Serum GFAP and UCHL1: Evaluation of Their Predictive Value for SAH

Subarachnoid haemorrhage (SAH) refers to blood entering the subarachnoid space and may be due to aneurysmal or non-aneurysmal causes. Patients with SAH characteristically present with a sudden onset 'thunderclap' headache (Patel et al., 2021). This is an acute medical emergency and is the third most common type of stroke, with approximately 500,000 cases annually across the world (Claassen and Park, 2022). Morbidity has decreased over the past few decades, however, there is still an approximate 35% occurrence of death within three months of a SAH (Andersen et al., 2019). Early diagnosis is important to enable timely treatment and thereby improve prognosis. Current NICE guideline NG228 state the diagnosis of SAH is to be made from a non-contrast CT scan showing the presence of blood in the subarachnoid space. A negative CT done within 6 hours of symptom onset is considered not indicative of a SAH. If however, the CT is 'negative' and is performed more than 6 hours after onset of symptoms then a LP is advised to look for the presence of xanthochromia in the CSF (NICE, 2022).

Xanthochromia refers to the yellowing of the cerebrospinal fluid (CSF) due to accumulation of bilirubin from the breakdown of red blood cells in the subarachnoid space. Its presence, in the appropriate clinical context, confirms a diagnosis of SAH. In our population, approximately 10% of CSF xanthochromia tests confirm SAH, meaning 90% of LPs may not have been necessary. This test is reliable only if performed at least 12 hours after the onset of symptoms. The xanthochromia test is considered a manual test and requires trained and competent staff. There are multiple pre-analytical requirements in order to produce a reliable result. For example, the sample must be protected from light during transport and not transported by the air tube. Exposure to light can cause the bilirubin to breakdown which can then lead to a false negative result (Cruickshank et al., 2008). Samples transported in the pneumatic tube system may give false results due to the lysis of red cells.

Traumatic tap, in which the needle causes blood to enter the subarachnoid space, and which will then be present in the CSF sample can also cause interference as discolouration of the sample may mask xanthochromia. The least bloodstained CSF sample must therefore be used for analysis. Finally, an LP is an invasive procedure and is therefore an unpleasant experience for the patient (Long et al., 2017).

In summary, a test for SAH that is subject to fewer pre-analytical and analytical interferences would be superior to the current CSF xanthochromia test. Whilst it is not expected that a serum test could replace the need for CSF xanthochromia completely, a test that could identify which patients are likely to have negative LP could reduce the number of unnecessary LPs.

There are two candidate biomarkers - Ubiquitin C-terminal hydroxylase-L1 (UCH-L1) and Glial Fibrillary Acidic Protein (GFAP) - which have been found to increase in blood following brain damage and in traumatic brain injuries, including SAH. However, current guidelines (NICE, 2022) for SAH state that brain biomarkers are not currently recommended by guidelines as part of the SAH diagnosis pathway.