Acute Disseminated Encephalomyelitis (ADEM)
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Acute disseminated encephalomyelitis (ADEM) is classically described as a uniphasic syndrome occurring in association with an immunization or vaccination (postvaccination encephalomyelitis) or systemic viral infection (parainfectious encephalomyelitis). Pathologically, there is perivascular inflammation, edema, and demyelination within the CNS. Clinically patients present with the rapid development of focal or multifocal neurologic dysfunction. Prototypical illness arises after acute measles infection or rabies vaccine administration. Uncertainty regarding the diagnosis occurs when patients with clinical features of ADEM occur in the background of viral infections or vaccine administration not significantly linked with the syndrome by epidemiological criteria. (See "Acute disseminated encephalomyelitis in children").
Neurologic sequelae complicate 1 in 400 to 1 in 1000 cases of measles infection . Multiple subgroups of patients have been described, including those with diffuse cerebral features, focal or multifocal cerebral findings, cerebellar dysfunction, and spinal cord abnormalities; patients do not develop peripheral nerve damage or relapses of disease.
In addition to measles, a wide array of other viral and bacterial infections have tentatively been associated with ADEM, including rubella, mumps, herpes zoster, herpes simplex, influenza, Epstein-Barr virus, coxsackievirus, Borrelia burgdorferi, Mycoplasma, and Leptospira. Acute encephalomyelitis occurring in the background of nonspecific viral illness is difficult to diagnose with certainty and to distinguish from episodes of MS.
The occurrence of neuroparalytic accidents as a consequence of the Pasteur rabies vaccine prepared from spinal cords of rabbits inoculated with fixed rabies virus was recorded soon after introduction of the treatment: the incidence of encephalomyelitis associated with the original Pasteur rabies vaccine prepared in rabbit brain has been estimated at 1 per 3,000 to 35,000 vaccinations. Similar neurologic complications were observed as a consequence of the Jenner vaccine used for the prevention of smallpox. Postvaccination ADEM does not appear to be due to the direct cytopathic effects of the virus, but rather to immune-mediated mechanisms directed against specific components of the CNS .
ADEM also has been associated with other vaccines, including pertussis, rubella, diphtheria, and measles. The association between influenza vaccination, particularly the swine flu vaccine, and ADEM has been the subject of medicolegal controversy.
ADEM has been reported after the administration of some drugs. These drugs include sulfonamides and para-aminosalicylic acid (PAS)/streptomycin.
All of these associations can only be substantiated by strong epidemiological evidence or by the development of a pathognomonic laboratory finding for ADEM. However, neither of these circumstances currently exists.
Clinical features ¡X Clinical features of the postvaccination and parainfectious syndromes are similar, with the exception that the postrabies vaccination complications frequently involve the peripheral nervous system as well as the CNS. Many patients with postrabies immunization illness have only mild clinical features of fever, headache, or myalgia without CSF pleocytosis.
The hallmark clinical feature of the disorder is the development of a focal or multifocal neurologic disorder following exposure to virus or receipt of vaccine. In some, but not all cases, a prodromal phase of several days of fever, malaise, and myalgias occurs. The onset of the CNS disorder is usually rapid (abrupt or up to several hours), reaching peak dysfunction within several days. Initial features include encephalopathy ranging from lethargy to coma, seizures, and focal and multifocal signs reflecting cerebral (hemiparesis), brain stem (cranial nerve palsies), and spinal cord (paraparesis) involvement. Other reported findings include movement disorders and ataxia. Each of these findings may occur as isolated features or in various combinations.
Features deemed characteristic of ADEM include simultaneous bilateral optic neuritis, loss of consciousness, meningismus, loss of deep tendon reflexes and retained abdominal reflexes in the presence of Babinski's reflexes, central body temperature of greater than 100ºF (37.8ºC), and severe shooting limb pains. By comparison, features characteristic of MS are unilateral optic neuritis, diplopia, hyperactive reflexes, and preserved awareness. Headache is an equivocal feature.
Recovery can begin within days, with complete resolution noted on occasion within a few days, but more often over the course of weeks or months. Relapses are rare. Recovery from ADEM is more rapid compared with MS and usually more complete.
The mortality rate varies among reported series but is usually estimated at 10 to 30 percent, with complete recovery rates of 50 percent cited. Poor prognosis is correlated with severity and abruptness of onset of the clinical syndrome. Measles virus-associated ADEM may carry a worse prognosis than vaccine-associated disease. In earlier series, the occurrence of acute hemiplegia, which were interpreted as vascular occlusions and akin to the syndrome of acute hemiplegia of childhood, carried a particularly unfavorable prognosis with respect to recovery.
Diagnosis ¡X Multifocal CNS lesions are generally evident on MRI that are initially indistinguishable from those observed in MS . Pathologically ADEM produces scattered small perivenous lesions, often uniform in size, but this feature is not reliably detected by MRI. After several weeks, ADEM lesions show at least partial resolution without the appearance of new lesions, unlike MS. In some cases lesions can persist. MRI in ADEM, as with MS, is more sensitive than CT scanning, which may in some cases show enhancing lesions.
The usual CSF formula is normal pressure, little or no (<100 cells/µL) increase in cell count, and a modest increase in protein. Well-documented cases exist with totally normal CSF pressure, cell counts, and protein content. Cases with very high cell counts, including some polymorphonuclear cells and high protein values, appear to represent a more necrotizing disease process. The high counts usually return to normal within a few days. The CSF Ig content is not usually increased, and OCB patterns are not usually observed. The content of myelin basic protein (MBP) in the CSF may be increased, as it can be in many conditions in which myelin destruction occurs, as in MS, or as part of a more widespread tissue destructive process, like cerebral infarction.
In many patients with postrabies vaccination and postmeasles ADEM, systemic blood lymphocyte sensitivity to MBP can be demonstrated in vitro, even though generalized cellular reactivity tends to be depressed in patients with systemic measles virus infection. Although technically difficult to assess, CSF lymphocyte sensitivity to MBP may be even more marked than is systemic lymphocyte sensitivity. The occurrence of cases without MBP sensitivity indicates that this assay is insufficiently sensitive to establish or exclude the diagnosis of ADEM.
The diagnosis of ADEM can usually be made with confidence in the setting of a clear-cut antecedent event strongly associated with the disorder, such as measles infection or vaccination. The occurrence of an acute focal or multifocal CNS syndrome subsequent to a more nonspecific viral illness or vaccination in which the epidemiological link with ADEM is weak creates a wider differential diagnosis: An initial episode of what will prove to be MS ¡X The presence of increased CSF IgG levels may favor MS. Follow-up MRI may be needed to distinguish the two disorders, since the initial MRI scans can appear similar . The occurrence of a nonspecific viral illness prior to the onset of the clinical neurologic syndrome does not distinguish between MS and ADEM, since the incidence of exacerbations of MS is increased following such infections. CNS vasculitis with or without systemic features (such as disseminated intravascular coagulation or serum sickness) Multiple cerebral infarcts, particularly embolic from infected cardiac valves Chronic meningitis or granulomatous disease (sarcoidosis)
In addition, encephalitis, abscess, or tumor needs to be excluded If the main clinical feature is unifocal.
Acute disseminated encephalomyelitis in children
INTRODUCTION ¡X Acute disseminated encephalomyelitis (ADEM) is an uncommon monophasic inflammatory demyelinating disease that usually presents in children and young adults. Early recognition is important so that appropriate therapy can be started. The majority of children make a full recovery.
EPIDEMIOLOGY ¡X ADEM is an uncommon illness. Approximately three to six cases per year are seen at regional medical centers in the United States, United Kingdom, and Australia [1-3]. Boys and girls are equally affected .
Seasonal distribution is often observed, with most cases presenting in the winter and spring [1,2]. In three series, an antecedent infection could be identified in 72 to 77 percent [1-3].
PATHOGENESIS ¡X ADEM is thought to be an autoimmune disorder of the central nervous system (CNS) . The mechanism proposed is that myelin autoantigens, such as myelin basic protein, proteolipid protein, and myelin oligodendrocyte protein, share antigenic determinants with those of an infecting pathogen . Antiviral antibodies or a cell mediated response to the pathogen cross react with the myelin autoantigens, resulting in ADEM.
This mechanism is supported by studies of lymphocytes in children with ADEM. In one report, the frequency of T cell lines that reacted to myelin basic protein was 10 times higher in patients with ADEM, compared to those with encephalitis or normal controls .
PATHOLOGY ¡X The pathology of ADEM in humans is similar to an animal model of experimental allergic encephalomyelitis (EAE) [6-8]. In this model, injections of brain extracts in rabbits cause some animals to manifest an encephalitic-like disease process associated with demyelination. The demyelination appears to result from a cell mediated delayed hypersensitivity reaction.
The histologic appearance of EAE includes perivenous demyelination and inflammation, with an abundance of lymphocytes and macrophages. Lesions often have a flame-like appearance that is similar to pathologic findings in humans with ADEM . They are usually distinct from the lesions of multiple sclerosis.
PATHOGENS ¡X ADEM usually follows an infection, often of the upper respiratory tract. Numerous pathogens have been associated with the disorder. Viruses that have been implicated include measles, rubella, varicella, influenza, Epstein-Barr, coxsackie, coronavirus, HIV, herpes simplex, cytomegalovirus, and West Nile virus [5,6,10-23]. Other organisms associated include group A hemolytic streptococcus, Mycoplasma pneumoniae, chlamydia, Rickettsia, and leptospirosis .
ADEM may also follow immunization, although this is rare. It has occurred following immunization for measles, rubella, influenza, smallpox, rabies, and meningitis A and C . No infectious agent is isolated in most cases.
CLINICAL FEATURES ¡X The clinical features of ADEM were described in three series of patients from the United States, United Kingdom, and Australia, that included 18, 28, and 31 patients, respectively [1-3]. The mean age at presentation was six to eight years. The youngest patient was 2 years of age and the oldest was 22. In patients with a preceding illness, systemic and neurologic signs often followed in 10 days to 2 or 3 weeks.
Approximately 40 to 50 percent of patients presented with fever [1-3]. Other systemic signs, such as nausea and/or vomiting, headache, irritability, and stiff neck, were common.
Progression of neurologic signs to the maximum deficit occurred over one week on average . Development of signs can be more gradual, lasting up to one month, or occur acutely with rapid progression .
The neurologic signs are variable and depend upon the location of the CNS involvement. The disease is usually diffuse, and children often present with multifocal signs. In the three series, the most common neurologic signs were motor deficits (eg, ataxia, hemiparesis) and impaired consciousness [1-3]. Cranial nerve abnormalities, including optic neuritis with vision impairment, gaze paresis, facial weakness, and swallowing difficulties, occurred frequently. Language was disturbed in some patients, and seizures occurred in 13 to 17 percent. Rarely, ADEM presents as an acute psychosis .
Patients may have sensory deficits. Urinary retention can occur with spinal cord involvement.
Clinical course ¡X ADEM typically lasts from two to four weeks. Children may deteriorate after hospital admission, and many develop new neurologic signs. Patients usually recover completely from the acute illness, although some have neurologic sequelae. In the three contemporary series noted above, all affected patients survived [1-3].
ADEM is considered a monophasic illness. Patients who appear to have an early relapse may in fact have a protracted clinical course or treatment failure, rather than a new episode. Relapse after a few months suggests the possibility of multiphasic disseminated encephalomyelitis. If relapse occurs after six months or there is progressive neurologic deterioration, the diagnosis of multiple sclerosis should be considered .
DIAGNOSIS ¡X ADEM should be suspected in a child who develops systemic signs and neurologic abnormalities, including altered level of consciousness, one to two weeks after a viral infection.
Laboratory studies ¡X Many children have nonspecific findings of inflammation. The erythrocyte sedimentation rate and C reactive protein concentration may be increased. Leukocytosis is common, occurring in up to two-thirds of patients in the three series noted above [1-3]. This is predominantly due to lymphocytosis .
Evidence of inflammation is common in cerebrospinal fluid (CSF), with pleocytosis and/or increased protein concentration in the majority of patients [1-3]. However, the CSF can also be normal. Some patients have oligoclonal bands in CSF, due to intrathecal synthesis of limited classes of immunoglobulins that are depicted as discrete bands on agarose gel. However, oligoclonal bands are more often associated with multiple sclerosis , and can occur in chronic CNS infections, viral syndromes, and neuropathies.
Investigation for infectious agents usually includes viral cultures of the throat and nasopharynx, stool, and CSF, and serologic testing for a variety of agents, including influenza, Epstein-Barr virus, herpes, varicella, mycoplasma, cytomegalovirus, and rubella. These studies are rarely positive [4,9].
Neuroimaging ¡X Magnetic resonance imaging (MRI) is important in establishing the diagnosis. Findings may progress over a relatively short period of time, consistent with evolution of the disease process. The abnormalities are best defined by T2 weighted images and fluid attenuated inversion recovery (FLAIR) sequences (show radiograph 1). Contrast enhancement is seen at times in acute lesions. Computer tomography (CT) scans are often normal, and thus, are not helpful.
MRI abnormalities vary in location. Lesions are typically bilateral but asymmetric and tend to be poorly marginated. Almost all patients have multiple characteristic lesions of demyelination in the deep and subcortical white matter. The periventricular white matter is often spared. Gray matter lesions sometimes accompany the white matter abnormalities, especially in children.
Multiple lesions are typically present, although the number varies among patients. In one study, patients had 4 to 56 lesions on the initial scan . The lesions are often large. Many were approximately 1 cm in diameter, but ranged up to 5 cm [1,2]. The large lesions may have a mass effect.
The thalami and basal ganglia are frequently affected (show radiograph 1). These lesions are often symmetrical, in contrast to the supratentorial lesions which are usually asymmetrical.
Brain stem and spinal cord abnormalities are common [1,4]. In the spinal cord, large confluent intramedullary lesions that extend over multiple segments are typical . Enhancement is variable.
Imaging often improves with convalescence, although lesions sometimes persist. Among 19 patients studied 2 months to 9 years after demyelination, lesions resolved completely in 7, partially in 10, and remained unchanged in 2 . None developed new lesions.
Electroencephalogram (EEG) ¡X The EEG is not diagnostic. It may show increased background slow wave activity that is typical of an encephalopathy . Seizure activity is rarely seen. In patients with optic neuritis, visual evoked potentials may be prolonged.
DIFFERENTIAL DIAGNOSIS ¡X In a child who presents with neurologic abnormalities, including signs of encephalitis, nonspecific CSF findings, and MRI evidence of white matter abnormalities, other inflammatory demyelinating disorders should be considered. These include multiple sclerosis (MS), optic neuritis, transverse myelitis, and other rare conditions.
Multiple sclerosis ¡X The most important alternative diagnosis to ADEM is multiple sclerosis (MS). At the initial presentation, the two disorders cannot be distinguished with absolute certainty. Because subsequent attacks of MS in children may not occur for months or years, prolonged follow-up is required to establish a diagnosis.
Certain clinical features may be helpful in supporting the diagnosis of ADEM or MS [4,26-28]. However, there is substantial overlap. ADEM typically follows a prodromal viral illness, while MS does not ADEM patients often have fever and stiff neck, which is unusual in MS ADEM usually produces widespread CNS disturbance with impaired consciousness, while MS typically is monosymptomatic (eg, optic neuritis or a subacute myelopathy) and has a relapsing, unremitting course Optic neuritis is more often bilateral when it occurs in ADEM and unilateral in MS Myelopathy is usually complete and accompanied by areflexia in ADEM and partial in MS Ataxia is a common presenting feature of ADEM, but rare in MS
MRI features may also be helpful in distinguishing ADEM from MS, although complete differentiation is not possible on the basis of a single examination [2,4]. ADEM usually has more lesions than MS, with larger bilateral but asymmetrical white matter abnormalities Lesions tend to be poorly defined in ADEM and have better defined margins in MS The age of the lesions is usually similar in ADEM and different in MS Thalamic lesions are common in ADEM and rare in MS Periventricular lesions are less common in ADEM than MS
Optic neuritis ¡X Optic neuritis is inflammation of the optic nerve that can be caused by any inflammatory condition or may be idiopathic. It usually presents as an isolated symptom but may accompany other nervous system involvement. The pathophysiology of isolated optic neuritis is probably closely related to ADEM [10,12,26,29,30]. However, the absence of white matter abnormalities on MRI at the time of presentation makes ADEM unlikely.
In adults, optic neuritis is closely associated with MS. In contrast, children are less likely to develop MS following optic neuritis [29,30]. However, in one report, MS developed in 5 of 10 children with optic neuritis .
Optic neuritis is bilateral in the majority of patients . Symptoms usually progress over a few days with partial or complete vision loss, a relative afferent pupillary defect (Marcus Gunn pupil), and visual field defects. At the onset, presentation can be asymmetrical. Patients may report headache or painful eye movements prior to the vision loss. (See "Congenital anomalies and acquired abnormalities of the optic nerve").
The fundoscopic examination is variable. The optic nerve appears swollen in 75 percent of children in the acute phase . However, optic disc swelling can be mild or absent, especially if the inflammation is retrobulbar.
In addition to decreased visual acuity, an enlarged central scotoma may be detected by visual field testing. Visual evoked potentials are prolonged in affected patients. Prolongation may persist even years after the illness, despite a normal ophthalmologic examination and normal vision.
Patients typically have normal or near normal recovery of vision. However, subtle color impairment and stereoscopic abnormalities may persist. Optic nerve atrophy may be noted on ophthalmologic examination.
Transverse myelitis ¡X Transverse myelitis is defined as spinal cord dysfunction that develops over hours or days in patients in whom there is no evidence of a compressive lesion. Typically, it is due to an inflammatory lesion of the spinal cord and may be associated with ADEM or MS. The disorder may present as an isolated lesion or be associated with other neurologic abnormalities.
Symptoms are characterized by motor and sensory deficits attributable to involvement of one or both sides of the spinal cord. They include weakness, paresthesias, and sphincter dysfunction. These typically present over a few days, with paresthesias preceding the weakness and urinary retention . A hyperacute presentation sometimes occurs with rapid onset of paraplegia, sensory abnormalities, and urinary retention [10,22,33-35]. This form is often associated with significant back pain. A discrete sensory level may or may not be detected with either presentation.
MRI should be performed to rule out spinal cord compression, especially when presentation is rapidly progressive. The MRI typically shows swelling of the cord, especially on T-2 sequence. There may be contrast enhancement with gadolinium. Unfortunately the prognosis for complete recovery is not as favorable as for ADEM or optic neuritis; this seems to be independent of treatment.
Devic's syndrome ¡X Devic's syndrome (also known as neuromyelitis optica) is a combination of bilateral optic neuropathy and traverse myelitis without any other neurologic signs. The optic neuritis and transverse myelitis can occur concurrently, or one may follow the other. Unlike ADEM there are no white matter lesions in the brain.
This condition is closely related to MS, although the disorders might be differentiated by application of stricter diagnostic criteria . Patients with Devic's syndrome have a poorer prognosis for recovery of vision. The myelopathy tends to be more severe than MS, with less likelihood of recovery. The neuropathologic features at autopsy are those of a much more severe necrotic lesion of the cord rather than the incomplete demyelination seen in MS .
A serum IgG autoantibody (NMO-IgG) may be a specific marker for neuromyelitis optica and further aid in the distinction of this disorder from MS. A case-control study reported that NMO-IgG had good sensitivity and specificity for the detection of neuromyelitis optica (73 and 91 percent, respectively) as well as for Asian optic-spinal MS (58 and 100 percent, respectively) . The diagnostic utility of this test requires further confirmation, but it appears promising.
Acute hemorrhagic leukoencephalitis ¡X Acute hemorrhagic leukoencephalitis (AHL) is a rare entity that represents a more severe and fulminant form of ADEM . The presentation is similar to ADEM, with multiple neurologic signs, including meningismus, headache, seizures, asymmetrical neurologic deficits, and coma. However, AHL evolves more rapidly and is more severe. Like ADEM, it typically follows an infection.
AHL is differentiated from ADEM by diffuse CNS hemorrhage. The CSF typically shows both white and red blood cells, with increased protein concentration. White matter lesions can be detected on MRI within 72 hours of the first symptoms.
Some patients recover with treatment. However, the prognosis for survival and recovery of neurologic function is worse for AHL than ADEM.
TREATMENT ¡X Most children with ADEM present with fever, meningeal signs, and acute encephalopathy and have evidence of inflammation in blood and CSF. Thus, consideration should be given to treatment with broad spectrum antibiotics and acyclovir until an infectious etiology is excluded. (See "Diagnosis, treatment, and prevention of bacterial meningitis in children").
Once the diagnosis of ADEM is established, steroid treatment is started . However, no data are available to determine optimal treatment, including dose or duration. We recommend methylprednisolone in a dose of 30 mg/kg per day intravenously up to a maximum dose of 1000 mg per day. Treatment should be continued for a total of five days without a taper.
Intravenous immunoglobulin has been used with some benefit in patients who fail to respond to methylprednisolone . Plasmapheresis has been beneficial in patients who fail treatment with intravenous immunoglobulin and/or methylprednisolone .
PROGNOSIS ¡X Patients with ADEM usually recover slowly, over four to six weeks. At follow-up, approximately 60 to 80 percent have no neurologic deficits [1-3,49]. However, the mortality of postinfectious ADEM may be as high as 5 percent . The extent and site of lesions on the initial MRI do not predict the clinical outcome [49,51]. In the study from the United Kingdom, 28 children were followed for a mean of 5.8 years . No impairments were found in 20 (57 percent). Of the remainder, six patients had motor disabilities, which were severe in three; two had persistent limb paresthesia. Visual or cognitive impairment or behavior problems each occurred in four children. In the study from the United States, three of 18 children had neurologic sequelae at a mean follow-up of 22 months . Two patients had gait problems and urinary symptoms and one had seizures. In the report from Australia, mild abnormalities were detected in 6 of 31 patients followed for an average of 18 months . These included recurrent headaches, behavior problems, esotropia, subtle hemiparesis, and minor gross motor abnormalities. In a report from Argentina, 84 children with ADEM were followed for a mean of 6.6 years . Neurologic examination was normal in most of 75 children (89 percent), or detected minor abnormalities but no associated disability. Residual deficits in the remainder included hemiparesis, paraparesis, partial epilepsy, reduced visual acuity, and mental handicap. Disability was more likely in children who presented with optic neuritis and was unrelated to the initial pattern of lesions on MRI.
Follow-up MRI shows complete or partial resolution of abnormalities in the majority of cases [2,28,52]. However, residual gliosis and demyelination persist in some.
RECOMMENDATIONS ¡X ADEM should be suspected in a child with fever and neurologic abnormalities, including impaired consciousness, especially one to two weeks after a viral infection.
Laboratory studies should include complete blood count and lumbar puncture. Cultures and serologic studies should be performed on blood and CSF to detect bacterial and viral organisms. Viral cultures should be obtained from nasopharynx and stool.
MRI of the brain and spinal cord should be performed. The abnormalities are best defined by T2 weighted images and FLAIR sequences and contrast enhancement.
Most children with ADEM present with fever, meningeal signs, and acute encephalopathy and have evidence of inflammation in blood and CSF. Treatment should be considered with broad spectrum antibiotics and acyclovir until an infectious etiology is excluded.
Once the diagnosis of ADEM is established, treatment should be started with methylprednisolone in a dose of 30 mg/kg per day intravenously up to a maximum dose of 1000 mg per day. Treatment should be continued for a total of five days without a taper.
Extended follow-up should be performed to document recovery. The occurrence of relapses suggests alternative diagnoses, such as MS.
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