Upper Limb Evaluation and One-Year Follow Up of Non-Ambulant Patients with Spinal Muscular Atrophy: An Observational Multicenter Trial

Assessment of the upper limb strength in non-ambulant neuromuscular patients remains challenging. Although potential outcome measures have been reported, longitudinal data demonstrating sensitivity to clinical evolution in spinal muscular atrophy patients are critically lacking. Our study recruited 23 non-ambulant patients, 16 patients (males/females = 6/10; median age 15.4 years with a range from 10.7 to 31.1 years) with spinal muscular atrophy type II and 7 patients (males/females = 2/5; median age 19.9 years with a range from 8.3 to 29.9 years) with type III. The Brooke functional score was on median 3 with a range from 2 to 6. The average total vital capacity was 46%, and seven patients required non-invasive ventilation at night. Patients were assessed at baseline, 6 months, and 1 year using the Motor Function Measure and innovative devices MyoGrip, MyoPinch, and MoviPlate, which assess handgrip strength, key pinch strength, and hand/finger extension-flexion function, respectively. The study demonstrated the feasibility and reliability of these measures for all patients, and sensitivity to negative changes after the age of 14 years. The younger patients showed an increase of the distal force in the follow-up period. The distal force measurements and function were correlated to different functional scales. These data represent an important step in the process of validating these devices as potential outcome measures for future clinical trials. Trial Registration ClinicalTrials.gov NCT00993161


Introduction
Neuromuscular diseases constitute a group of heterogeneous pathologies in regards to their genetic origin, their symptoms, their natural history and their prognosis. Among them, some diseases begin in childhood or even in utero and lead to a loss or absence of acquisition of walking. The two most common diseases in this subgroup are Duchene Muscular Dystrophy (DMD) and Spinal Muscular Atrophy Type II (SMA II).

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Duchene Muscular Dystrophy (DMD) is the most common children's myopathy (1). It affects all the muscles of the body. It appears only in boys before the age of five and leads to a loss of walking before the ages of ten and twelve. The use of upper limbs gradually decreases. The diagnosis is made due to a muscle biopsy and it is confirmed genetically with the identification of a deletion or a mutation in the dystrophin gene.
Spinal Muscular Atrophy Type II (SMA II) is connected with a mutation of the SMN gene causing the death of spinal motor neurons (2). Clinically, it is characterized by a loss of proximal and distal strength in children, girls and boys who have acquired sitting position but not walking.
Other less common diseases, such as the sarcoglycanopathies, alpha dystroglycanopathies, some myasthenia or congenital myopathies, the merosin negative dystrophy, Ullrich muscular dystrophy, even some forms of laminopathies can also appear in childhood and lead to a loss or absence of acquisition of walking. A similar problem arises, therefore, for all pediatric neuromuscular diseases leading to a loss or absence of acquisition of walking.
After the Treat-NMD workshop of 11 July 2007 (3), the need for specifically adapted measures to assess the residual strength of upper limbs in non-ambulant patients was raised.
Indeed, the six-minute walk test (4) which has been proposed for the functional evaluation of these patients is not obviously suitable for a non-ambulant patient. Therefore, different scales have been proposed, including the Hammersmith Functional Motor Scale (HFMS) (5), and Motor Function Measure (MFM) (6, 7). These scales have the advantage of full evaluation of motor skills and upper limbs, with a minimum of equipment. However, they have the disadvantage of the time required for their application and the subjective dimension of the measure. The quantified measure of the hand strength has recently been proposed as a parameter of disease progression for DMD patients (8), but with a special caution on using it before the age of ten due to a possible interference with the process of growth.
As we mentioned before, it is essential to define a simple, reliable and reproducible clinical test of muscle function to assess the effect of new therapeutic approaches for non-ambulant patients with neuromuscular diseases.

Methodology
We plan to include a group of one hundred non-ambulant patients with neuromuscular diseases and sixty control subjects uniformly distributed in regards to age and gender, with ages between eight and thirty. Patients are to have the neuromuscular consultation at the Institute of Myology in Paris, in the Patients will be assessed during a daily hospitalization or during a consultation in the department where they are usually followed-up. Evaluating materials will be duplicated and provided to the Pediatrics department of the Raymond Poincaré University Hospital in Garches. For other centers, the evaluators from the Institute will move with the material to assess the patients. A training session for physiotherapists of the Raymond Poincaré Hospital will be scheduled before the first evaluations at the hospital; and the first evaluations will be conducted in the presence of an evaluator of the Institute of Myology.
The intra and inter rater reliability (two groups of twenty patients and two groups of twenty controls) will be studied after a second evaluation, done the same day of the inclusion or within the next thirty days.
For the sensitivity to change, that is to say the ability of the test to detect an expected deterioration in patients, the evaluation in six months is expected to show that the Moviplate is more sensitive than other tests. It is also planned to test new controls in six months to assess the potential effect of age (for those in period of growth). In case if the change sensitivity is not demonstrated in six months, a visit for all the patients is planned in twelve months (this follow-up is usually offered to patients). These follow-up visits will be proposed to patients with the most represented diagnosis (DMD, SMA, sarcoglycannopathie) in order to have a sufficient number of patients to be analyzed in each subgroup.

Patients' inclusion and exclusion criteria
Non-ambulant patients, treated by doctors Servais, Estournet, Quijano-Roy, Mayer or Desguerre, will be called on to participate in this study. During a scheduled consultation, the doctor in charge will directly inform them. After the oral discussion, reading the information notice and signing the informed consent, the patients can be included in the study.

The inclusion criteria.
For the patients:

Genetically confirmed diagnosis
Ages between eight and thirty Patient able to sit on a chair for at least an hour.
Patient to able to walk ten meters in the standardized conditions of the Six-Minute walk test [4] Patients assigned to a social security system.

Signed informed consent
We expect to include a hundred patients.

For the control subjects:
Sixty control subjects uniformly distributed by age and gender, with ages between eight and thirty. These controls will be recruited on a voluntary basis Patients assigned to a social security system. Signed informed consent

For the patients
Patient not able to sit on a chair for at least an hour.
Patients with severe cognitive disorders which limit the understanding of the performing Chronic treatment impairing the muscular strength during the months before the inclusion.

Calendar and description of the evaluations
The patients and the control subjects will be evaluated using the Moviplate tool and other tests that help to verify the relevance of the former (Table 1) All the tests are for the upper limbs and will be conducted on both sides for each subject.
For the patients, the tests will approximately take sixty minutes; they will be conducted at the Institute of Myology, at the Raymond Poincaré Hospital, at the Armand Trousseau Hospital and the Necker Hospital. For the control subjects, the tests will approximately take thirty minutes and will be conducted at the Institute of Myology after obtaining the informed consent. The second evaluation will be done with using Moviplate and the other muscle strength tests (wrist, hand, fingers) and taping test on the same day, after at least an hour rest, or the latest in four weeks after the first visit (test duration estimated at 30 minutes).
After six months: patients (from the main diagnosis classes, DMD, SMA and sarcoglycannopathy) and controls will have a new visit to monitor the changes they have had since the inclusion in the study, and to repeat the same tests as at the inclusion (see table 1  X X X X X X X * The same day or the following day in thirty days after the inclusion.
For the patients, all the tests will be repeated in twelve months after the first visit.

-The Moviplate test (Appendix 1)
This test will be performed in the sitting position at the table where the Moviplate tool is placed (Appendix 1). This tool consists of a plateau with two small raised platforms which subjects have to touch alternately. Subjects perform the test in a sitting position with their forearm fixed or not fixed on the plateau placed before them on the table at the correct height. The purpose of the exercise is to make the maximum return motions in thirty seconds between the two platforms as a result of a coordinated extension movement of the wrist and fingers. The test is repeated two times at each evaluation (nondominant side, dominant side then non-dominant side, dominant side).

8/25 Version 2 _ 14 September 2009 -Taping (Appendix 4)
The test includes typing on a strength sensor with the index finger as many times as possible in fifteen seconds. The energy used, the frequency, the number, the intensity and duration of contacts is studied over the time. -Self-administered questionnaire (performance status of a hand (9-10) (Appendix 6)

Data collection
The measuring results are collected in an experimental form given in Appendix 7.
All the tests are non-invasive and do not have any serious side effects. The risks associated with this study are related to forced movements (tiredness, muscle pain, muscle cramps, muscle or musculotendinous injuries related to stretching). The muscle evaluation will be stopped in case of occurrence of pain or cramp.

Expected profit
Profit is not expected out of the patient participating in this protocol.

Duration of the exclusion
The exclusion period is not expected after the inclusion of controls and patients. Neither extended follow-up, nor persistent effect expected.

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Version 2 _ 14 September 2009 9. Management of withdrawal from a trial Subjects who cannot perform the tests described in the protocol or who do not want to follow the protocol for one reason or another will be replaced by another person of similar age.

Management of adverse effects
No serious adverse effects are expected in this study. As already pointed out, it is specified that the equipment used are only quantifiable tools that do not develop themselves any force, but remain passively resistant with a force equal to the force generated by the subject. There aren't any risks associated with the use of the tools (no invasive measurement, no electrical contacts). All the adverse effects will be marked, that is to say all the symptoms, clinical signs, reactions that develop or worsen during this study.
The information about all the adverse effects will be immediately written in the space provided for this purpose in the experimental forms and spread to the principal investigator as well as to the promoter.
The evolution of each effect will be followed until recovery, stabilization, or until it is clearly established by mutual agreement that the effect is not related to the current study.

Investigator's commitments
The research will be conducted in compliance with the French regulations, including provisions related to biomedical research in the Public Health Code, Article L. 1121-1 and following, the Bioethics law, the information technology and liberties law (CNIL), , the Helsinki Declaration as well as the Recommendations for Good Practice and the present protocol.
The investigator agrees to conduct the research according to ethical norms and regulations. He is aware that all the documents as well as all the data related to the research may be the subject of audits and inspections in respect of professional confidentiality and may not be confronted with medical secrecy.
The investigator recognizes that the study results are the property of the Institute of Myology, promoter of the research.
Before the implementation of the research, the coordinating investigator will put forward the project to Myology has been informed of a favorable unreserved opinion issued by the CPP in regards to the protocol submitted. The promoter will inform the CPP about all the serious or unexpected adverse effects and appearance of new facts that could presumably affect people's safety.
The Institute of Myology, as the promoter, subscribed for the entire duration of the trail to an insurance contract №. ............... according to French laws and regulations on biomedical research.

Information notice and informed consent
The written informed consent of people taking part in the research must be obtained by the investigator, enrolled in the medical association, declared as an investigator to the promoter before any act is performed on the basis of the research protocol, accordingly to regulations.
According to the law of December 20 th , 1988 as amended, the information given orally and in writing to patients will include information about the purpose of research, methodology and its duration, the constraints and the foreseeable risks, the opinion of the CCP, as well as the right to refuse to participate in the research or to withdraw the consent at any time without any obligation.
Patients will give their free and informed consent in writing by signing and dating the consent form.
This consent form will be prepared in two copies for the patient and for the physician-investigator so that each one keeps a copy.
The investigator must ensure that the person suitable for the research will have time to make a decision freely and will be able to read and understand the information notice and the consent form.
The information form of consent is a document that will be approved before the implementation of the research by the CPP, after examining the protocol.
No compensation is provided for patients under this protocol, except for refund of travel expenses.

Privacy policy
Personal data will remain confidential: the form with collected data will be referenced by a four-digit code ( of center and of included patient) 11/25 Version 2 _ 14 September 2009

Data analysis
The reliability of the tests will be estimated by analyzing the correlation of intraclass correlation coefficient (ICC) and Bland and Altman analysis. The sensitivity to change will be assessed by the calculation of the differences between the evaluations at inclusion, at six and twelve months. To compare the sensitivity to change in Moviplate and in other tests, the Standardized Response Means (SRM) will be calculated by using group diagnosis taking into consideration the principal diagnosis (DMD, SMA, sarcoglycannopathy) and comparing them with the controls. The SRM values are interpreted using the following rule (11): low sensitivity (0.2 to 0.49), moderate (0.50 to 0.79), and high (≥ 0.80).
The correlations between the results of Moviplate and other tests will be analyzed for convergent validity.
The six-month evolution of the measures will be compared between patient and control groups by analyzing variation of repeated measures. The effects of age, sex, weight (and other morphological data) will be studied.

Archiving of the documents
Investigators will keep a file containing the list of the included subjects with the corresponding code, the copy of all the papers of the experimentation and all the documentation related to the study according to European regulations, for a period of fifteen years after the end of the study.
After data is stored digitally, the original documents will be kept by the investigator.

Amendments to the protocol
Neither the investigators nor the promoter will change the protocol without the consent of the second party.
Any substantial changes in the protocol (for example: the change in the course of the study, extension of the duration of the study, etc.) should be the subject of an amendment signed by the principal investigator and the promoter. It will be submitted by the CPP. The amendment signed and approved will be acknowledged and spread to all the collaborators of the research.

Duration of the study
The total study duration will take thirty six months. The duration of subjects' inclusion will 12/25 Version 2 _ 14 September 2009 approximately take twenty four months (between September 2099 and September 2012) according to the reached agreements. As a reminder, the subjects are included in the protocol for about thirty -sixty minutes during the day.

Final report and publications
At the end of the study, a report will be prepared by the principal investigator in collaboration with various participants. It may result in a written, oral or poster presentations. According to the Public Health Code, each investigator or participant cannot publish or report the results of the study without the formal agreement with others and informing the promoter.