MRI phenotyping of progressive multifocal leukoencepahlopathy

MRI phenotyping of progressive multifocal leukoencepahlopathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article MRI phenotyping of progressive multifocal leukoencepahlopathy Semra Kosak, Julius Renne, Sandra Nay, Konstantin Fritz Jendretzky, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8994252/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the brain caused by JC polyomavirus. Brain magnetic resonance imaging (MRI) is the most sensitive tool for the in vivo detection of PML. However, comprehensive data on imaging findings using multisequence image acquisition are limited. Objective To investigate MRI findings of active PML in a large, prospectively collected cohort using a comprehensive and standardized MRI protocol. Methods Eighty patients with active PML underwent standardized 3T brain MRI including 3D-T2w-fluid-attenuated inversion recovery, 3D-T1-weighted, T2-weighted, diffusion-weighted (DWI), susceptibility-weighted (SWI) and contrast-enhanced T1-weighted sequences. Lesions were analysed regarding dissemination, location, morphology, borders, and signal characteristics. Results Eighty patients showed widespread involvement affecting the frontal (91%) and parieto-occipital (93%) lobes, typically involving juxtacortical (95%) and deep white matter (99%), but also cortical grey matter (94%) and deep grey matter (71%). Most patients showed large (> 3 cm, 89%), focal (99%), T2-hyperintense (100%) and T1-hypointense (99%) lesions with ill-defined borders (79%). DWI hyperintensity was present in 90%, while SWI hypointense rims were detected in 61% of the patients. Contrast enhancement was observed in 55%. Certain imaging features included the punctate pattern (76%) and the shrimp sign (20%). Conclusions PML exhibits characteristic but heterogeneous MRI findings on a patient level predominantely showing widespread white matter and frequent cortical grey matter involvement. Sequences such as DWI and SWI show frequently additional imaging findings potentially improving the diagnostic certainty. Our data stress the need of standardized imaging protocols for reliable detection and phenotyping of PML across diverse immunosuppressive conditions. PML JC polyomavirus JCPyV MR imaging neuroinfection phenotyping Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Progressive multifocal leukoencephalopathy (PML) is an opportunistic demyelinating disease of the central nervous system caused by lytic infection of oligodendrocytes and productive infection of astrocytes by the JC polyomavirus (JCPyV) [ 1 , 2 ]. The in vivo diagnosis of PML, as defined by the Neuroinfectious Disease Section of the American Academy of Neurology (AAN), is based on a combination of clinical presentation, characteristic neuroimaging findings, and the detection of JC virus DNA in the cerebrospinal fluid (CSF) using polymerase chain reaction (PCR). Alternatively, the diagnosis can be confirmed through histopathological examination of brain tissue [ 3 ]. Magnetic resonance imaging (MRI) is the most sensitive diagnostic imaging modality for identifying PML lesions in vivo. MRI can reveal characteristic abnormalities suggestive of PML even in asymptomatic patients and in cases where JCPyV DNA remains undetectable in the CSF [ 4 – 9 ]. PML occurs under various conditions of impaired cellular immunity, including HIV infection, hematologic malignancies, bone marrow or solid organ transplantation, and treatment with immunosuppressive therapies for autoimmune disorders such as multiple sclerosis (MS) or rheumatic diseases [ 4 , 6 , 10 – 12 ]. However, most previous descriptions of PML imaging features, particularly those regarding lesion morphology, dissemination, and temporal evolution, are derived from isolated case reports or small case series. The interpretation of imaging findings has been further hampered by heterogeneous and non-standardized MRI acquisition protocols [ 6 , 13 , 14 ]. While the basic MRI characteristics of PML lesions, i.e. their morphology and signal characteristics on T1- and T2-weighted images - are well established, other imaging features are known to be heterogeneous and may vary depending on the underlying immunosuppressive condition [ 4 , 10 , 12 ]. Data on the diagnostic value of additional MRI sequences, such as diffusion-weighted imaging (DWI), susceptibility-weighted imaging (SWI), and quantitative imaging techniques, remain limited [ 4 , 14 – 16 ]. Moreover, most prior studies have focused on PML associated with specific causes of immunosuppression, such as HIV infection or natalizumab treatment, introducing potential bias due to restricted patient selection [ 6 , 11 , 12 ]. The aim of this study was to systematically characterize the MRI features of PML using a comprehensive and standardized multisequence 3T brain MRI protocol in a large, prospectively collected cohort encompassing a broad spectrum of underlying immunosuppressive conditions. Methods Study Design and Patient Selection Patients presenting with new or progressive clinical symptoms suggestive of progressive multifocal leukoencephalopathy (PML) in the context of cellular immunosuppression suggestive for active PML in terms of virus replication referred to our hospital for the evaluation of treatment options were prospectively enrolled as part of the Hannover PML cohort between October 2020 and December 2024. Inclusion criteria comprised an age over 18 and clinical presentation and/or imaging signs suggestive of active PML (new or progressive clinical symptoms, progressive PML lesion manifestation on MRI or signs of active virus replication based on DWI hyperintensitiy[ 15 ]), diagnosis of PML (definite, probabely or possible) according to AAN diagnostic criteria [ 3 ]. Exclusion criteria included pregnancy and contraindications to magnetic resonance imaging (MRI) and Gadolinium injection. Additionally, patients with insufficient MRI data (severe motion artifacts or termination of the examination before completion) resulting in a completely non diagnostic examination were excluded. The study protocol was approved by the local institutional review board of Hannover Medical School, Germany. Written informed consent was obtained from all participants prior to inclusion, and the study has been conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. MRI Acquisition Protocol All examinations were performed on a 3 Tesla whole-body MRI system (Skyra, Siemens Healthineers, Erlangen, Germany) equipped with a 20-channel head & neck coil (Siemens Healthineers). A standardized multisequence brain MRI protocol was applied, including: T2-weighted 3D fluid-attenuated inversion recovery (FLAIR), 3D T1-weighted (MP2RAGE), axial 2D T2-weighted fast/turbo spin echo, axial diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping, axial susceptibility-weighted imaging (SWI), axial post-contrast T1-weighted turbo spin echo sequence following intravenous administration of a standard single dose (0.1 mmol/kg body weight) of gadolinium-based contrast agent (Gd-DOTA, Dotarem®, Guerbet, Roissy, France). Detailed image acquisition parameters are provided in Table 1 . Table 1 MRI acquisition parameters Contrast 3D-T1w 3D-FLAIR 2D-T2w SWI 2D-DWI 2D-T1w Sequence MP2RAGE SPACE TSE GRE EPI SE Anatomic orientation sagittal sagittal axial axial axial axial TR [ms] 5000 5000 4200 28 8300 489 TE [ms] 2.98 388 89 20 98 9.2 TI 1 [ms] 700 1800 - - - - TI 2 [ms] 2500 - - - - - Turbo Factor [-] 176 278 - - - - FOV [mm 3 ] (APxFHxRL) 240x256x176 260x260x173 240x240x135 256x144x208 240x132x240 263x350x350 Spatial Resolution [mm 3 ] 1.0 x1.0 x 1.0 0.5x0.5x0.9 0.6x0.6x3.0 (axial) 0.5x0.5x3.0 0.6x0.6x4.0 0.8x0.8x3.0 Acquisition time [min:sec] 8:22 5:47 2:08 3:02 3:11 4:48 Image Analysis and Interpretation All MRI datasets were reviewed using a dedicated workstation running Visage 7 client software (Visage Imaging, Richmond, Australia). Image analysis was independently performed by two readers with different levels of expertise: a board-certified neuroradiologist with 10 years of experience (J.R.) and a radiology resident with 6 years of experience (S.K.) under the supervision of an experienced neuroradiologist with 20 years of experience (MPW). All readers were blinded to all clinical and paraclinical data. Lesions suggestive of PML were identified and characterized according to predefined imaging criteria. The following imaging parameters were systematically assessed and reported as present or absent per patient (data on lesion charatceristics reported on a patient level and not of a single lesion level): Lesion dissemination: unifocal, multifocal, or widespread, as defined by Dong-Si et al. and Richert et al. [ 17 , 18 ]. Lesion location: classified by cerebral lobe and by tissue type (juxtacortical white matter, deep white matter, periventricular white matter, cortical grey matter, deep grey matter). Morphology and borders: including lesion size, shape, and margin definition. Signal characteristics: on T1w-, T2w-, T2w-FLAIR, DWI, and SWI sequences. Signs of inflammation: such as contrast enhancement and perilesional edema. Atrophy (volume loss of brain parenchyma exceeding the anticipated volume loss due to normal ageing): global or focal, including cerebellar involvement. Previously described imaging features: the hot cross bun sign [ 19 ], punctate T2w lesions [ 20 ], and the shrimp sign [ 21 ]. The complete scoring and classification scheme is summarized in Table 3 . Table 3 Imaging characteristics Imaging characteristics Number of Patients Present Absent % Present Lesion dissemination 80 Lesion dissemination Bilateral hemispheric involvement 74 6 93 Unilobar lesion dissemination 2 78 3 Multilobar lesion dissemination 6 74 8 Widespread lesion dissemination 72 8 90 Lesion location (lobes) Frontal lobe Parieto-occipital lobe Temporal lobe Corpus callosum 73 7 91 Parieto-occipital lobe 74 6 93 Temporal lobe 47 33 59 Corpus callosum 33 47 41 Thalamus 40 40 50 Basal ganglia 45 35 56 Brainstem 43 37 54 Cerebellum 37 43 46 Lesion location (brain tissue) Juxtacortical white matter Deep white matter Periventricular white matter Cortical grey matter Deep grey matter Dental nucleus 76 4 95 Deep white matter Deep white matter Periventricular white matter Cortical grey matter Deep grey matter Dental nucleus 79 1 99 Periventricular white matter 64 16 80 Cortical grey matter 75 5 94 Deep grey matter 57 23 71 Dentate nucleus 23 57 29 Lesion appearance focal 79 1 99 diffuse 60 20 75 lesion size > 3cm 71 9 89 Lesion borders Ill-defined border towards white matter 63 17 79 Sharp border towards white matter 61 19 76 Ill-defined border towards GM 6 74 8 Lesion signal intensities T1 hypointense 79 1 99 T1 isointense 47 33 59 T2/T2-FLAIR hyperintense 80 0 100 SWI (micro/macrohemorrhage) 20 60 25 Microbleeds related to PML lesions 19 61 24 SWI hypointense band towards the GM 49 31 61 DWI hyperintense 72 8 90 DWI isointense 41 39 51 DWI hypointense 55 25 69 ADC low 0 80 0 ADC intermediate 1 79 1 ADC high 19 61 24 ADC mixed m 61 19 76 Signs of inflammation Presence of contrast enhancement* 44 35 55 peripheral/ring like enhancement 16 63 20 homogeneous/punctate 34 45 43 patchy 28 51 35 Leptomeningeal contrast enhancement* 9 70 11 Mass effect 29 51 36 Signs of (perilesional) edema 41 39 51 Atrophy Presence of focal atrophy 33 47 41 Focal atrophy supratentorial 20 60 25 Atrophy infratentorial 26 54 33 Defined imaging signs punctate pattern / milky-way T2 lesions 61 19 76 Hot-cross-bun-sign 3 77 4 shrimp sign 16 64 20 Lesion characteristics are given as present or absent per patient. * One patient needed to be excluded in this analysis because the relevant (post Gadolinium T1) sequence was not diagnostic due to severe movement artifacts Clinical Evaluation and Laboratory Procedures All patients underwent detailed neurological examination by an experienced, board-certified neurologist at the Department of Neurology, Hannover Medical School. Cerebrospinal fluid (CSF) analysis included quantitative PCR testing for JCPy virus DNA. Each patient was classified as having definite, probable, possible, or no PML based on the clinical presentation, MRI findings, and virological results, following the diagnostic criteria established by the Neuroinfectious Disease Section of the AAN [ 3 ]. A subset of patients additionally underwent stereotactic brain biopsy for histopathological confirmation, according to the AAN-criteria [ 3 ]. Data availability statement Anonymized data not published within this article will be made available by request to the corresponding author from any qualified investigator. Results Patients Eighty-four patients were prospectively enrolled. Four patients did not complete a diagnostic MRI and were excluded for this analysis. All patients completed the full diagnostic work-up, including MRI and cerebrospinal fluid (CSF) analysis or brain biopsy. One patients MRI showed severe motion artifacts only on the post gadolinium T1 sequence. This patient remained in the study group, but contrast enhancement patterns were not evaluated. According to the AAN diagnostic criteria [ 3 ] 78 patients were classified as definite PML, one as probable, and one as possible PML. The demographic and clinical characteristics are summarized in Table 2 . Table 2 Patient characteristics Included patients 80 Sex (male/ female) 49 / 31 Age (years) # 63 [54 ; 71] Disease duration* (days) # 66 [39;113] Detection of JC virus DNA CSF Brain biopsy Not available 60 19 1 Category of PML diagnosis: Definite PML Probable PML Possible PML 78 1 1 Underlying immune suppression HIV 13 Hemato-oncologic disease 35 Autoimmune disease 9 Solid organ transplant 3 Primary immunodeficiency 5 Sarcoidosis 3 HSCT (hematopoietic stem cell transplantation) 1 Immunosuppressive treatment with monoclonal antibodies 4 Lymphopenia, other causes 7 Abbreviations: CSF=cerebrospinal fluid, Note:* defined as time interval between first clinical presentation and MRI acquisition; # median with interquartile range Image Analysis A detailed summary of imaging findings on a patient level is provided in Table 3 , and representative imaging examples are shown in Figs. 1 – 5 . Most patients exhibited large lesions (> 3 cm, 89%) with widespread (90%) and bilateral (93%) hemispheric involvement. The frontal (91%) and parieto-occipital (93%) lobes were most frequently affected. Lesions predominantly involved juxtacortical (95%) and deep white matter (99%), with frequent extension into the cortical (94%) and deep grey matter (71%). Nearly all patients showed at least one focal lesion (99%). Signal characteristics were consistent across sequences: all lesions were T2-hyperintense (100%) and nearly all were T1-hypointense (99%), while 59% of patients also demonstrated lesions with T1-isointense components. Borders were typically ill-defined (79%), although sharply demarcated margins toward adjacent white matter were also frequently observed (76%). Diffusion-weighted imaging revealed heterogeneous signal intensity patterns: DWI hyperintense areas within the lesions were present in 90% of the patients (Fig. 1 ), lesions with isointense areas in 51%, and with hypointense areas in 69% of patients. However, in cases of high DWI signal the ADC was not uniformly low (0%) but rather high (24%) or showed different subregions (mixed pattern in 76%). Contrast enhancement occurred in 55% of patients, most commonly showing patchy (35%) or punctate (43%) patterns (Fig. 1 ). Leptomeningeal inflammation was observed in 11% of the patients, either on T1w images, on T2w—FLAIR images or on both after the intravenous administration of gadolinium (Fig. 2 ). A hypointense band toward the cortical grey matter on susceptibility-weighted imaging (SWI) was observed in 61% of the cases (Figs. 3 and 5 ). In the subgroup of patients with contrast enhancing lesions (44) 59% showed lesions with an SWI hypointense band while in patients without contrast enhancing lesions (35) a similar fraction of 66% showed lesions with an hypointense SWI band. Additional characteristic imaging features included a punctate pattern on T2 weighted images (76%) (Fig. 3 ), the “shrimp sign” (20%) (Fig. 4 ), and the “hot cross bun sign” (4%). None patients presented with isolated cerebellar atrophy suggestive of GCN without any accompanying T2 hyperintensities in the white and/or grey matter. Discussion This study presents the largest prospectively collected cohort of PML patients evaluated using a standardized, comprehensive multisequence 3T MRI protocol. By including patients with a broad spectrum of underlying immunosuppressive conditions, our findings provide a robust characterization of PML imaging features across diverse clinical contexts and extend previous observations derived mainly from smaller or more selective studies. Most patients exhibited large (> 3 cm), bilateral, and widespread lesions. This pattern likely reflects the inclusion of symptomatic patients with systemic immunosuppression, in contrast to cohorts from pharmacovigilance studies of natalizumab-associated PML, which often identify smaller, unifocal, or even presymptomatic lesions [ 4 , 6 – 7 , 17 , 18 ]. Consistent with earlier reports [ 4 – 6 , 18 ], the frontal and parieto-occipital lobes were most frequently affected, typically involving both juxtacortical and deep white matter with frequent extension into cortical grey matter. Histopathological studies corroborate these findings, demonstrating that PML is not exclusively a white matter disease, but also involves infection and demyelination of cortical grey matter [ 4 , 22 – 27 ]. Deep grey matter involvement was also relatively common in our cohort, affecting the thalamus (50%), basal ganglia (56%), and dentate nucleus (29%) possibly reflecting the advanced disease stage and widespread dissemination among our patients compared to imaging findings in PML cohorts derived from natalizumab pharmacovigilance programs including more asymptomatic patients with lower PML lesion load [ 17 , 18 ]. A recently described imaging feature, a hypointense band on the edge of the lesion, predominantly on the cortical side on SWI, is thought to represent iron accumulation in macrophages and was linked to a longer survival in one study [ 4 , 14 , 16 ]. It has been proposed that this imaging finding might be very characteristic for PML and therefore SWI should be incorporated into the core MR acquisition protocol for PML diagnosis [ 4 ]. However, data on the frequency of this imaging finding in PML is sparse. This finding was present in 61% of our patients, supporting its potential role as an ancillary diagnostic marker and reinforcing the utility of incorporating SWI into standard PML imaging protocols. Other imaging features such as the “punctate lesion pattern” on T2w images -reported as a highly characteristic finding in PML [ 13 ]- was observed in 76% of our cohort, confirming its high prevalence. Regarding signal behavior, lesions were universally T2-hyperintense and predominantly T1-hypointense, with a subset (59%) showing T1-isointense components. These likely represent earlier stages of JCPy virus infection before extensive demyelination. DWI hyperintensity, typically located at lesion borders, was observed in 90% of patients and has been linked histopathologically to active lytic infection with swollen oligodendrocytes [ 15 ]. The coexistence of DWI iso- and hypointense regions with variable ADC values throughout the lesions in many patients reflects the heterogeneity of lesion composition with areas of different disease activity. Historically, “classical” PML -particularly in untreated HIV infection- was characterized by the absence of inflammatory imaging findings such as enhancement or edema. In contrast, “inflammatory PML,” described in approximately 30% of natalizumab-associated PML cases, exhibits contrast enhancement in approximately 30% of patients [ 12 , 17 , 18 ]. In our study, enhancement was observed in 55%, alongside perilesional edema (51%) and mass effect (36%), suggesting a higher prevalence of inflammatory changes in active PML than previously appreciated. Leptomeningeal enhancement, seen in 11% of patients, may indicate JCPy virus-related meningeal inflammation, which has been rarely described but could be under-recognized, maybe in part because enhancement was evaluated only on T1w images but not on T2w-FLAIR images acquired after the intravenous administration of gadolinium-based contrast agents [ 28 , 29 ]. Focal or global cortical atrophy was present in 41% of patients, likely reflecting sequelae of chronic disease rather than acute changes. Cerebellar atrophy was detected in 33%, including severe cases exhibiting the hot cross bun sign (4%) and the shrimp sign (20%), consistent with JCPy virus–associated cerebellar pathology such as granule cell neuronopathy [ 19 – 21 , 30 – 33 ]. None pateints presented with isolated cerebellar atrophy suggestive of GCN without any accompanying T2 hyperintensities in the white and/or grey matter. Our study has several limitations. First, only symptomatic patients were included; asymptomatic or preclinical PML may demonstrate different imaging patterns. Second, histopathological confirmation was available for only a subset of patients, although nearly all met established criteria for definite PML. Third, the cross-sectional design precluded analysis of lesion evolution over time, which may yield additional diagnostic insights. In addition, we performed a patient-wise analysis and not a lesion-wise analysis because a analysis and characterization of every single PML lesion in this large cohort would be inappropriately time-consuming and would most likely not lead to other key results. Due to the very heterogenous underyling conditions of immunesuppression leading to PML it is impossible to say which imaging findings are exclusively related to PML or related to the immune response against the virus replication due to a partially intact immune surveillance [ 4 ]. However, this combination of these two pathologies on MRI or on histopathology reflects the clinical reality. Exclusive PML pathology without immune response like in HIV patients in the pre-HAART era showing a complete collapse of the cellular immune systems is not frequently present anymore in the clinical routine setting. In conclusion, this large prospective study employing a standardized multisequence MRI protocol provides a comprehensive characterization of heterogenous PML imaging phenotypes across diverse immunosuppressive conditions. The high frequency of imaging signs suggestive of inflammation suggests a combination of PML pathology and pathology related to the immune response against the virus replication due to a partially intact immune surveillance. The pattern as well as the heterogeneity of imaging findings emphasize the diagnostic value of a standardized comprehensive multi-sequence MRI including DWI and potentially SWI sequences for consistent detection and phenotyping of PML before including patients into treatment trials in order to support an accurate PML diagnosis and provide important prognostic information regarding treatment outcome. In addition, comprehensive multi-sequence MRI is crucial for monitoring of PML and other JCPy virus -related neuroinfectious diseases particularly during treatment such as allogenic T-cell therapy monitoring the immune response and immune reconstitution [ 34 ]. Declarations Conflict of interest: The authors declare no conflicts of interest related to this work. Author Contribution MPW, SK, JR, NM image analysis; MPW, SK JR writing of the manuscript, SN, KFJ, LGL, NM, KWS, GH, FH, TS clinical assessment and data collection, All authors reviewed and approved the manuscript. 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Neurol Neuroimmunol Neuroinflamm 8(4):e1020 Dang X, Vidal JE, Penalva de Oliveira AC et al (2012) JC virus granule cell neuronopathy is associated with VP1 C terminus mutants. J Gen Virol 93:175–183 Schippling S, Kempf C, Büchele F et al (2013) JC virus granule cell neuronopathy and GCN-IRIS under natalizumab treatment. Ann Neurol 74:622–626 Wijburg MT, van Oosten BW, Murk JL, Karimi O, Killestein J, Wattjes MP (2015) Heterogeneous imaging characteristics of JC virus granule cell neuronopathy (GCN): a case series and review of the literature. J Neurol 262:65–73 Wijburg MT, Siepman D, van Eijk JJ, Killestein J, Wattjes MP (2016) Concomitant granule cell neuronopathy in patients with natalizumab-associated PML. J Neurol 263:649–656 Möhn N, Grote-Levi L, Wattjes MP et al (2024) Directly Isolated Allogeneic Virus-Specific T Cells in Progressive Multifocal Leukoencephalopathy. JAMA Neurol 81:1187–1198 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8994252","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":613841889,"identity":"dd0596aa-1b78-4ae4-978b-e4b46ae515fb","order_by":0,"name":"Semra Kosak","email":"","orcid":"","institution":"Charité - University Medicine Berlin","correspondingAuthor":false,"prefix":"","firstName":"Semra","middleName":"","lastName":"Kosak","suffix":""},{"id":613841890,"identity":"4279f1ab-4ea7-40be-b2c6-7053f3c69695","order_by":1,"name":"Julius Renne","email":"","orcid":"","institution":"Hannover Medical School","correspondingAuthor":false,"prefix":"","firstName":"Julius","middleName":"","lastName":"Renne","suffix":""},{"id":613841891,"identity":"865e0f0e-fb2d-4a40-8ff8-7807f802927a","order_by":2,"name":"Sandra Nay","email":"","orcid":"","institution":"Hannover Medical School","correspondingAuthor":false,"prefix":"","firstName":"Sandra","middleName":"","lastName":"Nay","suffix":""},{"id":613841892,"identity":"fecbe80b-be27-4d54-8543-5e537bb9ead6","order_by":3,"name":"Konstantin Fritz Jendretzky","email":"","orcid":"","institution":"Hannover Medical School","correspondingAuthor":false,"prefix":"","firstName":"Konstantin","middleName":"Fritz","lastName":"Jendretzky","suffix":""},{"id":613841893,"identity":"5e9d6880-8e3a-4733-81aa-98cd9c880b74","order_by":4,"name":"Lea Grote-Levi","email":"","orcid":"","institution":"Hannover Medical School","correspondingAuthor":false,"prefix":"","firstName":"Lea","middleName":"","lastName":"Grote-Levi","suffix":""},{"id":613841894,"identity":"bd14d0f3-b33d-400e-9f8a-6fe73f2cffeb","order_by":5,"name":"Nora Möhn","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Nora","middleName":"","lastName":"Möhn","suffix":""},{"id":613841895,"identity":"52e5313b-5ffe-43a8-8379-e448f15a76eb","order_by":6,"name":"Kurt-Wolfram Sühs","email":"","orcid":"","institution":"Hannover Medical School","correspondingAuthor":false,"prefix":"","firstName":"Kurt-Wolfram","middleName":"","lastName":"Sühs","suffix":""},{"id":613841896,"identity":"0fc112ab-542a-4742-95da-b66e7088d6c2","order_by":7,"name":"Günter Höglinger","email":"","orcid":"","institution":"Ludwig-Maximilians-Universität München","correspondingAuthor":false,"prefix":"","firstName":"Günter","middleName":"","lastName":"Höglinger","suffix":""},{"id":613841897,"identity":"f98cc461-3cd1-4979-bbeb-0d3711b3c06c","order_by":8,"name":"Franziska Hopfner","email":"","orcid":"","institution":"Ludwig-Maximilians-Universität München","correspondingAuthor":false,"prefix":"","firstName":"Franziska","middleName":"","lastName":"Hopfner","suffix":""},{"id":613841898,"identity":"d37960b1-3c00-4745-8851-2c83ec8e28b1","order_by":9,"name":"Peter Raab","email":"","orcid":"","institution":"Hannover Medical School","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Raab","suffix":""},{"id":613841899,"identity":"5d6eaf84-4958-4687-badb-35f9dcc57a13","order_by":10,"name":"Thomas Skripuletz","email":"","orcid":"","institution":"Hannover Medical School","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Skripuletz","suffix":""},{"id":613841900,"identity":"a55c6bee-53b9-4415-9e29-1d32efc8ae53","order_by":11,"name":"Nima Mahmoudi","email":"","orcid":"","institution":"Charité - University Medicine Berlin","correspondingAuthor":false,"prefix":"","firstName":"Nima","middleName":"","lastName":"Mahmoudi","suffix":""},{"id":613841901,"identity":"d73eecd8-f423-4d19-8032-e9e72458531a","order_by":12,"name":"Mike Wattjes","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIie3OMUvDQBTA8fd4cFmErFc6+AmEFiEi1ParNAQ66drFUjNdln6ADH6OzCkPzqW0X8ChIjgfZMmk3lVUEHJ1FLz/cFzC+/EOIBT6i5H4vNUAxh3kPkTX/DeRJ3YaywOhIwS+iB127mONh5wVIt2jGi8nyNyMFo+nF0W83sN81EkSFjxAldkteta/1i/DeyYawHbmIZGSWJElm4RucsaSSEhU7CNFi9WdJbumucx5YknUonrzPUwDVuy2QB9zTt0WQFX7SCbT14feqtZJb6U5s+RcTrdZN9npoTGb2zgq+dm0C74q4/WTMfNxJzk0dYesf/45Wpz/aiwUCoX+Ye+j31FjyaTF2QAAAABJRU5ErkJggg==","orcid":"","institution":"Charité - University Medicine Berlin","correspondingAuthor":true,"prefix":"","firstName":"Mike","middleName":"","lastName":"Wattjes","suffix":""}],"badges":[],"createdAt":"2026-02-28 10:08:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8994252/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8994252/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106403863,"identity":"d75fae7d-9bb3-4df8-bb6c-bcf5b4dc58cc","added_by":"auto","created_at":"2026-04-08 09:15:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3366338,"visible":true,"origin":"","legend":"\u003cp\u003eClassical lesion with DWI RIM. 49-year-old male patient with PML following chemotherapy of chronic lymphatic leucemia (CLL): A T2 FLAIR and B T2 shows widespread hyperintense occipital lesions without C SWI signal alterations but with prominent D DWI hyperintensity at the front of the lesions, thought to represent the sight of active viral replication with swollen oligodendrocytes. E: No apparent ADC lowering. F: Only faint contrast enhancement.\u003c/p\u003e","description":"","filename":"Abb1.png","url":"https://assets-eu.researchsquare.com/files/rs-8994252/v1/7edc4651d56fae6316e7d174.png"},{"id":106381468,"identity":"59e27fd4-d8eb-4af9-9088-37dcd00df5ba","added_by":"auto","created_at":"2026-04-08 05:21:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2893621,"visible":true,"origin":"","legend":"\u003cp\u003eInfratentorial lesion with leptomeningeal enhancement. 55-year-old male patient with PML under HIV with infratentorial manifestation in the middle cerebellar peduncle, extending into the right cerebellar hemisphere (arrow) and leptomeningeal contrast enhancement (arrowhead). A: T2 FLAIR, B: T2 TSE, C SWI, D: DWI, E: ADC, F: T1 after i.v. Gd.\u003c/p\u003e","description":"","filename":"Abb2.png","url":"https://assets-eu.researchsquare.com/files/rs-8994252/v1/f85e4e0c748f569d16826cd0.png"},{"id":106403931,"identity":"7f1dc490-c47a-4303-93f2-82679794d19f","added_by":"auto","created_at":"2026-04-08 09:15:14","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2687152,"visible":true,"origin":"","legend":"\u003cp\u003ePunctuate pattern and hypointense (sub)cortical band on SWI. 54-year-old male patient with prolonged cortisone therapy for sarcoidosis. „Punctuate pattern“, best visualized on T2 TSE (B) in a frontal lesion with partial SWI rim sign (C, arrow). A: T2 FLAIR, B: T2 TSE, C: SWI, D: DWI, E: ADC, F: T1 after i.v. Gd.\u003c/p\u003e","description":"","filename":"Abb3.png","url":"https://assets-eu.researchsquare.com/files/rs-8994252/v1/178021b7cc997c4acd0d670f.png"},{"id":106381471,"identity":"e0eabf1b-88f6-4043-a6fa-77c6ced72e69","added_by":"auto","created_at":"2026-04-08 05:21:49","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3133682,"visible":true,"origin":"","legend":"\u003cp\u003eShrimp sign. 56-year-old female patient with MS and repeated long history of different therapies including Natalizumab. Cerebellar atrophy and T2 TSE/T2 FLAIR hyperintense signal in the middle cerebellar peduncle and continuous spread around the dentate nucleus, forming the „shrimp sign“. A: T2 FLAIR, B: T2 TSE, C: SWI, D: DWI, E: ADC, F: T1 after i.v. Gd.\u003c/p\u003e","description":"","filename":"Abb4.png","url":"https://assets-eu.researchsquare.com/files/rs-8994252/v1/fee365efe6d50366416dfe06.png"},{"id":106381472,"identity":"adac0fcb-84f5-4e8a-8f8c-67e1c1b9be70","added_by":"auto","created_at":"2026-04-08 05:21:49","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2592956,"visible":true,"origin":"","legend":"\u003cp\u003eHypointense (sub)cortical band on SWI. 41-year-old female patient with chemotherapy for Hodgkin lymphoma. Right frontal and occipital lesions on both sides with a SWI hypointense subcortical rim (arrows), reported to represent iron-enriched macrophages. A: T2 FLAIR, B: T2 TSE, C: SWI, D: DWI, E: ADC, F: T1 after i.v. Gd.\u003c/p\u003e","description":"","filename":"Abb5.png","url":"https://assets-eu.researchsquare.com/files/rs-8994252/v1/d6c10070cc62b1315b9706f2.png"},{"id":106405819,"identity":"fb37510c-54d9-4940-b446-cee5f421963f","added_by":"auto","created_at":"2026-04-08 09:28:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":22729042,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8994252/v1/58cfa100-45c5-4eed-9885-1f1e0c1d14dd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"MRI phenotyping of progressive multifocal leukoencepahlopathy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eProgressive multifocal leukoencephalopathy (PML) is an opportunistic demyelinating disease of the central nervous system caused by lytic infection of oligodendrocytes and productive infection of astrocytes by the JC polyomavirus (JCPyV) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The in vivo diagnosis of PML, as defined by the Neuroinfectious Disease Section of the American Academy of Neurology (AAN), is based on a combination of clinical presentation, characteristic neuroimaging findings, and the detection of JC virus DNA in the cerebrospinal fluid (CSF) using polymerase chain reaction (PCR). Alternatively, the diagnosis can be confirmed through histopathological examination of brain tissue [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMagnetic resonance imaging (MRI) is the most sensitive diagnostic imaging modality for identifying PML lesions in vivo. MRI can reveal characteristic abnormalities suggestive of PML even in asymptomatic patients and in cases where JCPyV DNA remains undetectable in the CSF [\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePML occurs under various conditions of impaired cellular immunity, including HIV infection, hematologic malignancies, bone marrow or solid organ transplantation, and treatment with immunosuppressive therapies for autoimmune disorders such as multiple sclerosis (MS) or rheumatic diseases [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, most previous descriptions of PML imaging features, particularly those regarding lesion morphology, dissemination, and temporal evolution, are derived from isolated case reports or small case series. The interpretation of imaging findings has been further hampered by heterogeneous and non-standardized MRI acquisition protocols [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile the basic MRI characteristics of PML lesions, i.e. their morphology and signal characteristics on T1- and T2-weighted images - are well established, other imaging features are known to be heterogeneous and may vary depending on the underlying immunosuppressive condition [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Data on the diagnostic value of additional MRI sequences, such as diffusion-weighted imaging (DWI), susceptibility-weighted imaging (SWI), and quantitative imaging techniques, remain limited [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Moreover, most prior studies have focused on PML associated with specific causes of immunosuppression, such as HIV infection or natalizumab treatment, introducing potential bias due to restricted patient selection [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe aim of this study was to systematically characterize the MRI features of PML using a comprehensive and standardized multisequence 3T brain MRI protocol in a large, prospectively collected cohort encompassing a broad spectrum of underlying immunosuppressive conditions.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Patient Selection\u003c/h2\u003e \u003cp\u003ePatients presenting with new or progressive clinical symptoms suggestive of progressive multifocal leukoencephalopathy (PML) in the context of cellular immunosuppression suggestive for active PML in terms of virus replication referred to our hospital for the evaluation of treatment options were prospectively enrolled as part of the Hannover PML cohort between October 2020 and December 2024. Inclusion criteria comprised an age over 18 and clinical presentation and/or imaging signs suggestive of active PML (new or progressive clinical symptoms, progressive PML lesion manifestation on MRI or signs of active virus replication based on DWI hyperintensitiy[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]), diagnosis of PML (definite, probabely or possible) according to AAN diagnostic criteria [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Exclusion criteria included pregnancy and contraindications to magnetic resonance imaging (MRI) and Gadolinium injection. Additionally, patients with insufficient MRI data (severe motion artifacts or termination of the examination before completion) resulting in a completely non diagnostic examination were excluded.\u003c/p\u003e \u003cp\u003e The study protocol was approved by the local institutional review board of Hannover Medical School, Germany. Written informed consent was obtained from all participants prior to inclusion, and the study has been conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMRI Acquisition Protocol\u003c/h3\u003e\n\u003cp\u003eAll examinations were performed on a 3 Tesla whole-body MRI system (Skyra, Siemens Healthineers, Erlangen, Germany) equipped with a 20-channel head \u0026amp; neck coil (Siemens Healthineers). A standardized multisequence brain MRI protocol was applied, including: T2-weighted 3D fluid-attenuated inversion recovery (FLAIR), 3D T1-weighted (MP2RAGE), axial 2D T2-weighted fast/turbo spin echo, axial diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping, axial susceptibility-weighted imaging (SWI), axial post-contrast T1-weighted turbo spin echo sequence following intravenous administration of a standard single dose (0.1 mmol/kg body weight) of gadolinium-based contrast agent (Gd-DOTA, Dotarem\u0026reg;, Guerbet, Roissy, France). Detailed image acquisition parameters are provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMRI acquisition parameters\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eContrast\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3D-T1w\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3D-FLAIR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e2D-T2w\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSWI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2D-DWI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2D-T1w\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSequence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMP2RAGE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003eSPACE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTSE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGRE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eEPI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnatomic orientation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003esagittal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003esagittal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eaxial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eaxial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eaxial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eaxial\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTR [ms]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e5000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e489\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTE [ms]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e388\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTI 1 [ms]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e700\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e1800\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTI 2 [ms]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTurbo Factor [-]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e278\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFOV [mm\u003csup\u003e3\u003c/sup\u003e] (APxFHxRL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e240x256x176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e260x260x173\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e240x240x135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e256x144x208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e240x132x240\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e263x350x350\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpatial Resolution [mm\u003csup\u003e3\u003c/sup\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.0 x1.0 x 1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e0.5x0.5x0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.6x0.6x3.0 (axial)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5x0.5x3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.6x0.6x4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.8x0.8x3.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcquisition time [min:sec]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8:22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e5:47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2:08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3:02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3:11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4:48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eImage Analysis and Interpretation\u003c/h3\u003e\n\u003cp\u003e All MRI datasets were reviewed using a dedicated workstation running Visage 7 client software (Visage Imaging, Richmond, Australia). Image analysis was independently performed by two readers with different levels of expertise: a board-certified neuroradiologist with 10 years of experience (J.R.) and a radiology resident with 6 years of experience (S.K.) under the supervision of an experienced neuroradiologist with 20 years of experience (MPW). All readers were blinded to all clinical and paraclinical data. Lesions suggestive of PML were identified and characterized according to predefined imaging criteria.\u003c/p\u003e \u003cp\u003eThe following imaging parameters were systematically assessed and reported as present or absent per patient (data on lesion charatceristics reported on a patient level and not of a single lesion level):\u003c/p\u003e \u003cp\u003eLesion dissemination: unifocal, multifocal, or widespread, as defined by Dong-Si et al. and Richert et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Lesion location: classified by cerebral lobe and by tissue type (juxtacortical white matter, deep white matter, periventricular white matter, cortical grey matter, deep grey matter). Morphology and borders: including lesion size, shape, and margin definition. Signal characteristics: on T1w-, T2w-, T2w-FLAIR, DWI, and SWI sequences. Signs of inflammation: such as contrast enhancement and perilesional edema. Atrophy (volume loss of brain parenchyma exceeding the anticipated volume loss due to normal ageing): global or focal, including cerebellar involvement. Previously described imaging features: the hot cross bun sign [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], punctate T2w lesions [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], and the shrimp sign [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The complete scoring and classification scheme is summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eImaging characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImaging characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of\u003c/p\u003e \u003cp\u003ePatients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003ePresent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eAbsent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e% Present\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLesion dissemination\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLesion dissemination\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBilateral hemispheric involvement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnilobar lesion dissemination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultilobar lesion dissemination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWidespread lesion dissemination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLesion location (lobes)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrontal lobe\u003c/p\u003e \u003cp\u003eParieto-occipital lobe\u003c/p\u003e \u003cp\u003eTemporal lobe\u003c/p\u003e \u003cp\u003eCorpus callosum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParieto-occipital lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTemporal lobe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorpus callosum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThalamus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasal ganglia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrainstem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCerebellum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLesion location (brain tissue)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJuxtacortical white matter\u003c/p\u003e \u003cp\u003eDeep white matter\u003c/p\u003e \u003cp\u003ePeriventricular white matter\u003c/p\u003e \u003cp\u003eCortical grey matter\u003c/p\u003e \u003cp\u003eDeep grey matter\u003c/p\u003e \u003cp\u003eDental nucleus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeep white matter\u003c/p\u003e \u003cp\u003eDeep white matter\u003c/p\u003e \u003cp\u003ePeriventricular white matter\u003c/p\u003e \u003cp\u003eCortical grey matter\u003c/p\u003e \u003cp\u003eDeep grey matter\u003c/p\u003e \u003cp\u003eDental nucleus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeriventricular white matter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCortical grey matter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeep grey matter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDentate nucleus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLesion appearance\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efocal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ediffuse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003elesion size\u0026thinsp;\u0026gt;\u0026thinsp;3cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLesion borders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIll-defined border towards white matter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSharp border towards white matter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIll-defined border towards GM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLesion signal intensities\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1 hypointense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1 isointense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT2/T2-FLAIR hyperintense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSWI (micro/macrohemorrhage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicrobleeds related to PML lesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSWI hypointense band towards the GM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDWI hyperintense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDWI isointense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDWI hypointense\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eADC low\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eADC intermediate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eADC high\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eADC mixed\u003c/p\u003e \u003cp\u003em\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSigns of inflammation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of contrast enhancement*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eperipheral/ring like enhancement\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehomogeneous/punctate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epatchy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeptomeningeal contrast enhancement*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMass effect\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSigns of (perilesional) edema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAtrophy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresence of focal atrophy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFocal atrophy supratentorial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtrophy infratentorial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDefined imaging signs\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epunctate pattern / milky-way T2 lesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHot-cross-bun-sign\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eshrimp sign\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eLesion characteristics are given as present or absent per patient.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e* One patient needed to be excluded in this analysis because the relevant (post Gadolinium T1) sequence was not diagnostic due to severe movement artifacts\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eClinical Evaluation and Laboratory Procedures\u003c/h3\u003e\n\u003cp\u003eAll patients underwent detailed neurological examination by an experienced, board-certified neurologist at the Department of Neurology, Hannover Medical School. Cerebrospinal fluid (CSF) analysis included quantitative PCR testing for JCPy virus DNA. Each patient was classified as having definite, probable, possible, or no PML based on the clinical presentation, MRI findings, and virological results, following the diagnostic criteria established by the Neuroinfectious Disease Section of the AAN [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA subset of patients additionally underwent stereotactic brain biopsy for histopathological confirmation, according to the AAN-criteria [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eData availability statement\u003c/h3\u003e\n\u003cp\u003eAnonymized data not published within this article will be made available by request to the corresponding author from any qualified investigator.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eEighty-four patients were prospectively enrolled. Four patients did not complete a diagnostic MRI and were excluded for this analysis. All patients completed the full diagnostic work-up, including MRI and cerebrospinal fluid (CSF) analysis or brain biopsy. One patients MRI showed severe motion artifacts only on the post gadolinium T1 sequence. This patient remained in the study group, but contrast enhancement patterns were not evaluated. According to the AAN diagnostic criteria [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] 78 patients were classified as definite PML, one as probable, and one as possible PML. The demographic and clinical characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncluded patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (male/ female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49 / 31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 [54 ; 71]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease duration* (days)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66 [39;113]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDetection of JC virus DNA\u003c/p\u003e \u003cp\u003eCSF\u003c/p\u003e \u003cp\u003eBrain biopsy\u003c/p\u003e \u003cp\u003eNot available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003cp\u003e19\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory of PML diagnosis:\u003c/p\u003e \u003cp\u003eDefinite PML\u003c/p\u003e \u003cp\u003eProbable PML\u003c/p\u003e \u003cp\u003ePossible PML\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnderlying immune suppression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemato-oncologic disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAutoimmune disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSolid organ transplant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary immunodeficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSarcoidosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHSCT (hematopoietic stem cell transplantation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunosuppressive treatment with monoclonal antibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphopenia, other causes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: CSF=cerebrospinal fluid, Note:* defined as time interval between first clinical presentation and MRI acquisition; \u003csup\u003e#\u003c/sup\u003e median with interquartile range\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eImage Analysis\u003c/h3\u003e\n\u003cp\u003eA detailed summary of imaging findings on a patient level is provided in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e3\u003c/span\u003e, and representative imaging examples are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. Most patients exhibited large lesions (\u0026gt;\u0026thinsp;3 cm, 89%) with widespread (90%) and bilateral (93%) hemispheric involvement. The frontal (91%) and parieto-occipital (93%) lobes were most frequently affected. Lesions predominantly involved juxtacortical (95%) and deep white matter (99%), with frequent extension into the cortical (94%) and deep grey matter (71%). Nearly all patients showed at least one focal lesion (99%). Signal characteristics were consistent across sequences: all lesions were T2-hyperintense (100%) and nearly all were T1-hypointense (99%), while 59% of patients also demonstrated lesions with T1-isointense components. Borders were typically ill-defined (79%), although sharply demarcated margins toward adjacent white matter were also frequently observed (76%). Diffusion-weighted imaging revealed heterogeneous signal intensity patterns: DWI hyperintense areas within the lesions were present in 90% of the patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), lesions with isointense areas in 51%, and with hypointense areas in 69% of patients. However, in cases of high DWI signal the ADC was not uniformly low (0%) but rather high (24%) or showed different subregions (mixed pattern in 76%). Contrast enhancement occurred in 55% of patients, most commonly showing patchy (35%) or punctate (43%) patterns (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Leptomeningeal inflammation was observed in 11% of the patients, either on T1w images, on T2w\u0026mdash;FLAIR images or on both after the intravenous administration of gadolinium (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). A hypointense band toward the cortical grey matter on susceptibility-weighted imaging (SWI) was observed in 61% of the cases (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). In the subgroup of patients with contrast enhancing lesions (44) 59% showed lesions with an SWI hypointense band while in patients without contrast enhancing lesions (35) a similar fraction of 66% showed lesions with an hypointense SWI band. Additional characteristic imaging features included a punctate pattern on T2 weighted images (76%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), the \u0026ldquo;shrimp sign\u0026rdquo; (20%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), and the \u0026ldquo;hot cross bun sign\u0026rdquo; (4%). None patients presented with isolated cerebellar atrophy suggestive of GCN without any accompanying T2 hyperintensities in the white and/or grey matter.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study presents the largest prospectively collected cohort of PML patients evaluated using a standardized, comprehensive multisequence 3T MRI protocol. By including patients with a broad spectrum of underlying immunosuppressive conditions, our findings provide a robust characterization of PML imaging features across diverse clinical contexts and extend previous observations derived mainly from smaller or more selective studies.\u003c/p\u003e \u003cp\u003eMost patients exhibited large (\u0026gt;\u0026thinsp;3 cm), bilateral, and widespread lesions. This pattern likely reflects the inclusion of symptomatic patients with systemic immunosuppression, in contrast to cohorts from pharmacovigilance studies of natalizumab-associated PML, which often identify smaller, unifocal, or even presymptomatic lesions [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eConsistent with earlier reports [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], the frontal and parieto-occipital lobes were most frequently affected, typically involving both juxtacortical and deep white matter with frequent extension into cortical grey matter. Histopathological studies corroborate these findings, demonstrating that PML is not exclusively a white matter disease, but also involves infection and demyelination of cortical grey matter [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR23 CR24 CR25 CR26\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Deep grey matter involvement was also relatively common in our cohort, affecting the thalamus (50%), basal ganglia (56%), and dentate nucleus (29%) possibly reflecting the advanced disease stage and widespread dissemination among our patients compared to imaging findings in PML cohorts derived from natalizumab pharmacovigilance programs including more asymptomatic patients with lower PML lesion load [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA recently described imaging feature, a hypointense band on the edge of the lesion, predominantly on the cortical side on SWI, is thought to represent iron accumulation in macrophages and was linked to a longer survival in one study [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. It has been proposed that this imaging finding might be very characteristic for PML and therefore SWI should be incorporated into the core MR acquisition protocol for PML diagnosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, data on the frequency of this imaging finding in PML is sparse. This finding was present in 61% of our patients, supporting its potential role as an ancillary diagnostic marker and reinforcing the utility of incorporating SWI into standard PML imaging protocols.\u003c/p\u003e \u003cp\u003eOther imaging features such as the \u0026ldquo;punctate lesion pattern\u0026rdquo; on T2w images -reported as a highly characteristic finding in PML [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]- was observed in 76% of our cohort, confirming its high prevalence. Regarding signal behavior, lesions were universally T2-hyperintense and predominantly T1-hypointense, with a subset (59%) showing T1-isointense components. These likely represent earlier stages of JCPy virus infection before extensive demyelination.\u003c/p\u003e \u003cp\u003eDWI hyperintensity, typically located at lesion borders, was observed in 90% of patients and has been linked histopathologically to active lytic infection with swollen oligodendrocytes [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The coexistence of DWI iso- and hypointense regions with variable ADC values throughout the lesions in many patients reflects the heterogeneity of lesion composition with areas of different disease activity.\u003c/p\u003e \u003cp\u003eHistorically, \u0026ldquo;classical\u0026rdquo; PML -particularly in untreated HIV infection- was characterized by the absence of inflammatory imaging findings such as enhancement or edema. In contrast, \u0026ldquo;inflammatory PML,\u0026rdquo; described in approximately 30% of natalizumab-associated PML cases, exhibits contrast enhancement in approximately 30% of patients [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In our study, enhancement was observed in 55%, alongside perilesional edema (51%) and mass effect (36%), suggesting a higher prevalence of inflammatory changes in active PML than previously appreciated. Leptomeningeal enhancement, seen in 11% of patients, may indicate JCPy virus-related meningeal inflammation, which has been rarely described but could be under-recognized, maybe in part because enhancement was evaluated only on T1w images but not on T2w-FLAIR images acquired after the intravenous administration of gadolinium-based contrast agents [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFocal or global cortical atrophy was present in 41% of patients, likely reflecting sequelae of chronic disease rather than acute changes. Cerebellar atrophy was detected in 33%, including severe cases exhibiting the hot cross bun sign (4%) and the shrimp sign (20%), consistent with JCPy virus\u0026ndash;associated cerebellar pathology such as granule cell neuronopathy [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan additionalcitationids=\"CR31 CR32\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. None pateints presented with isolated cerebellar atrophy suggestive of GCN without any accompanying T2 hyperintensities in the white and/or grey matter.\u003c/p\u003e \u003cp\u003eOur study has several limitations. First, only symptomatic patients were included; asymptomatic or preclinical PML may demonstrate different imaging patterns. Second, histopathological confirmation was available for only a subset of patients, although nearly all met established criteria for definite PML. Third, the cross-sectional design precluded analysis of lesion evolution over time, which may yield additional diagnostic insights. In addition, we performed a patient-wise analysis and not a lesion-wise analysis because a analysis and characterization of every single PML lesion in this large cohort would be inappropriately time-consuming and would most likely not lead to other key results. Due to the very heterogenous underyling conditions of immunesuppression leading to PML it is impossible to say which imaging findings are exclusively related to PML or related to the immune response against the virus replication due to a partially intact immune surveillance [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, this combination of these two pathologies on MRI or on histopathology reflects the clinical reality. Exclusive PML pathology without immune response like in HIV patients in the pre-HAART era showing a complete collapse of the cellular immune systems is not frequently present anymore in the clinical routine setting.\u003c/p\u003e \u003cp\u003eIn conclusion, this large prospective study employing a standardized multisequence MRI protocol provides a comprehensive characterization of heterogenous PML imaging phenotypes across diverse immunosuppressive conditions. The high frequency of imaging signs suggestive of inflammation suggests a combination of PML pathology and pathology related to the immune response against the virus replication due to a partially intact immune surveillance. The pattern as well as the heterogeneity of imaging findings emphasize the diagnostic value of a standardized comprehensive multi-sequence MRI including DWI and potentially SWI sequences for consistent detection and phenotyping of PML before including patients into treatment trials in order to support an accurate PML diagnosis and provide important prognostic information regarding treatment outcome. In addition, comprehensive multi-sequence MRI is crucial for monitoring of PML and other JCPy virus -related neuroinfectious diseases particularly during treatment such as allogenic T-cell therapy monitoring the immune response and immune reconstitution [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eConflict of interest:\u003c/strong\u003e \u003cp\u003eThe authors declare no conflicts of interest related to this work.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMPW, SK, JR, NM image analysis; MPW, SK JR writing of the manuscript, SN, KFJ, LGL, NM, KWS, GH, FH, TS clinical assessment and data collection, All authors reviewed and approved the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAnonymized data not published within this article will be made available by request to the corresponding author from any qualified investigator.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCortese I, Reich DS, Nath A (2012) Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease. 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Brain 145:426\u0026ndash;440\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWattjes MP, Vennegoor A, Mostert J, van Oosten BW, Barkhof F, Killestein J (2014) Diagnosis of asymptomatic natalizumab-associated PML: are we between a rock and a hard place? J Neurol 261:1139\u0026ndash;1143\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWattjes MP, Vennegoor A, Steenwijk MD et al (2015) MRI pattern in asymptomatic natalizumab-associated PML. J Neurol Neurosurg Psychiatry 86:793\u0026ndash;798\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDong-Si T, Richman S, Wattjes MP et al (2014) Outcome and survival of asymptomatic PML in natalizumab-treated MS patients. Ann Clin Transl Neurol 1:755\u0026ndash;764\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePhan-Ba R, Lommers E, Tshibanda L et al (2012) MRI preclinical detection and asymptomatic course of a progressive multifocal leucoencephalopathy (PML) under natalizumab therapy. J Neurol Neurosurg Psychiatry 83:224\u0026ndash;226\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePhan-Ba R, Belachew S, Outteryck O et al (2012) The earlier, the smaller, the better for natalizumab-associated PML: in MRI vigilance veritas? Neurology 79:1067\u0026ndash;1069\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSahraian MA, Radue EW, Eshaghi A, Besliu S, Minagar A (2012) Progressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis. Eur J Neurol 19:1060\u0026ndash;1069\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWattjes MP, Richert ND, Killestein J et al (2013) The chameleon of neuroinflammation: magnetic resonance imaging characteristics of natalizumab-associated progressive multifocal leukoencephalopathy. Mult Scler 19:1826\u0026ndash;1840\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWattjes MP, Barkhof F (2014) Diagnosis of natalizumab-associated progressive multifocal leukoencephalopathy using MRI. Curr Opin Neurol 27:260\u0026ndash;270\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHodel J, Darchis C, Outteryck O, Verclytte S, Deramecourt V, Lacour A, Zins M, Pruvo JP, Vermersch P, Leclerc X (2016) Punctate pattern: A promising imaging marker for the diagnosis of natalizumab-associated PML. Neurology 86:1516\u0026ndash;1523\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThurnher MM, Boban J, Rieger A, Gelpi E, Susceptibility-Weighted MR (2019) Imaging Hypointense Rim in Progressive Multifocal Leukoencephalopathy: The End Point of Neuroinflammation and a Potential Outcome Predictor. AJNR Am J Neuroradiol 40:994\u0026ndash;1000\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBergui M, Bradac GB, Oguz KK et al (2004) Progressive multifocal leukoencephalopathy: Diffusion-weighted imaging and pathological correlations. Neuroradiology 46:22\u0026ndash;25\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahajan KR, Amin M, Poturalski M et al (2021) Juxtacortical susceptibility changes in progressive multifocal leukoencephalopathy at the gray\u0026ndash;white matter junction correlates with iron-enriched macrophages. Mult Scler 27:2159\u0026ndash;2169\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDong-Si T, Richman S, Wattjes MP et al (2014) Outcome and survival of asymptomatic PML in natalizumab-treated MS patients. Ann Clin Transl Neurol 1:755\u0026ndash;764\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRichert N, Bloomgren G, Cadavid D et al (2012) Imaging findings for PML in natalizumab-treated MS patients. Mult Scler 18(Suppl 4):27\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalari M, Golzarian M, Rezaei K, Etemadifar M (2025) A Review on Radiologic Hot Cross Bun Sign and Related Clinical Conditions. Cerebellum 24:70\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHodel J, Darchis C, Outteryck O et al (2016) Punctate pattern: A promising imaging marker for the diagnosis of natalizumab-associated PML. Neurology 86:1516\u0026ndash;1523\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdra N, Goodheart AE, Rapalino O et al (2021) MRI Shrimp Sign in Cerebellar Progressive Multifocal Leukoencephalopathy: Description and Validation of a Novel Observation. AJNR Am J Neuroradiol 42:1073\u0026ndash;1079\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoll NM, Rietsch AM, Ransohoff AJ et al (2008) Cortical demyelination in PML and MS: Similarities and differences. Neurology 70:336\u0026ndash;343\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTyler KL (2003) The uninvited guest: JC virus infection of neurons in PML. Neurology 61:734\u0026ndash;735\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eW\u0026uuml;thrich C, Koralnik IJ (2012) Frequent infection of cortical neurons by JC virus in patients with progressive multifocal leukoencephalopathy. J Neuropathol Exp Neurol 71:54\u0026ndash;65\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eW\u0026uuml;thrich C, Dang X, Westmoreland S et al (2009) Fulminant JC virus encephalopathy with productive infection of cortical pyramidal neurons. Ann Neurol 65:742\u0026ndash;748\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKleinschmidt-DeMasters BK, Miravalle A, Schowinsky J et al (2012) Update on PML and PML-IRIS occurring in multiple sclerosis patients treated with natalizumab. J Neuropathol Exp Neurol 71:604\u0026ndash;617\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMetz I, Radue EW, Oterino A et al (2012) Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy. Acta Neuropathol 123:235\u0026ndash;245\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgnihotri SP, Wuthrich C, Dang X et al (2014) A fatal case of JC virus meningitis presenting with hydrocephalus in a human immunodeficiency virus-seronegative patient. Ann Neurol 76:140\u0026ndash;147\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHopfner F, M\u0026ouml;hn N, Eiz-Vesper B et al (2021) Allogeneic BK Virus-Specific T-Cell Treatment in 2 Patients With Progressive Multifocal Leukoencephalopathy. Neurol Neuroimmunol Neuroinflamm 8(4):e1020\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDang X, Vidal JE, Penalva de Oliveira AC et al (2012) JC virus granule cell neuronopathy is associated with VP1 C terminus mutants. J Gen Virol 93:175\u0026ndash;183\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchippling S, Kempf C, B\u0026uuml;chele F et al (2013) JC virus granule cell neuronopathy and GCN-IRIS under natalizumab treatment. Ann Neurol 74:622\u0026ndash;626\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWijburg MT, van Oosten BW, Murk JL, Karimi O, Killestein J, Wattjes MP (2015) Heterogeneous imaging characteristics of JC virus granule cell neuronopathy (GCN): a case series and review of the literature. J Neurol 262:65\u0026ndash;73\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWijburg MT, Siepman D, van Eijk JJ, Killestein J, Wattjes MP (2016) Concomitant granule cell neuronopathy in patients with natalizumab-associated PML. J Neurol 263:649\u0026ndash;656\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eM\u0026ouml;hn N, Grote-Levi L, Wattjes MP et al (2024) Directly Isolated Allogeneic Virus-Specific T Cells in Progressive Multifocal Leukoencephalopathy. JAMA Neurol 81:1187\u0026ndash;1198\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"PML; JC polyomavirus, JCPyV, MR imaging; neuroinfection, phenotyping","lastPublishedDoi":"10.21203/rs.3.rs-8994252/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8994252/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eProgressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the brain caused by JC polyomavirus. Brain magnetic resonance imaging (MRI) is the most sensitive tool for the in vivo detection of PML. However, comprehensive data on imaging findings using multisequence image acquisition are limited.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo investigate MRI findings of active PML in a large, prospectively collected cohort using a comprehensive and standardized MRI protocol.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eEighty patients with active PML underwent standardized 3T brain MRI including 3D-T2w-fluid-attenuated inversion recovery, 3D-T1-weighted, T2-weighted, diffusion-weighted (DWI), susceptibility-weighted (SWI) and contrast-enhanced T1-weighted sequences. Lesions were analysed regarding dissemination, location, morphology, borders, and signal characteristics.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eEighty patients showed widespread involvement affecting the frontal (91%) and parieto-occipital (93%) lobes, typically involving juxtacortical (95%) and deep white matter (99%), but also cortical grey matter (94%) and deep grey matter (71%). Most patients showed large (\u0026gt;\u0026thinsp;3 cm, 89%), focal (99%), T2-hyperintense (100%) and T1-hypointense (99%) lesions with ill-defined borders (79%). DWI hyperintensity was present in 90%, while SWI hypointense rims were detected in 61% of the patients. Contrast enhancement was observed in 55%. Certain imaging features included the punctate pattern (76%) and the shrimp sign (20%).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePML exhibits characteristic but heterogeneous MRI findings on a patient level predominantely showing widespread white matter and frequent cortical grey matter involvement. Sequences such as DWI and SWI show frequently additional imaging findings potentially improving the diagnostic certainty. Our data stress the need of standardized imaging protocols for reliable detection and phenotyping of PML across diverse immunosuppressive conditions.\u003c/p\u003e","manuscriptTitle":"MRI phenotyping of progressive multifocal leukoencepahlopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-08 05:21:44","doi":"10.21203/rs.3.rs-8994252/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a35ec30f-2b47-451b-b247-33299841ab59","owner":[],"postedDate":"April 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-08T05:21:44+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-08 05:21:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8994252","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8994252","identity":"rs-8994252","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}