Acute Disseminated Encephalomyelitis
Eliza Gordon-Lipkin and Brenda Banwell
KEY POINTS FOR CLINICIANS
• Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder of the central nervous system that manifests as a polysymptomatic clinical presentation and must include encephalopathy.
• Multiphasic ADEM is a new event of ADEM 3 or more months after the first ADEM event.
• ADEM may be preceded by a viral infection, although specific infections have only rarely been directly identified.
• There is no single test that confirms the diagnosis of ADEM. As such, establishing the diagnosis requires both clinical and radiological features and the exclusion of other diseases that resemble ADEM.
• Repeat imaging studies are necessary to evaluate for accrual of subclinical lesions, or to evaluate patients with subsequent clinical attacks.
• Therapy for ADEM is based on expert consensus as there are no randomized controlled clinical trials to date. A course of 3 to 5 days of high-dose intravenous methylprednisolone is considered standard and can often provide significant clinical benefit.
• Rarely, an ADEM attack occurs as the first attack of multiple sclerosis. ADEM-like attacks can also be the first or subsequent attack in children with neuromyelitis optica spectrum disorder (NMOSD), and an increasingly recognized number of children with ADEM followed by recurrent optic neuritis (ON) have serum antibodies directed against myelin oligodendroglial protein (MOG).
ADEM is an inflammatory demyelinating disorder of the central nervous system (CNS) that is often preceded by an infection (1–3). The hallmark clinical presentation is a multifocal onset with encephalopathy manifesting as behavioral change or alteration in consciousness (1–3). ADEM can occur at any age, but tends to affect children more than adults, and usually strikes children younger than 10 years (4). There does not appear to be a clear gender predominance (5,6), although a possible increase in risk among males has been reported (1,3).
The hallmark clinical presentation for ADEM is a multifocal onset with encephalopathy manifesting as behavioral change or alteration in consciousness.
A challenge in diagnosing and studying ADEM has been the lack of formal diagnostic criteria. In 2007, an international panel of experts was organized by the National Multiple Sclerosis Society. This International Pediatric Multiple Sclerosis Study Group proposed consensus definitions for demyelinating diseases of childhood, which included ADEM. These definitions were updated in 2012 (1). ADEM is defined as a clinical CNS event with a presumed inflammatory demyelinating cause associated with typical MRI findings and encephalopathy that is not explained by fever alone (1). Other diagnoses, such as CNS infection, must be excluded. Appearance of new neurological findings, or MRI changes, within 90 days of ADEM onset is considered to be part of the same ADEM event (see Table 39.1 for full criteria). Of note, ADEM frequently follows a monophasic disease course; however, this can only be confirmed retrospectively after longitudinal observation.
A first polyfocal clinical CNS event with presumed inflammatory causea
Encephalopathy, that cannot be explained by fever, is defined as
1) Behavioral change
2) Alteration in consciousness
New event of ADEM (with encephalopathy) 3 or more months after the first ADEM event, with new or reemergence of prior clinical and MRI findings
No history of a clinical episode with features of a prior demyelinating event
No other etiologies can explain the event
New or fluctuating symptoms, signs, or MRI findings occurring within 3 mo of the inciting ADEM event are considered part of the acute event
No new symptoms or new MRI findings after 3 mo of initial event
Brain MRI is abnormal during the acute (3-mo) phase and shows “typical” features:
1) Diffuse, poorly demarcated, large (>1–2 cm) lesions involving predominantly the cerebral white matter
2) T1 hypointense lesions in the white matter are rare
3) Deep gray matter lesions (thalamus, basal ganglia) may be present
ADEM, acute disseminated encephalomyelitis; CNS, central nervous system; MS, multiple sclerosis.
aPresumed inflammatory cause infers exclusion of alternative etiologies (including infectious, metabolic/genetic, oncologic or vascular) and inclusion of supportive inflammatory features on diagnostic workup (see Imaging and Laboratory Findings sections).
Source: Adapted from Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler. 2013;19(10):1261–1267.
The incidence of ADEM is estimated to be about 0.4 to 0.6 per 100,000 per year among people younger than 20 years of age (6,7). More recent studies have grouped ADEM with other demyelinating diseases of childhood and have reported incidence rates of 0.9 to 1.6 per 100,000 person years (8–10). The incidence of ADEM does have seasonal peaks in the winter and spring, providing some suggestion of an infectious trigger (4,5,10,11). Reports of a prodromal illness preceding the onset of ADEM have ranged from 46% to 100% (3,6,12).
Many infections have been associated with ADEM. Nonspecific upper respiratory infections were reported as the most commonly associated infection, reported by 29% of patients (12,13). Other infectious presentations reported in this cohort were “gastrointestinal disturbance” in 9% of cases and a “nonspecific febrile illness” in 6% of cases. Specific infections were found in relatively few cases but included varicella (4%), herpes simplex virus (2%), mumps (1%), and rubella (1%) (12,13).
Table 39.2 describes the various infections that have been linked to ADEM. It is important to realize that while an antecedent infection may increase the likelihood of ADEM, its presence is not required (14). An antecedent infection may also occur in patients with a first presentation of multiple sclerosis (MS) (15). As such, antecedent infection should not be used as criteria to exclude MS as a diagnostic possibility.
Several cases in the literature have reported the occurrence of ADEM following vaccinations, sparking controversies surrounding immunization safety. However, large follow-up studies have specified this risk to be exceedingly rare and a coincidental versus causal relationship has yet to be determined (16). Therefore, prioritizing the protection against infectious diseases through immunizations as a public health safety measure outweighs the extremely small risk (if any) of ADEM.
Antecedent infection should not be used as a criterion to exclude multiple sclerosis as a diagnostic possibility.
There is no single test that confirms the diagnosis of ADEM. Establishing the diagnosis requires a combination of clinical and radiological features and most importantly, the exclusion of other diseases that resemble ADEM. It is important to recognize that the differential diagnosis of ADEM is broad (see Table 39.3). As such, a thorough workup should include infectious, immunological, and metabolic tests. Longitudinal follow-up with repeat MRI studies to evaluate for accrual of new lesions. Importantly, the second demyelinating event can occur years later and may manifest as Multiphasic ADEM, MS, or Neuromyelitis Optic Spectrum Disorder (NMOSD). Multiphasic ADEM is rare and occurs in 1% to 10% of children with an initial ADEM event, typically 2 to 8 years after the first attack (1).
Establishing the diagnosis requires a combination of clinical and radiological features and the exclusion of other diseases that resemble ADEM.
Viral encephalitis (herpes, Epstein–Barr, enterovirus, human T-cell lymphotropic virus type 1)
Bacterial encephalitis (mycoplasma) or abscesses
Fungal infection/encephalitis (cryptococcus)
Parasitic encephalitis or CNS infection
Progressive multifocal leukoencephalopathy (JC virus)
Mitochodrial encephalomyopathy, lactic acidosis and stroke-like episodes
Leber hereditary optic neuropathy
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
Neuromyelitis optica spectrum disorder
Systemic lupus erythematosus
Primary angiitis of the CNS
Bickerstaff brainstem encephalitis
Anti-N-methyl-D-aspartate receptor encephalitis
Schilder’s myelinoclastic diffuse sclerosis
CNS hemophagocytic lymphohistiocytosis
Acute cerebellar ataxia
Acute necrotizing encephalomyelitis (associated with RANBP2 mutations)
ADEM, acute disseminated encephalomyelitis; CNS, central nervous system; JC, John Cunningham.
Distinguishing ADEM from other demyelinating etiologies, such as MS or NMOSD, at initial presentation may be challenging clinically, but there are a few clinical features that can be helpful. In particular, the presence of fever, seizure, impaired consciousness, or a multifocal onset are more suggestive of ADEM than MS (17–19). ON is common in both ADEM and other demyelinating diseases of childhood. However, ON is more often bilateral in ADEM or NMOSD, whereas ON in MS is usually unilateral. The clinical presentation of ADEM has been documented to range from an isolated fever of unknown origin (20), to acute onset psychosis (21), but each of these presentations are rare and many case reports were written prior to identification of specific antibodies, such as the anti-N-methyl-D-aspartate receptor (NMDA-R) antibody and the anti-myelin oligodendrocyte glycoprotein (MOG) antibody, which may have actually been the cause for these unusual clinical presentations. Table 39.4 shows a breakdown of the commonly reported symptoms at clinical presentation among patients with ADEM.
Though clinical features may be helpful, laboratory and imaging studies are often essential in distinguishing ADEM from other demyelinating diseases. Table 39.5 summarizes key features that distinguish ADEM from other demyelinating etiologies.
Impaired consciousness/encephalopathy (NOTE: NOW A REQUIRED COMPONENT OF THE DIAGNOSIS)
ADEM, acute disseminated encephalomyelitis.
aOf note, these cohorts were described prior to the proposed consensus definition requiring encephalopathy for a diagnosis of ADEM.
Source: Tenembaum S, Chitnis T, Ness J, et al. Acute disseminated encephalomyelitis. Neurology. 2007;68(16 suppl 2):S23–S36; Dale RC, de Sousa C, Chong WK, et al. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain. 2000;123 Pt 12:2407–2422; Leake JAD, Albani S, Kao AS, et al. Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features. Pediatr Infect Dis J. 2004;23(8):756–764; Hynson JL, Kornberg AJ, Coleman LT, et al. Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children. Neurology. 2001;56(10):1308–1312; Tenembaum S, Chamoles N, Fejerman N. Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients. Neurology. 2002;59(8):1224–1231; Atzori M, Battistella PA, Perini P, et al. Clinical and diagnostic aspects of multiple sclerosis and acute monophasic encephalomyelitis in pediatric patients: a single centre prospective study. Mult Scler. 2009;15(3):363–370; Schwarz S, Mohr A, Knauth M, et al. Acute disseminated encephalomyelitis: a follow-up study of 40 adult patients. Neurology. 2001;56(10):1313–1318; Davis LE, Booss J. Acute disseminated encephalomyelitis in children: a changing picture. Pediatr Infect Dis J. 2003;22(9):829–831. (22); Koelman DLH, Chahin S, Mar SS, et al. Acute disseminated encephalomyelitis in 228 patients: a retrospective, multicenter US study. Neurology. 2016;86(22):2085–2093. (23)
When evaluating for ADEM, it is important to realize that CT scans of the brain are not optimal as they are frequently normal (5,6). MRI of the brain with and without contrast (gadolinium) is the imaging modality of choice. If ON is suspected, dedicated imaging of the orbits should also be included. In one ADEM cohort (n = 42), CT scans of the brain were normal in 68%, whereas 100% of the patients had abnormalities on MRI of the brain or spinal cord (6). MRI abnormalities are usually noted on the T2-weighted or fluid-attenuated inversion recovery (FLAIR) sequences within the basal ganglia, thalami, brain stem, cerebellum, periventricular white matter, or gray–white junction (6). Contrast (gadolinium) enhancement on T1-weighted images is variable. Prior to the updated definition, gadolinium enhancement was reported in 14% to 30% of ADEM cases (1). However, more recent studies have reported these rates as low as 10% (24). The pattern of enhancement is also variable and can be complete or incomplete ring-shaped, nodular, gyral, or spotty (see Figures 39.1 and 39.2). In contrast, meningeal enhancement in the brain or spinal cord is unusual and should prompt consideration of infection or vasculitis (3).