Continuing Education Activity

Xanthochromia is the observation of a yellowish discoloration in cerebrospinal fluid (CSF) attributed to the presence of bilirubin. This yellow hue, linked with various pigmented compounds from red blood cell breakdown, signifies conditions ranging from jaundice and high CSF protein to aneurysmal and nonaneurysmal subarachnoid hemorrhage. Considering that many of the etiologies are life-threatening, an expedited evaluation and diagnosis are paramount when this condition is present.

Expanding on the historical origins and contemporary definition of xanthochromia, this activity details diagnostic methods, spanning traditional visual assessment to more sensitive spectrophotometry. It further elucidates the comprehensive evaluation and management of xanthochromia, stressing the pivotal role of the interprofessional healthcare team in addressing this condition. Clinicians will gain insight into expedited diagnostic protocols, optimal management strategies, and collaborative approaches for enhanced patient care and outcomes.

Objectives:

• Identify the key etiologies associated with xanthochromia, including subarachnoid hemorrhage, jaundice-related conditions, and other catastrophic neurological causes, through clinical presentations and diagnostic tests.

• Implement standardized diagnostic procedures for confirming xanthochromia, including cerebrospinal fluid analysis techniques and imaging modalities, to ensure accurate identification and differentiation of causes.

• Identify potential complications associated with xanthochromia, such as neurological deficits, vasospasm, or rebleeding, through comprehensive clinical assessments and imaging studies.

• Implement a cohesive care plan integrating expertise from diverse specialties, emphasizing timely diagnostic evaluations and multidisciplinary treatment strategies to improve outcomes for patients with xanthochromia.

Introduction

Xanthochromia is derived from the Greek word "xanthos," meaning yellow. The term was first used to describe the pink or yellow pigmentation of cerebrospinal fluid (CSF).[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 is now 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] It can be diagnosed by 2 methods: the traditional visualization or eye test and the more sensitive and specific spectrophotometry. 

Etiology

The yellowish hue seen with xanthochromia is caused by the presence of bilirubin, which is the byproduct of the degradation of oxyhemoglobin by the enzyme oxygenase. In the CSF, this occurs by the macrophages that line the arachnoid space. There are many causes of xanthochromia, including acute intracerebral hemorrhage, brain tumors, infection, conditions that cause an increase of CSF protein (≥150 mg/dL), and severe systemic jaundice (serum bilirubin levels >10 g/dL). The finding of xanthochromia in the CSF is most commonly used in diagnosing subarachnoid hemorrhage (SAH) in the presence of a normal head computed tomography (CT).[6][7]

Epidemiology

The true prevalence and incidence of xanthochromia are not known, as various pathologies can cause it; however, it is more commonly discussed surrounding the diagnosis of a ruptured intracerebral aneurysm, which most commonly causes SAH. The incidence of SAH is anywhere from 9 to 15 people per 100,000 in the United States (US), with rates that vary by geography. Risk factors for SAH include hypertension, cigarette smoking, alcohol use, some sympathomimetic drugs, and some genetic causes that increase the risk of a cerebral aneurysm.[8] 

It is known that xanthochromia can be seen very soon after an SAH (up to 2 hours); within 12 hours of a ruptured SAH, more than 90% of patients will show xanthochromia in their CSF that can persist for up to 4 weeks.[9] With newer imaging options and better-quality CT scanners available, the diagnosis of SAH is most commonly made with either a noncontrasted CT of the brain or a CT-angiogram (CTA) of the brain. However, SAH can be missed on imaging, and analysis of CSF for xanthochromia can help with the diagnosis of SAH (which occurs in <1% of cases), as it has a 100% sensitivity and 99% specificity when using the United Kingdom National External Quality Assessment Service (UK-NEQAS) method of spectrophotometry is used.[6][10]

Pathophysiology

No matter the etiology, xanthochromia represents the presence of degraded red blood cells. This process takes place over time as blood is degraded by macrophages and broken down into its byproducts containing bilirubin. Conversion from heme to bilirubin in the CSF takes roughly 6 to 12 hours. Therefore, xanthochromia is best identified 6 to 12 hours after the onset of a bleed, and its presence suggests that blood has been present in the spinal fluid for at least 2 hours, with 100% of patients having xanthochromia present by visual inspection by 12 hours.[11] 

Xanthochromia is seen in over 90% of patients very soon after an SAH and can be present for up to 3 to 4 weeks, with some studies showing that more than 75% of patients can have xanthochromia present at 21 days following SAH. Even though a noncontrasted CT scan of the brain is the initial imaging modality of choice for a suspected SAH, nearly 5% of cases will have no CT evidence of hemorrhage within the first 24 hours.[12] This percentage increases to 50% by the first week and is about 30% at 2 weeks. 

Histopathology

There are currently 2 different methods to identify xanthochromia in the CSF.

Visual Detection

In the US, visual detection is still one of the most commonly used methods to evaluate patients for xanthochromia. During this process, a CSF sample is spun in a centrifuge, and the supernatant is visually inspected with the naked eye for a yellow or pink tint. This is accomplished by holding a vial of water next to a vial of supernatant against a white backdrop. A yellow or pink tint suggests that blood has been in the spinal fluid for at least 2 hours, with 100% of patients having xanthochromia present by visual inspection by 12 hours.[11] 

False positives can result from several causes, including patients taking rifampin, those eating excess carotenoids (carrots and spinach), the presence of clinical jaundice, and elevated protein levels in the CSF (>150 mg/dL). Some common causes of elevated CSF protein include carcinomatosis, intracranial neoplasms, Froin's syndrome, tuberculosis,  cryptococcal meningitis, and radicular demyelination. 

Spectrophotometry

The second and perhaps more reliable way to test for xanthochromia is by using spectrophotometry.[13] A spectrophotometer measures the absorption of light in a 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 with visual inspection.[14] 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

Patients who have xanthochromia can have a variety of conditions, with the most severe being an SAH. Although rare, SAH carries significant morbidity and mortality risk, as it 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. They can be associated with meningismus, nausea, vomiting, photophobia, or phonophobia but rarely with acute neurologic deficits.[15] It can be difficult to distinguish between a nontraumatic headache associated with SAH or another lessseveres cause.

Evaluation

Noncontrast CT of the head (NCHCT) is still the initial test of choice in the diagnosis of SAH.[16] 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%.[17] 

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 3 weeks later.[11] 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.[14] 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.[18]

Treatment / Management

Once the patient is diagnosed with an SAH based on the findings of xanthochromia in the CSF, they may be sent for magnetic resonance imaging (MRI) or CTA 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.[19]

Differential Diagnosis

The differential diagnoses for xanthochromia include:

• Aneurysmal leaks
• Severe hyperbilirubinemia
• SAH
• Sentinel hemorrhage
• Excess carotenoid intake (carrots and spinach)
• Conditions that cause elevated protein levels in the CSF (eg, carcinomatosis, intracranial neoplasms, Froin's syndrome, tuberculosis, cryptococcal meningitis, and radicular demyelination)

Complications

It is challenging to determine the pretest probability of SAH based on a single presentation alone, as no one factor could determine the need for further testing for an acute nontraumatic headache. Lumbar puncture is an invasive procedure, and often the results are misleading and nondiagnostic.[20][21] However, there is a particular subset of patients in whom a lumbar puncture can identify xanthochromia and help correctly diagnose those with SAH.

Most patients with negative head CT will not be diagnosed with SAH. However, the overuse of CTA can expose patients to unnecessary radiation.[22] 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 these cases, A lumbar puncture has a high diagnostic yield, potentially eliminating the need for neurosurgical consultation or intervention in most cases with a low risk of infection, bleeding, and postdural headache.[23] The test is cost-effective, time-efficient, and can potentially reduce the number of patients exposed to the radiation and contrast associated with angiography.[23] 

Pearls and Other Issues

• Xanthochromia describes the presence of yellowish supernatant in the CSF that is caused by the presence of bilirubin.
• The presence of xanthochromia on visual inspection can also be seen in other conditions; increased vitamin A intake, certain medications like rifampin, and other infectious conditions can lead to false positives.
• Visual inspection of the CSF is the most common method of detection in the US
• Spectrophotometry is proven to be a superior method of detection to that of visual inspection.[3][14][24]
• It is essential to know the screening pitfalls of those with possible SAH, as there are false positive and false negative scenarios.

Enhancing Healthcare Team Outcomes

Observing xanthochromia in CSF is an important diagnostic finding, given the potential morbidity of an underlying illness such as SAH. Because of the limitations of CT imaging for detecting SAH, the presence of xanthochromia might be the only evidence pointing to its diagnosis.

Twenty-four hours after symptom onset, CT scans give an increasing false negative rate for SAH. Therefore, there must be good communication between the ordering physician and the radiologist regarding the clinical history and appropriate imaging modality.

Standard practice in diagnosing SAH with a negative head CT still includes using a lumbar puncture to detect the presence of xanthochromia. This test is more cost-effective and may reduce the need for CTA with contrast in many patients.[23][25][26] 

Additionally, collaboration with the hospital's lab technicians is important, as understanding which method they use for evaluating xanthochromia can help with differential diagnoses. Traditionally, xanthochromia is detected in the lab by visualizing the supernatant CSF under incandescent light for the presence of a yellow tint. Multiple studies have shown the superiority of using spectrophotometry instead of visualization; despite this finding, visual inspection remains the most commonly used modality in the US. Spectrophotometry can detect the presence of xanthochromia at smaller concentrations than the naked eye. It is more specific, as it relies on detecting a certain wavelength of emitted light corresponding to xanthochromia.[24]