---

Acute Disseminated Encephalomyelitis (ADEM)

---

1. ETIOLOGY

Postinfectious (Most Common)

• In developed countries today, varicella is now the most frequent antecedent.
• Non-specific upper respiratory tract infections account for 50-75% of cases.
• Occasional cases have no identifiable trigger.

Postvaccinal

• Historically associated with rabies and smallpox vaccines prepared with neural tissue (these are no longer used).
• A large Vaccine Safety DataLink study of >9 million individuals across 24 vaccines found no meaningful excess risk, with the possible exception of Tdap (estimated <1 case/million doses).
• Modern vaccines do not meaningfully cause ADEM.

Other (Rare)

• Drug reactions, paraneoplastic disorders, rheumatic diseases.

Important modern caveat (Harrison's 22nd ed., 2025): Many cases previously diagnosed as ADEM are now recognized as MOG antibody-associated disease (MOGAD). ADEM cases with anti-MOG serum/CSF antibodies are now reclassified under MOGAD.

---

2. PATHOLOGY

• Lesions are diffuse, poorly marginated, and of uniform age (in contrast to MS where lesions are multiple, distinct, and of mixed age)
• Lesions vary from miniscule to several millimeters; they invariably surround small and medium-sized veins (perivenular)
• Perivenular inflammatory infiltrate: primarily lymphocytes and mononuclear cells
• Adjacent white matter invaded by monocytes and microglia - corresponding zones of demyelination
• Axons and neurons are relatively preserved (demyelination without axonal destruction)
• Multifocal meningeal (pial) infiltration - a feature of ADEM not seen in MS
• Both white matter and gray matter structures can be involved (contrast with MS which is predominantly white matter)
• In the most explosive form - Acute Hemorrhagic Leukoencephalitis (AHLE / Hurst disease) - lesions are vasculitic and hemorrhagic

• MS lesions: multiple, distinct, well-circumscribed, irregularly distributed, mixed age
• ADEM lesions: diffuse, less distinct margins, uniform age, perivenular, meningeal involvement

---

3. PATHOGENESIS / MECHANISMS

• An interval separates the exanthem from neurologic onset
• Pathologic changes differ completely from viral encephalitis
• Virus is rarely isolated from CSF or brain tissue
• Postmeasles ADEM patients show no intrathecal measles antibody synthesis

• Produced by inoculating animals with sterile brain tissue + adjuvants
• Appears 8-15 days after sensitization
• Produces identical perivenular demyelinating lesions
• T cells from ADEM patients are 10x more likely to react to MBP than controls

• Evidence of antibody binding, complement activation, and eosinophilic infiltration suggests a humoral component (unlike MS which is predominantly T-cell mediated)
• Anti-MBP antibodies detected in CSF
• Anti-MOG antibodies (~30% of ADEM patients) - these patients are now classified as MOGAD
• The MOG antibody titer drops rapidly after the acute attack, so its exact pathogenic role is uncertain

---

4. CLINICAL FEATURES

• More common in children than adults (median age 5-8 years)
• No sex preponderance (unlike MS, which favors females)
• Incidence: 0.3-0.6 per 100,000/year

• Abrupt onset over hours to 1-2 days, rapid progression
• In postinfectious ADEM: fever reappears as the exanthem fades
• Maximum deficits within 2-5 days

• Normal opening pressure
• Lymphocytic pleocytosis in 80% of patients, generally ≥200 cells/μL; mixed PMN-lymphocytic pattern in early days
• Protein: modestly elevated - 0.5-1.5 g/L (50-150 mg/dL)
• Glucose: normal
• Oligoclonal bands (OCBs): transient, minority of cases; if present, follow for MS
• Red blood cells: if present, suggest hemorrhagic leukoencephalitis (AHLE)

• Most children have favorable outcome with full recovery despite severity
• Mortality 10-20% in severe cases historically; significant disability in survivors
• Adults often make better recoveries than children paradoxically (except severe cases)
• Follow-up: 25-30% of adults initially diagnosed with ADEM later develop MS or another chronic inflammatory disorder (vasculitis, sarcoidosis, lymphoma, MOGAD, NMOSD)

---

5. MRI FEATURES

• Present in 14-30% of cases (less common than in MS)
• When present: all lesions enhance simultaneously (same age - key differentiating feature from MS)
• Enhancement patterns: complete ring, incomplete ring, nodular, gyral, or spotty

• T2/FLAIR: multifocal white matter hyperintensities - primary sequence for detection
• T1 post-contrast: enhancement in active lesions (14-30%)
• DWI: may show restricted diffusion in acute lesions
• T1 hypointense "black holes" should NOT be seen in ADEM (their presence suggests MS)

• Cerebrum (subcortical and central white matter)
• Cerebellum
• Brainstem
• Thalamus and basal ganglia (particularly in children; may be symmetric)
• Cortical grey matter (30% of cases)
• Spinal cord (1/3 of patients)

• Thoracic region predominantly affected
• Long extensive transverse myelitis (LETM) - extending over multiple segments (similar to NMOSD)
• Cord swelling
• Variable enhancement
• Lesions may be confined to grey matter, white matter, or both

• Most lesions appear early and support diagnosis
• In ~50% of cases, new lesions and enlargement can occur within the first 3 months (still consistent with ADEM)
• No new T2 lesions after 3 months from onset - if new lesions appear after 3 months, reclassify
• Complete MRI resolution within 6 months: strongly supports ADEM diagnosis
• Persistence or incomplete resolution: associated with subsequent MS diagnosis
• A reference MRI at 3 months post-onset is recommended

1. Diffuse, poorly demarcated, large (>1-2 cm) lesions
2. Predominantly cerebral white matter
3. No T1 hypointense lesions
4. Deep grey matter lesions (thalamus/basal ganglia) can be present, especially in children

---

MRI Images (from Grainger & Allison's Diagnostic Radiology)

---

---

---

6. DIAGNOSIS (Summary Criteria - IPMSSG 2012)

1. First event of encephalopathy + polyfocal neurological deficits
2. Presumed inflammatory demyelinating cause
3. Encephalopathy: alteration in consciousness or behavior unexplained by fever, systemic illness, or postictal symptoms
4. Brain MRI abnormalities consistent with demyelination during acute phase (within 3 months)
5. No new clinical and MRI findings ≥3 months after initial event
6. Typical MRI lesions (described above)

• Simultaneous onset of disseminated symptoms (rare in MS)
• Encephalopathy (uncommon in MS)
• Bilateral optic neuritis (unilateral in MS)
• Complete transverse myelopathy (partial in MS)
• Extensive symmetric white matter changes + basal ganglia/cortical GM lesions
• Enhancement of ALL abnormal areas simultaneously
• No T1 black holes
• Resolution of lesions on follow-up

---

7. RECENT EVIDENCE - Post-COVID ADEM

• Median age 49.5 years (older than typical ADEM)
• Anti-MOG seropositive in only 1/15 tested
• Hemorrhage on MRI in 42% (unusually high)
• 32% mortality, 64% had final mRS ≥4 (poor outcome)
• Post-COVID ADEM differs from prepandemic ADEM: older, severe antecedent infection, high hemorrhage rate, poor outcomes

---

8. ACUTE HEMORRHAGIC LEUKOENCEPHALITIS (AHLE / Hurst Disease) - Severe Variant

• The most explosive form of ADEM
• Lesions are vasculitic and hemorrhagic
• Clinical course is devastating
• CSF: red blood cells present
• MRI: hemorrhagic foci (susceptibility-weighted imaging/GRE sensitive)
• High mortality

---

Sources

• Adams and Victor's Principles of Neurology, 12th Edition - Chapter on inflammatory demyelinating diseases
• Bradley and Daroff's Neurology in Clinical Practice - Chapter 79
• Harrison's Principles of Internal Medicine, 22nd Edition (2025) - Chapter on demyelinating diseases
• Grainger & Allison's Diagnostic Radiology - Chapter 58 (Demyelinating diseases MRI)
• Plum and Posner's Diagnosis and Treatment of Stupor and Coma
• Manzano GS et al. Neurol Neuroimmunol Neuroinflamm. 2021 Nov [PMID: 34452974] - Post-COVID ADEM systematic review