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Show JOllmal 01 Clime,,1 Nt'llIo-ophthalllIologll 7(4): 202-218, 1987 Neuro-ophthalmic Presentation of Cone Dysfunction Syndromes in the Adult Jeffrey p, Zervas, M.D., and J. Lawton Smith, M.D. C<;" 1987 Raven Press, Ltd., New York Acquired cone dystrophies are usually seen within the first two decades of life and present characteristic fundus changes. We have encountered six adult patients, aged 19-67 years, referred for visual field defects not explained by the neurologic or ophthalmic findings. All six patients showed decreased to absent cone function with relative preservation of rod function on electroretinography. The purpose of this report is to document the importance of and indications for electroretinography in adult patients seen in neuroophthalmologic practice. CASE REPORTS Case 1 This 66-year-old right-handed white woman first noted difficulty when she tried to read outdoors one morning in July 1985. It was quite bright on her veranda as she attempted to read her newspaper. She covered the left eye and could only see one letter of the headlines. Closing the right eye, she felt as if she were "looking through a straw" with the left eye. She ran back inside-where there was much less light-and then was able to read her ophthalmologist's number in the telephone book! Examination that same day by both her ophthalmologist and a retinal consultant revealed only unspecified visual field abnormalities in both eyes for which she was referred to a neuro-ophthalmologist. On August 2, 1985, the neuro-ophthalmologic consultant found an enlarged blind spot in the From the Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine, Miami, Florida. I"ddr('ss COITl'Spl1Jldence dnd repnnt requests to Dr. J. L. " I'", "!, 1'"I"'l"r Inchll.ll" P (1. 8", 016RRO, Mi- 202 right eye and a dense ring scotoma in the left eye. Subsequent workup revealed mild anemia and positive anti-nuclear antibody titer of 1:160. Computerized tomography (CT) of the brain was normal. The patient was hospitalized elsewhere on August 14, 1985, for presumed autoimmune optic neuritis. Best corrected visual acuity was 20/20 in the right eye and 20/30 in the left eye. A questionable left afferent pupillary defect was found and color vision was reported as normal. Visual field testing was unchanged. Neurologic and medical consultations were otherwise unrevealing. SoluMedrol 1 g was administered intravenously for 5 days. The patient was discharged on 100 mg prednisone daily. It was felt that visual function slightly improved on the steroid therapy. On September 19, 1985, electroretinography revealed mildly abnormal photopic responses in the right eye and moderately abnormal photopic responses in the left eye. Scotopic electroretinography was borderline in both eyes. Electro-oculography showed abnormal light-dark ratios in both eyes. Visual evoked responses were normal in the right eye but showed reduced amplitudes in the left eye. The patient was seen at the Bascom Palmer Eye Institute by Dr. J. D. M. Gass on October 7, 1985. Best visual acuity was 20/20 in the right eye and 20/25 in the left eye. She correctly identified 12 of 14 pseudoisochromatic color plates with both eyes. A slight left afferent pupillary defect was again noted. The fundi showed slight nonspecific stippling of the retinal pigment epithelium in the periphery. Fluorescein angiography suggested zones of hypertluorescence inferior to the papillomacular bundle in the right eye and superior to the macula in the left. Repeat electroretinography showed normal rod function but moderately reduced cone function in both eyes. Cone dysfunction was diagnosed. To exclude possible paraneo- CONE DYSFUNCTION SYNDROMES IN THE ADULT 203 plastic photoreceptor dysfunction, the patient had liver function studies and abdominal CT, all of which were normal. Neuro-ophthalmologic consultation was performed at the Bascom Palmer Eye Institute on February 23, 1987. The patient was now wearing sunglasses indoors, had installed additional window panes in her home, and was uncomfortable trying to ambulate alone outside during the day. The past history and family history were unremarkable. Best corrected visual acuity was 20/20 in the right eye and 20/20 in the left eye. She identified 13/15 pseudoisochromatic color plates with difficulty in each eye. Peripheral visual fields were normal in both eyes. Careful central field testing, however, showed bilateral ring scotomas, more easily plotted on the left than on the right (Fig. 1). Ophthalmoscopy was remarkable only for slight thinning of the retinal pigment epithelium nasally in both eyes and narrowing of the retinal arteries (Fig. 2). Electroretinography showed moderately reduced cone responses with normal rod responses in both eyes (Fig. 3). The findings were similar to the electroretinography done elsewhere in August 1985 and to the one done at the Bascom Palmer Institute in October 1985. The patient was found to have an antibody titer of 1:100 to retinal "S" antigen. COlllment This 66-year-old woman suddenly became aware of decreased vision when she tried to read outdoors in bright sunshine. She had excellent acuity, good color vision, and benign appearing fundi, which were passed by several competent ophthalmologists. Electroretinography consis- Op...'.r -.::.j_l.__ Olt, 2_-2_3_-8_7 _ T"" • b I. t .. --",31...:;3.:.;30,--W-,(.:.;0):....;;...c'--_ VISUAL FIELDS 1/330 W (0.6 int) .c tporlpbonl) L.£ It£. T." obi« II 3/330 W (O).c 11330 W (O).c VI~~., 20/20-3 (C.,'r.l) cc 20120+3 VIIl., _ FIG. 1. Case 1. Visual fields. February 23.1987. Lelt RiJht. .... Ring scotomas are largPt' in ll~hted room than in darkened room ( ommcm" I (1m N",m1,ol'iltlllllmol. V"l. 7. No, 4. 1987 204 J. P. ZERVAS AND J. L. SMITH FIG. 2. Case 1. Fundus, right eye (A) and left eye (B), February 23,1987. RIGHT EYE A4 £R[;. If£. ~.Do ~ BLUE A3 £RC. If£. ~. J. ~ ~lTC AI ERe. If£. BKGD-JCIFT-L. Do ~ ~lTC AJ ERe. If£. 1JKaJ-2F7'-L. Do ~ 21i HZ tently showed abnormal cone responses but normal rod responses in both eyes, Paraneoplastic photoreceptor degeneration was ruled out by excellent general health and a negative extensive search for occult carcinoma, Case 2 This 41-year-old right-handed white woman was referred for evaluation of bitemporal field defects. She was in good health until 1976 when she began to experience right-sided throbbing headaches and visual blackouts. Workup revealed an unspecified anemia for which iron supplements and antidepressants were given but her symptoms worsened. In February 1977 electroretinography, skull radiography, and CT of the brain were normal and she was advised to rest. In April 1978 she noted that part of the temporal field was missing in her left eye, Subsequent visual field testing suggested a chiasmal lesion and the patient had neurological examination; numerous blood tests; electroretinography; x-rays of skull, optic canals, and cervical spine; tomography of the sella; CT of brain and orbits with and without contrast enhancement, and transfemoral arteriography-all of which were reported as normal. Neuro-ophthalmologic examination at the Bas- LEFT EYE IU ERe. u:.~Do ~ BLUE 83 ERe. LE. BKCD-fJFF. J. 215 i'H1 TC 82 ERG. u:. 8KCD-JOFT-£.. Do ~ ~1 TC 8J ERe. u:. SI<CD-2FT-£.. Do 2S. a HZ FIG. 3. Case 1. Electroretinogram, February 23,1987. I Lilli CONE DYSFUNCTION SYNDROMES IN THE ADULT 205 com Palmer Institute on August 4, 1978, revealed best corrected acuity of 20115 in both eyes. She correctly identified 14 of 15 pseudoisochromatic plates with the right eye and 13 of 15 with the left eye. The peripheral visual field was normal in the right eye to white targets but a temporal contraction was present to red targets. In the left eye temporal contraction was again found but the isopters for two stimuli were coincident. A functional component was suspected on central field examination (Fig. 4). The funduscopic examination was normal (Fig. 5). Electroretinography showed subnormal cone function but normal rod function in both eyes (Fig. 6). The patient's 13-year-old son had a normal eye examination including electroretinography the same day. The family history was negative. Comment This 41-year-old woman presented with symptoms that may have been migrainous or non-specific. However, visual field testing mimicked true bitemporal defects although there appeared to be a superimposed functional component. Extensive neuroradiologic and ophthalmologic examinations revealed no other abnormalities but electroretinography established the diagnosis of cone dystrophy. Case 3 This 37-year-old right-handed white man obtained glasses for myopia at age 16 and switched to contact lenses at age 17. He did well and had no other eye complaints until December 1986 when he noted blurred vision in the upper temporal field of his left eye. His ophthalmologist found no abnormality and had the patient seen by a retinal consultant. Automated perimetry revealed field defects in both eyes which suggested a left homonymous hemianopia. Neurologic consultation was obtained which was unrevealing. Subsequent Opuator __--..-'!.!:.S. _ rut object, 31330 W (0) 1/330 W (0) 5/330 R (0) I.E. Ldl VISUAL FIELDS (per (ph.nO (Co'lul) R.E. Olio __A_Ur._.U_ST_4....:._19_78'- _ 3/330 W(0) Ttl' ob iec iLl ..,,-_..,.-"""'" 1/330 W (0.6) 5/330 R (0) 20/15-2 Vlllo' _ RighI, FIG. 4. Case 2. Visual fields, August4,1978. 206 J. P. ZERVAS AND J. L. SMITH FIG. 5. Case 2. Fundus, right eye (A) and left eye (B), August 4, 1978. workup included brain stem auditory evoked responses, visual evoked responses, lumbar puncture, enhanced CT of the brain, magnetic resonance imaging of the brain, and cerebral arteriography, all with negative results. He received intravenous steroids for 2 days followed by a short course of oral steroids without improvement. Neuro-ophthalmologic examination at the Bascom Palmer Institute on January 29, 1987, revealed best corrected visual acuity of 20115 in both " .' ·",<· ..-,1,· id~ 'ltified "·!'.~!lt of I') pseudo-iUI!, FIG. 6. Case 2. Electroretinogram, August 4, 1978. isochromatic plates with the right eye and seven of 15 with the left eye. Amsler grid testing revealed a superotemporal defect in the left eye. Peripheral visual fields were normal in both eyes, but on careful tangent screen testing a focal superior midzonal defect could be demonstated in both eyes. The defect clearly crossed the midline bilaterally (Fig. 7). Ophthalmoscopic examination was normal in both eyes (Figs. 8 and 9). Electroretinography showed moderately reduced cone function and borderline low rod function in both eyes (Fig. 10). Commellt This 37-year-old man had symptoms initially suggesting a retinal detachment in the left eye but the fundi were considered normal and field defects were found in both eyes. A homonymous hemianopia was suspected and led to extensive neurologic workup. The family history was unremarkable and he had good vision with normal appearing fundi. Poor results on color vision testing led to electroretinography, which confirmed the diagnosis of bilateral cone dysfunction. Case 4 This 65-year-old right-handed white woman was referred for evaluation of pale optic disks. In 1983 she had an ophthalmic examination because CONE DYSFUNCTION SYNDROMES IN THE ADULT 207 O,...t.,_j_lH . . _ O.t. .January 29. 1987 _ T.. , obl,et• .u110 W (Q) fnt sc Alma.rk ~I;~•• = 20/15 VISUAL FIELDS tpo,I,laor.O (C••lr.l) It£. 3/))0 \I (0) lnt sc Almark c Cl. VIii•• = 20/1 5 FIG. 7. Case 3. Visual fields, January 29. 1987. she had been involved in two automobile accidents that she felt were due to visual problems in the right field of view. That examination was essentially normal except for questionable pallor of the optic disks. In September 1983 she underwent a neurologic consultation and CT of the brain, both of which were normal. In May 1985 her ophthalmologist recorded 20/40 vision in both eyes with the lights off, but 20/200 in both eyes with the lights on. Repeat CT and magnetic resonance scan of the brain were both negative. Neuro-ophthalmologic evaluation at the Bascom Palmer Institute was performed on December 1, 1986. She admitted having had difficulty identifying colors for the past few years. She had difficulty focusing on bright objects but also had problems under conditions of dim illumination as well. The family history was negative for known eye disease, color blindness, hemeralopia, or nyctalopia. Best corrected visual acuity was 20125 in the right eye and 20/20 in the left eye, and no difference was recorded with normal room illumination or with the room lights dimmed. However, she was unable to identify any of the pseudoisochromatic color plates with either eye. The peripheral visual fields were normal in both eyes but central field testing with subtle isopters revealed bilateral ring scotomas (Fig. 11). The ring scotomas were larger in a lighted than in a darkened room. Funduscopic examination was considered normal for her age (Figs. 12 and 13). On careful consideration, however, the retinal arteries appeared narrowed in both eyes. Electroretinography showed moderately reduced rod responses in both eyes; however, the cone responses were nonrecordable in both eyes (Fig. 14). , CLill Nfilro-ophthalllll'l. V,'l. 7. No.4. 1987 208 J. P. ZERVAS AND J. L. SMITH FIG. 8. Case 3. Fundus, right eye, January 29,1987. Comment A 65-year-old woman presented with visual complaints that had been regarded as functional. She later complained of difficulty identifying colors. Visual acuity was good, peripheral fields were intact, and the fundi were considered normal by several ophthalmologists. However, not only was color vision markedly defective, but subtle ring scotomas were found on careful tangent screen testing in both eyes, and the retinal arteries were narrowed bilaterally. The diagnosis was established by electroretinographic evidence of absent cone responses in both eyes. The patient was notably relieved after hearing her diagnosis as she had been fearful she was losing her mind after having been told there was nothing wrong with her eyes by ophthalmologists. FIG. 9 Case 3 Fundus, left eye (x 1.5), January 29,1987. I Lilli CONE DYSFUNCTION SYNDROMES IN THE ADULT 209 2 ) J ~ '~Y''{7 A] 1 j r"~ 4) L..L I 1 FIG. 10. Case 3. Electroretinogram, January 29,1987. op... to, __31_5 _ rOlt obI •• " 3/)30 W (0) int 5C Alman VISUAL. FIELDS tperlpb... ll Oat. 12-1-86 _ 3/330 W (0) int 5C Teu obJecl'L- _ 20/)(}+-2 I.E. lIif•• 20/2S+2 RoE. cc "101.. _ FIG. 11. Case 4. Visual fields, December 1, 1986 ". Comment!' Ring scotoma 18 larger 1n light than 1n dark room Rip. 210 J. P. ZERVAS AND J. L. SMITH FIG. 12. Case 4. Fundus, right eye (A) and left eye (B), December 1, 1986. [( IGIIT E',E A 4 ERG. liE lJKGM)-()FF. a. 25 8L l1E A3 ERG. liE BXt:iD-OF'F. 1.25 rHITF Ai? ERG. liE BKGD-JOFT-L. J. 25 IIHI TF AJ ERG. Re. fJX(;[)-<?FT-I... J. a i?fJ HZ FIG. 13. Case 4. Fundus, right eye (A) and left eye (B) (x1), December 1,1986. LEfT EYE B4 ERe. L£. BKCND-tFF. a. 25 SLUE B3 E7W:;. L£.~~ 25 .-HITF &! eRG. LE. BK'CIJ-lon'-L. J. 25 rHI TF 9J ERe. L£. B1fClJ-2FT-1... J. a i?fJ HZ FIG. 14. Case 4 Electroretinogram, December 1, 1986. CONE DYSFUNCTION SYNDROMES IN THE ADULT 2/1 Case 5 This 51-year-old white man was referred for unexplained visual loss. He had no eye complaints until March 1971 when he became aware of "waves of light" in the lower temporal field of the right eye when he turned his head to the right. His ophthalmologist found only a questionably enlarged blind spot in the right eye and the remainder of the workup, including x-rays of skull and optic canals, was negative. In April 1972 similar symptoms were noted in the left eye, and subsequent examination by another ophthalmologist revealed constricted fields in both eyes. Neurologic workup, including lumbar puncture, electroretinography, skull radiography, and radionuclide brain scan, was normal. Oral steroids for 6 weeks had no effect. In August 1972 a third ophthalmologist was consulted and he described subtle paracentral visual field defects bilaterally but otherwise the eye examination, including fluorescein angiography, was normal. In November 1972 a fourth ophthalmologist found an abnormality on color plate testing but considered the patient's complaints functional. By August 1974 the patient noted that reading was becoming more difficult. He stated he could not see whole words and that he would lose his place in a sentence. Neuro-ophthalmologic consultation was performed at the Bascom Palmer Institute on October 11, 1974. Additional history rvealed that he had quit driving for 2-3 years because of poor vision and that his vision was better in the evening than during the day. The family history was negative. The best corrected acuity was 20/30 in both eyes. He correctly identified 11 of 15 pseudoisochromatic color plates in the right eye and 10 of 15 in the left eye. The peripheral fields were normal in both eyes but subtle and inconsistent central scotomas could be found in the central 5-8 degrees bilaterally with a reduced intensity projector light technique (Fig. 15). Careful dilated fundus examination revealed normal disks (Fig. 16) and maculae (Fig. 17) bilaterally. Fluorescein angiography was normal. Electroretinography showed slightly abnormal rod function but definitely abnormal cone function in both eyes. Comment A 51-year-old man had nonspecific visual complaints and showed variable field defects. Examination of his eyes was considered unremarkable to four ophthalmologists including two evaluations at academic institutions, and he was thought to have functional complaints. Family history, color vision, and ophthalmoscopic findings were unrevealing, but subtle central scotomas were found. Electroretinography established the diagnosis of photoreceptor dysfunction, which primarilv in-volved the cones. . Case 6 A 19-year-old white woman was referred for evaluation of "optic neuritis" in the left eye. She had worn glasses since age 12 for myopia and began contact lenses at age 14. She had no other eye complaints until March 1977 when she noted a blurred spot in the lower nasal field of her left eve. Left ITO 5/1000 W pl cc Right. no Comment, subtle small variable 5-8 degree central scotomas FIG. 15. Case 5. Visual fields, October 11, 1974. 212 J. P. ZERVAS AND J. L. SMITH FIG. 16. Case 5. Fundus, right eye (A) and left eye (B), October 11, 1974. Four months later she developed headaches and underwent complete neurologic examination including skull radiography with optic canal views, radionuclide brain scan, and brain CT, all of which were normal. Past history and family history were unremarkable. Neuro-ophthalmologic examination at the Bascom Palmer Institute on December 19, 1977, revealed best corrected visual acuity of 20/20 in both eyes. She correctly identified 14 of 14 pseudoisochromatic color plates with the right eye and 12 of 14 in the left eye. An afferent pupillary defect was evident in the left eye. Ophthalmoscopy was normal in both eyes except for questionable pallor of the left disk. The peripheral field isopters were normal, but central fields were normal in the right eye and revealed a ring scotoma in the left eye (Fig. 18). Electroretinography demonstrated normal rod and cone responses in the right eye, but the left eye revealed severely reduced cone function although rod function was normal (Fig. 19). The patient's father, mother, and younger sister had complete eye examinations including electror" bn"''::''-'i,h" ,1n~: I,n "hr\l)rmalities were found. Followup neuro-ophthalmologic examinations 6 months, 21J2 years, and 5 years later, including repeat electroretinography on each occasion, showed no change. On each occasion, electroretinography was normal in the right eye but showed severely reduced cone function in the left eye. Examination by her ophthalmologist on October 8, 1986, showed a best corrected acuity of 20/20 in both eyes and questionable pallor of the left disk. Comment This 19-year-old white woman presented with a mild visual field defect in one eye. Despite normal acuity and good color vision, an afferent pupillary defect was present in the symptomatic eye, and no fundus change was noted but for equivocal optic disk pallor. The initial clinical impression was a bout of retrobulbar optic neuritis. However, electroretinography demonstrated the most unusual finding of unilateral cone dysfunction. Repeat electroretinography on three more occasions within the next 5 years showed exactly the same findings with normal rod and cone responses in FIG. 17. Case 5. Macula, right eye (A) and left eye (B), October 11, 1974. CONE DYSFUNCTION SYNDROMES IN THE ADULT 213 Op.rllor~ _ D It. December 19, 1977 _ Tu .. obhctl 3/330 white (outer) 0 int 1/330 W (inner)O.6 VISUAL. FIEL.DS sc Aimark tperlpb..al) I.E. JU 3/330 white Teu object--.'....5r+/'j~'16"6....[~ed:t---- Oint sc Aimark '0' (CaDtral) cc VlliOD~ FIG. 18. Case 6. Visual fields, December 19, 1977. w, Rigbt. • the right eye but severely reduced cone function despite normal rod function in the left eye. Visual function was unchanged at 10 year followup examination by her ophthalmologist. REVIEW OF RESULTS Only one of our six patients presented with decreased visual acuity and she was the only one who spontaneously complained of hemeralopia (Case 1). Two other patients, however, on specific questioning admitted having reduced vision in bright lights (Cases 4 and 5). The other five cases presented with visual field defects. None of our patients complained of nyctalopia. Only one of the six had noted an acquired difficulty in identifying colors (Case 4). One other patient recalled difficulty on color vision testing in the Navy but was not really aware of any subjective problem with color vision or any change in color appreciation (Case 5). The family history was negative in five patients. One patient recalled that a brother had had similar complaints (Case 2). We were able to examine four family members of two of our patients (Cases 2 and 6) and all had normal eye examinations including electroretinography. All of our patients had good central vision. Two had 20/15 in both eyes (Cases 2 and 3) and two had 20/20 in both eyes (Cases 1 and 6). The worst visual acuity was 20/30 in both eyes (Case 5). A point that should be emphasized is that the funduscopic examination was essentially normal in all patients. These patients had been carefully examined usually by several board-certified ophthalmologists each and their fundi had not been considered abnormal and certainly had not been thought to be related or causative with regard to their visual problems. On careful review, however, mild nonspecific peripheral pigmentation was seen in one, and there was slight nasal thin- JClin Neuro-opltthaimol. Vol. 7, No.4. 1987 214 J. P. ZERVAS AND J. L. SMITH FIG. 19. Case 6. Electroretinogram, December 19, 1977. ning of the retinal pigment epithelium in two. However, these patients usually do show evidence of diffuse arteriolar narrowing. Two patients had fluorescein angiography and one was normal (Case 5). The other had zones of macular hyperfluorescence in both eyes but these were not typical of cone dystrophy (Case 1). Color vision testing showed variable results. One patient was unable to identify any of the pseudoisochromatic plates with either eye (Case 4); however, three patients identified almost all plates with both eyes (Cases 1, 2, and 6). The remaining patients showed intermediate amounts of difficulty with color testing. The peripheral visual fields were grossly intact in all patients, except for one who gave functional responses (Case 2). The central fields varied but were more often helpful than the peripheral isopters. Three patients exhibited typical ring scotomas (Cases 1, 4, and 6); one showed essentially normal central fields (Case 2); one had superior rnidzonal defects mimicking a homonymous hemianopia but which crossed the midline (Case 3); and one had central scotomas in both eyes (Case 5). Electroretinography ranged from subnormal to nonrecordable cone responses. Rod responses ranged from normal to slightly abnormal. Two patients had asymmetric electroretinography (Cases 1 and 6) and one of these showed strictly uniuCl1!: Jr ·'(.ne d"·,,truphv. DISCUSSION Cone dystrophy in textbook descriptions (1-3) is a disease said to have a familial tendency and the age of onset is usually within the first two decades of life. Patients present with moderately decreased visual acuity, decreased color vision, and relative intolerance to light. Examination reveals poor responses to color vision testing and they may show on ophthalmoscopy a bulls-eye maculopathy. Electroretinography shows decreased cone responses with normal to abnormal rod responses. Specifically, electroretinography shows reduced cone b-waves and increased peak implicit times; the rod b-waves are in the low normal or subnormal range (4). Rarely the rod-mediated amplitudes are supernormal (5,6). Electroretinography findings can be asymmetric (7). Most original reports of cone dysfunction have described the variability of presentations (8). They state that symptoms can be mild and the examination unimpressive (9,10). They further note that these patients are sometimes considered functional and at other times undergo extensive neurologic and neuroradiologic evaluations to rule out nervous system disease, a point well illustrated by several of our cases. Goodman et al. (11) reported 47 patients with cone dysfunction syndromes and stated that the fundus could appear normal or it could show a variety of lesions, none of which could be considered pathognomonic for the condition. They further stated that the lack of awareness of clinical symptomatology has resulted in frequent misdiagnoses. Their patients were divided into three groups. The first group consisted of those with complete achromatopsia, and they characteristically had very poor visual acuity early in life, nystagmus, photophobia, macular abnormalities, poor color vision, normal peripheral fields, and a positive family history in most cases. Electroretinography in this group showed nonrecordable photopic responses in all patients, although scotopic activity was within normal limits. In the second group, those with incomplete achromatopsia, the vision was less severely compromised and they presented at a later age. They were less likely to have nystagmus, photophobia, fundus abnormalities, or visual field changes. All patients in this group had defective color vision but it was not as severe as those in the first group. Electroretinography was generally similar to those in the first group. Group three consisted of patients with generalized cone-rod dysfunction. Sloan and Brown (12) described five patients with a progressive retinal degeneration character- CONE DYSFUNCTION SYNDROMES IN THE ADULT 215 ized by selective involvement of the cone receptor system and little or no loss of rod function. All of their patients had moderate-to-severe reduction of visual acuity, and four of the five had photophobia. All had defective color vision and visual field defects. They all had evidence of slight macular degeneration and the defect appeared to be familial in three of the five patients. Cone and rod function were separated on the basis of dark adaptometry . Electroretinography was performed in only two of the five. Krill el al. (10) also commented on the variability of clinical findings in their 45 patients with cone dysfunction. Their patients were studied electroretinographically and had abnormalities in those portions of the electroretinogram that were thought to relate mainly to cone function. Rod function ranged from normal to severely abnormal. The major complaint in Krill's group of patients was loss of visual acuity which preceded difficulty with color vision. In 20 of their patients the family history was positive for similar conditions. Approximately two-thirds of their patients were thought to have photophobia. Also, none of their patients complained of visual field problems although several had documented field defects. The age of onset was 20 years in approximately twothirds but there were patients in each decade after that, including the oldest who was 70. The rate of loss of visual acuity was usually similar between the two eyes but at times large differences could be found. Visual acuity ranged from 20/25 in one eye to hand movements in another. Thirty-five of the 45 patients had visual acuity of 20/200 or better in both eyes. Only two patients had normal fundus examinations and the rest were divided into those with yellow flecks in the fundus and those without. The yellow flecks were similar to those found in fundus flavimaculata, and nine of the 45 had such changes. Lesions of the macula occurred in both patients with and without flecks. Macular lesions were further subdivided into three types on the basis of the ophthalmoscopic and fluorescein appearance. The most common lesion was bulls-eye maculopathy. Early bulls-eye maculopathy was best seen by fluorescein angiography and vision loss occurred before this lesion could be identified. The second type was diffuse pigment clumping throughout the macular area. Pigment clumping was noted on initial examination in a few of their patients. Two patients had a third type of discrete atrophy of the choroidal vascular elements within the macular lesion. One other peripheral fundus change was described as pigment deposits outside the macular area. This occurred in three of the five patients with diffuse pigment clumping in the macula. In all of those patients in whom reliable visual fields were obtained, relative or absolute central scotomas were demonstrated. In the five patients with bulls-eye maculae a paracentral scotoma was found that was more dense than the central portion, i.e., with a ring scotoma appearance. In seven other patients, midperipheral paracentral scotomas were noted. Francois et al. (13) similarly remarked that the electroretinographic concept of cone dysfunction consisted of a wide spectrum of clinical pictures and emphasized that the cone dysfunction syndromes may be congenital or acquired, stationary or progressive, localized to the macula or generalized. In their 25 cases of progressive generalized cone dysfunction the disease usually started in the first two decades, poor central vision or photophobia were the initial symptoms, and hemeralopia was an infrequent complaint. They found that visual acuity was much impaired and that both eyes were equally affected. The most commonly observed field defect was an absolute central scotoma and the second most frequent was occasional peripheral constriction or blind spot enlargement. Color vision was always affected even in patients with good central vision. Several of their cases had normal fundi but they were children. The others had varying macular lesions and only two had narrowing of the retinal vessels and this was reported as slight. Five of their 25 had normal fluorescein angiography. Electroretinographically, the cone responses were either reduced or completely absent. Seven of their cases were felt to be familial, and they remarked that electroretinography was not always the same in both eyes. Our cases differ from previous reports in several significant ways. Whereas decreased visual acuity classically seems to be the most common presenting complaint, this was true in only one of our six patients. Our patients were more likely to complain of varying types of visual field defects. Photophobia or more specifically hemeralopia and at times nyctalopia are typical complaints but only one of our patients initially complained of hemeralopia. That symptom had to be elicited by specific questioning in two others. One of our patients reported the interesting observation that white or bright objects were difficult to see. Four were significantly older than the usually described age of onset. Also, in contrast to the frequently positive family history in younger patients, only one of our patients reported similar disability in family members. A point with regards to the presentation of a I Cf", Nt'"ro-ophtha'"llli. Vol. 7. No.4. 1987 2i6 J. P. ZERVAS AND J. L. SMiTH middle-aged to older patient who complains of poor vision in bright lights should be mentioned. The first thing that most ophthalmologists think of in an elderly patient who reports being barely able to see to cross the street at high noon under a bright midday sun but who can function much better late in the afternoon or at twilight is, of course, early nuclear sclerosis cataracts so that the patient must look through the central opacity when the pupil is intensely miotic at noon but can look around the lens clouding with lower ambient illumination. One should recall, however, that this is essentially the same history that a patient with hemeralopia due to cone dysfunction will give. The way to differentiate the two conditions, however, is to check the acuity both with a lighted room and semidarkened room, to do a careful pinhole test, and to check color vision, as well as to carefully slit-lamp the lens, both with a small and a dilated pupil. If there is any question, electroretinography will resolve the problem. On examination of our patients visual acuity was good or normal in all, again in contrast to the more frequent modes of presentation. Color vision ranged from poor to normal and again this contrasted with the above reports. The fundi were considered normal or nearly normal for age by most examiners in all of our patients. Our cases showed similar field defects to those in previous reports, and in general had basically normal peripheral fields whereas tangent screen testing revealed typical ring or central scotomas. It should be emphasized that these defects can be very subtle and must be searched for specifically. Tangent screen examination should be done by a skilled examiner. Usual methods cannot be relied on in many cases, although Krauss and Heckenlively (14) reported 20 cases of rod-cone degeneration evaluated by Goldmann perimetry. They reported generalized constriction, ring scotomas, baring of the blind spot, a "pseudoaltitudinal" defect, and a centrocecal defect. In our experience, patients with subtle or absent fundus changes will not show field defects that are diagnostic unless a careful tangent screen examination is done, often at ~2 m or more for magnification of subtle findings. All of our patients demonstrated unusual presentations of cone dystrophy. This is most likely due to the neuro-ophthalmologic nature of our practice. Patients with obvious retinal pathology and/or marked reduction of visual acuity are probably more likely to be diagnosed initially or are referred to the retinal service where their condition ·s usuaRy readily cfiasnoeed. »iJ)lt_t JIIk> :reported at the 1968 Wilmer 1CI6I~. Val. 7. No. 'II. 1981 Resident's meeting (15) a family with several members affected with cone dysfunction. The maternal grandmother, the mother, and the oldest of the three sons were so affected. The mother was totally color blind. Her fundi were normal. Her vision was better with reduced illumination. Interestingly, her vision was reduced during pregnancy. Dr. Fite commented on several characteristics in this pedigree of interest to the present study: (a) the frequency of familial occurrence; (b) normal visual acuity and color discrimination preceding the onset of symptoms; (c) visual acuity reduced more than suggested by the macular changes; (d) improved vision with reduced illumination; (e) absence of nystagmus; (f) generalized impairment of cone function. Recent well-documented reports (16-18) have demonstrated the existence of decreased photoreceptor function as a remote effect of carcinoma. Paraneoplastic retinopathy, as it has been called, seems to be characterized by rapid deterioration of vision, narrow arterioles seen on ophthalmoscopy but with an otherwise unremarkable fundus examination, and eventually extinguished rod and cone electroretinography. Some cases seem to be partially steroid responsive. These cases are similar to ours in that the fundus examination may be normal or near normal but they differ from ours in that the vision loss is sudden in onset and rapidly progressive, and both rod and cone electroretinography are markedly involved. Weleber and Shults (19) have reported a case of reversible cone dysfunction due to digoxin toxicity. Their 70-year-old patient complained of rectangular silver flashes in his right visual field for 1 year and a 10 day history of hemeralopia before initial evaluation. He specifically denied xanthanopsia. Initial visual acuity was 20/20 - 2 in the right eye and 20/25 + 2 in the left eye and the 'fundus examination was entirely normal. Color vision was affected. Cone-mediated electroretinographic amplitudes were decreased and lightadapted cone-mediated electroretinographic b-wave peak implicit time was prolonged during the time that the patient's digoxin level was in the toxic range. Visual acuity returned to 20/15 in both eyes, color vision improved, and cone-mediated electroretinographic responses showed a significant increase in amplitude and shortening of the prolonged photopic b-wave implicit time when digoxin was stopped. This patient is similar to ours in many respects but his photoreceptor dysfunction was reversible and was due to digoxin. Even in the absence of xanthanopsia, digoxin toxicity must be suspected when a patient who is using digoxin presents with symptoms of cone dysfunc- CONE DYSFUNCTION SYNDROMES IN THE ADULT 217 tion. Suspicion should be especially raised when there is concomitant quinidine ingestion or a degree of renal failure. Another consideration concerning our cases is the effect of aging on human rod and cone electroretinography. According to Weleber (20), bwave amplitudes mediated by light-adapted cones and dark-adapted rods decreased with age, whereas the dark-adapted cone a-wave amplitude, the x-wave amplitude (a dark-adapted cone-mediated corneal positive wave response), and the implicit times for all positive wave peaks were not age dependent. It is possible that our patients were exhibiting some age-related diminishing retinal photoreceptor function but this would hardly apply to Case 6, a 19-year-old woman. In all our cases the cones were decreased out of proportion to rod function. Since central vision and color vision are cone mediated, it seems reasonable to expect that patients with electroretinographic evidence of cone dysfunction should, at a minimum, have reduced visual acuity and poor color vision. As some of our cases demonstrated, however, this is not always the situation. The apparent incongruity between theory and practice can be explained by the concept of peripheral, central, and diffuse cone involvement as described by Krill et al. (9,10) and others (21,22). It seems possible that if there is peripheral cone disease with relative sparing of central (macular) cones, there could be electroretinographic evidence of cone dysfunction with retention of good visual acuity and color vision. In such cases we would expect to find ring scotomas. Conversely, Krill (9) reports that there have been patients with severe disturbance of color vision and no initial evidence of electroretinographic abnormality. Presumably their disease was limited to the maculae. SUMMARY Cone dysfunction syndromes are probably part of the spectrum of cone-rod degenerations and can present with widely varying clinical pictures. Thus, although the age of onset is usually before the third decade, patients can present at any age, and, although family history is usually positive, in typical cases it may be quite negative. Patients can have initially very subtle, bizarre, or poorly described visual complaints so that numerous examiners may label them "functional" or "malingering." They can present with the classic symptoms of hemeralopia, poor acuity, and reduced color vision, but these complaints may be absent. Visual acuity and color vision can be normal or severely reduced and the fundi may show classic changes such as bulls-eye maculopathy, macular choroidal atrophy, pigment clumping in the maculae, mild peripheral pigmentary changes, or a fundus f1avimaculata-like change. The patients here reported were considered as having normal fundi by several competent ophthalmologists as a rule, however. Visual fields can vary from normal to ring scotomas, central scotomas, and other interesting types of defects, even simulating a hemianopia. Although involvement is usually symmetrical between the two eyes, this is not always the case, and one of our patients had a strictly uniocular cone dystrophy. Cone dysfunction can be considered in a patient of any age even with normal acuity, good color vision, and a normal ophthalmoscopic examination. A high index of suspicion should prompt specific questioning about hemeralopia, or reduced visual function in brightly illuminated situations, and better vision in twilight or under dim illumination. Patients may falsely describe hemeralopia as "glare" or "photophobia." Careful testing of color vision, a meticulous tangent screen examination, and specifically looking for diffuse narrowing of retinal arterioles in a patient with an otherwise normal fundus appearance will usually suffice to prompt the clinician to order electroretinography, which is the definitive diagnostic criterion for the cone dystrophies. It is important to consider this diagnosis before embarking on an otherwise fruitless and expensive neuroimaging investigation. Acknowledgment: Grateful acknowledgment is given to Mrs. Irene Manning Holmes, Dr. Robert Knighton, and Dr. Samuel G. Jacobson, and all the staff in the electrophysiology/ electroretinography laboratory at the Bascom Palmer Institute for their help. REFERENCES 1. Duke-Elder S. Sltstflll of ophthalml1logy. Vol. 10: Diseases of the retina. St. Louis: CV Mosby, 1967: p. 652. 2. Gass JDM. Stereoscopic atlas of macular diseases: diagnosis and treatment. 3rd ed. St. Louis: CV Mosby, 1987:264-6. 3. Carr RE, Siegel 1M. 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