 A patient came in, you know, to the essential triage, which is the intern over at the VA, saying he couldn't read his computer screen anymore. He was only 42, and he had had a history of uncontrolled diabetes for like 10 years. His A1C was 10.4, and he'd reported just blurry vision for a week. He had just decided to start treating his diabetes. He'd been on Metformin, but he'd stopped it. And then a couple months ago, he was started on insulin. He had no other history, and this was his visual acuity. And these were his funds photos. You can see, you know, multiple areas of flame-shaped hemorrhages, dot-block hemorrhages, exudate cotton wool spots, and tremendous macular edema, which you can see here on OCT. And he was just very frustrated because he decided to make a life change, get his diabetes under control, and then this happens. On fluorescein, you can see, you know, areas of hyperfluorescence and leakage, and the blocking areas from the hemorrhage. So, you know, obviously he needed treatment. And part of the difficulty was just helping him kind of cope with this debilitating vision, you know, down to 2400 kind of vision. And I became interested in this topic where, and it seemed like it would repeat itself multiple times where patients would start therapy to get their out-of-control diabetes back under control and they worsen all of a sudden. And the terminology had been coined by the diabetes control trial called early worsening, and they've published several things, and there's been several other publications that have discussed this common finding. In the DCC trial, they had two groups. They had this intensive treatment group that would get three or more daily injections of insulin or they were on a pump, and you had this conventional treatment group which would get the one to two daily injections of insulin. And it was shown that the intensive group had better outcomes as far as diabetic retinopathy and other microvascular complications of diabetes. But they also showed an odds ratio of 2.98 for a three-step worsening of diabetic retinopathy in the intensive group early on at the six-month and 12-month time points. And here's the table from that study. So here's that odds ratio that I just quoted you. In the intensive group versus the conventional group of a three-step, you know, 15-letter worsening since treatment, both at six months and at 12 months, you still saw kind of that trend. And if they looked at other ways to look at cotton wool spots or Irma, you know, that same trend continued where the intensive group would worsen early on. And I know it's a busy slide. I don't want to go over the rest of this, but that was the main point from this table. I'll look over some of this other stuff in a little bit. The baseline factors, you know, when they went and looked at which patients were doing worse than others, they found an interesting trend here. If you looked at screening A1C, so the A1C at the time of enrollment where they started either conventional or intensive treatment, there was, the early worsening was much worse in the, you know, with an odds ratio of 3.4 in the patients that had A1C over 8.8, you know, up here in the really high patients. Whereas the ones that weren't too bad off to begin with didn't show this early worsening. Okay? So that's all I wanted to show from that table. So subsequently they went back and looked, and they looked at four years out and to see whether the patients that had the early worsening continued to be worse. And they found that first off, intensive treatment overall had better outcomes even if the patients had this early worsening. So it wasn't that intensive treatment inherently is bad. It's just that these, you know, it's just they're going to be worse in the beginning and eventually get better. However, if you have early worsening, whether you're in the intensive or the conventional treatment group, so it didn't matter whether you were, you know, getting your A1C down lower, they overall had a worse prognosis than if you didn't have early worsening. So from that, another study came out which they showed this interesting table here. So it's kind of hard to figure this out. But the triangle lines or the ones on the intensive treatment in the circle or the square or the cube, I guess you'd call it, were unconventional. And these are the percent with the early worsening. And interestingly enough, the patients that both had the worse A1C to begin with were out here with a high percentage of both the intensive and conventional. But also if they reduced their A1C significantly at the six months, so you compared the intake A1C and the six month A1C, that seemed to play a role also. So there had subsequently come out with some studies that showed that lowering of the A1C at 0.3% per month, you didn't get an early worsening. So if you kind of brought them down slow, but if you were more than 0.4% per month, you did get it. So it's kind of like the triathlon bike race portion of the triathlon. You don't want to go too fast, because if you do go too fast, then you don't have enough left to do the run. So you got to hold back a little bit. And the recommendations at this point, let me skip that for a second, is to lower the A1C at about a rate of 0.4% per month. Now, whether that's really hard or not for a primary care physician to do, I'm not sure. I imagine it's kind of tough for them to gradually bring the A1C down. But it's important to maybe discuss that with them as you get these referrals for a newly controlled diabetic, and they have baseline retinopathy, and their A1C is greater than eight, to mention that in your referral letter or your dictation letter back to the primary care doctor. And I think it's also discussed with the patient the possibility of this early worsening. Or if they come in with early worsening, be kind of like my daughter here, who's the cheerleader for the patient who just doesn't really care or is just not excited about what's going on. And it's important also they recommend that you follow these patients a little more closely early on. Even if they don't have treatable diabetic retinopathy, at the time of presentation they're likely to develop it if they meet these criteria where they're over A1Cs and they're starting this heavy regimen of insulin. And our patient, he didn't do real well. He did get triessence on the day of presentation. And then in the other eye, you know, a couple of weeks later, then he came back for laser treatment, for focal treatment. He ended up eventually developing a vitreous hemorrhage. He needed PRP, and I want to say he's had a vitrectomy in one eye and the other. So he's done poorly, and his vision hasn't really come back. So he kind of fit that mold where the early worsening patients tend to do worse long-term. Any questions or comments from the faculty of retinopathy? They defined early worsening as vision, three-step worsening, you know, on the ETDRS vision charts. But they also looked at treatable diabetic retinopathy where it's all some come to the point where you need to do laser or something like that. And that also had early, they had that early worsening characteristic. It is mainly macular edema, that's right. Yeah, and they've done studies to see whether focal laser helps with it, and it does help, you know, obviously, but they don't respond as well as other patients that show up with macular edema that aren't part of this early worsening. I know the Accord study, you know, they stopped early because of the cardiac complications, but they had a group, the Accord study took patients and they kept their A1C under six, and then they had another group that kept them between seven and eight. And they found some, maybe some benefit to that for diabetic retinopathy, but not a lot. But they didn't look specifically yet at early. You know, they think the pathophys is this mismatch between IGF-1 levels, the soluble growth factor and the receptors. And having someone with these high chronic sugar levels, your receptor levels, you know, chronically get changed to adapt to that environment. But then when you get this, the patient under immediate control, the soluble levels of IGF-1 change, and then the receptor levels haven't yet caught up to that change. And that mismatch of having that too much, I think it's too high a growth factor with too low receptors, or maybe it's the other way around, that seems to be, so I don't see why it wouldn't cause other, you know, microvascular complications like that. Thanks, yeah.