Neurosyphilis

Clinical manifestations
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By Joseph R Berger MD

Infection with T pallidum is divided into several stages. Primary syphilis, the initial manifestation of infection, is an ulcerated, painless lesion with firm borders, referred to as a chancre. This lesion develops at the site of epidermal or mucous membrane inoculation and is accompanied by regional adenopathy. This lesion occurs approximately 3 weeks after infection, although the time to development ranges from 3 to 90 days. The latency to its appearance depends on the size of the inoculum. Although the lesion is a local manifestation, the spirochetes, even at this early stage, have disseminated systemically as evidenced by the ability to transmit syphilis by blood donation from incubating seronegative donors and the presence of detectable T pallidum in the cerebrospinal fluid of a substantial percentage of infected persons.

Within 2 to 8 weeks of the appearance of the chancre, the features of secondary syphilis appear. These features have been largely attributed to a bacteremic phase of the illness and include a macular, maculopapular, or pustular rash that often involves the palms and soles; mucous patches; and alopecia. Constitutional signs, diffuse adenopathy, iridocyclitis, hepatitis, periostitis, and arthritis often accompany these skin manifestations. A brisk immune response is observed, and immune complex deposition may lead to nephrotic syndrome. In this stage of syphilis, a symptomatic aseptic meningitis may occur in up to 5% of patients.

Latent syphilis, a quiescent phase of syphilis that precedes the development of tertiary complications, is divided into early (within 2 years of infection) and late (longer than 2 years) stages to reflect the probability of recurrence of secondary syphilitic manifestations. Tertiary syphilis is characterized chiefly by skin, osseous, cardiovascular, and neurologic complications. Clinically apparent neurologic complications of tertiary syphilis affect less than 10% of untreated patients. Neurosyphilis is simply the occurrence of neurologic complications due to infection with T pallidum. It may occur during early or late syphilis. The spectrum of neurosyphilis is broad. It is not uncommon for some of these forms of neurosyphilis to overlap with another in any given patient. The specific neurologic manifestations of syphilis are, in some respect, a function of the time from infection. The most common form of neurosyphilis currently diagnosed is asymptomatic neurosyphilis. Individuals with this form of neurosyphilis come to medical attention because of serological evidence of syphilis in the absence of neurologic sequelae. Examination of the cerebrospinal fluid reveals evidence of neurosyphilis; these patients are at risk for developing symptomatic disease. Among the symptomatic disorders of neurosyphilis, the earliest manifestation is syphilitic meningitis, which typically occurs within the first 12 months of infection and may accompany features of secondary syphilis. Although the majority of patients with CSF abnormalities occurring in association with secondary syphilis are neurologically asymptomatic, approximately 5% of all patients with secondary syphilis will have an associated meningitis. Headaches, meningismus, cranial nerve palsies (chiefly, in descending order of frequency, VII, VIII, VI, and II), hearing loss, tinnitus, and vertigo may be observed in isolation or combination in upwards of 40% of patients with secondary syphilis. Impaired vision secondary to chorioretinitis, retinitis, optic neuropathy, optic chiasmal, or optic tract disease has also been reported (Oette et al 2005; Iwamoto et al 2009). The symptoms of syphilitic meningitis include headache, photophobia, and a stiff neck. Encephalopathic features resulting from vascular compromise or increased intracranial pressure may be observed. These include confusion, lethargy, seizures, aphasia, and hemiplegia. Intractable seizures may, on rare occasions, be the initial manifestation of neurosyphilis (Phan et al 1999). Acute sensorineural hearing loss and acute optic neuritis may occur in association with syphilitic meningitis or independently.

Meningovascular syphilis may affect the brain or spinal cord. It typically occurs 6 to 7 years after the initial infection, but it may occur as early as 6 months after the primary infection. The nature of the neurologic features is dependent on the area of the brain or spinal cord affected. Many of the stroke eponyms described at the turn of the last century were the consequence of meningovascular syphilis producing discrete lesions of the brainstem. The neurologic manifestations include aphasia, hemiparesis, hemianesthesia, diplopia, vertigo, dysarthria, and a variety of brainstem syndromes. CT and MRI are invaluable diagnostic aids.

Syphilitic meningomyelitis is characterized by slowly progressive weakness and paresthesia of the lower extremities. Eventually, bowel and bladder incontinence and paraplegia supervene. Examination reveals a spastic paraparesis or paraplegia with brisk lower extremity reflexes, loss of the superficial abdominal reflexes, and impaired sensory perception, with vibratory and position sense being disproportionately affected. Syphilitic transverse myelitis may also be observed resulting in an acute onset of lower extremity paraplegia and sensory loss. Occasionally, the manifestations of this syndrome are more variable with asymmetrical findings noted, including a Brown-Sequard syndrome. An acute infarction of the anterior spinal artery results in paraplegia and loss of pain and temperature sensation below the level of the lesion with preservation of vibratory and position sense. The preceding spinal cord syndromes are manifestations of meningovascular syphilis. The characteristic spinal cord syndrome associated with parenchymatous neurosyphilis is tabes dorsalis. This disorder usually has a latency of 15 to 30 years following infection. The most distinctive and often heralding symptom is shooting or lightning-like pains that typically affect the legs and abdomen. On occasion, these pains have been mistaken for surgical emergencies. Touch of the affected areas may serve as a trigger for the pain. Pupillary abnormalities are observed in over 90% of patients; the hallmark abnormality is Argyll Robertson pupils: miotic, irregular pupils exhibiting light-near dissociation. The gait is ataxic, with an associated foot-stomping character due to an associated impaired position sense. The Romberg test, originally described in patients with tabes and at one time considered synonymous with tabes dorsalis (Pearce 2005), is positive. The impaired sensory perception also leads to the development of Charcot joints, painless swelling of joints, chiefly the knees, due to repeated trauma, and to perforating ulcers of the toes and soles of the feet. The impaired sense of deep pain may be demonstrated by its absence on squeezing the testicle (Pitre sign), the ulnar nerve (Biernacki sign), or Achilles tendon (Abadie sign). Impotence and bladder dysfunction are expected. The lower extremity reflexes are absent. Optic atrophy and cranial nerve palsies are frequently observed. Tabes dorsalis has been mistakenly diagnosed as Miller-Fisher syndrome as it may present as a constellation of ophthalmoplegia, ataxia, and areflexia (Stepper et al 1998). Paraparesis may also be seen as a consequence of syphilitic aortic dissection (Kellett et al 1997). The spectrum of syphilitic spinal cord disease is diverse.

Table 1. Syphilis of the Spinal Cord

  • Syphilitic meningomyelitis
  • Syphilitic spinal pachymeningitis
    - Spinal cord gumma
    - Syphilitic hypertrophic pachymeningitis
  • Spinal vascular syphilis
  • Syphilitic poliomyelitis
  • Tabes dorsalis
  • Miscellaneous
    - Syringomyelia
    - Syphilitic aortic aneurysm
    - Charcot vertebra with compression of the spinal cord

Modified from (Berger 1987).

General paresis is a manifestation of parenchymatous neurosyphilis and, like tabes dorsalis, usually develops after a long (15- to 30-year) hiatus from the time of infection. General paresis accounted for a substantial percentage of psychiatric illness in the preantibiotic era and, in a study from South Africa, was found in 1.3% of all patients being admitted for acute psychiatric care (Roberts et al 1992). In addition to a progressive dementia, these patients display a wide variety of psychiatric disturbances, including emotional lability, paranoia, illusions, delusions of grandeur, hallucinations, and inappropriate behavior. Tremors of the tongue, postural tremors of the extremities, hyperreflexia, hypomimetic facies, dysarthria, chorioretinitis, optic neuritis, and pupillary abnormalities, including Argyll Robertson pupils, are seen. Cranial MRI of patients with general paresis has demonstrated frontal and temporal atrophy, subcortical gliosis, and increased ferritin in the basal ganglia (Zifko et al 1996).

Gummas of the nervous system present chiefly as space-occupying lesions. Gummas affecting the brain may result in progressive focal neurologic manifestations, seizures, or increased intracranial pressure. A linear dural enhancement on MRI similar to that observed with meningiomas may be found with cerebral gummas (Inoue et al 1995). Gummas affecting the spinal cord result in progressive quadriparesis when located in the cervical area, or in progressive paraparesis when in the thoracic area.

An atypical form of neurosyphilis referred to as "modified neurosyphilis" has been attributed to the use of antibiotics for conditions other than syphilis in patients with unrecognized syphilis. This illness is characterized by a negative cerebrospinal fluid VDRL test and clinical features that are outside the spectrum of classically described features of neurosyphilis; however, the contention that these manifestations are syphilitic in origin remains debatable.

Concomitant human immunodeficiency virus infection may significantly alter the natural history of neurosyphilis (Johns et al 1987; Katz and Berger 1989; Katz et al 1993). Syphilis appears to be not only more aggressive, but also more difficult to treat when it occurs in association with HIV infection (Berry et al 1987; Musher et al 1990; Katz et al 1993). These observations suggest that the host's immune response is critical in controlling this infection. The inability of the HIV-infected patient to establish delayed hypersensitivity to T pallidum may prevent secondary syphilis from evolving to latency or may cause a spontaneous relapse from a latent state. This impairment of delayed hypersensitivity may account for a more rapid progression of neurosyphilis in HIV-infected individuals than would otherwise be expected. T pallidum can be isolated from the cerebrospinal fluid of HIV-seropositive patients with primary, secondary, and latent syphilis following current Centers for Disease Control-recommended penicillin therapy (Lukehart et al 1988). Despite the associated immunosuppression, serum nontreponemal titers at the time of presentation of neurosyphilis in the HIV-infected individual are typically high, averaging 1:128 (Flood et al 1998). Interestingly, neurosyphilis appears to have a pernicious effect on HIV, amplifying HIV replication intrathecally even after syphilis treatment (de Almeida et al 2010).

In HIV infection, an acute, symptomatic, syphilitic meningitis during the course of secondary syphilis is not uncommon. A decrease in the latent period to the development of some neurosyphilitic manifestations, such as meningovascular syphilis and general paresis, has been suggested. The development of meningovascular syphilis within 4 months of primary infection despite the administration of accepted penicillin regimens (Johns et al 1987), as well as the neurologic relapse of syphilis in HIV-infected individuals after appropriate doses of benzathine penicillin for secondary syphilis (Berry et al 1987), has been reported. Other unusual manifestations of syphilis that have been reported in association with HIV infection include unexplained fever (Chung et al 1983), bilateral optic neuritis with blindness (Zambrano et al 1987), Bell palsy, severe bilateral sensorineural hearing loss (Fernandez-Guerrero et al 1988), syphilitic meningomyelitis (Berger 1992), syphilitic polyradiculopathy (Lanska et al 1988; Winston 2005), and syphilitic cerebral gumma presenting as a mass lesion (Berger et al 1992). As with other disorders occurring with HIV infection, an immune reconstitution inflammatory syndrome (IRIS) may be seen with syphilis, following a reduction in HIV viral load and return of CD4 lymphocyte counts (Rushing et al 2008).

Certain ophthalmological and otolaryngological complications of syphilis occurring in the absence of neurologic disease may result in neurologic consultation. Although the characteristic ophthalmological abnormality of syphilis is the Argyll Robertson pupil, other conditions that can result from T pallidum infection include interstitial keratitis, chorioretinitis, and optic atrophy. Syphilitic optic atrophy, which is commonly unilateral and may occur with or without an associated basilar meningitis, is notoriously difficult to treat effectively. Progression is observed in as many as 50% of patients despite treatment. Otitic syphilis is associated with hearing loss, either acute or gradually progressive in nature, and may occur in association with cochlear end organ damage (Darmstadt 1989). Vertigo may also be a feature of this illness. In a study of 85 patients with otosyphilis, hearing loss was observed in 90.6%, tinnitus in 72.9%, and vertigo in 52.9%, whereas only 5.4% had positive CSF serology (Yimtae 2007). Syphilitic eighth nerve dysfunction is largely recognized as a late manifestation of congenital syphilis but is also observed in acquired illness.