Mielitis longitudinal extensa de presentación muy tardía: Una entidad del espectro de la neuromielitis óptica / Extensive longitudinal myelitis of very late presentation. An entity of the spectrum of optic neuromyelitis

Las enfermedades del espectro neuromielitis óptica son trastornos inflamatorios del sistema nervioso central caracterizados por una grave desmielinización y daño axonal inmunomediado que afecta principalmente a los nervios ópticos y médula espinal. Suelen presentars e en edades tempranas, aunque existen algunas comunicaciones en la literatura de pacientes con presentaciones tardías. Presentamos el caso de una mujer de 78 años que consultó por un cuadro de paraparesia grave, trastornos sensitivos y retención urinaria. Se realizó una resonancia magnética de columna cervicodorsal que evidenció una lesión medular longitudinal extensa. Se descartaron otras causas secundarias, basadas en la clínica y en resultados de laboratorio. El dosaje de anticuerpos anti-acuaporina 4 resultó positivo. Se indicó tratamiento con glucocorticoides a altas dosis y plasmaféresis, y mantenimiento con rituximab, obteniendo escasa respuesta clínica. En pacientes con lesiones medulares extensas se deben contemplar múltiples diagnósticos diferenciales según la presentación clínica, hallazgos mediante estudios por imágenes y epidemiología. Asimismo, debe incluir la búsqueda de anticuerpos anti-acuaporina 4 y contra la glicoproteína de la mielina del oligodendrocito, ya que el pronóstico funcional de estos pacientes suele ser desfavorable debido al gran componente destructivo de las lesiones. En consecuencia, el tratamiento temprano es fundamental a fin de limitar el daño agudo y prevenir futuras recaídas, lo cual es especialmente importante en presentaciones tardías de esta entidad debido a la escasa reserva funcional y baja capacidad de remielinización.

Optic neuromyelitis spectrum diseases are inflammatory disorders of the central nervous system characterized by severe demyelination and immunomediated axonal damage that mainly affects the optic nerves and spinal cord. They usually appear at an early age, although there are some reports in the literature of patients with late presentations. We present the case of a 78-year-old woman who consulted for severe paraparesis, sensory disorders, and urinary retention. An MRI of the cervicodorsal spine was performed, showing extensive longitudinal spinal injury. Secondary causes based on clinical observations and laboratory studies were ruled out. The dosage of anti-aquaporin 4 antibodies was positive. Acute treatment with high-dose glucocorticoids and plasmapheresis was indicated, and maintenance with rituximab, obtaining little clinical response. In patients with extensive spinal injuries, multiple differential diagnoses should be considered according to the clinical presentation, findings through imaging studies and epidemiology. Likewise, it should include the search for anti-aquaporin 4 antibodies and against the oligodendrocyte myelin glycoprotein, since the functional prognosis of these patients is usually unfavourable due to the large destructive component of the lesions. Consequently, early treatment is essential in order to limit acute damage and prevent future relapses, which is especially important in late presentations of this entity due to the low functional reserve and low remyelination capacity.

Neuromielitis óptica / Neuromyelitis optica

La neuromielitis óptica (NMO) es un trastorno autoinmune, inflamatorio y desmielinizante del sistema nervioso central con predilección por los nervios ópticos y médula espinal. En el año 2004 se publicó la asociación de NMO con un anticuerpo contra el canal de agua acuaporina 4 (anti-AQP4), como una enfermedad diferente de la esclerosis múltiple (EM). Actualmente se propone el término trastornos del espectro NMO (NMOSD), debido a que las manifestaciones de la enfermedad pueden ser más extensas, afectando además del nervio óptico y médula espinal, al área postrema del bulbo raquídeo, tronco encefálico, diencéfalo y áreas cerebrales típicas (periependimarias, cuerpo calloso, cápsula interna y sustancia blanca subcortical). NMOSD se aplica también a pacientes que cumplen los criterios de NMO y son negativos para anti-AQP4. Dentro de este último grupo se ha detectado en un 20% la presencia de otro anticuerpo, anti-MOG (Glicoproteína oligodendrocítica de mielina) con un mecanismo fisiopatológico diferente pero con una clínica, en algunos casos, similar, y en general con mejor pronóstico. El tratamiento inmunosupresor en la crisis, así como el tratamiento a largo plazo en los casos que esté indicado, es fundamental para evitar secuelas y recidivas. El diagnóstico correcto de esta entidad es fundamental ya que puede ser agravado con el uso de fármacos útiles en el tratamiento de EM. En esta publicación haremos una revisión de la fisiopatología, clínica y criterios diagnósticos de NMOSD, y discutiremos las distintas opciones terapéuticas.

Neuromyelitis optica (NMO) is an autoimmune, inflammatory and de myelinat ing disorder of the central nervous system with a predilection for the optic nerves and spinal cord. In 2004 the association of NMO with an antibody against the water channel aquaporin 4 (anti-AQP4) was published as a different pathology from multiple sclerosis (MS). Currently the term NMO spectrum disorders (NMOSD) is proposed, because the manifestations of the disease can be more extensive, affecting in addition to the optic nerve and spinal cord, the area postrema of the dorsal medulla, brainstem, diencephalon and typical brain areas (periependymal, corpus callosum, internal capsule and subcortical white matter). NMOSD is also applied to patients who meet the NMO criteria and are negative for AQP4-IgG. Within the latter group, the presence of another antibody, anti-MOG, has been detected in 20%, with a different physiopathological mechanism, but with a similar clinic and a better prognosis. The immunosuppressive treatment in the attack, as well as the long-term treatment in the cases that are indicated, is fundamental to avoid sequelaes and recurrences. The correct diagnosis of this entity is essential since it can be aggravated with the use of drugs useful in the treatment of MS. In this publication we will review the pathophysiology, clinical and diagnostic criteria of NMOSD, and discuss the different therapeutic options.

Sjögren syndrome and neuromyelitis optica spectrum disorder co-exist in a common autoimmune milieu / Síndrome de Sjögren e espectro da neuromielite óptica coexistem em meio de autoimunidade

The relationship between Sjögren’s syndrome (SS) and neuromyelitis optica spectrum disorder (NMOSD) is not completely understood. We report two patients with both conditions and review 47 other previously reported cases meeting currently accepted diagnostic criteria, from 17 articles extracted from PubMed. Out of 44 patients whose gender was informed, 42 were females. Mean age at onset of neurological manifestation was 36.2 years (10-74). Serum anti-AQP4-IgG was positive in 32 patients, borderline in 1, and negative in 4. Our Case 1 was seronegative for AQP4-IgG and had no non-organ-specific autoantibodies other than anti-SSB antibodies. Our Case 2 had serum anti-AQP4, anti-SSA/SSB, anti-thyreoglobulin and anti-acethylcholine-receptor antibodies, as well as clinical hypothyreoidism, but no evidence of myasthenia gravis. Our Cases and others, as previously reported in literature, with similar heterogeneous autoimmune response to aquaporin-4, suggest that SS and NMO co-exist in a common autoimmune milieu which is not dependent on aquaporin-4 autoimmunity.

A relação entre síndrome de Sjögren (SS) e espectro da neuromielite óptica (ENMO) ainda não é bem compreendida. Relatamos dois pacientes com ambas as condições e revisamos 47 casos que preenchem critérios diagnósticos das duas doenças, descritos em 17 artigos extraídos da PubMed. Dos 44 pacientes cujo gênero foi informado 42 eram mulheres. A idade média ao início das manifestações neurológicas foi 36,2 anos (10-74). O anticorpo anti-AQP4 foi positivo em 32 dos 37 pacientes, em 1 foi “borderline”. Nosso Caso 1 era soronegativo para AQP4-IgG, não tinha autoanticorpos não-órgão específicos, exceto anti-SSB. O Caso 2 era soropositivo para anticorpos anti-AQP4, anti-SSA/SSB, anti-tireoglobulina, e anti-receptor da acetilcolina; apresentava hipotireoidismo, mas não havia evidêncas de miastenia gravis. Nossos casos e outros similares, previamente relatados na literatura, com resposta autoimune heterogênea à aquaporina-4 sugerem que a SS e o ENMO coexistem em meio de autoimunidade não dependente da aquaporina-4.

Seronegative Neuromyelitis Optica Spectrum - The challenges on disease definition and pathogenesis / O espectro da neuromielite optica seronegativa - os desafios na definição da doença e sua patogênese

Neuromyelitis optica spectrum disorders (NMOSD) are characterized by severe optic neuritis and/or longitudinally extensive transverse myelitis, and some brain lesions are also unique to NMOSD. Serum autoantibodies against aquaporin-4 (AQP4) are detected in most cases of NMOSD. However, some patients with NMOSD remain seronegative despite repetitive testing during attacks with highly sensitive cell-based assays. The differential diagnosis of NMOSD is not restricted to multiple sclerosis and it includes many diseases that can produce longitudinally extensive myelitis and/or optic neuritis. We review the clinical features, imaging, and laboratory findings that can be helpful on the diagnostic work-up, discuss the differences between AQP4 antibody positive and negative patients with NMOSD, including features of NMOSD with antibodies against myelin oligodendrocyte glycoprotein.

O espectro da neuromielite óptica (NMOSD) é caracterizado por ataques graves de neurite óptica e mielite. Anticorpos séricos contra a aquaporina-4 (AQP4) são usualmente presentes nestes pacientes. Entretanto, alguns pacientes com NMOSD são seronegativos mesmo com testes repetidos em amostras obtidas durante ataques usando métodos altamente sensíveis baseados em células. O diagnóstico diferencial não é restrito à esclerose múltipla e inclui muitas doenças que podem produzir mielite longitudinalmente extensa e/ou neurite óptica. São abordadas as características clínicas, de imagem e de laboratório que podem ser úteis no diagnóstico, as diferenças entre os pacientes positivos para o anticorpo anti-AQP4 e os negativos, incluindo as características dos pacientes com NMOSD que possuem anticorpos contra a glicoproteína associada ao oligodendrócito.

The expanded spectrum of neuromyelitis optica: evidences for a new definition / O espectro expandido da neuromielite óptica: as evidências para nova definição

Neuromyelitis optica (NMO) has been traditionally described as the association of recurrent or bilateral optic neuritis and longitudinally extensive transverse myelitis (LETM). Identification of aquaporin-4 antibody (AQP4-IgG) has deeply changed the concept of NMO. A spectrum of NMO disorders (NMOSD) has been formulated comprising conditions which include both AQP4-IgG seropositivity and one of the index events of the disease (recurrent or bilateral optic neuritis and LETM). Most NMO patients harbor asymptomatic brain MRI lesions, some of them considered as typical of NMO. Some patients with aquaporin-4 autoimmunity present brainstem, hypothalamic or encephalopathy symptoms either preceding an index event or occurring isolatedly with no evidence of optic nerve or spinal involvement. On the opposite way, other patients have optic neuritis or LETM in association with typical lesions of NMO on brain MRI and yet are AQP4-IgG seronegative. An expanded spectrum of NMO disorders is proposed to include these cases.

Neuromielite óptica (NMO) tem sido tradicionalmente caracterizada como associação de neurite óptica recorrente ou bilateral e mielite tranversa longitudinalmente extensa (MTLE). O conceito de NMO tem mudado desde a identificação do anticorpo antiaquaporina-4. A NMO é atualmente considerada como um espectro de condições contendo pelo menos um dos eventos índices da doença (neurite óptica recorrente ou bilateral e MTLE) e soropositividade para AQP4-IgG. A maioria dos pacientes apresenta lesões cerebrais à imagem por ressonância magnética (IRM), algumas delas típicas de NMO. Pacientes soropositivos podem desenvolver sintomas de tronco encefálico, hipotálamo e de encefalopatia precedendo os eventos índices, ou isoladamente, na ausência de qualquer evidência de alteração visual ou espinal. Por outro lado, há pacientes soronegativos que apresentam ou neurite óptica ou MTLE associada a lesões cerebrais típicas de NMO à IRM. Todas essas situações estão incluídas no espectro expandido de NMO aqui proposto.

Neuromielitis óptica con alta expresión de acuaporina-4 y anticuerpos anti-acuaporina-4 positivos en suero / Neuromyelitis optica with high aquaporin-4 expression and positive serum aquaporin-4 autoantibodies

La presencia de anticuerpos IgG en suero, con blanco en los canales de acuaporina-4, es específica de la neuromielitis óptica (NMO). El 60% de los pacientes con NMO presentan lesiones cerebrales en la resonancia magnética (RM); en un 8% (mayoría niños) estas lesiones se consideraron "atípicas". Presentamos dos pacientes con NMO y lesiones en el SNC de alta expresión de acuaporina-4. Caso 1: varón de 50 años, que comenzó con pérdida de visión en ojo derecho (OD). Recibió tratamiento empírico con metilprednisolona 1 g/d x 3 días. Al mes presentó dolor generalizado y hemiparesia derecha; nuevamente recibió metilprednisolona 1 g/d x 5 días e IgG IV 400 mg/kg/d × 5 días. Recuperó la deambulación persistiendo el dolor y fenómenos paroxísticos en los 4 miembros. Potenciales evocados visuales: P100, ojo izquierdo (OI) 123 mseg. OD sin respuesta. La RM de cerebro (FLAIR) mostró hiperintensidad en nervio óptico derecho, hipotálamo y comisura blanca anterior. RM cervical: lesión medular extensa (5 cuerpos vertebrales). Caso 2: mujer de 53 años, con disminución de la agudeza visual en ambos ojos y parestesias en miembros inferiores que remitieron espontáneamente. Evolucionó al mes con cuadriparesia e incontinencia esfinteriana. Recibió metilprednisolona 1 g/d x 5 días, sin mejoría. Potenciales evocados visuales: P100 OI 124 mseg. OD 128 mseg. RM cerebro: (FLAIR) hiperintensidad hipotalámica y periacueductal. RM cervical: lesión medular extensa (7 cuerpos vertebrales). Anticuerpos anti-acuaporina-4 positivos en ambos pacientes (inmunofluorescencia indirecta). Las lesiones consideradas "atípicas", como aquí, en sitios con alta densidad de proteínas canales de agua AQP4 deberán considerarse para el diagnóstico diferencial.

Disease-specific aquaporin-4 antibodies (NMO-IgG) are the main effector of lesions in neuromyelitis optica (NMO) patients. Brain MRI lesions are detected in 60% of them, with 8% (almost infants) at sites of high aquaporin-4 expression. Patient 1: A fifty-year-old male with loss of vision in the right eye. Empiric treatment with metilprednisolone 1g/d for 3 days was indicated. After 30 days he complained of generalized pain, and a right hemiparesis was evident. The patient received bolus of metilprednisolone 1g/d for 5 days plus IgG 400 mg/kg/d IV for 5 days. He recovered ambulation but persisted with pain and paroxysmal phenomena (Lhermitte). Visual Evoked Potentials (VEP): P100 left eye 123 ms, right eye without response. Brain MRI (FLAIR) showed hyperintensity in the right optic nerve, hypothalamus and anterior white commissure. Cervical MRI showed extensive spinal cord lesion to an extension of 5 vertebral bodies. Patient 2: A fifty-three-year-old female who referred decreased visual acuity in both eyes and paresthesia in lower limbs which subsided spontaneously. One month later the patient evolved with cuadriparesis and sphincter incontinence. No improvement was observed with bolus of metilprednisolone 1g/d for 5 day. VEP: P100 left eye 124 ms, right eye 128 ms. Brain MRI (FLAIR) disclosed hypothalamic and periaqueductal hyperintensity. Cervical MRI showed extensive spinal cord lesion to an extension of 7 vertebral bodies. NMO-IgG antibodies were positive in both patients (indirect immunofluorescence assay). NMO brain lesions at sites of high aquaporin-4 expression, once considered "atypical" for their topography and infrequency in adults, should be borne in mind when considering differential diagnosis.

NMO in pediatric patients: brain involvement and clinical expression / NMO en pacientes pediátricos: afectación del cerebro y expresión clínica

OBJECTIVE: To analyze the clinical, neuroimaging characteristics and positivity of the acquaporin water channel (NMO-IgG) in pediatric patients with neuromyelitis optica (NMO). This disorder could have a variable clinical expression. To address such variability, the term NMO spectrum has been suggested. METHOD: We evaluated six pediatric patients, with a median age of 11 years at the time of the study, with the diagnosis of NMO by the Wingerchuck criteria. RESULTS: All the cases exhibited bilateral optic neuritis (ON). Four patients had abnormalities on brain MRI from the onset,although only three of them developed symptoms correlated to those lesions during the course of their disorder. NMO-IgG was positive in 80 percent. CONCLUSION: Optic neuropathy is the most impaired feature in NMO patients. Brain MRI lesions are not compatible with multiple sclerosis and positivity of the NMO-IgG are also present in NMO pediatric patients, confirming the heterogeneity in the expression of this disorder.

OBJETIVO: Analizar las características clínicas y de neuroimagen, y la positividad del canal de agua acuaporin (NMO-IgG) en pacientes pediátricos con neuromielitis óptica (NMO). Este trastorno puede tener una expresión clínica variable. El término espectro de NMO ha sido propuesto para poder incluir la variabilidad. METODO: Evaluamos seis pacientes pediátricos, con una mediana de edad de 11 años al momento del estudio, con el diagnóstico de NMO de acuerdo a los criterios de Wingerchuck. RESULTADOS: Todos los casos exhibían neuritis óptica bilateral (ON). Cuatro pacientes tuvieron anormalidades en la RM cerebral desde el inicio, aunque solo tres de ellos desarrollaron síntomas relacionados con las lesiones durante el curso de la enfermedad. NMO-IgG fue positiva en el 80 por ciento. CONCLUSIÓN: Neuropatía óptica es la característica mayormente observada en los pacientes con NMO. Lesiones cerebrales en la RM cerebral no compatibles con esclerosis multiple y positividad de la NMO-IgG están también presentes en los pacientes pediátricos con NMO; lo cual confirma la heterogeneidad en la expresión clínica de este trastorno.

Neuromielitis óptica / neuromyelitis optica

La concepción de que la neuromielitis óptica (NMO) es un trastorno inflamatorio monofásico, que afecta tanto a los nervios ópticos como a la medula espinal ha variado. En los últimos diez años, los resultados de varios estudios clínicos, radiológicos, serológicos y patológicos, han permitido modificar los axiomas de la NMO, una muestra de esto lo constituye su identificación como una entidad diferente de la Esclerosis Múltiple. Serológicamente se puede comprobar la presencia de un marcador tanto sensible como específico (IgG NMO), este anticuerpo se proyecta contra un antígeno, el aquaporina-4, el cual es el canal de agua más abundante del sistema nervioso, abriendo una nueva era en las investigaciones de los desórdenes desmielinizantes del sistema nervioso central. La posibilidad de determinar serológicamente este marcador, en pacientes con neuritis óptica o mielitis longitudinalmente extensa, y su capacidad de predecir las recaídas posteriores apoyan el concepto de espectro de trastornos de NMO. Se requieren nuevas investigaciones, que posibiliten nuevos conceptos patogénicos, además de estrategias terapéuticas eficaces que beneficien a los pacientes con esta patología.

The traditional view of neuromyelitis optica (NMO) is a monophasic inflammatory disorder that affects both the optic nerves and the spinal cord have been changing since last decated. Result from adecuated clinical trials, radiology, serologics and pathology investigations had modified the current nomenclature of demyelinating deseases leading identified NMO as a separate clinical entity from Multiple Sclerosis. The most abundant water channel in CNS aquaporin-4 has been identified as an specific target of IgG NMO specific autoantibody. This autoantibody could play an importan roll in pathogenesis of the Central nervous System Demyelinating Disorders. This features opens a new era to develop new serologic diagnostic and possible new terapeutical strategies. The identification of NMO-IgG in patients with recurrent optic neuritis or longitudinally extensive myelitis and its ability to predict subsequent relapse support the concept of a spectrum of NMO disorders. New clinical trials, and pathophysyiological investigations are required to hopefully lead to more effective targeted therapies for our patients and to improve our understanding about pathogenic mecanism underlaying in demielinization.

Immune system markers of neuroinflammation in patients with clinical diagnose of neuromyelitis optica / Marcadores imunológicos em pacientes com diagnóstico de neuromielite óptica

Neuromyelitis optica (NMO) is an inflammatory, demyelinating disease of the central nervous system characterized by the association of a serious myelitis and unilateral or bilateral optic neuritis. The present study aimed to analyze the immunological parameters of NMO patients with diagnosis established based on Wingerchuck et al. (1999) criteria. Production of IgG and IgA antibodies to antigens of MBP, PLP 95-116, MOG 92-106, and the cytokines interleukin-4 (IL-4) and interferon-γ (INF-γ) were assessed by Elisa assay. The cohort was formed by 28 NMO patients and a matched healthy control group. NMO patients had significant high levels of IgG to MOG (p<0.0001), PLP (p=0.0002) and MBP (p<0.0001), and solely IgA to MBP (p<0.0001). INF-γ (p=0.61) levels were similar to healthy controls. Increased production of IL-4 (p=0.0084) indicates an important role for this cytokine in the activation of Th2 regulatory cells and of the IgA producers B lymphocyte indicating activation of humoral immunity.

A neuromielite óptica (NMO) é doença inflamatória do sistema nervoso central, caracterizada por mielite aguda ou subaguda grave e neurite óptica unilateral ou bilateral. Este estudo objetiva analisar parâmetros imunológicos de pacientes com critérios de Wingerchuck et al. (1999) para NMO. O método de ELISA avaliou a produção de IgG e IgA para antígenos da proteína básica da mielina (MBP), o proteolipídeo (PLP) 95-116, a glicoproteina associada ao oligodendrócito (MOG) 92-106 e as citocinas interleucina-4 (IL-4) e interferon-gama (INF-γ). Foram incluνdos 28 pacientes com NMO pareados com controles saudáveis. Pacientes com NMO apresentaram níveis significativamente elevados de imunoglobulinas reativas dos isotipos IgG para MOG (p<0,0001), PLP (p=0,0002) e MBP (p<0,0001) e IgA somente para MBP (p<0,0001). Os níveis de INF-γ (p=0,61) foram semelhantes aos controles. A produção elevada de IL-4 (p=0,0084) indica papel importante na ativação de células regulatórias Th2 e linfócitos B produtores de IgA e da ativação da imunidade humoral.

Seroprevalence of NMO-IgG antibody in Brazilian patients with neuromyelitis optica / Soroprevalência do anticorpo NMO-IgG em pacientes brasileiros com neuromielite óptica

OBJECTIVE: To determine the seroprevalence of neuromyelitis optica antibody (NMO)-IgG in Brazilian patients with clinical diagnosis of relapsing neuromyelitis optica, also known as Devic's disease. METHOD: We determined NMO-IgG titers in 28 patients (25 of them females) that fulfilled the 1999 NMO diagnostic criteria proposed by Wingerchuk et al. RESULTS: NMO-IgG was detected in 18 NMO patients (64.3 percent). CONCLUSION: Our results showed that seroprevalence of NMO-IgG in Brazilian NMO patients was similar to the observed in other studies.

OBJETIVO: Determinar a soroprevalência do anticorpo neuromielite óptica (NMO)-IgG em pacientes brasileiros com diagnóstico de neuromielite óptica recorrente, também conhecida como doença de Devic. MÉTODO: Nós pesquisamos a presença do anticorpo NMO-IgG em 28 pacientes (25 do sexo feminino) que preenchiam os critérios diagnósticos para NMO propostos por Wingerchuk et al. em 1999. RESULTADOS: Dezoito pacientes (64,3 por cento) apresentaram a pesquisa positiva do NMO-IgG. CONCLUSÃO: Nossos resultados demonstraram que a soroprevalência do anticorpo NMO-IgG em pacientes brasileiros com NMO é semelhante àquela encontrada em outros estudos.