Acute disseminated encephalomyelitis (ADEM) is a neurological, immune-mediated disorder in which widespread inflammation of the brain and spinal cord damages tissue known as white matter. White matter is a tissue composed of nerve fibers, many of which are covered by a collection of fats and proteins known as myelin. Myelin, which collectively may be referred to as the myelin sheath, protects the nerve fibers, acts as an insulator, and increases the speed of transmission of nerve signals. Damage to the myelin sheath (demyelination) affects the nerve’s ability to transmit information and potentially can cause a wide range of neurological symptoms. The specific symptoms and severity of ADEM can vary from one individual to another. In some cases, ADEM is preceded by a viral infection or vaccination. The exact cause of the disorder is unknown although it is believed that an improper response of the immune system plays a role in its development. ADEM must be differentiated from other demyelinating disorders such as multiple sclerosis.
Acute disseminated encephalomyelitis also referred to as post-infectious encephalomyelitis, is an acute, rapidly progressive autoimmune, neurological, an immune-mediated disorder in which widespread inflammation of the brain and spinal cord damages tissue known as white matte that is characterized by demyelination in the brain and spinal cord as a result of inflammation that occurs in response to a preceding infection or immunization.
Causes
The exact cause of ADEM is not known. However, most clinical investigators agree that the disorder is most likely the result of an abnormal immune system response to an infection or other trigger. Many researchers suggest that ADEM may represent an abnormal immune reaction directed against the body’s tissues (autoimmune disorder). In autoimmune disorders, the body’s natural defenses (e.g., antibodies, lymphocytes) against substances that are perceived as foreign (antigens) inappropriately begin to attack healthy tissues, for unknown reasons.
ADEM often develops following an upper respiratory tract infection, a usual viral cause. Specific agents that have been identified as resulting in ADEM include influenza, measles, mumps, rubella, varicella-zoster, Epstein Barr virus, cytomegalovirus, and herpes simplex virus. Some bacterial agents can also bring about ADEM.
Less often, ADEM may develop following vaccination. Certain antirabies vaccinations have been linked to the development of the disorder. Other vaccinations that are believed to potentially result in the development of ADEM include the smallpox vaccination and certain older measles vaccinations. In rare cases, immunizations against pertussis (whooping cough) and influenza have been linked to ADEM. In extremely rare cases, ADEM has occurred following an organ transplant. The risk of developing ADEM is extremely low and should not preclude routine vaccinations as recommended.
A variety of factors in addition to immunologic ones may play a role in the development of ADEM potentially including genetic and environmental ones. More research is necessary to determine the exact causes and underlying mechanisms that ultimately cause ADEM.
Diagnosis
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% to 52% of cases in adults, there may be associated with 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.
Imaging
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.[rx][rx][rx] 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% 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 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.
A diagnosis of ADEM is made based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests including imaging techniques such as magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues and can demonstrate characteristic brain lesions in individuals with ADEM. Additional tests to exclude other conditions may also be performed. Such tests may include infectious, immunologic, and metabolic tests.
Treatment
No standard therapy for ADEM has been established. Most therapies that have been used to treat ADEM have some effect of suppressing the activity of the immune system (immunosuppressive therapy). Such therapies include corticosteroids, immunoglobulin (IVIg) therapy, or plasmapheresis.
High-dose regimens of corticosteroids have commonly been used to treat individuals with ADEM and generally are considered the mainstay of treatment. Corticosteroids have led to an improvement of symptoms in many cases. Corticosteroids are the most widely reported therapy for individuals with ADEM. Methylprednisone is a specific corticosteroid that is commonly used for ADEM. However, there is great variation in the specific forms, manner of administration, dosage, and tapering schedule in treating affected individuals with corticosteroids. In addition, high-dose regimens of corticosteroids can be associated with significant side effects in some people.
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.[rx][rx] If a patient is not improving or is responding poorly to glucocorticoid treatment, try intravenous immune globulin (IVIG), plasma exchange, or cyclophosphamide.
Investigational Therapies
Intravenous immunoglobulin (IVIg) has been used to treat some individuals with ADEM such as those who do not respond or cannot tolerate corticosteroid therapy. IVIg is a concentrated solution of antibodies that have been extracted from the blood of healthy donors. IVIg is used to treat a variety of autoimmune disorders because it can neutralize the effects of autoantibodies, which are antibodies that mistakenly attack healthy tissue.
Plasmapheresis has been used to treat individuals who do not respond to other forms of therapy. However, its use has only been described in random case reports. Plasmapheresis is a procedure that is a method for removing unwanted substances (toxins, metabolic substances, and plasma parts) from the blood. Blood is removed from the patient and blood cells are separated from plasma. The patient’s plasma is then replaced with other human plasma and the blood is transfused into the patient.
Controlled, randomized clinical trials evaluating the various therapies for children and adults with ADEM have not been done. These studies are necessary to determine the optimal therapeutic options for treating individuals with ADEM.
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