Neuroinfection (or neurological infection) occurs when a virus, bacteria, parasite, fungus, or prion attack the brain and/or spinal cord, the effects of which can range from mild illness to serious impairment and even death. A neuroinfection can be a primary diagnosis; however, it can also be secondary to other conditions such as abscess elsewhere in the body. A neuroinfection can also precipitate other neurological conditions such as seizures, cerebral edema, and increased intracranial pressure (Roos & Brosch, 2012).
Infection of the nervous system can involve the brain (“encephalitis”), the meninges covering the brain (“meningitis”), or both (“meningoencephalitis”). Another type of neuroinfection is human immunodeficiency virus (HIV), which causes acquired immune deficiency syndrome (AIDS) and has a devastating effect on the body’s immune system as well as the brain. A related, but distinct condition known as “HIV encephalopathy” is commonly used to describe the neural dysfunction underlying cognitive deficits associated with HIV.
Many neuroinfections are preventable or responsive to treatment. Although early diagnosis and intervention can make a major contribution to potential recovery, neuroinfections are frequently underdiagnosed or misdiagnosed and go untreated (Tan et al., 2008). The number of infectious agents that cause neuroinfection is massive, although their clinical expression is more limited. Here, we discuss some of the more common neuroinfections seen in clinical settings.
The study of neuroinfectious diseases is a relatively new specialty within the field of neurology. In the United States, the field of neurology as a separate specialty did not emerge from neuropsychiatry until after World War II, and the American Academy of Neurology (AAN) was established in 1948. Neuroinfectious diseases have traditionally been studied as part of the neuropathology curriculum in neurology, and it was not until 1964 that Hiram H. Merritt published a stand-alone chapter on infectious disease in his Textbook of Neurology (Millichap & Epstein, 2009). Nevertheless, early clinicians in the field of neurology had long been treating patients with various forms of infections of the nervous system. For instance, the first bacterial meningitis outbreak was recorded in 1805 in Geneva, Switzerland by Swiss physician Gaspard Vieusseux (Tyler, 2009), while encephalitis due to the influenza virus was first described in 1917 by Constantin von Economo. In fact, the Pasteur Institute in Paris opened in 1888 to treat patients with rabies (Millichap & Epstein, 2009). Research on, and treatment of, neuroinfectious diseases has developed partly as a result of several large-scale infectious disease epidemics that took place in the 20th century, including the influenza epidemic in 1917, the polio epidemic in the 1940s and 1950s, and the AIDS epidemic in the 1980s. In the present day, neurologists with specialization in neuroinfectious diseases care for patients in a variety of clinical settings in which patients may require management of medical complications, including seizures, increased intracranial pressure, autoimmune disorders, immunosuppression, and opportunistic infections.
Different pathogens (e.g., viruses, bacteria, and other microorganisms) may invade the body and infect various organs, including the central nervous system (CNS). Neuroinfections occur when these pathogens enter the CNS (Kaneshiro, 2014). Some infections affect meningeal cells (e.g., enteroviruses), resulting in benign aseptic meningitis, whereas other viruses may affect specific classes of neurons in the brain and spinal cord, giving rise to more serious conditions, including encephalitis and poliomyelitis. Although the blood–brain barrier (BBB) protects the CNS from pathogens, once an infection has set in, the same mechanism prevents the entry of immunocompetent cells and antibodies, which can make treatment more difficult (Adams, Victor, & Ropper, 1997; Koyuncu, Hogue, & Enquist, 2013).
Encephalitis is a rare but serious condition. The majority of pathogens that cause encephalitis are viruses, although other causes include bacteria, rickettsia, parasites, and fungi. After they enter the body, viruses multiply and enter the bloodstream (viremia), where they are typically cleared by the reticuloendothelial system. However, if the viremia is large enough, the virus may invade the CNS through the choroid plexus and cerebral capillaries. Despite the presence of the BBB, viruses have adapted strategies to enter the CNS through hematogenous (bloodstream) dissemination and retrograde neuronal dissemination (neuronal pathways). Once across the BBB, the viral infection disrupts normal cell functioning and may result in hemorrhage and an inflammatory response, with greater affliction of gray compared with white matter in the brain. Some viruses are thought to affect specific brain regions (e.g., herpes simplex virus targets inferior and medial temporal lobes), whereas others may result in multifocal demyelination of the white matter (e.g., measles, Epstein–Barr virus) (Adams et al., 1997; Howes & Lazoff, 2015).
Bacteria may reach the meninges through the bloodstream or direct contact with the meninges (e.g., neurosurgery, shunting, open head wounds; National Center for Immunization and Respiratory Diseases, 2014). The common pathogenesis begins when bacteria first colonize tissue outside the CNS such as the nasopharynx. From here, the infection may enter the bloodstream and access the subarachnoid space. Similar to the infection process of encephalitis, the bacteria are thought to gain access to the cerebrospinal fluid (CSF) though the porous capillaries of the choroid plexus. Unfortunately, the CSF is a poor environment for fighting infection, and an immune response is often outpaced by bacterial growth. Eventually, cellular destruction by the bacteria and the immune response will lead to significant inflammation of the meningeal tissue (typically the arachnoid membrane), and damage to the BBB and brain tissue may occur (Dando et al., 2014).
The pathogenesis of each family of viruses that causes meningitis varies; however, viral meningitis generally results from a complication of common infections (National Center for Immunization and Respiratory Diseases, 2014). In most cases, the viral infection originates within the respiratory or gastrointestinal tracts and progresses to the lymphatic system (Irani, 2008). The dissemination of the virus in meningitis is similar to that in encephalitis. The cellular destruction and immune response of the viral infection incites inflammation of the tissue, which is thought to give rise to clinical symptoms.
Human Immunodeficiency Virus
HIV enters the CNS through monocytes and lymphocytes that become infected before crossing the BBB. Although the virus attacks many regions of the brain, the basal ganglia, hippocampus, frontal cortex, and white matter tend to be most significantly affected (Schouten, Cinque, Gisslen, Reiss, & Portegies, 2011). CD4+ T-helper cells (commonly referred to as “CD4 cells”), which play a key role in maintaining the body’s immune system, are preferentially targeted by HIV (Palmisano & Vella, 2011). Among healthy adults, CD4 count typically ranges from 500 to 1,200 cells/mm3, whereas among individuals with HIV, CD4 count below 200 cells/mm3 often signifies progression to AIDS (U.S. Department of Health and Human Services, 2015).
While HIV itself can cause neuronal damage, particularly because of inflammation from HIV-infected cells, opportunistic infections also result in significant neural disruption (Schouten et al., 2011). Low CD4 count, and the associated degradation of the immune system, leads to increased risk of contracting opportunistic infections such as cryptococcosis, progressive multifocal leukoencephalopathy, toxoplasmosis, tuberculosis, and neurosyphilis, to name a few (Smith, Smirniotopoulos, & Rushing, 2008). Opportunistic infections further attack the already immunosuppressed individual and are a common cause of death among patients with HIV/AIDS.
Viruses are transmitted in a variety of ways, including through direct human-to-human contact (e.g., herpes simplex virus, mumps, measles, rubella, varicella zoster viruses), dogs and wild animals (e.g., rabies virus), bats and pigs (e.g., Nipah virus), rodents (e.g., Lassa virus), mosquitos (e.g., West Nile, St. Louis encephalitis viruses), and ticks (e.g., Colorado tick fever virus). Viruses that cause encephalitis include herpes simplex virus (HSV-1, HSV-2) and other herpes viruses (e.g., varicella zoster virus, cytomegalovirus, Epstein–Barr virus), adenoviruses, arboviruses (e.g., West Nile virus, St. Louis virus, Japanese encephalitis, tick-borne viruses), arenaviruses, bunyaviruses, rabies, measles/mumps/rubella, and reoviruses (e.g., Colorado tick fever virus) (Mayo Clinic, 2014). In the United States, the most common encephalitis etiologies include herpes simplex virus, West Nile virus, and enteroviruses. Nevertheless, despite diagnostic testing, the cause remains unknown in approximately half of the cases of viral encephalitis (Kennedy, 2004; World Health Organization, 2006).
Routine vaccinations have reduced encephalitis due to certain viruses, including measles, mumps, rubella, polio, rabies, and varicella (chickenpox). The leading cause of more severe cases of encephalitis in all ages is HSV (90% caused by HSV-1 and 10% by HSV-2). It is a serious yet treatable condition and has an incidence of approximately 1 in 1 million per year, with around 2,000 cases occurring annually in the United States (Kennedy, 2004; Tunkel et al., 2008).
Community-acquired bacterial meningitis in adolescents and adults most commonly occurs secondary to a nasopharyngeal or inner-ear infection. The two most common bacterial agents causing meningitis (Streptococcus pneumoniae and Neisseria meningitidis) may be passed through contact with an infected person’s saliva and respiratory secretions during coughing, sneezing, and kissing (National Center for Immunization and Respiratory Diseases, 2014; Thigpen et al., 2011). Bacteria may also come into contact with the meninges owing to neurosurgery, CSF shunting, traumatic brain injury, or congenital anomalies. Common microbial agents causing meningitis include S. pneumoniae (most common and most serious), S. agalactiae, N. meningitidis, Listeria monocytogenes, Haemophilus influenzae, and Escherichia coli (National Center for Immunization and Respiratory Diseases, 2014; van de Beek, de Gans, Tunkel, & Wijdicks, 2006).
Viral meningeal infection typically occurs following a primary infection of non-CNS tissue. Like most common viruses, those that may cause meningitis can be transmitted though contact with infected persons or objects (e.g., infected feces, saliva, mucus or sputum, blood, or blister fluid; National Center for Immunization and Respiratory Diseases, 2014). Viruses causing meningitis are similar to those that may also cause encephalitis.
Human Immunodeficiency Virus
HIV is acquired through contact with the blood and/or bodily fluids of an infected individual. Mechanisms of transmission include sexual contact (vaginal, anal, or oral), sharing intravenous drug needles, accidental needle-stick injuries, and mother-to-child transmission during pregnancy or breast-feeding.
Increased risk of HIV transmission is driven significantly by viral load, measured by the number of copies per mL of plasma HIV-1 RNA (Maartens, Celum, & Lewin, 2014). An individual in the acute state of HIV infection (i.e., approximately 2–4 weeks after the virus is acquired) has a higher chance of transmitting it to others because of a high viral load at this stage, especially through risky sexual behavior and intravenous drug use. Importantly, HIV testing during this time is likely to be negative if the body has not yet produced sufficient HIV antibodies to be detectable. Thus, an individual may be infected with HIV and transmit the virus without being aware.
Historically, blood transfusions (and organ donations) constituted another potential mechanism of HIV transmission. Infection via transfusion has become increasingly more rare since initial implementation of blood donation screenings in 1985 (Palmisano & Vella, 2011) and universal donation screening with nucleic acid testing (NAT) in 1999 (Zou et al., 2010). Recent research revealed a 1 in 2 million occurrence of NAT-positive HIV cases in a sample of 66-million blood samples taken between the years of 1999 and 2008 (Zou et al., 2010).
In the United States, encephalitis affects 7 per 100,000 people annually, with several thousand cases reported to the Centers for Disease Control and Prevention (CDC) every year. Infection is the most common cause of encephalitis, and viruses are the most common etiological agents. Although rare, HSV is the most common cause of encephalitis in Western countries, its incidence being 0.2 per 100,000. Arboviruses (transmitted through insects) are another common cause of encephalitis, with an incidence similar to HSV. However, most people who are bitten by infected insects do not go on to develop clinical illness, and of those who do, less than 10% go on to develop encephalitis. The rarest cause of encephalitis in the United States is rabies (0–3 cases annually). Risk factors for contracting encephalitis include the following (Granerod & Crowcroft, 2007; Howes & Lazoff, 2015; Mayo Clinic, 2014):
Age: Certain age groups are at greater risk for some types of encephalitis, such as young children and older adults. HSV encephalitis is more common in people 20 to 40 years of age.
Sex: Males are slightly more likely to be affected by encephalitis than are females.
Weakened immune system: Individuals with HIV/AIDS and those with weakened immune systems or who take immunosuppressant drugs are at greater risk.
Geographic regions: Encephalitis occurs worldwide. Herpesviruses tend to have a global distribution, whereas arboviruses are more geographically restricted. Mosquito or tick-borne diseases tend to be more prevalent in certain geographic regions.
Season of the year: Mosquito and tick-borne diseases are more common during the warm months of the year in the United States and may be present year round in warmer areas.
The annual incidence of bacterial meningitis is estimated to be 4 to 6 cases per 100,000 adults (van de Beek et al., 2006). In the United States, approximately 500 deaths occur annually as a result of bacterial meningitis (Thigpen et al., 2011). The most common causative bacteria of community-acquired bacterial meningitis in adults is S. pneumoniae followed by N. meningitidis, together accounting for 75% to 90% of cases.
In temperate regions, rates of viral meningitis are highest in the summer and fall seasons, with no seasonal variability in tropical or subtropical climates (Logan & MacMahon, 2008). Viral meningitis is thought to be much more common than bacterial meningitis; however, because of frequent spontaneous recovery in mild cases, true incidence and prevalence rates are difficult to calculate. In a retrospective study of individuals aged 16 and older, the incidence of viral meningitis was 7.6 per 100,000 individuals (Kupila et al., 2006). Risk factors for contracting meningitis include the following (National Center for Immunization and Respiratory Diseases, 2014):
Skipping vaccinations: If a person has not completed the recommended childhood or adult vaccination schedule, the risk of meningitis is higher.
Age: Most cases occur at the extremes of age (<2 or >60 years; Thigpen et al., 2011).
Living in a community setting: College students living in dormitories, personnel on military bases, and children in boarding schools and childcare facilities are at increased risk of meningococcal meningitis. This increased risk likely occurs because the bacterium is spread by the respiratory route and tends to spread quickly in large groups.
Compromised immune system: Factors that may compromise a person’s immune system, including AIDS, alcoholism, diabetes, and use of immunosuppressant drugs, also make the person more susceptible to meningitis. Removal of the spleen, an important part of one’s immune system, may also increase the person’s risk.
Human Immunodeficiency Virus
According to the CDC, approximately 915,000 people in the United States were living with an HIV diagnosis as of 2012. The annual rate of diagnosis for the overall population in 2013 was 15 per 100,000 people, with this rate having been stable since 2009. Rate of diagnosis varied by a number of factors including age, race/ethnicity, and sex. The highest rates of HIV diagnosis (per 100,000) were seen among individuals who were between the ages 25 and 29 (rate of 36.3), African American (rate of 55.9), and men (rate of 29.4). Sixty-eight percent of diagnosed cases in 2013 were attributed to male-to-male sexual contact and intravenous drug use. The rates of death due to HIV have recently decreased in the overall population. Although the incidence of HIV diagnosis has decreased in recent years, the overall prevalence has increased because of increased life expectancy with improved treatment options (Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, Sexual Transmitted Diseases and Tuberculosis Prevention, Centers for Disease Control and Prevention, 2013).
Among those with HIV, only a portion of individuals develops encephalitis or meningitis. Postmortem studies of individuals with HIV have shown a 10% to 30% incidence of HIV encephalitis (Schouten et al., 2011). Cryptococcal meningitis, the most common opportunistic infection among individuals with HIV, occurs in 5% to 7% of patients, typically following progression to AIDS, at which point the risk of contracting opportunistic infection is highest. Aseptic meningitis is the second most common form of meningitis in HIV and is frequently caused by the HIV infection itself (Singh, Thomas, & Uppal, 2013).