Clinic patients. Main Outcome Measure Sensitivity and specificity of each assay for NMO or NMO spectrum disorder, individually and combined. RESULTS In group 1, the sensitivity rates for NMO were IF, 58%; IP, 33%; and combined assays, 63%. The sensitivity rates for relapsing longitudinally extensive transverse myelitis were IF, 29%; IP, 6%; and combined assays, 29%. The specificity rates for NMO and relapsing longitudinally extensive transverse myelitis were IF, 99.6%; IP, 99.3%; and combined assays, 99.2%. In group 2, NMO-IgG was detected by IF in 498 of 5500 patients (9.1%) and by IP in 331 patients (6.0%); 76 of the 331 patients seropositive by IP (23%) were negative by IF. Clinical information was available for 124 patients (including 16 of those seropositive by IP only); 123 had a definite NMO spectrum disorder and 1 was at risk for NMO (monophasic optic neuritis). CONCLUSIONS In this large, clinical practice-based study, NMO-IgG detected by IF or IP was highly specific for NMO spectrum disorders. The IP assay was significantly less sensitive than IF. Combined testing improved sensitivity by 5%.

Positron Emission Tomography–Computed Tomography in Paraneoplastic Neurologic Disorders: Systematic Analysis and Review

OBJECTIVE To evaluate the cancer detection rate of whole-body positron emission tomography-computed tomography (PET-CT) in a paraneoplastic neurologic context. DESIGN Retrospective medical record review. SETTING Mayo Clinic, Rochester, Minnesota. PATIENTS Fifty-six consecutive patients with clinically suspected paraneoplastic neurologic disorders who underwent PET-CT after negative standard evaluations, including CT. MAIN OUTCOME MEASURE Rate of cancer detection. RESULTS Abnormalities suggestive of cancer were detected using PET-CT in 22 patients (39%); 10 patients (18%) had cancer confirmed histologically. Cancers detected (limited stage in 9 of 10 patients and extratruncal in 4) were as follows: 2 thyroid papillary cell carcinomas, 3 solitary lymph nodes with unknown primary (2 adenocarcinomas and 1 small cell carcinoma), 1 tonsil squamous cell carcinoma, 3 lung carcinomas (1 adenocarcinoma, 1 small cell, and 1 squamous cell), and 1 colon adenocarcinoma. Detection of a well-characterized neuronal nuclear or cytoplasmic paraneoplastic autoantibody was associated with a successful PET-CT-directed cancer search (P < .001). Detection of limited-stage cancer facilitated early initiation of oncologic treatments and immunotherapy; cancer remission was reported in 7 patients, and sustained improvements in neurologic symptoms were reported in 5 (median follow-up, 11 months; range, 2-48 months). Combined data from 2 previous studies using conventional PET alone (123 patients) revealed that 28% of patients had a PET abnormality suggestive of cancer and that 12% had a cancer diagnosis. CONCLUSION In a paraneoplastic neurologic context, PET-CT improves the detection of cancers when other screening test results are negative, particularly in the setting of seropositivity for a neuronal nuclear or cytoplasmic autoantibody marker of cancer.

Peripherin-IgG Association with Neurologic and Endocrine Autoimmunity

Peripherin-IgG has been reported a pertinent autoantibody in non-obese type 1 diabetic (NOD) mice. However, it has not previously been recognized in any human disease. In blinded evaluation of serum for markers of neurological autoimmunity in a high-volume diagnostic laboratory, we incidentally identified 26 patients (61% female) with an IgG that bound selectively to neural elements in enteric ganglia, sympathetic nerve trunks and discrete nerve tracts in mid-brain and hind-brain. The target antigen was identified as peripherin, a 55kDa - type III intermediate filament protein. Review of clinical histories revealed that 54% of seropositive patients had dysautonomia (predominantly gastrointestinal dysmotility), 30% had neuropathies with varied sensory symptoms and 35% had clinical or serological evidence of endocrinopathy (type 1 diabetes, thyroiditis or premature ovarian failure). Collectively, 73% had autonomic dysfunction or endocrinopathy. None of 173 healthy subjects was seropositive. Subsequent western blot evaluation of archival sera from patients with small fiber/autonomic neuropathies (with or without endocrinopathy) revealed a 33% seropositivity rate for peripherin-IgG. Our further demonstration that peripherin-immunoreactive autonomic fibers in pancreas, thyroid and ovary are juxtaposed to endocrine epithelium, complement our clinical observations in suggesting that neuronal elements may be a pertinent initial target for immune attack in multiple forms of endocrine autoimmunity (intermolecular epitope spreading). It remains to be determined whether or not peripherin-IgG is predictive for development of small fiber neuropathy (autonomic or somatic).

Use of Advanced Magnetic Resonance Imaging Techniques in Neuromyelitis Optica Spectrum Disorder.

Brain parenchymal lesions are frequently observed on conventional magnetic resonance imaging (MRI) scans of patients with neuromyelitis optica (NMO) spectrum disorder, but the specific morphological and temporal patterns distinguishing them unequivocally from lesions caused by other disorders have not been identified. This literature review summarizes the literature on advanced quantitative imaging measures reported for patients with NMO spectrum disorder, including proton MR spectroscopy, diffusion tensor imaging, magnetization transfer imaging, quantitative MR volumetry, and ultrahigh-field strength MRI. It was undertaken to consider the advanced MRI techniques used for patients with NMO by different specialists in the field. Although quantitative measures such as proton MR spectroscopy or magnetization transfer imaging have not reproducibly revealed diffuse brain injury, preliminary data from diffusion-weighted imaging and brain tissue volumetry indicate greater white matter than gray matter degradation. These findings could be confirmed by ultrahigh-field MRI. The use of nonconventional MRI techniques may further our understanding of the pathogenic processes in NMO spectrum disorders and may help us identify the distinct radiographic features corresponding to specific phenotypic manifestations of this disease.

Anti-N-Methyl-d-Aspartate Receptor Encephalitis: Early Treatment is Beneficial

Anti-N-methyl-D-aspartate receptor antibody has been associated with a severe stereotypic form of subacute encephalitis, often found in women with ovarian teratoma. Reported here is the diagnosis of anti-N-methyl-D-aspartate receptor encephalitis in a 5-year-old girl who presented with subacute encephalopathy and movement disorder without evidence of malignancy. Early diagnosis and treatment with immune globulin and steroids resulted in near-complete recovery.

ELIMINATING FALSE-POSITIVE RESULTS IN SERUM TESTS FOR NEUROMUSCULAR AUTOIMMUNITY

In this study we describe the false‐positive frequency in radioimmunoprecipitation assays for muscle acetylcholine receptor (AChR) and neuronal voltage‐gated potassium channel (VGKC) autoantibodies, attributable to 125I‐ligand immunoprecipitation. Sera were evaluated for AChR autoantibody (n = 34,095) and VGKC autoantibody (n = 11,028). We retested sera that yielded apparently positive results with 1251‐ligand with and without detergent‐solubilized cation‐channel protein, indentified clinically validated fals‐positive rates of 0.05% and 1.7% for AchR and VGKC autoantibodies, respectively. Specificity assurance in radioimmunoprecipitation assays requires subtraction of values for 125I‐ligand binding. Muscle Nerve, 2010

Features of anti-aquaporin 4 antibody-seronegative Thai patients with neuromyelitis optica spectrum disorders: a comparison with seropositive cases.

OBJECTIVE The aim of this study is to investigate the unique features of seronegative neuromyelitis optica spectrum disorders (NMOSD) in Thailand. BACKGROUND It remains unknown whether seronegative NMOSD patients possess clinical and paraclinical features that are distinct from those with seropositivity. METHODS In a Thai cohort of idiopathic inflammatory CNS disorders (n=122), 52 patients fulfilled the Wingerchuk 2007 criteria for NMOSD. We determined anti-AQP4 antibody statuses using three different assays (an in-house cell-based assay [CBA], a commercially available CBA and a tissue-based indirect immunofluorescence [IIF] assay). RESULTS Among the NMOSD patients, the percentage of seropositive cases was 54.5% based on the in-house and commercial CBAs and 30.8% based on the IIF assay. Using the in-house CBA, seronegative NMOSD patients exhibited distinct features compared with seropositive patients, such as a lack of female preponderance (F/M=1.2 vs. 6.0), frequent simultaneous bilateral optic involvement (33.3% vs. 0.04%), a lower annual relapse rate (0.4 ± 0.3 vs. 0.7 ± 0.6), fewer spinal cord lesions (1.0 ± 4.3 vs. 1.4 ± 0.6), and lower CSF cell counts (20 ± 72 vs. 80 ± 285). Use of the commercial CBA yielded essentially similar results, but some of these differences were not significant using IIF. CONCLUSIONS Sensitive anti-AQP4 antibody assays reveal features of seronegative NMOSD patients that differ from those of seropositive patients from Thailand.