Innate Immunity.

Age-dependent adaptations of innate immunity include the following: impaired leukocyte chemotaxis, phagocytosis, and bactericidal activity; defective neutrophilic metabolic responses after phagocytosis (e.g., activation of the hexose monophosphate shunt and, especially, oxidative metabolism, with diminished generation of the critical bactericidal hydroxyl radical); impaired costimulatory capacity of antigen-presenting cells (dendritic cell populations and monocytes) and decreased production of proinflammatory cytokines on stimulation of Toll-like receptors (TLRs); lower cytotoxic capacity of neonatal natural killer (NK) cells and γδ–T cells than in adults; and diminished concentrations of several complement components. Moreover, lower fibronectin concentrations in the newborn appear to contribute to diminished opsonization and phagocytosis. These adaptations are accentuated and especially affect immune function in premature infants and in infants subjected to illnesses of diverse types.

Adaptive Immunity.

Studies of T cells in cord blood demonstrate qualitative and quantitative differences in immune responses compared with adult T cells, and these differences are diminished only gradually during infancy. T cells generally express a naive phenotype but differentiate easily into regulatory T cells. In addition, T-cell lineage differentiation begins in utero and is highly controlled by epigenetic regulation, which is interestingly influenced by environmental factors.

Neonatal B cells have a naïve phenotype and have only a partially developed surface immunoglobulin repertoire. Deficiencies of specific humoral immunity have involved the immunoglobulin M (IgM) and immunoglobulin G (IgG) classes of antibodies. The latter are transferred passively across the placenta, particularly in the third trimester. Thus some premature infants may have decreased levels of IgG antibodies. IgM and immunoglobulin A (IgA) are not transferred passively across the placenta and are in very low concentrations in the normal newborn. IgM antibodies include several antibody types that are important in the defense against gram-negative bacteria; deficiency of these antibodies in the newborn infant may play a role in the susceptibility to gram-negative bacteria. IgA antibodies are abundant at later ages at mucosal surfaces (e.g., the respiratory and gastrointestinal tracts); their deficiency in the newborn may explain in part the relative ease with which mucosal barriers are colonized and penetrated. Newborn infants have diminished production of these antibodies because of both immaturity of the antibody-producing B cells and plasma cells and diminished T-cell help for antibody production. The deficiency in immune globulins has led to clinical trials of the use of intravenous immune globulin in the prophylaxis and treatment of bacterial infection in newborns, especially premature newborns. This approach has not proven useful for general practice.

Neonates are heavily dependent on innate immune responses for protection against infections. The brain microglial cell, which is derived from monocytes (see Chapter 13 ), is an important part of this defense. Activation of innate immune cells occurs by way of specific cell-surface receptors (i.e., TLRs), which respond to specific molecular motifs shared by the products of large classes of microorganisms. For example, TLR4 is the receptor that recognizes gram-negative bacterial lipopolysaccharide, and TLR2 is the receptor for gram-positive peptidoglycan and lipopeptides. Activation of these receptors triggers an inflammatory response by a mechanism that operates through nuclear factor (NF) kappaB and mitogen-activated protein kinase. A study of newborns has shown that the basal expression of TLR2 (but not TLR4) is slightly lower in neonatal than in adult phagocytes. In infants with sepsis, TLR2 is sharply upregulated, unlike TLR4. A similar disturbance of TLR4 responsiveness was shown in neonatal monocytes as a function of gestational age. Thus the deficits in TLR2 and TLR4 may be relevant to the importance of such gram-positive organisms as GBS and CONS and of such gram-negative organisms as E. coli in neonatal sepsis and meningitis. Furthermore, downstream signaling through the MyD88 and p38 pathways is impaired in neonates following TLR2 and TLR4 stimulation. High levels of adenosine in neonatal blood may increase cyclic AMP levels and protein kinase A–dependent or independent inhibition of TLR-stimulated TNF-alpha secretion.

Immunological Aspects of Group B Streptococcal Infection.

Immunological studies of perinatal GBS infection illustrated the potential roles of both maternal and host defense factors in pathogenesis. Thus, using a sensitive, radioactive antigen-binding assay, Baker and Kasper showed that the prevalence of antibody to GBS (capsular polysaccharide of the type III strain) in mothers with vaginal colonization was 76% for those whose infants did not develop GBS disease and only 5% for those whose infants did develop GBS sepsis or meningitis. These data suggest that this IgG antibody is important in protecting the infant and that passive transfer across the placenta did not occur because of maternal failure to synthesize the antibody. Moreover, the infants with sepsis or meningitis had low levels of antibody after recovery, a finding suggesting that, in addition, these infants also failed to synthesize this IgG component. Similarly, infants who develop GBS sepsis have been shown to exhibit defective humoral (opsonic activity) and neutrophilic responses to their infecting strain.

Specific Serotypes Related to Meningitis.

The propensity for specific strains of GBS, E. coli , and L. monocytogenes to be most commonly responsible for neonatal meningitis suggests important pathogenetic roles for the microorganism itself. (Recall the earlier discussion concerning innate immunity and the risk of infection by gram-negative and gram-positive organisms.) Thus serotype III of GBS, K1 strains of E. coli , and serotype IVb of L. monocytogenes are the predominant specific types of these three bacteria that cause neonatal meningitis ( Table 35.5 ). Approximately 70% to 80% of all cases of neonatal meningitis are caused by these three bacterial types.

Importance of Capsular Polysaccharides.

The likelihood that capsular polysaccharides reflect, to a considerable degree, an intrinsic virulence of these organisms is suggested by in vivo and in vitro observations. Studies with immature rats have demonstrated, for K1 strains of E. coli relative to other E. coli strains, a high virulence, particularly regarding bacteremia and meningitis, that was age-related. The younger the animal, the greater was the likelihood of serious disease. Moreover, investigators showed that GBS type III and K1 strains of E. coli have distinctive capsules that contain polysaccharide with sialic acid in high concentration (≥25% of total carbohydrate). (This distinctive polysaccharide for E. coli is termed K1 , hence the name K1 strain .) A relation of the capsular polysaccharide antigen to virulence is suggested by the different outcomes of E. coli meningitis secondary to K1 and non-K1 strains ( Table 35.6 ). In addition to a marked preponderance of cases secondary to K1 strains, whereas 60% of reported infants with meningitis secondary to K1 strains died or exhibited neurological sequelae, only 11% of infants with meningitis secondary to non-K1 strains exhibited the poor outcome (see Table 35.6 ). A protein component of the outer membrane of the K1 strain of E. coli , OmpA, was also shown to be critical for the capacity of this strain to penetrate brain endothelial cells and thus to cause intracranial infection. The relation of the capsular polysaccharide antigen to virulence is supported further by the studies reviewed previously, relating the occurrence of GBS type III neonatal disease to the deficiency in the mother and in the newborn of antibody against the specific capsular polysaccharide of that organism.

Arachnoiditis.

The hallmark of bacterial meningitis is infiltration of the arachnoid with inflammatory cells. The exudate is predominant over the base of the brain in approximately half of the cases and is distributed more evenly in most of the remainder ( Fig. 35.2 ). The evolution of this inflammatory response is well described by Berman and Banker.

Neonatal bacterial meningitis: arachnoidal exudate.

(A) From an infant with group B streptococcal meningitis who died at 12 days of age. This right lateral view of the cerebrum shows thick arachnoidal exudate. (B) From an infant who died at 13 days of age with Escherichia coli meningitis. This left lateral view of the cerebrum shows thick arachnoidal exudate, especially prominent in the region of the sylvian fissure. (C) Closer view of the exudate in the region of the sylvian fissure.

(A, From Bell WE, McCormick WF. Neurologic Infections in Children . Philadelphia: Saunders; 1975.)

In the acute state (i.e., approximately the first week ), the predominant cells in the arachnoidal (and ventricular) exudate are polymorphonuclear leukocytes. Bacteria are visible, free, and within polymorphonuclear leukocytes and macrophages. The inflammatory exudate is particularly prominent around blood vessels and extends into the brain parenchyma along the Virchow-Robin space. In the second and third weeks of the disease, the proportion of polymorphonuclear leukocytes decreases gradually and constitutes approximately 25% of the cell population. The predominant cells are now mononuclear, mainly histiocytes and macrophages. Lymphocytes and plasma cells are present in relatively small numbers, and this paucity is a characteristic feature of neonatal meningitis. Whether this apparent deficiency of cells involved in the immunological response plays a role in the relative tenacity of neonatal bacterial meningitis remains to be determined but seems plausible. A prominent feature of this stage of the disease is infiltration of cranial nerve roots by the exudate; particular involvement occurs in the subarachnoid space of the posterior fossa and especially affects cranial nerves III through VIII. This involvement is clinically relevant (see subsequent discussion). After approximately 3 weeks , the exudate decreases in amount and consists of mononuclear cells. Thick strands of collagen become apparent as arachnoidal fibrosis begins to develop. This process is probably important in the genesis of the obstructions to CSF flow that result in hydrocephalus.

The characteristics of the arachnoiditis caused by different bacteria vary little. However, early-onset GBS meningitis is accompanied by much less arachnoidal inflammation than is late-onset meningitis. Indeed, approximately 75% of cases of early-onset meningitis (i.e., positive culture results) are said to exhibit little or no evidence of leptomeningeal inflammation at autopsy. It is not clear whether the relative lack of arachnoidal inflammatory response relates to rapidity of death after onset of symptoms or to immaturity of host responses to infection within the CNS of premature infants (who represent the largest proportion of fatal cases of early-onset GBS meningitis).

Ventriculitis.

Ventriculitis (i.e., inflammatory exudate and bacteria in the ventricular fluid and lining) is a particularly common feature of neonatal meningitis. In the 50 brains studied by Berman and Banker and by Gilles et al., overt ventriculitis was present in 44 (88%). In a collaborative study of 70 infants with meningitis caused by gram-negative bacteria in whom ventricular tap was performed at the time of diagnosis, 51 (73%) had ventriculitis, as manifested by positive cultures with pleocytosis in the ventricular fluid (comparable data are not available for GBS meningitis). Although precise, controlled data are not available, ventriculitis appears to be more common in neonatal meningitis than in meningitis at later ages.

The ventriculitis is initially characterized by exudate most prominent in the choroid plexus stroma and just external to the plexus ( Fig. 35.3 ). Exudative excrescences from the ventricular surface can be visualized in vivo by cranial ultrasonography (see later discussion). In the second and third weeks of the disease course, the ventricular exudate is associated with active ependymitis, characterized by disruption of the ependymal lining and projections of glial tufts into the ventricular lumen. Later, glial bridges may develop and cause obstruction, particularly at the aqueduct of Sylvius ( Fig. 35.4 ). Less commonly, septations in the lateral ventricle may produce a multiloculated state that is similar to abscess formation. The multiple ventricular obstructions, in fact, may isolate portions of the lateral ventricles or the fourth ventricle, cause disproportionate and severe dilation of the affected ventricle, and present a difficult therapeutic problem. Ventriculitis with obstructive hydrocephalus may manifest subacutely in newborns (with no history of acute meningitis) after several weeks, especially ventriculitis caused by GBS and E. coli meningitis.

Ventriculitis and choroid plexitis from an infant who died of bacterial meningitis in the first month of life.

The choroid plexus is in the left lower corner. Plexus stroma is filled with cellular exudate. The lateral ventricle contains a mass of protein-rich cellular exudate and necrotic debris organized into layers. The middle layer (arrows) is composed of colonies of bacteria (hematoxylin and eosin, ×60).

(From Gilles FH, Jammes JL, Berenberg W. Neonatal meningitis: the ventricle as a bacterial reservoir. Arch Neurol . 1977;34:560–562.)

Aqueductal obstruction subsequent to ventriculitis from an infant who died of neonatal bacterial meningitis.

Stain for glial fibers shows the formation of glial bridges that have narrowed and partially occluded the aqueduct. The lower portion of the aqueduct is reduced to a small slit (arrow) (phosphotungstic acid hematoxylin ×100).

(From Berman PH, Banker BQ. Neonatal meningitis: a clinical and pathological study of 29 cases . Pediatrics . 1966;38:6–24.)

The nearly uniform occurrence of ventriculitis in acute bacterial meningitis in the newborn has pathogenetic and therapeutic implications. Regarding pathogenesis , it appears reasonable to suggest that the initial sequence of events in bacterial invasion of the CNS is for hematogenously borne bacteria to localize first in the choroid plexus and to cause choroid plexitis, with subsequent entrance of bacteria into the ventricular system and later movement to the arachnoid through normal CSF flow (see Fig. 35.1 ). Gilles and co-workers have presented considerable data to support this view, including the high glycogen content of the neonatal choroid plexus, which provides an excellent medium for bacteria. Moreover, an age-related effect is suggested by the postnatal decrease in glycogen content of plexus epithelial cells.

Experimental studies of bacterial meningitis produced in infant rhesus monkeys indicate that infection of the lateral ventricle is a uniform feature. Moreover, when discordance between the amount of bacteria in ventricular and subarachnoid CSF samples was observed in these studies of rhesus monkeys, ventricular bacterial densities were greater. These observations further support the notion that the initial events in the genesis of bacterial meningitis are bacteremia and infection of the choroid plexus and lateral ventricles.

The therapeutic implications of these data concerning ventriculitis are important and are discussed later, in the section on management . Suffice it to say here that the ventricle may be a major reservoir of bacterial infection, inaccessible either to systemic antibiotics, which are unable to penetrate the purulent covering over the ventricular lining, or to intraventricular antibiotics, which are unable to reach the choroid plexus epithelium (and particularly inaccessible to intrathecal antibiotics, which are unable to reach the ventricles because of normal CSF flow). Moreover, if obstruction of the ventricular system is added (e.g., at the aqueduct), a closed infection, approximating an extraparenchymal abscess, will result.

Vasculitis.

Vasculitis is an almost invariable feature of neonatal bacterial meningitis. The involvement of both arteries and veins can be considered an extension of the inflammatory reaction in the arachnoid and within the ventricles. The arteritis is manifested particularly by inflammatory cells in the adventitia; however, involvement of the intima is not uncommon. Although the arterial lumen may be narrowed, only rarely is complete occlusion observed. Involvement of veins is severe and includes arachnoidal, cortical, and subependymal veins. In contrast to arterial involvement, phlebitis is frequently complicated by thrombosis and complete occlusion. Multiple fibrin thrombi of adjacent veins are often observed in association with areas of hemorrhagic infarction (see the section on infarction later). The vasculitic changes are apparent in the first days of meningitis and become particularly prominent by the second and third weeks.

More similarities than differences exist among various bacteria with regard to the nature and severity of the vascular changes with meningitis. However, vasculitis with thrombosis or even hemorrhage is relatively frequent in early-onset GBS disease, despite the relatively modest arachnoidal inflammation.

Cerebral Edema.

Cerebral edema is a characteristic of the acute stage of neonatal bacterial meningitis ( Fig. 35.5 ). Indeed, the swelling of brain parenchyma is often so severe that the ventricles are reduced to small slits. The difficulty and hazard of performing ventricular puncture in the acute stage are significant because of this phenomenon. The cause of the edema is related primarily to the vasculitis and increased permeability of blood vessels (i.e., vasogenic edema; see Fig. 35.1 ). This vasogenic component may be complicated by a cytotoxic component, when parenchymal injury occurs (e.g., through infarction), or when impairment of CSF flow results in development of interstitial edema (see later discussion).

Cerebral edema with neonatal bacterial meningitis.

Coronal section of the brain from the same infant shown in Fig. 35.2A . Note the diffusely swollen appearance of the cerebral parenchyma, resulting in flattened gyri and small, slit-like ventricles. Purulent material is evident in the ventricles (medial aspect), and a hemorrhagic infarct is apparent in the parasagittal region.

(From Bell WE, McCormick WF. Neurologic Infections in Children . Philadelphia: Saunders; 1975.)

Despite the edema, another feature of neonatal bacterial meningitis that is distinctive relative to disease at later ages is the rarity of evidence, clinical or pathological, for herniation of supratentorial structures through the tentorial notch or of cerebellar tonsils into the foramen magnum. This feature may relate to the distensibility of the neonatal cranium, especially because of the separable sutures. This factor may also prevent marked increases in intracranial pressure and therefore impaired cerebral perfusion; studies of intracranial pressure and cerebral blood flow velocity in neonatal bacterial meningitis have supported this suggestion (see later discussion). Nevertheless, lethal uncal and cerebellar tonsillar herniation has been documented in neonatal bacterial meningitis. Moreover, the rare phenomenon of anterior fontanelle herniation has been reported to complicate neonatal meningitis.

Infarction.

Infarction may be a prominent and serious feature of neonatal bacterial meningitis (see Fig. 35.1 ). Studies of autopsy cases indicate an incidence of 30% to 50% (see Table 35.7 ). More than half of the infants in Friede’s neuropathological series sustained their lesions in the first week after the diagnosis of meningitis. Thus, although the vascular lesions become particularly prominent in the second and third weeks, infarction may often be an early event. The lesions are most frequently related to venous occlusions and are often hemorrhagic (characteristic of venous infarcts). Occlusion of multiple adjacent veins appears to be necessary to result in infarction, as evidenced by the usual demonstration of several thrombosed vessels contiguous to the infarct. The loci of the infarcts are most often cerebral cortex and underlying white matter ( Fig. 35.6 ), although subependymal and deep white matter lesions are not uncommon. Involvement of major cerebral arteries may be more common than previously expected, because brain imaging in living infants not uncommonly demonstrates lesions in an arterial distribution (see later discussion and Table 35.8 ). In addition, stroke patterns within the distribution of perforating arteries were recently shown to be especially common in neonatal GBS meningitis. The origin of the infarction is related particularly to the vasculitis, in combination with concomitant thrombotic effects of arachidonic acid metabolites (e.g., thromboxanes, platelet-activating factor), impaired cerebrovascular autoregulation, and decreased cerebral perfusion pressure (caused by systemic hypotension, increased intracranial pressure, or both; see later in the section on mechanisms of brain injury ). Such a combination of factors presumably could lead to infarction in the presence of vascular narrowing and not necessarily complete thrombotic occlusion.

Infarction with neonatal bacterial meningitis.

Same specimen as shown in Fig. 35.5 but with a higher-power view of the hemorrhagic infarct in the parasagittal region. The lesion was secondary to cortical vein thrombosis.

(From Bell WE, McCormick WF. Neurologic Infections in Children . Philadelphia: Saunders; 1975.)

Although venous or arterial infarction of cerebral structures predominates, involvement of the spinal cord may occur. Indeed, spinal cord necrosis and the clinical picture of a segmental myelopathy may rarely develop. The onset may be delayed, as shown in two infants who developed severe progressive late-onset myelopathy precipitated by a fall following presumed chronic arachnoditis.

Associated Encephalopathy.

Associated with neonatal bacterial meningitis are parenchymal changes (i.e., associated encephalopathy ), the causes of which have been elucidated increasingly in recent years (see later in the section on mechanisms of brain injury ). The major changes are (1) diffuse gliosis of regions subjacent to inflammatory exudate, (2) neuronal loss in cerebral cortex and several other brain regions, and (3) periventricular leukomalacia. The first change, parenchymal gliosis, is observed in cerebral cortex (molecular layer and superficial cortical layers), cerebellar cortex (molecular layer), brain stem and spinal cord (marginal white matter), and subependymal regions. These various regions are immediately subjacent to the inflammatory exudate and presumably are injured by the toxic and metabolic factors associated with the bacterial process (see later discussion). The clinical significance of the gliosis is not entirely clear. The second and third changes, involving cortical neurons and periventricular white matter, are similar in topography in many ways to hypoxic-ischemic encephalopathy. The cause of these neuronal and white matter lesions probably relates at least in part to ischemia (see later discussion and Table 35.9 ). Moreover, it is likely that concentrations of endotoxin and related cytokines in brain and ventricular fluid are high in gram-negative bacterial meningitis and that the endotoxin could injure cerebral white matter through the activation of innate immunity in brain (see later and Chapter 13 ). A similar conclusion applies to the capsular polysaccharides and proteins of GBS, which have also been shown to be neurotoxic (see Chapter 13 ). Further data are needed on these issues, because the clinical significance of the neuronal loss and of the white matter injury is almost certainly considerable.

Subdural Effusion and Empyema.

One neuropathological feature of neonatal bacterial meningitis, conspicuous by its relative lack of prominence, is subdural effusion. The reason for the notable difference in the incidence of significant subdural effusion between meningitis in the newborn and in the infant of 2 to 3 months of age and older is not clear.

Subdural empyema is a very rare acute feature of bacterial meningitis.

Hydrocephalus.

In studies of postmortem material, hydrocephalus is apparent in approximately 50% of cases. Of the 14 autopsy cases of hydrocephalus studied carefully by Berman and Banker, the major obstruction to CSF flow appeared to be at the level of the aqueduct in 4, at the outflow of the fourth ventricle in 2, and in the subarachnoid space (i.e., communicating) in 8. Multiple sites of impairment in CSF flow are probable. Ventricular dilation secondary to obstruction to CSF flow should be distinguished from that secondary to loss of cerebral substance. Because both hydrocephalus and cerebral atrophy are usually present concurrently, this distinction may be difficult.

Multicystic Encephalomalacia and Porencephaly.

Multicystic encephalomalacia and porencephaly are at the end of the continuum of multifocal parenchymal injury secondary to neonatal bacterial meningitis. The single or multiple cystic areas of destruction in the cerebral hemispheres appear to reflect primarily residua of infarction ( Fig. 35.7 ). In postmortem material, some of the cavities rarely appear to represent abscesses. The implications of multicystic encephalomalacia for neurological outcome are obviously grave.

Multicystic encephalomalacia following neonatal bacterial meningitis: neuropathology.

From an infant with neonatal gram-negative bacterial meningitis who died at 5 weeks of age. This coronal section of the cerebrum shows that the cerebral hemispheres have been converted into a necrotic mass, with many cystic cavities of various sizes. The corpus callosum is necrotic, and the ventricles cannot be delineated from cystic spaces in the brain.

(From Bell WE, McCormick WF. Neurologic Infections in Children . Philadelphia: Saunders; 1975.)

Cerebral Cortical and White Matter Atrophy.

Most commonly, the major neuropathological sequela of neonatal bacterial meningitis is cerebral atrophy, manifested particularly by loss of cerebral cortical neurons and periventricular white matter. This state appears to be a sequela principally of the associated encephalopathy described previously. Neuronal loss in deep cortical layers and myelin loss in the periventricular region, both areas also infiltrated with glial fibers, are the major histological findings.

Possible Cerebral Cortical Developmental (Organizational) Defects.

Experimental data suggest that more refined techniques may reveal subsequent aberrations of brain development following neonatal bacterial meningitis. In an infant rat model of bacterial meningitis, disturbances of subsequent dendritic arborization and synaptogenesis were observed. Because of the timing of neonatal bacterial meningitis with regard to brain developmental events (see Chapter 5 , Chapter 6 , Chapter 7 , Chapter 8 ), it is reasonable to postulate that application of Golgi, immunocytochemical, and electron microscopic techniques to the study of cerebral cortex and myelin of infants who survive the acute state of neonatal meningitis would reveal impairment of cerebral organizational events and perhaps myelination. Further data in this regard would be of particular importance concerning the effects of neonatal bacterial meningitis on subsequent neurological outcome.

Citrobacter species, Serratia marcescens , Proteus , Pseudomonas , Enterobacter , and Bacillus cereus species.

These bacteria have a particular propensity to cause severe cerebral necrosis, usually hemorrhagic (see Table 35.10 ). In the presence of bacteremia, one consequence of this tissue necrosis is the occurrence of brain abscess. Indeed, the brain abscess may dominate the clinical syndrome, which occasionally may evolve in a less acute fashion than uncomplicated meningitis. (The most common organism leading to meningitis complicated by brain abscess is Citrobacter , which is discussed later in the section on brain abscess.)

An even more dramatic and malignant form of neonatal bacterial meningitis is caused by S. marcescens . Widespread hemorrhagic necrosis of cerebral cortex and white matter occurs ( Fig. 35.8 ). Striking invasion of brain parenchyma by bacteria, which can be seen streaming from blood vessels (see Fig. 35.8 ), is a prominent feature.

Neonatal bacterial meningitis secondary to Serratia marcescens .

(A and B) Note the regions of hemorrhagic necrosis involving both hemispheres. (C) Gram-negative bacteria can be seen around a small vein and invading the surrounding parenchyma (cresyl violet).

(From Larroche JC. Developmental Pathology of the Neonate . New York: Excerpta Medica; 1977.)

A rapid destruction of brain tissue may also occur with B. cereus meningoencephalitis, a gram-positive spore-forming rod. The organism has often been considered to be a contaminant but is now recognized as a pathogen in immune-compromised patients. Invasive infections are related to the use of central or peripheral catheters, contaminated dressings, hospital linens, ventilator equipment, balloons used for manual ventilation, and breast milk. Following an uneventful initial neonatal period, the infant may become unwell, with signs of sepsis. The disease can be rapidly progressive owing to the production of several toxins (necrotizing enterotoxin, emetic toxin, hemolysin, and phospholipase C), resulting in hemolysis, tissue invasion, and tissue necrosis. In a review of 15 newborn infants with neonatal meningitis caused by this organism, the gestational age ranged from 26 to 37 weeks, with birth weights from 830 to 2780 g. Twelve (75%) of the infants died, the majority within 3 days of onset. Of the four who survived infection, one developed cerebral palsy, and the other three had no sequelae. Hemorrhagic necrosis and liquefaction of brain tissue have been reported in postmortem studies. Special stains reveal Gram-variable rods in brain tissue. An important aspect of treatment is recognition that this organism produces beta-lactamase, which renders it resistant to most penicillins and cephalosporins. Treatment involves a combination of vancomycin and an aminoglycoside. Imaging characteristics may show destructive changes of the white matter, cortex, and basal ganglia, which can develop within 12 to 24 hours. Cranial ultrasound shows a typical irregular cauliflower-like pattern with extensive areas of increased echogenicity, followed by rapid cystic evolution ( Fig. 35.9 ). Most infants are unstable and die before they can be transferred to the MR unit. In one study, three infants assessed with MRI showed extensive hemorrhagic lesions in the cerebral white matter on conventional T1- and T2-weighted sequences, as well as areas of restricted diffusion on diffusion-weighted imaging (DWI).

Bacillus cereus meningitis.

Ultrasound scans coronal (A) and parasagittal views (B) showing an irregular pattern with extensive areas of increased echogenicity in cerebral white matter, with the development of echolucencies seen within 24 hours after the first symptoms of the meningitis.

Listeria monocytogenes .

Although L. monocytogenes may cause typical bacterial meningitis in the newborn, especially in infants with late-onset disease, transplacental infection of the fetus may occur and may produce a particularly fulminating infection. ^a

a References .

Dominance of Nonneurological Signs.

The clinical presentation is dominated by nonneurological signs (i.e., signs related to sepsis and respiratory disease). The most common signs are hyperthermia, apnea, hypotension, disturbances of feeding, jaundice, hepatomegaly, and respiratory distress; less common signs are hypothermia, skin lesions (e.g., petechiae and sclerema), and overt focal infection (e.g., otitis media, omphalitis, arthritis, and osteomyelitis). Neurological signs are generally limited to stupor (usually termed lethargy ) and irritability. Signs suggestive of meningitis (see later discussion) are unusual, in part because overt meningitis occurs in only approximately 30% of the patients with early-onset disease. Indeed, even those infants with culture-proven meningitis often do not exhibit striking CSF pleocytosis.

The respiratory manifestations of early-onset sepsis-meningitis may be particularly prominent with GBS infection and, indeed, may simultaneously present serious diagnostic problems and important diagnostic clues. Approximately 40% to 60% of infants with early-onset GBS disease have manifestations of prominent respiratory disease in the first 6 hours of life. Only approximately 35% of these infants exhibit radiographic infiltrates suggestive of congenital pneumonia, whereas approximately 50% exhibit radiographic features of respiratory distress syndrome. Distinction from nonbacterial respiratory disease is suggested by the history of premature rupture of membranes, low Apgar scores (<4 at 1 minute in 85%), rapid progression of pulmonary disease, and low or declining absolute neutrophil counts in the first 24 hours of life.

Dominance of Neurological Signs.

Although neurological signs associated with meningitis are prominent in late-onset disease , some of the signs prominent in early-onset disease are also common, especially fever and feeding disturbances. Most impressive, however, are the neurological signs ( Table 35.11 ). Most patients exhibit impairment of consciousness , manifested usually as varying degrees of stupor, with or without irritability. The disturbances of level of consciousness presumably relate to the cerebral edema and, perhaps, the associated encephalopathy (see the section on neuropathology earlier). Seizures develop at some time in the illness in nearly 50% of cases, although these seizures may be predominantly subtle. The convulsive phenomena presumably relate to the cortical effects of the arachnoidal inflammatory infiltration. Focal seizures occur in approximately 50% of infants with seizures and may be prominent. These focal episodes may be related to ischemic vascular lesions. Similar bases are probable for the focal cerebral signs (e.g., hemiparesis and horizontal deviation of eyes), which are movable with the “doll’s eyes maneuver.” These signs are reported only uncommonly in the literature, but they can be elicited with careful examination in nearly half of the cases. Extensor rigidity occurs in approximately one third of cases and may be so severe that opisthotonos occurs. These phenomena probably relate to the arachnoidal inflammation, especially in the posterior fossa. A similar basis is likely for the nuchal rigidity, which occurs in fewer than 25% of cases. Apparent in most patients, however, is a distinct increase in irritability, elicitable by flexion of the neck; this, presumably, is the neonatal counterpart of more overt nuchal rigidity. Cranial nerve signs usually involve the seventh, third, and sixth nerves, in that order of frequency, and are more common than often suggested in the literature. These signs relate to the involvement of cranial nerve roots by the arachnoidal inflammation (see the section on neuropathology earlier). A bulging or full anterior fontanelle is present, often later in the course of the disease, in approximately 35% to 50% of patients. This feature relates to an increase in intracranial pressure (see following section). Rarely, anterior fontanelle herniation of cerebral tissue occurs and imparts a doughy consistency to the bulging fontanelle. Moreover, very uncommonly, signs of segmental cord involvement (sensory level, flaccidity below the level of the lesion), secondary to myelopathy, may be present.

Increased Intracranial Pressure.

Intracranial pressure, although only uncommonly monitored, may be markedly increased in neonatal bacterial meningitis. Major causes include cerebral edema, hydrocephalus, and, uncommonly, formation of an intracranial mass or extracerebral collection ( Table 35.13 ). Cerebral edema (vasogenic and cytotoxic) is a frequent feature in the first several days of the disease and may be aggravated by water retention secondary to inappropriate antidiuretic hormone secretion. Increased intracranial pressure may persist or worsen in the ensuing days, with the development of acute hydrocephalus or an intracranial space-occupying lesion (see subsequent discussion).

The increased intracranial pressure rarely causes signs of transtentorial (e.g., unilateral dilated pupil) or cerebellar (e.g., apnea and bradycardia) herniation, but both these forms of herniation have been reported. Although uncommon, the increased intracranial pressure may interfere with cerebral perfusion and may contribute to the associated encephalopathy described in the section on neuropathology . Clinical signs suggestive of increased intracranial pressure include a full or bulging anterior fontanelle, separated cranial sutures, and deterioration of the level of consciousness.

Ventriculitis With Localization of Infection.

Ventriculitis complicated by localization of infection is caused by a particularly exuberant inflammation of the ependymal lining usually in association with obstruction to CSF flow, especially at the aqueduct. Occasionally the formation of glial septa may localize intraventricular infection in a particularly severe manner. There are no reliable clinical signs for these events; the diagnosis must be suspected on the basis of the failure of clinical and bacterial responses to therapy (see the section on management later). Ultrasound scanning may show signs suggestive of ventriculitis (see the section on diagnosis later) and may at least indicate the potential for sequestered infection.

Acute Hydrocephalus.

Hydrocephalus occurs in an appreciable proportion of infants with neonatal bacterial meningitis who survive into the second and third weeks of life. The causes of hydrocephalus include obstruction to CSF flow—either inside the ventricular system, secondary to ventriculitis, or outside the ventricular system—secondary to arachnoiditis. The suggestive clinical signs are those of increased intracranial pressure, as just discussed, and acceleration of head growth. Diagnosis is made best with ultrasound or other brain modality (see the section on diagnosis , later), particularly because ventricular dilation develops before overt clinical signs.

Intracerebral Mass or Extracerebral Collection.

Formation of an intracerebral mass or extracerebral collection of clinical significance is very uncommon in neonatal bacterial meningitis. Brain abscess can occur, particularly in necrotic brain tissue (e.g., infarction), and it should be suspected if existing clinical signs worsen, despite apparently adequate therapy, and if signs of increased intracranial pressure or focal cerebral disturbance develop (see the later section on brain abscess ). Sudden onset of a focal deficit with evidence of a unilateral mass may also occur with a large hemorrhagic infarct. Abscess and massive infarction, although clinically very important, are very unusual in neonatal bacterial meningitis. Subdural effusion should be suspected in the presence of accelerated head growth and signs of increased intracranial pressure. Increased cranial transillumination can be helpful at the bedside. However, clinically significant subdural effusion is very uncommon in neonatal bacterial meningitis. Similarly, subdural empyema is a rare extracerebral collection that may cause signs of increased intracranial pressure in addition to fever and leukocytosis.

Cerebrospinal Fluid Findings.

Examination of the CSF is indicated in any infant with suspected sepsis, even in the absence of overt neurological signs. Indeed, in one series, 37% of cases of primarily early-onset neonatal meningitis would have been missed or the diagnosis delayed if the decision to perform a lumbar puncture had been reserved for infants with neurological signs or proven bacteremia. Similarly, in a series of 9461 very-low-birth-weight infants, one third of those with meningitis had meningitis in the absence of sepsis . Because CSF cultures were performed only half as often as blood cultures, the discordance in blood and CSF culture results suggested that “meningitis may be underdiagnosed among very-low-birth-weight infants.”

Interpretation of the CSF findings in the newborn is difficult, especially when that interpretation is critical in making a diagnosis (i.e., bacterial meningitis) that requires urgent intervention. Among the many reasons for the difficulties in interpretation of the CSF findings, the most important relates to the uncertainty of normal values in the specific population of infants at risk for bacterial meningitis (see Chapter 10 ). Previously published studies dealt with normal or poorly defined populations.

Sarff and co-workers described the CSF findings in 117 high-risk infants (87 term and 30 preterm, with 95% examined in the first week of life) without meningitis or other clinical evidence of viral or bacterial disease ( Table 35.14 ). Mean values for term and preterm infants, respectively, were as follows: white blood cell (WBC) count, 8 and 9 cells/mm ³ (60% polymorphonuclear leukocytes); protein concentration, 90 and 115 mg/dL; glucose concentration, 52 and 50 mg/dL; and ratio of CSF to blood glucose concentration, 81% and 74%. Although the ranges are wide, the values provided a useful framework. A later study by Rodriguez and co-workers amplified these findings by focusing on very-low-birth-weight infants, 80% of whom were examined after the first week of life. CSF findings as a function of postconceptional age were defined ( Table 35.15 ). CSF values for protein and glucose contents are highest in the most immature infants and may reflect an increased permeability of the blood-brain barrier in these infants (see Table 35.15 and Chapter 10 ). These additional features are important in assessing the CSF in the large numbers of very premature infants evaluated in modern neonatal intensive care units.

The CSF formula for neonatal bacterial meningitis is an elevated WBC count predominantly consisting of polymorphonuclear leukocytes, an elevated protein concentration, and a depressed glucose concentration, particularly in relation to blood glucose concentration. The abnormalities tend to be more severe for late-onset than early-onset disease and for gram-negative enteric than GBS meningitis. Of 119 newborn infants with proven bacterial meningitis, more than 1000 WBCs/mm ³ were observed in the initial sample of CSF in approximately 75% of patients with gram-negative infection but in only approximately 30% of those with GBS infection. Values in excess of 10,000 WBCs/mm ³ were observed in approximately 20% of gram-negative infections but were rare in GBS infections. Evaluation of the other end of the continuum is still more informative ( Table 35.16 ). Thus, using the ranges determined in their high-risk newborns (see Table 35.14 ), Sarff and co-workers showed that CSF values for WBC count were within the normal range for approximately 30% of infants with culture-proven GBS meningitis versus only 4% of infants with gram-negative meningitis. Values for CSF protein concentration and the ratio of CSF to blood glucose were within the normal range in nearly 50% of the infants with GBS meningitis versus only 15% to 25% of those with gram-negative bacterial meningitis (see Table 35.16 ). The importance of evaluating all the CSF findings, and not just one isolated value, is emphasized by the finding that only 1 of 119 infants had normal values for all three parameters in the initial lumbar puncture sample . Thus the CSF findings should be evaluated in toto and in the context of other clinical, epidemiological, and laboratory data in assessing the possibility of meningitis. In the rare patient with a totally normal CSF examination but a continuing suspicion of meningitis, a second lumbar puncture is indicated.

Identification of the Microorganism in Cerebrospinal Fluid.

Determination of the bacterial cause of meningitis obviously is made most readily and decisively by culture of the CSF. The yield in the previously untreated patient whose CSF is cultured promptly on the various media necessary to isolate the different microorganisms responsible for neonatal bacterial meningitis (including Listeria ) approaches 100%. The result is usually available within 48 hours.

Faster techniques available for identifying microorganisms include Gram-stained smears, countercurrent immunoelec­trophoresis, limulus lysate assay, and latex particle agglutination. Stained smears demonstrated bacteria on the initial CSF evaluation of 119 newborn infants with meningitis in 83% of patients with GBS meningitis and in 78% of those with gram-negative bacterial meningitis. This universally available, simple procedure should be performed on every CSF sample. Countercurrent immunoelectrophoresis is a sensitive and rapid technique that demonstrates the presence of bacterial antigen within approximately 2 hours. The test was formerly widely used, particularly in the previously treated patient with possible nonviable bacteria in the CSF. Countercurrent immunoelectrophoresis requires specific antiserum, which is available for type III GBS and K1 E. coli (among the common pathogens for neonatal meningitis). Rapid detection of meningitis caused by gram-negative enteric organisms was formerly based particularly on the limulus lysate assay . These last two tests have been largely replaced by latex particle agglutination tests, which is based on the agglutination of specific antibody-coated latex particles by bacterial antigen. The test is particularly useful for GBS and E. coli K1. The assay can provide a result in minutes.

Identification of the Microorganism From Other Sites.

Valuable supporting data and occasionally the only information concerning the precise bacterial cause of meningitis are derived from isolation of the organism or its antigens in body fluids other than CSF. Blood cultures are positive in approximately 50% to 80% of cases of neonatal bacterial meningitis. ^a

a References .

Adjunct Tests.

Adjunct tests that support the diagnosis of bacterial infection include an increase in the absolute neutrophilic band count and particularly the ratio of immature to total neutrophils. Neutrophilic leukocytosis or leukopenia is demonstrable in 50% to 75% of cases. Other tests (e.g., determination of C-reactive protein, erythrocyte sedimentation rate, and IgM level) are somewhat less sensitive. Several studies raise the possibility that detection of certain proinflammatory cytokines, chemokines, adhesion molecules, and cell surface markers may have value in early identification of neonatal bacterial sepsis (determinations in serum) or meningitis (determinations in CSF), even before the onset of clinical disease. More data will be important.

Cerebrospinal Fluid Pressure.

CSF pressure may be a critical factor in determining outcome, and measurements of pressure, especially in the acute stage, can be valuable. The initial lumbar puncture should include CSF pressure measurement, and CSF pressure in excess of normal (i.e., ≈50 mm H ₂ O) should be cause for concern. Continual or frequent intermittent monitoring of CSF pressure with an anterior fontanelle sensor, when available (see Chapter 10 ), can be useful in the evaluation of the degree of cerebral edema, the development of obstructive hydrocephalus, and the occurrence of a major intracerebral mass or extracerebral collection. Clear elevations of intracranial pressure should provoke further, more definitive diagnostic studies and appropriate intervention (see the section on management later). Our initial studies of this issue demonstrated that intracranial hypertension with impaired cerebral blood flow velocity, measured at the anterior fontanelle by the Doppler technique (see Chapter 10 ), was more commonly a complication of bacterial meningitis of older infants than of newborns . This observation concerning intracranial hypertension was confirmed in a later study.

Ventricular Puncture.

Ventricular puncture provides valuable information concerning intraventricular pressure and the presence of ventriculitis, particularly when associated with serious localized infection ( Table 35.17 ). Although only uncommonly necessary , ventricular puncture should be performed in any newborn with bacterial meningitis who is not responding favorably to apparently appropriate antibiotic therapy in terms either of clinical signs or of sterilization of lumbar CSF (see the section on management later). Severe ventriculitis may be present in an infant with improved or even a normal lumbar CSF WBC count. Indeed, the constellation of a deteriorating clinical state (e.g., apnea, bradycardia, or both and persistent fever) in the presence of decreasing CSF pleocytosis or even CSF sterilization should raise the suspicion of clinically important ventriculitis. Moreover, ventriculitis may evolve in a subacute fashion, with signs of increased intracranial pressure, either de novo or after apparent recovery from bacterial meningitis. The presence in ventricular fluid of bacteria (Gram stain or culture) or bacterial antigen (latex particle agglutination) and a WBC count in excess of approximately 100/mm ³ indicates ventriculitis. Cranial ultrasonography often shows excrescences associated with the ependymal surface. Whether ventricular infection is localized and inaccessible to antibiotics depends on evaluation of a variety of factors. Favoring such a possibility is the presence of marked pleocytosis in ventricular CSF or evidence of intraventricular block of CSF flow (e.g., elevated intraventricular pressure and dilated ventricles) or both pleocytosis and CSF block. Management of such a situation is reviewed in subsequent discussions.

Ventricular puncture should be performed by a physician with expertise in the procedure and awareness of its hazards. In acute bacterial meningitis, the lateral ventricles are often small and may be tapped only with considerable difficulty. An ultrasound scan before the procedure is important. Indeed, ventricular puncture with ultrasound guidance is recommended if the ventricles are small. Ventricular puncture may be followed by the development of a cystic cavity. This development is particularly likely to occur if obstruction to CSF flow and increased intraventricular pressure, common complications of bacterial ventriculitis, are present. The subsequent cavitation along the needle track relates most probably to the combination of disruption of edematous, poorly myelinated, readily separable brain parenchyma and transmission of elevated intraventricular pressure. In the large, older series studied by Lorber and Emery, the approximately 50% of infants subjected to multiple ventricular punctures for the treatment of bacterial ventriculitis subsequently developed cystic cavities, demonstrable by ventriculography, at the sites of the taps. The incidence of significant cavity formation in infants with ventriculitis after a single tap is unknown but is probably relatively low. Although small diverticula from the lateral ventricles into the needle track are common after single taps, major cavity formation is very unusual.

Ultrasound Scan.

Cranial ultrasound scan has proved very useful in the evaluation of infants with bacterial meningitis. The spectrum of abnormalities has included both acute changes (e.g., evidence of ventriculitis [intraventricular strands attached to the ventricular surface and echogenic ependyma] [ Fig. 35.13 ], echogenic sulci, abnormal parenchymal echogenicities [periventricular or focal cerebral] [ Figs. 35.14 and 35.15 ], and extracellular fluid collection) and chronic changes (e.g., ventricular dilation [see Fig. 35.13 ] and multicystic parenchymal change). The neuropathological correlates of the sonographic changes include essentially the entire spectrum of the neuropathology (see previous discussion). The particular value of cranial ultrasonography is the capacity to perform serial studies safely and at the patient’s bedside and thus to define progression of complications. Such definition is of major benefit in formulating rational management. Cranial ultrasonography of the thoracolumbar spine might reveal debris within the spinal subarachnoid space. This finding has been associated with an increased risk of subsequent hydrocephalus.

Cranial ultrasound scans in neonatal bacterial meningitis.

(A) Coronal scan obtained from a 27-day-old infant with group B streptococcal meningitis on the third hospital day. Note dense linear strands of echogenic material in the lateral ventricles (arrows) , apparently attached to the ependymal surface, and diffuse low-level echoes in both lateral ventricles. (B) Coronal scan on the fourth hospital day. Note the collection of intraventricular material apparently attached to the ventricular wall (arrow). (C) Parasagittal view of the same scan as in (B). Note abnormal intraventricular echoes (arrow) apparently contiguous with ventricular surface and choroid plexus. (D) Note later development of hydrocephalus and disappearance of abnormal echoes.

Neonatal bacterial meningitis: ultrasound.

This coronal scan obtained from an infant with Escherichia coli meningitis shows an area of increased echogenicity (arrows) in the distribution of the middle cerebral artery, consistent with an infarction.

Neonatal bacterial meningitis: ultrasound.

(A and B) Coronal and parasagittal ultrasound scans from a 2-week-old infant with bacterial meningitis showing areas of echogenicity, most consistent with deep venous infarction. Note on the coronal scan (A) bilateral symmetrical areas of involvement in the region of the basal ganglia (putamen and globus pallidus) (arrows). On the parasagittal scan (B), the involvement is seen not only in basal ganglia (small arrows) but also in thalamus (large arrow) .

Magnetic Resonance Imaging.

As for nearly all other forms of neonatal neuropathology, MRI provides important structural information. In the largest study so far, 75 infants were studied and only 19% had a normal MRI. The most common abnormalities noted were leptomeningeal enhancement (57%) ( Fig. 35.16 ), infarction (43%) ( Figs. 35.17 and 35.18 ), subdural empyema (52%), cerebritis (25%) ( Fig. 35.19 ), hydrocephalus (20%), and abscess (11%) ( Table 35.18 ). All the acute and chronic lesions of neonatal bacterial meningitis are delineated very well by MRI ( Figs. 35.20 and 35.21 ; see also Fig. 35.17 ). Different patterns of injury were recognized in a study of 63 patients with bacterial meningitis (25 neonates and 38 infants), including GBS ( n = 32, mean age 4.7 months), and E. coli ( n = 9, mean age 1.2 months). Ventriculomegaly was especially common in E. coli meningitis compared with GBS meningitis (64% vs. 22%), while infarcts were commonly seen in GBS meningitis (13/32, 41%) and rarely seen with other organisms (2 of 31, 6%, P = .001). There were also three cases with a Serratia meningitis, and these infants had large parenchymal abscesses. The association of GBS meningitis and a pattern of perforator infarction (see Fig. 35.20 ) was also shown in another study. Involvement of the cerebellar tissue can also be present in GBS meningitis and is also better recognized with MRI than with mastoid window ultrasonography (see Fig. 35.21 ).

Neonatal bacterial meningitis: magnetic resonance imaging (MRI).

(A and B) The initial MRI scan, obtained during the acute period, shows, after administration of gadolinium, leptomeningeal enhancement ( arrow in A), consistent with leptomeningitis, ependymal enhancement ( arrows in B), consistent with ventriculitis (with loculation), and evidence of diffuse cerebral white matter injury and more focal bifrontal lesions, possibly infarcts. Three weeks later (C), note marked dilation of the lateral and third ventricles, indicative of hydrocephalus (with a likely block at the aqueduct) and diffuse cerebral cortical and white matter injury, especially bifrontally.

(Courtesy Dr. Omar Khwaja.)

Neonatal bacterial meningitis (group B Streptococcus ): magnetic resonance imaging.

Axial neonatal diffusion-weighted (A) and T2-weighted 3-month (B) images showing increased signal intensity in the frontal cortex and the posterior branch of the middle cerebral artery territory and right posterior limb of the internal capsule in the neonatal period. At 3 months, an area of cavitation is seen in the middle cerebral artery distribution as well as a small cyst in the right frontal region. Ex vacuo dilatation is also seen.

Neonatal bacterial meningitis (group B Streptococcus ), magnetic resonance imaging (MRI).

Axial apparent diffusion coefficient maps (ADC) (A and B) at 35 weeks postmenstrual age, following GBS infection at 34 weeks in a preterm infant with a gestational age of 32 weeks. Low ADC values were present in the posterior cerebral artery distribution and in the left anterior middle cerebral artery distribution. A repeat MRI is performed at term-equivalent age (C). This T1-weighted sequence shows ex vacuo dilation in the left occipital lobe.

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