For a number of years I’ve had a fascinating book on my shelf. Every once in a while I pull it down and draw courage from it. I resolve to write a newsletter about it at some point, and then it goes back on the shelf. It is the autobiography of Jack Dreyfus, he of the Dreyfus Fund, Lion of Wall Street, who turned his interests to medicine in the later part of his career to promote greater utilization of Phenytoin (Dilantin, PHT) for a whole host of medical conditions.

The frustrations he faced in his mission were in many ways parallel to what we have faced in neurofeedback. Perhaps it is still not too late for us to draw some lessons from his experience. Dreyfus suffered a first major depression at the age of 45 in 1958. Onset was quite sudden, as he awakened one morning in a state bordering on terror, overwhelmed with fear. The dominant symptom was a turned-on mind that was always riveted on negative thoughts related to anger and fear. But there were other symptoms as well, including daily headaches, frequent stomach irregularities, chronic neck pain, lack of energy, trembling of limbs, and cold hands and feet. The depression was major for a year, but continued for five years. Over a period of years he would see his doctor, a neuropsychiatrist, five or six times a week. That must have been more for companionship than relief, because relief was not on offer.

Dreyfus observed that his sudden mood swings would occur without any apparent provocation, either psychological or environmental. On one occasion, a young woman took his hand and massaged his fingers. Tension drained from him, which he sensed as electricity leaving his body. This triggered recollections of earlier encounters with electricity, such as when he received a shock from an electric wall socket as a child and experienced intense fear such as he was feeling now in his depression. On a couple of occasions he had an experience of sleep paralysis. He felt that he was awake but he could not move or open his eyes. His memory of the event was one of being frozen with electricity.

The association of his condition with electricity then led to his thinking in terms of epilepsy as an electrical storm in the brain, and to the possible utility of an anti-convulsant for his condition. His doctor, fresh out of ideas, did not object. “You can try it if you like. I don’t think it will do you any good, but it can’t do you any harm.” Fortunately for us, medical doctors tend to feel the same way about neurofeedback. The year was 1963.

The story only goes on because Dilantin did in fact resolve his depression, and Dreyfus saw his doctor only three more times. “The headaches, the stomach distress, the neck pain all disappeared.” “Although Dilantin had a calming effect on me, to my surprise it didn’t slow me down. On the contrary, my energy returned full force.” That matches the reports we get for effective neurofeedback. Calmness, alertness, and high reserves of energy are mutually compatible in the balanced brain.

Over the subsequent year, Dreyfus had occasion to send six people to his doctor as candidates for Dilantin for reasons similar to his own, and they all responded as well. Dreyfus keyed on the issue of the cluttered mind, of multiple thoughts active in the brain all at the same time, as an index to a hyper-excitable brain that could be stabilized with PHT. Effectiveness in this case could easily be established even by a layman such as himself, and could be established very quickly. Response to the PHT was expected within an hour. As a Wall Street investment manager, Dreyfus had a good grasp of probabilities, and when something is observed with this level of consistency—seven successive cases— one is no longer dealing with mere anecdote. Even with only a 50% likelihood of success in each case, the odds against seven successive good outcomes was 127 to one. When the focus is further narrowed to determine that a substantial change in mental state took place over the course of an hour, then the Dilantin is even more clearly implicated.

It is of course with this same kind of reasoning that things have progressed with neurofeedback as well. In each case, a judgment is made about the likelihood of the actual outcome versus the status that would have prevailed in the absence of neurofeedback. The more striking the contrast, the more compelling the case for neurofeedback becomes to the actual observer. Unfortunately, the opposite tendency prevails for the outside observer. The more startling the finding, the less likely that it will find resonance with the uninitiated.

Dreyfus then launched on a campaign to kindle interest within medicine of the larger clinical potential of PHT. In this he was encouraged by what was said about Dilantin even in a standard reference text, the “Pharmacological Basis of Therapeutics,” by Goodman and Gilman: “Coincident with a decrease in seizures there occurs improvement in intellectual performance. Salutary effects of the drug PHT on personality, memory, mood, cooperativeness, emotional stability, amenability to discipline, etc., are also observed, sometimes independently of seizure control.” I feel compelled to interject into this recapitulation our own experience years later with our son Brian. In his case Dilantin (with the later addition of Tegretol) controlled his seizures and calmed his violent behavior. We also observed the improvements listed above. Even more significant behavioral change came years later when we added neurofeedback. Somehow it all seemed to be part of the same story. We were using divergent modalities to address the same issue—a hyper-excitable, unstable nervous system. Tame dysfunction, and function emerges.

Dreyfus first tried to get a study done, but the money he put up simply disappeared. He got back a volley of excuses. Meeting with his brain trust of supportive MDs who by now had their own evidence of the value of PHT, he suggested simply getting the data that already existed into the literature. That was deemed to be impossible unless a controlled study was involved. After all the frustrations had been aired, the most sensible suggestion was: “If you want to get anything done, you have to do it yourself.” This also parallels our own experience. After we built our first instrument, the NeuroCybernetics, I spent the first year trying to establish linkages with the medical profession and with mental health professionals. These efforts were universally rebuffed, so it became clear to us very quickly that nothing was going to happen unless we did it ourselves.

In 1965, Dreyfus established the Dreyfus Medical Foundation and set about to get more studies done. They projected that a few small studies funded to the tune of $150,000 should do it, and then the PHT prairie fire would be set among the professions. The first study cost $57,000 and turned out to be another dud—not in the sense of failed outcome, but simply that PHT was never really subjected to test. Dreyfus himself participated in the second study that was funded. It was a double-blind study done with prisoners. The outcome was stunning in its statistical robustness. The staff correctly identified ten of the eleven prisoners who were getting the PHT during the double-blind phase of the study. And, as is often the case with remedies that are sufficiently availing, a number of subjects noticed the difference also. “An hour after I took the pill, I could have told you that it wasn’t sugar.You could feel the engine just slowing right down.” So much for the double-blind paradigm. A single-blind portion followed, in which the placebo recipients were switched to PHT without being told. The study also included a withdrawal phase. Both only further buttressed the conclusions.

Dreyfus listed two more studies done in institutional settings in which he was involved. Each confirmed the prison study. Three additional such studies were done outside of the country. By this time, Dreyfus had observed that the medical enterprise did not have a Receiving Department. He decided to go to the top, to the government agencies. He met with John Gardner, Secretary of HEW under President Johnson. He met with Secretary Finch of HEW under President Nixon, and with the Surgeon General. On one occasion he met with President Nixon himself. There were repeated contacts with members of President Nixon’s White House staff. There were contacts with Elliott Richardson, Secretary of HEW, and later with Caspar Weinberger when he was Health Secretary. There were extended contacts with the FDA, from Commissioner Alexander Mackay Schmidt all the way to Commissioner David Kessler.

The experience was uniformly disappointing. In this regard it was both an advantage and a handicap to be Jack Dreyfus. He was able to get a hearing with each of these people, and the “system” gave the appearance of responding as a government should, but ultimately nothing ever came of any of these initiatives. Dreyfus had almost totally wasted his time trying to sensitize the official healthcare bureaucracy to this issue. Dreyfus came to realize that the Food and Drug Administration was organized entirely for defense—to assure the safety and efficacy of medications being peddled to the public. The FDA team did not have a quarterback, and it wasn’t even trained to handle the football. If the public was missing out on the benefit of certain medications, that was not its charter.

This became very clear at one meeting with FDA officials. “The ball is in your court,” he was told at the end. “Where the devil do you think it’s been for all these years and when should it get in your court?” These people seem to clear their consciences by giving me advice on what I should do. This has been our experience as well. So many people are just full of advice about how matters should be approached to convince critics, to get research done and published, or to approach government agencies. In reality, of course, we confront a risk-averse climate in all these arenas, be it academia, journal publication, government agencies, private industry, private practice, and even in the realm of venture capital. When it comes right down to it, there are very few risk takers in this world, and there are even fewer who would take risks for someone else’s ideas.

It was equally unavailing to interest Parke-Davis, the owner of the patent rights on Dilantin, to promote the drug for additional indications beyond seizure control. The problem quite simply was that the patent had run out on Dilantin, and it was now available in generic form. Parke-Davis could not be assured of getting a return on its investment. Besides, any doctor in the country was already free to use the medication off-label, and that privilege did not need additional fortification.

So, another thrust of the Foundation activity was to inform the medical doctors in the United States of the vast potential of PHT, as documented in reams of studies that the Foundation had collected over a period of years. These were the best of studies because they had not been pushed by the manufacturer at the outset. It was the strength of the clinical findings that motivated individual researchers to publish their results—a very unusual situation indeed.

Collectively these studies indicated a far wider range of effectiveness than could have been intimated on the basis of Dreyfus’ personal experience. There was the application to cardiac arrhythmias, for example, and to the control of hypertension and of angina. There were four studies on the application to Q-T interval syndrome alone. There were applications to neuromuscular disorders, principally chorea, but also to restless leg syndrome and myoclonus, to intractable hiccups, and to the spasms of tetanus or of multiple sclerosis. There were applications to various chronic pain syndromes, including trigeminal neuralgia as well as migraine and other headaches. Applications included various gastrointestinal disorders, in particular irritable bowel syndrome and ulcerative colitis. Startling improvements were observed in 41 out of 42 cases of pruritus ani when PHT was added to conventional oral therapy. Clinical benefit has been reported for endocrine disorders, including hypoglycemia and labile diabetes, hyperthyroidism, and menstrual disturbances. PHT was even found to be helpful in scleroderma. Altogether there were over 1900 such studies referenced in the first compilation.

The bibliography compiled by the Foundation was mailed to all 350,000 physicians in the country in 1970. A second such mailing was done in 1975. The Foundation spent $15 million over its first seventeen years without reaching its objective. By 1982, when the book titled “A Remarkable Medicine Has Been Overlooked” was first published, the literature contained some 10,000 studies in some 250 medical journals around the world that supported the case being made. The book contained the abstracts from over 2100 of these studies. The update on this venture that is on my shelf, published in 1997, reveals that a further $65 million was spent over the next fifteen years. A third mailing to all the physicians in the country (508,000 by then) was accomplished in 1988. That bibliography covered some 3100 medical references relating to some 70 different indications and disorders, and drawn from some 350 journals published in 48 countries around the world. The drug was clearly still being actively researched. Nevertheless, the objective remained out of reach.

Here’s the FDA official response to an inquiry that had come down from the White House after Dreyfus met with President Reagan: “The FDA knows of some anecdotal reports of the success of Dilantin for some few patients but is unaware of scientific studies supporting the claim.” Just what is one supposed to do in the face of such obtuseness? Many years later, Commissioner David Kessler responded similarly to a formal inquiry from Governor Frank Keating: “Our scientific staff has reviewed data on Dilantin for various uses and has concluded that effectiveness has not been established for any of the indications.” The man could have written that in his sleep. The only use recognized by the FDA for Dilantin remained as an anti-convulsant.

What lessons can be drawn from this grand experiment in vectoring medical practice and public policy? The field of medicine was still very much in thrall to the model of “one medicine per disease” over most of this period of time, but it is certainly no longer there now. The work of Dreyfus’ foundation may very well have contributed to the more general shift in perspective. Anti-convulsants are now used widely in psychiatry. Other applications are recognized as well. Anti-convulsants constitute the standard remedy for trigeminal neuralgia, for example. So in the larger scheme of things, the Foundation could simply claim success.

The central problem confronting Dreyfus in his task was the orientation of pharmacological research toward specific diseases or disorders. If instead one took the view that Dilantin is capable of stabilizing hyperexcitable nervous systems in generality, then a whole class of conditions at once becomes a target of the therapy: not only seizures but migraines, asthma attacks, myoclonus, restless leg, cardiac arrhythmias, etc. Developments in neurofeedback took a path that was very similar to the “natural history” of PHT. The initial indication for SMR-training was the control of motor seizures. Quickly that generalized to seizures of other kinds. Later it generalized to other episodic brain dysfunctions such as migraine, panic, suicidal episodes, rage attacks, bipolar excursions, encopresis, myoclonus, hot flashes, night terrors, and restless leg syndrome. This is a partial listing of what we have come to call brain instabilities. The defining issue is not usually the specific cause of the disturbance, but rather the paroxysmal nature of the disturbance itself.

Here is where the anti-convulsants and neurofeedback work hand-in-glove. The one attempts to stabilize the cell membrane. The other targets stability at the network level. There is no reason to believe that one of these will ever displace the need for the other in the general case. Surely they should work harmoniously together.

Our clinical experience has been that effective neurofeedback substantially reduces the need for anti-convulsants in the control of seizures, but it does not typically eliminate the need entirely. In the absence of neurofeedback, one could argue that the anti-epileptic drugs (AEDs) have to bear too much of the burden of assuring overall stability. Dosages may need to be ramped up to where side effects such as cognitive fog make their appearance. With neurofeedback assuring network stability to the extent possible, anti-epileptic drugs can likely be titrated down to the point where no adverse network effects are seen. At that point, no substantial argument remains against the use of anti-epileptic drugs such as PHT.

The case being made here for the joint optimization of AEDs and neurofeedback is not specific to PHT. There are lots of newer candidates. But Dilantin does have the advantage of a long clinical baseline that gives assurance regarding our tolerance for the substance. Additionally, there is the extensive literature on application to a whole host of conditions where we also find neurofeedback useful. So it is quite possible that phenytoin still has quite a future ahead of it. The principal argument against such a revival relates to the side effects that are observed with Dilantin, such as the overgrowth of gums. At the lower dosages that are projected when PHT is combined with optimized neurofeedback, such side effects should be minimal or absent.

It is not yet widely appreciated just how far this might go. Neurologists have certain benchmarks for minimal dosages at which AEDs are deemed to become effective. When neurofeedback is involved, however, AEDs can serve their purposes at much lower dosages. This entire realm of medication use remains to be explored, and that holds true not only for the anti-convulsants.

At the tactical level, I find the reading of Dreyfus’ history both heartening and consoling. It certainly reinforces for me the path that we have taken in the maturation and insertion of EEG feedback broadly into clinical practice. It would have been even more pointless for us to challenge the edifice of medicine than it was for Dreyfus. At least Dilantin was already inside the tent. It was just Dreyfus who was on the outside. Dreyfus had the personal stature and skill to get a hearing in the inner councils of government and in the upper reaches of the medical enterprise, but in the end they wanted to have nothing to do with his project. There was nothing more that he could do, since he was not in a position to wield the prescription pad himself.

In the case of neurofeedback there was no nexus with allopathic medicine at all, and we did not have the stature to gain a hearing. Fortunately, there was the biofeedback sea for us to swim in. Neurofeedback could not have taken off without it. Ironically, there was just as much hostility to the emergence of neurofeedback within the biofeedback community as there was in medicine. But that did not really matter. The concept of biofeedback was well accepted, both among professionals and the public, and that gave us the necessary beachhead. Neurofeedback largely attracted a new core of professionals that had no prior involvement with biofeedback. These early adopters then served to legitimize the new claims and to fund the early developments through their instrumentation purchases. I never realized until years later just how rare and precious these individuals were. My expectation had been that everyone would surely go for the new mouse trap as soon as it was demonstrated to them.

Over the years, on the order of $80-100 million has likely gone into instrumentation development, instrumentation sales, and clinical research in neurofeedback (a figure comparable to the cumulative resources of the Dreyfus Medical Foundation). Neurofeedback professionals funded nearly all of this through their instrumentation purchases. Most of these expenditures contributed to the forward thrust of the field while also making ever larger numbers of people well. Looking back, there haven’t been very many developmental dead ends anywhere. What we have to show for it is a growing discipline that is likely already surpassing $1B in annual gross sales to the beneficiaries of neurofeedback. The value of what we do is of course many times greater than the cost.

Jack Dreyfus now just has to raise his sights one level of generalization higher than where he has been all these years. Indeed the clinical objective for a whole host of conditions is the taming of a hyper-excitable, unstable nervous system. That essential task is now well within our grasp. It’s just not all up to phenytoin anymore. Neurofeedback represents the more encompassing, the more organic, and the more humane remedy for what is in essence a problem of network functioning. Well done, Jack Dreyfus. You pointed the way to the real objective. Your reality is now just being absorbed in a yet larger reality. It rests on your original vision.

Siegfried Othmer, Ph.D.
www.drothmer.com

This entry was posted on Friday, December 26th, 2008 at 6:42 pm and is filed under Application of Neurofeedback, Neurofeedback, Research. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.