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73 Cards in this Set
- Front
- Back
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What is the BBB?
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It is a functional barrier between the blood and the brain - formed by tight junctions.
Pevents entry of microbe, toxins, circulating NTs into the brain and prevents changes in plasma electrolytes from affecting CSF |
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What are the functional consequences of a BBB?
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Reduces penetration of water soluble substances (unless specific transporter)
Protects brain from plasma borne metabolites, toxins, pathogens Barrier to immune system Xenobiotics (drugs) are normally excluded (ESP. Water soluble) - CAN BE A PROBLEM |
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What are some examples of lipid soluble substances that can enter the brain rapidly?
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Oxygen, carbon dioxide, anesthetics, ethanol, nicotine, heroin
Where as penicillin, glucose are poorly lipid soluble (but glucose-D has a TRANSPORTER) |
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Which glucose transporter is located in the brain?
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GLUT1 mainly
High density, insulin insensitive (also present in RBC and kidney) Also GLUT3 |
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Wich glucose transport is insulin sensitive?
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GLUT 4
Found in skeletal muscle, fat and the heart |
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What is hereditary GLUT1 Deficeincy ?
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Deficiency of GLUT1 (glucose transporter in the brain)
Autosomal dominant -- causes low CSF, Low glucose ---> childhood refractory siezures, ataxia, developmental delay and microcephaly and microencephaly |
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What are some approaches to by-passing the BBB?
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Use a pro-drug --- ie. L-DOPA (has is own transporter and then is converted into dopamine in CNS)
Exploit present transporters Exposure of BBB to Hyperosmolar solutions -- leads to shrinkage of endothelial cells and opening of intercellular space --- to allow passage of drugs into CNS --- BUT unspecific and also allows toxic metabolites, drugs, blood cells and microorganisms in as well! |
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What role do foot processes have in the BBB?
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They DO NOT form the BBB
But they DO: force endothelial cells to express tight junction Regulate transport Regulate ion, NT homeostasis Produce immune mediators - cytokines, chemokines, antimicrobials |
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Wat processes/diseases can dysrupt the BBB?
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Stroke, ischemia, tramua, infection, autoimmune (MS), neurodegenerative (Parkinson's, AD),epilepsy, tumours, metastases, toxins, drugs, contrast media, inflammatory mediators!!
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What is merosin deficiency ?
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Merosin is a component of laminin - park of the basement membrane.
Without it --> muscular dystrophy and BBB problems |
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What problems are associated with BBB breakdown?
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Infection
Oedema Changes in permeability - toxins, metabolites, water, drugs |
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How can microorganisms enter the CNS?
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Direct implantation - trauma, iatrogenic
Extension from contiguous focus of infection - middle ear infection (microbes eat through the bone) Haematogenous spread - BBB breakdown (between cells, direct damage to endothelial cells, transcellular, Trojan horse - within infected WBC) |
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What is meningitis?
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Inflammation of the meninges
Usually associated with bacteriaemia leading to spread into CNS (must cross BBB) |
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Is penicillin effective in treating meningitis?
How? |
Yes
Because of the inflammation associated with meningitis - there is breakdown of the BBB -- allowing penicillin to enter CNS (usually it cannot) -only applicable to pathogens sensitive to penicillin |
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What is a poikilotherm?
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A coldblooded animal - does not regulate body temperature
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What is a homeotherm?
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Animal that regulates body temperature within a narrow range
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What is the Normal range for body temperature?
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36-38
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What is considered a fever?
Heat stroke/hyperthermia? |
38-40
40-44 |
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What is considered normal temp?
Mild hypothermia? Severe hypothermia? Cardiac fibrillation?? |
Normal: 36-38
Mild hyperthermia: 34-36 Severe hypothermia: 30-34 Cardiac fibrillation: 27-29 Degrees celcius |
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At what temperature may cardiac fibrillation spontaneously occur in a normal person?
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27-29 degrees celcius
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At what time of the day is our temperature highest ? And lowest?
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Highest 3-6pm
Lowest 3-6am Varies by 1 degree |
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What factors limit evaporation?
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Dehydration
Clothing Limited capacity to increase Cardiac output (heart failure, hypovolaemic shock) Limited ability to shunt blood to skin (loss of autonomic control) |
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What does metabolic rate dependon?
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Muscle activity
Hormones (adrenalin, thyroxine) Thermal load |
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What area of the brain is the main control center for temperature regulation ?
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Hypothalamus
Preoptic area and dorsomedial area |
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What are the problems associated with heat stroke?
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Heat stroke - body temp 40-44 degrees Celsius
Core temp rises -- increased skin vasodliation -- drop in BP -- reduced perfusion of tissues (ESP brain) Consequences include: intravascular clotting and haemorrhage Breakdown of muscle including heart Failure of liver, pancreas, kidneys, CNS function impaired |
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What is the preoptic area of the hypothalamus involved with?
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Regulating heat loss in a warm environment (prevents over heating)
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What are the Afferent pathways involved in Thermoregulation?
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Skin thermoreceptors --
1) dorsal horn, SC, thalamus, S1 2) brainstem - parabrachial region Then to hypothalamus Preoptic area |
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What are the efferent pathways involved in Thermoregulation ?
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Preoptic area of hypothalamus projects to dorsomedial hypothalamus --> raphe pallidus in brainstem -->
1) SNS - skin BV, brown adipose tissue 2) skeletal muscle Note: brown adipose tissue - involved in non-shivering thermogenesis |
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What are 4 broad categories of infections affecting the CNS?
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Meningitis
Encephalitis Abscess Prion disease |
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What are the 3 characteristic signs and symptoms of meningitis?
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Fever
Headache Neck stiffness |
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How is Dx of meningitis usually made?
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Culture of CSF or Blood
Viral - wont culture |
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Wich has a better prognosis - viral or bacterial meningitis?
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Viral
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What common organisms are involved in acute bacterial meningitis?
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Meningococcus (Neisseria Meningitis)
Pneumococcus (strep. Pneumoniae) Haemophilus influenzae B (ESP infants - but reduced due to vaccination) |
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What CSF features are common in acute bacterial meningitis?
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Neutrophils present
Low glucoses High protein |
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What viruses commonly cause viral meningitis?
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Echo, coxsackie, mumps, measles
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What CSF features are common with viral meningitis?
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Lymphocytes present
Nrmal glucose Protein may be higher, lower, normal |
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What commonly causes chronic meningitis?
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TB
Crytptococcus CSF - appears like viral infection |
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Which organisms are commonly associated with CNS infection in immunocomprimised patients?
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CMV, toxoplasmosis, cryptococcus, progressive multifocal leukoencephalopathy (JC virus), herpes simplex (HSV), VZV
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What type of pathogen most commonly causes encephalitis?
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Viruses
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What signs are clinically present with encephalitis?
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HA
Fever Focal neurological signs |
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Which specific pathogens commonly cause encephalitis?
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HSV
HIV Murray valley encephalitis Arbovirus ( Murray valley, west Nile, Ross river virus) measles JC virus Rabies Lyssa virus |
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Which area of the brain is commonly affected in HSV encephalitis ?
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Temporal lobes
Treat with acylovir |
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What is encephalomyelitis?
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Infection involving both The brain and spinal cord
Causes: polio (motor neurons), VZV |
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What can cause encephalomyelitis?
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Polio and VZV
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Which parasites commonly cause CNS infection?
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Toxoplasma (immunosuppressed)
Amoeba Malaria Tapeworms |
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What are common causes of local spread of infection into the CNS?
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Pericranial - so Otis, otitis, mastoiditis, face/teeth
Chronic suppurative otitis media/mastoiditis -- bacteria may eat through the bone to enter CNS -- cause Abscess |
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What are the possible origins of septic blood emboli?
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Bacterial endocarditis
Chronic intrathoracic infections (bronchiectasis, lung abcess, empyema) Paradoxical with congenital heart septal defect (from periphery 10% unknown cause |
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What is the main factor regarding drugs that affects it's ability to enter the CNS ?
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Lipid solubility
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What factors affect CSF antibiotic concentration?
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PLasma concentration
Lipid solubility Size Degree of meningeal inflammation - penicillin Presence of active transport system Therapeutic ratio |
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Which antibiotics must be give in high concentrations to be able to reach therapeutic levels in the CNS ?
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Beta-lactams (penicillin)
3rd gen cephlasporins Carbapenems Vancomycin |
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What drugs CANNOT achieve therapeutic levels in the CNS?
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Amino glycosides (gentamicin)
1st/2nd gen. Cephalosporins (acetylation during entry to CSF - loss of function) |
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What drugs can reach therapeutic levels in the CNS with normal dosage? ,
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Chloramphenicol
Trimethoprim-sulphomethoxazole (bactrim) - parasitic meningitis Quinolones - many resistant Metronidazole - anaerobic (abscesses) Anti-TB drugs - isoniazid, rifampicin Antifungals - fluconazole, voriconazole --- ....ZOLE Antiretrovirals - zidovudine |
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With regards to antibiotics - what is MIC?
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Minimum inhibitory concentration
The lowest AB concentration that inhibits growth of an organism |
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How do bactericidal antibiotics work?
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AB kills dividing bacteria
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How do bacteriostatic antibiotics work?
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Prevents mitosis - but does not kill the bacteria
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Does the combinationn of vancomycin and ceftriaxone work synergistically or antagonistically ?
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Synergistically - treatment for pneumococcal meningitis
Combinations of Bacterostatic and bactericidal, can be antagonistic |
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What kind of AB are cephlasporins?
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They are beta lactams - but are less susceptible to penicillinases
Bactericidal activity Good for gram positive (2nd gen - also gram neg) 3rd gen - broad spectrum |
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What kind of AB is gentamicin?
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Aminoglycoside
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Sulphonamides have good penetration into the CNS - but what is the problem with using them?
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Wide resistance
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What can reduce the bactericidal effects of Antibiotics within the CNS?
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Low pH due to accumulation of lactate --- inhibits bactericidal activity --- aminoglycosides don't work
Other drugs effect action -- anatgonistic effect between bactericidal and bacteristatic ABs --- penicillin + chloramphenicol Elevated CSF protein levels - reduces the effects of highly protein bound drugs (need free drug for action) Drugs may be removed by active transport systems in choroid plexus (penicillin, cephalosporins) or converted to inactive metabolite |
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Which antibiotic is chosen for penicillin resistant strains of strep pneumoniae?
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Vancomycin
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What is common treatment for strep pneumoniae?
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Penicillin or amoxicillin - respiratory infection
Cefotaxime or ceftriaxone for meningitis (better penetration) + lower MICs |
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Antibiotics in meningitis
What is penicillin/ampicillin used to treat? |
Strep pneumoniae (sensitive)
Neisseria meningitidis Group B strep listeria |
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Antibiotics in the meningitis.
What is cefotaxime/ceftriaxone used to treat? |
Both 3rd gen cephlasporins
Strep pneumoniae (moderately resistant) haemophilus influenzae Sensitive coliforms (E. Coli...) |
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Antibiotics in meningitis.
Ceftazidime and meropenem are used to treat which organisms? |
Generally hospital aquired Gram negatives
Ceftrazidime - is a 3rd gen cephlasporin with broad spectrum activity (but better gram Neg than pos.) Meropenem - is a carbapenem (beta-lactam) -- ULTRA broad spectrum |
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Antibiotics in meningitis.
What is vancomycin used to treat? |
Resistant strep pneumoniae
Staphlylococci (MRSA, coag. Neg) |
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What is chloramphenicol ?
And what is it's role in meningitis? |
It is a bacteriostatic agent - broad spectrum and used when subjects have BETA-LACTAM ALLERGY!
May also use co-trimoxazole (sulfonamide) |
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What is the fatality rate for acute bacterial meningitis when untreated?
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100%
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Which bacterial meningitis organism can be rapidly fatal ?
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Meningococcal
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Rx for meningitis?
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Antibiotics - even when blood tests are not back yet ... START ABs !!
Usually bactericidal - 3rd gen cephlasporins Also use CORTICOSTEROIDS - control side effects and reduce morbidities (inflammation associated with cell Lysis) |
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What is the main contraindication to an LP?
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Raised ICP
Imaging must rule out mass lesion 1st - otherwise coning may occur --- death |
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What is the triad associated with raised ICP ?
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HA
Vomiting Papilloedema |
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Which nerve is commonly associated with false localizing signs with raised ICP?
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Abducens CN - VI
Adduction of affected eye Inflammatory processes may also affect V (sensory loss, corneal reflex) VII (facial muscle weakness), VIII (vertigo and nystagmus) |
