ADEM, Acute disseminated encephalomyelitis entities

Clinic

• Other name: Acute demyelinating encephalomyelitis
• It is a rare autoimmune disease marked by a sudden, widespread attack of inflammation in the brain and spinal cord.
• It is characterized by a brief but widespread attack of inflammation in the brain and spinal cord that damages myelin.
• ADEM's symptoms resemble the symptoms of MS
• ADEM has several features that distinguish it from MS. Unlike MS, ADEM occurs usually in children
• ADEM particularly attacks white matter, usually subcortical and central white matter and cortical gray-white junction of both cerebral hemispheres, cerebellum, brain-stem, and spinal cord. Periventricular White / Gray matter of the cortex, thalami and basal ganglia may also be involved.
• Recurrent disseminated encephalomyelitis / Multiphasic disseminated encephalomyelitis (MDEM): When a person has more than one demyelinating episode of ADEM
• Genetic susceptibility, environmental factors, and the myelination process seem to influence the wide phenotypic variability of MOG-related syndromes.

• ADEM has an abrupt onset and a monophasic course.
• Symptoms usually begin 1–3 weeks after infection.
• Although initially the symptoms are usually mild, they worsen rapidly over the course of hours to days, with the average time to maximum severity being about four and a half days

Sign / Symptoms

• Weakness of lower extremity/upper extremity (17 – 77%) (Hemiparesis , Paraparesis)
• Ataxia (10 – 52%)
• Cranial nerve palsies (11 – 48%)
• Optic neuritis (7-23%)
  • They may present with unilateral or bilateral optic neuritis and may complain of subacute vision loss, pain with eye movement, and dyschromatopsia.
  • Optic disc edema may also be present.
  • Bilateral optic neuritis presents more frequently in ADEM than in MS.
  • Patients with ADEM or MDEM can also develop subsequent attacks of optic neuritis.
  • When recurrent optic neuritis follows a diagnosis of ADEM or MDEM, the disease entity is called ADEM-ON.
  • The visual acuity may be poor, with one study showing a median visual acuity of 20/600 in patients with ADEM and optic neuritis.
  • Additionally, 2 case reports have shown peripapillary hemorrhage in patients presenting with optic neuritis.
  • Cases of uveitis preceding ADEM have also been reported in a 69-year-old and a 17-year-old girl.

• Seizures (4 – 48%)
• Fever (27 – 63%)
• Headache and/or vomiting (15 – 37%)
• Meningeal signs (13 – 43%)

Encephalopathy

• Patients with cortical involvement may experience more profound states of encephalopathy, as the cerebral cortex is responsible for higher levels of sensory processing.

Occipital lobe

• Lesions affecting the occipital lobe and visual cortex may result in homonymous visual field defects and other cortical visual disturbances, including cortical blindness if severe and bilateral.

Cerebral cortex (other parts)

• Aphasia, alexia, agraphia, or acalculia
• Focal loss of motor or sensory function that can be localized to lesions along the motor or sensory homunculus.
• Motor cortex: Upper motor neuron signs (hyperreflexia, spasticity, Babinski sign, pronator drift)
• Symptoms of higher order sensory loss such as agraphesthesia and astereognosia, loss of proprioception, light touch, and pain and temperature.

Brain-stem

• Difficulties with functions of the cranial nerves III-XII, as well as dysfunction in the white matter tracts that course through the brainstem. This includes diplopia from cranial nerve palsies or inflammation of the gaze control centers causing impaired extraocular movements. Patients can also experience dysphagia, dysarthria, nystagmus, nausea/vomiting, vertigo, ataxia, hearing impairment, loss of taste and smell, focal motor impairments, impaired consciousness, and respiratory failure. Patients with brainstem involvement usually have a fulminant disease course with a worse prognosis compared with those without lesions in the brainstem.

Atypical symptoms

Atypical symptoms include

• Persistent headache or meningeal signs,
• Stroke-like events
• Recurrent seizures
• Dystonia or Parkinsonism
• Neuropsychiatric symptoms
• Progressive onset, and recurrent encephalopathic events.. There is one case report of "pathologic yawning" that is hypothesized to be secondary to brainstem or hypothalamic lesions. Although common in NMOSD, this symptoms is rare in ADEM but resolves with IV steroids.

Recent research

• In a recent case series study on 14 children, the common presenting symptoms were fever, vomiting, headache, gait disturbance and generalized seizures.
• Neurological manifestations included altered sensorium, multiple cranial nerve involvement, quadriplegia and paraplegia, dystonia and choreiform movements, nystagmus, bladder involvement (both incontinence and retention), speech defect and double vision.
• Facial nerve was the most common cranial nerve involved.
• Psychological manifestations included aggressive behavior, psychotic symptoms and mood changes.

Pathophysiology

While pathogenesis of ADEM has not been fully delineated, the prevailing theory suggests that antigenic exposure in genetically susceptible individuals could cause the disease through mechanisms involving molecular mimicry and/or T-cell mediated inflammation. Molecular mimicry occurs when close homology of an exogenous antigen to host tissue (e.g., myelin sheath) induces an autoimmune reaction to native tissue. Antigenic exposures from infections or vaccines cause the body to form antibodies against epitopes that resemble molecules found in the CNS. Proposed endogenous targets include myelin basic protein (MBP), myelin-associated oligodendrocyte basic protein (MOBP), oligodendrocyte specific protein (OSP), myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein (MAG), and proteolipid protein (PLP). The resultant autoimmune reaction stimulated by autoantibodies has been hypothesized to lead to ADEM.

A second hypothesis involves CNS injury secondary to generalized inflammation from a viral infection. In the priming phase, an offending infection disrupts the blood-brain barrier, allowing host myelin epitopes to enter the peripheral vascular circulation. These myelin epitopes are presented via antigen-presenting cells to T lymphocytes in secondary lymphoid tissues, creating myelin-reactive T lymphocytes that are now poised to attack host myelin upon encountering this endogenous host tissue. In the setting of ongoing inflammation, these myelin-reactive T cells encounter their derivative antigen (host myelin epitopes) on the major histocompatibility class II complexes of antigen-presenting cells in the perivascular spaces. This activates the myelin-reactive T lymphocytes, allowing them to cross into the brain parenchyma. This leads to the effector phase, when activated T cells promote the production of cytokines and chemokines via antigen-presenting cells, recruiting polymorphonuclear phagocytes and monocytes. Proteases and free oxygen radicals released by these leukocytes break down the blood-brain barrier, allowing stronger inflammatory processes to cause demyelination of the CNS. The transmigration of lymphocytes is thought to be further aided by increased expression of adhesion molecules such as Intercellular Adhesion Molecule 1 (ICAM-1) and E-selectin, and higher levels of these molecules have been reported in children with ADEM. Inflammatory, demyelinating processes observed in the animal models that are proposed to drive the pathogenesis of ADEM include the production of tumor necrosis factor-alpha, complement activation, antibody-dependent cell-mediated cytotoxicity (ADCC), myelin phagocytosis, oxygen and nitrogen free radicals, CD8+ cytotoxic T-cell-mediated axonal injury, protease secretion, and oligodendrocyte apoptosis. Evidence supporting an inflammatory component to the pathogenesis includes elevated CSF cytokines and chemokines in patients with ADEM. ^[35]

Recent research proposes that some patients possess a genetic predisposition to ADEM, which potentially explains why certain individuals may be more likely to develop ADEM following infection or vaccination. Case series in Russia, Korea, and Brazil have shown that children with certain human leukocyte antigen (HLA-DR) subtypes have a higher frequency of ADEM than children with other subtypes.

A key histopathologic finding in ADEM is perivenular sleeves of demyelination, caused by infiltration of inflammatory cells such as macrophages, B and T lymphocytes, plasma cells, and granulocytes. As demyelination continues, these perivenular lesions can grow larger and merge, forming the massive, globular lesions characteristic of ADEM. This is in contrast to the confluent demyelination seen in MS, where sheets of macrophages intermixed with reactive astrocytes infiltrate completely demyelinated areas in a layer-like pattern. Another key difference on biopsy is that the lesions in ADEM will all be in the same stage of demyelination, while in MS both active and inactive lesions exist simultaneously.

Causes

Since the discovery of the anti-MOG specificity against multiple sclerosis diagnosis it is considered that ADEM is one of the possible clinical causes of anti-MOG associated encephalomyelitis.

About how the anti-MOG antibodies appear in the patients serum there are several theories:

• A preceding antigenic challenge can be identified in approximately two-thirds of people.
• Some viral infections thought to induce ADEM include INFL (H1N1) , DHF, enterovirus , RBOL , MMP, RBL, VZV, EBV,, CMV , HSV , HAV CXB HHV-6, HCV, HIV, WNE and HTLV-1, SARS, COV-19.
• Bacterial infections include Mycoplasma pneumoniae, Borrelia burgdorferi, Leptospira, and beta-hemolytic Streptococci, Campylobacter jejuni, Chlamydia pneumoniae, Legionella pneumoniae Leptospira spp
• Among parasites, Falciparum malaria, Vivax malaria, and Toxoplasmosis spp.,
• Vaccination causes Rabies, measles mumps and rubella (MMR), polio (oral), influenza, H1N1, Japanese encephalitis, diphtheria pertussis tetanus (DPT), tetanus toxoid, smallpox, yellow fever, meningococcal, human papilloma virus, and hepatitis B and SARS COVID vaccines.

ADEM Rubric / Miasms

	Ataxia	Seizure	Coma	Hemiplegia	Blindness	Emotinal lability (Pseudobulbar affect)	Sleepiness	Face Palsy	Chorea	Urine incontinence	Nystagmus	Diplopia
JE	+++	+++	+++	+++	+++		+++	+++	+++
TBE	+++	+++	+++	+++		+++	+++	+++		+++
STLE	+++		+++			+++	+++			+++	+++	+++

Related disease

• MS
• Acute hemorrhagic leukoencephalitis