Risdiplam in Type 1 Spinal Muscular Atrophy.

BACKGROUND: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. METHODS: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. RESULTS: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. CONCLUSIONS: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).

Clinical Phenotype of Pediatric and Adult Patients With Spinal Muscular Atrophy With Four SMN2 Copies: Are They Really All Stable?

OBJECTIVE: The aim of this study was to provide an overview of the clinical phenotypes associated with 4 SMN2 copies. METHODS: Clinical phenotypes were analyzed in all the patients with 4 SMN2 copies as part of a nationwide effort including all the Italian pediatric and adult reference centers for spinal muscular atrophy (SMA). RESULTS: The cohort includes 169 patients (102 men and 67 women) with confirmed 4 SMN2 copies (mean age at last follow-up = 36.9 ± 19 years). Six of the 169 patients were presymptomatic, 8 were classified as type II, 145 as type III (38 type IIIA and 107 type IIIB), and 8 as type IV. The remaining 2 patients were asymptomatic adults identified because of a familial case. The cross-sectional functional data showed a reduction of scores with increasing age. Over 35% of the type III and 25% of the type IV lost ambulation (mean age = 26.8 years ± 16.3 SD). The risk of loss of ambulation was significantly associated with SMA type (p < 0.0001), with patients with IIIB and IV less likely to lose ambulation compared to type IIIA. There was an overall gender effect with a smaller number of women and a lower risk for women to lose ambulation. This was significant in the adult (p = 0.009) but not in the pediatric cohort (p = 0.43). INTERPRETATION: Our results expand the existing literature on natural history of 4 SMN2 copies confirming the variability of phenotypes in untreated patients, ranging from type II to type IV and an overall reduction of functional scores with increasing age. ANN NEUROL 2023;94:1126-1135.

Early treatment of type II SMA slows rate of progression of scoliosis.

BACKGROUND: Type II spinal muscular atrophy (SMA) often leads to scoliosis in up to 90% of cases. While pharmacological treatments have shown improvements in motor function, their impact on scoliosis progression remains unclear. This study aims to evaluate potential differences in scoliosis progression between treated and untreated SMA II patients. METHODS: Treatment effect on Cobb's angle annual changes and on reaching a 50° Cobb angle was analysed in treated and untreated type II SMA patients with a minimum 1.5-year follow-up. A sliding cut-off approach identified the optimal treatment subpopulation based on age, Cobb angle and Hammersmith Functional Motor Scale Expanded at the initial visit. Mann-Whitney U-test assessed statistical significance. RESULTS: There were no significant differences in baseline characteristics between the untreated (n=46) and treated (n=39) populations. The mean Cobb angle variation did not significantly differ between the two groups (p=0.4). Optimal cut-off values for a better outcome were found to be having a Cobb angle <26° or an age <4.5 years. When using optimal cut-off, the treated group showed a lower mean Cobb variation compared with the untreated group (5.61 (SD 4.72) degrees/year vs 10.05 (SD 6.38) degrees/year; p=0.01). Cox-regression analysis indicated a protective treatment effect in reaching a 50° Cobb angle, significant in patients <4.5 years old (p=0.016). CONCLUSION: This study highlights that pharmacological treatment, if initiated early, may slow down the progression of scoliosis in type II SMA patients. Larger studies are warranted to further investigate the effectiveness of individual pharmacological treatment on scoliosis progression in this patient population.

Survival among patients receiving eteplirsen for up to 8 years for the treatment of Duchenne muscular dystrophy and contextualization with natural history controls.

INTRODUCTION/AIMS: Eteplirsen, approved in the US for patients with Duchenne muscular dystrophy (DMD) with exon 51 skip-amenable variants, is associated with attenuated ambulatory/pulmonary decline versus DMD natural history (NH). We report overall survival in a US cohort receiving eteplirsen and contextualize these outcomes versus DMD NH. METHODS: US patients with DMD receiving eteplirsen were followed through a patient support program, with data collected on ages at eteplirsen initiation and death/end of follow-up. Individual DMD NH data were extracted by digitizing Kaplan-Meier (KM) curves from published systematic and targeted literature reviews. Overall survival age was analyzed using KM curves and contextualized with DMD NH survival curves; subanalyses considered age groups and duration of eteplirsen exposure. Overall survival time from treatment initiation was also evaluated. RESULTS: A total of 579 eteplirsen-treated patients were included. During a total follow-up of 2119 person-years, median survival age was 32.8 years. DMD NH survival curves extracted from four publications (follow-up for 1224 DMD NH controls) showed overall pooled median survival age of 27.4 years. Eteplirsen-treated patients had significantly longer survival from treatment initiation versus age-matched controls (age-adjusted hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.44-0.98; p < .05). Longer treatment exposure was associated with improved survival (HR, 0.15; 95% CI, 0.05-0.41; p < .001). Comparisons using different DMD NH cohorts to address common risks of bias yielded consistent findings. DISCUSSION: Data suggest eteplirsen may prolong survival in patients with DMD across a wide age range. As more data become available, the impact of eteplirsen on survival will be further elucidated.

Hospital admissions from the emergency department of adult patients affected by myopathies.

BACKGROUND AND PURPOSE: Myopathies are associated with classic signs and symptoms, but also with possible life-threatening complications that may require assistance in an emergency setting. This phenomenon is understudied in the literature. We aimed to assess the presentation, management, and outcomes of clinical manifestations potentially related to a muscle disorder requiring referral to the adult emergency department (ED) and hospitalization. METHODS: Anonymized patient data retrieved using the International Classification of Diseases, Ninth Revision codes related to muscle disorders over 4 years were retrospectively analyzed. Medical reports were evaluated to extract demographic and clinical variables, along with outcomes. Two groups were defined based on the presence (known diagnosis [KD] group) or absence (unknown diagnosis [UD] group) of a diagnosed muscle disorder at arrival. RESULTS: A total of 244 patients were included, 51% of whom were affected by a known myopathy, predominantly limb-girdle muscular dystrophies and myotonic dystrophies. The main reasons for ED visits in the KD group were respiratory issues, worsening of muscle weakness, and gastrointestinal problems. Heart complications were less prevalent. In the UD group, 27 patients received a new diagnosis of a specific primary muscle disorder after the ED access, mostly an inflammatory myopathy. Death during hospitalization was recorded in 26 patients, with a higher rate in the KD group and in patients affected by mitochondrial and inflammatory myopathies. Sepsis and dyspnea were associated with increased death risk. CONCLUSIONS: Respiratory complications are the most common reason for myopathic patients accessing the ED, followed by gastrointestinal issues. Infections are severe threats and, once hospitalized, these patients have relatively high mortality.

Determining minimal clinically important differences in the Hammersmith Functional Motor Scale Expanded for untreated spinal muscular atrophy patients: An international study.

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is a rare and progressive neuromuscular disorder with varying severity levels. The aim of the study was to calculate minimal clinically important difference (MCID), minimal detectable change (MDC), and values for the Hammersmith Functional Motor Scale Expanded (HFMSE) in an untreated international SMA cohort. METHODS: The study employed two distinct methods. MDC was calculated using distribution-based approaches to consider standard error of measurement and effect size change in a population of 321 patients (176 SMA II and 145 SMA III), allowing for stratification based on age and function. MCID was assessed using anchor-based methods (receiver operating characteristic [ROC] curve analysis and standard error) on 76 patients (52 SMA II and 24 SMA III) for whom the 12-month HFMSE could be anchored to a caregiver-reported clinical perception questionnaire. RESULTS: With both approaches, SMA type II and type III patients had different profiles. The MCID, using ROC analysis, identified optimal cutoff points of -2 for type II and -4 for type III patients, whereas using the standard error we found the optimal cutoff points to be 1.5 for improvement and -3.2 for deterioration. Furthermore, distribution-based methods uncovered varying values across age and functional status subgroups within each SMA type. CONCLUSIONS: These results emphasize that the interpretation of a single MCID or MDC value obtained in large cohorts with different functional status needs to be made with caution, especially when these may be used to assess possible responses to new therapies.

Neurological assessment tool for screening infants during the first year after birth: The Brief-Hammersmith Infant Neurological Examination.

AIM: To develop a short version of the original Hammersmith Infant Neurological Examination (HINE) to be used as a screening tool (Brief-HINE) and to establish if the short examination maintains good accuracy and predictive power for detecting infants with cerebral palsy (CP). METHOD: Eleven items were selected from the original HINE ('visual response'; 'trunk posture'; 'movement quantity'; 'movement quality'; 'scarf sign'; 'hip adductor angles'; 'popliteal angle'; 'pull to sit'; 'lateral tilting'; 'forward parachute reaction'; 'tendon reflexes') identifying those items previously found to be more predictive of CP in both low- and high-risk infants. In order to establish the sensitivity of the new module, the selected items were applied to existing data, previously obtained using the full HINE at 3, 6, 9, and 12 months, in 228 infants with typical development at 2 years and in 82 infants who developed CP. RESULTS: Brief-HINE scores showed good sensitivity and specificity, at each age of assessment, for detecting infants with CP. At 3 months, a score of less than 22 was associated with CP with a sensitivity of 0.88 and a specificity of 0.92; at 6, 9, and 12 months, the cut-off scores were less than 25 (sensitivity 0.93; specificity 0.87), less than 27 (sensitivity 0.95; specificity 0.81), and less than 27 (sensitivity 1; specificity 0.86) respectively. The presence of more than one warning sign, or items that are not optimal for the age of assessment, imply the need for a full examination reassessment. INTERPRETATION: These findings support the validity of the Brief-HINE as a routine screening method and the possibility of its use in clinical practice.

Early neurological signs in infants identified through neonatal screening for SMA: do they predict outcome?

Neonatal screening for SMA has allowed the identification of infants who may present with early clinical signs. Our aim was to establish whether the presence and the severity of early clinical signs have an effect on the development of motor milestones. Infants identified through newborn screening were prospectively assessed using a structured neonatal neurological examination and an additional module developed for the assessment of floppy infants. As part of the follow-up, all infants were assessed using the HINE-2 to establish developmental milestones. Only infants with at least 24 months of follow-up were included. Normal early neurological examination (n = 11) was associated with independent walking before the age of 18 months while infants with early clinical signs of SMA (n = 4) did not achieve ambulation (duration follow-up 33.2 months). Paucisymptomatic patients (n = 3) achieved ambulation, one before the age of 18 months and the other 2 between 22 and 24 months.  Conclusion: Our findings suggest that early clinical signs may contribute to predict motor milestones development. What is Known: • There is increasing evidence of heterogeneity among the SMA newborns identified via NBS. • The proposed nosology describes a clinically silent disease, an intermediate category ('paucisymptomatic') and 'symptomatic SMA'. What is New: • The presence of minimal clinical signs at birth does not prevent the possibility to achieve independent walking but this may occur with some delay. • The combination of genotype at SMN locus and clinical evaluation may better predict the possibility to achieve milestones.

Experience of a 2-year spinal muscular atrophy NBS pilot study in Italy: towards specific guidelines and standard operating procedures for the molecular diagnosis.

BACKGROUND: Spinal muscular atrophy (SMA) is due to the homozygous absence of SMN1 in around 97% of patients, independent of the severity (classically ranked into types I-III). The high genetic homogeneity, coupled with the excellent results of presymptomatic treatments of patients with each of the three disease-modifying therapies available, makes SMA one of the golden candidates to genetic newborn screening (NBS) (SMA-NBS). The implementation of SMA in NBS national programmes occurring in some countries is an arising new issue that the scientific community has to address. We report here the results of the first Italian SMA-NBS project and provide some proposals for updating the current molecular diagnostic scenario. METHODS: The screening test was performed by an in-house-developed qPCR assay, amplifying SMN1 and SMN2. Molecular prognosis was assessed on fresh blood samples. RESULTS: We found 15 patients/90885 newborns (incidence 1:6059) having the following SMN2 genotypes: 1 (one patient), 2 (eight patients), 2+c.859G>C variant (one patient), 3 (three patients), 4 (one patient) or 6 copies (one patient). Six patients (40%) showed signs suggestive of SMA at birth. We also discuss some unusual cases we found. CONCLUSION: The molecular diagnosis of SMA needs to adapt to the new era of the disease with specific guidelines and standard operating procedures. In detail, SMA diagnosis should be felt as a true medical urgency due to therapeutic implications; SMN2 copy assessment needs to be standardised; commercially available tests need to be improved for higher SMN2 copies determination; and the SMN2 splicing-modifier variants should be routinely tested in SMA-NBS.

Risdiplam in types 2 and 3 spinal muscular atrophy: A randomised, placebo-controlled, dose-finding trial followed by 24 months of treatment.

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations in the SMN1 gene. Risdiplam is an orally administered molecule that modifies SMN2 pre-mRNA splicing to increase functional SMN protein. METHODS: SUNFISH Part 1 was a dose-finding study conducted in 51 individuals with types 2 and 3 SMA aged 2-25 years. A dose-escalation method was used to identify the appropriate dose for the subsequent pivotal Part 2. Individuals were randomized (2:1) to risdiplam or placebo at escalating dose levels for a minimum 12-week, double-blind, placebo-controlled period, followed by treatment for 24 months. The dose selection for Part 2 was based on safety, tolerability, pharmacokinetic, and pharmacodynamic data. Exploratory efficacy was also measured. RESULTS: There was no difference in safety findings for all assessed dose levels. A dose-dependent increase in blood SMN protein was observed; a median twofold increase was obtained within 4 weeks of treatment initiation at the highest dose level. The increase in SMN protein was sustained over 24 months of treatment. Exploratory efficacy showed improvement or stabilization in motor function. The pivotal dose selected for Part 2 was 5 mg for patients with a body weight ≥20 kg or 0.25 mg/kg for patients with a body weight <20 kg. CONCLUSIONS: SUNFISH Part 1 demonstrated a twofold increase in SMN protein after treatment with risdiplam. The observed safety profile supported the initiation of the pivotal Part 2 study. The long-term efficacy and safety of risdiplam are being assessed with ongoing treatment.

Type I spinal muscular atrophy patients treated with nusinersen: 4-year follow-up of motor, respiratory and bulbar function.

BACKGROUND: We report the 4-year follow-up in type I patients treated with nusinersen and the changes in motor, respiratory and bulbar function in relation to subtype, age and SMN2 copy number. METHODS: The study included SMA 1 patients with at least one assessment after 12, 24 and 48 months from the first dose of nusinersen. The assessments used were Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination (HINE-II). RESULTS: Forty-eight patients, with ages ranging from 7 days to 12 years (mean 3.3 years, SD 3.6 years) were included in the study. The CHOP INTEND and HINE-II scores significantly increased between baseline and 48 months (p < 0.001). When age at starting treatment subgroups (<210 days, <2 years, 2-4 years, 5-11 years, ≥12 years) were considered, the CHOP INTEND increased significantly in patients younger than 4 years at treatment, while the HINE-2 increased significantly in patients younger than 2 years at treatment. In a mixed-model analysis, age, nutritional and respiratory status were predictive of changes on both scales while SMN2 copy number and decimal classification were not. CONCLUSIONS: Our results confirm the safety profile previously reported and support the durability of the efficacy of nusinersen at 4 years with an overall stability or mild improvement and no evidence of deterioration over a long period of time.

New therapies for spinal muscular atrophy: where we stand and what is next.

The natural history of spinal muscular atrophy has been radically changed by the advent of improved standards of care and the availability of disease-modifying therapies. The aim of this paper is to provide the current therapeutic scenario including new perspectives and to report the challenges related to new phenotypes a few years after the therapies have become available. The paper also includes a review of real-world data that provides information on safety and efficacy in individuals that were not included in clinical trials. Special attention is paid to future perspectives both in terms of new drugs that are currently investigated in clinical trials or providing details on current developments in the use of the available drugs, including combination therapies or new modalities of dose or administration.  Conclusion: Clinical trials and real world data support the efficacy and safety profiles of the available drugs. At the moment there is not enough published evidence about the superiority of one product compared to the others. What is Known: • Safety and efficacy results of clinical trials have led in the last 6 years to the marketing of three drugs for spinal muscular atrophy, with different mechanisms of action. What is New: • Since the drug's approval, real-world data allow us to have data on bigger and heterogeneous groups of patients in contrast with those included in clinical trials. • In addition to the new molecules, combinations of therapies are currently being evaluated.

Needleless inhaled anesthesia with sevoflurane: Advantages of a simplified approach for children with spinal muscular atrophy undergoing intrathecal administration of nusinersen.

BACKGROUND: Intrathecal nusinersen administration, a fundamental step in the treatment of spinal muscular atrophy, is challenging in children. AIMS: This retrospective monocentric analysis of prospectively collected data evaluated the feasibility of needleless general anesthesia exclusively with sevoflurane, without imaging guidance, for children undergoing nusinersen administration in a 24-month period. METHODS: Clinical data included demographics, type of spinal muscular atrophy, presence and severity of scoliosis. Primary outcome was defined by the number of predefined sentinel adverse events related to anesthesia. Secondary outcomes were assessed by duration of the procedure, number of lumbar puncture attempts, and number of failures. Other measures included number and type of moderate, minor and minimal adverse events, as well as number and type of puncture-related adverse events. RESULTS: 116 patients (mean age: 8.7 (SD 6.9) years; with scoliosis: 49.1%) underwent 250 lumbar punctures; two cases of prolonged desaturation, considered as sentinel adverse events, (0.8%) were recorded during anesthesia (primary outcome). None of the patients underwent orotracheal intubation nor required an unplanned admission in the Pediatric Intensive Care Unit. No patient required an unplanned or prolonged hospitalization after the procedure. Mean number of puncture attempts was 1.6 (SD 1.3), and mean duration of the procedure was 14.1 (SD 8.3) minutes. No failure in the drug administration occurred (secondary outcomes). CONCLUSION: In this single-center experience, needleless general anesthesia with inhaled sevoflurane without imaging guidance has been shown to be feasible for children with spinal muscular atrophy undergoing lumbar puncture for nusinersen administration.

Assessing Prevalence and Characteristics of Oro-bulbar Involvement in Children and Adults with SMA Type 2 and 3 Using a Multimodal Approach.

Bulbar and jaw muscles are impaired in patients with Spinal Muscular Atrophy (SMA) but the assessment of their severity and progression are limited by the lack of age-appropriate and disease-specific measures. We investigated mastication and swallowing in children and adults with SMA, sitters and walkers. In a 2-year multicentre cross-sectional prospective study, lip and tongue strength (Iowa Oral Performance Instrument), chewing and swallowing (Test of Masticating and Swallowing Solids), active mouth opening (aMMO) were compared to age-appropriate normative data. The perceived burden of oro-bulbar involvement (SMA-Health Index) was recorded. 78 patients were included, 45 children (median age 7.4 years),22 adults (median age 26.8 years) on nusinersen and 11 untreated (median age 32.7 years). Forty-three percent children had reduced mouth opening, 50% had prolonged total time to eat. These issues were more prominent in sitters than in walkers (p = 0.019, p = 0.014). Sixty-six percent needed increased swallows for bolus clearance. Nusinersen treated adults had median aMMO, tongue strength and total time at TOMASS values within normal range (z score: -1.40, -1.22, -1.32, respectively) whereas untreated adults had reduced aMMO (z score: -2.68) and tongue strength (z score: -2.20). Only a minority of children (2/17) and treated adults (5/21) reported burden in swallowing or mastication compared to all untreated adults (5/5). After 16 months, mastication and swallowing were stable in treated children and adults, whether sitters or walkers. The reported multimodal approach to assess oro-bulbar functions demonstrate that swallowing and mastication are impaired in SMA despite patients' perception. These results suggest a trend towards stabilization of oro-bulbar function in patients on long-term treatment with nusinersen.

Validation and cross-cultural adaptation of the Italian version of the paediatric eating assessment tool (I-PEDI-EAT-10) in genetic syndromes.

BACKGROUND: The Pediatric Eating Assessment Tool (PEDI-EAT-10) is a reliable and valid tool for rapid identification of dysphagia in patients aged 18 months to 18 years. AIMS: To translate and adapt the PEDI-EAT-10 into the Italian language and evaluate its validity and reliability. METHODS & PROCEDURES: The translation and cross-cultural adaptation of the tool consisted of five stages: initial translation, synthesis of the translations, back translation, expert committee evaluation and test of the prefinal version. The internal consistency of the translated tool was analysed in a clinical group composed of 200 patients with special healthcare needs aged between 18 months and 18 years. They were consecutively enrolled at the Rare Disease Unit, Paediatrics Department, Fondazione Policlinico Agostino Gemelli-IRCCS, Rome. For test-retest reliability, 50 caregivers filled in the PEDI-EAT-10 questionnaire for a second time after a 2-week period. Construct validity was established by comparing data obtained from patients with data from healthy participants (n = 200). The study was approved by the local ethics committee. OUTCOMES & RESULTS: Psychometric data obtained from patients (104 M; mean age = 8.08 ± 4.85 years; median age = 7 years) showed satisfactory internal consistency (Cronbach's α = 0.89) and test-retest reliability (Pearson r = 0.99; Spearman r = 0.96). A total of 30% of children were classified as having a high risk of penetration/aspiration. The Italian PEDI-EAT-10 mean total score of the clinical group was significantly different from that resulting from healthy participants. CONCLUSIONS & IMPLICATIONS: The PEDI-EAT-10 was successfully translated into Italian, validated and found to be a reliable one-page rapid screening tool to identify dysphagia in children and adolescents with special needs. WHAT THIS PAPER ADDS: What is already known on the subject The PEDI-EAT-10 is a valid and reliable quick discriminative paediatric tool for identifying penetration/aspiration risks. What this paper adds to the existing knowledge In the present study we successfully translated and adapted the PEDI-EAT-10 into the Italian language. What are the potential or actual clinical implications of this work? This translation and adaptation increase access to valid feeding and swallowing assessment for children of Italian-speaking families. In addition, the I-PEDI-EAT-10 can suggest further assessment of patients' swallowing abilities.

Hammersmith Infant Neurological Examination in infants born at term: Predicting outcomes other than cerebral palsy.

AIM: We explored the ability of the Hammersmith Infant Neurological Examination (HINE) to identify cognitive performance delay at 2 years in a large cohort of infants born at term. METHOD: We conducted a retrospective study of infants born at term at risk of neurodevelopmental impairments assessed using the HINE between 3 and 12 months post-term age and compared them with a cohort of typically developing infants born at term. All infants performed a neurodevelopmental assessment at 2 years of age using the Mental Development Index (MDI) of the Bayley Scales of Infant Development, Second Edition; the presence of cerebral palsy (CP) was also reported. The infants were classified as being cognitively normal/mildly delayed or significantly delayed (MDI < 70). The predictive validity of HINE scores for significantly delayed cognitive performance, in infants with and without CP, was calculated using specific cut-off scores according to age at assessment. RESULTS: A total of 446 at-risk and 235 typically developing infants (345 males, 336 females; mean [SD] gestational age 38.7 weeks [1.4], range 37-43 weeks) were included. Of the at-risk infants, 408 did not have CP at 2 years; 243 had a normal/mild delayed MDI and 165 had an MDI less than 70. Of the at-risk infants, 38 developed CP. HINE scores showed a good sensitivity and specificity, mainly after 3 months, for identifying significantly delayed cognitive performance in infants without CP. In those with CP, the score was associated with their cognitive performance. The comparison group had the highest HINE scores. INTERPRETATION: The HINE provides evidence about the risk of delayed cognitive performance at age 2 years in infants born at term with and without CP.

EXAMEN NEUROLÓGICO INFANTIL DE HAMMERSMITH EN BEBÉS NACIDOS A TÉRMINO: SU USO PARA PREDECIR OTRAS CONDICIONES ADEMÁS DE LA PARÁLISIS CEREBRAL: OBJETIVO: Valoramos la capacidad del examen neurológico infantil de Hammersmith (HINE) para identificar el retraso en el rendimiento cognitivo a los 2 años en una cohorte grande de bebés nacidos a término. MÉTODO: Realizamos un estudio retrospectivo de bebés nacidos a término con riesgo de trastornos del desarrollo neurológico evaluados mediante el HINE entre los 3 y los 12 meses de edad postérmino y los comparamos con una cohorte de bebés nacidos a término con un desarrollo típico. Todos los bebés realizaron una evaluación del desarrollo neurológico a los 2 años de edad utilizando el Índice de Desarrollo Mental (MDI) de las Escalas de Desarrollo Infantil de Bayley, Segunda Edición; también se informó la presencia de parálisis cerebral (PC). Los bebés se clasificaron como cognitivamente normales/levemente con retreaso o significativamente con retraso (MDI < 70). La validez predictiva de las puntuaciones HINE para el rendimiento cognitivo con retraso significativo, en bebés con y sin parálisis cerebral, se calculó utilizando puntuaciones de corte específicas según la edad en la evaluación. RESULTADOS: Se incluyeron un total de 446 lactantes en riesgo y 235 con desarrollo normal (345 varones, 336 mujeres; edad gestacional media [DE] 38,7 semanas [1,4], rango de 37 a 43 semanas). De los lactantes en riesgo, 408 no tenían parálisis cerebral a los 2 años; 243 tenían un MDI con retraso normal/leve y 165 tenían un MDI inferior a 70. De los bebés en riesgo, 38 desarrollaron PC. Las puntuaciones HINE mostraron una buena sensibilidad y especificidad, principalmente después de 3 meses, para identificar un rendimiento cognitivo severo en lactantes sin PC. En aquellos con PC, la puntuación se asoció con su rendimiento cognitivo. El grupo de comparación tuvo las puntuaciones HINE más altas. INTERPRETACIÓN: El HINE proporciona evidencia sobre el riesgo de retraso en el rendimiento cognitivo a los 2 años de edad en bebés nacidos a término con y sin parálisis cerebral.

Hammersmith Infant Neurological Examination in low-risk infants born very preterm: a longitudinal prospective study.

AIM: To describe the profile of global and single items of the Hammersmith Infant Neurological Examination (HINE) in a population of low-risk infants born very preterm during the first year of life. METHOD: The HINE was performed at 3, 6, 9, and 12 months' corrected age in a population of low-risk infants born preterm with a gestational age of fewer than 32 weeks and with normal or minimal changes on neuroimaging. RESULTS: A total of 174 infants born preterm (96 males, 78 females; mean gestational age = 27 weeks [SD = 1.8], range 23-31 weeks) fulfilled the inclusion criteria. The 10th centile cut-off score with median and range was reported for the HINE global and subsection scores. A progressive increase in global HINE scores was observed. Most of the single items, especially those related to tone, posture, and reflexes, showed progressive maturation. INTERPRETATION: Our results, which provide longitudinal data for single-item and global scores in a population of low-risk infants born very preterm, can be used as a reference in both clinical and research settings to monitor early neurological signs in these infants. These data could be used as normative data when examining low-risk infants born preterm.

Assessing floppy infants: a new module.

Our aim was to develop a new module for assessing the floppy infant, to describe the application of the module in a cohort of low-risk newborns and piloting the module in a cohort of floppy infants. The module was applied to a cohort of 143 low-risk newborns and piloted in in a cohort of 24 floppy infants. The new add-on module includes a neurological section and provides a section for recording information obtained by physical examination and antenatal history. For each item, column 1 reports abnormal findings, column 3 normal findings, and column 2 intermediate signs to be followed. Consistent with previous studies, in low-risk infants, none had definitely abnormal or mildly abnormal signs, with the exception of tendon reflexes that were not easily elicitable in 17.14% of term-born infants. CONCLUSION: Our study suggest that the module can be easily used in a clinical setting as an add-on to the regular neonatal neurological examination in newborns identified as hypotonic on routine examination. Larger cohorts are needed to establish the accuracy of the prognostic value of the module in the differential diagnosis of floppy infant. WHAT IS KNOWN: • Hypotonia is one of the key signs in newborns with neuromuscular disorders and can be associated with a wide range of other conditions (central nervous system involvement, genetic and metabolic diseases). • Weakness or/and contractures can identify infants with a neuromuscular disorder and help in the differential diagnosis of floppy infants. WHAT IS NEW: • To date, this is the first attempt to develop and apply a specific neurological module for the assessment of the floppy infant. • The module can be used in a routine clinical setting as an add-on to the regular neurological examination and has potential to differentiate the floppy infants from the low-risk infants.

Neurological assessment of newborns with spinal muscular atrophy identified through neonatal screening.

The possibility to identify patients with spinal muscular atrophy through neonatal screenings has highlighted the need for clinical assessments that may systematically evaluate the possible presence of early neurological signs. The aim of this study was to use the Hammersmith Neonatal Neurological Examination (HNNE) and a module specifically designed for floppy infants to assess the possible variability of neurological findings in infants identified through neonatal screening. The infants included in this study were identified as part of a pilot study exploring neonatal screening in two Italian regions. A neurological examination was performed using the HNNE and an additional module developed for the assessment of floppy infants. Seventeen infants were identified through the screening. One patient had 1 SMN2 copy, 9 had 2 copies, 3 had 3, and 4 had more than 3 copies. Nine of the 17 infants (53%) had completely normal results on both scales, 3 had minimal signs, and the other 5 had more obvious clinical signs. The number of SMN2 copies was related to the presence of abnormal neurological signs (p = 0.036) but two SMN2 copies were associated with variable clinical signs as they were found in some infants with respectively normal examination or obvious severe early signs. CONCLUSIONS: Our results suggest that the combination of both scales increases the possibility to detect neonatal neurological signs and to define different early patterns of involvement also identifying paucisymptomatic patients. WHAT IS KNOWN: • The use of new therapeutic options in presymptomatic SMA patients leads to a dramatic reduction of the onset and severity of the diesease. • The already existing tools commonly used in Type I SMA (HINE and CHOP-intend) may not be suitable to identify minor neurological signs in the neonatal period. WHAT IS NEW: • Combining the HNNE and the floppy infant module, we were able to identify early neurological signs in SMA infants identified through newborn screening and may help to predict the individual therapeutic outcome of these patients. • Iinfants with 2 SMN2 copies identified through the screening had a more variable neonatal examination compared to those with three or more copies, in agreement with similar findings in older infants.

Body mass index in type 2 spinal muscular atrophy: a longitudinal study.

The aim of this retrospective study was to review body mass index (BMI) in a large cohort of Italian pediatric type 2 spinal muscular atrophy (SMA) patients, aged between 0 and 20 years and to establish possible differences in relation to a number of variables such as ventilation, motor function, and survival motor neuron 2 gene copies. Cross-sectional data were collected from 102 patients for a total of 344 visits. Standard growth charts for height and weight were used as reference, with age adjusted BMI calculated using the Center for Disease and Prevention Children's BMI Tool. In the 344 visits, weight ranged between 3.90 and 83 kg, and the BMI between 8.4 and 31.6 with a BMI/age z-scores < - 2SD present in 28% and BMI/age z-scores > + 2SD in 9% of the measurements. The BMI/age z-scores were relatively stable < 5 years of age with an increasing number of patients < - 2SD after the age of 5, and a wider range of BMI/age z-scores after the age of 13. A difference on the BMI/age z-scores was found among the different age subgroups (< 5, 5-12, ≥ 13 years). A multivariate analysis in 58 patients with longitudinal assessments showed that baseline BMI/age z-scores and gender were significantly contributing to the changes while other variables were not. CONCLUSION: Our results confirm that careful surveillance of weight and BMI/age z-scores is needed in type 2 SMA. Further studies, including assessments of chewing and swallowing and of lean/fat body mass, will help to better understand the possible mechanisms underlying weight issues. WHAT IS KNOWN: • Feeding difficulties have been reported in a few studies and were invariably found in patients with type 1 SMA. • Type 2 SMA patients often have low BMI with a relevant number of patients requiring tube feeding. WHAT IS NEW: • Reduction in BMI/age z-score overtime appeared to depend on baseline BMI/age z-score and gender. • Patients with a low BMI/age z-score were at higher risk of developing further reduction.