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June 7, 2018 by Kelley Swain | The Lancet

‘Extraordinarily arduous and fraught with danger’: syphilis, Salvarsan, and general paresis of the insane

‘There is something wrong in his appearance; something displeasing, something downright detestable … he gives a strong feeling of deformity…’

So goes Robert Louis Stevenson’s 1908 novel, The Strange Case of Dr Jekyll and Mr Hyde, published at the height of what historian Elaine Showalter called the Edwardian era’s “obsessive public crisis” about a dubiously defined disease. Mr Hyde, the shadowy night-time alter ego of respectable Dr Jekyll, “could have been syphilis personified”.

General paresis (or paralysis) of the insane (GPI) was crippling and terminal. It ended in loss of control over mind and body, often accompanied by grandiose delusions of wealth and power and, finally, paralytic death. There was no known cause. Could GPI be caused by overwork? Emotional labour? Mental strain? Sexual promiscuity? Drink? These were possible causes listed by William Julius Mickle in 1880. As historian Gayle Davis writes in The Cruel Madness of Love, “the disease was depicted as a broad and multi-causal concept which related largely to the destructive influences of the urban environment, and particularly to the excesses of tobacco, alcohol, and sex”. According to Davis, by the late 19th century up to “20% of British male asylum admissions received this diagnosis”.

A disease of dissolution and disrepute, GPI was also considered a result of that most Edwardian horror: degeneration. It was linked to the humiliations of the Boer War. According to J Townsend in Syphilis and Subjectivity: from the Victorians to the Present, in 1904, “the British Government convened an Inter-Departmental Committee on Physical Degeneration” in response.

“The pox” was written about by medical authorities as early as the 15th century. French royal physician Jean Astruc wrote on venereal disease, including syphilis, in his 1736 work De Morbus Veneris, and “the French disease” was well noted by psychiatrist Jean-Étienne Esquirol in 1816. Yet syphilis was considered a separate disease from GPI, which was itself a malady that was difficult to define. It was not until the 1860s that British doctors came to see GPI as “a distinctive disease with an identifiable brain pathology, predictable clinical history, and a definitive correlation between the two”, Davis writes. By 1874, GPI was no longer categorised as a complication of insanity, but as its own distinct disease.

GPI was thought to have three distinct stages, each with predictable mental and physical symptoms. Many patients were erratic and restless, and often had memory loss and frequent delusions of grandeur or fame. Their pupils would accommodate, but not constrict in reaction to light (the Argyll-Robertson sign), and would often be irregular in size. Patients’ speech was often slurred, as if the sufferer was drunk or had a nervous stutter. The trembling crept beyond the lips to the face and hands; a swaying gait would also suggest the sufferer was intoxicated. No longer able to speak or walk, a bedridden patient would often die in a convulsive fit.

Nevertheless, the cause was still unknown. “Syphilitic insanity” was considered a disease quite separate to GPI into the 1930s. The treatments for syphilis were harsh and poisonous; as the old saying went, “one night with Venus, a lifetime with mercury”. The so-called improvement on mercury treatment was arsenic. Alongside these treatments—often as miserable as the original illness—the advent of asylum-based laboratories was rapidly transforming the understanding of mental and physical illness. England’s first asylum laboratory opened at Claybury in Essex in 1895, becoming world famous for neuropathological research.

In Germany in 1905, discovery of the spiral-shaped bacterium now known as Treponema pallidum by zoologist Fritz Schaudinn and dermatologist Erich Hoffmann changed the understanding of syphilis and GPI. German chemist Paul Ehrlich took this research and, together with Japanese bacteriologist Sahachiro Hata, made arsphenamine (so-called compound 606); a drug that later become known as Salvarsan.

Salvarsan was groundbreaking. In 1908, Ehrlich received the Nobel Prize for contributions to immunology. Chemical and Engineering News commented in 2005, “The drug made its way to the clinic with speed unheard of in this day and age: discovered in the fall of 1909, Salvarsan was in clinical use by 1910…Salvarsan quickly became the most widely prescribed drug in the world.” Davis cites Glasgow-based pathologist Ivy MacKenzie, “During the past 8 months about 8000 cases have been treated [with Salvarsan] and if the hopes which this experience has raised, be realised, Ehrlich’s most recent discovery will mark an epoch-making stage in the advance of scientific therapy.”

The Wasserman test was developed around the same time by German bacteriologist August von Wassermann; this test was hailed as a reliable method of identifying syphilis in blood and cerebrospinal fluid. Claybury Asylum and other such laboratories quickly and enthusiastically started using the Wasserman test but, as with the case of Dr Jekyll, not all was as it seemed.

Alhough psychiatrists were initially amazed by the positive results for syphilis in Wasserman reactions for overwhelming numbers of patients with GPI—one physician claiming a 100% positive reading in his patients—it became clear that the tests produced a large number of false positives (Davis cites 2–14%). The test was complicated and required special training and equipment, adding to both its exclusivity (and therefore trust, warranted or not, that many placed in it) and inaccessibility (and therefore the resentment that many felt towards it).

Similarly, Salvarsan, known as “the magic bullet”, did not signal the end of problems for patients. It was arsenic-based, thus toxic, with harsh side-effects, and was complicated to administer, requiring a series of potentially painful injections. The Wasserman test, which could confirm whether someone had syphilis, and Salvarsan, which could treat it, both required specialist knowledge and skill, thus keeping both identification and treatment in the realm of the highly specialised.

Standardisation and administration of the drug was risky. Ehrlich himself wrote, “the step from the laboratory to the patient’s bedside…is extraordinarily arduous and fraught with danger”. Notably, Salvarsan was not as effective in treating the later stages of syphilis, including neurosyphilis (ie, GPI). Indeed, recoveries from GPI after use of the drug were so rare that physicians only admitted wary optimism:

“We have treated a good many cases without apparent benefit, but one patient, who was one of the first to be treated, made, almost at once after the injection, the best apparent recovery of any case of undoubted general paralysis I have yet seen. It is two months since this happened, and the patient still keeps well, but I will not yet commit myself to any definite opinion as to whether the progress of the disease has been checked or not.”

Salvarsan was a turning point in the history of medicine. As a laboratory-produced chemical compound with specifically spirochaeticidal properties, it remained the most-used treatment for syphilis until the advent of penicillin in the 1940s. Penicillin, which was easier to administer and had fewer side-effects, was—like Salvarsan—most effective in the primary and secondary stages of syphilis.

The laboratory-based discovery of the illness-causing spirochaete and the drug that could kill it seemed to promise that the causes of mental illness would be relatively easy to identify in the new era of microbiology. It encouraged a mechanistic approach: there would inevitably be a targetable cause, successful treatment of which would render the sufferer well. A full course of Salvarsan treatment could last for 2 years, but many patients stopped treatment when symptoms subsided, leaving them vulnerable to relapse. Later treatments, including tryparsamide and malarial therapy, offered some relief from GPI, but administration was tricky (such as sourcing blood with the correct strain of non-lethal malaria), and results were inconsistent. On the upside, innovation was piqued; Davis cites one physician successfully transporting malarial blood to Western Argyll in Scotland using a thermos.

The wider field of mental illness is relentlessly complex, nuanced, and highly individual, with only some ailments caused by specific vectors and fewer still with chemical or genetic targets inviting the aim of a magic bullet. But even then, the illness is set within a body, a person, and a wider social and cultural framework, all of which affect the illness and its remedy. Indeed, health is highly subjective. Many patients with GPI were released as “cured” or “in remission”, explains Davis, even though natural and spontaneous temporary remissions “were a characteristic of GPI”. Many patients died, if not in the asylum then at home, in real or supposed remission.

It is significant that GPI was considered a specific disease for decades without having a single known cause; it was equally significant that, once the spirochaete was discovered, a total cure was presumed to be on the horizon. The history of GPI, or neurosyphilis, offers what should be the unsurprising lesson that new levels of medical understanding reveal new questions and challenges. Although a simple blood test and one dose of a penicillin pill is used to treat syphilis today, the advanced form of the illness still lurks in poorer countries, and hides in rare patients in high-income countries who are too fearful or ashamed to seek medical assistance.

In The Strange Case of Dr Jekyll and Mr Hyde, Jekyll’s friend and lawyer, Utterson, forces open the door of the doctor’s cabinet, his most private room, in which Hyde (now permanently so) has taken refuge. “For God’s sake Utterson, have mercy!” Hyde cries, but the lawyer breaks down the door and finds Hyde in the throes of death by self-poisoning. “We have come too late,” Utterson says, “whether to save or punish”.

We may think of Schaudinn and Hoffmann as finding the key to the syphilitic spirochaete, or of Ehrlich as breaking down the door to a treatment. It is also useful to remember that there will always be casualties, and mysteries, and to remember the dying cry of the lost Jekyll (for in the end, he was both) to have mercy—and to know that breaking through a door does not necessarily mean that a mystery is solved.


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