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The Human Nervous System
2 parts
- Central Nervous System (brain, spinal cord)
- Peripheral Nervous System (peripheral nervous system, PNS)
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Central Nervous System
- Body's control center
- Receives, interprets and disseminates information to coordinate the body's activities
- Is the brain and spinal cord
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Peripheral Nervous System (PNS)
Lines of communication between CNS, the rest of the body and the environment
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Normal flora in the human nervous system
None
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Axons:
Long extension of nerve cells, transmit impulses (bundles of axons make up nerves)
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Ganglia:
Small bodies containing sensory nerve cells located near the spinal column (but outside of it)
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Motor nerve cells
Located in the spinal column
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Parts of the Nervous system
- 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
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Blood-brain barrier
- 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
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Breach of the Blood-brain barrier
Not location of blood vessels with respect to CSF
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Cerebrospinal Fluid (CSF)
- Circulated in subarachnoid space
- -adult: 100-160 ml
- CSF is STERILECSF 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!!!
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Common modes of entry in the nervous system
- INFLAMMATION of blood or lymph: most commonTrauma; 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)
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Bacteria meningitis
- 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
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Bacterial Meningitis - symptoms
- 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
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Common Pathogenicity Factors
- 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
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Meningitis: Diagnosis and Treatment
- 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
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Results of Spinal Tap
Red is bacterial meningitis
- 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
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Pyogenic Meningitis
- Neutrophils are dominating cell
- Elevated protein
- Decreased glucose
- Positive Gram stain and/or culture
Caused by S. pneumonia, N. meningitidis, H. influenza, S. agalactiae
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Granulomatous and Lymphocytic meningitis
- Predominant cell: lymphocyte/monocyteCSF 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
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Haemophilus influenza meningitis
- 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
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Streptococcus pneumonia meningitis
- 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
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Neisseria meningitidis meningitis
- 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
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Neisseria meningitidis meningitis
Treatment, mortality
- 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
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Neonatal menigitis
- 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
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Viral Meningitis
- 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
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Listeriosis
- 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
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Tetanus
- 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
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Tetanus, the disease
- 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
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Tetanus symptoms
- 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
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Tetanus statistics
- 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
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Tetanus Treatment
- 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
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Botulism
- 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
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Infant botulism
- 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
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Botulism symptoms
- 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
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Botulism History and recipe
- 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
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Botulinal Types
- 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)
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Botulism - incidence
- 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!!!!
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Botulism: Treatment
- 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
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Botox
- 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
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Leprosy
- aka. "Hensen's Disease"
- Mycobacterium leprae (acid-fast bacilli)
- -Obligate intracellular pathogen
- -can grow in PNS and skin cells
- -optimal growth temp. = 30oC
- -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
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2 types of leprosy
- 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
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Is leprosy contagious?
- 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
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Diagnosis of leprosy
Acid-fast bacilli in smear from tissues
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Leprosy Treatment
- 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
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Poliomyelitis
- 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
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Poliomyelitis transmission
- 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
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Symptoms of Polio
- 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
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Paralytic polio
- 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
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4 Polio diseases
- 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
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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
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Polio vaccines
- 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
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Global Polio Eradication intiative
- 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
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Rabies (hydrophobia)
- 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
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Rabies disease
- 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
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Rabies: Symptoms
- 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%
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Rabies: diagnosis and treatment
- 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
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West Nile Virus
- 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
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WNV history
- 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)
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WNV clinical disease
- 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
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Complicated disease (WNV)
- 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
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Transmission of WVN
- 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
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Treatment/Vaccines for WVN
- 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
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WNV Surveillance
- Dead Bird Surveillance (Sentinel Chicken of no use for WVN)
- Surveillance of mosquito populations
- Testing of sick horses
- Blood supplies monitored for WNV
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Summary
- 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
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