Marcelo L. Berthier Unit of Cognitive Neurology and Aphasia Centro de Investigaciones Médico-Sanitarias (CIMES) University of Malaga, Spain

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1 Marcelo L. Berthier Unit of Cognitive Neurology and Aphasia Centro de Investigaciones Médico-Sanitarias (CIMES) University of Malaga, Spain

2 Combining Pharmacological and Behavioral Intervention in Early Post-stroke Aphasia Recovery Marcelo L. Berthier, M.D., Ph.D. Combining pharmacological and behavioral intervention in early and late post-stroke aphasia recovery Financial Disclosure: Grant/Research Support: SEJ , Pfizer and Lundbeck Speakers Bureau: Bayer, Pfizer, Eisai, Janssen, Novartis, Lundbeck, Grünenthal, Merz, Eli Lilly, and GlaxoSmithKline. Unlabeled/Unapproved Uses Disclosures : Use of Piracetam, Donepezil, Dexamfetamine, and Memantine in patients with acute and chronic post-stroke aphasia

3 Overview of post-stroke aphasia (PSA) Aphasia therapy and drugs in acute PSA Aphasia therapy and drugs in chronic PSA

4 Disorder of language function Prevalence: 30% (95CI: 24-36) 30% of stroke pts < 65 years 50% still alive 5 yrs post-onset Complete recovery: 21% Emotional distress in caregivers

5 Acute Weeks 1-12 (acute/subacute periods) Pharmacological blood pressure elevation (FC, midodrine, salt) Drugs (piracetam, donepezil, dexamphetaminel?) Aphasia therapy Dysphagia Depression Decompressive hemicraniectomy Days 1-2 (hyperacute period) Thrombolysis (rtpa) STROKE UNIT ADMISSION Physiotherapy (CIMT) Intensive aphasia therapy (CIAT/EL) Aphasia therapy? drugs Drugs and aphasia therapy Endarterectomy, stenting Drugs (Memantine, L-Dopa, bromocriptine) rtms, tdcs and aphasia therapy DISCHARGE Chronic Weeks (chronic period) Invasive epidural stimulation Social support, aphasia groups Week 53 years (very chronic period) Berthier ML et al. Poststroke aphasia. In: Schweizer T & MacDonald L. The Behavioral Consequences of Stroke. Springer; 2012 (in press)

6 Outcomes are superior for treated vs untreated individuals Better outcomes are achieved in post-acute period 1 Insufficient evidence exists in early acute period Randomized controlled trials (RCT) in acute aphasia are feasible 2 Two hrs/wk of SLT are effective 3 Intensive SLT (4 hrs/wk) provides similar outcomes than 2 hrs/wk Most patients do not tolerate intensive therapies (4 hrs/wk) A RCT found improvement in aphasia/communication 4 1. Robey RR. J Speech Lang Hear Res 1998; 41: : 2. Laska AC et al. Top Stroke Rehabil 2008; 15: ; 3. Bakheit AMO et al. Clin Rehabil 2007; 21: ; 4. Godecke E et al. Int J Stroke 2011 Oct 6.

7 Complications (pneumonia, cardiac decompensation) Reduced alertness or attention span Fatigability Aphasia severity ( 30% global aphasia) Lack of rehabilitation engagement - Major depression ( 30%) - Severe apathy ( the aphasic isolate )* - Pre- and post-stroke dementia ( 20%) Aging (unwillingness to participate) *De Renzi E. et al., Brain 1991; 114:

8 GABA-minergic system - piracetam, levetiracetam Catecholaminergic system - bromocriptine, L-dopa, amantadine - dexamfetamine Serotonergic system - fluvoxamine, moclobemide Cholinergic system - donepezil, physostigmine, galantamine Glutamatergic system - memantine Berthier ML & Pulvermüller F. Nat Rev Neurol 2011; 7: Berthier ML et al. Neuropsychol Rev 2011; 21:

9 Design/Methods - Double-blind, placebo controlled study - 12 pts piracetam: 2400 mg twice daily - 12 pts placebo - 6 weeks of intensive SLT Results - Placebo improved 3 language functions - Piracetam improved 6 language functions BA4 BA44 communication, semantic structure, syntactic structure, writing, Token Test and naming BA42 BA22 PET changes at week 8 Not useful in chronic aphasia (Güngör L et al. Brain Lang 2011; 117: 23-27)

10 Not useful in patients with severe apraxia of speech

11 The Mayo Acute Stroke Trial for Enhancing Recovery (MASTER) Study Group Barrett KM et al. J Stroke Cerebrovasc Dis 2011; 20: Donepezil therapy as adjuvant to standard medical care initiated within 24 hours of acute ischemic stroke is safe and well tolerated at usual doses (5 mg /day, 10 mg/day) Improvements from baseline in Trail-Making Tests and MMSE. Favorable outcomes: 15 patients (45 %) RCT are indicated Donepezil in acute post-stroke aphasia. A pilot case-control study Chen Y et al. Zhonghua Nei Ke Za Zhi 2010; 49: patients with acute PSA. Donepezil (5 mg/day) for 12 weeks Treatment group Control group P Value WAB-AQ: = % Improvement: = WAB subtests: < 0.05

12 Effective if sufficiently prolonged and/or intensive Computer-based aphasia therapy can result in improved language function (naming) Participation in group therapy may result in communicative and linguistic improvements Massed-use aphasia therapy (constraint-induced aphasia therapy) can result in improved language function

13 Mean change: WAB-AQ Western Aphasia Battery-Aphasia Quotient * ** Week 4 Week 16 Week chronic PSA patients. SLT (2 hrs/wk) * p < vs placebo; effect size (Cohen s d = 0.93) ** p < vs placebo; effect size (Cohen s d = 0.87) Endpoint (Week 16) Donepezil 10 mg/day LOCF. Berthier et al. Neurology 2006; 67:

14 Mean change: CAL Communicative Activity Log (CAL) * 26 chronic PSA patients Week 4 Week 16 Week 20 * p < vs placebo (5-mg vs 10 mg); effect size (Cohen s d = 1.1) Endpoint (Week 16) Donepezil 10 mg/day LOCF. Berthier et al. Neurology 2006; 67:

15 Neural Mechanisms Ch1-Ch2 medial pathway (OFC, subcallosal, cingulate, pericingulate and retroesplenial areas). Ch4 (nbm) lateral pathway (magnocellular nucleus accounts 70-80% of the cholinergic innervation of the cortex). Selden NR et al. Brain 1998; 121:

16 Multimodal pharmacological imaging No SLT CIAT Donepezil 5 mg/day Donepezil 10 mg/day Donepezil 10 mg/day > 1 yr. Safety/ tolerabilty Week 0 Week 8 Week 10 WAB/CAL WAB/CAL WAB/CAL 18 FDG-PET 18 FDG-PET 18 FDG-PET fmri fmri fmri VBM VBM VBM - 10 chronic PSA patients with anomia and left perisylvian involvement - SLT: speech-language therapy; CIAT: constraint-induced aphasia therapy Berthier et al. (in preparation)

17 R L LEFT R L DP vs Baseline (Wk 8 < 0) p < uncorrected DP + CIAT vs DP (Wk 10 < 8) R L RIGHT R L p < 0.05 corrected DP + CIAT vs Baseline (Wk 10 < 0) R L MEDIAL R L p < 0.05 corrected

18 Donepezil significantly improves language and communication deficits in post-stroke aphasia Greater benefits when donepezil is paired with CIAT Donepezil and CIAT induce structural plasticity in both cerebral hemispheres perhaps by promoting synaptic modification in cholinergic areas and networks

19 RCT phase Washout OL phase ** *** p = * 28 patients * p = 0.003, Cohen s d: 1.27; ** p = 0.001, Cohen s d: 1.44; *** p = 0.002, Cohen s d: 1.28

20 Improvement of aphasia severity with memantine alone Interactive effect of memantine and CIAT revealing synergistic outcome: both therapies applied together yielded greater improvement than their summed effects when applied separately Maintenance of memantine effects at long-term follow-up

21 Post-stroke aphasia is a life-disabling condition which leads to impairment of quality of life and psychosocial adjustment Preliminary data suggest that the efficacy of aphasia therapy may be augmented when it is paired with drugs Donepezil, memantine, and other agents may be promising options to treat acute/chronic aphasia

22 Patients and relatives University of Malaga Cristina Green J. Pablo Lara Carolina Higueras Miguel A. Barbancho Guadalupe Dávila Natalia García-Casares Rocío Juárez José A. Ruiz Antonio Gutiérrez Seán F. Walsh Ministerio de Educación y Ciencia, Spain I + D: SEJ MRC, Cambridge, UK and Freie Universität Berlin Friedemann Pulvermüller Pfizer-Eisai (Spain/US) M. Ángeles Rodríguez Teresa León Sonia Cabezas Josep M. Sol Mauri Francisco Hernández Marga González-Adalid Rose Fernández Lundbeck (Spain/Denmark) Marc Iniesta Rut Coll

23 Manchester, 6/8/2006