Nystagmus is an eye movement disorder characterised by abnormal, involuntary rhythmic oscillation... more Nystagmus is an eye movement disorder characterised by abnormal, involuntary rhythmic oscillations of one or both eyes, initiated by a slow phase. It is not uncommon in the UK and regularly seen in paediatric ophthalmology and adult general/ strabismus clinics. In some cases, it occurs in isolation, and in others, it occurs as part of a multisystem disorder, severe visual impairment or neurological disorder. Similarly, in some cases, visual acuity can be normal and in others can be severely degraded. Furthermore, the impact on vision goes well beyond static acuity alone, is rarely measured and may vary on a minute-to-minute, day-to-day or month-to-month basis. For these reasons, management of children with nystagmus in the UK is varied, and patients report hugely different experiences and investigations. In this review, we hope to shine a light on the current management of children with nystagmus across five specialist centres in the UK in order to present, for the first time, a consensus on investigation and clinical management.
Schizophrenia is associated with several brain deficits, as well as visual processing deficits, b... more Schizophrenia is associated with several brain deficits, as well as visual processing deficits, but clinically useful biomarkers are elusive. We hypothesized that retinal layer changes, noninvasively visualized using spectraldomain optical coherence tomography (SD-OCT), may represent a possible "window" to these abnormalities. Methods: A Leica EnvisuTM SD-OCT device was used to obtain high-resolution central foveal B-scans in both eyes of 35 patients with schizophrenia and 50 demographically matched controls. Manual retinal layer segmentation was performed to acquire individual and combined layer thickness measurements in 3 macular regions. Contrast sensitivity was measured at 3 spatial frequencies in a subgroup of each cohort. Differences were compared using adjusted linear models and significantly different layer measures in patients underwent Spearman Rank correlations with contrast sensitivity, quantified symptoms severity, disease duration, and antipsychotic medication dose. Results: Total retinal and photoreceptor complex thickness was reduced in all regions in patients (P < .0001). Segmentation revealed consistent thinning of the outer nuclear layer (P < .001) and inner segment layer (P < .05), as well as a pattern of parafoveal ganglion cell changes. Low spatial frequency contrast sensitivity was reduced in patients (P = .002) and correlated with temporal parafoveal ganglion cell complex thinning (R = .48, P = .01). Negative symptom severity was inversely correlated with foveal photoreceptor complex thickness (R = −.54, P = .001) and outer nuclear layer thickness (R = −.47, P = .005). Conclusions: Our novel findings demonstrate considerable retinal layer abnormalities in schizophrenia that are related to clinical features and visual function. With time, SD-OCT could provide easily-measurable biomarkers to facilitate clinical assessment and further our understanding of the disease.
Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation dis... more Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduce...
Background/aimsTo investigate the foveal morphology in carriers of oculocutaneous albinism (OCA) ... more Background/aimsTo investigate the foveal morphology in carriers of oculocutaneous albinism (OCA) using spectral domain optical coherence tomography (SD-OCT). A cross-sectional, observational study.MethodsHandheld SD-OCT (Envisu C2300) was used to acquire horizontal scans through the centre of the fovea in biological parents of patients with OCA (n=28; mean age±SD=40.43±8.07 years) and age-matched and ethnicity-matched controls (n=28; mean age±SD=38.04±10.27 years). Sequence analysis was performed for variants in known genes associated with OCA. Best-corrected visual acuity (BCVA), presence of foveal hypoplasia and grade, foveal, parafoveal and perifoveal thickness measurements of total retinal layers (TRL), inner retinal layers (IRL) and outer retinal layers (ORL) thickness were measured.ResultsFoveal hypoplasia was identified in 32.14% of OCA carriers; grade 1 in all cases. OCA carriers demonstrated significant thicker TRL thickness (median difference: 13.46 µm, p=0.009) and IRL th...
Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN h... more Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN has low prevalence, and twins with IN are rare. Whilst discordant presentation has been previously reported for IN, we present for the first time the comprehensive assessment of diagnostically discordant monozygotic twins. From a cohort of over 2000 patients, we identified twins and triplets discordant for nystagmus. Using next-generation sequencing, high-resolution infra-red pupil tracking and optical coherence tomography, we characterised differences in genotype and phenotype. Monozygotic twins (n = 1), dizygotic twins (n = 3) and triplets (n = 1) were included. The monozygotic twins had concordant TYR variants. No causative variants were identified in the triplets. Dizygotic twins had discordant variants in TYR, OCA2 and FRMD7. One unaffected co-twin demonstrated sub-clinical nystagmus. Foveal hypoplasia (FH) was noted in four of five probands. Both co-twins of the monozygotic pair and...
Normal foveal development begins in utero at midgestation with centrifugal displacement of inner ... more Normal foveal development begins in utero at midgestation with centrifugal displacement of inner retinal layers (IRLs) from the location of the incipient fovea. The outer retinal changes such as increase in cone cell bodies, cone elongation and packing mainly occur after birth and continue until 13 years of age. The maturity of the fovea can be assessed invivo using optical coherence tomography, which in normal development would show a well-developed foveal pit, extrusion of IRLs, thickened outer nuclear layer and long outer segments. Developmental abnormalities of various degrees can result in foveal hypoplasia (FH). This is a characteristic feature for example in albinism, aniridia, prematurity, foveal hypoplasia with optic nerve decussation defects with or without anterior segment dysgenesis without albinism (FHONDA) and optic nerve hypoplasia. In achromatopsia, there is disruption of the outer retinal layers with atypical FH. Similarly, in retinal dystrophies, there is abnormal ...
Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosoma... more Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development...
ObjectiveTo investigate (1) the feasibility of scanning the optic nerve (ON) and central retina w... more ObjectiveTo investigate (1) the feasibility of scanning the optic nerve (ON) and central retina with hand-held optical coherence tomography (HH-OCT) without sedation or anaesthesia in primary congenital glaucoma (PCG), (2) the characteristics of ON changes in comparison with adult primary open-angle glaucoma (POAG) in comparison with matched controls, (3) the sensitivity and specificity of ON parameters for diagnosis, and (4) changes of foveal morphology.Methods and analysisHH-OCT (Envisu 2300; Leica Microsystems) was used to investigate ON and foveal morphology of 20 children with PCG (mean age 4.64±2.79) and 10 adult patients with POAG (mean age 66.8±6.94), and compared with age-matched, gender-matched and ethnicity-matched healthy controls without sedation or anaesthesia.ResultsHH-OCT yielded useful data in 20 out of 24 young children with PCG. Patients with PCG had significantly deeper cup changes than patients with POAG (vs respective age-matched controls, p=0.014). ON changes ...
Herein we present a consanguineous family with three children affected by foveal hypoplasia with ... more Herein we present a consanguineous family with three children affected by foveal hypoplasia with infantile nystagmus, following an autosomal recessive mode of inheritance. The patients showed normal electroretinography responses, no signs of albinism, and no anterior segment or brain abnormalities. Upon whole exome sequencing, we identified a homozygous mutation (c.1861C4T;p.Q621*) in the aryl hydrocarbon receptor (AHR) gene that perfectly co-segregated with the disease in the larger family. AHR is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. Further, it has been shown to play a physiological role under normal cellular conditions, such as in immunity, inflammatory response and neurogenesis. Notably, knockout of the Ahr gene in mouse impairs optic nerve myelin sheath formation and results in oculomotor deficits sharing many features with our patients: the eye movement disorder in Ahr À/À mice appears early in development and presents as conjugate horizontal pendular nystagmus. We therefore propose AHR to be a novel disease gene for a new, recessively inherited disorder in humans, characterized by infantile nystagmus and foveal hypoplasia.
To investigate the morphology of the retina and optic nerve (ON) in microcephaly. This was a pros... more To investigate the morphology of the retina and optic nerve (ON) in microcephaly. This was a prospective case-control study including 27 patients with microcephaly and 27 healthy controls. All participants underwent ophthalmologic examination and handheld optical coherence tomography (OCT) of the macula and ON head. The thickness of individual retinal layers was quantified at the foveal center and the parafovea (1,000 μm nasal and temporal to the fovea). For the ON head, disc diameter, cup diameter, cup-to-disc ratio, cup depth, horizontal rim diameter, rim area, peripapillary retinal thickness, and retinal nerve fiber layer thickness were measured. Seventy-eight percent of patients had ophthalmologic abnormalities, mainly nystagmus (56%) and strabismus (52%). OCT abnormalities were found in 85% of patients. OCT revealed disruption of the ellipsoid zone, persistent inner retinal layers, and irregular foveal pits. Parafoveal retinal thickness was significantly reduced in patients wit...
Albinism is a group of congenital disorders of the melanin synthesis pathway. Multiple ocular, wh... more Albinism is a group of congenital disorders of the melanin synthesis pathway. Multiple ocular, white matter and cortical abnormalities occur in albinism, including a greater decussation of nerve fibres at the optic chiasm, foveal hypoplasia and nystagmus. Despite this, visual perception is largely preserved. We proposed that this may be attributable to reorganisation among cerebral networks, including an increased interhemispheric connectivity of the primary visual areas. We applied a graph-theoretic model to explore brain connectivity networks derived from resting-state functional and diffusion-tensor magnetic resonance imaging data in 23 people with albinism and 20 controls. We tested for group differences in connectivity between primary visual areas and in summary network organisation descriptors. We supplemented our main findings with analyses of control regions, brain volumes and white matter microstructure. We found significant functional interhemispheric hyperconnectivity of the primary visual areas in the albinism group (p=0.012). Tests of interhemispheric connectivity based on the diffusion-tensor data showed no significant group difference (p=0.713). Second, we found that a range of functional whole-brain network metrics were abnormal in people with albinism, including the clustering coefficient (p=0.005), although this may have been driven partly by overall differences in connectivity, rather than reorganisation. Based on our results, we suggest that changes occur in albinism at the whole-brain level, and not just within the visual processing pathways. We propose that our findings may reflect compensatory adaptations to increased chiasmic decussation, foveal hypoplasia and nystagmus.
Investigative Opthalmology & Visual Science, 2015
PURPOSE. To characterize the time course of normal foveal development in vivo in term infants and... more PURPOSE. To characterize the time course of normal foveal development in vivo in term infants and young children using handheld spectral-domain optical coherence tomography (HH-SDOCT). METHODS. We obtained 534 HH-SDOCT scans from 261 infants, children, and young adults with a mean age of 4.9 years (range, 0-27 years). Each retinal layer was manually segmented in ImageJ and correlated with gestational age (GA) and visual acuity (VA). The developmental trajectories of each retinal layer at the fovea, parafovea, and perifovea were calculated using fractional polynomial modeling. RESULTS. The central macular thickness (CMT) increases logarithmically between birth and 48.6 months GA. The foveal ganglion cell (GCL), inner plexiform, inner nuclear (INL), and outer plexiform layers decrease in thickness exponentially until 18 months GA. Interestingly, the parafoveal and perifoveal GCL and INL thicknesses initially decrease until 17 months GA and then increase in thickness until 65.5 GA. The foveal outer nuclear layer, inner segment, and outer segment of the photoreceptors increase in thickness logarithmically until 32.4, 26.9, and 45.3 months GA, respectively. The parafoveal and perifoveal outer retinal layers increase in thickness more gradually until 146 months GA. The thickness of the outer retinal layers and CMT were strongly correlated with VA, with r ¼ 0.54 (P < 0.0001) and r ¼ 0.52 (P < 0.0001), respectively. CONCLUSIONS. We have modeled for the first time the complex, nonlinear developmental trajectories for each retinal layer and demonstrate that development continues until adolescence. Our description of normal development will be helpful in diagnosing, monitoring, and understanding pediatric retinal disease.
Purpose We aimed to investigate structural retinal changes in malarial retinopathy (MR) using han... more Purpose We aimed to investigate structural retinal changes in malarial retinopathy (MR) using hand-held optical coherence tomography (HH-OCT) to investigate its diagnostic potential.Methods Children with MR (n=43) underwent ophthalmoscopy, fluorescein angiography and HH-OCT during admission, one month (n=31) and one year (n=8) post-discharge. Controls were comatose patients without malaria (n=6) and age/sex-matched healthy children (n=43). OCT changes and retinal layer thicknesses were compared.Results On HH-OCT hyper-reflective areas (HRAs) were seen in the inner retina of 81% of MR patients, corresponding to ischaemic retinal whitening. Cotton wool spots present in 37% and abnormal hyper-reflective dots, co-localized to capillary plexi, in 93%. Hyper-reflective vessel walls were present in 84%, and intra-retinal cysts in 9%. Vascular changes and cysts resolved within 48 hours. HRAs developed into retinal thinning at one month (p=0.027) which was more pronounced after one year (p=0...
Investigative Opthalmology & Visual Science, 2014
PURPOSE. We quantitatively investigated the peripapillary vascular morphology in patients with op... more PURPOSE. We quantitatively investigated the peripapillary vascular morphology in patients with optic nerve head drusen (ONHD) and optic disc edema (ODE). METHODS. Computer-based fundus analysis was used to investigate peripapillary vascular morphology, including length, branching, and diameter of arteries and veins calibrated by optical coherence tomography. RESULTS. Patients with ONHD showed significantly larger diameters of arteries without branching (P ¼ 0.05), and arteries after primary/before secondary branching (P ¼ 0.04) and secondary venous branching started closer to the optic disc (P ¼ 0.03) compared to healthy controls. The ODE patients had significantly reduced number of small peripapillary veins and larger number of veins without branching compared to ONHD and controls (P ¼ 0.02). Anomalous branching with arterial and venous trifurcation presented in the ODE and ONHD groups, with significant higher prevalence in ODE patients for venous trifurcations compared to ONHD and controls (P ¼ 0.02). CONCLUSIONS. The diameter of vessels in ONHD patients were significantly larger in arteries without branching (P ¼ 0.05), after primary branching (P ¼ 0.04), and venous branching closer to the disc area (P ¼ 0.03) compared to controls. The ODE patients demonstrated widening of the small peripapillary veins measured by a significantly larger number of veins without branching (P ¼ 0.001 and P ¼ 0.02, compared to controls and ONHD, respectively) and less small veins (P ¼ 0.001 and P ¼ 0.04, compared to controls and ONHD, respectively).
Investigative Opthalmology & Visual Science, 2009
PURPOSE. Nystagmus, which can be infantile (congenital) or acquired, affects all ages. The preval... more PURPOSE. Nystagmus, which can be infantile (congenital) or acquired, affects all ages. The prevalence of nystagmus in the general population is unknown. New genetic research and therapeutic modalities are emerging. Previous estimates have been based on wider ophthalmic epidemiologic studies within specific occupational or age groups. The authors carried out the first epidemiologic study to specifically establish the prevalence of nystagmus in Leicestershire and Rutland in the United Kingdom. METHODS. Three independent data sources identified persons with nystagmus from the hospital and community. The first was a hospital-based questionnaire and clinical survey (n ϭ 238). The visually impaired services (n ϭ 414) and education services (n ϭ 193) in Leicestershire provided the second and third separately obtained community-based sources of information. Capture-recapture statistical analysis was used to estimate prevalence. RESULTS. The prevalence of nystagmus in the general population was estimated to be 24.0 per 10,000 population (95% confidence interval [CI], Ϯ5.3). The most common forms of nystagmus were neurologic nystagmus (6.8 per 10,000 population; 95% CI, Ϯ4.6), nystagmus associated with low vision such as congenital cataracts (4.2 per 10,000; 95% CI, Ϯ1.2), and nystagmus associated with retinal diseases such as achromatopsia (3.4 per 10,000 population; 95% CI, Ϯ2.1). Within ethnic groups, nystagmus was significantly more common in the white European population than in the Asian (Indian, Pakistani, other Asian backgrounds) population (P ϭ 0.004). CONCLUSIONS. The findings suggest that nystagmus is more common in the general population than previously thought. This may be of significance in resource allocation and health care planning.
Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The famili... more Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The familial form is most commonly X-linked. We recently found mutations in a novel gene FRMD7 (Xq26.2), which provided an opportunity to investigate a genetically defined and homogeneous group of patients with nystagmus. We compared clinical features and eye movement recordings of 90 subjects with mutation in the gene (FRMD7 group) to 48 subjects without mutations but with clinical IIN (non-FRMD7 group). Fifty-eight female obligate carriers of the mutation were also investigated. The median visual acuity (VA) was 0.2 logMAR (Snellen equivalent 6/9) in both groups and most patients had good stereopsis. The prevalence of strabismus was also similar (FRMD7: 7.8%, non-FRMD7: 10%). The presence of anomalous head posture (AHP) was significantly higher in the non-FRMD7 group (P50.0001). The amplitude of nystagmus was more strongly dependant on the direction of gaze in the FRMD7 group being lower at primary position (P50.0001), compared to non-FRMD7 group (P = 0.83). Pendular nystagmus waveforms were also more frequent in the FRMD7 group (P = 0.003). Fifty-three percent of the obligate female carriers of an FRMD7 mutation were clinically affected. The VA's in affected females were slightly better compared to affected males (P = 0.014). Subnormal optokinetic responses were found in a subgroup of obligate unaffected carriers, which may be interpreted as a sub-clinical manifestation. FRMD7 is a major cause of X-linked IIN. Most clinical and eye movement characteristics were similar in the FRMD7 group and non-FRMD7 group with most patients having good VA and stereopsis and low incidence of strabismus. Fewer patients in the FRMD7 group had AHPs, their amplitude of nystagmus being lower in primary position. Our findings are helpful in the clinical identification of IIN and genetic counselling of nystagmus patients.
detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280... more detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.
Investigative Opthalmology & Visual Science, 2019
PURPOSE. Normal readers make immediate and precise adjustments in eye movements during sentence r... more PURPOSE. Normal readers make immediate and precise adjustments in eye movements during sentence reading in response to individual word features, such as lexical difficulty (e.g., common or uncommon words) or word length. Our purpose was to assess the effect of infantile nystagmus (IN) on these adaptive mechanisms. METHODS. Eye movements were recorded from 29 participants with IN (14 albinism, 12 idiopathic, and 3 congenital stationary night blindness) and 15 controls when reading sentences containing either common/uncommon words or long/short target words. Parameters assessed included: duration of first foveation/fixation, number of first-pass and percentage second-pass foveations/fixations, percentage words skipped, gaze duration, acquisition time (gaze þ nongaze duration), landing site locations, clinical and experimental reading speeds. RESULTS. Participants with IN could not modify first foveation durations in contrast to controls who made longer first fixations on uncommon words (P < 0.001). Participants with IN made more first-pass foveations on uncommon and long words (P < 0.001) to increase gaze durations. However, this also increased nongaze durations (P < 0.001) delaying acquisition times. Participants with IN reread shorter words more often (P < 0.005). Similar to controls, participants with IN landed more first foveations between the start and center of long words. Reading speeds during experiments were lower in IN participants compared to controls (P < 0.01). CONCLUSIONS. People with IN make more first-pass foveations on uncommon and long words influencing reading speeds. This demonstrates that the ''slow to see'' phenomenon occurs during word reading in IN. These deficits are not captured by clinical reading charts.
Nystagmus is an eye movement disorder characterised by abnormal, involuntary rhythmic oscillation... more Nystagmus is an eye movement disorder characterised by abnormal, involuntary rhythmic oscillations of one or both eyes, initiated by a slow phase. It is not uncommon in the UK and regularly seen in paediatric ophthalmology and adult general/ strabismus clinics. In some cases, it occurs in isolation, and in others, it occurs as part of a multisystem disorder, severe visual impairment or neurological disorder. Similarly, in some cases, visual acuity can be normal and in others can be severely degraded. Furthermore, the impact on vision goes well beyond static acuity alone, is rarely measured and may vary on a minute-to-minute, day-to-day or month-to-month basis. For these reasons, management of children with nystagmus in the UK is varied, and patients report hugely different experiences and investigations. In this review, we hope to shine a light on the current management of children with nystagmus across five specialist centres in the UK in order to present, for the first time, a consensus on investigation and clinical management.
Schizophrenia is associated with several brain deficits, as well as visual processing deficits, b... more Schizophrenia is associated with several brain deficits, as well as visual processing deficits, but clinically useful biomarkers are elusive. We hypothesized that retinal layer changes, noninvasively visualized using spectraldomain optical coherence tomography (SD-OCT), may represent a possible "window" to these abnormalities. Methods: A Leica EnvisuTM SD-OCT device was used to obtain high-resolution central foveal B-scans in both eyes of 35 patients with schizophrenia and 50 demographically matched controls. Manual retinal layer segmentation was performed to acquire individual and combined layer thickness measurements in 3 macular regions. Contrast sensitivity was measured at 3 spatial frequencies in a subgroup of each cohort. Differences were compared using adjusted linear models and significantly different layer measures in patients underwent Spearman Rank correlations with contrast sensitivity, quantified symptoms severity, disease duration, and antipsychotic medication dose. Results: Total retinal and photoreceptor complex thickness was reduced in all regions in patients (P < .0001). Segmentation revealed consistent thinning of the outer nuclear layer (P < .001) and inner segment layer (P < .05), as well as a pattern of parafoveal ganglion cell changes. Low spatial frequency contrast sensitivity was reduced in patients (P = .002) and correlated with temporal parafoveal ganglion cell complex thinning (R = .48, P = .01). Negative symptom severity was inversely correlated with foveal photoreceptor complex thickness (R = −.54, P = .001) and outer nuclear layer thickness (R = −.47, P = .005). Conclusions: Our novel findings demonstrate considerable retinal layer abnormalities in schizophrenia that are related to clinical features and visual function. With time, SD-OCT could provide easily-measurable biomarkers to facilitate clinical assessment and further our understanding of the disease.
Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation dis... more Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduce...
Background/aimsTo investigate the foveal morphology in carriers of oculocutaneous albinism (OCA) ... more Background/aimsTo investigate the foveal morphology in carriers of oculocutaneous albinism (OCA) using spectral domain optical coherence tomography (SD-OCT). A cross-sectional, observational study.MethodsHandheld SD-OCT (Envisu C2300) was used to acquire horizontal scans through the centre of the fovea in biological parents of patients with OCA (n=28; mean age±SD=40.43±8.07 years) and age-matched and ethnicity-matched controls (n=28; mean age±SD=38.04±10.27 years). Sequence analysis was performed for variants in known genes associated with OCA. Best-corrected visual acuity (BCVA), presence of foveal hypoplasia and grade, foveal, parafoveal and perifoveal thickness measurements of total retinal layers (TRL), inner retinal layers (IRL) and outer retinal layers (ORL) thickness were measured.ResultsFoveal hypoplasia was identified in 32.14% of OCA carriers; grade 1 in all cases. OCA carriers demonstrated significant thicker TRL thickness (median difference: 13.46 µm, p=0.009) and IRL th...
Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN h... more Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN has low prevalence, and twins with IN are rare. Whilst discordant presentation has been previously reported for IN, we present for the first time the comprehensive assessment of diagnostically discordant monozygotic twins. From a cohort of over 2000 patients, we identified twins and triplets discordant for nystagmus. Using next-generation sequencing, high-resolution infra-red pupil tracking and optical coherence tomography, we characterised differences in genotype and phenotype. Monozygotic twins (n = 1), dizygotic twins (n = 3) and triplets (n = 1) were included. The monozygotic twins had concordant TYR variants. No causative variants were identified in the triplets. Dizygotic twins had discordant variants in TYR, OCA2 and FRMD7. One unaffected co-twin demonstrated sub-clinical nystagmus. Foveal hypoplasia (FH) was noted in four of five probands. Both co-twins of the monozygotic pair and...
Normal foveal development begins in utero at midgestation with centrifugal displacement of inner ... more Normal foveal development begins in utero at midgestation with centrifugal displacement of inner retinal layers (IRLs) from the location of the incipient fovea. The outer retinal changes such as increase in cone cell bodies, cone elongation and packing mainly occur after birth and continue until 13 years of age. The maturity of the fovea can be assessed invivo using optical coherence tomography, which in normal development would show a well-developed foveal pit, extrusion of IRLs, thickened outer nuclear layer and long outer segments. Developmental abnormalities of various degrees can result in foveal hypoplasia (FH). This is a characteristic feature for example in albinism, aniridia, prematurity, foveal hypoplasia with optic nerve decussation defects with or without anterior segment dysgenesis without albinism (FHONDA) and optic nerve hypoplasia. In achromatopsia, there is disruption of the outer retinal layers with atypical FH. Similarly, in retinal dystrophies, there is abnormal ...
Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosoma... more Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development...
ObjectiveTo investigate (1) the feasibility of scanning the optic nerve (ON) and central retina w... more ObjectiveTo investigate (1) the feasibility of scanning the optic nerve (ON) and central retina with hand-held optical coherence tomography (HH-OCT) without sedation or anaesthesia in primary congenital glaucoma (PCG), (2) the characteristics of ON changes in comparison with adult primary open-angle glaucoma (POAG) in comparison with matched controls, (3) the sensitivity and specificity of ON parameters for diagnosis, and (4) changes of foveal morphology.Methods and analysisHH-OCT (Envisu 2300; Leica Microsystems) was used to investigate ON and foveal morphology of 20 children with PCG (mean age 4.64±2.79) and 10 adult patients with POAG (mean age 66.8±6.94), and compared with age-matched, gender-matched and ethnicity-matched healthy controls without sedation or anaesthesia.ResultsHH-OCT yielded useful data in 20 out of 24 young children with PCG. Patients with PCG had significantly deeper cup changes than patients with POAG (vs respective age-matched controls, p=0.014). ON changes ...
Herein we present a consanguineous family with three children affected by foveal hypoplasia with ... more Herein we present a consanguineous family with three children affected by foveal hypoplasia with infantile nystagmus, following an autosomal recessive mode of inheritance. The patients showed normal electroretinography responses, no signs of albinism, and no anterior segment or brain abnormalities. Upon whole exome sequencing, we identified a homozygous mutation (c.1861C4T;p.Q621*) in the aryl hydrocarbon receptor (AHR) gene that perfectly co-segregated with the disease in the larger family. AHR is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. Further, it has been shown to play a physiological role under normal cellular conditions, such as in immunity, inflammatory response and neurogenesis. Notably, knockout of the Ahr gene in mouse impairs optic nerve myelin sheath formation and results in oculomotor deficits sharing many features with our patients: the eye movement disorder in Ahr À/À mice appears early in development and presents as conjugate horizontal pendular nystagmus. We therefore propose AHR to be a novel disease gene for a new, recessively inherited disorder in humans, characterized by infantile nystagmus and foveal hypoplasia.
To investigate the morphology of the retina and optic nerve (ON) in microcephaly. This was a pros... more To investigate the morphology of the retina and optic nerve (ON) in microcephaly. This was a prospective case-control study including 27 patients with microcephaly and 27 healthy controls. All participants underwent ophthalmologic examination and handheld optical coherence tomography (OCT) of the macula and ON head. The thickness of individual retinal layers was quantified at the foveal center and the parafovea (1,000 μm nasal and temporal to the fovea). For the ON head, disc diameter, cup diameter, cup-to-disc ratio, cup depth, horizontal rim diameter, rim area, peripapillary retinal thickness, and retinal nerve fiber layer thickness were measured. Seventy-eight percent of patients had ophthalmologic abnormalities, mainly nystagmus (56%) and strabismus (52%). OCT abnormalities were found in 85% of patients. OCT revealed disruption of the ellipsoid zone, persistent inner retinal layers, and irregular foveal pits. Parafoveal retinal thickness was significantly reduced in patients wit...
Albinism is a group of congenital disorders of the melanin synthesis pathway. Multiple ocular, wh... more Albinism is a group of congenital disorders of the melanin synthesis pathway. Multiple ocular, white matter and cortical abnormalities occur in albinism, including a greater decussation of nerve fibres at the optic chiasm, foveal hypoplasia and nystagmus. Despite this, visual perception is largely preserved. We proposed that this may be attributable to reorganisation among cerebral networks, including an increased interhemispheric connectivity of the primary visual areas. We applied a graph-theoretic model to explore brain connectivity networks derived from resting-state functional and diffusion-tensor magnetic resonance imaging data in 23 people with albinism and 20 controls. We tested for group differences in connectivity between primary visual areas and in summary network organisation descriptors. We supplemented our main findings with analyses of control regions, brain volumes and white matter microstructure. We found significant functional interhemispheric hyperconnectivity of the primary visual areas in the albinism group (p=0.012). Tests of interhemispheric connectivity based on the diffusion-tensor data showed no significant group difference (p=0.713). Second, we found that a range of functional whole-brain network metrics were abnormal in people with albinism, including the clustering coefficient (p=0.005), although this may have been driven partly by overall differences in connectivity, rather than reorganisation. Based on our results, we suggest that changes occur in albinism at the whole-brain level, and not just within the visual processing pathways. We propose that our findings may reflect compensatory adaptations to increased chiasmic decussation, foveal hypoplasia and nystagmus.
Investigative Opthalmology & Visual Science, 2015
PURPOSE. To characterize the time course of normal foveal development in vivo in term infants and... more PURPOSE. To characterize the time course of normal foveal development in vivo in term infants and young children using handheld spectral-domain optical coherence tomography (HH-SDOCT). METHODS. We obtained 534 HH-SDOCT scans from 261 infants, children, and young adults with a mean age of 4.9 years (range, 0-27 years). Each retinal layer was manually segmented in ImageJ and correlated with gestational age (GA) and visual acuity (VA). The developmental trajectories of each retinal layer at the fovea, parafovea, and perifovea were calculated using fractional polynomial modeling. RESULTS. The central macular thickness (CMT) increases logarithmically between birth and 48.6 months GA. The foveal ganglion cell (GCL), inner plexiform, inner nuclear (INL), and outer plexiform layers decrease in thickness exponentially until 18 months GA. Interestingly, the parafoveal and perifoveal GCL and INL thicknesses initially decrease until 17 months GA and then increase in thickness until 65.5 GA. The foveal outer nuclear layer, inner segment, and outer segment of the photoreceptors increase in thickness logarithmically until 32.4, 26.9, and 45.3 months GA, respectively. The parafoveal and perifoveal outer retinal layers increase in thickness more gradually until 146 months GA. The thickness of the outer retinal layers and CMT were strongly correlated with VA, with r ¼ 0.54 (P < 0.0001) and r ¼ 0.52 (P < 0.0001), respectively. CONCLUSIONS. We have modeled for the first time the complex, nonlinear developmental trajectories for each retinal layer and demonstrate that development continues until adolescence. Our description of normal development will be helpful in diagnosing, monitoring, and understanding pediatric retinal disease.
Purpose We aimed to investigate structural retinal changes in malarial retinopathy (MR) using han... more Purpose We aimed to investigate structural retinal changes in malarial retinopathy (MR) using hand-held optical coherence tomography (HH-OCT) to investigate its diagnostic potential.Methods Children with MR (n=43) underwent ophthalmoscopy, fluorescein angiography and HH-OCT during admission, one month (n=31) and one year (n=8) post-discharge. Controls were comatose patients without malaria (n=6) and age/sex-matched healthy children (n=43). OCT changes and retinal layer thicknesses were compared.Results On HH-OCT hyper-reflective areas (HRAs) were seen in the inner retina of 81% of MR patients, corresponding to ischaemic retinal whitening. Cotton wool spots present in 37% and abnormal hyper-reflective dots, co-localized to capillary plexi, in 93%. Hyper-reflective vessel walls were present in 84%, and intra-retinal cysts in 9%. Vascular changes and cysts resolved within 48 hours. HRAs developed into retinal thinning at one month (p=0.027) which was more pronounced after one year (p=0...
Investigative Opthalmology & Visual Science, 2014
PURPOSE. We quantitatively investigated the peripapillary vascular morphology in patients with op... more PURPOSE. We quantitatively investigated the peripapillary vascular morphology in patients with optic nerve head drusen (ONHD) and optic disc edema (ODE). METHODS. Computer-based fundus analysis was used to investigate peripapillary vascular morphology, including length, branching, and diameter of arteries and veins calibrated by optical coherence tomography. RESULTS. Patients with ONHD showed significantly larger diameters of arteries without branching (P ¼ 0.05), and arteries after primary/before secondary branching (P ¼ 0.04) and secondary venous branching started closer to the optic disc (P ¼ 0.03) compared to healthy controls. The ODE patients had significantly reduced number of small peripapillary veins and larger number of veins without branching compared to ONHD and controls (P ¼ 0.02). Anomalous branching with arterial and venous trifurcation presented in the ODE and ONHD groups, with significant higher prevalence in ODE patients for venous trifurcations compared to ONHD and controls (P ¼ 0.02). CONCLUSIONS. The diameter of vessels in ONHD patients were significantly larger in arteries without branching (P ¼ 0.05), after primary branching (P ¼ 0.04), and venous branching closer to the disc area (P ¼ 0.03) compared to controls. The ODE patients demonstrated widening of the small peripapillary veins measured by a significantly larger number of veins without branching (P ¼ 0.001 and P ¼ 0.02, compared to controls and ONHD, respectively) and less small veins (P ¼ 0.001 and P ¼ 0.04, compared to controls and ONHD, respectively).
Investigative Opthalmology & Visual Science, 2009
PURPOSE. Nystagmus, which can be infantile (congenital) or acquired, affects all ages. The preval... more PURPOSE. Nystagmus, which can be infantile (congenital) or acquired, affects all ages. The prevalence of nystagmus in the general population is unknown. New genetic research and therapeutic modalities are emerging. Previous estimates have been based on wider ophthalmic epidemiologic studies within specific occupational or age groups. The authors carried out the first epidemiologic study to specifically establish the prevalence of nystagmus in Leicestershire and Rutland in the United Kingdom. METHODS. Three independent data sources identified persons with nystagmus from the hospital and community. The first was a hospital-based questionnaire and clinical survey (n ϭ 238). The visually impaired services (n ϭ 414) and education services (n ϭ 193) in Leicestershire provided the second and third separately obtained community-based sources of information. Capture-recapture statistical analysis was used to estimate prevalence. RESULTS. The prevalence of nystagmus in the general population was estimated to be 24.0 per 10,000 population (95% confidence interval [CI], Ϯ5.3). The most common forms of nystagmus were neurologic nystagmus (6.8 per 10,000 population; 95% CI, Ϯ4.6), nystagmus associated with low vision such as congenital cataracts (4.2 per 10,000; 95% CI, Ϯ1.2), and nystagmus associated with retinal diseases such as achromatopsia (3.4 per 10,000 population; 95% CI, Ϯ2.1). Within ethnic groups, nystagmus was significantly more common in the white European population than in the Asian (Indian, Pakistani, other Asian backgrounds) population (P ϭ 0.004). CONCLUSIONS. The findings suggest that nystagmus is more common in the general population than previously thought. This may be of significance in resource allocation and health care planning.
Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The famili... more Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The familial form is most commonly X-linked. We recently found mutations in a novel gene FRMD7 (Xq26.2), which provided an opportunity to investigate a genetically defined and homogeneous group of patients with nystagmus. We compared clinical features and eye movement recordings of 90 subjects with mutation in the gene (FRMD7 group) to 48 subjects without mutations but with clinical IIN (non-FRMD7 group). Fifty-eight female obligate carriers of the mutation were also investigated. The median visual acuity (VA) was 0.2 logMAR (Snellen equivalent 6/9) in both groups and most patients had good stereopsis. The prevalence of strabismus was also similar (FRMD7: 7.8%, non-FRMD7: 10%). The presence of anomalous head posture (AHP) was significantly higher in the non-FRMD7 group (P50.0001). The amplitude of nystagmus was more strongly dependant on the direction of gaze in the FRMD7 group being lower at primary position (P50.0001), compared to non-FRMD7 group (P = 0.83). Pendular nystagmus waveforms were also more frequent in the FRMD7 group (P = 0.003). Fifty-three percent of the obligate female carriers of an FRMD7 mutation were clinically affected. The VA's in affected females were slightly better compared to affected males (P = 0.014). Subnormal optokinetic responses were found in a subgroup of obligate unaffected carriers, which may be interpreted as a sub-clinical manifestation. FRMD7 is a major cause of X-linked IIN. Most clinical and eye movement characteristics were similar in the FRMD7 group and non-FRMD7 group with most patients having good VA and stereopsis and low incidence of strabismus. Fewer patients in the FRMD7 group had AHPs, their amplitude of nystagmus being lower in primary position. Our findings are helpful in the clinical identification of IIN and genetic counselling of nystagmus patients.
detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280... more detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.
Investigative Opthalmology & Visual Science, 2019
PURPOSE. Normal readers make immediate and precise adjustments in eye movements during sentence r... more PURPOSE. Normal readers make immediate and precise adjustments in eye movements during sentence reading in response to individual word features, such as lexical difficulty (e.g., common or uncommon words) or word length. Our purpose was to assess the effect of infantile nystagmus (IN) on these adaptive mechanisms. METHODS. Eye movements were recorded from 29 participants with IN (14 albinism, 12 idiopathic, and 3 congenital stationary night blindness) and 15 controls when reading sentences containing either common/uncommon words or long/short target words. Parameters assessed included: duration of first foveation/fixation, number of first-pass and percentage second-pass foveations/fixations, percentage words skipped, gaze duration, acquisition time (gaze þ nongaze duration), landing site locations, clinical and experimental reading speeds. RESULTS. Participants with IN could not modify first foveation durations in contrast to controls who made longer first fixations on uncommon words (P < 0.001). Participants with IN made more first-pass foveations on uncommon and long words (P < 0.001) to increase gaze durations. However, this also increased nongaze durations (P < 0.001) delaying acquisition times. Participants with IN reread shorter words more often (P < 0.005). Similar to controls, participants with IN landed more first foveations between the start and center of long words. Reading speeds during experiments were lower in IN participants compared to controls (P < 0.01). CONCLUSIONS. People with IN make more first-pass foveations on uncommon and long words influencing reading speeds. This demonstrates that the ''slow to see'' phenomenon occurs during word reading in IN. These deficits are not captured by clinical reading charts.
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Papers by Irene Gottlob