Acute Disseminated Encephalomyelitis, Transverse Myelitis, and Neuromyelitis Optica

Home , Demyelinating disease, Encephalomyelitis, Lesion, McDonald criteria, Myelitis, Transverse myelitis

Review Article

Address correspondence to Dr Brian G. Weinshenker, Department of Neurology, Acute Disseminated Mayo Clinic, 200 First St SW, Rochester, MN 55905, [email protected]. Encephalomyelitis, Relationship Disclosure: Dr Wingerchuk receives research support from Transverse Myelitis, and Alexion, Genentech, Genzyme Corporation, Guthy-Jackson Charitable Foundation, and Terumo BCT, Neuromyelitis Optica Inc. Dr Weinshenker serves on the data and safety Dean M. Wingerchuk, MD, MSc, FRCP(C), FAAN; monitoring board of Biogen Idec and Novartis and serves Brian G. Weinshenker, MD, FRCP(C), FAAN as a consultant regarding neuromyelitis optica therapeutics for Asahi Kasei ABSTRACT Medical Co, Ltd, Elan Corporation, and Novartis. Purpose of Review: This review defines current clinical criteria for diagnosis, Dr Weinshenker receives differential diagnosis, and clinical evaluation of acute disseminated encephalomy- royalties for licensed elitis, transverse myelitis, and neuromyelitis optica, and summarizes principles of technology for the diagnosis of neuromyelitis optica from treatment. RSR Limited, and receives Recent Findings: Consensus criteria for transverse myelitis and acute dissemi- research funding from nated encephalomyelitis have been proposed. A specific biomarker, aquaporin-4 Guthy-Jackson Charitable Foundation. autoantibody, has been discovered for neuromyelitis optica that allows for early and Unlabeled Use of accurate diagnosis even in the absence of cardinal findings of optic neuritis and myelitis. Products/Investigational The antibody is pathogenic and is facilitating an understanding of the pathophysiology Use Disclosure: Drs Wingerchuk and Weinshenker of neuromyelitis optica and development of antigen-specific treatments. discuss the unlabeled uses of Summary: Clinical and radiologic findings combined with serologic findings may corticosteroids and plasma permit classification of syndromes of transverse myelitis and acute disseminated exchange for the treatment of acute disseminated encephalomyelitis in ways that may predict risk of relapse, type of relapse, and encephalomyelitis, transverse prognosis. Treatment, especially to prevent relapse, is dependent on the specific myelitis, and neuromyelitis disease context in which syndromes such as transverse myelitis occur. optica; IV immunoglobulin for acute disseminated encephalomyelitis; and Continuum (Minneap Minn) 2013;19(4):944–967. azathioprine, mycophenolate mofetil, rituximab, mitoxantrone, methotrexate, and eculizumab for INTRODUCTION: SYNDROME their inflammatory characteristics and neuromyelitis optica. * 2013, American Academy VERSUS DISEASE overlapping pathology. of Neurology. The nosology of demyelinating dis- Distinction between syndromes eases of the CNS is complex. Multiple that reflect localization (eg, optic neu- sclerosis (MS) has been an umbrella ritis and transverse myelitis) and dis- term for recurrent inflammatory disease entities (eg, ADEM, MS, and NMO) ease of the CNS after definable non- is now feasible. Distinction is important demyelinating mimics are excluded. because of the prognostic and treat- Acute disseminated encephalomyelitis ment implications of different disease (ADEM), transverse myelitis, and neu- entities. For example, transverse myeli- romyelitis optica (NMO) are inflamma- tis refers to a syndrome of acute or tory conditions that have not been subacute myelopathy accompanied by well distinguished from MS or its indicators of inflammation, either ra- presenting syndromes (termed ‘‘clini- diologically or based on spinal fluid. It cally isolated [demyelinating] syn- may occur as a stand-alone syndrome, a dromes’’) but are linked by their component of ADEM, a relapse of MS or tendency to relapse and remit and by NMO, or a nondemyelinating syndrome

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS such as an infectious myelitis or a cephalomyelitis. ADEM is also known h Distinguishing between granulomatous myelitis. If due to her- as postvaccinal encephalomyelitis syndromes (eg, optic pes virus infection, it is best treated with when it follows vaccination. Accord- neuritis and transverse antiviral treatment; if indicative of a ingly, it is believed to be induced by myelitis) and disease relapse or harbinger of MS, an MS an immune reaction directed at a entities (multiple immunomodulatory treatment may be cross-reacting myelin antigen. Its sclerosis, neuromyelitis appropriate; if a relapse of NMO, an somewhat unique pathology of optica, and acute immunosuppressive drug, such as aza- perivenous ‘‘sleeves’’ of inflammation disseminated thioprine, would be appropriate, and demyelination has been recog- encephalomyelitis) whereas interferon-" or natalizumab nized for decades but has been re- is vital. Demyelinating may actually be deleterious. Noninfec- cently rediscovered and expanded.1 syndromes may be a component of different tious and noninflammatory disorders, Pathologically, ADEM can be distin- diseases and may such as arteriovenous fistula, may guished from fulminant acute MS, have vastly different produce syndromes suggestive of which is a major consideration in the prognoses depending transverse myelitis but would require differential diagnosis. Acute MS is on the disease context entirely different treatment. associated with confluent demyelin- (and may therefore ADEM, as currently defined, is char- ation and prominent macrophages require different acterized by acute encephalopathy but admixed with reactive astrocytes. treatment). frequently accompanied by optic neuri- When cases are identified based on h Although the proposed tis or transverse myelitis. NMO is the pathologic features, these features consensus criteria for first inflammatory demyelinating condi- seem to be associated with some of acute disseminated tion to be defined, in part, by a bio- the key clinical characteristics that have encephalomyelitis marker that is molding our evolving been identified in consensus clinical allows for recurrent or concept of this condition (an auto- diagnostic criteria (Table 3-12) to dis- multiphasic forms immune aquaporinopathy) and ex- tinguish ADEM from MSVin particular, of the disease, the panding the spectrum of the disease encephalopathy.1 Pathology has re- existence of relapsing to include nonYoptic nerve and spinal cently been proposed as the ‘‘refer- forms remains controversial. A cord syndromes and MRI-detected ence standard’’ to distinguish ADEM criterion standard brain lesions that, in the past, would from fulminant MS, although this has for distinguishing have excluded a diagnosis of NMO. not been widely debated and cannot acute disseminated Understanding of the distinction and be considered as generally accepted at encephalomyelitis 2 interrelationships of these syndromes the present time. Consensus criteria from multiple sclerosis has been facilitated by insights into the remain imperfect in distinguishing pa- has not been widely pathophysiology, informed by the neu- tients who, in the course of follow-up, accepted, although ropathology, and illustrated by ad- will remain free of future relapses. pathology has been vances in NMO over the past decade Furthermore, consensus criteria allow proposed. as outlined below. for recurrent and even multiphasic ADEM episodes with criteria that might ACUTE DISSEMINATED distinguish it from MS (ie, a new ENCEPHALOMYELITIS episode must also meet the criteria Although a number of definitions have for ADEM and not be those of an been proposed for ADEM, it remains a attack of MSVsee Table 3-1). Contro- poorly defined syndrome of symptom- versy persists about whether relapses atic diffuse or multifocal CNS inflam- may occur in ADEM and remain con- mation that is typically, if not always, a sistent with the diagnosis of ADEM, monophasic illness. ADEM has been especially in adult patients. historically regarded as the clinical The key clinical features required counterpart of the experimental dis- for a diagnosis of ADEM include ease experimental autoimmune en- diffuse encephalopathy but may also

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a TABLE 3-1 International Pediatric Multiple Sclerosis Study Group Consensus Definitions

b Monophasic Acute Disseminated Encephalomyelitis (ADEM) A first clinical event with a presumed inflammatory or demyelinating cause Acute or subacute onset that affects multifocal areas of the CNS Polysymptomatic and must include encephalopathy, including one or more of the following: Behavioral change (confusion, irritability) Alteration in consciousness (lethargy, coma) Postevent improvement clinically, on MRI, or both; residual deficits permitted No prior clinical episode consistent with demyelinating event No other etiologies apparent New or fluctuating symptoms, signs, or MRI findings occurring within 3 months of the inciting ADEM event permissible Brain MRI (T2-weighted) with focal or multifocal supratentorial or infratentorial lesions, often large (1 to 2 cm), predominantly involving white matter, but frequently present in gray matter (especially basal ganglia or thalamus), without evidence of previous destructive white matter changes; brain MRI showing a single large lesion (1 to 2 cm), predominantly affecting white matter also possible, although rare Spinal cord MRI may have confluent intramedullary lesion(s) with variable enhancement, in addition to abnormal brain MRI findings specified previously b Recurrent ADEM Recurrence of the initial symptoms and signs of ADEM 3 or more months after the first event No new lesions based on history, examination, or neuroimaging Event does not occur while on corticosteroids and occurs at least 1 month after completing therapy MRI shows no new lesions; original lesions may have enlarged No better explanation exists b Multiphasic ADEM New clinical event also meeting criteria for ADEM but involving new anatomic areas of the CNS as confirmed by history, neurologic examination, and neuroimaging Subsequent event must occur: At least 3 months after the onset of the initial ADEM event At least 1 month after completing steroid therapy Subsequent event must be a polysymptomatic presentation, including encephalopathy, with neurologic symptoms or signs that differ from the initial event (mental status changes may not differ from the initial event) Brain MRI shows new areas of involvement and complete or partial resolution of prior ADEM-associated lesion a Modified with permission from Krupp LB, et al; International Pediatric MS Study Group, Neurology.2 B 2007, American Academy of Neurology. www.neurology.org/content/68/16_suppl_2/S7.short?sid=d000124e-c5a6-4744-a896-c2c5cfcc4545.

include other symptoms characteristic appropriate setting of extensive white of an inflammatory demyelinating dis- matter disease (Case 3-1). MRI usually ease, such as optic neuritis or trans- shows multiple lesions, although a verse myelitis, including transverse single large lesion is still felt to be myelitis associated with longitudinally compatible in the consensus criteria. extensive lesions. Clinical features may Usually, cerebral lesions occur in both include seizures or coma; coma is cerebral hemispheres in ADEM.3 In- highly suggestive of ADEM in the volvement of the deep gray matter is

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Case 3-1 A 30-year-old woman with no antecedent illness or vaccination presented with headaches and migratory numbness. Four days later she reported nausea and was confused, asking the same question repetitively. She developed gait unsteadiness, followed within a week by paraplegia and later by paresis of her arms. Examination revealed that she was somnolent but opened her eyes after vigorous stimulation. She had bilateral papilledema, moderate upper extremity paresis, and plegia of the lower extremities. Bilateral Babinski signs and spasticity were present. MRI scan of the brain showed extensive white matter lesions (Figure 3-1). CSF analysis revealed 30 white blood cells (WBC)/2L, primarily mononuclear; elevated protein level of 200 mg/dL, and negative/ normal results for IgG index and oligoclonal bands. In spite of high-dose corticosteroids, she continued to deteriorate and developed multiple new lesions of the cerebral hemispheres and brainstem, as well as a herniation syndrome. Pathologic analysis revealed evidence of perivenous demyelination consistent with acute disseminated encephalomyelitis (ADEM). Comment. This case illustrates how fulminant a course ADEM may take in certain individuals and how it may cause cerebral herniation. FIGURE 3-1 T2-weighted axial brain image shows multiple lesions of varying size scattered throughout the subcortical and deep cerebral white matter.

not uncommon and is more com- leukoencephalopathies exists that may monly observed in ADEM than in MS produce similar features (Table 3-2).5 (Figure 3-2).4 Lesions may also be Clinical and radiologic clues are im- present in the optic nerves and spinal portant in distinguishing ADEM from cord. A key exclusionary criterion is other mimics. Investigations should be lack of clinical or radiologic evidence targeted to specific suspected compet- of prior CNS pathology that would ing diagnoses based on demographic, indicate previous inflammatory de- neurologic, and non-neurologic symp- myelination. Typically, CSF pleocytosis tomatology and radiologic clues. is present. The diagnosis of ADEM remains ADEM is more common in children one of exclusion of other competing than adults, and diagnosis can be diagnoses and monitoring of treat- made with greater confidence when ment response and clinical courseVin it follows an acute infectious illness or particular, whether remission occurs vaccination in a child or an adult. A spontaneously or after corticosteroid broad differential diagnosis of acute treatment and whether relapse occurs.

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FIGURE 3-2 Acute disseminated encephalomyelitis in a child. Fluid-attenuated inversion recovery (FLAIR) axial images at the level of basal ganglia and pons (A, C) and T1-gadolinium axial images at the same levels (B, D). Note the mostly symmetrical, thalamic gray matter T2 hyperintensity with minimal gadolinium enhancement as well as the bilateral, though asymmetrical, middle cerebellar peduncle T2 hyperintensity with prominent gadolinium enhancement.

Relapse is a strong indicator that a rebral, cerebellar, and basal ganglia diagnosis of ADEM was incorrect, al- abnormalities have been reported. Se- though, as noted above, pediatric con- rial follow-up in ADEM does not reveal sensus criteria do not consider a new MRI findings, but this observation relapse as a strict exclusionary charac- can only be made retrospectively. CSF teristic. The radiologic characteristics findings are similarly nonspecific. Ele- of ADEM are nonspecific. In the major- vations of IgG index or the presence ity of patients, they are difficult to of oligoclonal bands are usually absent, distinguish from those seen in MS, or when present, are transient. When although extensive and symmetric ce- ADEM is strongly suspected and no

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. TABLE 3-2 Selected Acute Leukoencephalopathies That Mimic Acute Disseminated Encephalomyelitis and Investigations

Confirmatory Condition Index of Suspicion Initial Tests Tests Neurosarcoidosis Extra-CNS disease Serum and CSF angiotensin- CNS or non-CNS Persisting enhancement converting enzyme level biopsy on brain MRI Brain and spinal cord MRIs with and without contrast Imaging for pulmonary disease Vasculitis Extra-CNS disease Sedimentation rate CNS or non-CNS Residual infarcts Vasculitis panel (myeloperoxidase, biopsy proteinase 3) Angiography Progressive multifocal Immunosuppressed CSF PCR for JC virus CNS biopsy leukoencephalopathy individual MRI sometimes sequential Natalizumab treatment HIV infection Gliomatosis cerebri History of brain tumor Brain MRI with and without CNS biopsy gadolinium CNS lymphoma Prior immunosuppression CSF cytology CNS biopsy Homogeneous, nodular enhancement Multifocal tumor Posterior reversible Risk factor (eg, Brain MRI with and without Follow-up MRI encephalopathy hypertension, cyclosporine) gadolinium syndrome No gadolinium Imaging may change rapidly enhancement Indistinct boundaries Paraneoplastic disorder History of cancer Paraneoplastic antibody CNS biopsy Erdheim-Chester disease Bone pain X-ray of long bones CNS or non-CNS Exophthalmos biopsy Diabetes insipidus

other competing diagnosis seems The hallmark pathologic character- likely or is detected after a comprehen- istic for ADEM is perivenous demye- sive evaluation, a therapeutic trial of lination, typically distributed in sleeves corticosteroids should be administered. surrounding areas of perivascular in- Generally, the course of corticosteroids flammation (Figure 3-3). This patho- should be initiated within a short time, logic picture is distinct from MS, typically within a few days, because which features confluent demyelination, patients with ADEM are often very ill. prominent and confluent macrophage In patients with clinical deterioration in infiltration, and reactive astrocytes.1 spite of treatment with high-dose corti- Recently, a distinctive microglial acti- costeroids, a brain biopsy should be vation and aggregation without corti- considered, which can evaluate for both cal demyelination similar to that seen ADEM and other diagnoses. in MS has been observed in patients

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FIGURE 3-3 Representative brain biopsies illustrating the observed patterns of demyelination that may be found in patients with clinically defined acute disseminated encephalomyelitis. A, Perivenous sleeve of inflammation and demyelination (20Â); B, Three coalescing perivenous lesions (60Â); C, Extensive region of confluent demyelination with areas of perivenous demyelination in the periplaque white matter (4Â). Luxol fast blue myelin stain and periodic acidYSchiff counterstain was used for all three images.

Reprinted with permission from Young NP, et al Brain.1 B 2010, Guarantors of Brain. brain.oxfordjournals.org/content/133/2/333.long.

KEY POINT with ADEM, which was highly associ- diseases of a variety of types, although h Acute disseminated ated with coma.1 very limited experience is available for encephalomyelitis is The prognosis of ADEM is highly ADEM. IV immunoglobulin and other associated with variable and depends in large part on immunosuppressive agents similarly perivenous sleeves of the accuracy of the diagnosis, which have been supported in case reports demyelination and has been poor in the existing literature and small series.6,7 perivascular inflammation, rather than confluent because of the lack of a specific di- TRANSVERSE MYELITIS demyelination and agnostic test and the rarity with which macrophages and biopsy is obtained to differentiate from The term ‘‘transverse myelitis’’ de- reactive astrocytes, as in fulminant MS or other acute leuko- scribes a heterogeneous collection of acute multiple sclerosis. encephalopathies. Therefore, firm acute and subacute infectious and guidance for patients and their families noninfectious inflammatory spinal regarding prognosis is difficult. In cord syndromes. Cases of myelitis general, the outcome in definite ADEM were first described in the 19th cen- is favorable if the course is not compli- tury. Inflammatory demyelination was cated by supervening complications recognized as the underlying pathol- (eg, sequelae of status epilepticus), ogy in fatal postvaccinal encephalomy- because demyelination and acute axo- elitis (smallpox and rabies vaccines) in nal pathology is usually less severe than the 1920s. The annual incidence of other fulminant inflammatory disor- postinfectious or idiopathic forms of ders such as Marburg variant MS (an transverse myelitis is estimated to be acute, monophasic form of MS that 1.3 to 8 cases per million population.8 typically leads to death from a hernia- When MS myelitis is included, the tion syndrome or brainstem dysfunc- annual incidence approaches 25 per tion within days or weeks from onset). million. Modern diagnostic neuroim- No randomized clinical trials of aging, CSF analysis, and laboratory ADEM have been conducted. The techniques enable a specific diagnosis standard of treatment based on em- and prognosis in most cases of trans- pirical studies is high-dose IV cortico- verse myelitis. steroids, typically administered at 1 g/d The consensus inclusion criteria (in children 10Y30 mg/kg/d) for 5 days for diagnosis of idiopathic transverse followed by a taper of oral prednisone myelitis is outlined in Table 3-3 and over 3 to 6 weeks. Plasma exchange is includes the clinical features common effective in acute, severe demyelinating to all potential etiologies of myelitis.9

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS a h TABLE 3-3 Diagnostic Criteria for Transverse Myelitis Transverse myelitis is classified clinically b Development of sensory, motor, or autonomic dysfunction attributable to the based on whether it is spinal cord. complete or incomplete, b Bilateral signs and/or symptoms (although not necessarily symmetric). which may assist with differential diagnosis. b Clearly defined sensory level. h b Exclusion of extra-axial compressive etiology by MRI. Neuromyelitis optica is strongly associated b Inflammation within the spinal cord demonstrated by CSF pleocytosis or with a longitudinally elevated IgG index or gadolinium enhancement. If none of the inflammatory criteria is met at symptom onset, repeat MRI and lumbar puncture evaluation extensive transverse between 2 and 7 days later. myelitis lesion. b Progression to nadir between 4 hours and 21 days following the onset of symptoms. a Modified with permission from Transverse Myelitis Consortium Working Group, Neurology.9 B 2002, American Academy of Neurology. www.neurology.org/content/59/4/499.short?sid= 68d5cae0-275d-41e5-9a2b-9834280d8f5d.

Most patients present with a combina- ness and asymmetric or dissociated tion of sensory, motor, and bladder- sensory symptoms) is more likely to or bowel-related symptoms suggestive herald MS with high risk for future of myelopathy. Lhermitte sign (an relapses.11 Nonetheless, the clinical electrical or dysesthetic sensation in presentation may not be concordant the spine or limbs, elicited by neck with neuroimaging findings, which are flexion) and paroxysmal tonic spasms likely more reliable than clinical man- (repeated, brief [30- to 90-second], ifestations in determining the underly- stereotypic attacks of painful limb or ing etiology. MS-related myelitis is truncal muscle spasms, with or without usually characterized by short-segment, sensory symptoms, often triggered by peripheral cord lesions, whereas NMO limb movement) are hallmarks of de- is strongly associated with a longitudi- myelinating disease and suggest that nally extensive transverse myelitis the myelitis syndrome may be caused (LETM) lesion that extends contiguously by MS or NMO. over three or more vertebral segments Transverse myelitis is classified clin- (seen best on sagittal T2-weighted MRI) ically based on whether it is complete and usually affects the central cord or incomplete, which may assist with (Figure 3-4).12 However, other diseases differential diagnosis.10 A ‘‘complete’’ (including infarction, viral and other cord lesion, which manifests as a infections, syringomyelia, and sarcoid- relatively symmetric moderate or se- osis) can cause a long cord lesion in vere loss of motor and sensory mo- the central cord that mimics LETM.13 dalities caudal to the level of the The differential diagnosis of trans- lesion, suggests a monophasic disorder verse myelitis is extensive and summa- (infectious, parainfectious, or idiopath- rized in Table 3-4. Figure 3-5 outlines a ic transverse myelitis) or relapsing systematic diagnostic approach, which NMO. In contrast, a ‘‘partial’’ myelitis focuses on establishing that the mye- syndrome (ie, incomplete or patchy lopathy is inflammatory and then involvement of at least one spinal identifying a causative agent or under- segment with mild to moderate weak- lying disease (Case 3-2).

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FIGURE 3-4 Spinal cord MRI in multiple sclerosis (MS) and neuromyelitis optica. A, Sagittal T2-weighted MRI of the cervical spinal cord demonstrates typical dorsal, short-segment signal abnormalities (arrows) characteristic of MS. B, In contrast, patients with acute myelitis in the setting of neuromyelitis optica typically have longitudinally extensive, expansile, centrally located cord lesions that may extend into the brainstem (arrows) (sagittal T2-weighted cervical spinal cord MRI). C, On T1-weighted sagittal MRI sequences, such acute lesions may be hypointense (arrows), suggesting necrosis and cavitation, while exhibiting enhancement with IV gadolinium administration (arrowheads), indicative of active inflammation.

Reprinted from Wingerchuk DM, et al, Lancet Neurol.12 B 2007, with permission from Elsevier. www.thelancet.com/journals/laneur/article/PIIS1474- 4422(07)70216-8/fulltext.

TABLE 3-4 Concise Differential Diagnosis and Evaluation for Transverse Myelitisa

Etiology Diagnostic Tests Infection Blood serology CSF culture, serologies, PCR Chest radiograph; other imaging as indicated Systemic autoimmune/ Clinical examination findings inflammatory disease Serologic studies Chest and joint radiographs Other tests and/or imaging directed by history and examination Paraneoplastic Chest radiography, CT, and/or body imaging Comprehensive serum and CSF paraneoplastic antibody panel Acquired CNS demyelinating Brain MRI with gadolinium disease (multiple sclerosis/ CSF examination for cell count/differential, neuromyelitis optica) oligoclonal bands, and IgG index Visual evoked potentials Postinfectious or Clear, recent history of infection or vaccination postvaccinal Serologic confirmation of recent infection Exclusion of other causes a Data from Frohman EM, Wingerchuk DM, N Engl J Med.10 www.nejm.org/doi/full/10.1056/ NEJMcp1001112.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 3-5 Diagnostic algorithm for acute myelopathies and myelitis. A systematic approach to the evaluation of acute myelopathy syndromes allows for diagnosis of transverse myelitis and its etiology. MS = multiple sclerosis; NMO-IgG = neuromyelitis opticaYimmunoglobulin G; TM = transverse myelitis. Reprinted from Frohman EM, Wingerchuk DM, N Engl J Med.10 B 2010, with permission from Massachusetts Medical Soceity. www.nejm.org/doi/full/10.1056/NEJMcp1001112.

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Case 3-2 A 52-year-old woman with a history of vitiligo and hypothyroidism experienced progressive truncal and bilateral lower extremity numbness over 9 days. She lost the ability to walk and developed urinary retention at day 14. Examination revealed moderately severe paraparesis, a T8 sensory level, and repetitive, involuntary, painful right lower extremity spasms each lasting 30 to 40 seconds. MRI (Figure 3-6) revealed an active longitudinally extensive transverse myelitis (LETM) lesion. Brain MRI was normal, CSF showed a lymphocytic pleocytosis (44 white blood cells/2L) but normal IgG index and no oligoclonal bands. Laboratory testing revealed vitamin B12 deficiency (level 169 ng/L) with positive parietal cell antibodies, positive antinuclear antibody (1:160), and positive neuromyelitis optica (NMO)YIgG (aquaporin-4 antibody). Her spasms resolved within 6 hours of receiving 200 mg oral carbamazepine. She made a complete neurologic recovery after corticosteroid infusions and vitamin B12 replacement. She was also treated with mycophenolate mofetil with no evidence of recurrent CNS disease 3 years later. Comment. This case illustrates a first-ever attack of LETM; aquaporin-4 seropositivity denotes an NMO spectrum disorder with high risk for relapse and need for immunosuppression. The paroxysmal tonic spasms are common in LETM and usually respond well to carbamazepine therapy. The vitamin B12 deficiency and positive antinuclear antibody reflect coexisting systemic autoimmunity in the context of NMO.

FIGURE 3-6 Sagittal thoracic spine MRI shows a longitudinally extensive transverse myelitis lesion (A, T2-weighted sequence) and gadolinium enhancement (B, T1-weighted sequence).

Neuroimaging characteristics are porting a diagnosis of myelitis. As critical for diagnosis. Identification of discussed above, the lesion pattern an intramedullary cord lesion, espe- (short peripheral lesions versus longi- cially if it exhibits postgadolinium tudinally extensive central lesions) of- enhancement, is very helpful in sup- fers substantial diagnostic guidance. In

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS the setting of partial myelitis, detection spiratory tract syndrome or fever), or h Spinal cord biopsy of brain MRI lesions characteristic for a vaccination. Because a systemic in- should be reserved for MS (eg, periventricular, juxtacortical, fection or vaccination may trigger in- situations in which there or posterior fossa lesions) strongly flammatory neurologic events in is concern for a disorder predicts future conversion to MS. Re- patients with underlying diseases such requiring pathologic vised MS diagnostic criteria permit a as MS or NMO, comprehensive diag- diagnosis, especially if diagnosis of MS in the presence of a nostic evaluation is still indicated be- progressive neurologic combination of gadolinium-enhancing fore concluding that the infection or dysfunction continues and nonenhancing white matter le- vaccination is the primary cause of the despite therapy and no sions.14 Detection of CSF pleocytosis myelitis. A presumed diagnosis of other site presents a supports an inflammatory etiology, monophasic parainfectious, postinfec- likely informative biopsy target. and other tests on CSF, including tious, or postvaccinal transverse myeli- serology and PCR, may establish a tis may be appropriate when the h Because a systemic specific inflammatory or infectious workup is negative, recognizing its infection or cause. CSF oligoclonal bands are an inherent limitations. In one-third to vaccination may trigger inflammatory independent predictive factor for later one-half of transverse myelitis cases, an 15 neurologic events in conversion to MS. No clinical, bio- extensive neurologic and medical inves- patients with underlying logical, or MRI factor at onset is tigation reveals no underlying cause or diseases such as predictive of long-term disability. Labo- disease, and the term ‘‘idiopathic trans- multiple sclerosis or ratory studies for viral, rickettsial, and verse myelitis’’ is applied. Patients in neuromyelitis optica, other infectious diseases; serologic test- this category generally have a low risk comprehensive ing; and selected cultures obtained at of either recurrent myelitis or other diagnostic evaluation presentation may be informative under disorders such as MS or NMO. is still indicated before specific circumstances. Autoimmune Treatment of transverse myelitis de- concluding that the serology should be obtained, especially pends on its etiology.10,11 Acute treat- infection or vaccination to detect aquaporin-4 (AQP4) anti- ment of noninfectious myelitis includes is the primary cause of bodies (also known as NMO-IgG) a trial of IV methylprednisolone (ie, the myelitis. associated with NMO.11 Some non- 1 g/d for 3 to 5 days), with an optional h Severe myelitis attacks infectious inflammatory disorders re- oral prednisone taper afterwards. Se- that do not respond quire systemic evaluation, such as body vere attacks that do not respond well well to corticosteroids imaging (eg, for sarcoidosis) or para- to corticosteroids may improve with a may improve with a course of plasma neoplastic antibody panel for myelitis course of plasma exchange (five to exchange. related to occult malignancy. Spinal seven exchanges over 10 to 14 days).11 h Y cord biopsy should be reserved for The need for plasma exchange would Aquaporin-antibody situations in which there is concern for be more common with NMO, post- positive longitudinally extensive transverse a neoplastic, vasculitic, or other disor- infectious, or idiopathic myelitis than myelitis is highly der that has evaded diagnosis and in with MS. Immunomodulatory or immu- likely to relapse early which no other site presents a likely nosuppressive therapy is only indicated (approximately 60% informative biopsy target. Attention if the cause of myelitis poses significant risk at 1 year), and has recently been drawn to the sub- risk of relapse. MS disease-modifying immunosuppressive stantial risk of further neurologic defi- therapy is indicated after a single epi- therapy is cit complicating spinal cord biopsy that sode of myelitis in which MS is the recommended. can be eliminated by a positive test likely cause. AQP4 antibodyYpositive for AQP4 antibodies in many patients LETM is highly likely to relapse early with NMO.16 (approximate 60% risk at 1 year), and Up to half of myelitis events are immunosuppressive therapy is recom- preceded or accompanied by an identi- mended (see section on NMO treat- fiable viral illness, a clinical prodrome ment). Diagnosis of specific infections, suggestive of infection (eg, upper re- connective tissue diseases, vascular

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causes, or paraneoplastic disease may NEUROMYELITIS OPTICA require interventions such as antiviral Historical Perspective or other antimicrobial therapies, immu- NMO was originally recognized as a nosuppression, or detection and re- clinical syndrome characterized by moval of the underlying malignancy, bilateral optic neuritis and severe as appropriate. myelitis that occurred in quick succes- The prognosis for a patient to sion. Although recognized by several regain function after transverse myeli- authors in the late 19th century, tis is highly dependent on its etiology. Devic’s description of a single case Partial cord syndromes seen in MS are with neuropathologic analysis and a typically mild to moderate in severity thesis by his student, Gault, captured and plateau after days to 2 to 4 weeks, the most attention and led Acchiotte and patients typically recover well, to propose the eponym ‘‘Devic dis- although achievement of final recov- ease.’’17,18 The similarities between ery may take several months. Patients MS and NMO have been recognized, with complete cord syndromes may and the potential differences were a also recover, but these syndromes are matter of debate until the 21st cen- more likely to result in substantial tury. In general, most pre-1990 reports residual neurologic deficits. Overall, emphasized the nonrelapsing nature 50% to 70% of patients achieve at least of NMO and its tendency to spare partial recovery and ability to walk with the brain as key features differentiat- or without assistance. Neurologic ing it from MS. Around the same time, follow-up is required, particularly for reports from Asia, especially Japan, those patients judged to be at high risk described a condition called optico- for recurrent CNS disease. spinal MS, which had a higher frequency compared to classic MS. Opticospinal MS, like its ‘‘conven- tional’’ MS counterpart, was described TABLE 3-5 Diagnostic Criteria as a relapsing disorder, but was differ- for Neuromyelitis entiated from MS by virtue of its Opticaa frequent and severe attacks specifical- ly targeting the optic nerve and spinal b Optic Neuritis cord and by infrequent detection of b Acute Myelitis CSF oligoclonal bands. At that time, b At Least Two of the Three the key differentiating feature be- Supportive Criteria Below: tween opticospinal MS and NMO was Contiguous spinal cord MRI the temporal course: monophasic for lesion extending over three or more vertebral segments NMO and relapsing for opticospinal (reliably assessed in the MS. In the late 20th century, several context of an acute myelitis) groups recognized that the majority of Brain MRI not meeting diagnostic patients with severe optic nerve and criteria for multiple sclerosis spinal cord selective demyelinating Neuromyelitis opticaYIgG disease in western countries typically seropositive status had a relapsing course, blurring the a Adapted from Wingerchuk DM, et al, distinction between NMO and opti- Neurology.22 B 2006, American Academy of Neurology. www.neurology.org/content/ cospinal MS. Diagnostic criteria for 66/10/1485.short?sid= c5435b8d-ac14- NMO were proposed, emphasizing 439a-9754-e244754ec58f. specific clinical, MRI, and CSF features that appeared to distinguish NMO

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS from MS. A landmark observation in more typical symptoms of NMO and h The term ‘‘neuromyelitis 2004 reported a high frequency of a were associated with AQP4-specific optica spectrum specific autoantibody in both western autoantibodies. Patients with NMO disorders’’ includes a NMO and typical Japanese opti- typically present with isolated trans- series of well-described cospinal MS. One year later, the verse myelitis or unilateral optic neuri- clinical and radiologic NMO autoantibody was found to be tis. They are frequently, if not usually, syndromes associated specific for AQP4.19 Later immuno- seropositive at initial presentation. To with aquaporin-4 pathologic studies and passive transfer embrace these patients under a more seropositivity. experiments provided strong evi- general rubric, the term ‘‘neuromyelitis h After an initial dence for the pathogenic nature of optica spectrum disorders’’ was pro- clinical presentation this autoantibody.20 At the present posed to comprise a group of patients of a neuromyelitis time, no clear distinguishing charac- who probably had the same biological opticaYtypical clinical teristics between Asian opticospinal disorder even though they did not syndrome such as MS and relapsing NMO have been satisfy the strict 2006 criteria.12 An intractable vomiting documented. international panel is currently deter- and hiccup, isolated longitudinally extensive mining the syndromes that warrant Definitions and Classification transverse myelitis, or inclusion under this rubric. Several of optic neuritis, detection The most widely accepted diagnostic the brain syndromes seem to be united of aquaporin-4 criteria were those proposed by in- by their tendency to target AQP4, which autoantibodies vestigators at Mayo Clinic originally is identified either by MRI lesions predicts a high risk of 21 in 1999 and then revised in 2006 in AQP4-rich areas or selective loss of subsequent attacks. (Table 3-5).22 The1999criteria AQP4 demonstrated on brain biopsy predated the novel biomarker. Fur- tissue. thermore, the 1999 criteria proved NMO is currently classified as being insufficiently rigorous to distinguish either monophasic (nearly simulta- NMO from some cases of MS with neous bilateral optic neuritis and my- normal brain MRI scan at presentation. elitis with no subsequent relapses) or The revised criteria in 2006 were relapsing (usually, but not always, simplified and modified to include an presenting with unilateral optic neuri- independent criterion of AQP4 auto- tis or myelitis, followed by relapses antibody seropositivity, although its that can include either optic neuritis detection was not required because or myelitis, or less frequently cerebral of its imperfect sensitivity. Respecting involvement). These subtypes seem to historical tradition and clinical obser- differ in important ways; the relapsing vations at that time, those criteria form is more commonly associated require both optic neuritis and trans- with AQP4 autoantibodies and also verse myelitis for diagnosis. At approx- affects women and older individuals imately the same time, a variety of more commonly than the monophasic clinical observations emerged in pa- form.23 Some have suggested that the tients with otherwise definite NMO much less common monophasic form and in some patients who had limited may be a limited form of ADEM. symptoms of NMO. These observa- Familial cases have been reported but tions suggested that an even broader constitute fewer than 5% of cases.24 spectrum of syndromes existed under the NMO designation, such as intrac- Pathophysiology table vomiting and lesions (both NMO has been suspected to have symptomatic and asymptomatic) of unique pathogenesis and to be a the circumventricular organs. These syn- vasculocentric disease based on im- dromes sometimes preceded other, munopathologic studies reported in

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KEY POINT 25 h Patients with the early 2000s. The presence of neuritis, 43% myelitis, 5% brain or neuromyelitis optica perivascular immunoglobulin and acti- brainstem presentations in isolation, with concomitant vated complement suggested a 4% optic neuritis and simultaneous systemic lupus humoral-mediated injury to an antigen myelitis, and 7% mixed presentations 31 erythematosus or expressed on or near microvessels. (eg, optic neuritis and brain). Optic high-titer antinuclear With the discovery of a specific autoan- neuritis and myelitis may be difficult to autoantibodies have tibody, advances rapidly led to the distinguish from those that occur in been commonly labeled identification of AQP4-specific anti- MS, and are variable in severity. Typi- as having lupus myelitis bodies that target extracellular domains cally, the clinical manifestations are in the past and are now of this protein. This targeting is partic- more severe than those in MS. Trans- increasingly accepted ularly avid when the protein forms large verse myelitis in NMO may be partial as having concomitant aggregates, as occurs when a certain neuromyelitis optica and (ie, unilateral, motor, or sensory) or systemic autoimmune long AQP4 isoform called M23 is complete (ie, bilateral, motor, and sen- disease. expressed. Although no active immuni- sory); by contrast, transverse myelitis zation model has yet been reported, due to MS is rarely complete. Radio- numerous investigators have been able logically, the manifestations overlap, to use different passive transfer strate- although lesions tend to be consider- gies when the blood-brain barrier is ably longer, especially in the spinal directly bypassed (ie, by intracerebral cord. A lesion length of three or more injection) or opened either by concom- spinal segments is widely accepted to itant induction of T-cellYmediated ex- effectively distinguish NMO from MS. 26 perimental allergic encephalomyelitis Some NMO exacerbations may not be or by injection of complete Freund ad- associated with long spinal cord le- 27 juvant. Lesions produced by passive sions, particularly in patients receiving transfer have many of the characteristic immunosuppressive treatment. immunopathologic findings of NMO. NonYoptic nerve and spinal cord AQP4-specific autoantibodies are of symptoms include the following, in IgG1 isotype and are therefore believed general order of frequency: to be dependent on T-cell help. A 1. Intractable vomiting and/or hiccup variety of studies support the impor- typically associated with lesions tance of T-helper 17 (Th17) cells in this in the area postrema, either in condition, including similar pathology contiguity with a myelitis lesion or (frequent neutrophilic infiltration) to as an isolated lesion (Case 3-3)V Th17-polarized experimental allergic 28 this occurs in approximately 20% to encephalomyelitis, elevated serum 29 30% of cases and can be the first and CSF levels of interleukin 6 (IL-6) 32 (which is a potent inducer of Th17 manifestation of the disease differentiation), elevated levels of IL-17 2. Symptomatic forms of narcolepsy or in CSF of NMO patients, and the states of altered consciousness associated with hypothalamic lesions predilection of an immunodominant 33 residue of AQP4 to induce a Th17- and reduced CSF hypocretin levels polarized response.30 3. Encephalopathy associated with diffuse white matter CNS lesions Clinical Features that may appear similar to ADEM The dominant manifestations in most Other uncommon presentations or patients are optic neuritis and myelitis. complications include posterior re- In a recent series of seropositive pa- versible encephalopathy syndrome tients, the frequencies of specific pre- (PRES) and hyponatremia during at- sentations were as follows: 41% optic tacks of NMO.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Case 3-3 A 34-year-old man presented with recurrent vomiting that remained unexplained after thorough gastroenterologic evaluation. The vomiting subsided but was shortly followed by imbalance and leg weakness. A lesion was detected in his cervical spinal cord extending from the medulla through C6 on T2-weighted sequences, and focal gadolinium enhancement was evident in the medulla, as well as some subpial/leptomeningeal enhancement (Figure 3-7). He improved after corticosteroid treatment. CSF revealed 12 white blood cells/2L, absent oligoclonal bands, and a total protein level of 80 mg/dL. He had multiple recurrent events of myelitis over the ensuing months, all associated with longitudinally extensive spinal cord lesions. Episodes of myelitis were prevented by azathioprine treatment, but stopping azathioprine was followed by recurrent episodes of myelitis. He responded satisfactorily to treatment with corticosteroids after each attack. Repeated tests for aquaporin-4 autoantibodies in serum and testing of CSF on one occasion yielded negative results. Chest x-ray and serum angiotensin-converting enzyme were normal. Comment. This case illustrates that recurrent attacks of longitudinally extensive myelitis, especially when preceded by intractable vomiting (a signature syndrome of neuromyelitis optica [NMO]), may lead to a working diagnosis of NMO spectrum disorder; this is true even when there has been no history of optic neuritis. Similarly, recurrent optic neuritis alone may be an indicator of NMO syndrome when NMO-IgG is detected; the proportion of cases with recurrent optic neuritis that are seropositive for NMO-IgG is lower than cases of recurrent myelitis. Often NMO-IgG may be negative in cases of clinically definite NMO; depending on the specific assay used, the seronegative rate in highly suspect cases is between 30% and 50%.

FIGURE 3-7 Cervical spinal cord MRI. Sagittal imaging reveals a longitudinally extensive transverse myelitis lesion (A, T2-weighted sequence) associated with cord swelling (B, T1-weighted sequence) and focal gadolinium enhancement (C, T1-weighted sequence).

NMO is commonly associated with nuclear autoantibodies have been com- other autoimmune diseases, especially monly labeled as having lupus myelitis systemic lupus erythematosus and in the past and are now increasingly Sjo¨gren syndrome.34 Myasthenia accepted as having concomitant NMO gravis occurs more commonly than and systemic autoimmune disease. expected in NMO.35 The association with systemic autoimmunity has led to Differential Diagnosis confusion in the past. Patients who The differential diagnosis is largely have NMO with concomitant systemic that of optic neuritis and of myelitis lupus erythematosus or high-titer anti- as most patients present with one of

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KEY POINTS h A broad range of brain these syndromes. Once other ophthal- verse myelitis in NMO), intrinsic tumors lesions have been mic disorders such as acute glaucoma of the spinal cord (which rarely present described in association or retinal venous occlusion have been acutely), and other inflammatory and with neuromyelitis excluded, the major entities to be con- paraneoplastic disorders. optica and aquaporin-4 sidered in the differential diagnosis of Occasional patients present with antibodies. optic neuritis are ischemic optic neu- simultaneous optic neuritis and myeli- h Aquaporin-4 antibody ropathy (sometimes associated with tis, in which case the differential testing is approximately giant cell arteritis), toxic and metabolic diagnosis is more limited. Rare pa- 70% sensitive and more amblyopia, compressive lesions of the tients have independent causes for than 90% specific for optic nerve, sarcoidosis, and other optic neuropathy and myelopathy syn- neuromyelitis optica. infiltrative disorders of the optic nerve. dromes (eg, ischemic optic neuropa- The entities to be considered in the thy and a viral myelitis). Conditions differential diagnosis of acute longitu- other than NMO that result in both dinally extensive myelitis are spinal inflammatory optic neuropathy and cord infarction, viral myelopathies, myelopathy include other CNS demy- postinfectious inflammatory transverse elinating syndromes (MS, ADEM), sar- myelitis (which is clinically and radio- coidosis, paraneoplastic disorders (ie, logically indistinguishable from trans- syndromes associated with collapsing

TABLE 3-6 Diagnostic Utility of Characteristics of Neuromyelitis Optica

Relative Diagnostic Characteristic Findings in Neuromyelitis Optica Utility Race/ethnicity NMO affects any race/ethnicity but accounts ++ for a smaller proportion (approximately 1% to 2%) of cases of CNS demyelinating disease in white patients as compared to other groups (eg, 30% or more of African, Asian, and American Indian patients) Gender Predilection for women (80% in NMO versus 65% + in MS) Attack severity Optic neuritis and transverse myelitis attacks are more ++ severe than in MS Attack characteristics Paroxysmal tonic spasms ++ Greater risk for neurogenic respiratory failure from ++ acute, ascending cervical transverse myelitis in NMO compared with MS Attack residual Greater residual impairment than in MS attacks ++ Brain MRI Normal or nonspecific findings not meeting MS MRI +++ criteria Hypothalamic lesions ++++ Spinal cord MRI T2-weighted lesion extending contiguously over at ++++ least three vertebral segments CSF cell count and 950 white blood cells/2L; neutrophil predominance +++ differential CSF immunoglobulin Negative IgG index and absence of unique oligoclonal + studies bands NMO-IgG Seropositive ++++ NMO = neuromyelitis optica; MS = multiple sclerosis.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS response mediator protein-5 [CRMP-5], typical of MS. Diencephalic and h Permanent neurologic which can include optic neuritis and periaqueductal lesions are also typical disability from myelitis), and rarely CNS malignancy. in NMO. Lesions may occur in the area neuromyelitis optica is The potential overlap with systemic postrema within the dorsal medulla, almost all attack-related lupus erythematosusYassociated optic particularly in patients with bouts of (secondary progressive neuritis and myelitis was discussed above, nausea, vomiting, or hiccups. neuromyelitis optica is and most such cases probably reflect Detection of a LETM lesion on rare); therefore, coexistent NMO rather than a causative spinal cord T2-weighted sagittal MRI attack-prevention role of systemic lupus erythematosus. is a common and very specific neuro- strategies are the Clinical, radiologic, and other labo- imaging finding for NMO. In the acute key to preservation ratory characteristics that should be phase, the lesion usually exhibits gad- of function. used in differentiating MS from NMO olinium enhancement, and on preY h Standard multiple are outlined in Table 3-6. gadolinium T1-weighted imaging may sclerosis therapies " appear hypointense. Acute cervical cord such as interferon- , Diagnostic Methods lesions sometimes ascend into the brain- natalizumab, or fingolimod may worsen stem. After several weeks or months, Beyond recognition of clinical syn- neuromyelitis optica. If it dromes associated with NMO and LETM lesions may disappear or resolve is unclear whether a exclusion of competing diagnoses, into several small, patchy lesions that patient has neuromyelitis the main contributors to NMO diag- can be mistaken for smaller MS plaques. optica or multiple nosis are brain and spinal cord MRI Serology. The detection of serum sclerosis, an and serologic assessment. AQP4 antibodies is approximately 70% immunosuppressive Neuroimaging. At or near clinical sensitive and more than 90% specific treatment strategy onset, brain MRI in roughly 90% of for NMO.19 In the setting of optic typically used for patients is either normal or reveals neuritis, LETM, or both, the presence neuromyelitis optica only nonspecific white matter lesions of AQP4 antibodies provides strong should be considered that do not fulfill MS criteria.21 Serial evidence for the diagnosis of NMO or to avoid inadvertent imaging reveals new asymptomatic a NMO spectrum disorder and in- disease aggravation. brain lesions in more than 60% of dicates high risk for recurrent optic patients, but the pattern usually re- neuritis or myelitis. The likelihood of a mains subcortical and nonspecific. In positive result diminishes if the pa- fact, the MRI pattern is typically not tient is already receiving immunosup- distinguishable from those caused by pressive therapy or after plasma small vessel cerebrovascular disease.36 exchange. Antibody levels may rise in In the context of acute optic neuritis, association with disease activity. There- increased T2 signal and gadolinium fore, it is reasonable to retest a previ- enhancement of the affected optic ously seronegative patient during a new nerve or chiasm may be seen and relapse. Rare patients who have been sometimes is longitudinally extensive. repeatedly seronegative have had AQP4 The discovery of AQP4 antibodies has antibody detected in CSF.38 allowed recognition of a broader spec- Several immunologic assays have trum of brain MRI lesions in the been developed for AQP4-antibody disease (Figure 3-8). Cerebral white detection. The original test was an matter lesions include large, confluent indirect immunofluorescence assay.19 subcortical lesions, sometimes with At present, the most widely available cloudlike gadolinium enhancement test is an enzyme-linked immunosor- or transient lesions reminiscent of bent assay (ELISA), and laboratories PRES.37 Corpus callosum lesions tend may report either dichotomous results to be block-shaped rather than (ie, positive or negative) or a quanti- the perpendicular ‘‘Dawson fingers’’ tative titer. Other assay methods

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FIGURE 3-8 Brain lesions in patients with neuromyelitis optica (NMO) and NMO spectrum disorders. Panels A, B, and C show cerebral hemispheric white matter lesions; panels D, E, and F show diencephalic lesions; panels G, H, and I show brainstem lesions. Extensive bihemispheric subcortical nonenhancing white matter fluid-attenuated inversion recovery (FLAIR) signal abnormality (A). Large confluent FLAIR signal abnormality in the right parietal area (B) with diffuse gadolinium enhancement (C). Images from one patient show FLAIR abnormality in the hypothalamus (F, arrow) and right cerebral peduncle (H, arrow). FLAIR signal abnormality in the thalamus (E, arrow), hypothalamus, and optic chiasm extending into the superior cerebellar peduncle and the floor of the fourth ventricle. Images from a patient with a confluent nonenhancing signal abnormality from the anterosuperior thalamus-hypothalamus (D, arrow) to the optic tracts behind the chiasm to the superior surface of the mesencephalon extending to the periaqueductal area (right to left) to the superior cerebellar peduncles, and the pontine tegmentum (I, arrows). Extension of T2-weighted MRI signal abnormality into the medulla (G, arrow).

Reprinted with permission from Pittock SJ, et al, Arch Neurol.36 B 2006, American Medical Association. archneur. jamanetwork.com/article.aspx?articleid=790890.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. include immunoprecipitation and cell- Lesions may reveal eosinophils within based assays, the latter of which in- a vigorous cellular infiltrate. More- volves cells that express human AQP4. over, in actively demyelinating NMO In a blinded, direct comparison of lesions, AQP4 is depleted, whereas in these methods, all assays had strong MS, similarly active plaques reveal specificity, but the cell-based assays AQP4 upregulation (Figure 3-9).40,41 demonstrated the highest sensitivity The authors do not generally advocate and may eventually become the refer- biopsy for NMO diagnosis, but in un- ence standard.39 usual situations, such as seronegative Pathologic examination. The vast patients with progressive leukoen- majority of NMO cases can be identified cephalopathy or extensive, treatment- using clinical criteria, MRI, and serologic unresponsive cord lesions, biopsy may testing. Some perplexing cases have be considered. undergone spinal cord or brain biopsy or come to autopsy, revealing immuno- Prognosis pathologic differences between NMO NMO is generally a more severe and MS. In particular, NMO is asso- disease than MS. Individual attacks ciated with vasculocentric deposition are more likely to result in a perma- of immunoglobulin and complement. nent neurologic deficit. In one study,

FIGURE 3-9 Comparison of aquaporin-4 (AQP4) immunoreactivity (IR) in active neuromyelitis optica (A, B) and multiple sclerosis (C, D) optic nerve lesions. A, Active demyelination with macrophages containing myelin oligodendrocyte glycoprotein (MOG)Yimmunoreactive myelin debris (arrowheads), adjacent to periplaque white matter (asterisk). B, AQP4 is lost in the active lesion but retained in the periplaque white matter (asterisk). C, Active demyelination with macrophages containing proteolipid protein-immunoreactive myelin debris (arrowheads), adjacent to periplaque white matter (asterisk). D, AQP4 IR is increased in both the active lesion and periplaque white matter (asterisk). Immunohistochemistry: A, MOG; B, D, AQP4; C, proteolipid protein.

Reprinted with permission from Roemer SF, et al, Brain.40 B 2007, Guarantors of Brain. brain.oxfordjournals.org/content/ 130/5/1194.long.

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50% of NMO patients were blind in at been reported with other MS therapies least one eye or required ambulatory such as natalizumab and, less convinc- assistance within 5 years of disease ingly, fingolimod.46,47 Therefore, in onset.42 Unlike typical MS, in which situations where the diagnosis remains most disability accrues during a sec- uncertain between NMO and MS, the ondary progressive disease phase, authors favor starting with an NMO NMO disability occurs as a result of immunosuppression strategy because individual attacks, and gradually pro- it is likely to provide benefit in treating gressive disability like that seen in either disease, and the subsequent secondary progressive MS is rare.43 clinical course will usually reveal the The expansion of the NMO spectrum correct diagnosis. has probably uncovered milder and General immunosuppression strat- more heterogeneous cases. Recently, egies. Patients with established relaps- French investigators asked whether ing NMO and those deemed to be at ‘‘benign’’ NMO exists by evaluating high risk for relapse (eg, patients with outcomes of 175 patients with NMO seropositive NMO spectrum disorder over 10 years.44 Although mild disabil- such as those with first-ever LETM or ity was noted in about 12% of these optic neuritis) require long-term im- patients (compared with 22% of MS munosuppressive therapy.12,48 The patients over that time frame), several most common approaches to immu- of them experienced a disabling attack nosuppression include oral drugs (eg, before year 15. Therefore, all NMO azathioprine or mycophenolate mofetil) patients should be considered at risk or parenteral drugs (eg, rituximab). In of disabling attacks. Together with the retrospective series, these agents appear rarity of a secondary progressive NMO to reduce relapse rates by 30% to 70%, course, this attack-related threat em- but no controlled or comparative stud- phasizes the importance of attack- ies have confidently established the prevention strategies to prevent disability. magnitude of treatment effect. Azathio- prine and mycophenolate have delayed Treatment onset of action and typically require Treatment of NMO is evolving because bridge therapy for 4 to 6 months, usually of collective longitudinal experience in with oral prednisone (40 to 60 mg/d). large care centers and advances in Rituximab (1000 mg/d twice, 2 weeks understanding disease pathobiology. apart, with retreatment approximately There are no randomized controlled every 6 months) is fully active within trials for NMO therapies. about 2 weeks but is substantially more Acute attacks are typically treated expensive. In some countries, with corticosteroids and, if necessary, mitoxantrone, methotrexate, or chronic rescue plasma exchange as outlined in oral prednisone represent the mainstay the discussion of transverse myelitis. of preventive therapy; a consensus sum- Relapse prevention strategies are meant mary review of the use of these therapies to reduce or eliminate the effects of was recently published.48 pathogenic AQP4 antibodies, either Regardless of which drug is selected, directly or indirectly. The importance the goal of therapy is elimination of of accurate diagnosis has been height- acuterelapsesbyoptimizingdrugdos- ened recently because of a number of age, retreatment frequencies, and com- reports indicating that the standard MS pliance. Patient compliance can be therapy interferon-" aggravates NMO.45 monitored unequivocally for rituximab Furthermore, worsening of NMO has but only indirectly for azathioprine (ie,

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