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 in a patient with syphilis. In the era of modern antibiotics, the majority of neurosyphilis cases have been reported in HIV-infected patients. Meningitis is the most common neurological presentation in early syphilis. Tertiary syphilis symptoms are exclusively neurosyphilis, though neurosyphilis may occur at any stage of infection.

Contents

To diagnose neurosyphilis, patients undergo a lumbar puncture to obtain cerebrospinal fluid (CSF) for analysis. The CSF is tested for antibodies for specific Treponema pallidum antigens. The preferred test is the VDRL test, which is sometimes supplemented by fluorescent treponemal antibody absorption test (FTA-ABS). [1] [2] [3]

Historically, the disease was studied under the Tuskegee study, often cited as an example of unethical human experimentation. The study was done on approximately 400 African-American men with untreated syphilis who were followed from 1932 to 1972 and compared to approximately 200 men without syphilis. 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 neurosyphilis. After four years of follow up, neurosyphilis was identified in 26.1% of patients vs. 2.5% of controls. After 20 years of followup, 14% showed signs of neurosyphilis and 40% had died from other causes.

Signs and symptoms

The signs and symptoms of neurosyphilis vary with the disease stage of syphilis. The stages of syphilis are categorized as primary, secondary, latent, and tertiary. It is important to note that neurosyphilis may occur at any stage of infection.[ citation needed ]

Meningitis is the most common neurological presentation in early syphilis. It typically occurs in the secondary stage, arising within one year of initial infection. The symptoms are similar to other forms of meningitis. The most common associated with neurosyphilitic meningitis is cranial nerve palsy, especially of the facial nerve. [4] [5]

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. [2] [6]

Meningovascular syphilis usually occurs in late syphilis but may affect those with early disease. It is due to inflammation of the vasculature supplying the central nervous system, that results in ischemia. It typically occurs about 6–7 years after initial infection and it may affect those with early disease. It may present as stroke or spinal cord infarct. Signs and symptoms vary with vascular territory involved. The middle cerebral artery is most often affected. [7]

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 ]

Neuropsychiatric

A man with idiocy secondary to syphilis Amentia Plate XXI (2).jpg
A man with idiocy 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, [8] [9] mania, psychosis, depression, [10] and delirium: [11]

These symptoms are not always present, and when they are, they usually appear in more advanced stages of the disease. [12]

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.

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 [2] and limited access to penicillin. [13]

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. [14] 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. [1] 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. [2] Two examples of penicillin therapies include: [1]

Follow-up blood tests are generally performed at 3, 6, 12, 24, and 36 months to make sure the infection is gone. [1] 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. [15] 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. [16]

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 it is uncertain if other antibiotic therapy is effective for treating neurosyphilis. [17]

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 of syphilis vary depending in which of the four stages it presents. 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. In latent syphilis, which can last for years, there are few or no symptoms. In tertiary syphilis, there are gummas, neurological problems, or heart symptoms. Syphilis has been known as "the great imitator" as it may cause symptoms similar to many other diseases.

<i>Treponema pallidum</i> Species of bacterium

Treponema pallidum, formerly known as Spirochaeta pallida, is a microaerophilic spirochaete bacterium with subspecies that cause the diseases syphilis, bejel, and yaws. It is transmitted only among humans. It is a helically coiled microorganism usually 6–15 μm long and 0.1–0.2 μm wide. T. pallidum's lack of either a tricarboxylic acid cycle or oxidative phosphorylation results in minimal metabolic activity. The treponemes have a cytoplasmic and an outer membrane. Using light microscopy, treponemes are visible only by using dark-field illumination. T. pallidum consists of three subspecies, T. p. pallidum, T. p. endemicum, and T. p. pertenue, each of which has a distinct associated disease.

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 third world countries where fewer options for timely treatment are available. It is more common among men.

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

Yaws is a tropical infection of the skin, bones, and joints caused by the spirochete bacterium Treponema pallidum pertenue. The disease begins with a round, hard swelling of the skin, 2 to 5 cm in diameter. The center may break open and form an ulcer. This initial skin lesion typically heals after 3–6 months. After weeks to years, joints and bones may become painful, fatigue may develop, and new skin lesions may appear. The skin of the palms of the hands and the soles of the feet may become thick and break open. The bones may become misshapen. After 5 years or more, large areas of skin may die, leaving scars.

<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">Rapid plasma reagin</span> Test for syphilis

The rapid plasma reagin test is a type of rapid diagnostic test that looks for non-specific antibodies in the blood of the patient that may indicate an infection by syphilis or related non-venereal treponematoses. It is one of several nontreponemal tests for syphilis. The term reagin means that this test does not look for antibodies against the bacterium itself, Treponema pallidum, but rather for antibodies against substances released by cells when they are damaged by T. pallidum. Traditionally, syphilis serologic testing has been performed using a nontreponemal test (NTT) such as the RPR or VDRL test, with positive results then confirmed using a specific treponemal test (TT) such as TPPA or FTA-ABS. This algorithm is currently endorsed by the U.S. Centers for Disease Control and Prevention (CDC). In addition to screening for syphilis, a titer can be used to track the progress of the disease over time and its response to therapy. The traditional algorithm using an NTT followed by a TT remains the standard in many parts of the world.

<span class="mw-page-title-main">Venereal Disease Research Laboratory test</span> Blood test for syphilis

The Venereal Disease Research Laboratory test (VDRL) is a blood test for syphilis and related non-venereal treponematoses that was developed by the eponymous US laboratory. The VDRL test is used to screen for syphilis, whereas other, more specific tests are used to diagnose the disease.

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

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> Medical condition

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.

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

Bejel, or endemic syphilis, is a chronic skin and tissue disease caused by infection by the endemicum subspecies of the spirochete Treponema pallidum. Bejel is one of the "endemic treponematoses", a group that also includes yaws and pinta. Typically, endemic trepanematoses begin with localized lesions on the skin or mucous membranes. Pinta is limited to affecting the skin, whereas bejel and yaws are considered to be invasive because they can also cause disease in bone and other internal tissues.

<span class="mw-page-title-main">Tropical spastic paraparesis</span> Medical condition

Tropical spastic paraparesis (TSP), is a medical condition that causes weakness, muscle spasms, and sensory disturbance by human T-lymphotropic virus resulting in paraparesis, weakness of the legs. As the name suggests, it is most common in tropical regions, including the Caribbean. Blood transfusion products are screened for human T-lymphotropic virus 1 (HTLV-1) antibodies, as a preventive measure.

The fluorescent treponemal antibody absorption (FTA-ABS) test is a diagnostic test for syphilis. Using antibodies specific for the Treponema pallidum species, such tests would be assumed to be more specific than non-treponemal testing such as VDRL but have been shown repeatedly to be sensitive but not specific for the diagnosis of neurosyphilis in cerebrospinal fluid (CSF). In addition, FTA-ABS turns positive earlier and remains positive longer than VDRL. Other treponemes, such as T. pertenue, may also produce a positive FTA-ABS. The ABS suffix refers particularly to a processing step used to remove nonspecific antispirochetal antibodies present in normal serum.

<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">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.

<i>Treponema pallidum</i> particle agglutination assay Assay used for detection and titration of antibodies against the causative agent of syphilis

The Treponema pallidum particle agglutination assay is an indirect agglutination assay used for detection and titration of antibodies against the causative agent of syphilis, Treponema pallidum subspecies pallidum. It also detects other treponematoses.

<span class="mw-page-title-main">History of syphilis</span>

The first recorded outbreak of syphilis in Europe occurred in 1494/1495 in Naples, Italy, during a French invasion. Because it was spread geographically by French troops returning from that campaign, the disease was known as "French disease", and it was not until 1530 that the term "syphilis" was first applied by the Italian physician and poet Girolamo Fracastoro. The causative organism, Treponema pallidum, was first identified by Fritz Schaudinn and Erich Hoffmann in 1905 at the Charité Clinic in Berlin. The first effective treatment, Salvarsan, was developed in 1910 by Sahachiro Hata in the laboratory of Paul Ehrlich. It was followed by the introduction of penicillin in 1943.

<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.

The malaria therapy is an archaic medical procedure of treating diseases using artificial injection of malaria parasites. It is a type of pyrotherapy by which high fever is induced to stop or eliminate symptoms of certain diseases. In malaria therapy, malarial parasites (Plasmodium) are specifically used to cause fever, and an elevated body temperature reduces the symptoms of or cure the diseases. As the primary disease is treated, the malaria is then cured using antimalarial drugs. The method was developed by Austrian physician Julius Wagner-Jauregg in 1917 for the treatment of neurosyphilis for which he received the 1927 Nobel Prize in Physiology or Medicine.

<span class="mw-page-title-main">Chronic meningitis</span> Inflammation of the membranes surrounding the brain and spinal cord lasting longer than 4 weeks

Chronic meningitis is a long-lasting inflammation of the membranes lining the brain and spinal cord. By definition, the duration of signs, symptoms and inflammation in chronic meningitis last longer than 4 weeks. Infectious causes are a leading cause and the infectious organisms responsible for chronic meningitis are different than the organisms that cause acute infectious meningitis. Tuberculosis and the fungi cryptococcus are leading causes worldwide. Chronic meningitis due to infectious causes are more common in those who are immunosuppressed, including those with HIV infection or in children who are malnourished. Chronic meningitis sometimes has a more indolent course than acute meningitis with symptoms developing more insidiously and slowly. Also, some of the infectious agents that cause chronic infectious meningitis such as mycobacterium tuberculosis, many fungal species and viruses are difficult to isolate from the cerebrospinal fluid making diagnosis challenging. No cause is identified during initial evaluation in one third of cases. Magnetic resonance imaging (MRI) of the brain is more sensitive than computed tomography and may show radiological signs that suggest chronic meningitis, however no radiological signs are considered pathognomonic or characteristic. MRI is also normal in many cases further limiting its diagnostic utility.

References

  1. 1 2 3 4 "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)
  2. 1 2 3 4 Mehrabian S, Raycheva M, Traykova M, Stankova T, Penev L, Grigorova O, Traykov L (September 2012). "Neurosyphilis with dementia and bilateral hippocampal atrophy on brain magnetic resonance imaging". BMC Neurol. 12: 96. doi: 10.1186/1471-2377-12-96 . PMC   3517431 . PMID   22994551.
  3. ↑ "Syphilis CDC Fact Sheet". Centers for Disease Control and Prevention. 4 September 2012. Retrieved 2014-10-23.
  4. ↑ Radolf JD, Tramont EC, Salazar JC. Syphilis (Treponema pallidum).
  5. ↑ Bennett J, Dolin R, Blaser M, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 8th ed. New York, NY: Saunders; 2015: 2684–2709.e4
  6. ↑ Kennard, Christine (10 September 2014). "Neurosyphilis". About.com. Retrieved 2014-10-23.
  7. ↑ Currens, Lauryn; Sivakumar, Shravan; Jun-O'Connell, Adalia H.; Ionete, Carolina; Ghasemi, Mehdi (2022-05-01). "Neurosyphilis presenting with focal middle cerebral artery stenosis and acute ischemic stroke: A case report". Radiology Case Reports. 17 (5): 1620–1625. doi: 10.1016/j.radcr.2022.02.044 . ISSN   1930-0433. PMC   8935340 . PMID   35321268.
  8. ↑ Radue R, Walaszek A, Asthana S (2019). "Neuropsychiatric symptoms in dementia". Geriatric Neurology. Handbook of Clinical Neurology. Vol. 167. pp. 437–454. doi:10.1016/B978-0-12-804766-8.00024-8. ISBN   9780128047668. PMID   31753148. S2CID   208230186.
  9. ↑ Rao, Avinash; Khan, Ariba; Singh, Kanwardeep; Anderson, Debra L.; Malone, Michael L. (2015). "Neurosyphilis: An Uncommon Cause of Dementia". Journal of the American Geriatrics Society. 63 (8): 1710–1712. doi: 10.1111/jgs.13571 . PMID   26289700. S2CID   9393216.
  10. ↑ "Neurosyphilis". MedlinePlus Medical Encyclopedia. Retrieved 2023-10-27– via medlineplus.gov.
  11. ↑ Kaur, Baneet; Khanna, Deepesh (2023-09-07). "A Narrative Review of the Many Psychiatric Manifestations of Neurosyphilis: The Great Imitator". Cureus. 15 (9): e44866. doi: 10.7759/cureus.44866 . ISSN   2168-8184. PMC   10560128 . PMID   37814742.
  12. ↑ "Neurosyphilis: Overview of Syphilis of the CNS, Pathophysiology of Syphilis, Epidemiology of Syphilis". 19 July 2021.
  13. ↑ 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.
  14. ↑ Walter George Bradley (2004). Neurology in Clinical Practice: The neurological disorders. Taylor & Francis. p. 1497. ISBN   9789997625892.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ Buitrago-Garcia, D; Martí-Carvajal, AJ; Jimenez, A; Conterno, LO; Pardo, R (27 May 2019). "Antibiotic therapy for adults with neurosyphilis". The Cochrane Database of Systematic Reviews. 2019 (5): CD011399. doi:10.1002/14651858.CD011399.pub2. PMC   6536092 . PMID   31132142.
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