Cerebral toxoplasmosis is a rare late complication in allogeneic bone marrow transplanted patients. Neuroradiological findings may suggest the correct diagnosis. We report a patient in whom cerebral magnetic resonance imaging (MRI) showed a lesion characteristic of toxoplasmosis. Anti- toxoplasma treatment led to clinical and radiological improvement. MRI seems to be a valid tool for detection and follow-up of cerebral toxoplasmosis

De Rosa G

Di Salle F

Pezzullo L

PICARDI, MARCO

Raiola A

Rotoli B.

Archivio della ricerca - Università degli studi di Napoli Federico II

570 Scientific lettersKey wordsPlasma exchange, cryosupernatant plasma, thromboticthrombocytopenic purpuraCorrspondenceFabrizio Vianello, MD, Institute of Medical Semeiotics,Second Chair of Medicine, Padua University, via Ospedale,105, Padua, Italy. Fax international +39-49-657391 • E-mail: faviane@tin.itReferences1. Byrnes JJ, Moake JL. Thrombotic thrombocytopenicpurpura and the haemolytic-uraemic syndrome: evolv-ing concepts of pathogenesis and therapy. ClinHaematol 1986;15:413-42.2. Rock GA, Shumak KH, Buskard NA, et al. Comparisonof plasma exchange with plasma infusion in the treat-ment of thrombotic thrombocytopenic purpura. NEngl J Med 1991; 325:393-7.3. Ruggenenti P, Remuzzi G.  The pathophysiology andmanagement of thrombotic thrombocytopenic pur-pura. Eur J Haematol 1996; 56:191-207.4. Moake JL, Rudy CK, Troll JH, et al. Unusually largeplasma factor VIII:von Willebrand factor multimers inchronic relapsing TTP. N Engl J Med 1982; 307:1432-5.5. Moake JL, Turner NA, Stathopulos NA, Nolasco L &Hellums JD. Involvement of large plasma von Wille-brand factor (vWF) multimers and unusually largevWF forms derived from endothelial cells in shearstress-induced platelet aggregation. J Clin Invest 1986;78:1456-61.6. Byrnes JJ, Moake JL, Klug P, Periman P.  Effectivenessof the cryosupernatant fraction of plasma in the treat-ment of refractory thrombotic thrombocytopenic pur-pura. Am J Hematol 1990; 34:169-74.7. Rock G, Shumak KH, Sutton DMC, Buskard NA,Rama CN and the members of the Canadian Aphere-sis Group. Cryosupernatant as replacement fluid forplasma exchange in thrombotic thrombocytopenicpurpura. Br J Haematol 1996; 94:383-6.8. Perotti C, Torretta L, Molinari E, Salvaneschi L. Cryo-precipitate-poor plasma fraction (cryosupernatant) inthe treatment of thrombotic thrombocytopenic pur-pura at onset. A report of four cases.  Haematologica1996; 81:175-7.9. Centurioni R, Refe C, Cecapolli A. Cryosupernatantin thrombotic thrombocytopenic purpura (TTP): is itreally useful? Haematologica 1997; 82:125-6.10. Furlan M. Von Willebrand factor: molecular size andfunctional activity. Ann Hematol 1996; 72:341-8.Post-transplant cerebral toxoplasmosisdiagnosed by magnetic resonance imagingMARCO PICARDI, GENNARO DE ROSA, FRANCESCO DI SALLE,*LUCA PEZZULLO, ANNAMARIA RAIOLA, BRUNO ROTOLIDivision of Hematology and Department of RadiologicalSciences*, Federico II University Medical School, Naples, ItalyCerebral toxoplasmosis is a rare late complication inallogeneic bone marrow transplanted patients. Neu-roradiological findings may suggest the correct diag-nosis. We report a patient in whom cerebral magnet-ic resonance imaging (MRI) showed a lesion charac-teristic of toxoplasmosis. Anti-toxoplasma treatmentled to clinical and radiological improvement. MRIseems to be a valid tool for detection and follow-up ofcerebral toxoplasmosis.Toxoplasmosis is the most common opportunis-tic infection affecting the central nervous system inpatients with AIDS. Cerebral toxoplasmosis occursin about 30% of toxoplasma-seropositive patientswhen CD4+ cells fall below 100/mL.1 It has also beenreported in bone marrow transplanted (BMT)patients.2,3 In principle, a definitive diagnosis of toxo-plasmosis must be supported by positive serologyand proven by histological evidence of tachyzoites ina brain lesion. However, in BMT recipients brainbiopsy may not be performable because of throm-bocytopenia, and serology may be uninformativebecause of concurrent immunosuppression. Wereport a case of cerebral toxoplasmosis in a patientwith Hodgkin’s disease (HD) who underwent allo-geneic BMT followed by donor lymphocyte infusions(DLI) for a post-transplant relapse.Figure 1. Cerebral MRI. Gradient recalled echo (GRE) sagit-tal and coronal T1-dependent pre-contrast images (top)demonstrate a round lesion in the right thalamus, with sev-eral concentric components (central: high intensity; inter-mediate: low intensity; peripheral: high intensity) sur-rounded by a low intensity edema. In the edematous regiona post-contrast (Gadolinium-DTPA) GRE image (bottom,left) shows the presence of a thin ring-shaped enhance-ment. In the spin-echo (SE) T2-dependent image (bottom,right) the center of the lesion appears hypointense.571Scientific lettersHD, nodular sclerosis, stage IV B was diagnosed ina 22 year-old man in October 1995. After 16 dosesof VEBED (vinblastine, epirubicin, bleomycin, etopo-side, deflazacort), he achieved partial response. InJune 1996 the patient underwent allogeneic BMTfrom his HLA-identical sister. Conditioning wasbusulfan-cyclophosphamide; graft versus host dis-ease (GVHD) prophylaxis was carried out withcyclosporine; Pneumocystis carinii prophylaxis was per-formed by aerosolized pentamidine. Engraftment wasdocumented on day +25. Six months later, with abone marrow karyotype XX, mediastinal and liver HDrelapse occurred; the patient was treated by a singleC-MOPP course and two DLI (infused lymphocytes:0.25 and 0.93108/kg, respectively). Complete remis-sion (CR) was achieved, but severe cutaneous andhepatic GVHD occurred, requiring intense immuno-suppression by cyclosporine and methylpredniso-lone. A month later fever and neurological symptomsappeared. ESR and serum LDH were elevated. BrainCAT scan showed a hypodense right thalamic lesionof undefined nature; magnetic resonance imaging(MRI) showed a target-shaped lesion in the right thal-amic area with a spontaneous hyperintense centreon T1-weighted images (Figure 1), likely due to hem-orrhage, and a hypointense centre on T2-weightedimages. A smaller hyperintense lesion was present inthe left lenticula. Brain biopsy could not be per-formed because of thrombocytopenia. A low titer ofserum anti-toxoplasma IgG was detected. Pyrimetha-mine-sulfadiazine treatment was started, leading tomarked clinical and neuroradiological improvementwithin two months (Figure 2). At present, pyrimetha-mine-sulfadiazine treatment is continued at lowerdoses. HD is still in CR; the patient presents mildcutaneous and hepatic GVHD, and some neurologi-cal disturbances persist. Toxoplasmosis has to be considered a possiblecause of focal cerebral disease in allogeneic BMTpatients.4 Main risk factors are delayed immunologi-cal reconstitution and prolonged immunosuppres-sion needed to control severe forms of GVHD. Inabsence of definite histological evidence, a presump-tive diagnosis of toxoplasmosis can be based on MRIfindings and is confirmed by response to specific anti-toxoplasma treatment. Peculiar findings at MRI aremultiple round shaped lesions, with ringed or nodu-lar gadolinium enhancement and mass effect.5 Thelesions are most often localized at the cerebral corti-cal or corticomedullary junction. A target-shapedlesion with hypointense centre on T2-weighted imagesis considered typical,5 while other findings, such asthe ringed gadolinium enhancement, may also befound in other diseases.6 In our case, as in others,7aerosolized pentamidine was an insufficient prophy-laxis against toxoplasmosis. The intense immuno-suppression used to control the DLI-induced GVHDhas certainly favored the infectious complication; onthe other hand, DLI treatment may have contributedto achieve HD remission. To the best of our knowl-edge, no other case of relapsed HD has been treatedby DLI.8Key wordsCerebral toxoplasmosis, bone marrow transplantation,magnetic resonance imaging, donor lymphocyte infusionCorrespondenceBruno Rotoli, MD, Divisione di Ematologia Clinica, Nuo-vo Policlinico, via S. Pansini 5, 80131 Naples, Italy. Phone:international +39-81-7462068 • Fax: international +39-81-7462165.References1. Katlama C, De Wit S, O’Doherty E, et al. Pyrimetha-mine-clindamycin vs. pyrimethamine-sulfadiazine asacute and long-term therapy for toxoplasmic ence-phalitis in patients with AIDS. Clin Infect Dis 1996;22:268-75.2. Chandrasekar PH, Momin F. Disseminated toxoplas-mosis in marrow recipients: a report of three casesand a review of the literature. Bone Marrow Trans-plant Team. Bone Marrow Transplant 1997; 19:685-9.3. Slavin MA, Meyers JD, Remington JS, Hackman RC.Toxoplasma gondii infection in marrow transplantrecipients: a 20-year experience. Bone Marrow Trans-plant 1994; 13:549-57.4. Schwechheimer K, Hashemian A. Neuropathologicfindings after organ transplantation. An autopsystudy. Gen Diagn Pathol 1995; 141:35-9.5. Miguel J, Champalimaud JL, Borges A, et al. Cerebraltoxoplasmosis in AIDS patients: CT and MRI imagesand differential diagnostic problems. Acta Med Port1996; 9:29-36.6. Ciricillo SF, Rosemblum ML. Use of CT and MR imag-ing to distinguish intracranial lesions and to define theFigure 2. Pre-and post-therapy SE proton density-dependentimages showing the presence of a second lesion in the leftpallidus. In the post-therapy image (right) the dimension ofthe main lesion is markedly reduced, with disappearance ofthe edematous component. No change is observed in thesmaller lesion.572 Scientific lettersneed for biopsy in AIDS patients. J Neurosurg 1990;73:720.7. Carr A, Tindall B, Brew BY, et al. Low-dose trimetho-prim-sulfamethoxazole prophylaxis for toxoplasmicencephalitis in patients with AIDS. Ann Intern Med1992; 117:106-11.8. Kolb H-S, Holler H. Adoptive immunotheraphy withdonor lymphocyte transfusions. Curr Opin Oncol1997; 9:139-45. Thrombopoietin: a potential T-helper lymphocytestimulator. Change in T-lymphocyte compositionand blood cytokine levels in thrombopoietincDNA transferred miceJIAN ZENG ZHAO, YING JIE MEI, ZI KUAN GUO, HUI REN CHENLaboratory of Gene Therapy, Center for Clinical Molecular Biology, General Hospital of Air Force, PLA, ChinaThe aim of this study was to evaluate the effect ofthrombopoietin (TPO) on T lymphocyte in Balb/c micedelivered hTPO cDNA with plasmid vector. Bothmature and immature T lymphocytes in central organsincreased, but only the CD4+ subset was preferablyproliferated in circulation. High serum IFN-g was coin-ciding with the declination of platelet counts, but TNF-a was positively associated with the platelet count,while high IL-2 level was similar to the course of TPOexpression. Our data suggested that TPO is a stimu-lator for T lymphocytes, especially the CD4+ subset. Accumulating materials have enlightened the par-ticipation of thrombopoietin (TPO) in immunologi-cal processes. TPO stimulates the proliferation ofendothelial cells and enhanced their expression of celladhesion molecules.1 It also indirectly induces theproduction of interferon-a in vitro.2 We previouslyobserved macrophage proliferation and endothelialcell activation in the spleens of TPO gene therapymice. Here we have investigated the T lymphocytecomposition and cytokine production of mice withTPO cDNA delivery.Female Balb/c mice were delivered with the pcD-NA3/hTPO plasmid as previously described.4 Thedose was 60 µg plasmid DNA for each mouse. Null-treated mice as control. Mononuclear cells isolatedfrom thymocytes, plenocytes, fumer marrow cells andblood cells were directly stained with FITC conjugat-ed-anti-mouse CD4 (L3T4) and PE conjugated-anti-mouse CD8a (Ly-2)(Pharmingen). Samples wereanalyzed using a FacStar flow cytometer (BectonDickinson). For each sample, 5,000 events wereacquired. Sera collected from 5 mice at set times wereanalyzed in duplicate with IFN-g, IL-2 ELISA kits(Genzyme) and TNF-a kits (Biotinge, China). Both mature T lymphocytes (CD4+ or CD8+) andimmature ones (CD4+CD8+) in central and peripheralimmune tissues were affected. They assumed differentcharacters in the 2nd week. As Figure 1 shows, in mar-row and spleen, all the three T lymphocyte subsetsincreased, while only the immature cells increased inthe thymus. However, CD4+ subset predominantly andselectively increased in blood.Serum IFN-g, TNF-a and IL-2 concentrationsbegan to change early within 24 hr. of gene delivery(Figure 2). IFN-g peak was 9-12 folds that of the con-trols and maintained from the 2nd week. Striking peakTNF-a level was about 120 folds of the controls butonly occurred in the first week. Meanwhile, IL-2 washigh at the most times.Our data indicated the stimulatory effect of TPOon T cell production. In this process, T helper subsetwas subject to be selectively enhanced, as implied bythe increase in blood CD4+ cells. Elevated immaturebut low mature T ratio in the thymus might suggesta speed-up development. Furthermore, high IFN-gand IL-2 production implied activation of Th1 andpossibly NK cells in the time. Figure 1. T-lymphocytefrequency alterations.

Post-transplant cerebral toxoplasmosis diagnosed by magnetic resonance imaging.

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