Microbial Diseases of the Nervous System and Eyes

­ LE A R N I N G O U TC O M E s Structure of the Nervous System 20.1 Describe the basic divisions, organs, and structures of the nervous system. 20.2 Describe the formation, circulation, absorption, and col- lection of cerebrospinal fluid. 20.3 Explain how microbes might gain access to the normally axenic central nervous system. igure The nervous system is divided into the central nervous system and the peripheral nervous system (F 20.1a). Structures of the Central Nervous System The central nervous system (CNS), which is composed of the brain and spinal cord, functions as the master control center of the body. The brain has several main parts, including the following: • The cerebrum—the largest, upper part of the brain—controls voluntary muscles, perception, and what people commonly call “thinking.” • The lower cerebellum controls many involuntary body movements, such as swinging the arms while walking. • The brain stem, which connects the brain to the spinal cord, has a number of functions, including control of breathing, heart rate, and blood pressure. The spinal cord extends down from the brain stem only as far as the lumbar region (lower back). Below this region, a bundle of nerves called the cauda equina1 extends from the spinal cord. As its name suggests, this bundle resembles the tail of a horse. Bones of the cranium, bones of the vertebral column, and three layers of tissue called meninges2 (mě-nin’jēz) surround the brain and spinal cord, providing support and protection from external shock. The three meninges vary in their structure and appearance (FIGURE 20.1b, c). Lying next to the bones is the dura mater3 (dŭ’ră mā’ter), a tough fibrous sheath that provides a strong, yet flexible, covering for the soft organs of the CNS. It also provides a barrier against the spread of infections from the bones. Deep to the dura mater is the arachnoid mater4 (ă-rak’noyd mā’ter), which contains numerous branching fibers giving the appearance of a spider’s web. The cavities between the fibers of the arachnoid mater are collectively called the subarachnoid space. The internal layer, which is pressed close to the spinal cord and brain, is the pia mater5 (pī’ă mā’ter). Blood vessels on top of the pia mater supply the CNS with blood. The walls of these blood vessels are composed of tightly joined cells that form the blood­brain barrier, 1Latin, meaning “horse’s tail.” Greek meninx, meaning “membrane.” 3Latin dura, meaning “hard,” and mater, meaning “mother.” 4From Greek arachne, meaning “spider,” and Latin mater, meaning “mother.” 5Latin pia, meaning “tender,” and mater, meaning “mother.” 2From M20_BAUM7206_05_SE_C20.indd 596 which prevents most microbes and large molecules in the blood from entering the subarachnoid space. Thus, blood infections do not easily spread to the CNS, but unfortunately, neither do many common antimicrobial drugs, such as penicillins, cephalosporins, tetracyclines, and aminoglycosides, making it more difficult to treat infections of the CNS. Fluid leaks from the blood into the subarachnoid space that lines the brain. This watery fluid—called cerebrospinal fluid (CSF)—circulates throughout the subarachnoid space of both brain and spinal cord to bathe both organs. Arachnoid villi or arachnoid granulations, which are knoblike extensions of the arachnoid mater, extend into a blood-filled cavity at the top of the cranium and return CSF to the blood (see Figure 20.1b). Cerebrospinal fluid acts as a shock absorber; provides nutrients, electrolytes, and oxygen to the nervous tissues; and removes wastes. In a medical procedure called a lumbar puncture (spinal tap), physicians remove a sample of CSF from the region of the subarachnoid space surrounding the cauda equina (FIGURE 20.1d). They insert a needle through the skin between two of the lumbar vertebrae, through the dura mater and subdural space, and through the arachnoid mater to reach the CSF in the subarachnoid space. Structures of the Peripheral Nervous System The peripheral nervous system (PNS) is composed of nerves that transfer commands from the CNS to muscles and glands throughout the body and provide information to the CNS concerning events in the body. Cranial nerves extend from the brain through holes in the cranial bones, and spinal nerves extend from the spinal cord through gaps between vertebrae. Branches of nerves often merge together to form a nerve plexus (see Figure 20.1a). Functionally, there are three types of nerves: Sensory nerves primarily carry signals toward the CNS. The optic nerves from the eyes are examples. Motor nerves carry signals from the CNS to other organs of the body, and mixed nerves carry signals both toward and away from the CNS. ­          Microbial Diseases of the Nervous System and Eyes Cells of the Nervous System The entire nervous system is composed of two basic types of cells—neurons (nūr’onz) and supportive cells called neuroglia (nū-rog’lē-a). The smaller neuroglia provide a supportive scaffolding, insulation, and nutritive support and phagocytize microbes. The cytoplasmic membrane of a neuron generates an electrical signal called an action potential or nerve impulse. The nucleus of a neuron lies in a region of cytoplasm called the cell body. Outside the CNS, a collection of many neurons’ cell bodies is called a ganglion. Two types of fingerlike cytoplasmic processes extend from a cell body: numerous, perhaps hundreds, of short dendrites and a longer single axon. Within the cytoplasm of an axon, the cytoskeleton transports substances by a process known as axonal transport. Do not confuse dendrites and axons, which are part of individual cells (neurons), with sensory and motor nerves, which are bundles of thousands of cells. 11/23/16 3:38 AM       Structure of the Nervous System Bone of cranium Blood in cavity Arachnoid villus (granulation) Dura mater Movement of CSF Arachnoid mater Meninges Pia mater Subarachnoid space Brain Subdural space Cerebrum Central nervous system (CNS) Peripheral nervous system (PNS) Brain (b) Spinal cord Cerebellum Vertebra Brain stem Ligament Spinal cord Nerve plexus Dura mater Spinal ganglion Arachnoid mater Mixed spinal nerve Meninges Pia mater Subarachnoid space Subdural space (c) End of spinal cord Pia mater Cauda equina (a) Dura mater and arachnoid mater Cauda equina igure ▲F 20.1 The nervous system. (a) The brain and spinal cord compose the central nervous system. Cranial and spinal nerves, some of which are organized into plexuses, compose the peripheral nervous system. (b) Three protective meninges surround the brain. A triangular-shaped cavity at the top of the cranium contains blood and absorbs cerebrospinal fluid from arachnoid villi. (c) The meninges also surround the spinal cord extending down the vertebral column. (d) In a typical lumbar puncture, physicians withdraw a sample of cerebrospinal fluid from the subarachnoid space in the lumbar region, a region containing the cauda equina instead of the spinal cord. The nerves of the cauda equina are not shown in their entirety. Why do physicians collect CSF from the lower back and not from higher up the vertebral column? (d) Lumbar puncture extracting CSF from subarachnoid space Figure 20.1 The lower vertebral column does not contain the spinal cord; therefore, the physician will not damage the CNS or likely introduce microbes into the CNS. Further, the lumbar vertebrae are large, are easy to identify, and have larger spaces between them. M20_BAUM7206_05_SE_C20.indd 597 11/23/16 3:38 AM E er 20    Microbial Diseases of the Nervous System and yes The terminal ends of axons have thousands of branches that form junctions called synapses 6 (sĭ-nap’sēz) with glands, muscles, or other neurons. A synapse mediates transfer of a signal to a neighboring postsynaptic cell. In most synapses, there is a synaptic cleft—an intercellular space about 40 nm wide between the axon terminal and the postsynaptic cell. A synaptic cleft stops the transmission of electrical signals; therefore, the signal between cells is chemical—an axon terminal releases molecules called neurotransmitters into the synaptic cleft. A particular neurotransmitter may be stimulatory or inhibitory; that is, it either (1) stimulates a muscle to contract, a gland to secrete, or another neuron to carry a nerve impulse; or (2) inhibits such activities. ­ No openings allow microbial colonization of the central nervous system; therefore, the CNS is an axenic (ā-zēn’ik) environment— it has no normal microbiota. Pathogens may access the CNS through breaks in the bones and meninges, through medical procedures such as spinal taps, or by traveling via axonal transport in peripheral neurons to the CNS. Microbes carried in the blood or lymph may penetrate the blood-brain barrier by infecting and killing cells of the meninges, causing meningitis7 (men-in-jī’tis)—inflammation of the meninges. Some pathogens gain access to the CNS when localized inflammation distorts the cells of the blood-brain barrier, changing its permeability; such change is more likely during chronic infection by many pathogens. Circulation of cerebrospinal fluid can carry infective microbes throughout the cranial cavity and spinal column. We will examine nervous system diseases caused by bacteria, viruses, fungi, protozoa, and prions. We begin by considering bacterial diseases. TELL ME WHY Why is it important that the cells forming the blood vessels of the brain and spinal cord be tight against one another, forming a blood-brain barrier? Bacterial Diseases of the Nervous System Not only can bacteria infect cells of the nervous system, but toxins released by bacteria growing elsewhere in the body can also affect neurons. In the following sections, we consider disease examples of both types—leprosy, which is a disease of cells found in the PNS, and botulism and tetanus, which involve toxin production. However, the most common bacterial infection of the nervous system is bacterial meningitis, which we consider next. 7From Greek syn, meaning “together,” and hapto, meaning “to clasp.” Greek meninx, meaning “membrane,” and itis, meaning “inflammation.” M20_BAUM7206_05_SE_C20.indd 598 LE A R N I N G O UTC O M E 20.4 Describe the signs, symptoms, diagnosis, treatment, and prevention of bacterial meningitis. 20.5 Compare and contrast the characteristics, including viru- lence factors, of the five more common causes of bacterial meningitis. Bacterial meningitis involves inflammatory bacterial infection of the meninges, commonly the pia mater and arachnoid mater and, more rarely, the dura mater. Signs and Symptoms Portals of Infection of the Central Nervous System 6From Bacterial Meningitis s ­ apt       Ch Bacterial meningitis is characterized by an increased number of white blood cells in the CSF, sudden high fever, and intense meningeal inflammation. The inflammation accounts for most of the signs and symptoms: Swelling of the meninges retards the normal flow of CSF, putting pressure on the underlying organs. Inflammation of the cranial meninges typically produces severe headache, nausea, vomiting, pain, and in many cases loss of various brain functions, leading to such conditions as drowsiness, confusion, fretfulness, or irritability. Inflammation of the spinal meninges puts pressure on surrounding nerves and muscles, producing stiffness in the neck and affecting sensory input and muscular control. When the brain becomes infected—a condition called encephalitis—deafness, blindness, drastic changes in the patient’s behavior, coma, or death may result. Signs and symptoms of meningitis may rapidly develop; for example, meningococcal meningitis can kill within six hours of the initial symptoms, allowing little time for treatment. A lumbar puncture reveals the normally clear CSF to be milky in appearance because of the large number of bacteria and the increased number of white blood cells. Petechiae (pe-tē’kē-ē)—small, dark purplish hemorrhages of blood vessels in the skin—are sometimes present. Pathogens and Virulence Factors Researchers have shown that more than 50 species of bacteria can cause meningitis. Among these are opportunistic members of the normal microbiome, including species of Staphylococcus (staf’i-1ō-kok’ŭs) and Streptococcus (strep-tō-kok’ŭs) as well as Gram-negative enteric8 bacteria such as Escherichia coli (esh-ěrik’ē-ă ko’lī) and Klebsiella pneumoniae (kleb-sē-el’ă nū-mō’nē-ī). However, five other species cause almost 90% of cases of bacterial meningitis. These are Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, Listeria monocytogenes, and Streptococcus agalactiae. All five of these bacteria have virulence factors that allow them to resist phagocytosis and cause disease; the following sections detail these features. Neisseria meningitidis Neisseria meningitidis (nī-se’rē-ă me-ninji’ti-dis) is one of only two species of Gram-negative cocci that 8From Greek entera, meaning “intestines.” 11/23/16 3:38 AM E E GING DIS AS CAS STUDY E M ER E       Bacterial Diseases of the Nervous System Melioidosis Streptococcus pneumoniae Louis Pasteur discovered Streptococ­ cus pneumoniae (strep-tō-kok’us nū-mō’nē-ī) in pneumonia patients about 120 years ago. The bacterium is an encapsulated Gram-positive coccus, which forms short chains or, more M20_BAUM7206_05_SE_C20.indd 599 E H H regularly causes disease in humans. Researchers have identified 13 antigenic strains; strains A, B, C, and W135 cause most cases of disease in humans. The cells of all strains of Neisseria are nonmotile and are typically arranged as diplococci (pairs) with their common sides flattened in a manner reminiscent of coffee beans (FIGURE 20.2). The bacterium is known as the meningo­ coccus and its disease as meningococcal meningitis. Meningococci have fimbriae and polysaccharide capsules, as well as a major cell wall antigen called lipooligosaccharide (lĭp’ō-ŏl’ĭ-gō-sak’ă-rīd, LOS), composed of lipid A (endotoxin) and sugar molecules—all of which enable the bacteria to attach to human cells. Cells of Neisseria that lack any of these three structural features are avirulent. The polysaccharide capsules also resist lytic enzymes of the body’s phagocytes, allowing phagocytized meningococci to survive, reproduce, and be carried throughout the body within neutrophils and macrophages. Much of the damage caused by N. meningitidis results from blebbing—a process in which the bacterium sheds extrusions of its outer membrane. The lipid A component of LOS thereby released into the body triggers fever, vasodilation, inflammation, shock, and widespread blood clotting. doctors, suspecting flu, told her to get plenty of rest and sent her home. Two days later, Isabella was intermittently drowsy and confused, her breathing was labored, and a small cut on her leg was an inflamed, pus-filled lesion. She was admitted to the hospital and died the next day. She died of melioidosis, an emerging disease caused by a Gram-negative bacterium, Burkholderia pseudomallei, which produces a toxin that inhibits protein synthesis by infected human cells. Melioidosis is endemic to the tropics of Southeast Asia and appears to be spreading into more moderate climes. Isabella had been infected either via inhalation or through an inflamed cut on her leg. ven with treatment, nearly 90% of melioidosis patients die, including Isabella. 1. If a sample of Isabella’s CSF were Gram stained, what color would the bacterial cells appear? 2. Why did the doctors suspect flu rather than melioidosis? 3. Why is it unlikely that there will be an epidemic of melioidosis in Sweden or Norway? Polysaccharide capsule Lipooligosaccharide (LOS) in outer membrane Fimbria ▲ FIGURE 20.2 Artist’s rendition of diplococci of Neisseria meningitidis. What function of fimbriae contributes to the bacterium’s pathogenicity? Figure 20.2 Fimbriae attach the bacterium to target cells. Isabella felt lucky. ow many community college students had the opportunity to help a professor do research in northern Australia’s Kakadu National Park for a month, get college credit for the experience, and not have to pay for the trip? Though hiking the trails was hot and tiring, she didn’t complain. Of course, things would have been better if it didn’t seem to rain all the time and if the thorns didn’t tear at her legs quite so regularly; still, the trip was an adventure. A week after her return to ouston, Texas, Isabella developed a high fever (39.2°C) and general weakness. All other signs, including the results of blood work, appeared normal. The commonly, pairs (FIGURE 20.3). In fact, it was once classified in its own genus, “Diplococcus.” Ninety-two different strains of S. pneumoniae, collectively called pneumococci, are known to infect humans as normal members of the microbiome of the 11/23/16 3:38 AM ­       CHAPTER 20    Microbial Diseases of the Nervous System and Eyes SEM 1.5 μm ▲ FIGURE 20.4 The pleomorphic bacilli of Haemophilus ­ influenzae. SEM 2 µm ▲ FIGURE 20.3 Cells of Streptococcus pneumoniae are ­ typically arranged in pairs. antigens. Before the introduction of an effective vaccine in the 1990s, 95% of H. influenzae diseases in the United States were caused by type b. throat that opportunistically grow in the lungs, sinuses, and middle ear and from those locations move into the meninges via the blood. Streptococcus pneumoniae is a leading cause of meningitis in children less than 5 years old and in very old adults. Even though microbiologists have studied pneumococci extensively, they still do not fully understand how these bacteria cause disease; nevertheless, certain structural and chemical virulence factors are necessary for disease. The cells of all virulent strains of S. pneumoniae are surrounded by a polysaccharide capsule, which protects them from digestion after phagocytosis. Unencapsulated strains do not cause disease. Pathogenic pneumococci also produce enzymes and toxins that enable the bacteria to counteract immune defenses. In addition, pathogenic S. pneumoniae possess a cell wall chemical called phosphorylcholine, which is an adhesin that binds to receptors on cells in the lungs, the meninges, and blood vessel walls. Binding stimulates target cells to endocyrize the bacteria. Thus, the phosphorylcholine and polysaccharide capsule together enable pneumococci to “hide” inside body cells. S. pneumoniae can then pass across these cells into the blood and brain. Haemophilus influenzae Haemophilus 9 influenzae (hē-mof’i-lŭs in-flu-en’zī) is a small pleomorphic bacillus (FIGURE 20.4) that requires heme and NAD + for growth. As a result, it is an obligate parasite, colonizing mucous membranes of humans and some animals. At one time—as the specific epithet indicates—scientists thought that the bacterium caused flu pandemics in 1890 and 1918, but H. influenzae causes meningitis, not the flu. Most strains of H. influenzae have polysaccharide capsules that resist phagocytosis. Researchers distinguish among six strains of Haemophilus by differences in capsular 10Named for Rebecca Lancefield (1895–1981), a noted specialist of streptococci. M20_BAUM7206_05_SE_C20.indd 600 Listeria monocytogenes Listeria monocytogenes (lis-tēr’ē-ă mo-nōsī-to’je-nēz) is a Gram-positive, non-endospore-forming coccobacillus that enters the body in contaminated food or drink. Listeria is rarely pathogenic in healthy adults; infection in pregnant women, fetuses, newborns, the elderly, and immunocompromised patients can result in meningitis. Disease in Depth on pp. 602–603 examines listeriosis, including meningitis caused by Listeria, in detail. Streptococcus agalactiae Streptococcus agalactiae (strep-tō-kok’ŭs a-ga-lak’tē-ī), also known as Lancefield10 group B Streptococcus (based on its so-called B antigen), is a normal member of the vaginal microbiota in about a third of all women. The bacterium produces a protective capsule that allows it to evade phagocytosis when it gets into the blood. S. agalactiae also causes bacteremia, pneumonia, and meningitis in newborns. Pathogenesis Humans inhale N. meningitidis, H. influenzae, and S. pneumoniae in respiratory droplets from infected individuals (who may appear healthy). Babies pick up S. agalactiae during passage through an infected birth canal. Listeria is transmitted in contaminated food, particularly meat and underpasteurized milk and cheese. In most cases, bacteria spread to the meninges from infections of the lungs, sinuses (sinusitis), or inner ear (otitis media) via the blood (bacteremia). Head or neck surgery or trauma may also open a passage into the subarachnoid space of the meninges. The bacteria, somewhat protected by their capsules from phagocytosis, metabolize glucose in the CSF. Epidemiology Before the 1990s, H. influenzae was a leading cause of bacterial meningitis. An effective childhood vaccine has reduced the number of such cases by more than 90%. Today, S. pneumoniae 9From Greek haima, meaning “blood,” and philos, meaning “love.” 11/29/16 9:00 PM       Bacterial Diseases of the Nervous System (see Chapter 17, Figure 17.3) and administration of penicillin at birth to any child whose mother’s vagina is colonized with Streptococcus agalactiae (group B Streptococcus). Implementation of the latter recommendation in 1996 reduced neonatal meningitis by 70% within five years. Additionally, health care providers prevent the spread of group B streptococcal infection to babies by treating infected pregnant mothers with penicillin or ampicillin, or with vancomycin for patients with penicillin allergy. The CDC also recommends meningococcal vaccination for all military recruits and college freshmen. Health care providers administer antimicrobials such as cirpofloxacin, ceftriaxone, or rifampin to people in prolonged contact with meningococcal patients. Such prophylactic treatment is not recommended following exposure to meningitis caused by other microbes. ­ (pneumococcus) and N. meningitidis (meningococcus) are more prevalent causes of bacterial meningitis, though S. agalactiae is a leading cause of bacterial meningitis in newborns in the United States and the United Kingdom. S. pneumoniae grows in the mouths and throats of 75% of humans without causing harm; but in some patients, particularly children and the elderly—groups whose immune responses are not fully active—these pneumococci become bloodborne and invade the meninges. None of the forms of bacterial meningitis are typically spread by casual contact, though N. meningitidis can be spread via respiratory droplets to other people who have prolonged contact with a carrier. Meningoccoccal meningitis is the only type of bacterial meningitis that becomes epidemic, particularly in sub-Saharan Africa, where massive epidemics occurred every 5–12 years during the dry season (December to June). For example, in the sub-Saharan nations in 2009, there were almost 90,000 cases. In 2014, as a result of mass immunization efforts in 19 of the 26 African countries most at risk, there were only 11,908 cases. In the United States, meningococcal meningitis is spread among military personnel in barracks and students in dormitories. In fact, meningococcal disease is 9–23 times more prevalent in students living in dormitories than in the general population. Mortality of meningococcal meningitis approaches 100% in untreated patients, but is about 11% in patients who have been treated appropriately with antimicrobial drugs. Infant mortality from S. agalactiae meningitis has been reduced to about 5% as a result of rapid diagnosis and supportive care, though about 25% of infants surviving this group B streptococcal meningitis have permanent neurological damage, including blindness, deafness, or severe mental retardation. Listeria infects humans who consume contaminated food. Human-to-human transmission of Listeria is limited to the transfer of bacteria from mother to fetus and can result in premature delivery, miscarriage, stillbirth, or meningitis in the newborn. Diagnosis, Treatment, and Prevention Symptoms of meningitis should always be considered serious, and a patient should consult a physician immediately. Quick diagnosis is vital. Diagnosis of bacterial meningitis is based on symptoms and culturing bacteria from CSF following a lumbar puncture. Additionally, serological tests can demonstrate the presence of antibodies against N. meningitidis, though strain B of this species is relatively nonimmunogenic and therefore often not revealed by such tests. Physicians treat bacterial meningitis with any of a number of intravenously administered antimicrobial drugs, typically vancomycin plus ceftriaxone, cefotaxime, meropenem, or ampicillin, depending on the age and health of the patient and the bacterium causing the meningitis. Quick treatment reduces the mortality to below 15% of cases of bacterial meningitis. Prevention of bacterial meningitis depends on interrupting the transmission of pathogens and their spread in the body. The U.S. Centers for Disease Control and Prevention (CDC) recommends vaccination of children against Streptococcus pneumoniae, Haemophilus influenzae type B (Hib), and Neisseria meningitidis M20_BAUM7206_05_SE_C20.indd 601 LE A R N I N G O UTC O M E s Hansen’s Disease (Leprosy) 20.6 Describe Hansen’s disease, including its diagnosis, treat- ment, and prevention. 20.7 Distinguish tuberculoid leprosy from lepromatous leprosy. Hansen’s disease is the clinical name for the more dreadfulsounding leprosy. It is named after Gerhard Hansen (1841– 1912), a Norwegian microbiologist who discovered its bacterial cause in 1873. Signs and Symptoms Hansen’s disease has two different manifestations depending on the immune response of the patient. Patients with a strong T cell immune response are able to kill cells infected with the bacterium, resulting in a nonprogressive form of the disease, called tuberculoid leprosy. Regions of the skin that have lost sensation as a result of nerve damage are characteristic of this form of leprosy. By contrast, patients with a weak T cell immune response develop lepromatous leprosy, in which the bacterium multiplies in skin, mucous membranes, and nerve cells, gradually destroying tissue and leading to the progressive loss of facial features, digits (fingers and toes), and other body structures (FIGURE 20.5). Development of signs and symptoms is very slow; incubation may take years before any are evident. Death from leprosy is rare and usually results from the infection of leprous lesions by other pathogens. Pathogen and Virulence Factors Mycobacterium leprae (mī’kō-bak-tēr’ē-ŭm lep’rī) is a high G + C, non-endospore-forming, Gram-positive bacillus with a cell wall containing a large amount of mycolic (mī-ko’lik) acid—a waxy lipid composed of chains of 60–90 carbon atoms. This unusual cell wall is responsible for several important characteristics of the bacterium: • Slow growth rate (due to the time required to synthesize numerous molecules of mycolic acid). The generation time varies from hours to several days. • Protection from lysis once it is phagocytized. 11/23/16 3:38 AM DISEASE IN DEPTH SIGNS AND SYMPTOMS Listeria usually produces no symptoms or only mild flulike symptoms in healthy adults. In contrast, infection in pregnant women, fetuses, newborns, elderly, and immunocompromised patients can be severe, causing bacterial meningitis and possibly death. Human-to-human transmission is limited to the transfer of Listeria from pregnant women to fetuses, leading to premature delivery, miscarriage, stillbirth, or meningitis in the newborn. LISTERIOSIS Listeria monocytogenes with actin “tails” R esearchers have identified more than 50 species of bacteria that can cause bacterial meningitis. One species that is reponsible for many cases is Listeria monocytogenes. L. monocytogenes has virulence factors that allow it to resist phagocytosis and cause disease. ONE WAY LISTERIA AVOIDS HOST’S IMMUNE SYSTEM WHILE INFECTING NEW CELLS Consumption of soft cheeses has been associated with listeriosis. How can consumers limit their risk while still continuing to eat soft cheeses? Scan this code to visit the World Health Organization website to investigate. Then go to MasteringMicrobiology to record your research findings. M20_BAUM7206_05_SE_C20.indd 602 10 μm 4 The bacterium reproduces within the phagocyte. Some Listeria mRNA activate at 37˚ C, so the bacterium reproduces most rapidly inside human cells. 3 The intracellular bacterium escapes the phagosome. IN FE CT E D H OST CE LL Actin “tail” Listeria INVESTIGATE IT! LM 5 The bacterium polymerizes the host cell’s actin filaments into a “tail.” 1 Listeria enters the body, usually through contaminated drink or food. 2 Listeria is phagocytized by a host cell, typically in the gall bladder. Photomicrograph of Listeria showing blue-stained actin “tails.” EPIDEMIOLOGY According to the CDC, in 2011, Listeriacontaminated cantaloupes ”caused the deadliest foodborne disease outbreak in the United States in nearly 90 years,” resulting in 30 deaths, including a miscarriage. The death toll could have been higher, but state and local health departments, the FDA, and the CDC worked together to quickly locate the source of the infection (fruit grown on a single farm in Colorado) and to issue a national warning within days of the first reports of the spike in Listeria infections. 11/23/16 3:38 AM       PATHOGEN AND PATHOGENESIS Listeria is a low G + C, Gram-positive, rod-shaped bacterium with end-over-end, tumbling motility. It is found in soil, water, and animals, including mammals, birds, fish, and insects. Notably, Listeria is cold-tolerant and can grow in refrigerated drink and food, typically deli meats, hot dogs, soft cheeses, or yogurt. TEM Once ingested, Listeria binds to the surface of a macrophage or epithelial cell, triggering its own endocytosis. Inside the cell’s phagosome, Listeria synthesizes listeriolysin O, an enzyme that breaks open the phagosome before a lysosome can fuse with it; thus, Listeria avoids digestion by the cell. Listeria then grows and reproduces in the cell’s cytosol, sheltered from the B cell immune system. SEM 1 μm 5 μm N E W LY I N F E C T E D C E L L 8 The cycle repeats as the bacterium reproduces within the new host cell. 7 The pseudopod is endocytized by a new host cell. 6 The tail pushes the bacterium into a pseudopod. 9 After spending some time within cells, Listeria can travel via the blood to the brain, where it causes meningitis. TEM 1 μm Photomicrograph showing the endocytosis of a pseudopod containing a Listeria cell. DIAGNOSIS TREATMENT AND PREVENTION Diagnosis is made by the culture of Listeria from the cerebrospinal fluid (CSF) of people with symptoms of meningitis. Only a few Listeria cells are required to produce disease, so the bacterium is rarely seen in Gram stained preparations. The bacterium exhibits a characteristic and distinctive end-over-end “tumbling” motility in wet mounts of CSF at room temperature but not at 37˚C. LM M20_BAUM7206_05_SE_C20.indd 603 Most antimicrobial drugs, including penicillin and erythromycin, inhibit Listeria, though the bacterium is resistant to tetracycline and trimethoprim. Immunocompromised patients (e.g., AIDS patients) should avoid undercooked meats and vegetables, unpasteurized dairy products, and all soft cheeses. 15 μm 11/23/16 3:38 AM E er 20    Microbial Diseases of the Nervous System and yes ­ apt       Ch were immigrants. The World Health Organization (WHO), working with national governments and private organizations, reduced the incidence of leprosy to less than one case per 10,000 people in 2000. Unfortunately, after WHO declared that leprosy was no longer a public health concern, medical attention shifted to other diseases, and leprosy has reemerged. Human leprosy is transmitted via person-to-person contact, though leprosy is not particularly virulent. Individuals are typically infected only after years of intimate social contact with a victim. Given that the nasal secretions of patients with lepromatous leprosy are loaded with mycobacteria, infection presumably occurs via inhalation of respiratory droplets. Alternatively, infection may occur through breaks in the skin. Industrialized nations no longer quarantine patients with leprosy because the disease is so rarely transmitted and is fully treatable. ▲ FIGURE 20.5 Lepromatous leprosy can result in severe Diagnosis of leprosy is based on signs and symptoms of disease—a loss of sensation in skin lesions in the case of tuberculoid leprosy, and disfigurement in the case of lepromatous leprosy. Diagnosis is confirmed by the identification of acidfast bacilli (AFB), also known as acid­fast rods (AFRs) in samples from affected sites. M. leprae quickly develops resistance to single antimicrobial agents, so therapy consists of administering multiple drugs, such as rifampin, clofazimine, and dapsone. Treatment is typically for a minimum of two years and can be lifelong for some patients. The tuberculosis vaccine (BCG11) provides some protection against leprosy, presumably because the bacteria of leprosy and tuberculosis are related and share antigens. The disease can be prevented primarily by limiting exposure to the pathogen, which is spread in droplets from the noses and mouths of patients, and by the prophylactic use of two or three antimicrobial agents that act against mycobacteria, such as dapsone, rifampin, and clofazimine, when exposure occurs. Having examined bacterial infections of the meninges and peripheral nerves, we now turn our attention to two neurological diseases caused by bacterial toxins—botulism and tetanus. ­ deformities. What is the medical name for leprosy? Diagnosis, Treatment, and Prevention The bacterium has never been grown in cell-free laboratory culture, a fact that has hindered research and diagnostic studies. The nine-banded armadillo, which has a normal body temperature of 30°C, is its only other natural host and has proven valuable in studies on leprosy and on the efficacy of leprosy treatments. Pathogenesis M. leprae grows best at 30°C, showing a preference for cooler regions of the human body, reproducing particularly in neuroglia of peripheral nerve endings, cells of the mucous membrane of the nose, and skin cells in the fingers, toes, lips, and earlobes. It is the only known bacterial pathogen of peripheral nerves. The bacterium may remain alive inside infected cells for 10 to more than 30 years with no obvious sign or symptoms in the patient. Eventually, the body’s cellular immune response attacks infected cells, destroying nerves and other tissues in the process. Epidemiology LE A R N I N G O UTC O M E 20.8 Describe the signs, symptoms, diagnosis, treatment, and prevention of three kinds of botulism. 20.9 Explain the action of botulism toxin on nerve cells. Botulism12 (bot’yū-lizm) is often not an infection, but instead an intoxication (poisoning) caused by a toxin of Clostridium bot­ ulinum (klos-trid’ē-ūm bo-tū-lī’num) that adversely affects synapses of the peripheral nervous system. Botulism toxin is one of  ­ Lepromatous leprosy is the more virulent form of the disease, and fortunately it is becoming rare: in the 1990s, about 12 million cases were diagnosed annually worldwide, but by 2015 this number had decreased to about 210,000, including 64 cases in the United States. Almost all of the U.S. patients Botulism s Figure 20.5 Medically, leprosy is called Hansen’s disease. • Growth within phagocytes. • Resistance to Gram staining, detergents, many common antimicrobial drugs, and drying. Because mycobacteria Gram stain only weakly, the acid-fast staining procedure was developed to differentially stain mycobacteria (see Figure 4.18). M20_BAUM7206_05_SE_C20.indd 604 11For bacille Calmette-Guérin, named after the two French developers of this vaccine. Latin botulus, meaning “sausage.” 12From 11/23/16 3:38 AM       Bacterial Diseases of the Nervous System Wound botulism involves growth of the bacterium in dead tissue following introduction of endospores into wounds. Signs and symptoms are similar to those of the foodborne disease, but the incubation period is longer—four days or more. the more powerful natural poisons. Clinicians recognize three manifestations of botulism: foodborne botulism, infant botulism, and wound botulism. Fortunately, all three are rare. Signs and Symptoms Pathogen and Virulence Factors Patients with foodborne botulism become weak and dizzy one to two days following the consumption of botulism toxin in contaminated food, which may not appear or smell spoiled. Blurred vision with fixed dilated pupils, dry mouth, constipation, nausea, vomiting, and abdominal pain are also seen. Progressive paralysis of all voluntary (skeletal) muscles then begins on both sides of the body as peripheral nerves are affected. The patient remains mentally alert throughout the ordeal. Death, if it occurs, is from paralysis of the diaphragm, which is the major muscle of breathing; the patient cannot inhale. Survivors recover very slowly as their nerve cells grow new endings over the course of months or years, replacing their nonfunctioning tips. Infant botulism is a disease of infants who are usually under six months of age. It differs from foodborne botulism in that the toxin is not ingested. In this disease, the bacterium actually grows in a child’s intestinal tract, where it secretes toxin. Infant botulism is characterized by nonspecific symptoms: crying, constipation, and “failure to thrive.” Infants are susceptible to colonization because their GI tracts do not have a sufficient number of benign microbiota to compete with C. botulinum for nutrients and space. In adults, microbial antagonism by normal intestinal microbiota prevents growth of the bacterium in the intestinal tract. 1 Neuron Synaptic cleft C. Botulinum, the bacterium that produces botulism toxin, is an anaerobic, endospore-forming, Gram-positive bacillus common in soil and water worldwide. Its endospore, which forms at the end of the cell, survives improper canning of non-acidic foods (pH 7 4.5) such as meats, eggs, mushrooms, beans, corn, beets, peas, and some cheeses. Endospores germinate to produce vegetative cells that grow and release the debilitating toxin that causes botulism into the food in the jar or can. Different strains of C. botulinum produce one of seven antigenically distinct botulism neurotoxins, that is, toxins which affect neurons. Scientists consider botulism toxins the deadliest toxins known—30 grams of pure toxin would be enough to kill every person in the United States. Even a small taste of food contaminated with the powerful toxin, such as licking a spoon, can cause full-blown illness or death. Pathogenesis To understand the action of botulism toxins, we must consider the way the nervous system controls muscle contractions. Each of the many ends of a motor neuron forms a synapse with a muscle cell. Such a synapse is called a neuromuscular junction. As with most synapses, the two cells do not actually touch; a synaptic cleft remains between them (FIGURE 20.6a). The Vesicles with acetylcholine Cytoplasmic membrane of neuron Vesicles with acetylcholine 2 Muscle cell Cytoplasmic membrane of muscle cell (a) Normal neuromuscular junction Acetylcholine Botulism toxin (b) Neuromuscular junction with botulism toxin present ▲ FIGURE 20.6 How botulism toxin acts at a neuromuscular junction. (a) Normal function at a neuromuscular junction. A nerve impulse from the central nervous system causes vesicles filled with acetylcholine (ACh) to fuse with the neuron’s cytoplasmic membrane 1 , releasing ACh into the synaptic cleft 2 . The binding of ACh to receptors on the muscle cell’s cytoplasmic membrane stimulates a series of events that result in contraction of the muscle cell (not shown). (b) Botulism toxin blocks the fusion of ACh vesicles with the neuron’s cytoplasmic membrane, thereby preventing secretion of ACh into the cleft; as a result, the muscle cell does not contract. M20_BAUM7206_05_SE_C20.indd 605 11/23/16 3:38 AM E er 20    Microbial Diseases of the Nervous System and yes neuron stores the neurotransmitter acetylcholine (as-e-til-kō’lēn; ACh) in vesicles near its terminal cytoplasmic membrane. ACh mediates communication between neurons and muscle cells. When a nerve impulse arrives at the terminus of a motor neuron, ACh vesicles fuse with the neuron’s cytoplasmic membrane, releasing ACh into the synaptic cleft. Molecules of ACh then diffuse across the cleft and bind to receptors on the cytoplasmic membrane of the muscle cell. The binding of ACh to the ACh receptor triggers a series of events inside the muscle cell that results in muscle contraction. Botulism toxins act by binding irreversibly to neuronal cytoplasmic membranes, thereby preventing the fusion of vesicles and the secretion of acetylcholine into the synaptic cleft (FIGURE 20.6b). Thus, botulism neurotoxins prevent muscular contraction, resulting in a flaccid paralysis. Binding of botulism toxin is irreversible; the synapse is forever blocked. Botulism may progress despite aggressive medical care; however, the blocked motor neuron’s axon may grow new branches, which form new synapses with muscles. Epidemiology About 60 cases each of foodborne and wound botulism occur in the United States each year. Death results in 10% of hospitalized patients. Infant botulism is now the most common form of botulism in the United States; about 100 cases are reported annually. These cases result from inhalation of endospores in dust or ingestion in food; unpasteurized (“natural”) honey is involved in about a third of cases of infant botulism. The mortality rate of hospitalized infants is less than 1%. Diagnosis, Treatment, and Prevention The symptoms of botulism are diagnostic; culturing the organism from contaminated food, from feces, or from the patient’s wounds confirms the diagnosis. Further, toxin activity may be detected by using a mouse bioassay. In this laboratory procedure, specimens of food, feces, and/or serum are divided into two portions. Botulism antitoxin is mixed with one of the portions, and the portions are then inoculated into two sets of mice. If the mice receiving the antitoxin survive while the other mice die, botulism is confirmed. Treatment of botulism entails four approaches: • Vigorous attention to keeping airways open and functional. • Repeated washing of the intestinal tract to remove Clostrid­ ium, if the intestinal tract is functioning (as indicated by normal bowel sounds). • Intravenous administration of botulism immunoglobulin (BIG-IV), which is composed of human antibodies against botulism toxins. BIG-IV neutralizes the neurotoxins in the blood before they can bind to neurons and shortens the length of the disease. • Administration of chloramphenicol (preferential) or penicillin to kill the bacterium in wound botulism cases. This approach is not recommended for treating infant botulism, M20_BAUM7206_05_SE_C20.indd 606 because the treatment increases toxin release, worsening the disease. Antimicrobials are not effective in treating foodborne botulism, because foodborne botulism results from ingestion of the toxin, not of the bacteria themselves. Foodborne botulism is prevented by destroying all endospores in contaminated food through proper canning techniques; by preventing endospores from germinating through use of refrigeration or establishment of an acidic environment (pH 6 4.5); or by destroying the toxin with heat—food must be heated to at least 80°C for 20 minutes or more. C. botulinum produces gas at it grows, so a swollen can of food may indicate contamination. Infant botulism is often associated with the consumption of honey, particularly unpasteurized honey; therefore, pediatricians advise parents not to feed honey to infants until their intestinal microbiome is sufficiently developed to inhibit the germination of C. botulinum endospores—usually after one year of age. Disease at a Glance 20.1 summarizes the features of infant botulism. The accompanying Clinical Case Study: The Frowning Actor on p. 608 considers a medical use of botulism toxin. Tetanus LE A R N I N G O UTC O M E s ­ apt       Ch 20.10 Describe the action of tetanospasmin. 20.11 Describe the diagnosis, treatment, and prevention of tetanus. Tetanus13 is another disease caused by a neurotoxin produced by a species of Clostridium. Signs and Symptoms Typically the initial and diagnostic sign of tetanus is tightening of the jaw and neck muscles, which is why tetanus is also called lockjaw. Other early symptoms include sweating, drooling, grouchiness, and constant back spasms. If the toxin spreads to neurons that control glands and involuntary muscles, then heartbeat irregularities, fluctuations in blood pressure, and extensive sweating result. Spasms and contractions may spread to other muscles, becoming so severe that the arms and fists curl tightly, the feet curl down, and the body assumes a stiff backward arch as the heels and back of the head bend toward one another (FIGURE 20.7). Complete, unrelenting contraction of the diaphragm results in a final inhalation—patients die because they cannot exhale. Pathogen and Virulence Factors Clostridium tetani (klos-trid’ē-ŭm te’tan-ē) is a small, motile, obligate anaerobe that produces a terminal endospore, giving the cell a distinctive “lollipop” appearance (see Disease at a Glance 20.2 on p. 608). Vegetative cells are extremely sensitive to oxygen and live only in anaerobic environments. In contrast, 13From Greek tetanus, meaning “to stretch.” 11/23/16 3:38 AM       Bacterial Diseases of the Nervous System E E DIS AS AT A GLANCE 20.1 Infant Botulism 1 Baby inhales or ingests C. botulinum 2 Endospores germinate in anaerobic endospores, particularly in honey. environment of intestinal tract. Vegetative cells grow, reproduce, and release botulism toxin. 3 Toxin is absorbed into blood and circulates throughout body. 4 Botulism toxin produces constipation and weak cry. 5 Gradually the toxin paralyzes muscles, including neck muscles and the diaphragm. 5 1 3 5 2 4 Extreme infantile muscle weakness known as “floppy baby syndrome” Cause Clostridium botulinum (anaerobic, endospore-forming, Gram-positive rod). Virulence factors Endospores survive improper canning and resist antimicrobial drugs, seven antigenically distinct forms of botulism toxin. Portal of entry Inhalation of endospores or ingestion of contaminated food. Signs and symptoms Constipation is the first symptom. Muscle weakness, described as “floppy baby syndrome,” causes weak cry, poor feeding (weak suckling), loss of head control, and respiratory distress. Infant may also experience lethargy and descending paralysis. Incubation period Unknown. Susceptibility Infants, especially those under six months of age. Treatment Supportive therapy, including keeping the airway clear and monitoring respiratory functions. Botulism immune globulin (BIG) reduces the length of the disease. Prevention Do not feed honey to infants less than one year of age. endospores can survive for decades or longer exposed to air and are nearly universally found in soil, dust, and the intestines of animals and humans. Cells of C. tetani release a potent neurotoxin called tetanospasmin (tet’ă-nō-spaz’min) when they die. Tetanospasmin is composed of two polypeptides held together by a disulfide bond. The heavier of the two polypeptides binds to the cytoplasmic membrane of a neuron, triggering the neuron to endocytize the toxin and cleave off the lighter of the two polypeptides. Axonal transport carries the lighter polypeptide to the central nervous system. C. tetani remains localized at the site of infection; only the toxin moves to the central nervous system. Pathogenesis ▲ FIGURE 20.7 A patient with tetanus. The prolonged muscular contractions are a result of the action of tetanus toxin. What is the name of tetanus toxin? Figure 20.7 Tetanus toxin is tetanospasmin. M20_BAUM7206_05_SE_C20.indd 607 Contrary to popular belief, deep puncture wounds by rusty nails are not the only (or even primary) source of tetanus. Any break in the skin or mucous membranes can allow endospores of C. tetani access to deeper tissues, which lack free oxygen—an environment suitable for the germination of Clostridium endospores. Wooden splinters, shaving nicks, and accidental staple wounds, as well as more serious cuts and punctures of the skin or mucous membranes, have introduced C. tetani into patients 11/23/16 3:38 AM ­ E 20.2 E DIS AS AT A GLANCE E Tetanus H Cause Clostridium tetani (anaerobic, endospore-forming, Gram-positive rod). Virulence factors ndospores allow bacterium to survive harsh conditions and resist antimicrobial drugs; neurotoxin tetanospasmin blocks action of inhibitory neurons. E A 55-year-old actor is concerned about maintaining his star status as a leading man and doesn’t like the “frown lines” on his forehead. e asks his dermatologist about a cosmetic treatment to relax the facial lines. The dermatologist explains that Botox— purified type A botulism toxin—is approved for use on the glabella (forehead between the eyes) and discusses with the actor the risks and benefits. The actor decides to have a treatment. Two weeks following the treatment, he calls the office reporting that his eyelids are sagging. Portal of entry ndospores enter through breaks in the skin, such as cuts and punctures. E The Frowning Actor Signs and symptoms Tightening of the jaw and neck muscles, difficulty swallowing, followed by fever and muscle spasms. Incubation period Five days to 15 weeks (average of seven days). Susceptibility Unimmunized individuals with broken skin who contact the microbe. Treatment Cleansing of wound, administration of human tetanus immunoglobulin ( TIG) and penicillin, and active immunization. H CLINICAL CASE STUDY er 20    Microbial Diseases of the Nervous System and yes apt       Ch Prevention Tetanus toxoid contained in DTaP, DTP, and Td vaccines. 1. 2. 3. 4. What is Botox? How does cosmetic botulism toxin work? Will the treated muscles be permanently “frozen”? Can the actor get a systemic botulism infection from the treatment? 5. What caused the eyelids to sag? ­ where the endospores germinated, grew, died, and released tetanospasmin. To understand the action of tetanospasmin, we must further consider events in the central nervous system. As we have seen, nerve impulses traveling down motor neurons cause the motor neurons to secrete acetylcholine onto muscle cells, triggering the muscles to contract. But what tells the motor neuron to generate the nerve impulse? Two kinds of neurons of the central nervous system act on motor neurons: Stimulatory neurons release a neurotransmitter that excites motor neurons to produce a nerve impulse, resulting in muscle contraction. In contrast, inhibitory neurons release an inhibitory neurotransmitter, hindering motor neurons from producing the nerve impulse, so the muscle remains relaxed. In other words, motor neurons do not directly relax a muscle; rather, inhibitory neurons inhibit the motor neuron, so the muscle is not stimulated to contract (FIGURE 20.8a). Tetanospasmin blocks the release of inhibitory neurotransmitter. With inhibition blocked, excitation of the motor neurons is unregulated, and the muscle is signaled to contract (FIGURE 20.8b). The result is that muscles contract and do not relax. Contractions can be so severe they break bones. The effect of tetanospasmin is not reversible at a synapse, so recovery depends on the growth of new neuronal terminals to replace those affected. The mortality rate of untreated tetanus is about 50% among all patients, but the mortality of tetanus in newborns, resulting most commonly from infection of the umbilical stump, exceeds 90%. M20_BAUM7206_05_SE_C20.indd 608 LM 10 μm Clostridium tetani cells, some with “lollipop” endospores. The incubation period of tetanus ranges from five days to 15 weeks depending on the distance of the infection site in the extremities from the central nervous system. Epidemiology Incidence of tetanus worldwide has decreased from nearly a million cases annually to 10,011 cases in 2012, mostly in countries where immunization is unavailable or medical care is inadequate, particularly for newborns. In the United States, morbidity has declined from 560 reported cases in 1947, the year reporting began, to 25 reported cases in 2015. Widespread immunization and better wound care has produced this decline in tetanus incidence. Diagnosis, Treatment, and Prevention The diagnostic feature of tetanus is the characteristic muscular contraction, which is often noted too late to save the patient. The bacterium itself is rarely isolated from clinical samples because it grows slowly in culture and is extremely sensitive to oxygen. 11/23/16 3:38 AM       Bacterial Diseases of the Nervous System Stimulating neuron Inhibitory neuron Inhibitory neurotransmitter counteracts the effect of stimulatory neurotransmitter, so impulses are inhibited. Spinal cord Muscle is relaxed because there is no nerve impulse to release acetylcholine at the neuromuscular junction. Stimulatory neurotransmitter Nerve impulse inhibited. Motor neuron (a) Normal action of inhibitory neurotransmitter Tetanospasmin blocks release of inhibitory neurotransmitter. Muscles fully contracted, cannot relax. Acetylcholine Nerve impulse (b) Tetanospasmin (tetanus toxin) blocking the release of inhibitory neurotransmitter ▲ FIGURE 20.8 The action of tetanus toxin on a pair of antagonistic muscles. (a) Normally, inhibitory neurotransmitter can block nerve impulses in motor neurons so that muscles can relax. (b) Tetanospasmin blocks the inhibitory neurotransmitter. As a result, motor neurons are not inhibited but instead generate nerve impulses that stimulate continuous muscle contraction. Treatment involves thorough cleaning of wounds to remove all endospores; immediate passive immunotherapy, in which antibodies directed against tetanospasmin are injected; the administration of antimicrobials such as metronidazole; and active immunization to stimulate antibody and memory cell production. Cleansing and antimicrobials eliminate the bacterium, whereas the immunoglobulin binds to and neutralizes toxin before it can attach to neurons. Active immunization stimulates the formation of antibodies to neutralize toxin. Once tetanospasmin binds to a neuron, treatment is limited to supportive care. M20_BAUM7206_05_SE_C20.indd 609 The number of cases of tetanus in the United States has steadily declined as a result of effective immunization with tet­ anus toxoid, which is inactivated tetanospasmin. The CDC currently recommends five doses beginning at two months of age, followed by a booster every 10 years for life (see Figure 17.3). Disease at a Glance 20.2 summarizes the features of tetanus. We have examined some bacteria and their toxins that cause diseases of the nervous system. Viral infection can also have neurological consequences. In the next section we consider some viruses whose primary effect is on the nervous system. 11/23/16 3:38 AM E er 20    Microbial Diseases of the Nervous System and yes TELL ME WHY Why is the incubation period of wound botulism more than twice as long as the incubation period of foodborne botulism? Viral Diseases of the Nervous System Viruses, being smaller than cells, can more readily cross the blood-brain barrier; therefore, it is not surprising that there are more viral infections of the nervous system than bacterial or fungal infections. Many viruses that attack other body systems can also affect the brain: herpes and chickenpox viruses may remain dormant in nerve cells for years, and measles virus causes subacute sclerosing panencephalitis, which is a slow progressive disease of the CNS. (Chapter 19 dealt with these pathogens, which primarily affect the skin.) In the following sections we consider viruses that primarily affect the nervous system, causing meningitis, polio, rabies, and encephalitis. We begin our survey by considering viral meningitis. Viral Meningitis LE A R N I N G O U TC O M E 20.12 Compare and contrast viral and bacterial meningitis. Viral meningitis, also known as aseptic meningitis to indicate that no bacteria are involved, is the most common form of meningitis. Signs and Symptoms Viral meningitis is usually a milder disease than either bacterial or fungal meningitis; although the signs and symptoms—fever, severe headache, stiff neck, drowsiness, confusion, nausea, and vomiting—may be the same, death from viral meningitis is rare. Some meningitis viruses also cause skin rashes, sore throats, and colds. Pathogens and Virulence Factors Herpesviruses, mumps virus, and several other viruses may cause viral meningitis, but about 90% of cases result from infections of viruses in the genus Enterovirus14 of the family Picorna­ viridae.15 As their name indicates, picornaviruses are very small (20 –30 nm in diameter), positive, single-stranded RNA (+ssRNA) viruses. They lack envelopes. Enteroviruses are so named because they often spread from person to person via fecal contamination of food, water, or hands. Though ingested enteroviruses attack cells lining the intestinal tract, they do not cause gastrointestinal illnesses; instead, enteroviruses spread via the bloodstream—a condition called viremia—to infect other organs, including the meninges. The common names for the three types of enterovirus that cause most human meningitis are coxsackie A virus (named for 14From 15From Greek enteron, meaning “intestine,” and Latin virus, meaning “poison.” Italian pico, meaning “small,” and RNA. M20_BAUM7206_05_SE_C20.indd 610 Coxsackie, New York, where the virus was first isolated), cox­ sackie B virus, and echovirus.16 (Other viruses, called arboviruses, may also affect the meninges, but their primary target is nerve cells. These viruses are considered in a later section.) Pathogenesis Enteroviruses primarily attack cells lining the intestinal tract and lungs, in the latter case producing colds. The viruses are cytolytic—they kill their target cells. Damage to cells in the meninges triggers meningitis. The incubation period of enterovirus infections is between three and seven days, and patients recover completely without treatment after another seven to ten days. Epidemiology Viral meningitis appears to be much more common than bacterial or fungal meningitis, but viral meningitis is often mild, and the disease is not reportable, so firm data are not available. Enteroviruses are contagious, being spread in respiratory droplets and in feces—patients shed viruses in their feces for weeks. For some reason, enteroviruses are more commonly spread in the summer and early fall. The viruses are stable and can survive in chlorinated swimming pools. Exposure to a patient with meningitis may result in an infection resembling a cold but rarely causes meningitis—fewer than one of every 1000 infected people develop viral meningitis. Patients become contagious when symptoms develop and remain contagious for up to 10 days. Diagnosis, Treatment, and Prevention Physicians diagnose viral meningitis based on the characteristic signs and symptoms in the absence of bacteria in CSF obtained with a spinal tap. No specific treatment exists for viral meningitis; health care providers recommend resting, drinking plenty of fluids, and taking medicine to reduce fever and headache pain. It is difficult to suppress the spread of enteroviruses because most infected people lack signs or symptoms. Frequent hand antisepsis, avoiding crowded swimming pools, and refraining from bringing contaminated hands near the mouth, nose, or eyes limit the chance of infection. Poliomyelitis LE A R N I N G O UTC O M E s ­ apt       Ch 20.13 Describe poliomyelitis with reference to the cause, signs, symptoms, epidemiology, diagnosis, treatment, and prevention. 20.14 Compare and contrast the two polio vaccines. Older Americans still remember the dreaded poliomyelitis, (pō’lē-ō-mī’ě-lī’tis) or polio, epidemics of the past, when the floors from enteric cytopathic human orphan virus because the virus is acquired intestinally and was not initially associated with disease; it was an “orphan.” 16Derived 11/23/16 3:38 AM       Viral Diseases of the Nervous System ▲ FIGURE 20.9 Patient in an iron lung. This mechanical respirator assisted respiratory muscles paralyzed by polio. She entered an iron lung at age three and remained until she died during a power outage at age 61. of hospitals were filled with iron lungs (FIGURE 20.9) and schoolchildren donated coins to the March of Dimes to develop a polio vaccine. Because polioviruses are stable for prolonged periods in swimming pools and lakes and can be acquired by swallowing contaminated water, parents in the 1930s and 1940s often feared to let their children swim. Those days may soon be over in the rest of the world as well, because we may soon make polio the second human disease eliminated worldwide (FIGURE 20.10). Signs and Symptoms After being ingested and infecting pharyngeal and intestinal cells, poliovirus travels via the lymph and blood to infect cells of the CNS, particularly of the spinal cord. It causes one of the following four conditions: • Asymptomatic infections account for about 90% of all cases. • Minor polio includes nonspecific symptoms such as temporary fever, headache, malaise, and sore throat. Approximately 5% of cases are minor polio. (a) • Nonparalytic polio results from polioviruses invading the meninges and central nervous system, producing muscle spasms and back pain in addition to the general symptoms of minor polio. Nonparalytic polio occurs in about 2% of cases. • Paralytic polio involves viral invasion of cells of the spinal cord and the portion of the cerebrum that controls skeletal muscles, producing paralysis by limiting nerve impulse conduction. The degree of paralysis varies with the strain of poliovirus involved, the infective dose, and the health and age of the patient. In a type of paralytic polio called bulbar poliomyelitis, the brain stem is infected, resulting in paralysis of respiratory muscles or of muscles in the limbs (see Disease at a Glance 20.3). In the past, iron lungs were used to help victims breathe. In most paralytic cases, complete recovery results after 6–24 months, but in some cases paralysis is lifelong. Paralytic polio occurs in fewer than 2% of infections. Postpolio syndrome is a crippling deterioration in the function of polio-affected muscles that occurs in up to 80% of recovered polio patients some 30–40 years after their original bout with poliomyelitis. This condition is not caused by a reemergence of polioviruses, because viruses are not present. Instead, the effects appear to stem from an aging-related aggravation of nerve damage that occurred during the original infection. Pathogen and Pathogenesis Poliovirus is another species of Enterovirus (family Picornaviri­ dae). Poliovirus is relatively stable outside the body and remains infectious in food and water for some time. Scientists distinguish three strains of poliovirus by their antigens. Each of the three can cause all types of polio. People most often get poliovirus by drinking contaminated water. The viruses are replicated in cells of the throat and small intestine, producing initial symptoms of sore throat and nausea. Viruses then infect lymph nodes and from there enter the blood. In most people, the infection ends there; however, viremia may progress to infection of neurons of the CNS. Paralysis 0 endemic cases 1 to 4 endemic cases 5 to 20 endemic cases More than 20 endemic cases Certified as polio-free (no endemic cases for at least three years) 2002 (b) 2007 (c) First ten months of 2016 ▲ FIGURE 20.10 Reports of naturally ocurring polio. (a) Cases in 2002. (b) Cases in 2007. (c) Cases in first ten months of 2016. No cases occurred in the Americas. Global eradication of polio is a goal within reach. M20_BAUM7206_05_SE_C20.indd 611 11/23/16 3:38 AM E er 20    Microbial Diseases of the Nervous System and yes ­ apt       Ch Epidemiology Polio Diagnosis, Treatment, and Prevention Diagnosis of polio is based upon demonstration of the virus in throat secretions or feces. There is no specific treatment for polio besides managing the symptoms of infection. Two effective vaccines make polio eradication possible. Jonas Salk (1914–1995) developed an inactivated polio vaccine (IPV) in 1955. Later, it was replaced by a live, attenuated (weakened), oral polio vaccine (OPV) developed by Albert Sabin (1906–1993). Both vaccines are effective in providing immunity against all three strains of poliovirus. Healthcare workers have returned to using IPV because the attenuated viruses in OPV occasionally mutate into virulent viruses that cause cases of vaccine-derived polio. TABLE 20.1 compares the advantages and disadvantages of the two vaccines. Disease at a Glance 20.3 summarizes the characteristics of polio. LE A R N I N G O U TC O M E s Rabies 20.15 Define zoonosis. 20.16 Describe rabies, including its diagnosis, treatment, and prevention. 20.3 Cause Poliovirus (Enterovirus: naked, positive, single-stranded NA (+ssRNA) virus). R The near elimination of polio stands as one of the great achievements of 20th-century medicine. Soon, like smallpox virus, poliovirus will exist only in laboratories. The last case of naturally occurring poliomyelitis in the Americas occurred in 1979. A milestone was reached in 2014 when the World Health Organization (WHO) declared Southeast Asia, including India, polio free. Worldwide, the number of naturally acquired polio cases dropped from 350,000 in 1988 to a low of only 74 in 2015. Additionally, there were 32 cases of vaccine-derived polio. Polio currently exists endemically only in Pakistan and Nigeria, though there was a quickly contained reemergence in Nigeria in 2016 (see Figure 20.10). E DIS AS AT A GLANCE E develops following destruction of motor neurons in the upper spinal cord and brain stem; poliovirus does not infect muscles. Virulence factors Attaches to human intestinal cells; intracellular replication cycle; is relatively stable outside body. Portal of entry Ingestion in contaminated water. Signs and symptoms Five possibilities: asymptomatic; minor polio with temporary flulike signs and symptoms; nonparalytic polio with muscle spasms and neck pain; paralytic polio that infects the brain or spinal cord, resulting in paralysis of skeletal muscles; and postpolio syndrome, which is a crippling degeneration that occurs 30–40 years after infection. Incubation period 6 to 20 days. Susceptibility Children are most at risk for acute, severe polio. Treatment Physical therapy for rehabilitation of weakened muscles; noninvasive ventilation to assist the patient’s breathing. Prevention Inactivated (Salk) vaccine or attenuated oral (Sabin) vaccine. Although the cry “Mad dog! Mad dog!” might make you inquisitive, in the 19th century—before Pasteur developed a rabies vaccine and treatment—a bite from a rabid dog was a death sentence, and the cry of “Mad dog!” often created panic. Very few people survived rabies17 before Pasteur’s important work. Signs and Symptoms Initial signs and symptoms of rabies include pain or itching at the site of infection, fever, headache, malaise, and anorexia. Once the virus reaches the central nervous system, neurological manifestations characteristic of rabies develop: hydrophobia18 (triggered by the pain involved in attempts to swallow water), seizures, disorientation, hallucinations, and paralysis. Death results from respiratory paralysis and other neurological complications. TABLE 20.1 Comparison of Polio Vaccines equires booster to achieve lifelong immunity; must be injected; requires higher community immunization rate than does OPV Sabin Vaccine: Attenuated, oral polio vaccine (OPV) Provides lifelong immunity without boosters; triggers secretory antibody response similar to natural infection; easy to administer; results in herd immunity Less stable than IPV; can mutate to disease-causing form; poses risk of development of polio in immunocompromised contacts of vaccinated individuals 17From 18From M20_BAUM7206_05_SE_C20.indd 612 R Disadvantages ffective; inexpensive; stable during transport and storage; poses no risk of vaccine-related disease E Advantages Salk Vaccine: Inactivated polio vaccine (IPV) Latin rabere, meaning “rage” or “madness.” Greek hydro, meaning “water,” and phobos, meaning “fear.” 11/23/16 3:38 AM       Viral Diseases of the Nervous System Pathogen and Virulence Factors ­ ­ ­ Rabies virus is a negative, single-stranded RNA (@ssRNA) v i r u s i n t he ge nu s Lyssavir us, fa m i ly R h abdo vir ida e. Rhabdoviruses have helical capsids supercoiled into cylinders, which give them a striated appearance, and are surrounded by bullet-shaped envelopes (see Disease at a Glance 20.4). Glycoprotein spikes on the surface of the envelope serve as attachment proteins. Pathogenesis Rabies virus attaches to skeletal muscle cells, triggering its own endocytosis. The virus replicates in the cytoplasm of muscle cells. Later, it moves across neuromuscular junctions into neurons and then travels to the central nervous system via axonal transport. Function of the spinal cord and brain degenerate as a result of infection, though infected cells show little structural damage when examined microscopically. Viruses travel back to the periphery, including the salivary glands, through cranial and spinal nerve cells. Viruses are secreted in the saliva of infected mammals. Transmission of rabies viruses in the saliva of infected animals usually occurs via a bite but can occur through the introduction of viruses into breaks in the skin or mucous membranes or, rarely, through inhalation. Skunk Fox Raccoon ▲ FIGURE 20.11 Portions of the United States in which skunks, foxes, or raccoons are the predominant wildlife reservoirs for rabies. Absence of a color does not indicate the absence of rabies in that region, only that no wildlife reservoir is predominant. Bats, for instance, harbor rabies throughout the country but are rarely the predominant reservoir, though they are the major source of human rabies in the United States. Epidemiology Rabies is a zoonosis, that is, a disease spread from animal reservoirs to humans. Rabies affects mammals, though not all mammals are reservoirs; rodents, for instance, rarely get rabies. The main mammals involved differ from locale to locale and change over time as a result of changes in animal populations and interactions among animals and humans. The primary reservoir of rabies in urban areas is the dog. In the wild, rabies can be found in many animals, including foxes, badgers, raccoons, skunks, cats, bats, and feral dogs (FIGURE 20.11). Bats are the source of most cases of rabies in humans, causing about 75% of cases. Only one case of rabies in humans occurred in the United States in 2015. zookeepers, and animal control workers) and to people traveling to areas of the world where rabies is prevalent. Treatment of rabies begins with treatment of the site of infection. The wound should be thoroughly cleansed with water and soap or another substance that deactivates viruses. The World Health Organization recommends anointing the wound with antirabies serum. Initial treatment also involves injection of human rabies immunoglobulin (HRIG). Subsequent treatment involves the four vaccine (HDCV) injections, Diagnosis, Treatment, and Prevention M20_BAUM7206_05_SE_C20.indd 613 Negri bodies LM 10 µm ▲ FIGURE 20.12 Negri bodies, characteristic of rabies infection, in cells of the cerebellum. What are Negri bodies? Figure 20.12 Negri bodies are stained aggregates of rabies viruses. The neurological symptoms of rabies are unique and generally sufficient for diagnosis. Tests for antibodies in the blood confirm the diagnosis. Postmortem laboratory tests are often conducted to determine whether a suspected animal in fact carries rabies virus. These tests include antigen detection by immunofluorescence and the identification of aggregates of viruses (called Negri bodies) in the brain (FIGURE 20.12). Unfortunately, by the time symptoms appear and antibody production occurs, it is too late to intervene, and the disease will follow its natural course. Human rabies vaccine, which is called human diploid cell vaccine (HDCV), is prepared from deactivated rabies viruses cultured in human diploid cells. It is administered intramuscularly on days 0, 3, 7, and 14 after exposure to rabies virus. The vaccine can also be administered before infection to workers who regularly come into contact with animals (veterinarians, 11/23/16 3:38 AM E ­ Cause abies virus (Lyssavirus, enveloped, negative, single-stranded NA(-ssrNA) virus). Virulence factors Glycoprotein spikes on envelope serve as attachment proteins; triggers its own endocytosis by body cells; intracellular replication cycle. Portal of entry Via the bite or scratch of an infected animal. Signs and symptoms Pain or itching at site of infection, fever, headache, malaise, Rabies viruses. TEM anorexia. Neurological 60 nm manifestations include hydrophobia, seizures, disorientation, hallucinations, paralysis, and death. Incubation period Variable, generally one to two months, sometimes up to seven years. Dogs have been known to exhibit symptoms within 10 days of infection. ­ Susceptibility Wild animals are particularly susceptible, but any non vaccinated mammal may be infected. Animal handlers are at an increased risk of infection. Treatment Immediately wash the wound with soap and water, and begin postexposure prophylaxis (P P) via administration of one dose of human rabies immune globulin ( IG) and four doses of rabies vaccine ( DCV) over the course of one month. In cases where P P was not administered and symptoms develop, treatment is supportive therapy. H E HR H 1. The health care providers suspect the patient has leprosy. ow might they verify this? 2. What type of leprosy is this patient more likely to have? 3. What is the appropriate treatment for her condition? 4. Who has the higher risk of contracting the disease: the emergency department personnel or family members with whom she lives? Rabies E ­ A 41-year-old woman arrives in the hospital emergency department with third- degree burns on the second and third fingers of her left hand. Through a family member who acts as an interpreter, she tells the triage nurse that she had moved to the United States from Brazil barely six months before. This evening she had been sitting in her living room, cigarette in hand, watching the nightly news, when she noticed the odor of something burning. As she rose to investigate, she saw that her fingers were blackened and smoking where the cigarette had burned down. With a jerk she discarded the cigarette and marveled that she felt no pain—it was as if her fingers were not her own. 20.4 R A Woman with No Feelings E E DIS AS AT A GLANCE R CLINICAL CASE STUDY er 20    Microbial Diseases of the Nervous System and yes apt       Ch Arboviral Encephalitis LE A R N I N G O U TC O M E 20.17 Compare and contrast Eastern equine, Western equine, Venezuelan equine, West Nile, St. Louis, and California (LaCrosse) encephalitis. Arthropod-borne viruses—arboviruses—are viruses transmitted between hosts by bloodsucking arthropods such as mosquitoes. M20_BAUM7206_05_SE_C20.indd 614 The term arbovirus is a functional name; it is not an official taxonomic term. Emerging Disease Case Study: A Deadly Mosquito Bite? on p. 617 examines one arboviral disease. Mosquitoborne arboviruses are responsible for various types of arboviral encephalitis.19 These zoonotic diseases typically affect birds, horses, and rodents, and only rarely do they affect humans. ­ mentioned previously. Rabies is one of the few infections that can be treated with active immunization because the progress of viral replication and movement to the brain is slow enough to allow effective immunity to develop before disease develops. The control of rabies involves immunization of domestic dogs and cats and the removal of unwanted strays from urban areas. It is more difficult to eliminate rabies in wild animals because rabies virus can infect so many species, though in the late 1990s an epidemic of rabies was stopped in southern Texas by the successful immunization of the wild coyote population. This was accomplished by lacing meat with an oral vaccine and dropping it from airplanes into the coyotes’ range. Disease at a Glance 20.4 summarizes the features of rabies. Prevention Immunization of dogs and cats. Animal handlers may also be vaccinated. Signs and Symptoms Most mosquito-borne arboviruses cause only mild, coldlike symptoms in humans within three to seven days of infection. Occasionally arboviruses in the blood cross the blood-brain barrier to cause arboviral encephalitis, which is characterized by signs and symptoms similar to those of meningitis: high fever, weakness, nausea, vomiting, abrupt headache, and changes in mental state such as confusion, disorientation, and coma. Some patients report body aches and develop a skin rash. Neurological effects may be permanent. 19From Greek enkephalos, meaning “brain,” and itis, meaning “inflammation.” 11/23/16 3:38 AM       Viral Diseases of the Nervous System Humans are not the only victims. Arboviruses also attack birds, horses, chimpanzees, cats, dogs, chipmunks, and even alligators. (Scientists are not sure how thick-skinned gators contract the disease.) Pathogens Six arboviruses cause most cases of viral encephalitis in Americans. Scientists name these viruses for the geographic regions where the diseases or viruses were first identified. The diseases and their viruses are: ­ • Eastern equine encephalitis (EEE), Western equine encephalitis (WEE), and Venezuelan equine encephalitis (VEE), all of which were first identified in horses in the eastern United States, western United States, and Venezuela, respectively. The viruses causing these conditions are all enveloped, +ssRNA viruses in the family Togaviridae (FIGURE 20.13). • St. Louis encephalitis and West Nile encephalitis, which were first identified in St. Louis, Missouri, and West Nile Province, Uganda (Africa), respectively. Their enveloped, +ssRNA viruses are in the family Flaviviridae; they differ from togaviruses in their antigens. West Nile virus (WNV), which arrived in the United States in 1999, has had the most impact on people in the United States. • California (also known as LaCrosse) encephalitis, which is endemic to California but was first described from LaCrosse, Wisconsin. The virus, which is enveloped and has a segmented @ssRNA genome, is in the family Bunyaviridae. Physicians are concerned that new forms of viral encephalitis have appeared in Asia and Australia. Pathogenesis As shown in FIGURE 20.14, female Aedes or Culex mosquitoes carry the viruses among infected hosts. Mosquitoes remain infected with arboviruses, which they pass to their offspring in FPO New photo to come 4772020032 20.13 eggs; mothers and their female young are a continual source of new infections. Viruses overwinter in eggs or hibernating mosquitoes. Researchers have demonstrated that West Nile virus and other arboviruses can be transmitted between people via blood transfusion and transplanted organs. Arboviruses enter target cells via endocytosis and replicate within them. They produce viremia and can cross the bloodbrain barrier by an unknown mechanism to cause encephalitis. In horses and humans, viruses are released from infected cells into the blood (viremia), but the concentration of viruses in their blood is never high enough to infect mosquitoes, so horses and humans are “dead-end” hosts for arboviruses. Most patients experience severe flulike symptoms but survive, though 50% of patients still suffer a year later with headaches, cognitive and memory impairment, fatigue, tremors, or depression. Mortality ranges from less than 1% with California encephalitis to 35% with EEE, which is the most severe arboviral encephalitis in people. Epidemiology The normal host for encephalitis arboviruses is either a bird (viruses of EEE, WEE, St. Louis encephalitis, and West Nile encephalitis) or a rodent (viruses of VEE and California encephalitis). People who engage in work or recreation outdoors in endemic areas are at risk of accidental infection, and those older than 50 are at a higher risk of contracting EEE, St. Louis encephalitis, and West Nile encephalitis. Children are at higher risk for WEE, VEE, and California encephalitis. As their names suggest, EEE, WEE, and VEE are typically limited to the eastern United States, western United States, and South and Central America, respectively. California encephalitis has been reported in most states west of the Mississippi River; St. Louis and West Nile viral infections occur in the lower continental 48 states. The incidence of all types of arboviral encephalitis in the United States is seasonal, with peaks that correspond to the times of the year during which adult mosquitoes are active. For example, FIGURE 20.15 illustrates the seasonal nature of reported cases of encephalitis caused by West Nile virus. Birds spread many types of arboviruses rapidly through an environment. This was dramatically demonstrated by the spread of West Nile virus from New York City in 1999 across the continent in just four years. Species of Culex mosquito and 300 species of birds transmit and harbor WNV. House sparrows are an important bird reservoir—they don’t die when infected, and their huge population means they outnumber all other bird carriers. TABLE 20.2 (p. 617) summarizes the distribution, vectors, hosts, and epidemiology of arboviral encephalitis in the United States. Diagnosis, Treatment, and Prevention TEM 30 nm E ▲ FIGURE 20.13 Togaviruses. ach virus has a closely appressed envelope around its capsid. M20_BAUM7206_05_SE_C20.indd 615 Diagnosis of human arboviral encephalitis is based upon observation of signs and symptoms followed by a positive laboratory test for antibodies against specific arboviruses in the CSF. A commonly used laboratory test measures the concentration of IgM, the antibody class produced early in an infection. The test is positive in most infected people within eight days of onset of symptoms. 11/23/16 3:38 AM E ­ er 20    Microbial Diseases of the Nervous System and yes apt       Ch Humans can be infected via mosquito bites. Horses and, rarely, other domestic mammals, are hosts for equine viruses. Encephalitis arboviruses can overwinter inside mosquito eggs. Mosquitoes are vectors. Wild birds Small mammals are primary hosts for VEE and California viruses only. Domestic fowls Birds are primary hosts for all encephalitis arboviruses. ▲ FIGURE 20.14 Transmission of six encephalitis arboviruses. Mosquitoes EE EE EE EE EE EEE H EEE transmit the viruses among birds ( , W , V , St. Louis, and West Nile) or small animals (V and California). orses ( , W , and V ) and humans are dead-end hosts. Arboviruses can overwinter in hibernating mosquitoes or their eggs. Number of reported cases Reported cases Annual deaths 3200 2800 2400 2000 (276) 1600 (94) 1200 800 400 0 (104) (232) (7) (270) (162) (117) (41) (111) (87) (119) (32) (54) (42) (2) (10) 2000 2005 2010 Time (months/years) 2015* 2017 ▲ FIGURE 20.15 Reported human West Nile virus encephalitis in the United States. Note the seasonal nature of the disease. *Partial data: through August 2016. Why are there more cases of WNV infection in the summer than in the winter? Figure 20.15 Mosquitoes transmit West Nile virus among birds and to other animals; in winter, it is generally too cold for mosquitoes to be active. M20_BAUM7206_05_SE_C20.indd 616 11/23/16 3:38 AM       Viral Diseases of the Nervous System TABLE 20.2 Characteristics of Arboviral Encephalitis Diseases and Viruses in the United States Name of Disease and Virus Natural Hosts Number of Human Cases in 2009 in U.S. (Mean Human Mortality) Special Groups at Risk Distribution Vector astern equine encephalitis ( ) astern seaboard, Gulf Coast, Great Lakes states Aedes and Culex mosquitoes Birds 4 (35%) orses; humans over age 50 or under age 15 Western equine encephalitis (W ) States west of Mississippi iver Culex and Culiseta mosquitoes Birds 0 (3%) orses; children under age 1 Venezuelan equine encephalitis (V ) Texas Aedes and Culex mosquitoes St. Louis encephalitis Lower 48 states except MA, M , N , l, SC, and VT Culex mosquito Birds 10 (5%) West Nile encephalitis Lower 48 states except M and N Culex mosquito Birds 360 ( 61%) Aedes mosquito Small mammals 39 ( 6 1%) odents H H 0 (unknown) orses; children H R EE EE R E EEE E Togaviridae H umans over age 50 umans over age 50 H H E R H E Flaviviridae astern and central states Children under age 16 E E GING DIS AS CAS STUDY E M ER E California (LaCrosse) encephalitis E Bunyaviridae A Deadly Mosquito Bite? M20_BAUM7206_05_SE_C20.indd 617 R R R R R Later, Dr. Stephens explains that Zika viral infection is rare in adults and also rarely passed to a fetus. Studies suggest that most babies born to Zika-infected mothers are normal. In any case, the disease in adults seldom lasts more than a week, and babies are most at risk when the pregnancy is in the first trimester; so, even if Maria has Zika virus, her third-trimester baby is most likely safe. Nevertheless, the doctor orders a diagnostic test for Zika—reverse transcription polymerase chain reaction ( T-PC )—that can detect viral NA in a patient’s blood plasma. Maria quickly agrees to the test, and a nurse draws a blood sample. The doctor sends Maria home with acetaminophen (Tylenol®) for the pain and orders her to drink plenty of fluids and get lots of rest. It will take a week to get the results of the T-PC test from the laboratory. A week later, Maris gets the good news—she doesn’t have Zika virus. er baby is safe! For the next six weeks she will be extra careful to avoid mosquitoes by staying inside at dawn and dusk, wearing longsleeved blouses and long pants, and using mosquito repellant. She has had enough worry about Zika virus, mosquitoes, and death. H H H Maria is not felling well; she woke up this morning with fever, muscle aches, and joint pain in her hands and feet. She is especially concerned because she is eight months pregnant with her first child and she’s been hearing about a new disease—called Zika—that affects unborn children. Despite having a headache, she goes online to learn more. She learns that Zika is a virus transmitted by mosquitoes—a so-called arbovirus because it is arthropod borne. Scientists discovered the virus in 1947 in the Zika forest in Uganda, Africa. The first cases in the Western emisphere were in Brazil in 2015. By 2016, the virus and its disease had spread throughout South and Central American nations, to the Caribbean, and into North America. The World ealth Organization has verified that the virus can spread from pregnant women across the placenta to infect unborn children. There is no doubt that Zika virus causes some babies to be born with small heads—a condition called microcephaly—eye defects, and sometimes death. Maria feels nauseated, not as a result of the hormones of pregnancy, but from worry and fear. Could her baby be infected? Would he be malformed? She continued reading. Adults usually have fever, joint pain, red eyes (conjunctivitis), and a bumpy rash. Maria quickly looks at her eyes and skin in the mirror—no redness and no rash. Maybe she doesn’t have it. Maybe she shouldn’t worry. Still, she calls her obstetrician and is able to get an appointment for that afternoon. 1. How does microcephaly differ from both meningitis and encephalitis? 2. Why don’t standard antibiotics such as penicillin and ciprofloxacin help cure a Zika infection? 3. How would you describe PCR (polymerase chain reaction) to a patient like Maria? 11/23/16 3:38 AM E ­ er 20    Microbial Diseases of the Nervous System and yes apt       Ch ­ As with viral meningitis, treatment for arboviral encephalitis is supportive: possible hospitalization, administration of intravenous fluids, respiratory support (ventilator), prevention of secondary infections—in other words, good nursing care. Such treatment for a prolonged, serious case of WEE can cost nearly $3 million! Human disease is prevented by limiting contact with mosquitoes—through the use of netting and insect repellent containing DEET (N,N-diethyl-m-toluamide)—and by reducing mosquito numbers through the elimination of stagnant water, which is a common breeding site for Culex, and the use of insecticides. Veterinarians can administer effective vaccines against EEE, WEE, VEE, and WNV to horses, but the U.S. Food and Drug Administration (FDA) has not approved human vaccines. Scientists have developed an effective human vaccine against West Nile virus; safety trials are ongoing. Disease at a Glance 20.5 summarizes the features of West Nile encephalitis. We have examined bacterial and viral diseases of the nervous system. Now we turn our attention to fungal diseases. TELL ME WHY The word enterovirus literally means “intestine poison,” yet enteroviruses do not cause intestinal diseases. Why are these viruses called enteroviruses? Fungi rarely infect the CNS, though mycoses (fungal diseases) may spread from the lungs via the blood to the CNS, and mushroom poisoning involves toxins that produce neurological dysfunction or hallucinations. (Chapter 22 considers in more detail coccidioidomycosis, histoplasmosis, and blastomycosis, which are diseases of the respiratory system that can have neurological effects.) Here we examine the leading form of fungal meningitis. Cryptococcal Meningitis LE A R N I N G O UTC O M E 20.18 Describe the features of cryptococcal meningitis. Cryptococcal meningitis (cryptococcosis) affects people worldwide. Unlike other forms of fungal meningitis, it affects healthy people as well as those who are sick or immunocompromised. Signs and Symptoms Cryptococcal meningitis manifests with signs and symptoms common to bacterial meningitis: headache, dizziness, drowsiness, irritability, confusion, nausea, vomiting, and neck stiffness. In late stages of the disease, loss of vision and coma occur. Acute onset of rapidly fatal cryptococcal meningitis occurs in individuals with widespread infection. 20.5 E DIS AS AT A GLANCE E Mycosis of the Nervous System West Nile Encephalitis 1 Infected, feeding mosquito introduces West Nile virus into blood. 3 Virus triggers swollen lymph nodes. 2 Virus circulates. 4 4 Body aches, meningitis, and encephalitis are common. Headache, high fever, stiff neck, skin rash, disorientation, coma, and death may occur. 3 1 2 4 1 West Nile virus encephalitis can be life changing. Cause West Nile virus (single-stranded RNA virus). Virulence factors Birds are ubiquitous reservoirs, protein in viral envelope attaches to human cells, virus is intracellular pathogen. Portal of entry Via the bite of an infected mosquito. . M20_BAUM7206_05_SE_C20.indd 618 Signs and symptoms A mild case including fever, headache, body aches, and swollen lymph nodes may progress to encephalitis. The manifestations of this more severe form of West Nile virus infection include abrupt headache, high fever, neck stiffness, stupor, disorientation, coma, tremors, convulsions, muscle weakness, paralysis, and possibly a skin rash. Incubation period Three days to two weeks. Susceptibility The elderly are more at risk for developing West Nile encephalitis. Treatment Supportive therapy. Prevention Limit contact with mosquito populations. 11/23/16 3:38 AM       Protozoan Diseases of the Nervous System Human infections begin in the lungs following inhalation of spores and/or dried yeast cells made airborne when bird droppings containing the fungus are disturbed by the activities of the birds or humans. People who work around buildings where birds roost are at increased risk of infection. In most individuals, phagocytes in the lungs limit spread of the yeast, but in some patients, the fungus spreads via the blood throughout the body. It infects both meninges and brain tissue. Before the advent of AIDS, there were fewer than 500 infections annually worldwide. Now, terminal AIDS patients (who have little immune function remaining) account for almost a million cryptococcal infections each year globally, and about 625,000 die. Diagnosis, Treatment, and Prevention The preferred method of confirming cryptococcal meningitis is detection of fungal antigen in CSF. In AIDS patients, antigen can be detected in serum as well. Fungal stains revealing the presence of encapsulated yeast in CSF are highly suggestive of cryptococcal meningitis, even if no obvious symptoms are present. Treatment is with intravenous amphotericin B and oral 5-fluorocytosine administered together for at least four weeks. The two drugs enhance one another, allowing lower doses of amphotericin B, which is toxic to humans, to be used; however, toxicity is not eliminated. Though AIDS patients may appear well following primary treatment, the fungus typically remains and must be actively suppressed by lifelong oral fluconazole treatment. Because the fungus is a threat to sick individuals, facilities such as hospitals and nursing homes often place devices that deter the roosting of birds near outside air-intake vents in an effort to prevent Cryptococcus-contaminated air from entering the building. No vaccine against Cryptococcus is available. Disease at a Glance 20.6 summarizes the features of cryptococcal infection. Having examined bacterial, viral, and fungal neurological diseases, we turn our attention to representative diseases of the nervous system caused by protozoa. M20_BAUM7206_05_SE_C20.indd 619 Cryptococcal Meningitis Cryptococcus GMS stain of Cryptococcus neoformans in brain. LM 10 µm Cause Cryptococcus neoformans (spherical, single-celled basidiomycete yeast). Virulence factors Polysaccharide capsule resists phagocytosis; produces melanin, which inhibits intracellular digestion of the yeast. Portal of entry Inhalation of spores and/or dried yeast cells. Signs and symptoms Prolonged cough (lasting weeks or months), chest pain, fever, shortness of breath, night sweats, weight loss; proceeds to headache and meningitis. Incubation period Unknown, but probably two to nine months. Susceptibility Immunocompromised persons, especially IV-positive individuals and AIDS patients; people exposed to bird droppings. H Pathogenesis and Epidemiology 20.6 DIS AS AT A GLANCE E Cryptococcus neoformans is a basidiomycete yeast; that is, it is a spherical, single-celled fungus that reproduces sexually with basidiospores. It lives in soil, the feces of birds, and the sap of eucalyptus trees. Scientists recognize two variants of the yeast, both of which are found worldwide. C. neoformans var. gattii primarily infects immunocompetent individuals, whereas C. neoformans var. neo­ formans predominantly infects immunocompromised hosts. Approximately 50% of all cryptococcal infections reported each year are due to the latter variant. The polysaccharide capsule that surrounds each cryptococcal cell is resistant to phagocytosis by defensive cells of the body. The pathogenesis of Cryptococcus is also enhanced by the ability of the yeast to produce melanin, which appears to inhibit phagocytic killing mechanisms. The yeast has a predilection for the central nervous system. E Pathogen and Virulence Factors Treatment Amphotericin B and 5-fluorocytosine coadministered for 6 to 10 weeks. Prevention It is difficult to avoid infection by this prevalent fungus; therefore, you should protect your immune system with healthy lifestyle choices. TELL ME WHY Why is penicillin ineffective in treating cryptococcal meningitis? Protozoan Diseases of the Nervous System Protozoan infections of the nervous system are relatively rare. Here we examine diseases of two protozoa of the kingdom Euglenozoa: African trypanosomiasis, which is caused by a trypanosome, and a form of meningoencephalitis (simultaneous meningitis and encephalitis) caused by amoebas. African Trypanosomiasis LE A R N I N G O UTC O M E 20.19 Describe African trypanosomiasis, including its cause, diagnosis, treatment, and prevention. 11/23/16 3:38 AM E er 20    Microbial Diseases of the Nervous System and yes ­ apt       Ch African trypanosomiasis, also known as African sleeping sickness, prevents ranching and extensive human habitation in an area of equatorial Africa larger than that of the lower 48 U.S. states. 6 Trypanosomes reproduce by binary fission, becoming noninfective forms in midgut of tsetse. Noninfective forms migrate to salivary glands. Signs and Symptoms African trypanosomiasis progresses through three clinical stages: 1 2 3 First, the wound created by the vector’s bite becomes a lesion containing necrotic (dead) tissue and rapidly dividing parasites. Next, the presence of parasites in the blood generates fever, swelling of lymph nodes, and headaches. Finally, invasion of the central nervous system results in meningoencephalitis, characterized by headache, abnormal neurological function, and extreme drowsiness. As the name indicates, victims become so tired that they no longer eat, finally succumbing to coma and death. Untreated African trypanosomiasis is invariably fatal. Glossina (tsetse fly) 1 Noninfective Trypanosoma matures into an infective form within salivary gland of tsetse fly. 5a Trypanosomes are ingested by tsetse fly during blood meal. 5b Trypanosomes invade central nervous system. 2 Tsetse fly injects infective trypanosomes while feeding. Cyclical waves of parasitemia (parasites in the blood) that occur roughly every 7–10 days characterize the disease. Symptoms develop within months to years after infection, depending on the strain of protozoan involved. Thinner Trypanosoma brucei20 (tri-pan’ō-sō-mă brūs’ē), which is a kinetoplastid21 protozoan that causes African trypanosomiasis, randomly changes its surface glycoprotein antigens when it replicates. The result is that by the time a host’s immune system has produced antibodies against a given set of glycoproteins, the parasite has produced a new set, leaving the host’s immune system constantly one step behind the parasite—once infected, a patient rarely clears the infection and becomes immune. Pathogenesis and Epidemiology ­ ­ Newly hatched bloodsucking tsetse (tset’sē) flies (Glossina, glosī’nă) spread T. brucei among people and wild and domesticated mammals. FIGURE 20.16 illustrates the life cycle of the parasite. During the course of an infection, some trypanosomes enter the brain, spinal cord, and cerebrospinal fluid; others continue to circulate in the blood, where feeding tsetse flies pick them up. African trypanosomiasis occurs in equatorial and subequatorial savanna and riverine areas of Africa, wherever tsetse flies live. Diagnosis, Treatment, and Prevention Microscopic observation of trypanosomes in blood, lymph, spinal fluid, or a tissue biopsy is diagnostic for trypanosomiasis. In mammals, the protozoa are long and thin, with a single long flagellum running along the cell and extending past the posterior end (see Figure 12.7b). Health care providers treat the early stages of African trypanosomiasis with pentamidine or suramin. Melarsoprol is used when the disease progresses to the CNS because this drug crosses the blood-brain barrier. A newer, and more expensive, drug called eflornithine is remarkably effective against West African Trypanosoma. To be successful, treatment must begin as Greek trypanon, meaning “auger” (indicating the shape of the protozoan); soma, meaning “body”; and British physician Sir David Bruce, who studied the disease. 20From 21A kinetoplast is a unique region of mitochondrial DNA found in these microbes. M20_BAUM7206_05_SE_C20.indd 620 3 Trypanosomes are carried via bloodstream to other sites. Thicker 4 Trypanosoma replicates by binary fission in bodily fluids, including blood, lymph, and spinal fluid. Thinner progeny remain infective in the body; shorter, thicker ones are infective to tsetse flies. ▲ FIGURE 20.16 The life cycle of Trypanosoma brucei. This parasite causes African trypanosomiasis (African sleeping sickness). soon as possible after infection; however, immediate treatment is rare because of poor health care in endemic areas. Broad application of insecticides has reduced the occurrence of African sleeping sickness in local areas; but largescale spraying of insecticides is impractical, is expensive, and may have disastrous long-term environmental consequences. Personal insecticide use is preferable, as is the use of netting over beds, window screening, and long, loose-fitting clothing. No vaccine currently exists for African trypanosomiasis. Primary Amebic Meningoencephalopathy LE A R N I N G O UTC O M E s Pathogen and Virulence Factors 20.20 Describe primary amebic meningoencephalopathy and its pathogens. 20.21 Describe the treatment and prevention of primary ame- bic meningoencephalopathy. Now we consider another disease of the CNS caused by protozoa, specifically, two amoebas in the kingdom Euglenozoa. 11/23/16 3:38 AM       Prion Disease CLINICAL CASE STUDY States—but it is nearly always fatal; the CDC reports only three survivors in the United States since records have been kept. A Threat from the Wild Physicians diagnose Acanthamoeba and Naegleria infections by detecting amoebas in scrapings from the covering of the eye, cerebrospinal fluid, or biopsy material from the brain. Ketoconazole or amphotericin B may have very limited success, but only if administered very early in the course of an infection. Both amoebas produce resistant cysts that are environmentally hardy; therefore, controlling and preventing infection can be difficult. People should avoid natural waterways in which the organisms are endemic and use only sterile solutions to clean or store contact lenses. Swimming pools should be properly chlorinated and tested periodically to ensure their safety. Air conditioning systems, dialysis units, and humidifiers should be cleaned thoroughly and regularly to prevent amoebas from becoming resident. H H H H A man arrived at an emergency room with neurological disorders: uncontrolled facial twitching, anxiety, and feelings of fear. e also had a sore throat and difficulty in swallowing, and he complained of itching over his entire body. e remained alive for several days but became increasingly agitated and refused to drink because of the pain involved in swallowing. e vomited repeatedly, and his temperature rose to 106°F. e died one week after being admitted to the hospital. An autopsy revealed dark-staining bodies in the cells of his brain and a raised antibody titer in his blood. There were no obvious bites or scratches on his skin, though interviews with friends and family indicated that a bat had landed on the man’s face about a month before he was admitted to the hospital. Diagnosis, Treatment, and Prevention 1. 2. 3. 4. What did the man suffer from? What were the antibodies against? What were the dark-staining bodies in his brain’s cells? What preventive measures might health care providers have used to save the man’s life? Reference: Adapted from MMWR 52:47–48. 2003. Signs and Symptoms Signs and symptoms of primary amebic meningoencephalopathy22 are the same as those for meningitis and encephalitis caused by bacteria, viruses, and fungi—headache, fever, stiff neck, altered mental state, and vomiting. Symptoms progressively worsen over a period of three to seven days until the patient dies. Pathogens, Pathogenesis, and Epidemiology Acanthamoeba (ă-kan-thă-mē’bă) and Naegleria (nā-glē’rē-ă) each cause this disease. These amoebae are common free-living inhabitants of warm lakes, ponds, puddles, ditches, mud, and moist soil; they are also found in artificial water systems such as swimming pools, air conditioning units, humidifiers, contact lens solution, and dialysis units. Amoebas enter a host through cuts or scrapes on the skin, through the covering of the eye via abrasions from contact lenses or trauma, or through inhalation of contaminated water while swimming. Replicating amoebas migrate to the brain via cranial nerves. Primary amebic meningoencephalopathy is rare—fewer than 200 cases were reported from 1962 to 2013 in the United 22Note that in American English, the noun amoeba and the adjective amebic are spelled dissimilarly. M20_BAUM7206_05_SE_C20.indd 621 TELL ME WHY Why has the number of cases of primary amebic meningoencephalopathy increased dramatically as societies have become more developed? Prion Disease In 1996, a new pathogen leapt to worldwide attention with the revelation that the infectious protein that causes the sheep disease scrapie had “jumped species” to cause “mad cow disease” and had then jumped again into humans who ate infected beef. These infectious proteins, called prions (prē’onz), may play a role in many neurological diseases such as Alzheimer’s and Parkinson’s. Here we consider the prion disease of the 1996 epidemic. Variant Creutzfeldt-Jakob Disease (vCJD) LE A R N I N G O UTC O M E 20.22 Describe the causative agent, signs, symptoms, and pre- vention of variant Creutzfeldt-Jakob disease. Scrapie and mad cow disease belong to a class of diseases called spongiform encephalopathies because they leave the brains of their victims so full of holes they resemble sponges. German neurologists Hans Creutzfeldt (1885–1964) and Alfons Jakob (1884– 1931) described the genetic disease that bears their name as a type of dementia that spontaneously strikes about one person in a million at about age 60. A contagious form of the disease, derived from cattle, is called variant Creutzfeldt-Jakob (kroits’felt-ya’kōp) disease (vCJD) to distinguish it from the naturally occurring Creutzfeldt-Jakob disease (CJD). Signs and Symptoms In vCJD, brain tissue is destroyed, and numerous cavities form (see Disease at a Glance 20.7 on p. 623). As the brain deteriorates, victims experience insomnia, weight loss, and memory failure. They also act irrationally, lose control of their muscles, 11/23/16 3:38 AM E ­ A Protozoan Mystery H H A 20-year-old student was admitted to his college’s student health center with fever and headaches shortly after beginning the fall semester. e had spent his summer working with an international aid organization in Nigeria and had returned to the United States only a week earlier. Gross examination revealed LM numerous insect bites and 15 μm some swollen lymph nodes. The man had spent most of his summer outdoors in rural areas and had spent some time on African game reserves working with the families of local guides. e could not specifically remember receiving any of the bite wounds on his body, and he did not always use insect repellent in the field. The patient was admitted to the local hospital, where intermittent fever, headache, and swelling continued. Initial blood smears proved negative for malaria. 1. What are some possible protozoan diseases the patient could have contracted in Africa? 2. Can this disease be identified from the symptoms alone? 3. Based on the pictured blood smear, what would you conclude about the cause of the disease? 4. What would the treatment be if the patient had tested positive for malaria? 5. What treatment would you now recommend? 6. What prevention would you have suggested to this individual? 7. Is there a local threat—could anyone in America contract this disease from this student? and are unable to speak, walk, or maintain posture. Muscle spasms progressively worsen as the disease progresses. Death usually occurs within 12 months. Pathogen, Pathogenesis, and Epidemiology A prion protein causes vCJD. Prions exist in one of two three-dimensional forms (see Figure 13.22): The normal form is anchored in lipid rafts in membranes of neurons of the CNS and is necessary for normal brain function, though scientists don’t understand its exact role. An abnormal prion acts as an enzyme to refold the normal form into a copy of the abnormal form. Newly misfolded prions then proceed to make copies of themselves from surrounding normal prion molecules. In other words, abnormal prions turn normal prion proteins into abnormal prions, which continue the process. The disease progresses unrelentingly, destroying the brain as it does. M20_BAUM7206_05_SE_C20.indd 622 Medical procedures such as transplants, blood transfusion from an infected person, use of contaminated surgical instruments, and injection of growth hormones derived from infected pituitary glands can spread the disease. Prions may remain dormant for more than 60 years. Unlike the genetic form of CJD, variant CJD strikes even young people who consume contaminated nerve tissue, typically in meat products such as sausages. Since its discovery in 1996, vCJD has killed about 225 people. Studies suggest that 1 in 2000 people in the United Kingdom are infected with the abnormal prion; thousands of British people wonder whether they have been infected and will succumb to vCJD in the future. Diagnosis, Treatment, and Prevention The characteristic signs and symptoms of vCJD are diagnostic in the young but can be confused with other forms of dementia in the elderly. Laboratory tests on samples from the CNS confirm the presence of abnormal prion in the brain. No treatment is available for vCJD, though interleukins may slow disease progression. It is difficult to destroy prions even outside the body—prions survive cooking, freezing, pickling, and even normal autoclaving. Currently, autoclaving in a concentrated solution of sodium hydroxide is recommended to destroy prions, but you would not want to eat a hot dog prepared that way! The European Union but not the United States has approved an enzyme treatment to remove prions from the environment. Prevention of vCJD is possible only by remaining free of the prion by avoiding contaminated meat, particularly meat cut from bones near the spinal cord and processed meats made from brains or spinal cords of infected animals. As British farmers and ranchers learned, destruction of potentially infected sheep and cattle herds is mandatory to prevent the spread of vCJD. Further, governments have initiated strict laws and inspection procedures to prevent the use of contaminated animal protein in food supplements for herbivores. Disease at a Glance 20.7 summarizes the features of variant Creutzfeldt-Jakob disease. TELL ME WHY Why is infectious CJD called variant? Microbial Diseases of the Eyes LE A R N I N G O UTC O M E s CLINICAL CASE STUDY er 20    Microbial Diseases of the Nervous System and yes apt       Ch 20.23 Discuss the features of trachoma, including pathogene- sis and prevention. 20.24 Define and contrast conjunctivitis and keratitis. The senses are important parts of the nervous system. Vision is our primary sense, so it is not surprising that nearly half of the function of the cerebrum is dedicated to vision and about 70% of sensory neurons originate in the eyes; in fact, the eyes can be considered extensions of the brain and dura mater. 11/23/16 3:38 AM E E DIS AS AT A GLANCE       E Microbial Diseases of the yes Retina 20.7 Sclera Optic nerve Variant Creutzfeldt-Jakob Disease (vCJD) Cause PrP prion (infectious protein). Extension of dura mater Virulence factors Ability of abnormal, disease prion protein to convert normal prion protein into abnormal form; survives cooking and normal autoclaving. Cornea Portal of entry Ingestion of infected meat; transplant or transfusion of infected tissues. Signs and symptoms Irrational behavior; loss of muscle control; increasing inability to walk, talk, or maintain posture; muscle spasms; and a continuous writhing of the extremities. Death is inevitable. Conjunctiva Spongiform lesions LM 25 µm Spongiform lesions (holes) of variant Creutzfeldt-Jakob disease. Incubation period Unknown, but most likely decades. Susceptibility At greatest risk are individuals who consumed beef in the United Kingdom between 1980 and 1996. Treatment None. Prevention Do not eat meat contaminated with infected nervous tissue. Destruction of potentially infected herds is necessary to prevent the spread of the infectious prion. In the following sections we will briefly consider representative microbial infections of the eyes, but first we consider the structure of an eye. Structure of the Eye FIGURE 20.17 illustrates the structure of an eye. An eye is a hol- low, roughly spherical ball about 2.5 cm in diameter. The outer wall of the eye, called the fibrous tunic, is composed of a white sclera, which is a direct extension of the dura mater of the brain, and a colorless, clear cornea, which covers the front of the eye. The fibrous tunic provides a tough barrier against the penetration of microbes. An extension of the epidermis of the skin, called the conjunctiva, lines the backside of the eyelids and all but the center of the cornea. The interior of the eye is composed of two chambers filled with fluids, called humors. The back interior wall of the eye is the retina, which contains billions of sensory neurons that respond to light energy and send nerve impulses to the brain down the optic cranial nerve. In the following sections, we briefly consider several bacterial, fungal, viral, and protozoan diseases of the eye. Trachoma Trachoma (trā-kō’mā) is the leading cause of nontraumatic blindness in humans. M20_BAUM7206_05_SE_C20.indd 623 ▲ FIGURE 20.17 The eye (sagittal section). Signs and Symptoms Trachoma is Greek for “roughness,” which is a good description of this disease in which the conjunctiva and cornea are scarred by bacterial infection, leading to blindness. Pathogen, Pathogenesis, and Epidemiology So-called trachoma strains of the bacterium Chlamydia trachomatis (kla-mid’ē-ă tra-kō’ma-tis) cause trachoma. The pathogen multiplies in cells of the conjunctiva and kills them, triggering a large amount of purulent23 (pus-filled) discharge that scars the conjunctiva. Such scarring in turn causes the patient’s eyelids to turn inward, such that the eyelashes scratch, irritate, and scar the cornea. Corneal scarring triggers an invasion of blood vessels into this normally clear surface of the eye (FIGURE 20.18). A scarred cornea that is filled with blood vessels is no longer transparent, and the eventual result is blindness. Trachoma is typically a disease of children who have been infected during birth. However, some strains of C. trachomatis may produce blindness by a similar process in adults when bacteria from the genitalia are introduced into the eyes via fomites, fingers, or flies. Diagnosis, Treatment, and Prevention Diagnosis of chlamydial infection involves demonstration of the bacteria inside cells from the site of infection. Specimens can be obtained from the urethra or vagina by inserting, rotating, and then removing a sterile swab. Stained specimens may reveal bacteria or inclusion bodies within cells, but the most specific method of diagnosis involves amplifying the number of chlamydia by inoculating the specimen into a culture of susceptible cells. Laboratory technicians then demonstrate the presence of Chlamydia in the cell culture by means of specific fluorescent antibodies or nucleic acid probes. 23From Latin pur, meaning “pus.” 11/23/16 3:38 AM E er 20    Microbial Diseases of the Nervous System and yes ­ apt       Ch A number of bacteria, fungi, viruses, or protozoa cause the two conditions, which may occur independently or simultaneously. For example, Haemophilus influenzae is the most common bacterial cause of conjunctivitis. Acanthamoeba can cause both conjunctivitis and keratitis. (See the discussion of Acanthamoeba keratitis on p. 265.) Physicians treat bacterial, fungal, and protozoan conjunctivitis and keratitis with topical antimicrobial drugs. No antiviral drugs are available for these conditions. TELL ME WHY Doxycycline—one of the tetracyclines—is the treatment for most adults infected with Chlamydia trachomatis; however, it is not recommended for pregnant women or babies. Why not? ▲ FIGURE 20.18 An eyelid afflicted with trachoma. CLINICAL CASE STUDY Physicians prescribe azithromycin or doxycycline to eliminate genital infections of C. trachomatis in adults. Azithromycin is recommended for treatment of pregnant women. Trachoma strains of C. trachomatis infecting the eyes of newborns are treated with tetracycline or erythromycin cream for 10–14 days, whereas eye infections in adults are treated with oral tetracycline, doxycycline, or erythromycin for three to six weeks. Surgical correction of eyelid deformities may prevent the scratching, scarring, and blindness that may result from eye infections. In December, a 19-year-old college student experiences a severe headache, nausea, vomiting, and fever. The student suspects a case of flu and goes to the health center for a diagnosis. By the time he arrives, he is feeling worse, with neck stiffness and disorientation. The doctor immediately prepares to perform a spinal tap. Other Microbial Diseases of the Eyes Bacterial infections of the skin and reproductive tract may also affect the eyes. For example, Staphylococcus aureus (staf’i-lō-kok’ŭs o’rē-ŭs) infections of sebaceous glands in the skin near the eye are called sties, and Neisseria gonorrhoeae (nī-se’rē-ă go-nor-rē’ī), a sexually transmitted bacterium, causes a form of ophthalmia neonatorum (of-thal’mē-ă nē’ō-nă-tor’um)—inflammation of the conjunctiva and cornea of a newborn. Babies can be infected during passage through a diseased birth canal. Conjunctivitis, commonly called pinkeye, is inflammation of the conjunctiva, and keratitis is inflammation of the cornea. 1. What disease does the doctor suspect? 2. What are possible causes of this disease? 3. The spinal tap reveals the presence of Gram-negative cocci in the CSF. What else was present in the CSF of the patient? 4. Given the information in question 3, what is the diagnosis? 5. What might the student’s residential assistant in the dorm be concerned about? 6. How might this disease have been prevented? ­ 1. Why was Mercedes’s initial CSF sample negative for WNV–specific IgM? 2. Why must Mercedes be monitored for changes in intracranial pressure and seizure? E H The initial assessment at Dr. Miller’s office reveals that Mercedes has a fever (101°F), tremor in the right hand, and weakness in both legs and that she is disoriented. A sample of cerebrospinal fluid (CSF) is collected; white blood cell count is elevated, glucose is normal, and protein is elevated. Bacterial and viral analysis of the CSF is negative. Upon his initial assessment, Dr. Miller admits Mercedes to the hospital for monitoring. er condition has continued to worsen. An electroencephalogram (a test of brain activity) reveals mild encephalopathy (disease or disorder of the brain). ight days after her admission to the hospital, serological analysis of CSF from Mercedes indicates a positive result for West Nile Virus (WNV)–specific IgM. There is no specif ic treatment for WNV. Mercedes remains in the hospital, where she receives supportive care and careful monitoring for intracranial pressure and seizures. Three weeks later, Mercedes is released from the hospital with some residual weakness in her right leg and no remaining mental alterations. ­ Brain Dysfunction After a Hard Hike? A Very Sick Sophomore M20_BAUM7206_05_SE_C20.indd 624 11/23/16 3:38 AM       Chapter Summary CHAPTER SUMMARY Structure of the Nervous System (pp. 596–598) 1. The central nervous system (CNS) is composed of the brain and spinal cord surrounded by three layers of meninges: the dura mater (outermost), arachnoid mater, and pia mater. 2. The subarachnoid space is filled with cerebrospinal fluid (CSF), which acts as a shock absorber, provides nutrients and oxygen, and removes wastes. 5. Clostridium botulinum produces neurotoxins that cause botulism poisoning. It manifests as foodborne botulism, infant botulism, and wound botulism. 6. Botulism neurotoxins prevent muscular contraction by preventing the secretion of acetylcholine (a necessary chemical) in the neuromuscular junction (the synapse between a motor neuron and a muscle cell). 3. CSF is removed from the lumbar region of the spinal cord in a procedure called a lumbar puncture, or spinal tap. 7. Clostridium tetani causes tetanus by releasing the neurotoxin tetanospasmin, which blocks inhibitory neurotransmitters, resulting in severe muscular contractions. 4. Tightly joined cells of blood vessels of the pia mater form the blood-brain barrier, so named because substances in the blood cannot enter the subarachnoid space. 8. Tetanus toxoid provides effective immunity against tetanus. 5. The peripheral nervous system (PNS) is composed of cranial nerves and spinal nerves. A plexus is a bundle of branching nerves. 6. Three nerve types are sensory nerves (bundles of nerve cells carrying signals toward the CNS), motor nerves (bundles of nerve cells carrying signals away from the CNS), and mixed nerves. 7. Neuroglia are supportive cells of the nervous system. Neurons are cells that carry nerve impulses. The cell bodies of neurons grouped together form a ganglion. 8. Short cytoplasmic processes that extend from neuron cell bodies and carry impulses toward the cell body are dendrites. Axons are longer processes that carry impulses away from the cell body. Elements of the cytoskeleton carry substances up and down the axon in a process called axonal transport. 9. Synapses are junctions between axons and either glands, muscles, or neurons. In the synaptic cleft (small space between axon and next cell), the axon releases neurotransmitters, which may be stimulatory or inhibitory. 10. Meningitis is an infection of the meninges. Bacterial Diseases of the Nervous System (pp. 598–610) 1. Bacterial meningitis can be caused by many species of bacteria and is characterized by sudden high fever, intense meningeal inflammation, and sometimes petechiae, small hemorrhages of blood vessels in the skin. 2. Most cases of bacterial meningitis are caused by Streptococcus pneu­ moniae, Neisseria meningitidis, Haemophilus influenzae, Listeria mono­ cytogenes, and Streptococcus agalactiae. Listeria causes listeriosis. 3. Mycobacterium leprae causes Hansen’s disease (leprosy), which manifests as tuberculoid leprosy in patients with a strong immune response or as lepromatous leprosy in those with weak immune response. The bacterial cell wall contains a large amount of mycolic acid, which accounts for the slow, resistant growth of the bacteria. 4. Diagnosis of leprosy is based on loss of sensation in skin, disfigurement, and the presence of acid-fast bacilli (AFB). M20_BAUM7206_05_SE_C20.indd 625 Viral Diseases of the Nervous System (pp. 610–618) 1. The most common form of meningitis is viral meningitis. Most cases are caused by viruses of the genus Enterovirus of the family Picornaviridae, which spread via the blood (viremia). 2. Poliovirus causes poliomyelitis (polio), which is expressed as an asymptomatic infection, minor polio, nonparalytic polio, or paralytic polio. 3. Postpolio syndrome is a muscle deterioration that affects polio patients 30–40 years after their original illness. 4. Rabies virus causes rabies, a degenerating brain and spinal cord disease that is zoonotic (spread by animals to humans). 5. Bloodsucking arthropods transmit arboviruses. Arboviral encephalitis affects birds, horses, and rodents, and six arboviruses cause encephalitis (rarely) in humans. Mycosis of the Nervous System (pp. 618–619) 1. Cryptococcal meningitis is a mycosis (fungal disease) of the nervous system that can be fatal to AIDS patients and transplant recipients taking immunosuppressive drugs. 2. Cryptococcus neoformans is a yeast that normally lives in soil and in bird feces and causes cryptococcal meningitis. Protozoan Diseases of the Nervous System (pp. 619–621) 1. The protozoan Trypanosoma brucei causes African trypanosomiasis (African sleeping sickness) when it enters the body via the bite of an infected tsetse fly. 2. The free-living amoebas Acanthamoeba and Naegleria cause primary amebic meningoencephalopathy, a rare but usually fatal disease. Prion Disease (pp. 621–622) 1. “Mad cow disease” is caused by a prion, an infectious protein. Humans can contract a form of spongiform encephalopathy when they eat meat from infected cattle. 2. Variant Creutzfeldt-Jakob disease (vCJD) causes brain deterioration resulting in dementia and death. 11/23/16 3:38 AM E er 20    Microbial Diseases of the Nervous System and yes ­ apt       Ch Microbial Diseases of the Eyes (pp. 622–624) 3. Keratitis is the inflammation of the cornea due to microbial infection. E VI W RE E QU STIONS FO R 1. Chlamydia trachomatis infections of the reproductive tract inoculated into a baby’s eyes at birth cause trachoma, resulting in blindness. 2. Conjunctivitis (pinkeye) is an inflammation of the conjunctiva due to infection by any of a variety of microbes. Answers to the Questions for Review (except Short Answer questions) begin on p. A-1. Multiple Choice 10. Which of the following diseases is not a zoonosis? a. arboviral encephalitis c. St. Louis encephalitis b. rabies d. viral meningitis 11. Which of the following diseases is caused most commonly by protozoan infections? a. variant Creutzfeldt-Jakob disease b. trachoma c. African trypanosomiasis d. Hansen’s disease M20_BAUM7206_05_SE_C20.indd 626                2. The cell structure of pneumococci that accounts for virulence is the . 3. A common cause of bacterial meningitis acquired by babies at birth is . 5. The bacterium that causes botulism is , and                    ,                    4. Three types of botulism are                    9. Which of the following does not play a role in the action of botulism toxin? a. acetylcholine in synaptic cleft b. inhibition of vesicular fusion c. nerve impulse conduction d. nerve cell growth 1. A is an intercellular space between an axon and another cell. . . 6. A mycosis of the nervous system that has become more common since the advent of AIDS is . 7. Hydrophobia is characteristic of                   8. Which of the following diseases is a zoonosis? a. cryptococcal meningitis c. tetanus b. rabies d. tuberculosis Fill in the Blanks                                   7. The type of poliomyelitis that accounts for about 90% of the cases is . a. asymptomatic polio c. nonparalytic polio b. minor polio d. paralytic polio                                   6. The most common form of meningitis is . a. bacterial meningitis c. cryptococcal meningitis b. viral meningitis d. septic meningitis 15. Human diploid cell vaccine is used to treat what disease? a. leprosy c. tetanus b. rabies d. tuberculosis infections. 8. The nervous system is composed of nerves that carry impulses to and from muscles and glands throughout the body. 9. The cytoplasmic processes that carry messages toward the neuron cell body are .                    . c. rabies d. tetanus 14. Which of the following would not play a role in preventing infection with amoebas? a. sterile drinking water b. sterile contact lens solution c. avoiding swimming in contaminated lakes d. chlorination of swimming pools                    5. Hansen’s disease is also known as a. meningitis b. leprosy                               4. A collection of many neuron cell bodies outside the CNS is a . a. plexus c. ganglion b. dendrite d. axon 13. A bacterium associated with bacteremia, meningitis, and pneumonia in newborns is . a. Staphylococcus aureus c. Streptococcus pyogenes b. Staphylococcus epidermidis d. Streptococcus agalactiae                                 3. Nerves that primarily carry impulses toward the central nervous system are . a. sensory nerves c. mixed nerves b. motor nerves d. plexus nerves                                   2. The layer of the meninges lying closest to the spinal cord is the . a. arachnoid mater c. dura mater b. pia mater d. cauda equina 12. Which of the following statements concerning primary amebic meningoencephalitis is true? a. Primary amebic meningoencephalopathy is serious but not fatal. b. Primary amebic meningoencephalopathy is caused by a prion ingested from infected beef. c. A person can become infected by contaminated contact lenses. d. The disease is sexually transmitted and can be transmitted to a baby at birth.                                  1. Cerebrospinal fluid is . a. formed deep within the brain b. found in the subarachnoid space c. withdrawn in a spinal tap d. All of the above are true of the cerebrospinal fluid 10.                   are small, dark purplish hemorrhages of blood vessels in the skin, sometimes seen in meningitis patients. 11/23/16 3:38 AM 15. Streptococcus agalactiae is also known as Lancefield Streptococcus.                          13. Staphylococcus aureus can cause infections of the sebaceous glands near the eye. These infections are called . 14. A sexually transmitted bacterium, , causes ophthalmia neonatorum in newborns who are infected while passing through a diseased birth canal.                   due to microbial                   12. Pinkeye is an inflammation of the infection. .                    11. The leading cause of nontraumatic blindness in humans is                R Questions for eview VISUALIZE IT! 1. Label the neuromuscular junction being acted on by botulism toxin. 2. Indicate on the drawing where a lumbar puncture would be administered. Label the membranes and spaces the needle would pass through. a._________________________ a. _________________ b._________________________ c._________________________ b. d._________________________ e._________________________ c. e. d. _________________ Short Answer 1. Distinguish among the following infections: meningitis, encephalitis, and meningoencephalitis. 2. Explain two ways that pneumococci “hide” inside body cells. 3. A dietician informs Jill that she is at risk for listeriosis. What dietary changes should Jill make? 4. What four effects does mycolic acid in the cell wall of Mycobac­ terium leprae have on the microbe’s growth rate and resistance to antimicrobial drugs? 5. Describe leprosy with reference to historical control of the disease. 6. Justify this statement: “Botulism is not an infection.” 7. Explain why botulism can kill. Include the following terms in your explanation: neurotoxin, neuromuscular junction, acetylcholine, synaptic cleft, flaccid. 8. Explain how tetanus can kill; use the terms neuromuscular junction, acetylcholine, inhibitory neurotransmitters, and tetanospasmin. 9. List four measures that can be taken to prevent arboviral infections. 10. What feature of the life cycle of Trypanosoma brucei makes it difficult to develop a successful vaccine? H R C ITICAL T INKING 1. A doctor prescribes a new antimicrobial drug to treat bacterial meningitis in a nursing student. The student asked whether penicillin would kill the pathogen in question. The physician answers, “Perhaps, but . . .” What is the most probable completion to that sentence? 2. Why would feeding pigeons in the park be more dangerous for a person with AIDS than for a healthy person? 3. Botulism toxin can be used as an antidote for tetanus. Can tetanus toxin be used as an antidote for botulism? Why or why not? 4. A three-year-old boy complains to his day care worker that his head hurts. The worker calls the child’s mother, who arrives 30 minutes later to pick up her son. She is concerned that he is now listless M20_BAUM7206_05_SE_C20.indd 627 and unresponsive, so she drives straight to the hospital emergency room. Though the medical staff immediately treats the boy with penicillin, he dies—only four hours after initially complaining of a headache. What caused the boy’s death? Were the day care workers or the hospital staff to blame for his death? What steps should be taken to protect the other children at the day care facility? 5. A student in Maine is brought to the ER suffering from seizures, disorientation, and an inordinate fear of water. She had a headache and fever for several days. What is her diagnosis? Will a vaccine be an effective treatment? What wild animals are the likely sources of infection in Maine? What treatment should the patient’s friends and caregivers receive? 11/23/16 3:38 AM E ­       Chapter 20    Microbial Diseases of the Nervous System and yes 6. How are the actions of botulism and tetanus toxins alike? How are they different? M EPT CONC APP 7. Investigations of tuberculosis have clearly demonstrated that mycobacteria are transmitted among airline passengers who are breathing recirculated air; however, as of 2015, no cases of inflight transmission of meningococcal bacteria had been reported to the Centers for Disease Control and Prevention (CDC). What are some possible explanations for the lack of documented cases of in-flight transmission of Neisseria meningitidis? 8. Haemophilus influenzae was so named because researchers isolated the organism from flu patients. Specifically, how could a proper application of Koch’s postulates have prevented this misnomer? 9. Why does the fact that M. leprae grows best at 30°C make it difficult to grow the bacterium in cell culture? 10. Smallpox is the only disease that has been eliminated worldwide, though scientists hope to soon eradicate polio. What features do the smallpox and polio viruses share that has allowed medical science to rid the world of these diseases? ING Using the following terms, fill in the concept map that describes bacterial meningitis. Antimicrobials Cerebrospinal fluid (CSF) Culture Gram-positive diplococci Haemophilus influenzae Respiratory route Serological test Vaccines Vancomycin Healthy carriers Hib vaccine Infants and young children Neisseria meningitidis Pneumococcal vaccine (PCV) Bacterial meningitis diagnosed by often caused by 10 treated with 11 13 1 are Gram-negative bacilli 2 are Gram-negative diplococci Streptococcus pneumoniae are 3 of usually acquired via 4 often spread by 5 may develop in can be prevented by 12 most often 14 obtained by plus Ampicillin Lumbar puncture 6 8 7 such as Meningococcal vaccine (MCV4) 9 M20_BAUM7206_05_SE_C20.indd 628 3/6/18 4:45 PM