 This talk is a follow up to a couple of questions that I had during my presentation during faculty day. I had mentioned entity that I referred to as a mantidine induced corneal endothelial toxicity and a couple of people had questions about it so I thought I'd get to it in a little bit more detail here. I'm going to start with the patient presentation. This is a patient I saw actually during the end of my residency at the Veterans Hospital in Milwaukee, Wisconsin. She was a 42 year old female with a history of Huntington's disease that presented kind of at the time with very nonspecific visual complaints and part of the challenge with her was that she was difficult to communicate with to a great extent. A lot of information came from her mother who did not spend a great deal of time with her. She was actually in a managed care facility. So over the months prior to her presentation she had been noticed to have increasing difficulty with her motor skills and these things were just attributed to progression of her movement disorder. Her mother thought that the problems were more related to her vision. She was actually having a lot more difficulty seeing her food was really the chief complaint that she came in with. Her past ocular history was significant only for mild myopia and a history of mild corneal abrasions that were secondary to self-induced trauma from uncontrolled movements. As I said her past medical history was significant for Huntington's Korea and had been diagnosed in 2003. She also had some depression, motion sickness and eczema. The motion sickness was related to some of the medications that she was taking. So she had a pretty extensive medication list here. She was taking everything from Tylenol to amantadine. So me having actually had previous experience with several patients that had amantadine induced corneal endothelial toxicity, this was the first thing that I thought of. She had actually started amantadine about six weeks prior and it had been prescribed to her to help control her involuntary movements. I'll talk a little bit about that in detail later on. The rest of her exam showed that her vision was pretty significantly affected. She was hand motions in both eyes, was not correctable to any better. While her visual fields were full we really couldn't do anything as far as refracting her any better. Her pressure showed that they were slightly low but I think some of that may be an artifact and we were only able to actually get a tonal pen pressure on her. And then her slit lamp exam was significant corneal edema with three to four plus decimates folds in both eyes. There's a little bit of surface irregularity but no forcing dye uptake or staining. The rest of her exam was pretty normal. So you can see these are photos that I took at the slit lamp camera at the VA. It was kind of difficult because she couldn't hold herself still for very long. But you can see significant corneal edema here with those prominent decimates folds. There was no inflammatory changes. There was no gutata significantly on this exam. And as I said the rest of her fundus was normal. And we were unable to obtain a paquemetry reading from an ultrasonic paquemeter. But just looking at her cornea it looked like it was greater than a thousand microns thick. So in thinking about a patient with corneal edema I just put this slide in for the benefit of the residents. We think of the primary things, one of the things we see most often is fuchs or any other endothelial disorder including posterior polymorphous or eridocornial endothelial syndromes. Other things to think about would it be inflammatory changes due to things like HSV. Other causes we see very frequently are iatrogenic from intraocular surgery. Those could include pseudophagic or aphagic bolus curatopathy. And there have been several toxic etiologies that have been identified. One is inadvertent benzoclonium chloride injection into the anterior chamber during intraocular surgery. And another is the use of chlorhexidine as a prep in place of betadine. If the concentration is too high or if it's not irrigated out of the eye it can cause significant toxicity including corneal edema. And then the last one is one we're going to kind of focus on today and that's amantadine. So after I had seen this patient, gotten the history and seen the medication list, this was the kind of, as I mentioned at the top of my list, there was no evidence of gutata in either eye, no family history of any kind of corneal endothelial dystrophy. And the patient, you know, temporarily the start of amantadine correlated well with the patient's corneal edema. So amantadine is also known by the trade name Symmetril. It was first introduced, approved by the FDA and marketed as a treatment for influenza. It's really fallen out of favor for that. I think that it's not really shown much efficacy for the treatment of influenza. Other uses though, it's among the neurology community, it's actually continued to increase an interest in its application to patients with movement disorders. Primarily it was introduced for patients with Parkinson's disease and used to treat Leva, Dopa-induced dyskinesias. But it's since been applied to other forms of movement disorders including Huntington's Korea and Tardythian dyskinesia, it's also been used to treat multiple sclerosis patients. The proposed mechanism of action for the antiviral properties is that it interferes with the viral protein M2 ion channel, which is responsible for uncoding the capsid. But more interesting for movement disorders, it's believed to act on the presynaptic membrane and enhances the release and inhibition of and re-uptake of dopamine. It also up-regulates post-synaptic D2 receptors, it has anti-muscarinic properties and it's anti-glutaminergic due to the non-competitive antagonism of NMDA receptors. One other thing that I came across is that it's also been studied recently in patients that have traumatic brain injury or spinal cord injury as a neuro-regenitive drug. There have been several reported side effects as far as ocular side effects including transient vision loss, hallucinations, ocular gyric crisis, medriasis, and then some well-reported corneal side effects including subepithelial opacities, superficial punctate caretopathy, and then epithelial and stromal edema. One of the first case reports for amantadine and corneal edema appeared in cornea in 1990 by Blanchard. It was a 64-year-old woman who had been on long-term treatment with amantadine for influenza-like syndrome and she presented with diffuse corneal edema in both eyes. She stopped the drug, was prescribed basically Miro drops, and had complete resolution after 10 days with no recurrence. Now, there have been several other case studies that have looked at amantadine. This was maybe one of the largest epidemiological studies that was done. French and Margot looked at the Veterans Administration database and tried to correlate the finding of corneal edema, Fuchs dystrophy, those two diagnoses with patients that had been prescribed amantadine at any point. This wasn't really very revealing. They found that 0.27% of the patients that were diagnosed with corneal edema or Fuchs dystrophy had been on amantadine. Pretty low incidence of corneal edema with this medication, at least according to this study, I think subsequently several people had pointed out some potential flaws with the design, but still a lot of people think that this is a fairly rare occurrence. This is an interesting study because the authors in this paper actually looked at some of the histopathology of the patients that had what was believed to be amantadine induced endothelial toxicity. They had three patients that presented with various histories. One had a history of MS and had a previous corneal transplant. Another patient had MS and presented with a complaint of blurry vision. Then the third patient had been on amantadine with their history of bipolar disorder, which there's also been a couple of case reports. I forget to mention that amantadine used as a mood stabilizer as well. All these patients had significant corneal edema marked absence of gutata and otherwise unremarkable exams. In two of the three cases, the cessation of amantadine actually quickly resolved the corneal edema with no recurrence. The third patient actually had irreversible corneal edema and required a repeat corneal transplant. The corneal button that was obtained from that procedure was examined. Significant exam findings on that in the histopathology were pleomorphism and polymega thism of the endothelial cells. There was widespread denuding of the endothelial cell layer and actually retraction and lifting of the endothelium from the underlying decimates membrane. Another significant finding was the posterior collagenous layer was bared by the retraction of the endothelial processes. They actually provided a couple of nice electron micrographs that show that this is kind of that endothelial denuding and retraction of the endothelial processes on this slide. This shows the exposure of the posterior collagenous layer and the retraction of the endothelial cell processes. There have been a couple of papers that have looked at irreversible amantadine toxicity and this one is not actually one of them. This is actually a patient that was originally not recognized to have amantadine-induced corneal endothelial toxicity. She presented with a non-glutate corneal edema and underwent decimates stripping, automated endothelial care deplasty. This patient actually had recurrence and I was actually involved in the care of this patient as well. This patient had recurrence of corneal edema after the decimates stripping was performed and subsequently was found after a little bit more extensive look at her medical history that she was placed on amantadine. She was a patient that had, I believe it was schizophrenia and she had had tardive dyskinesia as a result of her anti-psychotic medications and that's the reason that she was placed on amantadine. It wasn't until the recurrence of corneal edema in the transplanted eye that this was discovered that amantadine was stopped. Unfortunately, the corneal edema did not improve. A repeat desec was performed and at that time vision did improve and corneal edema did resolve. So just to summarize, amantadine induced corneal endothelial toxicity, the mechanism is not completely elucidated. It's believed to have a direct toxic effect on endothelial cells. As I said, based on the VA report, it looks like the incidence is very low but a lot of authors that have written on this subject have questioned whether or not it's underreported. We don't know in those patients that have presented with non-gutate corneal endothelial dysfunction whether or not they just had transplants done and if the amantadine was stopped subsequently and the edema didn't recur whether or not this could have been missed this diagnosis. There's a little bit of argument among a couple of authors that I saw in some of the journals that said that in most cases this should be a reversible phenomenon but with cessation of the drug but there have been several cases reported of irreversible corneal endothelial edema that have required transplantation. And this patient, I don't have the endothelial cell counts, I couldn't find them, I have them somewhere in boxes in my apartment but I believe we got endothelial cell counts on this patient, my patient from the VA and it showed a reduced endothelial cell density in both eyes. So just as a note in the presence of non-gutate corneal endothelial edema it should prompt investigation into adverse effects from systemic medication and particularly amantadine. Any questions? This is actually something that I tried to set up at the VA before I left but the VA IRB is a little bit more extensive than I expected it to be. There's actually one report that I didn't mention here that kind of answers a little part of that at least I think and there have been a couple of pediatric case reports in children who were put on amantadine for influenza who developed diffuse corneal edema. We're talking successful measurement by pechimetry of a thousand microns and I think there are at least two cases that I found they responded very quickly to withdrawing the drug and it seems to be dose dependent. Most of the cases that I encountered report a very close temporal association within weeks of starting the drug on set of corneal edema. There have been a couple of case reports that show that it may take months and some patients for the corneal edema to present significantly. And that's what I tried to set up at the VA. Any other questions or comments?