Neuromyelitis Optica Spectrum Disorder and Other Non–Multiple Sclerosis Central Nervous System Inflammatory Diseases

Eoin P. Flanagan, MBBCh p. 815-844 June 2019, Vol.25, No.3 doi: 10.1212/CON.0000000000000742
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Outline

PURPOSE OF REVIEW: This article reviews the clinical features, diagnostic approach, treatment, and prognosis of central nervous system inflammatory diseases that mimic multiple sclerosis (MS), including those defined by recently discovered autoantibody biomarkers.

RECENT FINDINGS: The discovery of autoantibody biomarkers of inflammatory demyelinating diseases of the central nervous system (aquaporin-4 IgG and myelin oligodendrocyte glycoprotein IgG) and the recognition that, despite some overlap, their clinical phenotypes are distinct from MS have revolutionized this field of neurology. These autoantibody biomarkers assist in diagnosis and have improved our understanding of the underlying disease pathogenesis. This has allowed targeted treatments to be translated into clinical trials, three of which are now under way in aquaporin-4 IgG–seropositive neuromyelitis optica (NMO) spectrum disorder.

SUMMARY: Knowledge of the clinical attributes, MRI findings, CSF parameters, and accompanying autoantibody biomarkers can help neurologists distinguish MS from its inflammatory mimics. These antibody biomarkers provide critical diagnostic and prognostic information and guide treatment decisions. Better recognition of the clinical, radiologic, and laboratory features of other inflammatory MS mimics that lack autoantibody biomarkers has allowed us to diagnose these disorders faster and initiate disease-specific treatments more expeditiously.

Address correspondence to Dr Eoin P. Flanagan, Mayo Clinic, Department of Neurology, 200 First St SW, Rochester, MN 55905, flanagan.eoin@mayo.edu.

RELATIONSHIP DISCLOSURE: Dr Flanagan receives research/grant support from MedImmune/Viela Bio.

UNLABELED USE OF PRODUCTS/INVESTIGATIONAL USE DISCLOSURE: Dr Flanagan discusses the unlabeled/investigational use of azathioprine, cetirizine, corticosteroids, eculizumab, inebilizumab, IV immunoglobulin, methotrexate, mycophenolate mofetil, plasma exchange, rituximab, SA237, sivelestat, and tocilizumab for the treatment of neuromyelitis optica spectrum disorder and other non–multiple sclerosis central nervous system inflammatory diseases.

INTRODUCTION

Distinguishing multiple sclerosis (MS) from its central nervous system (CNS) inflammatory disease mimics has important therapeutic and prognostic implications. During the past 2 decades, advances in biomarker discovery and MRI characterization of CNS inflammatory disorders have aided our ability to distinguish MS from its mimics. This article reviews the clinical, laboratory, and radiologic clues that help distinguish MS from other inflammatory CNS disorders and highlights the differences in the treatment approach. The first section focuses on CNS inflammatory demyelinating disease mimics of MS that are accompanied by specific serum biomarkers: aquaporin-4 (AQP4)–IgG and myelin oligodendrocyte glycoprotein (MOG)–IgG. These disorders are summarized and compared to MS in table 12-1. The second section reviews a variety of other nondemyelinating inflammatory CNS diseases that can mimic MS and outlines how to recognize them.

NEUROMYELITIS OPTICA SPECTRUM DISORDERS

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease of the CNS associated with episodes of optic neuritis, transverse myelitis, and other neurologic manifestations that can mimic MS. AQP4-IgG is a serum biomarker found in approximately 80% of patients with this syndrome, and a proportion of the remaining 20% may be accounted for by another serum antibody biomarker, MOG-IgG.

History and Terminology

The eponym Devic disease arose from a 19th century report by Devic and his student Gault describing the autopsy findings of a patient who died from an episode of concurrent transverse myelitis and optic neuritis. Subsequently, the term neuromyelitis optica (NMO) superseded Devic disease to account for its most common clinical manifestations, namely optic neuritis and transverse myelitis. In 2004, the discovery of AQP4-IgG as a specific biomarker of NMO allowed its distinction from MS. This discovery led to the recognition that patients can have more limited forms of the disease (eg, recurrent transverse myelitis without optic neuritis) or symptoms beyond the optic nerve and spinal cord (eg, area postrema syndrome), resulting in the current nosology of NMOSDs. In Asia, it has long been recognized that a CNS demyelinating disease existed that was different than the MS that occurred in whites; it was termed opticospinal MS or Asian MS. It is now widely accepted that these diseases fall under the category of NMOSD. Approximately 20% of patients with NMOSD are seronegative for AQP4-IgG. A proportion of these patients are MOG-IgG seropositive, which can lead to confusion as, in contrast to AQP4-IgG NMOSD (which is a disease of astrocytes), MOG-IgG NMOSD is a disease of oligodendrocytes. This has led to some debate and controversy in the field about whether to use syndrome-based (NMOSD) or biomarker-based (AQP4-IgG, MOG-IgG) diagnostic criteria, although the syndrome-based NMOSD criteria are currently used.

Epidemiology

The prevalence of NMOSD in the United States (Olmsted County, Minnesota) is 3.9 per 100,000, and similar results have been reported in Europe (Denmark) at 4.4 per 100,000 and Asia (Japan) at 4.1 per 100,000. In contrast, the prevalence is higher in populations of African descent (Afro-Caribbeans/African Americans), with a prevalence of 10 per 100,000. It is important to recognize that in regions where MS prevalence is lower (eg, Asia and regions closer to the equator), NMOSD represents a larger proportion of CNS demyelinating diseases and thus should be particularly considered in the differential in those regions. NMOSD is fivefold to tenfold more common in females than males. The disease can occur at any age, including in children and older adults.

Clinical Manifestations

NMOSD has three cardinal manifestations: transverse myelitis, optic neuritis, and area postrema syndrome (table 12-2). The vast majority of patients follow a relapsing course, and patients can have severe attacks resulting in permanent deficits even after long periods of remission. A secondary progressive course is extremely rare with NMOSD, further highlighting its distinction from MS. The transverse myelitis episodes may present with typical findings of myelitis, with numbness, weakness, bowel/bladder impairment, and Lhermitte phenomenon, typically reaching the nadir within days to a few weeks (progression beyond 1 month should raise concern for an alternative cause). In contrast to MS (table 12-1), NMOSD myelitis attacks are often quite disabling (case 12-1).

Tonic spasms (involuntary painful episodes of flexion usually lasting less than 1 minute and triggered by movement) may follow myelitis episodes and respond well to low-dose carbamazepine (case 12-2). They are frequent in NMOSD myelitis (up to 50%) and occur more frequently with NMOSD than with MS. Optic neuritis episodes in NMOSD tend to be more severe, are associated with less recovery, and are more frequently bilateral than in MS.

The third cardinal manifestation in NMOSD is area postrema syndrome, which results in intractable nausea and vomiting with or without hiccups. These may occur as the first manifestation and lead to initial evaluation by a gastroenterologist (case 12-2). The episodes may occur in isolation, have other accompanying brainstem features, or evolve into a myelitis episode.

Occasionally, NMOSD is reported in a paraneoplastic context. A wide variety of other less common clinical manifestations of NMOSD are outlined in table 12-2.

Coexisting Autoimmunity

Systemic autoimmune disorders or their autoantibody biomarkers frequently coexist with NMOSD, including systemic lupus erythematosus, Sjögren syndrome, and antiphospholipid antibody syndrome. The presence of optic neuritis, transverse myelitis, or intractable vomiting in a patient with one of these disorders should prompt AQP4-IgG testing; a positive result (given its specificity of >99%) confirms a coexisting autoimmune neurologic disorder rather than a neurologic manifestation of a rheumatologic disorder. Patients with NMOSD with antiphospholipid antibodies or its syndrome may have an increased risk of clotting disorders, including deep vein thrombosis and miscarriage. Myasthenia gravis also coexists more frequently than expected, with NMOSD usually occurring years to decades after myasthenia diagnosis.

MRI Abnormalities

The MRI lesions in the optic nerve, brain, and spinal cord accompanying AQP4-IgG–seropositive NMOSD have some notable differences from MS that can help guide clinicians on when to order AQP4-IgG testing.

OPTIC NERVE

Optic nerve involvement is often bilateral and typically involves the posterior optic pathway, including the optic chiasm (figures 12-3a and 12-3b), with enhancement usually extending more than half the length of the nerve.

BRAIN

Most patients with NMOSD will not have typical MS lesions, and only 10% to 20% will satisfy Barkhof MS criteria. Typical brain involvement in NMOSD occurs around circumventricular organs where AQP4 expression is highest, with lesions adjacent to the third and fourth ventricles (dorsal medulla/area postrema) most typical (figures 12-3c and 12-3d). Other lesions can be similar to acute disseminated encephalomyelitis (ADEM), have a posterior reversible encephalopathy syndrome (PRES)–like appearance, or involve the internal capsule (figure 12-3E) or corpus callosum diffusely or focally in the splenium in a “bridge-arch” pattern. Pencil-thin linear ependymal enhancement (figure 12-3F), leptomeningeal enhancement, and cloudlike poorly marginated enhancement are also described.

SPINAL CORD LESION LENGTH

Longitudinally extensive transverse myelitis (LETM), with a T2-hyperintense lesion spanning three or more contiguous vertebral segments on MRI, is characteristic of NMOSD (figure 12-1) and found in approximately 85% of patients. LETM is a useful discriminator from MS myelitis, which is very rarely longitudinally extensive in adults; however, up to 14% of MS myelitis events in children can be longitudinally extensive. The timing of imaging can impact the lesion length; imaging early can reveal a short lesion that later evolves into LETM, while imaging late can reveal a discontinuous lesion that is no longer longitudinally extensive.

Myelitis accompanied by short lesions (less than three vertebral segments) occurs in 14% to 15% of AQP4-IgG myelitis attacks, and many of these patients are initially diagnosed as having MS. Features that can help suggest those at highest risk in whom AQP4-IgG should be tested include nonwhite race, coexisting autoimmunity (eg, lupus), tonic spasms, central cord lesion location on axial MRI, absence of typical MS brain lesions, and lack of CSF oligoclonal bands. Despite an initial short myelitis, 90% of subsequent myelitis attacks are associated with an LETM lesion in NMOSD.

OTHER SPINAL CORD MRI FEATURES

Other reported spinal cord lesion features include bright spotty (syrinxlike) regions within the T2 lesion, central lesion T1 hypointensity, and a long segment of cord atrophy. Lesion enhancement after gadolinium administration is usually patchy, but ringlike or lens-shaped enhancement occurs in one-third of patients (figures 12-2d and 12-2e). Extension of cervical lesions to the dorsal medulla/area postrema is suggestive of but not specific for NMOSD and can be seen with other myelopathies.

Cerebrospinal Fluid Findings

The typical CSF findings in NMOSD are summarized in table 12-1.

Aquaporin-4–IgG Testing

AQP4-IgG antibody testing is available commercially and is best tested in blood, as CSF testing is less sensitive. Assay techniques have improved over time, and cell-based assays are now recommended (using fluorescence-activated cell sorting or direct immunofluorescence); they yield a sensitivity of 75% to 80% and specificity of greater than 99%. The older-generation enzyme-linked immunosorbent assay (ELISA) technique is less sensitive and has a fivefold higher risk of false positives, particularly when low titer, and additional diagnostic scrutiny is needed in such patients, especially if NMOSD-atypical clinical manifestations or MRI findings are detected.

Diagnostic Criteria

Updated diagnostic criteria for NMOSD were published by the International Panel for NMO Diagnosis in 2015 (table 12-3). The criteria stratify the diagnosis by those with AQP4-IgG and those without AQP4-IgG (including those for whom testing is unavailable). The criteria use core clinical characteristics focusing on the three cardinal manifestations of optic neuritis, myelitis, and an area postrema syndrome, in addition to less common manifestations of other brainstem attacks, diencephalic episodes, and cerebral episodes. The presence of one of these core clinical characteristics in addition to AQP4-IgG seropositivity and exclusion of other etiologies allows the diagnosis of NMOSD with AQP4-IgG to be made. The criteria for patients who areAQP4-IgG seronegative are more stringent, requiring additional characteristic radiologic features be present to help avoid misdiagnosis.

Aquaporin-4 IgG–Seronegative Neuromyelitis Optica Spectrum Disorder

Approximately 20% to 25% of patients with NMOSD are AQP4-IgG seronegative. Up to 25% of patients with seronegative NMOSD will have antibodies to MOG-IgG, as discussed below. The treatment approach to AQP4-IgG–seronegative NMOSD is similar to AQP4-IgG–seropositive NMOSD.

Pathogenesis and Pathology

AQP4-IgG binds to AQP4, which is located on the end-feet of astrocytes, initiating a cascade of immune-mediated inflammation resulting in secondary demyelination.

A full discussion of the pathogenesis of NMOSD is beyond the scope of this article but has been reviewed previously. Biopsy and autopsy studies of patients with NMOSD show that lesions are associated with loss of myelin, infiltration of inflammatory cells (macrophages, T cells and B cells, neutrophils, eosinophils), and axonal and astrocyte loss. A rim-and-rosette pattern of immunoglobulin deposition colocalized with complement is also seen. AQP4 immunostaining is lost within NMOSD lesions, and cortical lesions are not found, helping distinguish it from MS, in which AQP4 immunostaining is preserved or increased and cortical lesions are common.

Treatment

Treatment of NMOSD is divided into acute attack treatment and maintenance (attack-prevention) treatment.

ATTACK TREATMENT

High-dose corticosteroids (1000 mg IV methylprednisolone daily for 5 days) are used initially. The use of plasma exchange for five to seven exchanges for severe, corticosteroid-refractory CNS inflammatory demyelinating attacks is supported by data from a prospective randomized sham-controlled crossover trial. The author recommends a low threshold to use plasma exchange in those not improved or with incomplete recovery after steroids (case 12-1), and a 2016 evaluation of more than 800 NMOSD attacks highlighted its benefit.

MAINTENANCE THERAPY

The importance of maintenance attack-prevention immunotherapy in NMOSD is evidenced by the increasing recognition of this disease as a relapsing disorder, compared to initial descriptions as a monophasic disease. Despite the lack of completed randomized controlled trials in NMOSD, preventive treatment is strongly recommended in all patients. This approach is supported by the severity of attacks and incomplete recovery, leading to a risk of accumulating disability with each attack, which differs from MS attacks (table 12-1). The goals of treatment are to prevent relapses while limiting side effects. The three most commonly used medications are azathioprine, mycophenolate mofetil, and rituximab; some observational data have suggested that azathioprine may not be as effective as rituximab and mycophenolate mofetil. Choice of treatment may depend on local availability, cost, patient preference, and duration of concomitant oral steroids needed while the immunosuppressant takes effect. The dosage recommendations for these medications are outlined in table 12-4. Because of its lower cost and more widespread availability, methotrexate has also been used. Consideration for switching maintenance immunotherapy arises if disease breakthrough occurs or if intolerable severe side effects occur.

TREATMENT TRENDS IN NEUROMYELITIS OPTICA SPECTRUM DISORDER

AQP4-IgG is an IgG1 and thus can activate complement, which appears to play a role in promoting the cascade of immune-mediated inflammation that follows AQP4-IgG binding; it is also notable that complement deposition is evident pathologically. The C5 complement inhibitor eculizumab showed possible efficacy for attack prevention in a phase 2 open-label pilot study and is currently undergoing a phase 3 randomized clinical trial. After B-cell activation in lymph nodes, B cells (CD20+, CD19+) differentiate into plasmablasts (CD19+, CD20–) and plasma cells (CD19–, CD20–); the latter two B-cell subsets account for the majority of antibody production. IL-6 is necessary for plasmablast survival and appeared to be important in experimental studies of NMOSD pathogenesis. Thus, there has been interest in treatments targeting CD19+ plasmablasts and IL-6. A randomized placebo-controlled study of inebilizumab (previously known as MEDI-551), a monoclonal antibody targeting CD19 in attack prevention, is currently under way. Tocilizumab is an antibody targeting IL-6 that has been repurposed from its use in rheumatoid arthritis; retrospective studies suggest it may be a useful treatment in NMOSD, with reductions in neuropathic pain a novel added benefit. Another IL-6 receptor monoclonal antibody, SA237, is currently being studied in a randomized controlled clinical trial. Other approaches currently in development include AQP4 blocking antibodies in animal models, inhibitors of neutrophils (sivelestat) or eosinophils (cetirizine), and studies of immune tolerance.

TREATMENT RISKS

Long-term immunosuppression is currently recommended in all patients with NMOSD, but the long-term risks have yet to be established. A single case of progressive multifocal leukoencephalopathy in NMOSD treated with azathioprine has thus far been reported. Opportunistic retinal infections (toxoplasmosis, cytomegalovirus) from immunosuppression in NMOSD can mimic optic neuritis attacks. Further studies are needed to determine whether, in some patients, maintenance immunotherapy could be discontinued safely and thus reduce the risks associated with long-term immunosuppression.

MYELIN OLIGODENDROCYTE GLYCOPROTEIN ANTIBODY DISEASE

MOG has been of interest to researchers for decades given its location on the surface of oligodendrocytes, making it a potential target for pathogenic antibodies. Initial studies suggested that MOG-IgG was a biomarker of MS, but these studies were hampered by older-generation techniques (ELISA, Western blot) and failure to use MOG in its human conformational form. With the use of cell-based assays transfected with MOG in its conformational form, the antibody has been shown to be a specific biomarker of a spectrum of CNS inflammatory demyelinating disease distinct from MS and AQP4-IgG–seropositive NMOSD. The three disorders are compared in table 12-1.

Nomenclature

No single term is widely accepted to describe this disease. Most recently, the term MOG-antibody (MOG-IgG) disease has been suggested; this term is used in this article, although other terms used include MOG/MOG-IgG paired with the relevant syndrome (encephalomyelitis, myelitis, NMOSD, optic neuritis, and demyelinating disease).

Demographics

In contrast to AQP4-IgG–seropositive NMOSD and MS, which have a female predominance, the sex distribution with MOG-IgG disease appears to be more equal, although a slight female predominance was reported in the largest clinical series to date. MOG-IgG disease appears to have a particular predilection for children and young adults, but any age can be impacted. The incidence and prevalence of this disease have not yet been well elucidated, and population-based epidemiologic studies are lacking. In the only population-based study of autoimmune encephalitis including ADEM, MOG-IgG was the most frequent antibody detected.

Clinical Features

Preceding prodromal symptoms are commonly encountered and can include fever, rhinorrhea, malaise, and cough, which can sometimes lead to the suspicion of an infectious rather than immune-mediated disorder. The major clinical manifestations include optic neuritis, ADEM, NMOSD (seronegative for AQP4-IgG), transverse myelitis, and brainstem demyelinating episodes. The clinical presentation is in the form of attacks that are subacute in onset similar to other CNS inflammatory demyelinating diseases, with optic neuritis being the most common and accounting for the majority of relapses. The clinical presentation and radiologic appearance of MOG-IgG myelitis may mimic that of the acute flaccid myelitis associated with enterovirus infections. The episodes tend to be more severe than with MS (case 12-3) but have better recovery than AQP4-IgG–seropositive NMOSD. MOG-IgG–related optic neuritis is associated with optic disc edema in approximately 86% of patients, and 30% to 50% may be bilateral, distinguishing it from MS optic neuritis in which both of these features are rare. MOG-IgG is found in 15% of patients with recurrent optic neuritis without other nervous system involvement, similar to the 13% frequency of AQP4-IgG in these patients. In contrast, MOG-IgG is rarely encountered (2%) with recurrent LETM, in which AQP4-IgG accounts for up to 90% of cases. Bowel and bladder disturbance and erectile dysfunction in men are common with MOG-IgG myelitis, likely due to the frequent conus involvement. Episodes of intractable nausea and vomiting have been reported, although much less frequently than with AQP4-IgG. Rare cases of hemi-encephalitis and seizures have been reported with MOG-IgG.

Clinical Course and Prognosis

Some patients have a monophasic course, while others go on to develop relapsing disease. Higher titers and persistent MOG-IgG positivity over time predict a higher risk of relapse in children and adults, as illustrated by case 12-3. Those with transient seropositivity are likely to follow a monophasic course. Some may have corticosteroid-dependent optic nerve involvement, termed chronic relapsing inflammatory optic neuropathy. Relapses are dominated by optic neuritis, and most permanent disability appears to arise from the initial episode. In contrast to MS, a secondary progressive course has not been reported.

Radiologic Accompaniments

The MRI features of MOG-IgG disease have notable differences from AQP4-IgG–seropositive NMOSD and MS that can help suggest those at highest risk in whom MOG-IgG should be tested.

OPTIC NERVE

Enhancement involves more than half of the length of the optic nerve in 80% of patients and may involve the optic nerve sheath (figure 12-5a) or extend into the orbital fat. Bilateral anterior pathway optic nerve enhancement without extension to the optic chiasm (figure 12-5b) is more typical of MOG-IgG than AQP4-IgG.

BRAIN

Multifocal white matter T2 hyperintensities (figure 12-4a) with involvement of the deep gray matter (figure 12-5c) are typical of MOG-IgG disease, particularly with ADEM-like presentations. Infratentorial lesions tend to be more diffuse than with MS (table 12-1). However, in contrast to MS, ovoid periventricular, inferior temporal pole, and Dawson finger lesions are typically not present. The brain MRI is more difficult to distinguish from NMOSD than MS. Cortical lesions and leptomeningeal enhancement have also been reported.

SPINAL CORD

Longitudinally extensive lesions (figure 12-6a) occur in the majority (60% to 80%), while the remainder may be short (figure 12-6b), although both may be present simultaneously. In contrast to AQP4-IgG (in which a solitary LETM is typical), with MOG-IgG, it is not uncommon to have two separate lesions with the conus often involved (figure 12-6c). Lesions are usually central on axial sequences, which differs from MS (table 12-1). The T2-signal abnormality can be restricted to gray matter, forming a sagittal line (figure 12-6b) and axial H sign (figures 12-6d and 12-6e) in approximately one-third of patients, differing from central lesions of AQP4-IgG, which typically involve both gray and white matter.

Cerebrospinal Fluid Findings in Myelin Oligodendrocyte Glycoprotein IgG

Positive oligoclonal bands are found in less than 15% of patients with MOG-IgG. The other CSF findings are reviewed and compared to AQP4-IgG and MS in table 12-1.

Myelin Oligodendrocyte Glycoprotein–IgG Testing

A 2018 consensus article outlined patients in whom MOG-IgG should be tested and recommended against testing MOG-IgG in all patients with MS, given the risk of false positives when testing in low-probability situations. In general, testing should be reserved for those with one of the classic phenotypes of MOG-IgG disease (table 12-1) that lacks characteristic features of MS. Testing with a cell-based assay (with direct visual immunofluorescence or fluorescence-activated cell sorting) is strongly recommended. Blood testing is recommended for MOG-IgG, and the role of CSF MOG-IgG is uncertain. Detection with ELISA, Western blot, or assays using the nonconformational MOG epitope should be avoided.

Some patients with MOG-IgG, particularly children with an ADEM phenotype, appear to have a monophasic course. In these patients, MOG-IgG elevation is often transient, and follow-up testing after 6 to 12 months is often negative. Some studies have shown that higher MOG-IgG titers at onset are associated with an increased risk of relapse, but this requires further study. In addition, persistent seropositivity may predict relapse. The author generally recommends repeat testing 6 months after the initial episode to assist prognostication.

Pathogenesis and Pathology

Pathology case reports have shown overlap with pattern II MS (demyelinating lesions with an inflammatory infiltrate of T cells and macrophages with accompanying complement deposition). A full discussion of the potential pathogenesis of MOG-IgG is beyond the scope of this article but has been reviewed elsewhere.

Treatment

No randomized clinical trial data are available to guide clinicians in treating MOG-IgG disease. Acute treatments for MOG-IgG are very similar to those for NMOSD. A major area of study is determining which patients may have a monophasic disorder and not require treatment. For patients with relapsing disease, the maintenance treatment approach is almost identical to that of acute and maintenance therapy for NMOSD (outlined above), although IV immunoglobulin (IVIg) appears to be useful in children acutely and as a maintenance treatment.

ACUTE DISSEMINATED ENCEPHALOMYELITIS AND OTHER CNS INFLAMMATORY DEMYELINATING DISEASES

Despite the discovery of neural antibody biomarkers of CNS inflammatory demyelinating diseases, many diseases in this category lack antibody biomarkers. At the author’s facility, testing AQP4-IgG and MOG-IgG is recommended in all patients with ADEM, but more than 50% will be seronegative for both. ADEM is most common in children, and the presentation often follows vaccination or an infectious prodrome. The MRI findings include multifocal white matter T2 hyperintensities, deep gray matter lesions, and longitudinally extensive spinal cord lesions. Acute treatment is similar to the approach outlined with NMOSD above.

Many patients with ADEM have a monophasic course, but some can go on to develop typical MS or further non-MS relapsing course (eg, multiphasic ADEM), and, although many of this latter group will be MOG-IgG seropositive, some are seronegative. Other patients can have recurrent attacks of CNS demyelination restricted to one site (eg, recurrent optic neuritis or recurrent transverse myelitis) that do not meet criteria for MS and are seronegative for AQP4-IgG and MOG-IgG. This subset of patients represents an important focus for research to determine if antibody biomarkers that define those diseases exist. Treatment for these disorders is similar to the approach for NMOSD.

OTHER INFLAMMATORY CNS DISORDERS

A wide variety of other inflammatory CNS diseases can mimic MS, which practicing neurologists should be aware of; these are discussed in the following sections.

Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy

In 2016, an antibody to glial fibrillary acidic protein (GFAP-IgG) was reported that, when detected in CSF, appeared to be specific for an inflammatory meningoencephalomyelitis, termed autoimmune GFAP astrocytopathy. Patients of any age can be impacted (median age of 44 years), and the frequency is similar in males and females. Clinical manifestations include subacute to chronic meningitis (headache, neck stiffness, photophobia), encephalitis (memory loss, tremor, ataxia), and myelitis (urinary retention, numbness, weakness), and thus some of its features can mimic MS. Bilateral optic disc edema is a helpful clue, but intracranial pressure is typically normal and thus does not reflect papilledema. The myelitis features tend to be mild and occur in conjunction with encephalitis; an isolated myelitis generally does not occur. Coexisting neoplasms, particularly teratoma, may be seen.N-Methyl-d-aspartate (NMDA) receptor autoantibodies and AQP4-IgG may coexist. Samples are best tested in CSF for optimal sensitivity and specificity; dual testing is recommended using tissue immunofluorescence and cell-based assay confirmation of GFAP (GFAPα appears to be the most sensitive isoform). Care is needed with serum positivity alone because of a high risk of false positives. Brain MRI may reveal a characteristic radial perivascular enhancement perpendicular to the ventricles (figure 12-7), although a similar pattern can be seen with intravascular lymphoma, neurosarcoid, and CNS vasculitis. Leptomeningeal enhancement is also common. In the spinal cord, a longitudinally extensive faint T2 hyperintensity may be seen with central canal or punctate parenchymal enhancement. The vast majority (>85%) of patients with autoimmune GFAP astrocytopathy will have an elevated CSF white cell count, and oligoclonal bands are detected in half. Response to steroids is generally brisk, although a less corticosteroid-responsive phenotype was noted in an Asian cohort. Prolonged oral corticosteroids are the most frequent treatment used, and relapse is frequent during steroid tapering. Corticosteroid-sparing agents are often prescribed to try to maintain remission, although randomized controlled trials are lacking.

Diagnostic Pearls With Inflammatory/Autoimmune Disorders Associated With Other Autoantibody Biomarkers

Neurologic syndromes associated with collapsin response mediator protein-5 (CRMP-5) autoantibody (CRMP-5-IgG/anti-CV2) include optic neuropathy, retinitis, and myelitis and thus can mimic MS or NMOSD. Spinal cord T2-hyperintense lesions tend to be longitudinally extensive and involve lateral or dorsal columns, with a characteristic symmetric tract-specific enhancement sometimes seen (figure 12-8). The myelopathy may mimic primary progressive MS. The oncologic associations include small cell lung cancer and thymoma. γ-Aminobutyric acid (GABA)A receptor autoantibodies can mimic MS on MRI with multifocal white matter and cortical lesions. The disease has a particular predilection for children and can occur as a postinfectious phenomenon after viral encephalitis or may be paraneoplastic (eg, thymoma).

Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disorder of uncertain cause that may mimic MS. The presentation is that of a progressive brainstem syndrome with accompanying ataxia. The hallmark MRI finding is a multifocal bilateral punctate (<3 mm) enhancement pattern that is centered on the pons and often extends to the cerebellum (figure 12-9). The absence of mass effect is an important feature. CSF shows an elevated white cell count in one-third of patients, but oligoclonal bands are infrequent (<10%). Pathology shows dense perivascular inflammation with a T-cell predominance. Diagnostic criteria have been proposed and should be stringently adhered to as, in addition to MS, lymphoma and neurosarcoid can mimic this disorder. Biopsy to exclude lymphoma is important if atypical features are present. Oral corticosteroids and corticosteroid-sparing immunosuppressants are the mainstay of treatment.

Neuro-Behçet Disease

Neuro-Behçet disease characteristically involves the brainstem (figure 12-10), although myelitis and cerebral venous sinus thrombosis are also reported. Individuals from the old Silk Road (Middle East and Asia) are predisposed. The presence of oral and genital ulcers, pathergy (exaggerated skin injury to minor trauma), and uveitis are useful clinical clues. The CSF is often neutrophilic, helping to distinguish Behçet disease from MS, and HLA-B51 may be positive.

Neurosarcoidosis

Neurosarcoidosis should be included among the differential diagnosis of MS as it can manifest with multifocal involvement of the CNS, including the optic nerve, brain, or spinal cord. An elevated CSF white cell count and enhancing lesions overlap with MS, but oligoclonal bands are usually absent; basilar leptomeningeal enhancement and spinal cord linear dorsal subpial enhancement extending two or more vertebral segments are suggestive. Occasionally, dorsal subpial enhancement is accompanied by central canal enhancement, forming a hallmark trident appearance on axial images (figure 12-11). Clinical and radiologic recurrence is frequent when IV steroids are discontinued, and persistence of enhancement beyond 3 months helps distinguish from MS, where enhancement is typically transient, resolving within 2 months. Prolonged high-dose oral corticosteroid treatment is usually required for neurosarcoid with or without corticosteroid-sparing medications.

Central Nervous System Inflammatory Vascular Mimics of Multiple Sclerosis

Some of the inflammatory vascular diseases of the brain can mimic MS. Susac syndrome is an inflammatory endotheliopathy that is characterized by a triad of branched retinal artery occlusions, hearing loss, and dementia/encephalopathy. Ophthalmologic examination can show branched retinal artery occlusions, Gass plaques (yellow plaques within mid-arterioles on funduscopy), or arterial wall hyperfluorescence on fluorescein angiogram. Low-frequency hearing loss is typical on audiogram. MRI can mimic MS with corpus callosum lesions, but these tend to predominate in the center of the corpus callosum and may have a snowball-type appearance (figure 12-12), rather than the Dawson finger appearance seen with MS. A “string of pearls” appearance of beaded microinfarcts along the internal capsule is suggestive. Primary angiitis of the CNS can mimic MS with inflammatory-appearing lesions, but the presence of diffusion restriction in defined arterial territories, microhemorrhages, and leptomeningeal enhancement is an important discriminating feature (figure 12-13).

PARACLINICAL FINDINGS MIMICKING INFLAMMATION IN NONINFLAMMATORY CENTRAL NERVOUS SYSTEM DISORDERS

A variety of noninflammatory CNS diseases are accompanied by findings that mimic a primary inflammatory cause; a list of common examples with clues to discriminate them from MS are outlined in table 12-5, with an example of spondylotic myelopathy with enhancement mimicking MS shown in figure 12-14.

CONCLUSION

The field of inflammatory demyelinating diseases of the CNS is evolving rapidly. Assays for the novel antibody biomarkers AQP4-IgG and MOG-IgG are commercially available and useful in diagnosis and distinction from MS. Furthermore, these biomarkers have given insight into the pathogenesis of these diseases, allowing specific targeted treatments to be developed and translated to clinical practice, as evidenced by the three clinical trials currently under way in AQP4-IgG–seropositive NMOSD. Improved recognition of the clinical, radiologic, and laboratory features of other CNS inflammatory mimics of MS has allowed clinicians to better distinguish these disorders from MS despite the absence of a serum biomarker in many. All these developments are leading to improvements in diagnosis and treatment. Indeed, the future for patients afflicted by these disorders has never been brighter.

KEY POINTS

  • Distinguishing multiple sclerosis from its central nervous system inflammatory disease mimics has important therapeutic and prognostic implications.
  • In 2004, the discovery of aquaporin-4 (AQP4)–IgG as a specific biomarker of neuromyelitis optica (NMO) allowed its distinction from multiple sclerosis.
  • The discovery of AQP4-IgG as a biomarker of NMO led to a recognition that patients can have more limited forms of the disease (eg, recurrent transverse myelitis without optic neuritis) or symptoms beyond the optic nerve and spinal cord (eg, area postrema syndrome), resulting in the current nosology of NMO spectrum disorders (NMOSDs).
  • It is important to recognize that in regions where multiple sclerosis prevalence is lower (eg, Asia and regions closer to the equator), NMOSD represents a larger proportion of central nervous system demyelinating diseases and thus should be particularly considered in the differential in those regions.
  • NMOSD has three cardinal manifestations: transverse myelitis, optic neuritis, and area postrema syndrome.
  • Systemic autoimmune disorders or their autoantibody biomarkers frequently coexist with NMOSD, including systemic lupus erythematosus, Sjögren syndrome, and antiphospholipid antibody syndrome.
  • In NMOSD, optic nerve involvement is often bilateral and typically involves the posterior optic pathway, including the optic chiasm, with enhancement usually extending more than half the length of the nerve.
  • Typical brain involvement in NMOSD occurs around circumventricular organs where AQP4 expression is highest, with lesions adjacent to the third and fourth ventricles (dorsal medulla/area postrema) most typical.
  • Longitudinally extensive transverse myelitis, with a T2-hyperintense lesion spanning three or more contiguous vertebral segments on MRI, is characteristic of NMOSD and found in approximately 85% in patients.
  • Assay techniques for AQP4-IgG have improved over time, and cell-based assays are now recommended (using fluorescence-activated cell sorting or direct immunofluorescence); they yield a sensitivity of 75% to 80% and specificity of greater than 99%.
  • Approximately 20% to 25% of patients with NMOSD are AQP4-IgG seronegative.
  • AQP4-IgG binds to AQP4, which is located on the end-feet of astrocytes, initiating a cascade of immune-mediated inflammation resulting in secondary demyelination.
  • The use of plasma exchange for five to seven exchanges for severe, corticosteroid-refractory central nervous system inflammatory demyelinating attacks is supported by data from a prospective randomized sham-controlled crossover trial.
  • Despite the lack of completed randomized controlled trials in NMOSD, preventive treatment is strongly recommended in all patients.
  • With the use of cell-based assays transfected with myelin oligodendrocyte glycoprotein (MOG) in its conformational form, the antibody has been shown to be a specific biomarker of a spectrum of central nervous system inflammatory demyelinating disease distinct from multiple sclerosis and AQP4-IgG–seropositive NMOSD.
  • The major clinical manifestations of MOG-IgG disease include optic neuritis, acute disseminated encephalomyelitis, NMOSD (seronegative for AQP4-IgG), transverse myelitis, and brainstem demyelinating episodes.
  • Some patients with MOG-IgG disease have a monophasic course, while others go on to develop relapsing disease.
  • Radiologic findings in MOG-IgG disease include enhancement that involves more than half of the length of the optic nerve in 80% of patients and may involve the optic nerve sheath or extend into the orbital fat.
  • Multifocal white matter T2 hyperintensities with involvement of the deep gray matter are typical in MOG-IgG disease, particularly with acute disseminated encephalomyelitis–like presentations.
  • Positive oligoclonal bands are found in less than 15% of patients with MOG-IgG.
  • A 2018 consensus article outlined patients in whom MOG-IgG should be tested and recommended against testing MOG-IgG in all patients with multiple sclerosis, given the risk of false positives when testing in low-probability situations. In general, testing for MOG-IgG should be reserved for those with one of the classic phenotypes that lacks characteristic features of multiple sclerosis.
  • A major area of study in MOG-IgG disease is determining which patients may have a monophasic disorder and not require treatment.
  • For patients with relapsing MOG-IgG disease, the treatment approach is almost identical to that of acute and maintenance therapy for NMOSD, although IV immunoglobulin appears to be useful in children acutely and as a maintenance treatment.
  • In 2016, an antibody to glial fibrillary acidic protein (GFAP) was reported that, when detected in CSF, appeared to be specific for an inflammatory meningoencephalomyelitis, termed autoimmune GFAP astrocytopathy.
  • In autoimmune GFAP astrocyopathy, brain MRI may reveal a characteristic radial perivascular enhancement perpendicular to the ventricles, although a similar pattern can be seen with intravascular lymphoma, neurosarcoidosis, and central nervous system vasculitis.
  • Susac syndrome is an inflammatory endotheliopathy that is characterized by a triad of branched retinal artery occlusions, hearing loss, and dementia/encephalopathy.

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