A new score combining compound muscle action potential (CMAP) amplitudes and motor score is predictive of motor outcome after AVXS-101 (Onasemnogene Abeparvovec) SMA therapy.

Spinal muscular atrophy 1 (SMA1) is a severe early genetic disease with degeneration of motor neurons. Motor development is still suboptimal after gene replacement therapy in symptomatic patients. In this study, compound muscle action potential (CMAP) amplitudes were explored as predictors of motor recovery after gene therapy. Thirteen symptomatic SMA1 patients were prospectively included at the Necker Enfants Malades Hospital, Paris, France (Cohort 1) and 12 at the other pediatric neuromuscular reference centers of the French Filnemus network (Cohort 2). In Cohort 1, median CMAP amplitudes showed the best improvement between baseline and the 12 months visit compared to the other tested nerves (ulnar, fibular and tibial). High median CMAP amplitudes at baseline was associated with unaided sitting achievement at M6 (AUC 90%). None of the patients with CHOPINTEND at M0 < 30/64 and median CMAP < 0.5 mV achieved unaided sitting at M6 and this result was confirmed on Cohort 2 used as an independent validation data. Thus, median CMAP amplitude is a valid biomarker for routine practice to predict sitting at M6. A median CMAP amplitude over 0.5 mV at baseline may predict better motor recovery.

State of the art for motor function assessment tools in spinal muscular atrophy (SMA).

Spinal muscular atrophy (SMA) is a progressive disease characterized by a degeneration of the spinal cord motor neurons. Many clinical trials - planned, in progress, or completed - have chosen motor function as the primary or secondary outcome because motor function assessment tools appeared to be more reliable than quantitative muscle testing in monitoring the course of the disease. Reliable, valid, and responsive outcome measures are needed to be able to capture the effectiveness of the therapeutic approach during clinical trials. Medical staff involved in neuromuscular diseases is faced with increasing pressure regarding the complex issue of choosing the right outcome measure for the objectives they have to assess. This paper provides a narrative literature review of available and validated motor function assessment tools in SMA population based on SMA subtypes, age and ambulant status. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Construction and feasibility study of the SOFMER Activity Score (SAS), a new assessment of physical and cognitive activity.

OBJECTIVES: For hospitalizations in rehabilitation centers (RCs) in France, the quantification of healthcare givers' activity is based on the dependency of the patients, defined as a total or partial inability to perform activities required for daily living without help. The tools currently used to quantify dependency are not sufficiently precise. Here we describe the construction of a new tool, the SOFMER Activity Score (SAS scoring), which allows for a good description of the level of activity of patients hospitalized in RCs, and a feasibility study of the tool. METHODS: After a study group proposed the first version of the SAS, the validity of its content was studied by the Delphi consensus method: 26 physicians or healthcare professionals known for their expertise in PMR responded to the first round. The feasibility study was prospective and involved multi-site professionals. Data related to the SAS determined by a multidisciplinary team were collected and compared to the Activité de la Vie Quotidienne (AVQ) scale, which is administered to all patients and included in medical and administrative data. RESULTS: We included 81 patients in the feasibility study. The mean (SD) time to obtain the SAS was 4.5 (3.3) min. For 97.5% of scorings, the participating professionals judged that the SAS was compatible or fairly compatible with clinical practice. The internal structure of the SAS scale seemed better than that of the AVQ scale, for which the present study confirmed a floor effect for all items. CONCLUSIONS: The SAS allows for measuring the level of physical and cognitive activity of a patient hospitalized in an RC. If validation studies for the SAS, exploring its reliability, construct validity or criterion validity, confirm the tool's good metrological qualities, the SAS will allow for a good quantification of the burden of care.

[Long term outcome of perinatal stroke]. / Devenir neurodéveloppemental après un infarctus cérébral artériel néonatal.

Neonatal Arterial Ischemic Stroke (NAIS) affects 6-17 newborns on 100 000-birth term neonates, most of these children keeping long-term motor and cognitive impairments. Based on a literature review, the objectives of this paper are to describe motor and cognitive outcomes after a NAIS and to propose a consensual monitoring of these children to improve their management. About 30 % of children after a NAIS will develop a unilateral cerebral palsy requiring a management by a team with expertise in physical medicine and rehabilitation. Unlike adults, especially after a left NAIS, children will not present aphasia but between 50 and 90 % will present disorders of speech and language in expression and/or reception. After NAIS, the global intellectual efficiency is usually preserved except when the size of the lesion is very important or when severe epilepsy occurs. Several studies are also in favor of vulnerability in visuospatial functions. To quantify impairments, activity limitations and participation restrictions resulting from this NAIS, early and at least yearly evaluations with reliable tools must be carried out systematically until puberty. A multidisciplinary team with a longitudinal follow-up, in all the different developmental dimensions, must conduct these evaluations in term of motor skills, cognitive impairment, behavior, autonomy, quality of life, and participation. Consequences on family functioning need to be evaluate in order to help children and family coping with this event.

[Brain plasticity and early rehabilitative care for children after neonatal arterial cerebral infarction]. / Plasticité cérébrale et prise en charge rééducative précoce des enfants après infarctus cérébral artériel néonatal.

Currently, in the literature of the evidence based medicine, little data are available to confirm the benefit and the specific procedures of an early intervention for a neonatal arterial ischemic stroke. However, data about the effect of an early physical rehabilitation program on the cerebral plasticity, and preliminary results of clinical studies in children with cerebral palsy strongly suggest the benefit of an early rehabilitation with a multidisciplinary approach. The type of the rehabilitation and its frequency must be determined because a wide variability in the practices exists. A comprehensive care, of the children and his family is necessary to limit the orthopaedics but also the social consequences of a neonatal stroke.

Prevalence of pain in 240 non-ambulatory children with severe cerebral palsy.

BACKGROUND: Several studies have given frequencies of pain in children with cerebral palsy, but comparing the findings is difficult. We aimed to estimate the prevalence of pain in non-ambulatory children with cerebral palsy and describe their characteristics by presence or absence of pain. METHODS: Data were extracted from an ongoing longitudinal national cohort following non-ambulatory children with severe cerebral palsy aged 3 to 10years over 10years. We described and compared data for the first 240 children at inclusion by presence or absence of pain. Pain was assessed by a visual analog scale and the Douleur Enfant San Salvadour scales and by investigator interview. RESULTS: Overall, 65 children experienced pain, for a prevalence of 27.1% (95% confidence interval 22-33%). All children experiencing pain had orthopaedic pain and 45.6% had pain from another origin. The main pain sites were hips (43.4%) and feet (26.9%). Joint mobilisation was the source of pain for 58.3% of children experiencing pain, and sitting was identified as painful for 10.3%. Pain was greater with scoliosis (43.1% vs 24.1% with and without pain; P=0.006) and spasticity treatment (32.3% vs 17.2%; P=0.020). CONCLUSION: Children with cerebral palsy frequently experience pain and also early pain, mostly articular and orthopedic. The assessment of pain should be systematic because of its high prevalence. Interventions to prevent scoliosis, hip luxation, and foot deformities and to reduce spasticity, such as the use of analgesics before joint mobilization exercises, may reduce the prevalence of this pain.

Perspectives in neonatal and childhood arterial ischemic stroke.

INTRODUCTION: Over the last decade considerable advances have been made in the identification, understanding and management of pediatric arterial ischemic stroke. Such increasing knowledge has also brought new perspectives and interrogations in the current acute and rehabilitative care of these patients. Areas covered: In developed countries, focal cerebral arteriopathy is one of the most common causes of arterial ischemic stroke in childhood and imaging features are well characterized. However, there are ongoing debates regarding its underlying mechanisms, natural evolution and proper management. The implementation of thrombolytic therapy in acute pediatric stroke has been shown to be efficient in anecdotal cases but is still limited by a number of caveats, even in large tertiary centers. Finally, neonatal stroke represents a unique circumstance of possible early intervention before the onset of any neurological disability but this appears meaningful only in a selective group of neonates. Expert commentary: While perinatal stroke, a leading cause of cerebral palsy, appears to be multifactorial, a large number of childhood ischemic stroke are probably essentially triggered by infectious factors leading to vessel wall damage. Current research is aiming at better identifying risk factors in both conditions, and to define optimal acute and preventive therapeutic strategies in order to reduce significant long-term morbidity.

[Neonatal arterial ischemic stroke: Review of the current guidelines]. / Accidents vasculaires cérébraux ischémiques artériels néonatals : synthèse des recommandations.

Neonatal arterial ischemic stroke (NAIS) is a rare event that occurs in approximately one in 5000 term or close-to-term infants. Most affected infants will present with seizures. Although a well-recognized clinical entity, many questions remain regarding diagnosis, risk factors, treatment, and follow-up modalities. In the absence of a known pathophysiological mechanism and lack of evidence-based guidelines, only supportive care is currently provided. To address these issues, a French national committee set up by the French Neonatal Society (Société française de néonatologie) and the national referral center (Centre national de référence) for arterial ischemic stroke in children drew up guidelines based on an HAS (Haute Autorité de santé [HAS]; French national authority for health) methodology. The main findings and recommendations established by the study group are: (1) among the risk factors, male sex, primiparity, caesarean section, perinatal hypoxia, and fetal/neonatal infection (mainly bacterial meningitis) seem to be the most frequent. As for guidelines, the study group recommends the following: (1) the transfer of neonates with suspected NAIS to a neonatal intensive care unit with available equipment to establish a reliable diagnosis with MRI imaging and neurophysiological monitoring, preferably by continuous video EEG; (2) acute treatment of suspected infection or other life-threatening processes should be addressed immediately by the primary medical team. Persistent seizures should be treated with a loading dose of phenobarbital 20mg/kg i.v.; (3) MRI of the brain is considered optimal for the diagnosis of NAIS. Diffusion-weighted imaging with apparent diffusion coefficient is considered the most sensitive measure for identifying infarct in the neonatal brain. The location and extent of the lesions are best assessed between 2 and 4 days after the onset of stroke; (4) routine testing for thrombophilia (AT, PC PS deficiency, FV Leiden or FII20210A) or for detecting other biological risk factors such as antiphospholipid antibodies, high FVIII, homocysteinemia, the Lp(a) test, the MTHFR thermolabile variant should not be considered in neonates with NAIS. Testing for FV Leiden can be performed only in case of a documented family history of venous thromboembolic disease. Testing neonates for the presence of antiphospholipid antibodies should be considered only in case of clinical events arguing in favor of antiphospholipid syndrome in the mother; (5) unlike childhood arterial ischemic stroke, NAIS has a low 5-year recurrence rate (approximately 1 %), except in those children with congenital heart disease or multiple genetic thrombophilia. Therefore, initiation of anticoagulation or antithrombotic agents, including heparin products, is not recommended in the newborn without identifiable risk factors; (6) the study group recommends that in case of delayed motor milestones or early handedness, multidisciplinary rehabilitation is recommended as early as possible. Newborns should have physical therapy evaluation and ongoing outpatient follow-up. Given the risk of later-onset cognitive, language, and behavioral disabilities, neuropsychological testing in preschool and at school age is highly recommended.

[Social participation after childhood craniopharyngioma]. / Morbidité et impact sur la participation sociale du craniopharyngiome de l'enfant.

Craniopharyngioma is a rare, benign central nervous system tumor, which may be a source of multiple complications, from endocrinology to vision, neurology and neurocognitive functions. This morbidity can lead to reduced participation in life activities, as described in the International Classification of Functioning, Disability, and Health. The primary objective of this study was to measure participation in life activities in a population of children and young adults affected by childhood craniopharyngioma, using the LIFE-H questionnaire (Assessment of Life Habits), validated as a social participation measurement tool in various pediatric disabilities. We also describe complications in our population and examined the potential links between tumor characteristics, complications, and participation in life activities. PATIENTS AND METHODS: This was a descriptive study, including all patients having presented childhood craniopharyngioma (before 18 years of age), followed in the Lyon region between 2007 and 2013. The main criterion was the LIFE-H results, completed by the patient or the carer. RESULTS: Of 21 patients included in the study, 14 completed the questionnaire, a mean 6.7 years after the diagnosis (SD: 3.9 years). The mean total LIFE-H score was 8.4 (SD: 1.03) for a normal score estimated at 10 in the general population. The lowest scores affected the nutrition, community life, and recreation dimensions. No patient had a normal score on all dimensions; 57% of the patients had more than three dimensions affected. The variability of the results between patients was lower for some dimensions with high means (fitness, personal care, communication, housing, mobility, responsibilities, and education) than in others (nutrition, interpersonal relationships, community life, employment, and recreation) with rather low means. All patients had an endocrinological deficit, 19% hypothalamic syndrome, 52% an impaired fulfillment feeling, 76% visual impairment, 14% neurologic impairment, and 91% neurocognitive impairment. In the entire group of patients, 57% were able to attend a normal school (of which 38% needed a personal helper), 43% had to enter a specialized school. In patients in a specialized school, the LIFE-H results were significantly lower in the nutrition, communication, housing, and recreation dimensions. Girls also had significantly better results in many dimensions than boys. DISCUSSION: Heavy comorbidity goes with childhood craniopharyngioma and affects patients' participation in life activities, which is not very low but multidimensional (more than three affected dimensions). This participation is mainly affected in social dimensions, whereas in cerebral palsy, where the LIFE-H has been tested several times, the daily activities dimensions are more affected. CONCLUSION: Patients with childhood craniopharyngioma are affected in their participation in daily activities, mainly in the social dimensions. This could be improved with systematic diagnosis of these participation impairments, with the goal of adapted multidisciplinary management.

[Vitamin D supplementation: not too much, not too little!]. / Supplémentation en vitamine D : ni trop, ni trop peu !

Vitamin D deficiency is common in the general population and even more frequent in patients with chronic diseases. The prevention of rickets with native vitamin D supplementation is one of the oldest and most effective prophylactic measures ever reported in medicine, leading to an almost complete eradication of vitamin D-deficient rickets in developed countries. We report on two children with vitamin D abnormalities: the first, 10-year-old child developed rickets without any vitamin D supplementation despite different risk factors (autism, ethnicity, nutritional problems, chronic antiepileptic therapies). In contrast, the second, 8-month-old child received double doses of native vitamin D from birth for several months and was referred for acute and symptomatic hypercalcemia. As such, vitamin D supplementation must follow specific rules: neither too much nor too little! We also discuss the emergence of "new" genetic diseases such as mutations in the 24-hydroxylase (CYP24A1) gene inducing neonatal hypercalcemia and nephrocalcinosis: we believe that before prescribing conventional vitamin D supplementation as recommended by the national guidelines, pediatricians should quickly rule out a potential genetic abnormality in phosphate/calcium metabolism (namely a history of lithiasis or hypercalcemia) that would lead to further biological investigations.

The motor function measure to study limitation of activity in children and adults with Charcot-Marie-Tooth disease.

OBJECTIVE: To study the applicability and responsiveness of the motor function measure (total score and sub-scores D1, D2 and D3) in patients with Charcot-Marie-Tooth disease. PATIENTS AND METHODS: Two hundred and thirty-three patients aged 4-86 years were included in the descriptive study. Scores and sub-scores were analyzed by age and by disease subtypes. Sensitivity to change (responsiveness) was estimated in patients having had at least two evaluations with at least six months between the first and the second. RESULTS: Motor function measure scores decrease with age, especially sub-scores D1 and D3. There were no significant differences between the scores according to type of Charcot-Marie-Tooth disease. The scores were significantly higher for ambulatory than for non-ambulatory patients. Significant responsiveness was demonstrated only in type 2 Charcot-Marie-Tooth disease. DISCUSSION/CONCLUSIONS: Our results suggest that, especially for D1 and D3 sub-scores, the motor function measure is a reliable and valid outcome measure that can be usefully applied in longitudinal follow-up. Studies of longer duration could demonstrate its responsiveness in other Charcot-Marie-Tooth disease subtypes.

[Multicentric study of medical care and practices in spinal muscular atrophy type 1 over two 10-year periods]. / Amyotrophie spinale type 1 : enquête multicentrique des pratiques de soins et d'accompagnement palliatif sur deux périodes successives de 10ans.

AIM: Questions about care practices and the role of palliative care in pediatric neurodegenerative diseases have led the Neuromuscular Committee of the French Society of Neurology to conduct a retrospective study in spinal muscular atrophy type 1, a genetic disease most often leading to death before the age of 1 year. MATERIAL AND METHODS: A retrospective multicenter study from pediatricians included in the reference centers of pediatric neuromuscular diseases was carried out on two 10-year periods (1989-1998 and 1999-2009). RESULTS: The 1989-1998 period included 12 centers with 106 patients, the 1999-2009 period 13 centers with 116 children. The mean age of onset of clinical signs was 2.1 months (range, 0-5.5 months), the median age at diagnosis was 4 months (range, 0-9 months) vs 3 months. The median age of death was 7.5 months (range, 0-24 months) vs 6 months. The care modalities included physiotherapy (90 %), motor support (61 % vs 26 % for the previous period), enteral nutrition by nasogastric tube (52 % vs 24 %), and 3.4 % of children had a gastrostomy (vs 1.8 %). At home, pharyngeal aspiration was used in 64 % (vs 41 %), oxygen therapy in 8 %, noninvasive ventilatory support in 7 %. The mean age at death was 8.1 months (range, 0-24 months) vs 7 months, the time from diagnosis to death was 4 months vs 3 months. Death occurred at home in 23 % vs 17 %, in a pediatric unit in 62 % vs 41 %. The use of analgesics and sedative drugs was reported in 60 % of cases: 40 % morphine (vs 18 %) and benzodiazepines in 48 % (vs 29 %). Respiratory support was limited mostly to oxygen by nasal tube (55 % vs 54 %), noninvasive ventilation in 9 % of the cases, and intubation and assisted mechanical ventilation (2 %). DISCUSSION AND CONCLUSION: These results confirm a change in practices and the development of palliative care in children with a French consensus of practices quite different from the standard care in North-America and closer to the thinking of English medical teams. A prospective study within the 2011 national hospital clinical research program (PHRC 2011) is beginning in order to evaluate practices and the role of families and caregivers.

Quality of life and functional outcome in early school-aged children after neonatal stroke: a prospective cohort study.

BACKGROUND: Quality of life (QoL) is recognized internationally as an efficient tool for evaluating health interventions. To our knowledge, QoL has not been specifically assessed in children after neonatal arterial ischemic stroke (AIS). AIM: To study the QoL of early school-aged children who suffered from neonatal AIS, and QoL correlation to functional outcome. METHOD: We conducted a multicenter prospective cohort study as part of a larger study in full-term newborns with symptomatic AIS. Participating families were sent anonymous QoL questionnaires (QUALIN). Functional outcome was measured using the Wee-FIM scale. Healthy controls in the same age range were recruited in public schools. Their primary caregivers filled in the QUALIN questionnaires anonymously. We used Student's t-test and a rank test to compare patients and controls' QoL and functional outcomes. RESULTS: 84 children with neonatal AIS were included. The control group was composed of 74 children, of which ten were later excluded due to chronic conditions. Mean ages and QUALIN median scores did not differ between patients and controls. Median Wee-FIM scores were lower in hemiplegic children than in non-hemiplegic ones (p < 0.001). QoL scores did not seem correlated to functional outcome. INTERPRETATION: Those results could support the presence of a "disability paradox" in young children following neonatal AIS.

Development and validation of a motor function classification in patients with neuromuscular disease: the NM-score.

OBJECTIVE: To develop a classification for neuromuscular disease patients in each of the three motor function domains (D1: standing and transfers; D2: axial and proximal function; D3: distal function). MATERIALS AND METHODS: A draft classification was developed by a study group and then improved by qualitative validation studies (according to the Delphi method) and quantitative validation studies (content validity, criterion validity and inter-rater reliability). A total of 448 patients with genetic neuromuscular diseases participated in the studies. RESULTS: On average, it took 6.3minutes to rate a patient. The inter-rater agreement was good when the classification was based on patient observation or an interview with the patient (Cohen's kappa=0.770, 0.690 and 0.642 for NM-Score D1, D2 and D3 domains, respectively). Stronger correlations (according to Spearman's coefficient) with the respective "gold standard" classifications were found for NM-Score D1 (0.86 vs. the Vignos Scale and -0.88 vs. the Motor Function Measure [MFM]-D1) and NM-Score D2 (-0.7 vs. the Brooke Scale and 0.64 vs. MFM D2) than for NM-Score D3 (0.49 vs. the Brooke scale and -0.49 vs. MFM D3). DISCUSSION/CONCLUSIONS: The NM-Score is a reliable, reproducible outcome measure with value in clinical practice and in clinical research for the description of patients and the constitution of uniform patient groups (in terms of motor function).

Rehabilitation of 190 non-ambulatory children with cerebral palsy in structures of care or in liberal sector.

AIMS: To describe the rehabilitation of non-ambulatory children with cerebral palsy and to explore adjustability on their individual needs. MATERIAL AND METHOD: Data described are extracted from an on-going national cohort study, following during 10years 385 children with cerebral palsy, aged from 4 to 10, Gross Motor Function Classification System IV and V. We analysed data from the first 190 patients (mean age 6years 10months (SD 2.0), 111 boys), focusing on physiotherapy, ergotherapy, psychomotility and speech therapy in medico-social and liberal sectors. RESULTS: In medico-social sector, duration of paramedical care is significantly more important than in liberal sector (structure of care: median=4.25h/week, liberal sector: median=2.00h/week) (P<0.0001). More than 4 different types of care per week are given in medico-social sector, while in liberal sector children benefit from only 2 different types of care a week. In investigators opinion, rehabilitation in structures of care is 71.65% adapted as opposed to 18.75% in the liberal sector (P<0.001). Children level V have less time of rehabilitation than the others (P=0.0424). INTERPRETATION: Rehabilitation of children with cerebral palsy who are not able to walk, with an objective to improve quality of life, is truly multidisciplinary and suitable in medico-social sector.

[Phenotypic heterogeneity and phenotype-genotype correlations in dystrophinopathies: Contribution of genetic and clinical databases]. / Variabilité phénotypique et corrélations génotype-phénotype des dystrophinopathies : contribution des banques de données.

The objective of this work was to study the natural history of dystrophinopathies and the genotype-phenotype correlations made possible by the development of the clinical part of the French DMD database. The collection of 70,000 clinical data for 600 patients with an average longitudinal follow-up of 12years enabled clarification of the natural history of Duchenne and Becker muscular dystrophies and clinical presentations in symptomatic females. We were able to specify the phenotypic heterogeneity of motor, orthopedic and respiratory involvements (severe, standard and intermediary form), of the cardiac disorder (severe, standard or absent cardiomyopathy, absence of correlation between motor and cardiac involvements), and of brain function (mental deficiency in the patients with Becker muscular dystrophy, psychopathological disorders in dystrophinopathies). Phenotypic variability did not correlate with a specific mutational spectrum. We propose a model of phenotypic analysis based on the presence or not of muscular and cardiac involvements (described by age at onset and rate of progression) and brain involvement (described by the type and the severity of the cognitive impairment and of the psychological disorders). The methodology developed for the DMD gene can be generalized and used for other databases dedicated to genetic diseases. Application of this model of phenotypic analysis for each patient and further development of the database should contribute substantially to clinical research providing useful tools for future clinical trials.

Tolerance and effectiveness on pain control of Pamidronate® intravenous infusions in children with neuromuscular disorders.

UNLABELLED: Osteoporosis is a common complication in children with motor impairments. They have a higher risk of fractures (20% during their lifetime) mostly at femoral level. Furthermore, these children have pain yet no clear relation has been established between osteoporosis and pain. The efficacy of bisphosphonates has been validated in adults and for children with osteogenesis imperfecta (OI). However, its use in children with motor impairments has not yet been validated. PATIENTS AND METHODS: Retrospective study on the medical charts of children presenting neurological diseases and motor impairments associated to secondary symptomatic osteoporosis. These children underwent treatment with Pamidronate(®) intravenous infusions (I.V.) in Lyon and Valence between 2002 and 2008. Data were collected on pain control, incidence and frequency of fractures and bone mass density (BMD). Data on adverse events were also collected to evaluate treatment's tolerance. RESULTS: Twelve children's charts were studied for a total of 50 Pamidronate(®) I.V. infusions. Regarding treatment's efficacy, we observed a clear decrease and even total relief of the pain with improvement reported after 98% of perfusions. Regarding BMD, there was a real improvement after the treatment (e.g., lumbar BMD measures, -46.5% before treatment and -27% after treatment). The adverse events, flu-like syndrome, muscle pain and asymptomatic hypocalcemia, were minor and quickly reversible. CONCLUSION: It seems quite essential to screen for osteoporosis-related pain in these children and treat them quickly to avoid a negative impact on their quality of life. Treatment with I.V. bisphosphonates has shown its relevance, yet practical modalities still need to be defined. It would be interesting but quite difficult to implement, in light of the positive effect of this study, a prospective, randomized, controlled, double-blind vs. placebo study on a large enough sample of patients.