on 09-Mar-2024 (Sat)

Although syphilis has recently reemerged in the United States and Europe89–92 most individuals (>90%) who acquire syphilis reside in less affluent regions of the world.93

However, it is important to highlight that during the period from 2013 to 2016, syphilis rates in the United States increased in both men and women, in every region of the country, in every age group among those aged 15 years or older, and in every racial and ethnic group. The reasons for this latest increase are likely multifold and include lack of sexual inhibition resulting from the availability of effective treatment for human immu- nodeficiency virus (HIV), the use of the Internet to meet partners, the practice of HIV serosorting, and the increase in oral sex as a form of “safe sex.”96

In European and European Union member states, 24,541 new cases of syphilis were reported in 2014, with an overall incidence rate of 5.1 per 100,000 population. Similar to trends shown earlier in this chapter for the United States, close to two-thirds (63%) of reported syphilis cases were diagnosed in men who reported having sex with other men (MSM). The highest rate of syphilis was observed in Malta (11.5 per 100,000 population), followed by Lithuania (8.7), Iceland (7.7), and Spain (7.7). Rates below 2.5 per 100,000 population were observed in Croatia, Cyprus, Greece, Italy, and Slovenia.97,98

The social changes and disruption of medical services that followed the breakup of the Soviet Union in the late 1980s led to important increases in syphilis rates in Eastern Europe and Russia.99,100 Although improved prevention strategies have led to a steady decrease in the overall disease burdens in this region of the world, Eastern European countries and Russia continue to report higher burdens of syphilis than their counterparts in the West. Findings from a recent review reveal that country-specific rates vary widely, with a mean syphilis incidence rate for Eastern European countries of 12.5 per 100,000 population, ranging from a high of 41 per 100,000 in Belarus to a low of 1.15 per 100,000 in Albania.100 A report from the Russian Federation revealed that although the overall syphilis incidence declined nationally from 79.4 per 100,000 in 2004 to 28.9 per 100,000 in 2013, rates remain very high in Far Eastern, Siberian, and Northwestern Federal districts.101

Regardless of geographic location, the worldwide epidemiology of syphilis has been greatly influenced by developments in the HIV epidemic. A statistical association between the two diseases became apparent at the outset of the acquired immunodeficiency syndrome (AIDS) epidemic in the early 1980s.111

Rates of HIV coinfection among MSM with newly diagnosed early syphilis are as high as 50%.117 In one study from Florida, 21% of men diagnosed with early syphilis in 2003 had acquired HIV infection by the end of 2011.118

Although the association between syphilis and HIV infection initially was thought to simply reflect similar behavioral risk factors for acquisition and transmission, it has become apparent over the years that complex biologic relationships exist between these two diseases.96,119,120 The presence of a syphilitic chancre can theoretically facilitate HIV transmission by either increasing the host’s susceptibility to infection with the virus or the HIV-infected host’s infectiousness to discordant sexual partners. The former is associated with the disruption of the protective epithelial and mucosal barriers present in genital chancres and the known enrichment of the lesion with activated lymphocytes, macrophages, and dendritic cells (DCs), all of which are potential targets and donors for HIV121–124 and which differentially increase expression of key HIV coreceptors (i.e., CCR5 and DC-SIGN) in untreated patients.124,125 With respect to increased infectiousness, the inflammatory response elicited by T. pallidum is capable of inducing HIV gene expression, thereby promoting viral replication.126 Not surprisingly, in HIV-infected patients, CD4 counts decrease and HIV viral loads increase in individuals with untreated syphilitic coinfection.127

Nearly 1.0 million pregnant women are estimated to be newly infected with syphilis every year, and approximately half of pregnant women who are left untreated will experience adverse outcomes in their pregnancies.

Of particular concern, in sub-Saharan Africa, syphilis contributes to approximately 20% of all perinatal deaths.

A second serious limitation is the lack of a facile murine model for dissecting the complex host response to this pathogen.130,131 Although the outbred rabbit model recapitulates many facets of human disease, rabbits do not develop typical secondary lesions after intradermal inoculation, nor do they develop neurologic complications or neuropathologic effects comparable to those of humans, even when inoculated intravenously.132,133

Investiga- tors who wish to circumvent these deficiencies by studying infection in humans must cope with an enormous spectrum of disease manifesta- tions, person-to-person variability in immune responses, high rates of HIV coinfection, and the fact that results from blood and skin (the two most accessible sites) represent snapshots from just two compartments of a dynamic, systemic process.134,135

Person-to-person transmission of spirochetes initiates the pathogenic sequence. With venereal syphilis, this typically occurs when treponemes are transferred during intimate contact, usually sexual (oral-genital as well as genital-genital, rarely kissing), with an actively infected partner. In their human inoculation studies conducted at Sing Sing Prison in the 1950s, Magnuson and colleagues140 (see discussion of ethics) found that as few as 10 organisms of the Nichols strain could cause lesions. Thus, only miniscule amounts of infectious exudate need be exchanged when microenvironmental conditions are conducive to survival of this fastidious pathogen.

Individuals with venereal syphilis are most infectious during the primary and secondary stages of disease (including secondary relapses of early latency) when moist, mucocutaneous lesions are present. Persons with early syphilis may be infectious, however, even if they lack open lesions. Micrographs showing that spirochetes are abundant within the epidermis and superficial layers of the dermis in secondary syphilitic lesions141 suggest how minute abrasions created during sexual activity might result in infection.

Syphilis spirochetes rapidly gain entry into their new host either by directly penetrating mucous membranes or via abrasions and cracks in skin. Remarkably, treponemes applied to the preputial mucosa of rabbits migrate into the subepithelium within several hours.144 Once below the epithelial surface, they begin to multiply locally and dis- seminate through lymphatics and blood vessels. Why some members of the bacterial population remain localized whereas others respond to the same environmental signals by migrating away from the inocula- tion site is a fascinating and unresolved question.

The experimental and clinical evidence that T. pallidum disseminates systemically early during the course of infection is overwhelming.59,145 Brown and Pearce146 recovered T. pallidum from inguinal lymph nodes and blood of rabbits within 48 hours of intratesticular inoculation, well before the onset of orchitis; these findings have been replicated with quantitative PCR.147 Numerous reports in the early 20th century documented transmission following the transfusion of blood from seronegative donors (i.e., during the incubation period).148 Almost any organ in the body can be invaded during the spirochetemia of early syphilis, including the CNS.1,67,149 Using both RIT and PCR, investigators in the molecular era have confirmed that substantial percentages of patients with early syphilis without neurologic signs or symptoms harbor T. pallidum in their CNS.150,151

Circulating treponemes bind to vascular endothelium within target organs, reaching the parenchyma by negotiating their way through the tight junctions separating endothelial cells, a process called interjunctional penetration.70

Although rare examples of intracellular treponemes have been reported,166,167 the syphilis spirochete is believed to be incapable of establishing long-term residence in phagocytic or nonphagocytic cells.59,168

There is also now a consensus among syphilologists that clinical mani- festations result from the inflammatory processes driven by the presence of treponemes and treponemal constituents within infected tissues.168,169

Although lacking LPS, T. pallidum contains abundant lipoproteins, which are capable of activating macrophages and DCs via CD14- and Toll-like receptor 1/2 (TLR1/2)–dependent signaling pathways.79,169 However, because of the bacterium’s unique cell envelop architecture,34,73,76 the vast majority of these PAMPs are not readily accessible to TLRs or other pattern recognition receptors (PRRs) expressed on the surface of innate immune cells. As a result, spirochetes can replicate at the site of inoculation, disseminate hematogenously, and then replicate at metastatic sites virtually unchecked by innate surveillance systems. At some point, and through poorly understood mechanisms, pathogen sensing is triggered and organisms are taken up by tissue-based DCs, which then traffic to draining lymph nodes to present cognate treponemal antigens to naïve B and T cells.171

Spirochetes are abundant in early syphilis lesions and often are observed in and around blood vessels (see Fig. 237.3C), occasionally even protruding into the lumen in histologic specimens (i.e., “caught in the act” of disseminating).182–184 In contrast, with the exception of paresis (see later), spirochetes are not easily demonstrable in tertiary syphilis lesions.182,185

In primary syphilis, progression of the vasculopathic changes to frank endarteritis obliterans causes tissue necrosis, ultimately giving rise to a genital ulcer, the chancre. In secondary syphilis skin lesions, a wide variety of histologic patterns, including granuloma during later phases, can be superimposed on the characteristic features noted earlier.186–188

Although circulating immune complexes are detectable in patients with secondary syphilis,190 immune complexes are not typically observed in skin.123 Glomerular deposition of immune complexes, however, has been demonstrated in patients with nephrotic syndrome, a rare complication of secondary syphilis.191,192

Endarteritis and perivascular inflammation help to distinguish syphilitic gummas from those caused by tuberculosis

Obliterative endarteritis involving the vasa vasorum, the nutrient vessels of the aortic adventitia, is the key pathologic lesion in cardiovascular syphilis.194 The ascending aorta and arch are most frequently affected because the vasa vasorum are most plentiful in these regions of the aorta.194,195 These changes eventually give rise to intimal thickening and wrinkling (producing a distinctive “tree bark” appearance), patchy medial necrosis, and adventitial scarring with destruction of elastic fibers and weakening of the aortic wall.

Asymptomatic neurosyphilis and syphilitic meningitis are due to diffuse leptomeningitis (Fig. 237.4A).149 The pathologic features of meningovascular syphilis explain the syndrome’s variable mixture of focal neurologic signs with superimposed encephalitis.149,196,197 In general, there is diffuse thickening and lymphocytic infiltration of the meninges with two kinds of arteritis: (1) Heubner endarteritis, affecting large and medium-sized arteries, characterized by crescentic collagenous thickening of the intima, thinning of the media, and dense, inflammatory infiltrates (lymphocytes and plasma cells) within the adventitia (see Fig. 237.4B), and (2) Nissl-Alzheimer endarteritis of small vessels, characterized by the proliferation of endothelial and adventitial cells.

Paresis and tabes dorsalis involve poorly understood spirochete-driven, neurodegenerative processes of brain tissue, hence their designation as “parenchymatous.”

In paresis, diffuse meningovascular inflammatory changes are associated with striking, progressive loss of cerebral cortical neurons, resulting in gross cerebral atrophy (greatest in the frontal and temporal lobes), and proliferation of astrocytes and glial cells. Microglial cells are hypertro- phied and elongated and often contain abundant iron. Spirochetes are often readily detectable, usually in the gray matter, with little correlation between the clinical picture and the location and distribution of organisms.

Tabes dorsalis (Greek for “consumption of the back”) is characterized by demyelination of dorsal root ganglia with secondary wallerian degeneration of the posterior columns of the spinal cord (see Fig. 237.4C). In early tabes, the leptomeninges and dorsal roots are heavily infiltrated with lymphocytes and plasma cells. These inflammatory changes diminish as the disease becomes chronic, eventually disappearing in so-called burnt-out cases. The degenerative changes in the tabetic spinal cord can be so severe that the posterior surface of the cord is concave, rather than convex

Because T. pallidum is an extracellular pathogen, priming and activation of CD8+ T cells (resulting in local production of IFN-γ) would have to occur by cross-presentation; whether this is advantageous for the spirochete is an open question. NK cells, another potential source of IFN-γ, also have been identified in secondary syphilis skin biopsy specimens.134,170 Evidence has been provided that T. p allidum promotes the development in secondary syphilis lesions of regulatory T cells, which could facilitate spirochetal persistence by producing antiinflammatory molecules.201,202

Of the numerous investigations that have contributed to our understanding of syphilis, the “Oslo Study” stands out as the single greatest source of information about the natural course of the disease.203 The study was born from the clinical impression of Boeck at the University of Oslo that the mercury-based antisyphilitics of the late 19th century were more harmful than efficacious, coupled with his astute insight that “the immune mechanisms of the body are the most important in combating the disease.” In 1891, he began a prospective study of 1978 untreated patients with early syphilis who were hospitalized and closely monitored until all signs and symptoms had disappeared; enrollment ended in 1910 when arsphenamine became accepted syphilotherapy.

Among the key findings of Gjestland’s comprehensive analysis was that 24% of enrollees developed one or more secondary relapses within 5 years of discharge. Two-thirds of the relapses took place within 6 months of resolution of secondary lesions, whereas nearly 90% occurred within 1 year. These observations form the basis for the 1-year time point used clinically and epidemiologically to distinguish early latent from late latent syphilis. (As of January 2018, the CDC had renamed early and late latent syphilis as early syphilis, non-primary, non-secondary and syphilis, unknown duration or late, respectively.) Twenty-eight percent eventually developed some type of late manifestation: 10% developed cardiovascular syphilis, 6.5% developed symptomatic neurosyphilis; and 16% developed benign (i.e., gummatous) tertiary disease. Many of these patients had more than one “late” complication. Of those on whom autopsy was performed, 35% of the men and 22% of the women had evidence of cardiovascular involvement, especially aortitis.

Thus, another important finding of the Oslo Study was that untreated syphilis can be uneventful and that many persons appear to spontaneously self-cure.

In his analysis of autopsy data from the first 20 years of the study, Peters and colleagues205 found that 50% of patients who had been infected for 10 years had cardiovascular involve- ment and that cardiovascular and neurosyphilis were the primary causes of death among the 40% of syphilitic patients who had died during this period. Of the 41% of survivors at 30 years of follow-up, 12% had evidence of late, predominantly cardiovascular, syphilis.206

An interesting sidelight was the observation that continued reactivity of serologic tests, what we now call the serofast state,208 can occur without apparent histologic evidence of disease

The incubation period is a median of 3 weeks but may vary from 10 to 90 days depending on the size of the inoculum.212

The primary stage begins with the appearance of the chancre at the site of inoculation. This usually painless, solitary lesion does not develop in every case or may go unnoticed, particularly in women or MSM.

The secondary or disseminated stage becomes evident 4 to 10 weeks after the appearance of the chancre and is associated with the highest treponemal burdens in the bloodstream and tissues. After weeks to several months, the untreated patient then enters a period of latency during which the diagnosis can be made only by serologic testing (unless a relapse occurs). As per the revised terminology described earlier, latency is divided into early syphilis, non-primary, non-secondary (infec- tious relapses and/or spirochetemia common) and late syphilis of unknown duration (relapses, spirochetemia, or both unlikely) stages.

Late syphilis refers to both clinically inapparent latent infection and the tertiary syndromes (benign gummas, cardiovascular syphilis, and neurosyphilis) that develop in approximately one-third of untreated cases.

Cardiovascular syphilis typically involves the aortic arch.194

As noted earlier, although invasion of the CNS occurs during early syphilis, individuals usually do not develop neurologic complications at this stage. Asymptomatic neurosyphilis may resolve spontaneously, persist indefinitely, or progress to one of the “early” neurosyphilis syndromes, meningitis and meningovascular syphilis, within the first 1 to 10 years of infection, or one of the “late” paren- chymatous syndromes, general paresis and tabes dorsalis, 10 or more years after infection.149,213,214

Since the late 1980s, a number of case reports and small series have documented ophthalmologic and neurologic complications, as well as unusual or highly destructive nonneurologic syphilis syndromes in HIV-infected patients.215–217 The sheer volume of cases led many authorities to conclude that infection with HIV poses a profoundly increased risk of complications, particularly neurologic, during active syphilis.96,216,217 To the surprise of many, a multicenter prospective study sponsored by the CDC did not bear this out.151,218

The differences in clinical presentation between HIV-infected and HIV-uninfected patients were marginal. Although HIV-infected patients with primary syphilis tended to present with more genital ulcers and genital ulcers were present more frequently in HIV-infected patients with secondary syphilis, manifestations of disseminated infection, including neurologic and ophthalmologic complications, were not worsened by concomitant HIV infection. Thus, if atypical and aggressive presentations of syphilis do occur more frequently among HIV-infected patients, they likely represent a small percentage of total cases, an assessment shared by several groups.96,211,219,220

Interesting to note, no correlation has been observed between HIV status and isolation or detection of T. pa llidu m in CSF,150,151 suggesting that the bacterium’s inherent invasiveness, rather than the integrity of host immune defenses, is the primary determinant of CNS invasion during early syphilis.

The effect of early syphilis on HIV viral load also has been examined by several groups.222–224 Most,222–225 but not all,226,227 studies found that active syphilis causes transient increases in viral loads and decreases in CD4 count that return to baseline with effective antimicrobial therapy. Besides diminishing the dangers of untreated syphilis to the coinfected individual, lowering viral loads in semen by treatment of syphilis has important public health implications for this at-risk population

Syphilis commences clinically when spirochetes replicating at the site of inoculation induce a local inflammatory response sufficient to generate a macule, which over the course of 1 to 2 weeks becomes papular and then ulcerates, producing the defining lesion of primary syphilis, the chancre.1,182,230

The base of the typical chancre (Fig. 237.6A) is smooth, clean, and without exudate; the borders are raised and have a characteristic, cartilaginous consistency. Unlike the exquisitely painful genital ulcers caused by Haemophilus ducreyi (chancroid) and herpes simplex virus (herpes genitalis), the classic chancre is painless and nontender on examination; spirochetal infiltra- tion of cutaneous sensory nerves may explain this phenomenon.

Multiple chancres frequently occur, especially in persons who are coinfected with HIV.218 Chancres that do not conform to the classic features are extremely common, representing more than half of the cases in one large series.230

The chancre forms wherever spirochetes are inoculated. The external genitalia are most frequently involved. In one study, penile lesions in men (presumably heterosexual) were located, in decreasing order of frequency, on the prepuce, coronal sulcus, shaft, corona, glans, frenum, and urethral meatus.230 In women, lesions were located on the labia majora, labia minora, fourchette, and perineum230; occasionally chancres occur on the cervix, presenting as a painless discharge

Among hetero- sexuals, a much greater percentage of men present with primary syphilis because intravaginal chancres tend to go unnoticed; a male-to-female ratio of 9 : 1 was noted in one large study.231 Similarly, chancres in MSM often go unnoticed because they occur within the rectum. Chancres in the anal area may be exquisitely painful and mistaken for anal fissures.

As with anogenital ulcers, sexual orientation is a determining factor for the location of oral chancres. In heterosexuals, they typically occur on the upper lip in men and on the tongue in women, whereas in MSM they tend to be located on the tongue (see Fig. 237.6B).232

Genital chancres are often accompanied by inguinal adenopathy, frequently bilateral, consisting of moderately enlarged, discrete, painless nodes, whereas cervical adenopathy often accompanies chancres in the oral cavity (see Fig. 237.6C).

The chancre heals on its own within 3 to 6 weeks, leaving either no trace or a thin atrophic scar; the lymphadenopathy may persist longer

Early venereal warts, granuloma inguinale, lymphogranu- loma venereum, tuberculosis, atypical mycobacterial infections, tularemia, sporotrichosis, anthrax, rat-bite fever, or any genital ulcer may resemble early primary syphilis

The manifestations of secondary syphilis, the often florid, systemic stage of the infection, are protean and are largely responsible for the disease’s legendary reputation as “the great imitator.”1,209–211,229,233,234 The vast majority (>95%) of cases involve the skin and mucous membranes.

With rare exceptions, secondary syphilis rashes are macular, papular, papulosquamous, annular, or pustular, or various combinations thereof.229 Although often described as nonpruritic, in one series 40% of patients complained of itch, which could be severe.235 The rash of secondary syphilis usually begins on the trunk and proximal extremities as bilateral, pink to red, discrete macular lesions 3 to 10 mm in diameter that are usually overlooked by the patient. These lesions often evolve from macules into brownish red papules (hence the term maculopapular); in a few patients, they progress to pustular lesions termed pustular syphilids. In one study of more than 200 patients, 94% and 66% of patients with maculopapular and papular lesions, respectively, presented within 4 weeks of the onset of rash as opposed to only 1 of 11 patients with pustular lesions.236 Scaling is minor with most papular lesions but can be pronounced enough to resemble guttate psoriasis; hyperkeratotic plaques also are not unusual. Lesions are generally widespread and symmetrically distributed, although it is not uncommon for the rash to be anatomically limited.

Involvement of palms and soles (Fig. 237.7A–B), either as part of the generalized eruption or as an isolated finding, is a characteristic feature of the maculopapular rash (see Fig. 237.7C) that helps in distinguishing secondary syphilis from psoriasis and pityriasis rosea.

When the hair follicles are involved, patchy alopecia or thinning and a loss of eyebrows and beard may develop (see Fig. 237.7D).

Lesions teeming with spirochetes, referred to as mucous patches, may develop on labial (see Fig. 237.7E), lingual, gingival, buccal, palatal, or pharyngeal mucosa, as well the moist surfaces of the genitalia. The typical mucous patch is an oval-shaped, shallow ulcer with a slightly raised border covered by a grayish-white or silvery membrane. In warm, moist intertriginous areas, the papules can enlarge, coalesce, and erode to produce painless, broad, moist, gray-white to erythematous papillary excrescences termed condylomata lata (see Fig. 237.7F).

Generalized lymphadenopathy with firm, nontender nodes is a common physical finding in secondary syphilis; enlargement of the epitrochlear lymph nodes should always suggest the diagnosis.1 Constitutional symptoms are also common and include low-grade fever, malaise, pharyngitis, anorexia, weight loss, arthralgias, and myalgias.

During relapses of secondary syphilis, the skin lesions tend to be less florid, asymmetrically distributed, and more infiltrated

Lues maligna is an unusual and severe variant of secondary syphilis eruption. Patients with this form of the disease may look systemically ill and present with rapidly developing polymorphic, ulcerating, rupioid (i.e., with heaped-up crusts) lesions sparing the palms and soles. Long recognized to affect debilitated persons, the condition has recently been reported most often in patients with HIV infection.237–240

Secondary syphilis can involve virtually any organ system, often causing diagnostic delay or confusion when not accompanied by telltale mucocutaneous signs. Subclinical elevations of liver enzymes, principally alkaline phosphatase, occur in up to 50% of patients.241

The rare, symptomatic hepatitis is characterized by a disproportionately elevated serum alkaline phosphatase level, mildly increased aminotransferases, and usually normal bilirubin.

The gastrointestinal tract, particularly the stomach, may also become extensively infiltrated, ulcerated, or both, and the condition can be mistaken for lymphoma or carcinoma.242,243 Epigastric or abdominal pain, early satiety, and nausea and vomiting are the most common gastrointestinal symptoms

Otosyphilis manifests with sudden or progressive sensorineural hearing loss, tinnitus, vertigo, and dysequilibrium.249

The most common type of skeletal lesion is periostitis, most frequently involving the tibia, but also the sternum, skull, and ribs. Rarely, destructive bony lesions occur.250,251 Symmetrical tenosynovitis and/or arthritis involving wrists, knees, and ankles also have been reported.252

Although pneumonia is most typically associated with severe CS (see later), rare cases of pulmonary involvement in adults have been reported in the pre- and post-HIV eras.253–255

Latent syphilis is, by definition, the stage during which serologic tests are reactive without clinical manifestations. Important to note, the term does not mean that the disease process is quiescent, only that clinical signs and symptoms are not evident.

The Oslo Study is only one of several in the prepenicillin era that documented a high rate of relapse in early syphilis. Although the percentages differ, they concurred insofar as the preponderance of relapses occurred during the first 1 to 2 years,1 observations that led to the somewhat arbitrary 1-year demarcation between early latent and late latent syphilis. However, the fact that asymptomatic pregnant women can transmit the infection to their infants in utero 5 or more years after infection clearly demonstrates that recurrent episodes of “silent” spirochetemia occur for prolonged periods.1,60 In reality, there is no clear biologic demarcation between early latency, when the disease is still systemically active, and late latency, when it is active but anatomically contained

Mucocutaneous relapses are by far the most common form of infectious relapse and the ones with greatest public health significance because of their potential for disease transmission.229 The cutaneous lesions of secondary relapses tend to be less florid than initial secondary outbreaks, asymmetrically distributed, and often confined to the mouth, genital, and anal regions. Relapsing lesions have a greater tendency to assume annular forms; mucous patches and condylomata lata also are common. Late mucocutaneous relapses can manifest as localized destructive lesions, resembling gummas.

A small percentage of relapses involve noncutaneous sites, such as bone (usually tibial periostitis), eye (usually iritis), liver, other viscera, and the CNS. These are probably flare-ups of infectious foci established earlier.

Tertiary syphilis is a (usually) slowly progressive, destructive inflam- matory process that can affect any organ in the body to produce clinical illness 5 to 30 or more years after the initial infection.145,182,210 It is generally subdivided into neurosyphilis, cardiovascular syphilis, and gummatous syphilis. Although customary and convenient, inclusion of neurosyphilis among the tertiary syndromes is technically inaccurate because, as noted earlier (also see Fig. 237.5), not all forms of neurosyphilis occur as late disease.

In an oft-cited series of 241 cases published in 1972, Hooshmand256 proposed that patients no longer presented with the classic neurosyphilitic syndromes as a result of widespread exposure to antibiotics. Most authorities now believe that the laboratory criteria used in that study for the diagnosis of these putative “forme frustes” of neurosyphilis were inadequate.214 In fact, since that series many cases of patients with identifiable neu- rosyphilis syndromes have been published. Nevertheless, there is no question that the presentation of neurosyphilis has undergone a sig- nificant shift in recent years as paresis and tabes dorsalis have been replaced by meningeal and meningovascular syndromes.210,211,257

The neurosyphilis syndromes are arguably the most confusing to practitioners for several reasons (for an excellent recent review, see Ghanem258). One is the baffling array of signs and symptoms T. pall idum can inflict on the CNS, which pose a diagnostic challenge to even the most experienced and well-trained clinician.

Another is the unpredictable nature of the disease. Syphilologists have long pondered the question of why some individuals develop neurosyphilis and others do not.149 Whether the answer(s) lie in the putative neuroinvasive properties of particular strains of T. pallidum133,259 or in polymorphisms within the human genome that influence the responses elicited by spirochetes once within the CNS,260 or a combination of the two, remains to be determined.

A third reason is that neurosyphilis belies the entrenched concept that syphilis proceeds via an orderly and stereotypical temporal sequence. To the contrary, because the CNS is invaded during the spirochetemic episodes of early syphilis, neurologic manifestations can occur during any stage of the disease. In addition, clinicians often have trouble grasping the fact that asymptomatic CNS infection (often termed “neuroinvasion”) is a frequent occurrence in early syphilis that does not usually require specific management, and that T. pallidum can be present in the spinal fluids of patients with early syphilis in the absence of neurologic symptoms and CSF abnormalities.8,9,211,258,261

Lastly, the classification scheme for neurosyphilis developed by Merritt and colleagues149 in the 1940s, still widely used today,258 tends to convey the impression that patients always present with distinct neurologic syndromes. The reality, however, recognized by the scheme’s creators149 and underscored by contemporary neuroimaging modalities,262 is that overlap syndromes with combinations of meningeal, vascular, and parenchymatous features frequently occur.

The recognition that neurologically asymptomatic patients with early syphilis can have abnormal spinal fluids and that these changes are potential harbingers of symptomatic neurosyphilis predates the discovery of T. pallidum. Rabbit isolation studies in the 1920s and 1930s,1,149,263,264 since confirmed,150,151 established definitively that CSF abnormalities are the consequence of CNS invasion by T. palli dum during early syphilis. Studies using rabbit inoculation from this same period,263 also confirmed in the modern era,150,151 revealed that up to 25% of ostensibly normal CSF samples from patients with early syphilis can harbor T. pallidum. The cumulative incidence of CSF abnormalities in untreated early syphilis peaks at somewhere between 30% and 50% of patients during the first 12 to 18 months of infection.149,265

Asymptomatic neurosyphilis is defined by the presence of one or more CSF abnormalities (pleocytosis, elevated protein concentration, or reactive CSF Venereal Disease Research Laboratory [VDRL] test) in persons with serologic evidence for syphilis but no neurologic signs or symptoms

Asymptomatic CNS infection can follow three distinct, not easily predictable paths.185,258,266–268 In a substantial percentage of patients with either early or late syphilis, the abnormalities resolve spontaneously; in the remainder, they either persist without development of overt neurologic symptoms or worsen with the eventual appearance of a neurosyphilitic syndrome. Hence, the general trend over time is for asymptomatic neurosyphilis to decrease in frequency, due to either progression or resolution, while the proportion of symptomatic neurosyphilis increases

Accordingly, on the basis of examining more than 2200 patients, Merritt and colleagues149 maintained that the incidence of late asymptomatic neurosyphilis was in the vicinity of 10%, well below the peak values noted earlier for early syphilis. Several tenets about the complex relationship between asymptomatic and symptomatic neurosyphilis emerged from the preantibiotic era and continue to be useful today: (1) asymptomatic neurosyphilis is always the forerunner of meningeal, vascular, and parenchymatous syndromes; (2) asymptomatic neurosyphilis during late syphilis carries a worse prognosis than asymptomatic neurosyphilis during early infection; (3) the likelihood of progression from asymptomatic to symptomatic neurosyphilis increases in rough proportion to the degree of CSF abnormalities; and (4) if the spinal fluid remains normal during the first 2 years of infection, or if it is abnormal but reverts to normal, symptomatic neurosyphilis will not develop

Although the clinical importance of diagnosing asymptomatic neurosyphilis was well appreciated in the preantibiotic era, there was a diversity of opinion as to when lumbar puncture should be done,1 just as there is today.9,269 The Europeans, influenced by Ravaut, argued for later spinal fluid examination to avoid overtreating persons whose CNS infections were going to resolve spontaneously. Americans, led by Moore, advocated early examination of the spinal fluid to identify persons with severe CSF abnormalities (the so-called “paretic formula”) who would benefit from more intensive arsenical therapy. The issue faded into the background as it became evident that neurorelapse was uncom- mon in patients with early syphilis given intramuscular benzathine penicillin G (BPG). However, as discussed later, it has resurfaced in the HIV era as a result of numerous case reports suggesting that single-dose intramuscular BPG predisposes to CNS relapse in the absence of a fully competent immune system,215 along with clinical studies suggesting a higher prevalence of asymptomatic neurosyphilis among patients with early syphilis who are coinfected with HIV.270–272

Syphilitic meningitis typifies the ambiguity of syphilis staging for CNS disease because it is a true overlap syndrome, occurring as either an early or a late manifestation (see Fig. 237.5). Approximately 10% of cases occur in persons with a rash of secondary syphilis, and most occur during the first 2 years of infection. Even when meningitis is the sole presenting manifestation, more than half of patients recall having a chancre or a secondary syphilis rash, or both, an unusual occurrence in patients with parenchymatous syndromes. On the other hand, there are many documented instances of patients presenting with this form of neurosyphilis in late syphilis or in which it complicates late forms of neurosyphilis, or both.

Although headache and meningismus mimick- ing many other causes of aseptic meningitis are not uncommon in patients with secondary syphilis, the full-blown meningeal syndrome is rare, representing less than 10% of all cases of neurosyphilis.213 In their classic series, Merritt and Moore213 could find only 80 well-authenticated cases over a 15-year period in three general hospitals, and they estimated, on the basis of their survey of the literature, that it may complicate between 0.3% and 2% of early syphilis cases (probably an overestimate, even at the low end, in our experience).

In addition to signs and symptoms indicative of increased intracranial pressure (e.g., nausea, vomiting, headache), which occurred in nearly all cases, these authors distinguished three syndromic variants: (1) acute hydro- cephalus without focal signs unrelated to increased intracranial pressure; (2) meningitis of the vertex, presenting with seizures, focal neurologic deficits (e.g., hemiplegia, aphasia), and changes in sensorium; and (3) basilar meningitis with cranial nerve palsies, especially of nerves III, VI, VII, and VIII. Eighth cranial nerve involvement can be unilateral or bilateral and can affect either or both the acoustic and vestibular nerves.

The differential diagnosis is broad and includes viral causes of aseptic meningitis and meningoencephalitis; neuroborreliosis; tuberculous and fungal meningitis; parameningeal processes (e.g., abscess); and noninfectious processes such as sarcoidosis and carcinomatous men- ingitis. Reactive serologic tests for syphilis in blood and CSF, along with the subacute onset of signs and symptoms, help to distinguish meningeal syphilis from the numerous other infectious and noninfectious entities in the differential diagnosis

Meningovascular syphilis comprises those syndromes in which focal neurologic signs due to infarction are the dominant presenting feature.149

Like syphilitic meningitis, meningovascular syphilis represents an early-late overlap syndrome, although weighted more toward the late end of the temporal spectrum (see Fig. 237.5). The spinal cord, brainstem, or cerebrum may be involved separately or together, although the majority of patients in the large series by Merritt and colleagues149 had vascular syndromes referable to the middle cerebral artery. Accordingly, the most common focal findings were contralateral hemiplegia or hemi- paresis, homonymous hemianopsia, and aphasia. Recent case reports underscore the potentially catastrophic outcomes resulting from involvement of the posterior cerebral circulation.273,274

In the 42 cases reviewed by Merritt and colleagues,149 only 25% of patients gave a history of primary or secondary syphilis. These authors attributed 3% of their neurosyphilis cases at Boston City Hospital to meningovascular syphilis. This proportion is likely much lower than the current incidence. In a large series from India in which magnetic resonance imaging (MRI) was used, 11 of 35 patients were classified as having focal neurologic symptoms attributable to ischemia.262

The relatively young age of patients with meningovascular syphilis (30–50 years) helps to distinguish this syndrome from atherosclerotic stroke, hence the clinical dictum that a stroke in a young or middle-aged individual always should raise suspicions of syphilis. As with atherosclerotic stroke, onset may be sudden (“syphilitic apoplexy”). However, a substantial proportion of patients have prodromal symptoms, such as headache, vertigo, insomnia, irritability, and personality and behavioral changes, weeks to months before the thrombotic event. Merritt and colleagues149 attributed these affective and cognitive changes to the leptomeningeal component of the underlying pathologic condition. MRI showing significant cortical atrophy in many cases suggests that paretic-type changes are also contributory.262

In the series by Merritt and colleagues,149 only 5 of the 42 patients had neurologic deficits, suggesting involvement of more than one blood vessel. In recent case reports in which MRI and magnetic resonance angiography were used, however, imaging revealed diffuse and often bilateral involvement,257 as one might expect with a CNS vasculitis.

Meningovascular syphilis may also rarely involve the spinal cord, resulting in infarction of the anterior or, less commonly, posterior spinal arteries. In contrast to patients with involvement of cerebral vessels, the spinal variant lacks prodromal symptoms and is usually sudden in onset.

Because of its semiacute course and association with global alterations in cerebral function, meningovascular syphilis has to be differentiated from chronic meningitides, as well as rheumatologic causes of cerebral vasculitis, particularly systemic lupus erythematosus, Wegener granulomatosis, and polyarteritis nodosa, and, in patients with a history of genital ulcers, Behçet disease

The parenchymatous syndromes, general paresis and tabes dorsalis, the last to occur in the neurosyphilis temporal sequence (see Fig. 237.5), involve distinct, poorly understood, neurocytotoxic mechanisms in addition to the vascular-based inflammatory and ischemic changes that cause symptomatology in meningeal and meningovascular syphilis.185,258

In the preantibiotic era, these two syndromes (le tabès et la paralysie générale) accounted for one-half to two-thirds of all cases of neurosyphilis, and both were fourfold to sevenfold more common in men than women. As one indicator of how common they were, according to Stokes,1 paresis accounted for 11% of neuropsychiatric admissions in the United States and 5% to 7% of cases of mental disease in the French, German, American, and Russian armies

The virtual disappearance of tabes dorsalis, which is disproportionate to the decline in the incidence of paresis, is one of the most striking changes in the epidemiology of neurosyphilis. Because the American Association of Neurology no longer recommends screening for paresis as part of a routine dementia evaluation,275 it is important to maintain vigilance for this relatively rare but still encountered dementing illness. In case reports,276–279 and in the experience of the authors, a substantial degree of reversibility can be seen when paresis is promptly recognized and treated

Merritt and colleagues149 described general paresis as a chronic, spirochetal meningoencephalitis that severely disturbs the structure and function of the cerebral cortices, particularly the frontal and temporal lobes. In one of the largest case series in the postantibiotic era (from the United Kingdom), the interval between infection and admission varied between 4 and 41 years (mean, 21 years).280 The typical clinical picture is a slow, often insidious, onset of neuropsychiatric disturbances coupled with progressive deterioration in cognitive function. The presentation, however, may be abrupt. In the British series, the duration of symptoms varied between 24 hours and 5 years and approximately 20% of patients had seizures.280 As the disease worsens, patients experience loss of motor control to the point of paralysis along with worsening loss of bowel and bladder control. Untreated paresis is fatal.

The constel- lation of signs and symptoms can be remembered with the mnemonic PARESIS: personality (emotional lability, paranoia); affect (carelessness in appearance); reflexes (hyperactive); eye (Argyll Robertson pupils [Fig. 237.8])281; sensorium (illusions, delusions, especially megalomania, hallucinations); intellect (decreased recent memory, judgment, insight); and speech (slurred). The dramatic postmortem pathologic findings described by Merritt and colleagues149 have been demonstrated on a number of occasions in patients with MRI, now an essential tool for making the diagnosis.276,277,282,283 In several instances, subacute changes in personality and cognition in concert with temporal abnormalities at MRI have been confused with herpes encephalitis (Fig. 237.9).284–287 Kodama and colleagues276 concluded from a small series (n = 7) that mesial temporal lobe atrophy at MRI carries a poor prognosis for improvement after antimicrobial therapy.

The demyelinating process in the posterior spinal cords of patients with tabes dorsalis eventually results in the development of an ataxic, wide-based gait and foot slap; paresthesias; shooting or lightning pains (sudden onset, rapid radiation, and disappearance); bladder disturbances; fecal incontinence; impotence; loss of position and vibratory sense; absent ankle and knee jerk reflexes; and loss of deep pain and temperature sensation. The characteristic “lightning” or lancinating pains experienced by at least 75% of patients are usually present at the outset of the disease, typically affecting the lower extremities, and occurring episodically.

Some patients, 10% to 20%, experience visceral crises. In the most common gastric form, the individual experiences recurrent episodes of sudden, agonizing epigastric pain with nausea and vomiting that can last for days and mimic surgical emergencies. Intestinal, rectal, and laryngeal crises can also occur. Decrease or loss of tendon and patellar reflexes with preservation of muscle strength is a common, relatively early, neurologic finding. Ataxia was regarded as such a cardinal symptom of tabes that it was once called “progressive locomotor ataxy”; between 50% and 80% of patients exhibit a positive Romberg sign. Trophic degenerative joint disease, Charcot joints, and traumatic ulcers or sores on the lower extremities and feet resulting from the loss of proprioception and sensation were once prominently featured in textbooks.

Degenerative ocular changes are also common components of the tabetic syndrome. The Argyll Robertson pupil (see Fig. 237.8), although not limited to tabes or even syphilis, is a characteristic late feature.281 Primary optic atrophy occurs over a period of months to years, beginning peripherally and proceeding to the center of the nerve, producing progressive concentric constriction of the visual fields with retention of normal vision, referred to as “gun barrel” sight.288

Because of the likelihood that a CNS gumma will initially be mistaken for a tumor or other type of space-occupying lesion (e.g., toxoplasmosis in an AIDS patient), this entity well exemplifies the reputation of syphilis as the great mimicker.

The CNS gumma, the rarest form of neurosyphilis, was uncommon even in the preantibiotic era. In a review of 2203 brain tumors published in 1932, Cushing289 found only 12 cases, and Merritt and colleagues149 found only 5 well-documented cases over a 15-year span at the Boston City Hospital.

Merritt and colleagues149 considered gumma of the CNS to be a chronic, localized form of syphilitic meningitis that extends from the pia mater into the adjacent brain or spinal cord.

Ocular complications may occur as part of a neurosyphilis syn- drome, often asymptomatic neurosyphilis, or as an isolated manifesta-

Anterior or posterior uveitis or panuveitis, the most common abnormalities, can occur during either early or late syphilis (see Chapter 115).

The differential diagnosis includes tuberculosis, rheumatoid arthritis, sarcoidosis, toxoplasmosis, histoplasmosis, and ocular Tox oc ara canis infections. The presence of pupillary abnormalities distinguishes syphilis from these other processes.

Syphilis can cause hearing loss via two mechanisms during early or late infection. One is osteitis of the temporal bone with destructive changes in the membranous cochlea and labyrinth. The other is inflammation and atrophy of cranial nerve VIII, typically insidious and often bilateral.293

Merritt and colleagues149 found that 10 of their 80 cases of syphilitic meningitis had involvement of the acoustic or vestibular branches of the eighth cranial nerve, or both, whereas 57 of their 203 cases of tabes dorsalis had hearing impairment. Involvement of cranial nerve VIII typically begins with high-frequency hearing loss and progresses to a complete unilateral or bilateral loss of cochlear and vestibular function.294

Syphilitic labyrinthitis has been known to mimic Meniere disease. In the postantibiotic era, otosyphilis has become liberally defined as an unexplained sensorineural hearing loss in the presence of a reactive treponemal serologic test.295,296 As noted by Pletcher and Cheung,297 this definition lacks a clear causal relationship between syphilis and the clinical symptoms. Nevertheless, in such cases, treatment is usually indicated because there are no diagnostic measures that can reliably eliminate the possibility of syphilis

In the preantibiotic era, asymptomatic aortitis was considered to be highly prevalent; in fact, Moore298 maintained that the majority of patients with long-standing syphilis have subclinical aortitis undetectable on radiographs or at clinical examination.

Dilation of the proximal portion of the aorta and linear calcification of the anterolateral wall of the ascending aorta are suggestive radiographic signs.

Fibrosis of the media also contributes to the development of ostial stenosis and, rarely, can cause severe coronary occlusion even in the absence of dilation of the aortic root.301

aortic regurgitation, the most common complication of syphilitic aortitis

Surprisingly, syphilitic aneurysm is the least common complication, occurring only one-third as frequently as aortic insufficiency and producing clinically apparent, albeit often devastating, manifestations in only 5% to 10% of patients with aortitis

A recent case report emphasized the importance of considering syphilis in patients who present with aortic regurgitation and myocardial infarction.302 Syphilitic aneurysms are usually saccular, although they may be fusiform; because of the diffuse scarring in the aortic wall, they tend not to dissect (Fig. 237.10). Approximately 50% of aneurysms occur in the ascending aortic arch and have been designated the “aneurysm of signs” because they attain great size with few symptoms.

In a recent surgical series, Roberts and colleagues303 stated that the key to recognizing cardiovascular syphilis at surgery was the diffuse nature of the involvement of the tubular portion of the ascending aorta with complete or virtual sparing of the sinus portion. Aneurysm of the innominate artery is a rare complication of ascending aortitis.299,304 Next most frequently involved (30%–40%) is the transverse arch, designated the “aneurysm of symptoms” because of its location in proximity to a number of mediastinal structures.

The minority of aneurysms, 10% to 15%, occur in the descending arch; a small percentage occur below the sixth vertebral body or, even more rarely, below the thorax.305