Atypical presentation of progressive multifocal leukoencephalopathy ...

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Mar 1, 2010 - We read with interest the article by Kharfan-Dabaja et al.1 on two cases of fatal progressive multifocal leukoencepha- lopathy (PML) that ...

Bone Marrow Transplantation (2010) 45, 1668–1670 & 2010 Macmillan Publishers Limited All rights reserved 0268-3369/10


Atypical presentation of progressive multifocal leukoencephalopathy in a multiple myeloma patient after auto-SCT successfully treated with combination therapy Bone Marrow Transplantation (2010) 45, 1668–1670; doi:10.1038/bmt.2010.33; published online 1 March 2010 We read with interest the article by Kharfan-Dabaja et al.1 on two cases of fatal progressive multifocal leukoencephalopathy (PML) that developed after SCT. We report on a patient who developed this type of complication after autologous SCT. The 63-year-old female patient had a diagnosis of multiple myeloma, for which she was treated with thalidomide and dexamethasone, mobilization therapy with a high dose of cyclophosphamide and then autologous SCT in May 2008. In July 2008 she presented with dysarthria and left facial weakness. She had no fever and laboratory studies revealed a leukocyte count of 3.89  109/l with a reduced absolute lymphocyte count (0.86  109/l). Lymphocyte subset analysis revealed an absolute CD4 þ T-cell count of 184/ml. A brain-magnetic resonance imaging (MRI) showed multiple focal mass lesions both in the cerebellum and in the cerebral hemispheres. The largest lesions were located in both cerebellar hemispheres and in the subcortical white matter of the left fronto-parietal lobes, and exhibited high signal intensity on T2-weighted images, irregular contrast enhancement after contrast injection and perilesional edema. Diffusion-weighted images did not show signs of restricted diffusion, thus indicating relatively low cellularity (Figure 1). The neuroradiological findings were considered not suggestive of lymphoproliferative disorder localization, raising the suspicion of an opportunistic disease. Lumbar puncture was performed, and evaluation of the cerebrospinal fluid was negative for malignant cells and for infection, showing only protein level to be mildly elevated (48 mg/dl). HSV DNA was not detected in the patient’s cerebrospinal fluid by PCR, which was also negative for JC virus (JCV) DNA. The patient’s symptoms progressed rapidly and she developed left-arm weakness and subsequent hemiparesis. Considering the intracranial posterior fossa hypertension due to the large enhancing lesion associated with perifocal edema, open surgery, with suboccipital left paramedian decompressive craniectomy and multiple biopsies, was performed. Histological examination showed a fragment of cerebellar tissue with a perivascular inflammatory infiltrate of lymphocytes, polyclonal plasma cells and macrophages. Oligodendroglial cells appeared bizarre, with occasional

giant enlarged and multilobulated nuclei and smudgy chromatin. A deposit of P53 in the nuclei of these cells was observed; multiple foci of demyelination were evidenced. These histological features suggested the diagnosis of PML, which was confirmed by the positivity of PCR analysis on brain tissue for JCV. Owing to a further worsening of the patient’s condition, an empirical treatment with i.v.Ig 25 g for 2 days was started. Four days later, this was combined with citalopram, a 5-HT2a receptor antagonist, taken orally at 20 mg daily for 5 days and then increased at 40 mg daily. Treatment with mefloquine, an antimalarial agent, at 750 mg followed by 500 mg at 12 h was started on the basis of an in vitro study on day 1; the drug was then repeated weekly at 250 mg.2 After the first administration of i.v. Ig, there was a steady surprising upgrade in the clinical and neurological condition of the patient, with improvement in her speech, a gradual resolution of hemiparesis and a recovery of her ability to walk. Sequential brain MRI studies showed a progressive reduction in size of all intracranial lesions. After 15 months, the patient is neurologically stable and has completely recovered her mental capacity and the faculty to talk and walk. She is carrying on with mefloquine therapy weekly, and a new brain MRI showed minimal residual signal alterations on T2-weighted images, without contrast uptake, that are interpreted as reparative gliosis (Figure 2). She had no signs of her hematological disease, thus remaining in CR from multiple myeloma. PML is a rare central nervous system infection caused by JCV, which is regarded as an opportunistic infection. It is most commonly seen in AIDS and less frequently reported in other immunosuppressed patients, in particular those with lymphoproliferative diseases and in patients undergoing SCT.3 In the setting of SCT, PML outcome is generally fatal. In a large case series of PML cases occurring among 57 HIV-negative patients treated with rituximab, survival rates were 25% among those developing PML after hematopoietic SCTs.4 Brain MRI is considered as the first choice of imaging tools to recognize PML. In our case, however, the MRI picture was not typical of PML, leading us to obtain a brain biopsy for differential diagnosis. There is no specific proven treatment for PML. The role of cidofovir is controversial. Although not effective against JCV in vitro, some authors suggest that it is of potential clinical benefit in patients with PML and HIV.5 A receptor for JCV binding includes the serotonergic 5-hydroxytryptamine receptor 2A found on glial cells,

Letter to the Editor


Figure 1 First brain MRI (before biopsy). (a, b) Axial T2-weighted FLAIR images. (c, d) Axial T2-weighted SE images. (e, f) Axial post-contrast T1-weighted images. (g) Axial diffusion-weighted image, DWI. There are large infratentorial and supratentorial focal mass lesions; the largest one in the left cerebellar hemispheres. All lesions presented high intensity on T2-weighted images (a–d), irregular contrast enhancement (e, f) and edema with mass effect; note that the large left cerebellar lesion does not show restricted diffusion on DWI image (g), indicating low cellularity.

Figure 2 Post-treatment control brain MRI. (a, b) Axial T2-weighted FLAIR images. (c, d) Axial and coronal post-contrast T1-weighted images. There is no active/enhancing lesion. In the left cerebellar hemisphere there is only the residual cerebrospinal fluid (CSF)-like surgical cavity, while the large infiltrating lesion in the left fronto-parietal lobes left only minimal gliosis, without contrast enhancement and without mass effect. No additional signal alterations are seen.

astrocytes, kidney epithelial cells and B cells.6 An interesting new line of therapy involves the use of 5-hydroxytryptamine-2a serotonin receptor blocker medications, which we used in our patient. This in our patient was

preceded by IVIG therapy, which has been used with a steady improvement in her neurological conditions after the first administration. The quick improvement in her condition suggests an important role of this therapy in the arrest of progression of PML. There is anecdotal evidence that IVIGs may have beneficial clinical effects in some immunosuppressed patients with viral infections, and it is also suggested that this may promote remyelination in demyelinating disease associated with viral infections.7 Notably, in our patient we added to these drugs mefloquine, an antimalarial agent, that in a recent study demonstrated a significant anti-JCV activity with sufficiently high penetration into the CNS.1 In this study it has been shown that mefloquine does not block viral cell entry; rather, it inhibits viral replication in cells after viral entry. Further reduction of brain lesions showed to MRI respect to previous control in our patient would appear to confirm the efficacy in vivo of this drug. A synergistic effect could be hypothesized in our case: immunomodulation and perhaps remyelination by i.v. Ig, block of viral cell entry by 5-HT2a receptor antagonist and inhibition of viral replication in cells by mefloquine. Our experience suggests the possible value of a combination of drugs to improve the outcome of this frequently lethal complication, as reported by Kharfan-Dabaja et al. Early diagnosis of PML is, however, equally crucial to start adequate therapy before irreversible neurological damage has occurred. Therefore, in patients at risk of developing PML, especially in profoundly immunosuppressed transplant recipients, the diagnostic suspicion must also be raised in patients without the classical/typical neuroradiological picture and must warrant a brain biopsy.

Conflict of interest The authors declare no conflict of interest. Bone Marrow Transplantation

Letter to the Editor


L Fianchi1, C Colosimo2, A De Luca3, A Pompucci4, P Cattani5, MT Voso1, LM LaRocca6, G Leone1 and L Pagano1 1 Istituto di Ematologia, Universita` Cattolica Sacro Cuore, Rome, Italy; 2 Istituto di Radiologia, Universita` Cattolica Sacro Cuore, Rome, Italy; 3 Istituto di Malattie Infettive, Universita` Cattolica Sacro Cuore, Rome, Italy; 4 Dipartimento di Neurochirurgia, Universita` Cattolica Sacro Cuore, Rome, Italy; 5 Istituto di Microbiologia, Universita` Cattolica Sacro Cuore, Rome, Italy and 6 Istituto di Anatomia Patologica, Universita` Cattolica Sacro Cuore, Rome, Italy E-mail:[email protected]


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References 1 Kharfan-Dabaja MA, Ayala E, Greene J, Rojiani A, Murtagh FR, Anasetti C. Two cases of progressive multifocal leukoencephalopathy after allogeneic hematopoietic cell transplantation

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