Retinal Function in Diabetic Macular Edema after Focal Laser Photocoagulation

Abstract

purpose. To assess the effects of focal photocoagulation on retinal function in the macular and perimacular areas in patients with diabetes who have clinically significant macular edema.

methods. Eleven patients were assessed after focal laser treatment. Multifocal electroretinogram (ERG) and full-field ERG techniques were used to evaluate the effects of treatment on macular, paramacular, and peripheral retinal function. A modified visual field technique was used to obtain local threshold fields. The posttreatment results were compared with pretreatment results. Changes in local ERG response amplitudes and implicit times were calculated for each patient and presented as difference fields. The changes in local ERG responses were compared with the changes in local field sensitivity.

results. After treatment, the results of the psychophysical tests suggested little or no change in visual function, but changes in retinal function were observed with the multifocal ERG technique. Local ERG responses showed increases in implicit time and decreases in amplitude, compared with pretreatment values. Timing was affected more than amplitude.

conclusions. The results suggest that focal treatment produces changes in retinal function, and these changes are not restricted to the treated macular area.

The beneficial effects of focal photocoagulation for clinically significant diabetic macular edema (CSME) have been demonstrated in a series of clinical trials. ^{1 2} Visual acuity is stabilized, and the risk of loss in visual acuity is substantially reduced. ¹ However, visual acuity measurements provide information about only one aspect of the impaired visual function that accompanies CSME. As shown in an accompanying article in this issue, ³ visual function can be affected in the fovea, the macula, and in surrounding retinal areas. It is therefore important to be able to monitor any change that may occur in these regions after focal photocoagulation treatment. The few studies that have investigated the effects of treatment on extrafoveal function have used either visual field or pattern electroretinogram (PERG) techniques. ^{4 5 6} Focal photocoagulation was reported to decrease visual field sensitivities in the central 10°, whereas sensitivities in areas outside the treated area remained stable. ^{5 6} A study using the PERG technique showed that amplitudes were markedly decreased after focal treatment. ⁴ The effects of focal treatment on local ERG activity remain to be determined. It is only in the past few years that techniques have become available for measuring local ERG activity simultaneously at multiple sites. In this study, we used visual field and multifocal ERG techniques to measure changes in local retinal function that may occur in the macular and perimacular area after focal photocoagulation. 

Methods

Subjects

Eleven patients with clinically significant macular edema who participated in the first part of the study were treated with focal argon green laser photocoagulation. The term focal refers to two types of photocoagulation treatment, localized and grid. The age range of the patients was 33 to 67 years (mean, 56.5 ± 9 years). Slit lamp biomicroscopy, color fundus photographs, and fluorescein angiography were used to determine the level of retinopathy and degree of macular edema and to identify treatable areas. The pretreatment clinical characteristics of the patients are summarized in Table 1 . For the nine patients with macular edema classified as intermediate, treatment consisted of argon green laser spots of 50 to 100 μm applied to leaking microaneurysms and a modified grid to areas of diffuse edema. The endpoint was defined as a slight graying at the microaneurysm site or in the grid pattern. The two patients with diffuse leakage were treated with argon green laser in a grid pattern. Treatment consisted of 100 to 200 light burns of 100 to 200 μm spot size lasting 0.1 seconds. A space of one burn width was left between each grid lesion. To minimize the effects of reactive edema, patients were tested between 8 and 12 weeks after treatment. In addition to ERG and psychophysical testing, follow-up fluorescein angiography, photography, and biomicroscopy, were performed in all cases. In eight patients the right eye was treated and tested, and in the remaining three patients, the left eye was treated and tested. In Figures 3 and 4 the multifocal records and visual field for the left eye of one of these patients are reversed to provide easier comparisons among patients. 

Nine control subjects ranging in age from 40 to 62 years (mean, 51.6 ± 8 years) with no known abnormalities of the visual system also participated in the study. All had normal full-field ERGs and normal findings in ophthalmic examinations. Informed consent was obtained from all subjects before their participation. Procedures followed the tenets of the Declaration of Helsinki, and the protocol was approved by the committee of the Institutional Board of Research Associates of New York University School of Medicine and Bellevue Hospital. 

Multifocal ERG Technique

Multifocal ERGs were recorded using the Veris (EDI, San Mateo, CA) technique (for details see Sutter and Tran ⁷ and Sutter ⁸ ). The visual stimulus consisted of 103 hexagonal areas scaled with eccentricity. Each hexagonal area was modulated from black to white independently according to a binary m-sequence (L _max = 400 candelas[ cd]/m² and L _min = 9 cd/m². For details see Hood et al., ⁹ and Greenstein et al. ³  

As in the first study, to optimize the identification of localized changes that may occur after treatment to the macular area, patients (P)1 through P5 were tested with the monitor positioned at a viewing distance of 64 cm. At this viewing distance the 103 hexagons fell within a field of approximately 28° by 22°. The m-sequence stimulation rate was slowed to allow for the assessment of macular oscillatory potentials (OPs) ^{10 11} by inserting four frames between consecutive stimulus frames. For patients P6 through P11, the monitor was positioned at a viewing distance of 32 cm, the hexagons fell within a larger field of approximately 47° (width) by 39°(height), and the m-sequence stimulation rate was the same as the monitor’s frame rate (see Greenstein et al. ³ for details). 

Recording Technique and Analysis of Multifocal Responses

The recording technique was the same as that described in Greenstein et al. ³  

The amplitudes and implicit times of the individual multifocal responses were calculated using a computer software program (MATLAB; The MathWorks, Natick, MA). For details see Greenstein et al. ³ and Hood and Li. ¹²  

Full-field ERG

As in the first study, full-field cone ERGs were measured using a photostimulator (Grass Instruments, Quincy, MA) in a Ganzfeld. After 5 minutes of light adaptation to a white Ganzfeld of 40 cd/m², full-field cone ERGs were obtained to 30-Hz flicker. The signal was amplified (1 K; preamplifier model P511J; Grass) and filtered (1–10,000 Hz). 

Visual Fields

To compare multifocal data with visual field data, thresholds were measured on a Humphrey perimeter (Humphrey, San Leandro, CA) at either 103 locations that corresponded to the centers of the 103 hexagonal areas in the multifocal display viewed at 32 cm or 58 locations that corresponded to the centers of 58 of the 103 hexagonal areas viewed at 64 cm. The background luminance was 10 cd/m². 

Results

Clinical Findings

The relevant posttreatment clinical findings are summarized in Table 1 . Edema appeared to be resolved in four of the nine patients classified as having intermediate CSME. Four had residual edema, and one showed no change. For the two patients with diffuse edema, one showed no change, and the other had residual edema. Posttreatment visual acuities ranged from 20/200 to 20/25. Only two of the patients, P2 and P9, showed a significant improvement in visual acuity (an improvement of more than one line on a Snellen acuity chart). The results for the other patients were consistent with a stabilization of acuity (either no change or an increase or decrease equivalent to one line on a Snellen acuity chart). In summary, treatment had little effect on visual acuity. 

Full-field ERG

After treatment, none of the patients showed a significant change in amplitude for 30-Hz full-field flicker. Before treatment, 7 of the 11 patients had significantly delayed implicit times. Of these seven patients, P1 and P6 showed additional delays in implicit time of approximately 3 msec (Table 2) . Implicit times for the other four patients, although slightly increased after treatment (0.4–2.5msec), remained within the normal range. 

Multifocal ERGs

Examples of multifocal ERG responses obtained from two of the patients, P1 (slow sequence and smaller stimulus field) and P9 (fast sequence and larger stimulus field), before and after laser treatment are shown in Figure 1 . For both patients, amplitudes were decreased and implicit times were increased after treatment. This was easier to see when amplitude and implicit times for the individual responses were measured. To assess the effects of treatment, the amplitudes and implicit times of the individual responses for all subjects were measured as previously described. ^{3 12} The values obtained from the control subjects were used to obtain a mean control implicit time and mean control peak-to-trough amplitude for each of the 103 test locations. Pre- and posttreatment amplitude loss and implicit time delay were calculated for each of the patient’s responses (see Greenstein et al. ³ for details of calculating amplitude loss and implicit time delay). Figures 2 and 3 show the multifocal ERG delay and amplitude loss fields obtained pre- and posttreatment from P1 and P3. The numbers in the delay fields (Figs. 2 3 , left) are the delays rounded to the nearest milliseconds. Delays within 1 SD of the mean value for that location are represented by white hexagons, delays between 1 and 2 SDs of the mean value by light gray hexagons, and delays greater than 2 SDs of the mean value by dark gray hexagons. Black hexagons without numbers represent poor template fits (see Methods in Greenstein et al. ³ ). For the amplitude loss fields (Figs. 2 3 , right) the numbers represent the difference in microvolts at each location between the patient’s trough-to-peak amplitude and the mean normal amplitude for that location. Decreases in amplitude within 1 SD of the mean value are represented by white hexagons; decreases between 1 and 2 SDs of the mean are represented by light gray hexagons; and decreases greater than 2 SDs are represented by dark gray hexagons. 

As can be seen in Figures 2 and 3 , the responses for P1 and P3 were delayed and decreased in amplitude, both before and after laser treatment. For both patients, timing was more affected than amplitude, and timing abnormalities involved a larger area of the field. After treatment, the local ERG responses for P1 showed additional delays in timing, particularly in the superior field (inferior retinal region), and additional decreases in response amplitude. In contrast, for P3, response delays had decreased and amplitudes had increased after treatment. To obtain a quantitative measure of these changes the differences between the pre- and posttreatment implicit times and amplitudes were calculated for each patient. Figure 4 shows the data for P1 and P3 presented in the form of difference fields. The numbers in the delay difference fields (Fig. 4 , left) represent the differences between the patient’s post- and prelaser implicit times in milliseconds. The change in amplitude for each of the patients’ responses was calculated in a similar way. The postlaser peak-to-trough amplitude for each response was compared with the prelaser peak-to-trough amplitude at the same location. The numbers in the amplitude loss fields (Fig. 4 , right) represent the difference in microvolts between the patient’s post- and prelaser trough-to-peak amplitudes. 

To provide some indication of the magnitude of the changes, the results were compared with changes in implicit times and amplitudes obtained from seven control subjects who were retested after 1 year. The light gray hexagons represent increases in implicit time or decreases in amplitude between 2 and 3 SDs of the values obtained for the seven control subjects. Dark gray hexagons represent changes that exceeded 3 SDs of the values obtained for control subjects, and black hexagons represent poor template fits—that is, fits exceeding the statfit criterion of 0.75 described in the Methods section. White hexagons represent no change, or decreases in timing and increases in amplitude. Decreases in timing and increases in amplitude that exceeded 2 SDs (i.e., a significant improvement) are represented by numbers in bold underlined text. White hexagons also represent relative increases in timing or decreases in amplitude whose values are within 2 SDs of the values obtained for the control subjects. The difference fields for P1 indicate that retinal function continued to deteriorate after treatment (Fig. 4 , top). Timing was more affected than amplitude; there were locations that showed additional increases in implicit time but no change in amplitude. The difference fields for P2, P4, and P5 (not shown) also indicated deterioration after treatment, in that additional increases in implicit time were found. The difference fields for P3 (Fig. 4 , bottom panels) in contrast, were consistent with an improvement in retinal function. For this patient, there were increases in response amplitude and decreases in implicit time, particularly in the superior field. 

The changes in implicit time and amplitude for P1 through P5 after laser treatment are summarized in Figure 5A . The point in the center of each box represents the median change in implicit time or amplitude for the 103 responses. The box plots indicate quartiles (25th and 75th percentiles of each distribution). The whiskers indicate the range of values. For the control subjects (hatched box) who were retested after 1 year, there were minimal changes in median implicit time and amplitude but the changes in amplitude were slightly more variable. For the patients, median implicit times were increased for P1, P2, and P4 and decreased for P3. The majority of the data points for these patients fell outside the range of values obtained for the control group. The increases in median implicit times for P1 and P4 were accompanied by decreases in median amplitude and for P3 the decrease in implicit time was accompanied by an increase in amplitude. These results were obtained from the patients 2 months after treatment. We were able to obtain additional multifocal ERG data from P1 and P5 5 months after laser treatment. The changes in implicit times and amplitudes after laser treatment at 2 and at 5 months are summarized in Figure 5B . At 5 months, both patients showed additional slight increases in implicit time and little or no change in amplitude. 

The stimulus conditions for P1 through P5 were chosen not only to optimize the resolution of localized changes that may occur both before and after focal laser treatment of CSME but also to allow for assessment of macular OPs. Before treatment, the OPs and a late component at approximately 50 to 55 msec appeared to be absent or nonrecordable in all five patients. After treatment, there appeared to be no change. Similar smooth waveforms were observed, and the OPs and a late component were either absent or nonrecordable. 

The differences between the pre- and posttreatment implicit times and amplitudes were also calculated for the patients, P6 through P11, who were tested with the fast m-sequence. For four of the patients P6, P7, P9, and P10, the multifocal ERG responses obtained with the larger stimulus field and more conventional stimulus sequence rate also showed increases in implicit time after treatment. The difference fields for two of these patients P6 and P9 are shown in Figure 6 . For P6 in the central part of the field some of the responses showed significant decreases in implicit time and increases in amplitude (see numbers in bold text). 

The changes in implicit time and amplitude for the macular and perimacular areas of P6 through P11 are summarized in Figure 7 . For the macular area, the changes in implicit times and amplitudes for the central 41 hexagons were calculated (a stimulus area equivalent to that used for P1 through P5). The control subjects showed minimal changes in median implicit time and response amplitude when retested after a year. For the patients, treatment had the effect of increasing implicit times for P7, P9, and P10 in the macular area and decreasing them for P8. As in the case of P1 through P4, the majority of the data points for these patients fell outside the range of change observed for the control group. For P10, the slight increase was accompanied by a decrease in median amplitude. When these results were compared with those obtained for the surrounding perimacular area (Fig. 7 right), it is clear that the two regions were affected in a similar way. This increase in implicit time for P7 in the macular area was apparent 1 month after treatment. 

To assess the effects of treatment on local sensitivity, visual fields were obtained from each patient, and the differences between the post- and pretreatment thresholds for all test locations in the macular and perimacular areas were calculated. The results are summarized in Table 3 . For patients, P1 through P5, there were minimal changes in median threshold values after treatment (the median change in threshold ranged from 0 to −0.2 log unit). Median threshold values for the macular area (for locations corresponding to the central 41 hexagons in the multifocal ERG display) for patients P6 through P10 also showed minimal changes after treatment (the median change in threshold ranged from 0 to 0.2 log unit). Only one patient, P11, showed a change in threshold that exceeded the range obtained from the seven control subjects who were retested after 1 year. For the untreated perimacular area, despite a greater range of threshold changes, indicating more variability, with the exception of P11 there was little or no change in median threshold values. 

Discussion

The majority of studies that have examined the effects of focal laser treatment on CSME have evaluated visual function in the macular area using psychophysical techniques. Several studies have measured visual acuity and have shown either stabilization or improvement in acuity after focal photocoagulation. ^{1 13 14 15 16} More information regarding the extent of retinal dysfunction has been provided by studies that have used additional psychophysical measures of visual function such as threshold static perimetry, color vision, and contrast sensitivity. These studies have reported that there was no significant change in hue discrimination or color confusion, ^{1 6 17} that contrast sensitivity showed a slight improvement, ¹⁷ and that sensitivity was either slightly decreased (less than 4 dB) in the treated central 10° of the visual field ^{5 6} or was unchanged after treatment. ¹⁸ In the present study our measures of visual acuity and local sensitivity in the macular and surrounding area are consistent with the results of previous studies that have shown improvement or stabilization of acuity and no change in the overall sensitivity of the visual field. ^{1 14 18}  

Although the results of the psychophysical tests suggested little or no change in visual function, changes in retinal function were observed with the multifocal ERG technique. Both response timing and amplitude were affected by treatment, but timing was more affected. For example, six of the patients showed increases in median implicit times in the treated macular area. The question is whether these posttreatment changes in local ERG responses reflect local damage i.e., are they a result of lesions produced by focal and grid photocoagulation or do they represent a more generalized retinal dysfunction? Laser energy is absorbed primarily by the pigment epithelium and the adjacent photoreceptor layer. Damage to the outer retina might be expected to result in increased implicit times. This may account for the increased delay in implicit times and the additional decreases in amplitude particularly in the treated macular area. However, the finding for some patients that timing changes occurred in this area and that the surrounding retina was also affected suggests that grid photocoagulation has a generalized effect on retinal metabolism. 

A similar result was reported in a study of the effects of laser treatment on PERG amplitudes. ⁴ The decrease in PERG amplitudes after focal treatment was far larger than expected. The investigators suggested that the thermal and/or toxic effects spread outside the treated area. Alternatively, other factors such as residual edema, postlaser reactive edema, a progression of the retinopathy and/or retinal hypoxia may have contributed to the results. 

In summary, the results presented in this study and in Greenstein et al. ³ demonstrate the importance of using more than one psychophysical or electrophysiological technique; first, to characterize the type and extent of dysfunction associated with a disease state, and second, to evaluate the outcome of treatment intervention. The approach we used allows the investigator to assess local retinal function and provides a method for quantifying any changes that may occur after treatment. 

 Supported by National Eye Institute grant R01-EY-02115, an unrestricted grant to the Department of Ophthalmology from Research to Prevent Blindness, and grants from the Helen Hoffritz Foundation and the Allene Reuss Memorial Trust.

 Submitted for publication March 17, 2000; accepted April 13, 2000.

 Commercial relationships policy: N.

 

Table 1.

 

Clinical Characteristics of Patients

Patient	Age	Level DR*	Classification of CSME, †	Visual Acuity			Posttreatment CSME Evaluation
									Pretreatment	Posttreatment
1	60	4	I	20/200 (.10)	20/200 (.10)	Unchanged
2	53	3	I	20/80 (.25)	20/50 (.40)	Residual
3	33	6	D	20/50 (.40)	20/50 (.40)	Unchanged
4	52	3	I	20/50 (.40)	20/40 (.50)	Resolved
5	62	4	D	20/40 (.50)	20/30 (.67)	Residual
6	59	3	I	20/40 (.50)	20/30 (.67)	Residual
7	54	3	I	20/30 (.67)	20/25 (.80)	Resolved
8	67	3	I	20/40 (.50)	20/40 (.50)	Residual
9	60	3	I	20/100 (.20)	20/70 (.28)	Residual
10	65	3	I	20/30 (.67)	20/30 (.67)	Resolved
11	57	3	I	20/30 (.67)	20/40 (.50)	Resolved

 Values in parentheses represent visual acuity expressed as a decimal.

*  Classification of level of diabetic retinopathy (DR): Level 3: microaneurysms with one or more other nonproliferative lesions present of mild to moderate degree; level 4: microaneurysms with one or more other nonproliferative lesions present of severe degree; level 5: severe overall nonproliferative retinopathy; level 6: proliferative retinopathy without diabetic retinopathy high-risk characteristics.

†  Classification of CSME (based on fluorescein angiograms): I, intermediate with approximately equal leakage from microaneurysms and dilated capillaries; D, diffuse with leakage mainly from dilated capillaries.

Table 2.

 

Amplitudes and Implicit Times

Patient	Pretreatment			Posttreatment
		30-Hz Amplitude*	30-Hz Implicit Time, †	30-Hz Amplitude*	30-Hz Implicit Time, †
1	125	32.2, ‡	117	35.2, ‡
2	92.2	32, ‡	66.1	31.3
3	71.4	35.6, ‡	96.3	34.7, ‡
4	119	32.2, ‡	113	32.7, ‡
5	139	32.7, ‡	137.1	31.2
6	84.2	33.2, ‡	76.7	36.6, ‡
7	134.5	30	141.7	31.3
8	77.2	28.3	93.8	30.8
9	77	36.6, ‡	62	34.7, ‡
10	91	26	99	27
11	138.1	31.3	111	31.7

*  Mean normal amplitude: 126 ± 45 μV (SD).

†  Mean normal implicit time: 28 ± 2 msec (SD).

‡  Significant delay in implicit time compared with control subjects.

Figure 1.

 

Multifocal records for two patients before and after laser treatment. Left: Records for P1 were obtained using the slowed m-sequence and a stimulus display subtending 28° by 22°; right: records for P9 were obtained using the fast m-sequence and stimulus display subtending 47° by 39°.

Figure 2.

 

Pretreatment and posttreatment ERG delay fields (left) and amplitude loss fields (right) for P1.

Figure 3.

 

Pretreatment and posttreatment ERG delay fields (left) and amplitude loss fields (right) for P3.

Figure 4.

 

Difference fields for P1 (top) and P3 (bottom). The numbers in the delay difference fields (left) represent the differences between the patient’s post- and prelaser implicit times in milliseconds. The numbers in the amplitude difference fields (right) represent the difference in microvolts between the patient’s post- and prelaser trough-to-peak amplitude. The light gray hexagons represent increases in implicit time or decreases in amplitude between 2 and 3 SDs of the values for control subjects; dark gray hexagons, changes that exceed 3 SDs of the values obtained for control subjects; and black hexagons, poor template fits. White hexagons represent a relative decrease in timing or increase in amplitude; decreases in timing or increases in amplitude that exceeded 2 SDs are represented by numbers in bold underlined text. White hexagons also represent relative increases in timing or decreases in amplitude whose values are within 2 SD of the values obtained for the control subjects.

Figure 5.

 

(A) Box and whisker plots of implicit time differences (top) and amplitude differences (bottom) for the control group and P1 through P5. The point in the center of each box represents either the median change in implicit time in milliseconds or amplitude in microvolts for the 103 responses, the box indicates the quartiles (25th and 75th percentiles), and the whiskers represent the range of values. (B) Box and whisker plots of implicit time differences (top) and amplitude differences (bottom) for P1 and P5 obtained at 2 and at 5 months after treatment. Data are as described in (A).

Figure 6.

 

Delay difference fields (left) and amplitude difference fields (right) for P6 (top) and P9 (bottom). The results were obtained using a stimulus display subtending 47° by 39°.

Figure 7.

 

Box and whisker plots of implicit time differences (top) and amplitude differences (bottom) for the control group and for P6 through P11 for the macular and perimacular area. Data are as in Figure 5A .

Table 3.

 

Change in Threshold

Subjects	Median (log unit)	Range (log unit)	25th Percent. (log unit)	75th Percent. (log unit)
Macular area
Control*	0	−0.3 to 0.35	−0.1	0.1
P1	−0.2	−1.2 to 1.0	−0.6	0
P2	0	−0.4 to 0.5	−0.2	0.2
P3	−0.1	−0.6 to 0.6	−0.2	0
P4	0	−0.7 to 0.5	−0.3	0.2
P5	−0.15	−0.6 to 0.7	−0.3	0
Control, †	0	−0.4 to 0.4	−.01	0.1
P6	0.15	−0.9 to 0.8	0	0.3
P7	0	−0.4 to 0.7	−0.2	0.2
P8	0	−0.8 to 0.5	−0.1	0.2
P9	0	−0.5 to 0.9	−0.2	0.2
P10	0.2	−1.0 to 1.1	−0.1	0.4
P11	0.8	−0.3 to 1.1	0.4	1.0
Perimacular area
Control	0.1	−0.4 to 0.4	0	0.2
P6	0.2	−1.3 to 1.4	0	0.4
P7	0	−1.0 to 0.9	−0.2	0.3
P8	−0.2	−1.5 to 1.5	−0.4	0.1
P9	0	−1.4 to 1.4	−0.4	0.2
P10	0.1	−1.5 to 1.5	−0.2	0.4
P11	0.4	−0.8 to 1.2	0	0.6

*  Results obtained at 58 locations in the macular area.

†  Results obtained at 41 locations in the macular area.