Malaria as the Treatment for Neurosyphilis

In 1927, The Nobel Prize in Physiology or Medicine was awarded to Dr. Wagner-Jauregg for “The Treatment of Dementia Paralytica by Malaria Inoculation.”

Dr. Wagner-Jauregg’s medical training was in the biological sciences and focused on zoology, pathology, and physiology. When he began his work at the First Psychiatry Clinic at the Asylum of Lower Austria in 1883, Wagner-Jauregg had access to a wide variety of patients suffering from mental illnesses; however, the opportunity to conduct research was limited by small facilities, inadequate resources, and his colleagues’ lack of interest in pursuing research [7]. Despite this, Wagner-Jauregg began conducting research on brain anatomy and observing patients in the asylum, later publishing papers on paralysis and spinal cord damage [8]. In 1883, shortly after starting his first psychiatry position at the clinic, he observed a woman being cured of severe psychosis after an attack of erysipelas, an acute bacterial skin infection typically accompanied by a high fever [9]. While he would not formally work on fever therapy until 1917, this early case stuck with Wagner-Jauregg. He began conducting literature searches on the topic and published an article, “The Effect of Feverish Disease on Psychoses,” in 1887 [10]. His past experiences and medical training in pathophysiology made him receptive to the idea of a biological cause for some forms of psychosis, and he reasoned that a therapeutic remedy should exist as well.

One form of psychoses was linked to neurosyphilis, which emerges during the tertiary stage of syphilis. Neurosyphilis, also known as the “disease of the century,” was a frightening, fatal disease marked by grand delusions, paralysis, and dementia [11]. While neurosyphilis and GPI were used synonymously, the latter referred to the psychoses that emerged in the final stage of syphilis and the former included other symptoms such as spinal cord damage and ataxia [12]. Even more disturbing, the incidence of neurosyphilis increased significantly during the 19th century and was one of the major factors in the increase of the asylum population during this time. Approximately 5 percent to 10 percent of all psychiatric admissions before 1945 were attributed to neurosyphilis; therefore, these individuals comprised a significant group within the asylum population [13]. In addition, the disease predominantly afflicted middle-class males and the symptoms were obvious: paralysis in conjunction with dementia or psychosis. Once the patient became symptomatic, the end was near. Death, in most cases, was welcomed as the final respite from the horrifying symptoms of neurosyphilis. Consequently, malarial treatment played a role in the emptying of the asylums and provided a viable alternative for a previously hopeless disease. Ironically, it was neurosyphilis that contributed both to the demise of the first biological psychiatry and its resurgence after the discovery of fever therapy. As Shorter notes: “Following the model of neurosyphilis, they [the early biological psychiatrists] were trying to identify specific lesions in patients whose illnesses seemed to be primarily psychiatric rather than neurological” [14]. In the early 20th century, psychological illness referred to any disease manifesting in symptoms of psychosis, mania, or depression, regardless of the causative agent of disease. Despite the fact that neurosyphilis was a side effect, an end stage of an infection caused by an organic agent, it was still considered the primary psychological illness of its time, hence the moniker of the “disease of the century.”

To read more, visit the following references:

“Julius Wagner-Jauregg – Nobel Lecture: The Treatment of Dementia Paralytica by Malaria Inoculation”. Nobel Media AB 2014. Web. 18 Mar 2015. <;

Tsay, Cynthia J. “Julius Wagner-Jauregg and the Legacy of Malarial Therapy for the Treatment of General Paresis of the Insane.” The Yale Journal of Biology and Medicine 86.2 (2013): 245–254. Print.



Neurosyphilis is a slow progressive, destructive infection of the brain and spinal cord caused by the spirochete T. pallidum. Its incidence has declined markedly since the introduction of penicillin therapy. It can occur at any stage of syphilis, although symptomatic early neurosyphilis is a rare manifestation.

Clinical Manifestations

Early diagnosis of neurosyphilis and appropriate antibiotic treatment make notable clinical improvement. However, the clinical diagnosis of neurosyphilis is often difficult because most patients are asymptomatic or present with non-specific symptoms such as memory disturbance or seizures.

Presentations range from asymptomatic neurosyphilis to meningitis and general paresis. Acute syphilitic meningitis (6% of syphilis patients) is typically the earliest manifestation of neurosyphilis. It is often associated with cranial nerve palsies, fever, headache, meningismus, and may even have signs of cortical involvement. Meningovascular syphilis (up to 12% of patients) can present at endarteritis, causing infarction clinically similar to a stroke. Tabes dorsalis, the disease of the posterior columns of spinal cord occurs more than 20 years after initial infection. Now exceedingly rare, it often coexists with general paresis. This typically manifests as an abnormal gait, paresthesias, lightning pains of extremities, loss of proprioception on exam, and a positive Romberg. The famous Argyll-Robertson pupils may be seen with Tabes Dorsalis or with general paresis. Notably, the psychiatric manifestations of neurosyphilis have garnered significant interest, historically. Syphilitic infection of the meninges and cortex causes personality changes, paranoia, emotional lability, eventually progressing to memory loss and dementia.


CSF examination is recommended in all patients with untreated syphilis of unknown duration or of duration greater than one year. The diagnosis of neurosyphilis is based on a CSF WBC count of 20 cells/μL or greater, and/or a reactive CSF Venereal Disease Research Laboratory (VDRL) test, and/or a positive CSF intra-thecal T. pallidum antibody index. Other CSF abnormalities include elevated protein levels and pleocytosis, which are found in up to 70 percent of patients. In addition, the CSF VDRL result is reactive. Some experts advise lumbar puncture in patients with secondary and early latent syphilis. This is because standard penicillin G benzathine therapy for early syphilis does not achieve treponemicidal levels in the CSF.


The recommended regimen is 14 days of aqueous benzylpenicillin IV, administered daily in doses of 2–4 million IU, every 4 hours. If IV therapy is unavailable or not well suited to the individual situation, an alternative regimen is to use procaine benzylpenicillin, 1.2 million IU by IM injection, once daily, and probenecid, 500 mg orally, 4 times daily, both for 10–14 days. Outpatient compliance must be certain (i.e. consider OPAT clinic!).

For penicillin-allergic, non-pregnant patients, we can use doxycycline 200 mg PO twice daily for 30 days, OR tetracycline 500 mg PO 4x daily for 30 days. These alternatives to penicillin have not been evaluated in systematic studies.

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Guidelines for the management of sexually transmitted infections. World Health Organization. 2001 : Geneva, Switzerland. ISBN 92 4 154626 3.

Case Challenge #8

A 42 year old female presents with fever, rash, and worsening shortness of breath.  She has chronic asthma, and during a recent PCP visit, she was started on Montelukast and tapered off steroids.

On physical exam, she has a fever, with Tmax 102 F. Her heart rate is in the low 100s, with a BP of 150/90, RR of 20 (really), and an O2 sat of 90%. Pulmonary exam reveals prominent bilateral wheezing with decreased air movement. Cardiovascular exam is unremarkable, as is the abdominal exam. She has palpable purpura on both of her legs. Neurologic exam reveals foot drop on the right.

Labs reveal a leukocytosis, with 18k white blood cells (15% of which are eosinophils). CRP is elevated to 120. Renal function and liver function test results were normal. Urine microscopy did not reveal any active sediments.

Chest X-Ray

 CT chest


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