Essentials of Diagnosis
• Infiltrative tumors of skin, bones, liver (gummas).
• Aortitis, aneurysms, aortic regurgitation.
• Central nervous system disorders, including meningovascular and degenerative changes, paresthesias, shooting pains, abnormal reflexes, dementia, or psychosis.
This stage may occur at any time after secondary syphilis, even after years of latency, and is seen in about one-third of untreated patients. Late lesions probably represent, at least in part, a delayed hypersensitivity reaction of the tissue to the organism and are usually divided into two types: (1) a localized gummatous reaction, with a relatively rapid onset and generally prompt response to therapy (“benign late syphilis”) and (2) diffuse inflammation of a more insidious onset that characteristically involves the central nervous system and large arteries, is often fatal if untreated, and is at best arrested by treatment. Gummas may involve any area or organ of the body but most often the skin or long bones. Cardiovascular disease is usually manifested by aortic aneurysm, aortic regurgitation, or aortitis. Various forms of diffuse or localized central nervous system involvement may occur.
Late syphilis must be differentiated from neoplasms of the skin, liver, lung, stomach, or brain; other forms of meningitis; and primary neurologic lesions.
Although almost any tissue and organ may be involved in late syphilis, the following are the most common types of involvement.
Cutaneous lesions of late syphilis are of two varieties: (1) multiple nodular lesions that eventually ulcerate (lues maligna) or resolve by forming atrophic, pigmented scars and (2) solitary gummas that start as painless subcutaneous nodules, then enlarge, attach to the overlying skin, and eventually ulcerate.
Late lesions of the mucous membranes are nodular gummas or leukoplakia, highly destructive to the involved tissue.
Bone lesions are destructive, causing periostitis, osteitis, and arthritis with little or no associated redness or swelling but often marked myalgia and myositis of the neighboring muscles. The pain is especially severe at night.
Late ocular lesions are gummatous iritis, chorioretinitis, optic atrophy, and cranial nerve palsies, in addition to the lesions of central nervous system syphilis.
Respiratory involvement by late syphilis is caused by gummatous infiltrates into the larynx, trachea, and pulmonary parenchyma, producing discrete pulmonary densities. There may be hoarseness, respiratory distress, and wheezing secondary to the gummatous lesion itself or to subsequent stenosis occurring with healing.
Gummas involving the liver produce the usually benign, asymptomatic hepar lobatum. A picture resembling Laennec’s cirrhosis is occasionally produced by liver involvement. Gastric involvement can consist of diffuse infiltration into the stomach wall or focal lesions that endoscopically and microscopically can be confused with lymphoma or carcinoma. Epigastric pain, early satiety, regurgitation, belching, and weight loss are common symptoms.
Cardiovascular lesions (10-15% of late syphilitic lesions) are often progressive, disabling, and life-threatening. Central nervous system lesions are often present concomitantly. Involvement usually starts as an arteritis in the supracardiac portion of the aorta and progresses to one or more of the following: (1) narrowing of the coronary ostia, with resulting decreased coronary circulation, angina, and acute myocardial infarction; (2) scarring of the aortic valves, producing aortic regurgitation, and eventually congestive heart failure; and (3) weakness of the wall of the aorta, with saccular aneurysm formation and associated pressure symptoms of dysphagia, hoarseness, brassy cough, back pain (vertebral erosion), and occasionally rupture of the aneurysm. Recurrent respiratory infections are common as a result of pressure on the trachea and bronchi.
Treatment of tertiary syphilis (excluding neurosyphilis; see below) is as for late latent syphilis. Reversal of positive serologic tests does not usually occur. A second course of penicillin therapy may be given if necessary. There is no known method for reliable eradication of the treponeme from humans in the late stages of syphilis. Viable spirochetes are occasionally found in the eyes, in cerebrospinal fluid, and elsewhere in patients with “adequately” treated syphilis, but claims for their capacity to cause progressive disease are speculative.
Neurosyphilis (15-20% of late syphilitic lesions; often present with cardiovascular syphilis) is also a progressive, disabling, and life-threatening complication. It develops more commonly in men than in women and in whites than in blacks. Asymptomatic and meningovascular syphilis occur earlier (months to years after infection, sometimes coexisting with primary and secondary syphilis) than tabes dorsalis and general paresis (2-50 years after infection).
There are four clinical types.
1. Asymptomatic Neurosyphilis - This form is characterized by spinal fluid abnormalities (positive spinal fluid serology, increased cell count, occasionally increased protein) without symptoms or signs of neurologic involvement.
2. Meningovascular Syphilis - This form is characterized by meningeal involvement or changes in the vascular structures of the brain (or both), producing symptoms of chronic meningitis (headache, irritability), cranial nerve palsies (basilar meningitis), unequal reflexes, irregular pupils with poor light and accommodation reflexes, and, when large vessels are involved, cerebrovascular accidents. The cerebrospinal fluid shows increased cells (100-1000/mcL), elevated protein, and usually a positive serologic test for syphilis. The symptoms of acute meningitis are rare in late syphilis.
3. Tabes Dorsalis - This form is a chronic progressive degeneration of the parenchyma of the posterior columns of the spinal cord and of the posterior sensory ganglia and nerve roots. The symptoms and signs are impairment of proprioception and vibration sense, Argyll Robertson pupils (which react poorly to light but well to accommodation), and muscular hypotonia and hyporeflexia. Impairment of proprioception results in a wide-based gait and inability to walk in the dark. Paresthesias, analgesia, or sharp recurrent pains in the muscles of the leg (“shooting” or “lightning” pains) may occur. Crises are also common in tabes: gastric crises, consisting of sharp abdominal pains with nausea and vomiting (simulating an acute abdomen); laryngeal crises, with paroxysmal cough and dyspnea; urethral crises, with painful bladder spasms; and rectal and anal crises. Crises may begin suddenly, last for hours to days, and cease abruptly. Neurogenic bladder with overflow incontinence is also seen. Painless trophic ulcers may develop over pressure points on the feet. Joint damage may occur as a result of lack of sensory innervation (Charcot joint). The cerebrospinal fluid may have a normal or increased cell count (3-200/mcL), elevated protein, and variable results of serologic tests.
4. General Paresis - This is generalized involvement of the cerebral cortex with insidious onset of symptoms. There is usually a decrease in concentrating power, memory loss, dysarthria, tremor of the fingers and lips, irritability, and mild headaches. Most striking is the change of personality; the patient becomes slovenly, irresponsible, confused, and psychotic. The cerebrospinal fluid findings resemble those of tabes dorsalis. Combinations of the various forms of neurosyphilis (especially tabes and paresis) are not uncommon.
B. Special Considerations in Treatment of Neurosyphilis
It is most important to prevent neurosyphilis by prompt diagnosis, adequate treatment, and follow-up of early syphilis. Indications for lumbar puncture vary depending upon the stage of the disease and the host’s immune status. In early syphilis (primary and secondary syphilis and early latent syphilis of less than 1 year’s duration), invasion of the central nervous system by T pallidum with cerebrospinal fluid abnormalities occurs commonly, but neurosyphilis rarely develops in patients who have received the standard therapy outlined above. Thus, unless clinical symptoms and signs of neurosyphilis or ophthalmologic involvement (uveitis, neuroretinitis, optic neuritis, iritis) are present, a lumbar puncture in early syphilis is not recommended as part of the routine evaluation. In latent syphilis, the decision to perform a lumbar puncture should be individualized. Routine lumbar puncture for all patients is not indicated since the yield is low and findings rarely influence therapeutic decisions. Cerebrospinal fluid evaluation is recommended, however, in the later stages of syphilis if neurologic or ophthalmologic symptoms and signs are present, if therapy other than with penicillin is to be given, if the patient is HIV positive (see next section), if there is evidence of treatment failure (see discussion above), or if there is evidence of active tertiary syphilis (aortitis, iritis, optic atrophy, the presence of a gumma, etc). Some also routinely recommend lumbar puncture for all individuals with latent syphilis if the serum nontreponemal antibody titer is ? 1:32. In the presence of definite cerebrospinal fluid or neurologic abnormalities, one should treat for neurosyphilis. The pretreatment clinical and laboratory evaluation should include neurologic, ocular, cardiovascular, psychiatric, and cerebrospinal fluid examinations.
The regimen of 2.4 million units of benzathine penicillin intramuscularly weekly for three consecutive weeks results in low to undetectable cerebrospinal fluid levels of penicillin, and treatment failures have been described when this regimen has been used to treat neurosyphilis. For these reasons, current recommendations for the therapy of neurosyphilis include higher doses of short-acting penicillin to achieve better penetration and higher levels of drug in the cerebrospinal fluid. Recommended regimens include 18-24 million units per day of aqueous crystalline penicillin G given as 3-4 million units intravenously every 4 hours or as a continuous infusion for 10-14 days. Alternatively, 2.4 million units of procaine penicillin can be given intramuscularly once daily along with 500 mg of probenecid orally four times daily, both for 10-14 days. Because of concerns about slowly dividing organisms that may persist after only 10-14 days of therapy, many experts recommend subsequent administration of 2.4 million units of benzathine penicillin intramuscularly once weekly for 3 weeks as additional therapy. Ceftriaxone, 2 g intramuscularly or intravenously once daily for 10-14 days, can be used as an alternative to penicillin. Because other regimens for neurosyphilis have not been adequately studied, patients with a history of an IgE-mediated reaction to penicillin should be skin tested for allergy to penicillin and, if positive, desensitized.
All patients should have spinal fluid examinations at 6-month intervals until the cell count is normal. Response may be gauged by clinical improvement and reversal of cerebrospinal fluid changes. In general, cerebrospinal fluid white blood cell count and cerebrospinal fluid VDRL normalize more quickly (usually in 12 months) than cerebrospinal fluid protein concentration, which can remain abnormal for extended periods, making it less useful as an indicator of success or failure of therapy. A second course of penicillin therapy may be given if the cell count has not decreased at 6 months or is not normal at 2 years. Not infrequently, there is progression of neurologic symptoms and signs despite high and prolonged doses of penicillin. These treatment failures may be related to the unexplained persistence of viable T pallidum in central nervous system or ocular lesions in at least some cases.
- Natural History & Principles of Diagnosis & Treatment
- Laboratory Diagnosis
- Complications of Specific Therapy
- Follow-Up Care
- Course & Prognosis
- Clinical Stages of Syphilis
Revision date: July 3, 2011
Last revised: by Andrew G. Epstein, M.D.