Meningitis pathophysiology.pdf

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Pathophysiology AndPathophysiology AndTherapeutics Of MeningitisTherapeutics Of Meningitis

Robert J. Konop, Pharm.D.Robert J. Konop, Pharm.D.

Manager, Clinical Formulary DevelopmentManager, Clinical Formulary DevelopmentPharmacotherapy, Assessment & PolicyPharmacotherapy, Assessment & Policy

Prime Therapeutics Inc.Prime Therapeutics Inc.



ObjectivesObjectives

•• Identify the most common organisms forIdentify the most common organisms forboth viral and bacterial meningitisboth viral and bacterial meningitis

•• Understand the difference between viralUnderstand the difference between viraland bacterial meningitisand bacterial meningitis

•• Know the composition of normal andKnow the composition of normal andabnormal CSFabnormal CSF



ObjectivesObjectives

•• List the risk factors for CNS infectionsList the risk factors for CNS infections•• Describe the clinical presentation andDescribe the clinical presentation and

laboratory results of characteristiclaboratory results of characteristicmeningitismeningitis

•• Know both empiric and pathogenKnow both empiric and pathogen --specificspecific

antibiotic regimens in meningitisantibiotic regimens in meningitis•• Understand the recommended prophylacticUnderstand the recommended prophylactic

regimens and their indications for useregimens and their indications for use



DefinitionsDefinitions

1.1. MeningitisMeningitis

Inflammation of the meninges; abnormal WBC in CSFInflammation of the meninges; abnormal WBC in CSF2.2. Septic versus Aseptic meningitisSeptic versus Aseptic meningitis

3. Encephalitis3. EncephalitisInflammation of the brainInflammation of the brain

4. Meningoencephalitis4. MeningoencephalitisInflammation of the brain accompanied by meningitisInflammation of the brain accompanied by meningitis



MeningesMeningesDura Mater (pachymeninges)Dura Mater (pachymeninges)

Directly beneath and is adherent to the skullDirectly beneath and is adherent to the skull

Pia MaterPia MaterLies directly over the brain tissueLies directly over the brain tissue

ArachnoidArachnoid

The middle layer between the dura mater and the pia materThe middle layer between the dura mater and the pia materSubarachnoid SpaceSubarachnoid Space

Between the pia mater and the arachnoidBetween the pia mater and the arachnoid



Anatomy/Physiology of the CNSAnatomy/Physiology of the CNS

Cerebrospinal FluidCerebrospinal FluidOriginOrigin

Infants: 40Infants: 40 --60ml60mlChildren: 60Children: 60 --100ml100mlAdults: 110Adults: 110 --160ml160ml



Viral Meningitis

1.1. IncidenceIncidence2.2. Clinical presentationClinical presentation



Viral Meningitis

PathogensPathogensA) EnterovirusesA) Enteroviruses -- 85%85%

B) Mumps VirusB) Mumps Virus -- 55--10%10%C) Lymphocytic choriomeningitis virusC) Lymphocytic choriomeningitis virusD) Herpes Simplex VirusD) Herpes Simplex Virus

HSVHSV --22





EnterovirusesEnteroviruses•• Group AGroup A coxsackiecoxsackie

23 serotypes23 serotypes

14% of the cases14% of the cases

•• Group BGroup B coxsackiecoxsackie6 serotypes6 serotypes

12% of the cases12% of the cases•• EchovirusesEchoviruses

31 serotypes31 serotypes75 %of the cases75 %of the cases



EnterovirusesEnteroviruses

RespiratoryRespiratoryCommon coldCommon coldPharyngitisPharyngitis

PneumoniaPneumonia

GastrointestinalGastrointestinal

VomitingVomitingDiarrheaDiarrheaAbdominal painAbdominal pain

EyeEyeAcute hemorrhagicAcute hemorrhagicconjunctivitisconjunctivitis

HeartHeartMyopericarditisMyopericarditis

SkinSkinExanthemExanthem

NeurologicNeurologic

MeningitisMeningitis



EnterovirusesEnteroviruses

Most commonMost common -- 8585 --95% of the cases95% of the casesSeasonalSeasonal

Late summer to fallLate summer to fallFecal to oral routeFecal to oral route

Effects all age groupsEffects all age groupsTypically < 1 year oldTypically < 1 year old



Mumps VirusMumps Virus

ParotitisParotitisMeningitis occurs in 10Meningitis occurs in 10 --30% of the cases30% of the cases

Encephalitis is rareEncephalitis is rareSecond most common viral meningitisSecond most common viral meningitis

10 to 20%10 to 20%Peak late winter to early springPeak late winter to early spring

Humans only natural hostsHumans only natural hosts





Herpes Simplex VirusHerpes Simplex Virus

HSVHSV --22Neonates during birthNeonates during birth

Sexually active adultsSexually active adults



Treatment Viral MeningitisTreatment Viral Meningitis

SUPPORTIVE CARESUPPORTIVE CAREAntibiotics until bacterial meningitis is ruledAntibiotics until bacterial meningitis is ruled

outoutSeizure controlSeizure control

Symptom controlSymptom controlAcyclovirAcyclovir



Bacterial Meningitis

Incidence:Incidence:0.20.2 --2.9 cases/100,000/year (1986)2.9 cases/100,000/year (1986)

0.20.2 --1.1 cases/100,000/year (1995)1.1 cases/100,000/year (1995)Very Young and Very OldVery Young and Very Old

Dramatic decrease inDramatic decrease in H . flu H . f lu MortalityMortality

SequelaeSequelae



Incidence and Mortality RateIncidence and Mortality Rate

Organism % of Total Cases Annual Incidence Fatality Rate (%)

1986 1995 1986 1995 1986 1995 H. flu 45 7 2.9 0.2 3 6S. pneumo 18 47 1.1 1.1 19 21

N. menin. 14 25 0.9 0.6 13 3GBS 5.7 12 0.4 0.3 12 7

L. mono 3.2 8 0.2 0.2 22 15other 15 1.0 18

* Bacterial Meningitis in the United States in 1995,NJM, October* Bacterial Meningitis in the United States in 1995,NJM, October 2, 1997, 337 (14) 9702, 1997, 337 (14) 970 --976.976.




Most common organisms by population:Most common organisms by population:00--4 weeks:4 weeks: GBS, E. coli, L. monocytogenes, otherGBS, E. coli, L. monocytogenes, othergram negativesgram negatives

44--12 weeks:12 weeks: GBS, E. coli, L. monocytogenes, H.GBS, E. coli, L. monocytogenes, H.influenzae, S. pneumoniaeinfluenzae, S. pneumoniae

3mo3mo --44 yrsyrs :: N. meningitidis, S. pneumoniae , H.N. meningitidis, S. pneumoniae , H.influenzaeinfluenzae

55--99 yrsyrs :: N. meningitidis, S. pneumoniae/H.N. meningitidis, S. pneumoniae/H.influenzaeinfluenzae




99--18 years:18 years: N. meningitidis, S. pneumoniae, H.N. meningitidis, S. pneumoniae, H.influenzaeinfluenzae

1818 --60 years:60 years: S. pneumoniae, N. meningitidisS. pneumoniae, N. meningitidis

> 60 years:> 60 years: S. pneumoniae, N. meningitidis, L.S. pneumoniae, N. meningitidis, L.monocytogenes, other gram negativesmonocytogenes, other gram negativesNeurosurgNeurosurg :: S. aureus, S. epidermidis, gramS. aureus, S. epidermidis, gram

negativesnegativesClosed Head:Closed Head: S. pneumoniae, H. influenzaeS. pneumoniae, H. influenzaeOpen Head:Open Head: S. aureus, gram negativesS. aureus, gram negatives



Pathogenesis

Bacterial InvasionBacterial InvasionParameningeal focus/colonizationParameningeal focus/colonization

Adhesions, binding receptors, piliAdhesions, binding receptors, piliHematogenous spreadHematogenous spreadParameningeal seedingParameningeal seedingColonization of hardwareColonization of hardwareDirect inoculationDirect inoculation



Pathogenesis

Bacterial elementsBacterial elements -- inflammatory responseinflammatory response

Endotoxin/LipopolysaccharideEndotoxin/LipopolysaccharidePeptidoglycanPeptidoglycanLipoteichoic acidLipoteichoic acid

Release of inflammatory mediators byRelease of inflammatory mediators byastrocytes, microglial/endothelial cellsastrocytes, microglial/endothelial cells

TNF alphaTNF alphaILIL --11



Pathophysiology

•• Reduced cerebral perfusion secondary to edemaReduced cerebral perfusion secondary to edema•• Cerebral ischemia secondary to thrombosisCerebral ischemia secondary to thrombosis•• VasculitisVasculitis•• Alteration of cerebral blood flowAlteration of cerebral blood flow•• Direct neuronal cell damage secondary toDirect neuronal cell damage secondary to

bacterial elements, activated leukocytes,bacterial elements, activated leukocytes,cytokines, and other inflammatory mediatorscytokines, and other inflammatory mediators



Pathophysiology

Increased intracranial pressureIncreased intracranial pressureVasogenic edemaVasogenic edema ---- cytokines act oncytokines act onendothelial cells to damage the BBBendothelial cells to damage the BBB

Cytotoxic edemaCytotoxic edema ---- direct damage to cells allowingdirect damage to cells allowingbuildup of intracellular waterbuildup of intracellular water

Interstitial edemaInterstitial edema ---- obstruction of CSF flow and removalobstruction of CSF flow and removal

Brain herniationBrain herniation



Risk Factors

1. Respiratory tract infection1. Respiratory tract infection2. Otitis media2. Otitis media3. Mastoiditis3. Mastoiditis4. Head trauma4. Head trauma5. Splenectomy5. Splenectomy6. Sickle cell disease6. Sickle cell disease7. Immunosuppressive therapy7. Immunosuppressive therapy8. Immunocompromised host8. Immunocompromised host9. Alcoholic patients9. Alcoholic patients10.Patients with hardware (shunts, etc.)10.Patients with hardware (shunts, etc.)



Clinical Presentation

Physical signs/symptoms:Physical signs/symptoms:FeverFeverHeadacheHeadachePhotophobiaPhotophobiaNausea/vomitingNausea/vomitingMental status changesMental status changesStiff neck/backStiff neck/backPositive Brudzinski's signPositive Brudzinski's sign

Positive Kernig's signPositive Kernig's signDeafnessDeafnessSeizuresSeizures

Focal neurologic deficitFocal neurologic deficitHydrocephalusHydrocephalus



Laboratory StudiesLaboratory Studies

Lumbar PunctureLumbar PunctureCSF cell countCSF cell countCSF chemistriesCSF chemistries

CSF gram stainCSF gram stainCSF cultureCSF culture

Blood CultureBlood CultureSputum Culture/Urine CultureSputum Culture/Urine Culture

Peripheral CBC and ElectrolytesPeripheral CBC and Electrolytes



Clinical Presentation and Diagnosis

Abnormal CSF-findings by type of meningitis

ProteinProtein GlucoseGlucoseTypeType WBC(mm2)WBC(mm2) Diff Diff . (%). (%) (mg/L)(mg/L) (mg/ (mg/ dLdL ))

NMLNML < 10< 10 >50 lymphs>50 lymphs < 50< 50 3030--7070BactBact .. 400400 --100,000100,000 >90>90 PMN'sPMN's 8080--500500 < 35< 35ViralViral 55--500500 >50 lymphs>50 lymphs 3030--150150 NML/lowNML/lowFungalFungal 4040--400400 >50 lymphs>50 lymphs 4040--150150 NML/lowNML/lowT.B.T.B. 100100 --1,000 >50 lymphs1,000 >50 lymphs 4040--400400 NML/lowNML/low




Bacterial antigen detection testsBacterial antigen detection tests69% accurate when positive cultures69% accurate when positive culturesUseful when antibiotics were given before the CSF culture wasUseful when antibiotics were given before the CSF culture was

takentaken

May react to other organismsMay react to other organisms

Other testsOther tests

Counterimmunoelectrophoresis (CIE) and latex fixationCounterimmunoelectrophoresis (CIE) and latex fixation(encapsulated organisms)(encapsulated organisms)Limulus lysate assay (gramLimulus lysate assay (gram --negative endotoxin)negative endotoxin)



Common Bacterial Organisms

Haemophilus influenzaeHaemophilus influenzaePeak incidence: 6Peak incidence: 6 --12 months of age: declines after 2412 months of age: declines after 24

months of agemonths of age

Deafness = 6%Deafness = 6%Coma/seizures commonComa/seizures commonClose contacts are 200Close contacts are 200 --1000 x risk1000 x risk

Resistance pattern is growing throughout the U.S.Resistance pattern is growing throughout the U.S.Dramatic decrease in cases since 1990Dramatic decrease in cases since 1990




Neisseria meningitidisNeisseria meningitidisUsually occurs winter/springUsually occurs winter/springFive main serogroups: A, B, C, Y, and WFive main serogroups: A, B, C, Y, and W --135 (A135 (A

and Cand C ----epidemics; Bepidemics; B ---- individual cases; Yindividual cases; Y ----pneumonia)pneumonia)

May present with a characteristic immuneMay present with a characteristic immune

reaction 10reaction 10 --14 days after infection (fever,14 days after infection (fever,arthritis, pericarditis). Rx with NSAID'sarthritis, pericarditis). Rx with NSAID's






Streptococcus pneumoniaeStreptococcus pneumoniaeGram positive diplococciGram positive diplococci"Pneumococcus""Pneumococcus"Deafness = 31%Deafness = 31%Coma and seizures are more commonComa and seizures are more commonResistance is becoming a problemResistance is becoming a problem




Listeria monocytogenesListeria monocytogenesPeak incidence in summer/early fallPeak incidence in summer/early fallGram positive rod (coccobacilli)Gram positive rod (coccobacilli)

Most common ages:Most common ages:Very young (< 3 months)Very young (< 3 months)

Older (> 60 years)Older (> 60 years)Susceptible to ampicillinSusceptible to ampicillin



Antibiotic TherapyAntibiotic TherapyFactors Enhancing Antimicrobial PenetrationFactors Enhancing Antimicrobial Penetration

Small MWSmall MWUnionized at physiologic pHUnionized at physiologic pH

Lipid solubleLipid solubleLarge Free FractionLarge Free Fraction

Factors Reduce Antibiotic ActivityFactors Reduce Antibiotic ActivityLow pH of fluidLow pH of fluidHigh concentration of protein in fluidHigh concentration of protein in fluid

High temperature of fluidHigh temperature of fluid





Needs InflammationNeeds InflammationPenicillinPenicillinAmpicillinAmpicillinCarbenicillinCarbenicillinCiprofloxacinCiprofloxacinTicarcillin (clavulanate)Ticarcillin (clavulanate)

QuinolonesQuinolonesPiperacillin (tazobactam)Piperacillin (tazobactam)

CefuroximeCefuroximeCeftizoximeCeftizoximeCeftazidimeCeftazidimeMezlocillinMezlocillinImipenemImipenemAztreonamAztreonamVancomycinVancomycin



Questionable concentrationsQuestionable concentrations

AminoglycosidesAminoglycosidesGentamicinGentamicinStreptomycinStreptomycinAmikacinAmikacinKanamycinKanamycin

TobramycinTobramycinPolymyxinPolymyxin

T



TreatmentTreatment

Empiric choice of antibiotic:Empiric choice of antibiotic:00--4 weeks: ampicillin/cefotaxime or4 weeks: ampicillin/cefotaxime or

ampicillin/gentamicinampicillin/gentamicin44--12 weeks: ampicillin/cefotaxime12 weeks: ampicillin/cefotaxime3mo3mo --4 years: vancomycin/ceftriaxone or4 years: vancomycin/ceftriaxone or

cefotaximecefotaxime



TreatmentTreatment

55

--9 years: vancomycin/ceftriaxone or cefotaxime9 years: vancomycin/ceftriaxone or cefotaxime

99--18 years: vancomycin/ceftriaxone or18 years: vancomycin/ceftriaxone orcefotaximecefotaxime

1818--60 years: vancomycin/ceftriaxone or60 years: vancomycin/ceftriaxone orcefotaximecefotaxime

> 60 years: ampicillin/ceftriaxone or> 60 years: ampicillin/ceftriaxone orampicillin/cefotaximeampicillin/cefotaxime



Treatment

Definitive Choice of AntibioticDefinitive Choice of Antibiotic

H. influenzae:H. influenzae:ßß --lactamase (lactamase ( --) ampicillin) ampicillin

ßß --lactamase (+) cefotaxime orlactamase (+) cefotaxime orceftriaxoneceftriaxone

N. meningitidis: penicillin G or ampicillinN. meningitidis: penicillin G or ampicillinL. monocytogenes: ampicillinL. monocytogenes: ampicillin



TreatmentTreatment

Enterobacteriaceae: cefotaximeEnterobacteriaceae: cefotaximeP. aeruginosa: ceftazidime/tobramycinP. aeruginosa: ceftazidime/tobramycinS. aureus:S. aureus:

MSSA: nafcillinMSSA: nafcillinMRSA: vancomycinMRSA: vancomycin

S. epidermidis: vancomycin/rifampinS. epidermidis: vancomycin/rifampin



h



DexamethasoneDexamethasone

•• Blocks TNF alpha and ILBlocks TNF alpha and IL --1 release1 release

•• Decreases ICP, CNS edema, fever duration, andDecreases ICP, CNS edema, fever duration, andCSF lactate and protein levelsCSF lactate and protein levels

•• Increased CSF glucose levelIncreased CSF glucose level•• Decreases neurologic complications (e.g. ataxia,Decreases neurologic complications (e.g. ataxia,

seizures, focal deficit) and hearing loss byseizures, focal deficit) and hearing loss byapproximately 50%approximately 50%

Children withChildren with H . inf luenzae H . inf luenzae typetype BB



DexamethasoneDexamethasone

Indication: > 6 weeks of age, and clinical CSFIndication: > 6 weeks of age, and clinical CSFfindings of H. flu meningitisfindings of H. flu meningitis

0.15 mg/kg/dose IV Q6H x 4 days0.15 mg/kg/dose IV Q6H x 4 daysFirst dose given with/before antibioticsFirst dose given with/before antibiotics



Dexamethasone/Antibiotic InteractionSignificant reduction of vancomycin/BBBSignificant reduction of vancomycin/BBB

penetrationpenetrationSomewhat lower CSF concentrations ofSomewhat lower CSF concentrations of

ceftriaxoneceftriaxone

D h /A ibi iD th /A tibi ti



Dexamethasone/AntibioticDexamethasone/Antibiotic

InteractionInteraction

Paris et.al.Paris et.al.S. pneumoniae susceptibility in areaS. pneumoniae susceptibility in areaIf resistant is a probability then use ceftriaxoneIf resistant is a probability then use ceftriaxone

or cefotaxime andor cefotaxime and vancomycinvancomycin withwithdexamethasonedexamethasone

Found vancomycin significant for killingFound vancomycin significant for killingbacteria (4 times MIC )bacteria (4 times MIC )

Treat for minimum of 10 daysTreat for minimum of 10 days



PreventionVaccinesVaccines

a.a. N. meningitidisN. meningitidiscovers serotypes A, C, Y, Wcovers serotypes A, C, Y, W --135135

type B causes 50% of casestype B causes 50% of casescompliment deficiency, aspleniacompliment deficiency, asplenia

b.b. H. influenzaeH. influenzaeall children at 2 monthsall children at 2 months



PreventionPrevention

Vaccine (cont.)Vaccine (cont.)

c.c. S. pneumoniaeS. pneumoniae1) Capsular polysaccharide vaccine1) Capsular polysaccharide vaccineCovers 23 serotypes (88% of cases)Covers 23 serotypes (88% of cases)

patients with chronic disease (e.g. CHF, COPD,patients with chronic disease (e.g. CHF, COPD,diabetes, alcoholism, cirrhosis, > 65diabetes, alcoholism, cirrhosis, > 65 yrsyrs , asplenia,, asplenia,sickle cell disease, lymphoma, chronic renal failure,sickle cell disease, lymphoma, chronic renal failure,

HIV, transplant patients)HIV, transplant patients)2) Heptavalent Conjugate Vaccine2) Heptavalent Conjugate VaccineCovers 7 serotypesCovers 7 serotypes

Standard immunizationStandard immunization



ProphylaxisProphylaxis

A.A. Neisser ia meningitidis Neisser ia meningitidis Close contacts of index caseClose contacts of index caseIndex caseIndex case

RifampinRifampin

B. Haemophilus influenzae type BB. Haemophilus influenzae type B

Close contacts of index caseClose contacts of index caseIf a contact is 4 yo and not immunizedIf a contact is 4 yo and not immunized

C. Streptococcus PneumoniaeC. Streptococcus PneumoniaeNot recommendedNot recommended



Case PresentationCase Presentation

EB was a 8 mo femaleEB was a 8 mo female

– – 2 days PTA pt became “ill” with “cold”2 days PTA pt became “ill” with “cold” Sx’sSx’s – – 1 day PTA pt went into the clinic and was Dx1 day PTA pt went into the clinic and was Dx

with a ROM;with a ROM; Rx’dRx’d with Amoxicillin andwith Amoxicillin andAPAP prnAPAP prn

– – Morning of admission dad was holding herMorning of admission dad was holding herand she started cough. EB started to shakeand she started cough. EB started to shakeand then went into a GTCand then went into a GTC SzSz



Case PresentationCase Presentation

EB was brought into the ER with GTCEB was brought into the ER with GTC SzSz – – SzSz was stopped with multiple doses ofwas stopped with multiple doses ofmidazolam, diazepam, and phenobarbitalmidazolam, diazepam, and phenobarbital

•• Lasted 30 minutesLasted 30 minutes

– – Sx’sSx’s : Cough, anorexia, rhinorrhea, fussy, temp: Cough, anorexia, rhinorrhea, fussy, temp

(102 F)(102 F) – – Labs: CBC, ABG, CSF,Labs: CBC, ABG, CSF, LytesLytes , UA/UC, UA/UC



Clinical Presentation

Physical signs/symptoms:Physical signs/symptoms:FeverFeverHeadacheHeadacheNausea/vomitingNausea/vomitingMental status changesMental status changes

Stiff neck/backStiff neck/backPositive Brudzinski's signPositive Brudzinski's signPositive Kernig's signPositive Kernig's sign

DeafnessDeafnessSeizuresSeizuresFocal neurologic deficitFocal neurologic deficit

HydrocephalusHydrocephalusAnorexiaAnorexia



Case Presentation: LabsCase Presentation: LabsCSFCSF

WBC: 217WBC: 217RBC: 31RBC: 31

Glu: 57Glu: 57Protein: 118Protein: 118Gram stain (+) for GPCGram stain (+) for GPCAG + for S. pneumoAG + for S. pneumoCxCx pendingpending

CBCCBCWBC: 14.5WBC: 14.5HGB: 8.2HGB: 8.2

PLTsPLTs : 244: 244LytesLytes : NL: NL

Glu: 244Glu: 244




Abnormal CSF-findings by type of meningitis

ProteinProtein GlucoseGlucoseTypeType WBC(mm2)WBC(mm2) Diff Diff . (%). (%) (mg/L)(mg/L) (mg/ (mg/ dLdL ))

NMLNML < 10< 10 >50 lymphs>50 lymphs < 50< 50 3030--7070BactBact .. 400400 --100,000100,000 >90>90 PMN'sPMN's 8080--500500 < 35< 35ViralViral 55--500500 >50 lymphs>50 lymphs 3030--150150 NML/lowNML/lowFungalFungal 4040--400400 >50 lymphs>50 lymphs 4040--150150 NML/lowNML/lowT.B.T.B. 100100 --1,000 >50 lymphs1,000 >50 lymphs 4040--400400 NML/lowNML/low







Case StudyCase Study

Vancomycin was stoppedVancomycin was stoppedEB continued to improveEB continued to improve

Never had another seizure to dateNever had another seizure to dateCT did reveal a small bilateral subdural effusionCT did reveal a small bilateral subdural effusionFollow up CT: present but decreasing in sizeFollow up CT: present but decreasing in size

No neurological deficits were noted to dateNo neurological deficits were noted to datePt got a total of 14 days of antibioticsPt got a total of 14 days of antibioticsRepeat LP was WNLRepeat LP was WNL



CNS-macrophage

Decreased Cerebral

CSF lactate

Bacterial Components

Endothelial Cells

I L-1

PGE 2

Increased BBBPermeability

Vasogenic Edema

IncreasedCSF protein

Endothelium-leukocyte TNF and IL-1

PAF

Thrombosis

Blood FlowIncreased

ICP

OxygenDepletion

Decreased

CSF glucose

Increased

CSF pleocytosis

CSF outflow

resistanceInterstitial

Edema

CytotoxicEdema

Meningitis pathophysiology.pdf

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