Overcoming the challenges in diagnosis of AQP4-IgG positive neuromyelitis optica spectrum disorders in resource poor settings using an indigenized and cost effective cell based assay.

BACKGROUND: Diagnosis of neuromyelitis optica spectrum disorders (NMOSD) in India is hindered by limited access to cost effective and sensitive assays for detection of aquaporin-4 antibody (AQP4-IgG) in India. OBJECTIVE: To develop a cost effective, sensitive, cell based assay (CBA) for detection of AQP4-IgG and to evaluate the serological status in patients with NMOSD diagnosed by 2015 diagnostic criteria. METHOD: Stably transfected Chinese hamster ovary (CHO) cell line expressing aquaporin M23 isomer was established. A fixed CBA was developed and validated in 381 samples including clinically definite NMOSD (n = 87), high risk NMOSD (n = 51), other demyelinating disorders (n = 92), other neurological disorders (n = 51) and healthy volunteers (n = 100). We tested the same samples again using a commercially available CBA and compared the results. All assays were performed by 2 independent investigators blinded to clinical and serological status. RESULTS: Our "in house"(Mangalore) assay showed sensitivity of 81.6% (95% CI 71.86-89.11%) for clinically definite NMOSD and 29.41% (95% CI 17.50-43.8%) for high risk NMOSD. Specificity was 100% for both groups. Both assays showed similar results for 67/ 87 (77.01%) patients with definite NMOSD while 4 samples tested positive by our assay alone (Cohen's kappa coefficient [K] - 0.86). Among the high risk group 14/51 (27.5%) samples showed similar results, one patient additionally was positive by the Mangalore assay (K - 0.95).

Multiple sclerosis and neuromyelitis optica spectrum disorder testing and treatment availability in Latin America.

BACKGROUND: The objective of our study was to describe the availability of diagnostic tests and treatment for MS and NMOSD in Latin America (LATAM). METHODS: A survey instrument was used in a sample of physicians from LATAM countries. The goal of the survey was to understand availability of: 1) imaging tests for diagnosing MS and NMOSD and its barriers; 2) diagnostic laboratory tests for diagnosing MS and NMOSD and its barriers; and 3) treatments for MS and NMOSD in the acute and chronic phases of the disease. RESULTS: Responses were received from 80 physicians. AQP4-ab test was available in 54% of the countries and MOG-ab test in 42%. All of countries had available use of high doses of intravenous methylprednisolone, oral steroids, plasmapheresis, and intravenous immunoglobulins for relapses. For NMOSD, 93% of the countries were able to use azathioprine and mycophenolate mofetil, and 87% rituximab. In MS, 93% of countries had available to them IFN beta, 69% glatiramer acetate, 75% teriflunomide, 93% fingolimod, 69% dimethyl-fumarate, 75% cladribine, 69% natalizumab, 93% ocrelizumab and 81% alemtuzumab. The most common challenge and barrier identified was the cost of medications. CONCLUSION: The present study allows an understanding of the delivery of care for MS and NMOSD in the region.

Cost effectiveness of rituximab and mycophenolate mofetil for neuromyelitis optica spectrum disorder in Thailand: Economic evaluation and budget impact analysis.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory condition of the central nervous system. The extent of disability depends on the severity of the disease and the number of relapses. Although azathioprine is currently the main treatment for patients with NMOSD in Thailand, patients often relapse during its use. Hence, it is argued that there are other drugs that would be more effective. The purpose of this study is to evaluate, from a societal perspective and from the economic impact on Thailand's healthcare system, the cost utility of treatment with mycophenolate mofetil (MMF) and rituximab in patients resistant to azathioprine. The Markov model with a one-year cycle length was applied to predict the health and cost outcomes in patients with NMOSD over a lifetime. The results showed that rituximab exhibited the highest quality-adjusted life year (QALY) gains among all the options. Among the rituximab-based treatments, the administration of a rituximab biosimilar with CD27+ memory B cell monitoring proved to be the most cost-effective option. At the willingness-to-pay threshold of 160,000 Thai baht (THB), or 5,289 US dollar (USD), per QALY gained, the treatment exhibited the highest probability of being cost effective (48%). A sensitivity analysis based on the adjusted price of a generic MMF determined that the treatment was cost effective, exhibiting an incremental cost-effectiveness ratio of -164,653 THB (-5,443 USD) and a 32% probability of being cost effective. The calculated budget impact of treating patients resistant to conventional therapy was 1-6 million THB (33,000-198,000 USD) for the first three years, while after the third year, the budget impact stabilized at 3-4 million THB (99,000-132,000 USD). These data indicate that, in Thailand, treatment of drug resistant NMOSD with a rituximab biosimilar with CD27+ memory B cell monitoring or treatment with a generic MMF would be cost effective and would result in a low budget impact. Therefore, the inclusion of both the rituximab biosimilar and a generic MMF in the National Drug List of Essential Medicine for the treatment of NMOSD may be appropriate.

In vivo structural and functional assessment of optic nerve damage in neuromyelitis optica spectrum disorders and multiple sclerosis.

Early detection of neuromyelitis optica spectrum disorders (NMOSD), especially after optic neuritis, a presenting manifestation commonly observed also in multiple sclerosis (MS), is crucial for timely treatment and prognosis. Integrated visual pathway assessment with optical coherence tomography (OCT) and visual evoked potentials (VEP) may help in this task, showing in vivo different pathophysiological backgrounds. We evaluated combined VEP and OCT in a cross-sectional, single-centre study assessing 50 consecutive NMOSD patients, 57 MS patients and 52 healthy controls. After optic neuritis, VEP were more frequently absent in NMOSD compared to MS; most NMOSD eyes with recordable VEP showed prolonged latency, but extreme latency delays were less common than in MS. OCT showed predominantly axonal involvement in NMOSD, with 88% eyes (95% CI: 69-97%) displaying retinal nerve fibre layer thickness <60 µm even after first optic neuritis episode. Accuracy of OCT was further enhanced by combination with VEP into a new Z-score derived OCT-VEP index, measuring prevalence of axonal damage or demyelination. Our results suggest that integrated optic nerve assessment may elucidate differences in optic neuritis pathophysiology; conduction slowing with relatively preserved nerve fibre layer suggests MS, while severe neuroaxonal loss after optic neuritis, often hindering VEP response, characterizes NMOSD.

Neuromyelitis optica testing and treatment: Availability and affordability in 60 countries.

BACKGROUND: We characterize the variations in availability and affordability of NMO diagnostic testing and treatment by geographic region and country-level income group. METHODS: A structured survey was distributed in English, French, and Spanish in late 2018 to neurologists and other physicians who encounter NMO patients. RESULTS: Respondents (response rate 45%, 64/143 countries contacted) came from all WHO world regions and World Bank country income levels (49% university-based; 13 low-, 16 lower middle-, 16 upper-middle-, and 15 high-income countries). The average cost of an aquaporin-4 antibody (AQP4-Ab) test to a patient globally was 209 USD, and the average cost of NMO treatment per year was 3,819 USD. AQP4-Ab and myelin oligodendrocyte glycoprotein-antibody (MOG-Ab) testing were available in 68% and 38% of all countries. Low-income countries had poor availability of both AQP4-Ab (2/13 countries) and MOG-Ab (1/13) compared to high-income countries (15/15 AQP4-Ab, 13/15 MOG-Ab). Nearly half (48%, 13/27) of African and Eastern Mediterranean countries had access to neither test. GLOBAL TREATMENT AVAILABILITY AND USAGE: Azathioprine (88%), rituximab (50%), mycophenolate mofetil (57%), intravenous methylprednisolone (98%), oral prednisone (68%), plasma exchange (78%), intravenous immunoglobulin (72%). Whereas 70-100% of high-income countries' patients could afford treatment without incurring a catastrophic health expenditure, <10% of low-income country patients could. Most low-income countries (12/13) reported the patient pays for NMO care entirely without public assistance CONCLUSIONS: There is a gap in access to diagnostic testing for NMO in non-high-income countries, even in countries where acute and immunosuppressive treatment for NMO are available.

Peripapillary and parafoveal vascular network assessment by optical coherence tomography angiography in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders.

BACKGROUND/AIMS: Current understanding of the alterations in the retinal vascular network in neuromyelitis optica spectrum disorders (NMOSDs) is limited. We aim to assess the peripapillary and parafoveal vessel density in aquaporin-4 antibody-positive NMOSD patients by optical coherence tomography (OCT) angiography. METHODS: A total of 55 aquaporin-4 antibody-positive NMOSD patients with or without a history of optic neuritis (ON) and 33 healthy controls underwent spectral domain OCT and OCT angiography. Clinical histories, Expanded Disability Status Scale score, visual functional system score (VFSS) and disease duration were collected. RESULTS: Peripapillary and parafoveal vessel density was significantly decreased in NMOSD eyes with or without a history of ON. The decrease in retinal vessel density could occur before ON and retinal nerve fibre layer (RNFL) atrophy. Peripapillary vessel density correlated well with the spectral domain OCT measurements and VFSS in NMOSD eyes with a history of ON. CONCLUSION: Subclinical primary retinal vasculopathy may occur in NMOSD prior to ON and RNFL atrophy. Peripapillary vessel density might be a sensitive predictor of visual outcomes in NMOSD patients with ON.

Anticuerpos anti-MOG (glicoproteína de la mielina de oligodendrocitos) para el diagnóstico de neuromielitis óptica y otras enfermedades desmielinizantes / Anti-MOG (myelin oligodendrocyte glycoprotein) antibodies for the diagnosis of optic neuromyelitis and other demyelinating diseases

CONTEXTO CLÍNICO: La neuromielitis óptica (NMO) o síndrome de Devic, y su espectro de enfermedades relacionadas, son trastornos inflamatorios del sistema nervioso central (SNC), caracterizados por la desmielinización inmunomediada y el daño axonal que afecta predominantemente los nervios ópticos y la médula espinal. Fue incluida como una variante de la esclerosis múltiple (EM), pero en la actualidad se considera una entidad clínica diferente; con características inmunológicas, diagnósticas y de tratamiento únicas.Mientras la patogénesis de la EM es mediada principalmente por células, en la NMO es mediada por anticuerpos. El descubrimiento de los anticuerpos enfermedad-específicos anti-aquaporina-4 (AQP4) ha llevado a una mejor comprensión de este trastorno. La prevalencia es 0,5 a 4 por 100 000 personas con una mediana de edad de aparición de 32 a 41 años. Las características propias de la NMO, incluyen brotes agudos de neuritis óptica o mielitis transversa. En el 90% de los casos tiene un curso recurrente, con secuelas como ceguera y paraplejía dentro de los cinco años del evento inicial. El diagnóstico se realiza mediante imágenes del SNC y determinación de anticuerpos AQP4 en suero o líquido cefalorraquídeo (LCR) durante el episodio agudo. La determinación de dichos anticuerpos muestra una sensibilidad moderada (71% a 91%) y alta especificidad (91%). Sin embargo, existe una tasa considerable de falsos negativos (9 a 29%). Un bajo número de pacientes con NMO y test negativo para anticuerpos AQP4, presentan anticuerpos antiglicoproteína de la mielina de oligodendrocitos (MOG, del inglés myelin oligodendrocyte glycoprotein) tanto en suero como en LCR. Dichos anticuerpos se encuentran también en pacientes pediátricos con esclerosis múltiple y en la encefalomielitis aguda diseminada. Se postula que la determinación de anticuerpos anti-MOG tiene utilidad diagnóstica en pacientes con NMO y otras enfermedades desmielinizantes. TECNOLOGÍA: La glicoproteína de la mielina de los oligodendrocitos es un componente menor de la mielina del sistema nervioso central, que se expresa en la superficie exterior de las vainas de mielina y las membranas plasmáticas de oligodendrocitos y es altamente inmunogénica. La determinación de anticuerpos Inmunoglobulina G anti-MOG se realiza mediante un enzimo inmuno ensayo (ELISA) con muestra de suero, plasma o LCR. OBJETIVO: Evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura de la determinación de anticuerpos antiglicoproteína de la mielina de oligodendrocitos para el diagnóstico de neuromielitis óptica y otras enfermedades desmielinizantes. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas (incluyendo Medline, Cochrane y CRD), en buscadores genéricos de Internet, agencias de evaluación de tecnologías sanitarias y financiadores de salud utilizando la siguiente estrategia: (Anti MOG[tiab] OR Anti Myelin-Oligodendrocyt*[tiab]) AND (Neuromyelitis Optica[Mesh] OR Neuromyelitis Optica[tiab] OR NMO*[tiab] OR Devic[tiab] OR Multiple Sclerosis[Mesh] OR Multiple Sclerosis[tiab] OR Disseminated Sclerosis[tiab]). Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias y económicas, guías de práctica clínica y políticas de cobertura de otros sistemas de salud cuando estaban disponibles. RESULTADOS: No se encontraron estudios que demostraran la precisión de este test para establecer un diagnóstico diferencial entre la NMO y otras enfermedades desmielinizantes. Ante la falta de evidencia, se incluyeron estudios acerca de la prevalencia de este anticuerpo y las características clínicas de los pacientes que lo presentan; incluyéndose, cinco estudios observacionales, dos guías de práctica clínica, un consenso y una política de cobertura. CONCLUSIONES: La evidencia acerca de la utilidad del test de anticuerpos antiglicoproteína de la mielina de oligodendrocitos para el diagnóstico de neuromielitis óptica es de baja calidad. No se encontraron estudios que evaluaran la precisión de este test para diferenciar esta patología de la esclerosis múltiple u otras enfermedades desmielinizantes. Su uso se plantea cuando el diagnóstico no pueda ser realizado con el dosaje de anticuerpos específicos anti-aquaporina-4; pero aún en estos casos, no hay evidencia suficiente que asegure su utilidad. Asimismo, no existe evidencia suficiente que avale su rol en pronóstico clínico de estas patologías. Las guías de práctica clínica relevadas no contemplan su uso o la consideran de utilidad incierta. Los agentes financiadores de salud relevados consideran esta tecnología como experimental.

Assessment of Optic Nerve Impairment in Patients with Neuromyelitis Optica by MR Diffusion Tensor Imaging.

BACKGROUND: Diffusion tensor imaging (DTI) has been used for the evaluation of the white matter integrity. In this study, we evaluated optic nerve impairment in patients with neuromyelitis optica (NMO) using DTI. METHODOLOGY/PRINCIPAL FINDINGS: Optic nerve DTI were performed on 28 NMO patients and 38 normal controls. Fractional anisotropy (FA) values were measured in the anterior, middle, and posterior parts of the intraorbital optic nerve segment. For the posterior intraorbital optic nerve, FA values of BI (0.20±0.07), MI (0.24±0.16), and NA (0.25±0.14) decreased significantly compared with that of NC (0.43±0.07) (P<0.05), and ROC analysis demonstrated that the area under the curve (AUC) measurements for BI vs. NC, MI vs. NC, NA vs. NC, and NMO (including BI, MI, and NA) vs. NC were 0.99, 0.93, 0.88, and 0.96, respectively. The corresponding diagnostic sensitivities of ROC analysis were 100%, 80%, 80%, and 91%; and the specificities were 93%, 97%, 91%, and 93%. CONCLUSIONS/SIGNIFICANCE: Decreased FA value in the intraorbital optic nerve, especially in the posterior part of the nerve, was demonstrated as a characteristic MR feature for NMO-related optic nerve impairment.

Validez diagnóstica de la detección de anticuerpos anti-acuaporina 4 (AQP4) para el diagnóstico clínico de neuromielitis óptica (NMO) / Diagnostic validity of the detection of anti-aquaporin 4 antibodies (AQP4) for the clinical diagnosis of optic neuromyelitis (NMO)

Introducción: La neuromielitis óptica (NMO) es un trastorno autoinmune inflamatorio del sistema nervioso \r\ncentral (SNC) que hasta hace poco se consideraba parte del espectro de la esclerosis múltiple (EM). Sinembargo, desde la identificación del anticuerpo anti-NMO se diferenció de otras enfermedades esmielinizantes; la detección del anticuerpo es ahora un factor determinante para el adecuado diagnóstico de NMO. Objetivo: Confirmar la validez diagnóstica de la detección de los anti-NMO para un adecuado diagnóstico de NMO. Métodos: Se realizó una búsqueda sistemática de la literatura para encontrar cuál es la efectividad en \r\nel diagnóstico clínico de los anti-NMO y las distintas pruebas inmunológicas que existen para la detección de los mismos. Resultados: Se encontró que la detección de los anti-NMO es altamente específica y que en la actualidad existen 7 pruebas inmunológicas disponibles para su detección. Conclusiones: Se realizó un metanálisis con los resultados disponibles de la sensibilidad y especificidad de las pruebas de detección de anti-NMO y se encontró que la de mejores características operativas corresponden a la prueba basada en células.(AU)

Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS).

Neuromyelitis optica (NMO, Devic's syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity. Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004. In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings. Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases. Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical presentation of NMO spectrum disorders (NMOSD). In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup. It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage. Therapy of NMO should be initiated early. Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients. Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments. Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals.

Evidence-based guideline: clinical evaluation and treatment of transverse myelitis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

OBJECTIVE: To assess the evidence for diagnostic tests and therapies for transverse myelitis (TM) and make evidence-based recommendations. METHODS: A review of the published literature from 1966 to March 2009 was performed, with evidence-based classification of relevant articles. RECOMMENDATIONS: Level B recommendations: neuromyelitis optica (NMO)-immunoglobulin G (IgG) antibodies should be considered useful to determine TM cause in patients presenting with clinical acute complete transverse myelitis (ACTM) features. The presence of NMO-IgG antibodies (aquaporin-4-specific antibodies) should be considered useful in determining increased TM recurrence risk. Level C recommendations: in suspected TM, distinction between ACTM or acute partial transverse myelitis may be considered useful to determine TM etiology and risk for relapse (more common with APTM). Age and gender may be considered useful to determine etiology in patients presenting with TM syndrome, with spinal infarcts seen more often in older patients and more female than male patients having TM due to multiple sclerosis (MS). Brain MRI characteristics consistent with those of MS may be considered useful to predict conversion to MS after a first partial TM episode. Longer spinal lesions extending over >3 vertebral segments may be considered useful in determining NMO vs MS. CSF examination for cells and oligoclonal bands may be considered useful to determine the cause of the TM syndrome. Plasma exchange may be considered in patients with TM who fail to improve after corticosteroid treatment. Rituximab may be considered in patients with TM due to NMO to decrease the number of relapses. Level U recommendations: there is insufficient evidence to support or refute the efficacy of other TM therapies or the usefulness of ethnicity to determine the cause of a subacute myelopathy.

Quantitative assessment of the cervical spinal cord damage in neuromyelitis optica using diffusion tensor imaging at 3 Tesla.

PURPOSE: To investigate whether quantitative MRI measures of cervical spinal cord white matter (WM) using diffusion tensor imaging (DTI) in neuromyelitis optica (NMO) differed from controls and correlated with clinical disability. MATERIALS AND METHODS: Ten referred patients and 12 healthy volunteers were imaged on a 3 Tesla scanner and patients were clinically assessed on the Expanded Disability Status Scale (EDSS). Two raters quantified DTI-derived indices from all participants, including fractional anisotropy (FA), mean diffusivity (MD), parallel diffusivity (lambda[parallel]) and perpendicular diffusivity (lambda[perpendicular]) at C1-C6 for lateral and dorsal columns. After the inter-rater reliability test, univariate correlations between DTI measures and disability were assessed using the Spearman's rho correlation coefficient. Multiple regression analysis was performed to investigate which DTI measures independently correlated with the clinical score. RESULTS: Statistical test results indicated high reliability of all DTI measurements between two raters. NMO patients showed reduced FA, increased MD and lambda[perpendicular] compared with controls while lambda[parallel] did not show any significant difference. The former three DTI metrics also showed significant correlations with disability scores, and especially FA was found to be sensitive to mild NMO (EDSS ≤ 3) CONCLUSION: FA is a potentially useful quantitative biomarker of otherwise normal appearing WM damage in NMO. Such damage is associated with clinical disability.

Serial quantitative MR assessment of optic neuritis in a case of neuromyelitis optica, using Gadolinium- "enhanced" STIR imaging.

A patient is presented with neuromyelitis optica. MR imaging, using a short inversion time inversion recovery (STIR) technique, clearly depicted the lesion in the left optic nerve. Subsequent serial STIR imaging, with and without Gadolinium-DTPA, allowed quantitative assessment of changes parallel to improved optic nerve function. STIR imaging is a sensitive technique to demonstrate optic nerve lesions, and enables quantitative assessment to be made of the effect of (steroid) medication.