Interview: Following a standard of care for Huntington’s disease

Q Can you summarize why the European Huntington’s Disease Network was established and what you aim to provide to those involved in Huntington’s disease research and clinical management?

The European Huntington’s Disease Network (EHDN) was established as a platform for clinicians, basic scientists and, very importantly, families to work together towards a common goal: to improve the overall quality of life of Huntington’s disease (HD) patients and their families, and to do this by expanding treatment options for HD. At this point in time the treatment options are very limited; unlike Parkinson’s disease, for example, there is no established efficacious therapy that improves the signs and symptoms of HD. Similarly to other neurodegenerative diseases, at this point in time we don’t have an established therapy to improve and ameliorate the natural progressive cause of HD.

In 2004, we established the EHDN following a scientific meeting in 2003 (CAG Triplet Repeat Disorders, Il Ciocco, Tuscany, Italy) where we had the opportunity to come together and meet for the first time with a private US-based organization called the High Q foundation (now merged into the CHDI foundation [101]). It was a decision of the foundation, following us coming forward with a plan for a network and its primary activities, to provide us with the start-up funding to establish the infrastructure, to organize a meeting and to put us in the position to bring together a network with a proper constitution, which was finally approved following several discussions in 2005.

Q How and when was the EHDN ‘Standard of Care’ Working Group established?

The Standard of Care (SOC) Working Group was one of the initial working parties of the EHDN. One of the aims of the network is to engage groups of both professionals and family representatives; this is an important feature of our activities: we strive to incorporate the views of people affected by HD directly, whether it be people carrying the HD mutation or family members. This working party came together to address the issue that, in HD, like many rare disorders, there was no such thing as a well-defined SOC. Instead, people often working in isolation developed their own ideas of what was working and what was not working based on personal experience in their respective centers. So the idea of the SOC Working Group was to explore to what extent any common ground of shared experiences would allow the formulation of recommendations or practices that would be widely applicable. The working party was also very aware of the fact that, at this point in time, there a is very limited set of grade A evidence for many of the practices that we have for treating HD. However, there exists much individual experience of professionals and families, who are working on issues like swallowing problems, speech difficulties and issues like improving and maintaining mobility in the face of a progressive movement disorder. The working party therefore tried to establish a broad representation from many professional areas, not only focusing on neurologists and psychiatrists, but also incorporating additional healthcare professionals, such as nutritional therapists, occupational therapists, speech therapists and physiotherapists. The idea was that by sharing experiences, we could lay the first foundations for disseminating procedures as they are currently practiced in a number of European countries, building a consensus and using this to come up with hypotheses that should ideally be tested further by controlled clinical observations or trials, and to put these impressions on even firmer ground.

Q Do you think the EHDN SOC guidelines have the potential to determine SOC worldwide? Do you think they will also be applicable to countries outside Europe and resource-poor countries?

Granted, there are large differences in available resources and thus the treatment options that can be funded in various healthcare systems, but I think the guidelines have the potential to be applied worldwide for a reason: we view a fair number of the best practice guidelines as aspirational goals in countries where there are more limited resources and where it is very important for healthcare professionals to consider and argue with healthcare providers to procure access to services for which there is evidence of a beneficial effect. An example would be physiotherapy in certain stages of HD, for which, from countries where that type of service is available to people affected by HD, there is strong evidence of beneficial effects. Therefore, countries where this is currently not funded can use that experience and the evidence gathered so far to argue for ways to allow individuals affected with HD access to these services, even under more constrained financial circumstances.

Q Upon publication of the guidelines, what plans are there to disseminate and publicize this information to clinicians?

We hope to disseminate these guidelines via a number of channels. First we do hope that these guidelines are going to be discussed by the respective national associations for various healthcare professions, for example, nutritional scientists, physiotherapists, speech therapists and occupational therapists. So we hope that the fact that there is a published document as a starting point will trigger comments by the respective professional organizations at national levels, for example at meetings, and that this will result in two additional activities:

• ▪ A critique of the guidelines as published by drawing on more experience from related areas;

• ▪ Hopefully incorporate elements of the guidelines as part of the training curriculum for students, and as part of the continuing medical education of professionals, of these respective disciplines.

Likewise, we are planning to reformulate the guidelines in such a fashion that they can be easily accessed by different general practitioners across the world, so, for example, we have plans to translate all these guidelines into the languages of the 18 European countries we currently have members in, and to make this information available via the websites of the respective national medical associations. In other words, there will be a link to PDF documents providing a translation of either the full guidelines or condensed excerpts of the guidelines, to make them accessible to people who may not be familiar with English and who are looking for guidance in their day-to-day practice.

Lastly, we have the goal of setting up national consensus conferences on these issues, which are going to be supported by an international consensus group that will include colleagues from other areas like North America and Latin America, as well as Australia and New Zealand. We would like to put a mechanism in place, whereby these guidelines can be continuously updated by systematic reviews, with all materials that are analyzed as part of the systematic review process, stored in a password-protected website. In other words, we want to make sure that the primary source of any analysis that is performed is available to all interested parties, but in order to respect copyright, placed in a password-protected web portal. Allowing an ongoing updating and review process, combined with a national consensus building effort, would break down the science behind recommendations that works well within a given national context, for instance. The question that we just discussed – may some of the recommendations not apply given the constraints of a given healthcare system – is a very important question, and we would like national bodies to come up with a clear delineation of what is desirable based on available scientific evidence, what is practicable in a given national healthcare system and what the aspirational goals would be for each respective national healthcare systems to develop towards.

Q Do you think the guidelines will help to highlight the importance of a multidisciplinary approach and promote more integrated medical services?

That is certainly my hope. I think that the publication of the guidelines will impact in two different ways:

First, people will start to realize that, given that HD is a complex and multifaceted disorder with a broad set of signs and symptoms, it is not only a good idea, but it is critical to involve a number of specialties in the treatment of HD patients. They can also see that there are several places where a truly interdisciplinary model has been put into practice, so it is not only an aspirational goal, but it is something concrete that can be observed, at some locations at least, and can serve as a model for the implementation of this approach elsewhere.

Second, many people working as occupational therapists or speech therapists, for instance, are faced with the problem that, unlike physicians, who are very often in a position to meet colleagues at an international level and get additional insight and inspiration from colleagues facing the same issues and problems in their respective countries, these people tend to work in isolation. The need for healthcare professionals who are not physicians to communicate more and work together with specialists such as movement disorder specialists, psychiatrists and geneticists is even greater. I therefore hope that the publication of these guidelines encourages non-physician healthcare professionals to strive to collaborate with appropriate contacts and be proactive in approaching HD centers, informing them of their interest and availability, to make sure that interdisciplinary care becomes a reality in a given location.

Q Does the EHDN have further plans for developing the guidelines/working groups in the future?

We do have very concrete plans. We have submitted an extensive written proposal to establish a process of updating and reformulating these guidelines based on systematic reviews to the CHDI foundation, the not-for-profit organization supporting EHDN [102]. We have proposed a procedure of systematic review using an international group of clinicians and scientists and we have put forward a proposal for how best to link this to national consensus-building efforts. We believe that it is particularly important to avoid the appearance of confusing and conflicting guidelines for such a relatively rare disorder; there is an international consensus building group that strives towards establishing a technically and methodologically sound ongoing systematic review, on which all national bodies can draw. Therefore, we feel it is very important that the primary sources of information are utilized to extend any systematic reviews – we don’t want to restrict it to published literature, we also want to integrate experience that is available from practice. We want to extend into graded and systematically acquired information, reflecting practices as established at various places and locations and combine them systematically. All these efforts will eventually lead to precisely defined hypotheses that should – and that’s the second big goal that we have – lead to a subsequent testing of these hypotheses in a rigorous and controlled fashion as best as possible. The second process of prospective hypothesis testing is supported by the fact that we, that is CHDI, are currently planning a global observational study called Enroll-HD, and part of this process is a strong commitment to improving quality of care and to facilitate the conduct of systematic studies that, would prospectively test the real benefits of the proposed interventions, such as physiotherapy, speech therapy or occupational therapy, in various stages of HD. So we hope that this is just the beginning an unbiased, critical review and a rigorous hypothesis testing embedded in this process of Enroll-HD.

Q Looking forward to the ongoing project Enroll-HD, can you please explain the purpose of this project and perhaps provide an update of its current status?

Enroll-HD is planned as a global prospective observational study with participants in Europe, North America, Latin America, Australia, New Zealand, some Asian countries, as well as, hopefully, in some African countries; truly a global approach. Very concretely, we will start with study centres in Europe, North America, Latin America and Asia, particularly in Singapore, Seoul and hopefully in PR China. We feel that big observational studies are important in a chronic disorder like HD that stays in families, and so where the problem does not easily go away, and there are multiple reasons for people to contribute and to stay involved in such an observational study. Enroll-HD is targeted to ultimately have a third of the HD population worldwide enrolled, which would translate into 25,000–30,000 participants overall in this study. It sounds like an enormous number, but the intention is that, given that number, we will be in the position to generate conclusive answers to many questions. These questions could be biological in nature; we would like, for instance, to identify genes that contribute to the phenotype of HD and contribute to the rate of progression of the disease. For these studies we need genetic diversity, which would be addressed by the global nature of the study, as well as a significant number of observations; current estimates for unbiased GWASs are in the order of 5000–6000 participants, at least, and ideally you want to have an independent cohort to confirm original hypotheses. That would bring you easily in the range of 12,000–18,000 participants needed to conclusively identify genetic modifiers for the disease. Likewise, we feel that the environment plays a big modifying role; there is good evidence from observations in Venezuela by Nancy Wexler and colleagues who, in a paper in the Proceedings of the National Academy of Sciences, suggested that, at least for that population, approximately 60% of the variability in age at onset of features are due to environmental factors rather than genetic factors [1], so it is an important component.

We are also using Enroll-HD to establish to what extent insights into the biology of HD derived from studies of models of HD, like transgenic mice or transgenic pigs or sheep, can be validated in people affected by HD and can be used to establish whether pathological alterations can be traced in people affected with HD. Why is that important? It is important because it gives us clues as to potential truly disease-modifying therapies and allows us to establish pharmacodynamic markers for potential disease-modifying interventions. It will also help us to define and qualify biological markers as well as novel endpoints for clinical trials with HD patients, for example clinical trials addressing important questions such as apathy in HD patients or irritability. These two aspects, the establishment of new assessment tools and the validation of pathological mechanisms, will be realized through the special feature that we have in Enroll-HD. That special feature is that we have so-called sub-studies and add-on studies in Enroll-HD. The idea of sub-studies is that people understand and engage in the process of validating clinical scales and questionnaires, which is an iterative process and goes through various rounds of further improvement and refinement. Add-on studies would imply that people agree to additional investigations; that does imply additional informed consent and review by ethical review boards to undergo procedures like MRI examinations or an agreed biopsy of muscle or tissue to establish biochemical readouts for HD, or to contribute to the identification of well-qualified biological markers that could potentially be used as surrogate markers or endpoints in clinical trials.