European Journal of Neurology 2014, 21: e36–e38
doi:10.1111/ene.12361
LETTERS TO THE EDITOR
Diffusion tensor imaging before, during and after progressive multifocal leukoencephalopathy D. Ontanedaa, K. Sakaieb, J. Linb, M. J. Loweb, M. D. Phillipsb and R. J. Foxa a Mellen Center, Neurological Institute, Cleveland, OH; and bImaging Institute Cleveland Clinic, Cleveland, OH, USA
Correspondence: D. Ontaneda, Mellen Center Cleveland Clinic, 9500 Euclid Avenue, U-10, Cleveland, OH, USA (tel.: 216 444 0151; fax: 216 445 7013; e-mail: [email protected]).
Keywords: progressive multifocal leukoencephalopathy, DTI Received: 8 November 2013 Accepted: 17 December 2013 A 57-year-old female with a 14-year history of relapsing remitting multiple sclerosis and an Expanded Disability Status Scale of 2.0 enrolled in a longitudinal MRI study following initiation of natalizumab and informed consent. JCV serology 4 years into treatment was positive, and the patient elected to continue treatment with natalizumab. At the 57th natalizumab infusion, a 2-week history of word finding and memory difficulties was reported. Cerebrospinal fluid examination showed WBC 0, RBC 1, protein 40 mg/dl and 99 copies of JCV DNA by polymerase chain reaction. She was treated with five sessions of plasma exchange. Maraviroc was started based on recommendations by infectious disease consultants for possible prevention
e36
of immune reconstitution inflammatory syndrome (IRIS). One-and-a-half months later, she developed worsening aphasia and mild right hemiparesis. Clinical/MRI features were consistent with IRIS. She was treated with 5 days of intravenous methylprednisolone and recovered with residual mild right arm weakness and moderate expressive aphasia. Brain MRI was acquired on a 3 T Siemens Trio (Siemens Medical Systems, Erlangen, Germany) at 42, 36, 30, 18 and 6 months prior to progressive multifocal leukoencephalopathy (PML) diagnosis, at the time of PML presentation (0 months) and at 0.5, 1.5, 3 and 4 months afterwards. Each scan included high angular resolution diffusion imaging with 71 non-collinear diffusion-weighting gradients. Images were co-registered using FSL [1]. A region of interest (ROI) was drawn on the area with PML involvement at the time of diagnosis (core PML, 9.8 cm3) and at the time of IRIS (total PML, volume 40.2 cm3) using AFNI [2]. A normal appearing white matter (NAWM) ROI (volume 13.2 cm3) was drawn in the contralateral parietooccipital cortex that remained diseasefree over follow-up. Average values of fractional anisotropy (FA) and mean, longitudinal and transverse diffusivity (MD, LD and TD, respectively) were derived for NAWM and PML ROI at each time point. Longitudinal imaging found an increase in LD, TD and MD and a decrease in FA 6 months prior to the onset of PML (Fig. 1). These changes were most notable between 12 and 6 months, and were greater in core PML than total PML. At the time of PML
diagnosis, an increase in LD, TD and MD was observed with a decrease in FA in both the core PML and total PML regions (Fig. 1). Minimal changes were observed in NAWM ROIs over the observation period. At the time of IRIS (1.5-month time point) there was a transient improvement (regression to prePML values) in LD, TD, MD and FA in the core PML and total PML. Four months after PML, diffusion tensor imaging (DTI) values showed a regression towards pre-PML values compared with 3 months. Discussion Identifying the earliest changes of PML is important for early diagnosis and optimal outcomes [3,4]. We observed changes in brain tissue at the site of later PML development 6 months prior to clinical onset. The greater change in TD relative to LD suggests that these changes may be secondary to demyelination, although other pathologies may contribute to the changes in TD. DTI metrics also changed markedly at the time of IRIS. During the initial stage of IRIS, an improvement (return towards baseline) in the core PML region was observed for FA, MD, TD and LD. Changes on DTI metrics may pre-date changes on conventional imaging and may be an early indicator of PML, although further study is needed to clarify its utility in this setting. Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
© 2014 The Author(s) European Journal of Neurology © 2014 EFNS
Letter to the Editor
(a)
e37
(b)
(c)
Figure 1 Imaging and DTI evolution of progressive multifocal leukoencephalopathy. (a) Conventional imaging, diffusion weighted images (DWI), apparent diffusion coefficient (ADC) maps, and DTI ROIs. (b) Evolution of DTI metrics prior to onset of progressive multifocal leukoencephalopathy. (c) Evolution of DTI metrics after the onset of progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome.
References 1. Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, et al. Advances in functional and struc-
© 2014 The Author(s) European Journal of Neurology © 2014 EFNS
tural MR image analysis and implementation as FSL. Neuroimage 2004; 23(Suppl. 1): S208–S219. 2. Cox RW. AFNI: software for analysis and visualization of functional magnetic reso-
nance neuroimages. Comput Biomed Res 1996; 29: 162–173. 3. Clifford DB, De Luca A, Simpson DM, Arendt G, Giovannoni G, Nath A. Natalizumab-associated progressive multifocal
e38
Letter to the Editor
leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 2010; 9: 438–446.
4. Phan-Ba R, Lommers E, Tshibanda L, Calay P, Dubois B, Moonen G, et al. MRI preclinical detection and asymptomatic course of a progressive multifocal leucoen-
cephalopathy (PML) under natalizumab therapy. J Neurol Neurosurg Psychiatry 2012; 83: 224–226.
© 2014 The Author(s) European Journal of Neurology © 2014 EFNS
doi:10.1111/ene.12361
LETTERS TO THE EDITOR
Diffusion tensor imaging before, during and after progressive multifocal leukoencephalopathy D. Ontanedaa, K. Sakaieb, J. Linb, M. J. Loweb, M. D. Phillipsb and R. J. Foxa a Mellen Center, Neurological Institute, Cleveland, OH; and bImaging Institute Cleveland Clinic, Cleveland, OH, USA
Correspondence: D. Ontaneda, Mellen Center Cleveland Clinic, 9500 Euclid Avenue, U-10, Cleveland, OH, USA (tel.: 216 444 0151; fax: 216 445 7013; e-mail: [email protected]).
Keywords: progressive multifocal leukoencephalopathy, DTI Received: 8 November 2013 Accepted: 17 December 2013 A 57-year-old female with a 14-year history of relapsing remitting multiple sclerosis and an Expanded Disability Status Scale of 2.0 enrolled in a longitudinal MRI study following initiation of natalizumab and informed consent. JCV serology 4 years into treatment was positive, and the patient elected to continue treatment with natalizumab. At the 57th natalizumab infusion, a 2-week history of word finding and memory difficulties was reported. Cerebrospinal fluid examination showed WBC 0, RBC 1, protein 40 mg/dl and 99 copies of JCV DNA by polymerase chain reaction. She was treated with five sessions of plasma exchange. Maraviroc was started based on recommendations by infectious disease consultants for possible prevention
e36
of immune reconstitution inflammatory syndrome (IRIS). One-and-a-half months later, she developed worsening aphasia and mild right hemiparesis. Clinical/MRI features were consistent with IRIS. She was treated with 5 days of intravenous methylprednisolone and recovered with residual mild right arm weakness and moderate expressive aphasia. Brain MRI was acquired on a 3 T Siemens Trio (Siemens Medical Systems, Erlangen, Germany) at 42, 36, 30, 18 and 6 months prior to progressive multifocal leukoencephalopathy (PML) diagnosis, at the time of PML presentation (0 months) and at 0.5, 1.5, 3 and 4 months afterwards. Each scan included high angular resolution diffusion imaging with 71 non-collinear diffusion-weighting gradients. Images were co-registered using FSL [1]. A region of interest (ROI) was drawn on the area with PML involvement at the time of diagnosis (core PML, 9.8 cm3) and at the time of IRIS (total PML, volume 40.2 cm3) using AFNI [2]. A normal appearing white matter (NAWM) ROI (volume 13.2 cm3) was drawn in the contralateral parietooccipital cortex that remained diseasefree over follow-up. Average values of fractional anisotropy (FA) and mean, longitudinal and transverse diffusivity (MD, LD and TD, respectively) were derived for NAWM and PML ROI at each time point. Longitudinal imaging found an increase in LD, TD and MD and a decrease in FA 6 months prior to the onset of PML (Fig. 1). These changes were most notable between 12 and 6 months, and were greater in core PML than total PML. At the time of PML
diagnosis, an increase in LD, TD and MD was observed with a decrease in FA in both the core PML and total PML regions (Fig. 1). Minimal changes were observed in NAWM ROIs over the observation period. At the time of IRIS (1.5-month time point) there was a transient improvement (regression to prePML values) in LD, TD, MD and FA in the core PML and total PML. Four months after PML, diffusion tensor imaging (DTI) values showed a regression towards pre-PML values compared with 3 months. Discussion Identifying the earliest changes of PML is important for early diagnosis and optimal outcomes [3,4]. We observed changes in brain tissue at the site of later PML development 6 months prior to clinical onset. The greater change in TD relative to LD suggests that these changes may be secondary to demyelination, although other pathologies may contribute to the changes in TD. DTI metrics also changed markedly at the time of IRIS. During the initial stage of IRIS, an improvement (return towards baseline) in the core PML region was observed for FA, MD, TD and LD. Changes on DTI metrics may pre-date changes on conventional imaging and may be an early indicator of PML, although further study is needed to clarify its utility in this setting. Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
© 2014 The Author(s) European Journal of Neurology © 2014 EFNS
Letter to the Editor
(a)
e37
(b)
(c)
Figure 1 Imaging and DTI evolution of progressive multifocal leukoencephalopathy. (a) Conventional imaging, diffusion weighted images (DWI), apparent diffusion coefficient (ADC) maps, and DTI ROIs. (b) Evolution of DTI metrics prior to onset of progressive multifocal leukoencephalopathy. (c) Evolution of DTI metrics after the onset of progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome.
References 1. Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, et al. Advances in functional and struc-
© 2014 The Author(s) European Journal of Neurology © 2014 EFNS
tural MR image analysis and implementation as FSL. Neuroimage 2004; 23(Suppl. 1): S208–S219. 2. Cox RW. AFNI: software for analysis and visualization of functional magnetic reso-
nance neuroimages. Comput Biomed Res 1996; 29: 162–173. 3. Clifford DB, De Luca A, Simpson DM, Arendt G, Giovannoni G, Nath A. Natalizumab-associated progressive multifocal
e38
Letter to the Editor
leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 2010; 9: 438–446.
4. Phan-Ba R, Lommers E, Tshibanda L, Calay P, Dubois B, Moonen G, et al. MRI preclinical detection and asymptomatic course of a progressive multifocal leucoen-
cephalopathy (PML) under natalizumab therapy. J Neurol Neurosurg Psychiatry 2012; 83: 224–226.
© 2014 The Author(s) European Journal of Neurology © 2014 EFNS
