Download Presentation - Neuropathology

Bacterial Meningitis
Jennifer Nichols, PGY2
Presentation Overview
• Case Study
• Chronology of Bacterial Meningitis
• Diagnosis
– Clinical Signs and Symptoms
– Laboratory Workup
– Lumbar Puncture
– Imaging
• Treatment
– Role of Dexamethasone
• Vaccines
Case: History
• Cc: Headache
• HPI:
53 y/o F with PMH significant for RA who presents with severe headache and neck pain
for the last 2 days. She does not normally get headaches. She complains of a severe
headache "all over" that is worse with sitting or bending over. She also has neck pain and
stiffness. She reports fever to 100.8F. She states that for the last 4 months, she has had L ear
pain and fullness concerning for an ear infection, however she has not sought treatment
because she "doesn't have a doctor." She also complains of rhinorrhea and sore throat. She
also reported a 2 week history of intermittent and spontaneous drainage of clear, watery
fluid from her nose which occurs when she leans over or stands up suddenly. She also
notes some confusion and difficulty with her speech, such as saying words in the wrong
order. She denies any visual disturbances, focal weakness, or numbness. She presented to
OSH with WBC of 25.7 and head CT was significant for mastoiditis. She had received
unasyn at OSH prior to transfer.
Other Histories
• PMH: RA, COPD
• Past Surgical Hx: Sinus surgery
• Family Hx: Adopted; unknown
• Social Hx: Smokes 1ppd cigarettes, 4-5 beers per week, + marijuana use
• Allg: NKDA
• Medications: None
Physical Exam
• VS: T 38C, BP 110/73, P91, RR 18, 95% SpO2 on RA
• Gen: NAD, resting in bed, appears uncomfortable
HEENT: Anicteric scelra, MMM, +Nuchal rigidity. Limited movement of neck
laterally, unable to flex neck forward
CV: RRR
Lungs: Non-labored breathing on room air
Abd: Non-distended
Ext: No swelling
Skin: No rash
MS: Alert and appropriate. Oriented to Pittsburgh hospital. Initially said year is 2005
and then corrected herself. Knows that Christmas recently passed but did not know
the date. Attention intact. Remote and recent memory intact. Language fluent without
dysarthria
CN: PERRL. Visual fields intact. EOMI. Facial sensation and strength intact. Hearing
grossly intact b/l. Symmetric palatal elevation. Tongue midline
Motor: Normal bulk and tone. 5/5 strength b/l shoulder abduction, elbow
flexion/extension, hand grip, hip flexion, dorsiflexion, plantar flexion
Sensory: extremities intact to light touch
Reflexes: 2+ b/l triceps, biceps, brachioradialis, patellar, achilles. Flexor plantar
response b/l
Cerebellar: No dysmetria or ataxia on FTN
Gait: deferred
Bacterial Meningitis
• Meningitis is an inflammatory disease of
the leptomeninges
• Abnormal number of white blood cells in
the CSF
• Infection of the arachnoid mater and the
CSF in both the subarachnoid space and
the cerebral ventricles
History of Bacterial Meningitis
• Thomas Willis described patients with "inflammation of the meninges with a
continual fever“. He also described an early epidemic of meningitis in 1661
• Heinrich Quincke utilized his new technique of lumbar puncture in 1891 to
analyze CSF
• William Mestrezat and H. Houston Merritt compiled large series of CSF profiles,
identifying 3 major organisms (Streptococcus pneumoniae, Neisseria
meningitidis and Haemophilus influenza) in the late 19th century
• Vladimir Kernig and Josef Brudzinski described their eponymous signs in 1882
and 1909
• Antibiotic therapy began in the 20th century with the use of sulfonamides by
Francois Schwentker and penicillin by Chester Keefer
• Vaccination against meningitis debuted in the early 20th century
Epidemiology
• Approximately 1.2 million cases per year worldwide, responsible for 135,000
deaths each year
• Community Acquired Bacterial Meningitis
– Strep Pneumoniae, Neisseria meningitidis, Listeria monocytogenes >> Haemophilus
influenzae (due to vaccines)
• Healthcare Associated Bacterial Meningitis
– Usually staphylococci and aerobic gram-negative bacilli
– If due to neurosurgery, can vary with whether or not antimicrobial prophylaxis was
given to prevent surgical site infection
– Can also occur following ventricular drains or cranial trauma, and other predisposing
conditions include acute sinusitis and mastoid infections
Pathogenesis and Pathophysiology
• Bacteria that cause meningitis are able to
colonize the host mucosal epithelium,
invade, survive within the bloodstream,
then cross the BBB. Within the CSF they
multiply.
• Much of the damage results from cytokine
release within the CSF as the host mounts
an inflammatory response
• Inflammatory response is initiated both in
the bloodstream and the CSF, damaging
the endothelium of the BBB (tight
junctions)
Neuropathology
• Streptococcal meningitis
– H&E
– Gram Stain
• Fungal meningitis
– Crypto
•
•
•
•
H&E
PAS
Mucicarmine
GMS
– Aspergillus
• H&E
• GMS
– Tuberculosis
• H&E
• FITE
• Viral meningitis
– Enteroviral meningitis
• H&E
– CMV radiculitis
• H&E
Clinical Features
• Patients with bacterial meningitis usually present soon after symptom onset
• Classic Triad
– Fever, nuchal rigidity, change in mental status
– More common in Pneumococcal meningitis than meningococcal meningitis (58% vs
27%)
– 99 to 100% sensitive if patient has 0 of these 3
• 95% of adults presented with at least 2 of the following 4 symptoms: headache,
fever, nuchal rigidity, change in mental status
• Other resulting symptoms: seizures, focal neurologic deficits (CN palsies),
papilledema, ischemic stroke (pneumococcal meningitis), hearing loss (late), skin
manifestations (N. meningitidis)
Clinical Signs
Brudzinski Sign
Kernig Sign
Diagnostic Workup
• Laboratory Workup
– CBC: leukocytosis (majority PMNs)
– 50-90% of patients have positive blood cultures
– otherwise routine blood work is usually unrevealing
• Lumbar Puncture
– crucial for establishing the diagnosis, identifying causative organism, performing
susceptibility testing
– CT scan should be performed before LP if there is concern for increased ICP
• immunocompromised state, hx of CNS disease (mass lesion, stroke, focal infection), new onset
seizure within 1 week of presentation, papilledema, abnormal level of consciousness (GCS <11),
focal neurologic deficit
Lumbar Puncture
Case: Labs
• CTH: no intracranial hemorrhage, midline shift or mass effect. Did reveal
mastoiditis
• BMP: 141 | 103 | 10
-----------------------< 136
3.3 | 25 | 0.9
• CBC:
13.1
25.7 >-------< 253
37.1
• PT/INR: 14.3/1.2
• Blood Cultures : No growth x5 days
• CSF: Cloudy. Glucose, protein 131, WBC 1358 (PMN predominant, 75%)
Gram stain: Gram negative bacilli
Bacterial Culture: Many WBCs and rare Haemophilus influenza (beta lactamase
positive)
Viral PCRs (EBV, CMV, VZV, HSV1/2) , Crypto Ag, India Ink Stain, fungal culture,
meningoencephalitis panel: Negative
MRI in Bacterial Meningitis
• T1 plus contrast:
– Meningeal enhancement; especially characteristic when thicker, longer, more intensely
enhancing, and if there is nodular enhancement
– The degree of abnormal enhancement correlates with the degree of inflammatory
cellular infiltration of the meninges
• T2 FLAIR:
– leptomeningeal hyperintensities; not specific for infection vs inflammation
– CSF hyperintensities, usually present in the lateral ventricles and cortical sulci
• DWI:
– Abscesses (Strep pneumo), especially in the subarachnoid or intraventricular regions
– Resulting ischemic infarction or vasculitis
Acute Bacterial Meningitis: MRI Findings
Bacterial Meningitis Complications: MRI Findings
Case: Imaging
• MRI ww/o contrast: Consistent with meningitis with leptomeningeal
enhancement and ventriculitis with frank pus in the dependent occipital horns
of the lateral ventricles. No evidence of hydrocephalus.
MRI – T1
MRI – T2
Flair
MRI - T2
Propeller
MRI – T1 +
Contrast
MRI – T1 +
Contrast
Treatment
• Dexamethasone
• Antibiotics
– Should be administered immediately after LP, or if LP is delayed for imaging,
immediately after blood cultures are obtained
– Duration is dependent on causative pathogen
Dexamethasone
• Adjuvant therapy; decreases the rates of neurologic complications of meningitis
as well as mortality
• Reduces CSF concentrations of cytokines (such as TNF-alpha and IL-1), CSF
inflammation, and cerebral edema
• Efficacy: Randomized trial in 301 Dutch patients with bacterial meningitis
confirmed by CSF analysis
– Median duration of symptoms prior to treatment: 24 hours
– Placebo (with amoxicillin) vs IV dexamethasone 10mg q6 x4 days
– Primary Endpoint: Unfavorable outcomes (death or neurologic disability) at 8 weeks
– Based on culture results, significant reductions in mortality (14% vs 34%) and all
unfavorable outcomes (26% vs 52%) were only seen in patients with S. pneumo
meningitis
– Upon further investigation, significant benefit was only seen in patients with a Glasgow
coma scale of 8-11; no benefit was seen among patients with a mild neurologic deficit
– In patients with bacterial meningitis due to any other organism, rates of mortality (4%)
and unfavorable outcomes (9%) were independent of dexamethasone administration
Dexamethasone Continued
• 2013 Cochrane meta-analysis:
– Included data from 4121 patients entered in 25 randomized trials
– Included children and adults in both the developing and developed world
– Dexamethasone administration reduced mortality in patients with meningitis caused by S.
pneumoniae (RR 0.84, 95% CI 0.72-0.98) but not in meningitis caused by Haemophilus
influenzae or N. meningitidis
– Associated with lower rates of short-term neurologic sequelae (RR 0.83, 95% CI 0.69-1.00)
• No difference in long-term neurologic sequelae (such as hearing loss) between glucocorticoidtreated patients and controls (RR 0.90, 95% CI 0.74-1.10)
– When stratified by income:
• High-income countries: Reduced severe hearing loss (RR 0.51, 95% CI 0.35-0.73), any hearing loss
(RR 0.58, 95% CI 0.45-0.73), and short-term neurologic sequelae (RR 0.64, 95% CI 0.48-0.85)
• Low-income countries: None of these beneficial effects
Dexamethasone Continued
• No effective data exists regarding whether entry of vancomycin into the CSF is
reduced by the decreased inflammation when patients are given dexamethasone
• 2004 Infectious Diseases Society of America (IDSA) guidelines for the
management of bacterial meningitis:
– Adjunctive dexamethasone should be initiated in all adults with suspected or proven
pneumococcal meningitis
• Dexamethasone should be dosed at 0.15mg/kg q6 x4 days, and should be started
15-20 min before or at the same time as the first dose of antibiotics
• Should be continued if the Gram stain reveals organisms consistent with S.
pneumoniae, or if the CSF/blood culture grows S. pneumoniae
• Should be discontinued if the Gram stain and/or cultures reveal another
pathogen or if bacterial meningitis is ruled out
Treatment - Antibiotics
• In patients with no known immunodeficiency:
– Streptococcus pneumoniae, Neisseria meningitidis >> Haemophilus influenzae and group B
streptococcus. If >50 years old, must also cover for Listeria monocytogenes
– Vancomycin — 15 to 20 mg/kg IV Q8-12 (not to exceed 2 g per dose or a total daily dose of 60
mg/kg; adjust dose to achieve vancomycin serum trough concentrations of 15 to 20 mcg/mL)
PLUS Ceftriaxone — 2 g IV Q12 OR Cefotaxime — 2 g IV Q4-6
PLUS In adults >50 years of age, ampicillin — 2 g IV Q4
• In patients with impaired cellular immunity (lymphoma, cytotoxic chemotherapy, or highdose glucocorticoids):
– Listeria monocytogenes and gram-negative bacilli (including Pseudomonas aeruginosa) as well as
Streptococcus pneumoniae
– Vancomycin
PLUS Ampicillin — 2 g IV Q4
PLUS Cefepime — 2 g IV Q8 OR Meropenem — 2 g IV Q8
Antibiotics
• Healthcare-associated meningitis:
– gram-positive and gram-negative (such as Klebsiella pneumoniae and Pseudomonas
aeruginosa) pathogens.
– Vancomycin
PLUS Ceftazidime — 2 g IV Q8 OR Cefepime — 2 g IV Q8 OR Meropenem — 2 g IV Q8
• Allergy to beta lactams:
– Vancomycin
PLUS Moxifloxacin — 400 mg IV daily
PLUS (in patients >50 years of age and/or in those with defects in cell-mediated
immunity who require Listeria coverage), trimethoprim-sulfamethoxazole – 5 mg/kg (of
the trimethoprim component) IV Q6-12
Vaccines
• Vaccines for Hib, pneumococcal, and meningococcal disease are available
• The conjugated Hib vaccine was introduced in 1987, and has reduced the rate of
invasive Hib disease by 99%
• 2 single antigen Hib conjugate vaccines and 3 combination vaccines containing the Hib
conjugate are available
– 3 doses are given at 2, 4, and 6 months of age or 2 doses as 2 and 4 months of agedepending on
the product
• 2 meningococcal vaccines are available for children and adults:
– 1981, meningococcal polysaccharide vaccine (MPSV4) was approved for patients ≥ 2 years old
– In 1981 meningococcal conjugate vaccine (MCV4) was approved for patients ≥ 2 years old
• 4/2011 it was extended to patients 9-23 months at high risk (complement deficiency, in endemic areas, or
kids at high risk exposed to an outbreak)
Vaccines Continued: Pneumococcal Vaccines
• PCV7 aka Prevnar (a seven valent pneumococcal polysaccharide protein conjugate
vaccine)
– FDA licensed in 2000 for infants and children
– Covers the serotypes responsible for 82% of meningitis cases (4, 6B, 9V, 14, 18C, 19F, and 23F)
• PCV13 aka Prevnar 13
– FDA licensed in 2010 for children aged 6 weeks to 71 months, covering an additional 6
serotypes (1, 3, 5, 6A, 7F, and 19A)
– Recommended for all children 2-59 months and children 60-71 months that are
immunocompromised
– FDA approved PCV13 in 2011 for all adults ≥ 50 years old to prevent pneumonia and
invasive pneumococcal disease
• After completing PCV13, immunocompromised patients should receive a second
dose 5 years later
– Also recommended for all adults ≥ 65 years old who have not had a previous pneumococcal
vaccine or a vaccine in the last 5 years
– Also consider in younger adults that are nursing home residents, smokers, or high risk
(chronic lung disease, chronic CAD, immunodeficiency states)
Case: Treatment/Hospital Course
• Patient was initially maintained on
ceftriaxone, vancomycin, dexamethasone,
and acyclovir
• Patient was evaluated by both NSGY and
ENT for spontaneous CSF leak, suspected
due to clinical history as well as multiple L
tegmen defects (roof of the mastoid cavity)
on CT and a posterior fossa bony defect
consistent with L mastoiditis
• Underwent L tegmen
repair/mastoidectomy with lumbar drain
placed by NSGY
• When CSF culture results/susceptibilities
returned, patient was maintained on
ceftriaxone 2g IV q12 alone for a total of 14
days of treatment
• Pt steadily improved symptomatically and
was discharged home on POD#4
CT scan - Bone
References
• Lummel, N, Koch, M, et al. Spectrum and Prevalence of Pathological Intracranial Magnetic
Resonance Imaging Findings in Acute Bacterial meningitis. Clinical Neuroradiology. 2014;
10. DOI 10. 1007/s00062-014-0339-x.
• Tyler, KL. Chapter 28: a history of bacterial meningitis. Handbook of Clinical neurology.
2010; 95: 417-433.
• UpToDate. (n.d.). Retrieved December 1-16, 2014, from http://www.uptodate.com
• US Pharmacist - Vaccines. (n.d.). Retrieved December 12, 2014 from
http://www.uspharmacist.com/continuing_education/ceviewtest/lessonid/108112/.
• Weil-Olivier, Catherine, Gaillat, Jacques. Can the success of pneumococcal conjugate
vaccines for the prevention of pneumococcal diseases in children be extrapolated to
adults? Vaccine. 2014; 32: 2022-2026.