Fast review of CNS Fast review of CNS InfectionsInfections

Husain AlawadhiHusain Alawadhi

Consultant intensivist, pulmonologist and Consultant intensivist, pulmonologist and Infectious disease.Infectious disease.

Guideline in Progress :summer 2008Guideline in Progress :summer 2008

"The Management of Encephalitis:  Clinical "The Management of Encephalitis:  Clinical Practice Guidelines by the Infectious Practice Guidelines by the Infectious Diseases Society of America“Diseases Society of America“

Coming soonComing soon

ACUTE CNS INFECTIONSACUTE CNS INFECTIONS

1.1. Bacterial meningitisBacterial meningitis

2.2. MeningoencephalitisMeningoencephalitis

3.3. Brain abscessBrain abscess

4.4. Subdural empyemaSubdural empyema

5.5. Epidural abscessEpidural abscess

6.6. Septic venous sinusSeptic venous sinus

thrombophlebitisthrombophlebitis

EtiologyEtiology PathogenesisPathogenesis MicrobiologyMicrobiology DiagnosisDiagnosis TreatmentTreatment Complication Complication Prevention Prevention

ETILOGYETILOGY

Mucrobiology by age Mucrobiology by age

Figure 24-8

Bacterial MeningitisBacterial MeningitisImportant Changes in EpidemiologyImportant Changes in Epidemiology

Marked decline in the occurrence of HibMarked decline in the occurrence of Hib ↑’↑’ing incidence of S. pneumo (50+% of cases ing incidence of S. pneumo (50+% of cases

in US)in US) Shift from peds disease to adult diseaseShift from peds disease to adult disease ↑’↑’ing incidence of ATB-resistant organisms, ing incidence of ATB-resistant organisms,

esp. S. pneumoesp. S. pneumo PCN resistance ~ 35% (15-20% high level)PCN resistance ~ 35% (15-20% high level) Ceph resistance 15-20% (5-10% high level)Ceph resistance 15-20% (5-10% high level)

Risk Factors for Drug-Resistant Risk Factors for Drug-Resistant S. pneumoniae (DRSP)S. pneumoniae (DRSP)

Extremes of ageExtremes of age Recent ATB RxRecent ATB Rx Significant comorbid diseaseSignificant comorbid disease HIV infection or other immunodeficiencyHIV infection or other immunodeficiency Day care or day care parent/sibDay care or day care parent/sib Recent hospitalizationRecent hospitalization Congregate settings (Institutions, military)Congregate settings (Institutions, military)

VIRAL MENINGITIS/ENCEPHALITISVIRAL MENINGITIS/ENCEPHALITIS

EnterovirusesEnteroviruses

PoliovirusesPolioviruses

CoxsackievirusesCoxsackieviruses

EchovirusesEchoviruses

TogavirusesTogaviruses Eastern equineEastern equine

Western equineWestern equine

Venezuelan equineVenezuelan equine

St. LouisSt. Louis

PowassonPowasson

CaliforniaCalifornia

West NileWest Nile

HerpesvirusesHerpesviruses

Herpes simplexHerpes simplex

Varicella-zosterVaricella-zoster

Epstein BarrEpstein Barr

CytomegalovirusCytomegalovirus

Myxo/paramyxovirusesMyxo/paramyxoviruses Influenza/parainfluenzaeInfluenza/parainfluenzae

MumpsMumps

MeaslesMeasles

MiscellaneousMiscellaneous AdenovirusesAdenoviruses

LCMLCM

RabiesRabies

HIV HIV

Rare parsitic meningitisRare parsitic meningitis

The most important are in the genera The most important are in the genera NaegleriaNaegleria and and Acanthamoeba. Naegleria Acanthamoeba. Naegleria fowleri,fowleri, the main protozoan causing primary the main protozoan causing primary amebic meningoencephalitis in humans, has amebic meningoencephalitis in humans, has been recovered from lakes, puddles, pools, been recovered from lakes, puddles, pools, ponds, rivers, sewage waters. ponds, rivers, sewage waters.

DIAGNOSISDIAGNOSIS

CSF: Some CatchesCSF: Some Catches Protein least specificProtein least specific TB: early neutrophilic TB: early neutrophilic

predominancepredominance Encephalitis, RMSF, tick-borne Encephalitis, RMSF, tick-borne

illnesses: inc CSF WBCillnesses: inc CSF WBC Listeria: misread as Listeria: misread as

“contamination”/diphtheroids“contamination”/diphtheroids Listeria: bacterial meningitis that Listeria: bacterial meningitis that

can have significant encephalitis and can have significant encephalitis and abscess, and CSF with lymphocytes!abscess, and CSF with lymphocytes!

RBCs that do not clear: SAH or RBCs that do not clear: SAH or HSVHSV

CSF: More PearlsCSF: More Pearls Correction factors for traumatic tapCorrection factors for traumatic tap

““trauma” and RBCs increase trauma” and RBCs increase protein and with an increase in protein and with an increase in RBCs come an increase in WBCsRBCs come an increase in WBCs

True CSF protein = subtract 1 True CSF protein = subtract 1 mg/dL protein for every 1000 mg/dL protein for every 1000 RBC/mm3RBC/mm3

True WBC in CSF: actual WBC in True WBC in CSF: actual WBC in CSF – (WBC in blood x RBC in CSF – (WBC in blood x RBC in CSF)/ RBC in bloodCSF)/ RBC in blood

Contraindications to LPContraindications to LPAbsolute:Absolute: Skin infection over siteSkin infection over site

Papilledema, focal neuro signs, ↓MSPapilledema, focal neuro signs, ↓MS

Relative:Relative: Increased ICP without papilledemaIncreased ICP without papilledema

Suspicion of mass lesionSuspicion of mass lesion

Spinal cord tumorSpinal cord tumor

Spinal epidural abscessSpinal epidural abscess

Bleeding diathesis or ↓ pltsBleeding diathesis or ↓ plts

CSF pressureCSF pressure

Normal openingNormal opening pressure pressure in adults is 90~180mmHin adults is 90~180mmH22O, O,

10~100mmH10~100mmH22O in children.O in children.

Elevated in :Elevated in : Congestive heart failureCongestive heart failure MeningitisMeningitis Superior vena cava syndromeSuperior vena cava syndrome Cerebral edemaCerebral edema Mass lesionMass lesion

Decreased InDecreased In Spinal-subarachnoid blockSpinal-subarachnoid block DehydrationDehydration Circulatory collapseCirculatory collapse CSF leakageCSF leakage

Diagnostic Accuracy of Signs of Meningeal Diagnostic Accuracy of Signs of Meningeal Irritation in Pts with Suspected MeningitisIrritation in Pts with Suspected Meningitis

SignSign SensSens SpecSpec PPVPPV NPVNPV +LR+LR -LR-LR

Nuchal 30% 68% 26% 73% 0.94 1.02 Nuchal 30% 68% 26% 73% 0.94 1.02

rigidityrigidity

Kernig’s 5% 95% 27% 72% 0.97 1.0Kernig’s 5% 95% 27% 72% 0.97 1.0

Brudzin- 5% 95% 27% 72% 0.97 1.0Brudzin- 5% 95% 27% 72% 0.97 1.0

ski’s ski’s

Thomas KE et al, CID 2002, 35:46-52Thomas KE et al, CID 2002, 35:46-52

CSF FindingsCSF FindingsNormalNormal BacterialBacterial ViralViral FungalFungal TBTB otherother

WBCWBC

(TNC)(TNC)

0-50-5 100-100-10,00010,000

5-30005-3000 5-5005-500 5-5005-500 paraneoparaneo

Cell typeCell type >50% >50% PMNPMN

>50% >50% lymphslymphs

>50% >50% lymphslymphs

>50% >50% lymphslymphs

MonoclonMonoclonal, atypiaal, atypia

ProteinProtein 50-80 50-80 mg/dLmg/dL

>200>200 Nl/slight Nl/slight increaseincrease

Nl/slight Nl/slight increaseincrease

IncreaseIncrease increasedincreased

GlucoseGlucose 70-80 70-80 mg/dLmg/dL

>60% >60% serum serum

<40, <40, <60% of <60% of serum serum glucoseglucose

NormalNormal normalnormal <40 or nl<40 or nl decreasedecrease

Gm stainGm stain 60% +60% + NegNeg 50% india 50% india ink + ink + cryptocrypto

AFB + 25-AFB + 25-35%35%

PressurePressure 75-200 75-200 mm Hgmm Hg

IncInc NlNl IncInc Nl/incNl/inc

CSF SMEARS & STAINSCSF SMEARS & STAINS

GmS + in 60-90% of pts with GmS + in 60-90% of pts with untreated bacterial meningitisuntreated bacterial meningitis

With prior ATB Rx, positivity of GmS With prior ATB Rx, positivity of GmS decreases to 40-60%decreases to 40-60%

REMEMBER: + GmS = Heavy REMEMBER: + GmS = Heavy organism burden & worse prognosisorganism burden & worse prognosis

CCT Before LP in Patients with CCT Before LP in Patients with Suspected MeningitisSuspected Meningitis

301 pts with suspected meningitis; 235 301 pts with suspected meningitis; 235 (78%) had CCT prior to LP(78%) had CCT prior to LP

CCT abnormal in 56/235 (24%); 11 pts CCT abnormal in 56/235 (24%); 11 pts (5%) had evidence of mass effect(5%) had evidence of mass effect

Features associated with abnl CCT were age Features associated with abnl CCT were age >60, immunocompromise, H/O CNS dz, >60, immunocompromise, H/O CNS dz, H/O seizure w/in 7d, & selected neuro abnlsH/O seizure w/in 7d, & selected neuro abnls

Hasbun, NEJM 2001;345:1727Hasbun, NEJM 2001;345:1727

Guidelines : Do CT before LP in the Guidelines : Do CT before LP in the following cases following cases

Any immunocompromised patient.Any immunocompromised patient. New ConvulsionNew Convulsion PapillodemaPapillodema Any previous CNS pathologyAny previous CNS pathology Abnormal Lovel of consciousnessAbnormal Lovel of consciousness Focal neurological deficitsFocal neurological deficits Age > 65 Age > 65

BACTERIAL VS VIRAL MENINGITISBACTERIAL VS VIRAL MENINGITISPredictors of bacterial etiology:Predictors of bacterial etiology: CSF glucose < 40CSF glucose < 40 CSF protein > 60CSF protein > 60 CSF neutrophil count > 80%CSF neutrophil count > 80% CSF WBC count > 100CSF WBC count > 100 CSF: Serum glucose ratio < 0.23CSF: Serum glucose ratio < 0.23[Presence of any [Presence of any ONEONE of the above findings of the above findingspredicts bacterial etiology with > 75% certainty]predicts bacterial etiology with > 75% certainty]

BACTERIAL VS VIRAL MENINGITISBACTERIAL VS VIRAL MENINGITIS

Predictors of bacterial etiology:Predictors of bacterial etiology: CSF glucose < 34CSF glucose < 34 CSF: Serum glucose ratio < 0.23CSF: Serum glucose ratio < 0.23 CSF protein > 220CSF protein > 220 CSF WBC count > 2000CSF WBC count > 2000 CSF neutrophil count > 1180CSF neutrophil count > 1180

[Presence of any [Presence of any ONEONE of the above findings of the above findings

predicts bacterial etiology with > 99% certainty]predicts bacterial etiology with > 99% certainty]

Strep Pneumoniae MeningitisStrep Pneumoniae Meningitis

Now most common cause (H flu rare)Now most common cause (H flu rare) 30-50% cases of bacterial meningitis in elderly30-50% cases of bacterial meningitis in elderly Otitis 30%, sinusitis 8%, pneumonia 18%Otitis 30%, sinusitis 8%, pneumonia 18% Elderly more often have pneumonia (bad)Elderly more often have pneumonia (bad) Bad markers: older age, low platelets, dec CSF glucose, no Bad markers: older age, low platelets, dec CSF glucose, no

otogenic focusotogenic focus Vaccination: recommended in all over age 65Vaccination: recommended in all over age 65

Efficacy in elderly/immunocompromised NOT clearEfficacy in elderly/immunocompromised NOT clear Decrease bacteremia/meningitisDecrease bacteremia/meningitis

ListeriaListeria Food-borne outbreaksFood-borne outbreaks Herd animalsHerd animals Common, likely cause of mild GI illnesses Common, likely cause of mild GI illnesses Invasive disease with bacteremia Invasive disease with bacteremia Increased risk with depressed cellular immunity: pregnant women, elderly, Increased risk with depressed cellular immunity: pregnant women, elderly,

AIDS, lymphoma, steroid use, transplant patients Small, anaerobic gm + AIDS, lymphoma, steroid use, transplant patients Small, anaerobic gm + baccillusbaccillus

Look like diphtheroids, contaminants Diphtheroids in CSF: listeria unless Look like diphtheroids, contaminants Diphtheroids in CSF: listeria unless proven otherwiseproven otherwise

Cerebritis, brain abscessCerebritis, brain abscess Confusion, altered LOC, seizure, movementConfusion, altered LOC, seizure, movement Mortality 22% in older patients with CNS dzMortality 22% in older patients with CNS dz 20% of all cases of bacterial meningitis in patients over age 6020% of all cases of bacterial meningitis in patients over age 60 Brain abscess: 10% CNS infectionsBrain abscess: 10% CNS infections

Concomitant meningitis in 25-40% (rare with other causes of brain abscessConcomitant meningitis in 25-40% (rare with other causes of brain abscess

ER management of meningitisER management of meningitis

TREATMENTTREATMENT

Empirical threapyEmpirical threapy

Specific therapySpecific therapy

Review: Van Der Beek et al, Review: Van Der Beek et al, Lancet March 2004Lancet March 2004

Systematic reviewSystematic review Age> 16Age> 16 At least 1 fatalityAt least 1 fatality Jadad ScaleJadad Scale

Randomization 0-2Randomization 0-2 Double Blinding 01Double Blinding 01 Withdrawls/Dropouts 0-1Withdrawls/Dropouts 0-1

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OutcomesOutcomes MortalityMortality Neurological deficitsNeurological deficits

OrganismOrganism S.PneumoS.Pneumo N. MeningitidisN. Meningitidis OtherOther

Adverse EventsAdverse Events

Conclusion: Steroid therapy in all pt’s with suspected bacterial meningitis

Benefit in studies reviewed are seen when dexamethasone is started with or soon after antibiotics

NEJM, 2006;354, 44-53

NEJM, 2006;354, 44-53

BACTERIAL MENINGITISBACTERIAL MENINGITISDuration of ATB RxDuration of ATB Rx

Pathogen Duration of Rx (d)Pathogen Duration of Rx (d)

H. influenzae 7H. influenzae 7

N. meningitidis 7N. meningitidis 7

S. pneumoniae 10-14S. pneumoniae 10-14

L. monocytogenes 14-21L. monocytogenes 14-21

Group B strep 14-21Group B strep 14-21

GNRs 21GNRs 21

NEJM 1997;336:708NEJM 1997;336:708

THE PATIENT WITH SUSPECTED CNS THE PATIENT WITH SUSPECTED CNS INFECTIONINFECTION

Role of Repetitive LP’sRole of Repetitive LP’s

1. Rarely indicated in proven bacterial meningitis unless 1. Rarely indicated in proven bacterial meningitis unless clinical response not optimal or as expected, fever clinical response not optimal or as expected, fever recurs, or infection is due to ATB resistant recurs, or infection is due to ATB resistant pathogenpathogen

2.2. Essential in pts with “aseptic meningitis” syndromes to Essential in pts with “aseptic meningitis” syndromes to monitor course &/or response to empiric therapiesmonitor course &/or response to empiric therapies

3.3. Essential in pts with subacute/chronic meningitis of Essential in pts with subacute/chronic meningitis of proven etiology to assess response to Rxproven etiology to assess response to Rx

4.4. Not routinely indicated at end-of-therapy for bacterial Not routinely indicated at end-of-therapy for bacterial meningitismeningitis

後記後記 The available evidence supports the use of The available evidence supports the use of

adjunctive dexamethasone in infants and children adjunctive dexamethasone in infants and children with with H. influenzaeH. influenzae type b type b meningitis. ( meningitis. ( 0.15 mg/kg 0.15 mg/kg every 6 h for 2-4 daysevery 6 h for 2-4 days))

Dexamethasone in adults with the adjunctive Dexamethasone in adults with the adjunctive dexamethasone be administered to all adult dexamethasone be administered to all adult patients with suspected or proven patients with suspected or proven pneumococcal pneumococcal meningitis.meningitis. ( ( 0.15 mg/kg every 6 h for 2-4 days0.15 mg/kg every 6 h for 2-4 days))

FDA warning 9/11/2007FDA warning 9/11/2007 Rocephin (ceftriaxone Rocephin (ceftriaxone

sodium) for Injectionsodium) for Injection

Potential risk associated Potential risk associated with concomitant use of with concomitant use of Rocephin with calcium or Rocephin with calcium or calcium-containing calcium-containing solutions or productssolutions or products Cases of fatal reactions with Cases of fatal reactions with

calcium-ceftriaxone calcium-ceftriaxone precipitates in the lungs and precipitates in the lungs and kidneys in both term and kidneys in both term and premature neonates were premature neonates were reported. reported.

COMPLICATIONSCOMPLICATIONS

Extradural AbscessExtradural Abscess

Extradural abscess, Extradural abscess, associated with osteomyelitis, associated with osteomyelitis, complication of sinusitis or a surgical complication of sinusitis or a surgical

procedure. procedure. When the process occurs in the spinal epidural When the process occurs in the spinal epidural

space, it may cause spinal cord compression space, it may cause spinal cord compression and constitute a neurosurgical emergency. and constitute a neurosurgical emergency.

subdural empyema.subdural empyema.

fungal infection of the skull bones or air fungal infection of the skull bones or air sinuses can spread to the subdural space sinuses can spread to the subdural space

subdural empyema may produce a mass subdural empyema may produce a mass effect. effect.

thrombophlebitis may develop in the bridging thrombophlebitis may develop in the bridging veins that cross the subdural space, resulting in veins that cross the subdural space, resulting in venous occlusion and infarction of the brain. venous occlusion and infarction of the brain.

CLINICAL MANIFESTATIONSCLINICAL MANIFESTATIONSSPINAL EPIDURAL ABSCESS

Four clinical stages have been described: 1. Fever and focal back pain; 2. Nerve root compression with nerve root

pain; “shooting pain”

3. Spinal cord compression with accompanying deficits in motor/sensory nerves, bowel/bladder sphincter function;

4. Paralysis (respiratory compromise may also be present if the cervical cord is involved).

Armstrong, ID, Mosby inc,2000

PREVENTIONPREVENTION

Meningitis- PreventionMeningitis- Prevention

Chemoprophylaxis for close contacts of index case if Chemoprophylaxis for close contacts of index case if Neisseria; treat contacts less than 4 years of age if H. Neisseria; treat contacts less than 4 years of age if H. fluflu

Vaccinate all children, especially those at risk or those Vaccinate all children, especially those at risk or those with aspleniawith asplenia H. fluH. flu S. pneumo- 7 valent up to 2 years, then 23 valent vaccineS. pneumo- 7 valent up to 2 years, then 23 valent vaccine Neisseria- quadrivalent vaccine (A, C, Y, W-135) for high Neisseria- quadrivalent vaccine (A, C, Y, W-135) for high

risk patients (asplenia, college age, military) over 2 years of risk patients (asplenia, college age, military) over 2 years of ageage

Does not cover group B, which causes close to ½ of cases in USDoes not cover group B, which causes close to ½ of cases in US

Ventricular shunt infections Ventricular shunt infections

Intraventricular dose for shunt Intraventricular dose for shunt infections infections

ENCEPHALITISENCEPHALITIS

EncephalitisEncephalitis ViralViral

HSVHSV ArbovirusesArboviruses VZV, CMV, EBV, HIV, rabiesVZV, CMV, EBV, HIV, rabies EnterovirusesEnteroviruses

BacterialBacterial Listeria monocytogenesListeria monocytogenes

Tick-borne illnessesTick-borne illnesses RMSF: Rickettsia rickettsiiRMSF: Rickettsia rickettsii STARI: Borrelia lonestariSTARI: Borrelia lonestari Lyme: Borrelia burgdorferiLyme: Borrelia burgdorferi Ehrlichiosis: Ehrlichia chaffoensisEhrlichiosis: Ehrlichia chaffoensis

HSV MeningitisHSV Meningitis

K Tyler (USA)K Tyler (USA)

CSF in HSV Encephalitis vs. MeningitisCSF in HSV Encephalitis vs. Meningitis

WBCs/mmWBCs/mm33 202 (2-667)202 (2-667) 484 (58-1888)*484 (58-1888)* <10 cells/mm<10 cells/mm33 19% 19% 12%12% % Lymphs% Lymphs 76 (16-97)76 (16-97) 87 (43-100) ns87 (43-100) ns RBCs/mmRBCs/mm33 2518 (0-27,566)2518 (0-27,566) 54 (0-711) ns54 (0-711) ns Protein mg/dLProtein mg/dL 73 (22-146)73 (22-146) 129 (75-281)*129 (75-281)*

Encephalitis Meningitis

Simko et al., CID 35:417, 2002

HSV EncephalitisHSV Encephalitis

2-4 cases/million people/year2-4 cases/million people/year Acute infection or more commonly reactivation of latent Acute infection or more commonly reactivation of latent

infection (trigeminal nerve ganglion)infection (trigeminal nerve ganglion) Characteristic site of damage: temporal lobeCharacteristic site of damage: temporal lobe

MRI findings of necrosis in temporal lobeMRI findings of necrosis in temporal lobe Necrosis = RBC s on CSF! Necrosis = RBC s on CSF!

30% Mortality with treatment30% Mortality with treatment 70% mortality without treatment 70% mortality without treatment

Definition of Recurrent Definition of Recurrent MeningitisMeningitis

>2 episodes meningitis>2 episodes meningitis Symptom-free intervalsSymptom-free intervals Normal CSF between episodesNormal CSF between episodes Must be differentiated from chronic Must be differentiated from chronic

meningitismeningitis Culture + versus “Aseptic”Culture + versus “Aseptic”

BRAIN ABSCESSBRAIN ABSCESS

MICROBIOLOGY OFMICROBIOLOGY OF BRAIN ABSCESSBRAIN ABSCESSAGENT FREQUENCY (%)

Streptococci (S. intermedius, including S. anginosus) 60–70

Bacteroides and Prevotella spp. 20–40

Enterobacteriaceae 23–33

Staphylococcus aureus 10–15

Fungi 10–15

Streptococcus pneumoniae <1

Haemophilus influenzae <1

Protozoa, helminths † (vary geographically) <1

*Yeasts, fungi (Aspergillus Agents of mucor Candida Cryptococci Coccidiodoides Cladosporium trichoides Pseudallescheria boydii)†Protozoa, helminths (Entamoeba histolytica, Schistosomes Paragonimus Cysticerci) CTID,2001

Frontal abscesses

When to aspirate ?When to aspirate ?

If single or multiple ring-enhancing lesions are found, If single or multiple ring-enhancing lesions are found, the patient should be taken urgently to surgery. All the patient should be taken urgently to surgery. All

lesions greater lesions greater than 2.5 cmthan 2.5 cm in diameter should be in diameter should be excised or stereotactically aspirated and specimens excised or stereotactically aspirated and specimens sent to the microbiology and pathology laboratories sent to the microbiology and pathology laboratories (see earlier paragraphs). For abscesses in the early (see earlier paragraphs). For abscesses in the early cerebritis stage or when the abscesses are 2.5 cm in cerebritis stage or when the abscesses are 2.5 cm in diameter or less, the largest lesion should be aspirated diameter or less, the largest lesion should be aspirated for diagnosis and organism identification for diagnosis and organism identification

Empirical therapy of brain abscessEmpirical therapy of brain abscess

T. Gondii EncephalitisT. Gondii Encephalitis

Most Common PathogensMost Common Pathogens Otitis media, mastoiditis Otitis media, mastoiditis StreptococciStreptococci Paranasal sinusitis Paranasal sinusitis StreptococciStreptococci

Pulmonary infection Pulmonary infection Strep, ActionomycesStrep, Actionomyces Dental Dental Mixed, Bacteroides spp.Mixed, Bacteroides spp. CHD CHD Strep Strep

Penetrating/Post-crani Penetrating/Post-crani S. aureus S. aureus

HIV HIV Toxoplasma gondii Toxoplasma gondii Transplant Transplant Aspergillus, Candida Aspergillus, Candida

TREATMENTTREATMENT

•Aspiration Or Open DrainageAspiration Or Open Drainage•Empirical Combination Empirical Combination Antimicrobial TherapyAntimicrobial Therapy•Duration: 6 to 8 wks IVDuration: 6 to 8 wks IV•Prophylactic Anticonvulsant TherapyProphylactic Anticonvulsant Therapy•Glucocorticoids( Severe Edema & ICP )Glucocorticoids( Severe Edema & ICP ) •Serial CT-Scan or MRISerial CT-Scan or MRI