Alessandra Graziano

Long Term Natural History Data in Ambulant Boys with Duchenne Muscular Dystrophy: 36-Month Changes

The 6 minute walk test has been recently chosen as the primary outcome measure in international multicenter clinical trials in Duchenne muscular dystrophy ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment, age and 6 minute walk test values at baseline. Ninety-six patients from 11 centers were assessed at baseline and 12, 24 and 36 months after baseline using the 6 minute walk test and the North Star Ambulatory Assessment. Three boys (3%) lost the ability to perform the 6 minute walk test within 12 months, another 13 between 12 and 24 months (14%) and 11 between 24 and 36 months (12%). The 6 minute walk test showed an average overall decline of −15.8 (SD 77.3) m at 12 months, of −58.9 (SD 125.7) m at 24 months and −104.22 (SD 146.2) m at 36 months. The changes were significantly different in the two baseline age groups and according to the baseline 6 minute walk test values (below and above 350 m) (p<0.001). The changes were also significantly different according to steroid treatment (p = 0.01). Similar findings were found for the North Star Ambulatory Assessment. These are the first 36 month longitudinal data using the 6 minute walk test and North Star Ambulatory Assessment in Duchenne muscular dystrophy. Our findings will help not only to have a better idea of the progression of the disorder but also provide reference data that can be used to compare with the results of the long term extension studies that are becoming available.

Early neurodevelopmental assessment in Duchenne muscular dystrophy

The aim of this study was to assess neurodevelopmental profile in young boys affected by Duchenne muscular dystrophy and to establish the correlation between neurodevelopmental findings, and the type and site of mutations. A structured neurodevelopmental assessment (Griffiths Scale of Mental Development) was performed in 81 DMD boys before the age of four years (range: 7-47 months). The mean total DQ was 87 (SD 15.3). Borderline DQ (between 70 and 84) was found in 32% and DQ below 70 in 12.3% of the patients. Children with mutations upstream or in exon 44 had higher DQ than those with mutations downstream exon 44 which are associated with involvement of dystrophin isoforms expressed at high levels in brain. The difference was significant for total and individual subscale DQ with the exception of the locomotor subscale. Items, such as ability to run fast, or getting up from the floor consistently failed in all children, irrespective of the age or of the site of mutation. Our results help to understand the possible different mechanisms underlying the various aspects of neurodevelopmental delay, suggesting that the involvement of brain dystrophin isoforms may cause a delay in the maturation of coordination and dexterity.

Functional hemispherectomy in children with epilepsy and CSWS due to unilateral early brain injury including thalamus: sudden recovery of CSWS

PURPOSE To try to prove in patients with refractory symptomatic epilepsy due to early brain injury involving thalamus and complicated by CSWS the effects of the isolation of the injured hemisphere, performed with functional hemisperectomy, on epilepsy, namely on CSWS. METHODS Full clinical follow-up before and after surgery of two cases with CSWS onset at four years in whom functional hemispherecomy was performed with resection of inter-hemispheric connections. RESULTS An immediate effectiveness of the surgical treatment was observed on both epileptic evolution (no more seizures) and EEG abnormalities. In particular, CSWS completely disappeared, together with a concurrent progressive improving of the cognitive and behavioural disorders. DISCUSSION The isolation of the injured hemisphere through the section of inter-hemispheric cortico-cortical connections could prevent the contralateral diffusion of discharges coming from the injured cortex and cortico-thalamic network, favouring a normal function of thalamo-cortico-thalamic circuitries in the healthy hemisphere. That could explain the disappearance of CSWS after surgery in our patients and the consequent improvement of cognitive abilities and behaviour.

Surgery of children with frontal lobe lesional epilepsy: neuropsychological study

AIM OF THE STUDY was to provide new data about the evolution of neuropsychological findings in patients with lesional frontal lobe epilepsy (FLE) operated on with lesion excision. PATIENTS AND METHODS Twelve patients with lesional FLE underwent full clinical examination including neurological, neuropsychological and developmental assessments, high-resolution magnetic resonance imaging (MRI), ictal and interictal prolonged EEG monitoring and evaluation of seizure semeiology before and after surgery. The mean follow-up duration was 2 years and 10 months (range=14 months-7 years). Another group of lesional temporal lobe epilepsy, matched for the age at surgery and side of surgery, was likewise studied in order to compare neuropsychological patterns and to try to find out specific features in frontal lobe epilepsy evolution. RESULTS All patients resulted seizure free at outcome except one belonging to Engels class II. Before surgery general intelligence was similar in FLE as well as in TLE group. Executive functions and motor coordination were frequently affected in FLE whereas patients with TLE often presented with deficits in naming, visual memory and visuo-spatial attention. After surgery there was a frequent decline of IQ in FLE group together with a slight deterioration, especially of executive functions in some patients. An improvement of behaviour was often observed in both groups. CONCLUSIONS As already reported in literature, neuropsychological pre-surgical data confirms the involvement of attention and executive functions in lesional FLE. No significant neuropsychological improvement was produced by surgery that determined in some cases a slight decline of general intelligence and specific frontal abilities. Yet, generally behaviour improved and seizures were controlled.

Unaffected motor cortex remodeling after hemispherectomy in an epileptic cerebral palsy patient. A TMS and fMRI study.

PURPOSE Here we describe pre- and post-operative neurophysiological and functional magnetic resonance imaging (fMRI) findings in a young epileptic girl with right hemiplegic cerebral palsy. Our findings demonstrate the feasibility of transcranial magnetic stimulation (TMS) and fMRI for predicting a post-surgical outcome and for evaluating functional cortical reorganization. METHODS We used TMS and fMRI to evaluate the excitability of the human motor cortex and cortical map representation before and after functional hemispherectomy. TMS was performed using single- and paired-pulse stimulation protocol. Cortical silent periods (CSPs), short interval intra-cortical inhibition (SICI), volume, area and center of gravity (CoG) of cortical map representation were studied before and after surgery. fMRI was done using the blood oxygenation level dependent (BOLD) technique with block-designed protocols. RESULTS After surgery the patient showed an improvement of her clinical status and TMS and fMRI demonstrated a reshaping of cortical representation of motor cortex and a significant reduction of cortical silent periods. DISCUSSION Before surgery, the combination of a clinical, neurophysiological and neuro-radiological approach may be predictable of the neurological outcome in epileptic patients. Moreover, the patient we describe provides new pieces of information in the mechanisms of plasticity underlying motor recovery after epilepsy surgery.

Suitability of North Star Ambulatory Assessment in young boys with Duchenne muscular dystrophy

The aim of this study was to establish the suitability of the North Star Ambulatory Assessment for use in young boys with Duchenne muscular dystrophy. We studied 147 typically developing and 144 boys affected by Duchenne muscular dystrophy between the ages of 3 and 5 years. More than 85% of the typically developing boys by the age of 4 years had full scores on all the items with total scores ≥33/34. Before the age of 4 years more than 15% of the typically developing boys did not achieve full scores on all the items. Some items, such as standing on one leg, showed significant improvement with age. In contrast, other activities were rarely achieved even in the older boys. Even if there was a progressive increase in scores with age, both total and individual item scores in Duchenne were still far from those obtained in the typically developing children of the same age. Our findings suggest that the North Star Ambulatory Assessment can be reliably used at least from the age of 4 years. Longitudinal natural history data studies are needed to assess possible changes over time and the possible effect of early steroids.

Prevalence of congenital muscular dystrophy in Italy: a population study

Objective: We provide a nationwide population study of patients with congenital muscular dystrophy in Italy. Methods: Cases were ascertained from the databases in all the tertiary referral centers for pediatric neuromuscular disorders and from all the genetic diagnostic centers in which diagnostic tests for these forms are performed. Results: The study includes 336 patients with a point prevalence of 0.563 per 100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was subdivided into diagnostic categories based on the most recent classifications on congenital muscular dystrophies. The most common forms were those with α-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin α2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively). Conclusions: Our study provides for the first time comprehensive epidemiologic information and point prevalence figures for each of the major diagnostic categories on a large cohort of congenital muscular dystrophies. The study also reflects the diagnostic progress in this field with an accurate classification of the cases according to the most recent gene discoveries.

The 6 Minute Walk Test and Performance of Upper Limb in Ambulant Duchenne Muscular Dystrophy Boys

The Performance of Upper Limb (PUL) test was specifically developed for the assessment of upper limbs in Duchenne muscular dystrophy (DMD). The first published data have shown that early signs of involvement can also be found in ambulant DMD boys. The aim of this longitudinal Italian multicentric study was to evaluate the correlation between the 6 Minute Walk Test (6MWT) and the PUL in ambulant DMD boys. Both 6MWT and PUL were administered to 164 ambulant DMD boys of age between 5.0 and 16.17 years (mean 8.82). The 6 minute walk distance (6MWD) ranged between 118 and 557 (mean: 376.38, SD: 90.59). The PUL total scores ranged between 52 and 74 (mean: 70.74, SD: 4.66). The correlation between the two measures was 0.499. The scores on the PUL largely reflect the overall impairment observed on the 6MWT but the correlation was not linear. The use of the PUL appeared to be less relevant in the very strong patients with 6MWD above 400 meters, who, with few exceptions had near full scores. In patients with lower 6MWD the severity of upper limb involvement was more variable and could not always be predicted by the 6MWD value or by the use of steroids. Our results confirm that upper limb involvement can already be found in DMD boys even in the ambulant phase.

Perceptual-motor abilities in pre-school preterm children

BACKGROUND Several studies report a high percentage of premature infants presenting perceptual motor difficulties at school age. The new version of the Movement Assessment Battery for Children allows the assessment of perceptual-motor abilities in children from the age of 3years. AIMS To evaluate early perceptual-motor abilities in prematurely born children below the age of 4years. STUDY DESIGN The Movement Assessment Battery for Children 2nd edition was administered to 105 low-risk prematurely born children (<32weeks gestation) and in a control group of 105 term-born children matched for age and sex. All children were assessed between the age of 3years and 3years-11months. RESULTS 63 children (60%) had total scores above the 15th percentile, 15 (14.3%) had scores between the 5th and the 15th percentile, and 13 (12.4%) below the 5th percentile. The remaining 14 children (13.3%) refused to perform or to complete the test. The difference between preterm and control group was significant for total scores, Manual Dexterity and Aiming and Catching scores. In the preterm group there was a correlation between age at testing, total scores and Aiming and Catching subscores. The Movement ABC-2 subscores were significantly lower in children born below 29weeks. CONCLUSION Perceptual-motor difficulties can already be detected on the assessment performed before the age of 4years. Prematurely born children assessed between 3years and 3years-3months appeared to have more difficulties in performing the test than the older ones or their age matched term-born peers. These findings support the possibility of a delayed maturation in the younger age group.

Isolated semitendinosus involvement in the initial stages of limb-girdle muscular dystrophy 2L

Unit of Neuromuscular Disorders, Laboratory of Molecular Medicine, Bambino Gesu’ Children’s Research Hospital, Rome, Italy Folkhalsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland Pediatric Neurology Unit, Catholic University School of Medicine, Rome, Italy d Institute of Neurology, Catholic University School of Medicine, Rome, Italy Neuromuscular Research Center, University of Tampere and Tampere University Hospital, Tampere, Finland Neurology Department, Vaasa Central Hospital, Vaasa, Finland