Infections of the Nervous System and Senses

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Infections of the Nervous System and Senses

WHY YOU NEED TO KNOW

HISTORY

Polio (poliomyelitis) is an ancient disease, but scientists did not completely identify and name the disease until the twentieth century. The disease is an acute, highly contagious disease caused by the poliovirus. Epidemics have swept across the United States several times in the 1900s, killing thousands and paralyzing even more. Many of the victims were children and the disease became one of the most feared childhood diseases in the first half of the twentieth century. In 1937, the National Foundation for Infantile Paralysis, which became known as the March of Dimes, was founded by Franklin Delano Roosevelt, who himself contracted polio in 1921. Funding by the foundation helped Jonas Salk to develop the first vaccine in 1952. Albert Sabin introduced the first oral polio vaccine in 1961, which further reduced the incidence of polio.

Another toxin produced by a microorganism that affects the nervous system is ergot, the product of a fungus (Claviceps purpurea) that grows on the rye grain plant. The toxin has been accurately labeled as a pharmaceutical storehouse of biologically active products such as vasoconstrictors, uterine smooth muscle contractors, and substances effective on CNS neurotransmission, just to mention a few. The response following exposure to ergot is ergotism, or long-term ergot poisoning. Ergotism presents a variety of dose-dependent symptoms including vomiting, diarrhea, hallucinations, convulsive seizures, and other irrational behaviors. Some attempts have been made to associate the behaviors of manic melancholia, psychoses, delirium, crawling sensations in the skin of the extremities, dizziness, migraines, vomiting, and diarrhea (all symptoms of ergotism) with similar symptoms seen in the accused “witches of Salem” tried in Salem, Massachusetts in the late 1600s. By 1692, some 20 of these so-called witches of Salem had been convicted and executed for their “crimes.”

IMPACT

The knowledge scientists have gained about microorganisms, their toxins, and their effect on the nervous system has led to more and better vaccination regimens, as well as to increased antimicrobial drug development. For example, the success of the tetanus vaccination programs reduced the annual cases of tetanus in the United States to about 100, whereas about 1 million cases are reported worldwide each year.

Unfortunately, the understanding of microorganisms and of their actions on the human body has also led to the threat of their use as bioweapons (see Bioterrorism in Chapter 24, Microorganisms in the Environment and Environmental Safety). Terrorists have tried to weaponize botulinum toxin by refining the toxin and dispersing it in aerosol form. Preparations of the toxins could be used to poison food or beverages, and with a sophisticated delivery system could disseminate the toxin by air. Botulinum toxin spreads throughout the body and affects mostly the nervous system, and has a high mortality rate.

FUTURE

New concepts direct research as much as technological development. An example of such a new concept is the inflammatory reflex. It is a response between the nervous system and the immune system via the vagus cranial nerve to create a “neuroimmune axis.” The nervous system through the vagus cranial nerve modulates circulating tumor necrosis factor (TNF)-α levels induced by microorganisms or tissue injury. TNF-α is a protein normally present in the body, but its circulating levels are increased by the immune system to mobilize white blood cells in the presence of an infection, with resultant inflammation in the affected area. In general, the inflammation subsides, but if it is caused by certain diseases such as rheumatoid arthritis or Crohn’s disease, the inflammation doesn’t subside. This draws more white blood cells to the site, which allows TNF-α to increase further, causing additional inflammation, which leads to pain and tissue damage. There are now TNF-α inhibitors that block the effects of TNF-α, reducing their effects of inflammation or other symptoms.

Extensive research is also being conducted in prion-related diseases. Increased attention has been paid to the spread of transmissible spongiform encephalopathies (TSE) in deer populations in the United States. With an increase in the number of deer testing positive for chronic wasting disease (a form of TSE) there is increasing concern regarding the transmission of the prion through consumption of venison by hunters/consumers. Results of this research may have a significant impact on the future of deer hunting and management of natural resources in general.

Introduction

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

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

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

TABLE 13.1

Cerebrospinal Fluid (CSF) Changes During CSF Infections

  Cause Cells/ml Protein (mg/dl) White Blood Cells
Normal   0–5 15–45  
Aseptic meningitis or meningoencephalitis Viruses, tuberculosis, leptospira, fungi, brain abscess 100–1000 50–100 Elevated lymphocytes and monocytes
Septic meningitis Bacteria, amoebae, brain abscess 200–20,000 High (>100) Elevated granulocytes

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

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

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

Bacterial Infections

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

Bacterial Meningitis

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

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

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

Meningococcal Meningitis

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

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

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

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

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

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

TABLE 13.2

Recent Outbreaks of Meningococcal Meningitis Worldwide

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

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LIFE APPLICATION

Meningitis: The Dorm Disease?

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

Haemophilus influenzae Meningitis

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

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

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

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

Pneumococcal Meningitis

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

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

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

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

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