Prospective study of the correlation between admission plasma homocysteine levels and neurological outcome following subarachnoid hemorrhage: A case for the reverse epidemiology paradox?
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.
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.
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).
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.
KeywordsSAH Homocysteine Outcome Prognosis Reverse epidemiology
Conflicts of interest
- 5.Connolly ES Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, Hoh BL, Kirkness CJ, Naidech AM, Ogilvy CS, Patel AB, Thompson BG, Vespa P, American Heart Association Stroke Council; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology (2012) Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 43:1711–1737CrossRefPubMedGoogle Scholar
- 6.Dhandapani S, Pal SS, Gupta SK, Mohindra S, Chhabra R, Malhotra SK (2013) Does the impact of elective temporary clipping on intraoperative rupture really influence neurological outcome after surgery for ruptured anterior circulation aneurysms?–A prospective multivariate study. Acta Neurochir (Wien) 155:237–46CrossRefGoogle Scholar
- 10.Grobelny BT, Ducruet AF, DeRosa PA, Kotchetkov IS, Zacharia BE, Hickman ZL, Fernandez L, Narula R, Claassen J, Lee K, Badjatia N, Mayer SA, Connolly ES Jr (2011) Gain-of-function polymorphisms of cystathionine β-synthase and delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage. J Neurosurg 115:101–107CrossRefPubMedGoogle Scholar
- 12.Holmes MV, Newcombe P, Hubacek JA, Sofat R, Ricketts SL, Cooper J, Breteler MM, Bautista LE, Sharma P, Whittaker JC, Smeeth L, Fowkes FG, Algra A, Shmeleva V, Szolnoki Z, Roest M, Linnebank M, Zacho J, Nalls MA, Singleton AB, Ferrucci L, Hardy J, Worrall BB, Rich SS, Matarin M, Norman PE, Flicker L, Almeida OP, van Bockxmeer FM, Shimokata H, Khaw KT, Wareham NJ, Bobak M, Sterne JA, Smith GD, Talmud PJ, van Duijn C, Humphries SE, Price JF, Ebrahim S, Lawlor DA, Hankey GJ, Meschia JF, Sandhu MS, Hingorani AD, Casas JP (2011) Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet 378:584–594CrossRefPubMedCentralPubMedGoogle Scholar
- 22.Lord RS, Fitzgerald K (2005) Significance of Low Plasma Homocysteine: Hypohomocysteinemia. Metametrix white paper; Norcross, GA, USAGoogle Scholar
- 27.Okamoto H, Takeuchi H, Tanabe M, Akatsuka K, Nishiyama M, Watanabe T, Hori T (1998) Ameliorated outcome of subarachnoid hemorrhage patients treated with reduced form glutathione. Yonago Acta Medica 41:73–81Google Scholar
- 28.Østergaard L, Aamand R, Karabegovic S, Tietze A, Blicher JU, Mikkelsen IK, Iversen NK, Secher N, Engedal TS, Anzabi M, Jimenez EG, Cai C, Koch KU, Naess-Schmidt ET, Obel A, Juul N, Rasmussen M, Sørensen JC (2013) The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage. J Cereb Blood Flow Metab 33:1825–1837CrossRefPubMedCentralPubMedGoogle Scholar
- 32.Watanabe T, Sasaki T, Asano T, Takakura K, Sano K, Fuchinoue T, Watanabe K, Yoshimura S, Abe K (1988) Changes in glutathione peroxidase and lipid peroxides in cerebrospinal fluid and serum after subarachnoid hemorrhage–with special reference to the occurrence of cerebral vasospasm. Neurol Med Chir (Tokyo) 28:645–649CrossRefGoogle Scholar