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Radiologic evaluation of progressive Radiologic evaluation of progressive multifocal multifocal leukoencephalopathy leukoencephalopathy (PML) in a patient with congenital (PML) in a patient with congenital HIV infection HIV infection Christopher Doughty, MSIII Christopher Doughty, MSIII Gillian Lieberman, M.D. Gillian Lieberman, M.D. Core Radiology Clerkship Core Radiology Clerkship Beth Israel Deaconess Medical Center Beth Israel Deaconess Medical Center

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Radiologic evaluation of progressive Radiologic evaluation of progressive multifocal multifocal leukoencephalopathyleukoencephalopathy

(PML) in a patient with congenital (PML) in a patient with congenital HIV infectionHIV infection

Christopher Doughty, MSIIIChristopher Doughty, MSIIIGillian Lieberman, M.D.Gillian Lieberman, M.D.

Core Radiology ClerkshipCore Radiology ClerkshipBeth Israel Deaconess Medical CenterBeth Israel Deaconess Medical Center

Our Patient: ED PresentationOur Patient: ED Presentation

20 20 y/oy/o male male h/oh/o congenital HIV, off HAART >1 congenital HIV, off HAART >1 year year –– ““didndidn’’t feel like taking the meds anymoret feel like taking the meds anymore””Presents to ED from clinic appointment with Presents to ED from clinic appointment with question of intoxication or question of intoxication or suicidalitysuicidalityIn ED, also complains of R leg weakness, In ED, also complains of R leg weakness, worsening over 1.5 monthsworsening over 1.5 months

Difficulty walking Difficulty walking –– foot catches floorfoot catches floor

Complains of slowed speech for 5Complains of slowed speech for 5--6 months6 monthsAdmitted, section 12Admitted, section 12

Later, determined not to be suicidal. Possible Later, determined not to be suicidal. Possible misunderstanding in clinic/ED?misunderstanding in clinic/ED?

Our Patient: HistoryOur Patient: History

PMH: congenital HIV, no known PMH: congenital HIV, no known opportunistic infectionsopportunistic infectionsMeds: none; off HAART 1 yearMeds: none; off HAART 1 yearAllergies: noneAllergies: noneSH: lives with friends, no contact with SH: lives with friends, no contact with family; recently fired from job; occasional family; recently fired from job; occasional cigarettes and marijuanacigarettes and marijuanaROS: negativeROS: negative

Our Patient: Physical ExamOur Patient: Physical Exam

Mental Status: slowed speech; minor Mental Status: slowed speech; minor inattention; recalls 2/3 words at 2 minutesinattention; recalls 2/3 words at 2 minutesMotor: Weakness of R hip flexors, Motor: Weakness of R hip flexors, hamstrings, foot hamstrings, foot dorsiflexorsdorsiflexors, toe , toe extensorsextensorsReflexes: R patellar brisk, R toe Reflexes: R patellar brisk, R toe upgoingupgoingCoordination: Slow rapid alternative Coordination: Slow rapid alternative movements bilaterallymovements bilaterally

Our Patient: Forming a DifferentialOur Patient: Forming a Differential

Localize the Lesion ClinicallyLocalize the Lesion ClinicallyPattern of R leg weakness, brisk reflex, and Pattern of R leg weakness, brisk reflex, and upgoingupgoing toe suggest upper motor neuron toe suggest upper motor neuron lesion: spinal cord or abovelesion: spinal cord or aboveCognitive difficulties are not caused by spinal Cognitive difficulties are not caused by spinal cord lesionscord lesionsProcess Process mustmust involve the braininvolve the brain

Time CourseTime CourseSubacuteSubacute –– stroke, e.g., unlikelystroke, e.g., unlikely

Our Patient: Importance of HIVOur Patient: Importance of HIV40% of AIDS patients develop significant 40% of AIDS patients develop significant neurological symptoms! neurological symptoms! ((CiricilloCiricillo & & RosenblumRosenblum))

The progression of his disease will The progression of his disease will influence our differential diagnosisinfluence our differential diagnosisOur patientOur patient’’s labs:s labs:

CD4 count: 33CD4 count: 33Viral load: 36,000Viral load: 36,000

Our Patient: Possible Our Patient: Possible Opportunistic InfectionsOpportunistic Infections

Our patient’sCD4: 33

Key: Cry, Cryptococcus; NHL, Non-Hodgkin’s lymphoma;DEM, AIDS dementia; PML, Progressive multifocal leukoencephalopathy;Tox, Toxoplasmosis; CMV, Cytomegalovirus

Our Patient: Differential DiagnosisOur Patient: Differential DiagnosisToxoplasmosisToxoplasmosisPrimary CNS lymphoma or systemic Primary CNS lymphoma or systemic lymphoma with CNS involvementlymphoma with CNS involvementPMLPMLBrain abscess Brain abscess –– bacterial, TBbacterial, TBTB TB granulomagranuloma in the brainin the brainCMV encephalitisCMV encephalitisCryptococcus Cryptococcus -- CryptococcomaCryptococcomaHIV encephalitisHIV encephalitisSubdural hematomaSubdural hematomaMetastasisMetastasis

Most commoncauses of focal CNS lesions in AIDS patients

Proper Radiologic AssessmentProper Radiologic Assessment of the Brainof the Brain

CT or MRICT or MRIAmerican College of Radiology (ACR) American College of Radiology (ACR) appropriateness criteria: both have a roleappropriateness criteria: both have a role

CT w/o contrast CT w/o contrast –– screening for acute hemorrhagescreening for acute hemorrhageMRI w/ and w/out contrast MRI w/ and w/out contrast –– screening for screening for infections and massesinfections and masses

MRI is more sensitive for the top three focal MRI is more sensitive for the top three focal lesions in AIDS patients: Toxoplasmosis, lesions in AIDS patients: Toxoplasmosis, Lymphoma, and PML Lymphoma, and PML ((CiricilloCiricillo & & RosenblumRosenblum))

Normal Head CTNormal Head CT

www.migraine-aura.org

Bone

Gray Matter

White Matter

is more dense thanCSF

Choroid Plexus(Calcifications)

Deep Gray Matter(Caudate Nucleus)

Thalamus

axial view, c-

Our Patient: Head CT, w/o contrastOur Patient: Head CT, w/o contrast

What do you see?

Continue to see findings

PACS, BIDMCaxial view

Our Patient: Focal low density Our Patient: Focal low density areas on CTareas on CT

Focal, low density regions

PACS, BIDMCaxial view, c-

Focal, low density regions

PACS, BIDMC

Our Patient: Focal low density Our Patient: Focal low density areas on CTareas on CT

axial view, c-

Focal, low density regions

PACS, BIDMC

Our Patient: Focal low density Our Patient: Focal low density areas on CTareas on CT

axial view, c-

We’ve found multiple, focal, low density areas in our patient’s head CT w/out

contrast. Let’s look at two companion patients for examples of two important findings we DON’T see in our patient.

Companion Patient 1: Acute Companion Patient 1: Acute Hemorrhage on CTHemorrhage on CT

PACS, BIDMC

AcuteHemorrhage

Companion Patient 1

Clearly, there is no evidence of hemorrhage in

our patient’s CT

Our patient’s CT, axial view c-

axial view, c- PACS, BIDMC

Companion Patient 2: Mass Effect Companion Patient 2: Mass Effect on the Ventricles on Head CTon the Ventricles on Head CT

PACS, BIDMC

Companion Patient 2

In this patient, the lowdensity lesion is exertingmass effect on the lateralventricle. The calcificationwithin the choroid plexus has been displaced andthe ventricle has shiftedtoward the midline.

Low density area

axial view, c-

Companion Patient 2: More Mass Companion Patient 2: More Mass Effect on the Ventricles on Head CTEffect on the Ventricles on Head CT

PACS, BIDMC

Looking superiorly in thebrain, we see furtherevidence that the lateralventricle is beingdisplaced.

Low density area

axial view, c-

Companion Patient 2

Companion Patient 2: Midline ShiftCompanion Patient 2: Midline Shift on Head CTon Head CT

PACS, BIDMC

Here we see that thelesion has actually shiftedthe midline of this patient’sbrain 2.93mm to the right.

axial view, c-

Companion Patient 2

This patient hasToxoplasmosis

Our Patient: No Evidence of Mass Our Patient: No Evidence of Mass Effect on Head CT Effect on Head CT

There is no evidence of

mass effect in our patient’s CT – the ventricles appear normal and the midline has not shifted

PACS, BIDMCaxial view, c-

We’ve found multiple, focal, low density areas in our patient’s head

CT with no evidence of acute hemorrhage or mass effect. Let’s

move on to MRI to learn more about our patient’s brain.

MRI of the Brain: BasicsMRI of the Brain: BasicsMRI: more sensitive; more detail of white MRI: more sensitive; more detail of white matter and gray matter structuresmatter and gray matter structures

T1 T2

CSF is black CSF is white

med.harvard.eduwww.mr-tip.com

axial viewsw/out contrast

FLAIR: FluidFLAIR: Fluid--attenuated inversion recoveryattenuated inversion recovery

MRI of the Brain: FLAIRMRI of the Brain: FLAIR

T2 FLAIR

CSF is white CSF is subtracted, appears blackAll other fluid remains white

Fluid = PATHOLOGY

axial viewsw/out contrast

med.harvard.edu

www.radiologyteacher.com

Our patient had leg weakness. Let’s exploit the level of detail offered by MRI to review the

corticospinal tract that delivers motor information to the body from the brain so we know where to look

for possible lesions.

Anatomy Review Anatomy Review –– Motor CortexMotor Cortex

Centralsulcus

Precentralgyrus: motor

cortex

med.harvard.eduCourtesy of Dr. Bernard Chang

axial view, T1, c-

The corticospinal tract

Anatomy Review Anatomy Review –– Further InferiorFurther Inferior

med.harvard.eduCourtesy of Dr. Bernard Chang

axial view, T1, c-

The corticospinal tract

Anatomy Review Anatomy Review –– Internal CapsuleInternal Capsule

putamen

thalamus

med.harvard.eduCourtesy of Dr. Bernard Chang

axial view, T1, c-

The corticospinal tract

Anatomy Review Anatomy Review -- MidbrainMidbrain

med.harvard.eduCourtesy of Dr. Bernard Chang

axial view, T1, c- The corticospinal tract

Anatomy Review Anatomy Review –– PonsPons

med.harvard.eduCourtesy of Dr. Bernard Chang

axial view, T1, c-

The corticospinal tract

Anatomy Review Anatomy Review –– MedullaryMedullary PyramidsPyramids

med.harvard.eduCourtesy of Dr. Bernard Chang

axial view, T1, c-

The corticospinal tract

Now that we have reviewed the corticospinal tract, let’s look at our

patient’s MRI findings

Our patient: MRIOur patient: MRIT2, axial view

What do you see? Continue to view findingsWhat do you see? Continue to view findingsPACS, BIDMC

FLAIR, axial view

Our patient: Our patient: HyperintenseHyperintense focifoci

Several Several hyperintensehyperintense lesions on T2 and FLAIRlesions on T2 and FLAIR

T2, axial view

PACS, BIDMC

FLAIR, axial view

Our patient: Multiple Our patient: Multiple HyperintenseHyperintense focifoci

Several T2 Several T2 hyperintensehyperintense lesionslesionsPACS, BIDMC

Thalami

FLAIR, axial views

Our patient: Our patient: HyperintenseHyperintense foci foci in the brainstemin the brainstem

Several T2 Several T2 hyperintensehyperintense lesionslesionsPACS, BIDMC

L Middle L Middle CerebellarCerebellar PedunclePeduncle

L PonsL Pons

FLAIR, axial views

Our patient: preOur patient: pre-- and postand post-- contrast MRIcontrast MRI

T1 Pre-Contrast, axial view T1 Post-Contrast, axial view

No enhancementNo enhancement PACS, BIDMCPACS, BIDMC

Upon viewing our patient’s MRI, we’ve found several hyperintense foci throughout the bilateral

subcortical white matter, the bilateral thalami, the L pons, and the L middle cerebellar peduncle.

These lesions did NOT enhance.

Let’s look at MRI findings from two other companion patients to see why we looked for

contrast enhancement.

PACS, BIDMC

T1 post-contrast, axial view T1 post-contrast, axial view

Companion Patients 3 and 4: RingCompanion Patients 3 and 4: Ring-- Enhancing Lesions on MRIEnhancing Lesions on MRI

Companion patient 3

Lorberboym, et al.

Primary CNS LymphomaPrimary CNS Lymphoma ToxoplasmosisToxoplasmosis

Companion patient 4

* *

RingRing--Enhancing Lesions: Enhancing Lesions: DDxDDx

There is a large differential for ringThere is a large differential for ring--enhancing lesions in AIDS patients!enhancing lesions in AIDS patients!

ToxoplasmosisToxoplasmosisPrimary CNS lymphoma or systemic Primary CNS lymphoma or systemic lymphoma with CNS involvementlymphoma with CNS involvementBrain abscess Brain abscess –– bacterial, TBbacterial, TBTB TB granulomagranuloma in the brainin the brainCMV encephalitisCMV encephalitisCryptococcus Cryptococcus –– CryptococcomaCryptococcomaMetastasesMetastases

Because the lesions we saw in our patient’s MRI did not enhance, we have eliminated many items from our original differential—those that tend to show ring-enhancement.

Our Patient: Original DifferentialOur Patient: Original DifferentialToxoplasmosisToxoplasmosisPrimary CNS lymphoma or systemic Primary CNS lymphoma or systemic lymphoma with CNS involvementlymphoma with CNS involvementPMLPMLBrain abscess Brain abscess –– bacterial, TBbacterial, TBTB TB granulomagranuloma in the brainin the brainCMV encephalitisCMV encephalitisCryptococcus Cryptococcus -- CryptococcomaCryptococcomaHIV encephalitisHIV encephalitisSubdural hematomaSubdural hematomaMetastasisMetastasis

Our Patient: Remaining DifferentialOur Patient: Remaining Differential

PMLPML

HIV encephalitisHIV encephalitis

Our patient: Summary of Our patient: Summary of FindingsFindings

Multifocal lowMultifocal low--density lesions on CT density lesions on CT without mass effectwithout mass effectMultiple, focal, Multiple, focal, subcorticalsubcortical white matter T2 white matter T2 hyperintensehyperintense lesionslesionsAdditional T2 Additional T2 hyperintensehyperintense lesions in lesions in thalami, thalami, ponspons, and middle , and middle cerebellarcerebellarpedunclepeduncleHypointenseHypointense to white matter on T1; no to white matter on T1; no enhancement with gadoliniumenhancement with gadolinium

PML: Classic FindingsPML: Classic Findings

Multifocal lowMultifocal low--density lesions on CT density lesions on CT without mass effectwithout mass effectMultiple, focal, Multiple, focal, subcorticalsubcortical white matter T2 white matter T2 hyperintensehyperintense lesionslesions10% with brain stem or 10% with brain stem or cerebellarcerebellarinvolvementinvolvementHypointenseHypointense to white matter on T1; no to white matter on T1; no enhancement with gadoliniumenhancement with gadolinium

Provenzale & Jinkins

The imaging findings in our patient are the classic findings for a patient with PML. Let’s look at the imaging

findings from a patient with HIV encephalitis to differentiate

between the two diseases, as their imaging findings can appear

similar.

Companion Patient 5: HIV Companion Patient 5: HIV EncephalitisEncephalitis

FLAIR, axial views

PACS, BIDMC

What do you see? Continue to view findings

CompanpionCompanpion Patient 5: Diffuse Patient 5: Diffuse HyperintensityHyperintensity

PML HIV EncephalitisPACS, BIDMC

Focal,Asymmetric

Our patient, for comparison

Companion PatientFLAIR, axial view

FLAIR, axial view

PACS, BIDMC

Companion Patient 5: Brain Companion Patient 5: Brain Atrophy on MRIAtrophy on MRI

Wide sulci

PML

Our patient, for comparisonCompanion PatientFLAIR, axial view

FLAIR, axial view

HIV EncephalitisPACS, BIDMC

PACS, BIDMC

Companion Patient 5: Ventricular Companion Patient 5: Ventricular Enlargement as a Sign of Brain Atrophy on Enlargement as a Sign of Brain Atrophy on

MRIMRIVentricular Enlargement

HIV EncephalitisPACS, BIDMC

PACS, BIDMCPML

Our patient, for comparisonFLAIR, axial view

HIV Encephalitis: Classic HIV Encephalitis: Classic FindingsFindings

Diffuse, symmetric Diffuse, symmetric T2 T2 hyperintensityhyperintensityAtrophy Atrophy ((ProvenzaleProvenzale & & JinkinsJinkins))

Not always present, howeverNot always present, howeverHIV is HIV is neurotropicneurotropic; infects ; infects glialglial cells cells and and neurons throughout the CNS, explaining the neurons throughout the CNS, explaining the white matter white matter hyperintensityhyperintensity and atrophy, and atrophy, respectively, seen on MRI.respectively, seen on MRI. ((HealdHeald))

We’ve learned that HIV encephalitis is characterized by diffuse T2 hyperintensity, rather

than focal hyperintense lesions like those of PML. We also learned

that atrophy is characteristic of HIV encephalitis and not PML.

Let’s learn more about PML.

PML: Progressive Multifocal PML: Progressive Multifocal LeukoencephalopathyLeukoencephalopathy

An infectionAn infectionJC VirusJC Virus

EpidemiologyEpidemiologyAsymptomatic primary infectionAsymptomatic primary infection6060--80% 80% seropositiveseropositive rate in American adults rate in American adults (Demeter)(Demeter)

Reactivated by Reactivated by immunosuppressionimmunosuppression (Shah et al.)(Shah et al.)::HIV/AIDS (79%)HIV/AIDS (79%)Hematologic malignanciesHematologic malignanciesOrgan transplantOrgan transplantNatalizumabNatalizumab ((TysabriTysabri) ) –– MS medicationMS medication

PML: PathogenesisPML: Pathogenesis

The JC virus preferentially infects The JC virus preferentially infects oligodendrocytesoligodendrocytes, leading to their death, leading to their death

Result: widespread CNS Result: widespread CNS demyelinationdemyelination and and reactive reactive gliosisgliosis ((ProvenzaleProvenzale & & JinkinsJinkins))

PML: Treatment and PrognosisPML: Treatment and Prognosis

HAART HAART –– only therapy with proven only therapy with proven survival benefit survival benefit (Cinque et al.)(Cinque et al.)

Before HAART, only 10% of patients lived Before HAART, only 10% of patients lived longer than 1 year longer than 1 year ((KoralnikKoralnik))

One year survival rate now: 50% One year survival rate now: 50% ((KoralnikKoralnik))

The disease remains uniformly fatal, The disease remains uniformly fatal, however.however.

Our Patient: DiagnosisOur Patient: Diagnosis

Clinical presentation and radiologic Clinical presentation and radiologic findings are extremely suggestive of PMLfindings are extremely suggestive of PMLGold standard of diagnosis for PML:Gold standard of diagnosis for PML:

Detection of JC Virus DNA in CSF by Detection of JC Virus DNA in CSF by polymerase chain reaction (PCR)polymerase chain reaction (PCR)

Specificity: 92Specificity: 92--100% 100% (Cinque et al.)(Cinque et al.)

Negative in our patient, howeverNegative in our patient, howeverOnly 72Only 72--92% sensitive 92% sensitive (Cinque et al.)(Cinque et al.)

Based on clinical and radiologic findings, Based on clinical and radiologic findings, our patient still presumed to have PMLour patient still presumed to have PML

Our Patient: ResultOur Patient: Result

Our patient was restarted on HAART Our patient was restarted on HAART therapy; he was also enrolled in a local therapy; he was also enrolled in a local Directly Observed Therapy (DOT) program Directly Observed Therapy (DOT) program to help ensure compliance.to help ensure compliance.His prognosis is poor, but it is hoped that His prognosis is poor, but it is hoped that HAART will slow the progression of his HAART will slow the progression of his disease and prolong his survival.disease and prolong his survival.

SummarySummary

Tests of choice: CT, MRITests of choice: CT, MRICT: acute hemorrhage, mass effectCT: acute hemorrhage, mass effectRingRing--enhancing lesions: wide differentialenhancing lesions: wide differentialPML: PML: demyelinatingdemyelinating infection, JC virusinfection, JC virusPML: Focal T2 PML: Focal T2 hyperintensitieshyperintensities that do not that do not enhanceenhanceHIV encephalopathy: Diffuse T2 HIV encephalopathy: Diffuse T2 hyperintensityhyperintensity with atrophywith atrophy

AcknowledgementsAcknowledgements

Dr. Dr. GulGul MoonisMoonis, , Assistant Professor of Radiology, Assistant Professor of Radiology, Harvard Medical SchoolHarvard Medical School

Dr. Rafael Rojas, Dr. Rafael Rojas, Assistant Professor of Radiology, Assistant Professor of Radiology, Harvard Medical SchoolHarvard Medical School

Dr. Bernard Chang, Dr. Bernard Chang, Assistant Professor of Assistant Professor of Neurology, Harvard Medical SchoolNeurology, Harvard Medical School

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