Byron L. Lam

Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies

BACKGROUND Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients. METHODS In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardts macular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dose cohorts (50,000, 100,000, and 150,000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardts macular dystrophy) and NCT01344993 (age-related macular degeneration). FINDINGS There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16-25 points 3-12 months after transplantation in patients with atrophic age-related macular degeneration and 8-20 points in patients with Stargardts macular dystrophy. INTERPRETATION The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement. FUNDING Advanced Cell Technology.

Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG

Autoantibodies have defined two paraneoplastic visual disorders related to small‐cell lung carcinoma: retinopathy (“CAR”‐IgG [23kDa, recoverin]) and optic neuritis collapsin response‐mediated protein 5 (CRMP‐5‐IgG [62kDa]). Among 16 patients with CRMP‐5‐IgG and optic neuritis (aged 52–74 years; all smokers, 9 women), we documented coexisting retinitis in 5. None had CAR‐IgG. Fifteen had subacute vision loss, swollen optic discs, and field defects. Vascular leakage was evident at and remote from the disc; 5/5 tested had abnormal electroretinograms. Nine had striking vitreous cells. Vitrectomy showed reactive lymphocytosis (4/4), predominantly CD4+ (1/1). Most patients had multifocal neurological accompaniments. Cerebrospinal fluid contained lymphocytes (7‐32), elevated protein, multiple oligoclonal immunoglobulin bands, and CRMP‐5‐IgG. Three patients superficially resembled Devics disease at presentation. One autopsied patient had predominantly CD8+ T lymphocytes infiltrating optic nerve and spinal cord. Eleven patients had confirmed small‐cell carcinoma; 1 had imaging evidence of lung cancer; 3 had renal or thyroid carcinoma. Full‐length CRMP‐5 protein was identified in normal retina and optic nerve by Western blot analyses. Photoreceptor cells, retinal ganglion cells, and nerve fibers exhibited CRMP‐5–specific immunoreactivity. In summary, CRMP‐5‐IgG defines a paraneoplastic ophthalmological entity of combined optic neuritis and retinitis with vitreous inflammatory cells. Positive serology obviates the need for vitreous biopsy and expedites the search for cancer. Ann Neurol 2003

Impact of rituximab on relapse rate and disability in neuromyelitis optica

Background: Neuromyelitis optica (NMO) is a severe demyelinating disease often leading to serious disability. Accumulating evidence now implicates humoral mechanisms in its pathogenesis. In the absence of an approved therapy, anti-inflammatory/immunosuppressant drugs have been used empirically for more than three decades. Recent evidence for a role of antibody to aquaporin-4 in the pathogenesis of NMO has led to the use of rituximab, a monoclonal antibody targeting the CD20 epitope on the entire B cell lineage. Objectives: To evaluate the impact of rituximab on the relapse rate and disability in NMO. Methods: This is an IRB approved retrospective longitudinal study of NMO patients treated with rituximab. Results: We identified 53 patients with NMO, 23 of whom had been treated with rituximab. These patients (2 males, 21 females) had a mean age of 37.1 ± 14.6 years at the time of diagnosis. Eight of the 23 treated with rituximab were treatment naïve. All 23 were scheduled to receive infusions every six or 12 months after treatment initiation with a minimum follow-up of six months (median 32.5 months, range 7–63 months). Median relapse rate declined significantly from 1.87 relapses/patient per year to 0.0 relapses/patient per year. Kurtzke Expanded Disability Status Scale (EDSS) scores stabilized or improved in all patients. Use of rituximab is associated with a significant reduction in relapses and disability in patents with NMO.

Prevalence of concurrent hearing and visual impairment in US adults: The National Health Interview Survey, 1997-2002.

Analysis of data from a nationally representative sample of US adults (n=195801) showed that concurrent hearing and visual impairment prevalence rates were highest for participants older than 79 years of age (16.6%); a 3-fold increase in age-adjusted rates of reported hearing and visual impairment was observed for Native Americans compared with Asian Americans. Research on preventing concurrent hearing and visual impairment and countering its consequences is warranted, especially in population subgroups, such as Native and older Americans.

Idiopathic intracranial hypertension in children and adolescents.

PURPOSE To investigate sex distribution, frequency of obesity, and other associated conditions among children and adolescents with idiopathic intracranial hypertension. METHODS We conducted a retrospective chart review of patients aged 18 years or younger diagnosed with idiopathic intracranial hypertension between 1988 and 1995 at two medical centers. Meta-analyses were performed using our data pooled with published information. RESULTS Of 374 patients, 175 (46.8%) were male and 199 (53.2%) were female. Obesity was noted in 50 (29.6%) of the 169 patients for whom relevant data are available, and other associated conditions were noted in 185 (53.2%) of the 348 patients. CONCLUSIONS Idiopathic intracranial hypertension among children and adolescents affects boys and girls equally; concurrent obesity occurs less frequently than in adults; and other associated conditions or secondary causes are common.

Effect of Cataract on Automated Perimetry

Humphrey visual fields (30-2 program) were performed on 24 otherwise healthy patients before and after cataract extraction to examine the effect of cataract on automated visual fields. All patients met reliability index criteria and recovered visual acuity of 20/25 or better. The effect of learning associated with repeated testing was controlled with visual fields of the fellow eye. Although a greater absolute threshold recovery occurred in the central region of the visual field after cataract extraction, the percent of threshold recovery did not vary across the visual field except for the most peripheral testing points, which demonstrated less recovery. Thus, cataracts depress an automated visual field fairly uniformly. Clinical grading of cataracts by a single experienced clinician was generally a poor predictor of visual field loss. Only the presence of posterior subcapsular plaque in the visual axis and the preoperative visual acuity correlated significantly with postoperative central threshold recovery. Pattern standard deviation remained unchanged after cataract removal, confirming it as a useful way of estimating visual loss from cataracts.

The Prevalence of Simple Anisocoria

We photographed the pupils of 128 normal subjects in dim light, morning and afternoon, for five consecutive days. Fifty-two of the subjects (41%) had an anisocoria of 0.4 mm or more at one time or another during these five days, but only four (3%) had unequal pupils of 0.4 mm or more in all ten photography sessions. At any given examination, a fairly constant 19% (24 of 128) of the subjects showed this amount of anisocoria. These numbers shifted dramatically when anisocoria was defined as a pupillary inequality of greater than, or less than, 0.4 mm. The prevalence of anisocoria did not vary with the time of day, from day to day, or from week to week, nor was it influenced by the sex, age, or iris color of the subject.

Visual Acuity in Patients with Leber's Congenital Amaurosis and Early Childhood-Onset Retinitis Pigmentosa

PURPOSE To correlate visual acuity of patients with Lebers congenital amaurosis (LCA) and early childhood-onset retinitis pigmentosa (RP) with mutations in underlying LCA genes. DESIGN Multicentered retrospective observational study. PARTICIPANTS After exclusion of 28 subjects, 169 patients with the diagnosis of LCA and 27 patients with early childhood-onset RP were included in the study because the underlying mutations in AIPL1, GUCY2D, RDH12, RPE65, CRX, CRB1, RPGRIP1, CEP290, LCA5, and TULP1 genes could be identified in this cohort of patients. METHODS We collected data on best-corrected visual acuity as recorded at the time of the patients most recent visit to one of the participating ophthalmology departments. The median and range of visual acuities for each genetic subtype were calculated separately for the LCA and early childhood-onset RP groups. MAIN OUTCOME MEASURES The range and median best-corrected visual acuities for each genetic subtype and age-related mean visual acuities for each genetic subtype. RESULTS A wide variation in visual acuity was observed in patients with LCA and RPE65, RDH12, and CRB1 mutations, whereas AIPL1, GUCY2D, CRX, and RPGRIP1 gene mutations were associated with severely decreased visual acuities beginning within the first year of life. It was also noted that patients with either an RPE65 or CRB1 mutation have progressive visual loss with advancing age. Onset of visual symptoms after infancy was associated with a relatively better visual prognosis. CONCLUSIONS The data obtained from this study will help clinicians provide counseling on visual prognosis to patients with known mutations in LCA genes and be of value in future studies aimed at the treatment of LCA and early childhood-onset RP.

Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results.

PURPOSE Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly progressive visual loss when caused by a mutation in the mitochondrial gene encoding NADH:ubiquinone oxidoreductase subunit 4 (ND4). We have initiated a gene therapy trial to determine the safety and tolerability of escalated doses of an adeno-associated virus vector (AAV) expressing a normal ND4 complementary DNA in patients with a G to A mutation at nucleotide 11778 of the mitochondrial genome. DESIGN In this prospective open-label trial (NCT02161380), the study drug (self-complementary AAV [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. The first 3 participants were treated at the low dose of vector (5 × 10(9) vg), and the fourth participant was treated at the medium dose (2.46 × 10(10) vg). The fifth participant with visual loss for less than 12 months received the low dose. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. PARTICIPANTS Five legally blind patients with G11778A LHON. MAIN OUTCOME MEASURES Loss of visual acuity. RESULTS Visual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed. Minor adverse events included a transient increase of intraocular pressure (IOP), exposure keratitis, subconjunctival hemorrhage, a sore throat, and a transient increase in neutralizing antibodies (NAbs) against AAV2 in 1 participant. All blood samples were negative for vector DNA. CONCLUSIONS No serious safety problems were observed in the first 5 participants enrolled in this phase I trial of virus-based gene transfer in this mitochondrial disorder. Additional study follow-up of these and additional participants planned for the next 4 years is needed to confirm these preliminary observations.

High incidence of sympathetic ophthalmia after contact and noncontact neodymium : YAG cyclotherapy

BACKGROUND Two cases of sympathetic ophthalmia occurring after noncontact neodymium:YAG (Nd:YAG) cyclotherapy have previously been reported. In each case, the patient had undergone filtering surgery in the exciting eye. Although in each case Nd:YAG cyclotherapy was the last surgery performed, the inciting event of sympathetic ophthalmia was unclear. METHODS The authors studied three additional patients who developed sympathetic ophthalmia after Nd:YAG cyclotherapy for glaucoma. RESULTS Two patients developed sympathetic ophthalmia 4 months after noncontact Nd:YAG cyclotherapy, and 1 patient developed sympathetic ophthalmia 18 months after contact Nd:YAG cyclotherapy. All patients had previous cataract extractions but no filtering surgery in the exciting eye. Clinical features included chronic iridocyclitis, choroidal folds, Dalen-Fuchs nodules, and optic disc edema. Combining these cases with the two previously reported cases, the incidence of sympathetic ophthalmia at our institution thus far is 5.8% (4 of 69) and 0.67% (1 of 150) after noncontact and contact Nd:YAG cyclotherapy, respectively. CONCLUSIONS The incidence of sympathetic ophthalmia after Nd:YAG cyclotherapy is high compared with other ocular procedures. The clinician should vigilantly monitor patients after Nd:YAG cyclotherapy and report additional cases that may have occurred at other institutions.