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.
Multifocal motor neuropathy (MMN) is a rare inflammatory neuropathy characterized by slowly progressive, asymmetric distal limb weakness without sensory loss. The clinical presentation of MMN may ...mimic amyotrophic lateral sclerosis, other variants of motor neuron disease, or chronic inflammatory demyelinating polyneuropathy with asymmetric onset. Differentiation is important, as these diseases differ in prognosis and treatment. The electrophysiological finding of conduction block in the absence of abnormalities in sensory nerves is the hallmark of MMN, but can be difficult to detect. Intravenous immunoglobulin is efficacious in most patients, but long-term maintenance therapy does not prevent slowly progressive axonal degeneration. Moreover, cyclophosphamide, although effective, has substantial adverse effects, and the efficacy of other immunosuppressive drugs, including rituximab, is not established. The underlying pathological mechanisms of MMN are unclear, but IgM autoantibodies against the ganglioside GM1 may cause changes in nodal and perinodal structures that compromise nerve conduction. Further elucidation of the disease mechanisms may ultimately lead to improved treatment strategies. In this Review, we discuss the diagnostic criteria for MMN, and provide an update on the current understanding of MMN pathogenesis. We also describe available treatments and promising new therapeutic strategies.
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.
Introduction
We present a case series of six treatment‐naive patients with clinical phenotypes compatible with chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy ...without electrodiagnostic features of demyelination but with abnormal peripheral ultrasound findings who responded to treatment.
Methods
All six patients underwent a complete set of ancillary investigations, including extensive nerve conduction studies. We also performed standardized nerve ultrasound of median nerves and brachial plexus as part of a larger effort to evaluate diagnostic value of sonography.
Results
Nerve conduction studies did not show conduction block or other signs of demyelination in any of the six patients. Sonographic nerve enlargement was present in all patients and was most prominent in proximal segments of the median nerve and brachial plexus. Treatment with intravenous immunoglobulin resulted in objective clinical improvement.
Discussion
Our study provides evidence that nerve ultrasound represents a useful complementary diagnostic tool for the identification of treatment‐responsive inflammatory neuropathies.
Summary Background Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We ...investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA. Methods This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3–25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov , number NCT01302600. Findings The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and −1·82 for placebo (treatment difference 2·00 points, 96% CI −0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment. Interpretation Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed. Funding AFM Téléthon and Trophos SA.
To determine the diagnostic value of high-resolution ultrasound (HRUS) for detection of chronic inflammatory demyelinating polyneuropathy (CIDP), Lewis-Sumner syndrome (LSS), and multifocal motor ...neuropathy (MMN).
Between January 2013 and January 2015, we enrolled 75 consecutive treatment-naive patients with chronic inflammatory neuropathies and 70 disease controls. We performed extensive nerve conduction and standardized HRUS studies bilaterally of large arm and leg nerves and brachial plexus. We determined optimal sonographic cutoff values of nerve size and used receiver operating characteristic analysis and logistic regression models to identify nerve combinations with optimal diagnostic performance.
Enlargement of median nerve at forearm >10 mm
, upper arm >13 mm
, and any trunk of brachial plexus >8 mm
was 99% specific for chronic inflammatory neuropathies. A shortened HRUS protocol for detecting this abnormal nerve enlargement showed high sensitivity (83%-95%), positive predictive value (100%), and negative predictive value (98%) in discriminating CIDP, LSS, and MMN from clinical mimics.
Sonographic enlargement of proximal median nerve segments in the arms and brachial plexus is a key feature of chronic inflammatory neuropathies, which helps to reliably distinguish them from axonal neuropathies and amyotrophic lateral sclerosis.
This study provides Class II evidence that, in absence of clinical features that suggest a hereditary demyelinating neuropathy, sonographic enlargement of proximal median nerve segments and brachial plexus accurately identifies patients with chronic inflammatory neuropathies.
Purpose
Multi‐echo spin‐echo (MSE) transverse relaxometry mapping using multi‐component models is used to study disease activity in neuromuscular disease by assessing the T2 of the myocytic component ...(T2water). Current extended phase graph algorithms are not optimized for fat fractions above 50% and the effects of inaccuracies in the T2fat calibration remain unexplored. Hence, we aimed to improve the performance of extended phase graph fitting methods over a large range of fat fractions, by including the slice‐selection flip angle profile, a through‐plane chemical‐shift displacement correction, and optimized calibration of T2fat.
Methods
Simulation experiments were used to study the influence of the slice flip‐angle profile with chemical‐shift and T2fat estimations. Next, in vivo data from four neuromuscular disease cohorts were studied for different T2fat calibration methods and T2water estimations.
Results
Excluding slice flip‐angle profiles or chemical‐shift displacement resulted in a bias in T2water up to 10 ms. Furthermore, a wrongly calibrated T2fat caused a bias of up to 4 ms in T2water. For the in vivo data, one‐component calibration led to a lower T2fat compared with a two‐component method, and T2water decreased with increasing fat fractions.
Conclusion
In vivo data showed a decline in T2water for increasing fat fractions, which has important implications for clinical studies, especially in multicenter settings. We recommend using an extended phase graph–based model for fitting T2water from MSE sequences with two‐component T2fat calibration. Moreover, we recommend including the slice flip‐angle profile in the model with correction for through‐plane chemical‐shift displacements.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a heterogeneous immune‐mediated disorder with extensive variation in clinical presentation, electrophysiological phenotype, treatment ...response and long‐term outcome. This heterogeneity may reflect the existence of distinct subtypes of CIDP with a different pathogenesis that require personalized treatment. The International CIDP Outcome Study (ICOS) is a prospective, observational, multicenter cohort study that aims to describe this variation and to define clinical and biological determinants and predictors of these subtypes, disease activity, treatment response and outcome. All patients fulfilling the European Federation of Neurological Societies/Peripheral Nerve Society 2010 diagnostic criteria for CIDP can participate, independent of age, duration and severity of the disease or treatment. We collect data on the clinical presentation, diagnostics, validated clinical outcome measures, (response to) treatment, and we collect biomaterials (DNA, cerebrospinal fluid and serial serum samples). We aim to include at least 1000 CIDP patients with a follow‐up of at least 2 years. ICOS started in November 2015 in three academic medical centers in The Netherlands and by October 2018 169 patients are included: 69 new and 100 prevalent cases. ICOS is based on the format of the International Guillain‐Barré syndrome (GBS) Outcome Study (IGOS). Dutch centers are invited to participate in ICOS that will continue as an independent national registry. International centers will be able to collect data and biomaterials according to the ICOS protocol by using the optional ICOS module within the INCbase infrastructure. ICOS will help to standardize the collection of data and biosamples for future research in CIDP.
Background
Physical exercise training might improve muscle and cardiorespiratory function in spinal muscular atrophy (SMA). Optimization of aerobic capacity or other resources in residual muscle ...tissue through exercise may counteract the muscle deterioration that occurs secondary to motor neuron loss and inactivity in SMA. There is currently no evidence synthesis available on physical exercise training in people with SMA type 3.
Objectives
To assess the effects of physical exercise training on functional performance in people with SMA type 3, and to identify any adverse effects.
Search methods
On 8 May 2018, we searched the Cochrane Neuromuscular Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, AMED, and LILACS. On 25 April 2018 we searched NHSEED, DARE, and ClinicalTrials.gov and WHO ICTRP for ongoing trials.
Selection criteria
We included randomized controlled trials (RCTs) or quasi‐RCTs lasting at least 12 weeks that compared physical exercise training (strength training, aerobic exercise training, or both) to placebo, standard or usual care, or another type of non‐physical intervention for SMA type 3. Participants were adults and children from the age of five years with a diagnosis of SMA type 3 (Kugelberg‐Welander syndrome), confirmed by genetic analysis.
Data collection and analysis
We used standard Cochrane methodological procedures.
Main results
We included one RCT that studied the effects of a six‐month, home‐based, combined muscle strength and recumbent cycle ergometry training program versus usual care in 14 ambulatory people with SMA. The age range of the participants was between 10 years and 48 years. The study was evaluator‐blinded, but personnel and participants could not be blinded to the intervention, which placed the results at a high risk of bias. Participants performed strength training as prescribed, but 50% of the participants did not achieve the intended aerobic exercise training regimen. The trial used change in walking distance on the six‐minute walk test as a measure of function; a minimal detectable change is 24.0 m. The change from baseline to six months' follow‐up in the training group (9.4 m) was not detectably different from the change in the usual care group (‐0.14 m) (mean difference (MD) 9.54 m, 95% confidence interval (CI) ‐83.04 to 102.12; N = 12). Cardiopulmonary exercise capacity, assessed by the change from baseline to six months' follow‐up in peak oxygen uptake (VO2max) was similar in the training group (‐0.12 mL/kg/min) and the usual care group (‐1.34 mL/kg/min) (MD 1.22 mL/kg/min, 95% CI ‐2.16 to 4.6; N = 12). A clinically meaningful increase in VO2max is 3.5 mL/kg/min.
The trial assessed function on the Hammersmith Functional Motor Scale ‐ Expanded (HFMSE), which has a range of possible scores from 0 to 66, with an increase of 3 or more points indicating clinically meaningful improvement. The HFMSE score in the training group increased by 2 points from baseline to six months' follow‐up, with no change in the usual care group (MD 2.00, 95% CI ‐2.06 to 6.06; N = 12). The training group showed a slight improvement in muscle strength, expressed as the manual muscle testing (MMT) total score, which ranges from 28 (weakest) to 280 (strongest). The change from baseline in MMT total score was 6.8 in the training group compared to ‐5.14 in the usual care group (MD 11.94, 95% CI ‐3.44 to 27.32; N = 12).
The trial stated that training had no statistically significant effects on fatigue and quality of life. The certainty of evidence for all outcomes was very low because of study limitations and imprecision. The study did not assess the effects of physical exercise training on physical activity levels. No study‐related serious adverse events or adverse events leading to withdrawal occurred, but we cannot draw wider conclusions from this very low‐certainty evidence.
Authors' conclusions
It is uncertain whether combined strength and aerobic exercise training is beneficial or harmful in people with SMA type 3, as the quality of evidence is very low. We need well‐designed and adequately powered studies using protocols that meet international standards for the development of training interventions, in order to improve our understanding of the exercise response in people with SMA type 3 and eventually develop exercise guidelines for this condition.
Introduction
Magnetic resonance imaging of the brachial plexus shows nerve thickening in approximately half of the patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and ...multifocal motor neuropathy (MMN). The reliability of qualitative evaluation of brachial plexus MRI has not been studied previously.
Methods
We performed an interrater study in a retrospective cohort of 19 patients with CIDP, 17 patients with MMN, and 14 controls. The objective was to assess interrater variability between radiologists by using a predefined scoring system that allowed the distinction of no, possible, or definite nerve thickening.
Results
Raters agreed in 26 of 50 (52%) brachial plexus images; κ‐coefficient was 0.30 (SE 0.08, 95% confidence interval 0.14–0.46, P < .0005).
Discussion
Our results provide evidence that interrater reliability of qualitative evaluation of brachial plexus MRI is low. Objective criteria for abnormality are required to optimize the diagnostic value of MRI for inflammatory neuropathies.
See editorial on pages 679–680 in this issue.
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