Transsynaptic Ganglion Cell Degeneration in Adult Patients After Occipital Lobe Stroke

Loss of retinal ganglion cells after occipital lobe damage is known to occur through transsynaptic retrograde degeneration in congenital lesions; however, studies of this phenomenon in acquired pathology, such as strokes affecting postgenicular visual pathway, are scant. We studied a cohort of adult patients with known onset of occipital lobe stroke to look for the presence, rate, and timing of macular ganglion cell loss on optical coherence tomography.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Transsynaptic Ganglion Cell Degeneration in Adult Patients After Occipital Lobe Stroke Laura Donaldson, MD, PhD, Michael Chen, BS, Edward Margolin, MD Background: Loss of retinal ganglion cells after occipital lobe damage is known to occur through transsynaptic retrograde degeneration in congenital lesions; however, studies of this phenomenon in acquired pathology, such as strokes affecting postgenicular visual pathway, are scant. We studied a cohort of adult patients with known onset of occipital lobe stroke to look for the presence, rate, and timing of macular ganglion cell loss on optical coherence tomography. Methods: Retrospective review of patients seen in tertiary neuro-ophthalmology practice with homonymous hemianopia secondary to occipital lobe stroke of known onset. Optical coherence tomography of the macular ganglion cell complex (GCC) was performed, and hemifields corresponding to the side of the visual field (VF) defect were compared with the control retinal hemifield. Results: Fifteen patients with homonymous VF defects were included in the study, and 8 of these (53.3%) demonstrated GCC hemifield thickness of less than 90% on the side corresponding to VF loss including 2/9 (22%) patients who had a stroke less than 2.5 years ago and 6/6 (100%) patients who had a stroke longer than 2.5 years ago. The amount of hemifield atrophy correlated to the logarithm of time since stroke onset (P =0.030) but not age (P = 0.95) or mean deviation on VF (P = 0.19). Three patients with longitudinal data showed GCC thinning rates of 1.99, 5.13, and 5.68 mm per year. Conclusion: Transsynaptic retrograde degeneration occurs after occipital lobe stroke as early as 5.5 months after injury and was observed in all patients 2.5 years after stroke. Journal of Neuro-Ophthalmology 2023;43:243–247 doi: 10.1097/WNO.0000000000001657 © 2022 by North American Neuro-Ophthalmology Society Department of Ophthalmology and Vision Sciences (LD, EM), Faculty of Medicine, University of Toronto, Toronto, Canada; University of Western Ontario (MC), London, Canada; and Department of Medicine (EM), Division of Neurology, Faculty of Medicine, University of Toronto, Toronto, Canada. The authors report no conflicts of interest. Address correspondence to Edward Margolin, MD, Department of Ophthalmology and Medicine (Neurology), University of Toronto Faculty of Medicine, 801 Eglinton Avenue, West Suite 301, Toronto, ON M5N 1E3; E-mail: [e-mail] Donaldson et al: J Neuro-Ophthalmol 2023; 43: 243-247 R etrograde axonal degeneration progresses from the site of axonal injury toward a neuronal cell body and is the mechanism of retinal ganglion cell loss in conditions such as glaucomatous optic neuropathy. In addition to retrograde axonal degeneration, loss of downstream synaptic partners after neuronal death or transsynaptic retrograde degeneration has also long been known to occur in rodents and primates (1–3) and was later recognized in humans through the presence of optic atrophy in individuals with perinatal or congenital lesions involving the retrogeniculate visual pathway (4). It is increasingly well-recognized that transsynaptic degeneration within the visual pathway occurs in acquired lesions as well. Optical coherence tomography (OCT) of the macular ganglion cell–inner plexiform complex (GCC) and optic nerve head with measurement of the peripapillary retinal nerve fiber layer (RNFL) permits precise quantification of optic nerve atrophy in a repeatable and noninvasive manner, and topographic organization of the visual pathway allows for precise structure–function correlation (5). Retrogeniculate lesions, such as occipital lobe stroke, produce contralateral hemianopic visual field (VF) defects and transsynaptic retrograde axonal degeneration with loss of corresponding retinal ganglion cells and resultant atrophy within the temporal retina in the ipsilateral eye and nasal retina in the contralateral eye. Thinning of the pRNFL after occipital lobe stroke is known to occur in a time-dependent manner (6–9); although as ganglion cell axons converge toward the optic nerve head, distinction between nasal and temporal retina is not always clear and variable patterns of atrophy have been reported (8,10,11). GCC analysis is particularly useful in detecting a vertical raphe (12), and a clear pattern of hemifield atrophy has been reported in patients with homonymous hemianopia (13,14), although little is known about what factors may influence the rate at which this degeneration occurs. In this study, we investigated patients with a known onset of occipital lobe stroke that caused homonymous VF defects to determine the timing of development of corresponding hemifield atrophy within macular GCC. 243 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution METHODS A retrospective chart review of patients older than 18 years of age seen in a tertiary centre neuro-ophthalmology practice affiliated with the University of Toronto between 2014 and 2021 was performed. The study was approved by the Health Sciences Research Ethics Board at the University of Toronto and adhered to the tenets of the Declaration of Helsinki. Only patients with ischemic stroke resulting in homonymous VF defect with known date of onset were included. Patients with bilateral strokes or ischemia involving the anterior or pregeniculate optic pathway were excluded. All patients with other known pathology that can produce a VF defect such as glaucoma, macular generation, or retinal detachment were excluded as well. Age, gender, and stroke location were recorded as was the mean deviation (MD) on 24-2 SITA-Fast automated VF testing. Ganglion cell complex (ganglion cell layer plus inner plexiform layer) thickness was measured on OCT (Zeiss Cirrus 600). Only patients with OCT data obtained longer than 3 months poststroke were included. All macular OCT scans were manually reviewed to ensure proper segmentation and absence of other retinal pathology such as cystoid macular edema or epiretinal membrane. Significant atrophy in the affected retinal hemifield was defined as less than 90% of the thickness of the unaffected hemifield. While relatively arbitrary, this definition has been previously used and is likely quite specific given the low variability of repeated GCC measurements (14,15). The term hemifield atrophy will be used to describe this loss of retinal ganglion cells in the retinal hemifields corresponding the homonymous VF defect. Of the 6 predefined retinal sectors for GCC analysis, only 4 sectors which did not cross the vertical midline were used. For patients with hemianopia, both superior and inferior sectors were used, and for patients with quadrantanopia thickness, measurements from the corresponding superior or inferior quadrant only were analyzed. Statistical analysis was performed using STATA. Standard linear regression as well as nonlinear regression with time on a natural logarithmic (ln) scale was performed. A Pvalue of 0.05 or less was determined to be statistically significant. RESULTS Fifteen patients with homonymous VF defects secondary to ischemic stroke were identified, 14 had occipital lobe stroke and 1 case involved both the occipital and parietal lobes (Table 1). The mean age was 64.2 ± 3.5 years (range 30– 82) at the time of stroke. Six patients had quadrantanopia, and 9 had hemianopia. The median number of days since stroke was 625 (range 165–14,600). As the baseline OCT immediately after stroke was not available for most patients, the relative thickness of the macular ganglion cell complex 244 in the hemifield corresponding the homonymous VF defect (ipsilateral temporal macula and contralateral nasal macula) was compared with the contralateral hemifield (ipsilateral nasal macula and contralateral temporal macula). Eight of 15 patients (53.3%) showed a greater than 10% difference between the affected and unaffected hemifields, including all 6 patients with the duration of follow-up more than 2.5 years. The amount of hemifield atrophy was correlated to time since stroke in months (coefficient = 20.023, R squared = 0.31, P =0.030) but was not related to age (0.02, P = 0.95) or MD on VF (1.05, P = 0.19). A nonlinear model (Fig. 1) fitting amount of hemifield thinning to a logarithmic time function showed improved fit (R-squared value 0.57) with slope of 27.03 per natural log month. Three patients (Cases 1, 2, and 3) had at least 3 serial OCTs performed, and the mean annual rates of GCC thinning in these patients was 3.66 ± 1.44 mm in the affected hemifield (1.99, 5.13, and 5.68) and 1.89 ± 0.74 mm (0.93, 1.95, and 3.34) in the unaffected hemifield with the atrophy over time fitting well within a linear model. Only one of these serially imaged patients with the longest follow-up duration (Case 3) developed significant hemifield atrophy. CONCLUSIONS Retrograde transsynaptic degeneration has been proposed to occur in neurodegenerative disorders such as Alzheimer disease; however, it is difficult to definitively demonstrate this phenomenon when pathology is widespread and can affect the retina and anterior visual pathway (16). The exquisite localization of retinal ganglion cell loss demonstrated through macular OCT after damage to visual cortex in this study and other recent investigations (14,17) convincingly demonstrate that neuronal death after the loss of downstream targets occurs in adults with acquired lesions of the retrogeniculate visual pathway. Our composite analysis of 15 patients found that not all cases developed threshold (at least 10% difference between 2 vertical hemifields) hemiatrophy of the macular GCC after stroke. This is likely related to the variable rates of atrophy, with 3-fold difference seen between the highest and lowest rates of GCC thinning. Further studies with longer follow-up would be required to demonstrate whether all patients eventually show transsynaptic retinal degeneration; however, in our cohort, all patients in whom the stroke occurred 2.5 years ago demonstrated relative hemifield atrophy of at least 10% with the earliest onset seen 5.5 months poststroke in one case. In a previous study of patients with a history of occipital stroke, similar annual rates of GCC thinning of 2.1, 2.4, and 5.6 mm/year were reported (17). A study that included more heterogenous group of patients with both pregeniculate and retrogeniculate visual pathway lesions, including some with stroke, Donaldson et al: J Neuro-Ophthalmol 2023; 43: 243-247 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Individual patient data Case Age Location VF Defect 1 2 3 4 5 6 7 8 9 10 11 12 13 69 82 66 71 67 66 65 30 56 68 69 63 42 14 15 70 79 Occipital Hemianopia Occipital Hemianopia Occipital Quadrantanopia Occipital Hemianopia Occipital Quadrantanopia Occipital Quadrantanopia Occipital Hemianopia Occipital Hemianopia Occipital Quadrantanopia Occipital Hemianopia Occipital Hemianopia Occipital Quadrantanopia Occipital/ Hemianopia parietal Occipital Quadrantanopia Occipital Hemianopia MD on VF GCC GCC Days Post Hemianopic Unaffected (mm) (mm) Stroke Relative Relative GCC Atrophy (%) Change/Year (mm) 215.54 213.51 211.89 215.66 29.07 26.09 25.01 23.57 210.98 28.44 215.04 24.76 215.05 684 625 935 276 497 165 268 280 2,672 181 14,600 2,433 1156 79.5 60.5 61.5 77.5 74.5 69.0 73.3 90.3 53.0 64.3 50.3 56.5 49.0 88.0 64.5 80.5 80.5 81.5 79.5 77.5 92.0 89.5 71.0 76.8 65.0 69.5 90.3 93.8 76.4 96.3 91.4 86.8 94.5 98.1 59.2 90.5 65.5 86.9 70.5 4.5 2.3 7.4 4.0 5.1 23.2 5.8 2.3 5.0 13.6 0.7 1.3 6.5 26.78 210.61 589 2,385 65.5 54.3 75.0 79.8 87.3 68.0 5.9 3.9 Ganglion cell complex (GCC) thickness in the hemianopic side vs. unaffected side after ischemic stroke. MD: mean deviation; VF: visual field. reported, as expected, earlier detectable retinal hemifield thinning in pregeniculate vs postgeniculate lesions, first detectable at 1 vs. 5 months, respectively (14). The mechanisms of transsynaptic degeneration in adults are not well known although several hypotheses have been proposed. Studies on neural development in model organisms have clearly demonstrated that trophic support derived from synaptic connections with target neurons is critical for maintaining neuronal survival (18); however, the role of transsynaptic trophic factors in maintaining survival in established neural circuitry is less clear. Direct toxic effects on axons do seem to play a role, for example, in neurodegenerative disorders where betaamyloid and other toxic protein aggregates show prionlike properties and can be transmitted across synaptically connected neurons (19,20). In the presence of toxic stimuli and glutamate receptor activation, apoptotic pathways including caspase signalling cascades can be activated locally within dendrites and synaptic terminals (21). As an accessible site for repeatable noninvasive interrogation FIG. 1. A. Optical coherence tomography (OCT) of the retinal ganglion cell complex showing homonymous thinning after occipital lobe stroke corresponding to the visual field defect with a case of quadrantanopia in the upper panels and hemianopia shown in the lower panel (B, 24-2 automated visual fields). C. Relative hemifield atrophy of the retinal ganglion cell complex vs time after occipital stroke (logarithmic scale). Donaldson et al: J Neuro-Ophthalmol 2023; 43: 243-247 245 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution of structure and function, the retina provides an exciting avenue for future research into the pathophysiology of transsynaptic degeneration. Our study of GCC thinning after hemispheric stroke is amenable to analysis of individual factors influencing the rate of transsynaptic degeneration; however, because of the relatively small sample size, only limited conclusions can be drawn: We did not find a correlation between subjects’ age or degree of VF loss with development of hemifield atrophy; however, at least 10% difference between GCC in the affected and nonaffected hemifields was seen in all patients 2.5 years after the stroke. We were also not able to correlate the rate of transsynaptic degeneration with the size of the infarct as no standardized imaging was used (i.e., some patients had only CT scans performed), but at least one other study correlated the larger area of infarction with degree of RNFL thinning in a similar population of patients with homonymous hemianopia after stroke (7). Retinal ganglion cell loss measured by either OCT of the peripapillary RNFL or macular GCC has been proposed to be useful as a biomarker for disease activity or progression in a wide variety of neurologic disease including multiple sclerosis (22,23), Alzheimer disease (24), and Parkinson disease (25). Both direct effects of the disease on ganglion cells (16) and transsynaptic degeneration secondary to loss of cortical neurons (22) may contribute to observed effects. An understanding of the time course and mechanisms of transsynaptic degeneration is critical to use GCC thickness in monitoring disease activity and progression and the use of this parameter as a therapeutic target in development of novel treatment modalities. Our study had several limitations, including its retrospective nature and small sample size. In addition, we used the standardized quadrants defined for the macular segmentation protocol and GCC analysis which were designed mainly for use in glaucoma and thus respect the horizontal and not the vertical meridian and do not optimally capture the hemifield atrophy related to homonymous VF defects. We are continuing to follow several patients in this cohort to gather more longitudinal data which will allow for a better assessment of demographic and clinical features that can potentially influence the rate of ganglion cell loss in each individual. 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