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 dis- ease 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 944 www.ContinuumJournal.com August 2013 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 Continuum (Minneap Minn) 2013;19(4):944–967 www.ContinuumJournal.com 945 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. ADEM, Transverse Myelitis, and NMO 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