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Letters to the Editor |
Departments of
1
Laboratory Medicine, and
2 Medicine, University of Washington, School of Medicine, Seattle, WA 98195
aAddress correspondence to this author at: University of Washington, Department of Laboratory Medicine, Box 357110, Seattle, WA 98195-7110. Fax 206-598-6189; e-mail syuan{at}u.washington.edu.
To the Editor:
The crystal arthropathies, gout and calcium pyrophosphate dihydrate deposition disease, are caused by deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively. A diagnosis of urate gout or calcium pyrophosphate dihydrate deposition disease is based on characteristic clinical findings and the microscopic identification of intracellular crystals in synovial fluid.
Several studies have shown the lack of sensitivity of microscopic examination of synovial fluid for MSU or CPPD crystals [sensitivity, 78% (1) and 79% (2) for MSU and 12% (1) and 67%(2) for CPPD]. Not surprisingly, this leads to a lack of reproducibility of synovial fluid analyses (1)(2). The suboptimal sensitivity, frequently attributed to the low concentrations or the small sizes of the crystals, has been difficult to improve without resorting to clinically impractical methods such as crystal extraction from synovial fluid (3) or electron microscopy(4). Problems with sensitivity have led experts to caution that a negative examination by polarized light microscopy does not exclude the presence of small numbers of crystals (5).
We have occasionally encountered synovial fluids from patients with gout that were negative for urate crystals by microscopic examination on initial viewing of a fresh specimen and then were found to be positive when the microscopic examination was repeated on the same specimen a day later. Similar cases have been reported by others (6)(7)(8). In the case we observed and the cases reported in the literature, the patients had clinical features of gout, and the positive results on repeat examination were considered true positives.
Prompted by these cases, we investigated whether repeat examination of the same synovial fluid 24 h later could improve the sensitivity of crystal detection. During a 6-month period, microscopic examinations for crystals with ordinary and compensated polarized light microscopy were performed with wet-mount slides on 130 consecutive synovial fluid specimens in which a crystal exam was ordered at three hospitals
Eighteen [14%; 95% confidence interval (CI), 8–21%] of these were positive for MSU crystals, and 5 were positive for CPPD (4%; 95% CI, 1–9%) crystals on initial examination. These 23 (18%; 95% CI, 12–25%) crystal-positive specimens were excluded from further study. A repeat examination was performed on the 107 specimens that were initially negative. For these 107 specimens, a fresh wet-mount was prepared and examined after the specimen was stored for 24 h at 4 °C. The repeat examinations were performed by a different observer in most cases. In 23 of these patients, gout or pseudogout was the main clinical differential diagnosis.
The major findings of the study are presented in Table 1
. Of the 107 initially negative cases we examined, 7 showed crystals on reexamination at 24 h. Of these seven new cases, at least five cases (four MSU-positive cases and one of the three CPPD-positive cases) were clinically significant because they were considered by the clinicians to be true positives. In one case, the synovial fluid was aspirated from a middle-aged man with a history of gout, who presented with a 1-day history of knee swelling and pain similar to his previous gouty attacks. The initial examination of the aspirated synovial fluid with compensated light microscopy did not show crystals. However, a second synovial fluid specimen aspirated the next day showed abundant urate crystals. Similarly, reexamination of the fluid from the first day, performed after 24 h of storage at 4 °C, revealed abundant crystals. In two of the delayed CPPD-positive cases, the patients had septic arthritis, and the clinical significance of the CPPD crystals was unclear in this setting. This diagnostic challenge has been noted by others (9). Of the total number of crystal-positive cases identified in our study, 24% (7 of 30; 95% CI, 10–42%) were detected only with the repeat examination. The overall yield of crystal detection on repeat examination was 6% (7 of 107; 95% CI, 3–13%). However, for the 23 cases in which gout or pseudogout was listed as the leading diagnostic possibility and the initial examination was negative, 5 (22%; 95% CI, 7–44%) were confirmed as crystal arthritis with the repeat examination.
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We envision two leading possibilities to explain the increase in sensitivity associated with repeat examination of the same specimen. The increased sensitivity might be attributable to the increased time spent examining the slide. Thus, low concentrations of crystals missed in the first examination may be detected by the second examination. Alternatively, in some patients the number, size, and/or birefringence (visibility) of crystals may increase over time in vitro and in vivo, and this facilitates their identification 24 h after the initial analysis. The latter explanation likely applies to the case we described above because abundant crystals were found on repeat examination and an in vitro maturation of crystals appeared to parallel the in vivo maturation of crystals in the affected joint.
In summary, our study suggests that repeat microscopic examination of the same synovial fluid specimen at 24 h increases the analytic and diagnostic sensitivity for crystal detection and is especially useful in cases with high pretest clinical suspicion for crystal arthropathy. A remaining issue is whether the benefit of this increase in sensitivity exceeds the cost associated with the potential decrease in specificity and the increased resources needed to perform the second examination of the specimen.
Acknowledgments
We would like to thank Starla Larson, Bryce Miller, Judy Tsoi, and Jean Turgeon for their technical support, and Drs. Daniel D. Bankson and Hossein Sadrzadeh for their collaboration.
References
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