Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum. It is passed from person to person through direct contact with syphilis sores, which mainly occur on the external genitals, vagina, anus or rectum. Syphilis infection occurs in stages, with different symptoms manifesting at each stage. The first stage is primary syphilis which appears as a single sore at the site of infection. The second stage is secondary syphilis which occurs several weeks later, causing a diffuse rash on the body as well as fever, swollen lymph nodes and fatigue. After a period of latency, tertiary syphilis may occur, affecting the cardiovascular system and central nervous system. Neurosyphilis refers specifically to infection of the brain and spinal cord by T. pallidum. This article reviews the evidence on whether and how neurosyphilis can cause cognitive and psychiatric symptoms.
Does syphilis enter the central nervous system?
Treponema pallidum can invade the central nervous system early in the course of infection. During primary or secondary syphilis, the spirochetes can cross the blood-brain barrier and blood-CSF barrier via infected macrophages. This establishes early invasion of the cerebrospinal fluid (CSF) and meninges. From the meninges, the bacteria spread into the brain and spinal cord parenchyma. It seems that T. pallidum has a predilection for infecting the frontal and temporal lobes of the brain.
The risk of early neuroinvasion is not trivial. Studies examining CSF in patients with primary and secondary syphilis have detected T. pallidum in up to 40% of patients. The likelihood of detecting treponemal DNA in the CSF increases with duration of syphilis infection. Therefore, the spirochetes can enter the CNS quite early on, well before tertiary neurosyphilis becomes apparent.
What are the stages of neurosyphilis?
If left untreated, T. pallidum can reside in the central nervous system for decades before manifestations of neurosyphilis appear. Neurosyphilis is generally divided into early and late forms.
Early neurosyphilis
Early neurosyphilis refers to involvement of the CNS within the first few years following syphilis infection. The most common syndromes of early neurosyphilis are:
- Asymptomatic neurosyphilis – abnormal CSF findings without neurological signs or symptoms
- Meningitis – headache, neck stiffness, photophobia, nausea
- Meningovascular syphilis – cranial nerve palsies, stroke
- General paresis – dementia, delirium, personality changes
- Tabes dorsalis – lightning pains, ataxia, bowel/bladder dysfunction
Early neurosyphilis develops in approximately 25% of people infected with syphilis if they are not treated. The most frequent clinical manifestations are meningitis, meningovascular disease and ocular syphilis. These syndromes reflect active infection and inflammation. If caught at this stage, early neurosyphilis generally responds well to antibiotic treatment. However, relapse can occur.
Late neurosyphilis
Late neurosyphilis refers to the slow progression of chronic CNS infection over many years, typically more than 10-20 years after initial syphilis infection. The most common manifestation is:
- General paresis – dementia, psychiatric symptoms, motor abnormalities
Tabes dorsalis also occurs but is less common. In general paresis, the brain develops severe inflammatory changes including microglial nodules and amyloid plaques. Over time, diffuse cortical atrophy occurs. These changes ultimately lead to dementia, personality changes and psychosis. Late neurosyphilis tends to be relentless and progressive, only mildly improved by antibiotic treatment at this advanced stage.
What neuropsychiatric symptoms can neurosyphilis cause?
A wide spectrum of neurological and psychiatric manifestations can occur with neurosyphilis infection at any stage:
Cognitive symptoms
- Dementia
- Memory loss
- Executive dysfunction
- Slowed thinking
- Confusion
- Decline in job performance
General paresis classically caused a dementia syndrome, but milder cognitive impairment is also possible. The cognitive deficits reflect involvement of frontal and temporal cortices. Executive functions like planning, organization, judgment and impulse control are often affected early on.
Psychiatric symptoms
- Personality changes
- Irritability
- Depression
- Mania
- Psychosis
- Violent behavior
Mood and personality changes can result from the brain inflammation caused by neurosyphilis. Mania and psychosis are common in general paresis. Delusions especially tend to involve grandiose, paranoid or persecutory themes. Hallucinations are less prominent.
Other neuropsychiatric manifestations
- Headache
- Dizziness
- Tremor
- Epileptic seizures
- Stroke
- Hearing loss
- Visual disturbances
Headaches, vertigo and meningismus may reflect infection of the meninges. Stroke results from inflammatory arteritis. Cranial nerve palsies can cause vision and hearing problems. Tabes dorsalis affects the dorsal columns and dorsal roots, leading to sensory ataxia and shooting pains.
In summary, neurosyphilis can mimic almost any type of psychiatric or neurological illness. Cognitive, behavioral and motor functions may be impacted at all stages of CNS infection. A high index of suspicion is required to make the diagnosis.
How common is neurosyphilis today?
The incidence of neurosyphilis rose significantly in the 1980s and early 1990s during the HIV epidemic, when syphilis co-infection was common. However, even today, neurosyphilis remains a critical concern. Some key epidemiological points:
- About 30-40% of people with untreated late stage syphilis will develop clinical neurosyphilis
- In the U.S., the rate of neurosyphilis increased from 2.1 to 3.0 cases per 100,000 population from 2004 to 2013
- Up to 14% of people diagnosed with syphilis today have asymptomatic neurosyphilis detected in CSF
- HIV co-infection markedly increases the likelihood of neurosyphilis
While tertiary neurosyphilis is now uncommon thanks to antibiotic treatment, early invasion of the CNS still occurs frequently. Ongoing surveillance is crucial since neurosyphilis can still develop in some patients despite appropriate therapy for syphilis.
How is neurosyphilis diagnosed?
Diagnosing neurosyphilis begins with a thorough clinical history to identify possible CNS symptoms. However, the diagnosis ultimately depends on direct detection of T. pallidum. The gold standard diagnostic tests are:
- CSF VDRL – tests CSF for antibodies that react to cardiolipin released from damaged host cells
- CSF cell count – elevated white blood cells indicate inflammation
- CSF protein – elevated protein suggests infection/inflammation
- CSF PCR – detects treponemal DNA in CSF
These CSF tests directly confirm CNS infection by T. pallidum. Neuroimaging via CT or MRI may reveal diffuse atrophy or white matter changes in late neurosyphilis. However, neuroimaging cannot reliably distinguish neurosyphilis from other types of dementia.
Some key points regarding diagnosis:
- CSF abnormalities are detected in up to 70% of people with early syphilis
- CSF VDRL is highly specific but not sensitive; a negative result does not rule out neurosyphilis
- PCR is the most sensitive test for direct detection of T. pallidum DNA
Performing a lumbar puncture is essential to identify asymptomatic neurosyphilis. Testing serum VDRL or RPR alone is inadequate since results may be normal in up to 25% of people with neurosyphilis.
How is neurosyphilis treated?
Penicillin remains the treatment of choice for all stages of neurosyphilis. The regimen is:
- Aqueous crystalline penicillin 18-24 million units per day, administered as 3-4 million units IV every 4 hours for 10-14 days
Alternatives for penicillin-allergic patients include ceftriaxone and doxycycline. However, relapse risk may be higher with non-penicillin regimens.
Treatment response depends on the stage and severity of neurosyphilis:
- Early neurosyphilis generally responds well to antibiotics
- Late neurosyphilis may only stabilize or mildly improve with treatment
- Up to 25% of patients experience relapse after initial antibiotic treatment
CSF abnormalities improve more quickly with therapy than clinical symptoms. Neuropsychiatric symptoms may take weeks or months to improve. Neurological damage from late neurosyphilis is difficult to reverse. Close clinical follow-up is imperative after treatment. Repeat CSF examinations should be performed to confirm response.
Does proper treatment prevent neurosyphilis?
Early diagnosis and treatment of primary and secondary syphilis is the best way to prevent late stage complications like neurosyphilis. However, proper syphilis treatment does not always prevent invasion of the CNS.
Key points:
- Up to 40% of properly treated syphilis patients have abnormal CSF consistent with asymptomatic neurosyphilis
- 1-2% of people develop symptomatic early neurosyphilis despite appropriate prior syphilis therapy
- Late stage neurosyphilis can still occur in 0.6% of adequately treated patients
These statistics illustrate that standard syphilis treatment regimens do not eradicate CNS infection in all cases. This may be due to inadequate penetration of benzathine penicillin into the CSF. Close monitoring after treatment is essential to detect possible neurosyphilis relapse or progression.
Conclusion
In summary, syphilis has a proven ability to invade the central nervous system and lead to an array of neuropsychiatric symptoms. While late stage neurosyphilis has become less common, early asymptomatic infection of the CNS still occurs frequently. Ongoing surveillance and immediate treatment of neurosyphilis is critical to prevent irreversible psychiatric and neurological damage. Even after seemingly effective treatment, syphilis treponemes may persist in the CNS and later re-emerge as symptomatic neurosyphilis. Therefore, assessment of CSF via lumbar puncture is essential for accurate diagnosis and tracking of treatment response. While modern antibiotics can successfully treat neurosyphilis, they may not fully eradicate the spirochetes that have invaded the brain and spinal cord.