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Visual pathway changes in glaucoma
Submit responseDear Editor,
Gupta et al. state that both magnocellular and parvocellular cells from the lateral geniculate nucleus (LGN) of a patient with glaucoma are significantly smaller than those in three control subjects. However it would appear that the authors have used the sample sizes and standard deviation of the cell samples from each individual to make comparisons between subjects. This is statistically invalid, as these samples contain no estimate of the variability between individuals. The P values of <0.0001 quoted for differences between the patient with glaucoma and the control subjects are erroneous. The basis for making comparisons of LGN size between different subjects has been described[1] and requires a single mean value to be used for each sample in each subject for comparisons between groups of subjects. In this instance the comparison is between groups of 1 and 3; these are too small to allow a meaningful statistical comparison. This does not of course mean that transneuronal shrinkage of LGN cells does not occur as a result of ganglion cell loss in glaucoma, but the present findings do not demonstrate it in man.
Of more concern is the statement that in the visual cortex of the glaucoma patient "cortical ribbon thickness reduction was easily discernable compared to controls". The only evidence presented to support this is photographs of single sections through the primary visual cortex in the one glaucomatous subject and one control. Given possible differences in shrinkage during processing, differences in apparent thickness due to obliquity in sectioning and inter-individual variability this is meaningless. Comparable differences in apparent cortical thickness are visible in different parts of primary visual cortex as illustrated in a standard textbook of ophthalmology (Figs 15.105 and 15.108)[2] where they are almost certainly due to differences in obliquity of sectioning. The demonstration of changes in cortical thickness secondary to retinal ganglion cell degeneration would be a novel and important observation, particularly as I am not aware of any good evidence for this even following enucleation in experimental primates. However, the demonstration of central visual pathway changes in patients with glaucoma will require the analysis of substantial numbers of patients and controls to obtain meaningful results.
References
1. Headon MP, Sloper JJ, Hiorns RW and Powell TPS. Effects of monocular closure at different ages on deprived and undeprived cells in the primate lateral geniculate nucleus. Dev Brain Res 1985 18: 57-78.
2. Central visual pathways. In: Bron AJ, Tripathi RC and Tripathi BJ. Wolff’s anatomy of the eye and orbit, 8th Edition, London, Arnold, 2001.
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Authors' response
Submit responseDear Editor,
We thank Dr. John Sloper for his comments regarding this clinical pathological case of advanced human glaucoma, visual field loss, and central visual system degeneration. [1] Dr. Sloper states "Gupta et al. state that both magnocellular and parvocellular cells from the lateral geniculate nucleus of a patient with glaucoma are significantly smaller than those in three control subjects." We respectfully disagree with his statement.
In the present article, randomized stereological methodology was used to measure cross-sectional areas of neurons in the glaucoma case and each of the 3 control cases. We show that radii of the magnocellular neurons in the glaucoma index case are smaller than those in each of the controls (boxplots in Figure 4C). However, radii of the parvocellular neurons in the glaucoma index are smaller than only one of the three controls (boxplots, Figure 5C).
Dr. Sloper's concern that the multiple t-tests showing these differences are "statistically invalid" is a valid concern, as the measurements compared in the t-tests are not independent. While the boxplots clearly show the results as described in the text, another valid way to show these results statistically is to use Confidence Intervals. Using the means in Table 2, we calculate a 95% Confidence Interval (with 2 degrees of freedom) for the mean of the magnocellular control averages. This interval is (347.54 μm2, 575.79 μm2), and this interval does not include the glaucoma mean value of 273 μm2 in magnocellular neurons. For the parvocellular means, the 95% Confidence Interval for the mean value for the control averages is (132.13 μm2, 357.87 μm2), which does include the glaucoma average. These findings suggest that neuron shrinkage in magnocellular layers of the lateral geniculate nucleus occurs in this case of human glaucoma. This is consistent with neuron shrinkage described in the lateral geniculate nucleus in experimental primate glaucoma. [2,3,4]
Dr. Sloper reminds us that tissue processing and obliquity of sectioning are important factors to consider when interpreting the finding of reduced cortical ribbon thickness in visual cortex. Great care was taken to process the brain tissue under similar conditions, and to avoid areas where the sectioning may have been oblique when examining coronal serial sections.
In discussing our findings of reduced cortical thickness in this glaucoma patient, Dr. Sloper refers to the lack of evidence for visual cortex changes even following enucleation in non-human primates. However, following unilateral enucleation in non-human primate, there is in fact evidence of cytoarchitectural changes in ocular dominance columns of the visual cortex [5]. Furthermore, retinal ganglion cell degeneration involving both eyes has been shown to lead to reduced cortical ribbon thickness. [6] While in this case, injury to vision centers in the brain may be secondary to retinal ganglion cell loss by anterograde transsynaptic degeneration, primary injury to the visual cortex leading to retrograde degeneration of retinal ganglion cells cannot be excluded. [7]
Degenerative changes at multiple levels of the visual system were observed in this patient with advanced glaucoma. Additional cases of glaucoma patients and controls are needed to characterize these changes further.
References
1. Gupta N, Ang L-C , Noël de Tilly L, Yücel Y H. Human Glaucoma and Neural Degeneration in the Intracranial Optic Nerve, Lateral Geniculate Nucleus and Visual Cortex of the Brain. British J Ophthalmol 2006; 90: 674 -678.
2. Weber AJ, Chen H, Hubbard WC, Kaufman PL. Experimental glaucoma and cell size, density, and number in the primate lateral geniculate nucleus. Invest Ophthalmol Vis Sci 2000; 41:1370-1379.
3. Yücel YH, Zhang Q, Weinreb RN, Kaufman PL, Gupta N. Atrophy of relay neurons in magno- and parvocellular layers in the lateral geniculate nucleus in experimental glaucoma. Invest Ophthalmol Vis Sci 2001; 42:3216- 3222.
4. Yücel YH, Zhang Q, Weinreb RN, Kaufman PL, Gupta N. Effects of retinal ganglion cell loss on magno-, parvo-, koniocellular pathways in the lateral geniculate nucleus and visual cortex in glaucoma. Prog Retin Eye Res 2003; 22: 465-481.
5. Haseltine EC, DeBruyn EJ, Casagrande VA. Demonstration of ocular dominance columns in Nissl-stained sections of monkey visual cortex following enucleation. Brain Res, 1979;176: 153-158.
6. Cragg BG. The development of synapses in kitten visual cortex during visual deprivation, Exp Neurol, 1975; 46: 445-451.
7. Johnson H, Cowey A. Transneuronal retrograde degeneration of retinal ganglion cells following restricted lesions of striate cortex in the monkey. Exp Brain Res. 2000;132:269-275.
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