Acute disseminated encephalomyelitis

Overview

 * Acute disseminated encephalomyelitis (ADEM) is an acute neurologic disease of the central nervous system characterized by scattered foci of demyelination and perivenular inflammation. The disease may occur without precipitant, or may develop after infection or vaccination.

Pathophysiology & Etiology

 * Pathology shows scattered foci of demyelination and perivenular inflammation throughout the brain and spinal cord.
 * The foci may be 0.1 to several millimeters, and usually surround small and medium sized veins.
 * The nerves cells and axons are generally intact
 * Perivenular inflammation is manifested by cellular reaction by pleomorphic microglia, in the region of demyelination, and lymphocytes and mononuclear cells about the vessel. Multifocal meningeal cellular infiltration may also be present.
 * Peripheral nervous system demyelination is present in a subset
 * Postvaccinial disease may occur after:
 * Rabies vaccine (also known as a neuroparalytic accident)
 * Noted mostly only after use of the Semple vaccine, which uses phenol-inactivated virus propagated in brains of adult rats, and occurs in 1-10 per 5000 given this vaccine; affected patients have a mortality rate of 25%. This vaccine has been replaced in most developed countries such as the U.S. by vaccine grown in duck embryos or human diploid tissue, which has largely eliminated this complication.
 * Smallpox vaccine
 * Eradication of smallpox has eliminated need for prophylaxis
 * Occurred in 1 in 4000 vaccinations
 * Measles vaccine
 * ADEM may occur after live measles vaccination very rarely, in approximately one in one million vaccinations
 * Japanese B encephalitis vaccine
 * Rare complication, perhaps in one in one million
 * Postinfectious encephalomyelitis may be seen after a number of infectious processes, most commonly the viral exanthems of childhood.
 * Infectious versus post-infectious viral associated encephalomyelitis is not always easy to distinguish clinically, though the sequence of presentation is usually helpful. Viral associated encephalomyelitis pathologically shows viral invasion of neurons, and the virus may be cultured.  Postinfectious encephalomyelitis spares neurons, but demyelination and perivenular inflammation is prominent.
 * Measles viral infection is one of the most common associations with ADEM: ADEM occurs in about 1 in a 1000 cases.  10-20% of those affected die, and 10-20% are left with persistent neurologic sequelae.
 * Vaccination with a live measles vaccine in developed countries has made this uncommon in the developed countries. ADEM may occur after live measles vaccination very rarely, in approximately one in one million vaccinations.
 * Varicella-zoster virus (VZV)/Chickenpox
 * 0.1-0.7% of chickenpox infections may be associated with neurologic manifestations; many of these are mild and self-limited, though these patients may present with ADEM
 * Prominent cerebellar features are common
 * Temporal relationship between skin and neurologic findings is quite variable
 * Mumps
 * Rubella
 * Smallpox
 * '''Infectious mononucleosis – Epstein-Barr virus’’’
 * Mycoplasma
 * Cytomegalovirus
 * Influenza
 * Parainfluenza
 * The pathogenesis of ADEM has not been completely worked out, but the demyelination and inflammation appear to occur due to immune reactivity to self-antigens, induced either via mimicry or adjuvant effects, in association with exposure to infectious or other environmental antigens.
 * Myelin basic protein (MBP) is one of the antigens involved. After measles and rabies vaccinations, MBP-reactive T cells and antibodies have been documented in the cerebrospinal fluid (CSF) of some patients.  Induction of immune response to other central nervous system constituents has also been documented following measles infection, but only development of antibodies to MBP appears thus far to correlate with the development of ADEM.
 * An animal model has been developed, experimental allergic encephalomyelitis, produced by inoculating animals with a mixture of sterile brain tissue and adjuvants. About 8-15 days after inoculation, a similar neurologic disease develops, with similar pathologic findings.
 * Some cases of postvaccinial enchephalomyelitis may occur as a consequence of exposure to brain material that contaminates viral vaccines.
 * Other cases may occur as a consequence of direct viral central nervous system (CNS) invasion, though attempts to document viral invasion have been unsuccessful, and the pathology is different from that seen in infectious encephalomyelitis.

Diagnosis

 * No one test established the diagnosis of ADEM. Supporting features include an appropriate viral or vaccination history, an appropriate acute neurologic illness, and consistent features on CNS imaging.

Differential Diagnosis

 * Acute infectious encephalitis
 * Herpes simplex virus
 * Most common and treatable form of infectious encephalitis
 * Usually due to Human herpesvirus 1 (HSV-1), though HSV-2 accounts for 5%
 * One-third occur during primary infection
 * Most commonly involves the temporal and frontal lobes; speech disorders, bizarre behaviors, and gustatory and olfactory hallucinations are common
 * Fever present in 90%. Altered state of consciousness present in most.
 * Associated with scattered hemorrhages, CSF red cells
 * Treated with acyclovir 10 mg/kg IV q8h; reduces mortality and morbidity if started early enough. Untreated mortality is 70%.
 * Epstein-Barr virus
 * Lyme disease
 * Arborviruses
 * Viruses transmitted by arthropods, mosquitos and tick
 * Most common in the summer and fall (in contrast to winter and spring presentations of measles, mumps and VZV).
 * Present with:
 * Fever
 * Headache
 * Gastrointestinal symptoms
 * Neurologic disease typically presents day 2 or 3
 * CSF typically shows elevated protein, a few hundred white blood cells, normal glucose
 * No specific treatment
 * Eastern equine encephalitis
 * Presents with flu-like symptoms, fever, headache, vomiting, seizures, and progressive neurologic disease
 * Seen mostly along the east coast of the U.S.
 * Mosquito and bird vectors
 * Most common in those 55 years of age
 * Most virulent of arborviruses: 70% mortality
 * Western equine encephalitis
 * Mosquito vector
 * Young children
 * Often asymptomatic
 * Western U.S.
 * California encephalitis
 * Worldwide
 * Most common in school-age children
 * Mosquito vector
 * Gastrointestinal (GI) symptoms common
 * St. Louis encephalitis
 * Wild bird reservoir
 * Wild bird – mosquito cycle
 * Throughout U.S.
 * Japanese encephalitis
 * Flavivirus endemic in Southeast Asia from India to Japan
 * Mosquito transmission
 * Vaccine available
 * Mycoplasma infection
 * Cytomegalovirus infection
 * Ehrlichiosis
 * Measles
 * VZV/chickenpox
 * Mumps encephalitis
 * CNS features present in ~1% of cases
 * Not all patients have parotitis
 * Most common in winter and spring
 * Most patients recover completely, but some patients left with deafness, seizure, and mental retardation
 * Confirmed via culture or serology
 * Mycoplasma
 * Bacterial meningoencephalitis
 * Other infectious encephalitidies
 * Acute multiple sclerosis (MS)
 * MS may not be possible to exclude, and to some extent depends upon the natural history of the patient’s disease; MS is typically a chronic disease with a recurrent or progressive course, and ADEM is usually an acute monophasic disease. Both diseases are characterized by demyelination; it is acute in ADEM, and sustained or progressive in MS.  It is sometimes best to refer to the illness as an “acute demyelinating disease”, until the disease course declares itself.
 * Simultaneous optic nerve, brain and spinal cord involvement, as well as meningismus, drowsiness, coma and seizures, are features suggestive of ADEM instead of MS.
 * Optic nerve involvement is typically bilateral in ADEM, and unilateral in MS. Transverse myelopathy is usually complete in ADEM, and partial in MS.
 * CSF protein is usually elevated in ADEM, and is often normal in MS. CSF lymphocyte counts >50, and CSF polys are also uncommon in MS.
 * In ADEM in contrast to MS, most MRI lesions enhance with gadolinium, suggestive that all lesions are active, and that the disease is therefore monophasic.
 * Hypoxic encephalopathy
 * Cerebrovascular disease
 * CNS vasculitis
 * Lupus cerebritis
 * Toxin effect
 * Acute toxic hepatoencephalopathy – Reye’s syndrome
 * Acute liver and CNS disease in children under 15 years of age, characterized by progressive liver and CNS disease, commonly in association with the use of salicylates.
 * Often follows a viral infection, especially chickenpox or influenza.
 * Patients often present with vomiting and progressive neurologic disease. Hypoglycemia is common.  Jaundice is usually not a prominent feature.
 * The liver is enlarged and evidence of liver disease includes elevated transaminases, prothrombin time, and ammonia, hypoglycemia, and metabolic acidosis. Cerebral edema and brain neuronal degeneration occurs.
 * Mitochondria dysfunction occurs in the liver, brain and muscle. Liver cells show microvacuolization, as do renal tubules.
 * Mortality approaches 50%.

Presentation
It has an abrupt onset and a monophasic course. Symptoms usually begin 1-3 weeks after infection or vaccination. Major symptoms include fever, headache, drowsiness, seizures and coma. Although initially the symptoms are usually mild, later in the course of the disease patients may even die, if they are not treated properly. Some patients recover completely, while others have permanent neurological impairments.
 * The disease presents with progressive, often abrupt, neurologic deterioration. The clinical course is quite variable, and in some cases, rapid progression occurs over hours to days.
 * ADEM classically follows a monophasic course, though there are now discussions in the literature about “multiphasic ADEM”
 * Features include:
 * Somnolence, confusion, lethargy
 * Fever – that had previously resolved if there was a precipitating illness
 * Headache
 * Meningismus
 * Motor features may include ataxia, myoclonic movements, and choreoathetosis
 * Seizures
 * Decerebrite rigidity may develop in severe cases
 * Paraplegia, quadraplegia, absent deep tendon reflexes (DTRs), sensory levels, and bladder or bowel involvement suggest prominent spinal cord involvement
 * Coma
 * Signs of disseminated neurologic disease are usually present
 * Motor findings:
 * Hemiparesis
 * Quadriparesis
 * Extensor plantar responses
 * DTR’s may be lost initially, and later become hyperactive
 * Sensory findings are commonly present
 * Brainstem involvement may be present
 * Cerebellar involvement is particularly prominent in ADEM that occurs as a consequence of chickenpox
 * In post-exantham disease, the rash usually appears 2-4 days before the neurologic manifestations, and is typically fading at the onset of neurologic disease.
 * Though most cases demonstrate widespread disease (brain, spinal cord, optic nerves, etc), neurologic features may be limited to spinal cord features (transverse myelitis), cerebellar features, etc.

Electrolyte and Biomarker Studies

 * CSF protein is usually modestly elevated (50-150 mg/dl)
 * CSF lymphocytic pleocytosis is present, usually <200 cells/ul.
 * Serum white count may be normal or elevated

MRI and CT

 * Radiographic features:
 * MRI
 * Extensive gadolinium enhancement of white matter of the brain and spinal cord
 * Often extensive and relatively symmetric, often also involving the posterior fossa
 * Most lesions enhance with gadolinium, suggestive that all lesions are active, and that the disease is therefore monophasic.
 * CT is less sensitive and is sometimes falsely negative

Risk Stratification and Prognosis

 * Prognosis varies with the severity of the neurologic disease. Some patients will not survive the acute illness, and some will be left with neurologic sequelae.  Some remarkably recover completely.
 * The disease is characteristically monophasic, but descriptions of multiphasic disease have been reported.
 * Affected children will often suffer from persistent seizures and behavioral and learning disorders. Adults are somewhat less likely than children to have neurologic sequelae.

Treatment

 * There are case reports of improvement with treatment with plasma exhange and intravenous immunoglobulin in patients who have not responded to steroids.
 * The first treatment is usually steroids and intensive care is often required.

Acute Pharmacotherapies

 * Most patients are treated with pulse intravenous methylprednisolone with subsequent taper.

Acknowledgements
The content on this page was first contributed by: ELLISON L. SMITH, M.D.