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Suppurative Infections | Subdural Empyema | Bacterial Meningitis | Brain Abscess | Mycobacterial Infections | Treponemal Infections | Fungal Infections | Cryptococcosis | Viral Diseases | Herpes Simplex Encepalitis | CMV Encephalitis | HIV infections | Prion Diseases | Pathogenesis of Prion diseases | Pathology of Prion Diseases | Creutzfeldt-Jakob Disease

BACTERIAL INFECTIONSThe brain is protected from bacterial invasion from the environment by the skull, the dura, the arachnoid membrane, the pia, and the glia limitans, which is a dense mesh of astrocytic processes on the surface of the brain. Consequently, most bacterial infections spread to the brain by the bloodstream. Bacteria can penetrate into the brain from the environment if there is a break in the continuity of these protective layers. Such a discontinuity may be due to congenital defects (encephalocele, meningomyelocele) or may be caused by trauma or a shunt. Bacteria can also spread to the brain from infected adjacent air sinuses, the middle ear and the mastoids. They can reach the brain either directly through the bone, especially in areas where the bone plate is thin, or through veins (diploic veins, dural venous sinuses, intracerebral veins). The various protective layers may also help contain infections within certain spaces or planes.
An epidural space filled with adipose tissue exists normally around the spinal cord. A spinal epidural abscess arises when organisms from osteomyelitis or tuberculosis of the vertebral column spread to this space. There is no epidural space normally in the cranium. However, a cranial epidural abscess may develop when bacteria colonize a traumatic epidural hematoma, or when infection from air sinuses extends in the plane between the dura and bone.
Subarachnoid space
The coverings of the brainInfection may spread to the subdural space from air sinuses or from the middle ear. The subdural space is traversed by bridging arteries and veins but has no vascular network of its own. Therefore, antibiotics have no access to this space. Treatment of the subdural abscess consists of evacuation plus intravenous antibiotics. Epidural and subdural abscesses are collections of pus. If they are large enough, they compress the brain and spinal cord, resulting in loss of function and increased intracranial pressure. Locally, neutrophils destroy tissues with their enzymes. This damage is followed by formation, in the subdural space, of a vascularized inflamed connective tissue and then a fibrous scar. Histologically, acute subdural empyema shows a layer of neutrophils overlying the arachnoid membrane. The inflammatory cells may infiltrate the arachnoid membrane and extend into the subarachnoid space.
Bacterial meningitis is the infection of the arachnoid membrane, subarachnoid space, and cerebrospinal fluid by bacteria. The subarachnoid space is bounded externally by the arachnoid membrane and internally by the pia, and dips into the brain along blood vessels in the perivascular ( Virchow-Robin) spaces. It extends from the optic chiasm to the cauda equina and surrounds the brain and spinal cord completely.
Meningitis may have a focal origin (sinusitis, mastoiditis, brain abscess, penetrating injury, congenital defect), but more commonly results from hematogenous dissemination. The most common organisms of bacterial meningitis in children and adults are Streptococcus pneumoniae, Neisseria meningitidis, and Hemophilus influenzae. The incidence of Hemophilus influenzae and Streptococcus pneumoniae meningitis in children has decreased significantly after the introduction of conjugated vaccines against these organisms. In newborns, the most common organisms are Eschericia coli and beta hemolytic Streptococcus group B. Babies are frequently infected during passage through the birth canal.

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.

When bacteria die, lipids and oligosaccharides, including endotoxin, are released from their walls. Some of these components cause vascular injury and shock. Symptoms of sepsis may develop and even death from gram-negative shock may occur before any inflammation appears. Bacterial cell wall components also induce meningeal macrophages, astrocytes, and microglial cells to produce interleukin-1 (IL-1), tumor necrosis factor(TNF-α), and other inflammatory mediators. These cytokines attract circulating granulocytes and monocytes into the CSF. As they lyse, granulocytes and monocytes release powerful lysosomal enzymes and free radicals, which destroy neural tissue and damage blood vessels. Polyunsaturated fatty acids released from the membranes of dying neutrophils also cause increased vascular permeability. The results of vascular injury are increased permeability (cerebral edema) and vasculitis (ischemia).

The results of inflammation are tissue and vascular injury (vasculitis) and increased intracranial pressure. Brain tissue, cranial nerve, and vascular injury is caused by lysosomal enzymes and free radicals released by granulocytes and monocytes. Increased intracranial pressure is caused by increased vascular permeability and leakage of proteins in the interstitial space (cerebral edema) and CSF. Vasculitis causes infarcts and increased intracranial pressure causes or aggravates hypoxic-ischemic encephalopathy (HIE).

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 or bending the neck. 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.

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).

Bacteria in CSF Meningitis
Bacteria in the CSF Inflammatory cells in the subarachnoid space
Meningitis Meningitis
Meningitis-purulent exudate Meningitis-purulent exudateThis 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/microliter µL, 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.

Hydrocephalus Bacterial arteritis
Postmeningitic hydrocephalus Vascular narrowing after meningitisThe late complications of meningitis include cranial nerve deficits and ischemic infarction. 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.
Brain atrophy, post neonatal meningitis
Severe brain atrophy post neonatal meningitisThey 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.

Brain abscess is a newly formed cavity in brain tissue, filled with pus. The bacteria that cause brain abscess spread from adjacent air sinuses or the middle ear, or via the blood stream from the lungs (bronchiectasis, lung abscess), or from the heart (bacterial endocarditis). The location of the abscess corresponds to its source. Frontal sinusitis causes frontal lobe abscess, and mastoiditis temporal lobe abscess. Hematogenous abscesses are often multiple.
Cerebritis Brain abscess Brain abscess
Abscess, early phase Frontal lobe abscess Multiple absceses post meningitis
The bacterial flora of brain abscess depends on the source of the infection. In the case of sinusitis and otitis, it is usually mixed, including anaerobes. Bacteremia alone does not cause brain abscess. Some tissue damage, probably a small ischemic lesion, is required to start the process. Bacteria in the blood seed this necrotic nidus and spread around it causing brain necrosis and acute inflammation (cerebritis). The necrotic center cavitates while, at the periphery, a vascular zone of brain tissue with macrophages, mononuclear cells, and reactive astrocytes contains the infection. In 4-5 weeks, collagen (derived from vascular cells) is laid down in this reactive zone forming a thick capsule that walls off the infection. Increased vascular permeability in the inflamed tissue causes cerebral edema. Hypervascularity and vascular leakage account for the “ring enhancing” pattern after contrast injection, which gives abscess its characteristic radiological image (necrotic tumors may have a similar appearance). Systemic antibiotics are effective in the phase of cerebritis. Once a capsule develops, it is a barrier to antibiotics. Thus, the treatment of chronic abscess requires drainage or surgical excision in addition to systemic antibiotics.

Brain abscess causes loss of neurological function due to destruction of brain tissue. More important, it causes increased intracranial pressure. Its mass effect is due to the collection of pus and to cerebral edema around the abscess. Since the infection is contained within brain tissue, the CSF usually shows only a few mononuclear cells with normal protein and glucose.

Further reading

Nau R, Brück W. Neuronal injury in bacterial meningitis: mechanisms and implications for therapy. Trends Neurosci 2002;25:38-45.PubMed

Nigrovic L E et al. Clinical Prediction Rule for Identifying Children With Cerebrosipnal Fluid Pleocytosis at Very Low Risk of Bacterial Meningitis. JAMA 2007;297:52-60. PubMed

Updated: January, 2007