Aug 17, 2009 - ... subcortical lesions mainly in the frontal and temporal lobes, but also ... new cortical T1-hyperintensities suggesting laminar necrosis (gâi).
Bone Marrow Transplantation (2010) 45, 593–596 & 2010 Macmillan Publishers Limited All rights reserved 0268-3369/10 $32.00
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LETTER TO THE EDITOR
Central nervous system immune reconstitution inflammatory syndrome (IRIS) after hematopoietic SCT Bone Marrow Transplantation (2010) 45, 593–596; doi:10.1038/bmt.2009.186; published online 17 August 2009 Immune reconstitution inflammatory syndrome (IRIS) is an increasingly recognized clinical entity emerging in the context of the restoration of the immune system after significant immunosuppression. As the patient’s immune system regains its potency, IRIS may lead to a paradoxical clinical deterioration when intense inflammatory infiltrates
are formed to eradicate an underlying subclinical infection.1 The vast majority of the patients with IRIS are HIVinfected subjects, whose immune system recovers after the initiation of highly active antiretroviral therapy.2 Infections associated with IRIS include those caused by Mycobacterium tuberculosis, Mycobacterium Avium-Intracellulare (MAI), Cryptococcus neoformans, CMV, JC virus and Candida.1,3 We report a case of IRIS in a non-HIV-positive patient, who developed a severe form of CNS IRIS after treatment of CML with allogeneic hematopoietic SCT (HSCT).
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Figure 1 Cerebral MRI images were taken on admission (a–c), and 2 (d–f), 6 (g–i) 10 weeks (j–l) and 10 months after admission (m–o). Top row, T2-weighted images; middle row, flair sequences; bottom row, T1-weighted images with gadolinium (c and f) and without gadolinium (i, l and o). On admission, T2-weighted images showed multiple small unenhancing, slightly expansive subcortical lesions mainly in the frontal and temporal lobes, but also in the occipitoparietal region (a). (d–f) Show some progression in the cerebral lesions. Six weeks after admission, fluctuation was seen in the size and location of the brain lesions, including new cortical T1-hyperintensities suggesting laminar necrosis (g–i). Follow-up images showed disappearance of the majority of the lesions with residual cortical T1-hyperintensity 10 weeks (j–l) and mild cerebral atrophy 10 months (m–o) after admission.
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A 31-year-old previously healthy man was diagnosed with CML at the end of 2002. Allogeneic HSCT with peripheral blood from a matched unrelated donor was performed in May 2003. Standard conditioning with highdose CY, TBI (12 Gy in five fractions) and antithymocyte Table 1 Reconstitution of blood lymphocyte counts ( 106/l) after allogeneic HSCT in May 2003
10/2003 06/2004 12/2004 03/2005 07/2005 05/2006 Reference range
CD3
CD4
CD8
CD19
366 1122 1450 1857 2183 2161 690–2540
108 346 496 626 776 809 410–1590
255 815 909 1336 1676 1406 190–1140
86 483 456 1183 1288 2357 90–660
Abbreviation: HSCT ¼ hematopoietic SCT.
Figure 2
globulin was given and immunosuppression thereafter consisted of short MTX and CYA. Grade 2 skin GVHD was treated with methylprednisolone; otherwise, he recovered without complications. Immunosuppression was tapered 1 year post transplant and stopped entirely in August 2004. In September 2004, he had a severe pneumocystis pneumonia. The cell counts of lymphocyte subtypes recovered into the normal ranges by December 2004 (Table 1). In April 2005, nearly 2 years after the transplant and 8 months after the cessation of immunosuppressive treatment, the patient developed convulsions, and MR imaging of the brain showed multiple subcortical low-density lesions of 1–2 cm in diameter (Figure 1). Antimicrobial therapy was started with broad-spectrum antibiotics and acyclovir. In addition, as fungal infection was suspected, a combination of liposomal ambisome (3 mg/kg) and voriconazole was administered. Despite the treatment, over the next
Microscopy of the brain tissue. (a) Shows an increased number of parenchymal inflammatory cells (arrows) as well as round, darkly stained cells in the white matter (open arrow). (b) Shows round Candida-like structures around the vessel and in the vessel wall (arrows). This is confirmed by Grocott staining (c). (d) Shows numerous CD8-positive lymphocytes in the white matter (arrows). (e) Shows few CD4-positive cells (arrows) in the white matter. (f) Shows CD68-positive perivascular macrophages (arrows) and microglial cells (open arrows). The bar in each picture represents 50 um.
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2 weeks the patient’s condition worsened; he became disoriented, had myoclonic contractions of the whole body and his consciousness level deteriorated. The cerebral lesions on MRI were slightly expanded (Figure 1). A brain biopsy was taken and histological examination revealed fungal hyphae and aggregates of lymphocytes (Figure 2). In tissue culture, the fungus was identified as Candida parapsilosis. Four weeks after the initial neurological symptoms, the patient’s condition deteriorated further; he became comatose and needed mechanical ventilation. At this stage, dexamethasone treatment was initiated and he started to recover. After 3 weeks, he could converse normally and had only mild residual motor symptoms. On neuropsychological examination 4 months after the initiation of the neurological sequelae, no residual cognitive symptoms remained and the patient has since returned to working life. Brain biopsy showed an increased number of inflammatory cells in the brain parenchyma (Figure 2a). Both Gram and Ziehl-Neelsen stains were negative, but PAS staining showed Candida-like structures (Figure 2b).This was confirmed by Grocott staining (Figure 2c). Immunohistochemical studies showed white matter areas with numerous CD8-positive lymphocytes (Figure 2d). A few CD4-positive lymphocytes were also observed (Figure 2e). Anti-CD68staining showed perivascular macrophages and rod-shaped microglial cells (Figure 2f). Patients undergoing allogeneic HSCT are treated with highly immunosuppressive therapy, first, to eradicate the disease and, second, to allow the engraftment of donor cells and to prevent GVHD; they are more heavily immunocompromised at the time of and after transplantation than are solid organ transplant patients.4 Hence, they are high-risk patients, susceptible to opportunistic infections, despite the use of prophylactic or pre-emptive medications against viruses, parasites and fungae.5 CNS Candida infections are rare.6,7 On MRI, they may manifest as small enhancing ring lesions (cerebral microabscesses), leptomeningeal enhancement (meningitis) or cerebral macroabscesses with surrounding edema.6,7 None of these features were present in our patient. Instead, he had non-enhancing, slightly expansive subcortical lesions. Such lesions have been described in cases of IRIS,2,3 although in many other CNS–IRIS cases, the MRI findings have shown intensive gadolinium enhancement.2,8,9 The CNS symptoms of our patient emerged 8 months after complete cessation of immunosuppressive treatment (and half a year after the recovery of blood CD4 cells), a timing compatible with the onset of IRIS. Moreover, several antiepileptics were administered, including phenytoin, carbamazepine and sodium valproate and, owing to drug interactions, the trough level of antifungal voriconazole was found to be low (o0.5 mg/l). Consequently, the voriconazole dose was nearly doubled (700 mg/d), but by this time the patient had already recovered and had been discharged from the hospital. Hence, the CNS symptoms were probably alleviated not by the antifungal treatment, but more likely by the steroid treatment and resolution of the IRISassociated CNS inflammatory infiltrates. Theoretically, the putative anti-inflammatory effects of phenytoin might also have contributed to the favorable outcome of IRIS.10
Diagnosis of a CNS infection is difficult, and identification of the infectious pathogen often requires a brain biopsy. In this case, the biopsy confirmed the presence of a weak fungal pathogen; Candida parapsilosis is considered the least virulent of the Candida species.6 In addition, the immunohistochemical finding of tissue infiltration with CD8-positive lymphocytes was compatible with IRIS.2 From a clinical point of view, awareness of IRIS is important. Optimal management of the various CNSassociated IRIS manifestations remains poorly defined and no treatment recommendations now exist for CNS–IRIS. Therapeutic intervention is initially directed against the specific infectious agent and may be supplemented by corticosteroids to suppress the exuberant and potentially destructive inflammatory response.11 We stress the importance of recognizing CNS–IRIS as a part of the differential diagnostics in patients with worsening CNS symptoms and a preceding immunosuppressive state, including allogeneic HSCT.
Conflict of interest The author declares no conflict of interest. L Airas1, M Pa¨iva¨rinta1, M Ro¨ytta¨2, J Karhu3, M Kauppila4, M Ita¨la¨-Remes4 and K Remes4 1 Department of Neurology, Turku University Central Hospital, Turku, Finland; 2 Department of Pathology, Turku University Central Hospital, Turku, Finland; 3 Department of Radiology, Turku University Central Hospital, Turku, Finland and 4 Department of Internal Medicine, Turku University Central Hospital, Turku, Finland E-mail: laura.airas@utu.fi
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