Long-term corneal keratocyte deficits after PRK and LASIK: in vivo evidence of stress-induced premature cellular senescence.
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Cell Count↗
Biomedical subjects
Daniel G Dawson
Publications and source records attributed to Daniel G Dawson.
Toxic anterior segment syndrome.
Toxic anterior segment syndrome (TASS) is a sterile postoperative inflammatory reaction caused by a noninfectious substance that enters the anterior segment, resulting in toxic damage to intraocular tissues. The process typically starts 12 to 48 hours after cataract/anterior segment surgery, is limited to the anterior segment of the eye, is always Gram stain and culture negative, and usually improves with steroid treatment. The primary differential diagnosis is infectious endophthalmitis. Review of the literature indicates that possible causes of TASS include intraocular solutions with inappropriate chemical composition, concentration, pH, or osmolality; preservatives; denatured ophthalmic viscosurgical devices; enzymatic detergents; bacterial endotoxin; oxidized metal deposits and residues; and factors related to intraocular lenses such as residues from polishing or sterilizing compounds. An outbreak of TASS is an environmental and toxic control issue that requires complete analysis of all medications and fluids used during surgery, as well as complete review of operating room and sterilization protocols.
Anterior Eye Segment↗
Chronic pain after Intacs implantation.
A 39-year-old woman developed corneal ectasia after laser in situ keratomileusis. Intracorneal ring segments (Intacs, Addition Technology, Inc.) were placed in the left eye in November 2004. Postoperatively, inferior topographic steepening decreased significantly and a rigid gas-permeable lens yielded 20/25 visual acuity. However, the patient reported persistent discomfort that did not improve with topical medications or a bandage contact lens. In May 2005, confocal microscopy demonstrated a corneal nerve in direct contact with the inferior segment. Both segments were removed, and after removal, the patient reported complete resolution of the pain.
Adult↗
Interface fluid syndrome in laser in situ keratomileusis after complicated trabeculectomy.
A 69-year-old man developed stromal edema and a pocket of fluid in the laser in situ keratomileusis (LASIK) interface wound in the left eye after acute endothelial cell loss from complicated trabeculectomy. He eventually required penetrating keratoplasty along with cataract surgery. Histologic examination of the corneal button showed an edematous 720 microm central residual stromal bed, a 54 microm empty space at the level of the central interface wound, and a 154 microm LASIK flap. The endothelial cell count was 0 to 2 cells per high-power field, corresponding to a cell density of 450 to 500 cells/mm(2). Four years after LASIK, the central interface wound was susceptible to forming a pocket of serous fluid after the corneal endothelial function was compromised.
Aged↗
Keratan sulfate and chondroitin/dermatan sulfate in maximally recovered hypocellular stromal interface scars of postmortem human LASIK corneas.
PURPOSE: To analyze the amounts and distributions of nonsulfated and sulfated keratan sulfate (KS) and chondroitin/dermatan sulfate (CS/DS) disaccharides in the interface wound of human postmortem LASIK corneas in comparison with normal control corneas. METHODS: Corneal stromal tissue samples from central and paracentral hypocellular primitive stromal interface scars of human LASIK corneas and from similar regions of normal control corneas were collected by laser capture microdissection (LCM) and subsequently were digested with specific glycosidase enzymes. Digests were directly analyzed by electrospray ionization tandem mass spectrometry (ESI-MS/MS). RESULTS: Concentrations of both monosulfated GlcNAc(6S)-beta-1,3-Gal (MSD2) and disulfated Gal (6S)-beta-1,4-GlcNAc(6S) (DSD) KS disaccharides from the LASIK interface scars were significantly lower than in normal control corneal stromas. No significant difference was found for the concentration of nonsulfated (NSD) KS disaccharides in LASIK interface scars compared with normal controls. The concentration of DeltaUA-beta-1,3-GalNAc(6S) (Deltadi-6S) CS/DS disaccharides from the LASIK interface scar was significantly higher than normal corneal stroma, whereas concentrations of DeltaUA-beta-1,3-GalNAc(4S) (Deltadi-4S) and nonsulfated Deltadi-0S CS/DS disaccharides demonstrated no significant differences from normal corneas. CONCLUSIONS: The profiles of KS and CS/DS disaccharides in LASIK interface scars are significantly different from those in normal cornea stromal tissue, as revealed by LCM and ESI-MS/MS.
Chondroitin Sulfates↗
Histopathological analysis of post-laser-assisted in situ keratomileusis corneal ectasia with intrastromal corneal ring segments.
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Adult↗
Histologic, ultrastructural, and immunofluorescent evaluation of human laser-assisted in situ keratomileusis corneal wounds.
OBJECTIVE: To evaluate human corneas after laser-assisted in situ keratomileusis at different postoperative intervals. METHODS: Thirty-eight postmortem corneas from 20 patients with postoperative intervals from 2 months to 6.5 years after laser-assisted in situ keratomileusis surgery were collected from eye banks. The corneas were trisected and processed for conventional histologic analysis, transmission electron microscopy, and immunofluorescence. RESULTS: Light microscopy and transmission electron microscopy showed focal undulations in Bowman layer, focal epithelial hypertrophic modifications, and a variably thick (range, 0.4-16.4-mum) lamellar stromal interface scar in all specimens. The flap wound margin, which was adjacent to the epithelium, healed by producing an approximately 8-mum-thick hypercellular fibrotic stromal scar, whereas the central and paracentral wound regions healed differently because a thinner (approximately 5-mum) hypocellular primitive stromal scar was present in all the corneas examined. Immunofluorescence identified increased type 3 collagen and myofibroblasts in the hypercellular fibrotic scar regions and decreased or absent levels of all corneal stromal components other than type 1 collagen in the hypocellular primitive scar regions. CONCLUSIONS: After laser-assisted in situ keratomileusis surgery, the keratocyte-mediated production of a variably thick lamellar corneal stromal scar occurs, resulting in 2 regional types of scarring. The hypercellular fibrotic scar at the wound margin is usually visible clinically and functions to hold the flap in place, while the more central hypocellular primitive scar is not visible clinically and allows easy lifting of the flap postoperatively.
Actins↗
Long-term histopathologic findings in human corneal wounds after refractive surgical procedures.
OBJECTIVE: To describe the human corneal histopathology after laser in situ keratomileusis, photorefractive keratectomy, astigmatic keratoplasty, clear corneal refractive lens surgery, conductive keratoplasty, and intrastromal corneal ring segment placement. DESIGN: Retrospective histopathologic study and selected literature review. METHODS: Ninety-four postmortem corneas from 49 patients and 10 corneal button specimens from 6 patients with previous refractive surgery were collected from eye banks and refractive surgeons in North America. This observational case series evaluated the pathologic findings in the wounds of these corneas in the context of previous studies. RESULTS: Three histopathologic types of corneal wound-healing responses were present in corneas after refractive surgery. The first was an epithelial cell modification that reestablished a smooth anterior corneal surface through basal epithelial cell hypertrophy, by epithelial hyperplasia, or both. The second was the production of a hypercellular fibrotic stromal scar, and the third was the production of a hypocellular primitive stromal scar. Although only the hypercellular fibrotic stromal scar could be identified on gross examination, all three wound responses were identified with light, electron, and immunofluorescence microscopy. Confocal microscopy also identified these three processes but with less detail and resolution. CONCLUSION: Understanding the locations, clinical appearance, and functional attributes of these wound-healing responses will help guide evolving techniques or adjunctive treatments.
Cornea↗
Ex vivo confocal microscopy of human LASIK corneas with histologic and ultrastructural correlation.
OBJECTIVE: To perform confocal microscopy on postmortem human LASIK corneas and correlate these findings to histologic and ultrastructure evaluations. DESIGN: Prospective, consecutive, observational case series. PARTICIPANTS: Ninety postmortem LASIK corneas (47 patients) were evaluated for histopathology, of which 22 consecutive corneas (12 patients) were also evaluated by confocal microscopy. Six normal corneas (3 patients) served as controls. METHODS: This observational case series involving 22 corneas from 12 patients with postoperative intervals from 1 month to 6.5 years after LASIK surgery were collected. The corneas were mounted in an artificial anterior chamber and perfused with balanced salt solution before confocal microscopy was performed on the center of the cornea. The corneas were then bisected and processed for light and transmission electron microscopy. RESULTS: Confocal microscopy, along with histologic and ultrastructural correlations, demonstrated that the most prevalent alterations in the centers of LASIK corneas were a slightly thickened epithelium caused by focal basal epithelial cell hypertrophic modifications, random undulations in Bowman's layer over the flap surface, and a variably thick hypocellular primitive stromal interface scar. By using confocal microscopy, the interface wound was easily identified in 100% of the cases because numerous brightly reflective interface particles were always present in the hypocellular primitive stromal scar. These particles were found primarily to consist of organic cellular constituents, some of which were transient in nature. CONCLUSION: After LASIK, active stromal wound healing in the central cornea results in the production of a hypocellular primitive stromal scar, whereas secondary tissue adjustments seem to cause the Bowman's layer undulations and the subsequent epithelial cell modifications. Most of the interface particles revealed by confocal microscopy in the region of the stromal scar are organic in nature and presumably innocuous to the cornea.
Adult↗
Pathologic findings in postmortem corneas after successful laser in situ keratomileusis.
PURPOSE: To examine the histologic and ultrastructural features of human corneas after successful laser in situ keratomileusis (LASIK). METHODS: Corneas from 48 eyes of 25 postmortem patients were processed for histology and transmission electron microscopy (TEM). The 25 patients had LASIK between 3 months and 7 years prior to death. Evaluation of all 5 layers of the cornea and the LASIK flap interface region was done using routine histology, periodic acid-Schiff (PAS)-stained specimens, toluidine blue-stained thick sections, and TEM. RESULTS: In patients for whom visual acuity was known, the first postoperative day uncorrected visual acuity was 20/15 to 20/30. In patients for whom clinical records were available, the postoperative corneal topography was normal and clinical examination showed a semicircular ring of haze at the wound margin of the LASIK flap. Histologically, the LASIK flap measured, on average, 142.7 microm (range, 100-200). A spectrum of abnormal histopathologic and ultrastructural findings was present in all corneas. Findings at the flap surface included elongated basal epithelial cells, epithelial hyperplasia, thickening and undulations of the epithelial basement membrane (EBM), and undulations of Bowman's layer. Findings in or adjacent to the wound included collagen lamellar disarray; activated keratocytes; quiescent keratocytes with small vacuoles; epithelial ingrowth; eosinophilic deposits; PAS-positive, electron-dense granular material interspersed with randomly ordered collagen fibrils; increased spacing between collagen fibrils; and widely spaced banded collagen. There was no observable correlation between postoperative intervals and the severity or type of pathologic change except for the accumulation the electron-dense granular material. CONCLUSIONS: Permanent pathologic changes were present in all post-LASIK corneas. These changes were most prevalent in the lamellar interface wound. These changes along with other pathologic alterations in post-LASIK corneas may change the functionality of the cornea after LASIK.
Adult↗
Cataract surgery in patients with nanophthalmos: results and complications.
PURPOSE: To evaluate the results and complications of cataract surgery in patients with nanophthalmos. SETTING: University hospital practice. METHODS: The records of consecutive patients with nanophthalmos who had cataract surgery from 1978 through 2002 were reviewed for ocular diagnoses, corneal diameter, keratometry, axial length, retinal-choroidal-scleral thickness determined by echography, ocular surgeries, visual acuity, and complications. RESULTS: Eight patients (6 women, 2 men) with a mean age of 59 years were reviewed. Four patients were not previously diagnosed with nanophthalmos; increased retinal-choroidal-scleral thickness (mean 2.41 mm) confirmed the diagnosis. Twelve eyes had cataract extraction with posterior chamber intraocular lens (IOL) implantation, 11 by phacoemulsification and 1 by extracapsular cataract extraction, and 4 eyes had lamellar scleral resections. Additional surgeries included glaucoma laser treatment (8 eyes), cyclocryotherapy (2 eyes), trabeculectomy with scleral resection (1 eye), trabeculectomy combined with phacoemulsification (1 eye), and neodymium:YAG laser capsulotomy (4 eyes). No eye lost vision; however, complications included severe iritis, broken IOL haptic with vitreous loss, posterior capsule opacity, choroidal hemorrhage, phthisis, and aqueous misdirection. CONCLUSIONS: Results indicate that echography should be used to assess retinal-choroidal-scleral thickness in eyes that are hyperopic and at risk for narrow-angle glaucoma. Thickening may confirm the diagnosis of nanophthalmos and allow careful preoperative assessment and appropriate operative procedures in these high-risk eyes. With advances in cataract, glaucoma, and uveal effusion treatments, surgical results in patients with nanophthalmos are improving.
Adult↗
Pocket of fluid in the lamellar interface after penetrating keratoplasty and laser in situ keratomileusis.
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Aged↗
Persistent fetal vasculature.
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Cataract↗
Toxicity and dose-response studies of 1-alpha hydroxyvitamin D2 in LH-beta-tag transgenic mice.
PURPOSE: To determine the effectiveness of a vitamin D analog, 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)), in inhibiting retinoblastoma in a transgenic retinoblastoma model (LHbeta-Tag mouse) and to evaluate its toxicity. DESIGN: Experimental study using an animal (LHbeta-Tag transgenic mouse) randomized (controlled) trial. PARTICIPANTS AND CONTROLS: Two hundred seventeen LHbeta-Tag transgene-positive 8- to 10-week-old mice total; 179 drug-treated animals, 38 control animals. METHODS: Mice were fed a vitamin D- and calcium-restricted diet and were randomized to treatment groups receiving control (vehicle), or 0.1, 0.3, 0.5, or 1.0 micro g/day of 1alpha-OH-D(2) via oral gavage 5 times weekly for 5 weeks. Body weight was measured at the start of treatment and twice weekly during treatment. Animals were euthanized on the last day of treatment. The eyes were enucleated, processed histologically, and serially sectioned. Representative sections from the superior, middle, and inferior regions of each globe were examined microscopically and tumor areas were measured using Optimas software. Serum was collected for serum calcium levels. Kidneys were removed for histologic processing and were analyzed microscopically for kidney calcification. MAIN OUTCOME MEASURES: Mean tumor area was measured to determine drug effectiveness. Toxicity was assessed by survival, weight loss over the treatment period, serum calcium, and kidney calcification. RESULTS: The mean tumor size in each 1alpha-OH-D(2) group was smaller than controls (all P values < 0.02): control, 90,248 micro m(2); 0.1 micro g, 31,545 micro m(2); 0.3 micro g, 16,750 micro m(2); 0.5 micro g, 30,245 micro m(2); and 1.0 micro g, 16,049 micro m(2). No dose-dependent response curve was evident. The survival percentage for each group was as follows: control, 97%; 0.1 micro g, 91%; 0.3 micro g, 88%; 0.5 micro g, 70%; and 1.0 micro g, 63%. Mortality was higher in the 0.5- micro g and 1.0- micro g doses (P values < 0.01) compared with other treatment groups and with the control group. Serum calcium levels were significant in all treatment groups compared with controls (all P values < 0.0001). CONCLUSIONS: In the LHbeta-Tag mouse, 1alpha-OH-D(2) inhibits retinoblastoma with no significant increase in mortality in lower doses (0.1-0.3 micro g). 1alpha-OH-D(2) has approval by the Food and Drug Administration as an investigative drug for cancer treatment, and has shown efficacy with low toxicity in adult cancer trials. 1alpha-OH-D(2) meets the criteria for human clinical trials.
Animals↗
Toxicity and dose-response studies of 1 alpha-hydroxyvitamin D2 in LH beta-Tag transgenic mice.
PURPOSE: The study objective is to determine the effectiveness of a vitamin D analogue, 1 alpha-hydroxyvitamin D2 (1 alpha-OH-D2), in inhibiting retinoblastoma in a transgenic retinoblastoma model (LH beta-Tag mouse) and to evaluate its toxicity. Previous studies of 1 alpha-OH-D2 in athymic mice with human retinoblastoma xenografts suggested efficacy in tumor suppression and suitability for human treatment. METHODS: LH beta-Tag mice (N = 142), 8 to 10 weeks old, were randomly assigned to treatment groups receiving either control (vehicle) or 0.1, 0.3, 0.5, or 1.0 microgram/day of 1 alpha-OH-D2 via oral gavage five times a week for 5 weeks. Animals were then euthanized. The eyes were enucleated, processed histologically, and serially sectioned. Three sections of each eye were microscopically examined, and mean tumor area was measured using Optimus software. Toxicity was assessed by mortality, weight loss, serum calcium levels, and kidney calcification. RESULTS: The mean tumor size in each 1 alpha-OH-D2 group was smaller than in controls (P values < .02): control, 90,248 microns 2; 0.1 microgram, 31,545 microns 2; 0.3 microgram, 16,750 microns 2; 0.5 microgram, 30,245 microns 2; and 1.0 microgram, 16,049 microns 2. No dose-dependent response curve was evident. Mortality was higher in the groups receiving the 0.5 microgram and 1.0 microgram doses (P values < .01) than in the other treatment groups and the control group. CONCLUSION: In the LH beta-Tag mouse, 1 alpha-OH-D2 inhibits retinoblastoma with no increased mortality at lower doses (0.1 to 0.3 microgram). 1 alpha-OH-D2 has been approved by the Food and Drug Administration as an investigative drug for cancer treatment and has shown efficacy with low levels of toxicity in adult cancer trials. 1 alpha-OH-D2 meets the criteria for human clinical trials.
Animals↗
Blindness after liver transplant.
A 58-year-old woman developed a generalized seizure 12 days after undergoing liver transplantation and awakened with persistent hand motions vision binocularly. Cyclosporine levels were normal and blood pressure was only mildly elevated. The ophthalmic and neurologic examinations were otherwise normal. Brain MRI revealed bilateral parieto-occipital white matter signal abnormalities consistent with vasogenic edema. The cyclosporine was abruptly replaced with tacrolimus and the patient recovered normal vision within 48 hours. A subsequent brain MRI taken 30 days later showed that the patient had reverted to normal. This is an example of posterior leukoencephalopathy owing to cyclosporine toxicity. It points out that visual loss may be an isolated or most prominent clinical manifestation, cyclosporine and blood pressure levels may be normal, deficits are reversible if cyclosporine is promptly discontinued, and tacrolimus, a similar immunosuppressive agent, may be a safe substitute.
Blindness↗
Cohesive tensile strength of human LASIK wounds with histologic, ultrastructural, and clinical correlations.
PURPOSE: To measure the cohesive tensile strength of human LASIK corneal wounds. METHODS: Twenty-five human eye bank corneas from 13 donors that had LASIK were cut into 4-mm corneoscleral strips and dissected to expose the interface wound. Using a motorized pulling device, the force required to separate the wound was recorded. Intact and separated specimens were processed for light and electron microscopy. Five normal human eye bank corneas from 5 donors served as controls. A retrospective clinical study was done on 144 eyes that had LASIK flap-lift retreatments, providing clinical correlation. RESULTS: The mean tensile strength of the central and paracentral LASIK wounds showed minimal change in strength over time after surgery, averaging 2.4% (0.72 +/- 0.33 g/mm) of controls (30.06 +/- 2.93 g/mm). In contrast, the mean peak tensile strength of the flap wound margin gradually increased over time after surgery, reaching maximum values by 3.5 years when the average was 28.1% (8.46 +/- 4.56 g/mm) of controls. Histologic and ultrastructural correlative studies found that the plane of separation always occurred in the lamellar wound, which consisted of a hypocellular primitive stromal scar centrally and paracentrally and a hypercellular fibrotic stromal scar at the flap wound margin. The pathologic correlations demonstrated that the strongest wound margin scars had no epithelial cell ingrowth-the strongest typically being wider or more peripherally located. In contrast, the weakest wound margin scars had epithelial cell ingrowth. The clinical series demonstrated the ability to lift LASIK flaps without complications during retreatments up to 8.4 years after initial surgery, correlating well with the laboratory results. CONCLUSIONS: The human comeal stroma typically heals after LASIK in a limited and incomplete fashion; this results in a weak, central and paracentral hypocellular primitive stromal scar that averages 2.4% as strong as normal comeal stroma. Conversely, the LASIK flap wound margin heals by producing a 10-fold stronger, peripheral hypercellular fibrotic stromal scar that averages 28.1% as strong as normal comeal stromal, but displays marked variability.
Adult↗