 Good morning everybody, we're going to get started with Grand Rounds and today we have a presentation from our senior Retina Fellows by the name of Karine Borky. She's moving on next year to Ashland, Oregon, head to prior practice. Perfect pronunciation. So I'm going to talk today about the ocular effects of cigarette smoking and this doesn't cover everything, but I tried to give a little sampling just to appease the masses. We hear from different subspecialties, but certainly any comments are welcome either during or after or anybody, you know, speak up if you have anything to say, but smoking to me, it sounds like a personal test, but it really only becomes obvious when you walk into that exam room that's like overwhelmingly filled with secondhand smoke, you know, on their clothes or something and like, wow, people still smoke out there, which obviously we know, but it just, I guess at least for me it doesn't come up in most conversations with patients, but I guess my point today is maybe it should come up more than it does. As far as who is still smoking out there, actually a lot of people still are considering themselves chronic or smoking on a regular basis. The Center for Disease Control in 2009, approximately 43.4 million Americans or 19.8% of the population are smokers and Nevada is number one or Nevada, as people say out here, at 31.5%. Utah is in last place, which is something to be thankful for, at 13.9%. Women are closing the gap on men over the past several decades, approximately 22% of women 18 years or older are smokers and at least 1.5 million adolescent girls in the U.S. smoke cigarettes. I don't know what kind of percentage that is, but that still sounds like a lot to me. The socioeconomic status does make a difference, 16 plus years of education, there was a rate of 11.3% for smokers versus 9 to 11 years, 36.8%. And there was a national health objective of having a rate of smoking of 12% or less, which was not reached by 2010. So we know about severe systemic effects of smoking, there's cardiovascular, respiratory and malignant diseases directly affected by smoking, 85% of chronic obstructive pulmonary disease cases and approximately 85% of lung cancer cases are attributed directly from smoking in the U.S. Smoking is also associated with bladder, breast and colon cancer and there's a well established association between smoking and dyslipidemia, which is of course too much of the bad and not enough of the good cholesterol. And atherosclerotic and thrombotic effects on ocular capillaries induce changes to both the lens in the retina and possibly to other problems with the eye, but as you can imagine ocular capillaries might be more vulnerable, more susceptible to these atherosclerotic and thrombotic changes due to smoking just because they're quite small and just potentially more susceptible. Smoking enhances the formation of free radicals, which I'll talk about in a second for anyone that needs a little review on what free radicals are, and it does decrease the antioxidants in the blood, aqueous humor and ocular tissue and we know antioxidants are a good thing, which we'll go over more of that as well. So free radicals are molecules with one or more non-perit electrons in their outer orbit, which makes them just unstable and active, and this perpetuates the creation of more free radicals because they kind of steal electrons from someone else and then that makes that next person or next molecule unstable because they're missing an electron and so on and so forth, and so there's a chain reaction leading to cell damage and apoptosis. So smoking has found to be an independent risk factor in several ocular diseases, and this is our lovely old Caucasian woman, Smoker, who may have any of the above. Graves disease, cataract, glaucoma is a little bit more of a controversial topic of whether it has a direct association with smoking or not. Cystoid macular edema and uveitis in particular and age-related macular degeneration, both the dry and the wet kinds, have smoking as a direct, independent risk factor. I shouldn't say direct, but an independent risk factor. So Graves disease, as we've all seen, it can be not only, you know, have an effect on someone's appearance and maybe self-confidence and all that, but also potentially affect their vision in a very devastating way. Not only was surface disease, but maybe a compressive optic neuropathy. This is the same woman, I'm not quite sure of the ages, these are compliments of Dr. Patel, but obviously there's a marked difference in her appearance based on the proptosis, lid retraction, just the characteristic signs of Graves disease, which is an autoimmune inflammatory disorder. And there is a lot of evidence linking smoking as a risk factor for Graves disease. More smokers than non-smokers develop Graves. Graves, also known as thyroid-associated orbitopathy and a lot of other names for it. But the amount of smoking correlates with the severity of disease and the response to treatment. And this was supported in a case control study of 400 patients, where smoking significantly increases the risk of Graves with hyperthyroidism after adjusting for age and gender, with an odds ratio of 6.5. And smokers also had less of a therapeutic outcome from orbital radiotherapy, which might be performed in patients that are refractory to steroid treatment and have compressive optic neuropathy and for another reason don't have decompression surgery. But so it not only gives you a greater risk of having Graves, but also it's harder to treat. You might have worse Graves and it's harder to treat. So as I mentioned Graves is an autoimmune inflammatory disorder and smoking is thought to compromise the immune system further enhancing the effects of the autoimmune process. Lowers T suppressor cell activity, which lowers the immune surveillance because it interferes with T helper cells, which are targeted against thyroid and orbital antigens. Also there can be an increased release of a thyroid auto antigen at cross-rex with eye muscle, decreasing elasticity of the muscle. And in rats, I thought this was interesting, an anthracene derivative found in cigarette smoke, 3-methylcholanthrene induced autoimmune thyroiditis in those rats. So there's been found to be a dose response pattern with smoking, so the more smoking the more effect. Superoxide radicals induce the cell proliferation of orbital fibroblasts in Graves patients. And orbital fibroblasts are a big part of the pathology in Graves disease. These fibroblasts to create glycosaminoglycans into the extracellular matrix and up-regulation of these glycosaminoglycans with or without smoking is elemental to the pathology of this orbitopathy. And there's an increased orbital volume from the secretion of the glycosaminoglycans of the fat in the muscle and obviously taking up that orbital volume that does contribute to the amount of proptosis and contributes to the disease process. So there's a dose response pattern found in studies where the more smoking, the more proliferation of these fibroblasts, the more glycosaminoglycans in the worst of the disease process, maybe. And these are images, this one of course is a coronal cut and it's showing the enlargement of the muscles. So with Graves disease you have the spared tendons but enlarged muscles. Here is showing more of the proptosis, hopefully you can see that because I don't have a list of the, you can see the proptosis which is characteristic or exothalamus which is characteristic of Graves disease. And these are some pictures, again compliments of Dr. Patel. These are smokers with Graves disease. You can see their characteristic appearance with the stare and the bulging of their eyes. And I thought even more impressive, these people are now non-smokers. This woman here, of course it's the same person but she has had orbital decompression surgery. And then the gentleman over there, obviously that's, I mean that's a marked abnormality of his appearance and I'm sure that was very, you know, difficult for him to deal with. But it did contribute, I'm assuming, to their cessation of smoking which is a positive thing. Moving on to cataracts. These are of course pictures of, on the left, a nuclear sporadic cataract and in the right, posterosum capsular cataract. And cataract is the leading cause of blindness worldwide. Fortunately it is reversible with surgery. But smoking or smokeless tobacco is the most significant avoidable risk factor for cataract development. And in the blue mountain eye study just as an example, there was a higher prevalence of nuclear sporadic and posterosum capsular cataracts among smokers. And the highest risk level was greater than 20 cigarettes per day. Also good news, not only is, you know, of course cataract reversible with surgery, but there is evidence that quitting does help as well. But evidence showed that it took approximately 10 years to notice signs of regression of the lens damage that was related to the smoking. So that takes quite a long time. I'm sure most people, if able, would have surgery by then, but that does imply that there is a motivation to quit, you know, for, more for people that don't have the access to surgery, that it can help with lens damage. There is some reversibility to it. So part of the, so a hypothesis for why there are these lens changes relates to the decreased amount of antioxidants, and that induces oxidative stress, that cascade of reactive oxidation species, those superoxide radicals. And also the heavy metals in tobacco smoke may be directly related to lens degradation. There's cadmium-led and copper in tobacco smoke, and they've been found to accumulate in the lens at toxic levels. And a recent study showed the high concentration of lens cadmium may be directly related to the destruction of the human lens epithelial cells. So glaucoma, again this is more controversial whether there's a direct association, but this is just an example of a glaucoma in this optic nerve. And there is, there was a review of the literature in 2008 that revealed that most of the studies revealing any sort of association between smoking and opening of glaucoma were actually very poorly done and had, you know, very small numbers or just weren't done in a very controlled manner. So that just didn't give any great evidence that there was a causal association. But the issue is certainly not dead. I certainly found a lot of articles out there trying to look into it further. But in 2009, the issue of apoptosis was addressed because trabecular meshwork cells and retinal ganglion cells found to die by apoptosis in primary open-angle glaucoma. And so they were looking at two apoptotic proteins, the PARP1 and CASP3 and IL6, which is an inflammatory marker. And in women's subjects in this study, women's subjects who were smokers, all three of these were significantly higher than in ex or non smokers. So potentially contributing to the apoptotic pattern of degeneration and glaucoma. But in 2011, another study showed that there actually was no statistically significant effect on socioeconomic status smoking or alcohol intake. So still there's no real compelling evidence that it's an independent risk factor in glaucoma. But it's certainly an issue that I'm sure we'll be studying further. Moving on to the retina. Cystoid macular edema. This is just a picture on the right is an OCT on the left. But it's just showing the marked cystoid changes in the macula. And specifically with uveitis, well I'll talk about this first. So CME and uveitis, it's the major cause of visual loss, especially with parisplanitis, but it's the main cause of visual loss in all uveitis, if it's present, of course. And it's most commonly seen in parisplanitis, birdshot, retinocoriditis, and retinal vasculitis. And in parisplanitis, 10% develop chronic refractory cystoid macular edema. And it's secondary to active intraocular inflammation, but it may persist after resolution of the inflammation. And there are treatment methods for directed towards the cystoid macular edema, aside from treating the intraocular inflammation. And those include subtenons, canolone, intravitrile, triacense, or oral acetazole in mind has been shown to be effective. But it can be difficult to treat. And in smokers, it can be more prevalent. So there's an odds ratio of smoker versus nonsmoker of even having ocular inflammation. So more smokers have ocular inflammation across all subtypes, anterior, intermediate uveitis, posterior, and pan-uveitis. And then with CME, there's an even greater association of smoking and uveitis, with the two bullets there, the pan-uveitis and intermediate uveitis. If there's CME present, there's a stronger association between smoking and having the uveitis. Age-related macular degeneration, one of the leading causes of visual problems worldwide, but it is the leading cause of severe central visual acuity loss in one or both eyes, and people greater than 50, most are dry, a smaller percentage are wet. There are normal ageing changes that occur in the retina, but there are distinct characteristics of age-related macular degeneration. This is showing drusen, which is consistent with the thickening of the inner aspect of Brooks membrane. These would be characteristic of large drusen. And then geographic atrophy, where you can see the crudal vessels underneath. There's loss of the retinal pigment epithelial layer, and this is an advanced form of dry macular degeneration. And this is a crudal neovascularization in wet ARMD. So there's proliferation of vessels off the coriocapolaris that break through the outer aspect of Brooks membrane and leak fluid or blood under the retina or under the RPE, and can even break into the vitreous, actually. So then you might not even know what you're dealing with initially. So the age-related eye disease study did show compelling evidence for the importance of antioxidants, vitamin C, Zinc, beta-carotene is no longer recommended for smokers, but it did show 25% reduction of risk for progression to advanced macular degeneration and a 19% risk reduction in rates of moderate vision loss by five years. And then AREDS-2 is looking at further supplementation with lutein, zeaxanthin, and fish oils. So this showed the importance of antioxidants with ARMD, so it's not surprising that smoking, decreasing antioxidants in the blood and in the ocular tissue would have a detrimental effect with AMD. So this is a very scientific graph on the right. I, like I said, too scale and there's no axis on y-axis or anything, but just thought it might grab your attention that smoking is thought to increase your risk for progression of macular degeneration. So there are independent risk factors that have been proven for age-related macular degeneration, age, family history, hyperopia, light, iris color, hypertension, hypercholesterolemia, female gender, cardiovascular disease, and cigarette smoking. So cigarette smoking is the strongest environmental risk factor for all forms of ARMD. And vitamins E, C, and beta-carotene, there's a highly significant reduction in smokers when compared with non-smokers. And in regards to wet AMD specifically, there's a dose-related association of smoking and its effect on CNV. And the larger amount smoked was statistically significantly associated with the incidence of wet AMD with an odds ratio of 1.55 and even stronger with the incidence of geographic atrophy of 1.82. And I thought another interesting little animal model was that mice administered nicotine to mimic the serum levels of nicotine and chronic smokers had an increase in size in vascularity of CNV that developed. And this effect was immediately blocked by subconjunctival injection of hexamethonium, which is a nicotinic receptor antagonist. And there are, of course, genetic variants that are found to be associated with an increased risk of AMD. And the two at the bottom there, HTRA and LOC387715, which has been more of a laboratory, those two together may explain 75% of the genetic risk of AMD. But of course, complement factor H has been shown to be contributory as well with the allele variants encoding the alternate complement pathway. So just these genetic findings combined with smoking were evaluated in a recent study and there were risks associated with each of them independently with smoking at 20%, the LOC genetic variant at 36% and the complement factor H gene at 43%. But together they explained 61% of the population attributable risk of AMD. And so this is showing how genetic susceptibility and an environmental risk factor, which can be eliminated, such as cigarette smoking, yields a significantly higher risk of AMD than either factor alone. So treatment for AMD certainly includes smoking cessation. Can we go over that with everybody that's a new patient? Because it worsens disease, it makes it harder to prevent progression. And of course the other things are UV protection, a healthy diet including green leafy vegetables, the supplements based on the AREDS trial, and of course with wet AMD, there's anti-vegetable treatments and still PDT is used. So if you want to address smoking cessation with someone that has, you know, you're particularly concerned, what's recommended by AMA is that you just try to base whether they are still smoking and do they have any aspirations to quit smoking. Because if they do, they kind of have already reached another level where maybe at their next visit they'll be more motivated and just asking them about it and reminding them about it has proven to help. Get them to the point of considering quitting. That doesn't get them to quit necessarily right off the bat, but it gets them closer to the consideration of quitting. And that's important for their longevity. It reduces MIs and stroke risk. It slows the progression of COPD. It reduces risk of lung and other cancers. Increases their life expectancy. And it's of course also beneficial with the eye diseases that we're probably concerned about. And apart from 70% of smokers, they have other issues that they're dealing with or they just see a physician annually for other reasons, but they have many opportunities to discuss this with their primary care provider. So even if it's brought up in an ophthalmology setting and then they go to their primary care provider, that provider can deal with the majority of the issues and the management of it. But just bringing it up as an issue might be helpful so that they think to bring it up to their primary care provider in case he or she doesn't bring it up to them. Counseling and pharmacotherapy combined achieves the highest quit rates. And pharmacotherapy combined. So a combination of these two FDA approved treatments, nicotine replacement therapy and bupropion or Zyban, together in combination have been shown to be more effective than either one alone, along with counseling. There's also things like hypnosis and other behavioral modification techniques, but the nicotine replacement therapy, there's the patch gum, there's other things. I can't remember off the top of my head, but there's plenty of options out there for them to try. Just acknowledging mainly just the retina team and then Jim Gilman gave me some of those photographs and Dr. Patel did as well. This is a partial list of references that got kind of long. And just before I take any questions, I was going to show you guys, maybe, maybe not. I was going to show you where I'm moving to. So a little sampling of photos, but I'm going to Oregon for private practice position. The middle picture is kind of the overview of the town with the mountains in the background. Looks very picturesque. And then the top left, there is a ski resort. Don't worry, it's Mount Ashland. It's kind of a baby compared to the Wasatch, but that's okay. And then there's a lot of rivers. The top right corner is the Rogue River, but there's a lot of big rapids too. But a lot of rivers in the area, it's in the Rogue River Valley. And then the Siski Mountain Range. I think I'm saying that right. And the bottom left is the Oregon Coast, Southwest Oregon Coast, which is about an hour away. And there's a teeny map at the bottom here that just shows that it's right over the California border. And then there's just a mountain biking trail. There's a lot of mountain biking there too. Questions, thoughts, questions, concerns? Yes, sir. It has declined in addiction potential.