The painless joint destructions combined with neurologic abnormalities and the typical picture on roentgenograms raise a high suspicion of neuropathic arthropathy. Diabetes mellitus is the most common cause of neuropathic joint abnormalities. However, multiple glucose measurements and testing for glycosylated hemoglobin excluded this diagnosis. The joint abnormalities were too dispersed to be caused by a local or regional neurologic insufficiency. There were no signs of syringomyelia or congenital neurologic diseases. The multiple Charcot-type bony destructions in the absence of diabetes or other neuropathic causes, coupled with reduced light touch and vibration sense, areflexia, and fixed pupils, subsequently raised the suspicion of tertiary syphilis. Indeed, results from both treponemal and nontreponemal tests were positive (rapid plasma reagin [RPR] titer 16, Treponema pallidum particle agglutination [TPPA] titer 5120). Specificity of the antibodies for T. pallidum was confirmed by immunoblot (Table 1). Cerebrospinal fluid (CSF) pressure was not elevated during lumbar puncture. The CSF showed a protein level of 65 mg/dL, no WBCs, and a reduced glucose level (2.3 mmol/L in the CSF). The RPR result in the CSF was negative, but the TPPA result was positive with a titer of 1024 (Vienna index: 241). A CSF–veneral diseases research laboratory (VDRL) test was not performed. The CSF also showed intrathecal production of IgG, IgM, and IgA and 10 oligoclonal IgG bands in the CSF compared with 3 bands in serum (Table 1). The combination of intrathecal IgG and IgM synthesis and a TPPA Vienna index of 241 made the diagnosis neurosyphilis highly probable. Transesophageal echocardiography, computed tomoangiography and [18F]-fluorodeoxyglucose positron emission tomography showed no signs of cardiovascular involvement. The ophthalmologist did not find signs of ocular syphilis.
In conclusion, our patient was diagnosed as having neurosyphilis, resulting in tabetic arthropathy affecting multiple joints. As recommended by Dutch guidelines, he was treated with penicillin G, 2 million units 6 times a day intravenously for 10 days. In addition, he entered a physical rehabilitation program.
REVIEW AND DISCUSSION
It is estimated that worldwide, 12 million people are infected with the spirochete T. pallidum each year, resulting in an incidence of 200 cases of primary syphilis per 100,000 individuals.7 Since the introduction of effective antibiotic treatment of syphilis in the 1940s, replacing arsenic as primary therapy, late manifestations of syphilis have become rare, especially in developed countries.8 Although tertiary syphilis is not the dominating public health issue it once was, it remains an important disease for health care providers to keep in their differential diagnoses, particularly in light of the increasing rates of syphilis since the start of the 21st century.6 When primary or secondary syphilis is not treated, latent and tertiary syphilis may develop. Tertiary syphilis is a multisystem disorder that presents in different ways: gummatous lesions, cardiovascular involvement with aortic aneurysms and heart failure, neurosyphilis with cognitive deficits, and tabes dorsalis.
Tabes dorsalis refers to demyelinization of sensory nerves in the dorsal columns of the spinal cord with tabetic arthropathy as one of its sequelae. The process of bone degeneration and joint destruction may precede other manifestations of neurosensory deficit, but it may also follow clinically apparent tabes dorsalis.9–12 The prevalence of tabetic arthropathy is unknown, but data from the first half on the 20th century suggest that 1% to 10% of patients with tabes dorsalis develop tabetic arthropathy.11,13,14 Joint destruction usually presents at the age of 40 to 60 years.15–18 Approximately half of the patients with tabetic arthropathy have been aware of the symptoms of primary syphilis infection. The clinical course of tabetic arthropathy varies. The onset can be acute or insidious, and the disease may remain asymptomatic for years.11,19 The interval between primary syphilitic infection and the development of tabetic arthropathy ranges from 3 to 66 years, with an average of 25 years.15,16,18 The average delay in diagnosis of tabetic arthropathy after the first symptoms of joint destruction is 3 years (range, 0.25–20 years).15 In our case, the diagnostic delay of at least 4 years has probably been influenced by the fact that our patient was living in celibacy.
Although neuropathic joints are named after Charcot, his theory that the arthropathy results from damage to the central nervous system trophic centers controlling bone and joint nutrition proved to be incorrect.20 Also in tabetic arthropathy, there is no sign of actual infection. Even with sensitive techniques such as rabbit inoculation and polymerase chain reaction, spirochetes have never been detected in affected joint tissues. The etiology of arthropathy in late stages of syphilis remains under debate. Both neurotraumatic and neurovascular mechanisms are proposed to be involved and may complement each other. Both theories are also proposed in research on other causes of Charcot joints, for example, diabetes mellitus and spinal cord injury.5,21–25
The neurotraumatic theory is the explanation most often cited4,12,15,16,19–35 and is supported by animal experiments.24,29,36 Repetitive trauma in the absence of an intact protective sensory system results in progressive joint destruction. Loss of sensory feedback leads to relaxation of the articular capsule and ligaments. Cartilage is damaged mechanically, leading to excessive bone formation, erosion, and reabsorption. The combination of neurosensory deficit and bony deformation with changed pressure points makes the extremities prone to skin lacerations and subsequent secondary infection.19
The other theory is the neurovascular theory, which states that increased bone-blood flow, caused by a neurally initiated vascular reflex, accompanies tabetic arthropathy. This vascular reflex promotes bone resorption by osteoclast activation. Productive changes are caused by continued weight bearing on an affected joint. However, in only 2 patients, increased vascularity and vasodilatation was objectified by histologic specimens.28,35 Moreover, vasodilatation and hyperemia in other disorders do not lead to the severe bone resorption seen in tabetic arthropathy.28,35
Tabetic arthropathy usually presents in patients who are physically active and affects multiple joints in 18% to 40% of cases. Reviews of tabetic arthropathy cases, reported in 25 articles since the introduction of antibiotic treatment for syphilis, describe a total of 614 patients (range, 1–335). The knee was affected in 261 patients (42.5%), the hip in 100 patients (16.3%), the ankle in 66 patients (10.7%), the spine in 43 patients (6.9%), and the upper extremity in 18 patients (2.9%).3–5,15,16,19,21,22,24,27,28,31–35,37–45 This order involvement reflects a possible role of weight bearing in the destructive process.
Physical examination of the affected joint may show signs of instability. A range of 15% to 67% of the patients experience pain, although it tends to be disproportionally mild compared with the degree of joint effusion and joint destruction.18,27,46 Joint effusion may be recurrent or chronic and varies from a small quantity of fluid to massive hydrarthrosis.20,23 The overlying skin is often hyperemic. In advanced cases, large osteophytes can be palpable next to the joint, sometimes with subluxation and loose fragments, also described as a “bag of bones.”47 Crepitus may be heard. End-stage disease shows complete deformity of the affected joint, with exuberant bony overgrowth stabilizing the joint.
Neurologic examination shows loss of deep pain sensation and proprioception in most patients. In advanced cases, there may be ataxia and a positive Romberg sign. Absent tendon reflexes in the lower limbs and Argyll Robertson pupils are seen in up to 90% of patients with tabes dorsalis and are highly characteristic findings.13,27,48 Other signs of tabes dorsalis are loss of bladder control, stabbing pains, and gastric crises.
Radiographic and Laboratory Findings
Conventional radiographs of early tabetic arthropathy show thinning of the articular cartilage and cyst formation.12,18,19,32,49 These abnormalities progress to complete disorganization of the joint.32,47 Pathologic, mostly transverse, periarticular fractures, and subluxations of the articular surfaces are common.24,32 Hypertrophic, atrophic, and mixed patterns are depicted radiographically. The hypertrophic joint is manifested as joint destruction and fragmentation, osseous sclerosis, and bony proliferation. There is bony and cartilaginous debris in the joint cavity, new bone formation in the synovial membrane and subsynovial tissues, and formation of enormous-sized and bizarre-shaped osteophytes.18,19,32,47,50 The atrophic type of tabetic arthropathy has an appearance of osseous reabsorption and is more common in non–weight-bearing joints.19,32 Progressive absorption of phalanges gives a decrease in bone length and width, resulting in a “pencil sharpening” appearance of the bony ends.32,51
T. pallidum cannot be cultured in the laboratory. Techniques to diagnose syphilis directly from clinical specimens include dark-field microscopy and direct fluorescent antibody testing, but these tests can only be applied on lesions in early stages. The most sensitive techniques are rabbit inoculation and polymerase chain reaction.
Serologic screening of serum
Serologic screening of serum is routinely done by a nontreponemal screening test (i.e., RPR or VDRL), followed by a confirmatory test for treponemal antigen (i.e., immunofluorescent treponemal absorption test, enzyme immunoassay, or TPPA). The nontreponemal tests may be nonreactive in late neurosyphilis, particularly in tabes dorsalis. Serum treponemal tests, however, remain reactive for life in nearly all patients. A serum RPR titer helps predict the likelihood of neurosyphilis. A titer of 1:32 or greater increases the odds of neurosyphilis 6- to 11-fold.48,52
Cerebrospinal fluid examination
Cerebrospinal fluid examination includes WBC count, glucose concentration, and protein concentration. The diagnosis of neurosyphilis can be difficult, particularly in case of concomitant HIV infection or in case of late neurosyphilis when signs may subside.48 Pleocytosis, hypoglycemia, and elevation of protein concentration can be found. Half of the patients with tabes dorsalis have normal WBC counts in CSF. In tabes dorsalis, protein concentration is usually 45 to 75 mg/dL.48 The nonspecific nontreponemal and specific treponemal antibody tests that are used for serum can be performed on the CSF, as well. The best use of the CSF TPPA is to exclude neurosyphilis when the test result is negative. Cerebrospinal fluid RPR has a high false-negative rate. Cerebrospinal fluid VDRL is currently considered the gold standard for diagnosis of syphilis. However, the CSF-VDRL test may be falsely negative in as many as 70% of patients with neurosyphilis.48,52 Therefore, a reactive CSF-VDRL test establishes the diagnosis of neurosyphilis, but a nonreactive test does not exclude syphilis.48 In patients with suspected neurosyphilis who have a nonreactive CSF-VDRL test, a CSF-WBC count of more than 5 cells/μL or a protein concentration of greater than 45 mg/dL is consistent with the diagnosis of neurosyphilis. Results of the CSF immunofluorescent treponemal absorption test is helpful in establishing the diagnosis of neurosyphilis when elevated protein is the only CSF abnormality.8 Intrathecal production of T. pallidum–specific IgG antibodies is an important indicator for the diagnosis of neurosyphilis.53–56 The correlation of Treponema-specific antibody titer per milligram of total antibodies in CSF and serum is a dependable source of information on the synthesis of treponemal antibodies in the central nervous system.55,57 A 3- to 450-fold higher antibody concentration in the CSF than in the corresponding serum demonstrates intrathecal synthesis of syphilis-specific IgG or IgM.58 Approximately 50% of patients with neurosyphilis show intrathecal synthesis of IgA.59 Recombinant protein (TpN47, TpN17, and TpN15) and synthetic peptide (TmpA) testing is a molecular technique designed for testing antibodies against several specific treponemal antigens. These tests are able to detect minute amounts of antitreponemal antibodies in the CSF. A sensitivity of 100% and specificity of 98% to 99.3% are observed.56,60,61
Synovial fluid can be serous, fibrinous, or bloody, but usually, it is clear, straw colored, and nonviscous.30 A high protein content may be found, but there are no characteristic features. The white cell count is usually low, and the differential cell count is predominantly mononuclear and lymphocytic.24 It may be mixed with blood even after minor trauma.21,23,24 Synovial fluid is only cloudy or turbid in secondary infectious arthritis.
Histologic examination of joint tissues shows cartilaginous fibrillation and bone formation in early stages. Later, the destructive changes are marked, resulting in fragmentation of articular cartilage, young fibrous tissue replacing cartilage, and destruction of intra-articular ligaments. There is bone resorption with exposure of areas of sclerotic cortical bone and bone formation, leading to a marked irregularity of the articular surface.5,21,28,30 A signaling microscopic feature is the presence of bone debris and cartilage fragments in the synovial membrane, muscles, ligaments, tendons, and joint capsules.23,30,61,62 The synovium and joint capsule are spongy, edematous, and thickened due to granulation tissue. Dilated blood vessels with thickened walls and coalescence of the Haversian canals can be demonstrated.25,34
The diagnosis of tabetic arthropathy can be difficult because the clinical presentation is nonspecific, and the differential diagnosis wide ranging (Table 2). In early stages of the disease with minimal joint destruction, signs and symptoms are often mild, and tabetic arthropathy is easily missed. Syphilis remains, in Osler’s words, “the great imitator.” Syphilis should be entertained as a possible diagnosis for patients with disproportionately painless, but rapid and complete destruction of weight-bearing joints occurs; other causes of neuropathic arthropathy have to be ruled out, as well. Evaluation of a patient with neuropathic arthropathy should consist of detailed history taking and complete physical examination including neurologic tests with special attention to pupillary abnormalities, optic atrophy, sensory changes (paresthesias, hyperesthesias, impaired pain, position and vibration sensation), ataxia, and deep tendon reflexes. Laboratory examination is mandatory including complete blood count, glucose, glycated hemoglobin, rheumatoid factors, and treponemal and nontreponemal tests.
In retrospect, the painless knee destruction 4 years before the present episode was caused by tabetic arthropathy. Detection of neuroyphilis, before complete destruction of the right knee, could have prevented the need of arthroplasty in this case and probably also the deformation of the right foot, which could have been avoided by preventive and conservative measures. Besides the typical involvement of the knee, the upper extremity was also involved, which is uncommon but has been described in at least 18 patients. The hyperkeratosis of the skin fits the typical syphilitic palmoplantar keratoderma in secondary syphilis, although it has not been described before to appear on and off for 20 years.
A certain diagnosis of neurosyphilis was difficult in this patient, partially because patients with late neurosyphilis and, especially, tabes dorsalis show little CSF anomalies, partially because CSF-VDRL, the gold standard test for neurosyphilis, was not tested before treatment with penicillin. The negative RPR test in this patient has a high chance of being false negative. The positive TPPA result does not necessarily mean that the patient does have neurosyphilis. The Vienna index seems to indicate that the patient has neurosyphilis, but unfortunaly, this test lacks prospective validation. The normal WBC count in CSF does not exclude neurosyphilis because it is normal in half of the patients with late neurosyphilis.48 The protein concentration is in the typical range of tabes dorsalis. The intrathecal production of immunoglobulins and the positive recombinant and synthetic peptides are highly suggestive for neurosyphilis, but these tests are not standardized, nor are they familiar to most health care providers because they are not part of tests recommended by guidelines such as the Centers for Disease Control and Prevention guideline.
Nonetheless, there is sufficient clinical evidence that this patient does indeed has neurosyphilis: the Charcot-type joint abonoramalities in the absence of other neuropathic causes; neurologic abnormalities such as reduced light touch and vibration sense, absent knee jerk reflexes, and Argyll-Robertson pupils, coupled with the positive syphilis serology in serum; and the abnormalities in the CSF, all identify a patient with neurosyphilis.
Antisyphilitic treatment with intravenous penicillin G 12 to 24 million units a day (150,000 IU/kg−1 d−1) for a total of 10 to 14 days is an effective treatment for neurosyphilis.55 This stops further progression of neurologic damage but will not lead to recovery. Because there is no active infection in the affected joints, antibiotics neither influence the previously developed tabetic arthropathy nor will cure the sensory defects that are responsible for further progression.12,15,16,33,34,50
The key to proper treatment of tabetic arthropathy is therefore to avoid injuries because trauma to inadequately protected tabetic arthropathic joints is often the precursor of joint damage. Patients with known tabes dorsalis should protect themselves from trauma and look for signs of early joint damage.3,4
If injury has occurred, early identification and the immediate protective treatment of the involved joint are essential until all signs subside.23,24 Affected bones and joints may be protected by bed rest, molded shoes, plaster casts, corsets, crutches, braces, splints, and other articular supports to prevent the vicious circle that leads to the full-blown Charcot joint.3–5,9,15,21,23,24,26–28,33 Nonsteroidal anti-inflammatory agents help to control synovial inflammation.3 If the joint is grossly swollen, aspiration may be required.3,27 When adequately treated, these early lesions will generally heal without secondary joint damage.5,12,21,23,24,26,28
Unfortunately, many patients are not seen until the damage has already been done. If the damage is too great for rest and bracing to be effective and pain or instability causes a joint to be useless, operative treatment is an option. Surgical procedures are often unsatisfactory. A great hazard after surgery is postoperative infection, which is often unnoticed by the patient because of sensory deficit.4,24 Other complications are poor wound healing, delayed union, and nonunion. To prevent acceleration of the destructive process, surgery should ideally be postponed until swelling and redness have subsided, and x-rays show repair rather than resorption.3,16,24,35
The least complicated procedure is debridement with removal of loose bodies and synovium. Other techniques used are corrective osteotomy, arthrodesis, arthroplasty, and amputation of the affected joint.21,23,28,31,41 When osteotomy or arthrodesis is attempted, adequate, extensive resection of affected bone and prolonged postoperative immobilization are of utmost importance to prevent nonunion.24,27,28 Transposition of peripheral nerves, stabilization of the spine, or surgical decompression of the spinal cord and nerve roots may be required if these structures are compressed by affected joints.12,16,23,27 Arthroplasty shows a high percentage of failure with recurrent dislocations, periprosthetic fractures, and loosening of components.4,5,23,24,27,33,34,40 Although success has improved over time with evolvement of the implemented procedures, it averages only 50%.5,12,20,28,39,43,44 Caution is required in early stages of joint destruction when ataxia is present and when using uncemented or unconstrained prosthesis.33,40,45 As a last resort, in the presence of severe sepsis, failed surgery, or a completely destroyed joint, amputation may be necessary.4,12,23,26
Syphilis is not merely a historical cause of neuropathic arthropathy. This case highlights a 55-year-old patient with Charcot arthropathy of multiple joints attributable to previously undiagnosed tertiary syphilis and tabetic arthropathy. It illustrates that tabes dorsalis should be considered in patients presenting with rapid joint destruction consistent with neuropathic arthropathy. In this case, tabetic arthropathy was suspected by the history of painless destruction of multiple joints, neurosensory deficit, and skin lesions of the extremities. Radiographs of the affected joints were classical examples of tabetic arthropathy. Laboratory tests showing signs of neurosyphilis confirmed the diagnosis of tabes dorsalis with tabetic arthropathy. Early detection of tabes dorsalis is of utmost importance to prevent onset of damage of unaffected joints and proceeding of the destruction in the affected joints. Special attention is required to prevention of trauma. Tertiary syphilis infection is treated with high-dose intravenous penicillin. Treatment of the affected joints is immediate immobilization. Surgery is only to be considered when conservative measures fail and when pain and instability cause the joint to be useless.
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