A Multidisciplinary Evaluation of Patients with DMD in An Italian Tertiary Care Center.

With more widespread prolonged survival, Duchenne muscular dystrophy patients progressively experience multisystem complications. We retrospectively reviewed the charts of 132 Duchenne patients (112 alive/20 dead, age 3.5÷32.3 years) with the aims: 1) to provide a comprehensive description of the clinical status considering different aspects of the disease; 2) to propose a new scoring tool able to consider and pool together heterogeneous different functional. Five functions were analyzed: cardiac, respiratory, nutritional, ambulation and scoliosis. For each function, different items were considered and classified according to clinical severity (as indicated by international guidelines) and an incremental scoring was assigned. In addition, a global score incorporating all functions was defined. The scoring system confirmed that despite the significant protective role of steroids, all functions deteriorated with age. The severity of the global score became significantly higher since the age of 13 years. The severity of cardiac, respiratory and nutritional dysfunction was higher since 18 years. Deceased patients were characterized by significantly worse cardiac function, absence of steroid therapy and later use of respiratory assistive devices. The index proposed in this pilot study is a promising tool able to aggregate and correlate heterogeneous functions. It could become either an individual prognostic indicator of decline or a global score to evaluate changes in clinical trials therefore allowing multicenter studies, optimizing the management of both the primary and the secondary complications of the disease and understanding their relative impact.

Abdominal volume contribution to tidal volume as an early indicator of respiratory impairment in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is characterised by progressive loss of muscular strength that leads to an increasingly restrictive pulmonary syndrome. However, it is still not clear whether this determines alterations in the breathing pattern. We studied: 66 DMD patients at different stages of the disease (mean+/- sem age 12.6+/-0.6 yrs, range 5-22 yrs of age), subdivided into four groups according to age; and 21 age-matched healthy male controls. Spirometry, lung volumes and nocturnal oxygen saturation were measured in all DMD patients. Ventilatory pattern and chest wall volume variations were assessed by optoelectronic plethysmography during spontaneous breathing both in seated and supine positions. Whilst in a seated position, no significant differences were found between patients and controls or between different age groups. In the supine position, the average contribution of abdominal volume change (DeltaV(AB)) to tidal volume progressively decreased with age (p<0.001). The patients who showed nocturnal hypoxaemia showed significantly lower Delta V(AB). In conclusion, chest wall motion during spontaneous breathing in awake conditions and in supine position is an important indicator of the degree of respiratory muscle impairment in DMD. DeltaV(AB) is not only an important marker of the progression of the disease but is also an early indicator of nocturnal hypoxaemia.

Point mutations and a large intragenic deletion in SPG11 in complicated spastic paraplegia without thin corpus callosum.

BACKGROUND: Hereditary spastic paraplegia (HSP) with thin corpus callosum (HSP-TCC) is a frequent subtype of complicated HSP clinically characterised by slowly progressive spastic paraparesis with cognitive impairment and thin corpus callosum (TCC). SPG11, the gene associated with the major locus involved, encodes spatacsin, a protein of unknown function. METHODS: Different types of mutations were identified in patients with the complex form of HSP (cHSP) including TCC. We screened a series of 45 index patients with different types of cHSP with (n = 10) and without (n = 35) TCC. RESULTS: Ten mutations, of which five are novel, were detected in seven patients. Of importance, three out of seven mutated patients present with cHSP without TCC. Among the novel mutations identified, we characterised a large intragenic rearrangement deleting 2.6 kb of the SPG11 gene. The rearrangement is due to non-allelic homologous recombination between Alu sequences flanking the breakpoints. CONCLUSIONS: These findings expand the mutation spectrum of SPG11 and suggest that SPG11 mutations may occur more frequently in familial than sporadic forms of cHSP without TCC. This helps to define further clinical and molecular criteria for a correct diagnosis of the SPG11 related form of cHSP. In addition, the intragenic deletion detected here, and the mechanism involved, both provide clues to address the issue of SPG11 missing mutant alleles previously reported.

Evaluation of narrative abilities in patients suffering from Duchenne Muscular Dystrophy.

The present work investigated cognitive, linguistic and narrative abilities in a group of children suffering from Duchenne Muscular Dystrophy, an allelic X-linked recessive disorder caused by mutations in the gene encoding dystrophin. The patients showed mildly reduced IQ with lower Verbal than Performance Intelligence Quotient and were mildly affected in visual attention and short-term memory processing. At the linguistic assessment, neither receptive (word comprehension) nor expressive (naming tasks and fluency) lexical abilities were impaired. However, their narratives were qualitatively inferior with respect to those produced by a group of typically developing children. Their speech samples were characterized by the presence of fewer verbs and complete sentences. It is suggested that the reduced production of complete sentences is due to a selective problem in verb argument structure generation. Since the lack of dystrophin is assumed to produce effects on the maturation of the cerebellum, whose involvement has been recently suggested in verb and syntactic processing, these findings may lend indirect support to the hypothesis of a cerebellar-cortical circuit specialized in verb and sentence production.

Quantitative analysis of gait pattern and energy consumption in children with cerebral palsy.

The measurement of oxygen consumption during walking allows the quantification of gait expenditure, mainly in patients with musculoskeletal disabilities, as in cerebral palsy (CP). In this study, first, an experimental set up for the acquisition of energy consumption during gait analysis (GA) was proposed; secondly, some parameters of energy expenditure were analyzed to characterize pathological gait from an energetic point of view. Twenty CP children and 20 healthy children were evaluated during two consecutive sessions (session 1: only GA was performed; session 2: K4b2 was used during GA acquisition). The results revealed that the experimental set up was comfortable for all subjects. The absence of any differences in GA values between the two sessions showed that the use of a device for energy acquisition does not modify gait pattern. Energy expenditure index and oxygen cost presented abnormal values in comparison with normality and they were significant to quantify energy expenditure in CP children.

Language disturbances in a group of participants suffering from Duchenne muscular dystrophy: a pilot study.

Results from several studies suggest that the process of language acquisition may be altered in patients suffering from Duchenne Muscular Dystrophy. In this study, a group of 8 male participants with Duchenne Muscular Dystrophy (M age = 16 yr., SD = 4.7) underwent an extensive neuropsychological and language assessment. They also performed a discourse production task. Results showed mild mental retardation associated with a specific deficit in Verbal rather than Performance IQ. At the linguistic assessment, 7 of 8 participants showed moderate to severe difficulties on oral language processing with particularly impaired morphosyntactic competence.

Quantification of energy expenditure during gait in children affected by cerebral palsy.

AIM: Children affected by cerebral palsy (CP) are generally characterised by some movement limitations and abnormalities that compromised gait pattern. These disabilities during deambulation may lead to excessive energy cost and so to a compromised energy efficiency. METHODS: In this study oxygen expenditure was evaluated during walking in 20 children affected by CP and in 20 healthy children, using Cosmed K4b2 (Cosmed, Italy). From obtained data about energy consumption, some parameters (heart rate, energy expenditure index, oxygen consumption, oxygen cost) were extracted, first in order to quantify energy cost during gait in pathological and healthy subjects and then to underline differences between the 2 groups of children. RESULTS: In particular, the results obtained revealed that heart rate (bpm) and oxygen consumption (mL/kg/min) mean values didn't differ significantly between normal subjects and those with CP; instead, energy expenditure index (b/m) and oxygen cost (mL/kg/m) presented higher mean values rather than control group at a statistically level and so they revealed to be significant parameters, in order characterized energy expenditure in children affected by CP. CONCLUSIONS: This inefficiency characteristic of CP deambulation is probably directly connected to the presence of simultaneous contraction of agonist and antagonist muscle in these patients.

Quantitative Evaluation of Performance during Robot-assisted Treatment.

INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Methodologies, Models and Algorithms for Patients Rehabilitation". OBJECTIVES: The great potential of robots in extracting quantitative and meaningful data is not always exploited in clinical practice. The aim of the present work is to describe a simple parameter to assess the performance of subjects during upper limb robotic training exploiting data automatically recorded by the robot, with no additional effort for patients and clinicians. METHODS: Fourteen children affected by cerebral palsy (CP) performed a training with Armeo®Spring. Each session was evaluated with P, a simple parameter that depends on the overall performance recorded, and median and interquartile values were computed to perform a group analysis. RESULTS: Median (interquartile) values of P significantly increased from 0.27 (0.21) at T0 to 0.55 (0.27) at T1 . This improvement was functionally validated by a significant increase of the Melbourne Assessment of Unilateral Upper Limb Function. CONCLUSIONS: The parameter described here was able to show variations in performance over time and enabled a quantitative evaluation of motion abilities in a way that is reliable with respect to a well-known clinical scale.

Whole-Brain DTI Assessment of White Matter Damage in Children with Bilateral Cerebral Palsy: Evidence of Involvement beyond the Primary Target of the Anoxic Insult.

BACKGROUND AND PURPOSE: Cerebral palsy is frequently associated with both motor and nonmotor symptoms. DTI can characterize the damage at the level of motor tracts but provides less consistent results in nonmotor areas. We used a standardized pipeline of analysis to describe and quantify the pattern of DTI white matter abnormalities of the whole brain in a group of children with chronic bilateral cerebral palsy and periventricular leukomalacia. We also explored potential correlations between DTI and clinical scale metrics. MATERIALS AND METHODS: Twenty-five patients (mean age, 11.8 years) and 25 healthy children (mean age, 11.8 years) were studied at 3T with a 2-mm isotropic DTI sequence. Differences between patients and controls were assessed both voxelwise and in ROIs obtained from an existing DTI atlas. Clinical metrics included the Gross Motor Function Classification System, the Manual Ability Classification System, and intelligence quotient. RESULTS: The voxel-level and ROI-level analyses demonstrated highly significant (P < .001) modifications of DTI measurements in patients at several levels: cerebellar peduncles, corticospinal tracts and posterior thalamic radiations, posterior corpus callosum, external capsule, anterior thalamic radiation, superior longitudinal fasciculi and corona radiata, optic nerves, and chiasm. The reduction of fractional anisotropy values in significant tracts was between 8% and 30%. Statistically significant correlations were found between motor impairment and fractional anisotropy in corticospinal tracts and commissural and associative tracts of the supratentorial brain. CONCLUSIONS: We demonstrated the involvement of several motor and nonmotor areas in the chronic damage associated with periventricular leukomalacia and showed new correlations between motor skills and DTI metrics.

Gait rehabilitation with a high tech platform based on virtual reality conveys improvements in walking ability of children suffering from acquired brain injury.

The Gait Real-time Analysis Interactive Lab (GRAIL) is an instrumented multi-sensor platform based on immersive virtual reality for gait training and rehabilitation. Few studies have been included GRAIL to evaluate gait patterns in normal and disabled people and to improve gait in adults, while at our knowledge no evidence on its use for the rehabilitation of children is available. In this study, 4 children suffering from acquired brain injury (ABI) underwent a 5 session treatment with GRAIL, to improve walking and balance ability in engaging VR environments. The first and the last sessions were partially dedicated to gait evaluation. Results are promising: improvements were recorded at the ankle level, selectively at the affected side, and at the pelvic level, while small changes were measured at the hip and knee joints, which were already comparable to healthy subjects. All these changes also conveyed advances in the symmetry of the walking pattern. In the next future, a longer intervention will be proposed and more children will be enrolled to strongly prove the effectiveness of GRAIL in the rehabilitation of children with ABI.

An ecological evaluation of the metabolic benefits due to robot-assisted gait training.

Cerebral palsy (CP), one of the most common neurological disorders in childhood, features affected individual's motor skills and muscle actions. This results in elevated heart rate and rate of oxygen uptake during sub-maximal exercise, thus indicating a mean energy expenditure higher than healthy subjects. Rehabilitation, currently involving also robot-based devices, may have an impact also on these aspects. In this study, an ecological setting has been proposed to evaluate the energy expenditure of 4 children with CP before and after a robot-assisted gait training. Even if the small sample size makes it difficult to give general indications, results presented here are promising. Indeed, children showed an increasing trend of the energy expenditure per minute and a decreasing trend of the energy expenditure per step, in accordance to the control group. These data suggest a metabolic benefit of the treatment that may increase the locomotion efficiency of disabled children.

Loss of Dp140 dystrophin isoform and intellectual impairment in Duchenne dystrophy.

BACKGROUND: Mental retardation is a clinical feature of Duchenne dystrophy (DD) and affects about one-third of patients. No clear association has been found between DNA mutations, protein expression, and IQ scores, although distal deletions in the dystrophin gene have been reported in association with intellectual impairment. A role for the brain distal dystrophin isoform Dp140 was suggested. OBJECTIVE: To explore the possible association between cognitive impairment and DNA macrodeletions in the distal part of the gene, including Dp140 gene region. METHODS: Sixty-six patients with DD received general intelligence assessment by Wechsler Intelligence Scales measuring full, verbal, and performance IQ. PCR analysis was performed to detect deletions in the dystrophin gene, and the Dp140 regulatory region was analyzed in a subgroup of 12 patients. Statistical analysis was performed by nonparametric Wilcoxon rank signed and rank sum tests. RESULTS: Comparison of neuropsychological and genetic data revealed an association between distal macrodeletions and cognitive impairment (p < 0.001). Comparing deletions involving the Dp140 gene region with deletions presumably not altering Dp140 expression resulted in even greater significance. CONCLUSIONS: These data suggest that in DD, distal dystrophin deletions are associated with intellectual impairment. This study highlights a possible role for the brain distal isoform Dp140 in normal cognitive development.

Focal cognitive impairment in mitochondrial encephalomyopathies: a neuropsychological and neuroimaging study.

Mitochondrial encephalomyopathies (ME) are a multisystemic group of diseases characterized by a wide range of biochemical and genetic mitochondrial defects with a variable mode of inheritance. We studied the neuropsychological profile, magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) data in a group of ME patients in order to look for common or specific cognitive defects and a possible correlation with related brain areas. Three main cognitive areas were assessed: general intelligence, memory functions and visuo-perceptual skills. Our sample included 16 ME patients (nine males, seven females) aged 25-68 years (mean age 45.2, SD 13.0). No sign of mental deterioration was found in the group of elderly subjects. Despite subjects showing no global cognitive impairment they scored lower in nonverbal versus verbal tasks. Visuo-spatial skills and short-term memory were selectively impaired. There was no correlation between neuropsychological results and age, illness duration, age of onset, clinical phenotypes, genetic mitochondrial alterations and pharmacological therapy. The most frequent SPECT pattern observed was the hypoperfusion of temporal lobes, with a direct localization in the temporal cortex and with prevalent mesial involvement. The neuropsychological profile and SPECT imaging revealed similarities with focal defects.

Low abdominal contribution to breathing as daytime predictor of nocturnal desaturation in adolescents and young adults with Duchenne Muscular Dystrophy.

In the respiratory management of DMD patients it is still under debate what parameter should indicate the correct timing for institution of nocturnal non-invasive ventilation (NIV), in addition to forced vital capacity, which is generally considered as a prognostic marker of disease progression. The aim of this study was to determine if volume variations of rib cage and abdominal compartments measured by Opto-Electronic Plethysmography can be helpful to distinguish between those patients who are in the early stages of nocturnal oxygen desaturation development and those who do not yet. Pulmonary function, abdominal contribution to tidal volume and to inspiratory capacity (%Abd IC) and a set of breathing pattern indexes were assessed in 40 DMD patients older than 14 years and not yet under nocturnal NIV. ROC analysis revealed that among all the considered parameters, %Abd IC in supine position was the best discriminator between DeSat (at least 10% of the night time with SpO(2) < 95%) and NonDeSat patients, providing an area under the curve with 95%CI equal to 0.752. In conclusion, in adolescents and adults DMD patients who present either no sign or only mild nocturnal oxygen desaturation, a reduced abdominal contribution to inspiratory capacity is a marker of the onset of diaphragm weakness and should be considered to identify the correct timing for the institution of nocturnal NIV.

Cognitive ability assessment by brain-computer interface validation of a new assessment method for cognitive abilities.

Brain-Computer Interfaces (BCIs) are systems which can provide communication and environmental control to people with severe neuromuscular diseases. The current study proposes a new BCI-based method for psychometric assessment when traditional or computerized testing cannot be used owing to the subject's output impairment. This administration protocol was based on, and validated against, a widely used clinical test (Raven Colored Progressive Matrix) in order to verify whether BCI affects the brain in terms of cognitive resource with a misstatement result. The operating protocol was structured into two phases: phase 1 was aimed at configuring the BCI system on the subject's features and train him/her to use it; during phase 2 the BCI system was reconfigured and the test performed. A step-by-step checking procedure was adopted to verify progressive inclusion/exclusion criteria and the underpinning variables. The protocol was validated on 19 healthy subjects and the BCI-based administration was compared with a paper-based administration. The results obtained by both methods were correlated as known for traditional assessment of a similarly culture free and reasoning based test. Although our findings need to be validated on pathological participants, in our healthy population the BCI-based administration did not affect performance and added a further control of the response due to the several variables included and analyzed by the computerized task.

Respiratory pattern in an adult population of dystrophic patients.

We studied respiratory function and Chest Wall kinematics in a large population of adult patients affected by slow course muscular dystrophies such as Limb-Girdle Muscular Dystrophy (LGMD, n=38), Becker Muscular Dystrophy (BMD, n=20) and Facio-Scapulo Humeral Dystrophy (FSHD, n=30), through standard spirometry and through the Optoelectronic Plethysmography, to measure the thoraco-abdominal motion during Quiet Breathing and Slow Vital Capacity maneuvers. Within the restrictive pulmonary syndrome characterizing LGMD and FSHD, several different thoraco-abdominal patterns compared to those of healthy subjects were present in the more advanced stages of the disease. These differences were present in the seated position, during the execution of a maximal maneuver such as Slow Vital Capacity. A global respiratory (both inspiratory and expiratory) muscle involvement was more pronounced in the LGMD and FSHD than in the BMD patients, and a significant reduction of abdominal contribution in wheelchair bound patients was observed. In conclusion, OEP technique is able to reveal mild initial modifications in the respiratory muscles in FSHD and LGMD patients, which could be helpful for functional and new therapeutic strategy evaluation.

The perception of involved professionals towards research feasibility and usefulness: lessons from the Multi-Site Trial on Efficacy of Constraint Induced Movement Therapy in Children with Hemiplegia.

BACKGROUND: In the last decades, the world of rehabilitation has been more and more calling for clear evidence to support intervention and numerous research programs have been developed. At stake, relatively little research on opinions and attitude of rehabilitation personnel involved in research conducted in real clinical settings has been carried out. AIM: To explore the opinion of professionals involved in a national clinical trial on research. DESIGN: Multicentre cross-sectional study. SETTING: 19 rehabilitation centres/services (4 research institutes, 15 local rehabilitation services). POPULATION: All professional participating to a multi-centre clinical trial on the effects of Constraint Induced Movement Therapy on children with hemiplegic cerebral palsy. METHODS: A 15-questions questionnaire inquiring feasibility, usefulness, products, costs, judgement and perceptions about clinical research in rehabilitation was administered. RESULTS: Among those working in one of the 19 rehabilitation centres part of the multicentric study, 76 professionals were asked to fill in the questionnaire. 68 professionals answered (89.4% of response rate). More than 75% of the sample thinks that its rehabilitation centre is suited to develop clinical research. Research results useful for the development of their daily activities (new tools for the assessment of children, to demonstrate the efficacy of a new treatment option and to learn a new way of working, and to strengthen the ties within the working team). Research is costly in terms of personal time and effort, but it can modify the rehabilitation praxis (assessment tools, the relationship with colleagues/patients). 98% of the interviewees declared the willingness to participate to other research projects. CONCLUSION AND CLINICAL REHABILITATION IMPACT: This survey highlights the importance of conducting research in local rehabilitation services, not only in terms of generation of new evidences, but also in terms of building networks, sharing experiences and knowledge, connecting with centers of excellence and providing a specific training for research conduction.

Effects of gender and posture on thoraco-abdominal kinematics during quiet breathing in healthy adults.

To investigate the effects of posture and gender on thoraco-abdominal motion and breathing pattern, 34 healthy men and women were studied by Opto-Electronic Plethysmography during quiet breathing in five different postures from seated (with and without back support) to supine position. Chest wall kinematics and breathing pattern were significantly influenced by position and gender. The progressively increased inclination of the trunk determined a progressive reduction of rib cage displacement, tidal volume, and minute ventilation and a progressive increase of abdominal contribution to tidal volume. Female subjects were characterized by smaller dimensions of the rib cage compartment and during quiet breathing by lower tidal volume, minute ventilation and abdominal contribution to tidal volume than males. The effect of posture on abdominal kinematics was significant only in women. The presence of a back support in seated position determined differences in breathing pattern. In conclusion, posture and gender have a strong influence on breathing and on chest wall kinematics.

Relationship between kinematic knee deviations and femoral anteversion in children with cerebral palsy.

The aim of the study was to determine the possible correlation between the degree of femoral anteversion and the quantitative data obtained by 3D Gait Analysis (GA) and then to investigate the relationship between femoral anteversion and the reduced knee flexion during swing phase in children with Cerebral Palsy. Twenty-seven diplegic children with severe rectus femoris spasticity and 20 healthy children (CG) were considered. Clinical evaluation of femoral anteversion, Duncan Ely test and Gait Analysis were performed in all patients. From Gait Analysis data some indices were identified and calculated and statistical analysis performed. Clinical evaluations made the distinction between patients with excessive femoral anteversion (Group 1) and those with normal value (Group 2). Both groups showed a blunt maximum of knee flexion in swing (KMSw), representative of rectus femoris spasticity, but two different gait strategies were found for the timing of KMSw. Group 1 exhibited a reduced KMSw value with its timing close to normal value and an excessive hip internal rotation (Mean Hip Rotation index), correlated to high femoral anteversion; Group 2 presented a limited KMSw and a significant delay of its timing, with Mean Hip Rotation index close to Control Group. No differences were found for other indices. The results demonstrated that the presence of reduced KMSw only can be directly connected to excessive femoral anteversion; the coexistence of reduced KMSw and its delayed timing reveals that the rectus femoris spasticity may be due to rectus spasticity added to an incorrect motor selective control. The results are clinically crucial for treatment strategies (derotative femoral osteotomy vs rectus transfer).