Relationship between the degree of recanalization and functional outcome in acute ischemic stroke is mediated by penumbra salvage volume.


Journal

Journal of neurology
ISSN: 1432-1459
Titre abrégé: J Neurol
Pays: Germany
ID NLM: 0423161

Informations de publication

Date de publication:
Jun 2021
Historique:
received: 19 11 2020
accepted: 13 01 2021
revised: 13 01 2021
pubmed: 25 1 2021
medline: 22 6 2021
entrez: 24 1 2021
Statut: ppublish

Résumé

The presence of metabolically viable brain tissue that may be salvageable with rapid cerebral blood flow restoration is the fundament rationale for reperfusion therapy in patients with large vessel occlusion stroke. The effect of endovascular treatment (EVT) on functional outcome largely depends on the degree of recanalization. However, the relationship of recanalization degree and penumbra salvage has not yet been investigated. We hypothesized that penumbra salvage volume mediates the effect of thrombectomy on functional outcome. 99 acute anterior circulation stroke patients who received multimodal CT and underwent thrombectomy with resulting partial to complete reperfusion (modified thrombolysis in cerebral infarction scale (mTICI) ≥ 2a) were retrospectively analyzed. Penumbra volume was quantified on CT perfusion and penumbra salvage volume (PSV) was calculated as difference of penumbra and net infarct growth from admission to follow-up imaging. In patients with complete reperfusion (mTICI ≥ 2c), the median PSV was significantly higher than the median PSV in patients with partial or incomplete (mTICI 2a-2b) reperfusion (median 224 mL, IQR: 168-303 versus 158 mL, IQR: 129-225; p < 0.01). A higher degree of recanalization was associated with increased PSV (+ 63 mL per grade, 95% CI: 17-110; p < 0.01). Higher PSV was also associated with improved functional outcome (OR/mRS shift: 0.89; 95% CI: 0.85-0.95, p < 0.0001). PSV may be an important mediator between functional outcome and recanalization degree in EVT patients and could serve as a more accurate instrument to compare treatment effects than infarct volumes.

Sections du résumé

BACKGROUND BACKGROUND
The presence of metabolically viable brain tissue that may be salvageable with rapid cerebral blood flow restoration is the fundament rationale for reperfusion therapy in patients with large vessel occlusion stroke. The effect of endovascular treatment (EVT) on functional outcome largely depends on the degree of recanalization. However, the relationship of recanalization degree and penumbra salvage has not yet been investigated. We hypothesized that penumbra salvage volume mediates the effect of thrombectomy on functional outcome.
METHODS METHODS
99 acute anterior circulation stroke patients who received multimodal CT and underwent thrombectomy with resulting partial to complete reperfusion (modified thrombolysis in cerebral infarction scale (mTICI) ≥ 2a) were retrospectively analyzed. Penumbra volume was quantified on CT perfusion and penumbra salvage volume (PSV) was calculated as difference of penumbra and net infarct growth from admission to follow-up imaging.
RESULTS RESULTS
In patients with complete reperfusion (mTICI ≥ 2c), the median PSV was significantly higher than the median PSV in patients with partial or incomplete (mTICI 2a-2b) reperfusion (median 224 mL, IQR: 168-303 versus 158 mL, IQR: 129-225; p < 0.01). A higher degree of recanalization was associated with increased PSV (+ 63 mL per grade, 95% CI: 17-110; p < 0.01). Higher PSV was also associated with improved functional outcome (OR/mRS shift: 0.89; 95% CI: 0.85-0.95, p < 0.0001).
CONCLUSIONS CONCLUSIONS
PSV may be an important mediator between functional outcome and recanalization degree in EVT patients and could serve as a more accurate instrument to compare treatment effects than infarct volumes.

Identifiants

pubmed: 33486602
doi: 10.1007/s00415-021-10410-2
pii: 10.1007/s00415-021-10410-2
pmc: PMC8179901
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

2213-2222

Références

Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, McTaggart RA, Torbey MT, Kim-Tenser M, Leslie-Mazwi T, Sarraj A, Kasner SE, Ansari SA, Yeatts SD, Hamilton S, Mlynash M, Heit JJ, Zaharchuk G, Kim S, Carrozzella J, Palesch YY, Demchuk AM, Bammer R, Lavori PW, Broderick JP, Lansberg MG, DEFUSE 3 Investigators (2018) Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 378:708–718
doi: 10.1056/NEJMoa1713973
Albers GW, Marks MP, Lansberg MG (2018) Thrombectomy for stroke with selection by perfusion imaging. N Engl J Med 378:1849–1850
doi: 10.1056/NEJMoa1713973
Bivard A, Kleinig T, Miteff F, Butcher K, Lin L, Levi C, Parsons M (2017) Ischemic core thresholds change with time to reperfusion: a case control study. Ann Neurol 82:995–1003
doi: 10.1002/ana.25109
Bivard A, McElduff P, Spratt N, Levi C, Parsons M (2011) Defining the extent of irreversible brain ischemia using perfusion computed tomography. Cerebrovasc Dis 31:238–245
doi: 10.1159/000321897
Boers AMM, Jansen IGH, Brown S, Lingsma HF, Beenen LFM, Devlin TG, Roman LS, Heo JH, Ribo M, Almekhlafi MA, Liebeskind DS, Teitelbaum J, Cuadras P, du Mesnil de Rochemont R, Beaumont M, Brown MM, Yoo AJ, Donnan GA, Mas JL, Oppenheim C, Dowling RJ, Moulin T, Agrinier N, Lopes DK, Aja Rodriguez L, Compagne KCJ, Al-Ajlan FS, Madigan J, Albers GW, Soize S, Blasco J, Davis SM, Nogueira RG, Davalos A, Menon BK, van der Lugt A, Muir KW, Roos Y, White P, Mitchell PJ, Demchuk AM, van Zwam WH, Jovin TG, van Oostenbrugge RJ, Dippel DWJ, Campbell BCV, Guillemin F, Bracard S, Hill MD, Goyal M, Marquering HA, Majoie C (2019) Mediation of the relationship between endovascular therapy and functional outcome by follow-up infarct volume in patients with acute ischemic stroke. JAMA Neurol 76:194–202
doi: 10.1001/jamaneurol.2018.3661
Boned S, Padroni M, Rubiera M, Tomasello A, Coscojuela P, Romero N, Muchada M, Rodriguez-Luna D, Flores A, Rodriguez N, Juega J, Pagola J, Alvarez-Sabin J, Molina CA, Ribo M (2017) Admission CT perfusion may overestimate initial infarct core: the ghost infarct core concept. J Neurointerv Surg 9:66–69
doi: 10.1136/neurintsurg-2016-012494
Broocks G, Faizy TD, Flottmann F, Schon G, Langner S, Fiehler J, Kemmling A, Gellissen S (2018) Subacute infarct volume with edema correction in computed tomography is equivalent to final infarct volume after ischemic stroke: improving the comparability of infarct imaging endpoints in clinical trials. Invest Radiol 53:472–476
doi: 10.1097/RLI.0000000000000475
Broocks G, Flottmann F, Hanning U, Schon G, Sporns P, Minnerup J, Fiehler J, Kemmling A (2020) Impact of endovascular recanalization on quantitative lesion water uptake in ischemic anterior circulation strokes. J Cereb Blood Flow Metab 40:437–445
doi: 10.1177/0271678X18823601
Broocks G, Hanning U, Flottmann F, Schonfeld M, Faizy TD, Sporns P, Baumgart M, Leischner H, Schon G, Minnerup J, Thomalla G, Fiehler J, Kemmling A (2019) Clinical benefit of thrombectomy in stroke patients with low ASPECTS is mediated by oedema reduction. Brain 142:1399–1407
doi: 10.1093/brain/awz057
Broocks G, Leischner H, Hanning U, Flottmann F, Faizy TD, Schon G, Sporns P, Thomalla G, Kamalian S, Lev MH, Fiehler J, Kemmling A (2020) Lesion age imaging in acute stroke: water uptake in CT versus DWI-FLAIR mismatch. Ann Neurol 88:1144–1152
doi: 10.1002/ana.25903
Campbell BCV, Majoie C, Albers GW, Menon BK, Yassi N, Sharma G, van Zwam WH, van Oostenbrugge RJ, Demchuk AM, Guillemin F, White P, Davalos A, van der Lugt A, Butcher KS, Cherifi A, Marquering HA, Cloud G, Macho Fernandez JM, Madigan J, Oppenheim C, Donnan GA, Roos Y, Shankar J, Lingsma H, Bonafe A, Raoult H, Hernandez-Perez M, Bharatha A, Jahan R, Jansen O, Richard S, Levy EI, Berkhemer OA, Soudant M, Aja L, Davis SM, Krings T, Tisserand M, San Roman L, Tomasello A, Beumer D, Brown S, Liebeskind DS, Bracard S, Muir KW, Dippel DWJ, Goyal M, Saver JL, Jovin TG, Hill MD, Mitchell PJ, HERMES Collaborators (2019) Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data. Lancet Neurol 18:46–55
doi: 10.1016/S1474-4422(18)30314-4
Dargazanli C, Fahed R, Blanc R, Gory B, Labreuche J, Duhamel A, Marnat G, Saleme S, Costalat V, Bracard S, Desal H, Mazighi M, Consoli A, Piotin M, Lapergue B, AT Investigators (2018) Modified thrombolysis in cerebral infarction 2C/thrombolysis in cerebral infarction 3 reperfusion should be the aim of mechanical thrombectomy: insights from the ASTER Trial (contact aspiration versus stent retriever for successful revascularization). Stroke 49:1189–1196
doi: 10.1161/STROKEAHA.118.020700
Demeestere J, Scheldeman L, Cornelissen SA, Heye S, Wouters A, Dupont P, Christensen S, Mlynash M, Albers GW, Lansberg M, Lemmens R (2018) Alberta stroke program early CT score versus computed tomographic perfusion to predict functional outcome after successful reperfusion in acute ischemic stroke. Stroke 49:2361–2367
doi: 10.1161/STROKEAHA.118.021961
Fiorelli M, Bastianello S, von Kummer R, del Zoppo GJ, Larrue V, Lesaffre E, Ringleb AP, Lorenzano S, Manelfe C, Bozzao L (1999) Hemorrhagic transformation within 36 hours of a cerebral infarct: relationships with early clinical deterioration and 3-month outcome in the European Cooperative Acute Stroke Study I (ECASS I) cohort. Stroke 30:2280–2284
doi: 10.1161/01.STR.30.11.2280
Flottmann F, Broocks G, Faizy TD, McDonough R, Watermann L, Deb-Chatterji M, Thomalla G, Herzberg M, Nolte CH, Fiehler J, Leischner H, Brekenfeld C, GSR Investigators (2020) Factors associated with failure of reperfusion in endovascular therapy for acute ischemic stroke: a multicenter analysis. Clin Neuroradiol. https://doi.org/10.1007/s00062-020-00880-8
doi: 10.1007/s00062-020-00880-8 pubmed: 33346850 pmcid: 7943507
Ganesh A, Luengo-Fernandez R, Wharton RM, Rothwell PM, Oxford Vascular Study (2018) Ordinal vs dichotomous analyses of modified Rankin Scale, 5-year outcome, and cost of stroke. Neurology 91:e1951–e1960
doi: 10.1212/WNL.0000000000006554
Gerriets T, Stolz E, Walberer M, Muller C, Kluge A, Bachmann A, Fisher M, Kaps M, Bachmann G (2004) Noninvasive quantification of brain edema and the space-occupying effect in rat stroke models using magnetic resonance imaging. Stroke 35:566–571
doi: 10.1161/01.STR.0000113692.38574.57
Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, Davalos A, Majoie CB, van der Lugt A, de Miquel MA, Donnan GA, Roos YB, Bonafe A, Jahan R, Diener HC, van den Berg LA, Levy EI, Berkhemer OA, Pereira VM, Rempel J, Millan M, Davis SM, Roy D, Thornton J, Roman LS, Ribo M, Beumer D, Stouch B, Brown S, Campbell BC, van Oostenbrugge RJ, Saver JL, Hill MD, Jovin TG, HERMES Collaborators (2016) Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 387:1723–1731
doi: 10.1016/S0140-6736(16)00163-X
Harston GWJ, Carone D, Sheerin F, Jenkinson M, Kennedy J (2018) Quantifying infarct growth and secondary injury volumes: comparing multimodal image registration measures. Stroke 49:1647–1655
doi: 10.1161/STROKEAHA.118.020788
LeCouffe NE, Kappelhof M, Treurniet KM, Lingsma HF, Zhang G, van den Wijngaard IR, van Es A, Emmer BJ, Majoie C, Roos Y, Coutinho JM, MR CLEAN Registry Investigators (2020) 2B, 2C, or 3: what should be the angiographic target for endovascular treatment in ischemic stroke? Stroke 51:1790–1796
doi: 10.1161/STROKEAHA.119.028891
Liebeskind DS, Bracard S, Guillemin F, Jahan R, Jovin TG, Majoie CB, Mitchell PJ, van der Lugt A, Menon BK, San Roman L, Campbell BC, Muir KW, Hill MD, Dippel DW, Saver JL, Demchuk AM, Davalos A, White P, Brown S, Goyal M, HERMES Collaborators (2019) eTICI reperfusion: defining success in endovascular stroke therapy. J Neurointerv Surg 11:433–438
doi: 10.1136/neurintsurg-2018-014127
Ma H, Campbell BCV, Parsons MW, Churilov L, Levi CR, Hsu C, Kleinig TJ, Wijeratne T, Curtze S, Dewey HM, Miteff F, Tsai CH, Lee JT, Phan TG, Mahant N, Sun MC, Krause M, Sturm J, Grimley R, Chen CH, Hu CJ, Wong AA, Field D, Sun Y, Barber PA, Sabet A, Jannes J, Jeng JS, Clissold B, Markus R, Lin CH, Lien LM, Bladin CF, Christensen S, Yassi N, Sharma G, Bivard A, Desmond PM, Yan B, Mitchell PJ, Thijs V, Carey L, Meretoja A, Davis SM, Donnan GA, EXTEND Investigators (2019) Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med 380:1795–1803
doi: 10.1056/NEJMoa1813046
McDonough R, Elsayed S, Faizy TD, Austein F, Sporns PB, Meyer L, Bechstein M, van Horn N, Nawka MT, Schon G, Kniep H, Hanning U, Fiehler J, Heit JJ, Broocks G (2020) Computed tomography-based triage of extensive baseline infarction: ASPECTS and collaterals versus perfusion imaging for outcome prediction. J Neurointerv Surg. https://doi.org/10.1136/neurintsurg-2020-016848
doi: 10.1136/neurintsurg-2020-016848 pubmed: 33168659 pmcid: 7848056
Meyer L, Schonfeld M, Bechstein M, Hanning U, Cheng B, Thomalla G, Schon G, Kemmling A, Fiehler J, Broocks G (2020) Ischemic lesion water homeostasis after thrombectomy for large vessel occlusion stroke within the anterior circulation: the impact of age. J Cereb Blood Flow Metab. https://doi.org/10.1177/0271678X20915792
doi: 10.1177/0271678X20915792 pubmed: 32248730
Minnerup J, Broocks G, Kalkoffen J, Langner S, Knauth M, Psychogios MN, Wersching H, Teuber A, Heindel W, Eckert B, Wiendl H, Schramm P, Fiehler J, Kemmling A (2016) Computed tomography-based quantification of lesion water uptake identifies patients within 4.5 hours of stroke onset: a multicenter observational study. Ann Neurol 80:924–934
doi: 10.1002/ana.24818
Nawabi J, Flottmann F, Hanning U, Bechstein M, Schoen G, Kemmling A, Fiehler J, Broocks G (2018) Futile recanalization with poor clinical outcome is associated with increased edema volume after ischemic stroke. Invest Radiol 54:282–287
doi: 10.1097/RLI.0000000000000539
Nawabi J, Flottmann F, Kemmling A, Kniep H, Leischner H, Sporns P, Schon G, Hanning U, Thomalla G, Fiehler J, Broocks G (2019) Elevated early lesion water uptake in acute stroke predicts poor outcome despite successful recanalization—when “tissue clock” and “time clock” are desynchronized. Int J Stroke. https://doi.org/10.1177/1747493019884522
doi: 10.1177/1747493019884522 pubmed: 31657283
Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, Yavagal DR, Ribo M, Cognard C, Hanel RA, Sila CA, Hassan AE, Millan M, Levy EI, Mitchell P, Chen M, English JD, Shah QA, Silver FL, Pereira VM, Mehta BP, Baxter BW, Abraham MG, Cardona P, Veznedaroglu E, Hellinger FR, Feng L, Kirmani JF, Lopes DK, Jankowitz BT, Frankel MR, Costalat V, Vora NA, Yoo AJ, Malik AM, Furlan AJ, Rubiera M, Aghaebrahim A, Olivot JM, Tekle WG, Shields R, Graves T, Lewis RJ, Smith WS, Liebeskind DS, Saver JL, Jovin TG, DT Investigators (2018) Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 378:11–21
doi: 10.1056/NEJMoa1706442
Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL (2019) Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 50:e344–e418
doi: 10.1161/STROKEAHA.118.022606
Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL, American Heart Association Stroke Council (2018) 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 49:e46–e110
doi: 10.1161/STR.0000000000000158
Seker F, Pereira-Zimmermann B, Pfaff J, Purrucker J, Gumbinger C, Schonenberger S, Bendszus M, Mohlenbruch MA (2019) Collateral scores in acute ischemic stroke: a retrospective study assessing the suitability of collateral scores as standalone predictors of clinical outcome. Clin Neuroradiol. https://doi.org/10.1007/s00062-019-00858-1
doi: 10.1007/s00062-019-00858-1 pubmed: 31781803
Sporns PB, Minnerup J, Warneke N, Dziewas R, Hanning U, Berkemeyer S, Zoubi T, Heindel W, Schwindt W, Niederstadt T (2017) Impact of the implementation of thrombectomy with stent retrievers on the frequency of hemicraniectomy in patients with acute ischemic stroke. Clin Neuroradiol 27:193–197
doi: 10.1007/s00062-015-0478-8
Tipirneni-Sajja A, Christensen S, Straka M, Inoue M, Lansberg MG, Mlynash M, Bammer R, Parsons MW, Donnan GA, Davis SM, Albers GW (2017) Prediction of final infarct volume on subacute MRI by quantifying cerebral edema in ischemic stroke. J Cereb Blood Flow Metab 37:3077–3084
doi: 10.1177/0271678X16683960
Turc G, Bhogal P, Fischer U, Khatri P, Lobotesis K, Mazighi M, Schellinger PD, Toni D, de Vries J, White P, Fiehler J (2019) European Stroke Organisation (ESO)—European Society for Minimally Invasive Neurological Therapy (ESMINT) guidelines on mechanical thrombectomy in acute ischemic stroke. J Neurointerv Surg. https://doi.org/10.1136/neurintsurg-2018-014568
doi: 10.1136/neurintsurg-2018-014568 pubmed: 31427503
Wannamaker R, Guinand T, Menon BK, Demchuk A, Goyal M, Frei D, Bharatha A, Jovin TG, Shankar J, Krings T, Baxter B, Holmstedt C, Swartz R, Dowlatshahi D, Chan R, Tampieri D, Choe H, Burns P, Gentile N, Rempel J, Shuaib A, Buck B, Bivard A, Hill M, Butcher K (2018) Computed tomographic perfusion predicts poor outcomes in a randomized trial of endovascular therapy. Stroke 49:1426–1433
doi: 10.1161/STROKEAHA.117.019806
Wintermark M, Flanders AE, Velthuis B, Meuli R, van Leeuwen M, Goldsher D, Pineda C, Serena J, van der Schaaf I, Waaijer A, Anderson J, Nesbit G, Gabriely I, Medina V, Quiles A, Pohlman S, Quist M, Schnyder P, Bogousslavsky J, Dillon WP, Pedraza S (2006) Perfusion-CT assessment of infarct core and penumbra: receiver operating characteristic curve analysis in 130 patients suspected of acute hemispheric stroke. Stroke 37:979–985
doi: 10.1161/01.STR.0000209238.61459.39

Auteurs

Gabriel Broocks (G)

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. g.broocks@uke.de.

Hashim Jafarov (H)

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Rosalie McDonough (R)

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Friederike Austein (F)

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Lukas Meyer (L)

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Matthias Bechstein (M)

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Noel van Horn (N)

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Marie Teresa Nawka (MT)

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Gerhard Schön (G)

Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Jens Fiehler (J)

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Helge Kniep (H)

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Uta Hanning (U)

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female
Humans United States Aged Cross-Sectional Studies Medicare Part C
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH