Rebuttal to my 2/15 Post

Facts quite often, I fear to confess, like lawyers, put me to sleep at noon. Not theories, however. Theories are invigorating and tonic. Give me an ounce of fact and I will produce you a ton of theory by tea this afternoon. That is, after all, my job. -Ray Bradbury, From the foreward to "Mars and the Mind of Man"

In my post from 2/15, I present two case studies and one larger scale study to make a theoretical case for the use of acetazolamide and RP, independent of CME. I am by no means in a position to advise anyone to take anything. I am simply presenting information I find interesting as well as connections that intrigue me.

An anonymous researcher replied to me via email. I am including his response below. It gives another perspective. He was kind enough to provide his input. If you have the time to read the full text of the University of London acetazolamide case study, you will find that the subject's visual field expanded substantially. The authors maintain this only happened after several months at a dose of 1000 mg. In the larger study the anonymous researcher comments on, the dosing was cut in half and the duration in a third, if memory serves. So, it was not really a valid replication of the case study.

Researchers do not find one case of an RPer making substantial gains in visual field of much interest. I, as a patient, do find it interesting. I also believe, when blindness is the alternative, RPers should have the option of trying experimental therapies with informed consent. RPers should not have to be in a clinical trial to have access to prescription drugs or other readily available therapies that could, possibly, help them. I do not believe we need to be babysat. RPers can understand risk/ benefit analysis and come to their own conclusions, with information on risks and management of those risks. Physicians need to be partners with patients, not gatekeepers.

For argument's sake, say I had some experimental therapies. Even with a positive change in my ERG, I am convinced I could walk in to the university near my house, get an ERG that shows normal vision from my flat line now and no one would raise an eyebrow. They would say, "Hmmm....that is unusual. She must not have had RP. It must have been something else." They would say this even if I presented in-depth information on the protocol I followed, backing it up with published research. My retinal specialist is a proactive guy, maybe he would write up a case study. When people read it they would say, "But she did so many things. How can we even attempt to make a causal connection?"

As RPers interested in actually trying to treat this thing, this is the mentality we face. Do not misunderstand, research is vitally important. But, do not count on these people to make any kind of common sense connections. Until something is effective in very large scale studies, no one cares.

Below is the research scientist's response. It was very kind of him to send this information. I appreciate his involvement and interest.

I read portions of the Friday, February 15 blog entry . In your point #2 you say, "There have been studies that have shown acetazolamide improves visual function in those who have RP but no CME." ... but the study that you cited does not say that at all. I think you have misunderstood the results. The authors, two of whom I know personally, merely reported the results that three patients showed improvement in their visual field -- an improvement that was not reproduced in the crossover study. In quantifying these visual field changes, they used the word "significant" which in conversational English almost always means "huge", but in research it means “unlikely to be explained by chance” (more on that later). But no matter how you define the term, these "significant improvements" in three patients would never cause a medical researcher to as much as raise an eyebrow or utter the sound “hmmmm” -- for a variety of reasons. Pilot studies by definition lack the statistical power of the gold standard placebo-controlled, double-blind large study, and therefore the goal of the pilot study can never be more ambitious than to suggest a interesting trend that might be worthy of further investigation (and the health risks and enormous expense of further investigation). It is a mistake of the highest order to suggest that the results of this pilot study demonstrate causation as your statement implies. Again, by definition, no one in the research community would ever interpret the results of any pilot study as causing anything. And especially since, as in this case, the numerically small positive observations were:
a) derived from subjective psychophysical rather than objective electrophysiologic measurements.
b) not reproduced in the crossover study Regarding A: An automated threshold-related 60° visual field is a brutally boring and stressful test (as I'm sure you probably know). Improvement or decline in performance after repeated trials can easily be attributed to "the learning effect" or fatigue respectively. In our glaucoma practice (where visual fields were, until recently, widely used), significance is usually reserved for changes observed in comparison to an average of three baseline measurements -- and even then, it is regarded with suspicion if the patient has false positive responses (suggesting anxiety or eagerness) and/or false negative responses (suggesting boredom, fatigue, Munchausen syndrome or malingering ). This "catch trial invalidation" can be factored out if the visual field is performed manually (Goldmann perimetry) by the same skilled perimetrist on each successive patient-visit. But these kind of visual fields are rarely done nowadays because it is slow, personnel-intensive and therefore quite expensive in terms of resources. For these reasons the visual field is seldom (or should I go out on a limb and say never) taken by itself to make patient management decisions. There are just too many opportunities to be wrong in any single interpretation. But fortunately, in glaucoma management at least, new, more sensitive and more objective technologies have emerged that will make the visual field a medical anachronism in the next few years. However, patients will still get serial visual fields as long as the test is still being paid for by the insurance companies, in spite of the fact that glaucoma docs rely upon them less and less.Regarding B:I just flipped a coin 13 times and got ThhTThhhThhhT = 8 Heads + 5 Tails. There are also two runs of three heads in a row. What should I make of this apparent bias towards heads? If I didn't tell you that I was flipping a coin, but instead I just simply showed you some results where there were 8 positive outcomes and 5 ambiguous or negative outcomes, you might be justified in thinking that "something is going on here" that is worthy of further investigation.After 13 more flips I get: TTThhhhThhhhT = a repeat of 8 positive outcomes + 5 negative or ambiguous outcomes! Even more exciting is the fact that in this series there are two runs of four heads in a row! We could be seduced into thinking that we are definitely on to something in our little "pilot study."Now I'm going to put my 13 pennies in a shot glass, shake it up and then dump it on the table. I get: 5 positive outcomes + 8 negative or ambiguous outcomes. Repeating the shot last method yields: 6 positive outcomes + 7 negative or ambiguous outcomes. If I repeat these trials enough times, regardless of the method, I will eventually, according to statistical theory, achieve the results predicted by the known mathematical probability, which is of course 0.5 -- or 6.5 Heads + 6.5 Tails. But if we do not know the probability of any event occurring, which of course is the case in every study (otherwise it would not be a study), then much larger numbers are needed to detect a "significant" event and then to announce that such an event was statistically unlikely to have occurred as a result of chance alone.So in summary, the three solitary "positive" findings would be more interesting if they were objective measurements (i.e. electrophysiologic) and if they were reproducible. With more concrete objective data, the authors might get funding and FDA approval for an even larger (but still pilot) study -- say, with 20 or 30 people. But because no reproducible, unarguably positive result was found, this paper serves as a warning to other researchers who discover it during their literature review "don't travel down this particular rabbit-hole." The NIH is never going to fund a full blown study using such weak data, and the FDA would object to a large study for similar reasons -- authorizing the "off label" use of a drug that can produce significant side effects on the basis of a one-time observation of 3 visual field improvements -- which could not be reproduced even within the same pilot study. The in-vitro studies that you cited offer a biochemical mechanism of action which no doubt fueled, and might continue to fuel, occasional research interest. But the lack of hard evidence means that medical research is a long long long long way away from suggesting any of the carbonic anhydrase inhibitors as a treatment for RP, and any physician who prescribes it to a patient who does not have a proven case of glaucoma is taking a huge medical-legal risk. The statement at the bottom of one of the papers you cited "These experiments suggest a promising approach to treatment of RP17 that might delay the onset or possibly prevent this autosomal dominant form of RP"... is pretty standard "research speak" for .... "I want my paper to be cited in more treatment-related journals." It is the, "how is this research relevant" statement that nearly every research paper optimistically and triumphantly makes in closing, and it should not be taken as if a new cure has been discovered. However, the presumed strategy of getting it cited in journals other than biochemical abstracts didn't work, as to date it has been cited only by four other papers -- all of them biochemical works, and none of those were follow-up studies pertaining to RP.You probably regard the response you're getting from U.S. doctors as somewhat gutless, uncaring and maybe even inhumane. But demonstrating a promising in-vitro mechanism is light years away from prescribing it as a therapy -- at least in the United States. A colleague sent me an e-mail suggesting that I watch 60 minutes tonight for a segment on FDA surveillance gone wrong. I got busy and missed it. Did you watch it? I'll try to find the video or transcript online later but the very existence of such a story supports the "damned if you do and damned if you don't" criticism that no doubt influences the FDA's usual abundance of caution when it comes to authorizing new treatments.