Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis

INTRODUCTION — 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. (See "Acute disseminated encephalomyelitis (ADEM) in children: Treatment and prognosis".)

PATHOPHYSIOLOGY — 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. (See "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis", section on 'Environmental triggers'.)

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. (See "Differential diagnosis of acute central nervous system demyelination in children", section on 'MOG antibody-associated 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 [3].

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 [4]. 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 [1,17]. While severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with ADEM, the overall incidence is quite low [18]. (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Other acute neurologic manifestations'.)

Pathology — The pathology of ADEM in humans is similar to an animal model of experimental allergic encephalomyelitis (EAE) [3,19,20]. 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.

EPIDEMIOLOGY — ADEM is an uncommon illness; the estimated annual incidence is 0.2 to 0.5 per 100,000 children [21-24]. The average age of onset in children is between 3 to 7 years [25]. Approximately three to six cases are seen each year at regional medical centers in the United States, United Kingdom, and Australia [26-28]. There is no specific ethnic distribution [21]. Several studies indicate a slight male predominance [17,25].

●Postinfectious – Most cases of ADEM are preceded by a febrile or viral infection (see 'Associated pathogens' above), 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 [22,25,29-31]. Some studies have also observed a seasonal distribution, with a tendency for cases to present in the winter and spring [26,28].

●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 [25]. 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 [32]. 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 (odds ratio [OR] 15.8, 95% CI 1.2-471.6). 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. Overall, the attributable risk for ADEM following Tdap was 0.385 per one million doses (95% CI 0.04-1.16).

CLINICAL FEATURES

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 [25]. Neurologic symptoms typically appear 4 to 13 days after the infection or vaccination [26-29,33,34]. Fever, headache, vomiting, and meningismus are often present at the time of initial presentation and may persist during the hospitalization [27,35].

●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 [36].

●Early neurologic deterioration – Progression of neurologic signs to maximum deficits usually occurs over four to seven days [26,33]. 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) [17,27,28,33,35,37]. The alteration in mental state often raises concern for the possibility of seizures, which occur in approximately one-third of patients [33,37]. 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. (See "Optic neuritis: Pathophysiology, clinical features, and diagnosis".)

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. (See 'Neuroimaging' below.)

●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 [25,29,34]. 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 [25,38]. Patients usually recover completely from the acute illness, although some have neurologic sequelae. While ADEM can be fatal, the mortality rate is low. (See "Acute disseminated encephalomyelitis (ADEM) in children: Treatment and prognosis".)

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. (See "Acute disseminated encephalomyelitis (ADEM) in children: Treatment and prognosis", section on 'Multiphasic ADEM'.)

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 [17,39-42]. 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 (see 'Neuroimaging' below), and CSF typically shows both white and red blood cells. (See 'CSF analysis' below.)

Some patients recover with treatment. However, the prognosis for survival or recovery of neurologic function is worse for acute hemorrhagic leukoencephalitis (AHL) than ADEM. (See "Acute disseminated encephalomyelitis (ADEM) in children: Treatment and prognosis", section on 'Prognosis'.)

EVALUATION AND DIAGNOSIS

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 (algorithm 1):

●Magnetic resonance imaging (MRI) of the brain and spine, with and without contrast (see 'Neuroimaging' below)

●Lumbar puncture and cerebrospinal fluid (CSF) analysis, including assessment for oligoclonal bands (see 'CSF analysis' below)

●Additional laboratory studies to rule out infection (see 'Additional evaluation for infection' below)

●Testing for anti-myelin oligodendrocyte glycoprotein (MOG) and anti-aquaporin 4 (AQP4) antibodies (see 'Serum autoantibodies' below)

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 [43]. Computed 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 (image 1 and image 2 and image 3), 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 [44,45].

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 [28]. While the lesions in ADEM are often large, smaller lesions are also seen, with diameters ranging from <5 mm to 5 cm (image 1 and image 2 and image 3) [26,28,33]. The large lesions may have associated mass effect.

Gray matter lesions sometimes accompany the white matter abnormalities in ADEM, especially in children [33,46,47]. The thalami and basal ganglia are frequently affected (image 4 and image 3), 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 (see 'Acute hemorrhagic leukoencephalitis' above). In such cases, brain MRI may reveal diffuse white matter lesions, often large and associated with cerebral edema [48-50]. 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 [51].

●Spinal cord MRI – Brainstem and spinal cord abnormalities on MRI are common in ADEM (image 4 and image 5) [1,28]. 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 (image 2) [33,44,52]. 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 (image 3).

●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 [53].

●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 1 and image 2 and image 5). 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 [26]. 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]. (See "Acute disseminated encephalomyelitis (ADEM) in children: Treatment and prognosis", section on 'Relapses' and "Differential diagnosis of acute central nervous system demyelination in children".)

CSF analysis — Lumbar puncture for CSF analysis in suspected ADEM is important primarily for ruling out infection [25]. 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 [26-28]. 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 [25,36,54]. Lumbar puncture may also reveal increased opening pressure [55]. In patients with acute hemorrhagic leukoencephalitis (AHL), the CSF typically shows both white and red blood cells with increased protein concentration. (See 'Acute hemorrhagic leukoencephalitis' above.)

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 [56]. (See "Differential diagnosis of acute central nervous system demyelination in children", section on 'MOG antibody-associated disease'.)

In children with ADEM, seropositivity for MOG antibodies is found in 33 to 66 percent of cases [25,57].

●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 [25]. (See "Differential diagnosis of acute central nervous system demyelination in children", section on 'Neuromyelitis optica spectrum disorders' and "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis".)

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 [25]. 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 [17,43]. 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 [52]. (See "Differential diagnosis of acute central nervous system demyelination in children".)

Encephalopathy as a presenting symptom is required for the diagnosis of ADEM [58,59]. 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. (See "Acute disseminated encephalomyelitis (ADEM) in children: Treatment and prognosis", section on 'Multiphasic ADEM' and "Differential diagnosis of acute central nervous system demyelination in children" and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis".)

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) [58,59]. 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. (See 'Approach to evaluation' above and "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Evaluation' and "Viral meningitis in children: Clinical features and diagnosis", section on 'Clinical features'.)

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. (See "Differential diagnosis of acute central nervous system demyelination in children", section on 'Distinguishing ADEM and multiple sclerosis' and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis".)

●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. (See "Differential diagnosis of acute central nervous system demyelination in children", section on 'MOG antibody-associated disease'.)

●Neuromyelitis optica spectrum disorder (NMOSD), characterized by immune-mediated demyelination and axonal damage predominantly targeting optic nerves and spinal cord. (See "Differential diagnosis of acute central nervous system demyelination in children", section on 'Neuromyelitis optica spectrum disorders' and "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis".)

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 [25]:

●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: Angiography-positive subtype".)

●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 "Clinical manifestations and diagnosis of central nervous system tumors in children", section on 'Common presenting signs and symptoms'.)

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. (See "Clinical manifestations and diagnosis of central nervous system tumors in children", section on 'Diagnosis'.)

●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. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Clinical features'.)

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. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Evaluation and diagnostic testing' and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Diagnosis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)

SUMMARY AND RECOMMENDATIONS — 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 is an uncommon illness that is preceded by fever or a viral infection in approximately 75 percent of cases. (See 'Epidemiology' above.)

●ADEM is considered an autoimmune disorder that is triggered by an environmental stimulus in genetically susceptible individuals. (See 'Pathophysiology' above.)

●Most children with ADEM present with fever, meningeal signs, and acute encephalopathy and have evidence of inflammation in blood and cerebrospinal fluid (CSF). Progression of neurologic signs to maximum deficits usually occurs over four to seven days. The level of consciousness ranges from lethargy to frank coma. (See 'Clinical features' above.)

●Inflammatory hemorrhagic demyelination of central nervous system white matter is seen in rare conditions that are considered to be hyperacute variants of ADEM. (See 'Acute hemorrhagic leukoencephalitis' above.)

●Deep and subcortical white matter lesions are associated with ADEM on brain magnetic resonance imaging (MRI), and are typically multiple and bilateral but may be asymmetric (image 1 and image 2 and image 3 and image 4). Brainstem and spinal cord abnormalities are common. Gray matter lesions may be observed in the thalami and basal ganglia (image 4 and image 3). (See 'Neuroimaging' above.)

●The diagnosis of ADEM should be suspected in a child who develops multifocal neurologic abnormalities with encephalopathy. Children with suspected ADEM should have the following investigations (algorithm 1) (see 'Approach to evaluation' above):

•MRI of the brain and spine, with and without contrast (see 'Neuroimaging' above)

•Lumbar puncture and CSF analysis, including assessment for oligoclonal bands (see 'CSF analysis' above)

•Additional laboratory studies to rule out infection (see 'Additional evaluation for infection' above)

•Testing for anti-myelin oligodendrocyte glycoprotein (MOG) and anti-aquaporin 4 (AQP4) antibodies (see 'Serum autoantibodies' above)

●The diagnosis of ADEM is based upon the clinical and radiologic features. Diagnostic criteria for ADEM in children are listed in the table (table 1) and require a first polyfocal clinical attack of central nervous system demyelinating disease, encephalopathy that cannot be explained by fever, and an abnormal brain MRI with diffuse, poorly demarcated, large (>1 to 2 cm) lesions predominantly involving the white matter. (See 'Diagnostic criteria' above.)

●Given the lack of a specific diagnostic test, ADEM is considered a diagnosis of exclusion. Meningitis and encephalitis must be ruled out. In the setting of nonspecific cerebrospinal fluid abnormalities and MRI evidence of white matter lesions, other inflammatory demyelinating disorders should be considered, such as multiple sclerosis, MOG antibody-associated disease, and neuromyelitis optica spectrum disorder. Additional disorders in the differential include central nervous system vasculitis, malignancy, and hemophagocytic lymphohistiocytosis. (See 'Differential diagnosis' above and "Differential diagnosis of acute central nervous system demyelination in children".)

●The treatment and prognosis of pediatric ADEM is reviewed separately. (See "Acute disseminated encephalomyelitis (ADEM) in children: Treatment and prognosis".)