Correspondence Hong Kong Polytechnic University, Hong Kong SAR, China; 4Department of Optometry and Vision Science, Faculty of Science, The University of Auckland, New Zealand
References 1. Li J, Hess RH, Chan LYL, et al. Quantitative measurement of interocular suppression in anisometropic amblyopia: a casecontrol study. Ophthalmology 2013;120:1672–80. 2. Narasimhan S, Harrison ER, Giaschi DE. Quantitative measurement of interocular suppression in children with amblyopia. Vision Res 2012;66:1–10.
CABP4 Mutations Do Not Cause Congenital Stationary Night Blindness Dear Editor: I read with interest the analysis of Dutch patients diagnosed with congenital stationary night blindness (CSNB) by Bijveld et al,1 particularly what was written regarding patients with recessive mutations in calcium binding protein 4 (CABP4; Mendelian Inheritance in Man *608965). CABP4 encodes a protein that is speciﬁcally located in photoreceptor synaptic terminals, where it probably modulates photoreceptor calcium release.1e3 Only 3 of 101 patients diagnosed with CSNB in the authors’ series1 had CABP4 mutations, and all 3 patients (2 families) harbored the same homozygous mutation (c.646C>T; p.Arg216X). These 3 patients had nystagmus and low vision. Two were photophobic. All 3 had a normal fundus appearance and severe color deﬁciency. None complained of night blindness. All 3 were hyperopic. Such signs and symptoms, combined with their coneerod dysfunction by electroretinography, should suggest a diagnosis of cone-rod disease rather than predominantly rod disease such as CSNB. However, because during scotopic ﬂash stimulus there was an electronegative waveform, which is classically associated with CSNB, the 3 patients were labeled as CSNB2 (“incomplete CSNB,” with the “incomplete” referring to some rod function being present rather than completely absent). The authors recognized that these 3 patients had a distinct phenotype that was atypical for a diagnosis of CSNB2 and wondered whether studies of additional patients would conﬁrm or refute their ﬁndings. I would like to conﬁrm that the CABP4-related phenotype is distinct and highlight that it should not be considered a form of CSNB. In our series2 of 11 patients from 4 Saudi Arabian families harboring a founder homozygous CABP4 mutation (c.81_82insA; p.Pro28Thrfs*4), all had congenital nystagmus, stable low vision, photophobia, and a normal or near-normal fundus appearance. None complained of night blindness when speciﬁcally questioned. Eight had hyperopic cycloplegic refractions. Electroretinography showed an electronegative waveform response to scotopic bright ﬂash, near-normal to subnormal rod function, and delayed and/or decreased cone responses or was nonrecordable. This distinct phenotype might be best termed congenital coneerod synaptic disorder,2,3 or simply CABP4-related disease,4 but should not be considered CSNB.2 Since our published series,2 I have seen this speciﬁc phenotype twice more in 2 unrelated Saudi Arabian 6-yearold boys. One was homozygous for a novel CABP4 mutation (c.1A>G; p.Met1?), while the other was homozygous for the Saudi Arabian founder CABP4 mutation (c.81_82insA; p.Pro28Thrfs*4).
ARIF O. KHAN, MD Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia The authors of the original article declined to reply.
References 1. Bijveld MM, Florijn RJ, Bergen AA, et al. Genotype and phenotype of 101 Dutch patients with congenital stationary night blindness. Ophthalmology 2013;120:2072–81. 2. Khan AO, Alrashed M, Alkuraya FS. Clinical characterisation of the CABP4-related retinal phenotype. Br J Ophthalmol 2013;97: 262–5. 3. Littink KW, van Genderen MM, Collin RW, et al. A novel homozygous nonsense mutation in CABP4 causes congenital cone-rod synaptic disorder. Invest Ophthalmol Vis Sci 2009;50:2344–50. 4. Traboulsi EI. Childhood retinal dystrophies: what’s in a name? Br J Ophthalmol 2013;97:247.
Anterior Cerebral Circulation Infarction and Retinal Ganglion Cell Degeneration Dear Editor: We congratulate Park et al1 on replicating our group’s work2 demonstrating that transsynaptic retrograde degeneration (TRD) of retinal ganglion cells occurs after occipital injury. Their paper is interesting in that it seems to show this process occurring not only after occipital injury, but also after infarction of other areas of the brain. It would be of major theoretical importance if retinal nerve ﬁber layer (RNFL) thinning could be seen after damage to anterior brain areas with no damage to the pre- or postgeniculate visual pathway. Occipital lobe damage causes TRD of the retina, because there is only a single synapse between the retina and the occipital cortex. Damage at any point along the second-order neuron of the visual pathway (from the lateral geniculate nucleus through optic radiation to occipital cortex), should lead to a similar pattern of TRD. Damage to the pregeniculate visual pathway leads to RNFL thinning by a process of direct retrograde degeneration. We note with interest that Park et al1 report that the pattern of RNFL loss was similar irrespective of infarction territory, but that there was no difference between the mean deviation on Humphrey ﬁelds between the patient groups with anterior, middle, or posterior cerebral artery stroke. Although posterior and middle cerebral artery infarcts often damage second-order neurons of the visual pathway, this is unlikely after anterior cerebral artery infarction. The fact that all 3 infarction territories had visual ﬁeld defects with nonsigniﬁcant differences in mean deviation suggests that those with anterior cerebral artery strokes (8 patients only) either did not have pure anterior cerebral artery strokes, had preexisting pathology of the visual pathway, or had intercurrent eye disease causing ﬁeld defects. Any of these possibilities could explain the observed RNFL thinning. We therefore do not think this study provides evidence of a generalized neurodegeneration of projections of the visual pathways, but is instead consistent with previous ﬁndings that TRD of retinal ganglion cells occurs when there is damage to second-order neurons of the visual pathway.
Ophthalmology Volume 121, Number 3, March 2014 Finally, there seems to be an error in Figure 4 of their paper. Although the neuroimaging demonstrates a left posterior circulation infarct which should cause a right homonymous hemianopia, the optical coherence tomography images are those that would be expected from TRD from a left homonymous hemianopia: The left eye shows thinning in a “band atrophy” pattern, as would be expected in the eye with the temporal hemianopia, whereas the right eye shows thinning of the arcuate bundles, as would be expected in the eye with a nasal hemianopia.2 The authors imply in their legend that the RNFL loss would be predominantly on the nasal side of the disc in the eye with a temporal hemianopia and on the temporal side of the disc in the eye with a nasal hemianopia. However, the ganglion cell loss is limited to either the nasal or temporal hemiretina on either side of the fovea. If one considers what is known of the RNFL trajectories, it can be understood that ganglion cell axons from the nasal hemiretina enter the disc around its entire circumference; ganglion cells of the temporal hemiretina enter around the entire circumference apart from the horizontal “band.”
MITCHELL LAWLOR, FRANZCO, PhD1 GORDON PLANT, MD, FRCOphth, FRCP1,2 1 Moorﬁelds Eye Hospital, London, UK; 2The National Hospital for Neurology and Neurosurgery, London, UK
References 1. Park H-YL, Park YG, Cho A-H, Park C- K. Transneuronal retrograde degeneration of the retinal ganglion cells in patients with cerebral infarction. Ophthalmology 2013;120:1292–9. 2. Jindahra P, Petrie A, Plant GT. Retrograde trans-synaptic retinal ganglion cell loss identiﬁed by optical coherence tomography. Brain 2009;132:628–34.
Author reply Dear Editor, We are pleased to receive comments regarding our manuscript reporting transsynaptic retrograde degeneration (TRD) of retinal ganglion cells after infarction in various areas of the brain.1 We measured retinal nerve ﬁber layer (RNFL) thickness to indirectly observe TRD of retinal ganglion cells. Previous work by Jindahra et al2 showed TRD of retinal ganglion cells after congenital or acquired occipital lobe injury. Our work differed from their study because our patients had acquired brain lesions owing to ischemic stroke. They had various stroke lesions, including lesions other than in the occipital lobe. Lawlor et al3 pointed out that anterior cerebral artery infarction may have resulted in damage to the pregeniculate visual pathway. They suggested that RNFL thinning might not indicate pure TRD, but rather direct retrograde degeneration. We agree that the patients analyzed in our study may have damage to the pregeniculate visual pathway because they have ischemic cerebral infarction. Patients with ischemic cerebral infarction are frequently associated with systemic hypertension (as in our study) and have various vascular risk factors. Although we classiﬁed patients into 3 types of cerebral infarction by arterial territories, according to the ﬁndings of brain magnetic resonance imaging and computed tomography angiography, these patients have increased chances of combined subclinical vascular abnormalities or subclinical
infarction other than the classiﬁed arterial territories. However, the degree of RNFL thinning was pronounced in posterior cerebral artery infarction, followed by middle cerebral artery infarction and anterior cerebral artery infarction. These data indicate rather than direct retrograde degeneration, TRD is the main process that occurred in these patients. In addition, the anterior cerebral artery territory includes some of the optic radiations, and second-order neurons of the visual pathway can be damaged.4 The pattern of RNFL thinning in cerebral infarction patients was predominantly superior, and inferior RNFL thinning in the eye at the infarction side, as well as nasal. However, there was also generalized RNFL thinning in the superior and inferior side in the eye opposite the infarction side. The ganglion cell axons from the lateral geniculate body are projected to the nasal or temporal retina on either side of the fovea (Figure 1). However, the crossed and uncrossed axons of ganglion cells that are located between the fovea and the optic disc are mixed at the temporal side of the optic disc. This is why TRD of ganglion cells resulted in the pattern found in our study. Thinning of the RNFL, which resulted from TRD of the ganglion cells on the opposite side of infarction, are crossed ﬁbers located in the nasal side of the fovea. These ﬁbers are located around the optic disc, which are superior, temporal, inferior, and nasal to the disc. Although predominantly nasal, generalized RNFL thinning is observed in the eye opposite the infarction side. Thinning of the RFNL that results from TRD of the ganglion cells on the same side of the infraction are uncrossed ﬁbers that are located in the temporal side of the fovea. These ﬁbers enter the disc superiorly and inferiorly. Predominantly superior and inferior RNFL thinning is observed in the eye at the infarction side. This results in a homonymous hemianopsia in the opposite direction of the infarction side. The case in Figure 4 shows the pattern of RNFL thinning of right homonymous hemianopsia. There is temporal visual ﬁeld hemianopsia and nasal RNFL thinning (including superior and inferior thinning) in the right eye, and nasal visual ﬁeld hemianopsia and temporal RNFL thinning (but also inferior RNFL thinning) in the left eye of a patient with left posterior circulation infarction. This is the pattern that we have found in this study; however, because TRD is a process that takes time, our results may not indicate the full time course of TRD process.
HAE-YOUNG L. PARK, PhD, MD CHAN KEE PARK, PhD, MD Department of Ophthalmology and Visual Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
References 1. Park HY, Park YG, Cho AH, Park CK. Transneuronal retrograde degeneration of the retinal ganglion cells in patients with cerebral infarction. Ophthalmology 2013;120:1292–9. 2. Jindahra P, Petrie A, Plant GT. Retrograde trans-synaptic retinal ganglion cell loss identiﬁed by optical coherence tomography. Brain 2009;132:628–34. 3. Lawlor M, Plant G. Anterior cerebral circulation infarction and retinal ganglion cell degeneration. Ophthalmology 2014;121:e15e6. 4. Tatu L, Moulin T, Bogousslavsky J, et al. Arterial territories of the human brain: cerebral hemispheres. Neurology 1998;50: 1699–708.