Synke Meltendorf

Impact of chiasma opticum malformations on the organization of the human ventral visual cortex

Congenital malformations of the optic chiasm, such as enhanced and reduced crossing of the optic nerve fibers, are evident in albinism and achiasma, respectively. In early visual cortex the resulting additional visual input from the ipsilateral visual hemifield is superimposed onto the normal retinotopic representation of the contralateral visual field, which is likely due to conservative geniculo‐striate projections. Counterintuitively, this organization in early visual cortex does not have profound consequences on visual function. Here we ask, whether higher stages of visual processing provide a correction to the abnormal representation allowing for largely normal perception. To this end we assessed the organization patterns of early and ventral visual cortex in five albinotic, one achiasmic, and five control participants. In albinism and achiasma the mirror‐symmetrical superposition of the ipsilateral and contalateral visual fields was evident not only in early visual cortex, but also in the higher areas of the ventral processing stream. Specifically, in the visual areas VO1/2 and PHC1/2 no differences in the extent, the degree of superposition, and the magnitude of the responses were evident in comparison to the early visual areas. Consequently, the highly atypical organization of the primary visual cortex was propagated downstream to highly specialized processing stages in an undiminished and unchanged manner. This indicates largely unaltered cortico‐cortical connections in both types of misrouting, i.e., enhanced and reduced crossing of the optic nerves. It is concluded that main aspects of visual function are preserved despite sizable representation abnormalities in the ventral visual processing stream. Hum Brain Mapp 35:5093–5105, 2014.

Multifocal Visual Evoked Potentials Reveal Normal Optic Nerve Projections in Human Carriers of Oculocutaneous Albinism Type 1a

PURPOSE In albinism, part of the temporal retina projects abnormally to the contralateral hemisphere. A residual misprojection is also evident in feline carriers that are heterozygous for tyrosinase-related albinism. This study was conducted to test whether such residual abnormalities can also be identified in human carriers of oculocutaneous tyrosinase-related albinism (OCA1a). METHODS In eight carriers heterozygous for OCA1a and in eight age- and sex-matched control subjects, monocular pattern-reversal and -onset multifocal visual evoked potentials (mfVEPs) were recorded at 60 locations comprising a visual field of 44 degrees diameter (VERIS 5.01; EDI, San Mateo, CA). For each eye and each stimulus location, interhemispheric difference potentials were calculated and correlated with each other, to assess the lateralization of the responses: positive and negative correlations indicate lateralizations on the same or opposite hemispheres, respectively. Misrouted optic nerves are expected to yield negative interocular correlations. The analysis also allowed for the assessment of the sensitivity and specificity of the detection of projection abnormalities. RESULTS No significant differences were obtained for the distributions of the interocular correlation coefficients of controls and carriers. Consequently, no local representation abnormalities were observed in the group of OCA1a carriers. For pattern-reversal and -onset stimulation, an assessment of the control data yielded similar specificity (97.9% and 94.6%) and sensitivity (74.4% and 74.8%) estimates for the detection of projection abnormalities. CONCLUSIONS The absence of evidence for projection abnormalities in human OCA1a carriers contrasts with the previously reported evidence for abnormalities in cat-carriers of tyrosinase-related albinism. This discrepancy suggests that animal models of albinism may not provide a match to human albinism.

Self-organisation in the human visual system—Visuo-motor processing with congenitally abnormal V1 input

Due to an abnormal projection of the temporal retina the albinotic primary visual cortex receives substantial input from the ipsilateral visual field. To test whether representation abnormalities are also evident in higher tier visual, and in motor and somatosensory cortices, brain activity was measured with fMRI in 14 subjects with albinism performing a visuo-motor task. During central fixation, a blue or red target embedded in a distractor array was presented for 250 ms in the left or right visual hemifield. After a delay, the subjects were prompted to indicate with left or right thumb button presses the target presence in the upper or lower hemifield. The fMRI responses were evaluated for different regions of interest concerned with visual, motor and somatosensory processing and compared to previously acquired data from 14 controls. The following results were obtained: (1) in albinism the hit rates in the visuo-motor task were indistinguishable from normal. (2) In area MT and the intraparietal sulcus there was an indication of abnormal lateralisation patterns. (3) Largely normal lateralisation patterns were evident in motor and somatosensory cortices. It is concluded that in human albinism, the abnormal visual field representation is made available for visuo-motor processing with a motor cortex that comprises an essentially normal lateralisation. Consequently, specific adaptations of the mechanisms mediating visuo-motor integration are required in albinism.

Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial

Importance Anti–vascular endothelial growth factor (VEGF) therapies are a novel treatment option in retinopathy of prematurity (ROP). Data on dosing, efficacy, and safety are insufficient. Objective To investigate lower doses of anti-VEGF therapy with ranibizumab, a substance with a significantly shorter systemic half-life than the standard treatment, bevacizumab. Design, Setting, and Participants This randomized, multicenter, double-blind, investigator-initiated trial at 9 academic medical centers in Germany compared ranibizumab doses of 0.12 mg vs 0.20 mg in infants with bilateral aggressive posterior ROP; ROP stage 1 with plus disease, 2 with plus disease, or 3 with or without plus disease in zone I; or ROP stage 3 with plus disease in posterior zone II. Patients were recruited between September 2014 and August 2016. Twenty infants were screened and 19 were randomized. Interventions All infants received 1 baseline ranibizumab injection per eye. Reinjections were allowed in case of ROP recurrence after at least 28 days. Main Outcomes and Measures The primary end point was the number of infants who did not require rescue therapy at 24 weeks. Key secondary end points included time-to-event analyses, progression of physiologic vascularization, and plasma VEGF levels. Stages of ROP were photodocumented and reviewed by an expert committee. Results Nineteen infants with ROP were enrolled (9 [47.4%] female; median [range] postmenstrual age at first treatment, 36.4 [34.7-39.7] weeks), 3 of whom died during the study (1 in the 0.12-mg group and 2 in the 0.20-mg group). Of the surviving infants, 8 (88.9%) (17 eyes [94.4%]) in the 0.12-mg group and 6 (85.7%) (13 eyes [92.9%]) in the 0.20-mg group did not require rescue therapy. Both ranibizumab doses were equally successful in controlling acute ROP (Cochran-Mantel-Haenszel analysis; odds ratio, 1.88; 95% CI, 0.26-13.49; P = .53). Physiologic intraretinal vascularization was superior in the 0.12-mg group. The VEGF plasma levels were not systematically altered in either group. Conclusions and Relevance This pilot study demonstrates that ranibizumab is effective in controlling acute ROP and that 24% of the standard adult dose (0.12 mg) appears equally effective as 40% (0.20 mg). Superior vascularization of the peripheral retina with 0.12 mg of ranibizumab indicates that the lower dose may be favorable. Unchanged plasma VEGF levels point toward a limited systemic drug exposure after ranibizumab. Trial Registration clinicaltrials.gov Identifier: NCT02134457 and clinicaltrialsregister.eu Identifier: 2013-002539-13.

Optic Nerve Projections in Patients with Primary Ciliary Dyskinesia

PURPOSE Recently, it has been suggested that misprojections of the temporal retina to the contralateral hemisphere might not be specific for patients with albinism and might also be associated with the Kartagener syndrome (i.e., with situs inversus totalis in the presence of primary ciliary dyskinesia [PCD]). The authors tested whether such projection abnormalities are associated with PCD and situs inversus. METHODS In 10 patients with PCD (five with situs inversus totalis) and in 10 age- and sex-matched controls, visual evoked potentials (VEPs) were recorded monocularly, as follows: conventional pattern-onset VEPs (cVEPs) and multifocal VEPs (mfVEPs) for 60 locations constituting a visual field of 44° diameter. cVEPs from 13 albinotic subjects were included as a reference. For each eye, interhemispheric difference potentials were calculated and correlated with each other to assess the lateralization of the responses: positive and negative correlation coefficients indicated lateralizations on same or opposite hemispheres, respectively. Misrouted optic nerves are expected to yield negative interocular correlations. RESULTS For both cVEPs and mfVEPs, the distribution of the correlation coefficients in the PCD patients yielded largely positive values and did not differ from that of the controls. Consequently, neither large- nor small-scale lateralization abnormalities were observed in PCD. Further, the optic nerve projection did not depend on the presence of situs inversus. CONCLUSIONS The absence of evidence for projection abnormalities in a cohort of 10 subjects with PCD, five of whom had Kartagener syndrome, underscores that misrouting of the optic nerves is not a common trait of these subjects.

Visual Pathways in Humans With Ephrin-B1 Deficiency Associated With the Cranio-Fronto-Nasal Syndrome.

PURPOSE Numerous animal studies demonstrated the importance of components of the ephrin/Eph system for correct visual system development. Analogous investigations in humans are entirely missing. Here, we examined the visual system in humans with ephrin-B1 deficiency, which is x-linked and associated with the cranio-fronto-nasal syndrome (CFNS) in heterozygous females. METHODS For one male hemizygous for ephrin-B1 deficiency and three affected heterozygous females with molecular-genetically confirmed mutations, the integrity of the partial decussation of the optic nerves was assessed with visual evoked potentials (VEPs) and compared with albinotic, achiasmic, and control participants with healthy vision. Further, retinal morphology and function and the gross-retinotopic representation of the primary visual cortex were examined with spectral-domain optical coherence tomography (SD-OCT), ERG, and multifocal (mf) VEPs for the male participant and part of the carriers. RESULTS Strabismus and lack of stereovision was evident in the male and two of the females. Other characteristics of the visual system organization and function were normal: (1) retina: SD-OCT and funduscopy indicated normal foveal and optic nerve head morphology. Electroretinograms indicated normal retinal function, (2) optic chiasm: conventional (c)VEP showed no evidence for misrouting and mfVEPs were only suggestive of, if any, very minor local misrouting, and (3) visual cortex: mfVEP characteristics indicated normal retinotopic gross-representations of the contralateral visual hemifield in each hemisphere. CONCLUSIONS While ephrin-B1 deficiency leads to abnormal visual pathways in mice, it leaves the human visual system, apart from deficits in binocular vision, largely normal. We presume that other components of the ephrin-system can substitute the lack of ephrin-B1 in humans.