What is ADEM

ADEM is short for acute disseminated encephalomyelitis, also referred to as post-infectious encephalomyelitis, is an acute, rapidly progressive, autoimmune process that occurs in the central nervous system ¹. ADEM is characterized by a brief but widespread attack of inflammation in the brain and spinal cord and occasionally the optic nerve, that damages the myelin – the protective covering of nerve fibers that occurs in response to a preceding viral or bacterial infections, or less often, vaccination for measles, mumps, or rubella ².

The symptoms of ADEM appear rapidly, beginning with encephalitis-like symptoms such as fever, fatigue, headache, nausea and vomiting, and in the most severe cases, seizures and coma. ADEM typically damages white matter (brain tissue that takes its name from the white color of myelin), leading to neurological symptoms such as visual loss (due to inflammation of the optic nerve) in one or both eyes, weakness even to the point of paralysis, and difficulty coordinating voluntary muscle movements (such as those used in walking). ADEM is sometimes misdiagnosed as a severe first attack of multiple sclerosis (MS), since the symptoms and the appearance of the white matter injury on brain imaging may be similar. However, ADEM has several features which differentiate it from MS (multiple sclerosis). First, unlike MS patients, persons with ADEM will have rapid onset of fever, a history of recent infection or immunization, and some degree of impairment of consciousness, perhaps even coma; these features are not typically seen in MS (multiple sclerosis). Children are more likely than adults to have ADEM, whereas multiple sclerosis (MS) is a rare diagnosis in children. In addition, ADEM usually consists of a single episode or attack of widespread myelin damage, while MS features many attacks over the course of time. Doctors will often use imaging techniques, such as MRI (magnetic resonance imaging), to search for old and new lesions (areas of damage) on the brain. The presence of older brain lesions on MRI suggest that the condition may be MS rather than ADEM, since MS can cause brain lesions before symptoms become obvious. In rare situations, a brain biopsy may be necessary to differentiate between ADEM and some other diseases that involve inflammation and damage to myelin.

Treatment for ADEM is targeted at suppressing inflammation in the brain using anti-inflammatory drugs. Most individuals respond to several days of intravenous corticosteroids such as methylprednisolone, followed by oral corticosteroid treatment. When corticosteroids fail to work, plasmapheresis or intravenous immunoglobulin therapy are possible secondary treatment options that are reported to help in some severe cases. Additional treatment is symptomatic and supportive.

What causes ADEM?

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 ¹. Additional associated bacterial infections include Leptospira, beta-hemolytic streptococci, and Borrelia burgdorferi ³. 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 ¹.

Rabies (Semple) vaccine has been the earliest reported vaccine-associated with ADEM ¹. 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 ¹.

Although ADEM 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 ¹. 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) ¹.

ADEM 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. [6] 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.

ADEM symptoms

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 (multiple sclerosis) is characterized by repeated attacks of neurological dysfunction separated in both time and space, there is a significant overlap between the two conditions regarding CNS (central nervous system) 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, multiple sclerosis (MS) is more often monosymptomatic (e.g., optic neuritis alone) and has a chronic, relapsing, and remitting course ⁴.

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 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 central nervous system (brain and spinal cord) involvement.

ADEM diagnosis

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 ⁵. 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.

ADEM treatment

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 (cerebrospinal fluid).

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 ⁶. If a patient is not improving or is responding poorly to glucocorticoid treatment, try intravenous immune globulin (IVIG), plasma exchange, or cyclophosphamide.

Long term effects of ADEM

Corticosteroid therapy typically helps hasten recovery from most ADEM symptoms. The long-term prognosis for individuals with ADEM is generally favorable. For most individuals, recovery begins within days, and within six months the majority of ADEM patients will have total or near total recoveries. Others may have mild to moderate lifelong impairment ranging from cognitive difficulties, weakness, loss of vision, or numbness. Severe cases of ADEM can be fatal but this is a very rare occurrence. ADEM can recur, usually within months of the initial diagnosis, and is treated by restarting corticosteroids. A small fraction of individuals who are initially diagnosed as having ADEM can go on to develop multiple sclerosis (MS), but there is currently no method or known risk factors to predict whom those individuals will be.

References

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