Acute disseminated encephalomyelitis (ADEM) in adults

INTRODUCTION — Acute disseminated encephalomyelitis (ADEM), also known as postinfectious encephalomyelitis, is an autoimmune demyelinating disease of the central nervous system. Commonly triggered by viral infections, ADEM is caused by an inflammatory reaction in the brain and spinal cord. The onset of encephalopathy and multifocal neurologic deficits is acute and often rapidly progressive.

This topic will review the pathology, epidemiology, clinical features, diagnosis, and treatment of ADEM in adults. Clinical aspects of ADEM in children are discussed separately. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis" and "Acute disseminated encephalomyelitis (ADEM) in children: Treatment and prognosis".)

PATHOGENESIS — The pathogenesis of ADEM is reviewed here briefly and discussed in greater detail separately. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Pathophysiology'.)

Although the pathogenesis is incompletely understood, ADEM appears to be an autoimmune disorder of the central nervous system that is triggered by an environmental stimulus in genetically susceptible individuals. One proposed mechanism is that myelin autoantigens such as myelin basic protein, proteolipid protein, and myelin oligodendrocyte protein share antigenic determinants with those of an infecting pathogen. Antiviral antibodies or a cell-mediated response to the pathogen cross-react with the myelin autoantigens, resulting in ADEM.

PATHOLOGY — Gross neuropathologic brain sections of patients with ADEM often reveal edema [1] (consistent with observations that ADEM typically improves with glucocorticoid treatment and causes only minimal neurologic sequelae). However, in other cases the brain may appear normal [2].

The most common histopathologic finding is perivenous infiltration of lymphocytes; neutrophils, plasma cells, microglial cells, foamy macrophages, and eosinophilic granulocytes have also been observed [1,3]. Many reports emphasize the finding of perivenous sleeves of inflammation and demyelination as the pathologic hallmark and predominant lesion of ADEM [1-7]. In some ADEM cases, these perivenous lesions may eventually coalesce to form confluent regions of demyelination [7]. This is in contrast with multiple sclerosis, which is typically associated with multifocal, discrete lesions.

Myelin breakdown products are seen as lipids in macrophages [3]. An inflammatory infiltrate surrounding blood vessels is often described as cuffing of vessels [4]. Additional features may include vasculitic-type lesions consisting of inflammation in the vessel walls [1,8], perivascular necrosis [1,2], lymphocytic infiltration of the meninges [1], and glial nodules in gray matter [1]. Reactive astrocytes are seen in some cases, and gliosis often replaces the inflammatory exudate [2,4]. Axonal damage has been observed in fatal cases of ADEM [9].

EPIDEMIOLOGY — ADEM is an uncommon illness in adults, thus the precise incidence is unknown [10]. It is thought to occur more frequently in children. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Epidemiology'.)

ADEM is an expanding phenotype that may overlap with myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder (see 'MOG antibody-associated disorder' below). In a population-based study from Minnesota that evaluated autoimmune and infectious encephalitis, the prevalence of ADEM without MOG antibodies was 3.3 per 100,000 population, while the prevalence of MOG-associated demyelination was 1.9 per 100,000 [11].

ADEM has been reported in adults 18 to 82 years of age; the median age ranges from 33 to 41 [12-16].

●Association with preceding infection – In retrospective studies, ADEM is associated with a preceding infection in 50 to 75 percent of adult cases [15-18]. As an example, in a study that included 20 adult patients with an initial diagnosis of ADEM, a preceding infection was present in 14 (70 percent) [18]. Note that all of these reports are retrospective and limited by potential referral or recall bias [15-18]. Nevertheless, these data suggest that infection may be involved in triggering the onset of ADEM.

While ADEM is often preceded by a viral or bacterial infection, an underlying pathogen is not always identified, and ADEM may follow a nonspecific upper respiratory or gastrointestinal illness [12,19]. The list of infectious pathogens associated with ADEM includes rubella, mumps, varicella, measles, smallpox, Epstein-Barr virus, herpes simplex virus, human herpes virus-6, influenza, HIV, and Mycoplasma pneumoniae [1,2,20-24]. In addition, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may be associated; a few case reports have described patients with coronavirus disease 2019 (COVID-19) who had clinical and neuroimaging findings consistent with ADEM. (See "COVID-19: Neurologic complications and management of neurologic conditions", section on 'Other acute neurologic manifestations'.)

●Weak association with immunization – Although early reports suggested that a small minority of ADEM cases followed immunization, subsequent studies have found little or no association between ADEM and immunization. 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 [25]. 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).

In early reports, ADEM sometimes occurred after administration of the rabies (Semple) vaccine, which has not been used in the United States for decades [26]. Typically, adults and children developed encephalomyelitis 8 to 21 days following the immunization (range 6 to 45 days). Neurologic complications suggestive of ADEM were also reported (rarely) after vaccines against smallpox, influenza, diphtheria, pertussis, tetanus, measles, rubella, and polio [1,27-30].

CLINICAL FEATURES

Classic ADEM — Classic descriptions of ADEM involve a preceding infectious illness in most but not all cases (see 'Epidemiology' above). After a lag time of a few days to two months (mean 26 days) [13], the typical presentation involves the acute onset of multifocal neurologic symptoms with encephalopathy, often with rapid deterioration prompting hospitalization [12,13,19,31]. Most patients present with motor deficits; these may involve a single limb or result in paraparesis (partial paralysis of both legs) or quadriparesis [2,12]. Sensory deficits are frequent, and brainstem involvement is common, including oculomotor deficits and dysarthria [12].

Additional signs and symptoms may include headache, malaise, meningismus, ataxia, aphasia, optic neuritis (sometimes bilateral), nystagmus, extrapyramidal movement disorders, urinary retention, seizures, and increased intracranial pressure [2,12,13,15,16].

In children, where ADEM is more common than in adults, the presence of encephalopathy is one of the required clinical features for a diagnosis of ADEM, as outlined in the table (table 1). In adults, the presence of encephalopathy is clinically important, as it helps to identify individuals who are less likely to have a different disease, such as multiple sclerosis, and more likely to have ADEM. However, encephalopathy has not always been a required feature for diagnosis, thus it has been reported in only 20 to 56 percent of adult cases [2,12,15,16]. (See 'Making the diagnosis' below.)

Variant forms — Acute hemorrhagic leukoencephalitis (AHL) is considered a variant type of ADEM. Some experts recognize additional variants of ADEM, including site-restricted forms such as postinfectious myelitis or myeloradiculoneuritis, and a form with mixed central and peripheral nervous system involvement [24,32].

Acute hemorrhagic leukoencephalitis — AHL, also called acute hemorrhagic encephalomyelitis (AHEM) or acute necrotizing hemorrhagic leukoencephalitis (ANHLE) of Weston-Hurst, is considered a hyperacute variant of ADEM. Typically, AHL presents after an infectious illness with meningismus, headache, seizures, multifocal neurologic signs, asymmetrical neurologic deficits, and rapid progression to coma [1]. Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain usually reveal hemorrhagic lesions in the white matter [2]. Additional pathologic features include edema, petechial hemorrhages of the corona radiata, perivascular hemorrhages, destruction of the vessel walls with fibrin deposition, and neutrophilic infiltrates [1].

Neuroimaging in one rapidly fatal case did not reveal the presence of hemorrhagic lesions (figure 1); however, focal hemorrhages were seen on gross sections of the brain at autopsy in the white matter of the bilateral posterior frontal and parietal lobes [33].

ADEM with peripheral nervous system involvement — Adults with postinfectious neurologic syndromes may have clinical or subclinical electrodiagnostic evidence of peripheral nervous system involvement [24,32]. As an example, one report evaluated 176 adults (median age 69 years), consisting of one group with purely central nervous system syndromes (30 with encephalitis, 35 with encephalomyelitis, and 47 with myelitis) and a second group with both central and peripheral nervous system syndromes (30 patients with encephalomyeloradiculoneuritis and 34 with myeloradiculoneuritis) [32]. Peripheral nerve involvement was defined by the presence of electrodiagnostic abnormalities. Clinical symptoms of peripheral nerve injury, including distal limb paresthesia, perineal anesthesia, and muscle atrophy, were present in 29 of the 64 patients (46 percent) with electrodiagnostic evidence of peripheral nerve injury. Patients with peripheral nerve involvement were significantly older and had a worse prognosis and an elevated risk of relapses compared with those having only central nervous system syndromes.

EVALUATION AND DIAGNOSIS

When to suspect ADEM — The diagnosis of ADEM should be considered in patients with unexplained acute encephalopathy and multifocal neurologic signs and symptoms.

Note that ADEM is an evolving topic in both children and adults given the development of cell-based assays for the detection of anti-myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) antibodies.

Most of the literature describing adults with ADEM was published prior to the systematic implementation of these assays and widespread testing for anti-MOG antibodies. Thus, it is challenging to differentiate the clinical, radiographic, and prognostic features of ADEM with and without MOG-IgG antibodies. However, in patients without MOG-IgG autoantibody, ADEM is typically monophasic, whereas adults who have an ADEM-like presentation and are seropositive for MOG-IgG antibodies are more likely to have recurrences [18]. An ADEM-like presentation may also be the first attack of neuromyelitis optica or, rarely, multiple sclerosis.

Approach to evaluation — The evaluation of a patient with suspected ADEM begins with a detailed clinical history and examination, which often reveals encephalopathy polyfocal neurologic symptoms. Patients with suspected ADEM should have the following studies:

●MRI of the brain, cervical and thoracic spine with and without contrast. (See 'Neuroimaging' below.)

●Lumbar puncture for cerebrospinal fluid (CSF) analysis including (see 'CSF analysis' below):

•Cell counts, protein, glucose, culture (and viral studies if suggested by the clinical setting and history of outbreaks, such as herpes simplex virus, varicella-zoster virus, enterovirus, and West Nile virus)

•Qualitative assessment of CSF and serum for oligoclonal immunoglobulin G (IgG) bands using isoelectric focusing, including IgG synthesis rate and IgG index

●Serologic studies for anti-aquaporin-4 (AQP4) and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. (See 'Serum autoantibodies' below.)

Neuroimaging — Patients with suspected ADEM should undergo brain magnetic resonance imaging (MRI) (without and with contrast), which is the neuroimaging modality of choice. MRI of the cervical and thoracic spine is also indicated if there are symptoms or signs of myelopathy, and is helpful in differentiating ADEM from other central nervous system (CNS) demyelinating disorders such as NMOSD and MS. Therefore, all patients with evidence of CNS demyelination should have MRI of the cervical and thoracic spine, even in the absence of myelopathy.

●Head CT – Many patients with suspected ADEM or a variant (eg, acute hemorrhagic encephalomyelitis [AHEM]) present to an emergency room, and an urgent head computed tomography (CT) scan may be necessary in order to exclude other causes of neurologic disease (see 'Differential diagnosis' below). However, head CT is usually normal or nondiagnostic, especially early in the course of ADEM, although some patients may have scans showing evidence of focal or multifocal white matter damage [34]. Regardless of head CT findings, MRI is indicated because it is more sensitive for discriminating demyelinating lesions in the brain and particularly in the spinal cord.

●Brain MRI – Brain lesions on MRI associated with ADEM are typically bilateral and asymmetric and tend to be poorly marginated [15]. Most patients have multiple lesions in the deep and subcortical white matter, characteristic of demyelination. On MRI, the lesions of ADEM are hyperintense on T2-weighted and fluid attenuated inversion recovery (FLAIR) sequences (image 1) [34,35] and are usually less conspicuous on unenhanced T1-weighted sequences [36]. However, large lesions can be slightly hypointense on unenhanced T1 sequences. There can be considerable heterogeneity: large confluent lesions (image 2), single solitary lesions, and multiple small lesions have been described [5,37]. Lesions may be seen in the periventricular and subcortical white matter, including corpus callosum and centrum semiovale, as well as in the gray matter, including the cortex, basal ganglia, and thalamus [12,15,16,38]. Infratentorial lesions in the brainstem, cerebellum, and spinal cord are common [2,12].

Brain MRI is almost always abnormal in ADEM. One series reported that brain MRI was normal in only 3 of 228 children and adults with ADEM; in these three cases, imaging of the cervical and thoracic spine was performed but results were not reported [16]. Others have noted that there may be a delay in the appearance of MRI lesions [31,39,40]; in one report the time lag to MRI lesion appearance was eight weeks from ADEM symptom onset [39].

●Spinal cord MRI – Lesions in the spinal cord are common in ADEM, although an isolated spinal cord lesion without supratentorial involvement is rare [35]. Both long and short segment cord lesions have been reported, but large confluent intramedullary lesions that extend over multiple segments are more common [41], particularly with MOG antibody-associated ADEM.

●Enhancing lesions – Gadolinium enhancement of MRI lesions in ADEM is variable. Enhancing and nonenhancing lesions may appear together in the same scan [2,12,31]. Even though ADEM is usually a monophasic illness, repeat imaging early in the disease course has shown fluctuation in the presence of both enhancing and nonenhancing lesions [12], especially in MOG-associated demyelination. New asymptomatic lesions may appear while others seemingly resolve [2].

●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 [2,38].

●Resolution of MRI abnormalities – Many MRI lesions resolve within 18 months [2], although some patients have residual lesions on follow-up imaging [31].

CSF analysis — Lumbar puncture for CSF analysis in suspected ADEM is performed to obtain evidence of inflammation and differentiate ADEM from other disorders (such as multiple sclerosis) while concurrently ruling out an infection [42].

●Typical findings – CSF findings in ADEM are variable; while CSF can be normal, abnormalities are present in 50 to 80 percent of patients [12,15,16,19,24]. Typical abnormalities in ADEM are nonspecific and include a lymphocytic pleocytosis, usually with a CSF white blood cell count <100 cells/mL, and a mildly elevated CSF protein, usually <70 mg/dL, although higher counts and levels have been reported [2,5,12,19].

●Oligoclonal bands – Oligoclonal bands (OCBs) have been reported in 6 to 65 percent of adult patients with ADEM [12,13,15,16]; in a study that included 102 adult patients with ADEM who had lumbar puncture performed, OCBs were present in 29 percent [16]. However, other reports suggest that OCBs are rarely found in the CSF children who are diagnosed according to consensus criteria for childhood ADEM (table 1) [41]. Rather, the presence of OCBs in children and adolescents is associated with the evolution to multiple sclerosis [43]. Positivity for anti-MOG-IgG antibody rarely occurs in patients with OCBs; thus, both tests are useful in differentiating a MOG antibody-associated disorder with an ADEM phenotype from ADEM as a first attack of MS.

Serum autoantibodies — Testing for the MOG-IgG autoantibody and the AQP4-IgG serum autoantibody is indicated for patients presenting with suspected ADEM.

●The anti-MOG-IgG antibody is a marker of MOG antibody-associated disorder, a demyelinating disorder characterized by a variety of manifestations that include ADEM, relapsing and bilateral optic neuritis, transverse myelitis, and brainstem encephalitis. Therefore, MOG antibody-associated disorder is a potential cause of ADEM and other 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-associated disorder [18]. Among young patients with a demyelinating syndrome who go on to develop MS, positive anti-MOG antibody serology is uncommon [44]. (See 'MOG antibody-associated disorder' below.)

Although data are limited, one study found that the frequency of MOG antibody seropositivity among a cohort of 20 adult patients with ADEM was 60 percent [45]. In children with ADEM, seropositivity for MOG antibodies is found in 33 to 66 percent of cases [42,44,45].

●The anti-AQP4-IgG antibody is a specific biomarker for neuromyelitis optica spectrum disorder (NMOSD). Patients with cerebral lesions, optic neuritis, or transverse myelitis who are seropositive for anti-AQP4 antibodies fulfill criteria for NMOSD [42]. (See 'Neuromyelitis optica spectrum disorder' below.)

Other studies — Ancillary tests, including evoked potentials and electroencephalogram (EEG), have been studied in ADEM, but the findings are usually nonspecific. Visual evoked and somatosensory evoked potentials may be abnormal depending on the localization of CNS lesions; however, these studies do not often contribute to the diagnosis.

The utility of EEG is controversial; typically, the EEG shows bilateral slow activity, which is nonspecific and nonlocalizing. Given this, some authors do not feel it contributes to the diagnosis [2], whereas others argue that the presence of focal slowing or epileptiform discharges is useful in documenting central nervous system involvement, especially if the MRI and cerebrospinal fluid findings are normal [19].

Making the diagnosis — The key clinical features that distinguish ADEM from other disorders are the acute and rapid progression of encephalopathy and multifocal neurologic findings. There are no specific biomarkers or confirmatory tests to establish the diagnosis of ADEM. The presence of antibodies to MOG-IgG1 would be classified as MOG-associated demyelination.

●Supportive features – The diagnosis of ADEM is supported by the presence of one or more supratentorial or infratentorial demyelinating lesions on brain MRI and the absence of destructive "black hole" lesions on T1-weighted MRI, which suggest prior episodes of inflammation or demyelination as seen in multiple sclerosis [12]. A preceding infection and abnormal CSF (a mild lymphocytic pleocytosis and a mildly elevated protein) are suggestive of ADEM but not required for the diagnosis.

●Diagnosis of exclusion – Given the lack of a specific diagnostic test, ADEM is considered a diagnosis of exclusion, and other CNS demyelinating and inflammatory syndromes must be ruled out, particularly MOG antibody-associated disorder and multiple sclerosis [41]. However, diagnostic certainty may be delayed. The evaluation for MOG and AQP4 autoantibodies typically requires send-out laboratory testing and is often pending during a patient's initial hospitalization and treatment. Similarly, the analysis for CSF-specific OCBs, which helps distinguish ADEM from a first attack of multiple sclerosis (MS), is a send-out test as well. (See 'Approach to evaluation' above and 'Differential diagnosis' below.)

●Diagnostic criteria – Diagnostic criteria for ADEM have been proposed for children, as listed in the table (table 1) [46,47]. The two major features required for the diagnosis of ADEM in children are multifocal central nervous system involvement and encephalopathy. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis", section on 'Diagnostic criteria'.)

A consensus set of diagnostic criteria for ADEM has not been established for adults. However, some investigators have proposed that certain criteria may be used to distinguish patients with ADEM from those with multiple sclerosis (see 'Multiple sclerosis' below), including two of the following [13]:

•Presence of symptoms that are atypical for multiple sclerosis such as encephalopathy, defined as an alteration in consciousness (eg, stupor, lethargy or behavioral change) that cannot be explained by fever, systemic illness, or postictal symptoms

•Gray matter involvement on brain MRI

•Absence of OCBs in the CSF

The utility of the third criterion (absence of oligoclonal bands) is questionable since oligoclonal bands in the CSF are present in some adult patients with ADEM. (See 'CSF analysis' above.)

DIFFERENTIAL DIAGNOSIS — The most challenging aspect of the diagnostic process is differentiating ADEM from myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder, neuromyelitis optica spectrum disorder (NMOSD), or a first attack of multiple sclerosis.

Other entities to be considered in the differential diagnosis of ADEM include infectious meningoencephalitis, neurologic sarcoidosis, vasculitis, progressive multifocal leukoencephalopathy, and Behçet syndrome.

MOG antibody-associated disorder — IgG serum antibodies directed against MOG denote a separate disease entity termed MOG antibody-associated disorder [48]. The disorder is characterized by a variety of manifestations related to central nervous system demyelination that include ADEM and other syndromes, such as relapsing and bilateral optic neuritis, transverse myelitis, and brainstem encephalitis.

Proposed diagnostic criteria for MOG antibody-associated disorder require serum positivity for MOG-immunoglobulin G (IgG), a clinical presentation consistent with central nervous system demyelination (ie, ADEM, optic neuritis, transverse myelitis, a brain or brainstem demyelinating syndrome, or any combination of these), and exclusion of an alternative diagnosis [18]. In the absence of serum, positivity for MOG-IgG in the CSF allows fulfillment of the criteria. A transient seropositivity may indicate a lower risk of relapse.

Multiple sclerosis — Multiple sclerosis (MS) is a chronic, autoimmune, demyelinating disease characterized by recurrent attacks separated in time and space. (See "Manifestations of multiple sclerosis in adults" and "Evaluation and diagnosis of multiple sclerosis in adults".)

Certain clinical features may be helpful in supporting the diagnosis of ADEM or MS [12,13]. However, there is substantial overlap:

●ADEM typically follows a prodromal viral illness, while MS may not.

●ADEM may present with fever and stiff neck, which is unusual in MS.

●ADEM usually produces a widespread central nervous system disturbance, often with impaired consciousness and/or encephalopathy, while MS typically is monosymptomatic (eg, optic neuritis or a subacute myelopathy) and has a relapsing-remitting course. MS flares do not typically cause encephalopathy.

●Ataxia is a common presenting feature of ADEM but is less commonly seen as a presenting feature in MS.

Brain magnetic resonance imaging (MRI) features may also be helpful in distinguishing ADEM from MS (see 'Neuroimaging' above), although complete differentiation is not possible based on a single study:

●ADEM usually has more MRI lesions than early MS, with larger bilateral but asymmetric white matter abnormalities.

●Lesions tend to be poorly defined in ADEM and have better defined margins in MS.

●The presence of brain lesions of approximately the same age on MRI is most consistent with ADEM, while the presence of brain lesions of different ages and/or the presence of black holes (hypointense T1-weighted lesions) suggests MS.

●Periventricular lesions are less common in ADEM than MS.

In a retrospective series of 54 patients evaluated for acute demyelinating disease, the final diagnosis was monophasic ADEM in 35 and MS in 19 [13]. Atypical symptoms for MS (ie, encephalopathy, aphasia, hemiplegia, paraplegia, tetraplegia, seizure, vomiting, or bilateral optic neuritis) were more common in the ADEM group compared with the MS group (74 and 42 percent, respectively), and gray matter (cortex or basal ganglia) involvement on brain MRI was more frequent in the ADEM group (60 versus 11 percent). By contrast, corpus callosum involvement was less frequent in the ADEM group compared with the MS group (23 percent versus 79 percent), as were oligoclonal bands in the cerebrospinal fluid (20 percent versus 84 percent).

Neuromyelitis optica spectrum disorder — Neuromyelitis optica spectrum disorder (NMOSD), discussed in detail elsewhere (see "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis"), is an inflammatory disorder of the central nervous system characterized by severe, immune-mediated demyelination and axonal damage predominantly targeting the optic nerves and spinal cord, but also the brain and brainstem. NMOSD is distinguished based upon the presence of the disease-specific aquaporin-4 (AQP4) antibody, which plays a direct role in the pathogenesis of NMOSD. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", section on 'History' and "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", section on 'Pathogenesis'.)

Clinical features of NMOSD overlap with other neuroinflammatory disorders, such as MS and MOG antibody-associated disorder. Hallmark features of NMOSD include acute attacks characterized by bilateral or rapidly sequential optic neuritis (leading to visual loss), acute transverse myelitis (often causing limb weakness and bladder dysfunction), and the area postrema syndrome (with intractable hiccups or nausea and vomiting). Other suggestive symptoms include episodes of excessive daytime somnolence or narcolepsy, reversible posterior leukoencephalopathy syndrome, neuroendocrine disorders, and (in children) seizures. While no clinical features are disease-specific, some are highly characteristic. NMOSD has a relapsing course in 90 percent or more of cases. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", section on 'Clinical features'.)

Diagnostic criteria for NMOSD (table 2) require the presence of at least one core clinical characteristic (eg, optic neuritis, acute myelitis, area postrema syndrome), a positive test for AQP4-IgG, and exclusion of alternative diagnoses. The diagnostic criteria are more exacting in the setting of negative or unknown AQP4-IgG antibody status (table 2). (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)

Infectious meningoencephalitis — Infectious meningoencephalitis should be included in the differential diagnosis of ADEM, especially in patients presenting with fever, headache, and meningismus. Acute viral encephalitis typically affects the gray matter and can present with seizures, as seen in herpes simplex virus (HSV) infections. The most important diagnostic consideration in patients with encephalitis is HSV since delay in treatment can affect morbidity and mortality. (See "Viral encephalitis in adults".)

CSF examination of patients with suspected meningitis or encephalitis is essential for diagnosis. In the appropriate setting, a lymphocytic predominance is suggestive of a viral rather than a bacterial etiology; the presence of red blood cells in the absence of a traumatic tap is suggestive of HSV or other necrotizing viral encephalitides. Diagnostic CSF polymerase chain reaction (PCR) for HSV-1 and immunoglobulin M (IgM) antibody in CSF and serum for West Nile virus are recommended for patients with encephalitis. Testing for other viral pathogens will depend on travel or exposure history to insects and animals. Serologic testing for West Nile virus, mumps, and Epstein-Barr virus can also be considered in the appropriate clinical setting. (See "Viral encephalitis in adults", section on 'Diagnosis'.)

Sarcoidosis — Sarcoidosis is an autoimmune disease that may involve any organ system, most commonly the lungs and skin. The pathologic finding is non-caseating granulomas. Neurologic complications occur in approximately 5 percent of patients with sarcoidosis. (See "Neurologic sarcoidosis".)

The most common features of neurologic sarcoidosis are cranial mononeuropathy, neuroendocrine dysfunction, a focal or multifocal encephalopathy, myelopathy, hydrocephalus, aseptic meningitis, peripheral neuropathy, or myopathy (see "Neurologic sarcoidosis", section on 'Clinical features'). Parenchymal involvement mimicking inflammatory disorders such as ADEM or multiple sclerosis may also be seen. Sarcoidosis is more commonly a chronic recurrent disease and less likely to be monophasic. However, patients presenting with neurosarcoidosis may have no systemic features of the disease and thus present a diagnostic challenge. Thus, the diagnostic evaluation requires distinguishing neurosarcoidosis from a variety of other inflammatory and infectious conditions. (See "Neurologic sarcoidosis", section on 'Differential diagnosis'.)

A thorough evaluation for systemic sarcoidosis (eg, chest imaging, skin evaluation) can expedite the evaluation by providing tissue that is accessible for biopsy. In the absence of systemic sarcoidosis, testing that may be helpful includes contrast-enhanced MRI of the affected area (brain and/or spinal cord), cerebrospinal fluid evaluation (see "Neurologic sarcoidosis", section on 'Lumbar puncture') and serum angiotensin converting enzyme level. None of these tests have perfect sensitivity and specificity. (See "Neurologic sarcoidosis", section on 'Clinical evaluation' and "Neurologic sarcoidosis", section on 'Neurodiagnostic testing'.)

Vasculitis — Vasculitis may mimic ADEM, as it can present with evolving multifocal deficits secondary to deep brain infarcts (see "Overview of and approach to the vasculitides in adults"). Headaches, seizures, and cognitive, mood, or behavioral changes can occur in ADEM but are more common in some vasculitides. Magnetic resonance angiography (MRA) may reveal abnormal vessels, but is often nondiagnostic. While conventional angiography is perhaps more sensitive in the diagnosis of vasculitis, it may still be negative; leptomeningeal biopsy may be necessary to increase the diagnostic yield. Vasculitis secondary to systemic autoimmune diseases can be diagnosed by the appropriate rheumatologic serologies and other systemic manifestations.

Patients with primary angiitis of the central nervous system (PACNS) may present with altered mental status, followed by the accrual of multifocal CNS deficits (see "Primary angiitis of the central nervous system in adults", section on 'Clinical manifestations'). Signs and symptoms of systemic vasculitis, such as peripheral neuropathy, fever, weight loss, or rash, are usually absent. CSF pleocytosis with elevated protein is typical but not specific for PACNS. MRI of the brain commonly shows multiple infarcts in multiple vascular territories, and often in areas of the brain not affected by more common causes of stroke (such as the corpus callosum). However, these findings are not specific for PACNS. Cerebral angiography findings that are compatible with (but not diagnostic of) PACNS include beading, circumferential or eccentric luminal narrowing, occlusions of one or more arteries, and/or an avascular mass effect, but the sensitivity and specificity of angiography for the diagnosis are suboptimal. The gold standard for the diagnosis of PACNS is histopathology of the leptomeninges and underlying cortex. However, brain/leptomeningeal biopsies are only approximately 75 percent sensitive for the diagnosis of PACNS. (See "Primary angiitis of the central nervous system in adults", section on 'Establishing the diagnosis'.)

Progressive multifocal leukoencephalopathy — Progressive multifocal leukoencephalopathy (PML) is a demyelinating inflammatory disease of the brain caused by the JC virus. PML occurs almost exclusively in immunosuppressed individuals. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Epidemiology'.)

As the name implies, classic PML is progressive, multifocal, and involves the white matter. Similar to ADEM, patients with PML may present with multifocal neurologic deficits, including motor weakness, visual changes, and cognitive impairment. Its onset may be less acutely fulminant than ADEM, but it progresses rapidly over several months, usually resulting in severe disability and death. The typical appearance of PML on neuroimaging studies consists of symmetric or asymmetric multifocal areas of white matter demyelination that do not conform to cerebrovascular territories and exhibit neither mass effect nor contrast enhancement. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical forms'.)

The diagnosis of PML is confirmed by PCR detection of JC virus DNA in the CSF in patients with appropriate neurologic and neuroradiologic features, or less commonly by brain biopsy. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

Behçet syndrome — Behçet syndrome is a rare condition characterized by recurrent oral aphthae and any of several systemic manifestations, including genital aphthae, ocular disease, skin lesions, gastrointestinal disease, neurologic disease, vascular disease, and arthritis. Most clinical manifestations of Behçet syndrome are believed to be due to vasculitis. Behçet syndrome is more common (and often more severe) along the ancient Silk Road, which extends from eastern Asia to the Mediterranean; the prevalence is much lower in North America and northern Europe. It typically affects young adults 20 to 40 years of age. (See "Clinical manifestations and diagnosis of Behçet syndrome", section on 'Epidemiology'.).

Neurologic disease occurs in less than one-fifth of patients with Behçet syndrome and is observed more frequently in men than women. Neurologic involvement may mimic demyelinating disease. There may be acute or chronic recurrent meningitis, meningoencephalitis with changes in mental status, parenchymal involvement with multifocal lesions in the gray and white matter, or brainstem and cranial nerve involvement. (See "Clinical manifestations and diagnosis of Behçet syndrome", section on 'Neurologic disease'.)

There are no pathognomonic laboratory findings in Behçet syndrome; the diagnosis is made based on the clinical findings. Nonspecific elevation of acute phase reactants is often seen. CSF analysis typically reveals a pleocytosis; chronic counts <60 cells/mL are most common, but counts >500 cells/mL may be seen in the acute meningitis presentation of Behçet syndrome. Diagnostic criteria require the presence of recurrent oral aphthae (three times in one year) plus two more manifestations that can include recurrent genital ulcerations, eye lesions, skin lesions, or a positive pathergy test. (See "Clinical manifestations and diagnosis of Behçet syndrome", section on 'Diagnosis'.)

TREATMENT — Immune suppression is the mainstay of treatment for ADEM.

Initial therapy — We recommend initial therapy with high-dose glucocorticoids for adults with ADEM [49]. Glucocorticoids may be started at the time of the patient's presentation and can be used concurrently with acyclovir and antibiotics. A typical regimen is intravenous methylprednisolone, 1000 mg daily for three to five days, followed by an oral glucocorticoid taper of variable duration.

Efficacy of glucocorticoids — In uncontrolled observational studies, treatment of adults with ADEM using intravenous methylprednisolone (1000 mg daily for three to five days), followed by an oral glucocorticoid taper over four to six weeks, was associated with substantial clinical improvement in a majority of patients [12,32]. Similar data suggesting benefit of intravenous glucocorticoids for ADEM have been reported in children. (See "Acute disseminated encephalomyelitis (ADEM) in children: Treatment and prognosis", section on 'Glucocorticoids'.)

Anecdotally, the need for glucocorticoid tapering is uncertain; shorter duration tapering is often used in clinical practice.

Empiric antibiotics for select patients — Some adults with ADEM present with fever, meningeal signs, acute encephalopathy, and evidence of inflammation in blood and cerebrospinal fluid. For such patients, empiric treatment with acyclovir should be started if the patient has encephalitis without apparent explanation and continued until an infectious etiology is excluded. (See "Viral encephalitis in adults", section on 'Empiric therapy'.).

Empiric antibiotics for possible bacterial meningitis are not necessary unless the cerebrospinal fluid findings suggest a bacterial inflammatory profile. (see "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Cerebrospinal fluid analysis').

Inadequate response to initial therapy — For patients with ADEM who have a poor response to glucocorticoids, therapeutic options include intravenous immune globulin (IVIG) or plasma exchange. In addition, alternate diagnoses should be explored for patients who have suspected ADEM that does not respond well to glucocorticoids.

Intravenous immune globulin — IVIG can be used if the response to a five-day course of glucocorticoids is poor. In one report, three patients with classic ADEM and poor response to glucocorticoids were treated with IVIG (0.4 g/kg intravenously daily for five days) and demonstrated improvement in the first week of therapy, reaching maximum benefit within the first three weeks [50]. (See "Overview of intravenous immune globulin (IVIG) therapy".)

Among patients with ADEM who have electrodiagnostic or clinical evidence of peripheral nervous system involvement (see 'ADEM with peripheral nervous system involvement' above), a prospective uncontrolled study found that IVIG treatment was associated with a favorable outcome in approximately 50 percent of patients for whom high-dose glucocorticoids were ineffective [32].

Plasma exchange — Plasma exchange has also been used for ADEM in adults when glucocorticoids are ineffective, but data are limited [51]. One retrospective cohort study of plasma exchange for all demyelinating diseases, including 10 patients with ADEM, showed that male sex, preserved reflexes on examination, and early initiation of therapy were associated with improved outcomes [49].

Plasma exchange for ADEM is generally given as five to seven exchanges over 10 to 14 days. One reasonable regimen is six exchanges, one every other day, with each exchange consisting of 1 to 1.5 plasma volumes. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)

Other options — Cyclophosphamide, 1 gram given intravenously, has also been used for patients when the response to glucocorticoids is poor. Repeat dosing may be necessary to achieve maximum benefit [12].

Management of malignant edema — In some cases, fulminant ADEM or acute hemorrhagic leukoencephalitis may progress to develop malignant, space-occupying brain edema with increased intracranial pressure and brain tissue shifts or herniation [52]. This process can lead to neurologic deterioration with signs that typically include decreased arousal, pupillary changes, and worsening of motor responses. These neurologic signs are indicators of the need to intervene urgently with measures to treat brain edema.

Standard medical therapy for worsening edema involves close monitoring for neurologic complications; and interventions to reduce intracerebral pressure such as elevation of the head of the bed, osmotic therapy, brief periods of hyperventilation as needed, and hemicraniectomy for patients with life-threatening cerebral edema [53,54]. (See "Evaluation and management of elevated intracranial pressure in adults".)

Monitoring — For patients with ADEM who remain asymptomatic, an annual brain MRI with and without gadolinium for several years is suggested to monitor for the development of new lesions and possible multiple sclerosis.

For patients with detectable anti-myelin oligodendrocyte glycoprotein (MOG) antibody titers at presentation with ADEM, repeat testing should be performed every six months for at least one year. Patients with persistently high titers should be closely observed clinically and have repeat imaging every 6 to 12 months. Persistent seropositivity for anti-MOG antibodies is associated with an increased risk for relapse, as discussed in the section that follows.

PROGNOSIS — Compared with ADEM in children, the available studies suggest that the clinical course is more severe and outcome is less favorable in adults with ADEM [15,55]. Nevertheless, most patients improve with treatment, and spontaneous recovery has occurred in patients with mild symptoms [50]. Complete recovery has been reported in 10 to 46 percent of adults [12,15,19]. Cognitive impairment, mostly affecting attention and concentration, has persisted in some.

●Mortality – ADEM may be fatal especially in fulminant cases, with mortality rates of 4 to 12 percent reported in larger modern series [12,15,50]. In one report of 20 patients with ADEM admitted to the intensive care unit, the mortality rate was 25 percent [14]. Thirty-five percent of survivors in this series were left with permanent disability.

●Relapses – Although traditionally considered to be a monophasic illness, up to one-quarter of adults with ADEM experience at least one relapse [16,56]. Of note, patients in these studies were not routinely tested for the presence of myelin oligodendrocyte glycoprotein (MOG) antibodies, which is associated with a higher likelihood of relapses. Nevertheless, ADEM has recurred in cases without MOG antibodies. In such recurrences, the symptoms often localize to the site of the central nervous system that was originally affected. In fact, new clinical symptoms may localize to a previously silent lesion on neuroimaging [5]. Relapses may also present as cognitive difficulties or neuropsychiatric disease, such as depression or psychosis [57].

Persistent seropositivity for anti-MOG antibodies is associated with an increased risk for relapse [18,48].

Recurrent ADEM frequently responds to glucocorticoid treatment. Relapsing disease associated with MOG antibodies may require other immune suppression. (See 'Efficacy of glucocorticoids' above.)

The International Pediatric MS Study Group (IPMSSG) have defined ADEM by the simultaneous presence of polyfocal neurologic symptoms and encephalopathy [46,47]. In contrast to pediatric ADEM, the presence of encephalopathy may not distinguish those adults likely to have monophasic disease. In two adult cohorts, encephalopathy was present in approximately half of patients with an initial diagnosis of ADEM, and among patients who were longitudinally confirmed to have a monophasic course, only 36 to 58 percent had encephalopathy as part of their initial attack [15,16].

●Progression to multiple sclerosis – In patients initially diagnosed with ADEM, relapses that involve a new central nervous system territory should raise suspicion for MOG antibody-associated disorder or multiple sclerosis (see 'Multiple sclerosis' above). In one study of adults with an ADEM-like first attack, 35 percent were confirmed to have multiple sclerosis over an average of 38 months, with most patients developing new attacks within one year [12].

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) is an autoimmune demyelinating disease of the central nervous system that typically follows an infection. Histopathology of ADEM reveals perivascular infiltration of lymphocytes. Perivenous demyelination is a frequent finding. (See 'Pathogenesis' above and 'Pathology' above.)

●ADEM is an uncommon disease, but the precise incidence in adults is unknown. ADEM is thought to be more frequent in children than adults. (See 'Epidemiology' above.)

●ADEM typically presents after a preceding illness with multifocal neurologic signs and encephalopathy (altered mental status). Other common neurologic manifestations include motor, sensory, cranial nerve, and brainstem deficits as well as nonspecific symptoms such as headache and malaise. (See 'Clinical features' above.)

●Acute hemorrhagic leukoencephalitis is a hyperacute variant of ADEM that may be fatal. Petechial or gross hemorrhages may occur (figure 1). (See 'Acute hemorrhagic leukoencephalitis' above.)

●The evaluation for ADEM requires neuroimaging, preferably with magnetic resonance imaging (MRI), lumbar puncture for cerebrospinal fluid (CSF) analysis, and serum autoantibody testing for anti-myelin oligodendrocyte glycoprotein (MOG) and anti-aquaporin-4 (AQP4), preferably with a cell-based assay. (See 'Evaluation and diagnosis' above.)

•On MRI, lesions associated with ADEM are typically bilateral but may be asymmetric and tend to be poorly marginated. Most patients have multiple lesions in the deep and subcortical white matter. The lesions are hyperintense on T2-weighted and fluid-attenuated inversion recover (FLAIR) sequences (image 1); on unenhanced T1-weighted sequences, small lesions are usually inconspicuous while large lesions are mildly hypointense. Gadolinium enhancement is variable. (See 'Neuroimaging' above.)

•Lumbar puncture may be normal, or may reveal a lymphocytic pleocytosis or elevated protein. The presence of oligoclonal bands in the CSF (but not serum) or elevated immunoglobulin G (IgG) index is more common in multiple sclerosis but can also be seen in ADEM. (See 'CSF analysis' above.)

•Anti-MOG antibodies are indicative of MOG antibody-associated disorder, which can manifest as ADEM. Anti-AQP4 antibodies are indicative of NMOSD. (See 'Serum autoantibodies' above.)

●The diagnosis of ADEM is considered in patients with encephalopathy and unexplained acute multifocal neurologic signs and symptoms. The diagnosis is supported by the presence of one or more supratentorial or infratentorial demyelinating lesions on brain MRI and the absence of destructive "black hole" lesions on T1-weighted MRI. A preceding infection and abnormal CSF are suggestive of ADEM, but not required for the diagnosis. There are no specific biomarkers to establish the diagnosis. (See 'Making the diagnosis' above.)

●In adults, ADEM is difficult to distinguish from multiple sclerosis. Other entities to be considered in the differential of ADEM include infectious meningoencephalitis, neurologic sarcoidosis, vasculitis, progressive multifocal leukoencephalopathy, and Behçet syndrome. (See 'Differential diagnosis' above.)

●Immune suppression is the mainstay of treatment for ADEM. For adults with ADEM, we recommend initial therapy with high-dose glucocorticoids (Grade 1C). Reasonable regimens include intravenous methylprednisolone 1000 mg daily for three to five days. For patients with suspected ADEM who present with symptoms suggestive of encephalitis, it is reasonable to treat empirically with acyclovir until an infectious etiology is excluded. For those who have an insufficient response to intravenous glucocorticoid treatment, therapeutic options include intravenous immune globulin (IVIG) treatment, 0.4 g/kg daily for five days, or plasma exchange. (See 'Treatment' above.)

●Most patients with ADEM improve with treatment, but complete recovery occurs in only 10 to 46 percent of adult patients, with motor deficits and/or cognitive impairment often persisting in the remainder. In fulminant cases, death may result. Relapses, though unusual, have occurred. Relapses that involve a different region of the central nervous system should raise suspicion for multiple sclerosis. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Dina Jacobs, MD, who contributed to earlier versions of this topic review.