Publications by authors named "Jonathan C Horton"

102 Publications

somatic mosaicism in a patient with bilateral optic nerve sheath meningiomas: illustrative case.

J Neurosurg Case Lessons 2022 Jun 6;3(23):CASE2247. Epub 2022 Jun 6.

Departments of Ophthalmology.

Background: In the past decade, next-generation sequencing has spurred significant progress in the understanding of cytogenetic alterations that occur in meningiomas. Eighty percent of adult meningiomas harbor pathogenic somatic variants involving , , , , , or Somatic variants in associated with meningiomas usually localize to the gene's WD40 domains but are mutually exclusive to germline mutations, which cause a distinctive autosomal dominant syndrome.

Observations: This case involved a 15-year-old girl with bilateral optic nerve sheath meningiomas, diffuse meningiomatosis, and syndromic features, including craniosynostosis, brain anomalies, syndactyly, brachydactyly, epicanthus, and patent ductus arteriosus. Genetic testing of the meningioma specimen 7 years after biopsy showed a pathogenic p.R641C variant within the WD40 domain of the gene. Additional testing of unaffected tissues identified the same variant at lower allele frequencies, consistent with postzygotic somatic mosaicism.

Lessons: The authors report postzygotic somatic mosaicism for a p.R641C variant in the gene in a patient with bilateral optic nerve sheath meningiomas, diffuse meningiomatosis and a constellation of systemic findings previously recognized in patients with germline mutations of this gene. This is the first report of optic nerve sheath meningioma in a patient with mutation in the gene.
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http://dx.doi.org/10.3171/CASE2247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204931PMC
June 2022

Massive periorbital edema following hematopoietic stem cell transplantation.

Am J Ophthalmol Case Rep 2022 Jun 30;26:101559. Epub 2022 Apr 30.

University of California San Francisco, Department of Ophthalmology, San Francisco, CA, 94158 USA.

Purpose: To describe a case of severe, bilateral periorbital edema after hematopoietic stem cell transplantation.

Observations: A three-year old girl with metastatic neuroblastoma underwent the second of two tandem autologous peripheral blood stem cell transplants, complicated by engraftment syndrome. On post-engraftment day 11, she developed acute onset of severe periorbital edema. She was soon thereafter diagnosed with transplant-associated thrombotic microangiopathy with significant volume overload requiring treatment with eculizumab and etanercept. Periorbital edema resolved after four days with concurrent treatment of her underlying condition.

Conclusions And Importance: We report an ocular manifestation related to complications of hematopoietic stem cell transplantation. This highlights a non-infectious etiology of eyelid swelling in the post-transplant, immunocompromised population.
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http://dx.doi.org/10.1016/j.ajoc.2022.101559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9079772PMC
June 2022

Retinal Input to the Primate Lateral Geniculate Nucleus Revealed by Injection of a Different Label Into Each Eye.

J Neuroophthalmol 2022 Apr 27. Epub 2022 Apr 27.

College of Medicine (ZRS), State University of New York, Upstate Medical University, Syracuse, New York; and Department of Ophthalmology (JRE, JCH), University of California, San Francisco, San Francisco, California.

Abstract: The primate lateral geniculate nucleus has long been a favorite structure among anatomists because of its striking lamination. It has been shown that each lamina receives input from a different eye using various single label techniques but never by double labeling. Here, we illustrate the organization of retinal inputs to the lateral geniculate nucleus by injection of cholera toxin-B conjugated to Alexa Fluor-488 into the right eye and cholera toxin-B conjugated to Alexa Fluor-594 into the left eye.
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http://dx.doi.org/10.1097/WNO.0000000000001472DOI Listing
April 2022

Fundus imaging of retinal ganglion cells transduced by retrograde transport of rAAV2-retro.

Exp Eye Res 2022 Jun 20;219:109084. Epub 2022 Apr 20.

Program in Neuroscience, Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, 94143, USA. Electronic address:

Access of adeno-associated virus (AAV) to ganglion cells following intravitreal injection for gene therapy is impeded by the internal limiting membrane of the retina. As an alternative, one could transduce ganglion cells via retrograde transport after virus injection into a retinal target nucleus. It is unknown if recombinant AAV2-retro (rAAV2-retro), a variant of AAV2 developed specifically for retrograde transport, is capable of transducing retinal ganglion cells. To address this issue, equal volumes of rAAV2-retro-hSyn-EGFP and rAAV2-retro-hSyn-mCherry were mixed in a micropipette and injected into the rat superior colliculus. The time-course of viral transduction was tracked by performing serial in vivo fundus imaging. Cells that were labeled by the fluorophores within the first week remained consistent in distribution and relative signal strength on follow-up imaging. Most transduced cells were double-labeled, but some were labeled by only EGFP or mCherry. Fundus images were later aligned with retinal wholemounts. Ganglion cells in the wholemounts matched precisely the cells imaged by fundus photography. As seen in the fundus images, ganglion cells in wholemounts were sometimes labeled by only EGFP or mCherry. Overall, there was detectable label in 32-41% of ganglion cells. Analysis of the number of cells labeled by 0, 1, or 2 fluorophores, based on Poisson statistics, yielded an average of 0.66 virions transducing each ganglion cell. Although this represents a low number relative to the quantity of virus injected into the superior colliculus, the ganglion cells showed sustained and robust fluorescent labeling. In the primate, injection of rAAV2-retro into the lateral geniculate nucleus might provide a viable approach for the transduction of ganglion cells, bypassing the obstacles that have prevented effective gene delivery via intravitreal injection.
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http://dx.doi.org/10.1016/j.exer.2022.109084DOI Listing
June 2022

Columnar and Laminar Segregation of Retinal Input to the Primate Superior Colliculus Revealed by Anterograde Tracer Injection Into Each Eye.

Invest Ophthalmol Vis Sci 2022 01;63(1)

Program in Neuroscience, Department of Ophthalmology, University of California, San Francisco, San Francisco, California, United States.

Purpose: After the lateral geniculate nucleus, the superior colliculus is the richest target of retinal projections in primates. Hubel et al. used tritium autoradiography to show that axon terminals emanating from one eye form irregular columns in the stratum griseum superficiale. Unlabeled gaps were thought to be filled by the other eye, but this assumption was never tested directly.

Methods: Experiments were performed in two normal macaques. In monkey 1, [3H]proline was injected into the left eye and the pattern of radiolabeling was examined in serial cross-sections through the entire superior colliculus. In monkey 2, cholera toxin subunit B conjugated to Alexa 488 was injected into the right eye and cholera toxin subunit B - Alexa 594 was injected into the left eye. The two fluorescent labels were compared in a reconstruction of the superior colliculus prepared from serial sections.

Results: In monkey 1, irregular columns of axon terminals were present in the superficial grey. The projection from the peripheral retina was stronger than the projection from the macula. In monkey 2, the two fluorescent Alexa tracers mainly interdigitated: a conspicuous gap in one label was usually filled by a clump of the other label. There was also partial laminar segregation of ocular inputs. In the far peripheral field representation, the contralateral eye's input generally terminated closer to the tectal surface. In the midperiphery the eyes switched, bringing the ipsilateral input nearer the surface.

Conclusions: Direct retinal input to the macaque superior colliculus is segregated into alternating columns and strata, despite the fact that tectal cells respond robustly to stimulation of either eye.
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http://dx.doi.org/10.1167/iovs.63.1.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742525PMC
January 2022

Dichoptic visual field mapping of suppression in exotropia with homonymous hemianopia.

J AAPOS 2021 10 26;25(5):276.e1-276.e6. Epub 2021 Sep 26.

Department of Ophthalmology, Program in Neuroscience, University of California, San Francisco, San Francisco, California. Electronic address:

Background: The purpose of this study was to investigate which portions of the visual scene are perceived by each eye in an exotropic subject with acquired hemianopia. The pattern of suppression is predictable from knowledge of how suppression scotomas are organized in exotropic subjects with intact visual fields.

Methods: Dichoptic perimetry was performed by having a subject wear red/blue goggles while fixating a cross that was either red or blue. Red, blue, or purple spots were presented briefly at peripheral locations. The subject's identification of the spot color revealed which eye was perceptually engaged at any given location in the visual fields.

Results: A 17-year-old female with a history of exotropia was evaluated after rupture of a right parietal arteriovenous malformation. Dichoptic perimetry showed a left homonymous hemianopia. All stimuli to the right of the right fovea's projection point were perceived via the right eye. Stimuli between the foveal projection points, which were separated horizontally by the 20° exotropia, were perceived by the left eye.

Conclusions: Perception of the visual scene is shared by the eyes in hemianopia and exotropia. Suppression occurs only in the peripheral temporal retina of the eye contralateral to the brain lesion, regardless of which eye is engaged in fixation. Although exotropia expands the binocular field of vision in hemianopia, it is probably not an adaptive response, even when it develops after hemianopia.
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http://dx.doi.org/10.1016/j.jaapos.2021.05.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8665098PMC
October 2021

Interocular suppression in primary visual cortex in strabismus: impact of staggering the presentation of stimuli to the eyes.

J Neurophysiol 2021 10 25;126(4):1101-1111. Epub 2021 Aug 25.

Program in Neuroscience, Department of Ophthalmology, University of California, San Francisco, California.

Diplopia (double vision) in strabismus is prevented by suppression of the image emanating from one eye. In a recent study conducted in two macaques raised with exotropia (an outward ocular deviation) but having normal acuity in each eye, simultaneous display of stimuli to each eye did not induce suppression in V1 neurons. Puzzled by this negative result, we have modified our protocol to display stimuli in a staggered sequence, rather than simultaneously. Additional recordings were made in the same two macaques, following two paradigms. In , the receptive field in one eye was stimulated with a sine-wave grating while the other eye was occluded. After 5 s, the occluder was removed and the neuron was stimulated for another 5 s. The effect of uncovering the eye, which potentially exposed the animal to diplopia, was quantified by the peripheral retinal interaction index (PRII). In , the receptive field in the fixating eye was stimulated with a grating during binocular viewing. After 5 s, a second grating appeared in the receptive field of the nonfixating eye. The impact of the second grating, which had the potential to generate visual confusion, was quantified by the receptive field interaction index (RFII). For 82 units, the mean PRII was 0.48 ± 0.05 (0.50 = no suppression) and the mean RFII was 0.46 ± 0.08 (0.50 = no suppression). These values suggest mild suppression, but the modest decline in spike rate registered during the second epoch of visual stimulation might have been due to neuronal adaptation, rather than interocular suppression. In a few instances neurons showed unequivocal suppression, but overall, these recordings did not support the contention that staggered stimulus presentation is more effective than simultaneous stimulus presentation at evoking interocular suppression in V1 neurons. In strabismus, double vision is prevented by interocular suppression. It has been reported that inhibition of neuronal firing in the primary visual cortex occurs only when stimuli are presented sequentially, rather than simultaneously. However, these recordings in alert macaques raised with exotropia showed, with rare exceptions, little evidence to support the concept that staggered stimulus presentation is more effective at inducing interocular suppression of V1 neurons.
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http://dx.doi.org/10.1152/jn.00275.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560411PMC
October 2021

Congenital Visual Field Loss from a Schizencephalic Cleft Damaging Meyer's Loop.

Neuroophthalmology 2021 14;45(4):277-280. Epub 2020 Nov 14.

Department of Ophthalmology, University of California San Francisco, San Francisco, California, USA.

A healthy, asymptomatic woman was referred after incidental discovery of a right superior incongruous hemianopia. Magnetic resonance imaging disclosed a schizencephalic cleft passing through Meyer's loop of the left optic radiation. The lesion may have resulted from a focal vascular accident or disruption of cortical neurogenesis during gestation.
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http://dx.doi.org/10.1080/01658107.2020.1844759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312584PMC
November 2020

Damage to the Superior Retinae After 30 Gy Whole-Brain Radiation.

Adv Radiat Oncol 2021 Jul-Aug;6(4):100706. Epub 2021 Apr 18.

Departments of Ophthalmology, University of California, San Francisco.

Purpose: The most common treatment protocol for whole-brain radiation therapy (WBRT) is 30 Gy in 10 fractions. This regimen entails a low risk of radiation retinopathy, with fewer than a dozen reported cases. We describe a case of radiation retinopathy that was confined to the superior retinae. These regions were the only portions of the eyes that were included in the treatment field.

Methods And Materials: Observational case report consisting of clinical examination, review of radiation treatment planning and implementation, computerized visual field testing, and fundus photography.

Results: A 36-year-old man with metastatic lung adenocarcinoma developed radiation retinopathy 16 months after WBRT to 30 Gy in 10 fractions. The retinopathy was largely confined to the superior halves of the retinae. There was corresponding geographic inferior visual field loss in both eyes. Review of the patient's treatment protocol revealed that the superior retinae received a substantial radiation dose, approaching 30 Gy, whereas the inferior retinae were essentially outside the treatment field.

Conclusions: In this patient, the correlation between the treatment field and the resulting local development of radiation retinopathy demonstrated unequivocally that the relatively low dose used in routine WBRT (ie, 30 Gy in 10 fractions) can induce radiation retinopathy.
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http://dx.doi.org/10.1016/j.adro.2021.100706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175280PMC
April 2021

The Mechanism of Macular Sparing.

Annu Rev Vis Sci 2021 09 12;7:155-179. Epub 2021 May 12.

Department of Ophthalmology, Program in Neuroscience, University of California, San Francisco, California 94143, USA; email:

Patients with homonymous hemianopia sometimes show preservation of the central visual fields, ranging up to 10°. This phenomenon, known as macular sparing, has sparked perpetual controversy. Two main theories have been offered to explain it. The first theory proposes a dual representation of the macula in each hemisphere. After loss of one occipital lobe, the back-up representation in the remaining occipital lobe is postulated to sustain ipsilateral central vision in the blind hemifield. This theory is supported by studies showing that some midline retinal ganglion cells project to the wrong hemisphere, presumably driving neurons in striate cortex that have ipsilateral receptive fields. However, more recent electrophysiological recordings and neuroimaging studies have cast doubt on this theory by showing only a minuscule ipsilateral field representation in early visual cortical areas. The second theory holds that macular sparing arises because the occipital pole, where the macula is represented, remains perfused after occlusion of the posterior cerebral artery because it receives collateral flow from the middle cerebral artery. An objection to this theory is that it cannot account for reports of macular sparing in patients after loss of an entire occipital lobe. On close scrutiny, such reports turn out to be erroneous, arising from inadequate control of fixation during visual field testing. Patients seem able to detect test stimuli on their blind side within the macula or along the vertical meridian because they make surveillance saccades. A purported treatment for hemianopia, called vision restoration therapy, is based on this error. The dual perfusion theory is supported by anatomical studies showing that the middle cerebral artery perfuses the occipital pole in many individuals.In patients with hemianopia from stroke, neuroimaging shows preservation of the occipital pole when macular sparing is present. The frontier dividing the infarcted territory of the posterior cerebral artery and the preserved territory of the middle cerebral artery is variable, but always falls within the representation of the macula, because the macula is so highly magnified. For physicians, macular sparing was an important neurological sign in acute hemianopia because it signified a posterior cerebral artery occlusion. Modern neuroimaging has supplanted the importance of that clinical sign but at the same time confirmed its validity. For patients, macular sparing remains important because it mitigates the impact of hemianopia and preserves the ability to read fluently.
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http://dx.doi.org/10.1146/annurev-vision-100119-125406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8638601PMC
September 2021

Interocular Suppression in Primary Visual Cortex in Strabismus.

J Neurosci 2021 06 3;41(25):5522-5533. Epub 2021 May 3.

Program in Neuroscience, Department of Ophthalmology, University of California, San Francisco, California 94143

People with strabismus acquired during childhood do not experience diplopia (double vision). To investigate how perception of the duplicate image is suppressed, we raised two male monkeys with alternating exotropia by disinserting the medial rectus muscle in each eye at age four weeks. Once the animals were mature, they were brought to the laboratory and trained to fixate a small spot while recordings were made in primary visual cortex (V1). Drifting gratings were presented to the receptive fields of 500 single neurons for eight interleaved conditions: (1) right eye monocular; (2) left eye monocular; (3) right eye's field, right eye fixating; (4) right eye's field, left eye fixating; (5) left eye's field, right eye fixating; (6) left eye's field, left eye fixating; (7) both eyes' fields, right eye fixating; (8) both eyes' fields, left eye fixating. As expected, ocular dominance histograms showed a monocular bias compared with normal animals, but many cells could still be driven via both eyes. Overall, neuronal responses were not affected by switches in ocular fixation. Individual neurons exhibited binocular interactions, but mean population indices indicated no net interocular suppression or facilitation. Even neurons located in cortex with reduced cytochrome oxidase (CO) activity, representing portions of the nasal visual field where perception is suppressed during binocular viewing, showed no net inhibition. These data indicate that V1 neurons do not appear to reflect strabismic suppression and therefore the elimination of diplopia is likely to be mediated at a higher cortical level. In patients with strabismus, images fall on non-corresponding points in the two retinas. Only one image is perceived, because signals emanating from the other eye that convey the duplicate image are suppressed. The benefit is that diplopia is prevented, but the penalty is that the visual feedback required to adjust eye muscle tone to realign the globes is eliminated. Here, we report the first electrophysiological recordings from the primary visual cortex (V1) in awake monkeys raised with strabismus. The experiments were designed to reveal how perception of double images is avoided.
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http://dx.doi.org/10.1523/JNEUROSCI.0044-21.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221600PMC
June 2021

Bilateral Occlusion Reduces the Ocular Deviation in Intermittent Exotropia.

Invest Ophthalmol Vis Sci 2021 01;62(1)

Department of Ophthalmology, Program in Neuroscience, University of California, San Francisco, San Francisco, California, United States.

Purpose: The most common form of strabismus, intermittent exotropia, is thought to become manifest when the drive to fuse is overcome by excessive divergent muscle tone. This principle is tested by examining the alignment of the eyes in the absence of vision. We compare the ocular deviation in patients with intermittent exotropia under conditions of monocular versus binocular occlusion.

Methods: This prospective study of a patient cohort referred to our laboratory enrolled 18 patients with typical findings of well-controlled intermittent exotropia. Eye positions were recorded with video eye trackers while patients looked at a fixation spot at a distance of 57 cm. One eye was occluded, and the resulting ocular deviation was measured. Both eyes were then occluded, and the ocular deviation was re-measured.

Results: The majority of patients (11/18) had a smaller deviation when both eyes were covered. Occlusion of one eye resulted in a mean exotropia of 13.5° ± 4.7°. Occlusion of both eyes reduced the mean exotropia to 6.0° ± 6.5° (paired t-test, P < 0.001), corresponding to a 56% reduction in the ocular deviation. This reduction persisted during prolonged bilateral occlusion but reversed as soon as vision was restored.

Conclusions: Bilateral occlusion reveals a fixation-free state of alignment that is different from orthotropia and usually less than the exotropia that occurs spontaneously during binocular viewing. This finding demonstrates that the deviation angle in patients with intermittent exotropia is actively mediated by visual feedback, which the fixating eye is capable of providing alone.
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http://dx.doi.org/10.1167/iovs.62.1.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794258PMC
January 2021

Wilbrand's Knee: To Be or Not to Be a Knee?

J Neuroophthalmol 2020 Sep;40 Suppl 1:S7-S14

Department of Ophthalmology, Program in Neuroscience, University of California San Francisco, San Francisco, California.

Wilbrand's knee of the optic chiasm refers to crossing fibers from one optic nerve that stray for a short distance into the opposite optic nerve before joining the optic tract. This loop of aberrant axons, although small, has generated much controversy. In a previous study, labeling of the optic pathway in normal monkeys with a radioactive tracer revealed no Wilbrand's knee. Monocular enucleation induced a typical knee to form. These findings suggested that Wilbrand's knee is absent normally, but appears after atrophy of one optic nerve. This conclusion has been challenged by images showing Wilbrand's knee in the normal human chiasm using anisotropic light scattering. It has also been resisted by some clinicians who believe that Wilbrand's knee is necessary to explain the anterior chiasmal syndrome. Early in his distinguished career, William F. Hoyt examined the fiber organization of the monkey optic nerve and chiasm. He found no evidence for Wilbrand's knee and rejected its importance for the topical diagnosis of chiasmal lesions. His conclusion is supported by new data showing that anisotropic light scattering is not a reliable method for tracing axons. Hence, that method has given a misleading impression that Wilbrand's knee exists in normal subjects. Although Wilbrand's knee has fascinated neuro-ophthalmologists for more than a century, it is an inconsequential structure that develops only after a longstanding monocular optic neuropathy.
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http://dx.doi.org/10.1097/WNO.0000000000000988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562344PMC
September 2020

Long-term labeling of microelectrode tracks with fluorescent latex microspheres.

J Neurosci Methods 2020 09 1;343:108839. Epub 2020 Jul 1.

Department of Ophthalmology, Program in Neuroscience, University of California, San Francisco, CA, 94143, USA. Electronic address:

Background: After physiological recordings are performed in behaving animals, it is valuable to identify microelectrode tracks in histological sections so that neuronal responses can be correlated with brain anatomy. However, no good method currently exists for long-term labeling, so that microelectrode tracks can be recovered months or even years after recording sessions.

New Method: Penetrations were made into the brains of mice with microelectrodes coated with fluorescent dyes packaged into 0.2 μm polystyrene microspheres, followed by survival periods of 3 days, 2, 4, or 6 months. Sections were examined by fluorescence microscopy before and after cytochrome oxidase histochemistry to identify microelectrode tracks.

Results: After all 4 survival periods, 0.2 μm fluorescent microspheres clearly marked the tracks of microelectrode penetrations.

Comparison With Existing Methods: Fluorescent microspheres label microelectrode penetrations for longer than do fluorescent lipophilic dyes, such as FM 1-43FX. The label appears punctate, and resistant to degradation, because it is protected by the barrier of the polystyrene micro-container.

Conclusions: Coating of microelectrodes with fluorescent microspheres allows one to identify the penetration track in histological sections half a year later. This technique may be useful when electrophysiological recording sessions are being carried out in behaving animals, with plans to identify electrode tracks in histological sections many months later.
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http://dx.doi.org/10.1016/j.jneumeth.2020.108839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442242PMC
September 2020

Saccade Strategy in Alternating Exotropia.

Shinkei Ganka 2020 Jun 8;37(2):196-202. Epub 2020 Jul 8.

Department of Ophthalmology, Program in Neuroscience, University of California, San Francisco.

Patient with exotropia frequently alternate fixation, looking at something with one eye and then switching their attention to acquire a new target with the other eye. Which eye informs the brain about the location of the new target? To address this issue, we presented targets dichoptically to 16 exotropes that were visible to the fixating eye, the deviated eye, or to both eyes. We then compared the subjects' choice of eye for target acquisition with the organization of their suppression scotomas. There was a correspondence between suppression scotoma maps and the eye used to acquire peripheral targets. In other words, a target perceived via an eye was also fixated by it. These studies reveal how patients with alternating strabismus, despite eye misalignment, manage to localize and fixate efficiently visual targets in their environment.
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http://dx.doi.org/10.11476/shinkeiganka.37.196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8641942PMC
June 2020

Vertical Optokinetic Stimulation Induces Diagonal Eye Movements in Patients with Idiopathic Infantile Nystagmus.

Invest Ophthalmol Vis Sci 2020 06;61(6):14

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Purpose: In patients with early ocular misalignment and nystagmus, vertical optokinetic stimulation reportedly increases the horizontal component of the nystagmus present during fixation, resulting in diagonal eye movements. We tested patients with infantile nystagmus syndrome but normal ocular alignment to determine if this crosstalk depends on strabismus.

Methods: Eye movements were recorded in seven patients with infantile nystagmus. All but one patient had normal ocular alignment with high-grade stereopsis. Nystagmus during interleaved trials of right, left, up, and down optokinetic stimulation was compared with waveforms recorded during fixation. Six patients with strabismus but no nystagmus were also tested.

Results: In infantile nystagmus syndrome, horizontal motion evoked a mostly jerk nystagmus with virtually no vertical component. A vertical optokinetic pattern produced nystagmus with a diagonal trajectory. It was not simply a combination of a vertical component from optokinetic stimulation and a horizontal component from the subject's congenital nystagmus, rather in six of seven patients, the slow-phase velocity of the horizontal component during vertical optokinetic stimulation differed from that recorded during fixation. In the six strabismus patients without nystagmus, responses to vertical optokinetic stimulation were normal.

Conclusions: In patients with congenital motor nystagmus, a vertical noise pattern drives a diagonal nystagmus. This appears to arise because of crosstalk between the vertical and horizontal components of the optokinetic system. This abnormal response to vertical stimulation is not caused by strabismus because it occurs in patients with infantile nystagmus without strabismus. Moreover, it is absent in patients with strabismus and no spontaneous nystagmus.
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http://dx.doi.org/10.1167/iovs.61.6.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415290PMC
June 2020

Air Bubbles Introduced From Peripheral Intravenous Lines Into the Cerebral Venous System.

J Neuroophthalmol 2019 09;39(3):437

Departments of Ophthalmology, Neurology, and Physiology, University of California, San Francisco, San Francisco, California.

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http://dx.doi.org/10.1097/WNO.0000000000000784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699917PMC
September 2019

Papilledema from gain-of-function mutations in the STAT3 gene.

Ophthalmic Genet 2019 04 3;40(2):165-169. Epub 2019 Apr 3.

b Beckman Vision Center, Program in Neuroscience , University of California , San Francisco , CA , USA.

Background: Signal Transducer and Activator of Transcription 3 (STAT3) gain-of-function germline mutations are associated with diverse clinical manifestations, including autoimmune cytopenia, lymphadenopathy, immunodeficiency, endocrinopathy, and enteropathy. We describe a new feature: raised intracranial pressure with papilledema.

Materials And Methods: Report of two cases.

Results: The first patient had a de novo heterozygous c.2144C>T (p.Pro715Leu) mutation in the STAT3 gene. At age 1 she had papilledema with marked sheathing of the proximal vessels on the optic discs. Follow-up 8 years later showed chronic papilledema, cystoid macular edema, and vision loss. The second patient had a de novo heterozygous c.2147C>T (p.Thr716Met) mutation. At age 12 he developed papilledema, which recurred despite treatment. In both patients, repeated sampling of the cerebrospinal fluid demonstrated a lymphocytic pleocytosis.

Conclusions: Papilledema can occur as a manifestation of STAT3 gain-of-function mutation, sometimes accompanied by prominent vascular sheathing and cystoid macular edema. The mechanism may be chronic meningeal infiltration by white blood cells, impairing cerebrospinal fluid absorption.
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http://dx.doi.org/10.1080/13816810.2019.1592202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504588PMC
April 2019

Patterns of Cortical Visual Field Defects From Embolic Stroke Explained by the Anastomotic Organization of Vascular Microlobules.

J Neuroophthalmol 2018 12;38(4):538-550

Department of Ophthalmology (JCH, DLA), Program in Neuroscience, University of California San Francisco, San Francisco, California; and Center for Mind/Brain Sciences (DLA), The University of Trento, Trento, Italy.

The cerebral cortex is supplied by vascular microlobules, each comprised of a half dozen penetrating arterioles that surround a central draining venule. The surface arterioles that feed the penetrating arterioles are interconnected via an extensively anastomotic plexus. Embolic occlusion of a small surface arteriole rarely produces a local infarct, because collateral blood flow is available through the vascular reticulum. Collateral flow also protects against infarct after occlusion of a single penetrating arteriole. Cortical infarction requires blockage of a major arterial trunk, with arrest of blood flow to a relatively large vascular territory. For striate cortex, the major vessels compromised by emboli are the inferior calcarine and superior calcarine arteries, as well as the distal branches of the middle cerebral artery. Their vascular territories have a fairly consistent relationship with the retinotopic map. Consequently, occlusion by emboli results in stereotypical visual field defects. The organization of the arterial supply to the occipital lobe provides an anatomical explanation for a phenomenon that has long puzzled neuro-ophthalmologists, namely, that of the myriad potential patterns of cortical visual field loss, only a few are encountered commonly from embolic cortical stroke.
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http://dx.doi.org/10.1097/WNO.0000000000000733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913876PMC
December 2018

Recurrent Superior Oblique Myokymia Treated by Distal Tendon Extirpation.

J Neuroophthalmol 2019 09;39(3):345-347

Beckman Vision Center, Program in Neuroscience, University of California, San Francisco, San Francisco, California.

Background: We describe successful surgical treatment of superior oblique myokymia, which had recurred after superior oblique tenectomy.

Methods: Single case report.

Results: The distal stump of the superior oblique tendon was extirpated by stripping it from the globe. The ipsilateral superior rectus muscle also was recessed, to correct a hypertropia that had resulted from the original superior oblique tenectomy.

Conclusions: Complete removal of the distal superior oblique muscle tendon provided definitive relief of superior oblique myokymia. Superior rectus muscle recession, combined with previous inferior oblique myectomy, compensated effectively for loss of superior oblique function.
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http://dx.doi.org/10.1097/WNO.0000000000000718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944202PMC
September 2019

Spontaneous Reattachment of the Medial Rectus After Free Tenotomy.

J Pediatr Ophthalmol Strabismus 2018 Sep 29;55(5):335-338. Epub 2018 May 29.

Purpose: To assess the outcome of free tenotomy of the medial rectus muscle in post-natal monkeys.

Methods: The medial rectus muscle was disinserted in both eyes of 6 macaques at age 4 weeks to induce an alternating exotropia. After the impact on the visual cortex and superior colliculus was investigated, the animals were examined post-mortem to assess the anatomy of the medial rectus muscles.

Results: After tenotomy, the monkeys eventually recovered partial adduction. Necropsy revealed that all 12 medial rectus muscles had reattached to the globe. They were firmly connected via an abnormally long tendon, but at the native insertion site.

Conclusions: Medial rectus muscles are able to reattach spontaneously to the eye following free tenotomy in post-natal macaques. The early timing of surgery and the large size of the globe relative to the orbit may explain why reinsertion occurs more readily in monkeys than in children with a lost muscle after strabismus surgery. [J Pediatr Ophthalmol Strabismus. 2018;55(5):335-338.].
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http://dx.doi.org/10.3928/01913913-20180328-01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924507PMC
September 2018

Reply.

Ophthalmology 2018 02;125(2):e13

Department of Ophthalmology, University of California, San Francisco, San Francisco, California. Electronic address:

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http://dx.doi.org/10.1016/j.ophtha.2017.08.043DOI Listing
February 2018

Normal Topography and Binocularity of the Superior Colliculus in Strabismus.

J Neurosci 2018 01 13;38(1):173-182. Epub 2017 Nov 13.

Beckman Vision Center, Program in Neuroscience, University of California San Francisco, San Francisco, California 94143, and

In subjects with alternating strabismus, either eye can be used to saccade to visual targets. The brain must calculate the correct vector for each saccade, which will depend on the eye chosen to make it. The superior colliculus, a major midbrain center for saccade generation, was examined to determine whether the maps serving each eye were shifted to compensate for strabismus. Alternating exotropia was induced in two male macaques at age 1 month by sectioning the tendons of the medial recti. Once the animals grew to maturity, they were trained to fixate targets with either eye. Receptive fields were mapped in the superior colliculus using a sparse noise stimulus while the monkeys alternated fixation. For some neurons, sparse noise was presented dichoptically to probe for anomalous retinal correspondence. After recordings, microstimulation was applied to compare sensory and motor maps. The data showed that receptive fields were offset in position by the ocular deviation, but otherwise remained aligned. In one animal, the left eye's coordinates were rotated ∼20° clockwise with respect to those of the right eye. This was explained by a corresponding cyclorotation of the ocular fundi, which produced an A-pattern deviation. Microstimulation drove the eyes accurately to the site of receptive fields, as in normal animals. Single-cell recordings uncovered no evidence for anomalous retinal correspondence. Despite strabismus, neurons remained responsive to stimulation of either eye. Misalignment of the eyes early in life does not alter the organization of topographic maps or disrupt binocular convergence in the superior colliculus. Patients with strabismus are able to make rapid eye movements, known as saccades, toward visual targets almost as gracefully as subjects with normal binocular alignment. They can even exercise the option of using the right eye or the left eye. It is unknown how the brain measures the degree of ocular misalignment and uses it to compute the appropriate saccade for either eye. The obvious place to investigate is the superior colliculus, a midbrain oculomotor center responsible for the generation of saccades. Here, we report the first experiments in the superior colliculus of awake primates with strabismus using a combination of single-cell recordings and microstimulation to explore the organization of its topographic maps.
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http://dx.doi.org/10.1523/JNEUROSCI.2589-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761432PMC
January 2018

Incomitance and Eye Dominance in Intermittent Exotropia.

Invest Ophthalmol Vis Sci 2017 08;58(10):4049-4055

Department of Ophthalmology, University of California, San Francisco, San Francisco, California, United States.

Purpose: To determine if the deviation angle changes in subjects with intermittent exotropia as they alternate fixation between the right and left eye in primary gaze.

Methods: In this prospective observational cohort study, 37 subjects with intermittent exotropia were tested for evidence of incomitance. The position of each eye was recorded with a video tracker during fixation on a small central target. A cover-uncover test was performed by occluding one eye with a shutter that passed infrared light, allowing continuous tracking of both eyes. The deviation angle was measured during periods of right eye and left eye fixation. Incomitance was assessed as a function of eye preference, fixation stability, and exotropia variability.

Results: The mean exotropia was 18.2° ± 8.1°. A difference between right exotropia and left exotropia was detectable in 16/37 subjects. Allowing for potential tracking error, the incomitance had a mean amplitude of 1.7°. It was not related to a difference in accommodative effort, eye preference, fixation stability, or variability in deviation.

Conclusions: Comitance is regarded as a feature that distinguishes strabismus from paralytic or restrictive processes. Unexpectedly, eye tracking during the cover-uncover test showed that incomitance is present in approximately 40% of subjects with intermittent exotropia. It averages 10% of the exotropia, and can equal up to 5°. When substantial, it may be worth considering when planning surgical correction.
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http://dx.doi.org/10.1167/iovs.17-22155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559177PMC
August 2017

Bilateral Optic Disc Pits With Posterior Pituitary Ectopia.

J Neuroophthalmol 2017 12;37(4):401-402

Departments of Ophthalmology, Neurology, and Physiology (JCH), Beckman Vision Center, University of California San Francisco, San Francisco, California; and Department of Radiology (AJB), University of California San Francisco, San Francisco, California.

Posterior pituitary ectopia has been reported previously in association with optic nerve hypoplasia, as a variant of septo-optic dysplasia. We describe a 14-year-old boy with posterior pituitary ectopia and bilateral optic disc pits. He had hypopituitarism and a reduction in visual acuity to 20/40 in each eye, owing to loss of foveal ganglion cells. Optic pits and posterior pituitary ectopia may have occurred together in the same subject by chance, but the rarity of both conditions suggests a possible association.
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http://dx.doi.org/10.1097/WNO.0000000000000528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685660PMC
December 2017

Invited Commentary: Ganglion Cell Complex Measurement in Compressive Optic Neuropathy.

J Neuroophthalmol 2017 03;37(1):13-15

Departments of Ophthalmology, Neurology, and Physiology, Beckman Vision Center, University of California San Francisco, San Francisco, California.

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http://dx.doi.org/10.1097/WNO.0000000000000489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689083PMC
March 2017

Adaptation, perceptual learning, and plasticity of brain functions.

Graefes Arch Clin Exp Ophthalmol 2017 Mar 14;255(3):435-447. Epub 2017 Jan 14.

Vision Rehabilitation Research Unit, Center for Ophthalmology, University of Tübingen, Tübingen, Germany.

The capacity for functional restitution after brain damage is quite different in the sensory and motor systems. This series of presentations highlights the potential for adaptation, plasticity, and perceptual learning from an interdisciplinary perspective. The chances for restitution in the primary visual cortex are limited. Some patterns of visual field loss and recovery after stroke are common, whereas others are impossible, which can be explained by the arrangement and plasticity of the cortical map. On the other hand, compensatory mechanisms are effective, can occur spontaneously, and can be enhanced by training. In contrast to the human visual system, the motor system is highly flexible. This is based on special relationships between perception and action and between cognition and action. In addition, the healthy adult brain can learn new functions, e.g. increasing resolution above the retinal one. The significance of these studies for rehabilitation after brain damage will be discussed.
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http://dx.doi.org/10.1007/s00417-016-3580-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323482PMC
March 2017

Capturing the Moment of Fusion Loss in Intermittent Exotropia.

Ophthalmology 2017 04 9;124(4):496-504. Epub 2017 Jan 9.

Department of Ophthalmology, University of California, San Francisco, San Francisco, California. Electronic address:

Purpose: To characterize eye movements made by patients with intermittent exotropia when fusion loss occurs spontaneously and to compare them with those induced by covering 1 eye and with strategies used to recover fusion.

Design: Prospective study of a patient cohort referred to our laboratory.

Participants: Thirteen patients with typical findings of intermittent exotropia who experienced frequent spontaneous loss of fusion.

Methods: The position of each eye was recorded with a video eye tracker under infrared illumination while fixating on a small central near target.

Main Outcome Measures: Eye position and peak velocity measured during spontaneous loss of fusion, shutter-induced loss of fusion, and recovery of fusion.

Results: In 10 of 13 subjects, the eye movement made after spontaneous loss of fusion was indistinguishable from that induced by covering 1 eye. It reached 90% of full amplitude in a mean of 1.75 seconds. Peak velocity of the deviating eye's movement was highly correlated for spontaneous and shutter-induced events. Peak velocity was also proportional to exotropia amplitude. Recovery of fusion was more rapid than loss of fusion, and often was accompanied by interjection of a disconjugate saccade.

Conclusions: Loss of fusion in intermittent exotropia is not influenced by visual feedback. Excessive divergence tone may be responsible, but breakdown of alignment occurs via a unique, pathological type of eye movement that differs from a normal, physiological divergence eye movement.
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http://dx.doi.org/10.1016/j.ophtha.2016.11.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685669PMC
April 2017

Normal correspondence of tectal maps for saccadic eye movements in strabismus.

J Neurophysiol 2016 12 7;116(6):2541-2549. Epub 2016 Sep 7.

Beckman Vision Center, Program in Neuroscience, University of California, San Francisco, California; and

The superior colliculus is a major brain stem structure for the production of saccadic eye movements. Electrical stimulation at any given point in the motor map generates saccades of defined amplitude and direction. It is unknown how this saccade map is affected by strabismus. Three macaques were raised with exotropia, an outwards ocular deviation, by detaching the medial rectus tendon in each eye at age 1 mo. The animals were able to make saccades to targets with either eye and appeared to alternate fixation freely. To probe the organization of the superior colliculus, microstimulation was applied at multiple sites, with the animals either free-viewing or fixating a target. On average, microstimulation drove nearly conjugate saccades, similar in both amplitude and direction but separated by the ocular deviation. Two monkeys showed a pattern deviation, characterized by a systematic change in the relative position of the two eyes with certain changes in gaze angle. These animals' saccades were slightly different for the right eye and left eye in their amplitude or direction. The differences were consistent with the animals' underlying pattern deviation, measured during static fixation and smooth pursuit. The tectal map for saccade generation appears to be normal in strabismus, but saccades may be affected by changes in the strabismic deviation that occur with different gaze angles.
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http://dx.doi.org/10.1152/jn.00553.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133306PMC
December 2016

Diagnosis of Tensilon-Negative Ocular Myasthenia Gravis By Daily Selfie.

J Neuroophthalmol 2016 09;36(3):292-3

Departments of Neurology (ELG, JCH) and Ophthalmology (JVB), University of California, San Francisco, California.

The initial symptoms of myasthenia gravis are usually ptosis and diplopia. The diagnosis is often confirmed by testing for anti-acetylcholine receptor antibodies or by observing the effects of intravenous edrophonium (Tensilon) injection. However, these standard tests may be negative in patients with isolated ocular findings. We present the case of an 83-year-old woman with negative serologic and Tensilon testing. She was asked to photograph herself daily. The resulting sequence of daily selfies captured striking fluctuations in her ocular alignment and ptosis. Daily selfies may be a useful strategy for confirming the clinical diagnosis of ocular myasthenia gravis.
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http://dx.doi.org/10.1097/WNO.0000000000000413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120673PMC
September 2016
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