ring enhancing lesions in a patient with...

Jonathan Waks, MSIIIGillian Lieberman, MD

Ring Enhancing Lesions in a Patient with AIDS

Jonathan Waks, Harvard Medical School Year IIIGillian 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 symptoms

when they first present with AIDS.• 30-60% of patients with AIDS will develop neurological

complications during the course of their illness.• 70-90% of patients with AIDS show CNS involvement at

autopsy.

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

Understanding and recognizing the appearance of CNS complications in patients with AIDS is important in promptly recognizing, diagnosing and initiating proper treatment.

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DDx. of CNS complications of AIDS:

1. HIV encephalitis2. 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, on

HAART) who presented to an OSH for unsteady gait, lower extremity weakness, headache, vomiting, dysarthria and seizures.

• PE:– Temp: 102.4ºF– Multiple CN deficits

• Head CT showed multiple ring enhancing lesions• Started on broad spectrum antibiotics with coverage

for 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 at BIDMC, let’s first review the radiologic modalities that can be used to evaluate the CNS in a patient with AIDS.

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Menu of Radiologic TestsPrimary 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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Menu of Radiologic TestsPrimary 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 are not used in the routine imaging or evaluation of CNS lesions in patients with AIDS. They are primarily used when the identity of a lesion is in question and additional non-invasive imaging would potentially alter treatment. PET and SPECT scanning are used most frequently. MR spectroscopy and perfusion MR are not routinely used and will not be discussed in this presentation.

Adjunctive imaging modalities will be discussed later on in the presentation

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Menu of Radiologic Tests

1. Fast

2. Readily available

3. Can scan people with contraindications to MRI

1. Less sensitive than MRI

2. Limited evaluation of posterior fossa

3. Can miss some white matter disease

4. Brain radiation

BIDMC, PACS

Computed Tomography:

Pros Cons

Normal Head CT

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Menu of Radiologic TestsMagnetic Resonance Imaging:

Pros Cons1. Better than CT at determining if a

lesion truly is solitary

2. Increased sensitivity to subtle white matter disease and posterior fossa lesions

3. May be able to identify small peripheral lesions missed by CT that are more accessible for biopsy

4. No radiation

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

1. More costly, less readily available

** MRI is the BEST test to assess 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 to image local water diffusion. Macromolcules and cells in the brain restrict the diffusion of water.

Areas of restricted diffusion appear BRIGHT on DWI

Apparent Diffusion Coefficient (ADC): The signal intensity of DWI depends on factors other than diffusion information (spin density, TR, TE). By combining multiple DWIs, these other factors can be eliminated. ADC also eliminates “T2-Shine through” on DWI caused by 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 MRI post gadolinium

Images provided by Mizuki Nishino, MD; BIDMC

Axial T1WI MRIpre gadolinium

Multiple ring enhancing Lesions throughout CNS

=

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Looking at additional MRI sequences allows us to better characterize the center of the lesion and surrounding tissue.

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Jonathan Waks, MSIIIGillian Lieberman, MD Imaging: “JL”

AxialDWI MRI

Axial T1 MRI +Gad

AxialFLAIR MRI +Gad

AxialADC Map

Images provided by Mizuki Nishino, MD; BIDMC, PACS

Hyperintense on DWI = restricted diffusion

Hypo/isointense lesion with ring enhancement

Enhancing lesion surrounded by

hyperintense edema

Hypointense on ADC = restricted diffusion

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There is a well defined differential diagnosis for ring enhancing lesions in the CNS:

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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 lesions

•Resolving infarction

•Hematoma

•Thrombosed aneursm

•Radiation necrosis

•Postoperative changes Gamuts in Radiology, online editionImages from Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66.

*

*

*

**

Head CT with contrastHead T1WI w/ contrast

Head CT with contrast

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•Infection:

•Toxoplasma

•Cystercercosis

•Brain abscess (bacterial, fungal)

•Neoplasms

•Brain tumors/metastases

•Primary CNS Lymphoma

•Demyelinating Disease

•MS

•ADEM

•Vascular lesions

•Resolving infarction

•Hematoma

•Thrombosed aneursm

•Radiation necrosis

•Postoperative changes Gamuts in Radiology, online editionImages from Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66.

When we consider which of these entities are common in patients with AIDS (see slide 4 for a refresher), the differential narrows, and we can focus on Toxoplasmosis, brain abscess and primary CNS lymphoma

DDx. Ring Enhancing Lesions ( )*

*

*

**

Head CT with contrastHead T1WI w/ contrast

Head CT with contrast

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We will now explore the narrowed differential in more detail.

1. Toxoplasmosis

2. Primary CNS Lymphoma

3. Bacterial brain abscess

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Toxoplasmosis: Background• Intracellular protazoan parasite, toxoplasma gondii• Most common opportunistic infection in HIV (CD4 < 100 per μL)

• 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 definitive diagnosis.

• Treatment: Pyrimethamine and sulfadiazine or clindamycin

Image from http://cal.vet.upenn.edu/paraav/images/10-43.jpg

1. Fillipi. Clinical MR Neuroimaging, pg 420.

Micrograph of T. gondii

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

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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 and become infected by ingesting tissue cysts. The cysts reproduce inside the feline intestinal tract.

Oocysts are shed in fecal matter and are extremely resistant to severe environmental conditions and disinfectants.

Humans become infected by either:•Eating tissue cysts in undercooked meat

•Fecal-oral transmission from cat feces

•Blood or organ transplantation

•Transplacentally

Approximately 22.5% of people in the United States are infected.

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Toxoplasmosis: Sites of Infection

• Most common sites of infection are:– Cortico-medullary junction– Basal ganglia– Thalamus

Image from Netter, 2004, plate 104.Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66.

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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 to inflammatory response (patients with decimated immune systems 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.

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• MRI:– Usually shows more lesions than CT– T1WI: hypointense or isointense to gray

matter– T2WI/FLAIR: isointense or hyperintense to

gray matter

– ring enhancing, sometimes with a central focus of enhancement “target sign”.

Toxoplasmosis: Imaging

Zimmerman, RD. Clinical MR Neuroimaging. pg 365

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Toxoplasmosis Lesions

T2 MRI, non-contrast T1 MRI w/ contrast

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

Head CT w/ contrast

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

Patient 1Patient 2

Hypodense, ring enhancing lesion and surrounding edema Hyperintense,

enhancing lesionHypointense, ring enhancing lesion

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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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Primary CNS Lymphoma: Sites of Infection

• Most commonly located in:– periventricular/periependymal

white matter

– corpus callosum

Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66.Illustrations from Netter, 2004, Plates 100, 104. BIDMC, PACS

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Primary CNS Lymphoma: Imaging

• CT:– Isodense to Hypodense

• MR:– T1: hypointense– T2/FLAIR: isointense to hyperintense

– Enhancement: usually irregular enhancement or ring enhancement.

Chang. Clinical MR Neuroimaging. pg 466

Doweiko, UpToDate

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Primary CNS Lymphoma can have a wide range of appearances:

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Primary CNS Lymphoma: Varying Lesions

T1WI +Gad.

Right Image from Doweiko, UpToDate

T1WI +Gad.Hypointense lesion with

ring enhancementHomogenously enhancing 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 mental

status, 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 toxoplasmosis or 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 with hypointense capsule and

surrounding edema

Ring enhancing lesion with surrounding edema

Bacterial Abscess: Imaging

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

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

The definitive diagnosis is usually provided by brain biopsy, but biopsy is 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 with AIDS and a ring-enhancing lesion presumed to be toxoplasmosis

Same patient’s contrast head CT after 2 weeks of anti-Toxo antibiotics and no improvement. Biopsy 2 days later confirmed primary CNS lymphoma

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

The lesion has significantly increased in size over 2 weeks

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

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Lymphoma vs. Toxoplasmosis: Features

Favors Lymphoma Favors Toxoplasma1. Large lesion size (>4 cm)

2. Extensive white matter involvement

3. Periventricular location/ subependymal spread

4. Contrast enhancement along ventricular surface

5. Extension across or involvement of corpus callosum

1. Large number of lesions

2. Involvement of basal ganglia

3. Hemorrhagic lesions

4. Responds to anti-Toxo drugs, usually within 7-14 days

BUT in practice, these features are unreliable in making the correct diagnosis


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Diffusion Weighted Imaging is one specific application of MRI that has attempted to distinguish ring-enhancing lesions:

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Can Diffusion Weighted Imaging be used to differentiate toxoplasmosis from CNS lymphoma?

Data is inconsistent.In general:1

* Toxoplasmosis tends to be hyperintense on DWI and hypointense on ADC

This corresponds with RESTRICTED DIFFUSION

* CNS lymphoma tends to 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 more consistently 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 NOT show restricted

diffusion in the center

Hyperintense lesion with restricted diffusion

Images from Zimmerman. Clinical MR Neuroimaging pg 355, 366

DWI

Restricted Diffusion

Hyperintense Hypointense

Surrounding edema

Toxo. does not consistently show restricted diffusion, 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 radioactive form of glucose that enters and becomes trapped in metabolically active cells. The concentration of FDG in tissue is directly proportional to its metabolic activity

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

FDG undergoes β-decay

β-particles collide with electrons after traveling only a few mm. The collision produces 2 gamma rays which are detected and produce part 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 Emission Computed 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 neoplastic from 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 brain shows an inhomogeneously enhancing lesion later shown to be CNS lymphoma at biopsy

201Tl SPECT scan shows a focal area of thallium uptake corresponding to the neoplastic 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 culture– No signs of lymphoma.

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

• Found to have multiple abscesses throughout body and later found to be bacteremic

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• Widespread bacterial infection and restricted diffusion on DWI/ADC suggested abscess.

• Restarted on broader spectrum antibiotics to cover bacteria and toxoplasmosis.

• CNS lesions began to decrease in size

• Diagnosis: favored bacterial abscess, although toxoplasmosis could not be ruled out

BIDMC, PACS

Patient “JL” -- Follow-up

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T1 MRIw/ Gad

T1 MRIw/ Gad

T1 MRIw/ Gad

BIDMC, PACS

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

Time

Admission

s/p treatment for 1 month

s/p treatment for 2 months

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Summary• CNS complications are extremely common in patients

with AIDS.

• The 2 most common CNS lesions in AIDS patients are toxoplasmosis and primary CNS lymphoma.

• Lesions are often treated empirically, but delay in definitive diagnosis can have significant consequences.

• MRI and nuclear medicine offer non-invasive methods to facilitate the identification of CNS lesions without invasive biopsy

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Jonathan Waks, MSIIIGillian Lieberman, MD References

1. Antinori A, De Rossi G, Ammassari A, et al. Value of combined approach with thallium-201 single-photon emission computed tomography and 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.com Accessed 3/14/07

4. Fillipi, Christopher G. “The role of diffusion-weighted imaging in intracranial infection.” Clinical MR Neuroimaging. Ed. Jonathan Gillard et al. 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. New York: 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 Radiol 1997;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, MD

Pamela Lepkowski

Larry Barbaras, Webmaster

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