Medicine is an imperfect science, its history shot through with barbaric and dubious practices from grave robbing to bloodletting. Since even before the time of that father of modern medicine, it can seem that physicians have more often violated Hippocrates’ decree “above all, do no harm” than abided by it.

A photomicrograph of a Treponema pallidum bacterium, a spirochete that ranges from 5 to 15 micrometers in length, and is the causative agent of syphilis. Image: CDC/Susan Lindsley.

A photomicrograph of a Treponema pallidum bacterium, a spirochete that ranges from 5 to 15 micrometers in length, and is the causative agent of syphilis. Image: CDC/Susan Lindsley.

The psychiatric field gets the worst rap. Shock therapy, trepanation, and trans-orbital lobotomies do not command the same kind of grudging respect we can now muster for the similarly slow and painful advance of other healing disciplines. It is only now, with a critical retrospective eye, that we can see that some of these psychiatric therapies had the right idea despite their heavy-handed approach.

Shock therapy evolved and has emerged in the more sophisticated form of deep brain stimulation to treat patients with Parkinson’s and Huntington’s disease. Lobotomies no longer arbitrarily hulk-smash our precious frontal lobes, but a similar practice can target and carefully excise cortical regions to treat difficult cases of obsessive compulsive disorder and depression; the cingulotomy procedure that involves singeing small holes in the cingular lobe that sits atop our brainstem is one example (1). The craniotomy, in which a section of skull or “bone flap” is temporarily removed, can alleviate intracranial pressure and is essentially the modern version of trepanation. In this era of modern medicine, the goal is less excision, more precision. Fewer ice picks, too.

The practice of pyrotherapy, in which malaria infection was intentionally used to treat advanced syphilis, is also one for the books. It is one of the stranger stories populating the history of medicine and includes a Nazi sympathizer, human experimentation and blood-swapping transfusions infused with malaria parasites. Oh, and a Nobel Prize.

Syphilis was a terrible specter in an era without antibiotics. This sexually transmitted disease caused by the slithering spirochete Treponema pallidum was absolutely incurable and fatal in the most dreadful way, resulting in a progressive and debilitating loss of mind and body. At the time, syphilis was “perhaps the most terrible of all of mankind’s diseases and … its diagnosis [was] accepted as a sentence of death, to take effect at the latest within four years, generally much sooner” (2). Grim.

Syphilis infection skips through stages: first, a localized genital infection characterized by a painless chancre; followed by a systemic secondary phase with fever and a distinctive rash on the palms of hands and soles of feet; lastly, following a latent period of indefinite time, a progressive tertiary stage that may or may not occur. In this last phase, known as neurosyphilis, the bacterium invokes a destructive inflammatory response in the central nervous system, demolishing fiber tracts and leading to progressive blindness, dementia, and partial motor paralysis. This dreadful state was referred to as “general paresis of the insane.”

For the past two centuries, patients with neurosyphilis were pariahs viewed with contempt by their physicians. Many patients were involuntarily institutionalized in epidemic numbers: in the early 20th century, neurosyphilis was responsible for 5 to 10% of all psychiatric admissions (3). The sexual nature of the disease’s transmission and its wretched end result implicated neurosyphilitics as unprincipled and morally wayward. Their lasciviousness had brought on the disease and there was nothing to be done. Nothing remotely effective, in any event: treatments for the advanced state of syphilis included hydrotherapy, enforced bed rest, and “work therapy” (4).

The use of fever and heat, especially in the treatment of diseases of the brain, has, oddly enough, long had its champions. Hippocrates discovered that a feverish episode could temporarily “have a calming effect” on epileptics while Galen found a similar remedy for a case of melancholy (5). Since the early 1900s, a few physicians had, in isolation, sought to use the curative powers of fever to treat syphilis, one of the most intractable and devastating diseases of their time. And there was little in the natural or in the man-made world that induced fever quite like another good, old-fashioned infectious disease.

Julius Wagner-Jauregg

Austrian psychiatrist Julius Wagner-Jauregg, chief proponent of malarial fever therapy to treat neurosyphilis.

Dr. Julius Wagner-Jauregg, an Austrian psychiatrist trained in experimental pathology, had long heard rumors of the alleviative power of fever, of patients recovering some faculty of the mind after a bout of infection. In 1883, at the beginning of his career, he had witnessed one such miraculous case: a woman in the throes of deep psychosis spontaneously recovering from her mental illness after suffering from erysipelas, a nasty bacterial skin infection that is often accompanied by a high fever (3).

Beginning in the late 1880s, Wagner-Jauregg sought to replicate this result in his patients, first tinkering with the applications of tuberculosis antigen, tuberculin, and then moving onto the typhus and typhoid vaccines to invoke fever in his deranged patients. The results of these improvised human experiments failed to provoke any improvement in clinical outlook. That is, until one fateful day in June of 1917 when a wounded and malarial solider fresh from the Balkan warfront was mistakenly committed to his psychiatric ward.

The mustachioed man himself described what happened next,

“Should he be given quinine?” [my assistant Dr. Alfred Fuchs] asked. I immediately said: “No.” This I regarded as a sign of destiny. Because soldiers with malaria were usually not admitted to my wards, which accepted only cases suffering from a psychosis or patients with injuries to the central nervous system … I obtained during a paroxysm a small sample of the soldier’s blood, and I inoculated 3 general paralytic patients by rubbing a few drops into several superficial scarifications of the skin. Then the malaria of the solider was stopped with quinine. (8)

Wagner-Jauregg went on to inoculate a total of nine patients, advanced syphilitics all, with malaria parasites. Six recovered. One patient, a paralyzed 37-year old actor returned to the theatre, while others, a clerk and military officer, also returned to their previous lives (4). By “superimposing one disease on another,” the psychiatrist had chanced upon a potent antidote to one of the world’s greatest scourges (2). His findings were published in 1918 and soon this type of “fever therapy” swept the world, becoming de rigueur for the treatment of the once incurable neurosyphilis. Tens of thousands of people with neurosyphilis would eventually be treated with malaria pyrotherapy (7).

A photo from 1934 showing a malarial transfusion from a patient (seated in the back) to a neurosyphilitic patient (seated most anteriorly). Dr. Julius Wagner-Jauregg is seen standing in the suit on the right.

Special pyrotherapy asylums emerged specifically for neurosyphilitics – from Baltimore, Maryland to Epsom, England, from Tallahassee, Florida to Bucharest, Romania (2). Patients flocked to these centers voluntarily seeking the new fever therapy, “seeing the asylum as a place of cure rather than as an institution of confinement” as it once had been (8).

The procedure was simple enough. Blood from malarial patients was directly injected into syphilitic patients, regardless of blood type. Infections besides malaria, like hepatitis C or cytomegalovirus, were indubitably passed on to patients during the course of these transfusions (2). With fever came the attendant side effects of a bout of malaria: anemia, jaundice, malaise, kidney failure and, depending on the malarial strain used, death. After an odd dozen oscillations of fever paroxysms, the patient would be mercifully relieved of the infection with a course of quinine.

The malaria strain Plasmodium vivax was most commonly used in pryotherapeutic treatments. This relatively benign strain was found to be suitably (relatively) non-life threatening with the benefits that “repeated [febrile] paroxysms occurred dependably, infection was easily treated with quinine, and transmission by mosquito was reliably simple” (2).

Treatment with malaria was cheap, fast-acting and relatively non-toxic compared to the mercury therapeutics that had been the most viable extant option, and Wagner-Jauregg’s treatment became the go-to therapy for syphilis. Other physicians turned to artificial means of mimicking fever’s effects – electric blankets and hot baths and “fever cabinets” – but malaria trumped them all in its efficacy (2). Roughly 50% of patients responded to the treatment, presenting with an acute reduction in their neurological symptoms and able to resume their normal lives, freed from the asylum. Of that number, another 50% experienced a full remission. Though the data is incomplete, it is believed that 15% of all patients treated with fever therapy died from complications of the vivax malaria infection (7).

But was it all pseudoscience? Pyrotherapy emerged without scientific basis and, for the many years the treatment was in service, there was little long-term collection or analysis of data on recovered patients, nor on those who were unresponsive to the treatment. The bar for recovery from an incurable disease was low, and many patients had variable responses to the therapy.

To this day, the mechanism of action of this malaria-on-syphilis, parasite-on-spirochete action is unknown (7). Some physicians at the time proposed that the actual state of fever was inimical to the survival of the syphilis spirochete, malaria making a boiling pot of a human, cooking the syphilis like a microscopic crawfish. Then again, the “thermal death point” for syphilis hovers at 41 Celsius for at least six hours, a temperature that few human bodies or brains can bear. Some studies did indicate, however, that the patients with the greatest incidence of full remission were those who experienced the highest temperatures with the largest number of febrile paroxysms – a sort of biological loop-de-loop roller coaster (2). In any case, malarial induced fever therapy was just a shot in the dark in the treatment of neurosyphilis. It worked occasionally, sure, but in the same way that arbitrarily shoving an ice pick into your cranium works.

But this limited success was success enough. In 1928 British Surgeon Rear-Admiral E.T. Meagher remarked that “in applying malaria to general paresis, Wagner-Jauregg has found a key which moves the lock” (2). Syphilis was so incurable, so intractably deadly, that Wagner-Jauregg’s pyrotherapy method was awarded one of the greatest awards we have to bestow upon our forward-thinking discoverers: the Nobel Prize in Physiology or Medicine. He remains the only psychiatrist to have ever received the honor and one of only three such prizes to have been awarded in this field, the others having gone to neurosurgeon Dr. Egas Moniz in 1949 for his work championing lobotomies and in 2002 to Eric Kandel for his research studying memory storage in neurons.

Pyrotherapy represented the “earliest triumph of biological psychiatry over psychoanalysis,” a shift away from Wagner-Jauregg’s contemporary and friend Sigmund Freud and his armchair psychiatry (3). Wagner-Jauregg’s work, as eldritch and ethically dubious as it was, propelled the discipline of psychiatry and medicine into a new era. The idea that you could treat one disease with another has an arcane aspect to it, akin to the quest to cure bad humors. But perhaps we shouldn’t lump it along with the gripe water and tapeworm diets, that ignoble crew of quack treatments.

Even today, medicine elaborates upon and embellishes this very same idea of “fighting fire with fire.” Microscopic viruses that infect bacteria, known as bacteriophages, have been used to combat wound infections and sepsis. We use antibiotics, some produced by bacteria, to fight other kinds of bacteria. Using one disease to combat another does not seem so outlandish, so unenlightened, in this light.

Pyrotherapy also led to breakthroughs in the biological study of malaria, its mode of transmission, and treatment (2). Fever therapy revolutionized the study of malaria and mosquitoes, leading to “the establishment of the first permanent laboratory colonies of mosquitoes used in transmission; isolation and identification of the fourth human malarial parasite, P. ovale; isolation, use, and study of various strains of plasmodia; evidence that immunity to malaria develops with time and that it is mostly strain specific; many aspects of mosquito biology and of the behavior of malaria parasites within vectors were studied; drug testing, from quinine to the relatively recent generation of synthetics,” among many, many other advancements (2).

Our current knowledge of malaria and mosquitoes would be incomplete without this strange chapter in the annals of medical history. Regardless of its obsolete status today, pyrotherapy changed, in its own small way, the practice of infectious disease, psychiatry, and entomology. (Unfortunately Wagner-Jauregg’s discovery also opened the door to a dark chapter in the treatment of psychiatric disorders, leading “to all the methods of stress therapy used in psychiatry, [such] as electric shock and insulin” induced seizures (5).)

Alexander Fleming’s auspicious discovery of penicillin during World War II put an abrupt end to both malaria therapy and to advanced cases of syphilis, pressing a pause button on all bacterial diseases for a brief, blissful period. A strain of mold producing an antibiotic would now be the go-to treatment for bacterial infections and quickly rendered pyrotherapy obsolete. But Wagner-Jauregg would never see this come to pass, this newer paradigm shift in medicine, yet again hinging upon the hidden virtues of microscopic diseases.

N.B. It must be said: Wagner-Jauregg was no hero. He was a supporter of eugenics, registered with the Nazi party prior to the outbreak of WWII, and, to put it more bluntly in this addendum, tested radical treatments on non-consenting adults. For more information, read this article here.

Resources

“For something that grows so carelessly and freely on our fruits and breads, mass producing the white mold and its hidden wonder drug penicillin was devilishly difficult.” Read about Alexander Fleming’s oddball discovery of penicillin and watch an incredible video on its wartime production here.

Read Wagner-Jauregg’s speech upon his receipt of the Nobel Prize here.

References 1) W Spangler et al. (1996) MR- guided stereotactic cingulotomy for intractable psychiatric disease. Neurosurgery 38: 1071-1078 2) E Chernin (1984) The Malariatherapy of Neurosyphilis. J of Parasitology.70(5): 611-617 3) CJ Tsay (2013) Julius Wagner-Jauregg and the Legacy of Malarial Therapy for the Treatment of General Paresis of the Insane. Yale J Biol Med. 86(2): 245–254 4) JV Kragh (2010) Malaria fever therapy for general paralysis of the insane in Denmark. Hist Psychiatry 21(84 Pt 4): 471-86 5) M Karamanou et al. (2013) Julius Wagner-Jauregg (1857-1940): Introducing fever therapy in the treatment of neurosyphilis. Psychiatrike.24(3): 208-12 6) J Wagner-Jauregg (1946) The history of malaria treatment of general paralysis. Am J Psychiatry. 02: 577-582 7) G Vogel (2013) Malaria as life saving therapy. Science. 342(6159): 686 8) JT Braslow (1995) 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. Am J Psychiatry. 152: 660-665