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We describe the case of a young woman with a rapid deterioration in her cognitive status and physical functioning. An extensive laboratory and radiologic evaluation confirmed the diagnosis of neurosyphilis. Despite the reemergence of syphilis with the acquired immunodeficiency syndrome (AIDS) epidemic, neurosyphulis is often neglected in the differential diagnosis of patients with aseptic meningitis and mental status changes who are negative for the human immunodeficiency virus (HIV). The high mortality rate associated with delay in recognition, diagnosis, and treatment of neurosyphilis obligates its inclusion in the differential of young patients with cognitive decline.


SYPHILIS is a chronic infection caused by the spirochete Treponema pallidum. Most commonly acquired through sexual contact, syphilis is also transmitted vertically through the placenta to the fetus, resulting in congenital syphilis. (1) The introduction of penicillin decreased the incidence of syphilis to a low of 4 cases per 100,000 population in the 1950s. (2) Through the mid1980s, bisexual and homosexual men comprised almost 50% of cases. Despite a decrease in cases in the homosexual population, by 1990 the overall incidence had increased, with 50,233 newly reported cases of primary and secondary syphilis. The increase was due to new cases identified in heterosexual, urban, African American men and women. (3,4) Syphilis has also reemerged in the urban HIV-positive population. (5) A total of 6,657 (2.2 per 100,000 population) cases were reported in 1999, which is the lowest number reported since 1941. Sixty-five percent of cases occurred in the southern United States. The peak incidence of primary syphilis now occurs in people between the ages of 15 and 34 years. The male:female ratio has increased from 1.1:1 in 1994 to 1.5:1 in 1999; the male:female ratio of patients identified as Hispanic is 2.9:1. (6)

Primary syphilis presents as a painless chancre, which heals within 2 to 3 weeks. Secondary syphilis presents in 25% of untreated patients within weeks to months of primary infection. Common findings of secondary syphilis include rash of the palms and soles, fever, lymphadenopathy and central nervous system (CNS) changes. Forty percent of patients with secondary syphilis have CNS symptoms of visual disturbances, hearing loss, tinnitus, and facial weakness. (7) After a latency period, 25% of untreated patients have late (tertiary) syphilis. Tertiary syphilis presents from 1 to 30 years after primary infection. (8) This disease is slowly progressive and inflammatory and presents as neurosyphilis, cardiovascular syphilis, or gummatous syphilis. We present a case of neurosyphilis is a previously healthy, HIV-negative patient.


A 48-year-old Hispanic woman presented with complaints of fatigue and forgetfulness. She was vague in describing her symptoms. Her medical history was significant only for previous treatment for Trichomonas vaginalis, tubal ligation, and atypical squamous cells of unknown significance on Papanicolaou smear. Family history was unremarkable. She was taking no medications and denied use of alcohol, tobacco, or illegal substances. She was divorced and living with her stepdaughter and boyfriend of 4 years. She reported only two sexual partners since her divorce 10 years earlier. Initial outpatient evaluation led to a presumptive diagnosis of depression. She was given paroxetine, but she continued to decline. Her family reported that the patient would put clean clothing in the laundry; fabricate stories about nonexistent visitors, and claim that her husband was the devil. The patient had a bilateral facial droop, left arm weakness, and left leg weakness; she began to stumble and fall. She lost her job as a clerk. C omputed tomography (CT) showed slight prominence of the lateral and third ventricles and the temporal horns (Fig 1). Magnetic resonance imaging (MRI) showed mild hydrocephalus but no parenchymal lesions.

After the MRI, her mental status rapidly deteriorated. She became incontinent of urine and stopped eating. The patient had expressed no complaints of headache, vision difficulties, hearing loss, tinnitus, paresthesias, pain, stiff neck, myalgias, arthralgias, or other symptoms. She became unresponsive to verbal and tactile stimuli and was admitted to the hospital.

On admission, her temperature was 99.6[degrees]F, radial pulse rate was 110/min, respiratory rate was 18/min, and blood pressure was 140/80 mm Hg. Initial examination showed a nonverbal, minimally responsive woman with clonic spasms of the upper and lower extremities four times per minute. She would respond to a loud voice or sternal rub but would not follow commands. She was thin but not cachectic. Her pupils were 1.5 mm and minimally reactive to light. She had bilateral clonus, was hyperreflexic, and had bilateral down-going toes on Babinski test. The remainder of the examination was unremarkable.

Initial laboratory studies were remarkable for a normal leukocyte count and differential, a mild anemia with a low mean cell volume, and normal chemistry profile, transaminase levels, coagulation parameters, thyroid-stimulating hormone level, pancreatic tests, [B.sub.12] level, and folate level. Urine toxicology screen was negative for cocaine, narcotics, benzodiazepines, barbiturates, and cannabis. Serum alcohol level was undetectable. Chest radiograph and electrocardiogram were normal. Hepatitis B and hepatitis C serologies, Lyme Western blot, serum cryptococcal anti-bodies, enterovirus polymerase chain reaction, antinuclear antibodies, test for rheumatoid arthritis, cysticercosis antibodies, angiotensin converting enzyme, and HIV tests were all negative. An electroencephalogram showed left-sided slowing with no seizure activity. On lumbar puncture, the cerebrospinal fluid (CSF) glucose level was 66 mg/dL, protein level was 87 mg/dL; 80 white blood cells (69% reactive lymphocytes) and no red blood cells or bacteria were seen. India ink staining was negative for cryptococcus. Stain for acid-fast bacilli (AFB) was negative. She was initially started given intravenous ceftriaxone and acyclovir.

The next day, the serum and CSF returned with a reactive rapid plasma reagin (RPR), and penicillin was started. Acyclovir was discontinued when the herpes simplex polymerase chain reaction was reported negative. Cultures of the blood and CSF for bacteria, fungi, and AFB were negative, and CSF cytology was negative. Fluorescent treponemal antibodies (VIA) were present in both the serum and CSF. A gallium scan and CT of the chest were normal.

The patient's clonic temors responded to divalproex. She slowly improved in functional status and cognitive abilities over the next 20 days. She showed improved muscle strength after 1 week of therapy. She became oriented to person and could follow simple commands. Her cognitive status continued to wax and wane, with occasional visual hallucinations and violent outbursts. Repeated CT showed decreased prominence of the lateral and third ventricles. Lumbar puncture showed CSF protein of 126 mg/dL and WBC count of 165 cells (94% lymphocytes and 6% monocytes). Cultures and repeat cytology were again negative. Magnetic resonance imaging showed normal ventricles but extensive parenchymal abnormalities with increased signal in the medial portion of the temporal lobes involving the hippocampal gyri (Fig 2). There was also increased signal in the medial portions of the frontal lobes, in the left thalamus, and in the bilateral insular cortices.

By the 20th day of treatment, she had regained continence of urine and was in dependent in walking, grooming, and bathing. She was conversant, pleasant, and organized in her thoughts. She had no clonic motions after stopping the divalproex. She was alert and oriented but continued to show deficits in short-term memory. A lumbar puncture on the 21st day of treatment showed CSF protein level of 57 mg/dL and only 9 WBCs (8 lymphocytes and 1 monocyte). The patient was discharged home after a 21-day course of intravenous penicillin.


The patient presented with progressive and accelerating decline in mental status. Her initial lumbar puncture was consistent with aseptic meningitis. The differential diagnoses for aseptic meningitis in this setting are summarized in the Table. Seventy-five percent of cases of aseptic meningitis are due to enteroviruses (echoviruses). Noninfectious causes of aseptic meningitis, including medications, malignancies, and inflammatory or autoimmune diseases, always need to be considered. (9) In this patient, drug and toxic causes were eliminated by careful history from multiple sources and by toxicology screening. The CSF was not consistent with tuberculosis (CSF glucose is usually depressed in tuberculous meningitis), and stains and cultures were negative. Tests eliminated other infectious causes for her symptoms during her hospitalization.

The serum and CSF RPRs and FTA were reactive in our patient. Serum RPR and FTA have a specificity of 97% to 99%; RPR sensitivity is 71 % and FTA sensitivity is 96%. Cerebrospinal fluid RPR is insensitive, positive in only 30% of late syphilis cases, so a positive CSF RPR is considered diagnostic. (10) The combination of a reactive serum and CSF PTA is 94% specific and 87% sensitive. (11) False-positive rates decrease dramatically when combining the RPR test with the FTA to confirm the diagnosis. False-positive tests can occur when there is a strong immunologic stimulus present. Conditions producing false-positive results include Lyme disease, rheumatoid arthritis, malignancies, AIDS, and certain drugs. (12) These confounding causes must be considered and eliminated. False-negative syphilis tests occur in patients with HIV infection. (13) Dark-field examination technique cannot be done without an identifiable lesion from which to isolate the spirochete.

Impairments of memory and intellect due to involvement of the frontal and temporal lobes occur early in neurosyphilis. (14) Common MRI findings in neurosyphilis patients with general paresis (personality [paranoia, carelessness in appearance]; affect [labile]; reflexes [hyperactive]; eye [Argyll Robertson pupils]; sensorium [hallucinations, illusions, delusions]; intellect [decreased recent memory, judgment, insight]; and speech [slurred]) include dilated ventricles and either increased signal or atrophy of the medial temporal lobes. (15,16) Frontal cortical atrophy and disseminated frontal high signal lesions are also seen. (17) Magnetic resonance imaging that shows cerebral atrophy indicates a poor prognosis. These patients frequently maintain deficits in social functioning, personality changes and generalized dementia. (15) Our patient's MRI showed no evidence of atrophy but did show enhancement in the temporal and frontal regions. These lesions are consistent with neurosyphilis.

The patient's cognitive decline is consistent with parenchymatous neurosyphilis. Central nervous system pathologic findings of neurosyphilis include meningovascular neurosyphilis and parenchymatous neurosyphilis. Meningovascular neurosyphilis occurs 5 to 10 years after initial infection and produces classic findings ranging from progressive neurologic deficits to aphasias and seizures. Parenchymatous neurosyphilis develops 10 to 20 years after initial infection and includes tabes dorsalis and general paresis. Early paresis includes subtle deterioration of cognition with poor concentration, irritability, and loss of higher cortical functions. Associated psychiatric symptoms include depression and psychosis.

This patient likely contracted syphilis from her husband or shortly after her divorce 10 years before hospitalization. Her lack of previous treatment with penicillin is an important item in her history, since many people may be inadvertently treated for syphilis while receiving penicillin for an upper respiratory tract infection or other common illness. Despite lack of history of primary or secondary syphilis, this patient showed symptoms of parenchymatous neurosyphilis and paresis. Asymptomatic syphilis occurs in 8% to 40% of infected patients. (7,18) Since 1993, cases of late syphilis have outnumbered reported cases of primary and secondary syphilis. By 1999, 2.5 cases of late or late-latent syphilis were reported for each case of primary or secondary syphilis. (6) Although the patient denied any memory of a chancre or symptoms of secondary syphilis, on admission she had depression, illusions, hallucinations, carelessness, hyperreflexia, and loss of judgment, all of which are consistent with paresis.

The Centers for Disease Control and Prevention recommendations for the treatment of neurosyphilis include 18 to 24 million IU of intravenous penicillin each day for 10 to 14 days. (19)

Penicillin's profound impact on this disease is shown by a 60-fold decrease in admissions for neurosyphilis to US mental hospitals. Admissions declined from 5.9 cases per 100,000 population in 1942 to 0.1 cases per 100,000 in 1965. (20) Penicillin treatment for primary and secondary syphilis is curative. In 1986, Fiumara (21) reported on 588 patients with primary syphilis and 623 patients with secondary syphilis. Penicillin treatment resulted in all becoming seronegative within 2 years. The World Health Organization (WHO) reported in 1972 that of 1,030 patients treated with 2.4 to 4.0 million IU of penicillin, 93% to 100% achieved serologic nonreactivity. (22) In a 1956 study, 756 patients with asymptomatic neurosyphilis were treated with penicillin and followed up for 7 years. Symptomatic neurosyphilis developed in 3.3% of these patients; most had only subtle neurologic changes and none had true paresis.(23) The WHO summarized 24 studies encompassing almost 7,000 patients treated for neurosyphilis. Methodolo gic differences made trial comparisons difficult. Persistent reactivity was found in the majority of trials. Side effects to penicillin were rare and usually not severe. Irreversible brain damage often occurred before treatment and sometimes progressed even after therapy for neurosyphilis. (24)

Penicillin treatment has potential adverse reactions. Treatment has been known to precipitate the Jarisch-Herxheimer reaction, particularly in patients with early syphilis. This reaction is an inflammatory response to the destruction of treponemes. (25) It occurs within hours of treatment and subsides within 24 hours. The symptoms of Jarisch-Herxheimer, reaction are fever, headache, hypotension, and myalgias. The reaction occurs in up to 95% of treated cases of primary syphilis but is rare in treated late syphilis. (26) Penicillin can also produce an allergic reaction and anaphylactic shock. In 1965, the Department of Health, Education, and Welfare (now the Department of I-Health and Human Services) reported the frequency of penicillin allergy in patients treated for gonorrhea or syphilis to be 0.67%; only 0.015% had anaphylaxis.(27) No deaths were observed. In 1987, approximately 10% of adults in the United States reported an allergy to penicillin. (28)

Our patient received the maximum penicillin dosage recommended for treatment. Unresponsive on admission, this 48-year-old woman became alert and oriented with marked improvement in neurologic status in less than 3 weeks. Her CSF studies also improved during treatment. Clinical improvement correlates with decreased CSF pleocytosis.(29) The CDC guidelines state that CSF leukocyte count should decrease within 6 months after therapy. Protein levels are expected to drop at a slower rate and normalize within 2 years. Although CSF RPR titers decrease, it may be years before they become nonreactive.(13)

All patients with secondary syphilis or syphilis of more than 1 year should be evaluated for neurosyphilis. Patients should be monitored closely for signs and symptoms of recurrence. Sexual contacts of patients need be identified and evaluated. Our patient continues to be followed up in the outpatient setting and remains neurologiclaly stable.


Neurosyphilis remains a disease of contemporary society. This disease may mimic other diseases and be difficult to recognize and to diagnose. The differential diagnosis of any patient presenting with aseptic meningitis needs to include late syphilis. A complete history and physical examination complemented by appropriate testing are essential. With appropriate antibiotic therapy, primary and secondary syphilis are curable. Patients with early neurosyphilis may respond better to therapy than those with a late presentation of the disease; thus, early diagnosis remains important for a good clinical outcome.

Causes of Aseptic Menigitis

Infectious causes
 Viruses Enterovirus (poliovirus,
 coxsackievirus, echovirus),
 herpes simplex, types 1 and 2,
 varicella-zoster virus,
 adenovirus, Epstein-Barr virus,
 lymphocytic choriomeningitis
 virus, human immunodeficiency
 Bacteria Partially treated bacterial
 meningitis, endocarditis,
 parameningeal infection,
 Mycoplasma pneuomniae,
 Mycobacterium tuberculosis,
 Ehrlichiosis, Borrelia
 burgdorferi, Treponema pallidum,
 Fungi Cryptococcus neoformans,
 Histoplasma capsulatum,
 Coccidioides immitis, Blastomyces
 Parasites Toxoplasma gondii, Toxoplasma

Noninfectious causes
 Drugs Nonsteroidal anti-inflamatory
 OKT3, intravenous immunoglobulin,
 isoniazid intrathecal methotrexate
 and cytosine arabinoside,
 Systemic diseases Sarcoidosis, leptomeningeal
 cancer, posttransplantation
 lymphoproliferative disorder,
 sytemic lupus erythematosis,
 Wegener's granulomatosis, central
 nervous system vasculitis,
 Behcet's syndrome
 Other Arachnoiditis, migraine,
 postinfectious syndromes


(1.) Kampmeier RH: Essentials of Syphilology. Philadelphia, JB Lippincott Co, 3rd Ed, 1943

(2.) Kilmarx PH, Louis ME: The evolving epidemiology of syphilis. Am J public Health 1995; 8:1053-1054

(3.) Summary of Notifiable Diseases, United States, 1997. MMWR Morb Mortal Wkly Rep 1998: 46:60-61

(4.) Summary of Notifiable Diseases, United States. MMWR Morb Mortal Wkly Rep 1997; 46:42

(5.) Musher DM: Syphilis, neurosyphilis, penicillin and AIDS. J. Infect Dis 1991; 163:1201-1206

(6.) Division of STD Prevention: Sexually Transmitted Disease Surveillance 1999. Atlanta, Ga, US Department of Health and Human Services, Centers for Disease Control and Prevention, 2000

(7.) Lukehart S, Hook EW, Baker-Zander SH, et al: Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and therapy. Ann Intern Med 1998; 109:855-862

(8.) Clark EG, Danbolt N: The Oslo study of the natural course of untreated syphilis. Med Clin North Am 1964; 48:613-621

(9.) Pruitt AA: Infections of the central nervous system. Neurol Clin 1998; 16:419-447

(10.) Hook EW, Marra CM: Acquired syphilis in adults. N Engl J Med 1992; 326:1060-1065

(11.) Maclean S, Luger A: Finding syphilis without the Venereal Disease Research Laboratory test. Sex Transm Dis 1996; 23:392

(12.) Roos K: Neurosyphilis. Semin Neurol 1992; 12:209-212

(13.) Erbelding EJ, Vlahov D, Nelson KE, et al: Syphilis serology in HIV infection: evidence for false negative fluorescent treponemal testing. J Infect Dis 1997; 176:1397-1399

(14.) Denays R, Collier A: A 51-year-old woman with disorientation and amnesia. Lancet 1999; 354:1786

(15.) Kodama K: Relationship between MRI findings and prognosis for patients with general paresis. J Neuropsychiatr Clin Neurosci 2000; 12:246-250

(16.) Russouw HG, Roberts MG, Emsley RA, et al: Psychiatric manifestations and magnetic resonance imaging in HIV-negative patients. Biol Psychiatry 1997; 41:467-473

(17.) Querol-Pascual MR, Casado-Naranjo I: Diagnostic value of magnetic resonance in neurosyphilis. Neurologia 1993; 8:78-81

(18.) Tramont E: Treponema pallidum. Principles and Practice of Infectious Diseases. Mandell CC, Bennett JE, Palm R, eds. New York, Churchill-Livingstone, 5th Ed, 2000, pp 2474-2489

(19.) Centers for Disease Control and Prevention: 1998 guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep 1998; 47:1-116

(20.) Scheck DN, Hook E: Neurosyphilis. Infect Dis Clin North Am 1994; 8:769-795

(21.) Fiumara NJ: The treatment of primary and secondary syphilis: the serologic response. J Am Acad Dermatol 1986; 14:487-491

(22.) Idsoe O, Guthe T, Wilcox RR: Penicillin in the treatment of syphilis, the experience of three decades. Bull World Health Org 1972; 47(suppl):1-68

(23.) Hahn RD, Webster B, Weickhardt G, et al: Penicillin treatment of asymptomatic central nervous system syphilis II. results of therapy as measured by laboratory findings. Arch Dermatol 1956; 174:367-377

(24.) Wilner E, Brody JA: Prognosis of general paresis after treatment. Lancet 1968; 2:1370-1371

(25.) Johnson RA, White M: Syphilis in the 1990s: cutaneuous and neurologic manifestations. Semin Nearol 1992; 12:287-298

(26.) Wilcox RR A Textbook of Venereal Diseases and Treponematoses. London, Heinemann Medical Books, 2nd Ed, 1964

(27.) VD Fact Sheet 1965. Washington, DC, US Department of Health, Education and Welfare, 22nd rev, 1965, Public Health Service Publication 341

(28.) Centers for Disease Control and Prevention: Primary and secondary syphilis--United States, 1997. MMWR Morb Mortal Wkly Rep 1998; 47:493-497

(29.) Currie JN, Coppeto JR, Lessell S: Chronic syphilitic meningitis resulting in superior orbital fissure syndrome and posterior fossa gumma: a report of two cases followed for 20 years. J Clin Neuroophthalmol 1988; 8:145-155


* There are 2.2 cases of syphilis per 100,000 population in the United States.

* False-positive rapid plasma reagin test can be seen in patients with Lyme disease, rheumatoid arthritis, malignancies, AIDS, and those taking certain drugs.

* Impairments in memory and intellect are seen early in neurosyphilis. Patients may show deficits in social functioning, personality changes, and generalized dementia.

* The diagnosis of neurosyphilis must be considered early and aggressively pursued. Delay in recognition and treatment can result in a poor outcome.

From the Department of Medicine, Hartford Hospital, Hartford, Conn.

Reprint requests to Michael Lindberg, MD, Hartford Hospital, Department of Medicine, 80 Seymour Street, Hartford, CT 06102.
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Author:Lindberg, Michael
Publication:Southern Medical Journal
Geographic Code:1USA
Date:Sep 1, 2002
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