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Clinical science
Alteration of the optic radiations using diffusiontensor MRI in patients with retinitis pigmentosa Naonori Ohno,1,2 Hideki Murai,1,2 Yukihisa Suzuki,1,2 Motohiro Kiyosawa,1,3 Aya M Tokumaru,4 Kenji Ishii,2 Kyoko Ohno-Matsui1 1
Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan 2 Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 3 Kiyosawa Eye Clinic, Tokyo, Japan 4 Department of Diagnostic Radiology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan Correspondence to Dr Kenji Ishii, Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Sakae-cho 35-2, Itabashi-ku, Tokyo 173-0015, Japan; [email protected] Received 9 July 2014 Revised 8 January 2015 Accepted 12 January 2015 Published Online First 30 January 2015
ABSTRACT Purpose To evaluate alteration of the optic radiation (OR) in patients with retinitis pigmentosa (RP) using fractional anisotropy (FA) measured by diffusion tensor MRI. Methods We performed MRI and evaluated alteration of the ORs in 17 patients with RP and 27 healthy controls. Regions of interest were placed over the bilateral anterior and posterior areas of the ORs, and we measured the FA value of each region. Visual field (VF) tests were examined in all subjects, and we corrected the residual VF area according to the projection area to the striate cortex. Differences between the FA values of patients and healthy controls were tested. We performed regression analyses between the sum of the corrected VF areas and FA values in the anterior or posterior contralateral ORs in patients with RP. Moreover, we performed regression analyses between the average of FA values of ORs and the average of both eyes of visual acuity in patients with RP. Results FA values of the bilateral anterior and posterior ORs were lower in patients with RP (anterior right, p=0.012; posterior right, p=0.0004; anterior left, p=0.0008; and posterior left, p=0.0004) compared with those of healthy controls. In patients with RP, significant correlations were observed between average FA values of anterior ORs and average visual acuity (correlation coefficient (r)=−0.54; p=0.025). Conclusions In patients with RP, alterations may occur not only in the retina but also in the brain.
INTRODUCTION
To cite: Ohno N, Murai H, Suzuki Y, et al. Br J Ophthalmol 2015;99: 1051–1054.
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerative diseases, characterised by the progressive death of rod and cone photoreceptors,1 which leads to corresponding visual field (VF) defects. The visual stimulus received in the sensory retina activates photoreceptor cells (rod and cone), and synapses of photoreceptor cells are directly connected to bipolar cells, which in turn synapse onto retinal ganglion cells (RGCs). RGCs send information to the lateral geniculate nucleus (LGN) in the thalamus through the optic nerve. The optic radiation (OR), a collection of axons of the LGN, carries information to the visual cortex. Patients with RP often experience night blindness due to rod photoreceptor cell death in adolescence, and critical degeneration of cone photoreceptor cells decreases the quality of life of these patients in later years.2 Postmortem studies in patients with RP showed a mild-to-severe RGC loss in the retina,3 4 while it was reported that most RGCs survived despite photoreceptor cell loss in a mutant rat model.5 A postmortem study reported
that total axon counts of the optic nerve were significantly decreased in patients with RP compared with normal controls.6 Moreover, several studies have observed that the retinal nerve fibre layer (RNFL), which is formed by the expansion of the optic nerve fibres, was significantly thinner in patients with RP using optical coherence tomography (OCT).7 However, Pan et al8 observed decreasing white matter volume of the OR in patients with early blindness, including one patient with RP, using MRI and voxel-based morphometry. However, thus far, there has been no report that has investigated alteration of the OR in patients with RP with many samples. We hypothesise that the OR structure is affected as the VF defect progresses. To test this hypothesis, we studied the axonal architecture of the OR in patients with RP using diffusion tensor imaging (DTI) and examined the correlation between the fractional anisotropy (FA) value of the OR and the corresponding VF defect.
MATERIALS AND METHODS The study protocol was approved by the institutional ethical committee of the Tokyo Metropolitan Institute of Gerontology. All procedures conformed to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants before the start of the study. Seventeen patients (8 men and 9 women; age 58.2±16.3 (range 23–77) years) with RP were included in the study. The diagnosis of RP is based on clinical history, fundus examination, fluorecein angiography, VF and electroretinogram. The VF was measured by Goldmann kinetic perimetry (Inami L-1560). Patients who were diagnosed were confirmed to have no other ophthalmological disease, such as age-related macular degeneration, glaucoma and optic neuritis by ophthalmologists. The mean visual acuity of the patients was 0.46 ±0.63 log-MAR (minimum angle of resolution) units. Twenty-seven normal volunteers (18 men and 9 women; age 56.8±14.0 (range 24–77) years) were recruited as a control group. Bilateral corrected visual acuity of normal subjects was 20/25 or better. The subject who had an organic brain disorder was excluded by MRIs. We estimated the residual VF area and corrected the area according to the projection area to the striate cortex in each patient. Visual processing of the central vision is performed in a larger area of visual cortex than that of the peripheral vision. The central 10° occupies over half of the surface area of striate cortex.9 We scanned the VF chart of each patient on the same scale and calculated the
Ohno N, et al. Br J Ophthalmol 2015;99:1051–1054. doi:10.1136/bjophthalmol-2014-305809
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Clinical science number of pixels of inside V-4 isopter area of hemi-VF using PC software. Moreover, we corrected the number of pixels of each right and left hemi-VF area separately with weighted values according to the angle from the centre (center of 0–5°, 12; 5–10°, 4/3; 10–20°, 1/3; 10–20°, 1/12; 40° or more, 1/80). For the analysis we used the sum value of the corrected number of pixels of the right eye and the left eye of hemi-VF corresponding to each OR.
MRI data acquisition MRIs were obtained from all subjects by using a 1.5-Tesla Signa Excite HD scanner (General Electric, Milwaukee, Wisconsin, USA). Transaxial images vertical to brainstem were obtained with T1-weighted contrast (3DSPGR; TR=9.2 ms, TE=2.0 ms, matrix size=256×256×124, voxel size=0.94×0.94×1.3 mm), T2-weighted contrast (first spin echo; TR=3000 ms, TE=100 ms, matrix size=256×256×20, voxel size=0.7×0.7×6.5 mm) and DTI. A dedicated eight-element head coil was used. For DTI, we used a sensitivity-encoding single-shot echo-planar imaging sequence (4805/59; field of view=220×220 mm, section thickness=2 mm with no intersection gap, sensitivity-encoding reduction factor=2.4, partial Fourier transform=60%) with a maximal b value of 800 s/mm2 along 25 directions. A baseline image with no diffusion weighting (b=0) was also acquired. Matrices of 128×128 voxels with an in-plane spatial resolution of 1.7×1.7 mm were used for the diffusion-tensor calculations. The total imaging time, including setup and anatomic image acquisition, was kept less than 20 min.
MRI data processing and statistical analysis Data were processed using an automatic customised script on the MR console (GE Advantage Work Station). The DTI sequence obtains a total of 520 images including 500 diffusionweighted and 20 T2-weighted series-view images. Twenty slices of diffusion-tensor trace images were created by averaging 500 diffusion-weighted images, and FA maps were automatically created. We defined 2.5 mm diameter regions of interest (ROIs) over the bilateral anterior and posterior ORs in patients and normal subjects, and the FA values in each region were measured.
The ROIs were placed with reference to the corresponding two slices of T2-weighted MRIs acquired with diffusion-tensor images and then electronically superimposed over the FA maps. The anterior OR was defined as the straight portion that passed over the crooked portion from the LGN. The posterior OR was defined as the area just before the divergence in the striate cortex (figure 1). We selected the two central slices of images in which both the anterior part and the posterior part of OR were fully included. The examiner was blind to the subjects’ inclusion in the control or RP group and to the subjects’ clinical data. Differences between the FA values of patients and normal controls were tested using Mann Whitney U tests with Bonferroni’s correction for multiple comparisons: p values less than 0.0125 (=0.05/4) were considered significant. We performed regression analyses between the sum of the corrected VF area of both eyes of hemi-VFs and FA values in the anterior or posterior contralateral ORs in patients with RP. Moreover, we performed regression analyses between the average right and left FA values of ORs and the average visual acuity of both eyes in patients with RP: p values less than 0.05 were considered significant. Visual acuity was converted to log-MAR to use for calculation or analysis.10 Log-MAR is a commonly used scale which is expressed as the logarithm of the minimum angle of resolution. Because white matter, including OR, atrophies with aging,11 we considered the influence of age-related changes on FA values for the regression analyses. In our previous study, we observed a significant negative correlation between age and the FA values of ORs, and the decrease rate was 0.31–0.35% per year.12 We corrected the FA values of patients and used the age-corrected FA values for the regression analysis.
RESULTS The FA values of bilateral posterior and anterior ORs were significantly lower in patients with RP compared with healthy controls (anterior right, p=0.012; anterior left, p=0.0008; posterior right, p=0.0004; and posterior left, p=0.0004) (table 1). There was no significant correlation between sum of corrected VF area of both eyes of hemi-VF and FA values of contralateral anterior and posterior ORs (right hemi-VF and anterior left OR, r=0.12 (p=0.45); left hemi-VF and anterior right OR, r=0.23 (p=0.15); right hemi-VF and posterior left OR, r=−0.04 (p=0.22); left hemi-VF and posterior right OR, r=0.02 (p=0.11)) (figure 2). The regression analyses demonstrated significant negative correlations between the average of both eyes of visual acuity and the bilateral average of the FA values of the anterior ORs (r=−0.54 (p=0.025)), but not posterior ORs (r=−0.45 (p=0.07)) (figure 3).
DISCUSSION We observed that FA values of the bilateral anterior and posterior ORs were low in patients with RP. However, the reliability
Table 1 FA values in the anterior and posterior ORs of the retinitis pigmentosa group and normal controls Mean FA values±SD
Figure 1 The four circles in the figure show regions of interest (diameter: 2.5 mm) which were placed over the bilateral anterior and posterior optic radiations (ORs) with reference to T2-weighted MRIs that corresponded to the fractional anisotropy maps. The anterior OR was defined as the straight portion that passed over the crooked portion from the lateral geniculate nucleus. The posterior OR was defined as the area just before the divergence in the striate cortex. 1052
ROI
Site
Retinitis pigmentosa
Normal
p Value
Anterior OR
Right Left Right Left
0.480±0.024 0.482±0.022 0.450±0.029 0.449±0.021
0.510±0.048 0.513±0.051 0.520±0.053 0.503±0.049
0.012 0.0008 0.0004 0.0004
Posterior OR
FA, fractional anisotropy; OR, optic radiation; ROI, region of interest.
Ohno N, et al. Br J Ophthalmol 2015;99:1051–1054. doi:10.1136/bjophthalmol-2014-305809
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Clinical science
Figure 2 Regression analyses for patients with retinitis pigmentosa depict the correlation between the sum of corrected number of pixels of visual field (VF) area of both eyes of hemi-VF and fractional anisotropy (FA) values of the contralateral anterior and posterior optic radiations (ORs): (A) right VF and left anterior OR (r=0.12 ( p=0.45)); (B) left VF and right anterior OR (r=0.23 ( p=0.15)); (C) right VF and left posterior OR (r=−0.04 ( p=0.22)); (D) left VF and right posterior OR (r=0.02 ( p=0.11))). The average FA value of the normal controls is shown as a heavy line and ±1 SD of FA value of the normal controls is shown in the grey area.
of statistics may not be high because the number of patients is not so large. Regression analyses of FA values of anterior ORs showed a significant correlation with the mean of both eyes of visual acuity (log-MAR) in patients with RP. Michelson et al13 studied the OR of patients with glaucoma using DTI, and they observed significant correlation between glaucoma severity and FA value of OR. Pan et al8 observed decreasing white matter volume of the optic tract and ORs in patients with early blindness including only one patient with RP using MRI and voxelbased morphometry. Shu et al14 also observed a significantly low FA value in the geniculocalcarine tract in the subjects with early blindness, including several patients with RP. The
pathophysiological mechanism of OR alteration in patients with RP is not known. As a result of axonal degeneration, which is most commonly studied, alterations occur in photoreceptor cells, bipolar cells, RGCs, optic nerve, LGN, and the OR in the visual pathway. There are a few reports of other parts of the visual pathway such as RNFL7 and optic nerve6 in patients with RP. It seems that loss of RGC is slight compared with photoreceptor cell loss in RP,5 and it is also not known if loss of RGCs is a primary or secondary change. If loss of RGCs was a primary change, alteration of the OR may be caused by a transsynaptic degeneration through the LGN. While, if loss of RGCs was a secondary change, alteration of the OR may be caused by
Figure 3 Regression analyses for patients with retinitis pigmentosa show the correlation between visual acuity (log-MAR) and values of fractional anisotropy (FA) of the anterior (A) (r=−0.54 ( p=0.025)) and posterior (B) (r=−0.45 ( p=0.07)) optic radiations. The average FA value of the normal controls is shown as a heavy line and ±1 SD of FA value of the normal controls is shown in the grey area.
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Clinical science a multiple trans-synaptic degeneration at the retina and the LGN. However, glaucoma is characterised by the progressive death of RGCs, which leads to corresponding VF defects.15 It is known that the optic nerve,16 17 LGN18 and OR12 are atrophied in patients with glaucoma, while Ito et al19 observed that atrophy occurred in the LGN prior to other structures, such as the optic nerve or RGCs, in glaucoma. We observed significant correlation between FA values of anterior OR and visual acuity in patients with RP. The retina contains two types of photoreceptor cells, the rod and cone photoreceptor cells, and the cone photoreceptor cells which are concentrated in the fovea centralis are responsible for central vision. In patients with RP, the rod photoreceptor cells decrease from an early stage, while the cone photoreceptor cells often remain in later years.2 Using focal electroretinogram, Falsini et al20 observed that central cone photoreceptor function is decreased in patients with RP. Iarossi et al21 also observed that both cone photoreceptor function and visual acuity were low in patients with advanced RP using flicker electroretinogram. From these observations, we suspected that surviving cone photoreceptor cells and the OR were decreasing in many patients after the rod photoreceptor cells disappeared. We could not observe significant correlation between the sum of both eyes of corrected total count of hemi-VF and FA values of contralateral ORs. Previous studies also observed that there was no correlation between RNFL thickness and VF defect using OCT.7 22 There are several possible explanations for these findings. First, typical VF loss of patients with RP began in the form of a partial or complete ring scotoma.23 Further loss of VF led to a residual central and a temporal or nasal peripheral field island. In advanced stages, only a small central field remained. Patients in the present study were in various stages of the disease and it may be the main confounding factor of the result. The present study includes patients of a broad age range from 23 to 77 years old. Moreover, the patterns of VF loss progression and progress speed of the disease varies in different patients.23 24 Second, it may be related to the fact that the retina contains rod and cone photoreceptor cells. The rod photoreceptor cells, which are responsible for peripheral and night vision, are mostly distributed over the whole retina excluding the macula. In contrast, the cone photoreceptor cells, which are responsible for central and colour vision, are concentrated in the fovea centralis. We suspect that only the cone photoreceptor cells survive at the fovea centralis for a long period after the rod photoreceptor cells have disappeared in some patients with RP.25 Therefore, we could not find a significant correlation between VF and FA values of ORs because our study included only 7 out of the 17 patients who only had central vision. Third, there may be a time lag between reduction of photoreceptor cells and alteration of the OR. In the present study, there were several patients whose FA values of the OR were high, despite their large VF deficit. Lin and Peng5 observed that RGC populations and their fine dendritic geometry remained intact well beyond the complete loss of photoreceptors for at least up to 1.5 years in retinal degeneration rd1mice. However, Liang et al26 observed that FA values at the ipsilateral medulla and the proximal portion of the pyramidal tract significantly decreased progressively from week 1 to week 12 after pontine infarct using DTI. The anterograde and retrograde degeneration of the OR may also occur over a certain amount of time.
CONCLUSIONS
Contributors NO: research project, statistical analysis, manuscript writing of the first draft. HM: research project, statistical analysis. YS: research project and review and critique of manuscript. MK: review and critique of manuscript. AMT: review and critique of manuscript. KI: research project and review and critique of manuscript. KO-M: review and critique of manuscript. Competing interests None. Patient consent Obtained. Ethics approval The Institutional Ethical Committee of the Tokyo Metropolitan Institute of Gerontology. Provenance and peer review Not commissioned; externally peer reviewed.
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We observed alteration of the ORs in patients with RP, and significant correlation was observed between FA values of anterior ORs and visual acuity in patients with RP. Alteration may occur not only in the retina but also in the ORs in patients with RP. 1054
Acknowledgements We are grateful to Dr Kiichi Ishiwata for useful comments and discussions regarding the manuscript.
25 26
Delyfer MN, Léveillard T, Mohand-Saïd S, et al. Inherited retinal degenerations: therapeutic prospects. Biol Cell 2004;96:261–9. John SK, Smith JE, Aguirre GD, et al. Loss of cone molecular markers in rhodopsin-mutant human retinas with retinitis pigmentosa. Mol Vis 2000;6:204–15. Stone JL, Barlow WE, Humayun MS, et al. Morphometric analysis of macular photoreceptors and ganglion cells in retinas with retinitis pigmentosa. Arch Ophthalmol 1992;110:1634–9. Humayun MS, Prince M, de Juan E, et al. Morphometric analysis of the extramacular retina from postmortem eyes with retinitis pigmentosa. Invest Ophthalmol Vis Sci 1999;40:143–8. Lin B, Peng EB. Retinal ganglion cells are resistant to photoreceptor loss in retinal degeneration. PLoS One 2013;8:e68084. Eng JG, Agrawal RN, Tozer KR, et al. Morphometric analysis of optic nerves and retina from an end-stage retinitis pigmentosa patient with an implanted active epiretinal array. Invest Ophthalmol Vis Sci 2011;52:4610–16. Walia S, Fishman GA, Edward DP, et al. Retinal nerve fiber layer defects in RP patients. Invest Ophthalmol Vis Sci 2007;48:4748–52. Pan WJ, Wu G, Li CX, et al. Progressive atrophy in the optic pathway and visual cortex of early blind Chinese adults: a voxel-based morphometry magnetic resonance imaging study. Neuroimage 2007;37:212–20. Horton JC. Ocular integration in the human visual cortex. Can J Ophthalmol 2006;41:584–93. Holladay J. Proper method for calculating average visual acuity. J Refract Surg 1997;13:388–91. Giorgio A, Santelli L, Tomassini V, et al. Age-related changes in grey and white matter structure throughout adulthood. Neuroimage 2010;51:943–51. Murai H, Suzuki Y, Kiyosawa M, et al. Positive correlation between the degree of visual field defect and optic radiation damage in glaucoma patients. Jpn J Ophthalmol 2013;57:257–62. Michelson G, Engelhorn T, Wärntges S, et al. DTI parameters of axonal integrity and demyelination of the optic radiation correlate with glaucoma indices. Graefes Arch Clin Exp Ophthalmol 2013;251:243–53. Shu N, Li J, Li K, et al. Abnormal diffusion of cerebral white matter in early blindness. Hum Brain Mapp 2009;30:220–7. Quigley HA. Neuronal death in glaucoma. Prog Retin Eye Res 1999;18:39–57. Kashiwagi K, Okubo T, Tsukahara S. Association of magnetic resonance imaging of anterior optic pathway with glaucomatous visual field damage and optic disc cupping. J Glaucoma 2004;13:189–95. Gupta N, Ang LC, Noël de Tilly L, et al. Human glaucoma and neural degeneration in intracranial optic nerve, lateral geniculate nucleus, and visual cortex. Br J Ophthalmol 2006;90:674–8. Gupta N, Greenberg G, Tilly LN, et al. Atrophy of the lateral geniculate nucleus in human glaucoma by magnetic resonance imaging. Br J Ophthalmol 2009;93:56–60. Ito Y, Shimazawa M, Chen YN, et al. Morphological changes in the visual pathway induced by experimental glaucoma in Japanese monkeys. Exp Eye Res 2009;89:246–55. Falsini B, Galli-Resta L, Fadda A, et al. Long-term decline of central cone function in retinitis pigmentosa evaluated by focal electroretinogram. Invest Ophthalmol Vis Sci 2012;53:7701–9. Iarossi G, Falsini B, Piccardi M. Regional cone dysfunction in retinitis pigmentosa evaluated by flicker ERGs: relationship with perimetric sensitivity losses. Invest Ophthalmol Vis Sci 2003;44:866–74. Oishi A, Otani A, Sasahara M, et al. Retinal nerve fiber layer thickness in patients with retinitis pigmentosa. Eye (Lond) 2009;23:561–6. Grover S, Fishman GA, Brown J Jr. Patterns of visual field progression in patients with retinitis pigmentosa. Ophthalmology 1998;105:1069–75. Sandberg MA, Gaudio AR, Berson EL. Disease course of patients with pericentral retinitis pigmentosa. Am J Ophthalmol 2005;140:100–6. Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet 2006;368:1795–809. Liang Z, Zeng J, Zhang C, et al. Longitudinal investigations on the anterograde and retrograde degeneration in the pyramidal tract following pontine infarction with diffusion tensor imaging. Cerebrovasc Dis 2008;25:209–16.
Ohno N, et al. Br J Ophthalmol 2015;99:1051–1054. doi:10.1136/bjophthalmol-2014-305809
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Alteration of the optic radiations using diffusion-tensor MRI in patients with retinitis pigmentosa Naonori Ohno, Hideki Murai, Yukihisa Suzuki, Motohiro Kiyosawa, Aya M Tokumaru, Kenji Ishii and Kyoko Ohno-Matsui Br J Ophthalmol 2015 99: 1051-1054 originally published online January 30, 2015
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Clinical science
Alteration of the optic radiations using diffusiontensor MRI in patients with retinitis pigmentosa Naonori Ohno,1,2 Hideki Murai,1,2 Yukihisa Suzuki,1,2 Motohiro Kiyosawa,1,3 Aya M Tokumaru,4 Kenji Ishii,2 Kyoko Ohno-Matsui1 1
Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan 2 Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 3 Kiyosawa Eye Clinic, Tokyo, Japan 4 Department of Diagnostic Radiology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan Correspondence to Dr Kenji Ishii, Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Sakae-cho 35-2, Itabashi-ku, Tokyo 173-0015, Japan; [email protected] Received 9 July 2014 Revised 8 January 2015 Accepted 12 January 2015 Published Online First 30 January 2015
ABSTRACT Purpose To evaluate alteration of the optic radiation (OR) in patients with retinitis pigmentosa (RP) using fractional anisotropy (FA) measured by diffusion tensor MRI. Methods We performed MRI and evaluated alteration of the ORs in 17 patients with RP and 27 healthy controls. Regions of interest were placed over the bilateral anterior and posterior areas of the ORs, and we measured the FA value of each region. Visual field (VF) tests were examined in all subjects, and we corrected the residual VF area according to the projection area to the striate cortex. Differences between the FA values of patients and healthy controls were tested. We performed regression analyses between the sum of the corrected VF areas and FA values in the anterior or posterior contralateral ORs in patients with RP. Moreover, we performed regression analyses between the average of FA values of ORs and the average of both eyes of visual acuity in patients with RP. Results FA values of the bilateral anterior and posterior ORs were lower in patients with RP (anterior right, p=0.012; posterior right, p=0.0004; anterior left, p=0.0008; and posterior left, p=0.0004) compared with those of healthy controls. In patients with RP, significant correlations were observed between average FA values of anterior ORs and average visual acuity (correlation coefficient (r)=−0.54; p=0.025). Conclusions In patients with RP, alterations may occur not only in the retina but also in the brain.
INTRODUCTION
To cite: Ohno N, Murai H, Suzuki Y, et al. Br J Ophthalmol 2015;99: 1051–1054.
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerative diseases, characterised by the progressive death of rod and cone photoreceptors,1 which leads to corresponding visual field (VF) defects. The visual stimulus received in the sensory retina activates photoreceptor cells (rod and cone), and synapses of photoreceptor cells are directly connected to bipolar cells, which in turn synapse onto retinal ganglion cells (RGCs). RGCs send information to the lateral geniculate nucleus (LGN) in the thalamus through the optic nerve. The optic radiation (OR), a collection of axons of the LGN, carries information to the visual cortex. Patients with RP often experience night blindness due to rod photoreceptor cell death in adolescence, and critical degeneration of cone photoreceptor cells decreases the quality of life of these patients in later years.2 Postmortem studies in patients with RP showed a mild-to-severe RGC loss in the retina,3 4 while it was reported that most RGCs survived despite photoreceptor cell loss in a mutant rat model.5 A postmortem study reported
that total axon counts of the optic nerve were significantly decreased in patients with RP compared with normal controls.6 Moreover, several studies have observed that the retinal nerve fibre layer (RNFL), which is formed by the expansion of the optic nerve fibres, was significantly thinner in patients with RP using optical coherence tomography (OCT).7 However, Pan et al8 observed decreasing white matter volume of the OR in patients with early blindness, including one patient with RP, using MRI and voxel-based morphometry. However, thus far, there has been no report that has investigated alteration of the OR in patients with RP with many samples. We hypothesise that the OR structure is affected as the VF defect progresses. To test this hypothesis, we studied the axonal architecture of the OR in patients with RP using diffusion tensor imaging (DTI) and examined the correlation between the fractional anisotropy (FA) value of the OR and the corresponding VF defect.
MATERIALS AND METHODS The study protocol was approved by the institutional ethical committee of the Tokyo Metropolitan Institute of Gerontology. All procedures conformed to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants before the start of the study. Seventeen patients (8 men and 9 women; age 58.2±16.3 (range 23–77) years) with RP were included in the study. The diagnosis of RP is based on clinical history, fundus examination, fluorecein angiography, VF and electroretinogram. The VF was measured by Goldmann kinetic perimetry (Inami L-1560). Patients who were diagnosed were confirmed to have no other ophthalmological disease, such as age-related macular degeneration, glaucoma and optic neuritis by ophthalmologists. The mean visual acuity of the patients was 0.46 ±0.63 log-MAR (minimum angle of resolution) units. Twenty-seven normal volunteers (18 men and 9 women; age 56.8±14.0 (range 24–77) years) were recruited as a control group. Bilateral corrected visual acuity of normal subjects was 20/25 or better. The subject who had an organic brain disorder was excluded by MRIs. We estimated the residual VF area and corrected the area according to the projection area to the striate cortex in each patient. Visual processing of the central vision is performed in a larger area of visual cortex than that of the peripheral vision. The central 10° occupies over half of the surface area of striate cortex.9 We scanned the VF chart of each patient on the same scale and calculated the
Ohno N, et al. Br J Ophthalmol 2015;99:1051–1054. doi:10.1136/bjophthalmol-2014-305809
1051
Downloaded from http://bjo.bmj.com/ on August 12, 2015 - Published by group.bmj.com
Clinical science number of pixels of inside V-4 isopter area of hemi-VF using PC software. Moreover, we corrected the number of pixels of each right and left hemi-VF area separately with weighted values according to the angle from the centre (center of 0–5°, 12; 5–10°, 4/3; 10–20°, 1/3; 10–20°, 1/12; 40° or more, 1/80). For the analysis we used the sum value of the corrected number of pixels of the right eye and the left eye of hemi-VF corresponding to each OR.
MRI data acquisition MRIs were obtained from all subjects by using a 1.5-Tesla Signa Excite HD scanner (General Electric, Milwaukee, Wisconsin, USA). Transaxial images vertical to brainstem were obtained with T1-weighted contrast (3DSPGR; TR=9.2 ms, TE=2.0 ms, matrix size=256×256×124, voxel size=0.94×0.94×1.3 mm), T2-weighted contrast (first spin echo; TR=3000 ms, TE=100 ms, matrix size=256×256×20, voxel size=0.7×0.7×6.5 mm) and DTI. A dedicated eight-element head coil was used. For DTI, we used a sensitivity-encoding single-shot echo-planar imaging sequence (4805/59; field of view=220×220 mm, section thickness=2 mm with no intersection gap, sensitivity-encoding reduction factor=2.4, partial Fourier transform=60%) with a maximal b value of 800 s/mm2 along 25 directions. A baseline image with no diffusion weighting (b=0) was also acquired. Matrices of 128×128 voxels with an in-plane spatial resolution of 1.7×1.7 mm were used for the diffusion-tensor calculations. The total imaging time, including setup and anatomic image acquisition, was kept less than 20 min.
MRI data processing and statistical analysis Data were processed using an automatic customised script on the MR console (GE Advantage Work Station). The DTI sequence obtains a total of 520 images including 500 diffusionweighted and 20 T2-weighted series-view images. Twenty slices of diffusion-tensor trace images were created by averaging 500 diffusion-weighted images, and FA maps were automatically created. We defined 2.5 mm diameter regions of interest (ROIs) over the bilateral anterior and posterior ORs in patients and normal subjects, and the FA values in each region were measured.
The ROIs were placed with reference to the corresponding two slices of T2-weighted MRIs acquired with diffusion-tensor images and then electronically superimposed over the FA maps. The anterior OR was defined as the straight portion that passed over the crooked portion from the LGN. The posterior OR was defined as the area just before the divergence in the striate cortex (figure 1). We selected the two central slices of images in which both the anterior part and the posterior part of OR were fully included. The examiner was blind to the subjects’ inclusion in the control or RP group and to the subjects’ clinical data. Differences between the FA values of patients and normal controls were tested using Mann Whitney U tests with Bonferroni’s correction for multiple comparisons: p values less than 0.0125 (=0.05/4) were considered significant. We performed regression analyses between the sum of the corrected VF area of both eyes of hemi-VFs and FA values in the anterior or posterior contralateral ORs in patients with RP. Moreover, we performed regression analyses between the average right and left FA values of ORs and the average visual acuity of both eyes in patients with RP: p values less than 0.05 were considered significant. Visual acuity was converted to log-MAR to use for calculation or analysis.10 Log-MAR is a commonly used scale which is expressed as the logarithm of the minimum angle of resolution. Because white matter, including OR, atrophies with aging,11 we considered the influence of age-related changes on FA values for the regression analyses. In our previous study, we observed a significant negative correlation between age and the FA values of ORs, and the decrease rate was 0.31–0.35% per year.12 We corrected the FA values of patients and used the age-corrected FA values for the regression analysis.
RESULTS The FA values of bilateral posterior and anterior ORs were significantly lower in patients with RP compared with healthy controls (anterior right, p=0.012; anterior left, p=0.0008; posterior right, p=0.0004; and posterior left, p=0.0004) (table 1). There was no significant correlation between sum of corrected VF area of both eyes of hemi-VF and FA values of contralateral anterior and posterior ORs (right hemi-VF and anterior left OR, r=0.12 (p=0.45); left hemi-VF and anterior right OR, r=0.23 (p=0.15); right hemi-VF and posterior left OR, r=−0.04 (p=0.22); left hemi-VF and posterior right OR, r=0.02 (p=0.11)) (figure 2). The regression analyses demonstrated significant negative correlations between the average of both eyes of visual acuity and the bilateral average of the FA values of the anterior ORs (r=−0.54 (p=0.025)), but not posterior ORs (r=−0.45 (p=0.07)) (figure 3).
DISCUSSION We observed that FA values of the bilateral anterior and posterior ORs were low in patients with RP. However, the reliability
Table 1 FA values in the anterior and posterior ORs of the retinitis pigmentosa group and normal controls Mean FA values±SD
Figure 1 The four circles in the figure show regions of interest (diameter: 2.5 mm) which were placed over the bilateral anterior and posterior optic radiations (ORs) with reference to T2-weighted MRIs that corresponded to the fractional anisotropy maps. The anterior OR was defined as the straight portion that passed over the crooked portion from the lateral geniculate nucleus. The posterior OR was defined as the area just before the divergence in the striate cortex. 1052
ROI
Site
Retinitis pigmentosa
Normal
p Value
Anterior OR
Right Left Right Left
0.480±0.024 0.482±0.022 0.450±0.029 0.449±0.021
0.510±0.048 0.513±0.051 0.520±0.053 0.503±0.049
0.012 0.0008 0.0004 0.0004
Posterior OR
FA, fractional anisotropy; OR, optic radiation; ROI, region of interest.
Ohno N, et al. Br J Ophthalmol 2015;99:1051–1054. doi:10.1136/bjophthalmol-2014-305809
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Clinical science
Figure 2 Regression analyses for patients with retinitis pigmentosa depict the correlation between the sum of corrected number of pixels of visual field (VF) area of both eyes of hemi-VF and fractional anisotropy (FA) values of the contralateral anterior and posterior optic radiations (ORs): (A) right VF and left anterior OR (r=0.12 ( p=0.45)); (B) left VF and right anterior OR (r=0.23 ( p=0.15)); (C) right VF and left posterior OR (r=−0.04 ( p=0.22)); (D) left VF and right posterior OR (r=0.02 ( p=0.11))). The average FA value of the normal controls is shown as a heavy line and ±1 SD of FA value of the normal controls is shown in the grey area.
of statistics may not be high because the number of patients is not so large. Regression analyses of FA values of anterior ORs showed a significant correlation with the mean of both eyes of visual acuity (log-MAR) in patients with RP. Michelson et al13 studied the OR of patients with glaucoma using DTI, and they observed significant correlation between glaucoma severity and FA value of OR. Pan et al8 observed decreasing white matter volume of the optic tract and ORs in patients with early blindness including only one patient with RP using MRI and voxelbased morphometry. Shu et al14 also observed a significantly low FA value in the geniculocalcarine tract in the subjects with early blindness, including several patients with RP. The
pathophysiological mechanism of OR alteration in patients with RP is not known. As a result of axonal degeneration, which is most commonly studied, alterations occur in photoreceptor cells, bipolar cells, RGCs, optic nerve, LGN, and the OR in the visual pathway. There are a few reports of other parts of the visual pathway such as RNFL7 and optic nerve6 in patients with RP. It seems that loss of RGC is slight compared with photoreceptor cell loss in RP,5 and it is also not known if loss of RGCs is a primary or secondary change. If loss of RGCs was a primary change, alteration of the OR may be caused by a transsynaptic degeneration through the LGN. While, if loss of RGCs was a secondary change, alteration of the OR may be caused by
Figure 3 Regression analyses for patients with retinitis pigmentosa show the correlation between visual acuity (log-MAR) and values of fractional anisotropy (FA) of the anterior (A) (r=−0.54 ( p=0.025)) and posterior (B) (r=−0.45 ( p=0.07)) optic radiations. The average FA value of the normal controls is shown as a heavy line and ±1 SD of FA value of the normal controls is shown in the grey area.
Ohno N, et al. Br J Ophthalmol 2015;99:1051–1054. doi:10.1136/bjophthalmol-2014-305809
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Clinical science a multiple trans-synaptic degeneration at the retina and the LGN. However, glaucoma is characterised by the progressive death of RGCs, which leads to corresponding VF defects.15 It is known that the optic nerve,16 17 LGN18 and OR12 are atrophied in patients with glaucoma, while Ito et al19 observed that atrophy occurred in the LGN prior to other structures, such as the optic nerve or RGCs, in glaucoma. We observed significant correlation between FA values of anterior OR and visual acuity in patients with RP. The retina contains two types of photoreceptor cells, the rod and cone photoreceptor cells, and the cone photoreceptor cells which are concentrated in the fovea centralis are responsible for central vision. In patients with RP, the rod photoreceptor cells decrease from an early stage, while the cone photoreceptor cells often remain in later years.2 Using focal electroretinogram, Falsini et al20 observed that central cone photoreceptor function is decreased in patients with RP. Iarossi et al21 also observed that both cone photoreceptor function and visual acuity were low in patients with advanced RP using flicker electroretinogram. From these observations, we suspected that surviving cone photoreceptor cells and the OR were decreasing in many patients after the rod photoreceptor cells disappeared. We could not observe significant correlation between the sum of both eyes of corrected total count of hemi-VF and FA values of contralateral ORs. Previous studies also observed that there was no correlation between RNFL thickness and VF defect using OCT.7 22 There are several possible explanations for these findings. First, typical VF loss of patients with RP began in the form of a partial or complete ring scotoma.23 Further loss of VF led to a residual central and a temporal or nasal peripheral field island. In advanced stages, only a small central field remained. Patients in the present study were in various stages of the disease and it may be the main confounding factor of the result. The present study includes patients of a broad age range from 23 to 77 years old. Moreover, the patterns of VF loss progression and progress speed of the disease varies in different patients.23 24 Second, it may be related to the fact that the retina contains rod and cone photoreceptor cells. The rod photoreceptor cells, which are responsible for peripheral and night vision, are mostly distributed over the whole retina excluding the macula. In contrast, the cone photoreceptor cells, which are responsible for central and colour vision, are concentrated in the fovea centralis. We suspect that only the cone photoreceptor cells survive at the fovea centralis for a long period after the rod photoreceptor cells have disappeared in some patients with RP.25 Therefore, we could not find a significant correlation between VF and FA values of ORs because our study included only 7 out of the 17 patients who only had central vision. Third, there may be a time lag between reduction of photoreceptor cells and alteration of the OR. In the present study, there were several patients whose FA values of the OR were high, despite their large VF deficit. Lin and Peng5 observed that RGC populations and their fine dendritic geometry remained intact well beyond the complete loss of photoreceptors for at least up to 1.5 years in retinal degeneration rd1mice. However, Liang et al26 observed that FA values at the ipsilateral medulla and the proximal portion of the pyramidal tract significantly decreased progressively from week 1 to week 12 after pontine infarct using DTI. The anterograde and retrograde degeneration of the OR may also occur over a certain amount of time.
CONCLUSIONS
Contributors NO: research project, statistical analysis, manuscript writing of the first draft. HM: research project, statistical analysis. YS: research project and review and critique of manuscript. MK: review and critique of manuscript. AMT: review and critique of manuscript. KI: research project and review and critique of manuscript. KO-M: review and critique of manuscript. Competing interests None. Patient consent Obtained. Ethics approval The Institutional Ethical Committee of the Tokyo Metropolitan Institute of Gerontology. Provenance and peer review Not commissioned; externally peer reviewed.
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We observed alteration of the ORs in patients with RP, and significant correlation was observed between FA values of anterior ORs and visual acuity in patients with RP. Alteration may occur not only in the retina but also in the ORs in patients with RP. 1054
Acknowledgements We are grateful to Dr Kiichi Ishiwata for useful comments and discussions regarding the manuscript.
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Ohno N, et al. Br J Ophthalmol 2015;99:1051–1054. doi:10.1136/bjophthalmol-2014-305809
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Alteration of the optic radiations using diffusion-tensor MRI in patients with retinitis pigmentosa Naonori Ohno, Hideki Murai, Yukihisa Suzuki, Motohiro Kiyosawa, Aya M Tokumaru, Kenji Ishii and Kyoko Ohno-Matsui Br J Ophthalmol 2015 99: 1051-1054 originally published online January 30, 2015
doi: 10.1136/bjophthalmol-2014-305809 Updated information and services can be found at: http://bjo.bmj.com/content/99/8/1051
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