Introduction

The nervous system is divided into two components: the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and spinal cord, and the PNS consists of 12 pairs of cranial nerves, 31 pairs of spinal nerves, ganglia, and associated sensory receptors (Figure 13.1). The brain and the spinal cord are covered by three protective membranes, collectively called meninges (Figure 13.2). The outermost membrane is the dura mater, the middle layer is the arachnoid, and the innermost membrane is the pia mater. The space between the pia mater and the arachnoid, referred to as the subarachnoid space, contains cerebrospinal fluid (CSF), which circulates through the brain ventricles, the central canal of the spinal cord, and the subarachnoid space. The CSF has a low level of complement proteins, circulating antibodies, and some phagocytotic cells; if bacteria get access to the CSF they can multiply with little immune reaction by the body.

A collective inflammation of these protective membrane coverings is called meningitis and may be caused by microorganisms, or it may be noninfectious and the result of physical injury, cancer, or certain drugs dosages. Regardless of the cause, meningitis is a serious condition that requires immediate medical attention. The various pathogens causing meningitis include bacteria, viruses, fungi, and protozoans.

During a CNS infection specific changes occur within the CSF. The response in the CSF to a viral infection is generally reflected by an increase in lymphocytes, monocytes, and a slight increase in proteins, and the CSF remains clear. This condition is called aseptic meningitis. In the case of a bacterial infection a rapid increase in granulocytes and proteins occurs and the CSF becomes visibly turbid. This condition is called septic meningitis (Table 13.1).

The CNS is remarkably resistant to infection, largely because of a barrier between the blood circulation and the nervous tissue, referred to as the blood–brain barrier. The capillaries of the blood–brain barrier permit only selected substances to pass from the blood into the brain, with all others being restricted. In essence, only lipid-soluble substances can cross the barrier; the exception is glucose and certain amino acids, none of which are lipid soluble, but that have specific carrier mechanisms transporting them across the barrier. Unless they are lipid soluble, drugs cannot cross the blood–brain barrier. For example, chloramphenicol, a lipid-soluble antibiotic (see Chapter 22, Antimicrobial Drugs), can readily enter the brain whereas penicillin, only slightly lipid soluble, is effective only if taken in large doses.

Although not common, if inflammation of the brain occurs it alters the blood–brain barrier, often allowing drugs to cross that normally cannot. The most common routes of CNS invasion are the bloodstream and the lymphatic system, when an inflammation alters the blood–brain barrier. Invasion of the CNS via the peripheral nerves is a feature of some viruses discussed later in this chapter. An inflammation of the brain is called encephalitis, and if both the brain and the meninges are inflamed the condition is referred to as meningoencephalitis.

Another structure that can be affected by microorganisms or their toxins is the neuromuscular junction. The neuromuscular junction (Figure 13.3) is the connection between the synaptic end bulb (axon terminal) of a motor neuron, located in the spinal cord, and a muscle fiber. This junction is essential for muscle contraction. The two cells do not touch each other but are separated by a small space called the synaptic cleft. The electrical message from the motor neuron is translated into a chemical message via the neurotransmitter (acetylcholine) located in the presynaptic terminal. Once the neurotransmitter is released into the synaptic cleft it diffuses to the receptors on the muscle fiber and generates another electrical event that leads to muscle contraction. Any interference with this delicate structure will lead to problems with muscle contraction.

Bacterial Infections

Although bacterial infections of the nervous system are rare, they are serious with sometimes lethal outcomes. Before the discovery of antibiotics, bacterial central nervous system infections were almost always fatal.

Bacterial Meningitis

The general symptoms of meningitis initially are nausea, vomiting, fever, headache, and a stiff neck. These symptoms may develop over several hours, but can take from 1 to 2 days. Although the symptoms vary from patient to patient, the initial symptoms may be followed by

• Confusion

• Sleepiness

• Light sensitivity

• Possible progression to convulsions and coma

Bacterial meningitis is less common than viral meningitis but is more severe in nature, because of the production of toxins by the bacteria. The mortality rate for bacterial meningitis varies with the causative agent, and vaccination is available for some. Early diagnosis and treatment of bacterial meningitis are essential to prevent permanent neurological damage. Antibacterial drugs used to treat bacterial meningitis include penicillin G, ampicillin or amoxicillin, chloramphenicol, cefotaxime, vancomycin, and ceftriaxone (see Chapter 22, Antimicrobial Drugs).

Before the 1990s the most common cause of bacterial meningitis was Haemophilus influenzae type b (Hib), but vaccine development and the vaccination of children as part of their routine immunization have drastically decreased the number of cases due to H. influenzae. At present, the leading causes of bacterial meningitis are Streptococcus pneumoniae and Neisseria meningitidis. Other bacteria that can cause meningitis include Listeria monocytogenes, responsible for about 10% of cases of bacterial meningitis, Escherichia coli, Klebsiella, and Mycobacterium tuberculosis. E. coli and Klebsiella infections usually develop subsequent to a head injury, brain or spinal cord surgery, sepsis, or a nosocomial infection. Furthermore, these infections are more common among people with a compromised immune system, premature infants, and children.

Meningococcal Meningitis

Meningococcal meningitis is caused by Neisseria meningitidis, a gram-negative, aerobic diplococcus with an antigenic polysaccharide capsule, responsible for the virulence of the organism. Depending on the geographic location, up to 20% of the population are asymptomatic carriers of the organism in their nose and throat, and therefore represent a reservoir of the infection.

Those most often infected are children under the age of 2 years, who have lost their maternal antibodies, usually after 6 months of age, which leaves them more susceptible to the infection. The bacterium is spread by person-to-person contact or by respiratory droplets. Carriers with other respiratory infections, such as the common cold, have an increase in respiratory secretions and can more readily spread the pathogen. Overcrowded conditions or confinement contribute to the spread of the infection and the likelihood of a disease outbreak.

The onset of meningococcal meningitis is sudden after an incubation period of 1 to 3 days. The symptoms include the following:

• A sore throat

• Headache

• Drowsiness

• Fever

• Neck stiffness

• Photosensitivity

In some patients the bacteria can proliferate in the bloodstream and a hemorrhagic skin rash reflecting septicemia can occur. This gram-negative sepsis is a life-threatening condition; if untreated it can lead to extensive tissue destruction and a need for amputations, and death can occur a few hours after the onset of fever. Antibiotic therapy reduces the mortality rate by 9% to 12%.

Neisseria meningitidis occurs in five capsular serotypes (A, B, C, Y, and W-135); their predominant occurrence varies with the geographic location. In the United States and other developed countries, meningococcal meningitis has been caused predominantly by serotypes B, C, and Y, whereas serotypes A and W-135 are more common in less developed countries. Polysaccharide vaccines are available against serotypes A, C, Y, and W-135, but not against serotype B.

Outbreaks of meningococcal meningitis occur globally. It is endemic in temperate climates, with sporadic cases or small clusters of cases exhibiting seasonal increases in winter and spring. In the United States sporadic outbreaks occur among college students who live in dormitories. Epidemics of meningococcal meningitis have occurred in Africa in periodic waves. In 2002 outbreaks occurred in the Great Lakes region of Central Africa in villages and refugee camps. More than 2200 cases were reported, including 200 deaths (Table 13.2). More recently, during 2007, 54,676 suspected cases of meningitis and 4062 deaths were reported from the “meningitis belt” region in Africa. This region covers 21 sub-Saharan African countries with a population of about 350 million people.

TABLE 13.2

Recent Outbreaks of Meningococcal Meningitis Worldwide

Time	Place	Number of Cases	Number of Deaths
Until May 12, 1999 (10.7 million doses of vaccine were distributed to the affected states)	19 states of Sudan	22,000	1600
August–September 1999	Angola (Yambala area)	253	147
September–October 1999	Rwanda	No reported numbers
October 1999 to January 2000	Central African Republic	86	14
December 1999	Hungary	30	4
January to March 2000	Ethiopia
	Kobo District of Amhara Region	81	3
	Alamata District of Tigray Region	48	6
2002	Great Lakes region (Africa)	2200	200
2002	Burkina Faso (W-135 emerged)	130,000	1500
2007	“Meningitis belt” (Africa)	54,676	4062

LIFE APPLICATION

Meningitis: The Dorm Disease?

Bacterial meningitis, the swelling of the membranes surrounding the brain and spinal cord, can be caused by a number of different microorganisms. Most of the meningitis cases seen in children or young adults have been attributed to the bacterium Neisseria meningitidis. It affects 1400 to 3000 persons in the United States each year and is responsible for 150 to 300 deaths. Among young adults going to college there are 100 to 125 cases occurring on campuses each year, with 5 to 15 deaths. Because the organism is spread through the air by respiratory droplets or by direct contact such as oral contact with shared items such as a drinking glass or by kissing, this disease can be spread rapidly in areas where persons are living in crowded conditions, such as college dorms. Because of the unique conditions in the dorm environment, such as close contact, sharing of personal items, bar patronage, and irregular sleep patterns, college students living in residence halls are much more likely to acquire meningitis than is the rest of the college population. In 2005 the Centers for Disease Control and Prevention voted to recommend that all incoming college freshmen living in residence halls be vaccinated against meningitis. The American College Health Association (ACHA) further recommended that all first-year students living in dorms should be immunized and that all students under the age of 25 years should consider receiving the vaccination.

Haemophilus influenzae Meningitis

Haemophilus influenzae is an aerobic, gram-negative coccobacillus, commonly present in the normal flora of the throat. There are six serotypes of H. influenzae, differentiated by their capsular polysaccharide. Uncapsulated strains are common in the throat of most healthy people. Capsulated strain b (Hib) is a common inhabitant of the respiratory tract of infants and children. It occasionally enters the bloodstream and causes invasive diseases such as pneumonia, otitis media, epiglottitis, and meningitis.

Before the availability of the Hib conjugate vaccine in the United States and other industrialized countries, the leading cause of bacterial meningitis was Haemophilus influenzae serotype b in children under the age of 5 years. Because of the use of the vaccine the incidence of this type of meningitis in young children has declined by more than 95%, but it still causes between 5% and 10% of bacterial meningitis cases in adults.

Transmission occurs by direct contact with respiratory droplets from a carrier or a patient. At-risk groups include infants and young children, persons in the same household as the patient, and day care center classmates. Treatment should be started as soon as disease is suspected and should be via intravenous (IV) antibiotics. Steroids are sometimes used, especially in children to reduce hearing loss, a common complication of meningitis. Preventive therapy is recommended for individuals who have had close contact with an infected individual. This type of contact includes sharing living space, kissing, sharing food and eating utensils, or other contact with oral secretions.

Prevention can be provided by several types of Hib vaccines available for children 2 months of age or older. Immunization is recommended for infants and children by the American Academy of Pediatrics, the National Institutes of Health, and other health agencies. Ideally, the first dose of the vaccine should be administered at the age of 2 months, followed by three or four booster vaccinations (see Chapter 20, The Immune System), depending on the brand of vaccine used.

Pneumococcal Meningitis

Pneumococcal meningitis is caused by Streptococcus pneumoniae, a gram-positive, encapsulated, facultatively anaerobic diplococcus, carried in the throat of many healthy individuals. Differences in the composition of the polysaccharide capsule accounts for approximately 90 different serotypes, some of which are frequently associated with pneumococcal disease, others only rarely. With the decline in Hib meningitis, Streptococcus pneumoniae has become the most common cause of meningitis in adults, especially the elderly, and children between the ages of 1 month and 4 years.

Pneumococci are also the cause of millions of cases of acute otitis media (middle ear infection) annually (Figure 13.4), and approximately 500,000 cases of pneumonia per year in the United States (see Chapter 11, Infections of the Respiratory System). Middle ear infections are one of the most common reasons for physician’s office visits in the United States, resulting in more than 20 million visits annually. In general, by the age of 12 months 60% of children have had at least one episode of acute otitis media. Complications of pneumococcal otitis media include mastoiditis and meningitis.

The immune response to a pneumococcal infection is directed primarily against the capsular serotype involved in a given infection. A conjugate vaccine has been developed and vaccination is recommended for all children less than 24 months old and others at risk. In general, vaccination is recommended for:

• High-risk persons age 2 years and over

• Everyone age 65 years and older

• Patients with sickle cell anemia

• Patients with splenectomy

• Patients with chronic organ failure

• Residents of nursing homes and other long-term care facilities

• People who live in institutions with residents who have chronic health problems

• People with a compromised immune system such as patients with HIV, patients with cancer, or patients who have received an organ transplant

• Persons who receive long-term immunosuppressive drugs, including steroids

• Alaskan natives and certain Native American populations who are genetically predisposed

A serious problem with pneumococcal diseases including meningitis is the increasing emergence of antibiotic-resistant strains of S. pneumoniae (also see Chapter 11, Infections of the Respiratory System). Antibiotic-resistant strains are most likely to emerge in settings where antibiotics are commonly prescribed such as in hospitals, nursing homes, and day care centers. At present between 10% and 40% of all infections caused by S. pneumoniae are resistant to at least one antibiotic, but more and more multidrug-resistant strains are emerging in the United States. Therefore, vaccination of at-risk groups will play an even more important role in preventing pneumococcal disease in the near future.

HEALTHCARE APPLICATION
Bacterial Meningitis

Pathogen	Transmission/Symptoms	Treatment	Prevention
Neisseria meningitidis	Person to person, contact with respiratory droplets or oral secretions Acute onset (6–24 h); skin rash

Penicillin, ampicillin, chloramphenicol, ceftriaxone Polysaccharide vaccine; prophylaxis with rifampin for close contact Haemophilus influenzae

Person to person, contact with respiratory droplets, body fluid

Onset: 1–2 d

Ampicillin, ceftriaxone, or chloramphenicol Polysaccharide vaccine against type b (Hib) Streptococcus pneumoniae

Mostly through respiratory droplets

Acute onset: May follow pneumonia and/or septicemia in elderly

Penicillin, ceftriaxone, or chloramphenicol Prompt treatment of otitis media and respiratory infections; polysaccharide vaccine Listeria monocytogenes Foodborne Penicillin or ampicillin plus gentamicin Avoidance of contaminated food products; complete cooking of all foods Personality change, fever, uncoordinated muscle movement, tremors, seizures, loss of consciousness Mycobacterium tuberculosis Isoniazid and rifampin BCG vaccination; isoniazid prophylaxis for contacts (recommended in the United States) Escherichia coli and other coliforms Newborns: During delivery at hospital, or at home Antibiotics  

Listeria Meningitis

Listeria monocytogenes is a gram-positive coccobacillus and is the causative agent of listeriosis (see Chapter 12, Infections of the Gastrointestinal System), a foodborne illness. This organism can spread from the bloodstream to the central nervous system, causing meningitis, especially in the elderly and in immunocompromised patients, especially patients with cancer. Listeria meningitis is often fatal, and occurs in approximately half the cases of adult listeriosis. The more serious symptoms appear about 4 days after the initial symptoms of slight fever, headache, nausea, vomiting, diarrhea, and tiredness. The symptoms of Listeria meningitis include the following:

A person becomes infected with Listeria by consuming contaminated food. Listeria can then pass through the wall of the intestine and into the bloodstream, by which the bacteria can be transported anywhere in the body; however, they are commonly found in the CNS. Listeria lives inside macrophages, hiding from the immune system, and is capable of multiplying in the macrophages. The organism is also small enough to cross the placenta, and therefore is capable of infecting a fetus. When an infant becomes infected before or during childbirth, two types of listeriosis may occur: early-onset disease and late-onset disease.

Listeriosis is treated with antibiotics; the duration of treatment varies and is dependent on the physiological state of the patient. The overall fatality rate for the disease is 26% because of the seriousness of the illness in newborns, the elderly, and immunocompromised patients.

Tetanus

Tetanus is an acute, often fatal illness, characterized by prolonged contraction of skeletal muscle fibers, resulting in generalized rigidity and convulsive spasms of the skeletal muscles. The symptoms are caused by tetanospasmin, a neurotoxin (exotoxin) produced by Clostridium tetani, a gram-positive, anaerobic rod that may develop a terminal spore, giving it a drumstick-like appearance (Figure 13.5). Whereas the vegetative organism is sensitive to heat and cannot survive the presence of oxygen, the spores are extremely resistant to heat as well as to the usual antiseptics. The spores are also relatively resistant to phenol and other chemical antimicrobial agents.

Spores of Clostridium tetani can be found in soil and in the intestines and feces of horses, sheep, cattle, dogs, cats, rats, guinea pigs, and chickens. As a result, manure-treated soil contains an especially large number of Clostridium spores. These spores can enter the human body through an anaerobic wound, as small as a scratch or cut, or through a much larger injury. Once spores gain entrance and get to an anaerobic environment, they germinate into the vegetative form. C. tetani then produces two types of exotoxins: tetanolysin and tetanospasmin. Although the function of tetanolysin is not completely understood, it is clear that tetanospasmin is the neurotoxin that causes the clinical manifestations of tetanus, and is one of the most potent toxins known to humans. The estimated minimal lethal dose to humans is 2.5 nanograms (ng) per kilogram of body weight—1 ng is 1 billionth (10^–9) of a gram.

Clostridium tetani itself does not spread from the site of infection, and there is no accompanying inflammation. The organism releases its toxins, which are then carried via the peripheral nerves and probably also by the bloodstream to the central nervous system. The toxin then inhibits the release, by the spinal cord neurons, of inhibitory neurotransmitters that normally regulate the relaxation of muscle fibers, resulting in abnormal sustained muscle contraction known as tetany (a muscle spasm), which is unrelated to the physiological sustained controlled muscle contraction also called tetanus.

The incubation period of tetanus ranges from 3 to 21 days; the farther the injury occurs from the CNS the longer the incubation period. With shorter incubation periods the chance of a fatal outcome increases. On the basis of clinical findings, four different types of tetanus are described:

Botulism

Botulism is a rare, serious illness caused by Clostridium botulinum, an anaerobic, gram-positive, spore-forming rod that produces a potent neurotoxin (see also Chapter 12, Infections of the Gastrointestinal System). The organism and its spores are widely distributed in nature. They are present in cultivated and forest soils; the bottom sediment of streams, lakes, and coastal waters; and also in the intestinal tract of fish and mammals and in the gills and viscera of crabs and other shellfish. Seven serotypes of botulism are documented (A, B, C, D, E, F, and G), based on the antigenic specificity of the toxin produced by each strain. Only types A, B, E, and F cause human botulism; types C and D are the cause of most cases of botulism in animals. The toxins produced by the different strains vary considerably in their virulence factors.

Four types of botulism are recognized (also see Chapter 12, Infections of the Gastrointestinal System):

As stated previously, the botulinum toxin is a neurotoxin, a protein that is toxic to nerve cells and is one of the most poisonous naturally occurring substances known. The infective dose is a very small amount, with illness occurring on exposure to only a few nanograms.

Once the botulinum toxin enters the body, the toxin binds to nerve endings at the neuromuscular junction, which stops the release of the neurotransmitter acetylcholine and thereby inhibits muscular contraction. Thus, exposure of the neuromuscular junction to these neurotoxins results in a flaccid paralysis. The common symptoms of all forms of botulism include the following:

The muscle weakness and paralysis descend from the cranium, affecting all muscles including the muscles that regulate breathing (diaphragmatic and intercostal muscles). Botulism is not an infection; it is an intoxication, caused by the botulinum toxin.

Although the incidence of the disease is low, the mortality rate is high if not treated immediately and properly. Death from botulinum intoxication is generally due to respiratory failure caused by paralysis of the diaphragmatic and intercostal muscles. Therefore, the treatment required is botulinal antitoxin administration and artificial ventilation. The functional recovery time may take several weeks to months.

Leprosy

Leprosy (Hansen’s disease) is a chronic, slowly progressive disease caused by Mycobacterium leprae, an intracellular, pleomorphic, acid-fast, gram-positive, aerobic bacillus that is surrounded by the characteristic waxy coating unique to mycobacteria. The illness affects the following:

Leprosy was one of the most common infectious diseases of ancient times, and is still a significant health problem in parts of Africa, Asia, the South Pacific, and in some South American countries. Although the disease was thought to be transmissible even by the slightest contact, it is actually less communicable than most other infectious diseases. Most cases of leprosy in the United States involve people who have emigrated from developing countries.

About 95% of people exposed to Mycobacterium leprae do not develop the disease because of their intact immune system. The infection can start at any age, but most often starts with people in their 20s and 30s. The incubation period varies from 6 months to 10 years. Patients with the disease are classified as having paucibacillary (tuberculoid) or multibacillary (lepromatous) Hansen’s disease. Death from leprosy is rare and is usually a result of infections of the leprous lesions, and not the pathogen itself.

Paucibacillary Hansen’s disease is characterized by one or more hypopigmented cutaneous lesions and damaged peripheral nerves that have been attacked by the host’s immune system. This causes a loss of sensation in the affected nerves and people with peripheral nerve damage may unwittingly damage and harm the affected areas. Repeated damage may eventually result in loss of fingers and toes. Furthermore, damage to the peripheral nerves may also cause muscle weakness, resulting in a clawing posture of the fingers (“claw hand”) and a “drop foot” deformity.

Multibacillary Hansen’s disease is the more virulent form of the disease and is manifested by the following:

Transmission of the disease is still not completely understood, but most studies indicate that the disease is transmitted by close and extended contact from person to person via respiratory droplets. Although antibiotic treatment can stop the progression of leprosy it does not reverse any nerve damage or deformity. Early detection and treatment are essential. Because of the development of antibiotic resistance the World Health Organization (WHO, Geneva, Switzerland) recommends a multidrug treatment consisting of dapsone, rifampin, and clofazimine. However, because of the considerable expense of this treatment it has not been implemented in many of the endemic areas of the world.

Conjunctivitis

Conjunctivitis (pink eye) can be caused by bacteria, viruses, allergies, chemicals, or a foreign object. Both the bacterial and viral forms of conjunctivitis are contagious. Because bacterial conjunctivitis is the most common type of ocular infections it is discussed in this section. Conjunctivitis is the inflammation or infection of the conjunctiva, the transparent membrane that lines the eyelid and part of the eyeball (Figure 13.7). The inflammation causes small blood vessels to become more prominent, causing the pink or red appearance of the eye. The most common symptoms of conjunctivitis include the following:

Bacteria that can cause conjunctivitis include but are not limited to Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Haemophilus spp., Chlamydia trachomatis, Neisseria gonorrhoeae, Streptococcus pyogenes, Moraxella spp., and Corynebacterium spp. In newborns, neisserial and chlamydial infections are frequent and acquired during passage through an infected birth canal. Because of the application of antibiotic drops into the eyes of newborns, the incidence of conjunctivitis in newborns in the United States has dropped dramatically. Chlamydia trachomatis is one of the leading causes of blindness in the world, mainly in underdeveloped countries.

The infection can be treated with antibiotic eyedrops or eye ointment and should clear within several days. Practicing good hygiene is the best way to control the spread of pink eye.

Viral Infections

Viruses are transmitted by person-to-person contact, respiratory droplets, the fecal–oral route, trauma, injection with contaminated objects or needles, transplants and blood transfusions, insects or animal bites, during gestation, and sexually. Most viruses enter the central nervous system via the circulatory system; however, some can gain access by other pathways such as the peripheral nerves. Several viral infections can be prevented by vaccination; many others can be treated with specific antiviral drugs. In addition, most viral infections need to be treated by supportive therapy such as rehydration and pain control.

Viral Meningitis

Viral meningitis is relatively common but, in contrast to bacterial meningitis, is usually not serious. Viral meningitis is called aseptic meningitis (see Table 13.1) and can be caused by any number of viruses, most of which are associated with another disease. Most often it is spread by direct contact with infected feces or nose and throat secretions. Moreover, mosquitoes can be a vector and transmit viral meningitis, usually in the summer and fall. Viral meningitis in the winter months is usually due to another underlying disease. It spreads most rapidly among young children and also in group living environments where running water is in short supply. Although anyone can get the illness, most people over 40 years of age seem to be immune.

Symptoms of viral meningitis include fever, headache, stiff neck, and tiredness. A rash, sore throat, and vomiting may also occur. Appropriate hand washing and avoidance of mosquito bites help prevent the illness. There is no treatment for viral meningitis, and in most cases the immune system will produce the antibodies necessary to destroy the virus. Usually viral meningitis starts suddenly; however, babies may have a gradual illness manifested by refusal to eat, being more sleepy than usual, and fussy. Although rare, bulging of a fontanelle (soft spot) may occur and usually is a late sign of the infection. Most children and adults recover completely within 10 to 14 days.

Poliomyelitis

The causative agent of poliomyelitis is the poliovirus, a small, nonenveloped, single-stranded RNA (ssRNA) virus, a human enterovirus of the family Picornaviridae (Figure 13.8). Usually poliovirus replicates within the gastrointestinal tract and is shed with the feces, and therefore it is spread from person to person via the fecal–oral route. The incubation period varies from 6 to 20 days. Approximately 95% of all infections are asymptomatic and about 4% to 8% of the infections result in a minor, nonspecific illness without clinical or laboratory evidence of central nervous system invasion. This condition is referred to as abortive poliomyelitis and complete recovery occurs in less than 1 week.

In approximately 1% to 2% of all poliovirus infections the virus enters the CNS and replicates within the motor neurons of the spinal cord, brainstem, or motor cortex, all of which lead to temporary or permanent muscle paralysis, and overall 5% to 10% of patients with paralytic polio die of respiratory arrest, due to paralysis of the intercostal muscles. Many cases of poliomyelitis result in only temporary paralysis and within 1 month nerve impulses return to the temporarily paralyzed muscles and recovery can be complete within 6 to 8 months.

The virus is transmitted primarily by ingestion of water contaminated with fecal material containing the virus. The infection is initiated by ingestion and the areas of multiplication are the throat and the small intestine, accounting for the initial sore throat and nausea. The neurological phase of the infection seems to be an accidental result of the normal gastrointestinal infection. Once the virus infects the throat, it then enters the tonsils and the lymph nodes and via this route then can enter the bloodstream, causing viremia. In the majority of cases the infection does not go beyond the lymphatic system, but occasionally the virus passes through the capillary endothelium and enters the CNS, where it infects predominantly motor neurons. As a result of viral multiplication the motor neurons die, and paralysis results.

Several factors increase the risk for infection or affect the severity of the disease and these include the following:

• Immune deficiency

• Malnutrition

• Tonsillectomy

• Physical activity immediately after the onset of paralysis

• Intramuscular injection

• Pregnancy

Maternal antibodies to the poliovirus do cross the placenta and provide passive immunity (see Chapter 20, The Immune System) to the infant during the first few months of life.

Three different serotypes of the poliovirus exist, each with a slightly different capsid: PV1 (Mahoney), PV2 (Lansing), and PV3 (Leon). All three serotypes are extremely infectious, but PV1 is the most common form found in nature. Notably, infection with one type of poliovirus does not provide immunity against the other types, and therefore prevention via vaccines must be provided for all three types. At present two vaccines are used to combat polio: the Salk vaccine or inactivated poliovirus vaccine (IPV), first developed in 1952, and the Sabin or oral polio vaccine (OVP), licensed in 1962. Starting in 1988 the extensive use of poliovirus vaccines in an effort to eradicate polio resulted in a 99% reduction of annually diagnosed cases worldwide. This global effort was led by the WHO, United Nations Children’s Fund (UNICEF), and Rotary Foundation.

In the United States only IPV is available for routine polio vaccination of children. In 2002, a five-component vaccine (Pediarix) was approved for use in the United States. The vaccine contains IPV, DTaP (diphtheria, tetanus, and pertussis), and a pediatric dose of hepatitis B vaccine.

About 25% to 40% of individuals who have survived paralytic polio during childhood experience new muscle pain and exacerbation of existing weakness, or develop new weakness or paralysis 30 to 40 years after the initial illness. This condition is referred to as postpolio syndrome (PPS). The pathogenesis of the syndrome seems to involve the failure of oversized motor units that were generated during recovery from the original paralytic poliomyelitis, and/or the overuse and disuse of neurons. Postpolio syndrome is not infectious and the poliovirus cannot be shed by persons with the syndrome.

Rabies

Rabies is a preventable zoonotic disease caused by the rabies virus, which belongs to the order Mononegavirales, family Rhabdoviridae, and genus Lyssavirus. It is a nonsegmented, negative-sense ssRNA virus with a distinct “bullet” shape (Figure 13.9), and is capable of causing acute encephalitis in all warm-blooded hosts. Although all species of mammals are susceptible to the rabies virus, only a few species are the reservoir of distinct rabies virus variants of the disease in the United States. These variants can be detected in raccoons, skunks, foxes, and coyotes, as well as in some insectivorous bats. Rabies can also spread to domestic farm animals, groundhogs, weasels, dogs, and cats. Most animals that can be infected by the virus can also transmit the disease to humans.

Transmission of the virus commonly begins when infected saliva enters an uninfected host. Different routes of entry have been reported, including mucous membranes such as those of the eyes, nose, and mouth; aerosol transmission; and corneal transplantation. However, the most common mode of transmission is through a bite or scratch of an infected animal (host). Less than 10% of reported rabies cases involve domestic cats, dogs, and cattle.

Symptoms of rabies are usually vague but they include the following:

• Fatigue

• Muscle aches

• Anxiety

• Irritability

• Agitation

• Insomnia

• Headache

• Nausea

• Vomiting

• Abdominal pain

Early symptoms manifest themselves with pain, itchiness, and numbness at the site of the bite or scratch, and occur in about 55% to 60% of patients. Untreated rabies can lead to coma and death. There is no treatment for rabies after the symptoms of the disease occur. However, immunization given within 2 days of a bite or scratch usually prevents the onset of rabies, and generally rabies does not develop if the vaccine is given promptly. Preexposure vaccination does not eliminate the need for additional treatment, but is recommended for persons in high-risk environments, such as veterinarians, animal handlers, and laboratory personnel, or other individuals whose daily activities puts them at risk to contract rabies.

Postexposure prophylaxis (PEP) is necessary for people possibly exposed to a rabid animal. This includes animal bites, or mucous membrane contamination with infectious tissue, or exposure to saliva. In the United States, PEP consists of a regimen of one dose of immunoglobulin, given as soon as possible after exposure, and five doses of rabies vaccine over a 28-day period. The CDC recommends that any dog, cat, or ferret that bites a person should be confined and observed for 10 days if vaccination of the animal cannot be proven.

To prevent the spread of rabies, pet owners should do the following:

• Keep vaccinations up-to-date for all dogs, cats, ferrets, and other pets

• Keep pets under direct supervision so that they do not come in contact with wild animals

• Inform the local animal control agency to remove any stray animals from the neighborhood

• Spay or neuter pets to help reduce the number of unwanted pets, which may not be properly cared for or vaccinated on a regular basis

• Avoid contact with wild animals

Arboviral Encephalitis

Arthropod-borne viruses, or arboviruses, are transmitted and maintained through biological transmission between a susceptible vertebrate host and mosquitoes, psychodids, ceratopogonids, and ticks. Vertebrate infection occurs due to arthropods that take a blood meal. Encephalitis caused by these arthropods is fairly common in the United States. Arboviruses that cause human encephalitis belong to the families Togaviridae, Flaviviridae, and Bunyaviridae (see Chapter 7, Viruses).

Arboviral encephalitides have a global distribution (Figure 13.10), but the viral agents currently present in the United States include the following: eastern equine encephalitis (EEE), western equine encephalitis (WEE), St. Louis encephalitis (SLE), La Crosse (LAC) encephalitis, and more recently West Nile virus (WNV) encephalitis, all transmitted via mosquitoes. WNV infects a large number of bird species such as crows and blue jays and has now spread throughout the United States.

• Eastern equine encephalitis (EEE): EEE virus is a member of the family Togaviridae, genus Alphavirus and causes illness in humans, horses, and some bird species. Transmission of the virus to humans occurs via an infected mosquito and symptoms develop 3 to 10 days after the bite occurred.

• Western equine encephalitis (WEE) is caused by an Alphavirus species, transmitted by mosquitoes. The infection can cause a range of illnesses from no symptoms to a fatal condition. Mild illness manifests itself as a headache and fever, whereas more severe disease can show the following:

• Sudden high fever

• Headache

• Drowsiness

• Irritability

• Nausea

• Vomiting

• Confusion

• Weakness

• Coma

Symptoms usually occur by 5 to 10 days after being bitten by an infected mosquito. At present no licensed vaccine is available for human use and no specific treatment is available for this infection.

• St. Louis encephalitis (SLE): The St. Louis encephalitis virus is mosquito borne, a Flavivirus species that can cause aseptic meningitis or encephalitis. The fatality rate ranges from 3% to 30%, mostly in the at-risk groups including the elderly and people with an outdoor occupation. However, the majority of infections are subclinical or a mild illness, including fever and headache. The majority of cases in the United States occur in the late summer or early fall, but in milder climates the illness can occur year round. At present no treatment or vaccine is available for the St. Louis encephalitis virus.

• La Crosse (LAC) encephalitis is a rare viral infection spread by mosquitoes and usually affects children. The infection is found primarily in the upper Midwestern United States and in the Appalachian region. The majority of infections are subclinical or result in mild illness; symptoms include nausea, headache, and vomiting and severe cases can cause seizures, coma, paralysis, and brain damage. At present no therapy is available and management of the condition is limited to treatment of the symptoms.

• West Nile virus (WNV) encephalitis is another arbovirus transmitted by mosquitoes and is common in areas such as Africa, western Asia, and the Middle East. Symptoms of infection include the following:

• Skin rash

• Headache

• Fever

• Diarrhea

• Nausea

• Vomiting

• Back and muscle aches

• Lack of appetite

• Swollen lymph glands

In less than 1% of cases the virus can cause a serious neurological infection including encephalitis, meningitis, and a condition called West Nile poliomyelitis (an inflammation of the spinal cord). Most victims of West Nile virus recover without treatment and even those patients with neurological infections usually need only supportive therapy such as intravenous fluids and pain relievers. The best prevention for West Nile virus infections is to avoid exposure to mosquitoes and to eliminate breeding sites.

Fungal Infections

Fungal infections of the nervous system are far less common than bacterial and viral infections. Most fungal infections are opportunistic, and therefore they take on more importance in all immunocompromised persons, including cancer patients undergoing chemotherapy, patients with AIDS, or patients receiving immunosuppressive therapy for organ transplantation.

Cryptococcosis

Cryptococcosis is a rare infection caused by the fungus Cryptococcus neoformans, an encapsulated yeast present worldwide. The fungus is found in soil, especially in soil contaminated with bird droppings. Once the fungus enters the body through inhalation or through a wound it can cause the following:

• Wound or cutaneous cryptococcosis

• Pulmonary cryptococcosis

• Cryptococcal meningitis

Cryptococcal meningitis most often affects immunocompromised persons including patients with AIDS, cancer, and/or diabetes. Initial symptoms of the infection may be vague including mild headache, fever, and nausea. As the infection progresses the following symptoms may appear:

• Severe headache

• Nausea with vomiting

• Blurred vision and light sensitivity (photophobia)

• Stiff neck

• Seizures

• Confusion

• Change in behavior

• Coma

Antifungal intravenous medications are typically used to treat this condition; however, long-term oral medication is suggested for patients with AIDS, to prevent recurrence of the infection.

Protozoan Infections

Although many infectious diseases are caused by endogenous organisms, diseases caused by protozoan and helminthic parasites are being caused by an exogenous source. Many of these infections are acquired via the bites of an arthropod vector, others by ingestion or inhalation of contaminated material from animal or human wastes, or through a break in the skin.

Cerebral Toxoplasmosis

Toxoplasmosis is caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Most infected individuals do not show any symptoms, but the infection can be serious, even fatal in individuals with a compromised immune system. In general, human infections occur via the oral or transplacental route, through the consumption of undercooked meat contaminated with viable cysts, or by direct ingestion of oocytes from contaminated soil or water.

A pregnant woman who contracts toxoplasmosis has a more than 30% chance of passing the infection to her fetus (see Congenital Toxoplasmosis in Chapter 23, Human Age and Microorganisms). Typical symptoms are speech difficulties, seizures, confusion, and lethargy, usually over a period of days to weeks. Treatment includes the use of corticosteroids to reduce cerebral edema and a regimen of trimethoprim-sulfamethoxazole.

Trypanosomiasis

Hemoflagellates of the genus Trypanosoma are the causative agents of African trypanosomiasis (sleeping sickness) and Chagas’ disease (American trypanosomiasis).

African Trypanosomiasis

African trypanosomiasis, also referred to as sleeping sickness, is caused by the protozoan Trypanosoma brucei. It is spread by the bite of the tsetse fly. The organism enters the bloodstream and then travels to the CNS, where it can cause meningitis or encephalitis. The main symptom of the disease is coma, which is why it is called sleeping sickness. One of the difficulties in treating the infection is the fact that the organism is able to change its surface proteins, challenging the immune system to keep making new antibodies to respond to the new surface antigens. Thus far, there is no effective treatment available and there is no vaccine because of this ability of the organism to keep changing antigens. The best measures to prevent the disease are through the use of insect netting and insecticides.

Chagas’ Disease

Chagas’ disease, also referred to as American trypanosomiasis, is caused by the protozoan Trypanosoma cruzi. It is typically spread by the bite of a reduviid (“kissing bug”), which bites around the mouth and other facial sites. They will bite, feed on the blood and tissue juices, and then defecate into the wound, giving the organisms in the feces a portal of entry. If the organism invades the CNS it may produce granulomas in the brain with cyst formation and meningoencephalitis. In extreme cases, in which the disease causes significant tissue damage in the brain, death can result. At present the drug of choice for treating Chagas’ disease is nifurtimox, but the most effective measures in controlling the disease are preventive in nature. Insect control, eradication of nests, and even the limited use of dichlorodiphenyltrichloroethane (DDT) in bug-infested homes will contribute significantly to the prevention of this disease.

Prion-associated Diseases

Prion diseases or transmissible spongiform encephalopathies (TSEs) are a related group of rare, infectious, fatal, and progressive neurodegenerative diseases that affect various animals and humans. The causative agents for these diseases are believed to be prions, molecules that begin as a normal protein in animal tissue but abnormally fold and become infectious particles (see Chapter 7, Viruses). Prion diseases have a long incubation time, usually years; however, once the disease process starts they are usually rapidly progressive and always fatal. In humans, prion diseases impair brain function, causing memory changes, personality changes, dementia, and movement disorders that worsen with time. At present, there are no known ways to cure TSE diseases. Prion diseases identified to date include the following:

Historically, many of these diseases were called “slow virus infections,” a poorly defined group of proposed viral diseases, later found to be caused by prions. Many questions about the prion biosafety of food and drugs remain and many aspects of the basic mechanisms of prions remain unclear. At present no test is available to detect prion infectivity in human blood.

Summary

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