Publications by authors named "Fay-Lynn Asselman"

22 Publications

  • Page 1 of 1

Motor Unit and Capillary Recruitment During Fatiguing Arm-Cycling Exercise in Spinal Muscular Atrophy Types 3 and 4.

J Neuromuscul Dis 2022 ;9(3):397-409

Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.

Background: Exercise intolerance is an important impairment in patients with SMA, but little is known about the mechanisms underlying this symptom.

Objective: To investigate if reduced motor unit and capillary recruitment capacity in patients with SMA contribute to exercise intolerance.

Methods: Adolescent and adult patients with SMA types 3 and 4 (n = 15) and age- and gender matched controls (n = 15) performed a maximal upper body exercise test. We applied respiratory gas analyses, non-invasive surface electromyography (sEMG) and continuous wave near-infrared spectroscopy (CW-NIRS) to study oxygen consumption, arm muscle motor unit- and capillary recruitment, respectively.

Results: Maximal exercise duration was twofold lower (p < 0.001) and work of breathing and ventilation was 1.6- and 1.8-fold higher (p < 0.05) in patients compared to controls, respectively. Regarding motor unit recruitment, we found higher normalized RMS amplitude onset values of sEMG signals from all muscles and the increase in normalized RMS amplitudes was similar in the m. triceps brachii, m. brachioradialis and m. flexor digitorum in SMA compared to controls. Median frequency, onset values were similar in patients and controls. We found a similar decrease in median frequencies of sEMG recordings from the m. biceps brachii, a diminished decrease from the m. brachioradialis and m. flexor digitorum, but a larger decrease from the m. triceps brachii. With respect to capillary recruitment, CW-NIRS recordings in m. biceps brachii revealed dynamics that were both qualitatively and quantitatively similar in patients and controls.

Conclusion: We found no evidence for the contribution of motor unit and capillary recruitment capacity of the upper arm muscles in adolescent and adult patients with SMA types 3 and 4 as primary limiting factors to premature fatigue during execution of a maximal arm-cycling task.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JND-210765DOI Listing
May 2022

Natural history of respiratory muscle strength in spinal muscular atrophy: a prospective national cohort study.

Orphanet J Rare Dis 2022 02 21;17(1):70. Epub 2022 Feb 21.

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: Respiratory complications are the most important cause of morbidity and mortality in spinal muscular atrophy (SMA). Respiratory muscle weakness results in impaired cough, recurrent respiratory tract infections and eventually can cause respiratory failure. We assessed longitudinal patterns of respiratory muscle strength in a national cohort of treatment-naïve children and adults with SMA, hypothesizing a continued decline throughout life.

Methods: We measured maximal expiratory and inspiratory pressure (PE and PI), Sniff Nasal inspiratory pressure (SNIP), peak expiratory flow (PEF), and peak cough flow (PCF) in treatment-naïve patients with SMA. We used mixed-models to analyze natural history patterns.

Results: We included 2172 measurements of respiratory muscle function from 80 treatment-naïve patients with SMA types 1c-3b. All outcomes were lower in the more severe phenotypes. Significant differences in PEF were present between SMA types from early ages onwards. PEF decline was linear (1-2%/year). PEF reached values below 80% during early childhood in types 1c-2, and during adolescence in type 3a. PE and PI were severely lowered in most patients throughout life, with PE values abnormally low (i.e. < 80 cmHO) in virtually all patients. The PE/PI ratio was < 1 throughout life in all SMA types, indicating that expiratory muscles were most affected. All but SMA type 3b patients had a lowered PCF. Patients with types 2b and 3a had PCF levels between 160 and 270 L/min, those with type 2a around 160 L/min and patients with type 1c well below 160 L/min. Finally, SNIP was low in nearly all patients, most pronounced in more severely affected patients.

Conclusions: There are clear differences in respiratory muscle strength and its progressive decline between SMA types. We observed lower outcomes in more severe SMA types. Particularly PEF may be a suitable outcome measure for the follow-up of respiratory strength in patients with SMA. PEF declines in a rather linear pattern in all SMA types, with clear differences at baseline. These natural history data may serve as a reference for longer-term treatment efficacy assessments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-022-02227-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8862532PMC
February 2022

Multi-parametric quantitative magnetic resonance imaging of the upper arm muscles of patients with spinal muscular atrophy.

NMR Biomed 2022 Jan 20:e4696. Epub 2022 Jan 20.

UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/nbm.4696DOI Listing
January 2022

Magnetic resonance reveals mitochondrial dysfunction and muscle remodelling in spinal muscular atrophy.

Brain 2021 Nov 11. Epub 2021 Nov 11.

Centre for Child Development, Exercise and Physical Literacy, Wilhelmina Children's Hospital, University Medical Centre Utrecht, P.O. Box 85090 3508 AB Utrecht, The Netherlands.

Genetic therapy has changed the prognosis of hereditary proximal spinal muscular atrophy, although treatment efficacy has been variable. There is a clear need for deeper understanding of underlying causes of muscle weakness and exercise intolerance in patients with this disease to further optimize treatment strategies. Animal models suggest that in addition to motor neuron and associated musculature degeneration, intrinsic abnormalities of muscle itself including mitochondrial dysfunction contribute to the disease etiology. To test this hypothesis in patients, we conducted the first in vivo clinical investigation of muscle bioenergetics. We recruited 15 patients and 15 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. MRI and 31phosphorus magnetic resonance spectroscopy, the modality of choice to interrogate muscle energetics and phenotypic fiber type makeup, was performed of the proximal arm musculature in combination with fatiguing arm-cycling exercise and blood lactate testing. We derived bioenergetic parameter estimates including: blood lactate, intramuscular pH and inorganic phosphate accumulation during exercise, and muscle dynamic recovery constants. Linear correlation was used to test for associations between muscle morphological and bioenergetic parameters and clinico-functional measures of muscle weakness. MRI showed significant atrophy of triceps but not biceps muscles in patients. Maximal voluntary contraction force normalized to muscle cross-sectional area for both arm muscles was 1.4-fold lower in patients than in controls, indicating altered intrinsic muscle properties other than atrophy contributed to muscle weakness in this cohort. In vivo 31phosphorus magnetic resonance spectroscopy identified white-to-red remodeling of residual proximal arm musculature in patients on basis of altered intramuscular inorganic phosphate accumulation during arm-cycling in red versus white and intermediate myofibers. Blood lactate rise during arm-cycling was blunted in patients and correlated with muscle weakness and phenotypic muscle makeup. Post-exercise metabolic recovery was slower in residual intramuscular white myofibers in patients demonstrating mitochondrial ATP synthetic dysfunction in this particular fiber type. This study provides first in vivo evidence in patients that degeneration of motor neurons and associated musculature causing atrophy and muscle weakness in 5q spinal muscular atrophy type 3 and 4 is aggravated by disproportionate depletion of myofibers that contract fastest and strongest. Our finding of decreased mitochondrial ATP synthetic function selectively in residual white myofibers provides both a possible clue to understanding the apparent vulnerability of this particular fiber type in 5q spinal muscular atrophy type 3 and 4 as well as a new biomarker and target for therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awab411DOI Listing
November 2021

Quantitative magnetic resonance imaging of the brachial plexus shows specific changes in nerve architecture in chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and motor neuron disease.

Eur J Neurol 2021 08 27;28(8):2716-2726. Epub 2021 May 27.

Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ene.14896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362016PMC
August 2021

Motor unit reserve capacity in spinal muscular atrophy during fatiguing endurance performance.

Clin Neurophysiol 2021 03 28;132(3):800-807. Epub 2021 Jan 28.

Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, Van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands.

Objective: To investigate the availability of any motor unit reserve capacity during fatiguing endurance testing in patients with spinal muscular atrophy (SMA).

Methods: We recorded surface electromyography (sEMG) of various muscles of upper- and lower extremities of 70 patients with SMA types 2-4 and 19 healthy controls performing endurance shuttle tests (ESTs) of arm and legs. We quantitatively evaluated the development of fatigability and motor unit recruitment using time courses of median frequencies and amplitudes of sEMG signals. Linear mixed effect statistical models were used to evaluate group differences in median frequency and normalized amplitude at onset and its time course.

Results: Normalized sEMG amplitudes at onset of upper body ESTs were significantly higher in patients compared to controls, yet submaximal when related to maximal voluntary contractions, and showed an inverse correlation to SMA phenotype. sEMG median frequencies decreased and amplitudes increased in various muscles during execution of ESTs in patients and controls.

Conclusions: Decreasing median frequencies and increasing amplitudes reveal motor unit reserve capacity in individual SMA patients during ESTs at submaximal performance intensities.

Significance: Preserving, if not expanding motor unit reserve capacity may present a potential therapeutic target in clinical care to reduce fatigability in individual patients with SMA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinph.2020.11.044DOI Listing
March 2021

Parents' perspectives on nusinersen treatment for children with spinal muscular atrophy.

Dev Med Child Neurol 2021 07 6;63(7):816-823. Epub 2021 Feb 6.

Center of Expertise in Palliative Care, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dmcn.14825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248060PMC
July 2021

Quantification of disease progression in spinal muscular atrophy with muscle MRI-a pilot study.

NMR Biomed 2021 04 22;34(4):e4473. Epub 2021 Jan 22.

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

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, T 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 T 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/nbm.4473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988555PMC
April 2021

Correlates of Fatigability in Patients With Spinal Muscular Atrophy.

Neurology 2021 02 20;96(6):e845-e852. Epub 2020 Nov 20.

From the Child Development and Exercise Center (B.B., L.E.H.) and Department of Pediatric Gastroenterology (E.E.S.N.), Wilhelmina Children's Hospital, and UMC Utrecht Brain Center (R.I.W., F.-L.A., R.P.A.v.E., H.S.G., W.L.v.d.P.), University Medical Center Utrecht; Knowledge Institute for Medical Specialists (J.F.d.G.), University of Applied Sciences; and Biostatistics & Research Support (R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, Utrecht, the Netherlands.

Objective: To determine the associations between fatigability and muscle strength, motor function, neuromuscular junction (NMJ) function, and perceived fatigue in spinal muscular atrophy (SMA), we assessed 61 patients with SMA.

Methods: Fatigability was defined as the inability to continue a 20-minute submaximal repetitive task of either walking or proximal or distal arm function and expressed as drop-out on the Endurance Shuttle Test Combined Score (ESTCS). We assessed muscle strength with the Medical Research Council (MRC) sum score, motor function with the Hammersmith Functional Motor Scale Expanded (HFMSE) and Motor Function Measure (MFM), NMJ function with repetitive nerve stimulation of the accessory and ulnar nerve, and perceived fatigue with the PROMIS Fatigue Short Form questionnaire in 61 children and adults with SMA types 2-4. We applied Cox regression analysis to explore the associations between fatigability and these factors.

Results: The hazard of drop-out on the ESTCS decreased 0.8%, 2%, and 1.3% for each point increase in the MRC sum score, the HFMSE score, and the MFM percentual score, respectively. However, we observed prominent fatigability with preserved muscle function and vice versa in 13%-16% of patients. We did not find an association between NMJ dysfunction of the accessory ( = 0.37) and ulnar nerve ( = 0.063) and fatigability, which could be due to a large number of missing values. Perceived fatigue in SMA was comparable to reference values and was not associated with fatigability ( = 0.52).

Conclusion: Fatigability in SMA is associated with, yet not equivalent to, muscle strength and motor function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000011230DOI Listing
February 2021

Quantitative assessment of brachial plexus MRI for the diagnosis of chronic inflammatory neuropathies.

J Neurol 2021 Mar 23;268(3):978-988. Epub 2020 Sep 23.

Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht, The Netherlands.

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 (C5, C6, C7) in the coronal [diameter (mm)] and sagittal planes [area (mm)], next to the ganglion (G) and 1 cm distal from the ganglion (G). 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 and 0.81 (95% CI 0.72-0.91) for measurements at G. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-020-10232-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914242PMC
March 2021

Muscle strength and motor function in adolescents and adults with spinal muscular atrophy.

Neurology 2020 10 30;95(14):e1988-e1998. Epub 2020 Jul 30.

From the Department of Neurology (C.A.W., M.S., L.A.M.O., F.-L.A., R.P.A.v.E., L.H.v.d.B., H.S.G., R.I.W., W.L.v.d.P.), UMC Utrecht Brain Center, Child Development and Exercise Center (B.B.), and Department of Biostatistics & Research Support (R.P.A.v.E.), Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, the Netherlands.

Objective: To assess longitudinal patterns of muscle strength, motor function, and maximal compound muscle action potential amplitudes (CMAP) in older patients with spinal muscular atrophy (SMA), hypothesizing a continued decline of motor function parameters throughout life.

Methods: We measured muscle strength (Medical Research Council), motor function (Hammersmith Functional Motor Scale Expanded [HFMSE] and Motor Function Measure), and CMAP in treatment-naive patients. We used both longitudinal and cross-sectional data in mixed models to analyze natural history patterns.

Results: We included 250 patients with SMA types 1c through 4. Median patient age at assessment was 26.8 years, the number of assessments per patient ranged from 1 to 6. Baseline muscle strength and motor function scores differed significantly between SMA types, but annual rates of decline were largely similar and mostly linear. HFMSE floor effects were present for all patients with SMA type 1c, and adolescents and adults with types 2 and 3a. CMAP differed significantly between SMA types but did not decline significantly with increasing age. Muscle strength correlated very strongly with motor function (τ ≥ 0.8) but only moderately with CMAP (τ ≈ 0.5-0.6).

Conclusion: Muscle strength and motor function decline in older patients with SMA are constant without periods of slower progression or a plateau phase. The floor effects of the HFMSE preclude its use for long-term follow-up of adult patients with SMA types 1c through 3a. Muscle strength sum scores represent an alternative, feasible outcome measure for adolescent and adult patients with SMA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000010540DOI Listing
October 2020

Quantitative MRI of skeletal muscle in a cross-sectional cohort of patients with spinal muscular atrophy types 2 and 3.

NMR Biomed 2020 10 18;33(10):e4357. Epub 2020 Jul 18.

Department of Radiology, University Medical Center Utrecht, Utrecht University, the Netherlands.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/nbm.4357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507182PMC
October 2020

Assessment of motor unit loss in patients with spinal muscular atrophy.

Clin Neurophysiol 2020 06 13;131(6):1280-1286. Epub 2020 Feb 13.

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, the Netherlands.

Objective: To assess motor unit (MU) changes in patients with spinal muscular atrophy (SMA) using compound muscle action potential (CMAP) scans.

Methods: We performed CMAP scan recordings in median nerves of 24 treatment-naïve patients (median age 39; range 12-75 years) with SMA types 2-4. From each scan, we determined maximum CMAP amplitude (CMAP), a motor unit number estimate (MUNE), and D50 which quantifies the largest discontinuities within CMAP scans.

Results: Median CMAP was 8.1 mV (range 0.9-14.6 mV), MUNE was 29 (range 6-131), and D50 was 25 (range 2-57). We found a reduced D50 (<25) in patients with normal CMAP (n = 12), indicating MU loss and enlarged MUs due to reinnervation. Lower D50 values were associated with decreased MUNE (P < 0.001, r = 0.68, n = 43). CMAP, MUNE and D50 values differed between SMA types (P < 0.001). Lower motor function scores were related to patients with lower CMAP, MUNE and D50 values (P < 0.001).

Conclusions: The CMAP scan is an easily applicable technique that is superior to routine assessment of CMAP in SMA.

Significance: The detection of pathological MU changes across the spectrum of SMA may provide important biomarkers for evaluating disease course and monitoring treatment efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinph.2020.01.018DOI Listing
June 2020

Fatigability in spinal muscular atrophy: validity and reliability of endurance shuttle tests.

Orphanet J Rare Dis 2020 03 23;15(1):75. Epub 2020 Mar 23.

University Medical Center Utrecht, UMC Utrecht Brain Center, Utrecht, The Netherlands.

Background: To determine construct validity and test-retest reliability of Endurance Shuttle Tests as outcome measures for fatigability of remaining motor functions in children and adults with Spinal Muscular Atrophy (SMA) across the severity spectrum.

Results: We assessed the Endurance Shuttle - Nine Hole Peg Test (ESNHPT), - Box and Block Test (ESBBT) and - Walk Test (ESWT) in 61 patients with SMA types 2-4, 25 healthy controls (HC) and 15 disease controls (DC). Convergent validity, discriminative validity and test-retest reliability were investigated. Additionally, we compiled the Endurance Shuttle Combined Score (ESTCS) by selecting the most relevant endurance test of each individual. 54, 70 and 73% of patients with SMA demonstrated increased fatigability on the ESNHPT, ESBBT and the ESWT. Endurance response in SMA was characterized by a decrease in muscle strength, an increase in muscle fatigue and an increase in motor adaptions, thereby confirming convergent validity. Patients with SMA showed increased drop-out rates and a shorter endurance time compared to HC and DC demonstrating good discriminative validity. Test-retest reliability was moderate to excellent (ICC's ranging from .78 to .91) with a trend towards better performance on retest. The ESTCS increased sample size and drop-out rate up to 100 and 85%.

Conclusions: Fatigability is an important additional dimension of physical impairments across the severity spectrum in children and adults with SMA. The EST's are reliable and valid to document fatigability of walking, proximal- and distal arm function in SMA and thus are promising outcome measures for use in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-020-1348-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092552PMC
March 2020

Natural history of lung function in spinal muscular atrophy.

Orphanet J Rare Dis 2020 04 10;15(1):88. Epub 2020 Apr 10.

Department of Neurology, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht University, Heidelberglaan 100, 3508, GA, Utrecht, The Netherlands.

Background: 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.

Results: 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.

Conclusions: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-020-01367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149916PMC
April 2020

Drug treatment for spinal muscular atrophy types II and III.

Cochrane Database Syst Rev 2020 01 6;1:CD006282. Epub 2020 Jan 6.

University Medical Center Utrecht, Brain Center Rudolf Magnus, Department of Neurology, Heidelberglaan 100, Utrecht, Netherlands, 3584 CX.

Background: 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.

Objectives: 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.

Search Methods: 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.

Selection Criteria: 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.

Data Collection And Analysis: We followed standard Cochrane methodology.

Main Results: 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.

Authors' Conclusions: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD006282.pub5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995983PMC
January 2020

Drug treatment for spinal muscular atrophy type I.

Cochrane Database Syst Rev 2019 12 11;12:CD006281. Epub 2019 Dec 11.

University Medical Center Utrecht, Brain Center Rudolf Magnus, Department of Neurology, Heidelberglaan 100, Utrecht, Netherlands, 3584 CX.

Background: 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.

Objectives: To assess the efficacy and safety of any drug therapy designed to slow or arrest progression of spinal muscular atrophy (SMA) type I.

Search Methods: 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).

Selection Criteria: 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.

Data Collection And Analysis: We followed standard Cochrane methodology.

Main Results: 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.

Authors' Conclusions: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/14651858.CD006281.pub5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905354PMC
December 2019

Natural course of scoliosis and lifetime risk of scoliosis surgery in spinal muscular atrophy.

Neurology 2019 07 4;93(2):e149-e158. Epub 2019 Jun 4.

From the Department of Neurology and Neurosurgery (C.A.W., F.A.S.d.K., M.S., L.A.M.O., F.-L.A., R.P.A.v.E., J.S., I.C., L.H.v.d.B., R.I.W., W-L.v.d.P), Department of Rehabilitation (M.V.), Department of Orthopedic Surgery (R.C.B., R.M.C.), Department of Pediatrics, Child Development and Exercise Centre (B.B), and Biostatistics & Research Support Julius Centre for Health Sciences and Primary Care (R.P.A.v.E.), University Medical Centre Utrecht, Utrecht University, the Netherlands.

Objective: To investigate the natural course of scoliosis and to estimate lifetime probability of scoliosis surgery in spinal muscular atrophy (SMA).

Methods: We analyzed cross-sectional data from 283 patients from our population-based cohort study. Additional longitudinal data on scoliosis progression and spinal surgery were collected from 36 consecutive patients who received scoliosis surgery at our center.

Results: The lifetime probability of receiving scoliosis surgery was ≈80% in SMA types 1c and 2. Patients with type 2 who only learned to sit (type 2a) were significantly younger at time of surgery than those who learned to sit and stand (type 2b). The lifetime risk of surgery was lower in type 3a (40%) and strongly associated with age at loss of ambulation: 71% in patients losing ambulation before 10 years of age vs 22% losing ambulation after the age of 10 years ( = 0.005). In type 3a, preserving the ability to walk 1 year longer corresponded to a 15% decrease in lifetime risk of scoliosis surgery (hazard ratio 0.852, = 0.017). Scoliosis development was characterized by initial slow progression, followed by acceleration in the 1.5- to 2-year period before surgery.

Conclusion: The lifetime probability of scoliosis surgery is high in SMA types 1c and 2 and depends on age at loss of ambulation in type 3. Motor milestones such as standing that are not part of the standard classification system are of additional predictive value. Our data may act as a reference to assess long-term effects of new SMA-specific therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000007742DOI Listing
July 2019

Validation of a Fast, Robust, Inexpensive, Two-Tiered Neonatal Screening Test algorithm on Dried Blood Spots for Spinal Muscular Atrophy.

Int J Neonatal Screen 2019 Jun 15;5(2):21. Epub 2019 May 15.

Department of Clinical Chemistry and Neonatal Screening, Isala Hospital, Dokter van Heesweg 2, 8025 AB Zwolle, The Netherlands.

Spinal muscular atrophy (SMA) is one of the leading genetic causes of infant mortality with an incidence of 1:10,000. The recently-introduced antisense oligonucleotide treatment improves the outcome of this disease, in particular when applied at an early stage of progression. The genetic cause of SMA is, in >95% of cases, a homozygous deletion of the survival motor neuron 1 () gene, which makes the low-cost detection of SMA cases as part of newborn screening programs feasible. We developed and validated a new SALSA MC002 melting curve assay that detects the absence of the exon 7 DNA sequence without detecting asymptomatic carriers and reliably discriminates from its genetic homolog using crude extracts from newborn screening cards. Melting curve analysis shows peaks specific for both the gene and the disease modifying homolog. The detection of the homolog, of which the only clinically relevant difference from the gene is a single nucleotide in exon 7, was only used to confirm a correct reaction in samples that lacked the gene, and not for quantification. We retrieved 47 DBS samples from children with genetically-confirmed SMA, after informed consent from parents, and 375 controls from the national archive of the Dutch National Institute for Public Health and the Environment (RIVM). The assay correctly identified all anonymized and randomized SMA and control samples (i.e., sensitivity and specificity of 100%), without the detection of carriers, on the three most commonly-used PCR platforms with melting curve analysis. This test's concordance with the second-tier 'golden standard' P021 SMA MLPA test was 100%. Using the new P021-B1 version, crude extracts from DBS cards could also be used to determine the copy number of SMA patients with a high level of accuracy. The MC002 test showed the feasibility and accuracy of SMA screening in a neonatal screening program.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijns5020021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510214PMC
June 2019

Psychological well-being in adults with spinal muscular atrophy: the contribution of participation and psychological needs.

Disabil Rehabil 2020 08 29;42(16):2262-2270. Epub 2019 Jan 29.

Department of Rehabilitation, Physical Therapy Science & Sports, Brain Center Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.

Patients with spinal muscular atrophy (SMA) suffer from slowly progressive weakness of axial, respiratory and proximal muscles, leading to restrictions in activity and participation. This study aims to investigate patients' level of psychological well-being, using the International Classification of Functioning model and self-determination theory as theoretical frameworks. In this cross-sectional study, adults with SMA were invited to complete a questionnaire. Instruments to assess psychological well-being included the Satisfaction with Life Scale, the Rosenberg Self-Esteem Scale and the Positive and Negative Affect Scale. Hierarchical lineal regression analyses were performed to investigate the contribution of participation (International Classification of Functioning model) and satisfaction of the need for autonomy, competence and relatedness (self-determination theory) to well-being. Ninety-two respondents (67%) returned the questionnaire. Levels of psychological well-being were comparable to that of healthy reference samples. Well-being was unrelated to sociodemographic variables or illness characteristics. By contrast, well-being was closely related to respondents' satisfaction with participation, and their sense of autonomy, competence and relatedness. This study illustrates the relevance of psychological needs for understanding well-being of individuals with SMA. Supporting patients in meeting their psychological needs should become an objective of person-centred care for this population.Implications for rehabilitationSpinal muscular atrophy is a rare inherited disease, characterized by slowly progressive muscle weakness.Psychological well-being, including satisfaction with life, self-esteem and emotional functioning of adults with spinal muscular atrophy appears very comparable with that of healthy reference samples.In line with the International Classification of Functioning framework, well-being in adults with spinal muscular atrophy may be improved by increasing their (satisfaction with) participation.Moreover, clinical assessment and management should focus on optimizing patients' satisfaction with their basic psychological needs (autonomy, competence, relatedness), as this is strongly related to indices of psychological well-being.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09638288.2018.1555864DOI Listing
August 2020

Protocol for a phase II, monocentre, double-blind, placebo-controlled, cross-over trial to assess efficacy of pyridostigmine in patients with spinal muscular atrophy types 2-4 (SPACE trial).

BMJ Open 2018 07 30;8(7):e019932. Epub 2018 Jul 30.

Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Introduction: Hereditary proximal spinal muscular atrophy (SMA) is caused by homozygous loss of function of the survival motor neuron 1 gene. The main characteristic of SMA is degeneration of alpha motor neurons in the anterior horn of the spinal cord, but recent studies in animal models and patients have shown additional anatomical abnormalities and dysfunction of the neuromuscular junction (NMJ). NMJ dysfunction could contribute to symptoms of weakness and fatigability in patients with SMA. We hypothesise that pyridostigmine, an acetylcholinesterase inhibitor that improves neuromuscular transmission, could improve NMJ function and thereby muscle strength and fatigability in patients with SMA.

Methods And Analysis: We designed a monocentre, placebo-controlled, double-blind cross-over trial with pyridostigmine and placebo to investigate the effect and efficacy of pyridostigmine on muscle strength and fatigability in patients with genetically confirmed SMA. We aim to include 45 patients with SMA types 2-4, aged 12 years and older in the Netherlands. Participants receive 8 weeks of treatment with pyridostigmine and 8 weeks of treatment with placebo in a random order separated by a washout period of 1 week. Treatment allocation is double blinded. Treatment dose will gradually be increased from 2 mg/kg/day to the maximum dose of 6 mg/kg/day in four daily doses, in the first week of each treatment period. The primary outcome measures are a change in the Motor Function Measure and repeated nine-hole peg test before and after treatment. Secondary outcome measures are changes in recently developed endurance tests, that is, the endurance shuttle nine-hole peg test, the endurance shuttle box and block test and the endurance shuttle walk test, muscle strength, level of daily functioning, quality of and activity in life, perceived fatigue and fatigability, presence of decrement on repetitive nerve stimulation and adverse events.

Ethics And Dissemination: The protocol is approved by the local medical ethical review committee at the University Medical Center Utrecht and by the national Central Committee on Research Involving Human Subjects. Findings will be shared with the academic and medical community, funding and patient organisations in order to contribute to optimisation of medical care and quality of life for patients with SMA.

Trial Registration Number: NCT02941328.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2017-019932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067401PMC
July 2018
-->