Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5221_Библиотеки_им_академика_М_И_Перельмана.pdf
8
Syphilis
Arielle P. Davis
Introduction
Syphilis, caused by the bacterial spirochete Treponema pallidum, subspecies pallidum
(hereaer T. pallidum), is an obligate human pathogen typically transmitted sexually
and vertically. Recognized in Europe since the late eenth century (Harper et al.,
2011), syphilis has stood the test of time and remains a relevant infectious disease.
Over time, syphilis has gone by many monikers, including the “great imitator” or
the “great mimicker” given its protean clinical manifestations, and its eects on the
nervous system are no exception.
Syphilis proceeds through clinical stages divided into early infectious disease: primary, secondary, and early latent, and later less infectious stages: late latent and tertiary. While a common misconception considers neurosyphilis (NS) to be a late or
tertiary manifestation of syphilis, T. pallidum invades the nervous system early in the
course of infection (Figure 8.1). is chapter reviews the epidemiology, clinical presentation, diagnosis, and treatment of NS with a focus on the association of syphilis
with neurocognitive function.
Biology of syphilis
e spirochete causing syphilis was rst identied in 1905 and described as
“very light, thin spiraled microorganisms, turning around their largest length”
(Edmondson et al., 2018, p.1; Schaudinn, 1905a, 1905b). While a genetically streamlined organism, T. pallidum possesses remarkable abilities to evade the host immune
system, invade multiple tissues including the nervous system, and to persist for years
and later reactivate. T. pallidum evaded standard in vitro culture techniques for cen-
turies. More recently, specialized techniques have been developed to facilitate longterm in vitro culture outside of a rabbit host (Edmondson et al., 2018). T. pallidum
whole genome sequencing is another technique only recently made possible to study
the organism. Utilizing genomic sequencing, phylogenetic analyses have identied
two deep branching T. pallidum lineages, Nichols and SS14. While these lineages
have demonstrated changes over time, including evidence of macrolide resistance
Arielle P. Davis, Syphilis In:
Infectious Disease and Neurocognition
Figure 8.1 The natural history of untreated syphilis. Syphilis proceeds through clinical stages,
and it is important to realize that central nervous system (CNS) invasion occurs early in the
course of disease. Neurosyphilis may become symptomatic early, late, or never.
Source: From The New England Journal of Medicine, Ghanem et al., 2020, The modern epidemic of syphilis,
382, p.847. © (2020) Massachusetts Medical Society. Reprinted with permission from Massachusetts
Medical Society.
in many sublineages, the syphilis genome exhibits relatively limited genetic diversity
(Beale et al., 2021; Grillova, 2022).
T. pallidum consists of an outer and inner membrane, periplasmic space, and
periplasmic agella. While structurally like Gram- negative bacteria, T. pallidum
lacks proinammatory lipopolysaccharide and does not synthesize any toxic
proteins (Ho & Lukehart, 2011). T. pallidum does possess immunogenic outer
membrane proteins, and much of the pathogenesis is thought due to the host inammatory and immune response. Residing below the outer membrane surface,
many of the immunogenic outer membrane proteins initially avoid triggering
of pathogen- associated molecular patterns and thereby escape immune surveillance (Peeling et al., 2017). However, with local replication and dissemination, the
host immune response takes action, and treponemes may be cleared and killed via
opsonophagocytosis. Antibodies opsonize or mark T. pallidum as targets for phago-
cytosis and destruction via activated macrophages (Baker- Zander & Lukehart, 1992;
Baker- Zander et al., 1993).
Syphilis 101
Epidemiology
While an old disease, syphilis remains an active public health concern. Since the
twenty- rst century, syphilis incidence has resurged, particularly in high- income
countries. e European Center for Disease Prevention and Control reported a continued increase in syphilis between 2010 and 2019, with a crude notication rate in
2019 (includes any stage of syphilis) of 7.4 cases per 100,000 (European Centre for
Disease Prevention and Control, 2019). In the United States, the Centers for Disease
Control and Prevention (CDC) reported the number of individuals with any stage of
syphilis increased 52 percent between 2016 and 2020, with a rate of 40.8 per 100,000
in 2020 (CDC, 2020). Western countries are not alone in suering from increasing
rates of syphilis. e World Health Organization reported the highest rates of median
syphilis prevalence at 13.2 percent in female sex workers in Africa (World Health
Organization, 2018). China also has a high disease burden of syphilis with an average
annual 30.2 percent incidence increase from 1990 to 2016 (Jiang et al., 2020). Both in
Europe and the United States, syphilis disproportionately aects men who have sex
with men (MSM). MSM account for up to 70– 74 percent of individuals with syphilis and a known transmission status in the United States and Europe (CDC, 2020;
European Centre for Disease Prevention and Control, 2019). Human immunodeciency virus (HIV) coinfection in individuals with syphilis is more prevalent among
MSM, representing nearly a third of cases in Europe and nearly half in the United
States (CDC, 2020; European Centre for Disease Prevention and Control, 2019).
Estimates of NS are more elusive than the infectious stages of syphilis, as NS suers
from under- recognition and underreporting. Population- based studies have reported
NS prevalence among those with syphilis ranging from 0.84 percent to 11.9 percent
(Daey Ouwens et al., 2014; de Voux et al., 2018). A study utilizing 2019 CDC surveillance data from 16 states identied ocular syphilis in 1.1 percent, otosyphilis in
0.4 percent, and NS in 1.1 percent (Jackson et al., 2022). Most studies identify male
sex, MSM, and people living with HIV (PLWH) as at higher risk of NS (Daey Ouwens
et al., 2014; de Voux et al., 2018; Jackson et al., 2022; Landry et al., 2019; Quilter et al.,
2021; Salado- Rasmussen et al., 2019; Taylor et al., 2008). While not consistently reported in other studies, Jackson et al. found a nearly three times higher prevalence of
NS among people who inject drugs (Jackson et al., 2022). Overall, while published NS
rates are relatively low, these numbers are biased toward underestimation and heavily
dependent upon the population assessed and the denition of NS utilized. As syphilis
rates continue to rise, we can anticipate an increase of NS (Landry et al., 2019).
Clinical findings in symptomatic neurosyphilis
Syphilis disseminates widely throughout the body early aer infection and within
days invades the central nervous system (CNS). T. pallidum may be detected in the
Infectious Disease and Neurocognition
cerebrospinal uid (CSF) in 30– 40 percent of those with early syphilis (Lukehart
et al., 1988; Rolfs et al., 1997). All syphilis stages harbor risk of NS. Nervous system
invasion, while a prerequisite for developing symptomatic NS, oen remains
asymptomatic. While most with CNS invasion clear the infection, even without
antimicrobials, those that do not harbor risk for symptomatic NS. Symptomatic NS
may be dichotomized into early neurologic involvement within weeks, months, to
several years aer initial infection versus late neurologic involvement years or decades aer infection (Figure 8.2). Early NS typically involves the meninges and cerebral blood vessels, whereas late disease involves the brain or spinal cord parenchyma,
or both (Marra, 2015; Merritt et al., 1946).
Early neurosyphilis: Meningitis and meningovascular
Symptomatic early NS may present with meningitis or with meningovascular disease. Symptoms of meningitis include headache, neck stiness, nausea, vomiting,
photophobia, and altered mental status including decreased level of consciousness.
Examination may reveal delirium, confusion, decreased consciousness, nuchal rigidity, meningeal signs such as Kernig’s or Brudzinski’s sign, papilledema, or cranial nerve palsies (Merritt et al., 1946; Merritt & Moore, 1935). In the pre- penicillin
era, Merritt and Moore described acute syphilitic meningitis with cranial nerve palsies as the most common phenotype and acute hydrocephalus with accompanying
headache, nausea, vomiting, and papilledema as the second most common (Merritt
& Moore, 1935). Cranial nerve palsies were single or multiple, involving cranial
nerves II– X and XII, with the facial and vestibulocochlear nerves being the most
Infection
Clearance
CNS invasion
Persistent meningitis
Asymptomatic neurosyphilis
Early
Early symptomatic
neurosyphilis
Weeks-months-years
Symptomatic meningitis
Figure 8.2 The natural history of neurosyphilis. While the majority of those with central
nervous system (CNS) invasion clear the infection spontaneously, those that do not harbor risk
for neurosyphilis. Neurosyphilis can be subdivided into early versus later forms.
Source: Reprinted with permission by Dr. Christina Marra (Marra, 2015).
Meningovascular General paresis Tabes dorsalis
Late symptomatic
neurosyphilis
Years–decades
Syphilis 103
common and cranial nerves I and XI being the least implicated (Merritt et al., 1946;
Merritt & Moore, 1935). In the modern era, syphilitic meningitis leading to cranial
neuropathies continues to most commonly involve cranial nerves VII and VIII (Chu
et al., 2021; Smith & Anderson, 2000).
Syphilitic gummas may present as localized meningeal inammation. While traditionally thought of as a tertiary manifestation of syphilis, gummas may present
within months of T. pallidum infection in PLWH and HIV- uninfected patients
(Kodama et al., 2018; Koizumi et al., 2018; L. Zhang et al., 2017). Gummas involving
the brain tend to arise from the pia mater and are most common in the cerebral
convexities. Named for their rubbery or gummy consistency on gross pathology,
gummas demonstrate localized granulomatous inammation (Fargen et al., 2009;
Merritt et al., 1946). ey frequently mimic brain tumors both clinically and on
imaging.
Meningovascular NS is an infectious inammatory arteriopathy presenting
within months of initial T. pallidum infection or years later. While there is signicant variability in the time to presentation, in the pre- penicillin era, Merritt,
Adams, and Solomon reported meningovascular NS presenting an average of
7 years aer initial infection (Merritt et al., 1946), although the reliance on pathology for diagnosis in Merritt’s pre- computed tomography and pre- magnetic
resonance brain imaging time frame implies the diagnosis occurs earlier.
Meningovascular NS leads to thrombophlebitis and vascular occlusion in the setting of a chronic meningitis with thickening and brosis of the meninges and may
involve large, medium, and small arteries and arterioles with a particular predilection for the middle cerebral artery (M. D. Holmes et al., 1984; Merritt et al.,
1946). Prevalence of meningovascular NS is dicult to accurately assess as it depends on the underlying prevalence of syphilis in the population and upon the
aggressiveness of syphilis screening, which is not routinely performed in stroke
evaluation. In the modern era, estimates of meningovascular NS prevalence have
ranged from 0.09 percent in an Australian study of 3270 transient ischemic attack or stroke patients to 2.5 percent in a ai study of 284 transient ischemic
attack or stroke patients (Cordato et al., 2013; Dharmasaroja & Dharmasaroja,
2012). While meningovascular NS presents with focal decits attributable to the
area of ischemic infarct, it is the presence of prodromal meningitis symptoms that
may suggest syphilis. Prodromal symptoms oen herald infarction by weeks to
months and include headaches, personality or behavior changes, or dizziness (M.
D. Holmes et al., 1984; Merritt et al., 1946). A younger age without traditional vascular risk factors further heightens clinical suspicion, and many clinical series report meningovascular syphilis in patients less than 50 years of age (Dharmasaroja
& Dharmasaroja, 2012; M. D. Holmes et al., 1984; Merritt et al., 1946; Timmermans
& Carr, 2004). However, meningovascular NS may also be seen in those greater
than 65 years of age, so clinical judgment and careful history taking are required
(Cordato et al., 2013; Dharmasaroja & Dharmasaroja, 2012; Pintado Maury et al.,
2019). Distinguishing meningovascular NS from other etiologies of ischemic
Infectious Disease and Neurocognition
stroke is critical because successful prevention of recurrent stroke and NS progression requires antibiotic treatment.
Late neurosyphilis: General paresis and tabes dorsalis
General paresis is a late chronic meningoencephalopathy or syphilitic dementia typically seen decades aer initial syphilis infection. In the pre- penicillin era, it occurred
in 2– 5 percent of those with untreated syphilis and manifested aer 20 or more years
(Clark & Danbolt, 1955; Merritt et al., 1946). General paresis incidence has declined
over time. While the American Academy of Neurology previously recommended
syphilis screening in those presenting for an initial dementia assessment, in 2001
they rescinded this recommendation citing the falling incidence and prevalence of
syphilis (Knopman et al., 2001). While general paresis is less common in the modern
era, several Chinese retrospective series have cited as many as 33– 40 percent of patients with NS having general paresis (Gao et al., 2021; H. L. Zhang et al., 2013).
Patients with syphilitic dementia tend to present with neuropsychiatric and cognitive changes. Neuropsychiatric concerns may include emotional lability, irritability,
personality changes, or delusions, including colorful grandiose delusions (Daey
Ouwens et al., 2019; Gao et al., 2021; Timmermans & Carr, 2004). Emphasizing the
multitude of clinical presentations, Merritt paraphrasing Osler stated, “know paretic
neurosyphilis in all its aspects and you know all of psychiatry” (Merritt et al., 1946).
General paresis oen is initially misdiagnosed as schizophrenia, mood disorders, or
other forms of dementia (Gao et al., 2021; H. L. Zhang et al., 2013). As the disease
progresses, untreated patients become demented, aphasic, bedbound due to degeneration of the corticospinal tracts, and incontinent (Merritt et al., 1946). Pathology
reveals thickened and clouded meninges and cerebral atrophy particularly in the
frontal and temporal lobes. Microscopy demonstrates scant meningeal and perivascular lymphocytic and plasma cell inltrates, loss of neurons, reactive gliosis, and in
some cases, spirochetes within the parenchyma (Merritt et al., 1946).
Distinguishing between chronic syphilitic meningitis, meningovascular NS, and
general paresis may pose a challenge. ere are not accepted clinical diagnostic criteria, and the distinction relies upon clinical judgment, time course of symptoms
aer initial infection, response to penicillin therapy, and clues from neuroimaging,
laboratory, and CSF studies. General paresis typically presents decades aer initial
infection, and while considered a potentially treatable form of dementia, response to
treatment depends on timing and degree of irreversible brain injury. Treatment may
halt further progression but may not lead to regression of symptoms (Helsen, 2011;
Kodama et al., 2000; Luo et al., 2008).
In the pre- penicillin era, tabes dorsalis, the late spinal cord form of NS, was found
in up to 48 percent of those with NS (Kierland et al., 1942) but has become increasingly rare (Conde- Sendín et al., 2004; Timmermans & Carr, 2004). Pathologically,
tabes dorsalis demonstrates atrophy and degeneration of the posterior roots and
Syphilis 105
posterior columns of the spinal cord. Typically tabes presents decades aer initial
infection, with an average of 21 years (Merritt et al., 1946). Initial clinical signs oen
include eeting, lancinating, or lightning- like pains. With clinical progression, there
is loss of distal proprioception, vibration sense, decreased or absent reexes, and
a wide- based ataxic gait that ultimately leads to loss of ambulation (Merritt et al.,
1946). Merritt suggested the triad of “lightning pains, dysuria and ataxia” along
with the exam triad of “Argyll Robertson pupils, absent tendon reexes and positive Romberg” as nearly pathognomonic for a diagnosis of tabes dorsalis (Merritt
et al., 1946). Tabes dorsalis while less common than in the pre- penicillin era does
still occur and a video demonstrating Argyll Robertson pupils and the gait disturbance is available via e New England Journal of Medicine (Osman & Clark, 2016).
Diagnosis of neurosyphilis
e diagnosis of syphilis is a challenge requiring the clinician to synthesize the clinical signs and symptoms and the results of serologic tests and to consider prior syphilis history and treatment. Diagnosing NS adds additional nuance as this requires
analysis of CSF.
Blood serologies
e initial starting point when considering a diagnosis of NS is ensuring that the
patient has serum serologies suggestive of past or present syphilis. Although
T. pallidum can now be cultured, this technique has not been applied to syphilis diagnosis, which instead relies upon detection of antibodies. Serologies for syphilis
test for two general types of antibodies: non- treponemal or lipoidal, and treponemal.
Non- treponemal tests, such as the rapid plasma reagin (RPR) or the venereal disease
research laboratory (VDRL) measure immunoglobulin IgG and IgM antibodies to
a cardiolipin- cholesterol- lecithin antigen, which likely cross- react with host lipids
incorporated into T. pallidum membranes. Treponemal antibodies measure IgG and
IgM antibodies to whole T. pallidum or to T. pallidum proteins. Treponemal tests
generally remain reactive for life, which means considering the patient’s prior syphilis history when interpreting results to distinguish between prior and current syphilis (Janier et al., 2021; Workowski et al., 2021).
Many laboratory testing algorithms now employ a reverse testing algorithm
starting with a treponemal enzyme immunoassay or chemiluminescence immunoassay to detect antibodies to recombinant T. pallidum proteins. A nonreactive test
suggests no evidence of syphilis and therefore no NS. A reactive enzyme immunoassay or chemiluminescence immunoassay indicates past or present syphilis, and
testing moves on to conrmation with a non- treponemal test. A reactive RPR or
VDRL suggests past or present syphilis. If the RPR or VDRL is nonreactive, then an
Infectious Disease and Neurocognition
additional treponemal- specic test that uses a dierent platform than the original
test is used for conrmation, such as the T. pallidum particle agglutination (TP- PA),
which measures IgG and IgM reactivity to whole organisms. If the second treponemal test is nonreactive, a diagnosis of syphilis is excluded. A reactive second treponemal test also leads to a diagnosis of past of present syphilis.
In summary, the starting point for a diagnosis of NS requires conrmation of current or past syphilis. ere are other nuances of blood serology testing to be aware of
including reasons for false- positive and false- negative results, and additional details
can be found in these cited references (Chow, 2021; Janier et al., 2021; Tuddenham
et al., 2020; Workowski et al., 2021). Additional hints from serologies that predict
likelihood of NS include RPR titers greater than or equal to 1:32. In PLWH, NS is
more likely in those who are not taking antiretrovirals (Ghanem et al., 2008; Marra
et al., 2014), and, in studies from earlier in the HIV epidemic, peripheral blood
CD4+ T cells less than or equal to 350/ μL (Marra et al., 2004a).
Cerebrospinal fluid testing
Because there is no one gold standard diagnostic test for NS, the diagnosis is challenging. e clinician must always keep in mind the clinical scenario and the pretest probability of NS when interpreting results. As long as the CSF is not visibly
contaminated with blood, the CSF VDRL is highly specic and so when reactive
is synonymous with a diagnosis of NS. However, the CSF VDRL is not sensitive,
and so a nonreactive result cannot rule out the diagnosis. When the CSF VDRL is
nonreactive, CSF pleocytosis and elevated protein further support a NS diagnosis
when other etiologies for these abnormalities are excluded. Because there is a high
prevalence of syphilis in PLWH, it is important to keep in mind that HIV itself can
cause a CSF pleocytosis particularly when the CD4 count is greater than 200 cells/
mm3, there is detectable plasma HIV RNA, and when the patient is not on antiretroviral treatment (Chow, 2021; Marra, 2015; Marra et al., 2007; Spudich et al.,
2005). As shown in Table 8.1, interpreting CSF white blood cell count in PLWH
requires clinical judgment and integration of all these variables. CSF treponemalspecic tests, CSF uorescent treponemal antibody absorbed (FTA- ABS), or TPPA are more sensitive than specic, and so are the most helpful in ruling out NS
when nonreactive and when clinical suspicion and pretest probability are not high.
An uncommon scenario but worth mention is that late stages of NS may demonstrate normal CSF. Merritt in 1946 reported that in general paresis, 10 percent
had a normal CSF white blood cell count, and with tabes dorsalis, this number increased to 53 percent (Merritt et al., 1946). A modern series of 85 patients with general paresis found 24.7 percent had normal CSF white blood cell count and protein,
although normal was dened as CSF less than or equal to ten white blood cells/ mm3
(Chen et al., 2015).
Table 8.1 Interpretation of cerebrospinal fluid in neurosyphilis
Syphilis 107
Cerebrospinal uid
parameter
CSF VDRL Reactive (more specic than
CSF FTA- ABS or TP- PA Reactive (lower specicity so also
CSF white blood cells:
HIV uninfected > 5 cells/ mm
HIV infected with CD4 < 200
and plasma VL undetectable
and on ARV
HIV infected with CD4 > 200
or plasma VL detectable or not
taking ARV
Abbreviations: ARV, antiretroviral; CSF, cerebrospinal uid; FTA- ABS, uorescent treponemal antibody absorbed;
HIV, human immunodeciency virus; NS, neurosyphilis; TP- PA, Treponema pallidum particle agglutination;
VDRL, venereal disease research laboratory; VL, viral load.
Suggestive of neurosyphilis Less consistent with
neurosyphilis
Nonreactive
sensitive so reactive is highly
suggestive of NS)
Nonreactive (more sensitive
requires either a CSF pleocytosis
or elevated protein)
3
> 5 cells/ mm
> 20 cells/ mm
3
3
than specic, so nonreactive is
more helpful in ruling out NS)
< 5 cells/ mm
< 5 cells/ mm
< 20 cells/ mm
3
3
3
In summary, laboratory studies in blood and CSF are an essential adjunct but are
no substitute for clinical context. e clinician needs compelling neurologic signs or
symptoms, evidence of syphilis by serologies, and ideally additional clues from CSF
to make the diagnosis of NS.
Treatment of neurosyphilis
Penicillin is the antimicrobial drug of choice for all stages of syphilis. Penicillin
preparation, dose, mode of administration, and length of treatment vary by
stage and clinical manifestations. It is assumed that effective NS treatment requires treponemicidal levels of drug that will penetrate the sequestered space
of the CNS. Standard recommendations for NS among adults are aqueous crystalline penicillin G 18– 24 million units per day intravenously for 10– 14 days or
procaine penicillin G 2.4 million units intramuscularly once a day along with
probenecid 500 mg by mouth four times a day for 10– 14 days (Janier et al.,
2021; Workowski et al., 2021). Guidelines also note intravenous or intramuscular ceftriaxone as an option for NS but with a weaker level of evidence (Janier
et al., 2021; Workowski et al., 2021). Standard treatment for early syphilis with
penicillin G benzathine does not achieve treponemicidal levels in the CSF
(Polnikorn et al., 1980).