analog in the treatment of lymphoproliferative disorders: results of aphase II north central cancer treatment group trial. J Clin Oncol.1995;13:2012–2015.

3. Wotherspoon AC, Doglioni C, Diss TC, et al. Regression of primarylow-grade B-cell gastric lymphoma of mucosa-associated lymphoidtissue after eradication of Helicobacter pylori. Lancet. 1993;342:575–577.

4. Stanisz AM, Befus D, Bienenstock J. Differential effects of vasoactiveintestinal peptide, substance P and somatostatin on immunoglobu-lin synthesis and proliferation by lymphocytes from Peyer’s patches,mesenteric lymph nodes, and spleen. J Immunol. 1986;136:152–156.

5. Reubi JC, Horisberger U, Waser B, et al. Preferential location ofsomatostatin receptors in germinal centers of human gut lymphoidtissue. Gastroenterology. 1992;103:1207–1214.

6. Okazaki K, Morita M, Yamamoto Y. Gene rearrangements, Helico-bacter pylori, and gastric MALT lymphoma. Lancet. 1994;343:1636.

7. Hussel T, Isaacson PG, Crabtree JE, Spencer J. The response of cellsfrom low-grade B-cell gastric lymphomas of mucosa-associated lym-phoid tissue to Helicobacter pylori. Lancet. 1993;342:571–574.

8. Kaneko H, Nakada K, Mitsuma T, et al. Helicobacter pylori infectioninduces a decrease in immunoreactive-somatostatin concentrationof human stomach. Dig Dis Sci. 1992;37:409 – 416.

From the Department of Gastroenterology and Hepatology (TM, HF, TC),Graduate School of Medicine, Kyoto University, Kyoto; Second Depart-ment of Internal Medicine (YK), Shimane Medical University, Izumo;Division of Gastrointestinal Oncology and Endoscopy (SM), NationalCancer Center Hospital, East, Kashiwa; Department of Radiology (SH);and Third Department of Internal Medicine (KC), Kobe University Schoolof Medicine, Kobe; and Second Department of Pathology (TF), DokkyoUniversity School of Medicine, Mibu, Japan.

Correspondence should be addressed to Tsutomu Chiba, MD, PhD, De-partment of Gastroenterology and Hepatology, Graduate School of Medi-cine, Kyoto University, 54 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-01, Japan.

Manuscript submitted December 12, 1997, and accepted in revisedform August 20, 1998.

Enhancing ProgressiveMultifocalLeukoencephalopathy: AnIndicator of ImprovedImmune Status?Nilesh Kotecha, MD, Marie J. George, MD,Thomas W. Smith, MD, Francisco Corvi, MD,N. Scott Litofsky, MD

Progressive multifocal leukoencephalopathy (PML)occurs in 1% to 4% of patients with acquired im-munodeficiency syndrome (AIDS) (1– 4). Its over-

all prognosis is poor, primarily because of the lack of ef-fective therapy (4).

Although PML usually appears radiographically as sin-gle or multiple cerebral white matter lesions with mini-mal mass effect and no intravenous contrast enhance-

ment (5–10), contrast-enhancing PML may occur (11–18). Enhancement has not subsequently developed overtime, however. We observed a patient in whom contrastenhancement of a PML lesion developed relatively late inthe clinical course of AIDS, after institution of highly ac-tive antiretroviral therapy.

CASE REPORT

A 42-year-old man with new-onset seizures was diag-nosed with AIDS (CD-4 count 58 cells/mL). Viral loadwas not determined at that time. An initial contrast en-hanced computed tomography scan of the brain showedan unenhancing low-density lesion in the left parietallobe. The patient was started on zidovudine (AZT), andshortly thereafter on a highly active antiretroviral treat-ment (stavudine, lamivudine, and indinavir). After an-other seizure 2 months later, a not-enhanced magneticresonance image of the brain demonstrated enlargementof the lesion, and the patient was transferred to our hos-pital for a possible stereotactic brain biopsy.

The patient was disoriented, and had expressive andreceptive aphasia, a right central cranial nerve VII paresis,and a right pronator drift with diffusely brisk reflexes. Hehad oral thrush. With highly active antiretroviral treat-ment, his white blood cell count improved to 320/mL andhis CD-4 count was 375 cells/mL.

A repeat cranial magnetic resonance scan revealed alarge area of confluent T-2 hyperintensity in the left pa-rietal and posterior temporal white matter extending tothe subcortical region with mild mass effect on the occip-ital horn of the left lateral ventricle. Moderate gadoliniumenhancement of the medial portion of the lesion wasnoted (Figure 1). The radiologic differential diagnosis in-cluded lymphoma, atypical PML, toxoplasmosis, otherAIDS-related inflammatory lesions, and non-AIDS–re-lated tumors.

Two targets were selected for stereotactic biopsy— onefrom the lesion’s hypodense center and a second from itsenhancing portion (Figure 2). Specimens from each tar-get showed the same general pathologic process, consist-ing of extensive demyelination with relative axonal pres-ervation and lymphoplasmacytic inflammation (Figure3). The tissue from the contrast-enhancing region dem-onstrated more prominent perivascular mononuclear in-flammation and occasional enlarged oligodendrocytesthat were immunoreactive for papovavirus antigen. Im-munostains for hematopoietic cell markers showed thatthe perivascular cells consisted mainly of CD31 T lym-phocytes (50% to 60%) and CD681 monocytes (30% to40%), with a small number of CD201 B lymphocytes andplasma cells (5% to 10%). Approximately 10% to 20% ofthe perivascular T cells were CD81. Within the paren-chyma, most cells were CD681 macrophages, although a

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moderate number of CD31 T cells (mostly CD81) and apolyclonal (kappa/lambda1) population of plasma cellswere also present.

The patient was continued on his highly active antiret-roviral therapy and discharged to a chronic care facility.Six months after biopsy, his viral load was 5,000 copies/mL. He has remained neurologically stable and medicallywell 1 year after biopsy, with a CD-4 count of 412cells/mL and viral load of 1,430 copies/mL.

DISCUSSION

An unusual and prominent histologic feature in this pa-tient with radiographically enhancing PML was the pres-ence of scattered lymphocytes and plasma cells within thelesion. Atypical PML lesions with lymphoplasmacytic in-filtrates may represent an enhanced host resistanceagainst the disease that is associated with a less severeclinical course (20). In our patient, the unenhancing re-gion of the lesion demonstrated more advanced patho-logic changes, whereas the enhancing region demon-strated more prominent perivascular mononuclear in-flammation. In another patient with PML, theperivascular inflammation was greatest in the contrast-enhancing region (17), suggesting a close association be-tween perivascular inflammation and altered vascularpermeability (22), perhaps related to the action of cyto-

kines produced by leukocytes and astrocytes on capillaryendothelial cells (23).

It is not known why only some cases of PML lesionsexhibit prominent perivascular infiltration and contrastenhancement. The patient reported by Woo et al (17),had a CD-4 count of 260 cells/mL, suggesting that pa-tients with less severe AIDS may have a better inflamma-tory reaction. Our patient originally had a CD-4 count of

Figure 1. Axial T1-weighted gadolinium enhanced cranialmagnetic resonance image demonstrating peripheral enhance-ment of the lesion with central low density.

Figure 2. Stereotactic targeting computerized tomographicscan of the head showing the contrast enhancing ring with tar-get indicated (1).

Figure 3. Photomicrograph of the left parietal stereotactic bi-opsy corresponding to the enhancing target showing plasmacells and occasional small lymphocytes scattered among thelarger foamy macrophages and reactive astrocytes within thelesion. Hemotoxylin and eosin stain 3 150.

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542 December 1998 THE AMERICAN JOURNAL OF MEDICINEt Volume 105

58 cells m/L, compatible with more advanced AIDS.However, he had substantial improvement in his CD-4count with highly active antiretroviral treatment beforethe development of enhancement in his PML lesion. Thiscase supports the contention that enhancement in PMLresults from improved immunocompetence. One wouldexpect to see enhancing PML lesions either earlier in thecourse of AIDS or after successful treatment with antiret-roviral agents. Furthermore, enhancing PML lesions maydenote a more favorable prognosis (17).

The prognosis of patients with AIDS and PML has beenimproved by advances in antiretroviral therapy. Clinicaland radiographic remission of PML has been reported inconjunction with reconstitution of immunity with anti-retroviral agents (24 –29). Enhancement in PML mayrepresent an early feature of this immune reconstitution.

This case emphasizes the need to obtain histologic con-firmation of either hypointense or hyperintense lesionswith enhancement in HIV-positive patients. PML shouldbe included in the differential diagnosis, even with a con-trast-enhancing lesion. Patients with contrast-enhancingPML may have a relatively favorable course.

ACKNOWLEDGMENTSThe authors thank Mary Bard for her assistance in the prepara-tion of this manuscript. We also thank Richard Ellison, MD, forhis helpful comments.

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From the Divisions of Neurosurgery (NK, NSL) and Infectious Diseases(MJG) and the Department of Pathology (TWS), University of Massachu-setts Medical School, Worcester, Massachusetts; and Lowell CommunityHealth Center (FC), Lowell, Massachusetts.

Correspondence should be addressed to N. Scott Litofsky, MD, Divisionof Neurosurgery, University of Massachusetts Medical School, 55 Lake Av-enue North, Worcester, Massachusetts 01655.

Manuscript submitted January 20, 1998, and accepted in revised formAugust 24, 1998.

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