Sensory-motor assessment in clinical research trials

Sensory-motor assessment in clinical research trials

Handbook of Clinical Neurology, Vol. 115 (3rd series) Peripheral Nerve Disorders G. Said and C. Krarup, Editors © 2013 Elsevier B.V. All rights reserv...

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Handbook of Clinical Neurology, Vol. 115 (3rd series) Peripheral Nerve Disorders G. Said and C. Krarup, Editors © 2013 Elsevier B.V. All rights reserved

Chapter 16

Sensory-motor assessment in clinical research trials JOSEPH C. AREZZO1,2*, SHIRLEY SETO1, AND HERBERT H. SCHAUMBURG2,3 1 Department of Neuroscience, Albert Einstein College of Medicine, New York, USA 2

Department of Neurology, Albert Einstein College of Medicine, New York, USA

3

Department of Pathology, Albert Einstein College of Medicine, New York, USA

INTRODUCTION The accurate assessment of change in sensory-motor function requires skill, experience, and the selection of appropriate measures. Complexities include the need to assess different sensory modalities (e.g., temperature, touch, proprioception), the presence of multiple transmission pathways that differ in speed, fidelity and points of crossing, and the possible distribution of deficits on an elongated distal-to-proximal gradient. Diminished strength can present as weakness, change in muscle tone, muscle atrophy, loss of speed, poor coordination, tremors, and fatigability. The examination of motor function must involve a wide range of muscles, bilateral comparisons, and judgment of resistance to force from the examiner (static strength), as well as the ability to move against resistance provided by the examiner (kinetic strength). The key requirement is the ability to judge accurately the appropriate level of resistance or voluntary force provided by the patient. Important considerations include the subject’s size, age, sex, and motivation. When the task is to determine the efficacy of a putative therapy on sensory-motor function in a clinical research trial, all of the above listed concerns are present and they are exacerbated by the substantial constraints inherent in clinical research. While the standard examination can be tailored to the circumstances of individual patients, in clinical trials, the evaluation must be uniform at all times and for all subjects. Examiners in clinical trials often substantially differ in their training and experience, especially when studies involve centers distributed across several continents. This is a critical issue for measures that rely on uniform clinical judgment and skills (e.g., muscle strength, reflexes). The common use of frequent,

repeated examination in many clinical trials adds the dimension of patient learning curves, anticipation, and boredom. Many standard sensory-motor measures utilize an enormous range designed to span disease progression from normal to severe. For instance, the widely used Medical Research Council (MRC) strength scale ranges from normal to the absence of contraction. However, in the restricted period of most clinical trials, the anticipated change in function is limited, and for many subjects, a positive outcome may be entirely restricted to change within a single level. Thus, the reported sensitivity of a scale in clinical practice may be irrelevant over the time frame of a research trial. Additional factors in selecting sensory-motor endpoints for clinical studies include: time requirements, ease of training across centers, expense, susceptibility to placebo effects, and the nature of the units of measurement (categoric, ordinal, or parametric). The focus of this review is to outline the unique challenges of sensory-motor evaluation in clinical research. This is not intended as a comprehensive listing of specific measures, but is rather an attempt to identify strengths and limitations of different approaches, as well as critical factors that should be considered prior to the selection of sensory-motor endpoints in clinical studies.

THE CLINIMETRIC ASPECTS OF SENSORY-MOTOR EVALUATION Broadly defined, clinimetrics is the study of how specific qualities of a measure impact the value of observed endpoints as an index of clinical outcome (Feinstein, 1987). Stated simply, the choice of measurement tools for symptoms, signs, or laboratory values is directly related to the ability of the resultant endpoints to trace disease

*Correspondence to: Joseph C. Arezzo, Ph.D., Professor of Neuroscience and Neurology, Albert Einstein College of Medicine, Rose F. Kennedy Center, Room 322, 1300 Morris Park Avenue, Bronx, New York 10461, USA. Tel: þ1-718-430-2468, Fax: þ1-718-4308588, E-mail: [email protected]

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Table 16.1 Clinimetric qualities Validity

Construct validity Content validity

Detection

Sensitivity Specificity

Reliability

Testretest Inter-rater Accuracy

Interpretability

Units of measure Minimally important clinical difference Range Responsiveness

The degree to which a test measures the condition under study and not other variables The degree to which a test covers an appropriate range of items in the condition under study The ability of a test to correctly identify individuals who have the condition under study  % correct positive The ability of a test to correctly exclude subjects that do not have the condition – % correct negative Variation in a test when assessed across repeat evaluations from a single examiner or a single laboratory Variation in a test when assessed using the same method, but across different examiners or laboratories The degree to which the results of a test match a known absolute standard  applies principally to laboratory tests Nature of the endpoints – categoric, ordinal, parametric – influences how the data can be handled and interpreted The smallest magnitude of change in a test score that reflects a clinically significant alteration in the disease Evaluation of the highest and lowest possible scores and the linearity of steps; identification of possible floor and ceiling limitations Determination of the time requirements for change in a measure

onset and progression. Key dimensions of clinimetric evaluations are listed in Table 16.1. Construct validity requires a consensus that the test or battery of tests is measuring important features of the disease and a rational hypothesis that the chosen measures may be responsive to treatment-induced change. In addition, there should be a clear understanding of the range, steps, linearity and processing options for each endpoint, as well as an estimate of the expected repeat-measure and crosscenter variance for each measure. A valid assessment of change in sensory-motor function in complex, multifaceted diseases, such as diabetic neuropathy or amyotrophic lateral sclerosis, may require a broad set of clinical, objective, and patient-based outcome measures. This is supported by a recent cross-sectional study that reported only a moderate degree of correlation among 26 measures of diabetic neuropathy organized into autonomic testing, nerve conduction studies, quantitative sensory evaluation, and nerveaxon reflex vasodilation categories (Gibbons et al., 2010). The findings suggest that various components of the battery of tests were sensitive to different aspects of the underlying deficits, prompting the authors to conclude that “the use of a single quantifiable examination or neurophysiologic measure does not adequately diagnose all presentations of diabetic neuropathy.”

Sensitivity and specificity Sensitivity and specificity are common clinimetric parameters that together define the ability of a measure to detect

the presence or absence of a specific condition (i.e., likelihood ratio). Although both test-related sensitivity and specificity must always be considered, these items often trade off with each other. For example, a recent comparison of the utility of three point-of-care devices (i.e., Vibratron II, NC-stat®, and the Neurometer®) and two clinical protocols (i.e., Michigan Neuropathy Screening Index and a 10 g SemmesWeinstein monofilament) in a cohort of 195 subjects with type 1 diabetes reported that the age-adjusted Vibratron II had the highest sensitivity (91%), but the lowest specificity (Pambianco et al., 2011). In contrast, the monofilament had a very low sensitivity (20%), but the highest specificity (89%). Sensitivity and specificity were defined in comparison to the identification of neuropathy by a standard clinical exam, which was considered the “gold standard.” The Vibratron II identified the vast number of patients thought to have neuropathy, but it also found evidence of sensory loss in several patients judged to be within normal limits by standard clinical examination. One interpretation is that the Vibratron II, which measures sensory thresholds using a two alternative forced choice algorithm, yields false positives, but an alternative is that this instrument is simply able to detect neuropathy at an earlier point than the clinical exam. A number of factors impact the sensitivity and specificity of a measure, including: complexity of the condition under study, presence of unique features, range of deviance from normal, and homogeneity of the surveyed population. A newly defined tool for the detection of CreutzfeldtJakob disease (CJD) that includes 26

SENSORY-MOTOR ASSESSMENT IN CLINICAL RESEARCH TRIALS separate measures organized into eight domains was evaluated in 37 patients with confirmed CJD, 101 healthy firstdegree relatives, and 14 patients with Parkinson disease. The reported sensitivity was 97%, while the specificity was 100% (Cohen et al., 2011). This outstanding performance was largely due to the broad-based nature of the assessment, which included vision, brainstem function, movement patterns, neuropathy and cortical function, and to the relatively unique disease presentation. A reduced level of specificity usually indicates that a measure is influenced by factors other than those found in the target condition. For instance, the specificity of vibration thresholds for diabetic neuropathy may be reduced by calluses or local nerve entrapments. Specificity is also influenced by the prevalence of a condition in the sampled population; low specificity is often associated with rare conditions (Brenner and Gefeller, 1997). Highly specific and rationally tailored measurement instruments with outstanding sensitivity and specificity have been developed for a variety of sensory-motor conditions such as CharcotMarieTooth disease (Shy et al., 2005) and cervical dystonia (Consky and Lang, 1994).

Reliability Although there has been recent interest in alternative approaches (van Doorn and Merkies, 2008), most clinical trials are still designed to detect a compound- or treatment-related change in a condition over a limited time period using a statistical “yesno” comparison across treatment-specific cohorts. For these studies, issues of reliability and interpretability are critical. A combination of testretest reliability and cross-center variance defines the statistical power of a study. Statistical power is often mistakenly considered a metric for the probability of a positive finding in a clinical trial; it is actually a calculation of the probability that, if present, a specific magnitude of difference across cohorts will achieve significance at a specified alpha level (e.g., <0.05). Selecting a measure of sensory-motor function based primarily on reliability may result in diminished sensitivity. Subjects with possible sensory neuropathy would reliably score an ice cube as “cold.” This measure would have a high degree of specificity (i.e., almost no one without neuropathy will fail to feel the ice cube as cold), but extremely limited sensitivity. Estimates of a measure’s general reliability may be misleading with respect to the element that is subject to change. For instance, a measure of F-wave latency has been included in many clinical trials because it was reported as the most reliable electrophysiological endpoint (Kohara et al., 2000). Unfortunately, the testretest reliability of F-waves is largely due to the strong correlation of F-wave latencies and the subject’s height, which remains unchanged during the course of a study and is unaffected by treatment.

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Monotonicity In many clinical trials, separation of scores across treatments is anticipated to reflect, in part, a longitudinal deterioration in the placebo-treated group. Monotonicity is a measure of the extent to which an endpoint follows a consistent trend of either worsening or improvement (Dyck et al., 2005). Contrary to expectations, the rate of deterioration in the placebo-treated arm has been slower than predicted by the natural history. This “placebo effect” is especially evident for signs and symptoms and may be related to a patient’s positive expectation, to increased access to medical personnel during the study period, or to aspects of data processing (e.g., last observation carried forward). An analysis of longitudinal data from two large multicenter, doubleblind, placebo-controlled clinical trials of diabetic neuropathy (i.e., Lilly Study and the Nathan 1, Viatris Study) found that only sural nerve amplitude and peroneal nerve velocity showed monotonic worsening in the placebo-treated subjects over a 4-year period; signs and symptoms of sensory-motor function actually improved slightly in the placebo group (Dyck et al., 2007). These and similar findings have plagued recent studies of sensory-motor function, and have made susceptibility to the “placebo effect” an important clinimetric consideration. A recent Phase II/III multicenter study of diabetic neuropathy has, for the first time, selected an objective measure of nerve conduction velocity as the primary efficacy endpoint (Eisai, Inc., 2011).

Minimal clinically important difference A final consideration in the selection of sensory-motor measures for clinical studies is the requirement, often imposed by regulatory agencies, for an a priori statement of a degree of treatment-induced change that represents a minimal clinically important difference (MCID). The MCID was introduced to ensure that a positive outcome in a clinical trial was meaningful for the patient and impactful as a measure of disease modification (Jaeschke et al., 1989). For some outcome measures, statistical significance is necessary, but not sufficient. This recognizes that with a large enough N, even small and “clinically meaningless” differences across treatment groups could reach statistical significance. There are multiple approaches to define an acceptable MCID, but no clear consensus (Hajiro and Nishimura, 2002). In several clinical trials, regulatory agencies have required that the difference between treated and placebo groups must be both statistically significant and greater than the defined MCID. For studies of diabetic polyneuropathy, a MCID for nerve conduction velocity has been set at a change greater than 1.2 m/second, but this has not met with universal acceptance. Likewise, an observed

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3-month increase in survival of patients with amyotrophic lateral sclerosis with no improvement in function has been judged by many as less than a MCID.

Conversion to “normal deviant units” One approach to the reporting of sensory-motor endpoints is to express them as normal deviant units with respect to a reference population. Using this method, findings from a wide range of tests or from composites of measures scored in different units can be converted to percentile values. A downside of this approach is the need to ensure that the reference population is appropriate for the condition under study. The anthropometric characteristics and health status of a “normal” population at a Midwest site may not reflect those in the Bronx or in Malaysia. In studies of diabetic neuropathy, the mean BMI of enrolled patients in San Antonio can be more than 50% higher than those in Asia.

Population Efforts to define a homogeneous study population often involve the use of restricted screening criteria (e.g., HbA1c levels less than 8.5 in patients with diabetic polyneuropathy). These criteria alone, or in combination with other exclusion factors, can create a nonrepresentative study population. The clinimetric term for this condition is “spectrum bias,” which can impact the ability to generalize study findings to the relevant clinical population (Mulherin and Miller, 2002). Even for the subjects that meet entry criteria, those who choose to participate in clinical research may represent a biased subset. For example, the selection of study measures that are complex, time-consuming, or unusually frequent may discourage patients with full time jobs. This could in turn impact both age distributions and severity levels. A recent study compared the characteristics of 164 patients that were enrolled in eight different clinical trials for amyotrophic lateral sclerosis (ALS) with a group of 568 patients from the same ALS registry who would have met the study eligibility criteria, but did not enter in a clinical study. The enrolled patients were younger, slower progressing, and were half as likely to have bulbar onset of weakness (Chio et al., 2011).

MEASURES OF MOTOR FUNCTION IN CLINICAL RESEARCH Even a brief and incomplete discussion of the possible causes of deficit in movement must include alterations in neocortex, corticospinal tracts, brainstem, basal ganglia, thalamus, cerebellum, spinal cord, spinal roots, peripheral motor nerves, neuromuscular junction, and muscle. A well-defined endpoint such as paralysis can

result from an ischemic event in cortex, the demyelination of motor neurons, or a failure of exocytosis of ACh-containing vesicles at the neuromuscular junction. A comprehensive discussion of assessment of motor deficits in multiple conditions is beyond the scope of this review. Instead, this section focuses on ALS and cervical dystonia (CD). These have been the subject of extensive clinical research targeting diagnosis, progression, and possible treatment (de Carvalho et al., 2005; Traynor et al., 2006; Chinnapongse et al., 2010). ALS is a fatal disease characterized by progressive degeneration of both upper and lower motor neurons. It is the most common motor disease, with an incidence of approximately 2 individuals per 100 000 (Haverkamp et al., 1995). ALS is characterized by a steady and often rapid deterioration in function including weakness, muscle atrophy, spasticity, loss of speech, difficulty in swallowing, inability to perform activities of daily living, respiratory problems, and susceptibility to infection. Most patients do not survive more than 4 years following onset of symptoms. It has been more than a decade since the World Federation of Neurology Research Group on Motor Neuron Diseases outlined the “El Escorial” criteria for the diagnosis of ALS (Brooks et al., 2000), which helped define a set of valid measures for use in clinical research. A number of measures, such as the Revised ALS Functional Rating Scale (Cedarbaum et al., 1999) and Motor Unit Number Estimation (Bromberg, 2007), have been specifically designed to trace the natural progression of ALS and a possible change in the disease course with therapy. Endpoints in clinical research trials for ALS fall into four categories: (1) manual examination of muscle strength, (2) the use of electrophysiology to estimate the number and integrity of motor units, (3) patient-reported changes in their ability to perform activities of daily living affecting quality of life, and (4) survival. Table 16.2 lists a representative sample of previous and ongoing clinical trials for ALS, along with the key measures utilized. The historical and practical clinical standard for the assessment of weakness is manual muscle testing (MMT) and the grading of strength in several muscles. The MRC scale, which was developed in Britain during World War II, is the most widely used clinical strength scoring system, but several alternative scales exist (e.g., Mayo Clinic Strength Scale). As originally proposed, the MRC scale has five steps: (0) no contraction, (1) a flicker of contraction, (2) active movement with gravity eliminated, (3) active movement against gravity, (4) active movement against gravity and resistance, and (5) normal power. This scale is ordinal, nonparametric, nonlinear and scoring is heavily weighted toward severe deficits (e.g., profound weakness, manifest as a subject that can only lift a finger against gravity, but not

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Table 16.2 Endpoints in clinical trials of ALS Year

Treatment

Representative sample of clinical trials of ALS

1974

Guanidine

1986

Thyrotropin-releasing hormone

1994

Riluzole

1996

rhCNTF

1999

r-metHuBDNF

2003

Topiramate

2004

Creatine

2006

Celecoxib

2007

Minocycline

2008

Poly-pharmacy

2010

Talampanel

2010

VEGF

The administration of guanidine in amyotrophic lateral sclerosis – Norris et al. (1974) Controlled trial of thyrotropin-releasing hormone in amyotrophic lateral sclerosis – Brooke et al. (1986) A controlled trial of riluzole in amyotrophic lateral sclerosis  Bensimon et al. (1994) A placebo-controlled trial of (rhCNTF) in amyotrophic lateral sclerosis – Miller et al. (1996) A controlled trial of recombinant-methionyl human BDNF (r-metHuBDNF) in ALS – BDNF Study Group (1999) A randomized placebo-controlled trial of topiramate in amyotrophic lateral sclerosis – Cudkowicz et al. (2003) A clinical trial of creatine in ALS – Shefner et al. (2004) Trial of celecoxib in amyotrophic lateral sclerosis – Cudkowicz et al. (2006) Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomized trial – Gordon et al. (2007) A novel efficient randomized selection trial comparing combinations of drug therapy for ALS – Gordon et al. (2008) A Phase II trial of talampanel in subjects with amyotrophic lateral sclerosis – Pascuzzi et al. (2010) A Phase 2 repeat-dosing clinical trial of SB-509 in subjects with amyotrophic lateral sclerosis – Sangamo Biosciences (2011)

N

Key measures utilized 24

MMT; ALS-S; PF

30

MMT; FVC; TFT; CMAP

155 570

MMT; FVC; CGICS; Survival MVIC; FVC; Survival

1135

FVC; ALSFRS; TFT; AS; Survival

296

MVIC; FVC; ALSFRS; GS; Survival

104

MVIC; FVC; ALSFRS-R; MUNE; GS MVIC; ALSFRS-R; MUNE; GS; Survival MMT; FVC; ALSFRS-R; Survival

300 412

60

ALSFRS-R; FVC; TFT

59

ALSFRS-R; TQNE; FVC; Survival

40

MMT; ALSFRS-R; CMAP; FVC; NI; Survival

ALSFRS, functional rating scale (R ¼ Revised); ALS-S, study specific ALS functional battery; AS, Ashworth Scale of Spasticity; CGICS, clinical global impression of change; CMAP, compound muscle action potential; FVC, forced vital capacity; GS, grip strength; MMT, manual muscle testing; MUNE, motor unit number estimate; MVIC, maximum voluntary isometric contraction; NI, neurophysiological index; PF, study specific testing of pulmonary function; TFT, timed function tests; TQNE, Tufts Quantitative Neuromuscular Exam.

resistance, is assigned a score of 3 on a 05 continuum). The scale has been greatly improved by the option to score movement against gravity and slight resistance as a (4 ), and movement against gravity and strong resistance as a (4 þ). Further modifications of MRC scoring include conversion to a 10-point scale and averaging of the scores across muscles (Mendell and Florence, 1990). In a 1-year, longitudinal study of 63 subjects with ALS in 12 centers, strength was scored at 3-month intervals using a modified MRC scale and a quantitative measure of maximal voluntary isometric contraction (MVIC). Reproducibility across measures was equivalent; however, the sensitivity to progressive weakness favored

the more traditional use of MMT (Great Lakes ALS Study Group, 2003). This comparison is instructive because it illustrates a key principle. Because MMT was simple, fast, and inexpensive, the investigators were able to evaluate and score 34 muscles in each patient, at each time point. In contrast, the MVIC required special equipment and considerable time, so testing was limited to six muscles. Unless there is a clear advantage in sensitivity, the simplest valid measure is often best. The value and utility of MMT is further supported by the observation that MRC scores were strongly correlated (r ¼ 0.81, p < 0.001) with the amplitude of the compound muscle action potential (CMAP) in the ADM muscle in 70 patients with ALS (de Carvalho and Swash, 2000).

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Amplitudes decreased from a mean level of 12.3 mV in subjects with a MRC score of 5, to a mean value of 1.4 mV in subjects with a MRC score of 2 or 1. MMT has been incorporated as a component of several composite measures of sensory-motor function including: the Neuropathy Impairment Score-Lower Limb (Dyck et al., 1997), the Total Neuropathy Score (Cornblath et al., 1999), and the modified Toronto Clinical Neuropathy Score (Bril et al., 2009). As an alternative to the assessment of strength in individual muscles, early clinical studies of ALS explored functional tests which incorporated strength, timing, and capacity for specified movements. The Tufts Quantitative Neuromuscular Exam (TQNE) has been specifically designed for the evaluation of patients with ALS and it includes measures of bulbar motor function, respiration, timed hand movements, and isometric muscle force in the upper and lower extremities. This composite motor assessment has proven to be both a reliable and a responsive index of disease progression. A longitudinal study of 17 ALS patients evaluated with the TQNE each month for 1 year after diagnosis of ALS, reported that each of the 16 individual measures of muscle force declined ( p ¼ 0.0001 for the megascore) over the study period (Shields et al., 1998). TQNE scores were more responsive than the patient’s perception of deterioration in physical health, which has implications for setting a MCID for clinical trials of ALS. The clinical measures of strength and function have been augmented by quantitative measures of electromyography designed to provide sensitive and objective biomarkers for change in lower motor function. The strengths and limitations of these neurophysiological measures have recently been reviewed as they apply generally to sensory-motor deficits (Cheah and Kiernan, 2010), and specifically to the measurement of ALS in clinical trials (de Carvalho et al., 2005). Initial electrophysiological studies of ALS have focused on the amplitude of the CMAP (Kelly et al., 1990). As stated above, the amplitude of the CMAP correlates with diminished strength and this measure can also trace progressive weakness in ALS (Daube, 1985). The problem with CMAP is that collateral reinnervation can mask motor unit death (Dengler, 2002). This can reduce the sensitivity and accuracy of CMAP, especially in slowly progressive ALS. Two distinct, calculated electrophysiological measures of motor neuron loss have emerged: the neurophysiological index (NI) and the motor unit number estimation (MUNE). The NI relies on a combination of standard measures, including the CMAP amplitude, F-wave frequency, and distal motor latency (de Carvalho and Swash, 2000). It has been shown to be sensitive to the progression of ALS and to compare

favorably with the CMAP (de Carvalho et al., 2003). MUNE is an attempt to calculate the number of functioning motor units in human muscle (McComas et al., 1971). A motor unit is defined as a single motor neuron and the muscle fibers that it innervates. The underlying approach is straightforward, i.e., dividing the amplitude of the CMAP by the average size of the signal from a single motor unit to determine the number of motor units in an evoked muscle contraction. In practice, the technique has proven difficult. At least six methods of calculating the MUNE have been outlined (de Carvalho et al., 2005; van Dijk et al., 2008). Although the results of some studies supported the added value of MUNE for tracing motor loss in ALS (Felice, 1997; Ahn et al., 2010), there have also been substantial problems with the calculation of this endpoint in clinical trials (Shefner et al., 2007). Recently, subjects with definite or probable ALS were followed for a period of 8 months using a variety of measures including MMT (MRC scale), the ALS Functional Rating Scale (ALSFRS), CMAP, and high-density MUNE (van Dijk et al., 2010). MUNE was reliable (i.e., intraclass correlation coefficient 0.86) and over the study period, it showed a significantly greater decrease than each of the other measures. Further, a comparison with KaplanMeier survival curves indicated that a deterioration in the MUNE score at 4 months of >38% identified patients with the rapidly progressive form of the disease. Patient-Reported Outcome Measures are important in clinical research and clear guidelines have been established for the collection and interpretation of these data (FDA, 2011). Understanding the course of a debilitating disease such as ALS, or determining if a particular therapy modifies the impact of the illness, requires more than measurements of strength or physiology. ALS alters physical health, but it can also change social relationships, mood, stress levels, job status, functional capacities, independence, and self-image. Patients may become socially isolated and are eventually physically dependent. For ALS patients, reported outcomes generally fall into three categories: (1) functional rating scales examining activities of daily living, e.g., ALSFRS (Cedarbaum and Stambler, 1997), (2) traditional questionnaires, e.g., ALS Assessment Questionnaire (Jenkinson et al., 1999), and (3) nontraditional assessments of disease impact in areas determined most important by the patient. The ALSFRS is a validated 40-point clinical rating scale that measures levels of functional disability organized into four categories (i.e., gross motor tasks, fine motor tasks, bulbar functions, and respiratory function). Specific questions address the degree of difficulty in areas such as speech, walking, handwriting, dressing, or climbing stairs. The original version only included

SENSORY-MOTOR ASSESSMENT IN CLINICAL RESEARCH TRIALS one question about respiration; the revised version (ALSFRS-R) gives respiration equal weight by adding questions about dyspnea, orthopnea, and respiratory insufficiency (Cedarbaum et al., 1999). ALSFRS-R was evaluated in 387 placebo-treated ALS patients as part of the BDNF Phase II and III clinical trial (Cedarbaum et al., 1999). The motor categories were sensitive to deterioration of isometric muscle strength and muscle mass, while the total score at baseline was a predictor of 9-month survival. The bulbar category of the ALSFRS-R, which included rating difficulty in swallowing from normal to the need for an external feeding tube, was related to MRI evidence of neurodegeneration in the medulla (Pioro et al., 1998). Quality of life (QOL) instruments in ALS studies have generally focused on the impact of the progressive loss of strength and physical function. In contrast, the more recent ALS Specific Quality of Life (ALSSQOL) instrument includes measures of “psychometric prosperities” such as negative emotions, intimacy, and religiosity (Simmons et al., 2006). A more radical approach is based on the underlying assumption that QOL is highly personal and that the most troubling aspects of the disease may differ across patients. The Schedule for the Evaluation of the Individual Quality of Life-Direct Weighting (SEIQoL-DW) measure requires that each patient first lists the five most important areas of their lives (cues). They then score how the disease impacts that area on a 0100 visual analog scale (cue level) and rank order the areas (cue weight). The final score is the mean product of the cue level and the cue weight. Examples of selected cues include family, finances, health, recreation, work, religion, and physical function. An evaluation of the SEIQoL-DW in 127 subjects with ALS revealed the surprising finding that this personalized version of QOL was poorly correlated with measures of strength or function, suggesting that QOL in ALS is not synonymous with health status (Felgoise et al., 2009). The use of SEIQoL-DW as a tool for clinical trials has not been adequately evaluated. Survival has often been used as an outcome measure in studies of ALS (Bensimon et al., 1994). However, survival in individuals is often a function of non-neural factors such as family support, access to medical care, and the accuracy of the identification of disease onset. A treatment that significantly improves survival in ALS would obviously be of great value, and conversely, a treatment that improves measures such as ALSFRS, MMT, or MUNE without changing survival would be of limited value. In contrast to the wide range of measures that have been employed in clinical trials for ALS, multicenter studies of the excessive muscle contraction and altered head position in CD have generally focused on a single

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measure, the Toronto Western Spasmodic Torticollis Rating Scale  TWSTRS (Consky and Lang, 1994). The TWSTRS scale has a range of 087 organized into three subscales: Severity, Disability, and Pain. It has been used as the “primary” endpoint in multiple clinical trials of CD with unquestionable positive outcomes following treatment with botulinum toxin (Brashear et al., 1999; Brin et al., 1999; Chinnapongse et al., 2010; Truong et al., 2010). This is an example of a targeted, sensitive, broad-based, responsive, and practical measure of a primary motor disease. Pain is an important clinical feature of CD, illustrating the link between sensory and motor function. Treatment-related improvement in the pain subscale of the TWSTRS instrument has been a key component of reported efficacy. Complex electrophysiology endpoints (e.g., electrical impedance myography) have also been proposed as objective, and possibly sensitive, biomarkers for dystonia (Tinazzi et al., 2009; Lungu et al., 2011), but their utility in clinical research remains unproven.

MEASURES OF SENSORY FUNCTION IN CLINICAL RESEARCH The quality of cutaneous sensation is a function of the integrity of transduction at the level of the receptor, the fidelity of transmission along afferent peripheral axons, and the integration of activity within the dorsal horn, thalamus, and cortex. Damage to the soma of dorsal root ganglion cells or to the mechanism of axonal transport can result in a length-dependent distal axonopathy (Schaumburg, 1992). Sensory loss initially presents in a “stocking and glove” pattern with progression to more proximal sites. This pattern is the hallmark of diabetic symmetrical polyneuropathy, which is the most common form of nerve damage in North America and Europe, estimated to affect over 20 million people (Said, 2007). Symmetrical length-dependent changes in sensation are also characteristic findings in nutritional, toxic, metabolic, and systemic disease-associated polyneuropathies (Herskovitz et al., 2010). Dysfunction in peripheral sensory neurons can result in hypersensitivity and excruciating pain in some patients (i.e., neuropathic allodynia) and in negative symptoms in others (e.g., diminished sensitivity). When the condition is insidious, such as the most common form of diabetic polyneuropathy, sensory loss can accumulate over decades and can remain undetected by both patient and physician. Neuropathy-induced sensations are often described as: pins and needles, electrical stimulation, hot or cold spots, and regions experiencing “novocain-like” discomfort. The early and accurate detection of the loss of sensation associated with diabetic neuropathy has gained increasing importance as the link between diminished sensation,

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neuropathic joint damage, ulcerations, and amputations has been firmly established (Dyck et al., 1983; Sosenko et al., 1990; Young et al., 1994; Abbott et al., 2002). A routine clinical sensory examination relies principally on a tuning fork, pin, cotton wisp, the up and down movement of the large toe, and occasionally the cold metal handle of a tendon reflex hammer. A skilled clinician can stage the gross level of sensory dysfunction and establish the symmetry and proximal extent of the observed deficits. This examination can also be used to estimate the relative dysfunction in large and small diameter sensory neurons and the presence of focal mononeuropathies. The multiple sources of variance, lack of accurate control over stimulation intensity, and the wide steps inherent in these measures generally yield an “impression” rather than quantitative results. The standard clinical assessment of sensory function is not recommended as the sole measure for research studies. Several composite measures of peripheral neuropathy combine a scored version of sensory signs with tendon reflexes and MMT. Endpoints for the assessment of sensory deficits in clinical research trials fall into four categories: (1) Quantitative Sensory Testing (QST) of sensory thresholds, (2) electrophysiological measures of sensory nerve

function, (3) patient-reported outcome measures of pain, sensory symptoms and QOL, and (4) composite measures which include the quantitative assessment of signs and symptoms, often combined with objective measures. Table 16.3 lists a representative series of composite instruments that include measures of change in sensory function. The term QST is appropriately applied to procedures where both intensity and characteristics of the stimuli are known and calibrated, a testing algorithm is defined, and the resultant threshold is determined in quantitative units that can be compared to established “normal” values (Arezzo, 2003). QST devices are available for the assessment of touch, vibration, warm, cold, and heatpain. They range from complex computer-aided instruments, e.g., CASE IV (Dyck et al., 1993), to simple handheld tools, e.g., a graduated RydelSeiffer tuning fork (Martina et al., 1998). In clinical studies, QST has been used to document early evidence of sensory loss in diabetes (Ziegler et al., 2005), to follow the progression of sensory deficits in specific clinical populations (Abbott et al., 1998), to predict patients “at risk” for foot ulcerations (Boulton et al., 1986), to trace the progression of pain (Arap et al., 2010), to aid in the diagnosis of spinal lesions (Geber et al., 2011), to detect neuropathy

Table 16.3 Representative sample of composite measures for peripheral neuropathy

Year

Composite measure

Reference

1994

MDNS Michigan Diabetic Neuropathy Score NIS-LL Neuropathy Impairment Score of the Lower Limbs CNE Clinical Neurological Examination

A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy – Feldman et al. (1994) Longitudinal assessment of diabetic neuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort – Dyck et al. (1997) The assessment of diabetic polyneuropathy in daily clinical practice: reproducibility and validity of Semmes-Weinstein monofilaments examination and clinical neurological examination – Valk et al. (1997) Total neuropathy score: validation and reliability study – Cornblath et al. (1999) Diabetic neuropathy examination: a hierarchical scoring system to diagnose distal polyneuropathy in diabetes  Meijer et al. (2000) Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy – Bril and Perkins (2002) The Utah Early Neuropathy Scale: a sensitive clinical scale for early sensory predominant neuropathy – Singleton et al. (2008) Reliability and validity of the modified Toronto Clinical Neuropathy Score in diabetic sensorimotor polyneuropathy – Bril et al. (2009)

1997

1997

1999 2000

2002 2008

2009

TNS Total Neuropathy Score DNE Diabetic Neuropathy Examination TCSS Toronto Clinical Scoring System UENS Utah Early Neuropathy Scale mTCNS modified Toronto Clinical Neuropathy Score

Key measures utilized Signs

Signs, symptoms

Signs, symptoms

Signs, symptoms, NCV, QST Signs, symptoms

Signs, symptoms Signs

Signs, symptoms

SENSORY-MOTOR ASSESSMENT IN CLINICAL RESEARCH TRIALS associated with chemotherapy (Hershman et al., 2011), and as a key efficacy endpoint in multicenter clinical trials of diabetic neuropathy (Apfel et al., 2000). Dyck and colleagues examined vibration thresholds, mediated by large diameter axons, in approximately 1500 subjects distributed in three large groups: the Rochester Diabetic Neuropathy Study, a recombinant human growth factor study, and the pancreas-renal transplant cohort. They confirmed that QST assessments were valuable for both the detection of diabetic polyneuropathy and for outlining the characteristics of sensory loss in this condition (Dyck et al., 2000). QST measures of thermal thresholds, mediated by smalldiameter axons, were also strongly correlated with measures of sensory and motor nerve conduction velocity (r ¼ 0.44 and 0.41, p < 0.001, respectively) in diabetic polyneuropathy (Ziegler et al., 2005). The results of a recent study of transthyretin amyloid polyneuropathy reported that QST measures of vibration, cold, and heatpain thresholds were all elevated (Kim et al., 2009). This confirmed the presence of a pan-modality sensory loss which contradicted the previous emphasis on deficits in small diameter axons in this condition. The link between elevated vibration perception threshold and diabetic neuropathy has been documented for more than a century (Williams, 1905). Schaumburg and colleagues identified the loss of filopod extensions in the distal extreme of axons innervating Pacinian corpuscles as the initial structural alteration in experimental acrylamide distal axonopathy (Schaumburg et al., 1974; Spencer and Schaumburg, 1977). The reduction of axonal surface area in the region of sensory transduction results in elevated thresholds for mechanical stimulation, including vibration. As the axonopathy progresses, afferent transmission is affected by the loss of conduction speed and synchrony, which further limits sensation (Arezzo, 2003). Separate cold and warm thermoreceptors have been identified with associated thinly myelinated (i.e., Ad) and unmyelinated (i.e., C fiber) axons. The sensation of pain is elicited by the activation of nociceptors or by the high-intensity stimulation of thermoreceptors, especially those sensitive to warming. Transduction in these receptors can be upregulated by a wide range of factors (e.g., calcitonin gene-related peptide, prostaglandins) which may underlie conditions of hyperalgesia and changes in heatpain thresholds (Dyck et al., 2000). As there is no “zero” energy level for comparison, the assessment of thermal thresholds is generally more time-consuming and the results more variable than those reported for vibration (Arezzo et al., 1986). There have been separate reviews of the use of QST from the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

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(Shy et al., 2003) and the American Association of Electrodiagnostic Medicine (Chong and Cros, 2004). Each concluded that QST can provide a valuable tool for measuring sensory loss, but potential pitfalls were also noted. Specific concerns were: wide differences in testing methodology and instruments, considerable variance for some assessments, and inconsistent units of measurement. In clinical research, these issues can largely be addressed by the use of a standard method across centers and time points, and by careful adherence to testing algorithms. A recent review by members of the Neuropathic Pain Research Consortium (Walk et al., 2009) supported the use of QST measures for the assessment of progression or treatment of neuropathic pain. The German Neuropathic Pain Consortium has developed a “comprehensive protocol” for the use of QST in clinical trials which includes 13 parameters for the assessment of thermal, mechanical, and pain thresholds (Rolke et al., 2006). The utility and practicality of QST as a measure of pain in clinical trials remains to be determined. Electrical stimulation bypasses the receptor and transduction, and therefore electrophysiological endpoints only provide a surrogate measure for sensory function. However, measures such as sensory nerve conduction velocity (NCV) have played a key role in clinical practice, as well as in clinical research on factors that alter sensation. When performed correctly, electrophysiology measures are objective, reliable, parametric, and responsive (Arezzo and Zotova, 2002). These measures can be focused on specific segments of the neuroaxis, such as the distal sural nerve, which are known to be vulnerable to pathology underlying sensory loss. Numerous studies dating back for more than 50 years have used electrophysiology to trace clinical neuropathies associated with altered sensation (Boulton et al., 2004), or deterioration in sensory neurons in natural history studies (Partanen et al., 1995). In a manner similar to QST, deficits in electrophysiology measures also predicted the occurrence of plantar ulcers (Carrington et al., 2002). In the extensive Diabetes Control and Complications Trial (DCCT), electrophysiological measures of NCV in both sensory and motor nerves were significantly faster over a 5-year period in the intensive treatment group versus the conventional treatment group (DCCT Research Group, 1995). Further, the positive effects of this treatment were still evident in 8 out of the 10 electrophysiological measures over the additional 5-year extension period, even when the subjects with confirmed clinical neuropathy were excluded, suggesting that the measures were sensitive to subclinical deficits (Albers et al., 2007). An analysis of data from 456 patients with type 1 diabetes in the EURODIAB Prospective Complications Study reported that slowing of conduction velocity was strongly related to duration of

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diabetes, A1C levels, and microvascular complications (Charles et al., 2010). NCV measures have been included in more than a dozen Phase II or Phase III efficacy clinical trials of diabetic polyneuropathy with limited success. A 52-week, multicenter, placebo-controlled study of the effects of an aldose-reductase inhibitor found that a composite average rank score of sural, median, and peroneal NCV was significantly improved compared to the placebo group ( p ¼ 0.004), and that the improvement remained significant when baseline-to-final changes in glycosylated hemoglobin were added as covariates (Greene et al., 1999). Although statistically significant and strongly dose-related, the magnitude of the improvement in the individual nerves was small and questionable with respect to MCID. The validity of standard electrophysiology as a surrogate measure of altered sensory function is based on overwhelming evidence that damage to sensory axons, which is well measured by NCV, causes neuropathic changes in sensation. However, standard electrophysiology is only sensitive to activity in large-diameter myelinated axons (Arezzo and Zotova, 2002) and thus these measures may be invalid for changes in temperature perception or pain. Potential new surrogate measures for small-fiber sensory function include intraepidermal fiber density and thermal-evoked potentials. The perception of unusual sensations is obviously an intensively personal experience and perhaps can only be measured as patient-reported symptoms. The assessment of general and specific sensory symptoms is a standard component of the clinical examination of sensory function, and the presence of symptoms has been incorporated into several composite measures of peripheral neuropathy (Table 16.3). The Neuropathy Total Symptom Score-6 (NTSS-6) is a limited questionnaire designed with consideration of clinimetric issues to evaluate the frequency and intensity of positive sensory symptoms in diabetic neuropathy (Bastyr et al., 2005). NTSS-6 was validated against established symptom scores, and its six domains have a high degree of internal consistency and substantial testretest reliability. The assessment of pain is an especially difficult task due to the often complex interaction of sensory and emotion elements (Gilron and Jensen, 2011). There have been numerous reviews of the strengths and limitations of the measuring options for pain in clinical research (Dworkin et al., 2008; Turk et al., 2008). Established options included the use of a visual analog scale, patient diaries, measures of physical and emotional functioning, and symptom questionnaires. A recent 13-week multicenter study of the possible analgesic effects of pregabalin used daily pain diaries and change in a visual analog pain scale to trace the rapid separation of pain scores in treated and

placebo subjects, in spite of a clearly present placebo effect (Arezzo et al., 2008). As mandated by the regulatory agencies, this study also confirmed that the observed reduction in pain was not due to a general deficit in sensory function, as measured by electrophysiology.

CONCLUSIONS The assessment of sensory-motor function in clinical research presents a unique set of challenges. A review of the use of various outcome measures that have been used in clinical trials suggests that several tools provide a reasonable and responsive measure of sensory-motor function in ALS, CD, and diabetic polyneuropathy. It is likely that clinimetric considerations will have a greater impact on the selection of endpoints for future clinical studies. There is a growing awareness of the importance of minimizing placebo effects and spectrum bias. As the cost of studies in both time and money increase, it is likely that extremely complex outcomes will be rejected and greater attention devoted to standardizing skills and training across centers. Consequently, the “shotgun approach” characterized by the use of multiple measures may be replaced by more rational and focused assessment tools. The use of composite scores may also be more restricted, as their interpretation is often complicated by the summation of values from different types of scales (e.g., “yes or no” ordinal for symptoms, quantitative for electrophysiology). Concerns have also been raised that the relative weighting of measures within the composite can be arbitrary, and that the summed score may be significant while no individual measure reaches a MCID. There is also an interesting expansion of patient-reported outcome measures to explore the impact of deficits in sensory-motor function beyond physical health. It is likely that emerging technology, the continued refinement of clinimetric tools, and growing interest in alternative strategies for data analysis (e.g., Bayesian statistics and Rasch approaches) will greatly enhance the sensitivity and accuracy of future clinical measures.

ACKNOWLEDGMENTS We want to thank Linda O’Donnell, Mona Litwak, and Jeannie Hutagalung for their assistance in the preparation of this manuscript.

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