Neuromyelitis optica (NMO) is a demyelinating, organ-specific, autoimmune disease that preferentially targets the optic nerve and spinal cord. The clinical syndrome was first described by Devic and Gault in 1894, and was considered a variant of multiple sclerosis (MS). A resurgence of interest has followed the recent identification of a disease-specific autoantibody, NMO-IgG, and its target antigen, the aquaporin 4 (AQP-4) receptor (1). NMO is classically defined by the presence of both optic neuritis (ON) and longitudinal myelitis (LM), with contiguous spinal cord involvement spanning 3 or more vertebrae. The clinical course is characterized by disease relapse and significant morbidity in more than 90% of cases (2). Research suggests that by 5 years, more than one-half of the patients will be unable to ambulate without assistance and/or be functionally blind (3). Formal diagnosis requires the presence of transverse myelitis (TM), ON, and 2 of 3 supporting criteria (Figure 1), one of which is the serum NMO-IgG antibody. The sensitivity of this assay ranges from 60–70%, with a specificity of >90% (1, 4).
Given the potential for permanent disability following isolated attacks of myelitis or ON, efforts have been made to identify individuals at high risk for disease relapse or progression to full-spectrum NMO. Researchers have shown that patients with a single episode of LM in the setting of NMO-IgG positivity have a 50% risk of myelitis relapse or conversion to full-spectrum NMO over the subsequent 12 months (5). Similar data have shown an increased risk for myelitis in NMO-IgG–positive patients that experience recurrent ON (6). Recognition that incomplete forms of NMO are at an increased risk for progression based on the presence of antibody positivity has resulted in the designation of NMO spectrum disorders (NMOSD) (Figure 1).
An association between the NMO-IgG antibody and LM in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) has been reported in the literature (7, 8), and has spurred interest in NMO/NMOSD from the field of rheumatology. Herein we describe a cohort of patients with autoimmune myelitis and discuss the implications of coexistent NMO/NMOSD for subsequent clinical management. Our objective was to identify the presence of NMOSD in patients with acute myelitis and suspected connective tissue disease (CTD), and to discuss the utility of this distinction in establishing a diagnostic and therapeutic plan.
Seventeen patients with acute myelitis were identified through clinical records associated with a single physician (SGW) in the Rheumatology Clinic of the University of Colorado Denver and were prospectively followed. Clinical followup extended from July 1998 through February 2010. The diagnosis of myelitis was based on fulfillment of criteria established by the Transverse Myelitis Consortium Working Group (9) and/or diagnosis by a board-certified neurologist. LM was defined as T2 enhancement on spinal magnetic resonance imaging (MRI) of ≥3 contiguous vertebral segments, as shown in Figure 2. Inflammatory myelitis not meeting the criteria for LM was classified as TM.
ON, when present, was diagnosed by a board-certified neurologist or neuro-ophthalmologist. Relapse of either ON or myelitis was defined as new-onset neurologic impairment as determined by a board-certified neurologist and supported by MRI or cerebrospinal fluid (CSF) analysis, when available. The primary diagnoses of SLE and SS were based on fulfillment of the 1997 revised American College of Rheumatology classification criteria and the American-European Consensus Group criteria, respectively (10, 11). All patients with suspected SS (primary or overlap) were offered a minor salivary gland (lip) biopsy, as were patients with SSA antibody positivity. The diagnosis of NMO was based on revised clinical criteria (12) (Figure 1). The designation NMOSD was applied to cases thought to be at high risk for progression to NMO, as described by Wingerchuk et al (13) (Figure 1). Serum NMO-IgG antibody testing was performed by Mayo Medical Laboratories at the Mayo Clinic (Rochester, Minnesota). All of the samples were tested using an indirect immunofluorescence assay as previously described (1). Statistical comparisons were calculated using Fisher's exact testing; all analyses were performed using SAS, version 9.2.
Clinical findings and serologic profiles of the 17 patients can be found in Table 1. The mean age at onset of neurologic presentation (myelitis and/or ON) was 38.3 years (range 16.2–72.0 years), and 15 of 17 patients were female. During the course of their illness, 6 patients were diagnosed with primary SS, 5 with SLE, 2 with overlap SLE/SS, 2 with overlap MS/SS, and 2 with NMO in the absence of a concurrent systemic autoimmune disease. Both patients with NMO alone (patients 16 and 17) were positive for anti-SSA antibody; however, Schirmer's test was negative in both cases, in addition to a negative lip biopsy sample in patient 16.
Table 1. Serologic profiles and clinical characteristics of patients referred to a single rheumatology practice for autoimmune myelitis*
aPL include lupus anticoagulant; anticardiolipin IgG, IgM, or IgA; and anti–β2-glycoprotein IgG, IgM, or IgA. Positivity reflects positive tests on at least 2 separate occasions, separated by 12 weeks or longer.
Positive lip biopsy determined by pathologist interpretation, including a focus score of ≥1 when mentioned in the report. All patients with suspected SS (primary or overlap) were offered a biopsy; not done (ND) reflects patient refusal. All patients with a positive Schirmer's test and/or SSA antibody positivity were offered a biopsy as well.
LM was seen in both SS (3 of 6 patients) and SLE (2 of 5 patients). ON, however, was more prevalent in primary SS compared to SLE alone (83% versus 0%; P = 0.02). NMO-IgG positivity was seen in 4 of the 6 patients with primary SS; no patient with SLE alone was positive (67% versus 0%; P = 0.06). Eight (53%) of 15 patients diagnosed with a CTD met criteria for NMOSD. Of these 8 cases, 3 had an established diagnosis of CTD prior to the development of myelitis (4, 17, and 59 years following CTD diagnosis), 4 were diagnosed after myelitis (2.5, 4, 5, and 8 years later), and 1 was diagnosed concurrently. Four of 6 patients with primary SS fulfilled the criteria for full-spectrum NMO. In contrast, only patient 12 met the full criteria for NMO among SLE patients, and she was known to have concurrent SS. Full-spectrum NMO was not diagnosed in any of the 5 patients with SLE alone. Additionally, 2 patients had full-spectrum NMO without evidence of coexistent CTD.
Long-term data were available for 15 patients, with a median duration of followup after initial neurologic presentation of 9.1 years (range 2.3–34.6 years). Patients 2 and 17 were not included based on a lack of clinical followup at the time of manuscript preparation. There were 24 total relapses of myelitis and/or ON in 9 of the patients, with a mean time to relapse of 2.82 years (range 4–82 months). Six of the 15 patients were positive for the NMO-IgG antibody, all of whom experienced subsequent relapse; in contrast, only 3 of 9 patients that were NMO-IgG negative had disease relapse (P = 0.03). Furthermore, patients who were positive for the NMO-IgG antibody experienced a total of 20 relapses (51 patient-years of followup) compared to 4 total relapses among NMO-IgG–negative patients (114.5 patient-years of followup).
Long-term treatment data for non-MS inflammatory myelitis were available in 13 patients (patients 14 and 15 were treated for MS). High-dose corticosteroids were used as monotherapy in 6 patients at the time of the initial neurologic event, with no intervening immunosuppression until the time of subsequent relapse; 5 of these patients received initial therapy from outside providers before referral to our center. Of the 6 patients, 4 required the use of a wheelchair at the time of the last evaluation, 1 has evidence of hyperreflexia and mild clonus on examination, and 1 patient has no functional limitations or signs of cord involvement on examination. The other 7 patients were treated with an induction regimen of high-dose steroids in conjunction with cyclophosphamide (n = 4), combination cyclophosphamide and rituximab (n = 1), plasmapheresis (n = 1), and azathioprine (n = 1). All 7 received maintenance immunosuppression with azathioprine, mycophenolate, or rituximab. Of these 7 patients, 4 have mild functional impairments (unsteady tandem gait), 1 has been left with fixed left lower extremity weakness, 1 has intermittent urinary retention and fecal incontinence, and 1 required the use of a wheelchair after the sole initial insult (now deceased).
Spinal cord involvement is an infrequent yet potentially devastating manifestation of systemic autoimmune disease. Given the potential for long-term functional disability, prompt diagnosis and treatment is imperative. The propensity for overlap NMO/NMOSD adds a layer of complexity to this evaluation. The case series described in this report adds important data to the current literature regarding patients with coexistent CTD and NMO/NMOSD, and highlights the importance of formulating an accurate diagnostic and therapeutic plan. We will begin by describing a review of the literature in order to identify previously described cases of overlap CTD and NMO. We will then review the optimal evaluation of patients with inflammatory myelitis and suspected NMO/NMOSD, as well as current treatment recommendations for these disorders.
A review of the literature was performed in order to identify other relevant case reports or series involving patients with SS or SLE and coexistent full-spectrum NMO. A PubMed search was performed utilizing the following key words: NMO, Devic's, systemic autoimmune disease, Sjogren's syndrome, and systemic lupus erythematosus (up to March 2011). In addition, the reference sections of these articles were searched. Articles of interest were limited to English and descriptions of adult cases. A total of 21 cases of SS and full-spectrum NMO were identified in addition to 14 cases of SLE/NMO (7, 8, 14–30). Our cohort adds 5 cases of overlap SS/NMO. To our knowledge, this represents the largest collection of such patients described in the literature, matching those described by Kim et al (8). Additional at-risk patients (based on features such as LM or NMO-IgG positivity) were identified but were not included based on insufficient data to diagnose NMO according to the 2006 revised criteria.
Overlapping autoimmune disease is a commonly encountered phenomenon in rheumatology and other medical fields. Celiac disease, type 1 diabetes mellitus, psoriasis, autoimmune thyroid disease, and rheumatic conditions can often exist concurrently in the same individual. This is true for patients with complex central nervous system (CNS) disease as well, as demonstrated by patients in our case series with coexistent CTD alongside NMO. In these patients, it is important to recognize coexistent autoimmune disease and identify which process mediates neurologic damage. Recognition of concurrent NMO/NMOSD in patients with CTD will lead to more accurate diagnoses, and will provide important prognostic information to the clinician and the patient.
The following tools are useful in this evaluation: contrast MRI (of the brain and suspected area of cord involvement), lumbar puncture, visually-evoked potentials in cases of suspected ON, and serum NMO-IgG testing. Brain imaging is an important tool in distinguishing MS from NMO/NMOSD; a brain MRI that is consistent with MS provides strong evidence against the diagnosis of NMO/NMOSD. Gadolinium-enhancing lesions in a periventricular distribution, development of T1 “black holes,” and specific targeting of the corpus callosum are all seen more commonly in patients with MS (31). In contrast, patients with NMO/NMOSD may have normal brain imaging or a pattern of involvement that preferentially targets sites of high AQP-4 expression (such as the hypothalamic region and areas surrounding the third and fourth ventricles) (32). Spinal MRI is invaluable in identifying the presence of myelitis and allowing for classification into TM and LM. LM is a characteristic finding in NMO/NMOSD and its presence may be used to differentiate from myelitis in classic MS, which rarely extends beyond a single vertebral segment (33). Longitudinal cord involvement has been reported in SLE and SS as well (7, 8, 14, 17, 22, 23, 30, 34, 35). These reports have identified a high prevalence of the NMO-IgG antibody and additional features consistent with concurrent NMO/NMOSD in these patients.
Lumbar puncture (LP) may serve as an additional tool to help differentiate NMO from MS: 70% of cases of NMO are negative for oligoclonal bands (OCBs), in contrast to MS, where >95% are typically positive (17, 36). In our cohort, 12 patients had LP data, 10 of which had testing for OCBs. Four patients had evidence of increased CSF OCBs: 1 patient with SS/NMOSD (4 bands), 1 with NMO alone (2 bands), and the 2 with MS (13 and 15 bands). Finally, testing for serum NMO-IgG is recommended in all cases of suspected NMO/NMOSD, given its high specificity for disease and therefore the ability to differentiate from MS as well as CTD without high-risk features (LM or recurrent ON) (1, 37, 38). The recognition of these features in subjects with CTD and inflammatory myelitis is crucial, as patients with concurrent NMO have a high risk of disease relapse, as do some patients with NMO-IgG positivity (5, 6). Therefore, recognition of NMO/NMOSD in patients with established CTD will allow clinicians to provide more accurate prognostic information and may influence the duration of therapy following the acute attack (see below).
In our case series, the presence of ON, NMO-IgG, and full-spectrum NMO occurred only in patients with SS. The only SLE patient in our series with these characteristics had concurrent SS (patient 12). These findings raise the question of whether an association exists between NMO and the CNS disease seen in SS. The small number of patients in our series precludes firm conclusions; however, additional studies have reported a similar association (8, 30, 39). Definitive evidence for an association between NMO and SS has not yet been established, and mechanistic studies are needed to explain the potential connection between the 2 diseases. A recent study examined the prevalence of lymphocytic infiltration of labial salivary glands in patients with NMO or NMOSD without known CTD (21). Sixteen (80%) of 20 patients had a positive lip biopsy sample (focus score ≥1), but only 3 fulfilled established criteria for the diagnosis of SS. It is uncertain if the inflammation seen on the lip biopsy sample stems from nonspecific immune activation or a shared antigen target between the CNS and salivary gland. It is of interest that AQP proteins are found in both of these areas (AQP-5 in salivary gland tissue and AQP-4 in CNS tissue). The AQP family of proteins shares significant structural homology, with approximately 50% of protein sequences shared between AQP-4 and AQP-5 (21). Therefore, epitope spreading represents a potential hypothesis to explain the development of autoimmunity against diverse organ systems in the subset of patients with concurrent SS and NMO/NMOSD. Further research in this area is warranted.
To our knowledge, there are no studies directly evaluating optimal therapy in acute myelitis or ON secondary to NMO. Corticosteroid regimens established for MS and idiopathic ON have been used, and current recommendations suggest high-dosage regimens (intravenous methylprednisolone 1,000 mg/day for 3–5 days) as first-line therapy (2). Patients with steroid-resistant or rapidly progressive disease may be treated additionally with plasmapheresis (40). Research suggests that NMO is a humorally mediated disease, prompting some experts to advocate for the early use of B cell–depleting therapies as the standard of care in patients with NMO (7). Rituximab is used primarily in resistant disease; however, the selective targeting of B cells and their subsequent rapid depletion highlight a potential role as an initial agent in severe cases. In addition, the use of cyclophosphamide as an induction agent has been described in case reports of NMO based on its ability to deplete B cells and its effectiveness in SLE- and SS-related myelitis.
Maintenance therapy with immunosuppressive medications is recommended for relapse prevention. Some experts advocate treatment for at least 5 years in NMO-IgG–positive patients following their first episode of LM (2). In those with relapsing disease, lifelong therapy should be considered (2). Prednisone, azathioprine, and mycophenolate mofetil have all been effective in disease stabilization and relapse reduction in uncontrolled trials of NMO (41–43). The use of rituximab has been successful in a case series of patients with resistant disease (44). Notably, we have treated 1 patient (patient 5) with low-dose (500 mg) rituximab every 6 months, which has halted recurrence of myelitis. Stem cell transplant has been described in the literature and represents a final therapeutic option in patients with NMO who continue to relapse despite maximal therapy (14).
The utility of early induction and maintenance therapy can be seen in the disease course of patients with NMO/NMOSD in our series. Of the 15 patients with long-term followup data, 8 met the criteria for NMO/NMOSD (patients 1, 3, 4, 6, 7, 8, 12, and 16). Patients 6, 7, and 8 all received high-dose steroids at the time of the initial presentation as well as induction therapy with cyclophosphamide (patients 6 and 8) and plasmapheresis (patient 7). Each patient was then placed on maintenance immunosuppression with azathioprine or mycophenolate mofetil. These patients had few subsequent relapses (2 relapses; 25.2 patient-years of followup) and experienced minimal long-term functional deficits. In contrast, the remaining patients received corticosteroids at disease onset but no further induction or maintenance therapy prior to subsequent relapse and referral to our clinic. A total of 19 relapses occurred between these patients (47.3 patient-years of followup). With the exception of 1 patient, all have been left with moderate or severe functional limitations, despite later attempts at immunosuppression.
This case series has identified important aspects in the diagnosis and management of NMO/NMOSD in patients with CTD; however, several limitations of our cohort should be discussed. First, this was a single-center study in a tertiary referral center, raising the potential for selection bias of our cases. Patients with primary SS confined to glandular involvement are likely to be managed by primary care providers in our institution, resulting in a high percentage of patients with SS in our clinic with extraglandular features. Furthermore, our clinic's interest in CNS manifestations of rheumatic disease may have resulted in the accumulation of patients with CNS involvement. Therefore, our findings do not likely represent the most common neurologic manifestations of patients with SS, but rather provide important data on a subset of patients with perhaps the most severe forms of CNS disease. In addition, data regarding the timing of CTD diagnosis in relation to neurologic symptoms should be interpreted with caution. Four patients with NMO/NMOSD had neurologic insult prior to a formal diagnosis of CTD. However, it is possible that mild symptoms of CTD at the time of presentation went unnoticed. The risk of unrecognized disease speaks to the importance of rheumatologic evaluation in patients presenting with NMO/NMOSD in order to adequately rule out coexistent CTD. Similarly, in the 2 patients with NMO alone, the presence of antinuclear and SSA antibodies could represent preclinical autoimmunity prior to the onset of symptomatic disease, as described in other autoimmune conditions such as rheumatoid arthritis (45, 46). Continued monitoring of these patients is warranted.
NMO/NMOSD can exist in isolation or in conjunction with systemic CTD. Recognition of these disorders (utilizing tools such as brain and spine MRI, LP, and serum NMO-IgG testing) will result in improved diagnosis and care of patients with inflammatory myelitis. Rheumatologists should also have a prominent role in this evaluation in order to accurately identify or exclude CTD. The presence of the NMO-IgG antibody may suggest the need for prolonged immunosuppressive therapy, although its ability to predict future CNS disease outside the setting of LM or recurrent ON needs further investigation.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Kolfenbach had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Kolfenbach, Horner, Ferucci, West.
Acquisition of data. Kolfenbach, Horner, Ferucci, West.
Analysis and interpretation of data. Kolfenbach, Horner, Ferucci, West.
We thank Lauren Kolfenbach, PA-C, and Dr. Kevin Deane, MD, for their contributions to the editing of this manuscript.