Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease in which impaired mitochondrial function and excessive production of free radicals play a central pathogenetic role (1). It is a rare disease affecting approximately 1 in 50,000 Caucasians (2) and has been linked to genetic defects on chromosome 9q13-q1.1. Clinical features include spinocerebellar and sensory ataxia, dysarthria, hypertrophic cardiomyopathy, scoliosis, diabetes mellitus, pes cavus, hypoacusia, optic atrophy, and eye movement abnormalities (3–7).
Ocular motor abnormalities are the best characterized signs of damage to the visual system in FRDA. They include fixation instability, saccadic dysmetria, disrupted pursuit, and vestibular abnormalities. The most common manifestation is fixation instability with frequent square wave jerks. Other ophthalmic manifestations include optic neuropathy, a retinitis pigmentosa–like syndrome, and involvement of the optic radiation (3–7). Although the pathogenesis of optic neuropathy in patients with FRDA remains unclear, many hypothesis have been proposed including bioenergetic failure, oxidative stress, glutamate toxicity, abnormal mitochondrial dynamics and axonal transport, and susceptibility to apoptosis (4,8).
Optical coherence tomography (OCT) can be used to assess the retinal nerve fiber layers (RNFL) of the anterior visual pathways. Using this technique, we measured peripapillary RNFL thickness, peripapillary retinal and choroidal thickness, and foveal thickness in patients with FRDA. Functional status of anterior and posterior visual pathways was evaluated using automated visual field testing (VFT).
Ten eyes of 10 patients with genetically confirmed FRDA diagnosis were included in this study. Twenty-two eyes of 22 healthy volunteers served as controls. All patients were recruited from the Neurology Department of Kirikkale University School of Medicine. Informed consent was obtained from all participants as well as approval from our institutional ethics committee.
During the initial visit, a full neurological examination assessed gait spasticity, tendon reflexes, muscle weakness and wasting, scoliosis, sphincter disturbances, swallowing difficulties, and visual complaints. We used the International Cooperative Ataxia Rating Scale (ICARS) to evaluate cerebellar ataxia. The ICARS includes the following 4 subscores: posture (maximum score, 34), kinetic functions (maximum score, 52), speech (maximum score, 8), and oculomotor dysfunction (maximum score, 6), for a possible total of 100 points. Scores increased with disease severity and indicated greater neurological disability.
Each subject underwent a complete ophthalmological examination including best-corrected visual acuity, measurement of intraocular pressure, and slit-lamp examination. Refraction of each eye was obtained using an autorefractor (Topcon Auto Ref-Keratometer, Tokyo, Japan). For OCT and VFT, 1 eye was chosen randomly for each patient and each control subject. These tests were conducted by a clinician blinded to each subject's condition, and another investigator also was blinded, reviewed the images, and reported the results independently.
All eyes were examined with spectral domain OCT (Retinascan Advanced RS-3000; NIDEK, Gamagori, Japan) using image filling software program (NAVIS-EX, NIDEK, Tokyo, Japan). This was performed in both the peripapillary area and the macula following pupillary dilation. In the peripapillary area, a circular scan centered on the optic disc (3.45 mm diameter, “disc circle” option) was used.
We quantitated the thickness of the mean peripapillary RNFL (360°), superior quadrant (46°–135°), inferior quadrant (226°–315°), nasal quadrant (136°–225°), and temporal quadrant (316°–45°). We also measured the mean peripapillary retinal thickness (RT) and average RT in the superior, nasal, inferior, and temporal quadrants, using the same image and changing the lower border to retina pigment epithelium manually. Temporal-superior-nasal-inferior thickness (TSNIT) thickness graph (ILM-RPE/BM) was displayed automatically.
Peripapillary average choroidal thickness (CT) and average CT in 4 quadrants were calculated using inverted images of the peripapillary area. Once again, a circular scan centered on the optic disc (3.45 mm diameter) was used. The scans consisted of 1,024 “A scans” with high-definition (50 HD) frame enhancement software. This instrument has a light source of 880-nm wavelength. To improve choroidal visualization, the OCT device was positioned close to the eye to visualize the inverted image on the top of the monitor (to be in closer proximity to the zero-delay line). We selected “Layer Editor” from the menu displayed. Hyperreflective outer border of the retinal pigment epithelial layer (RPE/BM) was displayed automatically, and we drew the sclerochoroidal interface manually; the perpendicular distance between the 2 layers was designated choroid thickness. TSNIT thickness graph (RPE/BM-manual [choroid]) was displayed automatically by the software program.
In the macula, foveal thickness was measured with OCT setting: macula map X-Y (6.0 mm × 6.0 mm [256 × 256]) automatically. Glaucoma tab of the same setting was used to display ganglion cell complex (GCC) thickness map (ILM-IPL/INL) automatically. Average GCC thickness was measured in the superior and the inferior half of the macula. Subfoveal choroid thickness (SCT) was measured in OCT setting of macula line. Inverted representation of the fundus image of each eye and a 120 average B scans were used to improve visualization of the choroidal details. After drawing lower border of the choroid manually, TSNIT thickness graph (RPE/BM-manual [choroid]) and SCT were displayed. Optic nerve head properties (cup-to-disc [vertical, horizontal], disc area, and cup area) were shown automatically in OCT setting: disc map X-Y (6.0 mm × 6.0 mm [256 × 256]).
VFT was performed using Humphrey Field Analyzer (HFA II 750; Zeiss-Humphrey Systems, Dublin, CA) with central 30-2 threshold testing with full threshold strategy on the day of examination and repeated 2 weeks later. To be eligible for analysis, participants had to have a reliable second VFT (false-positive and false-negative responses <33% and fixation losses <20%). Only data from the second VFT were used for analysis.
Statistical analysis was performed with the Statistical Package for Social Sciences program. Analysis of variance was used to evaluate the statistical significance when comparing the 2 groups. In all analyses, P value <0.05 was considered statistically significant.
Ten eyes of 10 patients with FRDA (6 women and 4 men) were included in this study and 22 eyes of 22 normal volunteers (13 women and 9 men) served as controls. Mean age of the patients with FRDA was 32.1 ± 10.46 (range, 18–49) years and mean age of the control group was 30.1 ± 10.43 (range, 18–49) years. There was no statistically significant difference in both groups in terms of age (P = 0.767) and sex (P = 0.963). The mean total ICARS score was 45.48 ± 21.20 of a possible 100 points. Demographic and clinical features of patients with FRDA are shown in Table 1.
Best-corrected visual acuities were converted to logMAR units for statistical analysis. They were 0.05 ± 0.9 in patients with FRDA and 0.00 ± 0.0 in controls (P = 0.02). The mean spherical equivalent was measured as −0.94 ± 1.10 diopters in patients with FRDA and −0.82 ± 1.32 diopters in controls (P = 0.312). There was no statistically significant difference in the mean intraocular pressure between patients with FRDA and controls (P = 0.272). Slit-lamp examination demonstrated congenital ocular anomalies in 5 of the 10 patients with FRDA. Three patients had punctate cataract with focal opacities in the nuclear and perinuclear areas of both lenses. One patient had ectropion uveae and 1 had persistent pupillary membrane in each eye. Fundus examination revealed temporal optic disc pallor in 2 patients and diffuse pallor in 1. Eight of the 10 patients had cup-to-disc ratio (C/D) >0.6.
The OCT results are summarized in Table 2. There was a significant reduction in average peripapillary RNFL thickness in patients with FRDA compared with controls (P < 0.0001). Average RNFL thickness and peripapillary RT were also statistically significantly lower in all quadrants in patients with FRDA (P < 0.0001 and P < 0.0001, respectively).
No statistically significant difference between patients with FRDA and control groups was detected for overall mean peripapillary CT and average peripapillary CT in all quadrants. Mean RT in the fovea was significantly lower in FRDA patients (P = 0.025). Mean GCC thickness in the superior and inferior macula were significantly lower in patients with FRDA (P < 0.0001 and P < 0.0001, respectively).
Measurements of horizontal C/D ratio, vertical C/D ratio, and average cup area were found to be increased in patients with FRDA (P < 0.0001, P < 0.0001, and P < 0.0001, respectively). There was no statistically significant difference in mean disc area (P = 0.227).
In patients with FRDA, average visual field mean deviation was found to be −19.59 (range, −3.46 to −32.86). We found severe visual field impairment with reduction of sensitivity in 10 eyes of 5 patients, isolated area of reduced sensitivity in 4 eyes of 2 patients, and mild reduction of sensitivity and inferior and superior arcuate defects, more prominent superiorly, in 2 eyes of 1 patient. Visual field defects were symmetric in both eyes of patients with FRDA. Glaucoma hemifield test was outside normal limits in both eyes of 4 patients, demonstrated general reduction of sensitivity in both eyes of 3 patients, and was borderline in both eyes of 1 patient.
Visual acuity was significantly correlated with age at onset (P = 0.021) and average RNFL thickness (P = 0.045). There was statistically significant correlation between foveal thickness and disease duration (P = 0.014). Mean RNFL thickness was significantly correlated with the severity of neurological involvement (total ICARS score) (P = 0.039). There was not a statistically significant correlation between average RNFL thickness and mean deviation on VFT (P = 0.243).
Mitochondrial diseases such as FRDA frequently manifest neuro-ophthalmologic symptoms and signs. In addition to the visual pathways, mitochondrial disorders may involve a variety of ophthalmic structures, including extraocular muscles, eyelids, and retina (9). Fortuna et al (3) have reported a slowly progressive degenerative process involving both the optic nerves and the optic radiations in patients with FRDA. They observed diffuse and progressive pattern of RNFL loss that preceded the appearance of visual field defects and was scattered over the entire pool of retinal ganglion cells. Noval et al (10) also studied peripapillary RNFL thickness in 23 patients with FRDA and found decreased peripapillary RNFL thickness. Fortuna et al (3) found positive correlations between ICARS scores and disease duration and RNFL thickness. In this study, there was a significant correlation between severity of neurological involvement (ICARS score) and RNFL thickness but not between age at onset, disease duration, or RNFL thickness. In patients with FRDA, significant loss of visual acuity appears late, although anterior and posterior visual pathway involvement may be detected early in the disease course. Mean peripapillary RNFL thickness and RNFL thickness in the 4 quadrants were significantly lower than in the control group, and these findings were in accordance with the previous studies (3,10).
Because of high resolution of spectral domain OCT, we were able to identify the different retinal layers in transfoveal scans. Noval et al (10) also performed macular analysis, although they did not perform segmentation. We manually segmented the retinal layers in horizontal scans through the middle of the fovea and measured the thickness of the various layers. Among the studies in patients with FRDA, Noval et al (10) reported normal macular thickness and RNFL of the temporal quadrant, which represents the papillomacular bundle. We found significantly lower average peripapillary and macular RT in patients with FRDA. We also measured reduced mean GCC thickness in the macular area of patients with FRDA. However, since the resolution of current OCT devices is not sufficient to separate each of the retinal layers, we cannot conclude that the thinning was solely because of degenerative changes of the ganglion cells.
Vascular pathology has been postulated to play an important pathophysiological role in neurodegenerative disease. Cerebral hypoperfusion in Alzheimer disease has been speculated as a trigger for neuronal dysfunction, whereas cerebral vascular lesions may modify clinical presentation and severity in patients with Parkinsonism (11,12). We hypothesized that there might be abnormalities in the choroidal blood flow accompanying the neural damage in the retina of patients with FRDA, so we measured CT. However, there was no significant difference in CT between controls and patients with FRDA in both the peripapillary region and the macula. The pathology in FRDA seems limited to only neural structures.
There was no correlation between average RNFL thickness and MD on VFT. This finding supports asynchronous neurodegeneration of the anterior and posterior visual pathways, as previously reported (3). Statistically significant correlation between foveal thickness and disease duration is consistent with ongoing neuronal degeneration. This progressive loss of neuronal elements likely leads to reduced neuroretinal rim of the optic discs and an increase in C/D ratio.
We are aware of limitations of VFT analysis. Motor system dysfunction and reduced reaction times may have contributed to visual field performance in our study group. In addition, the indices used to consider a visual field reliable (false-positive and false-negative rates <35%; fixation losses <20%) may be adequate for clinical practice, but they may be too high for research purposes.
In conclusion, progressive, diffuse, and asynchronous neurodegeneration limited to neuroretinal layer may be seen in patients with FRDA. Our sample size was small, and additional studies with larger patient cohorts and more advanced OCT techniques may provide further neuro-ophthalmologic insights into FRDA.
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