Multimodal Retinal Imaging in Spinocerebellar Ataxia Type 1 Maculopathy
How to cite this article: Mikhail M, Choudhry N. Multimodal Retinal Imaging in Spinocerebellar Ataxia Type 1 Maculopathy. Am J Ophthalmic Clin Trials 2021;4:2.
The objective of the study was to investigate and report the multimodal ocular imaging findings associated with spinocerebellar ataxia type 1 (SCA 1) associated maculopathy.
A full ophthalmologic assessment was completed in a 70-year-old male with confirmed SCA1 and noted progressive bilateral vision loss. Investigations included dilated fundus examination, full-field electroretinography, and swept-source optical coherence tomography (OCT).
On neurologic and ophthalmologic examination, he was found to have hypermetric saccades, horizontal nystagmus, and reduced color vision bilaterally. His best-corrected visual acuity was confirmed to be 20/80 OD and 20/100 OS at the time of consultation. Initial fundus photography was most notable for bilateral hypopigmentation of the fovea. Corresponding OCT imaging demonstrated an attenuation of the ellipsoid zone, in keeping with photoreceptor loss.
The ocular imaging results suggest that the vision loss in the presented case occurred in the context of pigmentary macular dystrophy secondary to photoreceptor dysfunction and retinal pigment epithelial degeneration. This association offers an explanation with respect to the progressive vision loss, but further analyses would be required to determine the temporal correlation of clinical symptoms with imaging abnormalities. These findings suggest that SCA1 be considered as a potential cause for vision impairment, with possible benefits of visual assessment at the time of diagnosis.
Optical coherence tomography
Spinocerebellar ataxias (SCAs) are a heterogeneous group of dominantly inherited disorders involving the degeneration of the cerebellum, and often the brainstem, basal forebrain, and spinal cord. SCA type 1 (SCA1) is an autosomal dominant condition that involves the expansion of a cytosine-adenine-guanine (CAG) repeat sequence on chromosome 6. The elongated CAG repeat results in an expanded polyglutamine tract which produces the gene ataxin-1, a protein which aggregates in the brains of patients affected by SCA1. Typical disease onset occurs during early adulthood with multisystemic involvement occurring in the early stages of the disease. Neurological signs and symptoms include gait ataxia and dysarthria. Ocular findings are often present and include hypermetric saccades, nystagmus, and the development of upgaze palsy. Optic neuropathy and macular dysfunction leading to vision loss have previously been reported in association with the condition. The previous studies have highlighted abnormal observations in optical coherence tomography (OCT) imaging and electroretinography (ERG).[4-6] Although the hallmark symptoms of the disease have been well catalogued, documentation of the ophthalmic imaging findings related to the associated maculopathy in the literature is limited. This case report presents the multimodal ocular imaging including swept-source OCT, en-face OCT, OCT angiography, and fundus autofluorescence in a patient presenting with SCA1 maculopathy.
A 70-year-old man with genetically confirmed SCA1 was referred to ophthalmology for progressive bilateral visual loss. On examination, he was found to have hypermetric saccades jerky eye pursuit movements, with horizontal nystagmus on lateral gaze bilaterally. The patient did not report diplopia or visual distortion although he did note a reduction in color vision, with a corresponding score of 4 on the Ishihara 10 plate test bilaterally. The patient had previous bilateral cataract surgery, with clear posterior chamber intraocular lenses visible on slit-lamp examination. His pupil examination and intraocular pressure were within normal limits bilaterally. His best-corrected visual acuity was 20/80 OD and 20/100 OS at the time of consultation. On dilated fundus examination, normal discs and vessels were visualized, alongside previously lasered senile retinoschisis and a blunted macular reflex. Although scotopic and photopic full-field ERG responses were within normal limits, multifocal ERG revealed bilateral central macular cone dysfunction, localized to the central <10° radius of both retinas. Fundus photography (Optos California, Optos PLC Edinburgh, U.K) depicted bilateral hypopigmentation of the fovea OU [Figure 1a] and prior laser scars in the inferotemporal periphery OD. Green autofluorescence (Optos California, Optos PLC Edinburgh, U.K) revealed a blunting of the macular hypo-autofluorescence signal in the macula OU, with hypoautofluorescence at the location of the laser scars OD [Figure 1b]. Swept-source OCT (Topcon Triton, Tokyo, Japan) of the macula demonstrated attenuation of the external limiting membrane and ellipsoid zone in the subfoveal region [Figure 2]. Swept-source en-face OCT (Topcon Triton, Tokyo, Japan) with segmentation at the level of the ellipsoid zone revealed an oval region of attenuated signal consistent with the transverse OCT findings of photoreceptor loss [Figure 3]. Swept-source OCT angiography (Topcon Triton, Tokyo, Japan) of the superficial capillary plexus, deep capillary plexus, and choriocapillaris exhibited no abnormalities.
SCA1 is a rare autosomal dominant condition that may be associated with both neurological and ophthalmological signs. As a nucleotide repeat disorder, pathogenesis of SCA1 involves the mutation of the 6p22.3 gene which leads to abnormal protein translation, resulting in aberrant protein interactions and allele instability. The disease phenotype and age of onset show marked variability, reflective of differences in repeat size between individuals.
Confirmed SCA1 has been associated with progressive visual disturbance, retinal degeneration, and optic atrophy.[3,6] However, studies investigating maculopathy in association with SCA1 are especially limited due to the small number of patients presenting with this development. Multiple previous studies have assessed various visual functions through a variety of imaging modalities [Table 1]. To the best of our knowledge, this is the first study to present comprehensive multimodal imaging in one with confirmed SCA1 and maculopathy.
|Article title and authors||Patient population||Genetics||Clinical examination||Fundus findings||OCT||FAF||Angiography||ERG|
|Novel Maculopathy in Patients with SCA1 Autofluorescence Findings and Functional Characteristics. (Vaclavik et al., 2013)||61 and 62-year-old M with confirmed SCA1||43 and 46 CAG trinucleotide expansion in ATXN1||One patient showing decreased saccadic velocity, hypermetric saccades. Other patient showing saccadic pursuit without nystagmus||Bilateral areas of hypopigmented RPE in macula||Time-domain OCT showed bilateral hyporeflective foveal cavities and thinning of the outer nuclear layer||Central mild hyperautofluorescence surrounded by ring of hypoautofluorescence||Fluorescein angiography showed small areas of patchy hyperfluorescence corresponding to depigmented RPE areas|
|Functionally Relevant Maculopathy and Optic Atrophy in SCA1 (Oertel et al., 2020)||20 patients with confirmed SCA1 (Average age 46)||Average 49.5 CAG repeats||Abnormal color vision in 2/5 patients with identified maculopathy||5/20 patients showed distinct maculopathies in the ellipsoid zone. Peripapillary retinal nerve fiber layer thickness and combined ganglion cell and inner plexiform layer were reduced in patients with SCA1 (compared to controls)|
|Rod-Cone Dystrophy in SCA1. (Thurtell et al., 2011)||56-year-old F||46 CAG repeats||Progressive painless vision loss, bilateral central scotomas, impaired color vision. Slow saccades and smooth pursuit without nystagmus were noted on oculomotor examination||Absent foveal light reflexes, drusen, retinal arteriolar changes and subtle pigmentary changes in the posterior poles. Optic discs appeared normal||Full field ERG showed attenuated responses to all stimuli in both eyes (prolonged implicit time for dim white flashes and maximal white b waves)|
|Maculopathy and SCA1: A new association? (Lebranchu et al., 2013)||4 patients from one family||Confirmed CAG expansion||Central scotomas in most eyes||Unremarkable in most patients.||Central retinal thinning of the retina or disorganized photoreceptor layers||Multifocal ERG revealed central retinal dysfunction in one patient|
|Macular degeneration as a common cause of visual loss in SCA1 patients. (Nishiguchi et al., 2019)||5 unrelated patients (age 48–58 years, 3 F and 2 M)||Confirmed CAG expansion||Aside from reduced visual acuity, no other findings were documented||Normal optic disc and macula in all patients||4/5 patients demonstrated foveal thinning (of which 3 had reduced visual acuity)||Reduced multifocal ERG was noted in two patients out of the three who had reduced visual acuity|
|Temporal Retinal Nerve Fiber Loss in Patients with SCA1. (Stricker et al., 2011)||9 unrelated patients (age 18-71 years, 5M and 4 F)||Average 48.1 CAG repeats||Average visual acuity significantly reduced compared to age matched controls||Total average retinal nerve fiber layer thickness of SCA1 patients was significantly reduced compared to healthy controls (thinning was predominant in temporal sectors and was absent in nasal sectors)|
Cone dystrophies comprise a group of disorders characterized by abnormal cone system visual field thresholds and cone-mediated mfERGs, with full-field rod-mediated ethylene response factor amplitudes ranging from 50% reduction to normal functioning. A subset of patients may present with involvement of only the central cones, with normal full-field ERG recordings. Inherited cone dystrophies have been reported in association with autosomal recessive, autosomal dominant, and X-linked recessive inheritance, with some manifestations limited to purely a cone origin and others later indicating rod dysfunction. Cone dystrophies that may involve secondary rod dystrophy have been reported in association with neurofibromatosis type 1, Bardet-Biedl syndrome, Alström syndrome, Pierre Marie ataxia, SCA7, amelogenesis imperfecta, and trichomegaly. Cone dystrophies have been associated with the involvement of several chromosomal loci and genes, not limited to COD2, RCD1 and 2, GUCA1A, RPGR, CNGA3, and CNGB3. Of these, the two progressive manifestations involving symptoms consistent with cerebellar ataxia, such as those in our patient, are SCA and Pierre Marie ataxia,[4,9] with genetic testing identifying SCA1 as the culprit in this case.
Primarily affecting cone system function, progressive cone dystrophy involves reduced visual acuity, photophobia, and abnormal color vision, often in the presence of a normal fundus examination. Patients with SCA-1 have been found to have a loss of cones, with bilateral foveal cavities or central retinal thinning.[6,11,12] Multimodal ocular retinal imaging was performed to evaluate our patient’s maculopathy [Figure 4]. OCT angiography images did not exhibit any vascular abnormalities and his fundus photography was notable for bilateral hypopigmentation of the fovea. It is important to note that the blunted autofluorescence signal detected bilaterally may be associated with retinal pigment epithelial (RPE) degeneration. Swept-source OCT, coupled with en-face imaging, revealed an attenuation of the ellipsoid zone consistent with photoreceptor loss. The thinning of the ellipsoid region and the RPE degeneration may jointly account for the patient’s otherwise unexplained loss of visual acuity bilaterally.
The results of the scotopic and photopic full-field ERG were within normal limits and were not indicative of a rod-cone dystrophy. However, abnormalities of the multifocal ERG may indicate an early cone dysfunction affecting the macular region, with similar results noted in another patient with SCA-1 maculopathy. In a previously reported SCA1 case series involving heterogeneous intrafamilial expression, subtle and overt maculopathy were found in the presence and absence of ocular symptoms and were attributed to pigmentary macular dystrophy secondary to rod and cone dysfunction.[3,4,13] This finding, coupled with our multimodal imaging results, suggests that assessment of SCA1 patients with macular imaging may be appropriate before the onset of visual symptoms or at the time of initial diagnosis. Specifically, the use of OCT and en-face OCT is the most useful measures in assessing photoreceptor changes and may be used to monitor progressive macular dystrophy.
Patients with SCA-1 maculopathy may present with progressive loss of visual acuity and abnormal color vision, with correlated findings on mfERG. OCT and en-face OCT are useful tools to visualize and assess SCA-1 maculopathy findings and should be considered as part of the routine examination in these patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent.
Financial support and sponsorship
Conflicts of interest
Netan Choudhry is a consultant for Topcon, Allergan, Johnson & Johnson, Zeiss, Bayer & Optos PLC. None of the aforementioned had a role in the study design, collection, analysis, and interpretation of data in this report.
- Invest Ophthalmol Vis Sci. 2002;43:2364-73.Local cone and rod system function in progressive cone dystrophy.
- [Google Scholar]