Letter to the Editor
Efficacy of mefloquine and mirtazapine on progressive multifocal leukoencephalopathy in a patient with peripheral T-cell lymphoma
Eficacia de mefloquina y mirtazapina sobre la leucoencefalopatía multifocal progresiva en un paciente con linfoma T periférico
a Servicio de Hematología, Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Institut de Recerca contra la Leucèmia Josep Carreras, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain
b Servicio de Neurología, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain
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(A) At the time of PML diagnosis. (B and C) Month 3 and 6, respectively, after onset of the combined treatment with mirtazapine and mefloquine.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The optimal treatment of progressive multifocal leukoencephalopathy (PML) in patients without human immunodeficiency virus (HIV) infection is undefined and death rate related to this entity is high. The following describes the case of a patient diagnosed with peripheral T-cell lymphoma, of an unspecified subtype, who presented a PML caused by the JC polyomavirus during conventional chemotherapy. PML was resolved by treatment with mirtazapine and mefloquine, which allowed to continue with the chemotherapy.</p><p id="par0010" class="elsevierStylePara elsevierViewall">A 74-year-old male patient with a pathological history of diabetes mellitus and surgical intervention of tongue cancer, without any further treatment. Diagnosed in March 2013 of a T-cell large granular lymphocyte leukemia following an autoimmune hemolytic anemia. The patient underwent glucocorticoid treatment, with good response. In May 2017, the patient presented fever, weight loss, increased number and size of lymphadenopathies and high serum LDH. A biopsy of a right inguinal lymphadenopathy proved a diagnosis of peripheral T-cell lymphoma of unspecified subtype. The first-line therapy used was CHOP (cyclophosphamide, vincristine, doxorubicin and prednisone) of which he received 4 cycles. Prior to the administration of the 5th cycle, the patient consulted due to fluctuations in gait lasting 24<span class="elsevierStyleHsp" style=""></span>h, 2 falls to the ground and fever. The physical examination highlighted left crural weakness (4/5) and absent right patellar and bilateral Achilles reflexes. The leukocyte count was normal (5.50<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>/l), but lymphocytopenia was detected (0.20<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>/l). The patient underwent a cranial computed tomography that showed no relevant pathological changes. Cerebrospinal fluid (CSF) was clear with normal glucose and protein levels, presence of few nucleated cells, without atypical cells. The immunophenotypic study ruled out infiltration caused by the underlying disease. The microbiological study (Gram staining, microbiological and mycological culture and detection of <span class="elsevierStyleItalic">enterovirus</span> and <span class="elsevierStyleItalic">parechovirus</span> through the polymerase chain reaction [PCR]) was negative. A magnetic resonance imaging (MRI) of the brain was requested with contrast dye, showing involvement of the juxtacortical and subcortical white matter in the medial precentral gyrus, of right-sided predominance, with punctate images of the parenchyma, with no signs of cortical involvement or cerebral edema (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A). Given these findings, we searched for the presence of JC polyomavirus in CSF by PCR, with positive results, which allowed the diagnosis of PML. The CD4 lymphocyte count was 0.038<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>/l. Chemotherapy for lymphoma was discontinued and treatment of PML was initiated with mirtazapine (30<span class="elsevierStyleHsp" style=""></span>mg/day) and mefloquine (250<span class="elsevierStyleHsp" style=""></span>mg/day 3 days the first week and then one day per week) with a clear improvement in neurological symptomatology. A control brain MRI was performed 3 months after onset of treatment, which highlighted a remarkable lower number of pathological images (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B). Due to progression of the lymphadenopathy, the patient met treatment criteria. A new PCR determination of the JC virus in the CSF was negative. Given the persistence of signs of lymphoma activity, it was decided that chemotherapy should be resumed. The patient has not presented any new neurological signs and symptoms and the control brain MRI shows practical resolution of the lesions (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">PML is a serious demyelinating disease of the central nervous system caused by the reactivation of JC polyomavirus that affects oligodendrocytes in patients with profound cell immunosuppression. Its association to treatment with immunosuppressive or immunomodulatory drugs has been reported.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">1</span></a> Restoring host adaptive immunity is recommended in patients with no HIV infection by withdrawing immunosuppressive drugs to prolong survival.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">2</span></a> Despite the limited available evidence, mainly based on the description of rare cases,<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">2,3</span></a> the use of mirtazapine combined with mefloquine could be effective in the treatment of PML, as occurred in the patient referred to in this study. In <span class="elsevierStyleItalic">in vitro</span> studies, mirtazapine would prevent the virus from entering the glial cells by blocking the 5-HT<span class="elsevierStyleInf">2A</span> receptor, and mefloquine would have an inhibitory effect on its replication inside the oligodendrocytes.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">3</span></a> The negativization of the JC virus in the CSF after treatment with mefloquine/mirtazapine would confer a better prognosis of the PML.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">2</span></a></p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Peña M, Presas-Rodríguez S, Ribera J-M. Eficacia de mefloquina y mirtazapina sobre la leucoencefalopatía multifocal progresiva en un paciente con linfoma T periférico. Med Clin (Barc). 2019;153:e47–e48.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1749 "Ancho" => 2333 "Tamanyo" => 312382 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Brain MRI images with contrast in T1 sequence (upper) and FLAIR (lower). (A) At the time of PML diagnosis. (B and C) Month 3 and 6, respectively, after onset of the combined treatment with mirtazapine and mefloquine.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:3 [ 0 => array:3 [ "identificador" => "bib0020" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Progressive multifocal leukoencephalopathy with negative JC virus PCR following treatment of follicular lymphoma: implications for biologics in the era of targeted cancer therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K.A. Silverio" 1 => "S.A. 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