Diabetes mellitus is a heterogeneous disorder of carbohydrate metabolism with multiple eti- ological factors that ultimately lead to hyper- glycemia. Diabetic retinopathy is a disease of the retinal blood vessels that develops in the complex metabolic milieu of systemic diabetes mellitus. Because of the multiple factors, the electrophysiological abnormalities are complex, and the changes are often difficult to interpret.
In early studies, the oscillating potentials (OPs) of the electroretinograms (ERGs) were
found to have reduced amplitude [1] and delayed timing during the early stage of the disease (Fig. 3.1). Reduced b-wave amplitudes were reported only in eyes with fairly advanced retinopathy.
In this chapter, three relatively new studies on diabetic retinopathy are examined: ERGs after panretinal photocoagulation, ERG evalua- tion of vitrectomy candidates with diabetic retinopathy, and analysis of diabetic maculopa- thy using focal macular ERGs and OCT.
3.1 Diabetic Retinopathy
Fig. 3.1. Oscillatory potentials (OPs) of full-field ERGs recorded from a normal subject (top) and two patients with relatively early-stage diabetic retinopathy (DMR;
cases 1 and 2)
Panretinal photocoagulation (PRP) is often applied to diabetic eyes at the preproliferative or proliferative diabetic retinopathy stage (Fig.
3.2). Although the mechanism for improving retinal function after PRP has not been conclu- sively determined, its efficacy has been thor- oughly documented in randomized clinical trials. The rationale initially proposed for the regression of new vessels following PRP was that the ischemic retina, which was postulated to be producing a vasoformative factor, was destroyed. Another explanation was that the retinal pigment epithelium (RPE) cells that were producing a vessel-inhibiting factor were destroyed. It has also been proposed that PRP
may improve oxygenation of the ischemic inner retinal layers by destroying some of the meta- bolically highly active photoreceptor cells to allow the oxygen normally diffusing from the choriocapillaris to the photoreceptors to con- tinue into the inner retina.
In any case, the amplitudes of the full-field ERGs are reduced after PRP in eyes with dia- betic retinopathy. The degree of reduction of the ERGs after PRP relative to that before PRP is shown in Fig. 3.3. In our study [2] the means of the a-waves and b-waves are reduced by 44% and 41%, respectively. The b-wave/a-wave (a/b) ratio is slightly increased after PRP, but the increase is not significant. The OPs are
3.1.1 Panretinal Photocoagulation and ERGs
Fig. 3.2. Fluorescein angiogram after panretinal photocoagulation (PRP) in an eye with diabetic retinopathy
markedly reduced or not present before PRP in most patients. However, if they are present, they become undetectable after PRP.
The macula is spared from photocoagula- tion during PRP (Fig. 3.2), but the question arises whether PRP affects macular physiology.
Decreased consumption of oxygen in the exten- sively coagulated retina may lead to increased oxygen supply to the noncoagulated areas of the macula. On the other hand, some patients suffer from macular edema following PRP. Full- field ERGs and focal macular ERGs before and after PRP are compared in Fig. 3.4, with special emphasis on the OPs [2, 3]. Following PRP, the OPs of the full-field ERGs are reduced in ampli- tude to nearly undetectable levels. However, the OPs of the focal macular ERGs, elicited by three differently sized stimuli, were not reduced. The amplitudes of the b-waves of the focal macular ERGs elicited by a 15° spot in a large series of
patients before and after PRP are compared in Fig. 3.5 [3]. The amplitude of the b-wave after PRP is expressed as a percentage of that before PRP. To determine the variations in the focal macular ERGs in normal control subjects, the amplitude of the b-wave of the focal macular ERGs of normal subjects from two recordings at different times were compared. The variation in the focal macular ERGs in normal subjects was small. On the other hand, the interindivid- ual variations in the amplitudes of the focal macular ERGs after PRP were large, with some showing a decrease and others an increase. The decrease and increase (average of amplitudes) were not statistically significant.
These results suggest that PRP alters the macula of eyes with diabetic retinopathy in various ways, and it may either improve or worsen macular function.
Fig. 3.3. Comparison of amplitudes of a-waves and b-waves recorded before and after panretinal photocoagulation (PRP) in eyes with diabetic retinopathy.
(From Kondo and Miyake [2])
Fig. 3.4. Comparison of full-field elec- troretinograms (ERG) (top) and focal macular ERGs elicited by three differ- ently sized stimulus spots (bottom) recorded before and after PRP in an eye with diabetic retinopathy. The OPs of the full-field ERGs are significantly reduced in amplitude, but the OPs of the focal macular ERGs are not changed following PRP. To evaluate the OPs, the time constant (T.C.) of 0.003 s was used for recording
Fig. 3.5. Right: Comparison of the rela- tive b-wave amplitude of the focal macular ERG elicited by a 15° spot before and after PRP in patients with diabetic retinopathy. The amplitude after PRP is expressed as a percentage of that before PRP. Left: Variations of the relative b-wave amplitude in normal subjects from two recordings
When massive vitreous hemorrhage prevents ophthalmoscopic examination of the fundus in patients with proliferative diabetic retinopathy, it makes it difficult to predict the surgical and visual outcome after vitrectomy. In these eyes, the amplitudes of the ERGs may be markedly reduced by various factors: pathological changes induced by the diabetic retinopathy;
earlier PRP; vitreous hemorrhage. As men- tioned, the PRP reduces the ERG amplitude, but the b/a ratios are unchanged (Fig. 3.3). Because most patients with vitreous hemorrhage have undergone PRP, it is difficult to arrive at a prog- nosis of the outcome after vitrectomy using only the a-wave and b-wave amplitudes. The b/a ratios provide more useful information about the prognosis after vitrectomy [4].
The preoperative full-field ERGs elicited by a single bright flash can be used to classify patients with diabetic retinopathy into three groups (Fig. 3.6): Group A includes those with a b/a ratio ≥ 1.0, and the OPs are clearly record- able. Group B includes those with a b/a ratio
≥ 1.0, but the OPs are absent. Group C com- prises those with a b/a ratio < 1.0, with no recordable OPs. The distribution of the postop- erative visual acuity for each group is shown in Fig. 3.7. The postoperative visual acuity for group C was significantly worse than that for group A or group B. The low b/a ratios may indicate a more severe ischemic retina, which in turn may account for the relatively good corre- lation with visual acuity. However, among the
patients in group C, there were some whose postoperative visual acuity was good, indicat- ing that a b/a ratio < 1.0 is not necessarily a con- traindication for surgery.
The light-filtering effect of a dense vitreous hemorrhage should also be considered when evaluating the preoperative ERG in diabetic patients. Severe vitreous hemorrhage reduces the intensity of the stimulus light reaching the retina, which can increase the b/a ratio (see Section 1.1.1). Therefore, a lower b/a ratio in a patient with an opaque vitreous indicates a greater decrease in the b/a ratio in clear media, suggesting more severe ischemia of the retina.
Another interesting observation is that most patients who have distinct OPs preoperatively have good visual acuity (>0.5) after surgery.
This observation is important when we discuss the visual prognosis with patients before surgery.
Thick proliferative tissues are found at the disk (Fig. 3.8) intraoperatively in 36% of the patients in group A, 67% in group B, and 90%
in group C. Hirose [5] suggested that the fibrous proliferation at the disk may restrict retinal circulation by compressing the central retinal artery.
In conclusion, it should be emphasized that a considerable amount of useful information can be obtained from a simple preoperative ERG on diabetic patients with massive vitreous hemorrhage.
3.1.2 Diabetic Vitreous Hemorrhage
Fig. 3.6. Preoperative full-field ERGs recorded from a normal control and three diabetic patients with vitreous hemorrhage who were classified into three groups. (From Hiraiwa et al. [4], with permission)
Fig. 3.7. Postoperative visual acuity in the three groups shown in Fig. 3.6. *P< 0.01. HM, hand motion vision. (From Hiraiwa et al. [4], with permission)
Fig. 3.8. Proliferative tissue on the optic disk in a patient with diabetic retinopathy
Diabetic maculopathy is one of the leading causes of blindness in diabetic retinopathy. The functional and morphological analysis of dia- betic maculopathy is thus important for prog- nostic evaluation and treatment indications.
The OCT images and the focal macular ERGs obtained from representative patients with diabetic maculopathy are shown in Fig. 3.9.
Normal control (A), mild maculopathy (B), or focal macular edema (C) often show an
3.1.3 Focal Macular ERGs and Diabetic Maculopathy
FAG OCT Focal Macular ERG
A
B
C
D
E
F
0.03 secT.C. T.C.
0.003 sec
ON ON
50msec1 mV
Fig. 3.9. Fluorescein angiograms (FAG), optical convergence tomography (OCT), and focal macular ERGs (ERG) elicited by a 15° spot obtained from patients at different stages of diabetic maculopathy. A Normal control. B–F Diabetic maculopathy associated with B microaneurysms, C focal macular edema, D diffuse cystoid macular edema, E ischemic maculopathy, and F retinal pigment epitheliopathy
abnormality of only the macular OPs, par- ticularly a delay in the implicit times. The OCT images of these patients may show a macula slightly thicker than normal. Patients with diffuse macular edema may have more severe alteration of the OPs in regard to both amplitude and implicit time as well as a decrease in the b-waves. In patients with diffuse macular edema, the OCT always shows a thicker macula, sometimes associated with cystic spaces (D). Patients with ischemic maculopathy with an avascular zone in the macula (E) usually have undetectable OPs, reduced a-wave amplitude, and more reduced b-wave amplitude. OCT images show that the macula can be either thicker or thinner than normal. A patient with pigment epithe- liopathy of the macula (F) can have unde- tectable OPs with markedly reduced a-waves and b-waves. The OCT may show a rather thin macula.
We studied the focal macular ERGs recorded from 73 eyes at various stages of diabetic maculopathy and compared them to 62 age-
matched controls (Fig. 3.10). The amplitudes of the a-waves, b-waves, and OPs in eyes with diabetic maculopathy, and with ophthalmo- scopically normal macula and macular microa- neurysms, were not significantly different from normal, but they were reduced in eyes with focal and diffuse macular edema. However, the implicit times of the OPs were significant delayed even when the macula was ophthalmo- scopically normal. Thus, as seen in full-field ERGs, the macular OPs are the most sensitive indicator of the functional changes during early diabetic maculopathy.
Diabetic macular edema is the most common cause of decreased visual acuity in patients with diabetic maculopathy. At present, vitrectomy is an investigational technique used for treating diabetic macular edema, some- times resulting in recovery of the anatomic configuration of the macula without photoco- agulation [6].
The question then arises as to whether recovery of macular configuration is accompa- nied by recovery of the macular ERGs. We
Fig. 3.10. Amplitudes and implicit times of the a-wave, b-wave, and OPs of patients at different stages of diabetic maculopathy and normal controls.
NDR, no diabetic retinopathy; MA, microaneurysm; FME, focal macular edema; DME, diffuse macular edema;
IMP, ischemic maculopathy; RPEP, retinal pigment epitheliopathy
found [7] that anatomical resolution of the macular edema as detected by OCT preceded functional recovery of the macular ERG 6 months after vitrectomy (Fig. 3.11). Many patients did not show significant recovery of the macular ERGs despite good recovery of macular configuration. However, 12 months after surgery, visual acuity was significantly improved and the b-wave amplitude of macular ERG had increased significantly (Fig. 3.12).
Although there was a wide range of changes in the b-wave amplitude at 12 months, the increase in the b-wave correlated with the decrease in the foveal thickness (Fig. 3.12).
A disparity in the time course and degree of recovery of the foveal thickness and macular function was found in eyes with diabetic macular edema after vitrectomy. It is conceiv- able that diabetic macular edema, an indication for vitrectomy, is often associated with addi- tional macular pathology, such as ischemia, which cannot be improved by vitrectomy. Such pathology may influence the focal macular ERGs more than the changes induced by the macular edema.
Fig. 3.11. OCT images and focal macular ERGs obtained before (left) and 6 months after (right) surgery from six patients with diabetic macular edema. (From Terasaki et al. [7], with permission)
References
1. Yonemura D, Aoki T, Tsuzuki K (1962) Elec- troretinogram in diabetic retinopathy. Arch Oph- thalmol 68:19–24
2. Kondo T, Miyake Y (1985) Effects of panretinal photocoagulation on posterior fundus in diabetic retinopathy: analysis of local macular elec- troretinogram and visual evoked response. Acta Soc Ophthalmol Jpn 89:535–543
3. Miyake Y (1988) Study on local ERG. Acta Soc Oph- thalmol Jpn 92:1419–1449
4. Hiraiwa T, Horio N, Terasaki H, Suzuki T, Yamamoto E, Horiguchi M, et al (2003) Preopera- tive electroretinogram and postoperative visual outcome in patients with diabetic vitreous hemor- rhage. Jpn J Ophthalmol 47:307–311
5. Hirose T (1977) Evaluation of retinal function in the presence of vitreous opacities. In: Vitreous surgery and advances in fundus diagnosis and treatment. Appleton-Century-Crofts, New York, pp 79–97
6. Lewis H, Abrams GW, Blumenktanz MS, Campo RV (1992) Vitrectomy for diabetic traction and edema associated posterior hyaloidal traction. Ophthal- mology 99:753–759
7. Terasaki H, Kojima T, Niwa H, Piao CH, Ueno S, Kondo M, et al (2003) Changes in focal macular electroretinograms and foveal thickness after vitrectomy for diabetic macular edema. Invest Ophthalmol Vis Sci 44:4465–4472
Fig. 3.12. Change in visual acuity (A), foveal thickness measured by OCT (B), and amplitude of the a-waves and b-waves of the focal macular ERGs elicited by a 15° spot (C) obtained before and after surgery. *P< 0.05; ***P < 0.0001. (From Terasaki et al. [7], with permission)
