Chapter 16. Neuroinfectious Disease

Definitions and Epidemiology

Meningitis is defined as an inflammation of the leptomeninges by any cause. Bacteria cause meningitis by invading and replicating in the subarachnoid space and cause significant morbidity and mortality. Viral infections may also cause meningitis, mostly commonly enteroviruses, but few children with viral meningitis suffer any long-term sequelae. Therefore the focus of this chapter will be on bacterial meningitis. Figure 16-1 gives the age, organism, and specific rates of bacterial meningitis in the United States prior to the introduction of currently used conjugate vaccines (note the y-axis is a log scale). As can be seen, the greatest risk period for bacterial meningitis is in the first 6 months of life.

Overall, there has been a remarkable decline in the rate of bacterial meningitis in the developed world over the last 2 decades with the introduction of the Haemophilus influenzae type b conjugate vaccines, the Streptococcus pneumoniae conjugate vaccines, and greater use of meningococcal vaccines. Haemophilus influenzae type b was once the leading cause of bacterial meningitis in children but has been virtually eliminated in countries utilizing the conjugate vaccine. In the first 2 months of life, Enterobacteriaceae (eg, E. coli, Klebsiella species), group B streptococci, and occasionally Listeria monocytogenes, Salmonella species, or enterococci will cause bacterial meningitis. Infections due to S pneumoniae occur with increasing in frequency over the second month to become the most likely cause of bacterial meningitis, and continue to increase in frequency until 4 or 5 months of age when they begin to decline. Neisseria meningitidis is the most common cause of bacterial meningitis by 1 year of age. S pneumoniae remains the second most common cause after 1 year of age, and all other pathogens trail behind considerably. These two pathogens occur more commonly in the winter months, presumably in association with common respiratory viruses that disrupt mucosal barriers, thereby allowing these colonizing pathogens to move from the nasopharynx to the bloodstream more easily. Research is ongoing to develop vaccines that will be effective against a greater number of pneumococcal serotypes and improved meningococcal vaccines that may work for younger children and against group B strains. Table 16-1 reviews microbial causes of meningitis.

Pathogenesis

Bacteria most often gain access to the central nervous system via the bloodstream. Pathogens gain access to the bloodstream as a result of nasopharyngeal colonization or local infections. When these specific bacterial strains are relatively new to the host, and the child has no existing circulating antibody against that strain, the bacteria may at least temporarily evade other host defenses and cause a transient or sustained bacteremia. Some of these bacteria may traverse the blood-brain barrier and replicate in the subarachnoid space. Once bacteria begin to replicate within the central nervous system, the human host has no adequate mechanism to recover without medical intervention.

The risk for sequelae and mortality vary significantly by age of the child, pathogen, and underlying host compromise at baseline and at presentation with meningitis. Patients may have impaired neurological function as a result of brain inflammation secondary to the bacteria and the host response to infection as well as due to cerebral hypoperfusion related to septic shock with hypotension, raised intracranial pressure, and/or disorders in local circulatory regulation including microvascular obstruction. Brain injury centers prominently on the cortex, hippocampus, and the inner ear, and the injuries are not simply the result of bacterial invasion but also occur as a result of a symphony of inflammatory mediators whose roles and control remain the focus of intense evaluation and give the promise of potential for future clinical intervention.1

Meningitis may also develop as the result of direct extension of pathogens from sites such as the sinuses, mastoids, dermoid sinuses, or the skull. Recurrent episodes of bacterial meningitis should prompt immunologic evaluation as well as careful anatomic evaluation of contiguous structures (eg, for congenital or traumatic bony, vascular, or dural defects).

Clinical Presentation

In practice, patients present in one of two manners. The first is easier to recognize quickly but carries a worse prognosis. Approximately 25% of patients have a short clinical course of only a few hours and present with fever and mental status changes (irritability, lethargy, confusion), and the diagnosis is not elusive. The other 75% of patients with bacterial meningitis have a more insidious clinical presentation with simple fever and nonspecific symptoms that progress over 1, 2, or more days to cause signs and symptoms typical of meningitis.

Signs and Symptoms

The most reliably present finding in bacterial meningitis is fever (98%), whereas complaints of headache, photophobia, or neck pain won't be heard until the child is verbal and can communicate these symptoms (around 2 years of age). Since bacterial meningitis is most common before this age it is important to watch for other clues. Infants may initially present with irritability that is difficult for the parents to alleviate, poor feeding, sleepiness, lethargy, and possibly vomiting. Later in the illness a bulging fontanelle, nuchal rigidity, and coma may be seen.

For an older child, where neck pain can be more easily assessed, the neck pain seen with meningitis is worsened by neck flexion. The typical child can easily touch the chin to the chest without the need to open the mouth and reluctance to do so is worrisome. Patients with meningismus will often open the mouth in an attempt to reach the chest with less neck flexion. Flexion typically causes pain at the back of the neck and moving down to the upper mid-back area. It should be noted that ibuprofen and other analgesics may temporarily resolve the neck pain despite the presence of meningitis.

Seizures occur as part of the presentation in 15% to 30% of patients, but will only rarely occur as simple (brief, nonfocal) seizures without other signs or symptoms worrisome for meningitis.2 On the other hand, the risk of meningitis is increased significantly among febrile patients with convulsive status epilepticus (a seizure or series of seizures without recovery of consciousness between seizures lasting at least 30 minutes).3 Therefore, if faced with a febrile patient with focal, prolonged, or recurrent seizures, or a febrile infant less than 6 months of age with any type of seizure, a lumbar puncture for CSF examination should be strongly considered.

Bacterial meningitis should be considered a medical emergency and the usual attention to airway, breathing, and circulation should be applied, as depressed mental status and associated septic shock may complicate management. The rapid institution of supportive measures and prompt administration of antimicrobials is the goal.

Differential Diagnosis

Severe pharyngitis, parapharyngeal abscess or adenitis, musculoskeletal strain, upper lobe pneumonia, cervical spine osteomyelitis, epidural abscess, and subarachnoid hemorrhage may all produce meningismus. Depressed mental status may occur as a result of encephalitis, ingestions, mass lesions of the CNS, or simple febrile seizure.

The possibility of another primary focus for infection that might also require specific therapy or follow-up should be considered. This site may be distant (eg, pyelonephritis, pleural empyema, osteomyelitis), but by causing bacteremia may have caused meningitis. In addition, a contiguous focus may also be the cause. Sinusitis, mastoiditis, osteomyelitis of the skull, or even a brain abscess may require additional intervention.

Diagnosis

While the diagnosis is simple when patients come with classic symptoms of photophobia, nuchal rigidity, severe headache, or mental status changes, this is not generally the case at the initial evaluation. There is a continuum from a complete absence of clinical signs or symptoms at the time the first bacteria cross the blood–brain barrier to severe symptoms.

The point in that continuum of symptoms when the child is seen and the rate at which the disease is progressing will determine how difficult it will be for the clinician to recognize the child as having meningitis. It is for this reason that approximately half of all patients ultimately diagnosed with bacterial meningitis will visit a clinician during the course of their illness and be sent home from the encounter without meningitis being considered.4

The highest risk for meningitis during childhood is in the first month or two of life and at this age the clinical signs are few. Therefore, a lumbar puncture is generally warranted in the evaluation of the febrile infant under 2 months of age. After 2 months of age the diagnosis remains a challenge, but more clinical cues are available to the clinician experienced in evaluating young children.

Children with prior antibiotic therapy during the illness can be more difficult to diagnose. Pretreated patients are less likely to have fever at examination, less likely to have altered mental status, and will have longer duration of symptoms at diagnosis.5Table 16-2 summarizes the pertinent history and physical exam in the evaluation of patients suspected of having meningitis. Figure 16-2 is a flow diagram for the diagnostic approach for patients being evaluated for meningitis.

Cerebrospinal Fluid Studies

The cerebrospinal fluid (CSF) should be sent for cell count, glucose, protein, Gram stain, and bacterial culture. A CSF fungal culture should also be performed in premature infants and in children with other immunocompromising conditions. Most patients with bacterial meningitis will have an elevated CSF WBC count with 80% or more polymorphonuclear cells; the CSF glucose will be low in about 50%; and the CSF protein concentration is generally elevated. The CSF culture is positive in about 80% of patients, and the culture is positive within 24 to 48 hours unless antimicrobials were given prior to lumbar puncture.

For the infant under 1 month of age with CSF pleocytosis no prediction rule can reliably exclude bacterial meningitis, and these infants should be treated as possibly having bacterial meningitis until the results of CSF culture are known. Further, not even normal CSF parameters exclude bacterial meningitis, as 10% of neonates with bacterial meningitis will not have a CSF pleocytosis,6-8 and a majority of very low birth weight (<1.5 kg) neonates with bacterial meningitis have no CSF pleocytosis at diagnosis (by positive CSF culture).6

For older infants and children with CSF pleocytosis a multicenter review of pediatric cases of bacterial meningitis clearly demonstrated that children older than 1 month with CSF pleocytosis (and no antibiotic pretreatment) can be considered at very low risk of bacterial meningitis if the Gram stain has no organisms, the CSF absolute neutrophil count is <1000 cells/mm3, the CSF protein is <80 mg/dL, the peripheral blood absolute neutrophil count is <10,000 cells/mm3, and there is no history of seizure before or at the time of presentation.7 Nonetheless, even with these serially applied low-risk criteria, 2 of 121 children with bacterial meningitis had none of these risk factors for a sensitivity of 98% (95% confidence intervals: 94%-100%).

Among patients beyond the first months of life the serum procalcitonin (≥0.5 ng/mL), C-reactive protein (>20 mg/L), CSF lactate, and the CSF glucose or CSF glucose to serum glucose ratio can all be helpful in distinguishing bacterial from nonbacterial causes of acute meningitis.8-11 While not routinely available, the CSF levels of interleukin 6 (IL-6) and tumor necrosis factor (TNF) are also much higher in patients with bacterial versus aseptic meningitis.12 Patients with bacterial meningitis have a predominance of polymorphonuclear cells before treatment. Approximately half of patients with aseptic or demonstrated enteroviral meningitis will also have a CSF polymorphonuclear cell predominance. Symptom duration does reliably result in a change in the CSF white blood profile, so serial lumbar punctures for this purpose are not recommended.18,19

Latex agglutination studies of the CSF for bacterial antigens do not typically provide any benefit and are not routinely recommended.13 Polymerase chain reaction tests for bacteria are not readily available and have not shown much benefit beyond culture, but some available viral PCR tests are faster and more sensitive than viral culture and should be considered for specific etiologies. Because enteroviruses are common causes of meningitis and enterovirus polymerase chain reaction tests (EV-PCR) are now readily available, it is suggested that if the turn-around time for this test at your institution is usually <48 hours, this test should be routinely considered. Previous studies have demonstrated a decrease in hospital length of stay when EV-PCR testing is routinely performed during enteroviral season.14 Because it is slower than most routine bacterial culture or PCR tests, the routine use of viral culture is not recommended. Where herpes simplex meningoencephalitis is a possible concern, an HSV-PCR should be sent.

A positive Gram stain or growth of a pathogen in CSF culture definitively identifies bacterial meningitis. Unfortunately the diagnosis is more difficult to establish or exclude in the patient that has received antibiotic treatment prior to obtaining CSF for examination and culture. Pretreated patients are less likely to have a positive CSF Gram stain or culture.5 While bacteria can be recovered in some circumstances for 1 or more days after initiation of antimicrobial therapy the CSF is sterilized in 2 hours or less with meningococcal infections, in 4 to 12 hours with pneumococcal infections, and as early as 8 hours with group B streptococcal infections.15Table 16-3 includes suggested studies to be ordered in the evaluation of the patient with suspected meningitis.

It should be noted that it may not be possible to safely perform a lumbar puncture, and the diagnosis will need to be a presumptive one in some patients. The lack of a definitive diagnosis should not delay treatment given the potential for significant morbidity. The lumbar puncture may need to be deferred if there are concerns of clinical instability, significantly elevated intracranial pressure (bradycardia, hypertension, irregular respirations, papilledema), or concern for intracranial lesion. The presence of thrombocytopenia (<50,000 platelets/mm3) should prompt consideration for platelet transfusion prior to lumbar puncture. The presence of skin infection in the area overlying lumbar puncture should also be considered a relative contraindication because of the concern for inoculating bacteria from the skin site to the CSF.

Other Studies

The decision to perform a lumbar puncture should not rest on the results of blood testing. Among infants, a very low or high peripheral white blood count (WBC) does increase the risk for bacterial meningitis, but 41% will have peripheral WBC values in the normal range.16 A negative peripheral blood culture does not rule out bacterial meningitis. Among patients with confirmed bacterial meningitis, no bacterial growth is seen in blood cultures in approximately one-third of cases.15,17-19 Despite these limitations, blood should be routinely obtained for culture from patients evaluated for suspected meningitis. A positive blood culture will influence the choice of antimicrobial therapy in cases where the CSF does not yield growth of a pathogen. Serologic tests may be helpful, and Lyme serology should be routinely ordered in the proper epidemiologic setting (eg, areas where infection is common, where there is an opportunity for exposure).

Neuroimaging does not need to be routinely ordered but should be performed during the course of therapy when patients experience unexplained changes in mental status, focal neurologic deficits, or there is other reason for concern of intracranial abscess, empyema, hemorrhage, infarct, or thrombosis.

Management

Optimize supportive care to ensure adequate oxygen delivery including consideration of adequate cerebral perfusion pressure. Patients with septic shock will require appropriate resuscitation to maintain adequate oxygen and glucose delivery to the brain. In patients without the need for additional fluids to support the circulation, intravenous fluids should provide for "maintenance" needs but should be given cautiously to avoid worsening the hyponatremia of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), should it occur. Baseline and daily weight measurements and the evaluation of electrolytes may be helpful in monitoring for the development of SIADH.

When there is a high clinical suspicion for bacterial meningitis, the lumbar puncture should be done as soon as it is clinically safe and feasible, and the administration of antibiotic(s) should occur without awaiting the results of CSF studies or computed tomography (which itself is not routinely indicated unless there are focal signs or symptoms). Delays in antibiotic administration should be avoided and are associated with worsened outcome in adults.20

Treatment

Until an organism is isolated, patients should be treated with empiric antibiotic therapy that covers the range of potentially causative pathogens. Empiric antimicrobial coverage should rarely be narrowed based on the reading of the Gram stain alone, as errors in interpretation are common. Conversely if the Gram stain suggests an organism not well covered by empiric therapy, the coverage should be broadened awaiting the results of culture. It is important to consider Listeria as a potential pathogen, since optimal therapy includes the use of ampicillin, which is no longer routinely included in many empiric treatment strategies.

The initial empiric antibiotic therapy for most children is listed in Table 16-4. Dosing recommendations for these antimicrobials is listed in Table 16-5. Once the specific etiologic agent causing the meningitis is known, the treatment can be focused on that organism. Recommendations by organism (and the organism antibiotic susceptibility) are listed in Table 16-6. Duration of antibiotic therapy varies depending on the causative organism, the time to CSF sterilization, the extent of CSF inflammation, and the patient's clinical response. In uncomplicated cases, parenteral antibiotic courses are typically of 7 days for N meningitidis, 7 to 10 days for H influenzae type b, 10 to 14 days for S pneumoniae, 14 to 21 days for group B streptococci, and 21 days for gram-negative organisms.

Vancomycin is a necessary component in the empiric treatment of patients with possible penicillin-resistant Pneumococcus. However, one retrospective study has suggested that the use of vancomycin in the first 2 hours of treatment may be associated with an increased risk for hearing loss in pneumococcal meningitis.21 Further corroboration is needed before changes in practice can be recommended, but the priority should be to administer the dexamethasone and cefotaxime as quickly as is feasible and then administer vancomycin.

Corticosteriod Therapy

Dexamethasone, when given 15 minutes prior to or simultaneously with antibiotics, appears to reduce mortality and sequelae among patients with H influenzae type b and S pneumoniae meningitis.22 It is not known whether dexamethasone therapy has an effect on cognitive outcome. There is no demonstrated efficacy for the use of dexamethasone after antibiotics have been administered. There has been no demonstrated benefit to the use of steroids in meningococcal or neonatal meningitis.23-25 The key steps in the evaluation and management are summarized in Table 16-3. Most authors reserve the use of dexamethasone for patients with clinical or laboratory findings highly suggestive of bacterial meningitis thought most likely to be due to H influenzae type b or S pneumoniae. Dexamethasone is not routinely recommended for the child with suspected aseptic meningitis receiving antimicrobial therapy pending the results of bacterial culture. Dexamethasone has not been adequately studied or demonstrated beneficial in the treatment of neonates with bacterial meningitis.

Additional Considerations

A repeat lumbar puncture for a follow-up cerebrospinal fluid culture is not routinely recommended but should be considered when patients fail to improve within the first 24 to 48 hours or when the identified pathogen can be anticipated to be difficult to eliminate with conventional antibiotic therapy based on susceptibility testing or prior experience (eg, nosocomial gram-negative infections, resistant pneumococcus).

Consultation with an infectious diseases specialist is recommended for most cases of gram-negative meningitis, fungal meningitis, meningitis in a patient with reduced immunity or indwelling intracranial hardware, and in the treatment of organisms with reduced susceptibility to antibiotics.

Meropenem is preferred to a third-generation cephalosporin for the treatment of specific gram-negative infections due to organisms such as Citrobacter, Enterobacter, or Serratia-related cases, which may possess the ability to express extended-spectrum beta-lactamases (ESBL) that may be induced by cephalosporin therapy.

Course and Prognosis

The mortality is associated with many factors, but overall is about 5% for H influenzae and meningococcal meningitis and in the vicinity of 20% for pneumococcal and Listeria meningitis in developed countries. The most common complications are listed in Table 16-7.

The risk for mortality and sequelae is related to the severity of disease. Not surprisingly, mortality (approximately 30%) and the rate of sequelae among survivors (approximately 70%) are very high among patients requiring mechanical ventilation during therapy of acute bacterial meningitis and are highly correlated with severity of illness at admission.26 Mortality also increases if there is a significant neurological event during the acute phase of the illness. This may be due to general cerebral edema, hypoperfusion, loss of microcirculatory control, and vascular thromboses that cause secondary effects such as herniation and infarction.

The time course of presentation is also associated with severity of disease. Children who present and are diagnosed as having bacterial meningitis within the first 24 hours of illness are much more likely to have severe disease than those with a more insidious presentation that may develop over 2 days or more before diagnosis.27

Subdural effusions are commonly noted during the first week of therapy for bacterial meningitis of infants (approximately 30%) but do not typically require intervention.28 Subdural empyema is a rare but important complication of meningitis, which can usually be distinguished from effusion with diagnostic imaging.29

Monitoring of urine output, daily weights, and serum electrolytes is prudent in the early phase in order to quickly identify hyponatremia and manage patients developing SIADH secretion. Less common complications include acute spinal cord dysfunction—myelitis.

Long-Term Sequelae

Hearing loss occurs in a large proportion (10%-30%, depending on pathogen) of children and is associated with severity of infection (lower CSF glucose levels, raised intracranial pressure, nuchal rigidity, S pneumoniae as the causative agent) with profound hearing loss in 5%.30 Hearing loss, when it occurs, will be noted to some degree with the earliest testing.31 While many children will experience some improvement in hearing over time, others may have further progression of hearing loss over months to years.32 After bacterial meningitis children are more likely to have cognitive impairments such as poor linguistic and executive functions and these children are more likely to have behavioral problems than their peers.33 As a result, even after apparent complete recovery from bacterial meningitis, children benefit from formal neuropsychiatric evaluation in addition to routine tests of hearing, as the findings may be subtle. Three percent to five percent of children will have seizures, mental retardation, and/or some degree of spasticity or paresis.30

Special Circumstances

Patients with immunocompromise, intracranial implants including cochlear implants, ventriculoperitoneal shunts, and infants in the intensive care setting are at increased risk of meningitis including meningitis due to bacteria or fungi not typical of other children. Therefore, they should be considered separately with regard to primary prevention and optimal initial empiric therapy.

Citrobacter meningitis in the neonate, and Citrobacter koseri in particular, is associated with a very high rate of mortality (30%) and sequelae (75%), and is the most common cause of neonatal abscess (Figure 16-3). Infants with Citrobacter meningitis should have brain imaging during the course of therapy to evaluate for this complication.

Meningitis with cranial nerve palsies, appropriate local epidemiology, or protracted symptoms, should raise suspicion for Lyme disease, and depending on the cranial nerves involved, a basilar meningitis as can be seen with tuberculous or some fungal meningitis should be considered.34 Causes of chronic meningitis are also quite varied, but pathogens such as Brucella, those causing Lyme disease and syphilis, cryptococci, and other fungi may cause a more indolent and chronic meningitis. Noninfectious causes include malignancies, sarcoid, and autoimmune disease.

Discussion of eosinophilic meningitis (>10 eosinophils/mm3 of CSF) is beyond the scope of this chapter, but may be seen in relation to indwelling foreign body, certain parasitic diseases, malignancies, in response to medications, and with coccidioidal meningitis.

Prevention

Chemoprophylaxis is recommended for close contacts of patients with disease due to N meningitides or H influenzae type b. Active immunization against H influenzae type b and S pneumoniae is now part of routine childhood vaccination schedules and immunization for N meningitidis is typically required prior to college entry in the United States.

Intrapartum ampicillin administered to women at high risk of transmitting group B streptococci to their infants is effective in reducing the risk of early-onset but not late-onset group B streptococcal disease. Women with penicillin allergy can receive clindaymycin, erythromycin, or in the absence of immediate-type hypersensitivity, a first-generation cephalosporin. Up to 20% of pregnant women require intrapartum antibiotic prophylaxis. Recurrent group B streptococcal infections occur; most of the isolates from recurrent infections are identical to the isolates from the initial infection. Recurrent infection likely occurs as a consequence of persistent mucosal group B streptococcal colonization. Attempts to eradicate mucosal colonization with oral rifampin have met with varied success. Consultation with a pediatric infectious diseases or immunology specialist should be considered in infants with recurrent group B streptococcal infection.35

Encephalitis causes significant morbidity and mortality and raises difficult diagnostic and management challenges. The etiology is often elusive and, given the lack of literature on the subject, there is little information physicians can offer in the way of prognosis or etiology-specific treatment. This section defines encephalitis and describes its major causes with emphasis on the presentation, pathology, and management of viral encephalitis in pediatric populations.

Definitions and Epidemiology

Encephalitis is defined as inflammation of the brain tissue, infectious or otherwise, causing alterations in cerebral function. The patient with encephalitis often presents with fever, headache, altered mental status, behavioral changes, focal neurological signs, and seizures. Meningoencephalitis describes the clinical entity in which the inflammation extends to the subarachnoid spaces and meninges. When the spinal cord is involved in the inflammatory process, then the term "encephalomyelitis" is used. Noninfectious encephalitis is an antibody-mediated inflammation of the brain parenchyma, which may be triggered by immune response to a viral illness or tumor.

Estimating the true incidence of encephalitis is difficult, as most cases are not reported to local health departments. The most accurate estimates are those concerning the subset of arthropod-borne viral, or arboviral, encephalitides due to tracking efforts at the Centers for Disease Control (CDC), which estimates between 250 to 3000 cases occurring annually.36 The California Encephalitis Project documented all hospitalized cases of encephalitis in California from 1991 to 1999 and found 35 to 50 cases per 100,000 people annually. Encephalitis occurred in the highest numbers in infants, followed by the elderly. A specific cause was reported in approximately 45% of the 13,939 cases; HSV accounted for 14% of all cases while arboviral disease was identified in fewer than 1% of the cases (West Nile Virus had not yet become established in California).34

Pathophysiology

Due to the protection of the blood–brain barrier (BBB), the lack of a lymphatic system and the absence of major histocompatibility complexes (antigen-presenting cells), the brain was historically considered an immunologically isolated organ without the same vulnerabilities to infectious agents or immune responses as other body systems. It is increasingly apparent that the BBB is a far more dynamic entity than previously thought.

The BBB is made of capillary endothelial cells, astrocytes, and pericytes with unique properties not seen in other organ systems. These anatomic differences include narrow tight junctions, lack of fenestrations, decreased transport, and a continuous basement membrane. Electrically, the surfaces of these cells are negatively charged, and therefore repel proteins and other negatively charged molecules. Specific areas within the CNS differ in their levels of BBB permeability. For example, the choroid plexus endothelium has fenestrations, allowing free entry of immune cells to the CSF. The ependymal lining of the ventricles lacks tight junctions, which permits drainage of CNS antigens into the CSF.

Diagnosis

The definitive diagnosis of encephalitis requires brain tissue, which yields a diagnosis by microscopic evaluation for inclusion bodies, isolation of the causative agent from brain tissue cultures, or detection of the infectious agent by in situ polymerase chain reaction (PCR). Detection of a serologic response or identification of the infectious agent in the CSF or other body fluids allows a presumptive diagnosis. The California Encephalitis Project reported a definitive diagnosis (brain tissue diagnosis) in 30% of cases, while a presumed diagnosis (serum, urine, or stool) was found in 12%.38 Other sources report diagnostic rates of 50%.39

While isolating virus from CSF and other body fluid cultures is helpful for definitive diagnosis, this process is cumbersome and prone to contamination. PCR testing, which detects tiny portions of the DNA in the CSF, allows diagnoses to be made more quickly and reliably. Detecting antibodies for serologic testing is limited by even small doses of immunoglobulin therapy, and because it often requires both infected samples and convalescent samples, may take weeks to confirm.

Neuroimaging

All viruses affecting the central nervous system (CNS) produce similar pathologic features, including inflammation and neuronal death. Thus, most viral CNS infections appear on neuroimaging as an increase in water content of the affected tissue. On CT scan this increased water content is manifest as patchy hypodensities, and on MRI as hypointense signal on T1 and hyperintense signal on T2 and FLAIR (fluid-attenuated inversion recovery).

When imaged early in its course, viral encephalitis may first appear on MRI as restricted diffusion on diffusion-weighted imaging (Figure 16-4). Thus, acute DWI changes may be more sensitive to abnormalities than conventional T1 or T2 imaging sequences40-42 in early imaging. Later in the disease process, MRI often shows confluent areas of T2 hyperintensities involving white and gray matter, which may exert a variable amount of mass effect. When present, these hyperintensities enhance diffusely with gadolinium. While these findings fail to differentiate viral infections from one another, the asymmetry and the involvement of both white and gray matter structures help to differentiate viral encephalitis from primary metabolic/ toxic disorders or parainfectious disorders, such as acute disseminated encephalomyelitis (ADEM; Figure 16-5).

Though these general features apply to most viral encephalitides, certain infections show characteristic tropisms that are helpful in the differential diagnosis. Herpes simplex virus (HSV) encephalitis has been associated with hemorrhagic inflammation, frequently bilateral, of the medial temporal lobe, sylvian fissure, and orbital-frontal cortex (Figure 16-6).

In neonates, the areas of inflammation are seldom as well defined as in older children or adults, and manifest as loss of distinction of the gray–white interface on T2-weighted imaging. Echo gradient imaging reveals a hemorrhagic component corresponding to infarction on diffusion-weighted imaging in the acute phase of the disease (5 to 7 days from insult).

Varicella-zoster virus (VZV) is an infrequent cause of encephalitis, but must be considered as a possible cause in those patients at risk either from immunocompromise or from direct inoculation via lumbar puncture. VZV is a common pathogen in other CNS infections such as transverse myelitis and cerebellitis and has been associated with transient arteriopathy of childhood and stroke.43,44

Other Diagnostic Testing

Electroencephalogram (EEG) must be considered early in the evaluation of patients with viral encephalitis, as subclinical seizures are a treatable cause of altered mental status. EEG may also disclose other nonspecific abnormalities including focal slowing or focal epileptiform discharges. Acute destructive lesions can produce periodic lateralized epileptiform discharges (PLEDS), usually in temporal leads. PLEDS are considered nonspecific but are highly suggestive of HSV encephalitis.45

CSF profiles in viral encephalitis typically show mildly elevated WBC counts, with a lymphocytic predominance and, later in the course, mildly elevated protein. Elevated RBC counts and xanthochromia reflect the necrotizing nature of HSV infection; however, early in the disease CSF findings can be normal. PCR is the most common method used for CSF analysis, although PCR specificity may be as low as 94%, with 98% sensitivity,46 between 72 hours and 2 weeks of symptom onset. For this reason, patients may require repeat testing (Table 16-8).

Differential Diagnosis

The etiology of infectious viral encephalitis has changed significantly with the advent of widespread immunizations (Tables 16-9 and 16-10). The most common causes of viral encephalitis 30 years ago were measles, mumps, rubella, and varicella, which now rarely cause neurological disease. HSV is thought to be the most common diagnosable and treatable cause of viral encephalitis in both the United States and United Kingdom, with arboviruses, varicella zoster virus, Epstein-Barr virus (EBV), mumps, measles, and enteroviruses following in prevalence. A Finnish study published in 2001 found VZV to be the most common cause of diagnosed viral encephalitis, meningitis, and myelitis (29% of all confirmed agents), with HSV, enteroviruses, and influenza A making up the majority of other confirmed etiologic agents.47 Even within this population, however, an etiologic agent was not identified in 60% of cases. In U.S. National Hospital Discharge Data, the pathogenic species was found in only 40% of cases.48 According to the California Encephalitis Project, up to 70% of cases of encephalitis remain idiopathic.37

Postinfectious encephalitis, or acute disseminated encephalomyelitis (ADEM), is the most common white matter disease in children49 and is usually seen days to weeks after mild viral illness or immunizations. The presumed cause of ADEM is thought to be antibodies to the offending virus cross-reacting with myelin surface proteins. The inflammation results in widespread monophasic demyelination, with a full recovery expected in the majority of pediatric cases. ADEM differs from viral encephalitis in the location of lesions on imaging: ADEM has a predilection for the cerebellum and optic nerves, which is unusual for encephalitis. Spinal cord inflammation may be noted in both, but is more frequent in ADEM than in viral encephalomyelitis. Clinical progression to coma occurs more rapidly and more commonly in ADEM than in viral encephalitis.45

CSF profiles in ADEM and viral encephalitis are similar and typically show elevated WBC counts with a lymphocytic predominance. To distinguish the two entities a thorough history of prodromal illnesses must be combined with MRI findings as well as negative CSF, blood, nasopharyngeal swab, urine serology, and cultures (Table 16-8). ADEM is treated with immunomodulation using high-dose intravenous glucocorticoids or pooled intravenous immune globulin (IVIG). The precise mechanism of action of these latter therapies is unknown.

Paraneoplastic encephalitis typically involves the limbic area with a fulminant and progressive course. The pathophysiology is thought to involve antibodies formed against a neoplasm that cross-react to brain tissue antigens. Thus paraneoplastic disorders can be diagnosed by identifying pathologic antibodies in the CSF. Paraneoplastic disorders are rare in children, but should be considered in the differential diagnosis, as they can resemble HSV encephalitis. Ospoclonus-myoclonus, or the "syndrome of dancing eyes and dancing feet," is perhaps the most common paraneoplastic disorder and is associated with neuroblastoma, which is invariably low grade. Opsoclonus refers to unusual and exaggerated eye movements that can be elicited on visual tracking. Myoclonus is rapid, jerky, involuntary movements of the limbs or trunk.

Clinical Presentation and Management

Because the etiologic agent remains unknown in most cases of viral encephalitis, management is limited to symptomatic treatment. Tests to consider in the initial evaluation of the child with encephalitis are summarized in Table 16-11, while key clinical features of the viral encephalitides are summarized in Table 16-12. Even for diagnosable entities, very few treatment options exist. HSV and VZV should be treated with acyclovir, while cytomegalovirus (CMV) can be treated with ganciclovir (Table 16-13). In immunocompromised patients, aggressive treatment with antibiotics and antivirals is important until treatable causes of encephalitis/meningitis are ruled out.

The development of novel antiviral agents has lagged due to the research emphasis on immunization. As the majority of cases lack an isolated causative agent, the value of developing specific antiviral drugs is questionable. The use of immunomodulatory therapy, such as steroids, to treat encephalitis is compelling; however, the relative rarity of cases makes a single-center study difficult if not impossible. Acyclovir, supportive care, and rehabilitative therapies remain the only treatments at this time for viral encephalitis.

Herpes Simplex Virus 1 and 2

Herpes simplex virus (HSV) 1 and 2 are double-stranded DNA viruses that remain dormant in human host neurons. The clinical features distinguishing HSV 1 and 2 are few, and thus it is not clinically useful to discriminate between them.

One-third of patients with HSV encephalitis are less than 20 years of age and the majority have no prior existing conditions.50 About half of all patients with HSV encephalitis report a viral prodrome prior to the onset of neurological symptoms, with symptoms of upper respiratory and gastrointestinal illness being the most commonly reported. Neonates who acquire HSV develop CNS infection in over 50% of cases. Infection typically occurs at the time of birth (85%), but can also occur transplacentally (5%) or in the postpartum period (10%).45 Symptoms of HSV infection in neonates range from subtle (skin vesicles) to fulminant (fever, seizures, obtundation).

HSV infects peripheral sensory neurons and then spreads to the CNS by retrograde axonal transport. The patient invariably experiences fever, headache, and altered mental status. Focal seizures at the time of presentation are common (75% of patients), while hemiparesis (45%), aphasia (75%), and cranial neuropathies are also seen. Infections can rapidly progress to involve greater areas of brain tissue.45

In the last 20 to 30 years, with the advent of acyclovir, there have been significant declines in the mortality and morbidity associated with HSV encephalitis. Prior to the use of acyclovir, approximately 70% of patients with HSV encephalitis died; this has decreased to 19% since the widespread use of acyclovir.38 Neurological outcomes have also improved, and long-term studies demonstrate a normal outcome in 38%, moderate impairment in 9%, and severe impairment in 53%.38,50 Outcomes were most improved in younger age-groups and in patients with shorter latency to treatment.38 The typical dose of acyclovir is 30 mg/kg/d IV, divided every 8 hours for 14 to 21 days in children; and 60 mg/kg/d IV divided every 8 hours for 21 days in neonates.

Human Herpesvirus 6 (Hhv-6)

Human herpesvirus 6 (HHV-6), also known as roseola, usually infects children during infancy, with two-thirds of children seroconverting by 1 year.51 HHV-6 encephalitis is usually focal, and thus can be confused with HSV encephalitis. Viral invasion of the CNS is a common event during primary infection, as demonstrated by the high rate of febrile seizures. It typically causes high fever, with frank encephalitis occurring only rarely.52 The incidence of HHV-6 encephalitis is unknown.

Varicella Zoster Virus (VZV)

Prior to widespread vaccination campaigns, 4 million cases of primary varicella zoster virus (VZV; chickenpox) occurred annually. Rates of serious infection-related morbidity and mortality were highest in children under 10 years of age, accounting for 60% of hospitalizations and 40% of deaths.53 Direct infection of the CNS during a primary VZV infection is rare, but meningoencephalitis may occur by invasion of the vascular endothelium,54 leading to primary VZV encephalitis. Occurring mostly in the pediatric population, this small-vessel vasculopathy presents with headache, fever, vomiting, altered mental status, seizure, and focal deficits. Encephalitis may also complicate reactivation of VZV (zoster or shingles), usually in elderly populations. This encephalitis, by contrast, is due to a large-vessel vasculopathy, with acute focal deficits developing weeks to months after the clinical infection. MRI findings include ischemic or hemorrhagic infarcts in the cortex and subcortical gray and white matter.

The diagnosis of VZV encephalitis is made via CSF PCR for VZV or serology for VZV specific IgM in the CSF. Treatment in children is acyclovir IV 60 mg/kg/d, divided every 8 hours for 14 days.

Epstein–Barr Virus

Epstein– Barr virus (EBV) causes severe encephalitis in fewer than 1% of infected patients.54 More often, EBV causes aseptic meningitis, cerebellitis, myelitis, or ADEM with a benign course and full recovery from the infection expected. The diagnosis of EBV is made by measuring acute and convalescent serum IgM antibodies to the EBV capsid antigen. A CSF PCR test is available, but sensitivity and specificity of this test are unknown.

Cytomegalovirus

Congenitally acquired cytomegalovirus (CMV) causes severe and permanent brain injury, but encephalitis due to CMV is relatively uncommon except in the immunocompromised child.39 Serious CMV infections in the immunocompromised are treated with ganciclovir.

Enterovirus

The enterovirus (EV) family—including polioviruses, coxsackie viruses A and B, and echoviruses—are collectively the leading viral cause of CNS disease in children in the United States, particularly affecting neonates and immunocompromised hosts.45 Outbreaks of EV generally occur in late summer and early fall and are often associated with pharyngitis, gastrointestinal symptoms, or rash and desquamation of the hands, feet, and mouth (herpangina). Encephalitis, meningoencephalitis, cerebellitis, and a polio-like syndrome are most often seen with EV serotypes 70 and 71, but can occur with any virus in this family.45 The viruses can be cultured directly from the CSF, but diagnosis is usually made by CSF EV PCR, which has 96% to 100% sensitivity and >99% specificity.51 Current treatment is symptomatic and supportive, while drug trials are ongoing.

Arbovirus

Arboviruses are the most commonly identified cause of severe encephalitis worldwide.39 Single-stranded RNA viruses, they are usually transmitted to humans via mosquito or tick vectors, although transmission has also been reported following blood product transfusion, organ transplantation, needle sticks, transplacentally and via breast milk. Arboviruses have complex life-cycles involving birds and other mammals, with humans being dead-end hosts. After entering the bloodstream, they reach the CNS via endothelial cell infection. The infection in the brain is diffuse, and thus the sequelae are nonfocal, including altered mental status, vomiting, and fever. PCR testing has not been developed for routine use, as its sensitivity in arboviruses is poor. Evaluation of virus-specific IgM from CSF or blood is the most widely used diagnostic method.

West Nile Virus

Prior to 1999 there were no reported West Nile virus (WNV) cases in the Western Hemisphere. In 2006, a total of 4256 infected individuals were reported, with 1449 cases of confirmed West Nile meningitis/encephalitis, including 165 fatalities.55 Roughly 80% of infected individuals experience no symptoms, while 20% have mild flu-like symptoms of fever, headache, vomiting, diarrhea, abdominal pain, myalgia, and rash.56 Neuroinvasive disease typically includes seizures, altered mental status, meningoencephalitis, acute flaccid paralysis, cranial neuropathies, movement disorders, and optic neuritis.45,57 In patients with neuroinvasive disease, 15% progress to coma.57 The proportion of each presenting symptom varies with location and timing within the season. WNV meningitis and encephalitis occur more commonly in adults and are uncommon in children.

Diagnosis of neuroinvasive disease is made by CSF serology. WNV IgM is detectable in more than 90% of infected individuals 1 week after symptom onset. IgM-related immunity may persist for more than 1.5 years, complicating the diagnosis of acute disease. The presence of anti-WNV IgG peaks at 4 weeks after infection and persists throughout life. Currently the treatment of WNV is supportive, though current clinical trials include passive immunization, interferon alpha, and ribavirin. Overall, mortality from WNV is roughly 2% to 14%, with encephalitis-specific mortality estimated at 12% to 24%.45,57 In the United States, donor blood is screened for WNV.

Eastern Equine Encephalitis

Like WNV, eastern equine encephalitis (EEE) can cause severe disease, with 30% mortality and 30% serious neurological sequelae in survivors.58 It is an uncommon cause of illness in North America, with only 95 cases reported between 1995 and 2005.59 The presentation is both sudden and fulminant, with high fever, seizures, and rapid deterioration of mental status. Young children are most severely affected and have the highest rate of neurological sequelae in recovery.

ST. Louis Encephalitis Virus

St. Louis encephalitis (SLE) virus is more common than EEE and, according to the CDC, carries a risk of serious neurological morbidity in 10% of patients and of mortality in 5%. From 1964 to 2005, there were 4478 cases in the United States, with an annual average of 128 cases.60 While the disease is widespread throughout North America, there is a higher risk of encephalitis and serious neurological infection in low-income areas, as well as with the elderly.61 Most individuals infected with SLE are asymptomatic, but when symptoms are present they range from simple headache to severe encephalitis.

California (La Crosse) Virus

La Crosse virus is less frequent than EEE or SLE in the United States and causes a milder form of encephalitis. Between 1964 and 2005 there were 3375 cases reported to the CDC, ranging from 41 to 167 per year.62 Most cases are asymptomatic or result in mild illness, with rare neurological sequelae and very rare mortality (<1%).63 It is overwhelmingly a childhood disease, with over 90% of cases occurring in children under 16 years. When symptoms occur, the presentation is a sudden onset of fever, headache, upper respiratory illness, abdominal pain, and seizures.

Influenza Virus

Influenza types A and B are common causes of illness, but rarely cause neurological complications in the United States. Influenza has been associated with Reye syndrome, encephalitis, transverse myelitis, acute necrotizing encephalopathy, Guillain-Barré syndrome, and seizures. The data regarding serious neurological sequelae differ by geography and strain. Japanese data shows that roughly 100 children die annually from influenza encephalitis.64 Similarily, the mortality rates in influenza encephalopathy in Japan are as high as 25% to 37%.65,66 A recent study suggests the prevalence of influenza encephalitis in the United States is considerably lower; this single-center, retrospective chart review found only 842 laboratory-confirmed cases of influenza A and B in children from 2000 to 2004. Of those patients, 72 children experienced influenza-related neurological complications, but the authors found no cases of influenza encephalitis or influenza-related mortality.67 The neurological complications consisted of seizures (78%), acute encephalopathy (11%), cerebral infarction after hypotension (5%), postinfectious influenza encephalopathy (3%), and aseptic meningitis (3%).67 From 2003 to 2004, of the 153 deaths in children from influenza reported to state health departments, 16% were associated with altered mental status and 6% were associated with encephalopathy.68 Treatment for influenza is primarily supportive, although rimantadine and oseltamivir have been used for CNS infections.

Rabies Virus

While relatively rare in the United States, rabies is an important cause of serious neurological illness and death. There were only 36 laboratory-confirmed cases in the United States from 1990 to 2001,69 with half of those cases occurring in children and adolescents.39 Worldwide, however, roughly 55,000 deaths occur due to rabies each year.70 It is generally spread to humans by infected animal bites, although documented cases of rabies with no history or evidence of an animal bite exist. The virus spreads through retrograde axonal transport, causing progressive changes in mental status, seizures, cranial neuropathies, dysphagia, and paresis. Two forms of CNS rabies exist: one causes encephalitis, with seizures and fever, and eventually progresses to paralysis; the other begins with paralysis of the peripheral nerves and is associated with fever, but not seizures. The paralytic form differs from Guillan-Barré syndrome by the association with fever, and the lack of sensory deficits. Once these symptoms occur, the disease almost invariably induces cardiopulmonary failure and death, in 5 to 7 days. Diagnosis is typically made at autopsy via serologic or PCR testing of brain tissue, and histologic examination of the tissue may demonstrate Negri bodies. Viral culture may be used as a confirmatory technique. The most sensitive (100%) noninvasive antemortem diagnostic test is PCR analysis looking for rabies RNA in the saliva of the patient, with the next most sensitive (67%) test being antigen testing of hair follicles obtained by nuchal skin biopsy.71 Additional tests include antibody testing of CSF and serum, and antigen testing of a touch impression from the cornea.

There is no treatment available for rabies after symptom onset, but presymptomatic post exposure vaccine combined with immunoglobulin administration is highly effective if given within 24 hours after exposure,72 and may be effective for up to 72 hours after exposure, in some cases. The only case of survival documented after symptom onset occurred in a 15-year-old girl who was placed into chemical coma with ketamine, midazolam, and barbiturates. High-dose ribavirin (33 mg/kg/load plus 64 mg/kg/d) and amantidine (200 mg/kg/d) were administered for 1 week. Five months after hospitalization she had dysarthria, buccolingual choreoathetosis, intermittent dystonia, and ballismus, but was able to attend high school part-time. No formal neurocognitive testing was reported at that time.73 As of April 2007, she planned to graduate from high school and to attend college. Her persistent neurological deficits include numbness on her thumb, in the area of the bite, abnormal tone in her left arm, and a widened running gait.73 Further attempts to utilize this treatment strategy have failed.74

Measles Virus

Measles is rare in the post vaccine era and progresses to encephalitis in only 0.74 per1000 cases.39 Its more common neurological syndrome, subacute sclerosing panencephalitis (SSPE), occurs in older children and adults months to years after a primary measles infection. This clinical syndrome presents with dementia, myoclonus, ataxia, epilepsy, and motor function decline, and progresses slowly to death. The clinical features have been divided into four stages (the Jabour stages)

SSPE findings on EEG include high-voltage (300-1500 μV) and repetitive polyphasic sharp and slow-wave complexes of 0.5- to 2-second duration recurring every 4 to 15 seconds. Rarely, the complexes can occur at intervals of 1 to 5 minutes, with the intercomplex interval shortening as the disease progresses.

Treatment for SSPE is predominantly symptomatic. Intrathecal interferon alpha initially showed promise in a case report by inducing remission for 7 to 8 years, but this initial success was followed by a severe neurocognitive decline.76

Mumps Virus

While most cases of mumps occur in areas of the world where routine childhood vaccinations do not occur, epidemics have also been seen in vaccinated populations. In the first 10 months of 2006, there were 5783 cases of mumps reported, with a median age of 22.77 According to the CDC, 50% to 60% of cases of mumps show a CSF pleocytosis, despite encephalitis occurring in less than 2 per 100,000 cases.48 Mumps occurs more often in the spring and has a low mortality rate. Patients with mumps encephalitis present with mild, nonfocal symptoms of fever and headache. Diagnosis is made by CSF and serum serology with culture of the nasopharynx, CSF, urine, and saliva.

A postinfectious encephalomyelitis due to mumps may also occur, usually 7 to 10 days after infection. These patients exhibit more severe symptoms such as seizure, hemiparesis, and altered mental status. This variant carries a higher mortality rate of 10%.45

Emerging Viruses

Nipah and Hendra viruses are both in the family Paramyxoviridae. The Nipah virus was identified in 1999 as the cause of a large outbreak of encephalitis among pig farmers in Malaysia and Singapore. The natural reservoir for Nipah virus is still under investigation, but preliminary data implicate bats of the genus Pteropus in Malaysia. In Malaysia and Singapore, humans were infected with Nipah virus through close contact with infected pigs. The Hendra virus, first isolated in 1994, is related but not identical to the Nipah virus. It is predominantly known to cause fatal respiratory infections in horses and humans, but a solitary case of adult encephalitis has been reported.

Prognosis

Expected outcomes vary significantly with the etiology of the viral encephalitis, but certain generalizations can be made. Young infants usually have more severe disease and therefore more significant sequelae. One study examining the prognostic indicators in 462 cases of pediatric encephalitis (including HSV, VZV, enterovirus, respiratory virus, measles, mumps, rubella, and M.pneumoniae etiologies) found mortality five times greater in infants compared to older children, and found that patients with significantly altered mental status had 4 times the risk of death.79 The majority of survivors experience seizures or cognitive and focal neurological deficits, negatively affecting their quality of life. The economic impact of encephalitis is difficult to calculate, as survivors typically require intensive supportive services and, as a group, have decreased independence as adults. Overwhelmingly, the longitudinal data on outcomes in encephalitis have focused on herpes encephalitis before the advent of acyclovir. The most recent longitudinal study examined the rehabilitation of 8 patients, including 1 child, diagnosed with encephalitis from 1990 to 1997. The study focused only on the rehabilitation scores of the patients, without mention of seizure incidence, cognitive or physical impairment, or quality of life.80 Clearly more investigation into the outcomes of children with viral encephalitis is required before conclusions can be drawn regarding prognosis.

Definitions and Epidemiology

Acute transverse myelopathy is a clinical syndrome consisting of progressive symptoms and signs reflecting sensory, motor, or autonomic dysfunction attributable to the spinal cord. This syndrome can be caused by a heterogeneous group of disorders, including acute transverse myelitis (ATM). Definitions of ATM have varied significantly in the literature.81,82 To address this nonuniformity, the criteria proposed by the Transverse Myelitis Consortium Working Group83 (Table 16-14) should be used to establish the diagnosis and guide the differential diagnosis and workup. The diagnosis of ATM can be further refined by determining whether there is partial or complete involvement of the spinal cord in the axial plane. Complete ATM is characterized by moderate to severe symmetric symptoms, while partial ATM is marked by milder, asymmetric symptoms.84

Acute transverse myelitis can be associated with more diffuse central nervous system (CNS) demyelinating disorders, systemic autoimmune disorders, or specific associated infections. Idiopathic ATM is associated with a nonspecific preceding infection or no apparent cause and constitutes the most common subgroup of pediatric ATM.

Idiopathic ATM afflicts approximately 1.34 persons per million.85 In the pediatric age group, patients present at a mean age of 8 years with an equal gender ratio.81,82,84,86-89 Approximately 280 cases of ATM occur in pediatric patients in the United States per year.90,91

Pathogenesis

Infectious agents can cause spinal cord dysfunction by directly infecting the spinal cord parenchyma (infectious myelopathy)82 or by triggering postinfectious, immune-mediated processes. In some cases, such as human T-cell lymphotropic virus (HTLV) associated myelitis, damage to the spinal cord may be produced by direct infection as well as the immune response to the microbe. Several agents, including cytomegalovirus (CMV) and varicella zoster virus (VZV), are associated with direct CNS infection in certain patients (many of whom are immunocompromised) and postinfectious ATM in others.

Among all cases of ATM, the preceding infection is most commonly a nonspecific upper respiratory tract infection.81,85,89 Approximately 50% of patients report a preceding infection with an intervening symptom-free interval of 5 to 11 days.81,85,89,90 Some cases of ATM are associated with recent vaccination, although causality is difficult to prove given the paucity of cases and the frequency with which children are vaccinated.81,86,90,93-95

Although the precise pathophysiology of ATM is uncertain, the frequent association with preceding infections and accumulating immunologic data support an inflammatory cause for the disorder.81,85,96,97 Increased peripheral blood lymphocyte responses to myelin basic protein have been demonstrated in the research setting in patients with ATM.98 None of the 6 patients who were tested in the recovery stage in this study showed significant responses to myelin basic protein, suggesting that the cellular autoimmune reaction is short-lived. In addition, the production of interleukin-6 (IL-6) by astrocytes appears to lead to nitric oxide– induced injury to spinal cord oligodendrocytes and axons in patients with idiopathic ATM. IL-6 levels are markedly elevated in the CSF of patients with ATM and correlate with long-term disability.96

In a specific form of ATM that also includes optic neuritis, termed neuromyelitis optica (NMO),99 a novel biomarker (NMO-IgG) has been detected in 73% of adult patients and several pediatric patients.100-102 This auto-antibody targets the predominant CNS water channel protein aquaporin-4, which is concentrated in astrocytic foot processes in the blood-brain barrier. The role of NMO-IgG and aquaporin-4 in the more common, idiopathic form of ATM is uncertain.

Clinical Presentation

Seven published case series ranging in size from 9 to 50 patients disclose common symptoms in pediatric patients with ATM.81,82,86-90 Patients universally report acute to subacute, bilateral leg weakness, which is symmetric in approximately 67% of patients.81 Involvement of the arms occurs in about 40% of patients. Approximately 90% of patients complain of bowel and bladder dysfunction. A similar percentage of patients report sensory symptoms, including parasthesias and numbness. Back pain and fever afflict nearly 50% of patients and may prompt consideration of primary infectious etiologies, such as an epidural abscess. The symptoms of ATM develop rapidly, peaking at an average of 2 and 5 days, in 2 respective studies.81,90

The general examination, although usually unremarkable, may reveal signs suggestive of an underlying systemic infection or autoimmune disorder. Abdominal examination may reveal a distended bladder. On the neurological examination, the presence of any mental status changes suggests that the myelitis is a component of a more diffuse process, such as acute disseminated encephalomyelitis (ADEM). In the acute stages, muscle tone is flaccid in affected limbs. All sensory modalities should be carefully assessed. A spinal cord sensory level is usually located in the thoracic region (80%) and less commonly in the cervical (10%) or lumbar (10%) area.85 In the acute phase, deep tendon reflexes are depressed in approximately 70% of patients and later become hyperactive. Similarly, Babinski responses may be negative early in the acute phase, but soon become positive, indicating upper motor neuron dysfunction.

Differential Diagnosis

Numerous disorders can affect the spinal cord and produce identical symptoms and signs that mimic idiopathic ATM (Table 16-15). Such conditions must be ruled out through a combination of history, physical examination, neuroimaging, and laboratory evaluation (Figure 16-7).

Isolated Spinal Cord Dysfunction

Extra-medullary compressive lesions, including spinal epidural abscesses,103 spinal epidural hematomas,102 and tumors,105 are neurosurgical emergencies that must be diagnosed rapidly for effective treatment. Intra-medullary lesions that can mimic ATM include primary spinal cord tumors (most commonly astrocytomas and ependymomas),106-108 radiation injury,109 spinal cord infarction, and vascular malformations.110 Direct infections of the spinal cord, typically viral in etiology, can also occur.

The initial clinical presentation of ATM can be very similar to that of Guillain-Barré syndrome. Both can present with back pain, paraparesis, and sensory abnormalities. Although typically absent in both disorders acutely, the presence of deep tendon reflexes would point strongly towards ATM. When deep tendon reflexes are absent, the presence of a spinal cord sensory level and bowel and bladder involvement is suggestive of ATM.

Spinal Cord Dysfunction Plus Additional Neurological or Systemic Symptoms and Signs

The presence of mental status changes and cerebral white matter magnetic resonance imaging (MRI) abnormalities point towards ADEM as the correct diagnosis. Mild, asymmetric spinal cord symptoms, previous episodes of transient neurological symptoms attributable to locations other than the spinal cord, and subclinical brain MRI lesions point towards multiple sclerosis.111 Concurrent or preceding optic neuritis suggests NMO as a possible diagnosis.99

Acute transverse myelitis can also be secondary to a variety of systemic autoimmune disorders. Involvement of other organ systems, particularly the skin, lungs, kidneys, and joints, may point to a particular diagnosis, such as systemic lupus erythematosus or sarcoidosis.

Diagnosis

Neuroimaging

Every patient with suspected ATM should undergo emergent gadolinium-enhanced MRI of the entire spine in order to confirm the diagnosis and rule out alternative diagnoses, particularly compressive lesions. T1- and T2-weighted sagittal imaging of the entire spine can serve as an initial screen, followed by axial imaging in areas of suspected pathology.112 All patients with ATM should also undergo gadolinium-enhanced MRI of the brain to assess for additional demyelinating lesions suggestive of ADEM or multiple sclerosis.

Spinal MRI in ATM typically reveals T1 isointense and T2 hyperintense signal over several contiguous spinal cord segments,81 and may involve the entire spine.112 Spinal cord swelling with effacement of the surrounding cerebrospinal fluid spaces may be present in severe cases. Contrast enhancement is present in as many as 74% of patients.90 In some patients with very suggestive clinical features, the initial spine MRI may be normal and should be repeated several days later.81,82,86 In some cases, the MRI remains normal, but does not rule out the diagnosis.90 Higher rostral levels and number of overall spinal segments predict worse outcome.90

Lumbar Puncture

Unless a specific contraindication exists, all patients with ATM should undergo lumbar puncture. Approximately 50% of pediatric patients with ATM have CSF pleocytosis, typically with a lymphocytic predominance.90 Elevated CSF protein levels, either in isolation or in conjunction with pleocytosis, are also detected in about 50% of patients.90 Glucose is typically normal. A normal CSF profile does not rule out ATM, as this pattern is seen in approximately 25% of patients.

Additional Tests

The long list of infectious, demyelinating and rheumatologic disorders potentially associated with ATM precludes diagnostic testing for every possible disorder (Table 16-16). The etiology of a direct infectious myelopathy is usually established by positive cerebrospinal fluid (CSF) culture or polymerase chain reaction (PCR) results. In post-infectious ATM, a specific etiology can be suggested by elevated acute or rising convalescent serum titers and/or isolation of the agent from systemic sources in the setting of a suggestive clinical picture. The infectious disease workup should be focused on pathogens that are common, treatable, or suggested by particular clues in the history or examination, such as environmental exposures and immune status.

Treatment

There have been no randomized, controlled treatment trials in ATM. Based on case reports and series that have suggested a beneficial effect,97,113,114 high-dose corticosteroids have become the standard of care in ATM. In one series of 12 children with severe ATM compared to a historical control group of 17 patients, the use of high-dose intravenous methylprednisolone significantly increased the proportion of children walking independently at 1 month (66% compared to 18%) and with full recovery at 1 year (55% compared to 12%).97 Although a variety of agents and courses have been used, we use intravenous methylprednisolone 30 mg/kg/dose once a day for 5 days (maximum daily dose 1 g). The need for a prednisone taper is controversial and may be based on whether full or partial recovery is achieved with the intravenous steroids. For patients who do not adequately improve with intravenous methylprednisolone, intravenous immunoglobulins115 or plasmapheresis can be used (Figure 16-8).

As most cases are due to secondary, immune-mediated mechanisms, antimicrobial treatment is not likely to have significant benefit. However, antimicrobial therapy should be considered in cases with highly suspected or proven associated infections, such as doxycycline or levofloxacin for Mycoplasma pneumoniae,116 ganciclovir for CMV,117 and acyclovir for HSV and VZV.118 When antimicrobials are used, agents with good CSF penetration are preferred, as direct CNS invasion may be present in some cases.

Additional treatment includes pain management, urinary bladder catheterization, bowel regimens, peptic ulcer and deep venous thrombosis prophylaxis, physical therapy, and psychosocial support. Mechanical ventilation is required in approximately 5% of patients.

Prognosis

Disability

Although the variable definitions of recovery reported in the literature preclude a definitive assessment, the prognosis for pediatric patients with ATM is generally favorable.119 Paine and Byers' degree-of-recovery categories have been the most widely reported outcome scale but are limited by vague terminology.89 Based on this scale, approximately 80% of pediatric patients who receive high-dose IV methylprednisolone achieve full or good recovery and 20% have a fair or poor outcome.87,113 Among patients not treated with high-dose IV methylprednisolone, 60% have a full or good recovery, while 40% have a fair or poor outcome.89

One large, tertiary-referral, center-based study of 47 children with ATM, of whom 70% were treated with intravenous steroids, has cast doubt on the favorable prognosis of the disorder in childhood.90 In this study, approximately 40% of patients were nonambulatory and 50% required bladder catheterization at a median follow up of 3.2 years. These results may have been influenced by a high percentage of patients less than age 3 years and patients with cervical involvement compared to other studies. Multicenter and/or population-based studies are needed to further clarify the prognosis of ATM in childhood.

During recovery, motor function returns first, with an average time to independent ambulation of 56 days in one study81 and 25 days in a group of patients treated with high-dose IV methylprednisolone.87 Bowel/bladder control recovers more slowly, with an average time to recovery of normal urinary function of 7 months in those patients with complete recovery.81

Recurrences

The overwhelming majority of pediatric patients with idiopathic ATM do not have any recurrences. In a series of 24 pediatric patients with a mean follow-up of 7 years, there were no recurrences.81 In another study of children with a variety of initial acute demyelinating events, only 2 of 29 (7%) patients with transverse myelitis had a later demyelinating event.120,121