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Plasma Exchange in Severe Attacks of Neuromyelitis Optica

Plasma Exchange in Severe Attacks of Neuromyelitis Optica

1Service de Neurologie, Hopital F. Mitterand, 64000 Pau, France
2Service de Neurologie, H?pital Zobda Quitman, 97261 Fort de France, Martinique

Received 13 September 2011; Revised 13 November 2011; Accepted 17 November 2011

Academic Editor: Jerome de Seze Abstract

Background. Neuromyelitis optica (NMO) attacks are poorly controlled by steroids and evolve in stepwise neurological impairments. Assuming the strong humoral response underlying NMO attacks, plasma exchange (PLEX) is an appropriate technique in severe NMO attacks. Objective. Presenting an up-to-date review of the literature of PLEX in NMO. Methods. We summarize the rationale of PLEX in relation with the physiology of NMO, the main technical aspects, and the available studies. Results. PLEX in severe attacks from myelitis or optic neuritis are associated with a better outcome, depending on PLEX delay (“time is cord and eyes”). NMO-IgG status has no influence. Finally, we build up an original concept linking the inner dynamic of the lesion, the timing of PLEX onset and the expected clinical results. Conclusion. PLEX is a safe and efficient add-on therapy in NMO, in synergy with steroids. Large therapeutic trials are required to definitely assess the procedure and define the time opportunity window.


1. Introduction

Neuromyelitis optica (NMO) is an inflammatory disorder restricted to the spinal cord and optic nerves. Contrary to multiple sclerosis (MS), relapses of NMO are often strikingly severe and most NMO patients present stepwise neurological impairments. NMO treatments are aimed to prevent the relapses with the administration of various promising immunosuppressive drugs. However, relapse treatment is still a tricky problem. Since the largely used steroid treatment usually fails to control severe attacks, specific add-on treatments have to be considered in order to limit the stepwise increase of residual impairment. Given that a strong humoral response characterizes NMO physiology, one might assume plasma exchange (PLEX) to be particularly well adapted in severe NMO relapses.

We here propose to outline the rationale of the PLEX treatment based on physiological grounds and summarize the relevant data of PLEX studies in the setting of NMO spectrum disorder, assessing the results obtained in each type of attacks. Finally we will try to build up an original concept linking the inner dynamic of the lesion, the timing of PLEX, onset, and the expected clinical results.

2. Physiopathology of NMO

2.1. Pathology of NMO Lesions

A characteristic pathological pattern has been described in NMO [1]. Lesions are infiltrated by neutrophils and eosinophils and wall capillaries are hyalinized. A vasculocentric pattern of activated complement and immunoglobulin of IgG and IgM types is observed that mirrors the normal expression of AQP4. AQP4 expression is definitely reduced in normal appearing white matter and lost throughout the lesions. These modifications are the hallmark of NMO and could occur alone or associated with a wide range of lesions from mild demyelination to large necrosis. This pattern of lesion was classified in the pattern II of the Lassmann classification of the inflammatory lesions [1, 2]. Contrary to MS, T cells are rare in NMO lesions and probably have no major effect on the formation of the lesions [3]. However, T cells are probably involved upstream in physiopathological cascade in the earlier phases of the disease where a complex interplay leads to antigen sensitization and possibly in the initial opening of the blood-brain barrier (BBB) [4]. Moreover, the pattern associating vasculocentric deposition of Ig and complement, cells (eosinophils/lymphocytes) infiltration and AQP4 loss is sometimes fully dissociated from demyelination [5].

2.1.1. Specific Antibodies and Their Epitopes

The NMO-IgG antibody is IgG1 directed against protein aquaporin-4 (AQP4) [6]. This antibody is detected with tissue-based immunofluorescence assays with a sensitivity and specificity for clinically defined NMO of more than, respectively, 60% and 90%. Clinically diagnosed NMO patients share clinical common and evolutional characteristics regardless of their NMO-IgG status. Beyond the surrogate marker value of NMO-IgG, this marker is now used as a major diagnostic criterion [7] and delineates the NMO spectrum disorders that gather in a same entity both typical NMO and unusual or truncated clinical forms [8].

AQP4 is a transmembrane protein expressed in the apical domain of the membrane feet expansions of the astrocytes close to the surrounded blood vessels. They are generally found as single tetramers, closely arranged in orthogonal arrays. This protein is critically involved in the homeostasis of the water in the brain and interfaces with blood vessels, especially in the clearance of free water. Loss of perivascular AQP4 in the basal state results in cellular swelling, ostensibly due to a failure to eliminate water generated from cellular metabolism [9]. Thus in NMO, since the interaction of NMO-IgG and AQP4 leads to a functional knockout phenotype of AQP4, edema develops as a result of functional impairment of AQP4 although BBB is expected to be still intact, which may explain the paradoxical lack of gadolinium enhancement in most NMO lesions. Apart from water homeostasis, the removal of AQP4 from astrocytes membrane is associated with an impaired homeostasis of glutamate via the loss of function of EAAT2, a major glutamate transporter associated with AQP4 in a macromolecular complex [10]. The disruption of glutamate homeostasis initiates an excitotoxic mechanism damaging oligodendrocytes and ultimately leading to demyelination [11].

Virtually all the CNS astrocytes express AQP4, however, some regions are enriched in AQP4. Those regions are the spinal cord gray matter, the posterior optic nerve, the floor of the fourth ventricle and the circumventricular organs especially the area postrema, explaining the restriction of the sites of lesion characterizing NMO [12]. Interestingly circumventricular organs are also the only sites of the CNS expressing fenestrated capillaries favoring local passive diffusion of circulating antibodies.

Continued at Resource

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