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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
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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