Acute disseminated encephalomyelitis

By Sona Narula MD (Dr. Narula of Children's Hospital of Philadelphia has no relevant financial relationships to disclose.)
Brenda Banwell MD (Dr. Banwell of Children's Hospital of Philadelphia received consulting fees from Novartis.)
Originally released May 8, 1995; last updated January 29, 2017; expires January 29, 2020

Introduction

This article includes discussion of acute disseminated encephalomyelitis (ADEM), parainfectious encephalomyelitis,
and postinfectious encephalomyelitis. The foregoing terms may include synonyms, similar disorders, variations in
usage, and abbreviations.

Overview

Approximately 25% of all children with an acute inflammatory demyelinating attack in the central nervous system will
meet consensus criteria for a diagnosis of acute disseminated encephalomyelitis. Acute disseminated
encephalomyelitis is clinically defined by polyfocal neurologic deficits and encephalopathy, and is radiologically
characterized by multifocal areas of increased signal in both white and gray matter of the brain and spinal cord visible
on T2/FLAIR-weighted magnetization resonance images. Acute disseminated encephalomyelitis is primarily a pediatric
disorder, though adults can be affected. Though the etiologic mechanisms have not been fully elucidated, acute
disseminated encephalomyelitis is thought to be an immune-mediated process and is often precipitated by viral
infection. Acute disseminated encephalomyelitis is typically a monophasic illness, but a multiphasic form has been
reported. There are no laboratory features diagnostic of acute disseminated encephalomyelitis. Acute disseminated
encephalomyelitis may be the presenting clinical attack for a small proportion of children ultimately diagnosed with a
chronic demyelinating disorder such as multiple sclerosis or neuromyelitis optica spectrum disorder. Features more
strongly associated with a monophasic acute disseminated encephalomyelitis illness are presented in this article.
Additionally, the authors discuss clinical and imaging features, etiology, differential diagnosis, and management of
acute disseminated encephalomyelitis. Pathogenesis is also discussed, with updates focusing on the phenotype of
acute disseminated encephalomyelitis with myelin oligodendrocyte glycoprotein seropositivity.

Key points
Acute disseminated encephalomyelitis is an inflammatory demyelinating disorder
predominantly affecting white and gray matter in the brain and spinal cord.
Acute disseminated encephalomyelitis is more common in children than in adults.
Acute disseminated encephalomyelitis is thought to be an immune-mediated process that
often follows viral illness.
Acute disseminated encephalomyelitis is clinically defined by encephalopathy and polyfocal
neurologic deficits.
Acute treatment with corticosteroids is usually effective, and the course is generally
monophasic.

Historical note and terminology

Delayed neurologic complications after infections have been described since the 1700s. In the 1920s, pathologic
differences between acute encephalitis and postinfectious encephalomyelitis were described, as were similarities
between postinfectious and postvaccination (eg, rabies) encephalomyelitis. The first animal model of
encephalomyelitis was produced in 1935 by Rivers and Schwentker by injecting monkeys with rabbit brain or spinal
cord tissue; studies of this model suggested that delayed neurologic complications manifesting as encephalomyelitis
following infections or vaccinations could result from sensitization of the immune system to proteins expressed by
viruses (molecular mimicry) or by vaccines that contained proteins from neural tissue.

Early reports of postinfectious encephalomyelitis came from pediatric populations, following exanthematous infections.
The term "acute disseminated encephalomyelitis" was introduced to describe any immune-mediated
encephalomyelitis that resulted from infection, allergies, or vaccinations (van Bogaert 1950).

Historically, there has been inconsistent use and application of the term acute disseminated encephalomyelitis due
to a lack of clear diagnostic criteria. As a result, the International Pediatric Multiple Sclerosis Study Group created an
operational definition for acute disseminated encephalomyelitis in 2007, which was then updated in 2013. By
definition, acute disseminated encephalomyelitis is an initial acute inflammatory event characterized by
encephalopathy with polyfocal neurologic deficits occurring over a maximum period of clinical evolution of 3 months.
MRI features include multifocal, large, and asymmetric areas of increased T2/FLAIR signal affecting the white and gray
matter of the CNS (Krupp et al 2007; Krupp et al 2013).{embed="pagecomponents/media_embed" entry_id="12271"}
Although the requirement for encephalopathy in the definition of acute disseminated encephalomyelitis continues to
be debated, it is considered essential by the consensus panel to avoid diagnosing every child with polyfocal MRI
lesions with acute disseminated encephalomyelitis.

The International Pediatric Multiple Sclerosis Study Group redefined multiphasic disseminated encephalomyelitis in
their 2013 consensus paper. Multiphasic disseminated encephalomyelitis is now defined as repeated episodes of
demyelination that are separated by at least 3 months, with each episode meeting the definition of acute
disseminated encephalomyelitis, and no evidence of either clinically silent lesion accrual on MRI or any other
demyelinating attacks (attacks not meeting criteria for acute disseminated encephalomyelitis) (Krupp et al 2013).
Children with an initial event meeting criteria for acute disseminated encephalomyelitis, but who then experience
repeated attacks that do not meet criteria for acute disseminated encephalomyelitis, should be evaluated for other
disorders such as multiple sclerosis, neuromyelitis optica spectrum disorder, central nervous system vasculitis, and
other etiologies.

Clinical manifestations

Presentation and course

Initial symptoms of acute disseminated encephalomyelitis may occur spontaneously without antecedent illness or,
more typically, begin between 2 days and 4 weeks after a febrile illness of presumed viral etiology (Alper 2012). The
actual microbial illness is rarely determined. Clinical presentation includes encephalopathy (manifesting as behavioral
change, profound irritability, or altered consciousness) that cannot be explained by fever and polyfocal neurologic
deficits (Krupp et al 2013; Tenembaum 2013). Systemic symptoms such as fever, headache, and fatigue often precede
the development of neurologic deficits. Once neurologic symptoms begin, the course is rapidly progressive, and
patients typically develop maximal symptoms within 3 to 5 days (Tenembaum 2013).

Neurologic signs and symptoms vary in acute disseminated encephalomyelitis and are determined by the location of
lesions in the CNS. In a prospective series of 84 patients, the most common presenting features of acute disseminated
encephalomyelitis included long tract signs (85%), acute hemiparesis (76%), and cerebellar ataxia (50%), in addition
to encephalopathy (Tenembaum et al 2002). Less common presenting features included cranial nerve palsies, spinal
cord involvement, aphasia, seizures, and visual dysfunction. Case reports have described even less common
symptoms such as hypersomnolence and mood dysfunction as presenting features of acute disseminated
encephalomyelitis (Kanbayashi 2001). The peripheral nervous system is rarely involved in acute disseminated
encephalomyelitis (Young et al 2008).

The severity of symptoms varies in acute disseminated encephalomyelitis as some children may present with mild
somnolence and subtle neurologic dysfunction, whereas others rapidly develop obtundation and respiratory depression
necessitating intensive care. Respiratory failure secondary to brainstem involvement or severely impaired
consciousness has been reported in 11% to 16% of cases (Tenembaum et al 2007). In fulminant cases, cerebral edema
and increased intracranial pressure can occur and result in death or severe neurologic dysfunction if not intervened on
quickly.

Prognosis and complications

Although the majority of patients with acute disseminated encephalomyelitis completely recover, the acute phase can
be severe and life-threatening, and minor residual deficits have been reported in 20% to 30% of children (Pohl and
Tenembaum 2012; Tenembaum 2013). Of these residual deficits, the most frequently reported include mild motor
deficits, visual problems, and seizures (Tenembaum 2002). The average time to full recovery ranges from 1 to 6
months, though patients often experience immediate improvement of symptoms after beginning treatment with
corticosteroids. The mortality of acute disseminated encephalomyelitis had previously been reported to be as high as
20% (Miller et al 1957). However, in the era of modern treatment agents for inflammation and elevated intracranial
pressure, this figure has been markedly reduced.

Cognitive and learning deficits have also been reported as long-term consequences of acute disseminated
encephalomyelitis. Subtle deficits in executive function, attention, and behavior have been reported in children who
have otherwise completely recovered from acute disseminated encephalomyelitis (Kuni et al 2012; Suppiej et al 2014).
These deficits have been noted to be more prominent in children who were younger than 5 years of age at the time of
their diagnosis (Jacobs et al 2004). Attention may improve over time as patients tested further from the diagnosis tend
to have better neurocognitive test scores (Suppiej et al 2014).

It has been shown that although the clinical characteristics and presenting features of adult-onset acute disseminated
encephalomyelitis can be similar to pediatric-onset disease, the outcome and disease course can be more severe in
adults. In fact, in a retrospective review looking at prognosis and disease course in adults and children with acute
disseminated encephalomyelitis, it was found that adults were more likely to require longer hospitalization and ICU
admission. Outcome in adult-onset disease was also worse as fewer adults had complete motor recovery (Ketelslegers
et al 2011).

Acute disseminated encephalomyelitis is typically a monophasic disorder. However, some children with a first
demyelinating attack meeting criteria for acute disseminated encephalomyelitis will ultimately be diagnosed with
multiple sclerosis. The reported percentage of patients with an ultimate diagnosis of multiple sclerosis varies in
different cohorts based on the inclusion criteria and definition of acute disseminated encephalomyelitis used. For
instance, although one prospective study reported that 18% of their acute disseminated encephalomyelitis cohort
eventually had a confirmed diagnosis of multiple sclerosis, a national prospective study of 302 children with acute
demyelinating syndromes and strict definitions for acute disseminated encephalomyelitis reported that only 4 of 77
patients (5%) initially diagnosed with acute disseminated encephalomyelitis were subsequently diagnosed with
multiple sclerosis (Mikaeloff et al 2007; Banwell et al 2011).

In a study of 32 children with acute disseminated encephalomyelitis who were followed over time (median of 27
months) in an effort to identify factors that are associated with relapsing demyelination, 75% of the cohort remained
monophasic, with only 1 demyelinating event (Kariyawasam et al 2015). Seven of the remaining patients had another
episode of acute disseminated encephalomyelitis (3 within 3 months), and 1 experienced multiple relapses. Though
infratentorial imaging changes were more frequently noted in the relapsing group, there were no specific clinical or
radiologic features that predicted relapse at the time of initial attack (Kariyawasam et al 2015).

Though multiple sclerosis and neuromyelitis optica spectrum disorder must be considered in a patient with relapsing
nonacute disseminated encephalomyelitis events following an initial episode of acute disseminated encephalomyelitis,
other disorders such as acute disseminated myelitis followed by optic neuritis (ADEM-ON) and myelin oligodendrocyte
glycoprotein (MOG)associated demyelination are now also being described.

Although patients with acute disseminated encephalomyelitis often make a full clinical recovery, 1 study has shown
that these children (along with children with multiple sclerosis and clinically isolated syndromes) have impaired
cerebellar growth and cerebellar volume reduction (Weier et al 2016). This has not yet been correlated with disability
or persistent clinical symptomatology, but further studies are needed to better understand the clinical implication of
this finding (Weier et al 2016).

Clinical vignette

A developmentally normal 4-year-old boy was admitted with depressed consciousness and inability to walk or sit up
independently. His lethargy and truncal instability had progressed over the preceding 4 days. Of note, he had a
diarrheal illness 1 week prior to his presentation and had developed low-grade fever 4 days prior to his admission. His
vital signs and general medical exam on admission were normal. His neurologic exam was notable for a somnolent
mental status, dysarthria, and severe truncal and appendicular ataxia. Initial labs, including a complete blood count
and electrolyte panel, were normal. Cerebrospinal fluid (CSF) studies showed 48 white blood cells per mm3
(predominantly lymphocytes), few red blood cells, normal glucose, and a mildly elevated protein. Oligoclonal bands
were not detected in CSF or serum. Viral PCR studies and a bacterial culture from the CSF were negative. MRI of the
brain revealed multifocal T2-hyperintense lesions involving both cerebral hemispheres, the pons, the middle cerebellar
peduncles, and the cerebellum, with some lesions showing patchy enhancement with gadolinium.

Intravenous methylprednisolone was started after the MRI was completed. Within 24 hours of starting corticosteroids,
the patient become more alert and was able to sit independently. Over the following 2 days, the patient's clinical
condition improved rapidly; his dysarthria resolved, and he was able to walk with support. The patient was discharged
home with an oral prednisone taper. Two weeks later, the patient was asymptomatic and had returned to baseline. A
brain MRI was repeated 6 months after discharge and showed complete resolution of his initial lesions and no new
lesions.

Biological basis

Etiology and pathogenesis

Nonspecific upper respiratory tract infections have been reported to be the most common illnesses preceding acute
disseminated encephalomyelitis (Johnson 1987; Murthy et al 2002; Tenembaum 2002). Less common precedent
infections include varicella, herpes simplex virus encephalitis, mumps, rubella, mycoplasma, and enterovirus.

The level of evidence for a direct association between vaccines and acute disseminated encephalomyelitis remains
anecdotal. In the past, acute disseminated encephalomyelitis was associated with specific vaccinations that were
produced in neural tissue culture, such as the Semple form of the rabies vaccine and the Japanese B encephalitis
vaccine. These cases have become less frequent as recombinant protein vaccines have replaced those cultured from
neural tissue (Tenembaum 2013).

Though the pathogenesis of acute disseminated encephalomyelitis has not been fully elucidated, existing evidence
suggests that acute disseminated encephalomyelitis results from an autoimmune response toward myelin-derived
antigens. Much of the current thinking regarding the pathogenesis of acute disseminated encephalomyelitis comes
from study of the animal model of experimental autoimmune encephalomyelitis, as many features of the induced
murine model are notable in human acute disseminated encephalomyelitis. Experimental autoimmune
encephalomyelitis is an acute encephalomyelitis that has been induced in a variety of species with introduction of
myelin proteins or myelin-derived peptides. Although specific mouse genetic strains can develop a relapsing form of
experimental autoimmune encephalomyelitis, most models are characterized by a monophasic illness associated with
diffuse CNS demyelination.

Using this animal model, it has been hypothesized that both primary and secondary autoimmune responses contribute
to CNS inflammation and subsequent demyelination in acute disseminated encephalomyelitis. The 2 most widely
accepted possible pathogenic mechanisms for acute disseminated encephalomyelitis are molecular mimicry and self-
sensitization.

The hypothesis of molecular mimicry is based on the idea that antigenic epitopes are shared between pathogens or
vaccines and host myelin antigens. These antigens from pathogens or vaccines subsequently activate myelin-reactive
lymphocytes, which can then migrate into the CNS and attack myelin. Many myelin peptides such as myelin basic
protein and proteolipid protein have shown similarity to viral sequences and can elicit cross-reactive T-cell responses.

The hypothesis of self-sensitization suggests that direct infection with a neurotropic pathogen results in the release of
myelin peptides and a secondary inflammatory response. In the setting of this diffuse inflammation, there is
breakdown of the blood-brain barrier, and myelin-derived autoantigens are released into peripheral circulation where
they are exposed to naive lymphocytes. These sensitized T-cells may then migrate into the CNS and attack host
myelin, causing demyelination in the CNS. One murine model that supports this mechanism is Theiler virus-induced
demyelinating disease, which is an immune-mediated demyelinating disease induced by direct infection with the
neurotropic Theiler murine encephalomyelitis virus (TMEV) picornavirus. Although the initial immune response is
directed towards the TMEV picornavirus, epitope spreading is thought to occur in chronic stages of the disease and
results in T-cell reactivity to host myelin proteins and subsequent CNS demyelination (McCarthy et al 2012).

The role of autoantibodies to specific myelin proteins in the pathogenesis of acute disseminated encephalomyelitis and
other demyelinating diseases is an area of active research. Studies have demonstrated a different time course of
myelin-directed antibodies in the serum and CSF of children with acute disseminated encephalomyelitis compared to
children and adults with multiple sclerosis. For example, elevated titers of myelin oligodendrocyte glycoprotein (MOG)
autoantibodies have been identified in 20% to 47% of patients with a first inflammatory demyelinating event (Brilot et
al 2009; Probstel et al 2011). Although often present in high titers at the onset of demyelination, these antibodies have
been shown to steadily decrease in patients with acute disseminated encephalomyelitis and persist in patients with
multiple sclerosis (Probstel et al 2011). Additional cohorts have now shown that the presence of MOG antibodies at
presentation are predictive against a subsequent multiple sclerosis disease course (Hacohen et al 2015; Ketelslegers
et al 2015).

The spectrum of MOG antibodyassociated demyelinating disease continues to expand. One study compared the
clinical and radiologic features of children with acute disseminated encephalomyelitis who were found to be
seropositive for MOG antibodies with those who were seronegative (Baumann et al 2015). The 2 groups did not differ
with regard to age at presentation or sex ratio. Clinical symptomatology did not differ between the 2 groups aside from
fewer patients with behavioral/emotional problems at presentation in the seropositive group. The seropositive group
had a higher CSF cell count and was more likely to have large, hazy, bilateral brain lesions and longitudinally extensive
cord lesions. Seropositive patients were also found to have a better outcome and were more likely to have complete
resolution of lesions. Another cohort of multiphasic disseminated encephalomyelitis was found to be MOG antibody
positive (Baumann et al 2016). These patients all had at least 2 episodes of acute disseminated encephalomyelitis,
and a few had additional clinical attacks without encephalopathy.

In a study analyzing the serum of 15 patients with acute disseminated encephalomyelitis and 26 patients with multiple
sclerosis, distinct profiles of autoantibody reactivity to myelin peptides were found in patients with each disease.
Specifically, the serum of patients with acute disseminated encephalomyelitis was characterized by IgG autoantibodies
targeting myelin basic protein and myelin-associated oligodendrocyte basic protein, whereas the serum of patients
with multiple sclerosis was characterized by autoantibodies of the IgM subtype targeting myelin peptides, including
proteolipid protein, myelin-associated oligodendrocyte basic protein, and oligodendrocyte-specific protein (Van Haren
et al 2013). The finding that IgG autoantibodies, which are class-switched, are predominant in acute disseminated
encephalomyelitis supports the notion that acute disseminated encephalomyelitis is a postinfectious process where
the immune response is primed prior to the onset of demyelination.

Other autoantibodies, including N-methyl-D-aspartate receptor (NMDA) antibody and voltage-gated potassium channel
complex antibodies, have been found in some patients with acute disseminated encephalomyelitis (Hacohen et al
2014). Though case reports of patients with clinical features consistent with anti-NMDA receptor encephalitis and
imaging features typical of acute disseminated encephalomyelitis suggest overlap of the 2 disorders, it is still unclear
whether the autoantibodies identified in typical acute disseminated encephalomyelitis patients are pathogenic or just
represent a secondary response to demyelination (Lekoubou et al 2012).

Several cytokines and chemokines have been identified as possible contributors to the pathogenesis of acute
disseminated encephalomyelitis. For example, increased CSF concentrations of tumor necrosis factor-alpha,
interleukin-6, and interleukin-10 have been described in patients with acute disseminated encephalomyelitis (Ichiyama
et al 2002). It has also been shown that chemokines that act on neutrophils, monocytes, Th1, and TH2 cells are
present in higher concentrations in the CSF of patients with acute disseminated encephalomyelitis as compared with
healthy controls (Franciotta et al 2006).

Perivenous inflammatory infiltrates of T-cells and macrophages associated with perivenular demyelination is the
pathologic hallmark of acute disseminated encephalomyelitis, which differs from the more confluent demyelination
that is pathologically seen in patients with multiple sclerosis (Young et al 2010). Lesions in acute disseminated
encephalomyelitis predominantly involve white matter, though deep gray structures and cortex can also be involved,
and are typically of similar histologic age (Tenembaum 2013).

Epidemiology"

Acute disseminated encephalomyelitis is primarily a pediatric disease, with the mean age of clinical presentation
ranging from 5 to 8 years (Hynson et al 2001; Anlar et al 2003; Tenembaum 2013). Although acute disseminated
encephalomyelitis can occur at any time of the year, it has been reported to be more common in the winter and spring
in temperate climates (Leake et al 2004). Incidence rates vary in different cohorts and range from 0.07 to 0.64 per
100,000, though different inclusion criteria and definitions of acute disseminated encephalomyelitis were used in each
study (Leake et al 2004; Pohl et al 2007; Banwell et al 2009; Torisu et al 2010). In terms of gender predilection, a male
predominance has been described in few pediatric cohorts (Murthy et al 2002; Tenembaum et al 2002; Banwell et al
2009).

Prevention

There is currently no evidence or accepted strategy for primary prevention of acute disseminated encephalomyelitis.

Differential diagnosis

Children and adults with acute disseminated encephalomyelitis are acutely ill, often with fever, and, by definition, have
altered consciousness. As such, the first priority is to exclude acute CNS infection. CSF analysis and prompt
administration of antimicrobial therapy, including acyclovir, is essential until CNS infection is excluded. As the
diagnosis of acute disseminated encephalomyelitis is based solely on clinical history and radiographic studies, a
number of other inflammatory and infectious diseases should be considered in the differential before a definitive
diagnosis is made (Table 1). Although the thalamus is often involved in acute disseminated encephalomyelitis, it can
also be involved with deep cerebral vein thrombosis and metabolic disease, which are 2 entities important to consider
in the differential in the proper clinical context. Fulminant cases of acute hemorrhagic leukoencephalitis may mimic
acute herpes encephalitis, acute bacterial meningitis, or venous sinus thrombosis. Large tumefactive lesions on MRI
may suggest alternate diagnoses such as Marburg variant of multiple sclerosis, tumor, abscess, or CNS vasculitis.

Table 1. Differential Diagnosis of Acute Disseminated Encephalomyelitis

Infectious
Viral encephalitis (herpes simplex, enterovirus, Mycoplasma pneumoniae)
Progressive multifocal leukoencephalopathy
HIV-associated encephalopathy
Subacute sclerosing panencephalitis
Cerebral abscess (bacterial, fungal)

Vascular
Isolated small vessel CNS vasculitis
Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy
Moyamoya disease
Sickle cell disease
Susac syndrome
Antiphospholipid antibody syndrome
Cerebral venous sinus thrombosis

Metabolic
Mitochondrial disease
Leukodystrophies
Toxic encephalopathies carbon dioxide, mercury, radiation-induced
Osmotic myelinolysis central pontine and extrapontine myelinolysis
Cerebral folate deficiency

Inflammatory
Multiple sclerosis
Neuromyelitis optica spectrum disorder
Isolated small vessel CNS vasculitis
Neurosarcoidosis
Neuro-Behcet disease
Hemophagocytic lymphohistiocytosis
Systemic vasculitis with CNS involvement

Neoplastic
 Primary CNS lymphoma
Gliomatosis cerebri
Metastasis (exceptionally rare in children)

Miscellaneous
Posterior reversible leukoencephalopathy

Though differentiating an initial attack of multiple sclerosis from acute disseminated encephalomyelitis may be difficult
at the time of the first incident attack, some epidemiologic, clinical, and radiographic features may help to distinguish
a first attack of multiple sclerosis from monophasic acute disseminated encephalomyelitis (Table 2). Additionally, as
neuromyelitis optica spectrum disorder can initially present with an acute disseminated encephalomyelitislike event,
it should also be considered in the differential for acute disseminated encephalomyelitis (Lotze et al 2008).

Table 2. Characteristic Features of Acute Disseminated Encephalomyelitis and Multiple Sclerosis

Acute disseminated Multiple sclerosis
encephalomyelitis
Demographic Common in children and young Common in adolescents and
adults; slight male predominance in adults; female predominance
a few pediatric cohorts
Season More common in winter and spring No seasonal variation
Precipitating event Frequent report of preceding No clear association
infection
Course Typically monophasic Relapsing or progressive (primary
progressive multiple sclerosis is
exceptionally rare in children)
Clinical features Acute encephalopathy (behavioral Encephalopathy and seizures are
change, altered consciousness), rare
polyfocal neurologic symptoms,
seizures, fever, headache
Oligoclonal bands Rare; generally transient if present Common (>95% when evaluated
in an experienced laboratory and
persistent)
Brain MRI Lesions are large, confluent, and Lesions have plaque-like well-
multifocal with ill-defined margins defined margins
Visible lesions in deep gray matter Periaqueductal, corpus callosum,
(thalamus and basal ganglia) are and periventricular white matter
frequently noted often involved
T1-hypointense lesions rare T1-hypointense lesions commonly
present at onset
Follow-up MRI Complete or partial resolution of New T2-hyperintense and T1-
lesions with no new lesions hypointense lesions appear
Outcome Often good with minimal residual Risk of physical disability
dysfunction increases with increasing disease
duration

(Hynson et al 2001; Murthy et al 2002; Tenembaum et al 2002; Alper and Schor 2004; Dale and Branson 2005; de Seze
et al 2007; Verhey et al 2011; Tenembaum 2013).

Diagnostic workup

Investigations in acute disseminated encephalomyelitis are prioritized to first exclude active CNS infection and to
evaluate recent viral exposures. CSF analysis (cell count, protein, glucose) should be evaluated. A mild to moderate
CSF lymphocytic pleocytosis is often present (40% to 85% of cases). In severe cases and those with a hemorrhagic
component, a pleocytosis of greater than 1000 per mm3, a polymorphonuclear predominance, and red blood cells in
the CSF can be seen. CSF protein is elevated in about one half of cases, but levels above 100 mg/dL are rare.
Oligoclonal bands detected in CSF, but not concurrently detected in serum, are rarely present, but usually disappear
on follow-up testing (if repeat CSF is obtained, which is unlikely to be requested in children with full clinical recovery).
This is in contrast to multiple sclerosis, where intrathecal oligoclonal bands are frequently present and persist over
time.

Four radiographic patterns of cerebral involvement have been described in acute disseminated encephalomyelitis.
These patterns include acute disseminated encephalomyelitis with (1) small lesions (less than 5 mm), (2) large
confluent lesions with associated edema and mass effect, (3) additional symmetric bithalamic involvement, and (4)
acute hemorrhagic encephalomyelitis (Tenembaum et al 2002). Despite the concept that acute disseminated
encephalomyelitis is an acute illness, it is rare for all lesions to enhance with gadolinium (Verhey et al 2011).
Meningeal enhancement is uncommon in acute disseminated encephalomyelitis, as is the presence of complete ring-
enhanced lesions and lesions confined to the corpus callosum (Lim et al 2003; Tenembaum et al 2007). Brainstem
lesions in acute disseminated encephalomyelitis are usually bilateral and symmetric, whereas brainstem lesions in
patients with multiple sclerosis tend to be asymmetric or unilateral (Lu et al 2011). Lesions are commonly visible in the
thalamus and basal ganglia in acute disseminated encephalomyelitis.{embed="pagecomponents/media_embed"
entry_id="12512"} Patients with acute disseminated encephalomyelitis have been shown to have fewer abnormalities
on susceptibility-weighted imaging when compared to those with multiple sclerosis at the time of initial imaging (Kelly
et al 2015).

Cerebral MRI abnormalities in children with neuromyelitis optica can sometimes mimic those seen in cases of acute
disseminated encephalomyelitis (Lotze et al 2008). For example, large confluent lesions affecting the brainstem,
hypothalamus, juxtacortical, and periventricular areas have been described in pediatric patients presenting with an
acute disseminated encephalomyelitislike attack who ultimately meet criteria for neuromyelitis optica spectrum
disorder (Banwell et al 2008; Lotze et al 2008).

Different radiologic criteria have been developed to try to differentiate acute disseminated encephalomyelitis from a
first attack of multiple sclerosis. These include the 2001, 2005, and 2010 McDonald criteria, developed for the
diagnosis of multiple sclerosis, which include both MRI and clinical criterion; the KIDMUS criteria; and the Callen MS-
ADEM criteria (McDonald et al 2001; Mikaeloff et al 2004; Polman et al 2005; Polman et al 2010; Callen et al 2009).
Although the KIDMUS criteria, which requires the presence of 1 or more lesions perpendicular to the long axis of the
corpus callosum in addition to the presence of well-defined lesions, is very specific for multiple sclerosis, it was found
to be relatively insensitive in distinguishing multiple sclerosis from acute disseminated encephalomyelitis (Mikaeloff et
al 2004; Ketelslegers et al 2010). The Callen MS-ADEM criteria has ultimately been found to be the most useful for
distinguishing a first attack of multiple sclerosis from acute disseminated encephalomyelitis and proposes that
radiologic features such as an absence of a diffuse bilateral lesion pattern, the presence of black holes, and the
presence of 2 or more periventricular lesions are more commonly seen with an incident attack of multiple sclerosis
than with acute disseminated encephalomyelitis (Ketelslegers et al 2010).

The spine can be affected in up to 28% of patients with acute disseminated encephalomyelitis, and lesions can be
longitudinally extensive (Murthy et al 2002; Tenembaum et al 2002).{embed="pagecomponents/media_embed"
entry_id="12513"} In these cases, it is important to also consider the diagnosis of neuromyelitis optica spectrum
disorder and check an anti-aquaporin-4 IgG titer. Spinal cord lesions in multiple sclerosis are typically more focal
(Mikaeloff et al 2004; Dale and Branson 2005).

Serial imaging with MRI is important when trying to differentiate an episode of acute disseminated encephalomyelitis
from an initial attack of a chronic inflammatory demyelinating disorder as lesions in acute disseminated
encephalomyelitis should at least partially resolve on follow-up scans and new clinically silent lesions should not
appear (Tenembaum et al 2007).

Management

Drug treatment. To date, there have been no formal treatment trials for acute disseminated encephalomyelitis, and
standard of care is based on observational data and expert consensus. Initial treatment of acute disseminated
encephalomyelitis involves supportive care, including treatment of seizures if present. Depending on the clinical
situation, antibiotics and antivirals should be started empirically until an infectious etiology has been excluded. When
the diagnosis of acute disseminated encephalomyelitis has been confirmed, treatment with corticosteroids should be
initiated (methylprednisolone at a dose of 30 mg/kg/day up to 1 g/day) intravenously for 3 to 5 days. If symptoms
resolve, subsequent treatment with oral prednisone is not required. For children with improvement, but still ongoing
deficits, a prednisone taper can be used (dose starting at 1 mg/kg/day, with a max of 60 mg/day, tapering over 10 to
14 days) (Hynson et al 2001; Pohl and Tenembaum 2012).

For patients with acute disseminated encephalomyelitis who fail to demonstrate clinical improvement by the third to
fifth day of corticosteroid treatment, or children with life-threatening demyelination at onset, plasma exchange can be
considered (Cortese et al 2011; Pohl and Tenembaum 2012).

Intravenous immunoglobulin has been reported to be effective in some children with acute disseminated
encephalomyelitis who do not respond fully to corticosteroids, or in some patients who seem to experience recurrence
of neurologic deficits on corticosteroid withdrawal (Hahn et al 1996; Tenembaum et al 2007).

Some children with acute disseminated encephalomyelitis experience fulminant, life-threatening cerebral edema
refractory to conventional medical management. In these cases, decompressive craniectomy may lead to rapid
improvement and an excellent outcome. The most severe form of acute disseminated encephalomyelitis is acute
hemorrhagic leukoencephalitis and is thought to be rapidly fatal if not treated promptly. Survival has been reported
with combination treatment using corticosteroids, plasmapheresis, and decompressive craniectomy if needed.

Treatments on the horizon. There are no additional acute or preventative treatments available for acute disseminated
encephalomyelitis on the horizon at the current time.

Outcomes

The outcome of acute disseminated encephalomyelitis is generally favorable as most patients recover without
sequelae. Treatment with methylprednisolone is generally well tolerated though providers should be aware of potential
side effects associated with high-dose corticosteroids, including hyperglycemia, hypertension, and mood lability.
Prolonged use of steroids is not indicated for acute disseminated encephalomyelitis.

Special considerations

Pregnancy

Although there are case reports of acute disseminated encephalomyelitis in pregnant women, there is no known
increase in ADEM in the context of pregnancy. Risks and benefits of treatment during pregnancy must be considered
on an individual basis. Although immunomodulatory treatment may be indicated to prevent additional morbidity, there
may be associated risks with therapies during pregnancy (ie, methylprednisolone is category D during 1st trimester
and category c for remainder of pregnancy). Intravenous immune globulin may be a safe option.

Anesthesia

As patients with acute disseminated encephalomyelitis are encephalopathic, use of anesthetic medications should be
managed by trained anesthesiologists or intensive care physicians when required. Patients should be monitored
closely while receiving anesthesia and in the period after the medication has been administered.

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**References especially recommended by the author or editor for general reading.

Former authors

David H Mattson MD PhD (original author), Nirjal Nikhar MD, and Ravindra Kumar Garg MD

ICD and OMIM codes

ICD codes

ICD-9:
Infectious acute disseminated encephalomyelitis: 136.9 [323.61]
Encephalomyelitis (chronic)(hemorrhagic necrotizing, acute): 323.9
Other causes of encephalitis and encephalomyelitis: 323.81
ICD-10:
Acute disseminated encephalitis and encephalomyelitis: G04.0
Acute disseminated encephalitis and encephalomyelitis, unspecified: G04.00
Postinfectious acute disseminated encephalitis and encephalomyelitis: G04.01
Postimmunization acute disseminated encephalitis, myelitis, and encephalomyelitis: G04:02

Profile

Age range of presentation

01-23 months
02-05 years
06-12 years
13-18 years
19-44 years
45-64 years
65+ years

Sex preponderance

male > female in some cohorts

Family history

none

Heredity

none

Population groups selectively affected

none selectively affected

Occupation groups selectively affected

none selectively affected

Differential diagnosis list

herpes simplex encephalitis

enteroviral encephalitis
mycoplasma pneumoniae encephalitis
bacterial meningitis
tuberculous meningitis
cryptococcal meningitis
human immunodeficiency virusassociated encephalopathy
neuromyelitis optica
multiple sclerosis
isolated small vessel CNS vasculitis
neurosarcoid
polyarteritis nodosa
Behet disease
Sjgren syndrome
systemic lupus erythematosus
antiphospholipid antibody syndrome
multiple septic emboli
subacute bacterial endocarditis
multifocal primary central nervous system neoplasms
multiple brain metastases
cerebral venous sinus thrombosis
brain parenchymal abscess
stroke secondary to thrombophlebitis
acute toxic hepatoencephalopathy (Reye syndrome)
poliomyelitis
mitochondrial disease
toxic encephalopathy
leukodystrophy
posterior reversible leukoencephalopathy

Associated disorders

Immune-mediated encephalomyelitis
Multiple sclerosis
Neuromyelitis optica spectrum disorder

Other topics to consider

Acute necrotizing hemorrhagic leukoencephalitis

Autoimmune encephalitis
Multiple sclerosis
Neuromyelitis optica spectrum disorder
Transverse myelitis

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