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International Journal of Infectious Diseases 14S (2010) e313–e316

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International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Case Report Spontaneous recovery from progressive multifocal leukoencephalopathy in a patient with non-active sarcoidosis

Annemarie Goldbecker a,*, Argyro Tountopoulou a, Ulrich Wurster a, Frank Donnerstag b, Almuth Brandis c, Catharina Bonnemann a, Karin Weissenborn a a Department of and Neurophysiology, Hannover Medical School, Carl-Neuberg Straße 1, 30625 Hannover, Germany b Institute for Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany c Institute for Pathology, Hannover Medical School, Hannover, Germany

ARTICLE INFO SUMMARY

Article history: We report the case of a 50-year-old female patient with non-active sarcoidosis and no kind of Received 24 February 2009 , admitted to our hospital because of increasing and focal neurological Received in revised form 3 October 2009 deficits. Initially a tumor, herpes encephalitis, or neurosarcoidosis were suspected, but surprisingly Accepted 25 February 2010 biopsy revealed progressive multifocal leukoencephalopathy, additionally confirmed by JC-positive PCR Corresponding Editor: William Cameron, in cerebrospinal fluid. Cases of sarcoidosis and progressive multifocal leukoencephalopathy have been Ottawa, Canada reported before. This is the first case of a patient with no sign of active sarcoidosis and without immunosuppressive therapy who recovered spontaneously with a follow-up time of nearly 3 years. Keywords: ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Progressive multifocal leukoencephalopathy Sarcoidosis Magnetic resonance imaging

1. Introduction methotrexate had been given from 1992 to 1993 and occasional therapy with between 1988 and 1997. Clinical Progressive multifocal leukoencephalopathy (PML) is a nor- examination revealed sensory–motor dysphasia, apraxia, sac- mally fatal of the central , cadic eye movements, and rigor and , especially on the caused by human polyomavirus JCV, rarely affecting immunocom- right side. petent persons. The seroprevalence of JCV is up to 80%; the route of Magnetic resonance imaging (MRI) demonstrated cortical and is unknown.1 We report the first case of a patient with subcortical hyperintense lesions predominately in the left no sign of active sarcoidosis and without immunosuppressive hemisphere on a T2-weighted fluid attenuated inversion recovery therapy who recovered spontaneously with a follow-up time of (T2-FLAIR) sequence. The fronto-temporal lesion on the left side nearly 3 years. included the U-fibers and showed minimal mass effect (Figure 1A). Diffusion weighted images (DWI) depicted restricted diffusion in 2. Case report the subcortical frontal white matter (Figure 1B). Gliomatosis cerebri was suspected and the patient was treated with A 50-year-old woman with speech disturbances and changes dexamethasone for reduction of edema. Thereafter she became psychotic with , anxiety, and aggressive behavior. A of personality was admitted to our clinic in April 2006 under the suspicion of a brain tumor. An ambulant computer tomography second MRI one week later showed no significant differences. The suspected diagnosis was changed to encephalitis and a lumbar of the brain had already revealed a left fronto-parietal hypodense area. She had a 20-year medical history of sarcoidosis with puncture was performed. Cerebrospinal fluid (CSF) was normal with regard to cell count, cell differential, total protein concentra- pulmonary and joint involvement and had undergone resection of a basalioma 16 years ago. Immunosuppressive treatment with tion, and albumin quotient, but showed high intrathecal IgG (60%) and IgM (79%) synthesis and positive oligoclonal bands. Investiga- tion of the CSF for (HSV) type 1 found PCR to

* Corresponding author. Tel.: +49 511 532 2391; fax: +49 511 532 3115. be borderline positive, though not quantifiable, and no intrathecal E-mail address: [email protected] (A. Goldbecker). production against HSV, with an antigen antibody index

1201-9712/$36.00 – see front matter ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2010.02.2257 e314[(Figure_1)TD$IG] A. Goldbecker et al. / International Journal of Infectious Diseases 14S (2010) e313–e316

Figure 1. Magnetic resonance imaging (MRI) findings: (A) Early after admission T2-weighted fluid attenuated inversion recovery (FLAIR) showed cortical and subcortical hyperintense lesions in the left frontal lobe with minimal mass effect involving the U-fibers. (B) Diffusion weighted imaging (DWI) showed restricted diffusion in the subcortical white matter at the same level as in (A) with reduced apparent diffusion coefficient (ADC) values. (C) A follow-up MRI after one month depicted a cortical hyperintense cortex and subcortical edema involving the basal ganglia on T1-weighted images without contrast media. (D) With contrast media a juxtacortical enhancement was noted. (E) T2-weighted FLAIR one year after onset showed marked substance loss in the involved white matter with residual hyperintense signal consistent with gliosis. (F) Compared to (C) a marked volume loss of the cortex and subcortical white matter was seen one year after onset of symptoms. The hyperintense signal of the cortex was reduced.

(AI) of 0.7 (normal: <1.5). Despite the equivocal findings, herpes and viral hepatitis were negative, as were intrathecal AI for encephalitis was assumed and the patient was treated with cytomegalovirus, , , and . A acyclovir 10 mg/kg body weight for 14 days. As the patient’s follow-up MRI four weeks after the first one showed hyperintense condition continued to worsen, a second was cortex in the frontal lobe without signs of hemorrhage or performed 11 days later. A slight pleocytosis with 10 106 cells/l calcification on T2*-weighted images (Figure 1C). Cortical and (82% lymphocytes, 10% eosinophils) was found. Local IgG and IgM subcortical contrast enhancement including the U-fibers was synthesis was still increased at similar levels and oligoclonal bands noted (Figure 1D). were unaltered. Herpes encephalitis was now definitely excluded A stereotactic brain biopsy was then performed. Histology by a normal HSV antibody specificity index (ASI) and negative PCR, revealed inflammation with infiltration of mainly cytotoxic T- and neurosarcoidosis was subsequently considered. Tests for HIV lymphocytes and demyelination in the cortex and subcortex with [(Figure_2)TD$IG]

Figure 2. Neuropathological findings: (A) Necrosis (*) with macrophage infiltration and marked gliosis with reactive astrocytes with prominent cytoplasm (b), as well as oligodendrocytes with abnormal big dark nuclei ( ) (hematoxylin–eosin, original magnification 200). (B) Immunohistochemistry with positive reaction for SV40-antigen in astroglial cells. A. Goldbecker et al. / International Journal of Infectious Diseases 14S (2010) e313–e316 e315 astrogliosis (Figure 2A). Granulomas were not found. An immu- free, inactive sarcoidosis and PML, who improved without any nohistochemical assay was positive for Simian virus 40 (SV40) specific antiviral treatment, with a follow-up of nearly 3 years. No (Figure 2B). against SV40 show cross-reactivity with similar case with similar clinical symptoms and course of disease the JC virus (JCV), the agent responsible for PML. After confirmation has been described in patients with a history of sarcoidosis, but has of JCV in the CSF by PCR, PML was finally diagnosed. A blood count been for example with leukaemia.13 and analysis of lymphocyte subpopulations and CD4/CD8 ratio Our patient was treated with acyclovir because of suspected (1.67, normal 0.9–1.70) were normal. No signs of progression of the herpes encephalitis. Acyclovir is used against with sarcoidosis could be detected. of the herpes group; however there are no indications that Surprisingly the patient improved after the biopsy, while all it may also be active against JCV. medication had been stopped. Aphasia and motor functions The patient is now under olanzapine therapy. It has recently improved and she was completely oriented. Panic and aggression been reported that JCV uses the serotonergic receptor 5HT2A to attacks necessitated temporary treatment with olanzapine. Finally infect human glia cells.14 Antipsychotics have been considered to the patient was discharged to a rehabilitation clinic. be useful in PML therapy, with mirtazapine being the most used 15,16 17 Eight months later the patient developed a pneumonia, which drug. Olanzapine is also an antagonist at the 5HT2A receptor, was treated with and for unknown reasons also with although not the most potent compared to other neuroleptics. The . Thereby hallucinations, agitation, and confusion were blocking of the 5HT2A receptor by olanzapine may prevent a new again induced. Cessation of the therapy and commence- eruption of infection in our patient. In our opinion the recurring ment of olanzapine quickly restored her former constitution and psychotic decompensations were not related to new inflammatory she was able to live alone with only minimal assistance. One year activity but to the extensive brain damage with the associated later, after the patient had stopped the olanzapine therapy for addition of glucocorticoids and the termination of the antipsy- some weeks, yet another psychotic attack occurred in which she chotic therapy . suffered delusions that she would die of thirst and hunger. At this On MRI, hyperintense subcortical lesions in the white matter in time MRI showed marked substance loss and a FLAIR sequence, with minor mass effect involving the U-fibers consistent with gliosis predominantly in the subcortical white and the cortex of more than three lobes, are typical findings of matter, including the U-fibers (Figure 1E). The cortex in the gliomatosis cerebri.18 However, areas of restricted diffusion in the affected areas was thinned and a reduction of the hyperintense white matter unrelated to vascular territories are atypical for signal on T1-weighted images could be seen. Contrast enhance- gliomatosis and can be seen in systemic diseases like toxic, ment was not noted (Figure 1F). A control investigation of the CSF metabolic, or hypertensive .19 An unusual finding showed a normal cell count and albumin quotient, but IgG and IgM was the hyperintense signal of the cortex on T1-weighted imaging were still high (64% and 50%, respectively) with persistent (T1w) one month after the onset of symptoms. Focal hemorrhage is oligoclonal IgG bands. PCR for JCV-DNA was negative. The patient an atypical pattern in PML20 and a susceptibility sensitive MRI stabilized quickly after resumption of the olanzapine medication. sequence (T2*-weighted gradient echo sequence) ruled out even a Nearly three years after the onset of symptoms, the patient still minor bleed. The development of a hyperintense cortex in T1w in has an organic psycho- with anxiety, word-finding the overlaying white matter one month after the diffusion difficulties, and a mild resting and intentional tremor of the right restriction could be interpreted as cortical damage, similar to arm. She has moved into assisted living accommodation, but needs the signs of cortical laminar necrosis. In the case of PML, restricted only minimal help in daily life. diffusion is a sign of an active infection.21 Contrast enhancement of the PML lesions, as was present in the 3. Discussion second MRI, was interpreted as an inflammatory reaction, and supported in this case by the findings of a cytotoxic T-lymphocyte The correct diagnosis in our case was delayed because PML was infiltrate in the biopsy. Such alterations in MRI imaging have not included in the differential diagnosis for a patient who was mainly been observed in HIV-infected patients with PML after apparently immunocompetent, and the neuroimaging as well as initiation of highly active antiretroviral therapy and were the CSF findings were rather untypical for PML. Sarcoidosis is a associated with the initial clinical deterioration. Whether this granulomatous disease with manifestation in the intrathoracic immune-reconstitution inflammatory syndrome influences out- lymph nodes and multiple extrathoracic locations, including the come is unclear. A multicenter observation did not reveal an . The exact etiology remains unclear. The influence on mortality,22 and other authors have described a immunological reaction in sarcoidosis is mediated through T- favorable outcome.3,23,24 lymphocytes. In acute sarcoidosis bronchoscopy shows a lympho- In conclusion, PML should be considered in patients with a cytic alveolitis, with an increased CD4/CD8 ratio.2 Disturbance of T history of sarcoidosis and new neurological deficits even if there is lymphocytes may predispose to PML, because JCV-specific no hint of active sarcoidosis. Contrast enhancement of the PML cytotoxic T lymphocytes seem to protect immunocompetent lesions in such cases is associated with an increased inflammatory people against the development of PML3 and are associated with reaction and a potentially favorable outcome. A therapeutic a favorable outcome of PML in HIV-infected patients.4 intervention with serotonin receptor antagonists may be indicated. Although opportunistic infections in sarcoidosis are rare,5 the Conflict of interest: No conflict of interest to declare. coincidence of sarcoidosis and PML has been known for decades.6 We found one published case of a patient with sarcoidosis without References immunosuppression and a postmortem diagnosis of PML.7 Another case (presented as an abstract) was treated with cidofovir and 1. Eash S, Manley K, Gasparovic M, Querbes W, Atwood WJ. The human poly- recovered in the 4 months of follow-up.8 And in one case the omaviruses. Cell Mol Life Sci 2006;63:865–76. manifestations of PML led to the diagnosis of sarcoidosis.9 The 2. Ziegenhagen MW, Mu¨ ller-Quernheim J. The cytokine network in sarcoidosis and its clinical relevance. J Intern Med 2003;253:18–30. patient was also treated with cidofovir, but additionally with 3. Koralnik IJ. Progressive multifocal leukoencephalopathy revisited: has the corticosteroids due to sarcoidosis-induced T-lymphocytopenia. disease outgrown its name? Ann Neurol 2006;60:162–73. The follow-up time in this case was 2 years. Several cases of PML in 4. Du Pasquier RA, Kuroda MJ, Zheng Y, Jims JJ, Letvin NL, Koralnik IJ. A prospective study demonstrates an association between JC virus-specific cytotoxic T lym- immunosuppressed patients with sarcoidosis have been pub- phocytes and the early control of progressive multifocal leukoencephalopathy. 10–12 lished. We present the first case of a patient with medication- Brain 2004;127:1970–8. e316 A. Goldbecker et al. / International Journal of Infectious Diseases 14S (2010) e313–e316

5. Moller DR. Potential etiologic agents in sarcoidosis. Proc Am Thorac Soc 2007;4: patients with dermatomyositis. J Neurol Neurosurg Psychiatry 2006;77: 465–8. 1079–82. 6. Richardson Jr EP. Our evolving understanding of progressive multifocal leu- 16. Owczarczyk K, Hilker R, Brunn A, Hallek M, Rubbert A. Progressive multifocal koencephalopathy. Ann N Y Acad Sci 1974;230:358–64. leucoencephalopathy in a patient with sarcoidosis—successful treatment with 7. Rosenbloom MA, Uphoff DF. The association of progressive multifocal leukoen- cidofovir and mirtazapine. Rheumatology 2007;46:888–90. cephalopathy and sarcoidosis. Chest 1983;83:572–5. 17. Richelson E, Souder T. Binding of antipsychotic drugs to recep- 8. Haegele-Link S, Stoeter P, Klimpe S, Dieterich M. Progressive multifocal leu- tors—focus on newer generation compounds. Life Sci 2000;68:29–39. koencephalopathy successfully treated with cidofovir in a patient with pulmo- 18. Essig M, Schlemmer HP, Tronnier V, Hawighorst H, Wirtz R, vanKaick G. Fluid- nary sarcoidosis [abstract]. Aktuelle Neurologie 2006;33(Suppl 1):P599. attenuated inversion-recovery MR imaging of gliomatosis cerebri. Eur Radiol 9. De Raedt S, Lacor P, Michotte A, Flamez A, Ebinger G. Progressive multifocal 2001;11:303–8. leukoencephalopathy as first manifestation of sarcoidosis. Clin Neurol Neurosurg 19. Moritani T, Ekholm S, Westesson PL. Diffusion weighted MR imaging of the 2008;110:186–9. Brain. Berlin: Springer; 2004. 10. Vo¨lker HU, Kraft K, Arnold E, Steinhoff S, Kolios G, Sommer S. Progressive 20. Sarrazin JL, Soulie D, Derosier C, Lescop J, Schill H, Cordoliani YS. MRI aspects of multifocal leukoencephalopathy developing in advanced pulmonal sarcoidosis. progressive multifocal leukoencephalopathy. J Neuroradiol 1995;22:172–9. Clin Neurol Neurosurg 2007;109:624–30. 21. Bergui M, Bradac GB, Oguz KK, Boghi A, Geda C, Gatti G, Schiffer D. Progressive 11. Mackowiak-Cordoliani MA, De Seze J, Stojkovic T, Ferriby D, Ingrand D, Ver- multifocal leukoencephalopathy: diffusion-weighted imaging and pathological mersch P. Sarcoidosis and progressive multifocal leukoencephalopathy. Rev correlations. Neuroradiology 2004;46:22–5. Neurol (Paris) 2001;157:547–50. 22. Falco´ V, Olmo M, del Saz SV, Guelar A, Santos JR, Gutierrez M, et al. Influence of 12. Olindo S, Guillon B, Faighel M, Feve JR. [Progressive multifocal leukoencephalo- HAART on the clinical course of HIV-1-infected patients with progressive pathy and pulmonary sarcoidosis.]. Rev Neurol (Paris) 2000;156:1013–6. multifocal leukoencephalopathy: results of an observational multicenter study. 13. Williams-Gray CH, Aliyu SH, Lever AML, Dean AF, Lennox GG. Reversible J Acquir Immune Defic Syndr 2008;49:26–31. in a patient with progressive multifocal leucoencephalopathy. 23. Ku¨ ker W, Mader I, Na¨gele T, Uhl M, Adolph C, Klose U, et al. Progressive J Neurol Neurosurg Psychiatry 2007;78:408–10. multifocal leukoencephalopathy: value of diffusion-weighted and contrast- 14. Elphik GF, Querbes W, Jordan JA, Gee GV, Eash S, Manley K, et al. The human enhanced magnetic resonance imaging for diagnosis and treatment control. polyomavirus, JCV, uses serotonin receptors to infect cells. Science Eur J Neurol 2006;13:819–26. 2004;306:1380–3. 24. Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal 15. Vulliemoz S, Lurati-Ruiz F, Borruat FX, Delavelle J, Koralnik IJ, Kuntzer T, et al. leukoencephalopathy: harmful or beneficial? J Neurovirol 2003;9(Suppl 1): Favourable outcome of progressive multifocal leucoencephalopathy in two 25–31.