Bcr.03.2011.4036.indd

Unusual association of diseases/symptoms Progressive multi-focal leukoencephalopathy as a rare lethal complication in untreated sarcoidosis Sabine K Hohlfeld, 1 Huldrych F Günthard, 2 Jonas Zeitz,1 Pascal Locher, 1 Esther Bachli 3 1 Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland ; 2 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland ; 3 Department of Internal Medicine, Uster Hospital, Uster, Switzerland Correspondence to PD Dr Esther Bachli, [email protected]
Summary
Progressive multi-focal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of John
Cunningham virus. It is an opportunistic infection affecting patients who are severely immunocompromised due to an underlying disease or
secondary to immunosuppressive therapy. To date, no effective antiviral therapy has been established, though several substances are being
investigated. The authors present the case of a 39-year-old previously healthy patient who was diagnosed with PML and sarcoidosis stage
III without having received prior immunosuppressive treatment. The patient did not respond to treatment with mirtazapine, which has been
used empirically, and deceased shortly after diagnosis.
BACKGROUND
ter of the right temporal and occipital lobe as well as in the Generally, progressive multi-focal leukoencephalopathy thalamus and adjacent structures ( fi gure 1 ). (PML) occurs as an opportunistic infection in severely Normal cell counts, protein and glucose levels were immunosuppressed patients. It is seen mostly in untreated measured in the cerebrospinal fl uid (CSF) and no oligo- HIV-infected patients (AIDS defi ning illness) and also in clonal bands were detected. PCR testing for cytomegalovi- transplant patients and recently it has also been described rus, Epstein–Barr virus, herpes simplex virus and varicella in patients with multiple sclerosis treated with natalizu- zoster virus replication was negative. Yet John Cunningham mab. In our case, however, we did not have a classical virus (JCV)-specifi c DNA was detected repeatedly in the state of immunodefi ciency. Thus, it represents a very rare CSF, without JCV replication in blood or urine samples. case and should remind physicians to think of PML also in atypical diseases. CASE PRESENTATION
A 39-year-old Portuguese patient presented with left-sided
weakness and hypoesthesia, which had developed over a
period of days. Additionally, he had lost 13% of his body-
weight during the past 2 months and suffered from non-
productive cough for several weeks. To date, he had been
healthy and had not received any medication. The family
history was non-contributory. Neurological examination
revealed mild paresis and hypoesthesia of the left limb,
left-sided hyperrefl exia, gait ataxia, left haemianopsia and
hemineglect.
INVESTIGATIONS
Chest x-ray and a CT scan showed a pronounced medi-
astinal lymphadenopathy and reticulo-nodular lung tissue
densities consistent with advanced sarcoidosis (stage III) as
well as a marked splenomegaly (22 cm). The bronchoalve-
olar lavage displayed an elevated CD4+/CD8+ ratio (factor
5.6). Lung and bone marrow biopsies showed non-caseat-
ing granulomas, suggestive of sarcoidosis. Other granulo-
Figure 1 MRI fl uid attenuated inversion recovery scans showed
matous diseases were ruled out by serological testing. an area of hyperintense signal in the subcortical white matter of Cranial MRI revealed large hyper dense areas on the right temporal and occipital lobe as well as in the thalamus T2-weighted images, located in the subcortical white mat- BMJ Case Reports 2012; doi:10.1136/bcr.03.2011.4036 A stereotactic brain biopsy was performed, showing mirtazapine has been used empirically showing improve- neuropathological changes characteristic of PML, namely focal white matter destruction with JCV-infected oli- In summary, in HIV negative patients with PML as well godendrocytes (as confi rmed by immunohistochemistry). as in patients who are not receiving immunosuppressive Laboratory tests revealed an elevated level of ACE, therapy, no established treatment exists. The mechanisms polyclonal gammopathy, a reduced lymphocyte count leading to symptomatic PML in patients without a docu- (600 cells/μl) and severely suppressed CD4+ lymphocyte mented immune defect remain unknown. Considering fraction (171 cells/μl), whereas the CD4+/CD8+ ratio was the sarcoidosis as underlying cause we even discussed a normal. No autoantibodies could be detected and HIV treatment with immunosuppressive therapy to eventu- infection was ruled out by repetitive screening, HIV RNA ally improve the patient’s immune response. Because of and p24 ag tests as well as a particle associated elevated possibly aggravating JC-infection by this measurement reverse transcriptase test to detect potential retroviral we fi nally opted for a treatment with mirtazapine alone. activity not detected by standard HIV tests. Unfortunately, the patient experienced rapid deterioration after initiation of therapy and died 2 months later. DIFFERENTIAL DIAGNOSIS
We describe a case of disseminated sarcoidosis with- out prior immunosuppressive therapy and histologically proven symptomatic PML that did not respond to mirta-zapine therapy. The pathophysiologic mechanisms leading TREATMENT
to PML in this case remain to be established. A treatment with mirtazapine was initiated (15 mg/d). Clinically, and confi rmed by follow-up MRI of the brain 4 weeks after the initial imaging, no progression of the dis- Learning points
ease was noted. Concerning sarcoidosis, the patient was asymptomatic apart from a slight restrictive ventilatory ▶ Whereas PML is well known in patients with impairment. Corticosteroids were not administered. AIDS and can also rarely occur in patients with immunosuppressive therapy such as for example, OUTCOME AND FOLLOW-UP
natalizumab in patients with multiple sclerosis, in HIV- Six weeks after diagnosis, the left-sided hemiparesis had negative patients it is still a rare but serious disease. worsened and the patient showed severe altered mental ▶ Sarcoidosis represents an atypical cause of PML status and had suffered a generalised seizure. because it is not necessarily associated with a Progression of PML was confi rmed in a CT scan. Given the classical immunosuppressive state or therapy, as profound clinical deterioration no further treatment was under- taken and the patient died 1 month later, that is, 2 months ▶ While treating HIV with antiretroviral therapy and after diagnosis. Permission for autopsy was not granted. removing immunosuppressive therapy represent therapeutic options in other cases, PML in sarcoidosis DISCUSSION
is even more diffi cult to manage since there is no The clinical and virological fi ndings and pathologic changes specifi c treatment of JC-virus and immunosuppression on neuroimaging in this patient were consistent with the cannot be improved in this case of sarcoidosis. diagnosis of PML, a brain biopsy ruled out other potentially ▶ PML is a differential diagnosis which has to be treatable diseases. Simultaneously, our patient was found to considered also in supposedly immunocompetent have sarcoidosis stage III. PML in association with sarcoido- patients for example, with sarcoidosis and neurological sis has mostly been described in patients receiving immuno- suppressive therapy, but cases of PML as fi rst manifestation in patients with sarcoidosis have rarely been reported. 1 2 There is no specifi c treatment for JCV infection. In HIV- Acknowledgements The authors thank PD Dr Urs Schwarz, consultant in
positive patients with PML, highly active antiretroviral Neurology, University Hospital Zurich, Switzerland and Professor Dr Hans Hirsch, University Hospital Basel, Switzerland for helpful discussions. therapy is the best therapeutic option. In patients receiving immunosuppressive medication, a discontinuation or dose Competing interests None.
Patient consent Obtained.
Cytarabine has been shown to decrease JCV replication invitro and appeared to stabilise the clinical status of HIV REFERENCES
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Hohlfeld SK, Günthard HF, Zeitz J, Locher P, Bachli E. Progressive multi-focal leukoencephalopathy as a rare lethal complication in untreated sarcoidosis. BMJ Case Reports 2012;10.1136/bcr.03.2011.4036, Published XXX Become a Fellow of BMJ Case Reports today and you can:▶ Submit as many cases as you like▶ Enjoy fast sympathetic peer review and rapid publication of accepted articles▶ Access all the published articles▶ Re-use any of the published material for personal use and teaching without further permission For information on Institutional Fellowships contact [email protected] Visit casereports.bmj.com for more articles like this and to become a Fellow Keep up to date with all published cases by signing up for an alert (all we need is your email address) http://casereports.bmj.com/cgi/alerts/etoc BMJ Case Reports 2012; doi:10.1136/bcr.03.2011.4036

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