H i J bb i MD MPH ID & TMHossain Jabbari; MD, MPH, ID & TMInfectious Disease Dept.,

Digestive Diseases Research CenterDigestive Diseases Research Center

CNS i f iCNS infections

M i itiMeningitisE h li iEncephalitis

DefinitionsMeningitis: inflammation of the membranes covering the brain or spinal cord (pia and 

h id )arachnoid mater) Encephalitis: i fl ti f thinflammation of the cerebral cortex (tissue)Meningoencephalitis:Meningoencephalitis: inflammation of the meninges, subarachnoidmeninges, subarachnoid space and cortex

Seminars in Neurology: 2000: 20(3)

Meningitis

EncephalitisEncephalitis

M i h li iMeningoencephalitis

M i i i l ifi iMeningitis classification

Acute meningitis gSub acute meningitisgChronic meningitis

M i i i l ifi iMeningitis classification

Bacterial (Pyogenic) ( y g )Granulomatous Lymphocytic

Epidemiologyp gyIncidence

2.5 to 3.5 cases per 100,000 peoplep , p p0.16 to 0.45 per 1,000 live births

Common Organisms:g1986 : H. influenzae (45%), S. pneumoniae (18%), N. meningitidis (14%)1995 : S. pneumoniae (47%), N. meningitidis (25%), 

L. monocytogenes (8%), H.influenzae (7%)

Seminars in Neurology: 2000 20(3)

Meningitis etiologiesPneumococcal meningitisHaemophilus influenzae meningitisSt h l l i itiStaphylococcal meningitisMeningococcal meningitisMeningococcal meningitisTuberculous meningitis

Meningitis etiologiesFungal gParasitic causes (cryptococcal meningitis, Hi t l meningitis andHistoplasma meningitis, and amebic meningoencephalitis)amebic meningoencephalitis)

Meningitis etiologiesViral meningitisg• Enterovirus : 85% of all viral

causes including:oEchovirusesoEchovirusesoCoxsackieviruses A and BoPoliovirusesoThe numbered enterovirusesoThe numbered enteroviruses

Meningitis etiologiesViral meningitisg• Herpes family (HSV1,

HSV2, EBV, CMV,• Mumps• Mumps• Polio virusPolio virus

Meningitis etiologiesViral meningitisg• Lymphocytic choriomeningitis

viruses (LCMV)• Adenoviruses• Adenoviruses• MeaslesMeasles• HIV

Meningitis etiologiesViral meningitisg• Arborviruses including:(Togavirus family; St. Louis encephalitis’ West

Nile Japanese B and Murray Valley virusesNile, Japanese B, and Murray Valley viruses, from the Flavivirus family; and California group and Jamestown Canyon viruses from theand Jamestown Canyon viruses, from the Bunyaviridae family. Colorado tick fever is caused by a coltivirus)caused by a coltivirus)

Viral Meningitis

Finland study:Finland study: Aseptic meningitis: etiology found in 66% patientspViral encephalitis: etiology only found in 3636%% casesViral prodrome, sore throat, myalgias, ill contacts, GI complaints; summer/fall season

i (2 %)Most common= enteroviruses (25%)EchovirusesC ki iCoxsackievirus

Viral MeningitisViral MeningitisClassified in aseptic meningitisp gMay be difficult to initially separate from partially treated bacterialfrom partially treated bacterial meningitis (obligates empiric treatment for bacterial)for bacterial)Differentiate from true aseptic (drug related such as NSAIDsrelated such as NSAIDs, paraneoplastic)

Meningitis etiologiesNon- infectious causes of meningitis: Drugs, Autoimmune di d i i GBSdisorders, migraine, GBSx,….

Meningitis etiologiesAnd the last but not the least!

TB MeningitisTB Meningitis

روند بروز مننژيت و مقايسه آن با مننژيت مننگوكوكي در طول ا ا13ال 1382ل 1382لغايت1360سالهاي

4.5

33.5

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ت ننژ ز زا ك ك ننگ ز ميزان بروز مننژيتزا ميزان بروز مننگوكوك

درصد كشندگي مننژيت و مننژيت مننگوكوكي در روند ا ال ل ا1ط 1ل 82 1382لغايت1360طول سالهاي

30

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10

15

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(10

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درصد كشندگي كل

Pathophysiology: common routes

H dHematogenous spread commonNasopharynxNasopharynxTraumaInstrumentationInfection foci in neighboring organsInfection foci in neighboring  organs

Meningitis risk factors/Age > 60 y/o

Age ≤ 5y/oDM, renal or adrenal insufficiency, Hypoparathyroidism,CFyp p y ,HIVdorm residents)dorm residents)dorm residents)l dSplenectomy and SCA

VP ShuntMalignancy

Meningitis risk factorsAlcoholism and cirrhosisSinusitis, COM, MastoiditisSinusitis, COM, MastoiditisDural defect (eg, traumatic, surgical, congenital)congenital)Major thalassemiaIDUEndocarditisSome cranial congenital deformities

PathophysiologyPathophysiologyCell wall and membrane products of organism disrupt capillary endothelium of CNS (BBB)disrupt capillary endothelium of CNS (BBB)Margination and transmigration of PMNs across endothelia in CSFo Release of cytokines and chemokines into the

CNSInflammation of subarachnoid spaceNeurologic Sequelae: 10 % of surviving patients

i l h i l i dSensorineural hearing loss, seizures, and hydrocephalus

Clinical ManifestationsClinical ManifestationsFeverFeverHeadacheNeckpain or stiffnessNeckpain or stiffnessInfants:o May exhibit irritability, vomiting, poor feedingy y, g, p go Nuchal rigidity or bulging fontanelle present in

roughly 50% of infants and young childrenOther: o N&V, photophobia, irritability, altered mental

t t diff h t histatus, diffuse rash, petechia, purpura

Physical FindingsPhysical Findings

Kernig’s sign Brudzinski’s sign

Ski hSkin rashes Skin rash pathogenesis:a. Septicemiab Wide spread endothelial damageb. Wide spread endothelial damage c. Activation of coagulationd. Thrombosis and platelets aggregatione. Reduction of platelets (cosumption )f. Bleeding: 1.skin rashes

2.adrenal hemorrhage2.adrenal hemorrhage Arenal hemorrhage is called Waterhouse-Friderichsen Syndrome.It cause acute adrenal insufficiency and is uaually fataly

S ifi iSpecific presentationsHemorrhagic CSF:

TraumaTraumaBleeding diathesisSAHSAHAnthraxHSV encephalitisHSV encephalitisListeria Monocytogen

C li iComplicationsAntibiotic treatment full recoveryDelayed or untreated cases can be fatalDelayed or untreated cases can be fatal (25%)Healing by fibrosis cause obliteration of subarachenoid space HYDROCEPHALUS pBrain abscessSeptic shock and skin rashes, why ?

C li iComplications

VentriculitisEmpyemaCerebritisAbscess formation

Long-term Neurological Complications

Adverse Outcomes at One Year of Age of 12 Infants With Bacterial Meningitisg

Category of Disability Number

Development delay 10

Cerebral palsy 1

Microcephaly 3

Hemiparesis 3

Hearing loss 1

Blindness 2Blindness 2

Seizure disorder 3

Total number of disabilities exceeds the number of infants owing to the presence of multipleTotal number of disabilities exceeds the number of infants owing to the presence of multiple disabilities in most subjects

Klinger G, et al. Pediatrics. 2000;106:477-482

DiagnosisLumbar puncture

Cell count with differentialProteinProteinGlucoseGram stain of CSF

Cultures of CSF blood and urineCultures of CSF, blood and urineADA

So what is a sensible rule for LP?So what is a sensible rule for LP?At a minimum, if you want to avoid missing y gmeningitis (and deaths and handicap from it), and avoid wasting antibiotics, at least LP ) gthose with history of fever and one of:

Bulging fontanelleg gStiff neckFits if age <6 months or > 6 yrsFits if age 6 months or 6 yrsPartial or focal fitsReduced consciousnessReduced consciousness

CSF pressurepNormal opening pressure :p g p

10 to 100 mm H2O (in < 8 y/o )60 200 H2O ( 8 / )60 to 200 mm H2O (> 8 y/o) up to 250 mm H2O (in obese patients)p ( p )

CSF Findings in Infants and ChildrenComponent Normal

ChildrenNormal

NewbornBacterial

MeningitisViral

Meningitis

CSF Findings in Infants and Children

Leukocytes/mcL

0-6 0-30 >1000 100-500

WBCNeutrophils(%)

0 2-3 >50 < 40(%)Glucose (mg/dL)

40-802/3 serum

32-121 <30< ½ serum

< 30 - 70

Protein (mg/dL)

20-30 19-149 >100 50-100

Erythrocytes/mcL

0-2 0-2 0-10 0-2

CSF Findings in meningitis

Value of LP findings – Acute bacterial meningitis

All the true acute bacterial meningitis cases

B d id t l i h l f lBedside assessment alone is very helpful

75% of acute bacterial meningitis cases can be detected by examining for CSF cloudiness orfor CSF cloudiness or turbidity at the bedside.

CSF Cloudiness / TurbidityCSF Cloudiness / Turbidity

A simple test of CSF turbidity is to see if normal print can benormal print can be read easily through the sample – CSF sho ld be cr stalshould be crystal clear.

Cloudiness usuallyCloudiness usually appears at CSF WBC counts > 200 106 WBC L200x106 WBC per L

CSF culture is great but if it is not il bl i ill idavailable a microscope will provide nearly all you need to know

82% of acute bacterial meningitis cases can be detected by either turbidity y yor a CSF white cell count and using a cut-off of >50 WBC per μL (>50 x 106WBC per μL. (>50 x 106

WBC per L)

CSF microscopy, blood and CSF glucose measures are highly sensitive

96% of acute bacterial meningitis cases can bemeningitis cases can be detected by turbidity, a CSF white cell count of >50 Wbc per μL (>50 x 106 Wbc per L) or a CSF glucose to Blood glucose ratio <0.1*glucose ratio 0.1

* Books suggest a ratio of ~0.6, this is much too high to be useful

CSF discoloration

Empiric TreatmentEmpiric Treatment

T LP i i i i i fTry to get LP prior to initiation of antibiotics but begin intravenous gempiric therapy if LP cannot be performed within 30 minutesperformed within 30 minutes from presentation !!

Treatment ConsiderationsTreatment Considerations

AllergiesEmpiric Therapy: Age specificp py g pCSF PenetrationCultures/SensitivitiesCultures/SensitivitiesPathogen Specific TherapyDuration of Therapy

Age-Specific EtiologyTABLE 1 -- RECOMMENDED EMPIRIC ANTIMICROBIAL THERAPY FOR BACTERIAL MENINGITIS BASED ON AGE

Age Major Pathogens Antibiotic Regimen Alternative Regimens Comment

Neonate < 1 month Group B Streptococcus, Listeria monocytogenes,

Ampicillin plus Cefotaxime

Ampicillin plus Gentamicin

E. coli

1 - 3 months Streptococcus pneumoniae Neisseria meningitides Haemophilus influenzae

Ampicillin plus Ceftriaxone (or Cefotaxime)

Chloramphenicol plus Gentamicin

Cerebrospinal fluid levels not reliable in low-birth-weight infants and should be monitored

h d f dd h3 months to 18 years Neisseria meningitidis, Streptococcus pneumoniae DRSP included here Haemophilus influenzae

Ceftriaxone(or Cefotaxime)

Meropenem orChloramphenicol

Add Vancomycin in areas with greater than 2% incidence of highly drug resistant Streptococcus pneumoniae

18 to 50 years Streptococcus pneumoniae, Ceftriaxone Meropenem or Add Vancomycin in areas with18 to 50 years Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae

Ceftriaxone (or Cefotaxime)

Meropenem orChloramphenicol

Add Vancomycin in areas with greater than 2% incidence of highly drug resistant Streptococcus pneumoniae

50 years and older Streptococcus pneumoniae, Li t i t

Ampicillin plus C ft i

Ampicillin plus Fl i l

Add Vancomycin in areas with t th 2% i id fListeria monocytogenes,

gram-negative bacilli Ceftriaxone (or Cefotaxime)

Fluoroquinolone (Ciprofloxacin, Levofloxacin)

greater than 2% incidence of highly drug resistant Streptococcus pneumoniae; for patients who have major penicillin allergy, TMP-SMX can substitute f i illi i ifor ampicillin to treat Listeria monocytogenes

IDSA Antimicrobial RecommendationsIDSA G id liIDSA Guidelines

Microorganism Standard therapy Alternative therapies

S. pneumoniaePenicillin MIC<0.1 mcg/mL penicillin G or ampicillin cefotaxime0.1 mcg/mL0.1-1 mcg/mL≥ 2 mcg/mL

penicillin G or ampicillincefotaximevancomycin plus cefotaxime

cefotaximecefepime, meropenemfluoroquinolone

N. meningitidisPenicillin MIC <0.1 mcg/mL0.1-1 mcg/mL

penicillin G or ampicillincefotaxime

cefotaximemeropenem, fluoroquinolone

IDSA Antimicrobial RecommendationsIDSA Guidelines

Microorganism Standard therapy Alternative therapies

S. agalactiae(Group B Strept)

ampicillin or penicillin G cefotaxime( p p )

E. coli 3rd generation cephalosporin guided by in vitro

aztreonam, meropenem, ampicillinguided by in vitro

susceptibility resultsampicillin

Listeria t

ampicillin or penicillin G meropenemmonocytogenes

Intravenous Antibiotic Therapy R d d I t D f A ti i bi l U d t T t B t i l M i itiRecommended Intravenous Doses of Antimicrobials Used to Treat Bacterial Meningitis

Antimicrobial Dose in Children Dose in Adult

Ampicillin 75 mg/kg Q6 Hr 2 g Q4 Hr

Cefotaxime 50-75 mg/kg Q6 Hr 2 g Q6 Hr

Ceftriaxone 50-75 mg/kg Q12 Hr 2 g q12 hCaftazidime 75 mg/kg Q12 Hr 2 g Q8 Hr

Chloramphenicol 25 mg/kg Q6 Hr 1 g Q6 Hr

Gentamicin 2.5 mg/kg Q8 Hr 2 mg/kg Q8 HrGentamicin 2.5 mg/kg Q8 Hr 2 mg/kg Q8 Hr

Meropenem 40 mg/kg Q8 Hr 2 g Q8 Hr

Penicillin G 50,000 U/kg Q4 Hr 4 million unit Q4 Hr

Rifampin 10 mg/kg Q24 hr (Max 600 mg)

600 mg Q24 Hr

Trimethoprim/Sulfamethoxaz 10 mg/kg Q12 Hr 10 mg/kg Q12 Hrole

Vancomycin 20 mg/kg Q8 Hr 1 g Q12 Hr

Optimization of Antibiotic TherapyOptimization of Antibiotic Therapy

Once culture information is available and organism has been identified, review gantibiotic choices to ensure appropriate treatmentDetermine duration of therapy based on organism identifiedorganism identified

Pathogen-Specific Therapy Organism Duration

Group B Streptococcus 14-21 daysG oup St eptococcus d ys

H. Influenzae 7-10 days

Listeria monocytogenes 14-21 days

Neisseria meningitis 7-10 days

Streptococcus pneumoniae 10-14 daysStreptococcus pneumoniae 10 14 days

Other gram negative bacilli 21 daysOther gram negative bacilli 21 days

Adjunctive TreatmentDexamethasone: Controversial

Rationale: inflammatory cytokines have role inRationale: inflammatory cytokines have role in pathophysiology of bacterial meningitisDebate: adjunctive therapy could reduce penetration of antibiotics into the CNSpenetration of antibiotics into the CNSClinical trials show benefit: reduced audiologic and neurologic complications

B fi l i i i f d i h H i flBenefit seen only in patients infected with H. influenzaBenefit seen in patients infected with S.pneumo but not statistically significant

AAP recommends initiation 30 minutes prior to 1stAAP recommends initiation 30 minutes prior to 1dose of antibioticsDose: 0.15 mg/kg/dose IV q6h x 4 days

NEJM 1991: 324(22).

PrognosisPrognosis

Death~30% fatality unless meningococci are a prevalent cause then mortality is a little lower.

PrognosisPrognosis (Cont’d)

Death ~ 30%Severe Handicap ~ 25 30%Severe Handicap ~ 25-30%

HemiplegiaBlindnessBlindnessDeafnessSevere Learning DifficultySevere Learning DifficultySevere behavioural disturbancesSevere Epilepsy.Severe Epilepsy.

PreventionN. meningitidis

P h l i f l t tProphylaxis of close contacts• Rifampin

• < 1 month old: 10 mg/kg q12h x4 doses • > 1 month old: 20 mg/kg q12h x 4 doses• > 1 month old: 20 mg/kg q12h x 4 doses • Adults: 600 mg q12h x 4 doses

• Ceftriaxone 150 mg IM x 1 dose• Ciprofloxacin 500 mg x 1 dose p g

Immunizations Pneumococcal Vaccine for children < 2 yrsM i l V i f ll 11 12 ldMeningococcal Vaccine for all 11-12 year olds, unvaccinated adolsecents at high school entry, all college freshmen living in dormitores, and ≥ 2 years at high riskg

Take Home MessageMeningitis is suspected clinically but confirmed by LPChildren will die and suffer disability because clinicians do not do an LP –bl i th l b iblaming the lab is no excuse.If clinicians and lab staff work together

t b t i l i iti b t lacute bacterial meningitis can be accurately diagnosed.

ENCEPHALITISENCEPHALITIS

Encephalitis LethargicaEncephalitis Lethargica

The Awakenings…1916: von Economo described CNS disorder with lethargy and Parkinsonian features following viral syndrome with pharyngitis1916-1927 epidemic; now sporadic cases1918: influenza pandemic, ?connection (?immune mediated process)( p )

EncephalitisEncephalitisMore likely to be viralEtiology only found in 35% cases

HSV-1: 10% cases (but accounts for overHSV 1: 10% cases (but accounts for over 50% cases in patients over 50)HSV 2HSV-2VZV (?up to 10% in some series)Tick or insect borne diseases: 10%

EncephalitispAcute Viral Encephalitis

Direct viral infection of neuronal cellsPerivascular inflammationDestruction of gray matter

Post-Infectious EncephalomyelitisFollows viral or bacterial infectionDemyelination of white matter?autoimmune component triggered by p gg yinfectious agent

HERPETICHERPETICHERPETIC HERPETIC ENCEPHALITISENCEPHALITISENCEPHALITISENCEPHALITIS

EPIDEMIOLOGYEPIDEMIOLOGYIncidence: Incidence: 11/ / 250250,,000 000 to to 500500,,000000/ year/ yearMorbidity:Morbidity: Untreated patientsUntreated patients 7070%%Morbidity:Morbidity: Untreated patients, Untreated patients, 7070%%

Treated patients, Treated patients, 1919%%M bidiM bidi 5050% f i l f% f i l fMorbidity: Morbidity: > > 5050% of survivors are left % of survivors are left

with moderate or severewith moderate or severeneurologic deficitsneurologic deficits

Sex:Sex: In male & female is equalIn male & female is equalSex: Sex: In male & female is equalIn male & female is equal

Age:Age: Peaks in childhood & middlePeaks in childhood & middle--agedaged

HSEHSEAcute or Acute or SubacuteSubacute IllnessIllnessGeneral & Focal Cerebral DysfunctionGeneral & Focal Cerebral Dysfunction

Sporadic Sporadic WWithout Seasonal Patternithout Seasonal Pattern

PATHOGENESISPATHOGENESISChildren & young adult:Children & young adult:

Primary HSV infection BrainPrimary HSV infection BrainOlfactoryOlfactoryPrimary HSV infection BrainPrimary HSV infection Brainbulbbulb

Adult:Adult:Prior HSVPrior HSV--11 infection (infection ( AbAb ++veve ))Prior HSVPrior HSV 1 1 infection ( infection ( AbAb ++veve ))Reactivation in Trigeminal or Reactivation in Trigeminal or

A iA iAutonomic rootsAutonomic roots

BrainBrain

PATHOLOGYPATHOLOGYEdemaEdema && CongestionCongestion && HemorrhageHemorrhage &&NecrosisNecrosis

Intense Hemorrhagic necrosis Intense Hemorrhagic necrosis InInInIn

Temporal & Frontal lobeTemporal & Frontal lobeppHallmark of HSE:Hallmark of HSE:ff

Bilateral AsymmetricalBilateral AsymmetricalA i T l l b i fl iA i T l l b i fl iAnterior Temporal lobe inflammationAnterior Temporal lobe inflammation

CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONSNO PATHOGNOMONIC CLINICAL FINDINGNO PATHOGNOMONIC CLINICAL FINDINGNO PATHOGNOMONIC CLINICAL FINDINGNO PATHOGNOMONIC CLINICAL FINDING

Typical symptoms:Typical symptoms:••Fever Fever 9090%%••HeadacheHeadache 8181%%••Headache Headache 8181%%••Psychiatrics symptoms Psychiatrics symptoms 7171%%••Seizures Seizures 6767%%••Vomiting Vomiting 4646%%gg••Focal weakness Focal weakness 3333%%••Memory lossMemory loss 2424%%••Memory loss Memory loss 2424%%••Altered mental status & photophobiaAltered mental status & photophobia

CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONSNO PATHOGNOMONIC CLINICAL FINDINGNO PATHOGNOMONIC CLINICAL FINDINGNO PATHOGNOMONIC CLINICAL FINDINGNO PATHOGNOMONIC CLINICAL FINDING

Typical finding on P/E:Typical finding on P/E:••Alteration of consciousness Alteration of consciousness 9797%%••FeverFever 9292%%Fever Fever 9292%%••Dysphasia Dysphasia 7676%%S iS i 3838% ( l% ( l 2828% G l% G l 1010%)%)••Seizures Seizures 3838% (Focal % (Focal 2828%, General %, General 1010%)%)

••HemiparesisHemiparesis 3838%%pp••Cranial nerve defect Cranial nerve defect 3232%%••Visual field lossVisual field loss 1414%%••Visual field loss Visual field loss 1414%%••PapilledemaPapilledema 1414%%

DIFFERENTIAL DIAGNOSISDIFFERENTIAL DIAGNOSISBrain abscessBrain abscess

Epidural & Subdural abscessEpidural & Subdural abscess

NeoplasmsNeoplasms, Brain, Brainpp ,,

Pediatric febrile seizuresPediatric febrile seizuresPediatric febrile seizuresPediatric febrile seizures

Stroke & Hemorrhagic or IschemicStroke & Hemorrhagic or Ischemic

WORKWORK--UPUPLab Studies:Lab Studies:

CSCSCSFCSF Mononuclear Mononuclear pleocytosispleocytosisElevated proteinElevated proteinElevated proteinElevated proteinNlNl or reduce glucoseor reduce glucoseInitial may beInitial may be NlNlInitial may be Initial may be NlNlHemorrhagic Hemorrhagic naturenature ElevatedElevated RBCRBCHSV i l lt dHSV i l lt dHSV is rarely culturedHSV is rarely cultured

CSF/CSF/PCRPCR SensitiveSensitive && SpecificSpecificCSF/CSF/PCRPCR SensitiveSensitive & & SpecificSpecific

WORKWORK--UPUPImaging Studies:Imaging Studies:

MRI MRI ( Preferred mainly imaging )( Preferred mainly imaging )Bilateral Temporal & Inferior Frontal ChangesBilateral Temporal & Inferior Frontal ChangesBilateral Temporal & Inferior Frontal ChangesBilateral Temporal & Inferior Frontal Changes

CTCT--ScanScan ( much less sensitive than MRI ) ( much less sensitive than MRI )

Other tests:Other tests:EEGEEG Focal abnormalitiesFocal abnormalitiesEEGEEG Focal abnormalitiesFocal abnormalities

SlowSlow--wave or periodic sharpwave or periodic sharp--wavewaveO l l bO l l bOver temporal lobeOver temporal lobeSensitive Not SpecificSensitive Not Specific

HERPETIC ENCEPHALITISHERPETIC ENCEPHALITIS

TREATMENTTREATMENTGoals of therapy:Goals of therapy:Goals of therapy:Goals of therapy:1.1.Shorten the clinical courseShorten the clinical course

22 T t li tiT t li ti2.2.To prevent complicationsTo prevent complications

33.To prevent subsequent recurrence.To prevent subsequent recurrence

TREATMENTTREATMENT

• Supportive therapy:– Monitoring of ICPg– Fluid restriction– Treatment of seizureTreatment of seizure

• Acyclovir 10mg/kg q8h for 14 daysfor 14 days

RABIESRABIESRABIESRABIES

RABIESRABIES

Acute viral disease of CNSAcute viral disease of CNS

All mammals

RNA virus Lassavirus RhabdovirusRNA virus Lassavirus Rhabdovirus

EPIDEMIOLOGYEPIDEMIOLOGYO OO OWorldwide distributionWorldwide distribution(( Australia,AntarciticaAustralia,Antarcitica))Worldwide distributionWorldwide distribution( ( Australia,AntarciticaAustralia,Antarcitica))

Urban rabies: Urban rabies: dogs,catsdogs,catsS l tiS l ti bi f l b tbi f l b tSylvaticSylvatic rabies: foxes, wolves, batsrabies: foxes, wolves, bats,…,…Transmission: BiteTransmission: Bite

AerosolAerosolIngestionIngestionIngestion Ingestion

TransplantationTransplantationEPIDEMIOLOGY IN IRANEPIDEMIOLOGY IN IRAN

RaccoonRaccoon

fffoxfox

BatsBats

PATHOGENESISPATHOGENESISOOLive virusLive virus Epidermis, Mucus membraneEpidermis, Mucus membrane

Peripheral nervePeripheral nervepp

centripettally

CNS ( CNS ( gray mattergray matter ))

centrifugally

Other tissue (salivary glands,…)Other tissue (salivary glands,…)

CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS

1 – Non specific Non specific prodromeprodrome

22 Acute neurologic encephalitisAcute neurologic encephalitis2 2 –– Acute neurologic encephalitisAcute neurologic encephalitisAcute encephalitisAcute encephalitisProfound dysfunction of brainstemProfound dysfunction of brainstem

3 3 –– ComaComa

4 4 -- Death ( Rare cases Death ( Rare cases recovery )recovery )

CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS

1 – Non specific Non specific prodromeprodrome11 22 dd 11 kk1 1 -- 2 2 days days 1 1 weekweek

Fever, headache, sore throatFever, headache, sore throatAnorexia, nausea, vomiting, Anorexia, nausea, vomiting, Agitation, depressionAgitation, depressiong , pg , pParesthesiaParesthesia or or fasciculationsfasciculations at orat orAround the site of inoculation of virusAround the site of inoculation of virusAround the site of inoculation of virusAround the site of inoculation of virus. .

CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS2 2 –– Acute Neurologic Encephalitis Acute Neurologic Encephalitis

11 –– 22 days to <days to < 11 weekweek1 1 –– 2 2 days to < days to < 1 1 weekweekExcessive motor activity, Excitation, AgitationExcessive motor activity, Excitation, AgitationC f i H ll i ti D li iC f i H ll i ti D li iConfusion, Hallucinations, Delirium, Confusion, Hallucinations, Delirium, Bizarre aberrations of thought, Seizures,Bizarre aberrations of thought, Seizures,Muscle spasms, Muscle spasms, MeningismusMeningismus, , OpisthotonicOpisthotonic posturing posturing pp p gp gMental aberration ( Lucid period Mental aberration ( Lucid period coma )coma )HypersalivationHypersalivation, Aphasia, Pharyngeal spasms, Aphasia, Pharyngeal spasmsHypersalivationHypersalivation, Aphasia, Pharyngeal spasms, Aphasia, Pharyngeal spasmsIncordinationIncordination, Hyperactivity, , Hyperactivity,

CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONS2 2 –– Acute Neurologic Encephalitis PhaseAcute Neurologic Encephalitis Phase

Fever T >Fever T > 4040..66Fever T Fever T 4040..6 6 Dilated irregular pupils Dilated irregular pupils

LacrimationLacrimation Salivation & PerspirationSalivation & PerspirationLacrimationLacrimation, Salivation & Perspiration, Salivation & PerspirationUpper motor neuron paralysisUpper motor neuron paralysis

DD d fld flDDeep tendon reflexeseep tendon reflexesExtensor plantar responses ( as a rule )Extensor plantar responses ( as a rule )H d h bi A h bi (H d h bi A h bi (5050 7070% )% )Hydrophobia or Aerophobia (Hydrophobia or Aerophobia (50 50 --7070% )% )

DIAGNOSISDIAGNOSISIsolation of virus (Isolation of virus (Saliva,CSFSaliva,CSF, brain ), brain )

SerologySerologySerologySerology

Viral Ag detection ( infected tissue )Viral Ag detection ( infected tissue )

Viral RNA detection ( PCR )Viral RNA detection ( PCR )

DIAGNOSISDIAGNOSISLaboratory finding: ( CBC, CSF )Laboratory finding: ( CBC, CSF )Exclusion of other etiologiesExclusion of other etiologiesExclusion of other etiologiesExclusion of other etiologies

P h lP h lPathology:Pathology:Formation ofFormation of cytoplasmiccytoplasmic inclusions:inclusions:Formation of Formation of cytoplasmiccytoplasmic inclusions: inclusions:

( ( NegriNegri bodies bodies ))(( Ammon’sAmmon’s horn Cerebral cortexhorn Cerebral cortex( ( Ammon sAmmon s horn, Cerebral cortex,horn, Cerebral cortex,Brainstem, Hypothalamus, Brainstem, Hypothalamus, Th P ki j ll f b llTh P ki j ll f b llThe Purkinje cells of cerebellum, The Purkinje cells of cerebellum, Dorsal spinal ganglia )Dorsal spinal ganglia )

NegriNegriNegriNegribodiesbodies

DIFFERENTIAL DIAGNOSISOther viral encephalitisOther viral encephalitis

Hysteria reaction to animal bite

Guillan-barre syndrome(GBSx)y

PoliomyelitisPoliomyelitis

Allergic encephalomyelitis ( rabies vaccine )

PREVENTIONPREVENTIONPREVENTIONPREVENTIONPrePre--exposure Prophylaxisexposure Prophylaxis

PostPost--exposure Prophylaxisexposure Prophylaxis

HUMAN RABIES BIOLOGICS PRODUCTHUMAN RABIES BIOLOGICS PRODUCT

Rabies immune globulin (HRIG)Rabies immune globulin (HRIG)Rabies immune globulin (HRIG)Rabies immune globulin (HRIG)

HUMAN RABIES BIOLOGICS PRODUCTHUMAN RABIES BIOLOGICS PRODUCT

Vaccine:Vaccine:H di l id ll i (H di l id ll i (HDCVHDCV))Human diploid cell vaccine (Human diploid cell vaccine (HDCVHDCV))Purified chick embryo cell vaccine (Purified chick embryo cell vaccine (PCECPCEC))

ifi d ll i (ifi d ll i ( ))Purified Vero cell vaccine (Purified Vero cell vaccine (PVRVPVRV))Purified duck embryo vaccine (Purified duck embryo vaccine (PDEPDEV)V)

PREPRE--EXPOSURE PROPHYLAXISEXPOSURE PROPHYLAXISPREPRE EXPOSURE PROPHYLAXISEXPOSURE PROPHYLAXIS

Veterinarian Cave explorersVeterinarian Cave explorersVeterinarian, Cave explorers, Veterinarian, Cave explorers, Lab workers, Animal handlersLab workers, Animal handlers

A ti i i ti (V i )A ti i i ti (V i )Active immunization (Vaccine) Active immunization (Vaccine) On days: On days: 00, , 77, , 21 21 ((2828))yy (( ))

Booster doses (NeutralizingBooster doses (Neutralizing AbAb :Low):Low)Booster doses (Neutralizing Booster doses (Neutralizing AbAb :Low):Low)

POSTPOST--EXPOSURE PROPHYLAXISEXPOSURE PROPHYLAXISPOSTPOST EXPOSURE PROPHYLAXISEXPOSURE PROPHYLAXIS

1 W d l i & t t tW d l i & t t t1 – Wound cleaning & treatmentWound cleaning & treatment( Tetanus & Antibiotics )( Tetanus & Antibiotics )( Tetanus & Antibiotics )( Tetanus & Antibiotics )

2 2 –– Passive immunizationPassive immunization

33 Active immunizationActive immunization3 3 –– Active immunizationActive immunization

POSTEXPOSURE PROPHYLAXISPOSTEXPOSURE PROPHYLAXIS

1 – Wound cleaning & treatmentWound cleaning & treatmentgg

POSTPOST--EXPOSURE PROPHYLAXISEXPOSURE PROPHYLAXISPOSTPOST EXPOSURE PROPHYLAXISEXPOSURE PROPHYLAXIS

2 2 –– Passive immunizationPassive immunizationzzHRIGHRIG : : 2020IU/Kg IM on day IU/Kg IM on day 00

POSTEXPOSURE PROPHYLAXISPOSTEXPOSURE PROPHYLAXISPOSTEXPOSURE PROPHYLAXISPOSTEXPOSURE PROPHYLAXIS3 3 –– Active immunizationActive immunization

PREVENTION IN ANIMALSPREVENTION IN ANIMALS

Thanks for your kind attention!Thanks for your kind attention!