Disseminated Encephalomyelitis, Acute

Article Author:
Lisa Foris
Article Editor:
Scott Dulebohn
Updated:
4/17/2018 9:29:59 PM
PubMed Link:
Disseminated Encephalomyelitis, Acute

Introduction

Acute disseminated encephalomyelitis (ADEM), also referred to as post-infectious encephalomyelitis, is an acute, rapidly progressive, autoimmune process that occurs in the central nervous system. ADEM is characterized by demyelination in the brain and spinal cord (and occasionally the optic nerve), as a result of inflammation that occurs in response to a preceding infection or immunization.

Etiology

ADEM has been associated with some infectious organisms and immunizations. Most commonly associated organisms include cytomegalovirus, Epstein-Barr virus, herpes simplex virus, human herpes-virus-6, influenza virus, hepatitis A, human immunodeficiency virus, and mycoplasma pneumonia – though, in the majority of cases, the causative pathogen is not identified. Additional associated bacterial infections include Leptospira, beta-hemolytic streptococci, and Borrelia burgdorferi. Prior to the development of immunization programs, ADEM was most commonly associated with measles (in addition to an increased incidence in association with rubeola, rubella, mumps, varicella, and smallpox as well). Today, ADEM is more commonly associated with viral infections of the gastrointestinal or respiratory tracts.

Rabies (Semple) vaccine has been the earliest reported vaccine-associated with ADEM. It is seen in both adults and children approximately eight to 21 days following immunization. Other less commonly associated vaccines include those for measles, pertussis, tetanus, influenza, hepatitis B, diphtheria, rubella, pneumococcus, varicella, smallpox, human papillomavirus and poliomyelitis.

Epidemiology

Although it is a rare illness, there is an estimated 1 in 125,000-250,000 individuals affected by ADEM each year. Though most cases occur in children (majority younger than age ten, and the remainder between the ages ten to 20), ADEM has been documented in adults ranging from ages 18-82 as well. The disease occurs more commonly in males than in females (male to female ratio 1.3:1), and more often seasonally in the winter and spring (historically, the colder months of the year).

The risk of developing ADEM depends on some factors including an individual’s genetics, exposure to infectious organisms, immunization exposure, and lighter skin pigmentation. All ethnic groups are susceptible to developing ADEM, and the condition occurs worldwide.

In 50% - 75% of cases, ADEM is associated with either a preceding infection or vaccination, and the majority of cases follow a viral or bacterial infection (although the causative pathogen is not always identified).

Pathophysiology

The exact mechanism of ADEM is not completely understood, but it is thought to result from inflammation triggered by an environmental stimulus (e.g., vaccination or infectious disease) in genetically susceptible individuals. ADEM has been further characterized as an autoimmune disorder causing demyelination in the central nervous system (CNS). 

It has been proposed that either a cell-mediated response or antibodies produced in response to an environmental trigger cross-react with myelin autoantigens (e.g., myelin basic protein, myelin oligodendrocyte protein, proteolipid protein) in the CNS, resulting in the demyelination characteristically seen in ADEM. An alternatively proposed mechanism suggests that ADEM may occur as a result of increased vascular permeability and congestion in the CNS due to the inflammation and circulating immune complexes that follow vaccination or infection. Mononuclear infiltration of the vasculature of the CNS is thought to result in edema surrounding vessels and, at times, hemorrhage causing damage to surrounding neuronal cells (e.g., demyelination, necrosis or gliosis) and ultimately, the variety of possible clinical presentations and prognoses seen in individuals with ADEM. The inflammation and increased vascular permeability associated with ADEM has also been proposed as a mechanism by which breakdown of the blood-brain-barrier occurs, allowing infiltration of the CNS by both antigens and inflammatory cells involved in the concomitant cell-mediated immune response.

History and Physical

ADEM is classically seen following an illness (or less frequently, a vaccination) with a lag time ranging from a few days to up to 60 days (mean is 26 days). Although in about 25% of affected individuals, there may not be an obvious preceding event. The onset of ADEM is acute and rapidly progressive, and it is characterized by multifocal neurologic symptoms that require early hospitalization.

Some non-specific (e.g., constitutional) symptoms associated with ADEM include fever, headache, fatigue, malaise, nausea, and vomiting. In approximately 20% - 52% of cases in adults, there may be associated altered mental status (encephalopathy) which may involve irritability, confusion, psychosis, somnolence, or even coma. In addition to motor and sensory deficits (e.g., paraparesis, tetraparesis), patients may also present with brainstem deficits (e.g., dysarthria or oculomotor dysfunction), or other neurologic abnormalities (e.g., seizures, meningismus, ataxia, aphasia, nystagmus, optic neuritis, urinary retention, elevated intracranial pressure, or extrapyramidal signs).

Some adults with ADEM may also develop signs of peripheral nervous system involvement which are defined by abnormalities on electrodiagnostic testing. Signs and symptoms of peripheral involvement may include paresthesia or anesthesia of the limbs or muscle atrophy.

Patients with ADEM presenting with peripheral involvement have been seen to have a worse prognosis and increased risk of relapse compared to those with only CNS involvement.

Evaluation

The imaging modality of choice for evaluating ADEM is MRI. It demonstrates hyperintense lesions on T2-weighted, fluid-attenuated inversion recovery (FLAIR), proton-density and echo-planar trace diffusion MRI sequences. Lesions are not typically visualized on T1-weighted sequences, though larger lesions may appear as hypointensities. Imaging of ADEM may reveal a single lesion (e.g., large or small, confluent, or solitary) or multiple lesions throughout the white (e.g., periventricular and subcortical) and grey (e.g., basal ganglia, thalamus, cortex) matter of the brain – most characteristically seen as multiple, widespread, asymmetric lesions bilaterally throughout the brain. There may be additional infratentorial lesions in the brainstem, cerebellum, and spinal cord, but these rarely present as isolated lesions without an accompanying lesion in the brain.

ADEM lesions typically present with indistinct margins on imaging. This may help differentiate these lesions from the clear-cut margins typical of the lesions seen in multiple sclerosis.

It is important to note that ADEM may present with a normal MRI, in other words, without any visual evidence of disease (even after multiple scans). In some cases, it is also possible that MRI lesions may appear weeks following the onset of symptoms. Although most MRI lesions resolve within 18 months, repeat imaging is warranted, especially early in the course of the disease, as there may be fluctuations in lesions (e.g., new lesions may appear while older lesions resolve) despite the patient potentially remaining asymptomatic.

Although MRI is the imaging modality of choice, a CT scan may be considered in an urgent setting to rule out any other potentially life-threatening causes of neurological dysfunction. In the case of ADEM, a CT scan is most often unremarkable, especially earlier on in the course of the disease. In later stages, ADEM may appear as focal or multifocal regions of white matter damage on CT. Cerebrospinal fluid (CSF) analysis (e.g., following a lumbar puncture) may reveal abnormalities in 50% - 80% of patients with ADEM. These findings may include lymphocytic pleocytosis (with a white blood cell count of fewer than 100 cells/mL) and a slightly elevated CSF protein (Fewer than 70 mg/dL). More specifically, patients with ADEM are often seen to have an elevated level of cerebrospinal fluid (CSF) myelin basic protein on CSF analysis. This is a sign of demyelination in the CNS.

An EEG done on a patient with ADEM may reveal a disturbed sleep pattern, and either a focal or generalized slowing of electrical activity.

There is no specific biomarker or diagnostic test that establishes a diagnosis of ADEM.  It is, however, considered, when a patient presents with multifocal neurologic deficits without any prior history of neurologic dysfunction. One or more demyelinating lesions (either supra- or infratentorial) on brain MRI will further support a diagnosis of ADEM. These findings, taken together with a history of infection or immunization, as well as abnormal CSF findings, will further support a diagnosis of ADEM (but are not necessary to do so).

Although there are no set diagnostic criteria for ADEM in adults, for children, a diagnosis is made based on the presence of both encephalopathy and multifocal CNS involvement.

Children with ADEM have also been found to have an elevated sedimentation rate and a slightly elevated platelet count.

Treatment / Management

Empiric treatment with acyclovir may be initiated in patients presenting with meningeal signs, fever, acute encephalopathy, and signs of inflammation in either the blood or CSF.

However, the mainstay of treatment for ADEM is immunosuppression with high-dose intravenous glucocorticoids. These can be started simultaneously with acyclovir or antibiotics on the initial patient presentation. If a patient is not improving or is responding poorly to glucocorticoid treatment, try intravenous immune globulin (IVIG), plasma exchange, or cyclophosphamide.

Pearls and Other Issues

In adults, ADEM is difficult to differentiate from an initial attack of multiple sclerosis (MS) based on a single clinical encounter or radiographic evidence alone.  It is important to diagnose a patient with either condition accurately because the approach to the treatment of the two conditions differs significantly. Though MS is characterized by repeated attacks of neurological dysfunction separated in both time and space, there is significant overlap between the two conditions regarding CNS symptoms and radiographic evidence. Patients with ADEM are more likely to have a history of prodromal viral illness, along with fever, neck stiffness, ataxia, and impaired consciousness and/or encephalopathy, while MS patients typically do not present with these complaints. Additionally, MS is more often monosymptomatic (e.g., optic neuritis alone) and has a chronic, relapsing, and remitting course.

A brain MRI may be helpful in distinguishing between the two. ADEM typically involves larger, bilateral, asymmetric lesions that are also higher in number than those typically seen with MS. Brain lesions tend to be more well-defined when seen in MS vs. the ill-defined lesions seen in ADEM. MS is more likely to be associated with brain lesions of varying ages while ADEM typically has lesions that are all approximately the same age. Lesions in the thalamus are seen more commonly in ADEM, while periventricular lesions are more common in MS.

Acute hemorrhagic encephalomyelitis (AHEM, or acute hemorrhagic leukoencephalitis, acute necrotizing hemorrhagic leukoencephalitis of Weston-Hurst) is a hyperacute variant of ADEM that rapidly progresses to coma and may be fatal. AHEM is triggered similarly to ADEM, following exposure to an infectious organism or vaccination.  Symptoms of AHEM include asymmetric multifocal neurologic deficits, meningismus, headache, and seizures.

A head CT or MRI of a patient with AHEM may reveal focal hemorrhagic lesions, in addition to edema, petechial and perivascular hemorrhages, vascular destruction and fibrin deposition, and neutrophilic infiltration.