Acute non compressive myelopathies

Abstract

BACKGROUND: Acute transverse myelitis (ATM) may be the prelude of a wide range of diseases such as Multiple Sclerosis (MS), autoimmune, infectious, post-vacunal, post-radiotherapy and tumor related disorders. Nonetheless, the underlying etiology remains elusive in up to 16% of ATM patients. In 2002, the Transverse Myelitis Consortium Working Group (TMCWG) proposed some criteria in order to unify the concept of idiopathic ATM (IATM).

ATM may present as a longitudinal extensive transverse myelitis (LETM) on the spinal Magnetic Resonance Imaging. LETM is a cardinal symptom of Neuromyelitis optica (NMO), an autoimmune chronic disease characterized by recurrent optic neuritis (ON) or LETM. In 2004, a pathogenic antibody, known as aquaporin-4 antibody (AQP4–ab) was directly related to NMO or limited forms of the disease such as LETM. Nonetheless, up to 50% of LETM patients are AQP4-ab seronegative. Recently, antibodies against the myelin- oligodendrocyte glycoprotein (MOG-ab) have been described in AQP4-ab seronegative NMO patients or limited forms of the disease.

AIMS: The current work is divided in three studies. In the first study, we aimed to describe the MS conversion ratio and to identify baseline factors related to MS conversion, as well as to analyze baseline prognostic factors of disability in IATM patients fulfilling the 2002 TMCWG. In the second study, we sought to describe the etiological LETM spectrum and to analyze baseline prognostic factors related to outcome in this subgroup of patients. Finally, in the third study, we set out to describe the frequency of MOG-ab in AQP4-ab seronegative LETM and searched for differences between MOG-ab positive and negative AQP4-ab seronegative LETM patients.

METHODOLOGY: The first and second studies were performed in a single center and we reviewed the epidemiological, clinical, laboratory and radiological data of 85 IATM patients fulfilling the TMCWG and 72 LETM patients. The third study is a multicenter European study with data collected in a prospective manner. AQP4-ab or MOG- ab were detected by immunohistochemistry in the two first studies and by cell based assays in the third study. All data were retrospectively analyzed.

RESULTS: At the end of the first study, 13% of IATM converted to MS and an early onset of symptoms was related to MS conversion. However, laboratory findings such a negative result in the combination of oligoclonal bands (OCB) and IgG index in the cerebrospinal fluid (CSF) ruled out MS conversion. We observed that LETM and urinary sphincter dysfunction were independent baseline prognostic factors related to disability and that up to 37% of IATM patients had a final modified Rankin Score more (mRS) ≥ 2. In LETM patients, the idiopathic group and MS were the most frequent disorders involved (30.5% and 25%, respectively). NMO or limited forms were observed in less than 5%. The mRS was ≥2 at the end of follow-up in 72.2%. The presence of higher disability at onset of symptoms and elderly were independent baseline prognostic factors of disability. Up to 23% of patients presenting with AQP4-ab seronegative LETM tested positive for MOG-ab in serum. MOG-ab positive patients were younger, had CSF pleocytosis more frequently and had better outcome. Moreover, MOG-ab positive patients also showed an increase risk of ON relapse and NMO conversion.

CONCLUSIONS: We identified that a subgroup of IATM patients may convert to MS, even when fulfilling the 2002 TMCWG criteria. Functional recovery in IATM is poorer in patients with urinary sphincter dysfunction at admission or LETM on MRI. We established the LETM etiological spectrum. In this subgroup of patients, while idiopathic and MS group were the most frequently involved, others such as NMO were marginally observed. Older age and clinically severe disease at onset were independent prognostic factors of poorer functional recovery in LETM patients. Finally we found that MOG-ab are present in a proportion of AQP4-ab seronegative LETM patients defining a subgroup of patients with clinical distinctive features, higher risk of ON relapses, and better outcome.

Las mielitis transversas agudas (MTA) pueden ser el comienzo de una amplia diversidad de enfermedades, siendo la más frecuente la Esclerosis Múltiple (EM). Hasta en el 16% de los pacientes que presentan una MTA, la etiología será desconocida. Un consorcio internacional (TMCWG) propuso en el año 2002 unos criterios con el fin de unificar el concepto de MTA idiopática (MTAI). Las MTA pueden presentarse como una afectación extensa de la médula espinal (LETM), siendo ésta una característica de la Neuromielitis óptica (NMO). Los anticuerpos aquaporina 4 (AQP4-ac) se objetivan en la mayoría de estos pacientes y formas limitadas de esta enfermedad, como la LETM. Sin embargo, una proporción de estos pacientes no presentan AQP4-ac y otros anticuerpos como los anticuerpos contra myelin oligodendrocyte glycoprotein (MOG-ac) han sido recientemente asociados.

El presente trabajo se divide en tres estudios (dos unicéntricos y un tercero multicéntrico europeo) que tienen como objetivo describir las características de los pacientes con una MTAI, pacientes con LETM así como identificar las características de aquellos pacientes con una LETM que presenten MOG-ac.

Se identificó un subgrupo no despreciable de pacientes que convertirán a EM aunque cumplan los criterios de la TMCGW para MTAI. Además se objetivó que el pronóstico es peor en pacientes con una MTAI que presentan disfunción urinaria y LETM al comienzo de los síntomas. Por otra parte, describimos el espectro etiológico de pacientes con LETM, objetivando que en la mayor parte de ellos, la causa es idiopática. Los pacientes con una LETM tendrán peor pronóstico a más edad y a mayor discapacidad al inicio de los síntomas. Finalmente, encontramos que hasta un 23% de los pacientes que presentan LETM y son seronegativos para AQP4-ac, tienen MOG-ac en el suero. Estos pacientes presentan características clínicas distintivas, mayor riesgo de neuritis óptica, de recidivas y mejor pronóstico que los pacientes sin el anticuerpo.