Introduction to Acute Disseminated Encephalomyelitis (ADEM) in Children

Acute Disseminated Encephalomyelitis (ADEM) is a rare inflammatory demyelinating disorder of the central nervous system (CNS) that primarily affects children. It is characterized by a widespread attack on the brain and spinal cord, leading to multifocal neurologic deficits. ADEM typically follows a monophasic course, with most patients experiencing a single episode. However, recurrent or multiphasic forms have been described.

Key points:

• Incidence: 0.3 to 0.6 per 100,000 children per year
• Median age of onset: 5-8 years
• Slight male predominance
• Often preceded by viral or bacterial infections, or rarely, vaccinations
• Presents with acute onset of multifocal neurological deficits and encephalopathy

Etiology of ADEM in Children

The exact cause of ADEM remains unclear, but it is believed to result from an autoimmune response triggered by an environmental stimulus in genetically susceptible individuals. Common precipitating factors include:

1. Viral infections (50-75% of cases):
   • Measles, mumps, rubella
   • Varicella-zoster virus
   • Epstein-Barr virus
   • Cytomegalovirus
   • Herpes simplex virus
   • Influenza virus
   • Enterovirus
2. Bacterial infections:
   • Mycoplasma pneumoniae
   • Borrelia burgdorferi (Lyme disease)
   • Group A beta-hemolytic Streptococcus
3. Vaccinations (rare, <5% of cases):
   • Rabies
   • Diphtheria-Tetanus-Pertussis (DTP)
   • Measles-Mumps-Rubella (MMR)
   • Japanese B encephalitis

It's important to note that the risk of ADEM following vaccination is significantly lower than the risk associated with natural infections.

Pathophysiology of ADEM in Children

ADEM is considered an immune-mediated disorder characterized by inflammation and demyelination within the CNS. The proposed mechanism involves:

1. Molecular mimicry: Structural similarities between microbial antigens and myelin components lead to cross-reactivity of T-cells.
2. Blood-brain barrier disruption: Activated T-cells cross the blood-brain barrier and enter the CNS.
3. Inflammatory cascade: T-cells recognize myelin antigens and trigger an inflammatory response, recruiting other immune cells.
4. Demyelination: The inflammatory process leads to destruction of myelin sheaths, causing neurological deficits.
5. Cytokine release: Pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IFN-γ) contribute to tissue damage and perpetuate inflammation.

Histopathologically, ADEM is characterized by perivenular inflammation and demyelination, with relative axonal sparing. Lesions are typically found in the white matter of the brain and spinal cord, but can also affect gray matter structures.

Clinical Presentation of ADEM in Children

The clinical presentation of ADEM is typically acute or subacute, developing over hours to days, with a maximum deficit reached within 2-5 days. Common features include:

1. Prodromal phase (3-14 days before neurological symptoms):
   • Fever
   • Malaise
   • Headache
   • Nausea and vomiting
2. Encephalopathy (95% of cases):
   • Altered mental status
   • Irritability
   • Confusion
   • Somnolence
   • Coma (in severe cases)
3. Multifocal neurological deficits:
   • Motor deficits (60-95%): Hemiparesis, paraparesis, or tetraparesis
   • Ataxia (50%)
   • Cranial nerve palsies (25-50%)
   • Optic neuritis (7-23%)
   • Seizures (13-35%)
   • Sensory deficits
   • Bladder/bowel dysfunction

The combination and severity of symptoms can vary widely between patients. It's crucial to recognize that the presentation may mimic other acute neurological disorders, necessitating a thorough differential diagnosis.

Diagnosis of ADEM in Children

Diagnosing ADEM can be challenging due to its variable presentation and overlap with other neurological disorders. A comprehensive approach is necessary:

1. Clinical history and examination:
   • Recent history of infection or vaccination
   • Acute onset of neurological symptoms
   • Presence of encephalopathy
2. Neuroimaging:
   • MRI (gold standard): Large, multifocal, asymmetric white matter lesions; involvement of deep gray matter structures
   • CT scan: Less sensitive, may show low-density lesions or appear normal
3. Cerebrospinal fluid (CSF) analysis:
   • Mild to moderate pleocytosis (<100 cells/μL, predominantly lymphocytes)
   • Elevated protein levels
   • Normal glucose levels
   • Oligoclonal bands (rarely present, <10% of cases)
4. Additional tests:
   • EEG: Non-specific slowing of background activity
   • Serology: To rule out infectious causes
   • Autoantibody testing: Anti-MOG and anti-AQP4 antibodies

Differential diagnosis includes:

• Multiple sclerosis
• Neuromyelitis optica spectrum disorders
• Infectious encephalitis
• Vasculitis
• Mitochondrial disorders
• Leukodystrophies

The 2013 International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria are commonly used for diagnosing ADEM in children.

Treatment of ADEM in Children

The management of ADEM focuses on suppressing the inflammatory response and providing supportive care. Treatment should be initiated promptly upon diagnosis:

1. First-line therapy:
   • High-dose intravenous methylprednisolone (20-30 mg/kg/day, max 1g/day) for 3-5 days
   • Followed by oral prednisone taper over 4-6 weeks
2. Second-line therapies (for severe or refractory cases):
   • Intravenous immunoglobulin (IVIG): 2 g/kg divided over 2-5 days
   • Plasmapheresis: 5-7 exchanges over 10-14 days
3. Supportive care:
   • Seizure management
   • Respiratory support if needed
   • Fluid and electrolyte balance
   • Prevention of complications (e.g., deep vein thrombosis, pressure ulcers)
4. Rehabilitation:
   • Physical therapy
   • Occupational therapy
   • Speech and language therapy
   • Cognitive rehabilitation

Treatment response should be monitored closely, and therapy may need to be adjusted based on clinical course. In cases of suspected post-infectious ADEM, antiviral or antibiotic treatment may be considered if the causative agent is identified.

Prognosis of ADEM in Children

The prognosis for children with ADEM is generally favorable, with most patients experiencing significant recovery:

• Complete recovery: 50-75% of cases
• Mild residual deficits: 20-30% of cases
• Severe residual deficits: <5% of cases
• Mortality: <5%

Factors influencing prognosis:

1. Age at onset: Younger children tend to have better outcomes
2. Severity of initial presentation
3. Extent of MRI lesions
4. Time to initiation of treatment
5. Response to initial therapy

Long-term follow-up considerations:

• Risk of recurrence: 10-25% of cases may experience a second episode
• Potential for evolution to multiple sclerosis: <10% of cases
• Neurocognitive outcomes: Subtle deficits in attention, executive function, and behavior may persist
• Regular follow-up with neuroimaging and clinical assessments is recommended

Early recognition, prompt treatment, and comprehensive rehabilitation are key factors in optimizing outcomes for children with ADEM.