Pathology of Meningitis and Ventriculitis in Children

Pathophysiology

Meningitis is often classified as septic (or acute bacterial meningitis), versus subacute or chronic (or aseptic) meningitis, commonly associated with viral, fungal, or protozoal infections.

Bacterial meningitis

• Source of asymptomatic carriers: Asymptomatic carriage of bacteria, including S. pneumoniae, H. influenzae, and N. meningitidis is fairly common, with 5% of unvaccinated children up to 4 years of age carrying H. influenzae type b and up to 10% of healthy adults harboring N. meningitidis in the nasopharynx.
• Airborne infection: The encapsulated bacteria that cause acute bacterial meningitis usually gain access to the host after respiratory colonization. The bacterial capsule is an important factor in adhesion to the respiratory epithelium for both gram-positive and gram-negative bacteria. Any compromise of the respiratory epithelial cell lining, such as viral infection, trauma, or surgery, may allow access of bacteria across the epithelial barrier into the blood stream. The bacterial capsule may also play a role in invasion.
• Direct inoculation: Direct access of bacteria to the bloodstream may occur in trauma, surgical or dental procedures, or in the presence of indwelling vascular or extravascular catheters.
• Initial host response: Once the bacteria have gained access to the bloodstream, the status of the host defenses is key to the subsequent outcome. The bacterial capsule inhibits phagocytosis and complement activity, allowing greater time for further bacterial replication. The presence or absence of specific antibodies to the invading bacteria determines the humoral immune response. Neonates have not yet developed specific humoral immunity and are thus more susceptible to infection with encapsulated bacteria. The spleen plays an important role in the elimination of bacteria from the bloodstream, and patients without a normal functioning spleen are also more susceptible to infection.
• Innoculation of CSF: After entrance into the bloodstream, bacteria gain entry into the CSF through the choroid plexus, initial causing a choroid plexitis. Bacteria can then circulate in the CSF, with little immune response in this protected environment.
• Development of clinical meningitis: Once the bacteria reach the leptomeninges, rapid replication results in activation of cytokine cascades and an inflammatory process leading to meningitis. Inflammation of the meninges results in the clinical symptoms of headache, nausea, vomiting, irritability, lethargy, and fever, along with the clinical signs of nuchal rigidity and photophobia.
• Sequelae: Seizures may result from brain involvement. Increased ICP results from fluid leakage through a damaged blood-brain barrier, resulting in cerebral edema and altered metabolism, and alterations in cerebral blood flow. This may lead to cerebral venous obstruction, which in turn may result in focal ischemia, venous thrombosis, and worsening edema. The purulent material in the subarachnoid spaces may interfere with CSF circulation, resulting in hydrocephalus. Severely increased ICP may eventually result in transtentorial herniation and death.

Tuberculous meningitis

• Airborne: Transmission of Mycobacterium tuberculosis from person to person occurs via aerosolized droplet inhalation. In the lungs, the bacteria divide within alveolar macrophages and then spread through the blood stream in 2–4 weeks.
• Bloodborne seeding of CSF: Once in the bloodstream, the bacilli gain access to the vascular spaces of the CNS as well as other extrapulmonary sites. In the vascular spaces of the CNS they produce granulomas in the meninges and brain parenchyma, which are known as Rich foci. These foci can remain dormant for years.
• Development of clinical meningitis: When one of these Rich foci empties into the subarachnoid space, meningitis results. The M. tuberculosis bacilli then enter the CNS through the blood-brain barrier. Factors influencing the development of disseminated infection and meningitis include the virulence of the particular strain of M. tuberculosis involved, as well as host factors including immune system status. The bacteria survive within host macrophages, and immunocompromised hosts are limited in the ability to eliminate them.
• Sequelae: TB produces a thick basal meningitis, which may result in hydrocephalus. Cranial nerves are often thickly coated along the brainstem, and TB meningitis causes a reactive vasculitis resulting in both arterial and venous occlusion and subsequent cerebral infarction.

Viral meningitis

• Airborne or ingestion: Viruses commonly reach the CSF via a hematogenous route after respiratory or gastrointestinal entry into the body. There is less cytokine activation than in the case of bacterial meningitis.
• Bloodborne seeding of CNS: Passive transport of virus across the blood-brain barrier may provide initial entry of virus to the CNS.
• Development of clinical meningitis: Choroid plexitis develops, but to a lesser degree than in bacterial meningitis. The cytokine response is less than with bacterial meningitis, and thus the clinical manifestations of viral meningitis are milder.
• Sequelae: If the viral infection is able to spread into the brain, more serious signs and symptoms may occur, with seizures, neurological deficits, and alterations in consciousness. Demyelination may result from damage to oligodendroglia.

Fungal meningitis

• Airborne, contamination, or membrane break: A fungus can gain access to the host via the respiratory tract. It can also infect via catheters or breaks in the body’s membranes. In premature infants, Candida sepsis may be secondary to indwelling arterial or venous catheters, or after prolonged antibiotic therapy (26). Up to 50% of infants who develop systemic Candida infection have been shown to have prior mucous membrane colonization with Candida. Disruption of these mucous membranes may provide an entry of the organism into the blood stream. Cryptococcal meningitis is commonly seen in patients with HIV/AIDS or immunocompromised patients after bone marrow or solid organ transplantation (65).
• Hematogenous spread to CNS after host introduction: Fungal meningitis commonly results from hematogenous spread to the CSF, possibly after initial respiratory access to the body.
• Development of clinical meningitis: As in viral meningitis, the inflammatory response is more chronic with a lymphocytic predominance.

Ventriculitis

• Alone or as a sequela to meningitis: Ventriculitis, either alone or in the setting of meningitis, is characterized by choroid plexitis, with inflammatory response in the ependymal lining of the ventricles. Obstructive or multiloculated hydrocephalus is most commonly seen in bacterial infections and may be difficult to treat.
• Gram-positive organisms most common in patients with implants: Gram-positive bacteria, especially Staphlococcal species, are most common in infections involving ventricular reservoirs, external ventricular drainage catheters, or ventricular shunts.
• Gram-negative organisms: Gram-negative bacteria are an important cause of postoperative ventriculitis and meningitis in neurosurgical patients (6).
• Secondary to meningitis: Ventriculitis occurring in the setting of meningitis is common and has no additional clinical significance, unless the purulent material results in occlusion of the CSF pathways, causing obstructive or multiloculated hydrocephalus.

Micropathology

The CSF obtained from lumbar puncture should be stained for microorganisms (Gram stain for bacteria, India ink or KOH prep for fungi, acid-fast stain if tuberculosis is suspected), and a rapid technique for detection of bacterial antigens such as latex agglutination should be performed. The CSF should be cultured for bacteria and for other organisms as clinically indicated, including fungi, mycobacteria, or viruses (58, 68).

Acute bacterial meningitis

• Bacteria – Gram stain usually positive if cell count >100,000: The Gram stain may provide rapid identification of the bacteria causing acute meningitis. The sensitivity of the test is dependent on the number of bacteria present in the CSF. If there are fewer than 10,000 cells/ml, as may be present in early or partially treated meningitis, then bacteria are seen in less than 50% of cases. If there are more than 100,000 cells/ml, then the Gram stain is positive in up to 90% of cases. In the majority of cases of either N. meningitidis or S. pneumoniae meningitis, the organisms may be identified on Gram stain. In contrast, meningitis caused by L. monocytogenes has a positive Gram stain in only 50% of cases because only a smaller number of bacteria (approximately 1,000 cells/ml) are present in the CSF.

Organism	Expected Finding
S. pneumoniae	Encapsulated gram-positive cocci in chains
N. meningitidis	Encapsulated gram-negative diplococci
H. influenzae type b	Encapsulated gram-negative coccobacillus

Gram stain findings (31): The expected findings on microscopic examination of Gram-stained CSF for each type of meningitis listed.

• Bacterial cultures – high yield unless previously treated: The yield of positive CSF cultures falls from 85% to below 50% in those patients previously treated with antibiotics, despite no other changes in CSF parameters. It is imperative to use appropriate media for CSF cultures, including blood and chocolate agar, as well as in broth. If fungal or TB meningitis is suspected, appropriate media should be utilized.
• Neonatal meningitis: Group B streptococcus infections are the most common causes of meningitis in neonates and may present as either early-onset, in the first week of life, or late-onset, occurring after the first week of life. Gram-negative bacilli account for 30–40% of meningitis cases, with E. coli responsible for about half of these infections, followed by Klebsiella species (19, 38). Other bacteria causing neonatal meningitis include Enterobacter, Citrobacter, and Serratia species (50).
• Childhood meningitis: In young children pneumococcal meningitis is slightly more common than meningococcal meningitis (N. meningitidis), but this reverses with aging.

Bacterial meningitis: A neutrophil infiltrate in acute meningitis that involves the subarachnoid space is shown (H&E x 20). (Photomicrograph courtesy of Thomas J. Cummings, M.D., Department of Pathology, Duke University Medical Center, Durham, NC.)

Tuberculous meningitis

• TBidentified with acid-fast stain: M. tuberculosis may be identified as acid-fast bacilli on acid-fast stains. Microscopic examination of the CSF may reveal the organism in only 5–30% of patients, due to low bacterial counts in the CSF. In HIV-positive patients with TB meningitis, CSF smear is positive in 69% of cases.
• TB cultures take several weeks to grow: Cultures may take several weeks to turn positive in 45–90% of cases. In HIV-positive patients with TB meningitis, cultures are positive in 88% (69).
• Small population makes identification difficult: Microscopic examination of the CSF may reveal the organism in only 5–30% of patients due to low bacterial counts in the CSF, and cultures may take several weeks to turn positive in 45–90% of cases.

Viral meningitis

• Viral cultures are positive in only 25%: Viral cultures of CSF are of low yield, typically less than 25%. Throat and rectal cultures may be positive for enteroviruses. Since there is no virus-specific therapy for viral meningitis, the main value of viral cultures is for epidemiologic studies. If encephalitis is part of the differential diagnosis, then viral cultures should be performed. Since most infants and children with bacterial meningitis will also be bacteremic, blood cultures may be useful in identifying an organism causing meningitis if CSF cultures are negative.
• Enterococcus, arboviruses, herpes simplex, and adenoviruses: The most common causes of viral meningitis are enteroviruses (48). The infection is transmitted from person to person by a fecal-oral route. The incubation period is 3–6 days, but fecal excretion and possible transmission of virus may continue for several weeks. Other viruses that may cause viral meningitis include arboviruses such as the California and St. Louis encephalitis viruses, herpes simplex virus, and adenovirus. Rarely, HIV and Epstein-Barr virus (EBV) have been shown to cause meningitis.

Immunohistochemical stain for varicella-zoster virus encephalitis in a HIV-positive individual: (x 20). (Photomicrograph courtesy of Thomas J. Cummings, M.D., Department of Pathology, Duke University Medical Center, Durham, NC.)

Fungal meningitis

• KOH prep or India ink: Fungal stains, such as KOH or India ink stains may be used to identify Candida, Cryptococcus, or Aspergillus infections. India ink stain is particularly useful for cryptococcal meningitis as it will show budding yeast in 70% of cases (70).

Type of stain	Finding
India ink prep	Halo ring of capsule of Cryptococcus
KOH prep	Branching hyphae of fungal elements

 

Expected findings for fungal stains: Shown are findings that can appear for each type of stain.

• Slow-growing in cultures: Fungal cultures may take several days to turn positive.

Aspergillus infection of the brain: A coronal section of post-mortem tissue with a fungal abscess is shown in a patient with aspergillosis. (Photomicrograph courtesy of Thomas J. Cummings, M.D., Department of Pathology, Duke University Medical Center, Durham, NC.)