Clinical Spectrum and Treatment of Neuromyelitis Optica Spectrum Disorders: Evolution and Current Status

Abstract

Neuromyelitis optica (NMO) is an inflammatory neurologic disease clinically characterized by severe optic neuritis (ON) and transverse myelitis (TM). The relationship between NMO and multiple sclerosis (MS) has long been a matter of debate. However, the discovery of an NMO‐specific autoantibody, NMO‐immunoglobulin G/aquaporin 4 (AQP4) antibody, has dramatically advanced our understanding of the disease, and the clinical, magnetic resonance imaging (MRI), optical coherence tomography, and laboratory examinations have clarified unique features of NMO that are distinct from MS. The term NMO spectrum disorders (NMOSD) incorporating spatially limited forms was introduced, as patients with recurrent or simultaneous bilateral ON or recurrent longitudinally extensive TM (LETM) alone are also often AQP4 antibody‐seropositive. Moreover, studies of seropositive cases have shown that more than half of them have brain lesions, some of which are unique to NMO, and can be the onset manifestation. Some clinical features of AQP4 antibody‐seronegative NMO differ from seropositive, but it remains unknown whether they are pathologically distinct. Immunosuppressive treatments are effective for acute attacks and prevention of relapses of NMOSD, and new molecularly targeted drugs are under investigation. Importantly, some disease modifying drugs for MS may exacerbate NMOSD, making early differential diagnosis of the two diseases crucial. We review the evolving clinical spectrum, the updated clinical, MRI, neuro‐ophthalmological and laboratory findings, and the current status of treatment in NMOSD.

Introduction

Neuromyelitis optica (NMO) is classically characterized by severe attacks of optic neuritis (ON) and transverse myelitis (TM). The well‐known autopsied case (45‐year‐old woman) reported by Eugène Devic in 1894 developed urinary retention, complete paraplegia and bilateral blindness with papilledema in 10 days 28, She died from bedsores in a month, and the pathological examination revealed severe demyelination and necrosis in the spinal cord and optic nerves, but the brain was macroscopically normal. Gault, Devic's student, described clinical features of 17 reported cases of NMO including the Devic's case in his thesis, and 14 of them had monophasic disease as summarized in the Table 1 34. However, in recent years, such a monophasic NMO is rare, and the majority of NMO patients have relapsing disease 133. Various investigators attempted to define NMO by the end of the 20th century. Although all of them agreed that the patients develop both ON and acute myelitis, there was no consensus on whether: (i) ON should be bilateral; (ii) myelitis should be TM; (iii) other central nervous system (CNS) involvement and relapses are acceptable (Table 2) 34, 90.

Table 1.

Clinical profile of Gault's 17 cases of NMO (1894) 34, 90. Abbreviations: NMO = neuromyelitis optica; ON = optic neuritis; MY = myelitis; CNS = central nervous system; ATM = acute transverse myelitis; nd = no data

Age at onset	Mean 30.6 years old (12 ∼52 years old) (nd in two cases)
Sex ratio (male : female)	10:6 (nd in one case)
Possible precipitating factor	6 with non‐tuberculosis infections, 1 with pulmonary tuberculosis, 2 with trauma, 2 with fatigue
Onset symptoms	ON in 9 cases, MY in 6 cases, simultaneous ON and MY in 1 case, nd in 1 case
Interval between ON and MY	≤1 week in 4 cases, 8 ∼30 days in 6 cases, 1 ∼5 months in 3 cases, 6 months in 1 case, 1 year in 1 case, nd in 1 case
ON	Bilateral in 15 cases (88.2%) (simultaneous in 11 cases, ≤5.5 months in all), unilateral in 1 case, nd in 1 case
MY	ATM in 4 cases, non‐transverse MY in 4 cases, acute asymmetric MY in 2 cases, subacute MY in 3 cases, nd in 3 cases
Other CNS symptoms	5 cases (29.4%) (brainstem signs in 3 cases and cerebral signs in 3 cases), psychiatric symptoms and headache in 2 other cases
Course	Monophasic in 14 cases (including 8 fatal cases, follow‐up ≤2 years), relapsing in 3 cases, ON in 3 cases, MY in 1 case (follow‐up ≤5 years)
Outcome	Fatal in 8 cases (within 3 weeks ∼5.5 months, respiratory failure in 5 cases and complications of bedridden state in 3 cases), non‐fatal in 9 cases (blindness in 1 case and no or mild sequelae in 8 cases, mean follow‐up: 1.4 years)

Table 2.

Definitions of NMO before the discovery of AQP4 antibody 90. Abbreviations: NMO = neuromyelitis optica; ON = optic neuritis; MY = myelitis; ATM = acute transverse myelitis; nd = no description

Author	Published year	Interval of ON and MY	MY	ON	Other CNS involvement: clinical	Other CNS involvement: subclinical	Relapse
McAlpine	1938	Up to several months	Acute or subacute	Acute, bilateral	No (in principle)	Mild lesions or none	Yes
Cloys	1970	No limitation	Acute or subacute	Acute or subacute, Uni or bilateral	Yes	Yes	Yes
Devic M	1980	nd	ATM	Acute, bilateral	nd	Yes	No
Kuroiwa	1975, 1985	≤4 weeks	ATM	Acute, bilateral	Minor signs	Yes (rare)	No
Leys	1987	Up to 3 years	Acute (≤4 weeks)	Uni or bilateral	No	Yes	Corticosteroid‐dependent only
Silber	1990	(within 3 months)	Acute (≤2 weeks)	Acute, uni or bilateral	No	No (except medulla)	No
Mandler	1993, 1998	Up to several years	Acute (or subacute?)	Acute, uni or bilateral	No	No (except medulla)	Yes
Fazekas	1994	nd	Acute or subacute	Acute or subacute	No	No	Yes
O'Riordan	1996	Up to 5 years	acute ≤2 weeks	Uni or bilateral, acute	No	Yes	Yes
Vernant	1997	nd	Acute or subacute	Uni or bilateral	Hypothalamo‐hypophyseal signs and lesions		Yes
Baudoin	1998	Within several months	ATM (subacute MY possible)	Acute, bilateral	No (in principle), but brainstem, cerebellar and visual pathway lesions were seen		No
Wingerchuk	1999	(up to 2 years)	acute	Uni or bilateral	No	Yes	Yes

The discovery of NMO‐immunoglobulin G (IgG)/aquaporin‐4 (AQP4)‐antibody, an NMO‐specific serum autoantibody, clearly identified NMO as a distinct disease from multiple sclerosis (MS). AQP4 is expressed in the endfeet of astrocytes 67 and available evidence indicates that NMO is an antibody‐mediated astrocytopathic disease 33. Longitudinal follow‐up studies confirmed that the majority of patients with AQP4‐antibodies have relapses 74, 131. The Wingerchuk's diagnostic criteria for definitive NMO proposed in 2006 included seropositivity to AQP4‐antibodies as a supportive criterion (ON and acute myelitis are absolute criteria), and two of the following three are met: (i) spinal cord lesion longitudinally extending over three or more vertebral segments; (ii) brain magnetic resonance imaging (MRI) not fulfilling Paty's MS criteria at onset; and (iii) NMO‐IgG/AQP4 antibody seropositivity 134.

Based on AQP4 antibody‐seropositive cases, spatially limited forms of the disease are included in a broader entity called NMO spectrum disorders (NMOSD). NMOSD comprises definitive NMO, monophasic or recurrent longitudinally extensive TM (LETM), and bilateral simultaneous or recurrent ON 135. In addition, brain manifestations of NMOSD have been described predominantly in periventricular areas with a high AQP4 expression 78, 104. Treatment of NMOSD has also developed significantly in recent years. In this article, we extensively review the clinical manifestations, MRI, neuro‐ophthalomological and laboratory findings, as well as immunological therapies of NMO/NMOSD.

Clinical Spectrum of NMO/NMOSD

ON

Multiple factors are likely to be involved in the increased vulnerability of the optic nerve to AQP4‐antibodies compared with other areas of the CNS. In addition to the higher expression of AQP4 in the optic nerve and the differences in the blood–brain barrier permeability in different regions of the CNS, other distinctive features of the optic nerve that increase the risk and effects of damage include: the anatomic constitution as a thick, long and dense white‐matter bundle with restricted diffusion and clearance of antibodies and other inflammatory molecules; an increased microglia activation following injury; and a high metabolic demand by the retinal ganglion cells to transmit visual information into the brain 68. In a Latin American series of 265 NMO patients, ON was the onset event in 42% and occurred in association with TM at onset of the disease in 10% 64.

ON in NMO/NMOSD has several unique features that may distinguish it from single isolated idiopathic ON, which has a risk to convert to MS, or ON occurring during the course of MS 82, 102. In NMO or NMOSD, the visual function is usually more severely affected than in single isolated idiopathic ON or MS and may not respond to corticosteroid treatment. Attacks tend to recur, and both eyes are most commonly involved either in different relapses or simultaneously. Visual acuity (VA) at ON attack is worse in NMOSD (median 0.01) than in MS or single isolated idiopathic ON (median 0.1). Recovery of VA is also poorer in NMO/NMOSD (0.1) than in MS (0.67) or single isolated idiopathic ON (0.33) 102. Serum AQP4‐antibodies, which are highly specific for NMOSD, have not been detected in patients with MS. However, these antibodies are found in 5% of patients with single isolated idiopathic ON 102 and in 5% to 20% in cases of isolated recurring ON (RON) 74, 102, 118. We recommend that those AQP4‐antibody seropositive cases be considered as NMOSD. The initial ON is usually more severe in AQP4 antibody‐seropositive RON, and the long‐term outcome is worse than in seronegative cases. In one series, VA was worse than 0.1 at the nadir in all AQP4 antibody‐seropositive patients as compared with two‐thirds of the seronegative cases; after a follow‐up of 8–9 years, 50% of seropositive vs. 6.6% of seronegative RON patients developed TM 74.

As in single isolated idiopathic ON and MS, the funduscopic examination in the acute phase of NMO/NMOSD generally shows no abnormality, as the ON is usually retrobulbar. However, some patients with severe posterior lesions may have edema extending to the optic disc with slightly blurred margins, or the disc may seem elevated from the retinal surface. Some overlapping patterns of retinal arteriolar changes in NMOSD include diffuse or sectorial attenuation of the arterioles in the peripapillary retina and focal arteriolar “frosting” (narrowing of blood column with obscuration of the vessel wall) at the posterior pole 38.

Myelitis

NMO/NMOSD patients with myelitis usually present with severe paraparesis or tetraparesis, as well as a sensory‐level and/or sphincter disturbances 59. The majority of the patients have LETM. The presence of LETM is a supportive criterion in Wingerchuk's 2006 diagnostic criteria for definitive NMO 134. Painful tonic spasms and pain are found more commonly in NMOSD than in MS 48, 56. Neuropathic pruritus (itch) has also been recently reported in NMOSD patients during myelitis attacks 29. On rare occasions, lesions involving the conus medullaris and cauda equine in NMOSD may result in lumbar myeloradiculitis 122.

The disability secondary to myelitis attacks in NMO/NMOSD is severe, and many patients experience permanent motor incapacity or become restricted to wheelchair 59, 133. NMOSD patients with upper cervical lesions may experience respiratory failure and require mechanical ventilation, but the early treatment of myelitis attacks may reduce the risk of death secondary to these complications. Secondary progression without attacks (chronic progressive myelopathy), as observed in MS, is not common in NMO patients 111, 133.

Brain symptoms

Brain MRI lesions in NMOSD are present in more than half of those patients with AQP4‐antibodies, but 10% have lesions compatible with MS 103. These brain lesions can be symptomatic depending on the affected area. Disturbance of consciousness and hemiparesis may be seen in some NMOSD patients with cerebral white matter lesions. Bilateral hypothalamic lesions can cause hypersomnia with low hypocretin‐1 levels in the cerebrospinal fluid (CSF) mimicking narcolepsy or syndrome of inappropriate antidiuretic hormone secretion in patients with AQP4‐antibodies and may herald the onset of NMOSD 39. Other endocrinopathies and disorders of water balance, which are associated with NMOSD, can also be attributable to hypothalamic involvement.

Some brainstem symptoms, such as intractable hiccups, nausea or vomiting persisting for more than 2 days in association with medullary aqueductal lesions, are characteristic of NMOSD and can be found in about a third of these patients 86, 121. These brainstem symptoms can also be the first NMOSD attack, and pathological lesions compatible with NMOSD in the area postrema are described in these patients 2, 107. Various oculomotor symptoms are also relatively frequent, while other brainstem manifestations are much less common.

Ethnic and genetic factors

NMO/NMOSD has been described in various ethnic groups 1, 4, 18, 21, 80. However, the proportion of NMO/NMOSD in non‐Caucasians is usually higher because of the relatively low prevalence of MS in these populations 80, 116. A recent study with ancestry‐informative markers performed in a multiethnic Brazilian population suggested that patients with NMO/NMOSD had more African antecedents than those with MS, although European ancestry was predominant in both groups 16.

There are reported cases of familial NMO/NMOSD 75, but the frequency is much less than familial MS. Moreover, most of them consist of just two cases in one family, with each patient demonstrating a different AQP4 antibody‐serological status. The predisposing genetic factors in NMO/NMOSD are currently unknown, and genetic studies in families with NMO failed to identify a single susceptibility locus, suggesting a complex gene interaction leading to autoimmune disease 75. Some HLA‐DRB1 (human leukocyte antigen DR beta 1) alleles were more commonly found in NMO patients than those with MS 5, 15, 40, 76, but a genome‐wide association study is required to determine the susceptibility locus more systematically in NMOSD patients.

Pregnancy

NMOSD attacks do not increase during pregnancy, but a remarkable increase occurs 3–6 months after delivery 12, 58. The hormonal influences on the disease activity after delivery are yet to be clarified, but breastfeeding does not change the number of attacks. Pregnancy is a relevant issue in the management of patients with NMO/NMOSD, as the majority (90%) of NMOSD patients with AQP4‐antibodies are female. Despite potential risks to the fetus, using corticosteroid or immunosuppressive drugs in pregnant women with NMO/NMOSD may be considered to prevent relapse.

Seronegative NMO

NMO is associated with AQP4‐antibodies in the majority of patients. The recent advances in the assays to detect AQP4‐antibodies using cell‐based assays with human AQP4 M23‐isoform transfected living cells 73, 113, 130 indicate that those assays are far more sensitive than the original mouse brain tissue‐based immunofluorescence assay 66 and enzyme linked immunosorbent assay. However, about 10%–50% of those patients remain seronegative in serum samples collected on multiple occasions, despite the use of the most sensitive assay currently available. The timing of blood sampling is also important to confirm the positivity for AQP4‐antibodies, as patients under immunosuppressive therapy may have antibody levels below the sensibility of the assays.

The studies that compared the clinical characteristics of AQP4‐antibody seropositive and seronegative patients with definite NMO showed that the seronegative ones have no female preponderance, a higher proportion of Caucasian ethnicity, monophasic disease, simultaneous ON and myelitis at onset and less severe visual impairment 32, 46, 51, 73. In experimental studies, the IgG purified from AQP4‐antibody seronegative patients did not reproduce NMO‐like pathology with astrocytic destruction as seen with the infusion of the IgG purified from AQP4‐antibody seropositive patients 14. In addition, the patients without AQP4‐antibodies may be a heterogeneous group, and a subgroup of patients may be associated with other autoantibodies, such as antibodies against myelin oligodendrocyte glycoprotein 60. Therefore, it is not clear if AQP4‐seronegative NMO patients have the same autoimmune astrocytopathic disease as seropositive patients 32, 33.

MRI, Neuro‐Ophthalmological and Laboratory Findings in NMO/NMOSD

Orbital MRI

MRI signal abnormalities in the optic nerves are frequently found following ON. The evaluation of the optic nerve in NMO/NMOSD patients with acute ON should be performed with specific orbital studies using acquisitions such as short tau inversion recovery, T2 and T1 with gadolinium to evaluate the lesion extension and the presence of contrast‐enhancing lesions. Although most NMO/NMOSD patients exhibit the characteristic small T2‐weighted hyperintense lesions in the retrobulbar optic nerve similar to those seen in other diseases, ON in NMO/NMOSD may be associated with a long, edematous, gadolinium‐enhanced lesion that thickens and dilates the optic nerve sheaths extending throughout the orbit into the intracranial segment of the optic nerve 20, 69 (Figure 1). These long, edematous lesions are usually associated with severe visual loss and may be found in bilateral ON. Similar MRI changes have been described in chronic relapsing idiopathic optic neuropathy and sarcoidosis 52. Chiasmal and optic tract MRI lesions have also been reported in NMO/NMOSD 24, 109, 110. In chronic stages of ON, MRI may demonstrate unilateral or bilateral optic nerve thinning because of axonal loss. A recent study compared ON in patients diagnosed with MS and those with NMO, based on a scoring system that divided the anterior visual pathway in 10 segments. NMO patients had a higher score in this comparative study, indicating that their lesions were more extensive and involved more frequently the posterior sections of the optic tract including the previously described chiasmal involvement 119.

Figure 1.

Optic neuritis in neuromyelitis optica.  T1‐weighted magnetic resonance imaging of the orbital region showing an extensive lesion with marked thickening and contrast enhancement of the optic nerve (arrows).

Spinal cord MRI

As already mentioned, most NMO/NMOSD patients with acute TM have T2‐hyperintense lesions extending over three or more contiguous vertebral segments on the spinal cord MRI (Figure 2) during an active relapse. However, we have recently demonstrated that not all AQP4 antibody‐seropositive NMO/NMOSD patients with myelitis episodes have LETM 113. Moreover, LETM is also found in other diseases, such as acute disseminated encephalomyelitis (ADEM), arteriovenous fistula and spinal tumors 124. It is also very common that spinal cord lesions in NMO/NMOSD are centrally located in the axial view, preferentially affecting the spinal gray matter 94. The acute spinal lesions are edematous and may be partially contrast enhancing with associated T1 hypointensity. The chronic spinal cord lesions usually remain longitudinally extensive and are atrophic but occasionally the contiguous T2 hyperintense lesion fragments into small or irregular lesions. In contrast, the spinal cord lesions in MS tend to be shorter (less than one vertebral segment in length), smaller and peripherally located.

Figure 2.

Longitudinally extensive myelitis in neuromyelitis optica.  T2‐weighted hyperintense, longitudinally extensive lesion (arrows) from the cervical to the thoracic cord on the magnetic resonance imaging of a patient with recurrent myelitis and aquaporin‐4 antibodies.

Brain MRI

The previous Wingerchuk's diagnostic criteria for definite NMO published in 1999 133 required a normal brain MRI. However, subsequent revision of the diagnostic criteria required a brain MRI not diagnostic for MS after the discovery of AQP4‐antibody 134, as many studies described brain lesions in NMO/NMOSD patients. Roughly half of NMO/NMOSD patients develop brain lesions during the disease course 57, 103, and some of the brain MRI lesions are symptomatic, whereas others are clinically silent. These brain MRI lesions are usually found in areas with high levels of AQP4 expression, such as the lateral, third and fourth ventricles, the hypothalamus, and periaqueductal regions. The lesions may also extend into the cerebral periventricular white matter and to the cerebellar peduncles 104. Although some brain MRI lesions can be confounded with MS lesions, a recent British study suggested that the combined presence of “at least one lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or the presence of a subcortical U‐fiber lesion; or a Dawson's finger‐type lesion” can favor the diagnosis of MS and help distinguish lesions found in NMO/NMOSD patients with a high predictive value 77.

In some NMO/NMOSD patients with persisting hiccups and nausea, a linear medullary lesion involving the area postrema may be seen on sagittal MRI brainstem images 86. Those brainstem lesions may extend to the upper cervical cord. Such brainstem lesions are very characteristic for NMO/NMOSD, as they are not reported in MS patients. Figure 3 shows a brain MRI with some lesions found in NMO/NMOSD.

Figure 3.

Callosal, brainstem and cervical lesions in neuromyelitis optica spectrum disorder.  T2‐weighted hyperintense lesions (arrows) localized in the corpus callosum, brainstem and upper cervical regions on the magnetic resonance imaging of an aquaporin–4‐antibody seropositive patient with neuromyelitis optica.

Other brain MRI lesions described less frequently in NMO/NMOSD patients include extensive hemispheric lesions with edema sometimes resembling acute demyelinating encephalomyelitis or tumefactive MS; lesions with corticospinal involvement; lesions mimicking posterior reversible encephalopathy syndrome; patchy “cloud‐like” enhancing hemispheric lesions; and corpus callosal lesions with edema and contrast enhancement extending to cerebral hemispheres 41, 57, 71, 95. Many brain MRI lesions in NMO/NMOSD patients may appear edematous in the acute phase, with irregular contrast enhancement and diffusion restriction. They can be the initial manifestation of the disease, and as such, the diagnosis of NMOSD may be challenging. In the chronic stage, these lesions usually shrink and occasionally disappear.

Neuro‐ophthalmological findings

Visual field (VF)

Although studies on VF changes in NMO/NMOSD are scanty, there is evidence that both manual and automated perimetry may demonstrate VF changes in NMO/NMOSD distinct from those seen in MS. In the sole published study using Goldmann perimetry, the authors found a central scotoma in 54% of the NMO/NMOSD and 90% of the MS patients 93. Altitudinal hemianopsia was the most frequent non‐central scotoma defect in NMO/NMOSD. Automated perimetry, on the other hand, showed a more severe diffuse loss of visual sensitivity in NMO/NMOSD than in MS. Sectorial defects were not different in MS and NMOSD 30. VF examination may also disclose bitemporal and homonymous hemianopsias suggesting chiasmal and retrochiasmal involvement in NMO/NMOSD 24, 109, 110.

Optic coherence tomography (OCT)

OCT has recently been introduced to assess axonal loss in demyelinating diseases of the CNS. In isolated idiopathic ON, MS and NMO/NMOSD there is a significant decrease in retinal nerve fiber layer (RNFL) thickness as compared with the non‐ON eyes and controls 26, 27, 31, 83, 100, 108, 114, 125. In NMO, the RNFL thickness may be severely affected (Figure 4), and this correlates with VA, VF, visual‐evoked potential (VEP) amplitude abnormalities and disability. Recently, OCT has proven to be a more sensitive test than VA or VF for monitoring ophthalmological function in NMO/NMOSD and may be helpful in detecting subclinical episodes in patients with a past history of ON 13. OCT may be useful in differentiating between NMO/NMOSD and MS, as it shows more markedly decreased RNFL thickness and macular volume in NMO/NMOSD than in MS 108. Additionally, axonal loss predominates in the macula in MS, and in the RNFL in NMO/NMOSD 92. RNFL thickness in AQP4‐antibody seropositive patients with LETM who have no clinical evidence of ON may also be decreased 92. OCT has also identified microcystic macular edema in 4.7% of patients with MS and 25% with NMO/NMOSD. The retinal changes are associated with more severe axonal loss and visual dysfunction 35, 117.

Figure 4.

Optic coherence tomography in neuromyelitis optica. Spectral‐domain optic coherence tomography shows severe thinning of the retinal nerve fiber layer of both eyes secondary to optic neuritis attacks. I = inferior; N = nasal; NAS = nasal; NI = nasal inferior; NS = nasal superior; OD = right eye; OS = left eye; S = superior; SUP = superior; T = temporal; TI = temporal inferior; TMP = temporal; TS = temporal superior.

VEP

The study of VEP has long been a useful tool for diagnosing optic neuropathies. In demyelinating ON, VEP has been mainly employed to show subclinical involvement of the optic nerve in patients suspected with MS. Characteristically, in demyelinating ON, the evoked responses preferentially show latency rather amplitude changes. In NMO/NMOSD, however, a majority of patients demonstrate absent response as well as decreased amplitude associated with normal latency, suggesting more severe axonal damage 99.

CSF

Pleocytosis (>50 cells/mm³) with neutrophils in the CSF is found in some NMO/NMOSD patients during acute attacks 133. Oligoclonal IgG bands are present in about 10%–30% of these patients, in contrast to MS patients, who have a frequency of ∼90% 97. A useful biomarker of astrocytic destruction in NMO/NMOSD is the level of glial fibrillary acidic protein (GFAP) in the CSF. The GFAP levels in the CSF of NMO/NMOSD patients during the acute phase are remarkably elevated compared with those in MS and ADEM 123. As the GFAP levels return to normal relatively quickly after treatment, the timing of CSF collection is critical to interpret these results.

Coexisting autoimmune diseases and autoantibodies

Coexisting autoimmune diseases and autoantibodies are frequent in patients with NMO/NMOSD, both nonorgan‐specific, such as systemic lupus erythematosus (SLE) or Sjogren syndrome 105, and organ‐specific. for example, myasthenia gravis (MG), thyroid disease, type‐1 diabetes and celiac disease. This distinguishes NMO/NMOSD from MS, in which autoantibodies are detected much less frequently and in lower titers. Antinuclear antibodies (double‐stranded DNA, extractable nuclear antigen) are the most common nonorgan‐specific autoantibodies in NMO/NMOSD. In one study, autoantibody markers of Sjogren's syndrome or SLE were found in 47% of patients with NMO. Of note, however, AQP‐4 antibodies were not found in patients with Sjogren's syndrome or SLEin the absence of clinical features of NMO 105. These cases, previously considered neurological complications of the collagen vascular disorders, may represent the coexistence of NMO. Other organ‐specific autoantibodies, including thyroid peroxidase and thyroglobulin, acetylcholine receptor (AChR) antibodies, and celiac disease‐related antibodies (including deamidated gliadin and tissue transglutaminase), have also been described in some patients with NMO/NMOSD 44, 78, 81. For example, one study noted muscle AChR antibody in 11% of NMO patients, but not in MS patients or healthy controls 79. Clinical and electrophysiological findings consistent with MG were documented in 2% of NMO patients. Of these four patients, three had MG 11–24 years prior to onset of NMO (one had undergone thymectomy), two were NMO‐IgG seronegative, and one had thymic carcinoma. While most reported patients with both MG and NMO have a typical, severe clinical NMO course 45, 65, 79, occasionally patients with MG with AQP4‐antibodies have a mild NMO phenotype with subtle abnormalities on examination or paraclinical testing 127.

Treatment of NMO/NMOSD

The immunological treatment of NMO/NMOSD has two main objectives: (i) control the inflammatory damage during acute attacks; and (ii) avoid further attacks. (Symptomatic therapy for chronic neurologic sequelae of NMOSD is not discussed here.) Oral corticosteroids and immunosuppressant drugs are the current mainstay of long‐term treatment, but the use of monoclonal antibodies is increasing based on emerging knowledge in our understanding of the cellular and molecular mechanisms involved in NMO/NMOSD pathogenesis. However, reports of the effectiveness of currently available treatments are mainly based on uncontrolled, open‐label studies 112. The studies evaluating immunological treatments for NMO/NMOSD patients are summarized in Table 3.

Table 3.

Treatments used in neuromyelitis optica to prevent relapse

Drug (reference)	Number of patients (NMO; NMOSD)	AQP4‐antibody positive cases (n/tested)	Dosing/regimen	Reduction of number of attacks	Stabilization of disability (Expanded Disability Status Scale)
Steroids
Prednisone 128	9 (9; 0)	5/9	5–20 mg/day, very slow tapering below 10 mg/day	Yes	Not available
Immunosuppressive drugs
Azathioprine 9, 25, 72	135 (122; 13)	71/110	2 mg/kg/day	Yes	Yes
Mycophenolate 43	24 (15; 9)	22/23	2 g/day	Yes	Yes
Mitoxantrone 19, 55, 132	76 (49; 27)	43/66	12 mg/m2/month, maximum cumulative dose 120 mg/m2	Yes	Yes
Methotrexate 61, 85	21 (19; 2)	14/14	50 mg intravenous weekly or 7.5–25 mg/week orally	Yes	Yes
Cyclosporine 47	9 (6; 3)	9/9	150 mg/day	Yes	Yes
Cyclophosphamide 10, 136	11 (8; 3)	5/7	500–700 mg/m2 monthly up to 6–12 intravenous infusions	Doubtful	Doubtful
Monoclonal antibodies
Rituximab 8, 42, 54, 101	88 (78; 10)	67/81	375 mg/m2/week for 4 weeks or 2× 1000 mg with a 2‐week interval; reinfusion when B cells are detected in the peripheral blood	Yes	Yes
Eculizumab 106	14 (8; 6)	14/14	600 mg intravenous weekly for 4 weeks, 900 mg in the fifth week and every 2 weeks for 48 weeks	Yes	Yes
Tocilizumab 3, 6, 53	5 (4; 1)	5/5	6–8 mg/kg every 4–6 weeks	Yes	Yes

Treatment of acute attacks

High‐dose intravenous methylprednisolone (HIMP) and plasmapheresis are commonly used in the treatment of acute NMO/NMOSD attacks. Early initiation of treatment seems to lead to a better prognosis on visual and motor disability 49, 96.The efficacy of corticosteroids in neuroimmunological diseases has been reported in meta‐analysis reviews 17, but their use for NMO/NMOSD patients is mainly based on case series and anecdotal experience treating other CNS autoimmune diseases. The mechanism of action of corticosteroids is not completely understood, but HIMP promotes a reduction of inflammation, suppression of polymorphonuclear leukocyte migration to inflamed tissues, induction of leukocyte apoptosis and reversion of increased capillary permeability through genomic and non‐genomic effects 36. Repeated HIMP courses may be required to control NMO/NMOSD attacks and the interval to start HIMP also has some influence in the recovery. The early use of HIMP following ON attacks reduced the loss of the RNFL thickness after ON attacks in NMO/NMOSD 96.

Plasma exchange (PLEX) is a second‐line therapy for acute attacks when HIMP is not effective, although it does not prevent further attacks. The guidelines from the American Academy of Neurology and from the American Society for Apheresis recommend the use of PLEX for treatment of severe CNS autoimmune diseases including NMO/NMOSD 23, 120. The rationale for PLEX use in NMO/NMOSD is evident, as a significant proportion of NMOSD patients are AQP4‐antibody seropositive and pathological studies of NMO patients show immunoglobulin and activated complement deposition in active lesions 70, 88. PLEX removes pathogenic antibodies, complement components, pro‐inflammatory cytokines and other humoral immune products from the systemic circulation. The quick removal of these components can help interrupt the progression of tissue damage 137. Clinical response may be observed after only a few PLEX 129, but four to seven sessions are usually required to achieve sufficient antibody removal 50. The initiation of immunosuppressive therapy following PLEX therapy is usually required to block the production of new antibodies. Intermittent PLEX may be used in very selected patients who have failed multiple other immunosuppressive agents, but only a small open‐label study has been published with this strategy 89.

Prevention of relapse

Oral corticosteroids

Oral corticosteroids, immunosuppressive agents, and more recently monoclonal antibodies are commonly used to prevent further NMO/NMOSD attacks. NMO patients on long‐term corticosteroid monotherapy have fewer attacks 128. However, some NMO patients are refractory to corticosteroid treatment, and the side effects may limit their continuous use in other patients.

Immunosuppressive drugs

Immunosuppressive agents such as azathioprine, mycophenolate mofetil and mitoxantrone can be used alone or in combination with low‐dose oral corticosteroids 19, 43, 72. Azathioprine is an oral drug that interferes in the DNA (purine) synthesis that controls the proliferation of cells such as lymphocytes. It is relatively well tolerated, but patients with intermediate or low activity of thiopurine methyltransferase do not tolerate the drug well and are at risk for life‐threatening myelo‐suppression. The immunosuppressive effect of azathioprine usually begins after 3–6 months of therapy, and therapeutic efficacy is seen in cases with a change in the mean corpuscular volume of erythrocytes >5 25.

Mycophenolate mofetil has a selective cytostatic effect on T and B lymphocytes. It inhibits de novo guanosine nucleotide synthesis. Mycophenolate has a better safety tolerance profile than azathioprine and has been used on MG, SLE and, more recently, in NMO. A retrospective study of 24 patients treated with mycophenolate, demonstrated a significant reduction in number of attacks compared with the period before the treatment, the majority patients had a stabilized or improved disability 43.

Mitoxantrone hydrochloride is an antineoplastic agent and has been also used for aggressive forms of MS. However, because of its toxicity profile, the drug requires routine monitoring for cardiac‐ejection fraction as well as liver and kidney function 37. A recent study indicated that mitoxantrone combined with methylprednisolone significantly reduced the number of relapses and reduced Expanded Disability Status Scale disability after 1 year of treatment. However, one patient developed acute myeloid leukemia after almost 5 years 19.

Cyclophosphamide is an alkylating agent that prevents cell division by cross‐linking DNA strands and decreasing DNA synthesis. It is a prodrug that needs to be metabolized to active metabolites in the liver. Cyclophosphamide has been used in the treatment of many neoplastic and autoimmune diseases, but its therapeutic efficacy in NMO is limited to case reports and small series with somewhat conflicting results 10, 11, 91, 136.

Monoclonal antibodies

Rituximab, an anti‐CD20 monoclonal antibody to deplete B‐cells, is also used as an alternative to nonspecific immunosuppressive agents 42, 54. The reduction of NMO attacks is significant in the majority of patients; however, patients may have increased risk of attacks in the first few weeks after rituximab infusions because of a transient increase of AQP4‐antibody levels and B‐cell activation factor 98. The therapeutic effects of rituximab are probably secondary to B‐cell depletion from the systemic circulation rather than a direct effect on AQP4‐antibody production. CD19+ AQP4 antibody‐producing plasmablasts are CD20‐negative 22; therefore, rituximab has no effect on this cell population. This may explain why some NMO patients continue to relapse while on this agent.

Activated complement deposition is demonstrated in active NMO lesions 70, 87, and complement fragments, such as C5a, increase in the CSF of NMO patients during attacks 63. These findings suggest that blocking complement‐activation pathways may be beneficial in NMO. Eculizumab, a humanized monoclonal IgG antibody that binds to complement protein C5 to prevent cleavage into C5a and C5b, is currently approved for the treatment of paroxysmal nocturnal hemoglobinuria. It was used in a recently published pilot clinical trial with 14 NMO patients 106 and demonstrated a significantly fewer relapses in patients with highly active seropositive NMO who failed to respond to other immunosuppressive agents or rituximab. After 1 year of eculizumab treatment, 85.7% (12/14) of the patients were relapse‐free, and only two had mild attacks. Although eculizumab infusions were well tolerated, one patient had meningococcal sepsis and sterile meningitis with full recovery after treatment. However, in the year following drug withdrawal, the median number of attacks increased once again, indicating that the disease activity returns after interruption of the infusions.

Interleukin‐6 (IL‐6) is a pleiotropic cytokine that is an important regulator of the T helper 17/T regulatory pathway. It is produced by a number of cell types including monocytes, T‐cells and astrocytes. IL‐6 is elevated in the sera and CSF of NMO patients during attacks 126. These data suggest that IL‐6 may contribute to NMO relapses, and drugs to block IL‐6 signaling could be beneficial. Tocilizumab, a monoclonal antibody that binds to IL‐6 receptor, was used to treat NMO patients refractory to other treatments, with promising results in a few case reports 3, 53. Another study indicated that IL‐6 may promote the survival of AQP4–antibody‐producing plasmablasts from NMO patients cultured in vitro, but this effect could be neutralized by tocilizumab 22. Further studies with a larger number of patients are warranted to confirm the potential therapeutic efficacy of this agent.

Some disease‐modifying drugs for MS are not effective in NMO

It is important to emphasize that some treatments widely used in MS, such as interferon‐beta, fingolimod and natalizumab, do not appear effective in NMO and/or may even exacerbate the disease 62, 84, 115. Patients may experience the same or increased number of attacks, and some patients may have very severe attacks following the introduction of these disease‐modifying drugs typically used for MS. In a case report, a patient with brain lesions and myelitis received natalizumab with the presumptive diagnosis of MS and had acute cerebral lesions biopsied before the confirmation of seropositivity to AQP4‐antibodies. Neuropathological examination of the biopsied brain of this patient showed massive astrocyte injury with activated complement deposition, inflammatory‐cell infiltration and macrophage‐containing GFAP‐ and AQP4‐positive materials compatible with acute pathology of NMOSD 7.

Conclusions and Outlook

Clinical and basic research on the AQP4 antibody have not only confirmed that the clinical picture of NMO described by Devic and others is a distinct clinical entity, but has also expanded the spectrum of NMO. In addition to detailed neurological findings, imaging technologies like MRI and OCT, and various laboratory examinations, including AQP4 antibody testing, provide useful information for the early diagnosis of NMO/NMOSD and its unique pathology. The International Panel on Diagnosis of NMO is currently establishing new diagnostic criteria for NMOSD incorporating AQP4‐antibody serological status. Despite the use of highly sensitive AQP4 antibody tests, some patients consistently test seronegative for AQP4 antibody, and those seronegative NMO cases are rigorously being analyzed to determine whether they are clinically and pathogenetically different from seropositive cases. However, with the continued improvement in antibody‐testing assays, the number of truly seronegative NMO cases continues to diminish.

Although currently available immunosuppressive drugs appear effective in hastening recovery from acute attacks and reducing relapses in NMO/NMOSD, the identification of effective and safe drugs that more selectively target molecules critically important in NMO pathogenesis are urgently needed. At this point, the scientific evidence supporting the use of various therapies for NMO are limited and predominantly derived from case series, retrospective observational studies, and phase I clinical trials. However, given the poor prognosis in untreated NMO patients, it remains to be determined whether conducting a double‐blind, placebo‐controlled trial is ethically acceptable in this population. Are data in trials with active comparators sufficient to provide support of therapeutic efficacy and safety in NMO? Active discussions concerning these issues are ongoing.