Transcript The meninges

CNS Infections (Meningitis)
Gregory T. Valainis, M.D.
AHEC Professor of Medicine
MUSC
What is meningitis?
Literally, inflammation of the meninges
Causes:
Infectious
(bacteria,virus,mycobacteria, fungi,parasitic)
Auto-immune
Cancer
Drugs, chemicals
Historical Perspective
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Described by Hippocrates (460-377 BC) in his book De morbis Book 3 “…..The disease is fatal. One
cannot tell on which day death will come”
Thomas Willis (1621-75) gave the 1st detailed description of meningitis epidemica in London
Gaspard Vieusseux (1746-1814) from Geneva in 1805 wrote a report on 30 rapidly fatal cases chiefly
in children and young adults in poor districts
In the 1st decade of the 1900’s, meningococcal meningitis had a 75-80% mortality rate
In the 1920’s, 77 of 78 children with H. influenzae meningitis from 1 hospital died
300 patients with S. pneumoniae meningitis all died
What is meningitis?
The meninges
(meningitis)
Gray's Anatomy
The brain tissue
(encephalitis)
What is the blood brain barrier?
THE BLOOD – BRAIN BARRIER
In the periphery, capillary endothelial cells have gaps
(termed fenestrae) between them and use
intracellular pinocytotic vesicles to facilitate the
transcapillary transport of fluid and soluble
molecules. In contrast, CNS vessels are sealed
by tight junctions between the endothelial
cells. The cells have fewer pinocytotic vesicles
and are surrounded by pericytes and astroglial
processes. In addition, capillary endothelial cells in
the CNS have more mitochondria than those in
systemic vessels; these mitochondria may reflect
the energy requirements necessary for CNS
endothelial cells to transport certain molecules into
the CNS and transport other molecules out of the
CNS.
Golan et al. Principles of Pharmacology, 2nd Edition
Meningitis Overview
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High morbidity and mortality
Little change in mortality despite availability of newer antibiotics
Was predominantly a disease of children (~70% of case) ages 5 and under;
now the mean age is ~ 25
More common in developing countries with attack rates > 100 fold higher
than the U.S.
Overall Prevalence of Bacterial Meningitis in
the U.S.
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S.pneumoniae
N. meningitidis
S. agalactiae
H. influenzae
L. monocytogenes
61%
16%
14%
7%
2%
Meningitis: Uncommon Pathogens and
associated Conditions
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S. aureus
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CNS
Aerobic GNR’s
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IVDU,endocarditis,
postneurosurgical
Ventricular shunts
Head trauma
postneurosurgical
Pathogenic Agents of Bacterial Meningitis According to Age Group
Schuchat A et al. N Engl J Med 1997;337:970-976
Route of Infection
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Hematogenous
Direct extension (sinusitis, otitis media)
Head trauma (CSF leak)
Initial Acquisition
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NP colonization:
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Invasion
Bacteremia
Enter the SAS
Once in the CSF, host defense mechanisms are inadequate
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capsule
fimbriae (pili)
IgA protease
Subsequent Pathophysiologic Events
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Vasogenic edema
Increased intracranial pressure
Decreased cerebral blood flow
Neuronal injury
Meningitis: Neurologic sequelae
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Hearing loss
Mental retardation
Seizures
Focal motor-sensory deficits
Meningitis: Presenting symptoms and signs
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Headache
Fever
Meningismus
Altered sensorium
Vomiting
Seizures
> 90%
> 90%
85 + %
> 80%
35%
30%
Mortality from Bacterial Meningitis
70% without antibiotics
• 10% with antibiotics
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Meningitis: Principles of Therapy
CNS penetration
• Bactericidal activity
• Pharmacodynamics/kinetics
Inpatient for at least 6 days with no fever for 24-48 hours; must be
clinically stable w/o neurologic dysfunction therapy
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Antibiotics commonly used for treatment of CNS
infections
1. Penicillin G
2. Aminopenicillins (amoxicillin, ampicillin)
3. Cephalosporins (3rd and 4th generation)
4. Vancomycin
5. Chloramphenicol
6. Aminoglycosides
7. Semisynthetic penicillins, Sulfonamides, Rifampin
Penicillin G
The Drug of choice for treating
• S. pneumoniae (Pneumococci)
• N. meningitidis (Meningococci)
However;
• For S. pneumoniae: until antibiotic susceptibility is determined, use
vancomycin/3rd generation cephalosporin.
• For N. meningitidis: Doesn’t eliminate carrier, so don’t use for prophylaxis.
Penicillin G (continued)
For L. monocytogenes:
Used in combination with ampicillin/gentamicin/(penicillin G)
Amino-penicillins
(Ampicillin/Amoxicillin)
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Pneumococci susceptibility is variable (do not use alone).
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Meningococci and L. monocytogenes are susceptible.
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L. monocytogenes is particularly susceptible to ampicillin.
Therefore; ampicillin/3rd generation cephalosporin/vancomycin could be
used for the empirical treatment of suspected cases of meningitis.
Amino-penicillins
(continued)
• Beware of allergic reactions to penicillins in general.
• Consider penicillin resistant strains also ampicillin resistant.
Cephalosporins
• 2nd generation antibiotics effective against H. influenzae, Pneumococci, and
Meningococci. However, 3rd generation antibiotics are more efficient
• Especially useful for penicillin resistant strains
Chloramphenicol
• 3rd generation cephalosporins replaced the need for its use
• Bactericidal to H. influenzae , N. meningitidis, and S.
pneumoniae
• Use as alternative if patient has allergies to -lactam
antibiotics
• Use only if benefit outweighs potential toxicity
Aminoglycosides
• Poor penetration to CSF
• May be use intrathecally
• Commonly used for treatment of severe cases of
L. monocytogenes
Antibiotic Therapy for Bacterial Meningitis
Organism
Antibiotic
Comment
Unknown
Ampicillin/3rd G cephalosporin/Gentamycin
—
Ampicillin/3rd G cephalosporin/Vancomycin
—
Gram-positive organisms (unidentified)
Vancomycin/3rd G cephalosporin (Ampicillin)
— Use ampicillin if pleomorphic
(Listeria)
Gram-negative bacilli (unidentified)
3rd G cephalosporin /Gentamycin
—
(Infants)
Unknown
(Young children and adults)
http://www.merck.com/mmpe/sec16/ch218/ch218b.html?qt=Acute Bacterial Meningitis&alt=sh
Antibiotic Therapy for Bacterial Meningitis (continued)
Organism
Antibiotic
Comment
Haemophilus influenzae type b
3rd
—
Meningococci
Penicillin G (ampicillin)/3rd G cephalosporin
Penicillin G after sensitivities are known
Streptococci (pneumococci)
Vancomycin/3rd G cephalosporin
Penicillin G after sensitivities are known
G cephalosporin
 Rifampin
Listeria sp
Ampicillin (penicillin G)
or
Trimethoprim-sulfamethoxazole and gentamicin
Penicillin G used after sensitivities are known
Trimethoprim-sulfamethoxazole is used in
patients allergic to penicillin
Staphylococci
Vancomycin or nafcillin (oxacillin)
Nafcillin or oxacillin used after sensitivities are
known.
Rifampin if no improvement with vancomycin or
nafcillin
 Rifampin
Enteric gram-negative
bacteria (Escherichia coli,
Klebsiella sp, Proteus sp)
3rd G cephalosporin
/Gentamicin
—
http://www.merck.com/mmpe/sec16/ch218/ch218b.html?qt=Acute Bacterial Meningitis&alt=sh
Duration of antibiotic therapy
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H. influenzae
N. meningitidis
S. pneumoniae
L. monocytogenes
S. agalactiae
Aerobic GNR
7 (days)
7
10-14
14-21
14-21
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Meningitis: Indications for Brain imaging (CT or
MRI)
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Immunosuppressed host
Suspicion of a brain abscess
Persistent focal neurologic findings
Seizures
Case #1
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Date: February, 2014
Your situation: Medical intern on a rural rotation in Telluride, CO
Patient: Steve S., admitted last night with bacterial meningitis
Your supervising resident is out on the slopes, enjoying the 12” of new powder that fell last
night. He asked you to take over the family conference regarding Steve’s condition.
Case #1 (cont’d)
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The family wants to know
 What
is meningitis?
 How do you know he has it?
 What happens if we don’t treat it?
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How do you know he has it?
Clinical signs
 Stiff neck (meningismus), fever
 Brudzinski sign: Flexing the neck causes reflexive knee flexion; Kernig’s sign: Extending the
knee with hips flexed causes pain after 135 degrees of extension
 Nausea, vomiting
 Sometimes seizures
 Altered consciousness
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Spinal fluid
 High WBC, LOTS of neutrophiles or lymphocytes
 Normal or low glucose, normal to high protein
CSF Results
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Normal results
 WBC
<5 (lymphs <80%, neutrophils 0), RBC <500, glucose 2/3
serum, protein <45
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Viral meningitis
 WBC
high (increased lymphs), RBC normal, glucose normal, protein
high
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Bacterial meningitis
 WBC
high (lymphs <80%, neutrophils >5%), RBC normal, glucose
low, protein normal to high
Case #1 (cont’d)
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Now they want to know
 How
did he get it?
 Are we going to get it?
How did he get it?
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Direct inoculation
 Trauma
 Surgery
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Systemic inoculation, then spread to CNS - inflammation
breaks down the BBB
 **Respiratory tract**
 Skin
 GI
 Urinary infection
including ear/sinuses
Will the family get it?
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Bacterial meningitis is transmissible through close contact,
usually respiratory droplets.
Often close family will be treated with antibiotics prophylactically
(rifampin)
Case #1 (cont’d)
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You survived the family conference! As you choke down
your last bite of lunch, the floor nurse comes to the call
room door. She tells you, “You have a call on line 4. It’s
the lab.” The caller identifies himself as a tech in the lab.
They’ve lost bacterial culture dish that you had them
prepare last night. What are you going to do?!?
 Repeat
spinal tap?
 How do you treat?
Etiologies of Bacterial Meningitis
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Acute – hours
S. Pneumoniae (most common cause in adults, also found in most otitis media)
N. meningitidis (adults – note characteristic petechial rash)
Group B streptococci (newborns and elderly)
E. Coli (newborns and post-neurosurgery/trauma)
H. influenzae, type B (children 2 months to 3 years)
Listeria monocytogenes (alcoholics and elderly)
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Chronic – weeks to months
M. tuberculosis (immunocompromised adults)
Petechial rash associated with
N. meningitidis
Photographs from www.emedicine.com
How do you treat?
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TREAT IMMEDIATELY, IF NOT SOONER – EVEN
BEFORE THE SPINAL TAP!!
Draw 2 sets of blood cultures
IV antibiotics that penetrate the BBB
Appropriate initial coverage
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Ampicillin
3rd generation cephalosporin
Vancomycin (in ampicillin-resistant areas)
Adjust medication choice after bacterial culture and
sensitivities comes back from the lab
How do you prevent spread?
• Put the patient in respiratory contact isolation usually for ~
24 hrs after antibiotic therapy has been initiated
• Gowns
• Gloves
• Masks
• Antibiotics for the patient
• Antibiotics for close contacts
?’s
For more information…

EXCELLENT eMedicine article reviews bacterial
meningitis:
http://www.emedicine.com/med/topic2613.htm
Case #2
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Date: May, 2016
Your situation: Senior medicine resident at the original Knife & Gun Club
Patient: 10 year old boy admitted last night through the ER
You saw this boy two weeks ago and treated him for acute sinusitis. He now presents to the
ER again after a seizure at home. Dad says he’s been clumsy with his right arm for two
days. The seizure involved the right side more than the left. He is afebrile
Case #2 (cont’d)
What do you think is going on?
 How are you going to prove your theory?
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Differential diagnosis?
Mass lesion – progressive, focal, seizure
 Tumor
 Intracerebral hemorrhage (subdural)
 Intracerebral abscess
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Tests?
CT or MRI brain with contrast
 LP only if CT or MRI shows no significant mass lesion
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Head CT Result
Image from www.emedicine.com
Common Causes of Brain Abscess
Nasopharyngeal infections – direct
extension to brain
otitis media
mastoiditis
sinusitis
These sources account for 40% of brain
abscesses
Brain Abscess: Etiology
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Bacterial: Streptococci (aerobic, anaerobic), S. aureus, other
anaerobes, Nocardia, Mtb
Fungi: Candida, Aspergillus, Zygomycetes, endemic mycosis
Parasitic: Toxoplasma, E. histolytica, Schistosoma sp., T. solium
Treatment?
Intravenous antibiotics
 May need abscess drainage if the abscess doesn’t shrink
or if > 2.5 cm
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Brain Abscess: Initial empiric treatment
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IV penicillin G/ceftriaxone
Plus metronidazole
Once the infecting pathogen is identified, anti-infective
treatment can be modified
Duration is typically 6-8 weeks
Why might he be afebrile?
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Abscess is often walled off from good immune response
that would produce fever
Case #3
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A 17 year old high school basketball player is seen in the ER for
headaches, fevers, and chills. She is photophobic, and has been
nauseated and vomiting. Examination shows BP is normal, pulse is
96, and temp is 100.4°. She responds appropriately, but prefers to sleep and
appears quite uncomfortable. She turns in the bed gingerly and refuses
anything to eat.
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Describe your approach to her exam.
 Specifically,
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what features of her neuro exam are especially important?
What is your clinical impression/differential?
What tests will you order
Key points on exam?
Mental status – aphasia? Sustained arousal?
 Any focal weakness,
DTR changes, etc.?
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 Might
indicate brain
infection/encephalitis
Clinical impression?
Viral meningitis
 Encephalitis (if focal signs, seizures, etc.)
 Differential diagnosis also includes
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 Flu
 Bacterial
meningitis
What tests?
Head CT – make sure there is no mass lesion in the brain
that could serve as a contraindication to LP
 PT, PTT, INR – will the patient bleed during LP?
 LP
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LP Profiles
WBC
Normal <5
WBC profile
Normal low neutrophils, high
lymphocytes
Bacterial
Elevated
Neutrophils
Lymphocytes
Viral
Elevated or
normal
Neutrophils nl
Lymphocytes
Parasitic
Elevated
Neutrophils nl
Lymphocytes nl
Eosinophils
Glucose Normal =
2/3 serum glucose
Normal
Protein
Normal <45
Does she need isolation?
No; not for a viral meningitis
 Often not even admitted to the hospital for uncomplicated
viral meningitis
 Until you have ruled out bacterial meningitis, however,
many hospitals will require that a meningitis patient be
placed in isolation
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For encephalitis…
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Similar to viral meningitis, but generally (not always) higher fevers,
focal neurological signs, more alteration in mental status
Start acyclovir (+/- dexamethasone to prevent cerebral edema)
LP
Medications to prevent further seizures
If imaging is normal, no change in management; MRI findings may not
develop for 3+ days after illness starts with HSV encephalitis
Rational for adjunctive use of Steroids
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Dexamethosone is preferred
Administer IV with or just before the 1st dose of antibiotics
Blocks the influx of leukocytes into the SAS
Inflammatory mediator release is decreased
Case #4
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A 42 year old man with known HIV/AIDS comes to you for
evaluation of progressive confusion over the past several
months. If this is an infectious process, which viruses
most often cause this presentation in an
immunocompromised patient?
Which viruses?
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Varicella-zoster virus
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Cytomegalovirus
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Ventriculitis (gait disorder, hydrocephalus, enhancing lesions on MRI)
Meningoencephalitis (necrotizing vaculitis of the meninges)
Encephalitis/ventriculitis (progressive dementia, gait disorder, inflammation, necrosis,
and focal vasculitis on pathology, enhancing lesions on CT or MRI)
HIV
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Can start as aseptic meningitis then become encephalitis (vacuolar encephalitis,
confluent white matter changes with a hazy or cloudy appearance on MRI)
Case #4 (cont’d)
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Is this a meningitis? Or encephalitis? Why?
Encephalitis.
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Meningitis (meninges inflammation or infection) may
make people sleepy, but change in cognition or focal
neurological signs clinically suggest encephalitis (brain
infection)
Case #4 (cont’d)
If you suspect HIV encephalitis, what tests would support
your diagnosis?
 How would you treat this patient?
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Tests?
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LP
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May be normal or show mild leukocytosis, lymphocyte predominant, mildly
elevated protein, normal glucose
 HIV viral load in the CSF often elevated
 PCR to rule out CMV, VZV
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MRI
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White matter cloudy appearance due to diffuse, non-enhancing white matter
hyperintensities
 Cortical atrophy
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CBC
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CD4+ count usually low
Treatment?
Highly-active antiretroviral therapy (HAART) can slow and
maybe even reverse the encephalitis
 Without HAART, life expectancy about 6 months after
encephalitis develops
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Case #5
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A 20 year old Wofford senior has spent the last year in Mexico on an
exchange program. Most of his time was spent in the rural areas of
Mexico, helping to plan irrigation and sewage systems for the local
farmers.
He reports a two month history of intermittent fevers to 99° or 100°,
lasting a couple of days, and then resolving.
In the past 6 weeks, a recurring headache has prevented his usual
athletic activities. It seems that any activity brings on the headache, as
does bending down to tie his shoes.
His general exam is remarkable for scattered lymphadenopathy and
papilledema.
Why is Mexico important?
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CNS Infections endemic to Mexico
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Cystercercosis (taenia solium, pork tapeworm)
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Malaria
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Mass lesions in the brain
Seizures, focal neurological deficits
Blood infection
Seizures, altered mental status
Schistosomiasis
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Block blood vessels in the intrahepatic portal system
Excreted in stool
What workup will aid diagnosis?
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Imaging
 CT
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or MRI with and without contrast
Blood tests
 CBC,
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blood smear
Stool evaluation for ova and parasites
Case #5 (cont’d)
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MRI brain shows an oval-shaped lesion in the right frontal
lobe. There is moderate surrounding edema. The lesion
enhances with contrast.
What is this? What treatment?
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Neurocystercercosis
 Will
often show calcification on CT
 Cystercercosis antibodies
Albendazole or mebendazole
 Dexamethasone to reduce edema may be helpful
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Neurocystercercosis Removal
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http://www.myfoxphoenix.com/dpp/news/only_on_fox/oof_
brain_worm
Vaccines
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N. meningitidis (MCV-4) vaccinates against A, C, Y, W135, but not B
S. pneumoniae 23 valent polysaccharide or 7 valent
conjugate
H. influenzae Type b (Hib) conjugate