Parainfectious and Postinfectious Demyelinating Disorders of the Central Nervous System
- Stuart R. Tomko
- Timothy E. Lotze
Acute Disseminated Encephalomyelitis
Acute disseminated encephalomyelitis (ADEM) is a monophasic demyelinating disease of the central nervous system (CNS) that results in acute, polysymptomatic neurologic disability. It also has been termed postinfectious encephalomyelitis . It is related to other central inflammatory demyelinating conditions of childhood, including optic neuritis, transverse myelitis, neuromyelitis optica (NMO; Devic disease), and multiple sclerosis (MS). Certain clinical features, laboratory results, and imaging findings can be used to distinguish among these conditions to ensure a correct diagnosis. Most of these conditions are thought to be caused by autoimmune dysregulation triggered by an infectious agent in a genetically susceptible host.
Epidemiology
The estimated incidence of ADEM is 0.8 per 100,000 population per year. ADEM occurs more frequently in children and has a slight male predominance. In contrast to MS, which generally has a higher incidence at latitudes that are more northern, ADEM has no appreciable geographic distribution.
Diagnostic Criteria
Prior to the introduction of standardized diagnostic criteria in 2008, the term acute disseminated encephalomyelitis had been used variably in the literature in describing clinical characteristics of this disease. Discrepancies existed among descriptive studies regarding (1) the occurrence of encephalopathy, (2) the association with preceding infection, (3) symptoms that are monofocal or multifocal, and (4) the possibility for recurrence.
In 2008, the International Pediatric Multiple Sclerosis Study Group developed diagnostic criteria for ADEM, which were subsequently revised in 2013. The group created working definitions for monophasic and multiphasic ADEM. Box 37A.1 lists the diagnostic criteria. An absolute criterion for a diagnosis of ADEM is the presence of encephalopathy. This is defined to include either behavioral changes, such as lethargy or irritability, or more severe alterations in level of consciousness, such as coma. The onset of the encephalopathy must correspond with the occurrence of the disease state. Magnetic resonance imaging (MRI) shows multiple lesions in both hemispheres distributed throughout the white matter ( Fig. 37A.1 ). A distinguishing characteristic of ADEM is prominent involvement of the cortical gray matter and deep gray nuclei (basal ganglia and thalamus). Such involvement is atypical for MS and other demyelinating conditions. The lesions of ADEM are asymmetric, showing variable size, shape, and distribution between the hemispheres. MRI showing symmetric and confluent lesions should prompt the clinician to consider other diagnoses, such as leukodystrophies and inborn errors of metabolism. If MRI shows evidence of previous demyelination, the clinician should query the history further for previous attacks that would suggest either a recurrent form of the disease or a chronic demyelinating condition. Cerebrospinal fluid (CSF) analysis may show a pleocytosis of greater than 50 cells, in contrast to pediatric MS, in which only a slight pleocytosis (<50 cells) is observed.
Clinical Features
First clinical attack of demyelinating disease in CNS
Acute or subacute onset
Polysymptomatic presentation
Must include encephalopathy
Acute behavioral change (e.g., irritability, lethargy)
Alteration in consciousness (e.g., somnolence, coma)
Attack should be followed by improvement
Lesion Characteristics on MRI FLAIR and T2-Weighted Images
Multifocal, hyperintense, bilateral, asymmetric lesions in the white matter
At least one or more lesions >1–2 cm
Gray matter, especially basal ganglia and thalamus, may be involved
Spinal cord MRI may show confluent intramedullary lesions
No radiologic evidence of previous destructive white matter changes
Cerebrospinal Fluid
Pleocytosis ≥50 WBCs can be observed
Other
No other etiologies can explain the event
New or fluctuating symptoms and signs occurring within 3 months of the inciting ADEM event are part of the same acute event
Symptoms that vary during periods of steroid taper within 3 months of the inciting event or occur <30 days after discontinuation of all steroids are considered part of the initial inciting event.
ADEM, Acute disseminated encephalomyelitis; CNS, central nervous system; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; WBCs, white blood cells.
The International Pediatric Multiple Sclerosis Study Group has defined criteria to distinguish between an evolving pattern for the initial event and multiphasic forms of ADEM. Any new and fluctuating symptoms occurring within 3 months of the initial event are considered part of the same inciting event. In addition, symptoms occurring during steroid taper or within 1 month of the patient completing a steroid taper are considered part of the same inciting event. In the 2013 revision, “recurrent ADEM” was eliminated as a diagnostic category. Multiphasic ADEM remains with an updated definition now describing patients with two episodes consistent with ADEM separated by 3 months but not followed by further events. Patients with relapsing disease extending beyond two discrete events are no longer considered to have ADEM but rather a chronic disorder such as NMO or MS.
Clinical Manifestations
A febrile illness occurs in 50% to 75% of children in the 4 weeks before the onset of typical neurologic symptoms. Preceding vaccinations have been temporally associated with the occurrence of ADEM, but this is less common. Fever, headache, vomiting, and meningismus often are present at the time of initial presentation and may persist during the hospitalization. Neurologic symptoms typically appear 4 to 13 days after the infection develops or vaccination is administered. New clinical symptoms may continue during hospitalization and may alter treatment. Per current diagnostic criteria, all children with ADEM have an encephalopathy at the time of presentation. The degree of altered mental status varies, ranging from irritability to somnolence to coma. Encephalopathy may be the initial symptom that brings the child to medical attention. Although alteration in mental state often raises concern for the possibility of seizures, they occur in only one-third of patients. In addition to having encephalopathy, patients exhibit various other neurologic features. The most common of these are long tract signs, acute hemiparesis, cerebellar ataxia, and cranial neuropathy. Aphasia, movement disorders, and sensory deficits occur less commonly.
Demyelination of the optic nerves (optic neuritis) or spinal cord (transverse myelitis) may occur. Symptoms of optic neuritis include vision loss, pain with eye movement, and an afferent papillary defect. Inflammation of the optic disk may be seen on direct funduscopic examination if there is extensive involvement of the optic nerve. Patients with retrobulbar optic neuritis typically have a normal funduscopic examination. Optic neuritis may occur in one or both eyes, with differing degrees of involvement. Symptoms of transverse myelitis include flaccid paralysis of the legs, with a sensory level on examination. The arms can be involved as well if the demyelinating lesion is in the cervical cord. Respiratory failure may occur with high cervical lesions that extend into the brainstem. Bowel and bladder involvement secondary to spinal cord disease results in constipation and urinary retention.
The extent of demyelination in the CNS may not be recognized fully at the time of initial presentation, particularly if the patient has severe encephalopathy. Imaging of the entire CNS to include the brain, orbits, and spinal cord should be done in all patients meeting diagnostic criteria for ADEM because co-occurrence of transverse myelitis or optic neuritis can have a significant impact on rehabilitation needs and long-term outcome.
Clinical Variants
Multiphasic ADEM describes recurrent forms of the disease defined by a single reoccurrence of neurologic symptoms more than 3 months after the initial event and more than 1 month after completion of steroids. Repeated events are not consistent with an ongoing diagnosis of ADEM and should prompt assessment for a different underlying disease process, including metabolic disorders or primary inflammatory diseases such as MS.
Acute hemorrhagic leukoencephalitis is considered a severe variant of ADEM. It accounts for 2% of patients with ADEM. Clinical presentation is similar to that of ADEM, including an acute onset of neurologic deficits 1 to 3 weeks after an upper respiratory tract infection or vaccination. Seizures and coma ensue within hours. The mortality rate is extremely high with fulminant disease. Survivors often have severe residual neurologic deficits. The clinical presentation and imaging features mimic those typically seen in herpes simplex virus encephalitis. Evidence of inflammatory changes and hemorrhage on MRI often is not present for the first few days in herpes simplex virus encephalitis, which may help distinguish the two conditions. Early recognition with prompt institution of steroids or other immunosuppressive agents can be lifesaving.
Historically site-restricted forms of demyelination, such as optic neuritis or transverse myelitis, have been included as part of the spectrum of ADEM. Although these conditions share similar underlying pathology, clinical presentations and prognosis are different, and they should be considered separate entities. They are considered clinically isolated syndromes by the current consensus definitions for demyelinating disease. Clinically isolated syndromes may carry a greater risk for development of MS or other recurrent forms of demyelinating disease. NMO, also known as Devic disease, has classically been described by coincident or sequential optic neuritis and longitudinally extensive myelitis. The discovery of NMO disease-specific antibodies directed against aquaporin-4 water channels in the CNS has further expanded the phenotypic spectrum of this disease. Some patients may present with an ADEM-like event, including encephalopathy with imaging features similar to those seen in ADEM patients. The localization of NMO lesions around regions of high aquaporin-4 expression, such as the ventricular margins, diencephalon, and area postrema, can help to distinguish between the two entities. Further identification of the aquaporin-4 antibody in the serum or CSF is confirmatory for NMO.
MS is the second most common cause of acquired neurologic disability in adults. It is an uncommon finding in pediatric patients. Five percent of adults with MS had onset of disease before reaching 18 years of age. Clinical phenotypes consistent with ADEM and multiphasic ADEM should not be confused with MS because the former two are time-limited in their occurrence. Although they may share some of the same initiating pathologic mechanisms, they are different diseases. However, 2% to 10% of children initially diagnosed with ADEM have subsequently been diagnosed with MS following more than one recurrence of ADEM or the occurrence of a non-ADEM event that is otherwise typical of attack findings in MS. Thus long-term clinical monitoring of ADEM patients is necessary.
The diagnosis of MS requires clinical or radiographic evidence for demyelinating events separated in space and time in the CNS. Patients typically follow a relapsing course of neurologic attacks, with resolution or remission of disability between attacks. Evolution into a course of progressive disability occurs in 50% of patients who have had the disease for more than 15 years. Treatment consists of medications that modulate the immune response by decreasing migration into the CNS, altering cytokine profiles, and interrupting antigen presentation.
Pathology and Pathogenesis
Role of Infection
ADEM is preceded by a viral or bacterial infection in 75% of cases. This infection usually is in the form of a nonspecific upper respiratory tract infection. Many different pathogens have been identified in association with the illness ( Box 37A.2 ). No well-defined latency period has been identified in which an infection can be related to ADEM. Generally patients present within 1 month of their illness. Correlation between ADEM and an infection occurring more than 30 days earlier is more difficult because children are diagnosed with a viral infection four to six times per year, resulting in a positive infectious history in 33% to 50% of patients.
Viral
Coxsackie
Cytomegalovirus
Epstein-Barr
Hepatitis A or B
Herpes simplex
Human herpesvirus–6
Human T-lymphotropic virus–1
Human immunodeficiency virus
Influenza A or B
Measles
Mumps
Rocky Mountain spotted fever
Rubella
Vaccinia
Varicella
Bacterial
Borrelia burgdorferi
Campylobacter
Chlamydia
Legionella
Leptospira
Mycoplasma pneumoniae
Rickettsia rickettsii
Streptococcus
The phenotypic presentation for ADEM varies depending on the infectious agent. Some organisms have been associated with typical clinical features. Measles virus infection is associated with ADEM in 1/1000 cases. The clinical course often is fulminating, with severe neurologic sequelae or death in most patients. Introduction of vaccination has reduced markedly the occurrence of measles in developed countries, although temporally associated cases of ADEM following vaccination have been described.
Post-varicella ADEM is characterized by ataxia in more than 90% of patients, occasionally with an explosive onset. Headache and meningismus are typical constitutional signs. Pyramidal symptoms include bilateral symmetric upper motor neuron weakness. Patients also may have mood disturbances with a depressed affect or irritability.
ADEM that develops after a rubella infection is similar to measles, with an explosive onset in most children. Profound lethargy, coma, and generalized seizures often occur. Most patients with explosive onset of disease have pyramidal signs and myelitis, whereas a milder phenotype is more likely to have ataxia. Both forms also have been associated with brainstem signs.
Group A β-hemolytic streptococcal infection has been associated with a dystonic extrapyramidal syndrome. Abnormal movements include dystonia, tremor, and parkinsonism. Tics and chorea have not been associated with this condition. Similar to Sydenham chorea and PANDAS, behavioral disturbances, such as emotional lability, obsessive-compulsive tendencies, and inappropriate speech, can occur. Changes in mental status can vary from irritability to coma. MRI shows a predilection for demyelination within the basal ganglia, which includes the caudate, putamen, and globus pallidus. Other deep gray structures, including the thalamus, subthalamus, and substantia nigra, may be affected as well. This finding is distinct from Sydenham chorea and PANDAS, in which imaging is unremarkable. It has been associated with anti–basal ganglia antibodies that cross-react with certain strains of Streptococcus .
Role of Immunization
ADEM temporally associated to vaccination has been described with nearly every immunization, and such cases account for less than 5% of all published reports in the medical literature ( Box 37A.3 ). This association does not equate to causation. The Centers for Disease Control in the United States administers the Vaccine Adverse Event Reporting System by which physicians and others voluntarily submit reports of medical events following vaccination. While limitations, such as reporting bias, in such a system exist, this system serves an important key component in detecting early warnings of possible causative links between vaccination and acquired diseases, including ADEM. At the time of this writing, the Institute of Medicine has noted inadequate medical evidence to conclude causality of vaccinations in ADEM.
Diphtheria-tetanus-polio
Hepatitis B
Hog vaccine
Japanese B encephalitis
Measles
Mumps
Polio
Rabies
Smallpox
Tetanus
Tick-borne encephalitis
Historically Pasteur rabies vaccination was associated with prototypic ADEM in approximately 1/1000 individuals. The inoculum was derived from rabbit spinal cord injected with fixed rabies virus. The disease was thought to result principally from the neural tissue contaminating the vaccine rather than the virus itself. This suggestion is supported further by the continued higher incidence of vaccine-associated encephalomyelitis in patients receiving the Semple or duck embryo vaccinations, both of which contain neural tissue. These forms of the vaccination usually are found in developing countries. Experimental allergic encephalomyelitis, the animal model of demyelinating disease, is induced by inoculating myelin or myelin antigens into a suitable experimental animal, further supporting a role of CNS tissue as the causal agent.
Currently measles, mumps, and rubella vaccination is associated most often with post-vaccination encephalomyelitis. A significant difference exists between the incidence of live-measles vaccination–associated ADEM (1 to 2 per 1 million) and the incidence of ADEM previously associated with the measles virus infection (1 per 1000).
Immunologic Factors
A review of the normal process of immune system regulation and surveillance of the CNS is useful when discussing immune dysfunction in the pathogenesis of ADEM. Similar to other disorders of immune dysfunction, activated CD4 + T cells play a principal role in the disease process. T cells reactive against self-antigens, including myelin components, are present in the normal immune system. Several regulatory mechanisms are thought to prevent activation of these lymphocytes, and failure of such processes results in autoimmune conditions. The thymus plays a crucial role in normal T-cell development by deleting many autoreactive lymphocytes from the immune system. Other peripheral mechanisms also are needed because this thymic depletion often is incomplete. Clonal anergy describes the unresponsive state of T cells that have encountered their antigen without costimulatory factors. A risk for failure of this mechanism exists through release of nonspecific costimulatory factors from damaged tissue. Another peripheral process is immunologic ignorance , in which no productive reaction exists between the T cell and its corresponding peptide/major histocompatibility complex on an antigen-presenting cell. Changes in antigen availability, such as through increased antigen presentation by an invading microorganism, can disrupt this safeguard.
Active regulation is a third process by which regulatory T cells prevent expansion of self-reactive lymphocytes. Regulatory T cells exert their suppressive effects through direct cell-to-cell contact with membrane-bound molecules (CTLA-4) or indirectly through soluble suppressive cytokines, such as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β). Natural killer cells expressing a T-cell receptor also can regulate autoimmune diseases. The presence of such cells within demyelinating regions suggests that some of the inflammation associated with ADEM may have a protective effect.
Although failure of these mechanisms may result in the activation of T cells reactive against myelin antigens, migration of lymphocytes into the CNS is required to produce disease. The CNS has been considered a site of limited immunologic surveillance because of the blood-brain barrier and lack of classic lymph vessels. However, the blood-brain barrier is principally a mechanical diffusion barrier for hydrophilic molecules formed by specialized endothelial cells at the level of the capillaries. Leukocytes readily cross through endothelial cells in postcapillary venules to occupy the perivenular spaces or move on to the neuropil. In addition, antigens and antigen-presenting cells drain from the brain into cervical lymph nodes via the cribriform plate and perineural sheath of the cranial nerves. As discussed later, these factors allow for the presentation of antigen in the systemic immune compartment and passage of leukocytes into the CNS for production of disease.
Children with demyelinating disease of the CNS are thought to have a genetic predisposition for such conditions. The strongest data relate to susceptibility genes on chromosome 6p21 in the area of the histocompatibility leukocyte antigen (HLA). Much of the research into these genetic determinants has been related to adult-onset MS. Limited research is available for pediatric demyelinating diseases. However, some of the findings show similarities among age groups and various demyelinating diseases. Linkage studies in Russian children found an association between ADEM and HLA-DRB1*01 and HLA-DRB1*017(03) alleles. Korean children with ADEM were found to have higher frequencies of HLA-DRB4*0101 and HLA-DRB1*1501 compared with controls. In adults with MS, the specific genes that confer the highest risk include HLA-DRB1*1501 and HLA-DRB5*0101 , among others. In MS, these genes have been linked to earlier disease onset, female gender, a relapsing remitting course, and optic neuritis or spinal involvement as the initial symptom. In addition, genes associated with this haplotype include TGF-β family members, CTLA-4, the tumor necrosis factor (TNF) cluster, IL-1 receptor antagonist, IL-1, and estrogen receptor. Polymorphisms in these genes also have been associated with increased risk for development of demyelinating disease.
The precise mechanism by which these HLA class II genes confer risk for development of demyelinating disease is unclear. Possibilities include (1) preferential binding of self-antigens by these peptides, (2) preferential linkage of autoreactive T cells to the antigen-presenting cell expressing these peptides, (3) abnormal antigen presentation by certain DR molecules, and (4) engagement of HLA class II molecules leading to intracellular signaling events.
Humoral factors also play a role in the production of demyelinating disease. This finding is based on disease-associated laboratory findings and treatment responses. Analysis of CSF in one-third of patients with ADEM shows production of oligoclonal bands, which are not found in the serum. In addition, some patients with post–rabies inoculation ADEM have been found to have positive serum antibodies against myelin basic protein and galactocerebroside.
Pathogenesis
ADEM is considered to occur in genetically susceptible individuals prone to immune system dysregulation after an encounter with an appropriate environmental stimulus. Mechanisms of disease production are based principally on two animal models that closely resemble the disease. The first is experimental autoimmune encephalomyelitis. In this model, animals develop monophasic neurologic disease similar to ADEM after receiving immunization with CNS homogenate or encephalitogenic myelin peptides emulsified in Freund complete adjuvant. The second model is Theiler murine encephalomyelitis, in which susceptible mouse strains develop disease after receiving direct injection of Theiler murine encephalomyelitis virus into the cerebrum. In both of these models, increased exposure of the immune system to myelin proteins produces disease.
By comparing these models with ADEM in humans, two pathogenetic concepts have been developed. The inflammatory cascade concept implies a direct CNS infection with a neurotropic pathogen, which results in CNS tissue damage and systemic leakage of CNS-confined autoantigens through a damaged blood-brain barrier into the systemic circulation. Presentation of these antigens within systemic lymphatic organs leads to tolerance breakdown and a self-reactive encephalitogenic T-cell response. The molecular mimicry concept suggests structural amino acid homology between the invading pathogen and myelin basic protein in the host. Although similar to myelin peptides, the amino acid sequence contains subtle differences that fail to prevent immune tolerance and result in activation of myelin-reactive T cells against similar “self” myelin antigens. The Epstein-Barr virus provides an example of this. The virus contains a pentapeptide sequence in its nuclear antigen (EBNA) that shares sequence homology with an epitope of myelin basic protein, a major protein of the myelin sheath. Epstein-Barr virus has been implicated in the pathogenesis of MS partly based on this concept of molecular mimicry. Recently antibodies to myelin oligodendrocyte glycoprotein have been shown to be present during the period of active demyelination in ADEM but quickly fall in most patients. In those with persistent or rebounding of myelin oligodendrocyte glycoprotein antibody levels, a propensity was seen to develop childhood MS, suggesting this might be prognostic.
The immunopathologic events leading to ADEM can be divided into two major phases: (1) initial T-cell priming and activation and (2) subsequent recruitment and effector phase. The priming phase occurs in systemic secondary lymphoid organs, in which the antigen-presenting cell presents myelin protein antigen and peptides to neuroantigen-reactive T cells. The activated T cells expand and then migrate to the CNS via the postcapillary venules into the perivascular space. In the Virchow-Robin space, the T cells reencounter their cognate antigen, in the context of HLA class II molecules expressed by dendritic cells. This reactivation allows the T cells to migrate through the glial limitans and enter the brain parenchyma.
Further recruitment occurs through the production of cytokines and chemokines by antigen-presenting cells and activated T cells, promoting migration into the CNS of additional T cells and other leukocytes, such as polymorphonuclear and monomorphonuclear phagocytes. Breakdown of the blood-brain barrier occurs by release of proteases from recruited mast cells, T cells, and monocytes. In addition, production of reactive oxygen radicals occurs, causing further endothelial injury, which leads to the effector phase in which T cells have more of a secondary role to other inflammatory processes that cause demyelination and axonal injury. These inflammatory processes include oxygen and nitrogen radicals, TNF-α, direct and indirect complement activation, antibody-dependent cellular toxicity, myelin phagocytosis, direct axonal injury by CD8 + cytotoxic T lymphocytes, protease secretion, and oligodendrocyte apoptosis. Glutamate-mediated excitotoxic injury of the oligodendrocytes also occurs. The inflammatory process continues for a few days to 2 weeks, resulting in stretches of demyelinated axons, some of which may be transected.
The repair process begins with activation and proliferation of astrocytes. Clearing of debris by macrophages and increased production of antiinflammatory cytokines and various growth factors by resident cells and T cells occur. Oligodendrocyte precursors become activated and, along with surviving oligodendrocytes, begin the process of remyelination. The clinical and imaging outcome of ADEM most often shows complete recovery. Subtle differences in repaired myelin, including altered thickness and redistribution of sodium channels, may occur, however. In addition, the relative composition of myelin peptides is altered to forms that may have increased vulnerability to further damage and may explain recurrent forms of ADEM.
Clinical Evaluation
ADEM should be considered in a child seen several days after a febrile illness with subacute onset of encephalopathy and polysymptomatic neurologic deficits. The clinical features require ruling out other possible diagnoses, however, through additional diagnostic tests.
Diagnostic imaging is the most useful tool in establishing the diagnosis. Computed tomography (CT) scans usually are done on an emergent basis for encephalopathic patients. Areas of demyelination may appear as darker areas of hypodensity, with any hemorrhagic component being hyperdense. CT does not adequately show the full burden of disease, however, and may be completely normal. MRI is the most sensitive means for showing the widespread demyelination typical of the disease (see Fig. 37A.1 ). T2-weighted sequences provide the best assessment of the disease, with demyelinating areas being hyperintense and accompanied by surrounding edema. Administration of gadolinium contrast material may show breakdown of the blood-brain barrier with areas of enhancement. This enhancement may appear homogeneous throughout the lesion or show a “broken ring” appearance, with the open edge pointing toward the cortex. Lesions may be large, measuring more than 1 cm in diameter. They typically are rounded with poorly defined margins.
Of most common concern in children presenting with a febrile encephalopathy is the possibility of an underlying CNS infection. A lumbar puncture often is done to investigate this possibility. A lymphocytic pleocytosis may occur (commonly >50 cells). Elevated albumin levels also may be present. Findings of neutrophils and elevated red blood cells alternatively would raise concern for the possibility of herpes encephalitis.
Intrathecal oligoclonal bands may be positive, and IgG synthesis may be increased in 30% of patients with ADEM. Their relationship to the underlying disease pathophysiology is unclear but is thought to represent a response of B cells within the CNS to the inflammatory process. Serologic studies of the CSF may be useful to uncover the causal agent, although results should be interpreted with caution because many neurotropic viruses have a high prevalence in the general population.
Rarely patients may present with very large demyelinating lesions, characteristically described as tumefactive . In such circumstances, a biopsy may be needed to determine the underlying etiology. Findings typical of demyelination help rule out a CNS malignancy. Before a biopsy is done, the clinician should investigate for other evidence of demyelinating disease, including imaging of the spinal cord. A comorbid transverse myelitis would provide more evidence of a demyelinating condition and reduce the need for a biopsy. In addition, normal CSF cytology helps discount an underlying malignancy.
Primary and secondary CNS vasculitis associated with collagen vascular diseases, such as systemic lupus erythematosus or antiphospholipid antibody syndrome, may manifest with a similar clinical and radiologic picture. These diseases are typified by recurrent ischemic strokes. Distinguishing features for antiphospholipid antibody syndrome include a family history of strokes or other thromboses at a young age and fetal loss. Testing for antiphospholipid antibody and lupus anticoagulant is positive. Primary CNS vasculitis with strokes is best investigated through conventional angiography showing an irregular vessel lumen. Leptomeningeal biopsy is considered the gold standard to confirm the diagnosis.
A severe course that principally affects the optic nerves, spinal cord, or other areas of high aquaporin-4 expression, including the periventricular and aqueductal regions, area postrema, diencephalon, or brainstem, should raise concern for NMO. Serum and/or CSF testing for the aquaporin-4 water channel antibody that is associated with this disease is clinically available. The test is greater than 90% specific for NMO, and up to 65% of pediatric patients meeting current diagnostic criteria will have positive antibody titers.
Neurophysiologic studies can be useful to evaluate comorbidities and burden of disease. An electroencephalogram should be obtained in patients with seizures and severe encephalopathy to characterize the seizure focus and investigate for subclinical seizures. Findings often are consistent with a diffuse disturbance in brain function, noting slowing of the normal electric rhythms.
Treatment
To date, no controlled clinical trials have been conducted on the optimal treatment for ADEM. Based on empiric evidence, intravenous high-dose corticosteroids are accepted as first-line treatment. Methylprednisolone is given at 30 mg/kg per dose (maximum 1000 mg) for five doses. Alternatively, dexamethasone, 1 mg/kg per dose for five doses, may be used. A prednisone taper typically is instituted on completion of this regimen, with an initial dosing of 1 mg/kg per day and tapering by 5 mg every 5 days. Alternative antiinflammatory and immunosuppressive therapies may be used depending on the response to the initial steroid treatment. Intravenous immunoglobulin (IVIG) has been found to be beneficial in some patients. IVIG is given 2 g/kg divided over 2 to 5 days.
Plasmapheresis also may be used. The patient receives seven treatments consisting of 1.1 to 1.4 plasma volume exchanges over a 14-day course. IVIG and plasmapheresis typically are not considered as first-line treatment for ADEM, partly related to availability of IVIG or apheresis units, cost of treatment in contrast to steroids, prolonged hospitalization, and need for adequate venous access. Nonetheless they should be considered secondary treatment options, especially in the occasional patient who continues to deteriorate during steroid treatment or who fails to show adequate recovery 7 days after completing intravenous steroids. The choice between the two agents is arbitrary. Particular consideration for plasmapheresis might be given in the setting of a comorbid myelopathy because this has been noted to be beneficial in patients presenting with transverse myelitis. Severe cases failing to respond to any of these measures may require immunosuppressive agents, such as cyclophosphamide. A few cases of severe ADEM with massive edema have required hemicraniectomy to prevent severe neurologic sequelae or death.
Additional treatment that may be needed depends on the patient’s neurologic deficits. Anticonvulsants should be given for management of seizures. Attention given to bowel and bladder care is important to avoid secondary complications of retention. Impaired swallowing requires adequate nutrition to be provided by gavage feedings. Transverse myelopathy can be associated with autonomic dysfunction, including orthostatic hypotension, necessitating the use of an abdominal binder. Rehabilitation should begin at the time of admission, with the assistance of physical medicine and rehabilitation specialists. During the long-term recovery period, modifications to the home and school environment may be needed, depending on residual deficits.
Outcome and Prognosis
Historically, ADEM was associated with high morbidity and mortality rates principally related to disease associated with the measles virus. Measles-associated ADEM was associated with death in 25% of affected patients, with an additional 30% of patients having severe neurologic sequelae. This dismal outcome has improved dramatically with the institution of measles vaccination. The introduction of high-dose steroid treatment in modifying the disease course also may have improved the current outcome findings. Currently a low mortality rate of between 3% and 5% remains associated with this disease, and such patients typically have a hemorrhagic form.
Currently, 80% to 90% of patients show excellent recovery of functional and cognitive deficits. Children typically have a less severe course and fewer long-term neurologic sequelae than do adults. Mild neurologic disabilities, with weakness and fine motor difficulties being the most common deficits, may be present in some patients. Epilepsy may occur in 6% of patients after an episode of ADEM. Neurocognitive testing of children recovering from ADEM has shown mild impairments in attention and executive function and reduced visuospatial and visuomotor skills. The greatest risk for development of neurologic sequelae may be in older patients with sudden onset of severe neurologic symptoms.
Recurrent forms of the disease often raise concern for pediatric MS. The exact relationship between ADEM and MS remains to be better defined. The conditions are distinct, however, based on the clinical presentations, imaging, and clinical courses. Disease recurrence consistent with multiphasic ADEM occurs in about 30% of patients. Most patients have their second attack within the first year after their initial event. It often occurs soon after discontinuation of steroid taper or after an infection encountered shortly after the initial event. Treatment and outcome for recurrences are not different from those described for the initial event. In one study of 33 ADEM patients, 6% were eventually diagnosed with MS.
Infection-Associated Myelitis and Myelopathies of the Spinal Cord
- Timothy E. Lotze
Acute Transverse Myelitis
The sudden and progressive onset of paresis, sensory deficits, and bowel and bladder dysfunction that characterizes acute transverse myelitis (ATM) terrifies affected children and their families. Successful management requires prompt differentiation from other myelopathic disorders to determine proper treatment. Because of the association of ATM with numerous infections, specialists in infectious diseases frequently participate in the care of children with this disease. The clinical presentation, radiologic features, differential diagnosis, pathophysiology, treatment, and prognosis of pediatric ATM are reviewed here.
Diagnostic Criteria
ATM is an acquired inflammatory disorder consisting of progressive signs and symptoms reflecting bilateral sensory, motor, or autonomic dysfunction attributable to the spinal cord. This constellation of signs and symptoms can be caused by a heterogeneous group of disorders, which are distinguished as either disease associated or idiopathic. Disease-associated forms, including direct spinal cord infection, can be difficult to distinguish from idiopathic disease.
Diagnostic criteria were established by the Transverse Myelitis Working Group Consortium in 2002 and consist of both inclusionary and exclusionary criteria. The criteria were established to rapidly differentiate ATM from other myelopathies that require different treatment regimens. Differentiation from extramedullary compression such as that caused by extrinsic tumor, abscess, hematoma, and other intramedullary lesions such as infarction and intrinsic tumors is necessary to guide treatment and facilitate discussion of prognosis. Table 37B.1 lists both the inclusionary and exclusionary criteria for ATM.
| Inclusion Criteria | Exclusion Criteria |
|---|---|
| Bilateral signs/symptoms (not necessarily symmetric) | Clear arterial distribution clinical deficit consistent with thrombosis of anterior spinal artery |
| Clearly defined sensory level | Abnormal flow voids on surface of the spinal cord consistent with AVM |
| Exclusion of extraaxial compressive etiology by neuroimaging (MRI or myelography; CT of spine inadequate) | Serologic or clinical evidence of connective tissue disease (sarcoidosis, Behçet disease, Sjögren syndrome, SLE, mixed connective tissue disorder) a |
| Inflammation within spinal cord shown by CSF pleocytosis or elevated IgG index or gadolinium enhancement. If no inflammatory criteria are met at symptom onset, repeat MRI and lumbar puncture evaluation 2 to 7 days after symptom onset meet criteria | CNS manifestations of syphilis, Lyme disease, HIV, HTLV-1, Mycoplasma, other viral infection (e.g., HSV-1, HSV-2, VZV, EBV, CMV, HHV-6, enteroviruses) a Brain MRI abnormalities suggestive of MS a History of clinically apparent optic neuritis a |
| Progression to nadir 4 hours to 21 days after onset of symptoms (if patient awakens with symptoms, symptoms must become more pronounced from point of awakening) |
a Do not exclude disease-associated acute transverse myelitis.
Epidemiology
Two prospective studies have evaluated the incidence of acquired ATM in children. Based on these studies, the incidence in pediatric populations is approximately 1.72 to 2 persons per 1 million. Although early case series had suggested a slight female predominance, the more recent prospective studies have found a male predominance in the pediatric population. When stratifying for children younger than 10 years of age at onset and older than 10 years of age, one study found a striking 1 : 2 female to male ratio in children younger than 10 years. In children with age of onset older than 10 years, the female to male ratio was 1.2 : 1, similar to that of other inflammatory demyelinating disorders. The mean age of onset is between 9 and 10.5 years; however, onset has been reported as early as 6 months. Of interest, one study found a bimodal distribution with peak ages of onset at 4 and 15 years.
Clinical Presentation
Three phases occur in patients with ATM: initial, plateau, and recovery. The initial phase begins with the presenting symptom and concludes with reaching the neurologic nadir. The plateau phase begins when the patient has reached the neurologic nadir and is a period during which the symptoms are more or less stable. The last phase is recovery, which is the period of slow improvement in neurologic function. The length of time in each phase has been useful for prognostication of recovery and will be discussed later. Patients typically present acutely to subacutely with a combination of sensory and motor deficits. The most common motor symptom is bilateral leg weakness (82%), with a paraplegia developing in 36% of cases, although upper extremity weakness is a rare initial feature (4%). Involvement of the arms occurs in 37% of patients at some point. Approximately 70% to 90% of patients develop bowel and bladder dysfunction, ranging from urinary retention and constipation to incontinence. A similar percentage of patients report sensory symptoms, including paresthesia and numbness. Most patients reach their neurologic nadir within 1 week, and patients rarely have worsening of symptoms more than 4 weeks after onset of symptoms. Children with extremely rapid evolution of their symptoms (1 to 4 hours) should cause the clinician to take pause and consider a possible ischemic etiology.
The general examination, although usually unremarkable, may reveal signs suggestive of an underlying systemic infection or autoimmune disorder. Fever is not uncommon, with one study reporting its presence in 20% of children with ATM. Abdominal examination may reveal a distended bladder. A diffuse or dermatomal vesicular rash or its sequelae suggest concurrent or preceding chickenpox or shingles.
The presence of any mental status changes suggests that the myelitis is a component of a more diffuse process (i.e., acute disseminated encephalomyelitis or neuromyelitis optica). In the acute stages, muscle tone is low in affected limbs but with time may become spastic. Detailed muscle strength testing with objective grading serves as a crucial baseline to compare with serial examinations to determine whether the patient is improving. All sensory modalities should be assessed carefully. In one series, 65% of children with ATM had sensory symptoms, with more than 80% of those children having a clear sensory level. An early case series had suggested that severe pain is a common symptom (88%); however this is potentially skewed by selection bias of this retrospective study. A spinal cord sensory level usually is located in the thoracic region (58%) and less commonly in the cervical (7%) or lumbar (31%) area. In the acute phase, deep tendon reflexes are depressed in approximately 70% of patients and later become hyperactive. Similarly the Babinski sign may be negative early in the acute phase but soon becomes positive, indicating upper motor neuron dysfunction.
Radiologic Features
Every patient with suspected ATM should undergo emergent gadolinium-enhanced magnetic resonance imaging (MRI) of the entire spine to confirm the diagnosis and rule out alternative diagnoses, particularly compressive lesions, such as epidural abscess, epidural hematoma, and extramedullary tumors, which are all potentially neurosurgical emergencies. T1-weighted and T2-weighted sagittal imaging of the entire spine can serve as an initial screen, followed by comparative axial imaging in areas of suspected pathology. In addition, every patient with any neurologic symptoms not referable to the spinal cord should undergo MRI of the brain with gadolinium enhancement. Optimally, this should include dedicated fine sections through the orbits to evaluate for optic neuritis associated with neuromyelitis optica (NMO). The distinction between idiopathic ATM and other acquired demyelinating syndromes like multiple sclerosis (MS) and NMO is important for both treatment and prognosis. In general, it is uncommon for patients to have asymptomatic lesions outside of the spinal cord, and, in the absence of such findings, the likelihood for an eventual diagnosis of MS or NMO is low.
Spinal MRI in ATM typically reveals T1-isointense ( Fig. 37B.1A ) and T2-hyperintense ( Fig. 37B.1B ) signals over several contiguous spinal cord segments and may involve the entire spine.
The most common finding is a T2-hyperintense lesion involving more than three segments, with one study finding the average length of lesion being more than six segments. The hyperintense signal can extend into the lower brainstem. Spinal cord swelling with effacement of the surrounding cerebrospinal fluid (CSF) spaces may be present in severe cases ( Fig. 37B.1A ). Axial imaging typically reveals lesions involving both gray and white matter ( Fig. 37B.1D ). Contrast enhancement is variably present and may appear diffuse, patchy, or nodular ( Fig. 37B.1C ). In some patients with very suggestive clinical features, initial spine MRI may be normal and should be repeated several days later. In rare cases, the MRI remains normal but does not rule out the diagnosis, and evidence of inflammation in the CSF is considered to meet diagnostic criteria for ATM in such cases. A new modality still used exclusively in research that has been applied to ATM is diffusion tensor imaging (DTI). DTI is an MRI sequence that evaluates for the presence and integrity of white matter tracts. One study of a small number of adults with ATM revealed that those individuals with more severe disruption of white matter tracts within the lesion and distal to the lesion had a worse prognosis. In the future, DTI might be useful for stratifying patients for likely prognosis and determining who might benefit from more aggressive treatment.
Lumbar Puncture
Approximately 50% of pediatric patients with ATM have CSF pleocytosis, typically with a lymphocytic predominance. Elevated CSF protein levels, either in isolation or in conjunction with pleocytosis, also are detected in approximately 50% of patients. Glucose typically is normal. A normal CSF profile does not rule out ATM because this pattern is seen in approximately 25% of patients. Imaging evidence of an inflammatory myelopathy would be needed to meet diagnostic criteria for ATM in such cases. CSF cytology should be considered for patients with concern for neoplasm. Additional CSF testing is discussed further later.
Differential Diagnosis
Conditions That Mimic Acute Transverse Myelitis
ATM can be associated with more widespread central nervous system (CNS) demyelinating disorders or systemic autoimmune disorders; in such cases, the term disease-associated transverse myelitis has been used. Isolated ATM can be triggered by identifiable preceding infections. Alternatively, ATM can be associated with a nonspecific preceding infection or have no apparent cause; for both of these subgroups, the term idiopathic ATM has been used. This last group constitutes the most common category in pediatric ATM. Although the precise pathophysiology of idiopathic ATM is uncertain, the frequent association with preceding infections and accumulating immunologic data suggests an inflammatory cause for the disorder.
Numerous disorders can affect the spinal cord and produce identical symptoms and signs that mimic idiopathic ATM ( Box 37B.1 ). Such conditions must be ruled out through a combination of history, physical examination, neuroimaging, and laboratory evaluation.
Direct infectious myelopathies
Extramedullary compressive lesions
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Epidural abscess
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Epidural hematoma
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Extramedullary tumors
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Guillain-Barré syndrome
Intramedullary spinal cord tumors
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Astrocytomas
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Ependymomas
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Ischemia and infarction
Syringomyelia
Radiation injury
Traumatic spinal cord injury
Vascular malformations
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