Acute disseminated encephalomyelitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]: Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2] Shameera Shaik Masthan MBBS, DLO, DNB[3]

Acute disseminated encephalomyelitis (ADEM) is an acute neurologic disease of the central nervous system characterized by scattered foci of demyelination and perivascular inflammation. The disease may occur withoutprecipitant, or may develop after infection or vaccination.

Encephalomyelitis was primarily an experimental finding discovered after injection of rabbits with rabbit spinal cord infused with solutions of sodium chloride and lecithinase, adjuvants, like [[bayol F],] and killed tubercle bacilli, and human spinal cord treated with formaldehyde solution. Clinical signs were spasticity, ataxia, weakness and even death. The perivascular inflammatory lesions had a predilection for the white matter and demyelination was seen in all ages. Older lesions had glial scars.

Acute disseminated encephalomyelitis can occur after an episode of infection (post-infectious), vaccination or even, spontaneously without an obvious trigger (idiopathic).

The exact mechanism of acute disseminated encephalomyelitis is not determined. However, it is usually preceded by an environmental trigger, e.g. an infection or vaccination and affects individuals with a genetic predisposition.

In the past, ADEM was a sequelae of common childhood infections like measles, smallpox and chickenpox. With the improvements in infectious disease management practices, ADEM in developed countries frequently follow non-specific upper respiratory tract infections. Failure to identify a definite cause could suggest that the inciting agents are unusual and not recovered by standard laboratory tests. ADEM is much more common in the developing countries where measles and other viral infections still account for a major proportion of cases.

Another common variant is the postimmunisation encephalomyelitis, which has a preference for the peripheral nervous system. Currently, the most common implicated vaccines are measles, mumps and rubella. The risk of the condition developing after measles vaccination is considerably lower than the natural infection.

The differential diagnoses of Acute disseminated encephalomyelitis include:

• Viral encephalitis
• HIV encephalopathy
• Multiple sclerosis
• Antiphospholipid antibody syndrome

The average annual incidence of ADEM is between 0.07 and 0.6 per 1,00,000 individuals per year. It is more common during childhood, with a median age on onset between 5-8 years and a male predominance (1.8:1).

The risk factors for ADEM include:

• Infections (most common)
• Vaccinations
• Genetic predisposition

There is no screening tool currently used for Acute disseminated encephalomyelitis.

The classic form, accounting for 70-90% of cases, typically follows a monophasic pattern. Residual severe disability is quite rare in pediatric ADEM cases (7%). Adult patients frequently suffer from residual ataxia, clumsiness, hemiparesis or epilepsy. The poor prognosis and long-term outcomes of ADEM have changed dramatically owing to efficient vaccination coverage and widespread, early use of high-dose steroids.

MRI is the best method for further evaluation after an initial suspicion of ADEM. MRI brain with gadolinium enhancement is indicated in stable patients whereas, MRI of the dorsal and cervical spinal cord can determine the extent of inflammation in symptoms and signs suggestive of myelopathy.

Classic ADEM is monophasic, with a history of usually a preceding illness or less commonly, a vaccination. It is characterised by an acute onset of focal neurologic symptoms, often with rapid deterioration of consciouness, after a variable latent period of several days to few months.

Physical examination of ADEM may reveal positive findings in different parts of the nervous system namely, the cerebral cortex, brainstem, cranial nerves and the sensory and motor tracts. Respiratory failure may prove fatal in some cases.

Antibodies like anti-MOG antibodies are found in the serum of patients suffering from ADEM. A lumbar puncture is also useful for evaluation of the changes in the Cerebrospinal fluid (CSF).

The appearance of ADEM on cranial CT has rarely been reported. There is a delay between the onset of the clinical signs and the appearance of lesions on CT scan. The correlation was limited between the clinical course and the anatomical distribution and type of abnormality seen on CT scan.

MRI is the best method for further evaluation after an initial suspicion of ADEM. MRI brain with gadolinium enhancement is indicated in stable patients whereas, MRI of the dorsal and cervical spinal cord can determine the extent of inflammation in symptoms and signs suggestive of myelopathy.

Many experts discourage diagnostic biopsies in the absence of structured histopathological guidelines. Nevertheless, typical lesions of ADEM may be identified by histopathology anywhere in the white matter of brain and spinal cord.

The analogy between the pathogenesis of ADEM and MS forms the basis of the use of high-dose steroids, plasma exchange and intravenous immunoglobulin for the treatment of ADEM.

Surgical interventions can be helpful for managing complications like cerebral edema, optic neuritis and elevated intracranial pressure. The options include:

• Decompressive hemi-craniectomy
• Bilteral optic nerve sheath decompression]]
• Lumboperitoneal shunting

The management protocol for ADEM does not routinely include strategies for primary prevention.Case reports and literature reviews have highlighted the importance of early MRI scans of the brain as a guide for immediate intervention for ADEM.Plasmapheresis should be considered early in the disease course for severe or life-threatening cases of ADEM.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

Encephalomyelitis was primarily an experimental finding discovered after injection of rabbits with rabbit spinal cord infused with solutions of sodium chloride and lecithinase, adjuvants, like [[bayol F],] and killed tubercle bacilli, and human spinal cord treated with formaldehyde solution. Clinical signs were spasticity, ataxia, weakness and even death. The perivascular inflammatory lesions had a predilection for the white matter and demyelination was seen in all ages. Older lesions had glial scars.

In the year 1933, Rivers, Sprunt and Berry observed encephalomyelitis and demyelination in monkeys after serial injections of extracts and saline suspensions of normal rabbit brain.This finding was further confirmed in 1940 by Ferraro and Jervis. In their experiments, the monkeys exhibited forced head position, nystagmus, tremor, spastic paresis. The lesions were distributed throughout the central nervous system with a predilection for white matter. They were perivascular and contained multinucleated giant cells.

Schwentker and Rivers demonstrated that the antigenicity of nervous tissue increased with age and was more characteristic of the white matter. It hinted towards a possible antigenic property of lipid-rich myelin sheath.

Morgan reproduced extensive encephalomyelitis in monkeys by using heat-killed turbercle bacilli. The reaction time for producing changes was reduced by Kabat, Wolf and Bezer who employed heterologous antigen.

Alpha –lecithinase of Clostridium welchii has also been shown to damage the myelin sheath in vitro.

More recent studies showed development of encephalomyelitis regardless of the potency or nature of the injected antigen. A pervivascular hematogenous insterstitial infiltrate gradually evolved to demyelination, fatty degeneration and astrocytic scar formation. It is possible that some of the antibodies originated in the Virchow-Robin spaces which then migrated across at least the blood–cerebrospinal fluid barrier, suggested by Greenfield in his report of post-vaccination encephalomyelitis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

Acute disseminated encephalomyelitis can occur after an episode of infection, vaccination or even, spontaneously without an obvious trigger.

• The predominant variety, usually with an identifiable trigger ^[1]
• Viral causes include [[measles], mumps , influenza, herpes viruses, rubella, Hepatitis viruses, HIV^[2].
• Bacterial causes include Mycoplasma, Chlamydia, Legionella, Campylobacter, Streptococcus^[2].

• Implicated vaccines are Rabies, DPT, Smallpox, Measles, Japanese encephalitis, Polio, Hepatitis B, Influenza^[2].
• Less significant over the years, probably due to changes in the methods of vaccine production ^[3]

The absence of a precedent has been reported in up to 26% of cases ^[4].

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

The exact mechanism of acute disseminated encephalomyelitis is not determined. However, it is usually preceded by an environmental trigger, e.g. an infection or vaccination and affects individuals with a genetic predisposition.

• Acute disseminated encephalomyelitis is described as an autoimmune disorder, resulting in central nervous system demyelination.Enviromental stimuli activate cellular and humoral responses which cross-react with myelin autoantigens namely, myelin basic protein, myelin oligoendrocyte protein, proteolipid protein.
• In an alternative mechanism, post-vaccination and post-infective circulating immune complexes in the CNS give rise to an inflammatory reaction, resulting in increased vascular permeability and congestion. This disrupts the blood– brain barrier, allowing infiltration by antigens and mononuclear cells. They cause perivascular edema and hemorrhage which culminate in demyelination, necrosis and gliosis. Although typically observed in white matter, gray matter involvement is also seen in basal ganglia, thalamus and cerebral cortex^[2].
• Some of the vaccine-associated cases can be attributed to the contamination of the vaccine with CNS tissue, reported for the Semple vaccine for rabies^[3] and the vaccine strains of Japanese encephalitis^[4].

• CNS tissue is damaged by direct infection by a neurotropic pathogen, resulting in leakage of autoantigens through a disrupted blood-brain barrier.
• The auto-antigens are processed in systemic lymphatic organs, leading to tolerance breakdown and a self-reactive encephalitogenic T-cell response.
• Such activated T-cells perpetuate a vicious cycle of further CNS damage and inflammation.

• It is attributed to a structural or partial amino acid sequence homology between the foreign pathogen and the myelin proteins of the host.
• Antigen-presenting B cells or dendritic cells process the antigen at the site of inoculation, leading to T-cell stimulation, which may cross-activate production of antigen-specific B cells.
• Both T-cells and B-cells are capable to entering the CNS and encounters the indigenous myelin proteins during routine CNS surveillance.
• They may become reactivated by local antigen-presenting cells such as the microglia, inciting an inflammatory response against the presumed foreign antigen.
• Thus, the initial physiologic response culminates in detrimental autoimmunity.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

In the past, ADEM was a sequelae of common childhood infections like measles, smallpox and chickenpox. With the improvements in infectious disease management practices, ADEM in developed countries frequently follow non-specific upper respiratory tract infections. Failure to identify a definite cause could suggest that the inciting agents are unusual and not recovered by standard laboratory tests. ADEM is much more common in the developing countries where measles and other viral infections still account for a major proportion of cases.

Another common variant is the postimmunisation encephalomyelitis, which has a preference for the peripheral nervous system. Currently, the most common implicated vaccines are measles, mumps and rubella. The risk of the condition developing after measles vaccination is considerably lower than the natural infection.

ADEM is currently seen most commonly after a bout of viral infection of the respiratory and gastrointestinal tracts. However, in the majority of cases, the aetiology remains unknown ^[1], ^[2].

• Cytomegalovirus
• Epstein-Barr virus
• Herpes simplex
• Measles
• Mumps
• Rubella
• Varicella
• Influenza
• HepatitisA, B
• HIV

• Mycoplasma
• Leptospira
• Beta-hemolytic streptococci
• Borrelia
• Chlamydia
• Legionella
• Campylobacter

• Rabies (the earliest vaccine associated with ADEM)
• Measles
• Mumps
• Rubella
• Varicella
• Smallpox
• DPT
• Polio
• Hepatitis B
• Influenza
• Japanese B encephalitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

The differential diagnoses of Acute disseminated encephalomyelitis include:

• Viral encephalitis
• HIV encephalopathy
• Multiple sclerosis
• Antiphospholipid antibody syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

The average annual incidence of ADEM is between 0.07 and 0.6 per 1,00,000 individuals per year. It is more common during childhood, with a median age on onset between 5-8 years and a male predominance (1.8:1).

• Average annual incidence is between 0.07 and 0.6 per 1,00,000 individuals per year^{[1] [2][3]}.
• Population-based studies revealed a slightly lower incidence in the US and UK compared to Asian countries. The incidence of pediatric ADEM varies between 0.47/100000 and 0.64/100000 in the Asian countries ^[2][3] compared to 0.07/100000 and 0.30/100000 in Europe and San Diego ^[3][4][5] .
• The incidence seems to be increasing with the distance from the Equator^[6].

• ADEM is more common during childhood with a median age of onset between 5-8 years and a male predominance (1.8:1)^[7].
• The adult age of presentation ranges from 33 to 41 years without any gender preference.
• No specific ethnic distribution has been described.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

The risk factors for ADEM include:

• Infections (most common)
• Vaccinations
• Genetic predisposition

• The pathogens remain mostly unknown^[1].
• The prodromal phase is characterised by flu-like symptoms (56-61%) and non-specific upper respiratory or gastrointestinal manifestations. The latent period varies from 4 to 41 days^[2].
• Viral exanthems usually precede the onset of pediatric ADEM^[3].
• The most common associated pathogens are viruses namely, Epstein-Barr, measles, mumps, rubella and coxsackie B^[4]. Bacteria like Borrelia burgdorferi, Legionella and Mycoplasma are infrequently reported^[5][6].

• Immunisation is the precipitating factor for less than 5% of ADEM cases^[7].
• The most frequent occurrences are with measles, mumps and rubella vaccines^[8].
• The latent period varies from 2 to 30 days^[8].

• An association between ADEM and HLA-DR genes has been elucidated in a recent study^[9].
• Patients with congenital adrenal hyperplasia or acquired adrenal insufficiency have been reported to suffer from sequelae of encephalopathy with white matter lesions^[10].

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

There is no screening tool currently used for Acute disseminated encephalomyelitis.

There is no screening tool currently used for Acute disseminated encephalomyelitis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

The classic form, accounting for 70-90% of cases, typically follows a monophasic pattern. Residual severe disability is quite rare in pediatric ADEM cases (7%). Adult patients frequently suffer from residual ataxia, clumsiness, hemiparesis or epilepsy. The poor prognosis and long-term outcomes of ADEM have changed dramatically owing to efficient vaccination coverage and widespread, early use of high-dose steroids.

• The classic form, accounting for 70-90% of cases, typically follows a monophasic pattern^[1][2]. However, multiphasic disease progression (M-ADEM) has also been previously reported^[3].
• The lag period between onset to first relapse can vary from 2 months to 8 years^[2], with one case showing recurrence after three decades^[4].
• Most of M-ADEM patients demonstrate resolution of lesions with no neurological sequelae on long-term clinical and imaging follow-up^[5].
• MRI of patients with co-existent M-ADEM and anti-MOG antibodies typically reveal no new lesions in the asymptomatic period^[6].

• Residual severe disability is quite rare in pediatric ADEM cases (7%)^[7].
• 20-30% of pediatric cases, usually with onset before five years of age, exhibit residual neurologic deficits, especially cognitive impairment in attention and execution^[3]. Personality and behavioral changes may also be present.
• Adult patients frequently suffer from residual ataxia, clumsiness, hemiparesis or epilepsy^[2]. They also have an increased rate of hospitalization, ICU admissions, and mortality.

• The poor prognosis and long-term outcomes of ADEM have changed dramatically owing to efficient vaccination coverage and widespread, early use of high-dose steroids^[8][9].
• The average recovery period varies from 1 to 6 months^[10], with some cases having a per-acute onset or a prolonged disease course^[11][12].
• About 65-85% of pediatric ADEM cases exhibit a favourable prognosis with a good functional recovery within a few weeks. Clinical improvement is visible within days of starting treatment^[13].
• Prognostic factors for a relapse of ADEM include coexistent optic neuritis, MRI findings similar to multiple sclerosis, and a history of CNS disorders in the family^[14].

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