Microbial Diseases of the Nervous System

Functions of the Nervous System

The primary function of the nervous system is to coordinate and control the various body functions.

Learning Objectives

Describe the functions of the nervous system

Key Takeaways

Key Points

  • The nervous system is a highly integrated system. The nervous system has three overlapping functions based on sensory input, integration, and motor output.
  • At a more integrative level, the primary function of the nervous system is to control and communicate information throughout the body.

Key Terms

  • hormone: A molecule released by a cell or a gland in one part of the body that sends out messages affecting cells in other parts of the organism.
  • nervous system: The organ system that coordinates the activities of muscles, monitors organs, constructs and processes data received from the senses, and initiates actions.

The nervous system has three overlapping functions based on the sensory input,  integration, and motor output. The nervous system is a highly integrated system.

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Major elements in neuron-to-neuron communication: Electrical impulses travel along the axon of a neuron. When this signal reaches a synapse, it provokes release of neurotransmitter molecules, which bind to receptor molecules located in the the target cell.

Sensory Input

Sensory input comes from the many sensory receptors that monitor changes occurring both inside and outside the body. The total sum of the information gathered by these receptors is called sensory input. The nervous system processes and interprets sensory input and decides what actions should be taken. The nervous system activates effector organs such as muscles and glands to cause a response called motor output.

Integration

At a more integrative level, the primary function of the nervous system is to control and communicate information throughout the body. It does this by extracting information from the environment using sensory receptors. This sensory input is sent to the central nervous system, which determines an appropriate response.

Motor Response

Once the response is activated, the nervous system sends signals via motor output to muscles or glands to initiate the response.

In humans, the sophistication of the nervous system allows for language, abstract representation of concepts, transmission of culture, and many other features of society that would not otherwise exist.

Subdivisions of the Nervous System

The CNS includes the brain and spinal cord, while the PNS is a network of nerves linking the body to the brain and spinal cord.

Learning Objectives

Describe the subdivisions of the nervous system

Key Takeaways

Key Points

  • The nervous system is often divided into components called gray matter and white matter. Gray matter contains a relatively high proportion of neuron cell bodies and white matter is composed mainly of axons.
  • The peripheral nervous system is subdivided into nerves, the autonomic system, and the somatic system. The autonomic nervous system is further subdivided into the parasympathetic and sympathetic nervous systems.
  • The enteric nervous system is an independent subsystem of the peripheral nervous system.
  • The central nervous system includes the brain and spinal cord and has various centers that integrate of all the information in the body. These can be subdivided into lower centers that carry out essential body functions and higher centers that control more sophisticated information processing.

Key Terms

  • gray matter: A major component of the central nervous system, consisting of neuronal cell bodies, neuropil (dendrites and unmyelinated axons), glial cells (astroglia and oligodendrocytes), and capillaries.
  • central nervous system: In vertebrates, the part of the nervous system comprising the brain, brainstem, and spinal cord.
  • white matter: A region of the central nervous system containing myelinated nerve fibers and no dendrites.
  • peripheral nervous system: This system consists of the nerves and ganglia outside of the brain and spinal cord.

The nervous system is comprised of two major subdivisions, the central nervous system (CNS) and the peripheral nervous system (PNS).

Central Nervous System

The CNS includes the brain and spinal cord along with various centers that integrate all the sensory and motor information in the body. These centers can be broadly subdivided into lower centers, including the spinal cord and brain stem, that carry out essential body and organ-control functions and higher centers within the brain that control more sophisticated information processing, including our thoughts and perceptions. Further subdivisions of the brain will be discussed in a later section.

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The Central Nervous System: The central nervous system (2) is a combination of the brain (1) and the spinal cord (3).

Gray Matter and White Matter

The nervous system is often divided into components called gray matter and white matter. Gray matter, which is gray in preserved tissue but pink or light brown in living tissue, contains a relatively high proportion of neuron cell bodies. Conversely, white matter is composed mainly of axons and is named because of the color of the fatty insulation called myelin that coats many axons. White matter includes all of the nerves of the PNS and much of the interior of the brain and spinal cord. Gray matter is found in clusters of neurons in the brain and spinal cord and in cortical layers that line their surfaces.

By convention, a cluster of neuron cell bodies in the gray matter of the brain or spinal cord is called a nucleus, whereas a cluster of neuron cell bodies in the periphery is called a ganglion. However, there are a few notable exceptions to this rule, including a part of the brain called the basal ganglia, which will be discussed later.

Peripheral Nervous System

The PNS is a vast network of nerves consisting of bundles of axons that link the body to the brain and the spinal cord. Sensory nerves of the PNS contain sensory receptors that detect changes in the internal and external environment. This information is sent to the CNS via afferent sensory nerves. Following information processing in the CNS, signals are relayed back to the PNS by way of efferent peripheral nerves.

Autonomic and Somatic Nervous Systems

The PNS is further subdivided into the autonomic nervous system (ANS) and the somatic nervous system. The autonomic system has involuntary control of internal organs, blood vessels, and smooth and cardiac muscles. The somatic system has voluntary control of our movements via skeletal muscle.

As mentioned, the autonomic nervous system acts as a control system and most functions occur without conscious thought. The ANS affects heart rate, digestion, respiratory rate, salivation, perspiration, pupil diameter, urination, and sexual arousal. While most of its actions are involuntary, some, such as breathing, work in tandem with the conscious mind. The ANS is classically divided into two subsystems: the parasympathetic nervous system (PSNS) and sympathetic nervous system (SNS).

Parasympathetic and Sympathetic Nervous Systems

Broadly, the parasympathetic system is responsible for stimulation of “rest-and-digest” activities that occur when the body is at rest, including sexual arousal, salivation, lacrimation (tears), urination, digestion, and defecation. The sympathetic nervous syste is responsible for stimulating activities associated with the “fight-or-flight” response: mobilizing the systems of the body for escape or attacking sources of danger. In truth, the functions of both the parasympathetic and sympathetic nervous systems are not so straightforward, but this division is a useful rule of thumb.

The enteric nervous system (ENS) controls the gastrointestinal system and is sometimes considered part of the autonomic nervous system. However, it is sometimes considered an independent system because it can operate independently of the brain and the spinal cord.

This diagram details the parts of the central nervous system, including brain, spinal cord, brachial plexus, musculocutaneous nerve, radial nerve, median nerve, iliohypogastric nerve, genitofemoral nerve, obturator nerve, ulnar nerve, common peroneal nerve, deep peroneal nerve, superficial peroneal nerve, tibial nerve, saphenous nerve, muscular branches of femoral nerve, sciatic nerve, pudendal nerve, femoral nerve, sacral plexus, lumbar plexus, subcostal nerve, intercostal nerve, cerebellum.

The Nervous System of a Vertebrate: The brain and the spinal cord are the central nervous system (CNS) (shown in yellow). The left-right pair of cranial nerves, spinal nerves, and ganglia make up the peripheral nervous system (shown in dark gold).

Meningitis

Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges.

Learning Objectives

Discuss the various causes (viral, bacteria, fungi and protozoa) and modes of transmission for meningitis

Key Takeaways

Key Points

  • Meningitis can be caused by viruses, bacteria, fungi, and protozoa.
  • The most common symptoms of meningitis are headache and neck stiffness associated with fever, confusion or altered consciousness, vomiting, and an inability to tolerate light (photophobia) or loud noises (phonophobia).
  • A lumbar puncture diagnoses or excludes meningitis.
  • The first treatment in acute meningitis consists of antimicrobial and sometimes antiviral therapy.

Key Terms

  • meninges: The three membranes that envelop the brain and spinal cord.
  • meningitis: Inflammation of the meninges, characterized by headache, neck stiffness and photophobia and also fever, chills, vomiting, and myalgia.
  • lumbar puncture: A diagnostic and at times therapeutic procedure performed to collect a sample of cerebrospinal fluid for biochemical, microbiological, and cytological analysis, or rarely to relieve increased intracranial pressure.

Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs. Meningitis can be life-threatening because of the inflammation’s proximity to the brain and spinal cord. Therefore, the condition is classified as a medical emergency.

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The Meninges: This figure displays the meninges with respect to the skull and surface of the brain.

The most common symptoms of meningitis are headache and neck stiffness associated with fever, confusion or altered consciousness, vomiting, and an inability to tolerate light (photophobia) or loud noises (phonophobia). Children often exhibit only nonspecific symptoms, such as irritability and drowsiness. If a rash is present, it may indicate a particular cause of meningitis. For instance, meningitis caused by the bacterium Neisseria meningitidis (known as “meningococcal menigitis”) can be differentiated from meningitis with other causes by a rapidly spreading petechial rash, which may precede other symptoms. The rash consists of numerous small, irregular purple or red spots (“petechiae”) on the trunk, lower extremities, mucous membranes, conjuctiva, and (occasionally) the palms of the hands or soles of the feet. Meningococcal bacteria may be accompanied by a characteristic rash. Seizures may also occur for various reasons. In children, seizures are common in the early stages of meningitis and do not necessarily indicate an underlying cause.

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Neck stiffness: Neck stiffness, Texas meningitis epidemic of 1911–12. Nuchal rigidity occurs in 70% of bacterial meningitis in adults.

Meningitis can lead to serious long-term consequences such as deafness, epilepsy, hydrocephalus, and cognitive deficits, especially if not treated quickly. Some forms of meningitis (such as those associated with meningococci, Haemophilus influenzae type B, pneumococci, or mumps virus infections) may be prevented by immunization.

Meningitis is typically caused by an infection with microorganisms. Most infections are due to viruses (such as enteroviruses or herpes simplex virus), with bacteria (for example group B streptococci), fungi, and protozoa being the next most common causes. It may also result from various non-infectious causes. The term aseptic meningitis refers to cases of meningitis in which no bacterial infection can be demonstrated. This type of meningitis is usually caused by viruses, but it may be due to bacterial infection that has already been partially treated, when bacteria disappear from the meninges, or pathogens infect a space adjacent to the meninges (e.g. sinusitis). Endocarditis (an infection of the heart valves which spreads small clusters of bacteria through the bloodstream) may cause aseptic meningitis. Aseptic meningitis may also result from infection with spirochetes, a type of bacteria that includes Treponema pallidum (the cause of syphilis) and Borrelia burgdorferi (known for causing Lyme disease).

A lumbar puncture diagnoses or excludes meningitis. A needle is inserted into the spinal canal to extract a sample of cerebrospinal fluid (CSF) which envelops the brain and spinal cord. The CSF is examined in a medical laboratory. In someone suspected of having meningitis, blood tests are performed for markers of inflammation (e.g. C-reactive protein, complete blood count) as well as blood cultures.

The first treatment in acute meningitis consists of antimicrobial and sometimes antiviral therapy. In addition, corticosteroids can also be used to prevent complications from excessive inflammation. The introduction of pneumococcal vaccine has lowered rates of pneumococcal meningitis in both children and adults. Recent skull trauma potentially allows nasal cavity bacteria to enter the meningeal space. Similarly, devices in the brain and meninges such as cerebral shunts carry an increased risk of meningitis.

Bacterial and viral meningitis are contagious and can be transmitted through droplets of respiratory secretions during close contact such as kissing, sneezing, or coughing on someone, but cannot be spread by only breathing the air where a person with meningitis has been. Since the 1980’s, many countries have included immunization against Haemophilus influenzae type B in their routine childhood vaccination schemes. This has practically eliminated this pathogen as a cause of meningitis in young children in those countries.

Botulism

Botulism is a rare but sometimes fatal paralytic illness caused by botulinum toxin produced by the bacterium Clostridium botulinum.

Learning Objectives

Compare and contrast the three major modes of entry for Botulinium toxin (infant botulism or adult intestinal toxemia, foodborne botulism, and wound botulism) and describe its mechanism of action

Key Takeaways

Key Points

  • The toxin (s) enters the human body by colonization of the digestive tract by the bacterium, by ingestion of toxin from foods or by contamination of a wound by the bacterium.
  • All forms lead to paralysis that typically starts with the muscles of the face and then spreads towards the limbs.
  • Botulism can be prevented by killing the spores by pressure cooking or autoclaving at 121 °C (250 °F) for 30 minutes or providing conditions that prevent the spores from growing.

Key Terms

  • infant botulism: poisoning caused by the toxin from Clostridium botulinum where the gastro-intestinal tract is colonized by spores prior to the protective intestinal bacterial flora having developed
  • spore: A thick resistant particle produced by a bacterium or protist to survive in harsh or unfavorable conditions.
  • botulism: Poisoning caused by the toxin from Clostridium botulinum, a type of anaerobic bacteria that grows in improperly-prepared food.
  • wound botulism: poisoning caused by the toxin from Clostridium botulinum when spores enter a wound under the skin, and, in the absence of oxygen are activated and release toxin
  • toxin: A toxic or poisonous substance produced by the biological processes of biological organisms.

Overview of Botulism

Botulism is a rare, but sometimes fatal, paralytic illness caused by botulinum toxin. It can affect a wide range of mammals, birds and fish. This toxin is a protein produced under anaerobic conditions by the bacterium Clostridium botulinum. The toxin enters the human body in one of three ways: by colonization of the digestive tract by the bacterium in children (infant botulism) or adults (adult intestinal toxemia), by ingestion of toxin from foods (foodborne botulism), or by contamination of a wound by the bacterium (wound botulism). Person-to-person transmission of botulism does not occur. All forms lead to paralysis that typically starts with the muscles of the face and then spreads towards the limbs. In severe forms, it leads to paralysis of the breathing muscles and causes respiratory failure. In light of this life-threatening complication, all suspected cases of botulism are treated as medical emergencies, and public health officials are usually involved to prevent further cases from the same source. Botulism can be prevented by killing the spores by pressure cooking or autoclaving at 121 °C (250 °F) for 30 minutes or providing conditions that prevent the spores from growing. Additional precautions for infants include not feeding them honey.

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Botulism: A 14-year-old with botulism. Note the bilateral total ophthalmoplegia with ptosis in the left image and the dilated, fixed pupils in the right image. This child was fully conscious.

C. botulinum is an anaerobic, Gram positive, spore-forming rod. Botulinium toxin is one of the most powerful known toxins: about one microgram is lethal to humans. It acts by blocking nerve function (neuromuscular blockade) through inhibition of the release of the excitatory neurotransmitter acetyl choline from the presynaptic membrane of neuromuscular junctions in the somatic nervous system. This causes paralysis. Advanced botulism can cause respiratory failure by paralyzing the muscles of the chest, which can progress to respiratory arrest. In all cases, illness is caused by the botulinium toxin produced by the bacterium C. botulinum in anaerobic conditions, and not by the bacterium itself. The pattern of damage occurs because the toxin affects nerves that fire (depolarize) at a higher frequency first.

MODES OF ENTRY

Three main modes of entry for the toxin are known. The most common form in Western countries is infant botulism. This occurs in small children who are colonized with the bacterium during the early stages of their lives. The bacterium then releases the toxin into the intestine, which is absorbed into the bloodstream. The consumption of honey during the first year of life has been identified as a risk factor for infant botulism and it is a factor in a fifth of all cases. The adult form of infant botulism is termed adult intestinal toxemia, and is exceedingly rare. Foodborne botulism results from contaminated foodstuffs in which C. botulinum spores have been allowed to germinate in anaerobic conditions. This typically occurs in home-canned food substances and fermented uncooked dishes. Given that multiple people often consume food from the same source, it is common for more than a single person to be affected simultaneously. Symptoms usually appear 12–36 hours after eating, but can also appear within 6 hours to 10 days. Wound botulism results from the contamination of a wound with the bacteria, which then secrete the toxin into the bloodstream. This has become more common in intravenous drug users since the 1990s, especially people using black tar heroin and those injecting heroin into the skin rather than the veins

TREATMENT

The only drug currently available to treat infant botulism is Botulism Immune Globulin Intravenous-Human (BIG-IV or BabyBIG). BabyBIG was developed by the Infant Botulism Treatment and Prevention Program at the California Department of Public Health. There are two primary Botulinum Antitoxins available for treatment of wound and foodborne botulism. Trivalent (A,B,E) Botulinum Antitoxin is derived from equine sources utilizing whole antibodies (Fab & Fc portions). This antitoxin is available from the local health department via the CDC. The second antitoxin is heptavalent (A,B,C,D,E,F,G) Botulinum Antitoxin which is derived from “despeciated” equine IgG antibodies which have had the Fc portion cleaved off leaving the F(ab’)2 portions. This is a less immunogenic antitoxin that is effective against all known strains of botulism where not contraindicated. This is available from the US Army.

Leprosy

Leprosy, also known as Hansen’s disease, is a chronic bacterial disease caused by Mycobacterium leprae and Mycobacterium lepromatosis.

Learning Objectives

Describe the causative agents of leprosy: Mycobacterium leprae and Mycobacterium lepromatosis

Key Takeaways

Key Points

  • Left untreated, leprosy can be progressive, causing permanent damage to the skin, nerves, limbs, and eyes.
  • M. leprae and M. lepromatosis are obligate pathogens, and are unculturable in the laboratory, a factor that leads to difficulty in definitively identifying the organism under a strict interpretation of Koch’s postulates.
  • There is now a vaccination and extensive pharmaceutical options for treatment and prevention of leprosy.

Key Terms

  • leprosy: Leprosy, also known as Hansen’s disease (HD), is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis.
  • mycobacterium: Any of many rod-shaped, aerobic bacteria, of the genus Mycobacterium, that cause diseases such as tuberculosis and leprosy

Overview

Leprosy, also known as Hansen’s disease (HD), is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis. Named after physician Gerhard Armauer Hansen, leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract. Skin lesions are the primary external sign. Left untreated, leprosy can be progressive, causing permanent damage to the skin, nerves, limbs, and eyes.

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Leprosy: A 23-year-old man infected with leprosy.

Diagnosis

Diagnosis in the U.S. is often delayed because healthcare providers are unaware of leprosy and its symptoms. Early diagnosis and treatment prevents nerve involvement, the hallmark of leprosy, and the disability it causes. There are many kinds of leprosy, but there are common symptoms, including:

  • Runny nose
  • Dry scalp
  • Eye problems
  • Skin lesions
  • Muscle weakness
  • Reddish skin
  • Smooth, shiny, diffuse thickening of skin on the face, ears, and hands
  • Loss of sensation in fingers and toes
  • Thickening of peripheral nerves
  • Flat nose due to destruction of nasal cartilage

There is also phonation and resonation of sound during speech. Often there is atrophy of the testes and impotency.

Causative Agents

Mycobacterium leprae and Mycobacterium lepromatosis are the causative agents of leprosy. M. lepromatosis is a comparatively recently identified mycobacterium that was isolated from a fatal case of diffuse lepromatous leprosy in 2008. An intracellular, acid-fast bacterium, M. leprae is aerobic and rod-shaped, and is surrounded by the waxy cell membrane coating characteristic of Mycobacterium species. Due to extensive loss of genes necessary for independent growth, M. leprae and M. lepromatosis are obligate pathogens, and are unculturable in the laboratory, a factor that leads to difficulty in definitively identifying the organism under a strict interpretation of Koch’s postulates. The use of non-culture-based techniques such as molecular genetics has allowed for alternative establishment of causation.

Routes of Infection

M. leprae is usually spread from person to person in respiratory droplets. Studies have shown that leprosy can be transmitted to humans through contact with armadillos, too. Leprosy is not known to be either sexually transmitted or highly infectious after treatment. Approximately 95% of people are naturally immune, and sufferers are no longer infectious after as little as two weeks of treatment. In 1988, Jacinto Convit was nominated for the Nobel Prize in Medicine for developing a vaccine to fight leprosy using a combination of tuberculosis (TB) vaccines with Mycobacterium Leprae. A number of synthetic pharmaceuticals that are effective against leprosy have now been identified, allowing doctors a flexible choice of treatments.

Tetanus

Tetanus is a medical condition characterized by a prolonged contraction of skeletal muscle fibers.

Learning Objectives

Describe the mode of transmission and mechanism of action for Clostridium tetani

Key Takeaways

Key Points

  • Infection generally occurs through wound contamination and often involves a cut or deep puncture wound.
  • There are currently no blood tests that can be used to diagnose tetanus.
  • Tetanus can be prevented by vaccination with tetanus toxoid.

Key Terms

  • tetanus: A serious and often fatal disease caused by the infection of an open wound with the anaerobic bacterium Clostridium tetani, found in soil and the intestines and feces of animals.
  • opisthotonos: A tetanic spasm in which the body is bent backwards and stiffened.
  • neurotoxin: A toxin that specifically acts upon neurons, their synapses, or the nervous system in its entirety.
  • tetanospasmin: The A-B toxin produced by C. tetani which is responsible for the symptoms of tetanus.

Overview

Tetanus is a medical condition characterized by a prolonged contraction of skeletal muscle fibers. The primary symptoms are caused by tetanospasmin, a neurotoxin produced by the Gram-positive, rod-shaped, obligate anaerobic bacterium Clostridium tetani.

Infection and Symptomatic Effects

Infection generally occurs through wound contamination and often involves a cut or deep puncture wound. C. tetani is not invasive, and the infection is normally confined to a wound. Here the bacteria multiply and produce tetanospasmin, which is able to travel throughout the body. Tetanospasmin is an A-B toxin. The B subunit binds to the receptors on motor neurons, while the A subunit induces endocytosis to enter the neuron. Early symptoms of the disease include restlessness, irritability and difficulty swallowing. As the infection progresses, muscle spasms develop in the jaw (thus the name “lockjaw”) and elsewhere in the body. Infection can be prevented by proper immunization and by post-exposure prophylaxis. Tetanus often begins with mild spasms in the jaw muscles (lockjaw). The spasms can also affect the chest, neck, back, and abdominal muscles. Back muscle spasms often cause arching, called opisthotonos. Prolonged muscular action causes sudden, powerful, and painful contractions of muscle groups. This is called tetany.

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Opisthotonus: Muscular spasms (specifically opisthotonos) in a patient suffering from tetanus. Painting by Sir Charles Bell, 1809.

Tetanus affects skeletal muscle, a type of striated muscle used in voluntary movement. The other type of striated muscle, cardiac or heart muscle, is not affected by the toxin because of its intrinsic electrical properties. The incubation period of tetanus can be long, and may be as long several months, but is usually about eight days. In general, the further the injury site is from the central nervous system, the longer the incubation period. The shorter the incubation period, the more severe the symptoms.

Sources of Infection

Tetanus is often associated with rust, especially rusty nails, but this concept is somewhat misleading. Objects that accumulate rust are often found outdoors, or in places that harbor anaerobic bacteria, but the rust itself does not cause tetanus nor does it contain C. tetani bacteria. The rough surface of rusty metal merely provides a prime habitat for a C. tetani endospore to reside, and the nail affords a means to puncture skin and deliver endospore into the wound. An endospore is a non-metabolizing survival structure that begins to metabolize and cause infection once in an adequate environment. Because C. tetani is an anaerobic bacterium, it and its endospores survive well in an environment that lacks oxygen. Hence, stepping on a nail, rusty or not, may result in a tetanus infection, as the low-oxygen (anaerobic) environment is provided by the same object that causes a puncture wound, delivering endospores to a suitable environment for growth.

Diagnosis, Treatment, and Prevention

There are currently no blood tests that can be used to diagnose tetanus. The diagnosis is based on the presentation of tetanus symptoms. Diagnosis does not depend upon isolation of the bacteria, which is recovered from the wound in only 30% of cases and can be isolated from patients without tetanus. The “spatula test” is a clinical test for tetanus that involves touching the posterior pharyngeal wall with a sterile, soft-tipped instrument, and observing the effect. A positive test result is the involuntary contraction of the jaw (biting down on the “spatula”); a negative test result would normally be a gag reflex attempting to expel the foreign object.

Unlike many infectious diseases, recovery from naturally acquired tetanus does not usually result in immunity to tetanus. This is due to the extreme potency of the tetanospasmin toxin; even a lethal dose of tetanospasmin is insufficient to provoke an immune response.Tetanus can be prevented by vaccination with tetanus toxoid. The CDC recommends that adults receive a booster vaccine every ten years, and standard care practice in many places is to give the booster to any patient with a puncture wound who is uncertain of when he or she was last vaccinated, or if he or she has had fewer than three lifetime doses of the vaccine. The booster may not prevent a potentially fatal case of tetanus from the current wound as it can take up to two weeks for tetanus antibodies to form.

A person infected with C. tetani can be treated with antibiotics, which will kill the multiplying bacteria but will have no effect on the endospores or the toxin. To combat the effects of the toxin, tetanus immune globulin (TIG) antitoxin can be given to the patient. These antibodies are able to neutralize the tetanospasmin if they are not already bound to motor neurons, and can confer passive immunity.

Paralysis-Causing Bacterial Neurotoxins

Botulinum toxin is a protein and neurotoxin, which blocks neuromuscular transmission through decreased acetylcholine release.

Learning Objectives

Describe the mechanism of action for botulinum toxin

Key Takeaways

Key Points

  • Botulinum toxin is produced by Clostridium botulinum, C. butyricum, C. baratii and C. argentinense.
  • The light chain of botulinum toxin is an enzyme (a protease ) that attacks one of the fusion proteins (SNAP-25, syntaxin or synaptobrevin) at a neuromuscular junction, preventing vesicles from anchoring to the membrane and releasing acetylcholine.
  • The heavy chain of the toxin is particularly important for targeting the toxin to specific types of axon terminals.

Key Terms

  • neurotoxin: A toxin that specifically acts upon neurons, their synapses, or the nervous system in its entirety.
  • acetylcholine: A neurotransmitter in humans and other animals. It is an ester of acetic acid and choline with chemical formula CH3COOCH2CH2N<sup>+</sup>(CH3)3.
  • axon: A nerve fibre, which is a long slender projection of a nerve cell, and which conducts nerve impulses away from the body of the cell to a synapse.

Botulinum toxin is a protein and neurotoxin produced by Clostridium botulinum, C. butyricum, C. baratii and C. argentinense. Botulinum toxin can cause botulism, a serious and life-threatening illness in humans and animals. In 1949, Arnold Burgen’s group discovered, through an elegant experiment, that botulinum toxin blocks neuromuscular transmission through decreased acetylcholine release. In 1973, Alan Scott used botulinum toxin type A (BTX-A) in monkey experiments. In 1980, he officially used BTX-A for the first time in humans to treat “crossed eyes” (strabismus), a condition in which the eyes are not properly aligned with each other, as well as “uncontrollable blinking” (blepharospasm). In 1993, Pasricha and colleagues showed that botulinum toxin could be used for the treatment of achalasia, a spasm of the lower esophageal sphincter. In 1994, Bushara showed botulinum toxin injections inhibit sweating; this was the first demonstration of non-muscular use of BTX-A in humans. The cosmetic effect of BTX-A on wrinkles was first reported by J. D. and J. A. Carruthers in a 1992 study on BTX-A for the treatment of glabellar frown lines. The acceptance of BTX-A use for the treatment of muscle pain disorders is growing, with approvals pending in many European countries. The efficacy of BTX-A in treating a variety of other medical conditions (including prostatic dysfunction, asthma, and others) is an area of continued study.

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Botulinum Toxin: Structure of Botulinum toxin, a protein and neurotoxin produced by the bacterium Clostridium botulinum

Foodborne botulism can be transmitted through food that has not been heated correctly prior to being canned, or food from a can that has not been cooked correctly. Most infant botulism cases cannot be prevented because the bacteria that cause this disease are in soil and dust. The bacteria can also be found inside homes on floors, carpet, and countertops, even after cleaning. Honey can contain the bacteria that cause infant botulism, so children less than 12 months old should not be fed honey.

Botulinum toxin is a two-chain polypeptide with a 100-kDa heavy chain joined by a disulfide bond to a 50-kDa light chain. This light chain is an enzyme (a protease) that attacks one of the fusion proteins (SNAP-25, syntaxin or synaptobrevin) at a neuromuscular junction, preventing vesicles from anchoring to the membrane to release acetylcholine. By inhibiting acetylcholine release, the toxin interferes with nerve impulses and causes flaccid (sagging) paralysis of muscles in botulism, as opposed to the spastic paralysis seen in tetanus. The heavy chain of the toxin is particularly important for targeting the toxin to specific types of axon terminals. The toxin must get inside the axon terminals to cause paralysis. Following the attachment of the toxin heavy chain to proteins on the surface of axon terminals, the toxin can be taken into neurons by endocytosis. The light chain is able to cleave endocytotic vesicles and reach the cytoplasm. The light chain of the toxin has protease activity. The type A toxin proteolytically degrades the SNAP-25 protein, a type of SNARE protein. The SNAP-25 protein is required for vesicle fusion that releases neurotransmitters from the axon endings (in particular acetylcholine). Botulinum toxin specifically cleaves these SNAREs, and so prevents neurosecretory vesicles from docking/fusing with the nerve synapse plasma membrane and releasing their neurotransmitters.