1. Microbial Diseases of the Nervous System

2. The nervous system is divided into the central nervous system and the peripheral nervous system.

3. Central nervous system: brain and spinal cord Peripheral nervous system: cranial and spinal nerves, some of which are organized into plexuses Cauda equina

4. The central nervous system (CNS) is composed of the brain and spinal cord and functions as the master control center of the body. The brain stem, which connects the brain to the spinal cord, has a number of functions, including control of breathing, heart rate, and blood pressure. The lower cerebellum controls many involuntary body movements, such as swinging the arms while walking. The brain has several main parts: The cerebrum—the largest, upper part of the brain— controls voluntary muscles, perception, and what people commonly call “thinking.” 1. Structures of the Central Nervous System:

6. The spinal cord extends down from the brain stem only as far as the lumbar region (lower back). Below this region, a bundle of nerves called the cauda equina extends from the spinal cord (this bundle resembles the tail of a horse).

8. cauda equina extends from the spinal cord (this bundle resembles the tail of a horse). Cauda equina

9. Support and protection from external shock are provided to the brain and spinal cord by: * bones of the cranium * bones of the vertebral column * three layers of issue called meninges ( קרומי המוח ) surround the brain and spinal cord.

10. The three meninges vary in their structure and appearance: The internal meninx, which is closely appressed to the spinal cord and brain, is the pia mater. The cavities between the fibers of the arachnoid mater are collectively called the subarachnoid space. Deep to the dura mater is the arachnoid mater, which contains numerous branching fibers giving the appearance of a spider’s web. Lying next to the bones is the dura mater, a tough fibrous sheath that provides a strong yet flexible covering. It also provides a barrier against the spread of infections from the bones.

11. Three protective meninges surround the brain. A triangular-shaped cavity at the top of the cranium contains blood and absorbs cerebrospinal fluid from arachnoid villi.

12. The meninges also surround the spinal cord extending down the vertebral column.

13. Spinal tap ( lumbar puncture, LP )-collection of a sample of cerebrospinal fluid from the subarachnoid space in the lumbar region, a region containing the cauda equina instead of the spinal cord.

15. Blood vessels that supply the CNS lie on top of the pia mater. The walls of these blood vessels are composed of tightly joined cells that form the blood-brain barrier (BBB), which prevents most microbes and large molecules in the blood from entering the subarachnoid space.

16. Thus, blood infections do not easily spread to the CNS, but unfortunately, neither do many common antimicrobial drugs, making it more difficult to treat infections of the CNS.

17. Fluid leaks from the blood into the subarachnoid spaces lining cavities deep within the brain. Cerebrospinal fluid: * acts as a shock absorber; * provides nutrients, electrolytes, and oxygen to the nervous tissues; * removes wastes. This watery fluid — called cerebrospinal fluid (CSF) — circulates throughout the subarachnoid spaces of both brain and spinal cord to bathe both organs.

19. Cerebrospinal fluid The chemical and cytological composition of CSF is modified by meningeal or cerebral inflammation, i.e. meningitis or encephalitis. Normal CSF is sterile and clear, and usually contains few leukocytes and no erythrocytes. The examination of cerebrospinal fluid (CSF) is an essential step in the diagnosis of bacterial and fungal meningitis.

20. 2. Structures of the Peripheral Nervous System: Functionally, there are three types of nerves: -Sensory nerves primarily carry signals toward the CNS (optic nerves from the eyes are examples). -Motor nerves carry signals from the CNS to other organs of the body -Mixed nerves carry signals both toward and away from the CNS PNS is composed of nerves that transfer commands from the CNS to muscles and glands throughout the body and provide information to the CNS concerning events in the body.

21. Cells of the Nervous System Neurons: two types of fingerlike, cytoplasmic processes extend from a cell body – numerous of short dendrites and a longer single axon.

22. Outside the CNS, a collection of many neurons’ cell bodies is called a ganglion

23. The terminal ends of axons have thousands of branches that form junctions called synapses with glands, muscles, or other neurons. A synapse mediates transfer of a signal to a neighboring postsynaptic cell.

24. Portals of Infection of the Central Nervous System Pathogens may access the CNS through: * breaks in the bones and meninges * medical procedures such as spinal taps * by traveling via axonal transport in peripheral neurons to the CNS. No openings allow microbial colonization of the central nervous system.

25. Microbes carried in the blood or lymph may penetrate the BBB by infecting and killing cells of the meninges, causing meningitis Some pathogens gain access to the CNS when localized inflammation distorts the cells of the BBB – during chronic infection by many pathogens

26. Circulation of CSF can carry infective microbes throughout the cranial cavity ( the space formed inside the skull) and spinal column.

27. Bacterial Diseases of the Nervous System

28. I) Bacterial infections of the meninges Bacterial Meningitis

29. Signs: - increased number of white blood cells in the CSF - sudden high fever - intense meningeal inflammation: swelling of the meninges retards the normal flow of CSF, putting pressure on the underlying organs Bacterial meningitis involves inflammatory bacterial infection of the meninges, commonly the pia mater and arachnoid mater and more rarely the dura mater

30. Symptoms: When the brain becomes infected—a condition called encephalitis—deafness, blindness, drastic changes in the patient’s behavior, coma, or death may result Inflammation of the spinal meninges puts pressure on surrounding nerves and muscles, producing stiffness in the neck and affecting sensory input and muscular control Inflammation of the cranial meninges typically produces severe headache, nausea, vomiting, pain, and in many cases loss of various brain functions, leading to such conditions as drowsiness, confusion, fretfulness

31. Bacterial meningitis is also typified by a dramatic increase in the number of leukocytes in the CSF A spinal tap reveals the CSF is quite milky in color due to the large number of bacteria and white blood cells

32. Pathogens and Virulence Factors All five of these bacteria have virulence factors that allow them to resist phagocytosis and cause disease However, five other species cause almost 90% of cases of bacterial meningitis: - Neisseria meningitidis - Streptococcus pneumoniae - Haemophilus influenzae - Listeria monocytogenes - Streptococcus agalactiae More than 50 species of bacteria can cause meningitis. Among these are opportunistic members of the normal microbiota: - Staphylococcus - Streptococcus pyogenes - Gram-negative enteric bacteria such as Escherichia coli and Klebsiella pneumoniae

33. Neisseria meningitidis The bacterium is known as the meningococcus and its disease as meningococcal meningitis The cells of all strains of Neisseria are nonmotile and are typically arranged as diplococci (pairs) with their common sides flattened in a manner reminiscent of coffee beans Gram-negative

34. Gram-negative diplococci macrophage

35. Virulence factors of Meningococci: - Fimbriae (mediate attachment of the bacterium)

36. - polysaccharide capsule resists lytic enzymes of the body’s phagocytes, allowing phagocytized meningococci to survive, reproduce, and be carried throughout the body within neutrophils and macrophages)

37. The lipid A component of LOS thereby released into the body triggers fever, vasodilation, inflammation, shock, and widespread blood clotting - major cell wall antigen called lipooligosaccharide (LOS), composed of lipid A (endotoxin) and sugar molecules. Much of the damage caused by N. meningitidis results from blebbing — a process in which the bacterium sheds extrusions of its outer membrane

38. All these firulence factors enable the bacteria to attach to human cells Cells of Neisseria that lack any of these three structural features are avirulent

39. Streptococcus pneumoniae The bacterium is a Gram-positive coccus, which forms short chains or, more commonly, pairs (Gram-positive diplococci)

40. Streptococcus pneumoniae is the leading cause of meningitis in adults Even though microbiologists have studied the pneumococci, they still do not fully understand how they cause disease Ninety-two different strains of S. pneumoniae (pneumococci) are known to infect humans as normal members of the microbiota of the throat that opportunistically grow in the lungs, sinuses, and middle ear and from those locations move into the meninges via the blood

41. - The cells of all virulent strains of S. pneumoniae are surrounded by a polysaccharide capsule, which protects them from digestion after phagocytosis. Unencapsulated strains do not cause disease. Nevertheless, certain structural and chemical virulence factors are necessary for disease:

42. * pneumolysin, which suppresses the digestion of phagocytized bacteria by interfering with the action of lysosomes * secretory IgA protease, which destroys immunoglobulin A secreted against the bacteria Pathogenic pneumococci also produce:

43. Pathogenic S. pneumoniae inserts into its cell wall hosphorylcholine - binds to receptors on cells in the lungs, meninges, blood vessel walls, stimulating the target cells to endocytize the bacteria Thus, the phosphorylcholine and polysaccharide capsule together enable pneumococci to “hide” inside body cells. S. pneumoniae can then pass across these cells into the blood and brain

44. Haemophilus influenzae Most strains of H. influenzae have polysaccharide capsules that resist phagocytosis As a result, it is an obligate parasite, colonizing mucous membranes of humans and some animals Small pleomorphic bacillus that requires heme and NAD+ for growth

45. Staphylococcus aureus and Haemophilus influenzae satellitism test:

46. II) Neurological diseases caused by bacterial toxins

47. Botulism It is not an infection, but instead an intoxication (poisoning) caused by a toxin of Clostridium botulinum that adversely affects synapses of the peripheral nervous system C. botulinum is an anaerobic, endospore-forming, Gram- positive bacillus common in soil and water worldwide

48. Even a small taste of food contaminated with the powerful toxin, such as licking a spoon, can cause full-blown illness or death Botulism toxin is one of the more powerful natural poisons — 30 grams of pure toxin would be enough to kill every person in the United States

49. Fortunately, all three are rare Clinicians recognize three manifestations of botulism: - foodborne botulism - infant botulism - wound botulism

50. 1) Foodborne botulism

51. Endospores germinate to produce vegetative cells that grow and release the debilitating toxin that causes botulism into the jar or can The endospore, which forms at the end of the cell, survives improper canning of non-acidic foods (pH 4.5) such as meats, eggs, mushrooms, beans, corn, beets, peas, and some cheeses

52. Progressive paralysis of all voluntary (skeletal) muscles begins on both sides of the body as peripheral nerves are affected Survivors recover very slowly as their nerve cells grow new endings over the course of months or years, replacing their nonfunctioning tips Death, if it occurs, is from paralysis of the diaphragm, which is the major muscle of breathing; the patient cannot inhale

53. 2) Infant botulism: In this disease, the bacterium actually grows in a child’s intestinal tract, where it secretes toxin. It differs from foodborne botulism in that the toxin is not ingested. It is a disease of infants who are usually under 6 months of age.

54. Infants are susceptible to colonization because their GI tracts do not have a sufficient number of benign microbiota to compete with C. botulinum for nutrients and space. In adults, microbial antagonism by normal intestinal microbiota prevents growth of the bacterium in the intestinal tract.

56. 3) Wound botulism: Signs and symptoms similar to those of the foodborne disease, but the incubation period is longer — four days or more. Involves growth of the bacterium in dead tissue following introduction of endospores into wounds.

57. Virulence Factors Botulism toxin is protein composed of: - single neurologically active polypeptide - one or more nontoxic polypeptides that stabilize the toxin and prevent its inactivation by stomach acid.

58. Pathogenesis As with most synapses, the two cells do not actually touch; a synaptic cleft remains between them. Such a synapse is called a neuromuscular junction. Each of the many ends of a motor neuron forms a synapse with a muscle cell. To understand the action of botulism toxins, we must consider the way the nervous system controls muscle contractions.

59. The neuron stores the neurotransmitter acetylcholine in vesicles near its terminal cytoplasmic membrane. ACh mediates communication between neurons and muscle cells.

60. When a nerve impulse arrives at the terminus of a motor neuron, ACh vesicles fuse with the neuron’s cytoplasmic membrane, releasing ACh into the synaptic cleft. The binding of ACh to the ACh receptor triggers a series of events inside the muscle cell that results in muscle contraction. Molecules of Ach then diffuse across the cleft and bind to receptors on the cytoplasmic membrane of the muscle cell.

61. Botulism toxins act by binding irreversibly to neuronal cytoplasmic membranes, thereby preventing the fusion of vesicles and the secretion of acetylcholine into the synaptic cleft.

62. Thus, botulism neurotoxins prevent muscular contraction, resulting in a flaccid paralysis. Once bound to a neuronal cell membrane, botulism toxin is never released; the synapse is forever blocked and botulism may progress despite aggressive medical care.

63. A positive use for botulism toxin Purified type A botulinum toxin is marketed as Botox, extremely small doses of which are injected into facial muscles that cause skin wrinkles. The toxin paralyzes or weakens the muscles, smoothing the skin. Such treatments last approximately six months and must be repeated in order to maintain the desired effects.

64. Pathogen and Virulence Factors Clostridium tetani is a small, motile, obligate anaerobe that produces a terminal endospore, giving the cell a distinctive “lollipop” appearance Tetanus

65. Spasms and contractions may spread to muscles, becoming so severe that the arms and fists curl tightly, the feet curl down, and the body assumes a stiff backward arch as the heels and back of the head bend toward one another. Complete, unrelenting contraction of the diaphragm results in a final inhalation—patients die because they cannot exhale. Signs and Symptoms

66. Vegetative cells are extremely sensitive to oxygen and live only in anaerobic environments. Cells of C. tetani release a potent neurotoxin called tetanospasmin when they die. Tetanospasmin binds to the cytoplasmic membrane of a neuron, triggering the neuron to endocytize the toxin. Axonal transport carries the toxin to the central nervous system. C. tetani remains localized at the site of infection; only the toxin moves to the central nervous system.

67. Pathogenesis Wooden splinters, shaving nicks, tack wounds, and drug injections, as well as more serious cuts and punctures of the skin or mucous membranes, have introduced endospores into patients where the endospores germinated, grew, died, and released tetanospasmin. Any break in the skin or mucous membranes can allow endospores of C. tetani access to deeper tissues, which lack free oxygen. Contrary to popular belief, deep puncture wounds by rusty nails are not the only (or even primary) source of tetanus.

68. Two kinds of neurons of the central nervous system act on motor neurons: Tetanospasmin blocks the release of inhibitory neurotransmitter. - Inhibitory neurons release an inhibitory neurotransmitter, hindering motor neurons from producing the nerve impulse, so the muscle remains relaxed. - Stimulatory neurons release a neurotransmitter that excites motor neurons to produce a nerve impulse, resulting in muscle contraction.

70. With inhibition blocked, excitation of the motor neurons is unregulated, and the muscle is signaled to contract. The result is that muscles contract and do not relax. Contractions can be so severe they break bones.