Validation of Neuromyotype: a smart keyboard for the evaluation of spinal muscular atrophy patients.

INTRODUCTION: Spinal muscular atrophy 5q (SMA) is a genetic neurodegenerative disease that affects alpha motor neurons producing progressive weakness. New outcome measures are currently required to accurately characterise the disease progression and the efficacy of new available treatments. The objective of this work is to preliminarily validate a new intelligent keyboard (Neuromyotype) measuring typing strength and speed in patients with SMA. MATERIAL AND METHODS: Twenty two SMA patients older than 15 years, and 26 healthy controls were included. Three measurements were obtained with the keyboard (maximum strength, execution time of a random typing task, execution time of a sequential typing task) together with the time to complete the Nine-Hole Peg Test (9HPT). Patients were also administered motor (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb module, RULM), and functional scales (Egen Klassification, EK2; and the revised version of Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R). The viability and construct validity of the Neuromyotype were analysed, measuring the discriminative power between patients and controls (using ROC curves and the Bangdiwala's B statistic), between the different functional types of SMA (walker, sitter and non-sitter) and their correlation with the rest of motor scales. RESULTS: Neuromyotype measurements could be performed in all patients, unlike the rest of the scales. Its administration was quick and easy. The 3 variables on the keyboard discriminated very well between patients and controls, with strength (ROC = 0.963) being the one that best differentiates from the 3, equaling 9HPT (ROC = 0.966). They also showed a good ability to differentiate by functional type (especially non-sitters from sitters and walkers), with sequential time (B = 0.83) being the tool that best discriminates between the three groups above the rest of motor scales. All motor and functional scales showed strong or very strong correlations with each other (rs = 0.71-0.99), with strength correlating better with motor scales and timed variables with functional scales. CONCLUSION: This study shows the feasibility and validity of Neuromyotype for the evaluation of adolescent and adult patients with SMA. Data obtained with this tool could be of great clinical relevance, saving time and resources compared to the rest of the scales.

Delphi consensus on recommendations for the treatment of spinal muscular atrophy in Spain (RET-AME consensus).

INTRODUCTION: Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a biallelic mutation of the SMN1 gene, located on the long arm of chromosome 5, and predominantly affects the motor neurons of the anterior horn of the spinal cord, causing progressive muscle weakness and atrophy. The development of disease-modifying treatments is significantly changing the natural history of SMA, but uncertainty remains about which patients can benefit from these treatments and how that benefit should be measured. METHODOLOGY: A group of experts specialised in neurology, neuropediatrics, and rehabilitation and representatives of the Spanish association of patients with SMA followed the Delphi method to reach a consensus on 5 issues related to the use of these new treatments: general aspects, treatment objectives, outcome assessment tools, requirements of the treating centres, and regulation of their use. Consensus was considered to be achieved when a response received at least 80% of votes. RESULTS: Treatment protocols are useful for regulating the use of high-impact medications and should guide treatment, but should be updated regularly to take into account the most recent evidence available, and their implementation should be assessed on an individual basis. Age, baseline functional status, and, in the case of children, the type of SMA and the number of copies of SMN2 are characteristics that should be considered when establishing therapeutic objectives, assessment tools, and the use of such treatments. The cost-effectiveness of these treatments in paediatric patients is mainly influenced by early treatment onset; therefore, the implementation of neonatal screening is recommended. CONCLUSIONS: The RET-AME consensus recommendations provide a frame of reference for the appropriate use of disease-modifying treatments in patients with SMA.

[Cognitive reserve as a modulating factor in the impact of surgery on visual memory and naming in temporal lobe epilepsy patients]. / La reserva cognitiva como factor modulador del impacto de la cirugía sobre la memoria visual y la denominación en pacientes con epilepsia del lóbulo temporal.

INTRODUCTION: Temporal lobe epilepsy (TLE) surgery is an effective procedure that produces cognitive changes. Factors modulating such changes have been proposed, but the influence of cognitive reserve remains unclear. OBJECTIVE: To examine the effect of intellectual quotient (IQ) on postsurgical changes in verbal fluency, naming, and verbal and visual memory in a sample of patients with TLE. PATIENTS AND METHODS: 64 adult patients with drug-resistant TLE (mean age ± SD: 39.16 ± 11.67) underwent a neuropsychological evaluation before and one year after surgery. RESULTS: Patients with high IQ showed better immediate visual memory before surgery than those with medium IQ, as well as an absence of postsurgical changes. Patients with high manipulative IQ had better naming before surgery than those with medium manipulative IQ, as well as a significant postsurgical worsening. Both before and after surgery, patients with high IQ showed better phonemic and semantic verbal fluency and short- and long-term verbal memory than those with medium IQ. CONCLUSIONS: IQ is a relevant factor in the evolution of immediate visual memory and naming after surgery in patients with TLE. Surgery does not impact on the advantage of high IQ patients in verbal fluency and verbal memory, suggesting that cognitive reserve has a positive effect on cognitive function, even after TLE surgery.

TITLE: La reserva cognitiva como factor modulador del impacto de la cirugía sobre la memoria visual y la denominación en pacientes con epilepsia del lóbulo temporal.Introducción. La cirugía de la epilepsia del lóbulo temporal (ELT) es un procedimiento eficaz que produce cambios cognitivos. Se han propuesto factores moduladores de dichos cambios, pero permanece sin esclarecer la influencia de la reserva cognitiva. Objetivo. Examinar el efecto del cociente intelectual (CI) sobre los cambios posquirúrgicos en medidas de fluencia verbal, denominación y memoria verbal y visual en una muestra de pacientes con ELT. Pacientes y métodos. Sesenta y cuatro pacientes adultos con ELT farmacorresistente (edad media ± desviación típica: 39,16 ± 11,67) fueron sometidos a una evaluación neuropsicológica antes y un año después de la cirugía. Resultados. Los pacientes con un CI alto presentaron un mejor funcionamiento de la memoria visual inmediata antes de la cirugía que los que tenían un CI medio, así como ausencia de cambios posquirúrgicos. Los pacientes con un CI manipulativo alto presentaron mejor denominación antes de la cirugía que los que tenían un CI manipulativo medio, así como un empeoramiento posquirúrgico significativo. Tanto antes como después de la cirugía, los pacientes con un CI alto presentaron mejor fluencia verbal fonémica y semántica y memoria verbal a corto y largo plazo que los que tenían un CI medio. Conclusiones. El CI es un factor relevante en la evolución de la memoria visual inmediata y de la denominación tras la cirugía en pacientes con ELT. La cirugía no repercute en la ventaja que tienen los pacientes con un CI alto en fluencia verbal y memoria verbal, lo que sugiere que la reserva cognitiva tiene un efecto positivo sobre la función cognitiva, incluso tras la cirugía de la ELT.

La reserva cognitiva como factor modulador del impacto de la cirugía sobre la memoria visual y la denominación en pacientes con epilepsia del lóbulo temporal / Cognitive reserve as a modulating factor in the impact of surgery on visual memory and naming in temporal lobe epilepsy patients

Introducción:La cirugía de la epilepsia del lóbulo temporal (ELT) es un procedimiento eficaz que produce cambios cognitivos. Se han propuesto factores moduladores de dichos cambios, pero permanece sin esclarecer la influencia de la reserva cognitiva. Objetivo: Examinar el efecto del cociente intelectual (CI) sobre los cambios posquirúrgicos en medidas de fluencia verbal, denominación y memoria verbal y visual en una muestra de pacientes con ELT. Pacientes y métodos: Sesenta y cuatro pacientes adultos con ELT farmacorresistente (edad media ± desviación típica: 39,16 ± 11,67) fueron sometidos a una evaluación neuropsicológica antes y un año después de la cirugía. Resultados: Los pacientes con un CI alto presentaron un mejor funcionamiento de la memoria visual inmediata antes de la cirugía que los que tenían un CI medio, así como ausencia de cambios posquirúrgicos. Los pacientes con un CI manipulativo alto presentaron mejor denominación antes de la cirugía que los que tenían un CI manipulativo medio, así como un empeoramiento posquirúrgico significativo. Tanto antes como después de la cirugía, los pacientes con un CI alto presentaron mejor fluencia verbal fonémica y semántica y memoria verbal a corto y largo plazo que los que tenían un CI medio. Conclusiones: El CI es un factor relevante en la evolución de la memoria visual inmediata y de la denominación tras la cirugía en pacientes con ELT. La cirugía no repercute en la ventaja que tienen los pacientes con un CI alto en fluencia verbal y memoria verbal, lo que sugiere que la reserva cognitiva tiene un efecto positivo sobre la función cognitiva, incluso tras la cirugía de la ELT.(AU)

Introduction: Temporal lobe epilepsy (TLE) surgery is an effective procedure that produces cognitive changes. Factors modulating such changes have been proposed, but the influence of cognitive reserve remains unclear. Objective: To examine the effect of intellectual quotient (IQ) on postsurgical changes in verbal fluency, naming, and verbal and visual memory in a sample of patients with TLE. Patients and methods: 64 adult patients with drug-resistant TLE (mean age ± SD: 39.16 ± 11.67) underwent a neuropsychological evaluation before and one year after surgery. Results: Patients with high IQ showed better immediate visual memory before surgery than those with medium IQ, as well as an absence of postsurgical changes. Patients with high manipulative IQ had better naming before surgery than those with medium manipulative IQ, as well as a significant postsurgical worsening. Both before and after surgery, patients with high IQ showed better phonemic and semantic verbal fluency and short- and long-term verbal memory than those with medium IQ. Conclusions: IQ is a relevant factor in the evolution of immediate visual memory and naming after surgery in patients with TLE. Surgery does not impact on the advantage of high IQ patients in verbal fluency and verbal memory, suggesting that cognitive reserve has a positive effect on cognitive function, even after TLE surgery.(AU)

Analysis of the diagnostic pathway and delay in patients with amyotrophic lateral sclerosis in the Valencian Community.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an insidious, clinically heterogeneous neurodegenerative disease associated with a diagnostic delay of approximately 12 months. No study conducted to date has analysed the diagnostic pathway in Spain. METHODS: We gathered data on variables related to the diagnostic pathway and delay for patients diagnosed with ALS between October 2013 and July 2017. RESULTS: The study included 143 patients with ALS (57% men; 68% spinal onset). Patients were diagnosed in public centres in 86% of cases and in private centres in 14%. The mean diagnostic delay was 13.1 months (median 11.7). Patients were examined by neurologists a mean time of 7.9 months after symptom onset, with diagnosis being made 5.2 months later. Half of all patients underwent unnecessary diagnostic tests and multiple electrophysiological studies before diagnosis was established. Diagnostic delay was longer in cases of spinal onset (P=.008) due to onset of the disease in the lower limbs. No differences were found between the public and private healthcare systems (P=.897). CONCLUSIONS: The diagnostic delay in ALS in Spain is similar to that of neighbouring countries and seems to depend on disease-related factors, not on the healthcare system. Patients with lower-limb onset ALS constitute the greatest diagnostic challenge. Misdiagnosis is frequent, and partly attributable to an incorrect approach or erroneous interpretation of electrophysiological studies. Specific training programmes for neurologists and general neurophysiologists and early referral to reference centres may help to reduce diagnostic delay.

Análisis del trayecto y retraso diagnóstico de los pacientes con esclerosis lateral amiotrófica en la Comunidad Valenciana / Analysis of the diagnostic pathway and delay in patients with amyotrophic lateral sclerosis in the Valencian Community

Introducción: La esclerosis lateral amiotrófica (ELA) es una enfermedad insidiosa y clínicamente heterogénea, lo que resulta en un retraso diagnóstico de unos 12 meses. En España el trayecto diagnóstico no ha sido analizado.MétodosSe recogieron variables relativas al trayecto y retraso diagnóstico de pacientes diagnosticados de ELA entre octubre del 2013 y julio del 2017.ResultadosSe incluyó a 143 pacientes con ELA (57% varones, 68% de inicio espinal). El 86% de ellos fueron estudiados en centros públicos y un 14% en privados. El retraso diagnóstico medio fue de 13,1 meses (mediana 11.7). El paciente tardó de media 7,9 meses en llegar al neurólogo y este, 5,2 meses más en diagnosticarlo. En la mitad de los pacientes se realizaron pruebas innecesarias y más de un estudio electrofisiológico para llegar al diagnóstico. El retraso diagnóstico fue mayor en los casos espinales (p = 0,008), atribuible a los pacientes cuyos síntomas se iniciaron en miembros inferiores, pero sin diferencias entre el sistema público y privado (p = 0,897).ConclusionesEl retraso diagnóstico de la ELA en nuestro medio es similar al de países de nuestro entorno y parece determinado por factores propios de la enfermedad e independiente del sistema sanitario. Las formas de inicio en miembros inferiores constituyen el mayor reto. Los errores diagnósticos del neurólogo son frecuentes y en parte atribuibles a una mala orientación o interpretación del estudio electrofisiológico. La formación específica del neurólogo y neurofisiólogo general y la derivación precoz a centros de referencia podrían ayudar a reducir la demora. (AU)

Introduction: Amyotrophic lateral sclerosis (ALS) is an insidious, clinically heterogeneous neurodegenerative disease associated with a diagnostic delay of approximately 12 months. No study conducted to date has analysed the diagnostic pathway in Spain.MethodsWe gathered data on variables related to the diagnostic pathway and delay for patients diagnosed with ALS between October 2013 and July 2017.ResultsThe study included 143 patients with ALS (57% men; 68% spinal onset). Patients were diagnosed in public centres in 86% of cases and in private centres in 14%.The mean diagnostic delay was 13.1 months (median 11.7). Patients were examined by neurologists a mean time of 7.9 months after symptom onset, with diagnosis being made 5.2 months later. Half of all patients underwent unnecessary diagnostic tests and multiple electrophysiological studies before diagnosis was established. Diagnostic delay was longer in cases of spinal onset (P = .008) due to onset of the disease in the lower limbs. No differences were found between the public and private healthcare systems (P = .897).ConclusionsThe diagnostic delay in ALS in Spain is similar to that of neighboring countries and seems to depend on disease-related factors, not on the healthcare system. Patients with lower-limb onset ALS constitute the greatest diagnostic challenge. Misdiagnosis is frequent, and partly attributable to an incorrect approach or erroneous interpretation of electrophysiological studies. Specific training programmes for neurologists and general neurophysiologists and early referral to reference centers may help to reduce diagnostic delay. (AU)

Ultrasound-guided lumbar puncture for nusinersen administration in spinal muscular atrophy patients.

BACKGROUND AND PURPOSE: The purpose was to report the results of ultrasound-guided lumbar puncture for the administration of nusinersen in spinal muscular atrophy (SMA) patients with complex spines. METHODS: Eighteen SMA patients (five children, five adolescents and eight adults) with either severe scoliosis or spondylodesis were evaluated for ultrasound-guided lumbar puncture. Ultrasound was performed with a 3.5 MHz transducer to guide a 22 gauge × 15 mm needle, which was placed in the posterior lumbar space following a parasagittal interlaminar approach. RESULTS: Twelve patients had undergone spinal instrumentation (nine growing rods and three spinal fusion) whilst the other six showed severe scoliosis. Success was achieved in 91/94 attempts (96.8%), in 14/18 patients (77.8%), including 100% of children and adolescents and 50% of adult patients. In two of the unsuccessfully treated patients, computed tomography and fluoroscopy-guided transforaminal lumbar punctures were also tried without success. After a median follow-up of 14 months, only few adverse events, mostly mild, were observed. CONCLUSION: The ultrasound-guided lumbar puncture, following an interlaminar parasagittal approach, is a safe and effective approach for intrathecal treatment with nusinersen in children, adolescents and carefully selected adult SMA patients with complex spines and could be considered the first option in them.

Measuring Outcomes in Adults with Spinal Muscular Atrophy - Challenges and Future Directions - Meeting Report.

Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease which affects 1 in 6,000-10,000 live births, caused by loss of the survival motor neuron 1 gene (SMN1). A major focus of therapeutic developments has been on increasing the full-length SMN protein by increasing the inclusion of exon 7 in SMN2 transcripts, enhancing SMN2 gene expression, stabilizing the SMN protein or replacing the SMN1 gene.In June 2017, FDA and EMA have approved the antisense oligonucleotide Nusinersen as the first treatment for all SMA subtypes without age restriction. While prominent treatment effects have been observed in the earlier stages of the disease and in patients up to 15 years of age, there is only limited data from clinical trials in adult SMA patients. First real-world data from neuromuscular clinical centers suggest a therapeutic benefit of nusinersen with a favourable safety profile also in adult SMA patients: in several cases, relevant improvements of motor function is achieved, which might lead to enhanced autonomy in daily life activities and improved quality of life. Systematic follow-up of the motor status with validated instruments is crucial for an adequate monitoring of the therapeutic effects but most of the widely used scales and scores have been developed and evaluated for the pediatric population only. International neuromuscular experts have met in Frankfurt/Main, Germany in May 2019 to discuss relevant aspects of the diagnostic pathway and patient management in adult SMA. The recommendations and challenges in this patient population are discussed.

Clinical spectrum of BICD2 mutations.

BACKGROUND AND PURPOSE: Mutations in the BICD2 gene cause autosomal dominant lower extremity-predominant spinal muscular atrophy 2A (SMALED2A), a condition that is associated with a specific pattern of thigh and calf muscle involvement when studied by magnetic resonance imaging (MRI). Patients may present minor clinical sensory impairment, but objective sensory involvement has yet to be demonstrated. METHODS: We collected clinical data from 11 patients from five different families carrying mutations in BICD2. Genetic diagnosis was achieved using gene panel testing and skin biopsies were taken from two patients to study the epidermal nerve fiber density. RESULTS: In the studied patients, three new pathogenic mutations were detected as well as the already defined pathogenic p.Ser107Leu mutation. The most frequent clinical picture was characterized by lower-limb weakness in combination with foot deformities. One patient manifested clinical and electrophysiological sensory impairment, and the epidermal nerve fiber density study of another patient revealed the existence of a small-fiber neuropathy. Muscle MRI showed a common pattern of fat deposition including selective involvement of gluteus medius and minimus at the pelvic level, the anterior compartment of the thigh and the posterior compartment of the calf, with only mild or no involvement of the intrinsic foot muscles. CONCLUSIONS: We report three new pathogenic mutations in the BICD2 gene. Muscle MRI confirms the existence of a selective pattern of thigh and leg muscle involvement in SMALED2A, providing additional information regarding pelvic and foot muscles. Moreover, our results raise the possibility of sensory involvement in the disease.

New insights into the pathophysiology of fasciculations in amyotrophic lateral sclerosis: An ultrasound study.

OBJECTIVE: To describe the fasciculation pattern in ALS and to analyse its clinical and pathophysiological significance. METHODS: Ultrasound of 19 muscles was performed in 44 patients with a recent diagnosis (<90 days) of ALS. The number of fasciculations was recorded in each muscle and the muscle thickness and strength were additionally measured in limb muscles. A subgroup of patients were electromyographically assessed. RESULTS: US was performed in 835 muscles and EMG was available in 263 muscles. US detected fasciculations more frequently than EMG. Fasciculations were widespread, especially in upper limbs onset patients and in the cervical region. Fasciculations' number inversely associated with ALSFR-R and body mass index (BMI) and directly with BMI loss and upper motor neuron (UMN) impairment. Our statistical model suggest that fasciculations increase with the initial lower motor neuron (LMN) degeneration, reach their peak when the muscle became mildly to moderately weak, decreasing afterwards with increasing muscle weakness and atrophy. CONCLUSIONS: Our study suggests that both UMN and LMN degeneration trigger fasciculations causing BMI loss. The degree of LMN impairment could account for differences in fasciculations' rates within and between muscles. SIGNIFICANCE: In ALS, fasciculations could explain the link between hyperexcitability and BMI loss.

[Cerebrovascular disease in childhood: a retrospective analysis of hospital admissions in a tertiary hospital in the community of Valencia in the last ten years]. / Enfermedad cerebrovascular en la infancia. Análisis retrospectivo de los ingresos hospitalarios en los últimos diez años en un hospital terciario de la Comunidad Valenciana.

INTRODUCTION: There has been increasing interest in stroke in children in the last few years. A literature review produced little information on risk factors and other clinical questions. The aim of this study is to describe the characteristics of stroke in children, mainly in order to identify the risk factors, clinical presentation and outcomes. PATIENTS AND METHODS: A retrospective study was conducted on patients admitted to the Hospital La Fe in Valencia between January 2000 to September 2010 with the diagnosis of ischaemic or haemorrhagic stroke. RESULTS: A total of 76 patients were identified, of whom 44.7% had an ischaemic stroke and 55.3% had a haemorrhagic one. The average age of presentation was 6.8 years; 8.4 years for haemorrhagic strokes and 4.7 years for ischaemic strokes. Headache was the most frequent symptom of presentation. The most frequent risk factor was vascular malformations in haemorrhagic cerebral stroke, and vascular and cardiac disorders in ischaemic stroke. A study of prothrombotic factors was conducted on 34 patients, which was positive in 64.7% of them. As regards outcome, 17% of the patients died; only 3 patients had a secondary epilepsy, and 31% and 60% of the haemorrhagic and ischaemic stokes, respectively, had a hemiparesis. CONCLUSIONS: In this study we identified the principal risk factors as well as, the age of presentation, symptomatology and outcome. We would like to emphasise that the age of presentation was earlier in ischaemic strokes than in haemorrhagic ones.