The early signs of neonatal bacterial meningitis may consist only of low-grade fever, poor feeding, somnolence, “fussy” behavior, or irritability (Table 7.4). Later, vomiting, lethargy, and seizures ensue. The physical examination in infants with meningitis can be equally nonspecific, showing somnolence, irritability, hyper-reflexia, and a full or bulging fontanel. Meningeal signs are present infrequently. Systemic signs can include hypotension and features of disseminated intravascular coagulopathy (DIC).

The signs and symptoms of meningitis in older children include fever, headache, nausea and vomiting, nuchal rigidity, alterations of sensorium, convulsions, cranial
nerve palsies, disturbances in vision, and occasionally papilledema (59). Headache, often accompanied by photophobia, results from inflammation of the meningeal vessels and from increased intracranial pressure. Head retraction, neck stiffness, and spinal rigidity are caused by irritation of the meninges and spinal roots, which elicits protective reflexes intended to shorten the spinal axis and immobilize the irritated tissue (60). With lengthening of the spine, nerve roots are stretched, and the resulting pain and reflex spasm is the basis of Kernig and Brudzinski signs. Spinal rigidity is a more sensitive sign of meningeal irritation than nuchal rigidity, especially in young children. Nuchal stiffness is most readily demonstrated with the child in the sitting position with the legs extended (61). Systemic signs can include pneumonia in children with pneumococcal or H. influenzae meningitis and petechiae, purpura, or signs of DIC in children with meningococcal meningitis. Rash, purpura, and DIC can also be observed occasionally in children with H. influenzae meningitis.

Seizures can be generalized or partial in infants or children with bacterial meningitis. Dodge and Swartz reported seizures in 44% of patients with H. influenzae meningitis, 25% of those with S. pneumoniae infections, 10% of those with meningococcal infections, and 78% of those with streptococcal meningitis (62). Focal seizures can be the result of localized involvement of the cerebral hemispheres by bacteria, cytokines, or vascular lesions. In a study by Samson and associates (63), 18% of patients had their first febrile convulsion in the course of meningitis. A lumbar puncture, therefore, is advised in children with their first febrile convulsion, especially in infants or unimmunized children. Lumbar puncture also deserves consideration when febrile convulsions recur and meningitis is suspected (64) or the seizure has atypical features (65). Focal neurologic signs in infants or children with bacterial meningitis can indicate Todds paralysis, ischemic stroke, or sinovenous thrombosis.

Abnormalities of cranial nerves III, IV, and VI can result from local inflammation of the perineurium or impaired vascular supply to the nerves. Transient opsoclonus can occur (66). Cochlear and vestibular deficits occur owing to septic involvement of the endolymphatic and perilymphatic systems of the scala tympani (67) or are caused by cytolytic toxins elaborated by bacteria (68). Conductive hearing loss can result from middle ear dysfunction following meningitis (69). Sensorineural hearing loss, the most common sequela of bacterial meningitis, is more likely in children younger than 1 month or older than 5 years of age, children with hydrocephalus, and those with a decreased CSF glucose (70). Jiang and coworkers suggested that a slightly depressed amplitude of the brainstem auditory potential wave V is a sensitive indicator of brainstem dysfunction in children recovering from meningitis (71). Otoacoustic emissions can detect meningitis-induced sensorineural hearing loss in young infants (72). Selective paralysis of downward gaze can occur (73). In a few rare instances, acute cerebellar ataxia can be the presenting symptom in H. influenzae or N. meningitidis infection (74). Cortical blindness also has been encountered (75).

In young infants, widened sutures can be observed within 2 days after onset of meningitis (76); however, progressive ventricular enlargement can develop without excessive head growth during or after acute bacterial meningitis (77). This enlargement results from cerebral destruction (passive ventriculomegaly) or from the effects of increased intraventricular pressure on already compromised brain parenchyma. In young infants, the low water content of brain parenchyma, lack of myelin, and relatively large subarachnoid spaces permit ventricular enlargement without corresponding increases in head circumference. Cranial bruits over the anterior fontanel and the posterior temporal areas are more common in children with bacterial meningitis than in febrile or healthy controls (72).

The diagnosis of meningitis requires prompt lumbar puncture and analysis of the CSF (91,92). The technique of lumbar puncture and the interpretation of CSF findings are discussed in the Introduction chapter. Children with focal neurologic deficits, coma, or papilledema require head computed tomography (CT) prior to performing a lumbar puncture (93). When a CT is indicated, a blood culture should be obtained (94) and empiric therapy should be initiated as rapidly as possible while awaiting the imaging study. A brief delay between lumbar puncture and antibiotic treatment may not interfere with isolation of the causative organism.

The gold standard for the diagnosis of bacterial meningitis is identification by culture and Gram stain of CSF. Most bacteria responsible for meningitis can be readily detected by all microbiology laboratories. Culture also provides clinically useful information regarding antibiotic sensitivity. Several bacteria can also be detected by CSF analysis using the polymerase chain reaction (PCR), including the nucleic acids of N. meningitidis (95), H. influenzae, and Mycobacterium tuberculosis (96). PCR can be useful in the diagnosis of meningitis caused by spirochetes (97) and several viruses (98,99) and has considerable promise for detecting bacteria in children with meningitis that is partially treated or due to nonculturable organisms. Partial treatment of bacterial meningitis reduces the sensitivity of culture and Gram stain from 97% to 73% (100) but does not substantially alter the protein or glucose content of the CSF (101).

The CSF in bacterial meningites is usually cloudy and under increased pressure. During the acute stage, polymorphonuclear leukocytes predominate, whereas mononuclear cells appear in the later stages. The cell counts generally range between 1,000 and 10,000 cells/μL, but as many as 6% of cases have few or no cells during the earliest stage of the infection (102). Organisms can be seen intracellularly and extracellularly in smears and can be visualized or cultured in the absence of pleocytosis on rare occasions (103). Eosinophilic leukocytes can be seen in the CSF of patients with parasitic infestations of the CNS, including cysticercosis, trichinosis, toxocariasis, toxoplasmosis, ascariasis, angiostrongyliasis, echinococcosis, gnathostomiasis, or coccidiomycosis (104).

The cerebrospinal fluid typically has a low glucose content in children with bacterial meningitis, often to undetectable levels. In bacterial meningitis, the CSF-to-blood glucose ratio is usually below 0.40 (105). First observed by Lichtheim (106), the decrease was attributed initially to consumption of glucose by bacteria growing in the CSF. Although there remains controversy regarding the cause of hypoglycorrhachia in bacterial meningitis, the finding likely represents a combination of altered transport into the CSF compartment and alterations in glycolysis and the blood–brain barrier (107). Prockop and Fishman observed that the facilitated diffusion of glucose from blood to CSF and from CSF to blood is impaired in bacterial meningitis, although the increase in nonspecific bulk transport of glucose can compensate for the deficit (108). Low CSF glucose also occurs in sarcoidosis, mumps meningitis, herpes zoster meningitis, CNS leukemia, and meningeal carcinomatosis (109).

CSF protein is elevated in 80% to 92% of patients (59), commonly to levels of 100 mg/dL and higher, and some studies show correlations between mortality and increased CSF protein. CSF lactate concentrations can also be increased in bacterial meningitis (110), whereas CSF lactate is normal in aseptic meningitis unless cerebral hypoxia or edema has activated glycolytic pathways (111,112). The slow decrease of CSF lactate to normal with a 3-day course of antibiotic therapy can be useful in the diagnosis of partially treated bacterial meningitis (113) and can aid in differentiating bacterial meningitis from aseptic meningitis (114). The decrease in CSF pH, which also occurs in bacterial meningitis, is more transient than the elevation of CSF lactate and has less diagnostic utility (113).

Neuroimaging studies have important adjunctive roles in identifying the complications of bacterial meningitis, such as hydrocephalus, subdural effusions, or subdural empyema, and in detecting parameningeal abscesses or CSF leaks. Indications for neuroimaging in acute bacterial meningitis include depressed level of consciousness, prolonged, partial, or late seizures, focal neurologic deficits, enlarging head circumference, persistent or recurrent fever during the later stages of treatment, and recurrent meningitis (91,92,93,115). Neuroimaging studies can also improve clinicians’ ability to predict sequelae in children who survive bacterial meningitis. Imaging should be considered strongly in neonates with bacterial meningitis, especially when gram-negative organisms are identified.

In the series of Rennick and colleagues, cerebral herniation occurred in 4.3% of children with meningitis (116). When ventricular dilatation or other imaging signs of increased pressure are present, lumbar puncture should be deferred to diminish the risk of herniation. This is particularly true if the child has a Glasgow Coma Score of 7 or less (117). Severe cerebral edema complicating neonatal meningitis can be associated with uncal herniation (118).

Because of the life-threatening nature of bacterial meningitis and the potential for permanent neurodevelopmental sequelae, antibiotic therapy should be instituted as soon as the diagnosis is suspected. The management of the pediatric patients with meningitis is reviewed by Saez-Lorens and McCracken (1), Quagliarello and Scheld (3), Feigin and Pearlman (119), and Wubbel and McCracken (120).

Empiric antibiotic therapy for meningitis in infants younger than 1 month of age consists of therapy with ampicillin, 150 to 300 mg/kg per day in divided doses every 6 to
8 hours, and gentamicin, 2.5 to 7.5 mg/kg per day in one to three divided doses, or cefotaxime, 150 to 300 mg/kg per day divided every 6 to 8 hours, depending on the gestational and postnatal age of the infant (121). Antibiotic therapy should be modified once the identity and sensitivity profile of the pathogen have been determined (Table 7.7). Therapy for group B streptococcal meningitis can consist of ampicillin, as just described, or penicillin G, 250,000 to 450,000 U/kg per day intravenously in three divided doses for infants less than 1 week old and 450,000 U/kg per day in four divided doses for infants older than 1 week. Some add gentamicin, 2.5 to 7.5 mg/kg per day in one to three divided doses. E. coli meningitis can be treated with ampicillin or an expanded-spectrum cephalosporin and gentamicin, as just described. Listeria are not sensitive to cephalosporins, including the expanded-spectrum formulations, so therapy consists of 14 to 21 days of intravenous ampicillin, 150 to 300 mg/kg per day in three to four divided doses, and gentamicin, 2.5 to 7.5 mg/kg per day in one to three divided doses, depending on the infant’s gestational and postnatal age (121). Infants with uncomplicated cases of meningitis require 14 to 21 days of intravenous antibiotic therapy, and complicated cases may require more prolonged treatment.

Empiric antibiotic therapy for suspected bacterial meningitis in children older than 1 month of age consists of cefotaxime, 300 mg/kg per day in three or four divided doses, or ceftriaxone, 100 mg/kg per day intravenously divided every 12 hours, and vancomycin, 60 mg/kg per day in four divided doses (121). Vancomycin, used because of potential resistance of S. pneumoniae to penicillin and cephalosporins, should be discontinued as soon as the causative organism is shown to be susceptible to penicillin, cefotaxime, or ceftriaxone. Resistance of S. pneumoniae to penicillin and cephalosporins remains a potential problem in most regions. The prevalence of strains with decreased susceptibility to penicillin approaches 50% in some areas of the United States (122). Penicillin G, 250,000 units/kg per day (maximum dose 12 million units/day), can be used in children or adolescents with meningococcal meningitis.

Children or adolescents with suspected meningitis require droplet and standard precautions for the first 24 hours of appropriate antibiotic therapy. Repeat lumbar puncture should be considered after 24 to 48 hours of therapy to confirm sterilization of the CSF in infants and in children with pneumococcal meningitis who received dexamethasone or have infections with strains that are nonsusceptible to penicillin or cephalosporins. Infants older than 1 month of age, children, and adolescents with bacterial meningitis should receive 7 to 14 days of therapy, depending on the organism and the presence of any complications.

Adjunctive management of infants and children with suspected or proven bacterial meningitis includes control of increased intracranial pressure, treatment of seizures, correction of electrolyte disturbances, treatment of fever, and close monitoring for subdural effusions and severe systemic complications such as DIC, hemorrhagic purpura, or renal failure (123,124). Strategies for the management of childhood bacterial meningitis can be found in the 2003 Red Book of the American Academy of Pediatrics (121).

Dexamethasone therapy, an adjunct in meningitis therapy in infants and children with H. influenzae meningitis and perhaps also in adults with bacterial meningitis, is controversial in children with S. pneumoniae or N. meningitidis meningitis. Clinical trials with dexamethasone in children with H. influenzae meningitis demonstrated a significantly lower incidence of profound hearing loss in the dexamethasone-treated group (125,126,127,128). Recommendations regarding dexamethasone therapy can be found in the most recent edition of the Red Book (121).

Increased intracranial pressure can cause significant alterations in consciousness and can contribute to the morbidity of bacterial meningitis. Intracranial pressure can be reduced by cautious removal of CSF, as might occur with an extraventricular drainage device, or by the use of hyperosmolar agents. These agents can sometimes improve the child’s sensorium promptly. Mannitol is effective for the cytotoxic edema but not for the vasogenic edema of meningitis. Intracranial pressure can be reduced by elevating the head of the patient’s bed by 30 degrees, and pressure spikes associated with suctioning can be minimized by careful sedation. Hyperventilation as a means to lower intracranial pressure by reducing PCO₂ may be detrimental (57).

Seizures require prompt treatment using lorazepam, 0.05 to 0.1 mg/kg as needed, followed by loading doses of either phenobarbital, 10 to 20 mg/kg, or fosphenytoin, 15 to 20 mg/kg. Maintenance doses of either phenobarbital or fosphenytoin may be necessary thereafter. Sedation can accompany anticonvulsant therapy. The potential for SIADH in children with bacterial meningitis necessitates close monitoring of fluid therapy, serum electrolytes, and urine output.

The outcome of bacterial meningitis is influenced by the age of the child, the species of the bacterial pathogen, and the duration of disease before the initiation of appropriate antibiotic therapy. In general, the prognosis is less favorable in neonates, regardless of the pathogen, and in older children with pneumococcal meningitis. In some but not all studies (118,129,130), sequelae are more likely in children whose diagnosis and treatment are delayed. Kresky and colleagues observed sequelae in 12% of children whose treatment was begun within 24 hours of the onset of symptoms versus 59% in children who began treatment 3 or more days after the onset of symptoms (131).

In the experience of Thomas, sensorineural hearing loss, the most common sequela of bacterial meningitis, was observed in 8.5% of the surviving children (132); hearing loss was bilateral and severe in 5.6%. Children who survive bacterial meningitis also have learning disabilities, motor problems, speech delay, hyperactivity, blindness, obstructive hydrocephalus, and recurrent seizures. Grimwood and colleagues observed that approximately one in four school-aged meningitis survivors had serious and disabling sequelae, a functionally important behavior disorder, or neuropsychological or auditory dysfunction that adversely affected academic performance (133). Children who have meningitis in the first year of life and survive are at greatest risk for neurodevelopmental sequelae (134).

Hearing loss develops during the first 48 hours of the illness (135) and results from infectious and immune-mediated injury to the cochlea and, occasionally, the semicircular canals. Less often, deafness is caused by an arachnoiditis of the eighth nerve or damage to the auditory projection areas. Recovery of hearing can begin during the first 2 weeks, but hearing can continue to improve for as long as 6 months. However, because hearing loss can be permanent, audiometry is required in all infants, children, and adolescents who recover from bacterial meningitis (136,137).

The 20-year risk for subsequent unprovoked seizures is 13% for patients with early seizures and 2.4% for those without early seizures. When seizures develop, their incidence is highest during the first 5 years after meningitis, but the risk remains elevated during the subsequent 15 years (138). Patients who develop intractable seizures after meningitis incurred before 4 years of age have a high incidence of neocortical seizure foci or mesial temporal sclerosis. The latter group of patients can respond to surgical intervention should seizures remain unresponsive to anticonvulsant therapy (139).

In a meta-analysis of reports of meningitis in children 2 months to 19 years of age published between 1955 and 1993, Baraff and colleagues found that children from developed countries had a lower mortality (4.8% vs. 8.1%) and a lower likelihood of sequelae (17.5% vs. 26.1%) than those from underdeveloped countries (140). Mortality was highest for meningitis caused by S. pneumoniae (15.3%) and lowest for that caused by N. meningitis (7.5%) and H. influenzae (3.8%) (140).

N. meningitidis causes three distinct clinical entities: meningitis, as discussed previously; septicemia, which can precede invasion of the CNS or be an isolated but fulminant form with petechiae and purpura (Waterhouse-Friderichsen syndrome); and chronic meningococcemia, in which an equilibrium between bacteria and host has become established (141). Genetic factors determine, in part, the susceptibility to meningococcal disease. Families with low TNF production have a 10-fold increased risk for fatal outcome, whereas high IL-10 production, a potent inhibitor of TNF (142), increases the risk 20-fold. Children with complement deficiency are also at risk (143), suggesting that screening for complement disorders should be considered in children or adolescents with meningococcal infections.

The meningococcus produces petechial, maculopapular, or morbilliform skin lesions in approximately 75% of patients. Petechiae also are occasionally seen in patients with H. influenzae, pneumococcal, or streptococcal meningitis. Septicemia with N. meningitidis can lead to tissue sensitization and purpura fulminans as a consequence of disseminated intravascular coagulation. Purpura fulminans also has been observed during infections
with other Neisseria species, including N. catarrhalis (144), N. subflava (145), and N. gonorrhoeae (146).

Meningococcal septicemia can cause a rapidly evolving fulminant illness with high rates of morbidity and mortality. The pathogenesis of this disorder reflects bacterial embolization and endotoxin-induced shock (147,148,149). Pulmonary microvascular thromboses, composed of platelets and leukocytes, can lead to severe cor pulmonale. Meningococcal endotoxin activates the cascades of procoagulation, anticoagulation, and fibrinolysis as well as the cytokine network and the complement system. Meningococcal endotoxin also produces disseminated intravascular coagulation with rapid consumption of fibrinogen and formation of fibrin thrombi in adrenal glands and renal glomeruli. The fibrin thrombi cause hemorrhagic infarction of the adrenal glands and renal cortical necrosis. Bilateral adrenal hemorrhages occur in two-thirds of fatal cases.

Chronic meningococcemia produces intermittent chills or fever, evanescent rash, joint pain or swelling, or joint effusions. Symptoms can regress without specific therapy or recur over several days or weeks. The rash can assume the form of petechiae, erythema nodosum, papulonecrotic tuberculids, macules, or maculopapules. Recurrent neisserial infections of the nervous system are rare, but they occur with increased frequency in patients with deficiencies of immunoglobulin G (IgG) subclass (150) or complement (151). Complications of meningococcal bacteremia include pericarditis, arthritis, hypopyon, and panophthalmitis (152). Autopsy of 200 fatal cases of meningococcal infection revealed acute interstitial myocarditis with focal necrosis and hemorrhage in 78% (153). Deafness after meningococcal meningitis is more frequent with infections by the uncommon serogroups (W135, X, Y, 29E) than with meningitis caused by serogroup B (154).

Chemoprophylaxis of family members and other intimate contacts is recommended; current information can be found in the Red Book (121,155). Rifampin is the drug of choice in children, whereas rifampin, ceftriaxone, or ciprofloxacine can be used in adults. A quadrivalent vaccine (groups A, C, Y, and W135) is available in the United States for children 2 years of age and older (121). Vaccination of college students who live in dormatories is recommended, given the potential for epidemic meningococcal disease on college campuses (121).

Predisposing factors for childhood meningitis with S. pneumoniae, the most common cause of meningitis after the neonatal period in populations with compulsory immunization for H. influenzae, include an upper respiratory infection, acute or chronic otitis media, purulent conjunctivitis, and CSF rhinorrhea secondary to developmental abnormalities or trauma (59). Splenectomy, congenital or acquired immunodeficiencies, and disorders that alter splenic function (e.g., sickle cell disease) increase substantially the risk of pneumococcal disease, including meningitis (169,170,171).

The pathogenesis of pneumococcal meningitis differs because the gram-positive organism does not contain endotoxin. Pneumococci adhere to cerebral capillaries using a surface protein, CbpA, that recognizes carbohydrates.
Once attached, invasion involves bacterial recognition of the receptor for platelet-activating factor (PAF) (172). Once in the CSF, a variety of pneumococcal components, including the cell wall, lipoteichoic acid, and several cytotoxins, incite the inflammatory response (173). The cytotoxin pneumolysin contributes to loss of cochlear cells in meningitic hearing loss but does not contribute to cell damage or inflammation in the brain itself (174).

Approximately one-third of children who survive pneumococcal meningitis have sequelae, 19% with hearing loss and 25% with neurologic complications (175). Overall mortality in the series reported by Kornelisse and coworkers was 17%. Coma at admission, respiratory distress, shock, CSF protein level of 250 mg/dL or greater, peripheral white count of less than 5,000 cells/μL, and a serum sodium of less than 135 mEq/L are associated with increased risks of mortality. Of the surviving children described by Arditi and colleagues, 25% had neurologic sequelae, and 32% had unilateral or bilateral hearing loss. In this study the incidence of hearing loss was higher in those who had received dexamethasone (176), illustrating further the controversy associated with dexamethasone therapy in childhood bacterial meningitis.

Staphylococcus aureus accounts for 0.8% to 8.8% of bacterial meningitis cases in patients of all ages. Approximately 20% of cases occurred in neonates, 10% in children, and 70% in adults (177). As many as 90% of cases occur in association with predisposing factors, such as recent neurosurgical procedures or head trauma. S. aureus causes 12% to 36% of CSF shunt infections, and S. epidermidis causes the majority of the remainder. Meningitis can develop from staphylococcal abscesses within the brain parenchyma or from spinal epidural abscesses. More distant staphylococcal infections, such as oral or abdominal abscesses, sinusitis, osteomyelitis, pneumonia, cellulitis, infected shunts or intravascular grafts, decubitus ulcers, and even abdominal abscesses, have been implicated in occasional cases of S. aureus meningitis. S. aureus is the most likely cause of meningitis in persons with infective endocarditis. Other predisposing factors include immunodeficiency disorders, diabetes mellitus, renal failure, and malignancy (178,179,180). Coagulase-negative staphylococci, especially slime-producing variants (181), can cause indolent infections of ventriculoatrial and ventriculoperitoneal shunts (182,183) (see Chapter 5 for a further discussion of shunt-related infections).

Neonatal meningitis has an overall incidence of 0.2 to 0.32 cases per 1,000 live births (184). Meningitis occurs more often in male infants (68% to 76%) (185), except for group B streptococcal meningitis, which has a female preponderance (186). Other potential neonatal pathogens include E. coli, Listeria monocytogenes, Citrobacter species, Klebsiella-Enterobacter species, Pasteurella multocida (187), Flavobacterium, Pseudomonas cepacia (188), Salmonella species (189), N. meningitidis (190), and, rarely, H. influenzae. The median age of infants with neonatal meningitis is 10 days (191). Predisposing factors include maternal infections chorioamnionitis, premature rupture of membranes, neonatal urinary anomalies, neural tube defects, and immune dysfunction common among newborns (192,193,194). Infections of the respiratory tract and skin can also predispose to meningitis; bacterial meningitis complicates 20% to 30% of infants with septicemia.

CSF findings can be confusing in neonatal meningitis, given the broad ranges of normal values for cell count and protein content (194,195,196,197,198,199). White blood counts of less than 32 cells/μL occur in 29% of group B streptococcal and 4% of gram-negative neonatal meningitis; protein concentrations of less than 170 mg/dL occur in 47% and 23%, and CSF-to-blood glucose ratios of grerater than 0.44 occur in 45% and 15%, respectively (198). CSF values for healthy term and preterm infants are presented in the Introduction chapter.

Since the late 1970s group B Streptococcus (S. agalactiae) has been an extremely important pathogen in the neonate (200,201,202). The two clinically and epidemiologically distinct forms of group B streptococcal disease are now recognized as a paradigm for several bacterial pathogens that infect the neonate. In the first, termed “early-onset disease,” symptoms begin within 10 days of birth. The infants are often seriously ill with respiratory distress, shock, or DIC at the time of diagnosis, and the mortality is quite high (58%). In this form of infection, bacteria can be isolated often from CSF, blood, and other fluids or tissues. In the second clinical pattern, termed “late-onset disease,” symptoms begin after 10 days of age. The infants are less severely ill, and death or permanent neurologic sequelae are less frequent (19%). Organisms are usually isolated from the CSF or blood only. However, infants with late-onset disease with several bacteria, including group B Streptococcus, can have osteomyelitis, which can cause pseudoparalysis of the upper or lower extremities.

The diagnosis of group B neonatal meningitis can be confirmed by lumbar puncture. Blood cultures are positive in 50% to 90% of infants with early-onset meningitis (203,204), and cultures of the nasopharynx may yield the causative organism in as many as 40% of cases. Antigen detection systems for analysis of CSF or urine have variable sensitivity and specificity and are generally not recommended. The prognosis of neonatal meningitis remains discouraging despite 21 to 28 days of therapy with the available antimicrobials (Table 7.7). In the series
of Hristeva and coworkers the mortality was 26% with neurologic sequelae in 27% of survivors (204). Most experts recommend repeat CSF analysis after 48 hours of therapy to ensure eradication of bacteria from the CSF of infants with neonatal meningitis (121).

Subdural abscesses or subdural empyema result from sepsis, from a direct extension of an infection such as an osteomyelitis, or from bacterial contamination of a subdural effusion in meningitis or a post-traumatic subdural hematoma. Approximately two-thirds occur subsequent to a prior craniotomy. Otitis media and pneumococcal meningitis are other sources of organisms for subdural abscesses in children, whereas sinusitis is a more common antecedent in adults. Approximately 9% of children with brain abscesses develop subdural empyemas. These lesions generally occur over the convexity of the brain, but 12% are found interhemispherically.

Signs and symptoms are those of a space-occupying lesion in association with evidence of infection. Increased intracranial pressure and focal neurologic findings, notably focal seizures, are common (304,305).

The presence of subdural abscesses is demonstrated by neuroimaging (18). Sinusitis-induced subdural empyemas may not become apparent on CT scan until 1 or 2 weeks after symptoms develop, hence they may be missed on initial CT scans (306). Enhancement of membranes with gadolinium on MRI can occur when no enhancement is seen on CT (307). Diffusion MR imaging can be valuable in distinguishing subdural empyema from effusion and in the follow-up of subdural collections (308). Early diagnosis and prompt chemotherapy and surgical drainage are imperative (269). Craniotomy is the surgical procedure of choice, but more limited procedures (burr holes and craniectomies) should be performed in patients in septic shock, for patients with parafalcine empyemas, or for children with subdural empyemas secondary to meningitis (309,310). Subdural infections are caused by the same spectrum and distribution of bacteria as those causing brain abscesses (269).

Epidural abscesses can develop from contiguous infection of structures that surround the brain and spinal cord. They can arise from local infection or can be secondary to congenital anomalies such as dermal sinuses (311,312). Bacteremia and trauma also have been implicated. Approximately one-third of cases involve staphylococcal organisms (313). Epidural abscesses complicating sinus infections most commonly present with purulent nasal or aural discharge, fever, headache, scalp swelling, signs or symptoms of raised intracranial pressure, and, rarely, focal neurologic findings or seizures (314,315). Epidural abscesses can have a more indolent course than subdural empyemas (316).

Infection of the spinal epidural space, though extremely rare in childhood, produces a devastating neurologic picture. The main determinant of outcome for patients with spinal epidural abscess is neurologic status at the time of diagnosis (317). The infection is limited to the dorsal surface of the cord except in the cord’s lower sacral portion, where the abscess completely surrounds the cord. The anatomy of the epidural space limits extension to vertical spread and produces extradural compression. Epidural infections can result from the use of epidural catheters for prolonged postoperative analgesia in children (318).

The clinical course can be acute and rapidly progressive or chronic. The acute form, more common in children, is usually the result of a metastatic infection, whereas chronic lesions are commonly caused by a direct extension of a spinal osteomyelitis. The classic case of spinal epidural abscess follows a fairly typical pattern of development. Within 1 to 2 weeks of an infection, backache develops; this backache is enhanced by jarring or straining and is accompanied by local spinal tenderness. Within a few days, tenderness progresses to radicular pain followed by symptoms of cord involvement, including weakness of voluntary movements and impaired sphincter control. Paraplegia can be complete within a few hours or days.

In many patients, the history and neurologic signs are impossible to differentiate from those of acute transverse myelitis. Intradural extramedullary tumors can produce a similar clinical picture.

A history compatible with infection, in association with focal pain in the region of the spine, especially when accompanied by neurologic symptoms of spinal cord or root involvement, should suggest the diagnosis, which can be confirmed by neuroimaging studies (18). Prompt blood cultures can reveal the causative organism. Lumbar puncture should not be performed because of the risk of spreading the infection to the subdural or subarachnoid space. Aspiration can be performed with a large-gauge needle, but only under radiographic guidance. If the CSF is examined, it shows pleocytosis and an elevated protein level.

An epidural abscess that has produced neurologic deficit is treated by laminectomy with decompression and drainage. In view of the rapid progression of potentially irreversible symptoms, this condition is a surgical emergency. Antibiotic therapy is secondary. If tuberculosis of the spine is suspected, antituberculous therapy should be
instituted pending identification of the causative organisms. Sinus-related intracranial epidural abscesses in children may be managed without neurosurgical procedures in the setting of adequate sinus drainage, appropriate antibiotic therapy, and minimal extradural mass effect from the abscess (308).

Approximately 27% of intramedullary abscesses occur before age 10 years, and 40% occur during the first two decades of life (319). The abscess develops by spread from infected contiguous dermal sinuses or, less often, from suppurative foci at other sites. In some instances, particularly since the advent of antibiotics, the disease can be insidious, and in approximately one-fourth of cases, the infection has been present for at least 4 months before diagnosis. The thoracic cord is involved in most instances. Symptoms generally simulate an intramedullary tumor.

Self-limited intervertebral disc space infections can occur in children. These infections can be caused by S. aureus or diphtheroids, but often no organism can be isolated.
Infections of the disc space are characterized by back pain with or without fever, a variable incidence of hip pain or abdominal pain, radiographic evidence of narrowing of the intervertebral space, enhanced radionuclide uptake, and an elevated sedimentation rate (320). Cross-sectional MRI is probably the most useful diagnostic procedure (321) (Fig. 7.5). Treatment by immobilization relieves pain. Antibiotics have been used, but are not always needed. Scoliosis and complete interbody ankylosis can occur (322,323). In a follow-up of 35 children on average 17 years after discitis, flexion of the low back was normal in 90% but extension was markedly restricted in 86%, 80% had narrowing of the vertebral canal, 74% had a block vertebrae, and 43% still complained of backache (324). Nonspecific discitis without bacterial cause can occur in young children. It is characterized by restriction of spinal mobility and an elevated sedimentation rate. Biopsy usually reveals chronic or subacute inflammation, although approximately one-third of the biopsies yield normal tissue. The disease is usually self-limiting in most cases with only minor residual radiographic changes (325).

The management of infected cerebrospinal shunts is covered in Chapter 5.

In the United States and many developed countries, 0.4% to 2.5% of newborns shed CMV at birth (331). The incidence of acquired CMV infection among children and adults, including women of childbearing age, averages 1% to 2% per year. By adulthood, 40% to 100% of the population has been infected with CMV. Infants acquire CMV postnatally from their breast-feeding mothers, and young children become infected through contact with CMV-excreting playmates (335). Adults acquire CMV via blood transfusion, sexual contact, organ transplantation, or contact with young children (336). Adults with multiple sexual partners have increased rates of CMV acquisition (332).

Approximately 40% of women who acquire primary CMV infection during pregnancy transmit CMV to the fetuses, and 5% to 10% of the infected infants have CMV disease (337). Although seronegative women have the greatest risk of transmitting CMV to their unborn infants, fetal infections can occur in CMV-seropositive women who are reinfected with new CMV strains (338). CMV infection begins with replication of the virus in lymphoid tissues adjacent to the genital tract or oropharynx. Viremia then develops and leads to infection of systemic organs, including the placenta of pregnant women. Although most fetal tissues support CMV replication, major sites of infection are the liver, spleen, brain, and retina. The virus enters the brain via the choroid plexus and spreads centrifugally from the subependymal region. Pathologic changes within the brain include hemorrhage, cystic degeneration, dystrophic calcification, and perivascular mononuclear inflammation (332).

The majority of CMV-infected neonates have no signs of CMV infection at birth. Approximately 5% to 10% of the infected newborns have systemic signs (currently designated “congenital CMV disease”) (Table 7.12) consisting of jaundice, hepatomegaly, splenomegaly, petechial or purpuric rash, intrauterine growth retardation, or respiratory distress (339,340,341,342,343). Neurologic features include microcephaly, chorioretinitis, seizures, sensorineural hearing loss, and alterations in muscle tone.

The diagnosis of intrauterine infection is established by detecting CMV in clinical samples during the first 3 weeks of life (331,332). Because congenitally infected infants shed enormous quantities of CMV in their urine, culturing urine or saliva using the shell vial assay is the gold standard for the diagnosis of intrauterine CMV infection. Performing PCR or assaying CMV-specific IgG or IgM in the infant’s serum has much lower sensitivity. CMV antigenemia assays have no role in the diagnosis of intrauterine CMV infections.

Approximately 50% of the infants with congenital CMV disease have periventricular calcifications (Fig. 7.6), and infants with calcifications have higher rates of permanent neurodevelopmental disabilities (344,345). Neuroimaging studies may also show periventricular leukomalacia, polymicrogyria, pachygyria, schizencephaly, or lissencephaly. Because CT detects small calcifications more effectively than MRI, CT is the preferable imaging study in the perinatal period. MRI provides more accurate
information regarding cortical dysplasia, polymicrogyria, and other disorders of neuronal migration associated with congenital CMV infection.

There are no vaccines for preventing CMV infections. Pregnant women can reduce their risk of infection by avoiding direct contact with the urine and saliva of young, toddler-aged children (346). Should inadvertent skin contact occur, hand washing with soap and water eliminates the virus from the skin. Postnatal therapy with ganciclovir can reduce the severity of sensorineural hearing loss and can treat CMV-induced pneumonia in congenitally infected infants (341). In the treatment trial sponsored by the National Institute of Allergy and Infectious Diseases–Children’s Antiviral Study Group (NIH-CASG), infants received 6 mg/kg per dose intravenously every 12 hours for 6 weeks (Table 7.11) (341,347).

The majority of infants with silent CMV infections escape neurodevelopmental sequelae, but 7% to 10% of these will later exhibit sensorineural hearing loss. Because of the high incidence of intrauterine CMV infection, this disorder represents the most common cause of nongenetic deafness in many regions (348). By contrast, infants with congenital CMV disease have high rates (greater than 90%) of neurodevelopmental sequelae, consisting of cerebral palsy, seizures, sensorineural hearing loss, mental retardation, behavioral disorders, and vision loss (331,332,349). Approximately 9,000 infants annually in the United States have audiologic or neurologic sequelae of intrauterine CMV infections (331).

Humans acquire T. gondii by ingesting undercooked meat that contains bradyzoites, the encysted form found in tissues, or by ingesting fruits, vegetables, and other foods contaminated by oocysts, the highly infectious form of the organism (350). Infected cats, major contributors to human infection, excrete vast quantities of oocysts (351). Approximately 0.1% to 2% of the adult population acquires T. gondii annually. Rates of congenital infection vary from 1 per 12,000 live births to as high as 1 per 1,000 (330,347,350,351,352).

Fetal infections complicate approximately 40% of the T. gondii infections in pregnant women (330,350). Healthy women infected with T. gondii rarely have recognizable symptoms, although an acute mononucleosis-like illness develops occasionally. Infections during the first trimester, when transmission to the fetus is less likely, can produce spontaneous abortion, whereas infections during the third trimester, when transmission frequently occurs, usually cause subclinical fetal infection. Infections during the second trimester often produce severe fetal disease. Congenital toxoplasmosis produces a diffuse, granulomatous meningoencephalitis that can lead to aqueductal obstruction, fetal hydrocephalus, and dystrophic parenchymal calcification.

Approximately 85% of the infants with intrauterine T. gondii infections lack symptoms at birth, but many of these infants later have ophthalmologic or neurologic sequelae (330,342,350,353). Symptomatic neonates exhibit jaundice, splenomegaly, hepatomegaly, fever, anemia, chorioretinitis, hydrocephalus or microcephaly, and petechiae, secondary to thrombocytopenia (Table 7.12; Fig. 7.8) (330). Intrauterine coinfections with T. gondii and HIV or CMV can occur.

The diagnosis of intrauterine infection with T. gondii can be made postnatally by detecting anti-Toxoplasma antibodies of several classes—IgM, IgG, IgA, and IgE—in the newborn infant’s serum (354,355). Serologic studies of infants
and their mothers should be sent to an experienced laboratory, such as the Palo Alto Laboratories (phone number 650-853-4828), that performs a battery of serologic studies for T. gondii. As many as 25% of infected infants lack anti-Toxoplasma IgM. Inoculation of fresh placental tissues into laboratory mice can be used to confirm the diagnosis of congenital toxoplasmosis, and PCR can detect T. gondii in clinical specimens (356). Imaging studies in infants with congenital toxoplasmosis may show intracranial calcifications and ventriculomegaly, reflecting hydrocephalus or passive ventricular enlargement (330).

Pregnant women can reduce their risk of exposure to T. gondii by avoiding cat excreta and modifying their dietary habits (357). Treating infected mothers with spiramycin or pyrimethamine-sulfadiazine has been advocated to reduce the risk of congenital toxoplasmosis, although the effectiveness of these strategies is unproven (358,359). Therapeutic abortion has been considered when the diagnosis of intrauterine toxoplasmosis is confirmed and CNS damage has been detected by fetal ultrasonography.

The neurologic prognosis of infants with congenital toxoplasmosis can be improved by early shunting of obstructive hydrocephalus and prolonged antitoxoplasma therapy postnatally (330,343,360). Infants should receive sulfadiazine, 100 mg/kg per day, and pyrimethamine, 1 mg/kg per day, for 6 months followed by the same dose three times per week for an additional 6 months. Infants require folinic acid, 5 to 10 mg three times weekly. Among infants who do not receive antitoxoplasma therapy, 80% have epilepsy, 70% have cerebral palsy, 60% have visual impairment, and nearly 60% have intelligence quotients less than 70 (330). Treated infants have considerably lower rates of neurodevelopmental complications (343,360).

Intrauterine HSV disease, a rare disorder, nearly always results from HSV-2 infection. The incidence of HSV-2 infection is highest among young women, approximately 2% of whom acquire the virus each year (361); approximately 30% of 30-year-old women have serologic evidence of prior HSV-2 infection. The risk of HSV-2 infection among U.S. women is associated with several sociodemographic factors, including African-American race, lower income, greater number of lifetime sexual partners, earlier age of sexual intercourse, and drug use (362).

As many as 2% of pregnant women become infected with HSV during pregnancy, but the majority of these infections do not produce fetal or neonatal disease (363). Primary maternal infection usually occurs without recognizable symptoms. The risk of intrauterine transmission of HSV-2 to the fetus appears to be very low. Fewer than 50 cases of intrauterine HSV infection have been described. HSV may reach the fetus during maternal viremia or through an ascending intrauterine infection. The virus replicates in several tissues, including the skin, liver, lung, eye, and brain, producing tissue necrosis, cystic degeneration, and dystrophic calcifications (364).

Infants with congenital HSV infections have skin vesicles or scarring, chorioretinitis, microcephaly, and microophthalmia (365,366,367). Intrauterine growth retardation can also be present. Of 13 infants identified by the NIH-CASG, 12 had skin lesions, 8 had chorioretinitis, 7 had microcephaly, and 5 had hydranencephaly, evidence of severe brain necrosis (366). Less severe congenital HSV-2 infections likely occur.

The diagnosis of congenital HSV-2 infection can be made by detecting the virus in skin lesions or body fluids, using cell culture or PCR (368). Samples for virus isolation should include skin vesicle fluid, CSF, and swabs of the conjunctiva, rectum, and oropharynx. Ophthalmologic examination may reveal chorioretinitis and microphthalmia. Infants with intrauterine HSV infections frequently have dense calcifications of the basal ganglia and thalami, diffuse, hemispheric cystic lesions, and a lissencephalic-like cerebral cortex (369).

Preventing neonatal HSV-2 infection, including intrauterine infection, remains problematic, and most women who give birth to infants with congenital HSV infection have no history of genital HSV infection (369). Although infants with neonatal HSV infections require prolonged high-dose therapy with acyclovir (60 mg/kg per day for 21 days) (369), acyclovir has little or no benefit for the severe CNS damage that accompanies intrauterine HSV-2 infection. Infants with congenital HSV-2 infections often die in infancy; survivors usually have cerebral palsy, epilepsy, and mental retardation (366).

Chickenpox affects approximately 0.05% of pregnant women (370). Women who acquire VZV before week 20 of gestation have a 2% risk of delivering an infant with the fetal varicella syndrome (371,372). By contrast, fetal varicella syndrome is highly unlikely in women who have chickenpox during the last half of pregnancy. Maternal VZV reactivation (zoster) poses little or no risk to the developing fetus.

VZV displays tropism for the brain, retina, skin, and long tracts or neurons of the spinal cord. Lytic infection of neurons depletes neuronal populations, leading to the clinical manifestations described in the following paragraph. Pathologic changes include tissue necrosis, mononuclear inflammation, and cystic degeneration. CNS necrosis can manifest as severe cystic encephalomalacia or hydranencephaly (364).

The clinical manifestations of the congenital varicella syndrome consist of intrauterine growth retardation, limb hypoplasia, chorioretinitis, cataracts, microphthalmia, cutaneous scaring (cicatrix), and neurologic abnormalities (329,364,373,374). The latter can include microcephaly, hydrocephalus/hydranencephaly, seizures, Horner syndrome, and cranial neuropathies.

Infection can be established by detecting the virus in fetal tissues using culture or PCR and by detecting VZV-specific IgM in fetal blood samples obtained by cordocentesis (376,376). At birth, infants with the fetal varicella virus syndrome no longer shed VZV, and VZV-specific IgM can be undetectable. Imaging studies may show intracranial calcifications, cortical dysplasia, or hydranencephaly (364,377).

Although the efficacy of varicella-zoster immune globulin (VZIG) in preventing the fetal varicella syndrome is unproven, VZIG should be considered when susceptible pregnant women have been exposed to persons with chickenpox (378). VZIG should be given within 96 hours of the exposure. Postnatal therapy with acyclovir or other antiviral medications provides no benefit for infants with the congenital varicella syndrome. A substantial number of infants with the fetal varicella syndrome will die in infancy, and survivors usually have permanent sequelae affecting vision or neurologic development (329,364).

Lymphocytic choriomeningitis (LCM) virus, an arenavirus that naturally infects the feral house mouse, Mus musculus, can also infect humans (379). Seroprevalence rates of 0.3% to 5.0% have been observed among persons living in the United States, Canada, and Argentina (380,381,382,383). Intrauterine LCM virus infection is presumed to be a rare condition, but no surveillance studies have been performed to establish the incidence of the disorder.

Human infection results from inhalation of infected aerosols, direct contact with LCM virus-shedding animals, or ingestion of material contaminated by infected excreta (384). Infected adults can experience an influenza-like illness with fever, malaise, and myalgia. Fetal infections are associated with periventricular calcifications, cortical dysplasia, and diffuse lymphocytic meningitis that can involve the ependyma of the aqueduct of Sylvius and cause hydrocephalus (385).

The clinical features of congenital LCM virus infection mimic those of intrauterine CMV disease and congenital toxoplasmosis (379,385,386). Among 26 reported cases reviewed by Wright and colleagues in 1997, 88% had chorioretinopathy, 43% had macrocephaly at birth, and 13% were microcephalic (385). Occasional infants had vesicular or bullous skin lesions. Virtually all infants were born at term and had normal birth weights. Approximately 50% of mothers who gave birth to the infants reviewed in this study recalled influenza-like illness during pregnancy, and one-fourth reported contact with rodents, usually mice, during their pregnancy.

The diagnosis of congenital LCM virus infection is established by serologic studies of the mother and infant (379,385). Antibodies against LCM virus can be detected in the infant’s serum or CSF. Because of the low seroprevalence of LCM virus infection in the general population, detecting LCM virus-specific antibodies, particularly LCM virus-specific IgM, strongly supports the diagnosis. The virus can be detected by PCR, but this method does not yet
have diagnostic utility in human infections. Imaging studies in infants with congenital LCM virus infections may show hydrocephalus or cortical dysplasia (385).

No vaccine is available for preventing LCM virus infections; pregnant women should avoid mice and pet hamsters during their pregnancy. Effective postnatal antiviral therapy of LCM virus infections has not been described. Approximately 35% of the reported infants died from complications of congenital LCM virus infection (379,385). Surviving infants commonly had cerebral palsy, epilepsy, vision loss, and mental retardation. LCM virus-infected infants with hydrocephalus may require shunt placement.

In the pre-vaccine era, epidemics of rubella caused thousands of cases of the congenital rubella syndrome (CRS), but after licensure of the rubella vaccine in 1969 and aggressive immunization programs in the 1980s, the incidence of the CRS in the United States and other nations declined dramatically (386). In the United States, only one to three cases of CRS were reported to the Centers for Disease Control and Prevention annually by the late 1980s, an incidence of less than 0.1 case of CRS per 100,000 live births (387). In recent years, CRS in the United States has virtually disappeared except among the offspring of immigrants from regions without compulsory immunization (388).

Maternal rubella during the initial 8 weeks produces cataracts and congenital heart lesions, whereas hearing loss correlates with infection during the first 16 weeks (328). Infections after the week 16 of gestation usually leave no sequelae other than a risk of sensorineural hearing loss. Pathologic changes within the CNS consist of diffuse meningoencephalitis, cystic degeneration, and dystrophic calcification. Cardiac lesions include peripheral pulmonic stenosis, patent ductus arteriosus, and atrial or ventricular septal defects (389).

Infants with CRS can have cataracts, retinopathy, microphthalmia, microcephaly or sensorineural hearing loss, meningoencephalitis, osteopathy, pneumonitis, hepatitis, hepatosplenomegaly, thrombocytopenia, and jaundice (Table 7.12) (389,390,391). The propensity of the rubella virus to infect the heart causes myocarditis, patent ductus arteriosus, valvular stenosis, or septal defects at the atrial or ventricular level (389).

CRS is diagnosed by isolating virus from nasal secretions, urine, or CSF or detecting rubella virus-specific IgM in the infant’s serum (370,392). Postnatal persistence of rubella-specific IgG supports the diagnosis of CRS. Imaging studies can show periventricular calcifications, periventricular leukomalacia, or subependymal cysts.

CRS cannot be treated effectively by postnatal antiviral therapy; infection must be prevented by vaccination. Maternal antibody prior to conception or at the time of maternal rubella exposure indicates that the fetus is not at risk. Termination of pregnancy is considered in confirmed primary rubella infections early in gestation (370). When termination is not an option, immune globulin can be considered, although the efficacy of this approach is unproven (370). Progressive sensorineural hearing loss can develop in children who survive CRS, and children with CRS also have an increased risk of growth failure or diabetes mellitus in the second or third decade of life (393,394,395). Neurologic sequelae include microcephaly, language delay, autistic features, and developmental or mental retardation.

The overall incidence of congenital syphilis is low in the United States, but Treponema pallidum remains endemic in large urban areas and the rural South (396,397,398,399). In virtually all other developed countries syphilis rarely occurs. A transient resurgence of congenital syphilis in the United States in the late 1980s and early 1990s was attributed to maternal use of illicit drugs, especially cocaine (398).

Untreated early maternal infection causes perinatal death, stillbirth, or miscarriage in approximately 40% of pregnancies (400). Although congenital syphilis can occur during all stages of maternal infection, fetal infection is most likely during secondary-stage maternal infections, when rates of transmission range from 60% to 100%. Maternal–fetal transmission complicates approximately 30% of latent maternal infections. Pathologic features in infants with congenital syphilis include periostitis, osteochondritis, leptomeningitis, endarteritis, periarteritis, and mixed
inflammatory infiltration of multiple organs or tissues, including the liver, lungs, skin, eyes, inner ear, and central nervous system (401).

Early signs of congenital syphilis, present at birth or evident during the first 2 years of life (399,400,401), consist of intrauterine growth retardation, rash, hepatosplenomegaly, jaundice, lymphadenopathy, pseudoparalysis, and bony abnormalities. Hemolytic anemia, thrombocytopenia, leukocytosis, or leukopenia can be present, and long-bone radiographs in the perinatal period may show osteochondritis. The latter can mimic nonaccidental trauma. Late signs of congenital syphilis, features evident after 2 years of age, include sensorineural deafness, dental abnormalities, saddle nose, saber shins, hydrocephalus, and developmental delay (400,401).

Infants with suspected congenital syphilis require (a) quantitative treponemal and nontreponemal assays of serum, (b) routine studies and nontreponemal and treponemal assays of CSF, and (c) long-bone radiographs. Definitive diagnosis is made by demonstrating spirochetes in exudates or tissues using dark-field or direct immunofluorescence microscopy (402). Serologic tests consist of nontreponemal tests, such as the Venereal Disease Research Laboratory (VDRL) slide test or rapid plasmin reagin (RPR), and treponemal tests, such as the fluorescent treponemal antibody absorption (FTA-ABS) test or the T. pallidum particle agglutination (TP-PA). Infants likely have congenital syphilis when spirochetes are present in tissues or when they have reactive CSF VDRL or FTA-ABS tests or serum quantitative treponemal tests four times higher than the mother (402).

Pregnant women with acquired syphilis require penicillin treatment, using one to three doses of penicillin G benzathine (2.4 million units intramuscularly), at 1-week intervals if more than one dose is given, irrespective of the timing of pregnancy (404). No effective alternatives exist for penicillin-allergic persons, so desensitization should be performed. Neonates with proven or highly suspected symptomatic congenital syphilis require aqueous crystalline penicillin G, 50,000 U/kg intravenously every 12 hours during the first week of life and every 8 hours thereafter for a total of 10 days (401). Alternatively, procaine penicillin G can be given intramuscularly at a dose of 50,000 U/kg once a day for 10 days. If penicillin G cannot be given, treatment recommendations can be found at http://www.cdc.gov/nchstp/dstd/penicillinG.htm. Infectious disease experts should be consulted regarding current treatment strategies for infants whose mothers received inadequate treatment, infants with asymptomatic infections, or infants older than 4 weeks with possible syphilis and neurologic involvement.

The initial clinical picture can be protean, manifesting as a systemic infection without neurologic symptoms or findings. Fever, irritability, headaches, nausea, vomiting, poor appetite, and restlessness precede neurologic symptoms. In Finnish studies, the most characteristic neurologic symptoms of viral encephalitis during the acute phase were lowered consciousness manifested by disorientation, confusion, somnolence, or coma. These symptoms were recorded in 58% of patients. Ataxia was seen in 58%; an altered mental status, notable aggressiveness, and apathy were seen in 40%. Seizures, either generalized (32%), focal (5%), or both, were encountered less commonly.
Neurologic findings were generally nonspecific, and meningeal symptoms and signs were not always present (415,416). The incidence of CNS viral infections in association with neonatal seizures may be much higher than previously reported (417). The CSF examination was often frequently normal early in the disease (418). As a general rule, the initial CSF pleocytosis is characterized by a rapidly decreasing proportion of granulocytes. The transient elevation in CSF granulocyte colony-stimulating factor observed during the initial stages of aseptic meningitis is associated with this change (419). The development of PCR has greatly increased our ability to diagnose viral infections of the CNS, particularly for herpes and enteroviral infections (420). Young age, disorientation, and loss of consciousness are serious prognostic signs in encephalitis, especially if the encephalitis is caused by herpes simplex. In the study by Klein and coworkers, focal signs on neurologic examination and abnormal neuroimaging studies were the only two factors present at admission that predicted a poor short-term outcome (421). Unilateral hyperperfusion demonstrated by single photon emission CT (SPECT) also is associated with a poor prognosis in encephalitis (422).

This is a clinical syndrome characterized in children by fever, abrupt onset of headaches, vomiting, irritability, and physical findings of meningeal irritation such as Kernig and Brudzinski signs. Infants present with a mild syndrome without the physical findings found in older children. The spinal fluid reveals less than 1,000 white blood cells with a mononuclear predominance, although early in the course of the illness, a polymorphonuclear predominance may be observed. CSF glucose is normal or slightly decreased, and CSF protein is slightly elevated. The Gram stain is universally negative, as are bacterial, mycobacterial, and fungal cultures.

Alterations found within the CNS depend on the stage of the disease at the time of death. In the early days of the illness, neurons undergo a variety of nonspecific microscopic
changes that vary in severity and result directly from viral invasion. These changes are accompanied by an initial polymorphonuclear reaction, which later becomes mononuclear. As the illness progresses, motor neurons degenerate, become surrounded by inflammatory cells, and undergo neuronophagia. The distribution of lesions is characteristic of poliomyelitis. Lesions are usually mild and restricted to layers 3 and 5 in the precentral gyrus and adjacent cortex, thalamus, and globus pallidus (468). Neuronal necrosis can be caused by toxic levels of neurotransmitters such as quinolinic acid that occur in areas of the brain affected by the virus as well as from direct viral damage to neurons (469).

Cerebellar vermis and deep cerebellar nuclei are often severely involved, whereas the cerebellar hemispheres are usually free of lesions (470). In addition, marked involvement of motor and sensory cranial nuclei of the medulla occurs, especially the vestibular and ambiguous nuclei and throughout the reticular formation. The basis pontis and inferior olivary nuclei are usually spared.

In the spinal cord, lesions usually are restricted to the anterior horn cells, although some cases also show spotty involvement of the neurons in the intermediate, intermediolateral, and posterior gray columns (Fig. 7.9). Extension of lesions to the sensory spinal ganglia is the rule in more extensive cord involvement. The cervical and lumbar cords tend to be more affected than the thoracic region.

The clinical picture of poliomyelitis ranges from a nonspecific mild febrile illness to a severe and potentially fatal paralytic disease. An inapparent infection is estimated to occur in 90% to 95% of infected individuals, a minor nonparalytic illness in 4% to 8%, and paralytic poliomyelitis in 1% to 2% (Fig. 7.10). The incubation period ranges between 3 and 35 days, with an average of 17 days (471).

The minor illness coincides with the period of viremia and the appearance of virus in the stool. It lasts 24 to 48 hours and is manifested by nonspecific symptoms of headache, vomiting, sore throat, and gastrointestinal disturbances.

The major illness can follow in 2 to 5 days of recovery from the minor illness. When mild, it produces aseptic meningitis with fever, headache, vomiting, and meningeal irritation. The disease might not advance any further or it might progress to the paralytic stage.

The clinical course and picture of paralytic poliomyelitis varies with the age of the patient and the site of maximal involvement. The classic diphasic course is more common in children than in adults. It was noted in 37% of children aged 2 to 9 years but only in 11% of adolescents 15 years or older (472). In the remaining cases, the preparalytic stage is mild or inapparent. Infants show relatively little fever and lack meningeal signs despite extensive and often symmetric paralysis. Paralysis occurs in 90% of infants younger than 1 year of age who develop symptomatic infections with poliomyelitis virus (473).

The presenting symptom of paralytic poliomyelitis is pain, often severe and localized to the lower back. It usually is accompanied by hyperesthesia, drowsiness, or irritability. The initial indications of paralysis are localized muscular pain, fasciculation, twitching, and diminution or loss of the deep tendon reflexes. The paralysis appears during the first or second day of the major illness. Often it reaches its maximum within a few hours, and, less commonly, it can advance for 4 to 5 days. The fever that generally accompanies the paralysis falls by lysis.

Table 7.16 shows the distribution of paralysis, as encountered in an early epidemic (474). Curiously, when an infected child had received an injection before the onset of symptoms, the illness more likely involves the injected limb. A similar problem has been encountered when intramuscular injections are given within 30 days of immunization with oral poliovirus vaccine (475). These observations can be explained by the upregulation of the poliovirus receptor consequent to trauma. The poliovirus receptor is an integral membrane protein with structural characteristics of the immunoglobulin superfamily of proteins (476,477).

Spinal, bulbar, and encephalitic forms of poliomyelitis have been recognized. Spinal paralytic poliomyelitis is characterized by an asymmetric, scattered, flaccid paralysis that more frequently involves the lower extremities. On examination, the weakness is accompanied by muscle tenderness and spasm. Deep tendon reflexes in the affected area are usually absent. Autonomic involvement can be manifested by excessive sweating and vasomotor disturbances. Some 10% to 20% of patients have bladder involvement, notably sphincter spasm and overflow incontinence (478). Pyramidal tract and segmental sensory involvement are extremely rare.

The bulbar form of poliomyelitis generally evolves with explosive rapidity. Other areas of the neuraxis, most often the cervical cord, also are affected in 90% of cases.

The clinical picture of bulbar poliomyelitis reflects the site of involvement. Most commonly, the paralysis affects the facial, pharyngeal, and ocular muscles (see Table 7.16) (474,479). Involvement of the reticular formation can lead to respiratory and cardiovascular irregularities (480). Pulmonary edema is regarded as a manifestation of extensive damage to both the dorsal nuclei of the vagus and the medial reticular (vasomotor) nuclei of the medulla (481). When the tenth cranial nerve is involved, there is impairment of swallowing and faulty innervation of the larynx. This presents a serious threat to life by obstruction of the airway and is an indication for early elective tracheotomy. Fatal involvement of the respiratory center or the circulatory center may occur. Hypertension can develop secondary to medullary involvement or hypocapnia. Hypothalamic dysfunction is manifested by impaired temperature regulation and hypertension (482). Papilledema results from carbon dioxide retention caused by inadequate pulmonary ventilation. It also is associated with a high CSF protein, which interferes with normal CSF absorption.

In as many as one-third of cases, poliomyelitis is accompanied by symptoms and signs of encephalitis, including changes in consciousness, anxiety, irrationality, and restlessness or hyperactivity, muscular tremors, and twitching. These signs should first be considered as caused by hypoxia even in the absence of cyanosis. Only when these symptoms persist after adequate oxygenation can they be attributed to viral involvement of the cortex. Other complications of the acute stage of poliomyelitis include infections of the respiratory tract and atelectasis.

Paralytic ileus with gastric atony can result from viral damage to the vegetative centers or altered serum potassium concentrations.

The blood is usually normal, although leukopenia can be found in the early stages of the illness. The CSF is almost always abnormal. CSF pressure is normal but can become elevated with carbon dioxide retention. The cell count is
highest in the preparalytic stage, when polymorphonuclear cells predominate. The average count of 185 cells/μL decreases to 50 cells/μL at 1 week after the onset of paralysis. By then there is a predominantly monocytic response. The protein content is normal in the early stages of the illness. In the experience of Merritt and Fremont-Smith, it reached a maximum 25 days after the onset of paralysis (483). Thereafter, the protein content decreased gradually, remaining elevated long after the pleocytosis had disappeared. The sugar content is normal.

The virus is best isolated from the stool and oropharynx. Poliovirus has been isolated from the stool as early as 19 days before onset of illness and as late as 3 months after onset. The mean duration of virus excretion is approximately 5 weeks after onset of clinical illness. Poliovirus is rarely isolated from the CSF. The PCR technique performed on CSF (484), stool, blood, and throat specimens (485) is a sensitive, specific, and rapid technique for the diagnosis of enteroviral infections. It also has been used to differentiate wild poliovirus infections from vaccine strains and from other enteroviral infections (486). Serologic diagnosis is impractical but can be made by demonstrating an elevation in the specific complement fixation or neutralizing antibody titers. The etiologic diagnosis of inapparent, abortive, or nonparalytic poliomyelitis can be made only by laboratory studies.

Currently, poliomyelitis occurs rarely, and no confirmed case of wild-type polio virus infection has been reported in the United States since 1991 (487). Since then, all cases encountered in the United States have been associated with vaccination (488,489). All patients who develop poliomyelitis soon after oral vaccine administration should be evaluated for humoral and cellular immunosuppression (490). In the survey of Nkowane and coworkers, 33% of cases of poliomyelitis encountered between 1973 and 1984 were seen in recipients of OPV, 48% in contacts of such recipients, and 13% in immunodeficient patients (488). Virus reversion to the neurovirulent form involves point mutations at a single or several nucleotide positions (491).

On rare occasions, children who have been previously vaccinated with OPV present with an ascending paralysis simulating Guillain-Barré syndrome in association with a subsequent poliomyelitis type 1 infection (492,493).

In patients who are not immunodeficient and who have not been exposed to the vaccine, the diagnosis of poliomyelitis has become difficult. A number of other enteroviruses, notably coxsackieviruses and echoviruses, can produce a flaccid paralysis. When these conditions are unassociated with an exanthem, their diagnosis rests on PCR, viral isolation, or serologic confirmation. An illness resembling acute poliomyelitis also has been observed after infection with Epstein-Barr virus (494) as well as with an agent of the Russian spring-summer louping ill group of viruses (495).

Poliomyelitis must be differentiated from infectious polyneuritis, which has as presenting symptom a symmetric paralysis, usually progresses for more than 3 days, and is unaccompanied by fever. When sensory deficits can be documented, they confirm the diagnosis of polyneuritis. The absence of pleocytosis in the presence of a progressive paralysis also argues for polyneuritis.

A poliomyelitis-like paralysis (Hopkins syndrome) can occur during recovery from an asthma-like respiratory tract disease (496) (see Chapter 17). In some instances this syndrome can result from enterovirus or herpesvirus type 1 infections (497). Other conditions that mimic poliomyelitis include epidemic motor polyradiculoneuritis, insect and snake bites, schistosomiasis of the spinal cord, ingestion of chemicals such as arsenic and organic phosphates, trichinosis, and tetanus (498,499,500).

Recovery from nonparalytic forms of poliomyelitis is complete. The degree of disability that results from paralytic poliomyelitis depends on the extent of involvement. Function generally improves as pain and spasm recede after the acute phase. Overall mortality for the paralytic disease is approximately 4%. Spontaneous recovery of muscle function begins within a few weeks. Some involved neurons recover, but muscles totally paralyzed 1 month after the onset of the illness become completely normal only 1.4% of the time (501). Muscles severely paralyzed at the end of the acute period regain functional strength in 50% of cases and become normal in 20%. Moderately paralyzed muscles recover in 90% of cases. One-half the affected muscles continue to improve after 1 year. Three-fourths of functional recoveries occur in the first year, slightly less than one-fourth during the second year, and 5% during the third year. In general, prognosis is best for the proximal muscles in the lower extremities; it is poorest for the opponens pollicis and abdominal muscles (502).

Children with severe paralytic disease have developed a progressive neurologic disorder marked by increased weakness, fatigability, and pain some 30 to 40 years after the initial infection. Several explanations for this postpolio syndrome have been proposed. Sharief and colleagues suggested that it results from a chronic progression of the infection because there is intrathecal production of detectable IgM oligoclonal bands specific for poliovirus in the CSF and elevated CSF levels of IL-2 (503). Mononuclear perivascular cuffs occur in postpolio patients dying as long as 38 years after poliomyelitis (504). Late decompensation also could result from the combination of an abnormal enlargement of the motor units, resulting from the loss of the anterior horn cells, and the increased end-plate complexity seen with aging (504,505). Another
factor that could cause postpolio syndrome is chronic muscle overuse because 40% of children with severe residual paralytic disease have elevated creatine kinase levels (505). Patients with residual leg weakness are twice as likely to report symptoms in those limbs as those with residual arm weakness (506). Sleep apnea can be a late complication of the postpolio syndrome (507). Relapses and second attacks of poliomyelitis are extremely rare. Other than a continued exercise program, there is no effective treatment for this condition (508).

Control of poliomyelitis has been achieved by the use of orally administered live attenuated virus vaccine. Because of the vaccine-associated paralytic polio, changes in the poliovirus vaccine schedule occurred in 1997. Details of the advised vaccination schedules are presented in the 1997 Report of the Committee on Infectious Diseases, American Academy of Pediatrics (509).

Oral attenuated poliomyelitis vaccine should not be given to individuals with altered immunocompetence. Inactivated poliomyelitis vaccine is recommended for adults 18 years or older because of the increased risk of vaccine paralysis in that age group (488,489) and for immunization of HIV-positive children (509). For a detailed discussion of the response to vaccination, the characteristics of immunity, and the complications of vaccination, the reader is referred to Salk and Salk (510).

During the acute phase of the illness, treatment is solely symptomatic.

Roseola, the most common exanthem of infancy, is characterized by the relative absence of prodromal symptoms, a rapid increase in body temperature, and conspicuously little listlessness or irritability. The temperature remains elevated for 3 to 5 days and subsides with the appearance of maculopapular rash. A bulging fontanel, the result of increased intracranial pressure, occurs during the second to fifth day of fever in about one-third of children (533). The condition occurs at a median age of 9 months when caused by human herpesvirus-6 (HHV-6), and at a median age of 26 months when caused by human herpesvirus-7 (HHV-7) (534). Other viral agents also are believed to be responsible for this condition (535).

CNS involvement can occur from 1 day before the onset of fever to day 2 of the illness (533). Neurologic complications include aseptic meningitis, acute disseminated encephalomyelitis (536,537), acute encephalitis (538), and acute cerebellitis.

The incidence of seizures varies considerably from one series of cases to the next (539). In the prospective study of Hall and coworkers, HHV-6 infection accounted for one-third of all febrile seizures younger than the age of 2 years (540). Persistent neurologic complications and death have been reported. The former include hemiparesis, recurrent seizures, and mental retardation. The cause of the residual encephalopathy is unknown (536).

HHV-6 DNA has been detected in the CSF of children who had three or more febrile seizures. This observation suggests that in some instances recurrence of febrile convulsions is associated with reactivation of the virus (540,541,542).

Approximately one-fifth of children have CSF with either a pleocytosis of more than 5 white blood cells/μL or a protein of more than 45 mg/dL; CSF glucose is normal. Approximately one-fourth of children have encephalopathy or encephalitis; all of these have an abnormal EEG. Transient periodic complexes can occur over the temporal lobes similar to those described for herpes simplex virus encephalitis (536). Unilateral or bilateral CT changes usually begin as hypodense areas that can progress to irregular cerebral atrophy or become hemorrhagic (536).

The association of HHV-6 with the neurologic complications is suggested by the concomitant isolation of virus, the identification of DNA by PCR in the CSF (543), and the fourfold increase in specific neutralizing antibodies. HHV-6 reactivations include a number of neurologic complications later in life (544).

HHV-7 has been associated with febrile seizures, a severe encephalopathy, and in two instances acute hemiplegia by the isolation of HHV-7 through viral culture and PCR (545,546). The diagnosis of HHV-7 is based on the methods described for HHV-6 (547).

Many strains of HHV-6 are sensitive in vitro to ganciclovir and foscarnet (548). Doses of 10 mg/kg per day in two divided doses of ganciclovir or 180 mg/kg per day in three divided doses of foscarnet can be given in cases of serious CNS infections caused by HHV-6.

LAC, a member of the California serogroup of Bunyavirus, is the most commonly reported cause of mosquito-borne disease in the United States (551). This disease, originally encountered most frequently in Midwestern states, also has become endemic in the mid-Atlantic region. Since 1993, West Virginia has had more reported cases that any other state (552). Aedes triseriatus, the principal mosquito vector, transmits the virus during the summer and early fall. Tree holes that contain water as well as discarded automobile tires that hold rainwater serve as the breeding habitat for the mosquito. Unlike St. Louis encephalitis virus and other arboviruses that cause epidemic disease, La Crosse virus infections exhibit an endemic pattern.

In 99% of instances, LAC virus infection is asymptomatic. The symptomatic disease can be mild or severe (553). LAC is the most prevalent and most pathogenic of the California serogroup of viruses (554,555).

SLE was first recognized in St. Louis in the summer of 1932 during an epidemic of encephalitis that originated in Paris, Illinois. Since then, sporadic outbreaks have occurred in the St. Louis area, California, the Rio Grande valley, Florida, and the central river valleys and western coastal regions of the United States. The vector for this virus is the Culex mosquito, and the virus has been isolated from overwintering mosquitoes (567,568).

WEE is caused by a group A arbovirus from the family Togaviridae. It occurs in the western United States and in the central states west of the Mississippi Valley. The virus was first isolated in 1930 in California from horses with encephalitis. The chief vectors are several Culex mosquitoes, notably Culex tarsalis in the United States. The enzoonotic cycle is kept between mosquitoes, birds, and other vertebrate hosts. Horses and humans become dead-end hosts.

EEE is a group A arbovirus from the family Togaviridae first isolated in 1933 from brain tissue of infected horses. It is distributed along the Atlantic coast from the northeastern United States to Argentina. Small epidemics have been encountered in Massachusetts, New Jersey, Florida, Texas, and, more recently, Jamaica. The virus is transmitted by a variety of mosquitoes, Culiseta melanura being the most common in the United States. Birds are the amplifying host and horses and humans are dead-end hosts (550).

Although VEE, a group A arbovirus, is indigenous to Colombia, Venezuela, and Panama, it was responsible for the 1971 Texas encephalitis epidemic. The organism was also responsible for an outbreak of encephalitis in 1995 in Colombia and Venezuela that involved 75,000 to 100,000 cases (587). The organism has been isolated from many wild rodents as well as from Aedes and Culex mosquitoes (588).

VEE is much more benign than California (La Crosse) encephalitis, SLE, EEE, and WEE. It is marked by sudden onset of malaise, chills and fever, nausea and vomiting, headache, myalgia, and bone pain. The fever lasts from 24 to 96 hours, then abruptly drops. A period of 2 to 3 weeks of marked asthenia can follow. In contrast to other arboviruses, whose ratios of inapparent to apparent infections range from 23:1 to 500:1, in VEE a ratio of 11:1 has been reported.

The CSF findings are as in the other arbovirus infections. Virus can be isolated from serum during the first 3 days of the illness in 75% of confirmed cases (588).

PCR provides a fast, sensitive, and specific method for the detection of viral DNA in infected blood. The detection of specific IgM in CSF and serum and the observation of a fourfold increase in specific IgG in serum provide serologic confirmation of the disease.

Prognosis is good, and, with good care, fatalities are rare.

Japanese encephalitis virus is transmitted by culicine mosquitoes between birds and humans. Histologic changes are most marked in the thalamus and brainstem. Patients who die rapidly can have no histologic signs of inflammation, yet have immunohistochemical evidence of viral antigen in morphologically normal neurons. Clinical features of this condition are much like those of the other encephalitides (589,590). Fever, headache, and vomiting are followed by meningism and coma. Convulsions have been reported in 85% of children. A characteristic masklike facies with a vacant stare or grimacing or lip-smacking can occur, as can a paralytic disease that mimics acute poliomyelitis. Pyramidal tract signs, a rare complication in poliomyelitis, should suggest the diagnosis of Japanese encephalitis in endemic areas (591). In the 1986 Nepal epidemic, children accounted for the majority of hospitalized cases. The fatality rate in children was markedly less than that in adults (592). In the Indian epidemic studied by Kumar and colleagues, of children with proven Japanese encephalitis, the case fatality rate was 32%; major sequelae occurred in 45%; only 29% were healthy on follow-up (593). Sequelae of the disease were more severe when the initial illness was prolonged or was associated with focal neurologic deficits. Children are more likely to have dystonia as a sequela when compared to adults (594). A TNF concentration of greater than 50 pg/mL in serum correlated significantly with a fatal outcome, whereas high levels of Japanese encephalitis virus–IgM antibodies (more than 500 units) in the CSF were associated with a nonfatal outcome (595). Elevated levels of proinflammatory cytokines and chemokines are associated with a poor outcome (596).

The MRI in Japanese encephalitis patients shows lesions in the thalamus, cortex, midbrain, cerebellum, and spinal cord. Classically, the lesions are hyperintense in T2-weighted images and hypodense in T1-weighted images (597). In some 70% of cases these are hemorrhagic. According to Kumar and coworkers, bilateral thalamic
involvement, especially hemorrhagic, can be considered to be characteristic of Japanese encephalitis in endemic areas (598). Diffusion-weighted MR imaging best demonstrates bilateral thalamic disease in Japanese encephalitis (599).

A specific diagnosis can be made by detecting a fourfold increase in specific IgG antibodies in acute and convalescent sera and by measuring Japanese encephalitis virus IgM in serum and CSF by ELISA. IgM can be detected 1 week after the onset of clinical symptoms. Virus isolation can be performed but needs to be done during the first 7 days of the disease prior to the mounting of an immune response.

No effective treatment exists, and high-dose dexamethasone treatment has been of no benefit. Interferon-alpha has been used in a small number of patients, and bigger trials are being awaited to assess its efficacy. The use of sedation has been shown to independently improve outcome (600). An inverse association between interferon-gamma levels and the severity of postencephalitic sequelae has been reported (601). Motor evoked potentials may be useful in predicting motor outcome (602). A Japanese encephalitis vaccine is available in the United States (550).