Workshop report131st ENMC International workshop: Selection of Outcome Measures for Peripheral Neuropathy Clinical Trials: 10–12 December 2004, Naarden, The Netherlands
Introduction
Besides for diabetic neuropathies, there is currently no consensus regarding the use of outcome measures in peripheral neuropathies. It is, therefore, not surprising that an overwhelming assortment of scales have been applied in therapeutic trials in various forms of peripheral neuropathies. Some scales were introduced before they had been fully clinimetrically tested [1], [2]. Others consisted of a mixture of different clinical modalities. Flawed measures may threaten the validity of trials that use them and impede comparison of results.
With an increasing demand for accuracy, selected outcome measures need to be clinimetrically well evaluated meeting the demands of being simple, valid, reliable, and responsive [1], [2]. Moreover, outcome measures should be unambiguously constructed to represent only one of the outcome levels according to the international classification of functioning, disability and health (the renewed edition of the international classification of impairments, disabilities, and handicaps) [3], [4]. A Medline search revealed 19 published workshops on peripheral neuropathy of which only two addressed the need to obtain consensus on outcome measures [5], [6]. To improve treatments and new drug studies in peripheral neuropathies, consensus regarding the use of a core set of outcome measures for the various peripheral neuropathy forms is urgently needed.
A total of 23 researchers (15 neurologists, one rheumatologist, two neurophysiologists, one patient representative of the Guillain-Barré Syndrome Foundation International, and four pharmaceutical industry-based scientists) from France, Italy, The Netherlands, United Kingdom, and United States of America assembled in Naarden, The Netherlands, to consider the most appropriate outcome measures for trials of treatment in peripheral neuropathy. The group sought to identify available outcome measures for different types of peripheral neuropathy at each level of outcome, ‘pathology’, especially of skin biopsies, ‘symptoms including pain and fatigue', other ‘impairments’ including neurological deficit and electrophysiological measures, ‘disability’, ‘handicap’, and ‘quality of life’ [4], [7].
A Medline search was conducted for the last two decades focusing on outcome measures applied in clinical trials that included patients with a peripheral neuropathy. Reports published in English were identified using the keywords: trial, Guillain-Barré syndrome, GBS, acute (chronic) inflammatory demyelinating (poly)(radiculo)neuropathy, AIDP, CIDP, polyneuritis, painful neuropathy, dysimmune neuropathy, monoclonal gammopathy of undetermined significance neuropathy, MGUS, Charcot-Marie-Tooth neuropathy, CMT, hereditary motor sensory neuropathy, HMSN. Experts in diabetic neuropathy provided additional information regarding potential outcome measures. The applied outcome measures in these studies were categorised according to the international guidelines [4], [7]. The reported scientific soundness (simplicity, validity, reliability, and responsiveness) of identified outcome measures was also considered [1], [2]. Finally, an attempt was made to reach consensus on the most appropriate measures for use in clinical trials in conditions of interest to the European neuromuscular centre (ENMC) such as inflammatory neuropathies, painful neuropathies, and hereditary neuropathy. Diabetic neuropathy was used for comparison since it has been the subject of more work on outcome measures.
In advance of the workshop, a list of outcome measures applied in treatment trials was prepared including their scientific soundness, WHO and quality of life classification [1], [2], [4], [7].
Most participants took part in pre-workshop subgroups and prepared pre-workshop papers focused on controversial areas as a common background for discussion at the workshop.
Section snippets
Advice to the workshop
At the beginning of the workshop, Maarten Boers, a rheumatologist and co-founder of the Omeract (Outcome Measures in Rheumatology Clinical Trials (www.omeract.org)) group described the way in which the Omeract had achieved and maintained consensus on rheumatoid arthritis outcome measures in the last decade [8], [9]. He introduced the Omeract Filter to test applicability of a measure in a setting: such a measure should be truthful (measure what it's supposed to), discriminate between situations
Definitions
Richard Hughes introduced a discussion of the international classification of impairments, disabilities, and handicaps and its somewhat more complex renewed version [3], [4]. The quality of life concept as an alternative outcome level from patients' perspectives was addressed [7]. Definitions of these outcome domains are presented in Table 1. The workshop preferred the traditional definitions of impairments, disabilities, and handicaps postulated in the 1980 classification [4]. Ingemar Merkies
Outcome measures at the pathology level
In the last decade, skin biopsy for quantification of intraepidermal nerve fibre (IENF) density proved to be a valid and reliable technique to detect the predominant, or even selective, degeneration of small diameter nerve fibres [12], [13], [14], [15], [16], [17]. Skin biopsy is minimally invasive and repeatable. Giuseppe Lauria and Justin McArthur presented the various techniques for evaluating skin biopsies. In particular, differences between light and confocal microscopy were discussed.
Diabetic neuropathy
Eva Feldman presented a historical review of outcome measures meetings in diabetic neuropathies, that started with the San Antonio consensus conference at which the use was recommended of the neurological impairment scale (NIS), neurophysiological studies, quantitative sensory testing (QST), and autonomic dysfunction studies as primary assessments for diabetic neuropathies [6], [21], [22], [23], [24]. A further development was the use of the NIS with other tests, the NIS-LL+7 score [22]. This
Clinical neurophysiology
Joe Arezzo focused on diabetic symmetric distal neuropathy. He stated that electrophysiology is a valid and reliable objective tool in these conditions, and helps in excluding differential diagnoses. Standard procedures were subsequently discussed including common versus uncommon techniques. In diabetic symmetrical distal neuropathy, maximal motor nerve conduction velocity decreases by approximately 0.5 m/s per year and amplitude by approximately 5% per year. Electrophysiology should be
Outcome measures at the disability level
Richard Hughes discussed disability measures, including the GBS-disability score, Rankin scale, and the INCAT overall disability sum score (ODSS) [40], [41], [42]. The advantages of the ODSS compared to the other measures were highlighted. The ODSS has more steps in the ambulation part and also includes deficit in the upper extremities. The ODSS was recently examined in these conditions for its scientific soundness and demonstrated a good correlation with impairment measures and with patients'
Outcome measures at the handicap and quality of life levels
Marinus Vermeulen questioned whether we should measure handicap. Impairment measures test whether or not a treatment works. Disability measures tell us whether a patient has a personal benefit from therapy. Moreover, impairment is better related to disability and is scarcely reflected in handicap and quality or life [46]. He proposed not to assess handicap, since it simply reflects extended disability and change in impairment is less likely to be associated with a change in handicap [47].
Luca
Recommendations
Outcome measures should be specific for each neuropathy and intervention.
Selected outcome measures must be feasible, valid, reliable, and responsive [1], [2].
In diseases such as in MMN, outcome measures need to be evaluated covering various domains [1], [2].
Adverse events should always be assessed and reported.
In diseases in which symptoms are prominent, such as painful neuropathy, the use of symptom-based outcome measures should be considered.
For all trials the baseline anthropometric data and
Participants
Dr J. Arezzo (USA)
Ms P. Blomkwist (The Netherlands; patient representative)
Prof M. Boers (The Netherlands)
Prof D. Cornblath (USA)
Dr D. Cros (USA)
Prof P. Dyck (USA)
Prof E. Feldman (USA)
Prof R. Hughes (UK)
Dr G. Lauria (Italy)
Prof J.-M. Leger (France)
Dr I. Merkies (The Netherlands)
Prof J. McArthur (USA)
Prof E. Nobile-Orazio (Italy)
Dr L. Padua (Italy)
Dr D. Pareyson (Italy)
Dr M. Reilly (UK)
Prof P. van Doorn (The Netherlands)
Dr I. Van Schaik (The Netherlands)
Prof M. Vermeulen (The Netherlands)
Acknowledgements
This workshop was made possible thanks to the financial support of the European neuromuscular centre (ENMC) and ENMC main sponsors: association Française contre les Myopathies (France), Deutsche Gesellschaft für Muskelkranke (Germany), Telethon Foundation (Italy), Muscular Dystrophy Campaign (UK), Muskelvindfonden (Denmark), Prinses Beatrix Fonds (The Netherlands), Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland), Österreichische Muskelforschung (Austria),
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