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ARTICLES: E. Gordon-Lipkin, B. Chodkowski, D. S. Reich, S. A. Smith, M. Pulicken, L. J. Balcer, E. M. Frohman, G. Cutter, and P. A. Calabresi Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis Neurology 2007; 69: 1603-1609 [Abstract] [Full text] [PDF]

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Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis

Pablo Villoslada, Jorge Sepulcre, Jon Toledo, Bartolome Bejarano   (5 February 2008)

Reply from the authors

Peter A. Calabresi, Eliza Gordon Lipkin, Betty-Ann Chodkowski, Daniel Reich, Seth Smith, Mathew Pulicken, Elliot Frohman, Laura Balcer, and Gary Cutter   (5 February 2008)

Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis

Olivier Gout   (27 December 2007)

Reply from the authors/ Gout

Peter A. Calabresi   (27 December 2007)

Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis 5 February 2008
Pablo Villoslada, University of Navarra Pio XII 36. 31008, Pamplona, Spain, Jorge Sepulcre, Jon Toledo, Bartolome Bejarano Send Correspondence to journal: Re: Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis pvilloslada{at}unav.es Pablo Villoslada, et al.	Gordon-Lipkin et al reported the correlation between the thickness of the retinal nerve fiber layer (RNFL) and brain parenchymal atrophy in MS. [1] These results confirm our previous study where we found correlation between RNFL thickness and gray matter and white matter volume. [2] Using two different approaches for measuring brain atrophy, both studies demonstrate that the thickness of the RNFL correlates with brain atrophy. In both cases, we studied patients at the early to medium stage of the disease, indicating that the atrophy identified, both at the head of the optic nerve and in the brain, is an early phenomenon in MS. Moreover, these results suggest that the atrophy of the optic nerve is indicative of the neurodegenerative process in the brain. This has also been shown in Alzheimer disease (AD) [3] and Parkinson disease (PD), [4] where the RNFL is reduced in patients. These results are valuable for two different reasons. From the clinical point of view, it is important to develop new biomarkers or imaging techniques for monitoring disease evolution and response to therapy. Assessment of the RNFL is a well tolerated, inexpensive and reproducible method that can provide this kind of clinical information. More importantly, RNFL thickness quantifies the most critical biological process leading to permanent disability in MS such as axonal loss. [5] Moreover, the decrease of the RNFL thickness has good specificity in identifying patients who are going to suffer disability progression two years later. [2] Due to the multifocal nature of MS, the RNFL will be randomly affected and the information will not be accurate enough about the overall brain damage. However, the optic nerve is a preferential site for MS lesions and it is frequently clinically or subclinically affected. Current and future prospective studies will clarify the usefulness of this technique for clinical management of patients with MS. RNFL assessment is becoming a promising technique for evaluating the integrity of the brain in clinical settings and might become a surrogate marker of neuroprotection in future clinical trials. References 1. Gordon-Lipkin E, Chodkowski B, Reich DS et al. Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis. Neurology. 2007;69:1603-1609. 2. Sepulcre J, Murie-Fernandez M, Salinas-Alaman A et al. Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS. Neurology. 2007;68:1488-1494. 3. Danesh-Meyer HV, Birch H, Ku JY et al. Reduction of optic nerve fibers in patients with Alzheimer disease identified by laser imaging. Neurology. 2006;67:1852-1854. 4. Inzelberg R, Ramirez JA, Nisipeanu P, Ophir A. Retinal nerve fiber layer thinning in Parkinson disease. Vision Res. 2004;44:2793-2797. 5. Waxman SG, Black JA. Retinal involvement in multiple sclerosis. Neurology. 2007;69:1562-1563. Disclosure: The authors report no conflicts of interest.
Reply from the authors 5 February 2008
Peter A. Calabresi, Johns Hopkins University 600 N. Wolfe St, Baltimore, MD 21287, Eliza Gordon Lipkin, Betty-Ann Chodkowski, Daniel Reich, Seth Smith, Mathew Pulicken, Elliot Frohman, Laura Balcer, and Gary Cutter Send Correspondence to journal: Re: Reply from the authors Calabresi{at}jhmi.edu Peter A. Calabresi, et al.	We completely agree with the comments made by Professor Villoslada and apologize for not being able to reference their manuscript while ours was in press. Disclosure: The authors report no conflicts of interest.
Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis 27 December 2007
Olivier Gout, Department of Neurology, Fondation A de Rothschild 25 rue Manin 75019 Paris, France Send Correspondence to journal: Re: Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis ogout{at}fo-rothschild.fr Olivier Gout	I read with interest the paper by Gordon-Lipkin et al. [1] The authors studied a small heterogeneous group of MS patients and gave no information concerning the presence of previous optic neuritis. They stated that “there were no selection biases based on history or severity of optic neuritis or MS characteristics”. There are at least three possibilities: 1) all the patients had prior optic neuritis; 2) no patients had prior optic neuritis; or 3) the group is a mixture of patients with and without prior optic neuritis. According to the patients that have been included, the meaning of the results are different. The authors should have studied patients without prior optic neuritis to accurately conclude that there is a correlation between RNFL thickness and brain atrophy. If all the patients had prior optic neuritis, it has been shown that following optic neuritis with incomplete recovery that there is RNFL thinning. [2] This can happen at the onset of MS when no brain atrophy is observed so it is impossible to reach a correlation between brain atrophy and axonal loss in RNFL. References 1. Gordon-Lipkin E, Chodowski B, Reich DS et al. Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis. Neurology 2007;69:1603-1609. 2. Costello F, Coupland S, Hodge W et al. Quantifying axonal loss after optic neuritis with optical coherence tomography. Ann Neurol 2006;59:963-969. Disclosure: The author reports no conflict of interest.
Reply from the authors/ Gout 27 December 2007
Peter A. Calabresi, Johns Hopkins University Pathology Buliding Room 627, 600 N. Wolfe St., Baltimore, MD 21287 Send Correspondence to journal: Re: Reply from the authors/ Gout Calabresi{at}jhmi.edu Peter A. Calabresi	I thank Prof. Gout for his inquiry and recognize that history of optic neuritis in our patient population is an important statistic. In Table 1, we list that 20 of our 40 MS subjects (50%) had a history of optic neuritis prior to enrolling in the study. We also agree that it is valuable to assess the association between RNFL and brain atrophy in subjects with and without history of optic neuritis separately. We plan on answering these questions in subsequent studies with larger subject groups. By clustering all MS subjects together in this study, we included those that may have suffered subclinical attacks of optic neuritis in which there is inflammation and demyelination in the optic nerve in the absence of clinically noticed visual dysfunction. These subclinical events in eyes without a history of optic neuritis cause RNFL thinning detectable by OCT and low contrast visual acuity, but not detectable by conventional exam, as has been reported by several groups already. [4-6] It is possible that patients who suffer RNFL thinning and with no documented history of optic neuritis could develop brain atrophy at a different rate than patients with clinical attacks. However, our recent report that patients with PPMS also have severe RNFL thinning argues against a major role for clinically noticeable optic neuritis in determining the severity of RNFL thinning. [6] Finally, as Prof. Gout points out, it is likely that a temporal discordance between RNFL thinning and brain atrophy exists. Thus, the extent of RNFL thinning early in the course of MS, when patients present with focal lesions such as optic neuritis, may be more valuable in predicting future changes in brain atrophy, rather than having concurrent validity. RNFL thinning in early RRMS could potentially predict those patients who will have accelerated brain atrophy and follow a more severe progressive course. These questions are being addressed in an ongoing longitudinal study and will have important implications for designing clinical trials of neuroprotective drugs. References 4. Fisher JB, Jacobs DA, Markowitz CE, et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology 2006;113:324-332. 5. Trip SA, Schlottmann PG, Jones SJ, et al. Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Ann Neurol 2005;58:383-391. 6. Pulicken M, Gordon-Lipkin E, Balcer LJ, Frohman E, Cutter G, Calabresi PA. Optical coherence tomography and disease subtype in multiple sclerosis. Neurology2007; 69: 2085-2092. Disclosure: The authors report no conflicts of interest.