Acute Disseminated Encephalomyelitis

Etiology

ADEM is predominately considered a post-infectious disease of the CNS. An identifiable infection or immunization has been reported in 50% to 85% of cases.[4][5] 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.[6][7][8] Before the development of immunization programs, ADEM was most commonly associated with measles and an increased incidence associated with rubeola, rubella, mumps, varicella, and smallpox. Today, ADEM is more commonly associated with viral infections of the gastrointestinal or respiratory tracts.

ADEM is seen in adults and children approximately 8 to 21 days following immunization. The rabies vaccine is the most commonly reported vaccine associated with ADEM. Other less commonly associated vaccines include measles, pertussis, tetanus, influenza, hepatitis B, diphtheria, rubella, pneumococcus, varicella, smallpox, human papillomavirus, and poliomyelitis. The frequency of ADEM occurring after vaccination has decreased in recent years, likely related to different methodologies in vaccine production.[9]

Epidemiology

Although considered a rare illness, there is an estimated 0.07 to 0.9 per 100,000 children affected by ADEM each year.[10][11] Most cases occur in children with a median age between 5 and 8 years, with the majority being younger than 10 years and the remainder between the ages of 10 and 20. ADEM has also been documented in adults ages 18 to 82. The disease occurs more commonly in males than females, with a male-to-female ratio of 1.3 to 1, and is seen more often seasonally in the winter and spring or 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, which occurs worldwide. In 50% to 85% of cases, ADEM is associated with either a preceding infection or vaccination, and most cases follow a viral or bacterial infection. However, the causative pathogen is not always identified.

Pathophysiology

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

There have been proposals that either a cell-mediated response or antibodies produced in response to an environmental trigger cross-react with myelin autoantigens (eg, myelin basic protein, myelin oligodendrocyte protein, proteolipid protein) in the CNS, resulting in the demyelination characteristically seen in ADEM.[12][13][14] An alternative proposed mechanism suggests that ADEM may arise from heightened vascular permeability and congestion in the CNS, triggered by inflammation and circulating immune complexes following vaccination or infection. Mononuclear infiltration of the CNS vasculature is believed to lead to edema around vessels and, occasionally, hemorrhage, causing damage to neighboring neuronal cells (such as demyelination, necrosis, or gliosis); this underlies the diverse clinical presentations and prognoses observed in individuals with ADEM. The inflammation and increased vascular permeability associated with ADEM have also been proposed as a mechanism by which the 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.

Histopathology

The most specific histopathology of ADEM is perivenous demyelination with an accumulation of florid inflammatory cells, including lymphocytes, macrophages, and microglial cells. The histopathology differs from other demyelinating disorders, especially multiple sclerosis, which shows confluent demyelination. The pathology is typically bilateral and polyfocal with deep gray matter involvement, including the basal ganglia and thalami and polyfocal white matter involvement. Th1 and Th2 inflammatory cytokines and macrophage- and microglia-related cytokines are all increased in ADEM.[5][15]

History and Physical

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

Some non-specific, constitutional symptoms associated with ADEM include fever, headache, fatigue, malaise, nausea, and vomiting. Based on the recent IPMSSG criteria, diagnosing ADEM requires a combination of encephalopathy and polyfocal neurological deficits.[5] Encephalopathy encompasses altered mental status, which may involve irritability, confusion, psychosis, somnolence, or coma. Polyfocal neurological deficits include motor and sensory, such as paraparesis and tetraparesis. Patients may also present with brainstem deficits like dysarthria or oculomotor dysfunction or other neurologic abnormalities, including seizures, meningismus, ataxia, aphasia, nystagmus, optic neuritis, urinary retention, elevated intracranial pressure, extrapyramidal signs. Most cases of ADEM are monophasic with 1 single event. The clinical severity may fluctuate within 3 months. If there is another episode of inflammatory demyelination after 3 months, the diagnosis is multiphasic ADEM. 

The International Pediatric Multiple Sclerosis Study Group criteria apply mainly to ADEM diagnosis in children. There are no similar diagnostic criteria in adults. Results from most studies found that adults with ADEM have a worse prognosis.[16][17] Some adults with ADEM may also develop signs of peripheral nervous system involvement, defined by abnormalities on electrodiagnostic testing. Signs and symptoms of peripheral involvement may include paresthesia or anesthesia of the limbs and muscle atrophy. Patients with ADEM presenting with peripheral involvement usually 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, 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 (eg, large or small, confluent or solitary) or multiple lesions throughout the white (eg, periventricular and subcortical) and grey (eg, basal ganglia, thalamus, cortex) matter of the brain. ADEM is most characteristically seen as multiple, widespread, asymmetric lesions bilaterally throughout the brain.[18][19][20] 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. MRI lesions in children involve deep gray matter, including the thalami and basal ganglia, whereas MRI lesions in adults tend to be more periventricular.

ADEM lesions are typically present with indistinct margins on imaging; this may help differentiate these lesions from those seen in multiple sclerosis, which usually have clear-cut margins. During the first demyelinating event, the presence of 2 or more periventricular lesions, the presence of T1 black holes, and the absence of a bilateral lesion pattern are all more compatible with the diagnosis of MS.[21]

ADEM may present with a normal MRI or without any visual evidence of disease, even after multiple scans. In some cases, 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 (eg, new lesions may appear while older lesions resolve) despite the patient potentially remaining asymptomatic.

Although MRI is the imaging modality of choice, a computed tomography (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 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 (eg, following a lumbar puncture) may reveal abnormalities in 50% to 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 CSF myelin basic protein on CSF analysis; this is a sign of demyelination in the CNS. An electroencephalogram on a patient with ADEM may reveal a disturbed sleep pattern and either a focal or generalized slowing of electrical activity.

No specific biomarker or diagnostic test establishes a diagnosis of ADEM. The diagnosis of ADEM should be considered when a patient presents with multifocal neurologic deficits without any prior history of neurologic dysfunction. On brain MRI, 1 or more demyelinating lesions, either supratentorial or infratentorial, support a diagnosis of ADEM. These findings, taken together with a history of infection or immunization and abnormal CSF findings, further support a diagnosis of ADEM but are not necessary to do so.

Anti-MOG antibodies have been recently described in a subgroup of children with ADEM.[22] Their clinical presentation and MRI findings are similar. These patients tend to have more relapsing forms of ADEM. They also have more manifestations of optic neuritis and longitudinally extensive transverse myelitis (LETM). Another group of patients may present more specifically with optic neuritis, LETM, or brainstem syndrome with intractable hiccups or vomiting. These typically have neuromyelitis spectrum disorder with positive aquaporin4 antibodies. These patients tend to have worse prognoses concerning long-term neurological deficits.[23]

Although there are no set diagnostic criteria for ADEM in adults, a diagnosis is made with both encephalopathy and multifocal CNS involvement for children. Fifty percent of children with ADEM have also been found to have an elevated sedimentation rate, increased C-reactive protein, and mild leukocytosis.

Treatment / Management

Supportive care and empiric treatment with intravenous (IV) acyclovir and antibiotics may be initiated in patients presenting with meningeal signs, fever, acute encephalopathy, and signs of inflammation in either the blood or CSF. The first-line acute treatment for ADEM is immunosuppression with high-dose IV glucocorticoids. The standard protocol is methylprednisolone at 30 mg/kg/day IV (maximum 1000 mg/day) for 3 to 5 days, followed by an oral prednisone taper for 4 to 6 weeks. Early discontinuation of steroids may increase the risk of relapse.[24][25] These can be started simultaneously with acyclovir or antibiotics on the initial patient presentation.[26][27] If a patient is not improving or is responding poorly to glucocorticoid treatment, IV immunoglobulin is a good second-line therapy. The dose is 2 g/kg for 2 to 5 days. Plasma exchange with 3 to 7 exchanges, or cyclophosphamide, is used in refractory cases.

Differential Diagnosis

Differential diagnosis for ADEM includes the following:

• Aseptic meningitis and acute viral encephalitis include constitutional symptoms suggestive of an underlying infection, including fever, neck rigidity, and elevated acute phase reactants, including C-reactive protein and erythrocyte sedimentation rate
• The first clinical attack of multiple sclerosis: clinical presentation of multifocal neurological deficits and MRI appearance may be similar to ADEM, with some subtle MRI differences; multiple sclerosis relapse usually does not have features of acute encephalopathy
• Diseases associated with myelin oligodendrocyte glycoprotein antibody disease, MOGAD: check myelin oligodendrocyte glycoprotein (MOG) antibody as part of the evaluation, especially in children [5][28]
• Brain metastasis
• Brucellosis
• Cardioembolic stroke
• Cauda equina and conus medullaris syndrome
• Cavernous sinus syndromes
• CNS complications in human immunodeficiency virus
• Cerebral venous thrombosis
• Churg-Strauss disease

Prognosis

The prognosis of ADEM varies widely depending on the age of the patient, the clinical and MRI findings, and the presence of MOG antibodies. The most severe cases of ADEM are called radiological as acute hemorrhagic encephalitis and acute necrotizing leukoencephalitis. These monophasic cases may have a mortality rate of up to 30%. The antecedent infectious illness also determines the prognosis; when cases of ADEM occurred after measles infections, the prognosis was much worse than other infections. In general, 50% to 80% of patients fully recover after a single episode of ADEM. About 25% of children hospitalized require intensive care admission, with a mortality rate of 1% to 3%. Adults have a higher frequency of intensive care unit admission, longer hospitalization, poorer recovery, and higher mortality. Long-term focal neurological deficits are uncommon, and seizures are rare. Cognitive impairment is reported in up to 56% of children after an ADEM.[24][29][30]

Complications

The severity and areas of involvement in the CNS are significant factors determining ADEM complications. Involvement of the long fiber tracts of the white matter may result in long-term complications of physical disability, including spasticity with varying degrees of weakness of the extremities. Post-ADEM epilepsy is not an uncommon complication in children. Both ADEM relapses and epilepsy are more common among children with MOGAD-associated ADEM.[7] Impaired cognitive function may be children’s most important long-term complication of ADEM. Studies have shown that children between 6 and 15 years had mild cognitive deficits with lower intelligence quotient scores 3.5 to 4 years after ADEM. Patients with the onset of ADEM at an older age also had slower verbal processing.[31]