Ring Lesions Hiv

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Jonathan Waks, MSIIIGillian Lieberman, MD

Ring Enhancing Lesions in aPatient with AIDS

Jonathan Waks, Harvard Medical School Year III

Gillian Lieberman, MD

March 2007


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Agenda

Background: CNS complications of AIDS

Patient presentation

Menu of radiologic tests

Differential diagnosis: ring enhancing lesions Differentiating CNS lesions

Summary


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AIDS and the CNS

10% of patients have neurological signs and symptomswhen they first present with AIDS.

30-60% of patients with AIDS will develop neurologicalcomplications during the course of their illness.

70-90% of patients with AIDS show CNS involvement atautopsy.

Thurnher MM. Eur Radiol 1997;7(7):1091-7

Understanding and recognizing the appearance ofCNS complications in patients with AIDS isimportant in promptly recognizing, diagnosing andinitiating proper treatment.


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DDx. of CNS complications of AIDS:

1. HIV encephalitis

2. Opportunistic Infections: Toxoplasmosis

Cryptococcosis

CMV

TB

PML (JC virus)

Bacterial

Fungal

3. Neoplasm Primary CNS lymphoma

Kaposis Sarcoma

Thurnher MM. Eur Radiol 1997;7(7):1091-7

http://www.niaid.nih.gov/factsheets/howhiv.htm

HIV-1 Virus


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Index Patient JL

49 year old man with AIDS (last CD4=17, onHAART) who presented to an OSH for unsteady

gait, lower extremity weakness, headache, vomiting,dysarthria and seizures.

PE:

Temp: 102.4F Multiple CN deficits

Head CT showed multiple ring enhancing lesions

Started on broad spectrum antibiotics with coveragefor toxoplasma.

No improvement Brain biopsy: non diagnostic

Transferred to BIDMC for further management.


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Before we discuss the imaging that

was obtained when JL arrived atBIDMC, lets first review the radiologic

modalities that can be used toevaluate the CNS in a patient with

AIDS.


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Menu of Radiologic Tests

Primary Modalities:

CT (w/wo contrast)

MRI (w/wo contrast) T1, T2, FLAIR

DWI/ADC Maps

Adjunctive Modalities:

FDG-PET

Thallium 201 SPECT Special MRI protocols

MR Spectroscopy

Perfusion MR http://www.southernhealth.org.au/imaging/images/mr_ge.jpg


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Primary Modalities:

CT (w/wo contrast)

MRI (w/wo contrast) T1, T2, FLAIR

DWI/ADC Maps

Adjunctive Modalities:

FDG-PET

Thallium 201 SPECT Special MRI protocols

MR Spectroscopy

Perfusion MR

These adjunctive modalities arenot used in the routine imaging orevaluation of CNS lesions in

patients with AIDS. They areprimarily used when the identityof a lesion is in question andadditional non-invasive imaging

would potentially alter treatment.PET and SPECT scanning areused most frequently. MRspectroscopy and perfusion MR

are not routinely used and will notbe discussed in this presentation.

Adjunctive imaging modalities will bediscussed later on in the presentation


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1. Fast

2. Readily available

3. Can scan people withcontraindications to MRI

1. Less sensitive than MRI

2. Limited evaluation ofposterior fossa

3. Can miss some whitematter disease

4. Brain radiation

BIDMC, PACS

Computed Tomography:

Pros Cons

Normal Head CT


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Menu of Radiologic TestsMagnetic Resonance Imaging:

Pros Cons

1. Better than CT at determining if alesion truly is solitary

2. Increased sensitivity to subtle white

matter disease and posterior fossalesions

3. May be able to identify small

peripheral lesions missed by CT thatare more accessible for biopsy

4. No radiation

5. Multiple imaging sequences can aiddiagnosis (DWI/ADC/FLAIR)

1. More costly, less readilyavailable

** MRI is the BEST test toassess CNS lesions

BIDMC, PACS

Normal T1 and T2 MRI


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Diffusion Weighted Imaging (MRI)Diffusion Weighted Imaging (DWI): Makes use of Brownian motion toimage local water diffusion. Macromolcules and cells in the brainrestrict the diffusion of water.

Areas of restricted diffusion appear BRIGHT on DWI

Apparent Diffusion Coefficient (ADC): The signal intensity of DWIdepends on factors other than diffusion information (spin density,

TR, TE). By combining multiple DWIs, these other factors can beeliminated. ADC also eliminates T2-Shine through on DWI causedby intense T2 signals.

Areas of restricted diffusion appear DARK in ADC

Images from Fillipi. Clinical MR Neuroimaging. pg 411 Information from Stadnik et al. http://ej.rsna.org/ej3/0095-98.fin/index.htm


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Jonathan Waks, MSIIIGillian Lieberman, MD Imaging: JL

Axial T1WI MRIpost gadolinium

Images provided by Mizuki Nishino, MD; BIDMC

Axial T1WI MRI

pre gadolinium

Multiple ring enhancingLesions throughout CNS

=


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Looking at additional MRI sequencesallows us to better characterize the

center of the lesion and surroundingtissue.

S


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Imaging: JL

AxialDWI MRI

Axial

T1 MRI +Gad

AxialFLAIR MRI +Gad

Axial

ADC Map

Images provided by Mizuki Nishino, MD; BIDMC, PACS

Hyperintense on DWI =restricted diffusion

Hypo/isointense lesionwith ring enhancement

Enhancing lesionsurrounded by

hyperintense edema

Hypointense on ADC =restricted diffusion

J th W k MSIII


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There is a well defined differentialdiagnosis for ring enhancing lesions

in the CNS:

J th W k MSIII


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DDx. Ring Enhancing Lesions ( )Infection:

Toxoplasma

Cystercercosis

Brain abscess (bacterial, fungal)

Neoplasms

Brain tumors/metastases

Primary CNS Lymphoma

Demyelinating Disease

MS

ADEM

Vascular lesionsResolving infarction

Hematoma

Thrombosed aneursm

Radiation necrosis

Postoperative changesGamuts in Radiology, online edition

Images from Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66.

*

*

*

**

Head CT with contrast

Head T1WI w/ contrast


Jonathan Waks MSIII


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Infection:

Toxoplasma

Cystercercosis

Brain abscess (bacterial, fungal)

Neoplasms

Brain tumors/metastases

Primary CNS Lymphoma

Demyelinating Disease

MS

ADEM

Vascular lesionsResolving infarction

Hematoma

Thrombosed aneursm

Radiation necrosis

Postoperative changesGamuts in Radiology, online edition


When we consider which of theseentities are common in patients withAIDS (see slide 4 for a refresher),the differential narrows, and we canfocus on Toxoplasmosis, brainabscess and primary CNS lymphoma

DDx. Ring Enhancing Lesions ( )*

*

*

**


Head T1WI w/ contrast


Jonathan Waks MSIII


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We will now explore the narroweddifferential in more detail.

1. Toxoplasmosis

2. Primary CNS Lymphoma

3. Bacterial brain abscess

Jonathan Waks MSIII Image from https://reader009 {domain}/reader009/html5/0512/5


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Toxoplasmosis: Background

Intracellular protazoan parasite, toxoplasma gondii

Most common opportunistic infection in HIV (CD4 < 100 per L)

Symptoms are usually secondary to reactivation of latent infection

Signs/Symptoms: headache, fever, seizures, encephalopathy,altered mental status, neuro. deficits

Important to quickly diagnose because very treatable with antibiotics

Toxoplasma antibody is not always useful1

Only 1/3 cases have rise in IgG Only 1/2 produce antibodies in CSF

CSF PCR lacks sensitivity and specificity1

Response to treatment is the main method of arriving at a definitivediagnosis.

Treatment: Pyrimethamine and sulfadiazine or clindamycin

Image from https://reader009.{domain}/reader009/html5/0512/5

1. Fillipi. Clinical MR Neuroimaging, pg 420.

Micrograph of T. gondii

Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66.

Jonathan Waks MSIII


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Toxoplasmosis: Life cycle

Image and information from http://www.dpd.cdc.gov/dpdx/HTML/Toxoplasmosis.htm

Cats are the main reservoirs of infection andbecome infected by ingesting tissue cysts.The cysts reproduce inside the felineintestinal tract.

Oocysts are shed in fecal matter and areextremely resistant to severe environmentalconditions and disinfectants.

Humans become infected by either:

Eating tissue cysts in undercooked meat

Fecal-oral transmission from cat fecesBlood or organ transplantation

Transplacentally

Approximately 22.5% of people in the UnitedStates are infected.

Jonathan Waks MSIII


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Toxoplasmosis: Sites of Infection

Most common sites ofinfection are: Cortico-medullary junction

Basal ganglia

Thalamus

Image from Netter, 2004, plate 104.


Jonathan Waks MSIII


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CT:

Non-contrast: isodense to gray matter, but can be detected

secondary to possible edema and mass effect

May be hyperdense if hemorrhagic

Contrast: 90% Ring-enhancement1 with is secondary toinflammatory response (patients with decimated immunesystems may not show enhancement)2

After treatment, can show areas of calcification

Toxoplasmosis: Imaging

1. Koralnik, UpToDate 2. Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66.

Jonathan Waks, MSIII


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MRI:

Usually shows more lesions than CTT1WI: hypointense or isointense to gray

matter

T2WI/FLAIR: isointense or hyperintense togray matter

ring enhancing, sometimes with a centralfocus of enhancement target sign.

Toxoplasmosis: Imaging

Zimmerman, RD. Clinical MR Neuroimaging. pg 365

Jonathan Waks, MSIII Images from Thurnher MM. Eur Radiol 1997;7(7):1091-7


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Toxoplasmosis Lesions

T2 MRI, non-contrast T1 MRI w/ contrast

g ; ( )

Head CT w/ contrast

Below are 2 patients with CNS lesions that weresubsequently shown to be toxoplasmosis.

Patient 1

Patient 2

Hypodense, ringenhancing lesion andsurrounding edema

Hyperintense,enhancing lesion

Hypointense, ringenhancing lesion



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Jo at a a s, SGillian Lieberman, MD

Primary CNS Lymphoma: Background

Most common AIDS related neoplasm (2-5% patients)

After Toxoplasmosis, is second most common cerebral mass

lesion in AIDS patients. Almost always of B-cell, Non-Hodgkins type

Likely related to EBV

Presenting symptoms: neurological deficits, encephalopathy,seizure (similar to toxoplasmosis)

Median survival < 1 year

Treatment: Radiation and corticosteroids




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,Gillian Lieberman, MD

Primary CNS Lymphoma: Sites of Infection

Most commonly located in:

periventricular/periependymal

white matter

corpus callosum


Illustrations from Netter, 2004, Plates 100, 104. BIDMC, PACS



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,Gillian Lieberman, MD

Primary CNS Lymphoma: Imaging

CT:

Isodense to Hypodense

MR:

T1: hypointenseT2/FLAIR: isointense to hyperintense

Enhancement: usually irregular enhancementor ring enhancement.

Chang. Clinical MR Neuroimaging. pg 466

Doweiko, UpToDate



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Primary CNS Lymphoma can have awide range of appearances:



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Primary CNS Lymphoma: Varying Lesions

T1WI +Gad.

Right Image from Doweiko, UpToDate

T1WI +Gad.

Hypointense lesion withring enhancement

Homogenouslyenhancing lesion

Left image from Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66.

2 different patients with lesions subsequently shown to be primary CNS lymphoma

Patient 3 Patient 4



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Bacterial Abscess: Background

Often presents with headache, altered mentalstatus, nausea, vomiting, seizures, neuro. deficits

due to expanding mass.1

Hypointense on T1, Hyperintense on T21

Capsule is hypointense on T21

Ring enhancing with surrounding edema1

Less common in AIDS patients than toxoplasmosisor primary CNS lymphoma2

Often associated with bacteremia

1. Fillipi, Clinical MR Neuroimaging. Pg 409

2. Koralnik, UpToDate



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T1 MRI, no contrast T2 MRI w/ contrast T1 MRI +Gad

Hypointense lesion withsurrounding edema

Enhancing lesion withhypointense capsule and

surrounding edema

Ring enhancing lesion withsurrounding edema

Bacterial Abscess: Imaging

Images from Zimmerman, RD. Clinical MR Neuroimaging. pg 355

Jonathan Waks, MSIIIGilli Li b MD


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Lymphoma vs. ToxoplasmosisToxoplasmosis and primary CNS lymphoma are the two most commonbrain lesions in patients with AIDS, but, as has been shown, both canhave very similar clinical features and appearance on CT and MRI.

The definitive diagnosis is usually provided by brain biopsy, but biopsyis not a benign procedures and is associated with possible morbidity

and mortality. (8.4% morbidity, 2.9% mortality)1

Delay in diagnosis while waiting to see if a patient responds to initial

therapy is a significant problem:2

lesions can rapidly progress.

unnecessary therapies are associated with unnecessary toxicity.

Incorrect initial treatment may result in a biopsy that could have

potentially been prevented.

1. Doweiko, UpToDate

2. Fillipi, Clinical MR Neuroimaging. Pg 420



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Lymphoma vs. Toxoplasmosis: Patient 5

Contrast head CT of a 38 year old woman withAIDS and a ring-enhancing lesion presumed to

be toxoplasmosis

Same patients contrast head CT after 2weeks of anti-Toxo antibiotics and no

improvement. Biopsy 2 days laterconfirmed primary CNS lymphoma


The lesion has significantlyincreased in size over 2 weeks



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The appearance of a CNS lesionmay give clues as to the diagnosis:

Jonathan Waks, MSIIIGillian Lieberman MD


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Lymphoma vs. Toxoplasmosis: Features

Favors Lymphoma Favors Toxoplasma

1. Large lesion size (>4 cm)

2. Extensive white matterinvolvement

3. Periventricular location/subependymal spread

4. Contrast enhancement along

ventricular surface

5. Extension across orinvolvement of corpuscallosum

1. Large number of lesions

2. Involvement of basalganglia

3. Hemorrhagic lesions

4. Responds to anti-Toxodrugs, usually within 7-14

days

BUT in practice, thesefeatures are unreliable inmaking the correct diagnosis




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Diffusion Weighted Imaging is onespecific application of MRI that hasattempted to distinguish ring-enhancinglesions:



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Can Diffusion Weighted Imaging be used to differentiate toxoplasmosisfrom CNS lymphoma?

Data is inconsistent.

In general:1

* Toxoplasmosis tendsto be hyperintense on DWI and hypointense on ADC

This corresponds with RESTRICTED DIFFUSION

* CNS lymphoma tendsto be hypointense on DWI and hyperintense on ADC

This corresponds with INCREASED DIFFUSION

BUT, there is a broad, overlapping range of diffusion values for both lesions,and both conditions can show either increased or restricted diffusion. As of now,DWI/ADC cannot accurately distinguish toxoplasmosis from CNS lymphoma.

DWI/ADC is useful for identifying pyogenic abscesses which are moreconsistently hyperintense on DWI and hypointense on ADC (restricted diffusion)

Diffusion Weighted Imaging

1. Fillipi. Clinical MR Neuroimaging pg 408-420



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Diffusion Weighted Imaging: Examples

DWI ADC

Patient 6:proven Bacterial Abscess

Patient 7:proven Toxoplasmosis

Lesion does NOTshow restricted

diffusion in the center

Hyperintense lesion withrestricted diffusion

Images from Zimmerman. Clinical MR Neuroimaging pg 355, 366

DWI

Restricted Diffusion

Hyperintense Hypointense

Surrounding edema

Toxo. does not consistently show restricteddiffusion, even in the same patient!



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Lymphoma vs. Toxoplasmosis

Nuclear medicine offers other methods for differentiating

between infectious and neoplastic lesions

FDG-PET scan Thallium 201 SPECT

Image from http://upload.wikimedia.org/wikipedia/commons/c/c6/PET-image.jpg



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Image from http://www.scq.ubc.ca/?p=474

Patients are given trace amounts of FDG ([18F]2-Fluoro-2-Deoxy-D-Glucose), a radioactiveform of glucose that enters and becomes trappedin metabolically active cells. The concentrationof FDG in tissue is directly proportional to itsmetabolic activity

http://www.biomedpet.org/howitworks.cfm

FDG undergoes -decay

-particles collide with electrons after traveling

only a few mm. The collision produces 2gamma rays which are detected and producepart of an image.

FDG-Positron Emission Tomography



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FDG-Positron Emission Tomography

Lymphoma:

HIGH metabolic activity

Toxoplasmosis/other infections:

LOW metabolic activity

Lesion is hypometabolic on FDG-PET Lesion is hypermetabolic on FDG-PET

Images from Love C, Radiographics 2005;25(5):1357-68.

T1 + Gad FDG-PET T1 + Gad FDG-PET

FDG-PET can distinguish infectious lesions from neoplastic lesions



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Thallium 201 SPECTPET scanning is not widely available and is more expensive than SPECT (Single Photon EmissionComputed Tomography) because the isotopes used in PET scanning have short half-lives.

201Tl behaves like K+ and enters living cells via the Na+/K+ ATPase. It does not accumulate in

necrotic/dead tissue and thus provides another method of potentially differentiating neoplasticfrom infectious lesions

201Tl decays via the production of single photons which can be detected and imaged.

Images from Antinori A, J Clin Oncol 1999;17(2):554-60.

T1 MRI of the brainshows an

inhomogeneouslyenhancing lesionlater shown to beCNS lymphoma atbiopsy

201Tl SPECT scanshows a focal areaof thallium uptakecorresponding to theneoplastic lesion

Patient 8:



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,

Patient JL -- Follow-up

Brain biopsy at OSH was not diagnostic:Few WBC

No bacteria/organisms via Gram stain or cultureNo signs of lymphoma.

Toxo antibodies negative Toxo PCR of CSF negative EBV PCR of CSF negative

Found to have multiple abscesses throughoutbody and later found to be bacteremic



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,

Widespread bacterial infection and restricted diffusion onDWI/ADC suggested abscess.

Restarted on broader spectrum antibiotics to coverbacteria and toxoplasmosis.

CNS lesions began to decrease in size

Diagnosis: favored bacterial abscess, althoughtoxoplasmosis could not be ruled out

BIDMC, PACS

Patient JL -- Follow-up


Patient JL: Imaging over the course of 2 months of treatment


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,

T1 MRI

w/ Gad

T1 MRIw/ Gad

T1 MRIw/ Gad

BIDMC, PACS

Time

Admission

s/p treatmentfor 1 month

s/p treatmentfor 2 months



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Summary

CNS complications are extremely common in patientswith AIDS.

The 2 most common CNS lesions in AIDS patients aretoxoplasmosis and primary CNS lymphoma.

Lesions are often treated empirically, but delay indefinitive diagnosis can have significant consequences.

MRI and nuclear medicine offer non-invasive methods tofacilitate the identification of CNS lesions withoutinvasive biopsy

Jonathan Waks, MSIIIGillian Lieberman, MD References


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1. Antinori A, De Rossi G, Ammassari A, et al. Value of combined approach with thallium-201 single-photon emission computed tomographyand Epstein-Barr virus DNA polymerase chain reaction in CSF for the diagnosis of AIDS-related primary CNS lymphoma. J Clin Oncol

1999;17(2):554-60.

2. Chang, Linda and Thomas Ernst. Physciological MR to evaluate HIV-associated brain disorders. Clinical MR Neuroimaging. Ed.Jonathan Gillard et al. Cambridge: Cambridge University Press, 2005. 460-478.

3. Doweiko JP, Groopman JE. AIDS-related lymphomas: Primary central nervous system lymphoma. UpToDate. www.uptodate.comAccessed 3/14/07

4. Fillipi, Christopher G. The role of diffusion-weighted imaging in intracranial infection. Clinical MR Neuroimaging. Ed. Jonathan Gillard etal. Cambridge: Cambridge University Press, 2005. 408-428.

5. Gamut A-61 Ring-enhancing Lesion on CT or MRI. Reeder And Felson's Gamuts In Radiology. Ed. Maurice Reeder. NewYork: Springer, 2003. Accessed electronically.

6. How does PET work? PET Imaging Center 2005. http://www.biomedpet.org/howitworks.cfm. Accessed 3/18/07.

7. Koralnik, IJ, Approach to HIV-Infected patients with central nervous system lesions. UpToDate. www.uptodate.com Accessed 3/14/07

8. Love, C et al. FDG PET of infection and inflammation. Radiographics. 2005; 25, 5: 1357-1367.

9. Netter, Frank H. Atlas of Human Anatomy, 3rd Edition. Teterboro: Icon Learning Systems, 2004.

10. Provenzale JM, Jinkins JR. Brain and spine imaging findings in AIDS patients. Radiol Clin North Am. 1997 Sep;35(5):1127-66.

11. Stadnik, Tadeusz et al. Diffusion imaging: from basic physics to practical imaging 1998 RSNA Scientific Assembly.http://ej.rsna.org/ej3/0095-98.fin/index.htm. Accessed on 3/16/07.

12. Thurnher MM, Thurnher SA, Schindler E. CNS involvement in AIDS: spectrum of CT and MR findings. Eur Radiol1997;7(7):1091-7.

13. Toxoplasmosis. Laboratory Identification of Parasites of Public Health Concern.http://www.dpd.cdc.gov/dpdx/HTML/Toxoplasmosis.htm. Accessed on 3/18/07.

14. Zimmerman, Robert D. Physiological imaging in infection, inflammation and demyelination: overview. Clinical MR Neuroimaging. Ed.Jonathan Gillard et al. Cambridge: Cambridge University Press, 2005. 353-379.



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Acknowledgements:

Mizuki Nishino, MD

Gillian Lieberman, MDPamela Lepkowski

Larry Barbaras, Webmaster

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