The aim of this study was to document upper leg involvement in spinal muscular atrophy (SMA) with quantitative MRI (qMRI) in a cross‐sectional cohort of patients of varying type, disease severity and ...age. Thirty‐one patients with SMA types 2 and 3 (aged 29.6 7.6‐73.9 years) and 20 healthy controls (aged 37.9 17.7‐71.6 years) were evaluated in a 3 T MRI with a protocol consisting of DIXON, T2 mapping and diffusion tensor imaging (DTI). qMRI measures were compared with clinical scores of motor function (Hammersmith Functional Motor Scale Expanded HFMSE) and muscle strength. Patients exhibited an increased fat fraction and fractional anisotropy (FA), and decreased mean diffusivity (MD) and T2 compared with controls (all P < .001). DTI parameters FA and MD manifest stronger effects than can be accounted for the effect of fatty replacement. Fat fraction, FA and MD show moderate correlation with muscle strength and motor function: FA is negatively associated with HFMSE and Medical Research Council sum score (τ = −0.56 and −0.59; both P < .001) whereas for fat fraction values are τ = −0.50 and −0.58, respectively (both P < .001). This study shows that DTI parameters correlate with muscle strength and motor function. DTI findings indirectly indicate cell atrophy and act as a measure independently of fat fraction. Combined these data suggest the potential of muscle DTI in monitoring disease progression and to study SMA pathogenesis in muscle.
qMRI of thigh muscle in a cross‐sectional cohort of spinal muscular atrophy patients reveals an increased fat fraction and fractional anisotropy (FA), and decreased mean diffusivity (MD) and T2 compared with controls. We acknowledged the confounding effect of fatty infiltration on our data with simulations. DTI parameters FA and MD manifest stronger effects than can be accounted for by the effect of fat replacement. DTI findings indirectly indicate cell atrophy and act as a measure independently of fat fraction.
Objectives
Quantitative MRI (qMRI) of muscles is a promising tool to measure disease progression or to assess therapeutic effects in neuromuscular diseases. Longitudinal imaging studies are needed to ...show sensitivity of qMRI in detecting disease progression in spinal muscular atrophy (SMA). In this pilot study we therefore studied one‐year changes in quantitative MR parameters in relation to clinical scores.
Methods
We repeated quantitative 3 T MR analysis of thigh muscles and clinical testing one year after baseline in 10 treatment‐naïve patients with SMA, 5 with Type 2 (21.6 ± 7.0 years) and 5 with Type 3 (33.4 ± 11.9 years). MR protocol consisted of Dixon, T2 mapping and diffusion tensor imaging (DTI). The temporal relation of parameters was examined with a mixed model.
Results
We detected a significant increase in fat fraction (baseline, 38.2% SE 0.6; follow‐up, 39.5% SE 0.6; +1.3%, p = 0.001) in all muscles. Muscles with moderate to high fat infiltration at baseline show a larger increase over time (+1.6%, p < 0.001). We did not find any changes in DTI parameters except for low fat‐infiltration muscles (m. adductor longus and m. biceps femoris (short head)). The T2 of muscles decreased from 28.2 ms to 28.0 ms (p = 0.07). Muscle strength and motor function scores were not significantly different between follow‐up and baseline.
Conclusion
Longitudinal imaging data show slow disease progression in skeletal muscle of the thigh of (young‐) adult patients with SMA despite stable strength and motor function scores. Quantitative muscle imaging demonstrates potential as a biomarker for disease activity and monitoring of therapy response.
Quantitative 3T MRI of thigh muscle in spinal muscular atrophy patients detected a significant increase in fat fraction and decrease in T2 over the course of one year. We did not find any changes in the DTI parameters MD and FA except for low fat‐infiltration muscles (m. adductor longus and m. biceps femoris (short head)). Muscle strength and motor function scores remained stable. Quantitative muscle MRI demonstrates potential as a biomarker for disease activity and monitoring of therapy response.
Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a point mutation in the ...second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. By definition, children with SMA type I are never able to sit without support and usually die or become ventilator dependent before the age of two years. There have until very recently been no drug treatments to influence the course of SMA. We undertook this updated review to evaluate new evidence on emerging treatments for SMA type I. The review was first published in 2009 and previously updated in 2011.
To assess the efficacy and safety of any drug therapy designed to slow or arrest progression of spinal muscular atrophy (SMA) type I.
We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. We also searched two trials registries to identify unpublished trials (October 2018).
We sought all randomised controlled trials (RCTs) or quasi-RCTs that examined the efficacy of drug treatment for SMA type I. Included participants had to fulfil clinical criteria and have a genetically confirmed deletion or mutation of the SMN1 gene (5q11.2-13.2). The primary outcome measure was age at death or full-time ventilation. Secondary outcome measures were acquisition of motor milestones, i.e. head control, rolling, sitting or standing, motor milestone response on disability scores within one year after the onset of treatment, and adverse events and serious adverse events attributable to treatment during the trial period. Treatment strategies involving SMN1 gene replacement with viral vectors are out of the scope of this review.
We followed standard Cochrane methodology.
We identified two RCTs: one trial of intrathecal nusinersen in comparison to a sham (control) procedure in 121 randomised infants with SMA type I, which was newly included at this update, and one small trial comparing riluzole treatment to placebo in 10 children with SMA type I. The RCT of intrathecally-injected nusinersen was stopped early for efficacy (based on a predefined Hammersmith Infant Neurological Examination-Section 2 (HINE-2) response). At the interim analyses after 183 days of treatment, 41% (21/51) of nusinersen-treated infants showed a predefined improvement on HINE-2, compared to 0% (0/27) of participants in the control group. This trial was largely at low risk of bias. Final analyses (ranging from 6 months to 13 months of treatment), showed that fewer participants died or required full-time ventilation (defined as more than 16 hours daily for 21 days or more) in the nusinersen-treated group than the control group (hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.32 to 0.89; N = 121; a 47% lower risk; moderate-certainty evidence). A proportion of infants in the nusinersen group and none of 37 infants in the control group achieved motor milestones: 37/73 nusinersen-treated infants (51%) achieved a motor milestone response on HINE-2 (risk ratio (RR) 38.51, 95% CI 2.43 to 610.14; N = 110; moderate-certainty evidence); 16/73 achieved head control (RR 16.95, 95% CI 1.04 to 274.84; moderate-certainty evidence); 6/73 achieved independent sitting (RR 6.68, 95% CI 0.39 to 115.38; moderate-certainty evidence); 7/73 achieved rolling over (RR 7.70, 95% CI 0.45 to 131.29); and 1/73 achieved standing (RR 1.54, 95% CI 0.06 to 36.92; moderate-certainty evidence). Seventy-one per cent of nusinersen-treated infants versus 3% of infants in the control group were responders on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) measure of motor disability (RR 26.36, 95% CI 3.79 to 183.18; N = 110; moderate-certainty evidence). Adverse events and serious adverse events occurred in the majority of infants but were no more frequent in the nusinersen-treated group than the control group (RR 0.99, 95% CI 0.92 to 1.05 and RR 0.70, 95% CI 0.55 to 0.89, respectively; N = 121; moderate-certainty evidence). In the riluzole trial, three of seven children treated with riluzole were still alive at the ages of 30, 48, and 64 months, whereas all three children in the placebo group died. None of the children in the riluzole or placebo group developed the ability to sit, which was the only milestone reported. There were no adverse effects. The certainty of the evidence for all measured outcomes from this study was very low, because the study was too small to detect or rule out an effect, and had serious limitations, including baseline differences. This trial was stopped prematurely because the pharmaceutical company withdrew funding. Various trials and studies investigating treatment strategies other than nusinersen, such as SMN2 augmentation by small molecules, are ongoing.
Based on the very limited evidence currently available regarding drug treatments for SMA type 1, intrathecal nusinersen probably prolongs ventilation-free and overall survival in infants with SMA type I. It is also probable that a greater proportion of infants treated with nusinersen than with a sham procedure achieve motor milestones and can be classed as responders to treatment on clinical assessments (HINE-2 and CHOP INTEND). The proportion of children experiencing adverse events and serious adverse events on nusinersen is no higher with nusinersen treatment than with a sham procedure, based on evidence of moderate certainty. It is uncertain whether riluzole has any effect in patients with SMA type I, based on the limited available evidence. Future trials could provide more high-certainty, longer-term evidence to confirm this result, or focus on comparing new treatments to nusinersen or evaluate them as an add-on therapy to nusinersen.
Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a (point) mutation in the ...second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. This is an update of a review first published in 2009 and previously updated in 2011.
To evaluate if drug treatment is able to slow or arrest the disease progression of SMA types II and III, and to assess if such therapy can be given safely.
We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. In October 2018, we also searched two trials registries to identify unpublished trials.
We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a homozygous deletion or hemizygous deletion in combination with a point mutation in the second allele of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis. The primary outcome measure was change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full-time ventilation and adverse events attributable to treatment during the trial period. Treatment strategies involving SMN1-replacement with viral vectors are out of the scope of this review, but a summary is given in Appendix 1. Drug treatment for SMA type I is the topic of a separate Cochrane Review.
We followed standard Cochrane methodology.
The review authors found 10 randomised, placebo-controlled trials of treatments for SMA types II and III for inclusion in this review, with 717 participants. We added four of the trials at this update. The trials investigated creatine (55 participants), gabapentin (84 participants), hydroxyurea (57 participants), nusinersen (126 participants), olesoxime (165 participants), phenylbutyrate (107 participants), somatotropin (20 participants), thyrotropin-releasing hormone (TRH) (nine participants), valproic acid (33 participants), and combination therapy with valproic acid and acetyl-L-carnitine (ALC) (61 participants). Treatment duration was from three to 24 months. None of the studies investigated the same treatment and none was completely free of bias. All studies had adequate blinding, sequence generation and reporting of primary outcomes. Based on moderate-certainty evidence, intrathecal nusinersen improved motor function (disability) in children with SMA type II, with a 3.7-point improvement in the nusinersen group on the Hammersmith Functional Motor Scale Expanded (HFMSE; range of possible scores 0 to 66), compared to a 1.9-point decline on the HFMSE in the sham procedure group (P < 0.01; n = 126). On all motor function scales used, higher scores indicate better function. Based on moderate-certainty evidence from two studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: creatine (median change 1 higher, 95% confidence interval (CI) -1 to 2; on the Gross Motor Function Measure (GMFM), scale 0 to 264; n = 40); and combination therapy with valproic acid and carnitine (mean difference (MD) 0.64, 95% CI -1.1 to 2.38; on the Modified Hammersmith Functional Motor Scale (MHFMS), scale 0 to 40; n = 61). Based on low-certainty evidence from other single studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: gabapentin (median change 0 in the gabapentin group and -2 in the placebo group on the SMA Functional Rating Scale (SMAFRS), scale 0 to 50; n = 66); hydroxyurea (MD -1.88, 95% CI -3.89 to 0.13 on the GMFM, scale 0 to 264; n = 57), phenylbutyrate (MD -0.13, 95% CI -0.84 to 0.58 on the Hammersmith Functional Motor Scale (HFMS) scale 0 to 40; n = 90) and monotherapy of valproic acid (MD 0.06, 95% CI -1.32 to 1.44 on SMAFRS, scale 0 to 50; n = 31). Very low-certainty evidence suggested that the following interventions had little or no effect on motor function: olesoxime (MD 2, 95% -0.25 to 4.25 on the Motor Function Measure (MFM) D1 + D2, scale 0 to 75; n = 160) and somatotropin (median change at 3 months 0.25 higher, 95% CI -1 to 2.5 on the HFMSE, scale 0 to 66; n = 19). One small TRH trial did not report effects on motor function and the certainty of evidence for other outcomes from this trial were low or very low. Results of nine completed trials investigating 4-aminopyridine, acetyl-L-carnitine, CK-2127107, hydroxyurea, pyridostigmine, riluzole, RO6885247/RG7800, salbutamol and valproic acid were awaited and not available for analysis at the time of writing. Various trials and studies investigating treatment strategies other than nusinersen (e.g. SMN2-augmentation by small molecules), are currently ongoing.
Nusinersen improves motor function in SMA type II, based on moderate-certainty evidence. Creatine, gabapentin, hydroxyurea, phenylbutyrate, valproic acid and the combination of valproic acid and ALC probably have no clinically important effect on motor function in SMA types II or III (or both) based on low-certainty evidence, and olesoxime and somatropin may also have little to no clinically important effect but evidence was of very low-certainty. One trial of TRH did not measure motor function.
Quantitative magnetic resonance imaging (qMRI) is frequently used to map the disease state and disease progression in the lower extremity muscles of patients with spinal muscular atrophy (SMA). This ...is in stark contrast to the almost complete lack of data on the upper extremity muscles, which are essential for carrying out daily activities. The aim of this study was therefore to assess the disease state in the upper arm muscles of patients with SMA in comparison with healthy controls by quantitative assessment of fat fraction, diffusion indices, and water T2 relaxation times, and to relate these measures to muscle force. We evaluated 13 patients with SMA and 15 healthy controls with a 3‐T MRI protocol consisting of DIXON, diffusion tensor imaging, and T2 sequences. qMRI measures were compared between groups and related to muscle force measured with quantitative myometry. Fat fraction was significantly increased in all upper arm muscles of the patients with SMA compared with healthy controls and correlated negatively with muscle force. Additionally, fat fraction was heterogeneously distributed within the triceps brachii (TB) and brachialis muscle, but not in the biceps brachii muscle. Diffusion indices and water T2 relaxation times were similar between patients with SMA and healthy controls, but we did find a slightly reduced mean diffusivity (MD), λ1, and λ3 in the TB of patients with SMA. Furthermore, MD was positively correlated with muscle force in the TB of patients with SMA. The variation in fat fraction further substantiates the selective vulnerability of muscles. The reduced diffusion tensor imaging indices, along with the positive correlation of MD with muscle force, point to myofiber atrophy. Our results show the feasibility of qMRI to map the disease state in the upper arm muscles of patients with SMA. Longitudinal data in a larger cohort are needed to further explore qMRI to map disease progression and to capture the possible effects of therapeutic interventions.
Our multi‐parametric qMR approach showed its feasibility to map the disease state in the upper arm muscles of patients with SMA over a wide range of disease phases. We found 2‐ to 5‐fold higher fat fractions in the upper arm muscles of patients with SMA compared with healthy controls, which correlated negatively with maximal voluntary force. Water T2 relaxation times were not significantly different from healthy muscle, while DTI indices showed potential for the mapping of changes in muscle of patients with SMA.
Background
Respiratory failure is a major cause of morbidity and mortality in patients with Spinal Muscular Atrophy (SMA). Lack of endurance, or “fatigability,” is an important symptom of SMA. In ...addition to respiratory muscle weakness, respiratory function in SMA may be affected by Respiratory Muscle Fatigability (RMF).
Aim
The purpose of this study was to explore RMF in patients with SMA.
Methods
We assessed a Respiratory Endurance Test (RET) in 19 children (median age years: 11) and 36 adults (median age years: 34) with SMA types 2 and 3. Participants were instructed to breath against an inspiratory threshold load at either 20%, 35%, 45%, 55%, or 70% of their individual maximal inspiratory mouth pressure (PImax). RMF was defined as the inability to complete 60 consecutive breaths. Respiratory fatigability response was determined by change in maximal inspiratory mouth pressure (ΔPImax) and perceived fatigue (∆perceived fatigue).
Results
The probability of RMF during the RET increased by 59%−69% over 60 breaths with every 10% increase in inspiratory threshold load (%PImax). Fatigability response was characterized by a large variability in ΔPImax (−21% to +16%) and a small increase in perceived fatigue (p = 0.041, range 0 to +3).
Conclusion and Key Findings
Patients with SMA demonstrate a dose‐dependent increase in RMF without severe increase in exercise‐induced muscle weakness or perceived fatigue. Inspiratory muscle loading in patients with SMA seems feasible and its potential to stabilize or improve respiratory function in patients with SMA needs to be determined in further research.
Background
The immunological pathophysiologies of chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) differ considerably, but neither has been elucidated ...completely. Quantitative magnetic resonance imaging (MRI) techniques such as diffusion tensor imaging, T2 mapping, and fat fraction analysis may indicate in vivo pathophysiological changes in nerve architecture. Our study aimed to systematically study nerve architecture of the brachial plexus in patients with CIDP, MMN, motor neuron disease (MND) and healthy controls using these quantitative MRI techniques.
Methods
We enrolled patients with CIDP (n = 47), MMN (n = 29), MND (n = 40) and healthy controls (n = 10). All patients underwent MRI of the brachial plexus and we obtained diffusion parameters, T2 relaxation times and fat fraction using an automated processing pipeline. We compared these parameters between groups using a univariate general linear model.
Results
Fractional anisotropy was lower in patients with CIDP compared to healthy controls (p < 0.001), patients with MND (p = 0.010) and MMN (p < 0.001). Radial diffusivity was higher in patients with CIDP compared to healthy controls (p = 0.015) and patients with MND (p = 0.001) and MMN (p < 0.001). T2 relaxation time was elevated in patients with CIDP compared to patients with MND (p = 0.023). Fat fraction was lower in patients with CIDP and MMN compared to patients with MND (both p < 0.001).
Conclusion
Our results show that quantitative MRI parameters differ between CIDP, MMN and MND, which may reflect differences in underlying pathophysiological mechanisms.
With this study, we show that quantitative MRI techniques reveal differences in the brachial plexus between patients with CIDP, MMN, MND and healthy controls. CIDP is characterized by lower FA and higher RD than MMN, MND and healthy controls, whilst MMN is characterized by higher FA values than CIDP and MND. These differences between CIDP and MMN are the most remarkable and important finding as they emphasize important differences in the underlying pathophysiologies.
Respiratory muscle weakness is an important feature of spinal muscular atrophy (SMA). Progressive lung function decline is the most important cause of mortality and morbidity in patients. The natural ...history of lung function in SMA has, however, not been studied in much detail.
We analysed 2098 measurements of lung function from 170 treatment-naïve patients with SMA types 1c-4, aged 4-74 years. All patients are participating in an ongoing population-based prevalence cohort study. We measured Forced Expiratory Volume in 1 s (FEV
), Forced Vital Capacity (FVC), and Vital Capacity (VC). Longitudinal patterns of lung function were analysed using linear mixed-effects and non-linear models. Additionally, we also assessed postural effects on results of FEV
and FVC tests. In early-onset SMA types (1c-3a), we observed a progressive decline of lung function at younger ages with relative stabilisation during adulthood. Estimated baseline values were significantly lower in more severely affected patients: %FEV
ranged from 42% in SMA type 1c to 100% in type 3b, %FVC 50 to 109%, and %VC 44 to 96%. Average annual decline rates also differed significantly between SMA types, ranging from - 0.1% to - 1.4% for FEV
, - 0.2% to - 1.4% for FVC, and + 0.2% to - 1.7% for VC. In contrast to SMA types 1c-3a, we found normal values for all outcomes in later-onset SMA types 3b and 4 throughout life, although with some exceptions and based on limited available data. Finally, we found no important differences in FVC or FEV
values measured in either sitting or supine position.
Our data illustrate the longitudinal course of lung function in patients with SMA, which is characterised by a progressive decline in childhood and stabilisation in early adulthood. The data do not support an additional benefit of measuring FEV
or FVC in both sitting and supine position. These data may serve as a reference to assess longer-term outcomes in clinical trials.
Objective
This study aimed at developing a quantitative approach to assess abnormalities on MRI of the brachial plexus and the cervical roots in patients with chronic inflammatory demyelinating ...polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) and to evaluate interrater reliability and its diagnostic value.
Methods
We performed a cross-sectional study in 50 patients with CIDP, 31 with MMN and 42 disease controls. We systematically measured cervical nerve root sizes on MRI bilaterally (
C
5,
C
6,
C
7) in the coronal diameter (mm) and sagittal planes area (mm
2
), next to the ganglion (
G
0
) and 1 cm distal from the ganglion (
G
1
). We determined their diagnostic value using a multivariate binary logistic model and ROC analysis. In addition, we evaluated intra- and interrater reliability.
Results
Nerve root size was larger in patients with CIDP and MMN compared to controls at all predetermined anatomical sites. We found that nerve root diameters in the coronal plane had optimal reliability (intrarater ICC 0.55–0.87; interrater ICC 0.65–0.90). AUC was 0.78 (95% CI 0.69–0.87) for measurements at
G
0
and 0.81 (95% CI 0.72–0.91) for measurements at
G
1
. Importantly, our quantitative assessment of brachial plexus MRI identified an additional 10% of patients that showed response to treatment, but were missed by nerve conduction (NCS) and nerve ultrasound studies.
Conclusion
Our study showed that a quantitative assessment of brachial plexus MRI is reliable. MRI can serve as an important additional diagnostic tool to identify treatment-responsive patients, complementary to NCS and nerve ultrasound.
Aim
To gain insight into parents’ perspectives about their decision‐making process concerning nusinersen treatment for their child, including perceived needs and concerns, and to explore factors that ...influence this process.
Method
This was an exploratory qualitative interview study among parents of children with spinal muscular atrophy types 1 to 3. Data were analysed using inductive thematic analysis.
Results
Nineteen parents of 16 children representing 13 families participated. A wide variety of perspectives was reported ranging from a biomedical approach, which focused on battling the disease, to a holistic approach, which aimed for a good quality of life for their child. The most important factors that helped parents to decide were honest and neutral communication with their physician and access to available information.
Interpretation
It is important physicians understand that there are different perspectives influencing the decision‐making process. Physicians should create an environment that allows parents to accept or reject treatment by communicating honestly and openly with them and by discussing both options extensively. Clear information about pros and cons, recent developments in research, and the experiences of other parents should be made available to enable parents to make an informed decision.
What this paper adds
Parents perceived different needs and concerns about nusinersen treatment, which emphasized individual differences.
Parents’ perspectives varied from battling the disease to preserving quality of life.
Life expectancy, stopping deterioration, and improving quality of life were the perceived benefits of nusinersen treatment.
Open communication about the pros and cons of treatment with clinicians facilitated decision‐making.
Clear and honest information facilitated the alignment of values and goals.
What this paper adds
Parents perceived different needs and concerns about nusinersen treatment, which emphasized individual differences.
Parents’ perspectives varied from battling the disease to preserving quality of life.
Life expectancy, stopping deterioration, and improving quality of life were the perceived benefits of nusinersen treatment.
Open communication about the pros and cons of treatment with clinicians facilitated decision‐making.
Clear and honest information facilitated the alignment of values and goals.
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