An unusual cause of fatal rapid-onset ataxia plus syndrome
© The Author(s). 2017
Received: 6 November 2016
Accepted: 4 April 2017
Published: 21 April 2017
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder of the central nervous system caused by reactivation of the JC-virus and is in most cases associated with underlying immunosuppression. Acquired immune deficiency syndrome (AIDS) and hematological malignancies are well-known predisposing factors for PML. However, in the past ten years, various pharmacological agents have been associated with increased risk of PML. Based on the phenomenology PML can be divided into the cerebral form and the rare cerebellar form.
Here we describe a man affected by polycythemia vera (PCV) that was treated with hydroxyurea (HU) and developed PML. The initially PML presentation included ataxia as one of the main features. Brain MRI displayed widespread supratentorial and infratentorial lesions. Immunological analysis revealed absence of reactivity to a wide range of antigens. The course of disease was rapidly progressive with fatal outcome - autopsy ruled out leukemic transformation.
The occurrence of PML in PCV patients is very rare and has been reported only once. Movement disorders, such as ataxia, are also less frequent. In the present case the PML was likely multifactorial.
KeywordsPML Ataxia JC-virus Polycythemia vera Hydroxyurea FASCIA analysis
The association between polycythemia vera (PCV) and progressive multifocal leukoencephalopathy (PML) is very rare and has been reported only once . This previously reported patient with PCV was treated with interferon (IFN)-α2B and thalidomide, but not hydroxyurea. In most cases PML is associated with immunodeficiency [2, 3]; however in very rare occasions it may also afflict immunocompetent patients . The most frequent symptoms are motor weakness, changes in mentation and impaired vision , whereas movement disorders are less frequently seen .
CD 4 PWM
233 – 2189 c/μL
CD 8 PWM
50 – 549 c/μL
CD 19 PWM
42 – 741 c/μL
CD 4 ConA
620 – 3800 c/μL
CD 8 ConA
180 – 1757 c/μL
CD 4 Influenza
19 – 1050 c/μL
CD 4 PPD
11 – 2022 c/μL
CD 4 Candida
51 – 1014 c/μL
Discussion and Conclusions
PML is often a fatal disease as in this described case. It can be divided into the cerebral form which is more common and the cerebellar from. The latter can also affect the brainstem [8, 9]. Infratentorial PML is rare, and so far there are only 30 case reports of infratentorial PML in the PubMed database . In the presented case the initial symptom was hemiplegia, but only within a few days a focal movement disorder, i.e. limb ataxia, became one of the main features of the patient’s condition.
Very few sporadic cases of PML have been described and reported in individuals without obvious immunosuppression or immunosuppressive risk factors [6, 8]. The vast majority of PML infections affect immunosuppressed patients. A CD4 count below 200 cells/μL has been identified as a major risk factor for PML in deeply immunosuppressed patients with AIDS . On the other hand, deleterious effects of hydroxyurea on CD4 lymphocytes have been described in children , but not in adults. In addition, myeloid malignancy such as PCV is not perceived as an immunosuppressive state. However, the natural process of immunological senescence involves both quantitative shifts and decreased functional capacity of various lymphocyte population subsets. Poor response of lymphocytes to mitogens can be seen in patients with immunological dysfunction or in patients with immunosuppressive treatments. The FASCIA results described here should therefore be interpreted in the context of a mild lymphopenia. In the described case, old age, myeloid malignancy and chemotherapy were likely the three factors that could have potentially contributed to JC-virus reactivation and development of a fatal disease. It is however difficult to pinpoint a single cause of PML in this case. Nevertheless, awareness of the potential consequences of such a constellation is important. PML should be considered as a differential diagnosis, especially in a PCV patient with rapidly progressive neurological symptoms without obvious immunosuppression or leukemic transformation.
Acquired immune deficiency syndrome
Central nervous system
Flow-cytometric assay of specific cell-mediated immune response in activated whole blood
John Cunningham virus
Progressive multifocal leukoencephalopathy
We express our gratitude to the patient’s widow for consenting to this report. Thanks to Dr. I. Schliemann at the Department of Pathology. Martin Paucar was supported by the Stockholm County Council.
Availability of data and materials
Dr. IK and Dr. MP: data collection and writing of the manuscript. Dr. IN and Dr. MK: pathological studies and editing of the manuscript. Dr. FH and Dr. EK: MRI imaging analysis and editing of the manuscript. Dr. DH and Dr. JW: editing of the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written consent from the next of kin was obtained and can be sent upon request.
Ethics approval and consent to participate
Since this is a single case report we did not consider applying to the ethics committee in Stockholm. We have discussed this issue in similar situations at our department and decided to obtain consent from the patient or the closest relative. This is what we did. The widow was informed of our intentions (we talked to her and sent written information) and she signed consent for publication since the patient wasn’t able to consent.
We don’t have an ethical committee at our hospital. The ethical committee is regional and it covers mostly studies (pharmacological, observational, interventions, etc.). An application has a cost (5–16 000 SEK) and is not practical to perform for case reports.
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- Verma S, Cikurel K, Koralnik IJ, et al. Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera. J Infect Dis. 2007;196(5):709–11.View ArticlePubMedGoogle Scholar
- Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology. 2013;80(15):1430–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Zaheer F, Berger JR. Treatment-related progressive multifocal leukoencephalopathy: current understanding and future steps. Ther Adv Drug Saf. 2012;3(5):227–39.View ArticlePubMedPubMed CentralGoogle Scholar
- Gheuens S, Pierone G, Peeters P, Koralnik IJ. Progressive multifocal leukoencephalopathy in individuals with minimal or occult immunosuppression. J Neurol Neurosurg Psychiatry. 2010;81(3):247–54.View ArticlePubMedGoogle Scholar
- Berger JR. The clinical features of PML. Cleve Clin J Med. 2011;78 Suppl 2:S8–12.View ArticlePubMedGoogle Scholar
- Stockhammer G, Poewe W, Wissel J, Kiechl U, Maier H, Felber S. Progressive multifocal leukoencephalopathy presenting with an isolated focal movement disorder. Mov Disord. 2000;15(5):1006–9.View ArticlePubMedGoogle Scholar
- Kalisch A, Wilhelm M, Erbguth F, et al. Progressive multifocal leukoencephalopathy in patients with a hematological malignancy: review of therapeutic options. Chemotherapy. 2014;60(1):47–53.View ArticlePubMedGoogle Scholar
- Arai Y, Tsutsui Y, Nagashima K, Shinmura Y, Kosugi T, Wakai M, Nishikage H, Yamamoto J. Autopsy case of the cerebellar form of progressive multifocal leukoencephalopathy without immunodeficiency. Neuropathology. 2002;22(1):48–56.View ArticlePubMedGoogle Scholar
- Parr J, Horoupian DS, Winkelman AC. Cerebellar form of progressive multifocal leukoencephalopathy (PML). Can J Neurol Sci. 1979;6(2):123–8.View ArticlePubMedGoogle Scholar
- Fukami S, Akimoto J, Ichikawa M, Jimbo H, Ikeda Y, Ishimura Y, Nanri K, Tsuchiya K, Kohno M. Primary cerebellar progressive multifocal leukoencephalopathy (PML) shows increased accumulation in (123)I-IMP SPECT. J Neurol Sci. 2016;361:92–4.View ArticlePubMedGoogle Scholar
- Albrecht H, Hoffmann C, Degen O, et al. Highly active antiretroviral therapy significantly improves the prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy. AIDS. 1998;12:1149–54.View ArticlePubMedGoogle Scholar
- Lederman HM, Connolly MA, Kalpatthi R, et al. Immunologic Effects of Hydroxyurea in Sickle Cell Anemia. Pediatrics. 2014;134(4):686–95.View ArticlePubMedPubMed CentralGoogle Scholar