Visual Dysfunction Research Articles

Discernibility of the Interdigitation Zone (IZ), a Potential Optical Coherence Tomography (OCT) Biomarker for Visual Dysfunction in Aging

Purpose Photoreceptor (PR) outer segments, retinal pigment epithelium apical processes, and inter-PR matrix contribute to the interdigitation zone (IZ) of optical coherence tomography (OCT). We hypothesize that this interface degrades over adulthood, in concert with a delay of rod mediated dark adaptation (RMDA). To explore this idea, we determined IZ discernibility and RMDA in younger and older adults. Methods For this cross-sectional study, eyes of 20 young (20–30 years) and 40 older (≥60 years) participants with normal maculas according to the AREDS 9-step grading system underwent OCT imaging and RMDA testing at 5° superior to the fovea. Custom FIJI plugins enabled analysis for IZ discernibility at 9 eccentricities in 0.5 mm steps on one single horizontal B-scan through the fovea. Locations with discernible IZ met two criteria: visibility on B-scans and a distinct peak on a longitudinal reflectivity profile. The frequency of sites meeting both criteria was compared between both age groups and correlated with rod intercept time (RIT). Results The median number of locations with discernible IZ was significantly higher (foveal, 4 vs. 0, p = 0.0099; extra-foveal 6 vs. 0, p < 0.001) in eyes of young (26 ± 3 years) compared to older (73 ± 5 years) participants. For the combined young and older sample, the higher frequency of discernible IZ was correlated with shorter RIT (faster dark adaptation) (r s = –0.56, p < 0.0001). This association was significant within young eyes (r s = –0.54; p = 0.0134) and not within older eyes (r s = –0.29, p = 0.706). Conclusions Results suggest that the interface between outer segments and apical processes degrades in normal aging, potentially contributing to delayed rod-mediated dark adaptation. More research is needed to verify an age-related association between IZ discernibility and rod-mediated dark adaptation. If confirmed in a large sample, IZ discernibility might prove to be a valuable biomarker and predictor for visual function in aging.

Bringing continuous target-tracking to the clinic: Steps toward developing new tools for assessing visual dysfunction

Bringing continuous target-tracking to the clinic: Steps toward developing new tools for assessing visual dysfunction

К вопросу о клинической сути содружественного косоглазия, функциональных нарушениях и распространении в популяции

The presented literature review summarizes existent data of domestic and foreign researchers devoted to the clinical nature of strabismus, functional disorders in this pathology and its frequency in the population. The description of the main theories of the occurrence of strabismus was given by: A. Grefe, F. Donders, A. Parino and S. Worth. The spectrum of opinions on the types of inheritance of strabismus is analyzed. Patients with concomitant strabismus have also several functional disorders, such as binocular vision dysfunction and refractive-strabismus amblyopia. The views of leading ophthalmologists E.S. Avetisov, E.E. Somov, S.I. Rychkov, K.J. Ciuffreda and others on amblyopia, the criteria for diagnosis and its various classifications are presented. The considered studies allow us to conclude – treatment of children with concomitant strabismus remains a complex and multidisciplinary problem today. The knowledge of the functional features of various types of concomitant strabismus allows pathogenetically justified treatment of this pathology. Key words: concomitant strabismus, theories of the occurrence of strabismus, amblyopia, genetics of concomitant strabismus

Structured light enhanced entoptic stimuli for vision science applications.

The dichroic macular pigment in the Henle fiber layer in the fovea enables humans to perceive entoptic phenomena when viewing polarized blue light. In the standard case of linearly polarized stimuli, a faint bowtie-like pattern known as the Haidinger's brush appears in the central point of fixation. As the shape and clarity of the perceived signal is directly related to the health of the macula, Haidinger's brush has been used as a diagnostic marker in studies of early stage macular degeneration and central field visual dysfunction. However, due to the weak nature of the perceived signal the perception of the Haidinger's brush has not been integrated with modern clinical methods. Recent attempts have been made to increase the strength of the perceived signal by employing structured light with spatially varying polarization profiles. Here we review the advancements with the structured light stimuli and describe the current challenges and future prospects.

Inhibition of complement C3 signaling ameliorates locomotor and visual dysfunction in autoimmune inflammatory diseases

Neuromyelitis optica (NMO) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by transverse myelitis and optic neuritis. The pathogenic serum IgG antibody against the aquaporin-4 (AQP4) on astrocytes triggers the activation of the complement cascade, causing astrocyte injury, followed by oligodendrocyte injury, demyelination, and neuronal loss. Complement C3 is positioned as a central player that relays upstream initiation signals to activate downstream effectors, potentially stimulating and amplifying host immune and inflammatory responses. However, whether targeting the inhibition of C3 signaling could ameliorate tissue injury, locomotor defects, and visual impairments in NMO remains to be investigated. In this study, using the targeted C3 inhibitor CR2-Crry led to a significant decrease in complement deposition and demyelination in both slice cultures and focal intracerebral injection models. Moreover, the treatment downregulated the expression of inflammatory cytokines and improved motor dysfunction in a systemic NMO mouse model. Similarly, employing serotype 2/9 adeno-associated virus (AAV2/9) to induce permanent expression of CR2-Crry resulted in a reduction in visual dysfunction by attenuating NMO-like lesions. Our findings reveal the therapeutic value of inhibiting the complement C3 signaling pathway in NMO.

Predicting visual acuity with machine learning in treated ocular trauma patients.

To predict best-corrected visual acuity (BCVA) by machine learning in patients with ocular trauma who were treated for at least 6mo. The internal dataset consisted of 850 patients with 1589 eyes and an average age of 44.29y. The initial visual acuity was 0.99 logMAR. The test dataset consisted of 60 patients with 100 eyes collected while the model was optimized. Four different machine-learning algorithms (Extreme Gradient Boosting, support vector regression, Bayesian ridge, and random forest regressor) were used to predict BCVA, and four algorithms (Extreme Gradient Boosting, support vector machine, logistic regression, and random forest classifier) were used to classify BCVA in patients with ocular trauma after treatment for 6mo or longer. Clinical features were obtained from outpatient records, and ocular parameters were extracted from optical coherence tomography images and fundus photographs. These features were put into different machine-learning models, and the obtained predicted values were compared with the actual BCVA values. The best-performing model and the best variable selected were further evaluated in the test dataset. There was a significant correlation between the predicted and actual values [all Pearson correlation coefficient (PCC)>0.6]. Considering only the data from the traumatic group (group A) into account, the lowest mean absolute error (MAE) and root mean square error (RMSE) were 0.30 and 0.40 logMAR, respectively. In the traumatic and healthy groups (group B), the lowest MAE and RMSE were 0.20 and 0.33 logMAR, respectively. The sensitivity was always higher than the specificity in group A, in contrast to the results in group B. The classification accuracy and precision were above 0.80 in both groups. The MAE, RMSE, and PCC of the test dataset were 0.20, 0.29, and 0.96, respectively. The sensitivity, precision, specificity, and accuracy of the test dataset were 0.83, 0.92, 0.95, and 0.90, respectively. Predicting BCVA using machine-learning models in patients with treated ocular trauma is accurate and helpful in the identification of visual dysfunction.

Aberrant spontaneous brain activity in patients with thyroid-associated ophthalmopathy with and without optic neuropathy: a resting-state functional MRI study.

To investigate the brain functional alterations in dysthyroid optic neuropathy (DON) by evaluating spontaneous neural activity, using functional magnetic resonance imaging (fMRI) with regional homogeneity (ReHo), and its relationship with ophthalmologic performance. Forty-seven patients with thyroid-associated ophthalmopathy (TAO; 20 with DON, 27 with non-DON) and 33 age-, sex-, and education-matched healthy controls (HCs) underwent fMRI. ReHo values were compared using one-way analysis of variance (ANOVA) with post hoc pairwise comparisons (voxel-level p < 0.01, Gaussian random field correction, cluster-level p < 0.05). Correlations between ReHo values and ophthalmological metrics were assessed for DONs, with Bonferroni correction for multiple comparisons (p < 0.004). ROC curves were applied to evaluate the diagnostic performance of ReHo metrics. ReHo values were significantly lower in the left insula and right superior temporal gyrus, and higher in the left posterior cingulate cortex (LPCC), of DON than of non-DON patients. ReHo values were also significantly lower in the right middle temporal, left insula, and left precentral gyrus in DON than in HCs. Meanwhile, ReHo values were higher in LPCC in non-DON than in HCs. ReHo values correlated with ophthalmic examinations to varying degrees in DON. For distinguishing DON, the ReHo values in LPCC showed optimal individually (AUC = 0.843), the combination of the ReHo in both the left insula and LPCC performed better (AUC = 0.915). Spontaneous brain activity differed between TAO with and without DON, which may reflect the underlying pathological mechanism of DON. The ReHo index can be considered a diagnostic biomarker. Spontaneous brain activity in DON differed from that in TAO without DON, which may reflect the underlying pathological mechanism of DON. The ReHo index can be considered a diagnostic biomarker for early detection of DON. • Dysthyroid optic neuropathy (DON) affects brain activity, which contributes in the understanding of its visual dysfunction. • Regional homogeneity values differ between thyroid-associated ophthalmopathy with and without DON in various brain regions. • Regional homogeneity values can be used as a biomarker in the differential diagnosis of DON.

Pathogenesis, clinical features and treatment of anti‐IgLON5 disease

AbstractAnti‐immunoglobulin‐like cell adhesion molecule 5 (IgLON5) disease is an autoimmune encephalitis that targets the cell adhesion molecule, IgLON5. The disease presents with various clinical features, including sleep disorders, bulbar palsy, movement disorders, cognitive dysfunction and neuromuscular manifestations. Sleep disorders are characterized by parasomnias and sleep‐disordered breathing (stridor and sleep apnea). Bulbar palsy includes dysarthria, dysphagia, vocal cord paralysis and stridor. Movement disorders include a variety of symptoms and signs, such as chorea, dystonia, rigidity, tremor, myoclonus and myorhythmia. Cognitive dysfunction includes executive dysfunction, impairment of attention, and verbal and visual memory dysfunction. Neuromuscular manifestations include fasciculations in the tongue and peripheral muscles, limb weakness, and muscle atrophy. Some patients resemble those with neurodegenerative diseases, such as progressive supranuclear palsy or amyotrophic lateral sclerosis. On video polysomnography, undifferentiated non‐rapid eye movement sleep and poorly structured N2 sleep are characteristic. Brain magnetic resonance imaging and cerebrospinal fluid studies are often normal or non‐specific. Human leukocyte antigen testing shows that HLA‐DRB1*10:01‐DQB1*05:01 is highly associated with the disease. Pathologically, neuronal deposition of both hyperphosphorylated 3‐repeat and 4‐repeat tau isoforms, neuronal loss, and gliosis in the hypothalamus, brainstem tegmentum, and upper cervical cord are observed. Some patients are responsive to immunotherapies, such as steroids, intravenous immunoglobulin, plasma exchange therapy and rituximab. Factors associated with a favorable response to immunotherapies include early initiation of treatment, cerebrospinal fluid inflammation and immunoglobulin G1 (IgG1) predominance of IgLON5 antibody compared with immunoglobulin G4 (IgG4). Anti‐IgLON5 disease should be suspected in patients with atypical movement disorders complicated by sleep disturbances.

Consensus recommendations for clinical assessment tools for the diagnosis of posterior cortical atrophy syndrome from the Atypical AD PIA of ISTAART.

Delay in diagnosis of posterior cortical atrophy (PCA) syndrome is common, and the lack of familiarity with assessment tools for identifying visual cortical dysfunction is a contributing factor. We propose recommendations for the approach to the evaluation of PCA clinical features during the office visit, the neuropsychological evaluation, and the research setting. A recommended screening battery for eye clinics is also proposed. Recommendations were developed using results from a web-based survey of members of Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Atypical Alzheimer's Disease Professional Interest Area (PIA), literature review, and consensus by the PCA assessment working party of the Atypical Alzheimer's Disease PIA. Survey results revealed robust agreement for assessment tool preferences for PCA features, and many respondents indicated that they reserve assessment tools for use only when PCA is suspected. For some PCA features, curated tools were preferred over validated battery tools, particularly for the office visit. Consensus recommendations superseded survey preferences for two core cognitive features within the 2017 PCA diagnostic criteria. These consensus recommendations provide an evaluation framework for PCA clinical features and can facilitate timely and accurate recognition and diagnosis of PCA. Broader use of these tools should be sought, and development and validation of novel PCA clinical outcome assessments are needed to improve our understanding of atypical AD and other dementias and support the inclusion of those with PCA in treatment trials.

Visual Dysfunction is a Risk Factor of Postoperation Delirium in Parkinson Disease

To investigate the incidence of and factors influencing postoperative delirium (POD) in Parkinson's disease after deep brain stimulation (DBS) surgery. A total of 272 patients with Parkinson's disease who underwent DBS completed the Visual Impairment in Parkinson's Disease Questionnaire (VIPD-Q) and underwent neuro-ophthalmologic examinations including optical coherence tomography and fundus vessel analysis. We retrospect the prevalence of POD in groups with different VIPD-Q scores, retinal nerve fiber layer (RNFL) thicknesses, and vessel percentage areas (VPA). A predictive model based on the VIPD-Q was constructed using multivariate logistic regression and verified using bootstrap validation. POD was experienced by 65 (23.9 %) of 272 patients. Patients with PD who had visual impairment (VIPD-Q > 6) had a higher incidence of POD (chi-square, p <0.001). The thickness of the retinal nerve fiber layer and vessel percentage area were also correlated with POD risk. Differences in implantation locations (subthalamic nucleus or pars interna of globus pallidus), operation times, and general anesthesia times did not affect the prevalence of DBS-related POD. A nomogram was constructed based on ophthalmic events to predict the risk of POD. The study findings provide convincing evidence of the relationship between visual dysfunction and the risk of POD. In view of the higher risk of POD, visually impaired patients with PD should undergo closer monitoring after DBS surgery.

Frontalis Suspension Surgery for Patients with Essential Blepharospasm Unresponsive to Botulinum Toxin Injections

Purpose: To report the efficacy of frontalis suspension using a silicone rod or preserved fascia lata for patients with blepharospasm who exhibit persistent symptoms and visual dysfunction unresponsive to botulinum injections.Methods: The clinical records of five patients (10 eyes) with essential blepharospasm who underwent frontalis suspension were reviewed. Patients who continued to report eyelid-opening difficulties despite prior administration of botulinum toxin were included.Results: The mean patient age was 60.2 years; and 40% of the patients were women. The frontalis was suspended using silicone rods (n = 3) or preserved fascia lata (n = 2). Blepharospasm frequency and severity were measured using the Jankovic Rating Scale (JRS). Compared with preoperative scores, the summed JRS scores decreased 1 week, 1 month, and 3 months after surgery. Postoperatively, two patients (40%) did not require further botulinum toxin injections. In three patients, the intervals between injections were increased after surgery. No patient experienced any significant complication.Conclusions: Frontalis suspension is safe and effective for patients with blepharospasm and apraxia of eyelid opening, who have not responded to botulinum toxin injections.

Visual Behaviours (ViBes) in Cerebral Visual Impairment: Validating a Descriptive Tool to Support Diagnosis and Monitoring.

Cerebral visual impairment (CVI) is the most common cause of visual impairment in children in the UK. Diagnosis is based on identification of visual behaviours (ViBes) relating to visual dysfunction. Examination techniques and inventories have been developed to elicit these in children with a developmental age of two years or more. The absence of a structured approach to recording visual behaviours in children with complex needs is a barrier to diagnosis. The aim of the study was to develop a matrix of visual behaviours seen in pre-verbal and pre-motor children with visual impairment and establish its content validity and inter-rater reliability. ViBe content validation:: Visual behaviour descriptors relating to visual function were collated and categorised by expert consensus of vision professionals into a matrix composed of three functions (attention, field/fixation, motor response) and five levels (0 = no awareness; 1 = visual awareness; 2 = visual attention; 3 = visual detection; 4 = visual understanding).ViBe inter-rater reliability:: The participants (two orthoptists, an optometrist, an ophthalmologist and two qualified teachers of the visually impaired) used the ViBe matrix to independently score each of 17 short video clips of children demonstrating visual behaviours seen in CVI. The ViBe matrix will be presented. Cohen's kappa for the matrix was 0.67, demonstrating moderate-to-strong inter-rater reliability. The development of standardised descriptors can support clinicians and teachers in identifying areas of concern for children with complex needs. In addition, the ViBe matrix could be utilised in research, clinical and diagnostic reports to clearly communicate the areas of visual dysfunction and track progress resulting from interventions. The absence of a structured approach to recording visual behaviours in children with complex needs is a barrier to diagnosis.The ViBe matrix offers descriptors relating to visual behaviours and has demonstrated acceptable inter-rater reliability.The tool may support the identification and diagnosis of cerebral visual impairment in a population of children who cannot access standard testing.

Substantia nigral dopamine transporter uptake in dementia with Lewy bodies

Nigrostriatal dopaminergic degeneration is a pathological hallmark of dementia with Lewy bodies (DLB). To identify the subregional dopamine transporter (DAT) uptake patterns that improve the diagnostic accuracy of DLB, we analyzed N-(3-[18F] fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)-nortropane (FP-CIT) PET in 51 patients with DLB, in 36 patients with mild cognitive impairment with Lewy body (MCI-LB), and in 40 healthy controls (HCs). In addition to a high affinity for DAT, FP-CIT show a modest affinity to serotonin or norepinephrine transporters. Specific binding ratios (SBRs) of the nigrostriatal subregions were transformed to age-adjusted z-scores (zSBR) based on HCs. The diagnostic accuracy of subregional zSBRs were tested using receiver operating characteristic (ROC) curve analyses separately for MCI-LB and DLB versus HCs. Then, the effect of subregional zSBRs on the presence of clinical features and gray matter (GM) density were evaluated in all patients with MCI-LB or DLB as a group. ROC curve analyses showed that the diagnostic accuracy of DLB based on the zSBR of substantia nigra (area under the curve [AUC], 0.90) or those for MCI-LB (AUC, 0.87) were significantly higher than that based on the zSBR of posterior putamen for DLB (AUC, 0.72) or MCI-LB (AUC, 0.65). Lower zSBRs in nigrostriatal regions were associated with visual hallucination, severe parkinsonism, and cognitive dysfunction, while lower zSBR of substantia nigra was associated with widespread GM atrophy in DLB and MCI-LB patients. Taken together, our results suggest that evaluation of nigral DAT uptake may increase the diagnostic accuracy of DLB and MCI-LB than other striatal regions.

Retinal degeneration in rpgra mutant zebrafish.

Introduction: Pathogenic mutations in RPGR ORF15, one of two major human RPGR isoforms, were responsible for most X-linked retinitis pigmentosa cases. Previous studies have shown that RPGR plays a critical role in ciliary protein transport. However, the precise mechanisms of disease triggered by RPGR ORF15 mutations have yet to be clearly defined. There are two homologous genes in zebrafish, rpgra and rpgrb. Zebrafish rpgra has a single transcript homologous to human RPGR ORF15; rpgrb has two major transcripts: rpgrb ex1-17 and rpgrb ORF15, similar to human RPGR ex1-19 and RPGR ORF15, respectively. rpgrb knockdown in zebrafish resulted in both abnormal development and increased cell death in the dysplastic retina. However, the impact of knocking down rpgra in zebrafish remains undetermined. Here, we constructed a rpgra mutant zebrafish model to investigate the retina defect and related molecular mechanism. Methods: we utilized transcription activator-like effector nuclease (TALEN) to generate a rpgra mutant zebrafish. Western blot was used to determine protein expression. RT-PCR was used to quantify gene transcription levels. The visual function of embryonic zebrafish was detected by electroretinography. Immunohistochemistry was used to observe the pathological changes in the retina of mutant zebrafish and transmission electron microscope was employed to view subcellular structure of photoreceptor cells. Results: A homozygous rpgra mutant zebrafish with c.1675_1678delins21 mutation was successfully constructed. Despite the normal morphological development of the retina at 5 days post-fertilization, visual dysfunction was observed in the mutant zebrafish. Further histological and immunofluorescence assays indicated that rpgra mutant zebrafish retina photoreceptors progressively began to degenerate at 3-6 months. Additionally, the mislocalization of cone outer segment proteins (Opn1lw and Gnb3) and the accumulation of vacuole-like structures around the connecting cilium below the OSs were observed in mutant zebrafish. Furthermore, Rab8a, a key regulator of opsin-carrier vesicle trafficking, exhibited decreased expression and evident mislocalization in mutant zebrafish. Discussion: This study generated a novel rpgra mutant zebrafish model, which showed retinal degeneration. our data suggested Rpgra is necessary for the ciliary transport of cone-associated proteins, and further investigation is required to determine its function in rods. The rpgra mutant zebrafish constructed in this study may help us gain a better understanding of the molecular mechanism of retinal degeneration caused by RPGR ORF15 mutation and find some useful treatment in the future.

P.141 The value of using flash visual evoked potentials monitoring during minimally invasive endoscopic meningioma resection: a retrospective chart review

Background: Endoscopic endonasal surgeries performed in areas involving the visual pathway are associated with postoperative visual dysfunction. We previously demonstrated that continued eye monitoring during surgery by flash visual evoked potential (FVEP) represents a good method to prevent/reduce visual deficit post-surgery. We wondered whether FVEP monitoring may be more beneficial in patients with meningioma, strongly associated with postoperative visual loss.The aim was to explore the visual capacity in patients subjected to meningioma resection at The Ottawa Hospital. Methods: A retrospective chart review of patients who underwent minimally invasive endoscopic skull base surgery and FVEP monitoring for meningioma resection (July 2018 to present) was conducted. Only patients with available pre- (up to 3 months) and post-surgery (1-9 months) visual evaluation were analyzed. Results: 40 eyes were included (20 patients). The median age was 61 years (range:43-84) and 90% of patients were female. The LogMAR visual acuity was not significantly modified post-surgery (from +0.25 to +0.21; p=0.7). Color vision (# errors reading Ishihara/16-plates) was not modified post-surgery (from 2.6 to 3.2; p=0.6). Visual field (Humphrey, 32-2) was not significantly modified post-surgery (from 78.1% to 81.9%; p=0.7). Conclusions: The prevention of visual pathway injury during surgery by FVEP monitoring prevents visual deficits after endoscopic meningioma resection.

Visual evoked potentials waveform analysis to measure intracortical damage in a preclinical model of multiple sclerosis.

Visual evoked potentials (VEPs) are a non-invasive technique routinely used in clinical and preclinical practice. Discussion about inclusion of VEPs in McDonald criteria, used for Multiple Sclerosis (MS) diagnosis, increased the importance of VEP in MS preclinical models. While the interpretation of the N1 peak is recognized, less is known about the first and second positive VEP peaks, P1 and P2, and the implicit time of the different segments. Our hypothesis is that P2 latency delay describes intracortical neurophysiological dysfunction from the visual cortex to the other cortical areas. In this work, we analyzed VEP traces that were included in our two recently published papers on Experimental Autoimmune Encephalomyelitis (EAE) mouse model. Compared with these previous publications other VEP peaks, P1 and P2, and the implicit time of components P1-N1, N1-P2 and P1-P2, were analyzed in blind. Latencies of P2, P1-P2, P1-N1 and N1-P2 were increased in all EAE mice, including group without N1 latency change delay at early time points. In particular, at 7 dpi the P2 latency delay change was significantly higher compared with N1 latency change delay. Moreover, new analysis of these VEP components under the influence of neurostimulation revealed a decrease in P2 delay in stimulated animals. P2 latency delay, P1-P2, P1-N1, and N1-P2 latency changes which reflect intracortical dysfunction, were consistently detected across all EAE groups before N1 change. Results underline the importance of analyzing all VEP components for a complete overview of the neurophysiological visual pathway dysfunction and treatment efficacy.

0912 Striatal atrophy and clinical correlates in REM sleep behavior disorder

Abstract Introduction Idiopathic/isolated REM sleep behavior disorder (iRBD) is regarded as the most specific prodromal stage of ⍺-synucleinopathies including Parkinson’s disease (PD). Striatal dopamine dysfunction is a pathological hallmark in PD, which has been similarly reported in iRBD as a sensitive marker for detecting early ⍺-synucleinopathies. In contrary, although there is a broad consensus that patients with PD have striatal volumes reduction, studies in iRBD are relatively scarce and inconsistent. In this study, we aim to investigate the difference of striatal nuclei volumes between iRBD and controls and their correlation with clinical presentations. Methods Altogether 105 patients (mean age=68.19, male 76.2%) with polysomnography-confirmed iRBD and 85 age and sex comparable controls (mean age=66.74, male 64.7%) underwent 3-tesla MRI and clinical assessments. FreeSurfer automatic segmentation pipelines measured the size of bilateral striatal nuclei including caudate, putamen, pallidum and accumbens area. The comparisons of the volume of individual striatal nucleus were made between iRBD and controls with age, sex, handness, and total intracranial volume as covariates. Correlations were performed to investigate the association between striatal nuclei volume and clinical domains in motor (Unified Parkinson’s Disease Rating Scale, Part III), cognitive (Montreal Cognitive Assessment, MoCA), visual (pareidolia), autonomic function (Scales for Outcomes in Parkinson’s Disease - Autonomic Dysfunction, SCOPA-AUT) and mood symptoms (Hospital Anxiety and Depression Scale). Results There were smaller volumes in the bilateral putamen (t=-2.13/-2.32, p=0.03/0.02, left/right side respectively) and accumbens area (t=-2.58/-2.07, p=0.01/0.04, left/right side respectively) in iRBD comparing to controls. In addition, MoCA score was significantly positively correlated with the volumes of bilateral putamen (r=0.212/0.213, p=0.032/0.033), while pareidolia score was significantly negatively correlated with volumes of bilateral putamen (r=-0.205/-0.233, p=0.039/0.018,) and accumbens area (r=-0.249/-0.279, p=0.012/0.004, left/right respectively). The SCOPA-AUT score was significantly negatively correlated with volumes of the left putamen (r=-0.286, p=0.014) and the left accumbens area (r=-0.245, p=0.037). No other correlations with mood and motor features were found. Conclusion In this large case-control study, PD-like striatal atrophy was already present in patients with iRBD, which were significantly associated with worse cognitive performance, visual and autonomic dysfunction. Support (if any) This study was supported by Hong Kong Health and Medical Research Fund, 08191416.

DAPTA, a C-C Chemokine Receptor 5 (CCR5), Leads to the Downregulation of Notch/NF-κB Signaling and Proinflammatory Mediators in CD40+ Cells in Experimental Autoimmune Encephalomyelitis Model in SJL/J Mice.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system characterized by motor deficits, cognitive impairment, fatigue, pain, and sensory and visual dysfunction. CD40, highly expressed in B cells, plays a significant role in MS pathogenesis. The experimental autoimmune encephalomyelitis (EAE) mouse model of MS has been well established, as well as its relevance in MS patients. This study aimed to evaluate the therapeutic potential of DAPTA, a selective C-C chemokine receptor 5 (CCR5) antagonist in the murine model of MS, and to expand the knowledge of its mechanism of action. Following the induction of EAE, DAPTA was administrated (0.01 mg/kg, i.p.) daily from day 14 to day 42. We investigated the effects of DAPTA on NF-κB p65, IκBα, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α in CD40+ spleen B cells using flow cytometry. Furthermore, we also analyzed the effect of DAPTA on NF-κB p65, IκBα, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α mRNA expression levels using qRT-PCR in brain tissue. EAE mice treated with DAPTA showed substantial reductions in NF-κB p65, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α but an increase in the IκBα of CD40+ B lymphocytes. Moreover, EAE mice treated with DAPTA displayed decreased NF-κB p65, Notch-1, Notch-3, GM-CSF, MCP-1, iNOS, and TNF-α and but showed increased IκBα mRNA expression levels. This study showed that DAPTA has significant neuroprotective potential in EAE via the downregulation of inflammatory mediators and NF-κB/Notch signaling. Collectively, DAPTA might have potential therapeutic targets for use in MS treatment.

Natural History of Visual Dysfunction in ABCA4 Retinopathy and Its Genetic Correlates

To systematically assess the ability to detect change and retest reliability for a panel of visual function assessments in ABCA4 retinopathy. Prospective natural history study (NCT01736293). Patients with at least 1 documented pathogenic ABCA4 variant and a clinical phenotype consistent with ABCA4 retinopathy were recruited from a tertiary referral center. Participants underwent longitudinal, multifaceted functional testing, including measures of function at fixation (best-corrected visual acuity, low-vision Cambridge Color Test), macular function (microperimetry), and retina-wide function (full-field electroretinography [ERG]). Two- and 5-year ability to detect change was determined based on the η2 statistic. A total of 134 eyes from 67 participants with a mean follow-up of 3.65 years were included. In the 2-year interval, the microperimetry-derived perilesional sensitivity (η2 of 0.73 [0.53, 0.83]; -1.79 dB/y [-2.2, -1.37]) and mean sensitivity (η2 of 0.62 [0.38, 0.76]; -1.28 dB/y [-1.67, -0.89]) showed most change over time, but could only be recorded in 71.6% of the participants. In the 5-year interval, the dark-adapted ERG a- and b-wave amplitude showed marked change over time as well (eg, DA 30 a-wave amplitude with an η2 of 0.54 [0.34, 0.68]; -0.02 log10(µV)/y [-0.02, -0.01]). The genotype explained a large fraction of variability in the ERG-based age of disease initiation (adjusted R2 of 0.73) CONCLUSIONS: Microperimetry-based clinical outcome assessments were most sensitive to change but could only be acquired in a subset of participants. Across a 5-year interval, the ERG DA 30 a-wave amplitude was sensitive to disease progression, potentially allowing for more inclusive clinical trial designs encompassing the whole ABCA4 retinopathy spectrum.

Vision impairment is common in non-hospitalised patients with post-COVID-19 syndrome

ABSTRACT Clinical relevance Vision-related problems can be part of longstanding sequelae after COVID-19 and hamper the return to work and daily activities. Knowledge about symptoms, visual, and oculomotor dysfunctions is however scarce, particularly for non-hospitalised patients. Clinically applicable tools are needed as support in the assessment and determination of intervention needs. Background The purpose of this study was to evaluate vision-related symptoms, assess visual and oculomotor function, and to test the clinical assessment of saccadic eye movements and sensitivity to visual motion in non-hospitalised post-COVID-19 outpatients. The patients (n = 38) in this observational cohort study were recruited from a post-COVID-19 clinic and had been referred for neurocognitive assessment. Methods Patients who reported vision-related symptoms reading problems and intolerance to movement in the environment were examined. A structured symptom assessment and a comprehensive vision examination were undertaken, and saccadic eye movements and visual motion sensitivity were assessed. Results High symptom scores (26–60%) and prevalence of visual function impairments were observed. An increased symptom score when reading was associated with less efficient saccadic eye movement behaviour (p < 0.001) and binocular dysfunction (p = 0.029). Patients with severe symptoms in visually busy places scored significantly higher on the Visual Motion Sensitivity Clinical Test Protocol (p = 0.029). Conclusion Vision-related symptoms and impairments were prevalent in the study group. The Developmental Eye Movement Test and the Visual Motion Sensitivity Clinical Test Protocol showed promise for clinical assessment of saccadic performance and sensitivity to movement in the environment. Further study will be required to explore the utility of these tools.