Acute Disseminated Encephalomyelitis

Description

Acute Disseminated Encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder of the central nervous system, typically following a viral infection or vaccination. It is characterised by widespread demyelination, primarily affecting the white matter of the brain and spinal cord.

Pathogenesis

The exact pathogenesis is not well understood, but it is believed to follow a viral infection or vaccination, suggesting a mechanism of immune-mediated response to the myelin components of the CNS. Molecular mimicry, in which viral or vaccine antigens resemble the structure of myelin proteins, might lead the immune system to target myelin, leading to an acute but usually monophasic process of demyelination. The demyelination is typically perivenular, accompanied by infiltration of immune cells, predominantly T lymphocytes and macrophages. As the immune cells attack the myelin sheaths surrounding the nerve fibres, neurological deficits develop correlating with the areas of the CNS affected. Over time, the inflammation may subside, leading to some degree of spontaneous remyelination and clinical recovery, although the extent of this is highly variable.

Variants

• Typically monophasic (one episode only) or multiphasic (multiple episodes over time).
• Acute haemorrhagic leukoencephalopathy (AHLE or Weston-Hurst disease) – fulminant, often fatal, variant of ADEM that causes multifocal brain haemorrhages

Epidemiology, Risk Factors & Associations

ADEM primarily affects children, with the majority of cases seen in those under 10 years of age. It’s a rare condition, with an incidence of approximately 0.8 per 100,000 population. There is no significant gender difference.

A history of recent infection (particularly measles or varicella) or vaccination is typically seen (60-75% of cases).

• Viral infections: Measles and varicella (chickenpox) are well-known triggers (15-20% of paediatric cases). Other implicated viruses: Epstein-Barr virus (EBV), influenza, and enteroviruses. Infections typically precede the onset of ADEM by one to two weeks.
• Bacterial infections: Less commonly, bacterial infections such as group A streptococcus, mycoplasma pneumoniae, and borrelia burgdorferi (Lyme disease) have also been associated with ADEM.
• Vaccinations: Particularly those against measles, mumps, and rubella (MMR). Rare event (< 1 in 1,000,000 vaccinations). Other vaccines: influenza, diphtheria, pertussis, and tetanus.

Environmental factors may play a role as well, with a higher incidence reported in winter and spring months, possibly due to increased prevalence of viral infections during these times.

Clinical Features

Patients with ADEM usually present with a rapid onset of neurological symptoms, typically one to two weeks following an infection or vaccination. The presentation is often a constellation of symptoms, which may include:

• Multifocal neurologic symptoms such as weakness, ataxia, and visual changes.
• Encephalopathy, manifesting as behavioural changes, confusion, or drowsiness.
• Fever and headache are also common.

Complications

Potential complications of ADEM include permanent neurologic disability due to extensive demyelination, which can result in weakness, cognitive impairment, and visual deficits. In severe cases, seizures, coma, and even death can occur.

Pathological Features

Gross

• Characterised by widespread, asymmetrical, multifocal inflammation and demyelination primarily in the white matter of the brain and spinal cord.
• Preference for the subcortical and central white matter, basal ganglia, thalami, and brainstem.

Histopathology

• Pathological hallmark of perivenular inflammation with sleeves of demyelination.
• Inflammation predominantly comprises T lymphocytes and macrophages, forming inflammatory cuffs around small veins and venules.
• ‘Sleeves of demyelination’ around blood vessels – a feature shared with multiple sclerosis, however, multiple sclerosis also displays confluent sheets of macrophage infiltration with reactive astrocytes in completely demyelinated regions.
• Demyelination often described as ‘patchy’ or ‘focal’, associated with relative axonal preservation.
• Demyelinated areas contain lipid-laden macrophages, indicating their involvement in myelin breakdown.

Biochemistry

• Cerebrospinal fluid (CSF) often exhibits mild to moderate pleocytosis (increased cell count), predominantly lymphocytes.
• In around half of ADEM cases, an increase in myelin basic protein is seen in the CSF, indicating active demyelination.

Genetics

• ADEM not associated with specific genetic mutations but involves a dysregulated immune response.
• In about 50% of confirmed ADEM cases, anti-myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G antibodies can be identified.

Immunohistochemistry

• No definitive immunohistochemical marker for ADEM currently.
• Presence of anti-MOG antibodies supports the diagnosis.
• Increased T lymphocytes and macrophages in affected areas

Radiological Features

General Features

• Characteristic multiple asymmetrical lesions located in the subcortical and central white matter of the supratentorial or infratentorial brain.
• Lesions can be small punctate lesions to tumefactive regions and may also involve grey matter structures such as the basal ganglia and thalami.
• The spinal cord can be involved with confluent intramedullary lesions.
• Lesions mature with variable degrees of enhancement.
• In more severe cases, petechial haemorrhage can be seen.
• Compared to MS, ADEM lesions tend be larger, more rounded, and less well-defined and do not typically arise from the callososeptal interface

MRI

• T2WI/FLAIR: High signal intensity in the white matter of the brain and spinal cord, reflecting areas of demyelination. The lesions are typically asymmetrical and can vary in size. They may appear fluffy and may be associated with surrounding oedema.
• T1WI C+: Enhancement can be seen in active lesions, suggesting breakdown of the blood-brain barrier. Some lesions may have a linear appearance suggesting enhancement may be perivenular.
• DWI: Peripheral rim of restricted diffusion may be seen.
• SWI: Multifocal blooming artefact representing brain haemorrhages may be seen in the fulminant variant of ADEM, acute haemorrhagic leukoencephalopathy.

CT

Non-specific findings of hypoattenuating white matter lesions may be seen, but CT is less sensitive than MRI for detecting the lesions typical of ADEM.

Grading and Staging

There is no specific grading or staging system for ADEM. The severity of the disease can be assessed clinically and radiographically based on the number and extent of demyelinating lesions.

Differential Diagnosis

• Multiple Sclerosis (MS): Typically presents with a more insidious onset, smaller and well-defined lesions on imaging, and oligoclonal bands on cerebrospinal fluid analysis. Presents with periventricular white matter lesions, following the Dawson’s fingers pattern, and Gd-enhancing lesions that are less than 2 vertebral segments in length. Lesion ares separated in both time and space. Clinical course is polyphasic.
• Neuromyelitis Optica (NMO): Can also cause transverse myelitis and optic neuritis (usually bilateral and severe). But NMO often has longitudinally extensive transverse myelitis (LETM) and positive aquaporin-4 antibodies. MRI shows longitudinally extensive transverse myelitis, often greater than 3 vertebral segments in length.
• Viral encephalitis: Can be differentiated by a more acute presentation, focal rather than multifocal neurologic deficits, and presence of specific pathogens in the cerebrospinal fluid. MRI may show focal lesions with T2/FLAIR hyperintensities and contrast enhancement that are often in the temporal lobes for herpes simplex virus encephalitis. The presence of meningeal enhancement may suggest an inflammatory process.

Management

• High-dose corticosteroids are the first-line treatment to reduce inflammation and hasten recovery.
• In severe or refractory cases, intravenous immunoglobulin (IVIG) or plasma exchange may be used.
• After the acute phase, physical and occupational therapy may be required to manage residual disability.
• In the case of a multiphasic course, long-term immunosuppression may be required.