•

Clinical, Radiographic and Pathologic Abnormalities in Calcium Pyrophosphate Dihydrate Deposition Disease (CPPD): Pseudogout 1

Diagnostic Radiology

Donald Resnick, M.D., Gen Nlwayama, M.D., Thomas G. Goergen, M.D., Peter D. Utslnger, M.D., Robert F. Shapiro, M.D., Douglas H. Haselwood, M.D., and Kenneth B. Wiesner, M.D. Clinical, radiographic and pathologic abnormalities in calcium pyrophosphate dihydrate deposition disease (CPPD) (pseudogout) are outlined in an investigation of 85 patients with definite or probable disease and available cadaveric and human surgical material. Pyrophosphate arthropathy produced distinctive roentgenographic abnormalities which were most frequent In the knee, wrist and metacarpophalangeal joints. Although the alterations superficially resembled osteoarthritis, they were frequently more severe and progressive with extensive fragmentation of bone, causing intra-articular osseous bodies. Pyrophosphate arthropathy occurred in unusual locations, such as the radiocarpal compartment of the wrist, elbow, and patellofemoral compartment of the knee. These characteristics allow the radiologist to suggest a probable diagnosis of CPPD even In the absence of articular calcification.

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INDEX TERMS: Arthritis. Chondrocalcinosis, 4[8].760. Joints, diseases • Pseudogout, 4 [8] .761 • Pyrophosphate

Radiology 122:1-15, January 1977

C

HONDROCALCINOSIS may be defined as the presence

of intra-articular calcium-containing salts within fibroand hyaline cartilage (16). Chemically, these deposits represent calcium pyrophosphate, orthophosphate, and hydroxyapatite. The radiographic appearance of chondrocalcinosis associated with calcium pyrophosphate dihydrate crystal deposition typically includes heavy punctate and linear calcifications which are frequently bilateral and symmetrical. This specific calcium salt, when present within a joint, may produce an acute synovitis leading to the pseudogout syndrome. Some patients with pseudogout have a radiographically distinctive degenerative arthropathy producing structural changes consisting of joint space narrowing, bony eburnation and subchondral cyst formation which is most frequent in the wrists and hands (14, 26) and may be associated with para-articular calcification. This investigation, based upon a large series of patients with calcium pyrophosphate dihydrate deposition disease (CPPD) and available pathologic material, proposes to: (a) Delineate the incidence and characteristic features of pyrophosphate arthropathy (b) Define and correlate clinical, radiographic and pathologic abnormalities in the disease. MATERIAL AND METHODS

Patients with CPPD The clinical and roentgenographic records of all patients investigated at the University and Veterans Administration Hospitals in San Diego from 1971 to 1974 with a possible diagnosis of CPPD were reviewed, Additional patients seen in consultation from neighboring institutions were included.

Fig. 1. Chondrocalcinosis in CPPD: In the knee, shaggy calcification in the fibrocartilaginous (F) menisci and thin linear calcification in the hyaline (1-1) articular cartilage are apparent.

Individuals with clinical or laboratory evidence of rheumatoid arthritis or gout were excluded. When possible, patients were recalled for further clinical and radiographic examination and synovial fluid aspiration. From this initial group, 85 patients were found who fulfilled specific criteria for inclusion in the study. These criteria, which had been previously utilized by McCarty (15), included: 1.

2.

The presence on radiographs of typical chondrocalcinosis involving more than one set of joints exclusive of the intervertebral disks (e.g., one or both knees and one or both wrists represents two sets of joints). The identification of monoclinic and triclinic crystals, aspirated from symptomatic or asymptomatic joints, which showed absent or weakly positive birefringence when examined by compensated polarized light microscopy.

1 From the Departments of Radiology (D.R., T.G.G.) and Pathology (G.N.), Veterans Administration Hospital, San Diego and University Hospital, University of California at San Diego; the Department of Medicine (P.D.U.), University of North Carolina and the Department of Medicine (R.F.S., D.M.H., K.B.W.), Sacramento Medical Center, University of California at Sacramento. Dr. Resnick is a Picker scholar, Picker Foundation. Presented in pari at the Sixty-first Scientific Assembly and Annual Meeting of the Radiological Society of North America, Chicago, 111., Nov. shan 3D-Dec. 5, 1975. Supported in part by VAH Grant #7406.

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DONALD RESNICK AND OTHERS

Of these 85 patients, 31 fulfilled both criteria 1 and 2 (Group A) and had definite CPPD; 48 fulfilled criterion 1 alone (Group B); 6 patients fulfilled criterion 2 alone (Group C); 54 patients therefore had probable CPPD(Groups Band C). Because of the large number of patients with probable disease, the clinical and radiographic characteristics in Groups A, Band C were evaluated separately in order to determine whether differences existed among the groups justifying their separation into probable and definite categories. Of the 85 patients, 27 had been recalled for further clinical or roentgenographic studies and 78 had been examined by a rheumatologist or orthopedic surgeon since 1971. Recorded clinical parameters included patient age, disease duration and site(s)and patterns of articular symptoms and signs (see below). Pertinent laboratory data were also recorded including serum levels of calcium, phosphorus, alkaline phosphatase, uric acid, glucose, iron, iron-binding capacity, and rheumatoid factor. Complete skeletal surveys were obtained in 48 patients and consisted of: hands, wrists (PA, obliques, lateral); elbows (AP, lateral); shoulders (AP); pelvis (AP); hips (AP); symphysis pubis (AP); knees (AP, lateral); ankles (AP, lateral); feet (AP, oblique); entire spine (AP, lateral). In 23 additional patients extensive but incomplete skeletal surveys were available. Fourteen patients had limited radiographic studies. Recorded roentgenologic features included the presence and type of chondrocalcinosis and associated capsular and soft-tissue calcifications, and the pattern and severity of arthropathy.

"Normal" Control Group Eighty-five age and sex-matched patients were used as "normal" radiographic controls. These patients who all had roentgenographic examinations of the joints identical to those of the CPPD group were obtained from two sources: approximately half of the patients had undergone expanded skeletal surveys for the work-up of metastatic disease and were without articular complaints; the other patients had obtained complete skeletal surveys for the evaluation of minor and nonspecific articular symptoms and signs (e.g., muscle strain and spasm; low back pain) and were without definite diagnosis by clinical, laboratory and radiographic evaluation. It was fully realized that these latter individuals were not true "normals" and would have a higher incidence of radiographic abnormalities of the joints when compared to asymptomatic individuals. No patients with choncrocalclnosls in any articulation were considered "normal." The structural joint changes in each individualarticulation (e.g., knee) in patients with CPPD were compared to those occurring in the "normals." As some patients with CPPD did not have complete skeletal surveys, a careful attempt was made to obtain an equal number of control patients who were comparable in age to the CPPD group for each articulation.

Osteoarthritic Control Groups The structural joint abnormalities in the knees in patients with CPPD were compared to those in 56 knees of 53 patients with osteoarthritis. These latter individuals had been previously described in detail (29). Additionally, the structural joint changes in the hips in patients with CPPD were compared to those in 100 patients with "primary" osteoarthritis of the hip, the latter group of patients also

January 1977

having been previously reported (24). In both of these groups, the diagnosis of osteoarthritis was based upon the presence of typical clinical and radiographic features, and the absence of any evidence suggesting other types of arthritic or metabolic disorders.

Statistical Analysis Statistical evaluation included chi-square analysis with a two-sided confidence limit. This evaluation was applied specifically to the incidence of structural joint abnormalities in the CPPDand normal control groups, and to the pattern of roentgen alterations in the knee and hip in the CPPD and osteoarthritic control groups.

Pathologic Material in CPPD Five cadavers with CPPD provided pathologic material. Selected joints were removed, frozen, sectioned, radiographed and photographed. Microscopic sections were prepared by fixing slabs of 1 to 3 cm in thickness for 1 week in neutral buffered formic acid and dehydrating in ethanol. Specimens were then double-embedded with 4% celloidin in methyl benzoate and paraffin. Eight- to 10-,u sections were cut on a sledge microtome and stained with hematoxylin and eosin. Stages of tissue maceration were prepared by placing some specimens in Clorox solution for varying periods of time.

Surgical specimens following total hip (2 patients) and knee (2 patients) arthroplasties in patients with CPPD were also studied. RESULTS

Patients with CPPD Clinical Findings: The clinical findings are summarized in TABLE I. There were 69 men and 16 women with an average age of 74 years. The clinical spectrum of the disease was divided into six patterns: Type I-Intermittent acute arthritic attacks which subsided completely (9 patients); Type II-Almost continuous acute attacks (2 patients); Type III-Progressive chronic arthritis with superimposed acute attacks (36 patients); and Type IV-Progressive chronic arthritis without acute episodes (20 patients) were identical to those outlined by McCarty (15). Type V consisted of a single attack of joint pain (8 patients), and Type VI, asymptomatic joint disease (10 patients). Fifty-six patients (66 % ) experienced chronic arthritis with or without acute episodes. The greatest number of patients with definite CPPD was associated with clinical Type III, although the likelihood of a single patient's having definite disease was greatest in an individual with acute attacks of arthritis (Types I, II, III and V). This obviously reflects the relative ease of obtaining synovial fluid containing crystals from acutely inflamed joints. The joints which were most frequently symptomatic were the knees, hands and wrists, ankles and subtalar articulations, and hips (TABLE II). The acute attacks of arthritis were characterized by the

Table I:

Group TOTAL A (Definite disease) B (Probable disease) C (Probable disease)

Patient Groups with CPPD

Table II:

Number of Patients

Average Age Age Range Women (yrs.) (yrs.)

Men

85 31

69 22

16 9

74 76

47-95 51-95

48

41

7

73

47-94

6

6

67

57-79

Table III:

Joint

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CALCIUM PYROPHOSPHATE DIHYDRATE DEPOSITION DISEASE

Vol. 122

Total Radiographs

Symptomatic Sites in Patients with CPPD Site

Number of Patients with Symptoms

Knees Wrists Hands Ankles/subtalar joints Hips Elbows Shoulders Neck Low back Feet Heels

58 33 17 16 15 14 14 10 6 5 4

Radiographic Findings in Patients with CPPD*

Calcification FibroHyaline cartilage Cartilage

Total

Diagnostic Radiology

Other

Total

Total with , Calcification Arthropathy Moderate Mildand Moderate Severe Arthropathy

---------------------------------------------------------------------------

Wristt MCP** Elbow Glenohumeral Acromioclavicular Symphysis pubis Hip Knee Ankle MTP**

155/79 157/79 112/56

100/60 32/21 60/33

122/62

27/14

122/62

29/16

78/78 150/75 154/80 118/59 112/58

54/54 67/36 121/68 27/16 25/14

87/55

84/50 31/20 53/27

11/9 5/5 39/21

5/3

18/9

10/6

N.C.:l:

N.C.:l:

54/54 61/32 119/67

40/21 84/46 27/16 16/9

113/63 92/53 48/25

74/44 70/43 26/15

39/24 22/13 22/13

40/20

23/12

13/7

10/6

6/3

N.C.:l:

62/32

46/25

16/9

24/13

6/3

19/19 45/24 116/62 14/9 33/19

15/15 39/20 56/33 11/7 25/15

4/4 6/5 60/36 3/2 8/5

15/15 23/13 97/56 6/4

17/10

75/49 N.C.:l:

N.C.:l:

*Upper figures represent number of individual joints; lower figures represent number of individual patients. t Entire wrist considered as single joint. **AII metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints in each extremity considered as one articulation. :l: N.C. = not calculated. Table IV:

Joint Wristt MCP** Elbow Glenohumeral Acromioclavicular Hip Knee Ankle MTP**

Symptoms us. Radiographic Abnormalities in Patients with CPPD*

Calcification in All Joints Radiographed (%)

Calcification in Symptomatic Joints (%)

Calcification in Asymptomatic Joints (%)

Arthropathy in All Joints Radiographed (%)

Arthropathy in Symptomatic Joints (%)

Arthropathy in Asymptomatic Joints (%)

65 20 54 22

68 13 75 33

63 22 50 19

73 59 43 19

83 60 59 33

68 59 39 15

24 45 79 23 22

21 55 82 25 25

24 42 73 22 22

51 30 75 12 29

33 45 87 4 50

55 26 56 14 28

*AII figures represent frequency expressed as percentage. t Entire wrist considered as single joint. **AII metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints in each extremity considered as one articulation.

abrupt onset of pain and swelling of a single or multiple joints, particularly the knees, elbows, ankles and wrists. The attacks usually persisted for one to two weeks and were occasionally provoked by trauma. In a few patients, pain lasted for four to six weeks. During acute episodes, tenderness and joint swelling were frequent physical findings. Chronic progressive arthritis was most commonly noted in the knees and hips and resembled osteoarthritis. The

joints were not swollen unless a superimposed acute arthritis episode was occurring. Flexion contractures were common, particularly in the knees and elbows. Joint aspirations revealed intra- and extracellular polymorphonuclear calcium pyrophosphate dihydrate crystals in 37 patients. The knee was the site of positive crystal aspiration in 22 patients, the wrist in 12 patients, and the elbow in 3 patients. Serologic testing for rheumatoid factor (latex fixation)

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DONALD RESNICK AND OTHERS

January 1977

Fig. 2. Capsular and Tendon Calcification in CPPD: A. Linear calcific deposits are located in the articular capsule (C) of the elbow. A severe flexion contracture is apparent and vascular ( V) calcification may be noted. B. The Achilles tendon (7) is extensively calcified and a plantar calcaneal spur is noted.

was negative (titer < 1/32) in 61 patients and weakly positive in one. Diabetes mellitus was present in 18 patients; it was generally mild, and rarely required insulin therapy. Slight elevation of serum uric acid and calcium was noted in several patients but these chemical abnormalities did not persist on repeat examination. No patients had evidence of hyperparathyroidism, hemochromatosis or Wilson's disease. Chondrocalcinosis and Other Calcifications: The radiographic features are outlined in Tables III and IV. The frequency of demonstrable articular calcification in radiographically examined joints was greatest in the knees (79 %), symphysis pubis (69 %), wrists (65 %), elbows SITE OF COMPARTMENTAL INVOLVEMENT OF THE KNEE IN CPPD AND OSTEOARTHRITIS

CPPD (116 KNEES)

OSTEOARTHRITIS (52 KNEES)

LATERAL

MEDIAL

PATELLOFEMORAL

PATELLOFEMORAL

Fig. 3. Site of Compartmental Involvement of the Knee in CPPD add Osteoarthritis: The number of knees with abnormalities in each compartment is indicated. Figures appearing in areas of overlapping circles represent the number of knees with abnormalities in more than one compartment.

(54 %) and hips (45 %) (Fig. 1). In patients with complete radiographic skeletal surveys and calcification at some articulation (44 patients), radiographs of the knees alone would have detected calcification in 39 patients (89 % ) and radiographs of knees and symphysis pubis together in 43 patients (98 %). If combined radiographs of the knees, symphysis pubis and wrists had been utilized as a screening test, all patients with calcific articular deposits at any location would have had calcification demonstrable in at least one of these sites. Capsular calcification was frequent in the elbows (23 joints) and metatarsophalangeal joints (17 sets of joints) (Fig. 2, A). It was also noted in the metacarpophalangeal joints and shoulders. Soft-tissue calcification was not uncommon, particularly about the heels, elbows, shoulders and knees (Fig. 2, B). These deposits included Achilles (28 heels), triceps (22 elbows), quadriceps (6 knees) and supraspinatous (2 shoulders) tendon and subacromial bursal (8 shoulders) calcifications. Radiographic evidence of associated rotator cuff tears was apparent in 5 shoulders with extensive intra- and periarticular calcification. Calcification within additional soft tissues and vasculature was common. Pyrophosphate Arthropathy: Arthropathy, which fundamentally resembled osteoarthritis with joint space narrowing, subchondral eburnation and cyst formation, was often symmetrical and most commonly noted in the knees (75 %), wrists (73 %) and metacarpophalangeal joints (59 %). It differed from usual degenerative disease in 5 respects:

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CALCIUM PYROPHOSPHATE DIHYDRATE DEPOSITION DISEASE

5

Diagnostic Radiology

Fig. 4. Knee Arthropathy in CPPO: A and B. Patellofemoral compartment abnormalities in 2 different patients include patellofemoral space narrowing (arrows) and bony fragmentation and osseous bodies within the knee joint (arrowheads). C. Surgical observation in a different patient during a total knee arthroplasty reveals extensive loss of cartilage and bony irregularity on the anterior surface of the distal femur (arrow) and calcific deposits on cartilage, bone and synovial membrane (arrowheads).

1.

2.

Although arthropathy was noted in weight-bearing articulations such as the knee and hip, abnormalities also occurred in sites which are uncommonly involved in usual osteoarthritis. Thus, wrist, elbow and glenohumeral joint alterations were apparent. The intra-articular distribution of abnormalities was also unusual. Involvement of the radiocarpal

3.

4.

compartment of the wrist and patellofemoral compartment of the knee was distinctive. Subchondral cyst formation was prominent and the resulting radiolucencies were frequently numerous and large. Alterations were frequently severe and progressive with extensive subchondral bony collapse and fragmentation resulting in numerous intra-articular

Fig. 5. Wrist Arthropathy in CPPD: A. There is obliteration of the joint space in the radiocarpal compartment between radius and navicular (arrow) and in the midcarpal compartment between the proximal and distal carpal rows. Considerable involvement of the trapezio-scaphoid (arrowhead) and first carpometacarpal (open arrow) articulations can be observed with loss of joint space and bony sclerosis. Note the large cysts within the triquetrum, the relatively uninvolved inferior radioulnar compartment (between the distal radius and ulna) and calcific deposits within ligaments, hyaline (11) cartilage and triangular fibrocartilage (F). B. A wrist arthrogram with introduction of contrast material into the radiocarpal compartment demonstrates mild synovial irregularity with a corrugated pattern (arrow), visualization of lymphatics (arrowhead) and communication with the midcarpal compartment.

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DONALD RESNICK AND OTHERS

January 1977

Fig. 6. Elbow Arthropathy in GPPD: The radiograph outlines joint space loss, subchondral bony sclerosis and cyst formation (arrow), osseous resorption and sharp, irregular bony margins (arrowhead), osteophytosis and fragmentation (open arrow). Fig. 7. Hip Arthropathy in GPPD: Considerable loss of joint space has resulted in superior migration of the femoral head with respect to the adjacent acetabulum, and is associated with an elongated lateral acetabular osteophyte and new bone formation on the medial aspect of the femoral head. The femoral head itself is considerably flattened and sclerotic. Additional abnormalities include a large acetabular cyst (arrow) and bony thickening or "buttressing" along the inner aspect of the femoral neck.

5.

osseous bodies. These abnormalities resembled neuropathic arthropathy with considerable bony debris and "disorganization" and occurred in the absence of neurologic deficit and in both diabetic and non-diabetic patients. They were particularly frequent in the knees, hips, talocalcaneonavicular and glenohumeral joints. Osteophyte formation was variable. In some patients, large irregular bony excrescences were noted about involved articulations. In others, joint space narrowing, sclerosis and fragmentation were unaccompanied by osteophyte formation and, produced a "polished" bony surface.

Considerable abnormalities in the cervical spine were noted in 52/57 patients (91 %) with adequate radiographs. Arthropathy in Specific Locations Knees Structural abnormalities were most frequent in the knee (116 joints). Their compartmental distribution, which was determined by analysis of cardinal roentgenographic signs of joint degeneration in each compartment (29), is indicated in Figure 3. Of particular note was the presence of patellofemoral disease (105 joints). Abnormalities were isolated to this compartment in 47 knees. Tricompartmental (medial, lateral, patellofemoral) changes were infrequent. Joint-space narrowing, sclerosis and fragmentation were commonly severe and intra-articular

osseous bodies were frequently noted (41 knees) (Fig. 4). Knee arthrography had been employed in 6 patients and degenerative meniscal tears were noted in 3 associated with ipsilateral compartmental arthropathy. Total knee arthroplasties were performed in 5 joints (3 patients). Surgical observation confirmed extensive cartilage and bone destruction, particularly in the patellofemoral compartments.

Wrists The wrist arthropathy (113 joints) demonstrated unusual predilection for the radiocarpal joint (99 wrists) (TABLE V). The radiographic abnormalities in this compartment included joint space narrowing, sclerosis and discrete subchondral radiolucencies (Fig. 5, A). Alterations in the inferior radioulnar compartment were unusual although bony eburnation of adjacent portions of distal ulna and triquetrum and small discrete distal ulnar radiolucencies were occasionally observed. In only 7 wrists were radiographic abnormalities isolated in compartments more typically involved in degenerative wrist disease (trapezio-scaphoid, first carpometacarpal). Metacarpophalangeal joint abnormalities were frequent in patients with wrist arthropathy. As it was not uncommon practice to attempt wrist aspirations in the Radiology Department in these patients, contrast material was injected following removal of joint fluid in 9 wrists in 6 individuals. These radiocarpal compartment wrist arthrograms generally revealed mild to moderate synovial corrugation with contrast communication with the inferior radioulnar, midcarpal and carpometacarpal compartments (Fig. 5, B). Lymphatic filling was noted in 2 patients and tendon sheath communication in one. Although the overall pattern was not dissimilar to that in rheumatoid arthritis (25), the degree of contrast irregularity was less.

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CALCIUM PYROPHOSPHATE DIHYDRATE DEPOSITION DISEASE

7

Diagnostic Radiology

Fig. 8. Severe and Progressive Hip and Glenohumeral Arthropathy in a Patient with CPPD: A 47-year-old woman presented with a 2% year history of arthritis of both knees and shoulders, and progressive left hip pain of one year's duration. No neurologic abnormalities were evident. Radiographs revealed chondrocalcinosls in the knees, symphysis pubis, wrist and metacarpophalangeal joints. Laboratory values were all within normal limits. A left total hip arthroplasty was eventually required. A and B. In August, 1973 small bony cysts can be identified in the femoral head (arrow). The joint space is intact. In December, 1974 a fragmented and collapsed femoral head is protruding through a fractured acetabular floor (arrowhead). Bony eburnation and cyst formation (arrows) can be seen. C. Similar progressive abnormality occurred in both glenohumeral joints. In August, 1973 subchondral rarefaction and sclerosis were present in the humeral heads. In December, 1974 fragmentation and COllapse have resulted in a grossly irregular bony surface (arrows) and narrowing of the articular space. D. Photomicrograph (X540) of the synovial tissue removed during total hip arthroplasty reveals hypervascularity and marked cellular proliferation. Bony spicules are embedded within and on the surface of the synovial membrane (arrows) and giant cells are apparent (arrowhead).

Elbows Elbow arthropathy (48 joints) consisted of asymmetrical but widespread loss of articular space between humerus and radius and/or ulna. Osseous resorption and fragmentation produced bizarre and irregular bony margins and intra-articular osseous debris (Fig. 6).

head with respect to the acetabulum was apparent in 6 hips. Protrusio deformities of greater than 3 mm were noted in 3 hips. One patient demonstrated rapid and extensive destruction of the femoral head and acetabulum with fragmentation and severe protrusio deformity. A total hip arthroplasty was required (Fig. 8). Four additional patients had undergone total hip or cup arthroplasties.

Hips Ankle & Hindfoot Hip arthropathy (45 joints) was generally mild, the most frequent radiographic finding being small lateral acetabular osteophytes (36 hips) with associated subchondral rarefaction. Extensive joint space loss was evident in 13 hips. In 7 of these the articular space was narrowed superiorly resulting in upward (superior) migration of the femoral head with respect to the acetabulum (Fig. 7). Symmetrical joint space loss with axial (along the axis of the femoral neck) migration of the femoral

Although ankle arthropathy occurred infrequently (14 joints), structural abnormalities were slightly more common in the talocalcaneal articulations (19 sets of joints). Predominant involvement of the talonavicular aspect of the talocalcaneonavicular joint was associated with osteophyte formation on the dorsum of the foot, bony fragmentation and soft-tissue swelling (Fig. 9).

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DONALD RESNICK AND OTHERS

January 1977

Cervical Spine

Fig. 9. Talocalcaneal Joint Arthropathy in CPPD: On a lateral radiograph of the foot note the joint space narrowing (arrow), bony sclerosis and fragmentation (arrowhead) at the talonavicular portion of the talocalcaneonavicular joint. There is plantar displacement of the tarsal navicular (N) with respect to the talus (T).

Extensive cervical spine abnormalities (52 patients) consisted of moderate (17 patients) or pronounced (28 patients) disk space loss accompanied by adjacent marginal vertebral body sclerosis and osteophytosis. Significant apophyseal joint abnormalities were noted In 31 patients and were widespread and severe In 17; joint space narrowing, bony eburnationand occasional localized bony ankylosis could be seen. Although flexion and extension views of the cervical spine were not routinely obtained, subluxation at some level in the cervical spine, Including separation between the odontoid and anterior arch of the first cervical vertebra (5 patients), was apparent in 16 patients and severe in 10 (Fig. 10, A). In these individuals, fragmentation, particularly of the anterior aspect of the vertebral bodies, created angular deformities (Fig. 10, B). Two of these patients described previous traumatic incidents of the cervical spine which may have contributed to the roentgen abnormalities. Although calcification in the peripheral portion of the annulus fibrosus of the Intervertebral disk could be recognized in some patients with severe cervical arthropathy, bony destruction and disk space loss in others made such Identification Impossible. Dlscal calcification in the thoracic and lumbar regions was generally more recognizable, and arthropathy in these segments less frequent and severe.

Fig. 10. Spinal Abnormalities in CPPD: A. Subluxation between the anterior arch of the first cervical vertebra (arrow) and the odontoid process (arrowhead) has occurred. B. Note the obliteration of the disk space between the 4th and 5th cervical vertebral bodies with anterior osseous fragmentation (arrow). Similar abnormalities can be seen at the level of the 6th and 7th cervical vertebra. The 3rd vertebral body (arrowhead) has been extensively resorbed. Joint space narrowing and bony eburnation are present at many apophyseal joints.

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CALCIUM PYROPHOSPHATE DIHYDRATE DEPOSITION DISEASE

Other Sites Symphysis pubis abnormalities (19 joints) included irregular narrowing of the joint space, sclerosis of adjacent bony margins and fragmentation of variable extent (Fig. 11). Similar alterations occurred in the glenohumeral (23 joints) (Fig. 8) and acromioclavicular (62 joints) articulations. Arthropathy of the metatarsophalangeal joints (33 sets of joints) was most frequent in the first digit (31 joints) and associated abnormalities at the first tarsometatarsal joint were not uncommon (12 joints).

Clinical and Radiographic Correlation The clinical and radiographic evaluation of articular abnormalities allowed correlation of several parameters: (a) (b)

(c) (d) (e)

Diagnostic confidence (probablevs. definite disease) and radiographic abnormality Clinical pattern of disease and radiographic abnormality Joint symptomatology and local (e.g., in the same articulation) calcification or arthropathy Positive crystal aspiration and local calcification or arthropathy Local calcification and local arthropathy.

Fig. 11. Arthropathy at the Symphysis Pubis in CPPD: Bony sclerosis (arrow) and fragmentation (arrowhead) can be noted about the symphysis pubis.

Fig. 12. Pathologic Abnormalities in the Wrist In CPPD: A. On a photograph of a coronal section of a macerated wrist, calcific deposits are apparent within the triangular fibrocartilage (arrowhead) and adjacent synovial and capsular tissue (curved arrow). There is widening of the Interosseous space between navicular and lunate, termed navicular-lunate dissociation (open arrow), a common finding in pyrophosphate arthropathy which is related to disruption of the Interosseous ligament. The distal ulna Is slightly sclerotic (arrow) and the articular surface of the distal radius appears irregular. B. Note cystic degeneration and calcific deposits (arrows) within the interosseous ligament between navicular and lunate (X 540). C. A subchondral cyst is identified within the hamate (arrow) and the overlying cartilage reveals degenerative splitting (arrowhead) (X 135).

9

Diagnostic Radiology

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DONALD RESNICK AND OTHERS

January 1977

slightly more frequent in symptomatic VB. asymptomatic articulations (with the exception of the metacarpophalangeal joints which were considered together as a group and the acromioclavicular joints) although this difference was usually small with the exception of values in the elbow. Because of the difficulty in assigning shoulder region symptoms to either the glenohumeral or acromioclavicular joints, both articulations were considered symptomatic areas in patients with shoulder pain. Thus,the indicated values for calcification in symptomatic and asymptomatic glenohumeral and acromioclavicular joints are not precise. Similarly it was not always possible to separate ankle and subtalar symptomatology so that the indicated values for calcification in symptomatic and asymptomatic ankles are not exact. No definite relationship between joint symptomatology and type of cartilage calcification (hyaline VB. fibro) could be demonstrated. Severe contractures in 8 elbows in 5 patients were associated with extensive capsular calcification. With the exception of values in the ankles and acromioclavicular joints, the frequency of arthropathy in symptomatic articulations was consistently greater than that in asymptomatic articulations. This difference was most pronounced in the knees. Various medications were employed to alleviate joint symptomatology including the occasional use of steroids but a definite relationship between the therapeutic regimen and the presence and severity of arthropathy was not apparent. (d) Local calcification was noted on radiographs in 24/37 (65 %) joints from which calcium pyrophosphate crystals were recovered. Local arthropathy was present in 33/37 (89 %) of these articulations. In 10 additional joints in which aspiration did not document the presence of pyrophosphate crystals, the incidence and extent of local calcification and arthropathy were generally similar. (e) The relationship of arthropathy to the presence or absence of local calcification is indicated in TABLE VI. Arthropathy was consistently more common although not more severe in joints with calcification. No relationship between the type of chondrocalcinosis (hyaline VB. fibro) and the presence and severity of arthropathy was revealed.

"Normal" Control Group

Fig. 13. Pathologic Abnormalities in the Hip in CPPD: A and B. On a radiograph and photograph of a coronal section of the hip, fibrocartilaginous (F) calcification is present within the acetabular limbus (probe). Note the hyaline (H) cartilage calcification involving the articular surface of the femur and acetabulum. (a) No definite relationship between the presence and distribution of arthropathy and the diagnostic level of confidence (patient Groups A, B, C) could be demonstrated. The average number of sets of articulations (metacarpophalangeal, wrist, hip, knee, ankle, elbow, shoulder, metatarsophalangeal) with arthropathy in 19 patients in Group A with a definite diagnosis of CPPD and complete skeletal surveys was 4.1. The same calculation in 29 patients in Groups Band C with a probable diagnosis of disease was 3.8. (b) No definite relationship between the clinical pattern of disease (I-VI) and the presence of articular calcification or arthropathy could be demonstrated. Structural joint damage was equally frequent in patients with acute and chronic arthritis. The only asymptomatic patient (Type VI) with a complete skeletal survey demonstrated arthropathy in five sets of articulations. (c) The relationship of joint symptomatology and local radiographic abnormality is outlined in TABLE IV. Articular calcification was generally

The frequency of structural joint changes in "normal" patients and those with CPPD is indicated in TABLE VII. In the control group, radiographs revealed mild to moderate joint space loss, subchondral bony sclerosis and osteophytosis. These abnormalities were most prevalent in the acromioclavicular, knee, first carpometacarpal, metacarpophalangeal, hip and first metatarsophalangeal joints. Intervertebral disk space narrowing, vertebral body sclerosis and small osteophytes were common in the cervical spine. Apophyseal joint alterations were less frequent and subluxation of cervical vertebrae, unusual and mild. Osteoarthritic Control Groups The compartmental distribution of abnormalities detected on routine radiographs (without weight-bearing) in 56 knees in 53 patients with osteoarthritis is outlined in TABLE VIII and Figure 3. Radiographs of 4 knees were interpreted as normal. The high incidence of total medial, total patellofemoral and combined medial-patellofemoral compartment abnormalities is apparent. Osteophytosis, joint space loss and subchondral sclerosis were frequent. Subchondral cyst formation and bony fragmentation and collapse were rarely found. The radiographic abnormalities in 161 hips in 100 pa-

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Diagnostic Radiology

Fig. 14. Pathologic Abnormalities in the Sternoclavicular Articulations in CPPD: A and B. On a radiograph and photograph of a coronal section through the sternoclavicular joints, fibrocartilaginous (F) calcification of the articular disks can be noted. The latter are fragmented (arrows) and there are degenerative changes apparent in the articular cartilage of apposing surfaces of clavicle and sternum. Fibrocartilaginous (F) calcification in the sternomanubrial joint is also apparent.

tients with "primary" osteoarthritis are indicated in TABLE IX. Joint space narrowing, used as one roentgenographic criterion for diagnosis, produced superior migration of the femoral head with respect to the acetabulum in the vast majority of patients.

normal hips in patients with CPPD. The lower incidence of superior and medial migration of the femoral head with respect to the acetabulum and the presence of axial migration of the femoral head in patients with CPPD were significant (p < 0.0005).

Statistical Analysis

Pathologic Findings

In comparing the incidence of structural abnormalities of joints in patients with CPPD and that in "normal" controls (TABLE VII) one can note the higher incidence of such abnormalities in the former group. This difference was most significant in the wrist, elbow, hip, knee, glenohumeral and metacarpophalangeal joints (p < 0.0005), although significant differences were noted in all other articulations including the symphysis pubis, cervical spine and metatarsophalangeal joints (p < 0.005), acromioclavicular joint (p < 0.001) and ankle (p < 0.025). The compartmental distribution of structural joint abnormalities in the knee in patients with CPPD differed from that in osteoarthritis (TABLE VIII). Significant differences in the former group included the higher incidence of isolated patellofemoral compartment abnormality (p < 0.0005) and lower incidence of tricompartmental alterations (p < 0.0005). The difference in incidence of isolated medial compartment, isolated lateral compartment, combined medial and patellofemoral compartments, combined medial and lateral compartments, and combined patellofemoral and lateral compartments in the two groups was not statistically significant. The differences in the roentgenographic appearance of structural joint abnormalities of the hip in patients with CPPD and osteoarthritis are outlined in TABLE IX. Joint space narrowing had been utilized as one of the classical radiographic criteria for the diagnosis of osteoarthritis of the hip (24) and thus was universally present in patients with that disease. This finding was noted in 29% of ab-

Chondrocalcinosis involved fibro- and hyaline cartilage. Fibrocartilage calcification was most frequently noted within the menisci of the knee, triangular fibrocartilage of the wrist (Fig. 12), acetabular labra (Fig. 13), symphysis pubis and the annulus fibrosus of the intervertebral disks. Additional deposits occurred in the articular disks of the acrornlo- and sternoclavicular joints (Fig. 14) and glenoid labra. The location of fibrocartilage calcification could be appreciated macroscopically but was more readily identifiable on slab radiographs. Diffuse punctate and linear crystal aggregates appeared glistening and white. Associated focal hyaline and myxoid fibrocartilaginous degeneration was apparent in the intra-articular disks of the knee, wrist and sternoclavicular joint, where disrupted surfaces were identified. Similar areas of degeneration were apparent in the absence of adjacent calcific deposits. Hyaline cartilage calcification produced punctate and linear deposits, mainly confined to the midzonal layer. In some areas of calcification the adjacent cartilage appeared healthy whereas in other sites, it was fragmented and thin. Calcific deposits were also noted within the synovial membrane, capsule, tendons and intra-articular ligaments. Surgically removed specimens during total joint arthroplasties revealed cartilage and osseous changes consistent with a severe degenerative arthropathy (Fig. 15). The articular cartilage was thinned or partially denuded and the SUbjacent bone contained thickened trabeculae and cystic degeneration. The synovial tissue revealed focal

12

DONALD RESNICK AND OTHERS

January 1977

Table V:

Frequency of Compartmental Disease of the Wrist in CPPD

Specific Compartment

Number of Wrists with Abnormality in Specified Compartments

99 71

Radiocarpal Midcarpal Trapezioscaphoid First carpometacarpal Inferior radioulnar Total number of wrists with a bnormality in any compartment

38

39 28

113

Table V I: Frequency of Arthropathy in Joints with and Without Calcification in Patients with CPPD* Arthropathy in Joints with Calcification (%)

Joint

Arthropathy in Joints Without CaIcification (%)

------------------------------------------~

69 15 18

75

Wrist Elbow Glenohumeral Acromioclavicular Symphysis pubis Hip Knee Ankle

67 22

83 28 34 80 22

41 17 27

58 9

*AII figures represent frequency expressed as percentage.

Table VII:

Fig. 15. Pathologic Abnormalities in the Knee in CPPD: A 57year-old man had experienced bilateral progressive knee pain for 25 years which had increased in severity during the previous 2 years. He also complained of pain and swelling in his wrists, metacarpophalangeal joints and ankles. Neurologic examination was unremarkable. Radiographs revealed chondrocalcinosis in the knee, wrists, metacarpophalangeal and metatarsophalangeal joints, and arthropathy in the knees and wrists. A total knee arthroplasty was required, calcium pyrophosphate dihydrate crystals being recovered at the time of surgery. A. Considerable collapse of the medial tibial plateau (arrow) is associated with osseous fragmentation (arrowheads). B. Small bony spicules are embedded within and on the surface of the synovial tissue (arrow). Minimal cellular reaction and myxoid degeneration are apparent (X 540).

villous or nodular proliferation with occasional histiocytic cellular infiltration and areas of hyaline and myxoid degeneration. Occasional embedded fragments of cartilage and bony spicules were observed in the synovial membrane with adjacent stromal cellular reaction and multinucleated giant cells. The marked cellular proliferation and embedded bony and cartilaginous debris within the synovial membrane were similar to alterations observed in neuropathic arthropathy.

Radiographic Abnormalities in CPPD and "Norma!" Controls

Site

Number of Abnormal Joints (CPPD) (A)

Number of Abnormal Joints ("Normal" Controls) (B)

AlB

--------------~---------------------------

Wrist* MCPt Elbow Glenohumeral Acromioclavicular Symphysis pubis Hip Knee Ankle MTPt Cervical spine

113 92 48

22 16 8

5.1 5.8 6.0

23

4

5.7

62 19 45 116 14 33

34 6 16 14

1.8 3.2 2.8 3.6 3.5 2.4

52

31

1.7

32 4

*Entire wrist considered as single joint. t All metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints considered as one articulation.

DISCUSSION

Calcium pyrophosphate dihydrate deposition disease (CPPD) is a general term applied to a disorder that may become manifest clinically as crystal-induced acute synovitis (pseudogout) and radiographically as cartilage calcification (chondrocalcinosis) and structural joint ab-

Table VIII:

Disease

Frequency of Compartmental Disease of the Knee in CPPD and Osteoarthritis Total Medial Compartment

Total Total Isolated TriLateral PatelloPatellofemoral com- femoral Compart- Compart- part- Cornpartmental ment ment ment

~------------------~---~---------------------------------

CPPD Osteoarthritis

Table IX:

53%

14%

91%

6%

41%

92%

37%

90%

35%

8%

normalities (pyrophosphate arthropathy). Confusion in terminology exists because patients with intra-articular pyrophosphate crystals need not have pseudogout, chondrocalcinosis or arthropathy. McCarty (15) applied certain diagnostic criteria for CPPD: demonstration of crystal deposition by polarized light microscopy and chondrocalcinosis were required for a definite diagnosis; demonstration of crystal deposition or chondrocalcinosis provided a probable diagnosis; and the presence of a clinical syndrome consistent with pseudogout, a possible diagnosis. This investigation was undertaken to characterize joint abnormalities in CPPD and, in particular, to define roentgenographic and pathologic characteristics of pyrophosphate arthropathy. As previous reports had indicated that structural joint alterations in CPPD resembled degenerative arthritis (1, 19,35) several control groups were included in this study to outline and substantiate radiographic differences that might exist between pyrophosphate arthropathy and usual osteoarthritis. Although this study included patients with both definite and probable CPPD, no consistent clinical or radiographic differences between these two groups could be recognized. This investigation carried out in large part at the Veterans Administration Hospital contained a disproportionately high number of men with CPPD so that we cannot be certain that similar clinical and roentgenographic results would have been obtained if a more equal number of men and women with the disease had been studied, altthough no consistent differences in articular findings between our male and female patients could be discovered. The clinical manifestations in our 85 patients with CPPD were similar to those described in previous reports (15). Although six distinct clinical patterns were recognizable most patients demonstrated progressive chronic arthritis with or without superimposed acute exacerbations. Symptomatology was most prevalent in the knees, wrists, hands and ankles and in general correlated poorly with the presence, type, and extent of local calcification. This clinical and radiographic dissociation has been previously observed (6, 14, 17, 20, 21). In fact, joint symptoms and positive pyrophosphate crystal aspiration may occur at sites free of radiographic abnormality (28, 31). Of interest in our patients was the presence of elbow contractures in association with radiographically evident capsular calcification. Such flexion contractures, particularly in the elbow or knee, are frequent in CPPD.

Diagnostic Radiology

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CALCIUM PYROPHOSPHATE DIHYDRATE DEPOSITION DISEASE

Vol. 122

Radiographic Abnormalities of the Hip in CPPD and Osteoarthritis

Disease

Abnormal Hips

Joint Space Narrowing

CPPD Osteoarthritis

45 161

13 161

Femoral r-Head Migration---... Super ior Axial Medial Migra- Migra- Migration tion tion

7 124

6 0

0 37

Radiographic manifestations included calcification of cartilage, capsule, synovium, tendons, intra-articular ligaments and soft tissues, and arthropathy. Calcification was particularly frequent in the knees (79 % ), symphysis pubis (69 % ) and wrists (65 % ).. Radiographs of the knees alone would have successfully revealed such calcification in 89 % of patients who demonstrated calcific deposits in some articulation on complete skeletal surveys. Radiographs of the knees and symphysis pubis together would have detected calcification in 98 % of these patients. Pyrophosphate arthropathy in our patients was often symptomatic and consistently more common (but not necessarily more severe) in the presence of local calcification. The most frequently involved sites were the knees (75 %), wrists (73 %), metacarpophalangeal (59 %) and acromioclavicular joints (51 0/0), elbows (43 % ) and hips (30%). In accordance with previous reports (1,9,14,26, 30,33) the radiographic changes superficially resembled osteoarthritis with inter-osseous joint space narrowing, bony sclerosis and cyst formation. However, in many patients extensive collapse and fragmentation of subchondral bone resulted in joint "disintegration" with multiple intraarticular osseous bodies which resembled neuropathic arthropathy rather than osteoarthritis. These destructive changes were particularly common in the knees, hips, talocalcaneal articulations, glenohumeral joints and cervical spine. They occurred in the absence of neurologic findings and were unrelated to therapy. Histologic evaluation of specimens obtained during total joint replacements in several of our patients confirmed the presence of cartilaginous and osseous debris embedded within the synovial membrane in association with marked cellular proliferation consistent with a neuropathic-like arthropathy (7, 10) in addition to typical alterations of osteoarthritis including cartilage fibrillation and erosion, and subchondral sclerosis and cyst formation. Extensive destructive arthropathy in CPPD without associated neurologic deficit has been previously noted in the hips (1, 18,22,27,32,34), knees (1,22,27,32,34), shoulders (1, 13, 27,32, 34), elbows (34), wrists (27, 34), symphysis pubis (22), metacarpophalangeal (27) and midtarsal joints (22). Furthermore, the deposition of calcium pyrophosphate dihydrate crystals in tabetic joints has been observed suggesting a pathogenetic synergism of the two conditions (8). Intra-articular shedding of pyrophosphate crystals may produce an acute inflammatory arthritis in association with Charcot arthropathy (2).

14

DONALD RESNICK AND OTHERS

The presence of severe cervical spine alterations in several of our patients with CPPD is of particular interest. Intervertebral disk calcification in CPPD may be extensive and produce spinal pain (5), and vertebral body and intervertebral disk destruction in this disorder has been observed (32-35). The cervical spine abnormalities in this report appear more severe than any previously described and included fragmentation and collapse of the anterior portion of adjacent vertebral bodies, subluxations and disk space obliteration. Our patients with CPPD had a significantly higher incidence of structural alterations in all articulations when compared to that in "normal" controls. This difference was greatest in the elbows, metacarpophalangeal joints, shoulders, wrists, and knees. In addition, patients with CPPD demonstrated unusual intra-articular distribution of abnormality when compared to that in "normal" and osteoarthritic controls. Thus, degenerative changes of the wrist, present in 22 joints in the age and sex-matched "normal" patients, were virtually confined to the trapezlo-scaphold (50 %) or first carpometacarpal (75 %) articulations and frequently involved both simultaneously (27 %). In pyrophosphate arthropathy, a peculiar predilection for the radiocarpal compartment of the wrist is well known (14, 26, 30) and was noted in 88 % of involved joints in our patients, commonly in association with midcarpal compartment abnormality. Trapezio-scaphoid (34 %) and first carpometacarpal (35 %) alterations occasionally occurred in CPPD. Although Bensasson et al. (3) found that trapezio-scaphoid arthrosis in the absence of first carpometacarpal arthrosis indicated a possible diagnosis of CPPD, this occurred in only 130/0 of our CPPD patients, usually in combination with radiocarpal compartment abnormality, and was noted in 23 % of "normal" controls. The intra-articular distribution of abnormalities within the knee in patients with CPPD when compared to that in 53 patients with degenerative arthritis of the same joint demonstrated interesting and significant differences. The incidence of tricompartmental alterations in our patients with CPPD was less than that in the osteoarthritic control group. Although the incidence of patellofemoral abnormalities was approximately the same in both groups, isolated changes in this compartment were significantly more frequent in CPPD (41 % ) than in osteoarthritis (8 %). Lagier (11, 12) has previously noted the association of CPPD and patellofemoral osteoarthritis with erosion of the anterior aspect of the distal femur, and a patient with extensive patellofemoral changes in this disorder was described by Richards and Hamilton (27). On lateral knee radiographs in several of our patients, the patella was wrapped about the anterior femur, an appearance which has been noted in individuals with hyperparathyroidism (4, 23). No consistent laboratory evidence of this latter disorder could be established in our patients. Pyrophosphate arthropathy in the knee generally resulted in more extensive fragmentation and collapse of subchondral bone and subluxation, and more frequent intra-articular osseous bodies.

January 1977

Hip abnormalities in patients with CPPD differed from those in 100 patients with primary osteoarthritis of the hip. While joint space loss was fundamental in the osteoarthritic control group, the most frequent abnormality in CPPD was pointed lateral acetabular osteophytes with subchondral rarefaction. Partial or complete joint space obliteration occurred in 13 hips in CPPD and produced superior migration of the femoral head with respect to the acetabulum in 7 joints (54 % ) identical to that observed in 77 % of the osteoarthritic hip joints. Axial migration of the femoral head with respect to the acetabulum was confined to patients with CPPD and in one of these individuals was associated with severe protrusio deformity and rapid fragmentation of the femoral head. The abnormalities resulting in the deposition of calcium in articular tissues in CPPD remain obscure. It is not known whether the primary event is one of calcification with subsequent degenerative changes or whether tissue degeneration precedes calcium deposition. In our patients who had been followed for several years, the degree of calcification and arthropathy generally remained unchanged. It is significant that 3 patients with moderate or severe structural joint damage and only minimal calcification developed extensive calcific deposition on subsequent examinations. Although this certainly indicates that progressive calcification may occur after the presence of severe arthropathy, we were unable to document the initial appearance of calcification after arthropathy in any patient with serial radiographs. Such a sequence has been noted in one individual by Martel et al. (14). A prominent pathologic observation in this study was the presence of focal degenerative alterations in articuiar tissues including the cartilage, subchondral bone, ligaments and synovial membrane which in many instances were not accompanied by recognizable calcific deposits. This would suggest that, at least in part, dystrophic calcification may be a secondary phenomenon occurring in deteriorating tissue. These calcific deposits may propagate further tissue degeneration resulting in a vicious cycle of events which may ultimately lead to extensive pyrophosphate arthropathy. SUMMARY

Although a definite diagnosis of CPPD requires the recovery and identification of intra-articular calcium pyrophosphate dihydrate crystals, currently used criteria for diagnosis are incomplete as they do not utilize one of two fundamental roentgenographic characteristics of the disease, pyrophosphate arthropathy. This arthropathy produces distinctive roentgenographic abnormalities which superficially resemble osteoarthritis but differ in several important respects. The joint alterations in CPPD are more severe and progressive with fragmentation and collapse of subchondral bone simulating neuropathic arthropathy (knee, hip, talocalcaneal joints, cervical spine). Furthermore, although abnormalities commonly occur in weight-bearing articulations, they also involve unusual locations such as the radiocarpal compartment of the wrist, metacarpophalangeal joints and elbows, and produce

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CALCIUM PYROPHOSPHATE DIHYDRATE DEPOSITION DISEASE

unusual isolated compartmental disease (patellofemoral compartment). These characteristics allow the radiologist to suggest a probable diagnosis of CPPD even in the absence of articular calcification. ACKNOWLEDGMENTS: The authors wish to thank Nathan J. Zvaifler, M.D. for his advice and encouragement, Peggy Mackey and Mary Gonsalves for preparing the microscopic sections, Carol Barrier, R. T., Clark Neal and Bonnie Walker for procuring and radiographing the postmortem specimens, Sue Brown and Robert Turner for the photography, Raymond J. Linovitz, M.D. for surgical correlation and Janet Zatlokowicz for her secretarial assistance.

Donald Resnick, M.D. Department of Radiology Veterans Administration Hospital 3350 La Jolla Village Drive San Diego, Calif. 92161

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Diagnostic Radiology

genologically distinctive arthropathy in some patients with the pseudogout syndrome. Am J Roentgenol 109:587-605, Jul 1970 15. McCarty DJ Jr: Pseudogout; articular chondrocalcinosis. Calcium pyrophosphate crystal deposition disease. [lnJ Arthritis and Allied Conditions, JL Hollander, DJ McCarty Jr, eds. Philadelphia, Lea & Febiger, 8th edition, 1972, pp 1140-1160 16. McCarty OJ Jr, Kohn NN, Faires JS: The significance of calcium phosphate crystals in the synovial fluid of arthritic patients: the pseudogout syndrome: I. Clinical aspect. Ann Intern Moo 56:711-737, May 1962 17. Mcivor J: Idiopathic chondrocalclncsls. Clin Radiol 22: 370-374,JuI1971 18. Menkes CJ, Simon F, Chouraki M, et a1: Les arthropathies destructrices de la chondrocalcinose. Rev Rhum Mal Osteoartic 40: 115-123, Feb 1973 19. Moskowitz RW, Harris BK, Schwartz A, et al: Chronic synovitis as a manifestation of calcium crystal deposition disease. Arthritis Rheum 14:109-116, Jan-Feb 1971 20. Moskowitz RW, Katz D: Chondrocalcinosis and chondrocalsynovitis (pseudogout syndrome). Analysis of twenty-four cases. Am J Med 43:322-334, Sep 1967 21. Pachas WN: Pseudogout without chondrocalcinosis. A clinical radiologic and pathologic study of 18 cases. Arthritis Rheum 15: 121-122, Jan-Feb 1972 22. Reginato A, Valenzuela F, Martinez V, et al: Polyarticular and familial chondrocalcinosis. Arthritis Rheum. 13:197-213, May-Jun 1970 23. Resnick DL: Erosive arthritis of the hand and wrist in hyperparathyroidism. Radiology 110:263-269, Feb 1974 24. Resnick D: Patterns of migration of the femoral head in osteoarthritis of the hip. Roentgenographic-pathologic correlation and comparison with rheumatoid arthritis. Am J Roentgenol 124:62-74, May 1975 25. Resnick D: Arthrography in the evaluation of arthritic disorders of the wrist. Radiology 113:331-340, Nov 1974 26. Resnick D, Utsinger PD: The wrist arthropathy of "pseudogout" occurring with and without chondrocalcinosis. Radiology 113: 633-641, Dec 1974 27. Richards AJ, Hamilton EBD: Destructive arthropathy in chondrocalcinosis articularis. Ann Rheum Dis 33: 196-203, May 1974 28. Rubinstein HM, Shah DM: Pseudogout. Semin Arthritis Rheum 2:259-280, 1972-73 29. Thomas RH, Resnick D, Alazraki NP, et al: Compartmental evaluation of osteoarthritis of the knee: a comparative study of available diagnostic modalities. Radiology 116:585-594, Sep 1975 30. Utsinger PD, Resnick D, Zvaifler NJ: Wrist arthropathy in calcium pyrophosphate dihydrate deposition disease. Arthritis Rheum 18:485-491, Sep-Oct 1975 31. Utsinger PD, Zvaifler NJ and Resnick D: Calcium pyrophosphate dihydrate deposition disease without chondrocalcinosis. J Rheumat 2:258-264, Sep 1975 32. Villiaumey J, Larget-Piet B, DiMenza CD, et al: Oaracteres symptomatiques et evolutifs des destructions articulaires observees au cours de la chondrocalcinose. Rev Rhum Mal Osteoartic 42:263273, Apr 1975 33. Walters D, Webb J, Robinson RG: Pseudogout syndrome: analysis of 75 cases. Austrlalas N Zeal J Med 1:297, 1971 34. Webb J, Deodhar S, Lee P: Chronic destructive polyarthritis due to pyrophosphate crystal arthritis ("pseudogout" syndrome). Med J Aust 2:206-209, 10 Aug 1974 35. Zitnan D, Sitaj S: Chondrocalcinosis articularis. Section I: clinical and radiological study. Ann Rheum Dis 22:142-152, May 1963.