Nusinersen induces detectable changes in compound motor action potential response in spinal muscular atrophy type 1 patients with severe impairment of motor function.

BACKGROUND: Most long-term affected spinal muscular atrophy (SMA) type 1 patients have severe impairment of motor function and are dependent on mechanical ventilation with tracheostomy. The efficacy and safety of nusinersen in these patients have not been established. METHODS: We retrospectively evaluated the efficacy of intrathecal nusinersen treatment in patients with SMA type 1 who continued treatment for at least 12 months. There were three patients enrolled in our study (3, 4 and 16 years of age) who had severe impairment of gross motor function without head control or the ability to roll over. All three needed mechanical ventilation with tracheostomy and tube feeding. Motor function was assessed using the Children s Hospital of Philadelphia infant test of neuromuscular disorders (CHOP-INTEND) and the caregivers' evaluations. Concurrently, we examined nerve conduction longitudinally and compared compound motor action potential (CMAP) amplitudes. RESULTS: All patients continued nusinersen administration without significant adverse events for more than three years. While CHOP-INTEND scores did not remarkably increase, according to the caregivers, all three patients had improved finger or facial muscle movements that enabled them to make their intentions understood. Some CMAPs before treatment were not identified but became traces after nusinersen administration. CONCLUSIONS: The improvement in motor function that leads to smoother communication could be a basis for continuing nusinersen treatment. Currently available motor function scorings are not efficient for assessing therapeutic interventions in SMA patients with medical care complexity. Longitudinal nerve conduction studies could be an objective indicator.

Inflammation and malnutrition as markers of poor outcomes in head and neck cancer patients treated with nivolumab.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) are approved for the treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), the response to ICIs remains unclear. AIMS/OBJECTIVES: To summarize the clinical outcomes of patients with HNSCC treated with nivolumab (Nivo) in our institution, and provide a basis for research on biomarkers that can predict the efficacy of ICIs. MATERIAL AND METHODS: Forty-four patients with R/M HNSCC who received Nivo (2017-2022) were retrospectively analysed. RESULTS: Despite the older age of this cohort (median age of 72 years), we observed favourable long-term outcomes, with an overall survival of 24.1 months, which could be attributed to our aggressive nutritional intervention. Older age, poor performance status (≥1), and higher Glasgow Prognostic Scores, reflecting the chronic inflammation and malnutrition of patients, were associated with poor prognoses, with hazard ratios for death of 2.63 (95% confidence interval [CI]; 1.07-6.46, p = .016), 3.50 (95% CI; 1.28-9.55, p = .001), and 2.69 (95% CI; 1.17-6.21, p = .029), respectively. Peripheral blood biomarker analysis revealed that systemic inflammation may negatively affect the efficacy of Nivo. CONCLUSIONS AND SIGNIFICANCE: Our results suggest that nutrition and inflammation must be the focus of future studies aiming to identify novel biomarkers.

An integrated genetic analysis of epileptogenic brain malformed lesions.

Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway.

Quantitative measurement of resistance force and subsequent attenuation during passive isokinetic extension of the wrist in patients with mild to moderate spasticity after stroke.

BACKGROUND: Spasticity is evaluated by measuring the increased resistance to passive movement, primarily by manual methods. Few options are available to measure spasticity in the wrist more objectively. Furthermore, no studies have investigated the force attenuation following increased resistance. The aim of this study was to conduct a safe quantitative evaluation of wrist passive extension stiffness in stroke survivors with mild to moderate spastic paresis using a custom motor-controlled device. Furthermore, we wanted to clarify whether the changes in the measured values could quantitatively reflect the spastic state of the flexor muscles involved in the wrist stiffness of the patients. MATERIALS AND METHODS: Resistance forces were measured in 17 patients during repetitive passive extension of the wrist at velocities of 30, 60, and 90 deg/s. The Modified Ashworth Scale (MAS) in the wrist and finger flexors was also assessed by two skilled therapists and their scores were averaged (i.e., average MAS) for analysis. Of the fluctuation of resistance, we focused on the damping just after the peak forces and used these for our analysis. A repeated measures analysis of variance was conducted to assess velocity-dependence. Correlations between MAS and damping parameters were analyzed using Spearman's rank correlation. RESULTS: The damping force and normalized value calculated from damping part showed significant velocity-dependent increases. There were significant correlations (ρ = 0.53-0.56) between average MAS for wrist and the normalized value of the damping part at 90 deg/s. The correlations became stronger at 60 deg/s and 90 deg/s when the MAS for finger flexors was added to that for wrist flexors (ρ = 0.65-0.68). CONCLUSIONS: This custom-made isokinetic device could quantitatively evaluate spastic changes in the wrist and finger flexors simultaneously by focusing on the damping part, which may reflect the decrease in resistance we perceive when manually assessing wrist spasticity using MAS. Trial registration UMIN Clinical Trial Registry, as UMIN000030672, on July 4, 2018.

Changes in the Incidence of Infantile Spinal Muscular Atrophy in Shikoku, Japan between 2011 and 2020.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. Al-though there was no cure for SMA, newly developed therapeutic drugs (nusinersen, onasemnogene abeparvovec, and risdiplam) have been proven effective for the improvement of motor function and prevention of respiratory insufficiency of infants with SMA. Nusinersen was introduced in Japan in 2017 and onasemnogene abeparvovec in 2020. We hypothesized that the introduction of these drugs might influence the incidence of SMA (more precisely, increase the diagnosis rate of SMA) in Japan. To test this hypothesis, we conducted a second epidemiological study of infantile SMA using questionnaires in Shikoku, Japan between October 2021 and February 2022. The incidence of infantile SMA during the period 2016-2020 was 7.08 (95% confidence interval [CI] 2.45-11.71) per 100,000 live births. According to our previous epidemiological study, the incidence of infantile SMA during 2011-2015 was 2.70 (95% CI 0.05-5.35) per 100,000 live births. The increased incidence of infantile SMA suggests that the widespread news in Japan regarding the introduction of therapeutic agents, nusinersen and onasemnogene abeparvovec, raised clinicians' awareness about SMA, leading to increased and earlier diagnosis of SMA in Shikoku.

Factors Influencing the Improvement of Activities of Daily Living during Inpatient Rehabilitation in Newly Diagnosed Patients with Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor. To identify the factors influencing the improvement of the activities of daily living (ADL) in newly diagnosed patients with GBM, we investigated the characteristics and variable factors and overall survival. A total of 105 patients with GBM were retrospectively analyzed and categorized into the following three groups according to the quartile of change of their Barthel index score from admission to discharge: deterioration (n = 25), no remarkable change (n = 55), and good recovery (n = 25). A statistical difference was observed in the pre-operative, intra-operative, post-operative, and rehabilitation-related factors between the deterioration and good recovery groups. Multiple regression analysis identified the following significant factors that may influence the improvement of ADL after surgery: the improvement of motor paralysis after surgery, mild fatigue during radio and chemotherapy, and length up to early walking training onset. The median overall survival was significantly different between the deterioration (10.6 months) and good recovery groups (18.9 months, p = 0.025). Our findings identified several factors that may be associated with post-operative functional improvement in patients with GBM. The inpatient rehabilitation during radio and chemotherapy may be encouraged without severe adverse events and can promote functional outcomes, which may contribute to the overall survival of newly diagnosed patients with GBM.

Effects of lower limb segmental muscle vibration on primary motor cortex short-latency intracortical inhibition and spinal excitability in healthy humans.

We examined the effects of lower limb segmental muscle vibration (SMV) on intracortical and spinal excitability in 13 healthy participants (mean age: 34.9 ± 7.8 years, 12 males, 1 female). SMV at 30 Hz was applied to the hamstrings, gastrocnemius, and soleus muscles for 5 min. Paired-pulse transcranial magnetic stimulation protocols were used to investigate motor-evoked potential (MEP)  amplitude, short-interval intracortical inhibition (SICI) and short-interval intracortical facilitation (SICF) from the abductor hallucis muscle (AbdH). These assessments were compared to the results of a control experiment (i.e., non-vibration) in the same participants. F-waves were evaluated from the AbdH on the right (vibration side) and left (non-vibration side) sides, and we calculated the ratio of the F-wave amplitude to the M-response amplitude (F/M ratio). These assessments were obtained before, immediately after, and 10, 20, and 30 min after SMV. For SICI, there was no change immediately after SMV, but there was a decrease over time (before vs. 30 min after, p = 0.021; immediately after vs. 30 min after, p = 0.015). There were no changes in test MEP amplitude, SICF, or the F/M ratio. SMV causes a gradual decrease in SICI over time perhaps owing to long-term potentiation. The present results may have implications for the treatment of spasticity.

Resveratrol improves motor function in patients with muscular dystrophies: an open-label, single-arm, phase IIa study.

Muscular dystrophies (MDs) are inherited disorders characterized by progressive muscle weakness. Previously, we have shown that resveratrol (3,5,4'-trihydroxy-trans-stilbene), an antioxidant and an activator of the protein deacetylase SIRT1, decreases muscular and cardiac oxidative damage and improves pathophysiological conditions in animal MD models. To determine whether resveratrol provides therapeutic benefits to patients with MDs, an open-label, single-arm, phase IIa trial of resveratrol was conducted in 11 patients with Duchenne, Becker or Fukuyama MD. The daily dose of resveratrol was 500 mg/day, which was increased every 8 weeks to 1000 and then 1500 mg/day. Primary outcomes were motor function, evaluated by a motor function measure (MFM) scale, muscular strength, monitored with quantitative muscle testing (QMT), and serum creatine kinase (CK) levels. Adverse effects and tolerability were evaluated as secondary outcomes. Despite the advanced medical conditions of the patients, the mean MFM scores increased significantly from 34.6 to 38.4 after 24 weeks of medication. A twofold increase was found in the mean QMT scores of scapula elevation and shoulder abduction. Mean CK levels decreased considerably by 34%. Diarrhoea and abdominal pain was noted in six and three patients, respectively. Resveratrol may provide some benefit to MD patients.

Reliability of the portable gait rhythmogram in post-stroke patients.

BACKGROUND: Gait analysis, such as portable gait rhythmogram (PGR), provides objective information that helps in the quantitative evaluation of human locomotion. OBJECTIVE: The purpose of this study was to assess the reliability of PGR in post-stroke patients. METHODS: Two raters (A and B) examined 48 post-stroke patients. To assess intra-rater reliability, rater A tested subjects on three separate occasions (Days 1, 2, and 3). To assess inter-rater reliability, raters A and B independently tested participants on the same occasion (Day 3). RESULTS: There was no significant systematic bias between test occasions or raters. Intraclass correlation coefficient values were 0.93-0.97 for intra-rater reliability at both the comfortable speed and maximum speed, and 0.97-0.98 (comfortable speed) and 0.97-0.99 (maximum speed) for inter-rater reliability. The standard error was 1.25-1.49 (comfortable speed) and 1.62-1.77 (maximum speed) for intra-rater investigation, and 1.04-1.32 (comfortable speed) and 0.91-1.26 (maximum speed) for inter-rater investigation. At the 90% confidence level, the minimum detectable change ranged from 2.9-4.1%, and the error of an individual's score at a given time point ranged from ±2.1-2.9%. CONCLUSIONS: Based on this excellent reliability of the PGR in post-stroke patients, it can be recommended as a simple test of gait analysis in this population.

Reaching exercise for chronic paretic upper extremity after stroke using a novel rehabilitation robot with arm-weight support and concomitant electrical stimulation and vibration: before-and-after feasibility trial.

BACKGROUND: Our group developed a rehabilitation robot to assist with repetitive, active reaching movement of a paretic upper extremity. The robot is equipped with a servo motor-controlled arm-weight support and works in conjunction with neuromuscular electrical stimulation and vibratory stimulation to facilitate agonist-muscle contraction. In this before-and-after pilot study, we assessed the feasibility of applying the robot to improve motor control and function of the hemiparetic upper extremity in patients who suffered chronic stroke. METHODS: We enrolled 6 patients with chronic stroke and hemiparesis who, while sitting and without assistance, could reach 10 cm both sagitally and vertically (from a starting position located 10 cm forward from the patient's navel level) with the affected upper extremity. The patients were assigned to receive reaching exercise intervention with the robot (Yaskawa Electric Co., Ltd. Fukuoka, Japan) for 2 weeks at 15 min/day in addition to regular occupational therapy for 40 min/day. Outcomes assessed before and after 2 weeks of intervention included the upper extremity component of the Fugl-Meyer Assessment (UE-FMA), the Action Research Arm Test (ARAT), and, during reaching movement, kinematic analysis. RESULTS: None of the patients experienced adverse events. The mean score of UE-FMA increased from 44.8 [SD 14.4] to 48.0 [SD 14.4] (p = 0.026, r = 0.91), and both the shoulder-elbow and wrist-hand scores increased after 2-week intervention. An increase was also observed in ARAT score, from mean 29.8 [SD 16.3] to 36.2 [SD 18.1] (p = 0.042, r = 0.83). Kinematic analysis during the reaching movement revealed a significant increase in active range of motion (AROM) at the elbow, and movement time tended to decrease. Furthermore, trajectory length for the wrist ("hand path") and the acromion ("trunk compensatory movement") showed a decreasing trend. CONCLUSIONS: This robot-assisted modality is feasible and our preliminary findings suggest it improved motor control and motor function of the hemiparetic upper extremity in patients with chronic stroke. Training with this robot might induce greater AROM for the elbow and decrease compensatory trunk movement, thus contributing to movement efficacy and efficiency. Trial registration UMIN Clinical Trial Registry, as UMIN000018132, on June 30, 2015. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000020398.

Acute changes in cortical activation during active ankle movement after whole-body vibration for spasticity in hemiplegic legs of stroke patients: a functional near-infrared spectroscopy study.

Background: A recent study revealed that whole-body vibration (WBV) tends to decrease spasticity in stroke-related hemiplegic legs. However, acute changes in cortical activation after WBV are unclear.Objective: To examine whether WBV induces acute changes in sensorimotor cortical activation in patients with stroke-related hemiplegic legs.Methods: Eleven stroke patients (mean age 52.6 [SD 15.4] years; median time after stroke 3 [25th and 75th percentiles; 3 and 10.5, respectively] months) participated in a comparative before-and-after intervention trial. Six healthy adults were also studied. WBV at 30 Hz was applied for 5 min to the hamstrings, gastrocnemius, and soleus muscles. Spasticity was assessed according to the modified Ashworth scale (MAS). Active and passive range of motion (A-ROM and P-ROM, respectively) were also measured. Change in Oxy-Hb concentration in bilateral sensorimotor cortex associated with voluntary ankle dorsiflexion of the affected limb was assessed via functional near-infrared spectroscopy (fNIRS) before and immediately after WBV.Results: MAS score, A-ROM, and P-ROM improved immediately after WBV. In the patients, while there was no significant interaction between effects of region (ipsilesional and contralesional sensorimotor cortex) and the WBV intervention (before and immediately after WBV) (F1,10 = 0.702, p = .422), there was a significant main effect of the WBV intervention (F1,10 = 6.971, p = .025). In the healthy participants, there was no association with the WBV intervention or region.Conclusions: In patients with stroke-related spastic-hemiplegic legs, WBV might result not only in clinical improvement but also in acute increase in sensorimotor cortical activation.

Effects of concomitant neuromuscular electrical stimulation during repetitive transcranial magnetic stimulation before repetitive facilitation exercise on the hemiparetic hand.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) and Repetitive facilitative exercise (RFE) improves motor impairment after stroke. OBJECTIVE: To investigate whether neuromuscular electrical stimulation (NMES) can facilitate the effects of rTMS and RFE on the function of the hemiparetic hand in stroke patients. METHODS: This randomized double-blinded crossover study divided 20 patients with hemiparesis into two groups and provided treatment for 4 weeks at 5 days/week. NMES-before-sham group and NMES-following-sham group performed NMES sessions and sham NMES sessions for each 2 weeks. Patients received NMES or sham NMES for the affected extensor muscle concurrently with 1 Hz rTMS for the unaffected motor cortex for 10 min and performed RFE for 60 min. The Fugl-Meyer Assessment (FMA), Action Research Arm Test (ARAT), Box and Block Test (BBT) and Modified Ashworth Scale (MAS) were used for evaluation. RESULTS: FMA and ARAT improved significantly during both sessions. The gains in the BBT during an NMES session were significantly greater than those during a sham NMES session. MAS for the wrist and finger significantly decreased only during an NMES session. CONCLUSIONS: NMES combined with rTMS might facilitate, at least in part, the beneficial effects of RFE on motor function and spasticity of the affected upper limb.

Transcranial magnetic stimulation for diplopia in a patient with spinocerebellar ataxia type 6: a case report.

BACKGROUND: In Patients with spinocerebellar ataxia type 6 (SCA6) are often treated by transcranial magnetic stimulation (TMS) over the motor cortex and cerebellum. However, few reports have examined effective therapeutic modalities for diplopia in SCA6 patients. In the current case, we applied single-pulse TMS over the motor cortex and cerebellum to improve ataxia, and observed an unexpected improvement of diplopia. CASE PRESENTATION: A 62-year-old Japanese male with spinocerebellar ataxia type 6 (SCA6) was admitted to our hospital for exacerbation of ataxia. We administered single-pulse transcranial magnetic stimulation (TMS) over the hand motor area and the cerebellum with a circular coil to reduce ataxia. After the initiation of TMS, since diplopia unexpectedly improved, we started a quantitative assessment of diplopia by counting the number of fixation spots that he observed in his visual field. This assessment suggested that TMS had an immediate and cumulative effect on diplopia. We also delivered more localized stimulation only over the motor cortex with a Figure-8 coil, and diplopia improved immediately. Additionally, we administered a sham stimulation before the real stimulation over the motor cortex and the cerebellum. The sham stimulation improved diplopia, and greater improvement was observed with subsequent real stimulation. We also used a Hess chart examination and video recordings of binocular gross appearance to elucidate the changes in ocular movement objectively. However, these examinations did not reveal any obvious oculomotor changes. CONCLUSIONS: We applied single-pulse TMS to a SCA6 patient with diplopia, which improved without any adverse effects. TMS may have potential for the treatment of diplopia in SCA6 patients.

Intra-rater and inter-rater reliability of the portable gait rhythmogram in post-stroke patients.

[Purpose] Gait analysis, such as portable gait rhythmogram (PGR) provides objective information that helps in the quantitative evaluation of human locomotion. The purpose of this study was to assess the reliability of PGR in post-stroke patients. [Subjects and Methods] Two raters (A and B) examined 44 post-stroke patients. To assess intra-rater reliability, rater A tested subjects on three separate occasions (Days 1, 2, and 3). To assess inter-rater reliability, raters A and B independently tested participants on the same occasion (Day 3). [Results] There was no significant systematic bias between test occasions or raters. Intraclass correlation coefficient values were 0.93-0.97 for intra-rater reliability at both the comfortable speed and maximum speed, and 0.97-0.98 (comfortable speed) and 0.87-0.99 (maximum speed) for inter-rater reliability. The standard error was 1.25-1.49 (comfortable speed) and 1.62-1.77 (maximum speed) for intra-rater investigation, and 1.04-1.32 (comfortable speed) and 0.91-1.26 (maximum speed) for inter-rater investigation. At the 90% confidence level, the minimum detectable change ranged from 2.9-4.1%, and the error of an individual's score at a given time point ranged from ±2.1-2.9%. [Conclusion] Based on this excellent reliability of the PGR in post-stroke patients, it can be recommended as a simple test of gait analysis in this population.

A Mutation in the Tubulin-Encoding TUBB3 Gene Causes Complex Cortical Malformations and Unilateral Hypohidrosis.

Recent studies have emphasized the association between tubulin gene mutations and developmental abnormalities of the cortex. In this study, the authors identified a mutation in the tubulin-encoding class III ß-tubulin (TUBB3) gene in a 4-year-old boy presenting with brain abnormalities and unilateral hypohidrosis. The patient showed a left internal strabismus, moderate developmental delay, and congenital hypohidrosis of the right side of the body. Magnetic resonance imaging disclosed gyral disorganization mainly in the left perisylvian region, dysmorphic and hypertrophic basal ganglia with fusion between the putamen and caudate nucleus without affecting the anterior limb of the internal capsule, and moderate hypoplasia of the right brain stem and cerebellum. Diffusion tensor imaging studies revealed disorganization of the pyramidal fibers. The amplitude of the sympathetic skin response was low in the right arm, which led to a diagnosis of focal autonomic neuropathy. Sequencing the TUBB3 gene revealed a de novo missense mutation, c.862G>A (p.E288K).

Identification and conformer analysis of a novel redox-active motif, Pro-Ala-Ser-Cys-Cys-Ser, in Drosophila thioredoxin reductase by semiempirical molecular orbital calculation.

Mammalian thioredoxin reductases (TrxRs) contain selenium as selenocysteine (Sec) in the C-terminal redox center -Gly-Cys-Sec-Gly-OH to reduce Trx and other substrates; a Sec-to-Cys substitution in mammalian TrxR yields an almost inactive enzyme. The corresponding tetrapeptide sequence in Drosophila melanogaster TrxR (Dm-TrxR), -Ser-Cys-Cys-Ser-OH, endows the orthologous enzyme with a catalytic competence similar to mammalian selenoenzymes, but implementation of the Ser-containing tetrapeptide sequence SCCS into the mammalian enzyme does not restore the activity of the Sec-to-Cys mutant form (turnover number <2/min). MOPAC calculation suggested that the C-terminal hexapeptide Pro-Ala-Ser-Cys-Cys-Ser-OH functions as a redox center that alleviates the necessity for selenium in Dm-TrxR, and a mutant form of human lung TrxR that mimics this hexapeptide sequence showed improved catalytic turnover (17.4/min for DTNB and 13.2/min for E. coli trx) compared to the Sec-to-Cys mutant. MOPAC calculation also suggested that the dominant form of the Pro-containing hexapeptide is a C+ conformation, which perhaps has a catalytic advantage in facile reduction of the intramolecular disulfide bond between Cys497 and Cys498 by the N-terminal redox center in the neighboring subunit.