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Show Journal of Neuro- Ophthalmology 18( 1): 9- 14, 1998. © 1998 Lippincott- Ravcn Publishers, Philadelphia Foveal Cone Dysfunction Syndrome Martin W. ten Hove, R. Michael Siatkowski, and J. Lawton Smith Summary: Our objective was to describe and expand the clinical spectrum of a rarely detected, previously reported photoreceptor disorder restricted to the foveal cones. Three patients with bilaterally decreased acuity and hemeralopia were examined to exclude a structural, vascular, inflammatory, or degenerative process. Each patient underwent a full neuroophthalmic examination, including full- field and focal cone electroretino-gram ( ERG). All three patients had normal- appearing fundi, mild dyschromatopsia, central or paracentral visual field depressions, normal full- field photopic and scotopic ERGs, and markedly reduced focal, foveal cone ERG responses. One patient had a ring scotoma and an asymptomatic family member with abnormal full- field and focal cone ERG. The syndrome of acquired foveal cone dysfunction presents as a bilateral, painless, progressive central visual loss with minimal or absent fundus changes. It eludes diagnosis until focal, foveal cone ERG is performed. Key Words: Foveal cone- Photoreceptor disorders. Cone dysfunction is an often unrecognized cause of visual loss later in life ( 1). Such patients present with decreased central acuity, hemeralopia, and/ or dyschromatopsia ( 2,3). Fundus abnormalities are typically subtle; however, a number of cases with bull's eye macular changes and temporal atrophy of the optic disk have been described ( 1- 3). Electroretinography ( ERG) establishes the diagnosis by demonstrating abnormal cone and normal rod responses ( 2,3). Isolated involvement of the macular cones may represent a forme fruste of panretinal cone dystrophy or, alternatively, may be a separate disease entity. Patients with this condition also present with decreased acuity and/ or hemeralopia. However, there are sufficient numbers of intact peripheral cones to allow at least partial preservation of color discrimination. Matthews et al. have observed five patients with negative family histories of eye disease who had subnormal focal ( foveal) ERG amplitudes and normal full field ERG responses ( 4). We present three similar cases that add to the understanding and awareness of this entity. Manuscript accepted 6/ 5/ 96. From the Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida, U. S. A. Address correspondence to Dr. R. M. Siatkowski, 900 N. W. 17th St., Miami, FL 33136, U. S. A. Presented in part as a poster at the American Academy of Ophthalmology Annual Meeting, San Francisco, 1994. PATIENTS AND METHODS Three patients ( 53, 58, 72 years of age) with decreased visual acuity and hemeralopia were seen at the Bascom Palmer Eye Institute between 1989 and 1994. Each patient underwent full neuroophthalmic examintions, including Goldmann perimetry, Farnsworth D- 15 and Isi-hara color vision testing, fundus photography, fluorescein angiography, and full- field ERG. Focal cone ERG testing was performed by Dr. Eliot L. Berson and Dr. Ronald E. Carr. Full- field ERGs were recorded using International Society for Clinical Electrophysiology of Vision ( ISCEV) standard techniques under scotopic and photopic conditions. Focal cone ERGs were performed in dim illumination under maximal mydriasis. A corneal bipolar-electrode contact lens and forehead ground electrode were used. The fellow eye was patched. A hand- held stimulator- ophthalmoscope projected the central 4 degrees with a repetitive white stimulus lasting 12 ms, whereas the surrounding 10 degrees received a steady white light to minimize the effects of stray light from the central stimulus. Flickering central stimuli were used. The signal was amplified by 10,000 times, attenuated with respect to line noise ( 60- Hz notch filter), and amplified again by spike filters tuned to 10 Hz, 25 Hz, 42 Hz and 50 Hz ( stimulus frequencies). Wave forms were analyzed for peak- to- peak b- wave amplitude and implicit time. CASE REPORTS Case 1 A 58- year- old woman presented with impairment of vision in daylight for the preceding 2 years. Vision had declined from 20/ 20 in both eyes to 20/ 50 in the right eye and 20/ 40 in the left eye. She described bothersome " glare" with daylight illumination, and commented, " Like a cat, I see better at night." Cataract extraction in the right eye was performed for a mild lens opacity, which was originally felt to be the cause of her poor acuity. However, postoperatively, acuities gradually decreased further over 1 year to 20/ 140 in the right eye and 20/ 50 in the left eye. Therapeutic trials of oral prednisone and vitamin B12 injections offered no improvement. Past medical history was notable for " migrainous" headaches, hypertension, recurrent depression, and alcohol abuse. She was on no medications other than Ten- 10 M. W. TEN HOVE ET AL. ormin. Family history was significant for glaucoma and cancer. Best corrected visual acuity was 20/ 140 in both eyes, improving with pinhole to 20/ 120 in the right eye and 20/ 80 in the left eye. Six of 10 presented Ishihara color plates were correctly identified in each eye. Pupils were equal and briskly reactive without an afferent defect. Peripheral fields were full, but central fields showed bilateral cecocentral scotomas that were larger for color targets than for white targets. Slit- lamp examination showed pseudophakia in the right eye and pseudoexfo-liation in the left eye. The fundi were normal apart from mild temporal disk pallor ( Fig. 1). Serologic tests for syphilis, Lyme disease, and thyroid dysfunction were all normal. Full- field ERG was within normal limits ( Fig. 2). Focal ERG performed by Dr. Ber-son showed bilaterally reduced ( 0.11 | xV in the right eye and 0.12 | xV in the left eye; normal, 0.18- 0.56 | xV) and delayed responses ( 45 ms in the right eye and 44 ms in the left eye; normal, =£ 38 ms). Case 2 A 72- year- old man presented with difficulty reading and discriminating colors for 3 years. Vitamin A, B12, and E replacement did not improve visual function. Past medical history was remarkable for diabetes mellitus for 8 years and a remote history of bilateral Bell's palsies. There was no family history of visual loss. Best corrected visual acuity in both light and dark illumination was 20/ 100 in the right eye and 20/ 140 in the left eye. Farnsworth color testing suggested a deuteranopic axis of confusion. Pupils were 2 mm in diameter and minimally reactive without an afferent defect. Peripheral fields were full, but central fields showed large central scotomas. Slit- lamp examination showed only mild nuclear sclerosis bilaterally. Fundi were both normal, although the foveal reflexes were somewhat blunted. MRI of the brain showed only moderate cerebral atrophy. Vitamin A, B12, and E levels were normal. A Lyme disease panel, rapid plasma reagin ( RPR), floures-cent treponemal antibody- absorption ( FTA- ABS), and retinal S antigen were all negative. Cerebral angiography was unremarkable. Full- field ERG responses were within normal limits. The patient was referred to Dr. Ronald Carr for foveal ERG testing, which showed reduced and delayed responses ( Fig. 3). Case 3 A 53- year- old woman complained of bilateral, painless, progressive visual loss since 40 years of age. By old records, visual acuity had declined from 20/ 30+ in each eye to the 20/ 60- 20/ 70 level. Past medical history was significant for migraine headaches, temporomandibular joint syndrome, and depression. She was taking Cafergot ( Sandoz Pharmaceutical Corp, East Hanover, NJ), Mid-rin ( Carnrick Laboratories, Inc., Cedar Knolls, NJ), and Prozac ( Eli Lilly, Indianpolis, IN). Best corrected visual acuities in normal illumination were 20/ 200 in the right eye and 20/ 400 in the left eye, improving to 20/ 60- 2 in the right eye and 20/ 60 in the left eye in dim illumination. With pinhole use, acuities improved further to 20/ 30 in the right eye and 20/ 40 in the left eye. Ishihara color plates were correctly identified seven and eight times ( out of 15) in the right and left eyes, respectively. Farnsworth D- 15 test was normal in both eyes. Pupils were briskly reactive without afferent defect. On Aimark perimetry and tangent screen, peripheral fields were full with bilateral cecocentral scotomas associated with ring scotomas ( Fig. 4). Slit- lamp examination was unremarkable. The fundi were normal apart from a mildly blunted foveal reflex on the right. Full-field ERG responses were within normal limits. Visual evoked potentials, optic nerve ultrasonography, carotid ultrasound, magnetic resonance imaging of the brain, and Holter monitoring were all normal. She was referred to Dr. Ronald Carr for foveal cone ERG testing which was abnormal at all frequencies ( Fig. 5). The patient's daughter, who was asymptomatic with 20/ 20 vision in both eyes, was also tested and had full- field and foveal cone ERG responses at the lower limit of normal. FIG. 1. Case 1. Fundi showing mild disk pallor in both eyes ( arrows) and normal maculae. A: Right eye. B: Left eye. ./ Neuro- Ophllwlmol, Vol. IS, No. I, 1998 FOVEAL CONE DYSFUNCTION SYNDROME 11 Rod ERG b- wave Mixed cone- rod ERG b- wave a- wave Cone ERG b- wave a- wave Cone flicker Amplitude ( uv) OD / OS 232.4 / 187.5 484.4 / 445.3 148.4 / 140.6 48.4 / 41.0 9.76 / 10.9 53.3 / 46.0 Implicit time ( ms) OD / OS 84.0 / 91.2 55.2 / 50.4 16.4 / 18.4 31.6 / 3 0.0 17.6 / 16.8 30.6 / 30.4 FIG. 2. Case 1. A: Full- field ERG with normal amplitudes and implicit times. Tracings ( top to bottom) are as follows: rod ERG, mixed cone- rod ERG, cone ERG, and cone flicker. B: Table shows absolute values of amplitude and implicit times. DISCUSSION Acquired generalized cone dysfunction generally presents early in life, but occasionally as late as the sixth decade of life ( 1). Both sporadic and hereditary forms have been reported ( 2), the majority of the latter transmitted as an autosomal- dominant trait ( 3). Although acquired, generalized cone dysfunction affects all of the retina's 5- 7 million cones, it is the involvement of the 0.44 million cones subserving the central 10 degrees that results in impaired acuity ( 5). Isolated involvement of the central foveal cones would allow peripheral cone function with seemingly normal color discrimination. Whether isolated foveal cone dysfunction represents a unique M ERG. RE, BH& tiD- bFF. O. 25 BLUE A3 ERG. RE. 8KGD- OFF. 1. 25 WHITE AS ERG. RE. BKGD- WFT- L. O. 25 WHITE 1 A4 ERG. RE. BKGD- 2FT- L. C. 25. 29 HZ Bl ERG. LE^ mfiB- O. 25 BLUE B2 ERG. LE. BKGD- OFF, I. 25 WHITE B3 ERG. LE. BKGD- WFT- L. D. 25 WHITE • I 34 ERG. LE. 8KCD- 2FT- L. O. 25. 29 HZ J J I L J I I L J L J I L Rod ERG b- wave Mixed cone- rod ERG b- wave a- wave Cone ERG b- wave a- wave Cone flicker Amplitude ( uv) OD / OS 242.2 / 234.4 460.9 / 476.6 429.7 / 429.7 39.5 / 39.8 14.4 / 13.7 47.9 / 47.6 Implicit time ( ms) OD / OS 94.0 / 94.0 70.0 / 57.6 14.8 / 15.2 28.0 / 28.0 16.0 / 14.4 28.0 / 28.6 Focal ERG OD Cas* 2 Temporal Frequency ( Hz) FIG. 3. Case 2. A: Normal full- field ERG. B: Table of amplitudes and implicit times. C: Focal cone ERG shows subnormal amplitudes at all temporal frequencies. J Neuro- Oplilhalmoi, Vol. 18. No. I. 1998 12 M. W. TEN HOVE ET AL. FIG. 4. Case 3. Ring scotomata. A: Goldmann perimetry, right eye and Goldmann perimetry, left eye. B: Aimark perimetry, both eyes. entity or an earlier, incomplete stage of a generalized cone disorder is unknown. Indeed, whether this entity is limited to the cone photoreceptors in this area is also undetermined. Symptomatic central visual loss in generalized cone dystrophy may progress for years before stabilizing, similar to the duration of progression observed in our cases ( 2- 13 years) and those of Matthews et al. ( 1- 10 years) ( 4). Reliance on rod photoreceptors can cause patients to complain of daytime " glare" or hemeralopia. Hemeralopia is readily distinguished from other causes of daytime glare ( e. g., cataract) through proper dilated slit- lamp examination. A pinhole apparatus may improve acuities recorded under bright illumination even beyond the best refraction, presumably by decreasing the amount of light reaching the retina ( 6). Difficulty with color vision and visual field loss also may be presenting symptoms. Field defects in generalized cone dysfunction syndromes include enlarged blind spots and ring scotomas, as well as centrocecal, central, and paracentral scotomas ( 2,6). However, in the series of focal, foveal cone syndromes described by Matthews et al. ( 4) and Miyake et al. ( 7), only central and paracentral scotomas were noted. In KrilPs series of 45 generalized cone dystrophies, he noted ring scotomas to be associated with bull's eye type changes in the macula ( 2). In our case 3, although the maculae were normal, a ring scotoma was evident, extending from 20 to 35 degrees when measured with a white stimulus, an area densely populated by rod photoreceptors. This implies that central rods also may be impaired in this disease process or that larger numbers of peripheral cones may be present in some individuals. One must remember that the extent of such field defects vary with background illumination and target luminance. Automated perimetry of the central 24 or 30 degrees may miss ring scotomas, which may only be appreciated with the amplification achieved by tangent field and kinetic perimetry. Alternatively, the field defect may be outlined with the use of focal ERG testing as suggested by Matthews ( 4) and is the only pure way to determine the exact extent and density of the field deficit. Color vision in isolated foveal cone dysfunction may depend on stimulus size and the topographic extent of cone involvement. Two of our cases had only minimally impaired color vision based on Farnsworth D- 15 and Ishihara plate testing. Our case 2 ( a man) had a red- green defect similar to that in two cases described by Matthews J Neiira- Ophlhalmol, Vol. IS, No. I, 1998 FOVEAL CONE DYSFUNCTION SYNDROME 13 RICHT EYE A 4 arte. RE. BKGD'OFF. - a 25 BLUE A3 ERG. FIE, BKCD- OFF. 1. 25 IfHSTE A2 ERG. RE. 0KGD- 1OF7- L. O. 25 VHITE Al ERG. RE. BKCD- 2FT- L. O. 25. 29 HZ B- t ERG. LE. BKCD- OFF, - 0. 25 BLUE B3 ERG. LE. BKCD- OFF. 1. 25 HHITE B2 ERG. LE. BKGD- 10FT- L. 0. 25 tMITE Bl ERG. LE. BKCD- 2FT- L. 0. 25. 23 HZ Focal ERG OD Cat* 3 Rod ERG b- wave Mixed cone- rod ERG b- wave a- wave Cone ERG b- wave a- wave Cone flicker Amplitude ( uv) OD / OS 230.7 / 259.8 216.4 / 289.1 230.5 / 226.6 10.9 / 14.1 8.61 / 12.5 25.8 / 28.1 Implicit time ( ms) OD / OS 103.6 / 101.6 61.6 / 53.6 15.6 / 14.4 30.0 / 29.6 18.0 / 18.8 29.2 / 29.0 Temporal Frequency ( Hz) FIG. 5. A: Normal full- field ERG. B: Table of amplitudes and implicit times. C: Focal cone ERG shows subnormal amplitudes at all temporal frequencies. et al. ( 4), as did all three cases reported by Miyake et al. ( 7). This is a violation of Kollner's rule ( that retinal conditions cause blue- yellow defects); however, in our case a preexisting dyschromataposia could not be ruled out. Late- onset acquired generalized cone dysfunction with abnormal full- field ERG has been well described ( 2,8,9). The percentage of cases with a positive family history is inversely proportional to age at presentation. None of our cases of focal, foveal cone dysfunction had a positive family history; however, the asymptomatic daughter of case 3, who simply accompanied her mother to her examination, was found to have focal and full- field cone ERG amplitudes at the lower limit of normal. Miyake et al. ( 7) reported three family members who noted decreased central vision at 13, 29, and 35 years of age and were subsequently shown to have abnormal focal ERG and yet normal full- field ERG. He also demonstrated that as the focal ERG spot size increased ( from 5 to 15 degrees), the ERG amplitude increased, supporting the notion that central cones are the ones most impaired. Progression of both visual loss and full- field ERG changes has been reported with acquired generalized cone dysfunction ( 10); however, electrophysiologic evidence that macular cones are the first to be involved, with subsequent spread to the peripheral cones, is still lacking. Focal ERG abnormalities in patients with normal full-field ERGs are also seen in Stargardt's disease, juvenile macular dystrophy, age- related macular degeneration, and macular scars ( 11,12). These conditions are readily differentiated from foveal cone dysfunction by their ophthalmoscopic appearance. Cancer- associated retinopathy may present similarly ( and was tested for in case 2); however, it can be distinguished by its rapidly progressive course ( 13). Impaired vision secondary to optic atrophy or amblyopia can be excluded because focal ERG is normal in these disorders ( 12). Optic atrophy, when it occurred in our cases, was very subtle. The exact mechanism for its development is unknown. Primary foveal photoreceptor dysfunction may lead to subsequent bipolar and ganglion cell dysfunction, J Neuro- Ophthalmol, Vol. 18, No. I, 1998 14 M. W. TEN HOVE ET AL. resulting in optic disk pallor; optic atrophy is frequently seen in retinitis pigmentosa and other retinal dystrophies and degenerations. Conversely, long- standing optic neuropathies ( e. g., glaucoma) may result in b- wave changes on full- field ERG; in these cases, retrograde degeneration of mid- retinal structures may have occurred over time. Nevertheless, in our patients, the presence of minimal optic atrophy, obvious focal ERG abnormalities, and hemeralopia all indicate that the primary site of pathology is the retina rather than the optic nerve. The search for the etiology of central visual loss in patients with foveal cone dysfunction may lead to numerous unnecessary investigations, including magnetic resonance imaging ( MRI), computed tomography ( CT) ( 4), lumbar puncture, psychiatric assessments ( 4), and expensive laboratory workups. Patients with acquired cone dysfunction presenting in later adulthood may be particularly difficult to diagnose, especially if the family history is negative. Recognition of this entity may avoid unnecessary, expensive diagnostic testing and enable clinicians to properly counsel such patients. Although the cost of the equipment necessary to perform focal ERG is high ( approximately $ 25,000- 30,000), in the long run it will be offset by the savings in other diagnostic and consultative approaches. ( One of our patients underwent five ophthalmologic consultations, two CT scans, one MRI, optic nerve echography, full- field ERG, various blood studies, and finally cataract extraction before the diagnosis was made). In summary, the syndrome of acquired foveal cone dysfunction presents as bilateral ( but possibly asymmetric), painless, progressive loss of central vision with essentially normal fundi and normal full- field ERG. It may elude diagnosis until focal ERG is performed. Focal ERG abnormalities may precede full- field ERG abnormalities if this syndrome is a forme fruste of a more generalized cone dystrophy. Cases of isolated foveal cone dysfunction need to be followed prospectively to determine if such changes evolve. Our cases expand the clinical spectrum to include ring scotomas that suggest the involvement of adjacent central rods despite a normal full- field rod ERG. Additionally, the finding of subclinical ERG changes in an asymptomatic family member should prompt further study in this area. Although the exact pathophysiology of this entity remains to be clearly elucidated, we encourage other clinicians to be cognizant of its existence and report on their findings. Acknowledgment: Dr. ten Hove was supported by the McLaughlin Foundation of Canada and is currently affiliated with Queen's University at Kingston Ontario, Canada. This work was supported in part by an unrestricted grant from Research to Prevent Blindness. REFERENCES 1. Ryan SJ. Retina. 2nd ed. Vol. 1. St. Louis: CV Mosby; 1993: 458- 9. 2. Krill AE, Deutman AF, Fishman M. The cone degenerations. Doc Ophthalmol 1973; 35: 1- 80. 3. Gass JDM. Stereoscopic Atlas of Macular Disease. Vol. 1. St. Louis: CV Mosby; 1987: 264- 6. 4. Matthews GP, Sandberg MA, Berson EL. Foveal cone electroret-inograms in patients with central visual loss of unexplained etiology. 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