Neurosyphilis

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Neurosyphilis
Skull damage from neurosyphilis.jpg
Section of human skull damaged by late stages of neurosyphilis
Specialty Neurology, infectious diseases
Symptoms Headache, stiff neck, paresthesia, loss of bladder control, personality and mood changes
Causes Treponema pallidum
Risk factors HIV infection, unprotected sex
Treatment Antibiotics (generally penicillin)

Neurosyphilis is the infection of the central nervous system by Treponema pallidum , the bacterium that causes the sexually transmitted infection syphilis. In the era of modern antibiotics, the majority of neurosyphilis cases have been reported in HIV-infected patients. [1]

Contents

There is a wide variety of symptoms that neurosyphilis can present with depending on the affected structure of the central nervous system. While early neurosyphilis is often asymptomatic, meningitis is the most common neurological presentation of the early stage. Late neurosyphilis typically involves the brain and spinal cord parenchyma, manifesting as tabes dorsalis and general paresis. Tertiary syphilis can involve several different organ systems, though neurosyphilis may occur at any stage of infection. [2]

Clinical history, a physical neurological examination, and a lumbar puncture to obtain cerebrospinal fluid (CSF) for analysis are crucial for diagnosing neurosyphilis. There is no single laboratory test to confirm the diagnosis of neurosyphilis in all cases. [3] A positive CSF-VDRL test in the presence of neurological symptoms is sufficient for a diagnosis, but additional tests may be needed in certain instances. [4]

Standard treatment is an infusion of intravenous penicillin G for 10 to 14 days. Patients with neurosyphilis should also be evaluated for HIV, and their sexual partners should be properly evaluated by a medical professional. [5]

Signs and Symptoms

While the stages of syphilis are categorized as primary, secondary, latent, and tertiary, neurosyphilis is typically categorized into early and late stages. It is important to note that neurosyphilis may occur any time after initial infection. [3]

Early/Intermediate Neurosyphilis

Early neurosyphilis often has no clinical symptoms. Meningitis is the most-common neurological presentation in early syphilis, typically arising within one year of initial infection. [6] Symptoms of syphilitic meningitis are similar to other forms of meningitis, including headache, neck stiffness, photophobia, confusion, nausea, and vomiting. [7] Meningeal inflammation may also affect the cranial nerves, most commonly the facial nerve, presenting as facial paralysis. [6]

Meningovascular syphilis is often in the intermediate stage of neurosyphilis, typically presenting 5 to 12 years after infection. [6] It is due to inflammation of the blood vessels supplying the central nervous system, resulting in the death of brain tissue called ischemia. It may present as stroke or spinal cord injury. Signs and symptoms vary with the blood vessel that is affected. The middle cerebral artery is most often affected, causing a variety of symptoms including weakness, sensory loss, eye deviation, and hemineglect syndrome. [8]

Late Neurosyphilis

Parenchymal syphilis occurs years to decades after initial infection. It presents with the constellation of symptoms known as tabes dorsalis, because of a degenerative process of the posterior columns of the spinal cord. The constellation includes Argyll Robertson pupil, ataxic wide-based gait, paresthesias, bowel or bladder incontinence, loss of position and vibratory sense, loss of deep pain and temperature sensation, acute episodic gastrointestinal pain, Charcot joints, and general paresis.

Gummatous disease may also present with destructive inflammation and space-occupying lesions. It is caused by granulomatous destruction of visceral organs. They most often involve the frontal and parietal lobes of the brain.[ citation needed ]

A man with intellectual disability secondary to syphilis Amentia Plate XXI (2).jpg
A man with intellectual disability secondary to syphilis

Although neurosyphilis is a neurological disease, neuropsychiatric symptoms might appear due to overall damage to the brain. These symptoms can make the diagnosis more difficult and can include symptoms of dementia, [9] [10] mania, psychosis, depression, [11] and delirium: [12] These symptoms are not always present, and when they are, they usually appear in more advanced stages of the disease. [13]

Ocular Syphilis

Nearly any part of the eye may be involved. The most common form of ocular syphilis is uveitis. Other forms include episcleritis, vitritis, retinitis, papillitis, retinal detachment, and interstitial keratitis. [14] [15] The Argyll Robertson pupil, which is a condition where the pupils do not constrict to bright light but constrict when focusing on a near object (accommodation reflex), is another feature that may be present. [16]

Argyll Robertson pupils, a clinical feature of neurosyphilis, are characterized by pupils that do not react to light but have an intact accommodation reflex. Argyll Robertson Pupils.jpg
Argyll Robertson pupils, a clinical feature of neurosyphilis, are characterized by pupils that do not react to light but have an intact accommodation reflex.

Risk-factors

There are several risk-factors: High-risk sexual behavior from unprotected sex and multiple sexual partners.[ citation needed ] The HIV infection antiretroviral therapy (ART) suppresses HIV transmission, but not syphilis transmission. It may also be associated with recreational drug use.[ citation needed ]

Pathophysiology

The pathogenesis is not fully known, in part due to fact that the organism is not easily cultured. Within days to weeks after initial infection, Treponema pallidum disseminates via blood and lymphatics. The organism may accumulate in perivascular spaces of nearly any organ, including the central nervous system (CNS). It is unclear why some patients develop CNS infection and others do not. Rarely, organisms may invade any structures of the eye (such as cornea, anterior chamber, vitreous and choroid, and optic nerve) and cause local inflammation and edema. In primary or secondary syphilis, invasion of the meninges may result in lymphocytic and plasma cell infiltration of perivascular spaces (Virchow–Robin spaces). The extension of cellular immune response to the brainstem and spinal cord causes inflammation and necrosis of small meningeal vessels.[ citation needed ]

In tertiary syphilis, reactivation of chronic latent infection may result in meningovascular syphilis, arising from endarteritis obliterans of small, medium, or large arteries supplying the CNS. The parenchymal syphilis, presents as tabes dorsalis and general paresis. Tabes dorsalis thought to be due to irreversible degeneration of nerve fibers in posterior columns of the spinal cord involving the lumbosacral and lower thoracic levels. The general paresis is caused by meningeal vascular inflammation and ependymal granulomatous infiltration may lead to neuronal loss, along with astrocytic and microglial proliferation and damage may preferentially occur in the cerebral cortex, striatum, hypothalamus, and meninges.[ citation needed ]

Concurrent infection of T. pallidum with human immunodeficiency virus (HIV) has been found to affect the course of syphilis. Syphilis can lie dormant for 10 to 20 years before progressing to neurosyphilis, but HIV may accelerate the rate of the progress. Also, infection with HIV has been found to cause penicillin therapy to fail more often. Therefore, neurosyphilis has once again been prevalent in societies with high HIV rates [14] and limited access to penicillin. [17]

Diagnosis

To diagnose neurosyphilis, cerebrospinal fluid (CSF) analysis is required. Lumbar puncture ("spinal tap") is used to acquire CSF. The Venereal Disease Research Laboratory test of the CSF is the preferred test for making a diagnosis of neurosyphilis. [18] A positive test confirms neurosyphilis but a negative result does not rule out neurosyphilis. Due to the low sensitivity of the CSF VDRL, fluorescent treponemal antibody absorption test (FTA-ABS) can be used to supplement VDRL. Reported sensitivity is variable. [19] False-negative antibody test result occurring when antibody concentration is so high that agglutination reaction cannot occur, which is typically seen during secondary stage and can be overcome by diluting test sample 1:10. CSF white blood cell count is often elevated in the early stages of neurosyphilis, ranging from about 50 to 100 white blood cells/mcL with a lymphocyte predominance. Cell counts are typically lower in late syphilis. Regardless of syphilis disease stage, the absence of CSF white blood cells rules out neurosyphilis.[ citation needed ]

Treatment

Penicillin is used to treat neurosyphilis. [14] Two examples of penicillin therapies include: [19]

Follow-up blood tests are generally performed at 3, 6, 12, 24, and 36 months to make sure the infection is gone. [19] Lumbar punctures for CSF fluid analysis are generally performed every 6 months until cell counts normalize. All patients with syphilis should be tested for HIV infection. [20] All cases of syphilis should be reported to public health authorities and public health departments can aid in partner notification, testing, and determining need for treatment. [21]

The treatment success is measured with a fourfold drop in the nontreponemal antibody test. In early-stage syphilis drop should occur in 6–12 months; in late syphilis drop can take 12–24 months. Titers may decline more slowly in persons who have previously had syphilis.[ citation needed ]

In people who cannot take penicillin doxycyclin can be used for treating neurosyphilis. [22]

Complications

The Jarisch-Herxheimer reaction is an immune-mediated response to syphilis therapy occurring within 2–24 hours. The exact mechanisms of reaction are unclear, however most likely caused by proinflammatory treponemal lipoproteins that are released from dead and dying organisms following antibiotic treatment. It is typically characterized by fever, headache, myalgia, and possibly intensification of skin rash. It most often occurs in early-stage syphilis (up to 50%-75% of patients with primary and secondary syphilis). It is usually self-limiting and managed with antipyretics and nonsteroidal anti-inflammatory medications.

History

A subject of the Tuskegee Syphilis Study getting their blood drawn. Tuskegee-syphilis-study doctor-injecting-subject.jpg
A subject of the Tuskegee Syphilis Study getting their blood drawn.

Historically, syphilis was studied under the Tuskegee study, often cited as an example of unethical human experimentation. The study began without informed consent of the subjects and was continued by the United States Public Health Service until 1972. The researchers failed to notify and withheld treatment for patients despite knowing penicillin was found as an effective cure for syphilis. After four years of follow-up, neurosyphilis was identified in 26.1% of patients vs. 2.5% of controls. [23] After 20 years of follow-up, 6.5% showed signs of neurosyphilis and 40% had died from other causes. [24]

Related Research Articles

<span class="mw-page-title-main">Syphilis</span> Sexually transmitted infection

Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum subspecies pallidum. The signs and symptoms depend on the stage it presents: primary, secondary, latent or tertiary. The primary stage classically presents with a single chancre, though there may be multiple sores. In secondary syphilis, a diffuse rash occurs, which frequently involves the palms of the hands and soles of the feet. There may also be sores in the mouth or vagina. Latent syphilis has no symptoms and can last years. In tertiary syphilis, there are gummas, neurological problems, or heart symptoms. Syphilis has been known as "the great imitator", because it may cause symptoms similar to many other diseases.

<span class="mw-page-title-main">Transverse myelitis</span> Inflammation of the entire cross-section of the spinal cord

Transverse myelitis (TM) is a rare neurological condition wherein the spinal cord is inflamed. The adjective transverse implies that the spinal inflammation (myelitis) extends horizontally throughout the cross section of the spinal cord; the terms partial transverse myelitis and partial myelitis are sometimes used to specify inflammation that affects only part of the width of the spinal cord. TM is characterized by weakness and numbness of the limbs, deficits in sensation and motor skills, dysfunctional urethral and anal sphincter activities, and dysfunction of the autonomic nervous system that can lead to episodes of high blood pressure. Signs and symptoms vary according to the affected level of the spinal cord. The underlying cause of TM is unknown. The spinal cord inflammation seen in TM has been associated with various infections, immune system disorders, or damage to nerve fibers, by loss of myelin. As opposed to leukomyelitis which affects only the white matter, it affects the entire cross-section of the spinal cord. Decreased electrical conductivity in the nervous system can result.

<span class="mw-page-title-main">Encephalitis</span> Inflammation of the brain

Encephalitis is inflammation of the brain. The severity can be variable with symptoms including reduction or alteration in consciousness, aphasia, headache, fever, confusion, a stiff neck, and vomiting. Complications may include seizures, hallucinations, trouble speaking, memory problems, and problems with hearing.

<span class="mw-page-title-main">General paresis of the insane</span> Organic mental disorder caused by late-stage syphilis

General paresis, also known as general paralysis of the insane (GPI), paralytic dementia, or syphilitic paresis is a severe neuropsychiatric disorder, classified as an organic mental disorder, and is caused by late-stage syphilis and the chronic meningoencephalitis and cerebral atrophy that are associated with this late stage of the disease when left untreated. GPI differs from mere paresis, as mere paresis can result from multiple other causes and usually does not affect cognitive function. Degenerative changes caused by GPI are associated primarily with the frontal and temporal lobar cortex. The disease affects approximately 7% of individuals infected with syphilis, and is far more common in developing countries where fewer options for timely treatment are available. It is more common among men.

<span class="mw-page-title-main">Viral meningitis</span> Medical condition

Viral meningitis, also known as aseptic meningitis, is a type of meningitis due to a viral infection. It results in inflammation of the meninges. Symptoms commonly include headache, fever, sensitivity to light and neck stiffness.

<span class="mw-page-title-main">Tabes dorsalis</span> Medical condition of late-stage neurosyphilis

Tabes dorsalis is a late consequence of neurosyphilis, characterized by the slow degeneration of the neural tracts primarily in the dorsal root ganglia of the spinal cord. These patients have lancinating nerve root pain which is aggravated by coughing, and features of sensory ataxia with ocular involvement.

<span class="mw-page-title-main">Lumbar puncture</span> Procedure to collect cerebrospinal fluid

Lumbar puncture (LP), also known as a spinal tap, is a medical procedure in which a needle is inserted into the spinal canal, most commonly to collect cerebrospinal fluid (CSF) for diagnostic testing. The main reason for a lumbar puncture is to help diagnose diseases of the central nervous system, including the brain and spine. Examples of these conditions include meningitis and subarachnoid hemorrhage. It may also be used therapeutically in some conditions. Increased intracranial pressure is a contraindication, due to risk of brain matter being compressed and pushed toward the spine. Sometimes, lumbar puncture cannot be performed safely. It is regarded as a safe procedure, but post-dural-puncture headache is a common side effect if a small atraumatic needle is not used.

<span class="mw-page-title-main">Congenital syphilis</span> Presence of syphilis in a baby due to its mother being infected

Congenital syphilis is syphilis that occurs when a mother with untreated syphilis passes the infection to her baby during pregnancy or at birth. It may present in the fetus, infant, or later. Clinical features vary and differ between early onset, that is presentation before 2-years of age, and late onset, presentation after age 2-years. Infection in the unborn baby may present as poor growth, non-immune hydrops leading to premature birth or loss of the baby, or no signs. Affected newborns mostly initially have no clinical signs. They may be small and irritable. Characteristic features include a rash, fever, large liver and spleen, a runny and congested nose, and inflammation around bone or cartilage. There may be jaundice, large glands, pneumonia, meningitis, warty bumps on genitals, deafness or blindness. Untreated babies that survive the early phase may develop skeletal deformities including deformity of the nose, lower legs, forehead, collar bone, jaw, and cheek bone. There may be a perforated or high arched palate, and recurrent joint disease. Other late signs include linear perioral tears, intellectual disability, hydrocephalus, and juvenile general paresis. Seizures and cranial nerve palsies may first occur in both early and late phases. Eighth nerve palsy, interstitial keratitis and small notched teeth may appear individually or together; known as Hutchinson's triad.

<span class="mw-page-title-main">Aseptic meningitis</span> Inflammation of the meninges not due to common bacterial infection

Aseptic meningitis is the inflammation of the meninges, a membrane covering the brain and spinal cord, in patients whose cerebral spinal fluid test result is negative with routine bacterial cultures. Aseptic meningitis is caused by viruses, mycobacteria, spirochetes, fungi, medications, and cancer malignancies. The testing for both meningitis and aseptic meningitis is mostly the same. A cerebrospinal fluid sample is taken by lumbar puncture and is tested for leukocyte levels to determine if there is an infection and goes on to further testing to see what the actual cause is. The symptoms are the same for both meningitis and aseptic meningitis but the severity of the symptoms and the treatment can depend on the certain cause.

Immune reconstitution inflammatory syndrome (IRIS) is a condition seen in some cases of HIV/AIDS or immunosuppression, in which the immune system begins to recover, but then responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse.

<span class="mw-page-title-main">Tuberculous meningitis</span> Medical condition

Tuberculous meningitis, also known as TB meningitis or tubercular meningitis, is a specific type of bacterial meningitis caused by the Mycobacterium tuberculosis infection of the meninges—the system of membranes which envelop the central nervous system.

<span class="mw-page-title-main">Hutchinson's triad</span> Three clinical signs indicative of congenital syphilis

Hutchinson triad is a triad of signs that may be seen in late congenital syphilis, including: interstitial keratitis, malformed teeth, and eighth nerve deafness.

<span class="mw-page-title-main">Syphilitic aortitis</span> Inflammation of the aorta

Syphilitic aortitis is inflammation of the aorta associated with the tertiary stage of syphilis infection. SA begins as inflammation of the outermost layer of the blood vessel, including the blood vessels that supply the aorta itself with blood, the vasa vasorum. As SA worsens, the vasa vasorum undergo hyperplastic thickening of their walls thereby restricting blood flow and causing ischemia of the outer two-thirds of the aortic wall. Starved for oxygen and nutrients, elastic fibers become patchy and smooth muscle cells die. If the disease progresses, syphilitic aortitis leads to an aortic aneurysm. Overall, tertiary syphilis is a rare cause of aortic aneurysms. Syphilitic aortitis has become rare in the developed world with the advent of penicillin treatments after World War II.

A nontreponemal test (NTT) is a blood test for diagnosis of infection with syphilis. Nontreponemal tests are an indirect method in that they detect biomarkers that are released during cellular damage that occurs from the syphilis spirochete. In contrast, treponemal tests look for antibodies that are a direct result of the infection thus, anti-treponeme IgG, IgM and to a lesser degree IgA. Nontreponemal tests are screening tests, very rapid and relatively simple, but need to be confirmed by treponemal tests. Centers for Disease Control and Prevention (CDC)-approved standard tests include the VDRL test, the rapid plasma reagin (RPR) test, the unheated serum reagin (USR) test, and the toluidine red unheated serum test (TRUST). These have mostly replaced the first nontreponemal test, the Wassermann test.

<span class="mw-page-title-main">Mollaret's meningitis</span> Medical condition

Mollaret's meningitis is a recurrent or chronic inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. Since Mollaret's meningitis is a recurrent, benign (non-cancerous), aseptic meningitis, it is also referred to as benign recurrent lymphocytic meningitis. It was named for Pierre Mollaret, the French neurologist who first described it in 1944.

<span class="mw-page-title-main">Pyrotherapy</span> Raising body temperature for medical purposes

Pyrotherapy is a method of treatment by raising the body temperature or sustaining an elevated body temperature using a fever. In general, the body temperature was maintained at 41 °C (105 °F). Many diseases were treated by this method in the first half of the 20th century. In general, it was done by exposing the patient to hot baths, warm air, or (electric) blankets. The technique reached its peak of sophistication in the early 20th century with malariotherapy, in which Plasmodium vivax, a causative agent of malaria, was allowed to infect already ill patients in order to produce intense fever for therapeutic ends. The sophistication of this approach lay in using effective anti-malarial drugs to control the P. vivax infection, while maintaining the fever it causes to the detriment of other, ongoing, and then-incurable infections present in the patient, such as late-stage syphilis. This type of pyrotherapy was most famously used by psychiatrist Julius Wagner-Jauregg, who won the Nobel Prize for Medicine in 1927 for his elaboration of the procedure in treating neurosyphilitics.

<span class="mw-page-title-main">Meningitis</span> Inflammation of the membranes around the brain and spinal cord

Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, intense headache, vomiting and neck stiffness and occasionally photophobia. Other symptoms include confusion or altered consciousness, nausea, and an inability to tolerate light or loud noises. Young children often exhibit only nonspecific symptoms, such as irritability, drowsiness, or poor feeding. A non-blanching rash may also be present.

Drug-Induced Aseptic Meningitis (DIAM) is a type of aseptic meningitis related to the use of medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or biologic drugs such as intravenous immunoglobulin (IVIG). Additionally, this condition generally shows clinical improvement after cessation of the medication, as well as a tendency to relapse with resumption of the medication.

<span class="mw-page-title-main">Lymphocytic pleocytosis</span> Increase in lymphocytes within cerebrospinal fluid

Lymphocytic pleocytosis is an abnormal increase in the amount of lymphocytes in the cerebrospinal fluid (CSF). It is usually considered to be a sign of infection or inflammation within the nervous system, and is encountered in a number of neurological diseases, such as pseudomigraine, Susac's syndrome, and encephalitis. While lymphocytes make up roughly a quarter of all white blood cells (WBC) in the body, they are generally rare in the CSF. Under normal conditions, there are usually less than 5 white blood cells per μL of CSF. In a pleocytic setting, the number of lymphocytes can jump to more than 1,000 cells per μL. Increases in lymphocyte count are often accompanied by an increase in cerebrospinal protein concentrations in addition to pleocytosis of other types of white blood cells.

<span class="mw-page-title-main">Meningeal syphilis</span> Medical condition

Meningeal syphilis is a chronic form of syphilis infection that affects the central nervous system. Treponema pallidum, a spirochate bacterium, is the main cause of syphilis, which spreads drastically throughout the body and can infect all its systems if not treated appropriately. Treponema pallidum is the main cause of the onset of meningeal syphilis and other treponemal diseases, and it consists of a cytoplasmic and outer membrane that can cause a diverse array of diseases in the central nervous system and brain.

References

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  2. ↑ CDC (2024-12-04). "About Syphilis". Syphilis. Retrieved 2025-01-16.
  3. 1 2 Hamill, Matthew M; Ghanem, Khalil G; Tuddenham, Susan (2024-05-15). "State-of-the-Art Review: Neurosyphilis". Clinical Infectious Diseases. 78 (5): e57 –e68. doi:10.1093/cid/ciad437. ISSN   1058-4838.
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  6. 1 2 3 Ha, Tuan; Tadi, Prasanna; Leslie, Stephen W.; Dubensky, Laurence (2025), "Neurosyphilis", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   31082023 , retrieved 2025-01-17
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  15. ↑ Kennard, Christine (10 September 2014). "Neurosyphilis". About.com. Retrieved 2014-10-23.
  16. ↑ Thompson, H. Stanley; Kardon, Randy H. (June 2006). "The Argyll Robertson pupil". Journal of Neuro-Ophthalmology: The Official Journal of the North American Neuro-Ophthalmology Society. 26 (2): 134–138. doi:10.1097/01.wno.0000222971.09745.91. ISSN   1070-8022. PMID   16845316.
  17. ↑ Gordon SM, Eaton ME, George R, Larsen S, Lukehart SA, Kuypers J, Marra CM, Thompson S (December 1994). "The response of symptomatic neurosyphilis to high-dose intravenous penicillin G in patients with human immunodeficiency virus infection". N. Engl. J. Med. 331 (22): 1469–73. doi: 10.1056/NEJM199412013312201 . PMID   7969296.
  18. ↑ Walter George Bradley (2004). Neurology in Clinical Practice: The neurological disorders. Taylor & Francis. p. 1497. ISBN   9789997625892.
  19. 1 2 3 "Neurosyphilis". A.D.A.M. Medical Encyclopedia on PubMed Health. Reviewed by David C. Dugdale, Jatin M. Vyas, David Zieve. 6 October 2012. Retrieved 2014-10-23.{{cite encyclopedia}}: CS1 maint: others (link)
  20. ↑ Musher DM (June 1991). "Syphilis, neurosyphilis, penicillin, and AIDS". J. Infect. Dis. 163 (6): 1201–6. doi:10.1093/infdis/163.6.1201. PMID   2037785.
  21. ↑ Landis, Suzanne E.; Schoenbach, Victor J.; Weber, David J.; Mittal, Manjoo; Krishan, Baldev; Lewis, Karen; Koch, Gary G. (1992-01-09). "Results of a Randomized Trial of Partner Notification in Cases of HIV Infection in North Carolina". New England Journal of Medicine. 326 (2): 101–106. doi: 10.1056/NEJM199201093260205 . ISSN   0028-4793. PMID   1445500.
  22. ↑ Girometti, Nicolò; Junejo, Muhammad H; Nugent, Diarmuid; McOwan, Alan; Whitlock, Gary; the 56 Dean Street Collaborative Group (2021-07-01). "Clinical and serological outcomes in patients treated with oral doxycycline for early neurosyphilis". Journal of Antimicrobial Chemotherapy. 76 (7): 1916–1919. doi:10.1093/jac/dkab100. ISSN   0305-7453.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  23. ↑ VONDERLEHR, R. A.; CLARK, TALIAFERRO; WENGER, O. C.; HELLER, J. R., Jr. (1936-09-12). "UNTREATED SYPHILIS IN THE MALE NEGRO: A COMPARATIVE STUDY OF TREATED AND UNTREATED CASES". Journal of the American Medical Association. 107 (11): 856–860. doi:10.1001/jama.1936.02770370020006. ISSN   0002-9955.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ↑ Rockwell, Donald H. (1964-12-01). "The Tuskegee Study of Untreated Syphilis: The 30th Year of Observation". Archives of Internal Medicine. 114 (6): 792. doi:10.1001/archinte.1964.03860120104011. ISSN   0003-9926.
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