Neurosyphilis: How to Recognize and Diagnose It in Time

Dr. Aliona Baublienė Faculty of Medicine, Vilnius University

Introduction

Syphilis is an infection that has been known to humanity since ancient times. In 1496, the disease reached epidemic proportions and spread widely across France, Germany, Switzerland, and later Austria, Hungary, and Poland. It is estimated that more than 5 million people died from syphilis during that period. Although the incidence of the disease later declined, the number of people affected by syphilis, including its most severe forms, remains significant to this day. In this article, we briefly review one of the forms of syphilis—neurosyphilis—with particular attention to its clinical manifestations and diagnostic features.

Causative Agent and Classification of the Disease

Treponema pallidum is a gram-negative spirochete (a motile, spiral-shaped bacterium). It measures 6–15 μm in length and 0.1–0.2 μm in width. The organism consists of an outer membrane surrounding a complex of periplasmic flagella, peptidoglycan, and cytoplasmic membrane, as well as a protoplasmic cylinder. It reproduces by binary fission. The classification of Treponema species is based on the clinical manifestations of the diseases they cause. Treponema pallidum subspecies pallidum causes venereal syphilis, Treponema pallidum subspecies pertenue causes yaws, Treponema pallidum subspecies endemicum causes endemic syphilis, and Treponema carateum causes pinta, a chronic skin disease (1). Treponemal diseases are transmitted through sexual contact when the pathogen enters host tissues and penetrates damaged squamous or columnar epithelium (2). Syphilis is classified as either acquired or congenital. Acquired syphilis is further divided into primary, secondary, latent, tertiary, and late forms. Congenital syphilis may be early or late. A more detailed classification of syphilis is presented in Table 1 (3).

Epidemiology

In recent years, the incidence of syphilis has increased. In the United States, the rate of primary and secondary syphilis in 2017 was 9.5 cases per 100,000 population (4). In China, 22 per 100,000 people were diagnosed with syphilis in 2008 (4). The incidence of neurosyphilis declined substantially after the introduction of penicillin. In the United States, the incidence over the past decade has ranged from 0.47 to 2.1 cases per 100,000 population (5). Several epidemiological studies have reported that individuals with HIV are approximately twice as likely to develop neurosyphilis (6). According to data from the Center for Communicable Diseases and AIDS (ULAC) in Lithuania, syphilis was diagnosed in 130 individuals in 2018 and in 157 individuals in 2017. In 2015, the overall incidence rate was 9.7 cases per 100,000 population. The highest incidence rates were recorded in the country’s largest cities—Vilnius, Šiauliai, and Kaunas. Syphilis is considerably more common among men than women. More than half of all cases are diagnosed during the early stages of the disease. One case of congenital syphilis was recorded in 2017, while no cases were reported in 2018 (7).

Clinical Features of Neurosyphilis

Neurosyphilis may be classified as asymptomatic or symptomatic and, according to the time of onset, as early (1–2 years after primary infection) or late (Table 2) (8). Early neurosyphilis is typically characterized by asymptomatic meningitis, manifested only by abnormalities in cerebrospinal fluid (CSF) cell counts. In some cases, symptomatic meningitis develops, presenting with headache, meningism, cranial nerve palsies, blindness, and deafness (Table 2). In meningovascular syphilis, small and medium-sized arteries of the central nervous system are affected, resulting in vasculitis. This form of neurosyphilis presents with stroke-like symptoms and various neurological deficits. Meningovascular syphilis most commonly develops between the early and late forms of neurosyphilis, approximately 1–10 years after primary infection. Late neurosyphilis is characterized by general paresis (also known as general paresis of the insane) and tabes dorsalis. Studies have shown that this form may lead to frontotemporal dementia accompanied by delusions, such as believing oneself to be an emperor or king. General paresis is characterized by psychosis, depression, personality changes, and progressive dementia. Advanced tabes dorsalis causes instability during the Romberg test and abnormal pupillary responses to light. Some patients develop a characteristic stamping gait, placing the entire foot forcefully on the ground and often relying on a walking stick to maintain balance. Tabes dorsalis may also lead to neuropathic arthropathy, which can cause severe abdominal and limb pain (10, 11).

Laboratory Diagnosis

The diagnosis of neurosyphilis is based on both clinical findings and CSF examination. Characteristic CSF abnormalities include elevated white blood cell counts and increased protein concentrations. Blood and CSF tests used in patients with suspected neurosyphilis are divided into non-treponemal and treponemal tests. Non-treponemal tests include the Venereal Disease Research Laboratory (VDRL) test and the Rapid Plasma Reagin (RPR) test. Treponemal tests include fluorescent treponemal antibody absorption (FTA-ABS) and related methods. Because of its high specificity, VDRL remains one of the most commonly used tests for diagnosing syphilis (12). The Centers for Disease Control and Prevention (CDC) in the United States do not recommend routine CSF RPR testing because of its low sensitivity and high likelihood of false-negative results (16). Neurosyphilis is frequently associated with pleocytosis and elevated protein concentrations in the cerebrospinal fluid. Pleocytosis is considered a less specific marker in individuals with HIV, particularly when HIV infection remains untreated and peripheral blood CD4+ T-cell counts are high (13). Non-treponemal serum tests are almost always positive in neurosyphilis. However, in late-stage neurosyphilis, results may become negative because antibody titers decline over time, especially following treatment. If a patient with suspected neurosyphilis has a negative CSF VDRL result, CSF treponemal testing is recommended (15). The sensitivity and specificity of serological tests are discussed in Table 2. Serum and CSF treponemal tests generally remain positive throughout life in untreated individuals. However, CSF treponemal tests become negative in approximately 15% of patients several years after successful treatment of uncomplicated syphilis. False-positive results may occur due to blood contamination of the CSF sample when more than 1,000 red blood cells per mm³ are present. In the United States, all patients diagnosed with syphilis, including neurosyphilis, are recommended to undergo testing for HIV infection (15).

Lumbar Puncture

CSF examination is recommended when serum tests confirm syphilis and clinical signs suggestive of neurosyphilis are present. Historically, periodic monitoring of CSF white blood cell counts was used to assess treatment effectiveness. Repeat treatment was recommended when pleocytosis failed to decrease within 6 months of treatment or did not resolve completely within 2 years after therapy (15). According to some studies, repeat CSF testing is not necessary if serum RPR titers decrease fourfold or return to normal levels (16). Other authors suggest that CSF examinations should be repeated periodically until the white blood cell count begins to decline (8). It remains unclear how frequently lumbar puncture should be performed in patients with HIV infection who have received effective treatment for neurosyphilis and no longer exhibit neurological symptoms (15). Routine CSF testing for syphilis is not recommended in patients with dementia. However, it may be useful in individuals with risk factors for syphilis, particularly those with HIV infection (17).

Treatment

The marked decline in the incidence of general paresis over the past 50 years suggests that early treatment of syphilis has helped prevent the development of late neurosyphilis. Parenteral penicillin remains effective against all forms of neurosyphilis. Treatment recommendations vary slightly between the United States, the United Kingdom, and European countries. Based on historical clinical experience, penicillin does not reverse established neurological damage in late neurosyphilis syndromes, but it can halt further disease progression. For patients with penicillin allergy, skin testing and desensitization procedures are recommended whenever possible (15). Limited evidence suggests that ceftriaxone, tetracycline, and doxycycline may also be effective in treating neurosyphilis. However, penicillin remains the first-line treatment and the preferred therapy for neurosyphilis (18).

Table 1. General Classification of Syphilis

Stage	Description	Symptoms
Acquired
Primary	Infectious	Chancre (a small, usually painless skin lesion), regional lymphadenopathy
Secondary	Infectious. Begins several weeks or months after the primary stage	Rash (which may be mistaken for other diseases), mucosal ulcers, hair loss, fever, and other systemic symptoms
Latent	Asymptomatic, usually non-infectious. May persist indefinitely and progress to the tertiary stage	Early latent syphilis (duration of infection less than one year) and late latent syphilis
Tertiary or Late	Symptomatic, non-infectious	Clinically classified as benign tertiary syphilis, cardiovascular syphilis, or neurosyphilis (e.g., asymptomatic, meningovascular, or parenchymal neurosyphilis; tabes dorsalis)
Congenital
Early	Symptomatic, appears before 2 years of age	Active disease
Late	Symptomatic, appears later in life	Hutchinson’s teeth, ocular abnormalities, or skeletal abnormalities

Table 2. Stages of Neurosyphilis, Clinical Manifestations, and Laboratory Findings

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Table 3. Sensitivity and Specificity of Laboratory Tests

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Stage	Clinical Presentation	Laboratory Tests
Early
Asymptomatic early neurosyphilis	Asymptomatic with pleocytosis developing a few weeks after infection	Reactive serum and CSF VDRL test results
Syphilitic Meningitis	Headache, meningism, photophobia, cranial nerve paresis (optic and auditory neuropathies), confusion, lethargy, seizures; symptoms appear after several weeks or months from infection	Reactive serum and CSF VDRL test results, reactive CSF FTA-ABS test results; CSF white blood cell count 10–400/mm3
Early or Late
Meningovascular Syphilis	Stroke, cranial nerve paralysis, meningism, meningomyelitis with progressive myelopathy, including sphincter dysfunction	Reactive serum and CSF VDRL test results, CSF white blood cell count 5–100/mm3
Late
General Paresis	Progressive dementia, psychiatric syndromes, personality changes, delusional mania, tremors, dysarthria (manifesting as halting and scanning speech), Argyll Robertson pupils in less than half of patients	Reactive serum VDRL test results in half of patients, reactive CSF VDRL results, most commonly reactive CSF FTA-ABS test results; mild, chronic pleocytosis
Tabes Dorsalis	Ataxic gait, swaying standing in Romberg's position, lightning pains in legs and trunk, severely impaired deep and proprioceptive sensations, Charcot's joints, Argyll Robertson pupils in most patients, paraparesis with areflexic legs, sphincter dysfunction	Serum VDRL test results may be nonreactive, reactive CSF VDRL test results, most commonly reactive CSF FTA-ABS test results; moderate, chronic pleocytosis
Test	Sensitivity (%)		Specificity (%)
	Early Neurosyphilis	Late Symptomatic Neurosyphilis	Late Symptomatic Neurosyphilis
Serological Tests
Serum VDRL or RPR	100	50–75	90
CSF VDRL	75	30–70	100
Serum FTA-ABS, TPHA	100	Approximately 96	Approximately 60
CSF FTA-ABS	100	Approximately 99	Approximately 50–70
CSF Composition
White cell count >5–10/mm3	100	95	Approximately 97
Protein >45 mg/dl	90	95	<50