55 Mitochondrial Diseases

T disorders are a heterogenous group of disorders in which biochemical or genetic analysis, inheritance pattern, histopathology, or clinical presentation suggests a primary dysfunction of the mitochondria.5,8,20,28 Mitochondria are tiny intracellular organelles that are essential for oxidative phosphorylation and play a role in other metabolic processes. They are responsible for generating much of the energy needed by the cell, in the form of adenosine triphosphate (ATP). The central nervous system, including the ocular tissues such as retina and optic nerve, are particularly reliant on mitochondrial energy production.

Every human cell contains hundreds of mitochondria. Each mitochondrion contains its own DNA and all the elements necessary for local transcription, translation, and replication. Like nuclear DNA, mitochondrial DNA (mtDNA) is read onto messenger RNAs that are then translated into proteins. These processes take place within the mitochondrion. Unlike nuclear DNA, which is organized in chromosomes, mtDNA exists in the form of circular molecules that are similar to the DNA found in bacteria. Each circle of mtDNA consists of a pair of complementary chains of DNA, totaling approximately 16,500 base pairs. Each mitochondrion contains between two and ten such circles of mtDNA. Mitochondrial DNA replicates at random within the mitochondria, and the mitochondria themselves divide by a budding process, unlike the elaborate cell cycle and mitosis of eukaryotic cells. During cellular mitosis, intracytoplasmic organelles, including mitochondria, are randomly partitioned into each daughter cell. If a new mutation in mtDNA occurs, intracellular populations of both mutant and normal mtDNA coexist, a condition known as heteroplasmy.

However, not all of the proteins found within the mitochondria are encoded by mtDNA. In fact, most of the proteins found in mitochondria are encoded by nuclear genes, synthesized in the usual way in the cytoplasm on cytoplasmic ribosomes, and subsequently transported into the mitochondria. Hence, primary mitochondrial dysfunction can result from different origins, with different inheritance patterns. Mutations can arise involving mtDNA, including single-nucleotide substitutions, such as in Leber’s hereditary optic neuropathy (see chapter 76), which will be inherited maternally. Other mutations resulting in disease include segmental deletions and rearrangements involving entire

regions of mtDNA.14 Other mutations can arise involving nuclear genes that participate in mitochondrial function. These genes may code for mitochondrial proteins or may otherwise be involved in the normal functioning of mitochondria and even mtDNA. Diseases resulting from abnormalities in these genes will be transmitted in classic Mendelian fashion.

The criteria required to label a disease as mitochondrial has evolved over time. Initially, diseases were considered mitochondrial myopathies if somatic muscle biopsy showed morphological evidence of abnormalities involving the mitochondria, usually by using the modified Gomori trichrome stain to produce the so-called ragged red appearance.30 Later, abnormalities of muscle mtDNA were found in such patients.14,15,26,51 Therefore, the label of mitochondrial disease was expanded to include diseases that had genetic evidence to suggest mitochondrial abnormalities, even if the muscle fibers were morphologically normal. Several clinical syndromes were designated as mitochondrial diseases, include Leber’s hereditary optic neuropathy,49 MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes),33 MERRF (myoclonic epilepsy with ragged red fibers),10 and KSS (Kearns-Sayre syndrome).21

Clinically, the mitochondrial diseases manifest with a surprising amount of heterogeneity. There is poor correlation among the genetic defect, the biochemical abnormality, and the clinical presentation.5,28 Thus, a single genetic defect can give rise to a range of clinical presentations. Similarly, a single clinical syndrome can arise from a number of different genetic defects. In general, however, the most common ophthalmologic manifestations of mitochondrial disease can be grouped into syndromes of bilateral optic neuropathy, progressive external ophthalmoplegia (PEO), pigmentary retinopathy, and retrochiasmal visual loss, although there is frequently overlap among these categories.5 For example, KSS encompasses both ophthalmoplegia and pigmentary retinopathy and may rarely include optic atrophy.26,51

The literature on electrophysiological studies of the visual pathways in mitochondrial diseases is difficult to interpret, both because of the evolving definition of mitochondrial disease and because of the use of different electrophysiological techniques in the various reports. Older articles, prior to modern molecular genetic diagnosis, include information

collected on patients with “mitochondrial myopathy,” a diagnosis that was usually established by the presence of ragged red fibers on muscle biopsy. These studies typically included patients with varying clinical presentations but with common histopathological findings. Newer articles focus primarily on patients or pedigrees with either a defined clinical presentation or, more frequently, a specific genetic defect. Because of the range of presentation, some of the patients who were reported, although genetically carriers, were clinically unaffected. In addition, many of these reports focus on other issues, and information on the electrophysiological findings may be sparse.

The electrophysiological investigations described in both the earlier and more recent studies include primarily various forms of the electroretinogram (ERG) and the visual evoked potential (VEP). Data from the electro-oculogram (EOG) are reported in a few studies. Results are variably reported as either normal or subnormal, without further details or, less commonly, with more detailed descriptions of photopic or scotopic abnormalities. Studies in the English-language literature that provide electrophysiological data are summarized in the tables and detailed below.

Electrophysiological studies in patients without genetic diagnosis

F -F (F ) ERG A review of the literature found a total of 101 patients with ragged red fibers who were inves-

tigated with full-field ERGs (table 55.1).1,3,4,13,27,37 Two studies were in children;13,37 the others were in adult patients. Only two studies3,4 gave details on individual eyes; the patients reported by the other authors presumably had comparable results in both eyes. There were 42 (42%) patients who had normal ERGs. Another patient had a normal ERG in one eye and scotopic abnormalities in the other. Of the patients with abnormal results, 16 patients had subnormal ERGs in both eyes with no further details, and another patient had a subnormal ERG in one eye and no response in the other.3 Twenty-three patients had both scotopic and photopic abnormalities in both eyes, and one other patient had both scotopic and photopic abnormalities in one eye and only scotopic abnormalities in the other eye.4 Three patients had only photopic abnormalities in both eyes, and two more had only scotopic abnormalities in both eyes. Ten patients had absent responses in both eyes. Interestingly, in the study by Riguardiere and coworkers,37 all eight pediatric patients had normal ERGs. Because half of the patients in this study were younger than 6 years old, this supports the impression that clinical and electrophysiological evidence of retinal involvement in these diseases increases with age.27

R P R Cooper and coworkers7 studied 22 pediatric patients (median age 5 years) with presumed mitochondrial disease, 20 defined by biochemical enzyme complex deficiencies, one by a large mitochondrial deletion, and one by a mtDNA mutation at nucleotide posi-

tion 8993. They used the Hood and Birch17 formulation of the Lamb and Pugh23,36 model of rod phototransduction to study photoreceptor response parameters, specifically S and Rmp3 derived from the scotopic a-wave and log s and Vmax derived from the b-wave. Results were obtainable in 19 patients. These parameters showed some abnormality in most of the patients, being completely normal in only five patients, of whom three were among the youngest patients studied.

P ERG Sartucci and coworkers39 described 17 patients with histologically defined mitochondrial myopathy. Of these, ten patients had PEO, and the remaining seven had symptoms including ptosis, bulbar weakness, and cerebellar signs. None of these patients fulfilled the exact diagnostic criteria for KSS, MELAS, or MERRF syndromes. Fourteen patients underwent pattern ERG (PERG). The PERGs showed abnormal responses in 11 patients. Of these, 13 eyes showed no response, and the P50 was delayed in four eyes. The same group also performed VEPs (see below) and calculated the retinocortical time (RCT). The RCT was prolonged unilaterally in four eyes and not evaluable in 15 other eyes.

V E P Techniques for recording the VEP were varied. Harden and coworkers13 recorded flash VEPs (fVEP) with both eyes open in 12 patients. The potentials were present with well-defined early components in six of 12 patients; five others had either absent or ill-defined early components; in the last case, the VEP was of “unusual configuration with enlarged components.” Rigaudiere and coworkers37 reported fVEPs in eight pediatric patients, four with mitochondrial myopathy and the remainder with mitochondrial encephalopathy. The fVEPs were normal in four patients and showed hyperamplitudes in two patients with mitochondrial myopathy, associated with normal latencies. Another two patients, both with mitochondrial encephalopathy, had decreased amplitudes and increased latencies. The abnormal VEPs were seen in the older patients; the mitochondrial myopathy patients were aged 6 and 9 years compared to 5 months and 2 years, while the encephalopathy patients were both aged 15 years, compared to 21 months and 5 years.

Using a mixture of both flash and pattern-reversal VEPs, Smith and Harding44 reported VEP results in 20 patients, some of whom had genetic abnormalities, including one patient with MERRF and three patients with MELAS (see below). Of the remaining 16 patients, six patients had normal results, and ten had abnormal results. Berdgis and coworkers4 obtained normal fVEP results in 21 eyes.

Pattern-shift VEP (PSVEP) was reported in a total of 83 other patients, some of whom were known to have mitochondrial deletions.1,4,39,40,42,48 Five studies1,4,39,40,42 gave

PSVEP results in a total of 77 patients. Six patients40 had mitochondrial deletions, but details were not reported. Of 153 eyes, 80 (52%) were normal, 45 eyes had prolonged latencies, four eyes had side-to-side latency differences, and 24 more eyes showed absent responses.

Versino and coworkers48 investigated the effect of check size in 13 patients with PEO and histopathologically proven mitochondrial disease, using both 15¢ and 30¢ check sizes. Seven of these patients had mitochondrial deletions. The P100 latency was delayed bilaterally in eight patients, regardless of check size. In three patients, the P100 latency was normal for the 30¢ check size but delayed for the 15¢ check size, and in the last two patients the VEP was normal for both the 15¢ and 30¢ check sizes.

E -O EOGs were not commonly reported. Bastiaensen3 obtained EOGs in four patients and reviewed the literature for PEO patients. The EOGs were normal in three of his patients and at the lower limit of normal for the other patient. He found in the previous literature another two patients with normal EOG and four patients with subnormal EOG. However, he commented that the EOGs often could not be recorded because of abnormal ocular motility. Mullie and coworkers27 performed EOGs in 11 patients and reported their results as the EOG light rise, instead of the Arden index. Six patients had subnormal results, while two more had supernormal results. The remaining three patients had such poor eye motility that EOG proved impossible to perform.

Electrophysiological studies in patients genetically defined

With the advent of molecular genetics, mitochondrial diseases became better characterized genetically. Given the rapid advances in this field, earlier papers in the molecular era reported abnormalities in restriction splice sites, while later studies used the polymerase chain reaction and DNA sequencing techniques to better define and specify the genetic abnormalities. Many patients with morphologically abnormal muscle fibers were found to have abnormalities involving the mtDNA. Partial deletions, usually with some degree of heteroplasmy, were found in many patients with the CPEO/KSS phenotype. Single-nucleotide substitutions were found in other disorders, the common mutations being the 3243A-G mutation in MELAS11,12 and the 8344A-G mutation in MERRF.41

In addition to these syndromes, which typically have ragged red fibers on biopsy, other syndromes without such histological findings are now known to be the result of mtDNA defects. One such syndrome of particular interest

to the ophthalmologist is the syndrome of neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), a maternally inherited disorder resulting from a point mutation at position 8993 in the ATPase 6 gene of the mtDNA.16 This condition has a heterogenous clinical presentation, ranging from isolated retinal changes to Leigh’s syndrome with psychomotor regression, seizures, and death in early childhood.6,25,31,47,50 The NARP mutation has been associated with pigmentary degeneration of the retina in a salt- and-pepper pattern as well as a bone spicule pattern.31 Indeed, a salt-and-pepper appearance in childhood may progress to a full-blown retinitis pigmentosa pattern over the years.22

Another syndrome associated with a mtDNA point mutation is the syndrome of maternally inherited diabetes and deafness (MIDD) resulting from a point mutation at position 3243, the mutation that is most commonly found in association with the MELAS phenotype.2 Leber’s hereditary optic neuropathy, associated primarily with mtDNA mutations28 at positions 3468, 11778, and 14484, is described in chapter 76. Although the above diseases are very well described

clinically, biochemically, and genetically, electrophysiological information is sparse, with the exception of the NARP syndrome.

mtDNA D R Nine patients with the CPEO/KSS phenotype who were confirmed to have mitochondrial deletions had ERGs performed19,27,32 (table 55.2). Two patients had normal ERGs, while seven others had abnormal results. In one of the patients reported by Mullie and coworkers,27 who was later determined to have mtDNA deletions,44 serial ERGs were performed three years apart. Deterioration was apparent in all ERG variables over time, although visual function remained clinically normal.

MELAS MIDD (3243 M ) Most patients with the MELAS and MIDD syndromes have the same common mtDNA mutation at position 3243.5,28 Case series include patients with either clinical presentation. Flash ERGs on patients with the 3243 mutation were reported in a total of 16 patients18,19,24,27,43,46 (table 55.3), of which nine were

normal and seven were abnormal. Sue and coworkers46 reported PERG data on 11 patients in four 3243-positive pedigrees, all of which were normal. Because of the association with diabetes, a number of patients may also have diabetic retinopathy and laser treatment, potentially confounding the ERG results. EOGs were reported in 12 patients by Smith and coworkers,43 four of which were normal and eight of which were abnormal.

MERRF There are only a few reports of visual electrophysiological investigations in MERRF patients with the 8344 mutation. Seventeen patients had VEPs.29,38,44,45 Of these, seven patients were normal, four had delayed P100 latencies, one had absent responses, and five had high amplitudes. The patients with high amplitudes were all from the study by Rosing and coworkers,38 and the authors postulated that this finding was also found in other myoclonic and photosensitive epilepsies. A similar finding of increased amplitudes was seen in the somatosensory evoked potentials of these patients. This may reflect a general hyperexcitability to all stimuli as part of startle myoclonus. ERG and EOG data have not been reported in MERRF patients.

T T8993G (NARP) S The NARP syndrome may present clinically with a wide range of findings, including retinal pigmentation. The range of electrophysiological findings is equally variable (table 55.4) and may reflect the age at which these patients were tested (figures 55.1 and 55.2). Details are summarized in table 55.4.6,9,16,31,34,35 Of 14 patients studied with flash ERG, only three had normal ERGs, ten had various abnormalities, and one had an unrecordable ERG.

Conclusions

Electrophysiological studies of the visual pathways are not uncommonly abnormal among patients with mitochondrial disease. ERG abnormalities are frequently present in patients with overt retinal pigmentation as well as in patients with apparently normal funduscopy. Abnormalities have been found with various techniques, including full-field ERG and pattern ERG. Although longtitudinal studies have not been reported, children with mitochondrial diseases may have normal ERGs initially and later progress to manifest abnormalities, a process that is often mirrored by the retinal appearance. Use of more sophisticated indices of photoreceptor transduction might provide a more sensitive indicator of photoreceptor stress.7

VEP abnormalities are also frequently present in patients with mitochondrial disease, even if there is no apparent optic nerve or brain involvement. Hyperamplitudes may be present in MERRF syndrome as part of a generalized sensitivity to stimuli.

The advent of molecular genetics has led to more precise characterization of the mitochondrial disorders. However, a particular clinical presentation can frequently result from different genetic abnormalities, and each genetic defect may produce a wide range of clinical presentations. The electrophysiological findings in patients with mitochondrial disease are equally variable.

This study was supported in part by a departmental grant (Department of Ophthalmology) from Research to Prevent Blindness, Inc., New York, New York, and by core grant P30-EY06360 (Department of Ophthalmology) from the National Institutes of Health, Bethesda, Maryland. Dr. Newman is a recipient of a Research to Prevent Blindness Lew R. Wasserman Merit Award.

F 55.1 Serial ERGs of a patient with the 8993 (NARP) mutation performed in 1994 (A), 1996 (B), and 1998 (C),

A

F 55.2 Serial fundus photographs of the same patient dated 1986 (A) and 1994 (B) showing increased retinal pigmentation from salt-and-pepper retinopathy to frank bone spiculing. Note that the

showing progressing loss of responses to a full-field white flash stimulus.

B

magnification in part B is higher, showing more central encroachment of the pigmentary changes. Both images demonstrate substantial arterial attenuation. (See also color plate 22.)

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.

B retinal vein occlusion are common retinal vascular disorders, second only to diabetic retinopathy in frequency of occurrence. They are both easy disorders to diagnose using clinical techniques. For this reason, investigations into the value of the electroretinogram (ERG) in these disorders have focused on prognosis, not diagnosis.

Central retinal vein occlusion

It is estimated that about 20% of eyes with central retinal vein occlusion (CRVO) are ischemic and are therefore at risk for developing neovascularization of the iris (NVI).5,15 The determination of ischemia in this disorder, however, is problematic; fluorescein angiograms (FA) often do not capture peripheral capillary nonperfusion, they might be difficult to read because of intraretinal hemorrhage or other factors, the FA changes associated with ischemia in CRVO might not be completely understood,19 and CRVO eyes that have no apparent capillary dropout occasionally develop NVI.2,9,14

The ERG has been shown to be a sensitive and specific test for identifying CRVO eyes that are at risk for the development of NVI. It has the advantages over angiography of providing an evaluation of the entire retina, including far peripheral areas, and of quantifying the amount of ischemia with regard to the retinal area that is affected, the extent of the damage within the area affected, and the amount of functional loss in perfused but still ischemic eyes. In a prospective study involving 140 eyes of 128 patients, Hayreh and colleagues2 found that the ERG as well as other measures of visual function proved far superior to the morphological tests of fluorescein angiography and fundoscopic appearance in differentiating ischemic from nonischemic CRVO during the early acute phase. Their most sensitive test in uniocular CRVO was the RAPD, followed closely by the ERG, then visual field and visual acuity. The combination of RAPD and ERG differentiated 97% of ischemic from nonischemic cases. The authors stated that ophthalmoscopic appearance was the “least reliable, most misleading” parameter.

Researchers have categorized the ERG changes that occur in CRVO in a number of ways. Eyes with CRVO often have reduced ERG b/a amplitude ratios, reduced b-wave

amplitudes, reduced or enhanced a-wave amplitudes, delays in the implicit times of the a- and b-waves and the multifocal ERG, reductions in oscillatory potential amplitudes, and changes in the Naka-Rushton Rmax and log K parameters derived from intensity-response analysis. ERGs recorded from most cases of CRVO will show significant changes in some of these parameters, even if the eye is perfused and has a good prognosis. However, eyes with CRVO that develop NVI demonstrate large ERG changes, and it is generally not difficult to identify eyes that are at risk for NVI even when the ERG is recorded only once, at the patient’s initial visit.1,10,13,19,20

ERG amplitudes

The work of Sabates and colleagues20 has focused attention on the dramatic reductions that are often seen in the b/a ratio in ischemic eyes with CRVO. The b/a ratio is the amplitude of the b-wave, measured from a-wave trough to b-wave peak, to the amplitude of the a-wave, measured from the baseline to the trough of the a-wave. Sabates et al.20 reported that five out of eight eyes in his study that had b- wave reductions that were so large that the b-wave did not extend beyond the prestimulus baseline (the b/a ratio measured less than 1; see figure 56.1) developed NVI, whereas only one eye that did not have this characteristic developed the complication. Kaye and Harding recently obtained similar results,14 and Breton et al.1 confirmed findings that date to Karpe’s original monograph, published in 1945.12 Johnson and McPhee10 found the b/a ratio to be specific but not sensitive for NVI in a prospective study of 93 eyes with CRVO. They attributed some of the differences between studies to the different stimulus luminances that were used; the b/a ratio is not an invariant characteristic of the ERG but rather depends strongly on stimulus intensity, as illustrated in figures 56.2A and 56.2B.

Much of the reduction in b/a ratios can be attributed to preferential reductions in the b-wave amplitude. In a prospective study of 30 CRVO eyes, seven that later developed NVI and 23 that did not, Kaye and Harding14 reported that b-wave amplitudes were decreased on average by 102 mV in eyes that developed NVI when compared to the

F 56.1 An ERG recorded from an eye with CRVO and NVI. The b/a amplitude ratio measures <1.

normal fellow eyes and by 63 mV when compared to affected eyes that did not develop NVI. Mean a-wave amplitudes were not significantly different for any of the comparisons. This latter result may be due to the fact that in CRVO, the a-wave may either increase or decrease with disease severity. Curiously, the b/a ratio was found to be a better predictor of NVI development than was b-wave amplitude. This paradox might be explained by two factors: the large variability on ERG amplitude and the fact that the a-wave amplitude may be either abnormally large or abnormally small in CRVO. Abnormally small a-waves, of course, suggest that more than the middle retina is involved in the disorder.

Other investigators have also demonstrated substantial b-wave reductions in CRVO.1,9,10 These studies will be discussed more fully in the section dealing with intensity-response functions.

Oscillatory potential (OP) amplitudes are reduced in CRVO, but while there is a significant difference between the means of distributions of OPs recorded from eyes that develop NVI when compared to eyes that do not develop this complication, there is a substantial overlap between these distributions. This overlap results from the fact that CRVO eyes not at risk for NVI have substantial OP reductions.11

Temporal factors

Large delays in ERG implicit times are found in CRVO eyes that develop NVI. Values for the scotopic single-flash a- and b-waves, the photopic b-wave, and the peak of the 30-Hz flicker response have been reported.1,2,9,10,14 In a prospective study of 62 CRVO patients, Johnson and McPhee10 showed

that both the scotopic b-wave and the 30-Hz response recorded from patients at their first visit identified patients who had or would later develop NVI, with high sensitivity and specificity. Their data for scotopic b-wave implicit time, measured from stimulus onset to peak of the b-wave, are illustrated in figure 56.3A. While ERGs from most of the CRVO eyes showed delays in b-wave timing, eyes that had or that would develop NVI showed much larger changes than the eyes that did not develop NVI. A risk factor crite-

yielded a sensitivity of 94% and a specificity of 64% for this data set. Figure 56.3B, which pictures the affected and normal eyes of a patient with CRVO and NVI, illustrates the size of the effect that is often seen.

B-wave implicit time delays were the most discriminant feature of the CRVO ERGs recorded by Kaye and Harding.14 In agreement with Johnson and McPhee’s data, they found that the difference between the means of the ERGs recorded from eyes that developed NVI versus the eyes that did not develop NVI was 7.4 ms, a difference that was significant at the p < .001 level. Furthermore, there was no overlap between these two distributions at the 99% confidence level. They also found significant intereye differences for both groups. These differences measured 9.6 ms for the NVI group and 2 ms for the comparison between the ERGs recorded from the nonproliferative CRVO eyes and their fellow eyes.

A similar picture is seen for the 30-Hz flicker ERG.1,9,10,17 McPhee et al.17 showed that, by using a criterion of 40 ms, a value that is 7 ms greater than the upper limit of the normal range, the 30-Hz flicker ERG shows performance equivalent to that of the scotopic b-wave in identifying eyes that had or that would develop NVI (figure 56.4A). At this criterion value, the sensitivity for this data set was 100%, and the specificity was 68%. Figure 56.4B illustrates a 30-Hz flicker ERG recorded from the normal and affected eyes of a patient with CRVO. McPhee et al.17 measured implicit time as the phase of a 30-Hz sine wave fit to the data and not to the amplitude peak of the waveform because highfrequency components, which usually occur in healthy eyes at the leading edge of the flicker ERG, often disappear in eyes with CRVO. In these cases, measuring implicit time as the time to peak will accentuate the actual shift in time in waveforms recorded in normal eyes and in affected but nonproliferative eyes, thus reducing the ability to identify the individuals who have real time shifts and who are at risk for NVI.22

The NIH-sponsored ERG ancillary study to the Central Vein Occlusion Study (CVOS) confirmed the discriminability of the ERG implicit time delay in CRVO. Investigators from eight centers participated in the ERG-CVOS, testing a total of 333 patients, or about half of the patients enrolled

F 56.2 A, ERGs recorded as a function of stimulus luminance for an eye with CRVO and NVI (solid lines). For comparison, the dotted line is a normal ERG recorded at 0.2 log cd s/m2. Note that the b/a ratio is less than 1 here only for the two brightest stimuli. B, a- and b-wave amplitudes plotted as a function of stimulus luminance. Note that as stimulus luminance increases, the a-wave amplitude grows at a faster rate than does the b-wave amplitude, and this results in smaller b/a ratios. This figure shows ERG amplitudes for the normal and affected eyes of a patient with central retinal vein occlusion and iris neovascularization. For this patient, the greatest recorded difference between eyes occurs at the 0.03 log cd s/m2 intensity. Here, the difference in b/a ratio between eyes of 2.13 (fellow eye) versus 1.50 (affected eye) is due largely to a reduction in b-wave amplitude.

ERG b-wave amplitude increases with stimulus intensity up to moderately high levels of luminance. These intensityresponse data are typically analyzed by fitting them to a saturating, nonlinear function of a form first used by Naka and Rushton in 1966 in their work on the S-potential in fish.18 This so-called Naka-Rushton function has the following form:

where R and I are intensity-response ordered pairs, Rmax is the asymptotic amplitude, K is the semisaturation constant, that is, the intensity at which Rmax reaches half of its asymptotic value, and n is related to the slope at I = K. The value of performing this analysis is that the parameters derived from equation (1) can be evaluated in terms of putative pathophysiological mechanisms of disease. A number of studies have examined how the Naka-Rushton parameters change in CRVO and whether these changes can be used to predict neovascularization.

Eyes with CRVO usually show reductions in Rmax and n and elevations in K. An elevation in K indicates that more light is required to produce normal amplitude ERGs, i.e., retinal sensitivity is reduced. Retinal heterogeneity is reflected in the slope parameter. Using Monte Carlo simulations, it has been formally demonstrated that heterogeneity in either Rmax or K will decrease n.16

A

B

F 56.3 A, B-wave implicit time for CRVO eyes with NVI (solid bars) and without NVI (hatched bars). B, ERGs recorded from the affected and normal eyes of a patient with CRVO and

As with the other ERG parameters that have been examined, eyes that develop NVI have large elevations in K and often have large reductions in Rmax. Using ROC analysis, which is a method of comparing entire distributions of data and which reflects the amount of overlap between distributions, Johnson and McPhee10 have shown that the probability of detection (Pd) for K is 0.83, and Pd for Rmax is 0.65. These numbers indicate the probability of detecting an eye that will progress to NVI using only the parameter and no additional patient information. A linear discriminant analysis performed on the data showed that virtually all of the information contained in the Naka-Rushton parameters was contained in K.

Breton and colleagues1 have also shown that Rmax and K are highly predictive of NVI in eyes with CRVO, but in their study, Rmax was more discriminant than K. These conflicting results are likely due to differences in the algorithms used for fitting the data.10

NVI. The ERG recorded from the affected eye shows reduced a- and b-wave amplitudes and delays in implicit times when compared with the normal, fellow eye.

CRVO eyes with elevations in K act as though they are seeing less light, and this is a major reason that delays in ERG timing occur in this disease. Examination of the scotopic b-wave implicit time versus stimulus luminance functions pictured in figure 56.5 (parts c and d) for the normal and affected eyes of a CRVO patient with NVI illustrates two facts: that a dimmer stimulus produces a response occurring later in time and that, for this patient, the implicit time versus luminance function recorded from the normal eye requires at least some horizontal translation (i.e., along the log intensity axis) to fit the data recorded from the affected eye. In CRVO, these implicit time delays reflect losses in sensitivity;8,10 the highly significant correlation between the logarithm of K and the scotopic b-wave implicit time is 0.81, and the correlation between log K and the 30-Hz flicker response implicit time is 0.74.10

F 56.4 A, 30-Hz ERG implicit time for CRVO eyes with NVI (solid bars) and without NVI (hatched bars). B, ERGs recorded from the affected (top trace) and fellow eyes (third trace) of a patient with CRVO. While the peaks of the waveforms

Photoreceptor function in CRVO

Johnson and Hood8 used the Hood and Birch6 model of the a-wave to determine that a change in the gain of the photoreceptor response occurs in CRVO patients that develop NVI. In their study of 52 patients, they found that reduction in photoreceptor sensitivity (S) accounted for about one third of the elevation in K and in the b-wave implicit time delay (figure 56.5). This was an unusual finding in a disorder that is thought to involve only the inner

occur at considerably different points in time, the fundamental frequencies of these waveforms (traces 2 and 4, respectively) differ by only 2.3 ms. (Reprinted courtesy of the Archives of Ophthalmology.)

retina. Johnson and McPhee10 hypothesized that photoreceptor sensitivity loss in CRVO may be due to a proximal shift in the retinal O2 gradient due to reduced inner nuclear layer perfusion. Alternatively, reduced choroidal perfusion could account for reduced photoreceptor activation, particularly in individuals with minimal disruption in circulation to the inner retina. A global reduction in perfusion may also explain the functional abnormalities that are seen in so many of the fellow eyes of patients with vein occlusion.10,21

F 56.5 ERGs recorded from a patient with unilateral CRVO and NVI. Solid curves are the data, and dashed curves are the model’s fit to the leading edge of the a-wave. Photoreceptor gain (log S) was reduced by 0.53 log unit in the affected eye

(B) compared with the unaffected eye (A), but the a-wave amplitude (Rm) was about the same in both eyes. The reduction

in log S was not sufficient to account for either the shift in the b-wave intensity response function (C) or the shift in the implicit time function (D). Dashed curves (C, D) represent the responses from the normal eye shifted by the difference in log S between eyes. (Reprinted courtesy of the Optical Society of America.)

Branch retinal vein occlusion

The same types of effects observed in CRVO also occur in branch retinal vein occlusion (BRVO) but on a much smaller scale. In fact, for the most part, the changes observed cannot be used to manage patients on an individual basis, undoubtedly because a much smaller area of the retina is affected.12 Johnson et al.7 showed that ERGs recorded from eyes with BRVO and retinal NV showed reductions in Rmax, elevations in K, and delays in the scotopic b-wave and 30-Hz flicker implicit times, but the overlap in the distributions of these parameters for the proliferative and affected but nonproliferative eyes was substantial. Thus, while this result is scientifically interesting, it is not clinically useful.

Retinal artery occlusion

In cases of complete and long-standing central retinal artery occlusion (CRAO), the ERG consists of a supernormal a- wave and a very reduced if not absent b-wave. The highly negative ERG is present soon after the onset of the occlusion. The reduced b-wave and supernormal a-wave are presumably due to damage to ON-bipolar cells. Less severe artery occlusions, or situations in which the cilioretinal artery provides circulation, produce the intermediate ERG findings of partially increased a-wave and decreased b-wave amplitudes. The ERG is useful in diagnosing acute CRAO because fundus changes are not apparent immediately following an occlusion. The ERG can also be useful in diag-

nosing CRAO in the presence of other pathology, because only CRAO and CRVO produce large unilateral reductions in the b/a ratio.

Karpe and Uchermann13 described ERG findings in a study of 16 CRAO eyes (13 patients). Fifteen of these eyes had large reductions in the b/a ratio, in which the b-wave potential did not approach the potential of the prestimulus baseline. The other eye had an extinguished ERG but also had concomitant diabetic retinopathy that could not be evaluated because of cataract. The visual acuities in the group were very poor, except in one case in which the cilioretinal artery provided blood flow to the macula. In one instance, administration of a vasodilator increased the b-wave from 0 or less (measured from prestimulus baseline) to 120 mV. Similar attempts to reoxygenate the retina using hyperbaric oxygen also increased b-wave amplitudes in CRAO patients who had a favorable visual outcome.23 Occlusion of a branch of the retinal artery, described by the authors in seven cases, resulted in a subnormal ERG b-wave, presumably because of the smaller retinal area that was affected.12

Complete occlusions of the ophthalmic artery result in an extinguished ERG. The ophthalmic artery provides circulation to both the central retinal artery and the choroid plexus; therefore, the lack of recordable retinal potentials is presumed to be due to infarction of both outer and inner retinal layers.

Supported by an unrestricted grant to the University of Maryland Department of Ophthalmology from Research to Prevent Blindness.

REFERENCES

1.Breton ME, Quinn GE, Keene SS, Dahmen JC, Brucker AJ: Electroretinogram parameters at presentation as predictors of rubeosis in central retinal vein occlusion patients. Ophthalmology 1989; 96:1343–1352.

2.Brigell M, the CVOS-ERG Study Group: The role of the baseline ERG in prediction of subsequent neovascular changes following central retinal vein occlusion. Presented at the 1996 annual meeting of the International Society for Clinical Electrophysiology of Vision, July 20–24, 1996, Tubingen, Germany.

3.Dolan FM, Parks S, Keating D, Dutton GN, Evans AL: Multifocal electroretinographic features of central retinal vein occlusion. Invest Ophthalmol Vis Sci 2003; 44:4954–4959.

4.Hayreh SS, Klugman MR, Beri M, Kimura AE, Podhajsky P: Differentiation of ischemic from non-ischemic central retinal vein occlusion during the early acute phase. Graefes Arch Clin Exp Ophthalmol 1990; 228:201–217.

5.Hayreh SS, Rojas P, Podhajsky P, Montague P, Woolson RF: Ocular neovascularization with retinal vascular occlusion: III.

Incidence of ocular neovascularization with retinal vein occlusion. Ophthalmology 1983; 90:488–506.

6.Hood DC, Birch DG: The a-wave of the human ERG and rod receptor function. Invest Ophthalmol Vis Sci 1990; 31:2070–2081.

7.Johnson MA, Finkelstein D, Massof RW: Retinal function in branch vein occlusion. Invest Ophthalmol Vis Sci 1983; 24 (suppl):296.

8.Johnson MA, Hood DC: Rod photoreceptor transduction is affected in central retinal vein occlusion associated with iris neovascularization. J Opt Soc Am A Opt Image Sci Vis 1996; 13:572–576.

9.Johnson MA, Marcus S, Elman MJ, McPhee TJ: Neovascularization in central retinal vein occlusion: Electroretinographic findings. Arch Ophthalmol 1988; 106:348–352.

10.Johnson MA, McPhee TJ: Electroretinographic findings in iris neovascularization due to acute central retinal vein occlusion. Arch Ophthalmol 1993; 111:806–814.

11.Johnson MA, Procope J, Quinlan PM: Electroretinographic oscillatory potentials and their role in predicting treatable complications in patients with central retinal vein occlusion. Opt Soc Am Techn Dig 1990; 3:62–65.

12.Karpe G: The basis of clinical electroretinography. Acta Ophthalmol Suppl 1945; 24:1–118.

13.Karpe G, Uchermann A: The clinical electroretinogram: IV. The electroretinogram in circulatory disturbances of the retina. Acta Ophthalmol 1955; 33:493–516.

14.Kaye SB, Harding SP: Early electroretinography in unilateral central retinal vein occlusion as a predictor of rubeosis iridis. Arch Ophthalmol 1988; 106:353–356.

15.Magargal LE, Donoso LA, Sanborn GE: Retinal ischemia and risk of neovascularization following central retinal vein obstruction. Ophthalmology 1982; 89:1241–1245.

16.Massof RW, Marcus S, Dagnelie G, Choy D, Sunness JS, Albert M: Theoretical interpretation and derivation of flash- on-flash threshold parameters in visual system diseases. Appl Optics 1988; 27:1014–1029.

17.McPhee TJ, Johnson MA, Elman MJ: Electroretinography findings in iris neovascularization due to acute central retinal vein occlusion. Invest Ophthal Vis Sci Suppl 1988; 29:67.

18.Naka KI, Rushton WAH: S-potentials from colour units in the retina of fish (Cyprinidae). J Physiol 1966; 185:536–555.

19.Quinlan PM, Johnson MA, Hiner CJ, Elman MJ: Fluorescein angiography and electroretinography as predictors of neovascularization in central retinal vein occlusion. Invest Ophthalmol Vis Sci 1989; 30 (suppl):392.

20.Sabates R, Hirose T, McMeel JW: Electroretinography in the prognosis and classification of central retinal vein occlusion. Arch Ophthalmol 1983; 101:232–235.

21.Sakaue H, Katsumi O, Hirose T: Electroretinographic findings in fellow eyes of patients with central retinal vein occlusion. Arch Ophthalmol 1989; 107:1459–1462.

22.Severns ML, Johnson MA, Merritt SA: Automated estimation of latency and amplitude from the flicker electroretinogram. Appl Optics 1991; 30:2106–2112.

23.Yotsukura J, Adachi-Usami E: Correlation of electroretinographic changes with visual prognosis in central retinal artery occlusion. Ophthalmologica 1993; 207:13–18.

I decades, several acute and subacute disorders of the outer retina, pigment epithelium, and choroid have been described, primarily on the basis of their clinical features. These include central serous chorioretinopathy (CSC),10 birdshot chorioretinitis,31 multifocal evanescent white dot syndrome (MEWDS),22 acute zonal occult outer retinopathy (AZOOR),13 punctate inner choroidopathy (PIC),36 multifocal choroiditis with panuveitis (MCP),8 serpiginous choroiditis,32 and acute multifocal posterior placoid pigment epitheliopathy (AMPPPE).11 In many cases, these disorders exhibit features suggestive of an inflammatory or autoimmune etiology. As awareness of these disease entities has emerged from the clinical descriptions, with little understanding of their underlying causes, it has seldom been possible to differentiate between them with confidence.16 In some cases, there may also be overlap with syndromes that are defined in terms of retinal disturbances (e.g., acute macular neuroretinopathy) or in terms of the resulting visual disturbance (e.g., acute idiopathic blind spot enlargement syndrome).17 While it is not feasible here to fully reconcile the nosology of these overlapping conditions, this chapter will summarize the clinical and electrophysiological features of several of those conditions (central serous chorioretinopathy, birdshot chorioretinitis, multifocal evanescent white dot syndrome, and acute zonal occult outer retinopathy) in which electrophysiological studies may play a useful role.

Central serous chorioretinopathy

Central serous chorioretinopathy is an acute or subacute disorder characterized by the development of a localized serous retinal detachment in the posterior pole.18 The initial disturbance appears to be at the level of the retinal pigment epithelium (RPE), which often develops one or more small detachments or loci of angiographic leakage. In the most characteristic cases, leakage from underneath the pigment

epithelium into the subretinal space can be dramatically visualized by fluorescein angiography as a plume of fluorescent fluid, which is seen to emerge from a hot spot in the RPE and ascend through the cooler subretinal fluid as a “smokestack” or “mushroom cloud” (figure 57.1). Indocyanine green angiography frequently demonstrates additional choroidal hot spots elsewhere in the fundus. Symptoms depend on the location of the detachment: If the macula is elevated, decreased acuity (with a hyperopic shift) is likely, along with micropsia and metamorphopsia. With prolonged detachment, dark adaptation becomes impaired, and vision may be permanently reduced.

In chronic cases, the affected sectors of the retinal pigment epithelium become mottled and atrophic, often in a dependent pattern that suggests lengthy tracks of subretinal fluid emanating from the optic nerve or the central serous lesion. The pigmentary changes may mimic those of retinitis pigmentosa.

CSC frequently heals spontaneously, often with good recovery of vision. Unfortunately, recurrences are common, often leading to RPE degeneration and more permanent visual loss. Recovery is often accompanied by formation of a pigment epithelial scar, generally corresponding to the site of the RPE leak noted acutely. Some authors have suggested that light laser treatment to the site of leakage may hasten recovery, though the ultimate visual outcome appears to be unchanged.35

The etiology of CSC remains unclear. The condition is most frequently seen in young males, though the predominance of this group appears to be less than was previously thought.18 CSC has been associated with the “Type A” personality (prone to increased stress),37 as well as pregnancy. In some cases, systemic steroid medication or increases in levels of endogenous steroids, as seen in Cushing’s disease, appear to precipitate CSC.4

The diagnosis of CSC is made on clinical grounds, primarily based on history, ophthalmoscopic appearance, and angiography with fluorescein or indocyanine green. Focal

A

C

F 57.1 Central serous chorioretinopathy. A, Red-free image. The serous detachment of the macular region appears as a darker gray zone in the posterior pole. Distortion of the retinal blood vessels is evident. B–D, Fluorescein angiogram. A thin plume of

B

D

fluorescent fluid is seen emanating from a point source in the retinal pigment epithelium. In subsequent frames, it grows larger (“smokestack”) and starts to fill the subretinal space (“mushroom cloud”). (Courtesy of Mr. Ken Boyd.)

electroretinography shows a moderate reduction of the a-wave and b-wave, with marked reduction of the oscillatory potentials, in the detached retinal sector.25,26 This stands in contrast to a rhegmatogenous detachment, which is electrically silent owing to short-circuiting of the retinal currents through the retinal hole.

Multifocal electroretinogram (ERG) technique similarly demonstrates disturbance of retinal function in the area of the serous retinal detachment24,34 (figure 57.2). There is controversy as to whether the retinal dysfunction is confined to the detached retinal sector or extends beyond the detachment into clinically normal areas. Some investigators also report electroretinographic abnormalities in the clinically normal fellow eye. Localized abnormalities of the multifocal ERG show substantial recovery after resolution of the serous detachments but do not return completely to normal.6,33

Birdshot chorioretinitis

Birdshot chorioretinitis is the term given to a group of diseases of the retina and choroid characterized by a peculiar pattern of oval depigmented lesions underlying the sensory retina. The term was chosen “because of the multiple, small, white spots that frequently have the pattern seen with birdshot in the scatter from a shotgun”31 (figure 57.3). The cause is unknown, though an autoimmune mechanism appears likely. Clinical features include a quiet eye, minimal anterior segment inflammation, chronic vitritis, retinal vascular leakage, and frequent cystoid macular edema.9 Indications of compromised retinal physiology include abnormalities of dark adaptation and abnormalities of the ERG and electrooculogram (EOG). Late complications include subretinal neovascularization, rhegmatogenous retinal detachment, rubeosis iridis, posterior subcapsular cataract, glaucoma, and anterior ischemic optic neuropathy.

Most patients with birdshot chorioretinitis present initially with reduced visual acuity, floaters, or occasionally photopsia. Patients may also report night blindness as an initial or subsequent symptom. Later in the course of the disease, abnormal color vision is frequently noted. Visual acuity fluctuates throughout the course of the disease.

Fluorescein angiography reveals findings that are suggestive of retinal inflammation, including vascular leakage, with cystoid macular edema seen in severe cases. The retinal blood vessels, which may appear attenuated clinically, are often hypofluorescent throughout the angiogram. The birdshot lesions are frequently inert angiographically, at least early in the study.15 On indocyanine green angiography, the birdshot lesions appear as hypofluorescent spots at the level of the choroid and are typically more numerous than the pale spots that are seen opthalmoscopically.5

The ERG in birdshot chorioretinitis may vary from supernormal to extinguished. Often, the ERG waveforms are uniformly reduced in amplitude.12,23 The electronegative waveform, with smaller b-wave than a-wave, is also commonly observed.19 Variations in the ERG amplitudes, particularly the response to 30-Hz flicker and the scotopic response to the International Society for Clinical Electrophysiology of Vision (ISCEV) standard flash, have been found helpful in the monitoring of the course of the disease and in guiding the adjustment of immunosuppressive therapy.38 The Arden ratio of the EOG is typically reduced.29

The specific mechanism of cellular dysfunction in birdshot chorioretinopathy is not known, although a significant inflammatory component is clearly present. Reports of a strong association between this disease and the HLA-A29 antigen (as many as 90% of patients may be HLA-A29- positive) would seem to implicate an autoimmune etiology, possibly with a genetic component.2,27 This is said to be the closest linkage between any human disease and a specific HLA type.9

Multiple evanescent white dot syndrome

Multiple evanescent white dot syndrome (MEWDS) is an acute disorder of the deep retina and choroid that is characterized by central or paracentral scotomas associated with numerous pale fundus lesions at the level of the deep retina or pigment epithelium (figure 57.4). As the name implies, these fundus lesions are transient, typically fading from view several weeks after the onset of symptoms. An antecedent flulike illness is frequently reported.22

In many cases, formal perimetry reveals enlargement of the physiologic blind spot or other visual field defects. In this regard, patients with MEWDS appear similar to many of those described in the neuro-ophthalmologic literature with an “enlarged blind spot syndrome,” and a considerable overlap between these syndromes is probable.16 Most cases recover spontaneously, though pigmentary abnormalities in the fundus may persist indefinitely. Visual field abnormalities may seem disproportionate to the extent of the fundus lesions and may outlast the loss of visual acuity. Field loss is occasionally permanent.

Angiographically, the retinal circulation appears normal. With fluorescein angiography, the white dots seen clinically appear as hyperfluorescent lesions. Late staining of the optic nerve is typical.14 With indocyanine green angiography, the lesions appear as hypofluorescent spots, more numerous and much more clearly evident than the ophthalmoscopic lesions.20

During the acute phase of the illness, the Ganzfeld ERG often shows variable reductions in amplitude, with attenuation of a-waves and early receptor potentials.22 EOG

A

B

C

F 57.2 Central serous chorioretinopathy. A, An eccentric serous detachment superior to the optic disk causes a localized visual field defect inferior to the physiologic blind spot. B,C: Atten-

uation of the multifocal ERG is seen in the region corresponding to the visual field defect. (Courtesy of Donald Hood, Ph.D.) (See also color plate 23.)

F 57.3 Birdshot chorioretinitis. Pale fundus lesions are neither raised nor depressed relative to the surrounding retina. (Courtesy of Alan Friedman, M.D.) (See also color plate 24.)

F 57.4 Multiple evanescent white dot syndrome (MEWDS). Pale white dots are seen early in the course of the disorder. (Courtesy of Wayne Fuchs, M.D.) (See also color plate 25.)

recordings are also abnormal. Recovery of the ERG parallels normalization of the clinical findings.7 Focal and multifocal ERG technique typically reveals the inhomogeneous, patchy nature of the disorder.3

The diagnosis of MEWDS requires that it be differentiated from numerous other inflammatory disorders of the

retina, pigment epithelium and choroid, also characterized by pale fundus lesions with a multifocal distribution. In comparison with MEWDS, AMPPPE causes a much more dramatic disruption of the choriocapillaris, with sharply demarcated patches of choroidal hypofluoresence. In retinal pigment epitheliitis, the typical fundus lesions are dark spots surrounded by a yellow-white halo. The lesions of multifocal choroiditis and punctate inner choroidopathy are pale, punched-out lacunae of the choriocapillaris, typically larger and more numerous in the former than the latter condition. In contrast with MEWDS, ERG abnormalities and some degree of visual loss are much more often permanent in multifocal choroiditis and PIC.28

Acute zonal occult outer retinopathy

More subtle in initial presentation than the preceding entities, acute zonal occult outer retinopathy (AZOOR) is characterized by acute development of localized visual field abnormalities and visual disturbances and ERG changes that are suggestive of disturbance of outer retinal function, with little or no alteration in the ophthalmoscopic appearance of the fundus.13 The condition is typically monocular, with a strong preponderance of females. The course is frequently protracted, and permanent visual field changes, often accompanied by late onset of pigmentary changes in the retina, akin to those of retinitis pigmentosa, are common. Indeed, the resemblance of these eyes after the acute phase of the illness to RP has led to the suggestion that many cases of so-called unilateral RP may in fact be previously unrecognized cases of AZOOR.17

Angiographically, the findings are subtle, but deep hypofluorescent rings with hyperfluorescent haloes have been reported with both fluorescein and indocyanine green angiography.30

In the absence of overt ophthalmoscopic abnormalities, the electroretinographic abnormalities are important elements of the diagnosis of AZOOR.21 The disease is commonly monocular, so interocular differences in the ERG may be at least as important as overt abnormalities in individual ERG parameters. Abnormalities are reported in nearly all aspects of the Ganzfeld ERG, including photopic amplitude for single-flash and flicker stimuli, scotopic rod b-wave amplitudes, and scotopic mixed rod-cone responses (a-wave and b-wave amplitude) to the ISCEV standard flash stimulus (figure 57.5). Multifocal ERG recordings correlate closely with the visual fields that are obtained clinically.1

F 57.5 ERG abnormalities in acute zonal occult outer retinopathy (AZOOR). ISCEV standard Ganzfeld ERGs recorded

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29.Priem HA, et al: Electrophysiologic studies in birdshot chorioretinopathy. Am J Ophthalmol 1988; 106:430–436.

30.Rodriguez-Coleman H, et al: Zonal occult outer retinopathy. Retina 2002; 22:665–669.

31.Ryan SJ, Maumenee AE: Birdshot retinochoroidopathy. Am J Ophthalmol 1980; 89:31–45.

32.Schatz H, Maumenee AE, Patz A: Geographic helicoids peripapillary choroidopathy: Clinical presentation and fluorescein

angiographic findings. Trans Am Acad Ophthalmol Otolaryngol

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33.Suzuki K, et al: Multifocal electroretinogram in patients with central serous chorioretinopathy. Jpn J Ophthalmol 2002; 46:308–314.

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35.Watzke RC, Burton TC, Leverton PE: Ruby laser photocoagulation therapy of central serous retinopathy: I. A controlled clinical trial: 11. Factors affecting prognosis. Trans Am Acad Ophthalmol Otolaryngol 1974; 78:205–211.

36.Watzke RC, Packer AJ, Folk JC, et al: Punctate inner choroidopathy. Am J Ophthalmol 1984; 98:572–584.

37.Yannuzzi LA: Type A behavior and central serous chorioretinopathy. Trans Am Ophthalmol Soc 1986; 84:799– 845.

38.Zacks DN, et al: Electroretinograms as an indicator of disease activity in birdshot retinochoroidopathy. Graefes Arch Clin Exp Ophthalmol 2002; 240:601–607.

T can play a central role in diagnosing cases with autoimmune retinopathy (AIR). Patients with AIR frequently present with photopsias, night blindness, decreased central vision, and narrowed or scotomatous visual fields and may be mistaken as having retinitis pigmentosa.4,14 Making the situation more complicated, a few retinitis pigmentosa (RP) patients may develop AIR as a complication of their underlying disease (see below). Very often, the patient swears that his or her vision was normal a year before but now has noticeable changes. On examination, patients frequently have minimal retinal changes, and many are referred to neuro-ophthalmology clinic for evaluation. Most AIR patients develop a diffuse panretinal atrophy, which on viewing manifests as a blond fundus with mild to severe retinal vessel attenuation, and often a fine pigmentation or granularity to the subretinal space. A large majority of AIR patients have blond fundi with diffuse atrophy, and they do not have bone spicule–like dark pigment deposits. The signs and findings in AIR are often subtle and confusing, but an electoretinographic study will demonstrate severe retinal dysfunction in the face of often minimal changes in the fundus (figures 58.1A and 58.1B). Many patients have negative or greatly reduced waveforms in the dark-adapted bright-flash electroretinogram (ERG). The above findings alone do not give a diagnosis of AIR, but is the first step in establishing a more firm diagnosis.

Autoimmune retinopathy is a complex subject because there are many variations on the theme. Rare patients have cancer-associated retinopathy (CAR syndrome), and even rarer is melanoma-associated retinopathy (MAR syndrome). There has even been a report of AIR associated with a teratoma.28 Because different combinations of antiretinal antibodies have different levels of pathogenicity and because of other factors such as blood-retinal barrier integrity and family history of autoimmune diseases, can influence the severity. Most AIR patients present without cancer, but an associated carcinoma needs to be ruled out if the patient has newly diagnosed autoimmune retinopathy. If a patient has a carcinoma or melanoma and then presents with visual dysfunction, the diagnosis is much easier but still needs to be confirmed with a thorough evaluation, including ERG. Because many of these cases are treatable

with immunosuppression, which can have significant side effects, it is important to be as certain as possible of the diagnosis.

Autoimmune complications also can occur in patients with RP, and the most typical form shows up as severe cystoid edema of the posterior pole or macula. Some patients will have severe striae (wrinkles) of the macular area (not cellophane retinopathy, which has more of a mild shimmer effect). These patients typically complain of having noticeable loss of visual field over a short period of time, and if their kinetic visual fields are followed over a year, there is noticeable contraction of their isopters every 3–4 months. This subgroup of RP patients has been termed “CAR-like syndrome,” since they have the same findings as CAR patients but do not have carcinomas. Most patients fall into the category of simplex RP, but have the additional findings of cystoid edema, retinal striae, diffuse retinal atrophy with minimal to no pigment deposits, and faster progression than occurs in typical RP (figure 58.2).

To better understand the role of antiretinal antibodies in RP, we evaluated a group of 521 RP patients by doing Western blots on their serum. Fifty-one patients had antibody immunoreactivity in the range of 23 to 26 kDa, and those in turn had dot-blot antirecoverin testing. Eight of 51 patients had immunoreactivity to recoverin.10 Since antirecoverin antibodies have been shown to be associated with CAR syndrome and cytotoxicity has been demonstrated in cell retinal cell cultures, these antibodies in RP patients are likely to be contributing to the patients’ pathology.

Family histories

There is seldom a family history of RP in patients who present with AIR. Occasionally, a patient with familial RP will develop cystoid edema and will be found to have antiretinal antibodies on Western blots. Some of these patients also may exhibit faster than usual visual field loss.9 A majority of the time, a history will be found that first-degree relatives of the patient will have autoimmune diseases such as lupus erythematosis, scleroderma, severe asthma, thyroid disease, diabetes, rheumatoid arthritis, fibromyalgia, or multiple sclerosis, and there is usually a mix of different

Photopic

Rod isolated

BrFl Scotopi

11 V

91 V

76 V

83 V

115 V

47 V

65 V

Photopic

Rod isolated

Bright Flash

Dark-adapted

51 V

25 V

57 V

56 V

96 V

autoimmune diseases in the first-degree relatives of the patient.

The diagnosis of AIR is often based on putting a number of different factors together, which may include the following:

1.Rapid loss of vision over a 1- to 6-month period. The patient is usually insistent that there is a problem even though the examination might not show much.

2.Frequently, a lack of findings on ophthalmoscopy. The atrophy is diffuse, the retinal pigment epithelium becomes depigmented, and pigment deposits are uncommon. Retinal vascular attenuation and cystoid edema may be present.

3.Kinetic visual fields demonstrated contraction of isopters, often with ring scotomata. There may be asymmetry in the amount of involvement between eyes. Over 3–6 months, the loss of field may be dramatic and not typical of RP. Often, the ERG will be more severely affected, while there may be a large amount of visual field on kinetic testing. Some cases that have milder loss of visual field also have macular edema.

4.Involvement of the posterior pole with a cystic edematous process correlates well with a strong presence of autoimmune antibodies. RP patients with cystoid macular edema also have a positive correlation with the presence of antiretinal antibodies on Western blotting.11

5.Western blots of the patients’ serum against normal retinal protein extracts will typically show antiretinal IgG and sometimes IgM bands of activity (see figure 58.1). Demonstrated activity against recoverin is pathognomic for AIR and, when it is against a-enolase, arrestin, carbonic anhydrase, and photoreceptor-specific nuclear receptor (PNR), strongly support the diagnosis if other features are present. Most cases have a minimum of three different antiretinal antibodies on Western blot. It should be noted that just having random antiretinal antibodies does not mean that AIR is present. Antibodies against recoverin, arrestin, enolase, and PNR are likely to have significance.

6.The definitive test for MAR syndrome is checking for reactivity against donor normal retina bipolar cells on immunohistology. Some of these patients are showing anti-PNR reactivity. Many patients with positive Western blots will also light up specific cell types on immunohistology examinations of normal retina, but it is not known yet how this correlates with pathogenicity. Cytotoxic studies have been done that suggest toxicity by various antiretinal antibodies.1,9,27

7.The patient has a family history of autoimmune diseases in first-degree relatives as noted previously.

Summary of electroretinographic findings

Many AIR patients undergo electroretinographic testing because the ophthalmologist is not sure what they really

have, and a retina-based problem needs to be ruled out. The retinal changes can be subtle and nonspecific, and it is often a surprise when the ERG results are so abnormal. The changes on the ERG are dependent on the stage of disease at which the patient is tested and what combinations of antibodies are affecting the retina. At least half the time, the patient will have a negative waveform, but it should be remembered that this finding is not pathognomonic for AIR but that there is a large differential for conditions associated with this disease (see chapter 72). Various patterns of dysfunction can be found in these patients depending on what damage the antibodies are doing in the retina, from cone-rod or rod-cone patterns, or from nonspecific loss.

Cancer-associated retinopathy

Paraneoplastic retinopathies associated with carcinomas have been most commonly associated with small cell carcinoma of the lung, but cases have been reported from a variety of other carcinomas, including breast, endometrial, and colon cancers, and even from lymphomas. Presumably, the tumor is producing retinal proteins that are antigenic and stimulate antibody production. In many cases, the presence of autoimmune genes makes some patients more susceptible to developing the retinopathy. Paraneoplastic autoimmune optic neuritis also has been reported numerous times.5,29

Many patients who develop CAR syndrome attribute their visual symptoms to the chemotherapy or just having cancer. In some cases, the visual symptoms precede the discovery of the malignancy. Various immunosuppressive therapies have been tried in patients, including prednisone, stronger immunosuppression with immuran and cyclosporine, intravenous immunoglobulin administered monthly, and plasmaphoresis administered monthly, with varying degrees of success. The first author had one patient with ovarian carcinoma and antirecoverin antibodies who recovered peripheral visual fields on monthly subtenons injections of depomedrol, as her internist did not want her to be on systemic immunosuppression.

A variety of antiretinal antibodies have been identified in these patients, and different combinations can be seen. The ones that have been identified to date are listed in table 58.1. It should be noted that a number of unknown proteins have been seen in Western blots, and these inciting proteins have yet to be identified and proven to be pathogenic. Jankowska and colleagues did an assay against known retinal proteins using sera from patients with lung cancer and sarcoidosis. They found high levels of antiretinal antibody acitivity in the lung cancer and sarcoid groups compared to controls, and the lung cancer sera had high levels of antibodies to recoverin and a-enolase.16

T 58.1

Proteins which have been associated with autoimmune retinopathy1,12,13,14

Melanoma-associated retinopathy

The electrophysiological findings in melanoma-associated retinopathy (MAR) were first described by Berson and Lessell in a patient with shimmering of vision and nyctalopia following cutaneous malignant melanoma (MM).3 The principal observation was a negative ERG with a bright white flash delivered under scotopic conditions, in keeping with dysfunction postphototransduction. Fishman’s group reported a second case in which ONand OFF-response recording using long-duration stimulation was also performed.2 This showed reduction in the ON b-wave but sparing of the OFF-response and the ON-response a-wave. A recent report from Sieving’s group showed that intravitreal injection into a primate eye of IgG from an affected patient produced the characteristic ERG changes approximately 1 hour after injection.22 Milam and coworkers first reported the presence of autoantibodies against bipolar cells, and this was endorsed by histopathological findings of reduced bipolar cell density in the inner nuclear layer.7,23 Jacobson reported a patient with colon adenocarcinoma and antibipolar antibodies with attenuated ERG signals.15

Of great interest, a recent report describes asymptomatic retinopathy in three of 28 patients with cutaneous MM; four patients had symptoms and ERG findings suggestive of MAR.25 A large summary article on MAR syndrome patients that included a review of the literature and 11 new patients was published by Keltner in 2001.18 They noted that immunohistological staining of bipolar cells is typical, but other staining can also be seen. They cited several patients who reported improvement with immunosuppression therapies.

The clinical presentation is typically shimmering photopsias and nyctalopia with normal ophthalmological examination, but vitritis has been described in one patient, and an absence of nyctalopia has been described in another.17,20 The clinical features have recently been reviewed.4

At Moorfields Eye Hospital, we have examined seven cases of clinically ascertained MAR.12 Shimmering photopsias and nyctalopia dominated the clinical picture in all

patients. Two patients had mild vitritis. Investigations were usually negative, but in one patient, white dots that were visible on ophthalmoscopy were hyperfluorescent on fundus autofluorescence imaging. The significance of this is unknown. Electrophysiologically, the rod-specific ERG was undetectable in six cases and almost so in the seventh. The maximal response showed a profoundly negative waveform in all patients. These data reflect profound dysfunction postphototransduction and are in keeping with dysfunction of the rod ON or depolarizing bipolar cells (DBCs). Superficially, the full-field ERG cone responses appeared much less affected, with minimal if any abnormality of cone flicker response implicit time. However, close inspection reveals subtle but highly significant changes. In particular, the single-flash photopic response shows a distinctive broadened a-wave and a sharply rising b-wave with a reduced b/a ratio and lack of photopic oscillatory potentials. It is suggested that this appearance is pathognomonic of marked dysfunction of cone DBCs, with preservation of cone OFF or hyperpolarizing bipolar cells. The profoundly negative ON response, with preservation of the ON a-wave and loss of the ON b-wave, accompanied by a normal OFF response supports this proposal. The somewhat broadened trough of the 30-Hz flicker ERG with a sharply rising peak is thought to be a manifestation of the same phenomenon. The PERG was severely reduced in all patients in whom it was recorded. S-cone-specific ERGs, when recorded, were always reduced. No significant interocular electrophysiological asymmetry was present in any patient. Color contrast sensitivity testing, when performed, showed no elevation of protan and tritan axis thresholds but significant elevation in the tritan axis.8

It is widely accepted that S-cones have only an ON bipolar cell pathway, unlike L- and M-cones that have both ON and OFF pathways.6 The loss of S-cone ERGs and the elevated tritan axis on color contrast sensitivity testing are thus in keeping with additional ON pathway involvement in relation to the S-cone pathway. The profoundly abnormal PERGs, in keeping with the observations of Kim et al. in a study of four patients before the introduction of International Society for Clinical Electrophysiology of Vision standard ERGs,19 are notable given the often-normal visual acuity and fundus appearance. However, it has recently been suggested that the PERG has a particular dependence on ON bipolar cell function.13 Overall, the electrophysiological data are in keeping with global ON-pathway dysfunction affecting rods and all cone types.

Some authors have commented on the similarity between the ERG findings in their cases of MAR and those in complete X-linked congenital stationary night blindness with myopia.21,24,26 To facilitate this comparison, a full set of electrophysiological data from a typical patient with cCSNB with myopia is also shown in figure 58.3. The undetectable rod-specific ERG, the profoundly negative maximal

F 58.3 ERG and PERG findings from a patient with melanoma-associated retinopathy and a patient with complete

response, the photopic single-flash ERG with a broadened a-wave and sharply rising b-wave, the markedly subnormal PERG, the negative ON response with sparing of the OFF response, and the reduced S-cone ERG are all indistinguishable from the findings in a patient with MAR. These data extend those described in the case report of Alexander and colleagues.2

The identical pattern of electrophysiological abnormalities in MAR and cCSNB exemplify the need always to interpret electrophysiological data in clinical context. Patients with MAR have an acquired nyctalopia with shimmering photopsias, they can be of either gender, they need not be myopic, and they almost invariably have had cutaneous MM. Patients will not always be aware of the diagnosis of malignant melanoma, and a history of removal of a “pigmented mole” or similar cutaneous lesion might be revealed only by direct questioning.

Future diagnostic techniques in AIR

It is likely that more definitive laboratory tests will be forthcoming to better make the diagnosis of AIR, likely based on the exciting antigens (and their antibodies) and specific inflammatory products such as specific cytokines that are involved in the pathologic process. The ERG will play a major role in identifying affected patients and possibly in monitoring treatment.

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