Histamine vasodilation: a forgotten effective treatment

The irony of MS research for the past 30 years has been that it assumed one of the most complex possible etiologies—autoimmunity—without having made the slightest effort to eliminate simpler causes. Frederick Wolfgram 1979

Summary

Multiple sclerosis is presently considered virtually incurable because its primary lesion is thought to be relatively irreversible disintegration of myelin sheaths in the brain and spinal cord. But neurologists once thought its primary lesion was a reversible condition—diminished blood supply in the brain and cord—which if not relieved led to irreversible demyelination. The best evidence for this point of view was the benefit of central nervous system vasodilators, pioneered by Bayard Horton of the Mayo Clinic, which not only relieved acute attacks promptly, but usually prevented the progression.

Between 1946 and 1959, more than 3000 patients with multiple sclerosis and other demyelinating disorders were treated with the CNS vasodilator histamine diphosphate at the Multiple Sclerosis Clinic of St. Joseph Hospital in Tacoma, Washington. Most of them improved, some quite dramatically. Because the benefit of CNS vasodilation was never confirmed in controlled trials, its effectiveness has been largely forgotten. Yet CNS vasodilation with histamine not only consistently relieved a disease now thought to be incurable, it thereby demonstrated that its fundamental lesion may be something entirely different from demyelination.

Introduction

On March 28, 1996, host Robert Stack of television’s Unsolved Mysteries related the story of Mary Clamser of Oklahoma City, a multiple sclerosis patient for 23 years. Mrs. Clamser had relapsing-remitting MS, the most common form among women; her left leg and her bladder were most affected. Each attack lasted no longer than six months, until an attack in 1992 left her unable to walk without assistance.

On August 17, 1994, a sudden thunderstorm passed over Mrs. Clamser’s house. She was in her wheelchair, preparing a bath. As she reached out to turn on the water, a bolt of lightning struck her house. Doctors estimated that at least ten thousand volts of electricity passed through her body. At first she felt “on fire” she said, full of “pins and needles.” Then she suddenly realized she could feel her legs again. Since that day, improvement of her multiple sclerosis has been rapid. Two years later, she lives a completely normal life. “All symptoms of her multiple sclerosis,” said Robert Stack, “are gone.”

This is not, of course, the first report of an affliction reversed by lightning. But the symptoms of multiple sclerosis are believed to be caused by disintegration of the insulating myelin sheaths surrounding nerve fibers in the brain and spinal cord. How a bolt of lightning could restore these insulating layers rapidly—if at all—can hardly be imagined. The obvious implication is that demyelination is not the only cause of multiple sclerosis symptoms. Something else must be happening in the brain and spinal cord of these persons—something far more reversible than demyelination.

Neurologists have long known that demyelination alone cannot explain all aspects of this disease. Early symptoms usually remit within weeks, although demyelination is almost always permanent [1]. Remyelination is largely confined to the edges of plaques [2] and usually unable to halt the progression [3]. Attacks of symptoms lasting from seconds to hours are common [4]. Symptoms may persist for years, then remit for years. At autopsy, demyelination is often found to be far more extensive than expected from the history of symptoms [5]. Plaques have been found after death in persons who never reported any MS symptoms during their lifetime [5,6]. Most paradoxical, visual half-field defects are rare despite frequent plaques along the optic radiations and tracts [7,8]. These anomalies have been described as “symptoms without lesions and lesions without symptoms” [9]. Reversible secondary factors acting on demyelinated nerves have been invoked to explain some of these anomalies [10,11], yet electrophysiologists insist that demyelination imposes such heavy electrical loads (of capacitance) that conduction should be interrupted whether or not secondary factors are present [12].

Thus, relatively permanent structural lesions that in theory should destroy conduction and function, in reality may show no symptoms at all, transient symptoms, or symptoms that remit for years. Multiple sclerosis symptoms are reversible (or absent!) whether or not demyelination has already occurred. Might this mean that vasodilation therapy merely reversed secondary factors, rather than reversing a primary condition leading to demyelination? Perhaps. But if reversing secondary factors was all that was necessary to relieve acute attacks and the progression, shouldn’t the cause and reversal of these secondary factors be the crucial focus of multiple sclerosis research, rather than the cause and reversal of demyelination?

A successful treatment for multiple sclerosis

. . . there are virtually no diseases for which one is likely to be better off receiving the best 1981 than the best 1951 medical care. The lack of practical advances may indicate that the problems are exceptionally difficult. It may also indicate that our approaches are fundamentally wrong and therefore cannot have practical results. David Horrobin [13]

A Successful Treatment for Multiple Sclerosis Patients by Dr. George Hess, last full-time medical director of the Multiple Sclerosis Clinic at St. Joseph Hospital in Tacoma, Washington, was published in the journal Northwest Medicine in 1959 [14]. In his words, Clinic treatment was “not a cure, but a practical guide for helping a patient live with his disease.” To say the treatment was not a cure, however, mostly meant that the patient might have to continue taking central nervous system vasodilators for the rest of his or her life—to reduce the likelihood of relapses, and when relapses occurred. Other than that, the treatment was remarkably effective. “Benefit has come to the great majority of patients,” Dr. Hess asserted. Inasmuch as more than 2500 multiple sclerosis patients were treated at the Clinic between 1946 and 1959 (and 500 with other demyelinating diseases) this was a considerable achievement against a disease now thought to have no effective treatment.

Clinic treatment had several aspects: (a) treatment of the multiple sclerosis itself with the CNS vasodilator histamine diphosphate, (b) drugs directed at specific symptoms, (c) efforts to minimize allergic reactions, (d) physiotherapy, and (e) efforts to improve the patient’s state of mind.

Dr. Hinton Jonez, founder of the Clinic, learned about histamine therapy from Bayard Horton of the Mayo Clinic, at a postgraduate course on allergy in 1946. At the time, antihistamines were being developed to counteract the body’s own histamine, which was thought to cause asthma and other allergic disorders. Dr. Horton, however, was using histamine to treat these disorders, with much success. He had even used histamine against multiple sclerosis, he told Jonez:

[Horton] explained that histamine gives new life to m.s. victims much as fresh fighting troops revive an exhausted army. The blood pressure goes down and the blood vessels widen, while an increased flow of blood enables the blood stream to rush vital materials and oxygen more rapidly and in greater quantities to damaged cells and tissues. [15]

The allergy hypothesis of multiple sclerosis popular at the time proposed that the brain and spinal cord became inflamed through hypersensitivity reactions, primarily to foods. Because the brain and spinal cord were both encased in bone, there was little room for expansion of swollen tissues; consequently, blood vessels became compressed. If the blood supply could be restored, symptoms would be relieved. If not, portions of the brain and spinal cord would eventually be destroyed and replaced by scar tissue (plaques).

Horton admitted he did not know what role allergy played in multiple sclerosis, but suspected the disease was a “primary vascular disorder of the central nervous system” [16]. Because histamine was the most potent CNS vasodilator known, Horton had given it intravenously to multiple sclerosis patients, with much success.

Hinton Jonez and his fight against multiple sclerosis

Dr. Hinton Jonez had been a general practitioner in the Pacific Northwest for 25 years when he encountered his first patient with multiple sclerosis. A woman in her early thirties, over five years she had gradually lost her ability to walk, had trouble seeing, and could swallow only with difficulty. She was the reason Jonez asked Bayard Horton about multiple sclerosis at the allergy conference. When he returned to Tacoma, Jonez told the woman what he had learned. He warned her that histamine treatment was experimental. Histamine could be dangerous—people had suffered extreme headaches and had even died. Only trial-and-error could determine the proper dosage. Her multiple sclerosis might be too advanced to be relieved.

Her reply, Jonez said, was: “Look at me. Think carefully what’s ahead for me as matters stand. Then search your heart. How can you even hesitate to give me whatever chance this new treatment holds?” She received her first histamine injection before she left Jonez’ office that day.

Jonez soon learned to tailor the woman’s dose of histamine to meet her needs. He found she was sensitive to certain foods, which they eliminated from her diet.

As the days went by, there was no doubt she was getting better. At first I forced myself to be skeptical of everything that seemed like improvement. But finally the day came when I could put aside my skepticism. She was definitely better. She could swallow with ease for the first time in months. And to the amazement of her eye specialist, her vision was back to normal. Her morale was at a high point. Less than six months after her first dose of histamine, she was walking. Sensation had fully returned to the legs that had appeared hopelessly paralyzed. [15]

Although Jonez himself still had doubts, the woman felt she had undergone a miracle, and told her friends. Soon Jonez was treating a dozen multiple sclerosis patients with histamine. One day he was visiting one of them at St. Joseph Hospital in Tacoma, operated by the Sisters of St. Francis. A sister told him they had other MS patients there, and asked if he would show the nurses how to administer histamine. He replied that if they would make room for a clinic at the Hospital, he would direct the patients’ care. He said the work must be considered experimental, he would accept no money for it. The very next day Jonez had his Multiple Sclerosis Clinic at St. Joseph Hospital.

Jonez’ first patient was not the only near-miracle he encountered using histamine against multiple sclerosis. More than a few patients near death from acute attacks recovered. Jonez found, in fact, that acutely stricken, critically ill patients responded best to histamine, if it was given promptly in sufficient amounts. Yet even patients with chronic, severe disabilities improved to some degree.

The best way to determine the proper dosage, Jonez found, was to give the histamine slowly:

Usually, we gave histamine diphosphate intravenously, slowly and carefully, until the patient felt uncomfortable or slightly headachy. By giving the histamine very, very slowly the dose could be stopped sharply just at the point it began to cause trouble. That was the only manner in which we could determine histamine tolerance. . . . Sometimes, particularly in acute cases, an almost continuous infusion of histamine would be given for twenty-four to thirty or more hours. Histamine diphosphate in saline or glucose solution would be dripped into the veins at the rate of thirty drops a minute. . . . [T]he effects of the continuous infusion in selected cases were truly startling. [15]

Despite his concerns, Jonez asserted that not a single Clinic patient ever had an adverse reaction or harmful side effect from histamine. Dr. Horton had told him that histamine was not dangerous unless it was administered too quickly, or if the equipment was not sterile:

We finally decided that the real reason the drug had a bad name was because physicians were so fearful they didn’t get acquainted with it. When they did administer histamine, they used such small doses the drug was relatively ineffective. Time after time patients on coming to the clinic would tell us they had been treated with histamine previously. . . . I soon learned to inquire how much histamine had been given. Invariably they had received small doses and only a few of these. [15]

Jonez found that in many cases histamine had to be given continuously at tolerance doses—even 24 hours a day—to prevent exacerbations. Before long a doctor at an Eastern industrial laboratory came up with a preparation of histamine in an oil and wax base (repository menstruum) that could be injected, allowing histamine to be released gradually into the bloodstream.

histamine by iontophoresis

The likelihood of future relapses meant that patients needed a way to take histamine readily after leaving the Clinic, perhaps for the rest of their lives. A breakthrough soon came with a device Dr. Harold Abramson had developed to allow asthmatics to take epinephrine without injections [17]:

Abramson’s contribution, known as the iontophoresis method, allowed the histamine to be driven through the skin by a galvanic current. The drug is deposited in a large hive-like swelling and the blood picks up the histamine from the hive and circulates it as required throughout the body. The mechanism is so simple that almost anyone can make one after a few instructions. . . .

Gradually, we decided that a nine-weeks treatment period was advantageous for most patients. During that period each would have the thirty intravenous histamine treatments which were the basis of our method. The patient would also have ample opportunity to become acquainted with the simple “box” whereby histamine is driven through the skin, and there would be plenty of time for him to experiment with his own box before taking the iontophoresis set home. [15]

Jonez knew that histamine could never cure multiple sclerosis because patients would always remain vulnerable to relapses. But if the relapses were controlled with histamine, patients had a chance to recover and not progress.

We could help the sclerotics get the best of their symptoms. They could make comebacks in accordance with the extent of nerve damage, and many would return to earning a living and leading a normal life. . . . Our experience suggested that, with proper cooperation from the patients, we could make wheelchair cases out of those who were previously bed-fast. Occasionally, we might help them to walk again. Sometimes we might get them to a place where they would be symptom-free and probably would stay that way so long as they followed our directions. . . . Frequently our chronic, progressive cases became markedly better merely with histamine medication and elimination of offending foods. [15]

Not only did histamine help virtually every patient, and often provide dramatic benefit to chronic as well as acute patients, it could arrest symptoms entirely:

[W]e had good reason to believe our accomplishments were substantial. M.S. symptoms were definitely arrested in one person out of every six treated and everybody who stuck with the treatment consistently and conscientiously for at least ninety days showed improvement. We could relieve symptoms even where we could not arrest them. Many were leaving their beds for the first time in years. One man unable to move so much as a toe for seven years walked one week after he arrived at the clinic. [15]

Jonez and his staff found that if relapses were prevented or arrested, the progression of the disease would also be arrested:

[S]everal investigators had stated that the normal tendency of m.s. is to improve—provided the exacerbations can be prevented. All we did at the clinic was to build up morale and general physical condition—and try to prevent exacerbations. The disease, if indeed it be a disease, then took care of itself. [15]

Miriam Zeller Gross, a popular medical writer of Jonez’ day, visited the Clinic and described its treatment in McCall’s magazine. The public response was so great, Jonez and Gross decided to tell the Clinic’s story in a book. My Fight to Conquer Multiple Sclerosis, by Dr. Hinton D. Jonez as told to Miriam Zeller Gross, was published in 1952, one year before Jonez’ death. In his book, Jonez summed up his experience with histamine against multiple sclerosis in these words:

There seemed little doubt during those early days of the clinic—as, indeed, is still the case five years later—that histamine is the medication of first choice in multiple sclerosis. After administering more than 150,000 doses, more than have been administered for m.s. at any other place in the world and observing the effects over a period of five years—without a single bad result—we feel qualified to make this statement. [15]

The Clinic remained open until 1959. In 1962 Dr. George Hess, its last full-time medical director, described the latest Clinic treatment in his manual for patients Living At Your Best With Multiple Sclerosis [18]. An information sheet from St. Joseph Hospital [19] stated that the Clinic closed not for lack of success, but partly because of Jonez’ own conviction that multiple sclerosis was best treated by the patient’s own family doctor, with intravenous infusions of histamine, and the self-administration of histamine by iontophoresis:

Early in 1952 while Clinic work went on, Dr. Jonez, already in precarious health, raced ahead with plans to formulate medical techniques and to assemble data so that the medical profession could profit from the large Clinic MS case pool. He was already convinced that the Clinic itself should be phased out, that each case could best be handled by a hometown generalist—who could readily take supportive measures, quickly assure CNS vasodilation should exacerbation occur, school his patient in recognizing and avoiding his own stresses, make indicated referrals, institute symptomatic therapy for both concurrent and residual conditions. . . . Ending 1959, local hospital needs made closing a specialized facility like the Clinic imperative. Although in accord with plans of Dr. Jonez, the action was taken with regret and must not be interpreted in any sense as a disparagement of the treatment pioneered and so successfully administered. [19]

Therapeutic Claims in Multiple Sclerosis

In 1982 Therapeutic Claims in Multiple Sclerosis was published under the auspices of The International Federation of Multiple Sclerosis Societies [20]. Its principal author was Dr. Joe R. Brown, Professor of Neurology Emeritus at the Mayo Clinic; its Board of Editors eminent neurologists of England, Germany, Canada and the United States. Because of the many treatments tried for multiple sclerosis over the previous one hundred years, Therapeutic Claims did not cite specific reports but only summarized their results. Investigations of four vasodilators, involving 140 patients in all, were summarized:

Vasodilators, used in the expectation of increasing blood flow to the CNS, gave results varying from 56% to 100% (average 62%) frequency of improvement. Specific agents tried included: histamine intravenously, histamine by iontophoresis (administration of a medication through the skin by means of an electric current), niacin intra-muscularly or orally, and Etamon, as well as alcohol, belladonna, aminophylline, amyl nitrite, papaverine, and Syntropan.

In a later section, the use of histamine was evaluated:

Evaluation: Histamine has been given intravenously in MS . . . by iontophoresis . . . and in repository form . . . . Histamine intravenously has been shown to produce generalized vasodilation. However, the total cerebral blood flow is unchanged, apparently because of fall in blood pressure. Unfortunately, there is no practical and safe way to maintain continuous CNS vasodilation for extended periods of time. A first trial of histamine in MS (1944) was uncontrolled. Recovery was reported in 75% of acute exacerbations, and improvement in 46% of chronic stage patients. The criteria for and degree of improvement were not specified. ?Substantial improvement” was also reported in later series, also uncontrolled and without specifying criteria for improvement. Finally, in a properly controlled series, either progressive worsening or development of acute exacerbations during the term of therapy was seen in about one-third of patients. It is clear, therefore, that histamine therapy does not prevent progression or exacerbations. Histamine use was widespread for about 15 years, and has since been generally abandoned as ineffective by experienced clinicians.
Risks/Costs: Costs may be substantial.
Conclusion: Vasodilation therapy with histamine has not prevented progression or exacerbations in MS. It is generally held to be ineffective.

This report is misleading in several respects: (1) It makes no mention of the Multiple Sclerosis Clinic at St. Joseph Hospital, nor its 2500 MS patients helped by histamine; (2) the techniques of histamine infusion, repository histamine, and histamine by iontophoresis developed by Jonez and his staff to maintain long-term vasodilation proved both practical and safe for fourteen years; (3) Dr. Hess asserted that the cost of histamine was less than the cost of corticosteroids, and histamine could be self-administered.

The most egregious assertion in Therapeutic Claims is its conclusion—drawn from a single controlled trial—that progressive worsening and relapses in one-third of patients tested made it “clear, therefore, that histamine therapy does not prevent progression or exacerbations.” In the first place, this conclusion violates the fundamental principle that observations are only provisional until confirmed. Furthermore, why should one controlled trial with negative results outweigh fourteen years of positive results reported by many physicians, and thousands of patients helped? One might hope that any treatment showing any promise at all against a disease thought to be incurable would be given the benefit of the doubt. Rowland wrote [21]:

What harm is done if a ‘negative’ report is erroneous? The answer is clear. A treatment of value may be deferred—perhaps for years. That actually happened in the evaluation of levodopa for parkinsonism. George Cotzias once said that it was fortunate he never read the neurologic literature; if he had, he would have concluded there was no sense trying levodopa because the early reports were mostly negative. However, he gave a dose much higher than the first investigators, and (in an uncontrolled study) he found dramatic benefit.

Despite the assertions in Therapeutic Claims, the National Multiple Sclerosis Society was once very aware of the histamine treatment administered at the Mayo Clinic by Bayard Horton and his colleagues. In Multiple Sclerosis: Diagnosis and Treatment, a pamphlet published in 1947 by members of the NMSS and approved by its Medical Advisory Board, the following appears [22]:

Histamine. Because frequent exacerbations and remissions are characteristic of this disease, evaluation of therapy is difficult. Under the circumstances, it is believed that histamine therapy cannot be adequately evaluated until more time has elapsed . . . . The procedure which is employed at Mayo Clinic is as follows:

Add 2.75 mg. histamine diphosphate to 250 c.c. normal physiologic saline. This solution is given intravenously by the drip method, beginning at the rate of approximately 20 drops per minute; however, the rate of administration depends entirely upon the individual’s tolerance. At no time should the patient experience any discomfort from the use of this drug. We limit the time for each treatment to a maximum of 1.5 hours and do not administer more than 250 c.c. of the solution at a given treatment. . . . This treatment is carried out without danger and is easily administered. Since we began this work in 1942, we have given over 55,000 intravenous histamine injections without any untoward effects. Reactions have not occurred, even though we have administered as many as 561 such injections to a given subject. Repeated injections do not change the patient’s tolerance to the drug. . . .

In man, histamine dilates the arterioles, venules and capillaries. Recently we have had occasion to study and to confirm these observations on the human brain. Furthermore, we have been able to demonstrate that histamine is the most powerful vasodilating agent available for increasing blood supply to the central nervous system; hence the rationale for its use in subjects with multiple sclerosis.

How did histamine help?

Over the years Jonez learned that allergic reactions from emotional upsets were as likely to bring on attacks and relapses as allergic reactions to foods or chemicals. He concluded that histamine relieved symptoms not only by dilating blood vessels, but also by stimulating the body’s defenses against stress. Eight years later, the truth of this for Clinic patients was so clear that Dr. Hess stated:

Through the stimulation of the general adaptive mechanism of the body, corticosteroids and the other defenses against stress are measurably increased. This effect of histamine leads one to conjecture whether multiple sclerosis might be better classified as a stress disease. . . . Many of our patients relate the onset of their disease or its exacerbations to a traumatic experience or an emotional upset, and for such of our Clinic cases, we use the term ‘emotional allergy.’ [14]

Nevertheless, the vasodilation of histamine may have been its primary benefit. According to Hess, vasodilation with niacin (vitamin B3) also helped during acute attacks [18]. Ophthalmologist Richard Brickner tested vasodilators extensively against MS, after his colleague C. Ray Franklin noticed spasms of retinal arterioles in multiple sclerosis patients experiencing attacks of impaired vision. They found that inhalation of the vasodilator amyl nitrite immediately abolished both the retinal spasms and the visual symptoms. Brickner concluded that he and Franklin were observing “transient, sudden miniature attacks of multiple sclerosis.” [23]

For fourteen years Brickner tested vasodilators against acute attacks of MS [24]. In his day physicians used the term “relief by flush” to describe the immediate relief by vasodilators of attacks of MS symptoms [25,26], because flushing of the face indicated that the vasodilation was sufficient. Every kind of acute multiple sclerosis symptom could be relieved in this manner, Brickner reported. He pointed out that: (a) The transient improvement of vasodilation was easy to overlook; (b) this led physicians to think there was no lasting benefit, but it might only mean long-term vasodilation was necessary; (c) uncertainty due to the possibility of spontaneous remissions could be eliminated by looking for immediate effects; (d) the immediate relief of acute attacks said something crucial about the nature of multiple sclerosis symptoms. Brickner made this last point succinctly [24]:

This must mean that at the moment the drug is used, there is a potential for reversibility of the symptom which is not being realized spontaneously.

Discussion—the significance of reversible symptoms

Neurologists now presume that multiple sclerosis symptoms come and go so rapidly because conduction along demyelinated nerve fibers is extremely vulnerable to secondary factors like heat or compression. A 1°C rise in body temperature often brings out or aggravates symptoms. Uhthoff’s symptom—transient blurred vision from exercise—also demonstrates this sensitivity. Yet not all MS patients are sensitive to heat or exercise, and those who are heat-sensitive are not always exercise-sensitive and vice-versa [28]. Furthermore, if conduction through demyelinated areas is so vulnerable to secondary factors, what explains plaques without symptoms, or long-term remissions? On the other hand, plaques without symptoms are not explained by the view that a reversible condition generates symptoms.

One point these opposing hypotheses do agree on is that demyelination is not the only cause of symptoms. Transient reversible factors participate in symptoms, either by acting on demyelinated nerve fibers (the contemporary view), or by interrupting conduction before demyelination intervenes (the early view). These transient reversible factors may be vascular, e.g. vasospasm [10] or embolism [29]; compressive, e.g. edema [11]; or ionic [28,30], perhaps affecting the electric potentials of nerve fibers. Mary Clamser’s remission by lightning seems unlikely to be due to reversal of edema or vascular spasm, but might indicate reversal of an electrophysiological disturbance.

If the transient reversible factor is ionic, one clue may be the “night-walker phenomenon” reported by many of Jonez’ patients [15]. Late at night these people could get out of their wheelchairs and walk without canes or crutches. One woman nearly blind said she had normal sight every night around midnight. Patients who kept track of these episodes reported they felt particularly free of disabilities when radio static was absent. One Montana man who often drove from city to city late at night said that when he could tune in distant radio stations without static, he could walk for miles down the road. When there was long-distance static, he could “hardly hobble about.” Undoubtedly this is a transient factor at work, but not the kind of transient factor usually associated with the disease.

What role does demyelination really play in multiple sclerosis, if its symptoms can be relieved by vasodilation, lightning, or a static-free atmosphere? Because demyelination is not always sufficient for symptoms, is it always necessary for symptoms? And if demyelination is not sufficient for symptoms, and may not be necessary for symptoms, shouldn’t the cause and reversal of symptoms be the crucial priority of multiple sclerosis research, rather than the cause and reversal of demyelination?

References

1. Lumsden CE (1961). The pathology and pathogenesis of multiple sclerosis. in Scientific Aspects of Neurology (Garland H, ed) Edinburgh: Livingstone.

2. McDonald WI (1986). The pathophysiology of multiple sclerosis. in Multiple Sclerosis (WI McDonald, DH Silberberg, eds) London: Butterworths.

3. Franklin RJ (2002). Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 3:705-14.

4. Miley CE, Forster FM (1974). Paroxysmal signs and symptoms in multiple sclerosis. Neurol 24:458-461.

5. Silberberg DH (1986). Pathogenesis of demyelination. in Multiple Sclerosis (WI McDonald, DH Silberberg, eds) London: Butterworths.

6. Mackay RP, Hirano A (1967). Forms of benign multiple sclerosis. Report of two “clinically silent” cases discovered at autopsy. Arch Neurol 17:588-600.

7. Savitsky N, Rangell L (1950). The ocular findings in multiple sclerosis. in Multiple Sclerosis and the Demyelinating Diseases (Assn Res Nerv Ment Dis Proc v. 28) Baltimore: Williams & Wilkins.

8. Plant GT, Kermode AG, Turano G, et al. (1992). Symptomatic retrochiasmal lesions in multiple sclerosis: Clinical features, visual evoked potentials, and magnetic resonance imaging. Neurol 2:68-76.

9. Bornstein MB (1972). Anti-glial and anti-neuronal factors in experimental allergic encephalomyelitis and multiple sclerosis. in Multiple Sclerosis: Immunology, Virology, and Ultrastructure (F Wolfgram, GW Ellison, JG Stevens, JM Andrews, eds) New York: Academic Press.

10. Namerow NS, Thompson LR (1969). Plaques, symptoms, and the remitting course of multiple sclerosis. Neurol 19:765-774.

11. Halliday AM, McDonald WI, Mushin J (1977). Visual evoked potentials in patients with demyelinating disease. in Visual Evoked Potentials in Man: New Developments (JE Desmedt, ed). Oxford: Clarendon Press.

12. Schauf CL (1983). Plasticity of conduction processes in demyelinated nerve fibers: Implications for therapy in multiple sclerosis. in Multiple Sclerosis: Present and Future (G Scarlato, WB Matthews, eds) New York: Plenum Press.

13. Horrobin DF (1982). Peer review: A philosophically faulty concept which is proving disastrous for science. Behav Brain Sci 5:217-218.

14. Hess GH (1959). A successful treatment for multiple sclerosis patients. Northwest Med 58:377-382.

15. Jonez HD (with MZ Gross) (1952). My Fight to Conquer Multiple Sclerosis. New York: Julian Messner (out of print, but available through local libraries).

16. Horton BT, Wagener HP, Aita JA, Woltman HW (1944). Treatment of multiple sclerosis by the intravenous administration of histamine. JAMA 124:800-801.

17. Abramson HA (1949). Histamine iontophoresis in the therapy of multiple sclerosis. NY State J Med 49:1151-1155.

18. Hess GH (1962, revised 1972). Living At Your Best With Multiple Sclerosis. Springfield IL: Charles C Thomas (out of print, but available through local libraries).

19. The Clinic. Information sheet distributed by St. Joseph Hospital, Tacoma WA.

20. International Federation of Multiple Sclerosis Societies (1982, revised 1986). Therapeutic Claims in Multiple Sclerosis (SM Aronson, HJ Bauer, JR Brown et al., eds) New York: National Multiple Sclerosis Society.

21. Rowland L (1988). Letter to the editor. Neurol 38:165-166.

22. National Multiple Sclerosis Society (1947). Multiple Sclerosis: Diagnosis and Treatment. New York: North River Press.

23. Brickner RM (1950). The significance of localized vasoconstrictions in multiple sclerosis. Transient, sudden miniature attacks of multiple sclerosis. in Multiple Sclerosis and the Demyelinating Diseases (Assn Res Nerv Ment Dis Proc v. 28) Baltimore: Williams & Wilkins.

24. Brickner RM (1958). Pharmacological reduction of abnormality in multiple sclerosis within minutes: a statistical study. J Nerv Ment Dis 127:308-322.

25. Brickner RM (1955). Phenomenon of relief by flush in multiple sclerosis. Its use as a foundation for therapy. Arch Neurol Psychiat 73:232-240.

26. Current Therapy (HF Conn, ed) Philadelphia: WB Saunders.
           Brickner RM: 1950, 1952, 1956, 1957
           Kolb LC: 1951, 1953
           Alexander L: 1954, 1955
           O’Doherty DS: 1962

27. Wolfgram F (1979). What if multiple sclerosis isn’t an immunological or a viral disease? The case for a circulating toxin. Neurochem Res 4:1-14.

28. Selhorst JB, Saul RF, Waybright EA (1981). Optic nerve conduction: Opposing effects of exercise and hyperventilation. Trans Am Neurol Assn 106:101-105.

29. James PB (1982). Evidence for subacute fat embolism as the cause of multiple sclerosis. Lancet 1:380-386.

30.  Edmund J, Fog T (1955). Visual and motor instability in multiple sclerosis. Arch Neurol Psychiat 3:316-323.

    
    

http://web.me.com/petergood1/MultipleSclerosisStudies/Histamine_vasodilation.html