- Email: [email protected]
Retinal nerve fiber layer thinning in Parkinson disease
Vision Research 44 (2004) 2793–2797 www.elsevier.com/locate/visres
Retinal nerve fiber layer thinning in Parkinson disease Rivka Inzelberg
a,b
, Jose Antonio Ramirez c, Puiu Nisipeanu a, Avinoam Ophir
b,c,*
a
c
Department of Neurology, Hillel Yaffe Medical Center, Hadera 38100, Israel b Rappaport Faculty of Medicine, Technion, Haifa, Israel Department of Ophthalmology, Hillel Yaffe Medical Center, Hadera 38100, Israel Received 10 February 2004; received in revised form 7 June 2004
Abstract Retinal dopamine loss in Parkinson disease (PD) is reflected by visual neurophysiological dysfunction. We measured the thickness of the circumpapillary retinal nerve fiber layer (RNFL) in PD patients using optical coherence tomography. The thickness in the inferior quadrant of PD patients (147 ± 20 microns) was significantly thinner than that of controls (173 ± 12 microns; p = 0.002), while the inferotemporal area was the thinnest (146 ± 24 vs. 191 ± 21 microns; p = 0.0003). The results show significant loss of RNFL thickness in PD at specific sites. 2004 Elsevier Ltd. All rights reserved. Keywords: Parkinson; Retina; Retinal nerve fiber layer; Optical coherence tomography
ParkinsonÕs disease (PD) is primarily a motor disorder associated with degeneration of dopaminergic neurons in the substantia nigra. Besides its major involvement in motor function, dopamine (DA) has fully been established as a major neurotransmitter or modulator in the retina (Djamgoz, Hankins, Hirano, & Archer, 1997). Visual functions controlled at least partially by dopamine, such as absolute sensitivity, spatial contrast sensitivity, temporal sensitivity and color vision are impaired in PD (Djamgoz et al., 1997; Bodis-Wollner, 1990; Jackson & Owsley, 2003). The DA content of the retina as measured at postmortem, is low in PD patients (Harnois & Di Paolo, 1990). Data concerning visual dysfunction in PD are based on neurophysiological evaluation. It is unclear whether there is concurrent tissue loss in the retina.
*
Corresponding author. Tel.: +972 4 6304528; fax: +972 3 5409222. E-mail address: ophthalmology@hillel-yaffe.health.gov.il (A. Ophir). 0042-6989/$ - see front matter 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.visres.2004.06.009
Optical coherence tomography (OCT) is a non-invasive, objective method, which can provide diagnostic information and quantitative data on biological tissues at high resolution of 10 microns. The principle of OCT is analogous to ultrasound, however, the system uses light instead of acoustic waves. Standard circular OCT scans (3.4-mm diameter) around the ONH provide objective and reproducible measurements of the retinal nerve fiber layer (RNFL) thickness, with a 6.9% coefficient of variation between repeated scans in normal eyes (Blumenthal et al., 2000). Normal OCT ranges of the retina, and measurements in diverse pathological conditions of the optic nerve such as glaucoma and multiple sclerosis have been described (Parisi et al., 1999; Kanamori et al., 2003). In glaucomatous eyes, regional reduction in RNFL thickness and regional decreases in visual field (VF) sensitivity are topographically related. Further, the magnitude of focal RNFL thinning is related to the magnitude of decreased VF sensitivity (El Beltagi et al., 2003). We examined the thickness of the RNFL near its entry to the optic nerve head in PD patients and compared
2794
R. Inzelberg et al. / Vision Research 44 (2004) 2793–2797
them with healthy controls. To the best of our knowledge this has not been previously reported.
1. Methods
1.3. Statistical analysis The RNFL thickness in four retinal quadrants, namely: superior, inferior, nasal and temporal, in PD patients was compared to that of age-matched control subjects using StudentÕs t-test.
1.1. Patients 2. Results Consecutive PD patients followed by our Movement Disorders Clinic were recruited for the study. The criteria for PD diagnosis were: (1) at least two of the following signs: rest tremor, rigidity, bradykinesia, and postural reflex impairment, (2) known sustained response to antiparkinsonian medication and (3) no other known or suspected causes for parkinsonism. Eyes with posterior pole pathology such as macular degeneration, those with optic neuropathies including glaucoma, glaucoma suspect or patients with media opacification such as cataract that precluded precise ocular and OCT examinations were excluded. Diagnosis of glaucoma was based on any of the following: classical appearance of the open angle glaucoma changes in the optic disc, enlargement and especially vertical enlargement of the optic cup, localized loss of disc rim and rim pallor, asymmetry of cup/ disc ratio >0.2 between the two eyes, baring of the lamina cribrosa, intraocular pressure and typical visual field loss. Sixteen PD patients were initially recruited. Six were excluded: four were unable to complete the OCT examination (dyskinesia, tremor, fatigue), one due to newly diagnosed glaucoma, and one due to glaucoma suspect. Only one eye of each of 10 patients was chosen for analysis as follows: when the OCT was successfully completed bilaterally, one eye at random was chosen (n = 6). When only one eye of the patient was reliably examined, this eye was included in the study (n = 4). Ten age-matched controls were also examined; one eye at random was chosen for analysis. 1.2. Procedure The Institutional Ethics Committee and Ministry of Health approved the study. All subjects signed an informed consent for participation. Each patient underwent ocular examination, intraocular pressure measurement and visual field (VF) examination using the Humphrey 24–2 visual field program (Humphrey Instruments, Pennsylvania). Each eye was examined by OCT, with the pupil dilated. The subject was asked to fixate a luminous point; the required area was scanned by OCT. The examination included five circumpapillary standard circular scans (3.4 mm in diameter) followed by six radial lines centered at the optic nerve head (6 mm length each).
Ten PD patients (five males, aged 57 ± 11 years (mean ± SD)), with disease duration of 7 ± 4 years (range, 2–15), and 10 age-matched healthy controls (aged 52 ± 7 years; p = 0.22 vs. age of PD patients) participated in the study. Patient characteristics, treatment and mean circumpapillary RNFL thicknesses in four quadrants are summarized in Table 1. The RNFL thickness in the inferior retinal quadrant of PD patients (147 ± 20 microns) was significantly thinner than in control subjects (173 ± 12 microns; p = 0.002), followed by the temporal quadrant (101 ± 29 in PD vs. 126 ± 11 in controls; p = 0.019). Within the inferior quadrant, the RNFL was the thinnest in the inferotemporal area (146 ± 24 microns; Fig. 1a) as compared with controls (191 ± 21 microns; p = 0.0003). Milder thinning was observed at the mid-inferior site (154 ± 29 vs. 186 ± 24 microns, p = 0.014). The thickness of the inferonasal part of the inferior quadrant was preserved (131 ± 33 in PD vs. 151 ± 23 microns in controls, p = 0.119). The RNFL thinning was not correlated with disease duration (Table 1). The VF examination was reliably performed (fixation loss, false positive or false negative 625%) in five patients. Reduced sensitivity in the superior VF was detected in four eyes, three of them with an arcuate pattern and a superior nasal step in all four (Fig. 1b). The reduction in VF sensitivity practically matched the topography of RNFL thickness loss. Reduction of sensitivity was also found in the inferior field in one eye. VF was normal in the fifth eye. The RNFL thickness at the inferotemporal site in PD patients ranged between 108 and 185 microns (Table 1). Individual values of control subjects were: 164, 167, 172, 180, 192, 196, 199, 204, 205, 232 microns. Ninety-five percent (a = 0.05) of the control subjects would be expected to have an inferotemporal RNFL thickness higher than a value that is calculated according to the following formula: X = mean inferotemporal RNFL thickness in controls (t · standard deviation of the inferotemporal thickness in controls); where t is taken from t-table based on a degree of freedom of n 1 (=9) and a = 0.05. For our control group, this value is: 191 (1.83 · 21) = 153 microns. The inferotemporal thickness was >153 microns in all control subjects and in only three of the 10 PD patients.
R. Inzelberg et al. / Vision Research 44 (2004) 2793–2797
2795
Table 1 Patient characteristics and circumpapillary RNFL thickness per quadrant and at the inferotemporal area PD patients No.
PD (duration years)
Treatment
2 3 4 4 5 6 6 10 13 15
S, A, DA S, A S, A, DA S, A, DA S, A, DA S, A, DA, LD A, LD, DA A, LD, DA A, LD, DA A, LD, DA
Symptom
1 T, B, R 2 T, B, R 3 T, B, R 4 T, B, R 5 T, B, R 6 T, B, R 7 T, B, R, P 8 T, B, R, P 9 T, B, R, P 10 T, B, R Group mean ± SD Total retinal thickness
Mean RNFL thickness (microns) Superior
Inferior
Nasal
Temporal
Inferotemporal
118 183 175 185 168 155 140 167 140 170 160 ± 22
137 176 139 139 131 162 148 172 111 151 147 ± 20**
67 107 123 63 94 150 104 124 39 117 99 ± 34
94 139 105 102 152 66 76 102 69 100 101 ± 29*
139 108 143 185 172 138 115 160 158 142 146 ± 24***
154 ± 16 (137–173)
173 ± 12 (153–192)
117 ± 19 (92–147)
126 ± 11 (103–143)
191 ± 21 (164–232)
(125 ± 31 microns)
Control subjects Group mean ± SD (Range) Total retinal thickness (143 ± 26 microns)
Asterisks depict significant difference from controls *p = 0.019, **p = 0.002, ***p = 0.0003. PD patients are aligned in increasing order of disease duration. T = Tremor, B = bradykinesia, R = rigidity, P = postural disturbance. S = Selegiline, A = Amantadine, LD = L-dopa, DA = dopamine agonist.
Fig. 1. Patient 10, right eye. (a) The RNFL thickness (in microns) is shown by the dark line in the graph, and per clock-hour and quadrants in circles. The gray area represents the normal age-matched algorithm. As depicted in the numerical presentation, the inferotemporal RNFL thickness was 142 microns in this patient (mean inferotemporal thickness of the control group was 191 ± 21, range 164–232 microns). (b) Visual field examination. Reduced sensitivity is detected mainly in the superior field in an arcuate fashion (mean deviation 0.29 decibels and pattern standard deviation 2.21 decibels).
2796
R. Inzelberg et al. / Vision Research 44 (2004) 2793–2797
3. Discussion These results suggest significant reduction in the inferotemporal circumpapillary RNFL in PD patients. Seventy percent of the PD patients had an inferotemporal RNFL thickness <153 microns, whereas all control measurements exceeded this value. Milder relative thinning was also encountered at the mid-inferior site and the temporal quadrant. The primary visual impairment in PD is due to dopaminergic loss in the retina; however, this depletion may have downstream effects (Jackson & Owsley, 2003). Retinal DA deficiency is believed to alter visual processing by modification of receptive field properties of ganglion cells, (Djamgoz et al., 1997) whose axons form the RNFL. It is noteworthy that when a color vision abnormality is detected in PD, it usually involves blue-sensitive cones (Bodis-Wollner, 1990; Djamgoz et al., 1997; Jackson & Owsley, 2003). The function of the S-cone (blue) system is also reduced in cocaine-dependent patients, consistent with inhibition of the DA transporter by cocaine (Roy, Roy, Williams, Weinberger, & Smelson, 1997). The synaptic structuring of the changes in the receptive fields of ganglion cells and the degree of their susceptibility to dopaminergic degeneration is not known in detail (Djamgoz et al., 1997). Neurophysiological abnormalities in the retina of PD patients are difficult to follow due to the confounding effect of treatment (Djamgoz et al., 1997). There is accumulated evidence that visual impairment progresses with motor disability in PD and fluctuates in parallel with motor fluctuations (Bodis-Wollner, 2002; Diederich, Raman, Leurgans, & Goetz, 2002). The exact loci of this impairment remain unclear. Questions are raised as to the role of retinal dopaminergic deficits in PD and/or the involvement of hierarchically higher pathways (Bodis-Wollner, 2002). Dopamine is enrolled in the modulation of the receptive fields of ganglion cells through D1 and D2 receptors via feedback by establishing the gain of ganglion cells in the monkey and human retina (BodisWollner & Tzelepi, 1998). Visual impairment is also observed in the animal model of PD using MPTP (1-methyl,4-phenyl,1-2-3-6-tetrahydropyridine) where the retina shows dopaminergic deficiency with loss of a subset of retinal amacrine cells (Bodis-Wollner, 1990; Tatton, Kwan, Verrier, Seniuk, & Theriault, 1990), which provide input to ganglion cells. Dopamine is also important in controlling the efficiency of other neurochemical systems such as glutamate, GABA and glycine in the retina. Dysfunctions that result from DA depletion may involve long-term complex synaptic effects. It is possible that impoverished dopaminergic input to a subset of ganglion cells, contributes to abnormal production of glutamate and atrophy of these selected fibers.
Reduction in sensitivity in the visual fields in observed in these series, matches topographically the localized thinning of the RNFL, as previously discussed in other diseases where RNFL damage occurs (El Beltagi et al., 2003). It could be argued that some of the superior scotomas could be the expression of an edge artifact by the superior eyelid. However, the arcuate configuration and the relatively low intensity of the sensitivity reduction are strongly suggestive of localized nerve fiber bundle defect (Anderson, 1992). The distribution of the individual thicknesses in PD patients was lower than in controls. Although a delineative value of thickness could be calculated, further studies in larger series are mandatory to evaluate the possibility to define cut-offs that could serve clinical purposes.
Acknowledgment This study was supported by a grant of the Israel Ministry of Health, Chief Scientist.
References Anderson, D. R. (1992). Anatomic basis of nerve fiber bundle pattern. In K. Kist (Ed.), Automated static perimetry (pp. 43–45). St Louis: Mosby. Blumenthal, E. Z., Williams, J. M., Weinreb, R. N., Girkin, C. A., Berry, C. C., & Zangwill, L. M. (2000). Reproducibility of nerve fiber layer thickness measurements by use of optical coherence tomography. Ophthalmology, 107, 2278–2282. Bodis-Wollner, I. (1990). Visual deficits related to dopamine deficiency in experimental animals and ParkinsonÕs disease patients. Trends in Neurosciences, 13, 296–302. Bodis-Wollner, I., & Tzelepi, A. (1998). The push–pull action of dopamine on spatial tuning of the monkey retina: the effects of dopaminergic deficiency and selective D1 and D2 receptor ligands on the pattern electroretinogram. Vision Research, 38, 1479–1487. Bodis-Wollner, I. (2002). Visualizing the next steps in ParkinsonÕs disease. Archives of Neurology, 59, 1233–1234. Diederich, N. J., Raman, R., Leurgans, S., & Goetz, C. G. (2002). Progressive worsening of spatial and chromatic processing deficits in ParkinsonÕs disease. Archives of Neurology, 59, 1249–1252. Djamgoz, M. B., Hankins, M. W., Hirano, J., & Archer, S. N. (1997). Neurobiology of retinal dopamine in relation to degenerative states of the tissue. Vision Research, 37, 3509–3529. El Beltagi, T. A., Bowd, C., Boden, C., Amini, P., Sample, P. A., Zangwill, L. M., & Weinreb, R. N. (2003). Retinal nerve fiber layer thickness measured with optical coherence tomography is related to visual function in glaucomatous eyes. Ophthalmology, 110, 2185–2191. Harnois, C., & Di Paolo, T. (1990). Decreased dopamine in the retinas of patients with ParkinsonÕs disease. Investigative Ophthalmology Vision Science, 31, 2473–2475. Jackson, G. R., & Owsley, C. (2003). Visual dysfunction, neurodegenerative diseases and aging. Neurology Clinics of North America, 21, 709–728. Kanamori, A., Nakamura, M., Escano, M. F., Seya, R., Maeda, H., & Negi, A. (2003). Evaluation of glaucomatous damage of retinal
R. Inzelberg et al. / Vision Research 44 (2004) 2793–2797 nerve fiber layer thickness measured by optical coherence tomography. American Journal of Ophthalmology, 135, 513–520. Parisi, V., Manni, G., Sparado, M., Colacino, G., Restuccia, R., Marchi, S., Bucci, M. G., & Pierelli, F. (1999). Correlation between morphological and functional retinal impairment in multiple sclerosis patients. Investigative Ophthalmology Vision Science, 40, 2520–2527.
2797
Roy, M., Roy, A., Williams, J., Weinberger, L., & Smelson, D. (1997). Reduced blue cone electroretinogram in cocaine withdrawn patients. Archives of General Psychiatry, 54, 153–156. Tatton, W. G., Kwan, M. M., Verrier, M. C., Seniuk, N. A., & Theriault, E. (1990). MPTP produces reversible disappearance of thyrosine hydroxylase containing retinal amacrine cells. Brain Research, 527, 21–31.
Retinal nerve fiber layer thinning in Parkinson disease Rivka Inzelberg
a,b
, Jose Antonio Ramirez c, Puiu Nisipeanu a, Avinoam Ophir
b,c,*
a
c
Department of Neurology, Hillel Yaffe Medical Center, Hadera 38100, Israel b Rappaport Faculty of Medicine, Technion, Haifa, Israel Department of Ophthalmology, Hillel Yaffe Medical Center, Hadera 38100, Israel Received 10 February 2004; received in revised form 7 June 2004
Abstract Retinal dopamine loss in Parkinson disease (PD) is reflected by visual neurophysiological dysfunction. We measured the thickness of the circumpapillary retinal nerve fiber layer (RNFL) in PD patients using optical coherence tomography. The thickness in the inferior quadrant of PD patients (147 ± 20 microns) was significantly thinner than that of controls (173 ± 12 microns; p = 0.002), while the inferotemporal area was the thinnest (146 ± 24 vs. 191 ± 21 microns; p = 0.0003). The results show significant loss of RNFL thickness in PD at specific sites. 2004 Elsevier Ltd. All rights reserved. Keywords: Parkinson; Retina; Retinal nerve fiber layer; Optical coherence tomography
ParkinsonÕs disease (PD) is primarily a motor disorder associated with degeneration of dopaminergic neurons in the substantia nigra. Besides its major involvement in motor function, dopamine (DA) has fully been established as a major neurotransmitter or modulator in the retina (Djamgoz, Hankins, Hirano, & Archer, 1997). Visual functions controlled at least partially by dopamine, such as absolute sensitivity, spatial contrast sensitivity, temporal sensitivity and color vision are impaired in PD (Djamgoz et al., 1997; Bodis-Wollner, 1990; Jackson & Owsley, 2003). The DA content of the retina as measured at postmortem, is low in PD patients (Harnois & Di Paolo, 1990). Data concerning visual dysfunction in PD are based on neurophysiological evaluation. It is unclear whether there is concurrent tissue loss in the retina.
*
Corresponding author. Tel.: +972 4 6304528; fax: +972 3 5409222. E-mail address: ophthalmology@hillel-yaffe.health.gov.il (A. Ophir). 0042-6989/$ - see front matter 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.visres.2004.06.009
Optical coherence tomography (OCT) is a non-invasive, objective method, which can provide diagnostic information and quantitative data on biological tissues at high resolution of 10 microns. The principle of OCT is analogous to ultrasound, however, the system uses light instead of acoustic waves. Standard circular OCT scans (3.4-mm diameter) around the ONH provide objective and reproducible measurements of the retinal nerve fiber layer (RNFL) thickness, with a 6.9% coefficient of variation between repeated scans in normal eyes (Blumenthal et al., 2000). Normal OCT ranges of the retina, and measurements in diverse pathological conditions of the optic nerve such as glaucoma and multiple sclerosis have been described (Parisi et al., 1999; Kanamori et al., 2003). In glaucomatous eyes, regional reduction in RNFL thickness and regional decreases in visual field (VF) sensitivity are topographically related. Further, the magnitude of focal RNFL thinning is related to the magnitude of decreased VF sensitivity (El Beltagi et al., 2003). We examined the thickness of the RNFL near its entry to the optic nerve head in PD patients and compared
2794
R. Inzelberg et al. / Vision Research 44 (2004) 2793–2797
them with healthy controls. To the best of our knowledge this has not been previously reported.
1. Methods
1.3. Statistical analysis The RNFL thickness in four retinal quadrants, namely: superior, inferior, nasal and temporal, in PD patients was compared to that of age-matched control subjects using StudentÕs t-test.
1.1. Patients 2. Results Consecutive PD patients followed by our Movement Disorders Clinic were recruited for the study. The criteria for PD diagnosis were: (1) at least two of the following signs: rest tremor, rigidity, bradykinesia, and postural reflex impairment, (2) known sustained response to antiparkinsonian medication and (3) no other known or suspected causes for parkinsonism. Eyes with posterior pole pathology such as macular degeneration, those with optic neuropathies including glaucoma, glaucoma suspect or patients with media opacification such as cataract that precluded precise ocular and OCT examinations were excluded. Diagnosis of glaucoma was based on any of the following: classical appearance of the open angle glaucoma changes in the optic disc, enlargement and especially vertical enlargement of the optic cup, localized loss of disc rim and rim pallor, asymmetry of cup/ disc ratio >0.2 between the two eyes, baring of the lamina cribrosa, intraocular pressure and typical visual field loss. Sixteen PD patients were initially recruited. Six were excluded: four were unable to complete the OCT examination (dyskinesia, tremor, fatigue), one due to newly diagnosed glaucoma, and one due to glaucoma suspect. Only one eye of each of 10 patients was chosen for analysis as follows: when the OCT was successfully completed bilaterally, one eye at random was chosen (n = 6). When only one eye of the patient was reliably examined, this eye was included in the study (n = 4). Ten age-matched controls were also examined; one eye at random was chosen for analysis. 1.2. Procedure The Institutional Ethics Committee and Ministry of Health approved the study. All subjects signed an informed consent for participation. Each patient underwent ocular examination, intraocular pressure measurement and visual field (VF) examination using the Humphrey 24–2 visual field program (Humphrey Instruments, Pennsylvania). Each eye was examined by OCT, with the pupil dilated. The subject was asked to fixate a luminous point; the required area was scanned by OCT. The examination included five circumpapillary standard circular scans (3.4 mm in diameter) followed by six radial lines centered at the optic nerve head (6 mm length each).
Ten PD patients (five males, aged 57 ± 11 years (mean ± SD)), with disease duration of 7 ± 4 years (range, 2–15), and 10 age-matched healthy controls (aged 52 ± 7 years; p = 0.22 vs. age of PD patients) participated in the study. Patient characteristics, treatment and mean circumpapillary RNFL thicknesses in four quadrants are summarized in Table 1. The RNFL thickness in the inferior retinal quadrant of PD patients (147 ± 20 microns) was significantly thinner than in control subjects (173 ± 12 microns; p = 0.002), followed by the temporal quadrant (101 ± 29 in PD vs. 126 ± 11 in controls; p = 0.019). Within the inferior quadrant, the RNFL was the thinnest in the inferotemporal area (146 ± 24 microns; Fig. 1a) as compared with controls (191 ± 21 microns; p = 0.0003). Milder thinning was observed at the mid-inferior site (154 ± 29 vs. 186 ± 24 microns, p = 0.014). The thickness of the inferonasal part of the inferior quadrant was preserved (131 ± 33 in PD vs. 151 ± 23 microns in controls, p = 0.119). The RNFL thinning was not correlated with disease duration (Table 1). The VF examination was reliably performed (fixation loss, false positive or false negative 625%) in five patients. Reduced sensitivity in the superior VF was detected in four eyes, three of them with an arcuate pattern and a superior nasal step in all four (Fig. 1b). The reduction in VF sensitivity practically matched the topography of RNFL thickness loss. Reduction of sensitivity was also found in the inferior field in one eye. VF was normal in the fifth eye. The RNFL thickness at the inferotemporal site in PD patients ranged between 108 and 185 microns (Table 1). Individual values of control subjects were: 164, 167, 172, 180, 192, 196, 199, 204, 205, 232 microns. Ninety-five percent (a = 0.05) of the control subjects would be expected to have an inferotemporal RNFL thickness higher than a value that is calculated according to the following formula: X = mean inferotemporal RNFL thickness in controls (t · standard deviation of the inferotemporal thickness in controls); where t is taken from t-table based on a degree of freedom of n 1 (=9) and a = 0.05. For our control group, this value is: 191 (1.83 · 21) = 153 microns. The inferotemporal thickness was >153 microns in all control subjects and in only three of the 10 PD patients.
R. Inzelberg et al. / Vision Research 44 (2004) 2793–2797
2795
Table 1 Patient characteristics and circumpapillary RNFL thickness per quadrant and at the inferotemporal area PD patients No.
PD (duration years)
Treatment
2 3 4 4 5 6 6 10 13 15
S, A, DA S, A S, A, DA S, A, DA S, A, DA S, A, DA, LD A, LD, DA A, LD, DA A, LD, DA A, LD, DA
Symptom
1 T, B, R 2 T, B, R 3 T, B, R 4 T, B, R 5 T, B, R 6 T, B, R 7 T, B, R, P 8 T, B, R, P 9 T, B, R, P 10 T, B, R Group mean ± SD Total retinal thickness
Mean RNFL thickness (microns) Superior
Inferior
Nasal
Temporal
Inferotemporal
118 183 175 185 168 155 140 167 140 170 160 ± 22
137 176 139 139 131 162 148 172 111 151 147 ± 20**
67 107 123 63 94 150 104 124 39 117 99 ± 34
94 139 105 102 152 66 76 102 69 100 101 ± 29*
139 108 143 185 172 138 115 160 158 142 146 ± 24***
154 ± 16 (137–173)
173 ± 12 (153–192)
117 ± 19 (92–147)
126 ± 11 (103–143)
191 ± 21 (164–232)
(125 ± 31 microns)
Control subjects Group mean ± SD (Range) Total retinal thickness (143 ± 26 microns)
Asterisks depict significant difference from controls *p = 0.019, **p = 0.002, ***p = 0.0003. PD patients are aligned in increasing order of disease duration. T = Tremor, B = bradykinesia, R = rigidity, P = postural disturbance. S = Selegiline, A = Amantadine, LD = L-dopa, DA = dopamine agonist.
Fig. 1. Patient 10, right eye. (a) The RNFL thickness (in microns) is shown by the dark line in the graph, and per clock-hour and quadrants in circles. The gray area represents the normal age-matched algorithm. As depicted in the numerical presentation, the inferotemporal RNFL thickness was 142 microns in this patient (mean inferotemporal thickness of the control group was 191 ± 21, range 164–232 microns). (b) Visual field examination. Reduced sensitivity is detected mainly in the superior field in an arcuate fashion (mean deviation 0.29 decibels and pattern standard deviation 2.21 decibels).
2796
R. Inzelberg et al. / Vision Research 44 (2004) 2793–2797
3. Discussion These results suggest significant reduction in the inferotemporal circumpapillary RNFL in PD patients. Seventy percent of the PD patients had an inferotemporal RNFL thickness <153 microns, whereas all control measurements exceeded this value. Milder relative thinning was also encountered at the mid-inferior site and the temporal quadrant. The primary visual impairment in PD is due to dopaminergic loss in the retina; however, this depletion may have downstream effects (Jackson & Owsley, 2003). Retinal DA deficiency is believed to alter visual processing by modification of receptive field properties of ganglion cells, (Djamgoz et al., 1997) whose axons form the RNFL. It is noteworthy that when a color vision abnormality is detected in PD, it usually involves blue-sensitive cones (Bodis-Wollner, 1990; Djamgoz et al., 1997; Jackson & Owsley, 2003). The function of the S-cone (blue) system is also reduced in cocaine-dependent patients, consistent with inhibition of the DA transporter by cocaine (Roy, Roy, Williams, Weinberger, & Smelson, 1997). The synaptic structuring of the changes in the receptive fields of ganglion cells and the degree of their susceptibility to dopaminergic degeneration is not known in detail (Djamgoz et al., 1997). Neurophysiological abnormalities in the retina of PD patients are difficult to follow due to the confounding effect of treatment (Djamgoz et al., 1997). There is accumulated evidence that visual impairment progresses with motor disability in PD and fluctuates in parallel with motor fluctuations (Bodis-Wollner, 2002; Diederich, Raman, Leurgans, & Goetz, 2002). The exact loci of this impairment remain unclear. Questions are raised as to the role of retinal dopaminergic deficits in PD and/or the involvement of hierarchically higher pathways (Bodis-Wollner, 2002). Dopamine is enrolled in the modulation of the receptive fields of ganglion cells through D1 and D2 receptors via feedback by establishing the gain of ganglion cells in the monkey and human retina (BodisWollner & Tzelepi, 1998). Visual impairment is also observed in the animal model of PD using MPTP (1-methyl,4-phenyl,1-2-3-6-tetrahydropyridine) where the retina shows dopaminergic deficiency with loss of a subset of retinal amacrine cells (Bodis-Wollner, 1990; Tatton, Kwan, Verrier, Seniuk, & Theriault, 1990), which provide input to ganglion cells. Dopamine is also important in controlling the efficiency of other neurochemical systems such as glutamate, GABA and glycine in the retina. Dysfunctions that result from DA depletion may involve long-term complex synaptic effects. It is possible that impoverished dopaminergic input to a subset of ganglion cells, contributes to abnormal production of glutamate and atrophy of these selected fibers.
Reduction in sensitivity in the visual fields in observed in these series, matches topographically the localized thinning of the RNFL, as previously discussed in other diseases where RNFL damage occurs (El Beltagi et al., 2003). It could be argued that some of the superior scotomas could be the expression of an edge artifact by the superior eyelid. However, the arcuate configuration and the relatively low intensity of the sensitivity reduction are strongly suggestive of localized nerve fiber bundle defect (Anderson, 1992). The distribution of the individual thicknesses in PD patients was lower than in controls. Although a delineative value of thickness could be calculated, further studies in larger series are mandatory to evaluate the possibility to define cut-offs that could serve clinical purposes.
Acknowledgment This study was supported by a grant of the Israel Ministry of Health, Chief Scientist.
References Anderson, D. R. (1992). Anatomic basis of nerve fiber bundle pattern. In K. Kist (Ed.), Automated static perimetry (pp. 43–45). St Louis: Mosby. Blumenthal, E. Z., Williams, J. M., Weinreb, R. N., Girkin, C. A., Berry, C. C., & Zangwill, L. M. (2000). Reproducibility of nerve fiber layer thickness measurements by use of optical coherence tomography. Ophthalmology, 107, 2278–2282. Bodis-Wollner, I. (1990). Visual deficits related to dopamine deficiency in experimental animals and ParkinsonÕs disease patients. Trends in Neurosciences, 13, 296–302. Bodis-Wollner, I., & Tzelepi, A. (1998). The push–pull action of dopamine on spatial tuning of the monkey retina: the effects of dopaminergic deficiency and selective D1 and D2 receptor ligands on the pattern electroretinogram. Vision Research, 38, 1479–1487. Bodis-Wollner, I. (2002). Visualizing the next steps in ParkinsonÕs disease. Archives of Neurology, 59, 1233–1234. Diederich, N. J., Raman, R., Leurgans, S., & Goetz, C. G. (2002). Progressive worsening of spatial and chromatic processing deficits in ParkinsonÕs disease. Archives of Neurology, 59, 1249–1252. Djamgoz, M. B., Hankins, M. W., Hirano, J., & Archer, S. N. (1997). Neurobiology of retinal dopamine in relation to degenerative states of the tissue. Vision Research, 37, 3509–3529. El Beltagi, T. A., Bowd, C., Boden, C., Amini, P., Sample, P. A., Zangwill, L. M., & Weinreb, R. N. (2003). Retinal nerve fiber layer thickness measured with optical coherence tomography is related to visual function in glaucomatous eyes. Ophthalmology, 110, 2185–2191. Harnois, C., & Di Paolo, T. (1990). Decreased dopamine in the retinas of patients with ParkinsonÕs disease. Investigative Ophthalmology Vision Science, 31, 2473–2475. Jackson, G. R., & Owsley, C. (2003). Visual dysfunction, neurodegenerative diseases and aging. Neurology Clinics of North America, 21, 709–728. Kanamori, A., Nakamura, M., Escano, M. F., Seya, R., Maeda, H., & Negi, A. (2003). Evaluation of glaucomatous damage of retinal
R. Inzelberg et al. / Vision Research 44 (2004) 2793–2797 nerve fiber layer thickness measured by optical coherence tomography. American Journal of Ophthalmology, 135, 513–520. Parisi, V., Manni, G., Sparado, M., Colacino, G., Restuccia, R., Marchi, S., Bucci, M. G., & Pierelli, F. (1999). Correlation between morphological and functional retinal impairment in multiple sclerosis patients. Investigative Ophthalmology Vision Science, 40, 2520–2527.
2797
Roy, M., Roy, A., Williams, J., Weinberger, L., & Smelson, D. (1997). Reduced blue cone electroretinogram in cocaine withdrawn patients. Archives of General Psychiatry, 54, 153–156. Tatton, W. G., Kwan, M. M., Verrier, M. C., Seniuk, N. A., & Theriault, E. (1990). MPTP produces reversible disappearance of thyrosine hydroxylase containing retinal amacrine cells. Brain Research, 527, 21–31.