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Supplement Vital capacity as an ef cacy measure: Summary Deborah F Gelinas Forbes Norris MDA/ALS Center, San Francisco, CA ALS and other motor neuron disorders 2002 (suppl 1), S61–S62 © 2002 ALS and other motor neuron disorders. All rights reserved. ISSN 1466-0822 S61 Although Forced Ventricular Capacity (FVC), 1 Tufts Quan- titative Neuromuscular Evaluation (TQNE), 2 megascores and functional rating scales 3 have recently been used as endpoints in ALS clinical trials, death remains the de ni- tive endpoint in ALS disease progression. The average time from ALS diagnosis to death is 3–5 years and the major cause of death is respiratory complications. 4 Causes of respiratory failure may be either inspiratory insuf ciency leading to chronic hypoventilation or expira- tory dif culties leading to problems with secretion clear- ance and aspiration. No one pulmonary measurement adequately assesses inspiratory and expiratory functions. 5 Maximal Inspiratory Pressure (MIP) is a sensitive measure of inspiratory force, but is highly variable. 6 FVC is less vari- able, but a less sensitive measure. Maximal Expiratory Pres- sure (MEP) is a sensitive measure of expiratory force, but is again variable. 7 Clinically, both inspiratory and expiratory functions are signi cant in therapeutic interventions, as sur- vival may be extended in ALS patients through the use of non-invasive or invasive ventilation. As non-invasive venti- lation is compatible with a good quality of life, it is rou- tinely offered to patients suffering from hypoventilation, but patient compliance with Non-Invasive Volume Ventila- tion (NIVV) depends upon adequate secretion manage- ment. Patients who are unable to adequately control the upper airway are forced to accept invasive tracheostomy ventilation if they wish to extend their lives. 5 Therefore, again, both inspiratory and expiratory measurements are signi cant in predicting success with this intervention. FVC has been extensively used to monitor respiratory function in neuromuscular patients and its results are reproducible ( , 5% variability) 8 and correlated with sur- vival, although it cannot predict respiratory failure due to intercurrent infections and pneumonia. 9 It has been sug- gested today that spirometry with its ow-volume loop should be the maneuver used in clinical trials, as both inspiratory and expiratory measures can be derived. There are other advantages to following patients with serial ow- volume loops: for example, speci c morphologies of the ow-volume loop are diagnostic of the mechanisms responsible for respiratory compromise. 10 The repro- ducibility of the ow-volume loop could be assured by standardizing the conditions under which the maneuver is performed in all ALS populations except the bulbar and pseudobulbar subpopulations with erratic glottic closure. Research assistants would need to be trained in the admin- istration of spirometry and research investigators (or pul- monary consultants) adequately trained in the interpretation of ow-volume loops in the ALS popu- lation. I propose that the maximal voluntary ventilation maneuver (MVV) be considered as a single measure of both inspiratory and expiratory respiratory function. 5 MVV requires the patient to breathe as fast and as hard as pos- sible for at least 12 seconds. MVV has an extremely high intra- and inter-observer reliability (comparable to FVC). 11 In addition, MVV was the most consistently and signi - cantly reduced pulmonary measurement in spirometric evaluation of 218 ALS patients with a mean 67% of pre- dicted on initial screening compared with 80% for FVC. Like FVC, MVV correlates well with patient survival. 10 In contrast to the ow-volume loop, which requires interpre- tation by a highly trained pulmonologist, MVV is a maneuver which gives a single measurement, the validity and reliability of which has been established in previous neuromuscular trials. References 1. Bradley WG, Miller RG and the BDNF Study Group. Phase III trial of subcutaneous recombinant methionyl human BDNF in patients with ALS. Neurology 1999; 52: 1427–1433. 2. Miller RG, Moore DH, Gelinas DF et al. Phase III random- ized trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology 2001; 56: 843–848. 3. Trojan DA, Collet JP, Pollak MN et al. Serum IGF-1 does not correlate positively with isometric strength, fatigue and qualify of life in post-polio syndrome. J Neurol Sci 2001; 182: 107–115. 4. Mulder DW, Howard FM. Patient resistance and prognosis in amyotrophic lateral sclerosis. Mayo Clin Proc 1976; 51: 537–541. 5. Kaplan LM, Hollander D. Respiratory dysfunction in amy- otrophic lateral sclerosis. Clin Chest Med 1994; 15: 675–681. 6. Brooke MH, Fenichel GM, Griggs RC et al. Clinical investiga- tion in Duchenne dystrophy: 2. Determination of the ‘power’ of therapeutic trials based on the natural history. Muscle Nerve 1983; 6: 91–103. 7. Griggs RC, Donohoe SM, Utell MJ, Goldblatt D, Mosley RT. Evaluation of pulmonary function on neuromuscular disease. Arch Neurol 1981; 38: 9–12. Amyotroph Lateral Scler Downloaded from informahealthcare.com by University of Waterloo on 10/29/14 For personal use only.

Vital capacity as an efficacy measure: Summary

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Page 1: Vital capacity as an efficacy measure: Summary

Supplement

Vital capacity as an ef�cacy measure: Summary

Deborah F GelinasForbes Norris MDA/ALS Center, San Francisco, CA

ALS and other motor neuron disorders 2002 (suppl 1), S61–S62© 2002 ALS and other motor neuron disorders. All rights reserved. ISSN 1466-0822 S61

Although Forced Ventricular Capacity (FVC),1 Tufts Quan-titative Neuromuscular Evaluation (TQNE),2 megascoresand functional rating scales3 have recently been used asendpoints in ALS clinical trials, death remains the de�ni-tive endpoint in ALS disease progression. The average timefrom ALS diagnosis to death is 3–5 years and the majorcause of death is respiratory complications.4

Causes of respiratory failure may be either inspiratoryinsuf�ciency leading to chronic hypoventilation or expira-tory dif�culties leading to problems with secretion clear-ance and aspiration. No one pulmonary measurementadequately assesses inspiratory and expiratory functions.5

Maximal Inspiratory Pressure (MIP) is a sensitive measureof inspiratory force, but is highly variable.6 FVC is less vari-able, but a less sensitive measure. Maximal Expiratory Pres-sure (MEP) is a sensitive measure of expiratory force, but isagain variable.7 Clinically, both inspiratory and expiratoryfunctions are signi�cant in therapeutic interventions, as sur-vival may be extended in ALS patients through the use ofnon-invasive or invasive ventilation. As non-invasive venti-lation is compatible with a good quality of life, it is rou-tinely offered to patients suffering from hypoventilation,but patient compliance with Non-Invasive Volume Ventila-tion (NIVV) depends upon adequate secretion manage-ment. Patients who are unable to adequately control theupper airway are forced to accept invasive tracheostomyventilation if they wish to extend their lives.5 Therefore,again, both inspiratory and expiratory measurements aresigni�cant in predicting success with this intervention.

FVC has been extensively used to monitor respiratoryfunction in neuromuscular patients and its results arereproducible (, 5% variability)8 and correlated with sur-vival, although it cannot predict respiratory failure due to

intercurrent infections and pneumonia.9 It has been sug-gested today that spirometry with its �ow-volume loopshould be the maneuver used in clinical trials, as bothinspiratory and expiratory measures can be derived. Thereare other advantages to following patients with serial �ow-volume loops: for example, speci�c morphologies of the�ow-volume loop are diagnostic of the mechanismsresponsible for respiratory compromise.10 The repro-ducibility of the �ow-volume loop could be assured bystandardizing the conditions under which the maneuver isperformed in all ALS populations except the bulbar andpseudobulbar subpopulations with erratic glottic closure.Research assistants would need to be trained in the admin-istration of spirometry and research investigators (or pul-monary consultants) adequately trained in theinterpretation of �ow-volume loops in the ALS popu-lation.

I propose that the maximal voluntary ventilationmaneuver (MVV) be considered as a single measure ofboth inspiratory and expiratory respiratory function.5 MVVrequires the patient to breathe as fast and as hard as pos-sible for at least 12 seconds. MVV has an extremely highintra- and inter-observer reliability (comparable to FVC).11

In addition, MVV was the most consistently and signi�-cantly reduced pulmonary measurement in spirometricevaluation of 218 ALS patients with a mean 67% of pre-dicted on initial screening compared with 80% for FVC.Like FVC, MVV correlates well with patient survival.10 Incontrast to the �ow-volume loop, which requires interpre-tation by a highly trained pulmonologist, MVV is amaneuver which gives a single measurement, the validityand reliability of which has been established in previousneuromuscular trials.

References

1. Bradley WG, Miller RG and the BDNF Study Group. PhaseIII trial of subcutaneous recombinant methionyl humanBDNF in patients with ALS. Neurology 1999; 52:1427–1433.

2. Miller RG, Moore DH, Gelinas DF et al. Phase III random-ized trial of gabapentin in patients with amyotrophic lateralsclerosis. Neurology 2001; 56: 843–848.

3. Trojan DA, Collet JP, Pollak MN et al. Serum IGF-1 does notcorrelate positively with isometric strength, fatigue andqualify of life in post-polio syndrome. J Neurol Sci 2001;182: 107–115.

4. Mulder DW, Howard FM. Patient resistance and prognosis

in amyotrophic lateral sclerosis. Mayo Clin Proc 1976; 51:537–541.

5. Kaplan LM, Hollander D. Respiratory dysfunction in amy-otrophic lateral sclerosis. Clin Chest Med 1994; 15:675–681.

6. Brooke MH, Fenichel GM, Griggs RC et al. Clinical investiga-tion in Duchenne dystrophy: 2. Determination of the‘power’ of therapeutic trials based on the natural history.Muscle Nerve 1983; 6: 91–103.

7. Griggs RC, Donohoe SM, Utell MJ, Goldblatt D, Mosley RT.Evaluation of pulmonary function on neuromusculardisease. Arch Neurol 1981; 38: 9–12.

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Page 2: Vital capacity as an efficacy measure: Summary

8. Andres PL, Finison LJ, Conlon T, Thibodeau LM, Munsat TL.Use of composite scores (megascores) to measure de�cit inamyotrophic lateral sclerosis. Neurology 1988; 38: 405–408.

9. Miller RG. Rosenberg JA. Gelinas DF et al. Practice parame-ter: the care of the patient with amyotrophic lateral sclerosis(an evidence-based review): report of the Quality StandardsSubcommittee of the American Academy of Neurology: ALSPractice Parameters Task Force. Neurology 1999; 52:1311–1323.

10. Fallat RJ, Jewitt B, Bass M, Kamm B, Norris FH. Spirometryin amyotrophic lateral sclerosis. Arch Neurol 1979; 36:74–80.

11. Griggs RC. The use of pulmonary function testing as a quan-titative measurement for therapeutic trials. Muscle Nerve1990; 13(Suppl): S30–S34.

S62 DF Gelinas

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