Central Nervous System Infections

Background and Pathophysiology

The etiology of CNS infections continues to change as a result of new therapeutic interventions, vaccines, and the growing number of immunosuppressed patients. Despite advances, however, the morbidity and mortality from a CNS infection remains high; good outcomes can be maximized with early recognition and treatment.

The two most common CNS infections, meningitis and encephalitis, are delineated by the tissue that is infected. Meningitis refers to an infection of the meningeal layers lying between the bony covering of the CNS and the brain tissue. If the infection is present in the brain parenchyma itself, then it is termed encephalitis. However, these disease states are not mutually exclusive and exist on a continuum of meningoencephalitis . Generally, greater degrees of encephalitis portend a worse prognosis, as more tissue is involved.

Bacterial Meningitis

Bacterial meningitis has a high mortality rate despite treatment, with rates variable depending on the organism, time to appropriate treatment, and patient factors. Streptococcus pneumoniae remains the predominant pathogen in adult patients, accounting for over half of cases despite a recent decline in incidence. Other common causes in adults include Neisseria meningitidis, Haemophilus influenzae , and Listeria monocytogenes. N. meningitidis is the predominant organism in children. Listeria is more commonly seen in elderly adults and infants. In the first six weeks of life, Group B streptococcus species as well as Escherichia coli also represent common causes of bacterial meningitis. Bacterial meningitis caused by H. influenzae was previously responsible for a much larger proportion of cases, but the incidence has declined sharply since the introduction of the vaccine for type B (HiB).

Meningococcal disease refers to meningitis caused by N. meningitidis, and is most common in younger individuals, particularly those living in very close proximity to others such as in military barracks or college dormitories. A, B, and C represent the major groups. Group B is particularly prevalent in Europe, while group C is commonly isolated in the United States. A conjugate vaccine containing serogroups A, C, Y, and W-135 has been developed, as well as a separate vaccine for serogroup B. These vaccines are highly effective in children, but have yet to be broadly distributed to developing countries.

The infection process in bacterial meningitis generally begins with nasopharyngeal colonization and invasion of the mucosa. The varying capsular properties of each organism protect the bacteria. Once bacteria cross the blood-brain barrier to enter the CSF, host defense mechanisms within the CSF are often ineffective. Bacteria then proliferate, which causes the body to signal for leukocytes to enter the CSF. Meningeal and subarachnoid space inflammation is associated with the release of cytokines into the CSF, inciting an inflammatory cascade that promotes increased permeability of the blood-brain barrier, cerebral vasculitis, edema, and increased intracranial pressure (ICP). A subsequent decrease in cerebral blood flow can then lead to cerebral hypoxia.

Meningeal infection may also occur in association with a dural leak secondary to neurosurgery or trauma to the CNS. Skin flora, including coagulase-negative staphylococcus species, Staphylococcus aureus, and Cutibacterium acnes are seen most commonly in this population, though infections caused by Pseudomonas aeruginosa also occur.

Mortality from bacterial meningitis is highest in patients with advanced presentations, serious underlying disease or advanced age. The fatality rate is highest with Listeria meningitis with a mortality rate up to 27%. Overall, many survivors have some degree of residual neurologic deficit, with the highest rates found in those with pneumococcal meningitis.

Meningitis from Lyme disease ( Borrelia burgdorferi ) presents similarly to other causes of bacterial meningitis, but can also cause other neurologic symptoms, including facial palsies and radiculopathies. Late Lyme infection, occurring in some cases years after initial infection, can cause encephalopathy which can manifest as migraines, psychosis, and somatoform disorders.

Viral Meningitis

Given the decrease in the incidence of bacterial meningitis, largely secondary to vaccination efforts, viral infections are now the most common cause of meningitis. Enteroviruses and herpesviruses are the most common causes, often occurring in those with risk factors such as a suppressed immune system. The overall prognosis for the majority of cases of viral meningitis is excellent.

Viral Encephalitis

The same organisms responsible for viral meningitis may also be associated with encephalitis. A common mechanism of viral transmission is through the skin via insect vectors (e.g., Zika virus or West Nile virus), although clinical disease develops in only a small percentage of the people bitten. Tick-borne viral encephalitis is endemic to parts of Europe and Russia and is an important consideration for residents and recent travelers to those regions; a vaccine is available. Transmission of viral encephalitis often occurs by hematogenous spread from infections of the respiratory, gastrointestinal, or urogenital tracts. Other mechanisms include retrograde transmission along neuronal axons, as seen in the herpes virus, and direct invasion of the subarachnoid space after infection of the olfactory submucosa, as seen in rabies or herpes.

The outcomes in viral encephalitis, including permanent neurologic sequelae, are dependent on both the host and the infecting agent. Acyclovir treatment has reduced the mortality from HSV encephalitis from up to 70% down to 9%, but with 34% of surviving patients having moderate to severe neurologic disability. Common complications include seizures, motor deficits, and impaired cognition. Encephalitis caused by Japanese encephalitis virus, Eastern equine virus, and St. Louis encephalitis virus is severe, with high mortality rates and high rates of neurologic sequelae among survivors. West Nile virus produces encephalitis in less than 1% of those infected but has resulted in 2000 deaths in the United States as of 2016. Western equine virus and California encephalitis virus cause milder infections, and death is rare. Zika virus has been associated with the development of Guillain-Barré syndrome (GBS) as well as severe encephalitis in developing fetuses of infected mothers, resulting in devastating neurologic defects. It is not entirely clear if the virus also causes neuroinvasive disease in adults. Powassan virus, another tick-borne cause of CNS infection in North America, is known to cause severe encephalitis with a mortality of approximately 10% and a high rate of neurologic disability in survivors. CMV can also cause encephalitis, particularly in patients who are infected with HIV or are otherwise immunocompromised. Influenza virus, well-known for its respiratory effects, is another rare cause of high-mortality encephalitis in adults. Encephalitis secondary to measles and mumps has almost disappeared in the developed world due to widespread vaccination, but still can occur, particularly in those who are immunocompromised. Primary measles encephalitis is typically self-limited but carries a mortality of approximately 10% to 15%. Patients with this disease can go on to develop both subacute and chronic encephalitis (sometimes occurring years later) which is universally fatal.

Tuberculous Meningitis

Mycobacteria typically gain access to the CNS via hematogenous spread, and once present will begin to form granulomas. These can rupture, inciting an inflammatory response from the host. This can have the side effect of causing vasculitis and potentially a stroke. Tuberculous meningitis is also frequently complicated by hydrocephalus requiring neurosurgical intervention; in advanced disease, up to 25% of patients may require some neurosurgical procedure for obstruction (ventriculoperitoneal shunt or drainage). Tuberculous meningitis leads to severe disability or death in roughly half of the cases, and, as with bacterial meningitis, depends on the patient’s age, comorbidities, time to diagnosis, and the progression of their disease.

Fungal Meningitis

CNS infections caused by fungal species are most commonly caused by Cryptococcus (typically C. neoformans and C. gattii ) and have been increasing in recent years. Other common causes of fungal meningitis include Aspergillus species and Coccidioides immitis. Diabetic patients are at high risk of developing cerebral mucormycosis via direct invasion of the sinuses, and CNS invasion by Histoplasma capsulatum is also commonly seen in AIDS patients.

Over a million cases of fungal CNS infections are estimated to occur annually, likely via similar mechanisms as bacterial meningitis. Because these infections typically affect those with compromised immune systems, this increase is likely secondary to an increasing number of people living with iatrogenic chronic immunosuppression and HIV infection. Pulmonary exposure, followed by hematogenous spread, is the primary pathogenic mechanism in most cases of cryptococcal meningitis. Infection with C. neoformans is considered an acquired immunodeficiency syndrome (AIDS)-defining illness but can occur in those with immunocompromised states arising from other causes. Infection with C. gatti can occur even in immunocompetent patients. Candida species are also a major cause of fungal meningitis. These infections typically occur in those with candidemia or via the implantation of neurosurgical hardware (such as CNS shunts).

Common CNS complications of fungal meningitis include abscesses, increased ICP, neurologic deficits, seizures, bone invasion, fluid collections, and ocular abnormalities (seen in up to 40% of patients with cryptococcal meningitis). The mortality rate of fungal meningoencephalitis is usually around 20% to 30%, but may be up to 97% in untreated Candida meningitis, and varies with the severity of illness, timeliness of diagnosis, and administration of appropriate treatment.

Central Nervous System Abscess

CNS abscesses occur due to both local contiguous invasion as well as hematogenous spread from remote infections. They are also associated with intravenous (IV) drug use, neurologic surgery, and cranial trauma. In cases of contiguous spread, the location of the abscess within the brain is typically dictated by the source of invasive infection or the surgical procedure ( Fig. 95.1 ). Brain abscesses secondary to otitis media are most often found within the temporal lobe or cerebellum, whereas cases arising from sinusitis usually result in abscesses in the frontal or temporal lobes. Hematogenous spread of microorganisms (most commonly from the pulmonary system) often results in multiple brain abscesses, although solitary lesions may also occur. Rarely, patients present without a clear source or the presence of risk factors. Antibiotic prophylaxis in the immunosuppressed, improved diagnostic imaging, and neurosurgical interventions have all contributed to more favorable outcomes.

The spinal epidural space also represents a common site of CNS abscesses. Increasing numbers of spinal surgeries, immunosuppressed patients, and high rates of intravenous drug use are contributing factors to an increase in the incidence of these abscesses, which are associated with high rates of permanent neurologic morbidity. Infection typically enters the epidural space via the blood but can also arise from contiguous spread from nearby infections (e.g., psoas abscess, vertebral osteomyelitis).

Meningitis

The clinical picture of bacterial and viral meningitis is classically defined by fever, headache, photophobia, and nuchal rigidity. Unfortunately, subtle presentations lacking these classic features are common. In immunosuppressed or geriatric patients, alteration in mental status may be the only finding, and therefore requires a lower threshold for ruling out meningitis in these special populations. Clinical presentations in neonates may include a bulging fontanelle, but are often subtle, such as changes in behavior, decreased tone, or weakness as noticed by parents; consequently, guidelines universally recommend a lumbar puncture as part of the evaluation of a neonate with a suspected infection.

The physical findings in meningitis are variable depending on patient factors (e.g., age, comorbidities), pathogen, and time course of the disease (early vs. late). Two classic exam maneuvers, the Kernig sign (inability to straighten leg to a position of full knee extension when patient is lying supine with hip flexed to a right angle) and Brudzinski sign (attempts to flex the neck passively are accompanied by flexion of the hips), have a low sensitivity of less than 12%; however, they have a high specificity and strongly suggest meningitis if they are present ( Table 95.1 ).

Patients with suspected meningitis should first be examined for evidence of a structural lesion precipitating their symptoms, as these patients may require CT imaging to rule out other causes of their symptoms. Signs of mass lesions can include papilledema, decreased venous pulsations, new-onset seizures, abnormal level of consciousness, or focal neurologic deficits. An accurate fundoscopic exam can be challenging to obtain and bedside ultrasound offers an alternative tool for assessing intracranial pressure. Patients without abnormal findings on neurologic examination may proceed to lumbar puncture without CT.

Because meningitis can result from both contiguous and hematogenous spread, the physical examination should include a search for an inciting infection, such as a skin abscess, sinusitis, endocarditis, or osteomyelitis. Manifestations of endocarditis may be present, particularly in cases found to be due to S. aureus. Petechiae and cutaneous hemorrhages are widely reported with meningococcemia, typically on the extremities although they can occur anywhere on the body. Endotoxic shock with vascular collapse and DIC often develops in severe meningococcal disease, but shock may be present in the advanced stages of any bacterial meningitis. A finding of a systemic infection in a patient with signs of potential meningeal irritation should encourage rather than dissuade the clinician from considering the possibility of a concomitant CNS infection.

Cerebral venous thrombosis occurs in approximately 1% of patients with meningitis, likely due to coagulopathy induced by the robust CNS immune response; this rare complication can manifest as new-onset seizures, altered sensorium, and new focal neurologic deficits. Meningococcemia may cause Waterhouse-Friderichsen syndrome, or bilateral adrenal hemorrhage, often accompanied by other signs of severe systemic infection such as DIC and purpura.

The presentation of fungal meningitis can sometimes be subtle even in the healthy adult population. Headache, low-grade fever, malaise, and weight loss may be present but often to such a mild degree that CNS infection is not initially considered. Tuberculous meningitis, in contrast to other types of meningitis, can have a subacute or even chronic presentation, with symptoms developing months after onset of infection. Cases can be vague and nonspecific, including fever, weight loss, night sweats, and malaise, with or without headache and meningismus. In some cases, CNS involvement may be the only manifestation of tuberculosis, but CNS infection can also present alongside pulmonary tuberculosis or disseminated (miliary) infection.

Encephalitis

Encephalitis can occur from a viral, bacterial or fungal cause; it is not possible to definitively distinguish the etiology of the infection based on clinical features, although certain presentations can be suggestive. Viral encephalitis can occur secondary to primary viral invasion of the CNS, such as West Nile or rabies virus. Alternatively, it can be caused by reactivation of a previously dormant viral illness, such as varicella-zoster virus (VZV).

The diagnosis of encephalitis requires an alteration of consciousness or behavior without another known cause. Fever, headache, seizures, and disorientation can be present. The symptoms exhibited by the patient are representative of the affected area of the brain. For example, HSV has a predilection for the temporal lobes and therefore, patients with HSV encephalitis can present with psychosis, personality or behavior changes, or hallucinations, occasionally prompting an initial diagnosis of a psychiatric disorder. A thorough skin and mucosal examination may reveal the presence of herpetic lesions, as encephalitis can be associated with cutaneous outbreak in some cases. West Nile virus can result in neuroinvasive disease resulting in a wide range of symptoms, including muscle weakness, memory loss, behavioral changes, and difficulty concentrating. In cases of rabies encephalitis, patients also present with agitation, extreme hydrophobia, and muscular spasms.

Central Nervous System Abscess

The most common finding in patients with an intracranial abscess is headache. Findings seen consistently in other CNS infections, such as fever and altered mental status, may not be present. Most patients with intraparenchymal abscess have a subacute clinical course with symptoms progressing over 1 or more weeks. Just as with encephalitis, the symptoms exhibited by patients depends on the site affected by the abscess. For example, those with abscesses near the frontal lobe may present with disinhibited behavior, and abscesses near the motor cortex may demonstrate focal weakness. Seizures occur in approximately 25% of patients. Abrupt neurologic deterioration and death can result from abscesses that rupture into the ventricular system.

Abscesses can also present in the epidural space in the spine, most commonly in the lumbar region. However, multiple areas may be affected which can be discontiguous. Like brain abscesses however, presentations can be nonspecific and mimic more benign causes of back pain. The most common presenting symptom of an abscess within the epidural space is midline pain, which is present in the majority of patients. Conversely, fever is only present in approximately half of cases, particularly early in the course. Complications of a spinal abscess primarily result from cord compression, including paralysis, motor and sensory deficits, and bowel and bladder dysfunction. These deficits may be permanent once they develop, even with prompt treatment, making prompt diagnosis critical to avoid serious morbidity.

CSF Shunt Infection

These infections typically manifest with signs of increased intracranial pressure and hydrocephalus such as headache, altered mental status, nausea, and vomiting. They most often occur within 6 months of shunt placement and are typically the result of skin flora being introduced into the CSF space.