MS, HBO and Medical Politics

Sheldon F. Gottlieb,Ph. D. The Naked Mind (Chapter 14). Best Publishing Company, P.O.Box 30100, Flagstaff, AZ 86003-0100. www.bestpub.com

Dr. Gottlieb, an eminent scholar and researcher of hyperbaric oxygen, is a retired university professor of physiology and biology. He writes here about medical politics and conflicts of interest that block widespread acceptance of this marvelous therapy.

. . .In this chapter, I am going to change the pace and introduce you to what I consider the devastating influence of ideology in medicine. Although there are several areas of science or medicine that I could use as examples, I will confine myself to just one area with which I am quite familiar, multiple sclerosis. Part of this chapter was originally prepared for publication. Thus, it has parenthetical numbers which refer to references which are placed at the end of the chapter and before the Coda.

There may be portions of this chapter that are technical in nature. Those who feel overwhelmed by them can easily skip them or read them to get the gist of what is being described and not lose too much of the essence of the story. . .

My perception of the current situation concerning the use of hyperbaric oxygen therapy (HBOT) as a viable therapeutic modality for MS is that of a heresy trying to gain acceptance with true believers. Despite its successes, the use of HBOT as a

therapeutic modality for MS has created an intense emotional controversy amongst neurologists and some hyperbaricists (1,4,5). The proponents of the use of hyperbarics for MS have been met with a disdain that lies somewhere between that bestowed upon Semmelweiss by his contemporaries and that accorded to Darwin by Reverend Wilberforce, his cohorts, and ideological descendants. . .In keeping with the tenor of the book, what follows is a story of how ideology, more than fact, has influenced many of the developments in the understanding and treatment of multiple sclerosis undoubtedly to the detriment of the MS patients. Except for one or two places, one does not have to possess technical knowledge to understand what I have to say. Of course, if a person has the relevant technical knowledge about the structure and function of the body in health and disease, his or her understanding of the issues will be enhanced.

However, the ideological fervor surrounding the orthodoxy is so great that even evidence to the contrary is interpreted as being supportive, while significant evidence in support of HBOT is denied (1,4,6,7,8).

Mertin's et al. (7) double-blind study of immunosuppression reported that "there was only marginal clinical improvement, and the small differences between treated patients and the control group in relapse rates and the overall clinical deterioration were outside the conventional limits of statistical significance?'

Yet despite their negative findings, which were congruent with other published studies, they remarkably concluded in a contradictory fashion: "Nevertheless, our observations suggest that the principle of immunosuppressive treatment in MS is valid and that the improvements of the immunosuppression regimen may lead to improved clinical results?'

In the HBOT studies, Barnes et al. (8) had statistically significant results (p = .03) as to improvement in bowel/bladder function and they concluded that their data does "not support the claims made for hyperbaric oxygen in the management of multiple sclerosis."

Further irony derives from the fact that the antiviral and immunomodulatory therapies based on the orthodox version of the etiology of MS thus far have proved either to be unsuccessful or only partially successful; but some of the most popular and widely used chemotherapeutic agents, even when administered properly, are considered high-risk medications because of their toxic side effects. In contrast, HBOT is not just an effective drug, it is also the safest of these drugs (1, 9-13).

Despite its impressive credentials, especially with respect to wound healing (9,10,13,14), HBOT is considered to be a controversial drug as concerns the treatment of MS. Indeed, the first major and comprehensive review of the use of HBOT in the treatment of MSâ€”which appeared in the Journal of Hyperbaric Medicineâ€”discussed the controversy in detail in a special section entitled "Comments on the controversy" (1). The editor of the journal introduced the review by an unprecedented statement in which he acknowledged the existence of the controversy and carefully insinuated that the results with HBO may not be as negative as others would like to have us believe. As to the quality of the review, the editor stated, "The paper...by Drs Gottlieb and Neubauer presented in this issue of the journal summarizes many results from the literature, and it carries some of the strength of their enthusiastic opinion. However, this type of analysis is extremely useful to all of us; it represents the closest approach to a meta-analysis of the field and it summarizes the strengths and limitations of a large number of published reports. We hope that this type of approach will be duplicated for many other syndromes treated with HBO..."

Knowing the history of modern hyperbaric medicine, one could understand the reluctance of hyperbaricists to embrace the use of HBOT for MS. The initial enthusiasm with which HBOT was met in the late 1950s and early to mid-1960s, was followed by a very precipitous decline in the late 1960s and early to mid-1970s (13). To the anger, annoyance, and frustration of knowledgeable scientists and physicians, somewhat bizarre and unsubstantiated claims were made on its behalf and some of its successes could not be readily explained by the then-known physiological, biochemical, and pharmacological effects of oxygen. With the appearance of the first Hunt-Davis book (13) and the explosive increase in knowledge about the biology of oxygen (1, 9,10,12,14,15), HBOT has been steadily gaining renewed respectability and acceptance as an important therapeutic modality (9,10). As a therapeutic modality, HBOT is based on sound physical, chemical, physiological, biochemical, and pharmacological principles (9,11,12,14,15).

Some hyperbaricists are fearful that touting the use of oxygen for the treatment of a disease having the variability of MS may cause all the hard work of the previous decades to develop a positive image and momentum to be negated and possibly reversed. Yet these fears are unfounded since the very same advances in understanding the physiological and pharmacological effects of oxygen forms the basis for its use in the treatment of MS (1,6,9). Neubauer and I, for over a decade, have been promulgating the idea that MS should be considered a wound in the central nervous system and that the basic concepts of therapeutics of wound healing should be applied. Similar reasoning underlies the importance of considering stroke, traumatic brain injuries, toxic and anoxic encephalopathies, type II decompression illness, and some other (not all) CNS abnormalities as being wounds of the CNS.

Evolutionary theory would predict that a mechanism for healing from injury would not evolve for the central nervous system that is separate and distinct from that of the rest of the body. Studies in comparative biochemistry and physiology have shown that nature tends to be conservative. From comparative studies on a wide variety of living forms it had been observed that basic biochemical and physiological mechanisms tend to be preserved. Such mechanisms also serve as the basis for the evolution of variations on a theme. To date, except for the fact that the central nervous system contains little interstitial matrix as compared to other tissues, there is no evidence to indicate that wound healing in the brain, the formation of new blood vessels, is any different than in any other tissue.

The question is why should neurologists and even some hyperbaricists react with a vicious negativity when HBOT is mentioned as a possible treatmentâ€”not a cureâ€”for MS?

Before continuing with this story, it would be helpful if I first presented you with an overall view of the situation with respect to hyperbaric oxygen therapy and MS. Thus, I am including the entire article I wrote for the Mobile Press Register in 1985, which explains the situation and which is as relevant today as was when it was written.

During the social madness that characterized the mid-1960s to mid-1970s, there was a conspiratorial idea prevalent in the counterculture that held that the medical establishment was deliberately withholding "cures" for several diseases, specifically a cure for cancer.

Try as I might to explain to counterculturists the process involved in a drug's development and testing before it could be accepted as a legitimate addition to the therapeutic armamentarium, I was unable to dispel their fashion-able and well-entrenched distrust of "the establishment," of which I was perceived to be a part. I attributed my failure less to my powers of persuasion than to the irrationality of their thinking processes and the falseness of their knowledge base.

Yet a decade later, I find society confronted by a situation in which powerful national medical forces seemingly are attempting to discredit hyperbaric oxygenation as a potential new therapy for multiple sclerosis without sufficient credible information with which to make a rational decision.

An approved form of therapy for a variety of diseases, HBOT involves placing patients in a recompression chamber and having them breathe pure oxygen at increased atmospheric pressures, usually pressures equivalent to those experienced by divers 15-45 feet below sea level.

Dr Richard Neubauer, medical director of the Clinical Baromedical Center, Lauderdale-by-the-Sea, FL, and a pioneer in the use of HBOT in MS, claims that there is no known cure for MS. Even HBOT is not a cure. "Whereas some of the more highly recommended medications have been shown to cause cystitis, cancer, and death, HBOT, which can effectively ameliorate the symptoms of MS in certain patients, has no significant adverse side effects," he continues. "Over 10,000 patients have been treated worldwide with an almost 85 percent improvement rate.

However, most of these patients were not treated under a double-blind protocol. Although the data and statistics are suggestive, they are not viewed with much credibility by the scientific and medical community.

A double-blind study is one in which neither the physician nor the patient knows whether the patient is receiving the experimental or control (placebo) treatment. Patients are matched and assigned to one group or the other by a secret code that is not to be broken until the end of the experiment. A DBS is designed to prevent conscious or subconscious bias.

Dr Stephen Reingold, assistant vice president for research and director of grants management of the National Multiple Sclerosis Society, claims that "from a scientific view-point, hyperbaric oxygen has not been proven to be effective in MS.

Yet Drs Fischer, Marks, and Reich, professors of medicine in the Departments of Neurology and Rehabilitation Medicine, New York University Medical Center, reported highly significant beneficial effects with HBOT based on a double-blind study funded by the National Multiple Sclerosis Society.

Even before the publication of the Fischer study in the prestigious New England Journal of Medicine, there were rumors circulating in the hyperbaric medical community that the society was disparaging the work.

Reingold said that "The study was flawed. It appeared that the code had been broken and the patients knew which protocol they were on. Therefore, doubt was cast on it being a true double-blind study.

Fischer claims that "the code was not breached." He went on to say, "The NMSS has to be credited with funding the research project, although there was an undercurrent, though never publicly expressed at that time, of the inefficacy of this particular approach to treating MS. When we found HBOT to be effective, they instituted a campaign to discredit our work. They even went so far as to attempt to prevent its publication."

Since the Fischer report appeared, there have been at least 14 double-blind studies done throughout the world with mixed results. Reingold said that the MS Society's medical advisory board reviewed the available data "and concluded that the effectiveness of HBO has not been proven."

Neubauer just completed a detailed analysis of the 14 studies: "Except for the Fischer study, they all have methodological flaws. Several of the investigators are sufficiently intrigued by their findings that they are continuing their research."

One of the aforementioned double-blind studies (Barnes, Bates and colleagues, supported by the British MS Society), which received wide publicity in the U.S., became very controversial as soon as it appeared in the very prestigious British medical journal, Lancet. The editor subsequently published several lengthy letters pointing out very important methodological and statistical errors and which showed how Barnes and Bates' conclusions were not supported by their own evidence. Their credibility as investigators was immediately and thoroughly discredited. That aspect of the story never made worldwide headlines.

Dr Philip James, a leading medical proponent of the use of HBOT, is honorary medical advisor to Action for Research in MS in the United Kingdom, a private, non-profit organization supporting research in all aspects of MS. James said, "The NMSS apparently is hostile to HBOT probably because they have a vested interest in the immunologic and viral theories as to the cause of MS and think that these theories are incompatible with other causations and even certain pathological mechanisms of the disease. Such thinking is not necessarily true."

Recently, upon the recommendation of the Chief Scientists Committee, after they reviewed the available evidence, including the Barnes and Bates study, the Scottish government awarded a 90,000-pound (about $136,000) grant-in-aid to James to support a three-year longitudinal study on the effectiveness of HBOT in MS.

This past August, Dr Dean Edellâ€”a well-known radio and TV "advice-giver," reporter, and interpreter of medicineâ€”discussed the ineffectiveness of HBOT in MS based on four studies that he said had been recently reported and extolled the virtues of what he claimed was a new medication.

At that time, only a brief summary of those studies had appeared and the substance he touted, copolymer 1, had been around for at least a decade and had not been proven to be all that effective, but its mechanism of action conforms to NMSS concepts. The people around Edell refused to let me talk to him when I called; he never returned my call, even though I left two telephone numbers, and, to date, he has not answered my letter

There are at least three major problems in MS research: the absence of a good early diagnostic test, the absence of a good objective means of quantitatively assessing improvement, and the unavailability of a good animal model.

Neubauer said that "objective improvement has been reported in bladder and bowel function and in the assessment of sensory evoked potentials of patients treated with HBOT."

Even objective measurements are shrouded in controversy. However, improved bladder and bowel function are the most consistent finding reported, even by detractors of HBOT.

The use of HBOT in treating MS has generated intense emotion with charges of fraud, charlatanism, misuse of the public trust, deliberate attempts at disparaging a potential new therapy because it does not agree with current orthodoxies, being loosely bandied about in private conversations.

Much is made in pharmacology about the importance of placebo effects, beneficial mind-over-matter therapeutic effects due to patients believing that they are receiving therapy when in reality they are not.

About a year and half ago, Drs James and Jean Goodwin described the "Tomato Effect," i.e., ignoring or rejecting an "efficacious treatment for a certain disease because it does not `make sense' in light of accepted theories of disease mechanisms and drug action.

They concluded: "Before we accept a treatment we should ask, "Is this a placebo?" and before we reject a treatment we should ask " Is research, the very attributes that this a tomato?" seem to be lacking in assessing the Between the extremes of use of HBOT in MS and which acceptance and rejection scientists some people are accused of advocate careful, detailed, unbiased preventing.

All of my personal experiences as well as those of R.A. Neubauer, M.D., which cannot be told at this time, attest to the veracity of this extreme negativity. However, there are two incidents that I can relate. The first had to do with the fact that when I was president of the Gulf Coast chapter of the Undersea Medical Society (I do not think the parent society had yet changed its name), I provided Dick Neubauer with his first American forum for him to explain his ideas on the use of HBOT in MS and for him to present his data. Throughout the world, Neubauer was heralded as a pioneer. In the U.S. he was a pariah.

How did I come to ask Neubauer to be the keynote speaker at our chapter's luncheon despite the fact that I was well aware that he was considered to be a quack by people whom I considered to be respectable and responsible physicians? At that time, I had recently met Dick Neubauer while my wife and I were visiting her parents in Deerfield Beach. Neubauer's office was only about 15 to 20 minutes driving time from their condo in Century Village. Neubauer had already heard of me because of my work on oxygen and microbes, my discovery of the in vitro and in vivo synergistic action of hyperbaric oxygen with certain antimicrobial agents. He also knew of my work with xenon; he knew of the work on oxygen I was doing with graduate students as well as the studies I had done with xenon and oxygen with Ian Longmuir and one of his students at NC State University. I filled him in on work I was doing with graduate students on the effects of oxygen on cellular transport mechanisms in the intestine, heart, and brain as a follow-up to the studies on transport across skin that was done with Al Cymerman, a doctoral student of mine in the physiology department at what was then Jefferson Medical College (it has since undergone a name change, I think it is called Thomas Jefferson University). As a result of my visit to his office, looking over his hyperbaric facilitiesâ€”something I always did in my travels throughout the world, especially the U.S.â€”meeting some of his patients, and reviewing some of his many patient charts, I went back to Mobile and read about MS. After reviewing the literature I came to several conclusions, the most important being that the highly touted experimental animal model was not a model for MS, but for immune reactions in general, and that HBOT would offer another approach to understanding the disease process and could provide other perceptions into developing new therapeutic insights. Such thinking on my part was really an extension of my existing philosophy which I had developed years earlier and expressed in a theoretical paper on the possible use of hyperbaric oxygen in the treatment of tuberculosis as well as in subsequent papers supporting this theory with experimental data.

Neubauer asked me if I wanted to join him in his research endeavors on the brain. Because of my studies on a brain enzyme, I was looking for a way to get into brain research with humans. Along with the opportunity of working with Keith Van Meter in New Orleans, this offer of Neubauer's would provide me with a completely different type of opportunity. It was only after reviewing the literature on MS that l agreed to help Dick with his presentation. This was the beginning of a most fruitful friendship â€”although this is neither the time nor place to discuss the subjectâ€”but what I say about my relationship with Neubauer is equally true with Van Meter in New Orleans. The ongoing friendship and professional relationship that grew with time between Neubauer and myself represented an almost perfect blend of the knowledge and back-ground of a Ph.D. with that of a physician. With Neubauer, several high points were reached; two of them involved the publication of the review article and the development and publication of a new theory for the etiology of MS, and based thereon, providing a scientific rationale for the use of HBOT in its treatment.

Back to the story. I helped guide him in preparing for the talk. Since his was not a double-blind study and since one of the major criticisms leveled at him was the lack of statistical analysis, I had him get his work analyzed statistically by an independent biostatistician. Neubauer engaged Dr Manley Boss, who at that time was a professor at Florida Atlantic University in Boca Raton, FL. I spoke to Manley on several occasions. I explained the situation to him. I told him that both Neubauer and I had to know, one way or the other, what the situation was with respect to his data. At the end of his analysis, he told me that Neubauer's data were significant and that he was convinced that the man was on to something. That was good enough for me. I had told Dick that because of the controversial nature of the subject, his presentation must meet the most rigorous standards. I told him that he must be prepared to respond to all questions and criticisms. I already knew that certain people were lying in wait for him. Similarly, he could and should accept any accolades that may come his way. To allay the critics who were hounding me, and there were many, I was determined that his presentation would be flawless. Stockholders in AT&T benefited from our conversations. As expected, the luncheon was packed. Neubauer's presentation was brilliant. He received a great ovation. Many of the skeptics in the audience were converted. My conversations with many afterwards indicated that they now thought that there may well be something to the use of HBOT for treating MS. The few hard-core idealogues remained unconvinced and remained angry with me that I had the audacity to have invited Neubauer. The few questions they had were answered. It was their preconceived, closed-minded ideology that prevented them from acknowledging the excellence of the presentation and the potential that existed with HBOT in MS.

Late the following night, for almost two hours, from about 10 p.m. to midnight, I ended up in a knockdown, no-holds barred telephone fight with the late John Miller, M.D. I had known John since the early 1960s. John was very active in the parent society. He also was chair, Department of Anesthesiology, University of South Alabama, the institution with which I was associated as professor in the Department of Biological Sciences; I may even still have been dean of the Graduate School. I had called John because his one Ph.D. minion had made some biting comment about me, to me and to others, the previous day, which was based on a lie and which directly implicated John as being the source of the false information. The character assassination was uncalled for. John was on the defensive as I countered everyone of his charges and forced him to acknowledge that what he was saying was based on his profound ignorance of the status of my sources of income and other personal finances. Finally, he expressed two related points that seemed to have really been rankling him and which may have been among the underlying causes of the problem between us, along with my cardinal sin of having provided Dick Neubauer a legitimate scientific forum with which to spread what John perceived to be Neubauer's heresy. He accused me of developing the entire program without ever consulting him or asking him to be a participant. Those charges particularly provoked me. I reminded him that, in the early stages of developing the program for the meeting, I came from the main campus in west Mobile to his office in the hospital in downtown Mobile and told him about the potential dates and plans for the forthcoming meeting. I wanted to make sure that he would be in town at that time. I not only asked him for his comments and input, I offered him an hour of timeâ€”it was a day-and-a-half meetingâ€”to discuss any subject he wanted pertaining to any aspect of hyperbaric or diving medicine. I even asked him if he wanted time to rebut anything Neubauer had to say. I reminded him that he declined the offers. I also reminded him that before finalizing the program, I called him once again to ascertain whether he had changed his mind about being a major speaker. He hadn't. At this point of our (over)heated discussion, John suddenly became quiet and admitted that was the case. He had forgotten. I do know that between my first meeting with John and our telephone confrontation, John had discussed the situation with others in the parent society. I had received many phone calls. Basically, people were asking me if I knew what I was doing and why was I doing it. I was being charged with the basest of motives. I do not know whether, based on our telephone debate, John ever corrected the record. Following his admission, the tone of our conversation quickly simmered down to a civilized level and we returned to our former friendly relationship.

I received a lot of criticism from others before and after Dick's excellent presentation in Mobile. Some of it was directed at me because I was a Ph.D. meddling in a clinical area. Other criticisms were obviously designed to hurt by casting aspersions on my judgement and on the quality of the review article despite the unprecedented laudatory statement of the editor. I sent a reprint to a friend in Fort Wayne for whom I had the greatest respect. Steven Hollander was a professor of English at my former university. In addition to his knowledge of literature, Steve also had a breadth and depth of scientific and technical knowledgeâ€”as a result of his technical training in engineering before he decided on a career in Englishâ€”rare amongst professors in the humanities. Also, Steve and I were sufficiently close so that he would not hesitate to be very critical of my writings. For the almost twelve years that we lived in Fort Wayne, I had often used Steve as a sounding board for my political writings. With me, he called events as he saw them. I received the following on November 14, 1988. It was written with typical Steve irony and wit.

Your call prompted me to read the article, finally, and I can fully understand why you are being hassled:

You admit to having a point of view. Doing so is perfectly acceptable for people who hold majority views, but certainly not for people whose views differ from those of the majority. In short, you commit the unforgivable error of admitting to a heresy, instead of politely ignoring the fact.

You criticize the methodologies of other scientists. Criticizing their results would be bad enough, but that is acceptable among scientists (if they politely criticize others' results). But saying that a colleague doesn't know what he's doing, doesn't understand his own data, doesn't use proper controls, etc. is the worst possible type of impoliteness. If this kind of behavior were allowed, the next thing you know doctors would be criticizing their butcher-colleagues. Clearly, we cannot have this kind of thing.

Seriously, of course, the problems are not with the clarity or the organization of your review paper, clearly, but with its content: You and your co-author just aren't telling people what they want to hear. To make matters worse, you tell your readers that there's a long history in MS research of seeing what one wants to see, getting results one desires, and reporting them accordinglyâ€”despite what the data may show. The response to your article is a mere continuation of the very abuses which form the article's subject. You should not have expected otherwise.

There are important additions that are required to complete part of the above detailed story. It has to do with the Barnes et al. study: when the final report of that investigation was published in which it was shown that HBOT improves cerebellar and bowel/bladder dysfunctions (16), there were no accompanying press releases issued either by the NMSS or the British MSS.

Several years later there were two meetings, back to back, one in Basel, Switzerland, the other in Paris, France. At the Paris meeting, I had just finished my talk in which I had analyzed the Barnes et al. study and showed the inconsistencies between their data and their conclusions. I was followed by Michael Barnes, the lead author of the Barnes et al. paper. Barnes concluded his presentation by saying that if his daughter had MS, he would not use hyperbaric oxygen for her. Immediately, he was accosted by Yehuda Melamed from Israel, David Perrins from England, Philip James from Scotland, and Richard Neubauer and me from the United States. Yehuda got to him first. He put his arm around Barnes and asked him point-blank: "Michael, did you really mean it when you said that if your daughter had MS you would not use oxygen?" It was at that time that Barnes gave a very revealing answer, one that put the entire situation into its proper perspective. He said, "Of course I would. But if I want to advance in British neurology, I have to espouse the party line?'

While living in Mobile, AL, many people afflicted with MS came to see me to learn about the potential use of MS as a therapeutic modality. The reason people called and came to me was because of the review article I had published with Neubauer (1), a few articles that had appeared in the Mobile Register about me and my involvement with MS (17-20), and an article written by me about the controversy concerning HBOT and MS (quoted above) (4). I always made it very clear to people who called that I was not a physician, I do not diagnose diseases, nor do I treat patients. I told them that I could inform them of the theory and practice of hyperbaric oxygen therapy and the data that were obtained to date using HBOT for MS, I could refer them to an appropriate hyperbaric physician, and I could instruct them how to present their cases to their insurance companies so as to improve their chances of having the expenses for the experimental therapy paid for by the third party. I also suggested that they contact the National Multiple Sclerosis Society since that organization funded the first double-blind study.

At the time, I had no concept that my innocent suggestion of contacting the NMSS was going to have fascinating ramifications. Now the story becomes interesting. As the story unfolds, I believe you will understand the reasons why I developed a profound disdain for the NMSS and why I concluded that they are not truly representing the best interests of MS patients. It was, and still is, my opinion that the leadership of the NMSS were (are) not ethically carrying out their full fiduciary responsibilities with which they were (are) entrusted when they collect(ed) funds from the public.

The NMSS is a powerful and influential group, as are all such national fund-raising, educational, and research-supporting health organizations. The NMSS press releases are accepted as gospel and spread nationally, even internationally, virtually instantly. Its positions on the nature and treatment of MS are accepted unquestioningly. If I were an MS victim, I have no doubt I would behave similarly. The laity in reality is not in a good position to evaluate differences of opinion among experts. Such disagreements are usually a source of great frustration to patients. That is why I insist that such health organizations tell the public the full truth as to what is occurring in the field and not just that information which supports what-ever their current orthodoxy is. Fortunately, in recent years, especially with the rise of the computer and the Internet, many interested patients develop a very profound sophistication about the nature and treatment of their illnesses.

A major intention of mine as I relate the ensuing events is to encourage health professionals, science and health reporters, and the general public to be more skeptical and questioning of self-serving press releases, as well as other educational materials, especially if they are associated with fund-raising.

I contrasted the behavior of the leadership of the NMSS with that of the American Heart Association. For twelve years in Fort Wayne and about three or four years in Mobile, I served on the Board of Directors of the AHA. There was a time in Fort Wayne when I served on three boards of the AHA simultaneously: Allen County, Northeast Indiana, and the State Board. I also served as president of the Allen County branch and the Northeast Indiana chapter of the AHA. Thus, I was very familiar with the workings of a truly great and ethical fund-raising, service, and educational organization. I was in a position to make some very valid comparisons. During the time spent with the AHA in Fort Wayne, I had the pleasure of working with some very fine people and with physicians who were dedicated to bringing the best medicine and the best that a service and educational organization has to offer to the public. It was a delight to work with the executive director of the Allen County branch and Northeast Indiana chapter, Hank Wilhems. He was one of the finest, most decent, hardest working and dedicated men I had ever met.

I sent a copy of the review article (1) and the theory paper (13) to the National Multiple Sclerosis Society as did Ginger Neubauer, Dr Neubauer's daughter and secretary who supervises his reprint collection and preparation of manuscripts amongst her other duties. The purpose of these actions on our part was to ensure that the NMSS was in possession of information which could be used to advise patients. Unfortunately, that was not to be the case. Patients reported back to me that the NMSS was telling them that they had no information concerning the beneficial effects of oxygen and that they did not "believe" in its use. (Their use of the word believe was particularly upsetting to me.) Considering that the NMSS funded the first double-blind study which demonstrated positive effects of HBOT, their failure to acknowledge beneficial effects of oxygen was a surprising and unexpected development. I had one of my graduate students call the NMSS. She obtained the same response as reported by the patients. She specifically asked if they have a copy of the Gottlieb-Neubauer paper. They denied ever having received it. Once again, I sent the NMSS a copy of the review article and, upon my request, so did Ginger. It seemed to us highly unlikely that four separate mailings would result in none of them reaching the NMSS. Several weeks later, I had the student once again call the NMSS. Once again she was told that they have no publications on file indicating that HBOT is beneficial in the treatment of MS. Obviously, the NMSS either just discarded the papers when they arrived or refused to tell the public of their existence.

At about the time all these events were unfolding, I was asked by the executive director of the Mobile branch of the Alabama NMSS if I wanted to be a member of the board of directors of the Mobile chapter. I accepted. The executive director was a woman whom I had known previously from the American Heart Association. She asked me if I would talk to the members of the chapter about hyperbaric oxygen. I, of course, accepted, a date was set, and the talk was given. She told me that she had received criticism from the state office about letting me talk about that subject. As I recall, she told me that pressure had been applied to stop me from speaking. She told them that I am not the type of person you just cancel without cause. And, she told them that she had no cause and they gave her none. It was not long after that the executive director of the Alabama State NMSS closed the Mobile office. The direct excuse was the need to economize. Up to this time I was told that there were no indications that such an action was to be taken. The Mobile executive director and I, and perhaps some members in the chapter, had the same suspicions as to either what was the real reason or, at least, the final impetus for closing the Mobile office.

Somewhere in this time frame a physician from Birminghamâ€”as I recall, under the auspices of the State NMSSâ€”was scheduled to come to the University of South Alabama Medical Center in Mobile to speak about treatments for MS. I called the Alabama State office and asked if he was going to include hyperbarics as part of his talk. I no longer recall with whom I spoke. However, I was told that he would not mention hyperbarics since they do not believe in it. Once again, the word belief drew my ire. I found it difficult to accept that a scientific organization, even if dedicated to the laity, would resort to the language of religion.

I offered the state office a proposition. I offered to debate any physician they selected, at any site of their choosing, in front of any audience they wanted, at any time they selected with just one proviso: the only data the debaters could refer to was that in the published scientific or medical literature. I thought that the broad terms of the debate were more than eminently fair. The proposal was refused. I asked why. I thought that I was giving them every advantage including the most important: if oxygen was so bad as a therapy on a theoretical and practical basis, a knowledgeable physician should have no difficulty in demolishing a Ph.D. in the debate. The answer was still no. There was no explanation offered other than "we do not `believe' in the use of oxygen." I concluded that the actions of the State NMSS spoke volumes.

In the late 1990s, a former student of mine, at my request, called the NMSS for information. He made several phone calls in the space of a few weeks. Each time he left his name and telephone number on an answering machine. According to the message, for whatever reason(s), there was no one attending the phones. He was never given the courtesy of a return call.

An important aspect of the story involves the study by Kindwall and his associates (21). This study was based on a multi-institutional registry Kindwall organized. However, to understand the significance of what is to follow, one must first be aware that Kindwall was amongst the most vociferous antagonists to the idea that HBOT could be used for the treatment of MS. When I heard that he was organizing the registry, I said to some people in the society and elsewhere, "Why bother doing the work? I will write his conclusion for him now: HBOT does not work."

Before I go into the details of Neubauer's and my reaction to the paper, I first have to tell how I know of Kindwall's animus and the basis for my cynical comment. From its inception, about 1978, until 1989, I served with Kindwall on the Hyperbaric Oxygen Therapy Committee of the then-Undersea Medical Society (later to change its name to the Undersea and Hyperbaric Medical Society). Thus, I was well aware of Kindwall's attitudes and behavior concerning HBOT in general including MS. Further, in about 1986 in San Antonio, TX, at a meeting of the committee, the then-chair of the committee, Jefferson C. Davis, M.D. (prematurely deceasedâ€”a great loss to society) provided me with the opportunity to present the case for HBOT in the treatment of MS. It was Kindwall who took the lead in arguing against the inclusion of MS in what was called the "approved category." During the discussion, Kindwall commented, in effect, that just because HBOT improves an MS patient's ability to control bladder function is no reason why it should be used in MS. As an aside, for those who are unfamiliar with the effects of the disease, bowel/bladder incontinence could be a major problem for MS patients. At a later date, I related the details of the discussion to David Youngblood, M.D.â€”at that time one of the few open-minded experts in hyperbaric therapy. David quickly responded by telling me that the next time I should remind Kindwall that there is an entire medical specialty dedicated to ameliorating people's bladder problems: It's called urology.

When the Kindwall paper appeared, I received some phone calls and correspondence from Mrs Diane Matalonâ€”a resident of Milwaukee and an MS patient who had been treated by Neubauer (5). She provided me with disturbing details about one of the authors. She claimed that this author, Bhupendra O. Khatri, a neurologist, had conflicting interests. She mentioned that he had been involved in a study of the effectiveness of plasmapheresis which he found to be effective. According to Diane, at that time he had a clinic in which he treated patients with plasmapheresis. Therefore, she pointed out the very real possibility that he was not about to let a competing therapy interfere with his very lucrative practice. She followed it up with sending me an extremely revealing article written by Neil D. Rosenberg (22). Rosenberg reported on a study of plasma exchange therapy, by Dr Khatri, a neurologist at St. Francis Hospital in Milwaukee who had been doing research on the subject since 1980. The work was published in the Journal of Neurology and found that 80% of 149 Milwaukee-area sufferers either improved or stabilized after plasma exchange treatments with an immune suppressive drug. However, Rosenberg reported that there was "a decade-old controversy over whether the plasma exchange technique is a boon or an expensive folly." In fact he wrote that "A top medical official with the National Multiple Sclerosis Society called the Milwaukee study flawed and `very difficult if not impossible to interpret. Stephen C. Reingold, vice president for research and medical programs of the National MS Society, said that the study did not use control groups to compare results and did not use a double-blind format, in which neither patient nor physician knows if a placebo or active ingredient is used on them. It is difficult to make claims in open trials' such as the Milwaukee study."

Rosenberg went on to report that "A similar Canadian study, which did use a double-blind technique and control groups, was published just three weeks ago in Lancet, a prestigious British medical journal. It reported such a regimen ineffective." This is not a surprising finding since the rationale for such a treatment is badly flawed. Even Rosenberg pointed out that "The disease is thought to be an autoimmune disorder, though that theory has not been proved conclusively. . .The allure of plasma exchange is that it can remove such antibodies (proteins that the body presumably produces against its own myelin) if they exist."

According to Rosenberg, Wisconsin is known to have one of the highest rates of MS in the world. He further pointed out the economics involved in plasma exchange treatments. "Before the Persian Gulf War, a single treatment cost as much as $800.00. When supplies of a protein replacement called albumin became scarce as a consequence of the war, the price of treatment jumped to $1,500. A treatment period usually takes five months and involves about fifteen exchanges."

If one assumes, therefore, an average price of $1,000 per exchange and multiplies that by 15 treatments, one gets $15,000 per patient per course of therapy. There were about 5,000 cases of MS in Wisconsin at the time this article appeared. If a person had just one tenth that number of patients who were undergoing therapy, the physician would have a minimum gross income of $750,000, which, of course, would be supplemented by other aspects of the medical practice.

In light of the above information, does not an intelligent person have to question whether there were motives unrelated to the science and medicine that influenced the initiation and outcome of a study of a competing and less expensive therapy? Does not one have to question the motives of the individual who evinced hostility to the treatment that he is investigating before starting the study and who then allied himself with a neurologist who had a potential built-in negative bias toward that treatment? Does not one have to wonder about the design of the experiment and its execution as well as to how the data were obtained?

The first of the two parts is best classified as anecdotal. The second describes Neubauer's and my reaction to the publication. However, the anecdotal aspect is important to help understand and enhance the impact of the next segment. If only I had been clairvoyant at that time, and realized how important would be the information I was being made privy to and which I am about to tell you, I would have made detailed notes and kept them. Unfortunately I was not endowed with psychic powers.

At the time the information for the registry was being obtained, I was also research director of what at that time was called the Jo Ellen Smith Baromedical Research Institute, located in New Orleans, LA, (later, the Jo Ellen Smith was dropped and the name shortened to just the Baromedical Research Instituteâ€”BRI). Along with Keith Van Meter, M.D., BRI's Medical Director and the man whose brainchild BRI was, I served as co-coordinator of Region 5 of the Diver's Alert Network (DAN). Part of my responsibility was to gather information on the number and types of hyperbaric centers there were in the region and the number and types of diving-related accidents the various hyperbaric centers had treated the previous year, collate the data, and submit the final tabulation to DAN. When I made my phone calls, I also spent time talking to the people about the number and types of cases they were treating, their outcomes, and if their facility was engaged in any research or if they were treating any unusual disease entity. Thus, I also had the opportunity to discuss what was taking place concerning HBO in general, in their geographic areas, with the HBO nurses and technicians at several hyperbaric centers that were part of the Kindwall et al. registry. It was during these conversations that information was revealed to me that was most disturbing. They reported that some of the MS patients, from a clinical perspective, were clearly showing benefit from the HBO treatments, but this was not what was being conveyed in the official reports. In fact, I was told that the opposite of what was being found was being reported. The people with whom I spoke reported that the neurologists were not really interested in the study; they were more interested in showing that HBO was an ineffective therapeutic modality for MS. I shared this information with Van Meter and several of my other physician colleagues in New Orleans. Neither I nor they could do more with the information, since I (and by extension they) were under oath not to tell others outside my immediate circle of hyperbaric colleagues in New Orleans; especially, I was not to tell anyone involved with the registry. They feared for their jobs.

After its publication, Neubauer and I wrote a detailed letter to the chief editor, Robert J. Joynt, pointing out the flaws in the Kindwall et al. paper and the inconsistency of the conclusions with the data. The editor stated that hyperbarics and MS "... [are] not an area where I have special knowledge so I cannot make personal comments." He sent it to two reviewers and they recommended revisions. The revisions were made but the response was not published. They refused to publish it, telling me that it was too long. At first it was. But it was not too long after the revisions were made. I even shortened the letter to one paragraph and still he would not publish it. I called and requested an explanation. He told me that I should understand that he had no intention of publishing any rebuttal. I called another editor, who at that time (may still be there) resided in Canada. He told me that the vote amongst the editorial board on publishing the Kindwall paper was split. It was the decision of the editor to go forward with the publication. He further said to me that if it was his decision to make, the paper would never have seen the light of day. Dr Joynt had recommended that I should submit a letter to the editor of the Controversies section. We did. It was not published. We were offered the opportunity to submit a paper developing the case for HBOT. We did. Not surprisingly, it was rejected.

Here is the body of the first letter we sent. Some of the material in the sociopolitical section will sound familiar. For the uninitiated, the expression P02 refers to the partial pressure of oxygen, an expression of concentration; it is part of the dose of oxygen. Though I will not discuss the subject here, the dosage of oxygen is not unlike what constitutes dosage of a non-gaseous drug (i.e., a pill or tablet). Dosage in hyperbaric therapy is some-what complex as it involves four components: pressure (concentration, the strength or dose of a given tablet), length of time of exposure (how long the effective blood level of a specific drug lasts), frequency of exposure (how often one has to take a repeat tablet; two or three or four times per day), total number of exposures (how many days, weeks, months, or years one has to take the medication). Pressure is an essential element in the dosage regimen.

We doubt that there has been a treatment proposed for MS that has elicited the same intensely negative emotional response from neurologists as has hyperbaric oxygen therapy (HBOT). Even many hyperbaricists joined the hurling of invective at those who endorse the use of HBOT for MS or other neurological disorders other than for those related to decompression sickness or air embolism. We stress the word emotional because much of the debate, unfortunately, has centered on emotion, even to the extent that investigators not only deliberately misinterpreted their data, but also used the wrong patient populations or the wrong treatment protocols. Others entered the fray before the complete data from ongoing experiments were available even though one of the critics had a conflict of interest because of his involvement with a competing therapy. These and other related issues have been addressed (1,2,3).

The paper by Kindwall et al. concerning the treatment of multiple sclerosis with hyperbaric oxygen that appeared in the February issue (Vol 45: 195-199, 1991) once again raises all of the scientific and nonscientific issues surrounding HBO and MS and is demanding of a critical and detailed response. In rejoining, there are issues pertaining to the science and the sociopolitical aspects of medicine that once again must be addressed. Unless one is aware of some of the sociopolitical facets of the subjectâ€”the use of HBO in the treatment of MSâ€”one would have difficulty in putting certain papers in this field in their proper perspective and know what degree of veracity should be attributed to the study. The Kindwall et al. paper more so than almost any other published on this subject is deserving of such scrutiny. We will discuss the scientific and medical aspects of the Kindwall et al. paper and then some of the sociopolitical perspectives related to it.

To obtain maximum results with HBO in treating MS, the basic principles of pharmacotherapeutics must be adhered to, i.e, oxygen tensions must be adjusted to individual patient's responses and patients should be treated at least until they are stabilized.

MS is a disease that is dose-sensitive with respect to oxygen. Dose-response relationships are fundamental to any chemotherapeutic regimen. This important pharmacological concept was not considered by Kindwall or any of the neurologists taking part in the Kindwall et al. registry when they designed their various MS/HBO protocols. At no time did any of the medical participants contact Dr Neubauer, the physician who discovered the use of HBO for treating MS and who has the greatest experience in the United States with the use of this drug for this purpose, to learn if there were aspects concerning the administration of HBO to MS patients that should be taken into consideration.

In the Kindwall et al. study, MS patients were exposed to different oxygen pressures irrespective of their response to that P02. No effort was made to readjust the P02 based on patient responsiveness. As Neubauer has pointed out, HBO in MS is similar to giving insulin to a diabetic. No internist or endocrinologist would ever consider putting all diabetics on the exact same insulin dosage regimen. Nor would any cardiologist consider putting all MI patients on the exact same anticoagulant dosage regimen. Failure to understand and apply this elementary aspect of pharmacotherapeutics not only immediately renders the entire Kindwall et al. study scientifically and medically meaningless, but also raises serious questions concerning the ethics of the study by the apprehensions and reservations that are generated concerning the quality of medical therapy provided to the patients.

In their Table 3, for example, Kindwall et al. reported that the chronic stable and relapsing remitting patients showed a tendency towards a decrease in the mean Kurtzke EDSS Score following 20 exposures to HB0T while the chronic progressive patients remained unchanged. The authors, without substantiating evidenceâ€”they had no control groupsâ€”attribute this improvement to a possible placebo effect. Yet based on the reported beneficial effects of HBO in MS (1), one can, with greater logic and credence, claim that the observed beneficial effects were due to the HBO. One can only wonder as to how much greater the improvements would have been if the treatments had been individualized.

Kindwall et al. provided some follow-up hyperbaric treatments after the first 20 treatments. However, KindwaII et al. missed one of the most salient aspects of any therapy, i.e., patients are treated at least until they are stabilized before a maintenance regimen is instituted. This is especially true concerning HBO treatment of MS. There is nothing sacred about the first 20 HBO treatments. Twenty treatments is a somewhat arbitrary endpoint. Empirically, it had been found to be a convenient point in therapy to help determine if there is any benefit accruing from the oxygen exposures. If there is benefit, then the patient is counseled to continue the therapy. If there is no benefit, the patient is advised that further HBO treatments, in all likelihood, would not provide any benefit. The minimum number of hyperbaric treatments required for an MS patient before putting the patient on a maintenance schedule is that which is required to stabilize the patient. The number of HBO treatments is not pre-determined by an arbitrary set number of exposures. Therefore, following evaluation after the first 20 HBO exposures, treatments are continued, assuming that benefit was obtained during the initial series of exposures, until the patient is stabilized. It is only after a patient is stabilized that a follow-up hyperbaric regimen is instituted. The specifics of the follow-up regimen are also determined by the responses of the patient.

Determining the specific oxygen tension with which a given patient is to be treated requires very close daily monitoring of each patient and requires titrating the patient with different oxygen tensions until the optimum oxygen pressure for treatment is ascertained. The patient is kept on the optimum oxygen pressure and carefully monitored until he or she becomes stabilized. If during this stabilization period there is any change in the patient's condition, then consideration must be given to readjusting the arterial oxygen tensions. Similar attention must be given to determining the follow-up regimen. Such careful daily attention to the treatment and care of the MS patients was absent from the Kindwall et al. study. The failure to attend to such details calls into question Kindwall et al.'s statement that "We made a good-faith effort to apply HBO treatment in the clinical setting as advocated by its proponents...."

Further support of the allegation that a good-faith effort was not made can be seen from their neglect of detail in designing follow-up regimens. At the end of their two-year follow-up period, Kindwall et al. reported a deterioration in the mean EDSS Score of the patients in their three groups. Yet in view of the fact that the dosages were not individualized, one cannot help but wonder whether the deterioration was not iatrogenically induced. There is no evidence that any of the patients were stabilized before they were put on a maintenance program. There is no evidence that a proper maintenance program was ascertained. Such a program could not be obtained without first having stabilized the patient.

It is known that using the wrong oxygen dosage (pressure-duration of exposure relationships, frequency of exposures, and number of exposures), patient deterioration will occur. Using arterial oxygen tensions equal to or greater than two atmospheres absolute (atm abs.) is fraught with danger. Many MS patients tend to deteriorate when exposed to oxygen pressures greater than two atmospheres. In the Kindwall et al. study some patients were even exposed to pressures as high as three atmospheres.

The authors do not provide data as to how many patients were treated at each of the different oxygen pressures. Apparently, the data were analyzed by lumping all the patients together, in each of three categorization groups, under the generic heading of HDO. There were no statistical analyses of the data obtained within each of these groups on patients treated at each of the different oxygen pressures. There was no statistical justification provided for the analyses that were performed. In view of the failure to analyze the data according to their dosage breakdown and the failure to stabilize patients, the statistical analyses that were performed were inappropriate. The authors did not and cannot provide valid statistical justification for the analyses they did. Statistical analyses should have been performed on patients, in each disease categorization, exposed to similar arterial oxygen tensions-duration of exposure profiles only after these exposures were individualized and the patients were stabilized. There should have been analyses indicating whether there were differences in results between participating institutions.

One cannot consolidate data obtained from different pressures-duration exposure regimens without first establishing statistically that the data can be so manipulated. There is no evidence that such sophisticated analyses were done. Kindwall et al. apparently tried to circumvent this criticism by combining the data from exposures to pressure equal to or below 1.75 atm abs. into one group and by merging the data obtained from treatments with exposures to pressures greater than 1.75 atm abs. into a second group. They offer no statistical justification for such manipulation of the data. In their Table 5, where the results of such inappropriate statistics are presented, we are left to wonder why they provided only initial and final EDSS scores and not the scores after the first twenty treatments, as they did in Tables 2 and 3. Yet despite any statistical manipulations, it is well known in hyperbaric medicine that the physiological, biochemical, pathological, and clinical sequelae will vary markedly, depending on the oxygen pressures employed (4).

Even follow-up treatment regimens must be individualized. There is no basis for a priori treating a patient only once per month as a follow-up, as Kindwall et al. had done. In many cases, Neubauer had used once a month follow-up treatments only because of logistic purposes pertaining to the availability of the patients; Neubauer counseled the patients for the need for more frequent follow-ups. Indeed, Paollota and Perrino independently confirmed that the more frequent the follow-ups the less apt were the patients to deteriorate and the greater was their degree of improvement.

It is the individualization of treatment that makes using a standard HBO protocol difficult; that is why no standard protocol has been published or adopted. Neubauer recently published a letter to the editor on this subject (5). It appeared four months before the Kindwall et al. paper was submitted for publication. The concepts expressed therein were not taken into consideration by Kindwall et al. when they wrote their paper.

The lack of attention to detail by Kindwall et al. also is evidenced by their failure to determine or report blood or alveolar P02 of any MS patient in the multiplace chambers. The best they could say is that with the face masks used the arterial oxygen tensions should approach a certain value. But they have no independent confirmation that such values were actually attained. As Gottlieb and Neubauer (1) pointed out, arterial oxygen tension seems to be very important in determining patient responsiveness.

Understanding the pharmacotherapeutics of HBO with respect to MS helps to explain some of the vagaries of the responsiveness of patients to different oxygen pressures, a point raised by Kindwall et al. and of which they should have been aware as this subject was discussed in detail (1). Also, Kindwall et al. reference papers presumably reporting negative results obtained with HBO without any discussion of the nature of the experiments performed or of their strengths and weaknesses. However, the authors chose not to reference the Gottlieb and Neubauer review (1) which discusses in detail all of these and other aspects of HBOT with respect to MS including the beneficial effects of HBOT.

There is much more to be said in criticism of the Kindwall et al. paper. However, we will limit it to one further observation. Kindwall et at. reference the short-term results of the Barnes et al. study reported from England in 1985, but they fail to report the data from the final report (6) in which Barnes et at. report that HBO improves cerebellar and bowel-bladder function in MS patients. Today, Barnes, the senior author of the initial and final reports, is supervising the HBO treatments of MS patients for one of the ARMS (Action for Research in Multiple Sclerosis) centers in England.

To understand the significance of what follows, it is important to inform the readers of the following: From its inception, about 1978, until 1989, SFG served with Kindwall on the Hyperbaric Oxygen Therapy Committee of the Undersea Medical Society (HOTC/UMS). Thus, he was well aware of Kindwall's attitudes and behavior concerning HBOT, even as it related to MS. Further, about 1986 in San Antonio, TX, at a meeting of the HOTC/UMS, Chairperson Jefferson C. Davis, M.D. (deceased) provided SFG with the opportunity for presenting the case for MS. It was Kindwall who took the lead in arguing against the inclusion of MS in the approved category.

Mrs Diane Matalon (DM: I have her permission to use her name) of Milwaukee, WI, reconfirmed for me, on Saturday, February 16, 1991, that which she told me on a previous occasion. In 1983, she was successfully treated with HBO by Dr Neubauer. He gave her a prescription for follow-up treatments in Milwaukee. Her husband went to see Dr Kindwall, who, at that time, was the director of hyperbarics at St. Luke's Hospital, about HSO treatments. Dr Kindwall told her husband that "even if you could afford the treatments, I would not give it to her because I do not believe in it."

DM told me that when she came back from being successfully treated with HBO in England in 1988, there was a write-up about her in a local MS Society newsletter. Pr Khatri, one of the co-authors of the Kindwall et al. paper, called her and "harassed" her. Part of the harassment consisted of telling her that HBO could cause her to go blind. When she challenged him on that point he backtracked and admitted that he heard of a patient going blind but that individual did not have MS. It is interesting that Kindwall et al. referred to an MS patient going blind as a result of HBOT. Yet they gave no published reference to that case nor did they reveal the name of the institution where that incident occurred so that independent verification could be obtained. Is that the same case that Dr Khatri told DM about? If so, one has to wonder if that patient really had MS or if that patient went blind from HBOT. To the best of our knowledge there is no case on record of a patient ever going blind from modern hyperbaric oxygen therapy. There are reversible changes in refraction as noted by Kindwall et al.

It must be pointed out that Dr Khatri has a vested interest in plasmapheresis as a competing therapy. He published a small study on this technique which, to no one's surprise, and contrary to other studies, showed that it was effective in treating MS.

Kindwall et al. mention that there was a large number of patient dropouts and loss of interest on part of the patients and neurologists. Yet during the period of data collection of the registry, SFG, because of his need to obtain information on treating diver-related accidents as part of his role as a regional co-director of the Divers Alert Network, had the opportunity to discuss what was taking place concerning HB0 in general, in their geographic areas, with the HBO nurses and technicians at several hyperbaric centers that were part of the Kindwall et al. registry. They reported to SFG that some of the patients who were clearly showing benefit from the HBO treatments were being reported as not benefitting. They reported that the neurologists were not really interested in the study; they were more interested in showing that HBO is an ineffective therapeutic modality for MS.

Kindwall et al. state in the introduction that "... it was imperative that a study be devised to gather meaningful data..." thus implying that no one else ever obtained meaningful data and thereby casting aspersions upon the honor and integrity of other investigators, irrespective of their attitudes about the usefulness of HBOT in treating MS. Yet Kindwall et al. designed a human experiment in which "There was no control group" and to which they admitted that " ... the data obtained from a long-term uncontrolled study would be crude compared to those derived from strictly controlled double-blind studies" Yet despite such obvious weaknesses in experimental design, these investigators, who claimed to be interested in obtaining "meaningful data," without any justification for not designing a double-blind study, or at least including a control group, deliberately designed and executed a human experiment that would provide "crude" data. Thus, at the outset, one has to question the ethics and the motivation underlying this study.

It is our contention that the only "meaningful" datum that was obtained from the Kindwall et al. study is how not to do clinical research.

We believe that the behavior and interests of two key authors of the Kindwall et al. study are not that of individuals who have a sincere scientific interest in the subject. The questions of motivation and ethics raised above concerning this study are reinforced by the aforementioned sociopolitical considerations. There is more that could be said about the sociopolitical issues, but we believe it is not necessary to reveal these at this time.

Because of its serious scientific design flaw, severe medical limitations, and questionable ethics, it is our conclusion that the Kindwall et al. study is one that should never have been undertaken in the form that it was, it should never have been approved by an Institutional Review Board, nor published in a peer-reviewed journal.

In a course I taught once a year in Mobile, the History of Biology, I introduced a special unit for the students, one to which students are rarely exposed, i.e., how to critique a published scientific/medical paper. One of the papers that I had the students read and critique was the Kindwall study. Even the non-biology majors were able to discern some of the major faults of the study. They were appalled at the poor quality of the work; this reaction on part of the students was without my prompting. They used to ask me how the editors ever permitted that paper to be published. I told them the stories of the editors refusing to publish my rebuttal and that one editor admitted that the paper did not have unanimous approval of the editorial board and that if it had been up to him the paper would never have seen the light of day.

We were not the only ones who thought so negatively of the Kindwall paper. In a devastating review of the Kindwall paper (Neurology Chronicle, 1(4) 9-10, 1991), Marc Fisher wrote (I will omit the reference numbers that appear in the text of his document):

â€œThis study supports the widely held clinical suspicions that HBO therapy has no significant beneficial effects on the course of multiple sclerosis in general or specific symptoms. The study, however, is seriously flawed and should not be used to provide support for this impression [emphasis mine]. The notion that a multiple sclerosis treatment could be accepted as beneficial, if it could be demonstrated to be overwhelmingly favorable in an open, non-placebo controlled, non-randomized trial, is not tenable. Such a study has too many inherent biases to be accept-able. Additionally, the course of multiple sclerosis is notoriously variable, so a control group becomes additionally critical. This study did not complete its stated goals, however limited. The data presented is confusing and difficult to interpret. The authors acknowledge many of the study's shortcomings, but this does not ameliorate the limited value of this study.â€

Dr Fisher apparently already had a negative view of HBO as a potential therapeutic modality for MS. It is interesting to note that in his references to the literature to support his view, he did not cite the extensive review that I wrote with Neubauer, but instead referred to two negative studies. Interestingly, both of those studies were critically commented on by us in our review. We showed that the Harpur et al. study had a basic technological flaw. The Wiles et al. study was shown by Philip James to have had an error in its statistical calculations. When Phil recalculated the statistical significance using the data published by Wiles et al. he found that the results for improving bladder function was highly significant as opposed to the Wiles et al. claim that their data represents "a trend in favor of the group given hyperbaric oxygen that was just short of significance."

I do not know Fisher nor do I know why he failed to refer to the latest and most comprehensive critical review of the field he is commenting on when he wrote his analysis or why he failed to understand the limitations of the studies he cited. Perhaps he was unaware of the review. But a thorough library search would have shown its availability. I could not and still cannot help but wonder if his views were not a reflection of a preconceived ideology nurtured by the prejudices of the NMSS.

The negative attitudes by members of the UHMS towards using HBOT for the treatment of MS and the carelessness concerning the design and execution of experimentation on HBOT on MS was demonstrated very poignantly by the Hart et al. and the Davidson et al. studies published in 1987 and 1989 respectively in the Journal of Hyperbaric Medicine. Hart et al. used MS patients with disability scores (Kurtzke VI) considered too high for experimental purposes. George Hart is a brilliant physician and is one of the great imaginative pioneers in hyperbaric medicine. When I read the paper I was perplexed as to why he would so uncharacteristically stoop to such a low level of experimentation. When I saw him I asked, "George, why did you do this? You know as well as I that no one uses patients with Kurtzke's greater than V in experiments. There is no current drug that is effective on such patients. Why are you expecting more from oxygen than you would from any other drug? This was an experiment that was designed to fail. That is unconscionable. You know that once your paper is in the literature, forevermore people are going to say hyperbarics doesn't work. They do not make distinctions as to the pressures used. All they will know is that oxygen didn't work." I never received a satisfactory response from him. Neubauer challenged this study with a letter that was published in the next issue of the journal.

The Davidson et al. study was particularly disgraceful. Neubauer and I wrote a detailed critique which was published some months later, March 1990. It raised profound scientific and ethical issues. Specifically, we concentrated on three main deficiencies: "the incomplete reporting of the methodology"; "the improper design and execution of human experiments, the interpretation of the data, and the ethics involved"; and "the failure to quote relevant literature." Prior to its appearance, the editor sent a copy of our critique to Davidson for his response. Below our published letter, the editor inserted the following: "Note: Dr Davidson has declined to respond:' Davidson's refusal to counter a devastating critique, one which questions his intellectual and ethical values and practices, speaks volumes.

It should be pointed out that published letters to the editor usually are not archived in databases whereas the actual study is. Unfortunately, despite their appearance and importance, critiques essentially die while the studies live on. The only exception to this generality is when a scholar comes along who does an in-depth analysis of a field and specifically looks to see if any published criticisms of any of the published work surfaced.

The Davidson article along with our published critique also was used by me to teach my students in the aforementioned History of Biology class how to analyze and comment on a scientific study. The students thought that their refusal to respond to the critique was devastating. Again, they were appalled. As the students put it, "It [the refusal] says it all." They felt that the silence provided veracity to the criticism.

It is my contention that commitment to an unsubstantiated ideology by true believers is responsible for the negative reception to a new idea. The extent of the commitment and the sway that the aforementioned ideology has over its adherents can be seen in the July 1988 issue of Neurology, Supplement 2; the entire supplement is devoted to a symposium concerning immunomodulators in the treatment of MS. Despite the heavily documented acknowledgment of the lack of evidence supporting the direct immunologic basis of MS (there is no evidence indicating that MS disturbance is the cause of the disease although there are indications that the immunological aspects of MS may well be due to secondary effects of the disease) and despite the equally heavily documented evidence of the failure of the immunomodulators and antivirals as therapeutic agents, and despite the recently widely touted use of total lymphoid radiation and evidence indicating that its use is unconscionable and may even be considered as bordering on the unethical, the symposium concluded with a call for more of the same sterile research approaches to therapy and the continued waste of valuable public resources. Although HBOT affects the immune system of animals and in experimental allergic encephalitis in animals (a recognized but poor animal model for MS, see below), and in MS, there is not a single mention of its use nor is there mention of the need for new ideas.

Chattaway (2) also reviewed the evidence for a viral and/or immunologic basis for MS and concluded, as did Gottlieb and Neubauer (1), that neither hypothesis can be supported by currently available experimental evidence. In a devastating conclusion he states, "the immune system is abnormal in MS but whether this is the cause or just a result of the disorder is unknown. Until one of these ideas [viral and/or immunological] is proved, trials of new treatments based on uncertain facts will carry on and the results are likely to reflect this."

Despite these reservations about the role of the immune system in MS, A.J.S. Rayl wrote a speculative article (Scientist, April 26, 1999, page 6) about the possibility of an oral treatment for MS being just "around the corner." He states, "Multiple sclerosisâ€”which produces symptoms ranging from visual problems or speech difficulties to loss of coordination, numbness, and paralysisâ€”is an autoimmune disease wherein the protective layer surrounding the nerves in the brain and the spinal cord is damaged."

I responded to that letter. It was published. For the general leader, I apologize for the more technical aspects of the letter. I am including the references that were included with the letter, primarily because of Reference 6. That case had profound ethical implications that unfortunately were missed by all those involved in the Kervokian debate. I sincerely doubt whether Kevorkian, or anyone else involved in counseling the patient, had discussed with this patient the possibility of treatments other than those based on the viral or immunologic concepts advanced by the NMSS, the failure of which undoubtedly contributed to her despair.

A.J.S. Rayl's article on the possibility of an oral treatment for multiple sclerosis (MS) once again points out the need for new thinking about the causes and treatments for MS. For over 50 years, the public has been inundated with incomplete and misleading information about the nature of MS, its origins, and potential treatments. The "MS industry" has been touting either the infectious (bacterial or viral) or immunological etiology of the disease along with the experimental autoimmune encephalomyelitis (EAE) as the paradigm of the animal model (2,3).

The much-touted EAE model is nothing more than a model for inducing immunological reactions, not for mimicking MS. One specific example should suffice to substantiate this claim. In MS, perivascular infiltration and cellular inflammatory response follow myelin destruction, whereas in EAE infiltration and inflammation precede the breakdown of myelin, as one would expect in any experimentally induced immunological reaction against myelin or one of its derivatives. These differences between the actual disease process and the induced disease may provide the basis as to why the various immunological agents proposed as treatment for MS have not had the success the EAE model would predict. This includes copolymer I and Betaseron (interferon beta-I b).

With respect to the infectious concept of MS, not once has a bacterium or virus been isolated from an MS lesion that produces the disease in any animal and that meets Koch's postulates (2,4). Contrast these long-term negative results with the rapidity with which the AIDS virus was isolated and identified.

The desideratum in MS research is new ideas based on solid observation of the actual disease process. One of the prominent features of the MS lesion is the involvement of the cerebral vasculature; the lesion is primarily perivenule. Thus, concepts pertaining to the etiology of MS perhaps should focus on this vascular relationship. The Gottlieb-Neubauer vascular-ischemic model (3) of MS provides an explanation for the immunological changes being viewed as a response to rather than a basis for the MS disease process. It also explains why there has been an unending failure to isolate an infectious agent from the brain of MS patients. The Gottlieb-Neubauer concept that MS may be viewed as a wound in the central nervous system resulting from a vascular dysfunction provides the basis for a rational therapy that, in double-blind studies, has shown to be effective in decreasing rates of exacerbation and increasing the times of remission, especially when applied early in the disease and continuing throughout life (2,3,5).

The time is ripe for members of the "MS industry" to open their minds to new concepts and new approaches to treating this debilitating and demoralizing (6) disease and not repackage old and barely useful therapies based on fallacious concepts.

1. A.J.S. Ray. "Oral treatment of MS just around the corner?" Scientist, 13(9) 6, April 26, 1999.

2. S.F. Gottlieb, R.A. Neubauer, "Multiple sclerosis: its etiology, pathogenesis, and therapeutics, with emphasis on the controversial use of HBO," Journal of Hyperbaric Medicine, 3: 143-64, 1988.

3. S.F. Gottlieb, R.A. Neubauer, "The etiology of multiple sclerosis: a new and extended vascular-ischemic model," Medical Hypothesis 33: 23-9, 1990.

4. S.J.S. Chataway, "What's new in the pathogenesis of multiple sclerosis? A review?' Journal of the Royal Society of Medicine, 82: 159-62, 1989.

5. Personal communication as of April 1999: Dr David Perrins of England via Dr Philip James of Scotland based on almost 20 years of experience with therapy provided through ARMS.

6. One of Dr Kevokian's patients was a young woman, early 40s, newly diagnosed with MS, who opted for self-extinction rather than face the future debilitation from the MS disease process.

The extent to which the immunological causation of MS had been imprinted on the scientific- medical profession can be seen from two incidents that occurred four years apart in the same journal. (Undoubtedly, there are numerous other incidents that could be referred to. However, these are two in which I involved myself.) In the July/August 1990 issue of Lab Animal, there was an item that appeared in the Newsfronts section that alluded to some findings on the EAE model that presumably had implications for MS. The following month, the journal published my response the editor(s) titled it "No Autoimmunity in MS" in which I explained why the EAE model is a poor model for MS: "...in EAE, myelin destruction results from the lymphocytic infiltration, whereas in the human, phagocytic infiltration follows myelin breakdown." It seemed to me that it was (is) somewhat of a disservice to the scientific and medical communities and to MS patients to continue to represent MS as just an autoimmune disease. Therefore, there are valid reason for recognizing and financially supporting research into hypotheses that compete with autoimmunity. Four years later (November 1994), Lab Animal had another Newsfronts item about a new MS vaccine based on the EAE model. Once again, I wrote about the limitations of the autoimmune approach to studying MS, but this time my letter was not published.

The viral etiology of MS is another concept that has little experimental support yet is still widely promulgated by the NMSS. In fact, if people were to have kept the press releases of the NMSS over the last 40 or more yearsâ€”which, unfortunately, I did not; I was insufficiently prescient to foresee their importanceâ€”they would have found periodic announcements of a new virus that was suspected of being the cause of MS. Yet there was never an announcement showing that what was considered a potential cause of MS proved not to be the case. The failure to tell the public of such negative findings parallels the behavior of the NMSS when the final results of the Barnes et al. study with its positive findings on the beneficial effects of HBO was published. As noted before, the initial study with its preliminary negative findingsâ€”based on the failure to interpret their data properlyâ€”was given wide publicity. I could never help but wonderâ€”and I mentioned this in both open scientific presentations and discussions as well as in private conversationsâ€”whether the press releases were not used as public relations ploys to promote the organization's fund-raising efforts. What a cynic I had become with respect to the NMSS.

My qualitative observations of the relationship of viruses to the causation of MS and the unconscionable behavior of the NMSS recently were buttressed, independently, by the more quantitative data attributed to Steven Jacobson, chief of the viral immunology section at the National Institute of Neurological Disorders and Stroke, by Douglas Steinberg. Steinberg had written a two-part series "on the difficulties of proving that a virus contributes to a disease. The first article, on mouse mammary tumor virus and human breast cancer, appeared in the April 17 issue of the Scientist." The second article, "Does multiple sclerosis have a herpesvirus connection?" appeared in the May 1, 2000, issue of the Scientist pages 16-17.

Steinberg states: â€œYears of research have yielded many ideas but little certainty about the cause of the disease [he cites a 1997 reference of H. Black, â€˜Multiple sclerosis research yields few concrete answers,â€™ that appeared in the Scientist on page 12 of the September 13, 1999 issue]. The general view is that demyelination results from an autoimmune inflammatory reaction.â€

As an aside, at this point Steinberg, to his credit as a reporter, and apparently uncharacteristically for people in the MS research, mentions a different view of the situation by referring to my letter of September 13, 1999. This is the letter to the Scientist I quoted earlier in which I criticized the EAE model and mentioned the vascular-ischemic alternative.

â€œ But what triggers that reaction? And what chain of events leads to the destruction of myelin?â€

Another aside: Steinberg, of course, is implying that the break-down of myelin is secondary to some primary insult. He goes on to discuss the possible role of a specific virus as being the cause of the primary lesion, whereas Neubauer and I contend that the primary lesion is damage to the vascular system.

â€œGiven the apparent involvement of the immune system in MS, viruses have long been suspected as contributory agents. â€˜The first slide I give in my talks is a survey of all the viruses associated with MS for the past 50 years,â€™ says Steven Jacobson... The listâ€”only a partial one, he stressesâ€”includes 17 viruses, among which are rabies, measles, and several herpesviruses.â€

According to Steinberg, even the National Institutes of Health is tired of supporting viral research as a causative factor in the etiology of MS.

â€œ Indeed, while scientists in Japan and Europe have been publishing many papers on HHV-6, Americans seem to be far less active on this research front. An oft-cited reason is lack of money and personnel... As for funding, interviewees for this article...most had given up on the National Institutes of Health as a source of financial support.

â€œTrying to explain NIH's attitude toward HHV-6, Carrigan [Donald R. Carrigan, an HHV-6 researcher at the Institute for Viral Pathogenesis in Milwaukee] speculates that â€˜the edict came down from the upper echelons of [the National Institute of Allergy and Infectious Diseases] that since this view is ubiquitous, it can't cause any disease.â€™"

Aside: Steinberg refers to a book in which Carrigan's travails in securing financial support for his studies are detailed: The Virus Within, Dutton, 2000, by journalist Nicholas Regush.

â€œPellett [Philip E. Pellet, chief of the herpesvirus section at the Centers for Disease Control and Prevention (CDC) in Atlanta] says that HHV-6 research â€˜somehow was not deemed coolâ€™ at NIH and hasn't received enough support from disease-specific lobbying groups.â€

Another aside: How much further along would advances in MS be if Neubauer and I had a lobbying group similar to the NMSS lobbying for our cause? Just asking.

â€œBut Jacobson, who is at the NIH and says he sits on a lot of funding committees, is concerned that grant applicants rely too heavily on a single approach such as testing for antibodies.â€™ I really believe good projects will always be funded,â€™ he asserts. General skepticism about a tie between HHV-6 and MS has also contributed to the reluctance to fund research... More damaging from her [Friedman, the physicianâ€‘scientist at Rockefeller] view is the More damaging multitude of viruses blamed for MS over the decades.â€

Has not the time come to supplant the wishful thinking and practices of the true believers with new concepts and effective therapies based thereon? Specifically, has not the time come for improving current therapies or developing new therapies designed to affect the initial stages of the disease process involving the vascular system rather than concentrating only on what may be secondary manifestations of the disease?

At the beginning of the chapter I commented that it was unfortunate that the word versus was used. The reason being is that HBO should not necessarily be used as a therapy that is in opposition to anything. HBOT represents another approach to treating MS. Neither Neubauer nor I consider HBOT as necessarily being the sole approach to treating MS. HBOT may well have enhanced effectiveness or enhance the effectiveness of other therapies when used in conjunction with the other forms of therapy. It would not be surprising to us to find that MS may require a multifaceted approach to its therapy.

The current immunologic therapies seem to be based on secondary stages of the disease process. In contrast, HBOT seems to be exerting its effects on the earlier stages of the disease process as well as the secondary stages of the pathological process. HBOT should not be ruled out as a therapeutic modality either because of people's preconceived ideology or ignorance.

The time has come to do away with the opprobrious appellation â€œcontroversialâ€ from hyperbaric oxygen therapy. Neubauer and I proposed that, based on the available evidence (1,6), HBOT be used for treating early MS and for treating MS associated cerebellar and bowel/bladder dysfunctions.

Perhaps the time is ripe for detailed studies to be designed and carried out in which combination therapy is tested. Therefore, I further propose that resources be redirected to support long-term continuous monitoring of individual patients, with the individuals serving as their own historic control, coupled to real-time monitoring of CNS tissue changes so as to assess the efficacy of treatment protocols of HBOT alone and in combination with other therapeutic agents, and to define the population of MS victims who would most likely benefit from this therapy. To assure maximum utilization of resources and to attempt to keep improper protocols and their resultant data from cluttering and confusing the literature, I propose that such studies be carried out with the meaningful participation of those scientists and physicians who understand the issues involved in using HBOT in MS and who have been successful in its use in treating MS.

1. Gottlieb SF and Neubauer RA. Multiple sclerosis: its etiology, pathogenesis and therapeutics with emphasis on the controversial use of HBO. J Hyperbaric Medicine, 3: 143-164, 1988

2. Chattaway SJS. What's new in the pathogenesis of multiple sclerosis? A review. J Roy Soc Med, 82: 159-162, 1989.

3. Steinberg D. MMTV and breast cancer. Scientist 14: 8, April 17, 2000. Does multiple sclerosis have a herpesvirus connection? Scientist 14: 10, 17 April 1, 2000.

4. Gottlieb SF. Use of HBOT for MS surrounded by controversy. Suburban People, Mobile Press Register, 18, December 26, 1985. (Courtesy of the Mobile Register 2000 Â©. All rights reserved. Reprinted with permission.)

5. Gunn D. MS puzzle: battle develops over a therapy. Milwaukee Journal, Monday, July 31, 1989, 1-D.

6. Gottlieb SF, Smith JE, Neubauer RA. The etiology of multiple sclerosis: a new and expanded vascular-ischemic model. Medical Hypotheses, 33: 23-29, 1990. (A humorous anecdote accompanies this publication. The editors mistakenly included one of my places of employment as a co-editor. There is no person JE Smith who co-authored this article. JE Smith represented the then â€˜Jo Ellen Smith Baromedical Research Institute,â€™ New Orleans, LA, where I served as Research Director in addition to my job as professor in the Department of Biological Sciences at the University of South Alabama, Mobile, AL.)

7. Mertin J, Rudge P, Kremer M, et al. Double-blind controlled trial of immunosuppression in the treatment of multiple sclerosis: final report. Lancet II, 351-353, 1982.

8. Barnes MP, Bates D, Cartlidge NEF, et al. Hyperbaric oxygen and multiple sclerosis: short-term results of a placebo controlled double-blind study. Lancet 1, 297-300, 1985.

9. Jain KK. Textbook of Hyperbaric Medicine, 3rd Revised Edition, Hogrefe & Huber Publishers, Inc., Seattle, WA: 1999.

10. Hampson NB. Hyperbaric oxygen therapy: 1999 Committee Report. Undersea and Hyperbaric Medical Society, Kensington, M.D., 1999.

12. Sukoff MH and Gottlieb SF. Hyperbaric Oxygen Therapy. Eliezer Nussbaum, Editor, Pediatric Intensive Care, Futura Publishing Co., Mount Kisco, NY, 1989, 483-507.

13. Davis JC and Hunt TK (Editors). Hyperbaric Oxygen Therapy. Undersea Medical Society, Inc. Bethesda, M.D., 1977.

14. Davis JC, Hunt TK (Editors). Problem Woundsâ€”The Role of Oxygen. Elsevier, New York, 1988.

15. Gottlieb SF, Longmuir IS, Totter Jr. Editors. Oxygen: An In-depth Study of Its Pathophysiology. Undersea & Hyperbaric Medical Society, Bethesda, M.D.: 1983.

16. Barnes MP, Bates D, Cartlidge NEF, et al. Hyperbaric oxygen and multiple sclerosis; final results of a placebo controlled, double-blind trial. J Neurosurg Psychiatr, 50: 1402-1406, 1987.

17. Hart S. Medical journal publishes USA researcher's work. Mobile Press Register, Monday, April 9, 1990, 1-B.

18. Hart S. Views of multiple sclerosis change. Mobile Press Register, Sunday, May 13, 1990, 9-B.

19. Hart S. Mobilian links MS to blood vessels. Mobile Press Register, Sunday, May 13, 1990, 9-B.

20. Highlights: Mobile scientist honored for research. Mobile Press Register, Sunday, March 31, 1991, 12-B.

21. Kindwall EP, McQuilen MP, Khatri BO, et al. Treatment of Multiple sclerosis with hyperbaric oxygen. Results of a national registry. Archives of Neurology 48: 195-199, 1991.

22. Rosenberg ND. Effect of plasma transfers on MS still unclear. Milwaukee Journal, Monday, March 18, 1991, MS-1, 6.

â€œSuperstition, idolatry, and hypocrisy have ample wages, but truth goes a-begging.â€. Martin Luther

NMSS, with the help of the UHMS, has won: there are minuscule numbers of MS patients in the United States who are being treated with HBO. Yet somewhat unbelievably, the attacks continue, and one has to wonder why.

In 2001, the Undersea and Hyperbaric Medical Society published in its journal (Undersea Hyper Med 28(3): 113-130) a series of three articles by five authors attacking the use of hyperbaric oxygen therapy primarily for multiple sclerosis and secondarily for other "off-label" uses. The first was an editorial, the second was a position paper, and the third pertained to ethical dilemmas in hyperbaric medicine. One must also under-stand that the appellation â€œoff-labelâ€ is one that is designated by the UHMS and does not reflect the view of hyperbaricists throughout the world, let alone in the United States. The use of hyperbaric oxygen therapy for multiple sclerosis had been approved by the American College of Hyperbaric Medicine for over a decade (I was on the original board that approved its use) and by hyperbaric societies in various European and Asiatic countries. However, after its leadership was essentially taken over by people more in tune with the philosophy of the UHMS, it now follows the dictates of the UHMS instead of being an independent voice for the field, as it was originally intended.

To understand the above action on the part of the UHMS one must understand not just the material that was presented above but also a certain statistical concept, meta-analysis, that is referred to in the aforementioned published papers. What follows in the ensuing eleven indented paragraphs below is a reworked article I prepared for publication in Hyperbaric Medicine Today. Unfortunately, other issues arose in the interim with which the editor and publisher, Ken Lochlear, had to contend that he had no room for it. I reworked the original and submitted it to the prime professional journal in the field of hyperbaric medicine, Undersea and Hyperbaric Medicine. I am reprinting it here and omitting the scientific references. For those who may find the discussion somewhat technical, just read at least the first and last paragraphs (preferably the first three paragraphs), skip the next eight, read the last paragraph, and continue with the story. Meta-Analysis: Is it the statistical analytical pancea?

"There are three kinds of lies: lies, damned lies, and statistics." Benjamin Disraeli (quoted by Mark Twain)

Since 1976, when it was first introduced into modern statistics as a research tool, there seems to be an increasing interest in and a growing dependence on meta-analyses as a means of assessing the efficacy of a variety of medicinal and therapeutic procedures. There seems to be a perception that meta-analytic results are holy, should be considered above reproach, and used as a means to curb or terminate further discussion or investigation. Yet despite its growing popularity, especially with the development of evidence based medicine, I contend that meta-analytical techniques can be quite deceptive and misleading.

Meta-analysis, a statistical technique that dates back to the 18th century, consists of taking data from large numbers of individually published studies, combining them, and then redoing the statistics based on the combined data with the intent of integrating the available information. On the surface, meta-analysis seems to be a reasonable time- and resource-saving technique. Meta-analyses may realize these expectations if the studies that are being combined are similar in design and execution, including drug dosages.

However, there are severe theoretical and practical problems associated with meta-analyses. Meta-analyses may tend to mix good and bad studies. There is also the problem of whether to include all the studies ever done or just select a certain number of studies. And, if there is to be a selection, there are additional questions: Should there be a selection? Will the selection be done randomly? If it isn't random, what will be the criteria upon which the selection will be based? And who will be making the selections? Therefore, depending on how any given meta-analysis is being performed, the final statistical results could overestimate or underestimate an effect. Obviously an investigator's preconceived bias(es) in selectionâ€”depending on the pool of data avail-able and the selection processâ€”can and will skew results, thereby providing investigators with a technique to obtain desired results.

A specific example will demonstrate the difficulties with meta-analysis. Dosage in hyperbaric oxygen therapy (HBOT) consists of four separate but interrelated variables: pressure, duration of exposure, number of exposures per day, and total number of exposures. One other factor becomes very important, i.e., the patient cohort. For example, in research into multiple sclerosis, experimental subjects are selected who have Kurtzke scores of 5 or less. Usually, the lower the score the more likely one is to see an effect. Selecting patients with Kurtzke scores of 6 or more, as has been done in at least one HBOT study involving MS, is to bias the study so that there will be a negative outcome, especially when sweeping generalizations concerning the inefficacy of HBOT are drawn.

It is because of the aforementioned theoretical and practical analytical difficulties combined with the complexities of hyperbaric oxygen therapy (HBOT) that Neubauer and I avoided using meta-analysis in our 1988 review and critique of the then-available literature on the use of HBOT in the treatment of multiple sclerosis. Instead, we chose to examine and comment on each of the published studies individually, in light of the individual components that constitute dosage in HBOT and the known physiological, biochemical, pharmacological, and pathological actions of oxygen.

What is easily forgotten in hyperbaric therapy and research is that the physiological, biochemical, pharmacological, pathological effects of oxygen will vary depending on the pressure-duration relationships that are used. It is easy to lose sight of the fact that what seem to be small changes in pressure, in terms of absolute numbers, in reality may represent a large change in concentration of oxygen. Ultimate clinical outcomes may depend on the pressure-duration relations employed for a given disease, the number of treatments per day, the total number of treatments, and patients' responsiveness. Based on current knowledge, this is especially true in treating brain injury. Because of the interplay of the aforementioned first four factors, over which investigators have direct control, it is important, when assessing a study or comparing studies, to keep in mind the complexities of the biologic effects of oxygen. It may be best to avoid combining two different experimental protocols in which the above variables are not the same and call them the same for the purposes of a meta-analysis.

Oxygen, although a drug, has wide-ranging, direct biologic effects that can alter its effectiveness depending on the pressures employed in combination with the duration of exposure. For example, it is currently understood that when using HBO on the injured brain, one probably should not be using a pressure greater than 1.5 atmospheres; pressures greater than 1.5 may tend to enhance pathologic processes. Oxygen administered at a pressure of 1.5 atmospheres is not the same as oxygen given at 2.0, 2.5, or 3.0 atmospheres. These pressure differences represent large changes in the concentration of oxygen being delivered. Brain injury, irrespective of its etiology, does not represent situations where some oxygen is good and more is better. The final result in studies with the higher pressure may be misleading. Indeed, the initial studies on the use of the higher pressures for treating post-stroke brain injury led to misleading generalizations about the usefulness of HBOT.

Bennett, commenting on the Scheinkestel et al. study, a randomized, double-blind study using HBO for treating CO poisoning in which there was presumably a comparison between normobaric and hyperbaric oxygen (2.8 ATA, 60 min, 3 daysâ€”total chamber time 100 min, normobaric oxygen between treatments and repeat for another 3 days if symptoms persisted) with an average delay of 7 hours before treatment, noted that "Minimal improvement in mini-mental state assessment before and after treatment in either group is puzzling." Yet such results may not be puzzling if one considers that pressures greater than 1.5 ATA tend to be toxic to the injured brain. If such data were to be included in a meta-analysis, it would skew the results against the use of HBO in treating CO-induced brain injury.

When comparing multiple pressure-duration protocols for a given disease in which there are similar outcomes, instead of combining the data and treating them as one, as would be done in a meta-analysis, arguably I think it would be best to say, in essence, "that multiple pressure-duration exposures seem to produce similar effects."

However, if one adopts this position, then one should note possible differences in the time in which beneficial effects are obtained or in the total number of treatments employed to obtain a given effect. Total number of treatments may remain the same but be given in shorter or longer periods of time, depending, in part, on the number of treatments given per day and the individuality associated with the pathologic process. Ultimately what basic and clinical scientists say and do about the efficacy of HBO is greatly influenced by personal bias, politics within the field, ego, and greedâ€”the competition for research and clinical funds.

To understand how to analyze multiple studies with several inter-dependent variables, initially it may best be done qualitatively as was performed by Gottlieb and Neubauer. Then, if a more quantitative approach is required, at least there would be a scientific basis for setting parameters for categorizations and selecting studies for an ensuing meta-analysis.

Despite its potential shortcomings and the controversies that may be engendered therefrom, meta-analysis can have a useful place in basic and clinical research. However, when publishing a meta-analysis, it is imperative that the issues I raised above be addressed openly so that the audience is aware of the degree of credence that an investigator can place on the results obtained there-from. If not discussed, there is the problem of knowing how much credence one can place in a meta-analytic study. It would be wise to recall Andrew Lang's adage: "He uses statistics as a drunken man uses lamp-posts... for support rather than illumination."

Although this chapter is devoted to the treatment of multiple sclerosis, I will digress for one paragraph because I want to demonstrate the biased nature of the individuals and the professional society involved in the controversy. In the published editorial, Professor Irving "Jake" Jacoby ironically writing in the section "Ethical dilemmas" states:

"As an example, let us look at the indication of increased intra-cranial pressure following head injury. This was formerly an approved indication, but after the studies by Rockswold... it [HBO] was removed from the list of approved indications." But what Jacoby writes is not true. I was at the meeting in San Antonio when that decision was made; Jacoby was not. The reason it was removed from the approved indications had everything to do with personality and vindictiveness against Dr Michael Sukoff, the man who made the original discovery about the usefulness of HBOT in treating increased intra-cranial pressure. Further, when this action was taken by the Hyperbaric Oxygen Therapy Committee of the UHMS, the Rockswold studies had not even been published.

In referring to Rockswold's work, Jacoby failed to refer to the criticism of that study that Neubauer and I published in the same journal that Rockswold et alts work appeared (Journal of Neurology 78: 687-688, 1993) in which, inter alia, we pointed out that they did not use the optimum dosing schedule. In response to our criticism, Rockswold stated: "We agree that this study probably did not use the optimum dosing schedule for HBO treatment in severe head injury."

This book is not the proper forum to discuss the details of such scientific and medical disagreements. My intention for mentioning the above is to point out that the UHMS is willing to make decisions based on improper data. This has bearing not only on the treatment of MS with HBO but also on the treatment of brain injuryâ€”irrespective of the causeâ€”including the treatment of cerebral palsy.

Because this is not the proper forum, I will not be discussing all the very profound weaknesses of Jacoby's editorial. However, I will mention one that specifically concerns MS.

"...there may be small niches where HBO may have some very limited temporary utility, such as with the transient symptomatic sphincter tone improvement noted by Barnes et al....all observations of minimal transient effect are irrelevant to the overall clinical course from this disease."

Ask any MS patient who has problems with bladder/bowel control and they will tell you how, when they experience the urge, they must get to the bathroom immediately or there will be "an accident." Any improvement in their ability to control these excretory functions, even a transient one, is not irrelevant. Dr Dave Perrins used to tell about a man in England who was in a continuous sleep-deprived state because his wife had MS and he had to carry her to the loo every hour during the nightâ€”about six or eight times every nightâ€”for years. After she received HBOT, she was able to improve her bladder control to the extent that he took her to the loo only about twice per night. His and his wife's relief was great; finally, both could get longer periods of undisturbed sleep. Phil James told me that there have been many such stories. He wrote: "I recall in August 1982, during the treatment of the first group of patients in our charity chamber, one lady, who had nocturia regularly six times at night, reported sleeping through the night after the FIRST treatment." Small niches? Irrelevant? Indeed! One can truly appreciate Dave Youngblood's previous poignant comment about urology as a medical sub-specialty.

As of this writing, according to Dr Neubauer, there are approximately 12,000 MS patients in Great Britain who currently are being treated with HBO in 110 centers. In Great Britain, there are now 20 years of follow-up data that are available on many patients. As stated earlier, there are only a minuscule number of MS patients being treated similarly in the U.S.

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