Abstract
Stroke is a leading cause of serious long-term disability in adults and is the second leading cause of death worldwide. Early reperfusion and neuroprotection techniques have been the focus of much effort with the aim of very acute treatment of the stroke. Targeting different mechanisms, pharmacological therapies have the potential to reduce disability in a large fraction of patients who survive the acute stroke. The brain’s capacity to reorganize after stroke through plasticity mechanisms can be modulated by pharmacological agents. A number of therapeutic interventions are under study, including small molecules, growth factors, and monoclonal antibodies. Recently it has been shown that the SSRI fluoxetine improved motor deficit in patients with ischaemic stroke and hemiplegia which appeared to be independent of the presence of depression. In this context, it is of major importance to support innovative research in order to promote the emergence of new pharmacological treatments targeting neurological recovery after stroke, as opposed to acute de-occlusion and neuroprotection. This paper is the work of a group of 14 scientists with aim of (1) addressing key areas of the basic and clinical aspects of human brain plasticity after stroke and potential pharmacological targets for recovery, (2) asking questions about the most appropriate characteristics of clinical trials testing drugs in post stroke recovery and (3) proposing recommendations for future clinical trials.
Similar content being viewed by others
References
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD et al (2013) American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 127(1):e6–e245
The national Institute of Neurological Disorders and Stroke rt-pa Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581–1587
Kidwell CS, Liebeskind DS, Starkman S, Saver JL (2001) Trends in acute ischemic stroke trials through the 20th century. Stroke 32:1349–1359
Cramer SC (2008) Repairing the human brain after stroke. Ii. Restorative therapies. Ann Neurol 63:549–560
Chollet F, Tardy J, Albucher JF, Thalamas C, Berard E, Lamy C et al (2011) Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol 10:123–130
Cramer SC, Stradling D, Brown DM, Carrillo-Nunez IM, Ciabarra A, Cummings M et al (2012) Organization of a United States county system for comprehensive acute stroke care. Stroke 43:1089–1093
Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391–397
Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17:796–808
Hermann DM, Chopp M (2012) Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation. Lancet Neurol 11:369–380
Wieloch T, Nikolich K (2006) Mechanisms of neural plasticity following brain injury. Curr Opin Neurobiol 16:258–264
Pekna M, Pekny M, Nilsson M (2012) Modulation of neural plasticity as a basis for stroke rehabilitation. Stroke 43:2819–2828
Baron JC, Cohen LG, Cramer SC, Dobkin BH, Johansen-Berg H, Loubinoux I et al (2004) Neuroimaging in stroke recovery: a position paper from the first International Workshop on neuroimaging and stroke recovery first International Workshop on neuroimaging and stroke recovery. Cerebrovasc Dis 18:260–267
Liepert J, Bauder H, Wolfgang HR, Miltner WH, Taub E, Weiller C (2000) Treatment-induced cortical reorganization after stroke in humans. Stroke 31:1210–1216
Chollet F, Albucher JF (2012) Strategies to augment recovery after stroke. Curr Treat Options Neurol 14:531–540
Liepert J (2008) Pharmacotherapy in restorative neurology. Curr Opin Neurol 21:639–643
Loubinoux I, Chollet F (2010) Neuropharmacology in stroke recovery. In: Cramer SC, Nudo RJ (eds) Brain repair after stroke. Cambridge University Press, Cambridge, pp 183–193
Chollet F, Acket B, Raposo N, Albucher JF, Loubinoux I, Pariente J (2013) Use of antidepressant medications to improve outcomes after stroke. Curr Neurol Neurosci Rep 13(1):318
Martinsson L, Hårdemark H, Eksborg S (2007) Amphetamines for improving recovery after stroke. Cochrane Database Syst Rev 24(1):CD002090 (A comprehensive review on published and unpublished studies)
Zittel S, Weiller C, Liepert J (2008) Citalopram improves dexterity in chronic stroke patients. Neurorehabil Neural Repair 22:311–314
Dam M, Tonin P, De Boni A, Pizzolato G, Casson S, Ermani M et al (1996) Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy. Stroke 27:1211–1214
Mikami K, Jorge RE, Adams HP Jr, Davis PH, Leira EC, Jang M et al (2011) Effect of antidepressants on the course of disability following stroke. Am J Geriatr Psychiatry 19:1007–1015
Gopurappilly R, Pal R, Mamidi MK, Dey S, Bhonde R, Das AK (2011) Stem cells in stroke repair: current success & future prospects. CNS Neurol Disord: Drug Targets 10:741–756
Cramer SC (2010) Stratifying patients with stroke in trials that target brain repair. Stroke 41:S114–S116
Bath PM, Lees KR, Schellinger PD, Altman H, Bland M, Hogg C et al (2012) Statistical analysis of the primary outcome in acute stroke trials. Stroke 43:1171–1178
Brinjikji W, Rabinstein AA, Cloft HJ (2012) Hospitalization costs for acute ischemic stroke patients treated with intravenous thrombolysis in the United States are substantially higher than medicare payments. Stroke 43:1131–1133
Cramer SC, Koroshetz WJ, Finklestein SP (2007) The case for modality-specific outcome measures in clinical trials of stroke recovery-promoting agents. Stroke 38:1393–1395
Nudo RJ (1999) Recovery after damage to motor cortical areas. Curr Opin Neurobiol 9:740–747
Murphy TH, Corbett D (2009) Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci 10:861–872
Stinear CM, Barber PA, Petoe M, Anwar S, Byblow WD (2012) The PREP algorithm predicts potential for upper limb recovery after stroke. Brain 135:2527–2535
Levy R, Benson R, Winstein C; for the Everest Study Investigators (2008) Cortical stimulation for upper-extremity hemiparesis from ischemic stroke: everest study primary endpoint results. In: International Stroke Conference, 2008
Pearson-Fuhrhop KM, Cramer SC (2010) Genetic influences on neural plasticity. PM R 2:S227–S240
Nouri S, Cramer SC (2011) Anatomy and physiology predict response to motor cortex stimulation after stroke. Neurology 77:1076–1083
Lindenberg R, Zhu LL, Ruber T, Schlaug G (2012) Predicting functional motor potential in chronic stroke patients using diffusion tensor imaging. Hum Brain Mapp 33:1040–1051
Whiteley W, Wardlaw J, Dennis M, Lowe G, Rumley A, Sattar N et al (2012) The use of blood biomarkers to predict poor outcome after acute transient ischemic attack or ischemic stroke. Stroke 43:86–91
Stroke Therapy Academic Industry Roundtable (STAIR) (1999) Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30:2752–2758
Lees KR, Bath PM, Schellinger PD, Kerr DM, Fulton R, Hacke W, European Stroke Organization Outcomes Working Group et al (2012) Contemporary outcome measures in acute stroke research: choice of primary outcome measure. Stroke 43:1163–1170
Hacke W, Bluhmki E, Steiner T, Tatlisumak T, Mahagne MH, Sacchetti ML et al (1998) Dichotomized efficacy end points and global end-point analysis applied to the ECASS intention-to-treat data set: post hoc analysis of ECASS I. Stroke 29:2073–2075
Saver JL (2007) Novel end point analytic techniques and interpreting shifts across the entire range of outcome scales in acute stroke trials. Stroke 38:3055–3062
Adams HP Jr, Leclerc JR, Bluhmki E, Clarke W, Hansen MD, Hacke W (2004) Measuring outcomes as a function of baseline severity of ischemic stroke. Cerebrovasc Dis 18:124–129
Bath PM, Gray LJ, Collier T, Pocock S, Carpenter J, Optimising Analysis of Stroke Trials (OAST) Collaboration (2007) Can we improve the statistical analysis of stroke trials? Statistical reanalysis of functional outcomes in stroke trials. Stroke 38:1911–1915
Acknowledgments
We deeply thank the “Institut de Recherche Pierre Fabre”, particularly Dr. L Mansuy, Dr. E André, Mr. P Sokoloff and Mr. JP Caubère to have accepted to sponsor the workshop. Sponsoring of the 2012 workshop by “Institut de Recherche Pierre Fabre”.
Conflicts of interest
FC received honoraria from Servier and has consultancy for IRPFabre. SC is PI for a NIH grant, received speaker horaria from Sanofi, Pierre Fabre, Genentech, Asubic, has consultancy for GlaxoSmithKline and Pfizer. CS is PI for a Health Research Council and Neurological Foundation grant and received honoraria for examination fees. JK received payment for speakers’ bureau Bayer and Boeheringer and has consultancy for Boehringer. JCB: no disclosure. CW is PI for Deutsch Foundation G, worked as expert witness, has consultancy for Pierre Fabre. MH received payment for speakers’ bureau appointment. PA is PI for a French Ministry of Heath grant, worked as expert withness in legal assessments and received honoraria from IRPF. US: no disclosure. TM: no disclosure. JT received honoraria and has consultancy for IRPF. MV: no disclosure. SM: received honoraria from Astra Zeneca, Lundbeck, Pfizer, Servier, Pierre Fabre and has consultancy for Richter, Sanofi, Takeda. HAis PI for NINDS, Merck and Medtronic grant, received honoraria from IRPFabre.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chollet, F., Cramer, S.C., Stinear, C. et al. Pharmacological therapies in post stroke recovery: recommendations for future clinical trials. J Neurol 261, 1461–1468 (2014). https://doi.org/10.1007/s00415-013-7172-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-013-7172-z