Clarke Hess 828 Manual Muscle
BackgroundCerebral palsy is the most common cause of physical disability in childhood. Spasticity is a significant contributor to the secondary impairments impacting functional performance and participation. The most common lower limb spasticity management is focal intramuscular injections of Botulinum Toxin-Type A accompanied by individually-delivered (one on one) physiotherapy rehabilitation. With increasing emphasis on improving goal-directed functional activity and participation within a family-centred framework, it is timely to explore whether physiotherapy provided in a group could achieve comparable outcomes, encouraging providers to offer flexible models of physiotherapy delivery. This study aims to compare individual to group-based physiotherapy following intramuscular Botulinum Toxin-A injections to the lower limbs for ambulant children with cerebral palsy aged four to fourteen years.
Methods/DesignAn assessor-masked, block randomised comparison trial will be conducted with random allocation to either group-based or individual physiotherapy. A sample size of 30 (15 in each study arm) will be recruited.
The tni-1, tni-2/unc-27 and tni-3 genes, each encoding a troponin I isoform, are uniquely expressed in body wall, vulval and anal muscles but at different levels; tni-4 was expressed solely in the pharynx. Expressing tni-1 and -2 gene RNAi caused motility defects similar to unc-27 (e155) mutant, a tni-2 null.
Both groups will receive six hours of direct therapy following Botulinum Toxin-A injections in either an individual or group format with additional home programme activities (three exercises to be performed three times a week). Study groups will be compared at baseline (T1), then at 10 weeks (T2, efficacy) and 26 weeks (T3, retention) post Botulinum Toxin-A injections. Primary outcomes will be caregiver/s perception of and satisfaction with their child’s occupational performance goals (Canadian Occupational Performance Measure) and quality of gait (Edinburgh Visual Gait Score) with a range of secondary outcomes across domains of the International Classification of Disability, Functioning and Health. Cerebral palsy (CP) is the most common cause of physical disability in childhood with an incidence of 2.11 per 1000 live births.
It describes a “group of permanent disorders of the development of movement and posture, causing activity limitations that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain”. In 2013, the Australian Cerebral Palsy Register reported that 71% of children with CP achieved ambulation and 91% were classified with spasticity as the predominant motor type.
Children with lower limb spasticity often experience a range of impairments including weakness, tightness, reduced motor control and muscle selectivity. These impairments can lead to limitations in functional ability, balance, ambulation and fitness compared to typically developing peers ,.
Physiotherapy intervention focuses on reducing these impairments and optimising functional, goal-related performance.Focal, intramuscular Botulinum Toxin-Type A (BoNT-A) injections to the lower limb are commonly used in combination with physiotherapy as the temporary reduction in spasticity provides an opportunity to facilitate rehabilitation outcomes ,. For ambulant children with CP (Gross Motor Functional Classification System, GMFCS-E&R, Levels I-III ), there is strong evidence that injections of BoNT-A are safe and reduce muscle tone in spastic, active and non-fibrotic lower limb muscles for approximately 12–16 weeks ,. BoNT-A impacts body structure and function, however the accompanying physiotherapy often targets activity level outcomes (International Classification of Functioning, Disability and Health, ICF ).Functional improvement in ambulant children with CP has been reported in a number of randomised controlled trials (RCTs) comparing intramuscular lower limb BoNT-A injections with rehabilitation (physiotherapy, casting and/or orthotic management), to a control group of rehabilitation alone with or without placebo injections. Rehabilitation combined with BoNT-A injections demonstrated significantly greater improvement in gross motor function as measured by the Gross Motor Function Measure (GMFM-88 or-66) and quality of gait using the Physician’s Rating Scale , , Edinburgh Visual Gait Score (EVGS) or Three Dimensional Gait Analysis (3DGA).
Improvement in performance-related goals have been reported when measured by the Canadian Occupational Performance Measure (COPM) , Goal Attainment Scaling (GAS) or parental questionnaires ,.Despite the acknowledged success of physiotherapy rehabilitation combined with BoNT-A injections, relative effectiveness of the specific components of physiotherapy rehabilitation, including intensity and dose, is difficult to interpret because it is often poorly described ,. Results of a number of systematic reviews and consensus papers found limited evidence to support or refute individual physiotherapy modalities post lower limb BoNT-A injections ,.
The content of physiotherapy rehabilitation outlined in reported studies has included: active and passive stretching of muscle agonists , ; functional or resistive strengthening of the antagonists , ; functional mobility training and/or gait training ,. One retrospective, controlled intervention study has directly compared the specific content of two physiotherapy approaches following lower limb BoNT-A injections.
Thirty-eight children with CP (mean age 7 years, 7 months, GMFCS I-III, 11 unilateral, 27 bilateral motor distribution) who received Neurodevelopmental Treatment (NDT, mean total dose 24.2 hours) were randomly selected and retrospectively matched to a group of children who received conventional physiotherapy (CPT, mean total dose 20.5 hours). Content of physiotherapy, determined via therapist questionnaires, and improvement of impairment and gait-related goals (GAS) were compared between groups two months post injection. Both approaches utilized muscle tone inhibition techniques, stretching, strengthening and functional training, with the NDT group spending a greater proportion of time on functional training (NDT 42%; CPT 28%, p = 0.009). Whilst the NDT group showed greater goal attainment post intervention (mean converted GAS score NDT 56, CPT 52, p = 0.008), results should be interpreted cautiously.
Therapy content was only described and analysed for 62% (n = 47) of children due to reduced completion of questionnaires by treating physiotherapists. As GAS goals were impairment-based it is unclear from this study if a more functional approach to training translates to improvement in goals related to function and participation.In the absence of high level evidence, expert opinion and consensus statements recommend post BoNT-A physiotherapy includes functional and targeted motor training in combination with serial casting, stretching and strengthening ,. Additionally, intervention should incorporate: (1) collaborative, individualized, realistic and specific goal setting which span across all domains of the ICF , ; (2) specificity of task and training , ; (3) repetition and practise within a functional “just right” context , ; (4) environmental adaption and (5) strategies to increase motivation and engagement ,. This approach will facilitate rehabilitation focused on each child’s specific goals and functional needs ,. Studies investigating the efficacy of physiotherapy combined with BoNT-A injections have consistently included therapy delivered in an individual model. It is unclear whether similar outcomes could be achieved using alternative methods of physiotherapy delivery.Four models of therapy delivery have been reported in the literature for children with CP including: (1) individual (one on one); (2) group-based (three or more participants with similar abilities ); (3) web-based training or virtual reality , ; (4) individual consultation with intervention performed as a home programme. Group-based training has been shown to achieve positive rehabilitation outcomes through maximising engagement, motivation and participation ,.
Relative effectiveness of group versus individual physiotherapy post lower limb BoNT-A injections has not been examined to date, however. Independent of BoNT-A, effectiveness of group versus standard individualised care has been compared for ambulant children with CP receiving strength, endurance and fitness training , , progressive functional strength training and goal-directed activity-focused physiotherapy. Results are difficult to compare due to the heterogeneity of theoretical focus, therapy dose and outcome measures used. However, these studies provide useful guidelines for the elements that contribute to successful group-based physiotherapy.Effective group-based physiotherapy interventions report similar session structure including warm up, specific intervention activities and then warm down.
To maintain motivation and specificity of practise, a combination of group-based activity and individual or paired circuit activity has been recommended ,. To ensure adequate supervision and progression of exercises, group sizes have been limited to small (4–6 children) or medium (7–9 children). Effective dose is not well understood due to variability in intensity, frequency and duration of intervention. Total direct therapy dose has varied from 36 hours to 70 hours , delivered in varying intensity from three week blocks (intensive model) to 34.6 weeks (distributed model). Individual session duration has ranged from 45 to 180 minutes with a frequency of two to five sessions per week. Indirect treatment dose achieved via home programme is difficult to interpret due to inadequate reporting.
Despite insufficient evidence to confirm optimal group format, several studies found that group-based therapy can achieve equal or greater improvement in outcomes across ICF domains when compared to individual standard care. These include improvements in gross motor ability (GMFM-66) , , crouch gait (3DGA) , participation (Children’s Assessment of Participation and Enjoyment: CAPE) , health-related quality of life (TACQOL) and goal attainment (GAS). One RCT (n = 51) compared group-based progressive resistance exercise strength training to individualised standard care in 51 ambulant children with CP (GMFCS I-III; mean age 10y 5mo, SD 1y 10mo; 29 male) ,.
This study reported no improvement in either group for gross motor ability (GMFM-66), walking ability (One Minute Fast Walk Test) or participation (CAPE). No studies have reported inferior outcomes for group-based interventions compared to individual standard care. Additional qualitative benefits of a group-based model have been reported in the context of the self-determination theory ,. A group program may enhance self-regulation and engagement in the therapy process by attending to children’s basic psychological needs for Autonomy, Relatedness and Competence. There is potential for greater promotion of autonomy by allowing choice (personal goal setting), and through enjoyment, having fun and behaviour modelling to master activities ,. A sense of competence may be fulfilled through scaffolding activities to promote skill development, and providing opportunities for peer learning and healthy competition ,.
Social support and working with children with similar needs may also increase the feeling of relatedness ,.A group model has the potential to meet the physiotherapy rehabilitation needs for children post lower limb BoNT-A injections. To date there has been no study that has directly compared dose and content-matched group versus individual models of functional, goal-directed physiotherapy rehabilitation following lower limb BoNT-A injections for ambulant children with CP.
This study aims to compare the efficacy of these two models to enable informed choice of post BoNT-A physiotherapy rehabilitation delivery. Study aimsThis assessor-masked, parallel group, block RCT aims to compare group versus individual models of physiotherapy following intramuscular lower limb injections of BoNT-A for ambulant school-aged children with CP in the ICF domains of impairment (quality of gait, functional reach), activity/participation (caregiver/s perception of and satisfaction with their child’s occupational performance, gross motor function, walking efficiency) and quality of life. A secondary aim is to gain qualitative feedback from treating physiotherapists, caregivers and participants involved in the study to determine acceptability of the two treatment models.Study hypotheses are based on the reported benefits of a group model being at a participation and contextual level, so outcomes reflecting a child’s occupational performance, participation or quality of life may improve more in the group-based intervention. Individual training has the potential for greater intensity, specificity of training and repetition of practise of skills.
Outcomes at the body, structure and function or activity level could improve more with individual training. Consequently, the specific hypotheses to be tested are: Primary hypothesesH1: Compared to individual physiotherapy, group physiotherapy will result in greater improvement in caregivers’ perception of performance of and satisfaction with their child’s occupational goal areas (COPM).
This will be observed as between group differences of two or more COPM performance and satisfaction points at T2 (10 weeks-efficacy) and T3 (26 weeks-retention).H2: Compared to group physiotherapy, individual physiotherapy will result in greater improvement in quality of gait (mean score change of ≥ 4.0 points on the Edinburgh Visual Gait Score) at T2 (10 weeks-efficacy) and T3 (26 weeks-retention) ,. Secondary hypothesesH3: Compared to group physiotherapy, individual physiotherapy will result in greater improvement in efficiency of gait (One Minute Fast Walk Test ), gross motor performance (Gross Motor Function Measure-88 Items D&E , ) and functional balance (forward component of the Pediatric Reach Test ) at T2 (10 weeks- efficacy) and T3 (26 weeks- retention).H4: Compared to individual physiotherapy, group physiotherapy will result in greater improvement in quality of life (Cerebral Palsy Quality of Life Questionnaire). This will be observed as a between group difference of five points or more in each domain at T2 (10 weeks- efficacy) and T3 (26 weeks- retention) ,.
Study sample and recruitment Inclusion criteria. Criteria for withdrawal/failure to proceedChildren will be classified as failure to proceed if they do not attend a minimum of four hours of direct therapy (. Figure 1GRIN flow chart according to CONSORT guidelines.
Legend: CP Health: Queensland Cerebral Palsy Health Service; BoNT-A: Botulinum Toxin- Type A; EVGS: Edinburgh Visual Gait Scale; PRT: Pediatric Reach Test; COPM: Canadian Occupational Performance Measure; 1MFWT: 1 Minute Fast Walk Test; GMFM-88 D&E: Gross Motor Function Measure-88, Items D&E; CPQOL-Child: Cerebral Palsy Quality of Life Questionnaire; PTs: Physiotherapists; HEP: Home Exercise Programme. Stage 1: Botulinum Toxin-A injection/sIn accordance with current standard clinical practice, the rehabilitation consultant and physiotherapist will determine muscles to be injected with BoNT-A, following clinical assessment and consultation with the child and their caregiver/s. Muscle selection will vary between participants according to spasticity-related functional impairment and goals of the child and family, as well as from clinical assessment of: gait characteristics (observational gait analysis); resistance to passive stretch (Modified Ashworth Scale ); spasticity and dynamic range of movement (Modified Tardieu Scale ) and passive range of movement (goniometric and angle finder measures ). Dose of BoNT-A will be prescribed according to the Consensus Opinion of the ‘We Move’ Spasticity Study Group (2002), up to a maximum dose of 16 U/kg/body weight, or to a total maximum dose of 400 Units of Botox® (Allergan PLC). Children will receive injections either in theatre under general anaesthetic (100U Botox® diluted in 2 mls of normal saline), or as an outpatient using EMLA cream at the injection site/s (100 U Botox® diluted in 1 ml of normal saline).
Stage 2: Serial casting and orthotic prescriptionSerial casting will be provided within the three weeks following BoNT-A injections to children with a component of fixed equinus contracture (less than neutral/0 degrees of passive range of ankle dorsiflexion with the knee extended). Casting will be performed until at least neutral dorsiflexion is achieved. Dose comparisons between study arms will be analysed retrospectively from patient records.
Orthoses will be prescribed or modified for each participant by an orthotist as clinically indicated. Moulding for orthoses will occur immediately post BoNT-A for children not requiring casting, and on the day of the last cast fitting for those receiving casting. All orthoses will be available prior to commencement of the rehabilitation block. Stage 3: Physiotherapy interventionDirect therapy dose for both group and individual models of physiotherapy will be one 60 minute session per week for six weeks (total dose six hours), which is consistent with current funded clinical practice in Queensland. Indirect therapy dose will involve each participant performing three additional individualised, goal-directed activities at home three times a week.
Participants will be asked to abstain from any other interventions (e.g. Occupational therapy, aquatic therapy) during the rehabilitation phase but can return to their usual therapy following the intervention program. Any therapy or additional structured activity completed during the study will be recorded via a custom-designed questionnaire. Individual therapyParticipants in the individual arm of the study will receive physiotherapy on a one-to-one basis from their usual physiotherapist, who may be located in either a hospital or community out-patient setting. Group therapyEach group will include at least three participants. If there are insufficient participants to form a group for any recruitment block, additional children with CP (not involved in the study) will be invited to participate.
Each additional child will need to meet all study inclusion criteria except they will not have received recent lower limb BoNT-A injections. As for individual rehabilitation, group rehabilitation will be provided in hospital or community settings at a location mutually convenient for each geographical cohort. Group sessions will be directed by one lead physiotherapist with assistance from additional physiotherapist/s, allied health assistant/s or physiotherapy student/s to achieve a minimum ratio of one therapist to three participants. Group dynamics will be encouraged in a variety of ways.
For example, children will decide on a name for their group, agree on group rules, receive a team “t-shirt” to wear during sessions and be involved in choosing a theme for the group each week. Activities such as warm up, warm down, stretching and circuit stations will include a combination of group or paired formats. The overall ratio will include a minimum of 60% exercises performed as a group or paired activities and 40% exercises performed simultaneously in a circuit format.
Content of physiotherapy intervention. Content of the physiotherapy protocol is based on a review of the literature and a clinical practice audit of post BoNT-A rehabilitation providers in Queensland. Exercises have been chosen that require minimal specialised equipment to enable consistent delivery of the program across hospital and community settings.
To ensure session structure is the same across both physiotherapy models, a program of suitable exercises and progressions will be provided to treating physiotherapists. Therapists will select and modify exercises to suit each child’s age, intrinsic motivators, individual goals and progression rate. An outline of the session format is displayed in Table. Physiotherapy componentTime (minutes)Theoretical rationaleActivity examplesWarm up activities5Activities have been chosen to prepare the child’s mind and body for the therapy session.
Key: BoNT-A: Botulinum Toxin-Type A; COPM: Canadian Occupational Performance Measure; SLS: single leg stance. Home exercise programme (HEP)One key researcher (RT) will design an individualised HEP for each participant. Activities will include part or full task practise of each participant’s key functional goals as identified from the COPM. After the first week, the treating physiotherapist will incrementally progress the HEP activities in liaison with the key researcher as required. Caregivers and/or children will be asked to record the dates, duration and number of repetitions of each activity performed as a HEP, as well as involvement in concurrent activities and/or therapy. Treatment fidelityPhysiotherapists providing intervention (group and individual) will be masked to baseline outcome assessments.
They will require a minimum of two years’ experience in providing post BoNT-A rehabilitation for children with CP in association with CP Health. In addition, before and during the study, each therapist (and assistants as relevant) will receive face to face or telephone education from the study coordinator (RT) regarding intervention format, content, roles of different staff, exercise and HEP progression. At the start of each rehabilitation block, treating physiotherapists will be provided with standard information for each relevant participant, including the BoNT-A injection date, dose and site/s, baseline musculoskeletal assessment and goals (without score) identified through the COPM.
A copy of the physiotherapy protocol will also be provided with suggestions of activities to include in the targeted motor control station, based on each relevant participant/s individualised goals. Physiotherapists will complete a session evaluation form for every participant after each of the six sessions. This includes a summary of activities completed including proportion of time taken on each task. Independent content analysis will determine compliance with the protocol across both arms of the study.
Outcome measures and procedures. Functional mobility: Functional Mobility Scale (FMS)The FMS was designed for children with CP aged four to eighteen years and rates assistive devices required and walking ability at five, 50 and 500 metres which correlate with the child’s ability in the home, school and community settings. The scale ranges from N = does not apply; C = crawling; 1 = uses wheelchair; 2 = uses walker or frame; 3 = uses crutches; 4 = uses sticks (one or two); 5 = independent on level surfaces; 6 = independent on all surfaces. Outcome measures will be administered by one physiotherapist (MK) trained and experienced in performing all assessments and one Allied Health Assistant (One Minute Fast Walk Test only). Both assessors will be masked to treatment allocation and previous assessment data. Assessments will be performed at baseline (T1: 0–2 weeks pre BoNT-A injection/s), 10–12 weeks post BoNT-A (T2: on completion of the six week rehabilitation block, efficacy) and at 26 weeks post BoNT-A (T3) to determine medium-term retention of effects. Assessment timeframes are depicted in Figure.
A range of outcome measures will be used across domains of the ICF. Quality of gait: Edinburgh Visual Gait Score for Cerebral Palsy (EVGS)Competence of motor control during gait will be compared to normal values using the EVGS and will be a primary outcome measure for this study. The EVGS is a tabulated scoring system that records 17 joint angles or movements of the trunk and lower limbs during a representative stride. EVGS total score ranges from 0 (best) to 68 (worst). The EVGS has excellent criterion validity (64% agreement with instrumented gait analysis), repeatability (least significant difference = 3.20 points) and sensitivity to change following surgical intervention (minimal clinically important change: mean score reduction of 4.2 points, range +0.3-8.5) ,.
Clarke Hess 828 Manual Muscle Cars
It has good intra-observer reliability which is higher with more experienced observers ,. Split screen gait analysis will be videotaped simultaneously in the sagittal and frontal planes at the Queensland Children’s Gait Laboratory (QCGL) and independently scored off-site by one physiotherapist (LJ) experienced in EVGS scoring and masked to group allocation, order of assessment and previous data. Functional balance The Pediatric Reach Test (PRT)To evaluate the limits of stability in free standing, the forward component of the PRT will be used. In this test, the participant stands with their feet on a line with their dominant arm outstretched at 90 degrees shoulder flexion, holding a pen.
Paper is fixed to the wall at the side of the participant who touches the wall laterally to make a mark on the paper at the starting position. The participant is then instructed to reach as far forwards as possible without moving their feet or losing balance. A second mark on the paper is made at this point. The reach is measured as the mean distance reached on three attempts.
Correlations between the PRT in standing and laboratory tests of limits of stability is moderate-to-high (r = 0.42 to 0.77). For children with CP, test-retest reliability and interrater reliability range from intraclass correlation coefficients (ICC) of 0.54 to 0.88 and 0.50 to 0.93, respectively ,.
Goal attainment: Canadian Occupational Performance Measure (COPM)The COPM identifies concerns regarding occupational performance and documents changes post BoNT-A rehabilitation and will be a primary outcome measure in this study. It has demonstrated high re-test reliability (ICC 0.76-0.89), sensitivity to change and good content, construct and criterion validity for children with CP receiving BoNT-A ,. The COPM will be administered using a semi-structured interview in collaboration with the caregiver/s and participant (dependent on age, cognitive ability and motivation to contribute). The child-adapted model has three sections: self-care (personal care, functional mobility and community management), productivity (play/school) and leisure (quiet recreation, active recreation and socialisation).
Caregivers will be asked to identify three daily activities of concern where they or their child hope to improve after lower limb BoNT-A injections ,. They will rate their perception of their child’s performance and their satisfaction with this performance on a 1–10 ordinal scale. A score change of two or more points is considered clinically significant. Efficiency of gait: The One Minute Fast Walk Test (1MFWT)The 1MFWT is considered a good discriminator of functional ability for dynamic balance, muscle performance and endurance.
The test involves a five minute rest, followed by walking for one minute around a 20 metre oval track at maximum walking speed without running. Children are able use normal walking aids and wear orthoses. Distance is calculated to the nearest metre.
The 1MFWT shows concurrent validity with the GMFM with a significant correlation between GMFM-88 score and distance walked (r = 0.92). Reliability has been established (ICC = 0.97, Standard Error of Measurement, SEM =4.0 m (4.1%)) with a score change of. 2.2.3 Gross motor ability: Gross Motor Function Measure (GMFM-88)The GMFM-88 is a criterion-referenced measure designed for children with CP aged 0–18 years to assess motor function in five areas ,. Items D (standing) and E (walking, running and jumping) will be administered as study participants are ambulant with goals frequently reflected in these areas. The GMFM-88 has good intra-rater (ICCs 0.92-0.99) and interrater (ICCs 0.87-0.99) reliability and demonstrated validity to reflect change in gross motor function over time (ICCs 0.66-0.79). A ceiling and floor effect has been reported which highlights caution when interpreting results ,.
A change score of 1.3 points (total score), 1.2 points (Dimension D) and 1.6 points (Dimension E) is considered clinically meaningful ,. A change score of 3.99 points further separates a great improvement from moderate or no improvement. Quality of life: The Cerebral Palsy Quality of Life Questionnaire (CPQOL-Child and CPQOL-Teen)The CP QOL-Child and the CP QOL-Teen are quality of life assessments designed for children and adolescents with CP aged four to 12 years and 13 to 18 years respectively. Both quantify well-being across seven key quality of life domains relevant to age group. Items are scored on a nine point rating scale, then summed and averaged to generate seven domain scores. The primary caregiver proxy versions will be used in this study as it is anticipated that the majority of children will be less than nine years of age. The CPQOL-Child and -Teen (primary caregiver proxy versions) have demonstrated good internal consistency (−Child: ICC 0.74-0.92; -Teen: Cronbach’s alphas 0.81-0.96), test–retest reliability (−Child: ICC 0.76-0.89; -Teen: ICC 0.29-0.83) and adequate construct validity supported by the pattern of correlations with scales including the Child Health Questionnaire (−Child only), Pediatric Quality of Life Inventory (−Teen only), KIDSCREEN and GMFCS ,.
AnalysesStatistical analysis will be undertaken by an investigator masked to group allocation (LS). Primary analysis will use the intention to treat principle, using the last observation carried forward for participants who withdraw before the end of the trial. Baseline data from each outcome measure for each treatment group will be reported using descriptive statistics. Continuous data will be compared between groups by fitting a regression model using generalized estimating equations to baseline, 10 and 26 week measurements with an interaction term between the intervention group and a three-level factor indicating time of measurement.
The generalized estimating equation model will assume a Gaussian family, identity link, and unstructured working correlation matrix for repeated measurements on participants. Conventional variance estimates will be used.
Where continuous data exhibit skewness not overcome by transformation, non-parametric methods (Mann–Whitney U) will be used for simple comparisons. Statistical significance will be at p. This protocol paper presents the background and design of an assessor-masked, randomised comparison trial evaluating the efficacy of group versus individual models of physiotherapy following intramuscular lower limb BoNT-A injections for ambulant children with CP. To our knowledge, this will be the first study to compare these two physiotherapy models with this population using outcome measures across domains of the ICF. It will address the essential need for rehabilitation services to consider flexible models of service delivery in response to family preferences and an increasing emphasis on improving goal-directed functional activity performance and societal participation within a family-centred framework. Importantly, children, caregiver/s and therapists will have a greater informed choice of post BoNT-A rehabilitation delivery options.
EthicsThe research ethics boards at the Royal Children’s Hospital, Brisbane, Australia (HREC2008/089) and the Cerebral Palsy League, Brisbane, Australia (CPLQ2009/2010-1030) have granted approval for the study. AcknowledgementsThis study was fundedby a Queensland Health Community Rehabilitation Research Scheme Grant ($4180; Pathways Home 2007/08) and a Royal Children’s Hospital Foundation Grant ($24, 210; I.D. RB was supported by a Career Development Award (465128) and LS by anNHMRC TRIP Fellowship (1036183). We would also like to gratefully acknowledge Laura Gascoigne-Pees (Administration Officer, CP Health) for her assistance with sourcing articles and Endnote referencing. Competing interestsThe authors declare that they have no competing interests. Authors’ contributionsRT, MK and LJ were responsible for the study concept, design and ethics applications.
LS provided statistical advice for the study design. MK and LJ obtained funding for development of the study protocol and ethics submission. MK obtained funding for the study.
RT registered the trial with ACTRN and drafted the manuscript which was critically reviewed by all authors. All authors read and approved the final manuscript. Supplementary material.
Summary: Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by loss of spinal and cortical motor neurons, leading to progressive weakness and ultimately, death. Clinically, there appears to be an anatomic focus at disease onset, from which the disease then spreads. Because the focus of initial symptoms and the subsequent direction of spread can vary from patient to patient, disease monitoring is difficult, especially in a clinical trial, in which outcome measures must be identical and able to capture progression of all types. Thus, the search for markers of disease progression is especially important in ALS.
Many approaches have been taken, from voluntary strength assessment and functional rating scales to physiological and pathological sampling of affected portions of nervous system. No proposed marker has been demonstrated to meet the desired criteria of biological meaning, sensitivity to disease progression, clear relationship to overall prognosis and survival, and ease of measurement. However, progress is being made in all of these regards. INTRODUCTIONBecause ALS is ultimately a fatal disease, survival is an obvious choice as a marker of disease progression, as well as success or failure of experimental trials. However, as a clinical trial outcome measure, survival has a number of limitations. First, because average survival of patients newly diagnosed with ALS is 3 years, use of survival as an endpoint obligates the use of long trial duration.
Secondly, although survival seems unequivocal as an endpoint, its identification may be problematic, and it may be affected by other factors besides disease-modifying therapies. For example, the use of non-invasive ventilatory techniques may prolong life independent of disease progression; without question, tracheostomy and permanent assisted ventilation is a life-prolonging intervention. Invasive treatments to augment nutrition via gastrostomy tubes may also prolong survival. Thus, although survival is an objective, easily measurable outcome, it may reflect other factors than disease progression. The presence of surrogate markers of disease progression would allow for improved clinical trial design, and would increase our knowledge of the manner in which ALS evolves.
This chapter will review diagnostic markers, markers that have been previously employed as outcome measures in clinical trials, and new approaches that may prove useful both as measurement tools and as probes into the biology of ALS. CLINICAL FEATURES AND DIAGNOSISAmyotrophic lateral sclerosis is a rare degenerative disorder of large motor neurons of the cerebral cortex, brain stem, and spinal cord that results in progressive wasting and paralysis of voluntary muscles.
Fifty percent of ALS cases die within 3 years of onset of symptoms and 90% die within 5 years. The cause in most cases is unknown. No treatment prevents, halts or reverses the disease, although marginal delay in mortality has been recently noted with the drug Riluzole., The majority of cases are sporadic ALS (SALS); 10% are familial ALS (FALS). Mutations in the gene encoding cytosolic copper-zinc superoxide dismutase (SOD1) have been robustly identified as causing typical FALS.
The median age of onset is 55 years and the median survival is ∼3 years. Essential features of ALS are progressive signs and symptoms of lower motor neuron dysfunction, including focal and multifocal weakness, atrophy, cramps, and fasciculations associated with corticospinal tract signs (spasticity, enhanced and pathological reflexes) in the absence of sensory findings. ALS can present with only lower or upper motor neuron involvement, and the initial manifestations may be in either the limb or bulbar muscles. With disease progression, both upper and lower motor neurons are involved, as are both bulbar and limb muscles. These features define classic ALS.At present, ALS is diagnosed when both upper and lower motor signs are present. – In some cases, diagnostic electromyography (EMG) and muscle biopsy provide objective evidence of lower motor neuron involvement.
Because upper motor neuron signs may be masked when LMN involvement is severe, upper motor neuron involvement can be missed., Sensitive and objective methods are needed to detect upper motor neuron involvement. Recent novel technologies such as magnetic resonance spectroscopy (MRS) promise to improve detection of upper motor neuron involvement. ALS GENETICSIn 1993 it was reported that mutations in the gene encoding SOD1 account for about 25% of cases of FALS or 2–3% of all cases. More than 100 different mutations in the SOD1 gene have now been associated with FALS.
Forced expression of high levels of a mutant SOD1 transgene causes progressive motor neuron disease in mice and rats. It now seems likely that the fundamental pathology mediated by mutant SOD1 involves both aberrant copper catalysis as well as protein misfolding. In turn, these adverse properties invoke multiple downstream pathophysiological events including heightened excitoxicity mediated by glutamate, activation of cascades of programmed cell death, perturbation of calcium metabolism, depression of mitochondrial function and ATP production, activation of the stress response in endoplasmic reticulum, and slowing of axonal transport. Last year, a second ALS gene was discovered., The ALS2 gene codes for a novel protein with homology to guanine-nucleotide exchange factors for GTPases. Loss-of-function of ALS2 leads to denervation beginning in the first decade, with predominant corticobulbar and corticospinal signs and very slow progression.
More recently, a study reported that a slowly progressive, bulbar-predominant form of lower motor neuropathy arises from mutations in a dynactin gene, confirming the principle that motor protein defects can progressively impair motor neuron function, as reported for motor neuropathies from mutations in the kinesin gene. New loci in dominant ALS have been reported on the X-chromosome and chromosomes 18q21, 9, and 16.
Maximum voluntary isometric contraction.The MVIC has proven useful as an outcome measure in natural history studies and clinical trials in ALS and is a valid and reliable measure of disease progression. – MVIC can be measured using a hand-held dynamometer or a fixed device with strain gauges. The strength of individual muscle groups is determined quantitatively and then the scores are normalized and combined into composite scores called megascores. This allows for the averaging of strength of small and large muscle groups.Intrarater and inter-rater reliability have been assessed in a number of clinical trials in ALS.
With rigorous training of clinical evaluators, intra- and inter-rater reliability are less than 15%., Seven trials testing four different therapeutic agents have used MVIC as the primary outcome measure. The methods used to determine the rate of decline in MVIC differ slightly among the clinical trials, with some trials using a mean slope and others a mixed model. However, the rate of change in MVIC has been consistent in the placebo groups from these studies. –, This suggests that, similar to the survival, muscle strength measures of disease progression in ALS have not changed over time. Data from the placebo treatment arms of two recent clinical trials with topiramate and creatine demonstrate that the rate of decline in MVIC is essentially linear with only a small quadratic component.The relationship between muscle strength measured by MVIC and survival is not entirely clear. Two studies have demonstrated that the rate of decline in muscle strength measured by MVIC was strongly related to survival, and another found that neither the baseline limb muscle strength nor the rate of change in muscle strength preceding the trial was a significant predictor of survival. We examined the relationship of MVIC to survival in 97 subjects assigned to the placebo arm of the topiramate ALS study.
The baseline MVIC arm score predicted survival, therefore subjects with lower baseline MVIC scores survived a shorter amount of time. The rate of decline of MVIC in the first 3 months was also predictive of survival.The MVIC is a good quantitative measure of the rate of decline of muscle strength, an outcome measure that is highly relevant to the disease. The advantages of MVIC include good intrarater and inter-rater reliability, sensitivity to small, clinically relevant changes and generation of numerically continuous data which are suitable for parametric statistical analysis.Problems that limit the use of MVIC are: it takes approximately 45 min to perform testing, requires expensive equipment, is not applicable for home visits, and data can not be obtained from very weak muscles. In the trials that used MVIC as an outcome measure, the study dropout rate has been between 20 and 40%. This large amount of missing data can negatively impact the interpretability of the study results. A faster, portable method to measure strength is desired.A promising technique uses hand-held dynamometry (HHD) to test isometric strength of multiple muscles, again with standard patient positioning and rigorous training. This technique has been used previously in ALS clinical trials, as well as in trials in patients with inflammatory neuropathy and muscular dystrophy.
– It has been directly validated against MVIC in ALS patients, and shown to change at a similar rate with variability that is only slightly greater than MVIC. For both upper and lower extremity muscles, correlations between MVIC and HHD measurements ranged between 0.84 and 0.92, with test–retest variability that was extremely similar as well. The only time at which correlation between HHD and MVIC broke down was at extremely high strength levels, an area not likely to be a problem in an ALS clinical trial. HHD equipment is inexpensive and it takes less than 5 min to complete a test of both upper and lower extremities. Manual muscle testing.Manual muscle testing (MMT) using the Medical Research Council (United Kingdom) grading scale has been used in a number of ALS clinical trials. It involves measurement of muscle strength by a trained evaluator using standardized patient positioning.
It was recently demonstrated that if enough muscles are tested, a decline in average grade can be determined early in the disease, and the variability of measurement approximates that of MVIC. The advantages to manual muscle testing are speed, expense, and the lack of needed equipment., Disadvantages to MMT are low sensitivity to change in muscle strength, the fact that data are ordinal, qualitative, and potentially subjective, in addition to which a large number of muscles must be evaluated to reduce variability and improve sensitivity.
PulmonaryRespiratory failure is the primary cause of death in ALS and measurements of respiratory muscle function are commonly used as secondary outcome measures in ALS clinical trials. Vital capacity and maximal inspiratory and maximal expiratory mouth pressures are the methods most commonly used to evaluate respiratory muscle strength. These measures are widely available, non-invasive, and portable. However, these tests are associated with increased variability in patients with significant bulbar involvement and require maximal respiratory muscle activation.
Bulbar or facial weakness can prevent the formation of a tight lip-seal around a mouthpiece. Vocal cord spasms and excessive saliva and gagging can also interfere with study performance. Other measures of respiratory muscle function that might be more useful in patients with bulbar involvement and as outcome measures include maximal sniff esophageal, transdiaphragmatic, and nasal pressures.The forced vital capacity (FVC) measures volume of air forcefully expired in one breath. Usually, the FVC is reported as a percentage of a predicted vital capacity based on subject’s height, gender and age. The FVC declines with time in patients with ALS and is a sensitive measure of disease progression. Both the baseline FVC and the rate of decline in FVC are predictive of survival.,Maximal inspiratory pressure (MIP) measures the maximal negative pressure at the mouth after complete exhalation followed by a single sustained maximal inspiratory effort against an occluded airway. Maximal expiratory pressure (MEP) is the maximal positive pressure measured at the mouth after inhalation to total lung capacity followed by a maximal expiratory effort against an occluded airway.
Both MIP and MEP are sensitive early indicators of respiratory muscle weakness. They are easy to determine and reproducible. Appel ALS rating scale.The total Appel score consists of five subscores: bulbar, respiratory, muscle strength, and lower extremity and upper extremity function. Each group is composed of individual tests. A group score of six is assigned if there is no dysfunction and group scores of 30-36 points are assigned for maximal dysfunction. The total Appel ALS score is 30 for healthy subjects and 164 for those with maximum impairment. The rate of change in the Appel ALS Rating Scale is a significant predictor of survival for subjects with ALS.
ALS functional rating scale.The ALSFRS is a quickly administered ordinal rating scale used to determine patients’ assessment of their capability and independence in 10 functional activities. All 10 activities are relevant in ALS.
It assesses bulbar and respiratory functions, upper extremity functions (cutting food and dressing), lower extremity functions (walking and climbing), and dressing hygiene and ability to turn in bed. The instrument can be easily administered by a clinician, an allied health professional, or a trained evaluator. The patient’s response is recorded to the closest approximation from a list of five choices. Each choice is scored from 0 to 4. The total score can range from 40 (normal function) to 0 (unable to attempt the task).Initial validity was established by documenting that in ALS patients, change in ALSFRS scores correlated with change in strength over time, as measured by MVIC, was closely associated with quality-of-life measures, and predicted survival., – With appropriate training the ALSFRS can be administered with high inter-rater reliability and test–retest reliability. The test–retest reliability is 0.88 for all test items.The ALSFRS can be administered by phone, again with good inter-rater and test–retest reliability, but the equivalency of phone and in-person testing has not been determined.
In addition, the ALSFRS can be administered to the patient directly when the patient is verbal, but as communication becomes more difficult, caregivers provide increasing assistance in providing responses. The equivalency of caregiver and patient responses has also not been established.A revised version of the ALSFRS was created to add assessments of respiratory dysfunction, including dyspnea, orthopnea, and the need for ventilatory support. The revised ALSFRS (ALSFRS-R) was demonstrated to retain the properties of the original scale and show strong internal consistency and construct validity.
Biopsy studies.Before the development of clinical neurophysiology more than 50 years ago, pathology served as the only quantitative measure of disease activity in ALS. Early autopsy studies demonstrated that ventral roots were atrophied as compared with dorsal roots; shortly thereafter, Charcot and Joffroy described the loss of large ventral horn neurons, degeneration of the corticospinal tract, and dropout of large cortical neurons in frontal cortex. More current postmortem studies continue to yield important information relevant to the pathogenesis of ALS, – but will not be further reviewed here, as they do not serve as tools for diagnosis or disease progression.Muscle biopsy is the only pathological tool that continues to be employed in the management of patients with ALS. The demonstration of denervation atrophy of muscle fibers is usually associated with increased connective tissue; unlike other denervating diseases such as neuropathy, muscle fiber type grouping is less uniformly observed., Muscle biopsy is useful in patients for whom the involvement of lower motor neurons is in doubt either clinically or physiologically. It is not part of the routine evaluation at most centers, but remains a useful ancillary test in atypical patients. Motor unit number estimates.Although routine nerve conduction studies and needle EMG are essential for confirming lower motor neuron involvement in the initial diagnosis of motor neuron disease, they do not permit accurate measurement of motor neuron loss and compensatory reinnervation., Motor nerve conduction velocity remains normal until quite late in the disease, and compound motor action potential amplitude does not decline until 50% of axons has been lost. Needle EMG is a sensitive indicator of axon loss, but has not been useful in assessing change over time.
Motor unit number estimation (MUNE) quantifies the number of surviving motor units in the living human subject – and has emerged as an important potential marker in ALS – and other motor neuron disorders.All techniques for counting motor units rely on the same basic premise. A maximum muscle response is generated to an electrical stimulus. Most often the response measured is electrical, but force measurements have also been used. Then, the response amplitude of a single motor unit is estimated. Once a single motor unit amplitude estimate is made, this value is divided into the maximum response to yield a number reflecting the number of units that made up the response.The way this estimation is made varies from technique to technique. No technique has been universally accepted, but 4 have emerged as the most commonly used.
The original incremental technique described by McComas – relied on stimulating at one location, using a stimulus that varied slightly from near-threshold levels. Initially, an all-or-none response was generated, representing the response of a single unit. With increases in stimulus intensities, quantal increments in the response could be recorded, which were taken to represent additional motor units being stimulated. Approximately 10 successive increments were recorded. That response amplitude was then divided by the number of increments to yield an estimate of average motor unit size. Examples of incremental MUNE obtained from a wild-type mouse and a symptomatic animal with the FALS transgene.
A: A normal maximum compound motor action potential (CMAP). B: 10 incremental responses from the same animal as in A.
C: Maximum CMAP and 10 incremental responses displayed at the same amplification from a symptomatic animal. The CMAP is between 2 and 3 times greater than the 10th incremental response, implying a MUNE of between 20 and 30. In contrast, the 10th incremental response in B is less than 5% of the CMAP shown in A.The multiple point stimulation technique, also relies on low-amplitude stimuli to generate a single all-or-none response. Instead of increasing stimulus intensity to study successive increments, however, the stimulus position is varied, and the first unit, stimulated at a variety of positions, is recorded. Usually 10–20 such responses can be obtained; this sample of individual motor units is then averaged to yield an estimate of motor unit size. Spike-triggered averaging, employs a different approach. Single motor units are identified at low levels of voluntary muscle activation.
The response to a single motor unit is recorded with either a concentric or single-fiber EMG needle, and the electrode is positioned so that only the single motor unit response is recorded. Concurrently, surface potentials are recorded; the single motor unit spike is used as a trigger to time-lock the surface-recorded potentials so that an average surface response can be calculated, corresponding to the needle-recorded spike. Different motor units are recorded by altering the position of the intramuscular electrode to trigger on different signals. The surface-averaged potentials are themselves averaged to derive an estimate of motor unit size. Finally, the statistical technique, relies on the response variability to a repeated submaximal stimulus to estimate motor unit size.
For any given submaximal stimulus intensities, some motor units will always fire because their response thresholds have been exceeded, some units will never fire because they are clearly subthreshold, and some will fire variably as the stimulus is near their threshold level. Thus, the variability of the response to such stimulus depends on the variable firing of a relatively few units. The statistical technique estimates the size of these units by the variability of the response; this procedure is repeated at four different intensity levels to sample motor unit size as a variety of regions of the stimulus–response curve.
These separate estimates are then combined to generate an average single motor unit size.In theory, lower motor neuron dropout in ALS is a process ideally suited to evaluation by MUNE. Both the actual loss of motor units and the functional adaptation of increasing motor unit size can be estimated, the process is noninvasive, well tolerated, and fairly rapid to perform.
Early studies showed that MUNE was indeed reduced in patients with ALS. Hansen and Ballantyne compared MUNE in intrinsic foot muscles of normal subjects and 32 patients with ALS. Overall, MUNE of the patients was reduced by 62%, whereas individual motor unit potential amplitude increased by 145%.
Carleton and Brown obtained similar findings in the upper extremities. Because of compensatory increase in motor unit size, compound motor action potential amplitude was within normal limits until MUNE dropped below 10% of normal numbers. This provided a clear explanation for the lack of sensitivity of routine motor nerve conduction studies in identifying patients with ALS.Progressive decline of MUNE in ALS was first shown by Dantes and McComas; their data suggested that motor unit loss occurred more rapidly early in the disease, with the slope of motor unit decline leveling off after the first year. Similarly, Arasaki and Tamaki noted that MUNE dropped by 70% in the first year after diagnosis. Coupled with data showing that muscle strength declines quite linearly in ALS during most of the course of the disease, these studies suggested that the early rapid decline in motor unit numbers is compensated for by increases in individual motor unit force generating capacity.Motor unit dropout is a hallmark of progression in ALS, and virtually all force and electrophysiological measures show declines with time after diagnosis. Hence, the fact that MUNE behaves similarly does not confer upon it any unique utility.
However, MUNE has shown promise in stratifying patients according to rate of progression. In a recent study, the rate of change of MUNE was shown to be a strong predictor of survival in ALS patients. Even a single MUNE study can provide predictive power; using a single MUNE evaluation and extrapolation to normal values assumed to be present just before disease onset, patient survival was effectively predicted.,The most powerful application of MUNE would be as an outcome measure in clinical trials, if variability of measurement were sufficiently low, and changes in MUNE over time were a more sensitive indicator of disease progression than other surrogate measures. When MUNE, compound motor action potential amplitude, hand grip, strength testing, and vital capacity were all measured at regular intervals during the course of a clinical trial in ALS, MUNE showed a higher percent change than any other measure, and had a higher likelihood of detecting a criterion change in response than any of the others. Similarly, a study comparing MUNE to grip strength and compound motor action potential amplitude showed a significant decrease in MUNE within 3 months but no significant change in other measures.In a recently completed multicenter trial evaluating the efficacy of creatine in ALS, MUNE was employed as a secondary outcome measure. Formal training of evaluators was provided, and rigorous criteria for test–retest reliability were applied. Under these circumstances, evaluation of test-retest variability was less than 20%, and MUNE dropped approximately 30% over a 6-month test interval.
Comparison of the decline in MUNE with the changes measured in the other measures of disease progression employed in this study suggested that MUNE could be effectively employed as an outcome measure in future ALS trials. Transcranial magnetic stimulation.Physiological assessment of upper motor neuron function can be accomplished using both transcranial electrical cortical stimulation and, more recently, transcranial magnetic stimulation (TMS).
TMS employs a brief and powerful magnetic pulse to induce an electric current within the cortex. With cortical magnetic stimulation of appropriate brain areas, a response can be recorded in both upper extremity and lower extremity muscles. By subtracting peripheral conduction time from the total response latency after cortical stimulation, central motor conduction time (CMCT) may be calculated. This measures latency from activation of Betz cells or their input pathways through anterior horn cell activation.
Peripheral conduction time can be measured directly by magnetic stimulation of cervical roots or by using F waves, which assess conduction time from the recording site to the level of the anterior horn cell axon hillock. Abnormally prolonged CMCT has been reported in 51% to 93% of patients with ALS. This prolongation may be attributable to the loss of large myelinated motor axons in the corticospinal tracts subsequent to degeneration of cortical motor neurons. However, as can be concluded from the range of abnormal responses discussed above, CMCT prolongation is not a sensitive measure of upper motor neuron disease presence. Even in patients with definite ALS and upper motor neuron abnormalities in the limb studied, less than 50% of patients may show CMCT abnormalities. CMCT prolongation has been found in a variety of CNS diseases, and cannot be considered to be a specific sign of motor systems diseases. Despite its limited sensitivity and specificity, however, it is possible that, for those patients in which CMCT is abnormal, changes over time could correlate with clinical progression.
Longitudinal studies to address this issue are currently unavailable.TMS can provide other measures that have potential as markers of disease progression in ALS. Response amplitude from cortical stimulation can be compared with the response of the same muscle with distal nerve stimulation; the ratio provides some insight into the extent to which the corticomotor neuron is impaired.
However, response variability is even greater than that seen in CMCT studies, and there is no longitudinal information relating this measure to disease progression. Other measures of potential interest include resting threshold of the motor cortex, which may be either normal or reduced even when there is clear loss of corticomotor neurons., Cortical excitability and inhibition can be studied by using peristimulus time histograms (PSTH), whereby a weak transcranial stimulus is superimposed on a steady level of motor activation, and time-related changes in activation are recorded., – Patients with ALS usually show abnormal PSTH, whereas patients with isolated lower motor neuron disease do not.
By using paired magnetic stimuli, a cortical silent period after stimulation, which also represents corticospinal inhibition, can be explored; most, though not all ALS patients appear to show reduced inhibition using this metric. Paired cortical stimuli can also be used to assess both early and late intracortical inhibition. All of the above measures are often abnormal in ALS patients; however, the variability overlaps values seen in normal controls, and changes with disease duration are variable as well. Thus, although physiological measurement of upper motor neuron processes may reveal valuable insights regarding the pathophysiology of ALS in the future, they are not currently appropriate for use as markers of disease existence or progression. MRS.The search for a marker of upper motor neuron damage has also included investigations of proton MRS.
With this technique, the distributions of multiple small molecules, including N-acetyl (NA), N-acetylaspartate (NAA), N-acetylglutamate (NAG), creatine (Cr), choline (Cho), and others can be determined throughout the brain with a variable degree of spatial resolution. At present, no consensus has been reached regarding the optimal techniques for performing MRS studies, therefore results from different groups are difficult to compare. However, it seems clear that NA concentrations are reduced in the motor region of ALS patients, either expressed directly as concentration or in ratios with other metabolites in the area, such as Cho or Cr., – Differences in specific metabolite ratios may distinguish disease subtypes. For example, in one study the NAA/Cho ratio selected for patients with definite ALS by El Escorial criteria, as compared with patients who had less obvious motor cortex involvement.
In addition, decreases in the NAA/Cr ratio were closely correlated with rate of finger-tapping in ALS patients, which was chosen as a measure of upper motor neuron involvement. Thus, MRS may have utility as a biomarker for upper motor neuron integrity and function.A few studies have evaluated longitudinal changes in MR spectra. In a single patient, NA/Cr dropped 23% over 8 months. However, in the context of a clinical trial of intrathecal brain-derived neurotrophic factor, NAA/Cr in both patients treated with a placebo or an active drug did not change after 1 month of treatment.
Similarly, treatment with gabapentin for approximately 1 month was not associated with any change in the above ratio in ALS patients or normal controls, although the ratio was significantly reduced in the patients as compared with the control group. However, in another short-term comparison of ALS patients and control subjects treated with creatine, the NAA/Cr ratio was diminished in the control group but unchanged in the ALS group. This finding was taken to support the hypothesis that creatine supplementation attenuated the diminished NAA levels seen in ALS motor cortex, and suggests the possible utility of this ratio as a biomarker for therapeutic efficacy. However, because creatine has so far failed to demonstrate any efficacy in patients with ALS, the significance of this finding is unclear. In a similar study, short-term exposure to riluzole was also found to increase the NAA/Cr ratio in ALS patients. Because riluzole has no short-term clinical benefit that can be measured using the same time scale, it is unclear whether this finding suggests that MRS has potential as a sensitive marker of potential treatment efficacy, or if it is susceptible to multiple epiphenomena.
BIOMARKERSNo single biochemical abnormality is specific to the diagnosis of ALS. Some have been evaluated as specific and sensitive markers of the disease, although none has proven to be robust.
These have included CSF studies, such as measures of protein content, amino acids, and glutamate., Some markers of oxidative injury are elevated in the CSF of patients with ALS, including indices of DNA oxidative injury, protein oxidation, and lipid peroxides. Other reported biochemical changes include increased serum levels of lipid peroxides in sporadic ALS, and increased serum levels of matrix metalloproteinase-9 and transforming growth factor-1. These biochemical changes are not specific to ALS and have low sensitivity.Proteomics and metabolomics are the comprehensive study of proteins and small molecules present in cells and tissue, respectively. These technologies are just now being applied to ALS. Preliminary data from proteomic studies in CSF and metabolomic studies in plasma from subjects with ALS suggest that these technologies will likely yield new insights into disease mechanisms, and potential biomarkers for diagnosis and for following response to therapies in clinical trials.In recent years there has been an increasing interest in the concept that seemingly benign genetic variants may confer risk for a given disease or a phenotype within a disease. Variations in several genes relevant to motor neuron biology have been considered as possible modifying or risk factors for ALS. One example is the survival motor neuron gene (SMN); deficiency of the telomeric but not the centromeric copy of SMN causes recessively inherited spinal muscular atrophy.
The centromeric copy of SMN modifies the phenotype of SMA. Detailed analyses of centromeric and telomeric SMN genes in patients with ALS and controls document that some variants in SMN appear to modify clinical parameters in sporadic ALS cases. – Polymorphisms or variants in other genes have also been considered as risk factors for ALS, including apolipoprotein E, – ciliary neurotrophic factor, – the astrocytic glutamate transporter EAAT2/GLT1, and the ALS2 gene. Most recently, the possibility of a genetic predisposition in ALS was underscored by a recent report of a high rate of constitutional chromosomal aberrations (5.9% vs 0.5–0.1% in the general population.In summary, disease progression of ALS can be followed using a wide variety of measures. Many have useful attributes, such as intuitive relationship to clinically meaningful outcome and good test–retest reliability. However, no measure directly correlates with underlying pathophysiological changes, and it is unclear to what extent measures are affected by factors other than disease-related progression. Also unknown is the sensitivity of any measure in detecting a therapeutic benefit from a drug or other treatment modality.
To address this issue, a positive treatment trial with multiple outcome measures is required. With such a study, relative sensitivity of outcome measures could be determined, and their relationship to survival could be delineated as well. Until such a study is available, debate will continue as to what measures are most relevant to disease progression or to assessing the outcome of potential therapies.
