Acute Disseminated Encephalomyelitis Clinical Presentation

• Clinically, acute disseminated encephalomyelitis (ADEM) is usually readily distinguishable from multiple sclerosis (MS) by the presence of certain clinical features, including the following:

  • History of preceding infectious illness or immunization
  • Association with constitutional symptoms and signs such as fever
  • Prominence of cortical signs such as mental status changes and seizures
  • Comparative rarity of posterior column abnormalities, which are common in MS
  • Age younger than 11-12 years in ADEM and age older than 11-12 years in MS
• ADEM is more common in the winter months, with as many as 65-85% of cases occurring between October and March. The mean age at presentation is about 7 years, with a range that extends from the first year of life to adulthood. Typical cases of ADEM arise 1-20 days after a childhood infectious illness, which is febrile in more than 94% of cases.

  • There is usually a clearly defined phase of afebrile improvement lasting 1-20 days or more before onset of neurologic findings.
  • Generally, patients have shown partial or complete recovery from the prodromal illness at the time of onset of ADEM.
  • Whether latencies of longer than 20 days implicate a particular febrile illness as the prodrome of ADEM is unclear. Clinical experience suggests that this is possible.
  • Most of the large envelope-bearing viruses that figured prominently in older series of ADEM, of which measles was a particularly virulent example, no longer figure importantly in the etiology of ADEM because these diseases are prevented by vaccination.
  • Most cases encountered now occur in the wake of respiratory or gastrointestinal illness presumed to be of viral etiology, although a specific virus is seldom identified.
  • Documentation of at least 1 fever-free day is especially suggestive of ADEM, although such a hiatus is also found in postinfectious vasculitides.
  • A hiatus of at least a few hours is found even in cases where the ADEM prodrome consists of weeks of fever of unknown origin.
  • Occasionally, ADEM may occur in the wake of several weeks of fever of unknown origin.
  • Some patients have premonitory pain in the back prior to the development of ADEM-related inflammatory myelitis.
  • Various vaccines have been suggested as the exogenous provocation of cases of ADEM and may account for 3-6% of ADEM cases.
    • This remains a controversial subject, although clear evidence exists for the role of the Pasteur rabies vaccine and compelling, although somewhat less conclusive, evidence exists for the role of other vaccines.
    • The overall effect of the introduction of vaccinations for measles and other encephalomyelitogenic viruses has been a marked reduction in the number of severe or fatal cases of ADEM.
    • Measles was associated with ADEM in about 1 out of 800 cases, and in many of these cases, ADEM that was often particularly severe. Measles-associated ADEM had a high rate of both morbidity and mortality.
  • A cause-and-effect relationship between a possible prodrome and ADEM is more difficult to establish in cases where longer or very short intervals exist between a possible exogenous stimulus and inflammatory result.
    • Latencies longer than 50 days have been suggested for infections or vaccines but are difficult to prove.^[4]
    • Relationships are also difficult to determine when a febrile systemic process is rapidly followed by neurologic deterioration because such cases may represent meningoencephalitis.
  • A minority of cases (7-15% in several series employing various case definitions) lack a clearly defined prodrome.
    • Some of these cases are possible examples of longer than 20 days of latency from prodrome to ADEM, especially in prepubertal children, with imaging changes suggesting ADEM, with negative CSF immune profile, and with rapid and complete recovery.
    • Some members of this group, with low risk for recurrence, are prepubertal children who manifest seizure, encephalopathy, and long tract signs.
    • Another subgroup with poorly defined prodrome but low risk for recurrence are children or adolescents manifesting subacute-onset syndromes that combine neuropsychiatric abnormalities and movement disorders and imaging changes suggestive of ADEM. The course in these cases, which could be termed Johnson syndrome, is often prolonged or even progressive, improving with high-dose intravenous corticosteroids.
    • The lack of prodrome is found in more than 30% of adolescent cases of acute CNS demyelination and approximately 45% of similar adult cases.
    • MRI abnormalities in these adolescent and adult cases usually more closely resemble those characteristic of MS than those characteristic of ADEM, and CSF immune profile test results are more likely to be abnormal. These patients are likely to satisfy the criteria for diagnosis of MS within months to years. This is especially true with posterior column signs and few if any cortical signs.
• The first signs of ADEM usually include abrupt onset of irritability and lethargy (>94% of cases).

  • The onset of neurologic abnormalities is abrupt in more than 95% of ADEM cases.
  • Occasionally, the development of diffuse marked neurologic abnormalities requires only a few hours. In most cases, signs and symptoms develop over several days, and a minority of cases show continued deterioration of function for periods as long as 4 weeks.
  • Changes in mental status (88% of cases) are commonly observed in ADEM. A single institution follow-up study (at least 5.5 y for each individual) of 52 young individuals (age range 10 mo to 19 y) who presented with their first bout of an acute central nervous system demyelinating disease included 26 children ultimately diagnosed with MS and 24 diagnosed with ADEM. Encephalopathy was a presenting sign in 42% of those with a follow-up diagnosis of ADEM but none of the individuals with a follow-up diagnosis of MS.^[5]
  • Convulsive seizures occur around the onset of ADEM in as many as 25% of cases.
  • Meningismus may be present but is uncommon in ADEM except in very young children with severe disease.
  • Although almost any portion of the CNS may be clinically involved, certain systems appear to be particularly prone to dysfunction; thus, the descending white matter motor tracts, optic nerves, and spinal cord are particularly commonly involved.
    • ADEM-associated optic neuritis is usually bilateral, although the onset in a second eye may follow onset in the first by days to months. Bilaterality may provide a degree of reassurance with regard to MS risk because optic neuritis in MS is frequently unilateral. Visual evoked responses may discern abnormalities in a second eye before clinical deterioration in vision is discernible.
    • A wide variety of cranial nerve abnormalities may occur in addition to optic nerve disease.
    • Long tract signs (eg, clonus, increased muscle stretch reflexes, upgoing toes) are present early in as many as 80% of cases.
    • In some instances, reflexes may be lost at the onset. When this is caused by transverse myelitis, the evolution of disease after spinal shock replaces absent reflexes with increased muscle stretch reflexes within a few days or more. A small number of cases manifest loss of reflexes as a sign of associated peripheral nerve disease with ADEM, a condition termed EMRN. Some of these EMRN cases are associated with evidence for acute infection with Epstein-Barr virus.
  • Weakness may be hemiparetic, double hemiparetic, diaparetic, or generalized and symmetric. Fairly symmetric leg weakness is seen in many cases of ADEM-related transverse myelitis with associated abnormalities of bowel and bladder function. Transverse myelitis may be associated with optic neuritis. This combination (Devic syndrome) is also seen in MS, but in ADEM, it is more likely to have bilateral optic neuritis.
  • Most ADEM presentations may be summarized into 7 clinical syndromes as follows:
    • Mild encephalopathy, sometimes associated with long tract signs
    • Severe encephalopathy with bilateral paresis, often associated with brainstem signs, particularly the lower cranial nerves
    • Predominantly brainstem presentation with features suggesting Fisher syndrome in some cases or Bickerstaff brainstem encephalitis in other cases
    • Hemiparesis, ipsilateral long tract signs, with or without seizure
    • Predominantly ataxic, differing from the predominantly axial/gait ACA in that ADEM-associated ataxia is often associated with nystagmus, extremity ataxia, and long tract signs
    • EMRN: Encephalomyeloradiculoneuropathy is a syndrome that combines upper and lower motor neuron signs. It must be distinguished from directly infectious illnesses such as enterovirus 71 encephalitis. EMRN may manifest recurrences.
• Some ADEM presentations are fulminant.

  • Fulminant ADEM is more likely to manifest in children younger than 3 years, with rapid evolution of a low state of function and demonstration on scans of severe edema. Such cases have become uncommon with widespread vaccination against childhood illnesses.
  • Transverse myelitis (TM) may begin rapidly and be associated with severe edema, usually in the cervical region. ADEM-related TM must be distinguished from TM associated with MS, vascular accidents, and directly infectious conditions including enterovirus 71 encephalitis. It must also be distinguished from neuromyelitis optica (NMO), which may present with TM in isolation. NMO is a condition for which a biological marker (anti-AQP4 IgG in serum and/or CSF) has been identified.
  • Child/adolescent NMO represents approximately 5% of cases of NMO. Onset is 4-18 years of age (mean 12 y) and 88% are girls or young women. There is no racial predilection in the largest series from the United States. The median number of spinal levels involved in the cases of this series is 10 vertebral segments. Motor signs are usually more prominent than sensory signs. CNS lesions may be demonstrated on scans and mental status changes may be noted.
  • Acute administration of very high-dose intravenous corticosteroids may possibly close the blood-brain barrier and subtend the development of edema, which may, in these fulminant cases, account for the high risk for permanent morbidity.
• There are unusual presentations for possible ADEM that have uncertain classification. Some are labeled acute MS or diffuse sclerosis, and some are labeled encephalitis or necrotizing encephalitis, rather than ADEM.

  • Some cases are labeled as acute MS with prepubertal onset of acute encephalopathy, with mental status changes ranging from confusion to coma, seizures, and prominent pyramidal tract abnormalities.
  • Young children may manifest a rapidly progressive demyelinative illness that may be fatal within days to weeks and is almost universally associated with profound permanent psychomotor deficits in those who survive. Brain images differ from those typical of juvenile MS and may demonstrate confluent symmetric areas (butterfly pattern) of bright signal abnormality on T2-weighted sequences.
  • Fulminant presentation with lesions showing significant degrees of ring enhancement after contrast administration may also be found.
  • Malignant brain edema may be present, manifested by sulcal and ventricular effacement, similar to the fulminant ADEM in children younger than 3 years noted above.
  • Some patients with the large tumorlike lesions, acute MS, or Schilder disease presentations during childhood or adolescence do remarkably well as compared to adults with similar presentations.
  • The classification of these rare severe infantile cases, exhibiting features suggesting either severe acute MS or hyperacute ADEM, remains in doubt.
    • Nonetheless, pathological confirmation that some of these cases are MS has been published (Shaw, 1987), and hyperacute adult cases with similar clinical and radiographic manifestations have been reported (Vliegenthart, 1985).
    • Some of these cases display more generalized T2-weighted abnormalities on MRI and may represent cases of what has been referred to as acute toxic encephalopathy.
    • Emphasizing that scan results do not reliably distinguish every case of MS from ADEM is important, but in most cases, reliable inferences may be drawn. Confusion is especially likely to arise in patients with large areas of bright signal within white matter on spin-echo sequences. Extensive white matter involvement may be found in young infants that some would label as MS (Maeda, 1989) while others would label it hyperacute ADEM.
  • Rarely, childhood, adolescent, or adult MS manifests as large unilateral or multiple tumorlike mass lesions that may appear cystic and may impart mass effects (albeit atypically and, if present, unexpectedly mildly). The lesions are steroid responsive and may recur in other locations, such as the contralateral paraventricular white matter.
    • These lesions may represent an intermediate entity between MS and ADEM. Other differential considerations are neoplasm, systemic lupus erythematosus (SLE) and other vasculitic illnesses, progressive multifocal leukoencephalomyelitis, and Schilder myelinoclastic diffuse sclerosis.
    • Schilder disease (diffuse sclerosis) is sometimes considered an MS variant, and the uncertain diagnostic status is beyond the scope of this review. Detailed discussion of that entity is available in the Neurology section of the eMedicine journal.
• Recurrent ADEM is as follows:

  • Individuals who have experienced typical ADEM are at risk for recurrence. If these are second bouts, they may satisfy the diagnostic criteria for MS, although this liability may require closer scrutiny in prepubertal children than in older individuals.
    • Recurrence may occur during the taper of corticosteroid therapy initiated for ADEM. This phenomenon is not thought to represent a second or independent bout of illness; it usually responds to increasing the corticosteroid dosage and prolonging the ensuing taper.
    • The appearance of small new lesions on MRI within a month of presentation must also be interpreted with caution, and this may be seen in ADEM.
    • Although long tapers are sometimes required and more than one taper-related worsening occurs in a small number of patients, recovery is achieved within 2-12 months without further recurrence.
  • A rare subgroup of patients exists who cannot be weaned entirely from anti-inflammatory therapy. Most of the 8 examples the authors have encountered were in boys, and the onset of illness usually occurred at age 2-6 years.
    • Mental status changes, visual disturbance, and pyramidal weakness are typical findings; seizures occur in most cases.
    • Imaging changes resemble those found in cases of typical ADEM (ie, multiple plaques at the grey-white junction and in deep white matter), a feature that distinguishes these cases from chronic cases considered a manifestation of Schilder disease.
    • The CSF immune profile remains normal despite recurrences, although myelin basic protein may be elevated.
    • The neurologic abnormalities in this group improve significantly with intravenous methylprednisolone treatment (20 mg/kg/d for 3 successive doses) followed by oral methylprednisolone (2 mg/kg/d) with slow taper to achieve alternate-day dosing.
    • Trouble is encountered during the taper, each patient having a particular threshold for recurrence. In most of the authors' cases, this threshold is encountered when the daily methylprednisolone dose is lowered to approximately 12-14 mg every other day.
    • The neurologic worsening responds to higher corticosteroid doses, but this threshold effect cannot be overcome, and steroid therapy has been continued in these patients for periods as long as 8 years.
    • Although prolonged daily steroid therapy is generally well tolerated, osteopenia may develop, and one of the authors' patients developed vertebral compression fractures.

Irritability and lethargy are common first signs of acute disseminated encephalomyelitis (ADEM). Fever returns in nearly half of cases, headache is reported in 45-65%, and meningism is detected in 20-30% of cases. Over the course of minutes to 6 weeks or more, neurologic abnormalities develop. The long interval of possible worsening is much longer than the 0-14 days over which manifestations of an early bout of multiple sclerosis (MS) or cases labeled as adult ADEM may worsen. Among the most common abnormalities are visual disturbances and language, mental status, and psychiatric abnormalities. Mental status disturbances include lethargy, fatigue, confusion, irritability, obtundation, and coma and are found in 65-85% of children with ADEM. Psychiatric changes include irritability, depression, personality change, and psychosis. Focal or generalized seizures occur as an early sign in 10-25% of cases.

Weakness (50-75% of cases) is more commonly discerned than sensory defects (15-20%). The combinations of these signs may suggest cortical, subcortical, brainstem, cranial nerve, or spinal cord localization. Long tract signs develop in about half of all cases. Cranial nerve palsies are found in 35-50% of cases of childhood ADEM. Mental or psychiatric disturbances, seizures, and cranial nerve palsies are significantly less common in adolescents or adults with a first or second bout of MS and in many adults with an illness labeled ADEM. Sensory changes may be underappreciated in young children. However, posterior column deficits and hemisensory changes are possibly much less common than in adult cases of ADEM or in early bouts of adolescent or adult MS, where sensory changes (particularly posterior column signs) are found in two thirds of cases. Band or girdle dysesthesia or Lhermitte sign are seldom if ever found in cases of childhood ADEM.

Ataxia is found in 35-60% of childhood ADEM cases, which tends to differ from cases of ACA because it is more commonly appendicular with nystagmus or generalized ataxia than the distinctive gait/trunk ataxia of ACA. Extrapyramidal disorders such as choreoathetosis or dystonia are sometimes observed.

Signs and symptoms found in cases of ADEM:

• Alteration in personality
• Abnormal consciousness (65-75%)
• Ataxia (appendicular more than axial or gait)
• Cranial nerve palsies (35-40%)
• Hallucinations
• Headache
• Language disturbances (10%)
• Meningeal signs
• Nystagmus
• Psychiatric abnormalities
• Optic neuritis (10-30%)
• Ophthalmoparesis
• Seizures, focal or generalized (25%)
• Sensory loss/dysesthesia
• Visual field deficits
• Vomiting

Acute disseminated encephalomyelitis (ADEM) may develop in the wake of a wide variety of infectious illnesses or immunizations, especially those associated with large envelope-bearing viruses. Among the agents most commonly identified by titer rise suggesting responsibility for the prodromal phase are Ebstein-Barr virus, cytomegalovirus, herpes simplex virus (HSV), and mycoplasma. However, a particular agent is identified only in a minority of ADEM cases.

ADEM is somewhat more common in the colder months of the year, during which these various viral illnesses are more prevalent. Prior to widespread immunization programs, measles was the most common associated illness. ADEM occurred in approximately 1 out of 800 cases. Now, most cases occur in the wake of respiratory or gastrointestinal illnesses that are presumed to be of viral etiology; specific viral agents are seldom identified.

The hiatus between onset of viral symptoms and onset of ADEM may range from 2-20 days; the two phases of illness are typically separated by a phase of recovery from fever and other constitutional manifestations of the initial infectious phase of illness. ADEM may possibly arise after intervals as long as 30 or more days after an infectious prodrome. The longer the interval between presumed prodrome and ADEM, the less certain the etiologic association. A minority of cases lack a prodromal phase. Establishing the etiologic role of immunizations has proven controversial.

Clear links between the Pasteur rabies vaccine and ADEM have been established. Immunizations less frequently associated with ADEM include pertussis, measles,^[6] Japanese B virus, tetanus, and influenza.

The provocation provided by an infectious agent likely requires participation of other genetic or immuno-experiential factors of the individual in order to give rise to ADEM. These factors likely include genetically or experientially determined aspects of immunoregulation, particularly T-helper cell function.

Alves-Leon et al have found that the alleles HLA DQB1*0602, DRB1*1501, and DRB1*1503 confer genetic susceptibility to acute disseminated encephalomyelitis.^[7]