Fetal MRI is more sensitive than is antenatal sonography in detecting the combination of malformations and destructive lesions caused by CMV. These include microcephaly, cerebral cortical abnormalities, cerebellar hypoplasia, white matter lesions, and temporal lobe or polar abnormalities such as enlarged temporal horns, abnormal white matter, and temporal polar cysts (29). Fetal brain MR imaging is able to demonstrate CMV-associated abnormalities before 24 weeks of gestation and can demonstrate evolving infection-related changes. Even when level II fetal US results have been reported as normal, performing fetal MRI in the third trimester can be helpful in the detection of new cerebral malformations and destructive lesions and can accurately monitor the evolution of previously defined lesions (Fig. 11-1).

Findings on cross-sectional imaging vary depending upon the degree of brain destruction and the timing of the injury, timing of imaging, and imaging modality. Postnatal, transfontanelle cranial ultrasound may show branching curvilinear hyperechogenicities in the basal ganglia and/or punctuate subependymal hyperechogenicities (mineralization) (Figs. 11-2 and 11-3). The pattern of basal ganglia involvement is called “lenticulostriate vasculopathy” (30,31). It is seen in children with congenital infections of many types and is also
described in children with trisomy 13, trisomy 21, prenatal drug exposure, congenital heart disease, and a variety of anoxic and toxic injuries to the developing brain (31,32). Postmortem studies have described evidence of a mineralizing vasculopathy as the cause, whereas other studies suggest altered perfusion, perhaps the result of impaired autoregulation (33,34). Lenticulostriate vasculopathy is a nonspecific finding, and the diagnosis of congenital infection should not be strongly considered unless other supportive findings (parenchymal regions of hyperechogenicity, intraventricular septations, periventricular necrosis [germinolytic cysts], anterior temporal white matter lesions, and/or abnormalities of sulcation) are also seen by fetal imaging (US or MRI) or postnatal US, CT, or MRI (Fig. 11-4) (35,36,37). Antenatal cranial sonography may offer predictive information for the fetus infected with CMV but may underestimate the presence of anterior temporal lobe or temporal polar abnormalities (38). On CT and MR, some patients, presumably infected during the first half of the second trimester, demonstrate agyria or lissencephaly with a thin cortex, cerebellar hypoplasia, delayed myelination, marked ventriculomegaly, germinal zone cysts, anterior temporal lobe cysts, and periventricular calcification (Figs. 11-3, 11-4, 11-5 and 11-6). Those injured later, presumably in the middle of the second trimester, have more typical polymicrogyria, less ventricular dilatation, and less consistent cerebellar hypoplasia; schizencephaly and infoldings of cortical dysplasia can be seen (Figs. 11-6, 11-7 and 11-8) (39,40). Patients infected near the end of gestation or in the early postnatal period have normal gyral patterns, mild ventricular and sulcal prominence, and damaged periventricular or subcortical white matter with scattered periventricular calcification or hemorrhage (Figs. 11-7, 11-8 and 11-9) (12,18,24,28,41,42). FLAIR images, particularly in the first year of life, provide relatively poor contrast between gray and white matter; therefore, T2-weighted images are essential to identify

cortical malformations (Figs. 11-6 and 11-7), the detection of which helps establish the diagnosis of congenital CMV.

Damage to the white matter may be seen in those infected at any gestational age. Potential causative factors include primary CMV infection, host inflammatory and immune response including cytotoxic T-cell response, and injury to oligodendroglial cells. These white matter lesions are static like those of periventricular leukomalacia. van der Knaap et al. (43) have described a distinct pattern of white matter abnormalities in neonates with congenital CMV infection. Some of these patients lack gyral anomalies; in such patients, multiple white matter lesions typically involve the deep white matter, often sparing immediate periventricular and subcortical white matter, with the largest lesions often in the parietal lobes (Figs. 11-7 and 11-8). In patients with gyral anomalies, white matter abnormalities may be diffuse or multifocal (Figs. 11-3, 11-5, 11-6, 11-7, and 11-9). Abnormalities of the temporal polar regions are strongly suggestive of congenital CMV infection. Dilation of the temporal horns may be detected as early as 20 weeks of gestation, with subsequent evolving temporal lobe white matter T2 hyperintensity (swelling) and, ultimately, the formation of temporal polar cysts (Figs. 11-4, 11-7, and 11-9) (43). The apparent selective vulnerability of the temporal lobe regions to congenital CMV infection and the pathological underpinnings remains unexplained.

In affected newborns and infants, the white matter lesions demonstrate diffusivity (also called apparent diffusion coefficient, ADC) values that are increased; fractional anisotropy (FA) values (which represent a measure the degree of diffusion anisotropy) are decreased (43).

Calcifications can be seen on CT as foci of high attenuation (Figs. 11-3, 11-5, and 11-6). Although calcifications can be detected on MR in neonates and young infants as foci of short T1 and T2 relaxation times (Figs. 11-3 and 11-6), they are much more easily and reliably

detected on CT than on MR in older infants and children. Although dogma has suggested that congenital CMV CNS infection is predictably associated with cerebral calcifications, the prevalence of calcification may be less than 70%. Differentiation of calcification from hemorrhage may be difficult by either CT or MRI (24). Including susceptibility-weighted imaging (SWI) and SWI filtered phase maps into the routine MR examination aids in the differentiation of SWI hypointensities of blood products (paramagnetic) from calcifications
(diamagnetic). The SWI filtered phase map of calcifications is hyperintense (Fig. 11-10) (44). Clinicians should recognize that calcification is not uniquely specific for congenital infection, as any injury to the brain, including those caused by ischemia, genetic syndromes, metabolic errors, and nonspecified neurodegeneration, can cause dystrophic calcification (45,46,47). MR is the imaging examination of choice for the detection of cortical malformations, myelin abnormalities (delay and demyelination), germinal zone cysts, and cerebellar hypoplasia/dysplasia. When these features are present in a child with microcephaly, developmental delay, sensorineural hearing loss, and seizures, a diagnosis of congenital CMV should be considered (24).

The radiologist must consider neonatal herpes simplex encephalitis (HSE) in the neonate whose cranial imaging in the second to third weeks of life demonstrates diffuse cerebral edema and the presence of leptomeningeal enhancement, with or without parenchymal hemorrhage.

Sonographic findings are often subtle, initially showing nonspecific diffuse parenchymal hyperechogenicity and normal ventricles; parenchymal echogenicity subsequently increases with associated ventricular compression (58,59). The ventricles eventually enlarge as encephalomalacia develops (59). MRI is the study of choice in neonates with suspected herpes encephalitis (60,61,62,63), with imaging features of HSV type 2 encephalitis consisting of multifocal lesions (67%), temporal lobe involvement (67%), deep gray matter injury (58%), hemorrhage (66%), watershed pattern of injury (40%), and occasional involvement of the brain stem and cerebellum (63). In neonatal HSV encephalitis, diffusion-weighted MR imaging is critical to making an early diagnosis, monitoring disease progression, and detecting rare CNS relapses (64,65,66). Diffusion imaging depicts early cellular necrosis, which is seen as hypointensity (reduced diffusion) on average diffusivity (Dav) images (65,66). In this acute stage of disease, standard MR imaging is often normal (Fig. 11-11) (61,63). Subtle hyperintensities may or may not be seen on T2-weighted images in the late acute and early subacute stages of infection. As the infection progresses (at the end of the first week), diffusion imaging becomes less helpful and standard spin echo imaging more helpful (61,63). Early proton MR spectroscopy shows
elevated lactate and, often, reduction of N-acetyl aspartate (NAA) in affected regions (Fig. 11-12) (61,63). After 1 or 2 days, CT and MR show patchy, multifocal areas of injury (low attenuation on CT, T1 hypointensity, T2 hyperintensity, and regions of reduced diffusion), affecting gray and white matter (Figs. 11-11, 11-12 and 11-13), which progresses in prominence and extent of involvement during the course of the next several days. Hemorrhage is a common finding in neonatal herpes encephalitis, seen in up approximately two-thirds of patients (Fig. 11-14) (63). Contrast enhancement, although minimal, occurs early in a meningeal pattern (Fig. 11-14) (63). Near the end of the first week of disease, there are often regions of cortical gray matter injury (increased attenuation on CT, T1 hyperintensity, and T2 hypointensity on MR) that persists for weeks to months(61,63,67). Loss of brain substance occurs rapidly, often as early as the second week. Eventually, severe, diffuse cerebral atrophy ensues with profound cortical thinning and encephalomalacia; in the end stage, the brain often appears multicystic (Fig. 11-15E). Punctate or curvilinear gyral calcifications may also be seen as a late finding. The cerebellum is injured in about half of the affected patients (61,63,67).

Although the white matter changes in neonatal herpes encephalitis are nonspecific (Figs. 11-12, 11-13, 11-14 and 11-15), early reduced diffusion, parenchymal hemorrhage, and a meningeal pattern of enhancement in the proper clinical setting should lead to a suggestion of the diagnosis of neonatal HSE. It is important for the radiologist to remember that neonatal herpes simplex encephalitis demonstrates nonpatterned MR abnormalities. The clinical presentation and imaging appearance of herpes encephalitis in older children and adults (HSE) (usually caused by herpes simplex virus, type I) is quite different than neonatal HSV infection, primarily reflecting infection of the temporal lobe and insular cortex, limbic structures (61).

Imaging studies of neonates and infants with LCMV may overlap in neonates and infants with congenital toxoplasmosis and CMV infections (7). Timing of this congenital infection dictates the pattern of CNS injury. Hydrocephalus can be seen by sonography, CT, or MR (Fig. 11-17) (71,74,75). Periventricular calcifications, when present, are most easily seen by CT as high attenuation punctate periventricular lesions (Fig. 11-16) (69,72). Calcifications on MRI may be very subtle, showing punctate hyperintensity from T1 shortening when calcium molecules are less densely packed (and the paired outer shell electrons of water can transiently bind to them), hypointensity from T2 shortening or absence of water in tightly packed crystals, and hyperintensity on SWI filtered phase maps. MR may also show a cortex composed of multiple small, shallow sulci, the appearance of which suggests polymicrogyria (Fig. 11-17). These findings strongly suggest congenital infection, but the final diagnosis must be made by serologic and microbiologic studies.

The appearance of the brain on imaging studies varies depending upon the timing of in utero infection. Early infection will result in congenital anomalies, whereas late infection will result in a nonspecific generalized edema, gliosis, and loss of brain tissue. Ultrasound may show nonspecific lenticulostriate vasculopathy (see discussion under CMV) (30,31). CT typically shows ventriculomegaly, multifocal regions of hypodensity throughout the cerebral white matter, often in association with periventricular and basal ganglia calcification and cysts (Fig. 11-18) (81,82). Calcification may also be seen within the cortex. In severe cases, nearly total brain destruction and microcephaly are present (83). MR imaging may show ventriculomegaly, multifocal regions of white matter prolonged T2 relaxation (T2 hyperintensity), or myelination delay/destruction (82,84,85). Frontal dominant white matter lesions showing T2 hyperintensity have been reported following congenital rubella and CMV infections (28). High-resolution CT of the temporal bones may show malformations of the inner ear structures. Enhanced MR imaging may show enhancement of the cochlea (cochleitis) (86).

The most common imaging findings are leptomeningeal enhancement, hydrocephalus, and infarction (Fig. 11-19). Cisternal inflammatory exudative involvement (inflammation, fibrosis, and gumma formation) investing the pituitary gland and infundibulum may lead to persistent hypoglycemia, diabetes insipidus, and hypopituitarism (90,91).

The findings on cross-sectional imaging may be similar to those in CMV. As in congenital CMV, fetal brain imaging often detects early destructive changes (102). Calcifications are common; they usually involve the basal ganglia, periventricular regions, cerebral cortex, and subcortical white matter (more scattered in distribution than CMV) (Figs. 11-20 and 11-21). It is important to recognize that the predilection for calcium in the periventricular regions is less common than with congenital CMV infection. Fetal imaging (US and MRI) reveals ventriculomegaly, echodense (US) and T2 hypointense (MRI) calcifications of the cerebral parenchyma, and parenchymal cysts (102). In the neonate, cranial sonography may show shadowing parenchymal hyperechoic foci, which correspond to calcifications detected by CT (103). Due to the inflammatory nature of this disease and aqueductal obstruction, hydrocephalus is more common than in CMV (Figs. 11-20 and 11-21). As with CMV, the spectrum of potential abnormalities ranges from relatively mild disease, with a few periventricular calcifications and mild atrophy, to severe disease with near-total destruction of the cerebrum accompanied by diffuse cerebral calcifications (Fig. 11-20). Diebler et al. (104) have related the severity of the brain involvement to the date of maternal infection, noting that infection before 20 weeks is generally accompanied by severe neurological findings, including microcephaly, hydrocephalus, tetra- or diplegia, seizures, mental retardation, and blindness. CT revealed dilated ventricles, areas of porencephaly, and extensive calcifications, particularly in the basal ganglia (Fig. 11-20), that may exhibit a tram-track morphology (105). Infection between 20 and 30 weeks leads

to a more variable outcome; on CT, sparse (Fig. 11-21) or multiple periventricular calcifications and ventricular dilation are typical findings (Fig. 11-20). Infection after the 30th week of gestation is generally associated with mild clinical and imaging abnormalities, with CT findings of small periventricular and intracerebral calcifications that are only rarely accompanied by ventricular dilatation (104). An important differentiating feature between congenital toxoplasmosis and congenital CMV infection is the absence of cortical malformations in toxoplasmosis (a common occurrence in congenital CMV). The brain calcifications of congenital toxoplasmosis may resolve slowly in some infants after antitoxoplasma therapy (106). Therefore, the disappearance of calcification over time should not cause confusion if the diagnosis was established at birth on the basis of characteristic ocular findings and serologic testing.

Polymicrogyria involving the cerebral hemispheres and necrosis of white matter and deep gray nuclei and cerebellum have been reported in autopsy studies (110). Two MR studies have been reported, emphasizing variable findings likely reflecting the timing and severity of infection. One report describes hydrocephalus and cerebellar aplasia, while the other describes destruction of the temporal and occipital lobes with marked ventricular dilation in those areas, but normal cerebellum, basal ganglia, and frontal/parietal lobes (59,111). As with many of the previously described congenital CNS infections, MRI may lack specificity but does allow a full appraisal of brain injury and malformations (Fig. 11-22). Although retrospective diagnosis can be challenging, intrauterine infections with VZV can be established by serological or virological methods.

The scope of brain abnormalities and corresponding imaging findings resulting from congenital Zika virus infection are protean, the most severe manifestation being fetal brain disruption sequence (120,122). As with other congenital CNS infections, the unique qualities of the viral pathogen and the timing of fetal infection can lead to a range of possible injury patterns and malformations; however, postmortem histological findings have revealed gaps in the pial limiting membrane in affected (personal communication, Dr. Fernanda Tovar Moll, Rio de Janeiro). As discussed in Chapter 5, the cobblestone malformations (a form of polymicrogyria) that result from these gaps may look like lissencephaly, pachygyria, or polymicrogyria depending upon the number and size of the gaps, and that is what is seen in children with congenital Zika infection. MRI remains the most useful imaging tool to fully appraise the scope of CNS abnormalities (116,120).

In their retrospective review of neuroimaging and autopsy data of 45 neonates with proven or presumed congenital Zika virus infection, Soares de Oliveira-Szejnfeld and colleagues chronicled the brain imaging findings associated with congenital Zika infection (120). Cerebral calcifications were reported in all 45 neonates. Calcification located at the gray matter—white matter junction was the most common location followed by periventricular and deep cerebral nuclear (basal ganglia and thalami) regions (Fig. 11-23). In our experience, the precise locations of the calcifications are difficult to define in many patients because the volume of white matter can be extremely diminished and the cortex, therefore, very close to the cerebral ventricles. Calcifications are also seen within the brain stem and cerebellum in about 10% of patients.

Cranial ultrasound reveals calcifications as shadowing or twinkling hyperechoic foci, nonenhanced CT (NECT) of the brain shows highattenuation punctate or chunky calcium deposits (Fig. 11-23). On MRI, calcium in a loose hydration matrix demonstrates T1 (hyperintense) and T2 (hypointense) shortening (Fig. 11-24). Susceptibility-weighted MR imaging (SWI) demonstrates focal hypointensities at sites of calcium deposition. To distinguish calcification from blood products, the SWI filtered phase map shows calcification as focal hyperintensity. Blood products (paramagnetic) appear hypointense (see discussion under congenital CMV).

Ventriculomegaly was identified in all patients, many of these affected neonates showing ventricular septa. The causal factors for ventriculomegaly in these microcephalic patients likely include both impaired CSF absorption and parenchymal volume loss; one of the authors (AJB) has seen sequential studies where the ventricles enlarge as the volume of white matter diminishes in the absence of head growth (excluding hydrocephalus from impaired absorption of CSF). Abnormalities of the corpus callosum ranging from dysgenesis to absence was observed in 94% of the neonates; as the partial or complete callosal absence is usually associated with worse cortical disease and decreased white matter, it is possible that the callosal anomaly is secondary to axonal injury/regression. Cortical abnormalities occurred with a similar prevalence. As discussed above, the cortex may appear as localized cortical dysgenesis (˜30%), polymicrogyria (˜55%), or agyria (12%) depending on the number and size of defects in the pial limiting membrane; these are cobblestone malformations (see Chapter 5), a form of polymicrogyria (Fig. 11-24) (120). Cerebellar parenchymal abnormalities were noted in 82% of patients spanning a spectrum from hypoplasia to severe dysgenesis involving the cerebellar hemispheres and vermis (120).

The imaging abnormalities reported have shown bilateral confluent regions of cerebral hemispheric white matter abnormality (125). Cranial sonography may show nonspecific increased echogenicity of the central white matter, NECT demonstrates diminished attenuation of the white matter, and MRI shows diffuse confluent T1 and T2 prolongation and diminished diffusivity on diffusion-weighted imaging (DWI) and average diffusivity maps (Fig. 11-25) (124,125,126). Amarnath and colleagues have pointed out that MRI abnormalities in neonatal parechovirus leukoencephalopathy may be misinterpreted as hypoxic ischemic injury of the brain (127).

Neuroimaging recapitulates the pathological findings of meningoencephalitis, atrophy, and calcific vasculopathy (134). The most common finding on imaging studies of affected patients is lymphadenopathy in the head and neck, found in greater than 95%, and lymphoepithelial cysts, most commonly in the parotid gland (135). The most prominent intracranial findings are atrophy, with consequent prominence of the subarachnoid spaces and ventricles, and calcification of the basal ganglia and subcortical white matter (Fig. 11-26) (136). Calcification is seen in patients who were infected in utero with the encephalopathic form of the disease (137); children with the highest HIV viral load have the most marked calcification on CT (138). Subcortical calcification is most common in the frontal lobes but can occur in other areas of the cerebrum, as well. Myelopathy is often present in children with AIDS; affected children present with spasticity (139). Pathologic findings consist of corticospinal tract degeneration, myelin pallor, and sparing of the posterior columns (140). The majority of affected patients have
associated encephalopathy; therefore, imaging studies of the spine in children with HIV myelopathy are uncommon.

Other CNS pathology in pediatric HIV infection includes intracranial hemorrhage (from immune thrombocytopenia and aneurysmal arteriopathy) and infarction (136,141,142,143). Clinical stroke occurs in about 1% of children with congenital HIV infection; however, some autopsy series have found infarction in as many as 30% of affected children (144,145). Aneurysmal arteriopathy (Fig. 11-27), primarily involving large vessels, seems to be a common cause of infarction in these patients (141,145,146). Arteriopathy may result from the HIV virus itself or from superinfecting organisms, such as cytomegalovirus or varicella-zoster (146).

Proton MRS in pediatric HIV infection shows the NAA/Cr ratio to be normal in children with static disease; in patients with progressive encephalopathy NAA/Cr is significantly lower than in controls or nonencephalopathic HIV patients (147,148).

Rarely, intracranial neoplasms develop in pediatric patients with HIV. The most common intracranial neoplasm is lymphoma, reported in less than 5% of affected patients; the basal ganglia and thalami are the intracranial structures most commonly involved (139,142,149,150). Leiomyomas and leiomyosarcomas are also common and should be considered when extraparenchymal masses are seen in the patients with AIDS (151). CNS infections are quite rare in pediatric patients with HIV infection; toxoplasmosis, the most common infecting organism in adults with AIDS, is conspicuously uncommon in affected children. In our experience, CMV and PML are the most common infections in pediatric AIDS; PML is being seen more commonly, probably because infected children are surviving longer. The appearance of PML in these children is identical to that in adults, with areas of low attenuation on CT and prolonged T1 and T2 signal on MRI without significant mass effect or enhancement (152).

The agents causing bacterial meningitis in pediatric populations differ considerably according to the age of the child and child’s immune status. Meningitis is more common in premature than in full-term newborns and more common in the first months of life than later in infancy (4,88,167). In older children, meningitis is uncommon even when predisposing factors are present, because the subarachnoid space tends to resist infection in normal children; the exceptions are those few organisms, such as Citrobacter spp. and Cronobacter (Enterobacter) sakazakii, which display a tropism for the CNS and particularly the white matter (168,169). Immunization with vaccines for Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae has altered dramatically the epidemiology of bacterial meningitis in many regions of the world (1,167).

In the neonate, a large number of gram-positive and gram-negative organisms, including Streptococcus agalactiae (group B streptococcus), Escherichia coli, Staphylococcus species, Listeria monocytogenes, and Pseudomonas species, cause bacterial meningitis and sepsis (Table 11-3) (170). In many hospitals, group B Streptoccocus is the most common organism associated with neonatal meningitis (170,171,172). Citrobacter species cause less than 5% of cases of neonatal meningitis but produce brain abscesses in approximately 75% of Citrobacter-infected infants (173). The early signs of neonatal bacterial meningitis are often subtle, consisting of low-grade fever, poor feeding, somnolence, or “fussy” behavior; later, vomiting, lethargy, and seizures can ensue. The physical examination can be nonspecific, showing somnolence, irritability, hyperreflexia, and a full or bulging fontanelle. Meningeal signs are usually absent. This is particularly the case with early-onset neonatal meningitis where clinical manifestations may include hypotension, apnea, and/or jaundice. Systemic manifestations can also include shock and signs of disseminated intravascular coagulopathy (DIC) (2,173).

Two organisms, Streptococcus pneumoniae, a gram-positive Diplococcus, and Neisseria meningitidis, a gram-negative Diplococcus, account for the majority of cases of bacterial meningitis among immunocompetent children and adolescents living in regions with compulsory immunization for Haemophilus influenzae type b (Hib) (167). However, the overall incidence of meningitis has declined considerably among persons
of all ages in the United States and other regions with widespread use of the Hib vaccine and newer vaccines for both S. pneumoniae and N. meningitidis (167). Nontypeable Haemophilus influenzae or non-b subtypes have emerged as clinically important agents causing meningitis among healthy or immunocompromised children in many regions, including those with compulsory immunization against H. influenzae (Table 11-4) (4,174,175,176). Subtypes of H. influenzae remain important causes of bacterial meningitis with subtype F representing an aggressive, regional, circum-polar infection with reports often originating in remote northern latitudes. Subtype A and nontypeable H. influenzae are often associated with milder cases of meningitis. Among unimmunized children, H. influenzae meningitis occurs more commonly in persons with sickle cell anemia, asplenia, and HIV infection, and generally in older infants. Other risk factors for S. pneumoniae meningitis also include nephrotic syndrome, cochlear implantation, and CSF leaks. Unimmunized college students and persons with inherited complement deficiencies have an increased risk of contracting N. meningitides meningitis. Children or adolescents with congenital or acquired immunodeficiencies, including disorders of cell-mediated immunity or granulocyte function, can experience meningitis due to Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus aureus, Listeria monocytogenes, and enteric organisms (174). Meningitis also represents one of the most common extrapulmonary manifestations of infection with Mycobacterium tuberculosis (177).

The child or adolescent with bacterial meningitis typically has fever, headache, somnolence, and manifestations of meningeal irritation, such as the Kernig sign (involuntary spasm of the hamstring muscle provoked by knee extension with the patient supine) and the Brudzinski sign (flexion of the legs provoked by flexion of the neck). Systemic signs can include pneumonia in children with pneumococcal or H. influenzae meningitis and septic arthritis, petechiae, purpura, or signs of DIC in children with meningococcal or H. influenzae meningitis Management of bacterial meningitis in infants, children, and adolescents consists of treatment with organism-specific antibiotics and management of complications, such as seizures, increased ICP, subdural effusions, subdural empyema, hydrocephalus, stroke, or brain abscess (4). In rare instances, bacterial meningitis can recur. Factors that predispose to recurrent meningitis include immunodeficiency, such as HIV infection; complement deficiencies or agammaglobulinemia; anatomical defects, such as basal skull fracture or dermal sinuses; or abnormalities of the cochlea, such as Mondini dysplasia (178).

Meningitis is one of the most common extrapulmonary manifestations of infection with Mycobacterium tuberculosis and closely associated with miliary tuberculosis. CNS mass lesions (“tuberculomas”), meningovasculitis, and miliary involvement of the CNS can all occur in children with tuberculosis (230,231). Risk factors for tuberculous CNS disease in children and adolescents include exposure to a family member with tuberculosis, birth or extended travel in regions endemic for tuberculosis, exposure to a (former) prison inmate, and HIV infection. CNS involvement usually becomes clinically apparent within 6 months of the initial infection (232,233). Meningitis in childhood due to M. tuberculosis begins with headache, vomiting, irritability, or lethargy, and, when untreated, affected patients develop cranial nerve palsies (particularly CNs II, IV, and VII), focal deficits, or signs of ICP (177). Fever is not always present. Examination of the CSF reveals a mixed
or predominant lymphocytic pleocytosis, elevated protein (usually between 100 and 500 mg/dL), and mildly reduced glucose (234). The diagnosis of tuberculous meningitis can be established by PCR detection of mycobacteria in the CSF and supported by a positive tuberculin skin test or detection of interferon-gamma release in whole blood samples exposed to M. tuberculosis antigens (232,234). Treatment consists of combined antituberculous therapy with a four-drug regimen and administration of corticosteroids; even with therapy, death or significant morbidity is possible, especially when treatment is delayed.

The meningovascular manifestations of tuberculosis, such as cerebral infarction, have a substantial impact upon neurodevelopmental outcome (235). Acute hydrocephalus, caused by the intense meningeal reaction associated with tuberculous meningitis, requires ventriculoperitoneal shunt placement. If untreated, tuberculous meningitis rapidly progresses to death, with average disease duration of only 3 weeks (236). Even with current treatment regimens, tuberculous meningitis has considerable morbidity and mortality (234).

The bacilli are distributed within the brain and meninges throughout the CNS but do not multiply as readily as they do in other organs. Meningitis probably results from rupture of small tuberculomas in the cortex, spinal cord, leptomeninges, or choroid plexus (180,237). CNS manifestations usually become apparent as tuberculous meningitis, tuberculoma, tuberculous abscess, or spinal leptomeningitis within days after miliary spread; a gelatinous exudate fills the pia-arachnoid along the basal cisterns, particularly the prepontine cistern, where it infiltrates and produces inflammation along the walls of the meningeal blood vessels. The small cortical blood vessels and perforating vessels become affected as the exudate spreads into the Virchow-Robin spaces,

causing infarction of surrounding brain tissue. Outcome is directly related to the location and extent of these infarctions (238). The basal ganglia and thalami are affected in almost half of cases (239,240); suprasellar cisternal inflammation and involvement of the posterior hypophysis may lead to the syndrome of inappropriate antidiuretic hormone secretion (241). The thick exudate blocks the subarachnoid spaces, causing hydrocephalus. Infiltration of the perineurium of the cranial nerves causes neuropathies, particularly of cranial nerves II, VI, and VII. Small tubercles over the convexity of the brain may involve the leptomeninges, while deeper lesions may infiltrate the periventricular area.