Rheumatology Advance Access originally published online on March 27, 2007
Rheumatology 2007 46(5):888-890; doi:10.1093/rheumatology/kem049
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Progressive multifocal leucoencephalopathy in a patient with sarcoidosis—successful treatment with cidofovir and mirtazapine
Department of Medicine, University of Cologne Hospital, 1Department of Neuropathology, University of Cologne Hospital, Joseph-Stelzmann-Str. 9, 50931 Cologne and 2Department of Neurology, Johann Wolfgang Goethe University, Theodor Stern Kai 760590 Frankfurt am Main, Germany
Correspondence to:K. Owczarczyk, Division of Immunology and Rheumatology, Department of Medicine, University of Cologne Hospital, Joseph-Stelzmann-Str.9, 50931 Cologne, Germany. E-mail: katarzyna.owczarczyk{at}uk-koeln.de
SIR, Progressive multifocal leukoencephalopathy (PML) represents a demyelinating CNS disease caused by reactivation of JC virus (JCV) in immunocompromised patients including patients post-transplant, with haematological malignancies or AIDS. Recently, the occurrence of PML was reported in patients with autoimmune diseases on immunosuppressive treatment [1]. Despite the cessation of immunosuppression when possible, the prognosis of PML is usually poor.
A common consensus regarding the therapy of PML has not yet been reached. Cidofovir, a nucleotide analogue with in vitro anti-JCV activity represents the most effective single agent in a mouse polyomavirus model [2]. Several cases have suggested its potential therapeutic benefit [3], whereas other reports did not show clinical efficacy.
As PML is a consequence of JCV reactivation rather than acute infection, an ideal drug would preferentially prevent reinfection of glial cells in patients at risk. Recently, Atwood and colleagues were able to demonstrate that JCV employs serotoninergic 5HT2A receptors to infect human glial cells [4]. The anti-depressant mirtazapine, a 5HT2A antagonist, is able to cross the blood–brain barrier, binds to a substantial amount of 5HT2A receptors and blocks replication of JCV in vitro.
In this report we describe the favourable outcome of PML in a patient with systemic sarcoidosis using a combination therapy of cidofovir and mirtazapine.
A 58-yr-old Caucasian woman presented with acute onset of gait ataxia, fall tendency and slurred speech. Since 2000 she had been suffering from sarcoidosis with pulmonary, musculoskeletal and cutaneous involvement. In addition, the patient reported arterial hypertension and a moderate impairment of renal function was noted. Immunosuppresive therapy in the past had included steroids in a dose of up to 40 mg/day and azathioprine 50 mg/day that had to be stopped due to side effects in 2001.
At the time of presentation the patient was on prednisolone 5 mg/day and methotrexate 7.5 mg/week. Laboratory findings revealed a slightly elevated ESR of 24 mm/h, a normal serum calcium and a slightly increased soluble IL-2 receptor (sIL2R) with 826 kU/l (normal: <710 kU/l).
Lymphopenia was noted with an absolute lymphocyte count of 580/µl (normal: 1000–4800) and a normal CD4/CD8 ratio of 0.8.
Brain magnetic resonance imaging (MRI) revealed a single, infratentorial non-enhancing cerebellar lesion, hypointense on T1-weighted and hyperintense on T2-weighted images (Fig. 1a). The cerebrospinal fluid examination was normal including a PCR for JCV DNA. As the clinical status of the patient was deteriorating, a stereotactic biopsy was carried out.
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Histological examination showed areas of demyelination with myelin-loaded macrophages (Fig. 1b), and enlarged, bizarre glial cells. Immunohistochemistry was in glial cells intranuclear positive for JCV large T antigen (Fig. 1c), establishing the diagnosis of PML.
Methotrexate and steroids were discontinued and as the patient's condition continued to worsen with onset of tremor and nausea we started her on cidofovir using a reduced dose regimen (0.25 mg/kg) as previously described for renal transplant patients [5].
The patient received six infusions of cidofovir in 2-week intervals (cumulative dose 1186.5 mg) without any side effects. In addition, the patient received mirtazapine at a daily dose of 15 mg starting after the second infusion of cidofovir. Upon that regimen, the patient improved dramatically. Nausea, dizziness and vertigo completely stopped with a residual tremor remaining. An MRI after 3 months showed a reduction in the surrounding oedema and a slight decrease of the lesion size (Fig. 1d).
Currently, at 6 months after diagnosis of PML, the patient has a stable neurological status. Treatment with hydroxychloroquine was initiated because of worsening of arthralgias and mirtazapine was increased to 30 mg/day. Cidofovir was stopped.
In summary, we report on a patient with sarcoidosis and a focal cerebral lesion, in whom stereotactic biopsy revealed the diagnosis of PML, strengthening the importance of histological confirmation in cases of doubt.
In a recent study summarizing 58 HIV-negative patients with PML, 9% of patients suffered from sarcoidosis as the underlying disorder [6]. Patients with sarcoidosis seem to be at increased risk with regard to both opportunistic infections [7] and malignancies [8] and as they are frequently treated with steroids or other immunosuppressive drugs, it is unclear whether this is secondary to immunosuppressive treatment or may reflect an underlying intrinsic immune defect [9].
The possibility of an underlying opportunistic infection should therefore be considered in all sarcoidosis patients presenting with atypical neurological symptoms. Since the correct diagnosis, in particular the distinguishment from neurosarcoidosis, has a major impact on the further management of the patient, it is essential that a stereaotactic biopsy be included in the diagnostic regimen.
The concept of including a 5HT2A receptor antagonist in a treatment regimen for PML is intriguing and its successful employment in a patient with dermatomyositis and PML has previously been reported [10]. These cases suggest that the inclusion of mirtazapine in a treatment regimen in HIV-negative patients with PML might be associated with a favourable outcome. However, further studies are needed to confirm this observation.
The authors have declared no conflicts of interest.
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