Cerebrospinal fluid findings in aquaporin-4 antibody positive neuromyelitis optica: Results from 211 lumbar punctures

Abstract

Background

Neuromyelitis optica (NMO, Devic disease) is a severely disabling autoimmune disorder of the CNS, which was considered a subtype of multiple sclerosis (MS) for many decades. Recently, however, highly specific serum autoantibodies (termed NMO-IgG or AQP4-Ab) have been discovered in a subset (60–80%) of patients with NMO. These antibodies were subsequently shown to be directly involved in the pathogenesis of the condition. AQP4-Ab positive NMO is now considered an immunopathogenetically distinct disease in its own right. However, to date little is known about the cerebrospinal fluid (CSF) in AQP4-Ab positive NMO.

Objective

To describe systematically the CSF profile of AQP4-Ab positive patients with NMO or its formes frustes, longitudinally extensive myelitis and optic neuritis.

Material and methods

Cytological and protein biochemical results from 211 lumbar punctures in 89 AQP4-Ab positive patients of mostly Caucasian origin with neuromyelitis optica spectrum disorders (NMOSD) were analysed retrospectively.

Results

CSF-restricted oligoclonal IgG bands, a hallmark of MS, were absent in most patients. If present, intrathecal IgG (and, more rarely, IgM) synthesis was low, transient, and, importantly, restricted to acute relapses. CSF pleocytosis was present in around 50% of samples, was mainly mild (median, 19 cells/μl; range 6–380), and frequently included neutrophils, eosinophils, activated lymphocytes, and/or plasma cells. Albumin CSF/serum ratios, total protein and CSF L-lactate levels correlated significantly with disease activity as well as with the length of the spinal cord lesions in patients with acute myelitis. CSF findings differed significantly between patients with acute myelitis and patients with acute optic neuritis at the time of LP. Pleocytosis and blood CSF barrier dysfunction were also present during remission in some patients, possibly indicating sustained subclinical disease activity.

Conclusion

AQP4-Ab positive NMOSD is characterized by CSF features that are distinct from those in MS. Our findings are important for the differential diagnosis of MS and NMOSD and add to our understanding of the immunopathogenesis of this devastating condition.

Introduction

Neuromyelitis optica (Devic syndrome, NMO) is a severely disabling disorder of the central nervous system (CNS) of putative autoimmune aetiology, which predominantly affects the optic nerves and the spinal cord [1]. For many years, NMO was considered to be a subtype of multiple sclerosis (MS). Recently, however, it was shown that 60–80% of NMO patients are positive for antibodies to aquaporin-4, the most abundant water channel in the CNS [2], [3], [4], [5]. The discovery of this new serum reactivity (termed NMO-IgG or AQP4-Ab) rendered it possible to distinguish NMO from classical MS by means of a laboratory test for the first time. Subsequently, the demonstration of both NMO-like CNS lesions and clinical disease following passive transfer of AQP4-Ab-positive sera in several independent animal studies provided strong evidence for a pathogenic role of AQP4-Ab in vivo [6], [7], [8], [9], [10], [11], [12].

So far, only very little is known about cerebrospinal fluid (CSF) findings in patients with AQP4-Ab positive NMO. Previous studies did not take into account the patients AQP4-Ab status [1], [13], [14], [15], [16], were based on small patient numbers [14], [15], [17], [18], and/or did not include Caucasian patients [17]. Moreover, all of these studies investigated only a few selected CSF parameters [1], [14], [15], [16], [17], [18].

In the present study we systematically and comprehensively analysed the results of 211 lumbar punctures (LP) from a clinically and serologically homogeneous cohort of 89 mainly Caucasian patients with AQP4-Ab positive NMO and its formes frustes, longitudinally extensive transverse myelitis (LETM) and optic neuritis (ON).