Correspondence

Spectrophotometry for Xanthochromia

N Engl J Med 2004; 351:1695-1696October 14, 2004

Article

To the Editor:

Xanthochromia, or a yellow appearance of the cerebrospinal fluid, is often used to confirm suspected subarachnoid hemorrhage.1,2 It is associated with the presence of bilirubin, a blood product that arises only in vivo by the enzymatic transformation of hemoglobin. However, visual assessment of the cerebrospinal fluid for xanthochromia is highly subjective and unreliable, especially in cases in which other blood products, such as oxyhemoglobin, are present.1,2 The differential diagnosis may be further complicated by a high protein level and a high cell count, as in meningitis and necrosis, or by the presence of other pigments (namely, carotenoids). To distinguish pigments in the cerebrospinal fluid, such as bilirubin, that are clinically important for diagnosing subarachnoid hemorrhage and other types of intracerebral bleeding from those that are not important, objective spectrophotometry, rather than visual assessment, is recommended. Because bilirubin has a characteristic signature — absorbance in the blue range (450 to 460 nm) — it can be readily identified by spectrophotometry. Moreover, by standard colorimetric procedures, which have been established by the Commission Internationale de l'Eclairage (CIE, or the International Commission on Illumination), the spectrophotometric trace can be converted to its chromaticity coordinates.3 These procedures allow the trace to be plotted in a geometric diagram (the CIE 1931 chromaticity diagram for the 2-degree field of view) and allow its dominant wavelength (corresponding to hue) to be defined with respect to average daylight conditions (CIE standard illuminant D65) (Figure 1Figure 1Chromaticity Diagram.).

Spectrophotometric analysis of 632 samples of cerebrospinal fluid, obtained at the National Hospital for Neurology and Neurosurgery in London between January 1996 and April 2004, indicated that 72 contained bilirubin. Of these, only 15 (21 percent) contained bilirubin alone and appeared pure yellow (14 percent) or greenish yellow (7 percent) (Figure 1). A significantly higher number, 57 (79 percent; chi-square=49.0, P<0.001), contained oxyhemoglobin as well as bilirubin. Their appearance ranged from red and reddish pink to orange. These findings reveal that about 80 percent of cerebrospinal fluid samples containing substantial amounts of bilirubin are not typically perceived as xanthochromic (i.e., yellow). Equally important, the presence of bilirubin cannot reliably be ruled out in the case of cerebrospinal fluid samples that are visibly red.

In the United Kingdom, the rate of visual assessment of the cerebrospinal fluid fell from 24 percent to 6 percent, whereas the use of spectrophotometry rose from 76 percent to 94 percent, after the introduction of new guidelines for the detection of cerebrospinal fluid pigments. This shift has reduced the estimated error rate from 40 percent to 9 percent.5 Clearly, xanthochromia on the basis of mere visual assessment is an ambiguous concept clinically, physiologically, and biochemically. Two recent surveys, however, have shown that visual assessment of cerebrospinal fluid samples for xanthochromia is still the most common method used in the United States.2,6 We believe that this practice should immediately be reevaluated.

Axel Petzold, M.D., Ph.D.
National Hospital for Neurology and Neurosurgery, London WC1N 3BG, United Kingdom
a.petzold@ion.ucl.ac.uk

Geoffrey Keir, Ph.D.
Institute of Neurology, London WC1N 3BG, United Kingdom

Lindsay T. Sharpe, Ph.D.
Institute of Ophthalmology, London EC1V 9EL, United Kingdom

6 References

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Citing Articles (10)

Citing Articles

1. 1

   Jens Kuhle, Axel Petzold. (2011) What makes a prognostic biomarker in CNS diseases: strategies for targeted biomarker discovery? Part 1: acute and monophasic diseases. Expert Opinion on Medical Diagnostics 5:4, 333-346
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2. 2

   H. Tumani, A. Petzold, M. Wick, H.-J. Kühn, M. Uhr, M. Otto, A. Regeniter, J. Brettschneider. (2010) Liquordiagnostik bei CT-negativer Subarachnoidalblutung. Der Nervenarzt 81:8, 973-979
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3. 3

   R. Hewett, C. Counsell. (2010) Documentation of cerebrospinal fluid opening pressure and other important aspects of lumbar puncture in acute headache. International Journal of Clinical Practice 64:7, 930-935
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4. 4

   A. Petzold, V. Worthington, C. Pritchard, I. Appleby, N. Kitchen, M. Smith. (2009) The Longitudinal Profile of Bilirubin and Ferritin in the Cerebrospinal Fluid Following a Subarachnoid Hemorrhage: Diagnostic Implications. Neurocritical Care 11:3, 398-402
   CrossRef

5. 5

   Axel Regeniter, Jens Kuhle, Matthias Mehling, Helgard Möller, Ulrich Wurster, Heike Freidank, Werner H. Siede. (2009) A modern approach to CSF analysis: Pathophysiology, clinical application, proof of concept and laboratory reporting. Clinical Neurology and Neurosurgery 111:4, 313-318
   CrossRef

6. 6

   S. A. Dupont, E. F. M. Wijdicks, E. M. Manno, A. A. Rabinstein. (2008) Thunderclap Headache and Normal Computed Tomographic Results: Value of Cerebrospinal Fluid Analysis. Mayo Clinic Proceedings 83:12, 1326-1331
   CrossRef

7. 7

   Axel Petzold. (2007) CSF biomarkers for improved prognostic accuracy in acute CNS disease. Neurological Research 29:7, 691-708
   CrossRef

8. 8

   Ian Holbrook, Robert Beetham, Anne Cruickshank, Geoff Keir, Ian Watson. (2007) Subarachnoid haemorrhage. The Lancet 369:9565, 904
   CrossRef

9. 9

   Joke J. Apperloo, Fedde van der Graaf, Paul L.I. Dellemijn, Huib L. Vader. (2006) An improved laboratory protocol to assess subarachnoid haemorrhage in patients with negative cranial CT scan. Clinical Chemistry and Laboratory Medicine 44:8, 938-948
   CrossRef

10. 10

    Errol R. Norwitz, Lawrence C. Tsen, Joong Shin Park, Patricia A. Fitzpatrick, David M. Dorfman, George R. Saade, Catalin S. Buhimschi, Irina A. Buhimschi. (2005) Discriminatory proteomic biomarker analysis identifies free hemoglobin in the cerebrospinal fluid of women with severe preeclampsia. American Journal of Obstetrics and Gynecology 193:3, 957-964
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