Meningitis means inflammation of the meninges, usually (but not necessarily) due to infection. Although inflammation may selectively involve the dura (pachymeningitis), it more commonly affects the pia and arachnoid membranes (leptomeningitis). Because the cerebrospinal fluid (CSF) circulates between pia and arachnoid, it is invariably involved in the inflammatory process. For this reason, analysis of the CSF is the definitive procedure for diagnosis of meningitis. However, most patients with meningitis are initially diagnosed on the basis of headache and one or more “meningeal signs.” These include neck stiffness, Kernig’s and Brudzinski’s signs. All result from pain produced by stretching of inflamed leptomeninges and nerve roots.

CSF analysis is essential in diagnosing meningitis, and many other CNS infections. CSF is usually collected by lumbar puncture (LP) performed at the bedside. Lumbar puncture is contraindicated if there is infection in the overlying tissues (since this may inoculate the CSF), if there is severe thrombocytopenia or other bleeding disorder, if there is elevated intracranial pressure due to a mass lesion, or if there is spinal block (absence of normal CSF circulation due to a mass lesion in the spinal canal). LP in the setting of an intracranial mass lesion can produce fatal brain herniation. Cerebral abscesses can rupture, producing fatal ventriculomeningitis. In the setting of spinal block, LP can precipitate compressive myelopathy. Therefore, neurologic examination, including fundoscopy to detect papilledema, is mandatory before performing LP. In febrile patients or those with abnormal neurologic examinations, it is standard practice to perform neurimaging prior to LP. Since this procedure may delay diagnosis of bacterial meningitis, appropriate antibiotics should be begun prior to CT and LP whenever bacterial meningitis is suspected. Routine tests on CSF include protein and glucose levels, cell count, Gram stain, and bacterial culture. Opening pressure is recorded with a manometer in millimeters of water and in adults is 100-200 mm (<90 mm in the first year of life).

CSF is generated by the choroid plexus of the lateral, third and fourth ventricles, and is reabsorbed at the arachnoid granulations along the superior sagital sinus. Between these sites, CSF circulates around the brain and spinal cord, including the lumbar cistern, where it is obtained by lumbar puncture. Studies on CSF collected at the lumbar cistern therefore reliably detect inflammation at any site in the leptomeninges. In addition, the CSF and brain interstitial (extracellular) fluid are intimately related, so that inflammation within the brain parenchyma will also produce chemical changes within the CSF. Inflammation causes breakdown of the blood-brain barrier, allowing serum proteins to enter the CSF, increasing the CSF protein concentration. Glucose enters the CSF by facilitated diffusion, so that CSF concentrations normally are about 60% of serum levels. A low CSF glucose level (hypoglycorrhachia) is characteristic of bacterial and fungal meningitis, and appears to reflect damage to glucose transporter systems of the vascular endothelium. Metabolism by infecting organisms does not appear to affect glucose levels to an important degree. It should be noted that low CSF glucose indicates the presence of a diffuse meningeal disorder, and does not occur with localized cerebritis or brain abscess. In contrast, elevated CSF protein may be seen with focal or diffuse disease processes. Finally, leukocytes within the CSF are derived from peripheral blood. The type of leukocyte present reflects the nature of the inflammatory reaction: phagocytosis of bacteria (neutrophils), or cell-mediated immunity (lymphocytes and monocytes).

Bacterial meningitis is an inflammatory response to bacterial infection of the leptomeniges and subarachnoid space. Bacteria gain access to these sites by four mechanisms: 1. Hematogenous spread (the most common route), 2. Direct spread from parameningeal infections (ear, sinus, dental infections, epidural abscesses, etc.), 3. Traumatic or surgical disruption of the meninges, 4. Rupture of a cerebral abscess into the ventricular or subarachnoid space. The most common organisms vary by patient’s age and clinical status.

Bacterial meningitis typically presents as an acute febrile illness, with headache, neck stiffness, photophobia, meningeal signs, and alteration of mental status. It is easy to diagnose meningitis in this setting. However, infants, the elderly, and immunocompromised patients may present with lethargy, behavioral changes, and low-grade fever. A high index of suspicion (and a willingness to perform lumbar puncture) is therefore required to make the diagnosis in atypical cases. Bacterial meningitis is invariably fatal if not treated, but responds quickly to antibiotics in the majority of cases. It is one diagnosis that the clinician should try never to miss. Diagnosis depends on lumbar puncture. Cranial neuroimaging should be performed before LP in patients with focal neurologic signs, evidence of increased intracranial pressure, and fever. If neuroimaging significantly delays performance of LP (as if often does), empiric antibiotic therapy should be begun before the LP is done. Since antibiotics take many hours to sterilize the CSF, beginning them 1-2 hours before LP does not decrease the diagnostic sensitivity. Blood cultures should always be done prior to antibiotics, however. Blood cultures show the infecting organism in 50% of cases, underlining with the importance of bacteremia in pathogenesis. CSF shows elevated opening pressure (200-500 mm water), elevated protein (100-500 mg/dl), low glucose (<40% serum glucose), and 1,000-10,000 WBC with 60% or greater neutrophils. Very early meningitis, and meningitis occurring with immunosuppression may show fewer white cells. Listeria sometimes results in a monocytic pleocytosis (hence the name, Listeria monocytogenes). Gram stain is positive in at least 60% of meningitis cases, and culture in at least 75%. In cases where culture is negative, the presence of specific bacterial antigens can be tested for in the CSF.

Treatment consists of intravenous antibiotics, ideally tailored to the specific organism and its antibiotic sensitivities. Since treatment is usually begun before these are known, empiric treatment is based on patient age and other clinical characteristics.Treatment duration varies according to organism, but is usually 10-14 days. LP following treatment is done only if relapse is suspected. Adjunctive therapy with dexamethasone is given to interrupt the release of inflammatory cytokines from CSF leukocytes.

Prevention of bacterial meningitis is possible in some situations. Vaccine to H. influenzae type b is given at 2,4, and 12-18 months. Vaccination, begun in the U.S. in 1987, has reduced by 82% the incidence of H. influenzae meningitis in childhood. Patients with surgical or functional asplenia are prone to pneumococcal meningitis, and are immunized with pneumococcal polysaccharides (Pneumovax). A vaccine against meningococci also exists, and is often given to military recruits and travelers to endemic areas, such as West Africa. Household members and other close contracts of patients with meningococcal meningitis are treated prophylactically to prevent meningitis. Despite antibiotic treatment, mortality from bacterial meningitis is 10-30%. Multiple CNS complications are possible. Inflammation of arteries and veins can produce ischemic strokes, after which the brain itself can be invaded by bacteria, producing cerebritis. Both infarction and cerebritis can lead to focal neurologic deficits, seizures, and brain edema. Cranial neuropathies (especially of nerves VI and VIII) may result from damage during their subarachnoid course. Subdural effusions and empyemas often develop in children. Hydrocephalus, either communicating or noncommunicating, may develop as a result of scarring of the meninges and arachnoid villi.

When death occurs within a day or so after infection (such as is often the case in meningococcal meningitis), there may be very little or no cellular inflammation within the meninges despite the presence of numerous organisms. However, congestion of leptomeningeal blood vessels may be severe. After a day or so of infection, a prominent polymorphonuclear response is nearly always present within the subarachnoid space. Both intra- and extracellular bacteria may be identified by Gram stain. The pia mater/glial limitans prevents bacterial spread into the adjacent brain. However, diffusion of cytokines (Il-1, TNF) as well as local secretion by resident microglia leads to microvascular instability with resultant cerebral edema and reactive astrocytic proliferation. It is often this profound cerebral edema that leads to the patient’s death, when increased intracranial pressure prevents adequate cerebral perfusion. Since the cytokine cascade is initiated by fragments of bacterial wall (dead or alive), current efforts are being directed towards: 1) eliminating bacteria without lysis; and 2) inhibiting amplification and expression of this inflammatory cascade. In more chronic cases (lasting more than a week or so) polymorphonuclear cells are replaced by macrophages, lymphocytes and plasma cells. Obstructive hydrocephalus is nearly always present, and phlebitis and/or arteritis may result in cerebral infarction with secondary cerebritis. Damage to cranial nerve roots is also common at this stage.


 

Mycobacterium tuberculosis involves the nervous system in approximately 1% of cases, and can produce chronic meningitis, focal lesions (tuberculomas), and compressive myelopathy due to osteomyelitis of the spinal column (Pott’s disease).

TB initially infects the lungs, then spreads hematogenously to the CNS. Meningitis may occur at the time of primary infection. More commonly, the bacteria spread to the brain or meninges at the time of primary infection, but are encapsulated by the cellular immune system in granulomas. Years later, decline of the immune system produces reactivation and consequent meningitis. In the U.S., HIV infection is a common cause of such reactivation.

TB meningitis typically follows a gradually progressive course over one, two, or more weeks. Initial symptoms are headache and low-grade fever. Headache and fever gradually worsen, and are joined by neck stiffness, photophobia, seizures, decline in level of alertness and cranial nerve palsies. Cranial nerve palsies are particularly common in TB meningitis (25% of cases), since the meningeal exudate is concentrated at the base of the brain and around the brainstem. The disease is fatal if untreated. Hydrocephalus and strokes are common, as in advanced bacterial meningitis. Unfortunately, TB meningitis is often challenging to diagnose. The tuberculin skin test (PPD) is positive in only 50% of cases. Chest x ray is abnormal in 75% of patients. CSF is always abnormal, with elevated pressure, 100-500 WBC (predominantly lymphocytes), elevated protein (60-500 mg/dl), depressed glucose (10-30 mg/dl). Acid fast bacilli (AFB) are seen on only 10-30% of CSF smears. Although Mycobacterium cultures are positive in 50-75% of patients, they take 3-8 weeks to process. The sensitivity of both AFB staining and culture is improved by using large (10-20 cc) volumes of CSF, and repeating LP several times. In addition, polymerase chain reaction (PCR) techniques and other assays for mycobacterial antigens are often used to improve speed and sensitivity of diagnosis. MRI showing localized enhancement of the meninges at the base of the brain and within the Sylvian fissure also supports the diagnosis. Treatment is with a multidrug regimen. Despite treatment, mortality is 21% in immunocompetent patients, and 33% for HIV-infected patients.

Tuberculosis meningitis characteristically produces a thick exudate at the base of the brain, which also envelops the spinal cord. Inflammation of vessel walls, resulting in thrombosis and cerebral infarction, may be prominent. In patients surviving more than a couple of days, acid-fast bacilli are accompanied by granulomatous meningeal inflammation. Obstructive hydrocephalus may ensue. Cranial and spinal root damage by the inflammatory process is common.

Brain abscesses are areas of bacterial growth in the brain parenchyma, with associated inflammation, necrosis, and fibrosis. They are relatively rare, accounting for about 1 in 10,000 hospital admissions. Abscesses usually occur in three clinical settings: 1. A contiguous focus of infection. Approximately 45% of abscesses are of this type. Infections extend into the brain through an area of osteomyelitis, or via retrograde spread through diploic veins (venous channels linking intracranial and extracranial venous systems). Middle ear and mastoid infections produce abscesses in the contiguous temporal lobe and cerebellum. Frontal sinusitis can lead to frontal lobe abscess. Dental abscesses in the upper jaw can also produce brain abscesses. 2. Hematogenous spread from a distant focus of infection. Although classically reported as the etiology in 25% of abscesses, it is becoming more common. Lung infections are the most common cause, with endocarditis, osteomyelitis, and abdominal and pelvic infections also frequent. Hematogenous spread of infection more commonly results in multiple abscesses with increased mortality. In children, cyanotic heart disease with right-to-left shunt may be the most common underlying cause of brain abscess. 3.Cranial trauma or surgery. A wide range of infecting organism has been reported, and 30-60% of abscesses show more than one organism. Except for pneumoccocus and H. influenzae, organisms that cause meningitis are rare causes of brain abscess, and vice versa.

Symptoms and signs reflect an enlarging brain mass, rather than a systemic infection. Thus, fever is noted in less than 50% of patients on presentation. Headache is the most common manifestation, followed by focal neurologic deficits, fever, seizures, nausea, papilledema, impaired alertness, and stiff neck. Many patients have a mild hemiparesis. Only ~60% of patients have a leukocytosis on routine laboratory studies. Blood cultures should be done, but are rarely positive. Diagnosis is confirmed by imaging (CT or MRI, with contrast). CT shows a round area of hypodensity (necrosis) with an enhancing capsule, surrounded by edema (a “ring-enhancing” lesion). Lumbar puncture should be avoided due to the risks of herniation, and of abscess rupture into the ventricles or subarachnoid space. At any rate, LP rarely yields positive cultures. Medical management alone is typical in patients with small abscesses, early abscesses without a clear capsule, multiple abscesses, and deep abscesses. Other abscesses are surgically drained, usually stereotactically. Drainage is also indicated if there is mass effect with risk of herniation. Pus is cultured, which aids in choosing antibiotic treatment. Empiric antibiotics regimens are designed to provide broad coverage of Gram positive and negative organisms, aerobes and anaerobes.

Bacterial abscesses begin as localized areas of acute inflammation within the brain parenchyma (“cerebritis”). The brain parenchyma responds with proliferation of vascular adventitial fibroblasts which form a wall of granulation tissue around the inflammatory focus. With continued infection/inflammation the center of the lesion undergoes liquefactive necrosis to form pus, while the granulation tissue proliferation continues with collagenization of the abscess capsule. As formation of collagen entails oxygen dependent biochemical reactions, the capsule is better formed toward the better vascularized cerebral cortex. As the osmolality increases within the creamy center, pressure within the abscess rises. With inadequate or delayed treatment, the abscess may rupture through the thinnest part of the capsule and into the ventricular system, usually resulting in death. Even without rupture, the abscess behaves as an expanding mass lesion, which may lead to cerebral herniation.