Continuing Education Activity

Xanthochromia is the presence of bilirubin in the cerebrospinal fluid and is sometimes the only sign of an acute subarachnoid hemorrhage. This activity reviews the evaluation and management of xanthochromia and highlights the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Explain the etiology of xanthochromia.
• Explain why the diagnosis of xanthochromia is sometimes delayed.
• Explain why the diagnosis of xanthochromia is sometimes delayed.
• Explain why careful planning and discussion amongst interprofessional team members involved in the management of patients with xanthochromia will improve outcomes.

Introduction

Xanthochromia was originally a broad term used to describe the pigmentation of cerebrospinal fluid (CSF) as pink or yellow.[1] This color change is attributed to varying concentrations of pigmented compounds such as oxyhemoglobin, bilirubin, and methemoglobin which are typically the byproducts of red blood cell degradation.[2] The term now is more widely accepted to represent the yellow color created by the presence of bilirubin in the CSF. The presence of bilirubin resulting in yellow discoloration of the CSF is the contemporary definition of xanthochromia.[3][4][5]

Etiology

Bilirubin is the byproduct of the degradation of oxyhemoglobin by the enzyme oxygenase. There are many causes of xanthochromia such as acute intracerebral hemorrhage, brain tumors, infection, increased protein, and severe systemic jaundice. The finding of xanthochromia in the CSF is most commonly used in the diagnosis of subarachnoid hemorrhage (SAH) in the presence of a normal head computed tomography. [6]

Epidemiology

The rupture of an intracerebral aneurysm most commonly causes subarachnoid hemorrhage. The incidence of SAH is anywhere from 9 to 15 people per 100,000 in the United States with rates that vary by geography. Risk factors include hypertension, cigarette smoking, alcohol use, some sympathomimetic drugs, and some genetic causes that increase the risk of a cerebral aneurysm. [7]

Pathophysiology

Once a cerebral aneurysm has ruptured or started to leak, blood may be found in the CSF in varying quantities. Over time this blood is degraded by macrophages and broken down into its byproducts containing bilirubin. The process of conversion from heme to bilirubin in the CSF takes 6 to 12 hours and can only happen in vivo. Therefore, xanthochromia is best identified 6 to 12 hours after the onset of a bleed. Even though CT scan in the investigative modality of choice for subarachnoid hemorrhage, nearly 5% of cases will have no CT evidence of hemorrhage during the first 24 hours. This percentage increases to 50% by the first week and is about 30% at 2 weeks. On the other hand, xanthochromic is seen in all patients for up to 14 days and can be present in 75% of patients for at least 21 days.

Histopathology

There are currently 2 different methods to identify xanthochromia in the CSF. In the United States, visual detection is still the method of choice. A CSF sample is spun down in a centrifuge, and the supernatant is visually inspected with the naked eye for yellow color. This is accomplished by holding a vial of water next to a vial of supernatant against a white backdrop.

The second and perhaps more reliable way to test for xanthochromia is the use of spectrophotometry.[8] A spectrophotometer measures the absorption of light of the material and identifies that material based on the wavelength of light it absorbs.  Bilirubin itself has a narrow window of detection with a wavelength of 440 to 460 nm. Multiple studies show the superiority of spectrophotometry when compared to visual inspection.[9] There are several factors that can interfere with the appearance of xanthochromia on visual inspection alone. For instance, the presence of proteins or pigments such as carotenoids can obscure the color change associated with the presence of xanthochromia. The presence of oxyhemoglobin with an acute bleed or traumatic lumbar puncture appears pink or orange and can hide the yellow discoloration of xanthochromia leading to a false-negative result. Furthermore, unlike spectrophotometry, a visual inspection cannot detect low concentrations of bilirubin and cannot distinguish bilirubin from oxyhemoglobin.[3]

History and Physical

Subarachnoid hemorrhage is a rare but significant disease that can lead to sudden death and disability if not diagnosed and treated properly.  Patients often present complaining of the worst headache of their life.[5]  A sudden onset at a maximal intensity or within the first hour of onset often characterizes headaches. There can be associated with meningismus, nausea, vomiting, photophobia, and/or phonophobia but rarely with acute neurologic deficits.[10] It can be difficult to distinguish between a non-traumatic headache associated with SAH or another less serious cause.

Evaluation

Non-contrast computed tomography of the head (NCHCT) is still the initial test of choice in the diagnosis of subarachnoid hemorrhage.[11] The sensitivity of this test is greatest within the first 6 hours of the onset of symptoms.[5] The current standard of care is to obtain an NCHCT followed by a lumbar puncture to evaluate for xanthochromia if the NCHCT is negative. The finding of xanthochromia in the CSF is helpful in that it is 93% sensitive and 95% specific with a positive predictive value of 72% and a negative predictive value of 99%.[12] Xanthochromia is typically present in the CSF within 6 to 12 hours after the onset of symptoms. Unlike CT, xanthochromia is present in the CSF in all patients up to 2 weeks post ictus and is still present in 70% of patients Up to three weeks later.[13] Furthermore, sensitivity for detecting a bleed by CT decreases from up to 95% on day 1 to less than 10% in 3 weeks, with the sensitivity of CSF analysis remaining constant near 100% over this time.[9] Because the production of bilirubin is a process that happens only in vivo, the presence of xanthochromia in the CSF is the only way to differentiate between a true hemorrhage and a traumatic tap as both can contain large amounts of red blood cells (RBCs).[14]

Treatment / Management

Once the patient is diagnosed with a SAH based on the findings of xanthochromia in the CSF, they may be sent for magnetic resonance imaging (MRI), CT angiography, or taken directly for treatment. The next step in management is to find the location of an aneurysm and thus the cause of the SAH.[15]

Differential Diagnosis

• Aneurysmal leaks

• Pseudomonal meningitis

• Severe hyperbilirubinemia

• Subarachnoid hemorrhage

• Sentinel hemorrhage

Complications

It is very difficult to determine the pretest probability of SAH based on presentation alone. There is no one factor that could determine the need for further testing for an acute non-traumatic headache. Lumbar puncture is an invasive procedure, and often results are misleading and non-diagnostic.[16][17] There is a very specific subset of patients in whom a lumbar puncture with the finding of xanthochromia will correctly diagnose a SAH. The majority of patients with negative head CT will not be diagnosed with SAH. However, the overuse of CT angiography (CTA) exposes patients to unnecessary radiation and contrast.[18] Furthermore, the use of CTA leads to the finding of incidental aneurysms which may or may not be clinically significant. This, in turn, may expose the patient to even more unnecessary testing and intervention. In this case, LP has a high diagnostic yield, eliminating the need for neurosurgical consultation or intervention in the majority of cases.[19] The test is both cost-effective and time-efficient and reduces the number of patients exposed to the radiation and contrast associated with angiography.[19]

Pearls and Other Issues

• Xanthochromia is the presence of bilirubin in the CSF.
• This finding can be the only positive marker that a patient is suffering from an acute SAH.
• It is an important finding in distinguishing between traumatic tap and a SAH.
• Visual inspection of the CSF is the most common method of detection.
• Spectrophotometry has been shown to be superior when evaluating for xanthochromia.[9][3][20][9]

Enhancing Healthcare Team Outcomes

The finding of xanthochromia on a spinal tap can be the only evidence to suggest the presence of a subarachnoid hemorrhage. Traditionally, xanthochromia is detected by visualizing the supernatant CSF under incandescent light for the presence of a yellow color. Multiple studies have shown the superiority of using spectrophotometry instead of visualization. Spectrophotometry can detect the presence of xanthochromia at smaller concentrations than the naked eye and is more specific as it relies on the detection of a certain wavelength of emitted light that corresponds to xanthochromia itself. [1],[4],[20] [Level III]

Standard practice in the diagnosis of subarachnoid hemorrhage with a negative head CT still includes the use of lumbar puncture to detect the presence of xanthochromia. This test is more cost effective and may reduce the need for CT angiography with contrast in many patients.[19],[21],[22] [Level IV]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Shah KH, Edlow JA. Distinguishing traumatic lumbar puncture from true subarachnoid hemorrhage. J Emerg Med. 2002 Jul;23(1):67-74. [PubMed: 12217474]

2.

Seehusen DA, Reeves MM, Fomin DA. Cerebrospinal fluid analysis. Am Fam Physician. 2003 Sep 15;68(6):1103-8. [PubMed: 14524396]

3.

Chu KH, Bishop RO, Brown AF. Spectrophotometry, not visual inspection for the detection of xanthochromia in suspected subarachnoid haemorrhage: A debate. Emerg Med Australas. 2015 Jun;27(3):267-72. [PubMed: 25919441]

4.

Gill HS, Marcolini EG, Barber D, Wira CR. The Utility of Lumbar Puncture After a Negative Head CT in the Emergency Department Evaluation of Subarachnoid Hemorrhage. Yale J Biol Med. 2018 Mar;91(1):3-11. [PMC free article: PMC5872638] [PubMed: 29599652]

5.

Long B, Koyfman A, Runyon MS. Subarachnoid Hemorrhage: Updates in Diagnosis and Management. Emerg Med Clin North Am. 2017 Nov;35(4):803-824. [PubMed: 28987430]

6.

Ichiba T, Hara M, Nishikawa K, Tanabe T, Urashima M, Naitou H. Comprehensive Evaluation of Diagnostic and Treatment Strategies for Idiopathic Spinal Subarachnoid Hemorrhage. J Stroke Cerebrovasc Dis. 2017 Dec;26(12):2840-2848. [PubMed: 28802522]

7.

Yu SD, Chen MY, Johnson AJ. Factors associated with traumatic fluoroscopy-guided lumbar punctures: a retrospective review. AJNR Am J Neuroradiol. 2009 Mar;30(3):512-5. [PMC free article: PMC7051446] [PubMed: 19147709]

8.

Petzold A, Keir G, Sharpe LT. Spectrophotometry for xanthochromia. N Engl J Med. 2004 Oct 14;351(16):1695-6. [PubMed: 15483297]

9.

Petzold A, Keir G, Sharpe TL. Why human color vision cannot reliably detect cerebrospinal fluid xanthochromia. Stroke. 2005 Jun;36(6):1295-7. [PubMed: 15879320]

10.

Moore SA, Rabinstein AA, Stewart MW, David Freeman W. Recognizing the signs and symptoms of aneurysmal subarachnoid hemorrhage. Expert Rev Neurother. 2014 Jul;14(7):757-68. [PubMed: 24949896]

11.

Abraham MK, Chang WW. Subarachnoid Hemorrhage. Emerg Med Clin North Am. 2016 Nov;34(4):901-916. [PubMed: 27741994]

12.

Dupont SA, Wijdicks EF, Manno EM, Rabinstein AA. Thunderclap headache and normal computed tomographic results: value of cerebrospinal fluid analysis. Mayo Clin Proc. 2008 Dec;83(12):1326-31. [PubMed: 19046551]

13.

Vermeulen M, Hasan D, Blijenberg BG, Hijdra A, van Gijn J. Xanthochromia after subarachnoid haemorrhage needs no revisitation. J Neurol Neurosurg Psychiatry. 1989 Jul;52(7):826-8. [PMC free article: PMC1031927] [PubMed: 2769274]

14.

Mark DG, Kene MV, Offerman SR, Vinson DR, Ballard DW., Kaiser Permanente CREST Network. Validation of cerebrospinal fluid findings in aneurysmal subarachnoid hemorrhage. Am J Emerg Med. 2015 Sep;33(9):1249-52. [PubMed: 26022754]

15.

de Oliveira Manoel AL, Goffi A, Marotta TR, Schweizer TA, Abrahamson S, Macdonald RL. The critical care management of poor-grade subarachnoid haemorrhage. Crit Care. 2016 Jan 23;20:21. [PMC free article: PMC4724088] [PubMed: 26801901]

16.

Doherty CM, Forbes RB. Diagnostic Lumbar Puncture. Ulster Med J. 2014 May;83(2):93-102. [PMC free article: PMC4113153] [PubMed: 25075138]

17.

Wisborg T. [Overuse of CT at the trauma centre?]. Tidsskr Nor Laegeforen. 2019 Mar 12;139(5) [PubMed: 30872827]

18.

Ohana O, Soffer S, Zimlichman E, Klang E. Overuse of CT and MRI in paediatric emergency departments. Br J Radiol. 2018 May;91(1085):20170434. [PMC free article: PMC6190788] [PubMed: 29271231]

19.

Martin SC, Teo MK, Young AM, Godber IM, Mandalia SS, St George EJ, McGregor C. Defending a traditional practice in the modern era: The use of lumbar puncture in the investigation of subarachnoid haemorrhage. Br J Neurosurg. 2015;29(6):799-803. [PubMed: 26373397]

20.

Chu K, Hann A, Greenslade J, Williams J, Brown A. Spectrophotometry or visual inspection to most reliably detect xanthochromia in subarachnoid hemorrhage: systematic review. Ann Emerg Med. 2014 Sep;64(3):256-264.e5. [PubMed: 24635988]

21.

Goyale A, O'Shea J, Marsden J, Keep J, Vincent RP. Analysis of cerebrospinal fluid for xanthochromia versus modern computed tomography scanners in the diagnosis of subarachnoid haemorrhage: experience at a tertiary trauma referral centre. Ann Clin Biochem. 2016 Jan;53(Pt 1):150-4. [PubMed: 25766384]

22.

Nagy K, Skagervik I, Tumani H, Petzold A, Wick M, Kühn HJ, Uhr M, Regeniter A, Brettschneider J, Otto M, Kraus J, Deisenhammer F, Lautner R, Blennow K, Shaw L, Zetterberg H, Mattsson N. Cerebrospinal fluid analyses for the diagnosis of subarachnoid haemorrhage and experience from a Swedish study. What method is preferable when diagnosing a subarachnoid haemorrhage? Clin Chem Lab Med. 2013 Nov;51(11):2073-86. [PubMed: 23729569]

Disclosure: Carla Dugas declares no relevant financial relationships with ineligible companies.

Disclosure: Zohaib Jamal declares no relevant financial relationships with ineligible companies.

Disclosure: Pradeep Bollu declares no relevant financial relationships with ineligible companies.