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 Subsequently, the term neuromyelitis optica (NMO) superseded Devic disease to account for its most common clinical manifestations, namely optic neuritis and transverse myelitis.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.
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.
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).
A 60-year-old man presented with subacute weakness and numbness in his lower extremities and neurogenic bladder requiring intermittent catheterization. At nadir, 2 weeks after onset, he was wheelchair dependent.
His neurologic examination revealed severe upper motor neuron–pattern weakness in the lower extremities and a T4 sensory level. Spine MRI revealed a longitudinally extensive T2-hyperintense lesion (figure 12-1), and brain MRI showed no lesions suggestive of multiple sclerosis (MS). A CSF study revealed a white blood cell count of 1727 cells/mm3 (64% lymphocytes; 16% eosinophils; 13% neutrophils), protein of 322 mg/dL (normal, 0 to 35 mg/dL), and negative oligoclonal bands. Serum aquaporin-4 (AQP4)–IgG was positive, and a diagnosis of AQP4-IgG–seropositive neuromyelitis optica spectrum disorder (NMOSD) was made.
Acute treatment with high-dose IV steroids was initiated. Because of a lack of response, seven plasma exchanges were given, with resolution of neurogenic bladder and a return to ambulating independently. Rituximab was then prescribed as maintenance attack-prevention immunotherapy along with transitional oral steroids for 1 month while rituximab took effect.
Longitudinally extensive transverse myelitis is a hallmark feature of NMOSD and should prompt AQP4-IgG testing. In addition to the severity of the episode and length of the spinal cord lesion, the presence of an elevated CSF white blood cell count (>50 cells/mm3), absence of typical MS brain lesions, and negative oligoclonal bands were red flags indicating a diagnosis other than MS. This patient was African American and African Americans are particularly predisposed to NMOSD. Clinicians should have a low threshold to initiate plasma exchange in those with prominent residual deficits after IV steroids. Long-term attack-prevention immunotherapy is strongly recommended, as patients have a high risk of potentially disabling relapses.
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.
A 63-year-old right-handed woman developed an episode of intractable nausea, vomiting, and hiccups lasting weeks. She was evaluated by a gastroenterologist, but extensive investigations were unrevealing. A brain MRI was performed and revealed an enhancing lesion in the dorsal medulla (figure 12-2a). CSF at that time revealed a white blood cell count of 55 cells/mm3 (95% lymphocytes), protein of 50 mg/dL, and negative oligoclonal bands. The patient was treated with IV steroids. She subsequently developed subacute myelitis, and a second MRI showed two short lesions extending less than three vertebral segments (figures 12-2b through 12-2e). The myelitis was followed by short-lived episodic painful spasms in her right upper extremity, which responded well to low-dose carbamazepine. Serum aquaporin-4 (AQP4)–IgG was positive by cell-based assay and AQP4-IgG–seropositive neuromyelitis optica spectrum disorder (NMOSD) was diagnosed.
Intractable nausea and vomiting from an area postrema syndrome are recognized as a cardinal manifestation of AQP4-IgG–seropositive NMOSD. Patients with this syndrome are often evaluated first by gastroenterologists. Tonic spasms commonly follow NMOSD myelitis and respond to carbamazepine. Approximately 15% of patients will have a myelitis accompanied by a short MRI lesion (<3 vertebral segments); thus, its presence does not exclude NMOSD, despite being less typical than the hallmark longitudinally extensive transverse myelitis episodes (case 12-1).
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.
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.
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 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.
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.
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.
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 of NMOSD is divided into acute attack treatment and maintenance (attack-prevention) 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.
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.
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.
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).
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.
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.
A 47-year-old man was admitted to the hospital with a rapidly progressive quadriparesis and encephalopathy following a viral prodrome. At his nadir 2 weeks from onset, he required mechanical ventilation, and his examination revealed quadriplegia, hyperreflexia, spasticity, and extensor plantar responses bilaterally. MRI of the brain and cervical spine were abnormal, showing multifocal white matter lesions and a myelitis lesion (figure 12-4). CSF analysis revealed a white blood cell count of 139/mm3 (75% lymphocytes), protein of 74 mg/dL, and negative oligoclonal bands. Serum aquaporin-4 (AQP4)–IgG was negative. He underwent a brain biopsy after having no response to high-dose IV corticosteroids, which showed myelin loss, perivascular macrophage infiltrate, and relatively preserved axons consistent with acute disseminated encephalomyelitis (ADEM). Myelin oligodendrocyte glycoprotein (MOG) IgG was tested and returned positive by live cell-based assay at high titer, confirming a MOG-IgG disease diagnosis. He completed seven plasma exchange treatments and received oral prednisone with a slow taper.
Three months later, his neurologic examination was normal and his MRI lesions had resolved. During prednisone tapering, he developed right optic neuritis, which was treated with IV methylprednisolone, a slower taper of oral prednisone, and azathioprine as maintenance steroid-sparing immunotherapy. Serum MOG-IgG remained persistently positive 2.5 years after onset.
ADEM is a hallmark episode of MOG-IgG–related disease. The preceding viral prodrome, severity of the episode, longitudinally extensive spinal cord lesion, CSF white cell count of greater than 50/mm3, and absence of oligoclonal bands were all atypical for multiple sclerosis. Despite severe attacks, patients often have excellent recovery after acute treatment, as was seen in this patient. High titers of MOG-IgG at onset and persistent seropositivity over time predict relapsing disease. Relapses in MOG-IgG disease are dominated by optic neuritis. Steroid-sparing immunosuppressants are often used for attack prevention, particularly in relapsing disease, although randomized controlled trials have not yet been undertaken.
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.
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.
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.
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.
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.
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 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 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.
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.
- 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.
1. Miyazawa I, Fujihara K, Itoyama Y. Eugène Devic (1858–1930). J Neurol 2002;249(3):351–252. doi:10.1007/s004150200020.
2. Wingerchuk DM, Hogancamp WF, O'Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic's syndrome). Neurology 1999;53(5):1107–1114. doi:10.1212/WNL.53.5.1107.
3. Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004;364(9451):2106–2112. doi:10.1016/S0140-6736(04)17551-X.
4. Lennon VA, Kryzer TJ, Pittock SJ, et al. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 2005;202(4):473–477. doi:10.1084/jem.20050304.
5. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015;85(2):177–189. doi:10.1212/WNL.0000000000001729.
6. Waters PJ, McKeon A, Leite MI, et al. Serologic diagnosis of NMO: a multicenter comparison of aquaporin-4-IgG assays. Neurology 2012;78(9):665–671; discussion 9. doi:10.1212/WNL.0b013e318248dec1.
7. Hacohen Y, Palace J. Time to separate MOG-Ab-associated disease from AQP4-Ab-positive neuromyelitis optica spectrum disorder. Neurology 2018;90(21):947–948. doi:10.1212/WNL.0000000000005619.
8. Flanagan EP, Cabre P, Weinshenker BG, et al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum. Ann Neurol 2016;79(5):775–783. doi:10.1002/ana.24617.
9. Asgari N, Lillevang ST, Skejoe HP, et al. A population-based study of neuromyelitis optica in Caucasians. Neurology 2011;76(18):1589–1595. doi:10.1212/WNL.0b013e3182190f74.
10. Houzen H, Kondo K, Niino M, et al. Prevalence and clinical features of neuromyelitis optica spectrum disorders in northern Japan. Neurology 2017;89(19):1995–2001. doi:10.1212/WNL.0000000000004611.
11. Wingerchuk DM. Neuromyelitis optica: effect of gender. J Neurol Sci 2009;286(1–2):18–23. doi:10.1016/j.jns.2009.08.045.
12. Flanagan EP, Weinshenker BG. Neuromyelitis optica spectrum disorders. Curr Neurol Neurosci Rep 2014;14(9):483. doi:10.1007/s11910-014-0483-3.
13. Wingerchuk DM, Pittock SJ, Lucchinetti CF, et al. A secondary progressive clinical course is uncommon in neuromyelitis optica. Neurology 2007;68(8):603–605. doi:10.1212/01.wnl.0000254502.87233.9a.
14. Flanagan EP, Kaufmann TJ, Krecke KN, et al. Discriminating long myelitis of neuromyelitis optica from sarcoidosis. Ann Neurol 2016;79(3):437–447. doi:10.1212/01.wnl.0000254502.87233.9a.
15. Kim SM, Go MJ, Sung JJ, et al. Painful tonic spasm in neuromyelitis optica: incidence, diagnostic utility, and clinical characteristics. Arch Neurol 2012;69(8):1026–1031. doi:10.1001/archneurol.2012.112.
16. Misu T, Fujihara K, Nakashima I, et al. Intractable hiccup and nausea with periaqueductal lesions in neuromyelitis optica. Neurology 2005;65(9):1479–1482. doi:10.1212/01.wnl.0000183151.19351.82.
17. Asgari N, Skejoe HP, Lennon VA. Evolution of longitudinally extensive transverse myelitis in an aquaporin-4 IgG-positive patient. Neurology 2013;81(1):95–96. doi:10.1212/WNL.0b013e318297ef07.
18. Pittock SJ, Lennon VA. Aquaporin-4 autoantibodies in a paraneoplastic context. Arch Neurol 2008;65(5):629–632. doi:10.1001/archneur.65.5.629.
19. Wingerchuk DM, Weinshenker BG. The emerging relationship between neuromyelitis optica and systemic rheumatologic autoimmune disease. Mult Scler 2012;18(1):5–10. doi:10.1177/1352458511431077.
20. Guerra H, Pittock SJ, Moder KG, et al. Frequency of aquaporin-4 immunoglobulin G in longitudinally extensive transverse myelitis with antiphospholipid antibodies. Mayo Clin Proc 2018;93(9):1299–1304. doi:10.1016/j.mayocp.2018.02.006.
21. McKeon A, Lennon VA, Jacob A, et al. Coexistence of myasthenia gravis and serological markers of neurological autoimmunity in neuromyelitis optica. Muscle Nerve 2009;39(1):87–90. doi:10.1002/mus.21197.
22. Ramanathan S, Prelog K, Barnes EH, et al. Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis. Mult Scler 2016;22(4):470–482. doi:10.1177/1352458515593406.
23. Kim HJ, Paul F, Lana-Peixoto MA, et al. MRI characteristics of neuromyelitis optica spectrum disorder: an international update. Neurology 2015;84(11):1165–1173. doi:10.1212/WNL.0000000000001367.
24. Flanagan EP, Weinshenker BG, Krecke KN, et al. Short myelitis lesions in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders. JAMA Neurol 2015;72(1):81–87. doi:10.1001/jamaneurol.2014.2137.
25. Banwell B, Tenembaum S, Lennon VA, et al. Neuromyelitis optica-IgG in childhood inflammatory demyelinating CNS disorders. Neurology 2008;70(5):344–352. doi:10.1212/01.wnl.0000284600.80782.d5.
26. Huh SY, Kim SH, Hyun JW, et al. Short segment myelitis as a first manifestation of neuromyelitis optica spectrum disorders. Mult Scler 2017;23(3):413–419. doi:10.1177/1352458516687043.
27. Zalewski NL, Morris PP, Weinshenker BG, et al. Ring-enhancing spinal cord lesions in neuromyelitis optica spectrum disorders. J Neurol Neurosurg Psychiatry 2017;88(3):218–225. doi:10.1177/1352458516687043.
28. Iorio R, Damato V, Mirabella M, et al. Distinctive clinical and neuroimaging characteristics of longitudinally extensive transverse myelitis associated with aquaporin-4 autoantibodies. J Neurol 2013;260(9):2396–2402. doi:10.1007/s00415-013-6997-9.
29. Dubey D, Pittock SJ, Krecke KN, Flanagan EP. Association of extension of cervical cord lesion and area postrema syndrome with neuromyelitis optica spectrum disorder. JAMA Neurol 2017;74(3):355–357. doi:10.1001/jamaneurol.2016.5441.
30. Majed M, Fryer JP, McKeon A, et al. Clinical utility of testing AQP4-IgG in CSF: guidance for physicians. Neurol Neuroimmunol Neuroinflamm 2016;3(3):e231. doi:10.1212/NXI.0000000000000231.
31. Pittock SJ, Lennon VA, Bakshi N, et al. Seroprevalence of aquaporin-4-IgG in a northern California population representative cohort of multiple sclerosis. JAMA Neurol 2014;71(11):1433–1436. doi:10.1001/jamaneurol.2014.1581.
32. Jolliffe EA, Keegan BM, Flanagan EP. Trident sign trumps Aquaporin-4-IgG ELISA in diagnostic value in a case of longitudinally extensive transverse myelitis. Mult Scler Relat Disord 2018;23:7–8. doi:10.1016/j.msard.2018.04.012.
33. Weinshenker BG, Wingerchuk DM. Neuromyelitis spectrum disorders. Mayo Clin Proc 2017;92(4):663–679. doi:10.1016/j.mayocp.2016.12.014.
34. Papadopoulos MC, Verkman AS. Aquaporin 4 and neuromyelitis optica. Lancet Neurol 2012;11(6):535–544. doi:10.1016/S1474-4422(12)70133-3.
35. Lucchinetti CF, Guo Y, Popescu BF, et al. The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica. Brain Pathol 2014;24(1):83–97. doi:10.1111/bpa.12099.
36. Popescu BF, Guo Y, Jentoft ME, et al. Diagnostic utility of aquaporin-4 in the analysis of active demyelinating lesions. Neurology 2015;84(2):148–158. doi:10.1212/WNL.0000000000001126.
37. Weinshenker BG, O'Brien PC, Petterson TM, et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 1999;46(6):878–886. doi:10.1002/1531-8249(199912)46:6<878::AID-ANA10>3.0.CO;2-Q.
38. Kleiter I, Gahlen A, Borisow N, et al. Neuromyelitis optica: evaluation of 871 attacks and 1,153 treatment courses. Ann Neurol 2016;79(2):206–216. doi:10.1002/ana.24554.
39. Pittock SJ, Lennon VA, McKeon A, et al. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol 2013;12(6):554–562. doi:10.1016/S1474-4422(13)70076-0.
40. Araki M, Matsuoka T, Miyamoto K, et al. Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study. Neurology 2014;82(15):1302–1306. doi:10.1212/WNL.0000000000000317.
41. Flanagan EP, Aksamit AJ, Kumar N, et al. Simultaneous PML-IRIS and myelitis in a patient with neuromyelitis optica spectrum disorder. Neurol Clin Pract 2013;3(5):448–451. doi:10.1212/CPJ.0b013e3182a78f82.
42. George JS, Leite MI, Kitley JL, et al. Opportunistic infections of the retina in patients with aquaporin-4 antibody disease. JAMA Neurol 2014;71(11):1429–1432. doi:10.1001/jamaneurol.2014.1620.
43. Reindl M, Jarius S, Rostasy K, Berger T. Myelin oligodendrocyte glycoprotein antibodies: How clinically useful are they? Curr Opin Neurol 2017;30(3):295–301. doi:10.1097/WCO.0000000000000446.
44. Jurynczyk M, Messina S, Woodhall MR, et al. Clinical presentation and prognosis in MOG-antibody disease: a UK study. Brain 2017;140(12):3128–3138. doi:10.1093/brain/awx276.
45. Dubey D, Pittock SJ, Krecke KN, et al. Clinical, radiologic, and prognostic features of myelitis associated with myelin oligodendrocyte glycoprotein autoantibody [published online December 21, 2018]. JAMA Neurol. doi:10.1001/jamaneurol.2018.4053.
46. Hennes EM, Baumann M, Schanda K, et al. Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. Neurology 2017;89(9):900–908. doi:10.1212/WNL.0000000000004312.
47. Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018;83(1):166–177. doi:10.1002/ana.25131.
48. Chen JJ, Flanagan EP, Jitprapaikulsan J, et al. Myelin oligodendrocyte glycoprotein antibody-positive optic neuritis: clinical characteristics, radiologic clues, and outcome. Am J Ophthalmol 2018;195:8–15. doi:10.1016/j.ajo.2018.07.020.
49. Jitprapaikulsan J, Chen JJ, Flanagan EP, et al. Aquaporin-4 and myelin oligodendrocyte glycoprotein autoantibody status predict outcome of recurrent optic neuritis. Ophthalmology 2018;125(10):1628–1637. doi:10.1016/j.ophtha.2018.03.041.
50. Jitprapaikulsan J, Lopez Chiriboga AS, Flanagan EP, et al. Novel glial targets and recurrent longitudinally extensive transverse myelitis. JAMA Neurol 2018;75(7):892–895. doi:10.1001/jamaneurol.2018.0805.
51. Ogawa R, Nakashima I, Takahashi T, et al. MOG antibody-positive, benign, unilateral, cerebral cortical encephalitis with epilepsy. Neurol Neuroimmunol Neuroinflamm 2017;4(2):e322. doi:10.1212/NXI.0000000000000322.
52. Cobo-Calvo A, Ruiz A, Maillart E, et al. Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: the MOGADOR study. Neurology 2018;90(21):e1858–e1869. doi:10.1212/WNL.0000000000005560.
53. López-Chiriboga AS, Majed M, Fryer J, et al. Association of MOG-IgG serostatus with relapse after acute disseminated encephalomyelitis and proposed diagnostic criteria for MOG-IgG-associated disorders. JAMA Neurol 2018. doi:10.1001/jamaneurol.2018.1814.
54. Akaishi T, Sato DK, Nakashima I, et al. MRI and retinal abnormalities in isolated optic neuritis with myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies: a comparative study. J Neurol Neurosurg Psychiatry 2016;87(4):446–448. doi:10.1136/jnnp-2014-310206.
55. Jurynczyk M, Geraldes R, Probert F, et al. Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis. Brain 2017;140(3):617–627. doi:10.1093/brain/aww350.
56. Jarius S, Ruprecht K, Kleiter I, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflammation 2016;13(1):280. doi:10.1186/s12974-016-0718-0.
57. Jarius S, Paul F, Aktas O, et al. MOG encephalomyelitis: international recommendations on diagnosis and antibody testing [in German]. J Neuroinflammation 2018. doi:10.1007/s00115-018-0607-0.
58. Di Pauli F, Höftberger R, Reindl M, et al. Fulminant demyelinating encephalomyelitis: Insights from antibody studies and neuropathology. Neurol Neuroimmunol Neuroinflamm 2015;2(6):e175. doi:10.1212/NXI.0000000000000175.
59. Peschl P, Bradl M, Höftberger R, et al. Myelin oligodendrocyte glycoprotein: deciphering a target in inflammatory demyelinating diseases. Front Immunol 2017;8:529. doi:10.3389/fimmu.2017.00529.
60. Hacohen Y, Wong YY, Lechner C, et al. Disease course and treatment responses in children with relapsing myelin oligodendrocyte glycoprotein antibody-associated disease. JAMA Neurol 2018;75(4):478–487. doi:10.1001/jamaneurol.2017.4601.
61. Fang B, McKeon A, Hinson SR, et al. Autoimmune glial fibrillary acidic protein astrocytopathy: a novel meningoencephalomyelitis. JAMA Neurol 2016;73(11):1297–1307. doi:10.1001/jamaneurol.2016.2549.
62. Flanagan EP, Hinson SR, Lennon VA, et al. Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: analysis of 102 patients. Ann Neurol 2017;81(2):298–309. doi:10.1002/ana.24881.
63. Iorio R, Damato V, Evoli A, et al. Clinical and immunological characteristics of the spectrum of GFAP autoimmunity: a case series of 22 patients. J Neurol Neurosurg Psychiatry 2018;89(2):138–146. doi:10.1136/jnnp-2017-316583.
64. Chen JJ, Aksamit AJ, McKeon A, et al. Optic disc edema in glial fibrillary acidic protein autoantibody-positive meningoencephalitis. J Neuroophthalmol 2018;38(3):276–281. doi:10.1097/WNO.0000000000000593.
65. Sechi E, Morris PP, McKeon A, et al. Glial fibrillary acidic protein IgG related myelitis: characterisation and comparison with aquaporin-4-IgG myelitis. J Neurol Neurosurg Psychiatry 2018. pii:jnnp-2018-318004. doi:10.1136/jnnp-2018-318004.
66. Long Y, Liang J, Xu H, et al. Autoimmune glial fibrillary acidic protein astrocytopathy in Chinese patients: a retrospective study. Eur J Neurol 2018;25(3):477–483. doi:10.1111/ene.13531.
67. Flanagan EP, McKeon A, Lennon VA, et al. Paraneoplastic isolated myelopathy: clinical course and neuroimaging clues. Neurology 2011;76(24):2089–2095. doi:10.1212/WNL.0b013e31821f468f.
68. Spatola M, Petit-Pedrol M, Simabukuro MM, et al. Investigations in GABAA receptor antibody-associated encephalitis. Neurology 2017;88(11):1012–1020. doi:10.1212/WNL.0000000000003713.
69. Pittock SJ, Debruyne J, Krecke KN, et al. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain 2010;133(9):2626–2634. doi:10.1093/brain/awq164.
70. Tobin WO, Guo Y, Krecke KN, et al. Diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain 2017;140(9):2415–2425. doi:10.1093/brain/awx200.
71. Zalewski NL, Krecke KN, Weinshenker BG, et al. Central canal enhancement and the trident sign in spinal cord sarcoidosis. Neurology 2016;87(7):743–744. doi:10.1212/WNL.0000000000002992.
72. Egan RA. Diagnostic criteria and treatment algorithm for Susac syndrome. J Neuroophthalmol 2018. doi:10.1097/WNO.0000000000000677.
73. Rennebohm R, Susac JO, Egan RA, Daroff RB. Susac's Syndrome—update. J Neurol Sci 2010;299(1–2):86–91. doi:10.1016/j.jns.2010.08.032.
74. Flanagan EP, Krecke KN, Marsh RW, et al. Specific pattern of gadolinium enhancement in spondylotic myelopathy. Ann Neurol 2014;76(1):54–65. doi:10.1002/ana.24184.