However, the division between these processes is indistinct, which is suggestive of a clinical continuum. Moreover, other conditions along the suggested continuum include optic neuritis, transverse myelitis, and Devic syndrome, clinical entities that may occur as manifestations of either MS or ADEM. 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 distinct from ADEM, such as acute cerebellar ataxia (ACA). A further indistinct boundary is shared by ADEM and Guillain-Barré syndrome and is manifested in cases of Miller-Fisher syndrome and encephalomyeloradiculoneuropathy (EMRN).
Susceptibility to either condition is likely the product of multiple factors, including a complex interrelationship of genetics and exposure to infectious agents and possibly other environmental factors. Of particular interest are the indications that susceptibility to either condition is in part age related. Most cases of either MS or of ADEM possibly occur as the result of an inflammatory response provoked by prepubertal infection with a virus, viral vaccine, or other infectious agent. Typically, the manifestations of ADEM occur quickly after this prepubertal febrile systemic illness and are monophasic. In a minority of cases, patients with ADEM experience 1 or 2 prepubertal 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 immunodysregulation. Bouts of MS occur without febrile prodrome. Uncommonly, MS develops in prepubertal individuals and ADEM develops in postpubertal individuals, and some cases of adolescent-onset MS may go into remission. In very rare instances, individuals manifest prepubertal ADEM and, after long latency, MS in adolescence.
Pathophysiology: MS and 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, demyelinative bouts.
Patients with large tumorlike 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 demyelinative 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 recurrent 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 demyelinative 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 autoantigens such as myelin proteins. 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 proinflammatory 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-1beta 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 (Ishizu, 2006).
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. 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 of 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. Recent evidence in studies of the brains of individuals with MS suggest that gray matter degeneration, especially of descending subcortical fibers, may participate in the progression of MS. Gray matter involvement also occurs in ADEM. Discerning how these inflammatory changes differ in MS or ADEM and how the reactions in either illness are distinguishable from those in other inflammatory and infectious illnesses are among the important subjects of current research.
Frequency:
- In the US: In the authors' personal series of more than 150 cases grouped under the general heading ADEM, the ratio of ADEM cases in the first decade of life to adolescent MS cases is approximately 3:1. If the incidence of MS in the second decade of life in the United States is presumed to be approximately 1 case per 100,000, the incidence of first-decade ADEM may be approximately 3 cases per 100,000. Incidence of second-decade ADEM could be estimated, by similarly imprecise methods, at 1.5 cases per 100,000.
Whether the increasing incidence of MS at increasing distance from the equator is also true of ADEM is unknown. Occurrences of both ADEM and MS bouts describe sine wave plots of seasonal incidence in North America, with peak incidence in February to March in North America and lowest incidence in July to August. 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.
On the other hand, the prevalence of some forms of ADEM is possibly increasing in developed nations, rather than merely being diagnosed more frequently because of the increased use of MRI. No direct evidence supports increased prevalence, but concern is raised by evidence that MS prevalence has increased in the women of such nations during the past 4 decades and that the prevalence of childhood or adolescent autoimmune diseases such as juvenile rheumatoid arthritis, systemic lupus erythematosus, and juvenile-onset diabetes mellitus is also increasing.
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%, involving cases with fulminant cervical transverse myelitis or brain swelling. Children younger than 2 years are particularly subject to such severe presentations.
Morbidity chiefly includes visual, motor, autonomic, and intellectual deficits and epilepsy. Overall, these problems persist after the first few weeks of illness in only about 35% of cases, and in most of these patients, the deficits resolve within 1 year of onset. Intellectual deficits (varying from attention problems to mental retardation) and epilepsy arise most often in children whose bout of ADEM occurs before the second birthday. Visual and motor deficits and problems with bowel or bladder function may persist for varying periods of time (months to permanently) in some cases, particularly in those with transverse myelitis, optic neuritis, and the combination Devic syndrome.
At particular risk for long-term consequences are patients whose ADEM becomes steroid dependent and frequently recurrent with onset before age 6 years, a condition the authors have termed steroid-dependent encephalomyelitis. Another group at significant risk are those whose much less frequent recurrences are diagnosed as MS (usually when the patient is >10 y).
Race: The scientifically imprecise concept of race does not lend itself readily to discussions of ADEM. In the authors' 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.
Degree of skin pigmentation (irrespective of racial background) may influence risk for ADEM, as it may for MS, if recent theories concerning vitamin D metabolism and autoimmune diseases advanced by Hector DeLuca and others prove valid.
Sex: In the authors' series of more than 150 cases, the ratio of boys to girls is 1.3:1. No other substantial data are available.
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>
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 (Stricker, 1992; Kanter, 1995). 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 (Miller, 1991), although anticytokines represent an intriguing avenue of therapeutic research (Sugita, 1993).
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.
Non–taper-related recurrences occur in as many as 5% of children with ADEM. In such instances most children have just a single recurrence, although some prepubertal children manifest 2 or even 3 recurrences within a year or two of the initial bout but then manifest no further recurrences for follow-up intervals as long as 18 years. Although it has been suggested that IVIG administered in treatment of a single recurrence may prevent further recurrence, the evidence for this remains inconclusive because most children with a single recurrence of ADEM that are treated with corticosteroids also have no further recurrences.
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.
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.
Drug Name
| Methylprednisolone (Adlone, Medrol, Solu-Medrol, Depo-Medrol) -- 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. |
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| Adult Dose | 1 g IV qam for 3-5 d; this may be followed, where deemed appropriate, by 2 mg/kg PO (maximal dose 80 mg/d), followed with taper over 3-5 wk |
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| Pediatric Dose | 20 mg/kg IV for 3-5 d initially; this may be followed, where deemed appropriate, by 2 mg/kg/d PO (maximum 80 mg/d), followed with taper over 3-5 wk |
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| Contraindications | Documented hypersensitivity; systemic fungal infection; use in some patients receiving amphotericin B; concomitant cerebral malaria; latent or active amoebiasis; active chickenpox or measles; active tuberculosis; recent myocardial infarction; ulcerative colitis; active or latent peptic ulcer disease; impending gastrointestinal perforation; enteric abscess |
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| Interactions | Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics |
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| Pregnancy | C - Safety for use during pregnancy has not been established. |
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| Precautions | Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use |
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Drug Name
| Human immune globulin (Gammagard, Gamimune, Sandoglobulin, IVIg) -- 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. |
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| Adult Dose | 2 g/kg IV administered over 2-5 d |
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| Pediatric Dose | Not established, adult dosage is usually employed, administered IV |
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| Contraindications | Documented hypersensitivity; IgA deficiency |
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| Interactions | Globulin preparation may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine) |
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| Pregnancy | C - Safety for use during pregnancy has not been established. |
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| Precautions | Check serum IgA before administering IVIg (use an IgA-depleted product, eg, Gammagard S/D); may increase serum viscosity and thromboembolic events; may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes mellitus, volume depletion, or preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia |
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