# Circulatory and Lymphatic System Infections

## Parasitic Infections of the Circulatory and Lymphatic Systems

### Learning Objectives

By the end of this section, you will be able to:
1. Identify common parasites that cause infections of the circulatory and lymphatic systems
2. Compare the major characteristics of specific parasitic diseases affecting the circulatory and lymphatic systems
Some protozoa and parasitic flukes are also capable of causing infections of the human circulatory system. Although these infections are rare in the US, they continue to cause widespread suffering in the developing world today. Fungal infections of the circulatory system are very rare. Therefore, they are not discussed in this chapter.

### Malaria

Despite more than a century of intense research and clinical advancements, malaria remains one of the most important infectious diseases in the world today. Its widespread distribution places more than half of the world’s population in jeopardy. In 2015, the WHO estimated there were about 214 million cases of malaria worldwide, resulting in about 438,000 deaths; about 88% of cases and 91% of deaths occurred in Africa.World Health Organization. “World Malaria Report 2015: Summary.” 2015. http://www.who.int/malaria/publications/world-malaria-report-2015/report/en/. Accessed July 28, 2016. Although malaria is not currently a major threat in the US, the possibility of its reintroduction is a concern. Malaria is caused by several protozoan parasites in the genus : P. falciparum, P. knowlesi, P. malariae, P. ovale, and P. vivax. Plasmodium primarily infect red blood cells and are transmitted through the bite of es.
Currently, P. falciparum is the most common and most lethal cause of malaria, often called falciparum malaria. Falciparum malaria is widespread in highly populated regions of Africa and Asia, putting many people at risk for the most severe form of the disease.
The classic signs and symptoms of malaria are cycles of extreme fever and chills. The sudden, violent symptoms of malaria start with malaise, abrupt chills, and fever (39–41° C [102.2–105.8 °F]), rapid and faint pulse, polyuria, headache, myalgia, nausea, and vomiting. After 2 to 6 hours of these symptoms, the fever falls, and profuse sweating occurs for 2 to 3 hours, followed by extreme fatigue. These symptoms are a result of Plasmodium emerging from red blood cells synchronously, leading to simultaneous rupture of a large number of red blood cells, resulting in damage to the spleen, liver, lymph nodes, and bone marrow. The organ damage resulting from hemolysis causes patients to develop sludge blood (i.e., blood in which the red blood cells agglutinate into clumps) that can lead to lack of oxygen, necrosis of blood vessels, organ failure, and death.
In established infections, malarial cycles of fever and chills typically occur every 2 days in the disease described as tertian malaria, which is caused by P. vivax and P. ovale. The cycles occur every 3 days in the disease described as quartan malaria, which is caused by P. malariae. These intervals may vary among cases.
Plasmodium has a complex life cycle that includes several developmental stages alternately produced in mosquitoes and humans (). When an infected mosquito takes a blood meal, sporozoites in the mosquito salivary gland are injected into the host’s blood. These parasites circulate to the liver, where they develop into schizonts. The schizonts then undergo schizogony, resulting in the release of many merozoites at once. The merozoites move to the bloodstream and infect red blood cells. Inside red blood cells, merozoites develop into trophozoites that produce more merozoites. The synchronous release of merozoites from red blood cells in the evening leads to the symptoms of malaria.
In addition, some trophozoites alternatively develop into male and female gametocytes. The gametocytes are taken up when the mosquito takes a blood meal from an infected individual. Sexual sporogony occurs in the gut of the mosquito. The gametocytes fuse to form zygotes in the insect gut. The zygotes become motile and elongate into an ookinete. This form penetrates the midgut wall and develops into an oocyst. Finally, the oocyst releases new sporozoites that migrate to the mosquito salivary glands to complete the life cycle.
Diagnosis of malaria is by microscopic observation of developmental forms of Plasmodium in blood smears and rapid EIA assays that detect Plasmodium antigens or enzymes (). Drugs such as chloroquine, atovaquone , artemether, and lumefantrine may be prescribed for both acute and prophylactic therapy, although some Plasmodium spp. have shown resistance to antimalarial drugs. Use of insecticides and insecticide-treated bed nets can limit the spread of malaria. Despite efforts to develop a vaccine for malaria, none is currently available.

### Toxoplasmosis

The disease toxoplasmosis is caused by the protozoan . T. gondii is found in a wide variety of birds and mammals,A.M. Tenter et al.. “ and human infections are common. The Centers for Disease Control and Prevention (CDC) estimates that 22.5% of the population 12 years and older has been infected with T. gondii; but immunocompetent individuals are typically asymptomatic, however.Centers for Disease Control and Prevention. “Parasites - Toxoplasmosis (Toxoplasma Infection). Epidemiology & Risk Factors.” 2015 http://www.cdc.gov/parasites/toxoplasmosis/epi.html. Accessed July 28, 2016. Domestic cats are the only known definitive hosts for the sexual stages of T. gondii and, thus, are the main reservoirs of infection. Infected cats shed T. gondii oocysts in their feces, and these oocysts typically spread to humans through contact with fecal matter on cats’ bodies, in litter boxes, or in garden beds where outdoor cats defecate.
T. gondii has a complex life cycle that involves multiple hosts. The T. gondii life cycle begins when unsporulated oocysts are shed in the cat’s feces. These oocysts take 1–5 days to sporulate in the environment and become infective. Intermediate hosts in nature include birds and rodents, which become infected after ingesting soil, water, or plant material contaminated with the infective oocysts. Once ingested, the oocysts transform into tachyzoites that localize in the bird or rodent neural and muscle tissue, where they develop into tissue cysts. Cats may become infected after consuming birds and rodents harboring tissue cysts. Cats and other animals may also become infected directly by ingestion of sporulated oocysts in the environment. Interestingly, Toxoplasma infection appears to be able to modify the host’s behavior. Mice infected by Toxoplasma lose their fear of cat pheromones. As a result, they become easier prey for cats, facilitating the transmission of the parasite to the cat definitive hostJ. Flegr. “Effects of  ().
Toxoplasma infections in humans are extremely common, but most infected people are asymptomatic or have subclinical symptoms. Some studies suggest that the parasite may be able to influence the personality and psychomotor performance of infected humans, similar to the way it modifies behavior in other mammals.Ibid When symptoms do occur, they tend to be mild and similar to those of mononucleosis. However, asymptomatic toxoplasmosis can become problematic in certain situations. Cysts can lodge in a variety of human tissues and lie dormant for years. Reactivation of these quiescent infections can occur in immunocompromised patients following transplantation, cancer therapy, or the development of an immune disorder such as AIDS. In patients with AIDS who have toxoplasmosis, the immune system cannot combat the growth of T. gondii in body tissues; as a result, these cysts can cause encephalitis, retinitis, pneumonitis, cognitive disorders, and seizures that can eventually be fatal.
Toxoplasmosis can also pose a risk during pregnancy because tachyzoites can cross the placenta and cause serious infections in the developing fetus. The extent of fetal damage resulting from toxoplasmosis depends on the severity of maternal disease, the damage to the placenta, the gestational age of the fetus when infected, and the virulence of the organism. Congenital toxoplasmosis often leads to fetal loss or premature birth and can result in damage to the central nervous system, manifesting as mental retardation, deafness, or blindness. Consequently, pregnant women are advised by the CDC to take particular care in preparing meat, gardening, and caring for pet cats.Centers for Disease Control and Prevention. “Parasites - Toxoplasmosis (Toxoplasma infection). Toxoplasmosis Frequently Asked Questions (FAQs).” 2013. http://www.cdc.gov/parasites/toxoplasmosis/gen_info/faqs.html. Accessed July 28, 2016. Diagnosis of toxoplasmosis infection during pregnancy is usually achieved by serology including TORCH testing (the “T” in TORCH stands for toxoplasmosis). Diagnosis of congenital infections can also be achieved by detecting T. gondii DNA in amniotic fluid, using molecular methods such as PCR.
In adults, diagnosis of toxoplasmosis can include observation of tissue cysts in tissue specimens. Tissue cysts may be observed in Giemsa- or Wright-stained biopsy specimens, and CT, magnetic resonance imaging, and lumbar puncture can also be used to confirm infection ().
Preventing infection is the best first-line defense against toxoplasmosis. Preventive measures include washing hands thoroughly after handling raw meat, soil, or cat litter, and avoiding consumption of vegetables possibly contaminated with cat feces. All meat should be cooked to an internal temperature of 73.9–76.7 °C (165–170 °F).
Most immunocompetent patients do not require clinical intervention for Toxoplasma infections. However, neonates, pregnant women, and immunocompromised patients can be treated with pyrimethamine and sulfadiazine—except during the first trimester of pregnancy, because these drugs can cause birth defects. Spiramycin has been used safely to reduce transmission in pregnant women with primary infection during the first trimester because it does not cross the placenta.

### Babesiosis

Babesiosis is a rare zoonotic infectious disease caused by . These parasitic protozoans infect various wild and domestic animals and can be transmitted to humans by black-legged Ixodes ticks. In humans, Babesia infect red blood cells and replicate inside the cell until it ruptures. The Babesia released from the ruptured red blood cell continue the growth cycle by invading other red blood cells. Patients may be asymptomatic, but those who do have symptoms often initially experience malaise, fatigue, chills, fever, headache, myalgia, and arthralgia. In rare cases, particularly in asplenic (absence of the spleen) patients, the elderly, and patients with AIDS, babesiosis may resemble falciparum malaria, with high fever, hemolytic anemia, hemoglobinuria (hemoglobin or blood in urine), jaundice, and renal failure, and the infection can be fatal. Previously acquired asymptomatic Babesia infection may become symptomatic if a splenectomy is performed.
Diagnosis is based mainly on the microscopic observation of parasites in blood smears (). Serologic and antibody detection by IFA can also be performed and PCR-based tests are available. Many people do not require clinical intervention for Babesia infections, however, serious infections can be cleared with a combination of atovaquone and azithromycin or a combination of clindamycin and quinine.

### Chagas Disease

Also called American trypanosomiasis, Chagas disease is a zoonosis classified as a neglected tropical disease (NTD). It is caused by the flagellated protozoan  and is most commonly transmitted to animals and people through the feces of triatomine bugs. The triatomine bug is nicknamed the kissing bug because it frequently bites humans on the face or around the eyes; the insect often defecates near the bite and the infected fecal matter may be rubbed into the bite wound by the bitten individual (). The bite itself is painless and, initially, many people show no signs of the disease. Alternative modes of transmission include contaminated blood transfusions, organ transplants from infected donors, and congenital transmission from mother to fetus.
Chagas disease is endemic throughout much of Mexico, Central America, and South America, where, according to WHO, an estimated 6 million to 7 million people are infected.World Health Organization. “Chagas disease (American trypanosomiasis). Fact Sheet.” 2016. http://www.who.int/mediacentre/factsheets/fs340/en/. Accessed July 29, 2016. Currently, Chagas disease is not endemic in the US, even though triatomine bugs are found in the southern half of the country.
Triatomine bugs typically are active at night, when they take blood meals by biting the faces and lips of people or animals as they sleep and often defecate near the site of the bite. Infection occurs when the host rubs the feces into their eyes, mouth, the bite wound, or another break in the skin. The protozoan then enters the blood and invades tissues of the heart and central nervous system, as well as macrophages and monocytes. Nonhuman reservoirs of T. cruzi parasites include wild animals and domesticated animals such as dogs and cats, which also act as reservoirs of the pathogen.C.E. Reisenman et al. “Infection of Kissing Bugs With
There are three phases of Chagas disease: acute, intermediate, and chronic. These phases can be either asymptomatic or life-threatening depending on the immunocompetence status of the patient.
In acute phase disease, symptoms include fever, headache, myalgia, rash, vomiting, diarrhea, and enlarged spleen, liver, and lymph nodes. In addition, a localized nodule called a chagoma may form at the portal of entry, and swelling of the eyelids or the side of the face, called Romaña's sign, may occur near the bite wound. Symptoms of the acute phase may resolve spontaneously, but if untreated, the infection can persist in tissues, causing irreversible damage to the heart or brain. In rare cases, young children may die of myocarditis or meningoencephalitis during the acute phase of Chagas disease.
Following the acute phase is a prolonged intermediate phase during which few or no parasites are found in the blood and most people are asymptomatic. Many patients will remain asymptomatic for life; however, decades after exposure, an estimated 20%–30% of infected people will develop chronic disease that can be debilitating and sometimes life threatening. In the chronic phase, patients may develop painful swelling of the colon, leading to severe twisting, constipation, and bowel obstruction; painful swelling of the esophagus, leading to dysphagia and malnutrition; and flaccid cardiomegaly (enlargement of the heart), which can lead to heart failure and sudden death.
Diagnosis can be confirmed through several different tests, including direct microscopic observation of trypanosomes in the blood, IFA, EIAs, PCR, and culturing in artificial media. In endemic regions, xenodiagnoses may be used; this method involves allowing uninfected kissing bugs to feed on the patient and then examining their feces for the presence of T. cruzi.
The medications nifurtimox and benznidazole are effective treatments during the acute phase of Chagas disease. The efficacy of these drugs is much lower when the disease is in the chronic phase. Avoiding exposure to the pathogen through vector control is the most effective method of limiting this disease.

### Leishmaniasis

Although it is classified as an NTD, leishmaniasis is relatively widespread in tropical and subtropical regions, affecting people in more than 90 countries. It is caused by approximately 20 different species of , protozoan parasites that are transmitted by sand fly vectors such as Phlebotomus spp. and Lutzomyia spp. Dogs, cats, sheep, horses, cattle rodents, and humans can all serve as reservoirs.
The Leishmania protozoan is phagocytosed by macrophages but uses virulence factors to avoid destruction within the phagolysosome. The virulence factors inhibit the phagolysosome enzymes that would otherwise destroy the parasite. The parasite reproduces within the macrophage, lyses it, and the progeny infect new macrophages (see Micro Connections: When Phagocytosis Fails).
The three major clinical forms of leishmaniasis are cutaneous (oriental sore, Delhi boil, Aleppo boil), visceral (kala-azar, Dumdum fever), and mucosal (espundia). The most common form of disease is cutaneous leishmaniasis, which is characterized by the formation of sores at the site of the insect bite that may start out as papules or nodules before becoming large ulcers ().
It may take visceral leishmaniasis months and sometimes years to develop, leading to enlargement of the lymph nodes, liver, spleen, and bone marrow. The damage to these body sites triggers fever, weight loss, and swelling of the spleen and liver. It also causes a decrease in the number of red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia), causing the patient to become immunocompromised and more susceptible to fatal infections of the lungs and gastrointestinal tract.
The mucosal form of leishmaniasis is one of the less common forms of the disease. It causes a lesion similar to the cutaneous form but mucosal leishmaniasis is associated with mucous membranes of the mouth, nares, or pharynx, and can be destructive and disfiguring. Mucosal leishmaniasis occurs less frequently when the original cutaneous (skin) infection is promptly treated.
Definitive diagnosis of leishmaniasis is made by visualizing organisms in Giemsa-stained smears, by isolating Leishmania protozoans in cultures, or by PCR-based assays of aspirates from infected tissues. Specific DNA probes or analysis of cultured parasites can help to distinguish Leishmania species that are causing simple cutaneous leishmaniasis from those capable of causing mucosal leishmaniasis.
Cutaneous leishmaniasis is usually not treated. The lesions will resolve after weeks (or several months), but may result in scarring. Recurrence rates are low for this disease. More serious infections can be treated with stibogluconate (antimony gluconate), amphotericin B, and miltefosine.

### Schistosomiasis

Schistosomiasis (bilharzia) is an NTD caused by blood flukes in the genus  that are native to the Caribbean, South America, Middle East, Asia, and Africa. Most human schistosomiasis cases are caused by Schistosoma mansoni, S. haematobium, or S. japonicum. Schistosoma are the only trematodes that invade through the skin; all other trematodes infect by ingestion. WHO estimates that at least 258 million people required preventive treatment for schistosomiasis in 2014.World Health Organization. “Schistosomiasis. Fact Sheet.” 2016. http://www.who.int/mediacentre/factsheets/fs115/en/. Accessed July 29, 2016.
Infected human hosts shed Schistosoma eggs in urine and feces, which can contaminate freshwater habitats of snails that serve as intermediate hosts. The eggs hatch in the water, releasing miracidia, an intermediate growth stage of the Schistosoma that infect the snails. The miracidia mature and multiply inside the snails, transforming into cercariae that leave the snail and enter the water, where they can penetrate the skin of swimmers and bathers. The cercariae migrate through human tissue and enter the bloodstream, where they mature into adult male and female worms that mate and release fertilized eggs. The eggs travel through the bloodstream and penetrate various body sites, including the bladder or intestine, from which they are excreted in urine or stool to start the life cycle over again ().
A few days after infection, patients may develop a rash or itchy skin associated with the site of cercariae penetration. Within 1–2 months of infection, symptoms may develop, including fever, chills, cough, and myalgia, as eggs that are not excreted circulate through the body. After years of infection, the eggs become lodged in tissues and trigger inflammation and scarring that can damage the liver, central nervous system, intestine, spleen, lungs, and bladder. This may cause abdominal pain, enlargement of the liver, blood in the urine or stool, and problems passing urine. Increased risk for bladder cancer is also associated with chronic Schistosoma infection. In addition, children who are repeatedly infected can develop malnutrition, anemia, and learning difficulties.
Diagnosis of schistosomiasis is made by the microscopic observation of eggs in feces or urine, intestine or bladder tissue specimens, or serologic tests. The drug praziquantel is effective for the treatment of all schistosome infections. Improving wastewater management and educating at-risk populations to limit exposure to contaminated water can help control the spread of the disease.

### Cercarial Dermatitis

The cercaria of some species of Schistosoma can only transform into adult worms and complete their life cycle in animal hosts such as migratory birds and mammals. The cercaria of these worms are still capable of penetrating human skin, but they are unable to establish a productive infection in human tissue. Still, the presence of the cercaria in small blood vessels triggers an immune response, resulting in itchy raised bumps called cercarial dermatitis (also known as swimmer’s itch or clam digger's itch). Although it is uncomfortable, cercarial dermatitis is typically self-limiting and rarely serious. Antihistamines and antipruritics can be used to limit inflammation and itching, respectively.

### Key Concepts and Summary

1. Malaria is a protozoan parasite that remains an important cause of death primarily in the tropics. Several species in the genus Plasmodium are responsible for malaria and all are transmitted by Anopheles mosquitoes. Plasmodium infects and destroys human red blood cells, leading to organ damage, anemia, blood vessel necrosis, and death. Malaria can be treated with various antimalarial drugs and prevented through vector control.
2. Toxoplasmosis is a widespread protozoal infection that can cause serious infections in the immunocompromised and in developing fetuses. Domestic cats are the definitive host.
3. Babesiosis is a generally asymptomatic infection of red blood cells that can causes malaria-like symptoms in elderly, immunocompromised, or asplenic patients.
4. Chagas disease is a tropical disease transmitted by triatomine bugs. The trypanosome infects heart, neural tissues, monocytes, and phagocytes, often remaining latent for many years before causing serious and sometimes fatal damage to the digestive system and heart.
5. Leishmaniasis is caused by the protozoan Leishmania and is transmitted by sand flies. Symptoms are generally mild, but serious cases may cause organ damage, anemia, and loss of immune competence.
6. Schistosomiasis is caused by a fluke transmitted by snails. The fluke moves throughout the body in the blood stream and chronically infects various tissues, leading to organ damage.

### Multiple Choice

### Fill in the Blank

### Short Answer

### Critical Thinking


# Nervous System Infections

## Introduction

Few diseases inspire the kind of fear that rabies does. The name is derived from the Latin word for “madness” or “fury,” most likely because animals infected with rabies may behave with uncharacteristic rage and aggression. And while the thought of being attacked by a rabid animal is terrifying enough, the disease itself is even more frightful. Once symptoms appear, the disease is almost always fatal, even when treated.
Rabies is an example of a neurological disease caused by an acellular pathogen. The rabies virus enters nervous tissue shortly after transmission and makes its way to the central nervous system, where its presence leads to changes in behavior and motor function. Well-known symptoms associated with rabid animals include foaming at the mouth, hydrophobia (fear of water), and unusually aggressive behavior. Rabies claims tens of thousands of human lives worldwide, mainly in Africa and Asia. Most human cases result from dog bites, although many mammal species can become infected and transmit the disease. Human infection rates are low in the United States and many other countries as a result of control measures in animal populations. However, rabies is not the only disease with serious or fatal neurological effects. In this chapter, we examine the important microbial diseases of the nervous system.


# Nervous System Infections

## Anatomy of the Nervous System

### Learning Objectives

By the end of this section, you will be able to:
1. Describe the major anatomical features of the nervous system
2. Explain why there is no normal microbiota of the nervous system
3. Explain how microorganisms overcome defenses of the nervous system to cause infection
4. Identify and describe general symptoms associated with various infections of the nervous system
The human nervous system can be divided into two interacting subsystems: the peripheral nervous system (PNS) and the central nervous system (CNS). The CNS consists of the brain and spinal cord. The peripheral nervous system is an extensive network of nerves connecting the CNS to the muscles and sensory structures. The relationship of these systems is illustrated in .

### The Central Nervous System

The brain is the most complex and sensitive organ in the body. It is responsible for all functions of the body, including serving as the coordinating center for all sensations, mobility, emotions, and intellect. Protection for the brain is provided by the bones of the skull, which in turn are covered by the scalp, as shown in . The scalp is composed of an outer layer of skin, which is loosely attached to the aponeurosis, a flat, broad tendon layer that anchors the superficial layers of the skin. The periosteum, below the aponeurosis, firmly encases the bones of the skull and provides protection, nutrition to the bone, and the capacity for bone repair. Below the boney layer of the skull are three layers of membranes called meninges that surround the brain. The relative positions of these meninges are shown in . The meningeal layer closest to the bones of the skull is called the dura mater (literally meaning tough mother). Below the dura mater lies the arachnoid mater (literally spider-like mother). The innermost meningeal layer is a delicate membrane called the pia mater (literally tender mother). Unlike the other meningeal layers, the pia mater firmly adheres to the convoluted surface of the brain. Between the arachnoid mater and pia mater is the subarachnoid space. The subarachnoid space within this region is filled with cerebrospinal fluid (CSF). This watery fluid is produced by cells of the choroid plexus—areas in each ventricle of the brain that consist of cuboidal epithelial cells surrounding dense capillary beds. The CSF serves to deliver nutrients and remove waste from neural tissues.

### The Blood-Brain Barrier

The tissues of the CNS have extra protection in that they are not exposed to blood or the immune system in the same way as other tissues. The blood vessels that supply the brain with nutrients and other chemical substances lie on top of the pia mater. The capillaries associated with these blood vessels in the brain are less permeable than those in other locations in the body. The capillary endothelial cells form tight junctions that control the transfer of blood components to the brain. In addition, cranial capillaries have far fewer fenestra (pore-like structures that are sealed by a membrane) and pinocytotic vesicles than other capillaries. As a result, materials in the circulatory system have a very limited ability to interact with the CNS directly. This phenomenon is referred to as the blood-brain barrier.
The blood-brain barrier protects the cerebrospinal fluid from contamination, and can be quite effective at excluding potential microbial pathogens. As a consequence of these defenses, there is no normal microbiota in the cerebrospinal fluid. The blood-brain barrier also inhibits the movement of many drugs into the brain, particularly compounds that are not lipid soluble. This has profound ramifications for treatments involving infections of the CNS, because it is difficult for drugs to cross the blood-brain barrier to interact with pathogens that cause infections.
The spinal cord also has protective structures similar to those surrounding the brain. Within the bones of the vertebrae are meninges of dura mater (sometimes called the dural sheath), arachnoid mater, pia mater, and a blood-spinal cord barrier that controls the transfer of blood components from blood vessels associated with the spinal cord.
To cause an infection in the CNS, pathogens must successfully breach the blood-brain barrier or blood-spinal cord barrier. Various pathogens employ different virulence factors and mechanisms to achieve this, but they can generally be grouped into four categories: intercellular (also called paracellular), transcellular, leukocyte facilitated, and nonhematogenous. Intercellular entry involves the use of microbial virulence factors, toxins, or inflammation-mediated processes to pass between the cells of the blood-brain barrier. In transcellular entry, the pathogen passes through the cells of the blood-brain barrier using virulence factors that allow it to adhere to and trigger uptake by vacuole- or receptor-mediated mechanisms. Leukocyte-facilitated entry is a Trojan-horse mechanism that occurs when a pathogen infects peripheral blood leukocytes to directly enter the CNS. Nonhematogenous entry allows pathogens to enter the brain without encountering the blood-brain barrier; it occurs when pathogens travel along either the olfactory or trigeminal cranial nerves that lead directly into the CNS.

### The Peripheral Nervous System

The PNS is formed of the nerves that connect organs, limbs, and other anatomic structures of the body to the brain and spinal cord. Unlike the brain and spinal cord, the PNS is not protected by bone, meninges, or a blood barrier, and, as a consequence, the nerves of the PNS are much more susceptible to injury and infection. Microbial damage to peripheral nerves can lead to tingling or numbness known as neuropathy. These symptoms can also be produced by trauma and noninfectious causes such as drugs or chronic diseases like diabetes.

### The Cells of the Nervous System

Tissues of the PNS and CNS are formed of cells called glial cells (neuroglial cells) and neurons (nerve cells). Glial cells assist in the organization of neurons, provide a scaffold for some aspects of neuronal function, and aid in recovery from neural injury.
Neurons are specialized cells found throughout the nervous system that transmit signals through the nervous system using electrochemical processes. The basic structure of a neuron is shown in . The cell body (or soma) is the metabolic center of the neuron and contains the nucleus and most of the cell’s organelles. The many finely branched extensions from the soma are called dendrites. The soma also produces an elongated extension, called the axon, which is responsible for the transmission of electrochemical signals through elaborate ion transport processes. Axons of some types of neurons can extend up to one meter in length in the human body. To facilitate electrochemical signal transmission, some neurons have a myelin sheath surrounding the axon. Myelin, formed from the cell membranes of glial cells like the Schwann cells in the PNS and oligodendrocytes in the CNS, surrounds and insulates the axon, significantly increasing the speed of electrochemical signal transmission along the axon. The end of an axon forms numerous branches that end in bulbs called synaptic terminals. Neurons form junctions with other cells, such as another neuron, with which they exchange signals. The junctions, which are actually gaps between neurons, are referred to as synapses. At each synapse, there is a presynaptic neuron and a postsynaptic neuron (or other cell). The synaptic terminals of the axon of the presynaptic terminal form the synapse with the dendrites, soma, or sometimes the axon of the postsynaptic neuron, or a part of another type of cell such as a muscle cell. The synaptic terminals contain vesicles filled with chemicals called neurotransmitters. When the electrochemical signal moving down the axon reaches the synapse, the vesicles fuse with the membrane, and neurotransmitters are released, which diffuse across the synapse and bind to receptors on the membrane of the postsynaptic cell, potentially initiating a response in that cell. That response in the postsynaptic cell might include further propagation of an electrochemical signal to transmit information or contraction of a muscle fiber.

### Meningitis and Encephalitis

Although the skull provides the brain with an excellent defense, it can also become problematic during infections. Any swelling of the brain or meninges that results from inflammation can cause intracranial pressure, leading to severe damage of the brain tissues, which have limited space to expand within the inflexible bones of the skull. The term meningitis is used to describe an inflammation of the meninges. Typical symptoms can include severe headache, fever, photophobia (increased sensitivity to light), stiff neck, convulsions, and confusion. An inflammation of brain tissue is called encephalitis, and patients exhibit signs and symptoms similar to those of meningitis in addition to lethargy, seizures, and personality changes. When inflammation affects both the meninges and the brain tissue, the condition is called meningoencephalitis. All three forms of inflammation are serious and can lead to blindness, deafness, coma, and death.
Meningitis and encephalitis can be caused by many different types of microbial pathogens. However, these conditions can also arise from noninfectious causes such as head trauma, some cancers, and certain drugs that trigger inflammation. To determine whether the inflammation is caused by a pathogen, a lumbar puncture is performed to obtain a sample of CSF. If the CSF contains increased levels of white blood cells and abnormal glucose and protein levels, this indicates that the inflammation is a response to an infectioninflinin.

### Key Concepts and Summary

1. The nervous system consists of two subsystems: the central nervous system and peripheral nervous system.
2. The skull and three meninges (the dura mater, arachnoid mater, and pia mater) protect the brain.
3. Tissues of the PNS and CNS are formed of cells called glial cells and neurons.
4. Since the blood-brain barrier excludes most microbes, there is no normal microbiota in the CNS.
5. Some pathogens have specific virulence factors that allow them to breach the blood-brain barrier. Inflammation of the brain or meninges caused by infection is called encephalitis or meningitis, respectively. These conditions can lead to blindness, deafness, coma, and death.

### Multiple Choice

### Matching

### Fill in the Blank

### Short Answer

### Critical Thinking


# Nervous System Infections

## Bacterial Diseases of the Nervous System

### Learning Objectives

By the end of this section, you will be able to:
1. Identify the most common bacteria that can cause infections of the nervous system
2. Compare the major characteristics of specific bacterial diseases affecting the nervous system
Bacterial infections that affect the nervous system are serious and can be life-threatening. Fortunately, there are only a few bacterial species commonly associated with neurological infections.

### Bacterial Meningitis

Bacterial meningitis is one of the most serious forms of meningitis. Bacteria that cause meningitis often gain access to the CNS through the bloodstream after trauma or as a result of the action of bacterial toxins. Bacteria may also spread from structures in the upper respiratory tract, such as the oropharynx, nasopharynx, sinuses, and middle ear. Patients with head wounds or cochlear implants (an electronic device placed in the inner ear) are also at risk for developing meningitis.
Many of the bacteria that can cause meningitis are commonly found in healthy people. The most common causes of non-neonatal bacterial meningitis are , , and . All three of these bacterial pathogens are spread from person to person by respiratory secretions. Each can colonize and cross through the mucous membranes of the oropharynx and nasopharynx, and enter the blood. Once in the blood, these pathogens can disseminate throughout the body and are capable of both establishing an infection and triggering inflammation in any body site, including the meninges (). Without appropriate systemic antibacterial therapy, the case-fatality rate can be as high as 70%, and 20% of those survivors may be left with irreversible nerve damage or tissue destruction, resulting in hearing loss, neurologic disability, or loss of a limb. Mortality rates are much lower (as low as 15%) in populations where appropriate therapeutic drugs and preventive vaccines are available.Thigpen, Michael C., Cynthia G. Whitney, Nancy E. Messonnier, Elizabeth R. Zell, Ruth Lynfield, James L. Hadler, Lee H. Harrison et al., “Bacterial Meningitis in the United States, 1998–2007,”
A variety of other bacteria, including  and , are also capable of causing meningitis. These bacteria cause infections of the arachnoid mater and CSF after spreading through the circulation in blood or by spreading from an infection of the sinuses or nasopharynx. , commonly found in the microbiota of the vagina and gastrointestinal tract, can also cause bacterial meningitis in newborns after transmission from the mother either before or during birth.
The profound inflammation caused by these microbes can result in early symptoms that include severe headache, fever, confusion, nausea, vomiting, photophobia, and stiff neck. Systemic inflammatory responses associated with some types of bacterial meningitis can lead to hemorrhaging and purpuric lesions on skin, followed by even more severe conditions that include shock, convulsions, coma, and death—in some cases, in the span of just a few hours.
Diagnosis of bacterial meningitis is best confirmed by analysis of CSF obtained by a lumbar puncture. Abnormal levels of polymorphonuclear neutrophils (PMNs) (> 10 PMNs/mm3), glucose (< 45 mg/dL), and protein (> 45 mg/dL) in the CSF are suggestive of bacterial meningitis.Popovic, T., et al. World Health Organization, “Laboratory Manual for the Diagnosis of Meningitis Caused by  Characteristics of specific forms of bacterial meningitis are detailed in the subsections that follow.

### Meningococcal Meningitis

Meningococcal meningitis is a serious infection caused by the gram-negative coccus N. meningitidis. In some cases, death can occur within a few hours of the onset of symptoms. Nonfatal cases can result in irreversible nerve damage, resulting in hearing loss and brain damage, or amputation of extremities because of tissue necrosis.
Meningococcal meningitis can infect people of any age, but its prevalence is highest among infants, adolescents, and young adults.US Centers for Disease Control and Prevention, “Meningococcal Disease,” August 5, 2015. Accessed June 28, 2015. http://www.cdc.gov/meningococcal/surveillance/index.html. Meningococcal meningitis was once the most common cause of meningitis epidemics in human populations. This is still the case in a swath of sub-Saharan Africa known as the meningitis belt, but meningococcal meningitis epidemics have become rare in most other regions, thanks to meningococcal vaccines. However, outbreaks can still occur in communities, schools, colleges, prisons, and other populations where people are in close direct contact.
N. meningitidis has a high affinity for mucosal membranes in the oropharynx and nasopharynx. Contact with respiratory secretions containing N. meningitidis is an effective mode of transmission. The pathogenicity of N. meningitidis is enhanced by virulence factors that contribute to the rapid progression of the disease. These include lipooligosaccharide (LOS) endotoxin, type IV pili for attachment to host tissues, and polysaccharide capsules that help the cells avoid phagocytosis and complement-mediated killing. Additional virulence factors include IgA protease (which breaks down IgA antibodies), the invasion factors Opa, Opc, and porin (which facilitate transcellular entry through the blood-brain barrier), iron-uptake factors (which strip heme units from hemoglobin in host cells and use them for growth), and stress proteins that protect bacteria from reactive oxygen molecules.
A unique sign of meningococcal meningitis is the formation of a petechial rash on the skin or mucous membranes, characterized by tiny, red, flat, hemorrhagic lesions. This rash, which appears soon after disease onset, is a response to LOS endotoxin and adherence virulence factors that disrupt the endothelial cells of capillaries and small veins in the skin. The blood vessel disruption triggers the formation of tiny blood clots, causing blood to leak into the surrounding tissue. As the infection progresses, the levels of virulence factors increase, and the hemorrhagic lesions can increase in size as blood continues to leak into tissues. Lesions larger than 1.0 cm usually occur in patients developing shock, as virulence factors cause increased hemorrhage and clot formation. Sepsis, as a result of systemic damage from meningococcal virulence factors, can lead to rapid multiple organ failure, shock, disseminated intravascular coagulation, and death.
Because meningococcoal meningitis progresses so rapidly, a greater variety of clinical specimens are required for the timely detection of N. meningitidis. Required specimens can include blood, CSF, naso- and oropharyngeal swabs, urethral and endocervical swabs, petechial aspirates, and biopsies. Safety protocols for handling and transport of specimens suspected of containing N. meningitidis should always be followed, since cases of fatal meningococcal disease have occurred in healthcare workers exposed to droplets or aerosols from patient specimens. Prompt presumptive diagnosis of meningococcal meningitis can occur when CSF is directly evaluated by Gram stain, revealing extra- and intracellular gram-negative diplococci with a distinctive coffee-bean microscopic morphology associated with PMNs (). Identification can also be made directly from CSF using latex agglutination and immunochromatographic rapid diagnostic tests specific for N. meningitidis. Species identification can also be performed using DNA sequence-based typing schemes for hypervariable outer membrane proteins of N. meningitidis, which has replaced sero(sub)typing.
Meningococcal infections can be treated with antibiotic therapy, and third-generation cephalosporins are most often employed. However, because outcomes can be negative even with treatment, preventive vaccination is the best form of treatment. In 2010, countries in Africa’s meningitis belt began using a new serogroup A meningococcal conjugate vaccine. This program has dramatically reduced the number of cases of meningococcal meningitis by conferring individual and herd immunity.
Twelve different capsular serotypes of N. meningitidis are known to exist. Serotypes A, B, C, W, X, and Y are the most prevalent worldwide. The CDC recommends that children between 11–12 years of age be vaccinated with a single dose of a quadrivalent vaccine that protects against serotypes A, C, W, and Y, with a booster at age 16.US Centers for Disease Control and Prevention, “Recommended Immunization Schedule for Persons Aged 0 Through 18 Years, United States, 2016,” February 1, 2016. Accessed on June 28, 2016. http://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html. An additional booster or injections of serogroup B meningococcal vaccine may be given to individuals in high-risk settings (such as epidemic outbreaks on college campuses).

### Pneumococcal Meningitis

Pneumococcal meningitis is caused by the encapsulated gram-positive bacterium S. pneumoniae (pneumococcus, also called strep pneumo). This organism is commonly found in the microbiota of the pharynx of 30–70% of young children, depending on the sampling method, while S. pneumoniae can be found in fewer than 5% of healthy adults. Although it is often present without disease symptoms, this microbe can cross the blood-brain barrier in susceptible individuals. In some cases, it may also result in septicemia. Since the introduction of the Hib vaccine, S. pneumoniae has become the leading cause of meningitis in humans aged 2 months through adulthood.
S. pneumoniae can be identified in CSF samples using gram-stained specimens, latex agglutination, and immunochromatographic RDT specific for S. pneumoniae. In gram-stained samples, S. pneumoniae appears as gram-positive, lancet-shaped diplococci (). Identification of S. pneumoniae can also be achieved using cultures of CSF and blood, and at least 93 distinct serotypes can be identified based on the quellung reaction to unique capsular polysaccharides. PCR and RT-PCR assays are also available to confirm identification.
Major virulence factors produced by S. pneumoniae include PI-1 pilin for adherence to host cells (pneumococcal adherence) and virulence factor B (PavB) for attachment to cells of the respiratory tract; choline-binding proteins (cbpA) that bind to epithelial cells and interfere with immune factors IgA and C3; and the cytoplasmic bacterial toxin pneumolysin that triggers an inflammatory response.
With the emergence of drug-resistant strains of S. pneumoniae, pneumococcal meningitis is typically treated with broad-spectrum antibiotics, such as levofloxacin, cefotaxime, penicillin, or other β-lactam antibiotics. The two available pneumococcal vaccines are described in Bacterial Infections of the Respiratory Tract.

### Haemophilus influenzae Type b

Meningitis due to  (Hib), an encapsulated pleomorphic gram-negative coccobacilli, is now uncommon in most countries, because of the use of the effective Hib vaccine. Without the use of the Hib vaccine, H. influenzae can be the primary cause of meningitis in children 2 months thru 5 years of age. H. influenzae can be found in the throats of healthy individuals, including infants and young children. By five years of age, most children have developed immunity to this microbe. Infants older than 2 months of age, however, do not produce a sufficient protective antibody response and are susceptible to serious disease. The intracranial pressure caused by this infection leads to a 5% mortality rate and 20% incidence of deafness or brain damage in survivors.United States Department of Health and Human Services, “Hib (Haemophilus Influenzae Type B),” Accessed June 28, 2016. http://www.vaccines.gov/diseases/hib/#.
H. influenzae produces at least 16 different virulence factors, including LOS, which triggers inflammation, and Haemophilus adhesion and penetration factor (Hap), which aids in attachment and invasion into respiratory epithelial cells. The bacterium also has a polysaccharide capsule that helps it avoid phagocytosis, as well as factors such as IgA1 protease and P2 protein that allow it to evade antibodies secreted from mucous membranes. In addition, factors such as hemoglobin-binding protein (Hgp) and transferrin-binding protein (Tbp) acquire iron from hemoglobin and transferrin, respectively, for bacterial growth.
Preliminary diagnosis of H. influenzae infections can be made by direct PCR and a smear of CSF. Stained smears will reveal intracellular and extracellular PMNs with small, pleomorphic, gram-negative coccobacilli or filamentous forms that are characteristic of H. influenzae. Initial confirmation of this genus can be based on its fastidious growth on chocolate agar. Identification is confirmed with requirements for exogenous biochemical growth cofactors NAD and heme (by MALDI-TOF), latex agglutination, and RT-PCR.
Meningitis caused by H. influenzae is usually treated with doxycycline, fluoroquinolones, second- and third-generation cephalosporins, and carbapenems. The best means of preventing H. influenza infection is with the use of the Hib polysaccharide conjugate vaccine. It is recommended that all children receive this vaccine at 2, 4, and 6 months of age, with a final booster dose at 12 to 15 months of age.US Centers for Disease Control and Prevention, “Meningococcal Disease, Disease Trends,” 2015. Accessed September 13, 2016. http://www.cdc.gov/meningococcal/surveillance/index.html.

### Neonatal Meningitis

S. agalactiae, Group B streptococcus (GBS), is an encapsulated gram-positive bacterium that is the most common cause of neonatal meningitis, a term that refers to meningitis occurring in babies up to 3 months of age.Thigpen, Michael C., Cynthia G. Whitney, Nancy E. Messonnier, Elizabeth R. Zell, Ruth Lynfield, James L. Hadler, Lee H. Harrison et al., “Bacterial Meningitis in the United States, 1998–2007,”  S. agalactiae can also cause meningitis in people of all ages and can be found in the urogenital and gastrointestinal microbiota of about 10–30% of humans.
Neonatal infection occurs as either early onset or late-onset disease. Early onset disease is defined as occurring in infants up to 7 days old. The infant initially becomes infected by S. agalactiae during childbirth, when the bacteria may be transferred from the mother’s vagina. Incidence of early onset neonatal meningitis can be greatly reduced by giving intravenous antibiotics to the mother during labor.
Late-onset neonatal meningitis occurs in infants between 1 week and 3 months of age. Infants born to mothers with S. agalactiae in the urogenital tract have a higher risk of late-onset menigitis, but late-onset infections can be transmitted from sources other than the mother; often, the source of infection is unknown. Infants who are born prematurely (before 37 weeks of pregnancy) or to mothers who develop a fever also have a greater risk of contracting late-onset neonatal meningitis.
Signs and symptoms of early onset disease include temperature instability, apnea (cessation of breathing), bradycardia (slow heart rate), hypotension, difficulty feeding, irritability, and limpness. When asleep, the baby may be difficult to wake up. Symptoms of late-onset disease are more likely to include seizures, bulging fontanel (soft spot), stiff neck, hemiparesis (weakness on one side of the body), and opisthotonos (rigid body with arched back and head thrown backward).
S. agalactiae produces at least 12 virulence factors that include FbsA that attaches to host cell surface proteins, PI-1 pili that promotes the invasion of human endothelial cells, a polysaccharide capsule that prevents the activation of the alternative complement pathway and inhibits phagocytosis, and the toxin CAMP factor, which forms pores in host cell membranes and binds to IgG and IgM antibodies.
Diagnosis of neonatal meningitis is often, but not uniformly, confirmed by positive results from cultures of CSF or blood. Tests include routine culture, antigen detection by enzyme immunoassay, serotyping of different capsule types, PCR, and RT-PCR. It is typically treated with β-lactam antibiotics such as intravenous penicillin or ampicillin plus gentamicin. Even with treatment, roughly 10% mortality is seen in infected neonates.Thigpen, Michael C., Cynthia G. Whitney, Nancy E. Messonnier, Elizabeth R. Zell, Ruth Lynfield, James L. Hadler, Lee H. Harrison et al., “Bacterial Meningitis in the United States, 1998–2007,”

### Clostridium-Associated Diseases

Species in the genus  are gram-positive, endospore-forming rods that are obligate anaerobes. Endospores of Clostridium spp. are widespread in nature, commonly found in soil, water, feces, sewage, and marine sediments. Clostridium spp. produce more types of protein exotoxins than any other bacterial genus, including two exotoxins with protease activity that are the most potent known biological toxins: botulinum neurotoxin (BoNT) and tetanus neurotoxin (TeNT). These two toxins have lethal doses of 0.2–10 ng per kg body weight.
BoNT can be produced by unique strains of C. butyricum, and C. baratii; however, it is primarily associated with C. botulinum and the condition of botulism. TeNT, which causes tetanus, is only produced by C. tetani. These powerful neural exotoxins are the primary virulence factors for these pathogens. The mode of action for these toxins was described in Virulence Factors of Bacterial and Viral Pathogens and illustrated in .
Diagnosis of tetanus or botulism typically involves bioassays that detect the presence of BoNT and TeNT in fecal specimens, blood (serum), or suspect foods. In addition, both C. botulinum and C. tetani can be isolated and cultured using commercially available media for anaerobes. ELISA and RT-PCR tests are also available.

### Tetanus

Tetanus is a noncommunicable disease characterized by uncontrollable muscle spasms (contractions) caused by the action of TeNT. It generally occurs when C. tetani infects a wound and produces TeNT, which rapidly binds to neural tissue, resulting in an intoxication (poisoning) of neurons. Depending on the site and extent of infection, cases of tetanus can be described as localized, cephalic, or generalized. Generalized tetanus that occurs in a newborn is called neonatal tetanus.
Localized tetanus occurs when TeNT only affects the muscle groups close to the injury site. There is no CNS involvement, and the symptoms are usually mild, with localized muscle spasms caused by a dysfunction in the surrounding neurons. Individuals with partial immunity—especially previously vaccinated individuals who neglect to get the recommended booster shots—are most likely to develop localized tetanus as a result of C. tetani infecting a puncture wound.
Cephalic tetanus is a rare, localized form of tetanus generally associated with wounds on the head or face. In rare cases, it has occurred in cases of otitis media (middle ear infection). Cephalic tetanus often results in patients seeing double images, because of the spasms affecting the muscles that control eye movement.
Both localized and cephalic tetanus may progress to generalized tetanus—a much more serious condition—if TeNT is able to spread further into body tissues. In generalized tetanus, TeNT enters neurons of the PNS. From there, TeNT travels from the site of the wound, usually on an extremity of the body, retrograde (back up) to inhibitory neurons in the CNS. There, it prevents the release of gamma aminobutyric acid (GABA), the neurotransmitter responsible for muscle relaxation. The resulting muscle spasms often first occur in the jaw muscles, leading to the characteristic symptom of lockjaw (inability to open the mouth). As the toxin progressively continues to block neurotransmitter release, other muscles become involved, resulting in uncontrollable, sudden muscle spasms that are powerful enough to cause tendons to rupture and bones to fracture. Spasms in the muscles in the neck, back, and legs may cause the body to form a rigid, stiff arch, a posture called opisthotonos (). Spasms in the larynx, diaphragm, and muscles of the chest restrict the patient’s ability to swallow and breathe, eventually leading to death by asphyxiation (insufficient supply of oxygen).
Neonatal tetanus typically occurs when the stump of the umbilical cord is contaminated with spores of C. tetani after delivery. Although this condition is rare in the United States, neonatal tetanus is a major cause of infant mortality in countries that lack maternal immunization for tetanus and where birth often occurs in unsanitary conditions. At the end of the first week of life, infected infants become irritable, feed poorly, and develop rigidity with spasms. Neonatal tetanus has a very poor prognosis with a mortality rate of 70%–100%.UNFPA, UNICEF WHO, “Maternal and Neonatal Tetanus Elimination by 2005,” 2000. http://www.unicef.org/immunization/files/MNTE_strategy_paper.pdf.
Treatment for patients with tetanus includes assisted breathing through the use of a ventilator, wound debridement, fluid balance, and antibiotic therapy with metronidazole or penicillin to halt the growth of C. tetani. In addition, patients are treated with TeNT antitoxin, preferably in the form of human immunoglobulin to neutralize nonfixed toxin and benzodiazepines to enhance the effect of GABA for muscle relaxation and anxiety.
A tetanus toxoid (TT) vaccine is available for protection and prevention of tetanus. It is the T component of vaccines such as DTaP, Tdap, and Td. The CDC recommends children receive doses of the DTaP vaccine at 2, 4, 6, and 15–18 months of age and another at 4–6 years of age. One dose of Td is recommended for adolescents and adults as a TT booster every 10 years.US Centers for Disease Control and Prevention, “Tetanus Vaccination,” 2013. Accessed June 29, 2016. http://www.cdc.gov/tetanus/vaccination.html.

### Botulism

Botulism is a rare but frequently fatal illness caused by intoxication by BoNT. It can occur either as the result of an infection by C. botulinum, in which case the bacteria produce BoNT in vivo, or as the result of a direct introduction of BoNT into tissues.
Infection and production of BoNT in vivo can result in wound botulism, infant botulism, and adult intestinal toxemia. Wound botulism typically occurs when C. botulinum is introduced directly into a wound after a traumatic injury, deep puncture wound, or injection site. Infant botulism, which occurs in infants younger than 1 year of age, and adult intestinal toxemia, which occurs in immunocompromised adults, results from ingesting C. botulinum endospores in food. The endospores germinate in the body, resulting in the production of BoNT in the intestinal tract.
Intoxications occur when BoNT is produced outside the body and then introduced directly into the body through food (foodborne botulism), air (inhalation botulism), or a clinical procedure (iatrogenic botulism). Foodborne botulism, the most common of these forms, occurs when BoNT is produced in contaminated food and then ingested along with the food (recall Case in Point: A Streak of Bad Potluck). Inhalation botulism is rare because BoNT is unstable as an aerosol and does not occur in nature; however, it can be produced in the laboratory and was used (unsuccessfully) as a bioweapon by terrorists in Japan in the 1990s. A few cases of accidental inhalation botulism have also occurred. Iatrogenic botulism is also rare; it is associated with injections of BoNT used for cosmetic purposes (see Micro Connections: Medicinal Uses of Botulinum Toxin).
When BoNT enters the bloodstream in the gastrointestinal tract, wound, or lungs, it is transferred to the neuromuscular junctions of motor neurons where it binds irreversibly to presynaptic membranes and prevents the release of acetylcholine from the presynaptic terminal of motor neurons into the neuromuscular junction. The consequence of preventing acetylcholine release is the loss of muscle activity, leading to muscle relaxation and eventually paralysis.
If BoNT is absorbed through the gastrointestinal tract, early symptoms of botulism include blurred vision, drooping eyelids, difficulty swallowing, abdominal cramps, nausea, vomiting, constipation, or possibly diarrhea. This is followed by progressive flaccid paralysis, a gradual weakening and loss of control over the muscles. A patient’s experience can be particularly terrifying, because hearing remains normal, consciousness is not lost, and he or she is fully aware of the progression of his or her condition. In infants, notable signs of botulism include weak cry, decreased ability to suckle, and hypotonia (limpness of head or body). Eventually, botulism ends in death from respiratory failure caused by the progressive paralysis of the muscles of the upper airway, diaphragm, and chest.
Botulism is treated with an antitoxin specific for BoNT. If administered in time, the antitoxin stops the progression of paralysis but does not reverse it. Once the antitoxin has been administered, the patient will slowly regain neurological function, but this may take several weeks or months, depending on the severity of the case. During recovery, patients generally must remain hospitalized and receive breathing assistance through a ventilator.

### Listeriosis

 is a nonencapsulated, nonsporulating, gram-positive rod and a foodborne pathogen that causes listeriosis. At-risk groups include pregnant women, neonates, the elderly, and the immunocompromised (recall the Clinical Focus case studies in Microbial Growth and Microbial Mechanisms of Pathogenicity). Listeriosis leads to meningitis in about 20% of cases, particularly neonates and patients over the age of 60. The CDC identifies listeriosis as the third leading cause of death due to foodborne illness, with overall mortality rates reaching 16%.Scallan, Elaine, Robert M. Hoekstra, Frederick J. Angulo, Robert V. Tauxe, Marc-Alain Widdowson, Sharon L. Roy, Jeffery L. Jones, and Patricia M. Griffin, “Foodborne Illness Acquired in the United States—Major Pathogens,”  In pregnant women, listeriosis can cause also cause spontaneous abortion in pregnant women because of the pathogen’s unique ability to cross the placenta.
L. monocytogenes is generally introduced into food items by contamination with soil or animal manure used as fertilizer. Foods commonly associated with listeriosis include fresh fruits and vegetables, frozen vegetables, processed meats, soft cheeses, and raw milk.US Centers for Disease Control and Prevention, “ Unlike most other foodborne pathogens, Listeria is able to grow at temperatures between 0 °C and 50 °C, and can therefore continue to grow, even in refrigerated foods.
Ingestion of contaminated food leads initially to infection of the gastrointestinal tract. However, L. monocytogenes produces several unique virulence factors that allow it to cross the intestinal barrier and spread to other body systems. Surface proteins called internalins (InlA and InlB) help L. monocytogenes invade nonphagocytic cells and tissues, penetrating the intestinal wall and becoming disseminating through the circulatory and lymphatic systems. Internalins also enable L. monocytogenes to breach other important barriers, including the blood-brain barrier and the placenta. Within tissues, L. monocytogenes uses other proteins called listeriolysin O and ActA to facilitate intercellular movement, allowing the infection to spread from cell to cell ().
L. monocytogenes is usually identified by cultivation of samples from a normally sterile site (e.g., blood or CSF). Recovery of viable organisms can be enhanced using cold enrichment by incubating samples in a broth at 4 °C for a week or more. Distinguishing types and subtypes of L. monocytogenes—an important step for diagnosis and epidemiology—is typically done using pulsed-field gel electrophoresis. Identification can also be achieved using chemiluminescence DNA probe assays and MALDI-TOF.
Treatment for listeriosis involves antibiotic therapy, most commonly with ampicillin and gentamicin. There is no vaccine available.

### Hansen’s Disease (Leprosy)

Hansen’s disease (also known as leprosy) is caused by a long, thin, filamentous rod-shaped bacterium , an obligate intracellular pathogen. M. leprae is classified as gram-positive bacteria, but it is best visualized microscopically with an acid-fast stain and is generally referred to as an acid-fast bacterium. Hansen’s disease affects the PNS, leading to permanent damage and loss of appendages or other body parts.
Hansen’s disease is communicable but not highly contagious; approximately 95% of the human population cannot be easily infected because they have a natural immunity to M. leprae. Person-to-person transmission occurs by inhalation into nasal mucosa or prolonged and repeated contact with infected skin. Armadillos, one of only five mammals susceptible to Hansen’s disease, have also been implicated in transmission of some cases.Sharma, Rahul, Pushpendra Singh, W. J. Loughry, J. Mitchell Lockhart, W. Barry Inman, Malcolm S. Duthie, Maria T. Pena et al., “Zoonotic Leprosy in the Southeastern United States,”
In the human body, M. leprae grows best at the cooler temperatures found in peripheral tissues like the nose, toes, fingers, and ears. Some of the virulence factors that contribute to M. leprae’s pathogenicity are located on the capsule and cell wall of the bacterium. These virulence factors enable it to bind to and invade Schwann cells, resulting in progressive demyelination that gradually destroys neurons of the PNS. The loss of neuronal function leads to hypoesthesia (numbness) in infected lesions. M. leprae is readily phagocytized by macrophages but is able to survive within macrophages in part by neutralizing reactive oxygen species produced in the oxidative burst of the phagolysosome. Like L. monocytogenes, M. leprae also can move directly between macrophages to avoid clearance by immune factors.
The extent of the disease is related to the immune response of the patient. Initial symptoms may not appear for as long as 2 to 5 years after infection. These often begin with small, blanched, numb areas of the skin. In most individuals, these will resolve spontaneously, but some cases may progress to a more serious form of the disease. Tuberculoid (paucibacillary) Hansen’s disease is marked by the presence of relatively few (three or less) flat, blanched skin lesions with small nodules at the edges and few bacteria present in the lesion. Although these lesions can persist for years or decades, the bacteria are held in check by an effective immune response including cell-mediated cytotoxicity. Individuals who are unable to contain the infection may later develop lepromatous (multibacillary) Hansen’s disease. This is a progressive form of the disease characterized by nodules filled with acid-fast bacilli and macrophages. Impaired function of infected Schwann cells leads to peripheral nerve damage, resulting in sensory loss that leads to ulcers, deformities, and fractures. Damage to the ulnar nerve (in the wrist) by M. leprae is one of the most common causes of crippling of the hand. In some cases, chronic tissue damage can ultimately lead to loss of fingers or toes. When mucosal tissues are also involved, disfiguring lesions of the nose and face can also occur ().
Hansen’s disease is diagnosed on the basis of clinical signs and symptoms of the disease, and confirmed by the presence of acid-fast bacilli on skin smears or in skin biopsy specimens (). M. leprae does not grow in vitro on any known laboratory media, but it can be identified by culturing in vivo in the footpads of laboratory mice or armadillos. Where needed, PCR and genotyping of M. leprae DNA in infected human tissue may be performed for diagnosis and epidemiology.
Hansen’s disease responds well to treatment and, if diagnosed and treated early, does not cause disability. In the United States, most patients with Hansen’s disease are treated in ambulatory care clinics in major cities by the National Hansen’s Disease program, the only institution in the United States exclusively devoted to Hansen’s disease. Since 1995, WHO has made multidrug therapy for Hansen’s disease available free of charge to all patients worldwide. As a result, global prevalence of Hansen’s disease has declined from about 5.2 million cases in 1985 to roughly 176,000 in 2014.World Health Organization, “Leprosy Fact Sheet,” 2016. Accessed September 13, 2016. http://www.who.int/mediacentre/factsheets/fs101/en/. Multidrug therapy consists of dapsone and rifampicin for all patients and a third drug, clofazimin, for patients with multibacillary disease.
Currently, there is no universally accepted vaccine for Hansen’s disease. India and Brazil use a tuberculosis vaccine against Hansen’s disease because both diseases are caused by species of Mycobacterium. The effectiveness of this method is questionable, however, since it appears that the vaccine works in some populations but not in others.

### Key Concepts and Summary

1. Bacterial meningitis can be caused by several species of encapsulated bacteria, including Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae, and Streptococcus agalactiae (group B streptococci). H. influenzae affects primarily young children and neonates, N. meningitidis is the only communicable pathogen and mostly affects children and young adults, S. pneumoniae affects mostly young children, and S. agalactiae affects newborns during or shortly after birth.
2. Symptoms of bacterial meningitis include fever, neck stiffness, headache, confusion, convulsions, coma, and death.
3. Diagnosis of bacterial meningitis is made through observations and culture of organisms in CSF. Bacterial meningitis is treated with antibiotics. H. influenzae and N. meningitidis have vaccines available.
4. Clostridium species cause neurological diseases, including botulism and tetanus, by producing potent neurotoxins that interfere with neurotransmitter release. The PNS is typically affected. Treatment of Clostridium infection is effective only through early diagnosis with administration of antibiotics to control the infection and antitoxins to neutralize the endotoxin before they enter cells.
5. Listeria monocytogenes is a foodborne pathogen that can infect the CNS, causing meningitis. The infection can be spread through the placenta to a fetus. Diagnosis is through culture of blood or CSF. Treatment is with antibiotics and there is no vaccine.
6. Hansen’s disease (leprosy) is caused by the intracellular parasite Mycobacterium leprae. Infections cause demylenation of neurons, resulting in decreased sensation in peripheral appendages and body sites. Treatment is with multi-drug antibiotic therapy, and there is no universally recognized vaccine.

### Multiple Choice

### Fill in the Blank

### Short Answer

### Critical Thinking


# Nervous System Infections

## Acellular Diseases of the Nervous System

### Learning Objectives

By the end of this section, you will be able to:
1. Identify the most common acellular pathogens that can cause infections of the nervous system
2. Compare the major characteristics of specific viral diseases affecting the nervous system
A number of different viruses and subviral particles can cause diseases that affect the nervous system. Viral diseases tend to be more common than bacterial infections of the nervous system today. Fortunately, viral infections are generally milder than their bacterial counterparts and often spontaneously resolve. Some of the more important acellular pathogens of the nervous system are described in this section.

### Viral Meningitis

Although it is much more common than bacterial meningitis, viral meningitis is typically less severe. Many different viruses can lead to meningitis as a sequela of the primary infection, including those that cause herpes, influenza, measles, and mumps. Most cases of viral meningitis spontaneously resolve, but severe cases do occur.

### Arboviral Encephalitis

Several types of insect-borne viruses can cause encephalitis. Collectively, these viruses are referred to as arboviruses (because they are arthropod-borne), and the diseases they cause are described as arboviral encephalitis. Most arboviruses are endemic to specific geographical regions. Arborviral encephalitis diseases found in the United States include eastern equine encephalitis (EEE), western equine encephalitis (WEE), St. Louis encephalitis, and West Nile encephalitis (WNE). Expansion of arboviruses beyond their endemic regions sometimes occurs, generally as a result of environmental changes that are favorable to the virus or its vector. Increased travel of infected humans, animals, or vectors has also allowed arboviruses to spread into new regions.
In most cases, arboviral infections are asymptomatic or lead to a mild disease. However, when symptoms do occur, they include high fever, chills, headaches, vomiting, diarrhea, and restlessness. In elderly patients, severe arboviral encephalitis can rapidly lead to convulsions, coma, and death.
Mosquitoes are the most common biological vectors for arboviruses, which tend to be enveloped ssRNA viruses. Thus, prevention of arboviral infections is best achieved by avoiding mosquitoes—using insect repellent, wearing long pants and sleeves, sleeping in well-screened rooms, using bed nets, etc.
Diagnosis of arboviral encephalitis is based on clinical symptoms and serologic testing of serum or CSF. There are no antiviral drugs to treat any of these arboviral diseases, so treatment consists of supportive care and management of symptoms.
Eastern equine encephalitis (EEE) is caused by eastern equine encephalitis virus (EEEV), which can cause severe disease in horses and humans. Birds are reservoirs for EEEV with accidental transmission to horses and humans by , , and  species of mosquitoes. Neither horses nor humans serve as reservoirs. EEE is most common in US Gulf Coast and Atlantic states. EEE is one of the more severe mosquito-transmitted diseases in the United States, but fortunately, it is a very rare disease in the United States ().US Centers for Disease Control and Prevention, “Eastern Equine Encephalitis Virus Disease Cases and Deaths Reported to CDC by Year and Clinical Presentation, 2004–2013,” 2014. http://www.cdc.gov/EasternEquineEncephalitis/resources/EEEV-Cases-by-Year_2004-2013.pdf.US Centers for Disease Control and Prevention, “Eastern Equine Encephalitis, Symptoms & Treatment, 2016,” Accessed June 29, 2016. https://www.cdc.gov/easternequineencephalitis/tech/symptoms.html.
Western equine encephalitis (WEE) is caused by western equine encephalitis virus (WEEV). WEEV is usually transmitted to horses and humans by the  mosquitoes and, in the past decade, has caused very few cases of encephalitis in humans in the United States. In humans, WEE symptoms are less severe than EEE and include fever, chills, and vomiting, with a mortality rate of 3–4%. Like EEEV, birds are the natural reservoir for WEEV. Periodically, for indeterminate reasons, epidemics in human cases have occurred in North America in the past. The largest on record was in 1941, with more than 3400 cases.US Centers for Disease Control and Prevention, “Western Equine Encephalitis—United States and Canada, 1987,”
St. Louis encephalitis (SLE), caused by St. Louis encephalitis virus (SLEV), is a rare form of encephalitis with symptoms occurring in fewer than 1% of infected patients. The natural reservoirs for SLEV are birds. SLEV is most often found in the Ohio-Mississippi River basin of the central United States and was named after a severe outbreak in Missouri in 1934. The worst outbreak of St. Louis encephalitis occurred in 1975, with over 2000 cases reported.US Centers for Disease Control and Prevention, “Saint Louis encephalitis, Epidemiology & Geographic Distribution,” Accessed June 30, 2016. http://www.cdc.gov/sle/technical/epi.html. Humans become infected when bitten by C. tarsalis, C. quinquefasciatus, or C. pipiens mosquitoes carrying SLEV. Most patients are asymptomatic, but in a small number of individuals, symptoms range from mild flu-like syndromes to fatal encephalitis. The overall mortality rate for symptomatic patients is 5–15%.US Centers for Disease Control and Prevention, “Saint Louis encephalitis, Symptoms and Treatment,” Accessed June 30, 2016. http://www.cdc.gov/sle/technical/symptoms.html.
Japanese encephalitis, caused by Japanese encephalitis virus (JEV), is the leading cause of vaccine-preventable encephalitis in humans and is endemic to some of the most populous countries in the world, including China, India, Japan, and all of Southeast Asia. JEV is transmitted to humans by Culex mosquitoes, usually the species . The biological reservoirs for JEV include pigs and wading birds. Most patients with JEV infections are asymptomatic, with symptoms occurring in fewer than 1% of infected individuals. However, about 25% of those who do develop encephalitis die, and among those who recover, 30–50% have psychiatric, neurologic, or cognitive impairment.US Centers for Disease Control and Prevention, “Japanese Encephalitis, Symptoms and Treatment,” Accessed June 30, 2016. http://www.cdc.gov/japaneseencephalitis/symptoms/index.html. Fortunately, there is an effective vaccine that can prevent infection with JEV. The CDC recommends this vaccine for travelers who expect to spend more than one month in endemic areas.
As the name suggests, West Nile virus (WNV) and its associated disease, West Nile encephalitis (WNE), did not originate in North America. Until 1999, it was endemic in the Middle East, Africa, and Asia; however, the first US cases were identified in New York in 1999, and by 2004, the virus had spread across the entire continental United States. Over 35,000 cases, including 1400 deaths, were confirmed in the five-year period between 1999 and 2004. WNV infection remains reportable to the CDC.
WNV is transmitted to humans by Culex mosquitoes from its natural reservoir, infected birds, with 70–80% of infected patients experiencing no symptoms. Most symptomatic cases involve only mild, flu-like symptoms, but fewer than 1% of infected people develop severe and sometimes fatal encephalitis or meningitis. The mortality rate in WNV patients who develop neurological disease is about 10%. More information about West Nile virus can be found in Modes of Disease Transmission.

### Zika Virus Infection

Zika virus infection is an emerging arboviral disease associated with human illness in Africa, Southeast Asia, and South and Central America; however, its range is expanding as a result of the widespread range of its mosquito vector. The first cases originating in the United States were reported in 2016.The Zika virus was initially described in 1947 from monkeys in the Zika Forest of Uganda through a network that monitored yellow fever. It was not considered a serious human pathogen until the first large-scale outbreaks occurred in Micronesia in 2007;Sikka, Veronica, Vijay Kumar Chattu, Raaj K. Popli, Sagar C. Galwankar, Dhanashree Kelkar, Stanley G. Sawicki, Stanislaw P. Stawicki, and Thomas J. Papadimos, “The Emergence of Zika Virus as a Global Health Security Threat: A Review and a Consensus Statement of the INDUSEM Joint Working Group (JWG),”  however, the virus has gained notoriety over the past decade, as it has emerged as a cause of symptoms similar to other arboviral infections that include fever, skin rashes, conjunctivitis, muscle and joint pain, malaise, and headache. Mosquitoes of the genus are the primary vectors, although the virus can also be transmitted sexually, from mother to baby during pregnancy, or through a blood transfusion.
Most Zika virus infections result in mild symptoms such as fever, a slight rash, or conjunctivitis. However, infections in pregnant women can adversely affect the developing fetus. Reports in 2015 indicate fetal infections can result in brain damage, including a serious birth defect called microcephaly, in which the infant is born with an abnormally small head ().Mlakar, Jernej, Misa Korva, Nataša Tul, Mara Popović, Mateja Poljšak-Prijatelj, Jerica Mraz, Marko Kolenc et al., “Zika Virus Associated with Microcephaly,”
Diagnosis of Zika is primarily based on clinical symptoms. However, the FDA recently authorized the use of a Zika virus RNA assay, Trioplex RT-PCR, and Zika MAC-ELISA to test patient blood and urine to confirm Zika virus disease. There are currently no antiviral treatments or vaccines for Zika virus, and treatment is limited to supportive care.

### Rabies

Rabies is a deadly zoonotic disease that has been known since antiquity. The disease is caused by rabies virus (RV), a member of the family Rhabdoviridae, and is primarily transmitted through the bite of an infected mammal. Rhabdoviridae are enveloped RNA viruses that have a distinctive bullet shape (); they were first studied by Louis Pasteur, who obtained rabies virus from rabid dogs and cultivated the virus in rabbits. He successfully prepared a rabies vaccine using dried nerve tissues from infected animals. This vaccine was used to first treat an infected human in 1885.
The most common reservoirs in the United States are wild animals such as raccoons (30.2% of all animal cases during 2014), bats (29.1%), skunks (26.3%), and foxes (4.1%); collectively, these animals were responsible for a total of 92.6% of animal rabies cases in the United States in 2014. The remaining 7.4% of cases that year were in domesticated animals such as dogs, cats, horses, mules, sheep, goats, and llamas.US Centers for Disease Control and Prevention, “Rabies, Wild Animals,” 2016. Accessed September 13, 2016. http://www.cdc.gov/rabies/location/usa/surveillance/wild_animals.html. While there are typically only one or two human cases per year in the United States, rabies still causes tens of thousands of human deaths per year worldwide, primarily in Asia and Africa.
The low incidence of rabies in the United States is primarily a result of the widespread vaccination of dogs and cats. An oral vaccine is also used to protect wild animals, such as raccoons and foxes, from infection. Oral vaccine programs tend to focus on geographic areas where rabies is endemic.Slate, Dennis, Charles E. Rupprecht, Jane A. Rooney, Dennis Donovan, Donald H. Lein, and Richard B. Chipman, “Status of Oral Rabies Vaccination in Wild Carnivores in the United States,”  The oral vaccine is usually delivered in a package of bait that is dropped by airplane, although baiting in urban areas is done by hand to maximize safety.Finnegan, Christopher J., Sharon M. Brookes, Nicholas Johnson, Jemma Smith, Karen L. Mansfield, Victoria L. Keene, Lorraine M. McElhinney, and Anthony R. Fooks, “Rabies in North America and Europe,”  Many countries require a quarantine or proof of rabies vaccination for domestic pets being brought into the country. These procedures are especially strict in island nations where rabies infections are rare, such as Australia.
The incubation period for rabies can be lengthy, ranging from several weeks or months to over a year. As the virus replicates, it moves from the site of the bite into motor and sensory axons of peripheral nerves and spreads from nerve to nerve using a process called retrograde transport, eventually making its way to the CNS through the spinal ganglia. Once rabies virus reaches the brain, the infection leads to encephalitis caused by the disruption of normal neurotransmitter function, resulting in the symptoms associated with rabies. The virions act in the synaptic spaces as competitors with a variety of neurotransmitters for acetylcholine, GABA, and glycine receptors. Thus, the action of rabies virus is neurotoxic rather than cytotoxic. After the rabies virus infects the brain, it can continue to spread through other neuronal pathways, traveling out of the CNS to tissues such as the salivary glands, where the virus can be released. As a result, as the disease progresses the virus can be found in many other tissues, including the salivary glands, taste buds, nasal cavity, and tears.
The early symptoms of rabies include discomfort at the site of the bite, fever, and headache. Once the virus reaches the brain and later symptoms appear, the disease is always fatal. Terminal rabies cases can end in one of two ways: either furious or paralytic rabies. Individuals with furious rabies become very agitated and hyperactive. Hydrophobia (a fear of water) is common in patients with furious rabies, which is caused by muscular spasms in the throat when swallowing or thinking about water. Excess salivation and a desire to bite can lead to foaming of the mouth. These behaviors serve to enhance the likelihood of viral transmission, although contact with infected secretions like saliva or tears alone is sufficient for infection. The disease culminates after just a few days with terror and confusion, followed by cardiovascular and respiratory arrest. In contrast, individuals with paralytic rabies generally follow a longer course of disease. The muscles at the site of infection become paralyzed. Over a period of time, the paralysis slowly spreads throughout the body. This paralytic form of disease culminates in coma and death.
Before present-day diagnostic methods were available, rabies diagnosis was made using a clinical case history and histopathological examination of biopsy or autopsy tissues, looking for the presence of Negri bodies. We now know these histologic changes cannot be used to confirm a rabies diagnosis. There are no tests that can detect rabies virus in humans at the time of the bite or shortly thereafter. Once the virus has begun to replicate (but before clinical symptoms occur), the virus can be detected using an immunofluorescence test on cutaneous nerves found at the base of hair follicles. Saliva can also be tested for viral genetic material by reverse transcription followed by polymerase chain reaction (RT-PCR). Even when these tests are performed, most suspected infections are treated as positive in the absence of contravening evidence. It is better that patients undergo unnecessary therapy because of a false-positive result, rather than die as the result of a false-negative result.
Human rabies infections are treated by immunization with multiple doses of an attenuated vaccine to develop active immunity in the patient (see the Clinical Focus feature in the chapter on Acellular Pathogens). Vaccination of an already-infected individual has the potential to work because of the slow progress of the disease, which allows time for the patient’s immune system to develop antibodies against the virus. Patients may also be treated with human rabies immune globulin (antibodies to the rabies virus) to encourage passive immunity. These antibodies will neutralize any free viral particles. Although the rabies infection progresses slowly in peripheral tissues, patients are not normally able to mount a protective immune response on their own.

### Poliomyelitis

Poliomyelitis (polio), caused by poliovirus, is a primarily intestinal disease that, in a small percentage of cases, proceeds to the nervous system, causing paralysis and, potentially, death. Poliovirus is highly contagious, with transmission occurring by the fecal-oral route or by aerosol or droplet transmission. Approximately 72% of all poliovirus infections are asymptomatic; another 25% result only in mild intestinal disease, producing nausea, fever, and headache.US Centers for Disease Control and Prevention, “Global Health – Polio,” 2014. Accessed June 30, 2016. http://www.cdc.gov/polio/about/index.htm. However, even in the absence of symptoms, patients infected with the virus can shed it in feces and oral secretions, potentially transmitting the virus to others. In about one case in every 200, the poliovirus affects cells in the CNS.US Centers for Disease Control and Prevention, “Global Health – Polio,” 2014. Accessed June 30, 2016. http://www.cdc.gov/polio/about/index.htm.
After it enters through the mouth, initial replication of poliovirus occurs at the site of implantation in the pharynx and gastrointestinal tract. As the infection progresses, poliovirus is usually present in the throat and in the stool before the onset of symptoms. One week after the onset of symptoms, there is less poliovirus in the throat, but for several weeks, poliovirus continues to be excreted in the stool. Poliovirus invades local lymphoid tissue, enters the bloodstream, and then may infect cells of the CNS. Replication of poliovirus in motor neurons of the anterior horn cells in the spinal cord, brain stem, or motor cortex results in cell destruction and leads to flaccid paralysis. In severe cases, this can involve the respiratory system, leading to death. Patients with impaired respiratory function are treated using positive-pressure ventilation systems. In the past, patients were sometimes confined to Emerson respirators, also known as iron lungs ().
Direct detection of the poliovirus from the throat or feces can be achieved using reverse transcriptase PCR (RT-PCR) or genomic sequencing to identify the genotype of the poliovirus infecting the patient. Serological tests can be used to determine whether the patient has been previously vaccinated. There are no therapeutic measures for polio; treatment is limited to various supportive measures. These include pain relievers, rest, heat therapy to ease muscle spasms, physical therapy and corrective braces if necessary to help with walking, and mechanical ventilation to assist with breathing if necessary.
Two different vaccines were introduced in the 1950s that have led to the dramatic decrease in polio worldwide (). The Salk vaccine is an inactivated polio virus that was first introduced in 1955. This vaccine is delivered by intramuscular injection. The Sabin vaccine is an oral polio vaccine that contains an attenuated virus; it was licensed for use in 1962. There are three serotypes of poliovirus that cause disease in humans; both the Salk and the Sabin vaccines are effective against all three.
Attenuated viruses from the Sabin vaccine are shed in the feces of immunized individuals and thus have the potential to infect nonimmunized individuals. By the late 1990s, the few polio cases originating in the United States could be traced back to the Sabin vaccine. In these cases, mutations of the attenuated virus following vaccination likely allowed the microbe to revert to a virulent form. For this reason, the United States switched exclusively to the Salk vaccine in 2000. Because the Salk vaccine contains an inactivated virus, there is no risk of transmission to others (see Vaccines). Currently four doses of the vaccine are recommended for children: at 2, 4, and 6–18 months of age, and at 4–6 years of age.
In 1988, WHO launched the Global Polio Eradication Initiative with the goal of eradicating polio worldwide through immunization. That goal is now close to being realized. Polio is now endemic in only a few countries, including Afghanistan, Pakistan, and Nigeria, where vaccination efforts have been disrupted by military conflict or political instability.

### Transmissible Spongiform Encephalopathies

Acellular infectious agents called prions are responsible for a group of related diseases known as transmissible spongiform encephalopathies (TSEs) that occurs in humans and other animals (see Viroids, Virusoids, and Prions). All TSEs are degenerative, fatal neurological diseases that occur when brain tissue becomes infected by prions. These diseases have a slow onset; symptoms may not become apparent until after an incubation period of years and perhaps decades, but death usually occurs within months to a few years after the first symptoms appear.
TSEs in animals include scrapie, a disease in sheep that has been known since the 1700s, and chronic wasting disease, a disease of deer and elk in the United States and Canada. Mad cow disease is seen in cattle and can be transmitted to humans through the consumption of infected nerve tissues. Human prion diseases include Creutzfeldt-Jakob disease and kuru, a rare disease endemic to Papua New Guinea.
Prions are infectious proteinaceous particles that are not viruses and do not contain nucleic acid. They are typically transmitted by exposure to and ingestion of infected nervous system tissues, tissue transplants, blood transfusions, or contaminated fomites. Prion proteins are normally found in a healthy brain tissue in a form called PrPC. However, if this protein is misfolded into a denatured form (PrPSc), it can cause disease. Although the exact function of PrPC is not currently understood, the protein folds into mostly alpha helices and binds copper. The rogue protein, on the other hand, folds predominantly into beta-pleated sheets and is resistant to proteolysis. In addition, PrPSc can induce PrPC to become misfolded and produce more rogue protein ().
As PrPSc accumulates, it aggregates and forms fibrils within nerve cells. These protein complexes ultimately cause the cells to die. As a consequence, brain tissues of infected individuals form masses of neurofibrillary tangles and amyloid plaques that give the brain a spongy appearance, which is why these diseases are called spongiform encephalopathy (). Damage to brain tissue results in a variety of neurological symptoms. Most commonly, affected individuals suffer from memory loss, personality changes, blurred vision, uncoordinated movements, and insomnia. These symptoms gradually worsen over time and culminate in coma and death.
The gold standard for diagnosing TSE is the histological examination of brain biopsies for the presence of characteristic amyloid plaques, vacuoles, and prion proteins. Great care must be taken by clinicians when handling suspected prion-infected materials to avoid becoming infected themselves. Other tissue assays search for the presence of the 14-3-3 protein, a marker for prion diseases like Creutzfeldt-Jakob disease. New assays, like RT-QuIC (real-time quaking-induced conversion), offer new hope to effectively detect the abnormal prion proteins in tissues earlier in the course of infection. Prion diseases cannot be cured. However, some medications may help slow their progress. Medical support is focused on keeping patients as comfortable as possible despite progressive and debilitating symptoms.

### Key Concepts and Summary

1. Viral meningitis is more common and generally less severe than bacterial menigitis. It can result from secondary sequelae of many viruses or be caused by infections of arboviruses.
2. Various types of arboviral encephalitis are concentrated in particular geographic locations throughout the world. These mosquito-borne viral infections of the nervous system are typically mild, but they can be life-threatening in some cases.
3. Zika virus is an emerging arboviral infection with generally mild symptoms in most individuals, but infections of pregnant women can cause the birth defect microcephaly.
4. Polio is typically a mild intestinal infection but can be damaging or fatal if it progresses to a neurological disease.
5. Rabies is nearly always fatal when untreated and remains a significant problem worldwide.
6. Transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease and kuru are caused by prions. These diseases are untreatable and ultimately fatal. Similar prion diseases are found in animals.

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