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Neurosyphilis

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Infection of the central nervous system in a patient with syphilis Medical condition
Neurosyphilis
Section of human skull damaged by late stages of neurosyphilis
SpecialtyNeurology, infectious diseases
SymptomsHeadache, stiff neck, paresthesia, loss of bladder control, personality and mood changes
CausesTreponema pallidum
Risk factorsHIV infection, unprotected sex
TreatmentAntibiotics (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.

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.

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. 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.

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.

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.

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. Symptoms of syphilitic meningitis are similar to other forms of meningitis, including headache, neck stiffness, photophobia, confusion, nausea, and vomiting. Meningeal inflammation may also affect the cranial nerves, most commonly the facial nerve, presenting as facial paralysis.

Meningovascular syphilis is often in the intermediate stage of neurosyphilis, typically presenting 5 to 12 years after infection. 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.

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.

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, mania, psychosis, depression, and delirium: These symptoms are not always present, and when they are, they usually appear in more advanced stages of the disease.

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. 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.

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. The HIV infection antiretroviral therapy (ART) suppresses HIV transmission, but not syphilis transmission. It may also be associated with recreational drug use.

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.

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.

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 and limited access to penicillin.

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. 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. 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.

Treatment

Penicillin is used to treat neurosyphilis. Two examples of penicillin therapies include:

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

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.

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

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.

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. After 20 years of follow-up, 6.5% showed signs of neurosyphilis and 40% had died from other causes.

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