What is the treatment for Acute Disseminated Encephalomyelitis (ADEM)?

Acute Disseminated Encephalomyelitis (ADEM): Overview and Management

Definition and Pathophysiology

ADEM is a monophasic autoimmune demyelinating disease of the central nervous system that typically follows a febrile infection or vaccination, predominantly affecting children. 1 The condition involves inflammation of the brain parenchyma causing acute polyfocal neurological deficits with encephalopathy as a required diagnostic component. 2, 3

• ADEM develops through both primary and secondary autoimmune responses that lead to CNS inflammation and subsequent demyelination. 1
• The disease is classified among inflammatory demyelinating disorders that can affect both brain and spinal cord. 3
• While typically monophasic, recurrent and multiphasic courses have been described, termed multiphasic disseminated encephalomyelitis. 4, 5

Epidemiology

• The incidence in children ranges from 10.5 to 13.8 per 100,000, translating to approximately 1-2 cases annually in a typical district general hospital and 8-10 in large tertiary children's hospitals in the UK. 2, 3
• Adult-onset ADEM is rare but increasingly recognized. 6, 7

Etiology and Triggers

Common infectious triggers include measles, mumps, rubella, varicella zoster, Epstein-Barr virus, cytomegalovirus, herpes simplex, hepatitis A, influenza, enterovirus infections, and Mycoplasma pneumoniae. 2, 3, 7

• Vaccination-associated ADEM has been temporally linked to vaccines against anthrax, Japanese encephalitis, yellow fever, measles, influenza, smallpox, rabies, and COVID-19 mRNA vaccines. 3, 8, 7
• Symptoms typically develop 1-14 days after vaccination or approximately 1 week after rash appearance in exanthematous illness. 3

Clinical Presentation

Encephalopathy ranging from confusion to coma is mandatory for diagnosis and is accompanied by multifocal neurologic deficits affecting various CNS regions. 3, 8

Neurological Manifestations:

• Optic neuritis (often bilateral) occurs commonly. 3, 8
• Myelitis (frequently longitudinally extensive) is another frequent deficit. 3, 8
• Brainstem encephalitis, cerebellar ataxia, motor deficits, and seizures occur in approximately one-third of patients. 3, 8
• Behavioral changes including confusion (76% of cases), disorientation (41%), and speech disturbances (59%) are common. 8
• Focal neurological deficits present in 36-78% of cases. 8

Key Clinical Features:

• Fever is present in up to 80% at initial presentation but typically absent at onset of neurological illness. 3, 8
• Children may present with non-specific symptoms including feeding difficulties, respiratory problems, and irritability. 8
• Subtle presentations with low-grade fever and behavioral changes can be mistaken for psychiatric illness. 8

Diagnostic Evaluation

Neuroimaging:

MRI with contrast of brain and spinal cord is the imaging modality of choice and should be obtained within 48 hours. 3, 9

• Characteristic MRI findings include large, confluent T2 hyperintense brain lesions, multifocal subcortical white matter abnormalities, involvement of thalami and basal ganglia, longitudinally extensive spinal cord lesions, and perioptic enhancement during acute optic neuritis. 3, 8, 6
• Lesions are typically reversible and ill-defined. 5

Cerebrospinal Fluid Analysis:

Perform lumbar puncture with comprehensive CSF analysis including cell count, protein, glucose, viral PCRs, autoimmune encephalitis panel, oligoclonal bands, and CNS demyelinating disease antibodies. 9

• Typical CSF findings include lymphomonocytic pleocytosis, elevated protein levels, normal glucose levels. 3, 6, 1
• Oligoclonal bands may be absent or transient (unlike multiple sclerosis). 3, 1
• Culture and viral studies are typically negative. 6

Additional Testing:

• Consider MOG (myelin oligodendrocyte glycoprotein) antibody testing, as it may influence treatment decisions and prognosis. 3, 5

Differential Diagnosis

The differential diagnosis is broad and requires systematic exclusion of mimicking conditions. 4, 5

• Infectious encephalitis (viral, bacterial, fungal, parasitic) - particularly herpes simplex encephalitis which requires immediate antiviral therapy. 2, 3, 9
• Multiple sclerosis - the major differential diagnosis, though ADEM and MS are generally distinguishable even at disease onset. 4, 5
• Antibody-associated encephalitis (e.g., anti-NMDA receptor encephalitis). 2, 3
• Neuromyelitis optica (NMO) - particularly in younger children with ADEM presentation. 4
• Metabolic and toxic encephalopathies. 3, 8

Treatment Algorithm

Immediate Initial Management:

Start empirical intravenous acyclovir immediately while awaiting diagnostic confirmation, as herpes simplex encephalitis cannot be missed and requires different treatment. 3, 9, 4

• Continue acyclovir until CSF PCR results return negative for HSV. 9
• Obtain urgent neurology consultation within 24 hours of presentation. 9
• Empiric antibacterial therapy should also be initiated until infectious disease processes are ruled out. 3, 4

First-Line Immunotherapy:

Administer high-dose intravenous methylprednisolone 1 g daily (or 20-30 mg/kg/day with maximum 1 g/day) for at least 3-5 days once infection is ruled out based on basic CSF results. 3, 9, 4

• Follow with oral corticosteroid taper over a minimum of 4-6 weeks to prevent symptom recurrence. 3, 9, 4
• The extended taper duration is critical, as shorter tapers lead to symptom flaring and recurrence. 3, 9
• If flaring occurs during taper, consider extending the taper duration or temporarily increasing the dose. 3

Second-Line Therapies for Inadequate Response:

If patients show no clinical, radiological, or electrophysiological improvement after 3 days of corticosteroids or have contraindications, proceed to intravenous immunoglobulin (IVIG) or plasma exchange. 3, 9, 4

• IVIG dosing: 0.4 g/kg/day for 5 days or 2 g/kg divided over 2-5 days. 9, 4
• Critical caveat: Do not perform plasmapheresis immediately after IVIG, as it will remove the administered immunoglobulin. 3
• For severe or life-threatening cases, consider plasmapheresis early in the disease course. 4

Severity-Based Management:

For moderate cases (Grade 2):

• Stop any immune checkpoint inhibitors if applicable. 3
• Start prednisone 1 mg/kg daily and taper over 1 month. 3

For severe cases (Grade 3-4):

• Permanently discontinue immune checkpoint inhibitors if applicable. 3, 9
• Admit patient for inpatient care (ICU level for Grade 4). 9
• Start methylprednisolone pulse dosing 1 g/day. 9
• Consider IVIG or plasmapheresis if no improvement or worsening after 3 days. 3

Third-Line Therapies for Refractory Cases:

For patients with positive autoimmune encephalopathy or paraneoplastic antibodies, or those with limited improvement, consider rituximab in consultation with neurology. 3, 9

• Rituximab is recommended in known or highly suspected antibody-mediated autoimmunity. 9
• Cyclophosphamide may be considered in known or highly suspected cell-mediated autoimmunity. 9
• Consultation with neurology is essential before initiating these third-line agents. 3

Bridging and Maintenance Therapy:

After the acute phase, consider bridging therapy with gradual oral prednisone taper, monthly intravenous immunoglobulin, or monthly intravenous methylprednisolone. 9

• The minimum steroid taper duration remains 4-6 weeks to prevent relapse. 9

Life-Saving Measures:

• Decompressive craniectomy has been reported as a life-saving measure for ADEM patients with intracranial hypertension. 4

Critical Pitfalls and Caveats

Never delay empirical acyclovir while awaiting diagnostic confirmation, as HSV encephalitis has devastating consequences if untreated. 3, 9

Avoid steroid tapers shorter than 4-6 weeks, as premature discontinuation leads to symptom recurrence. 3, 9

• Symptoms may flare during steroid tapering, suggesting steroid-dependence in some cases. 3, 8
• A normal Glasgow Coma Score at presentation may not detect subtle behavioral changes, leading to missed or delayed diagnosis. 8
• In children with relapsing demyelinating events, consider chronic autoimmune CNS diseases like MS or NMO. 4

Prognosis and Follow-Up

ADEM is generally self-limiting with favorable prognosis, particularly in pediatric patients. 1, 5

• Clinical improvement typically occurs with appropriate immunotherapy. 6
• Cognitive deficits have been reported even in the absence of other neurologic sequelae. 5
• Systematic follow-up including repeat MRI is indicated to establish accurate diagnosis and monitor for disease evolution. 4
• Resolution of neurologic irAEs has been documented in 75% of patients, with median time to resolution of approximately 8 weeks. 2