Ординатура / Офтальмология / Английские материалы / Advances in Understanding Mechanisms and Treatment of Infantile Forms of Nystagmus_Leigh, Devereaux_2008

Scale (level)

Figure 27.1 Comparison of the energy of oculopalatal tremor (OPT) nystagmus after the head perturbation versus that of resting nystagmus. Solid line is the mean of the spectrum (in log scale) of resting nystagmus at different scales (levels). Horizontal bars are upper and lower 95% confidence interval at each scale. Dashed line is the mean of the spectrum of the OPT nystagmus after the head perturbation.

resting nystagmus’s spectrum, while at level 6 it is a little higher than the upper bound of the resting nystagmus’s spectrum. Given that level 6 corresponds to about 4 Hz oscillation and that the OPT oscillations are closer to 2 Hz, such a small deviation at level 6 is acceptable, so we conclude that the energy of the

OPT oscillation was not changed by the head perturbation.

The original eye movement was shifted by two or more cycles to compare the phase difference between the original and the shifted waveform, as shown in Figure 27.2. (also see color insert) In this case, the

Period (s)

D

Velocity (deg/s)

Torsional eye velocity Shifted eye velocity

60 Head horizontal movement *5 (˚) Phase change rate/100

20

0

20

Shift interval (2 peaks)

40

Time (s)

OPT oscillations are about 2 Hz, so again our interest is at around the period (which can be related to level/ scale) of 0.5 second. We thus divide the interested area into four areas: (A) several seconds before the head perturbation, (B) immediately before the head perturbation, (C) at the time of head perturbation, and

(D) after the head perturbation.

In the figures, the small black arrows show the phase difference between two waveforms in each of these areas. With arrows pointing to the left, the phase difference is 0; when arrows are pointing to the right, the phase difference is 180º. In Figure 27.2 we can see the phase difference is generally 0 in area A, meaning the shifted waveform has the same phase as the original waveform. In area B, even though it is before the head perturbation, the phase difference changed to about −20º, mainly due to the aperiodic nature of the waveform. In area C, when the head perturbation took place, the phase difference suddenly changed to −70º to −90º.

During post-perturbation in area D, the phase difference is stabilized to about −90º to −110º. Thus, the phase difference changed dramatically at the moment of the head perturbation. The phase shift changing rate (PSCR) is graphed in Figure 27.3. (also see color insert). We can see that the PSCR is higher than the threshold (2000 deg/s) only during the head perturbation, while before and after the head perturbation the PSCR are all small and well below the threshold.

DISCUSSION

We set out to learn whether we could apply complex wavelet analysis to determine if a stimulus (impulse head rotation) induced a shift in the phase (but not the amplitude) of the ocular oscillations of OPT. Since OPT has nonperiodic and nonstationary properties, it was not possible to simply compare the ocular

oscillations with a reference sine wave, as has been done in prior studies of ocular oscillations that are periodic.5 In these preliminary studies, we were detecting a substantially greater rate of change of phase during the head impulse stimulus compared with changes of phase that occurred during attempted fixation with the head stationary. Thus, this method appeared promising for application in testing a current model for OPT. One possible limitation of this technique is that in some subjects, the level of noise due to other eye movements or blinks will make it difficult to detect an increased rate of change of phase induced by the head rotation. Another possible limitation would occur if OPT itself had a large spontaneous rate of phase change. One possible method to overcome these limitations would be to study component oscillations of eyes (e.g., in the torsional direction) in response to head impulses in the orthogonal direction (e.g., rotation of the head about a vertical axis).

Aside from the specific case of OPT, our results suggest that the approach of using complex wavelet analysis can also be applied to analyzing other biological signals that can be perturbed by external stimuli, even when traditional analysis methods like Fourier analysis have failed.

ACKNOWLEDGMENTS Supported by National Institutes of Health grant EY06717, the Office of Research

and Development, Medical Research Service, Department of Veterans Affairs, the Evenor Armington Fund (Dr. Leigh); Intramural Division of the National Eye Institute, NIH, DHHS (Drs. Hong and Optican); and National Institutes of Health grant EY01849 (Dr. Zee).

References

1.Torrence C, Compo GP. A practical guide to wavelet analysis. Bull Am Meteorol Soc. 1998;79: 61–78.

2.Deuschl G, Toro C, Valls-Solo J, Zee DS, Hallett M. Symptomatic and essential palatal tremor. 1. Clinical, physiological and MRI analysis. Brain. 1994;117:775–788.

3.Leigh RJ, Zee DS. The Neurology of Eye Movements. 4th ed. New York, NY: Oxford University Press; 2006.

4.Leigh RJ, Hong S, Zee DS, Optican LM. Oculopalatal tremor: clinical and computational study of a disorder of the inferior olive. Soc Neurosci Abstr. 2005;933.8

5.Das VE, Oruganti P, Kramer PD, Leigh RJ. Experimental tests of a neural-network model for ocular oscillations caused by disease of central myelin. Exp Brain Res. 2000;133:189–197.

ABSTRACT

Some patients with nystagmus have an outer retinal defect that would be a limiting factor for visual acuity following nystagmus treatment. We evaluated the use of the multifocal electroretinogram (mfERG) as an objective means to evaluate outer retinal function in a series of patients with infantile nystagmus syndrome, with and without oculocutaneous albinism.

We recorded mfERGs from 3 patients, 2 of whom were albinos. We used a standard mfERG stimulus consisting of a scaled array with 103 hexagons covering the central 45°. Recordings were made under continuous fundus monitoring, allowing us to re-record segments with insufficient fixation. Ring averaging was used to define retinal function at six retinal eccentricities. Quantification of nystagmus waveforms was made using the eXpanded Nystagmus Acuity Function. Usable data were obtained from each patient tested and from four of six eyes; one eye of each of 2 patients could not be recorded due to large-amplitude nystagmus. Patient data were compared to agematched control data obtained in our lab. In both albino patients, ring average amplitudes were reduced only in central areas, with normal response amplitudes obtained at peripheral loci. The nonalbino patient exhibited a near-normal central amplitude peak. In all cases, implicit times were normal at all locations. Our results indicate that it is feasible to obtain useful mfERG recordings from patients with nystagmus. Neither albino

patient had a normal central response, consistent with anatomical studies indicating that albino retinas do not develop a central area of high cone density, and indicating limited potential for visualacuity improvement after successful nystagmus treatment. Results obtained from the nonalbino patient indicate near-normal central retinal function, and provide support for a greater benefit from therapy to reduce nystagmus.

Spatial vision is degraded by nystagmus due to the instability of visual targets on the retina. Strategies to decrease nystagmus could, therefore, improve spatial vision, provided that the individual possesses a normal retinal architecture. This may not be the case, however, in all patients with nystagmus, particularly albinos in whom the fovea is abnormal.1,2 As a result, it would be useful to obtain an objective determination of the retinal architecture prior to initiating any treatment, particularly treatment that involves surgery. There are a number of approaches by which this information could be obtained. Optical coherence tomography (OCT) allows the thickness of the retinal layers to be noninvasively assessed, and has been used to document foveal hypoplasia in albinos.3,4 While the presence of a normal foveal cup would indicate a better chance of improved acuity following treatment to reduce nystagmus, accurate OCT measurements require steady fixation, and significant nystagmus may obviate the ability of OCT to collect accurate measurements.5

We have evaluated an alternative approach using the multifocal electroretinogram (mfERG). The mfERG provides a topographical map of retinal function that,

in normal subjects, includes a distinct amplitude peak that corresponds to the fovea.6 While accurate mfERG recordings also require steady fixation on the stimulus array, the recording protocol can be broken up into a series of short, discrete recording epochs that can be separately recorded, evaluated, and repeated as needed. Our mfERG results were obtained from a series of patients with nystagmus. While usable results were not obtained in all eyes, some patients were able to maintain sufficient fixation (either low-enough amplitude or long-enough foveation period) to allow central retinal function to be quantitatively evaluated.

METHODS

Patient 1 was a 52-year-old female with oculocutaneous albinism and infantile nystagmus syndrome (INS); visual acuities were 20/60 in both eyes. Patient 2 was a 12-year-old female with oculocutaneous albinism, INS on her right eye, and Duane’s syndrome type 3 on her left eye; visual acuities were 20/200 and 20/80 on her right and left eye, respectively. Patient 3 was a 21- year-old nonalbino female with INS; visual acuities were 20/200 on both eyes. The tenets of the declaration of Helsinki were followed, and informed consent was obtained from all subjects.

Eye movements were recorded using high-speed video (EyeLink II, SR Research Ltd., Mississauga, Ontario, Canada), with each eye calibrated while the fellow eye was under cover to ensure accuracy. Data were sampled at 500 Hz with 16-bit resolution. The subjects sat in a darkened room with their head stabilized by a chinrest and occiput cushion, and they looked at a laser target projected at a distance of 57 inches.

The mfERG recordings were made using the VERIS Science 5.1 system (EDI, Inc., San Mateo, CA). The fundus camera/stimulator/refractor unit was used to monitor fixation, and bipolar Burian-Allen contact lens electrodes were used to perform monocular recording. Pupils were dilated with 1% tropicamide and 2.5% phenylephrine, and the eye not being tested was covered with an eye patch. Recording was done in normal room lighting. The mfERG stimulus given at a frame rate of 60 Hz consisted of 103 black-and-white hexagons that flickered according to a pseudorandom m-sequence. The size of the hexagons was scaled with eccentricity to elicit approximately equal amplitude responses at all locations.

Subjects were asked to maintain steady fixation at a red target in the center of the stimulus matrix. Recording segments containing many eye movement artifacts were detected online, discarded, and re-recorded. Analysis of the first-order kernels was done using the standard VERIS algorithms after two iterations of

Figure 28.1 Trace array plots of mfERG responses for patient 1 (A), patient 2 (C), patient 3 (E), and corresponding age-matched controls (B, D, F). Grouping of individual traces in six concentric ring averages is shown in gray scale at bottom (Also see color insert.)

artifact removal. No further spatial averaging was used. Patients’ mfERG data were plotted in trace arrays and were analyzed in six concentric ring averages compared with age-matched normals recorded under the same conditions.

RESULTS

Patient 1 was able to maintain fixation for limited periods of time, allowing a reliable recording to be obtained from both eyes. Figure 28.1A shows responses plotted in trace arrays for the left eye of patient 1; data obtained from the right eye were comparable. For comparison, Figure 28.1B shows average trace arrays obtained from 9 age-matched control subjects (also see color insert). In comparison to these control data, responses of patient 1 appear diminished centrally but normal peripherally. This impression was confirmed when ring averages were generated for each data set.

Figure 28.2 Ring averages (left) and plots of ringaverage amplitude against ring position (right) for patient 1 (A), patient 2 (B), patient 3 (C), and corresponding age-matched controls. Filled symbols indicate patient data while open symbols indicate data obtained from controls.

Figure 28.2 plots the amplitude of the first positive peak of mfERG ring averages (Figure 28.2A, left) obtained from patient 1 and from control subjects (Figure 28.2A, center) against ring position (Figure 28.2A, right). There is very good agreement for peripheral rings, but there is a clear reduction in the two central rings for patient 1.

We also recorded mfERGs from both eyes of patient 2. Despite the patient’s effort to maintain fixation, the right-eye data were unreliable due to large-amplitude nystagmus for the majority of the recording segments. Figures 28.1C and D show trace array plots of mfERG responses recorded from the left eye of patient 2 and from 4 age-matched controls, respectively. In this case as well, only the central responses appeared reduced in patient 2. Measurement of response amplitude showed that the peripheral

responses of patient 2 were somewhat larger than those of control subjects, while the response from the central 2º was reduced (Fig. 28.2B).

In patient 3, it was only possible to obtain data from the left eye. Figures 28.1E and F show trace array plots of mfERG responses recorded from the left eye of patient 3 and from 4 age-matched controls, respectively. When ring-averaged (Fig.28. 2C), the peripheral responses of patient 3 were comparable to those of controls, while responses were reduced for stimuli falling in the central 10º. Nevertheless, in patient 3, the normal pattern of response amplitude reduction with increasing eccentricity from the macula was similar to that seen in control subjects (Fig. 28.2C, right).

In all 3 patients, implicit times for all response areas fell within the normal limits.

DISCUSSION

A key goal of treatment approaches to reducing nystagmus is to improve visual acuity. However, good visual acuity cannot be expected in a retina with a severely hypoplastic fovea. We examined this issue using the mfERG, which provides a functional map of outer retinal function within the central 45º of posterior pole. When expressed in terms of response amplitude per retinal area, the central retina in normal subjects generates a much larger response than do peripheral retinal locations.6 This larger central response reflects the higher density of cone photoreceptors in the foveal than in peripheral retina.7

In the present study, we investigated the feasibility of making such recordings in 2 albino subjects and 1 nonalbino subject with INS. While useful data were not obtained in two of six eyes, we obtained a full data set from four eyes. In each case, the central peak was less pronounced than that seen in control subjects. For the albino subjects, patients 1 and 2, this pattern was similar to that published by Kelly and Weiss8 and is consistent with an abnormal development of the foveal architecture in albinos. In comparison, patient 3, who is not albinotic, had a clear central peak, indicative of a near-normal distribution of cone photoreceptors, which was likely underestimated by incomplete suppression of nystagmus.

While indicating that albino patients would receive limited benefit from nystagmus treatment compared to nonalbino patients, the current results do indicate the feasibility of obtaining mfERG data from some patients with nystagmus. To obtain the current data set, recording sessions were extended in order to repeat recording epochs in which fixation was not stable. While this places a somewhat greater strain on the patient being examined, and requires greater vigilance

on the part of the operator, a positive result identifying a suitable patient for nystagmus treatment is unlikely to be artificially generated. As a result, we believe that the mfERG should receive further evaluation as an objective tool with which to evaluate patients with nystagmus prior to treatment for their nystagmus.

ACKNOWLEDGMENTS This work was supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs, R24 EY15638, and a Research to Prevent Blindness Challenge grant. The material contained in this chapter was presented at the Conference for Advances in Understanding Mechanisms and Treatment of Congenital Forms of Nystagmus, May 3–4, 2007, Cleveland, OH.

References

1.Fulton AB, Albert DM, Craft JL. Human albinism. Light and electron microscopy study. Arch Ophthalmol. 1978;96:305–310.

2.Mietz H, Green WR, Wolff SM, Abundo GP. Foveal hypoplasia in complete oculocutaneous albinism. A histopathologic study. Retina. 1992;2:254–260.

3.Harvey PS, King RA, Summers CG. Spectrum of foveal development in albinism detected with optical coherence tomography. J AAPOS. 2006; 10:237–242.

4.Seo JH, Yu YS, Kim JH, Choung HK, Heo JW, Kim SJ. Correlation of visual acuity with foveal hypoplasia grading by optical coherence tomography in albinism. Ophthalmology. 2007;114(8):1547–1551.

5.Campbell RJ, Coupland SG, Buhrmann RR, Kertes PJ. Effect of eccentric and inconsistent fixation on retinal optical coherence tomography measures. Arch Ophthalmol. 2007;25:624–627.

6.Sutter EE, Tran D. The field topography of ERG components in man. I. The photopic luminance response. Vision Res. 1992;32:433–446.

7.Curcio CA, Sloan KR, Kalina RE, Hendrickson AE. Human photoreceptor topography. J Comp Neurol. 1990;292:497–523.

8.Kelly JP, Weiss AH. Topographical retinal function in oculocutaneous albinism. Am J Ophthalmol. 2006;141:156–158.

Abadi, RV, 11, 12, 15, 18, 23, 24, 25, 26, 27, 28, 29,

33, 34, 36, 38, 61, 62, 68, 90, 94, 100, 107, 108,

109, 110

Abel, LA, 16, 18, 25, 33, 36, 37, 90, 93, 94, 96, 134,

139, 140

Abplanalp, PL, 25

Abundo, GP, 189

Acheson, J, 18, 27, 34

Acland, GM, 90, 96

Adams, AH, 177

Adams, DL, 47, 52

Adams, RN, 118

Ahmadi, MA, 136

Aigner, M, 4

Aker, P, 177

Albert, DM, 189

Albrecht, H, 81

Allik, J, 34

Alvardo-Mallart, RM, 4

Anderson, JR, 92, 114, 167

Angelaki, DE, 56, 147

Angus, CW, 118

Anniger, W, 108

Anzola, G, 175, 177

Apkarin, P, 28

Appel, S, 119

Arnold, DB, 81, 130

Arnould, VJ, 88

Arstikaitis, MJ, 4

Asress, KN, 49

Assad, JA, 15

Atkinson, J, 120

Atsumi, T, 5

AuYong, N, 148

Avallone, JM, 34

Averbuch-Heller, L, 12, 25, 34, 62, 80, 81, 90, 96,

100, 105, 153, 155

Aydin, M, 16, 19

Bach, M, 27, 100

Bach-y-Rita, P, 3

Bahl, B, 9

Bakay, M, 121

Baker, RS, 4

Balatsouras, DG, 105

Ball, KK, 38

Baloh, RW, 59, 175

Bandini, F, 81

Barber, C, 100

Barmada, M, 80

Barnes, GR, 148

Barr, J, 177

Barton, JJS, 134, 176

Bauer, P, 164

Beard, BL, 38

Beck, RW, 100

Becker, W, 118, 130, 134

Bedell, HE, 11, 12, 15, 16, 17, 19, 25, 26, 27, 28,

34, 38

Beeson, D, 119

Bega, S, 5, 6, 9

Bennett, J, 90, 96

Berger, K, 175

Bergqvist, UO, 70

Berman, RA, 38

Bernshaw, NJ, 120

Dan, YF, 167 Danacause, N, 4, 5 Danckert, J, 38 Darlot, C, 147

Daroff, RB, 24, 25, 33, 36, 38, 88, 96, 99, 101, 108, 109, 110, 134, 139, 140

Das, VE, 24, 42, 47, 48, 49, 105, 107, 130, 153, 155, 173, 185, 188

Davidson, K, 175 Davies, A, 120 Davis, DG, 105 Davis, RD, 122 Davitz, M, 120 Dawes, PT, 153 de Jong, PT, 47 de Jong, R, 38

de Perrot, M, 122 De Weerd, P, 42 Degg, C, 82, 83, 84 Degner, D, 15

Dell’Osso, LF, 11, 12, 19, 24, 25, 27, 33, 34, 36, 37, 38, 39, 43, 61, 62, 67, 68, 80, 87, 88, 90, 91, 92, 93, 94, 96, 99, 100, 101, 102, 105, 108, 109, 110, 112, 115, 134, 139, 140, 141, 143, 170, 173, 180, 181

Delwaide, PJ, 5

Demer, JL, 59, 129, 181 Denk, M, 5

DeSantis, M, 4 Desimone, R, 42 Deubel, H, 18 Deuschl, G, 184 Devereaux, MW, 177

DiBartolomeo, JR, 100, 105

Dickinson, CM, 11, 25, 26, 28, 29, 34, 36 Dickman, JD, 147

Dieterich, M, 18, 27, 81

Diethelm-Okita, B, 119 Ding, M, 80

Discenna, AO, 153, 155 Ditchburn, RW, 24 Dixon, G, 175

Dobson, V, 48

Dominey, PF, 4 Donahue, SP, 162 Donaldson, IM, 4, 8 Donzis, P, 177 Dowman, R, 5 Drachman, D, 118 Drack, AV, 80 Drake, D, 24

Dua, H, 82 Duane, A, 162 Duncker, K, 152

Durand, DM, 170, 173 Dürsteler, MR, 130

Dyar, TA, 42

Dziedzic, K, 153

Easton, J, 175, 176, 177

Eberhorn, AC, 4

Eberhorn, N, 4

Economides, JR, 52

Edwards, M, 16

Edwards, MW Jr, 18

Eggert, T, 55

Eizenmn, M, 130

Eldred, E, 4

Ell, JJ, 62

Ellenberger, C, 96

Ellis, FD, 92

Elveback, L, 122

Engbert, R, 24

Engel, AG, 118, 119

Engel, KC, 155

Enright, JT, 15, 170, 173

Erchul, DM, 96

Erkelens, CJ, 170, 173

Erzurum, SI, 94

Esme, DL, 47

Etoh, S, 136

Everhard-Halm, YS, 136

Everitt, BJ, 37

Factor, J, 177

Faldon, M, 38, 89, 100, 108

Farhat, S, 175

Feiveson, AH, 129

Felder, E, 121

Fendick, MG, 12, 34

Findley, LJ, 62

Finley, J, 122

Fischer, MD, 121

Fisher, M, 167

Fitch, JC, 122

FitzGibbon, EJ, 19, 28, 34, 92, 100, 108, 112, 115,

170, 173

Flanders, M, 33, 155

Flynn, JT, 96, 115

Forster, JE, 24, 28

Frecker, RC, 130

Fredrick, LR, 120

Frisoni, G, 175, 177

Frumkin, L, 175

Fu, LN, 47, 49

Fuchs, AF, 8, 48, 55, 118

Fuhry, L, 62, 81, 130

Fujita, T, 120

Fujiwara, A, 70

Fukuoka, Y, 120

Fukushima, J, 58, 129