59 Ischemic Optic Neuropathy

.

A optic neuropathy usually presents in the older patient with painless, often severe visual loss of sudden onset that can be irreversible. Ophthalmoscopy reveals pallid swelling of the optic disc that may be accompanied by superficial peripapillary hemorrhages. The findings probably relate to acute ischemia of the anterior portion of the optic nerve.6,13,17 The initial report of severe visual loss in association with giant cell arteritis appears to be that of Jennings,27 but the term ischemic optic neuritis was first used by Wagener.46 It is now usually known as ischemic optic neuropathy (ION).35 Clinical reviews have identified two groups of patients: those with giant cell arteritis (arteritic, AAION) and those without (nonarteritic, NAION).3,17,34,39 Many nonarteritic cases are idiopathic, but systemic hypertension, ischemic heart disease, hypercholesterolaemia, and diabetes mellitus are risk factors.17,39,41 There are reports of ION in association with hypotension,44 migraine,4,33,47 acute hypotension and anemia consequent on gunshot wound or lipsuction,36,43 following internal carotid artery dissection,2 and following cataract surgery.30,38

Clinically, patients with NAION present with visual loss in one eye, possibly with previous involvement of the other eye. The optic disc is swollen, and the more extensive the disc swelling, the greater is the degree of visual impairment.3 Flame hemorrhages are usually present. The majority of patients have inferior altitudinal field defects, but approximately 20% have a central scotoma.7 The field defect may correlate poorly with the fundus appearance, but some patients have clear superior or inferior swelling with corresponding altitudinal field loss. In one large series,17 more than 35% of the NAION patients had a visual acuity of 6/36 or worse, but 30% had normal (6/9 or better) acuity.

Patients with AAION often have symptoms associated with temporal arteritis: malaise, muscle pain, scalp tenderness, etc., whereas the nonarteritic patients do not feel unwell. There is often generalized field constriction in the affected eye. Visual acuity may be severely reduced, with 60% having an acuity of counting fingers or worse,17 but also may be unimpaired. A percentage of both groups may have had previous transient visual dysfunction. The blood erythrocyte sedimentation rate (ESR) is usually raised in temporal arteritis, but a low ESR does not exclude the diagnosis,17,34 and a positive temporal artery biopsy is necessary for confirmation. It is important to distinguish the cases due to temporal arteritis from idiopathic cases because high-dose

steroids are the treatment of choice in arteritic ION.9,18,34 The addition of methotrexate may be effective.28 There have been reports of improvement following steroid administration in nonarteritic patients,17 but as yet there is no satisfactory treatment. Optic nerve sheath decompression initially seemed to improve outcome in some patients with progressive NAION,42 but the results from the Ischemic Optic Neuropathy Decompression Trial not only failed to confirm significant therapeutic benefit, but also suggested that nerve sheath decompression may actually be potentially harmful in NAION.24–26

The histological changes in AAION were reviewed by Henkind et a1.19 The orbital vessels, including the posterior ciliary arteries, the ophthalmic artery, and the intraneural central retinal artery, may be involved in the arteritic process, but involvement of the intraocular retinal or choroidal vessels is unusual. Hayreh and Baines16 suggested that the posterior ciliary arteries feed fairly well delineated areas of the choroid and nerve head and that posterior ciliary artery occlusions may infarct the optic disc and adjacent retrolaminar optic nerve. The reader is referred elsewhere for a comprehensive discussion of the blood supply to the optic nerve head.14,15 A case report, without clinical details, of the histopathological findings in nonarteritic ION showed focal infarction 3mm behind the lamina cribrosa that was caused by thromboembolism in three discrete pial and pial-derived arterioles.32 The temporal aspect of the macula showed ischemic necrosis. A recent large series further defined the histopathology of ischemic optic neuropathy in relation to localized ischemic edema, cavernous degeneration, or an area of atrophy located superior or inferior in the optic nerve.29

The first detailed report of the electrophysiological findings in NAION was that of Wilson,49 although “delays” in the pattern visual evoked potential (PVEP) had previously been mentioned.20 Wilson49 examined both PVEP and flash VEPs (FVEPs) in a mixed group of 15 arteritic and nonarteritic patients. Both PVEPs and FVEPs showed reduced amplitude, but only four patients showed minimal (<10ms) latency changes. The clinically uninvolved eye invariably had normal visual evoked potentials (VEPs). Those findings were contrasted with those in optic nerve demyelination, in which latency delays in excess of 10ms are common and there is often subclinical involvement of the fellow eye. Other authors5,8,10,21,48 confirmed the high incidence of

reduced amplitude, normal latency VEPs, but Glaser and Laflamme8 found a predominance of P100 component delays in acute cases. Harding’s group10 noted that all affected eyes showed a reduced VEP and that those with a delayed or triphasic response to flash had temporal arteritis. The FVEP delay in association with temporal arteritis was confirmed by this author,21 who further reported that the PVEP was more sensitive than the FVEP in nonarteritic patients. Amplitude reductions were usually relative to the uninvolved eye. Typical findings are shown in figure 59.1. Cox et a1.5 compared the PVEPs from 24 eyes with NAION with 22 eyes with optic nerve demyelination. The mean latency difference between the involved and the uninvolved eyes was 3ms for NAION but 21ms in demyelination. Wildberger48 found amplitude changes but also reported that patients with an inferior altitudinal defect touching the horizontal meridian showed apparent latency delays that were attributed to preservation of the normal longer latency response from the superior field.31

Definite latency delays have been reported,37 but stimulus and recording parameters were not given. A later study45 emphasized the difficulties in accurate component identification with a single midline recording channel. (See also chapter 15 for a discussion of normal PVEP components and their distribution.) Those authors, using a 15 degree radius, 50 minute check stimulus, found “delays” in some cases that could be explained by complete or partial substitution of the paramacular P135 subcomponent for the

usually dominant, macular-derived P100 component. It should be remembered that this interpretation only applies with a large field. Most of their patients had single-channel recordings with central field stimulation. PVEPs were often extinguished, but delays were observed. Follow-up studies suggested that the abnormalities remained essentially unchanged.

Posterior ischemic optic neuropathy may also occur but is much less common12,40 and has not been satisfactorily characterized electrophysiologically.

This author reported PERG abnormalities in seven cases of NAION, five with involvement of the P50 component and two with an abnormality confined to N95.22 As P50 component reduction is usually associated with dysfunction anterior to the retinal ganglion cells in the visual pathway,23 the histopathological observations of macular necrosis in ION32 may be relevant.

To conclude, the finding of a normal latency, reduced amplitude PVEP suggests NAION in a patient with sudden, painless loss of vision and a swollen optic disc. If there has been a previous episode in the fellow eye with resultant disc pallor, the appearances may be mistaken for the FosterKennedy syndrome (see figure 59.2). An abnormal VEP is not a feature of papilloedema per se, and electrophysiology should help to resolve any diagnostic difficulties in such cases. The findings from clinically uninvolved eyes are normal. PVEP delays can occasionally be observed but are less marked than in optic nerve demyelination. There are

F 59.1 VEP findings in four patients with nonarteritic ischemic optic neuropathy. The affected eye in each patient is shown as the lower of the two pairs of traces for each patient. Patient A shows a broadening of the major positive P100 component with increased N135 component latency, but the dominant

feature is amplitude reduction; patient B shows marked P100 amplitude reduction with mild latency increase; patient C shows amplitude reduction with no latency change; patient D shows a questionable P100, of normal latency if present. Calibration: 5 mV, 80 ms.

F 59.2 Pattern and flash VEPs in a 62-year-old patient with pseudo Foster-Kennedy syndrome due to acute anterior ischemic optic neuropathy with disc swelling in the right eye and old anterior ischemic optic neuropathy with disk pallor in the left eye. Visual acuities were 6/12 right, 6/36 left. Pattern VEPs from both eyes

usually associated systemic symptoms and elevation of the blood ESR with AAION.

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3.Boghen DR, Glaser JS: Ischaemic optic neuropathy. Brain 1975; 98:689–708.

4.Cowan CL, Knox DL: Migraine optic neuropathy. Ann Ophthalmol 1982; 14:164–166.

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fall within the normal latency range (vertical line = upper limit of normal for age) but show mild increase in P100 latency from the right eye relative to the left. Flash VEPs show mild interocular asymmetry in later components from the right eye but show no definite abnormality.

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12.Hayreh SS: Posterior ischemic optic neuropathy. Ophthalmologica 1981:29–41.

13.Hayreh SS: Anterior ischemic optic neuropathy. Clin Neurosci 1997; 4:251–263.

14.Hayreh SS: The blood supply of the optic nerve head and the evaluation of it: Myth and reality. Prog Ret Eye Res 2001; 20:563–593.

15.Hayreh SS: Blood flow in the optic nerve head and factors that

17.Hayreh SS, Podhajsky P: Visual field defects in anterior ischaemic optic neuropathy. Doc Ophthalmol Proc Ser 1979; 19:53–71.

18.Hayreh SS, Zimmerman B, Kardon RH: Visual improvement with corticosteroid therapy in giant cell arteritis: Report of a large study and review of literature. Acta Ophthalmol Scand 2002; 80:355–367.

19.Henkind P, Charles NC, Pearson J: Histopathology of ischaemic optic neuropathy. Am J Ophthalmol 1970; 6:78– 90.

20.Hennerici M, Wenzel D, Freund HJ: The comparison of small size rectangle and checkerboard stimulation for the evaluation of delayed visual evoked responses in patients suspected of multiple sclerosis. Brain 1977; 100:119–136.

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22.Holder GE: Abnormalities of the pattern electroretinogram in optic nerve lesions: Changes specific for proximal retinal dysfunction. In Barber C, Blum T (eds): Evoked Potentials III. London, Butterworths, 1987, pp 221–224.

23.Holder GE: The pattern electroretinogram and an integrated approach to visual pathway diagnosis. Prog Ret Eye Res 2001; 20:531–561.

24.Ischemic Optic Neuropathy Decompression Trial Research Group: Optic nerve decompression surgery for non-arteritic ischemic optic neuropathy (NAION) is not effective and may be harmful. JAMA 1995; 273:625–632.

25.Ischemic Optic Neuropathy Decompression Trial Study Group: Characteristics of patients with non-arteritic ischemic optic neuropathy eligible for the Ischemic Optic Neuropathy Decompression Trial. Arch Ophthalmol 1996; 114:1366–1374.

26.Ischemic Optic Neuropathy Decompression Trial Research Group: Ischemic optic neuropathy decompression trial: Twenty- four-month update. Arch Ophthalmol 2000; 118:793–798.

27.Jennings GH: Arteritis of temporal arteries. Lancet 1938; 1:424–428.

28.Jover JA, Hernandez-Garcia C, Morado IC, et al: Combined treatment of giant-cell arteritis with methotrexate and prednisone: A randomised, double-blind, placebo controlled trial. Ann Intern Med 2001; 134:106–114.

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39.Repka MX, Savino PJ, Schatz NJ, et al: Clinical profile and long term implications of anterior ischemic optic neuropathy. Am J Ophthalmol 1983; 96:478–483.

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A:Clinical spectrum of posterior ischemic optic neuropathy. Am J Ophthalmol 2001; 132:743–750.

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47.Weinstein JM, Feman SS: Ischaemic optic neuropathy in migraine. Arch Ophthalmol 1982; 100:1097–1100.

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History of the disease

Gyrate atrophy of the choroid and retina is one of scores of genetic dystrophies allied to retinitis pigmentosa. Although it was first described by Cutler in 18958 and Fuchs in 1896,11 interest in gyrate atrophy was sparked by the reports by Simmel and Takki in 197349 and Takki in 197454 of hyperornithinemia associated with this condition. Since then, the enzyme defect (ornithine aminotransferase, or OAT) has been detected,46 the abnormal gene product has been characterized biochemically and enzymatically,25,27 the gene for the missing enzyme has been cloned,19 and studies have been performed on a molecular level to uncover the mechanism of the loss of functional gene product.1,6,14–18,28–31,34,35,41 OAT is a pyridoxal phosphate–dependent enzyme, and pyridox- ine-responsive and -nonresponsive forms of the condition have been described. Over 100 cases of gyrate atrophy have been reported worldwide. Considerable allelic heterogeneity exists for OAT-deficient gyrate atrophy for both pyridoxineresponsive and -nonresponsive cases. Interestingly, the largest group of patients with gyrate atrophy is Finnish, the great majority of whom are homozygous or compound heterozygous for one of two common founder mutations (L402P and R180T), neither of which is pyridoxineresponsive.35 For more extensive coverage of the clinical, biochemical, and molecular genetic aspects of gyrate atrophy, the reader is referred to reviews.56,61

The electroretinogram (ERG) is severely abnormal in most patients with gyrate atrophy, even in childhood (figures 60.1 and 60.2).5,29,30,54 Stoppoloni et al.53 reported an allegedly normal ERG in a 3-year, 9-month-old girl, but the technique was inadequately described, and the amplitudes for the patient and the normal ranges were not presented. Rinaldi et al.44 reported that the ERG for this same patient at 4 years of age was normal for the left eye (photopic a- wave: 40 mV, b-wave: 80 mV; scotopic a-wave: 40 mV, b-wave: 200 mV) but that for the right eye was now subnormal (photopic a- and b-waves: 40 mV; scotopic a-wave: 40 mV, b-wave: 125 mV). However, again the range of normal responses for the technique employed were not given. Most reports, especially those of older patients, describe the ERG as undetectable, but averaging was usually not performed, and the

lower limits of detectability were not given for the system used. Patients with pyridoxine-responsive gyrate atrophy have had some of the largest reported ERG amplitudes, with maximal bright white stimulus scotopic and photopic b-wave amplitudes in the 100to 200-mV and 50to 65-mV range, respectively (see figures 60.1 and 60.2). For those patients with sizable ERGs, although both rodand cone-mediated responses are subnormal, the rod responses appear more subnormal than do those from the cone system.5,23,60 The oscillatory potentials range from moderately to severely subnormal but are often still clearly dis-

The implicit times are usually normal, although mild prolongation of cone b-wave implicit can occur (see figures 60.1 and 60.2).63

To assess the course of change of visual function outcome variables in patients who might become candidates for gene replacement therapy, Caruso et al.7 have studied the rate of decline of static perimetry, kinetic perimetry, and ERG b- wave amplitudes for the ISCEV standard maximum scotopic bright-flash and the 30-Hz flicker responses for patients with pyridoxine-nonresponsive gyrate atrophy. They found that in the 4 to 6 years of follow-up, the visual field half-lives were variable, but the median was 17.0 years for static perimetry and 11.4 years for kinetic perimetry. ERG amplitudes likewise had variable half-lives, but the median was 16 years for the scotopic bright-flash responses and 10.7 years for the flicker responses. Thus, the rates of change of visual function outcome measures in these subjects were slow, indicating that a long-term clinical trial would be needed to assess the efficacy of therapeutic intervention that is intended to preserve existing visual function. The rate of change of visual function outcome measures appears even slower for those rare individuals with pyridoxineresponsive gyrate atrophy (R. G. Weleber, unpublished data, 2003).

The electro-oculogram (EOG) can range from low normal to severely subnormal.23,54,64 Fast oscillations of the EOG were subnormal for three pyridoxine responders (Weleber and Kennaway61 and R. G. Weleber, unpublished observations, 1983–1987) (figure 60.3).

A

B

F 60.1 ERGs from patients with pyridoxine-responsive (patients 1–3) and pyridoxine-nonresponsive (patient 4) gyrate atrophy. Note that the calibration scale is different in height for the patients compared with the normal ERG. A, Photopic cone and 30Hz flicker. Note the prolonged implicit time for some of the 30-Hz flicker responses for patients 2 and 3. The calibration scale indicates 100 mV vertically and 20 ms horizontally for all tracings. The numbers to the left of the normal tracing indicate the intensity of

the stimulus in log foot-lambert-seconds. B, Scotopic ERG responses. The calibration scale indicates 200 mV vertically and 40 ms horizontally for all tracings. The numbers to the left of the normal tracing indicate the intensity in log foot-lambert-seconds for the white light stimuli and in log mJ/cm2 steradian for the red and blue light stimuli. (From Weleber RG, Kennaway NG: Clinical trial of vitamin B6 for gyrate atrophy of the choroid and retina. Ophthalmology 1981; 88:316–324. Used by permission.)

F 60.2 International Society for Clinical Electrophysiology of Vision standard ERGs of a 12-year-old girl with pyridoxine-non- responsive gyrate atrophy (same patient as in figures 60.4A and 60.5) (left column) and a 38-year-old woman with pyridoxineresponsive gyrate atrophy (patient 2 in figure 60.1) (right column).

Clinical description and natural history

Gyrate atrophy begins in the first decade of life as circular areas of total vascular atrophy of the choroid and retina in the midperiphery and far periphery (figure 60.4). As the patient ages, these lesions enlarge, coalesce, and eventually form the characteristic scalloped border between the atrophic peripheral choroid and retina and the more intact posterior fundus that led to the term gyrate atrophy. In some patients who are not responsive to pyridoxine, atrophy also develops around the optic nerve and in a ring around the macula.39 The earliest symptoms are loss of peripheral visual fields (figure 60.5) and night blindness (figure 60.6). Eventually, progressive extension of the lesions toward the posterior pole produces constriction of visual fields and, in most patients, legal blindness from tunnel vision by the fourth to fifth decade. Loss of central vision can occur from cataracts, macular edema, or involvement of the atrophic process in the macula itself. All patients are myopic, the degree of myopia ranging from mild to severe.

Dark adaptometry curves range from normal54 to an elevation of both cone and rod segments (see figure 60.6).54,61,64

The responses for the right and left eyes are superimposed. Note that for the patient with pyridoxine-nonresponsive gyrate atrophy, the flicker timing and single-flash cone b-wave implicit times (arrows) are prolonged, the scotopic OPs are profoundly subnormal, and the rod response is indiscernible from noise.

Color vision is usually good until visual acuity falls below 20/40; tritan defects can occur.54

Careful funduscopy and fluorescein angiography usually show a zone of disturbed retinal pigment epithelium (RPE) between the atrophic and more intact areas of the retina (figure 60.7). This zone of disturbed RPE is the area into which the atrophic lesions will extend with time. Enoch et al.,10 using detailed perimetry, have shown that the disruption of retinal function occurs abruptly in this zone but that some function persists within islands of more peripheral remaining retina.

Although intelligence is normal in the vast majority of cases, several patients have had abnormal electroencephalography results, seizures, or abnormal MRIs.57 Although this is of no discernible clinical significance, all but one23 (Case 2) of the patients who have been investigated have had abnormal inclusions within type 2 muscle fibers on muscle biopsy (figure 60.8).27,32,52 Abnormalities on electrocardiography have also been noted in several patients.52

Inheritance is clearly autosomal-recessive. Carriers, who are clinically normal, can be distinguished from normal by assay of enzyme activity in cultured fibroblasts.27,48

F 60.3 EOG from a normal subject (light to dark ratio 2.26) (top) and a 38-year-old woman with pyridoxine-responsive gyrate atrophy (patient 3) (light-to-dark ratio: 1.25, normal: >1.85) (bottom).

Known histopathology/pathophysiology of gyrate atrophy

H In only one case of gyrate atrophy have the eyes been studied histopathologically.65 This 97-year-old woman (patient 6 in previous reports) had pyridoxine-respon- sive gyrate atrophy,64,66 and the kinetics of her mutant enzyme have been studied.25 In the regions of atrophy, there was total loss of all retinal and choroidal elements, but the retina posterior to the scalloped abrupt border was essentially intact.

The abnormalities on muscle biopsy appear as subsarcolemmal inclusions that on electron microscopy represent accumulations of tubular inclusions (see figure 60.8). These defects within muscle are believed to be secondary to a localized deficiency of creatine phosphate, created by endproduct inhibition of arginine glycine transamidinase by the high levels of ornithine in patients with gyrate atrophy.50 However, since arginine glycine transamidinase activity has not been detected in the retina, such a mechanism cannot explain the pathophysiology in this tissue.43

Abnormal, swollen mitochondria have been observed in liver2 and iridectomy specimens59 and are believed to result from the toxicity of high ornithine levels within mitochondria.

(From Weleber RG, Kennaway NG: Gyrate atrophy of the choroid and retina. In Heckenlively JR (ed): Retinitis pigmentosa. Philadelphia, JB Lippincott, 1988, pp 198–220. Used by permission.)

P Although much is known about the enzyme defect and more recently about the molecular defects in gyrate atrophy, little is known about how the enzyme deficiency actually produces the atrophy. Proposed theories have centered on the possibility of direct toxic effects of elevated ornithine levels within mitochondria and a localized deficiency of either creatine or proline within the retina. Evidence does exist that ornithine concentrations similar to those seen in patients are toxic to RPE cells in vitro.9 Whereas creatine phosphate is a known major source of energy for muscle, its role as an energy store for the eye is unknown. The most tenable theory for the ocular pathology is localized deficient proline synthesis within the retina. This results from the inhibitory effects of ornithine, through glutamic g- semialdehyde, on the enzyme D1-pyrroline 5-carboxylate (P5C) synthase, which is necessary for the formation of P5C, and hence proline, from glutamate (figure 60.9).45

B Although in her original report, Takki alluded to the finding of deficient OAT, Sengers et al. were the first to demonstrate conclusively that OAT was the defective enzyme in gyrate atrophy.46 Others confirmed this deficiency in lymphocytes55 and cultured fibroblasts.26,37,47 OAT is a pyridoxal phosphate–dependent enzyme (see

F 60.4 Fundus appearance of right eye of a 12-year-old girl with early pyridoxine-nonresponsive gyrate atrophy (A) (same patient as in figure 12.1 in Weleber and Kennaway), a 28-year-old woman with pyridoxine-responsive gyrate atrophy (B) (patient 1), a 37-year-old woman with pyridoxine-responsive gyrate atrophy (C)

Figure 60.9) that catalyzes the interconversion of ornithine and glutamic-g-semialdehyde, the latter being metabolized to either glutamate or proline. The vast majority of patients with gyrate atrophy are not responsive to pyridoxine. However, six patients,5,12,27,47,62,64,66 none of Finnish extraction, have been found to respond to pyridoxine, either in vivo, with approximately a 50% reduction of serum ornithine levels, or in vitro, with elevation of residual OAT activity and increased concentrations of pyridoxal phosphate. The residual OAT activity is greater in patients who respond to pyridoxine. Characterization of the mutant enzyme in pyridoxine-responsive and -nonresponsive patients has provided interesting correlations with the

(patient 3), and a 40-year-old man with pyridoxine-nonresponsive gyrate atrophy (D) (patient 4). (From Weleber RG, Kennaway NG: Gyrate atrophy of the choroid and retina. In Heckenlively JR (ed): Retinitis Pigmentosa. Philadelphia, JB Lippincott, 1988, pp 198–220. Used by permission.) (See also color plate 29.)

clinical and biochemical features in these patients.25 In pyridoxine-responsive gyrate atrophy, the Km for pyridoxal phosphate is elevated, and the enzyme shows increased heat lability in some cases. Surprisingly, although her enzyme showed the greatest heat stability of the mutant enzymes studied, the pyridoxine-responsive patient with the mildest disease had the highest Km for pyridoxal phosphate. Western blot analysis of mitochondrial proteins by using antiserum to human OAT demonstrated reduced but easily detectable protein in four pyridoxine-responsive patients and normal protein in two of five patients who did not respond to pyridoxine. Three other nonresponsive patients showed very low to undetectable OAT protein. Low residual enzyme activity

F 60.5 Visual field by Goldmann perimetry for a 12-year- old girl with pyridoxine-nonresponsive gyrate atrophy (same patient as figure 60.4A). Note that the visual field is more

contracted than would be anticipated from the appearance of the retina. (Same patient as in figure 12.1 in Weleber and Kennaway.)

F 60.6 Full dark-adaptation curves for a 40-year-old man with pyridoxine-nonresponsive gyrate atrophy (patient 4). Note that the cone and rod segments of the curve are only mildly elevated for the right eye but markedly elevated for the left

eye. (From Weleber RG, Kennaway NG. Gyrate atrophy of the choroid and retina, in Heckenlively JR (ed): Retinitis Pigmentosa. Philadelphia, JB Lippincott, 1988, pp 198–220. Used by permission.)

A

B

F 60.7 Fluorescein angiograms of zone between areas of atrophy and more intact retina in left eye of a 37-year-old woman with pyridoxine-responsive gyrate atrophy (A and B) (patient 3, same patient as in figure 60.4C). Note the diffuse RPE transmission defects in the zone just posterior to areas of atrophy. (From Weleber RG, Kennaway NG: Gyrate atrophy of the choroid and retina. In Heckenlively JR (ed): Retinitis Pigmentosa. Philadelphia, JB Lippincott, 1988, pp 198–220. Used by permission.)

in mitochondrial preparations from patients who are not responsive to pyridoxine has made enzyme kinetic studies difficult, but the Km for ornithine and pyridoxal phosphate appear normal. These studies reflect mutation heterogeneity within, as well as between, pyridoxine-responsive and -nonresponsive patients with OAT-deficient gyrate atrophy.25

Therapeutic trials for patients with gyrate atrophy have involved a reduction of plasma ornithine levels by supplementation with vitamin B-6 for the uncommon pyridoxineresponsive patients or by reduction of protein, and hence arginine, in the diet. Arginine restriction has lowered ornithine levels to within the normal range, and this has been associated with apparent mild short-term improvement of visual function.22,33 Mild short-term improvement was

A

B

F 60.8 Muscle biopsy material from patient with pyridoxineresponsive gyrate atrophy (patient 2), demonstrates subsarcolemmal inclusions (solid arrows) in type 2 muscle fibers on light microscopy (NADH-tetrazolium reductase stain) (A) and tubular aggregates (solid arrows) and dilated saccules (open arrows) on electron microscopy (B). Calibration bars indicate 20 mm for light micrography and 0.5 mm for electron micrograph. (From Kennaway NG, Weleber RG, Buist NRM: Gyrate atrophy of the choroid and retina with hyperornithinemia: Biochemical and histologic studies and response to vitamin B6. Am J Hum Genet 1980; 32:529–541. Used by permission.)

also noted in pyridoxine-responsive patients who were given supplemental vitamin B-6.60 Others have reported either no improvement or worsening of fundus lesions while receiving diet or pyridoxine supplementation.4 Vannas-Sulonen et al.58 have reported continued progression despite normal or near-normal plasma ornithine concentrations achieved with dietary arginine restriction. Long-term follow-up on patients who were able to maintain rigorous arginine restriction have shown evidence that the rate of disease progression appears to be slowed by dietary therapy.20,21 Proline supplementation has been tried as a means of therapy,13 but

F 60.9 Biochemical pathways involved in the metabolism of ornithine. (From Weleber RG, Kennaway NG, Buist NRM: Gyrate

no conclusive evidence of its benefit on a long-term basis has been shown. Creatine supplementation reversed some of the abnormalities on muscle biopsy but had no effect on the

eye.51,59

M G O’Donnell et al. in 1985 demonstrated that the gene for OAT resides on chromosome 10.36 The mRNA for human OAT was cloned and the sequence for human cDNA determined in 1986 by Inana et al.,19 Barrett et al.,3 and Ramesh et al.40 in 1987 localized OAT gene sequences to the long arm of chromosome 10 and the short arm of the X-chromosome, the latter probably representing nonfunctional pseudogenes. O’Donnell et al. showed that only the gene sequence on chromosome 10 transcribes OAT activity.38 Most patients with gyrate atrophy have apparently normal OAT mRNA,16,24 and a variable amount of immunoreactive OAT protein.16,25 These findings suggest that the underlying molecular defect can be subtle, such as a point mutation that results in poor translation of mRNA, a labile gene product, defective transport to the mitochondria, or a gene product that is inactive. A variety of defects have been characterized at the molecular level,1,6,14–18,28–31,34,35,41 including several instances of single base changes, possibly affecting the pyridoxal phosphate– binding site,41 the recognition signal for mitochondrial

atrophy of the choroid and retina: Approaches to therapy. Int Ophthalmol 1981; 4:122–132. Used by permission.)

uptake,41 or in one case the initiator codon,34 which results in a loss of the entire mitochondrial leader frame and 113 amino acids of the mature protein. For one patient, OAT gene expression was completely lacking owing to deletion of part of the gene.14,16 These studies attest to the heterogeneity of gyrate atrophy at the molecular level.

Relevant testing and differential diagnosis

The differential diagnosis of gyrate atrophy includes choroideremia, especially in later stages, paving-stone peripheral retinal degeneration, which can be seen in high myopia, and an uncommon form of peripheral atrophy of the choroid and retina that begins in middle age or older patients with fundus features that closely mimic gyrate atrophy but are milder.24,61 These latter patients and indeed all patients with other disorders that might be confused with gyrate atrophy have failed to show hyperornithinemia and have shown normal OAT activity in cultured fibroblasts or lymphocytes. Choroideremia can usually be easily distinguished from gyrate atrophy, especially in the early stages, by the characteristic fundus appearance and fluorescein angiogram. The fundus in choroideremia shows a somewhat patchy but more generalized loss of RPE and choriocapillaris.

The best means of establishing the diagnosis of gyrate atrophy is by measurement of serum or plasma ornithine levels. Additional testing is indicated for determining pyridoxine responsiveness. This can be achieved by measuring ornithine levels before and after oral supplementation with vitamin B-6 (100–200 mg/day). Pyridoxine responsiveness can also be demonstrated by assay of OAT activity in cultured fibroblasts with and without increased levels of pyridoxal phosphate. Chronic supplementation of the diet with vitamin B-6 is not recommended unless pyridoxine responsiveness is shown by in vitro or in vivo methods. Because of the risks involved in the severe protein restriction that is required to significantly reduce plasma ornithine levels, dietary restriction of arginine is not recommended unless adequate metabolic monitoring is done. There are no studies that have studied whether more modest, long-term reductions of arginine (protein) intake may be beneficial.

Perimetric visual field testing is indicated for periodic assessment of level of visual impairment and is the most practical means of functionally monitoring the disease for progression. ERG and EOG are valuable for establishing the severity of retinal dysfunction and are useful for following patients who have measurable responses.

Supported by the Foundation Fighting Blindness and by Research to Prevent Blindness.

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