“Dickkopf-Related Protein 3 as a Sensitive and Specific Marker for Cerebrospinal Fluid Leaks. : 299–303”Otology & Neurotology: 299–303” 2016;37: 299–303”

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To the Editor: We would like to comment on the article by Michaelides et al. “Dickkopf- Related Protein 3 as a Sensitive and Specific Marker for Cerebrospinal Fluid Leaks.”
The reliable and fast diagnosis of cerebrospinal fluid (CSF)-leaks is indeed an important issue. An 18.6% rate of CSF leakage is cited intra and posttransphenoidal pituitary macroadenoma surgery, published by Han et al. in 2008. In this study, postoperative CSF leaks were diagnosed using “glucose outflow.” We agree with the authors, that glucose strips are not reliable for the diagnosis of CSF leaks and should be avoided in order not to cause false negative or false positive results which could even lead to unnecessary surgical procedures in attempts to repair presumptive dural defects. Because of this, since late 1980's beta-2-Transferrin (β-2Tr) test has been used to reliably detect CSF in collected samples by isoform separation of this protein specific to CSF, perilymph, and vitreous humor (1). Then since 2000s, measurement of beta-trace protein (β-TP) in serum and nasal secretions found out to be fulfilling the criteria for a screening procedure for CSF due to its high analytical performance that improves the known shortcomings of β-2Tr test. Efficacy and reliability, as well as limitations of the β-TP test were extensively investigated by different independent groups of researchers with similar results, not only in the laboratory, but in clinical settings, proving each other (2–4). Thus, we would encourage researchers to test any new marker for CSF diagnosis in clinical trials and justify the findings in comparison to widely used standards, whose limitations and shortfalls are well defined. Nevertheless, despite continuous improvements in diagnostic tools, it is also a known fact that not only due to preanalytical challenges like sample collection in a wide variety of CSF leak patients with their own complex etiological characteristics, but also due to test specific shortcomings of each diagnostic modality including imaging, there will be still cases that will require a combination of diagnostic tools in a logical algorithm to come to a definitive diagnosis (5). Among these difficulties, the sample volume is a diagnostic challenge especially in cases with temporal bone fractures, low-flow, or occult CSF fistula. Therefore, an assay is required capable to detect the presence of CSF in small sample volumes. The Dickkopf-related Protein 3 is interesting in this sense, as the assay is said to require a sample volume between 0.5 and 0.8 μl. It is stated that the volume needed for β-TP is 200-μl per test.
We would like to clarify the volume required for the β-TP test. The nephelometric β-TP measurement requires a default dilution to minimize the influence of blood contamination. When using the automated dilution, the sample volume has to be 80 μl, of which a volume of 5-μl fluid is aspirated, diluted 1:100 and processed by laser-nephelometry (6). When diluted by hand, this sample volume of 5 μl is sufficient. In other words, a minimum sample volume of 5 μl is fully enough in a laboratory capable of hands-on 1:100 dilution. The presence of perilymphatic fluid or CSF was shown in tympanic cavity aspirate samples of 5-μl volume (7). Even occult CSF-leaks are detectable in samples containing blood with a high sensitivity, and the efficacy of CSF fistula repair was shown using β-TP (8,9). Contaminating blood or wound secretions that affect the analytical performance of β-2Tr testing are of little concern for β-TP testing because of this predilution step. We would like to emphasize that it is possible to process β-TP nephelometry in a sample volume of 5-μl only in experienced hands and the results can be ready within 15 to 20 minutes.

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