Review Article Diagnostic Considerations in Acute Disseminated Encephalomyelitis and the Interface with MOG Antibody Jonathan D. Santoro1,2,3,4 Tanuja Chitnis1,2 1 Department of Neurology, Massachusetts General Hospital, Boston, Address for correspondence Jonathan D. Santoro, MD, Department of Massachusetts, United States Neurology, Massachusetts General Hospital, 55 Fruit Street, ACC 708, 2 Department of Neurology, Harvard Medical School, Boston, Boston, MA 02114, United States (e-mail: [email protected]). Massachusetts, United States 3 Department of Neurology, Children’s Hospital of Los Angeles, Los Angeles, California, United States 4 Keck School of Medicine, University of Southern California, Los Angeles, California, United States Neuropediatrics Abstract Acute disseminated encephalomyelitis (ADEM) is a common yet clinically heterogenous syndrome characterized by encephalopathy, focal neurologic findings, and abnormal Keywords neuroimaging. Differentiating ADEM from other demyelinating disorders of childhood ► ADEM can be difficult and appropriate interpretation of the historical, clinical, and neurodiag- ► acute disseminated nostic components of a patient’s presentation is critical. Myelin oligodendrocyte glycopro- encephalomyelitis tein (MOG) antibody-associated diseases are a recently recognized set of disorders, which ► diagnosis include ADEM presentations, among other phenotypes. This review article discusses the ► treatment clinical diagnosis, differential diagnosis, interpretation of data, and treatment/prognosis of ► MOG antibody this unique syndrome with distinctive review of the spectrum of MOG antibodies. Introduction activated T cells recruits additional immune cells to the CNS leading to primary injury of white matter.7 Although more Acute disseminated encephalomyelitis (ADEM) is an immune- nuanced than described, for the scope of this review, the mediated disorder of the central nervous system (CNS), affect- authors will focus on the clinical aspects of the disease and ing both children and adults. The estimated incidence of ADEM its interface with emerging literature on myelin oligodendro- in children ranges between 0.2 and 0.4/100,000 and is without cyte glycoprotein (MOG) antibody. ethnic or racial predilection.1,2 Studies have identified margin- 3 Downloaded by: Universitätsbibliothek. Copyrighted material. ally higher rates of ADEM in males. The majority of cases occur Clinical Diagnosis in children ofage 9 years or younger and, interestingly, the rates of hospitalization for this disorder have increased over the past The diagnosis of ADEM is based on historical, clinical, and decade.4 radiologic findings. There is no single diagnostic test that is The pathogenesis and pathophysiology of ADEM are not consideredconfirmatory. For thisreason, the Pediatric Multiple fully understood. The most consistent proposed mechanism of Sclerosis Study Group generated criteria in 2007 and 20128 for disease is that of autoimmune priming by an environmental the diagnosis of ADEM to aid in the identification of this antigen (such as a virus or bacteria) which triggers the condition (►Table 1). production of myelin autoantigens that share antigenic deter- The clinical diagnosis of ADEM can be difficult in that minates with the causative pathogen.5 Historically, this pro- symptoms are often variable and are frequently polyfocal at cess has been divided into two phases: the priming/activation onset. Encephalopathy (defined as any alteration in mental state phase and the recruitment phase.6 The former phase is defined or behavior ranging from coma to irritability) is required for the byactivation and expansion of T cells with spread to the CNS. In diagnosis. In children, the degree of encephalopathy varies and the latter phase, production of cytokines and chemokines by patients may have more than depressed mental status, in fact, received © Georg Thieme Verlag KG DOI https://doi.org/ March 18, 2019 Stuttgart · New York 10.1055/s-0039-1693152. accepted after revision ISSN 0174-304X. June 3, 2019 ADEM and the Interface with MOG Antibodies Santoro et al. Table 1 ADEM diagnostic criteria3 Clinical features (all required) Characteristics MRI of the brain lesions A first polyfocal, clinical central nervous system event with Diffuse, poorly demarcated, large (>1–2cm)lesions presumed inflammatory demyelinating cause involving predominantly the cerebral white matter Encephalopathy that cannot be explained by fever, Deep gray matter lesions (e.g., involving the basal ganglia systemic illness, or postictal symptoms or thalamus) can be present No new clinical and MRI findings emerge 3 mo after the onset T1 hypointense lesions in the white matter are rare MRI of the brain is abnormal during the acute (3-mo) phase Abbreviations: ADEM, acute disseminated encephalomyelitis; MRI, magnetic resonance imaging. younger children may often present with irritability, aggression, between 15 and 50 WBC/μL.1,3,7,10 Protein counts in the CSF and other active behavioral changes.3 Additional neurologic are typically normal or mildly elevated (0.40–0.60 g/L), features include cerebellar ataxia, cranial neuropathy, hemi- although the range can be broad, between 0.10 and paresis/weakness, optic neuritis (ON) (which can include vision 2.7 g/L.1,3,5,10 Glucose levels in the CSF are almost uniformly loss, pain with eye movement, and/or afferent pupillary defect), normal. Gram stain and cultures provide additional specifics pyramidal dysfunction, and spinal cord dysfunction, which may for bacterial infections, while specific viral testing can be – or may not be consistent with a transverse myelitis (TM).1 3,5 tailored to the clinical history. Although in its infancy, Disturbances of language function, movement disorders, and metagenomic analysis of CSF is becoming increasingly utilized alterations in sensorium are appreciated with less frequency. as a means of identifying specific infectious agents; however, Associated nonneurologic findings include fever, meningismus, turnaround time and contamination of samples remain nausea/vomiting, and generalized weakness. The presence of problematic.12 While data are limited, there has been report area postrema syndrome is very rare and may indicate an of meningoencephalitis associated with MOG antibodies alternative diagnosis such as neuromyelitis optica spectrum which can complicate even the earlier interpretation.13 disorders (NMOSDs). In the setting of noninfectious CSF abnormalities and white As with other neuroimmunologic disorders, up to 72% of matter lesions on MRI of the brain, other inflammatory patients will have a non-life-threatening febrile illness days demyelinating disorders include multiple sclerosis (MS), prior to up to 3 weeks prior to neurologic symptom onset.3,5 MOG antibody-associated demyelination, antibody-associated Previously reported infections have included mycoplasma, limbic encephalitis, primary angiitis of the CNS, malignancy, Epstein–Bar’s virus, coronavirus, coxsackie virus, hepatitis, mitochondrial disease, and leukodystrophies. The presence of herpes simplex virus, human immunodeficiency virus, human TM and ON may occur concurrently but should be diagnosed in herpesvirus, parainfluenza virus, influenzas A and B, as well as the context of other neurologic findings and radiographic – measles, mumps, and rubella viruses.3,5,8 11 A minority of findings.3 Of note, nearly all demyelinating disorders of child- cases (5%) are associated with vaccination, including but not hood, including ADEM, have been linked with the presence of limited to: hepatitis B, influenza, diphtheria/pertussis/tetanus, MOG antibodies over the past few years and testing for this measles/mumps/rubella, pneumococcus, and polio.5 These from the serum is imperative for diagnostic and therapeutic cases are traditionally thought to be less severe and rarely purposes. Testing for this antibody is not recommended in the Downloaded by: Universitätsbibliothek. Copyrighted material. convert to polyphasic disease. The majority of patients diag- CSF which, interestingly, has a lower sensitivity than serum nosed with ADEM display a monophasic pattern with steady testing and when serum testing is performed.14,15 In addition, improvement and return to neurologic baseline within when tested, cell-based assays are recommended.14,15 Aqua- 3 months after onset of symptoms. porin-4 (AQP4) antibody is associated with NMOSD and should be tested from the serum as well as therapeutic interventions Neurodiagnostic Studies and Differential will vary dramatically in this population. The presence of both Diagnosis MOG and AQP4 antibodies is very rare and should prompt retesting.14 The differential diagnosis in a child who presents with poly- Additional diagnostic tools to consider in the CSF are testing focal neurologic abnormalities and encephalopathy is broad. of oligoclonal bands (OCB) and immunoglobulin G (IgG) syn- Viral and bacterial meningitis/encephalitis must be ruled out, thesis index. The former is present less frequently in patients especially in the presence of fever or leukocytosis. Lumbar with ADEM, although when present, it is associated with puncture is valuable in ruling infection in or out on the relapsing disease15 and may be an indicator of alternative differential diagnosis. Cell count with differential is helpful diagnoses.15,16 In a longitudinal study of children with ADEM, for evaluating pleocytosis (>5 white blood cell [WBC]/μL), and overall rates of OCB were 3%.1,10,17 OCBs are not a sensitive if present, with a neutrophilic or