Jörg Wissel, MD1, Anthony B. Ward, BSc, MD, FRCPEd, FRCP2, Per Erztgaard, MD3, Djamel Bensmail, MD4, Martin J. Hecht, MD5, Thierry M. Lejeune, MD, PhD6 and Peter Schnider, MD7

From the 1Kliniken Beelitz GmbH, Clinical Department of Neurological Rehabilitation, Beelitz-Heilstaetten, Germany, 2North Staffordshire Rehabilitation Centre, Haywood Hospital, Stoke on Trent, UK, 3Department of Rehabilitation Medicine, University Hospital, Linköping, Sweden, 4Physical Medicine and Rehabilitation Department, Hôpital R. Poincaré, Université de Versailles-Saint-Quentin, Garches, France, 5Department of Neurology, Bezirkskrankenhaus Kaufbeuren, Faculty of Medicine, University of Erlangen, Erlangen Germany, 6Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Physical Medicine and Rehabilitation Department, Brussels, Belgium and 7Landsklinikum Wiener Neustadt und Hochegg, Department of Neurology, Wiener Neustadt, Austria

Co-authors: Maria C. Altavista, MD, PhD8, Stefano Cavazza, MD9, Thierry Deltombe, MD10, Esther Duarte, MD, PhD11, Alexander C. H. Geurts, MD, PhD12, Jean-Michel Gracies, MD, PhD13, Naseer H. J. Haboubi, MB, ChB, FRCP, MSc14, Francisco J. Juan, MD, PhD15, Helge Kasch, MD, PhD16, Christian Kätterer, MD, FMH Neurologie17, Yeşim Kirazli, MD18, Paolo Manganotti, MD19, Yeşim Parman, MD20, Tatjana Paternostro-Sluga, MD, PhD21, Konstantina Petropoulou, MD, PhD22, Robert Prempeh, MB, BS, MBA, D Phil, FRCSEd, FRCSGlas23, Marc Rousseaux, MD, PhD24, Jaroslaw Slawek, MD, PhD25 and Niko Tieranta, MD26

From the 8S. Filippo Neri Hospital Neurology Unit, Department of Neurological Science, Rome, 9Department of Rehabilitation S. Giorgio Arcispedale S. Anna Ferrara, University of Ferrara, Ferrara, Italy, 10Université Catholique de Louvain, Cliniques Universitaires de Mont-Godinne, Physical Medicine and Rehabilitation Department, Yvoir, Belgium, 11Servei de M. Física i Rehabilitació, IMAS Hospitals del Mar i l’Esperança, Barcelona, Spain, 12Radboud University Nijmegen Medical Centre and St. Maartenskliniek, Rehabilitation Department, Nijmegen, The Netherlands, 13Chef de Service, Médecine Physique et de Réadaptation, Unité de Neurorééducation, CHU Henri Mondor, Créteil, France, 14Nottingham University Hospitals Trust, Nottingham, UK, 15Servicio de Medicina Física y Rehabilitación, Complexo Hospitalario Universitario de Vigo, Vigo, Spain, 16Staff Specialist Neurology, Danish Pain Research Center, Department of Neurology, Aarhus University Hospital, Aarhus, Denmark, 17REHAB Basel, Basel, Switzerland, 18Ege University, Faculty of Medicine, Physical Medicine and Rehabilitation Department, Izmir, Turkey, 19Section of Rehabilitative Neurology, Department of Neurological Sciences and Vision, University of Verona, Verona, Italy, 20Istanbul University, Istanbul Faculty of Medicine, Neurology Department, Istanbul,Turkey, 21Department of Physical Medicine and Rehabilitation, Medical University of Vienna, Vienna, Austria, 222nd Department of Physical and Rehabilitation Medicine, National Rehabilitation Center, Athens, Greece, 23Rehabilitation Medicine, Stirling Royal Infirmary, Stirling, UK, 24Service de Rééducation Neurologique, Hôpital Swynghedauw, CHRU, Lille Cedex, France, 25Neurology Department, St. Adalbert Hospital and Department of Neurological-Psychiatric Nursing, Medical University of Gdansk, Gdansk, Poland and 26Lapland Rehabilitation Centre, Rovaniemi, Finland.

A group of clinicians from across Europe experienced in the use of botulinum toxin type A for the treatment of spasticity following acquired brain injury gathered to develop a consensus statement on best practice in managing adults with spasticity. This consensus table summarizes the current published data, which was collated following extensive literature searches, their assessment for level of evidence and discussion among the whole group. Published information is supplemented by expert opinion based on clinical experience from 16 European countries, involving 28 clinicians, who treat an average of approximately 200 patients annually, representing many thousand spasticity treatments with botulinum toxin per year.

Key words: botulinum toxin, upper motor neurone syndrome, adult spasticity, acquired brain injury.

J Rehabil Med 2009; 41: 13–25

Correspondence address: Jörg Wissel, Kliniken Beelitz GmbH, Clinical Department of Neurological Rehabilitation, Paracelsusring 6A, DE-14547 Beelitz-Heilstaetten, Germany. E-mail: wissel@rehaklinik-beelitz.de

Submitted August 4, 2008; accepted September 30, 2008

INTRODUCTION: DEVELOPMENT OF THE CONSENSUS TABLE

Botulinum toxin type A is a valuable treatment in the management of the focal problems of spasticity following acquired brain injury, which includes injury due to trauma, stroke, haemorrhage and hypoxia. This paper seeks to present a European consensus view on the management of adults with spasticity following an acute injury and was developed as a platform for defining and communicating the accepted best practice for the use of botulinum toxin type A.

This consensus statement was developed by drawing on the combined expertise of a number of renowned experienced users of botulinum toxin from 16 European countries. The process consisted of conducting a comprehensive literature search, identifying randomized controlled trials and other high-quality research papers, assessing the evidence, and forming consensus statements after extensive discussions.

The consensus statement was divided into 10 areas: Adult Spasticity; Service Configuration; Treatment Options; Medico-legal Considerations; Assessment and Goal Setting; Botulinum toxin type A Use and Dosage; Pharmacology of Botulinum Toxin type A; Dilution and End-plate Targeting; Patient Follow-up; and Research Challenges.

The literature search for each of the first 9 topic areas was conducted using the following databases: Medline, EMBASE, EMBAL, BIOSIS, SciSearch, PASCAL, HCAplus and IPA. Clinical studies focused on randomized controlled trials or meta-analyses of studies that used botulinum toxin type A to treat spasticity resulting from acquired brain injury. Review articles were also included where appropriate.

A preliminary summary was compiled and presented to the group at a consensus meeting held in Potsdam, Germany in October 2007. The material was discussed and the content of each section revised after the meeting in the light of the discussions. Authors then reviewed and endorsed the content of the revised presentations, which provided the basis for the first draft of the statement. The manuscript subsequently underwent review and revision by each member of the consensus group. The text provides a short summary of each section; the consensus statements are given in Table I.

ADULT SPASTICITY

This paper considers the spasticity that occurs in adults as a result of acute acquired brain injury due to trauma, stroke (including subarachnoid haemorrhage) and hypoxia. Lance’s definition of spasticity “a velocity-dependent increase in tonic stretch reflex” (1) was used as the basis for discussing the impact spasticity as part of the upper motor neurone (UMN) syndrome.

The UMN syndrome is a well-defined concept that involves both positive and negative clinical phenomena (Table II) following damage of the central nervous sensorimotor system. The constellation of phenomena form a clinical pattern that is useful for diagnostic purposes; however, this classification may be regarded as somewhat out of date and inconsistent in terms of the underlying physiology.

Gracies (2, 3) points out that patients with spasticity form a clinically and physiologically recognizable population. They are disabled by 3 main features: (i) paresis, i.e. reduced recruitment of skeletal motor units; (ii) soft tissue contracture, in particular muscle shortening and joint retraction; and (iii) muscle overactivity, i.e. reduced ability to relax muscle and co-contraction. These changes give rise to the commonly observed clinical picture of: shortened overactive muscles; velocity-dependent stiffness of limbs (by contrast to hypertonia which is not velocity dependent); loss of fine motor control; weakness masked by stiffness; muscle spasms; changes in limb posture; fatigue.

Besides acquired brain injury, the UMN syndrome also involves spinal cord injury, cerebral palsy and progressive neurological disease, but these conditions are not included in the current discussion as they have different clinical characteristics and courses and therefore, in some aspects, require different treatment considerations.

Spasticity is only one aspect of the UMN syndrome and other features also contribute to activity limitation and participation restriction. For instance, thixotropic changes in muscles, due to or as a consequence of spasticity, can impair people’s physical abilities (e.g. as a result of increased muscle stiffness) and have a major impact on their lifestyle. The functional consequences of UMN syndrome and spasticity are highly variable. The most affected patients are unable to perform many activities of daily living, resulting in poor self-care and/or difficulty for carers in maintaining hygiene, for example because of finger contractures. They become dependent on assistance from family members and/or carers, may have impaired social participation, lose self-esteem and develop a poor body image. Less affected patients may present with a more limited movement disorder, for example equinovarus affecting gait. All patients may also experience pain, depression and impaired quality of life (4, 5).

The incidence of troublesome spasticity requiring treatment following acquired brain injury is not precisely known, as studies are lacking, but some have suggested that 19% of patients after stroke have spasticity at 3 months and 38% at 12 months after the original trauma (6–8). Upper extremity hypertonia (Ashworth score > 1) was seen in 63% of patients with initial paralysis due to acute supratentorial stroke during the first 26 weeks post-stroke (9). Lacunar infarction, most posterior infarctions and rostrally located anterior infarctions do not usually give rise to spasticity (10).

However, these studies use different quantitative criteria to define spasticity and, when the Lance definition is used, almost all hemiparetic patients can be considered as having spasticity (2, 3).

The development of spasticity following acquired brain injury also does not follow a predictable pattern (9), emphasizing the need for organized regular assessment and, where necessary, a treatment plan, on an individual basis. There is a lack of evidence-based clinical data on spasticity assessment; assessment protocols are only available for stroke survivors. In other causes of spasticity clinical experience has shown that there are some more predictable sub-groups of patients, but currently they are poorly documented.

SERVICE CONFIGURATION

Spasticity management must be undertaken by a multidisciplinary team, since optimal treatment involves physical therapy in conjunction with intermittent pharmacological treatment. It is very important that patients are referred to spasticity or rehabilitation services, which essentially include clinicians with the necessary training, competence, expertise and facilities, including space and equipment.

Guidelines for rehabilitation of adults with stroke have been published in the US (11). Specific guidance on the use of botulinum toxin therapy in the management of spasticity has also been published and endorsed by the Royal College of Physicians (UK) (12, 13) and has gained wide acceptance.

It is important that multidisciplinary teams have access to both secondary and primary (community) medical services, so that patients can receive the necessary physiotherapy and occupational therapy services. Appropriate rehabilitation programmes are defined for each patient with emphasis on the new rehabilitation techniques that exploit the neuroplasticity of the brain.

Specialist spasticity and rehabilitation services have an advantage over ad hoc arrangements, in that their healthcare professionals have the experience and expertise of guiding patients to realistic and timely goals in order to achieve optimal outcomes. They are also able to raise awareness amongst patients and carers about spasticity, the availability of new treatments and treatment strategies and how good referrals may be made to them.

TREATMENT OPTIONS

A variety of treatment options is available and clinical experience has shown that a multi-modal approach has many benefits in combining physical therapies with surgical and/or pharmacological treatments.

There is ample evidence (12 studies in upper limb, 7 in lower limb, 2 mixed upper and lower limb and one meta-analysis) that botulinum toxin type A significantly decreases muscle tone and improves passive function (Table III). The demonstration of functional gains has proved more difficult (14). Some studies of single treatments with botulinum toxin produce conflicting results, which could be related to methodological problems in showing the improvement. However, combining toxin injections with physical therapy has shown functional improvements, lending support to the idea that this should be part of a comprehensive spasticity service.

MEDICO-LEGAL CONSIDERATIONS

The licensed indications for botulinum toxin type A use vary throughout Europe, with licensing often restricted to stroke and upper limb (Table IV) and much usage off-label. This may pose problems for patients and physicians in accessing effective treatment, and contributes to an inequitable access to specialist spasticity services across Europe.

There is a paucity of studies addressing the direct cost-effectiveness of botulinum toxin type A in adult spasticity. Three studies have been carried out using panels of physicians and other healthcare professionals to provide treatment scenarios and anticipated improvement for typical patients with post-stroke spasticity (15–17). These scenarios were then used to calculate costs. The studies concluded that botulinum toxin type A gave significant benefit for little additional cost and, when calculated as cost per successful month of treatment ratio, using botulinum toxin type A actually cost less than not including it in the treatment regimen. These studies suggest therefore that botulinum toxin type A would be a cost-effective treatment for post-stroke spasticity.

More information is available on the costs associated with the complications following stroke, such as falls, fractures, or the pressure sores that may develop as a consequence of spasticity. The costs of these complications are considerable and will have significant impact on healthcare budgets.

There is a potential risk of adverse events associated with distant spread of toxin and, for this reason, the summary of product characteristics (SmPC) for both Dysport® and BOTOX® have recently introduced some additional statements about patient monitoring. The SmPC for Dysport® states that “Side-effects related to spread of toxin distant from the site of administration have been reported (exaggerated muscle weakness, dysphagia, aspiration/aspiration pneumonia, with fatal outcome in some very rare cases)”. The BOTOX® SmPC states “Side-effects related to spread of toxin distant from the site of administration have been reported, sometimes resulting in death, which in some cases was associated with dysphagia, pneumonia and/or significant debility”. All patients receiving botulinum toxin therapy should be advised to contact their doctor and seek medical attention immediately if they develop breathing, swallowing, or speech difficulty or any severe allergic reaction.

ASSESSMENT AND GOAL SETTING

An essential part of treating spasticity is a proper assessment of the individual’s clinical status including a full neurological assessment, noting positive and negative signs of the UMN syndrome (Table II). Functional problems must be addressed and any confounding or exacerbating conditions, such as infection, pain, constipation and other nociceptive influences should be identified and treated (12). Treatment plans can then be devised on an individual basis.

The specialist will need to assess the patient, involving family and carer(s) fully in the planning of treatment, which allows the multidisciplinary management team to define realistic goals and the expectation of outcomes. Briefly, these goals can be related to functional use, especially in the lower limbs; to comfort, especially in the upper limbs or proximal part of the lower limb; or to pain-related spasticity.

Methods of assessing the effectiveness of treatment must be in place and individualized outcome measures should be based on the World Health Organization (WHO) International Classification of Functioning, Disability and Health (ICF) model. Assessments should be performed at regular intervals and continuing treatment should be refined in light of these assessments.

BOTULINUM TOXIN TYPE A USE AND DOSAGE

Botulinum toxin type A treatment should be given as part of an integrated treatment programme involving all the available relevant treatment modalities. Dosages are determined by the individual patient’s condition and the goals of treatment and can be reassessed according to the response. It is common clinical practice to initiate therapy at low, but effective, doses and titrate upwards as effects become evident. In order to have a uniform uptake of botulinum toxin within muscles, the muscle is injected in more than one site and this is particularly important in larger muscles, where the dose is divided across multiple sites. A single muscle is rarely treated in isolation and it is important that the pattern of muscle under- and over activity, at rest and while moving, is understood, so that relevant muscles can be treated appropriately.

As there is a lack of uniformity in terms used to describing the anatomical pattern of injections, the consensus group proposes that:

• where muscles in a close anatomical region, including only one or two joints (excluding finger and toe joints, e.g. hand and forearm or foot and ankle) are injected, the term focal treatment is appropriate;

• where several adjacent anatomical regions (e.g. hand, forearm, elbow and/or shoulder) are injected, the term segmental treatment is appropriate;

• where anatomically separate and distant sites (e.g. arm and leg) are injected, the term multifocal or multisegmental treatment is appropriate.

PHARMACOLOGY

To date, 2 formulations of botulinum toxin type A are widely available: BOTOX® (Allergan) and Dysport® (Ipsen); a third preparation, Xeomin® (Merz) has become available recently in some European countries, but its efficacy has not yet been demonstrated in adult spasticity. These preparations are manufactured by different processes, have different formulations and potencies, which are determined by different biological assays. This results in differences in potency of the “units” used for each preparation. Since there is no simple or accurate way of converting the unit potency of one preparation to another, it is important that clinicians are familiar with the characteristics and dosages of each preparation they use and do not try to convert or extrapolate from one preparation to another (18). Whichever preparation is used, dosages, dilutions and injections should be tailored to each individual patient.

Extensive clinical experience with botulinum toxin type A has shown it to be well-tolerated and associated with few adverse events across a variety of indications. A meta-analysis of 37 studies (19) has confirmed the excellent safety profile of BOTOX® (grade A evidence) which continues with long-term use (20).

An important consideration in terms of side-effects is the propensity for toxin to migrate away from the injection site. A low migration potential is desirable to restrict the action of the toxin to the injected muscle and minimize both local unwanted spread and systemic effects that could occur subsequent to diffusion. Clinical studies comparing the migration of BOTOX® and Dysport® have not been carried out in patients with spasticity; however, studies in both hyperhidrosis and cervical dystonia have concluded that BOTOX® shows less migration than Dysport® (21, 22).

DILUTION, END-PLATE TARGETING AND INJECTION GUIDANCE

As botulinum toxin type A acts by blocking acetylcholine release at the neuromuscular junction, injection into the region of the motor end-plate should maximize efficacy. While some muscles, such as biceps brachii, have well-defined motor end-plates, which can be located from external landmarks (23), the anatomical location of the motor end-plates is unknown for many others. Where the end-plate location is not known, or for muscles with diffuse end-plates, such as the gastrocnemius muscle, a more even spread of injections across the muscle (with possibly higher injection volumes) may be necessary. One study has shown greater efficacy for higher dilutions of botulinum toxin type A when injections were not targeted to end-plate regions (24).

Targeting of botulinum toxin type A injections is another important issue. So far 2 controlled studies have shown that for deeply localized or small muscles needle placement based solely on anatomical landmarks is unsatisfactory and most muscles were only correctly located in less than 50% of cases (25, 26). Therefore injection guidance with electrical stimulation or sonography for deep-seated muscles may be a better alternative (27, 28) and should be standard practice. A specific intramuscular injection into the target muscle is more effective and safe since the toxin is delivered to the right place; injecting outside the muscle increases the potential for the toxin to migrate away from the target. However, muscle targeting by EMG or electrical stimulation, while effective, can be difficult, is time-consuming and may cause discomfort and thus is not always carried out in a routine clinical setting, although practice does vary between countries.

Patient comfort should always be a consideration in determining the number and location of injection sites and volume of injections as well as injection guidance techniques.

FOLLOW-UP

Botulinum toxin type A has shown sustained activity with repeated use for up to a year (29). The peak duration of response has been shown to increase with time and the interval between injections may also lengthen. It is important that patients are followed up carefully and that subsequent injection regimens are based on the patient’s response to previous treatment in terms of the gains obtained, such as increases in passive or active functioning.

Where there is a lack of response, the patient should be assessed at review to determine the possible responsible factors confounding efficacy. Inaccurate selection of the correct muscle, or its identification for injection, are possible causes, or there may have been an inadequate injection technique. There may be a biomechanical component of hypertonia and an assessment of the neural and non-neural contributions to muscle stiffness that could be contributing to outcome may be necessary. Rarely, lack of response may have been due to the presence of neutralizing antibodies or muscle fibrosis and shortening of soft tissue (e.g. ligaments and capsule).

The incidence of neutralizing antibodies following repetitive botulinum toxin type A injections has been calculated from retrospective data from patients with cervical dystonia. The incidence of antibody formation was 3–10% with the old formulation of BOTOX® and up to 5% with Dysport® (30–32). However, neutralizing antibodies are really no longer seen in adult spasticity treatment. As measured after the reformulation of BOTOX® in 1997, the formation of antibodies with this lower total protein preparation is now a rare occurrence, and deemed to be of minimal clinical significance (33).

RESEARCH CHALLENGES

Muscle identification and injection guidance

While many techniques are available to aid muscle localization, there are no recommendations as to which techniques are most suitable for which muscles, nor is there concrete guidance as to which muscles require imaging techniques for accurate placement of the injections. Studies are needed to clarify these issues.

Cost-effectiveness

The cost-effectiveness of botulinum toxin type A has been estimated, but is not known with real accuracy; this is an area that could benefit from proper cost-efficacy studies and one is currently underway.

Recommendations on pre- and post-injection treatment

Currently, there is little information on the measures that can modify and/or increase the efficacy of botulinum toxin injections. Electrical stimulation of the nerve or the injected muscles (34–36) and muscle activity itself (37) can increase efficacy of botulinum toxin type A. Also, physiotherapy including muscle stretching, casting, taping or splinting is able to act in the same way (38, 39). However, more studies are required to ascertain the optimal timing, duration and intensity of post botulinum toxin physical therapy and the contribution of learning processes based on repeat-attention-reward methodology (40).

Trial design

It is an acknowledged problem that designing trials and using clinical scales capable of demonstrating functional improvements is very difficult. Attention needs to be focused on optimal trial design, e.g. the use or development of valid and sensitive clinical scales for measurement of motor control and functional improvements in upper and lower limb spasticity following botulinum toxin This assessment should follow the WHO’s ICF model, i.e. assess the impairment, activity limitation and participation restriction; utilise the combination of modern physiotherapy and training methods with botulinum toxin treatment to elucidate the impact of reduced spasticity in creating a therapeutic window for employing interventions to produce functional improvement.

CONCLUSION

In conclusion, botulinum toxin type A provides a valuable tool in the multi-modal treatment of adult spasticity. This paper provides a European consensus opinion on the condition and best practice in its treatment and defines the research challenges that still exist.

ACKNOWLEDGEMENTS

Anthony Ward, North Staffordshire Rehabilitation Centre and Jörg Wissel, Kliniken Beelitz, Germany initiated the meeting that was held at the Congress Centrum, Potsdam. The realization of the meeting and the consensus table was made possible by an unrestricted educational grant from Allergan. No member of the consensus group received any honoraria in connection with this project and Allergan had no influence over the content of the manuscript.

The Consensus Group: Chairmen: Dr Anthony B. Ward, Professor Dr Med. Jörg Wissel.

Faculty: Dr Per Ertzgaard, Dr Djamel Bensmail, Dr Martin J. Hecht, Professor Thierry M. Lejeune, Professor Dr Med. Peter Schnider; Dr Maria Concetta Altavista, Dr Stefano Cavazza, Professor Thierry Deltombe, Dra Esther Duarte, Professor Alexander C. H. Geurts, Professor Jean-Michel Gracies, Dr Naseer H. J. Haboubi, Dr Francisco J. Juan, Dr Helge Kasch, Dr Christian Kätterer, Professor Dr Yeşim Kirazli, Dr Paolo Manganotti, Professor Dr Yeşim Parman, Dr Tatjana Paternostro-Sluga, Dr Konstantina Petropoulou, Dr Robert Prempeh, Dr Marc Rousseaux, Dr Jaroslaw Slawek, Dr Niko Tieranta.

Conflicts of interest and funding

J. Wissel has received unrestricted educational grants and sponsorship from Allergan, Ipsen, Merz and Elan. He has also received honoraria from Allergan, Ipsen, Merz, Elan and Medtronic. A. Ward has received unrestricted educational grants and sponsorship from Allergan and Medtronic for carrying out research studies. He has also received honoraria from Allergan, Ipsen and Medtronic. P. Erztgaard receives educational grants from Allergan for educating doctors in the use of botulinum toxin. M. J. Hecht has received honoraria from Allergan, Ipsen, Merz and Elan. P. Schnider has received honoraria from Allergan, Ipsen and Merz. M. C. Altavista has received honoraria for lectures from Novartis and Boehringer. T. Deltombe has received an honorarium for chairing a meeting and sponsorship for running teaching workshops from Allergan. E. Duarte has received honoraria for lectures from Allergan. A. C. H. Geurts has received a research grant from Allergan and Ipsen. J.-M. Gracies has consultancies with Allergan, Ipsen, Merz, and Solstice. N. Haboubi has received honoraria for lectures from Allergan. F. J. Juan has received honoraria for organizing training and teaching courses for doctors from Allergan and Ipsen. C. Kätterer is a consultant to Allergan. Y. Parman has received honoraria from Allergan and Ipsen. T. Paternostro-Sluga has received honoraria for lecturing and training from Allergan. R. Prempeh has received grants and honoraria for lecturing and training from Allergan and Ipsen. M. Rousseaux has received honoraria for organizing training and teaching courses for doctors from Allergan. J. Slawek has been a medical consultant to Allergan, Ipsen, Merz, Roche, Glaxo-SmithKline, Worwag-Pharma and Schwartz-Pharma. N. Tieranta has received honoraria for lectures from Allergan.

All other authors (D. Bensmail, S. Cavazza, H. Kasch, Y. Kirazli, T. M. Lejeune, P. Manganotti, K. Petropoulou) have no conflicts of interest and are not in receipt of pharmaceutical industry funding.

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