Neurological Sciences

, Volume 34, Issue 9, pp 1509–1516 | Cite as

Peripheral polymorphonuclear leukocyte activation as a systemic inflammatory response in ischemic stroke

Review Article

Abstract

Stroke is one of the leading causes of mortality and morbidity in the world. The activation of polymorphonuclear leukocytes (PMNL) plays an important role in the inflammatory response after ischemic stroke. However, in the current literature, there are few studies discussing the process and role of peripheral PMNL activation. Here, we give a comprehensive description of peripheral PMNL activation after ischemic stroke and discuss their potential roles in the process of ischemic injury. Based on our analysis, peripheral PMNL activation is supposed to be attributed to systemic inflammatory response to cerebral ischemic insult, not reflecting the activity of PMNL in local ischemic brain. Inhibiting peripheral PMNL activation in stroke animals has been effective in reducing infarction and improving behavioral outcome; thus, the same approach of inhibiting peripheral PMNL activation is a promising therapeutic strategy for stroke patients.

Keywords

Polymorphonuclear leukocyte Peripheral Ischemic stroke Systemic Inflammatory response 

Abbreviations

PMNL

Polymorphonuclear leukocytes

TNF-α

Tumor necrosis factor-α

IL-1β

Interleukin-1 beta

IL-6

Interleukin-6

CAM

Cell adhesion molecules

PSGL-1

P-selectin glycoprotein ligand 1

SLe x

Sialyl Lewis x

CD11a

Cluster of differentiation molecule 11a

LFA-1

Lymphocyte function-associated antigen-1

Mac-1

Macrophage-1

ICAM-1

Intercellular adhesion molecule 1

VCAM-1

Vascular cell adhesion molecule 1

NGAL

Neutrophil gelatinase-associated lipocalin

NP4

Neutrophil proteinase 4

ROCK

Rho-associated protein kinase

CDC42

Cell division control protein 42

MACO

Middle cerebral artery occlusion

GM-CSF

Granulocyte–macrophage colony-stimulating factor

NIHSS

National Institutes of Health Stroke Scale

dMRI

Diffusion magnetic resonance imaging

CT

Computed tomography

MRI

Magnetic resonance imaging

Notes

Acknowledgments

We are grateful to Medjaden Bioscience Limited for careful edition and proofread work. We also acknowledge financial support from the National Natural Sciences Foundation of China (81171239).

Conflict of interest

There is no competing interest.

References

  1. 1.
    Kriz J, Lalancette-Hebert M (2009) Inflammation, plasticity and real-time imaging after cerebral ischemia. Acta Neuropathol 117(5):497–509. doi: 10.1007/s00401-009-0496-1 PubMedCrossRefGoogle Scholar
  2. 2.
    Nilupul Perera M, Ma HK, Arakawa S, Howells DW, Markus R, Rowe CC, Donnan GA (2006) Inflammation following stroke. J Clin Neurosci: Official J Neurosurg Soc Australasia 13(1):1–8. doi: 10.1016/j.jocn.2005.07.005 CrossRefGoogle Scholar
  3. 3.
    Htun P, Fateh-Moghadam S, Tomandl B, Handschu R, Klinger K, Stellos K, Garlichs C, Daniel W, Gawaz M (2006) Course of platelet activation and platelet–leukocyte interaction in cerebrovascular ischemia. Stroke J Cerebral Circ 37(9):2283–2287. doi: 10.1161/01.STR.0000236638.75591.61 CrossRefGoogle Scholar
  4. 4.
    Huang J, Upadhyay UM, Tamargo RJ (2006) Inflammation in stroke and focal cerebral ischemia. Surg Neurol 66(3):232–245. doi: 10.1016/j.surneu.2005.12.028 PubMedCrossRefGoogle Scholar
  5. 5.
    Smith CJ, Emsley HC, Gavin CM, Georgiou RF, Vail A, Barberan EM, del Zoppo GJ, Hallenbeck JM, Rothwell NJ, Hopkins SJ, Tyrrell PJ (2004) Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol 4:2. doi: 10.1186/1471-2377-4-2 PubMedCrossRefGoogle Scholar
  6. 6.
    Petrault O, Ouk T, Gautier S, Laprais M, Gele P, Bastide M, Bordet R (2005) Pharmacological neutropenia prevents endothelial dysfunction but not smooth muscle functions impairment induced by middle cerebral artery occlusion. Br J Pharmacol 144(8):1051–1058. doi: 10.1038/sj.bjp.0706124 PubMedCrossRefGoogle Scholar
  7. 7.
    Buck BH, Liebeskind DS, Saver JL, Bang OY, Yun SW, Starkman S, Ali LK, Kim D, Villablanca JP, Salamon N, Razinia T, Ovbiagele B (2008) Early neutrophilia is associated with volume of ischemic tissue in acute stroke. Stroke J Cerebral Circ 39(2):355–360. doi: 10.1161/STROKEAHA.107.490128 CrossRefGoogle Scholar
  8. 8.
    Elneihoum AM, Falke P, Axelsson L, Lundberg E, Lindgarde F, Ohlsson K (1996) Leukocyte activation detected by increased plasma levels of inflammatory mediators in patients with ischemic cerebrovascular diseases. Stroke J Cerebral Circ 27(10):1734–1738CrossRefGoogle Scholar
  9. 9.
    Frijns CJ, Kappelle LJ (2002) Inflammatory cell adhesion molecules in ischemic cerebrovascular disease. Stroke J Cerebral Circ 33(8):2115–2122CrossRefGoogle Scholar
  10. 10.
    Kostulas N, Kivisakk P, Huang Y, Matusevicius D, Kostulas V, Link H (1998) Ischemic stroke is associated with a systemic increase of blood mononuclear cells expressing interleukin-8 mRNA. Stroke J Cerebral Circ 29(2):462–466CrossRefGoogle Scholar
  11. 11.
    Fiszer U, Korczak-Kowalska G, Palasik W, Korlak J, Gorski A, Czlonkowska A (1998) Increased expression of adhesion molecule CD18 (LFA-1beta) on the leukocytes of peripheral blood in patients with acute ischemic stroke. Acta Neurol Scand 97(4):221–224PubMedCrossRefGoogle Scholar
  12. 12.
    Violi F, Rasura M, Alessandri C, Intiso D, Germani M, Servi M, Fieschi C, Balsano F (1988) Leukocyte response in patients suffering from acute stroke. Stroke J Cerebral Circ 19(10):1283–1284CrossRefGoogle Scholar
  13. 13.
    Santos-Silva A, Rebelo I, Castro E, Belo L, Catarino C, Monteiro I, Almeida MD, Quintanilha A (2002) Erythrocyte damage and leukocyte activation in ischemic stroke. Clinica Chimica Acta Int J Clin Chem 320(1–2):29–35CrossRefGoogle Scholar
  14. 14.
    Tsai NW, Chang WN, Shaw CF, Jan CR, Huang CR, Chen SD, Chuang YC, Lee LH, Lu CH (2009) The value of leukocyte adhesion molecules in patients after ischemic stroke. J Neurol 256(8):1296–1302. doi: 10.1007/s00415-009-5117-3 PubMedCrossRefGoogle Scholar
  15. 15.
    Harrison MJ, Marshall J (1987) Does the peripheral blood leukocyte count predict the risk of transient ischaemic attacks and strokes? J Neurol Neurosurg Psychiatry 50(11):1558–1559PubMedCrossRefGoogle Scholar
  16. 16.
    Ross AM, Hurn P, Perrin N, Wood L, Carlini W, Potempa K (2007) Evidence of the peripheral inflammatory response in patients with transient ischemic attack. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc 16(5):203–207. doi: 10.1016/j.jstrokecerebrovasdis.2007.05.002 CrossRefGoogle Scholar
  17. 17.
    Zeller JA, Lenz A, Eschenfelder CC, Zunker P, Deuschl G (2005) Platelet–leukocyte interaction and platelet activation in acute stroke with and without preceding infection. Arterioscler Thromb Vasc Biol 25(7):1519–1523. doi: 10.1161/01.ATV.0000167524.69092.16 PubMedCrossRefGoogle Scholar
  18. 18.
    Yoon SS, Dambrosia J, Chalela J, Ezzeddine M, Warach S, Haymore J, Davis L, Baird AE (2004) Rising statin use and effect on ischemic stroke outcome. BMC Med 2:4. doi: 10.1186/1741-7015-2-4 PubMedCrossRefGoogle Scholar
  19. 19.
    Balestrino M, Partinico D, Finocchi C, Gandolfo C (1998) White blood cell count and erythrocyte sedimentation rate correlate with outcome in patients with acute ischemic stroke. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc 7(2):139–144CrossRefGoogle Scholar
  20. 20.
    Kozuka K, Kohriyama T, Nomura E, Ikeda J, Kajikawa H, Nakamura S (2002) Endothelial markers and adhesion molecules in acute ischemic stroke—sequential change and differences in stroke subtype. Atherosclerosis 161(1):161–168PubMedCrossRefGoogle Scholar
  21. 21.
    Kakkar AK, Lefer DJ (2004) Leukocyte and endothelial adhesion molecule studies in knockout mice. Curr Opin Pharmacol 4(2):154–158. doi: 10.1016/j.coph.2004.01.003 PubMedCrossRefGoogle Scholar
  22. 22.
    Carlos TM, Harlan JM (1994) Leukocyte-endothelial adhesion molecules. Blood 84(7):2068–2101PubMedGoogle Scholar
  23. 23.
    Kim JS, Chopp M, Chen H, Levine SR, Carey JL, Welch KM (1995) Adhesive glycoproteins CD11a and CD18 are upregulated in the leukocytes from patients with ischemic stroke and transient ischemic attacks. J Neurol Sci 128(1):45–50PubMedCrossRefGoogle Scholar
  24. 24.
    Kawamura T, Umemura T, Kanai A, Nagashima M, Nakamura N, Uno T, Nakayama M, Sano T, Hamada Y, Nakamura J, Hotta N (2006) Soluble adhesion molecules and C-reactive protein in the progression of silent cerebral infarction in patients with type 2 diabetes mellitus. Metab Clin Exp 55(4):461–466. doi: 10.1016/j.metabol.2005.10.007 PubMedCrossRefGoogle Scholar
  25. 25.
    Fassbender K, Mossner R, Motsch L, Kischka U, Grau A, Hennerici M (1995) Circulating selectin- and immunoglobulin-type adhesion molecules in acute ischemic stroke. Stroke J Cerebral Circ 26(8):1361–1364CrossRefGoogle Scholar
  26. 26.
    Chamorro A, Cervera A, Castillo J, Davalos A, Aponte JJ, Planas AM (2002) Unfractionated heparin is associated with a lower rise of serum vascular cell adhesion molecule-1 in acute ischemic stroke patients. Neurosci Lett 328(3):229–232PubMedCrossRefGoogle Scholar
  27. 27.
    Kubo Y, Ogasawara K, Kakino S, Kashimura H, Tomitsuka N, Sugawara A, Ogawa A (2008) Serum inflammatory adhesion molecules and high-sensitivity C-reactive protein correlates with delayed ischemic neurologic deficits after subarachnoid hemorrhage. Surg Neurol 69(6):592–596. doi: 10.1016/j.surneu.2008.02.014 (discussion 596)PubMedCrossRefGoogle Scholar
  28. 28.
    Wu G, Li F, Li P, Ruan C (1993) Detection of plasma alpha-granule membrane protein GMP-140 using radiolabeled monoclonal antibodies in thrombotic diseases. Haemostasis 23(2):121–128PubMedGoogle Scholar
  29. 29.
    Olofsson AM, Arfors KE, Ramezani L, Wolitzky BA, Butcher EC, von Andrian UH (1994) E-selectin mediates leukocyte rolling in interleukin-1-treated rabbit mesentery venules. Blood 84(8):2749–2758PubMedGoogle Scholar
  30. 30.
    Bleecker JD, Coulier I, Fleurinck C, Reuck JD (1998) Circulating intercellular adhesion molecule-1 and E-selectin in acute ischemic stroke. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc 7(3):192–195CrossRefGoogle Scholar
  31. 31.
    Bevilacqua MP, Nelson RM, Mannori G, Cecconi O (1994) Endothelial-leukocyte adhesion molecules in human disease. Annu Rev Med 45:361–378. doi: 10.1146/annurev.med.45.1.361 PubMedCrossRefGoogle Scholar
  32. 32.
    Wysocka J, Lipartowska R, Lipska A (2001) Granules of neutrophils. Postepy higieny i medycyny doswiadczalnej 55(1):177–188PubMedGoogle Scholar
  33. 33.
    Vermeiren GL, Claeys MJ, van Bockstaele D, Grobben B, Slegers H, Bossaert L, Jorens PG (2000) Reperfusion injury after focal myocardial ischaemia: polymorphonuclear leukocyte activation and its clinical implications. Resuscitation 45(1):35–61PubMedCrossRefGoogle Scholar
  34. 34.
    Kjeldsen L, Johnsen AH, Sengelov H, Borregaard N (1993) Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 268(14):10425–10432PubMedGoogle Scholar
  35. 35.
    Ohlsson K, Linder C, Rosengren M (1990) Monoclonal antibodies specific for neutrophil proteinase 4. Production and use for isolation of the enzyme. Bio Chem Hoppe-Seyler 371(7):549–555CrossRefGoogle Scholar
  36. 36.
    Harlan JM (1987) Neutrophil-mediated vascular injury. Acta medica Scandinavica Supplementum 715:123–129PubMedGoogle Scholar
  37. 37.
    Elneihoum AM, Falke P, Hedblad B, Lindgarde F, Ohlsson K (1997) Leukocyte activation in atherosclerosis: correlation with risk factors. Atherosclerosis 131(1):79–84PubMedCrossRefGoogle Scholar
  38. 38.
    Cojocaru IM, Cojocaru M, Burcin C (2006) Evaluation of granulocyte elastase as a sensitive diagnostic parameter of inflammation in first ischemic stroke. Romanian J Intern Med 44(3):317–321Google Scholar
  39. 39.
    Trapp T, Olah L, Holker I, Besselmann M, Tiesler C, Maeda K, Hossmann KA (2001) GTPase RhoB: an early predictor of neuronal death after transient focal ischemia in mice. Mol Cell Neurosci 17(5):883–894. doi: 10.1006/mcne.2001.0971 PubMedCrossRefGoogle Scholar
  40. 40.
    Brabeck C, Mittelbronn M, Bekure K, Meyermann R, Schluesener HJ, Schwab JM (2003) Effect of focal cerebral infarctions on lesional RhoA and RhoB expression. Arch Neurol 60(9):1245–1249. doi: 10.1001/archneur.60.9.1245 PubMedCrossRefGoogle Scholar
  41. 41.
    Yano K, Kawasaki K, Hattori T, Tawara S, Toshima Y, Ikegaki I, Sasaki Y, Satoh S, Asano T, Seto M (2008) Demonstration of elevation and localization of Rho-kinase activity in the brain of a rat model of cerebral infarction. Eur J Pharmacol 594(1–3):77–83. doi: 10.1016/j.ejphar.2008.07.045 PubMedCrossRefGoogle Scholar
  42. 42.
    Feske SK, Sorond FA, Henderson GV, Seto M, Hitomi A, Kawasaki K, Sasaki Y, Asano T, Liao JK (2009) Increased leukocyte ROCK activity in patients after acute ischemic stroke. Brain Res 1257:89–93. doi: 10.1016/j.brainres.2008.12.045 PubMedCrossRefGoogle Scholar
  43. 43.
    Shimokawa H (2002) Rho-kinase as a novel therapeutic target in treatment of cardiovascular diseases. J Cardiovasc Pharmacol 39(3):319–327PubMedCrossRefGoogle Scholar
  44. 44.
    Fukata Y, Amano M, Kaibuchi K (2001) Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol Sci 22(1):32–39PubMedCrossRefGoogle Scholar
  45. 45.
    Frankfurt O, Tallman MS (2011) The hematopoietic growth factors in acute leukemia: US perspective. Cancer Treat Res 157:307–337. doi: 10.1007/978-1-4419-7073-2_18 PubMedCrossRefGoogle Scholar
  46. 46.
    Paczkowska E, Larysz B, Rzeuski R, Karbicka A, Jalowinski R, Kornacewicz-Jach Z, Ratajczak MZ, Machalinski B (2005) Human hematopoietic stem/progenitor-enriched CD34(+) cells are mobilized into peripheral blood during stress related to ischemic stroke or acute myocardial infarction. Eur J Haematol 75(6):461–467. doi: 10.1111/j.1600-0609.2005.00536.x PubMedCrossRefGoogle Scholar
  47. 47.
    Offner H, Vandenbark AA, Hurn PD (2009) Effect of experimental stroke on peripheral immunity: CNS ischemia induces profound immunosuppression. Neuroscience 158(3):1098–1111. doi: 10.1016/j.neuroscience.2008.05.033 PubMedCrossRefGoogle Scholar
  48. 48.
    Franzen R, Bouhy D, Schoenen J (2004) Nervous system injury: focus on the inflammatory cytokine granulocyte-macrophage colony stimulating factor. Neurosci Lett 361(1–3):76–78. doi: 10.1016/j.neulet.2003.12.018 PubMedCrossRefGoogle Scholar
  49. 49.
    Tarkowski E, Rosengren L, Blomstrand C, Wikkelso C, Jensen C, Ekholm S, Tarkowski A (1997) Intrathecal release of pro- and anti-inflammatory cytokines during stroke. Clin Exp Immunol 110(3):492–499PubMedCrossRefGoogle Scholar
  50. 50.
    Ridker PM (1998) C-reactive protein and risks of future myocardial infarction and thrombotic stroke. Eur Heart J 19(1):1–3PubMedCrossRefGoogle Scholar
  51. 51.
    Elkind MS, Cheng J, Boden-Albala B, Paik MC, Sacco RL (2001) Elevated white blood cell count and carotid plaque thickness: the northern Manhattan stroke study. Stroke J Cerebral Circ 32(4):842–849CrossRefGoogle Scholar
  52. 52.
    Loimaala A, Rontu R, Vuori I, Mercuri M, Lehtimaki T, Nenonen A, Bond MG (2006) Blood leukocyte count is a risk factor for intima-media thickening and subclinical carotid atherosclerosis in middle-aged men. Atherosclerosis 188(2):363–369. doi: 10.1016/j.atherosclerosis.2005.11.021 PubMedCrossRefGoogle Scholar
  53. 53.
    Price CJ, Menon DK, Peters AM, Ballinger JR, Barber RW, Balan KK, Lynch A, Xuereb JH, Fryer T, Guadagno JV, Warburton EA (2004) Cerebral neutrophil recruitment, histology, and outcome in acute ischemic stroke: an imaging-based study. Stroke J Cerebral Circ 35(7):1659–1664. doi: 10.1161/01.STR.0000130592.71028.92 CrossRefGoogle Scholar
  54. 54.
    Kazmierski R, Guzik P, Ambrosius W, Kozubski W (2001) Leukocytosis in the first day of acute ischemic stroke as a prognostic factor of disease progression. Wiad Lek 54(3–4):143–151PubMedGoogle Scholar
  55. 55.
    Christensen H, Boysen G (2004) C-reactive protein and white blood cell count increases in the first 24 hours after acute stroke. Cerebrovasc Dis 18(3):214–219. doi: 10.1159/000079944 PubMedCrossRefGoogle Scholar
  56. 56.
    Pozzilli C, Lenzi GL, Argentino C, Bozzao L, Rasura M, Giubilei F, Fieschi C (1985) Peripheral white blood cell count in cerebral ischemic infarction. Acta Neurol Scand 71(5):396–400PubMedCrossRefGoogle Scholar
  57. 57.
    Netz U, Perry Z, Weitzman S (2008) Characteristics of morbidity and mortality from stroke in the Negev population in the years 1995 and 1999. Harefuah 147(11):842–846, 944Google Scholar
  58. 58.
    di Napoli M, Papa F (2002) Inflammation, hemostatic markers, and antithrombotic agents in relation to long-term risk of new cardiovascular events in first-ever ischemic stroke patients. Stroke J Cerebral Circ 33(7):1763–1771CrossRefGoogle Scholar
  59. 59.
    Heinel LA, Rubin S, Rosenwasser RH, Vasthare US, Tuma RF (1994) Leukocyte involvement in cerebral infarct generation after ischemia and reperfusion. Brain Res Bull 34(2):137–141PubMedCrossRefGoogle Scholar
  60. 60.
    Emerich DF, Dean RL 3rd, Bartus RT (2002) The role of leukocytes following cerebral ischemia: pathogenic variable or bystander reaction to emerging infarct? Exp Neurol 173(1):168–181. doi: 10.1006/exnr.2001.7835 PubMedCrossRefGoogle Scholar
  61. 61.
    Matsuo Y, Onodera H, Shiga Y, Nakamura M, Ninomiya M, Kihara T, Kogure K (1994) Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion. Stroke J Cerebral Circ 25(7):1469–1475CrossRefGoogle Scholar
  62. 62.
    Chu LS, Wei EQ, Yu GL, Fang SH, Zhou Y, Wang ML, Zhang WP (2006) Pranlukast reduces neutrophil but not macrophage/microglial accumulation in brain after focal cerebral ischemia in mice. Acta Pharmacol Sin 27(3):282–288. doi: 10.1111/j.1745-7254.2006.00290.x PubMedCrossRefGoogle Scholar
  63. 63.
    La M, Tailor A, D’Amico M, Flower RJ, Perretti M (2001) Analysis of the protection afforded by annexin 1 in ischaemia-reperfusion injury: focus on neutrophil recruitment. Eur J Pharmacol 429(1–3):263–278PubMedCrossRefGoogle Scholar
  64. 64.
    Soriano SG, Lipton SA, Wang YF, Xiao M, Springer TA, Gutierrez-Ramos JC, Hickey PR (1996) Intercellular adhesion molecule-1-deficient mice are less susceptible to cerebral ischemia-reperfusion injury. Ann Neurol 39(5):618–624. doi: 10.1002/ana.410390511 PubMedCrossRefGoogle Scholar
  65. 65.
    Chen H, Chopp M, Zhang RL, Bodzin G, Chen Q, Rusche JR, Todd RF 3rd (1994) Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol 35(4):458–463. doi: 10.1002/ana.410350414 PubMedCrossRefGoogle Scholar
  66. 66.
    Chopp M, Li Y, Jiang N, Zhang RL, Prostak J (1996) Antibodies against adhesion molecules reduce apoptosis after transient middle cerebral artery occlusion in rat brain. J Cerebral Blood Flow Metab Off J Int Soc Cerebral Blood Flow Metab 16(4):578–584. doi: 10.1097/00004647-199607000-00007 CrossRefGoogle Scholar
  67. 67.
    Zaleska MM, Mercado ML, Chavez J, Feuerstein GZ, Pangalos MN, Wood A (2009) The development of stroke therapeutics: promising mechanisms and translational challenges. Neuropharmacology 56(2):329–341. doi: 10.1016/j.neuropharm.2008.10.006 PubMedCrossRefGoogle Scholar
  68. 68.
    Bednar MM, Gross CE, Russell SR, Fuller SP, Ellenberger CL, Schindler E, Klingbeil C, Vexler V (1998) Humanized anti-l-selectin monoclonal antibody DREG200 therapy in acute thromboembolic stroke. Neurol Res 20(5):403–408PubMedGoogle Scholar
  69. 69.
    Krams M, Lees KR, Hacke W, Grieve AP, Orgogozo JM, Ford GA (2003) Acute stroke therapy by inhibition of neutrophils (ASTIN): an adaptive dose–response study of UK-279,276 in acute ischemic stroke. Stroke J Cerebral Circ 34(11):2543–2548. doi: 10.1161/01.STR.0000092527.33910.89 CrossRefGoogle Scholar
  70. 70.
    Becker KJ (2002) Anti-leukocyte antibodies: LeukArrest (Hu23F2G) and Enlimomab (R6.5) in acute stroke. Curr Med Res Opin 18(Suppl 2):s18–s22PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2013

Authors and Affiliations

  1. 1.Department of NeurologySecond Xiangya Hospital, Central South UniversityChangshaPeople’s Republic of China

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