Acute Disseminated Encephalomyelitis

Key Points at a Glance

Acute disseminated encephalomyelitis (ADEM) is an acute autoimmune demyelinating disease triggered by infection or vaccination.
It is more common in children (mean age of onset 3.6–7 years) and predominantly occurs before age 10.
In addition to multifocal neurological deficits, encephalopathy (impaired consciousness, behavioral changes) is characteristic and an important distinguishing feature from MS.
Ocular symptoms may include optic neuritis (often bilateral), diplopia, and cortical blindness.
20–60% of pediatric MOG antibody-associated disease (MOGAD) presents as ADEM, and MOG antibody positivity is 33–66%.
First-line treatment is methylprednisolone pulse therapy, and 60–90% of children achieve complete neurological recovery.
The course is usually monophasic, but in adults, mortality is 7.8% and residual disability 47.5%, showing variable prognosis.

1. What is Acute Disseminated Encephalomyelitis?

Acute disseminated encephalomyelitis (ADEM) is an acute autoimmune demyelinating disease of the central nervous system (brain and spinal cord). Immune-mediated damage to the myelin sheath causes multifocal neurological deficits. It was first described about 250 years ago in patients after smallpox infection. ¹⁾

Epidemiology

The incidence in children is 0.23–0.4 per 100,000. The mean age of onset is 3.6–7 years, with a predilection for children under 10. In children, it is more common in boys. A meta-analysis of 437 adult cases reported a mean age of 37.1 years and 41.7% male. ¹⁾ In adults, there is a tendency for female predominance. ²⁾ Geographically, prevalence is higher farther from the equator.

Subtypes

Monophasic ADEM

Most common type: A single episode without recurrence. Usually this type.

Course: Symptoms improve within 3 months.

Multiphasic ADEM

Recurrent type: New lesions appear after an interval of more than 3 months.

Note: Three or more recurrences suggest other diseases such as MS or NMOSD.

ADEM-ON

Type with optic neuritis: Optic neuritis occurs within 3 months of ADEM onset. Often associated with MOGAD.

Prognosis: Visual recovery varies by case.

AHLE

Acute hemorrhagic leukoencephalitis: Fulminant type with hemorrhage and necrosis. Shows fibrinoid necrosis and necrotizing vasculitis.

Severity: The most severe type with high mortality.

Relationship with MOGAD

MOG (myelin oligodendrocyte glycoprotein) antibody positivity reaches 33–66% in pediatric ADEM. ADEM is one of the core clinical phenotypes of MOGAD (MOG antibody-associated disease), and 20–60% of pediatric MOGAD presents as ADEM.

Q Does ADEM recur?

Usually it follows a monophasic (single episode) course. However, multiphasic ADEM and ADEM-ON can recur. If recurrence occurs three or more times, or if new lesions appear after more than 3 months, other demyelinating diseases such as MS or NMOSD should be considered and reevaluated.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Prodromal symptoms (3–4 days before onset) often include fever, malaise, headache, nausea, and vomiting. Neurological symptoms peak 2–5 days after onset.

The frequency of main symptoms from a meta-analysis of 437 adult cases is shown. ¹⁾

Multifocal onset: 80.5% (95% CI 50.5–98.9)
Pyramidal tract signs (hyperreflexia, spasticity, Babinski sign): 68.7%
Motor impairment: 63.4%
Gait disturbance: 52.0%
Brainstem symptoms: 46.7%
Encephalopathy (coma, stupor, lethargy, behavioral changes): 43.7%. An important feature distinguishing ADEM from MS.
Sphincter dysfunction: 40.1%
Cranial nerve palsy: 38.3%
Headache: 38.2%
Sensory disturbance: 35.2%
Optic neuritis: 13.6%
Seizures: 12.4%

Main symptoms in children (frequency ranges vary between reports): limb weakness 17–77%, ataxia 10–52%, cranial nerve palsy 11–48%, optic neuritis 7–23%, seizures 4–48%, fever 27–63%.

Ocular symptoms (important neuro-ophthalmologic findings)

Optic neuritis: unilateral or bilateral. Bilateral involvement is more common in ADEM than in MS. Accompanied by vision loss (median 20/600), pain on eye movement, and color vision abnormalities.
Diplopia: caused by ocular motor dysfunction due to brainstem lesions.
Cortical blindness: occurs due to lesions in the occipital lobe/visual cortex.
Optic disc edema: observed on fundoscopic examination.
Uveitis: rarely reported.

Severe cases require ICU admission. In adults, 39.7% (95% CI 23.5–57.1) require ICU admission. ¹⁾

Clinical findings (findings confirmed by physician examination)

Neurological findings

Pyramidal tract signs: upper motor neuron signs such as hyperreflexia, spasticity, and Babinski sign
Cerebellar symptoms: ataxia, nystagmus
Brainstem findings: dysfunction of cranial nerves III–XII, dysphagia, dysarthria. Brainstem lesions are associated with poor prognosis.
Cortical symptoms: aphasia, alexia, agraphia, homonymous hemianopia, loss of higher sensory functions

Ophthalmic findings

rAPD (relative afferent pupillary defect): objective evidence of optic neuritis
Optic disc edema: fundoscopic/OCT findings
Ocular motility disorder: due to brainstem/internuclear dysfunction

MRI findings

T2/FLAIR: diffuse, poorly demarcated, large bilateral hyperintense lesions (>1–2 cm)
Lesions in both white matter and gray matter
Abnormality frequency in adults: brain MRI abnormal 91.6%, white matter lesions 87.1%, periventricular 43.2%, subcortical 41.9%¹⁾
Gadolinium enhancement: present in 58.0% of adults¹⁾
T1 hypointense “black holes” are rare (differentiating point from MS)
Spinal cord lesions: 41.6% in adults, spanning multiple vertebral segments¹⁾
DWI: reduced diffusion within 1 week of onset, increased diffusion thereafter

CSF findings (adult meta-analysis)¹⁾

CSF abnormality: 70.0%
Lymphocyte-predominant pleocytosis: 51.8%
Protein elevation (>45 mg/dL): 39.1%
Oligoclonal bands positive: 23.9%

3. Causes and Risk Factors

ADEM is triggered by infection or antigenic stimulation. In 67% of all adult cases, a precipitating antigenic stimulus is identified, and the average interval from preceding infection to onset is 12.5 days (range 0–60 days). ¹⁾

Preceding infection

In adults, a preceding infection is found in 51.7% (95% CI 38.2–65.0). The main types are upper respiratory tract infection 25.7% and acute gastroenteritis 8.7%. ¹⁾

Associated viruses: cytomegalovirus, EBV, HSV, HHV-6, H1N1, hepatitis viruses, HIV, influenza, measles, rubella, varicella-zoster, SARS-CoV-2, etc.
Associated bacteria: Mycoplasma pneumoniae, Campylobacter, Chlamydia pneumoniae, Borrelia, Legionella, etc.

Association with COVID-19

In a systematic review of 30 cases, the average interval from COVID-19 infection to ADEM onset was 23.2 days (range 4–60 days). 73.68% of cases were adult males, with a mean age of 49.8 years. ⁴⁾

Post-vaccination

Onset in adults is only 2.9% (95% CI 0–8.3), and the risk after vaccination is relatively low at about 0.1%. The risk after infection is higher. ¹⁾

MOG antibodies

MOG antibodies are positive in 33–66% of pediatric cases. This indicates a strong association between MOGAD and ADEM.

Genetic predisposition

An association with specific HLA-DR subtypes has been suggested.

Q What is the risk of developing ADEM after vaccination?

Post-vaccination ADEM in adults accounts for about 2.9% of all cases, with an absolute risk of about 0.1%. This is lower than the incidence of ADEM triggered by infections, and the benefits of vaccination are thought to outweigh the risks. ¹⁾

4. Diagnosis and examination methods

Diagnostic criteria

IPMSSG diagnostic criteria (for children) include the following four items.

Multifocal clinical CNS episode presumed due to inflammatory demyelination
Encephalopathy not explained by fever, systemic illness, or postictal state
No new clinical or MRI findings more than 3 months after onset
Acute phase brain MRI abnormalities consistent with demyelination

For adult diagnosis, the IPMSSG criteria are for children, so applying them fails to diagnose more than half of adult cases. ¹⁾

Examination items

MOG antibody: detection by cell-based assay (CBA). Included in MOGAD diagnostic criteria as a core clinical phenotype of ADEM.
AQP4 antibody: Negative is useful for differentiating ADEM from NMOSD.
Other serum tests: CBC, ESR, CRP, ANA, viral serology (HSV, EBV), Mycoplasma, COVID-19
Cerebrospinal fluid analysis: Cell count, protein, oligoclonal bands (see “Clinical Findings” section)
MRI: Brain and spinal cord MRI including T2/FLAIR, DWI, and gadolinium contrast

MRI differentiation points between ADEM and MS

ADEM and MS differ in imaging findings as follows:

Finding	ADEM	MS
Dawson’s fingers	Absent	Present
Periventricular lesions	Tendency to spare	Frequent
Lesion size and shape	Large, poorly defined, bilateral	Small, well-defined
Deep gray matter and cortical lesions	Present	Rare
T1 black holes	Rare	Present (chronic lesions)

Imaging supportive criteria for MOGAD include multiple ill-defined T2 hyperintense lesions, deep gray matter lesions, ill-defined T2 hyperintensity in the pons/middle cerebellar peduncle/medulla oblongata, and cortical lesions.

Differential diagnosis: MS, NMOSD, infectious encephalomyelitis, CNS vasculitis, malignancy

5. Standard treatment

Treatment stages

First-line

High-dose steroid pulse therapy: Methylprednisolone 1 g/day intravenously for 3–5 days, followed by oral taper over 4–6 weeks.

Usage rate: Used in 95.2% (95% CI 87.4–99.7) of adults. ¹⁾

Second-line

Intravenous immunoglobulin (IVIG): Used for steroid-resistant cases.

Usage rate: Used in 16.4% (95% CI 9.2–24.9) of adults. ¹⁾

Third-line

Plasma exchange therapy (TPE/PLEX): Third-line treatment for steroid- and IVIG-resistant cases.

Usage rate: Used in 7.3% (95% CI 2.0–14.7) of adults. ¹⁾ Positioned as second-line treatment in ASFA guidelines. ³⁾

Additional treatment for severe cases

Cyclophosphamide may be used in severe fulminant cases such as AHLE. ⁵⁾ For increased intracranial pressure, cerebral edema management with mannitol and other agents is performed. ⁵⁾

Outcomes of plasma exchange therapy

In a retrospective study of children, progressive improvement including consciousness improvement, seizure resolution, and motor function recovery was observed after 4–5 TPE sessions. ³⁾

In a retrospective study of pediatric ADEM by Bhardwaj et al. (2024), immediate clinical improvement was observed in 95% of TPE-treated cases, and significant improvement at follow-up was achieved in 78%. ³⁾ However, standardized protocols have not been established, and optimization of session number, exchange volume, and replacement fluid remains a future challenge.

Outcomes (adult meta-analysis) ¹⁾

Mortality: 7.8% (95% CI 3.3–13.5)
Residual disability: 47.5% (95% CI 31.8–63.4)
Recurrence rate: 7.2% (95% CI 2.0–20.8)
Mean hospital stay: 23.1 days
Mortality in Asia: 14.5% (highest by region)
Prognosis in children: 60–90% achieve complete neurological recovery ²⁾

Q What if steroids are ineffective?

For steroid pulse-refractory cases, intravenous immunoglobulin (IVIG) is used as a second-line option (adult usage rate 16.4%). For IVIG-refractory cases, plasma exchange (TPE) is a third-line option (adult usage rate 7.3%). ¹⁾ In pediatric studies, immediate clinical improvement was reported in 95% of TPE-treated cases, suggesting that early active introduction may contribute to better outcomes. ³⁾

6. Pathophysiology and detailed pathogenesis

The central mechanism of ADEM pathogenesis is molecular mimicry. Structural similarity between foreign antigens (infectious pathogens) and the host myelin sheath leads to conversion of antigen-specific immune responses into autoimmune reactions.

Main target antigens: MBP (myelin basic protein), MOBP, OSP, MOG, MAG, PLP

Pathogenesis process

Priming phase: Infection disrupts the blood-brain barrier (BBB). BBB disruption involves release of proteases and free oxygen radicals, and increased expression of ICAM-1 and E-selectin (elevated in children with ADEM). Myelin epitopes leak into the peripheral circulation and are presented to T lymphocytes in secondary lymphoid tissues.
Effector phase: Activated myelin-reactive T cells infiltrate the brain parenchyma. Cytokine and chemokine production recruits polymorphonuclear phagocytes and monocytes. TNF-α production, complement activation, ADCC, myelin phagocytosis, oxygen/nitrogen radicals, and CD8+ cytotoxic T cell-mediated axonal damage occur.

Epitope spreading and bystander activation

“Epitope spreading,” in which the immune response diversifies to self-antigens beyond the initial target, and “bystander activation,” where non-specific immune activation due to infection contributes to CNS damage, are also involved in pathogenesis. ³⁾

Histopathological features

Perivenular sleeves of demyelination are characteristic. Infiltrating cells include macrophages, B/T lymphocytes, plasma cells, and granulocytes. Importantly, all lesions are at the same stage of demyelination (a distinguishing point from MS, where lesions of different activity stages coexist).

Relationship with MOGAD pathology

MOGAD is an oligodendrogliopathy, distinct from astrocytopathy (AQP4-targeted NMOSD). Pathological features include CD4-positive T cell-predominant infiltration, granulocyte infiltration, and MOG-containing macrophages. Approximately 50% of ADEM cases are MOG-IgG positive.

Pathology of AHLE

Fulminant AHLE (acute hemorrhagic leukoencephalitis) involves fibrinoid necrosis, necrotizing vasculitis, and hemorrhage, leading to a severe course distinct from typical ADEM. ⁵⁾

7. Latest research and future perspectives (research-stage reports)

Cognitive function and psychopathological outcomes

In a systematic review by Kazzi et al. (2024), cognitive impairments after pediatric ADEM included attention deficits 43%, learning and memory 33%, executive function 30%, and processing speed 27%. ²⁾ The proportion with impairment in at least one cognitive domain ranged from 16% to 66%. Attention deficits have been reported to persist for more than 5 years. A study in Israel found that 44% met ADHD criteria, and elevated depression and anxiety symptoms were also confirmed. Data on cognitive and psychiatric outcomes in adults are currently limited.

Findings on COVID-19-associated ADEM

In a systematic review of 30 cases by Zelada-Ríos et al. (2021), 9 children and 21 adults were analyzed. ⁴⁾ Among children, 77.8% had moderate/severe ADEM, but 77.8% had good outcomes. Among adults, 68.42% had moderate/severe ADEM, and detailed mortality data are limited. ADEM after COVID-19 infection is presumed to involve neuroinvasion by SARS-CoV-2 or immune-mediated mechanisms.

Optimization of Plasma Exchange Therapy Protocols

Standardized protocols for TPE have not yet been established. Optimization of session frequency, exchange volume, replacement fluid, and identification of predictive biomarkers for treatment response are considered important future challenges. ³⁾

Treatment Evidence for MOGAD

High-level evidence-based treatments for MOG antibody-positive ADEM (MOGAD) have not yet been established, but several clinical trials are ongoing.

Q Does cognitive dysfunction remain after ADEM?

It is reported that 16–66% of children have impairment in at least one cognitive domain, with attention deficits being the most common (43%). Attention deficits have also been reported to persist for more than 5 years. ²⁾ Therefore, long-term neuropsychological follow-up is important even after recovery. Data in adults are currently limited.

8. References

Li K, Li M, Wen L, et al. Clinical Presentation and Outcomes of Acute Disseminated Encephalomyelitis in Adults Worldwide: Systematic Review and Meta-Analysis. Front Immunol. 2022;13:870867.
Kazzi C, Alpitsis R, O’Brien TJ, et al. Cognitive and psychopathological outcomes in acute disseminated encephalomyelitis. BMJ Neurol Open. 2024;6:e000640.
Bhardwaj T, Kumar S, Parashar N, et al. Evaluating Therapeutic Plasma Exchange in Pediatric Acute Disseminated Encephalomyelitis: A Comprehensive Review. Cureus. 2024;16(7):e64190.
Zelada-Ríos L, Pacheco-Barrios K, Galecio-Castillo M, et al. Acute disseminated encephalomyelitis and COVID-19: A systematic synthesis of worldwide cases. J Neuroimmunol. 2021;359:577674.
Alsaid HM, Atawneh MAA, Abukhalaf S, et al. Acute Hemorrhagic Leukoencephalitis - A Rare but Fatal Form of Acute Disseminated Encephalomyelitis - Complicated by Brain Herniation: A Case Report and Literature Review. Am J Case Rep. 2022;23:e935636.
Ciçek A, De Temmerman L, De Weweire M, et al. Thunderclap headache as a first manifestation of acute disseminated encephalomyelitis: case report and literature review. BMC Neurol. 2024;24:315.

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