Refer to: Fitzgerald F: The great imitator, -Medical Staff Conference, University of California, San Francisco. Medical Staf Conference West J Med 134:424-432, May 1981

The Great Imitator, Syphilis

These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs. David W. Martin, Jr, Pro- fessor of Medicine, and James L. Naughton, Assistant Professor of Medi- cine, under the direction of Dr. Lloyd H. Smith, Jr, Professor of Medicine and Chairman of the Department of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Fran- cisco, School of Medicine, San Francisco, CA 94143.

DR. TIERNEY: * The topic of this nmedical staff lology. By the mid-1950's hospitals were no coniference is the "great imitator," syphilis. Dr. longer required to do routine admission serological Faithl Fitzgerald, a University of Californiia, San tests for syphilis to become accredited. A genera- Francisco, alumna who has recently returned to tion of physicians were trained without seeing Califortnia after a two-year absenice, will discuss syphilis in all its protean manifestations. It was this of increasing importance. no longer the case, as it had been in Osler's time, that to know in its manifestations the 15th and 17th syphilis many DR. FITZGERALD:t Between and variations was to know clinical medicine.1 centuries, waves of pestilence swept Europe, deci- mating populations. The Black Death, bubonic But syphilis flourished in neglect. Its resurrec- plague, persists today but only in pockets. Typhus tion was abetted by increasing promiscuity, a and typhoid have been largely eliminated by relatively simple therapy and a loss of detective modern hygiene. Smallpox is, at last, a conquered diagnostic skill. Because syphilis had been "con- disease. But greatpox, syphilis (so called because quered," the federal government withdrew fund- it was so much more dreadful than smallpox), is ing for US Public Health Service (usPHs) epide- still epidemic among us. miologic studies and case finding.2 Apocrypha has it that the sailors of Columbus In the early 1970's there were 23,000 cases of brought gonorrhea to the New World and returned infectious syphilis per year reported to the USPHS. with syphilis to the Old. As in much early colonial A conservative estimate has it that for every case trade, Europe got more than it gave. reported, nine are not. This implies almost a The history of syphilis is a complex drama in- quarter of a million new cases of syphilis per volving the rise and fall of kings, changing govern- year in the United States.3 There is still a great ments and devastating wars. The final act was to deal of syphilis for primary physicians to recog- have been played in 1943, with the general intro- nize, understand and treat. duction of penicillin. It was a "magic bullet"; cases of reported syphilis plummeted. The words Pathophysiology "and syphilology" were dropped from the title Syphilis may have lessons to teach us in this of the AMA A tchives of Dermatology and Syphi- modern immunologic era of medicine. Consider *Lawrence M. Tierney, Jr, MD, Associate Professor of Medi- this most unusual infectious disease: An organ- cine; Assistant Chief. Medical Service, Veterans Administration ism, Medical C(enter, San Francisco. the delicate spirochete Treponenma pallidum, tFaith Fitzgerald, MD, Associate Professor of Medicine; Asso- is no longer than a red blood cell. It is exquisitely ciatc Dean for Student and Curricuilar Affairs, University of Cali- fornia, Davis, School of Medicine. scnsitive to drying, heat and air. Yet it can infect

424 MAY 1981 v 134 * 5 SYPHILIS

lation have continued to 19558 (Figure 1). The ABBREVIATIONS USED IN TEXT various stages of syphilis are discussed below (see FTA-ABS= fluorescent treponemal antibody Table 1). absorption (test) TPI = Treponema pallidum immobilization (test) A cquired Syphilis Primary. The cardinal feature of the primary stage is the chancre, occurring at the site of inocu- a human being anytime from the fourth month lation within three months of the exposure. Most of intrauterine life to old age. It may affect any chancres begin as papules, then erode and become system and can remain destructive for the victim's ulcerative. They are painless, indolent, punched- entire lifetime. Or it may lie dormant for a quar- out lesions which have a scanty yellow discharge. ter century or more, living in harmless parasitism They teem with spirochetes and are highly infec- with its host. tious. They may appear anywhere, although 95 At its worst, it is a prolonged infectious poly- percent are genital. They have been noted to vasculitis with immunopathologic overlay; at best, occur in or around the mouth, anus, breast, rec- it is an inconvenient or embarrassing blood test tum, cervix and colostomy stoma. Untreated, they result. heal spontaneously. In the overwhelming majority of cases, the Secondary. Generally this stage is clinically disease is transmitted by sexual activity. Trans- manifest within six months of exposure. The mission of the treponeme can occur through chancre or chancres may still be present but are mucous membranes, minutely abraded skin or, usually healing. This stage has protean manifes- some believe, by way of normal hair follicles. En- tations, but four major syndromes have been tering through the dermis, the spirochetes seed seen: (1) a constitutional, flu-like illness; (2) rapidly into the lymphatics and from there enter the bloodstream to disseminate throughout the CA body. Invading the perivascular lymphatics of a i primory & secondary multiple organs, the treponemes stimulate L.L _J cellular inflammatory response to granulomata |24% Late relapse formation and proliferation in the intima of the 15% Benign 10% Cardiovac. 8% Neurosyphilis vasa vasorum. The resulting decrease or loss of .deUt(dinic= = (clnical blood supply by tissues served by the injured ves- laz{teantat the acute sels may lead to necrosis. Eventually, 0 5 10 15 20 25 30 inflammation is replaced by fibrous scar tissue. YEARS AFTER T pallidum organisms may episodically, in the Figure 1.-Results of studies of the course of untreated early stages of disease, break out again as spiro- syphilis in 2,000 patients. chetemia. Or they may assume an intracellular sequestration in multiple tissues, protected by the cell, some think, from antibodies and antibacterial TABLE 1.-The Stages of Syphilis agents.4 ACQUIRED SYPHILIS The antibody response to the treponemes may Primary Immune-deposit dis- Secondary be itself immunopathologic. Latent ease in syphilis so far has been documented in Early latent the kidneys.5-7 Late latent Tertiary In later stages, tissue hypersensitivity to T pal- Late benign syphilis lidum may become prominent, including prolifera- Cardiovascular syphilis tive fibrosis with hypertrophic masses, reactive Neurosyphilis Meningovascular syphilis tissue and necrosis-that is, formation of gum- Aseptic meningitis mata. Tabes dorsalis Preataxic Stages of Syphilis Ataxic Paralytic Beginning in 1891, Boeck in Oslo studied 2,000 General paresis of the insane patients with untreated syphilis to determine the Latent neurosyphilis natural course of the disease. Studies of this popu- CONGENITAL SYPHILIS

THE WESTERN JOURNAL OF MEDICINE 425 SYPHILIS generalized lymphadenopathy with or without late-stage involvement are tabes dorsalis and the splenomegaly; (3) rash, involving skin and mu- general paresis of the insane. Active meningovas- cous membranes, and (4) visceral involvement, cular syphilis is more commonly associated with such as hepatitis, nephritis, osteitis or gastritis. secondary than with tertiary involvement. The secondary stage is also infectious and, like the primary, will resolve without therapy. Conigeniital Syphilis Lcatetnt. Latent syphilis is hidden. By definition, A child born to a syphilitic mother may acquire there are no clinical manifestations. the disease by transplacental transmission of T Early latent is that period, generally two to pallidlum. Because the organism does not cross four years from infection, during which spon- the placental barrier until the 16th to 19th week, taneous clinical relapse may occur, with resump- early detection and therapy of the pregnant tion of spirochetenmia and, usually, a secondary woman is effective. 12, l3 lues-like condition. During the four years follow- In untreated women, 25 percent of infected ing inoculation, the victim remains an epidemio- infants die in utero. Another 25 percent will die logic threat because secondary lues is infectious. shortly after birth. In about 40 percent of the In almost a quarter of untreated patients this infants that survive-if untreated-symptomatic clinical recrudescence will occur. syphilis will occur, with developmental retarda- Laite ltatent is that stage of the disease after the tion, ocular, dental, neurological, bony, articular fourth year from infection when the victim is no or visceral lesions all possible.14 longer contagious but remains host to living treponemes. Review of Systems In two thirds of untreated people, spirochetes It has been said that syphilis, the great imitator, and host will live amicably togetlher until the can look like anything. But if that is true, a patient dies of other causes. In about a third, clinician can have no discrete reason to suspect however, the organism will continue to act upon syphilis in any single circumstance. It must, then, the host to cause a variety of mischief-or, ter- be kept as a differential diagnosis to be considered tiary syphilis.8-10 in almost all cases. To illustrate this, it is useful Tertiary. Late benzigni syphilis occurs in about to approach the disease from the point of view of 15 percent of untreated victims. Gummata are its systems, as one would do in ordinary history and cardinal feature. A gumma seems to represent a physical examination, rather than reviewing the proliferative reaction in which, though the pa- constellation of symptoms and signs in each stage; tient appears to be in a latent state, there is the latter all tend to merge and cross over anyway. chronically progressive inflammation and fibrosis. This niay, depending on the organ involved, leave General such severe scarring as to result in a pronounced Puniness and growth retardation are features of disturbance of the affected tissues. congenital lues. Fever may accompany any stage A gumma may undergo central necrosis, with of the disease but is most prominent in the malaise breakthrough of the wall of the lesion, wlhich then of secondary lues. It may be mild and continuous drains by way of one or more sinuses. Any tissue or, in its most remarkable form, paroxysmal, with may be involved but the most frequently affected spikes up to 40.6°C (105°F). Fever may persist are bone, skin and upper respiratory tract. for months, and syphilis must be part of the dif- Cardiovascular s'yphilis comnplicates the lives ferentiail diagnosis in evaluation of fevers of un- of about 10 percent of untreated sufferers. Osler11 known origin. Loss of weight, anemia, lymphocy- described the basic lesion of all syphilis in all tosis anid elevated erythrocyte sedimentation rate stages and all organs as an endarteritis. It is within may be part of secondary syphilis. In the later this category of tertiary lues that the truth of his stages, constitutional symptoms may be in conse- observation is most evident. The basic lesion of quence of the compromise of specific organs, as cardiovascular syphilis is aortitis, with its patho- in the fatigue of luetic aortic insufficiency. logical potential for aortic insufficiency, coronary vessel osteitis and ischemia, and the highly ques- Nodes tionable entity of infective myocarditis. Nodes neighboring the primary chancre may Neurosyphilis affects some 8 percent of un- enlarge, growing hard and nontender. A more treated persons. The classic manifestations of this generalized lymphadenopathy is common in see-

426 MAY 1981 * 134 * 5 SYPHILIS ondary syphilis, with pronounced involvement of Patchy alopecia or general thinning of the hair epitrochlear and posterior cervical nodes. These may occur in acquired lues, and the hair of head enlarged nodes are rubbery and painless. Ab- or eyebrows may fall out in the congenital form dominal examination may show splenomegaly in of the disease. this stage, and the lymphadenopathy may be so Syphilitic onycholysis is rare in other than con- impressive as to be mistaken for mononucleosis- genital lues, though the nails may fall out entirely which secondary syphilis much resembles. More in severe secondary syphilis. serious errors have been made as in the several Head reported instances in which patients narrowly escaped total nodal irradiation for putative Hodg- Frontal, maxillary and mandibular bossing from kin disease, a misdiagnosis of their secondary periostitis of the skull are classic features of con- lues.15,16 genital lues. The saddle nose, with snuffles, of congenital disease occurs when syphilitic peri- Skin chondritis erodes and collapses the nasal septum. It is the skin that is the great mirror of luetic The nose is also a favored spot for gummata. involvement and the organ on which we rely most Ears for the diagnosis of syphilis. However, it may also Deafness may occur early in congenital lues, be the most deceptive because it is in this area- but has been reported to present as a Meniere- even more than elsewhere-that the great imitator like condition in young adulthood'0 or from iso- justifies its reputation for deceit. lated VIII nerve failure in later neurosyphilis. In addition to the already described chancres of primary disease, cutaneous lesions are most Mouth common in the secondary stages of the disease. In the oral cavity, the examiner may see Macular syphilid, or syphilitic roseola, is most chancres, glossitis, mucous patches, gummata, prominent on trunk and arms, often sparing the pharyngitis and palatal perforation from periosti- face. The symmetrically arranged macules are tis or the gummata. Hutchinson teeth (screw- reddish-brown, persist for one to two weeks and driver-shaped secondary incisors) and mulberry may undergo multiple relapses. Papular syphilid molars (with supernumerary or defective cusps) may look like acne; a pustular rash resembles are classic features of congenital disease. smallpox, or a squamous syphilid looks like psoriasis. Eyes While syphilitic rashes may look like a variety Ocular lesions include interstitial keratitis, iritis of skin , they have certain characteristics (occurs mostly in secondary syphilis, affecting in common. They are often generalized, painless one eye before the other, generally three to six and nonpruritic and have a predilection for the months after the chancre), choritis and retinitis. palms and soles. The lesions are more commonly The pupillary changes of tabes dorsalis are easy discrete than confluent and are sharply demar- to remember: The Argyll-Robertson pupil may cated; and, like a reverse bull's-eye, the color accommodate but does not react to light. Blind- becomes more intense as one proceeds from ness may be a consequence of either optic nerve periphery to center. damage or inflammatory changes in other struc- Mucous patches are found in most areas of tures of the eye. Optic atrophy, ptosis and oph- skin, such as perineum, groin or angle of mouth. thalmoplegias have all been reported. They are flat, warty outgrowths with well-defined Neck margins and surfaces covered with greyish secre- Gummata may involve the larynx, leading to tions. They are highly infectious. misdiagnosis as cancer or . More Gummata may affect any portion of the skin urgently, such a mass may cause scarring and and leave scars as they involute or create ulcers stridor. The hoarse "syphilitic cry" of congenital as they break down. Because caseation occurs, lues is probably due to laryngeal involvement.9 gummata may be mistaken for tuberculosis. Condylomata lata are highly infectious hyper- Breasts trophied papillae of the perianal or perivulvar Osler mentions syphilitic mastitis, with unilat- skin. They must be distinguished from the more eral chronic diffuse induration or local nodules." common, virally induced condylomata acuminata. Axillary nodes may be involved, and the differ-

THE WESTERN JOURNAL OF MEDICINE 427 SYPHILIS ential diagnosis from cancer of the breast may be atherosclerotic origin, which are generally at or difficult. below this level. The syphilitic aneurysm may lie high under the diaphragm.18 Chest A gumma may involve the trachea, with Gastrointestinal bronchial dilatation below the lesion. Symptoms Hepatosplenomegaly is a common associate of are those of obstruction, with dyspnea, stridor, congenital lues. The liver shows fibrosis and large cough and prolongation of inspiration. Rarely, numbers of spirochetes. Clinical jaundice, hepa- tracheoesophageal fistulas may occur. Syphilitic tomegaly with tenderness and increased levels of pneumonia has been reported in congenital lues. transaminase with a disproportionate rise in alka- Gummatous disease of the lungs, which is very line phosphatase, are the hallmarks of the syphi- uncommon, may resemble tuberculosis or fibrotic litic hepatitis of the secondary stage of disease. lung disease.9 A liver biopsy specimen in syphilitic hepatitis will show portal inflammation, polymorphonuclear Heart leukocytes surrounding bile ducts and necrotic Syphilitic endocarditis has not been described, areas extending from portal triads to central veins. though a nonbacterial thrombotic (marantic) Whether the spirochetes themselves can be seen endocarditis may coexist. Syphilitic myocarditis in the liver tissue is a sv-bject of dispute. Hepatic has been suspected on the basis of clinical find- gummata may occur in tertiary disease and, with ings, electrocardiogram and response to therapy necrosis and scarring, lead to the classic hobnail during the spirochetemic phases of early lues. Still, liver of late syphilis."1"9'20 this disease entity remains very much in doubt.9 Acute esophagitis and erosive syphilitic gastritis Gummatous myocarditis, though very rare, has may occur, the latter involving pain, vomiting, been recognized. Most gummata are in the left weight loss and hemorrhagic inflammation of the ventricular wall and may be associated with stomach on endoscopy. T pallidum may be demon- bundle branch block on electrocardiogram. Inter- strated in biopsy material obtained from the ventricular septal gumma may cause complete gastric mucosa." heart block17 and, most uncommonly, a gumma Gummata of the esophagus may be mistaken may obstruct one or more coronary ostia. for esophageal carcinoma, or the great imitator Syphilitic aortitis is the basic and most frequent may present as pyloric obstruction, linitis plastica, lesion of tertiary lues. During the spirochetemia or another intra-abdominal gummatous mass. of early disease, treponemes invade the aortic wall, Osler mentions the possibility of pancreatitis and probably by way of the vasa vasorum. An oblit- jejunitis from syphilis. If these are luetic entities, erating endarteritis follows, generally in the first they are rare."' portion of the aortic arch. Diffuse dilation or Rectal lues may manifest as chancres, and, as saccular aneurysm results. Dilatation of the aortic these are sometimes multiple, they may appear as root separates the valve leaflets, with resultant a condition resembling ulcerative colitis, especially aortic insufficiency. Inflammation of the wall may in homosexual men.22 extend to involve the coronary ostia. Should they Gummata should remain in the differential become occluded, myocardial ischemia or infarct diagnosis of adenocarcinoma of the colon. may follow. Symptoms may also arise from the simple mass Genitourinary effect of the aneurysm, which may compromise In addition to genital chancres, the urinary tract any of the mediastinal structures, including the has been variously involved by syphilitic lesions. trachea, bronchi, lungs, esophagus, vagus, cervical Clinically, the most common manifestation of sympathetic nerves or the recurrent laryngeal renal involvement is mild proteinuria, which may nerve. The pulsatile mass may erode through ad- occur in secondary lues. A full-blown nephrotic jacent ribs or spine. These aneurysms do not syndrome accompanies secondary syphilis in some dissect, but they may rupture. cases.5 IgG immune complexes-treponemal anti- Abdominal aortic aneurysms are about a tenth gen and antibody reactions-can be shown along as frequent as thoracic ones, and those of syphi- the glomerular basement membrane.6'7 The ne- litic origin are characteristically above the level of phrosis remits with either treponemocidal therapy the renal arteries, in contrast to aneurysms of or the simple passage of time. Hemorrhagic

428 MAY 1981 * 134 * 5 SYPHILIS nephritis, indistinguishable on biopsy from that rare.', Ptosis, extraocular muscle palsies and optic classically associated with poststreptococcal glo- neuritis have all been described."'26 Sudden, vio- merulonephritis, is an uncommon but very serious lent delirium, changes of character, prolonged complication which may progress to azotemia and stupor or coma, convulsions and major vascular death. Paroxysmal cold hemoglobinuria may occlusive events may complicate the picture. occur with congenital or acquired lues."3 Muscle Studies of cerebrospinal fluid commonly show a cramps, headache, fever and hemoglobinuria pre- positive VDRL result, increased protein and pleo- cipitated by cold will, in this case, respond to cytosis. A milder, transient aseptic meningitis antisyphilitic therapy. sometimes accompanies secondary syphilis. Prostatic and bladder gummata are rare and Tabes dorsalis is a neuropathy of late syphilis, syphilitic orchitis rarer still. A neurogenic bladder in which there is degeneration of the root fibers of may occur as a feature of neurosyphilis. the posterior columns, spinal ganglia, cranial and peripheral nerves. There are three stages as fol- Extremities lows: (1) in the preataxic stage, tabetic crises Arthritis may occur at any stage of syphilis and may occur involving lightning pains of the legs may be so acute as to be mistaken for rheumatic and trunk that last one to two seconds and follow fever. Or it may be chronic, with neuropathic the path of the dorsal nerve roots. Loss of pain painless destruction of joints. Arthritis of any sort and temperature sensation are concurrent. Ocular is usually symmetrical.13'14 neuropathies, bladder symptoms, loss of deep The Clutton joint of congenital lues involves tendon reflexes, deafness and paralysis of the hydrarthrosis, frequently bilateral, secondary to vocal cords may follow. (2) The ataxic stage of syphilitic synovitis with involvement of bone or tabes occurs when afferent impulses are lost, lead- cartilage. The Charcot joint of tertiary syphilis is ing to incoordination and muscle hypotonia. Vis- neuropathic, that is, painless, with thickened ceral crises, akin to pain crises, sometimes occur synovium and cartilagenous injury. Most frequent in this stage; gastric crises include severe epigastric in the knees, it may occur in the ankles or lumbar pain, nausea, vomiting, hematemesis and, some- spine as well. times, death. The blood pressure may be very high, Bony lesions are part of both congenital and and the condition has been said to be associated acquired lues. Periostitis, perichondritis, sclerosing with mesenteric vasospasm. Laryngeal crises may osteitis, lytic lesions, gummata and bursitis have lead to sudden death; and even uncontrollable all been seen. Almost any bone, including the sneezing fits, the nasal crises, have been said to axial skeleton, may be involved.24 be tabetic in origin.2 (3) After many years, the It is periostitis of the tibiae in congenital lues paralytic stage supervenes. The patient becomes that produces the peculiar conformation called bedridden and paralyzed, eventually dying of in- "sabre shins." fection. Osler noted syphilitic myositis in gastrocne- General paresis of the insane is a chronic lu- mius and sternocleidomastoid muscles. On his- etic meningoencephalitis characterized by mental tological section, an affected muscle specimen changes, dementia and paralysis. Irritability, shows vasculitis and interstitial myostis." changes in character, tremor, seizures, eye changes and hemicranial headaches may precede a hypo- Central Nervous System manic phase during which delusions of grandeur The central nervous system may be involved govern. Speech eventually becomes slurred, with in any stage of syphilis. There are four cardinal syncope and paralysis thereafter. Death may occur clinical categories. during seizures, or a chronic dementia may persist Meningovascular syphilis is a manifestation of for years. early lues, occurring within the first four years after Latent neurosyphilis has no signs or symptoms, primary infection. It presents as an aseptic men- but the cerebrospinal fluid has a positive VDRL. ingitis, with headache, irritability and mental In the modern era, classic tabes and general fatigue. Ocular features are common, often with paresis are rare and are being replaced by atypical remarkable variation from time to time. Pupils and in-between forms.26 The nontreponemal sero- may be unequal or irregular and, although abnor- logical tests for syphilis may be negative in as mal pupils have been noted in most patients with many as 40 percent of patients with neurosyphi- neurosyphilis, true Argyll-Robertson pupils are lis,28 and the assumption that the serum fluores-

THE WESTERN JOURNAL OF MEDICINE 429 SYPHILIS cent treponemal antibody absorption (FTrA-ABS) TABLE 2.-Biological False-Positive VDRL Tests test in serum is always positive has not held up.29 Acute For general purposes, however, a positive cere- Viral : herpes, mononuclCosis, hepatitis while Lymphogranuloma venereum brospinal fluid VDRL defines neurosyphilis, Vaccinations cerebrospinal fluid pleocytosis and elevated pro- Immunizations tein level define its activity. Chronic Age Laboratory Diagnosis Heroin addiction Leprosy The laboratory tests for syphilis may be simple or confusing, depending on one's approach. Collagen disease Though there are any number of serologicail tests, Lymphoma study is the VDRL, the Familial the most commonly used Nonvenereal treponemes most sensitive is the FTA-ABS and the most specific Yaws is the Treponciena pallidium immobilization test. Pinta VDRL stands for Veneral Disease Research Bejel Passive reaginemia Laboratory and is a flocculation test that depends Placental transfer on the cross-reactivity of antitreponernal anti- bodies in the serum of the victim to a cardiolipin extract from cow's heart. It is easy and cheap applied to a slide on which T pallidum organisms and, thus, may be used for screening large num- have been dried. Globulin antibodies in the vic- bers of patients. tim's serum adhere to the treponemes. Fluorescein- In primary syphilis, about 25 percent of pa- tagged antiglobulin antibodies are overlaid on the tients will have a positive VDRL test within the slide. The globulin on the treponemes binds the first week of the appearance of a chalncre, 50 tagged antiglobulin and the slide is then read. To percent in the second week and 75 percent in the increase specificity, the test serum is pretreated third week following infection.2 with absorption to nonluetic treponemes that re- In secondary syphilis, close to 100 percent of move antibodies nonpathogenic to spirochetes. VDRL tests are positive. False-positive tests have been shown in systemic One must be careful in congenital lues, as the , rheumatoid arthritis, lymphosarcoma, al- VDRL-an IgG function-measured in the first coholic cirrhosis and pregnancy. 2-35 It has been three postnatal months is that of the mother, not said that there are morphological differences be- the child. tween false and true positives in systemic lupus, With therapy, about 25 percent of patients with false results showing beading of the fluores- treated within four years will remain serofast; 75 cein tagging on the treponeme rather than linear percent will become serofast if treated later, but deposition. 5 titers may decline, providing useful information The FTA-ABS is the most sensitive of all tests, about the adequacy of treatment.:" being 75 percent positive in the earliest lues and In neurosyphilis, 50 percent to 75 percent of close to 100 percent persisting thereafter. Only victims will have reactive serum VDRI tests and the very earliest therapy of seronegative (that is, almost 100 percent will have reactive serum FTA- VDRL-negative) primary syphilis will cause the ABS tests.2'; As few as 57 percent will have reac- ETA-ABS, in about 75 percent of those so treated, tive cerebrospinal fluid VDRL tests,2' but the value to revert to negative.36 of FTA-ABS tests in cerebrospinal fluid remains in The TPI (Treponzema pallidum immobilization) doubt.:' test is done by adding patient serum (potentially Biological false-positive VDRL tests may occur containing antibody) and complement to a sus- in a number of circumstances as listed in Table pension of living treponemes extracted from rabbit 2. The titer of a biological false-positive result is testes. The test is run under a dark-field micro- generally 1:4 or less. However, in one study of scope and scored for whether immobilization of patients with biological false-positive results per- the organism occurs. Antibiotic drugs taken by the sisting for more than six months, about half of patient will invalidate the test, which is technically them turned out to have syphilis.2' difficult under the best of circumstances. It is far FTA-ABS is the fluorescent treponemal antibody- less sensitive than the FTA-ABS test but far more absorption test, in which serum from the patient is specific than any other laboratory investigation

430 MAY 1981 * 134 * 5 SYPHILIS short of staining the organism in tissue. It is not units of parenteral penicillin G results in a satis- available in most hospitals but can be obtained factory clinical response in about 90 percent of through the Communicable Disease-Center, At- patients with neurosyphilis.37 Because living trepo- lanta. nemes have been shown in aqueous humor and Diagnosis of Suspected Lues the central nervous system following supposed ablative therapy, and because neurological signs After a complete history and physical exami- may continue to progress even with apparently nation, dark-field microscopic examination should adequate therapy, some clinicians will hospitalize be done on all suspected lesions. It is, however, a patients with neurosyphilis, especially if the victim waste of time to do a dark-field study on lesions is symptomatic or has not responded to initial in the mouth, as normal oral treponemes may be therapy. In the latter case, one may wish to in- present. If the VDRL test is insufficiently convincing crease 'the total dose of aqueous penicillin G to for diagnosis, an FTA-ABS test should be done. A 12 to 24 million units given intravenously each suggested approach is outlined in Figure 2. day for ten days. It has been proposed that the Therapy 9.6 million unit standard dose, though spirocheto- cidal in blood, does not If syphilis is diagnosed, the nature of therapy achieve adequate thera- depends on the stage of the peutic levels in the CSF.38 disease (Table 3). In case of syphilis of unknown duration, Studies show that a total dose of 6 to 9 million a cerebrospinal fluid VDRL test should be carried out if there are any symptoms suggestive of neuro- VDRL syphilis because there may be a therapeutic dif- /1X ference. All patients should have repeat sero- (-) (+ or WR) (-) with signs/symptoms logical testing done 24 months after therapy. Careful follow-up is especially important in those treated with antibiotics other than penicillin, be- cause the efficacy of these alternatives in late lues and, especially, in neurosyphilis is unproved. In (-) (+) (WR) a patient with established neurosyphilis, serolog- ISyphilIs I ical testing should continue for three years, with clinical and CSF examinations every six months. Retreatment should be considered in the fol- lowing situations: when (-) (+) (1) clinical signs or symptoms of syphilis persist or recur, (2) when Syphillsi there is a sustained fourfold increase in the titer Figure 2.-Laboratory evaluation of suspected syphilis. of the VDRL test or (3) when an initially high titer (FTA-ABs= fluorescent treponemal antibody absorption for the VDRL test fails to show a fourfold decrease [test]; TPI = Treponema pallidum immobilization [test]; VDRL =Venereal Disease Research Laboratory [test]; within a year. WR =weakly reactive.) The Jarish-Herxheimer reaction is so common

TABLE 3.-Appropriate Therapy Depending on the Stage of Syphilis Serological Finding Without Therapy (Percent) Stage Thlerapy FTA-ABS VDRL TPI Congenital ...... 50,000 units benzathine penicillin G/kg of T titers body weight in single dose X 3 mos Acquired Primary (<3 mos.) ...... 2.4 million units benzathine penicillin G in single dose 85 25-75 55 Secondary (<6 mos.) .... 99 97 94 Early latent ( <4 yrs.) . .

Late latent (>4 yrs.) .... 2.4 million units benzathine penicillin G every 95 74 94 Late benign ...... 10 days X 4 doses Cardiovascular ...... Neurosyphilis ...... 2.4 million units benzathine penicillin G every 95 74 94 10 days X 4 doses (see text) FTA-ABS=fluorescent treponemal antibody absorption (test); TPI = Treponema pallidum immobilization (test)

THE WESTERN JOURNAL OF MEDICINE 431 SYPHILIS

10. Syphilis: A Synopsis, Public Health Service Publication No. an accompaniment of the therapy of syphilis that 1660. US Dept of Health, Education, and Welfare, 1967 it deserves mention here. Nine out of ten patients 11. Osler W: Syphilis, In Osler's Principles and Practice of Medicine, Ed. XIII, revised by HA Christian. New York, D. with secondary and, to a lesser extent, other Appleton-Century Co., Inc., 1938, pp 344-369 12. Holder WR, Knox JM: Syphilis in pregnancy. Med Clinics stages of syphilis will show a Jarish-Herxheimer N Am 56:1151-1160, 1972 13. Curtis AC, Philpott OS Jr: Prenatal syphilis. Med Clinics reaction within several hours of their first dose of N Am 48:707-719, 1964 the antibiotic drug. The reaction is characterized 14. Thomas EW: Syphilis: Its Course and Management. New York, Macmillan Co, 1949 by chills, fever, headache, muscle and joint pains. 15. 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