131st ENMC International workshop: Selection of Outcome Measures for Peripheral Neuropathy Clinical Trials: 10–12 December 2004, Naarden, The Netherlands

Abstract

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 [1Feinstein A.R. Clinimetrics. Yale University Press, New Haven and London1987Crossref Google Scholar, 2Hobart J.C. Lamping D.L. Thompson A.J. Evaluating neurological outcome measures: the bare essentials.J Neurol Neurosurg Psychiatry. 1996; 60: 127-130Crossref PubMed Scopus (140) Google Scholar]. 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 [1Feinstein A.R. Clinimetrics. Yale University Press, New Haven and London1987Crossref Google Scholar, 2Hobart J.C. Lamping D.L. Thompson A.J. Evaluating neurological outcome measures: the bare essentials.J Neurol Neurosurg Psychiatry. 1996; 60: 127-130Crossref PubMed Scopus (140) Google Scholar]. 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) [3International classification of functioning, disability, and health. World Health Organization, Geneva; 2001.Google Scholar, 4International classification of impairments, disabilities, and handicaps. World Health Organization, Geneva; 1980.Google Scholar]. A Medline search revealed 19 published workshops on peripheral neuropathy of which only two addressed the need to obtain consensus on outcome measures [5Nevo Y. Topaloglu H. 88th ENMC international workshop: childhood chronic inflammatory demyelinating polyneuropathy.Neuromuscul Disord. 2002; 12: 195-200Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 6Anonymous. Consensus statement: report and recommendations of the San Antonio conference on diabetic neuropathy. American diabetes association american academy of neurology. Diab Care; 1988;11:592–7.Google Scholar]. 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’ [4International classification of impairments, disabilities, and handicaps. World Health Organization, Geneva; 1980.Google Scholar, 7Aaronson N.K. Quality of life: what is it? How should it be measured?.Oncology. 1988; 2: 69-76PubMed Google Scholar]. 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 [4International classification of impairments, disabilities, and handicaps. World Health Organization, Geneva; 1980.Google Scholar, 7Aaronson N.K. Quality of life: what is it? How should it be measured?.Oncology. 1988; 2: 69-76PubMed Google Scholar]. The reported scientific soundness (simplicity, validity, reliability, and responsiveness) of identified outcome measures was also considered [1Feinstein A.R. Clinimetrics. Yale University Press, New Haven and London1987Crossref Google Scholar, 2Hobart J.C. Lamping D.L. Thompson A.J. Evaluating neurological outcome measures: the bare essentials.J Neurol Neurosurg Psychiatry. 1996; 60: 127-130Crossref PubMed Scopus (140) Google Scholar]. 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 [1Feinstein A.R. Clinimetrics. Yale University Press, New Haven and London1987Crossref Google Scholar, 2Hobart J.C. Lamping D.L. Thompson A.J. Evaluating neurological outcome measures: the bare essentials.J Neurol Neurosurg Psychiatry. 1996; 60: 127-130Crossref PubMed Scopus (140) Google Scholar, 4International classification of impairments, disabilities, and handicaps. World Health Organization, Geneva; 1980.Google Scholar, 7Aaronson N.K. Quality of life: what is it? How should it be measured?.Oncology. 1988; 2: 69-76PubMed Google Scholar]. 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. 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 [8Fried B.J. Boers M. Baker P.R. A method for achieving consensus on rheumatoid arthritis outcome measures: The OMERACT conference process.J Rheumatol. 1993; 20: 548-551PubMed Google Scholar, 9Boers M. Brooks P. Strand V. Tugwell P. The OMERACT Filter for outcome measures in rheumatology.J Rheumatol. 1998; 25: 198-199PubMed Google Scholar]. 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 of interest, and feasible in the chosen setting [[9]Boers M. Brooks P. Strand V. Tugwell P. The OMERACT Filter for outcome measures in rheumatology.J Rheumatol. 1998; 25: 198-199PubMed Google Scholar]. To come to consensus over a core set of outcome measures and response criteria in various rheumatologic conditions, Omeract has been successful by adopting a data driven approach. He recommended striving for a general accepted view leaving room for ‘political’ considerations. The Omeract filter and process have been instrumental in educating researchers about the clinimetrical requirements of measurement scales. Richard Hughes introduced a discussion of the international classification of impairments, disabilities, and handicaps and its somewhat more complex renewed version [3International classification of functioning, disability, and health. World Health Organization, Geneva; 2001.Google Scholar, 4International classification of impairments, disabilities, and handicaps. World Health Organization, Geneva; 1980.Google Scholar]. The quality of life concept as an alternative outcome level from patients' perspectives was addressed [[7]Aaronson N.K. Quality of life: what is it? How should it be measured?.Oncology. 1988; 2: 69-76PubMed Google Scholar]. 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]International classification of impairments, disabilities, and handicaps. World Health Organization, Geneva; 1980.Google Scholar]. Ingemar Merkies discussed the ‘clinimetrics’ of these outcome measures and provided definitions for its various entities [1Feinstein A.R. Clinimetrics. Yale University Press, New Haven and London1987Crossref Google Scholar, 2Hobart J.C. Lamping D.L. Thompson A.J. Evaluating neurological outcome measures: the bare essentials.J Neurol Neurosurg Psychiatry. 1996; 60: 127-130Crossref PubMed Scopus (140) Google Scholar, 10Nunnally J.C. Psychometric theory. McGraw‐Hill, New York1978Google Scholar, 11Liang M.H. Evaluating measurement responsiveness.J Rheumatol. 1995; 22: 1191-1192PubMed Google Scholar]. He stated that a useful outcome measure should be simple, valid, reliable, and responsive to changes over time and should unambiguously represent one of the WHO outcome domains or quality of life concept. In addition, it was argued that performance criteria such as standardization of test instruments, use of adequately chosen nerve test results corrected for biographic and anthropomorphic variables, and adequate record keeping should also be emphasized when evaluating the clinical applicability of outcome measures.Table 1Definition of outcome domains according to the international guidelines 3International classification of functioning, disability, and health. World Health Organization, Geneva; 2001.Google Scholar, 4International classification of impairments, disabilities, and handicaps. World Health Organization, Geneva; 1980.Google Scholar, 7Aaronson N.K. Quality of life: what is it? How should it be measured?.Oncology. 1988; 2: 69-76PubMed Google ScholarImpairmentDisabilityHandicapPatient orientated assessments (=quality of life domain)WHO 1980classificationWHO 2001classificationWHO 1980classificationWHO 2001classificationWHO 1980classificationWHO 2001classificationImpairment is defined as any loss or abnormality of psychological, physiological, or anatomical structure or functionImpairment is defined as problems in body function or structure as a significant deviation or loss which may be detected as a significant variation from established statistical normsDisability is defined as any restriction or lack (resulting from an impairment) of ability to perform an activity in the manner or within the range considered normal for a human beingThe term disability is replaced by the converse concept of ‘activities’ and defined as the nature and extent of executing a task or action by an individualHandicap is defined as a disadvantage for a given individual, resulting from an impairment or a disability, that limits or prevents the fulfilment of a role that is normal (depending on age, sex, and social and cultural factors) for that individualThe term handicap is replaced by the converse concept ‘participation’, which is defined as the nature and extent of a person's involvement in life situations in relation to impairments, activities, health conditions and contextual factorsThis is defined as the patient's reaction to the discrepancy between actual and expected achievements arising as a consequence of illness; at least four dimensions should be included in a quality of life assessment. These dimensions are physical, functional, psychological, and social health Open table in a new tab 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 [12Holland N.R. Stocks A. Hauer P. Cornblath D.R. Griffin J.W. McArthur J.C. Intraepidermal nerve fiber density in patients with painful sensory neuropathy.Neurology. 1997; 48: 708-711Crossref PubMed Scopus (259) Google Scholar, 13Herrmann D.N. Griffin J.W. Hauer P. Cornblath D.R. McArthur J.C. Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies.Neurology. 1999; 53: 1634-1640Crossref PubMed Google Scholar, 14Lauria G. Holland N. Hauer P. Cornblath D.R. Griffin D.R. McArthur J.C. Epidermal innervation: changes with aging, topographic location, and in sensory neuropathy.J Neurol Sci. 1999; 164: 172-178Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 15Smith G.A. Ramachandran P. Tripp S. Singleton J.R. Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy.Neurology. 2001; 57: 1701-1704Crossref PubMed Scopus (202) Google Scholar, 16Lombardi R. Erne B. Lauria G. et al.IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy.Ann Neurol. 2005; 57: 180-187Crossref PubMed Scopus (85) Google Scholar, 17Periquet M.I. Novak V. Collins M.P. et al.Painful sensory neuropathies. Prospective evaluation using skin biopsies.Neurology. 1999; 53: 1641-1647Crossref PubMed Google Scholar]. 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. Standardization of quantification methods and normative data taking anthropometrical information into account were presented and discussed. Furthermore, they stated that the site for biopsy depends on the aim of the study. A correlation between early skin nerve changes and clinical progression of neuropathies and IgM deposits on skin nerves in neuropathy with anti-myelin-associated-glycoprotein antibodies was presented, an example of the prognostic value of biopsies [16Lombardi R. Erne B. Lauria G. et al.IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy.Ann Neurol. 2005; 57: 180-187Crossref PubMed Scopus (85) Google Scholar, 18Lauria G. Morbin M. Lombardi R. et al.Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies.Neurology. 2003; 61: 631-636Crossref PubMed Scopus (180) Google Scholar]. Models to assess regeneration were also considered. Painful neuropathies were considered the most appropriate illnesses for performing skin biopsies. In painful neuropathies an association has been discovered between skin biopsy findings and clinical outcome measures in the form of both the uni-dimensional visual analogue (VAS) scale and the 11-point-pain intensity numerical scale (PI-NRS) [19Maxwell C. Sensitivity and accuracy of the visual analogue scale: a psycho-physical classroom experiment.Br J Clin Pharmacol. 1978; 6: 15-24Crossref PubMed Scopus (326) Google Scholar, 20Farrar J.T. Young Jr., J.P. LaMoreaux L. Werth J.L. Poole R.M. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale.Pain. 2001; 94: 149-158Abstract Full Text Full Text PDF PubMed Scopus (3402) Google Scholar]. The gold standard for ‘polyneuropathy’ was questioned; should the diagnosis polyneuropathy be based on clinical grounds or pathological findings such as neurophysiological or skin biopsy findings? Participants agreed that the diagnosis ‘polyneuropathy’ should be primarily based on clinical aspects. For multi-centre studies it was suggested to use a central skin biopsy laboratory. The use of skin biopsies in a more preventitive setting was also suggested, such as in patients with impaired glucose tolerance [[15]Smith G.A. Ramachandran P. Tripp S. Singleton J.R. Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy.Neurology. 2001; 57: 1701-1704Crossref PubMed Scopus (202) Google Scholar]. Overall, IENF quantification was considered a possible additional outcome measure for both axonal and demyelinating peripheral neuropathies. 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 [6Anonymous. Consensus statement: report and recommendations of the San Antonio conference on diabetic neuropathy. American diabetes association american academy of neurology. Diab Care; 1988;11:592–7.Google Scholar, 21Shy M.E. Frohman E.M. So Y.T. et al.Quantitative sensory testing. Report of the therapeutics and technology assessment subcommittee of the American academy of neurology.Neurology. 2003; 60: 898-904Crossref PubMed Scopus (378) Google Scholar, 22Dyck P.J. Davies J.L. Litchy W.J. O'Brien P.C. Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort.Neurology. 1997; 49: 229-239Crossref PubMed Scopus (297) Google Scholar, 23Dyck P.J. Kratz K.M. Lehman K.A. et al.The diabetic neuropathy study: Design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests.Neurology. 1991; 41: 799-807Crossref PubMed Google Scholar, 24Dyck P.J. Karnes J.L. O'Brien P.C. Litchy W.J. Low P.A. Melton L.J. The Rochester diabetic neuropathy study: reassessment of tests and criteria for diagnosis and staged severity.Neurology. 1992; 42: 1164-1170Crossref PubMed Google Scholar]. A further development was the use of the NIS with other tests, the NIS-LL+7 score [[22]Dyck P.J. Davies J.L. Litchy W.J. O'Brien P.C. Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort.Neurology. 1997; 49: 229-239Crossref PubMed Scopus (297) Google Scholar]. This composite score grades muscle weakness, reflexes, touch-pressure, joint position sense, vibration, and pin prick in the great toe. It also includes five attributes of nerve conduction velocity in the lower limb, vibration detection threshold as determined by the CASE IV quantitative sensory testing device, and an assessment of variability of the heartbeat to deep breathing. The FDA approved the use of NIS-LL, neurophysiological studies, and QST for clinical trials in diabetic neuropathies. Composite measures were also highlighted including the Michigan Neuropathy Screenings Instrument and the Michigan Diabetic Neuropathy Score, which includes a quantitative neurological examination coupled with nerve conduction studies [[25]Feldman E.L. Stevens M.J. Thomas P.K. Brown M.B. Canal N. Greene D.A. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy.Diab Care. 1994; 17: 1281-1289Crossref PubMed Scopus (859) Google Scholar]. The Total Neuropathy Score (TNS) of Cornblath and associates was addressed as a possible composite measure for assessing outcome in diabetic neuropathies [[26]Cornblath D.R. Chaudhry V. Carter K. et al.Total neuropathy score. Validation and reliability study.Neurology. 1999; 53: 1660-1664Crossref PubMed Google Scholar]. All proposed measures have demonstrated their validity, reliability, and sensitivity to changes over time. The quantification of impairments should be related to stage of disease. The choice of an outcome measure will depend on the specific questions being asked in a particular study (e.g. trial evaluating the efficacy or safety of a new therapeutic drug versus epidemiological follow-up study). Questions were raised on the responsiveness of symptom-constructed scales. It was considered that these scores, although rather unresponsive, should be included. Eduardo Nobile-Orazio elaborated on the various impairment items that could be investigated in immune-mediated neuropathies. In the symmetrical neuropathy forms, as in Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), various motor outcome measures have been devised for the assessment of strength and were mainly based on the medical research council (MRC) grading system [[27]Medical Research Council. Aids to the investigation of the peripheral nervous system. London: Her Majesty's Stationary Office; 1943:1–2.Google Scholar]. The most widely used motor outcome measure is the MRC sum score described by Kleyweg and associates and the motor subset of the NIS [23Dyck P.J. Kratz K.M. Lehman K.A. et al.The diabetic neuropathy study: Design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests.Neurology. 1991; 41: 799-807Crossref PubMed Google Scholar, 24Dyck P.J. Karnes J.L. O'Brien P.C. Litchy W.J. Low P.A. Melton L.J. The Rochester diabetic neuropathy study: reassessment of tests and criteria for diagnosis and staged severity.Neurology. 1992; 42: 1164-1170Crossref PubMed Google Scholar, 28Kleyweg R.P. van der Meché F.G.A. Schmitz P.I.M. Interobserver agreement in the asses-sment of muscle strength and functional abilities in Guillain–Barré Syndrome.Muscle Nerve. 1991; 14: 1103-1109Crossref PubMed Scopus (533) Google Scholar]. These two measures have demonstrated their scientific soundness and are proposed for these neuropathy forms. In multifocal motor neuropathies (MMN), no outcome measures have been systematically evaluated in terms of being valid, reliable, and responsive. Moreover, since MMN has an asymmetrical clinical pattern, an alternative motor sum score was proposed covering ten predefined pairs of muscles that included six most affected muscles. The Vigorimeter was suggested for grip strength assessment in GBS, CIDP, and MMN [29Fünfgeld E.W. Vigorimeter: Zur kraftmessung der hand und zur simulationsprüfung.Dtsch Med Wschr. 1966; 49: 2214-2216Crossref Scopus (39) Google Scholar, 30Merkies I.S.J. Schmitz P.I.M. Samijn J.P.A. van der Meché F.G.A. Toyka K.V. van Doorn P.A. Assessing grip strength in healthy individuals and patients with immune-mediated polyneuropathies.Muscle Nerve. 2000; 23: 1393-1401Crossref PubMed Scopus (86) Google Scholar]. Sensory deficit has been assessed in these conditions with different sensory rating scales that included various sensation modalities mediated by different sensory fibres. With the exception of the sensory subset of the NIS and the inflammatory neuropathy cause and treatment (INCAT) sensory sum score, none of the sensory scales has been submitted to a comprehensive clinimetric evaluation in GBS and CIDP [1Feinstein A.R. Clinimetrics. Yale University Press, New Haven and London1987Crossref Google Scholar, 2Hobart J.C. Lamping D.L. Thompson A.J. Evaluating neurological outcome measures: the bare essentials.J Neurol Neurosurg Psychiatry. 1996; 60: 127-130Crossref PubMed Scopus (140) Google Scholar, 23Dyck P.J. Kratz K.M. Lehman K.A. et al.The diabetic neuropathy study: Design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests.Neurology. 1991; 41: 799-807Crossref PubMed Google Scholar, 24Dyck P.J. Karnes J.L. O'Brien P.C. Litchy W.J. Low P.A. Melton L.J. The Rochester diabetic neuropathy study: reassessment of tests and criteria for diagnosis and staged severity.Neurology. 1992; 42: 1164-1170Crossref PubMed Google Scholar, 31Merkies I.S.J. Schmitz P.I.M. van der Meché F.G.A. van Doorn P.A. Psychometric evaluation of a new sensory scale in immune-mediated polyneuropathies.Neurology. 2000; 54: 943-947Crossref PubMed Scopus (146) Google Scholar]. Both measures were considered appropriate. Additional measures may be needed to score cranial nerve (NIS subset), autonomic, and respiratory dysfunction. Reflexes probably do not contribute to disability and need therefore not be measured. Minimum clinically important changes should be addressed, not only from the perspective of the researcher but also from patients' point of view. In the discussion that followed, the problems in assessing motor deficit in MMN were addressed. Also, the deficit of the MRC sum score being non-linear was highlighted. Suggestions were made for the use of a more linear or exponential outcome measure such as the NIS motor subset, although it was stated that the linear pattern of this measure was also arbitrarily defined. The INCAT sensory sum score requires assessment of pinprick and vibration sensation in the upper and lower limbs and of two-point discrimination of the index finger. Proximal assessment of sensory deficit is also examined, thereby capturing an anatomical severity gradient of sensory deficit. Vibration sense can be assessed using the graduated Rydel-Seiffer tuning fork and its reported normative data [32Martina I.S.J. van Koningsveld R. Schmitz P.I.M. van der Meché F.G.A. van Doorn P.A. Measuring vibration threshold with a graduated tuning fork in normal ageing and in patients with polyneuropathy.J Neurol Neurosurg Psychiatry. 1998; 65: 743-747Crossref PubMed Scopus (197) Google Scholar, 33Merkies I.S.J. Schmitz P.I.M. van der Meché F.G.A. van Doorn P.A. Reliability and responsiveness of a graduated tuning fork in immune-mediated polyneuropathies.J Neurol Neurosurg Psychiatry. 2000; 68: 669-671Crossref PubMed Scopus (47) Google Scholar]. However, the INCAT sensory sum score does not include light touch or joint position sensation and a scale that included these items would probably be more comprehensive and responsive. In contrast, the NIS sensory subset assesses cotton wool (tactile), pinprick, vibration (a standard tuning fork), and joint position and motion at the dorsum of the index fingers and great toes near the base of the nails. The NIS sensory subset assesses more qualities but omits proximal sensory deficit [23Dyck P.J. Kratz K.M. Lehman K.A. et al.The diabetic neuropathy study: Design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests.Neurology. 1991; 41: 799-807Crossref PubMed Google Scholar, 24Dyck P.J. Karnes J.L. O'Brien P.C. Litchy W.J. Low P.A. Melton L.J. The Rochester diabetic neuropathy study: reassessment of tests and criteria for diagnosis and staged severity.Neurology. 1992; 42: 1164-1170Crossref PubMed Google Scholar]. Mary Reilly addressed the problems of assessing change in charcot-marie-tooth (CMT) neuropathies. First, she stated that the natural history of CMT is not known. There are however, indications for a very slow progression pattern of CMT, which introduces a problem regarding the responsiveness of outcome measures. Also, she stated that till recently, no specific measures and outcome studies had previously been developed for these illnesses. The CMT neuropathy score (CMT–NS) was presented and various aspects of its composition were discussed [[34]Shy M.E. Blake J. Krajewski K. et al.Reliability and validity of the CMT neuropathy score as a measure of disability.Neurology. 2005; 64: 1209-1214Crossref PubMed Scopus (299) Google Scholar]. The validity and reliability of CMT–NS are obtained by demonstrating its correlation with the TNS and NIS [23Dyck P.J. Kratz K.M. Lehman K.A. et al.The diabetic neuropathy study: Design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests.Neurology. 1991; 41: 799-807Crossref PubMed Google Scholar, 24Dyck P.J. Karnes J.L. O'Brien P.C. Litchy W.J. Low P.A. Melton L.J. The Rochester diabetic neuropathy study: reassessment of tests and criteria for diagnosis and staged severity.Neurology. 1992; 42: 1164-1170Crossref PubMed Google Scholar, 26Cornblath D.R. Chaudhry V. Carter K. et al.Total neuropathy score. Validation and reliability study.Neurology. 1999; 53: 1660-1664Crossref PubMed Google Scholar, 34Shy M.E. Blake J. Krajewski K. et al.Reliability and validity of the CMT neuropathy score as a measure of disability.Neurology. 2005; 64: 1209-1214Crossref PubMed Scopus (299) Google Scholar]. The disadvantages of a composite score such as the CMT-NS were discussed. However, since no other outcome measure studies have been performed in these conditions, the CMT-NS was proposed to assess outcome at the impairment level in these conditions. David Cornblath endorsed the use of uni-dimensional scales in painful neuropathies. In particular, the visual analogue scale (VAS) and the 11-point pain Likert scale were suggested as primary outcome measures in pain-treatment studies [19Maxwell C. Sensitivity and accuracy of the visual analogue scale: a psycho-physical classroom experiment.Br J Clin Pharmacol. 1978; 6: 15-24Crossref PubMed Scopus (326) Google Scholar, 20Farrar J.T. Young Jr., J.P. LaMoreaux L. Werth J.L. Poole R.M. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale.Pain. 2001; 94: 149-158Abstract Full Text Full Text PDF PubMed Scopus (3402) Google Scholar]. Various aspects like the ‘constancy’ of pain, its intensity, and the time of its assessment were addressed. These aspects should be taken into consideration when pain is being assessed. It was also emphasized that the modality of presentation of scales might affect the outcome; an example is given as a difference in outcome between diary versus electronic assessment of pain. Fatigue is a subjective experience that is categorised by the WHO as an impairment entity [3International classification of functioning, disability, and health. World Health Organization, Geneva; 2001.Google Scholar, 4Internat