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Performance outcome assessments in MS clinical trials are more sensitive to disease progression and treatment effects than clinical assessments
INTEGRATED MANAGEMENT:
CARE PATHWAYS IICPI IN MULTIPLE AN IDEAL AUDIT TOOL.
Rossiter DA Thomoson AJ National Hospital far Neurology Oueen Sauare London WClN
and Neurosurgery 3BG UK
SCLEROSIS
Naurorehabilitation
SPINAL CORD ATROPHY: A SENSITIVE AND REPRODUCIBLE DISEASE PROGRESSION IN MULTIPLE SCLEROSIS IMSI.
Losseff NA. Miller DH, McDonald WI and Thomoson NMR Research Unit, tnstitufe of Neurolopy, London
Unit
ICPs documentinp expected interventions in a given episode of clinical care are used extensively in the acute sector. The neurorehabtlitation Unit of the National Hospital for NeuroloQY and Neurosurgery, specialislng in the management of MS, has developed an ICP which is in keeping with its well defined multidisciplinan/ process and goal orientated approach lo rehabilitation.
MEASURE
OF
AJ. UK
A recent cross sectional study’ in MS has SugQested a relationship between spinal cord atrophy detected with MRI and disability. However, these findings were not supported by a subsequent study’ possibly as a result of poor serial reproducibility of the cord area measurement. We have outlining inversion
Method. ICPs record procedural process from admissmn to discharge, also documenting the goal setting process and reasono for non achievement of goals. Departures from the pathway (variance) are analysed and form the basis for a detailed method of audit which informs and changes Unit practice.
controls
now greatly improved this measurement by use of a semi automated technique. This is applied to axial reformats from a volume acquired prepared data set of the upper cervical spine. Results from 10 show an intraobserver serial reproducibility of 0.6%
Results from 25 patients with clinically definite MS show a strikinp correlation between cord area and EDSS (r=0.66). In addition severely disabled patients have cord areas approximately 40% smaller than the control group.
Results. The average length of stay for 37 patients with clmically definite MS was four weeks. The average variance per admission wee seven - 49% were procedural and 51% related to goal achievement. Goal achievement averaged 75% per admission. Tone problems t24%l, fatiQue (23%) and cognitive factors (19%) were significant in non achievement. Fii per cent of goals set related to gait/mobility and transfers. The correlation between goal achievement and changes in disabilin, as measured by the Barthel and the Functional Independence Measure was not significant. Resulting changes to the running of the Unit Include: adoption of a key worker system, improved carer liaison, improved Induction of staff and reduced duration of stay.
These results suggest extensive axonal loss in advanced MS. Given the clear relationship with disability and the excellent reproducibility of the technique the measurement of proaressive atrophy by MRI is now a realistic possibility in future therapeutic trials.
DOES USE OF COOLING PATIENTS?
PERFORMANCE OUTCOME ASSESSMENTS IN MS CLINICAL TRIALS MORE SENSITIVE TO DISEASE PROGRESSION AND TREATMENT EFFECTS THAN CLINICAL ASSESSMENTS
GARMENTS
IMPROVE
QUALITY
OF LIFE
References 1 Kidd 0. Thorpe JW, Thompson AJ et al. Spinal cord MRI using multiarray coils and fast spin echo II: findings in multiple sclerosis. NSW~O/OQY 1993;43: 2632-2637. 2
IN MS
Wallace W. Tourtellotte, M D Ph.D.. Karl Syndulko, Ph D.. Robert W Baumhefner. M.D. VA Medical Center West Los Angeles. Los Angeles, CA, USA
Loss&f NA, Miller DH, McDonald WI, Thompson AJ. ProQnostic value of serial axial cord area measurement by magnetic resonance imaging in multiple sclerosis. J Neural 1995:242 supp 2: 110.
Wallace W. Touttellotte, M.D., Ph.D., Karl Syndulko, Ph.D., Roberl W. Baumhefner. M.D., VA Medical Center West Los Angeles, Los Angeles, USA
OBJECTIVE: Anecdotal reports indicate reversible improvements in MS symptoms wlh the use of newly available cooling garments Three pilot studies were designed 10 assess the effects of daily and acute cooling in the laboratory and 01 daily, home cooling on objective performance indices 01 MS impairment and ;isaSilitj; that relate diredly tc qual!If of ItIe. METHODS: Experiments one (El) and two (E2) were repeated measures designs. In El three MS patients (EDSS 5 or 6) were cooled twice daily for 2-4 weeks aHer a 2 week sham cooling period. In E2 nine MS outpatients with a history of heat lability were tested for immediate eflects of lowering Iympanlc temperalure in the laboratory under each of 3 conditions separated by one week: cooling with each of two coolmg garments (the Life Support Systems, Inc.. Mark VII MicroClimate SystemTH or LSSI, and the SteeleVest” Body Cooling Syslem). and no cooling protocol. Subjects used the LSSI cooling suit at home for 60 min to lower body temperature Px/day. Five additional MS patienls were in a non-cooling control group. Subjects were evaluated by clinical and neuroparformanca indices at least once per week (E3), or immediately before and afler each lab cooling episode (El,E2). RESULTS: In El and E2 significant temperature decreases (mean 0.6”C) were achieved with both cooling garments, and the garments did not differ in cooling efliciency. In El subatanlial improvements over days were In E2 no slatiitiially significant change in seen in gait and balance in 2 patients. performance post-cooling was iound on any test maasure. In E3 6/12 subjects reporled reduced fatigue and improved abltii to ambulate immediately after and up to 2-3 hours after cooling. There was a significant immediate post-cooling (non-cumulative) imprrvement on tandem gait and standing balance Additionally, 7 subjects reported long-term improvements in quality 01 life over the cooling weeks. No statistically significant cumulative effect of cooling was found on objective indices al motor and cogniIive function. CONCLUSIONS: The cool suits can significantly lower body temperalure, are associated with subjective improvements in fatigue and lower earemity symptoms, but the improvements could not be documented by objjctive laboratory tests for most individuals, and a placebo elfect could not be ruled out. The study raised Important questions regarding development 01 an appropriate sham cooling procedure, method of measurement 01 core temperalure changes, and other design issues in evaluating cooling in MS patients. The SteeleVest, an inexpensive passive cooling garment produced similar cooling performance to the more expensive, active flow garmenl under resting conditions. We recommend use of a passive cooling garment as a personal cooling system to enhance quality of life in heat labile patients for outdoor and heat producing activities.
ARE
CA,
OBJECTIVE: Perlormance tests of neurologic function are reviewed, and comparative statistical analyses of performance testing and clinIcal assessment are presented. METHODS: Development of the Quantitative Examination of Neurologlc Function (QENF) included evaluation of praotlce, motivation, gender, age, and treatment effects for MS. Statistical analyses of multiple outcome assessment in two major US clinical trials, the Cooperative ACTH study in relapsing/remilIirig patients, and the Multicenter Cyclosporlne A clinical trial in Comparative analyses of outcome chronic progressive MS, were evalualed assessments were adapted from Dixon and Kuzma (Comm Stat 3:301-324, 1974) arid others that included test-retest reliability, principal components factor analyses IO delineate the minimal dimensions of MS disease expression, signalto-noise ratios to compare sensitivity to change in disease progression, structural equations modeling to evaluate relationships of outcome assessments lo the construct of MS disease activity, and statistical effect sizes lo compare sensitivity to treatment effects. RESULTS: Component tests of the QENF were identified that had minimal practice and motivation effects, and normal age-related changes were quantllied by decade to provide a normative data base for calculating z-scores or percent of normal performance. A minimal batterv 01 uooer (Purdue Peoboard. hand taooina soeed. writino speed and hand coordination) and lowe;(foot iapping speed-/ &ordination,-tandem gaiI with parallel bars and standing balance) extremity OENF tests was identified that could be used practically in multicenter MS clinical trials. The performance tests ware shown to be reliable and wilh high construct validity. In chronic progressive MS a lower extremity performance composite (simple average of component tests) had larger signal-to-noise ratio values than EDSS, Atiulation Index or composites based on the IncapacIty Status Scala, Functional Systems or Standard NeUrOlOQiC Examination, and a combined upper and lower extremity cowsite hab the highest s@nal-to-noise ratio of any single measure. CONCLUSIONS: The use of oerlormance testina and the devf?loDment of composites based on statistical properties has piovided the most ‘sensitive clinical testing available for use in MS clinical trials. Sensitivity can be directly translated into the need for smaller numbers of subjects in clinical trials. Fuiure: Clinical trials to compare sensitivity of performance testing with repeal MRls are planned.
-53-
CARE PATHWAYS IICPI IN MULTIPLE AN IDEAL AUDIT TOOL.
Rossiter DA Thomoson AJ National Hospital far Neurology Oueen Sauare London WClN
and Neurosurgery 3BG UK
SCLEROSIS
Naurorehabilitation
SPINAL CORD ATROPHY: A SENSITIVE AND REPRODUCIBLE DISEASE PROGRESSION IN MULTIPLE SCLEROSIS IMSI.
Losseff NA. Miller DH, McDonald WI and Thomoson NMR Research Unit, tnstitufe of Neurolopy, London
Unit
ICPs documentinp expected interventions in a given episode of clinical care are used extensively in the acute sector. The neurorehabtlitation Unit of the National Hospital for NeuroloQY and Neurosurgery, specialislng in the management of MS, has developed an ICP which is in keeping with its well defined multidisciplinan/ process and goal orientated approach lo rehabilitation.
MEASURE
OF
AJ. UK
A recent cross sectional study’ in MS has SugQested a relationship between spinal cord atrophy detected with MRI and disability. However, these findings were not supported by a subsequent study’ possibly as a result of poor serial reproducibility of the cord area measurement. We have outlining inversion
Method. ICPs record procedural process from admissmn to discharge, also documenting the goal setting process and reasono for non achievement of goals. Departures from the pathway (variance) are analysed and form the basis for a detailed method of audit which informs and changes Unit practice.
controls
now greatly improved this measurement by use of a semi automated technique. This is applied to axial reformats from a volume acquired prepared data set of the upper cervical spine. Results from 10 show an intraobserver serial reproducibility of 0.6%
Results from 25 patients with clinically definite MS show a strikinp correlation between cord area and EDSS (r=0.66). In addition severely disabled patients have cord areas approximately 40% smaller than the control group.
Results. The average length of stay for 37 patients with clmically definite MS was four weeks. The average variance per admission wee seven - 49% were procedural and 51% related to goal achievement. Goal achievement averaged 75% per admission. Tone problems t24%l, fatiQue (23%) and cognitive factors (19%) were significant in non achievement. Fii per cent of goals set related to gait/mobility and transfers. The correlation between goal achievement and changes in disabilin, as measured by the Barthel and the Functional Independence Measure was not significant. Resulting changes to the running of the Unit Include: adoption of a key worker system, improved carer liaison, improved Induction of staff and reduced duration of stay.
These results suggest extensive axonal loss in advanced MS. Given the clear relationship with disability and the excellent reproducibility of the technique the measurement of proaressive atrophy by MRI is now a realistic possibility in future therapeutic trials.
DOES USE OF COOLING PATIENTS?
PERFORMANCE OUTCOME ASSESSMENTS IN MS CLINICAL TRIALS MORE SENSITIVE TO DISEASE PROGRESSION AND TREATMENT EFFECTS THAN CLINICAL ASSESSMENTS
GARMENTS
IMPROVE
QUALITY
OF LIFE
References 1 Kidd 0. Thorpe JW, Thompson AJ et al. Spinal cord MRI using multiarray coils and fast spin echo II: findings in multiple sclerosis. NSW~O/OQY 1993;43: 2632-2637. 2
IN MS
Wallace W. Tourtellotte, M D Ph.D.. Karl Syndulko, Ph D.. Robert W Baumhefner. M.D. VA Medical Center West Los Angeles. Los Angeles, CA, USA
Loss&f NA, Miller DH, McDonald WI, Thompson AJ. ProQnostic value of serial axial cord area measurement by magnetic resonance imaging in multiple sclerosis. J Neural 1995:242 supp 2: 110.
Wallace W. Touttellotte, M.D., Ph.D., Karl Syndulko, Ph.D., Roberl W. Baumhefner. M.D., VA Medical Center West Los Angeles, Los Angeles, USA
OBJECTIVE: Anecdotal reports indicate reversible improvements in MS symptoms wlh the use of newly available cooling garments Three pilot studies were designed 10 assess the effects of daily and acute cooling in the laboratory and 01 daily, home cooling on objective performance indices 01 MS impairment and ;isaSilitj; that relate diredly tc qual!If of ItIe. METHODS: Experiments one (El) and two (E2) were repeated measures designs. In El three MS patients (EDSS 5 or 6) were cooled twice daily for 2-4 weeks aHer a 2 week sham cooling period. In E2 nine MS outpatients with a history of heat lability were tested for immediate eflects of lowering Iympanlc temperalure in the laboratory under each of 3 conditions separated by one week: cooling with each of two coolmg garments (the Life Support Systems, Inc.. Mark VII MicroClimate SystemTH or LSSI, and the SteeleVest” Body Cooling Syslem). and no cooling protocol. Subjects used the LSSI cooling suit at home for 60 min to lower body temperature Px/day. Five additional MS patienls were in a non-cooling control group. Subjects were evaluated by clinical and neuroparformanca indices at least once per week (E3), or immediately before and afler each lab cooling episode (El,E2). RESULTS: In El and E2 significant temperature decreases (mean 0.6”C) were achieved with both cooling garments, and the garments did not differ in cooling efliciency. In El subatanlial improvements over days were In E2 no slatiitiially significant change in seen in gait and balance in 2 patients. performance post-cooling was iound on any test maasure. In E3 6/12 subjects reporled reduced fatigue and improved abltii to ambulate immediately after and up to 2-3 hours after cooling. There was a significant immediate post-cooling (non-cumulative) imprrvement on tandem gait and standing balance Additionally, 7 subjects reported long-term improvements in quality 01 life over the cooling weeks. No statistically significant cumulative effect of cooling was found on objective indices al motor and cogniIive function. CONCLUSIONS: The cool suits can significantly lower body temperalure, are associated with subjective improvements in fatigue and lower earemity symptoms, but the improvements could not be documented by objjctive laboratory tests for most individuals, and a placebo elfect could not be ruled out. The study raised Important questions regarding development 01 an appropriate sham cooling procedure, method of measurement 01 core temperalure changes, and other design issues in evaluating cooling in MS patients. The SteeleVest, an inexpensive passive cooling garment produced similar cooling performance to the more expensive, active flow garmenl under resting conditions. We recommend use of a passive cooling garment as a personal cooling system to enhance quality of life in heat labile patients for outdoor and heat producing activities.
ARE
CA,
OBJECTIVE: Perlormance tests of neurologic function are reviewed, and comparative statistical analyses of performance testing and clinIcal assessment are presented. METHODS: Development of the Quantitative Examination of Neurologlc Function (QENF) included evaluation of praotlce, motivation, gender, age, and treatment effects for MS. Statistical analyses of multiple outcome assessment in two major US clinical trials, the Cooperative ACTH study in relapsing/remilIirig patients, and the Multicenter Cyclosporlne A clinical trial in Comparative analyses of outcome chronic progressive MS, were evalualed assessments were adapted from Dixon and Kuzma (Comm Stat 3:301-324, 1974) arid others that included test-retest reliability, principal components factor analyses IO delineate the minimal dimensions of MS disease expression, signalto-noise ratios to compare sensitivity to change in disease progression, structural equations modeling to evaluate relationships of outcome assessments lo the construct of MS disease activity, and statistical effect sizes lo compare sensitivity to treatment effects. RESULTS: Component tests of the QENF were identified that had minimal practice and motivation effects, and normal age-related changes were quantllied by decade to provide a normative data base for calculating z-scores or percent of normal performance. A minimal batterv 01 uooer (Purdue Peoboard. hand taooina soeed. writino speed and hand coordination) and lowe;(foot iapping speed-/ &ordination,-tandem gaiI with parallel bars and standing balance) extremity OENF tests was identified that could be used practically in multicenter MS clinical trials. The performance tests ware shown to be reliable and wilh high construct validity. In chronic progressive MS a lower extremity performance composite (simple average of component tests) had larger signal-to-noise ratio values than EDSS, Atiulation Index or composites based on the IncapacIty Status Scala, Functional Systems or Standard NeUrOlOQiC Examination, and a combined upper and lower extremity cowsite hab the highest s@nal-to-noise ratio of any single measure. CONCLUSIONS: The use of oerlormance testina and the devf?loDment of composites based on statistical properties has piovided the most ‘sensitive clinical testing available for use in MS clinical trials. Sensitivity can be directly translated into the need for smaller numbers of subjects in clinical trials. Fuiure: Clinical trials to compare sensitivity of performance testing with repeal MRls are planned.
-53-