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Trang 7Chapter 7 Autoimmune and Postinfectious Diseases
Child Neurology
Chapter 7 Autoimmune and Postinfectious Diseases
Robert Rust and RJohn H Menkes
Department of Neurology, University of Virginia School of Medicine, Charlottesville, Virginia 22908; and R Departments of Neurology and Pediatrics, University of California, Los Angeles, UCLA School
of Medicine, and Department of Pediatric Neurology, Cedars-Sinai Medical Center, Los Angeles, California 90048
Experimental Allergic Encephalomyelitis
Primary Demyelinating Diseases of the Central Nervous System
Multiple Sclerosis
Variants of Multiple Sclerosis
Acute Disseminated Encephalomyelitis
Treatment and Prognosis
Acute Transverse Myelitis
Pathology and Pathogenesis
Clinical Manifestations
Diagnosis
Treatment and Prognosis
Acute Cerebellar Ataxia
Pathology and Etiology
Immunologically Mediated Diseases Affecting Central Nervous System Gray Matter
Rheumatic Fever (Sydenham Chorea)
Pediatric Autoimmune Neuropsychiatric Diseases Associated with Streptococcal Infection
Treatment and Prognosis
Postinfectious Abducens Palsy
Other Postinfectious Cranial Neuropathies
Systemic Vasculitides with Nervous System Manifestations
Primary Systemic Vasculitides (Collagen Vascular Diseases, Rheumatic Diseases)
General Pathogenetic Mechanisms of Vasculitic Diseases
Primary Systemic Vasculitides
Secondary Systemic Vasculitides
Collagen Vascular Diseases
Neurologic Complications of Immunizations
EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS
Experimental allergic encephalomyelitis (EAE) has served for many years as a useful animal model in the study of the evolution of autoimmune diseases that affect the nervous system Departing from the postulate that the neuroparalytic accidents observed after the use of a rabies vaccine prepared from neural tissue were
allergies, Rivers and Schwentker observed that the repeated injection of cerebral tissue into monkeys produced an inflammatory demyelinating encephalomyelitis ( 1)
Similar lesions have been produced consistently in other mammalian species; their appearance is enhanced by the addition of Freund's adjuvant, a commonly used emulsion of water, oil, and killed acid-fast organisms added to the antigenic material Its mode of action is unknown, but is believed to be a slow release of antigen and the induction of an inflammatory reaction that attracts mononuclear cells In the original studies of Wolf and associates ( 2), 90% of monkeys developed EAE in 2
to 8 weeks after the first of an average of three weekly subcutaneous inoculations The characteristic clinical features of this monophasic disease included paresis of the extremities, ataxia, nystagmus, and blindness The disease was usually fatal, but some animals had mild symptoms that often subsided A chronic disease and a relapsing disease marked by exacerbations and remissions reminiscent of the clinical picture of multiple sclerosis (MS) were produced subsequently in several animal species, including non-human primates (3,4)
Pathologic examination of animals dying from EAE shows multiple focal perivascular areas of demyelination throughout the neuraxis Microscopically, these lesions show an extensive infiltration by round cells, mainly lymphocytes and microglial cells, small perivascular hemorrhages, and myelin degeneration with preservation of the axon cylinders
The first pathologic alteration observed in experimental lesions is the perivenous appearance of hematogenous cells These are initially seen in areas where the
blood–brain barrier has been damaged or where lack of a barrier allows serum proteins to enter the nervous tissue ( 5) At the same time, primary and secondary (wallerian) demyelination can occur Electron microscopic examination reveals a focal disruption of the myelin lamellae, and processes of the invading cells extend between the lamellae Additionally, vesiculation of myelin occurs
Trang 8In older lesions, the patches of demyelination are well defined and marked by varying degrees of gliosis It is still unclear how perivascular demyelination develops in EAE.
Myelin basic protein (MBP) is the substance in the injected cerebral tissue that initiates the evolution of the demyelinating process ( 6) This encephalitogenic protein has been isolated in relatively pure condition from the brain of a number of species A component of normal myelin sheath, it contributes approximately 40% of total
myelin proteins of adult white matter In vivo, it is bound to acidic lipids or proteins The gene coding for it is located on chromosome 18 The complete amino acid
sequence has been determined, and the encephalitogenic activity resides in several peptides
As a consequence of the injection of MBP, T cells carrying gene-specified MBP receptors on their surface lose their immunologic tolerance to neural antigens by an unknown mechanism and escape from the host immunoregulatory restraints to develop into clones of cytotoxic cells These bind to native MBP within the brain of the host, resulting in the deposition of an immune complex The mechanism by which activated T cells enter the CNS is as yet unknown Both encepha-litogenic and nonencephalitogenic cells are able to enter the CNS, but only the encephalitogenic cells remain; nonencephalitogenic cells are cleared within a few days ( 7) It is believed that in the course of a systemic immune response, antigen-specific T cells adhere to the brain endothelial cells Research indicates that EAE is almost
exclusively mediated by Th1 cells, which produce interleukin-2 (IL-2) and interferon-g Multiple other cytokines produced by astrocytes and microglial cells also play major roles in inflammation and tissue destruction T-cell adherence to endothelial cells is further enhanced by the class II major histocompatibility complex antigens, molecules induced by interferon-g Other factors, notably endoglycosidases, guide the T cells through the blood–brain barrier Once within the CNS, these immune complexes can attract hematogenous mononuclear cells and induce the release of chemotactic factors to initiate the ensuing inflammation Macrophages are believed
to play an important role in myelin destruction by their release of myelinolytic proteases ( 8)
The passive transfer of EAE can be accomplished by CD4+ T lymphocytes, but not by serum Other characteristics of EAE are that the disease can be blocked by antibodies against CD4+ T cells, by treatment of susceptible animals with a synthetic peptide, structurally related to the encephalitogenic portion of the MBP, or by irradiation (9,10) The development of EAE also can be suppressed by the administration of corticosteroids, nitrogen mustard, or 6-mercaptopurine
Susceptibility to the induction of the condition depends on a number of host factors Immature animals are relatively more resistant to EAE than adult animals; diets inadequate in vitamin B12, biotin, or folic acid decrease susceptibility Most important, both highly susceptible and highly resistant genetic lines have been segregated
in a number of mammalian species
MBP also is the encephalitogen responsible for the encephalomyelitis after rabies immunization Antibodies to MBP can be demonstrated in serum and in the
cerebrospinal fluid (CSF) at the onset of symptoms, and a T-cell response to CNS myelin can be demonstrated in vaccinated subjects who develop encephalitis ( 11)
A T-cell response and circulating antibod-ies to MBP also have been found in postmeasles encephalitis
The role, if any, of MBP in the other autoimmune disorders is not as clear Whether the antigen responsible for MS is similar to the MBP that induces EAE, or whether the antigen is derived from a virus or viruses remains to be answered In any case, the sequence of events leading to demyelination in MS appears to be
morphologically similar to that observed in EAE (12), and, for the time being, this condition still serves as the best available laboratory model for the pathogenesis of some of the autoimmune and postinfectious disorders
Much work has concentrated on the effects of soluble factors (cytokines) on activated T cells IL-2 is thought to play a particularly important role in the propagation of the activated T cells that may mediate EAE (12a) Human interferon-g and tumor necrosis factor (TNF) can induce the plasminogen activator of lymphocytes from patients with acute disseminated encephalomyelitis (ADEM) and MS, but not from control subjects, possibly indicating a role for these cytokines in the mediation of demyelination (12b)
PRIMARY DEMYELINATING DISEASES OF THE CENTRAL NERVOUS SYSTEM
In the northern hemisphere, ADEM, MS, and optic neuritis are the three most frequently encountered primary demyelinating illnesses of the CNS The first is more common in children younger than age 12 years; the second is more common in adolescents and adults Difficulty in distinguishing ADEM from the first bout of MS is among the most important reasons for the requirement of a second distinct episode occurring at least 1 month after the first for diagnosis of MS It remains
controversial as to whether “recurrent ADEM” should be distinguished from MS, but it appears likely that this distinction is valuable in prepubertal children Optic
neuritis and the combination of optic neuritis and transverse myelitis (Devic disease) usually occur as manifestations of ADEM or MS, but may result from other types
of illness
An area of semiologic overlap exists between ADEM and Gullain-Barré syndrome (GBS) This area of overlap includes some or possibly all patients who manifest the clinical findings of Miller-Fisher syndrome It also includes the minority of ADEM cases that manifest diminished or absent muscle stretch reflexes in combination with weakness and sensory changes referable to peripheral nerve dysfunction The designation encephalomyeloradiculoneuropathy (EMRN) may be applied to cases exhibiting this overlap of central and peripheral demyelinative manifestations Other much rarer primary demyelinative conditions that may occur in children and are difficult to accurately classify are acute (Marburg type) MS, Schilder disease, and Balo disease (concentric sclerosis) Infants younger than 2 years of age may
experience a single bout of severe demyelination with edema that could be termed acute MS or, perhaps more appropriately, severe ADEM
The etiology and pathogenesis of these various primary demyelinating illnesses are as yet incompletely understood and it is not known whether MS, ADEM, and such related illnesses as optic neuritis, transverse myelitis, and others share exactly the same mechanism Both MS and ADEM involve autoimmune responses that are directed, at least in part, against myelin antigens, but it is as yet unknown whether this represents a primary or secondary aspect of the inflammatory process of either illness The onset of MS does not have a clear etiologic relationship to preceding infection and bouts are typically associated with detectable and abnormal production
of immunoglobulin within the CNS ADEM appears in many cases to be provoked by an immediately preceding infectious illness and only a minority of cases exhibit elevated CSF concentrations of immunoglobulin or immunoglobulin oligoclonality Normal CSF immunoglobulin studies are characteristic of recurrences of ADEM, as compared with a greater than 94% likelihood of abnormality in association with an MS recurrence
A small minority of individuals who have experienced typical cases of ADEM in early childhood ultimately satisfies the clinical criteria for diagnosis of MS during
adolescence It is not known why some individuals experience one or more bouts of postinfectious demyelin-ation but achieve stable remission (ADEM or recurrent ADEM) before adolescence, whereas others satisfy criteria for the diagnosis of MS with either relapsing-remitting or steadily progressive manifestations of primary central demyelination No completely reliable diagnostic test exists for either illness, and in every case a number of other illnesses must be excluded before assigning either of these labels It may be particularly difficult to distinguish ADEM and related forms of inflammation from encephalitis Indeed, some forms of encephalitis (such
as those caused by herpes or measles viruses) may manifest pathologic abnormalities of ADEM in combination with those of encephalitis
Multiple Sclerosis
Historical Aspects
MS is the principal immune-mediated demye-linating illness of humans (13) The pathologic lesions of MS were described by Cruveilhier and Carswell early in the nineteenth century Frerichs was the first to make a clinical diagnosis of MS in 1849 Charcot's extensive studies of the clinical manifestations and natural history of
MS resulted in diagnostic criteria for a coherent clinical entity designated disseminated sclerosis or sclerose en plaques that also is and quite justifiably termed
Charcot disease (14) Although the particular prevalence of this illness among young adults was recognized at the outset, subsequent clinical experience and
confirmatory pathologic studies have demonstrated that MS may occur in infants and children (15,16)
Pathogenesis
MS occurs more frequently in certain parts of the world, and in regions of greater endemicity, certain subpopulations are at greater risk Thus, in both Europe and North America, the risk is roughly proportional to the distance from the equator of the latitude in which a given individual has spent the first few decades of life A particularly significant increase in prevalence exists in North America above the 38th parallel, whereas in Europe this increase occurs above the 46th parallel Not all populations in these regions of high prevalence (30 to 100 cases per 100,000) partake of this enhanced risk, however Thus, for example, the risk for Hungarian gypsies is 15- to 25-fold lower than that for the predominantly Magyr population of that country However, the clear demonstration of regionally determined risk has
Trang 9been one of several lines of evidence advanced in support of the widely held concept that MS is initially provoked by an infectious agent This line of reasoning has been supported by the development of MS epidemics in certain sheltered populations suddenly exposed to an influx of people from areas of relatively high endemic risk for MS The appearance of MS on the Faroe Islands when British troops were stationed there during World War II is an important example of this phenomenon Genetic susceptibility also may have played a role in this epidemic (17).
Among the most important data supporting a direct etiologic role of infection or some other childhood experience are those obtained in studies of families migrating either from temperate or subarctic regions of the northern hemisphere to Israel or from Israel to these northerly latitudes These studies demonstrate that the risk for
MS is strongly influenced by the latitude, or perhaps even more specifically by the climate in which individuals live during the first two decades of life This suggests the possibility that MS is caused by infection, incurred early in life, with an agent that is more prevalent in more northern latitudes It is not known whether any
possible directly infectious neurologic dysfunction might chiefly affect oligodendrocytes or myelin Despite considerable effort and the identification of candidate
viruses that are capable of provoking CNS demyelination (visna, JHM virus—a corona virus,—canine distemper, Theiler murine encephalomyelitis virus, measles, herpes simplex virus), a direct etiologic role for viruses or other infectious agents remains unproven ( 18) It remains possible that an intermittently activated MS virus
resides undetected in oligodendrocytes
A second hypothesis suggests that infection with a virus or other agent serves indirectly to provoke MS because of the induction of immunodysregulation and
autoimmunity This hypothesis suggests that any of a number of viral or bacterial organisms possess the capacity to produce this unfavorable host response in
susceptible individuals By extension, the increased risk for MS in northern latitudes would be explained by greater prevalence of candidate micro-organisms within the temperate and subarctic ecological niche The disturbance in immunoregulation might result from (a) abrogation of blood–brain barrier caused by inflammatory
injury to blood vessels with secondary exposure of privileged antigens, (b) disturbance of self-tolerance caused by infectious alteration in host antigens, or (c)
sensitization to autoantigens because antigens of invading organism happen to closely resemble them The existence of a limited degree of normal
immunosurveillance of the CNS by lymphocytes capable of passing through the intact blood–brain barrier may be permissive of the second and third mechanisms
The third mechanism is termed molecular mimicry This hypothesis further suggests that the mediation of host autosensitization involves the activity of a trimolecular
complex consisting of a cell-surface antigen of an invading organism, phagocytic antigen-presenting cells (macrophages or possibly microglial cells), and T-helper cells As the result of the interaction between the foreign antigens and these cells, insufficiently specific clonal stimulation of cytotoxic T cells occurs, and inflammatory consequences are experienced by host tissues with similar antigenic determinants It also is possible that the nonspecific clonal stimulation simply increases the number of activated cells in circulation and that these activated cells incite a poorly regulated inflammatory response directed at epitopes expressed on the surface of endothelial tissues or privileged nervous system tissues that are not similar to those of the foreign organism The vascular, humoral, and cellular aspects of
autoimmunity are discussed in further detail in the following section on ADEM
Support for the notion that MS is provoked indirectly by infection is provided by the characteristic occurrence of pathologically and clinically similar ADEM in the wake
of one of a wide variety of febrile infectious illnesses A novel, and as yet unsubstantiated, third hypothesis suggests attempts to explain the enhancement of MS risk
in proportion to distance of early life residence from the equator on the basis of limited cumulative childhood sun exposure and the associated effects on vitamin D metabolism More than one of these mechanisms or indeed others may contribute to MS or by extension ADEM pathogenesis It is probable that if any of these
mechanisms contribute to MS pathogenesis, the likelihood that such indirect effects will occur is genetically regulated
It is clear that the risk for MS is influenced by the immunologic constitution of the individual, represented in part by the human leukocyte antigen (HLA) genes that control the immune system Although the HLA genes may play only a minor role in MS pathogenesis (19), the expression of certain HLA haplotypes appears to
increase the risk for MS by 10- to 20-fold or more within certain populations Among these permissive haplotypes are DRw15, DRw2 or DQw6 (North American and
northern European whites), DR4 (Italians and Arabs), DR6 (Japanese and Mexicans), and A3, B7, or DR Diminished rates of expression of the HLA haplotypes A2, B12, and DR7 are found in northern hemisphere whites with MS (20,21 and 22)
The genetic aspect of MS risk also is demonstrated by the disparity observed among genetically distinct populations living within the same latitude Genetic influence
on susceptibility for MS is strongly supported by studies of families of patients with MS Prevalence rates for MS among first-degree relatives of individuals with MS are approximately 20-fold greater than those of other individuals from the same region Approximately 10% to 15% of patients with MS report another blood relative with this disease Identical twins have a 25% to 35% concordance rate for MS, as compared with 0.5% for offspring (possibly much higher for daughters of mothers with MS), 0.6% for parents, 1.2% for siblings, and 2% to 4% for dizygotic twins (23,24 and 25) Genetic studies have further suggested that T-cell receptor germ-line polymorphisms may participate in the determination of risk for MS, but these data remain inconclusive (26,27 and 28) The lack of 100% concordance for identical twins makes it clear that MS is not caused solely by a single gene defect It has been estimated that as many as 10 to 15 interacting genes may be involved, in
addition to environmental factors (29)
Pathology
The pathognomonic lesion of MS is the plaque Histopathologically, the typical acute plaques are areas of venulocentric demyelination with relative preservation of axis cylinders Recent plaques and the margins of “active” plaques contain a mixture of inflammatory cells, primarily lymphocytes, microglia, and macrophages Older plaques become gliotic and contain astrocytes Plaques may be found anywhere in brain or spinal cord They are largely, but not entirely, confined to white matter, with particular abundance in the periventricular zones (30) (Fig 7.1) The histopathology closely resembles that of ADEM and of the experimental system that has been developed as a model for both MS and ADEM, EAE On the other hand, MS plaques tend to have more discrete margins than those of ADEM
FIG 7.1 Multiple sclerosis Disseminated area of demyelination in white and gray matter of cerebral hemispheres Myelin stain (From Merritt HH Textbook of
neurology, 5th ed Philadelphia: Lea & Febiger, 1973 With permission.)
Because plaques may be located in almost any portion of the CNS, the clinical manifestations of MS are remarkably diverse Larger plaques are clearly visible with appropriate brain imaging and may in some instances occupy locations that explain signs or symptoms of disease However, often no clear clinico-anatomic
association exists for any individual plaque Moreover, clinical improvement may occur before observable resolution of plaques, suggesting that the nervous system dysfunction of MS is caused by more than just demyelination
Immunology
An enormous amount of information has accumulated concerning immune system abnormalities found in patients with MS Much of this information falls beyond the scope of this text Information particularly relevant to MS is considered in this section, whereas information particularly relevant to the other autoimmune conditions is reviewed in other sections of this chapter It is clear that patients with MS as a class do not have immune dysfunction such as might result in systemic
immunodeficiency or autoimmunity, vasculitis, or susceptibility to malignancy (31,32) Systemic antibody responses and delayed-type hypersensitivity are normal The primary disease is restricted to the CNS, within which no increase in susceptibility to unusual infections or any evidence for vasculitis occurs Within the CNS and particularly within the demyelinating plaque, there is clear evidence for disturbances of both humoral and cellular immunity ( 26,33)
Trang 10Abnormal modulation of the humoral immune system is a consistent finding in patients with MS It is represented by the almost universal presence in CSF of (a)
electrophoretically detectable oligoclonal immunoglobulin, (b) elevated rates of synthesis and concentration in CSF of intrathecally generated immunoglobulin G (IgG) and IgM with varied or unknown epitopic specificity, and (c) increased levels of immunoglobulin components such as kappa chains ( 26,34,35 and 36) Although IgG1subclass elevation is the most common, other classes and subclasses of immunoglobulin also are elevated As noted, the antigenic specificity of these
immunoglobulins is various, including reactivity to a wide variety of viruses or other microbes, but in most cases the specificity is unknown
Abnormalities of cellular immunity include loss of T-suppressor/cytotoxic cells with resulting increases in the circulating CD4 + T-helper/inducer to CD8+
T-suppressor/cytotoxic cell ratio during MS relapses in children and adults (31,37,38,39 and 39a) The prominence of lymphocytic infiltration within an active MS
plaque suggests the importance of these cells to MS pathogenesis CD4+ T cells are predominant at the leading edges of active demyelinating lesions, whereas CD8 +
T cells are more frequently encountered in less active plaque regions Most of the T cells found within MS plaques bear the TCR (T-cell receptor) ab chains, although within chronic lesions a number of T cells bear TCRgd chains It has been speculated that TCRab T cells initiate inflammation, whereas TCRgd T cells downregulate the initial response but perpetuate the inflammatory activity of chronic active lesions ( 33)
The considerably diminished cadre of oligodendroglial cells found within chronic active plaques express a particular 65-kD heat shock protein (hsp 65), which is a known stimulus for TCRgd T-cell clones This suggests some relationship of this protein either to the elimination ( 40) or less likely to the preservation of these
oligodendroglia Enhanced expression of the major histocompatibility antigens also is found within active MS plaques This expression is found on the surfaces of microglial cells and macrophages and especially involves the class II major histocompatibility complex antigens with which CD4 + T cells characteristically interact (33,41) Astrocytes within plaques are involved to a lesser extent in the expression of major histocompatibility complex antigens, but oligodendroglial cells are not
Data obtained in the EAE experimental model suggest that activated lymphocytes mediate demyelination, because both the monophasic and chronic relapsing forms
of EAE can be transferred passively by lymphocytes but not by serum Moreover, demyelination in the corona-virus–induced experimental demyelination model
requires the presence of splenic Thy1+ cells (42) In EAE, myelin antigens such as MBP are of considerable importance in cell-mediated demyelination The particular target antigens of MS are unknown but may include myelin epitopes, viruses, and heat-shock proteins (43) Cellular immunity to myelin in MS has not been
conclusively proven (33) It is possible that the importance of the MBP sensitization is of greater importance in ADEM than MS The roles of T-cell activation and T-cell receptor specificity in MS are the subjects of several detailed reviews (26,27,33,39a,43,44)
Enhanced expression of adhesion molecules and cytokines also is found within MS plaques (26,33,43) Among the adhesion molecules of greatest importance are intercellular adhesion molecule-1 (ICAM-1) found on endothelial membranes and leukocyte function-associated antigen-1 (LFA-1) found on lymphocytes Both appear
to facilitate the trafficking of inflammatory cells into MS plaques Among the proinflammatory cytokines found within MS lesions are IL-2, tumor necrosis factor-a
(TNF-a), and interferon-g (IFN-g) Circulating systemic lymphocytes from patients with MS show increased production of these proinflammatory cytokines and
subnormal production of such anti-inflammatory cytokines as transforming growth factor-b (TGF-b) (45,46)
Clinical Manifestations of Multiple Sclerosis in Children and Adolescents
MS is primarily a disease of young adults (47) The peak age of onset is 25 to 30 years, and onset before puberty is uncommon In a series of some 5,000 cases of
MS, less than 0.2% presented before 11 years of age In the same series, only 2.5% of cases presented between 11 and 16 years of age ( 48) In our experience, most adolescent cases present at or after 13 years of age Thereafter, the prevalence increases with each additional year of age In the pediatric population, girls are
affected 2.2 times as frequently as boys, and whites are at greater risk than blacks (48a) The symptoms of the initial attack of MS in childhood are listed in Table 7.1
(48b,48c and 48d)
TABLE 7.1 Symptoms during the initial episode of multiple sclerosis in 56 children
For reasons as yet unknown, childhood MS is more common in China than in the West In a series compiled in 1982, 3.5% of Chinese MS patients experienced the onset of their illnesses before age 10 years, and 22% developed it before age 20 years (49) This age distribution contrasts with 1.5% and 2.7%, with onset before 10 and 16 years, respectively, for a series compiled in Canada (50) In China, MS is characterized by a rapidly progressive course, with lesions most frequently localized
to the optic nerve and spinal cord A similar distribution of lesions, corresponding to what has been designated as neuromyelitis optica (Devic disease), has been
observed in Japan (51)
Among the most common initial manifestations of MS in adolescents and young adults are such monosymptomatic deficits as pure sensory disturbances, optic
neuritis, diplopia, or pure motor paresis In the series of Duquette and colleagues these symptoms accounted, respectively, for 26%, 14%, 11%, and 11% of initial manifestations (48) In the same series, ataxia, gait abnormalities, visual blurring, and combinations of sensorimotor and visual difficulties accounted for an additional 27% of presentations Myelitis, sphincter disturbances, vestibular problems, and other manifestations accounted for only 12% Ataxia and vestibular abnormalities are rather more commonly documented in adult MS than childhood-onset MS (52)
Many of the initial manifestations of MS are subtle and transient They are often unreported or ascribed to some other cause, and their true significance is ascertained only retrospectively The common paraparetic presentation of young adult MS usually is associated with abnormalities of posterior column sensory dysfunction, which
in our experience is often overlooked in adolescent cases because of an inadequate examination This posterior column dysfunction may be more common in early
MS than in ADEM
Prepubertal children may be more likely to manifest unusual clinical features during their first or even during subsequent bouts of MS Acute encephalopathy,
seizures, and prominent pyramidal tract abnormalities are among these unusual presentations Some young children develop acute MS with rapid and profound
psychomotor deterioration (53,54) The clinical signs and symptoms of MS typically progress over hours to days, although some patients have gradual worsening for
as long as several months Transient paroxysmal signs and symptoms may occur in MS, lasting variably from seconds to minutes These include Lhermitte's and
Uhthoff's signs, constricting truncal band sensations, and momentary exacerbation of weakness or sensory disturbance Lhermitte's sign consists of a sudden,
electriclike sensation spreading down the body and into the limbs on sudden flexion of the neck Uhthoff sign consists of the transient appearance of signs or
worsening of existing signs in association with exercise or when exposed to hot ambient temperatures (atmospheric or during bathing) It is thought to be the result of heat-induced impairment of conduction through already demyelinated axons These various paroxysmal phenomena may occur as patients are improving or between bouts of MS and are not regarded either as evidence for recurrence or progression of illness or as separate bouts
In the experience of Cole and Stuart, only 14% of patients whose symptoms appeared before 16 years of age developed primary progressive MS, whereas the
majority of children developed the relapsing-remitting form of MS, with 71% of this group being entirely well between relapses ( 55,56)
Diagnosis
MS is primarily a clinical diagnosis and one of exclusion Remission, exacerbation, and CNS multifocality were recognized as key diagnostic features in Charcot's
Trang 11original description Thus, the criteria for what is usually termed clinically definite MS require evidence for appropriate deficits “separated in both space and time.” It is
essential that at least two bouts whose signs persist for more than 24 hours occur with an intervening period of at least 30 days, and that a recurrence manifests at least one novel clinical or paraclinical lesion as compared with the initial bout The interval between first and second bouts may be longer than 10 years in some children Relapses occurring during the taper of corticosteroid therapy must be distinguished from true MS relapses The diagnostic criteria for MS are summarized in
Table 7.2
TABLE 7.2 Rose research criteria for the clinical diagnosis of multiple sclerosis
The demonstration of multifocality of lesions can in part be satisfied by paraclinical evidence such as neurophysiologic tests and CSF and brain imaging studies Such studies can prove informative in the common childhood monosymptomatic presentations of MS, including optic neuritis, or purely sensory, spinal, or hemiplegic
illnesses The CSF is abnormal at some time in more than two-thirds of patients In Freedman and Merritt's study, which included patients of all ages, mild pleocytosis (6–40 cells/mm3) was seen in 28% of patients and the total protein content was elevated in 24% (57) In the series of Sindern and colleagues, the mean CSF cell count obtained some 6 years after the onset of the disease was 10.5 ± 9.2 (58) CSF glucose and protein abnormalities are uncommon in childhood MS; they are more common in ADEM
More specific CSF examinations include tests that reflect endogenous CNS production of immunoglobulin Some of these tests are quantitative, such as the
CSF/serum IgG index, the IgG synthetic rate, and free kappa or lambda light chains Others are qualitative, such as detection of oligoclonal bands In our experience, the CSF IgG ratio, CSF/serum IgG index, and oligoclonal band determinations are abnormal in 82% of children with MS ( 50) With MS recurrences this number increases to greater than 90% This compares with abnormalities in approximately 20% of children and adolescents experiencing ADEM An increased synthesis of IgG within the CNS is seen in 85% to 95% of patients (59) MBP can be demonstrated in CSF by radioimmunoassays in 70% to 93% of patients during an acute exacerbation of the illness, and its level correlates with the severity of the demyelinating process with the highest elevations observed in ADEM cases ( 60)
None of these tests is totally specific for MS Oligoclonal IgG can be seen in some patients with infectious polyneuropathy, herpes encephalitis, and subacute
sclerosing panencephalitis (SSPE) (61) Similarly, MBP in CSF indicates merely demyelination Accordingly, it is found in a variety of leukodystrophies and after vascular accidents
Abnormalities of visual-, auditory-, and somatosensory-evoked potentials provide information about the multiplicity of demyelinating lesions within the CNS, and, by inference, may help confirm the diagnosis Among the available tests, the latency of the P100 potential of the visual-evoked response, the I–III or III–IV interwave latency of the brainstem auditory-evoked response, or the central component latencies of somatosensory-evoked potentials are particularly likely to be abnormal in patients with MS (62) Sensitivity of the various tests for the diagnosis of MS is shown in Table 7.3
TABLE 7.3 Rate of positivity for paraclinical tests in patients with clinically definite multiple sclerosis
Magnetic resonance imaging (MRI) is a sensitive and important diagnostic tool for demonstrating dissemination in space in children as well as in adults ( 63) Lesions are seen as round or elongated areas of increased signal with sharp margins in the periventricular white matter, less commonly in the brainstem on both
proton-density and T2-weighted images These lesions correspond to plaques, and it is believed that during the acute phase edema is responsible for the increased signal, whereas gliosis causes the abnormal signal during the chronic phase Demyelinating lesions as small as 3 to 4 mm can be identified by MRI; most are
asymptomatic (Fig 7.2) The presence of gadolinium enhancement indicates that the lesion is acute and suggests an impairment of the blood–brain barrier, a
consistent finding in new lesions In the majority of instances, gadolinium enhancement does not persist beyond 3 to 5 weeks ( 64) MRI abnormalities are noted in 70% to 92% of patients with possible, probable, or definite MS The criteria as established by Paty for the MRI-based diagnosis of MS of four or more lesions, are probably too stringent for the pediatric age group, since the specificity of the MRI findings declines with increasing age ( 65,65a)
FIG 7.2 Childhood multiple sclerosis T2-weighted magnetic resonance imaging study showing multiple, discrete areas of increased signal intensity in white matter,
particularly in the periventricular region The patient, a 9-year-old boy, presented with intranuclear ophthalmoplegia, followed by an attack of left hemiparesis
Visual-evoked responses and somatosensory-evoked responses were abnormal There were oligoclonal bands in the cerebrospinal fluid The computed tomographic scan was normal The youngster is currently asymptomatic (Courtesy of Dr Laura Flores de Sarnat, Instituto National de Pediatria, Mexico City.)
Trang 12These MRI characteristics of MS plaques tend to distinguish them from the T2-bright lesions of ADEM The latter are typically more amorphous, less sharply defined, more likely to be centered on the inner margin of the cerebral cortical ribbon involving both white and gray matter, and less likely to show contrast enhancement Symmetric and fairly extensive bilateral areas of abnormality involving gray or white matter may be found in some ADEM cases (66) On the other hand, lesions that closely resemble MS plaques may be produced by human T-cell lymphotropic virus (HTLV-1) infection (67), cerebral vasculitis (68), or certain neoplastic lesions Parasitic lesions, brain abscesses, and metastatic lesions occasionally resemble MS plaques, but are less likely to be confused if edematous.
MRI of optic nerves and spinal cord with T2 weighting can disclose abnormalities in patients with MS-related manifestations suggesting disease in those locations (69,70) Proton MR spectroscopy has been performed in children with MS and could become an important means to follow the activity and progression of the disease (71)
Other causes of recurrent neurologic manifestations are summarized in Table 7.4 Differentiation of MS from ADEM can be difficult during the initial bout of
demyelinating illness in prepubertal children MS is more likely when there are recurrences, or when the initial bout or recurrence occurs after 12 years of age The diagnosis of ADEM is much more likely in prepubertal patients in general, and the likelihood of ADEM becomes near certain if multifocal central neurologic
dysfunction follows a clearly defined infectious prodrome or is accompanied by fever, constitutional symptoms, lethargy, disturbances of consciousness, seizures, or a movement disorder The MS risk for patients with any of these manifestations is less than 10%
TABLE 7.4 Differential diagnosis for multiple sclerosis
Infectious, parainfectious or postinfectious, vasculitic, and granulomatous inflammatory conditions are other conditions to be considered in the differential diagnosis of
MS Syphilis, Lyme encephalomyelitis/neuroborreliosis, cysticercosis, echinococcosis, toxoplasmosis, tropical spastic paraparesis (HTLV-1–associated myelopathy), SSPE, and progressive multifocal leukoencephalopathy also can show clinical fluctuation and tend to improve with immunosuppressive therapy Almost all of the vasculitides also must be considered The recurrent hemiplegic manifestations of moyamoya disease or mitochondrial disorders also can suggest MS Certain chronic intoxications may resemble MS These include toluene sniffing, subacute myelo-opticoneuropathy, and chronic excessive use of barbiturates, diphenylhydantoin, or bromium
Important factors in assigning diagnosis or estimating risk for ultimate diagnosis of MS are the child's age, clinical findings, distribution of changes on MRI scan, and the CSF immune profile Based on our experience, the risk for MS for children younger than 12 years of age who have had a single bout of acute idiopathic
demyelinating illness is less than 6% The MS risk for children who have had one to three relapses of otherwise unexplained inflammatory demyelination before 12 years of age increases to 15% to 33%, with the remainder probably having a recurrent form of ADEM Children with more than three recurrences before 12 years of age are more likely to have vasculitic or other inflammatory illnesses A single bout of otherwise unexplained demyelinating illness in an individual older than 11.9 years of age implies at least a 50% risk for the diagnosis of MS within 9 years, whereas additional recurrences increase that risk to the range of 80% to 100%
Failure to achieve clinical remission, especially in young patients, weighs against the diagnosis of MS This last qualification includes patients who improve on
corticosteroid therapy but cannot be weaned from that form of treatment without relapse In such instances a vasculitic illness must be considered
Currently, initial bouts of MS and most relapses are generally treated with high doses of intravenous corticosteroids that should probably be followed by slowly
tapering doses of oral corticosteroids (72) Although corticosteroids appear to shorten the latency to onset of improvement in individual bouts and may shorten the interval to full remission, it is less clear that they improve the degree of recovery and they do not significantly influence the long-term course of the disease ( 73)
If corticosteroid therapy is elected, it is our practice to administer intravenous corticosteroids, 10 to 20 mg/kg (maximum 1 g) as a single early morning dose for 3 to 5 days, followed by an oral taper (initially at 2 mg/kg per day, maximum 80 mg of prednisone or methylprednisolone) over the ensuing 3 weeks In our experience, this form of management results in an onset of improvement within three days and sometimes within a few hours We do not know whether intravenous administration of immunoglobulin (IVIG) confers any advantage Side effects, notably meningismus or vomiting, are more common with immunoglobulin, and treatment is much more expensive The effectiveness of plasmapheresis in childhood MS is still unproven (73a)
With more frequent or severe relapses, continuous immunomodulatory treatment is currently favored in the hope that one of these agents might modify the natural course of MS by minimizing ongoing disease activity, including subclinical disease progression, and preventing recurrences or the accumulation of deficits Three choices are currently available: interferon-b (Betaseron), glycosylated interferon-b (Avonex), and a random polymerized mixture of myelin-related amino acids
(glatirameracetate) (Copaxone) Limited data suggest that each may be beneficial, although as yet no rational guidelines exist for their use
At present, many clinicians favor interferon-b for severe MS with frequent exacerbations and rapidly progressive disability ( 73b) It is administered on alternate days and relatively often gives rise to skin lesions at injection sites and provokes antibodies that can reduce efficacy Glycosylated interferon-b may be preferable in
children and adolescents because it is administered weekly and is less likely to generate the skin reactions Alternatively, it is argued that copaxone may be the best drug for young patients with MS because it has few side effects and is well tolerated However, daily subcutaneous injections are necessary
When patients are intolerant of interferon-b, continuous treatment with azathioprine or cyclophosphamide may be considered Cyclophosphamide should be reserved for those children or adolescents who exhibit severe, frequently relapsing MS with progressive disability, or who manifest a secondary chronic progressive
demyelination Continuous monthly bolus therapy, with or without induction, may be beneficial to some of the younger patients ( 74)
Other forms of therapy for severe MS include methotrexate, mitoxantrone, and 2-chlorodeoxyadenosine Cyclosporin A provides no advantage over interferon-b, azathioprine, or cyclophosphamide and has little if any role in the treatment of the mild relapsing and remitting MS to which children and adolescents are subject
Prognosis
The majority of children develops the relapsing-remitting form of MS, with most patients in this group being entirely well between relapses ( 55) Most authors consider childhood-onset MS to be less aggressive than its adult counterpart and adolescents who develop MS generally have a more favorable prognosis than individuals who develop MS at later ages (55,56)
Trang 13Initial bouts of demyelination in children who are subsequently proven to have MS tend to last 6 to 10 weeks This includes days to weeks of maximal affliction, which
is shorter for patients with vague sensory and mild motor complaints than those with hemiparesis It is longest for subjects with significant spinal cord syndrome, such
as transverse myelitis, in whom improvement may require months to years The manifestations most likely to remit completely include sensory changes, optic neuritis, and other abnormalities of cranial nerve function, whereas weakness and abnormalities of the cerebellar, dentatorubral, or autonomic systems are less likely to
recover completely It is possible that patients who would otherwise have recovered from their bout of spinal cord disease do not do so because swelling during the acute phase of illness has compromised regional circulation and therefore cord necrosis has occurred As in adult patients, the recurrences of adolescents tend to be clinically similar to previous occurrences and patients with fixed deficits usually demonstrate worsening of those deficits with ensuing bouts, followed by recovery either to the preexisting level of deficit or to a somewhat lesser functional state Perhaps one-fifth of recurrences manifests new signs or symptoms
Some adolescent patients appear to have a form of MS that recurs for a number of bouts, followed by a prolonged period of quiescence during which the illness
appears to partially or entirely burn out Unusual courses include fulminant cases of acute MS that may cause death within weeks, to clinically silent MS discovered only at autopsy (75)
Less often childhood MS follows a chronic progressive pattern The progressive form may present primarily, or more commonly secondarily, after several years of relapsing-remitting illness (76) Most progressive cases have myelopathic initial presentations with little recovery and slow rates of deterioration thereafter Curiously, some children manifest an initial bout suggesting the diagnosis of MS but do not experience their second bout until 10 years or more have elapsed The overall
prognosis is not necessarily worse for individuals whose second bout occurs within a few weeks of the first
Relapses may be provoked by acute febrile viral illnesses Bacterial infections, typically involving the urinary tract of girls or women with MS, may provoke a relapse, but it is more likely that they worsen the degree of already existing disease activity Although concerns have been expressed about the possibility that attenuated or live virus vaccines (hepatitis B, polio virus, and others) may initiate MS or provoke relapses, as yet no proof exists Influenza vaccine does not appear to pose any risk
Other factors that may be associated with a relapse include stress, physical trauma, and surgery Spinal anesthesia can provoke relapse of MS, whereas epidural or inhalation anesthetics do not As greater numbers of relapses occur, patients tend to recover less completely and deficits may become cumulative As a rule, the longer a given bout lasts, the more likely that recovery will be incomplete
Not all patients become significantly handicapped Slightly more than one-third do not develop permanent disability of a degree sufficient to significantly impair
personal or professional function Perhaps 25% of adolescent-onset cases with a severe course develop significant permanent disability and a small fraction of these have a rapidly malignant course of deterioration culminating in early death The remainder, perhaps 40% of cases, develop moderate permanently handicapping
deficits It is not clear what life-span can be expected of individuals who develop MS in childhood or adolescence
Variants of Multiple Sclerosis
Three variants of MS that attracted considerable attention among neurologists of past generations are Schilder disease (myelinoclastic diffuse cerebral sclerosis), Balo disease (encephalitis periaxialis concentrica), and Devic disease (neuromyelitis optica)
Schilder Disease (Myelinoclastic Diffuse Cerebral Sclerosis, Encephalitis Periaxialis Diffusa)
Diffuse cerebral sclerosis was first described in 1912 by Schilder ( 77), who termed it diffuse periaxial encephalitis In the intervening years, the term Schilder disease
has become considerably confused, in that two of Schilder's three original cases represented an adrenoleukodystrophy and SSPE Also, Poser and van Bogaert ( 78),
in analyzing the cases compiled by Bouman in his extensive monograph on the disease (79), found that more than one-half were leukodystrophies, perinatal
encephalopathies, or subacute sclerosing encephalopathy Schilder disease is now considered to be an inflammatory demyelinating disease of cerebral white matter
of unknown etiology, possibly a variant of MS (80,81) The condition is distinguished by two features First, a peculiar tendency exists to produce one or several often fairly symmetric large plaques of demyelination in the deep frontal central cerebral hemispheric white matter with sparing of the subcortical U-fibers and relative
sparing of axis cylinders (81a) Second, there is an exquisite sensitivity to treatment with corticosteroids (81b)
In the sectioned brain, the most striking alteration is the gross demyelination of the central white matter The plaques are fewer and larger than in MS, and their deep location with sparing of the gray–white junction distinguishes them from ADEM The lesions are most common in the occipital lobe, but can involve any part of the cerebral hemispheres, brainstem, and cerebellum Even in the most severely affected brain, a small band of subcortical white matter is usually spared ( Fig 7.3) The histopathology is indistinguishable from MS (81c) or ADEM, except a tendency to central necrosis and cavitation within large plaques exists
FIG 7.3 Diffuse cerebral sclerosis Myelin preparation of frontal lobe demonstrating demyelination The arcuate fibers are characteristically spared (Courtesy of the
late Dr D B Clark, University of Kentucky, Lexington.)
The illness tends to present in children between the ages of 4 and 13 years Onset is often subacute, with some combination of headache, lethargy, behavioral and intellectual disturbances, changes in personality, progressive clumsiness, or ataxia Most cases exhibit hemiparesis or asymmetric double hemiparesis, variously combined with aphasia, visual disturbances, dysarthria, oropharyngeal dysfunction, bilateral pyramidal signs, ataxia, or pseudobulbar manifestations ( 81a,81d,81e) Increased intracranial pressure with papilledema is occasionally encountered Unlike ADEM, there is usually no clear history of prodromal illness or fever
The CSF protein is generally normal, as is the ratio of T-helper to T-suppressor cells Oligoclonal bands are found in some samples ( 81c) The CT scan demonstrates extensive hypodense areas The MRI shows massive single or multiple areas of demyelination in the subcortical white matter of the cerebral hemispheres The typical large plaques are usually clearly visible as areas of intense bright signal on T2-weighted MRI There is no special predilection for the periventricular area or the
brainstem Some lesions have a cystic appearance, with the edges enhancing with gadolinium (81a,81f)
Diagnosis
The subacute onset of focal neurologic signs and increased intracranial pressure initially suggests a space-occupying lesion Neuroimaging studies exclude this
diagnosis, however, and point to a demyelinating process The diagnosis of diffuse cerebral sclerosis can be made with considerable certainty because no other
demyelinating condition progresses with sufficient rapidity to produce massive cerebral edema Adrenoleukodystrophy, which occasionally can progress relatively rapidly, can be distinguished by the presence of very-long-chain fatty acids in serum In addition, ring enhancement on contrast administration distinguishes Schilder lesions from the demyelination observed in adrenoleukodystrophy, which is usually found in parieto-occipital white matter ( 81g) Occasionally, the diagnosis requires aspiration or stereotactic biopsy of a lesion to exclude abscess and tumor
Trang 14Immunosuppression with corticosteroids or with a combination of cyclophosphamide and adrenocorticotropic hormone (ACTH) has been reported to induce rapid and unequivocal improvement in the majority of cases, with complete or nearly complete resolution of the MRI lesions (81d) In the series of Barth and coworkers, all five pediatric patients did well after corticosteroid therapy (81e)
The rapid early improvement of clinical manifestations and radiographic changes with the administration of corticosteroids is a characteristic feature of Schilder
disease Maximal recovery, however, may require weeks or months and can be incomplete It is unclear whether corticosteroids merely promote earlier onset of
recovery, exert some influence on duration and extent of maximal recovery, or prevent progression to MS Although some uncertainty exists about dosage, it is likely true that high doses should be administered intravenously for 3 to 5 days followed by an oral taper The MRI appearance usually improves, but abnormalities may persist for years, especially if there is necrosis and cavitation of a large lesion
The majority of patients appears to experience prolonged remission after treatment Occasionally, there are recurrences ( 81d) It is important to distinguish
exacerbation caused by corticosteroid taper from true recurrences
Encephalitis Periaxialis Concentrica (Balo Disease)
Encephalitis periaxialis concentrica (Balo disease) is now considered to be a variant of MS, the only distinguishing feature being the bizarre concentric zones of
demyelination in central white matter (82) In the few reported cases, the clinical picture has been indistinguishable from that of ADEM The diagnosis can be made by the characteristic findings on MRI (83)
Neuromyelitis Optica (Devic Disease)
Neuromyelitis optica is relatively rare in the western world but not uncommon in Asia (84) It is characterized clinically by optic neuritis and acute transverse myelitis (ATM) appearing simultaneously or within several weeks or months, with no neuroimaging evidence of white matter lesions in the brain, brainstem, or cerebellum Pathologically, the process is particularly marked in white matter of the spinal cord and the optic nerves ( 85) MRI studies have confirmed the distribution of the
lesions in brain and spinal cord (86,87) Probably neuromyelitis optica is a form of MS, modified by histocompatibility antigens or by one or more external factors
Long-term treatment with prednisone and azathioprine has been suggested (88)
ACUTE DISSEMINATED ENCEPHALOMYELITIS
ADEM is an immunologically mediated, acute inflammatory demyelinating disease marked by the onset of neurologic symptoms in close temporal relationship to a viral disease or immunization As a rule, the condition occurs just once, or at the most, up to three times with its highest prevalence in prepubertal children Only in a minority of these children does the disease either evolve into MS or prepubertal MS that closely resembles ADEM
Historical Aspects
Illnesses recognizable as ADEM were first described in the late nineteenth century by Osler and others, who were particularly struck by the occasional child who
showed remarkable recovery from severe, acute, multifocal encephalitic illnesses Many cases occurred in association with epidemics of viral illnesses that spread through Europe in the wake of the First World War The characteristic pathology was described almost simultaneously in the late 1920s and early 1930s in children who had died from ADEM after measles, chickenpox, influenza, smallpox, and vaccinations (89)
The early inflammatory infiltrate is made up of polymorphonuclear leukocytes, but over time lymphocytes become predominant As demyelinative changes occur,
microglial cells become admixed with lymphocytes, as do phagocytes containing the lipid by-products of myelin degradation Although microscopic changes resemble those of MS, as well as those of SSPE, the plaquelike areas of ADEM-related demyelination are macroscopically unlike those of MS Meningeal inflammation also may be found Severe cases may show disseminated hemorrhages, a syndrome that has been designated acute hemorrhagic encephalopathy (91,92 and 93)
Pathogenesis
A number of theories have been proposed to explain the mechanism and the target of the process that leads to demyelination in ADEM These include (a) direct or indirect effects of virus within the nervous system; (b) nonspecific effects of vascular inflammation; (c) humoral (immune complex) mediation; and (d) cell-mediated immune mediation The possible targets for injury include vascular endothelium, myelin, microglia, or oligodendrocytes The last two are the least likely targets
The notion that a viral infection of the nervous system induces ADEM is suggested by three lines of evidence: (a) occurrence of most cases in the setting of recent viral infection; (b) clinical and pathologic resemblance to the changes that occur in viral encephalitis; and (c) experimental induction of encephalomyelitis with viruses Before widespread immunization, measles was the most common prodromal illness, with ADEM developing in 1 of 1,000 cases (94) ADEM arises as a complication of various other exanthematous diseases, notably rubella (95) and varicella In approximately 10% of patients it is a manifestation of herpes simplex virus encephalitis (96) Infections with herpesvirus-6 infection, Epstein-Barr, and a variety of other viruses (97) can precede ADEM In other instances, ADEM occurs in the wake of respiratory or gastrointestinal illnesses that are presumed to be viral; in these a specific viral agent is rarely identified
ADEM can develop after vaccination with a wide variety of killed or attenuated organisms These include rabies vaccines grown in brain or spinal cord ( 98), Japanese encephalitis (99), and influenza vaccines Leptospiral, mycoplasmal, Campylobacter, and streptococcal infections also have been associated with ADEM (100,101 and
102)
Direct effects of virus within the nervous system could include viral killing of endothelial cells, resulting in an impairment of the blood–brain barrier, or injury to myelin
or myelin-producing oligodendrocytes or other glial cells These forms of injury also could be produced as “bystander effects” caused by immune responses directed
at the virus within the nervous system (103,104) Thus, viruses might expose or alter CNS antigens to which an immune response would be directed
The notion that vascular events are important in ADEM is based on the pathologic observation that subtle vascular changes precede the accumulation of an
inflammatory perivenular exudate or demyelination These changes are similar to those observed in serum sickness and immune-complex disease In
immune-complex disease insufficient antibody production and sustained antigen excess produce circulating immune complexes that become lodged in the vascular endothelium This stimulates complement activation and release of vasoactive substances Injury to vascular endothelial cells, particularly at the capillary level, may then result in blood–brain barrier impairment and result in extravasation of protein and fluids into the tissues Blood–brain barrier changes also may expose antigens, permitting inflammatory response to be directed against otherwise immunologically privileged tissues Early impairment of blood–brain barrier function has been
demonstrated in EAE, as discussed previously The blood–brain barrier changes are associated with reduced numbers of mitochondria and increased numbers of transcytotic vesicles within the capillary endothelium These effects could be blocked, in some cases, by the administration of prazosin, an a 1-adrenoreceptor
antagonist, possibly acting at the level of the capillary pericytes (105) The transcytotic vesicles are thought to be associated with the development of inflammatory edema
Research has focused on the possible role of adhesion molecules, expressed on the surface of CNS capillaries, in mediation of the proposed vascular phase of
immune dysregulation Adhesion molecules may be capable of selectively recruiting inflammatory cells on the basis of sialyl moieties on the surface of the circulating cells Such an interaction might have either positive or negative consequences depending on whether it results in clearance of regional infection or impaired
Trang 15blood–brain barrier function with inflammatory demyelination (106) Evidence has been advanced for the upregulated expression of adhesion molecules during
experimental relapsing autoimmune dysregulation (107) This vascular concept has been advanced as a unifying concept (vasculinomyelopathies) for postinfectious neurologic illnesses of both the peripheral nervous system and CNS (108)
The possibility that ADEM is mediated by humoral immunity is supported by the fact that the illness is monophasic, multifocal, and may be provoked by a wide variety
of antigenic precipitants (109) It is further supported by evidence for circulating immune complexes in at least some children with ADEM and by pathologic
resemblance to immune-complex injury in other organ systems (110) Moreover, signs and symptoms suggesting immune-complex–mediated processes in other organ systems, such as myalgia, arthralgia, rash, proteinuria, and glomerulonephropathy, are found in many patients
The role of cellular immunology in the pathogenesis of ADEM is supported by the similarity of the pathologic changes to EAE, which is believed to be a
T-cell–mediated condition The frequency of T-cell lines reacting to MBP is 10-fold higher in patients with ADEM as compared with healthy subjects or patients with viral encephalitis, with the IL-4 being the predominant cytokine secreted by these cell lines ( 110a)
One unifying hypothesis for the pathogenesis of ADEM suggests that viral antigens form a complex with phagocytic cells (macrophages or microglial cells) and
T-helper cells (111) This so-called trimolecular complex then results in nonspecific T-cell activation, including clonal stimulation of cytotoxic T cells These activated cells then enter the CNS either because of the vascular changes induced by the interaction of T cells with microvascular adhesion molecules, because the increased numbers of circulating autoreactive T cells overwhelm some threshold that normally contains the activity of cellular-mediated immunity, or because T cells engage in regular traffic into the nervous system as part of host immune surveillance These clones of stimulated cells attack one of the targets noted previously (i.e., an
exposed antigen, myelin, or a particular CNS cellular population) The myelin injury thus produced may be nonspecific (“bystander effect”) ( 112) Thus, the occurrence
of ADEM appears to require the conjunction of genetically determined susceptibility (cellular immune locus) with sufficient antigenic stimulus and other poorly
understood conditions
Clinical Manifestations
Typical cases of ADEM arise 2 to 20 days after a febrile childhood illness, although some 15% to 20% of cases have no clearly defined prodrome ( 113,114,115 and
115a) ADEM is more common in winter months, a period during which childhood respiratory and gastrointestinal viral illnesses tend to be particularly prevalent The mean age at presentation is 7.4 years The male to female ratio is approximately 1.3:1 and the white to black ratio may be as high as 6:1
Typically, children recovering from the viral prodrome abruptly develop irritability and lethargy In the Turkish series of Apak and coworkers, ataxia was the most
common presenting complaint, followed by optic neuritis, cranial nerve palsies, and seizures (115a) Most children are febrile during prodrome; fever at onset of
ADEM is variable Occasionally, ADEM may occur after a prolonged fever of unknown origin Over the course of minutes to days, diffuse neurologic signs develop Changes in mental status and long tract signs are commonly observed in ADEM
leukodystrophy are found in ADEM The clinical course usually distinguishes ADEM from tumor or leukodystrophy, but not necessarily from SLE ADEM rarely affects the hearing or causes pseudobulbar changes; where these are found, leukodystrophy is more likely
ADEM may be either associated with or in some cases confused with Lyme disease, acquired immunodeficiency syndrome, and tropical spastic paraparesis (see
Chapter 6) Where appropriate, specific serologic studies should be undertaken A few cases have been mistaken for diffuse metazoa or parasitic diseases, such as cysticercosis The absence of any considerable degree of edema usually distinguishes ADEM from tumor or parasitic disease
When spinal manifestations predominate, MRI of spine with T2 weighting often distinguishes the acute presentation of an extramedullary tumor, stroke, or
hemorrhage Some cases of ADEM with prominent myelitis have peripheral nerve signs, representing clinical overlap with GBS This overlap is particularly prominent
in patients with acquired immunodeficiency syndrome Tumors with involvement of the cauda equina or nerve roots also must be considered
The electroencephalography (EEG) results can be normal and can exhibit disturbances of normal sleep rhythms and slowing during the waking state in patients with the early stages of ADEM, a finding that helps to distinguish ADEM from MS (115a) In the experience of one of us (R.S.R.), the absence of such EEG abnormalities during the first bout of acute disseminated demyelinating illness in a child significantly increases the risk for the ultimate diagnosis of MS CSF immune studies are positive in a minority of cases of ADEM; MBP is more frequently elevated Moderate elevations of these studies occur in some children with monosymptomatic ADEM (117); strongly positive results are seen in SSPE, neurosyphilis, neuroborreliosis, and in some cases of heritable leukodystrophy
Treatment
Given abundant evidence for immune-mediation of ADEM, it is quite logical to consider anti-inflammatory therapy Many agents have been used, including
corticosteroids, ACTH, IVIG, and cyclosporine Corticosteroid treatment is the most common therapy, and most patients appear to be responsive (115a,118) Often clinical response is observable within hours of initiation of intravenous corticosteroids, particularly after high intravenous doses (15 to 20 mg/kg of
methylprednisolone) Unfortunately, no systematic data exist regarding appropriate dosage or length of therapy Corticosteroid dependency, similar to that observed
in some patients with GBS, may occur during the taper of corticosteroids These children usually respond well to a slower taper, but a few chronic relapsing cases, resembling MS, are seen in young children who may require corticosteroid therapy for many months or years
In cases resistant to high doses of corticosteroids, IVIG or cyclosporine may be tried Patients in coma from ADEM have been successfully treated with plasma
exchange or plasmapheresis (119)
Prognosis
The outlook for recovery is generally excellent Although some older series suggest up to 10% mortality, in the experience of one of us (R.S.R.) only 1.5% of our 60 cases died of ADEM-related complications Recovery is unrelated to severity of illness, and complete recovery may be observed even in children who become blind, comatose, and quadriparetic Recovery is poorest in children younger than age 2 years, a population in whom long-term motor and intellectual deficits are fairly
common
OPTIC NEURITIS
The term optic neuritis refers to a variety of lesions of one or both optic nerves, be they inflammatory, toxic, or demyelinating, that share a clinical picture of diminution
of visual acuity When optic neuritis develops during childhood it is more likely to be bilateral In part, this tendency might reflect the ability of small children to ignore unilateral vision loss, even though it has developed abruptly
Clinical Manifestations
In most children symptoms appear suddenly, and in approximately 70% they follow an acute infectious illness, notably exanthematous diseases such as measles, mumps, and varicella (120,121,122 and 123) Vision loss can occur over a few hours or days and can progress to complete blindness in days In some instances, one eye becomes affected a few days or weeks after the other In a minority, vision loss develops over weeks to months The patient can experience headache or pain when moving the eyes, but clear-cut neurologic deficits are rare, although some patients can have transient extensor plantar responses Involvement is bilateral in approximately 60% of children (124,125) In the vast majority of children, more than 90% in the series of Meadows (126) and 76% in the Finnish series of Riikonen and colleagues (125), the appearance of the disc is abnormal, with swelling and hemorrhages, a picture that at times is indistinguishable from that seen in
Trang 16papilledema In papilledema, the visual field defect is minimal, however, usually an enlargement of the blind spot, whereas in optic neuritis the field defect is
extensive, usually a central scotoma When the optic nerve is involved proximal to the optic disc, the fundus appears normal (retrobulbar neuritis) Striking
abnormalities, including fiber layer hemorrhages at the optic nerve margin, vascular tortuosity, or sheathing of veins are readily observable on funduscopy in many cases (125) vision loss may be preceded by headache (frontal or ocular), scintillating scotomata, or by painful eye movements
The frequency with which optic neuritis in the pediatric age group is an antecedent to MS varies widely from one series to the other In the Mayo Clinic series of
Lucchinetti and colleagues, 26% of subjects who had experienced optic neuritis before 16 years of age developed MS by age 40 ( 127) Approximately one-half of the children developed frank MS within 1 year of their optic neuritis (127) The risk for MS with unilateral optic neuritis was less than for simultaneous bilateral optic
neuritis, and only 5% of children with unilateral optic neuritis went on to develop MS (127) This is in contrast to data on adult patients, in whom unilateral optic
neuritis is followed by MS in up to 87% (124,125 and 126) When bilateral optic neuritis is sequential, that is if the second eye is involved more than 2 weeks after the first eye, the likelihood for MS is approximately 50% The presence of abnormal MRI results and oligoclonal bands in the CSF is particularly ominous in that more than 80% of patients demonstrating the oligoclonal bands go on to develop full-blown MS (128,129) The complaint of transient blurring of vision with exertion (Uhthoff symptom) also correlates with early development of MS (130) In unilateral optic neuritis, visual-evoked potentials and, to a lesser extent, MRI can demonstrate
abnormalities in the apparently unaffected optic nerve (131)
Diagnosis
The diagnosis of optic neuritis is made on the basis of a combination of clinical and laboratory findings In subtle cases, diagnosis can be clinically supported by loss
of red-vision ( red desaturation), or by loss of duration or variety of the flight of colors that occurs when the eye is closed after a period of bright illumination of the
retina When greater visual impairment occurs, loss of the reflexive constriction of the contralateral pupil occurs when the retina of the affected eye is illuminated Visual-evoked responses (VERs) are particularly useful where the diagnosis is uncertain; optic neuritis results in increased latency of the positive component of this cortical response (132) This delay in VER may persist for several years in patients who have shown excellent clinical recovery MRI demonstrates swelling of the optic nerve in most cases; the extent of optic nerve enlargement may be alarming in some children who experience good recovery (133) Imaging also excludes lesions that compress the optic nerve and result in vision loss Disseminated bright lesions on T2-weighted images may be found by MRI elsewhere in brain in as many as 70% of patients (125) In children these lesions do not necessarily indicate MS, and their interpretation is difficult Where such abnormalities are at the
gray-white junction and the patients are younger, they suggest ADEM; periventricular plaques in adolescents are more indicative of MS SSPE, intoxications (e.g., methanol), leukodystrophies, and stroke must occasionally be considered Malingering may be excluded on the basis of inconsistencies on clinical examination or by VER testing
Treatment and Prognosis
No clear-cut evidence indicates that oral or intravenous corticosteroid therapy is of any benefit Intravenous methylprednisolone has been recommended for patients whose visual acuity is worse than 20/40 (134) These recommendations, based on experience with adult patients with mainly uniocular disease, may not be applicable
to children who have generally bilateral disease, and it is not known whether corticosteroids affect the natural history of the disease in the pediatric population ( 135)
In adult populations, treatment with intravenous methylprednisolone does not affect visual outcome although it appears to speed recovery from acute exacerbations (136)
Although recovery may be slow (137), the prognosis of childhood optic neuritis, particularly when it is bilateral, is excellent, and the overwhelming majority of children recover vision completely within weeks or months The most common residua include optic nerve atrophy and impairments of color and stereoscopic vision ( 138) Permanent severe vision loss is quite exceptional
ACUTE TRANSVERSE MYELITIS
ATM is characterized by the sudden onset of rapidly progressive weakness of the lower extremities, accompanied by loss of sensation and sphincter control, and often preceded by a respiratory infection The condition has been recognized for more than 100 years; an excellent description of the clinical picture is that of Gowers
in 1886 (139) Before then, many diseases of the spinal cord were termed myelitis; only subsequent to the description of MS by Cruveilhier, tabes by Duchenne, Todd,
and Romberg, and syringomyelia by Gull and Hallopeau, did this entity gain recognition Its first description in this century is that by Foix and Alajouanine ( 140)
Pathology and Pathogenesis
ATM is an acute disorder that presents with CNS dysfunction referable to a discrete portion of the rostrocaudal extent of the spinal cord and involving tracts on both sides of the cord
The condition occurs in association with a number of factors These include such autoimmune diseases as GBS, ADEM, or MS, bacterial, viral, or spirochetal
infections, notably Lyme disease, and vascular malformations
On pathologic examination, the spinal cord is generally softened, with the most striking changes occurring in the thoracolumbar region The lesion can be focally
transverse or can extend over several cord segments In the affected area, the spinal cord is often completely necrotic; all nervous elements are lost, replaced by a cellular infiltrate or by cavitation Microscopic examination shows perivenular inflammatory changes with demyelination, closely resembling those of ADEM; in severe cases myeloclasia with cavitation is seen
Although the exact pathogenesis is unknown, in most cases a cell-mediated autoimmune response is believed responsible This concept is supported by the
observation that lymphocytes from 70% of transverse myelitis patients responded to bovine MBP and to human peripheral nerve myelin P2 protein ( 141) In some instances, the acute onset of symptoms and the distribution of the clinical and pathologic deficits suggest that the vascular supply to the spinal cord has been
compromised, possibly as a result of an occlusion of the anterior spinal artery caused by an autoimmune or postinfectious vasculitis ( 142,143)
Clinical Manifestations
Transverse myelitis can occur in isolation or in association with or as a sequel to a multiplicity of conditions These include herpes simplex and herpes zoster,
Epstein-Barr virus, the echoviruses, hepatitis B virus, influenza, Lyme disease, Mycoplasma pneumoniae, and the various exanthematous diseases, notably measles,
mumps, and varicella (144,145 and 146) It also can be seen after rabies or tetanus toxoid immunization, in conjunction with SLE, and with the antiphospholipid
syndrome, and after Mycoplasma pneumoniae infections (147,148) Approximately two-thirds of affected children have a history of a recent or a concurrent acute infection, and the condition has been noted to cluster around the summer months (142,149) The presence or absence of an infection does not alter the clinical course
of the disease Occasionally, cases are preceded by relatively trivial blunt trauma to the spine
Most cases occur in children older than 5 years of age (150) The earliest symptom is sensory loss or pain in the back, extremities, or abdomen (151) This symptom
is followed by a rapidly progressive paraparesis, which usually involves the legs, but occasionally can ascend to affect legs and arms sequentially Fever is present in approximately one-half of the children, and neck stiffness in approximately one-third At first, the weakness is flaccid, but gradually evidence of pyramidal tract
involvement can be elicited with spasticity, increased deep tendon reflexes, ankle clonus, and extensor plantar responses that usually become obvious by the end of the second week of illness (142) Sphincter tone was lost in 86% of cases in the Australian series of Dunne and coworkers (149); sensory impairment, usually with a well-defined level, can be documented in most instances (in 80% of cases in the series of Paine and Byers) ( 142)
The onset of paraplegia, sensory loss, and sphincter dysfunction may develop over days to weeks or have a paroxysmal onset over hours In more than one-half of patients, the maximum deficit occurs within 3 days of the onset of symptoms (149) As a rule, the rate of onset is often proportional to the intensity of the initial
discomfort Intense pain may foreshadow hyperacute presentation with abrupt and severe onset of myelitis Cervical ATM can compromise breathing and may
occasionally present in cardiopulmonary arrest Rarely, ATM presents with the isolated complaint of urinary retention ( 152)
In all cases the neurologic examination should be directed at detecting bilateral weakness and a sensory level The weakness is initially flaccid and the involved
extremities may be areflexic Pyramidal tract signs such as increased tendon reflexes and extensor plantar reflexes develop after a number of days Superficial
reflexes (abdominal, cremasteric, bulbocavernosis) are usually absent In most children who can be examined adequately, pain and temperature sensations are
affected primarily, whereas posterior column function (vibration and proprioception) is generally spared A sensory level is present in almost all cases and is best
Trang 17determined in children by examining cold sensation The sensory level is located between T5 and T10 In approximately 20% of patients it is located in the cervical region, and in 5% to 10% in the lumbar region (149,151) Maximal deficits occur in hours to days in hyperacute and acute cases, and days to weeks in subacute
ATM should be distinguished from acute infectious polyneuritis and from spinal cord symptoms caused by a space-occupying lesion The diagnosis of acute
polyneuritis is not easy, particularly in the small child, whose sensory examination is not reliable In acute polyneuritis, loss of pain sensation is generally not as
complete as it is in transverse myelitis, and proprioception is the sensory modality most involved Loss of sphincter function and the appearance of clear-cut pyramidal tract signs argue strongly for ATM Neither electric studies nor examination of the CSF are of much assistance in the differential diagnosis, although abnormal
visual-evoked responses suggest the diagnosis of MS (149) Linssen and colleagues believe that an elevation of CSF MBP argues for the diagnosis of ATM (153) If the posterior columns are interrupted, somatosensory-evoked potentials with lower limb stimulation are abolished In the experience of Wilmshurst and colleagues, electrophysiologic evidence for anterior horn cell involvement is associated with poor recovery ( 156) ATM also should be differentiated from compressive injuries, arteriovenous malformations, hemorrhage, stroke, and radiation injury Tropical spastic paraparesis, a progressive myelopathy caused by HTLV-1 infection, does occur in children, and may produce MRI changes indistinguishable from ATM, although the changes may be disseminated throughout the cord (see Chapter 6) The progression of neurologic symptoms in HTLV-1 is generally much slower than that of ATM
Treatment and Prognosis
Treatment with high-dose (1 g/1.73 m2) intravenous methylprednisolone may be effective in children with ATM (157) In the experience of Lahat and colleagues,
published in 1998, all of 10 children treated in this manner within 5 to 16 days of the onset of symptoms had a good outcome or were normal ( 158) Other studies, however, have not found any significant effect on the outcome of the illness (149)
The prognosis of ATM in children is usually good Approximately 60% of patients have good return of function, and only 15% fail to show any significant improvement Return of function usually starts within 1 month; in the series of Dunne and colleagues (149), it began between 2 and 17 days after the onset of symptoms and was essentially complete by 6 months Dunne and coworkers and Wilmshurst and colleagues found that the more acute the onset of the myelitis, the worse the outcome (149,156) Whereas some 20% of adult patients with transverse myelitis ultimately develop MS, children do not In a retrospective Canadian study, only 3% of MS patients whose symptoms became apparent before 16 years of age had presented with transverse myelitis (50) Normal cranial MRI and normal visual-evoked
potentials tend to exclude the diagnosis of MS These study results are positive in almost all patients who go on to develop MS after an attack of transverse myelitis
ACUTE CEREBELLAR ATAXIA
Acute cerebellar ataxia is a relatively common condition that was first described by Batten in 1907 (159) It is characterized by the sudden onset of ataxia, often after a nonspecific infectious illness
Pathology and Etiology
Because acute cerebellar ataxia is not a fatal condition, its pathology is unknown The cause of the condition is probably heterogeneous, with a number of infectious agents being directly or indirectly responsible Cases after infection with polio virus type 1, influenza A, and influenza B have been reported In other patients,
echovirus type 9 (160) and coxsackievirus type B have been isolated from CSF Ataxia with an acute onset and an identical clinical picture also is seen after a variety
of exanthematous diseases, most commonly varicella, less often rubella (161,162) Acute and transient cerebellar ataxia can be the presenting symptom of childhood
MS also (see Table 7.1)
The association of acute cerebellar ataxia with occult neuroblastoma has been observed on numerous occasions ( 163,164) One can, therefore, conclude that in some instances acute cerebellar ataxia is caused by direct viral invasion of the cerebellum, whereas in others it is the result of an autoimmune response to a variety of agents It also is uncertain whether the site of injury within the nervous system is neuronal or whether fiber tracts are affected
The clinical picture is marked by severe truncal ataxia resulting in rapid deterioration of gait Hypotonia and tremor of the extremities, head, and trunk are seen less often Nystagmus is encountered in 45% of patients, whereas a number of other children have sudden random motions of the eyes during voluntary movements
Speech is often affected Other neurologic signs are usually absent, although headache, dizziness, photophobia, and myoclonic movements of the head and arms have been reported occasionally Brainstem signs are present occasionally Constitutional symptoms, including fever, are absent, and nuchal rigidity is rare
The CSF is usually normal, although a mild pleocytosis is found in 25% of cases (165,167) The CSF protein content can be normal on initial taps but may become elevated late in the course of the illness (165) Neuroimaging studies have shown swelling of the cerebellum, and a transiently increased signal in the cerebellar
cortex or the brainstem (168,169,170) When MRI abnormalities are confined to the brainstem, the condition resembles brainstem encephalitis, except that in the latter disease cerebellar symptoms are accompanied by clinical evidence of widespread CNS involvement The SPECT scan has shown decreased blood flow to the
cerebellum (171)
In the majority of cases, the disease is self-limiting In approximately two-thirds of children, the ataxia clears completely, with an average duration of cerebellar signs
of approximately 2 months Some mildly affected children recover completely within 1 week Nearly 90% of children recover completely over weeks to months More than 2 months are required for recovery of 18% to 33% of children with viral prodromata, and 50% of those without prodromata Persistence of major neurologic
deficits is noted in approximately one-third of children These deficits include ataxia of trunk and extremities, speech impairment, mental retardation, and behavioral abnormalities
One of us (J.H.M.) has encountered at least two children whose cerebellar ataxia recurred over several years, with exacerbations often preceded by a mild respiratory illness These bouts could be distinguished from the aggravation of ataxia expected in any uncoordinated patient experiencing an acute febrile episode Both patients were left with mental retardation
Diagnosis
Acute cerebellar ataxia is diagnosed by excluding other conditions that produce sudden onset of ataxia The most important of these are the posterior fossa tumors, occult neuroblastoma, acute labyrinthitis, and drug intoxications Although the onset of ataxia in a posterior fossa tumor is rarely sudden, imaging studies to exclude a mass lesion are indicated The presence of papilledema and a history of headache or vomiting point to a posterior fossa tumor
Catecholamine metabolites, notably homovanillic acid and vanillylmandelic acid, are excreted in amounts higher than normal by patients harboring a neuroblastoma Analysis of urinary homovanillic acid and vanillylmandelic acid can be done on random and 24-hour urine collections Tuchman and coworkers analyzed random urine
Trang 18specimens in a large series of patients, with no false-positive and some 7% false-negative results ( 172).
In a significant percentage of children who develop MS, ataxia is the first sign of the disease Diagnostic studies to exclude this entity are therefore indicated
Ataxia can develop in the course of acute viral diseases of the CSF, notably varicella, mumps, and poliomyelitis The distinction between these cases and the usual
cases of acute cerebellar ataxia is difficult and might well be semantic (i.e., if a causative agent can be proven, the condition is termed cerebellar encephalitis, but otherwise it is termed acute cerebellar ataxia of unknown cause).
Acute labyrinthitis (vestibular neuronitis or epidemic vertigo) is not easily distinguished from ataxia, particularly in an uncooperative youngster It is usually associated with nausea, intense vertigo, and abnormal tests of labyrinthine function (173), particularly an absence of caloric responses (174,175)
Acute cerebellar ataxia also can be seen after the ingestion of a variety of toxins, particularly alcohol, thallium, and organic mercurials (see Chapter 9)
Acute cerebellar ataxia, often precipitated by a respiratory infection, accompanies a number of metabolic disorders, including various mitochondrial disorders, Hartnup disease, and the intermittent forms of maple syrup urine disease (see Chapter 1) Recurrent attacks of ataxia can be transmitted as a dominant trait Two forms of this condition have been delineated, with defects in the voltage-gated potassium channel gene, and one of the calcium channel genes, respectively These entities have been reviewed by Baloh and colleagues (176) and are covered more extensively in Chapter 2
Ataxia also can develop as a consequence of heatstroke, a result of hyperthermia-induced cerebellar degeneration ( 177)
Some children with minor motor seizures suddenly develop ataxia that probably results from frequent transitory impairment of consciousness EEG signs of a seizure disorder should readily distinguish this entity
Ataxia associated with the various cerebellar degenerations develops gradually and should cause little diagnostic confusion Apparent ataxia can be the consequence
of generalized weakness (e.g., in acute infectious polyneuritis) In acute cerebellar ataxia, hypotonia is associated with normal or increased deep tendon reflexes, whereas in polyneuritis, the reflexes are reduced or absent
Treatment
Acute cerebellar ataxia is a self-limiting disease, and no specific treatment, including adrenocortical corticosteroids, has been found convincingly effective
OPSOCLONUS-MYOCLONUS SYNDROME (MYOCLONIC ENCEPHALOPATHY)
A syndrome of myoclonic encephalopathy has been noted in infants and young children (178) (Kinsbourne syndrome) It is characterized by acute or subacute onset
of polymyoclonus, often after a respiratory infection, cerebellar ataxia, and a chaotic irregularity of eye movements in which the globes are in a state of constant
agitation with rapid and unequal movements that usually take place in the horizontal plane (opsoclonus) The abnormal eye movements are most prominent at the onset of each attempt to alter the position of the eyes In addition to opsoclonus, shock-like myoclonic contractions persist when the affected part is at rest and
produce total disorganization of willed movements In approximately one-half of patients this entity represents a post-infectious process, and thus is related to acute cerebellar ataxia In the remainder it is a neuroimmunologic complication of neural crest tumors, most commonly, neuroblastoma (179)
IgM and IgG autoantibodies from sera derived from patients with myoclonic encephalopathy, regardless of its cause, bind to cerebellar Purkinje cells' cytoplasm and axons A high-molecular-weight subunit of neurofilaments appears to be one of the major targets (179)
The condition is self-limiting, and in a substantial proportion of children, corticosteroids induce a dramatic improvement ( 164) Nevertheless, the long-term outcome is not totally favorable, and more than one-half of the children are left with intellectual deficits and abnormalities in motor performance, speech, and behavior ( 164,180)
In some 50% of patients with myoclonic encephalopathy, a malignant tumor can be demonstrated, most commonly a neuroblastoma The tumor is often inapparent at the onset of the illness and is uncovered only after persistent diagnostic studies ( 181) Palpation of the abdomen, rectal examination, and tomography or
ultrasonography of the chest and abdomen are the most useful procedures In the experience of Boltshauser and coworkers, bone marrow examinations, skeletal surveys, and urinary vanillylmandelic acid (VMA) assays were rarely helpful (164)
The clinical course, response to corticosteroid therapy, and long-term prognosis of myoclonic encephalopathy associated with neuroblastoma are the same as in children with myoclonic encephalopathy who do not harbor a tumor For reasons as yet unknown, the survival rate of children with myoclonic encephalopathy and neuroblastoma is far better than that of the general population of children with neuroblastoma (180,182) Aside from neuroblastoma, myoclonic encephalopathy has many other causes In the majority of cases, the syndrome is caused by a viral infection, notably polio virus, coxsackievirus B3, and St Louis encephalitis virus ( 183) (see Chapter 6) Intracranial tumors, various intoxications, and hydrocephalus are other, considerably rarer, causes
SPASMUS NUTANS
Spasmus nutans is an unusual, but generally benign, condition described in 1897 by Raudnitz ( 184) It commences in late infancy (aged 1 to 15 months), often in late winter or early spring, and is marked by anomalous head positions, head nodding, and small-amplitude, rapid nystagmus, which can be conjugate, dysconjugate, or uniocular (185) When visual targets such as a picture book are presented, children start to nod or the amplitude of the nystagmus becomes larger Straightening the tilted head or fixing the head also increases the amplitude of the nystagmus For these reasons, Gottlob and colleagues believe that head nodding is compensatory to the nystagmus (186) Neuroimaging studies are invariably normal The condition is self-limiting, clearing after a period of 4 months to several years and is
unassociated with any visual deficits In most children a subclinical nystagmus persists for many years (187) In the majority of instances the cause remains unknown;
it might be the sequel to a viral illness (188,189) For unknown reasons, the condition appears to be far more common in the eastern United States than in the
southwest of the country
Spasmus nutans should be differentiated from congenital nystagmus, in that the latter usually starts before 6 months of age, and that visual acuity is abnormal in
approximately 90% of children with congenital nystagmus
An increasing number of reports have linked spasmus nutans to gliomas of the optic nerve and chiasm (190) In other cases, the condition has been associated with arachnoid or porencephalic cysts (191) MRI studies of the optic nerves and of the CNS, therefore, are indicated
IMMUNOLOGICALLY MEDIATED DISEASES AFFECTING CENTRAL NERVOUS SYSTEM GRAY MATTER
Rheumatic Fever (Sydenham Chorea)
The principal neurologic manifestation of rheumatic fever is Sydenham chorea (chorea minor; for many years the term chorea magna was used to designate chorea of
hysterical nature) This condition was first defined by Sydenham in 1684 (192)
Chorea Sancti Viti is a sort of Convulsion, which chiefly invades Boys and Girls, from ten Years of Age to Puberty: First it shews its self by a certain
Lameness, or rather Instability of one of the Legs, which the Patient drags after him like a Fool; afterward it appears in the hand of the same side; which he
that is affected with this Disease, can by no means keep in the same Posture for one moment, if it be brought to the Breast, or any other Part, but it will be
distorted to another Position or Place by a certain Convulsion, let the Patient do what he can If a Cup of Drink be put into his Hand he represents a
thousand Gestures, like Juglers, before he brings it to his Mouth in a right line, his Hand being drawn hither and thither by the Convulsion, he turns it often
about for some time, till at length happily raching his Lips, he flings it suddenly into his Mouth, and drinks it greedily, as if the poor Wretch designed only to
make sport For as much as this Disease seems to me to proceed from some Humour rushing in upon the Nerves, which provoke such Preternatural
Motions, I think the curative Indications are first to be directed to the lessening of those Humours by bleeding and purging, and then to the strengthening
the Genus Nervosum, in order to which I use this method: I take seven Ounces of Blood from the Arm, more or less, according the Age of the Patient; the
Trang 19next Day I prescribe half, or somewhat more, (according to the Age, or the more or less disposition of the Body to bear purging) of the common purging
Potion above-described, of Tamarinds, Sena etc In the Evening I give the following Draught:
Take of Black-cherry-water one Ounce, of Langius's Epileptick-water three Drachms, of old Venice-Treacle one Scruple, of Liquid Laudanum eight Drops;
make a Draught
Etiology and Pathology
The relationship of Sydenham chorea to rheumatic fever was first suggested by Stoll in 1780 (193) and gained general acceptance by the medical profession in the nineteenth century Most cases of chorea are preceded by a streptococcal infection or rheumatic fever; however, the interval between the bacterial infection and the onset of neurologic symptoms is between 2 and 7 months, so that in one study, serologic evidence of the streptococcal infection was no longer demonstrable in 27%
of the children who had chorea as the only clinical manifestation of rheumatic disease (194) In approximately one-third of choreic patients, rheumatic heart disease or other major manifestations of rheumatic fever develop after the onset of chorea (195) Conversely, Sydenham chorea has been seen in approximately one-third of rheumatic fever cases (196) In a series of patients from Brazil, reported in 1997, chorea was seen in 26% (197)
Using immunofluorescent staining techniques, Husby and coworkers demonstrated that sera from 46% of children with Sydenham chorea contain IgG antibodies that react with neuronal cytoplasmic antigens located preferentially in the region of the caudate and subthalamic nuclei Staining of neurons probably represents a
cross-reaction between neuronal cytoplasm and antigens present in the membrane of group A streptococci These antibodies are less prevalent and are of lower titer
in children with active rheumatic fever without chorea and in control subjects (198) Antiphospholipid antibodies are found in some 80% of patients with Sydenham chorea It is not known whether these antibodies contribute to the pathogenesis of the condition or whether they merely reflect stimulation by the streptococcal M protein of T-cells directed against self-antigens (199)
Genetic factors also operate in inducing rheumatic fever A family history of rheumatic fever can be elicited in 26% of choreic patients, and Sydenham chorea is found
in 3.5% of parents and in 2.1% of siblings of choreic patients (195) Emotional trauma also can be important in the development of chorea, for the onset of neurologic symptoms is sometimes closely correlated with experiences that cause obvious psychic trauma (200,201)
Neuropathologic studies have been singularly uninformative The few persons who have died during the illness, often because of other rheumatic manifestations, have shown an arteritis with a mild perivascular cellular infiltration and a diffuse loss of nerve cells not only from the basal ganglia, but also from the cortex and
cerebellum No typical Aschoff bodies have been found in the brain (202)
These findings do not explain the pathophysiology of chorea, and it has been postulated that immunoglobulin or complement deposition on cells within the basal
ganglia alters the metabolism of various neurotransmitters
Clinical Manifestations
Up to the last 10 to 20 years, Sydenham chorea had become a rare condition in the western world (203); in the 1980s and 1990s the number of cases of acute
rheumatic fever increased greatly This increase has occurred against a backdrop of no particular increase in the rate of group A streptococcal pharyngitis The
microbiological and host reasons for this resurgence are not completely understood; they are reviewed by Kaplan ( 204) In part, the resurgence is believed to result from the appearance of certain serologic types of group A streptococci that produce pyrogenic exotoxin, particularly toxin A, which had been uncommon for many years In a 1987 report from Ohio, some 17% of children with acute rheumatic fever presented with choreic manifestations Many of these patients came from middle-
or upper-middle-class homes, making invalid the previously noted predisposition for occurrence in low-income groups and crowded housing ( 205)
The condition begins between ages 3 and 13 and is somewhat more common in girls In the Brazilian series the mean age of onset was 9.2 years, and the female to male ratio was 1.16:1 (197) An adage, cited by Wilson (206), is that the child with Sydenham chorea is punished three times before the diagnosis is made: once for general fidgetiness, once for breaking crockery, and once for making faces at his grandmother In part, this adage illustrates the three major clinical features of
Sydenham chorea: spontaneous movements, incoordination of voluntary movements, and muscular weakness
The involuntary movements affect mainly the face, hands, and arms At first inconspicuous and usually best observed when the patient is under stress, they are
abrupt and short, but gradually they become more frequent and extensive, ultimately being almost continuous, disappearing only during sleep and sedation Chorea interrupts the voluntary movements and is particularly prominent during skilled motor acts and speech Muscular weakness can be profound and is sometimes the most prominent aspect of the disorder
The child with pronounced Sydenham chorea is not difficult to recognize The child is restless and emotional Involuntary movements are continuous, quick, and
random They involve mainly the face and the distal portion of the extremities Speech is jerky, indistinct, and at times completely absent Willed acts also are
performed abruptly; as quickly as the tongue is protruded, it returns into the mouth (“chameleon tongue”) Muscular hypotonia and weakness result in the
characteristic pronator sign: When the patient holds the arms above the head, the palms turn outward Hypotonia also can be demonstrated when the arms are
extended in front of the body The wrist is flexed, and the metacarpophalangeal joints are overextended (“choreic hand”) ( Fig 7.4) The child is unable to maintain muscular contraction, and the grip waxes and wanes abruptly (“milkmaid's grip”) The deep tendon reflexes are usually normal, but the patellar reflex is often “hung up.” With the legs hanging down, the contraction of the quadriceps elicited by the tap is maintained, causing the leg to be briefly held outstretched before it falls back down
FIG 7.4 Sydenham chorea Hand in various characteristic choreiform positions (From Wilson SAK, Bruce AN Neurology, 2nd ed London: Butterworth, 1969 With
permission.)
Occasional variants of chorea provide a diagnostic problem The most common is hemichorea, in which the movements are confined to or are more marked on one side of the body Hemichorea was seen in 18% of choreic patients reviewed by Aron and associates (195) In paralytic chorea, the hypotonia and muscular weakness are sufficiently pronounced to obscure the presence of choreiform movements
MRI studies often show increased signal on T2-weighted images in the head of the caudate, and in other portions of the basal ganglia, notably the putamen ( 207) Quantitative MRI demonstrates an increase in the size of the caudate, putamen, and globus pallidus, consistent with the presence of an antibody-mediated
inflammation of this region (208) These abnormalities resolve with clinical improvement SPECT has shown a marked increase in perfusion of the thalamus and
striatum during the stage of active chorea This abnormality resolves as the movements subside (209)
Chorea lasts from 1 month to 2 years Approximately one-third of patients have a single attack; the remainder have up to five or even more recurrences, despite
adequate penicillin prophylaxis It is not clear whether these recurrences represent exacerbations of chronic low-grade choreiform activity, the response to transient, mild streptococcal infections, or the response to other nonstreptococcal stimuli (210) If the patient has been free of symptoms for 1 to 2 years, there is little likelihood
Trang 20of relapse.
Complications of Sydenham chorea are rare Occlusion of the central retinal artery and pseudotumor cerebri are unusual associated conditions ( 211) Although
complete recovery without gross neurologic residua is the rule in Sydenham chorea, minor neurologic signs, notably tics or other adventitious movements, tremor, and impaired coordination, can persist (200) Some of the signs, such as an unusual abruptness of voluntary movements, can be apparent long after the chorea has
disappeared Furthermore, convalescents can develop choreic reactions to a variety of drugs, notably methylphenidate, phenylethylamines, and dextroamphetamine (212) Behavioral disturbances, notably obsessive-compulsive disorder (OCD), are common; in many instances, these had been noted before the onset of chorea
Diagnosis
The major causes for chorea are presented in Table 7.5 Chorea must be differentiated from tics and from a variety of other movement disorders (see Introduction) Additionally, Sydenham chorea should be distinguished from chorea that results from a variety of other causes, notably perinatal asphyxia, Huntington disease, SLE, and chorea which is an expression of the motor impersistence of sensorimotor and cognitive immaturity (minimal brain dysfunction)
TABLE 7.5 Major causes of chorea
Tics, unlike true chorea, are abrupt, repetitive, and patterned, involving the same muscle groups repeatedly They do not interfere with coordination and are not
associated with muscular hypotonia To complicate the differentiation between chorea and tics, preexisting motor tics can merge into Sydenham chorea after a
streptococcal infection (213) Sydenham chorea also should be distinguished from the various pediatric autoimmune neuropsychiatric diseases associated with
streptococcal infection (PANDAS) (see Pediatric Autoimmune Neuropsychiatric Diseases Associated with Streptococcal Infection, later in this chapter) The
differentiation of chorea that develops as a symptom of SLE and Sydenham chorea rests on the presence of antinuclear and anti-DNA antibodies in the former entity Antibodies against streptococcal DNAase are particularly useful for the diagnosis of Sydenham chorea because they tend to remain elevated for some 6 months after
a streptococcal infection Additionally, increased expression of the D8/17 B-cell alloantigen is seen in patients with Sydenham chorea, rheumatic fever, but not in SLE (214)
Choreic movements resulting from perinatal asphyxia generally become apparent between the first and the third years of life (see Chapter 5), an earlier age than in Sydenham chorea The movements are usually slower and tend to be more evident in the larger proximal musculature Like the involuntary movements of Sydenham chorea, they are exaggerated by fatigue and emotion In most cases, choreiform movements are accompanied by other involuntary movements, principally athetosis
The differential diagnosis between children with mild choreiform movements owing to Sydenham chorea and those whose choreiform movements are based on
minimal brain dysfunction (see Chapter 16) is difficult, because children with Sydenham chorea also have a high incidence of preexisting learning and personality problems Resolution of the chorea in a matter of months suggests Sydenham chorea, as does the absence of clear-cut cognitive immaturities
Huntington disease is rarely seen in children (see Chapter 2) The involuntary movements predominantly involve the proximal musculature, and, although abrupt, they are more extensive than those of Sydenham chorea In particular, twisting movements of the shoulders and trunk are characteristic of Huntington disease Mental deterioration or seizures, commonly found in Huntington disease and not observed in Sydenham chorea, and a history of autosomal dominant transmission are further clinical diagnostic aids
Numerous drugs, notably haloperidol, isoniazid, reserpine, phenytoin, or phenothiazines such as prochlorperazine also can induce choreiform movements The
various forms of paroxysmal choreoathetosis, a subgroup of the paroxysmal dyskinesias, can be distinguished by the sudden onset of choreiform movements in a child who has few, if any, involuntary movements between attacks (see Chapter 2) Familial benign choreoathetosis is a rare condition that begins in the first two
decades of life It is characterized by choreiform movements of the hands, shoulders, arms, and legs, and by a combined resting and intention tremor (see Chapter 2) The disorder is transmitted in an autosomal dominant manner
Treatment
Since Sydenham in 1684 recommended bleeding, purges, and Laudanum (alcoholic tincture of opium) for the treatment of chorea, a large number of therapeutic
regimens have been suggested The variability in the duration of untreated chorea makes evaluation difficult, and the effectiveness of salicylates, cortisone, or ACTH
in shortening the length of the illness has not been proved
Currently, the optimal form of treatment is bedrest in a darkened, quiet room For children whose movements are severe, drug therapy is necessary In the past,
phenobarbital, chlorpromazine, or haloperidol has been used Sodium valproate (15 to 25 mg/kg per day) appears to be equally efficacious and controls the
involuntary movements in 5 to 10 days (215) The mechanism by which it works remains a matter of speculation The drug is gradually withdrawn after 2 to 6 months Should symptoms recur, it is restarted
Even when streptococci cannot be isolated from throat cultures, a course of penicillin is indicated as soon as the diagnosis of Sydenham chorea is made The patient
is given a single intramuscular dose of 1.2 million U of benzathine penicillin, or an oral penicillin dose of 200 to 250 mg given four times daily for 10 days
The subsequent occurrence of rheumatic complications in many patients with Sydenham chorea dictates the prophylactic use of antimicrobial agents: the oral
administration of penicillin (200,000 U two or three times daily) or clindamycin (75 mg two or three times daily) ( 216) The antibiotic is given for several years, or at least until the patient has completed high school
Pediatric Autoimmune Neuropsychiatric Diseases Associated with Streptococcal Infection
The term PANDAS has been used to designate a group of neuropsychiatric disorders, notably tic disorders, Tourette syndrome, and OCD, which are believed to be
related to an antecedent streptococcal infection, and for which an autoimmune pathogenesis has been postulated
The condition began to be recognized in the early 1990s Whether it had been present before then and not recognized, or whether it is of new onset, is unknown Serum antineuronal antibodies that cross-react with caudate nucleus and other brain tissue have been found in Tourette syndrome and OCD ( 217) In the study by Kiessling and colleagues, a strong positive response to antibody was found in 53% of children with choreiform movements, 43% of children with tic disorders, but only
in 21% of children without a movement disorder (217) Patients with OCD or Tourette syndrome are frequently positive for B-lymphocytes that express an epitope reactive with a D8/17 monoclonal antibody, the same antibody whose expression is increased in rheumatic fever and Sydenham chorea (218)
The clinical characteristics for the diagnosis of PANDAS have been listed by Swedo and colleagues ( 219) They are (a) presence of OCD, a tic disorder, or both; (b) onset between 3 years of age and puberty; (c) episodic course with abrupt onset, or dramatic exacerbation of symptoms; (d) symptom exacerbations temporally
related to group A beta hemolytic streptococcal infections, as demonstrated by a positive throat culture result, elevated antistreptococcal antibody titers, or both; and
Trang 21(e) association with neurologic abnormalities, notably choreiform movements.
PANDAS is not a rare disorder, and the characteristic patient demonstrates a combination of choreiform movements and a tic disorder, which has had an abrupt
onset, or a marked worsening in the wake of a streptococcal infection The diagnosis is suggested by a positive throat culture result or by positive antistreptococcal antibodies Many questions about this disorder remain, notably how to treat it, and most important, well-controlled studies are required to verify the relationship
between streptococcal infection and the movement disorder (220,221)
Various treatments have been proposed These include antibiotics directed against the putative inciting streptococcal organisms, serotonin reuptake blockers,
intravenous immunoglobins (IVIG) (1 gm/kg for two consecutive days), and plasmapheresis (5 to 6 procedures performed on alternate days) When children are given IVIG, improvement is seen 3 weeks after treatment or even later, and persists for 1 or more years (221a) With plasma exchange, symptom improvement is noted toward the end of the first week of treatment, and persists for 1 year or longer (221a) In the experience of Perlmutter and colleagues, tic symptoms are more
effectively treated with plasma exchange, whereas IVIG and plasma exchange appear almost equally effective for symptoms of OCD (221a)
Rasmussen Syndrome
Rasmussen syndrome is a rare, progressive, gray matter disease of children It is marked by an onset in the first decade of life with intractable focal epilepsy,
progressive hemiparesis, atrophy of the contralateral cerebral hemisphere, and dementia The presence of serum GluR3 antibodies in some patients with Rasmussen syndrome but not in a control group suggests that this condition represents an immune-mediated disease Rasmussen syndrome is more fully described in Chapter 6
IMMUNOLOGICALLY MEDIATED DEMYELINATING DISEASES OF THE PERIPHERAL NERVOUS SYSTEM
Guillain-Barré Syndrome
In the past, GBS was considered as a single pathologic and clinical entity The condition can be subdivided into several diverse disorders These are classified as follows: (a) sporadic GBS, which is most common, accounting for some 85% to 90% of cases has been termed acute inflammatory demyelinating polyneuropathy (AIDP); (b) acute motor-sensory axonal neuropathy (AMSAN); (c) acute motor-axonal neuropathy (AMAN); (d) Miller Fisher syndrome; and (e) chronic inflammatory demyelinative polyneuropathy (CIDP) AIDP or GBS (the terms are still used interchangeably) is by far the most common cause of immune-mediated peripheral nerve disease in children, and with the near disappearance of poliomyelitis, is responsible for the great majority of cases of acute flaccid, areflexic paralysis The condition
is characterized by progressive weakness, which usually appears a few days to weeks after a nonspecific infection and is accompanied by mild sensory disturbances and an albuminocytologic dissociation (high protein but normal cell count) in the CSF
The first cases were recorded in 1859 by Landry (222), who noted that the disorder can produce both motor and sensory symptoms (especially motor), that it involves the distal parts of the limbs, and that in some instances it can become generalized by a sequential ascent of the neuraxis Guillain, Barré, and Strohl stressed the presence of albuminocytologic dissociation (223)
Pathology
The pathologic findings are characterized by a marked segmental demyelination In the majority of cases, GBS is marked by a mononuclear, predominantly
T-lymphocytic and macrocytic inflammatory infiltration of all levels of the peripheral nervous system, from the anterior and posterior roots to the terminal twigs
(224,225) and involving at times also the sympathetic chain and ganglia and the cranial nerves Cells are usually clustered around the endoneurial and epineurial vessels, particularly the small veins T-lymphocyte infiltration appears to be preceded by a complement-mediated Schwann cell damage and vesicular demyelination (226) Segmental demyelination occurs in the areas infiltrated by inflammatory cells, whereas interruption of the axonal cylinders with subsequent wallerian
degeneration is less extensive, usually occurring only where an intense inflammation occurs The number of Schwann cell nuclei is increased, possibly representing a reparative response Ultrastructural studies reveal that macrophages are the major effectors of demyelination, and that neither Schwann cells nor myelin sheaths show any damage, except where they are in contact with macrophages (227) In a minority of cases, macrophage-associated demyelination occurs despite a paucity
of lymphocytes (228)
In the CNS, the alterations are secondary to secondary axonal degeneration Most common is chromatolysis involving the anterior horn cells and the cells in the motor nuclei of the cranial nerves Long-standing cases show some degeneration of the posterior columns ( 225)
Pathogenesis
The morphologic alterations in GBS resemble those induced in experimental animals by immunization with peripheral nerve homogenates ( 229), or more specifically,
by a peptide (P2) derived from the basic protein of peripheral nerves (230) As is the case for GBS, the earliest event in the induction of experimental allergic neuritis
is the presentation of antigen to “naive” T cells resulting in their activation The activated T cells circulate in the blood and attach to the venular endothelium of
peripheral nerves T cells then migrate through the endothelial lining to a perivascular location There they enlarge, their ribosomes increase in number, and RNA production accelerates The now sensitized lymphocytes contact myelin, and after a lag of at least several hours, they produce segmental demyelination ( 231,232) Cytokines, released by inflammatory cells and by Schwann cells contribute to demyelination, and to changes in Schwann cells that have deleterious effects on myelin and axons (233) Tumor necrosis factor-a and IL-1b, mediators of inflammation, are secreted by activated macrophages and by antigen-activated T-lymphocytes Their serum levels correlate with neurophysiologic evidence of demyelination (234) The role of integrins, a family of cell adhesion molecules, in the development of inflammation in experimental allergic neuritis and GBS, and subsequent remyelination is reviewed by Archelos and colleagues ( 235)
The consensus of evidence indicates that the GBS represents an interaction between an infectious agent and a cell-mediated immune response directed against the myelin-producing Schwann cells, the peripheral myelin, or one of the components of myelin (232) The antigen on the Schwann cell membrane that is involved in GBS
is believed to be a glycoconjugate, which is carried on the bacterial or viral organism that is responsible for the antecedent infection, and which generates an immune
response Antibodies directed against the foreign glycoconjugate target similar epitopes on nerve fibers This process has been termed molecular mimicry.
An antecedent acute infectious illness has been documented in approximately two-thirds of children who develop GBS Most commonly, it is a respiratory tract
infection or a gastroenteritis Several agents have been implicated in these infections ( 236,237 and 238) Of these, Campylobacter jejuni infection has become
recognized as the most common bacterial antecedent of GBS In various series it accounted 26% to 41% of sporadic cases (239,240) Other responsible agents include cytomegalovirus, which has been implicated in 10% to 22% of GBS cases (240), and the Epstein-Barr virus, which is responsible for some 10% of cases Primary infection with herpes zoster has been noted in nearly 5% of childhood cases of GBS in some series ( 237) Other viruses implicated in the evolution of GBS are listed in Table 7.6 The chief feature shared by most of these is that they have a viral envelope
TABLE 7.6 Infectious organisms associated with Gullain-Barré syndrome or acute disseminated encephalomyelitis
Trang 22Several vaccines have been implicated in the evolution of GBS Of these the best substantiated is the rabies vaccine as prepared from brain tissue and probably
contaminated with myelin antigens (240a) The swine-flu influenza vaccine, as administered in 1976 and 1977, also was responsible for numerous cases of GBS
(240b) The association of GBS with other immunizations, notably tetanus, oral polio vaccine, other influenza vaccines, and measles vaccine has been more difficult
to establish The best that can be said at this time is that such an association cannot be excluded ( 240,240c) The association of GBS with trauma or surgical
procedures is probably anecdotal
Considerable work has been directed at establishing the connection between an antecedent C jejuni infection and GBS The lipopolysaccharide of C jejuni contains a
GM1 epitope, which induces a high production of IgG anti-GM1 antibodies that are believed to react with epitopes located mainly on axons, but also, to a lesser degree
on myelin Patients whose sera have anti-GM1 antibodies tend to develop the acute motor axonal neuropathy form of GBS (241,242) C jejuni also has been
implicated in the demyelinating form of GBS (242a) It has now become apparent that the antigenic structure of the antecedent infectious agent determines the clinical manifestations of GBS Thus, patients with the Miller-Fisher syndrome are likely to have serum antibodies against the ganglioside GQ 1b (243), whereas antibodies directed against GalNAc-GD1a gangliosides carried on C jejuni tend to induce a clinical picture marked by distal weakness, no sensory loss, and a normal cranial
nerve examination (244)
Unlike MS, genetic factors appear to play little or no role in the evolution of GBS, and the appearance of the disease is not influenced by genes associated with the HLA-A or HLA-B locus (245) Furthermore, no abnormalities exist in the subsets of the T-cell population The pathogenesis of GBS is reviewed in greater detail by Ho and colleagues (232)
Clinical Manifestations
Acute Inflammatory Demyelinating Polyneuropathy
Clinical symptoms result from disturbed saltatory conduction through myelinated axons (conduction block) GBS can occur at any time during childhood, but is most frequent between ages 4 and 9 years (246) A prodromal respiratory illness or gastroenteritis occurs in approximately two-thirds of the patients, usually within 2 weeks before the onset of weakness (Table 7.7) (246,247)
TABLE 7.7 Clinical characteristics of 56 children with acute infectious polyneuritis
Neurologic symptoms usually appear fairly suddenly In a large proportion of cases, 89% of adult patients in the series of Moulin and colleagues ( 248), paralysis was accompanied by pain or paresthesia In 47%, pain was severe and was described as a deep aching pain in back and legs Visceral pain was noted in 20%
The paralysis usually begins in the lower extremities, then ascends Characteristically, it is symmetric, although minor differences between the sides are not rare In approximately 50% of patients, the weakness is mostly distal, whereas in approximately 15%, the proximal musculature is more extensively involved (see Table 7.7) Cranial nerve palsies can appear at any time during the illness The facial nerve is involved most commonly; it was involved in more than one-half of patients in the series of Winer and colleagues (249) Papilledema is relatively rare Although its appearance correlates well with increased intracranial pressure ( 250), papilledema is not invariably accompanied by elevation in CSF protein, and its pathogenesis remains unexplained ( 251)
Paralysis of the respiratory muscles is a common complication in severely involved patients, but even in the absence of respiratory symptoms, vital capacity can be impaired with consequent carbon dioxide retention Involvement of the sympathetic nervous system can produce a variety of circulatory abnormalities, including
profuse sweating, hypertension, or postural hypotension, which often are predictors of a fatal cardiac arrhythmia ( 252) Sphincter disturbances are noted in up to one-third of patients (249)
Position sense is the sensory function most frequently impaired, followed by vibration, pain, and touch, in descending order of frequency The deep tendon reflexes are generally absent, although increased reflexes and extensor plantar responses are occasionally recorded during the initial days of the illness
An elevation in the CSF protein content is characteristic This exceeds 45 mg/dL in 88% of affected children (see Table 7.7) and increases to its maximum by 4 to 5 weeks, thereafter gradually returning to normal (Fig 7.5) The CSF cell count is usually normal, although significant pleocytosis (100+ cells/mL) occurs in
approximately 5% of patients
FIG 7.5 Acute infectious polyneuritis Protein content of the cerebrospinal fluid at various intervals after onset of symptoms Determinations performed on the same
patient are connected by a line [From Peterman AF, Daly DD, Dion FR, et al Infectious neuronitis (Guillain-Barré syndrome) in children Neurology 1959;9:533 With
permission.]
Electromyography (EMG) reveals a picture compatible with involvement of the lower motor neurons or peripheral nerves Abnormalities in nerve conduction are the most specific electrophysiologic findings The most characteristic is the presence of conduction block This is a reduction in amplitude of the muscle action potential after stimulation of the distal, as compared with the proximal, portion of the nerve Approximately 80% of patients have nerve conduction block or slowing at some time during the illness The conduction velocity often does not become abnormal until several weeks into the illness ( 253,254)
This neurologic picture evolves rapidly, and paralysis can be maximal within a few hours of the initial symptoms More commonly, however, the paralysis becomes
Trang 23more extensive over 1 to 2 weeks, often, as in the classic Landry type of paralysis, progressively affecting the trunk, upper extremities, and cranial nerves After the paralysis reaches a plateau, clinical improvement is usually first noted by the second to fourth week of the illness, and the majority of children experience complete recovery Recovery usually is achieved within 2 months, although it can take as long as 18 months.
Some children, approximately 10% of the Dublin series of Briscoe and coworkers (255), experience one or more relapses over the subsequent 2 months to several years Such patients are considered to have CIDP This condition is covered in a subsequent section
Acute Motor-Sensory Axonal Neuropathy
Feasby and others first described a subgroup of patients who developed a fulminant, extensive, and severe weakness with delayed and incomplete recovery
Electrophysiologic studies in these patients suggested a primary axonal degeneration, which was confirmed by nerve biopsy performed on patients who died shortly after the onset of their illness (256,257) This demonstrated severe axonal degeneration with little demyelination, and scanty lymphocytic infiltration, an indication that
in this condition the primary insult is to motor and sensory nerve axons (258) In these patients the earliest identifiable changes are in the nodes of Ranvier of motor fibers (259) Patients with this form of neuropathy are much more likely to have experienced an antecedent C jejuni infection than control populations and are more
likely to have high titers of serum anti-GD1a antibodies (242,260)
Acute Motor-Axonal Neuropathy
A pure motor axonal neuropathy has been reported from China and India In the Chinese cases, the disease appeared in annual summer epidemics and manifested
as a severe motor neuropathy, with involvement of the proximal portion of the motor neurons or cell bodies and good recovery Electrophysiologic studies indicate that the motor fibers are lost selectively, and that neither involvement of the sensory fibers nor demyelination occur ( 232) In the Indian paralytic disease, fever and a hemorrhagic conjunctivitis occur at the onset of the illness, the weakness is asymmetric, and the CSF demonstrates a pleocytosis This form of neuropathy also is
closely associated with a C jejuni infection (261)
Miller Fisher Syndrome
Another variant of GBS was first described by Fisher in 1956 (262) It is characterized by the evolution, within approximately a week, of external ophthalmoplegia, ataxia, and areflexia The first symptom is usually diplopia, with bilateral facial paresis being present in approximately one-half of the affected children ( 263) Internal ophthalmoplegia is present in approximately two-thirds The CSF shows a mild protein content elevation and, occasionally, pleocytosis Peripheral motor and sensory conduction times and the EMG are generally normal The EEG can show excessive slow-wave activity or can be normal (264) Neuroimaging studies exclude a mass lesion (265,266)
Symptoms remain severe for 1 to 2 weeks before recovery commences Recovery proceeds at a variable rate, but generally is complete
The Miller Fisher syndrome is associated with strains of C jejuni that have the ability to induce antibodies against ganglioside GQ 1b (243,267) Such antibodies can be demonstrated in 96% of patients with Miller Fisher syndrome, and their titers parallel the course of the disease These antibodies have the ability to block the release
of acetylcholine from motor nerve terminals, with oculomotor fibers having the highest concentration of GQ 1b-reactive antigens (232,268) The effect resembles that induced by a-latrotoxin (268a) (see Table 9.6)
At present, it is still a matter of dispute whether Miller Fisher syndrome should be distinguished from brainstem encephalitis, as delineated by Bickerstaff and others (see Chapter 10) (269) According to some, ataxia in Miller Fisher syndrome is caused entirely by peripheral nerve involvement, and pathologic changes are restricted
to the peripheral nervous system (270) Others believe that the CNS also is involved and that in some cases a combined central and peripheral demyelination exists MRI studies do not appear to help in the differential diagnosis Whereas the MRI is normal in some cases of Miller Fisher syndrome, in others T2-weighted images demonstrate areas of increased signal in the brainstem Conversely, there are several instances of clinically diagnosed brainstem encephalitis in whom
electrophysiologic evidence exists for involvement of the peripheral nerves (271) Miller Fisher syndrome also must be distinguished from posterior fossa tumors Before neuroimaging studies this differentiation was difficult However, the constellation of a severe and sometimes complete external ophthalmoplegia, ataxia, and loss of deep tendon reflexes in a fairly alert child is unique
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
CIDP has some of the clinical features of GBS, but the evolution of the neurologic symptoms is slower, being a matter of weeks or months, rather than days Some patients have a chronic fluctuating course without complete recovery between exacerbations (272,273) In the few children thus affected, the motor component of the picture is usually predominant (274), and weakness is greatest in the distal muscles On biopsy the peripheral nerves show a segmental demyelination and increased
numbers of Schwann cells Their processes are arranged in whorls around the demyelinated axons Termed onion bulbs, they are characteristic of not only the
hereditary peripheral neuropathies, but also of most chronic recurrent neuropathies, and their presence correlates with the duration of symptoms ( 275) Table 7.8
shows the differential diagnosis of CIDP of childhood, together with some salient diagnostic features of each of the major entities The initiating factor responsible for CIDP remains unknown in most children Unlike GBS, in which no association with histocompatibility antigens has been established, CIDP has been shown to be associated with haplotypes B8, DR3, and Dw3 (276) Antibodies directed at GM1, GD1b, and asialo-GM1 glycolipids have been identified in some cases, suggesting that the galactosyl (beta 1 ® 3) N-acetogalactosaminyl moiety of myelin may be an important target antigen in some cases (277)
TABLE 7.8 Differential diagnosis of chronic polyneuritis of childhood
Diagnosis
The criteria for the clinical diagnosis of classical GBS were established in 1978 by the National Institute of Neurologic and Communicative Disorders and Stroke ( 278) and were updated in 1990 by Asbury and Cornblath (279) They are presented in Table 7.9 In essence they rest on the gradual development of symmetric muscular weakness, which is often worse over the distal portion of the lower extremities, the presence of areflexia, and the aforementioned CSF and electrodiagnostic
abnormalities In the presence of sensory changes, usually little doubt exists about the diagnosis When sensory changes are absent, however, a number of other entities must be considered In poliomyelitis, the onset of paralysis is accompanied by fever and evidence of a systemic illness The paralysis is rarely symmetric, and CSF pleocytosis is common during the initial stages of the illness (see Chapter 6)
Trang 24TABLE 7.9 Guillain-Barré syndrome study group diagnostic criteria
Polymyositis can be confused with GBS The distribution of muscular weakness in polymyositis tends to be proximal, and the CSF protein content remains normal The presence of hypokalemia in the occasional patient with GBS requires the differential diagnosis of hypokalemic paralysis This condition usually carries a family history, and the ECG is abnormal during a paralytic attack (280) The differential diagnosis of ATM and GBS has been noted already Other less common conditions that induce progressive muscular weakness of rapid onset are described in Chapter 14
Treatment
Treatment of GBS should be proactive The neuropathy can progress rapidly, so that the potential for paralysis of the respiratory muscles should be considered in each patient, and facilities for tracheostomy and mechanical ventilation should be readily available Generally, these measures should be instituted when impaired vital capacity first becomes apparent, rather than after embarrassment of respiration is obvious and the patient has difficulty breathing A reduction of vital capacity to approximately one-half the norm for the age calls for immediate consideration of tracheostomy Fluctuations in blood pressure, hemodynamic instability, autonomic dysfunction, and oropharyngeal weakness are common
Several large controlled trials have shown that neither oral nor intravenous corticosteroids are beneficial for the various forms of GBS and possibly are
contraindicated (281) However, many patients who experience CIDP show a clear-cut response to corticosteroids (282)
Plasmapheresis and IVIG have been used extensively Controlled studies have confirmed that in pediatric patients plasmapheresis shortens the interval to
independent ambulation (283) and the duration of mechanical ventilation (284) One study, involving patients older than 16 years, indicated that for mild cases of GBS two exchanges are better than none For moderate or severe cases, four exchanges, conducted in the course of 1 week, are better than two More than four
exchanges do not confer additional benefits (285)
High-dose IVIG is another effective means of treating GBS In a double-blind study a clear difference existed in favor of IVIG over plasmapheresis in adult and
pediatric patients More patients improved with IVIG, median time to improvement was shorter, there were fewer complications, and less need for ventilation ( 286) Furthermore, IVIG treatment is safer and less traumatic to children, and is, therefore, in our opinion, the preferred form of intervention for the child who has a major deficit during the first week of the disease High-dose IVIG also has been effective in the treatment of CIDP ( 287) Although there are few adverse reactions to IVIG, several groups have reported significant relapses in GBS patients treated in this fashion ( 288) Other adverse reactions include an allergic response to g-globulin and
a chemical meningitis The mechanism of action of IVIG is poorly understood The most likely is that it modulates the immune response in GBS by selective
suppression of the proinflammatory cytokines (289)
Because with good supportive care the long-term outcome for even those children who require ventilation is excellent, supportive treatment still finds its adherents for all but the most severely affected
An important part of the general support of the child with GBS is the use of physiotherapy This should be instituted during convalescence, and both active and
passive exercises should be graduated as recovery progresses
Prognosis
In general, the outlook for life and recovery is better in children than in adults The greatest danger during the acute phase of GBS is respiratory paralysis and cardiac arrhythmias Cardiac arrhythmias can be brought on by manipulation of the patient, such as from changing a tracheotomy tube (290) Early tracheostomy and the availability of mechanical ventilation should eliminate a considerable proportion of fatalities In the pediatric age group, there is generally no correlation between the severity of the illness and the long-term outcome (290) Several studies suggest that evidence for an antecedent C jejuni infection correlates with a disease in which
there is axonal degeneration and a poor outcome (291)
BELL'S PALSY
An acute paralysis of the face, often after a mild infection, was first described by Bell in 1829 ( 292)
Cases of this partial paralysis must be familiar to every medical observer It is very frequent for young people to have what is vulgarly called a blight, by
which is meant a slight palsy of the muscles on one side of the face, and which the physician knows is not formidable Inflammations of glands seated
behind the angle of the jaw will sometimes produce this … The patient has a command over the muscles of the face; he can close the lips, and the
features are duly balanced; but the slightest smile is immediately attended with distortion, and in laughing and crying the paralysis becomes quite distinct
Pathology and Pathogenesis
Because the process is often partly or wholly reversible, little is known about the acute pathology or pathophysiology, which is assumed to be inflammatory The
essential anatomic changes of the seventh nerve in Bell's palsy are still under considerable dispute Most authors agree that during the acute phase of the illness, patients have considerable edema of the nerve and venous congestion in the facial canal A few microscopic hemorrhages occur, but little inflammatory reaction
In 73% of patients, there is an antecedent upper respiratory infection or exposure to cold drafts; these causes were the most frequently implicated during the
nineteenth century (293) Currently, a variety of infectious agents have been suggested On the basis of antibody levels, the list includes Epstein-Barr virus (in some 20% of patients) (294), mumps, and possibly herpes simplex and herpes zoster Facial palsy caused by Lyme disease is particularly frequent in Scandinavia and other endemic areas In one series, 60% of children with Bell's palsy had specific IgM antibodies for the spirochete in CSF ( 295) Lymphocytes from subjects with Bell's palsy have been found to respond specifically to a basic protein (P1) isolated from human peripheral myelin No response could be elicited to the P2 protein implicated in GBS (296) Additionally, T-lymphocytes, mainly T-helper cells, are depressed during the first 2 weeks of the disease ( 297) A genetic predisposition also appears to be important (298)
Clinical Manifestations
Any aspects of facial nerve function may be involved This includes the facial motor movement, notably facial expression and lid closure; the tensor tympani resulting
in impaired dampening of eardrum reaction to loud noises; taste sensation of the anterior two-thirds of the tongue; and autonomic regulation of lachrymal and salivary glands The site of dysfunction determines which modalities are involved Although potential sites include any point from the pontine nucleus to distal portions of
nerve within canaliculi of the skull, the most common site is within the facial canal of the temporal bone
Bell's palsy occurs in 2.7 in 100,000 children younger than 10, and 10.1 in 100,000 children older than 10 years of age As is the case for GBS and ADEM, Bell's
Trang 25palsy commonly follows an upper respiratory illness Whereas most childhood cases are unilateral, asymmetric bilateral Bell's palsy occasionally is encountered;
usually this is a manifestation of GBS
In many cases, pain localized in the ear or surrounding area is the initial symptom This is followed by a rapid evolution of the paralysis, which reaches its full extent in
a few hours Characteristically, paralysis involves the musculature of the forehead, cheek, and perioral region Approximately one-half of patients lose taste sensation Lacrimation is retained in the great majority of children (299) Auditory-evoked potentials and trigeminal nerve-evoked potentials indicate that in a considerable
proportion of subjects, Bell's palsy is not a mononeuropathy, but is accompanied by subclinical involvement of the trigeminal and auditory pathways ( 300) The pain, which can reflect trigeminal nerve involvement, usually disappears quickly In most children, recovery begins within a few weeks and reaches its maximum in 1 to 9 weeks (299) The CSF is usually normal or shows a slight pleocytosis In cases that evolve as a complication of Lyme disease, pleocytosis is often striking ( 295,301) MRI demonstrates enhancement of the intra-meatal segment of the facial nerve on T1-weighted images On T2-weighted images enlargement of the intra-meatal segment can be seen with three-dimensional imaging (302)
The patient can be expected to recover completely when the palsy is partial, as is the case in 80% of children ( 303), or when evoked EMG shows an incomplete denervation of the facial nerve When denervation is complete, the onset of recovery is delayed for approximately 6 weeks, and its maximal extent is not achieved until 6 months (304) In such instances, return of muscle function is usually incomplete In 7% of children facial paralysis recurs ( 305) In some, it is part of Melkersson syndrome This condition is characterized by recurrent facial palsy that is often associated with swelling of the lips, tongue, cheeks, or eyelids, and, less commonly, with furrowing of the tongue (306) With each attack of Melkersson syndrome, facial nerve function becomes progressively more impaired, and paralysis ultimately can be nearly complete (307) Treatment with methylprednisolone has been suggested (308)
Rarely, there is a familial predisposition to facial nerve palsy; in these cases, facial nerve weakness can be accompanied by oculomotor paralyses ( 309)
Diagnosis
The diagnosis of Bell's palsy rests on the exclusion of other causes of isolated facial paralysis ( Table 7.10)
TABLE 7.10 Causes of isolated facial paralysis, 1957 through 1972
Facial nerve palsy caused by otitis media, with or without mastoiditis, is still relatively common (304) A number of intracranial neoplasms, particularly those involving the brainstem, can result in the sudden onset of facial weakness (see Chapter 10) In some instances, transient improvement can be observed before other neurologic signs appear Isolated facial nerve palsy can be seen with a variety of viral encephalitides, notably mumps, varicella, and the enteroviruses (see Chapter 6) It also is
a concomitant to osteomyelitis of the skull, pseudotumor cerebri, and systemic hypertension (310,311) The cause of the facial palsy in systemic hypertension is not clear, but is believed to be induced by hemorrhages within the facial canal The facial palsy can be the presenting feature of hypertension, and it is often intermittent and unrelated to the level of hypertension In children, facial palsy is rarely caused by herpes zoster of the geniculate ganglion (Ramsay Hunt syndrome) ( 304)
Another unusual cause for facial nerve palsy is the presence of an intra-aural tick The salivary gland of the tick secretes a toxin that interferes with the synthesis or liberation of acetylcholine at the motor end-plates of facial muscle fibers (311a)
Treatment and Prognosis
A number of therapeutic approaches have been suggested Administration of corticosteroids to reduce the edema within the facial canal has been used for several years In view of the high recovery rate of untreated children, its evaluation is difficult An analysis of all available studies led Huizing and coworkers to conclude that therapy was ineffective (312) In many instances, however, one has the clinical impression that treatment with corticosteroids within several days of the onset of
symptoms is beneficial Late treatment is certainly of no value
Decompression of the facial nerve from the stylomastoid foramen through its pyramidal portion has been advised for patients who show complete denervation on evoked EMG, although no evidence indicates this procedure to be effective in either children or adults ( 313)
In children whose facial function recovers only partially, contractures can be expected Misdirection of growth results in facial mass action in which attempted activity
of one muscle group produces movements in several different muscle groups (synkinesis) Misdirection of growth also can result in tics or in the syndrome of crocodile tears In this syndrome, food in the mouth or the smell of food is followed by lacrimation rather than salivation ( 314)
Varieties of cosmetic surgical procedures have been described, but these should be deferred until facial growth is complete Artificial tears and eye patches should be supplied to all children whose Bell's palsy results in incomplete eye closure, particularly during sleep
Generally, the younger the patient, the more likely there will be a good recovery Other favorable factors include the absence of hyperacusis, and relatively normal minimal excitability values for the affected facial nerve These values are obtained by electrical stimulation of the branches of the nerve just anterior to the ear and measurement of the minimal current required to effect a visible contraction of the muscle The excitability study must be done within the first few days of the onset of paralysis; if corticosteroid therapy has been chosen, the dosage of corticosteroids can be modified according to the values obtained ( 315)
POSTINFECTIOUS ABDUCENS PALSY
A painless palsy of the abducens nerve that clears without residua can develop in children of any age, 7 to 21 days after a nonspecific febrile illness or upper
respiratory infection The paralysis is often complete but unassociated with any other cranial nerve palsy or neurologic signs Improvement becomes evident in 3 to 6 weeks, and the palsy clears completely in 2 to 3 months Except for the CSF, which can occasionally show a mild lymphocytosis, all laboratory and radiologic study results are normal (316)
Postinfectious abducens palsy is diagnosed by exclusion of abducens palsy secondary to increased intracranial pressure, tumors of the brainstem, brainstem
encephalitis, and Gradenigo syndrome (317) The last, caused by an osteomyelitis of the apex of the petrous bone, is characterized by an abducens palsy after otitis media; it is accompanied by pain in the distribution of the homolateral trigeminal nerve
Rarely, abducens palsy may recur, with the episodes occurring on the same side A variety of events can precede the palsy These include a febrile illness, trauma, and diphtheria-pertussis-tetanus (DPT) immunization (318)
OTHER POSTINFECTIOUS CRANIAL NEUROPATHIES
An isolated temporary paralysis of the glossopharyngeal nerve has been reported The presenting symptoms in children were dysphagia and nasal speech CSF
Trang 26examination was normal, and the condition cleared completely within 1 to 2 months (319).
Other postinfectious cranial neuropathies include an isolated hypoglossal nerve palsy, asymmetric palatal paresis, and involvement of the trigeminal sensory nerve (320,321,322 and 323)
SYSTEMIC VASCULITIDES WITH NERVOUS SYSTEM MANIFESTATIONS
Primary Systemic Vasculitides (Collagen Vascular Diseases, Rheumatic Diseases)
Vasculitic conditions are those diseases in which histologically evident injury to the endothelium of blood vessels contained within nervous tissues constitutes the primary process that leads to injury to surrounding nervous tissues They are variously labeled as vasculitic, collagen-vascular, and rheumatic diseases There are two important pathologic hallmarks of vasculitis The first is the presence of inflammatory cells or the deposition of such humoral immune system elements as
immunoglobulin and complement components within vascular endothelium or other layers of the vascular wall The second is the development of necrotic changes of the vascular wall with associated luminal compromise and secondary downstream ischemia of tissues subserved by the involved vessel ( 324,325) Vasculitides are primary (i.e., without identifiable etiology or pathogenesis) or secondary, arising on the basis of some known toxic, infectious, neoplastic, or other etiology
A great deal remains to be learned about the mechanisms of these diseases This includes factors that determine susceptibility, the nature of the vascular process and of any associated inflammatory reaction that imperils nervous tissues, and the triggers of the immunologic and inflammatory response that becomes deleterious to the host
Considerable pathophysiologic overlap exists between the vasculitic conditions that arise primarily in the nervous system Thus, when neurologic abnormalities of a systemic vasculitic condition become evident before abnormalities of other systems, laboratory tests and subsequent clinical developments must often be relied on to distinguish systemic from such primarily neurologic inflammatory illnesses
Because vasculitic and nonangiitic vasculopathic conditions have clinical and radiographic similarities that may cause diagnostic difficulties, the diagnosis of vasculitis usually rests on the pathologic examination of biopsy specimens obtained from skin, muscle, or kidney In some cases, biopsy of other organs, including brain or meninges, are required to establish the diagnosis In some instances even the biopsy of tissues may not distinguish the various illnesses, because the pathologic changes are often quite nonspecific A general classification of vasculitides and other vasculopathic conditions is shown in Table 7.11
TABLE 7.11 Systemic vasculopathic conditions associated with neurologic disease
General Pathogenetic Mechanisms of Vasculitic Diseases
The general categories of inflammatory vasculitis include those that are antibody mediated, immune-complex–mediated, and cell mediated An increasingly complex array of soluble factors, such as cytokines, and cellular elements, such as adhesion molecules, have been shown to be of importance in mediating vasculitic
conditions Although one of these several mechanisms may predominate, there are many instances in which the other elements become secondarily involved in injury either to the vascular endothelium or to those secondarily involved tissues that are exposed to the immune response as the result of endothelial injury Antiendothelial antibodies produced either because of exposure of antigens or molecular mimicry appear in many instances to invoke a cellular destructive response that involves tumor necrosis factor, interferon-g, IL-1, and possibly other substances The complex vascular response to injury may subsequently involve vasospasm, localized vascular contraction, luminal obliteration, and events that are mediated by calcium, prostaglandins, or inhibition of release of endothelium-derived relaxing factor
Few examples of vasculitic conditions are primarily antibody mediated Kawasaki disease and infantile periarteritis nodosa, which probably are the same disease, and Wegener's granulomatosis are representative examples In Kawasaki disease, circulating cytokines such as IL-1 and tumor necrosis factor either alter existing
endothelial antigens or induce the formation of new antigenic epitopes, to which antiendothelial antibodies then respond with ensuing endothelial lysis associated with induction of thrombosis Other forms of vasculitic inflammation may then be provoked Wegener's granulomatosis is mediated by antineutrophilic and monocytic
cytoplasmic component antibodies These antibodies may directly injure vascular endothelium, possibly because of molecular mimicry Alternatively, they may in their interaction with the target inflammatory cells provoke degranulation and release of lysosomal enzymes, oxidants, cytokines, or other substances that can alter
endothelial antigens, directly injure the endothelium, or incite further inflammatory responses that injure the vascular endothelium
Immune complex–mediated vasculitis is best exemplified by systemic (serum sickness) or focal (Arthus reaction) formation and circulation of antigen-antibody
complexes that occur in the context of antigen excess The complexes become deposited on vascular endothelium, where complement activation and recruitment of granulocytes and macrophages then occur Inflammatory injury to the endothelium develops, followed by necrosis In many cases this is associated with thrombosis, luminal occlusion, and hemorrhage within the vascular wall These mechanisms appear to be the cause of hypersensitivity vasculitis and polyarteritis nodosa (PAN), conditions in which circulating immune complexes have been detected
Various populations of activated T cells may be involved in cell-mediated vasculitis These cells have in some fashion become sensitized to tissue-specific antigens expressed in target cells or tissues such as myelin Examples may include primary angiitis of the CNS, or vasculitis of peripheral nerves Sensitization of the T cells is likely to require the formation of a trimolecular complex with antigen and antigen-presenting cell, as is discussed for GBS and ADEM Promotion of the inflammatory process involves the release of various cytokines from T cells, endothelial cells, macrophages, or other cells T-cell release of interferon-g prompts the formation of adhesion molecules on the endothelial surface, molecules that recruit or retain additional T cells that are not specific for the initiating antigen
CNS vasculitis tends to present with one or more of the following: encephalopathy, stroke, or seizure The primary mechanism for neurologic dysfunction in patients with vasculitis is presumed to be ischemia caused by angiitic luminal compromise (324,325,329) In some cases vasospasm, embolization from necrotic areas of vascular endothelial compromise, secondary propagation of the inflammatory response within nervous tissues, or other mechanisms contribute to neurologic
dysfunction Moreover, patients with systemic vasculitides may experience neurologic dysfunction as the secondary result of the impaired function of other organs, such as heart, lung, liver, or kidney Vasculitides that affect the peripheral nervous system may produce mononeuropathy multiplex, radiculopathy, plexopathy, or polyneuropathy Nerves of various size and function may be involved, resulting variously in neuropathies that are primarily motor, primarily sensory, autonomic, or a
Trang 27mixture of these elements.
Primary Systemic Vasculitides
Of the various primary systemic vasculitides, Behçet disease, Kawasaki disease, and Vogt-Koyanagi-Harada syndrome are covered in Chapter 6 Giant cell arteritis, Churg-Strauss vasculitis, Takayasu disease, and Cogan syndrome are rarely seen in the pediatric population These conditions are summarized in Table 7.12
TABLE 7.12 Vasculitides affecting the nervous system
Primary Angiitis of the Central Nervous System
Primary angiitis of the CNS (PACNS) is a rare entity whose manifestations are confined to the CNS The disorder is mainly seen in adults and presents with a wide spectrum of severity Although PACNS is diagnosed most frequently in middle age, reports have included patients with ages ranging from 3 to 78 years Slightly more than two-thirds of cases have occurred in male subjects There is no clear regional or racial predilection The pathologic manifestations consist of a prominent
vasculitic mononuclear cell infiltrate that almost invariably affects small vessels; medium-sized vessels are involved in approximately three-fourths of cases
Multinucleated giant cells are commonly seen; for this reason the condition also has been termed granulomatous angiitis (329a) No vascular deposition of
immunoglobulin can be found, supporting the view that PACNS is a cell-mediated vasculitis (329,330)
The most common clinical presentation is that of encephalopathy with headache Mental status may range from normal with irritability to various degrees of confusion and obtundation Almost any focal manifestation of dysfunction of the encephalon may be found in association In some cases strokes, single or multiple cranial
neuropathies, or spinal cord syndromes are the predominant or sole manifestations of PACNS (331) CSF pleocytosis or mild elevation of CSF protein is found in approximately one-half the cases of PACNS (330,332,333)
PACNS is a diagnosis of exclusion In almost all instances cerebral angiography is abnormal and shows vascular irregularities and luminal narrowing in multiple
vessels producing a beaded appearance (332) MRI changes include widespread, small, and irregular tufts of T2 bright signal that suggest a vasculitis rather than ADEM; the plaquelike lesions at the gray-white junction that are so characteristic of ADEM are usually not present The sedimentation rate is almost invariably normal, whereas various autoantibodies are absent These findings, which are suggestive of the diagnosis, can only be confirmed by brain biopsy
Untreated, PACNS can be fatal However, remission or even cure may be attained in patients who are treated with the combination of oral prednisone and
cyclophosphamide, as outlined by Woolfenden and colleagues (332) The combination therapy should be continued for at least 1 year Thereupon, if angiographic evaluation of patients who formerly displayed angiographic abnormalities shows resolution, cyclophosphamide can be discontinued and the prednisone tapered over
3 to 6 months PACNS should be suspected in children who are thought to have corticosteroid-responsive forms of ADEM that relapse as long-term corticosteroid monotherapy is weaned to low dosages The usual threshold for relapse is at prednisone equivalents of approximately 12 to 16 mg administered every other day (333)
Polyarteritis Nodosa
PAN accounts for approximately 15% of all cases of systemic vasculitis (334) The incidence is approximately 0.7 to 1.8 in 100,000 per year, prevalence is
approximately 5 in 100,000, and boys are approximately 2.5 times as likely to have PAN Most cases occur in adults and most childhood cases occur in older children and adolescents However, the disease has been described in children as young as 6 years of age
The pathologic changes of PAN are necrotizing arteriopathic vasculitis The inflammatory angiocentric exudate is predominantly granulocytic, tending to involve small and medium-sized muscular arteries and occasional arterioles Obliterative and necrotizing endarteritis may develop and microaneurysm formation and rupture may complicate the disease (335)
PAN is caused by a multiplicity of causes At least one-half of the cases of PAN appear to be an immune complex–mediated vasculitic condition with detectable
circulating immune complexes Up to 40% of adults with PAN are chronic carriers of hepatitis B antigen, and circulating immune complexes involving the hepatitis B antigen could be involved in the pathogenesis of this disease in some patients ( 336) Familial Mediterranean fever, an autosomal-recessive illness characterized by recurrent but self-limited fever and polyserositis, is another disease that has been associated with the development of PAN In such cases the Mediterranean fever tends to manifest before 12 years of age and PAN shortly thereafter (337,338)
Clinical Manifestations
PAN is uncommon in the pediatric population, though two distinct syndromes have been recognized An infantile form has a predilection for the coronary arteries and
is probably the same as Kawasaki disease This variant can be associated with seizures and aseptic meningitis ( 339) Kawasaki disease is more fully considered in
Chapter 6
In older children, PAN resembles the clinical picture seen in adults In the Turkish series of Ozen and coworkers, severe myalgia unresponsive to analgesics was seen as the presenting complaint in 77% of children (340) Peripheral nerve involvement marked by numbness and paresthesias was seen in 13% Encephalitic symptoms including seizures, cranial nerve palsies, and hemiplegia also were encountered (341) Multiple mononeuropathies (mononeuritis multiplex) are said to be characteristic of the condition Mononeuritis multiplex refers to involvement of several or many individual nerves simultaneously or at different times in the course of the disease (342) The peripheral nerves most frequently affected are the branches of the lateral popliteal nerve ( 343) Remissions and relapses of neuropathy are common Coalescence of the multiple nerve lesions, usually seen at a late stage of the illness, results in a symmetric polyneuritis Practically every cranial nerve has been reported involved
Asymmetric shrinkage of visual fields, scotomata, and loss of acuity may occur as consequences of proliferative retinitis and retinal hemorrhage Appropriate
funduscopic changes should be evident Papilledema may develop in patients with intracranial hypertension; these patients and those with significant systemic
hypertension are at greater risk for retinal hemorrhage (344)
Diagnosis
The diagnosis of PAN should be considered in patients whose obscure febrile illness is linked with disease of the CNS or peripheral nervous system and in whom antinuclear and anti-DNA antibodies are negative In the series of Ozen and colleagues, hepatitis B antigen was only present in 10% ( 340) Neuroimaging studies of brain may be normal, but can demonstrate bland or hemorrhagic infarction, focal or generalized encephalomalacia, or intraparenchymal or subarachnoid blood
Cerebral angiography may be normal early in the course of illness, but segmental narrowing of small and medium-sized vessels is often found after weeks or months