21.2 Bacterial Diseases of the Nervous System

Learning Objectives

  • Identify the most common bacteria that can cause infections of the nervous system
  • Compare the major characteristics of specific bacterial diseases affecting the nervous system

Bacterial infections that affect the nervous system are serious and can be life-threatening. Fortunately, there are only a few bacterial species commonly associated with neurological infections.

Bacterial Meningitis

Bacterial meningitis is one of the most serious forms of meningitis. Bacteria that cause meningitis often gain access to the CNS through the bloodstream after trauma or as a result of the action of bacterial toxins. Bacteria may also spread from structures in the upper respiratory tract, such as the oropharynx, nasopharynx, sinuses, and middle ear. Patients with head wounds or cochlear implants (an electronic device placed in the inner ear) are also at risk for developing meningitis.

Many of the bacteria that can cause meningitis are commonly found in healthy people. The most common causes of non-neonatal bacterial meningitis are Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. All three of these bacterial pathogens are spread from person to person by respiratory secretions. Each can colonize and cross through the mucous membranes of the oropharynx and nasopharynx, and enter the blood. Once in the blood, these pathogens can disseminate throughout the body and are capable of both establishing an infection and triggering inflammation in any body site, including the meninges (Figure 21.5). Without appropriate systemic antibacterial therapy, the case-fatality rate can be as high as 70%, and 20% of those survivors may be left with irreversible nerve damage or tissue destruction, resulting in hearing loss, neurologic disability, or loss of a limb. Mortality rates are much lower (as low as 15%) in populations where appropriate therapeutic drugs and preventive vaccines are available.[1]

(a) A normal human brain removed during an autopsy. (b) The brain of a patient who died from bacterial meningitis. Note the pus under the dura mater (being retracted by the forceps) and the red hemorrhagic foci on the meninges.
Figure 21.5 (a) A normal human brain removed during an autopsy. (b) The brain of a patient who died from bacterial meningitis. Note the pus under the dura mater (being retracted by the forceps) and the red hemorrhagic foci on the meninges. (credit b: modification of work by the Centers for Disease Control and Prevention)

A variety of other bacteria, including Listeria monocytogenes and Escherichia coli, are also capable of causing meningitis. These bacteria cause infections of the arachnoid mater and CSF after spreading through the circulation in blood or by spreading from an infection of the sinuses or nasopharynx. Streptococcus agalactiae, commonly found in the microbiota of the vagina and gastrointestinal tract, can also cause bacterial meningitis in newborns after transmission from the mother either before or during birth.

The profound inflammation caused by these microbes can result in early symptoms that include severe headache, fever, confusion, nausea, vomiting, photophobia, and stiff neck. Systemic inflammatory responses associated with some types of bacterial meningitis can lead to hemorrhaging and purpuric lesions on skin, followed by even more severe conditions that include shock, convulsions, coma, and death—in some cases, in the span of just a few hours.

Diagnosis of bacterial meningitis is best confirmed by analysis of CSF obtained by a lumbar puncture. Abnormal levels of polymorphonuclear neutrophils (PMNs) (> 10 PMNs/mm3), glucose (< 45 mg/dL), and protein (> 45 mg/ dL) in the CSF are suggestive of bacterial meningitis.[2] Characteristics of specific forms of bacterial meningitis are detailed in the subsections that follow.

Meningococcal Meningitis

Meningococcal meningitis is a serious infection caused by the gram-negative coccus N. meningitidis. In some cases, death can occur within a few hours of the onset of symptoms. Nonfatal cases can result in irreversible nerve damage, resulting in hearing loss and brain damage, or amputation of extremities because of tissue necrosis.

Meningococcal meningitis can infect people of any age, but its prevalence is highest among infants, adolescents, and young adults.[3] Meningococcal meningitis was once the most common cause of meningitis epidemics in human populations. This is still the case in a swath of sub-Saharan Africa known as the meningitis belt, but meningococcal meningitis epidemics have become rare in most other regions, thanks to meningococcal vaccines. However, outbreaks can still occur in communities, schools, colleges, prisons, and other populations where people are in close direct contact.

N. meningitidis has a high affinity for mucosal membranes in the oropharynx and nasopharynx. Contact with respiratory secretions containing N. meningitidis is an effective mode of transmission. The pathogenicity of N. meningitidis is enhanced by virulence factors that contribute to the rapid progression of the disease. These include lipooligosaccharide (LOS) endotoxin, type IV pili for attachment to host tissues, and polysaccharide capsules that help the cells avoid phagocytosis and complement-mediated killing. Additional virulence factors include IgA protease (which breaks down IgA antibodies), the invasion factors Opa, Opc, and porin (which facilitate transcellular entry through the blood-brain barrier), iron-uptake factors (which strip heme units from hemoglobin in host cells and use them for growth), and stress proteins that protect bacteria from reactive oxygen molecules.

A unique sign of meningococcal meningitis is the formation of a petechial rash on the skin or mucous membranes, characterized by tiny, red, flat, hemorrhagic lesions. This rash, which appears soon after disease onset, is a response to LOS endotoxin and adherence virulence factors that disrupt the endothelial cells of capillaries and small veins in the skin. The blood vessel disruption triggers the formation of tiny blood clots, causing blood to leak into the surrounding tissue. As the infection progresses, the levels of virulence factors increase, and the hemorrhagic lesions can increase in size as blood continues to leak into tissues. Lesions larger than 1.0 cm usually occur in patients developing shock, as virulence factors cause increased hemorrhage and clot formation. Sepsis, as a result of systemic damage from meningococcal virulence factors, can lead to rapid multiple organ failure, shock, disseminated intravascular coagulation, and death.

Because meningococcoal meningitis progresses so rapidly, a greater variety of clinical specimens are required for the timely detection of N. meningitidis. Required specimens can include blood, CSF, naso- and oropharyngeal swabs, urethral and endocervical swabs, petechial aspirates, and biopsies. Safety protocols for handling and transport of specimens suspected of containing N. meningitidis should always be followed, since cases of fatal meningococcal disease have occurred in healthcare workers exposed to droplets or aerosols from patient specimens. Prompt presumptive diagnosis of meningococcal meningitis can occur when CSF is directly evaluated by Gram stain, revealing extra- and intracellular gram-negative diplococci with a distinctive coffee-bean microscopic morphology associated with PMNs (Figure 21.6).

Meningococcal infections can be treated with antibiotic therapy, and third-generation cephalosporins are most often employed. However, because outcomes can be negative even with treatment, preventive vaccination is the best form of treatment. In 2010, countries in Africa’s meningitis belt began using a new serogroup A meningococcal conjugate vaccine. This program has dramatically reduced the number of cases of meningococcal meningitis by conferring individual and herd immunity.

Twelve different capsular serotypes of N. meningitidis are known to exist. Serotypes A, B, C, W, X, and Y are the most prevalent worldwide. The CDC recommends that children between 11–12 years of age be vaccinated with a single dose of a quadrivalent vaccine that protects against serotypes A, C, W, and Y, with a booster at age 16.[4] An additional booster or injections of serogroup B meningococcal vaccine may be given to individuals in high-risk settings (such as epidemic outbreaks on college campuses).

N. meningitidis (arrows) associated with neutrophils (the larger stained cells) in a gram-stained CSF sample.
Figure 21.6 N. meningitidis (arrows) associated with neutrophils (the larger stained cells) in a gram-stained CSF sample. (credit: modification of work by the Centers for Disease Control and Prevention)

Micro Connections

Meningitis on Campus

College students living in dorms or communal housing are at increased risk for contracting epidemic meningitis. From 2011 to 2015, there have been at least nine meningococcal outbreaks on college campuses in the United States. These incidents involved a total of 43 students (of whom four died).[5] In spite of rapid diagnosis and aggressive antimicrobial treatment, several of the survivors suffered from amputations or serious neurological problems.

Prophylactic vaccination of first-year college students living in dorms is recommended by the CDC, and insurance companies now cover meningococcal vaccination for students in college dorms. Some colleges have mandated vaccination with meningococcal conjugate vaccine for certain students entering college (Figure 21.7).

To prevent campus outbreaks, some colleges now require students to be vaccinated against meningogoccal meningitis.
Figure 21.7 To prevent campus outbreaks, some colleges now require students to be vaccinated against meningogoccal meningitis. (credit: modification of work by James Gathany, Centers for Disease Control and Prevention)

Pneumococcal Meningitis

Pneumococcal meningitis is caused by the encapsulated gram-positive bacterium S. pneumoniae (pneumococcus, also called strep pneumo). This organism is commonly found in the microbiota of the pharynx of 30–70% of young children, depending on the sampling method, while S. pneumoniae can be found in fewer than 5% of healthy adults. Although it is often present without disease symptoms, this microbe can cross the blood-brain barrier in susceptible individuals. In some cases, it may also result in septicemia. Since the introduction of the Hib vaccine, S. pneumoniae has become the leading cause of meningitis in humans aged 2 months through adulthood.

With the emergence of drug-resistant strains of S. pneumoniae, pneumococcal meningitis is typically treated with broad-spectrum antibiotics. The two available pneumococcal vaccines are described in Bacterial Infections of the Respiratory Tract.

(a) Digitally colorized fluorescent antibody stained micrograph of Streptococcus pneumoniae in CSF. (b) S. pneumoniae growing on blood agar.
Figure 21.8 (a) Digitally colorized fluorescent antibody stained micrograph of Streptococcus pneumoniae in CSF. (b) S. pneumoniae growing on blood agar. (credit a: modification of work by the Centers for Disease Control and Prevention; credit b: modification of work by Nathan Reading)

Haemophilus influenzae Type b

Meningitis due to H. influenzae serotype b (Hib), an encapsulated pleomorphic gram-negative coccobacilli, is now uncommon in most countries, because of the use of the effective Hib vaccine. Without the use of the Hib vaccine, H. influenzae can be the primary cause of meningitis in children 2 months thru 5 years of age. H. influenzae can be found in the throats of healthy individuals, including infants and young children. By five years of age, most children have developed immunity to this microbe. Infants older than 2 months of age, however, do not produce a sufficient protective antibody response and are susceptible to serious disease. The intracranial pressure caused by this infection leads to a 5% mortality rate and 20% incidence of deafness or brain damage in survivors.[6]

Preliminary diagnosis of H. influenzae infections can be made by direct PCR and a smear of CSF. Stained smears will reveal intracellular and extracellular PMNs with small, pleomorphic, gram-negative coccobacilli or filamentous forms that are characteristic of H. influenzae. Initial confirmation of this genus can be based on its fastidious growth on chocolate agar. Identification is confirmed with requirements for exogenous biochemical growth cofactors NAD and heme (by MALDI-TOF), latex agglutination, and RT-PCR.

Meningitis caused by H. influenzae is usually treated with doxycycline, fluoroquinolones, second- and third- generation cephalosporins, and carbapenems. The best means of preventing H. influenza infection is with the use of the Hib polysaccharide conjugate vaccine. It is recommended that all children receive this vaccine at 2, 4, and 6 months of age, with a final booster dose at 12 to 15 months of age.[7]

  • Which groups are most vulnerable to each of the bacterial meningitis diseases?
  • For which of the bacterial meningitis diseases are there vaccines presently available?
  • Which organism can cause epidemic meningitis?

Clostridium-Associated Diseases

Species in the genus Clostridium are gram-positive, endospore-forming rods that are obligate anaerobes. Endospores of Clostridium spp. are widespread in nature, commonly found in soil, water, feces, sewage, and marine sediments. Clostridium spp. produce more types of protein exotoxins than any other bacterial genus, including two exotoxins with protease activity that are the most potent known biological toxins: botulinum neurotoxin (BoNT) and tetanusneurotoxin (TeNT). These two toxins have lethal doses of 0.2–10 ng per kg body weight.

BoNT can be produced by unique strains of C. butyricum, and C. baratii; however, it is primarily associated with C. botulinum and the condition of botulism. TeNT, which causes tetanus, is only produced by C. tetani. These powerful neural exotoxins are the primary virulence factors for these pathogens.

Diagnosis of tetanus or botulism typically involves bioassays that detect the presence of BoNT and TeNT in fecal specimens, blood (serum), or suspect foods. In addition, both C. botulinum and C. tetani can be isolated and cultured using commercially available media for anaerobes. ELISA and RT-PCR tests are also available.


Tetanus is a noncommunicable disease characterized by uncontrollable muscle spasms (contractions) caused by the action of TeNT. It generally occurs when C. tetani infects a wound and produces TeNT, which rapidly binds to neural tissue, resulting in an intoxication (poisoning) of neurons. Depending on the site and extent of infection, cases of tetanus can be described as localized, cephalic, or generalized. Generalized tetanus that occurs in a newborn is called neonatal tetanus.

In generalized tetanus, TeNT enters neurons of the PNS. From there, TeNT travels from the site of the wound, usually on an extremity of the body, retrograde (back up) to inhibitory neurons in the CNS. There, it prevents the release of gamma aminobutyric acid (GABA), the neurotransmitter responsible for muscle relaxation. The resulting muscle spasms often first occur in the jaw muscles, leading to the characteristic symptom of lockjaw (inability to open the mouth). As the toxin progressively continues to block neurotransmitter release, other muscles become involved, resulting in uncontrollable, sudden muscle spasms that are powerful enough to cause tendons to rupture and bones to fracture. Spasms in the muscles in the neck, back, and legs may cause the body to form a rigid, stiff arch, a posture called opisthotonos (Figure 21.9). Spasms in the larynx, diaphragm, and muscles of the chest restrict the patient’s ability to swallow and breathe, eventually leading to death by asphyxiation (insufficient supply of oxygen).

Neonatal tetanus typically occurs when the stump of the umbilical cord is contaminated with spores of C. tetani after delivery. Although this condition is rare in the United States, neonatal tetanus is a major cause of infant mortality in countries that lack maternal immunization for tetanus and where birth often occurs in unsanitary conditions. At the end of the first week of life, infected infants become irritable, feed poorly, and develop rigidity with spasms. Neonatal tetanus has a very poor prognosis with a mortality rate of 70%–100%.[8]

Treatment for patients with tetanus includes assisted breathing through the use of a ventilator, wound debridement, fluid balance, and antibiotic therapy with metronidazole or penicillin to halt the growth of C. tetani. In addition, patients are treated with TeNT antitoxin, preferably in the form of human immunoglobulin to neutralize nonfixed toxin and benzodiazepines to enhance the effect of GABA for muscle relaxation and anxiety.

A tetanus toxoid (TT) vaccine is available for protection and prevention of tetanus. It is the T component of vaccines such as DTaP, Tdap, and Td. The CDC recommends children receive doses of the DTaP vaccine at 2, 4, 6, and 15–18 months of age and another at 4–6 years of age. One dose of Td is recommended for adolescents and adults as a TT booster every 10 years.[9]

A tetanus patient exhibiting the rigid body posture known as opisthotonos.
Figure 21.9 A tetanus patient exhibiting the rigid body posture known as opisthotonos. (credit: Centers for Disease Control and Prevention)


Botulism is a rare but frequently fatal illness caused by intoxication by BoNT. It can occur either as the result of an infection by C. botulinum, in which case the bacteria produce BoNT in vivo, or as the result of a direct introduction of BoNT into tissues.

Infection and production of BoNT in vivo can result in wound botulism, infant botulism, and adult intestinal toxemia. Wound botulism typically occurs when C. botulinum is introduced directly into a wound after a traumatic injury, deep puncture wound, or injection site. Infant botulism, which occurs in infants younger than 1 year of age, and adult intestinal toxemia, which occurs in immunocompromised adults, results from ingesting C. botulinum endospores in food. The endospores germinate in the body, resulting in the production of BoNT in the intestinal tract.

Intoxications occur when BoNT is produced outside the body and then introduced directly into the body through food (foodborne botulism), air (inhalation botulism), or a clinical procedure (iatrogenic botulism). Foodborne botulism, the most common of these forms, occurs when BoNT is produced in contaminated food and then ingested along with the food (recall Case in Point: A Streak of Bad Potluck). Inhalation botulism is rare because BoNT is unstable as an aerosol and does not occur in nature; however, it can be produced in the laboratory and was used (unsuccessfully) as a bioweapon by terrorists in Japan in the 1990s. A few cases of accidental inhalation botulism have also occurred. Iatrogenic botulism is also rare; it is associated with injections of BoNT used for cosmetic purposes (see Micro Connections: Medicinal Uses of Botulinum Toxin).

When BoNT enters the bloodstream in the gastrointestinal tract, wound, or lungs, it is transferred to the neuromuscular junctions of motor neurons where it binds irreversibly to presynaptic membranes and prevents the release of acetylcholine from the presynaptic terminal of motor neurons into the neuromuscular junction. The consequence of preventing acetylcholine release is the loss of muscle activity, leading to muscle relaxation and eventually paralysis.

If BoNT is absorbed through the gastrointestinal tract, early symptoms of botulism include blurred vision, drooping eyelids, difficulty swallowing, abdominal cramps, nausea, vomiting, constipation, or possibly diarrhea. This is followed by progressive flaccid paralysis, a gradual weakening and loss of control over the muscles. A patient’s experience can be particularly terrifying, because hearing remains normal, consciousness is not lost, and he or she is fully aware of the progression of his or her condition. In infants, notable signs of botulism include weak cry, decreased ability to suckle, and hypotonia (limpness of head or body). Eventually, botulism ends in death from respiratory failure caused by the progressive paralysis of the muscles of the upper airway, diaphragm, and chest.

Botulism is treated with an antitoxin specific for BoNT. If administered in time, the antitoxin stops the progression of paralysis but does not reverse it. Once the antitoxin has been administered, the patient will slowly regain neurological function, but this may take several weeks or months, depending on the severity of the case. During recovery, patients generally must remain hospitalized and receive breathing assistance through a ventilator.

  • How frequently should the tetanus vaccination be updated in adults?
  • What are the most common causes of botulism?
  • Why is botulism not treated with an antibiotic?

Micro Connections

Medicinal Uses of Botulinum Toxin

Although it is the most toxic biological material known to man, botulinum toxin is often intentionally injected into people to treat other conditions. Type A botulinum toxin is used cosmetically to reduce wrinkles. The injection of minute quantities of this toxin into the face causes the relaxation of facial muscles, thereby giving the skin a smoother appearance. Eyelid twitching and crossed eyes can also be treated with botulinum toxin injections. Other uses of this toxin include the treatment of hyperhidrosis (excessive sweating). In fact, botulinum toxin can be used to moderate the effects of several other apparently nonmicrobial diseases involving inappropriate nerve function. Such diseases include cerebral palsy, multiple sclerosis, and Parkinson’s disease. Each of these diseases is characterized by a loss of control over muscle contractions; treatment with botulinum toxin serves to relax contracted muscles.


Listeria monocytogenes is a nonencapsulated, nonsporulating, gram-positive rod and a foodborne pathogen that causes listeriosis. At-risk groups include pregnant women, neonates, the elderly, and the immunocompromised. Listeriosis leads to meningitis in about 20% of cases, particularly neonates and patients over the age of 60. The CDC identifies listeriosis as the third leading cause of death due to foodborne illness, with overall mortality rates reaching 16%.[10] In pregnant women, listeriosis can cause also cause spontaneous abortion in pregnant women because of the pathogen’s unique ability to cross the placenta.

L. monocytogenes is generally introduced into food items by contamination with soil or animal manure used as fertilizer. Foods commonly associated with listeriosis include fresh fruits and vegetables, frozen vegetables, processed meats, soft cheeses, and raw milk.[11] Unlike most other foodborne pathogens, Listeria is able to grow at temperatures between 0 °C and 50 °C, and can therefore continue to grow, even in refrigerated foods.

Ingestion of contaminated food leads initially to infection of the gastrointestinal tract. However, L. monocytogenes produces several unique virulence factors that allow it to cross the intestinal barrier and spread to other body systems. Surface proteins called internalins (InlA and InlB) help L. monocytogenes invade nonphagocytic cells and tissues, penetrating the intestinal wall and becoming disseminating through the circulatory and lymphatic systems. Internalins also enable L. monocytogenes to breach other important barriers, including the blood-brain barrier and the placenta. Within tissues, L. monocytogenes uses other proteins called listeriolysin O and ActA to facilitate intercellular movement, allowing the infection to spread from cell to cell (Figure 21.10).

L. monocytogenes is usually identified by cultivation of samples from a normally sterile site (e.g., blood or CSF). Recovery of viable organisms can be enhanced using cold enrichment by incubating samples in a broth at 4 °C for a week or more. Distinguishing types and subtypes of L. monocytogenes—an important step for diagnosis and epidemiology—is typically done using pulsed-field gel electrophoresis. Identification can also be achieved using chemiluminescence DNA probe assays and MALDI-TOF.

Treatment for listeriosis involves antibiotic therapy, most commonly with ampicillin and gentamicin. There is no vaccine available.

(a) An electron micrograph of Listeria monocytogenes infecting a host cell. (b) Listeria is able to use host cell components to cause infection. For example, phagocytosis allows it to enter host cells, and the host’s cytoskeleton provides the materials to help the pathogen move to other cells.
Figure 21.10 (a) An electron micrograph of Listeria monocytogenes infecting a host cell. (b) Listeria is able to use host cell components to cause infection. For example, phagocytosis allows it to enter host cells, and the host’s cytoskeleton provides the materials to help the pathogen move to other cells. (credit a: modification of work by the Centers for Disease Control and Prevention; credit b: modification of work by Keith Ireton)

  • How does Listeria enter the nervous system?
Figure 21.11. Details associated with various bacterial infections of the nervous system.

  1. Thigpen, Michael C., Cynthia G. Whitney, Nancy E. Messonnier, Elizabeth R. Zell, Ruth Lynfield, James L. Hadler, Lee H. Harrison et al., “Bacterial Meningitis in the United States, 1998–2007,” New England Journal of Medicine 364, no. 21 (2011): 2016-25.
  2. Popovic, T., et al. World Health Organization, “Laboratory Manual for the Diagnosis of Meningitis Caused by Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenza,” 1999.
  3. US Centers for Disease Control and Prevention, “Meningococcal Disease,” August 5, 2015. Accessed June 28, 2015. http://www.cdc.gov/meningococcal/surveillance/index.html.
  4. US Centers for Disease Control and Prevention, “Recommended Immunization Schedule for Persons Aged 0 Through 18 Years, United States, 2016,” February 1, 2016. Accessed on June 28, 2016. http://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html.
  5. 7 National Meningitis Association, “Serogroup B Meningococcal Disease Outbreaks on U.S. College Campuses,” 2016. Accessed June 28, 2016. http://www.nmaus.org/disease-prevention-information/serogroup-b-meningococcal-disease/outbreaks/.
  6. United States Department of Health and Human Services, “Hib (Haemophilus Influenzae Type B),” Accessed June 28, 2016. http://www.vaccines.gov/diseases/hib/#.
  7. US Centers for Disease Control and Prevention, “Meningococcal Disease, Disease Trends,” 2015. Accessed September 13, 2016. http://www.cdc.gov/meningococcal/surveillance/index.html.
  8. UNFPA, UNICEF WHO, “Maternal and Neonatal Tetanus Elimination by 2005,” 2000. http://www.unicef.org/immunization/files/MNTE_strategy_paper.pdf.
  9. US Centers for Disease Control and Prevention, “Tetanus Vaccination,” 2013. Accessed June 29, 2016. http://www.cdc.gov/tetanus/vaccination.html.
  10. Scallan, Elaine, Robert M. Hoekstra, Frederick J. Angulo, Robert V. Tauxe, Marc-Alain Widdowson, Sharon L. Roy, Jeffery L. Jones, and Patricia M. Griffin, “Foodborne Illness Acquired in the United States—Major Pathogens,” Emerging Infectious Diseases 17, no. 1 (2011): 7-15.
  11. US Centers for Disease Control and Prevention, “Listeria Outbreaks,” 2016. Accessed June 29, 2016. https://www.cdc.gov/listeria/outbreaks/index.html.


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