A generalized seizure in a renal allograft recipient
Sophie Domhan1,
Christian Morath1,
Peter Schnülle2,
Rüdiger Waldherr1 and
Martin Zeier1
1 Department of Nephrology, University Hospital Heidelberg, Heidelberg and 2 Fifth Department of Medicine,
University Hospital Mannheim, Mannheim, Germany
Correspondence and offprint requests to: Sophie Domhan, MD, University Hospital Heidelberg, Department of Nephrology, Bergheimerstraße 56a, D-69115 Heidelberg, Germany. Email: sdomhan{at}ix.urz.uni-heidelberg.de
Keywords: immunosuppression; primary central nervous system lymphoma (PCNSL); renal allograft; toxoplasmosis
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Background
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Primary central nervous system lymphoma (PCNSL) is a unique high-grade brain tumour almost always of B-cell origin which may occur in both immunocompetent and immunosuppressed patients [1]. Organ transplantation is associated with an increased risk of de novo cancer [2,3]. Skin cancer and non-Hodgkin's lymphoma are the most frequent forms of neoplasia following solid organ transplantation (23% of all malignancies) [4]. The incidence of non-Hodgkin's lymphoma is highest during the first year after kidney transplantation, with a cumulative incidence of 1% at 10 years [5]. The central nervous system (CNS) accounts for 24% of all extranodal post-transplantation lymphoproliferative disorders [4]. Two risk factors have been identified: the intensity of immunosuppressive regimen regardless of drug class [68] and positive EpsteinBarr virus (EBV) serology [9]. We describe the clinical, histological and radiological features of PCNSL in a renal allograft recipient.
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Case
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A 48-year old Caucasian female who was allografted 8 years ago was admitted with a recent occurrence of an epileptic seizure. She was under concurrent immunosuppression with mycophenolate mofetil and steroids and had a history of acute vascular transplant rejection in 1995 treated with high dose steroids and OKT3. Physical examination revealed no pathological findings except that her pupils were slightly different. Cranial magnetic resonance imaging (MRI) showed multiple ring-enhancing lesions with extensive perifocal oedema in both hemispheres. Subsequent investigations failed to identify a malignant process as the underlying cause of the observed symptoms. In addition, there was no evidence of bacterial, viral or fungal infection after extensive clinical work-up, including a spinal tap. The lesions in MRI were strongly indicative of toxoplasmosis infection which preferentially aligned with the patient's history of having a cat as a pet. Together with the serological finding of toxoplasmosis titre [immunoglobulin titre 1:64 (positive >1:16)], the patient received a 4-week regimen with daraprin and sulfadiazin. Meanwhile, a stereotactic biopsy was performed. However, only neuroepithelial tissue with perivascular chronic inflammatory infiltrates and marked necrosis was evident, most probably because of the high dose steroid therapy that was initiated to lower the intracranial pressure. During this treatment period, an increase in size and number of the intracranial lesions was observed and mycophenolate mofetil was stopped. A second craniotomy was initiated, revealing atypical lymphoproliferative tissue with enlarged nuclei and numerous mitotic cells. Immunocytochemistry completed the diagnosis of a large B-cell lymphoma. The patient is currently receiving high-dose methotrexate and ARA-C chemotherapy according to the Bonner protocol [10,11].
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Discussion
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The reported case should elucidate the diagnostic strategy and therapeutic management of immunosuppressed patients suffering from PCNSL, which in this case was a substantial challenge.
The diagnostic parameters such as MRI and liquor examination, and even histology, could be modified by the immunosuppressive therapy and macroscopically mimic cerebral textures similar to those in patients with toxoplasmosis. Therefore, a careful diagnostic work-up is warranted in immunosuppressed patients suspected of having PCNSL.
The radiological MRI findings in our patient showed multifocal supra- and infratentorial lesions with extensive perifocal oedema and a maximum diameter of 1.5 cm. The lesions were hypointense in T2, and enhanced after contrast medium injection with a ring pattern, mimicking cerebral abscesses (Figure 1). This radiological abscess-like presentation frequently suggests an infectious origin such as toxoplasmosis or pyogen abscesses.

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Fig. 1. The MRIs show multifocal lesions with perifocal oedema. The lesions were hypointense in T2, and enhanced after contrast medium injection with a ring pattern, mimicking cerebral abscesses.
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Fig. 2. Representative histology of the patient's biopsy. Atypical lymphoid cells with enlarged nuclei (tumour cells) are shown in the haematoxylin and eosin (HE)-stained tissue section (left) indicating a lymphoproliferative process. Subsequent immunohistochemical analysis shows tumour cells with positive CD20 immunoreactivity that is characteristic for a malignant B-cell lymphoma (right panel).
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Given the fact that a brain mass in an immunosuppressed patient can be caused by a number of infectious and neoplastic processes, the criteria for distinguishing between these entities remain imperfect. Most common, e.g. seen in AIDS patients, are Toxoplasma gondii abscesses, PCNS lymphoma, mycobacterial or bacterial abscesses, and progressive multifocal leukoencephalopathy (PML).
In general, PCNS lymphoma, PML and toxoplasmosis are complications of far advanced immunosuppression with CD4 counts of
50 cells/mm3. This patient population is often on trimethoprim-sulfamethoxazole prophylaxis for Pneumocystis, which provides excellent protection against Toxoplasma. An empiric anti-Toxoplasma therapy may be used as both a diagnostic and a therapeutic tool. Initiation of sulfadiazine or clindamycin with pyrimethamine generally halts the progression by 5 days and results in clinical or radiographic improvement by 14 days [12]. For those patients in whom a Toxoplasma antibody titre is negative and who have been on such prophylaxis, the likelihood of a lymphoma diagnosis in the presence of a CNS mass lesion is increased by 74% [13]. In addition, a lesion that crosses the midline is highly suspicious of being a neoplastic process.
Since the introduction of cotrimoxazole prophylaxis, toxoplasmosis has become a rare complication that occurs mainly within the first year of transplantation [14]. However, an empirical anti-infectious treatment as a diagnostic test may delay lymphoma treatment and jeopardize patient survival. Thus we recommend a rapid stereotactic cerebral biopsy when confronted with these radiological findings in a transplant patient.
Several important similarities exist between PCNSL in patients with AIDS and organ allograft recipients. Possibly the most significant causative similarity is the consistent finding of EBV genomic DNA within the lymphoma cells [15,16]. Another similarity is the tendency for the degree of immunosuppression to be related to the risk for developing PCNSL. Parallel to this, our patient had a positive EBV serology and we could also detect EBV DNA in our patient's specimen. Further, our patient had a history of acute vascular transplant rejection that had been treated with high dose steroids and OKT3. It has been shown that the addition of OKT3 to the immunosuppressive regimen increases the incidence of post-transplantation lymphoproliferative disorder (PTLD), and that the risk increases sharply after administration of a cumulative dose greater than 75 mg [9]. Hence the intensity of the immunosuppressive regimen and a positive EBV serology constitute the two major risk factors for PTLD [8,10,17]. However, PTLD appears to be different in its pathogenesis from that of PCNSL, thus the impact of enhanced immunosuppressive therapy in PCNSL remains unclear.
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Teaching points
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- All risk factors that are associated with increased incidence of post-transplantation malignancy, such as the duration and intensity of immunosuppression, gender, smoking and sun exposure, should be the subject of careful evaluation.
- The radiological presentation of PCNSL can mimic cerebral abscesses that should be distinguished from a malignant process. It is important to consider the influence of medication (e.g. steroids) that may dramatically modify and complicate the diagnostic assessment.
- Treatment should be initiated according to the latest effective protocols.
Conflict of interest statement. None declared.
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