Prospective Study of the Correlation Between Admission Plasma Homocysteine Levels and Neurological Outcome Following Subarachnoid Hemorrhage: a Case for the Reverse Epidemiology Paradox?

Background: Homocysteine (tHcy) has been known over the last few decades for its putative impact on vascular diseases, but has not been evaluated much in patients with subarachnoid hemorrhage (SAH). This study was carried out to assess its prognostic impact on the neurological outcome following SAH.

Methods: Admission plasma tHcy was evaluated in 90 SAH patients and prospectively studied in relation to various factors and the Glasgow Outcome Scale (GOS) at 3 months. Univariate and multivariate analyses were performed using SPSS 21.

Results: tHcy was significantly higher following SAH compared to matched controls [median (IQR): 25.7 (17.3-35.9) vs. 14.0 (9.8-17.6) μmol/l, p < 0.001]. It was significantly higher in younger patients. However, systemic disease, WFNS and Fisher grades did not have a significant impact on its levels. tHcy was significantly lower among patients who died [median (IQR): 16.0 (14.4-20.6) vs. 29.7 (21.8-40.2) μmol/l, p < 0.001] and those with unfavorable outcome (GOS 1-3) [median (IQR): 21.6 (14.5-28.2) vs. 30.3 (20.4-40.7) μmol/l, p = 0.004] compared to others, with a significant continuous positive correlation between tHcy and GOS (p = 0.002). The beneficial association of tHcy with outcome was homogeneous with no significant subgroup difference. Multivariate analysis using binary logistic regression adjusting for the effects of age, systemic disease, WFNS grade, Fisher grade, site of aneurysm, clipping or coiling revealed higher tHcy to have a significant independent association with both survival (p = 0.01) and favorable outcome (p = 0.04).

Conclusions: Higher homocysteine levels following SAH appear to have a significant association with both survival and favorable neurological outcome, independent of other known prognostic factors, apparently exemplifying "reverse epidemiology paradox" in which a conventional risk factor seems to impart a survival advantage.