Infectious Disorders
Zika virus: neurologic complications
Oct. 08, 2024
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US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
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Neurosyphilis is a “great imitator”, and a clinician must be suspicious about the diagnosis as central nervous system infection may present in multivariate fashions. The abandonment of routine serological screening for syphilis has almost certainly reduced the frequency with which early diagnosis of syphilis is established. Concomitant immunosuppression, as occurs with HIV infection, may alter the clinical expression of syphilis. CSF VDRL cannot be used as the gold standard for diagnosis as it is often negative despite the presence of neurosyphilis. In this article, the author details the manifestations, diagnosis, and management of neurosyphilis.
• The spectrum of neurologic manifestations of syphilis is broad. | |
• Neurosyphilis is not synonymous with tertiary syphilis. Neurologic manifestations may occur early in the course of infection. | |
• The incidence of syphilis in some populations is growing, and the possibility that it is the cause of an underlying neurologic abnormality should not be overlooked. | |
• Neurosyphilis is a treatable disorder, but its sequelae may be permanent. |
Syphilis was first described as a clinical entity at the turn of the 15th century. The origin of syphilis remains shrouded in mystery, but a disease commonly referred to as the "Great Pox" or "Evil Pox" was recognized in Europe shortly after Columbus' crew returned to Spain in 1493. The illness figured heavily in the wars that ravaged Europe at the time and, unlike the current disease, was associated with mortality rates as high as 25% in its early stages. Whether syphilis arose from a spontaneous mutation in an endemic treponeme or whether it was brought back to Europe from the Americas remains uncertain. However, there is a paucity of evidence for a similar disease in pre-Columbian Europe and an abundance of evidence, chiefly syphilitic bone disorders, in the pre-Columbian Americas (32).
Francisco Lopez de Villalobos published the first book on the illness in 1498. Physician and author Hieronymus Fracastor provided the name for the disease in his poem "Syphilis sive Morbus Gallicus," published in 1530. Sexual transmission of the disease was identified shortly after its initial clinical recognition. Transmission of the disease to infants breastfed by affected wet nurses and vertical transmission were also commented on in the early literature. Over the years, syphilis became confused with gonorrhea, a situation rectified in the middle of the 18th century after the mistaken conclusions of experiments performed by John Hunter, who self-inoculated urethral pus containing both Treponema pallidum and Neisseria gonorrhea.
In 1903 Metchnikoff and Roux demonstrated transmission of the disease to chimpanzees. Two years later, Schaudinn and Hoffmann identified the causative agent as an almost transparent, spiral-shaped organism that they labeled Spirochaeta pallida. The introduction of dark-field microscopy by Landsteiner in 1906 greatly assisted studies of the organism, and observations of the pathogen in the meninges and brain were made in 1913. Successful serologic tests for syphilis employing a basic lipoidal antigen were first reported by Wasserman, Neisser, and Bruck in 1906, but it was not until 1949 when a specific treponemal test, the Treponemal pallidum immobilization, was first employed.
Until the 20th century, the treatment of syphilis was generally ineffective and largely consigned to heavy metals, such as mercury, arsenic, and bismuth, and to fever therapy. Ehrlich discovered Salvarsan 606, shown to be effective against syphilis, in 1911, and Wagner-Jauregg received the Nobel Prize for the introduction of malarial therapy in 1917. However, the modern treatment of syphilis began in 1943, with the introduction of penicillin by Mahoney.
• Neurosyphilis may be observed early during secondary syphilis. Therefore, neurosyphilis need not be a manifestation of tertiary syphilis. | |
• The neurologic complications of syphilis are diverse, and a high level of suspicion for the disease is warranted. | |
• Concomitant immunological disorders, in particular untreated HIV-infection, can modify the manifestations of the disorder. |
Infection with T pallidum is divided into several stages. Primary syphilis, the initial manifestation of infection, is typically characterized by 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. In a survey that identified 286 patients with neurosyphilis from among 137 articles published in the 5-year interval between January 2010 and December 2014, general paresis was the most common form of neurosyphilis (49%), followed by syphilis meningitis (22%) and meningovascular and tabetic neurosyphilis, at 12% each. However, these data are not likely generalizable, as it was a retrospective series of published cases (27). 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 (74; 49). 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 (80). Acute sensorineural hearing loss and acute optic neuritis may occur in association with syphilitic meningitis or independently. Sudden bilateral deafness has been seen with syphilitic meningitis (13). Isolated involvement of the vagal nerve with voice changes and nasopharyngeal reflux has also been reported (55).
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. Moyamoya syndrome has, on rare occasion, been observed in association with neurosyphilis (100).
A wide variety of movement disorders have been observed in association with neurosyphilis. A sensory ataxia from involvement of the posterior columns is the most common form of ataxia, but ataxia may also result from cerebellar infarction. A pure cerebellar ataxia may be observed (34). Parkinsonism has been presumed to be the consequence of syphilitic involvement of the midbrain and may be associated with Argyll-Robertson pupils, frontal release signs, and psychiatric symptoms. Other movement disorders described with syphilis include myoclonus, hemiballismus, dystonia, hemichorea, and corticobasal syndrome (89). Parkinson-plus syndrome with features mirroring progressive supranuclear palsy has also been observed (82).
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 (79), 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 (97). Paraparesis may also be seen as a consequence of syphilitic aortic dissection (53). The spectrum of syphilitic spinal cord disease is diverse.
• Syphilitic meningomyelitis | ||
- Spinal cord gumma | ||
• Spinal vascular syphilis | ||
- Syringomyelia | ||
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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 (83). 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 (108). A clinical and radiographic presentation, mirroring limbic encephalitis in the absence of paraneoplastic antibodies, has been reported as a consequence of neurosyphilis (71). Limbic encephailitis due to syphilis tends to progress more slowly than autoimmune limbic encephalitis, and only 22% of patients demonstrated bilateral temporal lobe involvement in one series (71).
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 (47). 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.
Unusual neurologic manifestations of neurosyphilis may easily result in misdiagnosis. Cases of neurosyphilis that were attributed to autoimmune encephalitis, acute disseminated encephalomyelitis, and hippocampal sclerosis emphasize the importance of considering neurosyphilis in a wide variety of neurologic disorders (91). Although neurosyphilis is not typically associated with peripheral nerve manifestations occurring in isolation, there have been at least three cases of acute inflammatory demyelinating peripheral neuropathy described in association with syphilitic infection (70). At least one of these cases improved following penicillin therapy (70).
Concomitant human immunodeficiency virus infection may significantly alter the natural history of neurosyphilis (50; 51; 52). Syphilis appears to be not only more aggressive, but also more difficult to treat when it occurs in association with AIDS (05; 73; 52). 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 (65). 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 (33). Interestingly, neurosyphilis appears to have a pernicious effect on HIV, amplifying HIV replication intrathecally even after syphilis treatment (24).
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 (50), as well as the neurologic relapse of syphilis in HIV-infected individuals after appropriate doses of benzathine penicillin for secondary syphilis (05), has been reported. Other unusual manifestations of syphilis that have been reported in association with HIV infection include unexplained fever (17), bilateral optic neuritis with blindness (107), Bell palsy, severe bilateral sensorineural hearing loss (31), syphilitic meningomyelitis (03), syphilitic polyradiculopathy (60; 101), and syphilitic cerebral gumma presenting as a mass lesion (03). 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 (85).
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 (22). 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 (106). Syphilitic eighth nerve dysfunction is largely recognized as a late manifestation of congenital syphilis but is also observed in acquired illness.
The prognosis of neurologic complications of syphilis is dependent on the nature of the disorder. In general, those neurologic manifestations occurring early in syphilis (namely, asymptomatic neurosyphilis and syphilitic meningitis) are readily treatable and typically resolve without neurologic sequelae. However, only a small minority of patients with the late neurologic manifestations of syphilis, such as general paresis and tabes dorsalis, show any improvement with penicillin therapy. A study correlating cranial MRI findings with general paresis prognosis suggested that medial temporal lobe atrophy was a particularly poor prognostic factor (57). A case of syphilitic syringomyelia showed both significant clinical and radiographic improvement following penicillin treatment (10). However, stabilization of the progressive neurologic disorder is generally the best that can be expected in these instances. In an isolated case of meningovascular syphilis, transcranial Doppler studies of stenotic syphilitic vessels following treatment revealed persistent patency but a lack of resolution of vessel stenosis (54).
A 27-year-old man presented with left upper extremity weakness and numbness of 3 days duration. Two days later, he noted left foot numbness, slurred speech, and left facial drooping. He had no risk factors for atherosclerotic cerebrovascular disease. His physical examination showed normal vital signs, no cardiac murmurs, diminished sensation over the left face with a central facial paresis, and left limb weakness and numbness. An MRI showed multiple areas of restricted diffusion in a watershed distribution of the right cerebral hemisphere. CT angiography showed an irregular lumen of the right internal carotid and the M1 segments of both middle cerebral arteries. Routine laboratory studies were negative, but an RPR was positive at 1:64. Blood FTA-ABS was positive. HIV serology was negative. CSF analysis showed 48 white cells (83% lymphocytes), protein 89 mg/dL, and VDRL 1:2. He was treated with intravenous penicillin and had gradual improvement in his neurologic deficits.
This case is illustrative of the persistence of syphilis as a potential cause of cerebrovascular disease, and it highlights the importance of performing serological screening. The latter has often been neglected in the modern era.
Syphilis is caused by the bacterium Treponema pallidum, a long, slender, coil-shaped organism that measures 6 to 15 µm in length, but only 0.15 µm in width, a dimension below the resolution of light microscopy. The organism has regular spirals numbering 5 to 20 and is actively motile using a rotational screw-like activity, flexion, and back-and-forth motion. Electron microscopic studies reveal that the organism has an amorphous coat of mucopolysaccharides, an outer membrane, an electron-dense peptidoglycan layer, and a cytoplasmic membrane. Three flagella extending from each end of the organism are located between the outer membrane and the electron dense layer. These flagella twist around the body of the organism and provide the spiral shape of the organism and its mode of locomotion.
T pallidum belongs to one of five genera in the order Spirochaetales. Three of these genera are pathogenic to man, including Treponema (syphilis), Leptospira (leptospirosis), and Borrelia (tick- and louse-borne relapsing fever). The organisms responsible for endemic syphilis (T pallidum), yaws (T pertenue), and pinta (T carateum) are morphologically identical and antigenically similar. Extensive DNA homology has been demonstrated between these organisms.
Despite assertions to the contrary, T pallidum is not an obligate anaerobe. It grows best in 3% to 5% oxygen, and 5% carbon dioxide in histamine, but its cultivation in vitro is difficult. This fact, coupled with the exquisite fragility of the organism, has rendered its study difficult. Small mammals and primates have been used as animal models; however, the best animal model is the rabbit, in which the disease closely parallels that in man. The organism invades interstitial spaces and chiefly proliferates there, with a doubling time of 30 to 33 hours. It can, however, be found intracellularly. Dissemination is hematogenous.
Shortly after infection, a spirochetemia results with dissemination of T pallidum to virtually any organ, including the central nervous system. Both humoral and cellular immunity play a role in the ensuing infection. Antibodies to T pallidum are detectable within 10 to 21 days of infection. The humoral response is of little consequence in containing the infection but may alter the course of the disease. Cellular immunity appears to be effective in controlling the infection as evidenced by immunity during rechallenge. The degree of protection is directly proportional to the extent of the response. Impairment of cellular immunity due to drugs, pregnancy, AIDS, etc. appears to result in a more aggressive syphilitic infection than otherwise anticipated.
Studies of cerebrospinal fluid abnormalities occurring in association with early (primary or secondary) syphilis have detected abnormalities in 16% to 48% of cases. These results are suggestive of early invasion of the central nervous system by the organism. Several studies have confirmed the presence of viable treponemes in the cerebrospinal fluid in these early stages of infection. A study employing polymerase chain reaction for T pallidum found a positive reaction in 28.6% (two of seven) patients with primary and secondary syphilis and 100% (one of one) with early latent syphilis and 100% (one of one) with late latent syphilis (40).
Neurosyphilis is not believed to develop in the absence of cerebrospinal fluid abnormalities. Merritt stated that "if the cerebrospinal fluid is normal 2 or more years after infection, it will always remain so, and parenchymatous neurosyphilis will never develop." The converse, however, is not true. The presence of cerebrospinal fluid abnormalities does not necessarily predict the development of neurosyphilis. In the Oslo study, 9.4% of the men and 5.0% of the women ultimately developed neurosyphilis (18). No satisfactory explanation has yet been proposed to account for the lack of universal invasion of the central nervous system by T pallidum, nor is there an explanation for the absence of neurosyphilis in the majority of individuals who manifest cerebrospinal fluid abnormalities indicative of CNS invasion.
The pathology of neurosyphilis is the consequence of the invasion of the CNS by T pallidum and the associated immunological response. In syphilitic meningitis, the earliest neurologic complication of syphilis, invasion of the meninges by the spirochete results in an infiltration of the meninges by lymphocytes and, to a much smaller degree, plasma cells. This cellular infiltration may follow blood vessels into the brainstem and spinal cord along the Virchow-Robin spaces. Necrosis of the media and proliferation of the intima of small meningeal vessels accompanies T pallidum invasion of the vessel walls.
Late stages of neurosyphilis can be divided into meningovascular and parenchymatous disease. The inflammation observed in the former parallels that observed with syphilitic meningitis. The classical lesion is an endarteritis obliterans of medium and large vessels first described by Huebner in 1874. This lesion is characterized by fibroblastic thickening of the intima and thinning of the media. Vasculitis in small vessels is referred to as Nissl-Alzheimer arteritis. Even in the absence of clinically apparent meningovascular disease, cerebral blood flow abnormalities have been demonstrated by single photon emission computed tomography in early syphilis (90). Syphilitic lesions of the brain and spinal cord occur as a secondary event. Gummas of various sizes, from microscopic to mass-producing lesions, may be observed. Pathologically, the gummas are thick, tough, rubbery lesions of fibrous trabecula with lymphocytic and plasma cell infiltration of the outer layers. Treponemes are seldom seen in the gumma.
Parenchymatous neurosyphilis is typified by tabes dorsalis and general paresis. The pathology of tabes dorsalis predominates in the dorsal roots and posterior columns of the lumbosacral and lower thoracic levels but is not confined to those areas. Variable lymphocytic infiltration of the meninges accompanies these degenerative changes. The predominant findings are believed to result from irreversible changes to the dorsal root fibers, but the exact pathogenesis of this disorder is not known. Typically, in general paresis, the brain is atrophic and the meninges thickened on pathological examination; however, the brain may appear grossly normal in a minority of cases. The cerebral cortex, striatum, and hypothalamus bear the brunt of the damage. The architecture of the cerebral cortex is disrupted, and neuronal loss accompanies astrocytic and microglial proliferation. T pallidum can be demonstrated in the cerebral cortex. Ependymal granulations are commonly observed, and the meningeal inflammation is chiefly composed of plasma cells. Many theories of the mechanism by which the spirochete results in these changes in the brain have been proposed, but none have been proven.
As with many if not most other infections, host factors almost certainly contribute substantially to the risk of disease acquisition and expression. Among the host factors that have been preliminarily associated with the risk of neurosyphilis have been polymorphisms in the gene for IL-10 (78) and Toll-like receptor polymorphisms (67).
• Although syphilis rates have declined due to contact tracing and the introduction of penicillin in the mid-20th century, it still remains prevalent in some populations. | |
• Particular risks exist in sex workers, drug abusers, and those with a history of other sexually transmitted disease. |
The combination of the ready availability of penicillin and the sensitivity of the organism to this antibiotic has led to a widely held perception that syphilis in contemporary times is rare. Though the annual incidence of syphilis in the United States declined 18-fold from a peak of 72 cases per 100,000 in 1943 to 4 per 100,000 in 1956, the current incidence is on the order of 12 per 100,000. In some areas of the country the incidence may be substantially higher than the national average. In the 1970s, there was a clearly increased risk among gay and bisexual men; however, the adoption of safe sex techniques, with the advent of the AIDS era, resulted in a significant decline in the incidence of syphilis in this risk group. However, every year since 2000, cases of primary and secondary syphilis have increased in the United States in both men and women and in all age groups. Men who have sex with men still represent the group disproportionately impacted (15). In 2022, there were 207,255 cases of syphilis, the greatest number reported since 1950 (15). In some populations, the disorder is rare. For instance, not one case of general paresis was observed among 560 demented individuals entered into the Rochester (Minnesota) Epidemiology Project over the 5 years from 1990 through 1994 (56). Female prostitutes and crack cocaine abusers remain at increased risk for syphilis. The latter group is believed to have an increased risk due to the trading of sex for drugs, as well as the lowering of inhibitions. The number of women with syphilis is rising at a rate disproportionate to that in men and, not unexpectedly, there has been a substantial increase in the number of cases of congenital syphilis in the United States. There are an estimated 6 million new cases of syphilis globally in persons aged 15 to 49 years (59).
Neurosyphilis rates vary between 0.47 to 2.1 cases per 100,000 population, and a series indicated that 3.5% of patients with clinical or ophthalmological features of syphilis had CSF confirmed neurosyphilis (19; 21; 25). However, surveillance and hospital data may underestimate the true incidence of the disorder (11). Neurosyphilis is surprisingly common in association with HIV infection. Prevalence rates of CSF VDRL-reactive neurosyphilis have been reported to be between 1.0% and 2.0% for several large cohorts of HIV-seropositive individuals (02; 45; 08). This prevalence rate is substantially higher if only patients with serological evidence of syphilis are included. In some HIV-infected populations, the prevalence rate of a reactive serum fluorescent treponemal antibody absorption test approaches 50% (02). In one study, 9.1% of HIV-infected patients undergoing lumbar puncture because of a reactive serology and having no history of recent treatment for syphilis had a reactive CSF VDRL (45). Neurosyphilis may be responsible for HIV-related neurologic manifestations in a significant minority of some populations, and neurosyphilis needs to be considered in the differential diagnosis of any HIV-infected person presenting with neurologic disease (02).
Syphilis is a sexually transmitted disease that, like AIDS, is prevented by sexual abstinence or a monogamous relationship with an uninfected partner. The likelihood of infection with T pallidum is significantly reduced by the use of safe sex techniques (eg, condoms). Unless the disease recrudesces, as may be seen in early latent syphilis, latent syphilis and tertiary syphilis are not considered contagious.
In those individuals with primary, secondary, or latent syphilis, the manifestations of neurosyphilis can be avoided by the timely administration of adequate doses of penicillin.
Neurosyphilis always needs to be considered in the differential diagnosis of the following disorders: acute meningitis, stroke (particularly in young people), progressive dementia, psychoses and behavioral disturbances, myelopathy, optic neuritis, chorioretinitis, and sensorineural hearing loss. In one study of 92 hospitalized psychiatric patients with general paresis, 29 (38.2%) had been misdiagnosed initially as having a primary psychiatric disorder (104). In a retrospective study from China, 5.4% of patients with rapidly progressive dementia had neurosyphilis (64).
• Nontreponemal screening tests, eg, the RPR, are helpful when suspicion is low, but in instances where suspicion of neurosyphilis is high, treponemal tests are warranted. | |
• A negative treponemal test effectively excludes neurosyphilis. | |
• A positive serum treponemal test coupled with a positive CSF VDRL defines neurosyphilis; however, the CSF VDRL is not invariably positive with neurosyphilis. |
With the exception of primary and secondary syphilis, in which T pallidum can be demonstrated by the use of darkfield microscopy from skin and mucous membrane lesions, the diagnosis of syphilis is dependent on serological study. There are two categories of serological study: (1) nontreponemal tests that are flocculation tests using cardiolipin, lecithin, and cholesterol as antigen; and (2) treponemal tests, which rely on specific treponemal cellular components as antigens. Nontreponemal tests include the VDRL, rapid plasma reagin (RPR), Wasserman, and Kolmer. The treponemal tests include the fluorescent treponemal antibody absorption test, microhemagglutination assay, hemagglutination treponemal test for syphilis, antitreponemal IgM, and the treponemal immobilization test.
There are two main diagnostic algorithms for the serological diagnosis of syphilis. The “traditional” method requires an initial nontreponemal test positivity followed by confirmation with a treponemal test. An alternative approach is the “reverse” algorithm in which a treponemal test is initially performed, and, if positive, a nontreponemal test follows. If the latter is negative, a second treponemal test is performed with a different platform (87).
Unfortunately, no readily applicable "gold standard" exists for the diagnosis of neurosyphilis. Culturing the organism in tissue cultures from the cerebrospinal fluid is cumbersome and available in very few laboratories. Furthermore, the fragility of T pallidum may result in a low sensitivity of the test. The rabbit infectivity test requires access to an animal facility and is both time-consuming and expensive. The presence of a reactive VDRL in the cerebrospinal fluid is specific, with rare reports of false positives, but the test is not sufficiently sensitive to exclude the diagnosis of neurosyphilis on the basis of a negative study. The serum VDRL is positive in 72% of patients with primary syphilis, nearly 100% of patients with secondary syphilis, 73% of patients with latent syphilis, and 77% of patients with tertiary syphilis. Therefore, as many as one quarter of patients with neurosyphilis are anticipated to have a negative serum VDRL. In some instances, the falsely negative VDRL is the consequence of the "prozone phenomenon" in which high titers of antibody impair the formation of the antigen-antibody lattice that is needed to visualize a positive flocculation test (93). This phenomenon has been reported in the presence of neurosyphilis (61). Its frequency of reactivity appears to vary with the clinical form of neurosyphilis, and its presence in asymptomatic neurosyphilis may be substantially lower than in symptomatic disease. The CSF VDRL test is too insensitive to be relied on to exclude the diagnosis of neurosyphilis. In one study, in which cerebrospinal fluid was cultured in rabbit testicles, T pallidum was isolated from cerebrospinal fluid of 12 (30%) of 40 patients with primary and secondary syphilis, but the CSF VDRL was positive in only four (33%) of these 12 patients (65). Therefore, measures other than a reactive CSF VDRL must be relied on to establish the diagnosis of neurosyphilis. The frequency with which the CSF VDRL is negative in the presence of neurosyphilis is not known, but has been estimated to exceed 25%. Furthermore, CSF rapid plasma reagin (RPR) cannot be used as a substitute for CSF VDRL as this test has a high false negative rate (69). In many respects, neurosyphilis is a diagnosis established on clinical grounds. To date, no consensus has been reached regarding diagnostic criteria, and the physician should probably refrain from rigid adherence to narrow guidelines in making the diagnosis. An example of the value of the latter approach is highlighted by a report of meningovascular syphilis in a man with negative nontreponemal specific antitreponemal IgM antibodies from whom T pallidum was identified by rabbit inoculation of the CSF (63).
A cardinal requirement for the diagnosis of neurosyphilis is a reactive serum treponemal test. Neurosyphilis should be diagnosed in anyone with serologies reactive for a treponemal test occurring in association with a reactive CSF VDRL. A diagnosis of neurosyphilis should be considered in patients with serological evidence of syphilis and one or more of the following abnormalities in their cerebrospinal fluid: a mononuclear pleocytosis, an elevated protein, increased immunoglobulin G, or the presence of oligoclonal bands. Undoubtedly, neurosyphilis is overdiagnosed using these criteria. The cerebrospinal fluid fluorescent treponemal antibody absorption test has been suggested as a sensitive screening test for the presence of neurosyphilis (23). Carey and colleagues used the cerebrospinal fluid fluorescent treponemal antibody absorption test in a cross-sectional survey of hospitalized patients with serologic evidence of latent syphilis to conclude that the cerebrospinal fluid abnormalities in 32% of HIV-seronegative persons and in 67% of HIV-seropositive persons were nonspecific in nature and not attributable to neurosyphilis (12). Unlike the CSF VDRL, which requires gross blood contamination of the cerebrospinal fluid to be rendered falsely positive, small amounts of blood contamination of the cerebrospinal fluid may give false positive tests with the fluorescent treponemal antibody absorption test. Furthermore, the fluorescent treponemal antibody absorption test is dependent on immunoglobulin G antibody that may cross the blood-brain barrier to result in a false-positive test for neurosyphilis. The cerebrospinal fluid fluorescent treponemal antibody-immunoglobulin G test has been suggested as an alternative to avoid the latter possibility. Other cerebrospinal fluid studies, not widely employed but believed to be diagnostically useful for neurosyphilis, are a treponemal pallidum hemagglutination test index greater than or equal to 100 (TPHA index = CSF TPHA titers ÷ CSF albumin [mg/dL × 10³]/serum albumin [mg/dL]) and a TPHA-IgG index greater than or equal to 3 (THPA-IgG index = CSF TPHA-IgG titer/total CSF IgG ÷ TPHA-IgG titer/total serum IgG). An alternative approach that has been proposed for HIV-infected patients suspected of having neurosyphilis despite negative CSF VDRL is to couple the CSF fluorescent treponemal antibody test, which is 100% sensitive, with the percentage of CSF cells that are B lymphocytes (greater than 9% in fresh specimens) (68).
Although the TPHA and Treponema pallidum particle agglutination (TPPA) in general should be avoided for diagnosis, some authorities propose that CSF titers of TPHA may have excellent sensitivity and enhanced specificity (35). TPHA titers of greater than or equal to 1:640 were shown to have a greater than 98% sensitivity and specificity. The sensitivity of CSF TPPA titers of greater than or equal to 1:640 varied between 81.5% and 93.9% (35). Immunoblot test for treponemal antigens of CSF has also been proposed as a test for neurosyphilis and has been found to be positive in instances in which PCR for T pallidum DNA in CSF has been negative (92). Serum biomarker tests including ubiquitin C-terminal hydrolase-L1, glial fibrillary acidic protein, and neurofilament have been proposed to potentially alleviate the need for lumbar puncture, but further studies are warranted (48).
Newer generation tests have been developed for syphilis and neurosyphilis, including those employing polymerase chain reaction and monoclonal antibodies, but the tests have yet to be widely adopted. At least 10 organisms are needed for PCR positivity, whereas the rabbit infectivity test requires but one or two viable treponemes (102). CSF PCR is insufficiently sensitive to rule out neurosyphilis but is very helpful if positive (102).
Coinfection with HIV considerably complicates the interpretation of cerebrospinal fluid abnormalities as a mononuclear pleocytosis, increased protein, increased immunoglobulin G, and the presence of oligoclonal bands may all attend HIV infection in the absence of neurosyphilis (44). A schema has been proposed for diagnosing neurosyphilis in the face of HIV infection (See Table 2).
Definite neurosyphilis: | |
1. + blood treponemal serology, eg, FTA-ABS, MHA-TP, etc. | |
Probable neurosyphilis: | |
1. + blood treponemal serology | |
Possible neurosyphilis: | |
1. + blood treponemal serology |
Controversy surrounds the issue of when to perform a lumbar puncture in the HIV-infected patient with serological evidence of syphilis. A study from Spain of 112 HIV-infected persons with syphilis, in whom the diagnosis of neurosyphilis was predicated on the presence of a CSF WBC count of greater than 20 cells/cu mL, and/or reactive CSF VDRL, and/or a positive intrathecal T pallidum antibody index, concluded that lumbar puncture could be restricted to those with neurologic manifestations or a serum rapid plasma reagin greater than 1:32 (62). An alternative strategy recommends lumbar puncture in all HIV-seropositive patients with serological evidence of syphilis despite its stage in the setting of CD4 cell counts of less than 350 cells/ml and/or a rapid plasma regain of 1:32 or greater (36).
Although not diagnostic of neurosyphilis, radiologic studies may be suggestive and are certainly helpful in excluding other pathologies. Radiologic manifestations of neurosyphilis include meningeal enhancement, CSF enhancement (38), hydrocephalus, gummas, periostitis, generalized cerebral atrophy, and stroke. Gummas appear as avascular, dural-based masses with surrounding edema that on MRI are characteristically isointense with gray matter on T1-weighted image and hyperintense on T2-weighted image. Dense contrast enhancement and a dural tail may be observed (95). On rare occasion, the radiographic appearance of neurosyphilis may mimic the appearance of normal pressure hydrocephalus or herpes encephalitis (29). Orbital periostitis typically involves the roof and supraorbital rim. These lesions may be hyperplastic, resulting in tender osteophytic nodules and exostoses (42). The periorbital inflammation can infiltrate the extraocular muscles and cranial nerves (94). MRI may also reveal multiple bilateral, discrete white matter lesions involving deep periventricular and subcortical regions (42). Angiography of neurosyphilis is nonspecific. Large vessels may exhibit segmental constriction or occlusion (42). Smaller vessels, usually Sylvian branches of the middle cerebral artery, may display focal stenoses with or without adjacent dilatation (42). The sites of syphilitic brain lesions detected by MRI appear to correlate with psychiatric and cognitive symptoms (86). Lesions in the temporal lobes, particularly the mesial regions, on T2 weighted and fluid attenuated inversion recovery (FLAIR) magnetic resonance images have been described in patients with general paresis (16; 99; 61). The latter has led to the suggestion that neurosyphilis must be excluded in any person suspected of having limbic encephalitis (88). Severe frontotemporal atrophy has also been reported (43). In tabes dorsalis, MRI of the thoracic spine has shown intramedullary hyperintensities and cord atrophy (77).
In a review of 35 patients with documented neurosyphilis (3 HIV-seronegative and 32 HIV-seropositive), Brightbill and colleagues found that 31% had normal brain imaging, 23% had cerebral infarction, and 20% had nonspecific cerebral white matter lesions. Cerebral gummas and extra-axial enhancement indicating meningitis were each noted in two (6%) of 35 and arteritis was demonstrated in two (50%) of four undergoing either magnetic resonance angiography or conventional cerebral angiography (09). High-resolution vessel wall imaging in brain MRI may demonstrate syphilitic vasculitis in meningovascular syphilis (75).
• Penicillin remains the most effective treatment for neurosyphilis. | |
• Desensitization to penicillin may be warranted in the patient allergic to the antibiotic who requires treatment for neurosyphilis. | |
• Persistent high levels of antibiotic is required for effective treatment due to the slow doubling time of T pallidum. |
T pallidum is highly sensitive to penicillin, as was convincingly demonstrated by Mahoney in 1943. Despite 50 years of experience, however, the adequacy of currently recommended treatment regimens still remains questionable due to an absence of controlled, randomized, prospective studies for the optimal dose and duration of therapy in neurosyphilis. The treponemicidal level of penicillin is 0.03 µg/mL, and although the organism has been demonstrated to be capable of acquiring plasmids that produce penicillinase, no compelling evidence suggests that it loses its efficacy in the treatment of T pallidum. When penicillin levels become subtherapeutic, the spirochetes begin regenerating within 18 to 24 hours. The Centers for Disease Control has recommended using 2.4 million units of benzathine penicillin intramuscularly at weekly intervals for 3 weeks in the treatment of neurosyphilis (14), but the recordable penicillin levels in the cerebrospinal fluid during treatment fail to reach treponemicidal levels (81). The concentration of penicillin in the cerebrospinal fluid is typically unmeasurable, probably not exceeding 0.0005 µg/mL, which is 1% to 2% of the serum levels. Furthermore, viable treponemes have been recovered from the cerebrospinal fluid of individuals at the completion of therapy (98). Another "recommended" regimen is 600,000 daily units of procaine penicillin intramuscularly for 15 days. This regimen, too, may fail to achieve treponemicidal levels of penicillin in the cerebrospinal fluid. Ideally, the treatment regimen for neurosyphilis should be 12 to 24 million units of crystalline aqueous penicillin administered intravenously daily (2 to 4 million units every 4 hours) for a period of 10 to 14 days. This regimen generally requires hospitalization, but a prolonged hospitalization may be avoided in some reliable, well-motivated patients by placement of an indwelling catheter and home administration of penicillin after the first 24 to 48 hours of therapy. The penicillin should be administered at no less than 4-hour intervals to maintain the penicillin levels consistently at or above treponemicidal values and to avoid the subtherapeutic troughs that occur when it is administered at less frequent intervals. An alternative approach to the use of parenteral penicillin is the daily oral administration of amoxicillin (3.0 g) and probenecid (0.5 g) administered twice daily for 15 days (28). This regimen achieves treponemicidal levels of amoxicillin in the cerebrospinal fluid (28; 72).
In patients who are allergic to penicillin, 500 mg of erythromycin four times daily for a period of 30 days has been recommended. Erythromycin does not diffuse readily into the brain and cerebrospinal fluid, nor has its efficacy been demonstrated in the treatment of neurosyphilis. It has been associated with a high rate of treatment failures and, therefore, cannot be recommended in the treatment of neurosyphilis (37). Oral therapy with tetracycline yields low cerebrospinal fluid tetracycline concentrations and its efficacy has not been proven in the treatment of neurosyphilis. The successful use of 2 g daily of intravenous ceftriaxone for 10 days (46), and 200 mg of oral doxycycline, twice daily for 21 days (105), have been reported. These therapeutic regimens in individuals with established neurosyphilis and complicating HIV infection require further study; however, one study found a failure rate of 23% in HIV-infected patients with latent syphilis or asymptomatic neurosyphilis treated with ceftriaxone, typically administered as 1 g daily intravenously or intramuscularly over 10 to 14 days (26); however, a retrospective multicenter study from France suggests that its effect is equal to benzylpenicillin (06).
The Jarisch-Herxheimer reaction is a systemic reaction to the rapid dissolution of treponemes occurring within several hours of the initiation of treatment. The disorder is characterized by the abrupt onset of fever and chills, headache, tachycardia, flushing, myalgias, and mild hypotension. On rare occasion, neurologic deterioration, including seizures (58) or mania and psychosis (96), may occur during the Jarisch-Herxheimer reaction. Although many authorities advocate pretreatment with aspirin to ameliorate the symptoms of this disorder, acute brain infarction during the Jarisch-Herxheimer reaction has been observed in patients with meningovascular syphilis; therefore, some authorities recommend the administration of prednisone, 60 mg over the initial 24 hours.
Determining the adequacy of therapy depends on careful follow-up of the patient. Conversion of the serum VDRL or rapid plasma reagin test to nonreactive should occur within 1 year after treatment of primary syphilis, within 2 years after treatment of secondary syphilis, and within 5 years after treatment of latent syphilis. This delay to reversion from a seropositive status reflects the duration and severity of the illness. The presence of persistently positive serum VDRL or rapid plasma reagin test suggests either persistent infection, reinfection, or a biological false positive test. Conversely, normalization of the serum rapid plasma reagin, particularly in patients demonstrating an 8-fold decrease or greater in serum rapid plasma reagin, predicts resolution of CSF abnormalities 6 months after treatment (103).
As noted, the fixed neurologic deficits of neurosyphilis may fail to improve with treatment, and some abnormalities, such as tabes dorsalis and optic atrophy, may worsen despite adequate therapy. The excruciating lightening pains of tabes dorsalis have been reported to respond to gabapentin (76), and it is likely that similar anticonvulsants would be equally effective. Resolution of cerebrospinal fluid abnormalities is the best determinant for the adequacy of treatment. Examination of the cerebrospinal fluid within several days of the institution of penicillin treatment may be confusing, as the cerebrospinal fluid cell count may rise initially, particularly if accompanied by a Jarisch-Herxheimer reaction; however, the cerebrospinal fluid should be examined at the termination of treatment to document a fall in cell count, and it should then be examined at 6-month intervals for 2 to 3 years. The cell count should return to normal within 1 year of treatment (usually 6 months), and the protein should return to normal within 2 years. The disappearance of the CSF VDRL typically parallels its resolution in the serum. The long hiatus to its eventual clearing makes it less useful for purposes of determining the adequacy of treatment than the cerebrospinal fluid cell count or protein. However, the CSF VDRL titers should not increase over time with effective therapy. A significant negative correlation between improvement in cognitive function and the CSF VDRL titers 1 year following treatment suggests that the CSF VDRL titer is an indicator of continued T pallidum infection (84). Dependence on the cerebrospinal fluid for determining the adequacy of treatment for neurosyphilis in HIV-infected individuals often yields inaccurate results, due to the frequency with which cerebrospinal fluid abnormalities are detected with HIV infection alone. Other than reversion of a positive CSF VDRL in those instances where it was initially present, a decline in a cerebrospinal fluid pleocytosis may be of greatest value in monitoring the success of therapy. The potential for relapse of neurosyphilis following a course of "recommended" therapy suggests the potential need for secondary prophylaxis in treating neurosyphilis in the HIV-infected individual, as is employed in the management of some other CNS infections, such as toxoplasma encephalitis and cryptococcal meningitis. In a study of 100 HIV-infected military personnel with syphilis, four of seven persons with reactive cerebrospinal fluid VDRL relapsed following high-dose intravenous penicillin. Relapses were often observed more than 12 months after initial therapy (66). Other investigators, however, have found good clinical and serological responses to standard penicillin regimens in the HIV-infected population with syphilis (07). The Centers for Disease Control has recommended that the initial therapy of intravenous aqueous penicillin be followed in HIV-infected individuals by weekly intramuscular injections of 2.4 million units of benzathine penicillin for 3 weeks. However, in light of lack of treponemicidal levels of penicillin with the latter and evidence that high-dose penicillin regimens are not consistently effective in patients infected with HIV (39), a more logical course may be the administration of a 30-day course of doxycycline 200 mg twice daily, following the completion of intravenous therapy. Although secondary prophylaxis is extensively employed, further studies are warranted before secondary prophylaxis (or some permutation of it) can be broadly recommended. HIV-seropositive patients should be carefully monitored for relapse of neurosyphilis for 2 or more years following initial treatment.
Although the clinical experience is limited, tPA has been reported to be beneficial in the setting of acute stroke due to meningovascular syphilis (41). The demonstration of thrombus within affected vessels strongly supports the use of tPA in the setting of stroke from meningovascular syphilis (30). Otitic syphilis is relatively refractory to treatment regimens. Parenteral therapy is recommended for 6 weeks to 3 months with 12 to 24 million units of aqueous crystalline penicillin daily or oral therapy with 3.5 g of amoxicillin and 1.0 g of probenecid daily. Prednisone, 30 to 60 mg daily, is also recommended in combination with the antibiotic regimen for this disorder. Similarly, in the face of a progressive syphilitic optic neuritis, a trial of oral corticosteroids, eg, prednisone, 60 mg daily for 2 to 4 weeks with careful observation, is suggested.
In patients with hydrocephalus complicating neurosyphilis, cerebrospinal fluid shunting has been recommended. However, resolution of syphilitic hydrocephalus following high-dose intravenous penicillin has been reported (20).
It has been suggested that the relative cellular immunodeficiency associated with pregnancy exaggerates the complications of neurosyphilis; however, unequivocal data regarding this observation are not available. More importantly, syphilis in the mother may result in infection of the neonate. The infection usually occurs transplacentally but may occur at parturition or during nursing, particularly if the highly contagious lesions of early syphilis are present on or near the nipples. The commonly held belief that syphilis is never transmitted to the fetus prior to the 18th week of gestation has been proven to be incorrect. Neurosyphilis occurs with both early (before the age of 2 years) and late (after the age of 2 years) congenital syphilis. Cerebrospinal fluid abnormalities are noted in 40% to 60% of infants with syphilis. The neurologic complications of early congenital syphilis are chiefly meningitis with cranial nerve palsies and hydrocephalus and meningovascular disease resulting from endarteritis and thrombocytopenia. Asymptomatic neurosyphilis is common in late congenital syphilis; clinically evident disease usually does not appear until adolescence and parallels that observed in adults.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Joseph R Berger MD
Dr. Berger of the Perelman School of Medicine, University of Pennsylvania, received consultant honorariums from Celegene/BMS, Cellevolve, EMD Serono/Merck, Genentech, Genzyme, Janssen/J&J, Morphic, Novartis, Roche, Sanofi, Takeda, and TG Therapeutics. He received honorariums from MAPI and ExcisionBio as a scientific advisory or data safety monitoring board member. And he received research support from Biogen and Genentech/Roche.
See ProfileJohn E Greenlee MD
Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.
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