Manrique, Roslyn K MD; Noval, Susana MD, PhD; Aguilar-Amat, María J MD; Arpa, Javier MD, PhD; Rosa, Irene MD; Contreras, Inés MD, PhD
The inherited ataxias are a group of chronic progressive neurodegenerative diseases that involve the cerebellum and its connections. The term autosomal dominant cerebellar ataxia (ADCA) is used to designate this inheritance pattern in a group of patients who have late-onset cerebellar ataxia in which the spinal cord and the cerebellar pathway are the main structures affected (1). Spinocerebellar ataxia type 7 (SCA7) is one of at least 28 genetically distinct forms of hereditary ADCAs. According to Harding's classification, it is included within ADCA type II, which is characterized by olivopontocerebellar atrophy associated with rod-cone dystrophy (2). SCA7 is unique in being the only spinocerebellar ataxia in which retinal degeneration is almost always present.
The first neurologic sign of SCA7 is typically gait ataxia. Limb ataxia and dysarthria develop over the following years. Additional manifestations include slowing of saccades, ophthalmoplegia, dysphagia, and pyramidal tract signs (3). Abnormal electroretinograms, pigmentary macular degeneration, and optic disc pallor are the ocular signs classically associated with SCA7; visual acuity is compromised in the initial stages and gradually progresses toward complete blindness (2).
SCA7 shows strong anticipation. That is, the age of onset is earlier and the severity of the disease increases with each successive generation due to an increasing number of unstable CAG repeat expansions in the coding region of a gene on chromosome 3p12-13. This gene controls the production of the protein ataxin-7 (4-6). Recent experimental studies have proven that increased levels of ataxin-7 can dramatically suppress cone-rod homeobox protein transactivation. Cone-rod homeobox protein is expressed predominantly in retinal photoreceptor cells; it controls the expression level of multiple photoreceptor-specific genes, including rhodopsin and the color opsins (7).
The purpose of this study was to analyze the ocular features of patients with spinocerebellar degeneration using new technologies. The pattern of retinal thinning on optical coherence tomography (OCT) is reported as well as previously undescribed endothelial changes.
La Paz Hospital in Madrid, Spain is a country-wide referral center for ataxias. Patients in whom SCA7 was diagnosed by genetic analysis in this hospital over the past 10 years were invited to participate in this observational study. The study was approved by the hospital's ethics committee and informed consent was obtained from each patient.
All patients underwent the following diagnostic protocol:
* Medical history, including family history
* Complete neurologic and ophthalmologic examinations and grading according to the Scale for the Assessment and Rating of Ataxia (SARA)
* Serologic analysis with the aim of identifying acquired causes of ataxia
* Electromyography with motor nerve conduction velocity, multimodal evoked potentials, neuro-otologic studies, and autonomic nervous system studies
* Brain and spinal cord MRI
Depending on the results of these examinations, genetic studies were performed to detect mutations associated with the suspected type of ataxia.
The ophthalmologic examination included Snellen visual acuity, intrinsic and extrinsic ocular motility analysis, Goldmann applanation tonometry, biomicroscopic evaluation of the anterior and posterior segments, corneal topography, specular microscopy, fundus examination, and OCT.
Endothelial analysis was performed using the Topcon SP3000P noncontact autofocus specular microscope (Topcon Corp., Tokyo, Japan). The following data were recorded: 1) cell density (cells per square millimeter); 2) polymegethism, as evaluated by the coefficient of variation, which describes the variation of individual cell area; and 3) pleomorphism, evaluated by the percentage of 6-sided cells.
Subjects were also studied with the Pentacam Comprehensive Eye Scanner (CES) (Oculus Inc.), a system based on a 180° rotating Sheimpflug camera that reconstructs the anterior chamber and is capable of measuring corneal thickness and corneal volume.
OCT scanning was performed with the Stratus OCT (Carl Zeiss Meditec, Dublin, CA) after pharmacologic mydriasis under internal fixation. Image acquisition was performed with the Fast RNFL (3.4) and Fast Macular Thickness protocols. Before ending each session, the operator checked that the StratusOCT software had correctly identified the retinal nerve fiber layer (RNFL). Peripapillary RNFL thickness values were obtained with the built-in software RNFL Thickness Average Analysis protocol. A color-coded graph displays the RNFL measurements and compares them with age-matched data of a normative database. RNFL measurements considered normal are displayed in green. Yellow marks thickness values that are ≤5% of all thickness values measured in the normative database. Red is reserved for thickness values less than 1%. White indicates thickness values that are higher than expected. RNFL thickness values that were colored yellow or red by the normative database were considered together as reduced. Central macular thickness, an area 1 mm in diameter and centered on the fovea, was obtained using the Retinal Thickness/Volume protocol.
Eight patients were identified as having SCA7 by genetic analysis performed in our hospital. Of this group, 7 were included in the study; 1 was unavailable because she had left the country. These 7 patients are here called A, A1, A2, B, B1, C, and D. The first 5 are relatives; their family tree is shown in Figure 1. Demographic data are recorded in Table 1.
All patients reported progressive binocular visual loss as the main ophthalmic symptom. This symptom was present at the time of SCA diagnosis in 4 patients. Between 2 and 12 years elapsed between SCA7 diagnosis and onset of visual symptoms in the remaining 3 patients.
All patients had decreased visual acuity; values are recorded in Table 2.
Pupils, Eye Movements, and Ocular Alignment
Slow pupillary reactivity was present in Cases B1, C, and D. One patient (Case D) had nystagmus attributed to visual dysfunction. Case A2 had a small comitant exophoria. Case C had limited supraduction. Three patients (Cases A, A2, and C) had difficulty initiating voluntary saccades.
All patients had clear corneas except for two patients, who had subtle paracentral corneal leucomas. Cataracts were detected in four patients (Table 2).
All patients had pigmentary changes in the macula and peripheral retina and varying degrees of optic disc pallor (Table 2). Macular arteriolar attenuation was conspicuous in three patients and Case A had a macular pseudo-hole.
Specular Microscopy and Pentacam CES
Cell density ranged between 992 and 2,701 cells/mm2; 7 of 11 eyes had less than 2,000 cells/mm2 (Table 2). Coefficients of variation and percentage of 6-sided cells were within normal values in all patients, except in Case B1. Corneal volume ranged between 56.8 and 65.8 mm3 and pachymetry measured by Pentacam CES ranged between 539 and 610 μm. We were unable to perform either of these assessments in Case D and could not perform specular microscopy in 1 eye of Case B.
Macular exploration with OCT showed retinal thinning in all patients. It was limited to the fovea in the mildest cases (Fig. 2, left). This abnormality is represented as a grayish color of the central circle according to the color code. In patients with more severe ataxia, the retinal thinning was more pronounced and, in addition to the central fovea, it also affected the outer zone of the macula (Fig. 2, right).
Peripapillary RNFL thickness was decreased in all patients. Thinning was mild early in the disease (Fig. 2, left) and severe in more advanced disease (Fig. 2 right). Two patients were unable to maintain fixation, and thus the OCT explorations were considered unreliable and were not included for analysis. Table 3 shows macular and peripapillary RNFL thicknesses for the other 5 patients. Eight of 10 eyes maintained normal thickness in the temporal quadrants even in the presence of severe disease (Fig. 2, right).
In this study of the ophthalmic features of SCA7, abnormalities were found by observation and by specular microscopy, Pentacam corneal topography, and OCT in the anterior and posterior ocular segments. Patients also displayed reduced pupillary constriction to light and impairment of eye movements in some cases (3).
With its functions as a barrier and an active fluid pump, the corneal endothelium is responsible for maintaining an adequate level of corneal hydration and thickness. Specular microscopy is a noninvasive technique that allows evaluation of its structure and function (20,21). Several studies have shown a nonlinear decrease in cell density with increasing age (8-11). In all patients with SCA7, we observed a lower cell density than expected for age, although the corneas remained clear. A reduction in endothelial cell count has been described in three other forms of hereditary ataxias (dentatorubral-pallidoluysian atrophy [DRPLA], SCA1, and Kearns-Sayre syndrome). In 5 patients with DRPLA, a reduction in endothelial cell count with no other ocular changes has been described (22-24). In 14 patients with SCA1, Abe et al (23) found that cell density was significantly decreased, ranging from 600 to 3,115 cell/mm2. Despite these decreased values, patients did not have corneal edema. The authors suggested that this result could be due to the normal range of variation in cell size (the coefficient of variation ranged between 0.25 and 0.46) (23,25). This is also the case in our patients with SCA7, whose coefficient of variation and proportion of 6-sided cells were within normal ranges.
The Pentacam CES calculates a parameter named corneal volume (CV), considered a reliable indicator of endothelial cell function (14-16). Five of the 6 patients with SCA7 in whom we could perform this analysis had a CV above that mean, in accordance with the endothelial cell changes detected with specular microscopy. Because the area of corneal endothelium examined with specular microscopy is smaller than 1 mm2, the Pentacam CV measurement is more appropriate than specular microscopy for evaluating damage to the entire cornea. In addition, we have found that the Pentacam study is more easily performed in our neurologically disabled patients.
Visual acuity was reduced in all our patients (the best acuity was 20/60), in accordance with previous studies (2). In patients with milder disease, there is reported loss of the normal foveal reflex and a granular appearance of the macula. With disease progression, attenuation of retinal vessels, granular pigmentation, and pale areas of pigmentary atrophy with small pigment clumps are observed (2). Previous clinical descriptions had suggested that degenerative changes in the retina initially affect cone photoreceptors and that only in later stages does a cone-rod dystrophy develop (3,26,27). However, as the disease progresses and rods are affected, electroretinographic studies have shown that both rods and cones become equally affected (28,29). In patients with mild disease, visual fields have also reflected the pattern usually seen in cone-rod dystrophies, namely defects in the central and far peripheral fields with relative sparing of the mid-periphery (30).
Foveal thinning was constant in our patients as evaluated with OCT. In patients with more severe disease, peripheral thinning was accompanied by optic disc pallor. Previous OCT studies have revealed similar patterns of macular thickness as a centrifugal pattern of progressive loss (28-30).
Histologic post-mortem studies have proven that there is an absence of photoreceptors, severe loss of ganglion cell neurons, and thinning of nuclear and plexiform layers with migration of melanin pigment from the retinal epithelium toward the atrophic area (3). These changes interfered with fixation in patients with more advanced disease and prevented us from performing all explorations in every patient.
Retinal ganglion cell involvement can be investigated with peripapillary RNFL thickness measurement, which revealed reduced thickness in all our patients. The temporal peripapillary quadrant was almost always unaffected, in contrast with most primary optic neuropathies that show early temporal quadrant damage (31-35). A recent report has described temporal quadrant sparing in patients with retinitis pigmentosa, another type of retinal dystrophy (36). All this suggests that RNFL loss due to retinal dystrophies tends to spare the temporal quadrant. The fact that the inner macula around the central fovea is relatively spared, together with thinning of the central fovea and the outer retinal layers, may explain the normal retinal ganglion cell layer thickness of the temporal quadrant of peripapillary retina until the disease is more advanced.
Our study is in accord with previous publications suggesting that a retinal cone-rod dystrophy pattern and RNFL thinning seem to be characteristic of SCA7 from its earliest stages. The endothelial changes have not been described previously in this condition.
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