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©2015 MFMER | slide-1
Dexamethasone - Or Antibiotics Alone?Adjunctive Dexamethasone Therapy for Central Nervous System InfectionsChristine M Gamble, PharmDPGY1 Pharmacy Practice Resident
Pharmacy Grand RoundsMarch 15, 2016
©2015 MFMER | slide-2
Objectives
• Review the mechanism of action of corticosteroids
• Discuss the role of dexamethasone in acute pneumococcal meningitis
• Discuss the role of dexamethasone in non-pneumococcal central nervous system infections
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Which of the following best describes the use of dexamethasone at your practice site?
A. Not often used for bacterial meningitis or other CNS infections
B. Often started for bacterial meningitis and continued only if evidence of S.pneumoniae
C. Often started for bacterial meningitis and continued regardless of bacterial organism
D. Unsure how it is used at my practice site, or none of the above
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Inflammation of the brain parenchyma
Tessier JM. Chapter 30. In: Scheld WM, ed. Youmans Neurological Surgery. :544–558https://commons.wikimedia.org/wiki/File:MRI_head_side.jpg#filelinks
https://commons.wikimedia.org/wiki/Commons:GNU_Free_Documentation_License,_version_1.2
Central Nervous System (CNS) InfectionsCentral Nervous System (CNS) Infections
MeningitisMeningitisEncephalitisEncephalitisInflammation of the
meninges
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Protector of The CNS – The Blood Brain BarrierTypical CapillaryBrain Capillary
Tissue
H20
Brain
H20
Tight Junctions
Tessier JM. Chapter 30: Basic Science of Central Nervous System Infections. In: Scheld WM, ed. Youmans Neurological Surgery. :544–558
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Protector of The CNS – The Blood Brain BarrierInflamed Brain CapillaryHealthy Brain Capillary
Brain
H20
Brain
H20
Tight Junctions
Tessier JM. Chapter 30: Basic Science of Central Nervous System Infections. In: Scheld WM, ed. Youmans Neurological Surgery. :544–558
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Inflammation in CNS Infections- Helpful or Harmful?
Brain and Spinal Cord Perfusion
Brain and Spinal Cord Perfusion
Cognitive & Functional
Disabilities or Death
Cognitive & Functional
Disabilities or Death
Presence of
Pathogen
Presence of
PathogenInflammationInflammation
Eradication of InfectionEradication of Infection
Fluid into CSF
Fluid into CSF
Increased BBB Permeability
Increased BBB Permeability
Edema & ICP Edema
& ICP
IschemiaIschemia
Tessier JM. Chapter 30: Basic Science of Central Nervous System Infections. In: Scheld WM, ed. Youmans Neurological Surgery. :544–558
Leukocyte Entry
Leukocyte Entry
Antibiotic Entry
Antibiotic Entry
BBB= blood brain barrier
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Corticosteroid Mechanism of Action• Inhibit BBB permeability
• Inhibit:• TNF-α• IL-1
• Inhibit other inflammatory pathways• Upstream Inhibition:
• COX-2 • Inflammatory products
• COX-1• Maintains GI mucosa
Tessier JM. Chapter 30: In: Scheld WM, ed. Youmans Neurological Surgery. :544–558Dexamethasone. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO.
van de Beek D,et al. N Engl J Med. 2004;351:1849-1859
Key mediators of BBB permeability
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Dexamethasone
• Most potent glucocorticoid
• No water-retaining (mineralocorticoid) properties
• Best CSF penetration of glucocorticoids
• Long duration
Adrenal Cortical Steroids. In Drug Facts and Comparisons. 5th ed. St. Louis. 122-128,1997Czock D, et al. Clin Pharmacokinet. 2005; 44(1):61-98
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Dexamethasone theoretically has the ability to improve outcomes in CNS infections through which of the following mechanisms?
A. Prevents inflammation associated with antimicrobial-mediated bacterial lysis
B. Decreases permeability of BBB through blocking the production of TNF-a and IL-1 and therefore reduces edema and ICP
C. Decreases permeability of BBB through blocking the production of TNF-a and IL-1 and therefore reduces antibiotic entry into CSF
D. A and B
E. A and C
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Bacterial Meningitis
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Bacterial Meningitis - Mortality
Mortality Rate 3-29% - Dependent on organism
Thigpen MC, et al. 1998-2007. N Engl J Med. 2011;364:2016-2025Tunkel, AR, et al. Mandell’s Principles and Practice of Infectious Diseases, 89, 1097-1137. e8.
Organism Percentage of Total US Cases
US Mortality Rate
Streptococcus pneumoniae 58% 18-26%Neisseria meningitidis 14% 3-13%Haemophilus influenzae 7% 3-7%
Listeria monocytogenes 3% 15-29%
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Bacterial Meningitis - Morbidity
Edmond K, et al. Lancet Infect Dis. 2010; May; 10(5):317-328.
Organism Risk for at Least One Major Sequelae
Streptococcus pneumoniae 24.7%Neisseria meningitidis 7.2%Haemophilus influenzae 9.5%
Major Sequelae Fraction of All Major Sequelae Reported
Hearing Loss 33.3%Seizures 12.6%Motor Deficits 11.6%Cognitive Impairment 9.1%
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Evidence Supporting Adjunctive Steroids in Bacterial Meningitis
2015200219621950s
Case studies show hydrocortisone + antibiotics
= better outcomes vs. antibiotics alone
Retrospective Study N=120
Steroids + antibiotics = better outcomes vs.
antibiotics alone. Benefit not seen if steroid
delayed 5 days
Prospective Double-Blinded, Randomized
Placebo-Controlled Trial N= 301
Cochrane Database Meta Analysis
N= 4121 patients
Gross HP, et al. Med Bull (Ann Arbor). 1956 Aug;22(8):329-31Ribble JC, et al. Am J Med. 1958 Jan;24(1):68-79, Hoh, TK, et al. Singapore Med J. 1962 Jun;3:73-7
De Gans, et al. N Engl J Med 2002; 347: 1549-1556Brouwer MC, et al. Cochrane Database Syst Rev. 2015 Sep 12;9:CD004405
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2002 De Gans, et al. Prospective, Randomized, Double-Blind, Multicenter, Placebo-
Controlled Trial
Adults with Acute Bacterial Meningitis
N=301
Placebo
Dexamethasone 10mg q6h x 4 days.
1st Dose 15-20 minutes before or with the first
dose of antibiotic.
De Gans, et al. N Engl J Med 2002; 347: 1549-1556
Unfavorable Outcome, Death, Hearing Loss at 8 weeks
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Primary Endpoint: Unfavorable Outcome
Glasgow Outcome Scale5 = Mild or No Disability: able to return to work or school
4 = Moderate Disability: able to live independently but unable to return to work or school
3 = Severe Disability: follows commands but unable to live independently
2 = Vegetative State
1 = Death
:
Unfavorable Outcome
De Gans, et al. N Engl J Med 2002; 347: 1549-1556
Score <5 on the Glasgow Outcome Scale at 8 weeks
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ResultsAll Patients
Endpoint- no. (%) Dexamethasone(N = 157)
Placebo(N = 144) P-Value
Unfavorable Outcome 23 (15%) 36 (25%) P=0.03Death 11 (7%) 21 (15%) P=0.04Hearing Loss 9% 12% P=0.54
S.pneumoniae Subgroup
Endpoint- no. (%) Dexamethasone(N = 58)
Placebo(N = 50) P-Value
Unfavorable Outcome 15 (26%) 26 (52%) P=0.006Death 8 (14%) 17 (34%) P=0.02Hearing Loss 14% 21% P=0.55
N.meningitidis Subgroup
Endpoint- no. (%) Dexamethasone(N = 50)
Placebo(N = 47) P-Value
Unfavorable Outcome 4 (8%) 5 (11%) P=0.74Death 2 (4%) 1 (2%) P=1.00Hearing Loss 7% 11% P=0.48
De Gans, et al. N Engl J Med 2002; 347: 1549-1556
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Adverse Events:
All Patients
Endpoint- no. (%) Dexamethasone(N = 157)
Placebo(N = 144) P-Value
GastrointestinalBleeding 2 (1%) 5 (3%) P=0.27
Hyperglycemia 50 (32%) 37 (26%) P=0.24Herpes Zoster 6 (4%) 4 (3%) P=0.75Fungal Infection 8 (5%) 4 (3%) P=0.38
De Gans, et al. N Engl J Med 2002; 347: 1549-1556
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Author’s Conclusions
Early Treatment with dexamethasone (prior to or with the first dose of antibiotic) improves
outcomes in adults with acute bacterial meningitis and does not increase the risk of gastrointestinal
bleeding.
De Gans, et al. N Engl J Med 2002; 347: 1549-1556
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Author’s Recommendation• Recommend dexamethasone for all adults with
acute bacterial meningitis – regardless of infecting organism
• Rationale• Events were rare in N.meningitidis subgroup• Study was not powered to show difference in
subgroups• Benefit cannot be ruled out in subgroups• Dexamethasone did not increase adverse events
De Gans, et al. N Engl J Med 2002; 347: 1549-1556
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2015 Cochrane Review• Meta-analysis of 25 studies
• N= 4121 participants with acute bacterial meningitis
• Primary Endpoints• 1. Mortality• 2. Hearing Loss• 3. Neurological Sequelae
• New epilepsy• Severe ataxia• Severe memory or concentration disturbance
Brouwer MC, et al. Cochrane Database Syst Rev. 2015;9:CD004405 PMID: 26362566
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All Patients: Mortality- no (%)Corticosteroids
(N= 2064)Placebo
(N= 2057) RR (95% CI)
367 (17.8%) 409 (19.9%) 0.90 (0.80-1.01)
All Patients: Mortality
Brouwer MC, et al. Cochrane Database Syst Rev. 2015;9:CD004405 PMID: 26362566
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Mortality by Species Subgroup
Mortality By Species
Causative Species # Studies # ParticipantsCorticosteroids vs.
PlaceboRR (95% CI)
H. influenzae 11 825 0.76 (0.53-1.09)
S. pneumoniae 17 1132 0.84 (0.72-0.98)N. meningitidis 13 618 0.71 (0.35-1.46)
Brouwer MC, et al. Cochrane Database Syst Rev. 2015;9:CD004405 PMID: 26362566
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Hearing Loss
Brouwer MC, et al. Cochrane Database Syst Rev. 2015;9:CD004405 PMID: 26362566
All Patients: Any Hearing Loss- no (%)Corticosteroids
(N= 1424)Placebo
(N= 1361) RR (95% CI)
197 (13.8%) 259 (19.0%) 0.74 (0.63-0.87)
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Neurologic Sequelae*
Endpoint # Studies # ParticipantsCorticosteroids
vs. PlaceboRR (95% CI)
Short-term Neurologic Sequelae(Discharge - 6 weeks post discharge) 13 1756 0.83 (0.69-1.00)
Long-term Neurologic Sequelae(6 weeks – 12 months post discharge) 13 1706 0.90 (0.74-1.10)
Brouwer MC, et al. Cochrane Database Syst Rev. 2015;9:CD004405 PMID: 26362566
*New epilepsy, severe ataxia, or severe memory or concentration disturbance
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Gastrointestinal Bleeding
Adverse Event # Studies # ParticipantsCorticosteroids
vs. PlaceboRR (95% CI)
Gastrointestinal Bleeding 16 2560 1.45 (0.86-2.45)
Brouwer MC, et al. Cochrane Database Syst Rev. 2015;9:CD004405 PMID: 26362566
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2015 Cochrane Review Conclusion
• Dexamethasone:
• Significantly reduced mortality in patients with S. pneumoniae meningitis, but not other species
• Significantly reduced hearing loss in bacterial meningitis
• Significantly reduced rates of short term neurologic sequelae, but not long-term neurologic sequelae
• Did not lead to increased gastrointestinal bleeding
Brouwer MC, et al. Cochrane Database Syst Rev. 2015;9:CD004405 PMID: 26362566
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IDSA Approach Regarding Steroids in Bacterial Meningitis
Clin Infect Dis. 2004 Nov 1;39(9):1267-84.
Suspicion for Bacterial MeningitisSuspicion for Bacterial Meningitis
Blood Cultures and Lumbar Puncture* STAT
Blood Cultures and Lumbar Puncture* STAT
*no lumbar puncture if papilledema, delay in performance of lumbar puncture, or selected focal neurologic defects.
Dexamethasone + Empiric AntibioticsDexamethasone + Empiric Antibiotics
G+ dipplococci on CSF gram stain, or blood or CSF culture positive for S. pneumoniae?
G+ dipplococci on CSF gram stain, or blood or CSF culture positive for S. pneumoniae?
Yes
Continue TherapyContinue Therapy Discontinue DexamethasoneDiscontinue Dexamethasone
No
IDSA= Infectious Disease Society of America
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Why S. pneumoniae?
Tessier JM. Chapter 30: Basic Science of Central Nervous System Infections. In: Scheld WM, ed. Youmans Neurological Surgery. :544–558
• Produces pneumolysin
• Pore-forming toxin
• Increased BBB permeability
• Direct neuronal cell death
Brain Capillary
Tight Junctions
S.pneumo
Pneumolysin
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Which of the following are appropriate dexamethasone regimens for suspected pneumococcal meningitis?
A. 0.15 mg/kg IV q6h x 4 days initiated 10-20 minutes before start of antimicrobialsB. 0.15 mg/kg IV q6h x 4 days initiated at the same time as antimicrobialsC. 0.15 mg/kg IV q6h x 4 days initiated after the start of antimicrobialsD. A and BE. B and C
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Tuberculous Meningitis
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Tuberculous meningitis (TBM)
• Mycobacterium tuberculosis• Currently 2 billion people are infected with TB
infection (1/3 of the world’s population)• 10% develop clinical disease
• Prevalence: 0.7% of all reported TB cases are TBM
• 200-300 cases annually in the US• Higher incidence in developing countries
Centers for Disease Control. Available at: http://www.cdc.gov/tb/topic/globaltb/default.htmVan TTT, et al. J. Epidemiol Community Health 2014;68: 195-196
Ramachandran TS. Tuberculous Meningitis. Medscape Reference® 2014
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Typical Outcomes in Tuberculous Meningitis
Death 50.00%
Complete Neurological
Recovery21.50%
Cognitive Impairment
28.50%
Kalita J et al. (2007). Eur J Neurol 14: 33–37Thwaites GE et al. (2005). Lancet Neurol 4: 160–170
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Evidence Supporting Adjunctive Steroids in Tuberculous Meningitis
2000 200419941950s
Case series show cortisone + streptomycin improved
prognosis vs. streptomycin alone
RCT N=47 Showed better neurological outcomes and
Faster Recovery with Dexamethasone + anti-tuberculosis therapy vs.
tuberculosis therapy alone
Cochrane Meta Analysis N=595 Dexamethasone
decreased death and disability patients ≤14
years of age. No difference found for
subgroup patients >14 years of age (not
enough data)
RCT N= 545 patients only >14
years of age. Dexamethasone vs.
Placebo
2008
Updated Cochrane Meta Analysis
Showing benefit for all age groups
Ashby M and Grant H (1955) Lancet 268: 65–66Kumarvelu S et al. (1994) Tuber Lung Dis 75: 203–207Prasad K, et al. Cochrane Database Syst Rev 2000;3:CD00224Thwaites GE et al. (2004) N Engl J Med 351: 1741–1751Prasad K, et al. Cochrane Database Syst Rev 2008
Shane SJ and Riley C (1953). N Engl J Med 249: 829–834
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2004 Thwaites GE et al.Prospective, Randomized, Double-Blinded, Multicenter Trial in
Vietnam
Patients >14 years of age with tuberculous
meningitisN= 545
Thwaites GE et al. N Engl J Med 2004; 351: 1741–1751
Dexamethasone + Anti-Tuberculosis
Therapy
Placebo + Anti-Tuberculosis
Therapy
Severe Disability and Adverse Events at 9 Months
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Glasgow Coma Scale Stratification
• Grade I Disease: Score 15
• Grade II Disease: Score 11-14.
• Grade III Disease: Score <11
Institute of Neurological Sciences NHS Greater Glasgow and Clyde. Glasgowcomascale.orgThwaites GE et al. N Engl J Med 2004; 351: 1741–1751
• Glasgow Coma Score
• Range 3-15
• Score 15 • obeys commands• oriented to time,
place and person• opens eyes
spontaneously• 3 = totally unresponsive
Stratification in Study
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Treatment Specifics
Rifampin +Isoniazid +
Pyrazinamide + Streptomycin
Rifampin + Isoniazid +
Pyrazinamide
X 3 months X 6 months
Dexamethasone IV 0.3 mg/kg/day
If Grade II – III Disease: 8 week taper
Dexamethasone IV0.4 mg/kg/day
If Grade I disease: 6 week taperPlacebo
Placebo
Thwaites GE et al. N Engl J Med 2004; 351: 1741–1751
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Results: Baseline Characteristics
Characteristic Dexamethasone(N = 274)
Placebo(N = 271)
Median Age - years 36 35 Age Range - years 15-88 15-84Male % 61.3% 60.1%Median Glasgow Coma Score 14 14
Thwaites GE et al. N Engl J Med 2004; 351: 1741–1751
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Results: Composite Primary Endpoint
0%
10%
20%
30%
40%
50%
60%
70%
Placebo Dexamethasone
49.4%44.2%
P=0.22Death or Severe
Disability at 9 Months
Thwaites GE et al. (2004) N Engl J Med 351: 1741–1751
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Results: Other Endpoints
Endpoint- no. (%) At 9 Months
Dexamethasone(N = 274)
Placebo(N = 271) P-Value
*Death or Severe Disability 121 (44.2%) 132 (49.4%) P=0.22
Death 87 (31.8%) 112 (41.3%) P=0.01
**Severe Disability -- (18.2%) -- (13.8%) P=0.27
***Serious Adverse Events 26 (9.5%) 45 (16.6%) P=0.02• Severe Hepatitis 0 8 (3%) --• GI Bleeding 3 (1.1%) 3 (1.1%) --• Bacterial Sepsis 1 (0.4%) 3 (1.1%) --
*Primary Endpoint**Out of survivors***Any event causing or threatening to cause prolonged hospital stay
Thwaites GE et al. (2004) N Engl J Med 351: 1741–1751
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Author’s Conclusions
In tuberculous meningitis, adjunctive dexamethasone improves survival in
patients over 14 years of age without an increase in adverse events, but it likely
does not prevent severe disability
Thwaites GE et al. (2004) N Engl J Med 351: 1741–1751
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Central Nervous System TB Guidelines
National Institute for Health and Care Excellence. Jan 13, 2016. https://www.nice.org.uk/guidance/ng33/resources/tuberculosis-1837390683589
MMWR June 20, 2003 / 52 (RR11);1-77
Guideline DexamethasoneRecommendation
NICE
At the start of anti-TB treatment regimen, offer dexamethasone initially at a high dose with
gradual withdrawal over 4-8 weeks.
Consider 6 weeks if stage I diseaseConsider 8 weeks if stage II-III disease
ATS/CDC/IDSADexamethasone x 6 weeks“Strongly Recommended”
(A1 Rating)
©2015 MFMER | slide-43
Which of the following CNS infections is an FDA-approved indication for dexamethasone?
A. S. pneumoniae meningitisB. N. meningitidis meningitisC. H. influenzae meningitisD. M. tuberculosis meningitisE. HSV encephalitis
©2015 MFMER | slide-44
Herpes Simplex Virus (HSV) Encephalitis
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HSV Encephalitis• Most common fatal CNS viral infection in the
western hemisphere• Neurological emergency
• High mortality • 70% if untreated• 20-50% with antivirals
Tyler KL (2004) Herpes 11 (Suppl 2): S57A–S64ABaringer JR et al. (1976) Arch Neurol 33: 442–446
Eisenstein LE et al. (2004). Heart Lung 33: 196–197Schmutzhard E (2001) J Neurol 248: 469–477
Cinque P et al. (1996). J Neurol Neurosurg Psychiatry 61: 339–345
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Studies of Adjunctive Steroids in HSV Encephalitis
2016200720052003
Studies of acyclovir + methylprednisolone in mice show reduced chronic brain
abnormalities on MRI vs. acyclovir alone
Retrospective Trial of 45 patients studies outcomes
of using steroids in the acute stage of HSV
encephalitis
In mice, dexamethasone +
acyclovir controls viral replication and restricts neuronal cell death vs.
acyclovir alone. Delaying steroids for 3
days is better than early treatment
GACHE Trial (in progress). Randomized,
Double-Blinded, Placebo Controlled Trial of Acyclovir +
Dexamethasone vs. Acyclovir + Placebo
Meyding-Lamade UK et al. (2003). J Neurovirol 9: 118–125Kamei S et al. (2005) J Neurol Neurosurg Psychiatry 76: 1544–1549
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Corticosteroids in HSV Encephalitis
Study Type Outcomes Methods VariablesExamined
Results
Retrospective chart review of 45 patients with HSV encephalitis
• No Sequelae• Mild Sequelae• Moderate Sequelae
(motor, speech, memory limitations, or epilepsy)
• Severe Sequelae(requiring supportive care)
• Death
Logisticregression to identify predictors of good outcome
Sex, Age,
Glasgow Coma Score,
Protein concentration
in CSF, Corticosteroid Administration
Three variableslinked to better
outcome1. Patient Age
2. Baseline Glasgow Coma
Score 3. Steroid
administration in the acute
stage
Kamei S et al. (2005) J Neurol Neurosurg Psychiatry 76: 1544–1549
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HSV Encephalitis Guidelines
Tunkel AR, et al. Clin Infect Dis. 2008 Aug 1;47(3):303-27
Guideline DexamethasoneRecommendation
IDSA
“Use of adjunctive corticosteroids was assessed in one non-randomized, retrospective
study of 45 patients with herpes simplex encephalitis treated with acyclovir. Although a worse outcome was observed in patients who
were not treated with corticosteroids, these results need to be confirmed before this
adjunctive treatment can be recommended.”
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Other Encephalitis Types
Encephalitis Causative Species
CorticosteroidsBeneficial?
Varicella Zoster Virus Consider (C-III)Ebstein Barr Virus Consider (C-III)Cerebral malaria NoHelminthic encephalitis* Consider (B-III)
*If caused by Baylisascaris procyonis or Taenia solium
Tunkel AR, et al. Clin Infect Dis. 2008 Aug 1;47(3):303-27
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Summary• S.pneumoniae meningitis
• Dexamethasone 0.15mg/kg q6hrs x 4 days strongly recommended
• M.tuberculosis meningitis• Stage I Disease:
• Dexamethasone 6 week taper strongly recommended
• Stage II-III Disease:• Dexamethasone 8 week taper strongly
recommended
• HSV encephalitis• Despite the lack of randomized controlled trials,
evidence exists that supports the use of dexamethasone
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