Acute disseminated encephalomyelitis (ADEM)

What is ADEM?

ADEM is an inflammatory, demyelinating event of early childhood. Patients present with acute onset polyfocal neurologic deficits, accompanied by encephalopathy and changes compatible with demyelination on brain MRI.

The International Paediatric Multiple Sclerosis Study Group (IPMSSG) definition for Paediatric ADEM requires all of the following for diagnosis:

• A first polyfocal, clinical CNS event with a presumed inflammatory demyelinating cause
• Encephalopathy that cannot be explained by fever
• No new clinical and MRI findings three months or more after the onset
• Abnormal brain MRI during the acute (3-month) phase.

Typical brain MRI changes include:

• Diffuse, poorly demarcated, large (>1–2 cm) lesions involving predominantly the cerebral white matter
• T1 hypointense lesions in the white matter are rare
• Deep grey matter lesions can be present in the thalamus or basal ganglia

Epidemiology

Although ADEM can affect people at any age, it is more common in children, with a median age at presentation of 5 – 8 years. There is a male preponderance, with a male: female ratio ranging from 1:0.8 to 2.3:1. It affects 1 in every 125,000 to 250,000 individuals in a given year. ADEM appears more often in winter and spring. It has been described in all parts of the world and affects all ethnicities.

Pathogenesis

5% of cases are associated with vaccination, although causality has never been proven. Molecular mimicry from vaccination or infectious exposure is thought to trigger production of CNS autoantigens in a genetically susceptible individual. Many patients experience a transient febrile illness in the month prior to ADEM. Preceding infections include influenza, Epstein-Barr virus, cytomegalovirus, varicella, enterovirus, measles, mumps, rubella, herpes simplex, and Mycoplasma pneumoniae.

Post-vaccination ADEM has been reported following immunization for rabies, smallpox, measles, mumps, rubella, Japanese encephalitis B, pertussis, diphtheria–polio–tetanus, and influenza. The risk of ADEM postvaccination, however, is significantly lower than following the infection itself.

Clinical features

The clinical presentation of ADEM is heterogeneous. Typically, patients show prodromal symptoms such as fever, headache, malaise, nausea, and vomiting. The acute phase occurs with encephalopathy, characterized by altered behaviour such as irritability or confusion and changes in consciousness, with lethargy, stupor or coma. This is associated with multifocal or focal neurological deficits depending on the area involved in the demyelinating process. Progression of the disease usually takes place within days, with maximal deficits within 2 to 5 days. Intensive care management is required for 15% of children. Clinical recovery typically occurs over weeks.

Neurologic manifestations can be varied, including:

• Pyramidal signs
• Ataxia
• Acute hemiparesis
• Optic neuritis or other cranial nerve involvement
• Seizures
• Spinal cord syndrome
• Impairment of speech
• Brainstem and cranial nerve deficits

Rarely, respiratory failure occurs due to brainstem involvement. Brainstem involvement leads to deficits in cranial nerves III–XII (diplopia, impaired extraocular movements, dysphagia, dysarthria, nystagmus, vertigo, ataxia, hearing and taste involvement).

Damage to the spinal cord can induce flaccid paralysis, defecation, and urinary disturbance. Seizures are not uncommon and can be focal or generalized and may develop into status epilepticus.

Diagnostic work up

The differentials of ADEM are vast, including CNS infection, malignancies, neurometabolic causes, autoimmune encephalitis, multiple sclerosis and toxicology.

There is no biological marker for ADEM. Diagnosis is made from a combination of CSF, EEG and MRI findings.

CSF studies are often normal or can show pleocytosis with lymphocytic or monocytic predominance. CSF protein can be elevated, especially on repeat lumbar puncture (LP). CSF immune globulin may be high, but true oligoclonal band positivity is rare. ADEM can be associated with myelin oligodendrocyte glycoprotein Immunoglobulin G antibodies.

Electroencephalograms (EEG) often show generalized slowing, consistent with encephalopathy.

A brain CT may be normal or show hypodense regions. MRI brain and spine is the imaging study of choice. It typically shows bilateral, large, multifocal, and sometimes confluent, oedematous mass-like T2 lesions. These lesions have variable enhancement within the white and grey matter of the cerebral hemispheres, cerebellum, and brainstem. Deep grey matter structures (thalami, basal ganglia) are often involved, although this may not be specific to ADEM. The spinal cord may have an abnormal T2 signal or enhancement, with or without clinical signs of myelitis.

The MRI lesions of ADEM typically appear to be of similar age, but their evolution may lag behind the clinical presentation. Serial MRI imaging 3 to 12 months following the initial ADEM diagnosis shows improvement and often complete resolution of T2 abnormalities.

Although ADEM and multiple sclerosis (MS) can have similar phenotypes, there are some features that can help differentiate between the two.

Neuroimaging

Treatment

ADEM management protocols are based on expert consensus and observational studies. First-line treatment consists of high-dose intravenous methylprednisolone followed by oral tapering. Intravenous immunoglobulins (IVIG) and plasma exchange are considered second-line therapies in steroid-resistant patients and in patients with contraindications to steroids.

The most commonly used regime is IV methylprednisolone at 10–30 mg/kg/day for 3 to 5 days. This is followed by oral steroid tapering, starting with prednisone 1–2 mg/kg/day tapered over 4 to 6 weeks.

IVIG is usually administered at 0.4 g/kg/day for 5 days or 1g/kg/day for 2 days. Total IVIG dose in both dosing schedules is 2 g/kg. Plasma exchange therapy usually consists of 3 to 6 cycles over a period of 10–14 days. Plasma exchange has a rapid onset, and the clinical response is usually noticeable after 2–3 exchanges.

Some critical patients need intensive care due to severe encephalopathy and seizures. Rehabilitation therapy can reduce long-term sequelae.

Prognosis

Patients usually have a good outcome with complete motor recovery, but residual defects can be seen, and cognitive deficits or behavioural changes are not uncommon. Recovery starts within days to weeks, but symptoms can fluctuate. The outcome seems to be better in children than in young adults, probably due to better plasticity of the children’s brains.

References

Massa, S.; Fracchiolla, A.; Neglia, C.; Argentiero, A.; Esposito, S. Update on Acute Disseminated Encephalomyelitis in Children and Adolescents. Children 2021, 8, 280.

Nelson Textbook of Paediatric, 21^st Edition

Paolilo, R et al., Acute Disseminated Encephalomyelitis: Current Perspectives. Children 2020.

Pohl, D.; Alper, G.; Haren, K.V.; Kornberg, A.J.; Lucchinetti, C.F.; Tenembaum, S.; Belman, A.L. Acute disseminated encephalomyelitis. Updates on an inflammatory CNS syndrome. Neurology 2016, 87 (Suppl. 2), S38–S45