Kimberly C. Sippel

Frequency of Somatic and Germ-Line Mosaicism in Retinoblastoma: Implications for Genetic Counseling

Although mosaicism can have important implications for genetic counseling of families with hereditary disorders, information regarding the incidence of mosaicism is available for only a few genetic diseases. Here we describe an evaluation of 156 families with retinoblastoma; the initial oncogenic mutation in the retinoblastoma gene had been identified in these families. In 15 ( approximately 10%) families, we were able to document mosaicism for the initial mutation in the retinoblastoma gene, either in the proband or in one of the probands parents. The true incidence of mosaicism in this group of 156 families is probably higher than our findings indicate; in some additional families beyond the 15 we identified, mosaicism was likely but could not be proven, because somatic or germ-line DNA from key family members was unavailable. Germ-line DNA from two mosaic fathers was analyzed: in one of these, the mutation was detected in both sperm and leukocyte DNA; in the other, the mutation was detected only in sperm DNA. Our data suggest that mosaicism is more common than is generally appreciated, especially in disorders such as retinoblastoma, in which a high proportion of cases represent new mutations. The possibility of mosaicism should always be considered during the genetic counseling of newly identified families with retinoblastoma. As demonstrated here, genetic tests of germ-line DNA can provide valuable information that is not available through analysis of somatic (leukocyte) DNA.

Introduction to the use of the Boston keratoprosthesis

The Boston keratoprosthesis (KPro) is one of several types of artificial cornea manufactured worldwide that are being implanted in increasing numbers in patients with severe corneal diseases and graft failures. The prognosis for long-term success varies greatly between diseases, with autoimmune conditions, such as ocular cicatricial pemphigoid and Stevens–Johnson syndrome, and severe chemical burns remaining difficult. In the potentially much larger cohort with little preoperative inflammation, retention is excellent, complications are manageable and outcome is usually very good. Early implantation in congenital corneal opacities to offset amblyopia shows promise. The Boston KPro uses a ‘collar button’ design of polymethyl methacrylate that is sturdy and easily machined and polished, giving excellent vision if the remainder of the eye is healthy. This is implanted into a carrier corneal graft or into the patient’s own cornea. Holes in the back plate allow nutrition from the aqueous humor to reach the graft and long-term use of around-the-clock soft contact lenses protects the ocular surface from excessive dehydration. In nonautoimmune diseases, these measures have virtually eliminated necrosis and melt of the corneal tissue holding the device. Postoperative prophylactic antibiotics can now fully protect eyes from infection.

Phacoemulsification and thermal wound injury

The technique of lens nucleus phacoemulsification has revolutionized cataract surgery. However, the production of ultrasound energy is associated with heat generation that can result in damage to ocular tissue, in particular the corneoscleral wound site. Thermal damage to the corneoscleral wound site may result in difficulty with wound closure and consequent risk of wound leakage, as well as damage to the adjacent corneal stroma and endothelium, fistula formation, and the induction of high degrees of post-operative astigmatism. The loss of adequate flow of irrigation fluid around the phacoemulsification tip is the key factor in the development of phacoemulsification-induced thermal injury. Use of excessive ultrasound power and production of excessive frictional forces generated by contact of the vibrating phacoemulsification needle with the irrigation sleeve are also factors involved. In the event of a “phacoburn,” a specialized “gape suture” may help minimize surgically-induced astigmatism. The degree of induced astigmatism tends to wane over time; astigmatic keratotomy is an option in the setting of high degrees of residual astigmatism.

Treatment of Refractory Persistent Corneal Epithelial Defects: A Standardized Approach Using Continuous Wear PROSE Therapy

Abstract Purpose: To evaluate continuous wear of a fluid-ventilated, gas-permeable scleral PROSE device using a standardized protocol as treatment for refractory persistent corneal epithelial defects in patients with severe ocular surface disease. Methods: Retrospective review of eight eyes of seven consecutive patients with persistent epithelial defects refractory to traditional therapies. The standardized treatment regimen consisted of: (1) 24-hour-a-day PROSE wear until re-epithelialization was achieved, (2) brief daily device removal, cleaning, disinfection, and reservoir fluid replacement, (3) addition of a benzalkonium chloride (BAK)-free fourth-generation fluoroquinolone antibiotic drop to the reservoir, and (4) transition to long-term, daytime PROSE wear upon re-epithelialization. Results: All eight eyes exhibited resolution of the persistent epithelial defect. No eyes developed microbial keratitis. Four eyes exhibited recurrences; all recurrences promptly responded to reinstitution of continuous wear. Conclusions: Continuous wear of a PROSE device, using a strictly standardized regimen, constitutes an effective, safe treatment option for refractory persistent epithelial defects.

Corneal Nerve Structure and Function After Long-Term Wear of Fluid-Filled Scleral Lens

Purpose: The aim of this study was to determine whether long-term wear of a fluid-filled scleral lens alters basal tear production, corneal sensation, corneal nerve density, and corneal nerve morphology in 2 disease categories. Methods: Patients recruited from the Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) treatment program at the Weill Cornell Medical College were categorized into 2 groups: distorted corneas (DC) or ocular surface disease (OSD). We measured tear production, central corneal sensation, subbasal nerve density and tortuosity, and stromal nerve thickness before and after long-term wear of the prosthetic device used in PROSE treatment, defined as at least 60 days of wear for a minimum of 8 hours a day. Results: Twenty patients were included in the study. After long-term wear of the prosthetic device, tear production decreased in patients with DC (21.2 ± 8.5 to 10.4 ± 4.6 mm; P < 0.0001) but did not change in patients with OSD (7.5 ± 5.2 to 8.7 ± 7.2 mm; P = 0.71). Corneal sensation increased in the DC group (45.6 ± 9.2 to 55.0 ± 5.6 mm; P < 0.05). There was no significant change in sensation in patients with OSD (45.0 ± 8.7 to 49.1 ± 14.8 mm; P = 0.37). Subbasal nerve density, subbasal nerve tortuosity, and stromal nerve thickness remained unchanged in both DC and OSD groups after long-term wear (P > 0.05). Conclusions: Patients with DC had significantly reduced basal tear production and increased corneal sensation after long-term wear of the scleral lens, but patients with OSD did not show any changes in tear production or corneal sensation.

Chemical burns of the eye: The role of retinal injury and new therapeutic possibilities

Purpose: To propose a new treatment paradigm for chemical burns to the eye - in the acute and chronic phases. Methods: Recent laboratory and clinical data on the biology and treatment of chemical burns are analyzed. Results: Corneal blindness from chemical burns can now be successfully treated with a keratoprosthesis, on immediate and intermediate bases. Long term outcomes, however, are hampered by early retinal damage causing glaucoma. New data suggest that rapid diffusion of inflammatory cytokines posteriorly (TNF-&agr;, etc) can severely damage the ganglion cells. Prompt anti-TNF-&agr; treatment is markedly neuroprotective. Long term profound reduction of the intraocular pressure is also vital. Conclusion: A new regimen, in addition to standard treatment, for severe chemical burns is proposed. This involves tumor necrosis factor alpha (TNF-&agr;) inhibition promptly after the accident (primarily for retinal neuroprotection), prophylactic maximal lowering of the intraocular pressure (starting immediately), and keratoprosthesis implantation in a later quiet state.

Cicatrizing Conjunctivitis in a Patient Diagnosed With Drug Reaction With Eosinophilia and Systemic Symptoms/Drug-Induced Hypersensitivity Syndrome but With Features of Stevens-Johnson Syndrome.

Purpose: Severe cutaneous adverse reactions to drugs (SCARs) such as Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS) serve as one of the main reasons for inpatient ophthalmic consultation. Although it is well-recognized that SJS/TEN is associated with severe ocular mucosal inflammation and cicatrizing, potentially blinding, sequelae, this association has not been described in relation to other SCARs. We present a patient fulfilling the diagnostic criteria for probable DRESS/DIHS but not for SJS/TEN, yet exhibiting the severe ocular surface involvement characteristic of SJS/TEN. Methods: Case report. Results: A 64-year-old man presented with bilateral pseudomembranous conjunctivitis and conjunctival denudation (sloughing) in the setting of a maculopapular rash, fever, liver dysfunction, and hematologic abnormalities 1 month after initiating several medications. A skin biopsy was not consistent with SJS/TEN. The patient was diagnosed with probable DRESS/DIHS and treated with high-dose systemic corticosteroids. The ocular surface inflammation was addressed with intensive topical corticosteroid ointment. The pseudomembranes resolved over a 6-week period, but the patient exhibited residual conjunctival scarring of all palpebral surfaces. Conclusions: The development of severe ocular surface mucosal inflammation and denudation with cicatrizing sequelae in a patient carrying a diagnosis of DRESS/DIHS has diagnostic and therapeutic implications for the ophthalmologist. Careful ophthalmic assessment is indicated in any SCAR patient with ophthalmic symptoms, regardless of formal diagnosis. Furthermore, the early therapeutic interventions recently recommended in SJS/TEN to limit the ophthalmic cicatricial sequelae, such as systemic or topical corticosteroids, may be indicated.

Evaluation and Management of Acute Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are eruptive mucocutaneous blistering diseases that can yield severe scarring of the eyelids and ocular surface. This scarring frequently leads to significant consequences such as severe dry eye, photophobia, and decreased vision. The severe sequelae are difficult, if not impossible, to reverse and can lead to lifelong disability for the patients. When applied in the first week of the illness, amniotic membrane transplantation (AMT) has been shown to effectively and consistently prevent the more serious sequelae of SJS and TEN [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]. The cases presented will explore various aspects of the ophthalmologic evaluation of acute SJS/TEN and decisions regarding the use of AMT in the acute phase of the disease, generally defined as the initial blistering portion of the disease that lasts anywhere from 2 to 4 weeks in most cases.