Advertisement

Neutrophil-to-Lymphocyte Ratio in Acute Cerebral Hemorrhage: a System Review

  • Simona LattanziEmail author
  • Francesco Brigo
  • Eugen Trinka
  • Claudia Cagnetti
  • Mario Di Napoli
  • Mauro Silvestrini
Review Article
First Online:

Abstract

Spontaneous intracerebral hemorrhage (ICH) accounts for approximately 10 to 30% of all acute cerebrovascular events, and it is the type of stroke associated with the highest rates of mortality and residual disability. The inflammatory response is early triggered by hematoma components and can enhance the damage within the hemorrhagic brain. Assessment of peripheral biomarkers of inflammation could contribute to increase knowledge about some of the mechanisms involved in the ICH-induced injury and yield information on the disease course. The neutrophil-to-lymphocyte ratio (NLR) integrates information on both the innate and adaptive compartments of the immunity and represents a reliable measure of the inflammatory burden. The aim of the current review is to highlight the available evidence about the relationships between the NLR and clinical outcome in patients with acute ICH and provide critical insights into the underlying pathophysiology. Since no therapy targeting ICH-induced primary injury has yielded conclusive benefits and ICH treatment remains mainly supportive within a framework of general critical care management, these findings could also contribute to identify new potential targets for neuroprotection and develop novel therapeutic strategies.

Keywords

Cerebral hemorrhage Stroke Cerebrovascular disease Inflammation Neutrophil-to-lymphocyte ratio 
This is a preview of subscription content, log in to check access.

Notes

Compliance with Ethical Standards

Conflict of Interest

SL, CC, MDN, and MS declare no conflict of interest. FB has received speakers’ honoraria from Eisai and PeerVoice; payment for consultancy from Eisai; and travel support from Eisai, ITALFARMACO, and UCB Pharma. ET received speaker’s honoraria from UCB, Biogen, Gerot-Lannach, Bial, Eisai, Takeda, Newbridge, Sunovion Pharmaceuticals Inc., and Novartis; consultancy funds from UCB, Biogen, Gerot-Lannach, Bial, Eisai, Takeda, Newbridge, Sunovion Pharmaceuticals Inc., and Novartis; directorship funds from Neuroconsult GmbH; and commercial funds from Biogen, Novartis, and Bayer. E. Trinka’s Institution received grants from Biogen, Red Bull, Merck, UCB, European Union, FWF Österreichischer Fond zur Wissenschaftsförderung, and Bundesministerium für Wissenschaft und Forschung.

Ethical Approval

This article does not contain any study with human participants performed by any of the authors.

References

  1. 1.
    Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol. 2003;2:43–53.CrossRefPubMedGoogle Scholar
  2. 2.
    Lattanzi S, Cagnetti C, Provinciali L, Silvestrini M. How should we lower blood pressure after cerebral hemorrhage? A systematic review and meta-analysis. Cerebrovasc Dis. 2017;43:207–13.CrossRefPubMedGoogle Scholar
  3. 3.
    Mracsko E, Veltkamp R. Neuroinflammation after intracerebral hemorrhage. Front Cell Neurosci. 2014;8:388.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Zhou Y, Wang Y, Wang J, Anne Stetler R, Yang QW. Inflammation in intracerebral hemorrhage: from mechanisms to clinical translation. Prog Neurobiol. 2014;115:25–44.CrossRefPubMedGoogle Scholar
  5. 5.
    Zahorec R. Ratio of neutrophil to lymphocyte counts—rapid and simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy. 2001;102:5–14.PubMedGoogle Scholar
  6. 6.
    Tamhane UU, Aneja S, Montgomery D, Rogers EK, Egle KA, Gurm HS. Association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute coronary syndrome. Am J Cardiol. 2008;102:653–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Celikbilek A, Ismailogullari S, Zararsiz G. Neutrophil to lymphocyte ratio predicts poor prognosis in ischemic cerebrovascular disease. J Clin Lab Anal. 2014;28:27–31.CrossRefPubMedGoogle Scholar
  8. 8.
    Templeton AJ, McNamara MG, Šeruga B, Vera-Badillo FE, Aneja P, Ocaña A, et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst. 2014;106:dju124.CrossRefPubMedGoogle Scholar
  9. 9.
    de Jager CP, van Wijk PT, Mathoera RB, de Jongh-Leuvenink, van der Poll T, Wever PC. Lymphocytopenia and neutrophil–lymphocyte count ratio predict bacteremia better than conventional infection markers in an emergency care unit. Crit Care. 2010;14:R192.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lattanzi S, Cagnetti C, Provinciali L, Silvestrini M. Neutrophil-to-lymphocyte ratio and neurological deterioration following acute cerebral hemorrhage. Oncotarget. 2017;8:57489–94.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wang F, Hu S, Ding Y, Ju X, Wang L, Lu Q, et al. Neutrophil-to-lymphocyte ratio and 30-day mortality in patients with acute intracerebral hemorrhage. J Stroke Cerebrovasc Dis. 2016;25:182–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Wang F, Wang L, Jiang TT, Xia JJ, Xu F, Shen LJ, et al. Neutrophil-to-lymphocyte ratio is an independent predictor of 30-day mortality of intracerebral hemorrhage patients: a validation cohort study. Neurotox Res. 2018;  https://doi.org/10.1007/s12640-018-9890-6.
  13. 13.
    Wang F, Xu F, Quan Y, Wang L, Xia JJ, Jiang TT, et al. Early increase of neutrophil-to-lymphocyte ratio predicts 30-day mortality in patients with spontaneous intracerebral hemorrhage. CNS Neurosci Ther. 2018;  https://doi.org/10.1111/cns.12977.
  14. 14.
    Gökhan S, Ozhasenekler A, Mansur Durgun H, Akil E, Ustündag M, Orak M. Neutrophil lymphocyte ratios in stroke subtypes and transient ischemic attack. Eur Rev Med Pharmacol Sci. 2013;17:653–7.PubMedGoogle Scholar
  15. 15.
    Lattanzi S, Cagnetti C, Rinaldi C, Angelocola S, Provinciali L, Silvestrini M. Neutrophil-to-lymphocyte ratio and outcome prediction in acute intracerebral hemorrhage. J Neurol Sci. 2018;387:98–102.CrossRefPubMedGoogle Scholar
  16. 16.
    Giede-Jeppe A, Bobinger T, Gerner ST, Sembill JA, Sprügel MI, Beuscher VD, et al. Neutrophil-to-lymphocyte ratio is an independent predictor for in-hospital mortality in spontaneous intracerebral hemorrhage. Cerebrovasc Dis. 2017;44:26–34.CrossRefPubMedGoogle Scholar
  17. 17.
    Tao C, Hu X, Wang J, Ma J, Li H, You C. Admission neutrophil count and neutrophil to lymphocyte ratio predict 90-day outcome in intracerebral hemorrhage. Biomark Med. 2017;11:33–42.CrossRefPubMedGoogle Scholar
  18. 18.
    Lattanzi S, Cagnetti C, Provinciali L, Silvestrini M. Neutrophil-to-lymphocyte ratio predicts the outcome of acute intracerebral hemorrhage. Stroke. 2016;47:1654–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Sun Y, You S, Zhong C, Huang Z, Hu L, Zhang X, et al. Neutrophil to lymphocyte ratio and the hematoma volume and stroke severity in acute intracerebral hemorrhage patients. Am J Emerg Med. 2017;35:429–33.CrossRefPubMedGoogle Scholar
  20. 20.
    Zhang F, Li H, Tao C, Zheng J, Hu X, Lin S, et al. Neutrophil and platelet to lymphocyte ratios in associating with blood glucose admission predict the functional outcomes of patients with primary brainstem hemorrhage. World Neurosurg. 2018;  https://doi.org/10.1016/j.wneu.2018.04.089.
  21. 21.
    Wang J, Doré S. Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2007;27:894–908.CrossRefPubMedGoogle Scholar
  22. 22.
    Mackenzie JM, Clayton JA. Early cellular events in the penumbra of human spontaneous intracerebral hemorrhage. J Stroke Cerebrovasc Dis. 1999;8:1–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Chen S, Yang Q, Chen G, Zhang JH. An update on inflammation in the acute phase of intracerebral hemorrhage. Transl Stroke Res. 2015;6:4–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke. 2011;42:1781–6.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wang J. Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol. 2010;92:463–77.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Silva Y, Leira R, Tejada J, Lainez JM, Castillo J, Dávalos A. Molecular signatures of vascular injury are associated with early growth of intracerebral hemorrhage. Stroke. 2005;36:86–91.CrossRefPubMedGoogle Scholar
  27. 27.
    Zheng H, Chen C, Zhang J, Hu Z. Mechanism and therapy of brain edema after intracerebral hemorrhage. Cerebrovasc Dis. 2016;42:155–69.CrossRefPubMedGoogle Scholar
  28. 28.
    Volbers B, Giede-Jeppe A, Gerner ST, Sembill JA, Kuramatsu JB, Lang S, et al. Peak perihemorrhagic edema correlates with functional outcome in intracerebral hemorrhage. Neurology. 2018;90:e1005–12.CrossRefPubMedGoogle Scholar
  29. 29.
    Leira R, Dávalos A, Silva Y, Gil-Peralta A, Tejada J, Garcia M, et al. Early neurologic deterioration in intracerebral hemorrhage: predictors and associated factors. Neurology. 2004;63:461–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Kayhanian S, Weerasuriya CK, Rai U, Young AMH. Prognostic value of peripheral leukocyte counts and plasma glucose in intracerebral haemorrhage. J Clin Neurosci. 2017;41:50–3.CrossRefPubMedGoogle Scholar
  31. 31.
    Moxon-Emre I, Schlichter LC. Neutrophil depletion reduces blood-brain barrier breakdown, axon injury, and inflammation after intracerebral hemorrhage. J Neuropathol Exp Neurol. 2011;70:218–35.CrossRefPubMedGoogle Scholar
  32. 32.
    Sansing LH, Harris TH, Kasner SE, Hunter CA, Kariko K. Neutrophil depletion diminishes monocyte infiltration and improves functional outcome after experimental intracerebral hemorrhage. Acta Neurochir Suppl. 2011;111:173–8.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Power C, Henry S, Del Bigio MR, Larsen PH, Corbett D, Imai Y, et al. Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases. Ann Neurol. 2003;53:731–42.CrossRefPubMedGoogle Scholar
  34. 34.
    Rosenberg GA, Navratil M. Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurology. 1997;48:921–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Wang J, Tsirka SE. Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain. 2005;128:1622–33.CrossRefPubMedGoogle Scholar
  36. 36.
    Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci. 2005;6:775–86.CrossRefPubMedGoogle Scholar
  37. 37.
    Dirnagl U, Klehmet J, Braun JS, Harms H, Meisel C, Ziemssen T, et al. Stroke-induced immunodepression: experimental evidence and clinical relevance. Stroke. 2007;38:770–3.CrossRefPubMedGoogle Scholar
  38. 38.
    Liesz A, Rüger H, Purrucker J, Zorn M, Dalpke A, Möhlenbruch M, et al. Stress mediators and immune dysfunction in patients with acute cerebrovascular diseases. PLoS One. 2013;8:e74839.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Westendorp WF, Nederkoorn PJ, Vermeij JD, Dijkgraaf MG, van de Beek D. Post-stroke infection: a systematic review and meta-analysis. BMC Neurol. 2011;11:110.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Chamorro A, Urra X, Planas AM. Infection after acute ischemic stroke: a manifestation of brain-induced immunodepression. Stroke. 2007;38:1097–103.CrossRefPubMedGoogle Scholar
  41. 41.
    Vogelgesang A, Grunwald U, Langner S, Jack R, Bröker BM, Kessler C, et al. Analysis of lymphocyte subsets in patients with stroke and their influence on infection after stroke. Stroke. 2008;39:237–41.CrossRefPubMedGoogle Scholar
  42. 42.
    Giede-Jeppe A, Bobinger T, Gerner ST, Madžar D, Sembill J, Lücking H, et al. Lymphocytopenia is an independent predictor of unfavorable functional outcome in spontaneous intracerebral hemorrhage. Stroke. 2016;47:1239–46.CrossRefPubMedGoogle Scholar
  43. 43.
    Bruce SS, Appelboom G, Piazza M, Hwang BY, Kellner C, Carpenter AM, et al. A comparative evaluation of existing grading scales in intracerebral hemorrhage. Neurocrit Care. 2011;15:498–505.CrossRefPubMedGoogle Scholar
  44. 44.
    Saxena A, Anderson CS, Wang X, Sato S, Arima H, Chan E, et al. INTERACT2 investigators. Prognostic significance of hyperglycemia in acute intracerebral hemorrhage: the INTERACT2 study. Stroke. 2016;47(3):682–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Lattanzi S, Cagnetti C, Provinciali L, Silvestrini M. Blood pressure variability and clinical outcome in patients with acute intracerebral hemorrhage. J Stroke Cerebrovasc Dis. 2015;24:1493–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Lattanzi S, Silvestrini M. Blood pressure in acute intra-cerebral hemorrhage. Ann Transl Med. 2016;4:320.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Kidwell CS, Rosand J, Norato G, Dixon S, Worrall BB, James ML, et al. Ischemic lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage. Neurology. 2017;88:782–8.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lattanzi S, Silvestrini M. Optimal achieved blood pressure in acute intracerebral hemorrhage: INTERACT2. Neurology. 2015;85:557–8.CrossRefPubMedGoogle Scholar
  49. 49.
    Lattanzi S, Silvestrini M, Provinciali L. Elevated blood pressure in the acute phase of stroke and the role of angiotensin receptor blockers. Int J Hypertens. 2013;2013:941783.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Zangari R, Zanier ER, Torgano G, Bersano A, Beretta S, Beghi E, et al. LEPAS group. Early ficolin-1 is a sensitive prognostic marker for functional outcome in ischemic stroke. J Neuroinflammation. 2016;13:16.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Lattanzi S, Bartolini M, Provinciali L, Silvestrini M. Glycosylated hemoglobin and functional outcome after acute ischemic stroke. J Stroke Cerebrovasc Dis. 2016;25:1786–91.CrossRefPubMedGoogle Scholar
  52. 52.
    Sporns PB, Schwake M, Schmidt R, Kemmling A, Minnerup J, Schwindt W, et al. Computed tomographic blend sign is associated with computed tomographic angiography spot sign and predicts secondary neurological deterioration after intracerebral hemorrhage. Stroke. 2017;48:131–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Simona Lattanzi
    • 1
    Email author
  • Francesco Brigo
    • 2
    • 3
  • Eugen Trinka
    • 4
    • 5
    • 6
  • Claudia Cagnetti
    • 1
  • Mario Di Napoli
    • 7
    • 8
  • Mauro Silvestrini
    • 1
  1. 1.Neurological Clinic, Department of Experimental and Clinical MedicineMarche Polytechnic UniversityAnconaItaly
  2. 2.Department of Neuroscience, Biomedicine and Movement ScienceUniversity of VeronaVeronaItaly
  3. 3.Division of Neurology“Franz Tappeiner” HospitalMeranoItaly
  4. 4.Department of Neurology, Christian Doppler KlinikParacelsus Medical UniversitySalzburgAustria
  5. 5.Center for Cognitive NeuroscienceSalzburgAustria
  6. 6.Public Health, Health Services Research and HTAUniversity for Health Sciences, Medical Informatics and TechnologyHall i.TAustria
  7. 7.Neurological ServiceSan Camillo de’ Lellis General HospitalRietiItaly
  8. 8.Neurological Section, Neuro-epidemiology Unit, SMDNCentre for Cardiovascular Medicine and Cerebrovascular Disease PreventionL’AquilaItaly

Personalised recommendations

Cite article

Buy options