Reduction of the onset response in kilohertz frequency alternating current nerve block with amplitude ramps from non-zero amplitudes.

BACKGROUND: Kilohertz frequency alternating current (KHFAC) waveforms reversibly block conduction in mammalian peripheral nerves. The initiation of the KHFAC produces nerve activation, called the onset response, before complete block occurs. An amplitude ramp, starting from zero amplitude, is ineffective in eliminating this onset activity. We postulated that initiating the ramp from a non-zero amplitude would produce a different effect on the onset. METHODS: Experiments were conducted in an in vivo rat model. KHFAC was applied at supra block threshold amplitudes and then reduced to a lower sub block amplitude (25, 50, 75 and 90% of the block threshold amplitude). The amplitude was then increased again to the original supra block threshold amplitude with an amplitude ramp. This ramp time was varied for each of the amplitude levels tested. RESULTS: The amplitude ramp was successful in eliminating a second onset. This was always possible for the ramps up from 75 and 90% block threshold amplitude, usually from 50% but never from 25% of the block threshold amplitude. CONCLUSIONS: This maneuver can potentially be used to initiate complete nerve block, transition to partial block and then resume complete block without producing further onset responses.

Mechanism of highly synchronized bilateral hippocampal activity.

In vivo studies of epileptiform discharges in the hippocampi of rodents have shown that bilateral seizure activity can sometimes be synchronized with very small delays (<2 ms). This observed small time delay of epileptiform activity between the left and right CA3 regions is unexpected given the physiological propagation time across the hemispheres (>6 ms). The goal of this study is to determine the mechanisms of this tight synchronization with in-vitro electrophysiology techniques and computer simulations. The hypothesis of a common source was first eliminated by using an in-vitro preparation containing both hippocampi with a functional ventral hippocampal commissure (VHC) and no other tissue. Next, the hypothesis that a noisy baseline could mask the underlying synchronous activity between the two hemispheres was ruled out by low noise in-vivo recordings and computer simulation of the noisy environment. Then we built a novel bilateral CA3 model to test the hypothesis that the phenomenon of very small left-to-right propagation delay of seizure activity is a product of epileptic cell network dynamics. We found that the commissural tract connectivity could decrease the delay between seizure events recorded from two sides while the activity propagated longitudinally along the CA3 layer thereby yielding delays much smaller than the propagation time between the two sides. The modeling results indicate that both recurrent and feedforward inhibition were required for shortening the bilateral propagation delay and depended critically on the length of the commissural fiber tract as well as the number of cells involved in seizure generation. These combined modeling/experimental studies indicate that it is possible to explain near perfect synchronization between the two hemispheres by taking into account the structure of the hippocampal network.

Ocular telemedicine between Nepal and the USA: prevalence of vitreoretinal disease in rural Nepal.

This study is aimed at reporting experiences with telemedicine between Nepal and the USA and at reporting the prevalence of age-related macular degeneration (AMD) and diabetic retinopathy (DR) in rural Nepal. AMD and DR are becoming more significant factors for non-reversible vision loss in rural Nepal due to increasing life expectancy and urbanisation. The prevalence of DM is low compared with the developed world, but the percentage of diabetics with DR is high, presumably due to limited access to healthcare. The higher prevalence of DM in Hetauda is explained as being due to a more urban lifestyle, dietary habits (more deep-fried food) and more advanced age.

Autosomal dominant Stargardt-like macular dystrophy.

Autosomal dominant Stargardt-like macular dystrophy is one of the early onset macular dystrophies. It is characterized clinically in its early stages by visual loss and by the presence of atrophic macular changes with or without the presence of yellowish flecks. It is an important retinal dystrophy to study, not only because it has implications in the care and treatment of patients with the condition, but because it also provides important information regarding retinal function. Review of the literature suggests that many of the reported families are linked to chromosome 6q. Genetic and genealogical evidence suggests that these families have descended from a common ancestor or founder. The recent identification of a disease-causing gene that is involved in fatty acid metabolism may have implications in the study of the more common age-related macular degeneration. We review the recent clinical, genetic, and genealogical aspects of autosomal dominant Stargardt-like macular dystrophy.

Endophthalmitis after pediatric strabismus surgery.

OBJECTIVE: To report 6 cases of endophthalmitis after pediatric strabismus surgery. METHODS: Retrospective review of initial signs, clinical findings, treatment, culture results, and visual and anatomical outcomes in 6 eyes of 6 children treated at 2 tertiary care institutions between 1983 and 1998. RESULTS: Four boys and 2 girls aged 8 months to 6 years (median age, 2 years) developed lethargy and asymmetric eye redness, with or without eyelid swelling or fever, within 4 days of surgery. At diagnosis (median, postoperative day 6) clinical findings included periorbital swelling, redness and leukocoria due to vitritis, and, in some cases, hypopyon. Treatment included pars plana vitrectomy and intravitreal and systemic antibiotics in all cases. Vitreous cultures grew Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus. Within 6 months of strabismus surgery, visual acuity was no light perception in all eyes and 3 eyes had been enucleated. The 3 remaining eyes were prephthisical. CONCLUSIONS: Endophthalmitis after pediatric strabismus surgery is rare. Children may not recognize or verbalize symptoms. Causative organisms are virulent. Visual and anatomical outcomes are poor. Lethargy, asymmetric eye redness, eyelid swelling, or fever in the postoperative period, even if initial postoperative examination results are normal, should prompt urgent ocular examination. The diagnosis of endophthalmitis may be made when biomicroscopic or indirect ophthalmoscopic examination confirms the presence of vitreous opacification with or without hypopyon. Arch Ophthalmol. 2000;118:939-944

Demarcation laser photocoagulation of selected macula-sparing rhegmatogenous retinal detachments.

OBJECTIVE: To report a series of macula-sparing rhegmatogenous retinal detachments (MSRRDs) treated with demarcation laser photocoagulation (DLP). DESIGN: Retrospective, noncomparative case series. PARTICIPANTS: Thirty-one patients (34 eyes) with primary or recurrent MSRRDs without associated visual field loss, necrotizing retinitis, or proliferative vitreoretinopathy (PVR), managed with DLP from November 1992 through May 1999. INTERVENTION: Demarcation laser photocoagulation consisting of a triple row of confluent laser burns. MAIN OUTCOME MEASURES: Best corrected postoperative visual acuity and MSRRD progression or recurrence. RESULTS: Thirty-four primary and recurrent MSRRDs were treated by DLP, which consisted of a triple row of confluent laser burns. Macula-sparing rhegmatogenous retinal detachments were located in all quadrants and affected 10% to 45% of the retina. Findings associated with MSRRDs included lattice degeneration (12 eyes), vitreous hemorrhage (4 eyes), and demarcation line (9 eyes). Symptoms (photopsias or floaters) were associated with 14 MSRRDs. Eight eyes were myopic and 11 were pseudophakic. Thirty-two MSRRDs were shallow, two were dome shaped, and all were smooth without corrugations. Follow-up ranged from 1.5 to 80 months (mean, 15.8 months; median, 17 months). Thirty-three of 34 detachments remained stable after DLP. Three flattened spontaneously. One eye was managed with scleral buckle 6 weeks after DLP. Progression was attributed to incomplete laser treatment. Best corrected postoperative visual acuity was the same or improved in all but one eye, in which a cataract developed. CONCLUSIONS: Demarcation laser photocoagulation is an effective method to manage acute or chronic, primary or recurrent MSRRDs without associated PVR that are shallow and smooth without corrugations. Demarcation laser photocoagulation is an alternative to both observation and surgical repair for these select MSRRDs.

Discontinuation of anticytomegalovirus therapy in patients with HIV infection and cytomegalovirus retinitis.

CONTEXT: Persons with cytomegalovirus (CMV) retinitis and acquired immunodeficiency syndrome (AIDS) have required lifelong anti-CMV therapy to prevent the progression of retinal disease and subsequent loss of vision. OBJECTIVE: To determine whether patients who were taking highly active antiretroviral therapy (HAART) and who had stable CMV retinitis could safely discontinue anti-CMV therapy without reactivation of their retinitis or increase in human immunodeficiency virus (HIV) viral load. DESIGN: Prospective nonrandomized interventional trial performed from July 1997 to August 1999. SETTING: Clinical Center of the National Institutes of Health, Bethesda, Md. PATIENTS: Fourteen patients with stable CMV retinitis and HIV infection and CD4+ cell counts higher than 0.1 5 x 10(9)/L and being treated with systemic anti-CMV medications and HAART. INTERVENTIONS: Discontinuation of specific anti-CMV therapy. MAIN OUTCOME MEASURES: Reactivation of CMV retinitis, development of extraocular CMV infection, detection of CMV in blood and urine, HIV burden, immunologic function, quality of life, morbidity, and mortality. RESULTS: Twelve (89.7%) of 14 patients had evidence of immune recovery uveitis before anti-CMV drugs were discontinued. No patient had reactivation of CMV retinitis or development of extraocular CMV disease during mean follow-up of 16.4 months (range, 8.3-22.0 months) without anti-CMV therapy. Human immunodeficiency viral load remained stable following cessation of anti-CMV medications. Blood and urine assays for CMV were briefly positive in 9 patients but did not predict reactivation of CMV disease. Worsening immune recovery uveitis was associated with a substantial (>3 lines) vision loss in 3 patients. CONCLUSIONS: Maintenance anti-CMV medications were safely stopped in those patients who had stable CMV retinitis and elevated CD4+ cell counts and who were taking HAART. The study demonstrates that immune recovery following potent antiretroviral therapy is effective in controlling a major opportunistic infection, even in patients with a history of severe immunosuppression.

Autosomal dominant Stargardt-like macular dystrophy: I. Clinical characterization, longitudinal follow-up, and evidence for a common ancestry in families linked to chromosome 6q14.

PURPOSE: Characterize the phenotype of autosomal dominant Stargardt-like macular dystrophy in two families linked to chromosome 6q14 and determine whether they share a common ancestry. METHODS: Two families spanning 10 generations were identified and studied independently. Participating members were examined and genetic linkage and genotyping performed. RESULTS: Presenting symptoms included decreased vision, hemeralopia, and mild photophobia. The subjective onset of visual loss ranged from age 3 to 50 with a mean of 14 years. A Snellen acuity of 20/200 occurred at a mean age of 22 years. Over decades, the macular lesion enlarged and visual acuity decreased to 20/300 to 20/800. The typical phenotype was well-circumscribed, homogenous atrophy of the retinal pigment epithelium and choriocapillaris in the macula, with surrounding yellow flecks and temporal optic nerve pallor. The phenotypic spectrum included a pattern dystrophy-like appearance, diffuse geographic atrophy, and extensive fundus flecks. Genotyping revealed that the two families were linked to chromosome 6q14 and shared a common haplotype spanning 21 cM between D6S430 and D6S300. The two families were subsequently shown by genealogic investigation to represent different branches of a common kindred. CONCLUSIONS: Families with autosomal dominant Stargardt-like macular dystrophy linked to chromosome 6q14 share a common phenotype and in some cases can be distinguished from similar dystrophies by inheritance pattern and clinical features. The finding that these two families shared a common ancestor suggests the existence of a founder effect. Characterization of the gene for autosomal dominant Stargardt-like macular dystrophy may enable better understanding of this condition and elucidation of its potential role in other forms of macular degeneration.

Discontinuation of maintenance therapy in patients with quiescent cytomegalovirus retinitis and elevated CD4+ counts.

OBJECTIVE: To determine whether maintenance therapy can be discontinued safety in patients with quiescent cytomegalovirus retinitis (CMVR) and increased CD4+ counts after treatment with highly active antiretroviral therapy (HAART). DESIGN: A prospective observational case series. PARTICIPANTS: Eight human immunodeficiency virus (HIV)-positive patients with quiescent CMVR who were taking HAART and had CD4+ counts above 100 cells/microliter elected to discontinue anti-CMV maintenance treatment. INTERVENTION: Biweekly-to-monthly indirect ophthalmoscopy and fundus photographs, monthly-to-quarterly CD4+ counts, and quarterly HIV viral loads were ordered. MAIN OUTCOME MEASURES: Twelve previously affected eyes were examined for evidence of recurrent retinitis, which was defined as any retinal whitening, border opacification, or expansion of areas of retinal pigment epithelial (RPE) atrophy greater than 750 microns. Four previously unaffected fellow eyes were observed for new CMVR. RESULTS: There was no reactivation or progression of retinitis in any patient during the mean follow-up interval of 11.4 months (range, 3-16 months). No previously unaffected eye developed CMVR. CD4+ remained elevated in all patients (range, 70-725; mean, 255). The HIV viral load ranged from undetectable to 139,000 copies. CONCLUSION: Discontinuation of maintenance therapy may be considered in patients with HAART-induced elevated CD4+ counts above 100 cells/microliter, prolonged relapse-free intervals during the reconstitution period before CD4+ counts rise above 100 cells/microliter, and completely quiescent retinitis characterized by RPE scarring only. Reduced risks of drug toxicity and drug-resistant organisms are potential benefits. Close observation for evidence of recurrent retinitis is indicated.

Advances in the diagnosis and management of AIDS-related eye disease.

AIDS-related eye disease is changing rapidly. New clinical entities have been reported, most numerous of which are the uveitis syndromes in patients with elevated CD4+ counts. Advances in management of cytomegalovirus retinitis (CMVR) include laser demarcation as an alternative to vitrectomy with silicone oil injection in macula-sparing cytomegalovirus-related retinal detachments and discontinuation of maintenance therapy in select patients with quiescent CMVR and elevated CD4+ counts. Screening guidelines have been proposed for childhood CMVR. Serial fundus photography has been recommended to improve follow-up evaluation of CMVR. A method to improve intraocular lens calculation in silicone-filled eyes has been offered. The rapidity and extent to which drug resistant cytomegalovirus infection develops has been elucidated. And the controversy of oral ganciclovir prophylaxis for cytomegalovirus disease has been argued from several angles. The following article reviews these and other advances in the understanding of AIDS-related eye disease.

Laser photocoagulation repair of macula-sparing cytomegalovirus-related retinal detachment.

OBJECTIVE: The purpose of the study is to investigate the role of laser photocoagulation in the treatment of macula-sparing cytomegalovirus (CMV)-related retinal detachment (CMVRD) in patients with acquired immune deficiency syndrome (AIDS). DESIGN: Seven macula-sparing CMVRD identified between July 1995 and February 1997 were managed with laser photocoagulation and observed prospectively (group I). Seven CMVRD reattached with pars plana vitrectomy (PPV) and silicone oil injection (group II) between January 1992 and June 1996 were analyzed retrospectively. PARTICIPANTS: Patients with AIDS with macula-sparing rhegmatogenous CMVRD with no proliferative vitreoretinopathy and visual acuity better than 20/30 were studied. INTERVENTION: Demarcation laser photocoagulation (group I) or PPV with silicone oil injection (group II) was performed. MAIN OUTCOME MEASURES: Postoperative best-corrected visual acuity (BCVA), temporary or permanent visual loss, CMVRD progression or recurrence, and cataract were measured. RESULTS: Follow-up ranged from 2 to 19 months (mean, 9 months) in group I. Post-treatment BCVA was unchanged in all eyes after laser. One retina redetached 9 months after laser treatment. Final visual acuity was less than 20/40 in one eye because of progressive CMV retinitis. Follow-up ranged from 2 to 24 months (mean, 10.4 months) in group II. All group II RDs were reattached successfully with PPV and silicone oil injection. Best-corrected visual acuity was an average of 1.6 lines worse after vitrectomy. Silicone-induced hyperopic shift caused temporary visual loss in all eyes (mean duration, 5.6 weeks). Delayed visual loss due to cataract formation occurred in five eyes. Three eyes had cataract extraction within 6 months. Two partial redetachments developed. One was repaired with repeat vitrectomy. Final visual acuity was less than 20/40 in five of seven eyes because of progressive CMV retinitis (1), dense cataract (2), uncorrected refractive error (2), and uncertain cause (1). CONCLUSIONS: Demarcation laser photocoagulation appears to be an effective treatment for many macula-sparing CMVRD. Loss of BCVA, temporary postoperative visual loss due to silicone-induced refractive error, and delayed visual loss due to cataract after vitrectomy with silicone oil injection may be avoided. Demarcation laser photocoagulation may be an effective alternative to vitrectomy in macula-sparing CMVRD.

Ocular manifestations of AIDS.

1. Cytomegalovirus retinitis is the leading cause of AIDS-related blindness. 2. Patients with reduced CD4 counts are at risk of developing cytomegalovirus retinitis and should be informed of symptoms (floaters, scotoma) and should have periodic dilated retina examinations. 3. AIDS patients who develop herpes zoster should be monitored for progressive outer retinal necrosis.

Taches de bougie.

BACKGROUND: Posterior segment lesions, including taches de bougie, may be the presenting sign of sarcoidosis. In patients with unrecognized sarcoidosis, taches de bougie may be misinterpreted as the lesions of birdshot chorioretinopathy (BCR) or multifocal choroiditis (MFC). METHODS: In a retrospective study, the authors identified 22 patients with taches de bougie and sarcoidosis. A tissue biopsy showed noncaseating granulomas in 17 patients. All available ophthalmic and medical records of these patients were reviewed. RESULTS: Two patterns of taches de bougie were observed. Sixteen patients (73%) had small, discrete white spots in the inferior or nasal periphery, indistinguishable from the lesions of MFC. In six patients (27%), larger, posterior, pale yellow-orange streaks developed that were identical to the lesions of BCR. Visual prognosis was better with posterior streaks. The chest x-ray was normal in 5 of 16 patients with peripheral spots and in 3 of 6 patients with posterior streaks. Serum angiotensin-converting enzyme was negative in 5 of 14 patients. Gallium scan showed increased hilar uptake in five patients, three of whom had a normal chest x-ray. Human lymphocyte antigen A29 was positive in one of nine patients. CONCLUSIONS: Sarcoidosis should be considered in patients with fundus findings that resemble BCR or MFC. Initial evaluation should include chest x-ray and testing the angiotensin-converting enzyme level. These test results may be negative in patients outside the 20- to 40-year age group for typical sarcoid. Further evaluation with nondirected conjunctival biopsy and whole-body gallium scan may be indicated in certain patients, including (1) those with BCR or MFC with normal chest x-ray and elevated angiotensin-converting enzyme level; (2) patients older than 50 years with MFC; or (3) human lymphocyte antigen A29-negative BCR.

Cryotherapy for retinopathy of prematurity: a histopathologic comparison of a treated and untreated eye.

A female infant born at 28 weeks gestational age, weighing 570 g, developed retinopathy of prematurity (ROP) which progressed to threshold disease in one eye. Transscleral cryotherapy of the avascular peripheral retina resulted in complete clinical regression of the active ROP in that eye. The fellow eye continued to manifest subthreshold ROP. Histopathologic findings included a striking reduction of the cryotreated retina to a thin glial scar, with associated retinal pigment epithelium atrophy, denudation of Bruch's membrane, and extensive atrophy of the underlying choroidal vasculature, predominantly the choriocapillaris.

Impact of delayed treatment in growing posterior uveal melanomas.

OBJECTIVE: To investigate the impact of pretreatment tumor growth on survival in patients with primary posterior uveal melanoma. DESIGN: Retrospective case-by-case matched comparative survival study. PATIENTS: Thirty patients with documented tumor growth of at least 3 mm in basal diameter, 1.5 mm in thickness, or both during a pretreatment interval of 6 months or more and a matched control group of 30 promptly treated patients. Matching criteria included patient age (+/- 10 years), largest basal tumor diameter (+/- 2 mm), tumor thickness (+/- 1.5 mm), location of anterior tumor margin (same defined zone), and visual symptoms (present or absent). SETTING: The Oncology Unit of the Retina Service at Wills Eye Hospital, Philadelphia, Pa. INTERVENTIONS: All patients were treated in a nonrandomized fashion by conventional therapeutic methods appropriate to the tumor's size, location, and other factors. MAIN OUTCOME MEASURES: Actuarial melanoma-specific mortality and all-cause mortality. RESULTS: The mean +/- SE cumulative 5-year probability of melanoma-specific mortality relative to the date of initial examination was 17.1% +/- 7% in the delayed treatment group and 18.4% +/- 8% in the prompt treatment group. This difference is not statistically significant (P > .5, log rank test). CONCLUSIONS: These results lend support to the belief that delayed treatment of selected small and dormant-appearing choroidal and ciliary body melanomas does not substantially increase the probability of melanoma-specific mortality; however, they do not prove that observation is the correct management option for all patients with a posterior uveal melanoma.

Inhibition of experimental autoimmune uveoretinitis by oral administration of S-antigen and synthetic peptides.

S-Antigen, a photoreceptor cell protein, is highly efficient in inducing experimental autoimmune uveoretinitis (EAU), a severe inflammation of the uveal tract and retina of the eye. S-Antigen and six synthetic peptides, all of which correspond to known T-cell or B-cell recognition sites, were tested for their ability to induce oral tolerance to EAU in LEW rats. Feeding three 1-mg doses of native S-Antigen or three doses of one synthetic peptide, designated BSA(343-362) (200 micrograms per dose), reduced the incidence and severity of EAU induced by immunization with 50 micrograms of S-Antigen. Another peptide, BSA(270-289), was able to inhibit EAU only when a low dose (10 micrograms) of the uveitogenic S-Antigen was used to induce EAU. Animals which received 200 micrograms doses of four other immunologically active peptides, BSA(31-51), BSA(143-162), BSA(303-327) and BSA(333-352), were not significantly protected. Furthermore, animals fed BSA(343-362) were significantly less susceptible to EAU induced by adoptive transfer (tEAU) of the uveitogenic R9 T-cell lines. Con A-activated lymphocytes purified from spleens of rats fed peptide BSA(343-362) transferred partial resistance to tEAU induced by adoptive transfer of R9 line cells. The resistance of orally tolerized rats to induction of EAU by adoptive transfer of an activated, pathogenic T-cell line, and the ability of lymphocytes from orally-tolerized animals to transfer resistance to tEAU shows that effector mechanisms can be inhibited by oral feeding as well as the afferent mechanisms reported here and elsewhere. Circulating levels of IgG specific for S-Antigen were not affected by feeding any of the peptides.

Impact of local tumor relapse on patient survival after cobalt 60 plaque radiotherapy.

The authors investigated the impact of local intraocular tumor relapse on survival in a matched-group comparison study of patients with primary choroidal or ciliary body melanoma managed with cobalt 60 plaque radiotherapy. Sixty-two patients with local relapse were matched with an equal number of relapse-free patients in terms of known clinical prognostic factors for both melanoma-specific mortality (largest linear tumor dimension, location of anterior tumor margin, age) and local tumor relapse (location of posterior tumor margin). The follow-up of every relapse-free patient equaled or exceeded the interval to relapse for each matched patient with local relapse. The estimated 5-year survival (Kaplan-Meier) in the relapse-free patients was 87% (standard error = 4%), while that in the local relapse group was 58% (standard error = 6%). This difference is statistically significant (P less than 0.0001, log rank test). These results support the hypothesis that local tumor relapse after cobalt 60 plaque radiotherapy is an important post-treatment clinical indicator of the tumor's greater malignant potential and the patient's increased risk of melanoma-specific mortality.

S-antigen. Identification of human T-cell lymphocyte proliferation sites.

Immune responses to normal retinal proteins, including S-antigen, have been demonstrated in patients with a variety of retinal disorders, as well as in those who have received panretinal laser photocoagulation. T-cell lymphocytes (T cells) have been implicated in the pathogenesis of several ocular inflammatory diseases of possible autoimmune etiology. We used synthetic peptides that correspond to the amino acid sequence of S-antigen in lymphocyte proliferation assays to identify specific sites in the molecule recognized by human T cells. Ten patients with type II diabetes were studied before and after initial panretinal laser photocoagulation for proliferative diabetic retinopathy. T-cell responses, expressed as a stimulation index, to S-antigen and peptides were negative in all patients before treatment. Three weeks after panretinal laser photocoagulation, eight of 10 assays were positive (stimulation index greater than 2; P less than .01) when lymphocytes were stimulated with peptide BSA(273-292); six of nine were positive (P less than .01) with peptide BSA(303-332); and six of six were positive (P less than .001) with peptide BSA(343-362). Our study identifies several specific sites in S-antigen that elicit human immune responses. The implications of these findings with regard to the pathogenesis and treatment of autoimmune uveitis are discussed.