The spectrum of MRI findings of progressive multifocal leukoencephalopathy in patients with multiple sclerosis in the Czech Republic

Czech version

Authors: M. Vaněčková ¹; A. Martinková ²; R. Tupý ³; J. Fiedler ⁴; I. Štětkářová ⁵; E. Medová ⁵; M. Vachová ⁶; J. Marková ⁷; M. Grunermelová ⁷; E. Meluzínová ⁸; J. Adámková ⁹; J. Kubále ¹⁰; M. Talábová ¹¹; D. Horáková ¹² ; E. Kubala Havrdová ¹²
Authors‘ workplace: Oddělení MR, Radiodiagnostická klinika 1. LF UK a VFN v Praze ¹; MS centrum, Neurologická klinika Pardubická krajská nemocnice ²; Klinika zobrazovacích metod LF v Plzni UK a FN Plzeň ³; Neurologická klinika LF v Plzni UK a FN Plzeň ⁴; Neurologická klinika 3. LF UK a FN Královské Vinohrady, Praha ⁵; Neurologické oddělení, Krajská zdravotní, a. s. – Nemocnice Teplice, o. z. ⁶; Neurologická klinika 3. LF UK a Thomayerova nemocnice ⁷; Neurologická klinika 2. LF UK a FN Motol ⁸; Neurologické oddělení, Nemocnice České Budějovice, a. s. ⁹; Radiologické oddělení, Nemocnice České Budějovice, a. s. ¹⁰; MS centrum, Neurologická klinika FN Hradec Králové ¹¹; RS centrum, Neurologická klinika a Centrum klinických neurověd, 1. LF UK a VFN v Praze ¹²
Published in: Cesk Slov Neurol N 2019; 82(4): 381-390
Category: Original Paper
doi: https://doi.org/10.14735/amcsnn2019381

Overview

Aim: To show the full spectrum of MRI findings in all patients ever diagnosed with progressive multifocal leukoencephalopathy (PML), which is associated with natalizumab therapy in patients with MS in the Czech Republic.

Patients and methods: The first case was described in 2009, the last case in December 2018, with a total of 14 diagnosed cases of PML in MS patients. This paper evaluates the MRI findings that showed the presence of PML; the diagnosis was subsequently confirmed by detection of the John Cunningham virus (JCV) DNA from cerebrospinal fluid using polymerase chain reaction. All patients met the American Academy of Neurology criteria from 2013 for diagnosis of this disease. The MRI protocol used was variable, both because patients were examined at different MRI sites across the Czech Republic, and because of evolution of protocols over time. In all patients, the protocol contained fluid attenuated inversion recovery (FLAIR), which is the most sensitive sequence for early PML detection.

Results: 13 patients (92.9%) had a positive MRI finding. The most frequent finding was typical white matter involvement in the subcortical area of the frontal lobe (42.9%), followed by the parietal (28.6%) and temporal lobes (28.6%). The extent of the pathology was also very variable, from very small discrete lesions to extensive diffuse lesions affecting multiple lobes. Two patients were found to have cerebellar and pons foci (14.3%), one patient in the mesencephalon and another in the medula oblongata. There were thalamic lesions in two cases, and one case of putamen lesions. In some cases, MRI presentation of PML was very similar to the MRI presentation of MS and suspicion of PML was considered because there was new progression of MRI. One patient was completely atypical compared to the rest of the group. PML was diagnosed from a routine lumbar puncture done when therapy was changed, and the MRI finding at that time was negative. Positive findings appeared only 6 months after the PML diagnosis. This case involved the JCV-granulocytic neuronopathy with cerebellum affection subtype.

Conclusion: The Czech cohort of PML patients confirms the great variability in MRI findings and points out the importance of careful MRI monitoring to detect the disease in the subclinical phase.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

捷克共和国多发性硬化症患者进行性多灶性白质脑病的MRI表现谱

目的：显示所有曾被诊断为进行性多灶性白质脑病(PML)患者的MRI全谱表现，与捷克多发性硬化患者纳他利珠单抗治疗有关。

患者和方法：第一个病例描述于2009年，最后一个病例描述于2018年12月，在MS患者中总共诊断出14例PML病例。本文对显示PML存在的MRI表现进行了评价;随后使用聚合酶链反应从脑脊液中检测到约翰·坎宁安病毒(JCV) DNA，从而确诊。从2013年开始，所有患者均符合美国神经科学会诊断该病的标准。所使用的MRI方案是可变的，这既是因为在捷克共和国的不同MRI站点对患者进行了检查，又是由于随着时间的推移方案的发展。在所有患者中，该方案均包含体液衰减倒置恢复（FLAIR），这是早期PML检测最敏感的序列。

结果：13例（92.9％）的MRI阳性。最常见的发现是额叶皮层下区域典型的白质受累（42.9％），其次是顶叶（28.6％）和颞叶（28.6％）。病理范围也很不稳定，从很小的离散病变到广泛的弥漫性病变影响多个肺叶。两名患者发现小脑和桥脑病灶(14.3%)，一名患者在中脑，另一名患者在延髓。有丘脑病变2例，壳核病变1例。在某些情况下，PML的MRI表现与MS的MRI表现非常相似，并且考虑到PML的怀疑是因为MRI有新的进展。与其他组相比，一名患者完全不典型。根据更换疗法后的常规腰穿检查诊断为PML，当时MRI呈阴性。 PML诊断后仅6个月才出现阳性结果。该病例涉及具有小脑情感亚型的JCV-粒细胞性神经病。

结论：捷克的PML患者队列证实了MRI表现的巨大差异，并指出了认真进行MRI监测以检测亚临床阶段疾病的重要性。

关键词：多发性硬化–进行性多灶性白质脑病– MRI –无症状影像

Keywords:

Multiple sclerosis – progressive multifocal leukoencephalopathy – MRI – asymptomatic imaging

Sources

1. Keen DL, Legare C, Taylor E et al. Monoclonal antibodies and progressive multifocal leukoencephalopathy. Can J Neurol Sci 2011; 38: 565– 571.

2. Sahraian MA, Radue EW, Eshaghi A et al. Progressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis. Eur J Neurol 2012; 19(8): 1060– 1069. doi: 10.1111/ j.1468-1331.2011.03597.x.

3. Paz SP, Branco L, Pereira MA et al. Systematic review of the published data on the worldwide prevalence of John Cunningham virus in patients with multiple sclerosis and neuromyelitis optica. Epidemiol Health 2018; 40: e2018001. doi: 10.4178/ epih.e2018001.

4. Fragoso YD, Brooks JB, Eboni AC et al. Seroconversion of JCV antibodies is strongly associated to natalizumab therapy. J Clin Neurosci 2019; 61: 112– 113. doi: 10.1016/ j.jocn.2018.10.128.

5. Vaněčková M, Seidl Z. Roztroušená skleróza a onemocnění bílé hmoty v MR zobrazení. Praha: Mladá fronta 2018: 286.

6. Yousry TA, Pelletier D, Cadavid D et al. Magnetic resonance imaging pattern in natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 2012; 72(5): 779– 787. doi: 10.1002/ ana.23
676.

7. Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders by JC virus: clinical features and pathogenesis. Lancet Neurol 2010; 9(4): 425– 437. doi: 10.1016/ S1474-4422(10)70040-5.

8. Honce JM, Nagae L, Nyberg E. Neuroimaging of natalizumab complications in multiple sclerosis: PML and other associated entities. Mult Scler Int 2015; 2015: 809252. doi: 10.1155/ 2015/ 809252.

9. Rosenkrantz T, Novas M, Terborg C. PML in a patient with lymphocytopenia treated with dimethyl fumarate. N Engl J Med 2015; 372(15): 1476– 1478. doi: 10.1056/ NEJMc1415408.

10. Berger JR, Aksamit AJ, Clifford DB et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology 2013; 80(15): 1430– 1438. doi: 10.1212/ WNL.0b013e31828c2fa1.

11. Dong-Si T, Richman S, Wattjes MP et al. Outcome and survival of asymptomatic PML in natalizumab--treated MS patients. Ann Clin Transl Neurol 2014; 1(10): 755– 764. doi: 10.1002/ acn3.114.

12. Dong-Si T, Gheuens S, Gangadharan A et al. Predictors of survival and functional outcomes in natalizumab-
-associated progressive multifocal leukoencephalopathy. J Neurovirol 2015; 21(6): 637– 644. doi: 10.1007/ s13365-015-0316-4.

13. Zhang Y, Wright C, Flores A. Asymptomatic progressive multifocal leukoencephalopathy: a case report and review of the literature. J Med Case Rep 2018; 12(1): 187. doi: 10.1186/ s13256-018-1727-7.

14. Vaněčková M, Seidl Z, Čáp F et al. Návrh bezpečnostní MR monitorace pacientů s roztroušenou sklerózou léčených natalizumabem. Cesk Slov Neurol N 2016; 79/ 112(6): 663– 669.

15. Wattjes MP, Steenwijk MD, Stangel M. MRI in the diagnosis and monitoring of multiple sclerosis: an update. Clin Neuroradiol 2015; 25 (Suppl 2): 157– 165. doi: 10.1007/ s00062-015-0430-y.

16. Ho PR, Koendgen H, Campbell N et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol 2017; 16(11): 925– 933. doi: 10.1016/ S1474-4422(17)30282-X.

17. Wattjes MP, Richert ND, Killestein J et al. The chameleon of neuroinflammation magnetic resonance paging characteristics of natalizumab – associated progressive multifocal leukoencephalopathy. Mult Scler 2013; 19(4): 1826– 1840. doi: 10.1177/ 1352458513510224.

18. Tan IL, McArthur JC, Clifford DB et al. Immune reconstitution inflammatory syndrome in natalizumab-
-associated PML. Neurology 2011; 77(11): 1061– 1067. doi: 10.1212/ WNL.0b013e31822e55e7.

19. Wattjes MP, Wijburg MT, Vennegoor A et al. MRI characteristics of early PML-IRIS after natalizumab treatment in patients with MS. J Neurol Neurosurg Psychiatry 2016; 87(8): 879– 884. doi: 10.1136/ jnnp-2015-311411.

20. Štětkářová I, Medová E, Bučilová V et al. Progresivní multifokální leukoencefalopatie u nemocné s roztroušenou sklerózou léčenou natalizumabem. Ces Radiol 2013; 67(1): 577– 583.

21. Vaněčková M, Seidl Z, Krásenský J et al. Naše zkušenosti s MR monitorací pacientů s roztroušenou sklerózou v klinické praxi. Cesk Slov Neurol N 2010; 73/ 106(6): 716– 720.

22. Wattjes MP, Vennegoor A, Steenwijk MD et al. MRI pattern in asymptomatic natalizumab-associated PML. J Neurol Neurosurg Psychiatry 2015; 86(7): 793– 798. doi: 10.1136/ jnnp-2014-308630.

23. Clifford DB, De Lucca A, Simpson DM et al. Natalizumab-associated progresive multifocal leukoencefalopathy in patiens with multiple sclerosis: lessons from 28 cases. Lancet Neurol 2010; 9(4): 438– 446. doi: 10.1016/ S1474-4422(10)70028-4.

24. Sahraian MA, Radue EW, Eshaghi A et al. Progressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis. Eur J Neurol 2012; 19(8): 1060– 1069. doi: 10.1111/ j.1468-1331.2011.03597.x.

25. Blair NF, Brew BJ, Halpern JP. Natalizumab-associated PML identified in the presymptomatic phase using MRI surveillance. Neurology 2012; 78(7): 507– 508. doi: 10.1212/ WNL.0b013e318246d6d8.

26. Hodel J, Outteryck O, Dubron C et al. Asymptomatic progressive multifocal leukoencephalopathy associated with natalizumab: diagnostic precision with MR imaging. Radiology 2016; 278(3): 863– 872. doi: 10.1148/ radiol.2015150673.

27. Wijburg MT, Witte BI, Vennegoor A et al. MRI criteria diffetentiating asymptomatic PML from new MS lesions during natalizumab pharmacovigilance. J Neurol Neurosurg Psychiatry 2016; 87(10): 1138– 1145. doi: 10.1136/ jnnp-2016-313772.

28. Phan-Ba R, Lommers E, Tshibanda L et al. MRI preclinical detection and asymptomatic course of a progressive multifocal leucoencephalopathy (PML) under natalizumab therapy. J Neurol Neurosurg Psychiatry 2012; 83(2): 224– 226. doi: 10.1136/ jnnp-2011-300511.

29. Hodel J, Bapst B, Outteryck O et al. Magnetic resonance imaging changes following natalizumab discontinuation in multiple sclerosis patients with progressive multifocal leukoencephalopathy. Mult Scler 2018: 1352458517750765. doi: 10.1177/ 1352458517750
765.

30. Taieb G, Renard D, Thouvenont E et al. Transient punctate enhancing lesions preciding natalizumab-
-associated progressive multifocal leukoencephalopathy. J Neurol Sci 2014; 346(1– 2): 364– 365. doi: 10.1016/ j.jns.2014.09.007.

31. Mathew RM, Murname M. MRI in PML: bilateral medullary lesions. Neurology 2004; 63(12): 2380. doi: 10.1212/ 01.wnl.0000141860.97900.8a.

32. Wijburg MT, van Oosten BW, Murk JL et al. Heterogeneous imaging characteristics of JC virus granule cell neuronopathy (GCN): a case series and review on the literature. J Neurol 2015; 262(1): 65– 73. doi: 10.1007/ s00415-014-7530-5.

33. Eichinger P, Schon S, Pongratz V et al. Accuracy of unenhanced MRI in the detection of new brain lesions in multiple sclerosis. Radiology 2019; 291(2): 429– 435. doi: 10.1148/ radiol.2019181568.