Case 1: Neurosyphilis
A 67-year-old man with a history of benign paroxysmal positional vertigo presented with progressively worsening confusion and memory loss for nine months. His family had noticed significant forgetfulness. In his most recent incident, the patient got lost driving to his place of work because he could not remember the directions or address. The patient himself reported a new left upper-extremity tremor. He did not report any fevers, genital lesions, rashes, or other neurologic deficits. He reported one male sexual partner and did not have a history of any sexually transmitted infections.
Upon presentation, the patient was afebrile and normotensive. Physical examination was notable for a bilateral intention tremor in the hands, fluent but dysarthric speech, and decreased proprioception and vibration perception in both feet. Laboratory results were significant for a positive syphilis enzyme immunoassay (EIA) and reactive plasma reagin (RPR) with a titer of 1:256. His HIV antibody/antigen test was negative. The patient underwent lumbar puncture, which revealed a cerebrospinal fluid (CSF) white blood cell count of 11 cells/µL (reference range, 0 to 5 cells/μL) with 89% lymphocytes. His CSF protein was 159 mg/dL (reference range, 15 to 45 mg/dL), and a CSF venereal disease research laboratory (VDRL) test was reactive with a titer of 1:64. He was treated for neurosyphilis with IV penicillin G, 4 million units every four hours for 14 days.
The diagnosis is neurosyphilis, which occurs when the spirochete Treponema pallidum invades the nervous system. It can occur at any stage of infection. Neurologic sequelae are diverse and usually nonspecific. Early neurosyphilis can present up to a few months to years after the primary infection and can manifest as headache, stroke, cranial nerve palsies, meningismus, photophobia, encephalopathy, lethargy, and seizures. Late neurosyphilis occurs 10 to 30 years after the primary infection. One presentation, known as general paresis, involves dementia, depression, manic delusions, personality changes, or dysarthria. Another presentation is tabes dorsalis, characterized by a specific ataxic gait known as the “stamp and stick sound gait” with a positive Romberg sign due to loss of proprioception and pupils that accommodate but do not react to light. Of note, neurosyphilis is frequently seen in patients with HIV, especially in patients with lower CD4+ counts. Patients with HIV and suspected late latent syphilis or syphilis of unknown duration should undergo lumbar puncture to rule out neurosyphilis. Patients may also have asymptomatic neurosyphilis, meaning syphilis without symptoms of central nervous system disease despite positive testing.
The diagnosis of neurosyphilis is based on a combination of clinical, serologic, and CSF findings, as there is no gold standard test. While the CSF VDRL is highly specific for neurosyphilis, its sensitivity is only 30% to 60%. Additional CSF findings of pleocytosis and elevated protein levels are supportive but not diagnostic. To monitor response to treatment, neurologic examination and lumbar puncture are performed every six months until the CSF pleocytosis resolves and the CSF-VDRL is negative. This should occur within two years of treatment. CSF pleocytosis should decrease by six months, and CSF-VDRL should begin decreasing by one year post-treatment, if positive. Retreatment is recommended if this does not occur.
- Any patient with serologic evidence of a syphilis infection and neurologic symptoms should undergo a lumbar puncture.
- CSF studies can support and confirm the diagnosis, but negative test results, including on VDRL, should be interpreted with caution, taking into account the clinical context.
Case 2: Secondary syphilis
A 31-year-old man with a history of bipolar disorder and IV drug use presented to the ED due to a heroin overdose requiring naloxone administration. The patient had developed a diffuse nonpruritic, nonpainful full-body rash and right-sided rectal pain seven days prior to seeking care. He was sexually active with one male partner who noted a similar rash one month earlier that resolved spontaneously. He had no other symptoms and did not report any genital ulceration.
Upon arrival, the patient was obtunded, afebrile, mildly tachycardic, and tachypneic. Physical examination revealed pinpoint but reactive pupils with conjunctival injection, and a diffuse mildly erythematous maculopapular rash on his back, chest, abdomen, and extremities, with some involvement of the palms and soles. He also had a right gluteal cleft ulcer with minimal drainage. Laboratory results were notable for a positive syphilis EIA and a reactive RPR with a titer of 1:16. HIV, gonorrhea/chlamydia nucleic acid amplification testing, and hepatitis screenings were negative. He was treated with one injection of 2.4 million units of penicillin G. The patient's rash continued to improve over the course of his hospital stay.
The diagnosis is secondary syphilis. Secondary syphilis occurs one to two months after the primary chancre but can often overlap with primary infection, as seen with this patient. There are numerous clinical manifestations, highlighting the hematogenous spread of the bacteria. While not present in all patients, a characteristic feature of secondary syphilis is a painless, nonspecific maculopapular rash with copper-colored lesions that can be diffuse or localized and may cover the palms and soles. Flu-like symptoms such as malaise, sore throat, headache, and low-grade fever may also be present. Verrucous mucosal lesions known as condyloma lata can be seen in moist areas of the body. Alopecia, diffuse lymphadenopathy, hepatitis, and nephritis may also be observed. Treatment is with a single dose of penicillin G, 2.4 million units intramuscularly; the second-line option is oral doxycycline, 100 mg twice daily for 14 days.
Syphilis has become known as the “great imitator,” and the clinical manifestations of secondary syphilis bear resemblance to other disease pathologies. Over the past 20 years, syphilis diagnoses have been rising substantially despite public health measures and curative treatment. Therefore, high clinical suspicion, especially in men who have sex with men, patients with HIV, and persons using IV drugs, is imperative to allow for early diagnosis, treatment, and prevention of the long-term sequelae that can occur if the infection lies latent for decades.
- The maculopapular rash that is classic in secondary syphilis should prompt evaluation for infection and co-infections.
- The incidence of syphilis has been on the rise in the past 20 years, especially among men who have sex with men, patients with HIV, and persons using IV drugs.
Case 3: Late latent syphilis in pregnancy
A 32-year-old woman in her first pregnancy, estimated to be six weeks pregnant by last menstrual period, presented for admission for methadone stabilization following a positive pregnancy test. She had a history of hepatitis C, pituitary adenoma, and opioid use disorder. She had recently injected heroin, fentanyl, and methamphetamine and had used crack cocaine. She had done commercial sex work.
Her presenting symptoms were notable for nausea, abdominal cramping, and diaphoresis that she identified as withdrawal symptoms. She was afebrile, normotensive, and not tachycardic. Her physical exam was negative for rash, lymphadenopathy, and oral or genital lesions. A transvaginal ultrasound confirmed an intrauterine pregnancy, and her bloodwork showed a negative fourth-generation HIV antibody and antigen screen, as well as a negative hepatitis C virus RNA polymerase chain reaction test. Her syphilis-specific EIA was positive, and her RPR result was 1:2. The department of health was contacted and confirmed she had no history of syphilis. She received one intramuscular dose of penicillin G benzathine during her hospitalization and was discharged to follow-up for two more weekly doses of penicillin G benzathine, methadone maintenance, and outpatient obstetric care.
The diagnosis is late latent syphilis. Late latent syphilis is defined as positive presumptive syphilis serologies greater than one year after or of unknown duration since inoculation in a patient without symptoms of active syphilis. It is important to distinguish this condition from early latent syphilis because treatment regimens differ. This patient's positive syphilis-specific EIA and RPR follow the reverse screening algorithm for presumptive serologies, and she has no prior lab results or known history to suggest that she was newly inoculated within the last year. Of note, in cases of positive EIA but negative RPR, the reverse screening algorithm recommends that a subsequent Treponema pallidum particle agglutination be sent to differentiate false positives.
Syphilis is of increased concern in pregnancy due to the risk of perinatal mortality and morbidity, such as deafness and bony malformations, in offspring. In the setting of racial and socioeconomic health disparities, inadequate engagement with prenatal care, and increased sexual behavioral risk, congenital syphilis rates have been dramatically rising in recent years. Increased screening and access to treatment for special populations, including sex workers and patients with substance use disorders, could help change the trajectory. Currently, the only recommended treatment in pregnancy is weekly intramuscular penicillin G, requiring three doses for late latent treatment. Tetracyclines, the second-line regimen for the treatment of late latent syphilis, are not appropriate in pregnancy due to risk of interference with fetal skeletal development. In cases of true penicillin allergy, patients should undergo penicillin desensitization to tolerate treatment, as no safe alternative exists during pregnancy. Any Jarisch-Herxheimer reaction, typically seen in active stages of syphilis rather than latent, is managed supportively. Post-treatment RPR monitoring should be at the same frequency as in nonpregnant patients, with a fourfold titer decrease indicating resolution of infection. Early syphilis cases are monitored at six and 12 months for titer decrease, and late syphilis cases are monitored through 24 months for titer decrease. Patients with HIV are monitored more frequently, typically every three months initially.
- All pregnant women should be screened for syphilis upon first contact with prenatal care due to associated risks of perinatal mortality and morbidity in offspring.
- Sex workers and patients with substance use disorders are at higher risk for syphilis.
Case 4: Ocular syphilis and new diagnosis of HIV
A 23-year-old man with a history of self-resolving maculopapular rash one year prior presented with one week of progressive blurry vision and pain with movement of his right eye. He reported multiple recent unprotected sexual encounters with male partners. His last HIV and syphilis tests three years ago were negative.
Upon presentation, he was mildly tachycardic and afebrile. Physical examination was notable for right conjunctival injection, disc edema, and anterior chamber scarring. Visual acuity was 20/40 for the right eye and 20/100 for the left eye. The remainder of his physical examination, including neurologic exam, was unremarkable. Initial laboratory results were notable for a positive syphilis EIA with a RPR titer of 1:2,048. Fourth-generation HIV screening with confirmatory Western blot were also found to be reactive; CD4 count was 237 cells/μL (reference range, 410 to 1,590 cells/μL). A lumbar puncture was performed and was significant for a white blood cell count of 26 cells/μL (reference range, 0 to 5 cells/μL) with 77% lymphocytes and 15% monocytes and reactive VDRL antibody with a titer of 1:4. The patient was started on IV penicillin G, 4 million units every four hours for 14 days.
The diagnosis is ocular syphilis infection with HIV co-infection. Ocular syphilis occurs when the bacterium infects ocular tissue and can occur at any stage of the infection. The diagnosis is made when there is serologic evidence of a syphilis infection with ocular symptoms or an abnormal ocular exam concerning for syphilis, most notably posterior uveitis. According to CDC guidelines, any patient with concerns for or diagnosed with ocular syphilis should also have a lumbar puncture, since there can be an association with neurosyphilis, as seen with this patient. Treatment includes aqueous penicillin G, 18 to 24 million units every four hours for 10 to 14 days. Prompt treatment usually leads to complete resolution of symptoms. However, delays in treatment, especially more than 28 days after the onset of symptoms, can lead to poorer visual outcomes. Patients should be monitored by an ophthalmologist with ocular exams and have follow-up RPR testing.
This patient was also diagnosed with HIV at the time of hospitalization. A newly identified sexually transmitted infection such as syphilis should prompt a screen for HIV. Syphilis is thought to enhance HIV transmission through a weakened skin barrier from ulceration and immune activation that can increase HIV replication. Men who have sex with men are at increased risk, as are patients who use drugs such as heroin or methamphetamine.
- Patients with vision changes and risk factors for sexually transmitted infection should be evaluated for ocular syphilis.
- Patients diagnosed with syphilis should be screened for HIV and vice versa.