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Visual Evoked Potentials With Crossed Asymmetry in Incomplete Congenital Stationary Night Blindness Frangois Tremblay, Inge De Becker, Cindy Cheung, and G. Robert LaRoche Purpose. To investigate a proposed postretinal defect in patients with the incomplete form of congenital stationary night blindness (CSNB2) and to compare visual evoked potential (VEP) results with those found in various forms of albinism. Methods. Visual evoked potentials were performed in 10 patients with a diagnosis of CSNB2, 10 subjects with albinism, and 17 normal subjects. Visual evoked potentials were elicited monocularly with diffuse flash stimulation. Scalp electrodes were placed over each hemisphere and referred to the forehead. Interhemispheric bipolar recordings were derived, and the correlation coefficient (CC) was calculated for various segments of the interhemispheric responses. Results. A crossed visual evoked potential asymmetry pattern could be demonstrated in 9 of 10 patients with CSNB2. All subjects with albinism and none of the normal subjects showed the crossed asymmetry pattern. Statistical comparison of the CC computed for various segments of the interhemispheric response shows that the pattern of inversion in CSNB2 is more prominent in the 25 to 100 msec range (median CC, —0.37) and in the 175 to 250 msec range (CC, —0.27). In subjects with albinism, all segments show a negative CC (range, —0.46 to —0.60). In normal subjects, all segments are positively correlated (range, 0.36 to 0.66). Conclusions. Crossed visual evoked potential asymmetry was found in patients with CSNB2; therefore, excessive decussation, as demonstrated by this testing procedure, should not be considered as pathognomonic for albinism. Invest Ophthalmol Vis Sci. 1996; 37:1783-1792. JL his study was triggered by the examination of a 17year-old boy thought to have ocular albinism (OA). Visual evoked potentials (VEPs) showed a crossed asymmetry distribution, as seen in albinism, in which excessive contralateral decussation has been demonstrated. Surprisingly, electroretinograms (ERGs) showed an electronegative bright-flash response and other ERG findings characteristic of CSNB2. In a previous publication,1 we noted that VEPs obtained routinely from a central occipital lead were abnormal in four patients with CSNB2, raising the suspicion of abnormal postretinal visual pathways. CSNB2 is a retinal condition first described by From the Department of Ophthalmology, Dalhousie University, and the fWK- Grace Health Center, Halifax, Nova Scotia, Canada. Supported by Dalhousie Medical Research Foundation (CC). Submitted for publication December 22, 1995; revised March 25, 1996; accepted April 3, 1996. /Proprietary interest category: N. liefmnt requests: Francois Tremblay, Department of Ophthalmology, Izaak Walton Killam Children's Hospital, 5850 University Avenue, P. O. Box 3070, Halifax, Nova Scotia, Canada B3J 3C9. Investigative Ophthalmology & Visual Science, August 1996, Vol. 37, No. 9 Copyright © Association for Research in Vision and Ophthalmology Downloaded From: http://iovs.arvojournals.org/ on 05/05/2017 Miyake et al.2"3 Clinical manifestations include subnormal visual acuity (range, 0.3 to 0.8), nystagmus, and strabismus. Fundus examination results were within normal limits, with the exception of a slightly pale optic nerve head. However, in our previous study of 15 white patients with CSNB2, we did observe the occurrence of blond fundi (our propositus and three patients). Clinical manifestations can be subde and nonspecific; therefore, the diagnosis of CSNB2 is decided by electroretinographic investigations.1"3 Electroretinographic characteristics in CSNB2 are attenuated, but not extinguished, rod-related activity; electronegative bright-flash response with near-normal early oscillatory potentials; reduced photopic cone bwave; and no response to flicker. In albinism, the absence of ocular pigmentation seems to be linked to a sequence of embryonic disorganization that leads to retinal dysfunction and misrouting of the optic nerve fibers. In normally pigmented persons, fibers originating in the temporal hemiretina remain ipsilateral, whereas the fibers from the nasal hemi- 1783 1784 Investigative Ophthalmology & Visual Science, August 1996, Vol. 37, No. 9 retina decussate and reach the contralateral cortical hemisphere. In subjects with albinism, a proportion of the temporal fibers crosses with the nasal fibers, resulting in excessive decussation and nonoverlapping representation at the cortical level. This pattern of decussation results in an asymmetric distribution of the scalp potentials across the occiput; the full-field right eye stimulation evokes a predominantly left cortical hemisphere response, and the left eye stimulation evokes a right cortical activation. Various studies have shown that this pattern of asymmetry is found in albinism but is absent in other conditions that share certain clinical characteristics with albinism, such as nystagmus,'1 decreased stereopsis (dissociated vertical deviation),5"7 and hypopigmentation (Prader-Willi syndrome).8 For our propositus, the simultaneous occurrence of pale fundi and crossed VEP asymmetry on the one hand and the ERG findings characteristic of CSNB2 on the other hand motivated us to investigate further the chiasmatic decussation in patients with CSNB2. The current study reports a VEP comparative investigation in patients with CSNB2. Scotopic ERGs Photopic ERGs METHODS Subjects Thirty-seven subjects were examined after a protocol was approved by the Izaak Walton Killam Research Ethics Board. The protocol follows the tenets of the Declaration of Helsinki, and informed consent was obtained after the nature of the study was explained. Ten patients with a diagnosis of CSNB2, who already had been reported in a previous publication,1 were identified from a retrospective chart study.9 The diagnosis of CSNB2 was secured with electroretinographic investigations based on the following criteria: attenuated, but not extinguished, rod-related activity; electronegative bright-flash response with near-normal early oscillatory potentials; reduced photopic cone bwave; and no response to flicker (see Fig. 1). Most patients had unexplained visual acuity reduction (0.3 or better), mild nystagmus, or family history of CSNB2. Fundus examination results were normal except for mild temporal optic disc pallor in six patients. Ten patients with albinism were diagnosed based on the following criteria: pale chorioretinae, foveal hypoplasia, nystagmus, iris diaphany, family history, normal or supernormal ERGs, and VEP-crossed asymmetry. A summary of the clinical findings for both groups is found in Table 1. Seventeen normal age-matched volunteers also were evaluated. Protocol The protocol used in this study follows the guidelines developed for detection of the crossed cortical asym- Downloaded From: http://iovs.arvojournals.org/ on 05/05/2017 l. Representative electroretinographic recordings in one patient with CSNB2. Dark tracings are from a representative patient, and gray traces are from an age-matched subject. Trace 1: scotopic (30 minutes of dark adaptation under dim red room illumination) single blue flash (Kodak Wratten 47, 47a, and 47b filter 1 cd-m~v!-sec source flash; four sweeps averaged) show a small but consistent rod response. Trace 2: scotopic bright-flash (1 cd"m~2#sec, no interference filter; four sweeps averaged) response showing delayed but large amplitude a-wave and a small (electronegative) bwave. Trace 3: large amplitude oscillatory potentials (100 Hz to 1 kHz filter) were derived from trace 2. Trace 4: photopic (34 cd-m~2-sec background) single flash (10 cd • m~2 • sec; 10 sweeps averaged) response, showing a delayed a-wave and a b-wave that hardly returns to the baseline level. Trace 5: absence of oscillatory potentials when trace 4 is derived (100 Hz to 1 kHz filter) from trace 1. Trace 6: flicker stimulation (33.3 Hz); no response could be elicited. Triangles = stimulus onset. Calibration: {horizontal) traces 1 to 2, 40 msec; traces 3 to 5, 20 msec; trace 6, 80 msec. Calibration: {vertical) traces 1, 2, 6, 300 /zV; traces 3, 5, 30 /iV; trace 4, 150 //V. FIGURE metry resulting from optic fiber misrouting.1 Gold dermal disc electrodes were fixed on the scalp (EC2 electroconductive cream; Grass Instruments, Quincy, MA) after skin preparation. The active electrodes were positioned over both hemispheres, 5 cm from the midline VEPs Crossed Asymmetry in CSNB2 1785 TABLE l. Summary of Clinical Findings in Subjects With Albinism and CSNB2 Visual acuity range Age Sex Nystagmus Fundus Stereoacuity Electroretinograms Visual evoked potentials Albinism CSNB2 0.1-0.3 (mean 0.17) 1-35 (mean 10.7) 5M.5F 8/10 Mild to definite hypopigmentation 10/10 Macular hypoplasia 6/10 Pallor of disc 0/10 Worse than 400" Normal 6/6 (done in 6/10) Crossed asymmetry 10/10 0.25-0.7 (mean 0.44) 4-19 (mean 8.8) 10 M 3/10 Mild hypopigmentation 4/10 Macular hypoplasia 0/10 Pallor of disc 6/10 As good as 60" Electronegative bright-flash 10/10 Crossed asymmetry 9/10 and 3 cm above the inion (O| and O 2 ). The reference electrode was positioned at FPz, and the left earlobe was used as a common ground. Bandwidth of the amplifier (Spirit system; Nicolet, Madison, WI) was set at 0.1 to 1 kHz. Two to four series of 100 sweeps were averaged. The number of series averaged was determined by the intertrial variability as judged by an experienced observer (FT). Data were stored on disk for off-line analysis. The evoked potential stimulus consisted of a diffuse flash presented monocularly at 2.3 Hz through red light-emitted diodes incorporated into goggles (S10VSB; Grass Instruments). The mean luminance of the 5 msec duration square-wave flash was 30 cd • m~2 • sec. The first eye stimulated was selected randomly. In the pediatric population, the flash-VEP generally provides more robust and reliable responses than the pattern-onset stimulus presentation because no fixation is required.10 Pattern-onset stimulation (Nicolet 1015 stimulator; Nicolet) was provided when the flash stimulus was not generating a consistent response. Mean luminance was set at 22 cd • ~2 with a contrast of 90%. Check size was 40 minutes of arc, and the whole stimulation field subtended an area of 16° X 20°. Pattern was presented for 80 msec and alternated with an equiluminant gray unpatterned field at a rate of 2.3 Hz. Data Analysis Off-line analysis first consisted in the summation of the averages obtained. A Gaussian smoothing function (9 points) then was applied. After an inversion in polarity, channel O| was algebraically subtracted from channel O2; the resultant wave was the computed interhemispheric difference during a monocular stimulation. The same procedure was applied to waves from the other eye. However, as reported in cases of albinism," the VEP responses can be too weak and distorted to reflect clearly the crossed asymmetry when using a calculation based on amplitude measurements.1 Therefore, we developed a technique inde- Downloaded From: http://iovs.arvojournals.org/ on 05/05/2017 pendent of the peak amplitude detection to quantify more objectively the interhemispheric differences. As an index of asymmetry between the two resultant waves, the correlation coefficient (CC) was computed. A value of +1 is representative of an exact match between the two waves, a value of — 1 represents two identical waves of opposite polarity, and values close to 0 represent uncorrelated activity. To palliate the absence of amplitude recognition of the CC, the covariance (CoV) also was calculated as an index of the signal's magnitude. The formula IAV = log I j was developed, where IAV is die index of amplitude variation, Covx.x is the covariance calculated for a given segment of the interhemispheric responses, and Cov,, is the covariance calculated for the prestimulus segment of the original hemispheric responses (—40 to 0 msec). Values of IAV equal to or lower than 0 indicate amplitude variations within the CC segment considered in the range of the noise level or the original data. Thus, CC values are considered to reflect true asymmetry only when IAV is superior to 0. Segmental analysis was performed on various portions of the waves: 25 to 100, 50 to 125, 75 to 150, 100 to 175, 125 to 200, 150 to 225, and 175 to 250 msec after the stimulus onset. For all the segments analyzed, nonparametric statistical analysis (Mann-Whitney, Statview; Abacus Concept, Berkeley, CA) was performed on CC to compare the significance of the group differences. RESULTS Qualitative Analysis In normal subjects (Fig. 2; Nl to N12), monopolar derivations at Ol and O2 typically produce deflections with the main positivity in the vicinity of 80 to 120 msec. Cortical responses could have variable morphology, from typical adult-like responses to less mature, simpler morphology. Bipolar derivations (obtained off-line by the inversion of O2 and its addition to Oi) could show high interhemispheric symmetry (N5 to Investigative Ophthalmology 8c Visual Science, August 1996, Vol. 37, No. 9 1786 Normal Q-,-02 CVO2 OD OD 100 100 Albinism OS OD 100 100 FIGURE 2. Visual evoked potentials in response to monocular stimulation in two normal subjects with low and high interhemispheric potential variations (Nl to N6, N7 to N12) and two patients with albinism (Al to A6, A7 to A12) and with CSNB2 (Cl to C6, C7 to C12). Two patterns of asymmetry could be observed, interhemispheric amplitude variations (bold arroius) and implicit time variations (dashed lines). OS = left eye stimulation; OD = right eye stimulation. O| and O2 are recordings from electrodes overlying the left and right hemisphere, respectively, and d — O2 refers to the off-line computation of the interhemisheric potential variations. Refer to Qualitative Analysis, Results section, for more detailed explanation. Dots = stimulus onset. Calibration as indicated. N6) or relatively large interhemispheric differences ( N i l to N12), in spite of consistent hemispheric responses (traces 7 to 10). Consistent symmetric bipolar recordings could be obtained even with uncooperative children. In albinism, a different pattern emerged. Monopolar response characteristics are the same, though the overall amplitude can be reduced drastically in some cases, as reported by Bouzas.'' However, the cortical distribution of the evoked responses varies in function of the eye stimulated. In the case presented in Figure 2 (Al to A6), contralateral responses yielded a large biphasic wave, whereas ipsilateral responses Downloaded From: http://iovs.arvojournals.org/ on 05/05/2017 were smaller and less wavy (bold arrows; compare Al to A2 and A3 to A4). The crossed asymmetry could be visualized easily by direct comparison of traces Al and A4 (large contralateral responses) or A2 and A3 (smaller ipsilateral responses). The bipolar derivations (equivalent to O| — O2) computed from the monocular recordings showed inverted waves characteristic of a crossed asymmetry (arrows, A5 to A6). In other cases, waves had similar amplitudes in both hemispheres but different culmination times regarding the main positivity (compare A7 to A9 and A8 to A10; dashed lines). Again, this led to the characteristic inverted interhemispheric responses (arrows; A l l to 1787 VEPs Crossed Asymmetry in CSNB2 A12). Such inversions were observed in all 10 subjects with albinism, even in those in whom VEP amplitudes were low. These two patterns of VEP characteristics have been observed before.1213 In patients with CSNB2 (Fig. 2; Cl to C12), a pattern of crossed asymmetry also was observed. In the first example (Cl to C6), the hemispheric responses contralateral to the eye stimulated had smaller biphasic positivity (bold arrow; C2 to C3), whereas the ipsilateral responses were simple, large positivity (compare Cl and C4). Interhemispheric comparison accomplished by wave subtraction revealed consistent oscillatory variations of opposite polarity (arrows; C5 and C6). In another case presented in traces C7 to C12, the crossed asymmetry was more difficult to visualize because the response differences relied more on the temporal relationship than on wave morphology. Here, the ipsilateral responses (C7 for the left eye and CIO for the right eye) had monophasic, short, implicit time peaks. Contralateral responses yielded a major positivity with longer implicit time. The computed bipolar comparison (Cll to C12) revealed a clear inversion of waves in the early phase of the response (see arrows). As in albinism, the two patterns of hemispheric asymmetry (wave morphology and implicit time delay) produced the inverted interhemispheric responses considered characteristics of chiasmatic misrouting. This inversion was observed clearly in the early phase (between 25 and 100 msec after the stimulus onset) of the response in 6 of 10 patients with CSNB2 and was present in the late phase of the response (between 150 and 250 msec) in two other subjects. Most of the results presented in this study were obtained using diffuse flash stimulation. In the pediatric population, this has proven to be a sufficient stimulus; the use of the pattern-onset stimulus did not improve the magnitude of the inversion and, therefore, was not retained for quantitative analysis. However, in a few cases, it has been necessary to use a patternonset stimulus to prove the inversion. In two of the oldest patients in whom the inversion could not convincingly be observed with the flash stimulation (see Figs. 3, 5, 6; dashed arrows), a pattern-onset stimulus resulted in a more negative CC and a more convincing visualization of the inversion of the interhemispheric potentials (Figs. 3,11,12; arrows). In two patients with CSNB2, no negative correlation could be demonstrated with either stimulus. Quantitative Analysis Quantitative analysis was performed to measure the degree of inversion observed in crossed asymmetry and its distribution in the time series. For that purpose, correlation coefficients and covariations were computed for segments of 75 msec covering the first Downloaded From: http://iovs.arvojournals.org/ on 05/05/2017 Flash-VEPs 01 O2 OS OD Pattern-Onset VEPs OS 3. Visual evoked potentials in one patient with CSNB2 with a small asymmetry with the flash-evoked response (traces 1 to 6, dashed arrows in traces 5 and 6) and a larger asymmetry with a pattern-onset checkerboard stimulation (traces 7 to 12, arrows in traces 11 and 12). OS = left eye stimulation; OD = right eye stimulation. Oi and O2 are recordings from electrodes overlying the left and right hemisphere, respectively, and Oi — O2 refers to the off-line computation of the interhemisheric potential variations, (traces 1 to 6) Dots = stimulus onset, (traces 7 to 12) Line up is checkerboard presentation. Calibration as indicated. FIGURE 250 msec after stimulus. The choice of an analysis time of 75 msec was guided by the fact that 75 msec (»12 to 15 Hz) corresponds to a major peak of the fast Fourier transform performed on these waves. Table 2 summarizes the results for window analysis of 75 msec, starting at 25 msec after stimulus and covering the first 250 msec of the responses. For the group of normal subjects, the correlation coefficient was positive and varied between 0.36 to 0.66. This high positive correlation indicates a high degree of symmetry between the two interhemispheric responses. In the group with albinism, the CC was strongly negative, varying between —0.46 and —0.60, indicating the opposite pattern of the two interhemispheric responses. The CC was fairly constant throughout the response scanned. In the group with CSNB2, negative CC was observed in the first and last time window analyzed, at 25 to 100 and 175 to 250 msec. These two time windows correspond to the two main positivities observed in normals. The other time windows yielded relatively lower positive CC, which suggests a poorer synchronization of the signal. Statistical comparisons (MannWhitney unpaired comparison) demonstrated that the group with CSNB2 differed significantly from the normal group (Table 2, N/C column; P < 0.05) in 1788 Investigative Ophthalmology & Visual Science, August 1996, Vol. 37, No. 9 TABLE 2. Median and 25th (Q25) and 75th (Q75) Percentiles for the Correlation Coefficient Computed for Seven Time Windows From the Groups of Normal, Albinism, and CSNB2 Patients Statistical Comparison (P) Albinism Normal Window (msec) Median 25-100 50-125 75-150 100-175 125-200 150-225 175-250 o» 0.62 0.65 0.63 0.36 0.55 0.64 0.66 24.5 43.2 -3.2 -17.7 12.2 47.0 14.7 Median 82.0 92.0 85.2 86.7 83.2 87.0 88.7 CSNB2 Q« Median Q.25 o.» -12.0 4.2 -2.7 -13.2 27.7 73.7 28.7 -0.37 0.34 0.34 0.38 0.60 0.11 -0.27 -69.0 -43.0 -61.0 -1.0 -6.0 6.0 -63.0 32.0 70.0 73.0 64.0 72.0 44.0 5.0 Q.25 -0.54 -0.48 -0.60 -0.56 -0.46 -0.47 -0.51 -78.0 -79.5 -88.2 -87.2 -82.7 -57.0 -77.0 the two first and two last segments analyzed, whereas the group with albinism differed from the normal group in all the segments analyzed (N/A column). Figure 4 illustrates the significance of CC in function of the CoV, calculated for the same data. The knowledge of the covariance is an important piece of information because the CC itself can, in some circumstances, be misleading. For instance, almost isoelectric interhemispheric recordings can produce low or even negative CC while, in fact, the two waves are similar. When the two waves to be compared are low in amplitude, the noise level becomes disproportionately important and biases the CC. To reduce this bias, the ratio between the CoV calculated for the segment analyzed and the 25-100 MSEC Normal CSNB2 Albinism CSNB2 0.001 0.001 0.005 0.004 0.004 0.04 0.009 0.007 0.06 0.53 0.51 0.97 0.03 0.02 0.29 0.01 0.04 0.02 0.003 0.20 0.23 CoV calculated from the prestimulus baseline is computed (CoV ratio). By doing this, the CC is scaled to the level of original VEP background activity. When the interhemispheric responses are low in amplitude compared to the original data background noise, the CoV ratio is approximately unity (log CoV = 0); the significance of the CC is then reduced because it is influenced primarily by the background activity. On the other hand, when log(CoV ratio) is above 0, the CC is significant because it measures the evoked potential differences above the noise in the original data. Thus, the scattergraphs in Figure 4 present the CC as a function of log(CoV ratio) for three time windows: from 25 to 100 msec (where the major posi- ALBINISM NORMAL Normal Albinism CSNB2 2.5 . 2.0. 1.5- • 1.0. • * • 0.5. . .»- • -0.5. • # -1.0 -100 -75 -50 -25 0 25 50 75 100 125 -100 -75 -50 -25 25 50 75 100 125 -100 -75 -50 25 -25 50 75 100 125 Correlation Coefficient FIGURE 4. Scattergraph illus- 100-175 MSEC 2.5 2.5. 2.5. • 2.0 . 2.0. 1.5 . 1.5. V • 1.00.5- • -50 -25 25 50 75 | OS- # 1.0. • * * • * • • • • • • 0.5. 100 • 1.5. LO- 0.5- 1,0 -100 -75 2.0 • t 0.5- 125 1.0 -100 -75 -50 -25 25 50 75 100 125 10 -100 -75 -50 -25 25 50 75 100 125 125 -100 -75 -50 -25 25 50 75 100 125 •100 -75 -50 -25 25 50 75 100 125 175-250 MSEC 2.5. 2.0. • • 1.5. 1.0. 0.5 . •w* 0.5. 10 100 -75 -SO -25 25 SO 75 100 Downloaded From: http://iovs.arvojournals.org/ on 05/05/2017 trating the correlation coefficient (CC) computed for various segments of the monocular flash-evoked interhemispheric recordings and its relation with the log ratio of the covariance, for the groups of normal subjects, subjects with albinism, and patients with CSNB2. A log (CoV ratio) ratio value of 0 indicates a signal amplitude at the noise level, and any data close to this value should not be considered. VEPs Crossed Asymmetry in CSNB2 tivity in the evoked response usually is found), from 100 to 175 msec, and from 175 to 250 msec (where late evoked responses usually occur). Data from the normal subjects, subjects with albinism, and patients with CSNB2 are presented in three separate columns. In the normal group, CC was high and positive, and log(CoV ratio) was generally above 0. In some cases, the CC could be low or even negative, but this usually was associated with a log(CoV ratio) that was also low, which means that this portion of the VEP signal was almost isoelectric and was influenced primarily by the background activity. This was particularly true in the intermediate portion of the VEP signal (100 to 175 msec), between the two main positivities. In the group with albinism, the CC had high negative values, and the log(CoV ratio) generally was also high. In most instances, the CC could be interpreted easily. For the group of patients with CSNB2, the majority of the early and late segments were correlated negatively, whereas in the intermediate segment, results were more variable. Data from the few patients presenting with "significant" positive CC in the 25 to 100 msec segment usually were associated with negative CC in the 175 to 250 msec segment. Therefore, all but one patient had at least one negative CC above the noise level. DISCUSSION In patients with CSNB2, VEP-crossed asymmetry was detected reliably through flash stimulation. This is the first report of a postretinal dysfunction in CSNB2. In an electroretinographic investigation previously performed on a group of 15 patients with CSNB2, we briefly mentioned that binocular VEP anomalies were found in 5 of them. 1 To date, few studies have demonstrated VEP asymmetry in conditions other than albinism. To our knowledge, only one report on a family with congenital nystagmus14 and one report on patients with dissociated vertical deviation 1 ' have shown such asymmetry. The results of these two studies were based on monocular hemifield (pattern-reversal) stimulation, a technique difficult to apply reliably because of the requirement for steady fixation. Moreover, the results of those two studies could not be reproduced by others, who used the same technique"' or a diffuse flash or patternonset stimulation protocol.'1'7 On the basis of the latter studies, it seems reasonable to consider dissociated vertical deviation as not demonstrating crossed asymmetry. Reports from patients with idiopathic congenital nystagmus4 and Prader-Willi syndrome 8 also were negative. Because VEP asymmetry reflects abnormal decussation, it is generally accepted as diagnostic of albi- Downloaded From: http://iovs.arvojournals.org/ on 05/05/2017 1789 nism. However, Guillery (personal communication, cited in Regan17) "raised the point that the known incidence of misrouting in albinos might be only the 'tip of the iceberg' in the general population and that some non-albino individuals—especially those with fair hair and blue eyes—might experience a lesser degree of misrouting, possibly associated with comparatively minor visual problems." This comment, along with some animal reports (normally pigmented cats heterozygous for albinism) 18 also contribute to the idea. Miswiring might not be the exclusive characteristic of albinism—it might be found in other conditions. Crossed Asymmetry in CSNB2 In albinism, hypopigmentation is accompanied by a slightly disorganized retina, underdevelopment of the macular area, and a decreased number of rods and ganglion cells.19'20 Evidence is accumulating to support the idea that the absence of retinal pigment disrupts the development of the normal spatio-temporal sequence of events in the developing neural retina.21"2'1 For instance, ganglion cells from the temporal hemiretina that remain uncrossed at the optic chiasm are generated and grow out before ganglion cells from the same area, which are destined to grow contralaterally to the optic chiasm. The expression of the tyrosinase gene occurs simultaneously with this early ganglion cell sprouting. One could hypothesize a time relationship between melanogenesis and ganglion cell development; the disruption in melanogenesis or simply a delay in its occurrence could result in optic tract disorganization (see references 21 and 25 for review of current concepts). Could it be that, in CSNB2, melanogenesis is complete but is not coordinated with ganglion cell development? This would have an impact on the timely focal axonal guidance of the ganglion cell but not necessarily on the more extended development of retinal organization. Central visual acuity in CSNB2 is subnormal. Unlike central visual acuity albinism,26'27 there is no foveal hypoplasia to explain this reduction in acuity. The ERG is severely abnormal 1 but, as already proposed for other retinal conditions, 28 " 32 the retinal network may be functional and may not contribute to visual acuity reduction. The abnormal development of the optic tract fibers with oversampling of the crossed pathway and subsequent reorganization of the visual cortex topography could be considered as one contributing factor for the reduced visual acuity observed in CSNB2. CSNB2 Is Not Albinism Although crossed asymmetry generally is considered diagnostic of albinism,9 we think CSNB2 is not a form of albinism. The clinical manifestations of CSNB2 and 1790 Investigative Ophthalmology 8c Visual Science, August 1996, Vol. 37, No. 9 mild cases of OA can be similar: mild to moderate subnormal visual acuity, nystagmus, strabismus, and refractive errors. Retinal pigmentation does not necessarily distinguish between CSNB2 and OA: CSNB2 indeed has normal, retinal pigmentation, and many patients with mild OA have a blond fundus that is within normal limits for the white population.1"3 The ERG manifestations are different in CSNB2 and OA.1"3 In OA and oculocutaneous albinism, ERGs are normal or supernormal.33 In CSNB2, electronegative brightflash responses and attenuated cone signal are found.' The VEP manifestations in CSNB2 are not as severe as in albinism; in most subjects with CSNB2, a negative correlation was observed only at punctual locations in the time series, whereas in albinism, the negative correlation could be found over the entire extent of the 250 poststimulus responses. Stereoacuity is poor in albinism, whereas in at least some of our patients with CSNB2, stereoacuity is relatively good (60 seconds of arc on Titmus in one of our patients). These observations suggest that the crossed decussation may not be as complete in CSNB2 as in albinism. The different pattern of asymmetry observed in CSNB2 may reflect a different cortical reorganization, such as an incomplete topographic mapping of the vertical meridian or a different pattern of intracortical suppression, as has been proposed for the Siamese cat.21 It remains, however, a matter of speculation. Aland Island Eye Disease Previous reports suggest that CSNB2 and AIED (type 2 ocular albinism; MIM NO:30060) are indistinguishable clinically34"36 and that both entities are associated with reduced visual acuity, elevated dark adaptation threshold, and, as a frequent associated rinding, nystagmus. In addition, AIED is associated with high myopia, hypoplasic fovea, hypopigmented fundi, and slight protanomalous-like dyschromatopsia.35'37'38 In AIED, ERGs are strongly abnormal—electronegative bright-flash responses with reduced a-wave amplitude, strongly attenuated rod-isolated activity, and cone isolated responses.35'37 We agree with Glass39 that ERGs in CSNB2 are less severely affected than in AIED; cone activity, though severely attenuated, seems to be larger in CSNB2, and oscillatory potentials reach almost normal amplitude when recorded in scotopic conditions. Thus, CSNB2 and AIED overlap considerably in their clinical and psychophysical aspects. However, in AIED, no crossed asymmetry could be demonstrated,38"40 whereas most of our patients with CSNB2 had asymmetry. It is reasonable not to consider CSNB2 and AIED as die same entity, though a clear clinical delineation is sometimes difficult to establish. So far, molecular analysis could not exclude the possibility that CSNB2 and AIED are caused by muta- Downloaded From: http://iovs.arvojournals.org/ on 05/05/2017 tions in the same gene. There is a thigh link to Xpll loci in AIED, and, for now, its association with Xp21 (complex glycerol kinase deficiency, including Duchenne muscular dystrophy, for which electronegative bright flash responses were demonstrated30'31"41) could not be corroborated.39'42 CSNB2 has been reported to link with the Xpll loci,43'44 though it is unclear from the existing literature whether CSNB2 and CSNB1 have been segregated completely. The question of allelism or linked genes between AIED, CSNB1, and CSNB2 remains open. Interestingly, several retinal conditions result in an electronegative bright-flash response that originates from the Xpll.3 to Zp22.3 segment. Patients with Duchenne muscular dystrophy (Xp21.2) and retinoschisis (Xp22.3) also have severely abnormal ERGs though most of their psychophysical functions remain well preserved. As with CSNB2, the inconsistency between ERG findings and psychophysical data points toward glial cell dysfunction rather than to neuronal involvement. Whether this association is coincidental remains to be determined. The OA locus is located in the same vicinity. Could the electronegative ERGs and to crossed asymmetry result from the same gene defect is still unknown. In conclusion, the VEP protocol for the detection of crossed asymmetry may not be decisive to support the diagnosis of albinism. From a clinical point of view, any male patient with a presumptive diagnosis of ocular albinism based on VEP-crossed asymmetry should undergo ERG investigation so a possible diagnosis of CSNB2 is not overlooked. 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