Central Nervous System Infections
Benjamin H. Schnapp
Corlin Jewell
THE CLINICAL CHALLENGE
Infections of the central nervous system (CNS) can be rapidly fatal and require prompt intervention in order to maximize good outcomes. Providers are forced to act quickly to provide treatment, often without knowing the exact underlying pathology. Many patients will have a nonspecific presentation with a wide differential diagnosis. Although fever is common in pathologies such as meningitis (inflammation of the meninges) or encephalitis (inflammation of the brain), it may not be present in other types of CNS infections, such as neurocysticercosis or opportunistic fungal infections in immunocompromised patients.
More than half of cases of bacterial meningitis in the United States are caused by Streptococcus pneumoniae.1 However, Neisseria meningitidis, Escherichia coli, Haemophilus influenzae, and Listeria monocytogenes also represent frequently isolated bacterial species. Even with treatment, mortality is as high as 16%.2 Mycobacterium tuberculosis also represents a common cause of meningitis worldwide, with as many as 1% to 2% of patients with active tuberculosis (TB) being affected by CNS infection. As with many CNS infections, meningitis secondary to M tuberculosis is more frequently seen in patients with compromised immune systems, such as those afflicted by human immunodeficiency virus (HIV).
Viral meningitis is the most common CNS infection; it is generally associated with lower morbidity and mortality than bacterial meningitis. Enteroviruses are the most common infectious pathogens, particularly in warmer seasons. However, other important pathogens include herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and HIV. Often, the exact pathogen is not identified. Owing to modern vaccination practices, rates of certain previously common etiologies of viral meningoencephalitis, such as measles and mumps, have decreased. Although viral infections are typically less severe and often have excellent outcomes, many features of bacterial and viral meningitis overlap, making the distinction between them difficult, especially at the onset of disease.
Certain fungal species can also invade the CNS. The most common being Cryptococcus neoformans, followed by Coccidioides immitis. Mucormycosis can also spread to the CNS; diabetic patients are at higher risk for this severe invasive infection. Other common invasive fungal species, such as Aspergillus and Candida, only rarely cause meningitis. Fungal CNS infections were previously found mainly in patients with HIV/acquired immunodeficiency syndrome (AIDS), but the
incidence has been increasing because of the greater numbers of patients on chronic immunosuppression for transplanted organs and autoimmune conditions.
incidence has been increasing because of the greater numbers of patients on chronic immunosuppression for transplanted organs and autoimmune conditions.
The most common parasitic CNS infection worldwide is neurocysticercosis, mostly occurring in lower income countries.2 This is caused by ingestion of the larva of the tapeworm Taenia solium, classically from eating undercooked infected pork products. Another common CNS parasite is Toxoplasma gondii; Although widely prevalent in the population, it generally causes no symptoms but can cause active infection in patients with decreased immunity. Infrequently, other species of worms, such as Strongyloides, can also cause meningitis.
Infectious encephalitis, a more severe infection, can caused by bacterial, viral, fungal, or parasitic infections and will commonly present with focal neurologic symptoms, behavioral change, cognitive deficits, or even seizures.3 The most common causes of meningoencephalitis are summarized in Table 18.1.
Intracranial abscesses are distinct from the granulomas that form secondary to parasitic and TB infections and most often occur in those with immune disorders or recent surgery. Rarely, they can occur in healthy individuals with normal immune systems. Infections are most commonly caused by Streptococcus species, followed by Staphylococcus (predominantly S aureus) and gram-negative bacteria (Proteus, E coli, etc.). Mortality rate, although still relatively high, has declined to as low as 10% in recent years, likely secondary to advanced diagnostic and treatment modalities.4
The epidural space represents another site where CNS abscesses can occur. Unlike many of the other types of CNS infections discussed in this chapter, the incidence of epidural abscess has been increasing in recent years, likely caused by an increase in spinal procedures, increasing numbers of immunocompromised patients, and high numbers of intravenous (IV) drug users. S aureus is the most common pathogen involved in epidural abscesses, with a high proportion of methicillin-resistant S aureus (MRSA). Although rare, mycobacteria and fungi also can cause spinal epidural abscesses.
Finally, prions represent an unusual form of CNS infection. They are transmissible misfolded proteins that, once acquired, induce progressive, fatal CNS disease. They induce a group
of disorders known as transmissible spongiform encephalopathies (TSEs). TSEs are very rare, but include Kuru, Creutzfeldt-Jakob disease (CJD), and fatal familial insomnia (FFI), with CJD being the most common.9
of disorders known as transmissible spongiform encephalopathies (TSEs). TSEs are very rare, but include Kuru, Creutzfeldt-Jakob disease (CJD), and fatal familial insomnia (FFI), with CJD being the most common.9
TABLE 18.1 Common Etiologies of Meningoencephalitis in Adults | ||||||||||||||||||||||||||||||||||||
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PATHOPHYSIOLOGY
Normally, the cerebrospinal fluid (CSF) is a sterile liquid bathing the structures of the CNS. In order for microorganisms to enter this space, they must pass through the blood-brain barrier (BBB), a collection of endothelial cells whose primary function is to protect the brain from harmful substances in the blood. The simplest way for pathogens to pass through the BBB and gain access to the CNS is through direct contiguous spread from an infection in an adjoining structure. Common points of entry include the mouth, sinuses, or ear. Another potential direct entry point is through penetrating traumatic injury to the skull or a neurosurgical procedure. Pathogens may gain access to the CNS via hematogenous spread as well.
In bacterial meningitis, the presence of bacteria in this normally sterile space elicits an inflammatory response, leading to the characteristic symptoms of the disease. This inflammatory response can lead to the release of inflammatory cytokines to such a degree that cerebral edema results, as proteins and fluid leak through the altered BBB. In some cases of tuberculous meningitis, granuloma formation can also occur, causing mass effects. If these granulomas rupture, severe vasculitis may result and cerebral blood flow can be threatened, resulting in stroke.
Some viruses, such as HSV, herpes zoster virus (HZV), and rabies, have a unique way of entering CNS tissue not seen in other pathogens. In addition to hematogenous spread, these viral pathogens can travel along the axons of peripheral nerves backward until they reach the CNS. The virus can lie dormant within the host, potentially for years, until the immune system is compromised, allowing viral reactivation to occur. The virus then spreads via retrograde passage into the CNS, leading to the development of meningitis or encephalitis. Fungal CNS infections typically occur when a previously existing systemic fungal infection penetrates the BBB in an immunocompromised patient. CNS infection with mucormycosis, for example, is caused by direct spread from an existing sinus infection.
The development of an abscess within the brain can occur via different mechanisms, similar to other forms of CNS infection. Most brain abscesses are thought to occur through contiguous spread, with a smaller proportion caused by hematogenous seeding from infections present elsewhere. Typically, these abscesses are found near their inciting infection, such as otitis or mastoiditis. They can also result from neurosurgical procedures that require direct access to the CNS. The expected pathogen is based on the mechanism of entry into the CNS, but Streptococcus and Staphylococcus species are common. Just as with other infections of the CNS space, the resultant inflammation of the surrounding tissue can result in severe edema of the surrounding brain tissue, which can result in permanent neurologic deficits.
Epidural abscesses can occur along any portion of the spinal cord but are most commonly found in the posterior portion of the thoracolumbar spine. Most occur via hematogenous spread, followed by contiguous spread from adjacent infection, including osteomyelitis and psoas abscesses. Direct inoculation from spinal operations can also occur. This can lead to focal neurologic deficits from compression of the cord or the cauda equina.
Parasitic CNS infections also occur via hematogenous spread. The parasite T solium enters its host once its eggs are ingested via contaminated food. Once inside the human gastrointestinal (GI) tract, the eggs hatch and the larvae pass through the intestinal mucosa. They are distributed throughout the body and encyst. Those that pass through the BBB to form cysts within the CNS are thought to survive via protection from the host immune system by the BBB itself. Eventually, these cysts are discovered by the immune system and the resultant response will cause the cyst to become granulomatous and then finally clear into a calcified scar within the brain. Symptoms in the human host are caused by the inflammatory reaction of degenerating cysts or via mass effect if significant clusters build up within the parenchyma. Figure 18.1 shows the characteristic cysts of neurocysticercosis. Toxoplasmosis is acquired from ingestion of meat contaminated with animal feces, or transplacental. Following primary infection, the parasite forms cysts in various structures, including the CNS. These can persist in a lifelong dormant state but can become reactivated if the host becomes immunocompromised, leading to active symptoms of encephalitis.
 Figure 18.1: Multiple cystic lesions in a patient with neurocysticercosis as seen on CT scan. By Indmanuaba (Creative Commons Attribution-ShareAlike License), via Wikicommons. CT, computed tomography. |
In prion disease, the abnormal proteins are present in their normal configurations in healthy individuals but become misfolded and therefore resistant to protease activity. It is unknown what initially causes the abnormal folding of these proteins, but it appears to develop sporadically, through inheritance, or acquired by contact with affected brain tissue. Once present, the proteins spread the misfolded state to healthy proteins and eventually accumulate and form vacuoles that destroy neurons.
PREHOSPITAL CONCERNS
The focus for prehospital providers is on recognizing critical patients and transporting them to the closest appropriate hospital. Given that many CNS pathologies can result in altered mental status and loss of protective airway mechanisms, an assessment of the patient’s airway and ability to oxygenate should be completed first following local emergency medical service (EMS) protocols. If there is a concern for bacterial meningitis (eg, a febrile patient with a headache and altered mental status), the patient and crew should maintain droplet precautions by using personal protective equipment to prevent the spread of the disease. If possible, IV access should be obtained and crystalloid fluid resuscitation started.
If seizures occur prior to arrival at the emergency department (ED), abortive therapy with intramuscular (IM) midazolam or lorazepam, or IV lorazepam is recommended. There is no evidence supporting the use of prehospital antibiotics; sepsis studies on prehospital antibiotics have not demonstrated improved mortality, and we currently do not recommend prehospital antibiotic treatment. If bacterial meningitis from meningococcus is confirmed, providers in close contact with the patient’s respiratory secretions (eg, the provider who intubated) should receive antibiotic prophylaxis (see discussion below and Table 18.2).5
APPROACH
Meningitis
Classically, bacterial meningitis presents with fever, nuchal rigidity, and headache from the systemic and localized inflammatory responses. The majority of patients will present with at least one of these classic signs.1 However, relatively few patients present with all three components of this triad. Other common symptoms include nausea, vomiting, fatigue, and body aches. Viral meningitis presents similarly, but symptoms are typically less severe and more subacute in onset.
Risk factors for meningitis include immunocompromise (including diabetes), malignancy, pulmonary disease, and residence in a group home.6 All patients with suspected meningitis should have a focused history taken with attention to the symptoms and risk factors above, along with a full neurologic examination. Although patients with meningitis may initially appear altered because of lethargy
or severe headache, they generally do not exhibit focal neurologic deficits. If these signs are present, then infection of the brain parenchyma itself, that is, encephalitis, should be considered. In addition to the comprehensive neuro examination, jolt accentuation (worsening of the headache in response to rapid horizontal movements of the head) as well as the Kernig and Brudzinski maneuvers can be performed. A positive Kernig sign refers to an inability of the examiner to fully extend the knee secondary to resistance and hamstring pain when the patient is lying supine with their hip flexed to a right angle. Brudzinski sign is considered positive if attempts to passively flex the neck are accompanied by unintentional flexion of the hips. If Kernig and Brudzinski signs are negative, it should not be taken as evidence against CNS infection; these signs have been found to have very poor sensitivity (<5%) though are highly specific (>95%) for CSF pleocytosis (an elevation in leukocytes strongly suggestive of meningitis).7
or severe headache, they generally do not exhibit focal neurologic deficits. If these signs are present, then infection of the brain parenchyma itself, that is, encephalitis, should be considered. In addition to the comprehensive neuro examination, jolt accentuation (worsening of the headache in response to rapid horizontal movements of the head) as well as the Kernig and Brudzinski maneuvers can be performed. A positive Kernig sign refers to an inability of the examiner to fully extend the knee secondary to resistance and hamstring pain when the patient is lying supine with their hip flexed to a right angle. Brudzinski sign is considered positive if attempts to passively flex the neck are accompanied by unintentional flexion of the hips. If Kernig and Brudzinski signs are negative, it should not be taken as evidence against CNS infection; these signs have been found to have very poor sensitivity (<5%) though are highly specific (>95%) for CSF pleocytosis (an elevation in leukocytes strongly suggestive of meningitis).7
TABLE 18.2 Recommended Chemoprophylaxis for Contacts of Those with CNS Infections, by Infective organism | |||||||||||||||||||||||||||||||
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Unless there are complicating factors such as suspected spinal epidural abscess, bleeding tendency (including anticoagulated status), findings suggestive of increased intracranial pressure, or overlying skin infection, patients with suspected meningitis should have a lumbar puncture (LP) performed. Prior to the LP, computed tomography (CT) without contrast of the head should be considered in certain situations (see Table 18.3).8 CSF cultures, in addition to blood cultures, should be obtained to determine bacterial species and provide susceptibility information.
An opening pressure should be measured with the patient in a supine position, and ideally three to four vials containing at least 1 mL of CSF obtained for analysis. In addition to cultures, CSF cell counts, glucose, and protein should be sent on all patients at a minimum. Serum glucose should be obtained as well to allow for interpretation of the CSF level (normal CSF glucose reading is approximately two-thirds of serum glucose in a normoglycemic individual). Table 18.4 shows common CSF profiles of various etiologies of meningoencephalitis. Additional testing, including further viral polymerase chain reaction (PCR) (eg, HSV, VZV) studies, and fungal testing can be ordered on those in whom specific additional diseases are suspected when it will alter management,
such as in immunocompromised individuals. Figure 18.2 shows a purulent CSF sample, a highly abnormal finding concerning bacterial meningitis. Serum procalcitonin, CSF lactate, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) may also have a role as adjunct means to differentiate bacterial from viral meningitis (see Evidence section).
such as in immunocompromised individuals. Figure 18.2 shows a purulent CSF sample, a highly abnormal finding concerning bacterial meningitis. Serum procalcitonin, CSF lactate, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) may also have a role as adjunct means to differentiate bacterial from viral meningitis (see Evidence section).
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