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Tabes Dorsalis


Tabes Dorsalis

Article Author:
Jenish Bhandari
Article Author:
Pawan Thada
Article Editor:
Richard Ratzan
Updated:
11/23/2020 7:02:42 AM
For CME on this topic:
Tabes Dorsalis CME
PubMed Link:
Tabes Dorsalis

Introduction

Tabes dorsalis is a slowly progressive parenchymatous degenerative disease of the dorsal column and dorsal root of the spinal cord as a result of syphilis caused by infection with Treponema pallidum pallidum, one of three subspecies of Treponema pallidum that can cause sexually transmitted disease in humans. It generally occurs in the late tertiary stage of syphilis, but early involvement is reported. It may be accompanied by meningitis or meningomyelitis.[1] Although CSF invasion often occurs early in syphilis, the clinical syndrome of tabes dorsalis, one of two manifestations of late neurosyphilis, usually occurs years, often two to three decades later. The pathogenesis of tabes dorsalis follows the pattern of syphilis elsewhere: a perivascular inflammatory response against the treponeme along with gummas (caseous necrosis in granulomata). Some studies support the invasion of the large myelinated nerve fibers by Treponema pallidum and subsequent neuronal degeneration. The cellular infiltration in the spinal cord displays T-helper cells, macrophages that produce cytokines that intensify the inflammatory process.  Men who have sex with men and patients with HIV infection, or PLWH (patients living with HIV), are at a higher risk of neurosyphilis, especially the early types.[2] HIV coinfection commonly occurs with neurosyphilis in the U.S. Thus, the clinical suspicion of neurosyphilis in PLWH must always remain strong with neurological, visual, or otologic signs or symptoms.   Neurosyphilis can be both symptomatic and asymptomatic; in asymptomatic neurosyphilis, which is inflammation without symptoms, a lumbar puncture for CSF evaluation is controversial, but many feel it is important, especially in PLWH, to establish the diagnosis when present since treatment with penicillin at higher and longer doses than used for primary and secondary syphilis can retard or prevent the development of clinically evident and debilitating neurosyphilis, which, when it develops as late neurosyphilis is not as amenable to symptom reversal.

Etiology

The human being is the only natural host of Treponema pallidum. Treponemes are helical spirochetal bacteria, thin and spirally coiled. They can be seen in dark-field microscopy or immunofluorescence. Treponema pallidum infection, if left untreated or partially treated, can lead to late neurosyphilis which has two forms, general paresis (also known as "syphilitic dementia," "dementia paralytica" or "paretic neurosyphilis") and tabes dorsalis (also known as "locomotor ataxia"). Treponema pallidum can be transferred vertically from mother to fetus and through sexual intercourse.[3] Additionally, it can also be transmitted through blood transfusion, solid organ transplantation, and simple contact with infected patients through micro-abrasions of the skin and mucous membranes.

Epidemiology

Tabes dorsalis was more prevalent in the pre-antibiotic era. Although the rates of primary and secondary syphilis are increasing, the true incidence of neurosyphilis in general and tabes dorsalis specifically is difficult to determine. Syphilis is more common among homosexual males than in females and is more prevalent in the mid-age population.[4] One study suggested the highest rate is found among lower-income countries like Africa, Southeast Asia.[5]  In the U.S., it is more commonly encountered in men who have sex with men and African Americans, according to some case series. The incidence is increasing, perhaps in part due to associated HIV-coinfection.[6] Globally, 25% to 35% of total syphilis is complicated by neurosyphilis in the late period; of these, one-third suffer from tabes dorsalis. It was estimated that about 1.5% to 9% of syphilis is complicated by tabes dorsalis.[7]

Pathophysiology

Treponema pallidum pallidum invades the body through abrasions in the skin and intact mucous membranes and then travels via the lymphatics and blood within a few hours. Bacteria may invade the CNS in early syphilis with asymptomatic CNS involvement demonstrable in up to 40% of patients with early syphilis. Many exposures resolve in people with an intact immune system. The incubation period of syphilis is inversely proportional to the number of inoculated organisms. Average inoculation of 500 to 1000 organisms is required for disease occurrence. The stages of syphilis, based on clinical findings and time, and not always clinically apparent, are early (2 to 6 weeks after infection, with ulcers and chancres), secondary (1 to 2 months after primary, with skin and mucocutaneous lesions that are contagious) latent (early and late) and tertiary, 2 to 50 years after infection, which consists of cardiovascular (e.g., aortic dissection), ocular syphilis, otic syphilis, gummatous disease and late neurosyphilis (general paresis and tabes dorsalis and meningovascular disease and meningomyelitis).[8]

The pathogenesis of tabes dorsalis involves an inflammatory response against the treponeme with perivascular infiltrates of lymphocytes and histiocytes and plasma cells and gummas (caseous necrosis in granulomata). Some studies suggest that the invasion of the large myelinated nerve fibers by Treponema pallidum pallidum results in the degeneration of nerves. The result is a neurodegenerative process with demyelination of sensory nerve fibers in the dorsal roots and posterior columns of the spinal cord leading to an ataxic gait and sometimes undetected mechanical trauma. The cellular infiltration in the spinal cord displays T-helper cells, macrophages that produce cytokines that intensify the inflammatory process. Some studies demonstrated that Treponema pallidum pallidum disrupts iron metabolism and homeostasis with the formation of reactive oxidative agents that ultimately lead to neurodegeneration.[9]

Histopathology

On histologic examination, demyelination and subsequent degeneration of the dorsal root neurons can be visualized that result in discoloration of the affected dorsal column into pale /white. Unfortunately, organisms are not seen in most of the cases of spinal cord lesions. Perivascular infiltration of predominantly CD4+ and CD8+ T lymphocytes, macrophages, plasma cells, obliteration of small vessels are seen. Gummas, i.e., central caseous necrosis surrounded by inflammatory area showing a granulomatous appearance, may be seen anywhere in the CNS.[10][11]

History and Physical

The history of the appearance of primary syphilitic lesions, secondary syphilis, sexual history, onset (may be acute, subacute, and chronic), and the presence of neurologic, ophthalmic or otological symptoms lead to clinical suspicion of tabes dorsalis which, with serologic and CSF testing, can confirm the diagnosis of late neurosyphilis.[12] Patients may complain of brief, sudden, severe stabbing pain spreading rapidly in the back, limbs, or face lasting for minutes or days. They may also experience loss of body balance and coordination (sensory ataxia) with difficulty walking. Less common complaints are burning and tingling sensations generally experienced in upper and lower extremities and also infrequently in other parts of the body, known as paresthesias or dysesthesias. A severe painful crisis may develop associated with stress, or even sometimes without stimulus. Visceral crises may result in recurrent attacks of severe epigastric pain due to gastric crises, along with nausea and vomiting. Urinary retention and overflow incontinence may occur in early stages due to bladder dysfunction.

On physical examination, neurologic manifestations of tabes dorsalis include loss of or decreased deep tendon reflexes in the lower extremities; pupil irregularities with bilateral miotic pupils that respond to near reflex but not to light (Argyll Robertson pupil) in up to 60% of patients loss of proprioceptive (touch, vibration) sense with sensory ataxia; loss of pain and position sensation.[2] Optic atrophy may be seen as well. The gait is wide-based (sometimes described as "slapping," "staggering," or "stomping") due to decreased or absent proprioception and is highly suggestive of severe dorsal column or peripheral nerve diseases. This gait is easily distinguishable from cerebellar ataxia in that a tabetic gait looks like the patient's feet are trying to find a particular spot on the floor. A cerebellar ataxic gait (also the gait of diphenylhydantoin toxicity) looks as though the patient has alcohol toxicity with random placement of the feet, not wide-based and purposeful like a tabetic gait. In addition, patients with cerebellar toxicity or diphenylhydantoin toxicity will have other signs of cerebellar dysfunction like titubation or dysmetria. In patients with HIV infection, the presence of photophobia, vision loss, or hearing loss and gait incoordination make the likelihood of a reactive CSF-VDRL higher.[13]

Evaluation

Since Treponemal pallidum cannot be grown in a culture medium, serology and CSF examination are the mainstays for diagnosis. VDRL (Venereal Disease Research Laboratory) and RPR (rapid plasma reagin) tests [14] are nontreponemal tests used for screening for syphilis. They can be run on blood or CSF.[14] They are also used for quantification when considering re-infection. (see below) The FTA-ABS (fluorescent treponemal antibody-absorbed), TPPA (Treponema pallidum particle agglutination assay), and EIAs (enzyme immunoassays) tests are the treponemal tests which are often far more reactive than VDRL in symptomatic patients; nonreactive results help to exclude asymptomatic cases. If a patient has a positive serology for syphilis and neurologic signs and symptoms suggesting neurosyphilis, then a lumbar puncture is indicated to evaluate for neurosyphilis. Diagnosis of asymptomatic neurosyphilis is difficult, especially in HIV-infected patients. Recent studies demonstrated the role of CXCL13 in the diagnosis of asymptomatic patients so as to differentiate between symptomatic patients with asymptomatic HIV-infected patients. Value of CXCL 13 increases in HIV-infected patients accompanied by Tabes dorsalis.[15] The threshold for doing a lumbar puncture in patients with HIV, although not well defined, is lower. Some authors feel that a low CD4 cell count less than 350 cells/ml and an RPR greater than 1:32 in PLWH and syphilis are reliable indicators of neurosyphilis and warrant a lumbar puncture.[16][17] The CSF in neurosyphilis often shows an increased protein concentration (45 to 75 mg/dl), CSF pleocytosis 10 to 50 WBCs/ microliter), and a positive VDRL.[18] Pleocytosis and raised protein concentrations are not specific for tabes dorsalis and may be confounded by HIV co-infection and do not necessarily parallel disease severity.[19] Some studies suggest that in HIV coinfected patients, CSF cell count more than 20 cells per microliter should be the cutoff level for the diagnosis. A reactive CSF VDRL is specific, but the test itself is not sensitive.  On the other hand, CSF treponemal tests are sensitive but not specific. The VDRL and RPR are useful in detecting re-infection, which is defined as a four-fold (two tube dilution) increase in the VDRL and RPR tests, which are more specific than the CSF pleocytosis and protein concentration examination, especially in early syphilis.[14]  The RPR and VDRL are also followed for the response to treatment, but serofast individuals present a diagnostic problem since being serofast, that is, not showing a change in titer after treatment, does not always indicate treatment failure. One must remember to compare the change in titer within the same test, i.e., RPR to RPR or VDRL to VDRL.

A rapid plasma reagin test is ordered to help distinguish between acute or chronic infection. A Treponema pallidum particle agglutination test is ordered to distinguish between syphilis infection and a false-positive screening test. If the VDRL or RPR is nonreactive and the treponema test reactive, one of the following is the cause: very early syphilis; treated syphilis; or late untreated syphilis.[18]

MRI findings in tabes dorsalis are infrequently noted. Swelling and high signal intensity in the affected segment of the spinal cord with associated gadolinium enhancement (flip-flop sign) and peripheral band-like enhancement (candle guttering appearance, most common finding) on MRI suggesting the focal inflammation of the spinal cord.[12][20]

It is important to emphasize that tabes dorsalis is essentially a clinical diagnosis in many instances since, although the CSF profile (white cells, protein, VDRL, treponemal test) is usually abnormal, it can be normal.[18]

Treatment / Management

Treatment of neurosyphilis, including tabes dorsalis, is penicillin, just as it is for primary and secondary syphilis; only the dose and duration of treatment are different. Benzathine penicillin G is the drug of choice. In tertiary syphilis with normal CSF, treatment is 7.2 million units of penicillin administered IM as 3 weekly doses of 2.4 million units per injection. Patients should be screened for HIV prior to treatment. For clinically evident neurosyphilis treatment is intravenous injection of aqueous crystalline penicillin G (18 to 24 million units per day) or intramuscular injection of aqueous procaine penicillin G (2.4 million units/day) followed by probenecid (500 mg 4 times a day) for 10 to 14 days. If signs and symptoms persist in conjunction with clinical assessment of interval serologies and CSF testing, further courses of penicillin must be given. The chance of relapse is high in HIV-infected patients. Treatment of early neurosyphilis usually arrests disease progression and often symptoms. Treatment of late neurosyphilis, however, may only arrest disease progression with persistent symptomatology.

Doxycycline (100 mg oral, twice a day) or tetracycline (400 mg orally, twice a day) for 4 weeks is indicated in HIV-negative early syphilis patients with penicillin allergy except in pregnancy. If penicillin desensitization is not possible, ceftriaxone (2 g/day IM or IV for 10 to 14 days) can be used for penicillin-allergic neurosyphilitic patients, although cross-reactivity between penicillin and ceftriaxone is possible. One study reported the use of ceftriaxone and dexamethasone as a good alternative to the failure of penicillin G treatment.[19] The use of azithromycin is less preferred due to potential resistance and should be used only when doxycycline is not feasible or contraindicated as in pregnant women.

Other additional treatments are symptomatic and depend upon the types of visible signs and symptoms. Analgesics such as opiates and valproate can be given in associated severe pain crises. Physical therapy or occupational therapy can be administered to prevent muscle wasting and weakness. Close sexual partners should be given preventive drug therapy.

Differential Diagnosis

Tabes dorsal has to be differentiated from other causes of nonsyphilitic myelopathy, which presents similar clinical features. Regardless of etiology and pathogenesis, the diseases of the spinal cord mainly involving the dorsal column have similar manifestations. They should be excluded clinically and with nontreponemal and treponemal tests, and thorough evaluation to make the correct diagnosis and timely treatment of tabes dorsalis. These are:

Vascular Diseases Myelopathy

Ischemia, hemorrhage, arteriovenous malformations, venous congestion all lead to the spinal cord tissue hypoxia due to decreased perfusion. Neuronal death after vascular insults is one of the common causes of spinal cord infarction and dysfunction. Clinically, the presentation of neurologic deficits mimics the other causes of myelitis, which can be ruled out by proper clinical assessment, investigation (MRI).[21]

Hereditary and other Demyelinating Disorder

Hereditary diseases of the spinal cord are common, which include hereditary spastic paraplegia, amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich ataxia, adrenomyeloneuropathy. These all have elements of progressive neurodegeneration and demyelination. Muscle atrophy and weakness, ataxia, paraplegia, and sensory loss are common findings, but their associations with diabetes, cerebellar disease, scoliosis, and absence of primary and secondary syphilitic lesions, as well as nontreponemal and treponemal tests, help to rule out tabes dorsalis. MRI of the brain and spinal cord is important to make the correct diagnosis.[22]

Postinfectious Demyelination

Myelitis may be associated with varieties of culprits, including bacteria (Tuberculosis, Staphylococci, Streptococci, Pseudomonas, Escherichia coli, etc.), viruses (Cytomegalovirus, Varicella zoster virus), fungi and parasites (Toxoplasmosis, Cysticercosis, hydatid disease). Myelitis during ongoing infection of the spinal cord results in demyelination of spinal cord neurons, but these are not specifically located in certain segments except varicella, which remains latent in sensory ganglia.[23]

Spinal Tumor

Neoplastic myelopathies are infrequent. Patients presenting with signs and symptoms of spinal cord dysfunction should be kept under high suspicion to make the diagnosis. Even MRI enhancement may be confusing with that of tabes dorsalis. Complete clinical assessment, nontreponemal and treponemal tests, and competent evaluation by neurologists may be required to achieve precision.[24]

Miscellaneous Spinal Cord Myelopathy

Other causes of myelopathy consist of immune-mediated, nutritional, metabolic, and toxic myelopathies.[25][26] Metabolic and nutritional factors encompass vitamin B-12 deficiency, copper deficiency, lathyrism, and excessive zinc intake. Vit B12 deficiency leads to subacute combined degeneration of dorsal and lateral columns of the spinal cord. When accompanied by megaloblastic anemia, the hemogram, as well as nontreponemal and treponemal tests, helps to differentiate from tabes dorsalis. Copper deficiency myelopathy also involves the posterior column of the spinal cord resembling tabes dorsalis. Other toxins such as nitrous oxide and heroine intoxication produce posterior and lateral column myelopathy. MRI findings assist the exclusion of these myelopathies from tabes dorsalis.

Non-syphilitic Argyll Robertson Pupil

A pupillary finding of light-near dissociation is felt, when strictly defined and correctly observed, to be pathognomonic for neurosyphilis. An ophthalmological consult is recommended with pupillary abnormalities when considering the diagnosis of tabes dorsalis. Other diseases or associations which mimic Argyll Robertson pupil, such as diabetes mellitus, Adie pupil, Lyme disease, sarcoidosis, multiple sclerosis, may confound the proper diagnosis of tabes dorsalis, especially in the setting of reactive RPR and VDRL.[27]

Prognosis

Prognosis is good after proper treatment. A dramatic response has been observed in most of the cases after penicillin treatment along with steroids.

Complications

Tabes dorsalis commonly progresses with neurological dysfunction likely ataxia, paralysis, sensory and reflexes loss, bladder dysfunction, and loss of sexual function. Sometimes, it is exacerbated by visceral crises in about 15% of patients, i.e., severe epigastric pain with related nausea and vomiting, mainly due to erosive gastritis.[19] Charcot arthropathy is unusual but a noted complication of tabes dorsalis.[28] Loss of sensation and proprioception due to demyelination of the dorsal sensory tracts causes the absence of a defensive mechanism against the mechanical trauma and associated trophic ulcers.[29] Argyll Robertson pupil, as well as vision loss, is another common sequela of neurosyphilis.[30] Patients treated with penicillin for neurosyphilis may show a rise in temperature, shaking chills, and skin rashes 6 to 48 hours after initiation of drug therapy, this reaction is known as the Jarisch Herxheimer reaction, which occurs from 8% to 75% of treated neurosyphilis cases in frequency.[31] Experimental evidence proposes that lipoproteins of spirochetes induce inflammatory response and cytokines production, which is responsible for this reaction.[31] There is no accepted treatment of the Jarisch Herxheimer reaction. Some physicians have used steroids, others, NSAIDs.

Deterrence and Patient Education

Syphilis is mainly sexually transmitted and has increased in the U.S. lately, with an expert recently terming this increase an epidemic.[8] With proper health initiatives and sexual activity education and inexpensive and wide-spread availability of condoms and other physical barriers, syphilis can be more readily controlled. Perinatal screening for the presence of syphilis in pregnant women is also needed as an on-going public health instrument. Education involves early instruction of sexually active teens of the dangers, especially later, of unprotected intercourse as well as recreational substance use, especially in the context of sexual relations. Education should also include presenting signs and symptoms of sexually transmitted diseases and the lack of stigma and embarrassment in seeking proper medical attention for the patient and his or her partners. The need to continue with treatment to the completion is also very important to convey to patients with sexually transmitted infections, as well as abstinence until sanctioned by a medical provider. People should be encouraged to visit doctors and nurses without hesitation in case of perineal lesions because many people in the developing world hide the disease because of uncomfortable feelings.

Enhancing Healthcare Team Outcomes

Tabes dorsalis is a late manifestation of syphilis. The collaboration of an interprofessional health team is necessary to bring about better results. Infectious disease specialists, neurologists, microbiologists, radiologists, laboratory technicians, and the pathologist can work together to pinpoint the causative organism and assess the stage of the disease to make the correct diagnosis. Radiologists are also helpful in CNS imaging in the late stage of the disease, especially in the presence of gummas, which may mimic CNS tumors. Radiology is less helpful in tabes dorsalis. Nursing care is also important in hospital-admitted patients. Pharmacists also play a role, especially in preparing the high dose penicillin for neurosyphilis. Ophthalmologists, otolaryngologists, neurologists, urologists, and orthopedic specialists are important, especially to manage late complications such as optic atrophy, Argyll Robertson pupil, bladder incontinence, neuronal dysfunction, and Charcot arthropathy. Physiotherapists may be needed in patients with Charcot arthropathies.


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