Definitions

disseminated

multiple sclerosis

Disease of the brain and spinal cord in which gradual, patchy destruction of the myelin sheath of nerve fibres causes interruption or disordered transmission of nerve impulses. Its early symptoms may include limb weakness or trembling, visual problems, sensory disturbances, unsteady walking, and defective bladder control, which come and go irregularly. Attacks grow more severe, and some symptoms become permanent, sometimes with eventual complete paralysis. Average survival from onset is about 25 years, but a rare acute form progresses over months. The cause remains uncertain and treatment unsatisfactory. Corticosteroids may ease symptoms. MS may be due to a delayed immune response that attacks the myelin sheaths; suggested causes include various common viruses. Dietary causes have also been suggested.

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Acute disseminated encephalomyelitis (ADEM) is an immune mediated disease of the brain. It usually occurs following a viral infection but may appear following vaccination, bacterial or parasitic infection, or even appear spontaneously. As it involves autoimmune demyelination, it is similar to multiple sclerosis, and is considered part of the Multiple sclerosis borderline diseases. The incidence rate is about 0.8 per 100,000 people per year. Although it occurs in all ages, most reported cases are in children and adolescents, with the average age around 5 to 8 years old. The mortality rate may be as high as 5%, full recovery is seen in 50 to 75% of cases, while up to 70 to 90% recover with some minor residual disability. The average time to recover is one to six months.

ADEM produces multiple inflammatory lesions in the brain and spinal cord, particularly in the white matter. Usually these are found in the subcortical and central white matter and cortical gray-white junction of both cerebral hemispheres, cerebellum, brainstem, and spinal cord, but periventricular white matter and gray matter of the cortex, thalami and basal ganglia may also be involved.

When the patient suffers more than one demyelinating episode, it is called Recurrent disseminated encephalomyelitis or Multiphasic disseminated encephalomyelitis(MDEM).

Causes, Antecedent History

Viral infections thought to induce ADEM include influenza virus, enterovirus, measles, mumps, rubella, varicella zoster, Epstein Barr virus, cytomegalovirus, herpes simplex virus, hepatitis A, and coxsackievirus; while the bacterial infections include Mycoplasma pneumoniae, Borrelia burgdorferi, Leptospira, and beta-hemolytic Streptococci. The only vaccine proven to induce ADEM in the Semple form of the rabies vaccine, but hepatitis B, pertussis, diphtheria, measles, mumps, rubella, pneumococcus, varicella, influenza, Japanese encephalitis, and polio vaccines have all been implicated. In rare cases, ADEM seems to follow from organ transplantation. The risk of ADEM from measles vaccination is about 1 to 2 per million, which is far lower than the risk of developing ADEM from an actual measles infection, which is about 1 per 1000 for measles (and 1 per 5000 for rubella). Measles infection also appears to lead to worse ADEM outcomes than cases associated with measles immunization. Some vacines, later shown to have been contaminated with host animal CNS tissue, have ADEM incident rates as high as 1 in 600.

Presentation

ADEM has an abrupt onset and a monophasic course. Symptoms usually begin 1-3 weeks after infection or vaccination. Major symptoms include fever, headache, drowsiness, seizures and coma. 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.

Treatment

No controlled clinical trials have been conducted on ADEM treatment, but aggressive treatment aimed at rapidly reducing inflammation of the CNS is standard. The widely accepted first-line treatment is high doses of intravenous corticosteroids , such as methylprednisolone or dexamethasone, followed by 3-6 weeks of gradually lower oral doses of prednisolone. Patients treated with methylprednisolone have shown better outcomes than those treated with dexamethasone. Oral tapers of less than three weeks duration show a higher chance of relapsing, and tend to show poorer outcomes. Other antiinflamatory and immunosuppressive therapies have been reported to show beneficial effect, such as plasmapheresis, high doses of intravenous immunoglobulin (IVIg), mitoxantrone and cyclophosphamide. These are considered alternative therapies, used when corticosteroids cannot be used, or fail to show an effect.

There is some evidence to suggest that patients may respond to a combination of methylprednisolone and immunoglobulins if they fail to respond to either separately In a study of 16 children with ADEM, 10 recovered completely after high-dose methylprednisolone, one severe case that failed to respond to steroids recovered completely after IVIg; the five most severe cases -with ADAM and severe peripheral neuropathy- were treated with combined high-dose methylprednisolone and immunoglobulin, two remained paraplegic, one had motor and cognitive handicaps, and two recovered. A recent review of IVIg treatment of ADEM (of which the previous study formed the bulk of the cases) found that 70% of children showed complete recovery after treatment with IVIg, or IVIg plus corticosteroids. A study of IVIg treatment in adults with ADEM showed that IVIg seems more effective in treating sensory and motor disturbances, while steroids seem more effective in treating impairments of cognition, consciousness and rigor. This same study found one subject, a 71 year old man who had not responded to steroids, that responded to a IVIg treatment 58 days after disease onset.

Prognosis

Full recovery is seen in 50 to 75% of cases, ranging to 70 to 90% recovery with some minor residual disability (typically assessed using measures such as mRS or EDSS), average time to recover is one to six months. The mortality rate may be as high as 5%.. Poorer outcomes are associated with unresponsiveness to steroid therapy, unusually severe neurological symptoms, or sudden onset. Children tend to have more favorable outcomes than adults, and cases presenting without fevers tend to have poorer outcomes. The latter effect may be due to either protective effects of fever, or that diagnosis and treatment is sought more rapidly when fever is present.

Motor deficits

Residual motor deficits are estimated to remain in about 8 to 30% of cases, the range in severity from mild clumsiness to ataxia and hemiparesis .

Neurocognitive

Patients with demylinating illnesses, such as MS, have shown cognitive deficits even when there is minimal physical disability. Research suggests that similar effects are seen after ADEM, but that the deficits are less severe than those seen in MS. A study of six children with ADEM (mean age at presentation 7.7 years) were tested for a range of neurocognitive tests after an average of 3.5 years of recovery. . All six children performed in the normal range on most tests, including verbal IQ and performance IQ, but performed at least one standard deviation below age norms in at least one cognitive domain, such as complex attention (one child), short-term memory (one child) and internalizing behaviour/affect (two children). Group means for each cognitive domain were all within one standard deviation of age norms, demonstrating that, as a group, they were normal. These deficits were less severe than those seen in similar aged children with a diagnosis of MS.

Another study compared nineteen children with a history of ADEM, of which 10 were five years of age or younger at the time (average age 3.8 years old, tested an average of 3.9 years later) and nine were older (mean age 7.7y at time of ADEM, tested an average of 2.2 years later) to nineteen matched controls. Scores on IQ tests and educational achievement were lower for the young onset ADEM group (average IQ 90) compared to the late onset (average IQ 100) and control groups (average IQ 106), while the late onset ADEM children scored lower on verbal processing speed. Again, all groups means were within one standard deviation of the controls, meaning that while effects were statistically reliable, the children were as a whole, still within the normal range. There were also more behavioural problems in the early onset group, although there is some suggestion that this may be due, at least in part, to the stress of hospitalization at a young age

ADEM & MS

While ADEM and MS both involve autoimmune demylenation, they differ in many clinical, genetic, imaging, and histopathological differences. Some authors consider MS and its borderline forms to constitute a spectrum, differing only in chronocity, severity, and clinical course, while others consider them discretely different diseases.

Acute Hemorrhagic Leukoencephalitis

Acute hemorrhagic leukoencephalitis (AHL, or AHLE) or Acute necrotizing encephalopathy (ANE), Acute hemorrhagic encephalomyelitis (AHEM), Acute necrotizing hemorrhagic leukoencephalitis (ANHLE), Weston-Hurst syndrome, or Hurst's disease, is a hyperacute and frequently fatal form of ADEM. AHL is relatively rare (less than 100 cases have been reported in the medical literature as of 2006), it is seen in about 2% of ADEM cases, and is characterized by necrotizing vasculitis of venules and hemorrhage, and edema, death is common in the first week with mortality rate of about 70%, but increasing evidence points to favorable outcomes after aggressive treatment with corticosteroids, immunoglobulins, cyclophosphamide, and plasma exchange. About 70% of survivors show residual neurological deficits, but some survivors have shown surprisingly little deficit considering the magnitude of the white matter affected.

Experimental Allergic Encephalomyelitis

Experimental Allergic Encephalomyelitis (EAE) is an animal model of CNS inflammation and demyelination frequently used to investigate potential MS treatments. An acute monophasic illness, EAE is far more similar to ADEM than MS.

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References

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