Dr. Norman Radtke is doing RPE transplantation again. When I researched this procedure three years ago, he and his team were transplanting one sheet of fetal retinal pigment epithelial cells (RPE) in to the diseased retinas of people with RP and ARMD. He is now doing transplants with two sheets of cells, both neural and RPE cells. He has some recent case study data on his site.
If you go to the “clinical trials” section of this informative website, you will find information on the trial. He also has a section entitled “outside trials” as well as “trial bulletins”. Both are excellent resources for keeping up with the latest in retinal research, regardless of who is funding it. The “bulletins” section is one I find particularly notable.
http://www.rvrc.com/_drradtke.cfm
I did find some published work by Dr. Radtke on this procedure.
This article was published in 2004, and reflects the results when transplanting one sheet of fetal RPE cells.
http://www.ncbi.nlm.nih.gov/pubmed/15302656?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
Information from 2002:
http://www.ncbi.nlm.nih.gov/pubmed/11931789?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
From 1999:
http://lib.bioinfo.pl/meid:112531
A Swedish rabbit study on "full thickness implant", which I believe may be both the RPE and neural retina layers.
http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowFulltext&ArtikelNr=27472&Ausgabe=226339&ProduktNr=224269
Swedish pigs:
http://www.ncbi.nlm.nih.gov/pubmed/17072635?ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
An 2002 overview of retinal transplantation:
http://www.djo.harvard.edu/site.php?url=/physicians/oa/379
I keep an eye on Steve Wynn, Las Vegas casino developer and gazillionaire, since he has RP and is one of the wealthiest people on the planet. In the blogosphere, there are numerous references to a "government approved experimental eye surgery" he had done in May of 2007 at Johns Hopkins. So, I tried to find any trials at Wilmer (Johns Hopkins) that are recruiting RP patients to see if I could make an educated guess as to which procedure he had done. I did not have much success. But, I will keep searching. According to the articles in the blogosphere (always suspect), he disclosed this surgery plan to his dealers on the eve of a union vote. They still unionized, but the information was made public. If you believe what you read, anyway.
Obviously, there are numerous ethical concerns when using fetal retinal tissue from aborted babies. Someone, I believe it may have been Mark Twain, stated something along the lines of, "Ethics are the luxury of the well fed." In other words, it is easy to extol lofty ideals and virtue when in a position of relative ease. The real test comes when "the rubber hits the road" and life becomes more challenging.
My personal opinion is, until you have navigated a busy intersection with a toilet paper roll encircling each eye and a stick, then you do not get an opinion. Okay, maybe you can have one. But, do not express it. At least, not around me, unless you come bearing dark chocolate and red wine. :)
Thursday, May 22, 2008
Monday, May 19, 2008
Gene Therapy and RP
This is old news at this point, but I just have not found the time to write about it. Below is the article published in the New England Journal of Medicine regarding the recent gene therapy trial for LCA, a severe, early-onset form of RP.
http://content.nejm.org/cgi/content/full/NEJMoa0802268
There have been press releases issued to major news outlets. You can see the media coverage at the FFB website:
http://www.blindness.org/
It is worth the time to read the academic article. While it is difficult for a layman to understand all of the jargon, it gives a realistic picture of the actual results achieved.
Yes, it is very exciting. But, it is the result of, at least in the study published above, one person's improvement in one aspect of vision, contrast sensitivity. Apparently there is the study above as well as another one using a different set of three adults. This is the only published peer reviewed article I have been able to locate in PubMed (thanks for the share, G.). And, as all of the scientific types are quick to remind us RPers, one person's experience does not usually mean much and we should not invest too much time in being hopeful. Unless it is gene therapy, apparently.
I suppose I must be missing something. It certainly would not be the first time. Maybe the other study, which I cannot locate, had better results.
This is the first gene therapy trial, to my knowledge, done for a condition which is not fatal. I have to admit, I am floored the FDA approved gene therapy for a non-lethal condition. The exciting thing about this trial, based on the little I know about gene therapy, is no one had "adverse events", like dying, from the viral vector used.
A vector is a virus used to carry the normal copy of the gene to the target gene. The tricky part is using a virus that is not harmful to humans. In other (non RP related) gene therapy trials in the past, people have died from immune reactions resulting from the virus. This may be worth the risk to someone dying of a fatal condition. There is also the risk of the replacement gene not just going to the target area and inserting itself in other cells, leading to cancers.
However, by some miracle, these scientists actually were able to get this trial approved in this country for a disease that is not killing people. So, in the scientific community, that must make them rock stars. I am not talking some bubble gum boy band either. More like Keith Richards, able to defy the odds and astonish medical professionals time and time again.
Aging rock star jokes aside, It seems like there are multiple standards at work. Again, I am sure I am missing something. But, take our UCL acetazolamide case study. That is a case of one person having improvements in contrast vision. However, there were no press releases, no buzz or continued funding. Granted, her gains were not nearly as dramatic as the gains of the subject in this study.
But, the results obtained by one young person in the study are very encouraging to me. The increases in his ability to detect contrast are undeniable and unlikely to be explained away. The fact that the dogs who have received the same procedure, eight years ago, have maintained their gains is even more encouraging. And, this is gene therapy's first barbecue for RP in humans. This was just to test safety, and that anyone had any benefit at the most conservative dosing level is encouraging.
My personal belief is gene therapy may be able to help me one day maintain the results of a stem cell procedure. I think it holds an enormous amount of potential for young people who are newly diagnosed and identified. Hopefully the incredibly brave young people who participated in this study will have more improvement and stable general health.
The "subjects" are courageous, pioneering and inspiring. With all of the things I have tried, gene therapy would still terrify me, regardless of who was doing it. Kudos to the researchers as well. Firstly, for getting results. Secondly, for managing to get a trial with this amount of inherent risk done in this country. It has no doubt been a long, laborious road and I look forward to more good news.
http://content.nejm.org/cgi/content/full/NEJMoa0802268
There have been press releases issued to major news outlets. You can see the media coverage at the FFB website:
http://www.blindness.org/
It is worth the time to read the academic article. While it is difficult for a layman to understand all of the jargon, it gives a realistic picture of the actual results achieved.
Yes, it is very exciting. But, it is the result of, at least in the study published above, one person's improvement in one aspect of vision, contrast sensitivity. Apparently there is the study above as well as another one using a different set of three adults. This is the only published peer reviewed article I have been able to locate in PubMed (thanks for the share, G.). And, as all of the scientific types are quick to remind us RPers, one person's experience does not usually mean much and we should not invest too much time in being hopeful. Unless it is gene therapy, apparently.
I suppose I must be missing something. It certainly would not be the first time. Maybe the other study, which I cannot locate, had better results.
This is the first gene therapy trial, to my knowledge, done for a condition which is not fatal. I have to admit, I am floored the FDA approved gene therapy for a non-lethal condition. The exciting thing about this trial, based on the little I know about gene therapy, is no one had "adverse events", like dying, from the viral vector used.
A vector is a virus used to carry the normal copy of the gene to the target gene. The tricky part is using a virus that is not harmful to humans. In other (non RP related) gene therapy trials in the past, people have died from immune reactions resulting from the virus. This may be worth the risk to someone dying of a fatal condition. There is also the risk of the replacement gene not just going to the target area and inserting itself in other cells, leading to cancers.
However, by some miracle, these scientists actually were able to get this trial approved in this country for a disease that is not killing people. So, in the scientific community, that must make them rock stars. I am not talking some bubble gum boy band either. More like Keith Richards, able to defy the odds and astonish medical professionals time and time again.
Aging rock star jokes aside, It seems like there are multiple standards at work. Again, I am sure I am missing something. But, take our UCL acetazolamide case study. That is a case of one person having improvements in contrast vision. However, there were no press releases, no buzz or continued funding. Granted, her gains were not nearly as dramatic as the gains of the subject in this study.
But, the results obtained by one young person in the study are very encouraging to me. The increases in his ability to detect contrast are undeniable and unlikely to be explained away. The fact that the dogs who have received the same procedure, eight years ago, have maintained their gains is even more encouraging. And, this is gene therapy's first barbecue for RP in humans. This was just to test safety, and that anyone had any benefit at the most conservative dosing level is encouraging.
My personal belief is gene therapy may be able to help me one day maintain the results of a stem cell procedure. I think it holds an enormous amount of potential for young people who are newly diagnosed and identified. Hopefully the incredibly brave young people who participated in this study will have more improvement and stable general health.
The "subjects" are courageous, pioneering and inspiring. With all of the things I have tried, gene therapy would still terrify me, regardless of who was doing it. Kudos to the researchers as well. Firstly, for getting results. Secondly, for managing to get a trial with this amount of inherent risk done in this country. It has no doubt been a long, laborious road and I look forward to more good news.
Sunday, April 20, 2008
Yet Another Glaucoma Drug and RP
Below is some information on yet another glaucoma drug that has some result in RP. Keep in mind the drug in this study was delivered topically. So, in actuality, it is a relatively small amount of medication that actually makes it to the target area.
If you check out http://www.clinicaltrials.gov/ and enter "retinitis pigmentosa", look for the clinical trial for the "Brimonidine Tartrate Implant". Brimonidine is a glaucoma drug. You will see the drug manufacturer, Allergan, has invested the research and development dollars to create a retinal drug delivery system in the form of an implant. The drug of choice has traditionally been used for glaucoma.This study is going to take place in Europe.
I find this of particular interest given the acetazolamide (another glaucoma drug) case study from the University of London. No one has ever accurately replicated that woman's experience in the form of a larger scale pilot study. In the one attempt, the dosing was incorrect and the study was prematurely terminated.
Now, another glaucoma drug is emerging and a company has invested major funds in an implant in order to deliver it directly to the retinas of RPers.
Interesting....
Below is a link to a pilot study done in Israel. Its results will not enthrall, but keep in mind this is eye drops, not even a systemic delivery in the form of an oral pill.
http://www.liebertonline.com/doi/abs/10.1089/jop.2007.0022
If you check out http://www.clinicaltrials.gov/ and enter "retinitis pigmentosa", look for the clinical trial for the "Brimonidine Tartrate Implant". Brimonidine is a glaucoma drug. You will see the drug manufacturer, Allergan, has invested the research and development dollars to create a retinal drug delivery system in the form of an implant. The drug of choice has traditionally been used for glaucoma.This study is going to take place in Europe.
I find this of particular interest given the acetazolamide (another glaucoma drug) case study from the University of London. No one has ever accurately replicated that woman's experience in the form of a larger scale pilot study. In the one attempt, the dosing was incorrect and the study was prematurely terminated.
Now, another glaucoma drug is emerging and a company has invested major funds in an implant in order to deliver it directly to the retinas of RPers.
Interesting....
Below is a link to a pilot study done in Israel. Its results will not enthrall, but keep in mind this is eye drops, not even a systemic delivery in the form of an oral pill.
http://www.liebertonline.com/doi/abs/10.1089/jop.2007.0022
Monday, March 31, 2008
Interview with David Paterson
I found David Paterson, the first legally blind governor of New York, to have an interesting perspective. I can relate to him in living in a world that is between the sighted and non sighted worlds and how very difficult it is for people to grasp partial sightedness.
first legally blind governor in U.S. historyDavid Paterson to become new New York governorBy Reuters / March 12, 2008NEW YORK (Reuters) - New York Lieutenant Governor David Paterson was setto become the state's first black governor and the first legally blindgovernorin U.S. history, after the resignation of Gov. Eliot Spitzer Wednesday.Paterson, 53, became New York's first African-American lieutenantgovernor in November 2006. He has been legally blind since childhood,with only partialsight in his right eye.Spitzer resigned after media reports linked him to a prostitution ring.He said Paterson would take over Monday.The following are some facts about Paterson:Paterson was born in Brooklyn to Portia and Basil Paterson. His fatherwas the first non-white secretary of state of New York and the firstAfrican-Americanvice chair of the national Democratic Party.He earned his bachelor's degree in history from Columbia University,graduating in 1977, and completed his law degree at Hofstra Law Schoolin 1982.Paterson became a public servant in 1985 when he began representingHarlem in the New York State Senate, according to the New Yorkgovernor's Web site.In 2002, he became the body's minority leader, the first non-whitelegislative leader in New York state history.In 2004, he became the first legally blind person to address theDemocratic National Convention.In 2006, Paterson was elected New York's first African-Americanlieutenant governor.Paterson ran the New York City marathon in 1999.Paterson, an adjunct professor at Columbia's School for Internationaland Public Affairs, lives in Harlem with his wife, Michelle PaigePaterson, and theirtwo children.Additional information from a New York Times article FROM January, 08"As a disabled person, there's certain times that I don't want to appeartoneed that much help. When I was in college, when I was at Columbia, Ihad aprofessor - I actually Googled him, he passed away in 1986 and his namewasBasil Ruch, and he was a professor of history at Barnard College, and heshowedme a picture of Franklin Delano Roosevelt being carried into the 1932Democraticconvention. And he said that Roosevelt by 1932 was still able to walk acertaindistance, but not quickly, and he wanted to walk in, he wanted thecountry tosee him standing, and but what happened was, when he started to walk,and he gottoward the end, he was starting to be a little jittery, that a bunch ofsupporters, thinking they were helping him, grabbed him and picked himup andcarried him in. And you see in this picture - and I couldn't really seeit, buthe described it to me - he has this stern, angry look, because theymessed uphis moment. And I know what he was feeling. Because sometimes you wantto project a certainamount of strength. And you can project it if you're a woman, you canproject itif you're disabled, you can project it, but often the people who loveyou don'tsee the need for you to project it.I remember when I was in the D.A.'s office, and I conducted a hearingand it hadto do with a stalker who was bothering this woman. And I got to feelingwhen thewoman saw me holding the file up to my face and that kind of thing, andthestalker's looking at her, and she's kind of - I got that she didn'treally knowif I was able to handle this.And I went over to her and I said, "Listen, just in case we lose thishearing,don't worry, because when he goes outside, I'm going to kick his butt."I saidthat to her because I wanted her to know that I'm in charge of her case.Andthat's what I'm saying about projection."Q: Did you always think, with your disability, that you could followyour fatherinto politics, or was that something you came to over time?A: When I was 10 years old I watched Robert Kennedy speak at theDemocraticNational Convention and I wished I was him. And I think, again, therewas thatfamily connection - he was following in the footsteps of John, Hillaryfollowsin the footsteps of Bill, so I always relate to that, you know, kind offamilymember who has to deal with that shadow.When I was in college, though I had academic ability, I don't know thatI wasall that socially developed, or had a real difficult problem askingpeople forassistance, and had a lot of problems as a result of that. And I thinkas I hadmore problems, my ideas about being in politics, or following my fatherdwindled. I didn't see myself as - I think my self-esteem reallysuffered fromthat. ...Q: In terms of your vision, how much can you see?A: I am legally blind in my right eye, and totally blind in my left eye.I'mlooking at Armen [Meyer, a press aide who was in the room]. I know hehas awhite shirt on, I know he has a tie on, but from this distance I can'ttell youwhat color it is. I think it's a darker color. ...When I am in places where I am familiar, I will appear to see betterthan inplaces where I'm not. If I walked around my house, and you didn't know,you'dprobably think I have no vision problems.When I say I saw something, it's more like I sensed it. So when I saidthat wewere on a plane with the Clintons, and we're all eating pizza, I knewthat I waseating pizza and I knew they took pizza off the tray, so I assumethey're eatingit. I think people's perception of me sometimes is that I see more thanIactually do. But I play basketball, and I've done things that peoplewith my vision aren'tsupposed to do. I'm in this interesting sort of zone between the sightedand theunsighted, and have never really met anyone who I visually relate to,I've nevermet anyone who is kind of like me. ...My truest disability has been my ability to overcome my physicaldisability. Soin other words, as soon as people see that I can be independent, thenthey holdme to the standard that everyone else is. So I remember once I told theairlinesthat I had a sight problem, and they put me on this bus to go to a hotelbecausethere were no other flights out of the airport that night, and I gave upmy seatto everyone got on and they passed me, and then like this 90-year-oldwoman, whowas trying to get up the steps, and I couldn't take it anymore so Ihelped herup the steps, gave her my seat and took another seat. First stop, thebus drivertells me to get off. And I know that he's doing this now because hethinks Ihave no problem. He goes, "Go that way." And I almost fell in thewishing wellin front of this hotel. That's because he saw me able to fend formyself.And I think that's been my greatest disability, that as I've overcome myphysical disability, it just leads to other problems. So I think I havenowlearned - and I'm not doing this to be deceptive - but I don't act theway I didwhen I was 17, like I can do everything myself, because I realized theminute Ido that, no one helps me. So I learned to be a little more pragmaticabout life
first legally blind governor in U.S. historyDavid Paterson to become new New York governorBy Reuters / March 12, 2008NEW YORK (Reuters) - New York Lieutenant Governor David Paterson was setto become the state's first black governor and the first legally blindgovernorin U.S. history, after the resignation of Gov. Eliot Spitzer Wednesday.Paterson, 53, became New York's first African-American lieutenantgovernor in November 2006. He has been legally blind since childhood,with only partialsight in his right eye.Spitzer resigned after media reports linked him to a prostitution ring.He said Paterson would take over Monday.The following are some facts about Paterson:Paterson was born in Brooklyn to Portia and Basil Paterson. His fatherwas the first non-white secretary of state of New York and the firstAfrican-Americanvice chair of the national Democratic Party.He earned his bachelor's degree in history from Columbia University,graduating in 1977, and completed his law degree at Hofstra Law Schoolin 1982.Paterson became a public servant in 1985 when he began representingHarlem in the New York State Senate, according to the New Yorkgovernor's Web site.In 2002, he became the body's minority leader, the first non-whitelegislative leader in New York state history.In 2004, he became the first legally blind person to address theDemocratic National Convention.In 2006, Paterson was elected New York's first African-Americanlieutenant governor.Paterson ran the New York City marathon in 1999.Paterson, an adjunct professor at Columbia's School for Internationaland Public Affairs, lives in Harlem with his wife, Michelle PaigePaterson, and theirtwo children.Additional information from a New York Times article FROM January, 08"As a disabled person, there's certain times that I don't want to appeartoneed that much help. When I was in college, when I was at Columbia, Ihad aprofessor - I actually Googled him, he passed away in 1986 and his namewasBasil Ruch, and he was a professor of history at Barnard College, and heshowedme a picture of Franklin Delano Roosevelt being carried into the 1932Democraticconvention. And he said that Roosevelt by 1932 was still able to walk acertaindistance, but not quickly, and he wanted to walk in, he wanted thecountry tosee him standing, and but what happened was, when he started to walk,and he gottoward the end, he was starting to be a little jittery, that a bunch ofsupporters, thinking they were helping him, grabbed him and picked himup andcarried him in. And you see in this picture - and I couldn't really seeit, buthe described it to me - he has this stern, angry look, because theymessed uphis moment. And I know what he was feeling. Because sometimes you wantto project a certainamount of strength. And you can project it if you're a woman, you canproject itif you're disabled, you can project it, but often the people who loveyou don'tsee the need for you to project it.I remember when I was in the D.A.'s office, and I conducted a hearingand it hadto do with a stalker who was bothering this woman. And I got to feelingwhen thewoman saw me holding the file up to my face and that kind of thing, andthestalker's looking at her, and she's kind of - I got that she didn'treally knowif I was able to handle this.And I went over to her and I said, "Listen, just in case we lose thishearing,don't worry, because when he goes outside, I'm going to kick his butt."I saidthat to her because I wanted her to know that I'm in charge of her case.Andthat's what I'm saying about projection."Q: Did you always think, with your disability, that you could followyour fatherinto politics, or was that something you came to over time?A: When I was 10 years old I watched Robert Kennedy speak at theDemocraticNational Convention and I wished I was him. And I think, again, therewas thatfamily connection - he was following in the footsteps of John, Hillaryfollowsin the footsteps of Bill, so I always relate to that, you know, kind offamilymember who has to deal with that shadow.When I was in college, though I had academic ability, I don't know thatI wasall that socially developed, or had a real difficult problem askingpeople forassistance, and had a lot of problems as a result of that. And I thinkas I hadmore problems, my ideas about being in politics, or following my fatherdwindled. I didn't see myself as - I think my self-esteem reallysuffered fromthat. ...Q: In terms of your vision, how much can you see?A: I am legally blind in my right eye, and totally blind in my left eye.I'mlooking at Armen [Meyer, a press aide who was in the room]. I know hehas awhite shirt on, I know he has a tie on, but from this distance I can'ttell youwhat color it is. I think it's a darker color. ...When I am in places where I am familiar, I will appear to see betterthan inplaces where I'm not. If I walked around my house, and you didn't know,you'dprobably think I have no vision problems.When I say I saw something, it's more like I sensed it. So when I saidthat wewere on a plane with the Clintons, and we're all eating pizza, I knewthat I waseating pizza and I knew they took pizza off the tray, so I assumethey're eatingit. I think people's perception of me sometimes is that I see more thanIactually do. But I play basketball, and I've done things that peoplewith my vision aren'tsupposed to do. I'm in this interesting sort of zone between the sightedand theunsighted, and have never really met anyone who I visually relate to,I've nevermet anyone who is kind of like me. ...My truest disability has been my ability to overcome my physicaldisability. Soin other words, as soon as people see that I can be independent, thenthey holdme to the standard that everyone else is. So I remember once I told theairlinesthat I had a sight problem, and they put me on this bus to go to a hotelbecausethere were no other flights out of the airport that night, and I gave upmy seatto everyone got on and they passed me, and then like this 90-year-oldwoman, whowas trying to get up the steps, and I couldn't take it anymore so Ihelped herup the steps, gave her my seat and took another seat. First stop, thebus drivertells me to get off. And I know that he's doing this now because hethinks Ihave no problem. He goes, "Go that way." And I almost fell in thewishing wellin front of this hotel. That's because he saw me able to fend formyself.And I think that's been my greatest disability, that as I've overcome myphysical disability, it just leads to other problems. So I think I havenowlearned - and I'm not doing this to be deceptive - but I don't act theway I didwhen I was 17, like I can do everything myself, because I realized theminute Ido that, no one helps me. So I learned to be a little more pragmaticabout life
Tuesday, March 25, 2008
Sunday, March 16, 2008
First Legally Blind Governor
Not only is David Paterson New York's first Black governor, he is NY's first legally blind governor. His blindness was caused by a childhood illness. He has some vision in one eye and no vision in the other. He went to law school AFTER being legally blind.
What is his message to me? Blindness is no excuse to not hold yourself to the highest standard of achievement. Many people, out of ignorance, will coddle us. The "tough love" mentality has to come from within. Hard? Absolutely! Worth it? Well, what is the alternative?
http://www.ny.gov/ltgov/
What is his message to me? Blindness is no excuse to not hold yourself to the highest standard of achievement. Many people, out of ignorance, will coddle us. The "tough love" mentality has to come from within. Hard? Absolutely! Worth it? Well, what is the alternative?
http://www.ny.gov/ltgov/
Tuesday, March 11, 2008
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.
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.
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