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, although a clear preceding event may be absent in up to a quarter of patients. ^[85]

• 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 most cases occurring between October and March. Typical cases of ADEM arise 1-2 days to several weeks after a childhood infectious illness.

• There is usually a clearly defined phase of afebrile improvement lasting 2-21 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 21 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 post-infectious vasculitides.

• 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.

  • 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. ^[6]

  • Relationships are also difficult to determine when a febrile systemic process is rapidly followed by neurologic deterioration because such cases may represent meningoencephalitis.

    • Approximately 25% of cases lack a clearly-defined prodrome. ^{[47, 58, 85]}

    • 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.

    • 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 first signs of ADEM usually include abrupt onset encephalopathy (alteration in consciousness or behavioral change unexplained by fever, systemic illness or postictal symptoms. ^[59] Rapid-onset encephalopathy is typically associated with multifocal neurologic symptoms.

• In most cases, the clinical course is rapidly progressive and typically develops over hours to maximum deficits within days (mean of 4.5 days). ^[85] A minority of cases show continued deterioration of function for periods as long as 4 weeks.

• Strictly speaking, encephalopathy, unexplained by fever, should be present for a diagnosis of ADEM, though it may not be the presenting sign. 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 the 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. ^[7]

• Convulsive seizures occur around the onset of ADEM in as many as 35% of cases. ^[85]

• Meningismus may be present and has been reported in up to 30% of cases. ^[63]

• 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 typically 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 as 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 85% of cases. ^[85]

  • 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, diparetic, 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.

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 of severe edema on neuroimaging. 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. 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 a median range of 10-14 y and the vast majority of these patients are girls or young women. The median number of spinal levels involved is 10 vertebral segments. ^[72] 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. More literature is supporting a continuum of acute demyelinating diseases in childhood and adulthood.

• Cases of pediatric patients diagnosed with neuromyelitis optica presenting with a clinical and radiographic evidence of ADEM have been reported. ^{[73, 74, 76]}

• Cases of patients with anti-NMDA receptor encephalitis and ADEM-like lesions on MRI have also been reported. ^{[77, 75]}

• Additionally, pediatric cases of ADEM followed by recurrent or monophasic optic neuritis have been described. ^[78]

• Young children may manifest a rapidly progressive demyelinating 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.

• Some patients with the large tumor-like lesions, acute MS, or Schilder disease presentations during childhood or adolescence do remarkably well as compared to adults with similar presentations.

• The classification of 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, ^[79] and hyperacute adult cases with similar clinical and radiographic manifestations have been reported. ^[81]

  • 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. Extensive white matter involvement may be found in young infants that some would label as MS ^[80] while others would label it hyperacute ADEM.

• Rarely, childhood, adolescent, or adult MS manifests as large unilateral or multiple tumor-like 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 Medscape Reference journal.

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 one of the authors (RSR) has 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.

In 2007, the International Pediatric Multiple Sclerosis Study Group (IPMSSG) proposed operational definitions for the pediatric acquired demyelinating diseases (including ADEM) in attempts to improve consistency in terminology for clinical and research purposes. These guidelines were revised in 2013 and are outlined below. ^[59]

• The criteria requires that a child must meet all of the following to be accurately classified as pediatric ADEM:

  • A first, polyfocal clinical CNS event with presumed inflammatory demyelinating cause

  • Encephalopathy that cannot be explained by fever

  • No new clinical and MRI findings emerge 3 months or more after onset

  • Brain MRI is abnormal during the acute phase

  • Typical findings on brain MRI (discussed below) that include diffuse, poorly demarcated large lesions involving the cerebral white matter; T1 hypointense lesions of the white matter are rare; deep gray matter lesions may be present.

Recurrent ADEM was previously defined as a new event of ADEM with a recurrence of the initial symptoms and signs 3 or more months after the first ADEM event. Based upon the 2013 consensus criteria from IPMSSG, ^[59] this entity is now included under the entity known as multiphasic ADEM.

Multiphasic ADEM

• Individuals who have experienced typical ADEM are at risk for recurrence. As many as 10% of children with an initial diagnosis of ADEM experience another ADEM attack, typically within the first 2-8 years after the initial attack. ^[85]

• Included under the entity of “multiphasic ADEM” are new events of ADEM 3 months or more after the initial attack that can be associated with new or re-emergence of prior clinical and/or MRI findings. ^[59]

  • Relapsing disease that follows a second ADEM attack is, by definition, no longer consistent with a diagnosis of multiphasic ADEM. Typically, these cases represent a chronic neuro-inflammatory disorder (such as MS or NMO). ^[59]

Irritability and lethargy are common first signs of acute disseminated encephalomyelitis (ADEM). Fever returns and headache is present in up to half of cases. ^{[47, 63, 58]} Meningismus is also detected in approximately one third of cases. ^{[47, 63]} Over the course of minutes to weeks, multifocal neurologic abnormalities develop. The interval from onset of symptoms to maximum deficit is varied but is typically seen at a mean of 4-7 days. ^{[47, 58, 85]} Among the most common abnormalities are long tract signs, acute hemiparesis, cranial nerve abnormalities (including visual loss), ataxia, and mental status abnormalities. Mental status disturbances include lethargy, fatigue, confusion, irritability, obtundation, and coma. Focal or generalized seizures occur as an early sign in a minority of cases.

Weakness (roughly 75% of cases) is more commonly discerned than sensory defects. The combinations of these signs may suggest cortical, subcortical, brainstem, cranial nerve, or spinal cord localization. Long tract signs develop in more than half of all cases. Cranial nerve palsies (including vision loss) are found in a wide range of cases (23-89%) of childhood ADEM. ^{[58, 54, 47, 63, 71, 85]} 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. Band or girdle dysesthesia or Lhermitte’s sign are seldom if ever found in cases of childhood ADEM.

Ataxia is found in 28-65% of childhood ADEM cases, ^{[63, 47, 58, 85]} 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

• Ataxia (appendicular more than axial or gait)

• Cranial nerve palsies

• Hallucinations

• Headache

• Language disturbances

• Meningeal signs

• Nystagmus

• Psychiatric abnormalities

• Optic neuritis

• Ophthalmoparesis

• Seizures, focal or generalized

• 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. 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 2-21 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 the presumed prodrome and ADEM, the less certain one can be of 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, ^[8] Japanese B virus, tetanus, influenza, hepatitis B, diphtheria, rubella, pneumococcus, varicella, smallpox, poliomyelitis, and human papillomavirus. ^[82]

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. ^[9]