HUMIRA Is Administered by Subcutaneous Injection INITIAL DOSE FOLLOWED BY

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001_rp0916_fc.indd 1 8/26/16 1:44 PM New Indication. New Dosing Regimen. HUMIRA is administered by subcutaneous injection INITIAL DOSE FOLLOWED BY

given every other week starting 80 mg 40 mg 1 week after the initial dose The ﬁ rst injection should be given under the supervision of a healthcare professional. A patient may self-inject HUMIRA after appropriate training and monitoring by a healthcare professional. Visit www.HumiraPro.com to learn more about our education programs for NI uveitis.* *Intermediate, posterior, and panuveitis. Indication¹ Uveitis: HUMIRA is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adult patients. IMPORTANT SAFETY INFORMATION FOR HUMIRA® (adalimumab)1 SERIOUS INFECTIONS If an infection develops, monitor carefully and initiate Patients treated with HUMIRA are at increased risk for appropriate therapy. developing serious infections that may lead to hospitalization Drug interactions with biologic products: A higher rate of serious or death. Most patients who developed these infections infections has been observed in rheumatoid arthritis patients treated were taking concomitant immunosuppressants such as with rituximab who received subsequent treatment with a TNF methotrexate or corticosteroids. blocker. Concurrent use of HUMIRA with biologic DMARDs (e.g., Discontinue HUMIRA if a patient develops a serious infection anakinra or abatacept) or other TNF blockers is not recommended or sepsis. based on the possible increased risk for infections and other potential Reported infections include: pharmacological interactions. Active tuberculosis (TB), including reactivation of latent MALIGNANCY TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for Lymphoma and other malignancies, some fatal, have been latent TB before HUMIRA use and during therapy. Initiate reported in children and adolescent patients treated with treatment for latent TB prior to HUMIRA use. TNF blockers, including HUMIRA. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, lymphoma, have been reported in patients treated with TNF blastomycosis, and pneumocystosis. Patients with blockers, including HUMIRA. These cases have had a very histoplasmosis or other invasive fungal infections may aggressive disease course and have been fatal. The majority present with disseminated, rather than localized, disease. of reported TNF blocker cases have occurred in patients Antigen and antibody testing for histoplasmosis may be with Crohn’s disease or ulcerative colitis and the majority negative in some patients with active infection. Consider were in adolescent and young adult males. Almost all of empiric anti-fungal therapy in patients at risk for invasive these patients had received treatment with azathioprine or fungal infections who develop severe systemic illness. 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria. HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. Carefully consider the risks and benefits of treatment with HUMIRA prior to initiating therapy in patients: 1. with chronic or Consider the risks and benefits of HUMIRA treatment prior to initiating recurrent infection, 2. who have been exposed to TB, 3. with a or continuing therapy in a patient with known malignancy. history of opportunistic infection, 4. who resided in or traveled In clinical trials, more cases of malignancies were observed among in regions where mycoses are endemic, 5. with underlying HUMIRA-treated patients compared to control patients. conditions that may predispose them to infection. Monitor Non-melanoma skin cancer (NMSC) was reported during clinical trials patients closely for the development of signs and symptoms of for HUMIRA-treated patients. Examine all patients, particularly those infection during and after treatment with HUMIRA, including with a history of prolonged immunosuppressant or PUVA therapy, for the possible development of TB in patients who tested negative the presence of NMSC prior to and during treatment with HUMIRA. for latent TB infection prior to initiating therapy. In HUMIRA clinical trials, there was an approximate 3-fold higher Do not start HUMIRA during an active infection, including rate of lymphoma than expected in the general U.S. population. localized infections. Patients with chronic inflammatory diseases, particularly those with Patients older than 65 years, patients with co-morbid conditions, highly active disease and/or chronic exposure to immunosuppressant and/or patients taking concomitant immunosuppressants may be at therapies, may be at higher risk of lymphoma than the general greater risk of infection. population, even in the absence of TNF blockers.

RP0816_Abbvie.indd 2 7/21/16 3:47 PM NOW APPROVED

HUMIRA for NI intermediate, posterior, and panuveitis* A steroid-sparing option proven to prolong time to a combination of disease ﬂ are† and decrease of visual acuity.1

†Disease flare is defined by an increase in 1 or more inflammatory markers: AC cells, vitreous haze, and/or development of new chorioretinal, and/or retinal vascular lesions.

Postmarketing cases of acute and chronic leukemia were reported HEMATOLOGIC REACTIONS with TNF blocker use. Approximately half of the postmarketing Rare reports of pancytopenia, including aplastic anemia, have been cases of malignancies in children, adolescents, and young adults reported with TNF blockers. Medically significant cytopenia has been receiving TNF blockers were lymphomas; other cases included rare infrequently reported with HUMIRA. malignancies associated with immunosuppression and malignancies Consider stopping HUMIRA if significant hematologic abnormalities not usually observed in children and adolescents. occur. HYPERSENSITIVITY CONGESTIVE HEART FAILURE Anaphylaxis and angioneurotic edema have been reported following Worsening or new onset congestive heart failure (CHF) may occur; HUMIRA administration. If a serious allergic reaction occurs, stop exercise caution and monitor carefully. HUMIRA and institute appropriate therapy. HEPATITIS B VIRUS REACTIVATION AUTOIMMUNITY Treatment with HUMIRA may result in the formation of autoantibodies Use of TNF blockers, including HUMIRA, may increase the risk of and, rarely, in development of a lupus-like syndrome. Discontinue reactivation of hepatitis B virus (HBV) in patients who are chronic treatment if symptoms of a lupus-like syndrome develop. carriers. Some cases have been fatal. Evaluate patients at risk for HBV infection for prior evidence of HBV IMMUNIZATIONS infection before initiating TNF blocker therapy. Patients on HUMIRA should not receive live vaccines. Exercise caution in patients who are carriers of HBV and monitor them Pediatric patients, if possible, should be brought up to date with all during and after HUMIRA treatment. immunizations before initiating HUMIRA therapy. Discontinue HUMIRA and begin antiviral therapy in patients who The safety of administering live or live-attenuated vaccines in infants develop HBV reactivation. Exercise caution when resuming HUMIRA exposed to HUMIRA in utero is unknown. Risks and benefits should after HBV treatment. be considered prior to vaccinating (live or live-attenuated) exposed NEUROLOGIC REACTIONS infants. TNF blockers, including HUMIRA, have been associated with rare ADVERSE REACTIONS cases of new onset or exacerbation of central nervous system and The most common adverse reactions in HUMIRA clinical trials (>10%) peripheral demyelinating diseases, including multiple sclerosis, optic were: infections (e.g., upper respiratory, sinusitis), injection site neuritis, and Guillain-Barré syndrome. reactions, headache, and rash. Exercise caution when considering HUMIRA for patients with these disorders; discontinuation of HUMIRA should be considered if any of these disorders develop. There is a known association between intermediate uveitis and central demyelinating disorders.

Reference: 1. HUMIRA Injection [package insert]. North Chicago, IL: AbbVie Inc. Please see Brief Summary of full Prescribing Information on the following page. ©2016 AbbVie Inc. North Chicago, IL 60064 64C-1859319 June 2016 Printed in U.S.A.

RP0816_Abbvie.indd 3 7/21/16 3:47 PM ® (adalimumab) PROFESSIONAL BRIEF SUMMARY HUMIRA CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION Uveitis In controlled trials of other TNF blockers in adult patients at higher risk for WARNING: SERIOUS INFECTIONS AND MALIGNANCY HUMIRA is indicated for the treatment of non-infectious intermediate, malignancies (i.e., patients with COPD with a significant smoking history SERIOUS INFECTIONS posterior and panuveitis in adult patients. and cyclophosphamide-treated patients with Wegener’s granulomatosis), a Patients treated with HUMIRA are at increased risk for developing CONTRAINDICATIONS greater portion of malignancies occurred in the TNF blocker group compared serious infections that may lead to hospitalization or death [see to the control group. None. Warnings and Precautions]. Most patients who developed these Non-Melanoma Skin Cancer WARNINGS AND PRECAUTIONS infections were taking concomitant immunosuppressants such as During the controlled portions of 39 global HUMIRA clinical trials in adult methotrexate or corticosteroids. Serious Infections patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate (95% confidence Discontinue HUMIRA if a patient develops a serious infection or Patients treated with HUMIRA are at increased risk for developing serious interval) of NMSC was 0.8 (0.52, 1.09) per 100 patient-years among sepsis. infections involving various organ systems and sites that may lead to HUMIRA-treated patients and 0.2 (0.10, 0.59) per 100 patient-years among Reported infections include: hospitalization or death [see Boxed Warning]. Opportunistic infections control-treated patients. Examine all patients, and in particular patients • Active tuberculosis (TB), including reactivation of latent TB. due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other with a medical history of prior prolonged immunosuppressant therapy or Patients with TB have frequently presented with disseminated opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, psoriasis patients with a history of PUVA treatment for the presence of or extrapulmonary disease. Test patients for latent TB before coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis NMSC prior to and during treatment with HUMIRA. HUMIRA use and during therapy. Initiate treatment for latent TB and tuberculosis have been reported with TNF blockers. Patients have Lymphoma and Leukemia frequently presented with disseminated rather than localized disease. prior to HUMIRA use. In the controlled portions of clinical trials of all the TNF-blockers in adults, • Invasive fungal infections, including histoplasmosis, The concomitant use of a TNF blocker and abatacept or anakinra was more cases of lymphoma have been observed among TNF-blocker-treated coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and associated with a higher risk of serious infections in patients with patients compared to control-treated patients. In the controlled portions of pneumocystosis. Patients with histoplasmosis or other invasive rheumatoid arthritis (RA); therefore, the concomitant use of HUMIRA and 39 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC fungal infections may present with disseminated, rather than these biologic products is not recommended in the treatment of patients Ps, HS and UV, 2 lymphomas occurred among 7973 HUMIRA-treated patients localized, disease. Antigen and antibody testing for histoplasmosis with RA [see Warnings and Precautions and Drug Interactions]. versus 1 among 4848 control-treated patients. In 52 global controlled and may be negative in some patients with active infection. Consider Treatment with HUMIRA should not be initiated in patients with an active uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, empiric anti-fungal therapy in patients at risk for invasive fungal infection, including localized infections. Patients greater than 65 years of CD, UC, Ps, HS and UV with a median duration of approximately 0.7 years, infections who develop severe systemic illness. age, patients with co-morbid conditions and/or patients taking concomitant including 24,605 patients and over 40,215 patient-years of HUMIRA, the • Bacterial, viral and other infections due to opportunistic immunosuppressants (such as corticosteroids or methotrexate), may be at observed rate of lymphomas was approximately 0.11 per 100 patient-years. pathogens, including Legionella and Listeria. greater risk of infection. Consider the risks and benefits of treatment prior to This is approximately 3-fold higher than expected in the general U.S. initiating therapy in patients: population according to the SEER database (adjusted for age, gender, and Carefully consider the risks and benefits of treatment with HUMIRA race). Rates of lymphoma in clinical trials of HUMIRA cannot be compared to prior to initiating therapy in patients with chronic or recurrent • with chronic or recurrent infection; • who have been exposed to tuberculosis; rates of lymphoma in clinical trials of other TNF blockers and may not predict infection. the rates observed in a broader patient population. Patients with RA and other Monitor patients closely for the development of signs and • with a history of an opportunistic infection; chronic inflammatory diseases, particularly those with highly active disease symptoms of infection during and after treatment with HUMIRA, • who have resided or traveled in areas of endemic tuberculosis or and/or chronic exposure to immunosuppressant therapies, may be at a higher including the possible development of TB in patients who tested endemic mycoses, such as histoplasmosis, coccidioidomycosis, or risk (up to several fold) than the general population for the development of negative for latent TB infection prior to initiating therapy [see blastomycosis; or lymphoma, even in the absence of TNF blockers. Post-marketing cases of Warnings and Precautions and Adverse Reactions]. • with underlying conditions that may predispose them to infection. acute and chronic leukemia have been reported in association with TNF- MALIGNANCY Tuberculosis blocker use in RA and other indications. Even in the absence of TNF-blocker Lymphoma and other malignancies, some fatal, have been therapy, patients with RA may be at a higher risk (approximately 2-fold) than Cases of reactivation of tuberculosis and new onset tuberculosis infections the general population for the development of leukemia. reported in children and adolescent patients treated with TNF have been reported in patients receiving HUMIRA, including patients who blockers including HUMIRA [see Warnings and Precautions]. have previously received treatment for latent or active tuberculosis. Reports Malignancies in Pediatric Patients and Young Adults Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), included cases of pulmonary and extrapulmonary (i.e., disseminated) Malignancies, some fatal, have been reported among children, adolescents, a rare type of T-cell lymphoma, have been reported in patients tuberculosis. Evaluate patients for tuberculosis risk factors and test for and young adults who received treatment with TNF-blockers (initiation treated with TNF blockers including HUMIRA. These cases have latent infection prior to initiating HUMIRA and periodically during therapy. of therapy ≤ 18 years of age), of which HUMIRA is a member [see Boxed had a very aggressive disease course and have been fatal. The Treatment of latent tuberculosis infection prior to therapy with TNF blocking Warning]. Approximately half the cases were lymphomas, including majority of reported TNF blocker cases have occurred in patients agents has been shown to reduce the risk of tuberculosis reactivation Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a with Crohn’s disease or ulcerative colitis and the majority were during therapy. variety of different malignancies and included rare malignancies usually in adolescent and young adult males. Almost all these patients associated with immunosuppression and malignancies that are not usually had received treatment with azathioprine or 6-mercaptopurine Consider anti-tuberculosis therapy prior to initiation of HUMIRA in patients observed in children and adolescents. The malignancies occurred after a (6–MP) concomitantly with a TNF blocker at or prior to diagnosis. with a past history of latent or active tuberculosis in whom an adequate median of 30 months of therapy (range 1 to 84 months). Most of the patients It is uncertain whether the occurrence of HSTCL is related to use course of treatment cannot be confirmed, and for patients with a negative were receiving concomitant immunosuppressants. These cases were of a TNF blocker or a TNF blocker in combination with these other test for latent tuberculosis but having risk factors for tuberculosis infection. reported post-marketing and are derived from a variety of sources including immunosuppressants [see Warnings and Precautions]. Despite prophylactic treatment for tuberculosis, cases of reactivated registries and spontaneous postmarketing reports. tuberculosis have occurred in patients treated with HUMIRA. Consultation INDICATIONS AND USAGE with a physician with expertise in the treatment of tuberculosis is Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF Rheumatoid Arthritis recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. blockers including HUMIRA [see Boxed Warning]. These cases have had a very HUMIRA is indicated for reducing signs and symptoms, inducing major aggressive disease course and have been fatal. The majority of reported TNF clinical response, inhibiting the progression of structural damage, and Strongly consider tuberculosis in the differential diagnosis in patients who blocker cases have occurred in patients with Crohn’s disease or ulcerative improving physical function in adult patients with moderately to severely develop a new infection during HUMIRA treatment, especially in patients colitis and the majority were in adolescent and young adult males. Almost active rheumatoid arthritis. HUMIRA can be used alone or in combination who have previously or recently traveled to countries with a high prevalence all of these patients had received treatment with the immunosuppressants with methotrexate or other non-biologic disease-modifying anti-rheumatic of tuberculosis, or who have had close contact with a person with active azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker drugs (DMARDs). tuberculosis. at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is Juvenile Idiopathic Arthritis Monitoring related to use of a TNF blocker or a TNF blocker in combination with these HUMIRA is indicated for reducing signs and symptoms of moderately Closely monitor patients for the development of signs and symptoms other immunosuppressants. The potential risk with the combination of to severely active polyarticular juvenile idiopathic arthritis in patients 2 of infection during and after treatment with HUMIRA, including the azathioprine or 6-mercaptopurine and HUMIRA should be carefully considered. years of age and older. HUMIRA can be used alone or in combination with development of tuberculosis in patients who tested negative for latent Hypersensitivity Reactions methotrexate. tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis Anaphylaxis and angioneurotic edema have been reported following HUMIRA infection may also be falsely negative while on therapy with HUMIRA. Psoriatic Arthritis administration. If an anaphylactic or other serious allergic reaction occurs, Discontinue HUMIRA if a patient develops a serious infection or sepsis. For HUMIRA is indicated for reducing signs and symptoms, inhibiting the immediately discontinue administration of HUMIRA and institute appropriate a patient who develops a new infection during treatment with HUMIRA, therapy. In clinical trials of HUMIRA in adults, allergic reactions (e.g., allergic progression of structural damage, and improving physical function in adult closely monitor them, perform a prompt and complete diagnostic workup patients with active psoriatic arthritis. HUMIRA can be used alone or in rash, anaphylactoid reaction, fixed drug reaction, non-specified drug appropriate for an immunocompromised patient, and initiate appropriate reaction, urticaria) have been observed. combination with non-biologic DMARDs. antimicrobial therapy. Ankylosing Spondylitis Hepatitis B Virus Reactivation Invasive Fungal Infections Use of TNF blockers, including HUMIRA, may increase the risk of reactivation HUMIRA is indicated for reducing signs and symptoms in adult patients with If patients develop a serious systemic illness and they reside or travel in active ankylosing spondylitis. of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In regions where mycoses are endemic, consider invasive fungal infection in some instances, HBV reactivation occurring in conjunction with TNF blocker Adult Crohn’s Disease the differential diagnosis. Antigen and antibody testing for histoplasmosis therapy has been fatal. The majority of these reports have occurred in patients HUMIRA is indicated for reducing signs and symptoms and inducing may be negative in some patients with active infection. Consider appropriate concomitantly receiving other medications that suppress the immune system, and maintaining clinical remission in adult patients with moderately to empiric antifungal therapy, taking into account both the risk for severe which may also contribute to HBV reactivation. Evaluate patients at risk for severely active Crohn’s disease who have had an inadequate response to fungal infection and the risks of antifungal therapy, while a diagnostic HBV infection for prior evidence of HBV infection before initiating TNF blocker conventional therapy. HUMIRA is indicated for reducing signs and symptoms workup is being performed. To aid in the management of such patients, therapy. Exercise caution in prescribing TNF blockers for patients identified and inducing clinical remission in these patients if they have also lost consider consultation with a physician with expertise in the diagnosis and as carriers of HBV. Adequate data are not available on the safety or efficacy of response to or are intolerant to infliximab. treatment of invasive fungal infections. treating patients who are carriers of HBV with anti-viral therapy in conjunction Pediatric Crohn’s Disease Malignancies with TNF blocker therapy to prevent HBV reactivation. In patients who develop HUMIRA is indicated for reducing signs and symptoms and inducing and Consider the risks and benefits of TNF-blocker treatment including HUMIRA HBV reactivation, stop HUMIRA and initiate effective anti-viral therapy with maintaining clinical remission in pediatric patients 6 years of age and prior to initiating therapy in patients with a known malignancy other appropriate supportive treatment. The safety of resuming TNF blocker therapy older with moderately to severely active Crohn’s disease who have had than a successfully treated non-melanoma skin cancer (NMSC) or when after HBV reactivation is controlled is not known. an inadequate response to corticosteroids or immunomodulators such as considering continuing a TNF blocker in patients who develop a malignancy. Neurologic Reactions azathioprine, 6-mercaptopurine, or methotrexate. Malignancies in Adults Use of TNF blocking agents, including HUMIRA, has been associated with Ulcerative Colitis In the controlled portions of clinical trials of some TNF-blockers, including rare cases of new onset or exacerbation of clinical symptoms and/or HUMIRA is indicated for inducing and sustaining clinical remission in adult HUMIRA, more cases of malignancies have been observed among TNF- radiographic evidence of central nervous system demyelinating disease, patients with moderately to severely active ulcerative colitis who have had blocker-treated adult patients compared to control-treated adult patients. including multiple sclerosis (MS) and optic neuritis, and peripheral an inadequate response to immunosuppressants such as corticosteroids, During the controlled portions of 39 global HUMIRA clinical trials in adult demyelinating disease, including Guillain-Barré syndrome. Exercise azathioprine or 6-mercaptopurine (6-MP). The effectiveness of HUMIRA patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing caution in considering the use of HUMIRA in patients with preexisting or has not been established in patients who have lost response to or were spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC) plaque psoriasis recent-onset central or peripheral nervous system demyelinating disorders; intolerant to TNF blockers. (Ps), hidradenitis suppurativa (HS), and uveitis (UV) malignancies, other than discontinuation of HUMIRA should be considered if any of these disorders develop. There is a known association between intermediate uveitis and Plaque Psoriasis non-melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.7 (0.48, 1.03) per 100 patient-years central demyelinating disorders. HUMIRA is indicated for the treatment of adult patients with moderate to among 7973 HUMIRA-treated patients versus a rate of 0.7 (0.41, 1.17) per Hematological Reactions severe chronic plaque psoriasis who are candidates for systemic therapy 100 patient-years among 4848 control-treated patients (median duration Rare reports of pancytopenia including aplastic anemia have been or phototherapy, and when other systemic therapies are medically less of treatment of 4 months for HUMIRA-treated patients and 4 months for appropriate. HUMIRA should only be administered to patients who will be reported with TNF blocking agents. Adverse reactions of the hematologic control-treated patients). In 52 global controlled and uncontrolled clinical system, including medically significant cytopenia (e.g., thrombocytopenia, closely monitored and have regular follow-up visits with a physician [see trials of HUMIRA in adult patients with RA, PsA, AS, CD, UC, Ps, HS and Boxed Warning and Warnings and Precautions]. leukopenia) have been infrequently reported with HUMIRA. The causal UV, the most frequently observed malignancies, other than lymphoma and relationship of these reports to HUMIRA remains unclear. Advise all patients Hidradenitis Suppurativa NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies to seek immediate medical attention if they develop signs and symptoms HUMIRA is indicated for the treatment of moderate to severe hidradenitis in HUMIRA-treated patients in the controlled and uncontrolled portions of the suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, suppurativa. studies were similar in type and number to what would be expected in the bleeding, pallor) while on HUMIRA. Consider discontinuation of HUMIRA general U.S. population according to the SEER database (adjusted for age, therapy in patients with confirmed significant hematologic abnormalities. gender, and race).

RRP0816_AbbvieP0816_Abbvie PPII 11.indd.indd 1 77/21/16/21/16 3:553:55 PMPM Use with Anakinra In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, RA-III, and RA-IV). HUMIRA was studied primarily in placebo-controlled Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF- or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg trials and in long-term follow up studies for up to 36 months duration. blocker, was associated with a greater proportion of serious infections and every other week) in adult patients with CD with a control period duration The population had a mean age of 54 years, 77% were female, 91% were neutropenia and no added benefit compared with the TNF-blocker alone in ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of Caucasian and had moderately to severely active rheumatoid arthritis. Most patients with RA. Therefore, the combination of HUMIRA and anakinra is not HUMIRA-treated patients and 0.9% of control-treated patients. In the Phase patients received 40 mg HUMIRA every other week. recommended [see Drug Interactions]. 3 trial of HUMIRA in pediatric patients with Crohn’s disease which evaluated Table 1 summarizes reactions reported at a rate of at least 5% in patients Heart Failure efficacy and safety of two body weight based maintenance dose regimens treated with HUMIRA 40 mg every other week compared to placebo and with following body weight based induction therapy up to 52 weeks of treatment, Cases of worsening congestive heart failure (CHF) and new onset CHF have an incidence higher than placebo. In Study RA-III, the types and frequencies ALT elevations ≥ 3 x ULN occurred in 2.6% (5/192) of patients, of whom 4 of adverse reactions in the second year open-label extension were similar to been reported with TNF blockers. Cases of worsening CHF have also been were receiving concomitant immunosuppressants at baseline; none of these observed with HUMIRA. Exercise caution when using HUMIRA in patients those observed in the one-year double-blind portion. patients discontinued due to abnormalities in ALT tests. In controlled Phase Table 1. Adverse Reactions Reported by ≥5% of Patients Treated who have heart failure and monitor them carefully. 3 trials of HUMIRA (initial doses of 160 mg and 80 mg on Days 1 and 15 Autoimmunity with HUMIRA During Placebo-Controlled Period of Pooled RA respectively, followed by 40 mg every other week) in patients with UC with Studies (Studies RA-I, RA-II, RA-III, and RA-IV) Treatment with HUMIRA may result in the formation of autoantibodies and, control period duration ranging from 1 to 52 weeks, ALT elevations rarely, in the development of a lupus-like syndrome. If a patient develops ≥3 x ULN occurred in 1.5% of HUMIRA-treated patients and 1.0% of control- HUMIRA Placebo symptoms suggestive of a lupus-like syndrome following treatment with treated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 40 mg subcutaneous HUMIRA, discontinue treatment [see Adverse Reactions]. 80 mg then 40 mg every other week) in patients with Ps with control period Every Other Week Immunizations duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients. In Adverse Reaction (Preferred Term) (N=705) (N=690) In a placebo-controlled clinical trial of patients with RA, no difference was controlled trials of HUMIRA (initial doses of 160 mg at Week 0 and 80 mg at detected in anti-pneumococcal antibody response between HUMIRA and Week 2, followed by 40 mg every week starting at Week 4), in subjects with Respiratory placebo treatment groups when the pneumococcal polysaccharide vaccine HS with a control period duration ranging from 12 to 16 weeks, ALT elevations Upper respiratory infection 17% 13% and influenza vaccine were administered concurrently with HUMIRA. ≥ 3 x ULN occurred in 0.3% of HUMIRA-treated subjects and 0.6% of control- Patients on HUMIRA may receive concurrent vaccinations, except for live treated subjects. In controlled trials of HUMIRA (initial doses of 80 mg at Week Sinusitis 11% 9% vaccines. No data are available on the secondary transmission of infection 0 followed by 40 mg every other week starting at Week 1) in patients with Flu syndrome 7% 6% by live vaccines in patients receiving HUMIRA. uveitis with an exposure of 165.4 PYs and 119.8 PYs in HUMIRA-treated and It is recommended that pediatric patients, if possible, be brought up to date control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in Gastrointestinal with all immunizations in agreement with current immunization guidelines 2.4% of HUMIRA-treated patients and 2.4% of control-treated patients. Nausea 9% 8% prior to initiating HUMIRA therapy. Patients on HUMIRA may receive Immunogenicity concurrent vaccinations, except for live vaccines. Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time Abdominal pain 7% 4% The safety of administering live or live-attenuated vaccines in infants points for antibodies to adalimumab during the 6- to 12-month period. Laboratory Tests* exposed to HUMIRA in utero is unknown. Risks and benefits should be Approximately 5% (58 of 1062) of adult RA patients receiving HUMIRA considered prior to vaccinating (live or live-attenuated) exposed infants [see developed low-titer antibodies to adalimumab at least once during Laboratory test abnormal 8% 7% Use in Specific Populations]. treatment, which were neutralizing in vitro. Patients treated with concomitant Hypercholesterolemia 6% 4% Use with Abatacept methotrexate (MTX) had a lower rate of antibody development than patients In controlled trials, the concurrent administration of TNF-blockers and on HUMIRA monotherapy (1% versus 12%). No apparent correlation of Hyperlipidemia 7% 5% antibody development to adverse reactions was observed. With monotherapy, abatacept was associated with a greater proportion of serious infections than Hematuria 5% 4% the use of a TNF-blocker alone; the combination therapy, compared to the patients receiving every other week dosing may develop antibodies more use of a TNF-blocker alone, has not demonstrated improved clinical benefit frequently than those receiving weekly dosing. In patients receiving the Alkaline phosphatase increased 5% 3% in the treatment of RA. Therefore, the combination of abatacept with TNF- recommended dosage of 40 mg every other week as monotherapy, the blockers including HUMIRA is not recommended [see Drug Interactions]. ACR 20 response was lower among antibody-positive patients than among Other ADVERSE REACTIONS antibody-negative patients. The long-term immunogenicity of HUMIRA is Headache 12% 8% unknown. The most serious adverse reactions described elsewhere in the labeling Rash 12% 6% include the following: In patients with polyarticular JIA who were 4 to 17 years of age, adalimumab antibodies were identified in 16% of HUMIRA-treated patients. In patients Accidental injury 10% 8% • Serious Infections [see Warnings and Precautions] receiving concomitant MTX, the incidence was 6% compared to 26% with • Malignancies [see Warnings and Precautions] HUMIRA monotherapy. In patients with polyarticular JIA who were 2 to <4 Injection site reaction ** 8% 1% Clinical Trials Experience years of age or 4 years of age and older weighing <15 kg, adalimumab Back pain 6% 4% The most common adverse reaction with HUMIRA was injection site antibodies were identified in 7% (1 of 15) of HUMIRA-treated patients, and reactions. In placebo-controlled trials, 20% of patients treated with HUMIRA the one patient was receiving concomitant MTX. Urinary tract infection 8% 5% developed injection site reactions (erythema and/or itching, hemorrhage, In patients with AS, the rate of development of antibodies to adalimumab in Hypertension 5% 3% pain or swelling), compared to 14% of patients receiving placebo. Most HUMIRA-treated patients was comparable to patients with RA. injection site reactions were described as mild and generally did not In patients with PsA, the rate of antibody development in patients receiving * Laboratory test abnormalities were reported as adverse reactions in necessitate drug discontinuation. HUMIRA monotherapy was comparable to patients with RA; however, in European trials The proportion of patients who discontinued treatment due to adverse patients receiving concomitant MTX the rate was 7% compared to 1% in RA. ** Does not include injection site erythema, itching, hemorrhage, pain reactions during the double-blind, placebo-controlled portion of studies In adult patients with CD, the rate of antibody development was 3%. or swelling in patients with RA (i.e., Studies RA-I, RA-II, RA-III and RA-IV) was 7% for In pediatric patients with Crohn’s disease, the rate of antibody development Juvenile Idiopathic Arthritis Clinical Studies patients taking HUMIRA and 4% for placebo-treated patients. The most in patients receiving HUMIRA was 3%. However, due to the limitation of the common adverse reactions leading to discontinuation of HUMIRA in these RA assay conditions, antibodies to adalimumab could be detected only when In general, the adverse reactions in the HUMIRA-treated patients in the studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%). serum adalimumab levels were < 2 mcg/mL. Among the patients whose polyarticular juvenile idiopathic arthritis (JIA) trials (Studies JIA-I and JIA-II) Infections serum adalimumab levels were < 2 mcg/mL (approximately 32% of total were similar in frequency and type to those seen in adult patients [see In the controlled portions of the 39 global HUMIRA clinical trials in adult patients studied), the immunogenicity rate was 10%. Warnings and Precautions and Adverse Reactions]. Important findings and differences from adults are discussed in the following paragraphs. patients with RA, PsA, AS, CD, UC, HS and UV, the rate of serious infections In patients with moderately to severely active UC, the rate of antibody was 4.3 per 100 patient-years in 7973 HUMIRA-treated patients versus a development in patients receiving HUMIRA was 5%. However, due to the In Study JIA-I, HUMIRA was studied in 171 patients who were 4 to 17 rate of 2.9 per 100 patient-years in 4848 control-treated patients. Serious limitation of the assay conditions, antibodies to adalimumab could be years of age, with polyarticular JIA. Severe adverse reactions reported infections observed included pneumonia, septic arthritis, prosthetic detected only when serum adalimumab levels were < 2 mcg/mL. Among the in the study included neutropenia, streptococcal pharyngitis, increased and post-surgical infections, erysipelas, cellulitis, diverticulitis, and patients whose serum adalimumab levels were < 2 mcg/mL (approximately aminotransferases, herpes zoster, myositis, metrorrhagia, and appendicitis. pyelonephritis [see Warnings and Precautions]. 25% of total patients studied), the immunogenicity rate was 20.7%. Serious infections were observed in 4% of patients within approximately 2 Tuberculosis and Opportunistic Infections years of initiation of treatment with HUMIRA and included cases of herpes In patients with Ps, the rate of antibody development with HUMIRA simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster. In 52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, monotherapy was 8%. However, due to the limitation of the assay UC, Ps, HS and UV that included 24,605 HUMIRA-treated patients, the rate conditions, antibodies to adalimumab could be detected only when serum In Study JIA-I, 45% of patients experienced an infection while receiving of reported active tuberculosis was 0.20 per 100 patient-years and the rate adalimumab levels were < 2 mcg/mL. Among the patients whose serum HUMIRA with or without concomitant MTX in the first 16 weeks of of positive PPD conversion was 0.09 per 100 patient-years. In a subgroup adalimumab levels were < 2 mcg/mL (approximately 40% of total patients treatment. The types of infections reported in HUMIRA-treated patients of 10,113 U.S. and Canadian HUMIRA-treated patients, the rate of reported studied), the immunogenicity rate was 20.7%. In Ps patients who were on were generally similar to those commonly seen in polyarticular JIA patients active TB was 0.05 per 100 patient-years and the rate of positive PPD HUMIRA monotherapy and subsequently withdrawn from the treatment, the who are not treated with TNF blockers. Upon initiation of treatment, the conversion was 0.07 per 100 patient-years. These trials included reports rate of antibodies to adalimumab after retreatment was similar to the rate most common adverse reactions occurring in this patient population of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases observed prior to withdrawal. treated with HUMIRA were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in occurred within the first eight months after initiation of therapy and may In subjects with moderate to severe HS, the rate of anti-adalimumab reflect recrudescence of latent disease. In these global clinical trials, cases patients receiving HUMIRA was granuloma annulare which did not lead to antibody development in subjects treated with HUMIRA was 6.5%. discontinuation of HUMIRA treatment. of serious opportunistic infections have been reported at an overall rate of However, because of the limitation of the assay conditions, antibodies 0.05 per 100 patient-years. Some cases of serious opportunistic infections to adalimumab could be detected only when serum adalimumab levels In the first 48 weeks of treatment in Study JIA-I, non-serious hypersensitivity and TB have been fatal [see Warnings and Precautions]. were < 2 mcg/mL. Among subjects who stopped HUMIRA treatment for reactions were seen in approximately 6% of patients and included primarily Autoantibodies up to 24 weeks and in whom adalimumab serum levels subsequently localized allergic hypersensitivity reactions and allergic rash. In the rheumatoid arthritis controlled trials, 12% of patients treated with declined to < 2 mcg/mL (approximately 22% of total subjects studied), the In Study JIA-I, 10% of patients treated with HUMIRA who had negative HUMIRA and 7% of placebo-treated patients that had negative baseline ANA immunogenicity rate was 28%. baseline anti-dsDNA antibodies developed positive titers after 48 weeks of titers developed positive titers at week 24. Two patients out of 3046 treated In patients with non-infectious uveitis, anti-adalimumab antibodies were treatment. No patient developed clinical signs of autoimmunity during the with HUMIRA developed clinical signs suggestive of new-onset lupus-like identified in 4.8% (12/249) of patients treated with adalimumab. However, clinical trial. syndrome. The patients improved following discontinuation of therapy. No due to the limitation of the assay conditions, antibodies to adalimumab Approximately 15% of patients treated with HUMIRA developed mild- patients developed lupus nephritis or central nervous system symptoms. could be detected only when serum adalimumab levels were < 2 mcg/mL. to-moderate elevations of creatine phosphokinase (CPK) in Study JIA-I. The impact of long-term treatment with HUMIRA on the development of Among the patients whose serum adalimumab levels were < 2 mcg/mL Elevations exceeding 5 times the upper limit of normal were observed in autoimmune diseases is unknown. (approximately 23% of total patients studied), the immunogenicity rate was several patients. CPK levels decreased or returned to normal in all patients. Liver Enzyme Elevations 21.1%. Using an assay which could measure an anti-adalimumab antibody Most patients were able to continue HUMIRA without interruption. titer in all patients, titers were measured in 39.8% (99/249) of non-infectious There have been reports of severe hepatic reactions including acute liver In Study JIA-II, HUMIRA was studied in 32 patients who were 2 to <4 years uveitis patients treated with adalimumab. No correlation of antibody of age or 4 years of age and older weighing <15 kg with polyarticular JIA. failure in patients receiving TNF-blockers. In controlled Phase 3 trials of development to safety or efficacy outcomes was observed. HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with The safety profile for this patient population was similar to the safety profile control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 The data reflect the percentage of patients whose test results were seen in patients 4 to 17 years of age with polyarticular JIA. x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control- considered positive for antibodies to adalimumab or titers, and are highly In Study JIA-II, 78% of patients experienced an infection while receiving treated patients. Since many of these patients in these trials were also dependent on the assay. The observed incidence of antibody (including HUMIRA. These included nasopharyngitis, bronchitis, upper respiratory tract taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), neutralizing antibody) positivity in an assay is highly dependent on several infection, otitis media, and were mostly mild to moderate in severity. Serious the relationship between HUMIRA and the liver enzyme elevations is not factors including assay sensitivity and specificity, assay methodology, infections were observed in 9% of patients receiving HUMIRA in the study clear. In a controlled Phase 3 trial of HUMIRA in patients with polyarticular sample handling, timing of sample collection, concomitant medications, and included dental caries, rotavirus gastroenteritis, and varicella. JIA who were 4 to 17 years, ALT elevations ≥ 3 x ULN occurred in 4.4% and underlying disease. For these reasons, comparison of the incidence of In Study JIA-II, non-serious allergic reactions were observed in 6% of of HUMIRA-treated patients and 1.5% of control-treated patients (ALT antibodies to adalimumab with the incidence of antibodies to other products patients and included intermittent urticaria and rash, which were all mild more common than AST); liver enzyme test elevations were more frequent may be misleading. in severity. among those treated with the combination of HUMIRA and MTX than those Other Adverse Reactions Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies treated with HUMIRA alone. In general, these elevations did not lead to Rheumatoid Arthritis Clinical Studies HUMIRA has been studied in 395 patients with psoriatic arthritis (PsA) in two discontinuation of HUMIRA treatment. No ALT elevations ≥ 3 x ULN occurred The data described below reflect exposure to HUMIRA in 2468 patients, placebo-controlled trials and in an open label study and in 393 patients with in the open-label study of HUMIRA in patients with polyarticular JIA who including 2073 exposed for 6 months, 1497 exposed for greater than one ankylosing spondylitis (AS) in two placebo-controlled studies. The safety were 2 to <4 years. year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, profile for patients with PsA and AS treated with HUMIRA 40 mg every other

RRP0816_AbbvieP0816_Abbvie PPI2.inddI2.indd 1 77/21/16/21/16 4:024:02 PMPM week was similar to the safety profile seen in patients with RA, HUMIRA with other biologic DMARDS (e.g., anakinra and abatacept) or other TNF TNF-blockers including HUMIRA [see Boxed Warning and Warnings and Studies RA-I through IV. blockers is not recommended based upon the possible increased risk for Precautions]. Adult Crohn’s Disease Clinical Studies infections and other potential pharmacological interactions. Juvenile Idiopathic Arthritis HUMIRA has been studied in 1478 adult patients with Crohn’s disease (CD) Live Vaccines In Study JIA-I, HUMIRA was shown to reduce signs and symptoms of active in four placebo-controlled and two open-label extension studies. The safety Avoid the use of live vaccines with HUMIRA [see Warnings and Precautions]. polyarticular JIA in patients 4 to 17 years of age [see Clinical Studies]. In profile for adult patients with CD treated with HUMIRA was similar to the Cytochrome P450 Substrates Study JIA-II, the safety profile for patients 2 to <4 years of age was similar safety profile seen in patients with RA. The formation of CYP450 enzymes may be suppressed by increased levels to the safety profile for patients 4 to 17 years of age with polyarticular JIA Pediatric Crohn’s Disease Clinical Studies of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible [see Adverse Reactions]. HUMIRA has not been studied in patients with HUMIRA has been studied in 192 pediatric patients with Crohn’s disease in for a molecule that antagonizes cytokine activity, such as adalimumab, polyarticular JIA less than 2 years of age or in patients with a weight below one double-blind study (Study PCD-I) and one open-label extension study. The to influence the formation of CYP450 enzymes. Upon initiation or 10 kg. safety profile for pediatric patients with Crohn’s disease treated with HUMIRA discontinuation of HUMIRA in patients being treated with CYP450 substrates The safety of HUMIRA in patients in the polyarticular JIA trials was generally was similar to the safety profile seen in adult patients with Crohn’s disease. with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or similar to that observed in adults with certain exceptions [see Adverse During the 4 week open label induction phase of Study PCD-I, the most drug concentration (e.g., cyclosporine or theophylline) is recommended and Reactions]. common adverse reactions occurring in the pediatric population treated the individual dose of the drug product may be adjusted as needed. Pediatric Crohn’s Disease with HUMIRA were injection site pain and injection site reaction (6% and USE IN SPECIFIC POPULATIONS The safety and effectiveness of HUMIRA for reducing signs and 5%, respectively). Pregnancy symptoms and inducing and maintaining clinical remission have been A total of 67% of children experienced an infection while receiving HUMIRA Limited clinical data are available from the Humira Pregnancy Registry. established in pediatric patients 6 years of age and older with moderately in Study PCD-I. These included upper respiratory tract infection and Excluding lost-to-follow-up, data from the registry reports a rate of 5.6% for to severely active Crohn’s disease who have had an inadequate nasopharyngitis. major birth defects with first trimester use of adalimumab in pregnant women response to corticosteroids or immunomodulators such as azathioprine, A total of 5% of children experienced a serious infection while receiving with rheumatoid arthritis (RA), and a rate of 7.8% and 5.5% for major birth 6-mercaptopurine, or methotrexate. Use of HUMIRA in this age group HUMIRA in Study PCD-I. These included viral infection, device related sepsis defects in the disease-matched and non-diseased comparison groups [see is supported by evidence from adequate and well-controlled studies of (catheter), gastroenteritis, H1N1 influenza, and disseminated histoplasmosis. Data]. Adalimumab is actively transferred across the placenta during the HUMIRA in adults with additional data from a randomized, double-blind, 52-week clinical study of two dose levels of HUMIRA in 192 pediatric In Study PCD-I, allergic reactions were observed in 5% of children which third trimester of pregnancy and may affect immune response in the in-utero exposed infant [see Clinical Considerations]. In an embryo-fetal perinatal patients (6 to 17 years of age) with moderately to severely active Crohn’s were all non-serious and were primarily localized reactions. disease [see Clinical Studies]. The safety and effectiveness of HUMIRA has Ulcerative Colitis Clinical Studies development study conducted in cynomolgus monkeys, no fetal harm or malformations were observed with intravenous administration of adalimumab not been established in pediatric patients with Crohn’s disease less than HUMIRA has been studied in 1010 patients with ulcerative colitis (UC) in two during organogenesis and later in gestation, at doses that produced exposures 6 years of age. placebo-controlled studies and one open-label extension study. The safety up to approximately 373 times the maximum recommended human dose Geriatric Use profile for patients with UC treated with HUMIRA was similar to the safety (MRHD) of 40 mg subcutaneous without methotrexate [see Data]. A total of 519 RA patients 65 years of age and older, including 107 patients profile seen in patients with RA. The estimated background risk of major birth defects and miscarriage for 75 years of age and older, received HUMIRA in clinical studies RA-I through Plaque Psoriasis Clinical Studies the indicated populations is unknown. In the U.S. general population, the IV. No overall difference in effectiveness was observed between these HUMIRA has been studied in 1696 subjects with plaque psoriasis (Ps) in estimated background risk of major birth defects and miscarriage in clinically patients and younger patients. The frequency of serious infection and placebo-controlled and open-label extension studies. The safety profile for recognized pregnancies is 2-4% and miscarriage is 15-20%, respectively. malignancy among HUMIRA treated patients over 65 years of age was subjects with Ps treated with HUMIRA was similar to the safety profile seen Clinical Considerations higher than for those under 65 years of age. Because there is a higher in subjects with RA with the following exceptions. In the placebo-controlled incidence of infections and malignancies in the elderly population, use portions of the clinical trials in Ps subjects, HUMIRA-treated subjects had a Fetal/Neonatal adverse reactions caution when treating the elderly. higher incidence of arthralgia when compared to controls (3% vs. 1%). Monoclonal antibodies are increasingly transported across the placenta OVERDOSAGE Hidradenitis Suppurativa Clinical Studies as pregnancy progresses, with the largest amount transferred during the third trimester [see Data]. Risks and benefits should be considered prior to Doses up to 10 mg/kg have been administered to patients in clinical trials HUMIRA has been studied in 727 subjects with hidradenitis suppurativa (HS) administering live or live-attenuated vaccines to infants exposed to HUMIRA without evidence of dose-limiting toxicities. In case of overdosage, it is in three placebo-controlled studies and one open-label extension study. in utero [see Use in Specific Populations]. recommended that the patient be monitored for any signs or symptoms The safety profile for subjects with HS treated with HUMIRA weekly was of adverse reactions or effects and appropriate symptomatic treatment consistent with the known safety profile of HUMIRA. Data instituted immediately. Flare of HS, defined as ≥25% increase from baseline in abscesses and Human Data NONCLINICAL TOXICOLOGY inflammatory nodule counts and with a minimum of 2 additional lesions, In a prospective cohort pregnancy exposure registry conducted in the Carcinogenesis, Mutagenesis, Impairment of Fertility was documented in 22 (22%) of the 100 subjects who were withdrawn from U.S. and Canada between 2004 and 2013, 74 women with RA treated with adalimumab at least during the first trimester, 80 women with RA Long-term animal studies of HUMIRA have not been conducted to evaluate HUMIRA treatment following the primary efficacy timepoint in two studies. the carcinogenic potential or its effect on fertility. Uveitis Clinical Studies not treated with adalimumab and 218 women without RA (non-diseased) were enrolled. Excluding lost-to-follow-up, the rate of major defects in the PATIENT COUNSELING INFORMATION HUMIRA has been studied in 464 patients with uveitis (UV) in placebo- adalimumab-exposed pregnancies (N=72), disease-matched (N=77), and Patient Counseling controlled and open-label extension studies. The safety profile for patients non-diseased comparison groups (N=201) was 5.6%, 7.8% and 5.5%, Provide the HUMIRA “Medication Guide” to patients or their caregivers, and with UV treated with HUMIRA was similar to the safety profile seen in respectively. However, this study cannot definitely establish the absence of patients with RA. provide them an opportunity to read it and ask questions prior to initiation any risk because of methodological limitations, including small sample size of therapy and prior to each time the prescription is renewed. If patients Postmarketing Experience and non-randomized study design. Data from the Crohn’s disease portion of develop signs and symptoms of infection, instruct them to seek medical The following adverse reactions have been identified during post-approval the study is in the follow-up phase and the analysis is ongoing. evaluation immediately. use of HUMIRA. Because these reactions are reported voluntarily from a In an independent clinical study conducted in ten pregnant women Advise patients of the potential benefits and risks of HUMIRA. population of uncertain size, it is not always possible to reliably estimate with inflammatory bowel disease treated with HUMIRA, adalimumab • Infections their frequency or establish a causal relationship to HUMIRA exposure. concentrations were measured in maternal serum as well as in cord Gastrointestinal disorders: Diverticulitis, large bowel perforations including blood (n=10) and infant serum (n=8) on the day of birth. The last dose of Inform patients that HUMIRA may lower the ability of their immune perforations associated with diverticulitis and appendiceal perforations HUMIRA was given between 1 and 56 days prior to delivery. Adalimumab system to fight infections. Instruct patients of the importance of associated with appendicitis, pancreatitis concentrations were 0.16-19.7 μg/mL in cord blood, 4.28-17.7 μg/mL in contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of General disorders and administration site conditions: Pyrexia infant serum, and 0-16.1 μg/mL in maternal serum. In all but one case, the cord blood level of adalimumab was higher than the maternal serum hepatitis B virus infections. Hepato-biliary disorders: Liver failure, hepatitis level, suggesting adalimumab actively crosses the placenta. In addition, • Malignancies Immune system disorders: Sarcoidosis one infant had serum levels at each of the following: 6 weeks (1.94 μg/mL), Counsel patients about the risk of malignancies while receiving HUMIRA. Neoplasms benign, malignant and unspecified (including cysts and polyps): 7 weeks (1.31 μg/mL), 8 weeks (0.93 μg/mL), and 11 weeks (0.53 μg/mL), • Allergic Reactions Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin) suggesting adalimumab can be detected in the serum of infants exposed in utero for at least 3 months from birth. Advise patients to seek immediate medical attention if they experience Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, any symptoms of severe allergic reactions. Advise latex-sensitive patients Guillain-Barré syndrome), cerebrovascular accident Lactation that the needle cap of the prefilled syringe contains latex. Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, Risk Summary • Other Medical Conditions pulmonary embolism Limited data from case reports in the published literature describe the Advise patients to report any signs of new or worsening medical Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema presence of adalimumab in human milk at infant doses of 0.1% to 1% conditions such as congestive heart failure, neurological disease, multiforme, new or worsening psoriasis (all sub-types including pustular and of the maternal serum level. There are no reports of adverse effects of autoimmune disorders, or cytopenias. Advise patients to report any palmoplantar), alopecia adalimumab on the breastfed infant and no effects on milk production. The symptoms suggestive of a cytopenia such as bruising, bleeding, or Vascular disorders: Systemic vasculitis, deep vein thrombosis developmental and health benefits of breastfeeding should be considered persistent fever. along with the mother’s clinical need for HUMIRA and any potential adverse DRUG INTERACTIONS effects on the breastfed child from HUMIRA or from the underlying maternal Methotrexate condition. AbbVie Inc. HUMIRA has been studied in rheumatoid arthritis (RA) patients taking Pediatric Use North Chicago, IL 60064, U.S.A. concomitant methotrexate (MTX). Although MTX reduced the apparent Safety and efficacy of HUMIRA in pediatric patients for uses other than US License Number 1889 adalimumab clearance, the data do not suggest the need for dose polyarticular juvenile idiopathic arthritis (JIA) and pediatric Crohn’s adjustment of either HUMIRA or MTX. α disease have not been established. Due to its inhibition of TNF , HUMIRA Ref: 03-B374 Revised July 2016 Biological Products administered during pregnancy could affect immune response in the In clinical studies in patients with RA, an increased risk of serious infections in utero-exposed newborn and infant. Data from eight infants exposed to has been seen with the combination of TNF blockers with anakinra or HUMIRA in utero suggest adalimumab crosses the placenta [see Use in 64C-1865519 MASTER abatacept, with no added benefit; therefore, use of HUMIRA with abatacept Specific Populations]. The clinical significance of elevated adalimumab levels or anakinra is not recommended in patients with RA [see Warnings and in infants is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be Precautions]. A higher rate of serious infections has also been observed 64C-1859319 in patients with RA treated with rituximab who received subsequent considered prior to vaccinating (live or live-attenuated) exposed infants. treatment with a TNF blocker. There is insufficient information regarding the Post-marketing cases of lymphoma, including hepatosplenic T-cell concomitant use of HUMIRA and other biologic products for the treatment of lymphoma and other malignancies, some fatal, have been reported among RA, PsA, AS, CD, UC, Ps, HS and UV. Concomitant administration of HUMIRA children, adolescents, and young adults who received treatment with

RRO0816_AbbvieO0816_Abbvie PPI3.inddI3.indd 1 77/21/16/21/16 4:064:06 PMPM REVIEW NEWS Volume XXIII • No. 9 • September 2016 New MIGS on the Radar: CyPass Micro-Stent Approved

On August 2, 2016, Alcon announced the CyPass stent. Both the primary performed in combination with pha- that the CyPass Micro-Stent, (original- and secondary effectiveness endpoints coemulsifi cation, and thus, this is ly developed by Transcend Medical) were met; at 24 months, 73 percent in where it will initially be used in clini- had received clearance from the U.S. the CyPass group achieved a statistical practice,” says Ike K. Ahmed, MD, Food and Drug Administration. The cally signifi cant decrease in IOP of FRCSC, assistant professor at the Uni- CyPass shunt is a minimally invasive more than 20 percent; 61 percent of versity of Toronto in Ontario, Canada, ab interno device designed to reduce the CyPass patients also achieved an who participated in the clinical trial. IOP in adults with mild-to-moderate IOP in the target range, between 6 and “Many of us have also had experience glaucoma. It’s inserted through the 18 mmHg—without medications— using the CyPass as a standalone op- angle between the scleral spur and which was also statistically signifi cant. tion, and we hope to see further data the ciliary body into the supraciliary Adverse events included: BCVA loss on that soon.” space in conjunction with cataract of 10 or more letters at three months Dr. Ahmed points out that this is an- surgery; it takes advantage of the postop (8.8 percent for CyPass vs. 15.3 other entry in the category of minimal- negative pressure gradient between percent for cataract surgery only); an- ly invasive glaucoma surgery devices, the suprachoroidal space and the terior chamber cell and fl are requir- or MIGS. “The suprachoroidal space anterior chamber, causing aqueous to ing steroid treatment 30 or more days is a natural drainage outfl ow tract that move into the suprachoroidal space. after surgery (8.6 percent vs. 3.8 per- provides another MIGS alternative,” The device is 6.35 mm long, with an cent); worsening of visual fi eld mean he says. “It’s exciting to see more op- external diameter of 510 µm. deviation by 2.5 dB or more (6.7 per- tions available for our patients. Fur- The approval was granted based cent vs. 9.9 percent); an IOP increase ther studies will help to elucidate dif- on data from the COMPASS trial, a of 10 or more mmHg 30 or more days ferences between the growing MIGS prospective, randomized, multicenter after surgery (4.3 percent vs. 2.3 per- options that are being approved.” study that compared the pressure cent); and corneal edema 30 or more lowering in 505 patients who either days after surgery, or severe in nature underwent cataract surgery alone or (3.5 percent vs. 1.5 percent). cataract surgery plus implantation of “The FDA study for CyPass was ASCRS/ASRS HORV Alert

Though the incidence is low after intraocular procedures, the American Society of Cataract and Refractive Surgery and the American Society of Retina Specialists joined forces to warn surgeons of the possible risk factors for and clinical signs of hemorrhagic occlusive retinal vasculitis. They also note that there seems to be an association between The CyPass Micro-Stent does its work in a novel location: It’s placed through the angle between the scleral spur and the ciliary body into the supraciliary space. (continued on page 9)

September 2016 | reviewofophthalmology.com | 7

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INDICATIONS and IMPORTANT SAFETY INFORMATION for TECNIS SYMFONY and TECNIS SYMFONY TORIC IOLs Rx Only INDICATIONS FOR USE: The TECNIS Symfony Extended Range of Vision IOL, Model ZXR00, is indicated for primary implantation for the visual correction of aphakia, in adult patients with less than 1 diopter of pre-existing corneal astigmatism, in whom a cataractous lens has been removed. The lens mitigates the effects of presbyopia by providing an extended depth of focus. Compared to an aspheric monofocal IOL, the lens provides improved intermediate and near visual acuity, while maintaining comparable distance visual acuity. The Model ZXR00 IOL is intended for capsular bag placement only. The TECNIS Symfony Toric Extended Range of Vision IOLs, Models ZXT150, ZXT225, ZXT300, and ZXT375, are indicated for primary implantation for the visual correction of aphakia and for reduction of residual refractive astigmatism in adult patients with greater than or equal to 1 diopter of preoperative corneal astigmatism, in whom a cataractous lens has been removed. The lens mitigates the effects of presbyopia by providing an extended depth of focus. Compared to an aspheric monofocal IOL, the lens provides improved intermediate and near visual acuity, while maintaining comparable distance visual acuity. The Model Series ZXT IOLs are intended for capsular bag placement only. WARNINGS: May cause a reduction in contrast sensitivity under certain conditions, compared to an aspheric monofocal IOL. Inform patients to exercise special caution when driving at night or in poor visibility conditions. Some visual effects may be expected due to the lens design, including: perception of halos, glare, or starbursts around lights under nighttime conditions. These will be bothersome or very bothersome in some people, particularly in low-illumination conditions, and on rare occasions, may be signiﬁ cant enough that the patient may request removal of the IOL. Rotation of the Tecnis Symfony Toric IOLs away from their intended axis can reduce their astigmatic correction, and misalignment >30° may increase postoperative refractive cylinder. If necessary, lens repositioning should occur as early as possible prior to lens encapsulation. ATTENTION: Reference the Directions for Use for a complete listing of Indications and Important Safety Information. TECNIS and TECNIS Symfony are trademarks owned by or licensed to Abbott Laboratories, its subsidiaries or afﬁ liates. All other trademarks are the intellectual property of their respective owners. ©2016 Abbott Medical Optics Inc. PP2016CT1089

Untitled-2 1 8/25/16 12:58 PM REVIEW News

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the use of intraocular vancomycin and the complication. Nasal & Temporal According to the alert, 22 cases of HORV have been identifi ed, 14 of Speculums less ain , St which were bilateral. In terms of tim- um cul pe st S ing, 12 of the cases occurred in 2015- Po le rip T 2016, fi ve in 2013-2014 and fi ve before n* w ro B : 2013. 4 6 1 8 -0 “The diffi cult part about this com- 8 0 plication is that it has occurred bilat- ss le erally in about half of the patients that in ta m S u , ni l were reported,” says Nick Mamalis, a sa it a , T N m , MD, professor of ophthalmology at lu m u lu ec u p c S e t p the University of Utah’s Moran Eye s S o t P s e m l o u Center and member of the HORV ip P i r e n T l a t * ip i r T n task force. “The sobering aspect is that w T , l o * a r n s B w a : it can have a delayed onset, meaning o N 5 r , 0 B 1 - * m 7 * u you can complete your fi rst surgery, - t l 5 r u 0 e c n e i p e administer the antibiotic at the end t S

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5 but in other cases that have been re- 0 ported it went out as far as 26 days. So, in many cases, you may not know the patient will have this reaction until Special Fenestrated you’ve already done his second eye.” Blades Improve VIDEO Exposure And Access The one thing all the cases had in To Superior Surgical common was the intraocular use of Approaches By Supporting vancomycin, a connection that re- & Elevating The Middle Of The searchers are trying to parse out. “We Lids As Seen In The Following: really hadn’t seen anything like this be- Figure 1, Temporal Blades With Drape. fore,” Dr. Mamalis recalls. “It was dif- Figure 2, Temporal Blades Without Drape. ferent from some of the other retinal issues that we’ve seen after intraocular Call 727-209-2244 For More Information. surgery. For instance, in the past, there have been instances of patients getting some retinal toxicity from an injection of the incorrect dose of gentamycin, or surgeons who use a very high dose of cefuroxime that was improperly diluted and end up getting a retinal com- 3360 Scherer Drive, Suite B, St. Petersburg, FL 33716 plication. This, however, was unique. s4EL s&AX HORV gave this pattern of vasculitis %MAIL)NFO 2HEIN-EDICALCOMs7EBSITEWWW2HEIN-EDICALCOM $EVELOPED)N#OORDINATIONWITH2EAY("ROWN -$ that truly behaved as a vasculitis. And, $EVELOPED)N#OORDINATION7ITH2OGER&3TEINERT -$ ,EONARDO$A6INCI 5NNAMED

1339 Rev.A ADBC

007_rp0916_news.indd 9 8/26/16 1:36 PM REVIEW News

these cases were appearing up to two sequential cataract surgery should be weeks after surgery without a toxic aware that in addition to delayed on- dose having been used. That aspect set of one to three weeks, HORV may of it raised the suspicion that it had be asymptomatic in the fi rst eye and a Andre Witkin, Witkin, MD Andre to be some sort of autoimmune reac- dilated fundus exam may be the only tion. The task force communicated way to detect it. The risk of bilateral with immunologists about it, and they HORV is therefore higher if close—or have said that it’s consistent with what’s immediate sequential, same-day bilat- known as a Type III reaction, or what eral—surgery is performed. As alter- they call a leukocytoclastic vasculitis. natives to vancomycin, surgeons can That’s the pattern that it fi ts. HORV use moxifl oxacin or cefuroxime. Sur- seems most consistent with that type geons should have the issue of HORV of reaction. A HORV eye, 18 days after cataract surgery, enter into the consideration of how to “We were careful when issuing this displays diffuse microvascular occlusion approach antibiotic prophylaxis follow- alert, however,” Dr. Mamalis adds. and extensive intraretinal hemorrhages. ing routine cataract surgery.” “We don’t want to put out a blanket If a surgeon suspects or encounters recommendation of, ‘Don’t use intra- ber and vitreous infl ammation, with no HORV, once again, reconsider van- cameral vancomycin,’ because there hypopyon; comycin. “The fi rst thing to consider have probably been hundreds of thou- • sectoral intraretinal hemorrhage in is avoiding intravitreal vancomycin if sands of cases of routine cataract sur- areas of nonperfusion; you’re considering HORV in a case geries performed with intracameral • peripheral retinal involvement in that’s been diagnosed as endophthal- vancomycin that never had HORV. all cases, with macular ischemia and mitis,” Dr. Mamalis says. “If you really We’re careful not to condemn van- whitening in advanced disease; aren’t sure that it’s endophthalmitis and comycin. However, we want to alert • sectoral retinal vasculitis and reti- suspect it may be HORV, pick another physicians that this entity can occur nal vascular occlusion on FA, corre- antibiotic. Also, look for other systemic and, though it’s exceedingly rare, when sponding to areas of hemorrhage; and syndromes if you’re searching for a it does occur it can have very poor vi- • rapid progression to neovascular potential viral cause. However, once sual outcomes.” Twenty-two of the 36 glaucoma.1 you’ve determined that it’s HORV, eyes with HORV (61 percent), ended The alert notes that HORV might be you’ve got to be aggressive in terms of up 20/200 or worse, and eight (22 per- misdiagnosed as a central retinal vein topical and systemic corticosteroids. cent) were NLP. The task force notes occlusion, but says that an ischemic Try to calm the infl ammation. And, that seven of the eyes (19 percent), CRVO is unilateral, usually presents because these patients most likely will received an additional bolus of intra- on the fi rst postop day when associated get signifi cant glaucoma afterward— vitreal vancomycin for the treatment with cataract surgery, and is associated especially neovascular glaucoma—you of presumed bacterial endophthalmitis with diffuse, small intraretinal hemor- want to consider using anti-VEGF postop. These eyes had especially bad rhages. In contrast, HORV is often bi- treatments early, as well as consider outcomes, with 5/7 being NLP. This lateral, has a delayed onset, and often doing panretinal photocoagulation highlights the importance of spreading presents with large areas of intraretinal early to take away the factors that can the word about HORV and avoiding hemorrhage only in the sectors of reti- cause that secondary glaucoma.” treating it as an infection. nal vascular occlusion. Cystoid macular The ASRS has established a HORV To help catch HORV, the task force edema and severe vascular dilation and registry to help track the complication highlights these characteristics: tortuosity are features of CRVO but that can be accessed at asrs.org. • occurrence after an intraocular not of HORV.1 1. ASCRS/ASRS HORV Clinical Alert. http://www.ascrs.org/ procedure with normal undilated exam “Surgeons should continue to weigh node/26101. Accessed 18 August 2016. on postop day one; the relative merits of prophylactic in- • delayed onset of sudden painless traocular antibiotic use in preventing Correction decreased vision (range: one to 26 days endophthalmitis against the additional postop; mean: eight days); knowledge that intraocular vancomy- In Review’s August retinal article on DME • visual acuity is often poor on pre- cin is associated with HORV, a rare but treatment, it states Eylea treated eyes sentation, but may be normal in mild potentially devastating disease,” Dr. in Protocol T had gained 19 letters from cases of the complication; Mamalis says. “In addition, surgeons baseline at year two. They actually gained 18 letters. Review regrets the error. • mild to moderate anterior cham- using vancomycin prophylaxis with

10 | Review of Ophthalmology | September 2016

007_rp0916_news.indd 10 8/26/16 1:36 PM THE POWER OF PREEMPTION

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• Preempt miosis and inhibit • Eliminate the risks and liabilities postoperative pain1 of compounded products by using FDA-approved, • Block the surgically induced GMP-manufactured OMIDRIA inflammatory cascade with the first and only NSAID FDA-approved • Avoid reimbursement difficulties for intracameral use1 by using broadly covered OMIDRIA and the OMIDRIAssure™ services (OMIDRIAssure.com)* IMPORTANT SAFETY INFORMATION OMIDRIA (phenylephrine and ketorolac injection) 1% / 0.3% must be added to irrigation solution prior to intraocular use. OMIDRIA is contraindicated in patients with a known hypersensitivity to any of its ingredients. Systemic exposure of phenylephrine may cause elevations in blood pressure. Use OMIDRIA with caution in individuals who have previously exhibited sensitivities to acetylsalicylic acid, phenylacetic acid derivatives, and other nonsteroidal anti-inflammatory drugs (NSAIDs), or have a past medical history of asthma. The most commonly reported adverse reactions at 2-24% are eye irritation, posterior capsule opacification, increased intraocular pressure, and anterior chamber inflammation. Use of OMIDRIA in children has not been established.

INDICATIONS AND USAGE OMIDRIA is added to ophthalmic irrigation solution used during cataract surgery or intraocular lens replacement and is indicated for maintaining pupil size by preventing intraoperative miosis and reducing postoperative ocular pain.

Reference: 1. OMIDRIA [package insert]. Seattle, WA: Omeros Corporation; 2015.

Please see the Full Prescribing Information at www.omidria.com/prescribinginformation.

*Individual insurance coverage and policies may vary, and Omeros does not guarantee insurance coverage or payment. Omeros offers payments under the OMIDRIAssure “We Pay the Difference” program on behalf of qualifying patients. OMIDRIAssure is subject to change without notice. Visit www.omidria.com

RP0916_Omeros.indd 1 8/23/16 10:40 AM Editorial

REVIEW Board

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12 | Review of Ophthalmology | September 2016

0007_rp0916_news.indd07_rp0916_news.indd 1122 88/26/16/26/16 1:371:37 PMPM The PROLENSA® Effect POWERED FOR PENETRATION Advanced Formulation to Facilitate Corneal Penetration1-3

PROLENSA® delivers potency and corneal penetration with QD dosing at a low concentration1-3

INDICATIONS AND USAGE PROLENSA® (bromfenac ophthalmic solution) 0.07% is a • Use of topical NSAIDs may result in keratitis. nonsteroidal anti-infl ammatory drug (NSAID) indicated Patients with evidence of corneal epithelial breakdown for the treatment of postoperative infl ammation and should immediately discontinue use of topical NSAIDs, reduction of ocular pain in patients who have undergone including bromfenac, and should be closely monitored cataract surgery. for corneal health. Patients with complicated ocular IMPORTANT SAFETY INFORMATION ABOUT PROLENSA® surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases • PROLENSA® contains sodium sulfi te, a sulfi te that may (e.g., dry eye syndrome), rheumatoid arthritis, or repeat cause allergic type reactions including anaphylactic ocular surgeries within a short period of time may be symptoms and life-threatening or less severe asthmatic at increased risk for corneal adverse events which may episodes in certain susceptible people. The overall become sight threatening. Topical NSAIDs should be used prevalence of sulfi te sensitivity in the general population is with caution in these patients. Post-marketing experience unknown and probably low. Sulfi te sensitivity is seen more with topical NSAIDs suggests that use more than 24 hours frequently in asthmatic than in non-asthmatic people. prior to surgery or use beyond 14 days post-surgery may • All topical nonsteroidal anti-infl ammatory drugs (NSAIDs), increase patient risk for the occurrence and severity of including bromfenac, may slow or delay healing. corneal adverse events. Concomitant use of topical NSAIDs and topical steroids • PROLENSA® should not be instilled while wearing contact may increase the potential for healing problems. lenses. The preservative in PROLENSA®, benzalkonium • There is the potential for cross-sensitivity to acetylsalicylic chloride, may be absorbed by soft contact lenses. Lenses may be reinserted after 10 minutes following acid, phenylacetic acid derivatives, and other NSAIDs, ® including bromfenac. Use with caution in patients who administration of PROLENSA . have previously exhibited sensitivities to these drugs. • The most commonly reported adverse reactions in 3%-8% • There have been reports that ocularly applied NSAIDs of patients were anterior chamber infl ammation, foreign may cause increased bleeding of ocular tissues (including body sensation, eye pain, photophobia, and blurred vision. hyphemas) in conjunction with ocular surgery. Use with Please see brief summary of full Prescribing Information caution in patients with known bleeding tendencies or for PROLENSA® on adjacent page. who are receiving other medications which may prolong References: 1. PROLENSA Prescribing Information, April 2013. 2. Data on fi le, Bausch & Lomb Incorporated. bleeding time. 3. Baklayan GA, Patterson HM, Song CK, Gow JA, McNamara TR. 24-hour evaluation of the ocular distribution of (14)C-labeled bromfenac following topical instillation into the eyes of New Zealand white rabbits. J Ocul Pharmacol Ther. 2008;24(4):392-398.

RP0316_BL Prolensa.indd 1 2/16/16 10:37 AM PROLENSA® (bromfenac ophthalmic solution) 0.07% Brief Summary

INDICATIONS AND USAGE PROLENSA® ophthalmic solution following cataract surgery include: PROLENSA® (bromfenac ophthalmic solution) 0.07% is indicated for the anterior chamber inflammation, foreign body sensation, eye pain, treatment of postoperative inflammation and reduction of ocular pain in photophobia and vision blurred. These reactions were reported in 3 to patients who have undergone cataract surgery. 8% of patients. DOSAGE AND ADMINISTRATION USE IN SPECIFIC POPULATIONS Recommended Dosing Pregnancy One drop of PROLENSA® ophthalmic solution should be applied to Treatment of rats at oral doses up to 0.9 mg/kg/day (systemic the affected eye once daily beginning 1 day prior to cataract surgery, exposure 90 times the systemic exposure predicted from the continued on the day of surgery, and through the first 14 days of the recommended human ophthalmic dose [RHOD] assuming the human postoperative period. systemic concentration is at the limit of quantification) and rabbits Use with Other Topical Ophthalmic Medications at oral doses up to 7.5 mg/kg/day (150 times the predicted human PROLENSA ophthalmic solution may be administered in conjunction systemic exposure) produced no treatment-related malformations in with other topical ophthalmic medications such as alpha-agonists, beta- reproduction studies. However, embryo-fetal lethality and maternal blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics. toxicity were produced in rats and rabbits at 0.9 mg/kg/day and Drops should be administered at least 5 minutes apart. 7.5 mg/kg/day, respectively. In rats, bromfenac treatment caused delayed parturition at 0.3 mg/kg/day (30 times the predicted human CONTRAINDICATIONS exposure), and caused dystocia, increased neonatal mortality and None reduced postnatal growth at 0.9 mg/kg/day. WARNINGS AND PRECAUTIONS There are no adequate and well-controlled studies in pregnant women. Sulfite Allergic Reactions Because animal reproduction studies are not always predictive of Contains sodium sulfite, a sulfite that may cause allergic-type reactions human response, this drug should be used during pregnancy only if including anaphylactic symptoms and life-threatening or less severe the potential benefit justifies the potential risk to the fetus. asthmatic episodes in certain susceptible people. The overall prevalence Because of the known effects of prostaglandin biosynthesis- of sulfite sensitivity in the general population is unknown and probably inhibiting drugs on the fetal cardiovascular system (closure of ductus low. Sulfite sensitivity is seen more frequently in asthmatic than in non- arteriosus), the use of PROLENSA® ophthalmic solution during late asthmatic people. pregnancy should be avoided. Slow or Delayed Healing Nursing Mothers All topical nonsteroidal anti-inflammatory drugs (NSAIDs), including Caution should be exercised when PROLENSA is administered to a bromfenac, may slow or delay healing. Topical corticosteroids are also nursing woman. known to slow or delay healing. Concomitant use of topical NSAIDs and Pediatric Use topical steroids may increase the potential for healing problems. Safety and efficacy in pediatric patients below the age of 18 have not Potential for Cross-Sensitivity been established. There is the potential for cross-sensitivity to acetylsalicylic acid, Geriatric Use phenylacetic acid derivatives, and other NSAIDs, including bromfenac. There is no evidence that the efficacy or safety profiles for Therefore, caution should be used when treating individuals who have PROLENSA differ in patients 70 years of age and older compared to previously exhibited sensitivities to these drugs. younger adult patients. Increased Bleeding Time With some NSAIDs, including bromfenac, there exists the potential for NONCLINICAL TOXICOLOGY increased bleeding time due to interference with platelet aggregation. Carcinogenesis, Mutagenesis and Impairment of Fertility There have been reports that ocularly applied NSAIDs may cause Long-term carcinogenicity studies in rats and mice given oral increased bleeding of ocular tissues (including hyphemas) in conjunction doses of bromfenac up to 0.6 mg/kg/day (systemic exposure 30 with ocular surgery. times the systemic exposure predicted from the recommended It is recommended that PROLENSA® ophthalmic solution be used with human ophthalmic dose [RHOD] assuming the human systemic caution in patients with known bleeding tendencies or who are receiving concentration is at the limit of quantification) and 5 mg/kg/day (340 other medications which may prolong bleeding time. times the predicted human systemic exposure), respectively, revealed Keratitis and Corneal Reactions no significant increases in tumor incidence. Use of topical NSAIDs may result in keratitis. In some susceptible Bromfenac did not show mutagenic potential in various mutagenicity patients, continued use of topical NSAIDs may result in epithelial studies, including the reverse mutation, chromosomal aberration, and breakdown, corneal thinning, corneal erosion, corneal ulceration or micronucleus tests. corneal perforation. These events may be sight threatening. Patients with Bromfenac did not impair fertility when administered orally to male evidence of corneal epithelial breakdown should immediately discontinue and female rats at doses up to 0.9 mg/kg/day and 0.3 mg/kg/day, use of topical NSAIDs, including bromfenac, and should be closely respectively (systemic exposure 90 and 30 times the predicted human monitored for corneal health. exposure, respectively). Post-marketing experience with topical NSAIDs suggests that patients with complicated ocular surgeries, corneal denervation, corneal epithelial PATIENT COUNSELING INFORMATION defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), Slowed or Delayed Healing rheumatoid arthritis, or repeat ocular surgeries within a short period Advise patients of the possibility that slow or delayed healing may of time may be at increased risk for corneal adverse events which may occur while using NSAIDs. become sight threatening. Topical NSAIDs should be used with caution Sterility of Dropper Tip in these patients. Advise patients to replace bottle cap after using and to not touch Post-marketing experience with topical NSAIDs also suggests that use dropper tip to any surface, as this may contaminate the contents. more than 24 hours prior to surgery or use beyond 14 days post-surgery Advise patients that a single bottle of PROLENSA® ophthalmic may increase patient risk for the occurrence and severity of corneal solution, be used to treat only one eye. adverse events. Concomitant Use of Contact Lenses Contact Lens Wear Advise patients to remove contact lenses prior to instillation of PROLENSA should not be instilled while wearing contact lenses. PROLENSA. The preservative in PROLENSA, benzalkonium Remove contact lenses prior to instillation of PROLENSA. The chloride, may be absorbed by soft contact lenses. Lenses may be preservative in PROLENSA, benzalkonium chloride may be absorbed by reinserted after 10 minutes following administration of PROLENSA. soft contact lenses. Lenses may be reinserted after 10 minutes following Concomitant Topical Ocular Therapy administration of PROLENSA. If more than one topical ophthalmic medication is being used, the medicines should be administered at least 5 minutes apart ADVERSE REACTIONS Rx Only Clinical Trial Experience Manufactured by: Bausch & Lomb Incorporated, Tampa, FL 33637 Because clinical trials are conducted under widely varying conditions, Under license from: adverse reaction rates observed in the clinical trials of a drug cannot be Senju Pharmaceuticals Co., Ltd. directly compared to rates in the clinical trials of another drug and may Osaka, Japan 541-0046 not reflect the rates observed in clinical practice. Prolensa is a trademark of Bausch & Lomb Incorporated or its affiliates. The most commonly reported adverse reactions following use of © Bausch & Lomb Incorporated. 9317600 US/PRA/14/0024

RRP0316_BLP0316_BL PProlensarolensa PPI.inddI.indd 1 22/16/16/16/16 10:3810:38 AMAM September 2016 • Volume XXIII No. 9 | reviewofophthalmology.com Cover Focus 24 | Perfecting Posterior Corneal Grafts By Sadeer B. Hannush, MD A look at the heirs to DSAEK for endothelial grafts, with a focus on the promising DMEK. 32 | Making the Most of Corneal Cross-linking By Christopher Kent, Senior Editor Surgeons offer advice to first-time users for getting great results and staying out of trouble.

Cover image: iStock September 2016 | reviewofophthalmology.com | 15

015_rp0916_toc.indd 15 8/26/16 1:45 PM Departments

7 | Review News 20 19 | Editor’s Page 21st Century Cure-all?

20 | Technology Update Offering Patients an In-office “Face Lift” A primer for the ophthalmologist on the latest noninvasive skin-tightening treatments

44 | Masters of Surgery Filtering Surgery: Optimizing Outcomes Expert tips for this time-tested glaucoma procedure.

51 | Retinal Insider 44 In Search of the Best AMD Therapy The ways researchers and clinicians are trying to overcome the shortcomings of current therapies.

58 | Therapeutic Topics Objective: Symptomatic Assessment Strategies Symptom scores can help when treating dry eye, but creating good questionnaires is challenging.

62 | Glaucoma Management ECP and Cataract Surgery: Perfect Together? Endoscopic cyclophotocoagulation appears to be a safe, effective adjunct to cataract surgery. 51

69 | Classified Ads

71 | Wills Eye Resident Case Series

73 | Advertising Index

16 | Review of Ophthalmology | September 2016

015_rp0916_toc.indd 16 8/26/16 1:45 PM BACITRACIN OPHTHALMIC OINTMENT USP BACITRACIN OPHTHALMIC OINTMENT USP %GXMZIEKEMRWX XS SJMHIRXM¿IHOI] gram-positive isolates from conjunctivitis and blepharitis from in vitroWXYHMIW ².ERYEV] 1

In Vitro Susceptibility Data Provided Through the University of Pittsburgh Medical Center. In Vitro Data Should Not Be Considered Representative of Clinical Efficacy1 Established therapeutic utility in blepharitis, conjunctivitis, and other superficial ocular infections caused by Bacitracin-susceptible organisms OExcellent safety profile—low incidence OAnti-infective efficacy in a lubricating base2 2 of adverse events 2 OFlexible dosing—1 to 3 times daily O Ointment provides long-lasting ocular surface OTier 1 pharmacy benefit status— 3 contact time and greater bioavailability on most insurance plans4 Indication Bacitracin Ophthalmic Ointment is indicated for the treatment of superficial ocular infections involving the conjunctiva and/or cornea caused by Bacitracin susceptible organisms. Important Safety Information This product should not be used in patients with a history of hypersensitivity to Bacitracin. Bacitracin Ophthalmic Ointment should not be used in deep-seated ocular infections or in those that are likely to become systemic. For a closer look, visit www.perrigobacitracin.com There is a low incidence of allergenicity exhibited by Bacitracin. If such reactions do occur, therapy should be discontinued.

Please see adjacent page for full prescribing information.

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RP0916_Perrigo.indd 1 8/8/16 11:31 AM Bacitracin Ophthalmic Ointment USP Left your Review STERILE Rx Only

DESCRIPTION: Each gram of ointment contains 500 units of Ophthalmology of Bacitracin in a low melting special base containing White Petrolatum and Mineral Oil. CLINICAL PHARMACOLOGY: The antibiotic, Bacitracin, magazine at the ofﬁ ce? exerts a profound action against many gram-positive pathogens, including the common Streptococci and Staphylococci. It is also destructive for certain gram- negative organisms. It is ineffective against fungi. No problem! INDICATIONS AND USAGE: For the treatment of superficial ocular infections involving the conjunctiva and/or cornea caused by Bacitracin susceptible organisms. CONTRAINDICATIONS: This product should not be used in patients with a history of hypersensitivity to Bacitracin. PRECAUTIONS: Bacitracin ophthalmic ointment should not be used in deep-seated ocular infections or in those that are likely to become systemic. The prolonged use of antibiotic containing preparations may result in overgrowth of nonsusceptible organisms particularly fungi. If new infections develop during treatment appropriate antibiotic or chemotherapy should be instituted. ADVERSE REACTIONS: Bacitracin has such a low incidence of allergenicity that for all practical purposes side reactions are practically non-existent. However, if such reaction should occur, therapy should be discontinued. To report SUSPECTED ADVERSE REACTIONS, contact Perrigo at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DOSAGE AND ADMINISTRATION: The ointment should be applied directly into the conjunctival sac 1 to 3 times daily. In blepharitis all scales and crusts should be carefully removed and the ointment then spread uniformly over the lid margins. Patients should be instructed to take appropriate measures to avoid gross contamination of the ointment when applying the ointment directly to the infected eye. HOW SUPPLIED: NDC 0574-4022-13 3 - 1 g sterile tamper evident tubes with ophthalmic tip. NDC 0574-4022-35 3.5 g (1/8 oz.) sterile tamper evident tubes with ophthalmic tip. Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Read Review on the go

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References: 1. Antibiotic susceptibility: conjunctivitis and blepharitis. University of Pittsburgh Medical Center, Charles T. Campbell Eye www.reviewofophthalmology.com and click Microbiology Lab Web site. http://eyemicrobiology.upmc.com/ AntibioticSusceptibilities/Conjunctivitis.htm. Accessed March 21, 2016. 2. Bacitracin Ophthalmic Ointment [package insert]. Minneapolis, MN: Perrigo Company; August 2013. 3. Hecht G. Ophthalmic preparations. on the digimag link to get your current issue. In: Gennaro AR, ed. Remington: the Science and Practice of Pharmacy. 20th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2000. 4. Data on file. Perrigo Company.

018_rp0916_fractionals.indd 18 8/26/16 1:46 PM ® Editor’s Page Walter C. Bethke, Editor in Chief E DITORIAL STAFF REVIEW

Editor in Chief Walter C. Bethke (610) 492-1024 [email protected] 21st Century Senior Editor Christopher Kent (814) 861-5559 Cure-all? [email protected] The recent approval of corneal colla- therapeutic use” rather than clinical Associate Editor gen cross-linking in the United States trials.2 It also took issue with the bill’s Liam Jordan was a milestone moment for ophthal- plan to allow the use of biomarkers (610) 492-1025 mologists: They can now worry about or other “surrogate” measurements [email protected] how to do it better rather than when it to stand in for primary outcomes.2 In will get approved. addition to some pushback from phy- Chief Medical Editor This approval got me thinking about sicians, Americans in general have Mark H. Blecher, MD the recent fl urry of approvals—in July some reservations about the bill: In a alone there were several signifi cant ap- STAT-Harvard poll of around 1,000 Art Director provals in ophthalmology, opening up consumers, 58 percent oppose alter- Jared Araujo new treatment options. All this comes ing standards to make the process for (610) 492-1032 hot on the heels of 2015, which was approving prescription drugs faster.3 [email protected] a banner year for the FDA: 45 new Half of the respondents oppose similar drugs were approved in 2015, outpac- measures to quicken the approval of 3 Senior Graphic Designer ing the annual average of 28 in the devices. Supporters of the bill counter 1 Matt Egger period of 2006 through 2014. Some that it wouldn’t lessen the FDA’s stan- (610) 492-1029 physicians are wondering whether this dards, just give the agency more data [email protected] means change is in the air for the FDA to use. And the debate continues. and its approval process. Now, I don’t think anyone would call International coordinator, Japan Their musings could well be correct, the FDA the paragon of speed but, by with one major example being the the same token, no one would want Mitz Kaminuma passing of the 21st Century Cures Act to think any corners were being cut [email protected] in the House of Representatives last on the review of a drug or device that summer. The act’s main objective is to could potentially be used by his or her Business Offi ces accelerate the process of FDA approv- family, either. If the agency is indeed 11 Campus Boulevard, Suite 100 al for drugs and devices, with a major streamlining its process, either by itself Newtown Square, PA 19073 benefi t being an annual payment of or with the help of a new law, I hope (610) 492-1000 $1.86 billion to the National Institutes that it does so in a way that preserves Fax: (610) 492-1039 of Health from 2016 through 2020. It the high standards that all of us poten- also contains provisions to accelerate tial patients deserve. It’s important to Subscription inquiries: the approval of treatments for rare dis- be quick—but it’s just as important not United States — (877) 529-1746 eases. Such initiatives are welcomed to rush. Outside U.S. — (845) 267-3065 by companies developing treatments, E-mail: physicians eager to begin using them —Walt Bethke, Editor in Chief [email protected] and patients desperate for therapies. 1. FDA Novel Drugs Summary. http://www. Website: www.reviewofophthalmology.com Some observers, however, urge cau- fda.gov/Drugs/DevelopmentApprovalProcess/ tion. An article in the New England DrugInnovation/ucm474696.htm. Accessed 22 August 2016. Journal of Medicine expressed con- 2. Avorn J, Kesselheim A. The 21st century cures act: Will it take us back in time? N Engl J Med cern that the bill might undermine 2015;372:2473. the current drug approval process by 3. Harvard TH Chan School of Public Health Poll. https://cdn1.sph.harvard.edu/wp-content/uploads/ allowing the use of such measures as sites/94/2016/05/STAT-Harvard-Poll-May-2016-FDA- “observational studies, registries and Regulation.pdf. Accessed 22 August 2016.

September 2016 | reviewofophthalmology.com | 19

019_rp0916_edit.indd 19 8/26/16 1:56 PM Technology Update

REVIEW Edited by Michael Colvard, MD, and Steven Charles, MD

Offering Your Patients An In-ofﬁ ce “Face Lift” If you’re looking for an extra service to provide, some of the latest noninvasive skin-tightening treatments might ﬁ t the bill. Christopher Kent, Senior Editor

n the search for ways to draw more eling of collagen and elastin, further tightening technologies into ﬁ ve cat- Ipatients into the office and offer tightening the skin. egories: more services to existing patients, Jason D. Bloom, MD, is director of • Fractionated laser. “The first ophthalmologists often consider of- facial plastic and reconstructive sur- gold-standard technology used for fa-

fering procedures that would fall out- gery at the Main Line Center for La- cial skin tightening was the CO2 laser, side standard ophthalmic treatment. ser Surgery, which offers many non- using unfractionated laser energy,” One service that can be performed surgical skin-tightening procedures; Dr. Bloom says. “Very few people in-offi ce and will appeal to many oph- the Center has participated in clinical use that now. It produces a signifi- thalmic patients is tightening of the trials of many of the devices currently cant amount of skin tightening, but it skin on the face and neck. Dozens used in the industry. Here, Dr. Bloom comes with a very high risk of scarring of devices that can accomplish this explains the basic options that are cur- and hypopigmentation; patients have are available; all of them cause skin rently available and offers advice to two weeks of downtime and three to tightening by generating heat through any ophthalmologists considering of- six months of being red like a tomato. or under the skin, causing damage at fering one or more of these services. “Since then, the laser energy has the cellular level. The healing that fol- been modifi ed for fractionated deliv- lows tightens the epidermis and un- Five Approaches ery,” he continues. “Unfractionated derlying layers—sometimes including delivery creates something akin to muscle, if used for something like a Dr. Bloom says he fi nds it helpful scorched earth, while fractionated brow lift—and also causes the remod- to divide today’s nonsurgical skin- delivery creates a tiny checkerboard All images: Jason D. Bloom, MD

Fractionated CO2 laser treatment around the eyes, before (left), immediately afterwards (center) and at ﬁ ve days postop (right). The thermal damage caused by the laser results in remodeling of collagen and elastin, tightening the skin.

20 | Review of Ophthalmology | September 2016 This article has no commercial sponsorship.

020_rp0916_tech update.indd 20 8/26/16 2:51 PM PUSHING THE FUTURE OF EYE CARE FORWARD

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RP0716_Allergan Teaser.indd 1 6/24/16 10:50 AM Technology

REVIEW Update

may deliver radio frequency or laser energy, depending on the system. “This approach is great for tightening the neck, but it’s sometimes used in the face as well,” he explains. “To treat the jowls and neck, I make three small openings with 16-ga. needles following tumescent anesthesia—one opening under the chin and one under Fractionated laser around the mouth, before (left) and after treatment (right). each earlobe. I run the cannula back and forth under the surface of the skin pattern of injury. Thus, lasered skin like a child using a magnifying glass to in a fan pattern, above the muscle, is next to unlasered; the undamaged focus sunlight on an ant. You lay down just underneath the subcutaneous fat. tissue grows over the damaged tis- lines of these subsurface microinju- I still consider this nonsurgical, be- sue, and the area heals in about one- ries, causing contraction and remod- cause there’s no trip to the OR and no third of the time. Patients put on oint- eling of collagen and elastin. Using sedation or general anesthesia; I tell ments for a couple of days, but by day this technology, it can take three to the patients that I don’t use any scal- ﬁ ve women are able to wear makeup six months to see the results. Ulthera pels or sutures. This procedure takes again; then they’re a little pink for an- is the only company with a product in about an hour and a half, with results other week. Systems designed for this this category; it’s approved for brow- that resemble a surgical facelift. (See purpose include the ResurFX module lifting and treating the lower face, photos, facing page.) It involves a little of Lumenis’s M22 system, the Fraxel neck and décolletage area. It does more surgical downtime, but most

Repair and the Pixel CO2 System. produce a fair amount of skin and patients have it done on Wednesday Other fractional ablative lasers use soft-tissue tightening.” or Thursday and are back at work on different light sources; some, such as • Radio frequency micronee- Monday. Devices in this category in- erbium-based lasers, cause less ther- dling. Dr. Bloom explains that these clude ThermiTight (Thermi), Pre- mal damage and leave the patient less devices deliver the energy through cisionTx (Cynosure) and FaceTite/ red. The tradeoff is usually that they the epidermis via tiny needles that NeckTite (InMode). require a greater number of treat- pierce the skin. “Some of these de- Dr. Bloom says most of these pro- ments to achieve the desired effect.” vices have 150 needles; some have 24; cedures have a very short learning • Radio frequency energy. De- some have 60; some use paired needle curve. “The one exception might be vices in this category use radio fre- sets,” he says. “Some use needles that the last category of devices, which use quency energy to generate heat trans- are coated with insulation so the en- a cannula,” he says. “To use those you cutaneously. “Radio waves penetrate ergy comes out only at the tip, while have to be familiar with tumescent deep into the subcutaneous tissues,” others are not insulated, so the en- anesthesia, and they take a couple of Dr. Bloom explains. “The heat stimu- ergy causes damage along the entire cases to get used to. But most of these lates production of collagen and elas- needle track. More damage means procedures can be learned by almost tin, which tightens down tissue over more effect, but also more downtime; anyone. In fact, that’s a problem, be- time. However, these devices tend to the latter patients can ooze a little bit cause laws regulating these proce- use lower energy levels and require because you’re causing an injury all dures differ from state to state. In multiple passes to create the desired the way up through the epidermis. I some states, anyone can operate the effect. Devices in this category in- only use the coated needles. Devices equipment and perform procedures. clude Thermage CPT (Valeant), Exilis in this category include Infini (Lu- As a tertiary site, we sometimes see Protégé Elite (BTL), ThermiSmooth tronic), Profound (Syneron Candela), patients who have been badly burned (Thermi) and Pelleve (Cynosure).” Fractora (InMode) and Intensif RF or disﬁ gured by non-surgeon proce- • Microfocused ultrasound. Dr. Microneedle (EndyMed).” dures. Meanwhile, in other states, Bloom says this third category is still • Cannulated delivery under the only a doctor is allowed to perform noninvasive, but reaches a deeper skin. Dr. Bloom says the newest fron- these procedures.” tissue layer. “Ultrasound normally is tier involves using a stiff, insulated nonspeciﬁ c; it penetrates deeply but 18-ga. cannula that’s inserted through Tips for Success causes no lesions,” says Dr. Bloom. a tiny hole in the skin and moved “This technology focuses the energy, around by the surgeon. The cannula Dr. Bloom—who notes that he

22 | Review of Ophthalmology | September 2016

020_rp0916_tech update.indd 22 8/26/16 2:51 PM order online www.innovativexcimer.comAMOILS

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Cannulated delivery of energy through tiny holes in the skin—done in-offi ce using tumescent anesthesia—can produce results resembling a surgical face or neck lift. Corneal Xlinking, has learned a lot about lasers from vice, try it out on the rep. “This can working with Eric Bernstein, MD, a be a good way to make sure the device PRK, & Advanced dermatologic laser surgeon—offers is safe,” Dr. Bloom notes. Surface Ablation these tips to any ophthalmologist con- • It might be worth offering more sidering adding one of these devices/ than one option. “One size does not Improved clinical procedures to your practice offerings: fi t all,” says Dr. Bloom. “Patients want outcomes of CXL • Check the regulations affect- different results, have different toler- ing use of these devices in your ance for downtime, different fi nancial and PRK with the state before purchasing one—es- situations, different tolerance for in- Amoils Epithelial pecially if you won’t be the person vasiveness, different pain tolerance operating the device. As noted, laws and different ideas about how long Scrubber vary widely from state to state. “Make they’re willing to wait before seeing sure you’re clear about the legal rami- results. If you can offer more than fi cations of offering these services be- one option, you’ll get more patients fore you begin,” says Dr. Bloom. interested.” • Never take advice on settings • Don’t try to use one device to from the manufacturer’s rep. “The do everything. “You can’t use one rep will often tell you to turn the en- device to do everything, or use the ergy level up very high to get quick same device on every patient,” says results,” notes Dr. Bloom. “That’s usu- Dr. Bloom. “For example, some la- ally bad advice. Before I operate a sers work better on light or dark skin. new device I talk to colleagues who These devices aren’t cheap; they range are familiar with it to get their advice from $45,000 to $100,000 or more. on settings, patient selection and so On the other hand, some of these de- Minimize total procedure time forth.” vices, such as a CO2 laser, can be used • Consider taking a course on for multiple purposes. If you’re go- Avoid alcohol damage to the procedure. “The American So- ing to invest in a single device, think surrounding tissue ciety for Laser Medicine & Surgery carefully about what your patients are provides excellent courses on the likely to be interested in, and do your No need for subsequent use of these technologies,” says Dr. homework before purchasing.” scraping Bloom. “They have an annual meeting in April and offer regional courses Dr. Bloom serves as a trainer, con- as well. I lead a course on periorbital sultant or speaker for many of the CALLCALL1 1.800.461.1200.800.461.1200 therapies using these devices. You can companies mentioned, as well as fi nd information at ASLMS.org.” many others across the laser and aes- innovativexcimer.comimer.com • When a rep brings in a new de- thetics industry.

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020_rp0916_tech update.indd 23 8/26/16 2:51 PM Cornea REVIEW Cover Focus Perfecting Posterior Corneal Grafts Sadeer B. Hannush, MD Philadelphia

A look at the phthalmologists in general, and • true anatomic replacement of corneal specialists specifi cally, Descemet’s membrane and endothe- options waiting Oare always striving to get their lium, a 15 to 20-µm thick structure; posterior corneal transplant patients • pachymetric uniformity across the behind DSAEK, the best anatomic and visual outcomes entire graft, which DSAEK can’t al- possible. In recent years, this drive ways achieve; especially its has led to the development of alterna- • lower antigenic stimulus—and closest rival, tives to penetrating keratoplasty, such therefore lower incidence of allograft as Descemet’s stripping automated rejection—by virtue of less tissue be- DMEK. endothelial keratoplasty, Descemet’s ing transplanted; membrane endothelial keratoplasty • the need for less steroids to pre- and even newer techniques. With vent immune rejection; increasingly better outcomes, how- • a lower incidence of steroid-in- ever, come increasingly diffi cult produced intraocular pressure elevation cedures, and not everyone has em- and glaucoma; and braced techniques such as DMEK. In • if done correctly, the possibility of this article, I’ll review the cutting-edge quicker visual rehabilitation.1 transplant techniques, with an empha- DMEK, for all its advantages, isn’t sis on DMEK, since it is the closest to for every patient, however. The ideal achieving the kind of acceptance that patient is a pseudophake with a poste- DSAEK now enjoys. rior chamber lens implant, ideally one that’s situated in the capsular bag, with Why DMEK? or without a posterior capsulotomy. For patients with serious co-morbidi- DSAEK currently sits in the sweet ties, I still prefer to perform DSAEK. spot in which it can provide good out- With this in mind, patient presenta- comes for patients with Fuchs’ and tions in which to avoid DMEK—at other posterior corneal dystrophies, least for the novice DMEK surgeon— as well as aphakic and pseudophakic are patients with: bullous keratopathy, while, at the same • anterior chamber intraocular lens time, not putting a lot of technical de- implants; mands on the surgeon. • unicameral eyes; There are reasons to consider • vitreous prolapse into the anterior DMEK, however, as it can potentially chamber; offer even more benefi ts, such as: • a history of trabeculectomy;

24 | Review of Ophthalmology | September 2016 This article has no commercial sponsorship.

0024_rp0916_f1.indd24_rp0916_f1.indd 2424 88/26/16/26/16 3:493:49 PMPM • a history of tube shunt implantation;2 • failed penetrating grafts; and • failed previous DSAEK grafts. The common themes among these SMART relative contraindications include the possibility of losing the graft into the COMBO vitreous cavity, the diffi culty you’ll have in unscrolling the graft in the eye and UNITS the potential increased challenge of attaching the graft. Tapping technique to unscroll a DMEK graft. The Four Challenges of DMEK ily. Secondly, diabetic patients’ tissue For surgeons experienced with has been shown to be more diffi cult to DMEK, as well as surgeons just start- strip and more likely to develop tears. ing out, there are four areas that will Finally, if the donor has had previ- test their skills. It’s these areas that cur- ous intraocular surgery, particularly rently hold DMEK back in terms of cataract surgery, and especially if the being a widely accepted technique. cataract surgeon made a long phaco in- You can clear these hurdles, however. cision tunnel, you or the eye-bank tech Here’s a look at why these stages are may encounter the internal lumen of space particularly challenging, and ways you the old cataract incision while stripping can make them more manageable. the tissue. If this occurs, that’s a likely & functionality • Preparation of the donor tissue. location for a tear. A complete solution This challenge is not so much the actu- Also, preparing the donor graft from DWDQDƪRUGDEOHSULFH al pre-stripping of the tissue—the vast perfectly pre-stripped tissue can be rSmall footprint majority of us have trained an eye-bank challenging, as punching, isolating and technician to strip the tissue for us, and placing the graft into the delivery de- rRobust all metal construction most of them have become better than vice is not without potential complica- built for longevity us at this task. Instead, it’s more about tions. Focus on patient comfort an awareness of the donor’s age and • Insertion of tissue into the ante- r diabetic status, and how both will af- rior chamber. DMEK surgeons usu- rSpectacular engineering fect the tissue’s behavior. ally use one of two ways to insert the Smooth tilt/glide function Corneal specialists have unoffi cially tissue: 1) a push-through technique r agreed that the tissue donor shouldn’t by way of a glass tube or a modifi ed &RQƬJXUDWLRQV be younger than 50 years of age, dia- intraocular lens inserter; or 2) a pull- VROXWLRQVIRUHYHU\RƯFH betic or have had previous cataract sur- through technique after placing the gery. Why is this? Because the younger donor graft on a Busin glide, contact the tissue, the harder it is to strip the lens or similar platform. Most DMEK Descemet’s membrane/endothelial surgeons are currently using a push- complex off the donor cornea, and the through method. With this being the tighter its subsequent scroll is when case, it’s important to note that the you try to unscroll it in the recipient’s glass tube and modifi ed IOL inserter anterior chamber. I won’t hesitate to have advantages and limitations. accept a donor that’s 70 to 72 years of The glass tube is actually a modifi ed age, however, because the Cornea Do- version of the Jones tube we’ve used nor Study showed there wasn’t much for years for dacryocystorhinostomy of a difference in risk of graft failure procedures. The tube’s shape has been in grafts from donors up to age 75;3 I slightly modifi ed by Michael Straiko, know I’ll be able to handle an older MD, of the Devers Eye Institute in donor’s tissue inside the eye more eas- Portland, Ore., creating what’s known 250 Cooper Ave., Suite 100 Tonawanda NY 14150 ZZZVRSWLNFRP, Sensible equipment. Well made, well priced. )RUWRGD\oVPRGHUQRƯFH

024_rp0916_f1.indd 25 8/26/16 3:50 PM Cover Cornea

REVIEW Focus

as the Straiko-modified Jones tube. Alternatively, you can intraopera- It can be inserted through a 3.2- to tively discern the graft orientation once 3.5-mm incision. Proponents of these it’s in the eye using either a slit lamp tubes believe that they do less endo- attached to your operating microscope, thelial cell damage if the graft tissue or a tiny handheld slit lamp. As the touches the glass wall of the tube, com- graft unscrolls it will begin to take on pared to the plastic interior of a modi- the shape of the letter C, with the en- fi ed IOL cartridge. dothelium on the outside of the C. So, One of the pearls for working with if by using the slit beam you can tell the a glass tube is that it’s important to get Temporal corneal edema after DMEK orientation of the C, you’ll always know a feel for how to aspirate the tissue secondary to a DMEK detachment. Note the which side is up; you want the inside of into the tube. This is because you’re letter S nasally in its correct orientation. the C to be facing up, so it looks like a aspirating the tissue from a petri dish cup under the dome of the cornea. rather than placing it into the back lem with going through the wound Aside from these popular ap- of the tube. To get a feel for this, use after you’ve fl oated the graft into the proaches, there are other published peripheral fragments of Descemet’s glass tube or cartridge. Also, choose techniques to aid in determining the membrane from the donor tissue after an inserter that allows for a tight seal orientation of the graft, too. Of course, the punch, not the graft itself, to see between the plunger and the wall of an operating microscope with built-in how much to pull on the plunger to the cartridge. OCT will accomplish that goal … at a aspirate the tissue up into the tube. As mentioned above, there are ways signifi cantly higher cost. Surgeons who use plastic, modifi ed to introduce the graft into the eye oth- In terms of getting the graft to IOL injection cartridges argue that er than as a scroll, such as a method unscroll, one method used by many one of the main benefi ts of their ap- that involves placing the graft on a surgeons is the tapping technique, proach is that the tissue can be inserted Busin glide or other platform, similar developed by Efdal Yoeruek, MD, through a 2.4- to 2.8-mm incision. The to the way in which the surgeon inserts of Eberhard-Karls University in main challenge with IOL inserters is a DSAEK graft, using a two-handed, Tübingen, Germany. The technique that they’re not meant to push such pull-through technique. However, involves bouncing an instrument, usu- thin tissue—about 20 µm thick—into since most surgeons insert the DMEK ally a BSS or 27- or 30-ga cannula, on the eye. This can cause issues as you graft into the eye as a scroll, that is what the cornea over the location of the work with the inserter (indeed, not this article focuses on. scroll together with a simultaneously all inserters are created equal for this This brings us to the challenge of shallowing of the anterior chamber. purpose). This is because in the course getting the graft oriented correctly This tapping sends fl uid waves through of its normal operation, the inserter’s when it unscrolls. the anterior chamber that unscroll the plunger doesn’t completely seal the • Unscrolling the tissue and tissue. This technique usually works channel that it goes into, and it doesn’t achieving successful tamponade. best if the chamber is shallow enough need to for the purpose of injecting an Getting the thin DMEK graft to un- so that, when you start unscrolling the IOL. Because of this, though, saline scroll can be a challenge, especially graft, it doesn’t just scroll right back solution can occasionally leak from the when the tissue is tightly scrolled.4 Sev- again. A good rule of thumb for this back of the cartridge—taking the thin eral techniques have been developed chamber shallowing is to make it less DMEK graft with it and incarcerating to help you unscroll it, however. than one corneal thickness deep. For it between the plunger and the wall of First off, one way to achieve the cor- example, if the average cornea is 500 the cartridge. Note that this is more rect orientation of the tissue as it tran- to 600 µm thick, the anterior cham- likely to occur if you use a chamber sitions from a scroll to an unscrolled ber should be roughly 0.5 mm or less maintainer with fl uid infusion during sheet is the marking method. The in depth after the graft is unscrolled, the insertion. method involves the eye bank, or who- as opposed to its usual 2.5 to 3.5 mm If you use either of these methods, ever prepares the tissue, marking the depth, in order to successfully tap glass tube or modified inserter, the stromal side with a letter S to aid in the and unscroll the tissue and keep it number-one technique tip is to size subsequent placement in the eye. An unscrolled until the air/gas bubble is the wound in such a way that you can ideal way to make this mark is by using injected. insert the tube or cartridge into the a stamper colored with a gentian violet Selective irrigation is another meth- incision tightly but without diffi culty. surgical pen and allowing the alcohol od that can help unscroll the tissue. To You don’t want to encounter a prob- to evaporate.5 understand this, it helps to know that

26 | Review of Ophthalmology | September 2016

024_rp0916_f1.indd 26 8/26/16 3:50 PM INDICATIONS AND USAGE IMPORTANT SAFETY INFORMATION (continued) ZYLET® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic • Prolonged use of corticosteroids may result in glaucoma with suspension) is a topical anti-infective and corticosteroid combination damage to the optic nerve, defects in visual acuity and fi elds of for steroid-responsive infl ammatory ocular conditions for which a vision. Steroids should be used with caution in the presence of corticosteroid is indicated and where superfi cial bacterial ocular glaucoma. If this product is used for 10 days or longer, intraocular infection or a risk of bacterial ocular infection exists. pressure should be monitored. Ocular steroids are indicated in infl ammatory conditions of the • Use of corticosteroids may result in posterior subcapsular palpebral and bulbar conjunctiva, cornea and anterior segment of the cataract formation. globe such as allergic conjunctivitis, acne rosacea, superfi cial punctate • The use of steroids after cataract surgery may delay healing and keratitis, herpes zoster keratitis, iritis, cyclitis, and where the inherent increase the incidence of bleb formation. In those diseases causing risk of steroid use in certain infective conjunctivitides is accepted to thinning of the cornea or sclera, perforations have been known to obtain a diminution in edema and infl ammation. They are also indicated occur with the use of topical steroids. The initial prescription and in chronic anterior uveitis and corneal injury from chemical, radiation or renewal of the medication order should be made by a physician only thermal burns, or penetration of foreign bodies. after examination of the patient with the aid of magnifi cation such as a slit lamp biomicroscopy and, where appropriate, fl uorescein staining. The use of a combination drug with an anti-infective component is • Prolonged use of corticosteroids may suppress the host response indicated where the risk of superfi cial ocular infection is high or where and thus increase the hazard of secondary ocular infections. In acute there is an expectation that potentially dangerous numbers of bacteria purulent conditions, steroids may mask infection or enhance existing will be present in the eye. infections. If signs and symptoms fail to improve after 2 days, the The particular anti-infective drug in this product (tobramycin) is active patient should be re-evaluated. against the following common bacterial eye pathogens: Staphylococci, • Employment of corticosteroid medication in the treatment of patients including S. aureus and S. epidermidis (coagulase-positive and coagulase- with a history of herpes simplex requires great caution. Use of ocular negative), including penicillin-resistant strains. Streptococci, including steroids may prolong the course and exacerbate the severity of many some of the Group A-beta-hemolytic species, some nonhemolytic viral infections of the eye (including herpes simplex). species, and some Streptococcus pneumoniae, Pseudomonas aeruginosa, • Fungal infections of the cornea are particularly prone to develop Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Proteus coincidentally with long-term local steroid application. Fungus invasion mirabilis, Morganella morganii, most Proteus vulgaris strains, Haemophilus must be considered in any persistent corneal ulceration where a steroid infl uenzae, and H. aegyptius, Moraxella lacunata, Acinetobacter has been used or is in use. calcoaceticus and some Neisseria species. • Most common adverse reactions reported in patients were injection and superfi cial punctate keratitis, increased intraocular pressure, IMPORTANT SAFETY INFORMATION burning and stinging upon instillation. • ZYLET® is contraindicated in most viral diseases of the cornea and Please see Brief Summary of Prescribing Information for ZYLET® conjunctiva including epithelial herpes simplex keratitis (dendritic on adjacent page. keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures.

RP0916_BL Zylet.indd 1 8/3/16 10:57 AM BRIEF SUMMARY OF PRESCRIBING INFORMATION Secondary Infection: This Brief Summary does not include all the information needed to use Zylet safely The development of secondary infection has occurred after use of combinations containing and effectively. See full prescribing information for Zylet. steroids and antimicrobials. Fungal infections of the cornea are particularly prone to ® develop coincidentally with long-term applications of steroids. Zylet (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension) The possibility of fungal invasion must be considered in any persistent corneal ulceration Initial U.S. Approval: 2004 where steroid treatment has been used. DOSAGE AND ADMINISTRATION Secondary bacterial ocular infection following suppression of host responses also occurs. 2.1 Recommended Dosing USE IN SPECIFIC POPULATIONS Apply one or two drops of Zylet into the conjunctival sac of the affected eye every four to six 8.1 Pregnancy hours. During the initial 24 to 48 hours, the dosing may be increased, to every one to two hours. Teratogenic effects: Pregnancy Category C. Loteprednol etabonate has been shown to be Frequency should be decreased gradually as warranted by improvement in clinical signs. Care embryotoxic (delayed ossification) and teratogenic (increased incidence of meningocele, should be taken not to discontinue therapy prematurely. abnormal left common carotid artery, and limb fixtures) when administered orally to 2.2 Prescription Guideline rabbits during organogenesis at a dose of 3 mg/kg/day (35 times the maximum daily Not more than 20 mL should be prescribed initially and the prescription should not be clinical dose), a dose which caused no maternal toxicity. The no-observed-effect-level refilled without further evaluation [see Warnings and Precautions (5.3)]. (NOEL) for these effects was 0.5 mg/kg/day (6 times the maximum daily clinical dose). CONTRAINDICATIONS Oral treatment of rats during organogenesis resulted in teratogenicity (absent innominate artery at ≥5 mg/kg/day doses, and cleft palate and umbilical hernia at ≥50 mg/kg/day) 4.1 Nonbacterial Etiology and embryotoxicity (increased post-implantation losses at 100 mg/kg/day and decreased Zylet, as with other steroid anti-infective ophthalmic combination drugs, is contraindicated fetal body weight and skeletal ossification with ≥50 mg/kg/day). Treatment of rats at in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex 0.5 mg/kg/day (6 times the maximum daily clinical dose) during organogenesis did not keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of result in any reproductive toxicity. Loteprednol etabonate was maternally toxic (significantly the eye and fungal diseases of ocular structures. reduced body weight gain during treatment) when administered to pregnant rats during WARNINGS AND PRECAUTIONS organogenesis at doses of ≥5 mg/kg/day. 5.1 Intraocular Pressure (IOP) Increase Oral exposure of female rats to 50 mg/kg/day of loteprednol etabonate from the start Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, of the fetal period through the end of lactation, a maternally toxic treatment regimen defects in visual acuity and fields of vision. Steroids should be used with caution in the (significantly decreased body weight gain), gave rise to decreased growth and survival presence of glaucoma. and retarded development in the offspring during lactation; the NOEL for these effects If this product is used for 10 days or longer, intraocular pressure should be monitored. was 5 mg/kg/day. Loteprednol etabonate had no effect on the duration of gestation or 5.2 Cataracts parturition when administered orally to pregnant rats at doses up to 50 mg/kg/day during Use of corticosteroids may result in posterior subcapsular cataract formation. the fetal period. 5.3 Delayed Healing Reproductive studies have been performed in rats and rabbits with tobramycin at doses The use of steroids after cataract surgery may delay healing and increase the incidence up to 100 mg/kg/day parenterally and have revealed no evidence of impaired fertility or of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations harm to the fetus. There are no adequate and well controlled studies in pregnant women. have been known to occur with the use of topical steroids. The initial prescription and Zylet should be used during pregnancy only if the potential benefit justifies the potential renewal of the medication order should be made by a physician only after examination risk to the fetus. of the patient with the aid of magnification such as a slit lamp biomicroscopy and, where 8.3 Nursing Mothers appropriate, fluorescein staining. It is not known whether topical ophthalmic administration of corticosteroids could result in 5.4 Bacterial Infections sufficient systemic absorption to produce detectable quantities in human milk. Systemic Prolonged use of corticosteroids may suppress the host response and thus increase the steroids that appear in human milk could suppress growth, interfere with endogenous hazard of secondary ocular infections. In acute purulent conditions of the eye, steroids may corticosteroid production, or cause other untoward effects. Caution should be exercised mask infection or enhance existing infection. If signs and symptoms fail to improve after when Zylet is administered to a nursing woman. 2 days, the patient should be re-evaluated. 8.4 Pediatric Use ® 5.5 Viral Infections Two trials were conducted to evaluate the safety and efficacy of Zylet (loteprednol Employment of a corticosteroid medication in the treatment of patients with a history of etabonate and tobramycin ophthalmic suspension) in pediatric subjects age zero to six herpes simplex requires great caution. Use of ocular steroids may prolong the course and years; one was in subjects with lid inflammation and the other was in subjects with may exacerbate the severity of many viral infections of the eye (including herpes simplex). blepharoconjunctivitis. 5.6 Fungal Infections In the lid inflammation trial, Zylet with warm compresses did not demonstrate efficacy Fungal infections of the cornea are particularly prone to develop coincidentally with long- compared to vehicle with warm compresses. Patients received warm compress lid term local steroid application. Fungus invasion must be considered in any persistent treatment plus Zylet or vehicle for 14 days. The majority of patients in both treatment corneal ulceration where a steroid has been used or is in use. Fungal cultures should be groups showed reduced lid inflammation. taken when appropriate. In the blepharoconjunctivitis trial, Zylet did not demonstrate efficacy compared to vehicle, 5.7 Aminoglycoside Hypersensitivity loteprednol etabonate ophthalmic suspension, or tobramycin ophthalmic solution. Sensitivity to topically applied aminoglycosides may occur in some patients. If hypersensitivity There was no difference between treatment groups in mean change from baseline develops with this product, discontinue use and institute appropriate therapy. blepharoconjunctivitis score at Day 15. There were no differences in safety assessments between the treatment groups in either trial. ADVERSE REACTIONS 8.5 Geriatric Use Adverse reactions have occurred with steroid/anti-infective combination drugs which can No overall differences in safety and effectiveness have been observed between elderly be attributed to the steroid component, the anti-infective component, or the combination. and younger patients. Zylet: NONCLINICAL TOXICOLOGY In a 42 day safety study comparing Zylet to placebo, ocular adverse reactions included injection (approximately 20%) and superficial punctate keratitis (approximately 15%). Increased 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility intraocular pressure was reported in 10% (Zylet) and 4% (placebo) of subjects. Nine percent Long-term animal studies have not been conducted to evaluate the carcinogenic potential (9%) of Zylet subjects reported burning and stinging upon instillation. of loteprednol etabonate or tobramycin. Ocular reactions reported with an incidence less than 4% include vision disorders, Loteprednol etabonate was not genotoxic in vitro in the Ames test, the mouse lymphoma discharge, itching, lacrimation disorder, photophobia, corneal deposits, ocular discomfort, TK assay, a chromosome aberration test in human lymphocytes, or in an in vivo mouse eyelid disorder, and other unspecified eye disorders. micronucleus assay. The incidence of non-ocular reactions reported in approximately 14% of subjects was Oral treatment of male and female rats at 50 mg/kg/day and 25 mg/kg/day of loteprednol headache; all other non-ocular reactions had an incidence of less than 5%. etabonate, respectively, (500 and 250 times the maximum clinical dose, respectively) prior to and during mating did not impair fertility in either gender. No impairment of fertility was Loteprednol etabonate ophthalmic suspension 0.2% - 0.5%: noted in studies of subcutaneous tobramycin in rats at 100 mg/kg/day (1700 times the Reactions associated with ophthalmic steroids include elevated intraocular pressure, maximum daily clinical dose). which may be associated with infrequent optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, delayed wound healing and secondary PATIENT COUNSELING INFORMATION ocular infection from pathogens including herpes simplex, and perforation of the globe This product is sterile when packaged. Patients should be advised not to allow the dropper where there is thinning of the cornea or sclera. tip to touch any surface, as this may contaminate the suspension. If pain develops, redness, itching or inflammation becomes aggravated, the patient should be advised to In a summation of controlled, randomized studies of individuals treated for 28 days or consult a physician. As with all ophthalmic preparations containing benzalkonium chloride, longer with loteprednol etabonate, the incidence of significant elevation of intraocular patients should be advised not to wear soft contact lenses when using Zylet. pressure (≥10 mm Hg) was 2% (15/901) among patients receiving loteprednol etabonate, 7% (11/164) among patients receiving 1% prednisolone acetate and 0.5% (3/583) among MANUFACTURER INFORMATION patients receiving placebo. BAUSCH & LOMB INCORPORATED Tobramycin ophthalmic solution 0.3%: TAMPA, FLORIDA 33637 USA The most frequent adverse reactions to topical tobramycin are hypersensitivity and ©Bausch & Lomb Incorporated localized ocular toxicity, including lid itching and swelling and conjunctival erythema. Zylet is a registered trademark of Bausch & Lomb Incorporated. These reactions occur in less than 4% of patients. Similar reactions may occur with the topical use of other aminoglycoside antibiotics. Based on 9007705-9004405 Revised 08/2013 US/ZYL/15/0014

RRP0916_BLP0916_BL ZZyletylet PPI.inddI.indd 1 88/3/16/3/16 10:5910:59 AMAM Cover Cornea

REVIEW Story

most DMEK surgeons will make two SF6 bubble can make a difference; to four paracenteses that are used for e.g., an 80-percent air bubble may last many functions during the procedure: three to four days, while an 80-percent One use for the paracenteses is to SF6 bubble can last twice as long, and deepen the chamber when necessary. might help increase your chance of For example, if, after you unscroll the success with DMEK graft attachment. tissue you fi nd that it’s upside down— Also, remember all DMEK patients i.e., you notice the letter S marking should receive an inferior iridotomy. I is inverted—you need to deepen the should also mention here that a pletho- anterior chamber to release the tissue Slit view of the detached DMEK graft from ra of online videos can be of great help and scroll it again so you can flip it p. 26, highlighted by the arrows. to the novice DMEK surgeon, both in over. Another use for the paracenteses facilitating the successful completion is to use the irrigation to move the tis- the DMEK scroll. An actuator then of the procedure and in avoiding and sue toward the center of the chamber. opens the loop to unscroll the graft. managing complications. A third use of irrigation is if the tissue The instrument has been tested suc- • Postop management. When is in a double-scroll confi guration, or cessfully in the wet lab, and is currently DMEK surgeons discuss postop man- even a three-corner folded graft (think in the manufacturing process. agement, we’re usually referring to Napoleon’s hat), the fl uid pulses can Once the graft is unscrolled, the sur- decreasing the incidence of and man- be used to open up the tissue. My col- geon has to tamponade it to the host aging graft detachment. To decrease league in India, Rajesh Fogla, MD, cornea. For this, the options are to this risk, it’s important that the patient has developed a cannula with mul- use a bubble composed of either air or lie on his back, take the drops, refrain tiple irrigation holes dubbed the Fogla 20% SF6. The main advantage of the from rubbing the eye and keep up with DMEK Cannula (Storz Ophthalmics) latter is that it lasts longer, which may the follow-up visits. that is situated inside the scroll. Once be helpful in achieving full apposition In terms of how long the patient must the Fogla cannula is inside the scroll, of the DMEK graft to the host cornea. remain on his back, if we’ve used SF6, the surgeon injects the fl uid and the With DSAEK you mainly need to tam- which can last about a week, we ask the scroll opens. ponade the graft for 10 minutes with patient to be on his back continuously Another method that some may a pressure above 30 mmHG and the for the fi rst day, and then for two hours consider dexterity-intensive, but which graft will usually stay in place, as long in the morning and two hours in the is exciting to watch, is called the bub- as there’s no fl uid between the graft afternoon for the next fi ve days postop. ble roll, developed by Friedrich Kruse, and the host. With DMEK things are Since I frequently remove the central MD, of Erlangen, Germany.6 With this different. For DMEK, many surgeons epithelium at the time of surgery, a ban- technique, when the graft is inside the feel that it’s important to have a longer- dage contact lens is used for the fi rst injector cartridge, the surgeon places lasting bubble and to make sure the week. It must be noted, however, that a small bubble inside the scroll. Then, patient lies on his/her back postop for not every surgeon performs the kera- when the graft enters the eye, he can at least the fi rst 24 hours, then at least tectomy/contact lens step. place pressure on the dome of the cor- a few hours a day for the next several In addition to a postop steroid and nea to move the bubble around inside days. So for DMEK a longer-lasting antibiotic, my postop medical regi- the scroll to unscroll it. men usually includes Muro For my own part, I’ve 128 hypertonic solution to teamed with Phillipsburg, promote deturgescence of the N.J., ophthalmologist, Wil- host stroma. I usually start the liam B. Neusidl to develop Muro the second week after an instrument for unscroll- the surface has healed and the ing the DMEK graft. We’ve antibiotic has been discontin- dubbed it the Neusidl-Han- ued. nush Loop, or NHL. The The main concern during NHL’s operation involves a the postop course is how to polypropylene thread inside respond if the graft doesn’t ad- a metal lumen that’s pulled The OCT appearance of the detached graft in the slit image here completely. In my prac- taut and inserted into the above (top) and the OCT of the eye following reattachment with a tice, the incidence of partial anterior chamber and inside rebubbling procedure (bottom). graft non-attachment requir-

September 2016 | reviewofophthalmology.com | 29

024_rp0916_f1.indd 29 8/26/16 3:50 PM Cover Cornea

REVIEW Focus

ing rebubbling (complete detachment technically challenging—but potentially is very rare) is 20 percent, vs. less than better—aspirant to the throne, there 5 percent for DSAEK. Studies have are other approaches to endothelial ker- also found a higher rebubbling rate atoplasty that are worth noting. with DMEK.7 Netherlands surgeon • Ultra-thin DSAEK. In an ef- and DMEK originator Gerritt Melles, fort to achieve some of the benefits MD, has argued that if less than one- of DMEK but perhaps with an easier third of the graft isn’t adhered, espe- time working with the graft, Italy’s cially if the area of non-attachment is Massimo Busin, MD, and co-workers not visually significant, the surgeon developed UT-DSAEK.11 In prac- The eye from pg. 29, with the graft attached may observe the patient, since grafts after a rebubbling procedure. tice, UT-DSAEK involves preparing that are 60- to 70-percent attached will a DSAEK graft thinner than 100 µm almost always completely attach and for the creation of the new bubble. A by a combination of several methods: stay in place in time. That’s also been note for rebubbling: With DSAEK, removing the epithelium before mak- my experience for the most part. How- you only need to insert the air cannula ing the microkeratome pass; making a ever, I also think that the longer you a little bit into the anterior chamber double-pass with the microkeratome; leave the graft unattached, the worse and, as long as you’re behind the graft, using a 300, 350, or even 400 µm mi- the visual prognosis becomes, due to you can inject the air. With DMEK, crokeratome head; increasing the pres- chronic edema. Therefore, if the area however, if you’re too peripheral when sure in the anterior chamber to about of detachment extends over the un- the bubble starts to form, you can push 90 mmHG as you make the pass; and/ dilated pupillary aperture, I prefer to the graft aside like an accordion and or making a slower microkeratome rebubble—create a new bubble for detach it completely. Therefore, make pass. tamponade—usually between 10 and sure the cannula is in the center of the Working with a thinner DSAEK 20 days postop, a strategy I’ve learned anterior chamber behind the graft be- graft is technically less challenging from Dr. Kruse and that has served my fore you start injecting the air. than a DMEK graft. Theoretically, patients well. If I find it challenging Though rebubbling is an effective it may offer better visual results than to discern the existence or extent of response to graft non-attachment, it’s conventional DSAEK, mostly due to the detachment, especially if it’s very important to note that graft failure can the increased uniformity and thickness shallow and in the setting of corneal still occur for a multitude of reasons. of the donor tissue. There have been edema, anterior segment OCT has Graft failure may occur due to poor no formal studies showing the ben- been very helpful in determining the attachment, an upside-down graft or efit of UT-DSAEK over DSAEK or presence of a graft detachment and its rejection. In my hands, and I believe DMEK, so the jury is currently still out extent. those of many colleagues, graft failure on this. Anecdotally, however, many In practice, if I see a DMEK patient may be a function of marked manipu- surgeons, myself included, seem to a week postop and notice that the cor- lation of the graft. This manipulation think patients do get better vision from nea is a little edematous, and I can’t see usually occurs intraoperatively dur- a thinner graft. Therefore, I aim for the graft well—and then perform an ing the unscrolling step, in what is re- that type of graft whenever possible. OCT and ﬁ nd a shallow detachment— ferred to as “the dance,” and leads to • Redistributed endothelial cells. I’ll inform the patient that I’ll most a significant loss of endothelium. In In the past several years, some oph- likely want to put another bubble in the literature, the rate of primary graft thalmologists have questioned whether the eye the following week. In prepa- failure with DMEK varies from 2.5 to we need to perform a keratoplasty of ration for this appointment, I advise 10 percent.8-10 any sort in cases of Fuchs’ endothelial the patient to bring someone along for dystrophy. Instead, they say, there may assistance, and to be prepared to spend Techniques in Development be a way to just coax the endothelium a couple of hours at my ofﬁ ce, which is to return to its normal level of function, where I perform almost all rebubbling Though DSAEK may be entrenched or to redistribute healthy endothelium procedures. Some surgeons prefer to as the less-invasive alternative to pen- to a central location where it may per- do it in the OR, and still others do it in etrating keratoplasty for the indication form its function better. a minor procedure room. of endothelial dysfunction, as well as the The Netherlands’ Dr. Melles re- At that rebubbling visit, I sit the pa- one associated with better visual results ported on an 80-year-old patient who tient at the slit lamp and use one of than PK (mainly because of reduced underwent DMEK for Fuchs’, but had the existing paracenteses to inject air astigmatism), and DMEK is the more (continued on page 68)

30 | Review of Ophthalmology | September 2016

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RP0916_Akorn TT.indd 1 8/24/16 2:22 PM Cornea REVIEW Cover Focus Making the Most of Corneal Cross-linking Christopher Kent, Senior Editor

Surgeons offer ith the recent approvals of ly approved version of cross-linking Avedro’s KXL cross-linking [with removal of the epithelium] is advice to fi rst-time Wsystem to treat progressive not to be taken lightly,” he says. “It’s keratoconus and ectasia, American crucial to pay attention to patient se- users for getting surgeons can fi nally begin to use cross- lection and ocular surface assessment linking to help their patients. How- and treatment, both preoperatively great results and ever, like any new technology, cross- and postoperatively. In my experi- linking comes with a learning curve ence, healing after cross-linking is staying out of and potential complications. Here, even slower and more critical than it four surgeons experienced in using is following PRK. Patients with ocu- trouble. this technology share their thoughts lar surface disease, as well as patients on how to use the Avedro system; with very steep corneas, are at higher what pitfalls to avoid; and where this risk for delayed epithelial healing and technology may be headed next. potential complications, so surgeons should monitor their patients fre- The Power of Cross-linking quently until the epithelium regrows.” Peter S. Hersh, MD, FACS, clinical “Cross-linking is a major advance,” professor and director of cornea and notes Roy S. Rubinfeld, MD, MS, in refractive surgery at the Institute of private practice and a clinical associate Ophthalmology and Visual Science, professor at Georgetown University Rutgers-New Jersey Medical School, Medical Center. “It’s the fi rst and only was medical monitor for the trial that treatment demonstrated to effectively led to Avedro’s FDA approval. “The strengthen the cornea and stop the fi rst of the two FDA approvals to date progression of keratoconus or ecta- was for collagen cross-linking for the sia. Furthermore, it’s been well-tested treatment of progressive keratoco-

John Kanellopoulos, MD John Kanellopoulos, since it was originally introduced in nus,” he explains. “Although cross- the late 1990s by Michael Mrochen, linking may improve the corneal to- PhD, and Theo Seiler, MD, PhD, in pography modestly in some cases, the Dresden. It’s expected to markedly primary goal of crosslinking is stabili- reduce the number of corneal trans- zation of the disease process, so you Corneal collagen cross-linking is the only plants performed in the United States, want to be sure that you’re dealing treatment that’s been shown to strengthen which is very good news. with progressive keratoconus. Also, the cornea and stop the progression of “At the same time, it’s important for for this indication, the patient should keratoconus or ectasia. surgeons to realize that the current- be age 14 or older.”

32 | Review of Ophthalmology | September 2016 This article has no commercial sponsorship.

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For additional safety information, see accompanying Brief Summary of Safety Information on the following page and Full Prescribing Information on Xiidra-ECP.com.

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RP0916_Shire.indd 1 8/24/16 10:36 AM Animal Data .KƂVGITCUVCFOKPKUVGTGFFCKN[D[KPVTCXGPQWU +8 KPLGEVKQPVQTCVUHTQORTGOCVKPIVJTQWIJIGUVCVKQPFC[ ECWUGFCPKPETGCUGKPOGCPRTGKORNCPVCVKQPNQUU and an increased incidence of several minor skeletal CPQOCNKGUCVOIMIFC[TGRTGUGPVKPIHQNF Rx Only the human plasma exposure at the RHOD of Xiidra, based on AUC. No teratogenicity was observed in the rat at BRIEF SUMMARY: OIMIFC[ HQNFVJGJWOCPRNCUOCGZRQUWTGCV Consult the Full Prescribing Information for complete VJG4*1&DCUGFQP#7% +PVJGTCDDKVCPKPETGCUGF product information. incidence of omphalocele was observed at the lowest FQUGVGUVGFOIMIFC[ HQNFVJGJWOCP INDICATIONS AND USAGE RNCUOCGZRQUWTGCVVJG4*1&DCUGFQP#7% YJGP :KKFTCv NKƂVGITCUVQRJVJCNOKEUQNWVKQP KUKPFKECVGF CFOKPKUVGTGFD[+8KPLGEVKQPFCKN[HTQOIGUVCVKQPFC[U for the treatment of the signs and symptoms of dry eye VJTQWIJ#HGVCN0Q1DUGTXGF#FXGTUG'HHGEV.GXGN FKUGCUG &'& 01#'. YCUPQVKFGPVKƂGFKPVJGTCDDKV Lactation DOSAGE AND ADMINISTRATION 6JGTGCTGPQFCVCQPVJGRTGUGPEGQHNKƂVGITCUVKPJWOCP Instill one drop of Xiidra twice daily (approximately 12 milk, the effects on the breastfed infant, or the effects on JQWTUCRCTV KPVQGCEJG[GWUKPICUKPINGWUGEQPVCKPGT OKNMRTQFWEVKQP*QYGXGTU[UVGOKEGZRQUWTGVQNKƂVGITCUV Discard the single use container immediately after using HTQOQEWNCTCFOKPKUVTCVKQPKUNQY6JGFGXGNQROGPVCNCPF in each eye. Contact lenses should be removed prior to JGCNVJDGPGƂVUQHDTGCUVHGGFKPIUJQWNFDGEQPUKFGTGF VJGCFOKPKUVTCVKQPQH:KKFTCCPFOC[DGTGKPUGTVGF along with the mother’s clinical need for Xiidra and any minutes following administration. potential adverse effects on the breastfed child from Xiidra. ADVERSE REACTIONS Clinical Trials Experience Pediatric Use Because clinical studies are conducted under widely 5CHGV[CPFGHƂECE[KPRGFKCVTKERCVKGPVUDGNQYVJGCIGQH varying conditions, adverse reaction rates observed in [GCTUJCXGPQVDGGPGUVCDNKUJGF clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may Geriatric Use PQVTGƃGEVVJGTCVGUQDUGTXGFKPRTCEVKEG+PƂXGENKPKECN No overall differences in safety or effectiveness have been UVWFKGUQHFT[G[GFKUGCUGEQPFWEVGFYKVJNKƂVGITCUV observed between elderly and younger adult patients. ophthalmic solution, 1401 patients received at least FQUGQHNKƂVGITCUV QHYJKEJTGEGKXGFNKƂVGITCUV NONCLINICAL TOXICOLOGY 6JGOCLQTKV[QHRCVKGPVU JCFŰOQPVJUQH Carcinogenesis, Mutagenesis, Impairment of Fertility VTGCVOGPVGZRQUWTGRCVKGPVUYGTGGZRQUGFVQ Carcinogenesis: Animal studies have not been conducted NKƂVGITCUVHQTCRRTQZKOCVGN[OQPVJU6JGOCLQTKV[ VQFGVGTOKPGVJGECTEKPQIGPKERQVGPVKCNQHNKƂVGITCUV QHVJGVTGCVGFRCVKGPVUYGTGHGOCNG 6JGOQUV Mutagenesis: .KƂVGITCUVYCUPQVOWVCIGPKEKPVJGin vitro EQOOQPCFXGTUGTGCEVKQPUTGRQTVGFKPQHRCVKGPVU #OGUCUUC[.KƂVGITCUVYCUPQVENCUVQIGPKEKPVJGin vivo were instillation site irritation, dysgeusia and reduced mouse micronucleus assay. In an in vitro chromosomal XKUWCNCEWKV[1VJGTCFXGTUGTGCEVKQPUTGRQTVGFKP aberration assay using mammalian cells (Chinese VQQHVJGRCVKGPVUYGTGDNWTTGFXKUKQPEQPLWPEVKXCN JCOUVGTQXCT[EGNNU NKƂVGITCUVYCURQUKVKXGCVVJGJKIJGUV hyperemia, eye irritation, headache, increased concentration tested, without metabolic activation. lacrimation, eye discharge, eye discomfort, eye pruritus Impairment of fertility: .KƂVGITCUVCFOKPKUVGTGFCV and sinusitis. KPVTCXGPQWU +8 FQUGUQHWRVQOIMIFC[ HQNFVJGJWOCPRNCUOCGZRQUWTGCVVJG USE IN SPECIFIC POPULATIONS TGEQOOGPFGFJWOCPQRJVJCNOKEFQUG 4*1& QH Pregnancy NKƂVGITCUVQRJVJCNOKEUQNWVKQP JCFPQGHHGEVQP 6JGTGCTGPQCXCKNCDNGFCVCQP:KKFTCWUGKPRTGIPCPV fertility and reproductive performance in male and women to inform any drug associated risks. Intravenous female treated rats. +8 CFOKPKUVTCVKQPQHNKƂVGITCUVVQRTGIPCPVTCVUHTQO RTGOCVKPIVJTQWIJIGUVCVKQPFC[FKFPQVRTQFWEG teratogenicity at clinically relevant systemic exposures. +PVTCXGPQWUCFOKPKUVTCVKQPQHNKƂVGITCUVVQRTGIPCPV /CPWHCEVWTGFHQT5JKTG75+PE5JKTG9C[.GZKPIVQP/# rabbits during organogenesis produced an increased incidence of omphalocele at the lowest dose tested, (QTOQTGKPHQTOCVKQPIQVQYYY:KKFTCEQOQTECNN OIMIFC[ HQNFVJGJWOCPRNCUOCGZRQUWTGCV Marks designated ®CPFvCTGQYPGFD[5JKTG the recommended human ophthalmic dose [RHOD], QTCPCHƂNKCVGFEQORCP[ DCUGFQPVJGCTGCWPFGTVJGEWTXG=#7%?NGXGN 5KPEG 5JKTG75+PE JWOCPU[UVGOKEGZRQUWTGVQNKƂVGITCUVHQNNQYKPI 752CVGPVU ocular administration of Xiidra at the RHOD is low, the CPF CRRNKECDKNKV[QHCPKOCNƂPFKPIUVQVJGTKUMQH:KKFTCWUGKP pending patent applications. humans during pregnancy is unclear. .CUV/QFKƂGF5

RRP0916_ShireP0916_Shire PPI.inddI.indd 1 88/24/16/24/16 10:3810:38 AMAM 032_rp0916_f2.indd 35 point youapplyPhotrexa Viscous cellulose spongeandspatula. Atthat epithelium; thenIremove it witha 20-percent ethylalcoholtoloosenthe use eitherabirdbathorpledgetof with anopticalzonemarkerandthen he continues.“Idelineatea9-mmarea cording tothesurgeon’s preference,” removal oftheepithelium,doneac- it beforeUVexposure. enough, youusethePhotrexatoswell dothelium. Ifthecorneaisn’t thick tentially haveatoxiceffectontheen- riboflavin-UV interactioncouldpo- because ifthecorneaistoothin, measurement tobe400µmormore, UV light,youwantthepachymetry corneal swelling.Beforestartingthe fl Photrexa, whichisahypotonicribo- exposure. Theotherformulationis tial ribofl avin loadingandduringUV use incross-linking;it’s usedforini- is thestandardribofl avin solutionwe kinds ofribofl avin. PhotrexaViscous cal trial,”hesays.“Itcomeswithtwo which iswhatweusedintheclini- 365 µmultravioletlightat3mW/cm tocol. “TheAvedro systemproduces procedure isastandardepi-offpro- Using theSystem eccentric.” graphic elevationstendtobemore in keratoconus,orbecausethetopo- larities inectasiaarelessseverethan because thetopographicirregu- atoconus patients.Thismaybe change intopographythanker- patients tendtohavelessofa Dr. Hersh.“However, ectasia sia asitiskeratoconus,”notes effective instabilizingecta- found thisproceduretobeas gery. “Inourownstudieswe’ve neal ectasiaafterrefractivesur- July, isasatreatmentforcor- received FDAapprovalthis avin withoutdextran,usedtoinduce REVIEW “Thefi rst stepisa9-mm-diameter Dr. Hershnotesthattheapproved The secondindication,which Focus Cover

Cornea treat progressive keratoconus andectasia. Avedro’s KXLcross-linkingsystem, currently approved to 2 , from theribofl avin. That’s ribofl you shouldseeanteriorchamber fl neously throughoutthecornea. Also, you shouldseegreenspreadhomoge- he says.“Usingthecobaltbluefi starting toperformthisprocedure,” slit lamp,especiallywhenyou’rejust you havestromalsaturationatthe “However, youwanttoconfi ways havegoodriboflavinuptake. for cross-linking.” epithelium intact,he’s notacandidate initially hasa280-µmcorneawiththe are verythinattheoutset.Ifapatient avoid selectingpatientswhosecorneas quately. Themostimportantthingisto patients whowereunabletoswellade- that,” henotes.“Ihavenothadany although youcancontinuebeyond within oneortwosessionsofPhotrexa, under 400µmwillswellto further countsoftwominutes. the hypotonicPhotrexaribofl not reached400µm,Iagainapply between drops.Ifthecorneahasstill for twominutes,withtheeyeclosed Photrexa ribofl proceed; ifnot,Iapplythehypotonic etry. Ifthecorneaisover400µm,I thickness usingultrasoundpachym- become thinner. Then Imeasurethe so thecorneadoesn’t dehydrateand lum outwhileputtinginthedrops moval, butIliketotakethespecu- the speculuminforepitheliumre- minutes. Obviously, youhaveto every twominutesforatotalof30 Dr. Hershsaysyouwillalmostal- “Typically, mostpatientswhoare avin every10seconds avin for for avin rm that rm September 2016 avin lter, are are clinical trialwasbased.” the Dresdenprotocol,onwhich weeks. Thisisessentiallythesameas drops overthecourseoftwoorthree a weekandtaperthecorticosteroid lens. We continueantibiotic dropsfor healed; thenweremovethecontact fi erything isOK,andondayfouror patient ondayonetomakesureev- a bandagecontactlens.We checkthe we applyantibiotic,corticosteroidand pleted, theprocedureisdone.Then every twominutes.Oncethat’s com- patients continuedtoworsen. 1.6 D,whileasexpected,untreated study improvedtheirtopography by sive keratoconusbythecriteriaof one year, patientswhohadprogres- and untreatedeyes,”hecontinues.“At height ofthecone—betweentreated as measuredbytopography—i.e.,the change inthemaximumkeratometry was asignificantdifferenceinthe placebo-controlled, showedthatthere chance oflosingorgainingvision? Third, whichpatientshaveabetter ment andcontinueprogressing? result andwhotendstofailthetreat- Second, whogetsabettertopographic stability thesameforeverypatient? looked atthreeconcerns.First,is ter candidates,”saysDr. Hersh.“We ies lookingatwhichpatientsarebet- Who GetsBetterOutcomes? ve tomakesuretheepitheliumhas “The FDA clinical trial, which was “The FDAclinicaltrial,whichwas “In mypracticewe’vedonestud- patient gazesatthefi x,y andzplanes,”hesays.“The light unitandyoucenteritonthe look upattheKXLsystem’s UV ribofl µm thickandissaturatedwith have full-thicknesssaturation. chamber, whichdenotesthatyou that hasmadeitintotheanterior | the riboflavindextransolution that timeyoucontinuetogive for thenexthalfhour. During reviewofophthalmology.com “Once the cornea is at least 400 “Once thecorneaisatleast400 avin, youhavethepatient xation light light xation |

35 8/26/16 2:32 PM 0032_rp0916_f2.indd 36 3 2 _ r p 0 9 1 6 _ f 2 the authorsacknowledgethat such had aseverecomplication,although len linesat12months.No patients cent ofeyeshadlosttwoormoreSnel- of 99patients,reportedthat2.9per- tients whowerebetterthan20/40.” vision bytwoormorelinesthanpa- fi worse beforetreatmentwereabout of acuity, patients whowere20/40or to improvetheirtopography. Interms lines andwerefi rectable visionbytwoormoreSnellen feld. potentially runacross,”saysDr. Rubin- lists manyoftheproblemsyoucould related toepithelialremoval.” of thecomplicationsthatcanoccurare and thebenefi not zero,butthey’rerelativelysmall risks involvedwiththisprocedureare ogy attheMoranEyeCenter. “The and adjunctprofessorofophthalmol- mology, emeritus,atEmoryUniversity stitute inAtlanta,professorofophthal- Research CenteratWoolfson EyeIn- ing, MD,PhD,directoroftheStulting doctors canmake,”notesDoyleStult- procedure; therearen’t manymistakes Potential Complications 55 Dormore patients withworsetopography, i.e., says. “However, about20percent most patientsremainedstable,”he of remainingstableovertime. both groupshadanequivalentchance this improvementgroup.However, peak hadagreaterchanceofbeingin tometry of55Dormoreatthecone more, andthatpatientswhohadkera- cent ofcorneasflattenedby2Dor approval, wefoundthatabout25per- our ownstudies,unrelatedtotheFDA one Snellenlineorso,”hesays.“In and UCVA inthetreatedeyes,about modest overallimprovementinBCVA 36 . ve times more likely to improve their ve timesmorelikelytoimprovetheir i n d

“Theo Seiler published a paper that “TheoSeilerpublishedapaperthat “This isarelativelystraightforward “With regardtocorrectablevision, “We alsofoundthattherewasa REVIEW d |

Focus Cover Review ofOphthalmology 1

3 (Thatstudy, involving117eyes 6 ts aresigniﬁ — ve timesmorelikely improved theircor-

Cornea cant. Most Most cant. | September2016 — the the complication rates,soolder patients 35 yearsmaysubstantiallyreduce the restricting patientagetoyounger than epithelial healing.Healsofoundthat lar surfaceissuesandpostoperative be particularlyattentivetoanyocu- a verysteepcone,that’s areasonto your failurerate,soifpatienthas K-reading lessthan58Dmayreduce found thatapreoperativemaximum verse event,”hecontinues.“Hisstudy response tothetreatmentoranad- the patientistohaveeitherapoor the steepercornea,morelikely promise theocularsurface. and otherconditionsthatcancom- look forsignsofdryeye,blepharitis cur. Forthatreasonit’s importantto haze andotherproblemscanalsooc- disease,” henotes.“Scars,infections, neas andcorneaswithocularsurface generally compromisedinsteepercor- meetings.) “Regrowthandhealingare complications havebeenreportedat of a line because of epithelialization orcornealhazemightbemorenoticeabletohim.” of alinebecauseepithelialization before treatment. isstartingwith20/20or20/25vision,”“If apatient hesays, “the loss cal School, goodvision hasvery thisisespeciallyimportantwhenthepatient notesthat and theInstituteofOphthalmology at surgery Visual Science, Rutgers-NewJerseyMedi- holding, andreassurance.” discussionaboutexpectations working orwasamistake. With epi-offcross-linking, dealofhand- needagreat patients says. tobecomeanxious, easyforpatients it’s makesitvery ortobelieve that “That not drop offformonthspostoperatively, andthenstarttoreturnwhereitwasbefore,” he several studiesofstandardepithelium-offcross-linking, visionhasbeenseentoactually Furthermore, thetimelineforallofthisismonthsandyears.” iscausingthemtolosevisionandpotentiallyneedcornealtransplantation.disease that nus,” hecontinues. “The majorobjectiveofcross-linkingistostoptheprogressiona with markedlyreducedvisionduringthefi rst fewweeksorevenmonths. ing likethat. There issignifi generallylastsforuptoaweekormore, cant discomfortthat andirritation,”evening ofscratchiness hesays. “Standard epi-offcross-linkingisnoth- orLASIK,surgery justone seemarkedlybetterthenextdayandhave inwhichpatients expected results. issimilartoeithercataract eyesurgery any “Patients oftenthinkthat cross-linkingdoesandnotdothetimelinefor regardingwhat expectations UniversityMedicalCenter, Georgetown at surgeonsneedtosetpatient notesthat “Dr. Seiler’s paperalsoshowsthat Managing Patient Expectations Peter S. Hersh, MD, FACS, clinical professoranddirectorofcornearefractive Dr. maynotbesmooth. thecourseofrecovery Rubinfeldalsopointsoutthat “In cross-linkingisnotacure-allforkeratoco- “Patients alsoneedtounderstandthat S.Roy Rubinfeld, MD, MS, practiceandaclinical inprivate professor associate nifi efi ing toprogresswouldn’t getanyben- thought thatpeoplewhowerenotgo- approval isfor,” saysDr. Stulting.“We toconus, whichiswhatthecurrent patients whohadprogressivekera- first wereservedthisprocedurefor interest toU.S.surgeons: less-dramatic off-labelusesmaybeof United States.Inthemeantime,some FDA arebeingexploredoutsidethe far beyondtheusesapprovedby Off-label UsesforCXL of corneal transplantation.” of cornealtransplantation.” markedly betterthanthesafetyprofi fi tant torememberthatthesafetypro- follow-up. Butultimatelyit’s impor- may alsorequireextrapostoperative vision inpatientswethought wouldn’t le ofepi-offcornealcross-linkingis t. Butwe’vesometimes seen asig- • Non-progressingpatients. usesforcross-linkingthatgo Many cant benefi cant t intermsofimproved —CK “At le le 88/26/16 2:32 PM / 2 6 / 1 6

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RP0916_Compulink.indd 1 8/10/16 10:07 AM Cover Cornea

REVIEW Focus

benefi t from it. For example, doc- William B. Trattler, MD • Leaving the epithelium on. tors often assume that older pa- Dr. Rubinfeld is one of a number tients with keratoconus are not of surgeons working on versions likely to progress. However, we’ve of the protocol that do not re- seen 66-year-olds with signifi cant quire removing the epithelium. progression over six months, and “The effective epi-on version we’ve seen patients in their 50s of cross-linking has been in de- whose uncorrected and corrected velopment since 2010,” he says. vision improved signifi cantly after Cross-linking with epithelial removal can lead to “Dr. Stulting, in the prestigious cross-linking.” complications such as delayed epithelial healing and an Binkhorst Lecture at the 2016 infi ltrate (pictured above, postop day two). Dr. Rubinfeld acknowledges American Society of Cataract that the risk/benefi t ratio may be and Refractive Surgery annual different if the patient’s keratoconus considering the use of cross-linking in meeting, described the fi rst long-term isn’t progressing. “The reality, how- the setting of infectious keratitis.” data. It showed that this proprietary, ever, is that keratoconus is an unpre- Dr. Stulting agrees. “We don’t have patent-pending treatment is as good as dictable disease,” he points out. “Not good evidence that it is superior to or better than the Dresden protocol, treating is a bit like saying, ‘Well, you standard, routine treatment for infec- while markedly reducing the risk, dis- have glaucoma and your pressure is tious keratitis,” he says. comfort and recovery time that would high, but we think you might have a • Improving vision. “Ultimately, otherwise be related to removing the couple of years before you start really a bigger and more satisfying objective epithelium. This is clearly the next losing your sight so we’re not going to is to improve vision in keratoconus generation of cross-linking.” treat you.’ That wouldn’t hold up in patients, not just stop the progression A. John Kanellopoulos, MD, medi- court, and when you put your head on of the disease,” says Dr. Rubinfeld. cal director of the Laservision.gr the pillow at night, you wouldn’t feel “That’s why outside the United States Clinical and Research Eye Institute great about it. it’s become common to perform cross- in Athens, Greece, and clinical profes- “If the surgeon believes that this linking and topography-guided laser sor of ophthalmology at NYU Medical off-label use is in the patient’s interest, ablations together. Under institutional School in New York, has been a pio- he’ll need to have a discussion with the review board approval, we’ve done neer in investigating alternative proto- patient under scope of practice,” he some of these cases. However, my cols and uses for corneal cross-linking. adds. “The surgeon, of course, will be personal experience, as well as that of “Over the past 15 years we’ve intro- responsible for those choices.” some of my colleagues, is that this is a duced and practiced—international- • Younger patients. “Some of the fi eld in evolution. It seems to be more ly—fl uences of 6, 10 and 30 mW/cm2,” people who need this the most are fair- of an art than a science with currently he says. “We’ve also used techniques ly young,” says Dr. Rubinfeld. “It’s un- available technologies. Also, adding such as combining cross-linking with derstandable to want to treat them be- PRK to cross-linking may cause the a partial topography-guided PRK, fore they start losing their sight. We’ve epithelial healing to be even slower known as the Athens Protocol; we’ve treated patients as young as 8 years old and more critical.” used 10 mW/cm2 for 10 minutes with in our study with excellent results.” Dr. Rubinfeld says that there’s an- in-situ placement of the ribofl avin in “You want to do this procedure early other, less invasive way to move in a femtosecond-laser-created corneal on to decrease progression as soon as the same direction. “Since 2012, our pocket; and we’ve used 30 mW/cm2 possible,” adds Dr. Hersh. “And, just group has been combining two non- for 90 minutes as an adjunct to rou- as in the treatment of macular degen- invasive procedures on an investiga- tine LASIK in high-risk myopic and all eration and other diseases, probably tional basis,” he says. “We use conduc- hyperopic cases. The latter approach the earlier, the better.” tive keratoplasty to reshape the cornea was recently reported to increase bio- • Treating infectious keratitis. and then use our proprietary trans- mechanical strength in the underly- Dr. Rubinfeld notes that there have epithelial cross-linking technique to ing LASIK stroma by 120 percent, been some published studies on the lock in the effect. We now have two- ex-vivo.” use of cross-linking to treat infectious year data demonstrating that this ap- Despite all the promising uses for keratitis. “My personal experience proach not only stops the progression cross-linking that go beyond the FDA with that, as well as our study group’s but markedly improves both UCVA approval, Dr. Kanellopoulos believes experience, has not been very compel- and BCVA. It’s been extremely gratify- it’s prudent for American physicians to ling,” he says. “I would urge caution in ing for the patients and surgeons.” initially adhere to the approved pro-

38 | Review of Ophthalmology | September 2016

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RP0916_PRN.indd 1 8/23/16 10:17 AM Cover Cornea

REVIEW Focus

tocol. “The epi-off procedure is not vision from getting worse? Why didn’t contact lens wear until the ocular without potential complications such my doctor tell us about this three years surface is completely healed. “The as infection, melts, infl ammation and ago when my child’s vision was much key to resuming contacts after cross- potential scarring,” he says. “I think better?’ More and more, I’m having linking is ensuring that the ocular sur- clinicians should become proficient trouble answering that question. Now face is completely healed,” says Dr. with the standard technique before that the technology is approved, it’s Hersh. “It should have regained its attempting to engage in off-label ap- going to be impossible to explain a preoperative smoothness and integrity plications. All of those techniques will late referral. I think it’s just a matter of to avoid renewed injury or infection. probably receive FDA approval at time before litigation and established We typically resume contact lens wear some point. It would probably be wise standard of care forces the adoption of at the one-month follow-up.” to wait until then to use them in the topography as a part of normal child- • Expect to see some corneal haze United States.” hood eye examinations. It certainly at the slit lamp for the first few should be done for patients who are months in some patients. “In our Strategies for Success myopic, astigmatic or have corrected own clinical trial most cross-linking visual acuity less than 20/20.” patients had a course of corneal haze Surgeons offer these pearls to help • When starting out, choose cor- that dissipated back to baseline by 12 cross-linking novices get good results neas that are at least 350 µm thick months,” notes Dr. Hersh. “It typically and avoid complications: before treatment. “You don’t want doesn’t trouble the patient, but you • Make sure that referring doc- the cornea to be overly thin, because can see it at the slit lamp. It begins as a tors don’t think this is a refrac- you won’t be able to swell it to 400 generalized haze, like a dusting of the tive procedure. “Referring doctors µm,” says Dr. Hersh. “In the clinical cornea, and evolves to the demarca- who are not well-acquainted with the trials, we included patients down to tion line, which we believe indicates procedure may contribute to patients’ 300 µm and used the swelling tech- the depth of the cross-linking, typically incorrect expectations,” notes Dr. nique to get them to 400 µm. But in 250 to 300 µm deep. Nothing needs to Hersh. “A few cross-linking patients my own practice, I’ve found that it be- be done to address the haze, unless it’s may see better, but the purpose of comes diffi cult to reach 400 µm when unusual; just provide general care for cross-linking is stabilization of the pro- the cornea starts below 350 µm.” the ocular surface.” gression of keratoconus, not giving the • Evaluate postoperative epithe- patient better vision.” lial healing at the slit lamp early What’s Next? • If you diagnose a patient with on. “Epithelial irregularity can dimin- keratoconus, refer the patient for ish vision,” Dr. Hersh points out. “If Although American surgeons are cross-linking right away. Dr. Stult- you see an indication that the healing excited about fi nally having access to ing says new patients with keratoconus is irregular, be sure to address condi- cross-linking, there are mixed feelings are referred to him every week, but tions such as dry eye and blepharitis about still being behind the rest of many doctors wait until the patient is aggressively.” the world, given the limitations of the on the verge of needing a transplant • If you see delayed epithelial approval. before making the referral. “Even after closure postoperatively, consid- “The procedure that’s been ap- educating our referring doctors that er removing the bandage contact proved in this country is almost referral is appropriate when someone lens. “Once treated with cross-link- a decade and a half old,” notes Dr. is fi rst diagnosed, I still get patients ing, patients need to be followed fair- Stulting. “Many improvements to the sent to me as a last resort when they ly closely until the epithelial defect procedure have been proposed, and can no longer wear a contact lens,” closes, which typically occurs during some have been found to be effective, he says. “The referring doctors seem the fi rst week,” says Dr. Stulting. “We but because of the delay in FDA ap- to think that corneal collagen cross- learned early on that if we see delayed proval we aren’t able to take advantage linking will somehow keep the patient epithelial closure in these patients, of them in this country. I’m afraid that from needing a graft, but that’s not the particularly with persistent epithelial alternate versions of the procedure case for advanced disease. defects over the apex of the cone, we will not be approved any time soon. “I see many keratoconus patients need to remove the contact lens, even Cross-linking has orphan designation, who are in their teens,” he continues. though the epithelium hasn’t closed so Avedro is protected from competi- “I tell the parents about cross-linking yet. The contact lens itself can inter- tion for seven years, and there’s little and they say, ‘You mean you have a fere with epithelial closure.” motivation for them to invest millions treatment that will keep our child’s • Don’t let the patient resume of dollars in obtaining approval for an

40 | Review of Ophthalmology | September 2016

0032_rp0916_f2.indd32_rp0916_f2.indd 4040 88/26/16/26/16 2:332:33 PMPM advanced technique before the approved one becomes widely utilized.” “The FDA-approved system from Avedro is a great device,” says Dr. Kanellopoulos. “We’ve used it in Eu- rope since 2010. However, it’s unfor- tunate that higher fluences of 6, 9, 18 and 30 mW/cm2 are not yet available; that would widen the possible techniques and indications. The worst thing, in my opinion, is the obligatory use of adjunct dextran-diluted riboﬂ a- vin, because it causes signiﬁ cant dehy- dration and thinning of the tissue during soaking. Most available solutions internationally are now saline-based. We switched to saline back in 2004.” Despite its limitations, Dr. Stulting says he still believes the approved procedure is an important tool for Ameri- can surgeons to have. “There’s good data from Oslo, Norway, showing the value of the procedure,” he says. “At Oslo University Hospital, cross-linking was implemented almost a decade ago. They saw a 53-percent decrease in their incidence of corneal transplantation for keratoconus over a seven-year period. In the United States, the rate of corneal transplantation increased 19 percent over the same time period. The approved procedure may not be the best procedure, but it’s certainly better than nothing.” “Research is going on that will make this procedure safer, better, more comfortable, less invasive and more predictable,” adds Dr. Rubin- feld. “There’s plenty of reason for opti- mism.”

Dr. Hersh is a consultant for Avedro. Dr. Rubinfeld has ownership equity in CXL Ophthalmics and is managing member and president of CXLUSA. Dr. Kanellopoulos is a consultant for Avedro and Alcon. Dr. Stulting has no financial interest in any product mentioned.

1. Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg 2009;35:1358–1362. See us at AAO Booth #2044

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RP0916_Topcon.indd 3 8/8/16 11:34 AM of ers Su Edited by t rg s e a r y M Taliva D. Martin, MD Sara J. Haug, MD Filtering Surgery: Optimizing Outcomes

and optic nerve status include patient age, general health, life expectancy, Sunita Radhakrishnan, MD, lifestyle and family history. A fi ltering procedure that’s successful from the and Andrew G. Iwach, MD surgeon’s perspective may, in fact, di- San Francisco minish a patient’s quality of life due to long-term bleb-related complications. Therefore, it’s important to consider s much as glaucoma surgeons love other IOP-lowering procedures be- Ato hate fi ltering surgery, trabecu- fore making the decision to proceed Expert tips for lectomy continues to be an impor- with fi ltering surgery. tant component of our surgical ar- Trabeculectomy requires frequent this time-tested mamentarium, especially for patients postoperative visits and the patient with advanced optic nerve damage. must be able and willing to keep these glaucoma Trabeculectomy creates a pathway appointments. It’s also important to for aqueous to drain from the ante- assess the risk of bleb infection in the procedure. rior chamber to the subconjunctival context of the patient’s lifestyle. For space where bleb formation occurs. example, a person who often travels Short-term success of trabeculectomy to remote areas without access to surgery is mainly dependent on intra- medical care, or one who engages in operative technique and postopera- water-based sports as a hobby or for a tive care, whereas longer-term success living, isn’t a good candidate for fi lter- depends on the patient’s healing re- ing surgery. sponse, which varies widely between Carefully assess the ocular history, individuals. In this article, we present paying special attention to factors some of our considerations in fi ltering that may increase the risk for scar- surgery that can help you increase ring, such as multiple prior surgeries your chances of success. and uncontrolled uveitis. You should also evaluate the factors that could PREOPERATIVE increase the risk of complications. CONSIDERATIONS For example, patients with high my- opia and pigment dispersion are at As with any surgery, patient selec- higher risk for hypotony maculopathy, tion and timing is key. It’s important whereas patients with angle closure to be mindful that we’re treating the disease and high hyperopia are at risk patient, not just the eye. Factors to for malignant glaucoma after fi ltering consider beyond intraocular pressure surgery. Contact lens wearers may not

44 | Review of Ophthalmology | September 2016

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RP0616_Akorn.indd 1 5/23/16 11:35 AM Insertion of the Ex-PRESS shunt under a partial thickness scleral ﬂ ap.

be able to continue wearing lenses recover their vision, the more accept- sible, grasp subconjunctival Tenon’s after fi ltering surgery and you should able the surgery is to them. Also, us- tissue rather than the conjunctival discuss this possibility with them being the shunt obviates the need for a edge. A watertight conjunctival clo- forehand. Finally, a history of a bad sclerectomy and an iridectomy. sure is critical for the formation of an outcome after fi ltration surgery in the Important aspects of surgery in- elevated bleb, and you can ensure this fellow eye should be taken seriously. clude: by infl ating the anterior chamber with A careful preoperative slit lamp • Adequate exposure. We use a balanced salt solution and confi rming examination is a must. Specifically, Lieberman eyelid speculum and a that there is no aqueous leak at the assess the superior conjunctiva for superior corneal traction suture to end of surgery. mobility—this can be easily done by provide adequate exposure of the su- • Scleral flap and closure. We having the patient look down and perior quadrant. While passing the use a 3x3-mm square, partial thick- then moving the eyelid over the su- traction suture, take care to avoid cor- ness scleral fl ap, typically closed with perior conjunctiva. It’s also helpful neal perforation, which will result in two 10-0 nylon sutures. During scleral to locate vascular landmarks in the aqueous leak and low IOP, a situation fl ap dissection, care should be taken superior conjunctiva that you can use that’s not ideal for scleral fl ap dissec- to maintain adequate fl ap thickness in later to identify the scleral flap site tion. If inadvertent corneal perfora- order to cover the Ex-PRESS shunt, intraoperatively. tion does occur, place viscoelastic in as well as an adequate scleral bed on the AC, which will allow the case to which the device can rest. INTRAOPERATIVE proceed in the usual fashion. • Mitomycin-C application. CONSIDERATIONS • Conjunctival fl ap and closure. There are many ways to apply mi- The conjunctival fl ap can be limbus- tomycin-C during filtering surgery, We typically perform modified or fornix-based, with the latter being but the main goal is a diffuse distri- trabeculectomy with an Ex-PRESS our preferred approach. Maintain- bution as posteriorly as possible in shunt (the P50 model) because the ing conjunctival integrity is critical order to minimize the formation of visual recovery is quicker compared for the success of fi ltration surgery, localized, cystic and avascular blebs. to standard trabeculectomy.1 This is and therefore this tissue should be We perform a conjunctival snip in- important for these patients because handled with great care, especially in cision at the limbus as the fi rst step they don’t have visual symptoms be- eyes with thin or scarred conjunctiva after placement of the corneal stay fore surgery, but the surgery ends in which buttonholes can easily form. suture. We then use a cannula to instill up inducing some temporary visual Conjunctival manipulation should 0.1 ml of 0.2 mg/ml mitomycin-C in distortion. So, the quicker they can be gentle and minimal; when pos- the subconjunctival space and then

46 | Review of Ophthalmology | September 2016

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RP0916_Nova Bay.indd 1 8/3/16 11:12 AM use a Weck-Cel sponge to distribute such as the presence and extent of IOP until sutures can be lysed. the mitomycin-C diffusely. We create wound leak, bleb height, AC depth, • IOP is acceptable. If the IOP the conjunctival fl ap at the end of this presence and extent of choroidals, is on target, a watchful eye must still step, and use BSS to irrigate the sub- and the status of the macula. For ex- be maintained on the bleb and sur- conjunctival space. ample, a patient with a small wound rounding conjunctiva to detect signs leak in the presence of an elevated of early bleb scarring. Interventions in POSTOPERATIVE bleb and peripheral iridocorneal this situation have a better chance of CONSIDERATIONS touch can be managed conservative- succeeding when performed as early ly, whereas a patient with hypotony as possible, while the bleb is scarring, We often tell patients that half the and a fl at AC usually requires urgent as opposed to when it has completely work in fi ltering surgery is in the oper- intervention in order to prevent en- scarred. In many cases, the bleb can ating room performing the procedure dothelial damage. be revived with the use of interven- and the other half is in the clinic with tions such as aggressive topical ste- postoperative care. The goals during roids, 5-fl uorouracil injections, timely the postoperative follow-up period suturelysis, digital massage and bleb are monitoring for complications and In many cases, the bleb needling. identifying factors that may jeopar- can be revived with While the recent development of dize long-term bleb function and then blebless surgeries is welcome and intervening appropriately. For exam- the use of interventions exciting, in some of our patients ple, if the IOP is high two weeks after such as aggressive there’s just no substitute for filter- surgery due to tight fl ap sutures, then ing surgery. Therefore, it’s important the appropriate intervention is not to steroids, 5-FU for a glaucoma surgeon to be able restart IOP-lowering medications but injections, timely to perform this procedure well and to lyse (or remove) one or more fl ap expertly manage the postoperative sutures so that a bleb can form (or suturelysis, digital course and potential complications enlarge). massage and needling. in order to minimize risk and maxi- Although postoperative care for fi l- mize outcomes. tering surgery is more intense than for other surgeries, most early complica- Dr. Radhakrishnan is an associ- tions are transient, and serious com- • High IOP. If the IOP is too high ate at the Glaucoma Center of San plications such as choroidal hemor- after fi ltering surgery, the fi rst step, Francisco and research director of the rhage are fortunately rare. Following again, is to identify the cause. The Glaucoma Research and Education are some common postop situations most common causes are tight scleral Group in San Francisco. She has no and our response to them: flap sutures and retained viscoelas- fi nancial interest in the products dis- • Low IOP. If the IOP is too low af- tic. Other possibilities include ciliary cussed. Dr. Iwach is the executive di- ter surgery, the fi rst step is to identify block, suprachoroidal hemorrhage, rector of the Glaucoma Center of San the cause of the hypotony. The most early bleb encapsulation, and scleros- Francisco, an associate clinical profes- common causes are overfi ltration and tomy or Ex-PRESS lumen plugged by sor of ophthalmology at the Univer- wound leak. A careful slit lamp exami- blood, iris or vitreous. The decision to sity of California, San Francisco and nation after instillation of fl uorescein intervene depends on factors such as a faculty instructor at the California drops can identify most wound leaks; the level of IOP elevation, the optic Pacifi c Medical Center Department of however, sometimes a fluorescein nerve status and the risk of hypotony. Ophthalmology. He is a consultant to strip may be required to pinpoint the Tight fl ap sutures are effectively ad- Bausch + Lomb, Alcon, Allergan and exact site of aqueous leak. Hypotony dressed by laser suturelysis, but this is AcuMEMS. after fi ltering surgery is usually tran- best avoided in the fi rst few days after 1. Beltran-Agullo L, Trope GE, Jin Y, Wagschal LD, Jinapriya D, sient and most cases can be man- surgery, if possible. Digital massage to Buys YM. Comparison of visual recovery following ex-PRESS aged conservatively. The decision to separate the scleral fl ap edges allows versus trabeculectomy: results of a prospective randomized intervene depends on several factors, aqueous outfl ow and usually lowers controlled trial. J Glaucoma 2015;24:3:181-6.

48 | Review of Ophthalmology | September 2016

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REVIEW Edited by Carl Regillo, MD, and Emmett T. Cunningham, Jr., MD, PhD, MPH

In Search of the Best AMD Therapy A look at the ways researchers and clinicians are trying to overcome the shortcomings of current therapies. Ashleigh L. Levison, MD, Mark R. Barakat, MD, and Pravin U. Dugel, MD, Phoenix

n old adage that goes, “Good, Current Treatment of therapy, patients are still at signifi - A better, best—never let it rest—un- cant risk of visual decline and require til your good is better and your better Bevacizumab, ranibizumab and continued treatment.4 is best,” could very well apply to oph- afl ibercept have provided invaluable Several approaches are being taken thalmologists’ battle with exudative visual benefi t for patients with exuda- to address the issues of continued vi- age-related macular degeneration. A tive AMD. In 2006, the ANCHOR and sion loss in some patients and the treat- little over a decade ago, the treatment MARINA trials showed that treatment ment burden of frequent injections. for this disease underwent a revolu- with these agents could provide visual These include finding better anti- tionary change with the development benefi t in such patients1,2 and drasti- VEGF agents, improving anti-VEGF and use of anti-vascular endothelial cally changed physicians’ and patients’ delivery and developing drugs with growth factor medications. This cer- expectations regarding outcomes. targets other than VEGF. tainly made our treatments better; pri- Unfortunately we still have the is- or to anti-VEGF therapy, patients with sue of a costly, ongoing treatment that Novel Anti-VEGF Agents exudative AMD typically experienced puts a signifi cant burden on both the signifi cant, irreversible vision loss over patient and the physician. Trials have One approach to improving treat- time. Thanks to these new drugs, we looked at monthly, PRN, quarterly ment of exudative AMD includes de- no longer had to simply attempt to and, more recently, treat-and-extend velopment of new anti-VEGF agents. slow inevitable vision loss, but instead protocols for wet AMD, and found Some of these agents may be able to could maintain vision or even improve that monthly treatment appears to op- extend treatment duration, lessening it in many patients. However, clinicians timize visual outcomes. A study pub- the burden of frequent injections. and researchers don’t want to settle for lished in 2014, however, reported that • Brolucizumab. Formerly known treatments that are just better, because patients with exudative AMD receive as RTH-258 and ESBA-1008, brolu- current therapies still pose signifi cant signifi cantly fewer injections than clini- cizumab is being developed by Alcon obstacles in the treatment of exudative cal trials recommend.3 Unfortunately, and Novartis. It is a humanized, single- AMD, including the treatment burden less-frequent treatment can lead to chain antibody fragment that inhib- and progressive vision loss in some pa- poorer visual acuity outcomes. The its VEGF, and is able to bind to all tients. Instead, we want the best. SEVEN-UP study showed us that, isoforms of VEGF-A. Brolucizumab In this article, we chronicle oph- seven years after ranibizumab therapy, is significantly smaller than bevaci- thalmology’s efforts to overcome these in the ANCHOR and MARINA trials, zumab, ranibizumab and afl ibercept, problems and fi nd even better treat- one-third of patients had poor visual which may allow for better tissue pen- ments for exudative AMD. results. It’s apparent that despite years etration, more active drug reaching

This article has no commercial sponsorship. September 2016 | reviewofophthalmology.com | 51

051_rp0916_rtinsider.indd 51 8/26/16 2:16 PM Retinal

REVIEW Insider

the target tissue and possibly term delivery of anti-VEGF less systemic exposure. Ani- therapy to an eye with exuda- mal studies of brolucizumab tive AMD. and ranibizumab have shown Drugmakers Genzyme more of the former entering and Avalanche are attempt- the retina, as well as less sys- ing to utilize adenovirus’s temic drug exposure.5,6 innate transfection capabili- Early human trials suggest- ties to provide long-lasting ed that a single injection of gene therapy via intravitreal brolucizumab may have more or subretinal administration, potent and longer-lasting ef- respectively. In Genzyme’s fects than a single dose of ra- approach, it adds the ge- nibizumab. The drug showed netic sequence for sFLT01, a reduction in central subfi eld a tyrosine kinase inhibitor, to thickness on OCT compara- Conbercept, approved in China for AMD treatment, is a fusion the genetic sequence of the ble to ranibizumab, and there molecule combining IgG Fc and VEGF receptors. adenovirus producing AAV2- was also a greater mean gain sFLT01. AAV2-sFLT01 is in best-corrected visual acuity com- comparing two doses of conbercept injected intravitreally. As an anti-VEGF pared to ranibizumab, with a trend showed positive visual acuity outcomes agent, sFLT01 blocks the VEGF towards a longer duration of effect.5,6 A for exudative AMD.13 cascade more distal to where the subsequent trial showed results similar • OPT-302. Opthea’s OPT-302 is a current anti-VEGF agents block it.15 to afl ibercept.7 A Phase III trial is cur- vascular endothelial growth factor re- In animal studies, the intravitreal in- rently ongoing. ceptor 3 (VEGFR-3), or “Trap,” mole- jection of AAV2-sFLT01 led to sFLT01 • Abicipar. Formerly known as cule. This is the fi rst anti-VEGF agent expression in the anterior chamber AGN-150998A, abicipar is a DARPin targeted towards VEGF-C and -D. fl uid of the animals. In addition it was (Designed Ankyrin Repeat Proteins) OPT-302 is currently in Phase I dose- also associated with decreased growth agent being developed by Allergan. escalation trials both by itself and as an of laser-induced choroidal neovas- A DARPin is a new class of binding agent used in combination with ranibi- cularization.16 A Phase I, open-label, molecule that has a smaller molecular zumab. Enrollment is complete.14 multicenter, dose-escalating safety and weight and higher target binding af- tolerability study of a single intravitreal fi nity than antibodies or antibody frag- Gene Therapy to Impact VEGF injection of AAV2-sFLT01 in patients ments.8 Because this agent has a small with neovascular AMD is still ongoing, molecular size and repeat structure, its Another method to improve drug and has completed enrollment.17 affi nity for VEGF is high. therapy for patients with neovascu- Besides injecting the adenovirus in- The Phase II REACH study was lar AMD is to develop a better anti- travitreally, the same modifi ed virus is designed to analyze abicipar in wet VEGF delivery system. One such av- also being administered subretinally AMD.9,10 In the Phase IIb study, ab- enue is gene therapy. in the form of Avalanche Biotechnol- icipar provided equal or greater vi- Gene therapy involves introducing ogies’ AVA-101, a route of adminis- sion gains, with the potential for fewer genetic material into cells in order to tration that some feel may be more injections, compared to ranibizumab. compensate for abnormal or absent effective than an intravitreal injection Phase IIb data suggest that abicipar genes. The goal of gene therapy is to and lead to fewer side effects. After a may be injected every 12 weeks after allow for the production of a benefi - vitrectomy, a small needle is used to loading doses. Since the initial results cial protein in cells that otherwise lack inject the virus vector subretinally, and were promising, the Phase III clinical that protein. In gene therapy, the gene animal studies have shown this therapy trial started enrollment in July 2015.11 carrier, called a vector, is genetically to be without safety issues or an in- • Conbercept. This is a fusion engineered to deliver the gene into crease in geographic atrophy.18,19 The protein of key domains from human cells. Currently, the most popular vec- fi rst human trials did show a reduction VEGF receptors 1 and 2 with human tor is the adeno-associated virus, as in central retinal thickness similar to IgG Fc that’s approved in China for viruses, by their very nature, are able that seen with intravitreal anti-VEGF the treatment of AMD.12 It has a high to deliver genetic material into another agents. In addition, a signifi cant num- affi nity for all VEGF-A/B isoforms as genome. Researchers hope that gene ber of patients didn’t need continued well as placental growth factor. A trial therapy could be used to provide long- anti-VEGF therapy for a year follow-

52 | Review of Ophthalmology | September 2016

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ing Ophthotech, Santen, Allergan and Gene Therapy for AMD Regeneron. Fovista is a pegylated aptamer developed by Ophthotech.29,30 Phase IIb Target Cell data has shown that Fovista, when combined with ranibizumab, improves visual outcomes compared to ranibi- AAV Vector Nucleus zumab monotherapy. When comparing 0.3 mg to 1.5 mg of Fovista combined with ranibizumab versus ranibizumab alone, at the higher Fovista dose, the combination therapy improved visual DNA (Gene) acuity by 62 percent over baseline. Pa- tients were 71 percent (0.3-mg dose) Protein and 190 percent (1.5-mg dose) more likely to experience greater than four In gene therapy approaches to AMD treatment, adeno-associated virus can be programmed and fi ve lines of visual improvement to introduce therapeutic DNA sequences into target cells. with Fovista. Fovista combined with ranibizumab resulted in a 119 percent ing injection.20 A 12-month, Phase IIa compounds may improve treatment of relative benefit towards achieving a trial had a +11.5-letter difference be- choroidal neovascularization by attack- visual acuity of 20/25 or better. In ad- tween treatment and control, however ing CNV from different angles. dition to improvement in intraretinal, the control had a loss of -9.3 letters. • Platelet-derived growth factor. subretinal and sub-RPE fluid, there The treatment group had a higher like- This is a growth factor whose produc- was reduction in subretinal hyper- lihood of stability of vision with two or tion is induced by hypoxia, and it’s reflective material with combination fewer rescue treatments in the gene also been implicated in angiogenesis. therapy. Researchers are hoping that therapy group (42.9 percent) versus Overproduction of PDGF by endo- the antifi brotic nature of Fovista will the control group (9.1 percent).21 thelial cells increases pericyte content lead to reduced fi brosis and vision loss of vessels, leading to the formation of in patients treated with combination Other Forms of Delivery mature vascular networks.23 Disrup- therapy vs. monotherapy.31-33 tion of the VEGF pathways with anti- The phase III studies are currently Another method of providing longer VEGF agents can induce upregulation in progress for Fovista in combination duration of drug delivery with the goal of PDGF, which in turn allows peri- with ranibizumab for the treatment of of decreasing treatment burden would cytes to make vascular networks more exudative AMD. The hope is that the be to implant a reservoir in the eye that mature and, therefore, more resistant inhibition of both VEGF and PDGF releases medication over an extended to further anti-VEGF treatment.24-26 may result in a reduction of exudation period of time. One study, the LAD- Additionally, overactivity of PDGF has from CNV as well a reduction of the DER trial sponsored by Genentech, been associated with the development neovascular complex itself. The antifi - is designed to compare a refi llable ra- of fi brosis.27 In oncology literature, an- brotic effect of anti-PDGF agents may nibizumab drug port delivery system ti-PDGF agents disrupt pericyte-en- also result in less scarring in patients to monthly ranibizumab injections.22 dothelial communication, sensitizing and therefore may have a signifi cant It’s currently recruiting patients. the neovascular tissue to anti-VEGF positive impact on visual acuity. agents.28 Theoretically then, an anti- • DE-120. Santen’s DE-120 is a Identifying Additional Targets PDGF therapeutic agent could re- molecule that acts as a dual-kinase remove the pericyte protective network ceptor inhibitor and is able to block Developing drugs aimed at thera- from the neovascular lesion, exposing both VEGF and PDGF.34 The Phase peutic targets other than VEGF of- the underlying endothelial cells to the I/II study is an open-label, dose-esca- fers another opportunity for improving anti-VEGF agent. This approach may lating, sequential-cohort study of DE- treatment of exudative AMD. For- allow for neovascular regression in- 120 injectable solution administered tunately, in addition to VEGF, there stead of the current method of disease in patients with late-stage exudative are many other compounds involved maintenance. Multiple companies are AMD. The study is ongoing but is no in angiogenesis. Targeting these other developing anti-PDGF agents, includ- longer recruiting new patients.34

54 | Review of Ophthalmology | September 2016

0051_rp0916_rtinsider.indd51_rp0916_rtinsider.indd 5544 88/26/16/26/16 2:162:16 PMPM RP0815_Lombart.indd 1 7/21/15 10:07 AM Retinal

REVIEW Insider

2010;5:8:e12455 doi: 10.1371/journal.pone.0012455[published VEGF receptors, TIE2 and other ty- Online First: Epub Date]|. 9. Evaluation of AGN-150998 in exudative AMD. https://clinicaltrials. rosine kinase receptors. Finally, PAN- gov/ct2/show/NCT01397409. Accessed 29 July 2016. 10. Pecen PE, Kaiser PK. Current phase 1/2 research for 90806 (PanOptica) is a topical drop neovascular age-related macular degeneration. Curr Opin that acts as a selective VEGF inhibitor. Ophthalmol 2015;26:3:188-93. 11. Abicipar, http://www.molecularpartners.com/our-products/ While our current approach to treat- abiciparandmulti-vegf_pdgf/. Accessed 29 July 2016 12. Nguyen TT, Guymer R. Conbercept (KH-902) for the treatment ing AMD has had a positive impact of neovascular age-related macular degeneration. Expert Rev Clin on visual acuity, it has limitations that Pharmacol 2015;8:5:541-8. must be addressed: Patients still can 13. Li X, Xu G, Wang Y, et al. Safety and effi cacy of conbercept Designed ankyrin repeat proteins (DARPins) in neovascular age-related macular degeneration: Results experience vision loss and there re- from a 12-month randomized phase 2 study: AURORA study. like those used in abicipar have a small Ophthalmology 2014;121:9:1740-7. mains a signifi cant treatment burden. 14. Ophthea completes patient enrollment for OPT 302 Phase molecular size with a repeat structure that 1 dose escalation trial in Patients With Wet AMD. http://www. can be created for a specifi c duration. Help appears to be on the way, how- marketwired.com/press-release/opthea-completes-patient- ever. Longer-acting drugs, new meth- enrolment-opt-302-phase-1-dose-escalation-trial-patients- with-asx-opt-2110458.htm. Accessed 29 July 2016. • OHR-102 (squalamine). What ods of sustained delivery and novel 15. Pechan P, Rubin H, Lukason M, et al. Novel anti-VEGF chimeric molecules delivered by AAV vectors for inhibition of retinal makes this agent from Ohr Pharma- compounds that target other agents in- neovascularization. Gene Ther 2009;16:1:10-6. ceutical unique is that it’s topically volved in angiogenesis besides VEGF 16. Lukason M, DuFresne E, Rubin H, et al. Inhibition of choroidal neovascularization in a nonhuman primate model by intravitreal administered, which would offer a less- will help improve outcomes. administration of an AAV2 vector expressing a novel anti-VEGF molecule. Mol Ther 2011;19:2:260-5. invasive way to treat exudative AMD. 17. Safety and tolerability study of AAV2-sFLT01 in patients Squalamine is an amino sterol devel- Drs. Levison and Barakat practice with neovascular age-related macular degeneration. https:// clinicaltrials.gov/ct2/show/NCT01024998. Accessed 29 July 2016. oped from dogfi sh shark cartilage. It’s with Retinal Consultants of Arizona in 18. Lai CM, Shen WY, Brankov M, et al. Long-term evaluation of AAV-mediated sFlt-1 gene therapy for ocular neovascularization taken up by endothelial cells and is a Phoenix. Dr. Dugel is managing part- in mice and monkeys. Mol Ther 2005;12:4:659-68. potent anti-angiogenic molecule that ner of Retinal Consultants of Arizona, 19. Bennett J, Maguire A, Cideciyan A, et al. Stable transgene expression in rod photoreceptors after recombinant adeno- binds calmodulin intracellularly, pre- clinical professor at USC Roski Eye associated virus-mediated gene transfer to monkey retina. Proc venting receptor activation and causing Institute, and executive director of the Natl Acad Sci U S A 1999;96:17:9920-5. 20. Chalberg T. Anti-VEGF gene therapy: Early clinical results using broad inhibition of multiple factors Phoenix Eye Institute. the ocular biofactor in wet AMD. Presented at: Angiogenesis, Exudation, and Degeneration. Miami, Feb 8, 2014. including VEGF, PDGF and basic fi - Dr. Levison has no pertinent fi- 21. Avalanche Biotechnologies Inc announces positive top-line broblast growth factor.10 Phase II trials nancial interests. Dr. Barakat reports Phase 2a results for AVA-101. http://investors.avalanchebiotech. com/phoenix.zhtml?c=253634&p=irol-newsArticle&ID=2059444 of topical squalamine combined with financial interest in Ohr as a minor 22. Study of the effi cacy and safety of the ranibizumab port delivery system for sustained delivery of ranibizumab. https:// intravitreal ranibizumab vs. intravitreal investor. Dr. Dugel reports financial clinicaltrials.gov/ct2/show/NCT02510794. ranibizumab alone showed visual acu- interests as a consultant to Alcon, Al- 23. Hellström M, Kalén M, Lindahl P, Abramsson A, Betsholtz C. Role of PDGF-B and PDGFR-beta in recruitment of vascular ity improvements and reductions in lergan, Acucela, Avalanche, Genen- smooth muscle cells and pericytes during embryonic blood vessel 10 formation in the mouse. Development 1999;126:14:3047-55. retinal thickness on OCT. Patients in tech, Novartis and Regeneron, as well 24. Jain RK. Normalization of tumor vasculature: an emerging the phase II IMPACT study of squala- as an investor/consultant in Oph- concept in antiangiogenic therapy. Science 2005;307:5706:58. 25. Lindahl P, Johansson BR, Levéen P, Betsholtz C. Pericyte loss mine who had classic-CNV-containing thotech. Contact Dr. Levison at 1101 and microaneurysm formation in PDGF-B-defi cient mice. Science 1997;277:5323:242-5. lesions experienced an acuity improve- E Missouri Ave, Phoenix, AZ 85014 or 26. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. ment of +11 letters with squalamine [email protected]. Nature 2005;438:7070:967-74. 27. Greenberg JI, Shields DJ, Barillas SG, et al. A role for VEGF as in combination with ranibizumab ver- a negative regulator of pericyte function and vessel maturation. sus +5 letters with ranibizumab alone. 1. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus Nature 2008;456:7223:809-13. verteporfi n for neovascular age-related macular degeneration. N 28. Andrae J, Gallini R, Betsholtz C. Role of platelet-derived Three-line gains in visual acuity were Engl J Med 2006;355:14:1432-44. growth factors in physiology and medicine. Genes Dev 2. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for 2008;22:10:1276-312. present in 44 percent of these patients neovascular age-related macular degeneration. N Engl J Med 29. Jaffe GJ, Eliott D, Wells JA, et al. A Phase I study of intravitreous in the combination treatment arm 2006;355:14:1419-31. E10030 in combination with ranibizumab in neovascular age- 3. Holekamp NM, Liu Y, Yeh WS, et al. Clinical utilization of anti- related macular degeneration. Ophthalmology 2016;123:1:78-85. compared to 29 percent in the ranibi- VEGF agents and disease monitoring in neovascular age-related 30. Tolentino MJ, Dennrick A, John E, Tolentino MS. Drugs in macular degeneration. Am J Ophthalmol 2014;157:4:825-33. 35 Phase II clinical trials for the treatment of age-related macular zumab monotherapy arm. A Phase 4. Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K, Group degeneration. Expert Opin Investig Drugs 2015;24:2:183-99. III trial is planned. S-US. Seven-year outcomes in ranibizumab-treated patients in 31. Dugel PU. Phase IIb clinical trial of Fovista anti-PDGF therapy ANCHOR, MARINA, and HORIZON: a multicenter cohort study in patients with neovascular AMD. Presented at: American • Pazopanib, Regorafenib and (SEVEN-UP). Ophthalmology 2013;120:11:2292-9. Academy of Ophthalmology annual meeting. Chicago, November 5. Dugel P. Results of ESBA 1008, a single-chain antibody 2012. PAN-90806. Pazopanib is another fragment, for the treatment of neovascular AMD. ASRS Annual 32. Chakravathy U JG. Dual antagonism of platelet derived medication administered topically, and Meeting. San Diego, 2014. growth factor and vascular endothelial growth factor results in 6. Holz FG, Dugel PU, Weissgerber G, et al. Single-chain antibody reduced subretinal fi brosis and neovascular growth. Presented is being developed by GlaxoSmith- fragment VEGF inhibitor RTH258 for neovascular AMD: A at: American Academy of Ophthalmology annual meeting. New randomized controlled study. Ophthalmology 2016 doi: 10.1016/j. Orleans, October 2014. Kline. It’s a tyrosine kinase inhibitor ophtha.2015.12.030[published Online First: Epub Date]|. 33. Dugel PU. Anti-platelet derived growth factor: Where do we that inhibits VEGF receptors and the 7. Positive phase II data highlights benefi ts of Alcon’s RTH258 stand? American Academy of Ophthalmology annual meeting. for patients with neovascular (wet) age-related macular Chicago, November 2012. PDGF pathway. degeneration. https://www.novartis.com/news/media-releases/ 34. A Phase I/II safety study of DE-120 injectable solution for positive-phase-ii-data-highlights-benefits-alcons-rth258- AMD. https://clinicaltrials.gov/ct2/show/NCT02022501. Regorafenib (Bayer AG) is another patients-neovascular. Accessed 29 July 2016. 35. Ohr Pharmaceutical data from OHR-102 phase II IMPACT 8. Pugach P, Krarup A, Gettie A, et al. In vivo binding and Study in wet-AMD. Data on fi le, Ohr Pharmaceutical. tyrosine kinase inhibitor that inhibits retention of CD4-specifi c DARPin 57.2 in macaques. PLoS One

56 | Review of Ophthalmology | September 2016

051_rp0916_rtinsider.indd 56 8/26/16 2:17 PM SAVE THE DATE

GLAUCOMA FELLOWS CONTINUING SPECIALIZED EDUCATION NOVEMBER 11-12, 2016 CSE GLAUCOMA FELLOWS Fort Worth, Texas

Dear Fellowship Program Director and Coordinator,

We would like to invite you to review the upcoming 2016 Glaucoma Fellowship Program in Fort Worth at the Renaissance Worthington hotel. The program offers a unique educational opportunity for fellows by providing the chance to meet and exchange ideas with some of the most respected thought leaders in glaucoma. The Glaucoma Fellows Program is designed to provide your fellows with a state-of-the-art didactic and wet lab experience. The program also serves as an opportunity for your fellows to network with fellows from other programs.

After reviewing the material, it is our hope that you will select and encourage your fellows to attend this educational activity which is CME accredited to ensure fair balance.

Sincerely, Postgraduate Healthcare Education Course Director: Wet Lab Director: Kuldev Singh, MD Douglas J. Rhee, MD Stanford, CA Cleveland, OH Faculty:

Lee Alward, MD Steven Gedde, MD Harry Quigley, MD Donald Budenz, MD Dale Heuer, MD Arthur Sit, MD Ronald Fellman, MD Shan Lin, MD George Spaith, MD Brian Flowers, MD Eydie Miller-Ellis, MD Janey Wiggs, MD, PhD Louis Pasquale, MD

For More Information & to Register: www.revophth.com/2016cseglaucoma

Email: [email protected] or call Denette Holmes 866-627-0714

Participants in this course must be enrolled in a glaucoma fellowship program at the time of the course. There is no registration fee for these activities. Air, ground transportation in Fort Worth, hotel accommodations and modest meals will be provided through an educational scholarship for qualiﬁ ed participants.

Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Amedco and Postgraduate Healthcare Education. Amedco is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Statement Amedco designates this live activity for a maximum of 13.50 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Endorsed by Jointly provided by Supported by an unrestricted independent medical educational grant from Review of Ophthalmology® Alcon

2016_CSE_GlaucFellow-HouseAd.indd 86 6/23/16 1:54 PM Therapeutic Topics REVIEW

Objective: Symptomatic Assessment Strategies Symptom scores can be helpful when treating dry eye, but constructing good questionnaires can be a challenge. Mark B. Abelson, MD, CM, FRCSC, FARVO, David A. Hollander, MD, MBA, and James McLaughlin, PhD Andover, Mass.

ast month we explored the ap- Ask Better Questions of ocular disease, that were later used Lplication and interpretation of Dry-eye disease is an ocular condi- to evaluate symptoms. In general, various measures for the signs of tion defi ned by patients’ symptoms: these were limited by either having ocular disease: the scales we use to The name of the condition is itself a too many questions or too few dry- rate redness, lid swelling or corneal symptomatic description. We’re aware eye related queries. Another group of staining. An analogous methodolo- that the central confounder in DED these symptomatic measures, includ- gy is also applied to quantify symp- is that symptoms and signs are often ing the Ocular Surface Disease Index, toms of ocular disease such as pain, discordant, and patients often report the McMonnies Dry Eye Index and itch or other forms of discomfort. signifi cant symptomatic disease with the Dry Eye Questionnaire, focused Because we rely on our patients to little or no ocular surface staining or more on the key issues of DED symp- report the intensity, character and tear-fi lm dysfunction.1-2 This has led tom characteristics, symptom severity progression of disease symptoms, to a focus on clinical refi nement of the and disease impact. The McMonnies it’s crucial that we take great care tools we use to quantify symptomatic and the OSDI were characterized in in how we pose that deceptively DED. There are dozens of variations greater detail and validated for use in simple question, “How are you of the questionnaires used to pro- clinical trials. feeling?” vide an objective measure of dry-eye What makes a good questionnaire? This month, we delve into the nu- symptoms, and the particular value of The goal is to allow the patient to ances of symptomatic assessment. each is a function of its specifi c use; provide accurate information about We’ll discuss both the importance some are designed for epidemiologic his symptoms in a way that precisely of establishing an approach that studies3-7 while others are constructed and reproducibly refl ects the disease allows us to best employ the infor- for use as clinical diagnostic tools. Of- state. Most questions are formatted mation our patients provide for di- ten the diagnostic questionnaires are so that the patient responds with a agnosis and treatment assessment, also employed in therapeutic trials, scalar numeric; for example, a ques- and the role this information plays but these can leave room for improve- tion from the OSDI asks: in developing new therapies. Issues ment in that specifi c role. “Have you experienced the follow- surrounding the optimization of Dry-eye questionnaires such as the ing in the last week: painful or sore symptom evaluation are critical in National Eye Institute visual function eyes (4) all of the time (3) most of the developing dry-eye treatments, and questionnaire, the Women’s Health time (2) half of the time (1) some of they’re also of interest in therapies Study questionnaire and the Dry Eye the time (0) none of the time.” for allergy, ocular infl ammation and Epidemiology Project’s questionnaire Structuring questions in this way, postoperative ocular pain. are tools designed to assess the scope where higher numerical scores are

58 | Review of Ophthalmology | September 2016 This article has no commercial sponsorship.

0058_rp0916_ttops.indd58_rp0916_ttops.indd 5858 88/26/16/26/16 2:112:11 PMPM associated with increased disease severity, allows questionnaires with 10 to 15 questions like the OSDI to generate a summated score in which ranges of total scores are designated as mild, moderate or severe symptomatic disease. Several other factors are critical to a reliable, reproducible questionnaire that can provide an accurate DED evaluation. First, the number of questions should be kept to a minimum, allowing patients to maintain a consistent degree of focus in answering each question. Our experience tells us that questionnaires should be no longer than the 12 to 15 questions of the McMonnies or the OSDI; and it may One of the confounding aspects of treating dry-eye disease is that a patient with an be that four or five well-structured objective sign, such as staining, may not have corresponding symptoms, and vice versa. questions are suffi cient, or even superior, in terms of the goals stated perspective from the patient’s view the practice of medicine, an exclusion above. This is particularly true in a will allow for an interpretive response error is better in a drug-development clinical trial setting, where a greater with an increased subjective impact. setting. number of questions provides more— Recent studies suggest that recall bias Several approaches have been but not necessarily better—data, and is a particularly significant issue in used to address the pitfalls of cur- the resulting greater variability in the older patient populations, and that rent questionnaires by combining old dataset often confounds the outcome. recall issues may introduce systematic and new questionnaires or focusing biases into the responses and, there- on specific questions with a symp- Simplifying Symptom Scoring fore, the symptomatic assessments.8 tom survey. One study employed the In the context of a clinical trial, how- OSDI questionnaire in combination Greater numbers of questions in the ever, it’s also important to remember with a simpler, four-question survey setting of a clinical trial also provides that if the survey is used to assess pri- of subjects’ current dry-eye symp- a greater potential for the Hawthorne mary or secondary endpoints, then it tomatology (Ora Calibra Four-Symp- Effect, where subjects interject their needs to specify the time frame and tom Scale).10 Another trial used the perceptions regarding right or wrong/ optimize this based on the predicted OSDI, but then defi ned a secondary better or worse answers in response to temporal characteristics of the inter- symptomatic endpoint based upon a perceived need on the part of those vention being tested.9 Questions ide- the mean change from baseline in the administering the test. This subjective ally need to strike a balance between visual-related function subscale score infl uence can ultimately blur distinc- contemporaneous and retrospective of the OSDI.11 In this case, several tions between treatment and control reporting of a patient’s experience. OSDI questions that focus on visual groups. In an ideal world, our symptom function were plucked from the sur- A second factor that can have a questionnaire would have a single vey, predefi ned as a unique endpoint big impact on symptom question- question and a correlation with dis- and scored separately. This approach naires is the degree to which ques- ease severity of 1. As we live in the may be the best of both worlds: in- tions rely on recollection. Ques- real world, we strive for a few simple clusion of more extensive, validated tions that ask, “How often in the last questions and a correlation of 0.7 or methods such as OSDI allows for an week …” or “How many days in the past better. Further complicating the re- assessment comparable to other tri- month ...” are dependent upon a fi nement of symptomatic assessments als, while simplified scales such as subject’s recall and therefore have are the contrasting aspirations of the Four-Symptom Scale are key to an inherent potential for inaccuracy. questionnaires designed for the clinic a more objective and tighter dataset As with longer surveys, those with and those optimized for a clinical trial: able to rigorously describe the effi- questions that focus on a historical While an inclusion error is good in cacy of an intervention.

September 2016 | reviewofophthalmology.com | 59

058_rp0916_ttops.indd 59 8/26/16 2:11 PM Therapeutic

REVIEW Topics

Beyond Dry Eye could be mitigated by their combina- measure or metric selected, is the fact tion.15 In this case, where disease pro- that it must be based on a clear and When we talk about disease symp- gression is slow and often not tightly honest conversation between patient toms, we refer in almost every case correlated with anatomical changes, and physician. to some type of pain or discomfort: the combination allows for an amplifi - dryness; grittiness; burning; itching; cation of potential therapeutic effects. Dr. Abelson is a clinical professor and even photophobia. Many of these Often, composite endpoints func- of ophthalmology at Harvard Medi- are associated with conditions other tion to increase the statistical power of cal School. Dr. Hollander is chief than dry eye, and so should be part a study without increasing the num- medical offi cer at Ora, and assistant of the diagnosis for those conditions ber of subjects required; an example clinical professor of ophthalmology as well. Eye pain and photophobia, of this is the total nasal symptom score at the Jules Stein Eye Institute at the for example, are two hallmark symp- used in trials of allergy therapies. The University of California, Los Angeles. toms of migraine headache.12 There TNSS combines symptomatic scores Dr. McLaughlin is a medical writer at are many different pain-assessment for rhinorrhea, nasal congestion, nasal Ora Inc. Dr. Abelson may be reached instruments available that range from itching and sneezing, and has become at [email protected]. extensive questionnaires to simple the metric for therapeutic assessment cartoon graphics, but, as with the dry- of anti-allergics.16 Of course, combin- 1. Abelson MB, Ousler GW 3rd, Nally LA, Emory TB. Dry eye syndromes: Diagnosis, clinical trials and pharmaceutical eye surveys, the goal here is to pro- ing measures of multiple symptoms treatment—‘improving clinical trials’. Adv Exp Med Biol. vide a reliable assessment of patient implies that all are equal contribu- 2002;506(Pt B):1079-86. 2. Abelson MB,Ousler GW 3rd, Maffei C. Dry eye in 2008. Curr symptoms as a means to guide treat- tors to patient symptomatology. Be- Opin Ophthalmol 2009;20:4:282-6. ment or therapy development. cause this may not always be the case, 3. Methodologies to diagnose and monitor dry eye disease: Report Pain is often a key sequela to pro- there is a risk that treatments with of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop. Ocular Surface 2007;5:2:108-152. cedures such as cataract or refractive specifi c effects are approved for more 4. Kanellopoulos AJ, Asimellis G. In pursuit of objective dry eye surgery, and in these cases the most extensive indications. In the case of screening clinical techniques. Eye Vis (Lond) 2016;18:3:1. 5. Grubbs JR, Tolleson-Rinehart S, Huynh K, Davis RM. A review reliable measure is obtained with a the TNSS score, for example, a drug of quality of life measures in dry eye questionnaires. Cornea visual analog scale. Comparisons of with strong anticholinergic action may 2014;33:2:215-8. numerical scales without verbal de- potently abolish rhinorrhea but have 6. Amparo F, Schaumberg DA, Dana R. Comparison of two questionnaires for dry eye symptom assessment. Ophthalmology scriptors and those with graded de- little effect on other components of 2015;122:1498-1503. scriptors such as mild, moderate or the composite score. With an over- 7. Barabino S, Labetoulle M, Rolando M, Messmer EM. Understanding symptoms and quality of life in patients with dry severe show that it is primarily the whelming effect on one component, eye syndrome. Ocul Surf 2016;14:3:365-76. anchoring descriptors that impact the such a drug could generate statistical- 8. Brusco NK, Watts JJ. Empirical evidence of recall bias for reliability of the scale.13 ly signifi cant reductions in TNSS and primary health care visits. BMC Health Serv Res 2015;15:15:381. 9. FDA guidance document of PRO http://www.fda.gov/ Use of symptomatic data in clini- thus potentially receive an indication downloads/Drugs/.../Guidances/UCM193282.pdf. Accessed 24 cal trials is always more diffi cult than for relief of all the symptoms included August 2016. 10. Meerovitch K, Torkildsen G, Lonsdale J, Goldfarb H, Lama T, endpoints with clearly defined, ob- in the composite. In this way, use of Cumberlidge G, Ousler GW 3rd. Safety and effi cacy of MIM-D3 jective metrics. Despite this, they’re composite endpoints can lead to ar- ophthalmic solutions in a randomized, placebo-controlled often the most clinically meaning- tifacts in the regulatory process and Phase 2 clinical trial in patients with dry eye. Clin Ophthalmol 2013;7:1275-85. ful measures, and so their inclusion an artifi cial broadening of the thera- 11. Sheppard JD, Torkildsen GL, Lonsdale JD, D’Ambrosio Jr. JA, is often essential from a regulatory peutic indication. This reminds us to et al. Lifi tegrast ophthalmic solution 5.0% for treatment of dry eye disease. results of the opus-1 phase 3 study. Ophthalmology perspective. An approach that is seen look carefully at each component of 2014;121:475-483. with increasing frequency to address a composite score with the goal of 12. Walters AB, Smitherman TA. Development and validation of this and other trial design issues is the selecting those that equally refl ect the a four-item migraine screening algorithm among a nonclinical sample: the migraine-4. headache. 2016;56:1:86-94. composite endpoint, in which spe- symptomatology of the target condi- 13. Hjermstad MJ, Fayers PM, Haugen DF et al. Studies comparing cific treatment goals are combined tion. numerical rating scales, verbal rating scales, and visual analogue scales for assessment of pain intensity in adults: A systematic into one amalgamated effi cacy mea- Despite these caveats, composite literature review. J Pain Symptom Manage 2011;41:6:1073-93. 14,15 sure. For example, use of a com- endpoints do have a potential utility, 14. Landy S, White J, Lener SE, McDonald SA. Fixed-dose posite endpoint including a structural whether for enhancement of our abil- sumatriptan/naproxen sodium compared with each monotherapy utilizing the novel composite endpoint of sustained pain-free/no endpoint (such as retinal optical co- ity to address symptomatic diseases adverse events. Ther Adv Neurol Disord. 2009;2:3:135-41. herence tomography) combined with or as a tool in the broader context 15. Medeiros FA. Biomarkers and surrogate endpoints in glaucoma clinical trials. Br J Ophthalmol 2015;99:5:599-603. some measure of visual function has of clinical therapeutic development. 16. FDA TNSS guidance http://www.fda.gov/downloads/ been suggested for glaucoma trials, Key to the process of symptom as- drugs/guidancecomplianceregulatoryinformation/guidances/ where limitations of each measure sessment, regardless of the specific ucm071293.pdf. Accessed 16 August 2016.

60 | Review of Ophthalmology | September 2016

0058_rp0916_ttops.indd58_rp0916_ttops.indd 6060 88/26/16/26/16 2:112:11 PMPM JOIN US AT AAO FOR A BREAKFAST SYMPOSIUM REDEFINING LASER THERAPY FOR MACULAR DISEASE WITH PASCAL LASER

New Interactive format with live audience polling.

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COMPLIMENTARY REGISTRATION Online:

reviewofophthalmology.com/ This event is not afﬁliated with the ofﬁcial program of AAO 2016. Your attendance at this meeting may be reported by PASCALBreakfast the sponsor in accordance with the sunshine act. For further information visit, cms.gov/Regulations-and-Guidance/ Legislation/National-Physician-Payment-Transparency-Program/Downloads/Physician-fact-sheet.pdf Please Call: refer to your state laws for any attendance restrictions. Attendance at this event is limited to eye care professionals. 866-642-3937 Due to individual state legislation, physicians licensed in Minnesota, Vermont and Massachusetts may not attend this symposium. Email: [email protected] SPONSORED BY BROUGHT TO YOU BY

RP0916_House Topcon Pascal.indd 1 8/26/16 9:53 AM Glaucoma Management

REVIEW Edited by Kuldev Singh, MD, MPH, and Peter A. Netland, MD, PhD

ECP & Cataract Surgery: Perfect Together? Evidence suggests that endoscopic cyclophotocoagulation can be a safe and effective adjunct to cataract surgery. Carla J. Siegfried, MD, St. Louis

s a general rule, we think of stop aqueous production.) G-probe that contacts the eye. The A glaucoma as an optic neuropathy Recently, endoscopic cyclophoto- laser energy is absorbed by the pig- associated with disease of the outﬂ ow coagulation has come to the forefront mented ciliary epithelial tissues, re- pathway of aqueous humor. Perhaps because it’s currently often done in sulting in destruction of the cells. for that reason, many surgeons are combination with cataract surgery, It was Martin Uram, MD, who reluctant to use a procedure that making it an adjunctive procedure in first designed and developed the ablates part of the ciliary processes the early stages of glaucoma. Because endoscopic laser in Little Silver, to limit aqueous inflow, except as a it is a minimally invasive glaucoma N.J. (current home of Endo Optiks, last resort—e.g., for patients who surgery, one could also put it into the manufacturer of the instrument). It have refractory glaucoma with very category of MIGS. uses an 810-µm diode continuous- high pressure and very poor vision, I should make it clear that I wave laser that allows you to “paint” or patients who have had so many don’t perform a great deal of ciliary the ciliary processes. The reusable surgeries that you’re not excited about ablation. However, endoscopic cyclo- probes, available in curved or straight doing another incisional procedure. photocoagulation (and transscleral versions and in different sizes, contain It’s true that in this situation a cyclo- cyclophotocoagulation) are part of a light source, video camera and the ablative procedure is an option, but our armamentarium, and I think we laser, with an aiming beam that allows restricting such a procedure to this should have as many tools as possible you to see the area you’re treating. type of situation may be unnecessary. at our disposal. There are times when The optics of the system provide Ironically, many topical drops we one of these procedures may be the enough depth of focus—from 1 to prescribe to treat glaucoma work right procedure to help your patient. 30 mm—to let you pull back and get by reducing inflow; often, aqueous a wider ﬁ eld of view when necessary. suppressants are used as initial or A Brief History As a retina specialist, Dr. Uram used additive therapy. One might argue the instrument through the pars plana that this is not equivalent to ciliary In the past, surgeons have tried to to treat the ciliary processes when he ablation because medication effects limit ciliary production of aqueous was doing vitrectomies. Later it was are reversible. However, it’s worth re- using surgical excision, penetrating converted for use through the limbus membering that while cyclophoto- diathermy (i.e., cautery), cryotherapy, or through a corneal wound during coagulation is not reversible, it is ultrasound and lasers of different cataract surgery. Today, ECP is usually titratable; we only ablate a portion of kinds. Transscleral cyclophotocoagu- done through a clear cornea cataract the ciliary processes. (Besides, even lation is now most commonly per- surgery incision. (ECP can also be treating 360 degrees won’t completely formed using a semiconductor diode done as a stand-alone procedure in

62 | Review of Ophthalmology | September 2016 This article has no commercial sponsorship.

062_rp0916_gm.indd 62 8/26/16 2:39 PM pseudophakic patients.) Reduction in IOP Following Phaco with ECP Today, because ECP is relatively efficient as an adjunct to cata- 25 ract surgery, it’s become more commonly used in patients who have good visual potential and mild glau- comatous damage. The transscleral 20 approaches are still primarily reserved for end-stage, more refrac- IOP (mmHg) tory glaucoma. However, I believe 15 even transscleral procedures are being used earlier in the disease, perhaps because of what we’ve learned from ECP—that cyclophotocoagulation Pre 1 1 1 3 6 12 18 24 can be done earlier, and it can be Day Week Month Months Months Months Months Months very safe. I now use TCP for elderly patients, and even patients with A retrospective review of 56 phaco-ECP patients found that IOP was reduced from a mean good central vision that I don’t want of 21.5 mmHg at baseline to 14.4 mmHg at 18 and 24 months (p<0.01). Medications were reduced from a mean of 2.1 at baseline to 2.0 at 24 months (p>0.05).3 to take to the OR. I can do this in the treatment room under local anesthetic, without sedation. make sure the anterior chamber is to a greater reduction in pressure. acceptable, without signiﬁ cant torque As noted, this treatment is titrat- Performing the Procedure of the eye. During the treatment, as able. (Malik Kahook, MD, at the you “paint” the ciliary process, you’re University of Colorado, Denver, did When I perform ECP in the OR looking for blanching and shrinking a retrospective, consecutive case re- in conjunction with cataract surgery, of the process; you don’t want to see view of 40 patients who underwent I use topical lidocaine gel and then popping or explosions. This is one of combined ECP and phaco, and inject a small amount of lidocaine the differences between ECP and found greater reduction in IOP at intracamerally at the time of the pro- TCP; I once filmed a transscleral both three and six months when 360 cedure. (As a general rule, I don’t do treatment using the endoscope, and degrees were treated, compared to retrobulbar injections for any sur- you could see some of the ciliary pro- when less than 300 degrees were gical procedures.) When I do TCP cesses exploding as they absorbed the treated.1) Using the curved probe, in the treatment room (i.e., not in laser energy. I’m able to treat 270 degrees through conjunction with cataract surgery), I Histology of eyes that have un- one incision; if you want to treat 360 always use a sub-Tenon’s injection of dergone TCP shows widespread degrees, you’ll need to make a second lidocaine 2%/marcaine 0.375% for tissue disruption, signs of a pro- incision. Once you’re finished, it’s anesthesia. longed reduction in blood flow and important to remove the viscoelastic, When done in conjunction with coagulative necrosis of the ciliary because viscoelastic that’s left behind cataract surgery, ECP is performed stroma. In contrast, during ECP you is a signiﬁ cant cause of pressure spikes after the lens implant is in place. I see blanching and shrinking but no after the procedure. work through the cataract wound exploding tissue. Histopathology Postoperatively, I inject a miotic (usually a clear-cornea, limbal, 2.5- after ECP demonstrates localized such as acetylcholine or carbachol, mm incision); I place viscoelastic into contraction of the ciliary processes, along with topical steroids and anti- the sulcus, which elevates the iris and signs of a temporary reduction in iris biotics, just as I would following any lowers the IOL, providing a direct line root/ciliary process perfusion, less cataract surgery. I keep the patient of sight to the ciliary process. A pars architectural disorganization and on pressure-lowering medications plana approach may be undertaken by sparing of the ciliary muscle. (The until the pressure comes down, vitreoretinal surgeons following a pars impact of the last factor may be muted but I continue steroids a bit longer plana vitrectomy. by the fact that the accommodation than I would after standard cataract It’s important to learn to watch is no longer an issue after standard surgery. (After cataract surgery I the monitor and occasionally glance cataract surgery.) It’s not clear whe- start to taper the steroid drops after at the eye during the procedure, to ther one approach or the other leads a week. Following cataract surgery

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with ECP, I may keep the patient on rotation of the ciliary process, by edema. ECP patients will have more the steroids for three or four weeks, performing endocycloplasty. Cyclo- postoperative infl ammation than pa- tapering the patient off by six weeks.) ablation causes shrinkage of the ciliary tients who undergo standard cata-ract Non-steroidal topical agents may also process, rotating it backwards, which surgery. CME is a possible com- be used in some patients. helps to open up the peripheral angle. plication, making patients with this “ECP plus” is another variation of • for endoscopic visualization. kind of history more likely to have the procedure, done through the pars Using the probe can be very help- trouble postoperatively. plana incision, a variation most likely ful if you have a displaced or im- Although ECP is generally a safe to be performed by a retina specialist. properly placed implant; you can see procedure, complications can occur. The “plus” refers to additionally treat- precisely where the IOL haptics are These include: ing part of the pars plana. The ciliary and whether they’re in the wrong • Infl ammation. epithelium not only covers the ciliary position. Similarly, the endoscopic • Hyphema. (This has been re- process—the structure that comes system is helpful when patients have ported, although I’ve never seen it out from the wall of the eye—but corneal disorders that obstruct the during any of my procedures.) also the pars plana, which can be surgeon’s view inside the eye; surgical • Cystoid macular edema. As thought of as a very anterior part of procedures can still be done, using the noted above, this can occur, especially the retina. Since that area does have endoscopic probe to see what’s going in those who have a history of CME. ciliary epithelial cells, you can treat on behind the corneal or lenticular • Zonular damage. This can occur the anterior 1 to 2 mm of the pars opacity. (The endoscope can also if the surgeon accidentally pushes on plana to generate additional reduction be used as a diagnostic tool in these the lens during the procedure. in aqueous. Usually, this would be circumstances.) • Hypotony or phthisis. In done as part of a standard pars plana theory, this could happen after the vitrectomy, with the probe inserted Caveats and Complications procedure, but I’m not sure it’s ever through the sclerostomy. been reported. Several things should be considered • Postoperative change in re- Indications relative contraindications for ECP: fractive error. This could theoretic- • Pseudoexfoliation glaucoma. ally happen as a consequence of a Today, the most common use for Because this disease leaves a white, change in effective lens position ECP is as primary therapy combined fibrillar material on the ciliary pro- caused by inadvertent pressure with phaco. However, it is also used in cesses, they may not absorb the laser placed on the lens implant. One study a number of other situations: energy as well. looked at postoperative refractive • combined with other MIGS • Weakened zonules. It’s impor- error changes following ECP; the data procedures (as in the ICE procedure, tant to be especially careful if revealed some slight differences, but consisting of iStent, cataract extraction you perform ECP in patients with they were not signifi cant.2 and ECP); weakened zonules. The probe is very • to treat refractory glaucoma; close to the lens during the procedure, What the Data Show • if TCP fails to lower pressure (di- and over the course of the procedure rect visualization via ECP may yield the viscoelastic that’s maintaining How effective is treatment with an improved outcome); the space between the lens implant ECP when combined with cataract • as concomitant therapy with pars and the iris gradually diffuses into surgery? Here are the data from a plana vitrectomy; the anterior chamber, causing the number of studies: • to treat aphakic and pseudophakic opening in which you’re working to • A retrospective review of 56 pediatric glaucoma; become shallower. As that happens, phaco-ECP patients found that IOP • in patients with a history of scleral it becomes possible for the probe to was reduced from a mean of 21.5 disease. For example, some pa- touch the lens implant. That’s not a mmHg at baseline to 14.4 mmHg at 18 tients have a very thin sclera, (e.g., problem, as long as you don’t put any and 24 months (p<0.01). Medications osteogenesis imperfecta). In these pressure on the lens; but if for some were reduced from a mean of 2.1 at cases, you don’t want to do an inva- reason you do —I’ve seen trainees baseline to 2.0 at 24 months (p>0.05).3 sive incisional procedure such as a make this mistake—you may stretch • A retrospective review of 63 trabeculectomy or a tube shunt. or break some of the zonules. phaco-ECP eyes that received 270 • to address plateau-iris syndrome, • A history of infl ammatory to 360 degrees of treatment looked at in which the eye has an anterior eye disease or cystoid macular the 12-month follow-up.4 Mean IOP

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0062_rp0916_gm.indd62_rp0916_gm.indd 6464 88/26/16/26/16 2:392:39 PMPM Allergan Displays ForSight different between the two groups: 61.4 percent vs. 23.3 percent (p<0.001). In August, Allergan announced its intent to purchase eye-care company ForSight Likewise, comparing the percentage Vision5, which has a sustained-release drug device in development. Per the agreement, in each group that achieved qualifi ed Allergan will acquire ForSight Vision5 for an initial $95 million payment and a launch success (IOP lower than baseline milestone payment related to the company’s lead product, the sustained-release device. with a decrease of one medication), ForSight’s device is a periy-ocular ring that’s preservative-free and rests on the the difference between the groups surface of the eye beneath the lid. In its current iteration, it releases the glaucoma drug bimatoprost over a period of months to help lower intraocular pressure while avoiding was also significant: 72.6 percent issues with patients’ adherence to glaucoma drop schedules. vs. 23.3 percent (p<0.001). Put “We know if we’re going to take care of thousands of patients, we need a lot of tools in another way, those who underwent our bag,” says Jay Parekh, MD, vice president for medical affairs and global lead for eye cataract surgery alone had a one-in- care at Allergan. “And, when you have a disease therapy that could run a 20- or 30-year four chance of getting a significant course, compliance is a key aspect of it.” pressure reduction and a decrease in —The Editors medications. Those who underwent the combination surgery had three dropped from 21.1 ±6.2 at baseline having fi brinous uveitis, an event I’ve times better odds of this result. to 16.1 ±5.27 mmHg (p<0.01). Medi- rarely seen following ECP. Overall, • Finally, one retrospective chart cations dropped from 2.7 ±1.1 to the study authors concluded that the review looked at the combined 1.47 ±1.3 (p<0.01). (How much pres- procedure was safe and effective, with procedure in 104 eyes of 104 patients sure lowering can be attributed to a success rate—defi ned as a greater- with advanced glaucoma at the time the phaco alone is diffi cult to say, be- than-20-percent reduction in IOP— of surgery.7 Follow-up was 17.3 cause there was no control group.) of 55.5 percent. ±1.8 months. Among these patients, Of note, the outcomes were best in • A prospective, nonrandomized, mean IOP decreased from 17 ±1.4 older patients and those with a higher matched-control study compared mmHg to 14.7 ±1.3 mmHg. Only 11.9 baseline IOP. Whether this reflects phaco with ECP to phaco alone in percent achieved absolute success, a difference in the vascularity of the 160 patients (80 per group) matched defi ned as an IOP ≤15 mmHg on no ciliary cells, or a different response to for age and baseline IOP.5 In the study medications; however, 72.3 percent a change in infl ow due to age or high group, mean IOP decreased from achieved qualifi ed success, defi ned as pressure, is impossible to determine. 18.1 ±3 mmHg to 16.0 ±3.3 at two an IOP ≤15 mmHg with medications. Notably, all medications in this years, with medication use dropping Because ECP—often combined group were discontinued after sur- from 1.5 ±0.8 to 0.4 ±0.7. The phaco- with phaco—can be considered a gery and re-introduced as needed. I only group decreased from 18.1 ±3 MIGS procedure, it would be helpful suspect this may be the reason they mmHg to 17.3 ±3.2 at two years, with to have some prospective, randomized found more of a decrease in the medications decreasing from 2.4 ±1.0 studies comparing it to the other number of medications than many to 2.0 ±1.0. The difference in pressure MIGS procedures. So far, I’m not studies find. In general, we discon- and medication reduction between aware of any studies fitting that tinue all medications after a full- the groups was statistically signifi cant description. However, we presented a fl edged glaucoma surgery, but many at all time points. poster last year at both the American times with MIGS procedures, es- • Another retrospective chart Academy of Ophthalmology and pecially if the patient has moderate review with a 36-month follow-up American Glaucoma Society annual disease, we’re more hesitant to do so. compared phaco with ECP to phaco meetings showing data from a re- As a result, we may be not seeing the alone; 261 eyes underwent combined trospective study of 150 patients at the full effect of these treatments, at least surgery, while 52 eyes underwent Barnes-Jewish Hospital/Washington in terms of their ability to decrease only cataract surgery.6 The difference University School of Medicine; 41 medication use. between the IOP-lowering in the underwent phaco alone; 52 un- This study also looked at com- two groups wasn’t significant at 16 derwent phaco with ECP; and 57 plications. The data showed a small weeks (14.6 mmHg vs. 15.5 mmHg, underwent phaco with Trabectome. amount of induced astigmatism (pos- p=0.34). However, the percentage of As expected, higher IOPs, more sibly related to movement of the patients meeting the defi nition of full medications and worse disease had lens); posterior vitreous detachment, success (a greater-than-20-percent infl uenced the surgeons to choose a a few cases of increased IOP, and an reduction in IOP and a decrease of combined procedure. unusually high 11 percent of cases one medication) was significantly Among the results:

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REVIEW Management

• There was significant pressure of ECP has expanded significantly Allan E. Kolker, MD, Distinguished lowering with both phaco-Trabectome over the past 10 years. Starting Professor of Ophthalmology at Wash- and phaco-ECP, as well as higher rates in 2005, the single billing code for ington University School of Medicine of success (defined as a reduction ciliary ablation was separated into in St. Louis. She has no fi nancial in- in IOP of at least 20 percent, or a transscleral procedures and endo- terest in any product discussed. reduction of at least one medication) scopic procedures. By 2012, use of 1. Kahook MY, Lathrop KL, Noecker RJ. One-site versus two-site compared to phaco alone. transscleral procedures dropped endoscopic cyclophotocoagulation. J Glaucoma 2007;16:6:527-30. • Success rates of the two combined from 5,978 to 3,268, a 45-percent 2. Sheybani A, Saboori M, Kim JM, Gammon H, Lee AY, Bhorade AM. Effect of endoscopic cyclophotocoagulation on refractive procedures weren’t signifi cantly dif- decrease. During the same period, outcomes when combined with cataract surgery. Can J ferent at 24 months, although there ECP procedures grew from 5,383 Ophthalmol 2015;50:3:197-201. 3. Lindfi eld D, Ritchie RW, Griffi ths MF. ‘Phaco-ECP’: Combined was a trend toward better pressure to 10,728, a 99-percent increase. endoscopic cyclophotocoagulation and cataract surgery to reduction with phaco-Trabectome. Of note, reimbursement for ECP is augment medical control of glaucoma. BMJ Open 2012;2:3. 4. Clement CI, Kampougeris G, Ahmed F, Cordeiro MF, • In terms of complications, there significantly greater than for trans- Bloom PA. Combining phacoemulsifi cation with endoscopic was more hyphema with phaco- scleral procedures—$635.84 vs. cyclophotocoagulation to manage cataract and glaucoma. Clin Experiment Ophthalmol 2013;41:6:546-51. Trabectome and more CME with $434.57; ECP is a more involved pro- 5. Francis BA, Berke SJ, Dustin L, Noecker R. Endoscopic phaco-ECP. cedure performed in the OR. cyclophotocoagulation combined with phacoemulsifi cation versus phacoemulsifi cation alone in medically controlled It’s worth noting that because the Given that ECP has a good track glaucoma. J Cataract Refract Surg 2014;40:8:1313-21. study was retrospective, patients were record for safety, and may produce 6. Siegel MJ, Boling WS, Faridi OS, Gupta CK, Kim C, Boling RC, Citron ME, Siegel MJ, Siegel LI. Combined endoscopic not matched for preoperative IOP, significant IOP lowering following cyclophotocoagulation and phacoemulsifi cation versus medications or disease severity. cataract surgery—with minimal risk phacoemulsifi cation alone in the treatment of mild to moderate glaucoma. Clin Experiment Ophthalmol 2015;43:6:531-9. —it’s an adjunctive treatment worth 7. Morales J, Al Qahtani M, Khandekar R, Al Shahwan S, Al Odhayb Increasing Popularity considering. S, Al Mobarak F, Edward DP. Intraocular Pressure Following Phacoemulsifi cation and Endoscopic Cyclophotocoagulation for Advanced Glaucoma: 1-Year Outcomes. J Glaucoma There’s no question that the use Dr. Siegfried is the Jacquelyn E. and 2015;24:6:e157-62.

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062_rp0916_gm.indd 66 8/26/16 2:41 PM IntroducingIntroducing MACKOOL ONLINE CME CME SERIES | SURGICAL VIDEOS

MackoolOnlineCME.com MONTHLY Video Series

I would like to welcome you to a new concept in surgeon education, Mackool Online CME. To view CME video go to: Demonstrating ophthalmic surgical techniques has www.MackoolOnlineCME.com long been part of my everyday practice. Now, thanks to educational grants from several ophthalmic companies, you are able to virtually sit at the microscope with me and Episode 9: see the techniques and instrumentation I use with my own “The Deformed Cornea” Richard J. Mackool, MD patients. The only editing is to show a diff erent camera view or to remove down time – every step of every Surgical Video by: procedure will be shown just as if you are with me in the OR. We will release Richard J. Mackool, MD one new surgical video every month, allowing you to earn CME credits or simply watch the video. Video Overview: Here is a very unusual case! This 62 year old man has a cataract CME Accredited Surgical Training Videos Now and severe keratoconus with a Available Online: www.MackoolOnlineCME.com refraction of -20.00 D, -11.00 D of cylinder, and K readings in the 80s! However, he is a very Richard Mackool, MD, a world renowned anterior segment ophthalmic successful hard contact lens microsurgeon, has assembled a web-based video collection of surgical wearer and therefore does not cases that encompass both routine and challenging cases, demonstrating require corneal transplantation. both familiar and potentially unfamiliar surgical techniques using a variety I demonstrate how to improve of instrumentation and settings. corneal-induced visualization This educational activity aims to present a series of Dr. Mackool’s surgical problems during phaco-IOL videos, carefully selected to address the speciﬁ c learning objectives of this surgery, and select an IOL with activity, with the goal of making surgical training available as needed online a power that would leave him for surgeons motivated to improve or expand their surgical repertoire. approximately emmetropic should he eventually undergo Learning Objectives: transplantation. In the meantime After viewing the video, participants should be able to: he will remain a successful 1. Present refractive considerations when performing cataract-implant hard contact lens wearer with surgery on patients with keratoconus. improved vision because of the 2. Present, discuss and ameliorate corneal-induced visualization problems cataract extraction. during cataract surgery.

Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Institute for the Advancement of Human Behavior (IAHB) and Postgraduate Healthcare Education, LLC (PHE). IAHB is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Statement IAHB designates this live activity for a maximum of .25 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Endorsed by: Jointly Provided by: Supported by an unrestricted independent Commercially supported by: medical educational grant from: Review of Ophthalmology® Glaukos Video and Web Production by: IAHB Crestpoint Management Institute for the & Captured Light Studio, Inc. Advancement of Human Behavior Alcon MST

Mackool_OnlineSeries-Episode9.indd 1 8/11/16 1:42 PM Cover Cornea

REVIEW Focus

(continued from page 30) cedure developed by India’s Amar Though it’s true that DMEK is more Agarwal, MD, and Great Britain’s challenging to perform than DSAEK, a detached graft hours after the proce- Harminder Dua, MD, the idea is to not many things in life or in ophthal- dure.12 The patient elected to wait and include the newly discovered (though mology that are worth doing are ever observe the situation because the eye disputed by some) Dua’s layer of the easy. If you can stay with DMEK had low visual potential. One month cornea in the posterior graft of endo- through the learning curve and put to postoperatively, the cornea began to thelium and Descemet’s membrane.15 use some of these principles, you and clear. At six months, only minor edema This makes the graft 30 to 40 µm thick, your patients will often be rewarded remained in the superior far periphery. which is only slightly thicker than a with excellent outcomes. The corneal pachymetry returned to DMEK graft but much easier to work normal and the endothelial cell density with in several ways: 1) Since you’re Dr. Hannush is an attending sur- was 830 cells/mm2. After this result, not stripping Descemet’s from stroma, geon in the Cornea Service at Wills Eye Dr. Melles saw a potential therapy and the risk of damaging Descemet’s mem- Hospital, Department of Ophthalmol- tentatively called the practice of a des- brane is eliminated. 2) You’re not re- ogy, Sidney Kimmel Medical College of cemetorhexis followed by the deposi- stricted to using donors older than 50 Thomas Jefferson University. He is also tion of a free-fl oating Descemet’s scroll because you don’t need to worry about the medical director of the Lions Eye in the anterior chamber “Descemet’s tearing Descemet’s membrane during Bank of Delaware Valley. membrane endothelial transfer,”or stripping as can occur in DMEK. 3) A 1. Price MO, Giebel AW, Fairchild KM, Price FW Jr. Descemet’s DMET. Dr. Melles found a similar re- PDEK scroll is 30 to 40 µm thick, not membrane endothelial keratoplasty: Prospective multicenter study of visual and refractive outcomes and endothelial survival. sult in a small group of Fuchs’ patients 15 or 20 µm as in DMEK, so it’s easier Ophthalmology 2009;116:12:2361-8. 2. Ni N, Sperling B, Dai Y, Hannush S. Outcomes after Descemet undergoing DMET, but not a group to unscroll in the anterior chamber. stripping automated endothelial keratoplasty in patients with with bullous keratopathy.13 The challenge, however, is in har- glaucoma drainage devices. Cornea 2015;34:8:870–875. 3. Cornea Donor Study Investigator Group, Gal RL, Dontchev M, The question, of course, is whether vesting the tissue for PDEK, which is Beck RW, et al. The effect of donor age on corneal transplantation outcome results of the cornea donor study. Ophthalmology the source of new endothelium cen- the main reason the technique hasn’t 2008;115:4:620-626. 4. Kruse FE, Laaser K, Cursiefen C, et al. A stepwise approach to trally was the donor graft or the rela- caught on yet. To harvest the donor donor preparation and insertion increases safety and outcome tively healthy peripheral host endo- graft, you can’t strip it through a pos- of Descemet membrane endothelial keratoplasty. Cornea 2011;30:5:580-587 thelium in Fuchs’. The University of terior approach. Instead you have to 5. Veldman PB, Dye PK, Holiman JD, Mayko ZM, Sáles CS, Straiko MD, Galloway JD, Terry MA. The s-stamp in Descemet membrane Chicago’s Kathryn Colby, MD, PhD, create a “big bubble” similar to that endothelial keratoplasty safely eliminates upside-down graft implantation. Ophthalmology 2016;123:1:161-4. has also been working with a less-inva- used in deep anterior lamellar kera- 6. Kruse FE, Schrehardt US, Tourtas T. Optimizing outcomes sive way to treat some Fuchs’ patients. toplasty. The eye-bank technician or with Descemet’s membrane endothelial keratoplasty. Curr Opin Ophthalmol 2014;25:4:325-34. In her retrospective study, she stripped the surgeon has to create this bubble 7. Guerra FP, Anshu A, Price MO, Giebel AW, Price FW. Descemet’s membrane endothelial keratoplasty: Prospective study of the central Descemet’s membrane in so that, when it expands and separates 1-year visual outcomes, graft survival, and endothelial cell loss. Ophthalmology 2011;118:12:2368-73. 13 eyes of 11 patients at the time of the tissue, it yields a posterior layer that 8. Hamzaoglu EC, Straiko MD, Mayko ZM, Sáles CS, Terry MA. their cataract surgery. At a follow-up has all three layers needed for PDEK The fi rst 100 eyes of standardized Descemet stripping automated endothelial keratoplasty versus standardized Descemet membrane of six months and later (range: six to 24 before trephining the graft. The chal- endothelial keratoplasty. Ophthalmology 2015;122:11:2193-9. 9. Deng SX, Sanchez PJ, Chen L. Clinical outcomes of Descemet months), 10 of the patients had corneal lenge is that we don’t always achieve a membrane endothelial keratoplasty using eye bank-prepared tissues. Am J Ophthalmol 2015;159:3:590-6. clearing, with a visible central endothe- big bubble, and, if we don’t achieve it, 10. Terry MA, Straiko MD, Veldman PB, et al. Standardized DMEK technique: Reducing complications using prestripped tissue, lial cell mosaic, and saw between 20/20 the corneal tissue is potentially perma- novel glass injector, and sulfur hexafl uoride (sf6) gas. Cornea and 20/15 (preop: 20/25 to 20/400).14 nently damaged and unusable. 2015;34:8:845-52. 11. Busin M, Albe E. Does thickness matter: Ultrathin Descemet Though this approach seems to con- • Rho-associated kinase inhibi- stripping automated endothelial keratoplasty. Curr Opin Ophthalmol 2014;25:4:312-8. fi rm what many of us suspected—that tor drops. Japan’s Shigeru Kinoshita, 12. Dirisamer M, Ham L, Dapena I, van Dijk K, Melles G. Descemet membrane endothelial transfer: “Free-fl oating” donor Descemet’s stripping the central 5 mm of endo- MD, has been developing a technique implantation as a potential alternative to “keratoplasty.” Cornea thelium in Fuchs’ dystrophy might al- for the treatment of endothelial dys- 2012;31:2:194. 13. Dirisamer M, Yeh R, van Dijk K, Ham L, Dapena I, Melles G. low the cornea to redistribute the re- function that involves instilling ROCK Recipient endothelium may relate to corneal clearance in Descemet membrane endothelial transfer. Am J Ophthalmol 2012;154:2:290. maining healthy endothelial cells from inhibitor eye drops to promote endo- 14. Borkar DS, Veldman P, Colby KA. Treatment of Fuchs’ endothelial dystrophy by descemet stripping without endothelial keratoplasty. the periphery—we’re not sure if this thelial healing. After fi nding acceler- Cornea 2016 Jun 15. [Epub ahead of print] approach works enough of the time ated healing due to the drops in animal 15. Altaan S, Gupta A, Sidney L, Elalfy M, Agarwal A, Dua H. Endothelial cell loss following tissue harvesting by to justify its widespread use. We’ll ob- models, he instilled them in eight pa- pneumodissection for endothelial keratoplasty: An ex vivo study. Br J Ophthalmol 2015;99:5:710-713. serve developments in this area with tients with endothelial dysfunction and 16. Koizumi N, Okumura N, Ueno M, Kinoshita S. New therapeutic 16 modality for corneal endothelial disease using Rho-associated interest. reported a positive effect. The next kinase inhibitor eye drops. Cornea 2014;33:11.S25-31. • Pre-Descemet’s Endothelial step in this research is ex-vivo expan- 17. Navaratnam J, Tor P. Utheim, et al. Substrates for expansion of corneal endothelial cells towards bioengineering of human corneal Keratoplasty. With PDEK, a pro- sion of healthy host endothelial cells.17 endothelium. J Funct Biomater 2015;6:3:917–945.

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70 | Review of Ophthalmology | September 2016

ROPH0916.indd 70 8/16/16 8:45 AM 071_rp0916_wills.indd 71 both eyes was unremarkable. both eyeswasunremarkable. tive left-sidedproptosis.Dilatedfundusexamin Hertel exophthalmometrydisclosed3mmofrela- tonometry was14mmHgODand17OS. markable. IntraocularpressurebyGoldmann gaze (Figure2). was fullODbutlimitedOS,mostnotablyinup- and mildedema(Figure1).Extraocularmotility moderate leftupperandlowereyeliderythema displacement ofthenasalbridgetorightwith full bilaterally. Externalexaminationdisclosed tion visualfi elds andIshiharacolorplateswere without anafferentpupillarydefect.Confronta- both eyes.Pupilswereequalandbrisklyreactive, showed uncorrectedvisualacuityof20/25in were withinnormallimits.Ocularexamination degrees Fahrenheit;theremainingvitalsigns Examination use anddrankalcoholsocially. Hehadnoknowndrugallergies. gration totheUnitedStatesfromElSalvadoreightweekspriorpresentation.Thepatientdeniedtobaccoorillicitdrug Medical History Systemic reviewwasonlysignificant forleftnasalcongestionovertheprecedingfewweeks. the lefteyewithmovement,mostnotablyinup-gaze,butdeniedconcurrentdiplopia,photophobia,recentillnessortrauma. ment ofpresumedpreseptalcellulitis,withoutprogressionorimprovementinhissymptoms.Hereportedongoingpain presented toanoutsideophthalmologistfive daysprior, andwasprescribedoralcephalexin500mg fourtimesdailyfortreat- Presentation Jeffrey F. McMahon, MD swelling andpaininthelidsofhislefteye. A recentimmigranttotheUnitedStatescomplainsofredness, What isyourdifferentialdiagnosis? Whatfurtherworkupwouldyoupursue?Please turntop. 72.

Slit lampexaminationofbotheyeswasunre- On examination,axillarytemperaturewas101.7 Past medical,surgicalandocularhistorywerenoncontributory. Thepatient’s socialhistorywasnotableforrecentimmi- A 25-year-old Hispanicmalecomplainedofrednessandswellingthelefteyelidsfortwoweeks.Thepatienthadinitially REVIEW Wills Eye Wills Eye hypoglobus ofthelefteye. Figure 2: Extraocular motilitymontagedisclosinglimitedup-gaze withmild Resident CaseSeries Edited by Alison Huggins, MD September 2016 | reviewofophthalmology.com edema. and erythema and lower eyelid swelling, leftupper with softtissue nasal displacement photograph of Figure 1: External |

71 8/26/16 3:01 PM 071_rp0916_wills.indd 72 proliferative disorders.Trauma and rhabdomyosarcoma andlympho- cluding primarysinonasalcarcinoma, lomatosis), aswellneoplasmsin- polyangitis (GPA, Wegener granu- ered, suchasgranulomatosiswith fl mucorymycosis andtuberculosis.In- including sino-orbitalaspergillosis, concerning forinfectiousetiologies tion, thedifferentialdiagnosiswas mation wasinitiated. lulitis withsubperiostealabscessfor- Clinical managementfororbitalcel- dial orbitandskullbasewasevident. Possible boneerosionoftheleftme- a subperiostealabscess(Figure3). the laminapapyracea,concerningfor tion withintheleftorbitadjacentto was noted,asanopacifi nus. Preseptalsofttissueswelling thickening oftherightmaxillarysi- the rightfrontalsinusandmucosal sinus, withpartialopacificationof ethmoid sinusesandleftsphenoid frontal sinus,leftmaxillary fi Imaging disclosedcompleteopaci- obtained withandwithoutcontrast. raphy ofthemidfaceandorbitswas orbital process,computedtomog- 72 the possibleboneerosiononleft. well assubperiostealopacification abuttingthemedialrectus, forleftorbital subperiostealabscess.Note concerning extensive nasal/sinuscavity diseasewith completeopacification ofleftethmoid, sinuses, sphenoidandmaxillary as Figure 3: MaxillofacialCTwithoutcontrast (softtissuewindows). Onecoronalandtwo axialsectionsdemonstrate Diagnosis, Workup andTreatment ammatory causeswerealsoconsid- cation oftheleftnasalcavity, left REVIEW Based ontheavailableinforma- Given theconcernforanevolving | ReviewofOphthalmology Resident CaseSeries ed collec- | September2016 by theOtolaryngologydepartment transnasal endoscopicsinussurgery ary sinusitis,promptingurgentleft a neoplasticprocesswithsecond- was concerningforaspergillosisor The presenceofbonyerosiononCT found tobewithinnormallimits. urinalysis andurinedrugscreen, plasmic antibodies,hemoglobin-A1c, virus antibody, anti-neutrophil cyto- cell count,humanimmunodefi obtained, includingcompleteblood rial orbitalcellulitis.Serologieswere lin/sulbactam forpresumedbacte- was startedonintravenousampicil- concern forinfection,ourpatient tion werealsoconsidered.Giventhe cocaine abusewithsecondaryinfec- ciency nucleoli index intumorcellswithprominent plasm demonstratingahighmitotic biopsies wereobtained. nasal cavity. Multiplenasalandsinus necrotic tissuewasnotedtofi purulent collections.Duringsurgery, to explorethesinusesanddrainany (NKTL) ofnasaltype. nodal naturalkiller/T-cell lymphoma strongly favoredadiagnosisofextra- immunohistochemical profiling AE3. Theclinicalpresentationand CD4, CD5,CD20,S100andAE1/ CD45 andCD56,negativefor CD2, cytoplasmicCD3,CD30, chemical stainingwaspositivefor Cytology revealedalargecellneo- (Figure 4).Immunohisto- prominent nucleoli. tumor cellswith high mitoticindex in cell neoplasmwitha demonstrating alarge and eosinstaining Figure 4: Hematoxylin ogy andradia- medical oncol- der thecareof disease. Un- with StageIE was diagnosed negative; he sy, whichwas marrow biop- including bone temic staging, underwent sys- current cyclo- started oncon- the patientwas tion oncology The patient ll the ll 8/26/16 3:02 PM Advertising

REVIEW Index

phosphamide, hydroxydaunorubicin, He has undergone annual medical AbbVie, Inc. 2-3, 4, 5, 6 vincristine and prednisone chemo- oncology follow-up with positron www.humirapro.com therapy as well as external beam ra- emission tomography scans yearly Akorn Consumer Health 31 diation therapy to both orbits, the for surveillance. He was noted to be Phone (800) 579-8327 sinonasal cavities and the skull base. disease free at his 11-year follow up. www.akornconsumerhealth.com Akorn Pharmaceuticals 45 Discussion Phone (800) 932-5676 www.akorn.com Extranodal NK/T-cell lymphoma, sis result in an infl ammatory response Allergan, Inc. 21, 76 nasal type, is a non-Hodgkin lym- in surrounding tissue, often making Phone (800) 347-4500 phoma composed of malignant natu- clinical distinction from orbital cel- 3,4,8 Bausch + Lomb 13, 14, 27, 28 ral killer cells in a majority of cases; lulitis challenging. The mainstays Phone (800) 323-0000 however, a cytotoxic T-cell phenotype of treatment have relied heavily on Fax (813) 975-7762 is also observed, leading the World high-dose EBRT and chemothera- Compulink 37 Health Organization to reclassify the peutic regimens, with further studies Phone (800) 456-4522 terminology in 2008.1 These malig- needed to confi rm the effi cacy of vari- www.compulinkadvantage.com nancies typically involve the nasal ous combinations.5 Of note, in con- Icare USA 49 Phone (888) 389-4022 cavity and or paranasal sinuses, with trast to other lymphomas, at present www.icare-usa.com intraorbital involvement being less no monoclonal antibody (biologic) Lombart Instruments 55 common and invariably secondary therapy is available for NKTL. Prog- Phone (800) 446-8092 spread from adjacent sinonasal dis- nosis was generally extremely poor in Fax (757) 855-1232 1,2 ease. Synonymous terms appear- the past (hence the term lethal mid- NovaBay Pharmaceuticals, Inc. 47 ing in the literature include lethal line granuloma). However, prognosis Phone (800) 890-0329 [email protected] midline granuloma, angiocentric T- is now variable, largely depending on www.avenova.com cell lymphoma, malignant midline initial stage at presentation, with fi ve- Ocular Therapeutix, Inc. 53 reticulosis, polymorphic reticulosis year overall survival ranging from 42 Phone (877) 628-8998 and angiocentric immunoproliferative percent to 64 percent in four recent www.ocutx.com 1,3 7 lesion. The latter terms describe studies. It is likely that our patient’s Omeros 11 the characteristic vascular damage successful long-term survival was due Phone (206) 676-5000 and prominent necrosis typically ob- to the combination of Stage IE dis- Fax (206) 676-5005 served with histological analysis, with ease and aggressive clinical manage- Perrigo Specialty Pharmaceuticals 17, 18 Phone (866) 634-9120 a resemblance to that seen in GPA. ment. qwww.perrigo.com NKTL is more prevalent in Asians, as Physician Recommended Nutriceuticals well as the Native American popula- The author would like to acknow- (PRN) 39 tions of Mexico, Central America and ledge Jurij Bilyk, MD, for his contri- www.prnomegahealth.com South America, and is more common butions and editing of this case report. Rhein Medical 9 in males than females.1,2,4 While little Phone (800) 637-4346 1. Swerdlow SH, Campo E, Harris NL. WHO classifi cation of Fax (727) 341-8123 is known about its etiology, there is a tumours of haematopoietic and lymphoid tissues. Lyon: IARC; strong association with the Epstein- 2008. S4OPTIK 23, 25 2. Woog JJ, Kim YD, Yeatts RP, et al. Natural killer/T-cell Phone (888) 224-6012 Barr Virus, almost always subtype A, lymphoma with ocular and adnexal involvement. Ophthalmology regardless of ethnic origin, suggest- 2006;113:1:140-7. Shire Ophthalmics 33, 34 3. Salam A, Saldana M, Zaman N, et. al. Orbital cellulitis www.shire.com ing a probable pathogenic role of the or lymphoma? A diagnostic challenge. J Laryn & Otol virus.5,6 In nearly all cases, neoplastic 2005;119:740–742 Sun Ophthalmics 75 4. Charton J, Witherspoon SR, Itani K, et. al. Natural killer/T-cell SunIsOnTheRise.com cells harbor clonal episomal EBV, and lymphoma masquerading as orbital cellulitis. Ophthal Plast Reconstr Surg 2008;24:2:143-5. Topcon Medical Systems 42-43 disease activity and prognosis have 5. Au WY. Current management of nasal NK/T-cell lymphoma. Phone (800) 223-1130 Oncology 2010;24:4:352-358 been shown to correlate with circulat- Fax (201) 599-5250 1,6,7 6. Zhang Y, Ohyashiki JH, Takaku T, et.al. Transcriptional profi ling ing EBV DNA titers. of Epstein-Barr virus (EBV) genes and host cellular genes in Clinically, patients may present nasal NK/T-cell lymphoma and chronic active EBV infection. Br J Varitronics 41 Cancer 2006;94:4:599–608. Phone (800) 345-1244 with nasal obstruction or congestion, 7. Huang Y, de Reynies A, de Leval L, et al. Gene expression Fax (610) 356-1222 as in this case, or with extensive mid- profi ling identifi es emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type. Blood. facial destruction. NKTL may spread 2010;115:1226–1237. This advertiser index is published as a convenience 8. Pine RR, Clark JD, Sokol JA. CD56 Negative Extranodal NK/T- and not as part of the advertising contract. Every care to adjacent structures, including the cell Lymphoma of the Orbit Mimicking Orbital Cellulitis. Orbit will be taken to index correctly. No allowance will be made for errors due to spelling, incorrect page number, orbit, and the rapid growth and necro- 2013;32:1:45–48. or failure to insert.

September 2016 | reviewofophthalmology.com | 73

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