Acute Disseminated Encephalomyelitis

Acute disseminated encephalomyelitis is a disease of the nervous system that results from an exaggerated autoimmune reaction, most commonly after a viral infection.

This disease stems from auto-immune processes.

Presentation

The presentation of acute disseminated encephalomyelitis varies greatly from patient to patient. The disease can exhibit only minimal symptoms in some, whereas in others it can lead to life threatening complications such as failure of the respiratory system. It is usually preceded by a prodromal phase with constitutional symptoms indicative of a viral infection. This phase can last from two days for up to four weeks.

Acute disseminated encephalomyelitis is a monophasic disorder, as it most frequently occurs in a single episode in any individual, without progression or recurrence. Nonetheless, reports involving multiple phases as well as recurrences are present in the medical literature, although their significance has not been fully established.

The disease typically begins with constitutional and non-specific symptoms such as headache, fatigue, tiredness, fever, weight loss, irritability as well as nausea and vomiting. It may also be associated with symptoms of altered mental status, including delirium, stupor, confusion and even coma.

Neurological symptoms are not universal but may occur in a subset of patients and depend greatly on the location of the lesions in the central nervous system. Some of the most commonly reported neurological symptoms are hemiplegia, ataxia, involuntary movements, amnesia, cranial nerve palsies, unilateral numbness and slurred speech. Select patients may also develop psychiatric symptoms such as depression and changes in personality. In addition, visual loss can take place if the inflammation affects the optic nerve and result in optic neuritis.
The peripheral nervous system may also be involved. Most cases, nonetheless, have been reported in adults and rarely in children and adolescents. Typical symptoms are pain, weakness and a burning sensation in the extremities and numbness.

Most patients do not develop all of the symptoms mentioned above. Age of patient also usually influences the presentation. Disturbances in the sensory system generally target adults whereas children suffer more commonly from long term fever and headaches. Seizures are likely to occur in both children and adults.

Workup

Although ADEM was first described almost 250 years ago, diagnostic criteria are still not well defined. History is the cornerstone for diagnosis. Recent efforts have attempted to provide objective criteria to facilitate diagnosis and they include: neurologic findings indicative of central nervous system disseminated disease, history of an infection that may also be completely asymptomatic, absence of recurrence or progression and absence of concurrent infections or metabolic disease. In practice, it is difficult to conclusively establish a history of infection, as ADEM can present sometimes more than a month after the initial infection. Thus, it is commonly diagnosed after other diseases and conditions are excluded.

Imaging with MRI and CSF analysis are usually not sufficient to diagnose acute disseminating encephalomyelitis. MRI, in particular, can exclude other diseases that target the white matter, including infectious, vascular, inflammatory and metabolic conditions. Findings on MRI are similar to multiple sclerosis. There will be increased signal on T2 weighted images, increased enhancement after injection with gadolinium as well as abnormalities after FLAIR signal assessment. Nonetheless, unlike multiple sclerosis, ADEM may show less periventricular involvement, a stronger signal and margins that are not well defined and may involve both the thoracic and cervical spinal cord. In fact, findings in the spinal cord can be more useful in differentiating between the two conditions. Lesions in the spinal cord tend to be more diffuse and present in many parts whereas multiple sclerosis is usually characterized by changes that are restricted to the posterior side on both axial and cross-sectional sections. In addition, lesions with ADEM are continuous and affect several levels, unlike those in multiple sclerosis, which are usually limited to only one level of the spinal cord.

Electroencephalography is usually abnormal, although findings are nonspecific and do not necessarily help in establishing the diagnosis. Common abnormalities include discharges characteristic of epilepsy as well as focal slowing.

Cerebrospinal fluid analysis is generally employed to exclude other conditions. Findings with acute demyelinating encephalomyelitis are nonspecific and include elevated proteins and increased numbers of lymphocytes. It may be completely normal. Cultures are also frequently negative.

Treatment

Treatment aims to decrease and limit inflammation, the main pathophysiological mechanism of the illness. Steroids are the cornerstone of management. High dose methylprednisolone is given for 3 to 5 days, then followed with oral prednisolone for up to 6 weeks. Initial dosage of methylprednisolone is about 10 to 30 mg per kg per day, with a maximum dose of 1 gram per day.

Other options for the treatment of ADEM can also be available. In particular, plasmapheresis and IV immunoglobulin infusion have shown significant benefits in select patients. Usage of both plasmapheresis and IV immunoglobulin is generally reserved for patients who do not respond to corticosteroids or in patients with contraindications to steroids. Guidelines for the management of ADEM have not been defined, and method and treatment of choice in case of non-response to steroids depend on the experience of the neurologist and the general condition of the patient. It should be also noted that, to date, there have been no randomized controlled trials that compared the usage of steroid medication against other options such as plasmapheresis and IV immunoglobulin.

Prognosis

Prognosis of ADEM varies, with complete recovery expected in 50 to 70% of all patients within six months [6]. Nonetheless, death can result and occurs in approximately 5% of all patients [6]. Outlook is generally much more favorable in children than adults and improves with the presence of fever, response to steroids, insidious onset and the absence of severe neurological symptoms [7].

Around 70 to 90% of all patients will exhibit non-significant residual deficits. Furthermore, up to 30% of all patients may suffer from residual motor disabilities that vary considerably in their severity, and can range from clumsiness to hemiparesis [8].

Neurocognitive deficits can also occur and tend to have a predilection for younger patients, although it is unclear if this is caused by the disease itself or hospitalization at a young age, which has been previously shown before to correlate with behavioral problems [9] [10].

Etiology

The causative factors underlying acute disseminated encephalomyelitis are various but mostly include infections with large and enveloped viruses. There is no single virus responsible for the majority of cases but the most frequently involved viruses are Epstein-Barr virus, herpes simplex virus, cytomegalovirus and mycoplasma. Previously, measles was responsible for the majority of infections but advances in immunization have significantly reduced the association. Nowadays, most cases have been correlated with various gastrointestinal or respiratory viruses but, frequently, no identification of a specific organism is made. The disease tends to be more common in the winter season, possibly because of a greater association with viral illness.

The association between ADEM and vaccination remains uncertain. Nonetheless, the Pasteur rabies vaccine has been strongly linked with the disease. In addition, several other vaccines have been also correlated with acute disseminating encphalomyelitis, although the link is not as strong. These include vaccines for tetanus, poliomyelitis, rubella, pneumococcus, diphteria, hepatitis B, influenza, Japanese B virus, smallpox and varicella [1] [2].

The virus or the vaccine are not the only factors responsible for triggering the disease. Patients may be genetically predisposed and may have abnormal immune reactions to the presence of particular foreign antigens. In fact, helper T-cells have been involved in the disease in addition to certain genetic mutations in the HLA system, such as HLA DQB1*0602, DRB1*1501 and DRB1*1503 [3].

Acute disseminated encephalomyelitis usually develops after a prodromal phase, characterized by fever and other non-specific symptoms of viral illness. The prodromal phase and the period associated with the disease are generally separated by a recovery phase, where symptoms are absent. In some cases, acute disseminated encephalomyelitis can develop after more than 30 days from the end of the prodromal phase. The prodromal phase itself can vary between 2 and 21 days, and that greatly depends on the responsible infectious organism, although some viruses are not associated with any prodrome. In general, the longer the recovery phase, the more difficult it is to determine exactly the responsible etiologic factor.

Epidemiology

Most affected patients are either children or adolescents, although the condition occurs in patients in any age. Cases of acute disseminated encephalomyelitis tend to occur more commonly in the winter and spring, usually connected with the seasonal peaks of viral illness [4]. Immunization is a rare cause for acute disseminated encephalomyelitis and is responsible for less than 5% [5].

Sex distribution
Age distribution

Pathophysiology

The pathophysiological mechanisms underlying the disease are still not completely elucidated. ADEM generally results in the demyelination of neurons in the brain. A potential mechanism underlying the disease involves an abnormal inflammatory reaction within the central nervous system that follows an infection or, possibly, an autoimmune disorder. The underlying pathological and histological characteristics are poorly understood, especially because it tends to resolve on its own and biopsies are rarely needed.

The pattern associated with the condition is random and generally closely resembles that of multiple sclerosis. An important difference is that patients usually suffer from only one episode whereas multiple sclerosis is a chronic disease that is either progressive or recurrent.

Prevention

Because ADEM shares some similarities with autoimmune disorders, it has been thought that risk factors for autoimmune disorders may also contribute to the disease. In particular, a significantly decreased exposure to sunlight and infections in childhood has been associated with a remarkable increase in the incidence of autoimmune disorders in the developed world. Nonetheless, the links with ADEM remain very tenuous.

Immunization against measles has played an important role in limiting cases of ADEM and diseases on a similar spectrum such as acute hemorrhagic leukoencephalitis.

Summary

Acute disseminating encephalomyelitis (ADEM) is a demyelinating disease that is thought to occur after acquiring an infectious illness, particularly with viral organisms. The condition has been most strongly associated with measles, mumps, and rubella but is also thought to occur occasionally after immunization. The underlying mechanisms are poorly understood, but scientists hypothesize that a genetic predisposition, in combination with an infection, result in a dysregulated immune response that ultimately attacks the nervous system and leads to demyelination. Patients present with a range of findings, with most cases being preceded by a prodromal phase with nonspecific symptoms such as fever, fatigue, weight loss and headaches. Neurologic abnormalities occur in some patients and vary significantly depending on the location and the extent of the lesions. Diagnosis is established mostly with history, and frequently made by exclusion. Magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analyses are sometimes performed to rule out other diseases and to assess the distribution of the associated lesions. Treatment is with corticosteroids, although intravenous immunoglobulin and plasmapheresis can be beneficial in patients who fail to respond to steroids.

Patient Information

Acute disseminated encephalomyelitis is a disease of the nervous system that most commonly occurs after an infection with a virus or immunization with a vaccine. The mechanisms underlying the condition are still poorly understood, but it is thought that the immune system develops an exaggerated response and attacks the myelin sheath. The latter is a substance that envelops nerve cells to ensure proper transmission of electrical messages within them. Several diseases have been associated with the disease, especially mumps, measles and rubella. Patients present initially with a prodromal viral illness and exhibit nonspecific symptoms such as fever, weight loss and fatigue. Later neurological occurrences can take place and vary greatly from patient to patient. Diagnosis is mostly established with history. MRI and analysis of the cerebrospinal fluid can both aid in the exclusion of other diseases and in the assessment of the extent of the disease. Acute disseminated encephalomyelitis is most commonly treated with corticosteroids.

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References

  1. Chowdhary J, Ashraf SM, Khajuria K. Measles with acute disseminated encephalomyelitis (ADEM). Indian Pediatr. 2009 Jan; 46(1):72-4.
  2. Cohen SR, Brooks BR, Herndon RM, McKhann GM. A diagnostic index of active demyelination: myelin basic protein in cerebrospinal fluid. Ann Neurol. 1980 Jul; 8(1):25-31.
  3. Alves-Leon SV, Veluttini-Pimentel ML, Gouveia ME, et al. Acute disseminated encephalomyelitis: clinical features, HLA DRB1*1501, HLA DRB1*1503, HLA DQA1*0102, HLA DQB1*0602, and HLA DPA1*0301 allelic association study. Arq Neuropsiquiatr. 2009 Sep; 67(3A):643-51.
  4. Lee YJ. Acute disseminated encephalomyelitis in children: differential diagnosis from multiple sclerosis on the basis of clinical course. Korean J Pediatr. 2011 Jun;54(6):234-40.
  5. Young NP, Weinshenker BG, Lucchinetti CF. Acute disseminated encephalomyelitis: current understanding and controversies. Semin Neurol. 2008 Feb;28(1):84-94.
  6. Menge T, Kieseier BC, Nessler S, Hemmer B, Hartung HP, Stüve O. Acute disseminated encephalomyelitis: an acute hit against the brain. Curr Opin Neurol. 2007 Jun;20(3):247-54.
  7. Lin CH, Jeng JS, Hsieh ST, Yip PK, Wu RM. Acute disseminated encephalomyelitis: a follow-up study in Taiwan. J Neurol Neurosurg Psychiatry. 2007 Feb;78(2):162-7.
  8. Tenembaum S, Chitnis T, Ness J, Hahn JS. International Pediatric MS Study Group. Acute disseminated encephalomyelitis. Neurology. 2007 Apr 17;68(16 Suppl 2):S23-36.
  9. Douglas JW. Early hospital admissions and later disturbances of behaviour and learning. Dev Med Child Neurol. 1975 Aug;17(4):456-80.
  10. Daviss WB, Racusin R, Fleischer A, Mooney D, Ford JD, McHugo GJ. Acute stress disorder symptomatology during hospitalization for pediatric injury. J Am Acad Child Adolesc Psychiatry. 2000 May;39(5):569-75.

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