Optical imaging of retina in response to grating stimuli in cats.

We examined the intrinsic signals in response to grating stimuli in order to determine whether the light-evoked intrinsic signals of the retina are due to changes in the photoreceptor activities induced by the image projected on to the retina or are due to neural activities of the inner retina. The retinas of the left eye of 12 cats under general anesthesia were examined by a functional imaging fundus camera. Near infrared light was used to monitor the reflectance changes (RCs) of the retina. Vertical grating were used to stimulate the retina at 4 Hz. The spatial frequencies of the gratings were 0.05, 0.11, 0.22, 0.43, 0.86, 1.73, and 3.46 cycles/degree (cpd). Ten images were averaged and used to analyze the RCs to obtain the peak value (PV) of a two dimensional fast Fourier transfer of the RCs. The wavefront aberrations (WA) were measured with a compact wavefront aberrometer and the spatial modulation transfer function (MTF) of the eye was calculated. The retinal reflectance image had a grating pattern. The PV of the spatial sensitivity curve was highest at low spatial frequencies (0.05 and 0.11 cpd), and the sensitivity decreased steeply with an increase in the spatial frequency. RCs were not detectable at 3.46 cpd. The MTF decreased gradually with increases in the spatial frequencies and was 0.68 at 3.46 cpd. The reflectance pattern of the retinal intrinsic signal elicited by grating stimuli of different spatial frequencies was different from that of the MTF. This suggests that the intrinsic signal represents not only the response of the photoreceptors but also other neuronal or vascular changes in the retina.

Laboratory investigation of microelectronics-based stimulators for large-scale suprachoroidal transretinal stimulation (STS).

This paper describes the technological developments underlying the realization of a reliable and reproducible microchip-based stimulator with a large number of stimulus electrodes. A microchip-based stimulator with over 500 electrodes for suprachoroidal transretinal stimulation (STS) is proposed in this paper, and an example is presented. To enhance reliability and reproducibility for such a large array, we introduce a flip-chip bonding technique and place microchips on the reverse side of a substrate. A square microchip of size 600 microm was fabricated using 0.35 microm standard CMOS process technology. Twelve microchips were flip-chip bonded on a polyimide substrate through Au bumps. To evaluate the feasibility of the proposed device, we successfully fabricated a stimulator with 12 microchips and 118 electrodes made of Pt/Au bumps, and demonstrated their operation in a saline solution for 2 weeks. Also, to evaluate the device operation in vivo, a stimulator with one active IrO(x) electrode was implanted into the scleral pocket of a rabbit and electrical evoked potential (EEP) signals with a threshold of 100 microA were obtained. We also fabricated a simulator with 64 microchips that has 576 electrodes (9 electrodes in a microchip times 64 microchips).

Molecular cloning of a novel membrane glycoprotein, pal, specifically expressed in photoreceptor cells of the retina and containing leucine-rich repeat.

We have isolated a novel retina-specific gene in a screen for genes of which expression is not apparent neonatally in rat retina but is abundant postnatally on day 14 (P14). This gene, named Pal, encodes a putative type I transmembrane protein containing five leucine-rich repeats (LRRs), a single C2-type Ig-like domain, and a single fibronectin type III domain and is considered to be a new member of the LRR and Ig superfamily. No expression of Pal was found in rat retina at P1, but it was detected at P7 and markedly increased with subsequent development. These expression patterns of Pal appeared to be correlated with the development of the photoreceptor outer segments, because in the adult rat retina it was specifically localized in these segments. Ultrastructually, Pal immunoreactivity was distributed diffusely on the disk membrane in the lamellar regions. On the basis of its structural features and localization pattern, Pal may act as a receptor for a certain trophic factor or for an adhesion molecule participating in morphogenesis. The human homolog of Pal was mapped to chromosome 10q23.2-23.3 using fluorescence in situ hybridization.

Retinal changes after retinal translocation surgery with scleral imbrication in dog eyes.

PURPOSE: To examine retinal changes induced by scleral imbrication during retinal translocation surgery in dog eyes. METHODS: Fifteen dogs were anesthetized and underwent retinal translocation surgery. After lensectomy and vitrectomy, an intentional retinal detachment was created, and the upper temporal sclera around the equator was imbricated with five mattress sutures. Translocated distances were calculated by pre- and postoperative photographs. At 1, 2, and 4 weeks after the surgery, the retina was studied by TdT-dNTP terminal nick-end labeling (TUNEL) and immunohistochemistry of peanut agglutinin (PNA) lectin and glial fibrillary acidic protein (GFAP). RESULTS: The retina was translocated by a mean distance of 0.53 +/- 0.30 disc diameters or 959 +/- 543 micrometer. Retinal folds were created around the optic disc in all eyes. Histologic examination of the retinal folds 1 week after the surgery showed many TUNEL-positive cells in the outer nuclear layer, loss of photoreceptor cells, and shortening of the outer and inner segments. A strong immunoreactivity to GFAP was detected in the folds of the retina. CONCLUSIONS: . The results demonstrated that retinal translocation surgery by scleral imbrication inevitably caused retinal folds as a postoperative complication, and the retina within the folds showed extensive loss of photoreceptor cells. It is recommended that the foveal translocation surgery be planned to avoid involving the fovea in the retinal folds.

Mutations in the 11-cis retinol dehydrogenase gene in Japanese patients with Fundus albipunctatus.

PURPOSE: To detect mutations in the RDH5 gene encoding 11-cis retinol dehydrogenase in patients from Japan with fundus albipunctatus. METHODS: Polymerase chain reaction and direct genomic sequencing techniques were used to detect mutations of the RDH5 coding exons (exons 2-5) in two unrelated patients with fundus albipunctatus. Selected alleles that altered the coding region or intron splice sites were evaluated further through segregation analysis in the families of the index cases. RESULTS: Two novel RDH5 mutations were identified. One of these was a missense mutation Val264Gly in exon 5, and the other was an in-frame insertion of 3 bp in exon 5. CONCLUSIONS: The data indicate that mutations in RDH5 are the primary cause of fundus albipunctatus.

The visual performance and metamorphopsia of patients with macular holes.

BACKGROUND: Most patients attain better visual acuity with the elimination of metamorphopsia after successful closure of a macular hole (MH) by vitrectomy. OBJECTIVE: To determine the presurgical visual function of eyes with an MH. METHODS: We examined 54 eyes of 51 patients with an idiopathic MH using the Amsler chart. We evaluated the types of subjective metamorphopsia and compared them with the clinical factors associated with MHs. In a prospective study, we performed a montage test on a separate group of 16 patients with unilateral idiopathic MHs. The patients were asked to choose, while viewing with their better eye, the computer-modified picture that best matched the unmodified image seen by the eye with the MH. RESULTS: From the results of the Amsler chart test, we divided the subjective changes into 2 types of metamorphopsia; of the 54 eyes, pincushion distortion (bowed toward the center) was found in 33 (61%), and unpatterned distortion (no specific pattern) was found in 21 (39%). Pincushion distortion was significantly associated with an MH of shorter duration (< or =6 months) (P = .03) and an early stage (stage 2) of MH formation (P = .02). A scotoma was hard to detect, and patients had difficulty describing their scotomata and distortions. In the montage test, patients with early MHs chose portraits modified with a pincushion type of distortion. CONCLUSIONS: We found concentric pincushion metamorphopsia without subjective scotomata, which we suggest arises from an eccentric displacement of the photoreceptors. This accounts for the main characteristic of the visual performance of patients with idiopathic MHs.

X-linked retinoschisis with point mutations in the XLRS1 gene.

BACKGROUND: X-linked retinoschisis (XLRS) is a relatively rare vitreoretinal dystrophy that causes visual loss in young men. Recently, a gene responsible for this disease, designated XLRS1, was identified, and several deleterious gene mutations were reported. OBJECTIVE: To analyze Japanese patients clinically diagnosed as having XLRS formutational changes in the XLRS1 gene. METHODS: Ten patients with XLRS underwent full ophthalmologic examination, including slitlamp biomicroscopy and dilated funduscopy. Genomic DNA was isolated from leukocytes, and all exons of the XLRS1 gene were amplified by polymerase chain reaction and analyzed using a direct sequencing method. RESULTS: Point mutations in the XLRS1 gene were identified in all 10 patients. The mutations were identical in each of 2 pairs of brothers. Six of the point mutations represented missense mutations, 1 was a nonsense mutation, and 1 was a frameshift mutation. Five of the mutations are newly reported herein. CONCLUSIONS: The discovery of new point mutations in this study increases the available information regarding the spectrum of genetic abnormalities and clinical manifestations of XLRS. However, the limited data failed to reveal a correlation between mutation and disease phenotype. CLINICAL RELEVANCE: Identification of mutations in the XLRS1 gene and expanded information on clinical manifestations will facilitate early diagnosis, appropriate early therapy, and genetic counseling regarding the prognosis of XLRS.

Two pathways from the facial skin to the superior colliculus in the rat.

In response to single shock stimulation of the facial skin, the field potential of two negative waves (N1 and N2) appear in the intermediate layers of the rat superior colliculus (SC). From the experiments of functional ablations of the cortical facial area, the N1 wave was ascribed to the post-synaptic activity mediated by the direct trigemino-tectal pathway whereas the N2 wave to that mediated by the trigemino-cortico-tectal pathway. Single unit recordings also confirmed the existence of two pathways from the facial skin to the intermediate layers of SC.

Spontaneous disappearance of traumatic macular holes in young patients.

PURPOSE: To report the disappearance of traumatic macular hole in three eyes of three patients. METHODS: Clinical data of the patients were reviewed. RESULTS: The three patients were relatively young, ranging in age from 12 to 18 years old. In one eye of each patient, a small traumatic macular hole was observed at the first visit. Visual acuities ranged from 20/100 to 20/40. The macular holes resolved spontaneously 3 to 4 months after the trauma, and final visual acuity improved to 20/20 in all patients. CONCLUSION: Small traumatic macular holes in young patients can resolve spontaneously, and this can be associated with good visual recovery.

Visual function after foveal translocation with scleral shortening in patients with myopic neovascular maculopathy.

PURPOSE: To document the visual outcome after successful foveal translocation with intentional retinal detachment and scleral shortening for the treatment of myopic neovascular maculopathy. METHODS: Two severely myopic patients with subfoveal neovascular membranes underwent surgical translocation of the fovea to an area of healthy retinal pigment epithelium by means of scleral shortening and intentional retinal detachment. In the postoperative period, monocular and binocular visual function were studied. RESULTS: In one patient, best-corrected visual acuity improved from 20/150 to 20/20 postoperatively. In the second patient, acuity initially improved from 20/70 to 20/30. In both patients, the fixation point shifted from the site of the neovascular membrane. Oblique astigmatism developed and was managed with hard contact lenses. Diplopia and subjective torsion occurred transiently. Micropsia occurred in one patient. Peripheral fusion assessed by Worth four-dot testing after resolution of diplopia disclosed suppression in the nondominant eye in both cases. CONCLUSIONS: Foveal translocation with intentional retinal detachment and scleral shortening was useful in improving visual acuity in two patients with myopic neovascular maculopathy. Diplopia and aniseikonia occurred but resolved over time as suppression developed. This technique is promising for patients with myopic neovascular maculopathy.

Anatomic and functional recovery of the fovea after foveal translocation surgery without large retinotomy and simultaneous excision of a neovascular membrane.

PURPOSE: To document the anatomic and functional recovery of the fovea after foveal translocation surgery with scleral shortening and simultaneous excision of a neovascular membrane in a patient with age-related macular degeneration. METHOD: Case report. RESULTS: The visual acuity of a 54-year-old woman with age-related macular degeneration improved from 20/200 to 20/50 after excision of subretinal neovascular membrane and foveal translocation surgery in the right eye. Fixation shifted inferonasally 0.6 disk diameters, corresponding to the direction of foveal translocation, as shown by scanning laser ophthalmoscope microperimetry. Postoperative optical coherence tomography through fixation disclosed normal foveal concavity and intact retinal pigment epithelium. CONCLUSION: Anatomic and functional recovery of the fovea was confirmed in a patient with age-related macular degeneration after foveal translocation surgery with scleral shortening and simultaneous excision of a neovascular membrane.

Evaluation of the peripheral visual field after foveal translocation.

PURPOSE: To evaluate the peripheral visual field after foveal translocation with scleral imbrication or 360-degree retinotomy. METHODS: Retrospective, single-center, nonrandomized study. We calculated the rate of preservation of the peripheral visual field using Goldmann perimetry by dividing the width of the postoperative V-4 isopter by the preoperative width and expressing the result as a percentage. RESULTS: In nine eyes that underwent scleral imbrication, the rate of preservation was 100.0% superiorly, 102.6% superotemporally, 99.9% temporally, 97.9% inferotemporally, 96.9% inferiorly, 82.3% inferonasally, 93.7% nasally, and 87.3% superonasally. In 33 eyes that underwent 360-degree retinotomy, it was 89.1%, 87.0%, 81.9%, 78.1%, 86.6%, 90.0%, 89.9%, and 86.8%, respectively. CONCLUSION: After foveal translocation with scleral imbrication, the peripheral visual field was preserved except for slight narrowing nasally; 360-degree retinotomy resulted in preservation of the visual field, except for slight narrowing in all meridians.

Comparison of visual function after foveal translocation with 360 degrees retinotomy and with scleral shortening in a patient with bilateral myopic neovascular maculopathy.

PURPOSE: To compare the visual outcome after foveal translocation by scleral shortening and that after 360 degrees retinotomy with extraocular muscle surgery in a patient with bilateral myopic neovascular maculopathy. METHODS: Case report. RESULTS: A 52-year-old woman with bilateral myopic neovascular maculopathy underwent foveal translocation with scleral shortening in the left eye, and visual acuity improved from 20/70 to 20/30. However, choroidal neovascularization recurred, and the final visual acuity was 20/40 after excision of the choroidal neovascularization. Foveal translocation with 360 degrees retinotomy was performed on the right eye, and visual acuity improved from 20/150 to 20/30. The critical print size was better, and the retinal sensitive area was larger in the right eye. CONCLUSION: The better reading ability shown by foveal translocation by a 360 degrees retinotomy compared with scleral shortening may stem from a larger retinal sensitive area obtained by this method.

Basic fibroblast growth factor inhibits choriocapillaris atrophy in rabbit.

PURPOSE: To examine the effect of basic fibroblast growth factor on induced choriocapillaris atrophy in vivo. METHODS: Choriocapillaris atrophy was surgically induced in rabbits by a hydraulic retinal detachment followed by debridement of the retinal pigment epithelium under the detached retina. Three concentrations of basic fibroblast growth factor (0.1 microg/0.1 ml, 1 microg/0.1 ml, or 5 microg/0.1 ml) were injected into the subretinal space and into the vitreous cavity 1, 3, and 5 days after the surgery. For control, only Tris buffer was injected in the same manner. The rabbits were euthanized 7 days after the surgery. Choroidal vascular casts were made and examined by scanning electron microscopy. The choriocapillaris atrophy was quantified by computer-assisted image analysis of photographs of the choriocapillaries. The area of the choriocapillaris and number of intercapillary spaces in the choriocapillaris that corresponded to the density of the capillary network were measured. RESULTS: The average area of the choriocapillaris in the eyes treated with 1 microg/0.1 ml of basic fibroblast growth factor was significantly larger at 75.1 +/- 3.0% than that in the control eyes at 67.2 +/- 5.6% (P =.021). The average area of the choriocapillaris in the 0.1 microg/0.1 ml of basic fibroblast growth factor group was not statistically different from the control. The number of intercapillary spaces of the choriocapillaris was 132 +/- 12 in the 0.1 microg/0.1 ml of basic fibroblast growth factor group, 124 +/- 46 in the 1 microg/0.1 ml of basic fibroblast growth factor group, and 75 +/- 14 in the control group. The higher number of spaces in the treated group was statistically significant (P =.026). CONCLUSIONS: Basic fibroblast growth factor decreased the atrophy of the choriocapillaris after removal of the retinal pigment epithelium in rabbit eyes. These results suggest that basic fibroblast growth factor may play a role in the survival of the choriocapillaris in vivo.

Prediction of letter contrast sensitivity using videokeratographic indices.

PURPOSE: To analyze the relationship between corneal topography and letter contrast sensitivity. METHOD: Experiments were conducted on 59 eyes of 51 patients who had best spectacle-corrected visual acuity of 20/20 or better and no ocular pathology except for the corneal shape. Thirty-nine eyes had an abnormal topographic pattern resulting from keratoconus, and the other 20 eyes showed a normal topographic pattern. Videokeratography was performed with the TMS-2 videokeratoscope, and the surface regularity index, surface asymmetry index, and coefficient of variation of power were obtained for each subject. Letter contrast sensitivity was measured with the CSV-1000LV with spectacle correction. The correlation between the number of correct letters and topographic indices was calculated. RESULTS: The abnormal topography group had a significantly greater loss of letter contrast sensitivity (median = 20 letters) than the normal control (median = 23 letters; P =.0001). There were statistically significant correlations between number of correct letters and the coefficient of variation of power (r = -.77; P =. 001), number of correct letters and surface regularity index (r = -. 76, P =.001), and the number of correct letters and surface asymmetry index (r = -.64; P =.001). The linear regression equation between number of correct letters and the coefficient of variation of power was the number of correct letters = -0.05 x the coefficient of variation of power + 23.2. CONCLUSIONS: Our results suggest that subtle visual deteriorations, which are barely detected by contrast sensitivity testing, can be predicted objectively by the corneal topographic indices.

Visual function after foveal translocation with 360-degree retinotomy and simultaneous torsional muscle surgery in patients with myopic neovascular maculopathy.

PURPOSE: To assess functional and anatomical outcomes after foveal translocation with 360-degree retinotomy and simultaneous torsional muscle surgery in patients with myopic neovascular maculopathy. METHODS: Foveal translocation with 360-degree retinotomy was performed in 11 eyes of 11 patients with myopic neovascular maculopathy. Ten eyes had simultaneous torsional muscle surgery with recession of the superior oblique muscle and tucking of the inferior oblique muscle. Silicone oil removal with or without intraocular lens implantation was performed 2 to 8 weeks after the primary procedure. Visual acuity, binocular function, and degree of cyclotorsion were assessed preoperatively and postoperatively. Angles of retinal and globe rotation, distance of foveal shift, and surgical complications were also investigated. RESULTS: With a mean postoperative follow-up of 6.2 months (range, 3 to 13 months), vision improved (greater than 0.2 logarithm of minimal angle of resolution [logMAR] units) in eight eyes, was unchanged in two eyes, and worsened (greater than 0.2 logMAR units) in 1 eye. Seven of 11 eyes (64%) had a final visual acuity of 20/50 or better. Five patients developed or maintained binocular fusion, four patients continued to have suppression, and two patients developed diplopia that was managed by spectacles with Fresnel prisms. Subjective cyclotorsion was less than 8 degrees in 10 eyes. Mean retinal and globe rotations were 23.4 degrees and 19.8 degrees, respectively. Average size of the choroidal neovascular membrane was 0.8 disk diameter, whereas the average distance of foveal shift was 1.5 disk diameter. After the primary procedure, three eyes developed retinal detachment, one eye macular hole, and one eye proliferative vitreoretinopathy. These complications were successfully managed by additional surgery. CONCLUSION: Foveal translocation with 360-degree retinotomy is effective in restoring vision in some patients with myopic neovascular maculopathy. Although the development of torsional diplopia is generally obviated by simultaneous extraocular muscle surgery, a relatively high incidence of surgical complications should be taken into account with this procedure.

Comparison of three techniques of foveal translocation in patients with subfoveal choroidal neovascularization resulting from age-related macular degeneration.

PURPOSE: To report the results of three methods of foveal translocation in the presence of subfoveal choroidal neovascular membrane resulting from age-related macular degeneration. METHODS: We treated 51 eyes of 51 consecutive patients with subfoveal choroidal neovascular membranes resulting from age-related macular degeneration with one of three techniques of foveal translocation surgery: foveal translocation with partial retinotomy (n = 6), limited translocation (n = 9), and translocation with 360-degree retinotomy (n = 36). All patients were followed for at least 6 months postoperatively. The size of the choroidal neovascular membrane and the amount of foveal displacement, the best-corrected visual acuity, and complications were recorded preoperatively and postoperatively. RESULTS: The mean distance of the foveal translocation was greater in the 360-degree retinotomy group (3340 microm) than in the partial retinotomy (1060 microm, P <.001) and the limited translocation groups (1120 microm, P <.001). A final visual acuity of 20/200 or better was achieved in two eyes (33%) in the partial retinotomy group, seven eyes (78%) in the limited translocation group, and 23 eyes (64%) in the 360-degree retinotomy group. The final visual acuity improved by 0.2 logarithm of minimal angle of resolution (logMAR) unit or more in one eye (17%), one eye (11%), and seven eyes (19%), respectively. The final visual acuity was maintained within 1 line in zero eyes, five eyes (56%), and 19 eyes (53%), respectively. A retinal detachment developed postoperatively in five eyes (83%), zero eyes (0%), and 15 eyes (42%), respectively. CONCLUSIONS: A significant number of patients improved or maintained best-corrected visual acuity after translocation with 360-degree retinotomy, and limited translocation, whereas translocation with 360-degree retinotomy is suitable for larger choroidal neovascular membranes because it resulted in the greatest foveal displacement among the three translocation procedures.

Effect of Ca(2+)-free and Mg(2+)-free BSS Plus solution on the retinal pigment epithelium and retina in rabbits.

PURPOSE: To determine whether intravitreal irrigation with Ca(2+)-free and Mg(2+)-free BSS Plus (Alcon Laboratory, Fort Worth, Texas) solution alters the adhesiveness between the retinal pigment epithelium and the retina of rabbits. METHODS: Thirty-four eyes of 34 Dutch pigmented rabbits underwent lensectomy and vitrectomy. Subsequently, the vitreous cavity of 24 eyes was irrigated with Ca(2+)-free and Mg(2+)-free BSS Plus solution for 10 or 20 minutes. The other 10 eyes were irrigated with BSS Plus solution for 20 minutes as controls. To determine the adhesiveness between the retinal pigment epithelium and retina, a retinal detachment was produced in 12 of the 34 eyes. The apical surface of the retinal pigment epithelium and the photoreceptor outer segments were examined by scanning electron microscopy. Retinal physiology was assessed by electroretinography and retinal morphology by light microscopy. RESULTS: After retinal detachment was produced, the number of cone sheaths on the apical surface of the retinal pigment epithelium after irrigation with Ca(2+)-free and Mg(2+)-free BSS Plus solution for 20 minutes (33 +/- 15, mean +/- SD) was significantly less than the number of cone sheaths on the apical surface of the retinal pigment epithelium of eyes after irrigation with BSS Plus solution for 20 minutes (120 +/- 50) or the number of cone sheaths on the apical surface of the retinal pigment epithelium of eyes after 10 minutes of irrigation with Ca(2+)-free and Mg(2+)-free BSS Plus solution (115 +/- 49; P =.02). The b-wave amplitudes in the eyes irrigated with Ca(2+)-free and Mg(2+)-free BSS Plus solution for 20 minutes were depressed compared with the b-waves in eyes irrigated with BSS Plus solution for 20 minutes on the first postoperative day (P =.03). After the third postoperative day, there was no significant difference in the b-waves (P >.06). Light microscopy demonstrated no morphologic abnormalities after the use of both solutions. CONCLUSIONS: Intravitreal irrigation with Ca(2+)-free and Mg(2+)-free BSS Plus solution for 20 minutes altered the adhesion between the retinal pigment epithelium microvilli and retinal outer segments and made the creation of retinal detachment less traumatic. These results suggest that Ca(2+)-free and Mg(2+)-free BSS Plus solution may be of clinical value for the creation of an intentional retinal detachment for foveal translocation surgery.

Low frequency dielectric relaxation and light scattering under AC electric field of DNA solutions.

Low frequency dielectric relaxation of aqueous DNA was measured in a frequency range from 0.1 Hz to 30 kHz. Agreement was found between dielectric relaxation time and rotational one estimated from reduced viscosity for dilute solutions of DNA. The low frequency relaxation is thus ascribed to rotation of the major axis of DNA chains elongated by electrostatic repulsion between charges on the chain. A quasi-permanent dipole moment of DNA estimated from the dielectric increment is well explained by the fluctuation of dissociation of DNA. The above conclusion was confirmed for DNA samples of various molecular weights and for solutions in water ethanol mixtures. Effects of binding of salts and dyes are also interpreted in terms of the same mechanism. Light scattering of aqueous DNA under a.c. electric field supports the above conclusion.

Low response of the thyroid gland to endogenous thyrotropin increased by thyrotropin-releasing hormone in patients with euthyroid Graves' disease.

Euthyroid Graves' disease is defined as Graves' ophthalmopathy without hyperthyroidism, and the thyroid-stimulating antibody (TSAb) has been known to be a good marker for diagnosis. However, the question of why TSAb does not cause hyperthyroidism arises. To settle this, we examined thyroid responsiveness to endogenous thyrotropin (TSH) increased by thyrotropin-releasing hormone (TRH) in 23 patients with euthyroid Graves' disease. Nineteen patients (83%) had positive TSAb and 21 (91%) had at least one of the autoantibodies to the thyroid gland. Only one patient (4%) had positive thyroid-stimulation blocking antibody (TSBAb). Basal levels of free thyroxine (FT4), free triiodothyronine (FT3), and thyrotropin (TSH) in patients were not different from those in age- and sex-matched normal controls (n = 25). Response of TSH to TRH was normal; however, an increase of FT3, either absolute or as a multiple of baseline, in the TRH test in these patients (0.46+/-0.23 pg/mL, P < 0.001; 1.14+/-0.09 fold, p < 0.001) was significantly lower than that in controls (0.86+/-0.19 pg/ml; 1.26+/-0.07 fold). There was no correlation between the deltaFT3/deltaTSH ratio and TSAb activity. It is concluded that thyroid responsiveness in euthyroid Graves' disease is lower than in normal controls and this explains the euthyroid function in the patients even in the presence of TSAb.