I farmaci nelle patologie neurologiche centrali Donatella Bonaiuti

I farmaci nelle patologie neurologiche centrali Donatella Bonaiuti Medicina Fisica e Riabilitazione Azienda Ospedaliera S. Gerardo Monza

I farmaci: un prezioso aiuto per la riabilitazione « In the long run we are all dead. » « Nel lungo periodo siamo tutti morti. » (J. M. Keynes 1923) • Pharmacotherapy allows researchers to use already available drugs and develop new medications that can protect the brain from damage and facilitate and enhance recovery. • Approaches to rehabilitation allow researchers to develop new methods of facilitating recovery, enhancing compensatory strategies, and comparing techniques in the quest to determine the most effective and efficient means of rehabilitation. • Finally, to better understand the mechanisms of neuroplasticity, research is using imaging and neurophysiological techniques to document the reorganization of the brain that accompanies functional improvement. Zorowitz R. 2011 • Il paziente non può aspettare! • Noi dobbiamo accelerare il periodo di recupero e mettere in atto tutte le strategie efficaci, nei tempi utili e il più precocemente possibile.

FREQUENCY AND DETERMINANTS OF USING PHARMACOLOGICAL ENHANCEMENT IN THE CLINICAL PRACTICE OF IN-HOSPITAL STROKE REHABILITATION. Engelter ST. 2012 • • BACKGROUND: Pharmacological enhancement in stroke rehabilitation (PESR) is promising. Data about its use in clinical practice are missing. • • METHODS: In a prospective, explorative study of four rehabilitation centers, we systematically observed the frequency and determinants of using PESR in consecutive patients. PESR was defined as using agents potentially enhancing post-stroke recovery exclusively to aid rehabilitation without an established indication. • • • RESULTS: 257 (55. 4%) of 464 patients had agents potentially enhancing recovery. Selective serotonin reuptake inhibitors (SSRI) (n = 125, 26. 9%), levodopa (n = 114, 24. 6%), serotonin-noradrenaline reuptake inhibitors (SNRI) (n = 52, 11. 2%), and acetylcholinesterase inhibitors (n = 48, 10. 3%) were used most often. In PESR patients, levodopa (n = 102, 64. 1%) was used most commonly. PESR was primarily used for aphasia (36. 5%) and paresis (25. 2%). PESR patients did not differ from non-PESR patients in age, gender and stroke type. However, the utilization rates of PESR differed significantly across centers (2, 4, 38 and 55%). • • • CONCLUSION: The differences in utilization rates for PESR between centers suggest therapeutic uncertainty and indicate the need for additional studies.

I farmaci: un prezioso aiuto per la riabilitazione l ita b ar Piracetam Antidepressivi Metilfenidato Amfetamine Inibitori dell’acetilcolinesterasi neurolettici ob pine n clonidina benzodiaze fe prazosin Dopamina e Dopamino-agonisti 1. Feeney DM, Weisend MP, Kline AE. Noradrenergic pharmacotherapy, intracerebral infusion and adrenal transplantation promote functional recovery after cortical damage. J Neural Transplant Plast 1993; 4: 199 -213. 2. Walker-Batson D, Smith P, Curtis S, Unwin H, Greenlee R. Amphetamine paired with physical therapy accelerates motor recovery after stroke. Further evidence. Stroke 1995; 26: 2254 -2259. 3. Walker-Batson D, Curtis S, Natarajan R, Ford J, Dronkers N, Salmeron E, Lai J, Unwin DH. A doubleblind, placebo-controlled study of the use of amphetamine in the treatment of aphasia. Stroke 2001; 32: 2093 -2098. 4. Sonde L, Nordstrom M, Nilsson CG, Lokk J, Viitanen M. A doubleblind placebo-controlled study of the effects of amphetamine and physiotherapy after stroke. Cerebrovasc Dis 2001; 12: 253 -257. 5. Treig T, Werner C, Sachse M, Hesse S. No benefit from D-amphetamine when added to physiotherapy after stroke: a randomized, placebocontrolled study. Clin Rehabil 2003; 17: 590 -599.

Detrimental drugs 1. 2. 3. Paolucci S. Aspetti farmacologici nelle sequele dell’ictus. MR Giornale Italiano di Medicina Riabilitativa, 2014, Agosto (2): 57 -61. Goldstein LB. Potential effects of common drugs on stroke recovery. Arch Neurol 1998; 55: 454 -456. Goldstein LB. Influence of common drugs and related factors on stroke outcome. Curr Opin Neurol 1997; 10: 52 -57.

Antidepressants • • • may be involved in neurogenesis (hippocampus) decrease inflammatory cytokine production enhance production of neurotrophic factors (SSRIs) - selective serotonin reuptake inhibitors • Citalopram • Paroxetine • Fluoxetine (NRI) - norepinephrine reuptake inhibitor • Reboxetine Effects reported from the studies: - reduce dependence - reduce disability - reduce neurological impairment, anxiety and depression These findings should be taken with some caution as the studies analyzed were quite heterogeneous. 1. Ortega FJ, Jolkkonen J. Restorative therapies to enhance sensorimotor recovery following cerebral ischemia. Acta Neurobiol Exp. 2013; 73: 66– 78. 2. Paolucci S. Role, indications, and controversies of antidepressant therapy in chronic stroke patients. Eur J Phys Rehabil Med. 2013; 49: 233– 41. 3. Chollet F, Tardy J, Albucher JF, Thalamas C, Berard E, Lamy C, et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomized placebo-controlled trial. Lancet Neurol. 2011; 10: 123– 30. 4. Mead GE, Hsieh CF, Lee R, Kutlubaev MA, Claxton A, Hankey GJ, et al. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database Syst Rev. 2012; 11: CD 009286

Antidepressivi SSRIs Studi hanno dimostrato la proliferazione e la neurogenesi delle cellule ippocampali prodotte nei pazienti con esiti cronici di ictus. Aumentano i fattori neurotrofici, come il fattore di crescita vascolare endoteliale (Allaman I, 2011). Studi relativi a: fluoxetina, citalopram, reboxetina: sicuri, ma non si sa quale sia il trattamento migliore e in quali casi. Prima scelta nel dolore post stroke, seguiti dagli anticomiziali, l’effetto analgesico è indipendente dall’effetto antidepressivo , più veloce e a dosi inferiori (Linee Guida SPREAD e EFNS-European Federation of Neurological Societies). Normalizzano la funzione del nervo riducendo la plasticità disadattata causata dal dolore cronico.

Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Mead GE, Hsieh CF, Lee R, Kutlubaev MA, Claxton A, Hankey GJ, Hackett ML. Cochrane Database Syst Rev. 2012 Nov 14; 11: CD 009286. … small trials have demonstrated that SSRIs might improve recovery after stroke, even in people who are not depressed. … OBJECTIVES: To determine whether SSRIs improve recovery after stroke, and whether treatment with SSRIs was associated with adverse effects. SELECTION CRITERIA: We included randomised controlled trials that recruited stroke survivors (ischaemic or haemorrhagic) at any time within the first year. The intervention was any SSRI, given at any dose, for any period. We excluded drugs with mixed pharmacological effects. The comparator was usual care or placebo. In order to be included, trials had to collect data on at least one of our primary (dependence and disability) or secondary (impairments, depression, anxiety, quality of life, fatigue, healthcare cost, death, adverse events and leaving the trial early) outcomes. MAIN RESULTS: 56 trials of SSRI versus control, of which 52 trials (4059 participants) provided data for meta-analysis. AUTHORS' CONCLUSIONS: SSRIs appeared to improve dependence, disability, neurological impairment, anxiety and depression after stroke, but there was heterogeneity between trials and methodological limitations in a substantial proportion of the trials. Large, welldesigned trials are now needed to determine whether SSRIs should be given routinely to patients with stroke.

Review Safety of selective serotonin reuptake inhibitor treatment in recovering stroke patients Mortensen JK, Andersen G Expert Opinion on Drug Safety 2015; 14(6). Introduction: Selective serotonin reuptake inhibitors (SSRIs) are widely used for psychiatric complications after stroke. Studies have indicated additional effects, and SSRIs could potentially be used as enhancers of stroke recovery. However, beneficial effects should be weighed against potential adverse effects. In particular, the possible association with cerebrovascular events has raised concern. Areas covered: We review the literature on cerebrovascular events associated with SSRI treatment after stroke. Expert opinion: Evidence suggests that SSRIs may enhance stroke recovery. In non-stroke populations treatment has been associated with increased risk of intracerebral and intracranial hemorrhage; however the absolute risk is low. The association between SSRIs and ischemic stroke is less clear. Randomized stroke trials indicate that treatment is safe and well tolerated, and the most common side effects are often benign and transient. The trials are small however and not powered to detect potential differences in cerebrovascular events. We await several ongoing large randomized trials before SSRIs can be recommended as a routine pharmacotherapy in stroke recovery.

Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial § 59 pz flx (20 mg/die x 3 mesi) § vs 59 plb § In patients with ischaemic stroke and moderate to severe motor deficit, the early prescription of fluoxetine with physiotherapy enhanced motor recovery after 3 months. § Modulation of spontaneous brain plasticity by drugs is a promising pathway for treatment of patients with ischaemic stroke and moderate to severe motor deficit. Chollet. Lancet Neurol 10: 123 -30, 2011

Acler M, Manganotti P. Role, indications and controversies of levodopa administration in chronic stroke patients. Eur J Phys Rehabil Med. 2013 Dopaminergic stimulation appears as one of the most promising way to improve motor recovery. Subject of this paper will be the ratio underlying the clinical use of levodopa in chronic stroke patients, trying to outline the most convincing evidences about a potential role of this drug in rehabilitative strategies.

Levodopa improves procedural motor learning in chronic stroke patients. Rösser N, 2008 PARTICIPANTS: • Eighteen patients with chronic motor dysfunction because of stroke (13 men, 5 women; age range, 53 -78 y; mean time poststroke +/- SD, 3. 3+/-2. 1 y). INTERVENTION: • Patients received 3 doses of levodopa (100 mg of levodopa plus 25 mg of carbidopa) or placebo before 1 session of procedural motor learning. CONCLUSIONS: • Our results show that levodopa may improve procedural motor learning in patients with chronic stroke, in line with our hypothesis. These findings suggest that this interventional strategy in combination with customary rehabilitative treatments could significantly improve the outcome of neurorehabilitation in the chronic stage after stroke.

Dopamine (levodopa) • synaptic changes during LTP • may enhances the formation of motor memories • may improves procedural motor learning (chronic stroke) Clinical studies ranging from 2 weeks - to several years post-stroke Dopamine agonists and levodopa for the treatment of post-stroke aphasia • improvement of verbal fluency (especially patients with frontal lobe lesions) • improvement in repetition (especially patients with frontal lobe lesions) There is limited evidence to support or deny the systematic use of levodopa to enhance motor recovery after stroke. 1. Rösser N, Heuschmann P, Wersching H, Breitenstein C, Knetch S, Flöel A. Levodopa improves procedural motor learning in chronic stroke patients. Arch Phys Med Rehabil. 2008; 89: 1633– 41. 2. Acler M, Manganotti P. Role, indications and controversies of levodopa administration in chronic stroke patients. Eur J Phys Rehabil Med. 2013; 49: 243– 9. 3. Scheidtmann K, Fries W, Muller F, Koenig E. Effects of levodopa in combination with physiotherapy on functional motor recovery after stroke: a prospective, randomized, double-blind study. Lancet. 2001; 358: 787– 90. 4. Lokk J, Salman Roghani R, Delbari A. Effects of methylphenidate and/or levodopa coupled with physiotherapy on functional and motor recovery after stroke—a randomized, double-blind, placebo-controlled trial. Acta Neurol Scand. 2011; 123: 266– 73. 5. Scheidtmann K. Advances in adjuvant pharmacotherapy for motor rehabilitation: effects of levodopa. Restor Neurol Neurosci. 2004; 22: 393– 8. 6. Bhakta B, Hartley S, Holloway I, Couzens JA, Ford GA, Meads D, et al. The DARS (Dopamine Augmented Rehabilitation in Stroke) trial: protocol for a randomized controlled trial of Cocareldopa treatment in addition to routine NHS occupational and Physical therapy after stroke. Trials. 2014; 15: 316. 7. Berthier ML, Pulvermu¨ller F, Davila G, Garcia Casares N, Gutierrez A. Drug therapy of post-stroke aphasia: a review of current evidence. Neuropsychol Rev. 2011; 21: 302– 17. 8. Boissezon X, Peran P, Boysson C, De´monet JF. Pharmacotherapy of aphasia: myth or reality? Brain Lang. 2007; 102: 114– 25. 9. Senio´w J, Litwin M, Litwin T, Les´niak M, Czlonkowska A. New approach to the rehabilitation of post-stroke focal cognitive syndrome: effect of levodopa combined with speech and language therapy on functional recovery from aphasia. J Neurol Sci. 2009; 28: 214– 8. 10. Breitenstein C, Korsukewitz C, Baumga¨rtner A, Flo¨el A, Zwitserlood P, Dobel C, et al. L-Dopa does not add to the success of high-intensity language training in aphasia. Restor Neurol Neurosci. 2015; 33: 115– 20.

Levodopa • Farmaci dopaminergici: grande entusiasmo se si confrontano i risultati con quelli delle amfetamine, che presentano un ampio spettro di effetti collaterali. • Levodopa afferma il suo ruolo nella regolazione dell’eccitabilità corticale. • Vi sono studi con una singola somministrazione, con risultati inconsistenti. • Rosser (2008): la somministrazione long term migliora la capacità di acquisizione di nuovi pattern motori attraverso la pratica e l’esercizio e modula l’apprendimento. • Sembra che l’effetto dipenda dallo stadio della malattia: gli studi sostengono soprattutto l’uso nei pazienti cronici. • Acler (2013): è meglio la singola somministrazione, data la possibilità di sensibilizzazione dei neurorecettori della norepinefrina durante una stimolazione long term del sistema noradrenergico e determinata dalle concentrazioni permanenti dei farmaci.

Amphetamines • Dopamine • Norepinephrine (noradrenaline) • Serotonin Many studies with mixed results 1. 2. 3. 4. 5. 6. 7. Rösser N, Flöel A. Pharmacological enhancement of motor recovery in subacute and chronic stroke. Neurorehabilitation. 2008; 23: 95– 103. Berends HI, Nijlant JMM, Movig KLL, Van Putten MJAM, Jannink MJA, Ijzerman MJ. The clinical use of drugs influencing neurotransmitters in the brain to promote motor recovery after stroke; a Cochrane systematic review. Eur J Phys Rehabil Med. 2009; 45: 621– 30. Martinsson L, Eksborg S. Drugs for stroke recovery: the example of amphetamines. Drugs Aging. 2004; 21: 67– 79. Walker-Batson D. Amphetamine and post-stroke rehabilitation: indications and controversies. Eur J Phys Rehabil Med. 2013; 49: 251– 60. Ortega FJ, Jolkkonen J. Restorative therapies to enhance sensorimotor recovery following cerebral ischemia. Acta Neurobiol Exp. 2013; 73: 66 – 78. Gladstone DJ, Danells CJ, Armesto A, Mc. Ilroy WE, Staines WR, Graham SJ, Subacute Therapy with Amphetamine and Rehabilitation for Stroke Study Investigators, et al. Physiotherapy coupled with dextroamphetamine for rehabilitation after hemiparetic stroke: a randomized, double-blind, placebo-controlled trial. Stroke. 2006; 37: 179– 85. Schuster C, Maunz G, Lutz K, Kischka U, Sturzenegger R, Ettlin T. Dexamphetamine improves upper extremity outcome after stroke: a pilot randomized controlled trial. Neurorehabil Neural Repair. 2011; 25: 749– 55. A Cochrane review of amphetamines for improvement of stroke recovery that included 287 patients found that, based on three trials (n = 106), amphetamines did not reduce dependence or death. Based on six studies (n = 176), there was evidence of a better relative motor function change from baseline to last follow-up. 1. Berends HI, Nijlant JMM, Movig KLL, Van Putten MJAM, Jannink MJA, Ijzerman MJ. The clinical u Martinsson L, Ha°rdemark HG, Eksborg S. Amphetamines for improving recovery after stroke. Cochrane Database Syst Rev. 2007; 1: CD 002090.

• • • Drugs for stroke recovery: the example of amphetamines. Martinsson L, Eksborg S. 2004 Effects of amphetamine and/or L-dopa and physiotherapy after stroke-a blinded randomized study. Sonde L 2007 It is feasible and safe to perform larger clinical trials with this type of four-arm design. However, the lack of significant effects could be because of type, dosage, and time of drugs as well as the physical intervention strategy. Amfetamine • Fra le prime a essere studiate. • Modulazione noradrenergica • Blocca il reuptake delle catecolamine e sembra efficace nel recupero post stroke. • Promettenti risultati ma anche risultati contrastanti. • La maggior parte degli studi su dosi singole, con risultati inconsistenti, impossibilità di generalizzare gli esperimenti e ampio range di potenziali effetti collaterali.

Dolore post ictale CPSP central post stroke pain • Antidepressivi: Amitriptilina ( risultati non conclusivi : Moore NA 2015) • Antiepilettici carbamazepina ( rev cochrane 2014 Wiffen PJ) • Oppioidi • Antagonisti dei recettori NMDA (Gabapentin, Lyrica) (risultati non conclusivi Km JS 2014)

CPSP - central post stroke pain SPREAD • Antidepressivi triciclici (amitriptilina) • Antiepilettici (Lamotrigina, Gabapentin, Pregabalin) • Oppioidi (Ossicodone, Tapentadolo)

Piracetam (nootropic drug derived from GABA) • Neuroprotective effects • Facilitates cholinergic and glutamatergic transmission ü Memory and learning ü Language tests and verbal communication ü No improvement in post-stroke aphasia 1. Boissezon X, Peran P, Boysson C, De´monet JF. Pharmacotherapy of aphasia: myth or reality? Brain Lang. 2007; 102: 114– 25. 2. Engelter ST. Safety in pharmacological enhancement of stroke rehabilitation. Eur J Phys Rehabil Med. 2013; 49: 261– 7. 3. Kessler J, Thiel A, Karbe H, Heiss WD. Piracetam improves activated blood flow and facilitates rehabilitation of poststroke aphasic patients. Stroke. 2000; 31: 2112– 6. 4. Greener J, Enderby P, Whurr R. Pharmacological treatment for aphasia following stroke. Cochrane Database Syst Rev. 2001; 4: CD 000424.

Piracetam (nootropic drug derived from GABA) Piracetam given daily for 6 weeks with 30 SLT sessions of 1 -h duration in 24 subacute stroke patients was associated with improvement in spontaneous speech and syntactic/semantic structure. The improvement was correlated with an increase in brain activity in language-relevant areas as demonstrated on Positron Emission Tomography. A Cochrane review concluded that treatment with piracetam may be effective in the treatment of aphasia after stroke. 1. Boissezon X, Peran P, Boysson C, De´monet JF. Pharmacotherapy of aphasia: myth or reality? Brain Lang. 2007; 102: 114– 25. 2. Engelter ST. Safety in pharmacological enhancement of stroke rehabilitation. Eur J Phys Rehabil Med. 2013; 49: 261– 7. 3. Kessler J, Thiel A, Karbe H, Heiss WD. Piracetam improves activated blood flow and facilitates rehabilitation of poststroke aphasic patients. Stroke. 2000; 31: 2112– 6. 4. Greener J, Enderby P, Whurr R. Pharmacological treatment for aphasia following stroke. Cochrane Database Syst Rev. 2001; 4: CD 000424.

Citicoline Authors Year Patients Hazama and coll. 1980 165 Ueda and coll. 1994 Iranmanesh & Vakilian 2008 1. 2. 3. Date event Dosage Outcome > 3 months High dose of citicoline (1 g/d/8 weeks; n 5 55), low-dose citicoline (250 mg/d/8 weeks; n 5 56), placebo (n 5 54) coupled with a functional rehabilitation program A 12 -grade scale (Hemiplegia Function Test) showed that improvements by 1 or more grades in the 4 th and 8 th weeks were seen in 44. 4% and 53. 3% of the high -dose patients, in 29. 3% and 54. 8% of the low-dose treated patients, respectively. These rates of improvement were higher than the 29. 3% and 31. 8% rates in the placebo group. The difference reached statistical significance at week 8. 248 < 1 year High dose of citicoline (1 g/d/8 weeks) or placebo, coupled with a functional rehabilitation program The rates of improvement by 1 or more grades in upperextremity function were 67. 8% in the citicoline group and 55. 4% in the placebo group (P 5. 047), 32 nontraumatic very acute (<6 hours) hemorrhagic Stroke 250 mg intravenously twice a day or placebo for 14 days Muscular strength measured through physical examination before treatment and then 3 months later. The mean muscular strength in both groups before intervention was 2. 5 out of 5 in manual muscle testing. Hazama T, Hasegawa T, Ueda S, et al. Evaluation of the effect of CDP-choline on post-stroke hemiplegia employing a double -blind controlled trial. Int J Neurosci 1980; 11: 211– 25. Ueda S, Hasegawa T, Ando K, et al. Evaluation of the pharmacological effect of CDP-choline injection in post-stroke hemiplegia. Strides of Medicine 1994; 170: 297– 314. Iranmanesh F, Vakilian A. Efficiency of citicoline in increasing muscular strength of patients with nontraumatic cerebral hemorrhage: a double-blind randomized clinical trial. J Stroke Cerebrovasc Dis 2008; 17(3): 153– 5.

Sostanze promettenti per il motor learning…gli inibitori delle colinesterasi • • • Donepezil: (Aricept) Utilizzato per i sintomi di demenza nei soggetti con m. Alzheimer lieve. Lunga emivita (70 ore). In pazienti con emiparesi sin cronica 10 mg dì per tre mesi ha aumentato drammaticamente la funzione (Berthier ML 2003). Anche studi successivi hanno mostrato gli stessi risultati : aumenta l’apprendimento nei soggetti poststroke, cambiando l’input del nucleo basale (colinergico) del Meynert alla corteccia cerebrale (Nadeau SE 2004) • • Galantamina (Remynil): noto ai ricercatori sovietici dagli anni 50, inizialmente per miastenia grave, miopatie, poliomielite, success nel m Alzheimer e poi anche nella demenza vascolare. Emivita 7 ore. Negli esiti TCE utile per affaticabilità, memoria e attenzione (Tenovuo O. 2005, 2009) Rivastigmina (Exelon): utilizzata nel trattamento della malattia di Alzheimer di grado lieve o moderato dove si è dimostrata essere efficace sia nel miglioramento dei disturbi cognitivi sia nel rallentamento della progressione della malattia (Inglis F 2002). Negli esiti di stroke: 3 mg x 2 al di, accelera il recupero nel neglect (Paolucci 2003). Efficace nella demenza vascolare (Moretti R. 2008, Narasimhalu K. 2010). Nel TCE per fatica, memoria, attenzione e riduzione dell’iniziativa (Tenovuo O. 2005, 2009)

Cholinergic Agents and Memantine • memory formation, learning, and LTP (muscarinic receptor activation) • may enhance motor memory (healthy human) • may improve cognition (Alzheimer’s disease) • may improve motor recovery (donepezil + CIMT= Wolf Motor Function) A phase IIa trial with donepezil showed that donepezil within 24 h after stroke was well tolerated and about half of the patients had a good outcome at 90 days. These findings would support pursuing a phase III RCT. • Improvement in cognitive impairment in post-stroke aphasia • Rivastigmine has been evaluated for the management of unilateral spatial neglect after stroke (n = 20). Compared to the untreated patients, rivastigmine was shown to accelerate recovery, but this effect was only seen in some of the administered tests and this improvement did not translate into a better functional outcome in the Barthel Index or the Rivermead Mobility Index (RMI). • A Cochrane database review has shown that rivastigmine might be beneficial in vascular cognitive impairment. However, adverse effects caused the withdrawal of this medication in a significant proportion of patients. 1. Paolucci S, Bureca I, Multari M, Nocentini U, Matano A. An open-label pilot study of the use of rivastigmine to promote functional recovery in patients with unilateral spatial neglect due to first ischemic stroke. Func Neurol. 2010; 25: 195– 200. 2. Barrett KM, Brott TG, Brown RD Jr, Carter RE, Geske JR, Graff-Radford NR, Mayo Acute Stroke Trial for Enhancing Recovery (MASTER) Study Group, et al. Enhancing recovery after acute ischemic stroke with donepezil as an adjuvant therapy to standard medical care: results of a phase IIA clinical trial. J Stroke Cerebrovasc Dis. 2011; 20: 177– 82. 3. Birks J, Mc. Guinness B, Craig D. Rivastigmine for vascular cognitive impairment. Cochrane Database Syst Rev. 2013; 5: CD 004744.

Memantine Excitotoxicity is a significant contributor to cell death during acute stroke and is associated with over activation of NMDA glutamate receptors. Memantine is a non-competitive NMDA antagonist that is used to treat patient with Alzheimer’s disease. Memantine is thought to decrease overactivation of the NMDA glutamate receptor without disruption of its physiological activity. Preclinical studies have shown that short-term low-dose memantine: • reduced lesion volume • improved behavioral outcomes higher doses: • may increase the size of the stroke. Long-term memantine administration in mice may improve stroke outcomes in a nonneuroprotective manner, linked to increased brain-derived neurotrophic factors (BDNFs) and improved vascularization. 1. 2. 3. Berthier ML, Pulvermu¨ller F, Davila G, Garcia Casares N, Gutierrez A. Drug therapy of post-stroke aphasia: a review of current evidence. Neuropsychol Rev. 2011; 21: 302– 17. Trotman M, Vermehren P, Gibson CL, Fern R. The dichotomy of memantine treatment for ischemic stroke: dose-dependent protective and detrimental effects. J Cereb Blood Flow Metab. 2015; 35: 230– 9. Lo´pez-Valde´s H, Clarkson AN, Ao Y, Charles AC, Carmichael ST, Sofroniew MV, et al. Memantine enhances recovery from stroke. Stroke. 2014; 45: 2093– 100.

Pharmacological interventions for unilateral spatial neglect after stroke Luvizutto GJ, Bazan R, Braga GP, Resende LA, Bazan SG, El Dib R. Cochrane Database Syst. Rev 2015 Nov 6; 11. Pharmacological interventions such as dopamine and noradrenergic agonists or procholinergic treatment, have been used in people affected by USN after stroke, and effects of these treatments could provide new insights for health professionals and policy makers. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasirandomized controlled trials (quasi-RCTs) of pharmacological interventions for USN after stroke. MAIN RESULTS: We included in the review two studies with a total of 30 randomly assigned participants. We were not able to perform metaanalysis because of heterogeneity related to the different interventions evaluated between included studies. Very low-quality evidence from one trial (20 participants) comparing effects of rivastigmine plus rehabilitation versus rehabilitation …. . transdermal nicotine… One major adverse event occurred in the transdermal nicotine treatment group, and treatment was discontinued in the affected participant. None of the included trials reported data on several of the prespecified outcomes (falls, balance, depression or anxiety, poststroke fatigue, and quality of life). AUTHORS' CONCLUSIONS: The quality of the evidence from available RCTs was very low. The effectiveness and safety of pharmacological interventions for USN after stroke are therefore uncertain. Additional large RCTs are needed to evaluate these treatments.

Interventions for post-stroke fatigue. Wu S, Kutlubaev MA, Chun HY, Cowey E, Pollock A, Macleod MR, Dennis M, Keane E, Sharpe M, Mead GE. Cochrane Database Syst Rev 2015; Jul 2; 7: CD 007030 BACKGROUND: Post-stroke fatigue (PSF) is a common and distressing problem after stroke. The best ways to prevent or treat PSF are uncertain. Several different interventions can be argued to have a rational basis. OBJECTIVES: To determine whether, among people with stroke, any intervention reduces the proportion of people with fatigue, fatigue severity, or both; and to determine the effect of intervention on health-related quality of life, disability, dependency and death, and whether such intervention is cost effective. DATA COLLECTION AND ANALYSIS: Primary outcomes were severity of fatigue, or proportion of people with fatigue after treatment. We performed separate subgroup analyses for pharmacological and non-pharmacological interventions. MAIN RESULTS: included 12 trials (three from the 2008 search and nine from the 2014 search) with 703 participants. 8 trials primarily investigated the efficacy in treating PSF, of which 6 trials with seven comparisons provided data suitable for meta-analysis (5 pharmacological interventions: fluoxetine, enerion, (-)-OSU 6162, citicoline and a combination of Chinese herbs; and two non-pharmacological interventions: a None of these interventions showed any benefit on reducing PSF, which included tirilazad fatigue education programme and a mindfulness-based stress reduction programme)…. … mesylate, continuous positive airway pressure for sleep apnoea, antidepressants and a self management programme for recovery from chronic diseases. AUTHORS' CONCLUSIONS: There was insufficient evidence on the efficacy of any intervention to treat or prevent fatigue after stroke. Trials to date have been small and heterogeneous, and some have had a high risk of bias. Some of the interventions described were feasible in people with stroke, but their efficacy should be investigated in RCTs with a more robust study design and adequate sample sizes.

Clinical trials currently active (ref. period Sept. 2015) 1. Beristain X, Golombievski E. Pharmacotherapy to enhance cognitive and motor recovery following stroke. Drugs Aging 2015; 32: 765 -72.

Farmaci orali per il trattamento della spasticità I farmaci proposti per il trattamento comprendono: • Clonidina • Tizanidina • Clorpromazina • Baclofen • Benzodiazepine • Gabapentin • Carbamazepina • Fenitoina • Dantrolene • stabilire, sulla base di una accurata valutazione del paziente, se la riduzione della spasticità è veramente utile al paziente e può comportare un miglioramento significativo del deficit funzionale, della disabilità e della qualità della vita. • ricordare che i farmaci per il controllo della spasticità somministrati per os sono poco utili nel trattamento delle problematiche focali • adattare le dosi al singolo paziente per migliorare il rapporto efficacia/tolleranza • tenere conto del rischio di interazioni farmacologiche • verificare nel tempo l’efficacia del farmaco con graduale sospensione e verifica della ricomparsa/peggioramento del sintomo misurato attraverso strumenti il più possibile oggettivi • verificare il reale beneficio rispetto a obiettivi definiti (sempre di tipo funzionale o assistenziale) a fronte del riscontro di provata utilità del farmaco rispetto al contenimento del sintomo.

Trattamenti farmacologici dei disturbi comportamentali Nelle GCA epidemiologia dei disturbi che varia dall’ 11 al 50%. Sintomi negativi (apatia, ipocinesia, mutismo, perdita della spinta emotiva o dell’iniziativa) psicostimolanti, come amantadina e metilfenidato Sintomi positivi (irrequietezza, ipercinesia, impulsività, disinibizione, agitazione, aggressività) beta-bloccanti, gli antiepilettici, i neurolettici tipici e atipici, e le benzodiazepine Possibili effetti secondari: • alterazioni del tono muscolare (antipsicotici tipici) • riduzione delle funzioni attentive e cognitive (benzodiazepine, antiepilettici, antipsicotici)

abel On-l Off el -lab

Farmaci in Riabilitazione: impiego on label 1. Bonaiuti D. L’utilizzo dei farmaci in riabilitazione. MR Giornale Italiano di Medicina Riabilitativa, 2014, Agosto (2): 55 -56.

Farmaci in Riabilitazione: impiego off label antidepressivi antiparkinsoniani anti-Alzheimer 1. Paolucci S. Aspetti farmacologici nelle sequele dell’ictus. MR Giornale Italiano di Medicina Riabilitativa, 2014, Agosto (2): 57 -61.

Conclusions 1. Multiple centrally acting medications have been tried over the years to enhance neurological recovery after stroke. 2. These agents may be more effective when associated with physical therapy and speech therapy as a way to enhance experience-dependent neuroplasticity. 3. Limited evidences to support or refuse the use of these agents to improve neurological (functional) recovery. 4. The main limit: methodological disparities (time windows, population, interventions, end points, …) 5. We need: well-designed, large clinical trials with enough power to establish the usefulness of medications as adjuvants to rehabilitation before we can routinely recommend the use of these agents to enhance neurological recovery after stroke.

Safety in pharmacological enhancement of stroke rehabilitation. Engelter ST. 2013 • CONCLUSION: • The beneficial findings of some studies were not confirmed by others. • Several studies were limited by small patient populations and by narrow inclusion criteria. • There were concerns regarding safety of some agents (i. e. piracetam and amphetamines) Dopaminergic agents, Selective Serotonine Reuptake Inhibitors (SSRI), and acetylcholinesterase inhibitorsare promising candidates. Their safety and efficacy should be further investigated ; ideally in sufficiently powered large randomized controlled trials.

Still a Long Road Ahead Zorowitz R. 2011 • Much progress has been made in stroke rehabilitation over the past months and years. The physiology of recovery is being studied intensively. Animal models of recovery are aimed at establishing the means by which pharmacological and hormonal treatments to facilitate recovery can be tested in humans. Clinical interventions that engage the stroke survivor and stimulate the brain continue to be developed at an increasing pace. Imaging techniques are assisting in confirming neuroplastic changes that intensive rehabilitation causes. • However, much still needs to be done. • • • We still do not know the types, doses, and combinations of physical and pharmacological modalities that will help specific stroke survivors. We still do not know how to initiate movement or speech when the stroke survivor has none. We still do not know how to effectively prevent cerebral damage using neuroprotective agents. We still do not know how to use cellular therapies to make the “right connections” that allow regeneration of the neural system. Over the next period, researchers must set the agenda in stroke rehabilitation so that we can further decrease the mortality and morbidity that the American Stroke Association accomplished before its 2010 goal. With strong commitments from government and private funding sources alike, the world's stroke rehabilitation can take strides to decrease impairments and improve activity and participation.