Acute disseminated encephalomyelitis (ADEM) in children:

Acute disseminated encephalomyelitis (ADEM), also known as postinfectious

encephalomyelitis, is a demyelinating disease of the central nervous system that typically
presents as a monophasic disorder associated with multifocal neurologic symptoms and
encephalopathy.

ADEM must be distinguished from other central inflammatory demyelinating conditions of

childhood, including multiple sclerosis and other acquired inflammatory demyelinating
syndromes that include optic neuritis, transverse myelitis, and neuromyelitis optica spectrum
disorders. Most of these conditions are thought to be caused by immune system dysregulation
triggered by an infectious or other environmental agent in a genetically susceptible host.

This topic will review the epidemiology, pathogenesis, clinical features, and diagnosis of
ADEM in children. Treatment and prognosis of ADEM in children are discussed separately.

The pathogenesis of ADEM is incompletely understood. However, ADEM appears to be an

autoimmune disorder.

Autoimmunity — ADEM appears to be an autoimmune disorder of the central nervous

system that is triggered by an environmental stimulus in genetically susceptible individuals.
The proposed mechanism is that myelin autoantigens, such as myelin basic protein,
proteolipid protein, and myelin oligodendrocyte glycoprotein, share antigenic determinants
with those of an infecting pathogen [1].
The Epstein-Barr virus nuclear antigen (EBNA) provides an example of how exposure to this
virus might induce autoimmunity against myelin basic protein. EBNA contains a pentapeptide
sequence that shares sequence homology with an epitope of myelin basic protein, a major
protein of the myelin sheath [2]. Antiviral antibodies or a cell-mediated response to the
pathogen cross-react with the myelin autoantigens, resulting in ADEM. Epstein-Barr virus has
been implicated in the pathogenesis of multiple sclerosis, in part based upon this concept of
molecular mimicry.
Additionally, a subgroup of patients with ADEM or other acquired demyelinating diseases
have elevated titers of antibodies selectively directed against myelin oligodendrocyte
glycoprotein (MOG) immunoglobulin G (IgG). The stimulus that induces the production of
these antibodies is not known. MOG IgG antibodies predispose to monophasic and relapsing
forms of ADEM, further supporting the autoimmune mechanism of this disease.
An autoimmune mechanism is also supported by studies of lymphocytes in children with
ADEM. In one report, the frequency of T cell lines that reacted to myelin basic protein was 10
times higher in patients with ADEM compared with those with encephalitis or healthy
controls
The immunopathologic events leading to ADEM can be divided into two major phases: 1)
initial T cell priming and activation phase and 2) subsequent recruitment and effector phase.
These phases are followed by repair and remyelination.

●Priming and activation phase – The priming phase occurs in systemic secondary
lymphoid organs, where the antigen-presenting cell presents myelin protein antigen and
peptides to neuroantigen-reactive T cells. The activated T cells expand and then migrate
to the central nervous system via the postcapillary venules into the perivascular space.
In the Virchow-Robin space, the T cells re-encounter their cognate antigen, in the
context of human leukocyte antigen (HLA) class II molecules expressed by dendritic
 cells [5]. This reactivation allows the T cells to migrate through the glial limitans and
enter the brain parenchyma.
●Recruitment and effector phase – Further recruitment occurs through the production
of cytokines and chemokines by antigen-presenting cells and activated T cells,
promoting migration into the central nervous system of additional T cells as well as
other leukocytes such as poly- and monomorphonuclear phagocytes [6].
Breakdown of the blood-brain barrier occurs by release of proteases from recruited
mast cells, T cells, and monocytes. In addition, there is production of reactive oxygen
radicals, causing further endothelial injury. This leads to the effector phase, in which T
cells have more of a secondary role to other inflammatory processes that cause
demyelination and axonal injury. These include oxygen and nitrogen radicals, tumor
necrosis factor-a, direct and indirect complement activation, antibody-dependent
cellular toxicity, myelin phagocytosis, direct axonal injury by CD8+ cytotoxic T
lymphocytes, protease secretion, and oligodendrocyte apoptosis [6]. Glutamate-
mediated excitotoxic injury of the oligodendrocytes also occurs [7].
The inflammatory process continues for a few days to two weeks, resulting in stretches
of demyelinated axons, some of which may be transected.
●Repair – The repair process begins with activation and proliferation of astrocytes.
There is clearing of debris by macrophages and increased production of anti-
inflammatory cytokines and various growth factors by resident cells and T cells.
Oligodendrocyte precursors become activated and, along with surviving
oligodendrocytes, begin the process of remyelination.
The clinical and imaging outcome of ADEM most often shows complete recovery.
However, there may be subtle differences in repaired myelin compared with uninjured
myelin, including altered thickness and redistribution of sodium channels. In addition,
the relative composition of myelin peptides is altered to forms that may have increased
vulnerability to further damage [8]. This may explain recurrent forms of ADEM.

Associated pathogens — Numerous pathogens have been associated with the disorder.

Implicated viruses include coronavirus, coxsackie, cytomegalovirus, Epstein-Barr, herpes
simplex, hepatitis A, HIV, influenza, measles, rubella, varicella zoster, and West Nile virus
[3,9-17]. Other associated organisms associated include Borrelia burgdorferi, chlamydia,
Leptospira, Mycoplasma pneumoniae, rickettsia, and beta hemolytic Streptococcus.
Pathology — The pathology of ADEM in humans is similar to an animal model of
experimental allergic encephalomyelitis (EAE). In this model, injections of brain extracts in
rabbits cause some animals to manifest an encephalitic-like disease process associated with
demyelination. The demyelination appears to result from a cell-mediated delayed
hypersensitivity reaction.

The histologic appearance of EAE includes perivenous demyelination and inflammation, with
an abundance of lymphocytes and macrophages. Lesions often have a flame-like appearance
that is similar to pathologic findings in humans with ADEM. They are usually distinct from
the lesions of multiple sclerosis.

ADEM is an uncommon illness; the estimated annual incidence is 0.2 to 0.5 per 100,000
children. The average age of onset in children is between 3 to 7 years [24]. Approximately
three to six cases are seen each year at regional medical centers in the United States, United
Kingdom, and Australia. There is no specific ethnic distribution. Several studies indicate a
slight male predominance
 ●Postinfectious – Most cases of ADEM are preceded by a febrile or viral infection
usually in the form of a nonspecific upper respiratory infection. An antecedent fever or
infection is found in approximately 75 percent of children with ADEM Some studies
have also observed a seasonal distribution, with a tendency for cases to present in the
winter and spring

Postvaccinal – Although early reports suggested that a minority of ADEM cases followed
immunization, subsequent studies have found little or no association between ADEM and
immunization [24]. The frequency of ADEM in the United States following any vaccine was explored
using the Vaccine Safety Datalink, which captured approximately 64 million doses of 24 different
vaccines administered between 2007 and 2012 [31]. There was no increase in the risk of ADEM
during the primary exposure window (5 to 28 days prior to onset) for any vaccine with the possible
exception of the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine.
However, this result was based on only two cases of ADEM, one of whom received a second vaccine
concurrent with Tdap. In addition, adjustments for multiple comparisons were not performed.

Classic ADEM — Symptoms of a viral and/or febrile illness occur in approximately 75

percent of children prior to the onset of typical neurologic symptoms [24]. Neurologic
symptoms typically appear 4 to 13 days after the infection or vaccination
Fever, headache, vomiting, and meningismus are often present at the time of initial
presentation and may persist during the hospitalization.
 
●Encephalopathy – Encephalopathy is a required diagnostic feature of pediatric
ADEM and usually develops rapidly in association with multifocal neurologic deficits
[17]. With encephalopathy, irritability and confusion are common; the level of
consciousness ranges from sleepiness and lethargy to frank coma [35].
●Early neurologic deterioration – Progression of neurologic signs to maximum
deficits usually occurs over four to seven days [25,32]. In addition to encephalopathy,
the most common neurologic features of ADEM include long tract (pyramidal) signs,
acute hemiparesis, cerebellar ataxia, cranial neuropathies including optic neuritis, and
myelopathy (transverse myelitis). The alteration in mental state often raises concern for
the possibility of seizures, which occur in approximately one-third of patients [32,36].
Aphasia, movement disorders, and sensory deficits are less common.

Symptoms of optic neuritis include vision loss, pain with eye movement, and an afferent pupillary
defect. Inflammation of the optic disc may be seen on direct funduscopic examination if there is
extensive involvement of the optic nerve. Patients with retrobulbar optic neuritis typically have a
normal funduscopic examination. Direct imaging of the optic nerve with a gadolinium-enhanced
magnetic resonance imaging (MRI) of the brain and orbits is a more sensitive means to diagnose optic
neuritis in these patients

Symptoms of transverse myelitis include flaccid paralysis of the legs with a sensory
level on examination. The arms can be involved if the demyelinating lesion involves the
cervical cord. Respiratory failure may occur with high cervical lesions that extend into
the brainstem. Bowel and bladder involvement secondary to spinal cord disease results
in constipation and urinary retention. Signs and symptoms of spinal cord disease may
be missed in younger patients and in the patient with severe encephalopathy. Spinal
 cord imaging is needed to best define the extent of central nervous system disease in
such patients.
●Clinical course – The severe phase of ADEM typically lasts from two to four weeks.
Children may deteriorate after hospital admission, and many develop new neurologic
signs. Most children with ADEM require hospitalization for 13 to 27 days. Intensive
care unit admission for severe encephalopathy, seizures, or paralysis affecting the
diaphragm is needed in up to 25 percent of children, and a majority of those require
mechanical ventilation. Patients usually recover completely from the acute illness,
although some have neurologic sequelae. While ADEM can be fatal, the mortality rate
is low. (See ű

With long-term follow-up, a minority of patients may be categorized as having the

multiphasic subtype of ADEM, based upon the development of relapsing episodes or
new lesions on brain MRI.

Acute hemorrhagic leukoencephalitis — Inflammatory hemorrhagic demyelination of

central nervous system white matter is seen in rare conditions that are considered to be
hyperacute variants of ADEM.
These include:
●Acute hemorrhagic leukoencephalitis
●Acute hemorrhagic leukoencephalopathy
●Acute hemorrhagic encephalomyelitis
●Acute necrotizing hemorrhagic leukoencephalitis of Weston Hurst

These hemorrhagic variants are more rapidly progressive and more severe than
typical ADEM. Otherwise, their symptomatology is similar to typical ADEM, with
meningismus, headache, seizures, multifocal and asymmetric neurologic deficits, and
coma. They typically follow an upper respiratory infection [17]. Brain imaging with
MRI reveals multifocal hemorrhages and CSF typically shows both white and red
blood cells.
Some patients recover with treatment. However, the prognosis for survival or
recovery of neurologic function is worse for acute hemorrhagic leukoencephalitis
(AHL) than ADEM.

When to suspect ADEM — The diagnosis should be suspected in a child who

develops multifocal neurologic abnormalities with encephalopathy (eg, confusion,
excessive irritability, or altered level of consciousness), particularly if onset occurs
within two weeks after a viral infection.
Approach to evaluation — Children with suspected ADEM should have the
following investigations:
●Magnetic resonance imaging (MRI) of the brain and spine, with and without
contrast
●Lumbar puncture and cerebrospinal fluid (CSF) analysis, including
assessment for oligoclonal bands
●Additional laboratory studies to rule out infection
●Testing for anti-aquaporin 4 (AQP4) and anti-
myelin oligodendrocyte glycoprotein (MOG) antibodies
Neuroimaging — The MRI abnormalities of ADEM are best evaluated by T2-
weighted images, fluid-attenuated inversion recovery (FLAIR) sequences, and
contrast-enhanced MRI with gadolinium (image 1) [42]. Computer tomography (CT)
scans are often normal or nondiagnostic, and thus, are not helpful.

Brain MRI – Abnormalities on MRI vary in location. Lesions associated with

ADEM are typically bilateral and asymmetric and tend to be poorly marginated.
Almost all patients have multiple lesions in the deep and subcortical white
matter, characteristic of demyelination. The periventricular white matter is often
spared. Hypointense lesions on T1-weighted images (ie, black holes) are
unusual in ADEM, and their persistence is predictive of multiple sclerosis
[43,44].
Multiple brain lesions are typically present, but the number varies among
patients. As an example, patients in one study had from 4 to 56 brain lesions on
the initial MRI scan [27]. While the lesions in ADEM are often large, smaller
lesions are also seen, with diameters ranging from <5 mm to 5 cm [25,27,32].
The large lesions may have associated mass effect.
Gray matter lesions sometimes accompany the white matter abnormalities in
ADEM, especially in children [32,45,46]. The thalami and basal ganglia are
frequently affected (image 1), and lesions in these locations are often
symmetrical. In contrast, supratentorial lesions are usually asymmetrical.

Hemorrhagic demyelinating lesions are seen in the hyperacute ADEM variants

that include acute hemorrhagic leukoencephalitis, acute hemorrhagic
encephalomyelitis, and acute necrotizing hemorrhagic leukoencephalitis of
Weston Hurst In such cases, brain MRI may reveal diffuse white matter lesions,
often large and associated with cerebral edema [47-49]. White matter lesions
can be detected on MRI within 72 hours of the first symptoms, but hemorrhage
itself is not necessarily seen with conventional T2-weighted and FLAIR
sequences. Susceptibility-weighted MRI sequences are more readily able to
identify the acute hemorrhage associated with this form of ADEM [50]
.
●Spinal cord MRI – Brainstem and spinal cord abnormalities on MRI are
common in ADEM (image 1 and image 2) [1,27]. Spinal cord involvement in
ADEM is most often characterized as a longitudinally extensive transverse
myelitis; large confluent intramedullary lesions that extend over multiple
segments on MRI are typical [32,43,51]. Some lesions may even affect the
entire length of the spinal cord. This is in contrast to the more typical segmental
myelitis of multiple sclerosis, which only involves one or two cord segments.

●Enhancing MRI lesions – Gadolinium contrast enhancement of MRI lesions

in ADEM is variable but may be seen in acute lesions.

●Diffusion MRI – With diffusion-weighted MRI imaging (DWI), lesions

associated with ADEM show restricted diffusion (ie, decreased apparent
diffusion coefficient [ADC] values) in the acute stage, defined as within seven
days from symptom onset, whereas increased diffusivity and normalization of
the ADC is seen within a few weeks after the initial presentation [52].
 Evolution of MRI lesions – Findings may progress over a relatively short
period of time, consistent with evolution of the disease process. Imaging often
improves with convalescence, although lesions sometimes persist (image 2).
Among 19 patients studied two months to nine years after demyelination,
lesions resolved completely in 7, improved partially in 10, and remained
unchanged in 2 patients [25]. None developed new lesions.
Sequential imaging by MRI during follow-up is sometimes required to confirm
the diagnosis of ADEM, as the development of relapses with new lesions on
MRI is not compatible with a diagnosis of monophasic ADEM, and suggests an
alternate diagnosis, depending on the clinical and imaging features [17].

CSF analysis — Lumbar puncture for CSF analysis in suspected ADEM is important

primarily for ruling out infection [24]. CSF testing should include cell counts, protein,
glucose, culture and viral studies (eg, influenza, Epstein-Barr virus, herpes, varicella,
mycoplasma, cytomegalovirus, and rubella).

Also important is qualitative assessment of CSF and serum for oligoclonal

immunoglobulin G (IgG) bands using isoelectric focusing, along with IgG synthesis
rate and IgG index.

While the CSF can be normal in ADEM, evidence of inflammation is common, with
CSF pleocytosis and/or increased protein concentration in the majority of patients
[25-27]. In most cases, the CSF white cell count is usually less than 100 cells/microL,
although rare patients may have counts as high as 600 cells/microL [24,35,53].
Lumbar puncture may also reveal increased opening pressure [54]. In patients with
acute hemorrhagic leukoencephalitis (AHL), the CSF typically shows both white and
red blood cells with increased protein concentration. (

A minority of children with ADEM (0 to 20 percent) have oligoclonal bands in CSF

due to intrathecal synthesis of limited classes of immunoglobulins that are depicted
as discrete bands on agarose gel; these oligoclonal bands are a nonspecific finding
more often associated with multiple sclerosis; they may also occur in chronic central
nervous system infections, viral syndromes, and neuropathies.

Additional evaluation for infection — CSF analysis is necessary to look for

evidence of infection, as described above (see 'CSF analysis' above). Investigations
for infectious agents usually include a complete blood count, blood cultures, viral
cultures of the throat and nasopharynx, stool, and serologic testing for a variety of
agents, including influenza, Epstein-Barr virus, herpes, varicella, mycoplasma,
cytomegalovirus, and rubella. However, these studies are rarely positive [1]. In
addition to targeted testing, serum and CSF next generation sequencing techniques
utilizing polymerase chain reaction (PCR) and other DNA-based methods can be a
useful test to further identify a broad array of potential causative pathogens.
Serum autoantibodies — Testing for the myelin oligodendrocyte glycoprotein
(MOG) IgG autoantibody and the aquaporin-4 (AQP4) IgG serum autoantibody is
indicated for patients presenting with suspected ADEM.
●The anti-MOG IgG antibody is a marker of MOG antibody-associated
disease, which is considered to be a distinct antibody-mediated disorder. It may
be monophasic or have a relapsing course with intermixed relapses of either
ADEM, optic neuritis, or transverse myelitis. Therefore, MOG antibody disease
is both a potential cause of ADEM and a cause of other central nervous system
(CNS) demyelinating disorders that may be considered in the differential
diagnosis of ADEM. Patients with ADEM who are positive for MOG antibody
meet criteria for MOG-antibody disease [55].
In children with ADEM, seropositivity for MOG antibodies is found in 33 to 66
percent of cases [24,56].
●The anti-AQP4 IgG antibody is a specific biomarker for neuromyelitis optica
spectrum disorder (NMOSD). Patients with optic neuritis or transverse myelitis
who are seropositive for anti-AQP4 antibodies fulfill criteria for NMOSD [24].

Other studies in select patients — Principal mimics of ADEM include central

nervous system infection, malignancy, systemic autoimmune disease, and vasculitis.
Progressive and relapsing forms of disease might raise additional consideration for
genetic syndromes or inborn errors of metabolism. In the setting of atypical clinical
features, additional studies directed toward identifying an alternative cause should be
performed.

Lab studies for rheumatologic conditions may be sent as these can affect the central
nervous system in isolation or as part of a systemic autoimmune disease. In the
absence of typical clinical characteristics, abnormal results of non-specific tests such
as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) should be
interpreted with caution. An isolated positive antibody, such as a positive antinuclear
antibody, should likewise not be considered diagnostic of rheumatologic disease.
Consultation with a rheumatologist may be needed to further interpret these results.

Genetic disorders and inborn errors of metabolism can present with signs and
symptoms suggestive of ADEM. These alternative diagnoses may be initially
suggested if there is symmetry of hemispheric lesions on imaging, elevation of serum
or CSF lactate, failure to respond to standard treatment, or relapses with progressive
clinical deterioration. Whole exome sequencing and metabolic studies are needed in
these circumstances, with the latter being best performed in the acute presentation,
as some tests may normalize with fluid resuscitation.

Limited role of brain biopsy — Infrequently, a brain biopsy may be needed to rule

out ADEM mimics, particularly when there is diagnostic uncertainty about the
possibility of CNS malignancy or primary CNS vasculitis despite an extensive work-
up [24]. Large tumefactive demyelinating lesions with mass effect often raise
concerns for malignancy. In the absence of diagnostic results from other less
invasive studies, including serum analysis for antibodies associated with NMOSD
and MOG antibody-associated demyelination, biopsy of a selected active lesion is
reasonable to establish a diagnosis and direct therapy. Similarly, since CNS
vasculitis can mimic the clinical features of ADEM, a diagnostic brain biopsy is
reasonable if clinical suspicion is high and imaging, including conventional contrast
angiography, is nondiagnostic.

Rarely, infections pose a diagnostic dilemma requiring diagnostic brain biopsy. As an

example, a well-encapsulated abscess due to cryptococcoma may present without
systemic signs or laboratory evidence of infection.  

Making the diagnosis — There are no specific biomarkers or confirmatory tests to

establish the diagnosis of ADEM. The diagnosis is based upon the clinical and
radiologic features [17,42]. Given the lack of a specific diagnostic test, ADEM is
considered a diagnosis of exclusion. Bacterial and viral meningitis or encephalitis
must be considered and ruled out. Other CNS demyelinating and inflammatory
syndromes must also be excluded, particularly multiple sclerosis, NMOSD, and MOG
antibody-associated disease [51].
Encephalopathy as a presenting symptom is required for the diagnosis of ADEM
[57,58]. Encephalopathy is defined to include either behavioral changes, such as
confusion or excessive irritability, or more severe alterations in the level of
consciousness, such as stupor, lethargy, or coma, that is unexplained by fever,
systemic illness, or postictal symptoms. The onset of the encephalopathy must
correspond with the occurrence of the disease state. This feature helps to distinguish
ADEM from other clinically isolated syndromes, which have a greater risk for
recurrence and subsequent diagnosis of multiple sclerosis. (See "Differential
diagnosis of acute central nervous system demyelination in children".)
Long-term clinical follow-up and sequential imaging by MRI are usually required to
confirm the diagnosis of ADEM [17]. The development of relapses with new lesions
on MRI is not compatible with a diagnosis of monophasic ADEM, and suggests that
the correct diagnosis is either multiphasic ADEM, MOG antibody-associated disease,
neuromyelitis optica spectrum disorders, or multiple sclerosis, depending on the
clinical and imaging features

Diagnostic criteria — Diagnostic criteria for ADEM in children were proposed by the

International Pediatric Multiple Sclerosis Study Group in 2007 and updated in 2012 (table 1)
[57,58]. The major criteria are a first polyfocal clinical attack of central nervous system
demyelinating disease, encephalopathy that cannot be explained by fever, systemic illness,
or postictal symptoms, the absence of new clinical and MRI findings three months or more
after onset, and an abnormal brain MRI during the acute (three-month) phase with diffuse,
poorly demarcated, large (>1 to 2 cm) lesions predominantly involving the white matter; deep
gray matter lesions (eg, thalamus or basal ganglia) can be present on MRI, whereas
hypointense T1-weighted white matter lesions are rare.

DIFFERENTIAL DIAGNOSIS

In a child who presents with neurologic abnormalities, including signs of encephalitis,

bacterial and viral meningitis or encephalitis must be considered and ruled out. In most
cases, infectious meningoencephalitis is suspected in children who present with fever and
signs of meningeal irritation. The results of the lumbar puncture and cerebrospinal fluid
(CSF) analysis are critical to making the diagnosis; supportive findings include CSF
pleocytosis, elevated protein, and positive identification of a viral or bacterial pathogen in
blood, CSF, or other patient sources

In the setting of nonspecific CSF abnormalities and magnetic resonance imaging

(MRI) evidence of white matter lesions, other inflammatory demyelinating disorders
should be considered. Specific demyelinating disorders in the differential of pediatric
ADEM include:

●Multiple sclerosis, a chronic disease characterized by recurrent episodes of

demyelination in the central nervous system separated in space and time,
typically manifesting with a relapsing and remitting course.
●Myelin oligodendrocyte glycoprotein (MOG) antibody-associated
disease, an antibody-mediated group of demyelinating conditions that include
ADEM, relapsing and bilateral optic neuritis, transverse myelitis, and brainstem
encephalitis.

Neuromyelitis optica spectrum disorder (NMOSD), characterized by

immune-mediated demyelination and axonal damage predominantly targeting
optic nerves and spinal cord.
The differential diagnosis of central nervous system demyelinating disorders in
children is discussed in greater detail separately. (See "Differential diagnosis of acute
central nervous system demyelination in children".)
Additional considerations in the differential diagnosis of ADEM include the following
[24]:

Vasculitis, particularly small vessel childhood primary angiitis of the central nervous system
(PACNS), which typically presents with encephalopathy, extensive focal deficits, or seizures,
including status epilepticus. Systemic features, such as fever and fatigue, are frequently
present. Suspicion for vasculitis is heightened when imaging reveals contrast-enhancing
lesions with diffusion restriction that principally involve a single vascular territory and extend
from the white matter through the cortex, and when the clinical course involves relapsing
disease with residual neurologic deficits. The potential for rapid progression requires a rapid
and thorough evaluation; in cases of angiography-negative small vessel PACNS, a brain
biopsy is often necessary to confirm the diagnosis. (See "Childhood primary angiitis of the
central nervous system".)

Central nervous system malignancy. Children with brain tumors may present
with nonspecific signs and symptoms (eg, headache, nausea and vomiting,
developmental and behavioral problems) and/or with symptoms that are more
suggestive of central nervous system (CNS) involvement (eg, ataxia, cranial
nerve palsies, impaired vision, seizures, papilledema, macrocephaly). (See 
The diagnosis of a CNS tumor is based upon identification of the lesion by
neuroimaging with magnetic resonance imaging (MRI) or computed
tomography (CT). Histologic examination is required to make a diagnosis of the
specific tumor type

Hemophagocytic lymphohistiocytosis (HLH), an aggressive and life-

threatening syndrome of excessive immune activation that most frequently
affects infants but can affect people of any age. Many patients with HLH have a
predisposing genetic defect and/or an immunologic trigger, which can include
infection, malignancy, a rheumatologic disorder, or another disorder associated
with immune dysregulation. HLH typically presents as a febrile illness with
multiple organ involvement, but involvement may be isolated to the central
nervous system. Initial signs and symptoms can mimic common infections,
fever of unknown origin, hepatitis, or encephalitis. Neurologic manifestations
can include seizures, severe encephalopathy, and ataxia.
Children with HLH typically have multiple organ involvement, cytopenias, liver
abnormalities, and high ferritin, which can help differentiate them from ADEM or
other causes of encephalitis. The diagnosis of HLH is made by identifying a
pathogenic variant in a gene associated with HLH or by fulfilling diagnostic
criteria, as reviewed in detail elsewhere