Neurosyphilis
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Neurosyphilis is the infection of the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
by '' Treponema pallidum'', the bacterium that causes the
sexually transmitted infection A sexually transmitted infection (STI), also referred to as a sexually transmitted disease (STD) and the older term venereal disease (VD), is an infection that is Transmission (medicine), spread by Human sexual activity, sexual activity, e ...
syphilis 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 syphilis, latent or tertiary. The prim ...
. In the era of modern
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...
s, 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 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 occasion ...
is the most common neurological presentation of the early stage. Late neurosyphilis typically involves the
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
and
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
parenchyma upright=1.6, Lung parenchyma showing damage due to large subpleural bullae. Parenchyma () is the bulk of functional substance in an animal organ such as the brain or lungs, or a structure such as a tumour. In zoology, it is the tissue that ...
, 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 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 syphilis, latent or tertiary. The prim ...
are categorized as primary, secondary, latent, and tertiary, neurosyphilis is typically categorized into early, intermediate, and late stages. Neurosyphilis may occur any time after initial infection.


Early and intermediate neurosyphilis

Early neurosyphilis often has no clinical symptoms.
Meningitis 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 occasion ...
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 Photophobia is a medical symptom of abnormal intolerance to visual perception of light. As a medical symptom, photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence o ...
, confusion, nausea, and vomiting. Meningeal inflammation may also affect the
cranial nerves Cranial nerves are the nerves that emerge directly from the brain (including the brainstem), of which there are conventionally considered twelve pairs. Cranial nerves relay information between the brain and parts of the body, primarily to and f ...
, most commonly the
facial nerve The facial nerve, also known as the seventh cranial nerve, cranial nerve VII, or simply CN VII, is a cranial nerve that emerges from the pons of the brainstem, controls the muscles of facial expression, and functions in the conveyance of ta ...
, presenting as facial paralysis. Cerebral gummas, which are caused by
granuloma A granuloma is an aggregation of macrophages (along with other cells) that forms in response to chronic inflammation. This occurs when the immune system attempts to isolate foreign substances that it is otherwise unable to eliminate. Such sub ...
tous destruction of the brain from syphilis, can also cause symptoms of meningitis. Meningovascular syphilis is often in the intermediate stage of neurosyphilis, typically presenting 5 to 12 years after infection. It is due to
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
of the blood vessels supplying the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
, resulting in the death of brain tissue called
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
. It may present as
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
or
spinal cord injury A spinal cord injury (SCI) is damage to the spinal cord that causes temporary or permanent changes in its function. It is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions. Symptoms of ...
. 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

Parenchyma upright=1.6, Lung parenchyma showing damage due to large subpleural bullae. Parenchyma () is the bulk of functional substance in an animal organ such as the brain or lungs, or a structure such as a tumour. In zoology, it is the tissue that ...
l syphilis occurs in the late stage of neurosyphilis, with average presentation occurring 15 to 25 years after initial infection. This stage of the disease is generally in the form of tabes dorsalis or general paresis. Tabes dorsalis, also called locomotor ataxia, describes a constellation of symptoms resulting from a degenerative process of the posterior columns of the spinal cord. Symptoms include pain, ataxic wide-based gait,
paresthesia Paresthesia is a sensation of the skin that may feel like numbness (''hypoesthesia''), tingling, pricking, chilling, or burning. It can be temporary or Chronic condition, chronic and has many possible underlying causes. Paresthesia is usually p ...
s, bowel or bladder incontinence, loss of position and vibratory sense, acute episodic gastrointestinal pain, Charcot joints, and reduced reflexes. 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.Another late form of neurosyphilis is general paresis, which is a slow degenerative process of the brain. 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 Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
,
mania Mania, also known as manic syndrome, is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome defined as a state of Abnormality (behavior), abnormally elevated arousal, affect (psychology), affect, and energy level. During a mani ...
,
psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...
, depression, and delirium. These symptoms may progress to the point of where a patient becomes bedridden.


Ocular syphilis and otosyphilis

Nearly any part of the eye may be involved in neurosyphilis, resulting in ocular syphilis. The most common form of ocular syphilis is uveitis. Other forms include episcleritis, vitritis, retinitis, papillitis, retinal detachment, and interstitial keratitis. Patients typically present with worsening vision. Otosyphilis refers to a type of neurosyphilis that affects the vestibulocochlear nerve, causing issues with hearing and balance. Signs include loss of hearing,
tinnitus Tinnitus is a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...
, vertigo, and
gait Gait is the pattern of Motion (physics), movement of the limb (anatomy), limbs of animals, including Gait (human), humans, during Animal locomotion, locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on s ...
instability. Ocular syphilis and otosyphilis may occur at any point after initial infection, and its presentation can overlap with other symptoms of neurosyphilis.


Risk factors

There are several risk-factors of neurosyphilis that overlap with the risk factors for
syphilis 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 syphilis, latent or tertiary. The prim ...
and other STIs, including high-risk sexual behavior, i.e. unprotected sex, and multiple sexual partners. A significant proportion of syphilis cases are seen among males, especially men who have sex with men. There is also an association between patients who are infected with syphilis and HIV. The link between syphilis and HIV is thought to be because of shared risk factors. Another possibility is that a weakened
immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
, such as those in people with HIV, may decrease the body's ability to clear the infection from the central nervous system. The HIV infection antiretroviral therapy (ART) suppresses HIV transmission but not syphilis transmission.


Pathophysiology

'' Treponema pallidum'' is the spirochete-shaped bacteria that causes neurosyphilis. The pathogenesis is not fully known, in part due to fact that the organism is not easily cultured, making scientific experiments difficult. Within days to weeks after initial infection, ''T. pallidum'' spreads throughout the body via blood and
lymphatic Lymph () is the fluid that flows through the lymphatic system, a system composed of lymph vessels (channels) and intervening lymph nodes whose function, like the venous system, is to return fluid from the tissues to be recirculated. At the origi ...
vessels. The organism may proliferate in the perivascular spaces of nearly any organ, including the central nervous system (CNS). It is unclear why some patients with syphilis develop a persistent CNS infection and others do not. Scientists have also debated if neurosyphilis is the result the bacterial invasion of the CNS or the immune system responding to bacteria in the CNS. In primary or secondary syphilis, invasion of the protective membrane of the brain called the meninges may result in lymphocytic and plasma cell infiltration of perivascular spaces. The immune response may affect the
brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
and
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue that extends from the medulla oblongata in the lower brainstem to the lumbar region of the vertebral column (backbone) of vertebrate animals. The center of the spinal c ...
through inflammation and necrosis of small blood vessels. In tertiary syphilis, reactivation of a chronic latent infection causes severe inflammation of CNS arteries called endarteritis obliterans, leading to meningovascular syphilis. The parenchymal syphilis, present late in neurosyphilis as tabes dorsalis and general paresis. Tabes dorsalis thought to be due to irreversible loss of myelin in nerve fibers of the posterior columns of the spinal cord involving the lumbosacral and lower thoracic levels. General paresis is caused by chronic inflammation of meninges and brain, leading to fibrosis of the meninges,
atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), malnutrition, poor nourishment, poor circulatory system, circulation, loss of hormone, ...
of the cerebral cortex, and the formation of demyelinating plaques, particularly in the frontal and parietal lobes. Rarely, ''T. pallidum'' may invade any structures of the eye (such as
cornea The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...
, anterior chamber, vitreous and choroid, and
optic nerve In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual system, visual information from the retina to the brain. In humans, the optic nerve i ...
) and cause local inflammation and edema.


Diagnosis

There is no single test that is sufficient on its own to make a diagnosis of neurosyphilis in every case. Serum studies are used to determine if a patient has preexisting syphilis. Common serum studies to diagnose syphilis include the rapid plasma reagin and the Venereal Disease Research Laboratory (VDRL) test. To diagnose neurosyphilis, a clinical history,
physical examination In a physical examination, medical examination, clinical examination, or medical checkup, a medical practitioner examines a patient for any possible medical signs or symptoms of a Disease, medical condition. It generally consists of a series of ...
, and cerebrospinal fluid (CSF) analysis are required. Lumbar puncture ("spinal tap") is the procedure to obtain CSF. The VDRL test of the CSF is a common test for making a diagnosis of neurosyphilis. A positive VDRL test in the presence of neurological symptoms is sufficient to confirm a diagnosis of neurosyphilis. However, a negative VDRL result does not rule out neurosyphilis. Due to the low sensitivity of the VDRL test, CSF analyses that specifically look for antibodies against '' T. pallidum'', such as the fluorescent treponemal antibody absorption test (FTA-ABS) and the ''T. pallidum'' particle agglutination assay (TPPA), are also used in certain cases. The FTA-ABS test is more sensitive but less specific than the VDRL test. Reported sensitivity of different tests for neurosyphilis are variable. Other components of CSF analysis can be helpful for diagnosing neurosyphilis. The CSF
white blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
count is often elevated in neurosyphilis, but this finding is nonspecific and can be unreliable in patients with other infections such as HIV. Similarly, an elevated CSF protein may be suggestive of neurosyphilis, but it is a nonspecific result.


Treatment

Penicillin Penicillins (P, PCN or PEN) are a group of beta-lactam antibiotic, β-lactam antibiotics originally obtained from ''Penicillium'' Mold (fungus), moulds, principally ''Penicillium chrysogenum, P. chrysogenum'' and ''Penicillium rubens, P. ru ...
is used to treat neurosyphilis. The
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the National public health institutes, national public health agency of the United States. It is a Federal agencies of the United States, United States federal agency under the United S ...
recommend the following regimen: * Aqueous penicillin G 3–4 million units every four hours (18–24 million units per day) for 10 to 14 days. Alternatively: * One daily
intramuscular injection Intramuscular injection, often abbreviated IM, is the medical injection, injection of a substance into a muscle. In medicine, it is one of several methods for parenteral, parenteral administration of medications. Intramuscular injection may be ...
of procaine penicillin G 24 million units and oral probenecid 500 mg four times daily, both for 10 to 14 days Follow-up blood serum tests are generally performed at 3, 6, 12, and 24 months to ensure successful treatment. The CDC states that repeated CSF studies are unnecessary for people with intact immune systems and people with HIV who are on adequate ART. 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 are allergic to penicillin, initiation of penicillin desensitization is advised. If desensitization is not possible, the CDC recommends ceftriaxone as an alternative. Doxycycline or tetracycline may be considered in select patients 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

Historically, syphilis was studied under the Tuskegee study, often cited as an example of unethical human experimentation. The study began without
informed consent Informed consent is an applied ethics principle that a person must have sufficient information and understanding before making decisions about accepting risk. Pertinent information may include risks and benefits of treatments, alternative treatme ...
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 Penicillins (P, PCN or PEN) are a group of beta-lactam antibiotic, β-lactam antibiotics originally obtained from ''Penicillium'' Mold (fungus), moulds, principally ''Penicillium chrysogenum, P. chrysogenum'' and ''Penicillium rubens, P. ru ...
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.


References

{{reflist, refs= {{cite web , last=Kennard , first=Christine , title=Neurosyphilis , url=http://alzheimers.about.com/od/typesofdementia/a/neurosyphilis.htm , website=About.com , date=September 10, 2014 , access-date=October 23, 2014 {{cite journal , vauthors = Mehrabian S, Raycheva M, Traykova M, Stankova T, Penev L, Grigorova O, Traykov L , title = Neurosyphilis with dementia and bilateral hippocampal atrophy on brain magnetic resonance imaging , journal = BMC Neurol , volume = 12 , pages = 96 , date = September 2012 , pmid = 22994551 , pmc = 3517431 , doi = 10.1186/1471-2377-12-96 , doi-access = free Sexually transmitted diseases and infections Syphilis Disorders causing seizures Syndromes affecting the nervous system