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Jonathan Waks, MSIII Gillian Lieberman, MD March 2007 Ring Enhancing Lesions in a Patient with AIDS Jonathan Waks, Harvard Medical School Year III Gillian Lieberman, MD Jonathan Waks, MSIII Gillian Lieberman, MD Agenda • • • • • • Background: CNS complications of AIDS Patient presentation Menu of radiologic tests Differential diagnosis: ring enhancing lesions Differentiating CNS lesions Summary 2 Jonathan Waks, MSIII Gillian Lieberman, MD 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. Understanding and recognizing the appearance of CNS complications in patients with AIDS is important in promptly recognizing, diagnosing and initiating proper treatment. Thurnher MM. Eur Radiol 1997;7(7):1091-7 3 Jonathan Waks, MSIII Gillian Lieberman, MD DDx. of CNS complications of AIDS: 1. 2. HIV encephalitis Opportunistic Infections: • • • • • • • 3. Toxoplasmosis Cryptococcosis CMV TB PML (JC virus) Bacterial Fungal Neoplasm • • HIV-1 Virus http://www.niaid.nih.gov/factsheets/howhiv.htm Primary CNS lymphoma Kaposis Sarcoma Thurnher MM. Eur Radiol 1997;7(7):1091-7 4 Jonathan Waks, MSIII Gillian Lieberman, MD 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 Æ Brain biopsy: non diagnostic • Transferred to BIDMC for further management. 5 Jonathan Waks, MSIII Gillian Lieberman, MD 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. 6 Jonathan Waks, MSIII Gillian Lieberman, MD 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 7 Jonathan Waks, MSIII Gillian Lieberman, MD 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 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 8 Jonathan Waks, MSIII Gillian Lieberman, MD Menu of Radiologic Tests Computed Tomography: Pros Cons 1. Fast 1. Less sensitive than MRI 2. Readily available 2. Limited evaluation of posterior fossa 3. Can scan people with contraindications to MRI 3. Can miss some white matter disease 4. Brain radiation Normal Head CT BIDMC, PACS 9 Jonathan Waks, MSIII Gillian Lieberman, MD Menu of Radiologic Tests Magnetic Resonance Imaging: Pros Cons 1. Better than CT at determining if a lesion truly is solitary 1. More costly, less readily available 2. Increased sensitivity to subtle white matter disease and posterior fossa lesions ** MRI is the BEST test to assess CNS 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) Normal T1 and T2 MRI BIDMC, PACS 10 Jonathan Waks, MSIII Gillian Lieberman, MD 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 11 Jonathan Waks, MSIII Gillian Lieberman, MD Imaging: “JL” Axial T1WI MRI pre gadolinium = Multiple ring enhancing Lesions throughout CNS Axial T1WI MRI post gadolinium Images provided by Mizuki Nishino, MD; BIDMC 12 Jonathan Waks, MSIII Gillian Lieberman, MD Looking at additional MRI sequences allows us to better characterize the center of the lesion and surrounding tissue. 13 Jonathan Waks, MSIII Gillian Lieberman, MD Imaging: “JL” Axial T1 MRI +Gad Hypo/isointense lesion with ring enhancement Axial DWI MRI Hyperintense on DWI = restricted diffusion Images provided by Mizuki Nishino, MD; BIDMC, PACS Axial FLAIR MRI +Gad Enhancing lesion surrounded by hyperintense edema Axial ADC Map Hypointense on ADC = restricted diffusion 14 Jonathan Waks, MSIII Gillian Lieberman, MD There is a well defined differential diagnosis for ring enhancing lesions in the CNS: 15 Jonathan Waks, MSIII Gillian Lieberman, MD DDx. Ring Enhancing Lesions (*) •Infection: Head T1WI w/ contrast Head CT with contrast •Toxoplasma •Cystercercosis * •Brain abscess (bacterial, fungal) •Neoplasms * •Brain tumors/metastases •Primary CNS Lymphoma •Demyelinating Disease Head CT with contrast •MS •ADEM •Vascular lesions •Resolving infarction * * •Hematoma •Thrombosed aneursm •Radiation necrosis •Postoperative changes Gamuts in Radiology, online edition Images from Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66. 16 Jonathan Waks, MSIII Gillian Lieberman, MD DDx. Ring Enhancing Lesions (*) •Infection: Head T1WI w/ contrast Head CT with contrast •Toxoplasma •Cystercercosis * •Brain abscess (bacterial, fungal) •Neoplasms * •Brain tumors/metastases •Primary CNS Lymphoma •Demyelinating Disease Head CT with contrast •MS When we consider which of these •ADEM entities are common in patients with AIDS•Vascular (see slide 4 for a refresher), lesions the differential narrows, and we can •Resolving infarction focus on Toxoplasmosis, brain •Hematoma abscess and primary CNS lymphoma * * •Thrombosed aneursm •Radiation necrosis •Postoperative changes Gamuts in Radiology, online edition Images from Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66. 17 Jonathan Waks, MSIII Gillian Lieberman, MD We will now explore the narrowed differential in more detail. 1. Toxoplasmosis 2. Primary CNS Lymphoma 3. Bacterial brain abscess 18 Jonathan Waks, MSIII Gillian Lieberman, MD Image from http://cal.vet.upenn.edu/paraav/images/10-43.jpg Toxoplasmosis: Background Micrograph of T. gondii • • 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 Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66. 1. Fillipi. Clinical MR Neuroimaging, pg 420. 19 Jonathan Waks, MSIII Gillian Lieberman, MD Toxoplasmosis: Life cycle 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. Image and information from http://www.dpd.cdc.gov/dpdx/HTML/Toxoplasmosis.htm 20 Jonathan Waks, MSIII Gillian Lieberman, MD 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. 21 Jonathan Waks, MSIII Gillian Lieberman, MD Toxoplasmosis: Imaging • 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 1. Koralnik, UpToDate 2. Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66. 22 Jonathan Waks, MSIII Gillian Lieberman, MD Toxoplasmosis: Imaging • 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”. Zimmerman, RD. Clinical MR Neuroimaging. pg 365 23 Images from Thurnher MM. Eur Radiol 1997;7(7):1091-7 Jonathan Waks, MSIII Gillian Lieberman, MD Toxoplasmosis Lesions Below are 2 patients with CNS lesions that were subsequently shown to be toxoplasmosis. Patient 2 Patient 1 Head CT w/ contrast Hypodense, ring enhancing lesion and surrounding edema T2 MRI, non-contrast T1 MRI w/ contrast Hyperintense, enhancing lesion Hypointense, ring enhancing lesion 24 Jonathan Waks, MSIII Gillian 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 Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66. 25 Jonathan Waks, MSIII 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. Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66. BIDMC, PACS 26 Jonathan Waks, MSIII Gillian Lieberman, MD Primary CNS Lymphoma: Imaging • CT: – Isodense to Hypodense • MR: – T1: hypointense – T2/FLAIR: isointense to hyperintense – Enhancement: usually irregular enhancement or ring enhancement. Doweiko, UpToDate Chang. Clinical MR Neuroimaging. pg 466 27 Jonathan Waks, MSIII Gillian Lieberman, MD Primary CNS Lymphoma can have a wide range of appearances: 28 Jonathan Waks, MSIII Gillian Lieberman, MD Primary CNS Lymphoma: Varying Lesions 2 different patients with lesions subsequently shown to be primary CNS lymphoma Patient 3 T1WI +Gad. Hypointense lesion with ring enhancement Left image from Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66. Patient 4 T1WI +Gad. Homogenously enhancing lesion Right Image from Doweiko, UpToDate 29 Jonathan Waks, MSIII Gillian Lieberman, MD 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 30 Jonathan Waks, MSIII Gillian Lieberman, MD Bacterial Abscess: Imaging T1 MRI, no contrast Hypointense lesion with surrounding edema T2 MRI w/ contrast T1 MRI +Gad Enhancing lesion with hypointense capsule and surrounding edema Ring enhancing lesion with surrounding edema Images from Zimmerman, RD. Clinical MR Neuroimaging. pg 355 31 Jonathan Waks, MSIII Gillian Lieberman, MD Lymphoma vs. Toxoplasmosis Toxoplasmosis 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 32 Jonathan Waks, MSIII Gillian Lieberman, MD Lymphoma vs. Toxoplasmosis: Patient 5 The lesion has significantly increased in size over 2 weeks Contrast head CT of a 38 year old woman with AIDS and a ring-enhancing lesion presumed to be toxoplasmosis Images from Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66. Same patient’s contrast head CT after 2 weeks of anti-Toxo antibiotics and no improvement. Biopsy 2 days later confirmed primary CNS lymphoma 33 Jonathan Waks, MSIII Gillian Lieberman, MD The appearance of a CNS lesion may give clues as to the diagnosis: 34 Jonathan Waks, MSIII Gillian Lieberman, MD Lymphoma vs. Toxoplasmosis: Features Favors Lymphoma Favors Toxoplasma 1. Large lesion size (>4 cm) 1. Large number of lesions 2. Extensive white matter involvement 2. Involvement of basal ganglia 3. Periventricular location/ subependymal spread 3. Hemorrhagic lesions 4. Contrast enhancement along ventricular surface 5. Extension across or involvement of corpus callosum Provenzale JM, Radiol Clin North Am 1997;35(5):1127-66. 4. Responds to anti-Toxo drugs, usually within 7-14 days BUT in practice, these features are unreliable in making the correct diagnosis 35 Jonathan Waks, MSIII Gillian Lieberman, MD Diffusion Weighted Imaging is one specific application of MRI that has attempted to distinguish ring-enhancing lesions: 36 Jonathan Waks, MSIII Gillian Lieberman, MD Diffusion Weighted Imaging 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) 1. Fillipi. Clinical MR Neuroimaging pg 408-420 37 Jonathan Waks, MSIII Gillian Lieberman, MD Diffusion Weighted Imaging: Examples Patient 6: proven Bacterial Abscess Surrounding edema Patient 7: proven Toxoplasmosis DWI DWI ADC Hyperintense Hypointense Restricted Diffusion Images from Zimmerman. Clinical MR Neuroimaging pg 355, 366 Lesion does NOT show restricted diffusion in the center Hyperintense lesion with restricted diffusion Toxo. does not consistently show restricted diffusion, even in the same patient! 38 Jonathan Waks, MSIII Gillian Lieberman, MD Lymphoma vs. Toxoplasmosis Nuclear medicine offers other methods for differentiating between infectious and neoplastic lesions FDG-PET scan Image from http://upload.wikimedia.org/wikipedia/commons/c/c6/PET-image.jpg Thallium 201 SPECT 39 Jonathan Waks, MSIII Gillian Lieberman, MD FDG-Positron Emission Tomography 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 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. http://www.biomedpet.org/howitworks.cfm Image from http://www.scq.ubc.ca/?p=474 40 Jonathan Waks, MSIII Gillian Lieberman, MD FDG-Positron Emission Tomography FDG-PET can distinguish infectious lesions from neoplastic lesions Toxoplasmosis/other infections: Lymphoma: LOW metabolic activity HIGH metabolic activity T1 + Gad FDG-PET Lesion is hypometabolic on FDG-PET Images from Love C, Radiographics 2005;25(5):1357-68. T1 + Gad FDG-PET Lesion is hypermetabolic on FDG-PET 41 Jonathan Waks, MSIII Gillian Lieberman, MD Thallium 201 SPECT PET 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. Patient 8: T1 MRI of the brain shows an inhomogeneously enhancing lesion later shown to be CNS lymphoma at biopsy Images from Antinori A, J Clin Oncol 1999;17(2):554-60. 201Tl SPECT scan shows a focal area of thallium uptake corresponding to the neoplastic lesion 42 Jonathan Waks, MSIII Gillian Lieberman, MD 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 43 Jonathan Waks, MSIII Gillian Lieberman, MD Patient “JL” -- Follow-up • 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 44 Jonathan Waks, MSIII Gillian Lieberman, MD Patient “JL”: Imaging over the course of 2 months of treatment Time Admission T1 MRI w/ Gad s/p treatment for 1 month T1 MRI w/ Gad s/p treatment for 2 months T1 MRI w/ Gad BIDMC, PACS 45 Jonathan Waks, MSIII Gillian Lieberman, MD 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 46 Jonathan Waks, MSIII Gillian 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. 47 Jonathan Gillard et al. Cambridge: Cambridge University Press, 2005. 353-379. Jonathan Waks, MSIII Gillian Lieberman, MD Acknowledgements: Mizuki Nishino, MD Gillian Lieberman, MD Pamela Lepkowski Larry Barbaras, Webmaster 48