avc : nouveautés thérapeutiques stroke: new therapies...in 2014 when we are celebrating the...

AVC : nouveautés thérapeutiques

Stroke: new therapies

L’édition de cet ouvrage a été rendue possible grâce à l’Institut Servier.This publication has been made possible through an educational grant from the Institut Servier.

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La découverte et la vie

L’INSTITUT SERVIER

Fondateur : Docteur Jacques Servier

Délégué général : Madame Béatrice Guardiola

Comité scientifique

Président du Comité Scientifique : Professeur Pierre Godeau

Membres : Professeurs Michel Aubier, Jacques Barrat, Dominique Bellet, Jean-Pierre Bourdarias, Marie-Germaine Bousser, Jean-Marie Brogard, Bernard Devulder, Camille Francès, Jean-François Giudicelli, Philippe Grenier, Michel Haguenau, Pierre Lefebvre, Henri Lôo, Jean-Pierre Michel, Gérard Milhaud, Yves Pouliquen, Michel Safar, Jean-Paul Tillement, Richard Trèves, Yannis Tsouderos

La découverte et la vie

Life through Discovery

Auteurs

Pierre Godeau Président du Comité Scientifique de l’Institut Servier

Sonia Alamowitch Chef de Service de Neurologie et d’Urgences Neurovasculaires Hôpital Saint Antoine et Université Paris VI Pierre et Marie Curie Paris, France

Jean-François Pinel Service de Neurologie, CHU Pontchaillou Rennes, France

Christian Stapf Professeur de Neurologie Université Paris Diderot – Sorbonne Paris Cité

Unité Neurovasculaire et DHU Neurovasc Paris Sorbonne Service de Neurologie, APHP – Hôpital Lariboisière 2 rue Ambroise

Paré, 75475 Paris cedex 10, France Stroke Center / The Neurological Intitute Columbia University

Medical Center 710 West 168 Street, NI-615 New York, NY 10032, USA

Martin Ebinger Priv.-Doz. Dr. med. Dr. phil. Martin Ebinger Oberarzt der Klinik und Hochschulambulanz für Neurologie am

Campus Charité Mitte- Zusatzbezeichnung Notfallmedizin - Center for Stroke Research Berlin (CSB) Charité -

Universitätsmedizin Berlin | CCM Charitéplatz 1 | 10117 Berlin | Germany

François Proust Département de Neurochirurgie, Hôpital universitaire de Strasbourg, Strasbourg, France

Vianney Gilard, Département de Neurochirurgie, Hôpital universitaire de Rouen, Sophie Curey, Rouen, France Éléonore Tollard, Olivier Langlois

Isabelle Crassard Service de Neurologie, Hôpital Lariboisière, Paris, France

Philippe Marque Chef de Service de Médecine Physique et de Réadaptation, CHU Rangueil, Toulouse, France

Emmanuel Touzé Professeur de Neurologie et Inserm U919, Université de Caen Basse Normandie, CHU Côte de Nacre, Caen, France

France Woimant Service de Neurologie, Hôpital Lariboisière Paris, France

Contents


Introduction : Cerebrovascular accidentsPierre Godeau ............................................................................................................ 105

Treating acute cerebral ischaemiaSonia Alamowitch ....................................................................................................... 109

Stroke, new therapies: After twenty years of thrombolysis, what’s new?Jean-François Pinel .................................................................................................... 117

Treating Hemorrhagic strokeChristian Stapf ............................................................................................................ 130

A scanner in the ambulance? Prehospital thrombolysis and further opportunitiesMartin Ebinger ........................................................................................................... 136

Ruptured aneurysm: clips or coils?Vianney Gilard, Sophie Curey, Éléonore Tollard, Olivier Langlois, François Proust ........................................................................................................... 143

Treat cerebral venous thrombosisIsabelle Crassard ........................................................................................................ 154

What’s new in post-stroke rehabilitation?Philippe Marque ......................................................................................................... 163

Preventing cerebral infarctionEmmanuel Touzé ......................................................................................................... 173

Organising health care pathways for stroke victimsFrance Woimant .......................................................................................................... 183

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Stroke: new therapiesAVC : nouveautés thérapeutiques© 2015 Springer Science + Business Media France Sarl. Tous droits réservés

Cerebrovascular accidents

Pierre Godeau

Devoting a meeting to stroke perfectly fits into the ongoing work at Institut Servier. In fact, most of the themes over recent years have addressed the consequences of ageing, and stroke is all the more frequent with advancing age. With an incidence of 150,000 cases a year in France and a prevalence of about 500,000, stroke represents a major public health issue. Stroke often causes death or has sequelae that cause disability or loss of independence, with extended hospitalisation possible, imposing a considerable burden on health care resources.

Moreover, we cannot ignore the impact of personal loss of cognitive function— even dementia—following a stroke that was apparently mild. Reactional depression is a common consequence, along with resulting upheaval for the family unit.

Diverse factors determine prognosis, which varies hugely from one subject to another after a stroke but it is reassuring to observe that there has been significant improvement due to more timely and more effective management, especially in spe-cial Stroke Units. In addition, advances in re-education techniques have significantly attenuated the impact of sequelae. However, coordination across the country remains irregular and weak so logistical access-to-care deficiencies are far from resolved.

A precise assessment of possible solutions assumes an exact classification of cerebrovascular accidents (CVAs), which is addressed by Marie-Germaine Bousser who was the lynchpin in organising this meeting. Her question is “One cerebro-vascular accident or many”. She reminds us that CVAs can be assigned to one of five different categories with, broadly speaking, 5% due to meningeal haemorrhage, 15% to cerebral haemorrhage, 0.5% to cerebral venous thrombosis and transient ischaemic attack (TIA) or cerebral infarction accounting for 78%. The last two are grouped together because, despite their disparate evolution, they represent a continuum and both require urgent, specific management.

Of course, it is impossible to cover in just one day everything about stroke and certain topics have been deliberately left out of today’s programme, such as what to do when confronted by an embolic CVA in a young patient with patent foramen ovale (PFO). This has long been controversial with cardiologists tending to want to operate and neurologists being more reserved. Three prospective studies suggested that closing the communication is ineffective but two multicentre, meta-analytical studies published since the end of 2013 go a long way to resolving this controversy:

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the first was French [1] and compared 1,224 operated patients versus 1,226 medi-cally treated controls; the second, an American study, involved 1,150 treated patients and 1,143 controls after randomisation. Both came to the same conclusions, namely that the previous studies had lacked power and the number of accidents analysed was insufficient to allow any valid conclusions. In contrast, the two more recent studies provide solid evidence of the benefit of percutaneous PFO closure with a reduction of about one-third in the risk of recurrence. Nevertheless, a small increase in the risk of atrial fibrillation was detected in both studies and this should not be ignored. For that reason, the French Close Study is being continued and this will lead, one can hope, to the issuance of specific recommendations in coming months.

This leads to some general considerations on progress in medicine and communi-cation between different disciplines. In 2014 when we are celebrating the centenary of the Great War, it is useful to review the idea of the “Balkanisation” of medicine, which had seemed out-dated and incomprehensible to the young generations but is back in fashion. This picture points up the fragmentation of medicine into a series of competing specialisms; this is not a defect although specialisms are sometimes hostile to one another and inwardly focused on a small area of interest. Distinction should be made between this attitude and the subdivision of each specialism of organs lead-ing to the indispensable acquisition of greater knowledge and optimal adaptation of diverse modern methods to an increasingly narrow field—an irreversible trend that is essential for progress. In parallel, a return to the globalisation of medicine would seem to be indispensable and complementary—rather than counter—to hyperspe-cialisation. Thus, improving CVA management depends as much on progress on prevention and eliminating risk factors, as identified in the multicentre Interstroke Study [3], a case-control study conducted in 22 countries, which focused on factors somewhat different to the cardiac and coronary factors evaluated in the Interheart Study. In any case, progress is ensured with the development of knowledge about diabetes, improvements in metabolic and dietary issues as well as the management of hyperlipidaemia, hypertension, peripheral and coronary artery disease, systemic diseases, the fight against smoking and drinking, problems related to arrhythmia and better control of clotting function (to maintain a balance between the risks of thrombosis and haemorrhage), which can only be a subject of individual reflection and would unproductively encumber this meeting’s programme, which is already heavily loaded.

Let us just remember that managing atrial fibrillation (AF) can considerably reduce the risk of thromboembolic stroke. According to the Ecole Cardiologique de Bordeaux directed by Michel Haissaguerre, 1% of people have atrial fibrilla-tion, i.e. 600,000 people in France and 4–5 million across Europe. Even higher figures—750,000 in France—were reported recently by Jean-Marc Davy et al. at the recent European Society of Cardiology Conference in Barcelona [4] together with an

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Cerebrovascular accidents

estimate that this figure will have doubled by 2050. Assuming that atrial fibrillation underlies 20% of CVAs and that 30% of patients with AF show no symptoms, it is important to raise the consciousness of general practitioners with respect to detect-ing AF, and they ought to be ready to seek specialist advice from a cardiologist if they are in the least doubt. Without ignoring the controversies related to the latest anticoagulants, which will be resolved when a suitable, routine laboratory test is available, mention could be made of the development of obliteration techniques, which 300,000 people underwent in 2013. The indications for such techniques are growing exponentially (currently by more than 20% a year). Another way of preventing stroke and peripheral embolization related to AF involves occluding the left atrium with a nickel-titanium device that deploys like a tiny umbrella after inser-tion via a trans-septal approach with transoesophageal endoscopic guidance. This Watchman device was assessed in the prospective American multicentre PROTECT AF study: results after 3.8 years of follow-up—published this very day in JAMA [5]—demonstrate its superiority over warfarin in non-valvular AF.

Consolidation and extension of such advances will prolong life expectancy and, in particular, improve life expectancy in good health, so dear to our colleague Jean-Pierre Michel. However, we should not forget the risk—limited but growing—of vasoconstrictor-induced CVA, associated with the use of methamphetamine (not yet widespread), nasal vasoconstrictors that are of dubious therapeutic value and have proved risks and, most importantly, cocaine that multiplies the risk of CVA in people aged between 15 and 49 by a factor of 6 or 7, as reported recently by our colleagues in Baltimore [6].

I have already spoken for too long and it is time to hear from Marie-Germaine Bousser, who will quickly go over today’s programme before Michel Haguenau moderates this morning’s session. Marie-Germaine will take over in the afternoon and, at the end of the day, she will review the conclusions from this meeting, which I hope will teach us all a great deal.

References

1 Beygui F, Labombarda F, Sabatier R, et al. A meta-analysis of randomized trials comparing percutaneous closure of patent foramen ovale to medical therapy. ESC Congrès 2013; abstract 90273.

2 Renfigo-Moreno P, et al. Patent foramen ovale transcatheter closure vs. medical therapy on recurrent vascular events: a systematic review and meta-analysis of randomized controlled trials. Eur Heart J 2013;34:3342-52.

3 O’Donnell MJ, et al. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 coun-tries (the INTERSTROKE study): a case control study. Lancet 2010;376:112-23.

4 Davy JM, et al. The French screening campaign of atrial fibrillation in general practice assess-ment of predictive criteria for atrial fibrillation. ESC Congress, Barcelona 2014; abstract 4876.

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5 Reddy VY, Severt H, Halperin J, et al. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation – A randomized clinical trial. JAMA 2014;312(19):1988-98.

6 Cheng G(Y-C) et al. Illicit cocaine use and risk of ischemic stroke: the stroke prevention in young adults study. International Stroke Conference, 12-14 February 2014; abstract.

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Treating acute cerebral ischaemia

Sonia Alamowitch (Paris)

1995: birTh of Thrombolysis

In 1995, the National Institute of Neurological Disorders and Stroke (NINDS) pub-lished an article that established the evidence in favour of intravenous (IV) throm-bolysis with recombinant tissue plasminogen activator (rt-PA) in the treatment of acute-phase cerebral infarction. Compared with patients given placebo, those given IV rt-PA within three hours of the onset of symptoms of stroke had a 30% better chance of recovering without sequelae after three months [1].

Some ten years later, the ECASS 3 Study showed that IV thrombolysis is effective over a slightly longer window, up to four-and-a-half hours after the first symptoms [2].

PhysioPaThology of cerebral infarcTion: The ischaemic Penumbra

Both of the above-mentioned studies showed that timing is essential for effective IV thrombolysis. Ischaemic stroke is a dynamic phenomenon. Occlusion of the artery and the resultant interruption of the blood supply distress brain tissue in the territory supplied by the vessel concerned. In the middle of this territory, cerebral ischaemia soon causes necrosis and irreversible functional impairment. Around this lesion there is a patch called the “ischaemic penumbra”, which is compromised for several hours and which can eventually become necrotic. However, the tissue remains viable for a while and it can be rescued if the blood supply is restored in time. The aim of therapeutic intervention is therefore to try to restore blood supply to the ischaemic patch by unblocking the artery and saving the tissue in the ischaemic penumbra. The earlier this is achieved, the greater the chance of success.

Time is brain

A meta-analysis covering nearly 6,000 patients was published in 2014. This confirms that IV thrombolysis is effective up to four-and-a-half hours after the

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onset of symptoms but shows that its benefit diminishes with time: if treatment is administered within 90 minutes, four patients have to be treated to obtain neuro-logical recovery in one, whereas if treatment is started between three and four-and-a-half hours after the onset of symptoms, 14 patients will have to be treated to obtain one recovery. Beyond four-and-a-half hours, treatment is ineffective (Figure 1) [3].

Therefore, thrombolysis has to be started as soon as possible, hence the idea “time is brain”. This imperative has major consequences when it comes to how care is to be organised whenever there is any suspicion of cerebral infarction. A throm-bolysis alarm triggers mobilisation of a whole emergency system to ensure that the patient is cared for as quickly as possible both on the way to hospital and once there.

Because every minute counts, patients should be referred straight away to a spe-cialised Stroke Unit for rapid clinical assessment by an experienced neurovascular team. Emergency brain imaging confirms the diagnosis and contraindications are checked to identify patients who will benefit from thrombolysis. The aim is to take less than an hour between the patient’s arrival at the hospital and the administration

1.00

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1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5

Odd

s ra

tio

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Time to treatment (h)

Interaction: χ12 = 5.80 (p = 0.016)

4h30

Adjusted OR (95% CI)

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0–1h301h31–3h

3h01–4h304h31–6h

491421

2.84 (1.75–4.60)1.52 (1.10–2.11) 1.32 (1.09–1.61)1.22 (0.96–1.54)

figure 1. Time to treatment with alteplase and stroke outcome [3].NPT: number of patients to treat.

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of IV thrombolysis, referred to as “door-to-needle time”. This race against time necessitates tight coordination between the emergency services (ambulance, etc.) and the neurovascular team.

Major effort is required in terms of organisation at the hospital and coordination with the radiology department and the emergency services. An American study published in 2011 covering 25,504 stroke victims administered rt-PA between 2003 and 2009 showed that door-to-needle time was less than an hour for only 26.6% of patients although the trend was positive since the percentage rose from 19.5% in 2003 to 29.1% in 2009 [4].

access To TreaTmenT

Time to treatment

It is vital that patients arrive at the hospital as soon as possible. For this, they them-selves have to be able to recognise the symptoms of stroke, which is the reason for current media campaigns based on the message “If you experience sudden weakness on one side of the body, call an ambulance straight away”. This assumes that the emergency services will be able to identify stroke victims and take them straight to a Stroke Unit. Some centres in France are trying out the idea of tele-thrombolysis: if a patient is picked up by an ambulance far from any Stroke Unit, a remote neurovas-cular expert oversees the neurological work-up (tele-consultation) and evaluates the radiological results (remote image transfer); the expert can then give the green light for thrombolytic treatment with a minimum of time lost.

reconsider the contraindications

Although rt-PA has been licensed for the treatment of acute cerebral infarction since 2002 in Europe, only 5% of stroke victims receive it—the only modality with demonstrated efficacy in the acute phase. One of the great challenges for the coming years is to raise this percentage.

One possible avenue for improvement would be to review the contraindications to rt-PA. Initially, many patients were denied treatment because of a fear of cerebral bleeding.

After 20 years of experience and the accumulation of information, some of the contraindications seem to be unwarranted and reconsidering them could already increase the fraction of victims that might benefit up to 20% [5-8].

Patients over 80

Thrombolysis is not licensed for patients over 80, a population that accounts for more than 30% of strokes. These patients were excluded from the early clinical trials

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because of the increased risk of cerebral haemorrhage on antithrombotic drugs. The randomised IST3 (International Stroke Trial) Study compared IV rt-PA with placebo in 3,035 patients, including 1,617 over 80 year-olds. This showed that benefit was significantly greater in this elderly sub-population if the drug was administered within three hours of the onset of symptoms (p = 0.027) [9].

The American guidelines no longer contraindicate IV thrombolysis within three hours in patients of over 80 [10] and this should happen in Europe soon. Caution is indicated in the next part of the window—between three hours and four-and-a-half hours—which is a relative contraindication to be weighed up in the light of other relative contraindications.

Rapid improvement in symptoms

Thirty per cent of patients with a cerebral infarction who show spontaneous improvement within a matter of hours of the onset of symptoms or who only ever show mild symptoms will have significant residual disability three months later (mRankin ≥ 2). The risk of secondary deterioration is particularly high if the artery remains occluded, causing permanent damage in the ischaemic penumbra [11-13].

For this reason, if an artery is blocked, rt-PA treatment should be started even if the NIHSS score is 4 or under, and even if there is spontaneous regression of the symptoms.

Indication for IV thrombolysis: one patient in two is borderline

An excellent article published in 2013 in Brain emphasised that, while thrombolysis is indubitably indicated in a quarter of patients with a cerebral infarction in the hyper-acute phase and indubitably contraindicated in another quarter, half of all pa-tients are borderline, necessitating assessment of the benefit-risk balance for bleed-ing on the basis of a MRI-MRA scan of the tandem state of the cerebral parenchyma/vascular permeability.

The list of contraindications to thrombolysis is shrinking with time and the follow-ing ten should be amended:

– patients over 80 and under 18, – pregnant women, – epileptic seizure at the beginning of the stroke, – severe deficit (NIHSS >25) without extended infarction observed on a brain

MRI scan, – minor or improving deficit with arterial occlusion detected by imaging, – diabetes or a history of stroke, – recent, small cerebral infarction, – small, asymptomatic intracranial aneurysm, – anti-vitamin K treatment or INR <1.7,

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– cerebral infarction on waking after MRI confirmation of the time of the infarction [14].

limitations of thrombolysis

IV thrombolysis is not always effective. It often fails to achieve sustained de-occlu-sion of a large or medium-calibre artery, especially the common basilar artery, the M1 segment of the common carotid artery and the internal carotid artery. In these situations, unblocking either fails or works initially with subsequent re-occlusion (observed in 34% of cases) [15].

The artery can be unblocked by directly intervening on the intra-arterial clot in the course of arteriography (interventional neuroradiology). Both chemical throm-bolysis and mechanical thrombectomy are options. Mechanical modalities include thrombo-aspiration and removal with a stent retriever. The currently preferred thera-peutic strategy is called bridging therapy, which involves IV thrombolysis followed by a procedure to unblock the artery. This approach has been compared with IV thrombolysis in a series of randomised studies [16-18]. The first studies showed that endovascular embolectomy was no better than IV thrombolysis, but in 2014 the randomised CLEAN trial provided evidence that this therapeutic modality was of benefit. In this Dutch study, standard treatment (IV rt-PA) was compared to a com-bination of IV thrombolysis + endovascular embolectomy in 500 carefully selected patients who were treated very early (within 6 hours). The results clearly show the superiority of combined treatment (OR: 1.65; 95% CI: 1.21–1.30) but it is important to note that the median time to thrombectomy was extremely short (four-and-a-half hours) [19, 20]. More clinical trial results are expected in 2015.

oTher ways of TreaTing acuTe-Phase cerebral infarcTion

anticoagulants

Anticoagulants were in fashion thirty years ago in this indication but therapeutic trials have shown that they bring no benefit in the acute phase and have but few indications (low level of evidence).

antiplatelet drugs

Aspirin

Studies from over ten years ago showed that administering aspirin in the acute phase of cerebral infarction slightly reduced the risk of recurrence (which is known to be likely in the days after a first cerebral infarction) (OR: 0.77; 95% CI: 0.69–0.87; p ≤ 0.05) [21].

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Combinations of antiplatelet drugs

A meta-analysis of 12 randomised trials covering a total of 3,766 patients compared aspirin on its own with combinations of aspirin + dipyridamole and aspirin + clopi-dogrel. Compared with aspirin alone, combination with an antiplatelet drug slightly reduced the risk of recurrence (OR: 0.67; 95% CI: 0.49–0.93) although bitherapy was associated with a statistically insignificant rise in major bleeding events (OR: 2.09; 95% CI: 0.86–5.06) [22].

Combinations of antiplatelet drugs could be of benefit in the very early stages of a transient ischaemic attack (TIA) or a minor cerebral infarction. A placebo-controlled, randomised, double-masked study in China was conducted on 5,170 patients who had had a minor infarct or a high-risk TIA in the last 24 hours. They were given either a combination of clopidogrel + aspirin (clopidogrel at an initial daily dosage of 300 mg then 75 mg for 90 days + aspirin at a daily dosage of 75 mg for the first 21 days) or placebo + aspirin (75 mg a day for 90 days). After 90 days, the combina-tion proved more effective than aspirin alone at preventing cerebrovascular accidents (CVA) (HR: 0.68; 95% CI: 0.57–0.81; p<0.001). Moderate-to-severe bleeding was seen in 0.3% of patients in each group [23].

This study shows that, in the acute phase, bitherapy is more effective than mono-therapy at preventing CVA recurrence with a positive benefit-risk ratio. This opens up an avenue for the treatment of minor cerebral infarctions or TIAs in the acute phase. Five different therapeutic trials comparing aspirin and combinations of anti-platelet drugs in these indications are currently under way.

conclusion

By virtue of IV thrombolysis, it might now be possible to “cure” nearly 40% of patients with cerebral infarction in the stage of progressive damage. IV thromboly-sis has to be started as soon as possible: the challenge for the coming years is to arrive at treating as many patients as possible as quickly as possible. Endovascular techniques are opening up promising therapeutic perspectives and these will prob-ably constitute a new weapon in tomorrow’s arsenal for the treatment of certain patients in the acute stage. Finally, administering combinations of antiplatelet drugs in the acute stage of a minor ischaemic accident could reduce the risk of full-blown cerebral infarction.

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references

1 The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581-7.

2 Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-29.

3 Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014;384:1929-35.

4 Fonarow GC, Smith EE, Saver JL, et al. Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door-to-needle times within 60 minutes. Circulation 2011;123:750-8.

5 De Keyser J1, Gdovinová Z, Uyttenboogaart M, Vroomen PC, Luijckx GJ. Intravenous alteplase for stroke: beyond the guidelines and in particular clinical situations. Stroke 2007;38:2612-18.

6 Tong D. Are all IV thrombolysis exclusion criteria necessary? Being SMART about evidence-based medicine. Neurology 2011;76:1780-1.

7 Demaerschalk BM. Challenging the validity of imposing contraindications to thrombolysis for acute ischemic stroke. Neurology 2011;77:1862-3.

8 Wardlaw JM, Murray V, Berge E, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet 2012;379:2364-72.

9 IST-3 collaborative group, Sandercock P, Wardlaw JM, et al. The benefits and harms of intra-venous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischae-mic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012;379:2352-63.

10 Jauch EC, Saver JL, Adams HP Jr, et al. 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 2013;44:870-947.

11 Rajajee V, Kidwell C, Starkman S, et al. Early MRI and outcomes of untreated patients with mild or improving ischemic stroke. Neurology 2006;67:980-4.

12 Nedeltchev K, Schwegler B, Haefeli T, et al. Outcome of stroke with mild or rapidly improving symptoms. Stroke 2007;38:2531-5.

13 Smith WS, Schwab S. Advances in stroke: critical care and emergency medicine. Stroke 2012;43:308-9.

14 Balami JS, Hadley G, Sutherland BA, Karbalai H, Buchan AM. The exact science of stroke thrombolysis and the quiet art of patient selection. Brain 2013;136:3528-53.

15 Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology 2002;59:862-7.

16 Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368:893-903.

17 Paciaroni M, Inzitari D, Agnelli G, et al. Intravenous thrombolysis or endovascular therapy for acute ischemic stroke associated with cervical internal carotid artery occlusion: the ICARO-3 study. J Neurol 2014. [Epub ahead of print]

18 Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914-23.

19 Fransen PS, Beumer D, Berkhemer OA, et al. MR CLEAN, a multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands: study protocol for a randomized controlled trial. Trials 2014;15:343.

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20 Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11-20.

21 Sandercock P, Gubitz G, Foley P, Counsell C. Antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev 2003;(2):CD000029.

22 Geeganage CM, Diener HC, Algra A, et al. Dual or mono antiplatelet therapy for patients with acute ischemic stroke or transient ischemic attack: systematic review and meta-analysis of rand-omized controlled trials. Stroke 2012;43:1058-66.

23 Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013;369:11-19.

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Stroke, new therapies: After twenty years of thrombolysis, what’s new?

Jean-François Pinel (Rennes)

The science of the past is the best passport to the future.Christina of Sweden (XVIth Century)

Intravenous thrombolysis cannot be boiled down to injecting a dose of 0.9 mg/kg of alteplase (recombinant tissue plasminogen activator [rtPA]) to patients within four-and-a-half hours of an ischaemic stroke. The development of this treatment modality has profoundly changed not only vascular neurology but how all neurology departments operate as well as how they are structured: the impact has spread to call centres, emergency medical personnel and departments, and radiology services.

However, recommendations differ from country to country and individual prac-tices are far from uniform. Many articles have been published but the studies they report on have been subject to criticisms that could go as far as casting doubt on the validity of the indications for IV thrombolysis. Some national agencies and learned societies are considering reviewing their position.

So we need to go back over the past.

Development of Iv thrombolySIS

Going back to the publication nearly twenty years ago of the results of the NINDS Study in the New England Journal of Medicine in December 1995 [1], we can look at the very particular history of this innovation.

In the 1960s, a few articles were published on using thrombolytic agents in the treatment of stroke. In 1988, del Zoppo [2] compiled eight studies, including Abe’s last one [3], which reports on 58 patients, of whom 48 improved without bleed-ing complications or dying; this was a double-blind, multicentre study with no age restriction on patients who could be included up to 15 days after the event. The treatment given was low-dose urokinase for six days and the end point was based on global improvement after one month. This is very different from the methodology of later studies but, at the time, given that the use of such pharmacological agents

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was very young, a number of experts declared themselves optimistic about the future (Grotta [4]; Sloan [5]), referring back to the prior use of rtPA and the possibility of combining protective agents with thrombolysis. To date, studies on protective agents have all given negative results.

In the 1990s, a number of important studies were carried out, some with strepto-kinase (MAST-I 1995 [6], ASK 1996 [7], MAST-E 1996 [8]) and others with rtPA (ECASS 1995 [9], ECASS II 1998 [10]); globally, these all gave negative results. Some post-hoc analyses might show a positive trend but only at the expense of meth-odological “tweaks” (e.g. modification of the endpoints of the analysis for ECASS II). This led to open conflict and a frank split between the investigators, with two different sets of results presented for MAST-I, each coming to different conclusions [11]).

In fact, the true revolution was reported in 1993 by Langhorne. This pointed up the value of developing Stroke Units, which afford some degree of help to all admitted patients. Despite validated studies demonstrating the benefit of bringing stroke-related resources—both medical and non-medical—together in one facility, it was thrombolysis that, even though it is only relevant to a small fraction of patients, swung the argument for creating avenues that led to the implantation of Stroke Units: setting up such units that help all victims of stroke—be it ischaemic or not, treated by thrombolysis or not—would have been far more difficult without the striking image of a clot to be “dissolved”.

There had been little progress in the pharmacology of treating acute-phase ischae-mic stroke. Studies that pointed up the modest efficacy of aspirin were still under way and would not be published until two years later in 1997 (IST [12] and CAST [13]) and the value of low molecular weight heparin prescribed within 48 hours [14] had only just been published with the results of a study on 300 patients; nevertheless, efficacy vis-à-vis outcome at Month 6 was not subsequently confirmed.

It was therefore with enthusiasm that neurologists welcomed the results of the NINDS Study [1] showing the benefit of injecting rtPA within three hours of the onset of a stroke vis-à-vis functional prognosis at Month 3.

However, from the day of publication, there was extensive fundamental criticism: it was the only positive study; the main objective was changed after 291 inclusions; no efficacy was manifest in scores after 24 hours or global mortality; the differential in NIHSS score between the treated and control groups at baseline could alone account for the Month 6 Rankin score result; and finally, the “price” to be paid to prevent 11 cases of death or dependence was 6 cases of intracranial haematoma and three deaths directly attributable to treatment (which did not necessarily strike patients with the most severe strokes). Finally, the study only covered a total of 624 patients while the cohorts of our cardiologist colleagues on thrombolysis were of the order of 60,000 patients in the 1990 GISSI 2 Study [15] and 41,000 in the 1993 GUSTO Study [16] (which already compared different thrombolytic agents).

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In 1996 and 1997, several experts respected in the neurovascular community con-sidered that there was insufficient evidence to justify generalisation of this treatment modality; van Gijn [17], while welcoming the fact that a door had been opened, found it premature to conclude that intravenous thrombolysis was effective; Furlan and Kanoti [18] believed that it was too early to use intravenous thrombolysis out-side of a research framework, despite FDA approval; Caplan and Mohr [19] deemed the treatment too risky and thought that widespread implementation could lead to too many complications (some life-threatening) for minor benefit in a fraction of patients.

Nevertheless, in August 2000, the recommendations were upgraded from 2B to 1 without any supplementary results and despite many experts casting doubt on the NINDS results, particularly pointing to the problem that the fact that the placebo group had been less seriously compromised at baseline could alone account for the month 3 results (Lenzer [20]; Mann [21]).

In 2002 in the British Medical Journal, a number of experts (Warlow, Wardlaw [22]; Trotter [23]) suggested that what had been demonstrated for myocardial infarc-tion had not yet been demonstrated for the brain, that this treatment should still be restricted to a tightly targeted patient population, that the benefits seem to have been exaggerated in the literature, and that further studies were warranted.

It is against this background that the administration of rtPA within three hours of an ischaemic stroke was licensed in Europe in 2003. The French Neurovascular Society issued guidelines [24] based on the results of meta-analyses: globally, "14 deaths or dependences" prevented for every 100 treated patients notwithstanding the risk of intracranial haematoma (ten-fold higher, including 75% fatal), a "balance" of one death for four patients benefitted was recognised but globally, as long as the contraindications were applied (in particular timing of the administration of treat-ment), thrombolysis should be widely provided as long as it was administered by a well-trained team.

A number of studies were then published to try to specify contraindications and emphasise the risks of failing to adhere to the treatment protocol [25, 26], while raising the issue of whether or not to train emergency physicians [27] and already debating the special case of the elderly [28]; in this way, the practice of thrombolysis grew in France in parallel to the set-up of Stroke Units.

The tiny fraction of patients who were managing to get administered IV throm-bolysis within three hours then justified a massive effort to improve the pre-hospital phase, restructure acute-phase care in the hospital and review all the channels used for stroke victims (whether treated by thrombolysis or not). The very image of emergency neurology and neurologists was changed by these advances. Two articles [29], one of which is a pastiche that mimics an article in the NEJM [30], re-viewed the situation in 2002 and 2003 with humour, "Thrombolysis for acute stroke


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has revolutionized the psychology of the specialty and this tendency has impacted on other specialties. It remains to be seen if there is an equally beneficial effect on stroke patients. Until then, preventative treatment of hypertension, diabetes, and lifestyle modifications including smoking cessation and exercise are recommended both for neurologists and the general public".

The main reason for withholding thrombolytic treatment remained the three-hour time limit and models suggested that later administration might be effective. The ECASS III Study [31] published in 2008 answered this question by demonstrating effectiveness in terms of Rankin score on day 90 in patients treated between three hours and four-and-a-half hours after onset.

Then in 2012, the large-scale, pragmatic, international, multicentre, randomised, open-label IST-3 Study [32] on 3,035 patients set out to investigate whether the indication could be extended to all patients, whatever their age, and prolonged out to six hours. In practice, doctors excluded patients in whom they were sure of the indication or the contraindication and only borderline patients were included. Assessment was on the basis of an equivalent of the Rankin Scale and the trial was open-label in that the patient knew which treatment he or she had received. The article published in May 2012 came to the conclusion that thrombolysis within six hours improved functional prognosis whatever the patient’s age. Fully 95% of the patients included did not fulfil the criteria recommended in Europe: 53% were over 80 and 32% had a NIHSS score of 16 or over (a severe stroke). The paradigm seemed therefore to be reversed: hitherto in an emergency context, neurologists asked what the indication was in a stroke victim, but now the question had be-come in which patient who has had a stroke in the last six hours is thrombolysis contraindicated [33]?

Current SItuAtIon

The number of articles published on this subject has continued to grow in recent years, from 445 posted on PubMed in 2010 to 572, 714 and 846 in the following years, with more than 900 in 2014. Reviewing the main topics addressed between 2004 and 2014, it is clear that logistic issues are still as commonly brought up, the number of articles on imaging is declining and new subjects have emerged, includ-ing combining thrombolysis with an endovascular procedure, questions about using thrombolytic agents in patients on direct oral anticoagulants, and remote diagnosis and prescription (telemedicine). Clinical articles remain highly represented: what is the risk of administering thrombolysis to a patient wrongly diagnosed with acute-phase stroke [34-36]? Are there differences in efficacy and safety between Caucasians and Chinese subjects [37, 38]? How sensitive and specific is MRI in the acute phase [39]? What weight should be accorded to scores that predict intracranial

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haemorrhage [40]? Should thrombolysis be undertaken in a patient with a non-debilitating stroke [41]? Does thrombolysis have more impact on damage to white matter or grey matter [42]? Can imaging explain why some patients deteriorate despite treatment [43]? What are the most useful relative and absolute contraindica-tions because they vary between learned societies and from country to country [44]?

Despite 20 years of experience and an extensive literature, it has to be admitted that neurologists’ attitudes in these special emergency situations remain highly dis-parate. A survey carried out in Brittany in 2013 [45] put 28 specific scenarios—age, background factors, symptoms, relative contraindications, MRI details—to 30 neu-rologists working in a Neurovascular Unit. Consensus was only observed in 10% of these situations; in about one-third, there was a relative majority; in another third, trends could be observed; and in the last third, the different interviewees proposed entirely disparate therapeutic strategies. When thrombolysis was in question, the principal fear was exacerbation due to intracranial haemorrhage. In the course of administration, the main preoccupation was safety with efficacy only consid-ered secondarily. Modifications to practice were insidious, often due to personal experience because it is not possible to conduct rigorous trials in all situations. Contraindications were ignored because they only reflect exclusion criteria from the early studies. Neuroradiological scan-based criteria (that thrombolysis has taught us to read) have been changed to different MRI-based criteria, at least at centres that have the relevant equipment for emergencies (which also contributes to inconsistent practice).

Nevertheless, the learned societies regularly update their recommendations [46] and the Cochrane Library published summaries in 2000, 2003, 2009 and 2014 [47-50]; the latter document—of over 160 pages—covers 27 studies and a total of over 10,000 patients. Initially, in 2000, the Cochrane Collaboration did not seem to be convinced of the usefulness of intravenous thrombolysis, despite the NINDS Study published five years before. By 2014, their conclusion was more positive, “Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. This overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at 10 days, and final assessments. Age, scan modifications or severity do not constitute contraindications to this treat-ment, especially in the first four-and-a-half hours".

QueStIonS

Although it is funded by the National Health Service, the Cochrane Collaboration stipulates that its conclusions are not necessarily the same as those of that organisa-tion so, despite the methodological rigour applied for this meta-analysis, there may be room for more equivocal opinions.


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With respect to prolongation of the therapeutic window from three to four-and-a-half hours following the findings of the ECASS III Study, there is still controversy. A series of articles published in Stroke in 2014 points out that the FDA has not approved this extension and that, in the absence of new studies (which is unlikely), the question will persist [51-53]. Among the criticisms of this study, some experts note that the placebo group was in a slightly more serious condition at baseline, that patients in this group had two times as many cerebrovascular events in their past and that the percentage with intracerebral haemorrhage was particularly low in the treated group, partly due to a specific change in the definition for this study. These authors also point out that this was the only study with positive results; in other studies conducted at the same time, excess mortality led to premature termination. A project on desmoteplase [54] published in 2009 also sought to investigate prolong-ing the therapeutic window but gave negative results. This latter study attracted far less attention and it was only cited 7 times in subsequent reference titles whereas the ECASS III Study was cited 113 times.

The IST-3 Study [32] attracted more virulent criticisms and was attacked in a di-dactic article [55] that raises more methodological questions: description of skewing factors, of the principle of eligibility on the uncertainty, switch from a double-blind design to open-label after the inclusion of 276 patients, an experienced centre be-ing defined as one that administers thrombolysis just three times a year, the ordinal analysis being carried out secondarily, retrospectively changing the study’s main objective for the analysis, excess mortality in the first seven days for “cerebral” causes (p = 0.0001), and possible conflicts of interest.

Other even more critical—even virulent—opinions have been broadcast [56, 57]. Often well argued on the basis of solid evidence, these opinions affirm that the re-sults cannot be taken as positive if there is no difference in the pre-established month 6 “death and dependence” end point. They emphasise that the inclusion method must have favoured treatment in the thrombolysis arm (because patients in whom the physician concluded there was a contraindication were excluded) and it was not therefore legitimate to extrapolate the results to “all” patients in the “real world”. Moreover, the absence of any relationship between efficacy and time to administra-tion casts serious doubt on the ECASS III results, already heavily criticised. In fact, the authors of IST-3 [32] recognise that treatment between three and four-and-a-half hours seems to be harmful.

All these questions about ECASS III and to an even greater extent IST-3 shed doubt on the very issue of whether intravenous thrombolysis is really effective [58]; globally, out of the twelve relevant major studies, six showed no benefit, four had to be terminated prematurely because of adverse effects and the conclusions from the other two—despite their having been declared positive—remain highly debatable in the light of the methodology used for data analysis [59].

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Now, criticisms of the pivot 1995 NINDS Study are coming up again. A well-supported analysis with figures based on the whole original dataset concludes, after nearly fifteen years, that it is impossible to determine whether or not IV thrombolysis is effective in the treatment of ischaemic stroke [60].

Subgroup events/number of patients Adjusted odds

ratio (99% CI)

Adjusted

p value rt-PA Control

Age (years) 0.029

≤80 331/698 (47.4%) 346/719 (48.1%) 0.92 (0.67–1.26)

>80 223/817 (27.3%) 188/799 (23.5%) 1.35 (0.97–1.88)

nIhSS score 0.003

0–5 221/304 (72.7%) 232/308 (75.3%) 0.85 (0.52–1.38)

6–14 276/728 (37.9%) 268/724 (37.0%) 1.08 (0.81–1.45)

15–24 50/402 (12.4%) 33/421 (7.8%) 1.73 (0.93–3.20)

≥25 7/81 (8.6%) 1/65 (1.5%) 7.43 (0.43–129.00)

predicted probability of poor outcome at 6 month 0.009

<0.4 256/351 (72.9%) 290/377 (76.9%) 0.81 (0.52–1.26)

0.4–0.5 88/169 (52.1%) 76/160 (47.5%) 1.20 (0.68–2.13)

0.5–0.75 127/361 (35.2%) 118/357 (33.1%) 1.10 (0.73–1.65)

>0.75 83/634 (13.1%) 50/624 (8.0%) 1.73 (1.07–2.82)

time to randomisation (h) 0.613

0–3 132/431 (30.6%) 95/418 (22.7%) 1.64 (1.03–2.62)

3–4.5 182/577 (31.5%) 226/600 (37.7%) 0.73 (0.50–1.07)

>4.5 240/507 (47.3 %) 213/500 (42.6%) 1.31 (0.89–1.93)

trial phase 0.479

Blinded 34/136 (25.0%) 38/140 (27.1%) 0.91 (0.42–1.98)

Open 520/1379 (37.7%) 496/1378 (36.0%) 1.14 (0.89–1.45)

Centre with experience of thrombolysis 0.911

No 313/940 (33.3%) 309/950 (32.5%) 1.10 (0.82–1.48)

Yes 241/575(41.9%) 225/568 (39.6%) 1.14 (0.78–1.66)

total 554/1515 (36.6%) 534/1518 (35.2%) 1.12 (0.89–1.41)

figure 1. IST-3 Study. Effect of treatment on the main end point ("alive and independent", Oxford Handicap Score 0,1,2). No significant effect in the population as a whole or sub-groups; insignificant tendency to exacerbation in patients under 80, minor deficit, patients treated between 3 h and 4 h 30 [32].

0.4 1.0 3.0

Favours control Favours rt-PA


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In the August 2014 Lancet [61], Shinton re-analysed the NINDS and IST-3 results. He goes back over the old criticisms and concludes that evidence in favour of the benefit of thrombolysis remains poor. He also concludes that, although Neurovascular Units efficiently care for victims of strokes, the regulatory agencies ought to review the whole case for rtPA.

This is what Cohen and Macdonald seemed to announce in the British Medical Journal in September 2014 with respect to the UK drug agency [62]. In an August 2014 letter to the Internal Medicine Journal [63], Fatovich reports that the American College of Emergency Physicians is going to review its recommendations and that the Australian College of Emergency Medicine considers that IV thrombolysis no longer constitutes part of the standard treatment for ischaemic stroke.

It is against this background of uncertainty that we have to look after our patients, a thorny problem. Shamy [64] conducted a survey of 70 neurologists in the Canadian Province of Ontario that showed highly disparate approaches as we observed in our small survey in Brittany. Curiously, in our study, believing in a high or low benefit-to-risk ratio did not change practitioners’ prescribing behaviour in terms of indication in the 28 scenarios proposed. Medical decision-making remains an art that, if not actually mysterious is, at any rate, difficult.

0%

–40

–20

0

20

40

50% 100%

Worse

90 D

ay c

hang

e in

NIH

SSPlacebo < 90 min (n = 145)

tPA < 90 min (n = 157)

Placebo 90–180 min (n = 167)

tPA 90–180 min (n = 155)

Improved

figure 2. Data from the NINDS Study. Distribution of changes in NIHSS score between randomisation and day 90. Positive values mean an improvement in score. There is no difference between the treated group and the control group [60].

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ConCluSIon

This article aims to weigh up the possible direct benefits of intravenous thrombolysis, but it is important to recognise that the existence of this therapeutic modality has been a magnificent engine in the management of strokes in general with the development of Neurovascular Units with dedicated staff, the establishment of channels upstream and downstream, the creation of posts for neurovascular specialists, the setting of precau-tions and deadlines for all neurological patients, the development of neuroradiology with CT scanners and MRI equipment available round the clock seven days a week, the development of interventional neuroradiology, impact on teaching and research, and finally how strokes are perceived by the general public. All this can, in part, be chalked up to intravenous thrombolysis. In this sense, the positive impact of this treatment modality—which ultimately only concerns a small fraction of strokes—has gone significantly beyond simple benefit to patients who are treated with alteplase.

This review of past publications does not target the medical recommendations. Its only aim is to point out that our objectivity is very relative and that the rigour required for progress in medical science does not preclude examination of our perceptions, even our prejudices. With ischaemic strokes, it is vital to recognise the value of urgent repermeabilisation of the thrombosed vessel to prevent spread of the infarct into the penumbral area. For all that, we must remain vigilant in our read-ing of the literature and avoid making self-fulfilling prophesies. We should switch between strict adherence to clinical trial methodology (costly and difficult to repeat) and post-hoc analyses to extract information retrospectively. The journey that has brought us from the 1995 NINDS Study (approval of treatment within three hours) to the ECASS III Study (extension of the window to four-and-a-half hours) and then the IST-3 Study (recommending prolongation of the window to six hours for all patients) could also be re-examined by going back over the past. But history moves on and although the past may have a lot to teach us, we cannot wipe the slate clean and just go back to the situation before 1995.

Some questions remain. When a meta-analysis lacks rationale (disparate meth-odologies, imbalance in population size between different studies), how should positive and negative studies (NINDS, ECASS, DIAS 2) be weighed up against one another? Should changes be made to the protocol while a study is under way (NINDS, IST-3)? Should so much interest be placed in post-hoc statistical analyses that reverse hitherto negative results (IST-3; Figure 1) and positive results (NINDS; Figure 2)? How to reconcile guidelines from learned societies with those of national regulatory agencies when, according to the literature, opinions diverge (extension of IV thrombolysis to four-and-a-half hours)?

To these questions with no simple answer, it is important to add the major issue of how to apply guidelines to the treatment of a given patient—which would open


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another debate that is widely discussed in the literature. Finally, techniques evolve and since intravenous thrombolysis has been shown to have limitations, questions now focus on combining it with mechanical thrombectomy [65].

Common sense has a future.

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45 Vannier SR, T, Pinel JF. Enquete auprès des UNV bretonnes sur la thrombolysis off-label. Poster 18eme journées de la SFNV, Paris, 2013.

46 Jauch EC, et al. 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 2013;44(3):870-947.

47 Wardlaw JM, del Zoppo G, Yamaguchi T. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2000;(2):CD000213.

48 Wardlaw JM, et al. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2003;(3):CD000213.



51 Schellinger PD, Kohrmann M. 4.5-Hour time window for intravenous thrombolysis with recom-binant tissue-type plasminogen activator is established firmly. Stroke 2014;45(3):912-13.

52 Wechsler LR. The 4.5-hour time window for intravenous thrombolysis with intravenous tissue-type plasminogen activator is not firmly established. Stroke 2014;45(3):914-15.

53 Selim MH, Molina CA. Thrombolysis in the 3- to 4.5-hour window: what do ECASSkeptics want? Stroke 2014;45(3):916-17.

54 Hacke W, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol 2009;8(2):141-50.

55 Radecki RPC, YG, Press, GM. rt-PA and stroke: does IST-3 make it all clear or muddy the waters? Answers to the November 2012 Journal Club questions. Ann Emerg Med 2013;(4):489-98.

56 http://emergencymedicineireland.com/lytics-in-stroke/.57 http://www.smartem.org/podcasts/smart-thrombolytics-stroke-update.58 Hoffman JR, Cooper RJ. How is more negative evidence being used to support claims of

benefit: The curious case of the third international stroke trial (IST-3). Emerg Med Australas 2012;24(5):473-6.

59 Fatovich DM. Believing is seeing: stroke thrombolysis remains unproven after the third International Stroke Trial (IST-3). Emerg Med Australas 2012;24(5):477-9.

60 Hoffman JR, Schriger DL. A graphic reanalysis of the NINDS Trial. Ann Emerg Med 2009;54(3):329-36; 336 e1-35.

61 Shinton R. Questions about authorisation of alteplase for ischaemic stroke. Lancet 2014;384(9944):659-60.

62 Cohen D, Macdonald H. UK drug agency announces review of use of alteplase after stroke. BMJ 2014;349:g5355.

63 Fatovich DM, Brown SG. Stroke thrombolysis remains unproven: per ardua, ad astra. Intern Med J 2014;44(12a):1261-2.

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64 Shamy MC, Jaigobin CS. The complexities of acute stroke decision-making: a survey of neurolo-gists. Neurology 2013;81(13):1130-3.

65 Fransen PS, et al. MR CLEAN, a multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands: study protocol for a randomized controlled trial. Trials 2014;15:343.

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Treating Hemorrhagic stroke

Christian Stapf (Paris)

HemorrHagic sTroke: a HigH-risk sTroke Type

Stroke constitutes the third cause of mortality and the leading cause of disability in our society. Between 70% and 90% of cerebrovascular accidents (CVAs) are ischaemic. Although it is not as common, hemorrhagic stroke is a particularly serious type of CVA with a mortality rate of 30–60% within the first 30 days ( compared with 15–20% from cerebral infarct) and at times severe neurological deficit in the long term.

With the ageing of the population and, in parallel, the ever-more widespread prescription of anticoagulant drugs, the annual incidence of hemorrhagic stroke is steadily rising. The most important risk factors are arterial hypertension (60–70% of cases), heavy drinking and smoking as well as other predisposing factors such as cerebral amyloid angiopathy.

In the first 24 hours of a spontaneous hemorrhagic stroke, the volume of the hae-matoma grows by at least one-third in 38% of cases. Hematoma expansion is a factor that is associated with poor prognosis in terms of death in the acute phase as well as long-term morbidity.

TreaTmenT

any hemorrhagic stroke has an underlying cause

In the last forty years, various classification systems for ischemic stroke have been proposed to categorise cerebral infarcts according to aetiology, e.g. the Harvard Stroke Registry / NINDS Stroke Databank, the Oxford Community Stroke Project classification (OCSP), TOAST (Trial of Org 10172 in Acute Stroke Treatment) and ASCO (Atherosclerosis, Small vessel disease, Cardiac source, Other cause).

In contrast, classification systems for hemorrhagic stroke only take stock of their location (intracerebral / sub-arachnoid / intraventricular or lobar/deep) with an aetiological component limited to distinction between “primary” and “ secondary” or “hypertensive” hemorrhage. It is important to emphasise that hemorrhagic stroke always has an underlying structural cause so, in effect, all of them are secondary.

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In addition, the term “hypertensive hemorrhage” mixes up risk factor and cause: a risk factor can predispose to or trigger an underlying cause but it does not constitute a structural cause of the bleeding. In consequence, treating a case of hemorrhagic stroke necessarily involves identifying the underlying problem by means of a scru-pulous etiologic investigation.

Various vascular pathologies can cause cerebral bleeding, involving arteries (cer-ebral microangiopathy, aneurysm, reversible cerebral vasoconstriction syndrome, moya-moya disease, etc.), veins (cerebral venous thrombosis, cerebral cavernoma, etc.) or where the two systems meet (arteriovenous malformation, dural fistula). Bleeding can also be a complication of some other underlying problem like a cerebral infarction (through secondary hemorrhagic transformation), neoplasia or systemic disease (impaired clotting function, endocarditis, etc.) (Table 1) [1].

Table 1. Acute hemorrhagic stroke: etiologic sub-groups [1]

microangiopathy Arteriolosclerosis / lipohyalinosis Amyloid angiopathy GeneticVascular malformation Arteriovenous malformation Cerebral cavernous malformationintracranial aneurysmVenous disease Cerebral venous thrombosis Dural fistulareversible cerebral vasoconstriction syndrome

moya-moya diseaseinflammation Vasculitis Mycotic aneurysmneoplasia Brain tumour Cerebral metastasisHemostatic disorder Genetic Acquired/iatrogenicDrug-inducedHemorrhagic infarctionHead trauma

Towards a classification system for hemorrhagic stroke

Modern diagnostic imaging techniques include CT scanning and CT angiography, brain MRI and MRA and cerebral arteriography with arterial catheterisation.

The sensitivity and specificity of the various radiological techniques are currently being assessed in a series of ongoing studies. In collaboration with our colleague, Professor Charlotte Cordonnier (CHRU Lille), we are currently working with a num-ber of European centres on a first etiologic classification system and we are trying to define diagnostic criteria to establish an aetiology as Possible, Probable or Definite.

ranking imaging techniques

According to data derived from a prospective cohort of 152 patients, CT scan-ning allowed us to make an etiologic diagnosis in 3% of patients, MRI/MRA in

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63% and arteriography in 6%, i.e. a total of 72% precise etiologic diagnoses in cases of hemorrhagic stroke traditionally classified as either “Primary” or “Hypertensive.”

It is important to emphasise that 21% of these diagnoses immediately impacted on how the patients were being managed.

In patients who could not originally be diagnosed etiologically, imaging exami-nations were repeated 3–4 months later after the hematoma had been re-absorbed (because it can mask the cause of the bleeding). For example, even though the initial arteriography might have looked normal, the same examination after re-ab-sorption of the hematoma could reveal an arteriovenous malformation or a cerebral cavernoma—which could be treated and cured.

To summarize, our practice ought to be conditioned by the fact that all hemorrhages are secondary and the idea of ”primary” or “hypertensive” hemorrhage should be avoided. The purpose of imaging is to visualise the cause of the bleeding. Some etiologic diagnoses need to be made immediately because they will affect treatment strategy in the acute phase, including aneurysm, haemorrhagic infarction, venous disease and systemic disease. In addition, any identified cause will have long-term implications such as repair of the lesion if that is possible (including aneurysm, arteriovenous malformation, cavernoma and dural fistula) and control of risk factors (arterial hypertension, smoking, etc.).

Towards targeted treatment

Spot-sign

Most patients will be diagnosed with small artery disease. These patients are at risk of rapid exacerbation through the following cascade of events: growth in volume (mass effect), ventricular inundation, secondary hydrocephalus, intracra-nial hypertension and, in the worst case, cerebral herniation leading to death of the patient. It is vital therefore to interrupt this process. A radiological phenomenon called spot sign is currently being assessed as a predictor of hemorrhagic expansion [2]. A multicentre, observational study published in 2012 on 268 patients with a hemorrhagic stroke reported finding the spot sign in the acute hematomas of one quarter of patients (23%). The presence of this spot sign was predictive of hematoma expansion with a sensitivity of 51% and a specificity of 85%. Mortality at 3 months was 43.4% in patients with the spot sign compared with 19.6% in those without it (HR: 2.4, 95% Confidence Interval: 1.4–4.0; p = 0.002) [3].

Management

Addressing risk factors

Involvement of small arteries in the brain is often due to the effect of vascular risk factors that have caused damage to arterial walls, ultimately leading to rupture.

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Controlling such risk factors, especially hypertension, is essential to prevent further damage to small arteries and bleeding complications. It should be borne in mind that reducing systolic blood pressure by 10 mmHg or diastolic pressure by 5 mmHg prevents 80% of Hemorrhagic strokes in five years.

Stop extravasation and expansion of the haematoma

– Local haemostasisPromising results have been obtained with very early administration (within four hours of the onset of symptoms) of a coagulation factor, namely recom-binant activated factor VII (FVIIa), in a randomised phase II study evaluating efficacy and safety. Cerebral haematoma volume grew markedly less in the treated group than in the placebo group with significant efficacy on clinical criteria of dependence and mortality [4].Nevertheless, a phase III confirmatory study failed to detect any positive effect on clinical outcome [5].Other hemostatic treatments are currently undergoing evaluation, including the transfusion of platelets to victims of an acute Hemorrhagic stroke while on anti-platelet therapy (the PATCH Study). Until the results are available, haemostatic treatment cannot be recommended in the treatment of acute Hemorrhagic stroke.

– Neurosurgical evacuation Hematomas are surgically drained on a case-by-case basis without any scientific evidence on any of the techniques used: evacuation via an open craniotomy or by endoscope with stereotactic guidance. The international STICH (Surgical Trial in IntraHemorrhagic stroke) Study included more than 1,000 patients and com-pared early surgical evacuation with conservative medical care within 72 hours of a spontaneous supratentorial hemorrhagic stroke (with no underlying vessel malformation). The choice of surgical technique was left up to the neurosur-geon, most of whom opted for craniotomy (77%). No difference was observed between surgery and medical treatment of supratentorial hemorrhagic stroke (all localisations) in terms of either mortality or dependence after six months [6].Similarly, the STICH II Study (n = 597 patients who developed a lobar hae-matoma in the preceding 12 hours) did not show any difference in morbidity or mortality between care including surgery and care without it. A study is currently under way to investigate a minimally invasive surgical technique to drain the hematoma and an evaluation of decompressive hemicraniotomy after a supratentorial hemorrhage is being prepared [7].

– Antihypertensive treatmentA number of uncontrolled studies have pointed to a correlation between blood pressure and neurological deterioration in Stroke Unit patients after a

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spontaneous intracerebral hemorrhage. In the randomised, pilot INTERACT (Intensive Blood Pressure Reduction in Acute Hemorrhagic stroke Trial) pilot study on 404 patients given antihypertensive treatment within 6 hours of the onset of the symptoms of hemorrhagic stroke (target systolic blood pressure <140 mmHg), hematoma volume grew less than in the control group [8].Finally, the randomised, international INTERACT 2 trial involving 2,839 pa-tients showed a strong trend to improvement in morbidity and mortality (Odds Ratio 0.87; 95% CI: 0.75–1.01; p = 0.006) in patients treated to lower systolic blood pressure straight away (target <140 mmHg in less than 60 minutes) and significant improvement in neurological outcome as measured on the Rankin scale after three months (Odds Ratio 0.87; 95% CI: 0.77–1.00; p = 0.04) [9].While we are still waiting for the results of another randomised trial, current guidelines for acute Hemorrhagic stroke recommend immediately administering antihypertensive drugs to bring systolic blood pressure down below 140 mmHg in less than 40 minutes [10].

practical implications

– It is worth bearing in mind that any hemorrhagic stroke has an underlying structural cause that needs to be identified in an appropriate investigation. Risk factors may predispose to or affect certain causes but it is important not to mix up causes and risk factors. Therefore, ideas like “primary” and “ hypertensive” hemorrhage ought to be avoided.

– The purpose of the diagnostic work-up is to determine the aetiology of the bleeding and plan targeted therapy. The spot sign may be predictive of haema-toma expansion.

– Neither local haemostasis nor surgical drainage have been shown to be effective. – In contrast, it is now clear that antihypertensive treatment in the acute phase

improves morbidity and mortality. This should be intense (IV administration of a bolus dose followed by continuous infusion) to bring systolic blood pressure down below 140 mmHg within one hour. Throughout administration, blood pressure should be closely monitored (with blood pressure measured every 15 minutes during the first hour). All members of the care-providing team should be familiar with the therapeutic protocol. As with thrombolysis, time is key, and delays between imaging and the introduction of antihypertensive treatment should be minimised. In this situation, team spirit is crucial.

– This treatment should be administered in a dedicated Stroke Unit and blood pressure should be kept under control on a sustained basis: for the first 24 hours (acute phase benefits <24 hours) and then the next few days (post-acute phase benefit <7 days) and finally throughout the patient’s life (long-term benefit: on stroke prevention).

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– The AHA/ASA is in the process of updating its guidelines. European guidelines (ESO) were published in 2014 [11]. A French committee (SFNV) recently convened with a view to issuing recommendations.

references

1 Al-Shahi Salman R1, Labovitz DL, Stapf C. Spontaneous intracerebral hemorrhage. BMJ 2009; 339:b2586.

2 Wada R, Aviv RI, Fox AJ, et al. CT angiography “spot sign” predicts hematoma expansion in acute intracerebral hemorrhage. Stroke 2007;38:1257-62.

3 Demchuk AM, Dowlatshahi D, Rodriguez-Luna D, et al. Prediction of haematoma growth and outcome in patients with intraHemorrhagic stroke using the CT-angiography spot sign (PREDICT): a prospective observational study. Lancet Neurol 2012;11:307-14.

4 Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777-85.

5 Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2008;358:2127-37.

6 Mendelow AD, Gregson BA, Fernandes HM, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in IntraHemorrhagic stroke (STICH): a randomised trial. Lancet 2005;365:387-97.

7 Mendelow AD, Gregson BA, Rowan EN, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet 2013;382:397-408.

8 Anderson CS, Huang Y, Arima H, et al. Effects of early intensive blood pressure-lowering treatment on the growth of hematoma and perihematomal edema in acute intracerebral hemorrhage: the Intensive Blood Pressure Reduction in Acute Hemorrhagic stroke Trial (INTERACT). Stroke 2010;41:307-12.

9 Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013;368:2355-65.

10 Manning L, Hirakawa Y, Arima H, et al. Blood pressure variability and outcome after acute intraHemorrhagic stroke: a post-hoc analysis of INTERACT2, a randomised controlled trial. Lancet Neurol 2014;13:364-73.

11 Steiner T, Al-Shahi Salman R, Beer R, et al. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke 2014;9:840-55.

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A scanner in the ambulance? Prehospital thrombolysis and further opportunities

Martin Ebinger (Berlin)

IntroductIon

Stroke is a leading cause of death and disability worldwide [1]. Thrombolysis with intravenous tissue plasminogen activator (tPA) is a widely available, evidence-based and licensed treatment that reduces the risk of permanent disability after ischaemic stroke [2, 3]. However, the effects of thrombolysis are time-dependent [4]. With every minute’s treatment delay, chances of a good outcome become less likely [5-7]. Therefore, tPA should be administered as early as possible after symptom onset. Ideally, treatment is started straight away at the first encounter with the patient, i.e. when the ambulance arrives to pick up the patient for hospital admission. Since clini-cal features cannot be used in order to distinguish reliably between ischaemic and haemorrhagic stroke, a computed tomography (CT) scan is required prior to treatment [8]. Furthermore, tPA treatment is associated with the feared risk of symptomatic intracerebral haemorrhage (sICH). This requires clinical expertise when choosing this treatment option. A neurologist experienced in acute stroke treatment, able to deal adequately with possibly occurring complications and trained in emergency medicine combines all the necessary expertise in a prehospital setting. In 2012, Silke Walter, MD, and her colleagues from Homburg, Saarland, Germany, were the first to report tPA treatments using a so-called mobile stroke unit, an ambulance equipped with a CT scanner and a point-of-care laboratory. These pioneers from Prof. Klaus Fassbender’s group demonstrated excellent time savings compared to regular care [9].

PrehosPItAl thrombolysIs

Prehospital thrombolysis in a specialized stroke ambulance is feasible, safe and reduces time from alarm to treatment. This was recently shown in a prospective study, called PHANTOM-S [10]. In this study, which was designed and supervised

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by Prof. Heinrich Audebert from the Charité, Germany, weeks were randomized in blocks to either STEMO availability or regular care. STEMO is the stroke emergency mobile (Figure 1), an ambulance equipped with CT, point-of-care laboratory and telemedicine connection. It was staffed with a specialized team. The team consisted of an emergency trained neurologist, a radiology technician and a paramedic. By means of UMTS, STEMO is connected to a neuroradiologist on call. At the Berlin dispatch centre, run by the Berlin Fire Department, a previously developed and validated algorithm for stroke recognition was used during emergency calls [11]. If the dispatcher suspected a stroke within 4 hours of symptom onset or of unknown symptom onset, the stroke alarm was activated. This led to the deployment of STEMO during STEMO weeks and to the deployment of a regular ambulance dur-ing control weeks. Since there was only one STEMO within the predefined Berlin catchment area (including roughly 1 million inhabitants) and simultaneous stroke alarms occurred, STEMO could not be deployed for all strokes during STEMO weeks (n=3,213 with documentation during 46 weeks). As a matter of fact, 44% of all cases could not be treated by the STEMO team during STEMO weeks. During control weeks, there were 2969 stroke alarms with available documentation. For the

1

Figure 1. The stroke emergency mobile (STEMO) in front of the Brandenburg Gate in Berlin, Germany (by sbdsgn.de; courtesy of MEYTEC GmbH, Werneuchen, Germany).

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primary end-point of the study, i.e. alarm to treatment times, a 25 minute time reduc-tion was observed (STEMO deployment: 51.8, 95% CI: 49.0–54.6 min vs. control weeks: 76.3, 95% CI: 73.2–79.3 min). In adjusted analyses STEMO deployment did not entail an increased risk of secondary intracerebral haemorrhage (OR 0.42, 95% CI: 0.18–1.03), or mortality (within 7 days: 0.76, 95% CI: 0.31–1.82; within 90 days: 1.02, 95% CI: 0.58–1.82). The PHANTOM-S study was not powered to detect effects on functional outcome [12].

In a subsequently published sub-study, the effects of thrombolysis within the first 60 minutes of symptom onset were assessed. The so-called golden hour thrombolysis occurred about 10 times more often after STEMO deployment compared to regular care (10.1% vs. 1.1% of all ischaemic strokes, p<0.01; Figure 2). Among the patients receiving tPA, there was still a 6-fold increase in the proportion of golden hour thrombolysis after STEMO deployment compared to regular care (31% vs 4.9%; p<0.01). Comparing all patients who received golden hour thrombolysis to patients treated in later time windows there was no statistically significant difference in terms of secondary intracerebral haemorrhage, or mortality within 7 or 90 days. However, analyses adjusted for age, sex, atrial fibrillation and NIHSS, revealed an OR of 1.93 (95% CI: 1.09–3.41) for discharge to home after STEMO deployment [13]. While this is only the result of an exploratory analysis using a surrogate outcome parameter (discharge home) it fits well into the well-established association between earlier treatment and better outcomes [4, 5, 7]. Future studies powered for functional out-come differences between groups are necessary in order to demonstrate the effects of prehospital thrombolysis within and outside the golden hour on functional outcome.

02468

101214

%16

0–60 61–120 121–180 181–240 241–270Minutes

STEMO care

Conventional care

Figure 2. Proportion of patients with ischaemic stroke receiving thrombolysis in different time intervals. Note the almost 10-fold difference between STEMO care and conventional care within the first hour, the so-called golden hour [19].

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trIAge

Triage is an important preclinical task ensuring that patients receive the optimal treatment while at the same time resources are used wisely. Usually, patients are admitted to the nearest hospital. Ideally, they get admitted to the nearest adequate hospital. Adequate, in the case of an acute ischaemic stroke, is a hospital with a Stroke Unit. In the case of haemorrhagic stroke, a hospital with a department of neurosurgery may be desirable and, increasingly, patients with blockage of major arteries are transferred to centres with the ability to perform mechanical recanaliza-tion after the start of Iv tPA.

The STEMO concept enhances the recognition rate of stroke, facilitates admission to the adequate hospital in a given patient and allows for the start of time-critical treatment during transportation. For instance, patients with intracerebral bleeds on oral anticoagulation can be reliably diagnosed in the prehospital setting and reversal of anticoagulation can be started before hospital arrival. Aggressive blood pressure lowering can be achieved during transportation. Results from the INTERACT2 trial suggest that earlier treatment again provides the greatest benefit in haemorrhagic stroke [14]. If CT-angiography aboard the STEMO reveals occlusion of large arteries (e.g. ICA or M1) the patient can be brought to the next available catheter lab for mechanical recanalization after initiation of tPA treatment. Matthias Wendt, MD, one of the STEMO emergency trained neurologists, recently formally investigated the effects of STEMO deployment on hospital admission. Comparing admissions after STEMO deployment to admissions during regular care, he found significant differences for admissions of patients with ischaemic strokes to hospitals with Stroke Units and for admissions of patients with haemorrhagic strokes to hospitals with neurosurgery departments in favour of STEMO deployment (Wendt et al., submitted).

A PrehosPItAl reseArch PlAtForm

STEMO is more than a tool to speed up thrombolysis, to gain insights into the ef-fects of golden hour thrombolysis or to improve patient triage. It is an ideal research platform. Several neuroprotective agents have failed the acid test of clinical trials so far. One of the reasons for this may be the delayed use of potentially therapeutic agents compared to the successful application in animal studies. STEMO could offer the opportunity of a very early encounter between acute stroke patients and experts allowing the start of experimental agents. Although with a neutral outcome, the FAST-Mag trial by Prof. Jeff Saver from UCLA gave an excellent example of how a large scale prehospital neuroprotective trial can be performed [15, 16]. Using ambulances equipped with CT scanners may increase the power of such studies by selecting appropriate patients based on imaging criteria in the future. Apart from

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testing new drugs or interventions like early cooling, STEMO has already started to shed light on some biomarkers that may or may not be useful to support the diagnosis of stroke. For example, Michal Rozanski, another neurologist aboard the Berlin STEMO, recently investigated the sensitivity and specificity of glial fibrillary acidic protein (GFAP) to differentiate between ischaemic strokes and intracerebral haemorrhage. While preliminary data suggested that sensitivity was rather low, GFAP levels above 0.29 ng/ml were reliably indicative of haemorrhagic strokes [17]. Copeptin, the N-terminal end of vasopressin, on the other hand, did not turn out to be helpful when differentiating between ischaemic stroke and stroke mim-ics, vascular and non-vascular emergencies or later and earlier time windows after stroke (Wendt, submitted).

cost eFFectIveness

New developments always come at a certain price and it is more than justified to ask what costs the prehospital thrombolysis concepts create. These costs then have to be weighed against the expected and actual benefits achieved. Hitherto, cost effective-ness analyses of the STEMO concept had to rely on extrapolations. Nevertheless, first t analyses have been performed and suggest a reasonable incremental cost effectiveness ratio (ICER) for each quality adjusted life year (QALY) gained by STEMO. These analyses were performed in cooperation with a Danish research group from Odense and published recently by Dorte Gyrd-Hansen et al. [18]. Based on the collection of all available receipts, the net annual cost of the STEMO concept was €963,954. Using data from randomized placebo controlled trials of tPA, the numbers needed to treat in order to prevent disability were used to calculate the effect prehospital thrombolysis could have on functional outcome. According to this approach, the higher frequency of thrombolysis and the higher proportion of patients treated in early time windows could avoid 18 cases of disability per year. These 18 cases amount to 29.7 QALYs gained and this equates to an ICER of €32,456 per QALY. Whether or not this is an acceptable price to pay is beyond the scope of medical research and depends on the willingness of society to pay for the prevention of disability. This political decision is also subject to the availability of competing alternative countermeasures also requiring funding. In general, however, ICERs ranging below US$50,000–100,000 (in the USA) or £30,000 (in the UK) seem ac-ceptable in many western societies. Since the so far only cost-effectiveness analysis of the prehospital thrombolysis concept is based on extrapolations (first, number of avoided disabilities and, second, the equation of 1.77 QALY gain for every avoided disability) future studies are necessary to create a robust ground for decision makers. These studies may not only take into account the effects of prehospital thrombolysis

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but also treatments of other conditions such as blood pressure lowering in the case of haemorrhagic stroke, as Prof. Marie-Germaine Bousser pointed out during the Colloque de L’Institut Servier, AvC: nouveautés thérapeutiques, in Paris, France, 20 November 2014.

conclusIon

Prehospital thrombolysis in ambulances equipped with a CT scanner is feasible, safe, reduces time from alarm to treatment, increases the number of thrombolysis, and enhances the chances of golden hour thrombolysis. Imaging in the ambulance allows for tailored admission to different hospitals and specific emergency treat-ment during transport. The STEMO is an attractive “front line” research platform and from a societal point of view may be a wise investment. However, the field of prehospital thrombolysis is still evolving and future studies are needed to prove ben-efit in terms of avoided disability and cost-effectiveness. Integration of prehospital thrombolysis concepts into regular care requires accompanying research to answer these questions and to identify the optimal use of specialized ambulances for stroke treatment. Around the globe, researchers are preparing different projects in a variety of settings. In Paris, France, for example, Guillaume Turc, MD, and Prof. Jean-Louis Mas are applying for funding in order to start their prehospital thrombolysis project, called ASPHALT (Acute stroke: prehospital vs. inhospital intravenous thromboly-sis)—what a great acronym to pave the road for improved stroke treatment!

references

1 Feigin vL, Forouzanfar MH, Krishnamurthi R, et al. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet 2014;383(9913):245-54.

2 The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333(24):1581-7.

3 Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359(13):1317-29.

4 Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014;384(29):1929–1935.

5 Saver JL, Fonarow GC, Smith EE, et al. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke. JAMA 2013;309(23):2480-8.

6 Saver JL. Time is brain-quantified. Stroke 2006;37(1):263-6.7 Meretoja A, Keshtkaran M, Saver JL, et al. Stroke thrombolysis: save a minute, save a day. Stroke

2014;45(4):1053-8.8 Runchey S, McGee S. Does this patient have a hemorrhagic stroke?: clinical findings distinguishing

hemorrhagic stroke from ischemic stroke. JAMA 2010;303(22):2280-6.

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9 Walter S, Kostopoulos P, Haass A, et al. Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial. Lancet Neurol 2012;11(5):397-404.

10 Ebinger M, Rozanski M, Waldschmidt C, et al. PHANTOM-S: the prehospital acute neurological therapy and optimization of medical care in stroke patients – study. Int J Stroke 2012;7(4):348-53.

11 Krebes S, Ebinger M, Baumann AM, et al. Development and validation of a dispatcher identifica-tion algorithm for stroke emergencies. Stroke 2012;43(3):776-81.

12 Ebinger M, Winter B, Wendt M, et al. Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: a randomized clinical trial. JAMA 2014;311(16):1622-31.

13 Ebinger M, Wendt M, Rozanski M, et al. Golden hour-thrombolysis by starting treatment before hospital arrival: the Pre-Hospital Acute Neurological Treatment and Optimization of Medical care in Stroke study (PHANTOM-S). Stroke 2014;45(Suppl 1):A104.

14 Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013;368(25):2355-65.

15 Saver JL, Starkman S, Eckstein M, et al. Methodology of the Field Administration of Stroke Therapy – Magnesium (FAST-MAG) phase 3 trial: Part 1 – rationale and general methods. Int J Stroke 2014;9(2):215-19.

16 Saver JL, Starkman S, Eckstein M, et al. Methodology of the Field Administration of Stroke Therapy – Magnesium (FAST-MAG) phase 3 trial: Part 2 – prehospital study methods. Int J Stroke 2014;9(2):220-5.

17 Rozanski M, Waldschmidt C, Kunz A, et al. Plasma Glial Fibrillary Acidic Protein(GFAP) for differentiation between hemorrhagic and ischemic strokes in pre-hospital stroke care. 9th World Stoke Congress, 22-25 October 2014, Poster 399.

18 Gyrd-Hansen D, Olsen KR, Bollweg K, et al. Cost-Effectiveness of Pre-hospital Thrombolysis. Results of the Pre-hospital Acute Neurological Treatment and Optimization of Medical care in Stroke (PHANTOM-S) Study. accepted. Neurology 2015;84(11):1090-1097.

19 Ebinger M, Kunz A, Wendt M, et al. Effects of Golden Hour Thrombolysis: a Prehospital Acute Neurological Treatment and Optimization of Medical Care in Stroke (PHANTOM-S) substudy. JAMA Neurol 2015;72(1):25-30.

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Ruptured aneurysm: clips or coils?

Vianney Gilard1, Sophie Curey1, Éléonore Tollard1, Olivier Langlois1, François Proust2 (1Rouen, 2Strasbourg)

IntRoductIon

In the past three decades, the field of endovascular treatment was largely ex-panded across the domain of neurovascular pathology [1]. The initial results of the International Study Aneurysm Trial (ISAT) confirm the predominant role of endo-vascular coiling in treating ruptured intracranial (IC) aneurysms [2, 3]. As a result of this, different societies across the world have established their position state-ments, favouring a concerted discussion between interventionists and neurosurgeons in reaching a decision [4-8]. The last publication from ISAT [9], about the late risk of recurrent subarachnoid haemorrhage (SAH), strengthens support for these new strategies with a high level of proof. This shift in medical practice leads to serious consequences for the vascular neurosurgeon but also for neurosurgery as whole.

A better understanding of the precise place of vascular neurosurgery in the field of IC aneurysm treatment is crucial to develop strategies with regard to preserving surgical expertise in our departments and to determining the course of scholarship. The objective of this paper is to analyse the lessons and limits of ISAT in order to de-termine the place of microsurgical clipping in the treatment of cerebral aneurysms.

What aRe the lessons fRom the RandomIzed studIes?

The comparative treatment of ruptured IC aneurysms has been analysed in four randomized studies [3, 9-11], ISAT being the predominant international study. The objective of all studies was to determine the safer procedures between endovascular coiling and microsurgical clipping.

dependency and death after treatment

After a pilot phase, the ISAT cohort published for the first time in 2002 [2], between May 1997 and April 2002, was composed of 2,143 patients in good clinical condi-tion at admission (94% in WFNS grade 1-3) with small ruptured aneurysms of the

Vianney Gilard, Sophie Curey, Éléonore Tollard, Olivier Langlois, François Proust

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anterior circulation (97.3%), randomly assigned to an endovascular group (n = 1,073) and microsurgical group (n = 1,070). This trial, which recruited 2,500 patients to achieve a statistical power of 90% at a 0.01% level of significance to detect a 25% improvement in outcome at 1 year, was interrupted at a planned interim analysis. The definitive results were a reduction of the relative risk of dependence or death at 1 year of 23.9% (p<0.001) and an absolute risk reduction of 7.4% after endovascular treatment by comparison with microsurgical clipping. The case fatalities at 1 year were 7% and 7.9% among patients allocated to endovascular and microsurgical treatment. After a mean follow-up of 9 years of the ISAT cohort [9], the mortality rate at 5 years was significantly reduced in the coiling cohort, and the proportion of independent patients was similar in both arms. The last ISAT results addressing long-term follow-up (alive at 10 years), published in 2014 [12], reported that the probability of being alive with a good outcome (mRS 0–2) compared with death or dependence was significantly better for the group assigned to endovascular treat-ment than those assigned to neurosurgical clipping.

More recently, the Barrow Ruptured Aneurysm Trial (BRAT) conducted by experts in cerebrovascular neurosurgery compared 288 patients assigned to clip exclusion with 233 patients assigned to coil embolization [11]. At 1 year, an absolute risk reduction of 10.7% (p = 0.03) was observed after endovascular occlusion in com-parison with microsurgical clipping. At 3 years, this absolute risk reduction became 5.8% with no significance.

The French vascular section of vascular neurosurgery included 41 patients older than 70 years into a randomized study comparing the two procedures (submitted). At 6 months, the outcome was not significantly different between the two arms (p = 0.18), although the proportion of favourable outcomes was superior after en-dovascular coiling.

Recurrent subarachnoid haemorrhage

The primary objective of all treatment for ruptured aneurysms is to prevent a recur-rent SAH, which has a known mortality rate of 57% in these patients [13].

The ISAT study gives an excellent insight into recurrent SAH, dividing its occur-rence into three periods: before treatment, during the first year after treatment and beyond [3, 9]. The relative risk of rebleeding from the target aneurysm during the first year was 1.15 (95% CI: 0.75–1.75) after endovascular coiling in comparison with neurosurgical clipping. This non-significant result took into account all recur-rent SAHs before and after procedural exclusion.

In the course of the pre-procedural period, recurrent SAH occurred more fre-quently in the clipping arm (17 in the coiling arm vs. 28 in the clipping arm) with a non-significant level (relative risk: 0.6, 95% CI: 0.33–1.1). As the baseline char-acteristics of both treatment groups were matched, the only significant difference

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was the timing delay between randomization and aneurysm exclusion (1.1 days for coiling vs. 1.7 days for clipping) [2]. This increasing rate of recurrence of SAH in proportion to the exclusion time confirmed the major risk of rebleeding (reaching ≈2–4% per day) during the first 4 weeks after the initial SAH [14].

After the procedure, the rebleeding rate at 1 year was significantly increased in the endovascular arm (χ2 Pearson test, p = 0.004) in comparison with the clipping arm. This high rebleeding rate could be related to the proportion of incomplete oc-clusion after endovascular treatment, which occurred in 66% of patients instead of a complete occlusion rate of 82% after neurosurgical treatment, despite only 49% of control angiography within this arm.

Beyond 1 year the global ratio of recurrent SAH decreased. After a long-term follow-up in the ISAT series (minimum of 6 years and maximum of 14 years), 17 patients experienced rebleeding in the endovascular arm compared with seven in the clipping arm, giving an incidence, respectively, of 0.21% per year and 0.09% per year [9].

At 10 years of follow-up, the cumulative risk of rebleeding from the target aneu-rysm (initial ruptured aneurysm) was 0.0216 for the patients treated by endovascular coiling and 0.0064 for those treated by neurosurgical clipping [12].

The BRAT study did not examined bleeding recurrence in the first year after an-eurysm treatment, but no recurrence of SAH was documented in the second or third year in either treatment group [11].

others results from Isat

Since 2005, the ISAT cohorts have reported secondary objectives such as the cogni-tive outcome, the elderly sub-group, the cost, and finally to extrapolate a global strategy for both treatments in the patients.

The neuropsychological analysis concerned the N-ISAT sub-sample drawn from ISAT enrolled in eight UK centres participating in this assessment protocol [15]. This sub-sample was representative of the main ISAT cohorts [16]. They confirmed the common existence of cognitive impairment in 32.1% of patients with favourable outcome (modified Rankin scale 0–2). Indeed, a reduction in the relative risk of cognitive impairment at 1 year of 31% (p<0.005) and an absolute risk reduction of 12% were observed after endovascular treatment in comparison with microsurgical clipping. Moreover, a greater number of cognitive domains were impaired in the neurosurgical group than the endovascular group, predominantly in the following domains: verbal memory, processing speed and executive skills. This study with valid neuropsychological tests was the largest ever study with full cognitive assess-ment as opposed to the classic short screening used in randomized studies.

The sub-group analysis of patients older than 70 years suggested surprisingly that there was less advantage for coiling than clipping [3]. This question is pertinent for several reasons: the longer life expectancies account for a significant number of elderly


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patients admitted with SAH, the incidence of SAH increases with advanced age [17], curative treatment was beneficial in this age class in comparison with conservative treatment despite a major risk of poor outcomes [18]. In spite of this, the sub-group was not pre-specified into the ISAT protocol, a sub-group of 278 randomly assigned patients older than 65 years was the subject of a second secondary analysis [19]. No difference was observed in the functional independence rate between the endo-vascular arm (60.1%) and the neurosurgical arm (56.1%). Nevertheless, the elderly patients with a middle cerebral artery (MCA) aneurysm who received neurosurgical clipping had a significantly better functional independence at 1 year than the coiled patients. For the other locations according to the χ2 test (anterior cerebral and anterior communicating artery, p = 0.7; internal carotid artery (ICA) and posterior com-municating artery, p = 0.06), no significant difference in functional independence was found between the two arms. Moreover, the thrombo-embolic event rate, when patients with parent artery occlusion, coil migration and thrombo-embolic problems were added, was significantly increased after endovascular treatment (p = 0.01), but a lower rate of epilepsy and pneumonia was observed. These results suggest that neurosurgical clipping should be the favoured treatment for elderly patients with ruptured aneurysm of the middle cerebral artery. However, these results may not be considered as coming from a valid randomized study, because the sub-group was not initially specified. For this reason, a French collaborative group developed a randomized study (www.clinicaltrial.gouv) between endovascular and neurosurgical treatment with regard to elderly patients (≥70 years) with ruptured aneurysms [20].

Regarding the cost of treatment, no significant difference at 12 months was found between both arms in Australia [21], Canada [22] or the UK [23]. These three coun-tries, using the data from their patients enrolled in ISAT, reported the same observa-tions: the coiled patients had higher costs related to medical expenses but this was offset by the reduction in cost related to the length of stay for the first procedure. Similar observations have already been reported from retrospective studies [24, 25]. Indeed, a change in paradigm from neurosurgical clipping to endovascular coiling does not lead to a change in the cost of treatment.

In summary, ISAT is a well-executed and statistically powerful study. Its large randomized population give some robust results to propose recommendations in the management of certain ruptured aneurysms. These different publications confirm the primary role of endovascular treatment in the management of ruptured cerebral aneurysms. It appears evident that patients and relatives should be proposed an early coiling in the first instance when the aneurysm sac is suitable for the two procedures.

In summary

During the past 20 years, randomized studies have confirmed endovascular coiling of aneurysms as a reference procedure, because this treatment significantly decreased the

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risk of morbidity and mortality in comparison with microsurgical clipping. Moreover, the risk of rebleeding from the target aneurysm at 10 years of follow-up remained low and was not responsible for an increase in morbidity. The recommendation, by a mul-tidisciplinary team composed of interventional neuroradiologists and neurosurgeons, was to propose in the first instance endovascular coiling when the aneurysm sac is suitable for both procedures [8]. The worldwide impact of ISAT on the management of IC aneurysms explained the current predominance (47–81%) of endovascular coil-ing [26-29]. Consequently, the new generation of physicians in Europe and North America were less familiar with the surgical management of these lesions.

Nonetheless, at 5 and 10 years of follow-up, no significant difference in the rate of independent survivors was found between the endovascular group (82%) and the neurosurgery group (81%). Despite the alarmist predictions of the disappearance of clipping replaced by endovascular coiling for all IC aneurysms [30], in 2014 micro-surgical exclusion remains a suitable treatment largely proposed worldwide [31], and always considered as an element of the therapeutic arsenal against IC aneurysms in order to propose the suitable procedure for each patient. The future management of IC aneurysms requires the development of an educational programme.

advances In mIcRosuRgIcal exclusIon

Since the seminal neurosurgical work describing the fronto-temporal pterional flap to approach the anterior part of the circle of Willis [32], the microsurgical proce-dure has included in its arsenal the concept of a minimally invasive approach and intraoperative monitoring by indocyanine green (ICG) videoangiography. Moreover, the procedures of brain revascularization must be involved in the management of complex IC aneurysms as a protective and preventive technique against ischaemic complications.

minimally invasive craniotomy

Minimally invasive craniotomy is the response to the starkest contrast between femo-ral catheter access and craniotomy. The concept of keyhole craniotomy, described by Pernansky et al. [33], is suitable for IC aneurysms. Several options for craniotomy, minipterional, lateral supraorbital and orbito-pterional, have favoured the develop-ment of the supraorbital subfrontal approach [34]. The supraorbital approach is sufficient to expose the AcomA, the ICA and the MCA aneurysms with little or no retraction [35]. The challenge was to provide adequate exposure of IC aneurysms. Obviously, this small craniotomy remains indicated in the absence of intracranial hypertension. After a limited dissection of the sylvian fissure, helped by cotton, a gentle exovascular surgery under optical magnification permits a sharp and blunt


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dissection of the aneurysm. Besides this superciliary approach, the pretemporal transzygomatic transcavernous approach has been presented by Krisht et al. [36] for 50 patients with complex basilar aneurysms. Their results were impressive, valuing microsurgical treatment, with no procedure-related mortality and 92% of patients at a modified Rankin scale 0–2 at 6 months. The sac dissection requires a high technical skill in order to adjunct several measures such as gyrus rectus resection, extended craniotomy, interhemispheric dissection and control of aneurysm neck tear by the cotton-clipping technique [37]. Concerning clipping techniques, the procedures have evolved. A new design concept of clip, based on an inverted opening mechanism, allowed a wider opening of the clip jaw and better surgical vision [38]. The use of a fenestrated aneurysm clip can be safe in minimizing the retraction of microvasculari-zation before clipping [39].

Intraoperative videoangiography

Intraoperative monitoring concerned the parent vessel but also the microcirculation. Intraoperative digital subtraction angiography is the method of choice for intra-operative diagnoses of vessel patency or aneurysm occlusion, but to propose this procedure to unselected patients is unrealistic. This procedure may not become the standard procedure because of its expansive nature, time taken, the need for major logistical support and the invasive character of the procedure with its risk of compli-cations (0.4–2.6%) [40, 41]. For these reasons, microscope-based indocyanine green videoangiography is becoming a routine intraoperative procedure. Indocyanine green videoangiography provides information about the patency of the parent vessel and the existence of aneurysm remnants. Raabe et al. [42] showed that the sensitivity of vide-oangiography was 100% and the specificity was 95% to diagnose stenosis of the parent artery. Moreover, this procedure provides information about perforating arteries into the operative fields and helps verify their patency [43]. Finally, this procedure was used to verify the patency of extracranial-intracranial bypass [44]. This intraoperative control procedure is easy to apply, taking on average less than 2 minutes of time, and becomes a reliable assessment of the post-clipping result. The intraoperative micro-vascular Doppler is a reliable technique to analyse the velocity and turbulence of blood flow during the clip application [45-47]. Not being time-consuming and the low cost of Doppler flowmetry give to this procedure its efficiency and permits immediate clip reapplication in less than 2 minutes. Using a laser speckle contrast analysis may im-mediately assess relative cortical blood flow [48, 49], and these evaluation procedures are in development. Finally, the electrophysiology record in the territory of the middle cerebral artery allows verification of cortical microperfusion and the absence of is-chaemic consequences, and their efficiency appears essentially in temporary clipping [50, 51]. All these intraoperative procedures should be considered as complementary rather than competitive [52].

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Brain revascularization procedures

These procedures are to evolve into a conceptual protection against ischaemia during the management of complex IC aneurysms. Bypass surgery has evolved since the extracranial-to-intracranial (EC-IC) bypass to intracranial-to-intracranial (IC-IC). From the superficial temporal artery-middle cerebral artery bypass [32], a second generation of bypass was developed using venous or arterial interposition grafts in response to flow limitations. A third generation of bypass is entirely intracranial, using other intracranial arteries without contribution from extracranial donor arter-ies. The procedure of cerebral revascularization currently developed for the giant aneurysm or cranial base tumours used the ELANA technique in order to avoid temporary clamping [53-57].

cuRRent IndIcatIon foR clIppIng

The indication for clipping must be envisaged in a collaborative neurovascular team that offers a balance of competence in the endovascular and microsurgical procedures. For each patient, treatment should be discussed in order to propose the optimal treatment directed to each aneurysm, but the results of ISAT and the current habit in Europe has favoured endovascular coiling when the two procedures seem equivalent in terms of efficiency. Within these conditions, microsurgical clipping is reserved for intracranial hypertension related to aneurysmal intraparenchymatous haematoma, complex aneurysms, dysplasia of arterial bifurcations, coiled aneu-rysms with recanalization and large and giant aneurysms.

Nevertheless, the combination of morphological criteria and patient characteristics may help in decision-making. Morphological criteria concerned the vascular ap-proach and the aneurysm features. The vascular approach may be made problematic by atherosclerosis or kinking vessels providing difficult access up to the aneurysm sac. The aneurysm characteristics may favour the endovascular or microsurgical approach according to the neck size, or the projection against the microvascular background [58]. The patient characteristics are also determined by age and co-morbidity. Intuitively, endovascular coiling would be expected to preserve cognitive functions in the arterial parent segment with perforating arteries such as the anterior communicating artery or basilar artery. The middle cerebral artery aneurysm, which is broad based, might be more suitable for clipping. Moreover, patients younger than 40 years of age should still be managed by craniotomy and clipping.

The preservation of the excellence and development of these complex strategies impose a significant effort in training medical and paramedical personnel. The cerebrovascular section of major neurosurgery societies must valorise several edu-cational approaches such as simulation, sharing expertise, international educational


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networks, and elaboration of a common educational programme with our neuroradi-ologist interventional colleagues.

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Treat cerebral venous thrombosis

Isabelle Crassard (Paris)

Cerebral venous thrombosis has been considered for a long time as a rare disease, often secondary to infection with a poor prognosis. It was very difficult to diagnose, diagnosis often only being made at autopsy. However, this perception has changed a great deal in recent years with new neuroradiological techniques coupled with improved treatment.

LiTTLe reminder abouT cerebraL venous Thrombosis

epidemiological data

Cerebral venous thrombosis can strike at any age from birth to old age with a mean age of 39 observed in the large studies. Its sex ratio is two to three women for every man, with a peak in incidence among young women because of specific risk factors, namely oestrogen-progestin birth control and pregnancy.

In the Netherlands, its incidence was recently estimated at 1.32 per 100,000 per-son-years, a rate similar to that of bacterial meningitis [1] and more common than suggested by the classic data. Further evidence comes from the large studies recently conducted by Lariboisière Hospital (450 patients included) and the large-scale International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), which covered 624 cases at 89 centres in 21 countries. Its frequency probably remains under-estimated, especially when it occurs without a stroke.

Thrombosis

Localisation and extent of involvement

Some of the features of cerebral venous thrombosis are distinct from those of arterial disease. Its localisation and the area affected are highly variable. In the ISCVT (n = 624) and the Lariboisière studies (n = 450), the lateral sinuses were involved in 73% of cases and the superior sagittal sinus in 62–65%. Less frequently, it involved the cortical veins (17–21%), the deep venous system (7–11%) or the cavernous sinus (2%).

In more than half of all cases, more than one sinus and/or vein is thrombosed.

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Because they have such thin walls, thrombosed cortical veins can become dilated and this often leads to reverse flow and development of a collateral circulatory pathway.

Causes and risk factors

Cerebral venous thrombosis can occur in a number of pathologies. The Lariboisière Study identified local causes (trauma, malformed vessels, tumours, etc. [9%]), infection (in neighbouring tissue or general infections like septicaemia or menin-gitis [6.5%]), systemic causes (systemic lupus erythematosus, Behcet’s disease, congenital thrombophilia, clotting disorders, cancer, haematological disorders, drug reactions, etc. [42%]) and gynaeco-obstetric causes (pregnancy, post-partum, oral contraceptives [22.5%]).

More than one cause or risk factor may be present so a full investigation is warranted. Even so, in 15–20% of cases, no risk factor is ever identified.

Polymorphism

Cerebral venous thrombosis is characterised by polymorphism in terms of both clinical picture and outcome. In contrast to arterial infarction, the mode of instal-lation is often variable and it can take a number of days. Onset is often marked by headache (observed in 90% of cases), possibly associated with papillary oedema if there is intracranial hypertension. Various clinical pictures are seen: focal syndrome in 50–80% of cases, isolated intracranial hypertension in 10–40% and sub-acute encephalopathy in 10–20%. Involvement of the cavernous sinus will give rise to local neuro-ophthalmological signs.

Some 15–20% of cases of cerebral venous thrombosis present atypically, e.g. as transient neurological signs or isolated headache.

Diagnosis

Because the aetiology and clinical picture are so varied in cerebral venous thrombo-sis (which can present as a combination of headache, focal deficit, epileptic seizures and impaired consciousness), diagnosis depends on neuroradiological techniques, in particular cerebral magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Cerebral MRI shows changes in the signal from the thrombosed sinus, which is not seen on the corresponding MRA image (Figure 1).

Parenchymatous lesions (diffuse or localised oedema, haemorrhagic lesions of varying size) are found in 40–50% of cases. These are usually aspecific and are rarely pathognomic so imaging of the parenchyma is mainly of use when it comes to differential diagnosis. However, lesions such as bithalamic involvement with thrombosis of the deep venous system and small juxtacortical haemorrhages (often bilateral) are highly suggestive of cerebral venous thrombosis.

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Prognosis at six months

In the Lariboisière and ISCVT studies, full remission was observed at six months in 75% and 46% of cases, respectively, minor sequelae in 16% and 40%, severe sequelae in 6% and 7%, and death occurred in 3% and 7%.

Figure 1. Thrombosis of the superior sagittal sinus.Hypersignal from the thrombus in T1 (A) and T2 (B); hyposignal in T2* (C); sinus not seen in MRA (D).

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Function is conserved in most patients and death is far rarer than previously believed. The most common reason for death is a problem secondary to either significant brain damage (e.g. transtorial herniation), a status epilepticus, a pulmonary embolism or the underlying pathology (cancer, haematological disorder or severe infection).

How the acute phase evolves is variable and unpredictable. One-quarter of the ISCVT patients deteriorated in the acute phase. It is important to diag-nose cerebral venous thrombosis so that treatment can be started as soon as possible.

TreaTmenT oF cerebraL venous Thrombosis

Guidelines were published in Europe in 2010 and in North America in 2011 [2, 3]. Treatment relies on three strategies: antithrombotic heparin, managing symptoms (headache, intracranial hypertension and epilepsy) and treatment of the underlying condition (infection, systemic disease).

antithrombotic treatment

Heparin

For a long time, the place of heparin in the treatment of cerebral venous thrombosis was controversial because of fear of the existence of haemorrhagic forms. Since then, prospective and retrospective studies as well as two randomised studies have clearly established that patients benefit from heparin.

The randomised, controlled, double-blind Einhäupl Study published in 1991 assessed anticoagulation with intravenous heparin in the treatment of aseptic cerebral venous thrombosis in 20 patients (10 heparin, 10 placebo). The study was stopped early because, by three months, eight of the heparin patients had fully recovered and the other two showed mild, residual neurological deficit whereas, in the placebo group, only one patient had fully recovered, six had neurological deficit and three were dead (p<0.01). An additional retrospective study was conducted in patients with cerebral venous thrombosis associated with intracranial haemorrhage: 15% of patients treated with heparin died compared with 69% in the control group [4].

Another multicentric, placebo-controlled, double-blind study was published in 1999 by the Cerebral Venous Sinus Thrombosis Study Group. This included 59 patients who were given either low molecular weight heparin (LMWH) or placebo for three weeks. The course of LMWH was followed by oral anticoagulants for three months.

Twenty-four per cent of patients in the LMWH group had a negative outcome as defined by death or a Barthel Index of below 15 (risk differential: –4%; 95% CI: –25–17%; NS). After 12 weeks, 13% of patients in the LMWH group and 21% in the placebo group had a negative outcome as defined by death or an Oxford

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Handicap Score of 3 or above (risk differential: –7%; 95% CI; –26–12%; NS). No new symptomatic cerebral haemorrhages were detected [5].

A meta-analysis of studies of heparin in cerebral venous thrombosis shows a 14% decrease in the risk of death (95% CI: –6–36%) and a 16% decrease in the risk of death or handicap (95% CI: –6–37%).

In consequence, the guidelines propose administering heparin to patients with cerebral venous thrombosis, either unfractionated heparin or LMWH [2, 3].

Comparison of unfractionated heparin and LMWH

A small randomised study compared LMWH (n = 34) and unfractionated heparin (UFH, n = 32) in the treatment of cerebral venous thrombosis. Mortality was 19% in the UFH group compared with zero in the LMWH group. More patients in the LMWH group had recovered by three months (88% vs 62.5%) and the incidence of severe bleeding was 9.5% in the UFH group compared with zero in the LMWH group [6].

Despite weaknesses, the results of this study seem to indicate that LMWH may be more effective.

In the ISCVT study, 302 patients were treated with UFH and 119 on LMWH. Recovery was better in patients on LMWH and both mortality and the incidence of new intra cranial haemorrhage were higher in the UFH group (Table 1) [7].

Therefore, the available data seem to encourage prescribing LMWH as long as there is no significant contraindication (kidney failure or imminent surgery).

Table 1. Comparison of UFH and LMWH in the treatment of cerebral venous thrombosis, data from the ISCVT [7]

uFh (n = 302)

LmWh (n = 119)

or

Recovery (mRS to 2) at 6 months

84% 92% 2.4 (95% CI: 1.0–5.7) p = 0.04

Complete recovery (mRS 0–1)

78% 78% 0.94 (95% CI: 0.55–1.9) p = 0.94

Deaths 8% 6% 0.81 (95% CI: 0.29–2.3) p = 0.70

New IC haemorrhage

16% 10% 0.29 (95% CI: 0.07–1.3) p = 0.10

LMWH: low molecular weight heparin; UFH: unfractionated heparin; IC: intracranial; OR: odds ratio.

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Vitamin K antagonists and new oral anticoagulants to follow up heparin

As soon as the clinical situation has stabilised, the patient is switched from heparin to a vitamin K antagonist (VKA). The length of this course of treatment will depend on the underlying cause: in the absence of any factor indicating long-term anticoagulant treatment, it is 6–12 months.

The place of the new oral anticoagulants is still undefined and the literature is lim-ited to reports on odd cases: two patients treated with dabigatran [8] and a comparison of 7 patients treated with rivaroxaban versus 9 patients treated with a VKA [9]. All of these patients improved but there is as yet not enough data to draw a solid conclusion.

symptomatic treatments

Headache

Headache can be severe in cerebral venous thrombosis but it usually gets better within a matter of days of starting heparin. Simple analgesics are usually adequate and morphine derivatives are rarely needed.

For the special case of isolated intracranial hypertension, cerebrospinal fluid is drained by lumbar puncture before the heparin: this is associated with the prescrip-tion of acetazolamide and usually improves the headache and helps control visual function.

Epileptic seizures

Antiepileptic treatment is always administered in a patient with epileptic seizures. Which drug is used should take into account interactions with the VKA. The consensus position is to stop treatment after one year as long as there have been no new seizures and EEG results are normal.

aetiological treatment

Whenever possible, the aetiological treatment should be adapted to the underlying condition. This is particularly important for septic forms that should be treated with effective antibiotics matching the entry point, and sometimes surgery. Similarly, specific treatment may be indicated for certain intercurrent systemic diseases, such as cancer and haematological disorders.

TreaTing severe Forms

The type of care described above suffices in 90% of cases but treating the 10% of patients with the severest forms is far more difficult.

Severity may be due to the aetiology, e.g. a serious haematological disorder or severe anaemia due to chronic bleeding.

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Cerebral venous thrombosis can also present as a serious neurological problem from the outset or deteriorate secondarily to status epilepticus or pulmonary embolism.

surgery

Surgery can be considered in patients in the acute phase who are at risk of cerebral herniation, either because of major damage to the cerebral parenchyma or malignant cerebral oedema.

Surgical decompression was investigated in a retrospective study of 12 patients. Malignant forms of cerebral venous thrombosis were defined as: 1) presence of supratentorial cortical lesions; 2) evidence of clinical involvement (impaired consciousness, dilatation of the pupils) or radiological signs; 3) from the outset or after deterioration despite heparin treatment.

With malignant deterioration, all the patients bar one developed haemorrhagic le-sions; median deviation of the septum pellucidum was 12 millimetres, five patients (three of whom had been operated on) developed mydriasis on one side and four (two operated) on both sides. Eight patients underwent surgical decompression, ei-ther external (n = 4), external + internal (n = 3) or internal (n = 1). The four patients who were not operated on died within five days of diagnosis. One operated patient died of a pulmonary embolism but the other seven recovered well within a median time of 23.1 months [10].

In a study of 69 patients (including 31 case histories from the literature), decom-pressive hemicraniectomy was carried out in 45 of them, drainage of the haematoma in 7 and both procedures in 17. At the last follow-up (median = 12 months), 37% scored 0–1 on the modified Rankin Scale (mRS) with 56.5% scoring 0–2—a very good functional outcome given the patients’ clinical condition at baseline. On this date, 5.8% of the patients were alive with a score of 4–5, and 15.9% had died. Three of the 9 patients with both pupils fixed recovered fully [11].

Thus, surgical decompression seems to save lives and affords good functional outcomes in malignant cerebral venous thrombosis.

endovascular thrombolysis

Fibrinolytics have been in use since 1971. A meta-analysis published in 2003 covered 72 studies (including no controlled trials) and a total of 169 patients. The patients had been treated with urokinase (n = 127) or tissue plasminogen activator (rt-PA, n = 37). Thrombectomy was also performed in 16 patients. The patients were all in a serious clinical condition (coma: 28%, encephalopathy: 52%, focal syndrome: 7%, intracranial hypertension: 13%). Thirty-three per cent had bleeding on the initial imaging and there was deep venous system involvement in 31%. Only 6% of the patients died and good clinical recovery was documented in 58% [12].

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A new meta-analysis published in 2010 covered 15 retrospective and prospec-tive studies (each on 5–20 patients) with a total of 156 patients, 30% of whom had bleeding on the initial imaging. Of these, 71% were administered urokinase and 29% were administered rt-PA. The authors paid special attention to compli-cations of the treatment: severe bleeding (9.8%), new symptomatic intracranial haemorrhaging (7.6%) and death (9.2%, half of which cases were related to new bleeding) [13].

The place of this modality therefore remains to be established and it remains reserved for patients in a coma or whose condition deteriorates despite best medical treatment. A randomised study, the TO-ACT Study, is currently under way and the results should come out in 2018 [14].

concLusion

Cerebral venous thrombosis is a rare disease but its prognosis is far better than that of an arterial infarct. It can be caused by a variety of problems and its clinical picture is relatively non-specific. This diagnosis should be frequently considered. Treatment should be started as soon as the condition has been confirmed by imaging. Basic treatment is heparin (even when there is bleeding) combined with drugs to manage symptoms and, if possible, treatment of the underlying condition. More aggressive modalities such as decompression surgery may be considered in a patient with ma-lignant oedema. Endovascular thrombolysis may be considered although its place in treatment remains to be established.

references

1 Coutinho JM, Zuurbier SM, Aramideh M, Stam J. The incidence of cerebral venous thrombosis: a cross-sectional study. Stroke 2012;43:3375-7.

2 Einhäupl K, Stam J, Bousser MG, et al. EFNS guideline on the treatment of cerebral venous and sinus thrombosis in adult patients. Eur J Neurol 2010;17:1229-35.

3 Saposnik G, Barinagarrementeria F, Brown RD, Jr, et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:1158-92.

4 Einhäupl KM, Villringer A, Meister W, et al. Heparin treatment in sinus venous thrombosis. Lancet 1991;338:597-600.

5 de Bruijn SFTM, Stam J, for the Cerebral Venous Sinus Thrombosis Study Group. Randomized, Placebo-Controlled Trial of Anticoagulant Treatment With Low-Molecular-Weight Heparin for Cerebral Sinus Thrombosis. Stroke 1999;30:484-8.

6 Misra UK, Kalita J, Chandra S, et al. Low molecular weight heparin versus unfractionated hepa-rin in cerebral venous sinus thrombosis: a randomized controlled trial. Eur J Neurol 2012;19: 1030-6.

7 Coutinho JM, Ferro JM, Canhão P, et al. Unfractionated or low-molecular weight heparin for the treatment of cerebral venous thrombosis. Stroke 2010;41:2575-80.

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8 Hon SF, Li HL, Cheng PW. Use of direct thrombin inhibitor for treatment of cerebral venous thrombosis. J Stroke Cerebrovasc Dis 2012;21:915.e11-5.

9 Geisbüsch C, Richter D, Herweh C, et al. Novel factor xa inhibitor for the treatment of cerebral venous and sinus thrombosis: first experience in 7 patients. Stroke 2014;45:2469-71.

10 Théaudin M, Crassard I, Bresson D, et al. Should decompression surgery be performed in malig-nant cerebral venous thrombosis?: a series of 12 patients. Stroke 2010;41:727-31.

11 Ferro JM, Crassard I, Coutinho JM, et al. Decompression surgery in cerebrovenous thrombosis: a multicenter registry and a systematic review of individual patient data. Stroke 2011;42:2825-31.

12 Canhão P, Falcão F, Ferro JM. Thrombolytics for cerebral sinus thrombosis: a systematic review. Cerebrovasc Dis 2003;15:159-66.

13 Dentali F, Squizzato A, Gianni M, et al. Safety of thrombolysis in cerebral venous thrombosis. A systematic review of the literature. Thromb Haemost 2010;104:1055-62.

14 Coutinho JM, Ferro JM, Zuurbier SM, et al. Thrombolysis or anticoagulation for cerebral venous thrombosis: rationale and design of the TO-ACT trial. Int J Stroke 2013;8:135-40.

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What’s new in post-stroke rehabilitation?

Philippe Marque (Toulouse)

This presentation mostly concerns the motor aspects of post-stroke rehabilitation, and specifically the hemiplegia, which is the most common feature in this situation.

EFFICACY OF REHABILITATION FOLLOWING A STROKE

A recent meta-analysis [1] has compiled the randomised controlled trials on motor rehabilitation post-stroke. The studies selected included a total of 25,373 patients.

Firstly, this meta-analysis showed that the quality of trials has improved over time, with a median PEDro score (an 11 item scale used to assess the internal validity of the trial), which has increased from 4 before 2004 to 6 for trials published after that date.

Secondly, it appears that no adverse effects associated with motor rehabilitation post-stroke have been reported and that we have solid evidence that it is effective in recovering walking, hand and forearm motor function and independence (activities of daily living). Similar results have been consistently found in all of the meta-analyses over more than 2 decades [2].

Factors involved in efficacy that are consistently found are early institution of motor rehabilitation, together with its intensity and a multi-disciplinary approach. The utility of motor rehabilitation in the first week post-stroke, however, remains contentious, because of the existence of a vasogenic oedema. A PRHC (hospital clinical research programme) assessing the merits of physical exercise in the initial hours following the stroke is currently ongoing.

The optimal intensity of motor rehabilitation has not been entirely established, although published findings show that daily exercise is preferable to exercise three times per week, that 3 hours of exercise per day are preferable to thirty minutes per day, although at the same time, the 3 hours per day are more effective than 6 hours of daily management [1, 3]. The intensity of care is therefore an essential component of the effectiveness of rehabilitation, although a ceiling effect is seen as excessively long rehabilitation times or excessive intensity may have a counter-productive effect.

Finally, these large meta-analyses have emphasised the team effect. Multi-disciplinary care is needed in order to approach all aspects of motor rehabilitation,

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and involve a coordinated approach by physiotherapists, ergotherapists, orthopho-nists, neurologists and physical medicine and rehabilitation physicians [4].

WHAT IS THE RIGHT POST-STROKE TECHNIQUE?

Conventional motor rehabilitation techniques

Before 2000, motor rehabilitation was based on several empirical techniques (Bobath, Brunnstrom, Perfetti, etc.), which involve very different and occasionally opposing concepts. The Bobath and Brunnstrom techniques are developed from radically different approaches. Physical exercise and therefore muscle strengthening are prohibited in the Bobath technique, as these are assumed to increase the spastici-ty. Reflex reactions are inhibited and considered to be archaïc. Conversely, reflex reactions are used and reinforced in the Brunnstrom technique, as these are seen as the elementary motility in this method. The increased spasticity that may result from this is considered to be transient and not to have adverse consequences on motility. Eleven trials have compared these different methods, although none has emerged as being superior to the other [3, 5].

Similarly, muscle strengthening, which is penalised with the Bobath technique, has been shown to be effective in hemiplegic patients with a gain in strength and functional benefits [6-8]. At the same time, it has been shown to be well tolerated and not to worsen patients’ spasticity, which may increase temporarily with fatigue during exercise, although this increase does not persist in the long term [9, 10].

As a result, while there is a consensus from the clinical meta-analyses about the positive effect of motor rehabilitation after stroke, the different results show that the type of exercise or re-education technique used to obtain this effect are still largely unknown.

Animal models

Enriched environment model in the rat

The enriched environment model involves rearing animals in a group in spacious cages with various objects to stimulate their curiosity and manipulation, etc. This environment in which the animals can interact socially promotes exploration and a large range of experiences and helps to increase spontaneous physical activity. Any dispensing device requiring the animal’s paw be used in order to grasp a feed pellet can be used to strengthen the use of a paretic anterior limb (see Figure 1).

Rehabilitation in such an environment after a local ischaemic injury has been shown to promote the improvement in anterior limb muscle function and is associ-ated anatomically with greater synaptic budding of neurones than is seen in animals that are housed in individual cages [11].

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Constraint-induced therapy

Intracortical micro stimulation mapping techniques have been used to produce de-tailed maps of the cortical representation of the hand and upper limb in the monkey. Nudo and colleagues found that after electrocoagulation-induced stroke of the hand motor area, areas representing the hand and wrist developed in the healthy cortex adjacent to the injury. If the paretic limb was not used, the surface area of these regions reduced gradually over time. Conversely, in the case of rehabilitation with constraint of the healthy hand, requiring the animal to use its deficient hand was accompanied by an increase in the surface area of the hand and wrist regions and better clinical recovery (see Figure 2).

Recovery of functions following a stroke is therefore accompanied by cerebral plasticity mechanisms such as reorganisation of the sensory motor maps, which are dependent on use through a competitive mechanism: if not used, these new areas representing the hand are taken over by representations of the shoulder and elbow [13-15].

Applications in humans

Animal findings are consistent with the results of work carried out in humans, which show the existence of competitive cortical representation effects. In an arm amputee, for example, the area in the side in which the afferent hand signal has been removed is gradually invaded by representations of the shoulder [16]. These competitive cortical representation effects develop very rapidly. Motor Evoked Potentials (MEP) in the forearm muscles of normal people before, during and after blockade through ischaemia produced by a forearm and hand tourniquet have been recorded in order to study the chronology of the changes. Deltoid muscle MEP amplitudes increased

Figure 1. Example of the enriched environment. Reproduced from Murphy and Corbett [12].

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rapidly as the ischaemia was produced and then returned to their previous levels when the tourniquet was removed. The increase in magnitude of the deltoid MEP was inversely proportional to the reduction in the amplitude of the abductor pollicis produced by the tourniquet-induced ischaemia. During the same time period the MEPs for the contralateral arm were not changed [17].

Since these studies were performed, constraint-induced therapy has been widely used in post-stroke rehabilitation and the method has been validated on large num-bers of patients. The cohort of Taub et al., which was randomly assigned against a

Digit training cases:digit, Wrist/Forearm representations

Pre-training Post-trainingdigitwrist/fadigit+wrist/faproximalno response

R

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pre

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20

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Figure 2. Change in cortical representation areas for the fingers, hand and wrist in constraint therapy. Reproduced from Nudo and colleagues [13, 14].

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placebo, included several hundreds of patients and showed greater use of the paretic upper limb in activities of daily living in the treatment group [18]. In parallel, and mimi cking animal studies, the effects of treatment can be demonstrated using tran-scranial magnetic stimulation (TMS) mapping techniques [19].

Other techniques

Electromyogram biofeedback

Electromyogram biofeedback is a technique using electrodes positioned on the patient’s muscles to generate a feedback signal (visual or auditory) in a response to activation of the muscle. It has been well validated and has a demonstrable impact on recovery after a stroke [1].

Rehabilitation robots

The major limitation of constraint-induced therapy is that it can only be used in patients who have good quality, preserved residual motor function, i.e. one that includes the thumb–index finger pinch. Tools that mobilise the paralysed limb are required in other patients. Rehabilitation robots have therefore gained an increas-ingly large place in the rehabilitation literature over the past 15 years (see Figures 3 and 4).

For the upper limbs, the meta-analyses show improvement in motor deficit and motor function in activities of daily living [20].

The utility of re-education robots in recovery of gait, however, remains controver-sial and the results of meta-analyses are inconsistent. The most recent publications show that re-education robots have little benefit in patients who have preserved residual walking ability, although significant benefit is achieved in patients who have been totally deprived of their walking ability and are treated early [21].

THE CRITICAL PERIOD

There are critical periods for learning in new-born infants (reading, language, pra-xia), beyond which these are far more difficult. These findings can be extrapolated to patients who have suffered a stroke.

We have shown in a clinical study using an experimental paradigm with TMS to assess cerebral plasticity in hemiplegic patients that the brain has extensive plastic capacity three months after the stroke, although this capacity has fallen greatly at one year post-stroke [22].

A study in the rat has assessed the effectiveness of enriched rehabilitation started on the fifth, 14th or 30th day after local ischaemia on functional results and neuro-morphological changes. Administration of the treatment from day 5 produced better

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Figure 3. Re-education robot used in upper limb motor rehabilitation. [Médimex company, Sainte-Foy-lès-Lyon, France].

Figure 4. Re-education robot used in lower limb motor rehabilitation. [Médimex company, Sainte-Foy-lès-Lyon, France].

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results and the possibilities for recovery fell greatly beyond 15 days. These findings suggest that post-stroke the brain has greater sensitivity to early rehabilitation therapy but that this falls over time. This phenomenon is believed to involve mechanisms that facilitate and inhibit cerebral plasticity, the facilitating mechanisms coming into action far earlier than the inhibitory mechanisms [23].

Beyond this period, the results do not mean that no plasticity is possible but that regulatory mechanisms for this effect come into play, resulting in these limitations in adults.

WHAT WILL WE BE DOING IN THE FUTURE?

Cerebral stimulations

Repetitive transcranial magnetic stimulation (rTMS) can be distinguished from transcranial direct current stimulation (tDCS).

Electrical stimulations are used in a recent approach for treating the brain-damaged patient. Inter-hemispheric inhibition has been demonstrated not only at rest [24] but also during movement [25]. Murase et al. [25] showed that the removal of inter-hemispheric inhibition seen in healthy people in the 20 ms before movement was reduced or absent in hemiplegic patients. This type of result is consistent with some functional image findings, which show increased activation of the motor cortex from the healthy side and inactivation of the cortex on the injured side during the 15 days after a sub-cortical vascular injury [26]. A hypothesis has been advanced to explain these results, through which over-activation of the healthy hemisphere is the result of the injury to the contralateral hemisphere and the reduced inter-hemispheric inhibi-tion that occurs as a result of this. Following this, the overactive healthy hemisphere would cause an increasing inhibition of the injured hemisphere and an increase in the motor deficit. The concept of an appropriate plasticity has been proposed to describe this upset in the intra-hemispheric balance.

If we accept this hypothesis, therapeutic interventions in hemiplegic patients either through rehabilitation or cerebral stimulation must aim to stimulate the injured hemi-sphere and/or inhibit the healthy hemisphere in order to restore the inter-hemispheric balance. Non-invasive cerebral stimulations are particularly suitable for this type of programme.

rTMS involves emitting a series of impulses over a given period of time in order to produce lasting change to the activity of the targeted region. The after effects on MEP amplitude and therefore on the excitability of the cortex depend on the frequency, duration and number of stimulations applied. Low-frequency rTMS stimulations (1 Hz) have an inhibitory effect, whereas high-frequency stimulations have a facilitating effect.

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tDCS involves applying a continuous low-intensity current through 2 polarised electrodes: the positive electrode or anode and the negative electrode or cathode. MEP assessment demonstrates an increase in cortical excitability beneath the anode and reduced excitability beneath the cathode [27].

Hummel and colleagues carried out a double blind placebo-controlled crossover study to test the hypothesis through which non-invasive stimulation of the motor cortex could improve motor function in the paretic hand of stroke patients in the chronic phase. Motor function in the hand was measured using the Jebsen Taylor hand function test (JTT). The JTT in the paretic hand improved considerably with tDCS but did not improve in the placebo group. This effect lasted beyond the stimu-lation period, was found in all patients and correlated with an increase in cortical motor excitability in the affected hemisphere, seen as increased recruitment curves and a reduction in the short-term intracortical inhibition [28].

Many studies using rTMS or tDCS have been carried out. Some of these have been disappointing and have not shown the expected benefits. Many questions remain to be answered such as the type of cortical neuromodulation that can be used (fa-cilitating or inhibitory rTMS, transcranial magnetic stimulation, paired associative stimulation, tDCS) and the means of using these.

Brain–machine interface and rehabilitation

So-called non-invasive brain–machine interfaces use an electroencephalogram (EEG) in the treatment of patients with severe handicap. These devices record the cerebral activity by a mental task and provide the patients with quantitative and qualitative feedback about their cerebral activity, enabling them to learn to control this with a view to running various technical aids.

The group working with Birbaumer, a pioneer in the brain–machine interface, has carried out a double blind placebo-controlled trial to assess the benefit of daily train-ing with the brain–machine interface compared to physiotherapy alone in patients with severe paresis.

Thirty-two chronic patients with severe arm and hand weakness were included. The patients were asked to activate an elbow or finger extension movement through their imagination. Two patient groups were established: the intervention group in which the increase in β and µ frequencies in the EEG activity triggered the functioning of a robot enabling the chosen movement to be performed, and a sham group in which the robot movements were independent of changes in EEG activity. Encouraging results were obtained with an improvement in the Fugl–Meyer motor score for the upper limb and lateralisation index on functional magnetic resonance imaging represent-ing improved activation of the injured hemisphere [29].

The use of brain–machine interfaces in motor rehabilitation appears to be a prom-ising approach.

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CONCLUSION

Post-stroke rehabilitation methods are changing profoundly, bringing into question the conventional techniques used by physiotherapy teams. The current strap line is ‘use it or lose it’, and new tools are already available or will become available.

References

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8 Sharp SA, Brouwer BJ. Isokinetic strength training of the hemiparetic knee: effects on function and spasticity. Arch Phys Med Rehabil 1997;78:1231-6.

9 Brown DA, Kautz SA. Increased workload enhances force output during pedaling exercise in persons with poststroke hemiplegia. Stroke 1998;29:598-606.

10 Smith GV, Silver KH, Goldberg AP, Macko RF. “Task-oriented” exercise improves hamstring strength and spastic reflexes in chronic stroke patients. Stroke 1999;30:2112-18.

11 Biernaskie J, Corbett D. Enriched rehabilitative training promotes improved forelimb motor func-tion and enhanced dendritic growth after focal ischaemic injury. J Neurosci 2001;21:5272-80.

12 Murphy TH, Corbett D. Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci 2009;10:861-72.

13 Nudo RJ, Milliken GW, Jenkins WM, Merzenich MM. Use-dependent alterations of movement representations in primary motor cortex of adult squirrel monkeys. J Neurosci 1996;16:785-807.

14 Nudo RJ, Wise BM, SiFuentes F, Milliken GW. Neural substrates for the effects of rehabilitative training on motor recovery after ischaemic infarct. Science 1996;272:1791-4.

15 Milliken GW, Plautz EJ, Nudo RJ. Distal forelimb representations in primary motor cortex are redistributed after forelimb restriction: a longitudinal study in adult squirrel monkeys. J Neurophysiol 2013;109:1268-82.

16 Kew JJ, Ridding MC, Rothwell JC, et al. Reorganization of cortical blood flow and transcra-nial magnetic stimulation maps in human subjects after upper limb amputation. J Neurophysiol 1994;72:2517-24.

17 Brasil-Neto JP, Cohen LG, Pascual-Leone A, et al. Rapid reversible modulation of human motor outputs after transient deafferentation of the forearm: a study with transcranial magnetic stimula-tion. Neurology 1992;42:1302-6.

18 Taub E, Uswatte G, Mark VW, Morris DM. The learned nonuse phenomenon: implications for rehabilitation. Eura Medicophys 2006;42:241-56.

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19 Liepert J, Bauder H, Wolfgang HR, et alC. Treatment-induced cortical reorganization after stroke in humans. Stroke 2000;31:1210-16.

20 Mehrholz J, Hädrich A, Platz T, et al. Electromechanical and robot-assisted arm training for improving generic activities of daily living, arm function, and arm muscle strength after stroke. Cochrane Database Syst Rev 2012;6:CD006876.

21 Mehrholz J, Elsner B, Werner C, et al. Electromechanical-assisted training for walking after stroke. Cochrane Database Syst Rev 2013;7:CD006185.

22 Castel-Lacanal E, Marque P, Tardy J, et al. Induction of cortical plastic changes in wrist muscles by paired associative stimulation in the recovery phase of stroke patients. Neurorehabil Neural Repair 2009;23:366-72.

23 Biernaskie J, Chernenko G, Corbett D. Efficacy of rehabilitative experience declines with time after focal ischaemic brain injury. J Neurosci 2004;24:1245-54.

24 Ferbert A, Priori A, Rothwell JC, et al. Interhemispheric inhibition of the human motor cortex. J Physiol 1992;453:525-46.

25 Murase N, Duque J, Mazzocchio R, Cohen LG. Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol 2004;55:400-9.

26 Loubinoux I, Carel C, Pariente J, et al. Correlation between cerebral reorganization and motor recovery after subcortical infarcts. Neuroimage 2003;20:2166-80.

27 Nitsche MA, Paulus W. Excitability changes induced in the human motor cortex by weak tran-scranial direct current stimulation. J Physiol 2000;527:633-9.

28 Hummel F, Celnik P, Giraux P, et al. Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain 2005;128:490-9.

29 Ramos-Murguialday A, Broetz D, Rea M, et al. Brain–machine interface in chronic stroke reha-bilitation: a controlled study. Ann Neurol 2013;74:100-8.

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Preventing cerebral infarction

Emmanuel Touzé (Caen)

When to Prevent cerebral infarction and hoW?

Seventy-five per cent of cerebrovascular accidents (CVA) are first events. Primary prevention is therefore vital but secondary prevention too is as necessary given the high rate of recurrence: about 3% within 30 days, 10% within a year, 25% within 5 years and 40% within 10 years [1].

Preventive measures have to match the cause of the cerebral infarct. Ischaemic accidents (infarcts and transient ischaemic attacks [TIAs]) account for 85% of CVAs. The main causes are atherosclerosis (20%), disease of the small arteries (25%) and emboli from the heart (20%). Although management of these different types of CVA has common features, specificities nevertheless have to be taken into account.

Be it for primary or secondary prevention and whatever the cause of the event, prevention depends on three issues: 1) managing vascular risk factors; 2) anti-platelet and anticoagulant drugs; 3) surgical and endovascular revascularisation techniques.

imPortance of risk factors

Epidemiological surveys have shown that just ten risk factors account for 90% of cerebral infarcts, namely hypertension, current smoking, abdominal obesity, lack of physical exercise, diabetes, alcohol consumption, psychological stress, depression, heart disease (atrial fibrillation [AF], flutter, myocardial infarction, rheumatic valve disease, heart valve replacement) and apo B/apo A1 ratio [2].

Traditionally, distinction has been made between modifiable and unmodifi-able risk factors. The former are age, racial origin, genetic factors, gender (being male) and low birth weight. The latter include hypertension (HT), heart disease, diabetes, dyslipidaemia, carotid stenosis, smoking, abdominal obesity and lack of exercise.

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blood pressure

Hypertension is the main risk factor for CVA

Epidemiological surveys show that HT is the main risk factor for CVA. The risk rises linearly with blood pressure (BP). A meta-analysis of 61 studies of the general population covering over a million subjects showed that the risk of a first event dou-bles with every 20 mmHg increase in systolic BP (Figure 1); the same relationship is observed with diastolic BP. This is true at all ages although no threshold has really been determined [3].

The same relationship is also seen after a first CVA and again the risk of recurrence rises with both systolic and diastolic BP [4].

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It has been clearly shown in clinical trials that decreasing BP reduces the risk of a CVA with the greater the decrease in BP, the greater the reduction in CVA risk [5].

Even a modest reduction in BP across a population as a result of systematic im-plementation of very simple measures (weight control, reducing salt intake, physical exercise, a healthy diet [fruits, vegetables, potassium-rich foodstuffs], reducing alcohol consumption) would have a huge positive impact. A simple reduction of 5 mmHg in systolic BP across the population as a whole would reduce the incidence of CVA by 14%.

In secondary prevention too, it has been clearly shown that decreasing BP after a CVA reduces the risk of recurrence [6, 7].

Target blood pressure in secondary prevention

In coronary heart disease, the relationship between BP and risk draws a J-shaped curve with increased risk at very low BP as well as at high values. This relationship does not seem to apply to CVAs and the old guidelines on secondary prevention recommended lowering BP even in normotensive patients, i.e. below 140/90 mmHg. Secondary analysis of data from the large-scale PROFESS therapeutic trial, which covered 20,330 patients who had already had a CVA showed that the risk of recur-rence was higher in patients with BP below 120 mmHg although no causal relation-ship could be established [8].

However, results from other studies on secondary prevention show benefit from reducing BP in normotensive patients. The SPS3 Study on 3,020 patients with a MRI-confirmed lacunar infarct evaluated two BP targets (130–139 mmHg and <30 mmHg) in secondary prevention. The results showed an insignificant decrease in the incidence of recurrent CVA in the <130 mmHg target group (HR: 0.81; 95% Confidence Interval: 64–1.03; p = 0.08). On the other hand, the incidence of in-tracerebral bleeding was considerably reduced (HR: 0.37; 95% Confidence Interval: 0.15–0.95, p = 0.03). Thus, lowering BP to below 130 mmHg could be of benefit in certain situations [9].

These results are corroborated by those of the ACCORD Study, which also focused on two BP targets—below 120 mmHg and below 140 mmHg—in 4,733 patients with type 2 diabetes. The respective annual incidences of CVA were 0.32% and 0.53% (HR: 0.59; 95% Confidence Interval: 0.39–0.89; p = 0.01) but annual death rates (all causes) were, respectively, 1.28% and 1.19% (HR: 1.07; 95% Confidence Interval: 0.85–1.35; p = 0.55) [10].

In consequence, the new American Heart Association/American Stroke Association (AHA/ASA) guidelines on secondary prevention recommend lowering BP to below 140 mmHg, and in some situations such as lacunar infarct, to below 130 mmHg [11].

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dyslipidaemia

Many epidemiological studies have shown high cholesterol to be a risk factor for cerebral infarction. The therapeutic trials conducted to evaluate statins clearly showed that for primary prevention, the greater the decrease in low-density lipo-protein (LDL)-cholesterol, the greater the reduction in the risk of vascular events in general, including that of cerebral infarction. A recent meta-analysis showed that, for every 1 mmol/l drop in LDL-cholesterol, the risk of cerebral infarction is reduced by 21%, whatever the subject’s age or baseline risk level [12].

With respect to secondary prevention, the SPARCL Study, which covered 4,731 patients who had had a CVA or a TIA in the six months preceding inclusion, also showed that lowering LDL-cholesterol was associated with a reduction of the order of 16% in the risk of recurrent CVA within six years (Figure 2) [13].

The benefit of lowering LDL-cholesterol is therefore clearly demonstrated in both primary and secondary prevention.

AHA/ASA guidelines recommend giving all high-risk patients statins for primary prevention, and for secondary prevention in patients whose LDL-cholesterol is above 1 g/l, especially if the accident was associated with atherosclerosis [11].

Similarly, the French Supreme Health Authority recommends statin treatment for patients who have had a non-cardioembolic cerebral infarct or TIA associated with a LDL-cholesterol level of 1 g/l or higher. The recommended LDL-cholesterol target

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is below 1 g/l. Patients with diabetes and those with a history of coronary heart disease should be on a statin whatever their LDL-cholesterol.This treatment should be considered in a patient with LDL-cholesterol below 1 g/l who has experienced a cerebral infarct or TIA associated with symptomatic athero-sclerotic disease [14].

diabetes

It is now clear that controlling blood glucose reduces the risk of microvascular com-plications in diabetics although benefit vis-a-vis macrovascular problems remains to be demonstrated, especially with respect to CVAs.

Until recently, bringing BP down below 120/80 mmHg was recommended in this population but now the recommended reduction is only to below 140/90 mmHg. The value of statins in these patients ought to be emphasised [15].

lack of exercise and diet

We have a great deal of information from observational studies that suggest that ex-ercise prevents CVAs. The 2008 American guidelines recommend that adults should exercise moderately (e.g. brisk walking) for at least 150 minutes a week or perform intense, aerobic activity (e.g. running) for 75 minutes a week (or some combination of the two).

The 2013 AHA/ASA lifestyle guidelines for the prevention of cardiovascular dis-ease recommend at least 40 minutes of aerobic exercise three or four times a week in order to reduce BP and improve lipid profile

If possible, patients who have had an ischaemic CVA or TIA should do three or four sessions of moderate to intense, aerobic physical exercise to address CVA risk factors. Each session should last 40 minutes on average.

For patients who have a deficit after an ischaemic CVA, supervision by a profes-sional (e.g. a physical therapist or expert in cardiac re-education) might be advisable, at least at the beginning of the exercise programme.

Similarly on diet, there is a body of data from epidemiological studies and, to a lesser extent from randomised studies. The 2014 AHA/ASA guidelines on primary CVA prevention recommend:

– Cutting down sodium intake and raising potassium intake to lower BP (class I, level A).

– A DASH-type diet, which emphasises fruit, vegetables and dairy products, coupled with reducing saturated fat intake, to lower BP (class I, level A).

– A diet rich in fruit and vegetables, which is therefore rich in potassium and can reduce the risk of CVA (class I, level B).

– A Mediterranean diet complemented with nuts to reduce CVA risk (class IIa, Level B) [16].

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antithrombotic drugs

The second aspect of CVA prevention is represented by two big families of me-dicinal products, namely antiplatelet drugs for non-cardioembolic accidents, and anticoagulants for cardioembolic accidents.

antiplatelet drugs

Antiplatelet drugs have been solidly demonstrated as being effective at preventing cerebral infarction in patients who have already had a cerebral infarct or a TIA. Nevertheless, the question of which drug to prescribe arises. In secondary preven-tion, three options can be considered as equivalent, i.e. aspirin, clopidogrel and a combination of aspirin and dipyridamole [17].

Studies of combinations of antiplatelet drugs have shown that combining aspirin with clopidogrel affords no advantage and raises the risk of bleeding. On the other hand, this combination may help prevent recurrence if administered in the acute phase of a minor or transient accident although this is not established. The results of some studies support this strategy, in particular a recently published Chinese study of 5,170 patients who had had a TIA or a minor cerebral infarct in the preceding 24 hours. They were given either a combination of clopidogrel + aspirin (clopidogrel at an initial dose of 300 mg then 75 mg daily for 90 days + aspirin at a daily dosage of 75 mg for the first 21 days) or placebo + aspirin (75 mg a day for 90 days). After 90 days, the combination proved more effective than aspirin alone at preventing cer-ebrovascular accidents (CVA) (HR: 0.68; 95% CI: 0.57–0.81; p<0.001) (Figure 3) [18]. The treatment is recommended in the 2014 AHA/ASA guidelines to prevent CVA in patients with a history of either CVA or TIA; it can be offered for a short course but not for long-term treatment [11].

anticoagulants

Anticoagulants are essentially prescribed to manage atrial fibrillation (AF), which increases the risk of cerebral infarction by a factor of five. This is a problem of the elderly, affecting fewer than 0.5% of people under 50 as opposed to 5–15% of over 80 year-olds [19]. After 70 years of age, 30% of patients who have had an ischaemic CVA suffer from AF compared with 20% of patients across all ages [20]. Cerebral infarction associated with AF has a mortality rate within one month of 32.5% compared with 16.2% without AF. [21]. The resultant disability following cerebral infarction is worse in those with AF than in those without it [20].

However, oral anticoagulant drugs represent a very effective treatment modal-ity. It has been shown in many studies that anticoagulant therapy reduces the risk of a cerebral embolic event by two-thirds (12% vs 4%) (RRR: 66%; 95% CI: 43–80) [22].

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New oral anticoagulants have been evaluated in large-scale studies covering more than 10,000 patients [23, 24]. They proved not to be inferior to VKAs in the preven-tion of CVA and some even show slight superiority at preventing cerebral infarction; however, most importantly, they have the big advantage of being associated with less risk of cerebral bleeding [25-29].

revascularisation

Revascularisation mainly concerns extracranial carotid stenosis, which may be asymptomatic in primary prevention or symptomatic in secondary prevention.

Carotid stenosis is investigated in patients with vascular disease (coronary heart disease, peripheral arterial disease, aortic disease) who are diabetic or have had a CVA or a TIA affecting a different part of the brain. Carotid stenosis is classified as

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figure 3. Aspirin + clopidogrel in the acute phase of TIA or mild cerebral infarction [18].

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symptomatic if the cerebral infarct or TIA was recent and involved the same territory as the stenosis.

The two situations are completely different. Thanks to the treatment modalities available (statins, general improvement in risk factor management), the risk of an event in the territory of the stenosis is extremely low—below 1% for asymptomatic carotid stenosis [30]. Above all, this constitutes a marker for the risk of vascular events (a coronary event, death due to a vascular problem over 2% a year). Treatment is essentially medical and the benefit of surgery is extremely low in this situation.

On the other hand, symptomatic carotid stenosis is associated with a very high incidence of recurrence within days or weeks of the first event [31-33]. In this situ-ation, surgery is of great benefit, especially if the artery is narrowed by more than 70%. Angioplastic stenting is an alternative strategy although it has an excess risk of complications (CVA, death) in the short term; nevertheless, it is probably as effec-tive as surgery in the medium and long terms.

asPirin and Primary Prevention

Aspirin has been shown to be effective at preventing vascular events, especially coronary events [34]. Curiously, aspirin helps prevent coronary events in men but not women, whereas it is beneficial for primary prevention in women but not men. In consequence, the AHA/ASA guidelines on primary CVA prevention state that aspirin can be given to patients with a ten-year vascular risk of over 10%, and to women in order to prevent a first ischaemic accident, especially women with diabetes [11].

sPecificities of cva in Women

CVAs are more common in women (because they live longer) and the associated morbidity and mortality are worse as well as institutionalisation being a more com-mon consequence. HT is the most common cause in women of over 60 [35]. Women have specific risk factors (pregnancy, endocrine factors, contraception, hormone treatment, early menopause, migraine with aura) as well as specific causes like eclampsia. These specificities were addressed in a global campaign in 2014 with the message, “I’m a woman, stroke affects me”.

Prevention does not differ much between men and women. Prophylactic surgery for asymptomatic carotid stenosis is clearly of less benefit in women than it is in men. Oestrogen-progestin contraception and hormone replacement treatment are contraindicated after a cerebral infarct or TIA although pure progestin is safe. For primary prevention, aspirin can be proposed.

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conclusion

The ways of preventing a first event or recurrence are globally identical but the absolute benefit will differ in primary and secondary prevention.

There has been massive progress in prevention over the last 30–40 years, resulting in a real reduction in the incidence of the disease although the absolute number affected is inexorably rising because of ageing of the population.

Many of the risk factors for CVA are continuous variables, which have practical implications, e.g. it could be worth lowering BP below the recommended target to cut the risk down further.

Although recent advances have been more modest, rigorous application of existing recommendations will reduce the scope of the problem.

references

1 Mohan KM, Wolfe CD, Rudd AG, et al. Risk and cumulative risk of stroke recurrence: a system-atic review and meta-analysis. Stroke 2011;42:1489-94.

2 O’Donnell MJ, Xavier D, Liu L, et al. Risk factors for ischaemic and intracerebral haemor-rhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 2010;376: 112-23.

3 Lewington S, Clarke R, Qizilbash N, et al. Prospective Studies Collaboration. Age-specific rel-evance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903-13.

4 Rodgers A, MacMahon S, Gamble G, et al. Blood pressure and risk of stroke in patients with cerebrovascular disease. The United Kingdom Transient Ischaemic Attack Collaborative Group. BMJ 1996;313:147.

5 Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet 2001;358:1305-15.

6 Liu L, Wang Z, Gong L, et al. Blood pressure reduction for the secondary prevention of stroke: a Chinese trial and a systematic review of the literature. Hypertens Res 2009;32:1032-40.

7 Rashid P, Leonardi-Bee J, Bath P. Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review. Stroke 2003;34:2741-8.

8 Ovbiagele B, Diener HC, Yusuf S, et al. Level of systolic blood pressure within the normal range and risk of recurrent stroke. JAMA 2011;306:2137-44.

9 SPS3 Study Group, Benavente OR, Coffey CS, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013;382:507-15.

10 ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85.

11 Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:2160-236.

12 Cholesterol Treatment Trialists’ (CTT) Collaborators, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.

13 Amarenco P, Bogousslavsky J, Callahan A, III, et al. High-dose atorvastatin after stroke or tran-sient ischemic attack. N Engl J Med 2006;355:549-59.

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14 HAS. Prévention vasculaire après un infarctus cérébral ou un AIT—Actualisation. Juillet 2014, mise à jour février 2015.

15 American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care 2013;36(Suppl 1):S11-66.

16 Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:3754-832.

17 Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of an-tiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.

18 Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient is-chemic attack. N Engl J Med 2013;369:11-9.

19 Grau AJ, Weimar C, Buggle F, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke 2001;32:2559-66.

20 Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996;27:1760-4.

21 Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke 2005;36:1115-19.

22 Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-67.

23 Turpie AG. New oral anticoagulants in atrial fibrillation. Eur Heart J 2008;29:155-65.24 Hankey GJ, Eikelboom JW. Antithrombotic drugs for patients with ischaemic stroke and transient

ischaemic attack to prevent recurrent major vascular events. Lancet Neurol 2010;9:273-84.25 Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial

fibrillation. N Engl J Med 2011;365:981-92.26 Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J

Med 2010;363:1875-6.27 Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial

fibrillation. N Engl J Med 2013;369:2093-104.28 Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrilla-

tion. N Engl J Med 2011;365:883-91.29 RCP Rivaroxaban, 2013.30 Naylor AR. Time to rethink management strategies in asymptomatic carotid artery disease. Nat

Rev Cardiol 2011;9:116-24.31 Blaser T, Hofmann K, Buerger T, et al. Risk of stroke, transient ischemic attack, and vessel

occlusion before endarterectomy in patients with symptomatic severe carotid stenosis. Stroke 2002;33:1057-62.

32 Fairhead JF, Mehta Z, Rothwell PM. Population-based study of delays in carotid imaging and surgery and the risk of recurrent stroke. Neurology 2005;65:371-5.

33 Marnane M, Ni Chroinin D, Callaly E, et al. Stroke recurrence within the time window recom-mended for carotid endarterectomy. Neurology 2011;77:738-43.

34 Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849-60.

35 Bushnell C, McCullough LD, Awad IA, et al. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:1545-88.

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Organising health care pathways for stroke victims

France Woimant (Paris)

Organising the health care pathway of stroke victims is a big challenge. It involves planning the management of a pathology that is both urgent and chronic as well as being extremely common and striking people of all ages. Although strokes are more common after the age of 75, children are not invulnerable. The health care pathway has to be organised on a local basis, ideally in the patient’s health care region, and this applies from targeted prevention through hospitalisation to going back home.

COmmOn, seriOus and expensive

In France, almost 110,000 people are admitted into hospital every year with a stroke [1]. The number of French people who have had a stroke has been estimated at 780,000 on the basis of surveys of disability – health – households and disabil-ity—health—institution in 2008–2009 [2]. These surveys show that two-thirds of stroke victims experience sequelae and, in one case in two, such sequelae stop them carrying out one or more daily activities such as eating, walking, washing or getting dressed [2]. In these surveys, modified Rankin Scores were compared according to whether or not the subject had a history of stroke. The score was over 2 (corresponding to handicap that significantly restricts lifestyle or precludes full independence) in 34.4% of those with a history of stroke (28% of those living at home and 87.8% of those in an institution) compared with 3.9% of people with no history of stroke (3.1% of those living at home and 71.6% of those in an institu-tion) [3]. These surveys also show that almost a quarter of highly dependent patients with a Rankin Score of 5 (corresponding to severe handicap with total dependence requiring permanent supervision) have had a stroke. These figures alone illustrate the scope of the stroke problem, which is the main cause of acquired disability in adults.

Sequelae account for a large part of the financial burden that stroke imposes on the health insurance system and society. Annual stroke-related health care and medi-cosocial expenditure is high, estimated at 8.3 billion euros in 2007: e5.9 billion to the health care sector (3% of the overall budget) and e2.4 billion for medicosocial

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services. In 2004, mean annual expenditure per patient classified as having the Long-Term Condition (LTC) “debilitating stroke” was estimated at 9,642 euros (i.e. 14% more than for a patient with the LTC “Alzheimer’s disease”) [4]. In 2007, the mean cost of an incident case of stroke over the first year was 16,686 euros and the annual cost of a prevalent case was 8,099 euros although this varies enormously according to the sequelae and the degree of disability [5].

a pathway that starts with preventiOn

Prevention remains the best way of reducing the incidence and repercussions of stroke. Screening for and managing risk factors are the main issues when it comes to preventing strokes and indeed all cardiovascular diseases (coronary heart disease, peripheral arterial occlusive disease, kidney failure, etc.). Preventive measures concern all ages, from childhood (school programmes) to old age. These need to be multiculturally structured to reach everyone. Targeted stroke preventive measures can be backed up by outpatient education, e.g. focusing on hypertension, which is the main risk factor for stroke. Such actions are all the more accessible if they are provided close to the patient’s home.

hOspital

In the acute phase when every minute counts, care should also be organised locally, ideally at a Stroke Unit (SU). One hundred and forty SUs are to be established in the framework of the 2010–2014 National Stroke Plan. But unfortunately, this will not ensure one within a 30-minute journey of anywhere a stroke could occur. Patients may also be first seen at a nearby establishment with an Emergency Department. These should have appropriately trained staff in both the Emergency and Radiology Departments together with neuro-imaging facilities available around the clock, seven days a week, as well as appropriate remote diagnosis and therapeutic advice possibilities (telemedicine) [6]. In establishments with an Emergency Department but no SU, initial treatment is prescribed by the emergency physician and a neurolo-gist after a visio-consultation and transfer of neuro-imaging results. Once treatment has been started, the patient is transferred to a SU.

After the acute phase, 30% of patients are transferred to a rehabilitation unit [7]; this period usually lasts weeks and is psychologically stressful so the patient should not be taken far away from his or her family and friends [8]. Moreover, discharge home will be easier to organise from a nearby establishment, which will be more familiar with local medicosocial and social resources. The return home with support through rehabilitation unit can only be organised if the establishment is close to the patient’s home.

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returning hOme

Stroke management does not end with discharge from the hospital and it should take into account the return of the patient back to his or her home so coordination be-tween independent health professionnals and the hospital is important. Going back home is a difficult time for patient and family who are only just beginning to realise how the stroke is going to disrupt the daily routines of their professional and family lives.

Many factors will determine whether or not the patient will be able to stay at home, including:

• the degree of physical disability and cognitive deficit,• complications,• help at home,• training of carers,• psychological support for the patient and carers.

Following a stroke, it is essential to organise coordinated follow-up between local support workers and professional health care providers in order to prevent recur-rence, complications and loss of independence. Close cooperation is therefore very important between health care professionals and support workers [9]:

• independent professional health care providers (general practitioners, neurologists, nurses, physical therapists, speech therapists, occupational thera-pists, psychologists, social workers, etc.),

• health care professionals from centres of excellence,• professionals from:

– structures and services for the disabled: medicosocial support services for disabled adults (SAMSAH, services d’accompagnement médico-social pour adultes handicapés), social life support services (SAVS, services d’accompagnement à la vie sociale), Departmental homes for the disabled (MDPH, maisons départementales des personnes handicapées), etc.;

– structures and services for the elderly such as home for the independence and integration of Alzheimer’s patients (MAIA, maisons pour l’autonomie et l’intégration des malades Alzheimer), local information and coordina-tion centres (CLIC, centres locaux d’information et de coordination) and medicosocial teams for personalised allocation of independence (APA, allocation personnalisée d’autonomie);

– organisations that adapt homes.

• home help, cleaners,• carers, etc.

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new OrganisatiOns tO help keep patients at hOme

assessment of how to improve coordination between hospital and the independent sector

• Post-stroke multidisciplinary assessment in the hospital involves evaluation by a team specialising in neurovascular disease working together with independent professional health care providers. The aims of the assessment are to:

– review the disease situation, identify vascular risk factors and plan secondary prevention measures;

– perform a physical work-up to define a personalised care programme; – monitor for mood problems (depression is very common after a stroke); – assess capacities for social and professional reintegration; – assess the quality of life of the patient and his/her family and friends, and

see if the carers need support; – if necessary, offer therapeutic education; – give information about patient support groups.

These assessments are relevant to all patients, even those who have no sequelae because they will bring to light past, hitherto unrecognised, deficiencies that could lead to disability or the loss of social and professional adaptability.

• Mobile stroke follow-up care and rehabilitation teams have been established on an experimental basis in certain regions including the Île-de-France region around Paris. These teams mainly come in to provide short-term help to over-come difficulties that might threaten the patient’s ability to stay at home. They consist of a physician, an occupational therapist and a social worker who come to the home or carry out their work at an institution. Their job is to improve conditions in the home (assessment of the patient and carers), to prepare for hospital admissions (avoiding unnecessary admissions) and organise the return home. These assessments are undertaken in collaboration with independent professionals and medicosocial structures.

Care teams coordinated at home with the hospital team

A meta-analysis based on individual data from 11 trials showed that services aimed at providing early, coordinated care in the home cut down the risk of long-term dependence and institutionalisation in some stroke patients [10]. The beneficial ef-fect vis-à-vis daily activities can persist to five years after the stroke [11]. The main objective of this type of coordinated rehabilitation in the home is the acquisition and enhancement of independence in daily life through rehabilitation and by ensuring that what we have learned is applied to daily life. Hospital coordination permits continued multidisciplinary rehabilitation with a goal of improved function and opti-misation of acquired knowledge in the context of patients’ lives. It makes it possible

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for patients to access professional re-educators that are not found in independent practice such as occupational therapists, clinical psychologists, neuropsychologists and social workers experienced with disability. It also helps train carers and those who live with the patient. Experiments have been conducted on this in France: a mobile disability assessment and follow-up unit in Mulhouse, hospitalisation to home rehabilitation and reintegration in Île-de-France. It is nevertheless important to remember the possible risk of placing an excessive psychological burden on the family as well as professional and informal carers.

preventing reCurrenCe

Preventive measures that match the type of the stroke and its aetiology are essential. However, studies conducted in France using SNIIR-AM databases and covering 69,262 patients admitted into hospital after a stroke or a transient ischaemic attack (TIA) in the first six months of 2008 showed that only 75% of victims of a cerebral infarct and 70% of those who experienced a TIA were prescribed an antithrombotic drug [12].

health Care Channels Ought tO be adapted tO the patient’s age and the seriOusness Of the defiCit

How stroke victims are channelled through the health care system ought to take into account:

• The patient’s age. For a child, the channel will not be the same if the stroke occurs before birth, in the first days of life, in a child or in a teenager. These children should also be monitored through adulthood. For the elderly, it is estimated that in 2020, almost 30% of people admitted into hospital for stroke will be over 85 so stroke care pathways ought to be organised in coordination with geriatric channels.

• The severity of the stroke. Organisation of the care for a TIA is quite different from that of a severe stroke [13]. For patients with a severe stroke who are admitted straight into an intensive care unit, the following options need to be considered: – limitation of care; – organ donation (stroke is the leading cause of brain death); – transfer to a palliative care unit; – transfer to a post-intensive care rehabilitation unit; – transfer to a long-term care unit; – permanent or temporary accommodation in a specialised medicosocial

structure: a reception house (MAS, maison d’accueil spécialisé), a

France Woimant

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medicalised reception home (FAM, foyer d’accueil médicalisé) or a home for the dependent elderly (EHPAD, établissement d’hébergement pour personnes âgées dépendantes).

hOw tO COOrdinate and run the strOke Care pathway

Nurse “coordinators” in stroke care are still too few in number. Nevertheless, their role is central when stroke victims return home. Their main jobs are to ensure compliance with treatment (drugs and rehabilitation) and tell patients and fam-ily members about signs of developing complications, which might exacerbate the disability. These nurses call patients after they have gone back home and/or attend the consultation with a neurologist. They provide a link between professionals at the hospital and in the independent sector [14].

In line with the 2010–2014 Stroke Plan, coordinators involved in the stroke care pathway are helping to build an effective health care pathway for stroke victims. Their main jobs are to:

– develop and coordinate the stroke pathway around SUs in order to ensure con-tinuous care by improving hospital circuits and creating links with independent practitioners, the medicosocial sector and patient support groups;

– enhance training of all the professionals involved in the pathway; – organise mass educational campaigns for the general public across the country.

In conclusion, looking after patients after a stroke is not limited to admission into a Stroke Unit during the acute phase and then if necessary, in follow-up care and rehabilitation departments. The whole of the stroke victim’s health care pathway needs to be organised and planned together with the patient, his or her family and a variety of different health care professionals. This pathway should be local, ide-ally within the health care region. Structuring the regional organisation of stroke care will prevent gaps in the pathway, which too often ends up with emergency admission into an establishment that is poorly suited to coping with the attendant problems. In collaboration with independent professional health care providers, new organisations are being set up to raise the proportion of patients who are chan-nelled into stroke-specific pathways, the aim being to reduce disability after stroke and improve patients’ quality of life as well as that of their family and friends; not to forget prevention, which remains the best way of reducing stroke-related disability.

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references

1 de Peretti C, Nicolau J, Tuppin P, et al. Evolutions de la prise en charge hospitalière des accidents vasculaires cérébraux en court séjour et en soins de suite et de réadaptation entre 2007 et 2009 en France. Presse Med 2012;41:491-503.

2 de Peretti C, Grimaud O, Tuppin P, et al. Prévalence des accidents vasculaires cérébraux et de leurs séquelles et impact sur les activités de la vie quotidienne: apports des enquêtes déclaratives Handicap-santé-ménages et Handicap-santé-institution. Bull Epidemiol Hebd 2012;1:1-6.

3 Schnitzler A, Woimant F, Tuppin P, de Peretti C. Prevalence of self-reported stroke and disability in the French adult population: a transversal study. PLoS One 2014;9(12):e115375.

4 Fery-Lemonnier E. Rapport ministériel sur la prévention et la prise en charge des accidents vasculaires cérébraux en France. Juin 2009.

5 Chevreul K, Durand-Zaleski I, Gouépo A, et al. Cost of stroke in France. Eur J Neurol 2013;20: 1094-100.

6 Circulaire N°DGOS/R4/R3/PF3/2012/106 du 6 mars 2012 relative à l’organisation des filières régionales de prise en charge des patients victimes d’accident vasculaire cérébral (CVA).

7 de Peretti C, Nicolau J, Holstein J, et al. Hospitalisations en soins de suite et de réadaptation en France après un accident vasculaire cérébral survenu en 2007. BEH 2010; 49-50:501-6.

8 Brainin M, Olsen TS, Chamorro A, et al. Organization of stroke care: education, referral, emergency management and imaging, stroke units and rehabilitation. European Stroke Initiative. Cerebrovasc Dis 2004;17(Suppl 2):1-14.

9 Gache K, Leleu H, Nitenberg G, et al. Main barriers to effective implementation of stroke care pathways in France: a qualitative study. BMC Health Serv Res 2014;14:95.

10 Langhorne P, Taylor G, Murray G, et al. Early supported discharge services for stroke patients: a meta-analysis of individual patients’ data. Lancet 2005;365:501-6.

11 Thorsén AM, Holmqvist LW, de Pedro-Cuesta J, von Koch L. A randomized controlled trial of early supported discharge and continued rehabilitation at home after stroke: five-year follow-up of patient outcome. Stroke 2005;36:297-303.

12 Moysan TV, de Peretti S, Woimant F. Caractéristiques et traitements des assurés du régime général hospitalisés pour accident vasculaire cérébral au cours du premier semestre 2008. Rev Neurol 2008;169:126-35.

13 Woimant F, Biteye Y, Chaine P, Crozier S. Severe stroke: which medicine for which results? Ann Fr Anesth Reanim 2014;33:102-9.

14 Cortes E, Woimant F. L’éducation du patient post-accident vasculaire cérébral. STV 2007;19:492-4.

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