Incidence of infantile spinal muscular atrophy on Shikoku Island of Japan

Background

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by homozygous mutations in the SMN1 gene. SMA has long been known to be the most common genetic cause of infant mortality. However, there have been no reports on the epidemiology of infantile SMA (types 1 and 2) based on genetic testing in Japan. In this study, we estimated the incidence of infantile SMA on Shikoku Island, which is a main island of Japan and consists of four prefectures: Ehime, Kagawa, Tokushima and Kochi.

Short-term clinical outcomes of onasemnogene abeparvovec treatment for spinal muscular atrophy

IntroductionSpinal muscular atrophy (SMA) is a degenerative neuromuscular disorder long recognized as the most common genetic cause of infantile mortality described so far. However, the emergence of some innovative therapies, such as nusinersen and onasemnogene abeparvovec (AVXS-101), have made it possible to change the disease course of SMA.MethodsIn this study, five SMA type 1 and one SMA type 2 patients who received AVXS-101 were enrolled (7–24 months of age when administered). They were all previously treated with nusinersen, 4–5 times including loading doses, but stopped nusinersen maintenance after injection of AVXS-101. Patients were regularly followed up with laboratory tests and functional assessments after administration.ResultsLiver enzymes (aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase) and monocyte count tended to be elevated but normalized after several weeks. Platelets and white blood cells were transiently decreased for a few weeks after injection. Prolonged elevation of liver enzymes was associated with steroid tapering earlier than 1 month post treatment. During the follow-up period (ranging from 5 to 17 months after injection), all patients showed improved motor function and there was no case of mortality or requirement for permanent ventilatory support. For one patient, use of bilevel positive airway pressure could be reduced from 16 h to 8 h a day during sleep at 6 months post treatment.ConclusionOur experience of AVXS-101 treatment has shown that a single intravenous dose could be safe and effective for SMA patients without the need for any maintenance treatment.     

Epidemiological investigation of spinal muscular atrophy in Japan

BackgroundInternational reporting of epidemiological surveys of spinal muscular atrophy (SMA) in Japan has been limited to Shikoku, despite the epidemiology of the disease in countries worldwide becoming clearer. Treatments of 5q-SMA have been developed, and epidemiological studies are needed.PurposeThis study aimed to conduct a nationwide epidemiological survey of SMA in Japan to clarify the actual situation of SMA in Japan.MethodPatients with all clinical types of SMA, including neonates and adults, were selected from 1,005 medical facilities in Japan.ResultsAs of December 2017, the actual number of reported patients with SMA was 658 and the genetic testing rate was 79.5%. The estimated number of patients was 1,478 (95% confidence interval (CI), 1,122–1,834), with a prevalence of 1.17 (95%CI, 0.89–1.45) per 100,000 people and an incidence of 0.51 (95%CI, 0.32–0.71) per 10,000 live births. Incidence rates of 5q-SMA by clinical type were 0.27 (95%CI, 0.17–0.38) and 0.08 (95%CI, 0.04–0.11) per 10,000 live births for type 1 and 2, respectively, in cases with a definitive diagnosis by genetic testing. We found that 363 cases (82.7%) occurred less than 2 years and 88 (20.0%) occurred age of 2 months old or under.ConclusionThis study clarifies the prevalence and incidence of SMA in Japan. As infantile onset accounts for most cases of SMA, newborn screening and subsequent treatment are important to save lives.     

Administration of nusinersen via paramedian approach for spinal muscular atrophy

ObjectiveTo assess the success rate, procedure time, and adverse events of intrathecal administration of nusinersen via the paramedian approach in adolescents and adults with spinal muscular atrophy (SMA) associated with scoliosis.MethodsSeven patients with genetically confirmed SMA (age, 12–40 years) were included. Intrathecal administration of nusinersen was performed via paramedian approach using fluoroscopy after determination of the largest interlaminal foramen among L2-L3, L3-L4, or L4-L5 by three-dimensional computed tomography. We measured the times for preparation, positioning, and puncture, and the total time of stay. Adverse effects of intrathecal administration were noted.ResultsIntrathecal administration via paramedian approach was successful for all 38 opportunities. The median total time of stay was 44.0 min (interquartile range, 37.3–50.0 min). The total time of stay was significantly longer in patients with SMA type 1 than in those with SMA type 2, but was not different according to the severity of scoliosis. Adverse effects included oxygen supplementation, headache, and back pain. Sedation was correlated with oxygen supplementation and headache.ConclusionsIntrathecal administration of nusinersen via the paramedian approach had the advantages of a high success rate and short procedure time with fewer adverse events in SMA patients associated with scoliosis.     

Muscle impairment in MRI affect variability in treatment response to nusinersen in patients with spinal muscular atrophy type 2 and 3: A retrospective cohort study

BackgroundReal-world data have shown variability in treatment responses to nusinersen in spinal muscular atrophy (SMA). We investigated whether the magnitude of muscle impairment assessed by magnetic resonance imaging (MRI) at baseline can predict the treatment response.MethodsWe retrospectively assessed the clinical data in relevance to the thigh and pelvic MRI taken before the nusinersen treatment. A total of 16 patients with SMA types 2 and 3 (age = mean [SD]; 9.2 [4.6] year) receiving nusinersen treatment were enrolled. The T1-weighted MRI images of the pelvis and thigh were scored for muscle fatty infiltration and atrophy. The minimally clinically important difference (MCID) was considered as gaining at least 3 points of Hammersmith Functional Motor Scale-Expanded (HFMSE) from baseline.ResultsOf these 16 individuals, 14 had been treated for at least 15 months with baseline data. At 15 months, seven individuals obtained MCID in HFMSE. Baseline muscle MRI score could not differentiate the two groups; however, individuals who obtained MCID had significantly less severe scoliosis. In addition, there was a significant and negative relationship between baseline MRI score and the change of score in HFMSE after 15 months of treatment. Further, baseline Cobb angle along with MRI score also indicated the correlation to the degree of change in motor function.ConclusionThe degree of muscle damage may confer the variability in response to nusinersen in SMA types 2 and 3. Muscle MRI score along with the severity of scoliosis assessed at baseline may help to predict the motor function change.     

Long-term efficacy of nusinersen and its evaluation in adolescent and adult patients with spinal muscular atrophy types 1 and 2

BackgroundsThe efficacy of nusinersen and its evaluation in patients with spinal muscular atrophy (SMA) has been established in clinical trials only for pediatric patients, not for adolescent and adult patients who developed SMA in infancy or early childhood. We report a long-term follow-up in adolescent and adult patients with SMA types 1 and 2.MethodsNusinersen-treated patients with SMA types 1 and 2 between 2017 and 2022 were retrospectively reviewed. We compared baseline motor function tests with those after the final treatment. Physical and occupational therapists performed Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), Hammersmith Functional Motor Scale-Expanded (HFMSE), and Revised Upper Limb Module (RULM). The Landau and Galant reflexes were not performed in CHOP-INTEND. Meaningful improvement was defined as CHOP-INTEND, 4; HFSME, 3; and RULM, 2.ResultsSeven patients with SMA (type 1, 1; type 2, 6) with a median age of 23 (range, 12–40) years were treated with nusinersen for 3.55 (1.78–4.53) years. Improvement was detected in CHOP-INTEND (pre, 5 [0–31]; post, 21 [0–39]; difference, 5 [0–26]; p = 0.100) without significance, although not in HFMSE (pre, 0 [0–3]; post, 0 [0–5]; difference, 0 [0–2]; p = 0.346) and RULM (pre, 1 [0–20]; post, 3 [0–21]; difference, 1 [0–2]; p = 0.089). Owing to prolonged treatment intervals with the COVID-19 pandemic, RULM worsened in two patients.ConclusionNusinersen was effective in long-term follow-up. Only CHOP-INTEND showed meaningful improvement. The interval between doses of nusinersen should not be prolonged even with the COVID-19 pandemic.     

Longer-term follow-up of nusinersen efficacy and safety in adult patients with spinal muscular atrophy types 2 and 3

The effectiveness of nusinersen treatment in patients with spinal muscular atrophy (SMA) was established in clinical trials only for pediatric patients. Few cohort studies confirmed its benefit in adults up to 22 months of treatment. We report a longer-term observation of nusinersen treatment effects and safety in a large cohort of adult patients. Patients with SMA type 2 and 3 treated with nusinersen at Tel-Aviv Medical Center between March 2018 and September 2020 were prospectively recruited. Neurological impairment, motor, respiratory function, and side effects were recorded. We compared baseline measurements with those after 6, 14, and 26 months of treatment and calculated the annual rates of change. Overall, 37 patients were treated (21–64 years old). 16 completed 26 months, and 8 completed 30 months of treatment. The median score on the Medical Research Council strength scale increased from baseline to visits at 6 and 14 months (p ≤ 0.03), but not afterwards, with a median increase of 1.85 points per year. Revised Hammersmith Scale median score increased only from baseline to 6 months (p = 0.02), with a calculated annual rate of change of 0 points. No significant change was noticed in the respiratory function. The only side effect was post lumbar puncture headache. In conclusion, our study further supports the efficacy and safety of nusinersen treatment in adult patients with SMA2 and SMA3, with modest improvement in muscle strength, and stabilization of motor function over a relatively long period of observation.     

Intrathecal nusinersen treatment after ventriculo-peritoneal shunt placement: A case report focusing on the neurofilament light chain in cerebrospinal fluid

BackgroundIn July 2018, a rare and serious adverse effect (AE), namely, communicating hydrocephalus unrelated to meningitis or bleeding, was reported in relation to five patients treated with nusinersen for spinal muscular atrophy (SMA). Some patients were managed using a ventriculo-peritoneal shunt (VPS) implant and continued to receive nusinersen treatment. However, there is limited information concerning the effectiveness and safety of nusinersen treatment for patients with a VPS.Case reportA female patient exhibited general hypotonia soon after birth and was diagnosed, using genetic analysis, with spinal muscular atrophy. She required permanent invasive ventilation from 2 months of age. She developed a progressive hydrocephalus and underwent placement of a VPS in infancy. Treatment with nusinersen was initiated when she was 7 years old. The neurofilament light-chain (NfL) concentration in the cerebrospinal fluid (CSF) decreased over time with nusinersen treatment. Twelve months have passed since the start of nusinersen treatment and no AEs have been observed.ConclusionNusinersen treatment may be effective and safe, even after placement of a VPS. NfL levels in the CSF could be valuable markers of disease activity/treatment response even in advanced stages of SMA.     

Evaluation of cerebrospinal fluid biomarkers in pediatric patients with spinal muscular atrophy

BackgroundSpinal muscular atrophy (SMA) is a rare neuromuscular disorder characterised by muscle weakness and muscle atrophy and classified into five known subtypes based on clinical features. The recent development of novel drugs to treat SMA has been encouraging, and nusinersen is the first drug approved to treat SMA.ObjectiveTo explore cerebrospinal fluid (CSF) biomarkers of SMA and investigate their relationship with symptoms and the treatment response in pediatric patients.MethodsWe analyzed the CSF levels of chitotriosidase 1 (CHIT1) and inflammatory cytokines (tumor necrosis factor [TNF]-α and interferon [INF]-γ) using enzyme-linked immunosorbent assays in pediatric SMA patients treated at Hiroshima University Hospital over 2 years.ResultsThis study analyzed pediatric SMA patients. While the CSF inflammatory cytokines (TNF-α and INF-γ) in these SMA children were unchanged, the CHIT1 levels decreased significantly from year 1 to 2 of treatment. We also found a trend toward an inverse correlation between the motor function score (HINE-2 scores) and CHIT1 level from year 1 to 2 of treatment.ConclusionsCHIT1 may be a CSF biomarker of the treatment response in pediatric SMA.     

Respiratory and sleep outcomes in children with SMA treated with nusinersen - real world experience

It is unclear how improvements in peripheral motor function in children with spinal muscular atrophy (SMA), treated with nusinersen, translate into clinically significant respiratory/sleep outcomes. A retrospective chart review of SMA children at the Sydney Children's Hospital Network was undertaken looking at 2 years before and after receiving their first dose of nusinersen. Polysomnography (PSG), spirometry and clinical data were collected and analysed using paired and unpaired t-tests for PSG parameters and generalised estimating equations for longitudinal lung function data. Forty-eight children (10 Type 1, 23 Type 2, 15 Type 3) at mean age 6.98 yrs (SD 5.25) for nusinersen initiation were included. There was a statistically significant improvement in oxygen nadir during sleep in individuals post nusinersen (mean of 87.9% to 92.3% (95%CI 1.24 – 7.63, p = 0.01)). Based on clinical and PSG findings, 6/21 patients (5 Type 2, 1 Type 3) ceased nocturnal NIV post nusinersen. Non-significant improvements were demonstrated in mean slope for FVC% predicted, FVC Z-score and mean FVC% predicted. Within 2 years of commencing nusinersen, stabilisation of respiratory outcomes occurred. Whilst some of the SMA type 2/3 cohort ceased NIV, there were no statistically significant improvements lung function and most PSG parameters.     

Nusinersen treatment of older children and adults with spinal muscular atrophy

The purpose of this study was to determine how effective administration of nusinersen was at improving motor function in older adolescent and adult patients with spinal muscular atrophy, using standardized motor outcome measures. Data were gathered through a retrospective chart review of older spinal muscular atrophy patients (ages 5–58) being treated at Rady Children's Hospital and the University of California, San Diego with nusinersen from April 2017-June 2019. Linear mixed effects analyses found that, for older children and adult patients with SMA 1, 2, and 3, motor scores as measured by the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders for non-sitters improved by 6 points (p = .01) and the Hammersmith Infant Neurological Examination-2 by 2.6% (p = .008) over the 22-month study period. Over the same period, sitters improved on the Revised Upper Limb Module by 4.4 points (p = .02) and on the Hammersmith Functional Motor Scale-Expanded by 3.3% (p = .00005) post treatment with nusinersen. Older spinal muscular atrophy patients (5–58 years) being treated with nusinersen at our institutions are improving. Not only have symptoms stabilized, but their motor function has shown incremental improvements. Based on the results of this study, we suggested that nusinersen is well-tolerated and efficacious when treating older children and adult patients with spinal muscular atrophy 1, 2, and 3.     

Evaluation of real-life outcome data of patients with spinal muscular atrophy treated with nusinersen in Switzerland

Spinal muscular atrophy (SMA) is an autosomal recessive disorder causing progressive proximal muscular, respiratory, and bulbar weakness. We present outcome data on motor function, ventilation, nutrition, and language development of SMA patients treated with nusinersen in Switzerland. This multicenter, observational study included 44 patients. At treatment initiation, after 2 months and then every 4 months we assessed motor function with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP–INTEND), Hammersmith Functional Motor Scale expanded (HFMSE) and 6-Minute Walk Test (6MWT). At treatment initiation, patients were 0.1–44.6 years old, treatment duration ranged from 6 to 41 months. All 11 SMA type 1 children achieved higher CHOP-INTEND scores at the last assessment compared to treatment initiation, 4 acquired stable sitting. Six type 1 children were <18 months-old at treatment initiation. Two of them did not need ventilation or nutritional support at the last assessment; three had delayed language development and 3 articulation difficulties. 5/21 SMA type 2 patients achieved higher HFMSE scores. All ambulant type 3 patients showed a gain in the 6MWT. Nusinersen is an effective treatment, with gains in motor function occurring particularly in children and SMA type 1, but also in type 2 and 3, adolescents and adults.     

Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study

Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 [25.7–45.4] months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.     

Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss or mutations in SMN1. According to age of onset, achieved motor abilities, and life span, SMA patients are classified into type I (never sit), II (never walk unaided) or III (achieve independent walking abilities). SMN2, the highly homologous copy of SMN1, is considered the most important phenotypic modifier of the disease. Determination of SMN2 copy number is essential to establish careful genotype–phenotype correlations, predict disease evolution, and to stratify patients for clinical trials. We have determined SMN2 copy numbers in 625 unrelated Spanish SMA patients with loss or mutation of both copies of SMN1 and a clear assignation of the SMA type by clinical criteria. Furthermore, we compiled data from relevant worldwide reports that link SMN2 copy number with SMA severity published from 1999 to date (2834 patients with different ethnic and geographic backgrounds). Altogether, we have assembled a database with a total of 3459 patients to delineate more universal prognostic rules regarding the influence of SMN2 copy number on SMA phenotype. This issue is crucial in the present scenario of therapeutic advances with the perspective of SMA neonatal screening and early diagnosis to initiate treatments.     

Age related treatment effect in type II Spinal Muscular Atrophy pediatric patients treated with nusinersen

Previous natural history studies suggest that type II SMA patients remain stable over one year but show some progression over two years. Since nusinersen approval, there has been increasing attention to identify more specific age-related changes. The aim of the study was to establish 12-month changes in a cohort of pediatric type II SMA treated with nusinersen and to establish possible patterns of treatment effect in relation to different variables such as age, baseline value and SMN2 copy number. The Hammersmith Functional Motor Scale Expanded and the Revised Upper Limb Module were performed at T0 and 12 months after treatment (T12). Data in treated patients were compared to available data in untreated patients collected by the same evaluators.Seventy-seven patients of age between 2.64 and 17.88 years (mean:7.47, SD:3.79) were included. On t-test there was an improvement, with increased mean scores between T0 and T12 on both scales (p < 0.001). Using multivariate linear regression analysis, age and baseline scores were predictive of changes on both scales (p < 0.05) while SMN2 copy number was not. Differences were also found between study cohort and untreated data on both scales (p < 0.001). At 12 months, an increase in scores was observed in all the age subgroups at variance with natural history data. Our real-world data confirm the treatment effect of nusinersen in pediatric type II SMA patients and that the data interpretation should take into account different variables. These data confirm and expand the ones already reported in the Cherish study.     

Epidemiological study of Landau–Kleffner syndrome (LKS) in Japan

Objective: We aimed to determine the incidence and prevalence of LKS in Japanese children. Methods: A questionnaire was sent to all 3004 Japanese hospitals that have a department of pediatrics. The questionnaire asked for the number of first-visit LKS patients and LKS patients who were followed up at or visited their clinic during the past one year Vital statistics of the same year (2008) published by Ministry of Health, Labor and Welfare, Japan were referenced to calculate the estimated incidence and prevalence of LKS among Japanese children. Results: Chiefs of 1562 pediatric departments answered our inquiry (51.9% of returns). Six chiefs had one new LKS patient, aged 6–14 years. Thirty two patients with LKS were followed in the same period. The number of children with LKS less than 20 years of age who needed medical care was at least 23 and at most 31. Vital statistics of Japan 2009 revealed that the population of children aged 5–14 years was 11,861,464 and that aged 5–19 years was 18,007,968. Discussion: The number of the first-visit LKS patients was 6 in a year. We estimated the incidence of LKS in the 5- to 14-years-old Japanese population as about 1 in 978,000. The number of LKS patients aged 5–19 was estimated to range from 44.2 to 59.6 among a population of 18,007,968. This means the prevalence of LKS under medical care is roughly one in 302,147–407,420 children aged 5–19. This study is the first epidemiological estimation of the incidence and prevalence of children with LKS in Japan or, for that matter, in any other area. Conclusion: (1) Incidence of children with LKS aged 5–14 years was about 1 in a million in Japan. (2) Prevalence of children with LKS aged 5–19 and under medical care was one in about 300,000–410,000 in Japan. (3) This study constitutes the first epidemiological estimation of LKS in Japan.     

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.     

A patient with early-onset SMAX3 and a novel variant of ATP7A

ObjectiveTo describe clinical and genetic studies on a patient with early-onset spinal muscular atrophyX3 (SMAX3) with novel variant of ATP7A.MethodsClinical, neurophysiological, neuroimaging and pathological examinations were performed. Whole exome sequencing was applied to search genetic bases of this patient.ResultsThe patient had gait abnormality from early infantile period. Muscle imaging at 42 years old showed predominant involvement of proximal muscles as compared to the distal muscles. The patient had a novel variant of ATP7A, which was the fourth genotype of ATP7A exhibited as SMAX3. Contrary to previous reports of distal motor neuropathy, the clinical and neuroimaging findings in this case revealed dominant involvement in the proximal portion of the extremities and trunk, which is similar to patients with type III SMA.ConclusionThe dominant involvement of proximal motor system in this patient may expand the phenotypic variability of SMAX3. We need to be aware of this disorder in differential diagnosis of patients with type III SMA-like phenotype.     

High incidence of SMN1 gene deletion in Moroccan adult-onset spinal muscular atrophy patients

Abstract. Spinal muscular atrophy (SMA) is an autosomal recessive motor neuropathy characterized by selective degeneration of anterior horn cells of the spinal cord. Childhood SMA is divided into three types (I–III) on the basis of age of onset and severity. These disorders have been linked to the 5q13 region, where mutations in the Survival Motor Neuron 1 (SMN1) gene have been found in affected individuals. In the case of adult-onset SMA (type IV), on the other hand, reports of homozygous absence of SMN1 gene have been rare. We conducted deletion analysis of SMN and a neighboring gene, NAIP (neuronal apoptosis inhibiting protein). Among 54SMA patients (types I–IV), all of Moroccan origin, Exon 7 of the SMN1 gene was homozygously absent in 100% of type I, 90% of type II, 74% of type III and 80% of type IV SMA patients. Deletion of SMN1 exon 8 was detected in 100% of type I, 53% of type II, 53% of type III and 80% of type IV patients. NAIP exon 5 was homozygously deleted in 67% of type I, 32% of type II, 5% of type III and 20% of type IV SMA patients. Thirty control individuals who were studied had normal SMN1 and NAIP genes. Our results show a high incidence of SMN1 gene deletion in adult-onset SMA patients indicating that SMN1 is the autosomal recessive adult SMA-causing gene. While NAIP is commonly deleted in SMA, this is unlikely to affect disease severity; it was deleted in two adult SMA patients with mild phenotypes.     

The effect of the guidelines for management of febrile seizures 2015 on clinical practices: Nationwide survey in Japan

ObjectiveTo investigate the effect of guidelines for management of febrile seizures on the clinical practice, we conducted a nationwide survey in Japan.MethodsThe Japanese guidelines for management of febrile seizures 2015 (GL2015) was released in 2015. In 2016, a questionnaire was sent to all 512 certified hospitals (3 pediatricians each) of the Japan Pediatric Society and all 47 prefecture Pediatric Associations (10 private pediatricians each) in Japan asking about management policies for febrile seizures (FSs) during 2013–2014 and 2016. The questionnaires were about the following procedures: (1) lumbar punctures, blood examinations, and diazepam suppositories for children after a first simple FS at emergency departments; and (2) prophylactic diazepam during febrile illnesses in children with two or three past simple FSs, with no known predictors of recurrence.ResultsA total of 1327 pediatricians (66.2%) answered the questionnaire. Numbers of pediatricians performing lumbar punctures and blood examinations, and giving diazepam suppositories after a first simple FS were less in 2016 than in 2013–2014 (1.2% and 2.0%, 53.1% and 61.3%, and 36.7% and 51.9%, respectively). Pediatricians recommending prophylactic diazepam for children with two and three FSs decreased from 45.7% and 82.4% in 2013–2014 to 31.0% and 65.0% in 2016, respectively.ConclusionGL2015 had an effect on the clinical practices of pediatricians. On the other hand, 65% recommended prophylactic diazepam to children with three simple FSs even though GL2015 did not recommend use of diazepam based on number of previous FS. Anxiety about frequent seizures may affect pediatricians′ clinical practice.