Garrick Chak

Characterization of Retinal and Blood Mitochondrial DNA from Age-Related Macular Degeneration Patients

PURPOSE To determine mitochondrial (mt)DNA variants in AMD and age-matched normal retinas. METHODS Total DNA was isolated from retinas (AMD, n = 13; age-matched normal, n = 13), choroid (AMD, n = 3), and blood (AMD, n = 138; normal, n = 133). Long-extension-polymerase chain reaction amplified the full-length ( approximately 16.2 kb) mtDNA genome. Retinal mtDNA was sequenced for nucleotide variants and length heteroplasmy. Pyrosequencing was performed on heteroplasmic mtDNA. PCR amplification and enzyme digestions were used to analyze for nucleotide changes. RESULTS Retinal mtDNA had a greater number of rearrangements and deletions than did blood mtDNA in normal samples (9.3 +/- 1.78 vs. 3 +/- 1.18, P = 0.019), and AMD samples (14.33 +/- 1.96 vs. 5.2 +/- 0.80, P = 0.0031. Five (55%) of 9 AMD patients had unreported SNPs, and 2 (16.6%) of 12 of the normal group did. The mtDNA coding region had 20 SNPs that produced amino acid changes. The noncoding MT-Dloop region had nucleotide heteroplasmy and length heteroplasmy. There were more SNPs per person in the AMD population than in the older (P = 0.003) and younger (P = 0.05) normal subjects. The C12557T (T-I) in the MT-ND5 gene was present in two AMD subjects (2/138) but was absent in the normal (0/133). Common mutations for Lebers hereditary optic neuropathy (LHON: G11778A; T14484C; and G3460A) were not present in AMD samples. CONCLUSIONS AMD subjects have high levels of large mtDNA deletions/rearrangements in the retinas, unreported and amino acid-changing SNPs in the coding genome, and a greater number of SNPs per person in the noncoding MT-Dloop region. These mtDNA variants could diminish energy production efficiency, alter the mtDNA copy numbers and/or impact transcription in AMD retinas.

Mitochondrial DNA haplogroups confer differences in risk for age-related macular degeneration: a case control study

BackgroundAge-related macular degeneration (AMD) is the leading cause of vision loss in elderly, Caucasian populations. There is strong evidence that mitochondrial dysfunction and oxidative stress play a role in the cell death found in AMD retinas. The purpose of this study was to examine the association of the Caucasian mitochondrial JTU haplogroup cluster with AMD. We also assessed for gender bias and additive risk with known high risk nuclear gene SNPs, ARMS2/LOC387715 (G > T; Ala69Ser, rs10490924) and CFH (T > C; Try402His, rs1061170).MethodsTotal DNA was isolated from 162 AMD subjects and 164 age-matched control subjects located in Los Angeles, California, USA. Polymerase chain reaction (PCR) and restriction enzyme digestion were used to identify the J, U, T, and H mitochondrial haplogroups and the ARMS2-rs10490924 and CFH-rs1061170 SNPs. PCR amplified products were sequenced to verify the nucleotide substitutions for the haplogroups and ARMS2 gene.ResultsThe JTU haplogroup cluster occurred in 34% (55/162) of AMD subjects versus 15% (24/164) of normal (OR = 2.99; p = 0.0001). This association was slightly greater in males (OR = 3.98, p = 0.005) than the female population (OR = 3.02, p = 0.001). Assuming a dominant effect, the risk alleles for the ARMS2 (rs10490924; p = 0.00001) and CFH (rs1061170; p = 0.027) SNPs were significantly associated with total AMD populations. We found there was no additive risk for the ARMS2 (rs10490924) or CFH (rs1061170) SNPs on the JTU haplogroup background.ConclusionsThere is a strong association of the JTU haplogroup cluster with AMD. In our Southern California population, the ARMS2 (rs10490924) and CFH (rs1061170) genes were significantly but independently associated with AMD. SNPs defining the JTU mitochondrial haplogroup cluster may change the retinal bioenergetics and play a significant role in the pathogenesis of AMD.

Results of Trabectome Surgery Following Failed Glaucoma Tube Shunt Implantation: Cohort Study

Abstract To evaluate the safety and efficacy of Trabectome after failed tube shunt surgery. Twenty patients with prior failed tube shunt surgery who underwent Trabectome alone were included. All patients had at least 3 months of follow-up. Outcomes measured included intraocular pressure (IOP), glaucoma medications, and secondary glaucoma surgeries. The success for Kaplan–Meier survival analysis is defined as IOP ⩽21 mm Hg, IOP reduced by at least 20% from preoperative IOP, and no secondary glaucoma surgery. Mean preoperative IOP was 23.7 ± 6.4 mm Hg and mean number of glaucoma medications was 3.2 ± 1.5. At 12 months, IOP was reduced to 15.5 ± 3.2 mm Hg (P = 0.05) and number of medications was reduced to 2.4 ± 1.5 (P = 0.44). Survival rate at 12 months was 84% and 3 patients required additional glaucoma surgery with 15 patients reaching 12 months follow-up. Other than failure of IOP control and transient hypotony (IOP < 3 mm Hg) day 1 in 2 cases, there were no adverse events. Trabecular bypass procedures have traditionally been considered an approach appropriate for early-to-moderate glaucoma; however, our study indicates benefit in refractory glaucoma as well. Eyes that are prone to conjunctival scarring and hypertrophic wound healing, such as those who have failed tube shunt surgery, may benefit from procedures that avoid conjunctival incision such as Trabectome. This study indicates potential benefits in this patient population. Trabectome was safe and effective in reducing IOP at 1-year follow-up in patients with prior failed tube shunt surgery, but not effective in reducing medication reliance in these patients.

Reduction in mean deviation values in automated perimetry in eyes with multifocal compared to monofocal intraocular lens implants.

PURPOSE To evaluate differences in mean deviation values in automated perimetry in healthy eyes with multifocal compared to monofocal intraocular lens (IOL) implants. DESIGN Prospective, age-matched, comparative analysis. METHODS SETTING Single-center, tertiary referral academic practice. PATIENT POPULATION A total of 37 healthy eyes in 37 patients with bilateral multifocal (n=22) or monofocal (n=15) IOL implants were studied. INTERVENTION/OBSERVATION PROCEDURE: Humphrey Visual Field 10-2 testing was performed on all patients. MAIN OUTCOME MEASURES Mean deviation (MD) and pattern standard deviation (PSD) numerical values were evaluated and compared between groups. RESULTS The average MD was -2.84 dB (SD 2.32) for the multifocal IOL group and -0.97 dB (SD 1.58) for the monofocal IOL group (P=.006). There was no significant difference in PSD between the 2 groups (P=.99). Eyes that had the visual field 10-2 testing≥6 months from time of IOL placement showed no improvement in MD when compared to eyes that were tested within 6 months from IOL placement. CONCLUSION Multifocal IOL implants cause significant nonspecific reduction in MD values on Humphrey Visual Field 10-2 testing that does not improve with time or neuroadaptation. Multifocal IOL implants may be inadvisable in patients where central visual field reduction may not be tolerated, such as macular degeneration, retinal pigment epithelium changes, and glaucoma.

Outcome of primary trabeculotomy ab interno (Trabectome) surgery in patients with steroid-induced glaucoma

AbstractTo determine the efficacy and safety of Trabectome surgery on patients with steroid response, ranging from ocular hypertension refractory to maximal medical therapy to the development of steroid-induced glaucoma.A nonrandomized, nonblinded, retrospective study of 20 subjects with steroid response was conducted. All 20 eyes underwent Trabectome surgery alone. Nine subjects had steroid response with unremarkable visual field, 3 had mild steroid-induced glaucoma, and 8 had advanced steroid-induced glaucoma. Outcome measures included intraocular pressure (IOP), number of glaucoma medications, need for secondary glaucoma surgery, and steroid regimen. Mann–Whitney U test was used to compare postoperative IOP and number of medications to preoperative IOP and number of medications. Kaplan–Meier was used for survival analysis, and success was defined as: IOP reduced by 20% or more on any 2 consecutive visits after 3 months; IOP ⩽21 mm Hg on any 2 consecutive visits after 3 months; and no secondary glaucoma surgery.The average preoperative IOP was 33.8 ± 6.9 mm Hg and average preoperative glaucoma medication usage was 3.85 ± 0.75 medications. At 12 months, the IOP was reduced to 15.00 ± 3.46 mm Hg (P = 0.03) and glaucoma medication was reduced to 2.3 ± 1.4 (P < 0.01). The survival rate at 12 months was 93%. At 12 months, 10 patients were continued on their preoperative steroid treatments, 5 were on tapered steroid treatments, and 5 had ceased steroid treatments entirely. One patient required secondary glaucoma surgery (glaucoma drainage device). No other complications were noted.The Trabectome procedure is safe and highly effective for steroid-response glaucoma, even in the context of continued steroid treatment.

A Positive Sentinel Lymph Node in Periocular Invasive Squamous Cell Carcinoma: A Case Series

Purpose: The aim of this article was to describe positive sentinel lymph node biopsy (SLNB) findings in patients with periocular invasive squamous cell carcinoma (SCC). Methods: This was a retrospective chart review of 5 patients with invasive SCC of the periocular region who underwent SLNB and were found to have regional metastasis. Results: All patients had large (2.0–4.3 cm) primary tumors with poor differentiation on pathology. In all 5 patients, SLNB was positive in the absence of other signs or evidence of regional or systemic metastasis. While tumor cells may drain to the preauricular or the submandibular basin, the preauricular lymph node was identified as the sentinel lymph node on lymphoscintigraphy in all 5 patients. With a positive sentinel lymph node, the results of SLNB changed the clinical staging and influenced subsequent treatment recommendations for each patient. We identified no complications related to SLNB including facial nerve damage, lymphedema, or allergic reaction to radioactive tracing material. Conclusions: In this series of patients with periocular invasive SCC, SLNB was well tolerated and uncovered regional metastasis in patients with no clinical signs of metastasis otherwise. The SLNB findings influenced subsequent oncologic management recommendations. The usefulness of SLNB for poorly differentiated SCC remains uncertain. Further research is necessary to establish the role of SLNB in periocular SCC.

Coup de sabre presenting with worsening diplopia and enophthalmos.

A middle-aged woman with a diagnosis of linear scleroderma and systemic sclerosis presented with an atrophic skin lesion of the forehead extending in the right orbit and progressive diplopia in the right gaze. On exam, she had enophthalmos with a small, manifest esotropia in the right gaze. Orbital MRI revealed fat atrophy of the right upper eyelid and orbit not previously described. Inflammation and progressive collagen fibrosis involving subcutaneous tissue, fat, and muscle secondary to linear scleroderma may result in enophthalmos and diplopia.