Syphilis—Rediscovered

Syphilis -Rediscovered S I D N E Y OLANSKY

TABLE DEFINITION HISTORY"

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E I ' I DE.M IOI.OGY

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PATIIOGENESIS .

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L a t e n t Syphilis

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1'rimary Syphilis (Chancre) Secondary Syphilis

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C L I N I C A L STAGES O F S Y P I I I L I $

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Congenital Syphilis . . . . . . . . . . . . . . .

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Neurosyphilis

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Cardiovascul,'ir S y p h i l i s

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Late Benign Syphilis (Gumma) SERODIAGNOSlS

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TrepoIlemal Antigen Tests U S E O F S T S T O A I D 1N D I A G N O S I S IN SPINAL FLUID

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L a t e n t Syphilis

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PROGNOSES O F S Y P I n L I S

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TREATMENT

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Nontrepollenlal Antigen Tests

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C A U S A T I V E ORGANIS.XI

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Late Benign Syphilis (Gumma) Cardiovascular Syphilis

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Neurosyphilis . . . . . . . . . . . . . . . . .

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C o n g e n i t a l Syphilis . . . . . . . . . . . . . . .

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is Chief, Section of Dermatology, Emory University School of Medicine. Born in Boston, Massachusetts, he received his B.S. degree from New York Universlt)' and his M.D. from Glasgow Universit)', Scotland. Dr. Olansky is a member of the American Academy of Dermatology and Syphilology, the American Dermatological Association and the American VD Association, of ~r he was l'rcsidcnt for two terms. For the )ear 1967 he is Chairman of the I)ermatology Section of t heSouthern .Medical Associat ion.

IN T H E EARLY 1950s, it was believed by most physicians that s)'philis was controlled and that it should be relegated to the group of historical diseases. Reported cases of earl)' syphilis reached a low of 6,399 in 1956, but by 1964 they had increased fourfold to a total of 22,969. Much of this increase occurred in "teenagers." Undoubtedly, many cases are not reported, so that reliable sources estiinate the actual number of cases ill 1964 to be more titan 120,000 (1). During this period many stvdents were graduated from medical schools without seeing any cases of early syphilis and with no knowledge of the disease of any sort. Many of these young physicians now must rediscover syphilis, or perhaps discover it for the first time, since once again it has become a serious problem. DEFINITION

Syphilis is an infectious disease caused by tile spirochete Trelmnema pallidum. It is transmitted by intimate contact with lesions of early (primary or secondary) syphilis or prenatally. Syphilis is systemic from the onset but is distinguished by florid manifestations in its early stages, followed by )'ears of asymptomatic latency, and finally by a late

period when serious crippling effects may occur. Any organ can be involved during its course (2). HISTORY Much controversy exists regarding the origin of syphilis. One theory maintains that Columbus and his sailors brought it back from the New World and spread it through Europe on their return. This would have been a remarkable feat-for so few to have spread so much disease so far so quickly. Another theory is that the disease came from Africa, where endemic nonvenereal syphilis existed well before Columbus. Urbanization converted a nonvenereal endemic disease to a venereal one. Tile latter then could have been carried home to Europe by traders, etc., who visited these countries. T h e controversy will probably never be resolved, but it is known that an epidemic of syphilis swept over Europe from 1493 to 1497. In a very short period in the early part of the twentieth century, from 1905 to 1910, Schaudinn and Hoffman discovered the causative organism of syphilis--Treponema pallidum; XVasserman introduced his complement fixation test for syphilis; and Ehrlich introdnced arsphenamine for the treatment of syphilis. Tile syphilis control program in the United States really began in 1938 under the leadership of Dr. Thomas Parran. Because of this, tile upsurge of syphilis associated with World War II was largely contained. Syphilis reached its peak incidence in 1947, followed by a rapid decline through 1954. This reduction was primarily due to the effectiveness of penicillin therapy in syphilis. Since 1959, the reported cases of early syp!lilis began to rise appreciably and have continued.

EPIDEMIOLOGY Venereal diseases are diseases of young people. Approximately one-half of all cases have their onset between the ages of 15 and 24.

In the United States it is believed that the prevalence of syphilis is equal in males and females, but twice as many cases are reported in males as in females. This is believed due to the more apparent symptoms in the male during the primary stage. For example, in the United States in March, 1963, 3.8 male cases of primary syphilis were reported for each female, but the ratio was 0.9:1.0 in the secondary stage. Syphilis has usually been considered to be primarily a disease of the lower socioeconomic groups, but recent figures indicate that this is not so. T h e increase has been mostly in the u p p e r socioeconomic classes among teenagers. Underreporting in the higher economic classes makes it very difficult to establish the real incidence in this group. CAUSATIVE ORGANISM

T r e p o n e m a palliduxn is a thin, spiral organism ,t-10 /~ in length, about the diameter of a red blood cell. It has tight coils which vary from 6 to 14 in number. Its movement consists of three elements: (1) u n d u l a t i o n of the center, with the ends relatively fixed; (2) a corkscrew-like rotation; and (3) propulsion. T h e organism can be visualized with a dark-field microscope, using serum from primary or secondary lesions or lymph node aspirates. T. pallidum has not yet been successfully c u h u r e d on artificial media. PATHOGENESIS

W h e n an individual is exposed to and infected with syphilis, a certain n u m b e r of T. pallidum organisms pass through the skin and enter tile blood and lymphatics. These multiply locally at the site of inoculation as well as in the bloodstream and lymphatics. T h e host tissue reaction at tile inoculation site results in an infiltrate of lymphocytes and plasma cells in the perivascular areas and endothelium of blood vessels. This results in obliteration of vessels and leads to the chancre, usually on the average of 21 days after exposure (3). At this

time, the serologic tests for syphilis (STS) are nonreactive but a dark-field examination is positive (seronegative primary syphilis). The STS become reactive within 1 week of the appearance of the chancre. The chancre heals spontaneously within 3 to 4 weeks. The organisms in the bloodstream multiply, and the invoh, ed tissues react in a manner similar to the chancre to produce secondary lesions about 6 to 12 weeks after the chancre. The STS are always reactive in this stage anti the Secondary lesions are also dark-field positive. Secondary lesions also heal spontaneously in 4 to 12 weeks. Latency follows healing of the secondary lesions and may persist for life in approximately 75% of patients. In the others, serious or troublesome complications occur in the form of neurosyphilis, cardiovascular syphilis and benign tertiary syphilis (gumma). Approximately one-third of the latent group will eventually become nonreactive in the STS and the rest will remain reactive but clinically well (4-6). IMMUNITY There is no evidence to support the presence of natural imlnunity to syphilis. Immunity can be induced by infection. The duration of imnnmity is dependent on the duration of tile untreated disease. If adequate treatment is administered during the earl)' phases of syphilis-i.e., primary or second a r y - immunity is short-lived and the patient may be reinfected, with little aheration in the clinical expression of the disease. If treatment is given after latency is well established or if the patient remains untreated, considerable immunity to reinfection may remain (7). CLINICAL STAGES OF SYPHILIS Early syphilis includes primary and secondary syphilis and latent syphilis under 2 years' duration. Primary and secondary syphilis are definitely infectious, and latent syphilis under 2

years' duration is potentially so, since infectious relapse is possible during this period. Also, the infected pregnant female may infect her offspring (luring this period. Primary and secondary syphilis and early latent syphilis are the most important stages to recognize and treat. If all of these are recognized and brought to treatment, the public will be protected from infectious syphilis, the patient will have the best chance of cure and serious complications of syphilis can be virtually eliminated. Fzc. l.--Primary syphilis with satellite bubo.

Late syphilis is syphilis of more than 2 years' duration, It may be latent o r symptomatic. Symptomatic late syphilis can be divided into neurosyphilis, cardiovascular syphilis or benign tertiary syphilis (gumma).

P~I~rARV SVr.I•IS (CI~,X,XCRr) Primary syphilis (8) is tile initial clinical expression of the disease. It develops at the site of the first contact with an infectious lesion, and it appears approximately 3 weeks after infection (see Figs. 1 and 2). T h e chancre tends to be single, but may be multiple if the infected individual had been exposed to several infectious lesions at essentially the same time. It is usually painless and usually presents as an eroded papule. T h e chancre is accompanied by a "satellite bubo"-a discrete, rubbery, painless lymph node in the drainage area of the chancre. Chancres may occur anywhere. W h e n they are seen in the Fro. 2.--Periurethral chancre.

anogenital region, the index of suspicion is high and they are usually diagnosed accurately. W h e n they occur extragenitally, they may be overlooked. Chancres have been seen on the finger, toe, breast, lip, axilla, tonsil, tongne, umbilicus and eyelid. Ahhbugh the classic lesion is an eroded papule, chancres may present as ulcers, erosions, etc. Indeed, any lesion in the anogenital region should be suspect. Tile satellite bubo may be beyond our ability to feel it (e.g., anal or cervical chancre), and thus may appear to be absent. A diagnosis of primary syphilis is made by demonstrating T. pallidum from the lesion by dark-field examination. Darkfield examinations of oral lesions are not reliable, since common mouth spirochetes may be confused with T. pallidum. If a lymph node is present in the neck, a dark-field examination of an aspirate from the node can prove the diagnosis. In primary syphilis, STS may be reactive or nonreactive, depending on the duration of the lesion. If the lesion has been present a week or longer, the STS will usually be reactive. Details of the STS will be discussed later. W i t h proper treatment, a chancre will heal in 1 week; but without treatment, it will heal in 4 to 8 weeks. DIFFERENTIAL DIAGNOSIS.- Chancre must be differentiated from all penile lesions. T h e more important o[ these are 9 chancroid, granuloma inguinale, herpes progenitales and carcinoma. In none o[ the above will the dark-field examination be positive. SECONDARY SYPIIILIS Secondary syphilis is tile most contagious stage because of the multiplicity of infectious lesions. Usually there is a latent period between the primary and secondary stages of syphilis, but in some instances secondary lesions appear while the primary lesion is still present. Constitutional symptoms may precede or accompany the secondary lesions: headache, malaise, anorexia, fever, sore throat or adenopathy.

(ahove)--Secondary syphilis--iritis. Flo. 4. (below)--Secondary syphilis--moth-eaten alopecia. F~o. 3.

Tile signs of secondary syphilis may be quite variable. They consist of eruptions which may be limited or extensive, adenopathy which may be generalized, mucosal lesions o[ the mouth or throat, iritis, or alopecia (see Figs. 3-8). 10

FIG. 5. (above)--Secondary syphilis--mucous patches. FIG. 6. (below)--Secondary syphilis--annular lesions. 1]

Fro. 7. (above) --Secondary syphilis--condylomatalata. FIG. 8. (below)--Secondary syphilis--palmarlesions. 12

The eruption varies greatly but is usually papular or papulosquamous except ill moist or intertriginous areas, where it is condylomatous (flat, moist papules) (see Fig. 7). The eruption is not pruritic. It is indolent and may remain for months if untreated. The characteristic lesion in the oral mucosa is the mucous patch (see Fig. 5). This is gray-white surrounded by a red areola. It may occur anywhere in the oral cavity, pharynx, or larynx and is usually painless. Iritis may be part of the secondary syndrome (see Fig. 3). It produces photophobia, lacrimation and red painful eyes and is generally associated with secondary lesions elsewhere. Hepatitis and jaundice may be part of the secondary stage, usually responding well to antisyphilis treatment. T h e central nervous system may be invaded during the secondary stage, giving rise to acute syphilitic meningitis. Alopecia of the moth-eaten type may be part of the secondary stage (see Fig. 4). It invoh'es the scalp usually but may involve eyebrows, beard and eyelashes. The most infectious lesions of the secondary stage ot? syphilis are the condylomata lata and mucous patches (see Figs. 5 and 7). DIFFERENTIAL DIAGNOSls.--The eruption must be differentiated from measles, rubella, drug eruptions, pityriasis rosea, lichen planus, psoriasis and others. Secondary syphilis may be diagnosed with a positive darkfield examination and a reactive STS. The STS a r e ahvays reactive in secondary syphilis, but a positive dark-field examination is essential to establish the diagnosis unequivocally. It is possible for an individual to have latent syphilis and a rash which may be unrelated. LATENT SYPHILIS

Latent syphilis is hidden syphilis or laboratory syphilis. It is the stage of syphilis where the physical examination is entirely within normal limits for signs and symptoms of syph13

ilis, but the STS are reactive and a spinal fluid examination is negative. Arbitrarily, latent syphilis is divided into early (under 2 .)'ears' duration) and late (over 2 years' duration). It is sometimes difficult to establish the true duration, since patients may not know or may intentionally mislead. With routine STS testing required in so many areas, it is usually possible to determine that the patient did or did not have a reactive STS during a pre-employment examination, admission to a university, etc., and thus have some idea of the duration of the seroreactivity. CONGENITAL SYPHILIS Congenital syphilis had practically disappeared since 1957 but with the resurgence of acquired syphilis is coming to our attention again with a few case reports. For this reason a short discussion of congenital syphilis seems proper. Syphilis may he transmitted from the expectant mother to the fetus via the placenta. If syphilis in the mother is less than 2 years old and she has not been treated, the incidence of congenital syphilis will be extremely high. If the disease is of more than 2 )'ears' duration, even though untreated, the incidence of congenital syphilis will be extremely low. Tile outcome of pregnancy in an untreated syphilitic naother may be (a) a normal child, if the mother's infection is over 2 years old; (b) a miscarriage, if the mother's disease is very early; (c) fetal death and stillbirth, if the mother's disease is very early; (d) a child born with manifestations of early congenital syphilis, if the mother's disease is very early; or (e) the child may appear well but have a reactive STS if the mother's disease is close to but less than 2 years old. Signs of early congenital syphilis are marasmus, snuttles (a mucoid bloody discharge from the nose), condylomata lata, various eruptions (some of which may be bullous), radiate lesions around the m o u t h and arms, osteochondritis, pseudoparalysis, dactylitis and laepatosplenomegaly (see Fig. 9). 14

Ftc. 9.--Early congenital syphilis, showing snuffles and radiate lesions at the angles of the mouth. T i l e general appearance is that of a little, emaciated old man. Diagnosis is made by dark-field examination and STS. A dark-field may be obtained from condylomata lata, skin lesions or scrapings from the umbilical cord. LATE CONGENITALsYvIIXLIs.--Certain stigmata are present in some late congenital syphilitics who are untreated. T h e s e are 15

(a) frontal bossing, (b) saddle nose, (c) Hutchinson's teeth, (d) Moon's molars, (e) interstitial keratitis, ( f ) e i g h t h nerve deafness, (g) saber shins, (h) Clutton's joints, (i) neuro~yphilis. Any or all or none of the above may result in the untreated congenital syphilitic. Some merely have a reactive STS which may persist for life. NEUROSYPIIILIS Tile incidence of neurosyphilis has decreased since penicillin therapy became the established therapeutic agent for syphilis. In the prepenicillin days, arsenic and bismuth were not effective in the treatment of neurosyphilis and the latter required special treatment such as fever therapy or malaria therapy. Since tlle advent of penicillin, however, all syphilis is effectively treated with this single agent. In most instances the dose used is adequate in controlling neurosyphilis, so that there has been less tendency to perform spinal fluid ex,'uninations, which are essential to a diagnosis of neurosyphilis. Therefore, diagnoses of neurosyphilis are made less frequently but the incidence may be the same. Invasion of the central nervous system occurs during the primary or secondary stages of syphilis and happens in about 25% of cases. This was determined by doing spinal fluid examinations before therapy in groups of patients with primar)" and secondary syphilis. About 25~o of these had abnormal spinal fluid findings. If untreated, about 50~o of these will develop neurosyphilis later on. If treated, none or very few will do so (9). Nenrosyphilis is classified as: (1) Asymptomatic: abnormal spinal fluid findings with no signs or symptoms of neurologic disease and (2) Symptomatic: (a) Meningovascular: signs and symptoms o[ meningeal and vascular involvement. The signs and symptoms depend on the site and extent of involvement and may produce 16

evidence of increased intracranial pressure, cranial nerve palsies or evidence of throinboses. (b) Tabes dorsalis: The posterior columns and roots of the cord degenerate. The major symptoms are ataxia, lighming pains, visceral crises, diplopia, bladder disturbances, impotence and visual difficulty. The major signs are extraocular palsies, pupillary changes, loss of reflexes, diminution or loss of vibration sense, Romberg's sign, ataxia andsensory loss. Tabes dorsalis usually develops very late, 20 or more years after infection. Frequently the STS in the blood and spinal fluid are nonreactive by tile time the syndrome is obvious. (c) General paresis is due to invasion of the brain by spirochetes. Mental symptoms may mimic psychoses with insidious onset of headache, insomnia or weight loss, and proceeding to the classic mental states of dementia, euphoria, grandiose ideas, mania, depression and agitation. Neurologic signs are variable. Pupillary changes are common-irregularity and inequality-as are speech difficulties. Untreated paresis usually goes on to death, but treatment, especially early treatment, can bring about essential cure. Permanent damage, of course, cannot be reversed, and many paretics survive but remain mentally incompetent. The spinal fluid in paresis shows pleocytosis, increased protein and reactive STS. After treatment, the pleocytosis antl increased protein may return to normal in 6 months to 2 years, but the STS may remain reactive for many years. The pleocytosis and protein increase reflect activity: when they are normal, the process is no longer active. CARDIOVASCULAR SYPHILIS Cardiovascular syphilis (10) usually involves the thoracic aorta and sometimes its major branches. Although precocious forms are encountered, it may take 15-20 years or more to become evident. It is the most incapacitating and fatal form of syphilis. 17

T h e incidence of cardiovascular syphilis in untreated disease is estimated at 10-15% of cases. Cardiovascular syphilis is very rare in congenital syphilis or when syphilis is acquired early in life. Simple aortitis is very difficult to detect, b u t presumably treatment at this stage prevents it from becoming complicated. It is usually detected radiologically, which may reveal minimal dilatation of the ascending aorta or calcification. W h e n complications do occur, they usually present as angina pectoris, aortic regurgitation or aneurysm. T h e complications occur 10-20 years after infection. Angina pectoris results from coronary ischemia and is usually caused by atheroma of the coronary arteries, but in about 10% of the cases is due to syphilitic aortitis producing narrowing of the coronary ostia. In patients over 40 years of age, both atheroma and aortitis may coexist. Aortic regurgitation results usually from stretching of tile aortic ring by dilatation of the aorta, although the syphilitic process may extend from the aorta to the valve leaflets and commissures and contribute to the aortic insufficiency. T h e aortic valve becomes incompetent, producing the characteristic diastolic murmur. Aortic regurgitation may be rheumatic, atherosclerotic or due to bacterial endocarditis. Aortic regurgitation in a person under 30 is usually rheumatic and in one over 30 is more likely due to syphilis. Aneurysms of the aorta may result from syphilitic aortitis or atheroma. Syphilitic aneurysms may b e fusiform or saccular. Fusiform aneurysms are usually not symptomatic, but saccular aneurysms are. Saccular aneurysms of the ascending aorta project forward and may present as swellings with expansile pulsation on the chest wall. Saccular aneurysms of the transverse arch produce pressure symptoms and those of the descending aorta point backwards and produce erosions of the vertebrae visible by x-ray. Aneurysm may produce engorgement of the veins of the head, neck and chest from compression of the superior vena 18

cava; edema of the right arm from compressions of the subclavian vein; edema of the legs from pressure on the inferior vena cava by the displaced heart; hoarseness and brassy cough-from involvement of the recurrent laryngeal nerve; diminished aeration of tlle right lung with paroxysmal dyspnea; and stridor and dysphagia from pressure on the trachea and esophagus. Other manifestations of cardiovascular syphilis may occur, though very rarely. These are subacute bacterial endocarditis, gumma of the myocardium and aneurysms of other major vessels (innominate, carotid). T h e diagnosis of cardiovascular syphilis rests on a constellation of signs, symptoms and serology. Since cardiovascular syphilis becomes manifest late (10-20 years) after infection, the STS are reactive in only 80-95~o of cases when the nontreponemal tests are employed. Usually the FTA-ABS test or the T P I test is reactive in cardiovascular syphilis, but in a few instances even the T P I test may be nonreactive. T r e a t m e n t of cardiovascular syphilis consists of good cardiac management and the proper penicillin schedule, if the patient has not been previously treated and there is no history of penicillin sensitivity. LATE BENIGN SYPHILIS (GuMMA) MOSt authorities agree that gumma is a hypersensitivity reaction to T. pallidum. There are three essential differences between lesions of early and late benign lesions: (I) G u m m a contains few spirochetes which are difficult or impossible to demonstrate, whereas spirochetes are simple to demonstrate in early lesions. (2) Proliferative changes, giant cells and necrosis are conspicuous in g u m m a and not in early lesions. (3) Gumma is destructive; early lesions a r e n o t . T h e source of spirochetes which produce gumma has been assumed to be a walled-off focus activated by injury or other disease (intrinsic theory). 19

In a human inoculation study (7), it was demonstrated that the spirochetes may be extrinsic and that gumma, particularly in the anogenital area, may represent new infection in a previously sensitized individual (extrinsic theory). On tile skin, gumma appears in three forms: (1) nodular-reddish to flesh-colored nodules which may occur anywhere on the skin. They are painless, develop slowly, and tend to be grouped in a circular or polycyclic arrangement (see Fig. 10). On healing, hyperpigmentation and thin cigarette-paper scars may remain; (2) nodulotdcerative-when nodules ulcerate (see Fig. 11); (3) ulcerative lesions present as painless subcutaneous tumors, which may be single or multiple (see Fig. 12). As the swelling increases in size, the skin over it becomes dull red and breaks down to form a punched-out Fir,. 10.--Tertiary syphilis--nodular lesions resembling tinea corporis.

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Fxo. 11. (above)--Tertiary syphilis--noduloulcerative lesion of the classic type. Fio. 12. (below) --Tertiary syphilis--ulcerative lesion. 21

ulcer. This type occurs frequently on the leg, scalp, face and sternum. On healing, there is a thin, noncontractile scar surrounded by hyperpigmentation. STS are always positive in patients with an active gumma. DIFFERENTIAL DIAGNOSIS.- Gumma must be differentiated from tuberculosis, leprosy, sporotrichosis, blastomycosis, tinea corporis, varicose ulcers, sickle cell ulcers and some lymphomas. Diagnosis may be difficult, and at times a therapeutic trial may be necessary to establish the diagnosis. Gumma may involve many of the viscera. Details of the diagnosis of these may be found in standard textbooks (8,11-13).

SERODIAGNOSIS (14) When an individual is infected with syphilis, the host is invaded by T. pallidum, which stimulates the production of multiple antibodies. These are of two basic types: (1) antibodies to T. pallidum and (2) antibodies resulting from the interaction of T. pallidum with tissues, called reagins. Tests for antibodies to T. pallidum are called treponemal antigen tests, and those measuring reagins are called nontreponemal antigen tests. The latter utilize antigens derived from extracts of tissue such as beef heart. The former employ antigens uslng the T. pallidum itself or some fraction of T. pallidum. NONTREPONEMAL ANTIGEN TESTS The nontreponemal antigen tests are of two types: flocculation test and complement fixation test. The most commonly used flocculation test is the VDRL (Venereal Disease Research Laboratory) slide test. The most commonly used complement fixation test is the Kolmer test. The nontreponemal tests are not absolutely specific for syphilis antibodies but have the advantages of being practical, inexpensive and widely available. The nontreponemal tests 22

may be performed qualitatively and reported as reactive, weakly reactive or nonreactive. Quantitative tests, however, are m u c h more informative. T h e y are made by diluting the serum in geometric progression and testing until the serum is no longer reactive. Quantitative results are reported as an end point titer-e.g., reactive 1:16 means the serum was reactive at a dilution of 1:16 but nonreactive at a dilution of 1:32. T h e dilutions are often reported as dils. T h e previous example might be reported as 16 dils. Quantitative tests are extremely helpful because they es. tablish a baseline of reactivity from which change may be measured. If the patient has early disease, the titer will most likely rise on subsequent tests. If the patient has received treatment for early syphilis, the titer will decrease on subsequent testing. However, if the disease is old, the titer will remain unchanged on subsequent testing whether the patient is treated or not. TREPONEMAL ANTIGEN TESTS T h e treponemal antigen tests are more specific than the nontreponemal tests. T h e first of the treponemal tests, the T P I (Treponema Pallidum Immobilization) test uses live T. pallidum obtained from testicular syphilomas of rabbits as the antigen. In the presence of complement, syphilitic serum immobilizes the spirochetes and nonsyphilitic serum does not. Since the T P I antibody develops more slowly than reagin, the T P I test is less sensitive in early syphilis than are the nontreponemal tests in early syphilis. A serum of a patient with primary syphilis could be reactive with the V D R L test but nonreactive with the T P I test. T h e T P I test is very expensive and very difficult to perform. This has led to the development of other treponemal tests using dead T . pallidum or nonpathogenic, cultivatible P, eiter Treponema as the antigen. A protein fraction from the lZeiter Treponema has been incorporated in a complement fixation test that is based on 93

tile Kolmer procedure. This test is called tile Reiter protein complement fixation (RPCF) test. Although the specificity of the R P C F test is good, the sensitivity has been found to be low and the test is being used much less frequently. T h e FTA-ABS test (15) (Fluorescent T r e p o n e m a l Antibody Absorbed) is the newest and probably the most useful of the treponemal tests. In this test the patient's serum is overlaid on T . pallidum that has been fixed to a slide. Fluoresceintagged a n t i h u m a n globulin is then overlaid on the serum. If antibodies are present, fluorescent spirochetes can be seen u n d e r ultraviolet light. T h e treponemal antibodies adhere to the T. pallidum, and in turn the a n t i h u m a n globulin (fluorescein tagged) adheres to the h u m a n antibodies. If no treponemal antibodies exist in the serum, there is no fluorescence and the test is nonreactive. T h e ABS in this test refers to tile fact that an antigenic extract of Reiter T r e p o n e m a has been added to the serum to be tested previous to testing. This absorbs and removes antibodies common to the group T r e p o n e m a t a . Thus, presumably only those antibodies that react with antigens specific for T . pallidum remain. Recent large-scale testing supports the fact that the FTA-ABS is more sensitive than, and at least as specific as, the T P I test (16).

USE OF STS TO AID IN DIAGNOSIS In a patient with clinical syphilis or a good history of syphilis, tile routine STS leave nothing to be desired and other tests are unnecessary. In the absence of definite clinical or historic evidence of syphilis, a reactive STS requires further investigation before a diagnosis can be made. This may represent (a) latent syphilis treated, inadequately treated, or untreated; or (b) a biologic false positive reaction (BFP). Biologic false positive reactions may be divided into "acute" or "chronic" reactions. Certain febrile illnesses such as viral infections or smallpox vaccination or other immunization may produce a reactive STS in some people which lasts for 24

a short time, then reverts to nonreactive some time after tile illness ceases or the reaction to immunization subsides. T h e s e are "acute" BFP reactions. Quantitative STS will reveal a reducing titer or return to nonreactivity in 6 weeks to 3 months. Chronic BFI' reactions are more persistent and present a greater diagnostic problem. T h e titer is generally low, in the range of weakly reactive to reactive 1:2 to 1:4. However, the titer may be higher, and this fact alone does not rule out a chronic BFP reaction. Chronic BFP reactions have preceded or accompanied a u t o i m m n n e or collagen disease such as lupus erythematosus. Leprosy has been associated with a very high incidence of BFP reactions. A useful plan for distinguishing BFP reactions from true syphilitic reactions is as follows: I. Check for results of STS reactions that may have been made previously. 2. R e p e a t the STS quantitative, and re-examine and requestion the patient. 3. If the repeat STS is nonreactive, the likelihood of syphilis is remote. 4. If the repeat STS shows a significant rise in titer, it may mean syphilis or an acute BFP reaction. 5. If the repeat STS does not show a rise in titer, an F T A ABS test should be done. If tiffs is nonreactive, the diagnosis is a BFP reaction; if reactive, the seroreaction is due to syphilis.

STS IN SPINAL FLUID Neurosyplfilis cannot be accurately diagnosed without a spinal fluid examination. BFI" reactions in spinal fluid are extremely rare. T h e STS commonly done on spinal fluid are the V D R L tube test and the Kolmer c o m p l e m e n t fixation test. Both tests are equally reliable, but the V D R L can be accomplished m o r e quickly without overnight incubation. A reactive STS in tile spinal fluid means that the CNS has been 25

invadcd by syphilis. Whether the disease is active or not in the CNS is reflected by the results of the cell count and total proteins. A cell count of more than 10 cells a n d / o r total .protein of more than 40 rag./100 ml. indicates active disease. If the CNS disease is syphilis, it will be associated with a reactive STS in the spinal fluid. Neurosyphilis may become inactive as a result of time or therapy, and when tiffs happens the cell count and proteins return to normal but the STS may remain reactive for naany )'ears. In tabes dorsalis, a syphilitic neurologic disease, the symptoms aml signs often appear many )'cars after infection. It is possible to have completely nonreactive STS in blood and spinal fluid in tabes dorsalis. In this circumstance, an FTAABS might well still be reactive and support a diagnosis of tabes dorsalis rather than other neurologic diseases which might resemble it, e.g., pseudotabes of diabetes. TREATMENT

Penicillin remains tile most effective therapy for all stages of active syphilis. If there is a history of allergy to penicillin, alternate antibiotics may be used. T h e aim in the treatment of syphilis is to maintain a treponcmicidal dose of penicillin for 10 to 14- days. This can be accomplished with varying dosage schedules depending on the penicillin preparation used. It has been determined that a concentration of 0.03 t,g./100 nil. maintained for 10 to 14 days is adequate, and there is 11o evidence of any resistance of the T. pallidum to penicillin. T h e following penicillin schedules represent adeqnate therapy: (A) Treatment of primary, secondary and latent syphilis with negative spinal fluid examination: (1) 2.4 million units of Benzathine penicillin (Bicillin) given in one treatment session. (2) 600,000 units of Procaine penicillin G a day for 8 consecutive d a y s - a total of 4.8 million units. (B) Latent syphilis when spinal fluid is not examined, 26

neurosyphilis, cardiovascular syphilis or late benign tertiary syplfilis (gu,nma) : (1) Be,~zathine penicillin G, 2.,t million units at weekly intervals for 3 to 4 weeks. (2) Procaine penicillin G, 600,000 units daily for a total of 6 to 9 m!lliou units. (C) Congenital syphilis: E a r l y - u p to 2 )'ears: 100,000 units of Procaine penicillin G per kilogra,n total close, given in closes of 10,000 units per kilogram daily for I0 days. L a t e - o v e r 2 years--same as aduh. It is very important to treat syphilis when it is early because we can best protect the public and the patient in that way. T r e a t m e n t in the early stages will prevent the late co,nplicatious which are so difficult to manage. In the patient who is allergic to penicillin, alternate antibiotics must be used. Schedules for these are as follows: (A) Primary, secondary and latent syphilis with negative spinal fluid exalnination: (I) Erythromycin, 20 to 30 Gin. (total) in equal divided doses for I0 days. (2) Tetracycline, 30 to ,10 G,n. (total) in cqual divided doses for 10 days. (B) Latent with no CSF examination, laeurosyphilis, cardiowlscular syphilis and late benign syphilis: These drugs have not been adequately evaluated in these stages, anti the recomlnendation is to use tile dosage as above for double the duration. Management for the pregnant woman with syphilis is the same as that for the nonpregnant woman. If she has been adequately treated and shows satisfactory clinical a n d / o r serologic response, there is no need for further treatment. However, if there is any question of adequacy of treatment or of reinfection, the patient must be retreated, since congenital syphilis is preventable or best treated while the fetus is in ntoro. 27

PROGNOSES OF SYPHILIS

EARLY SYPIIILIS Modern treatment of early syphilis restdts in cure in more tllan 95~o of cases. T. pallidum disappear from the lesion within 24 hours of beginning treatment and lesions heal promptly. About 98% of the cases of primary syphilis will become seronegative after adequate treatment and about 90~o of those treated during the secondary stage. Treatment is so effective that these patients are left with little or no immunity and can be reinfected, if subseqttently exposed. LATENT SYPtlILIS Latent syphilis also has an excellent prognosis in that progrcssion following adequate treatment has been reported only rarely. LATE BENIGN SYPIIILIS (GUM.XlA) In gt,mnm (benign late syplfilis), tile prognosis is excellent, as regards healing and the absence of progression, but the destruction which has already occurred cannot be undone. The incidence of seroresistance (persistance of reactive STS) ill the treatment of late syphilis is very high. The STS will remain reactive in more than 50% of these for many years and perhaps for life despite adequate therapy. Quantitative STS is very helpful here, since the serologic titer will be no higher than that obtained before therapy was instituted and usually is lower. CARDIOVASCULAR SYPItILIS The prognosis is very good in uncomplicated aortitis, but in aortic regurgitation and aneurysm it will depend on the cardiac status and management. 28

NEUROSYPI[ILIS T h e o u t l o o k depends on h o w m u c h d a m a g e has o c c u r r e d before therapy is begttn. T h e disease can be stopped in paresis, b u t t h e - e n d result will d e p e n d o n h o w m u c h irreversible d a m a g e preceded the therapy. Prognosis as to life is g o o d and represents one of the ironies of penicillin therapy. I n the prepenicillin era, paretics frequently died as a result of tlte disease. N o w m a n y are kept alive b u t are d e m e n t e d , and the cost of m a i n t a i n i n g these people in institutions for 20 or m o r e years is p h e n o m e n a l . T h e prognosis in tabes dorsalis is poor. By the time tabes is symptomatic, it is usually too late for penicillin to do m u c h good, a l t h o u g h it s h o u l d be administered.

CONGENITAL SYPIIILIS T h e prognosis in early congenital syphilis treated within the first 6 m o n t h s o[ life is excellent. I n late congenital syphilis, prognosis depe,xds on the existing damage,

REFERENCES I. Brown, W. J.: Role of public health and private medicine in eradication of syphilis, M. Clin. North America 48:573, 1964. 2. Stokes, J. tI., Beerman. II., and Ingraham, N. H., Jr.: Modern Clinical Syphilology (3d ed.; Philadelphia: W. B. Sat|riders Company, 19t4). 3. Willcox, R. R.: Textbook of l'enereal Diseases aTtd Trepolwmatoses (2d ed.; Springfield, Ill.: Charles C Thomas, Publisher, 196-t). 4. Clark, E. G., and Danbolt, N.: The Oslo study of the natural history of untreated syphilis, J. Chron. Dis. 2:311, 1955. 5. Gjestland, T.: The Oslo study of untreated syphilis, published as a supplement of Acta dermato-venereologica, 1955. 6. Olansky, S., llarris, A., and Price, E. W.: Untreated sypl,ilis in ttre male Negro. Twenty-two )ears o[ serologic observations in a selected syphilis study group, Arch. Dermat. 73:516, 1956. 7. Magnuson, tl. J., Thomas, E. W., Olansky, S., Kiplan, B. I., DeMello, L., and Cutler, J. C.: Inoculatiott syphilis in human volunteers, Medicine 35:38, 1956. 8. Kampnteier, R. It.: Essentials o[ Syphilology (Philadelphia: J. B. Lippincott Company, 1944). 29

9. Dattner, B., Tho,uas, E. W., and Wexler, G.: The Management o] ,Veu~o. syphilis (New York: Grune g: Stratton, Inc., 1944). 10. Kampmeier, R. If.: The late manifestations of syphilis: skeletal, visceral, and cardiovascular, M. Clin. North America 48:667, 1964. 1I. Thomas, E. W.: Syphilis: Its Course and Management (New York: T h e Macmillan Company, 1949). 12. King, A., and Nicol, C.: I'enereal Diseases (Philadelphla: F. A. Davis Company, 196t). 13. King, A.: Recent Advances it~ l'enereology (Boston: Little, Brown & Company, 196t). 14. Olansky, S., and Norins, L. C.: Current scrodiagnosis and treatment of syphilis, J.A.M.A. 198:165, 1966. 15. Hunter, E. F., Deacon, W. E., and Meyer, P. G.: Improved FI'A test for syphilis, the absorption procedure (FI'A-ABS), Pub. Health Rep. 79:410, 1964. 16. Tuffanelli, D. L., Wuepper, K. D., Bradford, L. L., and Wood, R. M.: Fluorescent treponemal antibody absorption tests, New England J. Med. 276:258, 1967.

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