In March 2008, National Public Radio featured a story about a “medical breakthrough.” It focused on a girl from the United States with congenital bilateral optic nerve hypoplasia who went to China to receive experimental intravenous injections of embryonic umbilical cord stem cells for a cost of more than $20 000. The physicians in China said the child's vision was improving, despite the fact that the parents themselves saw no change in her visual function. They did, however, think their daughter's pupils were dilating “to let in more light.” National Public Radio subsequently interviewed various US experts who outlined their reservations about this treatment, stating among other things, “There is no evidence this treatment works.” Subsequently there was a flurry of commentary in the mainstream media and on the Internet. I was inundated with queries from patients who learned of the story. I also received numerous e-mails from colleagues indicating they were similarly inundated and wanted to know how to respond to the inquiries.
Twenty-seven members of a family with dominantly inherited Charcot-Marie-Tooth disease (CMTD) were examined. Fifteen members had CMTD and 13 of these had varying amounts of myotonic pupillary abnormalities similar in some ways to Adie tonic pupil syndrome. Those with graver neurologic disease showed greater pupillary abnormalities. Ten of the 15 patients had pupillary constriction with methacholine chloride (Mecholyl) and some of these had extensive iris atrophy. Several affected patients received symptomatic relief from 0.025% pilocarpine. Seven other patients with CMTD who were not related to our initial family were checked for myotonic pupils; two had findings similar to our initial family. Pupillary abnormalities in certain patients with CMTD appear secondary to a parasympathetic denervation of the iris sphincter and ciliary muscle, as shown by a positive methacholine test, and probably represent part of the autonomic nervous system dysfunction associated with the polyneuropathy in CMTD.
Ketotifen fumarate blocks histamine1 (H1) receptors, stabilizes mast cells, and acts as an eosinophil inhibitor (decreases chemotaxis and activation of eosinophils).
To assess the efficacy of ketotifen 0.025% ophthalmic solution in the prevention of symptoms of allergic conjunctivitis, using the conjunctival allergen challenge model.
This was a single-center, double-masked, randomized, placebo-controlled, contralateral-eye comparison, allergen challenge trial conducted in the United States. Subjects were randomized to receive ketotifen 0.025% in one eye and placebo in the other. At visits 1 and 2, allergen challenges were performed to determine the allergen concentration eliciting a qualifying reaction for each subject. At the 3 subsequent visits, subjects received 1 drop of ketotifen 0.025% ophthalmic solution in one eye and vehicle solution as placebo in the other eye 15 minutes (visit 3), 6 hours (visit 4), and 8 hours (visit 5) before allergen challenge. The primary efficacy measure was the subject's rating of itching at 3, 7, and 10 minutes after challenge.
Of the 89 subjects randomly assigned to masked trial medication at visit 3, 72 completed the study. At visits 3, 4, and 5, mean itching scores were significantly better for ketotifen-treated eyes at all postchallenge time points, compared with placebo (P<.001). Also at visits 3, 4, and 5, ketotifen was statistically superior to placebo in reducing ocular hyperemia at all postchallenge time points (P<.05).
Ketotifen was safe and statistically effective in reducing ocular itching and hyperemia associated with allergic conjunctivitis. Ketotifen's rapid onset of action (within 15 minutes) and extended duration of action (at least 8 hours) make it a valuable treatment for allergic conjunctivitis.
To compare the effects of topical 0.5% ketorolac tromethamine ophthalmic solution (Acular, Allergen Pharmaceuticals, Irvine, Calif) with topical 0.03% flurbiprofen sodium ophthalmic solution (Ocufen, Allergen Pharmaceuticals) on the inhibition of surgically induced miosis during phacoemulsification cataract surgery.
One hundred eighteen patients were prospectively randomized to receive 0.5% topical ketorolac or 0.03% topical flurbiprofen at 3 preoperative intervals. The flurbiprofen-treated group served as the control group. The surgeon was masked as to patient selection. Horizontal pupillary diameter measurements were obtained at the start of surgery, just before phacoemulsification, before lens implantation, and after lens implantation.
Mean horizontal pupillary diameter measurements for both medications were similar at the start of surgery. However, a consistent trend of larger pupillary diameter was seen in all subsequent surgical intervals in the ketorolac-treated group. Changes from baseline measurements also indicated a more significant inhibition of miosis at all subsequent intervals, and a more stable mydriasis throughout the procedure in the ketorolac-treated group.
Topical ketorolac is an effective inhibitor of miosis during phacoemulsification cataract surgery, and provides a more stable mydriatic effect throughout the surgical procedure.
The use of 0.25 and 0.125% echothiophate iodide (Phospholine Iodide) in the management of open-angle glaucoma has been widely accepted. Its use has been confined to those patients in whom the more conventional medical therapy has failed. Initial local side effects, sometimes quite severe, have been an unpleasant feature with this drug, but in many patients these settle after a week or two. Echothiophate iodide 0.06% has recently been introduced in an endeavor to cut down on the unpleasant side effects. Reports of the efficacy of this medication have appeared,1-3 and the suggestion was made that even this low concentration of echothiophate iodide is more effective in maintaining the intraocular pressures on a diurnal basis (round the clock) than the more frequent instillation of pilocarpine.1
The present study was concerned with a comparison of the diurnal pressure control and side effects in open-angle glaucoma between 4% pilocarpine administered
Anterior chamber fluorophotometry was performed after the oral administration of fluorescein sodium in patients undergoing extracapsular cataract extraction and posterior chamber intraocular lens insertion before and after surgery. The administration of 0.5% ketorolac tromethamine solution (ketorolac solution) eye drops before and after surgery decreased the breakdown of the blood-aqueous barrier as compared with 0.1% dexamethasone sodium phosphate solution (dexamethasone solution) eye drops at each period, as measured by fluorophotometry. A single injection below Tenon's capsule of a short-acting corticosteroid had been given to each patient at the end of each surgical procedure. Slit-lamp observations of postoperative ocular inflammation were not different between treatment groups. Both ketorolac and dexamethasone solutions were well tolerated by patients. Ketorolac solution was more effective than dexamethasone solution in facilitating reestablishment of the blood-aqueous barrier after surgery, as measured by fluorophotometry, and was equal to dexamethasone solution as observed by slit-lamp observations. This study suggests that ketorolac ophthalmic solution may be effective and safe as a nonsteroidal anti-inflammatory agent for topical use after cataract surgery and intraocular lens implantation in place of topically administered corticosteroids.
To evaluate the efficacy of 0.2% cidofovir eyedrops and 1% cyclosporine eyedrops administered 4 times daily (qid) to treat acute adenoviral keratoconjunctivitis.
A randomized, controlled, double-masked study was conducted on 39 patients with acute adenoviral keratoconjunctivitis of recent onset. Patients were divided into 4 treatment groups: (1) cidofovir qid, (2) cyclosporine qid, (3) cidofovir + cyclosporine qid, and (4) sodium chloride qid (control). The diagnosis was confirmed using adenoviral polymerase chain reaction from conjunctival swabs. Duration of treatment was 21 days.
Severity of conjunctival hyperemia, conjunctival chemosis, superficial punctate keratitis during treatment, and presence and severity of corneal subepithelial infiltrates were evaluated using a clinical score. Duration until subjective improvement of symptoms was recorded.
Subjective improvement of local symptoms was accelerated in the cyclosporine group. All other clinically relevant variables showed no statistically significant difference among the 4 treatment groups. Particularly, we did not find a difference in the frequency of corneal subepithelial infiltrates at the end of treatment.
Use of cidofovir, cyclosporine, or both did not accelerate the improvement of clinical symptoms of acute adenoviral keratoconjunctivitis compared with the natural course of the infection as demonstrated by this pilot study. This might be because of the wide spectrum of the clinical course of the infection, low sensitivity to cidofovir, too low of a concentration of cidofovir, or early cessation of viral replication in the course of the infection. The effect of a higher concentration of topical cidofovir with and without cyclosporine requires investigation in a larger group of patients.
To compare the cardiovascular, pulmonary, and ocular hypotensive effects of 0.2% brimonidine tartrate with those of 0.5% timolol maleate, 0.25% betaxolol suspension, and brimonidine vehicle.
A single-center, double-masked, randomized, crossover study of 24 young, healthy men.
Baseline heart rate, blood pressure, respiratory rate, and intraocular pressure were recorded at hour 0. At hour 2, heart rate, blood pressure, respiratory rate, and forced expiratory volume in 1 second were measured and a 15-minute treadmill test performed. Hour 0 measurements were repeated at hour 4. On four subsequent visits, we instilled one drop of a study medication into each eye after the baseline measurements at hour 0.
Timolol reduced resting (-5.3 to -6.5 beats/min, P < or = .004) and exercise-induced heart rate (-4.3 to -13.6 beats/min; P < or = .022) compared with brimonidine, betaxolol suspension, and brimonidine vehicle. At hour 4, brimonidine reduced resting systolic blood pressure compared with all other study medications (-5.2 to -7.3 mm Hg; P < or = .024). Timolol reduced systolic blood pressure during exercise and brimonidine reduced systolic blood pressure during recovery more than betaxolol suspension and brimonidine vehicle (-5.1 to -7.7 mm Hg; P < or = .033; and -5.4 to -6.0 mm Hg; P < or = .002, respectively). Mean respiratory rate and forced expiratory volume in 1 second were not significantly altered by any study medication. At hour 4, brimonidine lowered intraocular pressure as well as timolol and better than betaxolol suspension (-1.9 mm Hg; P < .001) or brimonidine vehicle (-1.8 mm Hg; P < .001).
The cardiopulmonary effects of 0.2% brimonidine were limited to a slight reduction in systolic blood pressure during recovery from exercise and at 4 hours after instillation. The ocular hypotensive effect of brimonidine was comparable to that of timolol and greater than that of betaxolol suspension in this patient population.
We read with great interest the article by Sherwood and colleagues1 describing the 12-month trial of twice-daily fixed-combination 0.2% brimonidine–0.5% timolol vs monotherapy with the individual components. The authors observed that the rate of allergic conjunctivitis in patients who received the combination product (5.2%) was significantly lower than that seen in patients who received brimonidine alone (9.4%). The authors acknowledge that a partial explanation for the improved tolerability may be related to the fact that the combination product is dosed twice daily while brimonidine was dosed 3 times daily. We would like to postulate that the lower rate of ocular allergy observed in their study may be a direct result of the addition of timolol to brimonidine based on a concept originally described by us a decade ago.2
Following instillation of four drops of a solution of 0.2% cyclopentolate hydrochloride, 1% phenylephrine hydrochloride, with 3% polyvinylpyrrolidone in buffered isotonic base with 0.5% chlorbutanol as a preservative (cyclomydril), an 82-year-old man showed a decompensation of a previously compensated chronic dementia. It is postulated that he became delirious as reported in other cases following administration of 1% or 2% cyclopentolate. Further, his failure to recover the status quo ante was felt to represent a more general phenomenon; namely, the inability to regain coping mechanisms established at a time when the mental apparatus was capable of a higher order of function.
To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of a fixed combination of 0.2% brimonidine tartrate and 0.5% timolol maleate (fixed brimonidine-timolol) compared with the component medications.
In 2 identical, 12-month, randomized, double-masked multicenter trials, patients with ocular hypertension or glaucoma were treated with fixed brimonidine-timolol twice daily (n = 385), 0.2% brimonidine tartrate 3 times daily (n = 382), or 0.5% timolol maleate twice daily (n = 392).
Mean change from baseline IOP and incidence of adverse events.
The mean decrease from baseline IOP during 12-month follow-up was 4.4 to 7.6 mm Hg with fixed brimonidine-timolol, 2.7 to 5.5 mm Hg with brimonidine, and 3.9 to 6.2 mm Hg with timolol. Mean IOP reductions were significantly greater with fixed brimonidine-timolol compared with timolol at all measurements (P< or =.002) and brimonidine at 8 am, 10 am, and 3 pm (P<.001) but not at 5 pm. The incidence of treatment-related adverse events in the fixed-combination group was lower than that in the brimonidine group (P = .006) but higher than that in the timolol group (P<.001). The rate of discontinuation for adverse events was 14.3% with the fixed combination, 30.6% with brimonidine, and 5.1% with timolol.
Twice-daily fixed brimonidine-timolol therapy provides sustained IOP lowering superior to monotherapy with either thrice-daily brimonidine or twice-daily timolol and is better tolerated than brimonidine but less well tolerated than timolol.
Fixed brimonidine-timolol is an effective and convenient IOP-lowering therapy.
To compare long-term intraocular pressure (IOP)-lowering efficacy of 0.25% and 0.5% apraclonidine hydrochloride with 0.5% timolol maleate.
Multicenter, randomized, double-masked trial. Adult patients of either sex diagnosed as having open-angle glaucoma or ocular hypertension were enrolled following appropriate washout from all ocular hypotensive medications. Morning IOPs of 22 to 35 mm Hg were required for entry. Patients received 0.25% or 0.5% apraclonidine 3 times a day or 0.5% timolol twice a day for 90 days. Intraocular pressure was measured at 8 AM (before morning dosing) and at 4 PM (8 hours after dosing) on days 1, 30, and 90, and only at 8 AM on day 14.
All 3 medications significantly reduced IOP from baseline at all observation times (P < .001): 0.5% apraclonidine reduced IOP more than 0.25% apraclonidine; no significant difference was observed between 0.5% apraclonidine and 0.5% timolol 8 hours after dosing on days 1, 30, and 90; and a significant difference (P < .05) in favour of 0.5% timolol over 0.25% apraclonidine was observed 8 hours after dosing on day 30. At all morning visits following evening dosing, 0.5% timolol significantly reduced IOP more than both concentrations of apraclonidine.
Both 0.25% and 0.5% apraclonidine significantly reduce IOP when used as primary ocular hypotensive medication. Although 0.25% and 0.5% apraclonidine reduce IOP to a similar degree as 0.5% timolol 8 hours after morning dosing, neither concentration is as effective for reducing morning IOP after evening dosing.
In a one-year, double-masked, randomized study, the ocular hypotensive efficacy of twice-daily treatment with 0.25% levobunolol hydrochloride or timolol maleate was evaluated in 78 patients with glaucoma or ocular hypertension (phase 1). If intraocular pressure (IOP) was not well controlled during the study, the concentration of medication was increased to 0.5%, and the patient was followed up for an additional three months (phase 2). During phase 1, the mean IOP was reduced by 4.6 mm Hg in the timolol treatment group and by 5.1 mm Hg in the levobunolol treatment group. Seventy-one percent (29/41) of the patients in the timolol treatment group and 70% (26/37) of the patients in the levobunolol treatment group successfully completed phase 1. Of those patients who required the higher concentration of medication, 89% (8/11) in the timolol treatment group and 75% (3/4) in the levobunolol treatment group successfully completed phase 2. Higher concentration, however, did not produce greater IOP reduction. No statistically or clinically significant differences between the groups were noted in any of the efficacy or safety variables evaluated.
To determine the efficacy and safety of topical 0.3% ciprofloxacin hydrochloride ophthalmic ointment in the treatment of bacterial keratitis.
Prospective case series with a nonrandomized comparison of culture-positive, evaluable cases (ciprofloxacin ointment group) with culture-positive, concurrent patients (nonenrolled group) treated with conventional therapy.
Multicenter clinical study.
After informed consent was obtained, 253 eligible patients underwent corneal scrapings and received topical ciprofloxacin ointment; 145 (57%) had positive cultures and completed the follow-up schedule. Forty (70%) of 57 apparently eligible patients had culture-positive bacterial keratitis but were not enrolled in the ciprofloxacin ointment study during the same period.
Ciprofloxacin ophthalmic ointment instilled every 1 to 2 hours for 2 days, then every 4 hours for 12 days.
Clinical evaluation of signs at 1, 3, 7, and 14 days of treatment and the overall condition classified as clinical success (cured or improved) or failure (unchanged or worse) during and after therapy.
Clinical success with the initial treatment occurred in 135 patients (93%) in the ciprofloxacin ointment group and in 28 patients (70%) in the nonenrolled group. Of the 10 ciprofloxacin clinical failures, seven were staphylococcal; two, pneumococcal; and one, polybacterial. The 90% minimum inhibitory concentration of ciprofloxacin was 3 mg/L or less for corneal bacterial isolates. No serious adverse event attributable to ciprofloxacin ointment occurred, although 32 (13%) of 253 patients developed a transient white crystalline corneal precipitate shown with liquid chromatography in two cases to be ciprofloxacin.
Ciprofloxacin ophthalmic ointment is an effective and safe topical antimicrobial agent for the treatment of bacterial keratitis caused by susceptible microorganisms.
I read with enthusiasm the excellent case series on pediatric Horner syndrome reported by Bacal and Levy.1 Young children with anisocoria are always a management dilemma because most cases are benign in nature but rarely a diagnosis such as neuroblastoma is made. Once the word is uttered, many parents are terrified and want some type of imaging study performed. Unfortunately a magnetic resonance imaging study from nearly head to toe is required to search for all possible locations of a neuroblastoma mass, and this procedure may have significant morbidity in young children and infants. A simple office test to confirm that the anisocoria is not due to Horner syndrome is therefore a very helpful tool for parental reassurance. Conversely, confirmation that the diagnosis definitely is Horner syndrome can stiffen the ophthalmologist’s spine regarding the necessity for urine testing and radiologic studies. This report therefore has great clinical value.
Preoperative and serial postoperative anterior chamber fluorophotometry were performed after oral administration of fluorescein sodium in patients undergoing extracapsular cataract extraction and posterior chamber intraocular lens insertion. The administration of topical 0.5% ketorolac tromethamine solution before and after surgery markedly decreased the breakdown of the blood-aqueous barrier compared with vehicle-placebo solution administration at each time period, as measured by fluorophotometry. Corticosteroids were not given to any patients throughout the duration of the study. These fluorophotometric results correlated well with slit-lamp observations of postoperative ocular inflammation. Both ketorolac and vehicle were well tolerated by patients. No effects on intraocular pressure were seen with ketorolac administration. This study suggests that ketorolac ophthalmic solution is effective and safe as a nonsteroidal anti-inflammatory agent for topical use following cataract surgery and intraocular lens implantation.
To investigate the penetration of 0.5% moxifloxacin hydrochloride into the aqueous and vitreous after topical administration in humans.
A prospective, nonrandomized study of 20 patients scheduled for vitrectomy surgery between September 1 and December 31, 2003. Aqueous and vitreous samples were obtained and analyzed after topical administration of 0.5% moxifloxacin hydrochloride, every 2 hours (q2h) or every 6 hours (q6h), for 3 days before surgery. Assays were performed using high-performance liquid chromatography.
Mean +/- SD moxifloxacin concentrations in the q2h group for the aqueous (n = 9) and vitreous (n = 10) were 2.28 +/- 1.23 and 0.11 +/- 0.05 microg/mL, respectively. Mean +/- SD moxifloxacin concentrations in the q6h group for the aqueous (n = 10) and vitreous (n = 9) were 0.88 +/- 0.88 and 0.06 +/- 0.06 microg/mL, respectively. The minimum inhibitory concentration for 90% of isolates (MIC(90)) was far exceeded in the aqueous for a wide spectrum of key pathogens, whereas it was not exceeded in the vitreous for several organisms. However, the minimum inhibitory concentration for 50% of the isolates was exceeded in the q2h vitreous group for Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Bacillus cereus, and other gram-negative pathogens.
The Endophthalmitis Vitrectomy Study revealed that 94.2% of isolates from postoperative endophthalmitis are gram-positive pathogens. Moxifloxacin has a spectrum of coverage that appropriately encompasses the most common organisms in endophthalmitis. The pharmacokinetic findings of this investigation show that relatively high aqueous levels can be achieved after topical administration. Further studies will help define the precise role of 0.5% moxifloxacin ophthalmic solution in the treatment of or prophylaxis against intraocular infections.
In replyI would like to thank Dr Brown for her comments regarding the case series we published dealing with pediatric Horner syndrome and the use of apraclonidine. Her reasoning behind the need for a simple office test to evaluate anisocoria in children was exactly correct.We are aware of the article that Dr Brown published last year regarding the use of 0.5% apraclonidine instead of the 1% formulation.1 We did not comment on her article in our study because it was published after ours had already been submitted for publication. Certainly 0.5% apraclonidine would be a more attractive agent than the 1% formulation as a diagnostic tool (if equally efficacious) because it is more readily available and would have less potential side effects. Hopefully, future studies enrolling larger groups of patients will determine the sensitivity and specificity of these agents in the diagnosis of Horner syndrome.
Clinically the anisocoria reversal, even when slight, was easily detected with the naked eye. Testing for Horner syndrome using 0.5% apraclonidine does not depend on highly accurate measurements of the pupil diameter and is unlikely to be confounded by physiologic variation in pupil size or mild differences in room illumination before and after apraclonidine administration. Topical cocaine hydrochloride and hydroxyamphetamine hydrobromide are increasingly difficult and costly to obtain and are rarely used for any purpose by ophthalmologists other than to diagnose Horner syndrome. Within our admittedly small cohort, we have demonstrated that 0.5% apraclonidine, which is readily available in a multidose preserved bottle, is an acceptably sensitive test for the detection of this infrequent condition. Even though the mechanism of action is different, we propose that 0.5% apraclonidine may be substituted for cocaine in the pharmacologic confirmation of Horner syndrome. For localization of the sympathetic lesion, hydroxyamphetamine is still required. If apraclonidine does not cause anisocoria reversal and there is an important therapeutic need to pharmacologically confirm the diagnosis, further assessment with the classic agents should be conducted.
A double-masked, randomized, placebo-controlled, rising-dose, single-dose study was undertaken to assess the effect of low concentrations of timolol maleate ophthalmic solution (0.008%, 0.025%, 0.08%, and 0.25%) on intraocular pressure and its diurnal variation in healthy, normal volunteers. A single dose of 0.008% timolol exhibits a definite but minimal-effect on intraocular pressure in this normal volunteer model, causing a significant peak mean decrease in intraocular pressure from its value immediately predose. This decrease was 1.8 mm Hg (a peak mean percent decrease of 12.8%) at 2 hours postdose compared with an increase of 0.1 mm Hg (+2.5%) during a pre-study curve due to normal diurnal variation. One drop of 0.008% solution represents a single dose of approximately 2.5 micrograms of timolol. A slight contralateral ocular hypotensive effect appears to be present for 0.25% timolol at 2 hours postdose although it just failed to reach statistical significance.
We report the development of pseudophakic bullous keratopathy in 18 eyes following implantation of Pharmacia Intermedics Ophthalmics model 024 (Hessburg) anterior chamber intraocular lenses. Eight of these intraocular lenses were implanted during uncomplicated intracapsular cataract extractions. Mean onset of corneal edema was 21.4 months after lens implantation. Patients with this type of lens already implanted in their eyes require close follow-up for complications.
An unselected series of 1,000 cases of paralysis of cranial nerves III, IV, and VI was retrospectively analyzed regarding ultimate recovery and final causal diagnosis. The frequency of involvement of the third, fourth, and sixth cranial nerves was relatively unchanged from earlier similar reports. The number of patients (263) whose cranial nerve paralysis was initially of undetermined cause was surprisingly high despite the availability of computerized tomographic scanning. Subsequently, the cause for the paralysis was diagnosed in only ten of the 127 patients who could be traced. About half (51%) of the patients with no known cause for paralysis underwent spontaneous remission. Forty-eight percent of all patients recovered. Cranial nerve impairment due to vascular disease (diabetes mellitus, atherosclerosis, or hypertension) was temporary in 71% of the patients, regardless of the cranial nerve affected. Patients with palsies caused by aneurysm, trauma, and neoplasm was predictably less likely to recover.
We present evidence that calcitriol (1,25-dihydroxycholecalciferol) decreases tumor takes and tumor growth of subcutaneous retinoblastomas in athymic mice. Histopathologic studies showed that the calcitriol also induced necrosis of the retinoblastomas. The calcitriol, however, did not induce tumor calcification. Unfortunately, the dose of calcitriol used in this experiment caused significant toxic effects. If the toxicity of vitamin D can be alleviated without compromising its antineoplastic effect, vitamin D may be a useful chemotherapeutic agent against retinoblastoma.
To evaluate the in vivo efficacy and toxicity of the 1,25-dihydroxy-16-ene-23-yne-vitamin D3 (16,23-D3) analogue in athymic nude mice injected with Y-79 human retinoblastoma cells and to compare the efficacy and toxicity of this compound with those of 1,25-dihydroxycholecalciferol (D3, calcitriol).
Thirty athymic nude mice (4-6 weeks old) were injected subcutaneously with 1 x 10(7) Y-79 human retinoblastoma cells suspended in a 1:1 mixture of Iscove culture medium supplemented with 20% fetal bovine serum and basement membrane matrix suspension. Five days after tumor injection, the mice were randomized to 3 groups of 10 mice each. The first group served as a control group and received intraperitoneal injections of 0.25 mL of mineral oil (vehicle) 5 times a week. The second group received intraperitoneal injections of 0.05 microg of calcitriol in 0.25 mL of mineral oil intraperitoneally 5 times a week. The third group received intraperitoneal injections of 0.5 microg of 16,23-D3 in 0.25 mL of mineral oil 5 times a week. Injections were continued for 5 weeks, during which tumor size and mouse weight were individually measured. Toxicity was assessed by clinical measures such as lethargy, weight loss, and death. The mice were then killed and the size, volume, and weight of each tumor were determined. Also, in representative animals in each group, kidneys were evaluated for calcification and serum calcium concentration was measured.
All experimental and control animals developed tumors subcutaneously. The 16,23-D3-treated mice had significantly smaller average tumor size (1.55 cm3) than the control mice (3.45 cm3) (P = .02), less gain in average body weight from the beginning of treatment (2.4 g vs 5.5 g) (P= .06), and a 40% mortality. The calcitriol-treated mice did not have significantly smaller average tumor size (1.26 cm3) than the 16,23-D3-treated mice (P = .35), had significant body weight loss compared with the control animals (calcitriol-treated mice lost 4.03 g) (P =.001), and had a mortality of 90% by the completion of the experiment. Histologically, there was no difference in the degree of tumor necrosis and calcification between control and experimental mice. Serum calcium concentrations were equivalent between the control (2.15 mmol/L [8.6 mg/dL]) and experimental groups (calcitriol, 1.88 mmol/L [7.5 mg/dL] [P = .97]; 16,23-D3, 2.15 mmol/L [8.6 mg/dL] [P = .42]). Mild bilateral renal tubular calcification occurred in 3 of 4 mice in the calcitriol-treated group and in 2 of 4 mice in the 16,23-D3-treated group.
The growth of subcutaneous Y-79 human retinoblastoma cells in athymic nude mice is significantly reduced by treatment with intraperitoneal injections of 16,23-D3. The antineoplastic effect of calcitriol is not statistically significantly different but is associated with significantly more toxicity. 1,25-Dihydroxy-16-ene-23-yne-vitamin D3 may be a useful chemotherapeutic adjunct in the treatment of retinoblastoma.
To evaluate the in vivo efficacy and clinical toxic effects of the 1,25-dihydroxy-16-ene-23-yne-vitamin D3 analogue in beta-luteinizing hormone-Tag (LH beta-Tag) transgenic mice with heritable retinoblastoma.
Forty-two mice (8-10 weeks old), randomly assigned to experimental (n = 21) or control (n = 21) groups, received intraperitoneal injections of 0.05 microgram of 1,25-dihydroxy-16-ene-23-yne-D3 in 0.5-mL mineral oil vehicle (experimental group) or 0.5 mL of mineral oil vehicle (control group) for 5 weeks. One experimental and 3 control animals died of injection-related trauma. Eyes were enucleated 1 week after treatment and were examined histologically in a masked fashion.
All experimental and control animals showed evidence of tumor. The tumors in the experimental mice showed a significantly smaller cross-sectional area (0.88 +/- 0.08 mm2) compared with that in the control mice (1.12 +/- 0.12 mm2) (P = .02). All mice completed the treatment and showed no clinical evidence of toxic effects.
Tumors in transgenic mice with retinoblastoma treated with 1,25(OH)2-16-ene-23-yne-D3 showed a 21% smaller cross-sectional area compared with that in the control mice, without producing clinically apparent toxic effects. This compound may be useful as adjunctive therapy in the treatment of retinoblastoma.
To compare the intraocular pressure (IOP) elevating potential of 1.0% rimexolone and 0.1% fluorometholone alcohol ophthalmic suspensions in patients known to have responded to corticosteroids.
In a double-masked, randomized, single-eye, crossover protocol, corticosteroid responsiveness initially was verified in 40 asymptomatic known steroid responders by challenge with either 0.1% dexamethasone sodium phosphate or 1.0% prednisolone acetate for up to 6 weeks. After a 1-month medication washout, subjects randomly received either rimexolone or fluorometholone for 6 weeks. Medications were again discontinued for 1 month, and subjects then received the alternate drug for 6 weeks.
There was no significant difference between rimexolone and fluorometholone in the number of subjects demonstrating a 10-mm Hg increase in IOP or in the mean number of weeks required to achieve a 10-mm Hg response. Responses occurred in significantly more subjects receiving dexamethasone sodium phosphate (P = .001) or prednisolone acetate (P < .001) and in a significantly shorter interval than in subjects receiving rimexolone.
Rimexolone has a low IOP-elevating potential, comparable to that of fluorometholone and less than that of dexamethasone sodium phosphate and prednisolone acetate.
To determine the prevalence of diabetic retinopathy among adults 40 years and older in the United States.
Pooled analysis of data from 8 population-based eye surveys was used to estimate the prevalence, among persons with diabetes mellitus (DM), of retinopathy and of vision-threatening retinopathy-defined as proliferative or severe nonproliferative retinopathy and/or macular edema. Within strata of age, race/ethnicity, and gender, US prevalence rates were estimated by multiplying these values by the prevalence of DM reported in the 1999 National Health Interview Survey and the 2000 US Census population.
Among an estimated 10.2 million US adults 40 years and older known to have DM, the estimated crude prevalence rates for retinopathy and vision-threatening retinopathy were 40.3% and 8.2%, respectively. The estimated US general population prevalence rates for retinopathy and vision-threatening retinopathy were 3.4% (4.1 million persons) and 0.75% (899 000 persons). Future projections suggest that diabetic retinopathy will increase as a public health problem, both with aging of the US population and increasing age-specific prevalence of DM over time.
Approximately 4.1 million US adults 40 years and older have diabetic retinopathy; 1 of every 12 persons with DM in this age group has advanced, vision-threatening retinopathy.
To compare anatomic and visual acuity outcomes, as well as complication rates, after retinal detachment repair using 1000- vs 5000-centistoke silicone oil.
Records of all patients who underwent retinal detachment repair with silicone oil at one institution between January 1, 1995, and December 31, 2000, were reviewed. Anatomic outcomes included retinal redetachment and macula-off retinal redetachment. Visual acuity outcomes included ambulatory vision (> or =5/200) and change in visual acuity from preoperative examination. Complications included rates of secondary intraocular pressure elevation, hypotony, corneal opacification, cataract, and oil emulsification. Outcomes were assessed at 1 week, 1 month, 3 months, 6 months, and 1 year.
The study included 82 eyes that underwent retinal detachment repair with 1000-centistoke silicone oil and 243 eyes that underwent retinal detachment repair with 5000-centistoke silicone oil. Demographic characteristics, cause of retinal detachment, and preoperative ocular characteristics were similar in the 2 groups. There was no significant difference in the rate of retinal redetachment at each of the follow-up intervals investigated. The cumulative retinal detachment rate was also similar between the 2 groups except among trauma cases, for which 1000-centistoke silicone oil was associated with a higher cumulative redetachment rate (P<.001). There was no significant difference between the groups with respect to (1) change in visual acuity from preoperatively to 6 months postoperatively and (2) the proportion of patients who achieved ambulatory vision at each of the follow-up intervals investigated. Rates of elevated intraocular pressure, hypotony, corneal abnormality, cataract, and silicone oil emulsification were similar in the 2 groups.
Anatomic and visual acuity outcomes, as well as complication rates, were similar in both groups; retinal reattachment and ambulatory vision were achieved in most eyes regardless of oil viscosity.
We screened 32 ophthalmology journals that had published articles during the period from 1850 through 1949 to identify top-cited articles in the field of ophthalmology (hereafter referred to as citation classics) using the online database Science Citation Index Expanded (Thompson Reuters, Chicago, Illinois). The 101 most frequently cited articles were published in 16 journals. Archives of Ophthalmology had the most top-cited articles (n = 31), followed by American Journal of Ophthalmology (n = 24) and Albrecht von Graefe's Archiv für Ophthalmologie (n = 9). These articles originated from 14 countries, with the United States publishing the majority (n = 58). Most of the citation classics are clinical studies on topics such as rubella cataract, retinopathy of prematurity, keratoconjunctivitis sicca, sympathetic ophthalmia, and the first report of eponymous diseases (eg, Leber hereditary optic neuropathy, Duane retraction syndrome, and Stargardt disease). A considerable number of these articles were ignored initially and for several decades after publication, but, like the classic fairy tale Sleeping Beauty, they have been rediscovered. Our study provides a historical perspective on the classic papers in the literature that are still influential in ophthalmology.
To describe clinical experience with palladium 103 ((103)Pd) ophthalmic plaque radiotherapy for choroidal hemangioma.
One course of (103)Pd ophthalmic plaque radiotherapy was used in each of 5 patients with circumscribed choroidal hemangioma who had progressive loss of vision due to subretinal exudation. A mean apex dose of 2900 cGy (2900 rad) was delivered. Functional tests of outcome included best-corrected visual acuity. Anatomic results included changes in tumor height and subretinal fluid documented by ophthalmoscopy, fluorescein angiography, and ultrasonography.
All patients had complete resolution of subretinal fluid with reattachment of the retina. All tumors decreased in height (mean, 50%) after treatment. Three patients (60%) demonstrated improvement in visual acuity at the last follow-up, and in 1 patient vision remained stable with resolution of metamorphopsia. Twenty-four months after treatment, 1 patient whose visual acuity had recovered from 20/160 to 20/32 had a loss of vision to 20/160 because of radiation maculopathy. For all patients, a mean visual acuity improvement of 2 lines was documented (95% confidence interval, 0.23-0.88). Mean follow-up was 18.6 months (range, 6-29 months).
A single (103)Pd plaque radiation treatment was effective in decreasing tumor height, eliminating subretinal fluid, and improving visual acuity in patients with symptomatic circumscribed choroidal hemangiomas.
We compared the ocular radiation distribution of palladium 103 (103Pd) vs iodine 125 (125I) ophthalmic plaques sewn to 12 human donor eyes. We then performed preoperative comparative simulations on the first seven patients to be treated with palladium 103 plaque therapy for choroidal melanoma. The in vitro experiment involved palladium 103 seeds placed into a Silastic seed holder, which was affixed into standard 14-mm gold eye plaques. Then the plaques were sewn onto 12 human donor eyes so as to approximate either the nasal (six eyes) or temporal (six eyes) equator. Three sets of two thermoluminescent dosimeters were used to quantify the amount of radiation delivered by the episcleral plaques. Thermoluminescent dosimeters were sewn to the sclera in three locations: on the center of the cornea, on the sclera beneath the macula, and at the equator in a position opposite the plaque. This experiment was then repeated with iodine 125 seeds and thermoluminescent dosimeters. After the plaques were adjusted to equalize their activity (plaque strength), the palladium 103 plaques were found to deliver less radiation to the three target points. Comparative clinical dosimetry also reflected this difference. Preoperative simulations comparing equal doses to the tumors' apex revealed that the palladium 103 ophthalmic plaques delivered more radiation to the tumor and less radiation to most normal ocular structures.
To describe the clinical features of vasoproliferative tumors of the ocular fundus and to propose a comprehensive classification of these tumors.
A retrospective review of all cases that were diagnosed as acquired retinal hemangioma or vasoproliferative retinal tumor was conducted on the Ocular Oncology Service at Wills Eye Hospital, Philadelphia, Pa.
There were 129 vasoproliferative tumors in 113 eyes of 103 patients. The tumors were classified as idiopathic in 84 eyes (74%) and secondary to preexisting ocular disease in 29 (26%). Subclassification into solitary (88 eyes), multiple (17 eyes), and diffuse (eight eyes) involvement was made. Of the 84 eyes with idiopathic tumors, 73 (87%) had solitary tumors, five (6%) had multiple tumors, and six (7%) had diffuse tumors. The lesion was located in the inferior, inferotemporal, or temporal region of the fundus in 78% and developed within 6 mm of the ora serrata retinae in 88%. Associated vitreoretinal findings included intraretinal exudation (82%), secondary exudative retinal detachment (48%), vitreous cells (46%), vitreous hemorrhage (21%), preretinal macular fibrosis (31%), and macular edema (18%). Of the 29 eyes with secondary tumors, the tumor was solitary in 15 (52%), multiple in 12 (41%), and diffuse in two (7%). The most common preexisting ocular disease included intermediate uveitis (pars planitis) in eight eyes (28%), retinitis pigmentosa in six (21%), toxoplasmic retinitis in two (7%), toxocariasis in two (7%), retinochoroidal coloboma in two (7%), and traumatic chorioretinopathy in two (7%). Retinal pigment epithelial hyperplasia was a prominent feature that was adjacent to 58% of the secondary tumors. Overall, management of the 129 tumors consisted of observation in 63 (49%), cryotherapy in 54 (42%), laser photocoagulation in seven (5%), plaque radiotherapy in three (2%), and other modes of treatment in two (2%).
Vasoproliferative retinal tumors can be idiopathic, or they can develop secondary to congenital, inflammatory, vascular, traumatic, dystrophic, and degenerative ocular diseases. They can produce a variety of complications. Awareness and recognition of these tumors and differentiation from other retinal vascular tumors are important.
The ability to understand verbal and written materials is central to modern life. Yet, the US Department of Education estimated that 47% of all adult Americans in 1993 had poor reading and comprehension skills. Analyses of the readability of patient education materials, discharge instructions, and consent forms throughout many specialties within medicine have found almost uniformly that these materials are written at too complex a level for many or most patients. For example, a study of the patient ophthalmic education materials of the American Academy of Ophthalmology by Ebrahimzadeh et al found large amounts of the material exceeded the reading abilities of much of the American adult population. Yet, this is only one small part of understanding the effects of literacy and reading abilities on our patient's health and their use of our increasingly complex health care system.
To report the management of retinal angiomatous proliferation (RAP), a recently described intraretinal neovascular lesion occurring in age-related macular degeneration.
This was a retrospective review of consecutive patients with age-related macular degeneration who underwent treatment of RAP from January 1, 2000, through January 31, 2003. Inclusion criteria were age 55 years or older, signs of age-related macular degeneration, and diagnosis of RAP based on dynamic indocyanine green angiography. Baseline angiograms were reviewed and RAP was classified into the following 3 stages: stage 1, intraretinal neovascularization, early stage; stage 2, subretinal neovascularization, middle stage; and stage 3, choroidal neovascularization, late stage. Treatment and concomitant treatment results were assessed separately for each RAP stage. The clinical data were statistically analyzed (chi2 test and analysis of variance) for 2 main outcome measures--complete obliteration of the lesion and final visual acuity.
Eighty-one patients (99 eyes) with 104 RAPs were identified. Forty-two lesions were at stage 1, 42 at stage 2, and 20 at stage 3. The following 5 treatments were performed: direct laser photocoagulation of the vascular lesion, laser photocoagulation of the feeder retinal arteriole, scatter "gridlike" laser photocoagulation, photodynamic therapy, and transpupillary thermotherapy. Complete obliteration of RAP was achieved in about 24 (57.1%) of the stage 1 lesions (direct laser photocoagulation of the vascular lesion, 73% success rate; photodynamic therapy, 45%), 11 (26.2%) of the stage 2 lesions (scatter gridlike laser photocoagulation, 38% success rate; direct laser photocoagulation of the vascular lesion, 17%), and only 3 (15.0%) of stage 3 lesions (P = .001). Predictive factors with a significant effect on final visual acuity were initial visual acuity (P = .003) and early lesion stage (P = .04). Best final visual acuity was 0.41 (mean, direct laser photocoagulation of the vascular lesion in stage 1) and 0.39 (mean, photodynamic therapy in stage 1), with a mean decrease of 2.5 and 3 lines from baseline, respectively.
Treatment of RAP remains difficult. Early detection of the lesion and subsequent direct conventional laser photocoagulation seems to be associated with better anatomical and functional outcome. Once the vascular complex is well established, anatomical closure is rarely achieved. Further study is warranted to assess the long-term efficacy and the need for re-treatment.
To evaluate the effect of a new infrared laser in the destruction of pigmented choroidal melanomas.
B16F10 melanomas were implanted in the subchoroidal space of 64 rabbits (tumor height, 2.0-4.0 mm). Laser radiation from an Nd:yttrium-lanthanum-fluoride laser (1047 nm) was delivered as a focused (beam waist, 25 micro m; irradiance, 100 kW/cm( 2)) raster-scanned transpupillary beam. To investigate melanin heating, treatment with focused light was compared with collimated light (beam waist, 2 mm; irradiance, 16 W/cm(2)). Fine-wire thermocouples were implanted at the base of 3 tumors for in vivo temperature measurements. Untreated animals were used as controls.
Of 64 animals, 27 received a single treatment with focused 1047-nm light. The rate of complete tumor eradication was 91% (10 of 11 animals) at a dosage of 125 J/cm(2) and 75% (9/12) at 63 J/cm(2) to 87 J/cm(2). The eradication rate dropped to 25% (1 of 4) at 38 J/cm(2) or less (P<.001). Continuous tumor growth was observed in all animals treated with collimated radiation and in untreated controls. Temperature measurements indicated that tissue heating at the tumor base was more rapid at 1047 nm than at 805 nm.
These data suggest that a single treatment with a focused, raster-scanned beam at 1047 nm may play a role in the destruction of pigmented choroidal melanoma. Focused irradiation at 1047 nm may provide more effective submillisecond heating of melanin than collimated irradiation, resulting in immediate photothermal disruption of tumor cells.
To determine the genotype underlying suspected X-linked infantile nystagmus in a family and to correlate genotype with clinical examination in potential female carriers.
Ophthalmic examination (ophthalmic, orthoptic, optokinetic [OKN] drum, and electrophysiologic when possible) and candidate gene analysis.
Two affected brothers had infantile nystagmus with no evidence of associated visual or neurological disease. The symptomatic maternal aunt had infantile nystagmus in addition to congenital fibrosis of the extraocular muscles (CFEOM) (bilateral hypotropia, exotropia, ptosis, almost complete ophthalmoplegia, and poorly reactive pupils). A sister, the mother, and the maternal grandmother-all 3 of whom were asymptomatic-had delayed corrective saccades (prolonged pursuit) during OKN drum testing.A brother and the father—both of whom were asymptomatic—had unremarkable examination findings [corrected]. A FRMD7 splice variant (c.1050 + 5 G>A) was identified in the 2 affected brothers and in the 3 asymptomatic women only. Allele sharing analysis further confirmed that the aunt's phenotype was not related to the FRMD7 variant, which was absent in 246 ethnic controls. Her phenotype was also not related to mutation in known CFEOM genes (KIF21A, PHOX2A, TUBB3).
Prolonged pursuit responses during OKN drum testing in asymptomatic female carriers is consistent with the concept of infantile nystagmus being an abnormally increased pursuit oscillation. Further studies are required to determine the reproducibility of this potential female carrier sign. Rather than being FRMD7 related, nystagmus in the maternal aunt represented a second disease in this family, likely related to CFEOM.
Clinicians can use the OKN drum to assess obligate female carriers in a family suspected of having X-linked nystagmus.
Three members of one family and one person from another family were found to have a guanine-to-adenine transition mutation in the first nucleotide of codon 106 in the rhodopsin gene that results in a glycine-to-arginine change. All affected members presented with a similar phenotype that included a regional predilection for pigmentary changes to occur in the inferior retina as well as visual field impairment predominantly in the superior hemisphere. The distribution of pigmentary changes, pattern of visual field loss, and substantial remaining electroretinographic amplitudes with normal implicit times were consistent with a form of "sector" retinitis pigmentosa. We documented the association of a distinct phenotype of autosomal dominant retinitis pigmentosa with a better visual prognosis and a specific rhodopsin gene mutation.
Choroidal melanoma usually presents as a monocular, monofocal tumor that is dome shaped or mushroom shaped. Occasionally, choroidal melanoma is bilobal and rarely, it is multilobular.1 The present case is a unique multilobulated choroidal melanoma.An 82-year-old woman sought care at our clinic because of a suspicious macular lesion in her right eye that caused deterioration of the visual acuity to light perception. The visual acuity in the left eye was 0.4 (6/15). An elevated mass, melanotic in its base and amelanotic in its apex, was seen in the macula of the right eye, with some retinal detachment surrounding it. The fundus of the left eye was normal. Ultrasound examination showed a dome-shaped solid mass in the temporal side of the macula, measuring 10.3 mm × 10.4 mm in diameter and 6.1 mm in maximal height, with low internal reflectivity, rimmed by detached retina. The tumor was treated by ruthenium 106 brachytherapy, irradiating 10 200 cGy to the apex and 70 000 cGy to the base of the tumor.
To evaluate the occurrence of new retinoblastomas in patients treated with 6 cycles of chemoreduction.
Prospective nonrandomized single-center case series.
Ocular Oncology Service at Wills Eye Hospital of Thomas Jefferson University, Philadelphia, Pa, in conjunction with the Division of Oncology at The Children's Hospital of Philadelphia.
A total of 162 eyes of 106 patients with retinoblastoma treated with 6 cycles of chemoreduction between January 1, 1995, and May 31, 2002.
All patients received intravenous chemoreduction with vincristine sulfate, etoposide, and carboplatin, combined with focal treatment (cryotherapy or thermotherapy) to each retinal tumor.
Development of new intraretinal retinoblastoma during or after treatment with chemoreduction. Recurrent subretinal tumor seeds or vitreous seeds were excluded from this analysis, and only primary new intraretinal tumors were included.
Of 28 patients with unilateral retinoblastoma, new intraretinal tumor development was found during or after chemoreduction in 2 (9%) of the 23 patients with sporadic disease and 4 (80%) of the 5 patients with familial disease. The new tumor was located in the macula in none, between the macula and equator in 7 (54%), and between the equator and ora serrata in 6 (46%). Of the 78 patients with bilateral retinoblastoma, new tumor development was found during or after chemoreduction in 11 (19%) of the 57 patients with sporadic disease and 8 (38%) of the 21 patients with familial disease. The new tumor was macula in 2 (4%), between the macula and equator in 30 (55%), and between the equator and ora serrata in 23 (42%). Overall, according to Kaplan-Meier analysis, new tumor development occurred in 23% of patients by 1-year follow-up and 24% by 5-year follow-up. By multivariate analysis, the most important risk factors for the development of new tumors was younger age at presentation (median age, 2 months with new tumor vs 9 months without new tumor) and family history of retinoblastoma (12 [48%] of patients with new tumor vs 14 [17%] without new tumor).
Children with retinoblastoma treated with chemoreduction should be followed for new intraretinal tumor development, as it peaks at a mean interval of 5 months after initiation of chemoreduction and affects 24% of patients by 5 years of follow-up. New tumors are most commonly found in those who develop disease as young infants and those with a family history of retinoblastoma.
From 1964 to 1980, 205 patients with choroidal melanoma were treated with 106Ru/106Rh beta-ray applicators (8,000 to 10,000 rad at the summit of the tumor within 14 days). In 132 (64.4%) cases, this treatment was successful. Thirty-six (17.6%) had to be enucleated after irradiation and 37 died, 21 of them of metastases. Of the 132 successfully treated patients, 60 (45.5%) had flat scars and 34 (25.8%) retained a visual acuity of 0.5 to 1.5. Radiogenic late complications with damage to the retinal capillary system were the main causes of visual deterioration, especially in eyes with tumors close to the posterior pole. The survival rate of 85.1% after five years is substantially higher than that for patients who were primarily treated with enucleation.