Successful treatment of respiratory failure in Hirayama disease.

Hirayama disease is a self-limiting cervical motor neuron disease, usually affecting the spinal cord at level C7-T1. We share an unusual case of Hirayama disease in a young man affecting roots C4-C6. He presented in coma due to diaphragm weakness and hypercapnic respiratory failure. Diagnosis was achieved via clinical presentation, neurophysiological examination, ultrasonography of the diaphragm and dynamic MR-imaging. Conservative treatment with a cervical collar resulted in remarkable improvement in respiratory and motor function.

Anterior cervical discectomy and fusion for the treatment of pediatric Hirayama disease.

PURPOSE: Hirayama disease, a rare cervical myelopathy in children and young adults, leads to progressive upper limb weakness and muscle loss. Non-invasive external cervical orthosis has been shown to prevent further neurologic decline; however, this treatment modality has not been successful at restoring neurologic and motor function, especially in long standing cases with significant weakness. The pathophysiology remains not entirely understood, complicating standardized operative guidelines; however, some studies report favorable outcomes with internal fixation. We report a successful surgically treated case of pediatric Hirayama disease, supplemented by a systematic review and collation of reported cases in the literature. METHODS: A review of the literature was performed by searching PubMed, Embase, and Web of Science. Full-length articles were included if they reported clinical data regarding the treatment of at least one patient with Hirayama disease and the neurologic outcome of that treatment. Articles were excluded if they did not provide information on treatment outcomes, were abstract-only publications, or were published in languages other than English. RESULTS: Of the fifteen articles reviewed, 63 patients were described, with 59 undergoing surgery. This encompassed both anterior and posterior spinal procedures and 1 hand tendon transfer. Fifty-five patients, including one from our institution, showed improvement post-treatment. Eleven of these patients were under 18 years old. CONCLUSION: Hirayama disease is an infrequent yet impactful cervical myelopathy with limited high-quality evidence available for optimal treatment. The current literature supports surgical decompression and stabilization as promising interventions. However, comprehensive research is crucial for evolving diagnosis and treatment paradigms.

Cardiac function evaluation in children with spinal muscular atrophy: A case-control study.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by degeneration of lower motor neurons, resulting in progressive muscle weakness and atrophy. However, little is known regarding the cardiac function of children with SMA. METHODS: We recruited SMA patients younger than 18 years of age from January 1, 2022, to April 1, 2022, in the First Affiliated Hospital of Sun Yat-sen University. All patients underwent a comprehensive cardiac evaluation before treatment, including history taking, physical examination, blood tests of cardiac biomarkers, assessment of echocardiography and electrocardiogram. Age/gender-matched healthy volunteers were recruited as controls. RESULTS: A total of 36 SMA patients (26 with SMA type 2 and 10 with SMA type 3) and 40 controls were enrolled in the study. No patient was clinically diagnosed with heart failure. Blood tests showed elevated values of creatine kinase isoenzyme M and isoenzyme B (CK-MB) mass and high-sensitivity cardiac troponin T (hs-cTnT) in spinal muscular atrophy (SMA) patients. Regarding echocardiographic parameters, SMA children were detected with lower global left and right ventricular longitudinal strain, abnormal diastolic filling velocities of trans-mitral and trans-tricuspid flow. The results revealed no clinical heart dysfunction in SMA patients, but subclinical ventricular dysfunction was seen in SMA children including the diastolic function and myocardial performance. Some patients presented with elevated heart rate and abnormal echogenicity of aortic valve or wall. Among these SMA patients, seven patients (19.4%) had scoliosis. The Cobb's angles showed a significant negative correlation with LVEDd/BSA, but no correlation with other parameters, suggesting that mild scoliosis did not lead to significant cardiac dysfunction. CONCLUSIONS: Our findings warrant increased attention to the cardiac status and highlight the need to investigate cardiac interventions in SMA children.

Spinal muscular atrophy with hypoplasia of the corpus callosum: a case report.

BACKGROUND: Spinal Muscular Atrophy (SMA) is a severe neuromuscular disorder due to a defect in the survival motor neuron 1 (SMN1) gene. Hypoplasia of the corpus callosum is underdevelopment or thinness of the corpus callosum. SMA and callosal hypoplasia are relatively rare, and there is limited information sharing the diagnosis and treatment for SMA patients with callosal hypoplasia. CASE DESCRIPTION: A boy with callosal hypoplasia, small penis, and small testes had been perceived with motor regression at 5 months. He was referred to the rehabilitation department and neurology department at 7 months. Physical examination showed absent deep tendon reflexes, proximal weakness and significant hypotonia. He was recommended to perform trio whole-exome sequencing (WES) and array comparative genomic hybridization (aCGH) for his complicated conditions. The subsequent nerve conduction study revealed some characteristics of motor neuron diseases. We identified a homozygous deletion in exon 7 of the SMN1 gene by multiplex ligation-dependent probe amplification and failed to find further pathogenic variations responsible for multiple malformations by trio WES and aCGH. He was diagnosed as SMA. Despite some concerns, he received the therapy of nusinersen for nearly 2 years. He gained the milestone of sitting without support, which he had never accomplished, after the seventh injection, and he continued to improve. During follow-up, there were no adverse events reported and no signs of hydrocephalus. CONCLUSIONS: Some extra features which could not belong to neuromuscular manifestation made the diagnosis and treatment of SMA more complicated.

Flexible endoscopic evaluation of swallowing in children with type 1 spinal muscular atrophy.

PURPOSE: This study aimed to report on implementing flexible endoscopic evaluation of swallowing (FEES) in infants and toddlers with type 1 spinal muscular atrophy (SMA). In addition, a comparison of FEES results and clinical scores was carried out. METHODS: A prospective pilot study was conducted including ten symptomatic children with SMA type 1 (two SMN2 copies). They started treatment with one of the three currently approved therapies for SMA at a median age of 3.8 months (range 0.7-8.9). FEES was performed according to a standard protocol using Penetration-Aspiration Scale (PAS) and Murray Secretion Scale as a primary outcome. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) for motor function, Neuromuscular Disease Swallowing Status Scale (NdSSS), Oral and Swallowing Abilities Tool (OrSAT), and single clinical swallowing-related parameters were also assessed. RESULTS: Distinct swallowing disorders were already evident in eight children at inclusion. The most common findings from FEES were pharyngeal secretion pooling, penetration, and aspiration of saliva and food as well as delayed initiation of swallowing. Despite an average increase in motor function, no comparable improvement was found in swallowing function. None of the surveyed clinical scores showed a significant dependence on PAS in a mixed linear model. CONCLUSIONS: Valuable information regarding the status of dysphagia can be gathered endoscopically, particularly concerning secretion management and when oral intake is limited. Currently available clinical tools for children with type 1 may represent a change in nutritional status but are not yet mature enough to conclude swallowing ability. Further development is still required.

Outcome of Tendon Transfer for Monomelic Amyotrophy (Hirayama Disease).

Hirayama disease is a motor neuron disease predominantly affecting adolescent males. The identifying feature of Hirayama disease is unilateral forearm and intrinsic muscle weakness that spares the brachioradialis, termed "oblique atrophy." Hirayama disease progresses slowly over several years, followed by an abrupt arrest. The pathognomonic finding is the anterior displacement of the cervical spinal cord with the detachment of the posterior dura. Systematic clinical evaluation and appropriate diagnostic studies are crucial to rule out a variety of compressive, immune-mediated, and genetic disorders. We present a patient with Hirayama disease whose hand function was improved dramatically by a tendon transfer after nearly 3 years without a definitive diagnosis and call attention to the hand surgeon's role in identifying this rare disease to enable timely functional restoration.

Spinal Muscular Atrophy Type III Recognized After Delayed Recovery From Neuromuscular Blockade After an Orthognathic Surgery.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by the degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. SMA is classified into types I-IV based on the age at symptom onset or maximum motor function achieved, and its clinical manifestations vary. SMA affects maxillofacial growth because of muscle dysfunction and results in abnormal maxillofacial morphology. In addition, definitive diagnosis is not often made because of the older onset age and symptoms are rarely severe. Therefore, the possibility of undiagnosed SMA in craniofacial surgeries must be considered. This report described a case of an SMA type III recognized after delayed recovery from the neuromuscular blockade in an orthognathic surgery under general anesthesia.

Hirayama Disease: A Rare Case Report and Review.

Hirayama disease, or brachial monomelic amyotrophy, is not a common neurological disease characterized by unilateral or asymmetric bilateral lower motor weakness of distal upper limbs. The basic pathophysiology is compression of the dural sac and spinal cord during flexion of the neck. A case of a 21-year-old male presented with chief complaints of tremors in both hands (right more than left) with gradually progressive weakness of the right hand and forearm. Electromyography (EMG), nerve conduction velocity (NCV), and magnetic resonance imaging (MRI) neck in flexion showed focal atrophy of lower cervical myotomes and confirmed the diagnosis of monomelic amyotrophy.

Scoring People With Spinal Muscular Atrophy on the Motor Function Measure Using the Microsoft Kinect.

PURPOSE: Assess the ability of the Kinect to capture movement and posture of people with spinal muscular atrophy (SMA) during completion of 14 items of the Motor Function Measure, a validated functional rating scale for people with neuromuscular diseases. METHODS: Multicenter feasibility study in which Motor Function Measure items were scored as usual by the participant's therapist during the completion (Score-T) while another therapist scored items based only on the visualization of digital data collected using the Kinect (Score-D). Agreement and disagreement were investigated. RESULTS: Twenty people with SMA type 2 or 3 were participants; 142 items were recorded and analyzed. There was 31.7% agreement between Score-T and Score-D for participants with SMA type 2, and 76.2% for those with SMA type 3. CONCLUSIONS: The results prevent us from considering the use of Kinect capture to deduce an automated scoring, but this device may be of interest to highlight potential compensations.

Assessing perspectives of disease burden and clinically meaningful changes using the Spinal Muscular Atrophy Health Index in adolescents and young adults.

INTRODUCTION/AIMS: Spinal muscular atrophy (SMA) treatment may increase survival and improve physical function among adolescents and young adults. Validated patient-reported outcome measures are needed to understand which treatment benefits are clinically meaningful and to develop targeted resources for this population. To date, use of the SMA Health Index (SMA-HI) in pediatric and young adult populations has been limited. Here, we report results from a survey of adolescents and young adults with SMA to quantifiably understand individuals' perceptions of disease burden. METHODS: Participants aged 12-25 y with a self-reported diagnosis of SMA completed an online survey containing demographic questions and the SMA-HI, a patient-reported outcome measure that assesses individuals' perceptions of disease burden in 15 symptomatic areas. RESULTS: Eighty-eight participants completed the survey. Total SMA-HI scores and SMA-HI subscale scores including shoulder and arm function; back, chest, and abdominal function; activity participation; hand and finger strength; swallowing function; gastrointestinal function; respiratory function; mobility and ambulation, and total disease burden were significantly higher (greater disease burden) in patients with poorer motor function and severe SMA. SMA-HI total and subscale scores were generally lower in adolescents (12-17 y old) versus adults (18-25 y old), suggesting a possible progression of symptomatic disease burden over time. DISCUSSION: This study demonstrates the utility of the SMA-HI for measuring clinically relevant disease burden in adolescents and young adults with SMA. This study demonstrates how disease burden varies by age, SMA type, and other demographics.

Parents' Perspectives on Diagnosis and Decision-Making regarding Ventilator Support in Children with SMA Type 1.

Spinal muscular atrophy (SMA) is a rare neuromuscular disorder with a broad clinical spectrum. The most severe phenotype-SMA type 1-is characterized by marked muscle weakness also affecting bulbar and respiratory function. Life expectancy of children with SMA type 1 is expected to be less than 2 years without ventilator support or disease-specific drug treatment. The aim of this study was to evaluate parents' perspectives on the process of decision-making regarding ventilator support in children with SMA type 1. Fourteen semi-structured interviews were performed with parents of children with SMA type 1 that decided either for or against ventilator support for their child. All children were diagnosed prior to the approval of SMA-specific drug treatment. Interviews were recorded and transcribed verbatim. Data analysis was performed using a qualitative content analysis approach according to Mayring. Parents experienced that they were not adequately informed about the disease and treatment options in first informed consent discussions. Especially regarding ventilator support, parents perceived that they were not offered ventilator support as an actual option for treatment. Regarding the decision of whether or not to offer ventilator support, parents reported that their attitude toward ventilator support and contact with other affected families or patient advocacy groups were more likely to influence the decision than the content of informed consent discussions with physicians. Our results underline the importance of an interdisciplinary team not only to provide parents with relevant information but also to consider the criteria of a patient-centered medicine.

The Effect of Nusinersen Therapy on Laboratory Parameters of Patients with Spinal Muscular Atrophy.

INTRODUCTION: We evaluated the effect of nusinersen on clinical and laboratory parameters and presented its safety and effect on laboratory parameters. METHODS: Two groups were formed from among patients with spinal muscular atrophy (SMA) followed up between September 2017 and June 2021: group 1, SMA type 1; group 2, SMA type 2 and 3. The laboratory parameters were evaluated in groups 1 and 2 between doses. Motor scale tests were performed on patients before each dose of nusinersen. RESULTS: Twenty seven patients (group 1; n = 13, group 2; n = 14) were included. The mean age (±standard deviation) at the onset of symptoms was 3 ± 1.21 (range, 1.5-6) months in group 1 and 12 ± 4.27 (range, 8-24) months in group 2. No significant laboratory treatment-related abnormalities and adverse effects were observed. The cerebrospinal fluid protein levels and the frequency of conventional LP were higher in group 1. Serum creatinine (Cr) levels were higher in group 1 before the first dose and higher in group 2 before the fifth dose (p < 0.05). With treatment, the Cr levels of group 1 decreased and group 2 remained constant or increased. We observed that the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and Hammersmith Functional Motor Scale-Expand scores increased as our patients received treatment (p < 0.05). CONCLUSION: Our results support the safety and efficacy of nusinersen. However, changes in Cr levels according to the clinical type and treatment suggested that serum Cr could be a candidate marker for treatment follow-up.

Using a robotic exoskeleton at home: An activity tolerance case study of a child with spinal muscular atrophy.

PURPOSE: Spinal Muscular Atrophy (SMA) Type II is a neurodegenerative disease that leads to progressive muscle weakness. It prevents children from walking and affects their respiratory function and their activity tolerance, among other health problems. We aimed to assess the activity tolerance showed by a child with SMA using a pediatric gait exoskeleton at home when walking and performing activities. DESIGN AND METHODS: This study presents the case of a 6-year-old boy with SMA Type II and respiratory failure who used a pediatric gait exoskeleton at home for a period of two months. A nursing assessment was done before and during the use of the device to evaluate the child's activity tolerance during the sessions. Nursing interviews, performance, vital signs, fatigue, field notes, and functional scales were analyzed. RESULTS: The nursing assessment showed a good activity tolerance of the child. Performance using the device improved over time; vital signs did not vary significantly during the sessions; fatigue perception decreased over time; and the child reached a higher score on some functional outcomes. CONCLUSIONS: A first step has been taken to evaluate the impact of exoskeleton technology in children with SMA Type II from the nursing point of view, exposing the potential of this technology for the care of children with neuromuscular diseases, and the need for more research on the topic. PRACTICE IMPLICATIONS: The information in this study will be useful to nurses to know the effects of gait exoskeletons in pediatric care of children with neuromuscular diseases like SMA.

CMAP changes upon symptom onset and during treatment in spinal muscular atrophy patients: lessons learned from newborn screening.

PURPOSE: Early identification and treatment of spinal muscular atrophy (SMA) are crucial but difficult. In this study, we aimed to assess the significance of compound motor action potential (CMAP) amplitude in patients identified through a newborn screening program. METHODS: We initiated a large-scale population newborn screening program for SMA in Taiwan in 2014. Patients had access to treatment through clinical trials or expanded use programs. Symptomatic patients were evaluated regularly, including CMAP exams. RESULTS: Among 364,000 screened newborns, 21 were diagnosed with SMA. The incidence of SMA was around 1 in 17,000 live births, and 70% developed SMA type 1. All infants with two SMN2 copies became symptomatic before the age of 1 month. CMAP amplitudes of 12 newborns were available, including 6 who were subsequently treated with nusinersen. We found that a rapid decrease of CMAP amplitude was an early predictor of symptom onset. Pretreatment CMAP and rapid increment of post-treatment CMAP could predict better treatment outcomes. CONCLUSION: This study prospectively demonstrated the incidence of SMA and its types. Our results imply the importance of pretreatment CMAP amplitude and rapid reversal of post-treatment CMAP amplitude with regard to disease presentation and also treatment outcomes.

Clinical Variability in Spinal Muscular Atrophy Type III.

OBJECTIVE: We report natural history data in a large cohort of 199 patients with spinal muscular atrophy (SMA) type III assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish the annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number, and functional status. METHODS: HFMSE longitudinal changes were assessed using piecewise linear mixed-effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12-month assessments. RESULTS: A break point at age 7 years was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type, and ambulatory status were significantly associated with changes in mean HFMSE score, whereas gender and SMN2 copy number were not. The increase in response before the break point of age 7 years is significant only for SMA IIIA (ß = 1.79, p < 0.0001). After the break point, the change in the rate of HFMSE score significantly decrease for both SMA IIIA (ß = -1.15, p < 0.0001) and IIIB (ß = -0.69, p = 0.002). INTERPRETATION: Our findings contribute to the understanding of the natural history of SMA type III and will be helpful in the interpretation of the real-world data of patients treated with commercially available drugs. ANN NEUROL 2020;88:1109-1117.

Motor unit number index: A potential electrophysiological biomarker for pediatric spinal muscular atrophy.

INTRODUCTION/AIMS: In adult spinal muscular atrophy (SMA), the motor unit number index (MUNIX) has been shown to be an useful electrophysiological biomarker. This study evaluated the feasibility and the clinical relevance of using the MUNIX technique for patients with pediatric SMA (Ped-SMA) and correlated MUNIX results with clinical scores. METHODS: Fourteen patients with type II Ped-SMA (11 females; median age 11 y [interquartile range (IQR), 4.8-17 y]) and 14 controls (nine females; median age 10.75 y [IQR, 6.5-13.4 y]) were enrolled and matched by sex, age, height, weight, and body mass index. Clinical examination included manual muscle testing, dynamometry (grasp and pinch), and motor function measure (MFM). The MUNIX technique was evaluated in the abductor digiti minimi (ADM) and abductor pollicis brevis (APB) on two sides when possible. RESULTS: In the patients with Ped-SMA, the MUNIX and compound muscle action potential (CMAP) amplitudes were significantly decreased and the motor size unit index (MUSIX) was significantly increased in the ADM and APB when compared to controls. The intraclass correlation coefficient was good for the intrarater variability of the CMAP amplitude, MUNIX, and MUSIX in the ADM (0.95, 0.83, and 0.89, respectively) and the APB (0.98, 0.96, and 0.94, respectively). The total CMAP amplitude correlated with the grasp and pinch scores (P < .05), and the MUNIX measurements correlated with the MFM scores. DISCUSSION: The MUNIX technique, which accurately estimated lower motor neuron loss and the number of remaining functional motor units, was shown to be a useful electrophysiological biomarker for disease progression and a potential biomarker for treatment response.

Combination therapy with onasemnogene and risdiplam in spinal muscular atrophy type 1.

INTRODUCTION/AIMS: There are currently three medications approved for spinal muscular atrophy (SMA), but the use of these medications in combination has not been well described. METHODS: This is a retrospective report of four cases of SMA treated with dual onasemnogene and risdiplam therapy at our institution. RESULTS: Following onasemnogene therapy, all four patients experienced a perceived plateau of therapeutic benefit, at which time daily risdiplam was started. Transient fatigue and weakness was seen in two patients following risdiplam initiation, but this resolved within 1 mo. One patient was hospitalized with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and post-viral pneumonia, weeks following risdiplam initiation. No other adverse effects related to onasemnogene and risdiplam combination therapy were identified and all patients experienced objective and subjective improvement. DISCUSSION: Combination therapy with onasemnogene and risdiplam in patients with SMA appears to be well-tolerated. Further large prospective trials are needed to determine whether dual therapy is more efficacious than monotherapy, and to identify rare adverse events that may occur with the use of combination therapy.

Time is muscle: A recommendation for early treatment for preterm infants with spinal muscular atrophy.

Implementation of newborn screening for spinal muscular atrophy (SMA) in 33 US states and increased genetic carrier screening have led to an increase in early, presymptomatic diagnosis of SMA. Early treatment is critically important and is recommended for presymptomatic infants with two to four copies of survival motor neuron 2. Currently, no specific treatment recommendations exist for preterm infants with SMA. The US Food and Drug Administration does not recommend using onasemnogene abeparvovec-xioi in preterm infants. Some insurance companies interpret "preterm" to be less than 40 weeks gestational age (GA) instead of the commonly accepted 37 weeks GA, which can be a barrier to treatment access. Given the risk of rapid decline in some infants, we recommend treatment of preterm infants when they reach 37 weeks GA, based on the definitions of term GA from the World Health Organization and Centers for Disease Control and Prevention, assuming all other treatment criteria are met.

Sensitivity and specificity of single and combined clouds analyses compared with quantitative motor unit potential analysis.

INTRODUCTION: Turns-amplitude, number of small segments (NSS)-activity, and envelope-activity clouds are three methods of electromyography (EMG) interference pattern analysis. Our objective was to evaluate the sensitivity and specificity of each individual cloud analysis and combined clouds analysis to compare with that of quantitative motor unit potential (QMUP) analysis. METHODS: A total of 379 muscles from 100 patients were analyzed by both QMUP and clouds analyses. Calculation of sensitivity and specificity was based on the clinical diagnosis as the "gold standard." RESULTS: For discrimination of abnormal vs normal and neuropathic vs non-neuropathic, combined clouds analysis had greater sensitivity than QMUP analysis and any single cloud analysis, but there were no differences in specificity. For discrimination of myopathic vs non-myopathic, combined clouds analysis and single cloud analysis had greater sensitivity than QMUP analysis, but there were no differences in specificity. DISCUSSION: Combined clouds analysis was superior to QMUP and each single cloud analysis for distinguishing normal, myopathic, and neuropathic muscles.

Clinical exome sequencing in the diagnosis of pediatric neuromuscular disease.

BACKGROUND: The diagnosis of uncommon pediatric neuromuscular disease (NMD) is challenging due to genetic and phenotypic heterogeneity, yet is important to guide treatment, prognosis, and recurrence risk. Patients with diagnostically challenging presentations typically undergo extensive testing with variable molecular diagnostic yield. Given the advancement in next generation sequencing (NGS), we investigated the value of clinical whole exome sequencing (ES) in uncommon pediatric NMD. METHODS: A retrospective cohort study of 106 pediatric NMD patients with a combination of ES, chromosomal microarray (CMA), and candidate gene testing was completed at a large tertiary referral center. RESULTS: A molecular diagnosis was achieved in 37/79 (46%) patients with ES, 4/44 (9%) patients with CMA, and 15/74 (20%) patients with candidate gene testing. In 2/79 (3%) patients, a dual molecular diagnosis explaining the neuromuscular disease process was identified. A total of 42 patients (53%) who received ES remained without a molecular diagnosis at the conclusion of the study. CONCLUSIONS: Due to NGS, molecular diagnostic yield of rare neurological diseases is at an all-time high. We show that ES has a higher diagnostic rate compared to other genetic tests in a complex pediatric neuromuscular disease cohort and should be considered early in the diagnostic journey for select NMD patients with challenging presentations in which a clinical diagnosis is not evident.