Reprinted with permission from the World Federation of Neurology, Research Group on Neuromuscular Diseases, Subcommittee on Motor Neuron Disease.

Guidelines for the use and performance of quantitative outcome measures in ALS clinical trials

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Developed under the auspices of The World Federation of Neurology, Research Group on Neuromuscular Diseases, Subcommittee on Motor Neuron Disease. These guidelines are to be used in conjunction with those developed at the WFN Airlie House Workshop On Therapeutic Trials in ALS, at Airlie House, Warrenton, Va., April 29 - May 1, 1994.

The following persons developed the guidelines:

James R. Brinkman, PT, MS
Dept. of Neurology, Neuromuscular Section
University of Colorado Health Sciences Center
Denver, CO

Patricia Andres, PT, MS
Neuromuscular Research Unit
New England Medical Center
Boston, MA

Michelle Mendoza, PT
Dept. of Neurology
California Pacific Medical Center
San Francisco, CA

Mohammed Sanjak, PhD
Dept. of Neurology
University of Wisconsin Medical Center
Madison, WI

May 17, 1995

Contents:

INTRODUCTION

ALS is a motor neuron disease defined as a progressive, neurological disorder, resulting from variable and combined degeneration of upper and lower motor neurons. The heterogeneity of clinical involvement early in the course of the disease makes it difficult to diagnose, as well as to identify one unique outcome measure to quantify neurological changes in the course of the disease. Since clinical evidence of upper and lower motor neuron degeneration must exist in four anatomical regions (bulbar, cervical, thoracic, and lumbosacral), outcome measures should assess regions. The WFN Airlie House recommendations specify the purpose, properties, and the preferred parameters which serve as outcomes measures in ALS clinical trials. The purpose of this document is to serve as a review of these outcome measures in terms of their advantages, disadvantages, sensitivity, reliability, and other characteristics, as well as their proper performance function, muscle strength, general function, and bulbar function. Our review leads us to believe that respiratory function and strength provide the most useful information, both for research and clinical purposes, and are essential as outcome measures. Inclusion of bulbar and general function parameters in trial design may increase the possibility of identifying a beneficial effect of therapeutic intervention. It is essential to note that the guidelines and recommendations put forth are intended to provide initial evaluation and critique of the proper employment and performance of these outcomes measures in ALS clinical trials, based on the available literature and our experience.

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SUMMARY TABLE OF TESTS RECOMMENDED FOR ALS CLINICAL TRIALS

1. Respiratory Function Tests

  1. FVC
  2. VC

2. Strength Tests

  1. Computer-based fixed strain gauge

3. Function Tests

  1. ALSFRS
  2. ALSSS
  3. Timed walk
  4. Purdue pegboard

4. Bulbar Function Tests

  1. Timed speech test
  2. Bulbar force transducer

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GUIDELINES AND RECOMMENDATIONS FOR PERFORMACE OF OUTCOME MEASURES IN ALS CLINICAL TRIALS

For ease in identifying recommended tests in this document, a star (Star) precedes descriptions of those tests designated as "recommended".

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RESPIRATORY FUNCTION TESTS

I. Purpose

Since respiratory failure is the major cause of death in ALS, respiratory function should be followed closely in patients with ALS.

II. Respiratory pathophysiology in ALS
  1. Weakness of diaphragm & external intercostals (inspiratory muscles), causes decreased volumes and inspiratory pressures.
  2. Weakness of internal intercostals and abdominal wall (expiratory muscles) causes decreased volumes, decreased expiratory pressures and ineffective cough.
  3. Weakness and discoordination of glottis causes decreased readings of volumes especially FEV1 and decreased pressures, ineffective cough, weak gag reflex, congestion.
  4. Fatigue of respiratory muscles causes decreased Maximal Voluntary Ventilation (MVV).

III. Available tests.
  1. Measuring volumes using spirometry.

    Both volume-displacement and flow-rate based spirometers are accurate, reliable, and should meet American Thoracic Society stnadards. 1,2 Automated spirometers utilizing a microprocessor may have a minimal flow rate or volume displacement which needs to be met in order to complete the test. This may cause a premature termination of one phase of the test in some patients who demonstrate a sporadic or intermittent airflow obstruction or restriction resulting from the disease process. Methods of circumventing this premature termination of PFTs are usually unique for each model of spirometer.

    Star 1. Vital capacity (VC)
    Measures the volume of air expired, non-forcefully, in one breath.
    a. Advantages.

    1. Patients with poor or uncoordinated glottal closure may get higher volumes using this method compared to FVC.
    2. Similar to FVC.
    b. Disadvantages.
    1. Less commonly used measure in ALS.
    2. Results in greater residual volume than FVC.
    c. Recommendation: VC is a recommended test for ALS clinical trials.
    Note: In longitudinal studies, FVC or VC tests must be used consistently throughout the testing period as these tests may not be interchangeable.

    Star 2. Forced vital capacity (FVC)
    Measures volume of air forcefully expired in one breath.
    a. Advantages.

    1. Easiest, most meaningful test to measure disease progression in ALS. 3
    2. Best indicator of pending respiratory failure. 3
    3. Best test related to respiratory symptoms. 3
    b. Disadvantages.
    1. May not be a sensitive early indicator; may have a 1 to 3 year lag compared with maximal expiratory pressure (MEP). 4,5
    2. Patients with airway obstruction may produce low and variable reading.
    c. Recommendation: FVC is a recommended test for ALS clinical trials.

    3. Forced expiratory volume - second (FEV1)
    Measures volume during the first second of forceful expirations.
    a. Advantages.

    1. Important parameter for patients with COPD; gives indication of cough ability. 3
    2. Measured while performing FVC.
    b. Disadvantages.
    1. Does not reflect disease progression well.
    2. Results can be highly variable.
    3. Does not add any useful information on a longitudinal basis.
    c. Recommendation: FEV1 is an acceptable test for ALS clinical trials.

    4. Flow volume Loop
     Measures volume versus flow of forced expiration and inspiration.
    a. Advantages.

    1. Gives a comprehensive, clinically useful reading of pulmonary function.
    2. Yields FVC.
    b. Disadvantages.
    1. Adds complexity to the test.
    2. Duplicative if FVC is performed.
    c. Recommendation: Flow volume loop recording is an acceptable test for ALS clinical trials.

    5. Maximum voluntary ventilation (MVV)
    Measures volume of air exchanged in 10-12 seconds, then corrected for one minute.
    a. Advantages.

    1. Better early indicator than FVC. 6
    2. Good indicator of fatigue. 7
    b. Disadvantages.
    1. May produce coughing.
    2. Patients with bulbar involvement may produce erroneous, low reading.
    3. Patients with concurrent obstructive lung diseases will have much lower readings.
    4. Duplicative if measuring FVC.
    5. Labor intensive, not good indicator late in the disease.
    c. Recommendation: MVV is an acceptable test for ALS clinical trials.

  2. Measuring pressures using a pressure manometer.

    Note: These tests are dependent upon lung volume at the initiation of the test. This variable needs to be well controlled.

    1. Maximal Inspiratory Pressure (MIP) or Negative Inspiratory Pressure (NIP)
    a. Advantages.

    1. Sensitive early indicator of muscle weakness. 3
    2. Reproducible, quick, inexpensive instrumentation.
    3. Differentiates between parenchymal disease and muscle weakness.
    b. Disadvantages.
    1. May be a poor indicator late in the disease.
    c. Recommendation: MIP or NIP are acceptable tests for ALS clinical trials.

    2. Maximal expiratory pressure (MEP) or positive expiratory pressure (PEP).
    a. Advantages.

    1. Sensitive early indicator of muscle weakness. 3,7
    2. Reproducible, quick, inexpensive instrumentation.
    3. Differentiates between parenchymal disease and muscle weakness.
    4. May indicate ability of patient to cough and expel secretions. 6
    b. Disadvantages.
    1. May be difficult to measure late in disease.
    c. Recommendation: MEP or PEP are acceptable tests for ALS clinical trials.

  3. Measuring chest expansion using tape measure.

    a. Advantages.

    1. Quick, inexpensive
    b. Disadvantages.
    1. Not very informative.
    2. Not widely used.
    3. Not sensitive.
    4. Questionable reliability.
    c. Recommendation: Measuring chest expansion is not acceptable for ALS clinical trials.

  4. Measuring blood gases via oximetry or arterial blood sample.

    a. Advantages.

    1. Provides information used to determine when respiratory assistance is required.
    b. Disadvntages.
    1. Not abnormal until very late in the disease.
    c. Recommendation: Measuring blood gases in not acceptable for ALS clinical trials.

  5. Residual volume (RV)
    Measures the volume left after a maximal expiratory effort.
    a. Advantages.
    1. Residual volumes increase as the disease progresses.
    b. Disadvantages.
    1. Can only be measured by indirect means. 8
    2. Very expensive instrumentation required (>$30,000).
    3. Concurrent COPD will increase residual volume.
    c. Recommendation: Residual volume is not acceptable for ALS clinical trials.

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MUSCLE STRENGTH TESTS

I. Purpose.
To evaluate changes in limb muscle strength in ALS.

II. Background.
ALS affects the upper and lower motor neurons leading to progressive weakness and loss of function of bulbar, thoracic, abdominal and limb musculature. Measurement of the capacity of muscle to exert force is the most direct measurement of the natural histroy of the disease. 9,10,11

III. Available tests.

  1. Static (isometric) tests. 12

    2. 1. Advantages.

    1. Maximum voluntary isometric muscle contraction (MVIC) correlates well with the number of firing motor units up to the maximum contractions, 13 and thus is the most suitable measure of muscle force in clinical trials.
    2. Performed under controlled conditions, with velocity and length held constant, thereby enhancing reproducibility.
    3. Relatively safe; no motion which may reduce injuries.
    4. Fatigue is not induced in majority of patients.

    2. Disadvantages.

    1. Measures static force, a parameter not directly related to function.

    3. Manual muscle test 14
    a. Advantages.

    1. Fairly simple.
    2. Safe.
    3. Inexpensive; requires no equipment.
    4. Quick.
    5. Reliable (high intra, moderate inter-rater reliability) with well-trained evaluators.
    6. Widely applied in clinical trials and small scale natural history studies.
    b. Disadvantages.
    1. Lack of sensitivity to change. 12,15,16
    2. Poor correlation with absolute muscle strength, especially in strong muscles.
    3. Results in ordinal data, which may reduce statistical power. Additional patients may be required for MMT to achieve the same power compared with quantitative testing. 15
    4. Physical contact with patient may lead to hesitancy and incompleteness of effort. 17
    c. Recommendation: Manual muscle testing is acceptable for ALS clinical trials.

    4. Hand-held dynamometer, mechanical or electronic
    a. Advantages.

    1. Portable, spring-based do not need power supply.
    2. Electronic units can be interfaced with computer.
    3. Comparable to fixed dynamometer up to 30 Kg force (criterion validity); may be muscle group specific.
    4. Sensitive to change.
    5. High intra-rater and moderate inter-rater reliability.
    b. Disadvantages.
    1. Spring-based lose elasticity over time.
    2. Difficult to calibrate.
    3. No standard design for the point of force application or tester grasp.
    4. Have high tester influence. Will face validity only if tester strength is greater than patient strength. Subsequently, there is a tendency to underestimate strong muscles and overestimate weak muscles.
    c. Recommendation: Mechanical hand-held dynamometers are not acceptable; electronic hand-held dynamometers are acceptable for ALS clinical trials.

    Star5. Computer-based, fixed strain-gauge. a. Advantages.

    1. Muscle force analog signal is easily digitized and computed continuously.
    2. Reproducible; high intra-rater reliability with well trained evaluators.
    3. Sensitive; statistically significant decline in muscle strength was detected within two weeks in ALS (unpublished data, ALS Clinical Trials Study).
    4. Accurate measurement of muscle strength in weak, as well as strong muscles.
    5. Produces documented results for quality assurance monitoring.
    b. Disadvantages.
    1. Lack of universally accepted standardized test procedures for testing and results reporting (Table 1).
    2. The precision required for this technique is such that vigorous quality assurance procedures must be incorporated to reduce variability.
    3. Requires extensive training and equipment.
    c. Recommendation: Computer-based fixed strain-gauges are a recommended means of testing ALS clinical trials.

  2. Dynamic Tests.
    Note: Accurate muscle strength evaluation under dynamic conditions involves detailed analysis of joint and muscle segments, and application of mathematical modeling. These procedures require combining kinematics (displacement, velocity, and acceleration computed from high speed photography and TV image analysis), and kinetic (force, moment of force computed with the use of ground reaction analysis, force platform and in some cases EMG) techniques. These procedures are widely applied in gait motion, and sport activity analysis but are not acceptable for ALS clinical trials. However, a variety of torque dynamometers can be used in the early stage of ALS.

    1. Isokinetic dynamometers.
    a. Advantages.

    1. Sensitive tool to quantify deficit in the early stage of ALS. 18 Dynamic muscle strength measurement may be necessary to quantify pre-symptomatic muscle strength deficit.
    2. High intra-rater and moderate inter-rater reliability.
    3. Correlates well with functional task (e.g., walking).
    b. Disadvantages.
    1. Constant velocity of joint motion may be difficult or impossible to control in some ALS patients with weakness or upper motor neuron symptoms, invalidating measurement.
    2. Very fatiguing and may be unsafe.
    3. Equipment expensive.
    c. Recommendation: Isokinetic dynamometers are an acceptable means of testing in ALS clinical trials.

    2. Other Ergometers.

    1. Muscle work, power, and endurance also can be measured using a variety of ergometers such as a bench step, one repetition maximum, cycle or a treadmill during a standardized workload. These techniques are widely applied in cardiopulmonary and sports medicine.
    2. Recommendation: Other ergometers are not acceptable for ALS clinical trials.

Table 1. Proposed Standardization Procedures for Measurement of MVIC.

1. Instrument:
  1. Fixed electronic load cell strain gauge.
  2. Automated digitizing hardware and software system
  3. Comfortable testing table that provides for adequate stabilization positioning
2. Position:
  1. Consistent joint angle and lever arm
  2. Consistent direction of force application
  3. Consistent stabilization procedures
  4. Only muscles around the joint that can assume the pre-defined position of testing should be tested. Loss of this ability should be considered an end-point.
  5. Comfortable, painless, secure and safe position.
3. Defining the measurement:
  1. Define the number of contractions (e.g. 2 MVIC) and the duration of contraction and rest periods (e.g. 3-4 sec. contraction or until peak force attained, and 3-4 sec. rest)
  2. Define test result as highest force of an averaged or smooth signal, rather than peak of high sampling rate, to avoid effect of jerking and instability within each trial. Report higher MVIC, rather than the average of two trials to eliminate the effect of fatigue or other errors.
4. Instructions:
  1. Instruct patients of the intent of the test. I.e. MVIC
  2. Give objective and consistent instructions that achieve a consistent level of motivation
5. Environmental factors:
  1. Test in a private and quiet room which eliminates any factors that might affect instrument performance and patient cooperation.

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FUNCTION TESTS

I. Purpose
To measure the functional capabilities of patients over the course of the clinical trial, and to assist in determining efficacy of therapeutic intervention.
II. Types of function test.
  1. Rating scales. 1. Advantages.
    1. Quickly and easily performed.
    2. May reflect overall functional status.
    3. May be performed into terminal phase of disease.
    4. Possibly obtained by telephone interview.
    2. Disadvantages.
    1. Subjective; may include patients feelings, opinions, cultural effects.
    2. Influenced by environmental, or external factors.
    3. Insensitive to change.
    4. Result in ordinal data. Ratio/interval data could be obtained by converting ordinal rating scale to a visual analog scale. Each scale converted should undergo additional validity/reliability testing, before use in trial.
  2. Timed, or quantitative, functional tests.
    1. Advantages.
    1. More objective than rating scales.
    2. Result in ratio/interval data.
    3. More sensitive to change than rating scales.
    4. Can be used in conjunction with strength tests to reflect UMN involvement.
    5. Reliability and validity of timed functional tests have been established. 19,20
    2. Disadvantages.
    1. Influenced by external factors.
    2. Less readily performed in terminal phase of disease.
    3. Each test measures only one function.
III. Specific Function Tests.
  1. Disease-specific functional rating scales.

    1. The ALS Functional Rating Scale 21 (ALSFRS) is a quickly administered (5 minute) ordinal rating scale (ratings 0-4) used to determine patients' assessment of their capacity and independence in 10 functional activities. All 10 activities rated are relevant in ALS. The "Climbing Stairs" category may need revision to allow better distinctions in grades between 4 ("normal") and 1 ("Needs assistance, including handrail.") This is not an "observational" rating scale, in which the evaluator rates the patient based on physical responses or responses to questioning. This scale elicits the patients' perceptions regarding their own status. As such, ratings may be influenced by patients' psychological state at the time of testing, and may differ from the perceptions of the evaluator.
    This is a relatively new rating scale, and accordingly, sparse information is available regarding validity, reliability, sensitivity, and relevance. Initial validity has been established by documenting that change in ALSFRS scores correlate with change strength over time, in ALS patients. 22

    1. Advantages.
      1. Categories relevant to ALS.
      2. Quickly administered.
    2. Disadvantages.
      1. Some subscales contain intervals which may be disproportionate.
      2. Requires communication skills to differentiate functional impairments.
    3. Recommendation: The ALSFRS is a recommended rating scale for ALS clinical trials.

    2. The Baylor ALS Rating Scale 23 is a composite scale, which includes both ratio/interval and ordinal data. Ratio/ordinal data, derived from FVC, timed tests etc., is reduced to ordinal data in the resulting rating. Five sub-scales, bulbar, respiratory, muscle strength, lower extremity function, and upper extremity function, can be analyzed separately, or combined for a "total ALS score.quot; This scale is designed to be used as a complete test instrument in ALS, rather than a supplementary rating scale. Bulbar and respiratory sub-scales are weighted and give up to 60 points, of a possible 164 for a patient with maximal dysfunction. The maximal strength rating, derived largely from MRC, is allowed a maximum of 36 points. Function of extremities accounts for the remaining 68 points. Appel, V. 23 reports acceptable reliability/validity.

    1. Advantages.
      1. Scale is intended to be used as complete evaluation tool.
    2. Disadvantages.
      1. Reduction of ratio/interval data to ordinal rating may reduce sensitivity of tests, reducing statistical power and necessitating large sample size.
      2. Weighting of sub-scales is arbitrary.
    3. Recommendation: The Baylor ALS Rating Scale is acceptable for ALS clinical trials.

  2. Non disease-specific functional rating scales.

    1. The Barthel Index 24 is a 10 item rating scale intended for neuromuscular and musculoskeletal disorders. Six of the 10 items deal with hygiene.
    Intra-rater reliability has been shown to be acceptable. 25
    a. Advantages.

    1. Quick and easy to perform.
    b. Disadvantages.
    1. Insensitive to gradations of independence.
    2. Many sub-scales largely irrelevant to ALS.
    3. Important functional parameters in ALS, e.g. bulbar function, not included.
    c. Recommendation: The Barthel Index is not acceptable in ALS clinical trials research.

    2. The Rankin Scale 26 is a general disability rating scale which rates persons from 1 (no significant disability) to 5 (severe disability.) Categories are poorly defined. Intra-rater reliability has been shown to be acceptable, with slightly lower inter-rater reliability than the Barthel scale. 25
    a. Advantages.

    1. Quick and easy to perform.
    b. Disadvantages.
    1. So general as to be of limited value in documenting change over time.
    2. Criteria for different categories concern different parameters; patients may easily fit into several categories equally well.
    3. Parameters relevant to ALS not specified in criteria.
    c. Recommendation: The Rankin Scale is not acceptable in ALS clinical trials research.

  3. Rating Scales not listed in Airlie House guidelines.

    1. Amyotrophic Lateral Sclerosis Severity Scale, (ALSSS) 27 is composed of 4 rating scales, each with a rating from 1 - 10, for speech, swallowing, lower extremity function (walking), and upper extremity function (dressing and hygiene), and measurement of vital capacity. The 4 rating scales are relevant to ALS, have well defined and sensitive criteria, and are quickly administered. Like the ALSFRS above, which is largely derived from the ALSSS, the ratings in the ALSSS are based on information obtained from the patient and family. However, unlike the ALSFRS, the final ratings in the ALSSS are left to the judgement of the evaluator, rather than the patient. Inter-reliability and validity are acceptable. 28
    a. Advantages.

    1. Categories relevant to ALS.
    2. Ratings from 1 - 10 allow for sensitivity to change over time.
    3. Quickly administered.
    c. Recommendation: The ALSSS is a recommended rating scale for ALS clinical trials.

    2. Norris Score 29 combines ratings (0-3) for 22 functional parameters, with additional ratings for reflex activity, fasiculations, atrophy, etc. Functional ratings are defined only as normal, impaired, trace, or zero, and may be insensitive to change. The non-functional ratings, i.e. reflexes, fasiculations, etc., have not been shown to be useful in clinical trials.
    a. Advantages

    1. Thirty-four parameters rated.
    b. Disadvantages.
    1. Rated parameters are weighted equally, e.g. breathing rating equally as ability to empty bowel/bladder.
    2. Non-functional signs and symptoms, e.g. jaw jerk, included in ratings.
    3. Ratings 0 - 3 may be insensitive to change.
    c. Recommendation: The Norris Scale is an acceptable rating scale for ALS clinical trials.

  4. Timed functional test.

    Star1. Timed walking tests measure the time required to walk a set distance, e.g. 15 feet.
    a. Advantages.

    1. Commonly used test.
    2. Documents lower extremity function.
    3. Normal values for gait velocity are published.
    b. Disadvantages.
    1. Safety of each patient needs to be assessed.
    2. Time to walk may change as patient changes adaptive equipment use due to disease progression, over time.
    c. Recommendation: The timed walking test is a recommended test for ALS clinical trials.

    2. Timed standing from sitting tests measure the time required to come a standing position. This test may be insensitive early in the disease course, and duplicative if timed walking test is performed.
    a. Advantages.

    1. Safe lower extremity function test.
    b. Disadvantages.
    1. May give less indication of overall lower extremity functional capabilities than walk test.
    c. Recommendation: The timed standing from sitting is an acceptable test for ALS clinical trials.

    qualitativestar.gif 0.2 K 3. Purdure Pegboard test measures hand and upper extremity function. It is sensitive to change over time, and normal values are published. 30
    a. Advantages.

    1. Good general indicator of upper extremity function.
    b. Recommendation: The Purdue Pegboard is a recommended test for ALS clinical trials.

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BULBAR FUNCTION TESTS

I. Purpose
Because Bulbar motor neuron degeneration contributes to increased mortality rates, and the quality of life issues surrounding deterioration of speech and swallowing are clear, tracking changes in bulbar function is an important aspect of ALS research. 29

II. Bulbar pathophysiology in ALS.

  1. Weakness of mastication muscles causes decreased endurance, force of bite, and chewing ability.
  2. Weakness of facial muscles, such as orbicularis oris may cause drooling and articulation difficulties.
  3. Weakness and/or spasticity of tongue leads to decreased ability to control food bolus, saliva, and decreased articulation ability.
  4. Weakness and/or spasticity of palatal and pharyngeal muscles with either decreased or hyperactive gag reflexes causes difficulty of movement of food bolus in oral cavity and pharynx, nasal regurgitation, and possible aspiration.
  5. Weakness, discoordination of laryngeal muscles leads to inadequate airway protection and possible aspiration.

III. Available tests.

  1. Measuring Bulbar Function using Rating Scales.
    Rating scales are designed to measure change in bulbar function, signs, or symptoms.

    1. Norris ALS Score-Bulbar Subscore.
    Measures impairments (breathing, coughing, tongue atrophy, jaw jerk, labile emotions), and disabilities (chewing, speech, swallowing) with four degrees of severity to choose from.
    a. Advantages.

    1. Strong correlation of bulbar subscore with changes in survival.32
    2. Simple to perform.
    3. Some items attainable from clinical history.
    4. Disability information is easily obtainable without extensive experience in assessing neurological signs and symptoms.
    5. Can be performed in clinic or home visits.
    6. No special equipment needed.
    7. Validated.
    b. Disadvantages.
    1. Impairment scores are more difficult to gather without extensive neurological experience.
    2. Reproducibility only demonstrated with neurologists thus far.
    3. Equal weights not given to item regionally.
    4. Some impairment information overlaps the disability information regionally.
    5. Combines signs and symptoms.
    6. Results in ordinal data.
    7. Only four degrees of severity to choose from.
    c. Recommendation: The Norris ALS Score-Bulbar Subscore is an acceptable test for ALS clinical trials.

    2. Frenchay Dysarthria Scale. 33 This test is divided into eleven sections (reflex, respiration, lips, jaw, palate. Laryngeal, tongue, intelligibility, rate, sensation, associate factors) with five degrees of severity to choose from. 34
    a. Advantages.

    1. High positive correlation between degree of MVIC decrement and impairment obtained on Frenchay test. 35,36
    2. No special equipment needed.
    3. Acceptable inter-rater reliability. 34
    b. Disadvantages.
    1. Extensive and lengthy exam.
    2. Need more reliability studies.
    3. Relies heavily on tester's interpretation.
    4. Reliability documented only with speech therapists.
    5. Ordinal data produced.
    c. Recommendation: The Frenchay Dysarthria Scale is an acceptable test for ALS clinical trials.

  2. StarTimed Speech Tests.
    The time required for patient to 10 repeat a pre-established number of syllables is measured using a stop watch. Different sounds represent different levels of physiologic complexity. 37
    a. Advantages.

    1. Interval data produced.
    2. More sensitive to change than rating scales.
    3. May reflect UMN involvement.
    4. Close agreement with data sets from oscillographic and stop watch measurements. 37
    b. Disadvantages.
    1. Presymptomatic strength changes antedate functional changes; thus may not be sensitive to early strength loss.
    c. Recommendation: Timed speech tests are recommended for ALS clinical trials.

  3. Timed Swallowing Tests.
    The time required for a patient to swallow a certain quantity of liquid is measured with a stopwatch.
    a. Advantages.
    1. Interval data produced.
    2. No special equipment required.
    3. Relatively easy to perform.
    b. Disadvantages.
    1. Increased risk of aspiration by requiring patients to swallow as fast as possible.
    2. Reliability unkown.
    c. Recommendation: Timed swallowing tests are not acceptable for ALS clinical trials.

  4. Phonetic Feature Analysis.
    Analysis of intelligibility and its underlying articulation correlates through word repetition and recording of speech, as well as acoustic measures of phonatory instability through use of an oscillograph. Digitized phonation may be used to track subtle speech changes in ALS patients. 36,38

    1. Acoustic Measures.
    a. Advantages.

    1. Phonation measurements may be indices of subclinical manifestations of cranial nerve damage (i.e. prior to change in speech intelligibility). 39
    2. Some phonetic features may be predictive of intelligibility. 39
    3. Provides interval data.
    4. May be useful in observing disease progression.
    b. Disadvantages.
    1. Expensive equipment.
    2. Analysis and testing require experienced personnel.
    3. Making inferences to underlying neural control problems from speech acoustic signals is very difficult.
    4. Time consuming.
    c. Recommendation: Acoustic measures acceptable test for ALS clinical trials.

    2. Intelligibility Measures.
    a. Advantages.

    1. Convenient method of quantifying speech. 36
    2. Intelligibility relates to quality of life and function.
    3. Provides an articulatory interpretation of speech impairment.
    4. Acoustic and physiologic correlates may be defined for each phonetic feature.
    5. Identification of impaired features is potentially important to patient management.
    6. Moderately high agreement between listener rating intelligibility. 31,31
    b. Disadvantages.
    1. Different patients with same intelligibility score could have very different speech errors contributing to that score.
    2. Not sensitive to early pre-symptomatic changes.
    3. Element of subjectivity.
    c. Recommendation: Intelligibility measures are acceptable for ALS clinical trials.

  5. EMG and Sound Recordings.
    Amplitude of muscle activity and timing of key oropharyngeal parameters may be determined using surfaces EMG with simultaneous sound recording during swallowing of various food substances.32
    a. Advantages.

    1. Provides information on the activity of swallowing muscles.
    2. Less invasive than radiographic study of swallowing.
    3. Timing of swallow, and amplitude of muscle activity from EMG and sound recording may reflect changes in bulbar function.
    4. May correlate with changes seen in radiographic study of swallow.32
    b. Disdvantages
    1. Expensive equipment.
    2. Extensive training required.
    3. Reliability undetermined.
    c. Recommendation: EMG and sound recordings are not acceptable for ALS clinical trials.

  6. Videofluroscopy
     Various materials with or without barium suspensions are used to qualitatively and quantitatively evaluate swallowing through motion recording (cineradiography or videotape fluoroscopy).40
    a. Advantages.

    1. Provides quantitative information regarding timing, range, direction, and accuracy of motion for the valving components during swallowing. 34,41
    2. Reliable
    3. Valid
    4. Produces quantitative information that directly relates to symptoms and disease progression in ALS patients with dysphagia.41
    b. Disadvantages.
    1. Expensive equipment required.
    2. May be impractical for large scale trials.
    3. Requires specialized personnel.
    c. Recommendation: Videofluoroscopy is acceptable for ALS clinical trials.

  7. Orofacial Strength Measurement
    Use of force transducers developed for measurement of lip, tongue, and jaw muscle force, or ordinal grading of muscle function.

    Star1. Bulbar Force Transducers. 42
    a. Advantages

    1. Interval data obtained.
    2. Can detect pre-clinical symptoms.
    3. Valid
    4. Reliable.43
    5. Tongue atrophy and dysphagia strongly related to increased speech severity
    6. MVIC and peak rate of change of force (PRCF) for the tongue and PRCF for the lower lip significantly related to speech severity and ratings.
    b. Disadvantages.
    1. The ALS populations standard deviation at 12 months for tongue, lip, jaw MVIC is such (9-37%) that many patients will be required in the placebo groups for one year studies looking at bulbar isometric strength alone.35
    2. Weakness is not directly related to speech intelligibility.31
    3. Tongue strength shown to be poor predictor of speech proficiency.31
    4. Difficult to isolate tongue motions.
    5. Some models require dental impression to be made.
    6. Requires extensive training equipment.
    c. Recommendation: Bulbar force transducers are recommended for ALS clinical trials.

    2. Manual Muscle Testing of Bulbar Muscles.
    a. Advantages.

    1. No equipment required.
    2. Relatively easy to perform.
    b. Disadvantages.
    1. Insensitive to small changes.
    2. Ordinal data.
    3. Difficult to assign grades for bulbar muscles.
    c. Recommendation: Manual muscle testing of bulbar muscles is not acceptable for ALS clinical trials.

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QUALITY ASSURANCE AND GENERAL TEST CONSIDERATIONS

In order to insure the quality of data derived from quantitative testing, and thus the value of a clinical trial outcome, the following items should be considered:

  1. PERSONNEL AND TRAINING

    1. Persons performing the testing (clinical evaluators, or CEs) should have a medical background including clinical experiences. Physical therapists, or other allied health personnel, are ideal candidates due to their experience in strength and performance testing, kinesiology, and patient care issues.
    2. CEs should meet prior to clinical trial initiation, for training in standardized test procedures. Ideally, test equipment should be installed at all sites prior to initiation of training sessions.
    3. In multi-center trials, any site utilizing a CE without a prior experience in the test equipment or procedures involved should have a site visit by an experienced CE for review of equipment and test procedures.
    4. Replacement, or new CEs should undergo training identical to that of other CEs in trial, including intra-rater and inter-rater determinations.
    5. Experienced CEs should be involved in designation of quantitative testing procedures and protocol, prior to initiation of a clinical trial. CEs should be involved in any ongoing analysis of outcome measures during a trial.

  2. TESTING EQUIPMENT/ENVIRONMENT

    1. The testing environment - The room used for testing should be large enough for all necessary equipment. Lighting should be optimal. Patient privacy should be respected. Family members or persons accompanying the patients should be requested to wait in a nearby waiting area, to eliminate the possibility of influencing the patient's performance.
    2. Patients should be encouraged to wear loose, comfortable clothing. The issue of allowing/not allowing assistive equipment which the patient acquires during the course of a trial, should be determined prior to trial initiation. Use of newly acquired assistive equipment may result in test data incompatible with data obtained prior to use of that equipment. However, is use of assistive equipment is not allowed, patient may be unable to be tested in some parameters e.g. walking. Any assistive equipment used should be documented. Special coding should be used to designate test results in which the patient is unable to perform or complete the test, as well as tests not attempted.
    3. All test equipment and procedures, including computer hardware and software, should be reviewed prior to trial initiation, for validity, reliability, sensitivity, and appropriateness.

  3. TESTING PROCEDURES

    1. Until the patient has performed the testing procedures numerous times, all tests should be performed under the following guidelines:
      1. CE explains the test, stressing maximal effort is desired.
      2. CE demonstrates test, showing action or response desired.
      3. CE has patient peform "dry-run" test trial.
    2. All tests should be performed twice, with the better result used for data analysis. FVC should be performed for at least three, but not more that five, trials.
    3. The possibility of a "learning effect" exists with most testing. An initial "learning" test may be performed prior to actual acquisition of data for clinical trial use.
    4. Testing individual patients at approximately the same time of day may reduce test variability. Patients should be advised to not perform any new vigorous exercise or activity on the day prior to quantitative testing.

  4. RELIABILITY/VALIDITY

    1. It is important to recognize three potential sources of error that will affect measurements, in order to minimize inaccuracies and inconsistencies in the data.
      1. Observer - Errors attributed to the observer, or CE, are minimized by understanding the measurements and maintaining consistency in adherence to protocol for performance of all measurements. A policy of maintaining objectivity, by not discussing results or medication side effects with patients, should be followed.
      2. Patient - Measurement errors attributed to patients may be minimized by having the CE explain and demonstrate what is expected of them at the beginning of each test, securing the patients' cooperation and encouraging performance of tasks with optimal effort.
      3. Instrument - Measurement errors attributed to instruments are minimized by regular inspection and calibration.
    2. Intra-rater and inter-rater reliability determinations should be made prior to, or during a clinical trial. This is especially important for multi-center trials in which CEs are using new or unfamiliar procedures. Periodic group CE meetings to review test procedures will increases adherence to standardized methodology, increasing test reliability. Feedback regarding reliability determinations, as well as other reliability issues, should e forwarded to CEs promptly. CEs demonstrating low reliability should be re-trained with subsequent patients who are generally reflective of most ALS patients. Reliability determinations should be structured so as to avoid fatiguing patients.
    3. Sites using more than one CE should perform periodic inter-reliability determination.
    4. If multiple CEs are utilized by one site, it is strongly recommended that the same CE test the same patient, over the entire period of the clinical trial, to reduce test result variability.
    5. In multi-center trials, one site should be designated to receive, assess, and relate to other sites, questions or issues which may be raised regarding the quantitative testing guidelines, protocols, and procedures.
    6. Measuring too many parameters becomes time consuming, difficult to analyze, increases the risk of making type I error, and may introduce fatigue.
    7. Interval data is more sensitive to change and more amenable to statistical analysis than ordinal data.
    8. A written quality assurance policy should be devised prior to initiation of a trial, to include periodic review of a sample of data from all, or some sites by CE and others.
    9. Quality assurance measures for quantitative testing should be as rigorous as those adopted for equipment.
    10. Team approach should be fostered with regular meetings including all members, to promote communication and discourage compartmentalization of staff.
    11. To eliminate bias, CEs should remain blinded to previous test results.

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APPENDIX A. RESPIRATORY FUNCTION TESTS

General items of concern relating to pulmonary function testing:

  1. Care should be taken to assure that an airtight lip-to-mouthpiece seal ids maintained during pulmonary testing. Many patients with ALS will eventually develop a bulbar weakness and may have difficulty maintaining a good seal using a cylindrical mouthpiece may more effectively maintain a good seal. The evaluator should check the seal while asking the patient to blow through the mouthpiece prior to testing to assure no air leaks occur. Often, patients themselves are the best source of detecting an inadequate seal. A face mask may be used for patients who can't maintain a seal with the mouthpiece or can't tolerate the mouthpiece. However, comparison of data between cylindrical tube, rubber mouthpiece and/or face mask should be ascertained.
  2. Patients who initially present with bulbar involvement may have airway restriction upon forced exhalation. Measurement of VC, rather than FVC, may be more appropriate for this patient group. (Note: FVC and VC data are NOT interchangeable and therefore the chosen test must be consistently used.)
  3. Sterilization procedures recommended b the spirometer manufacturer should be followed carefully.
  4. Calibration checks should be performed daily or as recommended by the manufacturer.
  5. Prior to testing, the testing procedure should be explained and demonstrated.
  6. All tests should be performed with patient sitting in a straight-back chair with both feet flat on the floor.
  7. No less than three trials and no more than five trails should be conducted for each test. The best trail for each test should be used for data analysis.
  8. Verbal encouragement should be enthusiastic and consistent. The instructions should be clear and standardized.
  9. Although predicted values are clinically useful, raw values should be for analysis in a clinical trial to avoid the following issues: 1) multiple formulas for predicting values, 2) predicted values will change with birthdays, and 3) adjustments may or may not be used non-Caucasians. Patient height, necessary for predicting values, should be measured.
  10. Standards for performing FVC tests, produced by the American Thoracic Society 1, call for inter-trial variability of 5% percent or less, between the 2 highest FVCs. This is a realistic goal in testing FVC in ALS patients. However, some patients, due to weakness or fatigue, may not be able to attain this degree of reliability. The clinical evaluator must judge acceptability of test results in that case.

I. Procedures for Performing Forced Vital Capacity (FVC) Tests

  1. Equipment
    1. Spirometer with microprocessor
    2. Rubber mouthpiece (optional: facemasks, cylindrical tubes)
    3. Nose clips
  2. Procedure
    1. Patient should be sitting straight upright, with feet on floor. Explain that the purpose of the test is to measure the biggest breath of air the patient can take in and out of his lungs, as well as how fast the air can be expelled from the lungs. Instructions should be given in a step by step manner, specific to the spirometer equipment being used. Demonstrations of the test should follow instructions.
    2. Place mouthpiece in patient's mouth and determine adequacy of seal. If seal is inadequate, facemask may be used. An adequate and seal of the facemask should be ascertained prior to testing. If facemask id used, patient, should be instructed to inhale and exhale through mouth during testing. Place nose clip, if mouthpiece used. Instruct patient to breathe normally through his/her mouth.
    3. Re-instruct patient, with verbal coaching, in a step by step manner throughout the test, emphasizing a maximal inhalation followed by a maximal and forceful exhalation. Patient should not allowed to lean forward during the exhalation phase of the test. Maintain verbal coaching to test completion.

II. Procedures for Performing Vital Capacity (VC) Tests

  1. Equipment and set-up the same as FVC testing.
  2. Instructions to the patient differ from FVC testing:
To begin test, patient is instructed to inhale as deeply as possible then blow out all the air that he/she can., Instruct patient that the test will measure how much air can be exhaled. (Do NOT instruct patient to blow air out as fast or forcefully as he/she can.)

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APPENDIX B. COMPUTER-BASED FIXED STRAIN GAUGE MVIC TESTING

  1. Equipment
    1. Electrical hi - lo adjustable exam table
    2. Electronic strain gauge tensiometer (Interface and Advance Force measurement - Scottsdale, AZ)
    3. Aluminum upright and adjustable rings
    4. Nylon straps and cables
    5. Computerized data acquisition system
  2. Procedures (The following procedures are adopted from the Tuft's Quantitative Neuromuscular Exam. 44,45)
    1. MVIC is measured with an electronic strain gauge connected to a data acquisition system. The patient is tested in the supine position for the upper extremities and ankle dorsiflexors, sitting upright at the end of the table for knee flexor/extensor testing, and semi-reclined with a wedge for lower extremities hip flexor/extensor testing.
    2. After attaching the strap to extremity being measured, the patient is instructed to "push" or "pull" against the strap as hard as they can "with all their strength".
    3. The clinical examiner should be alert for any signs of respiratory distress when the patient is in the supine position.
    4. Joint position should be at least 90 degrees at point of maximal contraction. Strong muscle groups may need to be positioned at less than 90 degrees initially.
    5. Specific procedures for measuring each muscle group
      1. Shoulder Flexion
        Patient is supine with shoulder at 90 degrees of flexion with elbow extended and in neutral rotation. Strap is placed just proximal to the elbow. Examiner supports the arm prior to the test without exerting tension on the strap. Stabilization is at the thorax so patient is not moving downward or twisting. Uncontrolled elbow flexion beyond 30 degrees is considered an end-point and test results are invalid.
      2. Shoulder Extension
        Patient is supine with shoulder at 90 degrees of flexion with elbow extended and in neutral rotation. Strap is placed just proximal to the elbow. Examiner supports the arm prior to the test. Elbow must remain extended during the test. Stabilization is superior on the shoulder so that the shoulder does not elevate during the test, and the patient does not slide upward.
      3. Elbow Flexion
        Patient remains supine with arm resting on the table. Elbow is positioned at 90 degrees, forearm in neutral rotation. The strap is placed just proximal to the styloid process. Examiner secures the elbow from an inferior position and holds the shoulder from protracting as well. Uncontrolled shoulder internal rotation beyond 30 degrees is considered an end-point.
      4. Elbow Extension
        Patient remains supine with arm resting on table. Elbow is positioned at 90 degrees, forearm in neutral rotation. The strap is placed just proximal to the styloid process. Examiner stabilizes the elbow over biceps belly.
      5. Ankle Dorsiflexion
        Patient is supine with hips and knees extended and ankle in slight plantarflexion. Strap placed across metatarsals. Heels are over the edge of the table. A towel roll is placed under the ankle. Patient attempts maximal dorsiflexion without pelvic elevation. Stabilization is downward over the proximal tibia. The ankle should be in slight plantarflexion initially so that with maximal contraction it is in a neutral ankle position (90 degrees). Inability to attain a neutral ankle position (90 degrees) should be considered an end point.
      6. Knee Flexion
        Patient is seated over the end of the table with knees at 90 degrees. A towel roll may be used to keep knees at 90 degrees. Strap is placed just proximal to the malleoli. Femur is parallel to the table. Examiner provides stabilization over the anterior thigh and knee. The patient should stay in an upright position.
      7. Knee Extension
        Patient is seated over the end of the table with knees at 90 degrees. A towel roll may be used to keep knees at 90 degrees. The examiner provides stabilization by exerting downward force over the ipsilateral shoulder and contralateral hip or by exerting downward force over both shoulders to prevent the hips from rising off the table. The patient should stay in a upright position. The femur should be aligned with the direction of force application.
      8. Hip Extension
        Patient is semi-reclined with head and shoulders supported by a wedge. Hips are at 20 degrees and knees are at 90 degrees of flexion. Strap is placed proximal to the knee joint. The evaluator stabilizes the patient at the ASIS, with knee of the tested leg at 90 degrees at the base line and extended during the test. The untested leg, with the knee at 90 degrees of flexion, stays on the table. Patient attempts maximal hip extension. Initial resting tension on the strain gauge is the weight of the limb and should be considered the baseline. Any dip in this baseline should be corrected in the final measurement.
      9. Hip Flexion
        Patient is semi-recline with head and shoulders supported by a wedge. A towel roll may be used and is placed under the test leg which is at about 20 degrees of flexion at the hip. Knee is at 90 degrees of flexion. Strap is placed proximal to the knee joint. Strap should not be placed over patella or patient won't pull hard. The untested leg is supported the tester wit the hip and knee at 90 degrees of flexion to maintain pelvis in a posterior tilt. Patient attempts maximal hip flexion. Tensions on the strain gauge should be enough at rest so that force is measured without actual elevation of the leg.
      10. Hand Grip
        Hand grip is measured manually with an adjustable hand grip dynamometer. The seated patient is positioned with elbow flexed at approximately 90 degrees. The handle of the dynamometer should be adjusted to a standard constant position. Examiner supports the dynamometer from underneath and should not pull on it. The examiner places an open hand under the forearm to maintain 90 degrees of elbow flexion. The wrist should not be supported. The patient is instructed to squeeze with his/her tested hand as hard as possible. Grip tests are performed twice on the right hand, then twice on the left hand. Uncontrolled wrist pronation beyond 30 degrees is considered an endpoint.

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    APPENDIX C. FUNCTION TESTS

    I. ALS Functional Rating Scales (ALSFRS).

    1. Instructions for Use: The evaluator shall state to the patient (or spouse or other caregiver if the patient cannot communicate effectively): "Now I have a few questions I would like to ask to help me better understand how you (or the patient) are currently functioning at home. Please answer each question to the best of your ability."
      The evaluator then asks, "How are you doing at (..)?'" for each question in the ALSFRS. If the patients is unable to volunteer satisfactory response, the evaluator may prompt, using one of the available choices (e.g. when asking about speech, "do you find that people are having trouble understanding you when speaking?", etc.)

    2. ALSFRS (Because the ALSFRS has not to date been published, it is included here, with permission of J.M. Cerdarbaum, M.D., Regeneron Pharmaceuticals, Inc.):

      1. Speech
        4 Normal speech processes
        3 Detectable speech disturbance
        2 Intelligible with repeating
        1 Speech combined with nonvocal communication
        0 Loss of useful speech
      2. Salivation
        4 Normal
        3 Slight but definite excess of saliva in mouth; may have nighttime drooling
        2 Moderately excessive saliva; may have minimal drooling
        1 Marked excess of saliva with some drooling
        0 Marked drooling; requires constant tissue or handkerchief
      3. Swallowing
        4 Normal eating habits
        3 Early eating problems; occasional choking
        2 Dietary consistency changes
        1 Needs supplemental tube feeding
        0 NPO (exclusively parenteral or enteral feeding)
      4. Handwriting (with dominant hand prior to ALS onset)
        4 Normal
        3 Slow or sloppy; all words are legible
        2 Not all words are legible
        1 Able to grip pen but unable to write
        0 Unable to grip pen
      5. a. Cutting Food and Handling Utensils
        (patients without gastrostomy)
        4 Normal
        3 Somewhat slow and clumsy, but no help needed
        2 Can cut most foods, although clumsy and slow; some help needed
        1 Food must be cut by someone, but can still feed slowly
        0 Needs to be fed
        5. b. Cutting Food and Handling Utensils
        (patients with gastrostomy)
        4 Normal
        3 Clumsy but able to perform all manipulations independently
        2 Some help needed with closures and fasteners
        1 Provides minimal assistance to caregiver
        0 Unable to perform any aspect of task
      6. Dressing & Hygiene
        4 Normal
        3 Independent and complete self-care with effort or decreased efficiency
        2 Intermittent assistance or substitute methods
        1 Needs attendant for self-care
        0 Total dependence
      7. Turning in Bed/ Adjusting Bed Clothes
        4 Normal
        3 Somewhat slow and clumsy, but no help needed
        2 Can turn alone or adjust sheets, but with great difficulty
        1 can initiate, but not turn or adjust sheets alone
        0 Helpless
      8. Walking
        4 Normal
        3 Early ambulation difficulties
        2 Walks with assistance (any assistive device, including AFOs)
        1 Nonambulatory functional movement only
        0 No purposeful leg movement
      9. Climbing Stairs
        4 Normal
        3 Slow
        2 Mild unsteadiness or fatigue
        1 needs assistance (including handrail)
        0 Cannot do
      10. Breathing
        4 Normal
        3 Shortness of breath with minimal exertion (e.g. walking, talking)
        2 Shortness of breath at rest
        1 Intermittent (e.g. nocturnal) ventilatory assistance
        0 Ventilator dependent

      3. II. Amytrophic Lateral Sclerosis Severity Scale (ALSSS)
      The scale and instructions for its use are detailed in:
      Hillel-AD, Miller RM, Yorkston K, et al Amyotrophic Lateral Sclerosis Severity Scale in Progress in Clinical Neurologic Trials. Vol 1 Amyotrophic Lateral Sclerosis, ed. F. Clifford Rose, Demos, New York, 1990, 93-97.

      III. Timed Walk
      Time required for the patient to walk a fixed distance, as fast as possible without compromising patient safety, is measured, using digital stopwatch. The fixed distance, e.g. 15 feet, is marked in the testing room or hallway. The patient is instructed to walk as fast as possible safely. Use of the patients' normal ambulation aids or equipment is allowed. Assistive equipment used should be recorded, as this may affect gait velocity. Sound judgement by the patient and evaluator must be used to determine the safety risks involved with this test. If the patient feels uncomfortable with this test, or if risk of falling is significantly increased, the test should not be performed. Falls can result in serious injuries in this patient population, especially in those persons with inadequate strength and function of upper extremities. The clinical evaluator should walk behind the patient for safety. No running is allowed (one foot should always be on the ground). If the effects of acceleration and deceleration on gait velocity are to be ruled out, the patient may being walking several feet before the distance marker, and may walk several feet past the distance marker, before stopping. Time required to walk the fixed distance is recorded. Gait velocity can be calculated as follows: velocity = distance/time.

      IV. Purdue Pegboard
      The number of pegs a patient can place in the pegboard holes (Purdue pegboard, Lafayette Instrument Co., P.O. Box 5729, Lafayette, Indiana 47903) in 30 seconds is determined. The patient picks up pegs, one at a time, from the reservoir, and places them in the pegboard holes, working from the top of the pegboard to the bottom, without skipping any holes. The patients should work as quickly as possible. Any assistance devices or equipment allowed should be recorded.

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      APPENDIX D. BULBAR TEST

      Timed speech rates:
      A stopwatch is used to time the seconds needed to complete a predetermined number of syllable repetitions. The patient is told what syllable to say and how it should be annunciated. Tell patient to repeat syllable as fast as he/she can, but patient does not have to complete the test in one breath. Timing begins when the patients starts speaking and ends with last syllable spoken. Another method pre-determines the time allowed, and the patient repeats a syllable as many times as possible in the given time., A tape recorder is used to track number of syllables spoken..
      Instructions:
      "I am going to time how fast you can say 'pa' (for example). Go as fast as you can. It should sound like this 'papapapapapapa...'. If you need to take a breath, do so. Keep going until I tell you to stop." The best of two trials is recorded.

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