Crystal Diseases

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Crystal Diseases CATHERINE C. ROBERTS, MD,

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Several types of crystals may deposit in joints. Crystal deposition may lead to symptoms, such as those due to inflammation or may be asymptomatic.

Gout l

l

l l l l l

Clinically significant attacks may occur many years before radiographic changes are evident. Radiographs classically show well-defined erosions with overhanging edges and sclerotic borders. Soft tissue nodules (tophi) may calcify or ossify. Classically, gout involves the first metatarsophalangeal joint. Lesions of gout are randomly distributed in the hand. Osteoporosis is not a feature of gout. Gout occurs concomitantly with calcium pyrophosphate dihydrate deposition (CPPD) in 40% of patients.

CPPD Disease CPPD disease may be a secondary finding in patients with gout, primary hyperparathyroidism, or hemochromatosis. l CPPD disease may mimic gout (then termed pseudogout), infection, or neuropathic arthropathy. l Calcification of hyaline and fibrocartilage structures (chondrocalcinosis) is a hallmark of the disorder although not pathognomonic. l The arthropathy of CPPD disease commonly involves the second and third metacarpophalangeal, radiocarpal, and patellofemoral joints. l CPPD disease causes “drooping” osteophytes and prominent subchondral cysts. l

Hydroxyapatite Deposition Disease (HADD) l

l

l

l l

HADD may be acutely symptomatic and cause fever, increased C-reactive protein, and increased erythrocyte sedimentation rate. Crystals are beyond the resolution of light microscopy, making pathologic diagnosis cumbersome in routine clinical work. HADD typically appears on radiographs as amorphous globular calcifications in and around joints. HADD most commonly involves the shoulder. HADD may mimic malignancy when it causes erosion of adjacent bone and bone marrow edema.

*We extend special thanks to Ann E. McCullough, MD, for assistance with questions about laboratory fluid analysis and to Patrick T. Liu, MD; F. Spencer Chivers, MD; and William W. Daniel, MD, for contributing cases. Editing, proofreading, and reference verification were provided by the Section of Scientific Publications, Mayo Clinic, Rochester, Minn.

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Crystal deposition may be symptomatic or asymptomatic.

Gout, calcium pyrophosphate dihydrate deposition (CPPD) disease, and calcium hydroxyapatite deposition disease (HADD) are common examples. Deposition of these respective crystals in and around joints will produce changes typical of each disease.

GOUT Writing about gout in 1683, Thomas Sydenham captured the baffling nature of the disease at that time: “Either men will think that the nature of gout is wholly mysterious and incomprehensible, or that a man like myself, who had suffered from it thirty-four years, must be of a slow and sluggish disposition not to have discovered something respecting the nature and treatment of a disease so peculiarly his own.”1 Gout has been known since antiquity. Early descriptions deemed it an affliction of wealthy adult men, but its cause (an extracellular urate supersaturation that results in the deposition of monosodium urate crystals [MSU] in the tissues) was not identified until the last half of the 20th century. Extracellular urate supersaturation leads to monosodium urate crystal deposition.

Crystal deposition incites a complex inflammatory response2 that damages the tissue. The accumulation of these crystals may be idiopathic, a result of enzyme deficiencies, or the consequence of a myriad of disease states (e.g., renal disease, hyperparathyroidism, hypoparathyroidism, myeloproliferative disorders, diuretic use). A diet rich in red meat, seafood, and liquor also increases the incidence of gout.3 Saturnine gout is caused by chronic ingestion of homemade liquor (i.e., moonshine) contaminated with lead4 (Table 26-1). Clinically, gout may take the form of intermittent acute attacks of a red, swollen, painful joint or chronic arthropathy. White men who are middle aged to elderly are most commonly affected. Gout is uncommon in children and teenagers but may affect some young persons.5,6 Gout is very uncommon in premenopausal women and is common in transplant patients.6a

Diagnosis is based on the presence of hyperuricemia (although the concentration of serum uric acid may be within normal

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TABLE 26-1. Cause Uric acid overproduction

Uric acid underexcretion

Some Causes of Gout Frequency 10%

90%

Examples Primary: Idiopathic, LeschNyhan syndrome (HGPRT deficiency) Secondary: Increased cell turnover (hematologic malignancies, psoriasis, Paget’s disease, chemotherapy), increased purine intake (alcohol), accelerated ATP degradation (alcohol, muscle overexertion)

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The crystals may be intracellular (e.g., within neutrophils) or extracellular. A secondary finding is an elevated white blood cell count in synovial fluid caused by the crystal-induced inflammation.

Osteoarticular Imaging Features Radiographs Radiographic findings of gout are pathognomonic (Figure 26-2) (Box 26-1). Round to oval intraarticular or paraarticular erosions have well-defined sclerotic borders, giving them a punched-out appearance. The bone adjacent to the erosions may extend outward to produce an “overhanging margin.”

Primary: Idiopathic Secondary: Renal insufficiency, inhibition of tubular urate secretion (ketoacidosis and lactic acidosis), enhanced tubular reabsorption (diuretics, and dehydration), drugs (cyclosporine, pyrazinamide, ethambutol, low-dose ASA), lead, alcohol

From Agudelo CA, Wise CM: Gout: diagnosis, pathogenesis, and clinical manifestations, Curr Opin Rheumatol 13:234-239, 2001. ASA, aspirin; ATP, adenosine triphosphate; HGPRT, hypoxanthine phosphoribosyltransferase.

limits),7,8 clinical history, radiographic findings, MSU crystal identification, or rapid symptom resolution after colchicine therapy. Most individuals with hyperuricemia do not develop clinical gout.

MSU forms needle-shaped crystals that exhibit strong negative birefringence under polarized light microscopy (Figure 26-1). When oriented parallel to the compensator, the crystals appear yellow, whereas they appear blue when oriented perpendicularly. MSU crystals are negatively birefringent. FIGURE 26-2. Gout. An AP radiograph of the foot shows multiple findings typical of gout. Well-defined intraarticular and paraarticular erosions have overhanging edges (white arrows). The first MTP joint is involved with a large adjacent tophus (white arrowheads). An intraosseous tophus (black arrow) is noncalcified. Erosions are present remote from a joint (black arrowheads) due to pressure from overlying tophi.

BOX 26-1. Radiographic Features of Chronic Tophaceous Gout

FIGURE 26-1. Needle-shaped MSU crystals under polarized light microscopy.

Normal or near-normal bone density Normal alignment Asymmetric joint involvement Soft tissue masses that may calcify or ossify Cartilage spaces may remain normal Intraarticular and extraarticular erosions Erosions have sclerotic bases and “overhanging margins”

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FIGURE 26-3. Gout. A, Photograph of the left hand showing reddened, periarticular tophi at the third digit proximal interphalangeal joint and second digit distal interphalangeal joint (arrows). B, The corresponding PA radiograph shows the nodular appearance due to partially calcified tophi (arrows).

Erosions classically have sclerotic bases and new bone formation (“the overhanging margin of gout”).

Additional productive changes include enlargement of the phalangeal bases. Bone density in gout is normal unless disuse osteoporosis supervenes. The joint spaces are often well preserved until late in the disease, and the relative lack of cartilage destruction may help differentiate gout from other erosive arthropathies. Soft tissue tophi may be of homogeneous increased density or may contain focal calcification, which is more common in patients with altered calcium metabolism. The tophi cause a nodular appearance (Figure 26-3). They are more common in patients who have had gout for many years or who have responded poorly to treatment.9 Gout is asymmetric and polyarticular. Unfortunately, these typical radiographic changes are not visible until about 10 years after clinical presentation and early diagnosis is largely clinical.10 Advanced changes of gout (Figure 26-4) are seldom observed now because of improved diagnosis and treatment. Gout most commonly affects the feet. In more than half of patients, the initial sign is acute inflammation of the first metatarsophalangeal (MTP) joint.11 The other MTP joints, interphalangeal joints, midfoot, and hindfoot may also be involved. In the hand, the distal interphalangeal, proximal interphalangeal, and intercarpal joints are often involved. The bones may enlarge because of reactive new bone formation (Figure 26-5). When this occurs in the phalangeal bases or the ulnar styloid process, it produces a mushroom appearance. Within the elbow, the olecranon may be eroded with tophus formation in the overlying bursa (Figure 26-6). Large joints, such as the knee, are less commonly affected than are the small joints of the feet and hands. Within the knee, marginal erosions (Figure 26-7) and involvement of the prepatellar bursa are typical. Within the pelvis, the sacroiliac joints may be markedly eroded (Figure 26-8). Spinal involvement is seldom observed. However, gout in the spine has been reported in vertebral bodies, intervertebral disks,12,13 posterior elements,14,15 and facets.16 Because gout in the spine is so rare, infection and neoplasm are often diagnostic alternatives.16

FIGURE 26-4. Gout. PA radiograph of the hand in a 63-year-old woman. This patient was erroneously thought to have rheumatoid arthritis and was treated with antirheumatoid drugs for 10 years. Note the marked soft tissue swelling, numerous erosions with overhanging margins, and soft tissue calcifications.

Focal collections of crystals (i.e., tophi) occur in the synovium, ligaments,17 tendons,18 and bursae.19 When tophi are intraosseous, they have a predilection for the patella20 and almost never calcify, in contrast to the soft tissue tophi that sometimes21 contain calcifications. Lytic lesions of the patella are usually benign.21a

Intraosseous tophi may have an aggressive appearance simulating that of a malignancy.22,23 Extraarticular tophi tend to occur in the olecranon bursa, the prepatellar bursa, and the dorsum of the foot. Pressure from tophi can produce extraarticular erosions and mass effect on adjacent neurovascular structures, resulting in carpal tunnel syndrome24 or paraplegia.25 Erosion of bone and soft tissues by tophi sometimes leads to pathologic fracture26 or tendon rupture.27 Conditions associated with nontraumatic tendon rupture include gout, systemic lupus erythematosus, rheumatoid arthritis, obesity, Ciprofloxacin use, and diabetes.

Urate crystals can also penetrate the cartilage and extend into the medullary canal, producing small, circular, calcified deposits in the bone. Punctate intraosseous calcifications that collect in the subchondral bone can mimic bone infarcts and enchondromas. Gout sometimes coexists with other articular disorders (e.g., osteoarthritis, CPPD disease). When radiographic findings of multiple entities occur together, diagnosis may be difficult, especially when gout coexists with infection.28

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FIGURE 26-7. Gout. AP view of the knee showing a marginal erosion (arrow) and faintly increased density of soft tissues in a patient with gout. FIGURE 26-5. Gout. PA radiograph of the second distal interphalangeal joint demonstrates proliferative bone formation (arrows), enlarging the bone around the joint. Soft tissue swelling is due to tophi. The bone changes are similar to osteoarthritis proliferation.

FIGURE 26-8. Gout involving the sacroiliac joints. An AP view of the pelvis demonstrates large gout erosions with sclerotic borders (arrows) involving sacroiliac joints.

FIGURE 26-6. Gout. Lateral radiograph of the elbow with a large mass (arrows) of faintly increased density located dorsal to the olecranon, corresponding to a gouty tophus in the olecranon bursa. There are no bone erosions in this case.

Computed Tomography Erosions and soft tissue tophi show up clearly on computed tomography (CT) (Figure 26-9). MSU crystals have a characteristic density of 160 Hounsfield units (HU).29 This measurement is

substantially lower than that of calcium, which is 450 HU. CT can be especially helpful in defining abnormalities in areas such as the spine that have multiple overlapping structures on radiographs.

Magnetic Resonance Imaging Magnetic resonance imaging (MRI) is helpful in evaluating the extent of gout, especially in the spine,30 but it has limited diagnostic usefulness. MRI has limited diagnostic value in patients with gout but demonstrates the degree of bone and soft tissue involvement better than radiographic or clinical examination.

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FIGURE 26-9. Gout. Axial unenhanced CT through the talar dome in a 44-year-old man. A well-defined erosion with sclerotic border (arrows) is present. Biopsy confirmed gout. This lesion had increased radiotracer uptake on bone scan (not shown).

A tophus may have low to intermediate signal on T1-weighted images and a variable low to high signal on T2-weighted images (Figure 26-10). Tophi demonstrate intermediate signal on T1-weighted images and variable signal on T2-weighted images.

FIGURE 26-10. Gouty tophus producing spinal cord compression. Sagittal T2-weighted MRI through the upper cervical spine demonstrates a low signal mass dorsal to the dens (arrows). This was causing spinal cord compression (asterisk). Pathologic examination confirmed a gouty tophus. Most tumors show increased signal on T2-weighted images.

disease when imaged using Tc-99m ciprofloxacin. This technique has been proposed as a method for monitoring response to treatment.39 Cases that are healing typically exhibit decreasing uptake.

Tophi may show homogeneous, inhomogeneous, or only peripheral enhancement (Figure 26-11). Some tophi may contain focal fluid collections.31 The varied appearance of gout on MRI may be related to the amount of calcium within a tophus.32 MRI is useful, however, for identifying tophi that are not clinically evident.33

Arthrography

Scintigraphy

Ultrasonography

In active gout, radionuclide bone scanning shows nonspecific increased radiotracer uptake. Neoplasm, trauma, and infection can have a similar appearance. Gout can mimic infection clinically and radiographically.34 Unfortunately, even three-phase bone scanning, which usually has a high specificity for infection, may produce false-positive findings because of gout.35 Tophi are hypermetabolic on positron emission tomography (PET).36 A case report using PET imaging of an intraosseous patellar tophus identified metabolic activity that was less than that of malignancy, which suggests a possible role for PET in differentiating gout from neoplasm.37 Indium 111-labeled leukocyte imaging can sometimes help differentiate gout from infection, but there have been falsepositive cases.38 Cases of infection typically show increased uptake on indium-labeled white blood cells scans. Increased radiotracer uptake is seen in inflamed joints including those with crystal

Ultrasound is useful for guiding joint aspirations and biopsy. It can also be used to identify joint effusions and alterations of the surrounding soft tissue structures, such as tendons40,41 and ligaments. On Doppler ultrasound, tophi have a nonspecific heterogeneous appearance with a hypervascular rim.29 After tophi are identified, they are easy to measure with ultrasound, which can be useful for follow-up.42 Ultrasound is also helpful for assessing renal complications of hyperuricemia.43

Conventional arthrography has little use in the diagnosis or followup of gout. Fluoroscopy can guide joint aspiration for crystal analysis, and the injection of contrast material may ensure accurate intraarticular needle placement.

Extraarticular Imaging Features Gouty tophi may occur in many soft-tissue sites, including cartilaginous involvement of the nose44 and the helix of the ear.45 Hyperuricemia may also affect the kidneys, causing nephrolithiasis and chronic urate nephropathy. Urate calculi are typically opaque

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The two familial forms of CPPD disease are caused by alterations on the long arm of chromosome 8 or on the short arm of chromosome 5.48 CPPD is associated with metabolic diseases, such as hyperparathyroidism, hemochromatosis, ochronosis, or hypophosphatasia.49 In cases with intermittent acute attacks of joint pain mimicking the clinical presentation of gout, CPPD disease is referred to as pseudogout. Clinical manifestations of CPPD disease include asymptomatic, pseudorheumatoid, pseudogout, pseudoneuropathic, pseudoosteoarthritis.49a

Although cartilage calcification (chondrocalcinosis) is most commonly associated with CPPD deposition disease, other crystals (e.g., dicalcium phosphate dihydrate or calcium hydroxyapatite)50 may precipitate in cartilage to produce chondrocalcinosis. Calcium pyrophosphate dihydrate crystals are rod shaped or rhomboid and, on polarized light microscopy, have positive birefringence (blue when parallel to the compensator axis). CPPD crystals are smaller and less brightly refringent on polarized light microscopy compared with MSU crystals and may, therefore, often missed.6a

FIGURE 26-11. Gouty tophus. Sagittal T1-weighted, gadoliniumenhanced MRI through the upper cervical spine. The tophus dorsal to the dens (arrows) showed mild inhomogeneous internal enhancement and moderate peripheral enhancement. The imaging appearance was nonspecific, and surgery was necessary for diagnosis and treatment.

on noncontrast CT examinations. Tophi in the corpus cavernosum may cause erectile dysfunction. Reflex sympathetic dystrophy has been reported as a complication of gout.46 One case report described a gouty tophus that tracked alongside the iliopsoas muscle and mimicked an intrapelvic abscess.47

FIGURE 26-12. Chondrocalcinosis. An AP radiograph of the knee demonstrates globular calcification in the meniscal fibrocartilage (arrows) and linear calcification in the articular cartilage (arrowheads).

Algorithms and Recommendations In cases suspected of gout, survey radiographs should include anteroposterior (AP), oblique, and lateral views of the feet and a posteroanterior (PA) view of the hands. Symptomatic areas should also be imaged with radiographs. When gout is suspected but not clearly defined, CT or MRI may be of use, especially for imaging the spine.46 In acute monarthritis, radiographs should be considered prior to arthrocentesis to assess for fracture, especially if there is a history of trauma or risk factors for osteoporosis.6a

CPPD DISEASE In CPPD disease, crystal deposition is usually idiopathic but also may be hereditary or associated with several underlying diseases. Some causes of CPPD disease include familial, hyperparathyroidism, hemochromatosis, ochronosis, or hypophosphatasia.

FIGURE 26-13. Chondrocalcinosis. A coned AP view of the pelvis demonstrates linear chondrocalcinosis of symphysis pubis (arrowheads) and faint calcification within the superior and inferior joint recesses (arrows).

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FIGURE 26-14. Chondrocalcinosis. A tangential patellar radiograph demonstrates the fine linear appearance of hyaline cartilage chondrocalcinosis (arrows).

FIGURE 26-15. CPPD disease with marked patellofemoral cartilage loss. A tangential patellar view shows advanced narrowing of the patellofemoral joint (arrows). A patellar cyst is persent. The tibiofemoral joint compartments in this patient were normal.

Osteoarticular Imaging Features Radiographs Radiographs are the most important imaging tests in the evaluation of CPPD disease. The hallmark finding is chondrocalcinosis of hyaline cartilage or fibrocartilage (Figure 26-12). Chondrocalcinosis of fibrocartilage is most commonly observed in the knee menisci, wrist triangular fibrocartilage complex, symphysis pubis (Figure 26-13), and acetabular labrum. Essentially all patients with chondrocalcinosis may be discovered if radiographs of three sites: the knees, wrists, and pelvis (pubic symphysis) are obtained.

Crystals may also collect in tendons,51 ligaments, synovium, bursae, and joint capsules. Chondrocalcinosis in hyaline cartilage parallels the underlying bone and appears as thin linear deposits (Figure 26-14). Crystal deposition in cartilage causes accelerated cartilage breakdown52 and a radiographic appearance that mimics degenerative joint disease. Changes may be so severe that they mimic neuropathic or Charcot-like destruction of the joint.53 Joint changes are typically bilateral and symmetric. The key differentiating factor between CPPD disease and degenerative joint disease is the location of the joint changes. CPPD disease typically affects the radiocarpal, patellofemoral, and second and third MCP joints.

CPPD disease tends to affect areas not typically involved by degenerative joint disease (e.g., the radiocarpal, patellofemoral, second and third MCP joints, and the shoulder and elbow). The lack of erosion differentiates CPPD disease from gout and rheumatoid arthritis. The lack of osteopenia differentiates CPPD disease from septic arthritis and rheumatoid arthritis. The most commonly affected joint is the knee, where cartilage space narrowing and osteophytes may involve all three compartments. Severe changes in the patellofemoral joint are suggestive of CPPD disease (Figure 26-15), particularly when found in isolation. Isolated patellofemoral cartilage space narrowing suggests CPPD arthropathy.

Chondrocalcinosis is commonly found in the menisci and less commonly in the articular cartilage. CPPD disease in the hip

FIGURE 26-16. Chondrocalcinosis. An AP radiograph of the hip shows faint calcification of the acetabular labrum (arrow). There is no significant narrowing of the hip joint.

should be suspected when large subchondral cysts are present. Labral chondrocalcinosis may be subtle (Figure 26-16). Large subchondral cysts suggest CPPD arthropathy.

Changes evident on radiographs in the radiocarpal joint include chondrocalcinosis, cartilage space narrowing, and scapholunate dissociation. Chondrocalcinosis is most common in the lunotriquetral ligament (Figure 26-17) and the triangular fibrocartilage complex.54 Narrowing of the radiocarpal and scaphotrapeziotrapezoid joint spaces is common. When the scaphoid and lunate bones dissociate, the capitate can migrate proximally, producing the scapholunate advanced collapse (SLAC) wrist deformity (Figure 26-18). This deformity is not pathognomonic for CPPD disease, however. It may also be caused by trauma, infection, neuropathy, amyloid deposition, or rheumatoid arthritis. The scaphoid can erode into the distal radius, producing a stepladder appearance. Changes in the second and third MCP joints include joint space narrowing and hook-like or “drooping” osteophytes from the radial aspect of the metacarpal heads (Figure 26-19). Similar osteophytes occur with

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FIGURE 26-19. CPPD arthropathy. PA radiograph of the MCP joints demonstrates hook-like osteophytes extending from the radial aspect of the second and third metacarpal heads (arrows). The second MCP joint is moderately narrowed (arrowheads).

FIGURE 26-17. Chondrocalcinosis. An oblique radiograph of the wrist demonstrates chondrocalcinosis of the triangular fibrocartilage complex (arrow) and lunotriquetral ligament (arrowhead).

FIGURE 26-18. Scapholunate advanced collapse (SLAC) wrist. A PA radiograph of the wrist shows SLAC. The capitate has migrated proximally and articulates with the distal radius (arrows). The proximal pole of the scaphoid is eroding into the distal radius (arrowhead).

hemochromatosis when there is secondary intra-articular deposition of CPPD crystals.55 The interphalangeal joints tend to be uninvolved in CPPD disease but often are affected in osteoarthritis, which is common and can coexist with any entity. In the shoulder and elbow, any changes that resemble degenerative joint disease should raise the suspicion of CPPD disease, because these joints rarely show radiographic evidence of severe degenerative change. Degenerative changes in the shoulder or elbow raise the possibility of CPPD disease.

Osteophytes may extend from the inferomedial humeral head and the inferolateral glenoid. A subtle line of chondrocalcinosis can sometimes be identified in the cartilage covering the humeral

FIGURE 26-20. CPPD arthropathy. Coronal oblique, T2-weighted fatsuppressed MRI of the shoulder demonstrates prominent subchondral cystic change (arrowheads) and a markedly narrowed joint space (arrows).

head. Subchondral cysts may line the articular surface of the humeral head in a “string-of-pearls” configuration (Figure 26-20). Tendon calcification in CPPD disease is typically more linear or punctate than in calcium HADD, which tends to be globular and amorphous. Spinal CPPD deposition disease is uncommon; it involves the ligamentum flavum56,57of the posterior spinal canal. Less commonly, it involves the intervertebral disks58 and facet joints.59 When crystal deposition is nodular, it may cause mass effect on the spinal cord and exiting nerve roots, resulting in cord compression60-63 and radiculopathy.64 The term crowned dens syndrome refers to CPPD deposition surrounding the top and sides of the odontoid process. This syndrome may cause acute neck pain and can mimic other entities, such as meningoencephalitis,65 temporal arteritis, and bone metastases.66

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FIGURE 26-21. CPPD arthropathy. An axial CT scan through the shoulder well demonstrates joint space narrowing and subchondral cysts in a “string of pearls” configuration (arrows).

Other regions of CPPD involvement in the body include the acromioclavicular,67 sternoclavicular, sacroiliac,68 and temporomandibular joints.69-71

Computed Tomography CT well demonstrates calcifications, articular surface deformities, and subchondral cysts (Figure 26-21). However, CT is not typically used in the evaluation of a painful joint. CT is more commonly used for preoperative planning for joint replacement, because its more detailed demonstration of joint changes can help in selecting and guiding surgical intervention.72

Magnetic Resonance Imaging Whether MRI is more or less sensitive than radiographs in detecting the calcification caused by CPPD disease has been debated.73,74 Typically, calcium has low signal on MRI sequences that, theoretically, would be obscured within other structures also having a normally low signal (e.g., menisci, tendons). However, chondrocalcinosis in the menisci has increased signal on T1-weighted, proton densityweighted, and inversion recovery sequences.75 In some cases, this increased signal can simulate a meniscal tear.76 CPPD disease can mimic a meniscal tear on MRI.

MRI sequences tailored to image cartilage, particularly gradient recalled echo, best demonstrate linear low-signal calcification within the intermediate signal intensity cartilage.73 Tumoral CPPD deposits can be T2 hyperintense and show peripheral enhancement.77 MRI is useful for evaluation of associated soft tissue abnormalities, such as rotator cuff tears (Figure 26-22) or fluid collections.

Scintigraphy Before arthropathy changes are visible radiographically, radionuclide bone scintigraphy shows radiotracer uptake in joints. Unfortunately, this radiotracer uptake is nonspecific and would not facilitate differentiation of CPPD arthropathy from other types of inflammatory or degenerative arthritis.

FIGURE 26-22. Rotator cuff tear accompanying CPPD arthropathy. Coronal oblique, T2-weighted, fat-suppressed MRI of the shoulder. There is a full-thickness tear of the supraspinatus tendon, which is retracted to the level of the glenoid (black arrow). The humeral head is superiorly subluxed and erodes the undersurface of the acromion (arrowheads). Subchondral cysts in the glenoid (white arrow) were seen more prominently on additional images.

Arthrography Conventional arthrography is of limited utility in the diagnosis of CPPD arthropathy. Fluoroscopy may be informative when used to guide and confirm joint aspiration. The aspirated joint fluid can be evaluated by microscopy to identify the presence of positively birefringent calcium pyrophosphate dihydrate crystals.

Ultrasonography High-frequency ultrasound transducers can detect CPPD deposits in cartilage, which appear as linear hyperechoic foci in the hypoechoic cartilage. Ultrasound can be helpful in evaluating subtle changes in the patellofemoral joint,78 an area that can be difficult to assess radiographically. A recent study suggests that ultrasonography is at least as sensitive and as specific as radiographs for detection of CPPD calcifications.79 Despite its potential usefulness, however, ultrasound is not commonly employed for evaluation of CPPD arthropathy, probably because it is relatively time consuming and user dependent. In the future, ultrasound may gain more widespread use for detection of changes in cartilage before they become apparent radiographically.

Extraarticular Imaging Features CPPD crystals may be deposited focally in the soft tissues, producing large soft tissue masses mimicking gout (tophaceous pseudogout). These masses usually form adjacent to a joint but may be remote from any joint. The patient may lack other changes of CPPD crystal deposition. The masses have a nonspecific appearance and may raise suspicion of malignancy.80-83 Biopsy is necessary in these cases to exclude neoplasm.

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Algorithms and Recommendations Survey imaging for CPPD disease should be primarily radiographic, with images that include the symptomatic joints. Projections most likely to show changes caused by CPPD crystal deposition are the AP and lateral knees, the PA wrists, and the AP pelvis. CT and ultrasonography are sensitive in detecting calcifications that may be subtle or not visible on radiographs. Whether MRI is sensitive enough to detect CPPD deposits is questionable. For preoperative planning, radiographs and CT are the most useful techniques.

HYDROXYAPATITE DEPOSITION DISEASE HADD involves crystal deposition in the soft tissues in and around joints. Its pathogenesis is unknown.84 HADD may cause acute pain, but the calcium deposits in this common disease are asymptomatic in more than two thirds of patients, according to a classic 1941 study.85 More than two thirds of patients with HADD are asymptomatic.

Although laboratory findings are usually normal, HADD may cause fever, increased concentrations of C-reactive protein, and an increased erythrocyte sedimentation rate.86 HADD is responsible for what is commonly termed calcific tendinitis. Other terms, such as calcific periarthritis, peritendinitis or periarthritis calcarea, and hydroxyapatite rheumatism, have also been used to describe this entity.87 It may affect single or multiple joints, but involvement of a single joint is more common. Most cases of HADD are found in adults, but children and infants may also be affected.88,89 Treatment usually focuses on symptom alleviation. Although HADD has a typical appearance on radiographs, actual identification of the crystals is difficult because hydroxyapatite crystals are beyond the resolution of light microscopy. Aggregates of hydroxyapatite crystals may appear as nonbirefringent collections on light microscopy, but the appearance is nonspecific. Definitive diagnosis is based on electron microscopy or electron diffraction studies, neither of which is practical for

FIGURE 26-23. Hydroxyapatite deposition disease (HADD). An externally rotated radiograph of the shoulder shows the cloud-like appearance of calcium hydroxyapatite in the supraspinatus tendon (arrows).

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clinical use. Alizarin red S stain can screen for hydroxyapatite but is also nonspecific because it also stains any calcium,90 including other types of calcium crystals such as calcium pyrophosphate dihydrate.

Osteoarticular Imaging Features Radiographs The calcifications in HADD are more cloudlike (Figure 26-23) than the linear and punctate calcifications of CPPD disease. HADD calcifications can be differentiated from dystrophic or heterotopic ossification by the lack of trabeculation and the lack of a cortical rim. Calcifications associated with acute symptoms tend to be poorly defined and less dense than chronic calcifications. Cartilage calcification (chondrocalcinosis) in HADD is uncommon but may be present. It is not clear whether the chondrocalcinosis is caused by HADD or the coexistence of multiple crystal types in a single joint.91,92 Erosion of adjacent bone may occur. Tendinous, capsular, ligamentous,93 synovial, or bursal deposits of hydroxyapatite may be found in and around any joint. They have also been documented in many tendons remote from joints.94 The most commonly affected joint is the shoulder. Within the shoulder, the supraspinatus tendon is most likely to show hydroxyapatite deposition, but it may also affect any other portion of the rotator cuff, joint capsule, or periarticular soft tissues. Calcifications near the greater tuberosity on an external rotation radiograph are within the supraspinatus tendon (Figure 26-24). Calcifications in the infraspinatus tendon or teres minor tendon overlap the humeral head on external rotation and then project near the middle and inferior facets of the greater tuberosity on internal rotation. Subscapularis tendon calcifications are observed best on axillary views. When calcifications project onto the superior glenoid on an AP radiograph, they are usually in the origin of the long head of the biceps tendon. Calcifications in the pectoralis major origin or deltoid insertion project over the proximal humeral shaft.

FIGURE 26-24. Hydroxyapatite deposition disease (HADD). An external rotation view of the shoulder shows two calcifications typical for hydroxyapatite deposition within the rotator cuff. The calcification above the humeral head (arrows) is within the supraspinatus tendon. The calcification adjacent to the inferior facet of the greater tuberosity (arrowhead) is within the infraspinatus tendon.

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FIGURE 26-25. Hydroxyapatite deposition disease (HADD). An AP radiograph of the hip demonstrates calcification in multiple locations. Calcifications adjacent to the greater trochanter (black arrow) are within the gluteus minimus or medius tendons. Calcifications near the proximal femoral shaft (white arrow) are within the gluteus maximus (better seen on the lateral view). Calcifications adjacent to the ischium (arrowheads) are within the common hamstring origin.

FIGURE 26-26. Hydroxyapatite deposition disease (HADD). Reverse oblique radiograph of the wrist shows hydroxyapatite deposition within the flexor carpi ulnaris tendon (arrow) near the attachment to the pisiform bone along the volar aspect of the wrist.

“Milwaukee shoulder” refers to advanced destruction of the glenohumeral joint along with a chronic, large rotator cuff tear associated with intraarticular hydroxyapatite crystals.95,96 “Milwaukee shoulder” or “cuff tear arthropathy” refers to a large rotator cuff tear, glenohumeral damage, and joint/bursal distension and intraarticular hydroxyapatite crystals.

This condition may be a crystalline-induced arthropathy, although the exact cause is controversial. The hip is the second most common site of HADD involvement.50 Calcifications adjacent to the greater trochanter involve the gluteus minimus and gluteus medius tendons (Figure 26-25). Calcifications along the proximal femoral shaft typically involve the gluteus maximus tendon. Within the hand and foot, the flexor carpi ulnaris (Figure 2626) and the flexor hallucis longus and brevis are common regions of involvement. Depending on the location, HADD in the wrist may produce carpal tunnel syndrome.97 Achilles’ tendon calcifications have several causes, including HADD. Hydroxyapatite may deposit around the first MTP joint, producing a clinical presentation similar to gout98 (i.e., a red, warm, acutely painful joint) that is called pseudopodagra. It occurs in men99 and women aged 30 to 40 years old, with a female predominance.100 Radiographically, pseudopodagra appears as calcific deposits around the joint, without bone erosion. In the elbow, the origins of the common flexor and common extensor tendons are the most involved regions. Bursal and collateral ligament hydroxyapatite deposits are also found.

FIGURE 26-27. HADD (calcific tendinitis) of the longus colli. A lateral view of the cervical spine shows an amorphous calcification lying inferior to the anterior arch of C1 (arrows). The prevertebral soft tissues are swollen (arrowheads).

C RYSTAL D ISEASES

HADD in the spine is found in three typical locations: (1) within the longus colli muscle, (2) surrounding the dens, and (3) within the intervertebral disks.86 The anterosuperior portion of the longus colli muscle is most commonly involved. Symptoms of longus colli calcific tendinitis include pain, stiffness, and odynophagia. Calcification and swelling on radiographs can confirm the diagnosis.

Spinal HADD appears as a globular calcification of the prevertebral soft tissues anterior to C1 and C2 (Figure 26-27). CT can confirm the location of the calcified deposit, and MRI can exclude a retropharyngeal abscess or discitis. Calcifications surrounding the dens produce the crowned dens syndrome, which, as previously discussed, may be caused by HADD or CPPD disease. Crowned dens syndrome: Neck pain associated with calcification surrounding the odontoid process.

Calcifications within the intervertebral disks tend to be symptomatic in children and asymptomatic in adults.86

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Disk calcification in children is likely to indicate the site of symptoms.

The ligaments and apophyseal joints may also be calcified. Paraspinal HADD masses can narrow the spinal canal,101 causing a symptomatic radiculopathy or neuropathy. Paraspinal HADD may also be symptomatic due to the inflammatory response elicited by the crystals. The differential diagnosis of calcifications in and around joints is broad. Other conditions that may mimic HADD include calcifications associated with collagen vascular diseases, small foci of tumoral calcinosis in metabolic disorders, and metastatic calcification caused by hypervitaminosis D, hypoparathyroidism, or sarcoidosis. Periarticular calcifications may be seen in hypervitaminosis D, hypoparathyroidism, milk alkali syndrome, calcinosis universalis, and renal osteodystrophy.

Computed Tomography Calcifications of HADD show up well on CT scans, which can be useful in initial diagnosis, especially in the spine where overlapping bone may obscure findings.102 CT is particularly helpful when calcifications are associated with bone erosion (Figure 26-28). In some cases, erosions and calcifications may simulate malignancy such as synovial sarcoma. Malignancy is also a diagnostic possibility if the calcification and erosion occur in a region where calcific tendinitis is uncommonly found.103 When malignancy is suspected, CT or MRI may confirm the lack of a soft tissue mass. CT can also be used to further evaluate the “flame-like”104 or “comet tail” appearance of calcifications, which is commonly105 but not always106 present with HADD. “Comet tail” calcification is characteristic of HADD and may be helpful in establishing the correct diagnosis when erosion is present.

Magnetic Resonance Imaging

FIGURE 26-28. Hydroxyapatite deposition disease (HADD). An axial CT of the shoulder shows a globular calcification (arrow) at the lateral aspect of the humeral head. The underlying bone is either eroded or deformed from prior trauma.

MRI best evaluates secondary findings sometimes observed with HADD, such as fluid collections, synovitis, capsular thickening, or soft tissue or bone marrow edema. Hydroxyapatite crystal deposition in tendons has low signal on T1-weighted and T2-weighted images. Sometimes there is surrounding edema, which appears on MRI as a rim of increased signal on T2-weighted images (Figure 26-29). The crystal deposits can erode into the adjacent bone.107-109 High signal on fluid-sensitive images may be present in adjacent bone marrow, even without any erosions.110,111

FIGURE 26-29. HADD in a 42-year-old woman with acute onset of hip pain. An AP radiograph and coronal T2-weighted, fat-suppressed MRI of the hip show calcification (arrow) and surrounding edema (arrowheads) consistent with gluteus medius calcific tendinitis.

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Scintigraphy Bone scintigraphy has limited use in the diagnosis of HADD. Although inflammation surrounding acute calcific deposits produces increased radiotracer uptake,112 this finding is nonspecific. Similar findings have been observed with infection, neoplasm, or other causes of inflammation.

Arthrography Arthrography or fluoroscopy can be used to guide joint aspiration but rarely adds additional diagnostic information because hydroxyapatite crystals are so difficult to identify definitively. Arthrography can provide information about related joint structures, such as the presence of a rotator cuff tear in the shoulder or a ligamentous injury in the wrist.

Ultrasonography Calcifications in tendons and cartilage are visible on ultrasound, and ultrasound may be more sensitive than radiography for detection of early calcifications. An additional use for ultrasound is treatment of calcific tendinitis with high-energy extracorporeal shock waves.113

Extraarticular Imaging Features Hydroxyapatite crystals may produce soft-tissue masses similar to the tophaceous pseudogout masses caused by CPPD disease. The exact crystal composition of both of these masses has been questioned,114 because it is difficult to accurately identify basic calcium crystals with the pathologic methods routinely used in clinical settings.

Algorithms and Recommendations Radiography is the mainstay of diagnosis. The symptomatic joint or area of the body should be imaged and carefully evaluated for the presence of calcific deposits. However, the presence of calcification alone does not necessarily indicate that it is the cause of pain. Poorly defined, low-density areas of calcification with adjacent blurring of soft tissue planes are more likely to be symptomatic. In patients who have bone erosion detected on radiographs, CT or MRI can be used to confirm the lack of a soft tissue mass, thereby excluding malignancy. MRI can best evaluate secondary findings, including edema in the soft tissues and bone marrow.

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