Neurosyphilis (Tabes dorsalis)6 is a late presentation of syphilis that occurs in 10% of infected and untreated individuals. Syphilis derives from the Greek word syphlos, meaning crippled or maimed, since untreated patients can develop bizarre-looking cutaneous, noncancerous growths on any parts of their bodies, called gummas (Figure 5).
Syphilis is a bacterial infection that is typically acquired through sexual contact and hence belongs to the sexually transmitted disease category. The infectious reagent is Treponema pallidum, a gram-negative bacterium called a spirochete because it looks like a corkscrew. The infection typically occurs through contact with open wounds or fluids during unprotected sex. Since the disease can be effectively controlled using the antibiotic penicillin G, incidence rates have decreased significantly since the 1940s in the developed world. Rates are currently increasing, however, presumably because of unprotected sex among men infected with HIV.
The disease usually involves three phases. The primary infection follows the inoculation of an individual with about 500–1000 bacteria. Within 36 h these replicate and result in a painless ulceration called a chancre. These typically occur in the genital areas. After 2–6 weeks the second stage of the disease continues, with wide infiltration throughout the body and nervous system. Afterward, during the latent stage of disease, patients are frequently asymptomatic for many years. About 10% of patients with untreated syphilis develop neurological symptoms called neurosphyilis, or tabes dorsalis, 10–15 years later. These include progressive muscle weakness, unsteady gait, and cognitive impairments typically including confusion, delusions, disorientation, and depression. Pupillary abnormalities (Argyll-Robinson pupils), dysarthria, and tremors in extremities can also be present.
The earliest stages of neurosyphilis involve inflammation of the meninges presenting with headache, nausea, vomiting, and, occasionally, seizures. This acute syphilitic meningitis responds well to aggressive penicillin treatment, whereupon the symptoms typically resolve completely. The classical neurosyphilis presentation was described by Romberg and includes the following “3 Ps”: paresthesia, pain, and polyuria. Patients experience sharp, lightning pains (paresthesia) and have an unsteady ataxic gait. With eyes closed, patients typically cannot walk or even stand upright, but fall. This is called a Romberg sign and is caused by a loss of proprioception. Unlike the senses with which we perceive the environment, feedback information from stretch receptors in skeletal muscles tells us the relative position of each extremity in space. Such receptors also report the state of contraction of visceral muscles such as the bladder, explaining polyuria (enhanced frequency of voiding).
The progressive degeneration of the spinal sensory nerve roots along the dorsal column of the spinal cord essentially causes a functional deafferentation, as seen in Figure 6. This includes the sensory nerve fibers innervating the skin and the viscera, causing pain comparable to amputation or diabetic neuropathies. Such deafferentation typically causes hyperexcitability in the ascending pain pathways and is irreversible.
A number of studies suggest that approximately one-third of individuals infected with syphilis show bacteria in their central nervous system (CNS) and are at risk of developing neurosyphilis. In contrast to the previously held assumption that bacterial spread to the CNS occurs late during the disease, this is not supported by research, which instead suggests that CNS infection occurs early in disease, possibly within just a few days after infection.
The natural history of neurosyphilis was comprehensively evaluated in the infamous Tuskegee studies that enrolled a large number of infected individuals in rural Alabama. This clinical study, conducted from 1932 to 1972 by the US Public Health Service, enrolled 600 sharecroppers, of whom 400 were infected and 200 were not. In spite of the introduction of a curative agent midway through the study in 1945, disease-carrying patients were never offered treatment, and the disease was allowed to run its course. This egregious lapse in ethical conduct led to the Belmont report, which in 1979 established the procedural and ethical framework for human experimentation, including the requirement for informed consent and oversight by an independent review board.
Since 1945, syphilis has been effectively treated with penicillin, and the bacterium has not developed any resistance over the past 70 years. High doses are necessary to reach the CNS, including large doses of intravenous penicillin G daily over 10–14 days. Two serological tests are available (Rapid Plasma Reagin and Venereal Disease Research Laboratory) that can detect established infection with high accuracy. CSF is analyzed only if neurosyphilis is suspected. Such infection presents with an increased number of white blood cells (>5 per ml) and CSF protein, which is normally very low and increases to >45 mg/dl. Additional serologic tests for syphilis should show reactivity.
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