Acute Disseminated Encephalomyelitis

Background

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory demyelinating condition that predominately affects the white matter of the brain and spinal cord. The disorder manifests as an acute-onset encephalopathy associated with polyfocal neurologic deficits and is typically self-limiting.^{[37, 46, 48]} ADEM bears a striking clinical and pathological resemblance to other acute demyelinating syndromes (ADS) of childhood, including multiple sclerosis (MS). ADEM in children is readily distinguishable from alternative diagnoses on the basis of clinical features and findings on neuroimaging and laboratory investigations. However, given that ADEM lacks a specific identified biological marker rendering a reliable laboratory diagnosis, long-term follow-up is important as there are instances where an illness initially diagnosed as ADEM is ultimately replaced with a diagnosis of MS.^[1]

The onset of ADEM usually occurs in the wake of a clearly identifiable febrile prodromal illness or immunization and in association with prominent constitutional signs and encephalopathy of varied degrees. ADEM is typically a monophasic disease of pre-pubertal children; whereas, MS is typically a chronic relapsing and remitting disease of young adults. Abnormalities of findings on cerebrospinal fluid (CSF) immunoglobulin studies are less common in ADEM. However, the division between these processes is indistinct, suggesting a clinical continuum. Moreover, other conditions along the suggested continuum include optic neuritis, transverse myelitis, and neuromyelitis optica - clinical entities that may occur as manifestations of either MS or ADEM.^[2] Other boundaries of ADEM merge indistinctly with a wide variety of inflammatory encephalitic and vasculitic illnesses as well as monosymptomatic, postinfectious illnesses that should remain distinctfromADEM, such as acute cerebellar ataxia (ACA). A furtherindistinct boundary is shared by ADEM and Guillain-Barré syndrome as manifested in cases of Miller-Fisher syndrome and encephalomyeloradiculoneuropathy (EMRN).

Susceptibility to either ADEM or MS is likely the product of multiple factors, including a complex interrelationship of genetics and exposure to infectious agents and other environmental factors. Of particular interest are the indications that susceptibility to either condition is in part age-related. Most cases of ADEM possibly occur as the result of an inflammatory response provoked by pre-pubertal infection with a virus, vaccine, or other infectious agent. Typically, the manifestations of ADEM occur quickly after this pre-pubertal febrile systemic illness and are monophasic. In a minority of cases, patients with ADEM experience one or two pre-pubertal recurrences followed by remission. MS, on the other hand, typically manifests as a relapsing-remitting illness in ensuing adolescence or young adulthood, a significant and unexplained latency of effect with apparent permanency of immune dysregulation. Bouts of MS occur without a febrile prodrome. Uncommonly, MS develops in pre-pubertal individuals andADEMdevelops in post-pubertal individuals. In very rare instances, individuals manifest pre-pubertal ADEM and, after long latency, MS in adolescence.

• References

Pathophysiology

Multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) bear a close pathological resemblance, each resembling the pathology of experimental allergic encephalomyelitis (EAE). The prominence of perivenular round cell inflammation in either illness is a feature that is shared with many forms of encephalitis, but patchy demyelination with preservation of axon cylinders and the prominence of microglial cells in the inflammatory exudate are not.

The pathology of various developmental stages of the MS plaque is more fully characterized than the pathology of the lesions of ADEM. This is because most patients with ADEM recover completely and without apparent pathological residua. Few biopsies have been obtained or submitted to postmortem analysis. MS plaques are known to exhibit organization features, especially in the margins of active plaques that are not found in cases of ADEM. On the other hand, the general pathological similarities suggest but do not confirm the possibility that ADEM is a forme fruste of MS that is somehow effectively and permanently controlled after one, or possibly a few, demyelinating bouts.

Patients with large tumor-like demyelinating lesions may exhibit a combination of pathological features consistent with both MS and ADEM. The possible relationship between these illnesses is further supported by the similarity of clinical manifestations in either illness and the development of MS during adolescence in a small minority of patients who have had typical ADEM bouts in the first decade of life.

The pathophysiological similarities of these illnesses suggest that the immunologic constitution of susceptible individuals is in some fashion permissive of ADEM, MS, or both and that the degree of susceptibility may describe a gradient with regard to severity and risk for recurrence. The threshold for an initial bout of demyelinating illness may be determined by the combination of this immunologic constitution and the nature of a given antigenic stimulus; the likelihood of recurrence may be determined by the fertility of that constitution for persistence of immuno-dysregulation. Immuno-dysregulation in MS or ADEM may consist of responses that are inadequate, too exuberant, or the combination of both.

If a pathophysiological continuum between MS and ADEM exists, achieving better understanding of the manner in which susceptible individuals with ADEM are able to bring a monophasic or temporarily recurrent immuno-dysregulative response under permanent control is of obvious importance. Cases with characteristics that fall in the indeterminate area of this continuum, such as those that might be labeled multiphasic ADEM, represent an important challenge for accurate classification. In some of these cases, appropriately crediting the immune system with tardy but permanent compensation may be important, thus avoiding inappropriate diagnosis of MS, fraught as that is with psychosocial consequences.

The mechanisms of these demyelinating illnesses remain incompletely understood despite the extraordinary richness and complexity of immunologic abnormalities that have been identified after more than a century of clinical, pathological, and laboratory studies. Experimental observations have depended greatly on EAE, a research model that may be more pertinent to ADEM than MS.

However, the possibility of provoking spontaneously recurrent demyelination with this model further supports the concept that ADEM and MS represent a continuum. Basic studies have shown that, in the earliest stages of inflammation, both MS and ADEM are likely to be mediated by stimulated clones of T-helper cells sensitized to auto-antigens such as myelin proteins. Some studies have even identified serum autoantibodies to various myelin proteins that help to differentiate ADEM from MS. In particular, ADEM appears to be characterized by class-switched IgG autoantibodies, supporting the hypothesis of an antigen-driven immune response in ADEM cases; whereas, MS cases are characterized by serum IgM autoantibodies.^[49] The complex ensuing inflammatory cascade entails the local action of cytokines and chemokines as well as lymphokine-induced chemotaxis of other cellular mediators of inflammation (eg, other T cell lines, B cells, microglia, phagocytes).

Pathogenic differences of MS and ADEM are likely to arise in part because of differences in details concerning pro-inflammatory and anti-inflammatory cytokines and chemokines. Interleukin (IL)–1beta, Il-2, IL-4, IL-5, IL-6, IL-8, IL-10, interferon (IFN)–gamma, tumor necrosis factor-alpha, and macrophage inflammatory protein-1-beta are significantly elevated in CSF compared with the CSF of controls. Granulocyte colony-stimulating factor shows a particularly striking elevation at as much as 38-fold greater concentration than is found in the CSF from control subjects. Elevations of IFN-gamma, IL-6, and IL-8 have been significantly correlated with CSF cell counts and protein concentration in individuals with ADEM. The pattern of cytokine elevation suggests that ADEM involves activation of macrophages, microglial cells, and various Th (T helper)–1 and Th2 cells.^[3]

Additionally, in 2006, Franciotta et al demonstrated that adults with ADEM have higher CSF concentrations of chemokines that recruit or activate neutrophils (CXL1 and CXL7), monocytes (CCL3 and CCL5), Th1 cells (CXCL10), and Th2 cells (CCL1, CCL17, and CCL22) than healthy normal controls.^[4] Moreover, ADEM-associated concentrations of certain of these neutrophils (CXL7 neutrophil activator and the CL1, CCL17, and CCL22 Th2 activators) are higher in the CSF from individuals with ADEM than those with MS. On the other hand, CSF concentrations of the chemokine CCL11 is lower in adults with MS than in the CSF from adults with ADEM or in normal controls.

CSF Th1/Th2 cytokine concentrations were not significantly different in adults with MS, those with ADEM, or in normal healthy controls. No significant differences in serum concentrations of cytokines or chemokines were noted in the 3 adult groups. These findings raise the possibility that elevated chemokine concentrations might serve as biomarkers for ADEM and that they may provide keys to understanding the nature of and differences in the pathogenesis of ADEM and MS.

Disturbance of the blood-brain barrier is likely to be an important event. The elaboration of antibodies occurs but remains of uncertain significance. In particular, multiple researchers have demonstrated the presence of serum IgG antibodies to myelin oligodendrocyte glycoprotein (MOG) in up to 40% of children with ADEM,^{[51, 52, 53]} though these antibodies do not appear to be specific to ADEM. Still the presence of anti-MOG antibodies in ADEM may affect the nature and course of the disease. A recent study has demonstrated that MOG-positive ADEM patients are more likely to have large, bilateral and widespread lesions and longitudinally extensive transverse myelitis on MRI and are more likely to have a favorable clinical outcome when compared to MOG-negative ADEM patients.^[49]

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Epidemiology

Frequency

United States

The Canadian Pediatric Surveillance Program for acute demyelinating syndromes (ADS) in individuals younger than 18 years found that in 219 identified Canadian cases, ADEM represented 22% of diagnoses. This study generated an estimate of Canadian disease incidence of 0.9 per 100,000 for ADS, while cases of ADEM manifested an annual incidence of 0.2/100,000.^[5] Higher incidence rates have been reported in San Diego County at 0.4/100,000 per year.^[55]

Whether the increasing incidence of MS at increasing distance from the equator is also true of ADEM is unknown. The seasonal incidence of ADEM within North America peaks in the winter and spring months.^{[55, 54]} Some severe forms of ADEM, such as those that occur in the wake of measles and the severe hemorrhagic variant called acute hemorrhagic leukoencephalopathy (AHLE) are probably less commonly encountered than they were prior to widespread immunization against measles and other formerly common and potentially serious illnesses that may serve as triggers for ADEM/AHLE.

International

Few studies have provided incidence data from other countries, thus little is known about occurrence throughout the world. Data from Germany quote an incidence rate of 0.07 per 100,000,^[56] while data from Japan show an incidence of 0.64 per 100,000 per year.^[57] Genetic factors, prevalence of infectious pathogens, immunization status, degree of skin pigmentation, diet, and other factors may influence risk.

Mortality/Morbidity

Although older studies suggest a 10% mortality rate, the data upon which such estimates were based were obtained in epochs during which measles was prevalent, techniques for intensive care were comparatively primitive, and anti-inflammatory therapies were inadequate. Formerly, deaths occurred in patients with AHLE, a severe ADEM variant, which has become less common since children have received immunization to many common childhood illnesses.

Current acute mortality rates are probably less than 2%, typically consisting of cases with fulminant cervical transverse myelitis or brain swelling. Children younger than 2 years are particularly subject to such severe presentations.^[37] See the image below.

View Image

Fatal case of ADEM involving the brainstem in a 13-month-old.

Morbidity chiefly includes visual, motor, autonomic, and behavioral/intellectual deficits and epilepsy. Based upon existing data, full recovery occurs in approximately 57-92% of patients. Residual focal neurologic deficits remain in 4-30%.^{[54, 47, 58, 60, 61, 62, 55, 63, 85]} Neurocognitive deficits after acute demyelinating syndromes are receiving more attention, as even children having an apparent full recovery after ADEM have demonstrated subtle deficits on formal neuropsychological testing years after the sentinel event.^[65] Additionally, these intellectual and behavioral impairments are variable depending on age of the child at the time of disease onset. There may be a greater impact upon behavior and intelligence in those with an ADEM-onset of younger than 5 years of age.^[64]

Though uncommon, adult-onset ADEM, when correctly diagnosed, appears to have similar outcomes and a typically favorable prognosis.^[39]

Race

The scientifically imprecise concept of race does not lend itself readily to discussions of ADEM. In the author's (RSR) series of more than 150 cases, the ratio of light-skinned to dark-skinned individuals who have some contribution of genetic material from individuals who have left Africa in the past 5 centuries is approximately 6:1. In the former group, the element of African heritage from the past 5 centuries is presumed small but is in fact unknown. ADEM is found in all ethnic groups and races; referral bias complicates any assessment of relative prevalence.

Regardless of race, the degree of skin pigmentation directly influences vitamin D status in any given individual.^[66] Several studies have implicated vitamin D deficiency as a contributing risk factor for multiple sclerosis,^{[70, 68, 67]} though these studies have not been performed within ADEM cohorts.

Sex

Though no clear gender predominance has been identified, a handful of ADEM cohorts have reported a slightly male predominance.^{[5, 54, 85]} In the author's (RSR) series of more than 150 cases, the ratio of boys to girls is 1.3:1. These data are in opposition to the strong female preponderance noted within multiple sclerosis.

Age

More than 80% of childhood cases occur in patients younger than 10 years, with a mean age range of 5 to 8 years.^{[47, 63, 71]} . Somewhat less than 20% of cases occur in the second decade of life. Incidence in adulthood is unclear, accounting for less than 3% of the reported cases; however, diagnostic overlap with MS may lead to underestimation of the prevalence in adults.^[39] Adult-onset cases of particular severity are recognized upon the basis of biopsy. These cases may manifest very large white matter lesions that involve, as is the case with childhood-onset cases, the gray-white junction of forebrain.

• References

History

Clinically, acute disseminated encephalomyelitis (ADEM) is usually readily distinguishable from multiple sclerosis (MS) by the presence of certain clinical features, including the following:

• History of preceding infectious illness or immunization, although a clear preceding event may be absent in up to a quarter of patients.^[85]
• Association with constitutional symptoms and signs, such as fever
• Prominence of cortical signs such as mental status changes and seizures
• Comparative rarity of posterior column abnormalities, which are common in MS
• Age younger than 11-12 years in ADEM and age older than 11-12 years in MS

ADEM is more common in the winter months, with most cases occurring between October and March. Typical cases of ADEM arise 1-2 days to several weeks after a childhood infectious illness.

• There is usually a clearly defined phase of afebrile improvement lasting 2-21 days or more before onset of neurologic findings.
• Generally, patients have shown partial or complete recovery from the prodromal illness at the time of onset of ADEM.
• Whether latencies of longer than 21 days implicate a particular febrile illness as the prodrome of ADEM is unclear. Clinical experience suggests that this is possible.
• Most of the large envelope-bearing viruses that figured prominently in older series of ADEM, of which measles was a particularly virulent example, no longer figure importantly in the etiology of ADEM because these diseases are prevented by vaccination.
• Most cases encountered now occur in the wake of respiratory or gastrointestinal illness presumed to be of viral etiology, although a specific virus is seldom identified.
• Documentation of at least 1 fever-free day is especially suggestive of ADEM, although such a hiatus is also found in post-infectious vasculitides.
• Occasionally, ADEM may occur in the wake of several weeks of fever of unknown origin.
• Some patients have premonitory pain in the back prior to the development of ADEM-related inflammatory myelitis.
• Various vaccines have been suggested as the exogenous provocation of cases of ADEM.

  • This remains a controversial subject, although clear evidence exists for the role of the Pasteur rabies vaccine and compelling, although somewhat less conclusive evidence exists for the role of other vaccines.
  • The overall effect of the introduction of vaccinations for measles and other encephalomyelitogenic viruses has been a marked reduction in the number of severe or fatal cases of ADEM.
  • Measles was associated with ADEM in about 1 out of 800 cases, and in many of these cases, ADEM that was often particularly severe. Measles-associated ADEM had a high rate of both morbidity and mortality.

   

  

   
• A cause-and-effect relationship between a possible prodrome and ADEM is more difficult to establish in cases where longer or very short intervals exist between a possible exogenous stimulus and inflammatory result.

  • Latencies longer than 50 days have been suggested for infections or vaccines but are difficult to prove.^[6]
  • Relationships are also difficult to determine when a febrile systemic process is rapidly followed by neurologic deterioration because such cases may represent meningoencephalitis.
    • Approximately 25% of cases lack a clearly-defined prodrome.^{[47, 58, 85]}
    • Some of these cases are possible examples of longer than 20 days of latency from prodrome to ADEM, especially in prepubertal children, with imaging changes suggesting ADEM, with negative CSF immune profile, and with rapid and complete recovery.
    • Another subgroup with poorly-defined prodrome but low risk for recurrence are children or adolescents manifesting subacute-onset syndromes that combine neuropsychiatric abnormalities and movement disorders and imaging changes suggestive of ADEM. The course in these cases, which could be termed Johnson syndrome, is often prolonged or even progressive, improving with high-dose intravenous corticosteroids.

   

  

   

The first signs of ADEM usually include abrupt onset encephalopathy (alteration in consciousness or behavioral change unexplained by fever, systemic illness or postictal symptoms.^[59] Rapid-onset encephalopathy is typically associated with multifocal neurologic symptoms.

• In most cases, the clinical course is rapidly progressive and typically develops over hours to maximum deficits within days (mean of 4.5 days).^[85] A minority of cases show continued deterioration of function for periods as long as 4 weeks.
• Strictly speaking, encephalopathy, unexplained by fever, should be present for a diagnosis of ADEM, though it may not be the presenting sign. A single institution follow-up study (at least 5.5 y for each individual) of 52 young individuals (age range 10 mo to 19 y) who presented with their first bout of an acute central nervous system demyelinating disease included 26 children ultimately diagnosed with MS and 24 diagnosed with ADEM. Encephalopathy was the presenting sign in 42% of those with a follow-up diagnosis of ADEM but none of the individuals with a follow-up diagnosis of MS.^[7]
• Convulsive seizures occur around the onset of ADEM in as many as 35% of cases.^[85]
• Meningismus may be present and has been reported in up to 30% of cases.^[63]
• Although almost any portion of the CNS may be clinically involved, certain systems appear to be particularly prone to dysfunction; thus, the descending white matter motor tracts, optic nerves, and spinal cord are particularly commonly involved.
• ADEM-associated optic neuritis is typically bilateral, although the onset in a second eye may follow onset in the first by days to months. Bilaterality may provide a degree of reassurance with regard to MS risk as optic neuritis in MS is frequently unilateral. Visual evoked responses may discern abnormalities in a second eye before clinical deterioration in vision is discernible.

  • A wide variety of cranial nerve abnormalities may occur in addition to optic nerve disease.
  • Long tract signs (eg, clonus, increased muscle stretch reflexes, upgoing toes) are present early in as many as 85% of cases.^[85]
  • In some instances, reflexes may be lost at the onset. When this is caused by transverse myelitis, the evolution of disease after spinal shock replaces absent reflexes with increased muscle stretch reflexes within a few days or more. A small number of cases manifest loss of reflexes as a sign of associated peripheral nerve disease with ADEM, a condition termed EMRN. Some of these EMRN cases are associated with evidence for acute infection with Epstein-Barr virus.
    • Weakness may be hemiparetic, double hemiparetic, diparetic, or generalized and symmetric. Fairly symmetric leg weakness is seen in many cases of ADEM-related transverse myelitis with associated abnormalities of bowel and bladder function.

   

  

   

Some ADEM presentations are fulminant.

• Fulminant ADEM is more likely to manifest in children younger than 3 years, with rapid evolution of a low state of function and demonstration of severe edema on neuroimaging. Such cases have become uncommon with widespread vaccination against childhood illnesses.
• Transverse myelitis (TM) may begin rapidly and be associated with severe edema, usually in the cervical region. ADEM-related TM must be distinguished from TM associated with MS, vascular accidents, and directly infectious conditions, including enterovirus. It must also be distinguished from neuromyelitis optica (NMO), which may present with TM in isolation. NMO is a condition for which a biological marker (anti-AQP4 IgG in serum and/or CSF) has been identified.

  • Child/adolescent NMO represents approximately 5% of cases of NMO. Onset is a median range of 10-14 y and the vast majority of these patients are girls or young women. The median number of spinal levels involved is 10 vertebral segments.^[72] Motor signs are usually more prominent than sensory signs. CNS lesions may be demonstrated on scans and mental status changes may be noted.

   

  

   
• Acute administration of very high-dose intravenous corticosteroids may possibly close the blood-brain barrier and subtend the development of edema, which may, in these fulminant cases, account for the high risk for permanent morbidity.

There are unusual presentations for possible ADEM that have uncertain classification. More literature is supporting a continuum of acute demyelinating diseases in childhood and adulthood.

• Cases of pediatric patients diagnosed with neuromyelitis optica presenting with a clinical and radiographic evidence of ADEM have been reported.^{[73, 74, 76]}
• Cases of patients with anti-NMDA receptor encephalitis and ADEM-like lesions on MRI have also been reported.^{[77, 75]}
• Additionally, pediatric cases of ADEM followed by recurrent or monophasic optic neuritis have been described.^[78]
• Young children may manifest a rapidly progressive demyelinating illness that may be fatal within days to weeks and is almost universally associated with profound permanent psychomotor deficits in those who survive. Brain images differ from those typical of juvenile MS and may demonstrate confluent symmetric areas (butterfly pattern) of bright signal abnormality on T2-weighted sequences.

  • Fulminant presentation with lesions showing significant degrees of ring enhancement after contrast administration may also be found.
  • Malignant brain edema may be present, manifested by sulcal and ventricular effacement.

   

  

   
• Some patients with the large tumor-like lesions, acute MS, or Schilder disease presentations during childhood or adolescence do remarkably well as compared to adults with similar presentations.
• The classification of rare severe infantile cases, exhibiting features suggesting either severe acute MS or hyperacute ADEM, remains in doubt.

  • Nonetheless, pathological confirmation that some of these cases are MS has been published,^[79] and hyperacute adult cases with similar clinical and radiographic manifestations have been reported.^[81]
  • Some of these cases display more generalized T2-weighted abnormalities on MRI and may represent cases of what has been referred to as acute toxic encephalopathy.
  • Emphasizing that scan results do not reliably distinguish every case of MS from ADEM is important, but in most cases, reliable inferences may be drawn. Extensive white matter involvement may be found in young infants that some would label as MS^[80] while others would label it hyperacute ADEM.

   

  

   
• Rarely, childhood, adolescent, or adult MS manifests as large unilateral or multiple tumor-like mass lesions that may appear cystic and may impart mass effects (albeit atypically and, if present, unexpectedly mildly). The lesions are steroid responsive and may recur in other locations, such as the contralateral paraventricular white matter.

  • These lesions may represent an intermediate entity between MS and ADEM. Other differential considerations are neoplasm, systemic lupus erythematosus (SLE) and other vasculitic illnesses, progressive multifocal leukoencephalomyelitis, and Schilder myelinoclastic diffuse sclerosis.
  • Schilder disease (diffuse sclerosis) is sometimes considered an MS variant, and the uncertain diagnostic status is beyond the scope of this review. Detailed discussion of that entity is available in the Neurology section of the Medscape Reference journal.

   

  

   

Recurrence may occur during the taper of corticosteroid therapy initiated for ADEM. This phenomenon is not thought to represent a second or independent bout of illness; it usually responds to increasing the corticosteroid dosage and prolonging the ensuing taper.

The appearance of small new lesions on MRI within a month of presentation must also be interpreted with caution, and this may be seen in ADEM.

Although long tapers are sometimes required and more than one taper-related worsening occurs in a small number of patients, recovery is achieved within 2-12 months without further recurrence.

A rare subgroup of patients exists who cannot be weaned entirely from anti-inflammatory therapy. Most of the 8 examples one of the authors (RSR) has encountered were in boys, and the onset of illness usually occurred at age 2-6 years.

• Mental status changes, visual disturbance, and pyramidal weakness are typical findings; seizures occur in most cases.
• Imaging changes resemble those found in cases of typical ADEM (ie, multiple plaques at the grey-white junction and in deep white matter), a feature that distinguishes these cases from chronic cases considered a manifestation of Schilder disease.
• The CSF immune profile remains normal despite recurrences, although myelin basic protein may be elevated.
• The neurologic abnormalities in this group improve significantly with intravenous methylprednisolone treatment (20 mg/kg/d for 3 successive doses) followed by oral methylprednisolone (2 mg/kg/d) with slow taper to achieve alternate-day dosing.
• Trouble is encountered during the taper, each patient having a particular threshold for recurrence. In most of the authors' cases, this threshold is encountered when the daily methylprednisolone dose is lowered to approximately 12-14 mg every other day.
• The neurologic worsening responds to higher corticosteroid doses, but this threshold effect cannot be overcome, and steroid therapy has been continued in these patients for periods as long as 8 years.
• Although prolonged daily steroid therapy is generally well tolerated, osteopenia may develop, and one of the authors' patients developed vertebral compression fractures.

In 2007, the International Pediatric Multiple Sclerosis Study Group (IPMSSG) proposed operational definitions for the pediatric acquired demyelinating diseases (including ADEM) in attempts to improve consistency in terminology for clinical and research purposes. These guidelines were revised in 2013 and are outlined below.^[59]

• The criteria requires that a child must meet all of the following to be accurately classified as pediatric ADEM:

  • A first, polyfocal clinical CNS event with presumed inflammatory demyelinating cause
  • Encephalopathy that cannot be explained by fever
  • No new clinical and MRI findings emerge 3 months or more after onset
  • Brain MRI is abnormal during the acute phase
  • Typical findings on brain MRI (discussed below) that include diffuse, poorly demarcated large lesions involving the cerebral white matter; T1 hypointense lesions of the white matter are rare; deep gray matter lesions may be present.

   

  

   

Recurrent ADEM was previously defined as a new event of ADEM with a recurrence of the initial symptoms and signs 3 or more months after the first ADEM event. Based upon the 2013 consensus criteria from IPMSSG,^[59] this entity is now included under the entity known as multiphasic ADEM.

Multiphasic ADEM

• Individuals who have experienced typical ADEM are at risk for recurrence. As many as 10% of children with an initial diagnosis of ADEM experience another ADEM attack, typically within the first 2-8 years after the initial attack.^[85]
• Included under the entity of “multiphasic ADEM” are new events of ADEM 3 months or more after the initial attack that can be associated with new or re-emergence of prior clinical and/or MRI findings.^[59]

  • Relapsing disease that follows a second ADEM attack is, by definition, no longer consistent with a diagnosis of multiphasic ADEM. Typically, these cases represent a chronic neuro-inflammatory disorder (such as MS or NMO).^[59]

   

  

   

• References

Physical

Irritability and lethargy are common first signs of acute disseminated encephalomyelitis (ADEM). Fever returns and headache is present in up to half of cases.^{[47, 63, 58]} Meningismus is also detected in approximately one third of cases.^{[47, 63]} Over the course of minutes to weeks, multifocal neurologic abnormalities develop. The interval from onset of symptoms to maximum deficit is varied but is typically seen at a mean of 4-7 days.^{[47, 58, 85]} Among the most common abnormalities are long tract signs, acute hemiparesis, cranial nerve abnormalities (including visual loss), ataxia, and mental status abnormalities. Mental status disturbances include lethargy, fatigue, confusion, irritability, obtundation, and coma. Focal or generalized seizures occur as an early sign in a minority of cases.

Weakness (roughly 75% of cases) is more commonly discerned than sensory defects. The combinations of these signs may suggest cortical, subcortical, brainstem, cranial nerve, or spinal cord localization. Long tract signs develop in more than half of all cases. Cranial nerve palsies (including vision loss) are found in a wide range of cases (23-89%) of childhood ADEM.^{[58, 54, 47, 63, 71, 85]} Mental or psychiatric disturbances, seizures, and cranial nerve palsies are significantly less common in adolescents or adults with a first or second bout of MS and in many adults with an illness labeled ADEM. Sensory changes may be underappreciated in young children; however, posterior column deficits and hemisensory changes are possibly much less common than in adult cases of ADEM or in early bouts of adolescent or adult MS. Band or girdle dysesthesia or Lhermitte’s sign are seldom if ever found in cases of childhood ADEM.

Ataxia is found in 28-65% of childhood ADEM cases,^{[63, 47, 58, 85]} which tends to differ from cases of ACA because it is more commonly appendicular with nystagmus or generalized ataxia than the distinctive gait/trunk ataxia of ACA. Extrapyramidal disorders such as choreoathetosis or dystonia are sometimes observed.

Signs and symptoms found in cases of ADEM:

• Alteration in personality
• Abnormal consciousness
• Ataxia (appendicular more than axial or gait)
• Cranial nerve palsies
• Hallucinations
• Headache
• Language disturbances
• Meningeal signs
• Nystagmus
• Psychiatric abnormalities
• Optic neuritis
• Ophthalmoparesis
• Seizures, focal or generalized
• Sensory loss/dysesthesia
• Visual field deficits
• Vomiting

• References

Causes

Acute disseminated encephalomyelitis (ADEM) may develop in the wake of a wide variety of infectious illnesses or immunizations, especially those associated with large envelope-bearing viruses. Among the agents most commonly identified by titer rise suggesting responsibility for the prodromal phase are Ebstein-Barr virus, cytomegalovirus, herpes simplex virus (HSV), and mycoplasma; however, a particular agent is identified only in a minority of ADEM cases.

ADEM is somewhat more common in the colder months of the year, during which these various viral illnesses are more prevalent. Prior to widespread immunization programs, measles was the most common associated illness. Now, most cases occur in the wake of respiratory or gastrointestinal illnesses that are presumed to be of viral etiology; specific viral agents are seldom identified.

The hiatus between onset of viral symptoms and onset of ADEM may range from 2-21 days. The two phases of illness are typically separated by a phase of recovery from fever and other constitutional manifestations of the initial infectious phase of illness. ADEM may possibly arise after intervals as long as 30 or more days after an infectious prodrome. The longer the interval between the presumed prodrome and ADEM, the less certain one can be of the etiologic association. A minority of cases lack a prodromal phase. Establishing the etiologic role of immunizations has proven controversial.

Clear links between the Pasteur rabies vaccine and ADEM have been established. Immunizations less frequently associated with ADEM include pertussis, measles,^[8] Japanese B virus, tetanus, influenza, hepatitis B, diphtheria, rubella, pneumococcus, varicella, smallpox, poliomyelitis, and human papillomavirus.^[82]

The provocation provided by an infectious agent likely requires participation of other genetic or immuno-experiential factors of the individual in order to give rise to ADEM. These factors likely include genetically or experientially determined aspects of immunoregulation, particularly T-helper cell function. Alves-Leon et al have found that the alleles HLA DQB1*0602, DRB1*1501, and DRB1*1503 confer genetic susceptibility to acute disseminated encephalomyelitis.^[9]

• References

Laboratory Studies

Platelet counts are elevated in a number of children with ADEM. Sedimentation rates are elevated in a third of patients.^[47]

Modest-to-moderate elevation of CSF white and red blood cell counts may be found in childhood ADEM. Red blood cells may be due to modest degrees of AHLE. Elevated CSF HSV or Lyme titers do not exclude the possibility of associated ADEM, especially in recurrent herpes encephalitis. Results of CSF immune profile testing (eg, CSF:serum immunoglobulin G [IgG] index, CNS IgG synthetic rate, oligoclonality) employing age-appropriate normative data are positive in fewer than 10% of prepubertal children with ADEM.^[10]

Positivity of studies for CSF oligoclonal bands and immunoglobulin elevation favors the diagnosis of MS in individuals younger than 20 years with first or recurrent bouts of acute CNS demyelinating illness.^[7] In such instances it remains incumbent on those evaluating such individuals to exclude non-MS illnesses with specific biological markers such as systemic lupus, sarcoid, neuromyelitis optica, and so forth.

CSF myelin basic protein concentration level, reflecting demyelination,^[83] is frequently elevated in ADEM.

• References

Imaging Studies

The CT scan low-density abnormalities are found in more than half of childhood or adolescent ADEM cases,^[47] but this technique is far less sensitive than MRI for the disclosure of extent and number of lesions.

T2-weighted and fluid attenuated inversion recovery (FLAIR), proton-density, or echo-planar trace diffusion MRI techniques disclose characteristic high-signal lesions in virtually all cases of ADEM.^[47] T2/FLAIR images are particularly important in the evaluation of young individuals presenting with inflammatory CNS demyelinative illnesses that may be ADEM or MS.^[11] Apparent diffusion coefficient maps show high-signal changes consistent with vasogenic edema.

ADEM lesions are characteristically multiple, bilateral but asymmetric, and widespread within the CNS.

• Typical lesions of ADEM include centrifugal at the junction of the deep cortical gray and subcortical white matter. Such lesions are found in more than 90% of children with ADEM. They are found in less than 40% of adults initially diagnosed as having ADEM, many of whom are later diagnosed as having MS.
• Additional lesions may be found in deeper white matter, basal ganglia (30-40%), thalamus (30-40%), brainstem (45-55%), cerebellum (30-40%), and the spinal cord (16-28%).^{[47, 58, 54, 11]} Periventricular lesions and corpus callosal lesions are uncommon in childhood ADEM compared with MS.^[11]
• The indistinct margins of childhood ADEM lesions tend to suggest a "smudged" edge rather than the crisp margin typical of the classic ellipsoid plaques of MS.
• Though variable, as many as 90% of childhood ADEM lesions enhance with gadolinium. The degree of contrast enhancement of ADEM lesions is typically uniform and usually not very dense. In contrast, MS plaques tend to vary in degree of contrast enhancement and may at times enhance quite densely.^{[12, 13, 14]}

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  Typical childhood ADEM in 7-year-old. Note tendency to involve gray-white junction, the fact that the lesion margins are less well defined than typica....

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  Typical adolescent multiple sclerosis findings on MRI. Note the tendency of lesions to exhibit sharp margins, to be elongated, to occur in deep white ....

   

  

   
• Many of the diseases that constitute the differential diagnosis of ADEM produce MRI abnormalities that emulate various ADEM-associated lesions.

  • Some cases of encephalitis result in the development of multiple tiny or small patches of bright signal on T2-weighted images that have been mislabeled as ADEM, but response to corticosteroid therapy is poor and follow-up scans may show severe encephalomalacia.
  • HSV-2 encephalitis or Lyme disease may be difficult to distinguish from ADEM and may involve ADEM mechanisms in pathogenesis.
  • Pial enhancement does not occur in ADEM and suggests meningoencephalitis.
  • Metazoal parasitic diseases of the brain (eg, cysticercosis), neoplasia, and ADEM are occasionally mistaken for one another.
  • Metabolic leukdystrophies may appear similar on MRI but often exhibit symmetric abnormalities in the white matter (as opposed to the asymmetric abnormalities seen in ADEM).

   

  

   
• ADEM lesions may contain areas of hemorrhage suggestive of HSV-2 encephalitis, changes never found in MS plaques.
• Unusual MRI abnormalities that are found in young individuals suspected of having ADEM may help greatly in distinguishing ADEM from MS or other alternative diagnoses. ADEM gives rise to a much wider variety of appearances than MS. ADEM may produce large unilateral T2 bright lesions, some of which appear to have striking central cavitation. These lesions may suggest neoplasm, stroke, parasitism, abscess, or MS. Ring enhancement or mass effect sometimes found in ADEM may suggest abscess or tumor.^[15] In rare cases, symmetrical, linear, posteriorly emphasized white matter changes on T2 weighting suggest leukodystrophy. Recognize that no changes on MRI are pathognomonic of ADEM or, for that matter, of demyelination.
• Some patients with ADEM have normal findings on MRI on initial presentation that become abnormal and characteristic of ADEM if the study is repeated several weeks later.^[16] This suggests that characteristic features may be missed because of sampling error, that normal findings on a scan do not exclude the ADEM diagnosis, and that the appearance of new lesions during the course of ADEM may not represent recrudescence of disease.

Magnetization transfer MRI, single photon emission CT scanning, or nuclear magnetic resonance (NMR) spectroscopy may possibly prove helpful in distinguishing ADEM from alternative diagnoses, although the development of a pathognomonic imaging result is unlikely. For these reasons, diagnosing ADEM on the basis of findings on scanning alone is dangerous. Diagnosis of ADEM should always rest on clinical grounds in children as in adults.

• Radiographic studies and other laboratory tests are especially valuable in ruling in or out alternative diagnoses.

From a retrospective analysis, Callen et al propose diagnostic criteria for MRI to distinguish a first MS attack in children from those with acute disseminated encephalomyelitis. Any 2 of the following criteria could distinguish MS from acute disseminated encephalomyelitis (sensitivity 81%, specificity 95%): (1) absence of a diffuse bilateral lesion pattern, (2) presence of black holes, and (3) presence of 2 or more periventricular lesions.^[11]

• References

Other Tests

See the list below:

• The EEG often exhibits a disturbance of normal sleep rhythms and focal or generalized slowing. Epileptiform discharges are rarely seen in ADEM.^[47] The absence of such abnormalities during the first bout of acute disseminated demyelinating illness in a child may increase the suspicion for ultimate MS diagnosis. Similar EEG abnormalities are found in adult ADEM.^[84]
• Visual evoked potentials (VEP) may prove helpful when optic neuritis is suspected but not apparent on clinical examination.

• References

Procedures

The lumbar puncture is an essential aspect of acute disseminated encephalomyelitis (ADEM) workup.^[17] It assists in distinguishing ADEM from various forms of meningoencephalitis, especially upon the basis of titers for the various bacteria, viruses, or other agents that may produce a directly infectious form of meningoencephalitis.

• The immune profile is also helpful in distinguishing ADEM from MS. The IgG index, IgG synthetic rate, or oligoclonal bands are positive in more than two thirds of all first clinically recognized MS bouts and in 90-98% of individuals who have experienced multiple MS bouts. One or more of these studies is positive in a minority of ADEM cases.
• Note that the findings on immune profile studies may be positive in various infectious conditions such as neurosyphilis, subacute sclerosing panencephalitis (SSPE), Lyme disease, stroke, and various forms of acute or chronic bacterial or viral meningoencephalitis. The CSF:serum IgG index or synthetic rate formulations may show positive results in neurosyphilis, Lyme disease, Guillain-Barré syndrome, some brain tumors, sarcoid, and a wide variety of bacterial or viral meningoencephalitides or other forms of CNS inflammation.

Occasionally, brain biopsy is necessary to distinguish ADEM from other diagnostic possibilities. The diagnosis of ADEM is confirmed when typical perivenular demyelinating changes with axonal sparing are observed.^{[47, 85]}

• References

Medical Care

Acute disseminated encephalomyelitis (ADEM) is often treated with high-dose intravenous corticosteroids, to which it appears to be responsive. One common protocol is 20-30 mg/kg/d of methylprednisolone (maximum dose of 1 g/d) for 3-5 days. Improvement may be observed within hours but usually requires several days. An oral taper for 4-6 weeks or some other interval is sometimes appended.

• Though there is conflicting data, at least two studies have presented data suggesting that steroid taper of 3 weeks or less may increase the risk of relapse in ADEM.^{[47, 63]}
• Taper-related recurrence occurs in as many as 3-5% of cases and usually responds to prolongation of taper. Similar phenomena occur in other postinfectious diseases, such as Guillain-Barré syndrome or opsoclonus-myoclonus. A subset of patients manifest repeated recurrences that prevent discontinuation of corticosteroids or necessitate changing to various steroid-sparing treatments such as cyclophosphamide or beta-interferons. This rare and interesting subgroup tends to have onset of disease before 6 years of age, and despite recurrence, these children do not manifest evidence for CSF immune profile (ie, IgG index, IgG synthetic rate, oligoclonal bands) abnormality. The relationship of this group to patients with ADEM or MS or some other form of inflammatory CNS illness remains unclear.

The chief alternative therapy is intravenous immune globulin (IVIG).^{[18, 86]} It is administered as 2 g/kg intravenously as a single dose or over the course of 3-5 days. IVIG may be preferable in instances where meningo-encephalitis cannot be excluded based upon the hypothesis that corticosteroids might worsen the course of infection.^[18]

Available published information concerning efficacy is inadequate to accurately assess much concerning the impact of either form of therapy, although it appears likely that both forms of therapy increase the pace of initial recovery. Whether these forms of therapy influence times to final outcome or extent of final recovery is not known.

Theoretically, very high-dose corticosteroids (30-50 mg/kg) administered intravenously at presentation to patients with transverse myelitis may be advantageous from the vantage point of its capacity to close the blood-brain barrier and limit swelling. Marked cord swelling may account for poor outcome in some cases of transverse myelitis because of circulatory impairment and cord infarction. The same argument may hold true for severe cerebral ADEM such as tends to arise in some young children (< 3 y old) who also may have marked permanent neurologic impairments after severe ADEM.

There is as yet no convincing evidence that treatment with the combination of intravenous corticosteroids and IVIG confers any advantage in such cases, although this approach is employed by some clinicians.

Severe ADEM has also been treated, apparently successfully, with such alternative approaches as (1) combination of intravenous corticosteroids and IVIG, (2) cyclosporin, (3) cyclophosphamide, or (4) plasma exchange/plasmapheresis.^{[19, 20, 87]} Greater understanding of trimolecular complex regulation, adhesion molecules, and inflammatory cytokines may permit development of more specific and effective ADEM therapies. The polymorphism of the human major histocompatibility complex and apparent heterogeneity of T cell response to autoantigens render this a daunting project, although anti-cytokines represent an intriguing avenue of therapeutic research.^[21]

• References

Surgical Care

Surgical treatment for severely elevated intracranial pressure has been undertaken for cases of AHLE, hemorrhagic brain purpura, and non-Reye syndrome, examples of what have been termed obscure encephalopathies of infancy. Some of these cases were likely examples of hyperacute ADEM. Surgical interventions have ranged from placement of pressure bolts to decompression of the intracranial fossae by unroofing of the cranium. Outcome of such interventions was mixed.

Although such severe cases were regularly noted in the medical literature from the 1920s until the mid 1970s, few examples have been noted since that time. Prevalence clearly has dramatically decreased. Because these severe cases often followed measles, mumps, and other diseases for which effective vaccines have been developed and because the disappearance of such cases has followed the availability and use of such vaccines (earlier disappearance in the United States and Western Europe, subsequent disappearance in Asia and the Middle East), this change in prevalence likely reflects the removal of pathogens that are provocative of such severe forms of ADEM.

• References

Consultations

Consultations with infectious disease specialists are occasionally warranted to consider alternative diagnoses. Pediatric intensivists generally become involved in severe cases for management of airway, breathing, and circulation.

• References

Activity

No clear restrictions on activity exist except as indicated by the severity of disease. The possible exceptions are ADEM-related postinfectious demyelinating syndromes, sometimes in association with the development of brain edema, that arise in the wake of illnesses such as brucellosis or malaria. In the case of acute brucellosis, recovery is clearly more rapid and relapse is less likely if patients are treated with enforced bedrest. This rule may also be true of the relapsing neurobrucellotic illnesses, including the types that closely resemble or are examples of ADEM. Although somewhat less clear in the case of cerebral malaria, little doubt exists that enforced bedrest with appropriate positioning (because of elevation of intracranial pressure) is of importance. In the case of cerebral malaria and in cases of the more severe varieties of neurobrucellosis, bedrest is often necessary because of the low mental status and weakness of such individuals.

• References

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

• References

Methylprednisolone (Adlone, Medrol, Solu-Medrol, Depo-Medrol)

• Dosing, Interactions, etc.

Clinical Context:  Considerable experience has accumulated in the use of various corticosteroids in the treatment of ADEM. No conclusive evidence exists that this form of therapy is effective. The weight of evidence at present supports the view that corticosteroids may shorten the time to onset of improvement. Whether this form of therapy shortens time to maximal recovery is unclear, and whether deleterious effects, such as enhancement of tendency to recurrence, exist is unknown. Generally, however, this form of therapy appears, within the considerable limits of present knowledge, to be safe. The usual approach is administration of methylprednisolone for 3-5 d IV (or the equivalent dose of some other anti-inflammatory corticosteroid). The initial dose should be administered under close supervision because rare instances of anaphylaxis after initial dose have been reported.

• References

Human immune globulin (Gammagard, Gamimune, Sandoglobulin, IVIg)

• Dosing, Interactions, etc.

Clinical Context:  Believed to treat conditions associated with inflammation and immune dysregulation by neutralizing circulating myelin antibodies through anti-idiotypic antibodies. May down-regulate proinflammatory cytokines, including IFN-gamma. Blocks Fc receptors on macrophages, suppresses inducer T and B cells, and augments suppressor T cells; blocks complement cascade. May promote remyelination. May increase CSF IgG modestly.

• References

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Both corticosteroids and intravenous IVIG modify the body's immune response to diverse stimuli.

• References

Further Outpatient Care

See the list below:

• Outpatient care indications depend on the course of illness and the extent of recovery at the time of discharge. It may include the involvement of physical, occupational, or speech therapists. Some patients require follow-up with urologists or gastroenterologists because of persistent bladder or bowel problems.
• Patients who are placed on tapering doses of oral corticosteroids require follow-up to ascertain the rate and extent of improvement. Urgent return or consultation may be warranted by patients who display relapse during taper of corticosteroids. In such instances, the relapse is usually controlled by restoration of a higher medication dosage with slower ensuing taper. Some difficult cases require slow tapers.

• References

Further Inpatient Care

See the list below:

• After initial evaluation and initiation of therapy, further inpatient care is dictated by the evolution of disease and rate of recovery exhibited by the patient.
• Physical and occupational therapy may be indicated in patients with paresis, ataxia, low vision, and other focal neurologic abnormalities that impair function.
• Provision for feeding and for the treatment of abnormalities of bowel or bladder function may be indicated.
• When seizures occur, they usually do so transiently at the onset of disease. In rare instances, additional management issues for seizures arise during the subsequent course of treatment.

• References

Transfer

See the list below:

• Some patients with more severe degrees of neurologic disability are transferred to rehabilitation facilities for some period of time before they are judged sufficiently recovered to be discharged home.

• References

Deterrence/Prevention

Acute hemorrhagic leukoencephalitis, which Dorothy Russell demonstrated to be at the severe end of the spectrum of ADEM-like illnesses, may be observed in certain infectious illnesses such as measles encephalitis. This and other possible examples of severe ADEM-spectrum illness may be prevented by immunization.

Recently, several factors have been suggested to modify risk for multiple sclerosis.

• A factor that may reduce the risk for such autoimmune illness is the type and degree of early childhood infectious illness, due to favorable effects on the early childhood development of immunoregulatory function.
• Suggestions have also been made about potential positive effects of early childhood sun exposure via vitamin D-related effects on immunoregulatory function.

Prevention of early childhood illnesses that might have favorable effects on immunoregulation and reduced sun exposure may be elements that account for what appears to be a dramatic increase in prevalence of certain forms of autoimmune illness over the past 4 decades in wealthier countries of the world. These assertions have provoked scientific investigation of considerable interest, but the conclusions remain incompletely verified and their relevance to ADEM remains quite uncertain.

• References

Complications

See the list below:

• The most common inpatient complications include abnormalities of vision, motor function (ie, pyramidal, extrapyramidal, cerebellar), or bladder or bowel function.^[22]
• Recurrence is the chief outpatient complication and is rare.

• References

Prognosis

See the list below:

• The outlook for recovery is generally excellent. Although some older series suggest up to a 10% mortality rate, only 1.5% of the author’s (RSR) cases have resulted in mortality due to ADEM-related complications. Other studies present mortalities of 0% in treated ADEM cases.^{[47, 58, 63, 85]} Degree of recovery appears to be unrelated to severity of illness. Complete recovery may be observed even in children who become blind, comatose, and quadriparetic. Recovery is poorest in children younger than 2 years, patients with myelitis, and those who have significant edema of the brain or spinal cord. Whether ultra–high-dose corticosteroid therapy and other treatments for edema might improve the outcome for these groups is not yet known, although limited experience suggests this possibility. In other cases of ADEM, modest visual or motor deficits may persist, as may sphincter abnormalities in patients with spinal cord disease. Disturbances of mood and personality mayoutlastmotordeficits, but they may also wane over ensuing months.
• The long-term (10-y follow-up) risk of patients with ADEM for development of MS is 25%. Risk for MS is highest in children whose ADEM onset was (1) afebrile, (2) without mental status change, (3) without prodromal viral illness or immunization, (4) without generalized EEG slowing, or (5) associated with an abnormal CSF immune profile.^[88]
• Most patients who experience a bout of ADEM can look forward to complete recovery or the persistence of only mild deficits, such as modestly diminished visual acuity. This excellent outlook even applies to patients who experienced a global low state of function during the acute illness.
• Whether any available form of treatment has a favorable effect on the time to maximal recovery or the risk for deficits is unknown. Exceptions to the excellent outlook are patients with transverse myelitis and infants younger than 2 years. Cord swelling may account for the high rate of residual paresis and the occasional death of patients with severe acute inflammatory myelitis. Prompt administration of high doses of corticosteroids can possibly improve the outlook for these patients, but no reliable data yet support this hypothesis.
• The authors have observed children with a typical bout of ADEM in the first decade of life who manifest MS during the second decade, after a symptom-free hiatus of more than 10 years.

In the authors' experience, the risk for MS for children who have had a single prepubertal bout of ADEM is less than 6%.

• A single study looking at prognostic factors associated with relapse after ADEM included the presence of optic neuritis, family history of CNS inflammatory demyelination, meeting Barkhof MS criteria on MRI, and the absence of neurologic sequelae after the initial attack of ADEM.^[71]
• Consensus guidelines consider relapsing disease following ADEM occurring beyond a second encephalopathic event more suggestive of a chronic disorder, and entities such as MS and NMO need to be considered.^[59]
• Rare vasculitic or inflammatory processes that must be diagnosed by biopsy of brain tissue or other organs (eg, CNS vasculitis, hypersensitivity vasculitides, sarcoidosis, histiocytic lymphogranulomatosis) should also be considered.

• References

Patient Education

See the list below:

• For excellent patient education resources, see eMedicineHealth's Brain & Nervous System Center and the article Multiple Sclerosis. All these materials may be printed free of charge.

• References