MMI Part five

• Central Nervous System (brain, spinal cord)
• Peripheral Nervous System (peripheral nervous system, PNS)

• Body's control center
• Receives, interprets and disseminates information to coordinate the body's activities
• Is the brain and spinal cord

Lines of communication between CNS, the rest of the body and the environment

None

Long extension of nerve cells, transmit impulses (bundles of axons make up nerves)

Small bodies containing sensory nerve cells located near the spinal column (but outside of it)

Located in the spinal column

• Skull bone
• Cerebrum
• Cerebellum
• Spinal cord
• Subarachnoid space (dura mater, arachnoid, pia mater, subarachnoid space)
• Subarachnoid space, between the skull bone, dura mater, arachnoid, subarahnoid space, pia mater, blood vessel cerebrum

• Capillaries within the brain are more selective than others within the body:
• -less permeable
• -restrict movement of many substances into CNS
• -special transporters are present for passage of nutrients
• -many drugs cannot pass blood-brain barrier: lipid-soluble drugs pass more easily; inflammation may allow drugs to pass

Not location of blood vessels with respect to CSF

• Circulated in subarachnoid space
• -adult: 100-160 ml
• CSF is STERILE
• CSF contains LOW LEVELS of:
• -antibodies
• -complement
• -phagocytic cells (only 0-5/ml)
• Therefore, if microbes get in there really isn't much to stop them from multiplying!!!

• INFLAMMATION of blood or lymph: most common
• Trauma; skill, backbone fracture
• Medical procedures; spinal tap (needle inserted into subarachnoid space of spinal meninges to get a sample of CSF for diagnosis)
• Some microorganisms move along peripheral nerves (eg. rabies)

• Usually caused by one of 3 bacterial species:
• - S. pneumonia (G+ cocci)
• - H. influenza (G- coccobacilli)
• - N. meningitidis (G- diplococci)
• Virulent strains are encapsulated; capsuple protects from phagocytosis
• Replicate in bloodstream then enter CSF
• Inflammation and shock: LPS of G+ cell wall components; death often occurs quickly
• Other pathogens that can cause meningitis:
• -Listeria monocytogenes
• -Streptococcus agalactiae
• -staplylococci: surgical operations

• Fever
• Headache*
• Stiff neck
• + sore throat
• + photophobia
• Nausea, vomiting
• Reduced alertness, loss of consciousness, confusion
• Convulsions, coma
• May lead to death
• Survivors may sustain neurological damage
• Note: Meningitis may also be caused by virus, bacteria, fungi protozoa
• Viral: milder and more common than bacterial

• H. influenza, S. pneumonia and N. meningitidis are all transmitted by respiratore route
• -bacteria invade nasopharyngeal epithelium (mucosa)
• -recall: mucosal surfaces are protected by IgA antibodies
• -all three organisms have IgA proteases; enzymes that break down IgA antibodies
• -all three are ENCAPSULATED to evade phagocytosis

• Prompt treatment is essential!!!!
• Initiate treatment with cephalosporins prior to identification
• -resistant to penicillinase, effective against G-, broad spectrum
• -check for antibiotic sensitivity in culture
• -may change antibiotic after lab tests are done
• Sometimes: steroid treatment (dexamethasone)
• Sample: CSH obtained by spinal tap
• -check for WBC (neutrophils or lymphocyte predominance)
• -gram stain
• -culture
• -latex agglutination: positive results can be seen in 20 minutes; negative result does not rule out meningitis - less common pathogens may still be present

• Pressure: 70-180 mm H2O  200-500 mm H2O
• Appearance: Clear, colorless  Cloudy
• Total protein: 15-60mg/100mL elevated
• Glucose: 50-80mg/100mL (or >2/3 blood sugar level) decreased
• Cell count: 0-5 WBC, no RBS  Elevated: may be neutrophil or lymphocyte predominance

• Neutrophils are dominating cell
• Elevated protein
• Decreased glucose
• Positive Gram stain and/or culture

Caused by S. pneumonia, N. meningitidis, H. influenza, S. agalactiae

• Predominant cell: lymphocyte/monocyte
• CSF protein moderately increased
• CSF glucose moderately decreased
• "negative" Gram stain (no bacteria seen): M. tuberculosis and L. monocytogenes hard to find in smear
• Viral agents will not be visible

• Aerobic, Gram-negative, encapsulated
• Common member of normal flora of throat
• Can cause: meningitis, pneumonia, epiglottitis, otitis media
• Pathogenicity factors: capsul, IgA protease, pili, endotoxin; OMP (Hib most common cause of invasive Haemophilus disease)
• Before vaccine - most common cause of meningitis in children <4 yr old: vaccine available (effective in infants)
• Treatment: i.v cefotaxime, ceftriaxone, ampicillin

• a.k.a. Pneumococcal Meningitis
• Streptococcus pneumonia: Gram-positive, diplococcus; encapsulated, IgA protease; alpha-hemolytic
• Leading cause of bacterial meningitis
• Highest complication rate of all meningitis, 15-20% in treated cases
• 20-30% mortality in treated cases
• Often found in normal flora of nose/throat
• Vaccine available and effective in infants
• Treatment: penicillins, cephalosporins

• Meninngococcal meningitis
• Neisseria meningitidis: Gram-negative, aerobic diplococcus; capsule, IgA protease, endotoxin, pili
• Often present in nose/throat (10% of population)
• Disease most common in kids <2 years old
• Throat infection->bacteremia->meningitis
• Symptoms caused by endotoxin (LPS): vascular necrosis leads to skin hemorrhage and petechial rash
• May progress to severe G- sepsis: DIC, endotoxinemia, shock
• Sepsis can lead to tissue destruction and requirement for amputation of limbs
• Death can occur a few hours after onset of fever

• Treatment:
• Penicillins and cephalosporins
• Don not always affect outcome
• Help to limit spread of disease
• Mortality:
• With chemotherapy: 9-12%
• Without: close to 100%
• Vaccine available for some types

• Can be cause by many different bacteria
• Most common is S. agalactiae (Strep group B or GBS)
• Symptoms and signs are diffuse: hard to diagnose infection
• May have bulging fontanelle
• Fever, poor feeding, vomiting, respiratory distress, diarrhea
• Complications devastating: 1/3 of cases have cerebral or cranial nerve palsy, epilepsy, mental retardation or hydrocephalus
• B is Bad for Babies

• Viruses are the major cause of "acute aseptic meningitis syndrome"
• -abrupt onset
• -characterized by a lymphocytic pleocytosis
• -difficult to diagnose viral agent, most cases caused by enteroviruses or Herpes viruses

• Listeria monocytogenes
• -Gram-positive bacillus
• -heat-resistant
• -can grow at refrigerator temperatures
• -often spread via food
• -capable of growth in phagocytic cells
• Causes only mild symptoms in healthy adults
• Causes meningitis and sepsis in neonates and immunocompromised people
• Treatment: ampicillin, trimethoprim-sulfamethoxazole

• Clostridium tetani (anaerobic, endospore-forming G+ bacilli)
• -rusty nail, dirty needles, sinning on a tack
• Common in soil contaminated with animal wastes
• Effective toxoid vaccine available
• -96% of 7-yr olds have good immunity
• -30% of 70-yr olds have immunity
• -some were never immunized, others have lost effective antibody levels
• -boosters required every 10 years
• -70% of tetanus cases occur in adults over 50

• Spores are present in soil or feces
• Spores enter skin via trauma: need to get into deep tissue - anaerobic environment
• Bacteria germinate from endospores
• Bacteria release toxin: bacteria do not need to spread
• Toxin travels up peripheral nerves and through blood

• Start with lockjaw
• Progresses to opisthotonos: spasms of back muscles, pneumonia or regurgitating stomach contents into lungs
• Symptoms are caused by tatanospasmin: extremely potent neurotoxin; blocks the release of inhibitory neurotransmitters (required to stop muscle contraction)
• No inflammation
• Very little immune response: not enough toxin to stimulate effective immune response

• Estimated 1 million cases worldwide/year (only ~50 in USA)
• At least half of these cases occur in newborns
• -umbilical cords are dressed with clay, soil or cow dung
• -most babies who get it do not survive

• Clean wound
• -debridement may be required to remove damaged tissue and prevent production of more toxin
• -not useful if toxin has already attached to nerves
• Antitoxin
• -human anti-tetanospasmin immunoglobulin
• -NOT the same as toxoid vaccine - there would not be enough time to develop immune response
• Drugs
• -penicillin
• -metronidazole
• -diazepam (works like an inhibitory neurotransmitter to counteract the toxin)
• Toxoid vaccine exists - make sure patient is vaccinated to prevent disease in future

• Clostridium botulinum
• -obligate anaerobe, endospore-forming, G+ bacilli
• -soil, freshwater sediments
• Produces the most potent of all natural toxins
• -blocks release of acetylcholine - BLOCKS activating nerve impulses
• -opposite of tetanus toxin activity
• Disease is transmitted through food
• -toxin may be present in canned food that was contaminated with C. botulinum endospores
• -host ingests the PRE-FORMED toxin
• -toxin causes symptoms
• Ingestion of endospores does not cause disease in adults
• -adults developed normal flora is protective

• Many causes associated with honey
• Lethal dose: 2000 bacteria
• Infants (<1 year) do not have good stomach acidity or protective gut flora: spores are able to germinate
• Treat with anti-toxin
• No ill consequences if diagnosis made in time

• Appear within 1-2 days
• nausea, no fever
• double or blurred vision
• Difficulty swallowing, general weakness
• Progressive flaccid paralysis (lasting 1-10 days)
• Death from respiratory and cardiac failure
• Recovery does NOT confer immunity
• -toxin not present in large enough amounts
• -same as tetanus

• History: early 1800s-> "the sausage disease"
• -botulus = sausage
• Recipe for blood sausage:
• -fill pig stomach with blood and ground meat
• -tie openings shut
• -boil for a short time
• -smoke over wood fire
• -store at room temperature
• Satisfies requirements for botulism outbreak:
• -kill competing bacteria (by heating)
• -allow heat-resistant C. botulinum endospores to survive
• -provides anaerobic conditions and an incubation period for toxin production

• Different strains -> differ in virulence and other factors
• Type A toxin: most virulent (50%)
• -death due to tasting or handling lab specimens
• -60-70% mortality if untreated
• -proteolytic: breaks down protein -> unpleasant odor
• Type B toxin: (25%)
• -25% mortality if untreated
• -proteolytic or non-proteolytic
• Type E toxin: marine or lake sediments (25%)
• -seafood
• -least heat-resistant, usually destroyed by boiling
• -can produce toxins at refrigerator temp, less strictly anaerobic
• -non-proteolytic (no detection by odor)

• Highest incidence of botulism worldwide: Inuit in Alaska - mostly E toxin: arises from cultural tradition: avoiding use of scarce fuel
• Recipe for muktuk
• -slice flippers of seals or whales into strips
• -dry (a few days will do)
• -tenderize: store in seal oil for several weeks (anaerobically) until they approach putrefaction
• -ENJOY!!!!

• Largely supportive: requires regeneration of nerve endings
• Respiratory assistance may be required
• Antibiotics not very useful -> toxin is pre-formed
• Antitoxins are available (trivalent)
• -does not affect toxin already attached to nerve endings
• -most effective on type E

• Botulinum toxin type A
• -most potent - would make a good bioweapon
• - 400 grams is enough to kill the world's population
• Small amounts injected directly into specific muscle acts to paralyze only the "problem area"
• -twitch, frown line, etc

• aka. "Hensen's Disease"
• Mycobacterium leprae (acid-fast bacilli)
• -Obligate intracellular pathogen
• -can grow in PNS and skin cells
• -optimal growth temp. = 30^oC
• -cannot be cultured artificially: armadillo = lab rat for leprosy
• Affects nerves of hands, feet and face
• Untreated:
• -loss of movement in fingers, toes, eyes
• -destroys ability to feel pain
• -can result in injuries that go unnoticed leading to serious infections
• -secondary infections
• -ultimately leads to loss of limbs

• Difference is based on effectiveness of host immune response
• tuberculoid (neural) leprosy
• -region of skin lacking sensation, surrounded by nodules
• -cell-mediated immune reaction (relatively effective)
• -spontaneous recovery may occur
• lepromatous (progressive) leprosy
• -skin cells affected, disfiguring nodules all over body
• -antibody-mediated immune response (ineffective)
• -remission may alternate with rapid deterioration
• -hypergammaglobulinemia

• leprosy is not very contagious
• -transmission usually only between people in close, prolonged contact (family members)
• Probably spreads via secretions from nasal mucosa
• Incubation period usually measured in years
• Death usually results from complication or secondary infections

Acid-fast bacilli in smear from tissues

• Leprosy can be cured using multidrug therapy (MDT)
• -dapsone, rifampin, and clofazimine in combination are the most common
• If treatment is started early, deformities can be prevented

• Picornaviriae Enterovirus
• -ssRNA, non-enveloped
• Most cases are asymptomatic
• Can lead to paralysis of death (<1%)
• Polioviruses are very stable, can remain infectious for long periods in water or food
• Natural immunity - poor sanitary conditions
• Transmission: fecal-oral

• Enters via mouth (fecal-oral transmission)
• Multiplies in throat, small intestine
• Tonsils, lymph nodes: often ends here, "Abortive poliomyelitis"
• Enters blood (viremia)
• Invades CNS
• -spreads along nerve fibres
• -destroys nerve cells -> paralysis
• -these cells cannot be regenerated
• -BUT some new connections may be formed
• No drug treatment available

• Sore throat, nausea, stiff neck, fever, fatigue, headaches
• -occur prior to CNS invasion
• -"non-paralytic poliomyelitis"
• "Paralytic poliomyelitis"
• Acute flaccid paralysis (AFP)
• -floppy limbs
• More extensive -> quadriplegia
• Most severe -> bulbar polio
• -attacks motor neurons of brain stem
• -interferes with ability to breathe, speak, swallow
• -results in death without respiratory support

• Affects the CNS, first symptoms are usually severe myalgia in one limb, motor or sensory disturbances, weakness (may be transient or permanent)
• Bulbar: involves one or more cranial nerve centers, including respiratory center in medulla oblongata
• Spinal: 30% affect lower limbs

• Abortive poliomyelitis
• -most common forms, minor flu-like illness
• Non-paralytic poliomyelitis
• -Aseptic meningitis, has minor flu-like symptoms plus stiff neck and back
• Paralytic poliomyelitis
• -Major illness, flaccid paralysis
• PPMA or PPS
• -Post polio muscle atrophy of post polio syndrome

• Affects polio survivors years after infection/recovery
• Gradual new weakening of affected muscles
• Muscle atrophy
• Joint degeneration
• Skeletal deformities (eg. Scoliosis)
• Estimated that 25-40% of polio survivors are affected
• Usually occurs > 15 years after recovery
• Cause unknown
• No drug treatment
• No prevention

• 2 types of vaccine:
• IPV (inactivated polio vaccine) (SALK vaccine)
• -injectable killed virus
• -no risk of disease development
• -very little intestinal immunity
• -DTaP-IPV vaccine started at 2 months
• OPV (oral polio vaccine) (SABIN vaccine)
• -oral, live, attenuated (weakened) virus
• -immunity resembles natural: good intestinal immunity
• -rare cases where disease can result in immunized individual or close contact (immune deficiency imp.)
• -cheaper than IPV

• Launched in 1988 by WHO
• Number of cases has dropped by 99%
• 1988: 350,000 cases, 125 endemic countries
• 2011: 650 reported cases
• 2012: only 3 endemic countries (Nigeria, Pakistan, Afghanistan)
• Estimates: 10 million people walking who would have been paralyzed; 1.5 million childhood deaths prevented

• Zoonotic viral disease (RNA), can infect all species of mammals
• Virus usually contracted by bite of rabid animal, - virus can penetrate an intact mucous membrane as well
• Death always results from infection if treatment not initiated quickly, and high mortality even if treated with immune globulin

• Rhabdoviridae Lyssavirus
• -enveloped ssRNA virus
• Transmitted by bite from infected animal
• Incubation: 30 days to 6 years
• Once virus enters PNS it is protected from immune system until CNS cells start to be destroyed
• 1. Virus enters tissue from saliva of biting animal
• 2. Virus replicates in muscle near bite
• 3. Virus moves up peripheral nervous system to CNS in spinal cord
• 4. Virus ascends spinal cord
• 5. Virus reaches brain and causes fatal encephalitis
• 6. Virus enters salivary glands and other organs of victim

• Preliminary (prior to CNS involvement): mild, varied, resembles many common infection
• When CNS is involved:
• -aternate between agitation and calm
• -painful spasms of muscles of mouth and pharynx when patient swallows: inability to clear saliva causes classic "foaming at the mouth"; sight or thought of water can set off spasms; hydrophobia - patient avoids drinking
• -may try to bite anything in reach (even humans may exhibit this behaviour): important for maintaining virus in the population
• -ultimately progress to extensive damage to nerve cells of brain and spinal cord
• If disease develops, then mortality is ~100%

• Diagnosis:
• -identify characteristic infected cells
• -PCR for viral RNA
• -serology
• Treatment
• -wash wound immediately with ordinary hand soap and water (reduces infections by 50%)
• -HRIG (humang rabies immunoglobulin): antibodies - provide passive immunity
• -vaccine: UNUSUAL!!! vaccine is usually only preventative; rabies incubation is ong enough to allow immune response to develop to vaccine after exposure
• Prevention
• -immunize susceptible animals

• Family: Flavividae
• Genus: Favivirus Japanese Antigenic Complex
• Small 40-60 nm, enveloped RNA virus
• 1937 - first isolated in West Nile Province, Uganda
• Outbreaks in Egypt, Israel, South Africa, Asia, Europe, North America in humans and horses

• 1999: appeared in NA, New York, 62 cases, 7 deaths
• 2000: 21 cases in NY, NJ, and Ct, 2 deaths
• No confirmed cases contracted in Canada in humans up to 2001, now >500 human cases
• Surveillance is ongoing
• Has been isolated from crows in every province in Canada
• Reached Alberta 2003: July first positive bird (Camrose), August first human case in Calgary (asymptomatic)
• Little progression 2004 (9 birds in AB)

• Most cases asymptomatic or mild, 15-20% of individuals bitten by an infected mosquito develop symptoms of some kind
• Low mortality (usually only in elderly and immunocompromised)
• Symptoms 3-15 days after bite of vector
• If symptoms: fever, headache, body aches, + rash, swollen lymph glands
• Development of encephalitis/meningitis in < 1% of infected individuals
• Long term neurological effects in 50% of WNV neurological syndrome

• Found mostly in elderly, people with pre-existing chronic conditions and immunocompromised
• Rapid onset severe headache, high fever, stiff neck, vomiting, drowsiness, confusion, muscle weakness, coma
• Meningitis (inflammation of lining of brain and spinal cord)
• Encephalitis (inflammation of brain)
• New, never seen before complication is a polio-like paralysis syndrome

• Mosquito borne virus, birds are reservoir
• Several species of mosquitoes
• Not transmissible human-human
• Some evidence for crow-crow transmission
• >75 species of birds can be infected
• Most common birds: Crow, Raven, Jay, Magpie

• For humans: supportive treatment, no vccine or antiviral available
• For horses: supportive treatment with IV drip, good nursing care to prevent secondary infection, vaccine availalble 2003

• Dead Bird Surveillance (Sentinel Chicken of no use for WVN)
• Surveillance of mosquito populations
• Testing of sick horses
• Blood supplies monitored for WNV

• Meningitis and encephalitis are two dfferent syndromes
• CSF is a nutrient media for the growth of bacteria
• Blood-brain barrier protects spinal cord and brain from infection
• Most common route of infection to the CNS is blood
• Capsules important for bacteria causing meningitis
• Neonatal meningitis is often caused by Streptococcus agalactiae (group B)
• Viral meningitis also called "aseptic meningitis"
• Tetanospasimin and botulinum: exotoxins
• M. leprea: two types of disease
• Rabies
• West Nile Virus