Healing with malaria : a brief historical review of malariotherapy for neurosyphilis , mental disorders and other infectious diseases

Ten years ago, two articles about malariotherapy in Chinese human immunodefi ciency virus (HIV) patients once again raised ethical issues about this widely used treatment for infectious and mental diseases. Malariotherapy was born in a context where bioethics was not recognized as we do now, and evidence-based medicine was not yet established. During the pre-penicillin era, there was no effi cient treatment for syphilis. During the natural evolution of the disease, patients sometimes developed neurosyphilis 10 to 25 years after the initial infection. The most severe form of neurosyphilis is general paralysis of the insane (GPI)1, which is fatal in almost all cases because of a progressive degeneration of the nervous system. Physically, GPI is characterized by seizures, ataxia, speech defi cits and general paralysis. Mentally, it causes mania, depression, paranoia, violent behavior, delirium, memory loss, disorientation and apathy2. The curative effect of fevers has been reported since Hippocrates’ time. The Physician of Kos wrote that during and after the intermittent fever, as malaria was then called, patients with mental insanities improved and their aggressiveness was reduced. Reports from the Middle Ages describe improvement in patients in asylums stricken by cholera. In the 15th century, Ruy Diaz de Isla was the fi rst to report that fever had a benefi cial effect on syphilis3. However, 350 years later, Wagner-Jauregg, the father of malariotherapy, described in detail experiments with induced fever in GPI patients. General paralysis of the insane was the main cause of institutionalization in asylums and psychiatric hospitals from the end of 19th century until the 1940s. The prevalence of GPI at that time ranged from 10% to 45% in psychiatric hospitals worldwide1,2.


Dear Editor,
Ten years ago, two articles about malariotherapy in Chinese human immunodefi ciency virus (HIV) patients once again raised ethical issues about this widely used treatment for infectious and mental diseases.Malariotherapy was born in a context where bioethics was not recognized as we do now, and evidence-based medicine was not yet established.
During the pre-penicillin era, there was no effi cient treatment for syphilis.During the natural evolution of the disease, patients sometimes developed neurosyphilis 10 to 25 years after the initial infection.The most severe form of neurosyphilis is general paralysis of the insane (GPI) 1 , which is fatal in almost all cases because of a progressive degeneration of the nervous system.Physically, GPI is characterized by seizures, ataxia, speech defi cits and general paralysis.Mentally, it causes mania, depression, paranoia, violent behavior, delirium, memory loss, disorientation and apathy 2 .
The curative effect of fevers has been reported since Hippocrates' time.The Physician of Kos wrote that during and after the intermittent fever, as malaria was then called, patients with mental insanities improved and their aggressiveness was reduced.Reports from the Middle Ages describe improvement in patients in asylums stricken by cholera.In the 15 th century, Ruy Diaz de Isla was the fi rst to report that fever had a benefi cial effect on syphilis 3 .However, 350 years later, Wagner-Jauregg, the father of malariotherapy, described in detail experiments with induced fever in GPI patients.
General paralysis of the insane was the main cause of institutionalization in asylums and psychiatric hospitals from the end of 19 th century until the 1940s.The prevalence of GPI at that time ranged from 10% to 45% in psychiatric hospitals worldwide 1,2 .
Julius Wagner von Jauregg (1857-1940) studied medicine in Vienna, and his interest in psychiatry, especially in psychoses 4 , was soon aroused.He started his experiments with induced fever in 1894 by injecting tuberculin, erysipelas streptococci and typhoid vaccine in patients with psychoses 3 .However, in 1887, Wagner-Jauregg observed that GPI patients who had febrile diseases presented a signifi cant improvement in their mental status.General paralysis of the insane was not a known consequence of syphilis until 1905, when Landsteiner published that high fever killed the spirochetes of syphilis, and 1913, when Hideo Noguchi demonstrated that GPI was caused by Treponema pallidum.Consequently, Wagner-Jauregg tested malariotherapy in GPI patients and published his fi ndings in 1919 under the title, On the impact of malaria on the Paralysis of the Insane 5 .The results were encouraging: three of nine patients recovered completely, three presented a good improvement, two reported no changes and one died of malaria.
The news on the effi cacy of malariotherapy in GPI spread across the world.Detailed descriptions of the experiments, protocols and adverse events can be found in several scientifi c articles 6,7 .An international review of 2,460 cases showed that 27.5% of patients subjected to malariotherapy showed great improvement and 25.6% presented mild improvement 5 .For a disease whose prognosis was death within 5 years, this alternative brought hope to the patients' families, and in 1927, Wagner-Jauregg won the Nobel Prize in Medicine for this discovery.He was the fi rst and only psychiatrist to be awarded this prize 4 .
Malariotherapy became a medical research area, and countless studies were carried out.Malariotherapy was used by hospitals for other mental diseases such as schizophrenia, manic-depressive psychosis, psychomotor cortical irritation syndromes, post-Parkinson's encephalitis and psychoses of epilepsy 8,9 .Hospitals continuously maintained the malaria cycle in hospitalized patients, termed source patients.Studies were made to preserve plasmodium in frozen or cooled blood samples, and hospitals established Anopheles gambiae farms to avoid source patients.The most suitable plasmodium was Plasmodium vivax due to its benign characteristic and high and regular cycles of fever that were necessary, as believed, for the treatment.
The real effi cacy of malariotherapy for GPI or other mental diseases has never been analyzed under modern clinical epidemiology studies 3 .However, the dissemination of the therapy among physicians and institutions was considered a guarantee that GPI patients, who used to be sentenced to death, would present a signifi cant improvement or at least live longer.On the other hand, the primum non nocere precept (non-malefi cence) was clearly ignored because the reports of deaths caused by malaria reached 5% to 13% 1,5 .Nevertheless, it is important to highlight that at the time of Wagner-Jauregg, GPI was terrible and incurable and the notion that desperate maladies justify desperate remedies was an acceptable idea up to the end of the 2 nd World War 4 .With the development of bioethics and the establishment of ethical parameters for research involving human beings, the principle of non-malefi cence started to be considered and required.