Retinal nerve fiber layer thickness and visual hallucinations in Parkinson's Disease

Defective visual information processing from both central and peripheral pathways is one of the suggested mechanisms of visual hallucination in Parkinson's disease (PD). To investigate the role of retinal thinning for visual hallucination in PD, we conducted a case‐control study using spectral domain optical coherence tomography. We examined a representative sample of 61 patients with PD and 30 healthy controls who had no history of ophthalmic diseases. General ophthalmologic examinations and optical coherence tomography scans were performed in each participant. Total macular thickness and the thickness of each retinal layer on horizontal scans through the fovea were compared between the groups. In a comparison between patients with PD and healthy controls, there was significant parafoveal inner nuclear layer thinning, whereas other retinal layers, including the retinal nerve fiber layer, as well as total macular thicknesses were not different. In terms of visual hallucinations among the PD subgroups, only retinal nerve fiber layer thickness differed significantly, whereas total macular thickness and the thickness of other retinal layers did not differ. The retinal nerve fiber layer was thinnest in the group that had hallucinations without dementia, followed by the group that had hallucinations with dementia, and the group that had no hallucinations and no dementia. General ophthalmologic examinations did not reveal any significant correlation with hallucinations. There were no significant correlations between retinal thicknesses and duration or severity of PD and medication dosages. The results indicate that retinal nerve fiber layer thinning may be related to visual hallucination in nondemented patients with PD. Replication studies as well as further studies to elucidate the mechanism of thinning are warranted. © 2013 International Parkinson and Movement Disorder Society     

Progressive Spinal Cord Degeneration in Friedreich's Ataxia: Results from ENIGMA-Ataxia

Background

Spinal cord damage is a hallmark of Friedreich's ataxia (FRDA), but its progression and clinical correlates remain unclear.

Objective

The objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort.

Methods

We performed a cross-sectional analysis of cervical spinal cord (C1–C4) cross-sectional area (CSA) and eccentricity using magnetic resonance imaging data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched control subjects. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age.

Results

Individuals with FRDA, relative to control subjects, had significantly reduced CSA at all examined levels, with large effect sizes (d > 2.1) and significant correlations with disease severity (r < −0.4). Similarly, we found significantly increased eccentricity (d > 1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, although CSA appears to decrease progressively, eccentricity remains stable over time.

Conclusions

Previous research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage, or both. Hence our data support the hypothesis that damage to the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Quadruple sectoranopia and sectorial optic atrophy: a syndrome of the distal anterior choroidal artery.

Loss of upper and lower homonymous sectors in the visual field, and wasting of corresponding sectors in the retinal nerve fibre layer, followed ligation of the distal part of the anterior choroidal artery in a patient with a meningioma of the velum interpositum. Clinical and radiological evidence indicated that the visual pathway was damaged within that part of the lateral geniculate body that is served by the anterior choroidal artery.     

Aberrant visual pathway development in albinism: From retina to cortex

Albinism refers to a group of genetic abnormalities in melanogenesis that are associated neuronal misrouting through the optic chiasm. We perform quantitative assessment of visual pathway structure and function in 23 persons with albinism (PWA) and 20 matched controls using optical coherence tomography (OCT), volumetric magnetic resonance imaging (MRI), diffusion tensor imaging and visual evoked potentials (VEP). PWA had a higher streamline decussation index (percentage of total tractography streamlines decussating at the chiasm) compared with controls (Z = ?2.24, p = .025), and streamline decussation index correlated weakly with inter‐hemispheric asymmetry measured using VEP (r = .484, p = .042). For PWA, a significant correlation was found between foveal development index and total number of streamlines (r = .662, p < .001). Significant positive correlations were found between peri‐papillary retinal nerve fibre layer thickness and optic nerve (r = .642, p < .001) and tract (r = .663, p < .001) width. Occipital pole cortical thickness was 6.88% higher (Z = ?4.10, p < .001) in PWA and was related to anterior visual pathway structures including foveal retinal pigment epithelium complex thickness (r = ?.579, p = .005), optic disc (r = .478, p = .021) and rim areas (r = .597, p = .003). We were unable to demonstrate a significant relationship between OCT‐derived foveal or optic nerve measures and MRI‐derived chiasm size or streamline decussation index. Our novel tractographic demonstration of altered chiasmatic decussation in PWA corresponds to VEP measured cortical asymmetry and is consistent with chiasmatic misrouting in albinism. We also demonstrate a significant relationship between retinal pigment epithelium and visual cortex thickness indicating that retinal pigmentation defects in albinism lead to downstream structural reorganisation of the visual cortex.     

Venturing into the no‐man's land of the retina in Parkinson's disease

The development of optical coherence tomography (OCT) has led to increasing interest in the retina in Parkinson's disease (PD). The retina is a multilayered tissue: looking into the eye from the outside, these layers comprise the nerve fiber layer (NFL); the ganglion cell layer (GCL); the inner plexiform layer (IPL), which contains the interconnecting plexus, including tyrosine hydroxylase‐positive (dopaminergic) fibers of amacrine cells; the inner nuclear layer; and several outer retinal layers. Commercial spectral‐domain OCT has a specific program for detecting peripapillary NFL defects and a different macular program for diabetic retinopathy. Specific programs for PD are not commercially available. Taking all studies together, it seems that macular programs have a higher diagnostic yield than NFL programs, but the numbers of studies and examined patients are relatively small. It is not certain that all retinal thinning in PD is due to dopaminergic neuronal loss. When applying OCT, the where (region of interest) and the what of the focus of automated programs must be considered. With these caveats, one could take advantage of the power of OCT for looking in‐depth into the terra incognita of individual retinal layers at the fovea and perhaps at other appropriate retinal locations. © 2013 International Parkinson and Movement Disorder Society     

Neurological effects of recombinant human erythropoietin in Friedreich's ataxia: A clinical pilot trial

In a “proof‐of‐concept” study, we demonstrated that recombinant human erythropoietin (rhuEPO) increases frataxin levels in Friedreich's ataxia (FRDA) patients. We now report a 6‐month open‐label clinical pilot study of safety and efficacy of rhuEPO treatment in FRDA. Eight adult FRDA patients received 2.000 IU rhuEPO thrice a week subcutaneously. Clinical outcome measures included Ataxia Rating Scales. Frataxin levels and indicators for oxidative stress were assessed. Hematological parameters were monitored biweekly. Scores in Ataxia Rating Scales such as FARS (P = 0.0063) and SARA (P = 0.0045) improved significantly. Frataxin levels increased (P = 0.017) while indicators of oxidative stress such as urine 8‐OHdG (P = 0.012) and peroxide levels decreased (P = 0.028). Increases in hematocrit requiring phlebotomies occurred in 4 of 8 patients. In this explorative open‐label clinical pilot study, we found an evidence for clinical improvement together with a persistent increase of frataxin levels and a reduction of oxidative stress parameters in patients with FRDA receiving chronic treatment with rhuEPO. Safety monitoring with regular blood cell counts and parameters of iron metabolism is a potential limitation of this approach. © 2008 Movement Disorder Society     

Tracking retinal nerve fiber layer loss after optic neuritis: a prospective study using optical coherence tomography

INTRODUCTION: Optic neuritis causes retinal nerve fiber layer damage, which can be quantified with optical coherence tomography. Optical coherence tomography may be used to track nerve fiber layer changes and to establish a time-dependent relationship between retinal nerve fiber layer thickness and visual function after optic neuritis. METHODS: This prospective case series included 78 patients with optic neuritis, who underwent optical coherence tomography and visual testing over a mean period of 28 months. The main outcome measures included comparing inter-eye differences in retinal nerve fiber layer thickness between clinically affected and non-affected eyes over time; establishing when RNFL thinning stabilized after optic neuritis; and correlating retinal nerve fiber layer thickness and visual function. RESULTS: The earliest significant inter-eye differences manifested 2-months after optic neuritis, in the temporal retinal nerve fiber layer. Inter-eye comparisons revealed significant retinal nerve fiber layer thinning in clinically affected eyes, which persisted for greater than 24 months. Retinal nerve fiber thinning manifested within 6 months and then stabilized from 7 to 12 months after optic neuritis. Regression analyses demonstrated a threshold of nerve fiber layer thickness (75 microm), which predicted visual recovery after optic neuritis. CONCLUSIONS: Retinal nerve fiber layer changes may be tracked and correlated with visual function within 12 months of an optic neuritis event.     

Correlations among multifocal electroretinography and optical coherence tomography findings in patients with Parkinson’s disease

To assess the correlation between functional and anatomical evaluations with multifocal electroretinography (mfERG) and spectral-domain optical coherence tomography (SD-OCT) in patients with Parkinson’s disease (PD). This cross-sectional study involved 116 eyes of 58 patients with PD and 30 age- and sex-matched control subjects. All study participants underwent a comprehensive neuro-ophthalmic examination, retinal single-layer thicknesses and volumes, and peripapillary retinal nerve fiber layer (pRNFL) measurements with SD-OCT, and the patients’ mfERG recordings were evaluated. The macular retinal nerve fiber layer (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), outer nuclear layer (ONL), retinal pigment epithelium (RPE), and photoreceptor layer (PR) thicknesses, and mRNFL, RPE, and PR volumes were found lower in PD compared to those of controls, while outer plexiform layer (OPL) volumes were increased (p?<?0.05). We found delayed implicit times and decreased amplitudes in the mfERG of PD patients versus those in control subjects (p?<?0.05). We found significant correlations between outer macular volumes, PR thicknesses, and N1 amplitudes of rings 2 and 3and P1 amplitudes of rings 3, 4, and 5. Our study revealed thinning of both inner and outer retinal single layers, increased OPL volume, and delayed implicit times and decreased amplitudes in the mfERG of PD patients versus control subjects and correlation between structural and functional parameters. Our findings point out that SD-OCT and mfERG could both serve as non-invasive tools for evaluating ophthalmic manifestations of Parkinson’s disease.     

Optical coherence tomography (OCT) study in Argentinean Huntington’s disease patients

Abstract

Background: Huntington’s disease (HD) is a genetic, rare and progressive neurodegenerative disorder that causes motor and cognitive impairment in midlife patients. Although retinal damage was observed in animal HD models and in patients with other neurodegenerative diseases, we still need confirmation of impairment in HD patients. Optical coherence tomography (OCT) is a non-invasive methodology that analyses the retinal nerve fibre layers (RNFL) and could reflect processes of neurodegeneration.

Methods: A cross-sectional study with 14?HD patients who underwent a spectral domain OCT. Results were compared with a control group. Demographic data were also obtained.

Results: Temporal and superior RNFL sectors in HD showed a significant RNFL thinning compared with a control group. However, no differences were identified in mean total RNFL thickness between HD patients and controls.

Conclusions: OCT is a rapid and non-invasive technique that can be investigated in larger cohorts of patients to assess its potential role as a biomarker in HD patients.     

Effects of Erythropoietin on Frataxin Levels and Mitochondrial Function in Friedreich Ataxia �C a Dose�CResponse Trial

Friedreich ataxia (FRDA) is an autosomal recessive inherited neurodegenerative disorder leading to reduced expression of the mitochondrial protein frataxin. Previous studies showed frataxin upregulation in FRDA following treatment with recombinant human erythropoietin (rhuEPO). Dose-response interactions between frataxin and rhuEPO have not been studied until to date. We administered escalating rhuEPO single doses (5,000, 10,000 and 30,000?IU) in monthly intervals to five adult FRDA patients. Measurements of frataxin, serum erythropoietin levels, iron metabolism and mitochondrial function were carried out. Clinical outcome was assessed using the "Scale for the assessment and rating of ataxia". We found maximal erythropoietin serum concentrations 24?h after rhuEPO application which is comparable to healthy subjects. Frataxin levels increased significantly over 3?months, while ataxia rating did not reveal clinical improvement. All FRDA patients had considerable ferritin decrease. NADH/NAD ratio, an indicator of mitochondrial function, increased following rhuEPO treatment. In addition to frataxin upregulation in response to continuous low-dose rhuEPO application shown in previous studies, our results indicate for a long-lasting frataxin increase after single high-dose rhuEPO administration. To detect frataxin-derived neuroprotective effects resulting in clinically relevant improvement, well-designed studies with extended time frame are required.     

Retinotopy of the human retinal nerve fibre layer and optic nerve head

The organisation of the primate nerve fibre layer and optic nerve head with respect to eccentricity or the positioning of central and peripheral axons remains controversial. Crystals of the carbocyanine dyes DiI (1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate), or DiA (4-[4-didecylaminostryryl]-N-methylpridiniumiodide) were used to trace retinae ganglion cell axons within the nerve fibre layer, optic nerve head, and optic nerve. The present study demonstrated that peripheral retinal axons were scattered throughout the vitreal-scleral depth of the nerve fibre layer. This scattered distribution was maintained as the fibres passed through the optic nerve head and into the optic nerve. Axons of the arcuate bundles showed a bias towards the scleral portions of the nerve fibre layer and a variable degree of fibre scatter across the nerve fibre layer which was not as evident in labelling from other retinal regions. There was a rough topographic representation within the optic nerve head according to retinal circumference such that both peripheral and central fibres were mixed within a wedge extending from the periphery to the centre of the nerve. Foveal fibres occupied a large proportion of the temporal aspect of the optic nerve head and nerve, whereas fibres from areas temporal to the fovea appeared to be displaced to more superior and inferior regions. Consistent with the scleral bias seen in the retina, arcuate fibres maintained a peripheral position as they passed through the optic nerve head and occupied a more peripheral position in the nerve. The present results suggest that any degree of order present within the optic nerve is not an active process; optic axons are not instructed to establish a retinotopic order within the initial portions of the visual pathway. © 1996 Wiley-Liss, Inc.     

A novel deletion–insertion mutation identified in exon 3 of <Emphasis Type="Italic">FXN</Emphasis> in two siblings with a severe Friedreich ataxia phenotype

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease most commonly caused by a GAA trinucleotide repeat expansion in the first intron of FXN, which reduces expression of the mitochondrial protein frataxin. Approximately 98% of individuals with FRDA are homozygous for GAA expansions, with the remaining 2% compound heterozygotes for a GAA expansion and a point mutation within FXN. Two siblings with early onset of symptoms experienced rapid loss of ambulation by 8 and 10 years. Diagnostic testing for FRDA demonstrated one GAA repeat expansion of 1010 repeats and one non-expanded allele. Sequencing all five exons of FXN identified a novel deletion-insertion mutation in exon 3 (c.371_376del6ins15), which results in a modified frataxin protein sequence at amino acid positions 124–127. Specifically, the amino acid sequence changes from DVSF to VHLEDT, increasing frataxin from 211 residues to 214. Using the known structure of human frataxin, a theoretical 3D model of the mutant protein was developed. In the event that the modified protein is expressed and stable, it is predicted that the acidic interface of frataxin, known to be involved in iron binding and interactions with the iron–sulphur cluster assembly factor IscU, would be impaired.     

Multicellular models of Friedreich ataxia

Patients with Friedreich ataxia (FRDA) have severely reduced levels of the mitochondrial protein frataxin, which results from a large GAA triplet-repeat expansion within the frataxin gene (FXN). High evolutionary conservation of frataxin across species has enabled the development of disease models of FRDA in various unicellular and multicellular organisms. Mouse models include classical knockout models, in which the Fxn gene is constitutively inactivated, and knock-in models, in which a GAA repeat mutation or the conditional allele is inserted into the genome. Recently, “humanised” GAA repeat expansion mouse models were obtained by combining the constitutive knockout with the transgenic expression of a yeast artificial chromosome carrying the human FRDA locus. In lower organisms such as Caenorhabditis elegans and Drosophila, straight-forward and conditional RNA interference technology has provided an easy way to knock down frataxin expression. Conditional mouse models have been used for pre-clinical trials of potential therapeutic agents, including idebenone, MnTBAP (a superoxide dismutase mimetic), and iron chelators. Various models of FRDA have shown that different, even opposite, phenotypes can be observed, depending on the level of frataxin expression. Additional studies with animal models will be essential for an enhanced understanding of the disease pathophysiology and for the development of better therapies.     

Analysis of the visual system in Friedreich ataxia

To use optical coherence tomography (OCT) and contrast letter acuity to characterize vision loss in Friedreich ataxia (FRDA). High- and low-contrast letter acuity and neurological measures were assessed in 507 patients with FRDA. In addition, OCT was performed on 63 FRDA patients to evaluate retinal nerve fiber layer (RNFL) and macular thickness. Both OCT and acuity measures were analyzed in relation to genetic severity, neurologic function, and other disease features. High- and low-contrast letter acuity was significantly predicted by age and GAA repeat length, and highly correlated with neurological outcomes. When tested by OCT, 52.7 % of eyes (n = 110) had RNFL thickness values below the fifth percentile for age-matched controls. RNFL thickness was significantly lowest for those with worse scores on the Friedreich ataxia rating scale (FARS), worse performance measure composite Z ₂ scores, and lower scores for high- and low-contrast acuity. In linear regression analysis, GAA repeat length and age independently predicted RNFL thickness. In a subcohort of participants, 21 % of eyes from adult subjects (n = 29 eyes) had macular thickness values below the first percentile for age-matched controls, suggesting that macular abnormalities can also be present in FRDA. Low-contrast acuity and RNFL thickness capture visual and neurologic function in FRDA, and reflect genetic severity and disease progression independently. This suggests that such measures are useful markers of neurologic progression in FRDA.     

High pressure-induced retinal ischaemia reperfusion causes upregulation of gap junction protein connexin43 prior to retinal ganglion cell loss

We aimed to characterise the spatial and temporal expression of connexin43 (Cx43) following retinal ischaemia-reperfusion injury and to evaluate its relationship to retinal glial response and subsequent retinal ganglion cell loss. Unilateral retinal ischaemia-reperfusion injury was induced by elevating intraocular pressure to 120mmHg for 60 min and then normalized in Wistar rats. Retinas (n=110) were evaluated at 4, 8, and 24h, and 7, 14, and 21 days in 4 groups: ischaemic, contralateral, sham operated, and uninjured eyes. Immunohistochemistry was used to analyse the spatial and cell-specific expression of Cx43 protein, glial fibrillary acidic protein (astrocytes), glutamine synthetase (Muller cells), Isolectin B4 (vascular endothelium), DAPI (nuclear marker), and BRN3a (retinal ganglion cells). Retinal whole mounts were used to count retinal ganglion cells. Our results show that Cx43 immunoreactivity of the ischaemic eye is significantly increased in the ganglion cell layer and nerve fibre layer, colocalizing with activated retinal astrocytes and Muller cells at 8h. In the inner retinal layers Cx43 was also upregulated and colocalized with retinal vascular endothelium at 4, 8 and 24h post ischaemia. Notably, in the contralateral eye, Cx43 immunoreactivity was also significantly increased in the ganglion cell layer and nerve fibre layer at 8 and 24h, and at 4h in the inner layers. Sham operated controls did not show any change in Cx43 immunoreactivity. Subsequently a significant retinal ganglion cell loss was observed in the ischaemic eye at day 21 with a trend towards retinal ganglion cell loss in the contralateral eye. In conclusion, upregulation of Cx43 occurs in both the ischaemic and contralateral retinas although far more significantly in injured retinas. Cx43 colocalizes primarily with activated retinal astrocytes and Muller cells as well as vascular endothelium, suggesting that gap junction communication and/or hemichannel activity may be a mediator of inflammation, vascular permeability, and subsequently neuronal death.     

Foveal vision is impaired in Parkinson's disease

PurposeThe article aims to review foveal involvement in Parkinson's disease.ScopeClinical observations as well as electrophysiological and anatomical studies in animal models provide evidence that Parkinson's disease (PD) affects vision. The retina is the most distal locus of visual dysfunction in PD as shown by electroretinographic (ERG) and optical coherence tomographic (OCT) studies. Thinning of the retinal nerve fibre layer (RNFL) and the fovea has been reported in PD. This review summarises retinal physiology and foveal visual dysfunction in PD and quantification of retinal thinning as reported in different studies and using different instruments. At this point due to methodological diversity and relatively low number of subjects studied, a meta-analysis is not yet possible. Results obtained on one equipment are not yet transferable to another. The author also briefly alludes to some links of visual processing deficits beyond visual detection, such as visual discrimination, visual categorisation and visuospatial orientation in PD.ConclusionsThere are some promising results suggesting the potential applicability of ST-Oct as a biomarker in PD. Furthermore, these data raise some interesting neurobiological questions. However, there are identifiable pitfalls before OCT quantification may be used as a biomarker in PD. Analysis standardisation is needed on a larger than existing healthy and patient population. Furthermore, longitudinal studies are needed. The exact relationship between retinal foveal deficits and visuo-cognitive impairment in PD remains a challenging research question.     

Photoreceptor layer thinning in idiopathic Parkinson's disease

This study was undertaken to quantify retinal and intra‐retinal layer thicknesses in Parkinson's disease (PD), and to evaluate whether retinal structural changes may be related to altered discrimination of color vision and to severity and duration of PD disease. We examined 97 PD patients and 32 healthy controls (HC) with spectral‐domain optical coherence tomography (OCT), including intra‐retinal layer segmentation. In total, we compared 111 retinal nerve fiber layer (RNFL)‐scans and 114 macula scans from 68 PD patients with 62 RNFL and 63 macula scans from 32 HC. For clinical evaluation of disease severity, we used the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. To determine color discrimination, we performed the Farnsworth Munsell 100 Hue Test (FMT) in a subgroup of PD patients. We found significant combined outer nuclear and photoreceptor layer thinning in PD versus HC (118.6 vs. 123.5 µm, P = 0.001). Differences in RNFL, total macular volume, or the other retinal layer thicknesses were not detected. The OCT measures were not associated with disease severity, duration, or color vision. By showing photoreceptor cell layer thinning, our findings support previous in vivo and autopsy studies demonstrating retinal alterations in PD. Optical coherence tomography may help to assess morphological retinal changes in PD patients; however, the utility of OCT in routine clinical practice may be limited because many PD patients have difficulties complying with OCT investigation because of disease‐related symptoms such as tremor, axial rigidity, or cognitive impairment. © 2014 International Parkinson and Movement Disorder Society