CNS Infections- Neurotoxins & Treatments Flashcards
Guillain-Barre Syndrome
- Floppy (hypotonic) paralysis
- demyelination of PNS
- autoimmune disease –primarily molecular mimicry of Ab first raised against Campylobacter jejuni antigens
Botulism
- Floppy (hypotonic) paralysis
- an exotoxin/neurotoxin that inhibits nerves at the neuromuscular junction / PNS
- Clostridium botulinum elaborates the exotoxin
Botulism toxin acts at the _________ paralyzing of the cholinergic nerve fibers at the point, inhibiting the release of _______
myoneural/neuromuscular junction (not the CNS, unlike tetanus
acetylcholine
Botulism toxin blocks both cholinergic transmission points in the autonomic system:
- Blocks at Synaptic ganglia
- Blocks at Parasympathetic motor end plates peripherally located in the junction between the nerve cell and muscle cell fibers.
Botulism- Anticholinergic/inhibition of the parasympathetics, with no effect on the sympathetic nerves results in such symptoms as _________________
dilated and un-responsive pupils, dry mouth, and constipation
Botulism- Progressive neuromuscular blockade of muscles innervated by ________ occurs first, then the _____ (systemic generalized muscle weakness), and finally the _____ (peripheral motor weakness) and diaphragm.
Later complications include paralytic ileus, severe constipation, and urinary retention. Ocular and cranial muscle weakness occurs first because neuromuscular junctions of these muscles have _____________.
cranial nerves
trunk
extremities
the lowest threshold for synaptic failure
Polio virus
- Floppy (hypotonic) paralysis
- kills neurons
Tetanus
- Spastic (Rigid, hypertonic) paralysis
- mimics some S & S of meningitis
- an exotoxin/neurotoxin inhibits nerves in the CNS/spinal column
- Clostridium tetani elaborates the exotoxin/neurotoxin
- Pathogenesis of Tetanus- It is transported to ___________ (e.g. Renshaw cells- Interneurons are small neurons that that are involved in local processing of nerve signals and which generally have _________).
inhibitory interneurons
inhibitory activities
- Pathogenesis of Tetanus- It irreversibly inhibits the ____________, producing a presynaptic blockade of these cells. It does NOT act on the synapses of ________ that handle acetylcholine transmission. Absence of inhibitory Renshaw cell activity allows lower motor neurons to _________ and permits simultaneous contractions of both agonist and antagonist muscles”.
release of inhibitory transmitter substances, γ-aminobutyric acid and glycine
Renshaw cells
increase muscle tone and rigidity
- Pathogenesis of Tetanus- Toxin is rapidly transported _________ where it inhibits interneurons so that normal ______ feed-back of the sympathetic and parasympathetic systems is disrupted and ONLY _______ of these systems occurs, resulting in severe disruption of autonomic function in late, severe, general tetanus
up the spinal column to reach the brain stem &/or hypothalamus
INHIBITORY
positive feed-back
Most common cause of generalized paralysis in US, caused by the host’s immune response to a mucosal infection
Guillain-Bare’ syndrome
peripheral nerve involvement
Guillain-Bare’ syndrome, caused by host’s immune response to a mucosal infection by
(4 agents)
- C. jejune (GI tract)
- influenza virus (Resp tract)
- Chlamydia spp (Resp tract)
- Chlamydia sp. (GU tract)
Leprosy is caused by
Mycobacterium leprae
peripheral nerve involvement
Botulism is caused by
Clostridium botulinum
peripheral nerve involvement
Myasthenia gravis causes
(peripheral nerve involvement)
weakness
Direct smear of CSF (~30% sensitive) that is gram stained may show these Gram-positive agents:
- Listeria monocytogenes
- S. pneumoniae
- S. agalactiae
Direct smear of CSF (~30% sensitive) that is gram stained may show these Gram-negative agents:
- H. influenzae, type b
- N. meningitidis
- E. coli K1
- K. pneumoniae
A Gram stain of CSF is positive in 60% to 90% of cases, but results vary with the organism as well as with the concentration of bacteria in the CSF. In terms of bacterial concentrations, the CSF Gram stain is positive in up to 97% of cases when there are______ of fluid as opposed to around 25% when there are _____ of fluid.
> 10/ml
Order of sensitivity of on common organisms (to be found in CSF)
- S pneumoniae, 90%;
- H influenzae, 86%;
- N meningitidis, 75%;
- Gram-negative bacilli, 50%;
- L monocytogenes, less than 50%.
What stains acid fast?
What stains with India Ink?
What stains on Saline wet mount?
acid-fast stain: Mycobacterium
India ink preparation: Cryptococcus
Saline wet mount: Naegleria fowleri
14-3-3 chaperone brain protein is elevated in pts with
(normal:
- cerebrovascular events/acccidents (CVAs)
- viral encephalitis
- Creutzfeldt-Jakob disease (prions)
Hypoglycorrhachia (low glucose in CSF) and Hyperproteinosis are related: In a patient with bacteria meningitis, albumin (protein) from the brain parenchyma enters the CSF (increases it) and this protein movement disrupts the protein gradient that normally exists between the CSF and blood. The protein gradient between the blood and CSF is used to ________. Thus high protein levels in the CSF stops __________ so glucose levels are low in the CSF. This is why a normal CSF glucose level is ____ of the blood glucose level.
co-transport glucose from the blood to the CSF
co-transport of glucose
~80%
Normal CSF is ___________ , Not straw-colored like serous fluid, which contains β2-transferrin.
a clear, colorless fluid
In meningitis patients, during Gram-staining of CSF specimens, CSF protein is heat-fixed to the glass slide and stains _____, making detection of _______ difficult. This pink background is present regardless of cell wall architecture of the bacteria being stained.
pale pink
any Gram-negative bacteria in the CSF
Culture and sensitivity of sedimented CSF (~50% sensitive) – Order MIC and MBC (need 10xs normal MBC)
CSF cultures are positive in ______ of cases
70% to 85%
Describe antigen testing/latex agglutination test of CSF fluid
- Latex spheres coated with antibody detects presence of capsular Ag in CSF.
- Very low (7%) sensitivity except with positive Gram-stain or culture positive specimen
Antigen testing/latex agglutination testing can detect
- S. pneumoniae
- H. influenzae, type b (Hib)
- N. meningitidis
- Cryptococcal antigen
VDRL testing is done for
syphilis
PCR test for specific agents of
- enteroviruses (RT-PCR)
- herpes simplex virus
- JC virus
- HIV (RT-PCR)
Additional detection methods (investigational level) for patient with bacterial meningitis
Procalcitonin (increased)
Vesicular skin lesions are stained with ________ for skin biopsy to look for presence of ________
Tzanck or Papanicolaou stained skin biopsy
HSV
Purpuric skin lesions, are caused by _________ and use _________ to detect them.
S. pneumonia, N. meningitidis
Gram-stained smear of skin biopsy specimen and Culture and sensitivity (MIC, MBC)
You must always do a culture & sensitivity (MIC, MBC) of blood –> 2 samples from different sites, about 1 hour apart
A positive culture is most likely to occur if pt is ___________
A positive blood culture establishes diagnosis in presence of ______ in symptomatic pt. Blood cultures are positive in 40% to 90% of cases.
spiking a fever or fever is present
negative CSF culture
When testing for viral agents, ______ may also be done
PCR or RT-PCR of blood
Can also do antigen testing or serology for specific antibodies
For urine testing, order:
- Gram-stain
- culture and sensitivity (MIC, MBC).
- PCR of urine for specific viral agents may also be done
Urine testing, use Latex agglutination to test for
cryptococcal antigen
Use vaginal and Rectal swabs to test for ________
for GBS - Treat if culture positive – Learn!!
Sequential diagnostic tests are________
order all appropriate tests _________
NOT feasible for CNS infectious diseases
right away – in parallel, NOT sequentially
EEG pattern can indicate a
focal or diffuse problem
Neuroimaging- CT-scan or MRI may show
- X-ray, CT scan, MRI – indicative of focal or diffuse problem.
- CT-scan will show contrast/ring-enhancing lesions for mass effect/lesion
3 Non-Infectious reasons for CNS problems that will be on differential → patient is usually afebrile:
(For differential, #1 meningitis, #2 encephalitis)
a. subarachnoid or intracerebral hemorrhage: Incidence is 40→50K/y in US, with the rate expected to double in next 50 y, thus hemorrhage is much more common than meningitis and/or encephalitis.
b. Cerebral venous thrombosis (CVT)
c. Ischemic stroke
Full differential for CNS problems (5)
- meningitis
- encephalitis
- non infectious (afebrile): subarachnoid or intracerebral hemorrhage, cerebral venous thrombosis, ischemic stroke
- Mass lesions.
- paralysis – floppy vs spastic.
Bacterial meningitis and viral meningitis have similar presentation, but bacterial meningitis ________________, viral meningitis doesn’t. Thus the physician must TRY to differentiate between bacterial and viral meningitis and unless definitively diagnosed as VIRAL meningitis, treat all cases of meningitis as ____________.
has a high mortality rate and survivors have serious neurological sequelae
bacterial etiology until proven otherwise
For all cases of meningitis and encephalitis - until a definitive diagnosis is made (i.e., the etiologic agent is known), _____________ and if clinical manifestations warrant add antifungal drugs and/or acyclovir (if manifestations warrant) to the other drugs until diagnostic tests results and/or the patient fails to respond (fails to improve) to treatment over 1→2 days.
treat aggressively, use combinational antibiotics efficacious for bacterial meningitis (but not necessarily exclusively for bacterial meningitis)
Important to initiate combinational antimicrobial therapy within _____________ before the results of culture, Gram-stain, PCR are known because mortality due to bacterial meningitis is high (10%) and long term neurological sequelae (subtle, moderate or serve) occur in many (>50%) survivors.
30 minutes of tap, via the parenteral route
Treat all cases of meningitis/meningoencephalitis as possible __________ until a definitive diagnosis is made or the patient fails to improve over 1→2d.
bacterial etiology (administer antibiotics) + antifungal + antiviral drugs
For a patient with acute bacterial meningitis, antimicrobial therapy and the host immune response is thwarted by:
- Acidic pH of CSF, this results in impaired PMN function and many antibiotics are less efficacious at acidic pH.
- Elevated CSF proteins (albumin from brain) will bind to and inactivate many antibiotics
Selection of drugs for therapy should be based on:
Lab findings- BIG CLUE TO ETIOLOGY
Normal vs. Disease:
1. type of WBC predominating [PMNs vs. Monocytic or lymphocytic lineage]
2. sugar, protein levels,
3. Stained smear reveals agent.
4. Gram-stain findings on spinal fluid, urine, skin lesions.
5. Latex agglutination tests of CSF, urine, etc.
Bacterial Meningitis lab findings: cell count- differential- glucose- protein-
cell count- > 1000 cells
differential- PMNs predominate (>90% usually)
glucose- LOW
protein- VERY HIGH
Viral/Aseptic Meningitis lab findings: cell count- differential- glucose- protein-
cell count- 25-2000 cells
differential- mononuclear
glucose- near normal
protein- slightly elevated
Fungal/TB Meningitis lab findings: cell count- differential- glucose- protein-
cell count-
Antimicrobial therapy must be:
- able to penetrate subarachnoid space (not all antimicrobials penetrate to same extent, use an antibiotic that is secreted in tears, if present in tears, present in CSF).
- bacteriocidal (10X the MBC – if pharmacologically possible).
- empiric, based on age (neonate, infant →middle age, elderly).
- Combinational therapy, e.g., penicillin or ceftriaxone and an aminoglycoside, is recommended if you are not sure which is the responsible etiologic agent. Switch to best drug when etiologic agent and susceptibility are determined. MDR is documented.
Combination therapy for meningitis if you are not sure of the responsible etiologic agent
penicillin or ceftriaxone and an aminoglycoside
Treatment of meningitis for S. pneumoniae
intravenous cefotaxime (200 mg/kg/d) and continuous infusion vancomycin (60mg/kg/d after a loading dose of 15mg/kg) plus adjunctive therapy with dexamethasone (10 mg every 6 hours) unless the strain is proven penicillins.
Treatment of meningitis for adults younger than 50
empiric treatment should consist of 2 g of ceftriaxone or 2 g of cefotaxime
plus 1 g of vancomycin
plus 10 mg of dexamethasone intravenously.
Treatment of meningitis for patients at age 50 years or older for possible infection with L monocytogenes
ADD Ampicillin 2 g intravenously -plus usual adult treatment: 2 g of ceftriaxone or 2 g of cefotaxime plus 1 g of vancomycin plus 10 mg of dexamethasone intravenously.
In the treatment of neonates, which antibiotic is preferred and why?
Cefotaxime is preferred over ceftriaxone in the treatment of neonates because ceftriaxone may alter bilirubin metabolism in this population
Adults with gram-positive cocci on a CSF Gram stain who are receiving adjunctive corticosteroids should be treated with _______
a broad-spectrum cephalosporin plus rifampin (600 mg/d) instead of vancomycin; this is because of vancomycin’s diminished CNS penetration in the presence of corticosteroids
If the etiologic agent is or suspected to be S. pneumoniae or Hib in a person >17 y-o-age, administer ___________
dexamethasone 15→ 30m before or at the same time as antibiotics are administered
If the agent is S. pneumoniae that is resistant to penicillins or cephalosporins, then ______ is the drug of choice, BUT, it must be used in combinational therapy and the administered doses of _______ must be sufficient to ensure that appropriate concentrations are achieved in the CSF in the presence of ___________.
vancomycin
vancomycin
dexamethasone
In children with pneumococcal meningitis, especially if there is a relapse, be aware of ____________
tolerance
(Vancomycin, penicillin, aminoglycoside, quinolone antibiotics are static, not cidal).
Important clinically
Do not administer dexamethasone to a person who ___________
has already received antimicrobial therapy or who is manifesting with septic shock.
Dexamethasone use in children
not associated with and any change in survival or time of hospital discharge.
Clostridium tetenaii treatment
metrodianazole
Haemophilus influenzae, type b treatment
ceftriaxone, cefotaxime, cefuroxime or the alternative option is TMP-SMX.
Listeria monocytogenes treatment
ampicillin plus gentamycin or TMP-SMX
Mycobacterium leprae treatment
dapsone plus rifampin or clofazimine
Neisseria meningitidis treatment
ceftriaxone or cefotaxime
Streptococcus pneumoniae treatment
vancomycin + extended spectrum cephalosporin
Streptococcus agalactiae treatment
penicillin G
Toxoplasma gondii treatment
sulfonamides or clindamycin + pyrimethamine
Cryptococcus neoformans treatment
amphotericin B with 5-fluorocytosine
Herpes simplex virus treatment
acyclovir
non polio Enteroviruses treatment
pleconaril
Naegleria fowleri treatment
Miltefosine
Neurocysticercosis treatment
Niclosamide, Praziquantel, Albendazole
For H. influenzae, type b and N. meningitidis: Obtain nasopharyngeal cultures to screen for carriers. Give chemoprophylaxis to both vaccinated and non-vaccinated individuals with _________ to prevent familial spread or spread in closed populations. Must use antimicrobial which will secreted in tears (i.e., present in mucosal surface).
rifampin or minocycline/doxycycline
Meningococcemia-induced purpura fulminans aka symmetrical peripheral gangrene [SPG] is treated with _________, antibiotics, fluid resuscitation, inotropic drugs, mechanical ventilation.
Drotecogin alfa
activated, recombinant protein C
Cryptococcus treatment regimen is high dose __________ for 2 weeks duration. Fluconazole or Itraconazole is used for long-term (life-long) suppressive therapy.
amphotericin B with 5-fluorocytosine (fluconazole [FLU])
Leprosy treatment regimen is multidrug therapy for up to 2 years and is based on the form of disease (TT, LL, or borderline) manifested. _________ for treatment of the lepromatous form, to prevent ENL.
Thalidomide
Neurocysticercosis - Must treat both asymptomatic and symptomatic patients
Regimen is:
- albendazole &/or praziquantel –antihelmenthic drugs
- anticonvulsant
- corticosteroids (dexamethasone) – to suppress the immune/imflamatory response
Toxoplasmosis treatment regimen, lasts 2-4 months and uses a combination of
sulfonamides or clindamycin + pyrimethamine
Focal encephalitis is often caused by HSV, which is treatable vs focal or diffuse encephalitis caused by OTHER viral agents which are generally untreatable, except supportively.
HSV treatment regimen is antiviral agents(s):
__________________
acyclovir, vidarabine/adenosine arabinoside, idoxuridine, trifluridine, famciclovir, valacyclovir.
This is a treatment, NOT A CURE.
