Acute Encephalopathy in the Immune-compromised Child: Never Forget Toxoplasmosis De´sire ´e Caselli, MD,* Elisabetta Andreoli, MD,w Olivia Paolicchi, MD,* Sara Savelli, MD,z Stefano Guidi, MD,y Patrizia Pecile, MD,w and Maurizio Arico `, MD* Summary: Toxoplasma gondii is an opportunistic parasite, which very unusually may cause acute encephalitis in patients undergoing chemotherapy or hematopoietic stem cell transplant. The prognosis is usually dismal also because of late diagnosis, depending on the limited availability of specific diagnostic tools. An early diagnosis allows effective intervention with specific antibiotics, which may provide a chance for cure. We report 2 cases of cerebral tox- oplasmosis in which the use of polymerase chain reaction on cer- ebrospinal fluid allowed a prompt diagnosis and specific therapy, which was followed by clinical response and negativization at follow-up studies of T. gondii genome on cerebrospinal fluid by polymerase chain reaction and by brain imaging. Key Words: toxoplasmosis, PCR, encephalopathy, brain abscess (J Pediatr Hematol Oncol 2012;34:383–386) W hen an immune-compromised child develops a cere- bral tumor-like lesion, differential diagnosis must range from opportunistic neoplasm, such as non-Hodgkin lymphoma, to opportunistic infections by agents including virus (such as Cytomegalovirus), fungi (Aspergillus spp., Cryptococcus neoformans), bacterial, or even rarer ones (Mycobacterium and Nocardia). 1 Toxoplasma gondii is an ubiquitous obligate intracellular protozoan parasite, 2 which may represent a very unusual cause for encephalitis in these patients but may turn to be life-threatening. 3 Limited availability of specific diagnostic tools may favor under- diagnosis of some infections, including toxoplasmosis, making their real incidence hard to define. We describe 2 cases of documented cerebral toxoplasmosis in young pa- tients undergoing chemotherapy and hematopoietic stem cell transplantation (HSCT). CASE REPORTS Case 1 A 20-year-old female with isolated marrow relapse of child- hood acute lymphoblastic leukemia (ALL) was retreated with chemotherapy and consolidated with HSCT from an HLA-identi- cal unrelated donor. After engraftment, chronic graft-versus-host disease was treated by multiagent immune suppression (prednisone, cyclosporine, tacrolimus, micophenolate, rituximab) and extra- corporeal photopheresis. Sixteen months after transplantation, she developed pancytopenia and signs of acute encephalopathy: speech alterations, blurred mind, and right nystagmus, without focal def- icits. A contrast-enhanced brain magnetic resonance imaging (MRI) showed multiple space-occupying parenchymal lesions of uncertain origin, with nodular and ring enhancement, confirmed by computerized tomography (CT) scan. Bone marrow aspirate documented second ALL relapse, again with “common” im- munophenotype. Cerebrospinal fluid (CSF) examination excluded leukemic infiltration. The diagnostic workup for associated fungal infection showed repeatedly negative galactomannan test on pe- ripheral blood and negative chest and facial bone CT scan. Che- motherapy was started according to the AIEOP-ALL-REC-2003 study, high-risk arm S4 for early relapse, including high-dose cy- tarabine and idarubicine. One month later, she showed a rapid neurological deterioration with confusion, short-term memory loss, and speech difficulty, then followed by ataxia, dysarthria, tremors, inability to stand, hypereflexia, and alternant states of psychomo- tor agitation and drowsiness. Brain imaging with CT and MRI revealed the persistence of multiple “open-ring” pattern focal le- sions compatible with toxoplasmosis (Fig. 1). Serum toxoplasmosis avidity index was 0.39 (where a value >0.25 suggests high avid- ity) 4 ; qualitative polymerase chain reaction (PCR) study of the CSF documented the presence of T. gondii genome. The patient was treated with the combination of sulphadia- zine (1 g q 6 h, orally) and pyrimethamine (50 mg/d, orally) for 8 weeks. On day + 7 from treatment start, when moderately neu- tropenic (800/mm 3 ), she developed respiratory failure, treated with tracheostomy, associated with enterostomy. During the following days, her clinical condition progressively improved, including her neurological status. PCR monitoring of T. gondii genome on CSF turned to be negative since month + 2 of combined therapy. The leukemia-directed chemotherapy program was thus restarted; yet, unfortunately she died of progressive, refractory leukemia 6 months later. No signs of recurrent toxoplasmosis had been documented clinically, serologically, or by imaging techniques. Case 2 An 18-year-old girl was diagnosed with acute myeloid leukemia, FAB M5. She was treated according to the AIEOP- AML-2002 study and stratified as at high risk because of MLL- rearrangement. She achieved complete remission after the first induction course; by study design consolidation of first remission was performed by allogeneic HSCT. The stem cell source was an unrelated cord blood unit. On day + 52 from transplant, she de- veloped focal seizures, hypertonicity, and asynchronous move- ments of all limbs, preceded, by a few minutes, by an “aura” consisting of visual allucination (green light); all symptoms re- solved within a few minutes. Electroencephalography was normal; CT scan showed hypodense parenchymal lesions in both hemi- spheres (Fig. 2). A similar episode appeared on the day after; an- ticonvulsant therapy was started with levetiracetam. Brain MRI confirmed the CT findings showing multiple nodular and ring-en- hanced focal intracranial lesions. PCR study of both her blood and CSF confirmed the presence of T. gondii genome. Ophthalmoscopy showed bilateral intraretinal hemorrhages along the 4 vascular arches, without visual impairment. Specific combination therapy was started with oral sulphadiazine (1 g q 6 h) and pyrimethamine Received for publication June 4, 2011; accepted November 4, 2011. From the Departments of *Pediatric Hematology Oncology; zPediatric Radiology, Azienda Ospedaliero-Universitaria Meyer; wLabor- atorio di Microbiologia e Virologia, Azienda Ospedaliero Uni- versitaria; and yDepartment of Hematology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy. The authors declare no conflict of interest. Reprints: De´sire´e Caselli, MD, U.O. Cure Domiciliari, Terapia cellu- lare Azienda Ospedaliero-Universitaria Meyer, Viale Pieraccini 24, 50139 Firenze, Italy (e-mail: d.caselli@meyer.it). Copyright r 2012 by Lippincott Williams & Wilkins CLINICAL AND LABORATORY OBSERVATIONS J Pediatr Hematol Oncol  Volume 34, Number 5, July 2012 www.jpho-online.com | 383