Why Wagner-Jauregg Won the Nobel Prize for Discovering Malaria Therapy for General Paresis of the Insane
Edward M. Brown History of Psychiatry, Volume 11, December 2000, 371-382.

         In 1927 the Viennese psychiatrist Julius Wagner-Jauregg was awarded one of only two Nobel prizes ever given to a psychiatrist for his discovery of the malaria treatment of general paresis. Compared to his contemporary Sigmund Freud, Wagner-Jauregg's name has almost disappeared from memory.1 Recently, Andrew Scull has suggested that historians have passed over the malarial treatment, along with other somatic treatments, in what he refers to as an 'embarrassed silence.' Indeed in the late twentieth century, the idea, as Scull describes it, of breeding 'colonies of malarial mosquitoes with which to infect tertiary syphilitics and so burn the offending parasites from their brains' seems more appropriate for moral censure than than universal acclamation.2 Our relative silence about malarial treatment may, however, have other sources than embarrassment. Twentieth century psychiatrists have until recently been more interested in psychological treatments than in somatic ones; while historians like Scull have often been more interested in psychiatry's failures than its successes. Moreover diseases like general paresis and pelagrous dementia have been so nearly eradicated that it is hard to remember what a large place they once played in psychiatric practice.
         In order to appreciate the significance of the malaria treatment at the time that Wagner-Jauregg announced it in 1921, one must see this innovation in the context of the history of the disease that it cured--general paresis of the insane. In that context Harold Mersky’s views seems closer to the mark than Scull’s facile dismissal. According to Mersky,   'any clinician today (who) could achieve the sort of results with AIDS ... which Wagner-Jauregg obtained with general paralysis, ...would receive the immediate acclaim and the same ultimate rewards as those given for the introduction of malarial treatment.'3 Mersky's comparisons with AIDS is apt in several ways. General paresis was a uniformly fatal disease that most frequently struck people (men far more often than women) between the ages of 20-40. A diagnosis of general paresis was stigmatizing, both before and after it was understood to be caused by syphilis. Before they died paretics became completely demented and unable to care for themselves, dying most often in insane asylums.  As with AIDS there was initially great optimism that when paresis was discovered to be caused by an infectious agent--treponema pallidum--that it would yield conventional anti-syphilitic treatment. There was also great disappointment when Salvarsan--the so-called magic bullet for syphilis, failed to interrupt the fatal course of general paresis. Unlike AIDS, however, general paresis had frustrated all attempts to find a cure for over one hundred years before Wagner-Jauregg introduced his treatment.
         General paresis of the insane was first identified as a distinct disease by Antoine Laurent Jessé Bayle in the 1820s. He characterized it as having both physical and mental symptoms, a regular natural history and consistent post mortem findings. Although psychiatrists differed over whether  or not Bayle had discovered a new disease, they all agreed that finding signs of paresis, even subtle early signs, in an insane patient meant that the patient did not have long to live. Indeed it was just the fact that general paresis had such a uniformly short and fatal course that had allowed Bayle to see it as a single disease. While psychiatrists were proud of their ability to characterize this disease as thoroughly as they could and hopeful that would soon be able to characterize others as thoroughly, they were nonetheless embarrassed by their  complete inability to cure patients of this disease.4
 This embarrassment was often concealed in callous demonstrations of their prognostic acumen.  J.E.D. Esquirol, one of the architects of psychiatry's early nineteenth century therapeutic optimism, as well as one of the first do describe paresis among the insane, for example, boasted that his specialized expertise allowed him to detect signs of paresis that had eluded a  provincial colleague.  The patient was a  'strong, robust' thirty year old man  who  had persuaded himself that he possessed immense fortune and had yielded  'to all the excesses of the most fashionable life.' He was brought to Paris  by the ‘skillful and estimable' Dr. K., who deferentially presented the patient to Esquirol.  'I commit to your care,' Dr. K. said to Esquirol ‘a very interesting patient, who is but slightly  excited, and whom I have withdrawn from scenes calculated to augment his excitement, which you will speedily cure.’  Esquirol conducted a half an hour  ‘conversation’ with the patient,during which he observed ‘some hesitation in the pronunciation of certain words’ and an ‘undue readiness’ to remain in a hospital. On the basis of these findings Esquirol disdainfully told his hopeful colleague,  'I think that your patient is incurable; that he will not recover, nor survive a year. Remain in Paris, and you will see, as the malady is making rapid progress.'5  Displays of diagnostic and prognostic abilities such as Esquirol's would be repeated by others  during the nineteenth century but such displays could never fully conceal psychiatry's impotence in the face of this completely devastating and extremely common disorder.6
         During most of the nineteenth century, before syphilis was taken seriously as the cause of general paresis, writing about the treatment of this disorder tended to emphasize prevention and palliation rather than cure. Initially some like Bayle held out some optimism that an understanding of the pathophysiology of the disorder might lead to a cure. Although Bayle noted that the proportion of deaths to cures was thirty to one, he nonetheless expressed confidence that bleeding 'wisely administered' was the best hope to diminish the ‘terrifying mortality’ of general paresis. 7 This proposal was based on his observation of congestion of the blood vessels of the pia mater of paretics dying in early stages of the disease. In spite of this sophisticated pathophysiological rationale, Bayle's optimistic predictions  for blood letting as a treatment for general paresis were, of course, not borne out. In the final stage of the illness, when the patient was weak, bedridden and demented, there was general agreement that treatment should be humanely restricted to palliative measures. Opinions about prevention were more varied, but generally the advice given was, as in other forms of insanity, directed at avoiding emotional turmoil and excesses of alcohol and sex.
         Throughout the nineteenth century, in spite of occasional claims of recoveries or remissions, general paresis remained 'a deadly disease, almost invariably fatal.'8 Toward the end of the century, Regis, in France, summarized the general opinion: 'the medical treatment...of general paresis includes an infinite number of agents, none of which, unfortunately, has up to this time, afforded any really favorable results.'9 In England Julius Mickle, author of the first English book devoted to general paresis, looked back nostalgically to ‘earlier writers’ who had 'enjoined the employment of active antiphlogistic' treatments such as ‘low diet, bleeding, leeching, cupping, purgatives, moxas, ...setons,...mercurial innunctions, antimony diuretics, and ...cold to the head.’ Although he wondered if these treatments had ‘suffered from undue neglect of late,’ he did not encourage his readers to attempt curative treatment.10   Indeed he insisted that ‘as soon as he is satisfied of the existence of true general paralysis it is the duty of the physician to say at once that the case is without hope, and curative art without reliable and permanent efficacy.'11

SYPHILIS AND PARASYPHILIS
         Although the treatment of general paresis changed dramatically once  it was agreed that syphilis was  the cause of the disorder, it took many years for this proposition to gain universal acceptance. While Esmarch and Jessen had asserted that syphilis caused general paresis as early as 1857, progress toward the general acceptance of this idea was begun by the eminent nineteenth century 'syphilographer' Alfred Fournier(1832-1914). The favorite student of the early nineteenth century syphilographer Philippe Ricord, Fournier devoted himself to the study of syphilis to the exclusion of almost everything else.12   He  dominated French venereology in the last decades of the century and was recognized throughout the western world as an expert on syphilis second to none. 13  Engaged in an ambitious program of research and public health propaganda aimed at showing how widely the effects of syphilis had spread,  Fournier's research drew on a  card index of 50,000 cases that he had assembled over the years.  Throughout the 1880s, he collected data on the relationship between general paresis and syphilis, which he presented  in two essays in 1893  and a famous communication read  before the Academie de Médicine in on 30 October 1894.14
         In that communication Fournier marshaled a variety of evidence for a pathogenic connection between syphilis and general paresis.  Most importantly, he noted that  between 50 and 92 per cent of paretics could be shown to have had syphilis, while the histories of ordinary insane people did not show nearly this  incidence of syphilis.  He also noted that while paresis was found rarely in rural areas, among the clergy or among women, it was found frequently among women who lived ‘irregular lives.’ Finally having earlier established to his satisfaction that tabes was due to syphilis he now pointed to the high correlation between that disorder and general paresis. 15  Given the large volume of his data, these were impressive observations. Nonetheless he met skepticism. 'Several times,' Fournier complained, 'I had the experience of having to diagnose syphilitic madness in the presence of very competent and justly famous psychiatrists; and almost invariably my opinion was received as a hypothesis which was possible, rational, perhaps tolerable, but singularly adventurous and tainted with heresy.'16
         While issues of professional turf no doubt influenced some of this psychiatric skepticism toward Fournier's diagnostic imperialism, there was one good scientific reason for this skepticism.  General paresis did not respond to antisyphilitic treatment. Mercury, for example, had been used to treat syphilis from the early sixteenth century.17 During the nineteenth century, potassium iodide also came to have some vogue in the treatment of syphilis.  By the late nineteenth century, doctors had convinced themselves that mercury and potassium iodide were effective treatments for syphilis, even for syphilitic disorders of the nervous system. The failure of  general paresis to respond to these treatments led Fournier to propose the peculiar concept of parasyphilis.Parasyphilitic disorders, which in addition to general paresis also included such varied conditions as tabes, neurasthenia and optic atrophy, were, according to Fournier, ‘not, strictly speaking of a syphilitic nature, but are none the less of syphilitic origin.’18 In other words, parasyphilis was a non-syphilitic sequel of syphilis, a degenerative process, provoked, in susceptible individuals, by syphilis. The concept of parasyphilis may have explained to Fournier's satisfaction why general paresis did not respond to mercury and potassium iodide but it didn't do much to persuade the skeptics.19
         The riddle of general paresis grew more perplexing with that series of brilliant laboratory findings in the first years of the twentieth century that established conclusively that paresis was caused by syphilis. In 1897 Krafft-Ebing inoculated nine paretics with no history of syphilis with luetic material. When none of them developed symptoms of syphilis, he inferred that they had been previously infected.20  The pathology of paresis was made definite by the work of Nissl and Alzheimer, published in 1904. In 1906 Wasserman introduced a serologic test that not only confirmed the syphilitic nature of active lesions but showed that a latent lesion could be present in an individual. With evidence gained through the use of the Wasserman reaction the relation of paresis to syphilis was rather generally accepted. In 1913 all doubt about the syphilitic nature of paresis was finally eliminated when Noguchi and Moore demonstrated spirochetes  in the brains of paretics.
         With the conclusive linking of paresis and syphilis, general paresis of the insane finally became a public health concern. As long as general paresis was thought to be due to heredity, nervous shock or excess venery, its epidemiology was not a source of great consternation. With the link between syphilis and general paresis established, the anxiety provoked by syphilis spread to paresis. Rigorous estimates of the percentage of syphilitics who developed general paresis were hard to come by. The first extensive study arrived at  a figure of just under five per cent.21 Some studies, however, put the figure as high as ten per cent.22 There was  a strong feeling that the frequency of paresis and other syphilitic disorders of the nervous system were increasing and that the same factors that were leading to the increase in syphilis were leading to increases in paresis.23    In 1914 Salmon, adopting a public health stance toward paresis, pointed out that death from paresis made it the eighth leading infectious disease for mortality.24   At the same time Meyer argued for the value and acceptability of putting the assets of patients with positive Wasserman reactions, but no symptoms of paresis, in trust.25

THE MAGIC BULLET
         The conclusive demonstration spirochetes in the brains of paretics also catalyzed a wave of enthusiasm for the idea that paresis might be cured with anti-syphilitic treatments. The reason for this enthusiasm was the fact that Noguchi and Moore's discovery occurred very shortly after Erlich and Hata, in 1909, were able to show that arsphenamine, better known as Salvarsan, was an effective anti-syphilitic. Salvarsan, it was hoped, would prove to be as powerful a 'magic bullet' in the treatment of paresis as it initially seemed to be in the treatment of other forms of syphilis.26   There was, however, resistance to treating paretics at all. Critics argued against anti-luetic treatment for paresis on theoretical and empirical grounds.  Prior experience showing that paresis was  uninfluenced by  mercury and iodide had led to a nihilistic attitude toward  antisyphilitic treatment. Fournier's ideas about parasyphilis helped create a theoretical basis for pessimism as well. Frederick Mott,the leading early twentieth century British neuropathologist, for example, argued that the paretic process simply could not be modified by anti-luetic treatment and strongly advised against using it. There were even questions as to whether treated cases did more poorly than untreated cases.27 A questionnaire sent to two hundred hospitals, during this period, indicated that only thirty five per cent of those responding were using any antiluetic treatment.28 As Henry Head and E.G.Fearnsides noted:

                         the treatment of syphilis by modern measures is so
                        expensive and  troublesome   that few  inmates  of   our
                        Asylums and Workhouse Infirmaries receive adequate
                        injections of neosalvarsan or even effective mercurial
                        treatment. No one wastes time and money on persons
                        supposed to be obvious cases of 'general paralysis,'  and
                        we have received letters from medical officers ...
                        expressing wonder that we should 'take so much trouble
                        over such a straightforward case of general  paralysis.29


         Watching patients die from general paresis in the days before fever therapy was a grim business that occurred in a pessimistic and gloomy atmosphere.  As one doctor put it, 'nothing is more depressing to me than to see ... cases of paresis in the last stage of the disease, demented and deteriorated, untidy, living a vegetative existence, bedridden with numerous decubitus ulcers, a burden to themselves and others,...'30  Remissions, however, could be even more painful to watch because  they did not last. Such patients might be reduced to ‘helpless... bedridden... breathing, heartbeating automata,’ as another doctor wrote, only to recover spontaneously over a period of six weeks to three months. They then appeared to have ‘risen from the dead" and to be "almost well and like themselves.’ Such remissions typically lasted six months --though occasionally five to six years--only to have ‘the symptoms return, often in rapid progression, and usually lead to death after a variable interval of from six months to a few years.’31 Some doctors became hardened by such experiences and objectified and denigrated their paretic patients. Textbook descriptions of patient's grandiose delusions often seem, at least to a late twentieth century reader, to be mocking in tone.32 Braslow has also recently noted from a study of hospital records that paretics in the pre-malarial therapy period were often referred to as 'lazy,' 'silly,' 'childish,' 'obscene,' 'vile,' 'vulgar,' and 'stupid.'33

         In the face of both the arguments against treatment and the atmosphere of pessimism,  advocates of Salvarsan not only hoped for dramatic results but needed them.  There were, however,  many difficulties in  determining the value of treatment. Possible cures might be discounted.  Some patients who improved, it was argued, were actually suffering from ‘cerebral syphilis’ and not paresis, though distinguishing between these two disease states was extremely difficult. It was also suggested that untreated paresis was running a milder course than in former years. Because sample sizes were initially quite small, it was also difficult to allow for the differing effects of treatment on early and late cases.34 Efforts at controlled studies were crude and, as one author admitted of his study, comparison between results with treated and untreated patients was ‘manifestly unfair.’35 Furthermore, because there was so little data on the natural history of the disease, it was  difficult to take into account the frequency of  spontaneous remissions.
         Efforts to evaluate the treatment of general paresis stimulated work on this problem.  In an effort to characterize the natural history of untreated, hospitalized paretics, Raynor described the fate of 1004 patients admitted to his hospital between 1911 and 1918. Of these 87% had died, 78% during the first admission.Nine per cent, however, had improved and 3.5% had improved sufficiently to be regarded as remissions.36
 Salvarsan was almost immediately tried on syphilitic lesions of the nervous system. The results in cases of general paresis  were, however, meager and disappointing. In one series of twenty paretics, six showed ‘improvement.’ Of these six, four were considered ‘remissions’ one of which lasted six months and two of which allowed the patients to return to work. In another series of fifty-one cases, Bernard Sachs noted that the results were not much better than those achieved with mercurials in previous years.37  In 1911 a standard textbook noted that, 'Erlich's Salvarsan ('606') has been used in a great many cases, but so far with rather more harmful than beneficial results.'38  In the same year Albert Neisser noted that 'The more I see, the more I am under the impression that the paralytic process is hastened by '606.'' 39
         Because many did believe that Salvarsan should work, efforts were undertaken to deliver the magic bullet more directly to the brain. Salvarsan was initially used intramuscularly without benefit and then, in the first of a series of increasingly invasive maneuvers, it was injected intravenously without great improvement in results.The failure of intramuscular and intravenous Salvarsan to relieve paresis was explained as due to its failure to reach the central nervous system. In response to this obstacle, Swift and Ellis in 1912 proposed the intrathecal injection of arsphenamized serum. This method produced favorable clinical and serological results in meningeal, vascular and tabetic neurosyphilis, but was was without effect in paresis. This led others to inject Salvarsan into the subarachnoid space, the cisterna magna and the lateral ventricles.40 While published reports argued that these techniques were safe, the use of such invasive methods still stirred up much anxiety.41 None of these invasive procedures produced results worthy of the risk. A series of additional drugs including bismuth and neosalvarsan were later introduced but also failed to affect general paresis. The shortcomings of Salvarsan could be seen in the recommendation that it be used only as an adjuvant of mercurial treatment.42

FEVER THERAPY
         Long before the wave of enthusiasm for using Salvarsan in general paresis, psychiatrists had occasionally observed mentally ill patients who recovered following an intercurrent illness with a high fever. Remissions and even cures had often been reported following cases of typhoid, which was common in asylums. There were also sporadic reports of doctors trying to treat psychiatric disorders by inducing fevers. Generally these reports did not distinguish between paretics and other patients. In 1876 Alexander S. Rosenblum reported that eleven out of a mixed group of twenty-two psychiatric patients  were cured after an attack of recurrent fever. Although he presumably induced this fever, the controversial nature of this procedure led him to omit this fact from his report.43 In 1877 Meyer reported curing eight of fifteen paretics,  who he had treated over a period of fifteen years, by rubbing Autenrieth's ointment onto their scalps to induce a deep suppuration. In 1883 Keirnan, in the United States, reported efforts to treat psychiatric patients by vaccinating them for smallpox.44
         Wagner-Jauregg became interested in the idea of treating psychoses with fever,shortly after taking up his first position as a psychiatrist in 1883. He observed a female patient who recovered from a psychosis after a bout of erysipelas. In a review of the literature which he published in 1887 he reported on 163 incidents of psychoses remitting after typhoid, and intermittent fevers as well as erysipelas.  While Wagner-Jauregg clearly found the idea of treating mental illness by inducing a febrile illness quite attractive, he pursued his research cautiously and with what appears to have been great concern about community disapproval of this approach.   In 1888 he began his experiments by injecting several patients with a culture of streptococci taken from a case of erysipelas. Among his reasons  for giving up this line of investigation  was the fact that 'medical science of that period looked with disfavor at experimentation on human beings.' The depth of his concern about community judgment is suggested by his mention of a colleague who inoculated nine paretics with syphilis and 'almost went to prison for his zealous scientific endeavors.' In the winter of 1890/91 Wagner-Jauregg began injecting the newly introduced tuberculin to induce a febrile reaction 'without resorting to an infectious disease.'  He later wrote that he  discontinued this treatment 'prematurely because tuberculin was soon considered a dangerous preparation' and  ‘it had become practically a crime to use it.'45
         In 1895 after Wagner-Jauregg had returned to using tuberculin and other bacterial proteins to induce fever, he first noticed that paretics did better with fever therapy than other psychotics. In 1902 he combined this treatment with mercury and iodide after he became convinced of the syphilitic origin of paresis. In this period others also attempted to induce fevers by injections of sodium nulleinate  boiled milk and milk protein. The results of these efforts were poor, perhaps, it has been suggested, because high fevers were not obtained.46 Collateral support for the value of fever in the treatment of neurosyphilis was available.  In 1913 one of Wagner-Jauregg's assistants published a significant statistical study 4134 cases of syphilis and observed that those patients who had contracted a febrile disease during the early years of their syphilitic infection almost never developed neurosyphilis. Others also noted that the incidence of neurosyphilis was low in areas where malaria was endemic.47
         Although Wagner-Jauregg had suggested the use of artificial tertian malaria to produce fevers as early as 1887, he only began to use this treatment in 1917.  The serendipitous presence of a  soldier with malaria in his neuro-psychiatric hospital gave Wagner-Jauregg the opportunity  that he had been, in a sense, preparing for for thirty years. He also suggests that the brutalities of war  may have made him less sensitive both to the glory of discovering a cure for a dread disease and to the possible censure for experimentally infecting sick people with a new disease. As Wagner-Jauregg recalled:

 'We were already in the third year of the war, and its       emotional implications became more manifest from day to      day. Against such a background a therapeutic experiment      could stir me little, in particular since its success could not be
 foreseen. What meant a few paralytics,would  possibly be saved, in    comparison to the thousands of  able-bodies and capable men who    often died on a single day as the result of the prolongation of the     war.'48


         Wagner-Jauregg took blood from his serendipitously encountered malaria patient and injected into two paretics. Six of his first nine patients showed improvements though four of these eventually suffered relapses.When one patient died because he was inadvertently given malaria tropica rather than the tertian type, Wagner-Jauregg gave up the treatment for a year.He resumed treating paretics only after he was able to obtain a steady supply of the tertian type.49 In 1921 Wagner-Jauregg was able to report that 25% of his first two hundred patients were able to return to work. In 1922 one of Wagner-Jauregg's assistants reported that over 60% of 400 cases observed for over two years had achieved remissions of varying degrees.50
 Following the war the use of malaria therapy spread quickly to many countries.’Soon it was definitely established that the progress of the disease could be halted in approximately 70 per cent of cases and that marked improvement could be obtained in 20 to 40 per cent of the cases, the final result depending to a large extent on the amount of damage that had occurred prior to the beginning of the treatment.’51In a review of 2460 cases recorded in the literature by 1926 27.5% were found greatly improved and another 25.6% moderately improved.52 In 1929 there were reports from the Soviet Union of remissions in 64% of treated cases.53
          Praise for the treatment appears to have been quite general. Malaria therapy was referred to as a 'therapeutic noble deed,' the 'right way to treat a hopeless disease,' and 'the best treatment available.' The success of the treatment seems to have stifled most open criticism of the method. Even in 1946 Merritt, Adams and Solomon could only speak of 'the transmission of the infection...by inoculation of blood from a syphilitic who has been previously been given malaria (as) a practice which offends the esthetic sense of many individuals.' (emphasis added)54 Wagner-Jaurreg's Nobel Prize was, however, held up because B. Gadelius, a Swedish professor of psychiatry, and a member of the prize committee,  could not be persuaded to recommend the award to a ‘physician who injected malaria into a paralytic, because he was in his eyes a criminal.’55  There was also some ambivalence about the results of malarial treatment, even by enthusiastic promoters of the cure. Henry A. Bunker, for example, following a presentation of the benefits of malarial treatment noted that ‘those patients who achieve merely an arrest of their disease...and  remain in a stationary stage for four, five and more years are not examples of any great accomplishment from a practical standpoint. In fact my personal opinion is that many of such stationary but permanently institutionalized patients would be better off if they were dead.'56
         Malaria treatment continued to be used into the early 1950s. As late as 1946 Merrit, Adams and Solomon still insisted that it was ‘the simplest and most effective method of treatment of paretic neurosyphilis.' 57 There is no question that it was a desperate treatment.Even so there was reason to be proud of it.   After a hundred years of hopelessness and despair, it offered hope for people afflicted with  a devastating disease. Moreover, as Braslow has recently shown, it even an increased measure of respect for patients had previously been scorned and mocked.58

Notes

 1.Magda Whitrow's biography Julius Wagner-Jauregg (1857-1940) (Smith-Gordon, London, 1993) now provides a comprehensive review of his life and work.
2.Andrew Scull, "Somatic treatments and the historiography of psychiatry," History of Psychiatry, 5(1994), 8.
3 .Harold Mersky, "Somatic treatments, ignorance, and the historiography of psychiatry," History of Psychiatry, 5(1994), 387-91.
4 Edward M. Brown, “French Psychiatry's Initial Reception of Bayle's Discovery of General Paresis of the Insane,” Bulletin of the History of Medicine 68 (1994), 235-253.
5 .J.E.D.Esquirol, Mental Maladies, A Treatise on Insanity, Facsimile of the English Edition of 1845, (Hafner, New York and London 1965),436
6.For example Henry Maudsley,Responsibility in Mental Disease (New York, D.Appleton and Company, 1899),80-1
7 .A.L.J. Bayle, Traite des Maladies Du Cerveau et de ses Membranes   reprint of the 1826 edition,(New York, Arno Press,1976),574-587
8 .W.Julius Mickle,"General Paralysis," in D.Hack Tuke (ed.) A Dictionary of Psychological Medicine (Philadelphia,P. Blakiston,Son & Co,, 1892), 532
9 .E. Regis, A Practical manual of Mental Medicine (Philadelphia, P.Blakiston, Son & Co.,1895), 462.
10 .W.Julius Mickle. General Paralysis of the Insane (London, H.K.Lewis,1880),171
11.  Mickle, General Paralysis of the Insane,.165-75
12. M.A. Waugh, "Alfred Fournier, 1832-1914: His Influence on Venereology," British Journal of Venereal Disease 50(1974),232.
13. John T. Crissey, The Dermatology and Syphilology of the Nineteenth Century (New York ,Praeger), 221
14 .Crissey,The Dermatology and Syphilology of the Nineteenth Century , 223. Alfred Fournier, “Syphilis and General Paresis,” in Selected Essays and Monographs, (London, New Sydenham Soc.(161), 1897),.375-92
15 .Gazette Medicale de Paris, no.44, (Nov.3,1894),522-4.
16 .Claude Quétel, History of Syphilis (Johns Hopkins University Press, Baltimore, 1992),163
 17. H Houston Merrit, Raymond Adams, Harry C. Solomon, Neurosyphilis, (Oxford,Oxford University Press, 1946),393
18 .Alfred Fournier, The Treatment of Syphilis, trans. C.F. Marshall, (New York, Rebman Company, 1906),253..M.A. Waugh, "Alfred Fournier, 1832-1914: His Influence on Venereology," British Journal of Venereal Disease 50(1974), 233.
19 .J. Darier, "Alfred Fournier:1832-1914," Annales de Dermatologie et de Syphiligraphie 5(1915), 522-8. One biographer suggested that Fournier was not interested in this concept as a discovery of a law of pathogenesis but only as a conquest in the domain of etiology. Fournier did not attempt to explicate the distinction between "origine" and "nature" which were crucial to the concept of parasyphilis. "It sufficed for him to have charged the dossier of syphilis with some more atrocities."  cited in Crissey, The Dermatology and Syphilology of the Nineteenth Century .223
20 . George Rosen, “Patterns of Discovery and Control in Mental Illness," in Madness in Society, (Harper,New York, 1968),247-62.
21 . Thomas W. Salmon, "General Paralysis as a Public Health Problem," American Journal of Insanity 71(1913-4),44 cites a study by Pilcz and Mattauschek of 4,134 officers in the Austrian army who had contracted syphilis between 1880 and 1890 which showed that 4 9/10 per cent had developed general paralysis by 1912.
22 . D.K. Henderson, "Cerebral Syphilis," American Journal of Insanity 70(1913),282
23 . Charles P. Bancroft, "Is There an Increase Among the Dementing Psychoses." American Journal of Insanity 71(1924-15),59-73. D.K.Henderson, American Journal of Insanity 70(1913)282."Mott asserts... that owing to the increased strain of living and owing to the conversion of a rural into an urban population, syphilitic affections of the nervous system are greatly on the increase."
24  Salmon, Thomas, "General Paralysis as a Public Health Problem," American Journal of Insanity 71(1913-4),44
25 . Adolf Meyer, "Differential Diagnosis of General Paresis," American Journal of Insanity 71(1914-15),51-58
26 . Harry C. Solomon,”The value of treatment in general paresis” Boston Medical and Surgical Journal, 188(1923),635
27 .Harry C.Solomon Boston Medical and Surgical Journal 188(1923)636 cited observations that  that treated cases lived only half as long as untreated cases and also urged against treatment.
28 . H Goldsmith, "A Plea for Standardized and Intensive Treatment of the Neurosyphilitic and Paretic," American Journal of Psychiatry. 82(1925),251-61,
29. Henry Head and E.G. Fearnsides,"The clinical aspects of syphilis of the nervous system in the light of the Wassermann reaction and treatment with neosalvarsan," Brain 37(1914), 134.
30 . H. Goldsmith, op.cit., 256
31 . William A. White and Smith Ely Jelliffe, Modern Treatment of Nervous and Mental Diseases, (Lea & Febiger, Philadelphia and New York,1913),249
32 .See for example, E.C. Spitzka, Insanity, Its Classification, Diagnosis and Treatment,(New York, Bermingham & Co. 1883), 195 ""The patient claims to be the most powerful, the richest and ablest man in his community, He can raise the asylum with his little finger, he has trunks filled with gold in every city in the Union, he is married to all the handsome women in the world, can speak all the living and dead languages, has the best-developed sexual organs extant, and is the intimate friend of every contemporary great man, sometimes himself Napoleon, Caesar, Shakespeare, Grant, Buffalo Bill, and every other celebrity in one person, and the fortunate owner of numerous patents." Spitzka goes on to itemize the extravagant list of "possessions" of a paretic former stock-broker.
33.Joel T. Braslow, "Effect of Therapeutic Innovation on Perception of Disease and the Doctor-Patient Relationship: A History of General Paralysis of the Insane and malaria Fever Therapy, 1910-1950," American Journal of Psychiatry, 152(1995)660-65.
34 .Harry C. Solomon, op. cit., 635
35  I.J.Furman,"Treatment of General Paralysis," Archives of Neurology and Psychiatry, 12(1924),359-69 .
36. Mortimer Williams Raynor, "Remissions in General Paralysis." Archives of Neurology and Psychiatry 12(1924), 419-425.
37 .New York Neurological Society: Proceedings of joint meeting with Philadelphia and Boston Neurological Societies, November 14,1911, "Use of Salvarsan in Syphilis of the Nervous System," Journal of Nervous and Mental Diseases, 39(1912),180-86
38 .Archibald Church and Frederick Peterson, Nervous and Mental Diseases,(Philadelphia and London, W.B.Saunders Company,1911),818
39 Albert Neisser,On Modern Syphilotherapy with particular Reference to Salvarsan, translation of a 1911 article, (Baltimore Johns Hopkins Press 1945),22.
40 .Walter F. Shaller and Henry G. Mehrtens, "Therapy in Neurosyphilis with Particular Reference to Intraspinal Therapy," Archives of Neurology and Psychiatry, 7(1922),89-97 "...every case of cerebrospinal syphilis improved...Patients with paresis, as a whole, did poorly."  Franklin G. Ebaugh, "The Treatment of General Paresis by the Intracistern Route," Archives of Neurology and Psychiatry 7(1922),325-31."The clinical results of intercisternal therapy have been disappointing.". H. McKusker, "Some observations on Cistern Puncture," Journal of Nervous and Mental Diseases 53(1921),453.
41 . H. Goldsmith, op. cit.,253 "It has only been in recent years that spinal puncture has become general and attended by very few untoward results. I can remember when any medicine to be injected intravenously was attended by preparations equal almost to that of a major operation and spinal puncture was approached wit fear and trembling."
42 .D.K. Henderson,”Cerebral Syphilis,” American Journal of Insanity, 70 (1913),282.
43 .Magda Whitrow, "Wagner-Jauregg and Fever Therapy," Medical History, 34(1990), 294-310.
44 . James G Kiernan, "Variola and Insanity," American Journal of Neurology 2(1883)365-72.
45 .Julius Wagner-Jauregg, "The History of the Malaria Treatment of General Paralysis," American Journal of Psychiatry 102(1945-6),577-82
46  H. Houston Merrit, Raymond Adams, Harry C. Solomon, op. cit.,397
47 .E.Mattauschek and A. Pilcz, "Aweite Mitteilung uber 4134 katamnestisch verfolgte Falle von luetischer Infection," Ztschr.f.d.ges.Neurol.u.Psychiat. 15(1913)608 as discussed in H. Houston Merrit, Raymond D. Adams and Harry C. Solomon, op. cit.,,396
48 .Julius Wagner-Jauregg,"The History of the Malaria Treatment of General Paralysis," American Journal of Psychiatry 102(1945-6),580
49 .Whitrow, "Wagner-Jauregg and Fever Therapy," Medical History 34(1990),294-310. incident reported on p.304-5.
50 . Magda Whitrow "Wagner-Jauregg and Fever Therapy," Medical History 34(1990),306.
51 . H. Houston Merrit, Raymond Adams, Harry C. Solomon, op. cit.,.397.
52 .J.R. Driver,J.A. Gammel,L.J. Darnosh, "Malaria Treatment of Central Nervous System Syphilis, Journal of the American Medical Association 87(1926),1921 cited in Bunker,"Recent Treatment of General Paralysis,”
53 . A.L. Lestchinsky, "Treatment with Malaria Inoculation in Paresis," abstract in American Journal of Psychiatry  86(1929-30), 589..
54 .  H. Houston Merrit, Raymond Adams, Harry C. Solomon, op. cit..397.
55 . Magda Whitrow "Wagner-Jauregg and Fever Therapy," Medical History  34(1990),310
56 .Henry A. Bunker Jr. "Recent Methods in the Treatment of General Paralysis,"American  Journal of Psychiatry. 85(1928-9), 681-94,
57 .H. Houston Merritt, Raymond Adams, and Harry C. Solomon, op. cit..406
58  Joel T. Braslow, "Effect of Therapeutic Innovation on Perception of Disease and the Doctor-Patient Relationship: A History of General Paralysis of the Insane and malaria Fever Therapy, 1910-1950," American Journal of Psychiatry, 152(1995),660-65.