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An asymptomatic preauricular swelling in a 58-year-old man appeared as a parotid mass and was diagnosed as calcium pyrophosphate dihydrate crystal deposition disease of the temporomandibular joint. This article describes the diagnostic criteria and management of this rare condition and reviews the 13 cases that have been reported to date.
We report a case of calcium pyrophosphate dihydrate crystal deposition disease (CPDD) presenting as an acute polyarthritis. A 66-yr-old woman was admitted with a 5-day history of fever and multiple joint pain including wrists, elbows, shoulders, knees, and ankles developed 5 days before admission. Her plain radiographs of wrists, elbows, shoulders, knees, and ankles showed chondrocalcinosis. The pubic symphysis, lumbar intervertebral discs, and both hip joints, which were asymptomatic, also had calcium deposits. The compensated polarized microscopic examination of the joint fluid, aspirated from the right knee revealed intracellular and extracellular weakly positive birefringent crystals, confirming the CPDD. This case showed that CPDD may manifest as an acute polyarthritis mimicking acute onset rheumatoid arthritis.
OBJECTIVE: To determine the dissolving ability (DA) of linear pentasodium tripolyphosphate (PSTP), cyclic trisodium metaphosphate (TSMP), polymeric sodium metaphosphate (SMP) on synthetic crystals of calcium pyrophosphate dihydrate (CPPD) and on crystalline aggregates of menisci from patients with chondrocalcinosis (CC). METHODS: Synthetic CPPD crystals were mixed with phosphate buffered saline (PBS), which contained the different polyphosphates, for one hour at 37 degrees C. The calcified menisci were obtained from the knees of four female patients with CPPD disease who underwent total arthroscopic meniscectomy for degenerative meniscal lesions. Meniscal cryosections and fragments were incubated in SMP (15 mg/ml PBS) at 37 degrees C for one hour and 24 hours, respectively. Histological evaluation on meniscal samples after polyphosphate incubation was carried out by ordinary transmitted light microscopy and polarised light microscopy. The dissolution of CPPD crystals by polyphosphates was assessed by atomic absorption spectroscopy, which determined the amount of calcium liberated from synthetic crystals and meniscal fragments. Cytotoxicity of SMP was evaluated by tetrazolium salt assay and by an ultrastructural study on cultured chondrocytes. RESULTS: SMP and PSTP showed higher DA on CPPD crystals than TSMP. Analysis of the DA values at increasing concentrations of SMP showed that a concentration of 15 mg/ml completely dissolved 2.0 mg CPPD crystals. The solution of meniscal CPPD crystals showed a significant increase of calcium concentration after three hours and 24 hours of SMP incubation (p=0.0001; Kruskal-Wallis analysis of variance) compared with fragments incubated in PBS control solution. Macroscopic and microscopic evaluation of meniscal specimens showed a notable reduction of CPPD deposits. A 50% inhibitory dose on cultured chondrocytes was reached at the maximum concentration of SMP used in this work (15 mg/ml); ultrastructural analysis did not show morphological alterations in the treated cells. CONCLUSION: The results of this study indicate that linear polyphosphates are effective in dissolving both synthetic and ex vivo CPPD crystal aggregates. This suggests a potential therapeutic use for these molecules in the treatment of symptomatic CC.
OBJECTIVE: To clarify the deleterious effects of Mayer's haematoxylin staining procedure which result in a decrease in, or complete loss of, the number of calcium pyrophosphate dihydrate (CPPD) crystals, and to determine the proper staining period for preserving the crystals in a histological paraffin section of articular tissues. METHODS: Paraffin sections of CPPD crystal-bearing articular tissues of six patients were stained with Mayer's haematoxylin for 3, 8, or 15 minutes, and subsequently with eosin for one minute. The specimens were examined with an Olympus BHS polarised light microscope. The pH of Mayer's haematoxylin solution was measured with a TOA pH meter. RESULTS: Positive birefringent CPPD crystals were seen clearly in all specimens stained with Mayer's haematoxylin for three minutes. The specimens stained for eight minutes showed a reduced number of crystals. No crystals were seen in the specimens stained for 15 minutes. Ordinary light microscopy showed no notable differences in the stainability of nucleus, cell membrane, and their surrounding tissues among specimens when stained with Mayer's haematoxylin for either 3, 8, or 15 minutes. The pH of Mayer's haematoxylin solution was 2.31. CONCLUSIONS: To find CPPD crystals in the paraffin sections of articular tissues, the staining period with Mayer's haematoxylin should be limited to three minutes. The longer the staining period, the greater the reduction in the number of crystals owing to the strong acidity of the haematoxylin solution. A staining period of 15 minutes causes a complete loss of CPPD crystals.
OBJECTIVE: To demonstrate and determine the frequency and location of calcification within cadaveric knees with or without calcification typical of calcium pyrophosphate dihydrate (CPPD), utilizing histologic, radiographic and MR imaging techniques. DESIGN AND PATIENTS: Ten cadaveric knees of elderly individuals that demonstrated no radiographic evidence of prior surgery or trauma were studied with MR imaging and subsequently sectioned in planes corresponding to those obtained with MR imaging. The slices were imaged with high-resolution radiography. Two musculoskeletal radiologists correlated the anatomic, MR and radiographic findings. Three of the knees, which did not demonstrate calcifications, were utilized as controls. Histologic sections were obtained from four knees that contained calcifications and from the three controls, and analyzed with special histologic stains that demonstrate phosphorus and calcium. RESULTS: Radiographic imaging and histologic analysis demonstrated widespread CPPD crystal deposition in four of the 10 knee specimens (40%). MR imaging demonstrated some calcifications only within the articular cartilage of the femoral condyles in three of the four (75%) specimens that had CPPD deposits. In all four specimens radiographs and histologic analysis were more sensitive than MR imaging. Histologic analysis demonstrated no evidence of CPPD crystals in the control specimens. CONCLUSION: MR imaging is insensitive to the presence of CPPD deposits in the knee, even when such deposits are widespread. Our study suggests that the sensitivity of MR imaging was significantly better in detecting CPPD deposits in the hyaline cartilage of the femoral condyles when compared with other internal structures, even when such structures contained a higher amount of calcification.
OBJECTIVE: To delineate the prevalence of tendon and cartilage calcification as well as its possible predilection for age, sex, or side of involvement in calcium pyrophosphate dihydrate (CPPD) crystal deposition disease of the knee. METHODS: We reviewed 225 lateral knee radiographs from 138 patients (M/F: 85/52, 1 unspecified sex, mean age: 73 yrs) to document quadriceps and gastrocnemius tendon calcification. Chondrocalcinosis of the knee was evaluated on 275 knee radiographs (lateral and anteroposterior projection) from 153 patients (M/F: 97/55, 1 unspecified sex, mean age: 73 yrs) to determine the frequency of meniscal and hyaline cartilage calcification. RESULTS: Gastrocnemius tendon calcification was found in 28.4% of knees, which is significantly more common than quadriceps tendon calcification (8.4%). No significant age or laterality difference existed for calcification of either tendon. Quadriceps tendon calcification was more prevalent in men, but no sex difference was present for the gastrocnemius tendon. Calcification of either tendon never occurred without associated chondrocalcinosis. Meniscal calcification was significantly more prevalent than hyaline cartilage calcification; meniscal calcification also was significantly more frequent in men. Increased prevalence of calcification with age was observed in hyaline cartilage but not in the menisci. CONCLUSION: Gastrocnemius tendon calcification is not infrequent in CPPD crystal deposition disease of the knee; identification of such calcification may further delineate this extent of the disorder.
Deposition of calcium pyrophosphate dihydrate (CPPD) crystals has been considered to be a cause of scapholunate advanced collapse (SLAC) wrist. The aim of this study was to look at X-ray changes in wrist joints affected by CPPD crystal deposition disease and to determine whether crystal deposition is a cause of SLAC wrist. A total of 150 wrists of 78 patients with CPPD crystal deposition disease were examined. In our population of Japanese patients with CPPD crystal deposition disease, the incidence of SLAC wrist was very low, and no case of Stage III SLAC wrist was found. We therefore conclude that SLAC wrist is not a radiographic characteristic of CPPD crystal deposition disease and that pyrophosphate crystal deposition cannot be a major cause of SLAC wrist.
We report a case of calcium pyrophosphate dihydrate (CPPD) arthropathy with condylar destruction of the temporomandibular joint. Diagnosis was made on the basis of clinical findings and x-ray evidence of severe destruction of the condyle. The most likely diagnosis was considered to be neoplasm and a secondary infection of the left TMJ. Review of sections of the condyle taken at operation confirmed the diagnosis of left TMJ pseudogout. The postoperative course was uneventful with improvement in the clinical symptoms.
Scapholunate advanced collapse (SLAC) is a pattern of wrist malalignment that has been attributed to posttraumatic or spontaneous osteoarthritis of the wrist. Its features, however, also have been observed in patients with idiopathic calcium pyrophosphate dihydrate (CPPD) crystal deposition disease. To determine the frequency and characteristics of SLAC in this disease, the authors reviewed wrist radiographs in 168 well-documented cases of this disorder. Forty-four of the cases (26%) revealed wrist abnormalities typical of SLAC. Associated findings included bilateral involvement (63%); calcification in or near the triangular fibrocartilage (70%); scapholunate widening or dissociation (70%); and arthropathies of the trapezioscaphoid (57%), metacarpophalangeal (second through fifth) (52%), first carpometacarpal (40%), and radiolunate (14%) joints. Results strongly suggest that CPPD crystal deposition disease is one of the major causes of SLAC. Furthermore, radiolunate arthropathy was found in 14% of the patients with SLAC and CPPD crystal deposition disease, which is different from other observations.
The post-mortem examination of an unsuspected case of alkaptonuria revealed extensive ochronosis. Histological examination of undecalcified sections of tracheal, costal, femoral and patellar cartilage revealed, in addition to ochronotic pigment, extensive calcium pyrophosphate dihydrate (CPPD) deposition. Similar deposits were present in intervertebral discs and were related to ossification of the discs resulting in partial or complete ankylosis. The calcific deposits were present around chondrocytes in the articular cartilage and this may be an important factor in the initiation of the osteoarthrotic process which characterises ochronotic arthropathy as it affects large diarthrodial joints.
Electron diffraction technique was used to identify a single crystal in synovial fluid and tissue obtained from patients with pseudogout. One hundred and ten kinds of reciprocal lattice planes of the triclinic calcium pyrophosphate dihydrate (CPPD) crystal were made from its crystallographical data. Electron diffraction patterns obtained from synthesized crystal closely fitted to the reciprocal lattice planes. Synovial fluid of ten patients who had chondrocalcinosis in the knee joint were examined. Diffraction patterns of a single rhomboid-shaped crystal fitted to the reciprocal lattice planes and these kinds of crystals were identified as triclinic CPPD crystals. A single triclinic crystal in the calcified meniscus prepared for transmission electron microscopy was identified in the same way as above. On the other hand, there weren't enough crystallographical data on the monoclinic CPPD crystal to construct the reciprocal lattice planes. Instead of comparing diffraction patterns with the reciprocal lattice planes, diffraction patterns of a single rod-like crystal were compared with those of a synthesized monoclinic CPPD crystal. This comparison combined with energy dispersive elemental analysis made it possible to identify a single rod-like crystal as a monoclinic CPPD crystal.
We report a method for studying microcrystals which combines scanning electron microscopy, electron-dispersive X-ray analysis, and X-ray diffraction. Application of all three techniques to the same crystalline bodies permits correlation of their three-dimensional morphology at high magnification with unambiguous identification by means of their crystallographic properties. The method was applied to triclinic calcium pyrophosphate dihydrate.
The role of protein kinases in the inhibition of TNF-alpha associated apoptosis of human neutrophils by crystals of calcium pyrophosphate dihydrate (CPPD) (25 mg/ml) was investigated. We monitored the activities of the p44 extracellular signal-regulated kinase 1 (ERK1) and p42 ERK2 mitogen-activated protein (MAP) kinases and phosphatidylinositol 3-kinase (PI3-K)-regulated protein kinase B (Akt) in neutrophils incubated with TNF-alpha and CPPD crystals, separately and in combination, in parallel with the endogenous caspase 3 activity and DNA fragmentation. CPPD crystals were observed to induce a robust and transient activation of ERK1, ERK2, and Akt, whereas TNF-alpha produced only a modest and delayed activation of Akt. In the presence of TNF-alpha, Akt activity was enhanced, and CPPD crystal-induced activation of ERK1 and ERK2 was more sustained than with CPPD crystals alone, but TNF-alpha itself reduced the basal phosphotransferase activities of these MAP kinases. Preincubation with the MAP kinase kinase (MEK1) inhibitors PD98059 (20 ng/ml) and U0126 (250 nM), or the PI3-K inhibitors wortmannin (100 nM) and LY294002 (50 microM) repressed the activation of ERK1, ERK2, and Akt in association with CPPD crystal incubation, in the absence or presence of TNF-alpha. Furthermore, the inhibition of the Mek1/Mek2-->ERK1/ERK2 or PI3-K/Akt pathways reversed CPPD crystal-associated suppression of TNF-alpha-induced caspase 3 activation and neutrophil apoptosis. Together, these results indicate that CPPD crystals function to induce acute inflammatory responses through ERK1/ERK2 and PI3-K/Akt-mediated stimulation of neutrophil activation and repression of apoptosis.
OBJECTIVE: To identify the morphology of a mineral-forming of adult porcine hyaline articular cartilage digest and characterize the mineral it forms. METHODS: Electron microscopy, Fourier transform infrared (FTIR) spectroscopy, x-ray microanalysis, compensated polarized light microscopy, and biochemical studies including 14C-labeled UDPG pyrophosphohydrolase radiometric assay. RESULTS: This fraction of articular cartilage digest contained membrane-limited vesicles resembling growth plate cartilage matrix vesicles and formed mineral after only 24 hours in physiologic salt solution containing 1 mM ATP: The mineral contained inorganic pyrophosphate, 95% of which derived from ATP, and phosphate, 93% of which derived from inorganic phosphate in the medium. The FTIR spectrum of this mineral closely resembled the spectrum of standard calcium pyrophosphate dihydrate (CPPD) crystals. Compensated polarized light microscopy showed positively birefringent, rod-shaped crystals morphologically identical to CPPD. Ca:P ratios, defined by energy-dispersive microanalysis, were also consistent with CPPD. CONCLUSION: The articular cartilage vesicle fraction of porcine hyaline cartilage is capable of generating mineral that strongly resembles CPPD.
OBJECTIVE: To test the hypothesis that calcium pyrophosphate dihydrate (CPPD) deposition disease is a risk factor for neck pain. METHODS: A prevalent case-control study was conducted to assess cervical calcifications and neck pain between patients with and without known peripheral CPPD deposition disease. CPPD cases were included if diagnosed with CPPD deposition disease of peripheral joints, and excluded if their chief complaint was neck pain. Controls were randomly selected among consecutive patients, hospitalized for conditions unrelated to CPPD deposition disease or neck pain, and matched to CPPD cases by age and sex. Cervical calcifications were assessed by lateral cervical radiographs and computed tomography scans of the upper cervical spine; neck pain and cervical function were appraised by a validated questionnaire. RESULTS: Cervical calcifications were found in 24 out of 35 patients (69%) in the CPPD group compared to 4 out of 35 patients (11%) in the control group (p < 0.001). Patients with CPPD deposition disease reported significantly more neck pain and discomfort than controls (p < 0.001), and were 5 times more likely to report any neck pain (odds ratio 5.5; 95% confidence interval: 1.9, 21.9). Among male patients, more extensive cervical calcified deposits correlated with more severe neck pain (rs = 0.58, p = 0.03). CONCLUSION: These results suggest that CPPD deposition disease frequently involves the cervical spine and may be associated with the development of neck pain.
Deposition of calcium pyrophosphate dihydrate (CPPD) crystals in the yellow ligament occasionally leads to neurological deficits through compression of the spinal cord. Although it is widely accepted that CPPD crystal induces severe inflammation in arthropathy, little attention has been paid to the acute inflammation that may accompany the CPPD crystals in the ligamentum flavum. The present study reviews eight patients with radiculomyelopathy due to calcification of the cervical yellow ligament. Acute inflammation of the yellow ligament accompanying the crystalline deposits, both with and without attendant granulation tissue-proliferation, was evaluated as contributing to cervical radiculomyelopathy. Three cases with attendant granulation tissue suffered from recurrent attacks of neck pain and fever with coincidental radicular pain in the upper arm. The local inflammation of the ligamentum flavum might have participated in the exacerbation of the cervical radiculopathy.
The vertebral column from a known case of Wilson's disease (hepatolenticular degeneration) was examined by radiological, histological, histochemical and x-ray microanalytical techniques which demonstrated the presence of focal depositions of calcium pyrophosphate dihydrate (CPPD) in the intervertebral discs. These deposits were present in both the annulus fibrosus and the nucleus pulposus but in certain discs the deposits were concentrated near the interface between disc and vertebral body bone endplates. At these sites there was new bone formation with narrowing of the discs, irregularity and sclerosis of the bone endplates and exostosis.
Articular cartilage vesicles (ACV), isolated by differential centrifugation of adult hyaline articular cartilage collagenase digests, mineralized in the presence of calcium and ATP. Mineral analysis by microscopy, chemical analysis, energy-dispersive analysis, and infrared spectroscopy revealed crystals resembling calcium pyrophosphate dihydrate (CPPD). Adult articular cartilage also underwent ATP-dependent mineralization, supporting the contention that vesicles in situ fostered adult articular cartilage mineralization. Phosphocitrate (PC) is a recognized in vitro inhibitor of hydroxyapatite and calcium oxalate monohydrate crystal formation, but it is not known whether PC can similarly restrict CPPD crystal development. In the present study we examine the effect of PC, citrate, and n-sulfo-2-amino-tricarballylate (SAT, a PC analogue) on the ATP-induced CPPD crystal formation in both ACV and articular cartilage models. Only PC (10-1000 microM) blocked both the ATP-dependent and -independent mineralization in ACV in a dose-dependent fashion. At 1 mM, SAT and citrate blocked the ATP-independent mineralization. Similarly, only PC blocked both the ATP- and non-ATP-dependent mineralization in native articular cartilage slices. PC, SAT, and citrate had no effect on ACV nucleoside triphosphate pyrophosphohydrolase activity, suggesting that none of these agents blocked mineralization through the inhibition of nucleoside triphosphate pyrophosphohydrolase activity, which generates inorganic pyrophosphate from ATP.