Excerpt from Acute Disseminated Encephalomyelitis

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Background

Acute disseminated encephalomyelitis (ADEM) is a nonvasculitic inflammatory demyelinating condition that bears a striking clinical and pathological resemblance to multiple sclerosis (MS). However, in most instances, ADEM and MS cases occurring in children are readily distinguishable on the basis of clinical features and findings on laboratory investigations. MS is typically a chronic relapsing and remitting disease of young adults, while ADEM is typically a monophasic disease of prepubertal children. Abnormalities of findings on cerebrospinal fluid (CSF) immunoglobulin studies are likely in MS but are much less common in ADEM. 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 degree, features that are uncommon in MS.

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

United States

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.

International

Little is known about occurrence throughout the world, except that cases are likely to occur in all regions of the world. Genetic factors, prevalence of infectious pathogens, immunization status, degree of skin pigmentation, diet, and other factors may influence risk. Of particular importance is immunization because immunization to pathogens known to provoke ADEM has reduced the incidence of severe forms of ADEM such as those that may follow cases of measles and other viral illnesses. On the other hand, early forms of the Pasteur rabies vaccine may also provoke severe ADEM, a problem that has been resolved by improvement of rabies vaccines. The role of other vaccines in ADEM remains controversial. Areas of the world where malaria is prevalent produce cases of cerebral malaria, likely to be an ADEM variant.

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.

Age

More than 80% of childhood cases occur in patients younger than 10 years; 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.

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