http://neuropathologyweb.org/chapter5/chapter5aSuppurative.

html Pathogenesis
The organisms that cause bacterial meningitis colonize the nasopharynx. From there, they get into the blood stream and enter the subarachnoid space through complex interactions with endothelial cells. The porous structure of choroid plexus capillaries facilitates their spillage into the CSF. The CSF is an ideal medium for the spread of bacteria because it provides enough nutrients for their multiplication and has few phagocytic cells, and low levels of antibodies and complement. Initially, bacteria multiply uninhibited and can be identified in smears, cultures, or by ELISA detection of their antigens before there is any inflammation. Bacterial toxins cause neuronal apoptosis and cell wall lipopolysaccharide, released from bacteria, damages the blood brain barrier (BBB). Increased vascular permeability from BBB damage, in turn, causes cerebral edema, increased intracranial pressure, decreased cerebral perfusion, hypoxia, and neuronal necrosis. Cells of the innate immune system of the brain, located in the BBB, choroid plexus, and ependyma, detect bacteria and secrete cytokines, chemokines, and complement, which attract circulating neutrophils into the CSF. Neutrophils have powerful lysosomal enzymes and free radicals, which they use to kill bacteria, but have a short life span. As they lyse, these compounds are spilled and can destroy everything in their way. If neutrophils accumulate, they can damage brain tissue, nerves, and blood vessels. Vasculitis and clotting cause cerebral infarcts. So, brain damage in bacterial meningitis is caused in part by the direct action of bacteria and in part by the antibacterial inflammatory response. The brain has elaborate mechanisms for controlling inflammation but, in some cases, unbalanced defense reactions can cause severe injury.

Clinical Findings
The initial symptoms of meningitis are fever, severe headache, and stiff neck. The inflamed spinal structures are sensitive to stretch, and pain can be elicited by maneuvers that stretch the spine, such as bending the leg with an outstretched knee (Kernig sign) or bending the neck (Brudzinski sign). As the disease progresses, confusion, coma, and seizures develop. These complications are due to HIE, increased intracranial pressure, and a toxic metabolic encephalopathy. HIE is due to shock. The toxic metabolic encephalopathy is probably caused by unknown diffusible substances (perhaps cytokines) that have a neurotoxic action. In infants, meningitis may present with nonspecific signs such as a depressed state, apneic spells, changes in heart rate, and atypical seizures.

Diagnosis and Pathology

The cornerstone in the diagnosis of bacterial meningitis is CSF examination. The CSF in meningitis shows hundreds, even thousands of neutrophils and is teeming with organisms. CSF

protein is elevated and glucose is low (because it is consumed by inflammatory cells). The CSF:blood glucose ratio is lower than 50%.

Bacteria in the CSF

Inflammatory cells in the subarachnoid space

Meningitis-purulent exudate Meningitis-purulent exudate

A creamy purulent exudate covers the cerebral hemispheres and settles along the base of the brain, around cranial nerves and the openings of the fourth ventricle. The MRI shows enhancement and high FLAIR signal intensity in the meninges, corresponding to the pathology. A child presenting with fever, headache, and CSF pleocytosis is a diagnostic dilemma. Less than 5% of such cases are due to bacterial meningitis and the rest are due to viral (aseptic) meningitis (see viral infections). Yet, to play it safe, physicians admit such patients to hospital and treat them with antibiotics. Unnecessary hospitalizations can be avoided if a standard set of criteria are taken into account. These are: CSF positive Gram stain, CSF absolute neutrophil count (ANC) >100 cells/L, CSF protein >80 mg/dL, peripheral blood ANC >10,000, and a history of preceding seizure. The presence of these findings strongly favors bacterial meningitis. Alternatively, viral PCR of CSF, which has a turnaround time of a few hours, can confirm aseptic meningitis.

Vascular narrowing after meningitis

Postmeningitic hydrocephalus

Severe brain atrophy post neonatal meningitis Neutrophils in the subarachnoid space infiltrate and damage cranial nerves resulting in cranial nerve deficits, and invade leptomeningeal vessels causing phlebitis and arteritis with thrombosis and ischemic infarction. Sinovenous thrombosis may also occur. The thick fibrinopurulent exudate in the subarachnoid space organizes into fibrous tissue that blocks the exits of the fourth ventricle and impairs CSF circulation around the cerebral convexities. This causes hydrocephalus. These complications take time to develop and may appear after the inflammation has subsided. They may be prevented by prompt treatment. The effects of HIE and cerebral infarction are especially devastating in newborn babies in whom the brain can literally melt away. The glia limitans, a thick tight mesh of astrocytic processes, joined by dense junctions and covered by basement membrane, resists penetration by bacteria and neutrophils. Undamaged, it provides an effective barrier that prevents the infection from spreading into brain tissue. Thus, brain abscess as a complication of meningitis is rare. Brain damage in meningitis is caused not only by bacteria but probably more by host responses. These responses have a protective purpose (to eliminate bacteria) but are excessive and indiscriminate and set in motion destructive cascades that damage everything in their way, mostly host tissues. Modulating these reactions, in addition to killing bacteria, can reduce the morbidity and mortality of meningitis.

Cerebrospinal Fluid in Infectious Disease and Related Conditions

The CSF findings in persons with the three major varieties of meningitis have been discussed and are summarized in Table 25-5. Although the differences noted are helpful, it is important to realize that there are exceptions to these rules. Patients with viral meningitis may have more than 1,000 WBCs/cu mm. Acute bacterial meningitis may present with few WBCs for a variety of reasons: (1) the patient's immune response may be inadequate, (2) the leukocyte response may be suppressed by the presence of alcohol in the blood and tissues, (3) the meningitis may have been partially treated, and (4) the tap may have been done early in the course of the disease before cells appeared. In the second and last instances, a repeat tap in two to six hours usually reveals a brisk pleocytosis. Many conditions other than viral infections can produce a modest pleocytosis, normal or elevated levels of protein, and normal (or low) amounts of sugar. These are listed in Table 25-6. Finally, a low level of glucose in the CSF is not pathognomonic of infection. Several mechanisms are invoked to explain the low level of CSF glucose in persons with meningitis: The glucose may be metabolized by organisms, by phagocytes, or by the inflamed meninges and brain. In addition, transport of glucose into the CSF is often blocked in cases of meningitis. Some of these mechanisms may also explain the low level of CSF glucose found in persons with other conditions (Table 25-7). It should be clear, therefore, that although the CSF findings provide important clues to the diagnosis of CNS infections, the definitive diagnosis rests on identifying the causative organism microscopically or by culture. Serologic methods may be useful, but, in general, evidence of rising titers of antibodies to an infectious agent appears after the illness is over. Recent studies indicate that counter immunoelectrophoresis and polymerized chain reaction may be capable of detecting minute amounts of bacterial antigens in the CSF rapidly and thereby enable the rapid and specific diagnosis of meningitis.

Pediatric Bacterial Meningitis

Pathophysiology
Bacteria reach the subarachnoid space via a hematogenous route and may directly reach the meninges in patients with a parameningeal focus of infection. Once pathogens enter the subarachnoid space, an intense host inflammatory response is triggered by lipoteichoic acid and other bacterial cell wall products produced as a result of bacterial lysis. This response is mediated by the stimulation of macrophage-equivalent brain cells that produce cytokines and other inflammatory mediators. This resultant cytokine activation then initiates several processes that ultimately cause damage in the subarachnoid space, culminating in neuronal injury and apoptosis. Interleukin (IL)1, tumor necrosis factor alpha (TNF-a), and enhanced nitric oxide production play critical roles in triggering inflammatory response and ensuing neurologic damage. Infection and inflammatory response later affect penetrating cortical vessels, resulting in swelling and proliferation of the endothelial cells of arterioles. A similar process can involve the veins, causing mural thrombi and obstruction of flow. The result is an increase in intracellular sodium and intracellular water. The development of brain edema further compromises cerebral circulation, and this effect can result in increased intracranial pressure (ICP) and uncal herniation. Increased secretion of antidiuretic hormone (ADH), resulting in the syndrome of inappropriate antidiuretic hormone secretion (SIADH), occurs in most patients with meningitis and causes further retention of free water. These factors contribute to the development of focal or generalized seizures. Severe brain edema also causes midline structures to shift caudally and become entrapped in the tentorial notch or foramen magnum. Caudal shifts produce herniation of the parahippocampal gyri, cerebellum, or both. These intracranial changes appear clinically as an alteration of consciousness and postural reflexes. Caudal displacement of the brainstem causes palsy of the third and sixth cranial nerves. If untreated, these changes result in decortication or decerebration and can progress rapidly to respiratory and cardiac arrest.
Neonatal meningitis

Bacteria from the maternal genital tract colonize the neonate after rupture of membranes, and specific bacteria, such as group B streptococci (GBS), enteric gram-negative rods, and Listeria monocytogenes, can reach the fetus transplacentally and cause infection. Furthermore, newborns can also acquire bacterial pathogens from their surroundings, and several host factors facilitate a predisposition to bacterial sepsis and meningitis.

Bacteria reach the meninges via the bloodstream and cause inflammation. After arriving in the central nervous system (CNS), bacteria spread from the longitudinal and lateral sinuses to the meninges, the choroid plexus, and the ventricles. IL-1 and TNF-a also mediate local inflammatory reactions by inducing phospholipase A2 activity, initiating the production of platelet-activating factor and the arachidonic acid pathway. This process results in production of prostaglandins, thromboxanes, and leukotrienes. Activation of adhesion-promoting receptors on endothelial cells by these cytokines attracts leukocytes, and the release of proteolytic enzymes from the leukocytes results in altered blood-brain permeability, activation of the coagulation cascade, brain edema, and tissue damage. Inflammation of the meninges and ventricles produces a polymorphonuclear response, an increase in cerebrospinal fluid (CSF) protein content, and utilization of glucose in CSF. Inflammatory changes and tissue destruction in the form of empyema and abscesses are more pronounced in gram-negative meningitis. Thick inflammatory exudate causes blockage of the aqueduct of Sylvius and other CSF pathways, resulting in both obstructive and communicating hydrocephalus.

Epidemiology
United States statistics

The advent of vaccine has changed the incidence of pediatric bacterial meningitis. Before the routine use of the pneumococcal conjugate vaccine, the incidence of bacterial meningitis in the United States was about 6000 cases per year; roughly half of these were in pediatric patients (18 years). N meningitidis caused about 4 cases per 100,000 children (aged 1-23 months). The rate of S pneumoniae meningitis was 6.5 cases per 100,000 children (aged 1-23 months). Today, disease caused by H influenzae, S pneumoniae, and N meningitidis is much less common. The advent of universal Hib vaccination in developed countries has led to the elimination of more than 99% of invasive disease. Protection continues even when Hib is coadministered with other vaccines. Just as important, the vaccine continues to confer immunity into later childhood. A similar effect occurs with pneumococcal vaccine. Given at ages 2, 4, and 6 months, this vaccine has reduced invasive disease by more than 90%. Age groups most affected are those younger than 2 years and those aged 2-5 years. This was proven in a surveillance study in Louisville, Kentucky.[4] Nearly half of cases of pneumococcal disease are caused by nonvaccine serotypes.[5, 6] Vaccine for Neisseria, however, has not been efficacious in younger children. This is due to poor immunogenic response. Current recommendations target immunization for children older than 2 years and high-risk patients with asplenic and terminal complement deficiencies. In addition, young adults living in close quarters, such as dormitories or military barracks, will benefit. A study analyzing reported cases of bacterial meningitis among residents in 8 surveillance areas of the Emerging Infections Programs Network during 1998-2007 found a 31% decrease in

meningitis cases during this period and an increase in median patient age from 30.3 years in 1998-1999 to 41.9 years in 2006-2007; the case fatality rate did not change significantly.[7] Overall, approximately 4100 cases of bacterial meningitis occurred annually in the United States from 2003 to 2007, with approximately 500 deaths.[7] The incidence of neonatal bacterial meningitis is 0.25-1 case per 1000 live births (0.15 case per 1000 full-term births and 2.5 cases per 1000 premature births). Approximately 30% of newborns with clinical sepsis have associated bacterial meningitis. After the initiation of intrapartum antibiotics in 1996, the national incidence of early-onset GBS infection decreased substantially, from approximately 1.8 cases per 1000 live births in 1990 to 0.32 case per 1000 live births in 2003.
International statistics

Worldwide, the use of H influenzae type B and pneumococcal vaccines is increasing at a rate faster than that observed with the use of hepatitis B vaccines.[8] In a survey by the Hib and Pneumococcal Working Group, the incidence of meningitis in 2000 varied in different regions of the world. The overall incidence of pneumococcal meningitis was 17 cases per 100,000, with the highest incidence in Africa, at 38 cases per 100,000, and the lowest incidence in Europe, at 6 cases per 100,000.[9] The overall death rate was 10 cases per 100,000. The death rate was highest in Africa, at 28 cases per 100,000, and lowest in Europe and Western Pacific regions, at 3 cases per 100,000. A similar trend was identified for Hib meningitis.[10] The overall incidence of Hib meningitis in 2000 was 31 cases per 100,000. The African region had the highest rate, at 46 cases per 100,000, and Europe had the lowest, at 13 cases per 100,000. The overall death rate was 13 cases per 100,000. The highest death rate was in Africa, at 31 cases per 100,000, and the lowest was in Europe, at 4 cases per 100,000.
Age-, sex-, and race-related demographics

Pediatric bacterial meningitis is most common in children younger than 4 years, with a peak incidence in those aged 3-8 months. Male infants have a higher incidence of gram-negative neonatal meningitis. Female infants are more susceptible to L monocytogenes infection. S agalactiae (GBS) affects both sexes equally. Bacterial meningitis occurs more frequently in black, Native American, and Hispanic children; this is thought to be related to socioeconomic rather than racial factors.