Syphilis pathophysiology: Difference between revisions

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__NOTOC__
{{CMG}} {{AE}} {{AA}}; {{NRM}}
{{Syphilis}}
{{Syphilis}}
{{CMG}}; {{AOEIC}} {{LG}}
==Overview==
==Overview==
*Syphilis is caused by a spirochete, treponema pallidum.  
Syphilis is caused by a [[spirochete]], [[Treponema pallidum|''Treponema pallidum'']]. It has an average incubation period of 3 - 12 weeks. However, it may vary according to the size of innoculum. Spirochete penetrates intact mucous membrane or microscopic dermal abrasions and rapidly enters systemic circulation with the [[central nervous system]] being invaded during the early phase of infection. The histopathological hallmark findings are endarteritis and plasma cell-rich infiltrates reflecting a delayed-type of hypersensitivity reaction to the spirochete.<ref name="pmid21694502">{{cite journal| author=Carlson JA, Dabiri G, Cribier B, Sell S| title=The immunopathobiology of syphilis: the manifestations and course of syphilis are determined by the level of delayed-type hypersensitivity. | journal=Am J Dermatopathol | year= 2011 | volume= 33 | issue= 5 | pages= 433-60 | pmid=21694502 | doi=10.1097/DAD.0b013e3181e8b587 | pmc=3690623 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21694502  }} </ref><ref name="pmid1386838">{{cite journal| author=Fitzgerald TJ| title=The Th1/Th2-like switch in syphilitic infection: is it detrimental? | journal=Infect Immun | year= 1992 | volume= 60 | issue= 9 | pages= 3475-9 | pmid=1386838 | doi= | pmc=257347 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1386838  }} </ref><ref name="pmid10194456">{{cite journal| author=Singh AE, Romanowski B| title=Syphilis: review with emphasis on clinical, epidemiologic, and some biologic features. | journal=Clin Microbiol Rev | year= 1999 | volume= 12 | issue= 2 | pages= 187-209 | pmid=10194456 | doi= | pmc=88914 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10194456  }} </ref><ref name="pmid1911961">{{cite journal| author=Engelkens HJ, ten Kate FJ, Vuzevski VD, van der Sluis JJ, Stolz E| title=Primary and secondary syphilis: a histopathological study. | journal=Int J STD AIDS | year= 1991 | volume= 2 | issue= 4 | pages= 280-4 | pmid=1911961 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1911961  }} </ref><ref name="pmid3285346">{{cite journal| author=Thomas DD, Navab M, Haake DA, Fogelman AM, Miller JN, Lovett MA| title=Treponema pallidum invades intercellular junctions of endothelial cell monolayers. | journal=Proc Natl Acad Sci U S A | year= 1988 | volume= 85 | issue= 10 | pages= 3608-12 | pmid=3285346 | doi= | pmc=280263 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3285346  }} </ref><ref name="pmid18800002">{{cite journal| author=Quatresooz P, Piérard GE| title=Skin homing of Treponema pallidum in early syphilis: an immunohistochemical study. | journal=Appl Immunohistochem Mol Morphol | year= 2009 | volume= 17 | issue= 1 | pages= 47-50 | pmid=18800002 | doi=10.1097/PAI.0b013e3181788186 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18800002  }} </ref><ref name="pmid3734178">{{cite journal| author=Tanabe JL, Huntley AC| title=Granulomatous tertiary syphilis. | journal=J Am Acad Dermatol | year= 1986 | volume= 15 | issue= 2 Pt 2 | pages= 341-4 | pmid=3734178 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3734178  }} </ref>
 
==Pathogenesis==
*Syphilis can either be acquired or congenital and usually classified as primary, secondary, latent and tertiary.
The pathogenesis of syphilis may be described  in the following steps:<ref name="pmid21694502">{{cite journal| author=Carlson JA, Dabiri G, Cribier B, Sell S| title=The immunopathobiology of syphilis: the manifestations and course of syphilis are determined by the level of delayed-type hypersensitivity. | journal=Am J Dermatopathol | year= 2011 | volume= 33 | issue= 5 | pages= 433-60 | pmid=21694502 | doi=10.1097/DAD.0b013e3181e8b587 | pmc=3690623 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21694502  }} </ref><ref name="pmid1386838">{{cite journal| author=Fitzgerald TJ| title=The Th1/Th2-like switch in syphilitic infection: is it detrimental? | journal=Infect Immun | year= 1992 | volume= 60 | issue= 9 | pages= 3475-9 | pmid=1386838 | doi= | pmc=257347 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1386838  }} </ref><ref name="pmid10194456">{{cite journal| author=Singh AE, Romanowski B| title=Syphilis: review with emphasis on clinical, epidemiologic, and some biologic features. | journal=Clin Microbiol Rev | year= 1999 | volume= 12 | issue= 2 | pages= 187-209 | pmid=10194456 | doi= | pmc=88914 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10194456  }} </ref><ref name="pmid1911961">{{cite journal| author=Engelkens HJ, ten Kate FJ, Vuzevski VD, van der Sluis JJ, Stolz E| title=Primary and secondary syphilis: a histopathological study. | journal=Int J STD AIDS | year= 1991 | volume= 2 | issue= 4 | pages= 280-4 | pmid=1911961 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1911961  }} </ref><ref name="pmid3285346">{{cite journal| author=Thomas DD, Navab M, Haake DA, Fogelman AM, Miller JN, Lovett MA| title=Treponema pallidum invades intercellular junctions of endothelial cell monolayers. | journal=Proc Natl Acad Sci U S A | year= 1988 | volume= 85 | issue= 10 | pages= 3608-12 | pmid=3285346 | doi= | pmc=280263 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3285346  }} </ref><ref name="pmid18800002">{{cite journal| author=Quatresooz P, Piérard GE| title=Skin homing of Treponema pallidum in early syphilis: an immunohistochemical study. | journal=Appl Immunohistochem Mol Morphol | year= 2009 | volume= 17 | issue= 1 | pages= 47-50 | pmid=18800002 | doi=10.1097/PAI.0b013e3181788186 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18800002  }} </ref><ref name="pmid3734178">{{cite journal| author=Tanabe JL, Huntley AC| title=Granulomatous tertiary syphilis. | journal=J Am Acad Dermatol | year= 1986 | volume= 15 | issue= 2 Pt 2 | pages= 341-4 | pmid=3734178 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3734178  }} </ref><ref name="pmid7001910">{{cite journal| author=Baker-Zander S, Sell S| title=A histopathologic and immunologic study of the course of syphilis in the experimentally infected rabbit. Demonstration of long-lasting cellular immunity. | journal=Am J Pathol | year= 1980 | volume= 101 | issue= 2 | pages= 387-414 | pmid=7001910 | doi= | pmc=1903600 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7001910  }} </ref><ref name="pmid18008231">{{cite journal| author=Sheffield JS, Wendel GD, McIntire DD, Norgard MV| title=Effect of genital ulcer disease on HIV-1 coreceptor expression in the female genital tract. | journal=J Infect Dis | year= 2007 | volume= 196 | issue= 10 | pages= 1509-16 | pmid=18008231 | doi=10.1086/522518 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18008231  }} </ref><ref name="pmid1191529">{{cite journal| author=Abell E, Marks R, Jones EW| title=Secondary syphilis: a clinico-pathological review. | journal=Br J Dermatol | year= 1975 | volume= 93 | issue= 1 | pages= 53-61 | pmid=1191529 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1191529  }} </ref><ref name="pmid26100683">{{cite journal| author=Pastuszczak M, Jakiela B, Jaworek AK, Wypasek E, Zeman J, Wojas-Pelc A| title=Association of Interleukin-10 promoter polymorphisms with neurosyphilis. | journal=Hum Immunol | year= 2015 | volume= 76 | issue= 7 | pages= 469-72 | pmid=26100683 | doi=10.1016/j.humimm.2015.06.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26100683  }} </ref>
 
   
*Incubation period: 3 - 12 weeks
===Transmission===
*Spirochete penetrates intact mucous membrane or microscopic dermal abrasions and rapidly enters systemic circulation with the central nervous system being invaded during the early phase of infection. The meninges and blood vessels are initially involved with the brain parenchyma and spinal cord being involved in the later stages of the disease.
[[Treponema pallidum|''Treponema pallidum'']] is usually transmitted via direct contact with the infected lesion (sexual contact) or blood transfusion (rare).
*Histopathological hallmark:
:*Endarteritis
:*Plasma cell-rich infiltrates reflecting a delayed-type of hypersensitivity to the spirochete  
 
==Pathophysiology: Acquired syphilis==
 
===Primary syphilis===
*Primary syphilis is typically acquired via direct sexual contact with the infectious lesions of a person with syphilis.<ref name=RedBookSyphilis>{{citation | editor=Pickering LK | contribution=Syphilis | title= Red Book | publisher=American Academy of Pediatrics | location= Elk Grove Village, IL | date=2006 | pages=631-644}}</ref>  
 
*Approximately 10-90 days after the initial exposure (average 21 days), a skin lesion appears at the point of contact, e.g. the [[genitalia]]. This genital lesion, is called '''[[chancre]]''' which is a firm, painless skin ulceration localized at the point of initial exposure to the spirochete, often on the [[penis]], [[vagina]] or [[rectum]].
 
*Rarely, there may be multiple lesions present although typically only one lesion is seen.  


[[Image:Extragenital syphilitic chancre of the left index finger PHIL 4147 lores.jpg|Primary [[chancre]] of syphilis at the site of infection on the hand|175px|center]]
===Incubation===
<br clear="left"/>
The [[incubation period]] varies with the size of innoculum (9-90 days).


*The [[lesion]] may persist for 4 to 6 weeks and usually heals spontaneously.  
===Dissemination===
*Following transmission, [[Treponema pallidum|''Treponema pallidum'']] uses the intact or abraded [[mucous membrane]] to enter the body.
*It then disseminates to the [[lymphatics]] and blood stream to gain access to any organ of the body.


*Local [[lymph node]] swelling can occur.  
===Seeding===
*Syphilis uses [[fibronectin]] molecules to attach to the [[endothelial]] surface of the vessels in organs resulting in inflammation and obliteration of the small blood vessels causing [[vasculitis]] ([[endarteritis obliterans]]).
*Organism has slow replication rate (30-33 hrs) and evades the initial host immune response.
*It may seed to different organs of the body especially the [[cardiovascular system]] and [[central nervous system]] resulting in tertiary syphilis.


*During the initial incubation period, individuals are otherwise [[asymptomatic]]. As a result, many patients do not seek medical care immediately.
===Immune response===
Different stages of syphilis results from the interaction between the [[antigen]] and the [[host immune response]].<ref name="pmid21694502">{{cite journal| author=Carlson JA, Dabiri G, Cribier B, Sell S| title=The immunopathobiology of syphilis: the manifestations and course of syphilis are determined by the level of delayed-type hypersensitivity. | journal=Am J Dermatopathol | year= 2011 | volume= 33 | issue= 5 | pages= 433-60 | pmid=21694502 | doi=10.1097/DAD.0b013e3181e8b587 | pmc=3690623 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21694502  }} </ref><ref name="pmid1386838">{{cite journal| author=Fitzgerald TJ| title=The Th1/Th2-like switch in syphilitic infection: is it detrimental? | journal=Infect Immun | year= 1992 | volume= 60 | issue= 9 | pages= 3475-9 | pmid=1386838 | doi= | pmc=257347 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1386838  }} </ref>


*Syphilis can '''not be contracted''' through toilet seats, daily activities, hot tubs, or sharing eating utensils or clothing.<ref>{{cite web  | last = Centers for Disease Control (CDC) | authorlink = Centers for Disease Control and Prevention  | title =STD Facts - Syphilis  | publisher = [[Centers for Disease Control]] | date = 05-2004  | url = http://www.cdc.gov/std/syphilis/STDFact-Syphilis.htm }}</ref>
'''Acute response'''
*The initial infection in primary syphilis is limited due to [[Th1 response]] and lack of the [[antibody]] response.
*It is speculated that there is a shift from Th1 to [[Th2 response]] during secondary syphilis.
'''Chronic
*[[Cytotoxic T cells]] and an incomplete humoral response is mainly responsible for persistence of infection and tissue damage in tertiary syphilis.
*Ineffective [[Type IV hypersensitivity|type 4 delayed hypersensitivity]] reaction containing [[macrophages]] and sensitized [[T cells]] is mainly responsible for the [[gumma]] formation in various organs.


===Secondary syphilis===
===Genetics===
There is no known genetic association of syphilis. However, [[neurosyphilis]] may be associated with the gene polymorphism for [[IL-10]] production with increased levels seen in the patients with neurosyphilis.<ref name="pmid26100683">{{cite journal| author=Pastuszczak M, Jakiela B, Jaworek AK, Wypasek E, Zeman J, Wojas-Pelc A| title=Association of Interleukin-10 promoter polymorphisms with neurosyphilis. | journal=Hum Immunol | year= 2015 | volume= 76 | issue= 7 | pages= 469-72 | pmid=26100683 | doi=10.1016/j.humimm.2015.06.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26100683  }} </ref>


*Secondary syphilis occurs approximately 1-6 months (commonly 6 to 8 weeks) after the primary infection.  
===Associated conditions===
Syphilis is associated with increased transmission of [[HIV]]. The underlying mechanism may be related to the accumulation of [[dendritic cells]] containing [[CCR5]] co-receptors at the site of infection, the same receptor entity binding the HIV.<ref name="pmid18008231">{{cite journal| author=Sheffield JS, Wendel GD, McIntire DD, Norgard MV| title=Effect of genital ulcer disease on HIV-1 coreceptor expression in the female genital tract. | journal=J Infect Dis | year= 2007 | volume= 196 | issue= 10 | pages= 1509-16 | pmid=18008231 | doi=10.1086/522518 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18008231  }} </ref>


*There are many different manifestations of secondary disease.
===Microscopic pathology===
:*There may be a '''symmetrical reddish-pink non-itchy rash''' on the trunk and extremities.<ref name=2darySyphilis>{{cite journal | author=Dylewski J, Duong M | title=The rash of secondary syphilis | journal=CMAJ. | date= 2007 Jan 2 | volume=176 | issue=1 | pages=33-5 | doi= 10.1503/cmaj.060665}}</ref>
On microscopic [[histopathological]] analysis, characteristic findings of syphilis depends on the stage of the disease:
:*The rash can involve the palms of the hands and the soles of the feet.
:*In moist areas of the body, the rash becomes flat broad whitish lesions known as '''condylomata lata'''.
:*Mucous patches may also appear on the genitals or in the mouth.
:*All of these lesions are infectious and harbor active treponeme organisms.


*A patient with syphilis is '''most contagious''' when he or she has secondary syphilis.
'''Primary syphilis'''
*Mononuclear leukocytic infiltration, [[macrophages]], and [[lymphocytes]]
*Swelling and proliferation of small blood vessels


*Other symptoms common at this stage include:
'''Secondary syphilis'''
:*[[fever]],
*Swelling and dilatation of blood vessels in the [[dermis]]
:*[[sore throat]],
*Epidermal [[hyperplasia]] and neutrophilic infiltration
:*[[malaise]],  
*Inflammatory cell infiltrate, predominantly [[plasma cell]]  
:*[[weight loss]],
:*[[headache]],
:*[[meningismus]], and
:*enlarged [[lymph node]]s.


*Rare manifestations include:
'''Tertiary syphilis'''
:*an acute [[meningitis]] that occurs in about 2% of patients,
*Small vessel inflammation ([[endarteritis obliterans]])
:*[[hepatitis]],
*Granulomatous lesions ([[gumma]]) containing central necrosis, inflammatory cells, such as [[lymphocytes]], [[macrophages]], [[plasma cells]] and [[Fibroblast|fibroblasts]].
:*[[kidney|renal]] disease,
:*hypertrophic [[gastritis]],
:*patchy [[proctitis]],
:*[[ulcerative colitis]],
:*[[rectum|rectosigmoid]] mass,
:*[[arthritis]],
:*[[periostitis]],
:*[[optic neuritis]],
:*intersitial keratitis,
:*[[iritis]], and
:*[[uveitis]].
 
<gallery perRow="5">
Image:Secondary Syphilis on palms CDC 6809 lores rsh.jpg|Typical presentation of secondary syphilis rash on the palms of the hands and usually also seen on soles of feet
 
Image:condyoma lata (syphilis secondary).jpg|Condyoma lata (syphilis secondary)
 
Image:TreponemaPallidum.jpg|Electron micrograph of Treponema pallidum
 
Image:Syphilis lesions on back.jpg|Syphilis lesions on a patient's back
 
Image:Syphilis lesions on chest.jpg|Syphilis lesions on a patient's chest
 
Image:Penis syphilis.png|Chancres on the penile shaft due to a primary syphilitic infection
 
Image:Vaginal syphilis (disturbing image).jpg|Secondary syphilis manifested perineal condylomata lata lesions, which presented as gray, raised papules that sometimes appear on the vulva or near the anus, or in any other warm intertriginous region.
Image:Gumma of nose due to a long standing tertiary syphilitic Treponema pallidum infection 5330 lores.jpg|Gumma of the nose due to long standing tertiary syphilis
</gallery>
 
===Latent syphilis===
 
*Latent syphilis is defined as having serologic proof of infection without signs or symptoms of disease.<ref name=RedBookSyphilis/>
 
*Latent syphilis is further described as either early or late.
:*'''Early latent syphilis''' is defined as having syphilis for two years or less from the time of initial infection without signs or symptoms of disease.
 
:*'''Late latent syphilis''' is infection for greater than two years but without clinical evidence of disease. The distinction is important for both therapy and risk for transmission.
 
*In the real-world, the timing of infection is often not known and should be presumed to be late for the purpose of therapy. Early latent syphilis may be treated with a single intramuscular injection of a long-acting penicillin. Late latent syphilis, however, requires three weekly injections.
 
*For infectiousness, however, late latent syphilis is not considered as contagious as early latent syphilis. 
 
===Tertiary syphilis===
 
*Tertiary syphilis usually occurs 1-10 years after the initial infection, though in some cases it can take up to 50 years.
 
*This stage is characterized by the formation of '''gummas''' which are soft, tumor-like balls of inflammation known as [[granuloma]]s.
 
*The granulomas are chronic and represent an inability of the immune system to completely clear the organism.
 
*Gummas were once readily seen in the skin and mucous membranes although they tend to occur internally in recent history. They may appear almost anywhere in the body including in the skeleton.
 
*The gummas produce a [[chronic inflammatory]] state in the body with mass-effects upon the local anatomy.
 
*Other characteristics of untreated tertiary syphilis include [[neuropathic joint disease]], which are a degeneration of joint surfaces resulting from loss of sensation and fine position sense ([[proprioception]]).
 
*The more severe manifestations include neurosyphilis and cardiovascular syphilis. In a study of untreated syphilis, 10% of patients developed cardiovascular syphilis, 16% had gumma formation, and 7% had neurosyphilis.<ref name=Oslo>{{cite journal | author=Clark EG, Danbolt N |title=The Oslo study of the natural course of untreated syphilis: An epidemiologic investigation based on a re-study of the Boeck-Bruusgaard material | journal=Med Clin North Am. | date=1964 | volume=48 | pages=613}}</ref>
 
:*'''Neurological complications''' at this stage can be diverse. In some patients, manifestations include:
::*''[[general paresis of the insane|generalized paresis of the insane]]'' which results in personality changes, changes in emotional affect, hyperactive reflexes, and
::*''[[Argyll-Robertson pupil]]'': this is a diagnostic sign in which the small and irregular pupils constrict in response to focusing the eyes, but not to light.
::*''[[Tabes dorsalis]]'', also known as [[locomotor ataxia]], a disorder of the [[spinal cord]], often results in a characteristic shuffling gait.
 
:*'''Cardiovascular complications''' include:
::*[[syphilitic aortitis]]: syphilitic aortitis can cause ''[[de Musset's sign]]'',<ref>{{cite journal | author=Sapira JD | title="Quincke, de Musset, Duroziez, and Hill: some aortic regurgitations" | journal=South Med J. | date=1981 Apr | volume=74 | issue=4 | pages=459-67 }}</ref> a bobbing of the head that de Musset first noted in Parisian prostitutes.
::*[[aortic aneurysm]],
::*[[aneurysm of sinus of Valsalva]], and
::*[[aortic regurgitation]]: syphilis infects the ascending [[aorta]] causing [[dilation]] and [[aortic regurgitation]]. This can be heard with a stethoscope as a [[heart murmur]].
 
*The course can be insidious, and [[heart failure]] may be the presenting sign after years of disease.
*The infection can also occur in the [[coronary artery|coronary arteries]] and cause narrowing of the vessels.
 
===Neurosyphilis===
 
*Neurosyphilis refers to a site of infection involving the [[central nervous system]] (CNS).
 
*Neurosyphilis may occur at any stage of syphilis.
 
*Before the advent of antibiotics, it was typically seen in 25-35% of patients with syphilis.
 
*Neurosyphilis is now most common in patients with [[HIV]] infection. Reports of neurosyphilis in HIV-infected persons are similar to cases reported before the HIV [[pandemic]]. The precise extent and significance of neurologic involvement in HIV-infected patients with syphilis, reflected by either laboratory or clinical criteria, have not been well characterized. Furthermore, the alteration of host [[immunosuppression]] by [[antiretroviral drug|antiretroviral therapy]] in recent years has further complicated such characterization.
 
*Approximately 35% to 40% of persons with secondary syphilis have [[asymptomatic]] [[central nervous system]] (CNS) involvement, as demonstrated by any of these on [[cerebrospinal fluid]] (CSF) examination:
:*An abnormal leukocyte cell count, protein level, or glucose level
:*Demonstrated reactivity to Venereal Disease Research Laboratory ([[VDRL]]) antibody test
 
*There are '''four clinical types of neurosyphilis:'''
:*The late forms of neurosyphilis (tabes dorsalis and general paresis) are seen much less frequently since the advent of antibiotics.
:*The most common manifestations today are asymptomatic or symptomatic meningitis.
 
=====1. Asymptomatic meningitis=====
::*Asymptomatic neurosyphilis usually has no signs or symptoms and is diagnosed exclusively with the presence or absence of CSF abnormalities notably pleocytosis, elevated protein, decreased glucose.
 
=====2. Symptomatic meningitis=====
::*develops within 6-months to several years of primary infection
::*typical meningitis symptoms: [[headache]], [[nausea]], [[vomiting]], [[photophobia]]
::*Acute syphilitic [[meningitis]] usually occurs within the first year of infection; 10% of cases are diagnosed at the time of the secondary rash.
::*Patients present with headache, meningeal irritation, and [[cranial nerve]] abnormalities, especially the [[optic nerve]], [[facial nerve]], and the [[vestibulocochlear nerve]].
::*Rarely, it affects the spine instead of the brain, causing focal muscle weakness or sensory loss.
 
=====3. Meningovascular syphilis=====
::*Meningovascular syphilis occurs a few months to 10 years (average, 7 years) after the primary syphilis infection.
::*Meningovascular syphilis can be associated with [[prodromal]] symptoms lasting weeks to months before focal deficits are identifiable.
 
::*Prodromal symptoms include:
:::*unilateral numbness,
:::*[[paresthesia]]s,
:::*upper or lower extremity weakness,
:::*[[headache]],
:::*[[vertigo (medical)|vertigo]],
:::*[[insomnia]], and
:::*psychiatric abnormalities such as personality changes.
 
::*The focal deficits initially are intermittent or progress slowly over a few days.
 
::*However, it can also present as an infectious [[arteritis]] and cause an [[ischemia|ischemic]] [[stroke]], an outcome more commonly seen in younger patients.
 
::*[[Angiography]] may be able to demonstrate areas of narrowing in the blood vessels or total occlusion.
 
=====4. Parenchymatous neurosyphilis=====
::*develops 15-20 years after primary infection
::*[[argyll robertson pupil]]: small irregular pupil
::*clinical presents as '''[[general paresis]]''' or '''[[tabes dorsalis]]''' with resultant [[ataxia]]
:::*General paresis<ref name=AMN>{{cite journal | author = Richard B. Jamess, MD, PhD | title = [http://www.health.am/sex/syphilis/ Syphilis- Sexually Transmitted Infections], 2006. | journal =Sexually transmitted diseases treatment guidelines | volume = | issue = | pages = | year = 2002}}</ref>, otherwise known as general paresis of the insane, is a severe manifestation of neurosyphilis.
 
:::*It is a chronic [[dementia]] which ultimately results in death in as little as 2-3 years.
 
:::*Patients generally have progressive personality changes, memory loss, and poor judgment.
 
:::*More rarely, they can have [[psychosis]], [[clinical depression|depression]], or [[mania]].  
 
:::*Imaging of the brain usually shows atrophy.
 
==Histopathological Findings==
 
===Brain: Gumma of syphilis===
 
{{#ev:youtube|Cd60sjchsN8}}
 
=== Brain: Paresis (syphilis)===
 
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==References==
==References==
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Latest revision as of 00:23, 30 July 2020

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]; Nate Michalak, B.A.

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Overview

Syphilis is caused by a spirochete, Treponema pallidum. It has an average incubation period of 3 - 12 weeks. However, it may vary according to the size of innoculum. Spirochete penetrates intact mucous membrane or microscopic dermal abrasions and rapidly enters systemic circulation with the central nervous system being invaded during the early phase of infection. The histopathological hallmark findings are endarteritis and plasma cell-rich infiltrates reflecting a delayed-type of hypersensitivity reaction to the spirochete.[1][2][3][4][5][6][7]

Pathogenesis

The pathogenesis of syphilis may be described in the following steps:[1][2][3][4][5][6][7][8][9][10][11]

Transmission

Treponema pallidum is usually transmitted via direct contact with the infected lesion (sexual contact) or blood transfusion (rare).

Incubation

The incubation period varies with the size of innoculum (9-90 days).

Dissemination

Seeding

Immune response

Different stages of syphilis results from the interaction between the antigen and the host immune response.[1][2]

Acute response

  • The initial infection in primary syphilis is limited due to Th1 response and lack of the antibody response.
  • It is speculated that there is a shift from Th1 to Th2 response during secondary syphilis.

Chronic

Genetics

There is no known genetic association of syphilis. However, neurosyphilis may be associated with the gene polymorphism for IL-10 production with increased levels seen in the patients with neurosyphilis.[11]

Associated conditions

Syphilis is associated with increased transmission of HIV. The underlying mechanism may be related to the accumulation of dendritic cells containing CCR5 co-receptors at the site of infection, the same receptor entity binding the HIV.[9]

Microscopic pathology

On microscopic histopathological analysis, characteristic findings of syphilis depends on the stage of the disease:

Primary syphilis

  • Mononuclear leukocytic infiltration, macrophages, and lymphocytes
  • Swelling and proliferation of small blood vessels

Secondary syphilis

  • Swelling and dilatation of blood vessels in the dermis
  • Epidermal hyperplasia and neutrophilic infiltration
  • Inflammatory cell infiltrate, predominantly plasma cell

Tertiary syphilis

References

  1. ↑ 1.0 1.1 1.2 Carlson JA, Dabiri G, Cribier B, Sell S (2011). "The immunopathobiology of syphilis: the manifestations and course of syphilis are determined by the level of delayed-type hypersensitivity". Am J Dermatopathol. 33 (5): 433–60. doi:10.1097/DAD.0b013e3181e8b587. PMC 3690623. PMID 21694502.
  2. ↑ 2.0 2.1 2.2 Fitzgerald TJ (1992). "The Th1/Th2-like switch in syphilitic infection: is it detrimental?". Infect Immun. 60 (9): 3475–9. PMC 257347. PMID 1386838.
  3. ↑ 3.0 3.1 Singh AE, Romanowski B (1999). "Syphilis: review with emphasis on clinical, epidemiologic, and some biologic features". Clin Microbiol Rev. 12 (2): 187–209. PMC 88914. PMID 10194456.
  4. ↑ 4.0 4.1 Engelkens HJ, ten Kate FJ, Vuzevski VD, van der Sluis JJ, Stolz E (1991). "Primary and secondary syphilis: a histopathological study". Int J STD AIDS. 2 (4): 280–4. PMID 1911961.
  5. ↑ 5.0 5.1 Thomas DD, Navab M, Haake DA, Fogelman AM, Miller JN, Lovett MA (1988). "Treponema pallidum invades intercellular junctions of endothelial cell monolayers". Proc Natl Acad Sci U S A. 85 (10): 3608–12. PMC 280263. PMID 3285346.
  6. ↑ 6.0 6.1 Quatresooz P, Piérard GE (2009). "Skin homing of Treponema pallidum in early syphilis: an immunohistochemical study". Appl Immunohistochem Mol Morphol. 17 (1): 47–50. doi:10.1097/PAI.0b013e3181788186. PMID 18800002.
  7. ↑ 7.0 7.1 Tanabe JL, Huntley AC (1986). "Granulomatous tertiary syphilis". J Am Acad Dermatol. 15 (2 Pt 2): 341–4. PMID 3734178.
  8. ↑ Baker-Zander S, Sell S (1980). "A histopathologic and immunologic study of the course of syphilis in the experimentally infected rabbit. Demonstration of long-lasting cellular immunity". Am J Pathol. 101 (2): 387–414. PMC 1903600. PMID 7001910.
  9. ↑ 9.0 9.1 Sheffield JS, Wendel GD, McIntire DD, Norgard MV (2007). "Effect of genital ulcer disease on HIV-1 coreceptor expression in the female genital tract". J Infect Dis. 196 (10): 1509–16. doi:10.1086/522518. PMID 18008231.
  10. ↑ Abell E, Marks R, Jones EW (1975). "Secondary syphilis: a clinico-pathological review". Br J Dermatol. 93 (1): 53–61. PMID 1191529.
  11. ↑ 11.0 11.1 Pastuszczak M, Jakiela B, Jaworek AK, Wypasek E, Zeman J, Wojas-Pelc A (2015). "Association of Interleukin-10 promoter polymorphisms with neurosyphilis". Hum Immunol. 76 (7): 469–72. doi:10.1016/j.humimm.2015.06.010. PMID 26100683.


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