Background
Riluzole has positive effects on survival and functional scales in ALS (Miller 2012). Riluzole also had effect on isometric strength in the original clinical trial (Bensimon 1994). Neck flexion, biceps, brachioradialis flexion, hip flexion, knee flexion have been identified as sentinel muscles in ALS-MND.
Objectives
Characterize isometric strength change in sentinel muscles in ALS-MND.
Methods
128 consecutive ALS patients initiating riluzole therapy were assessed for ALS-FRS-R, respiratory function, isometric muscle strength measured by Medical Research Council scale. Subjects were examined before and at approximately 4 weeks following initiation of riluzole 50 mg twice daily, vitamin E 1200 units daily, vitamin B12 5000 micrograms daily, folic acid 2000 mcg daily, vitamin E vitamin D 5000 mcg daily. Statistical analysis employed MedCalc Software version 19.0.5 https://www.medcalc.org; 2019.
Results
80/128 [ 62.5 % ] ALS patients showed improvement in one or more sentinel muscles following riluzole treatment and 48/128 [ 37.5 % ] ALS patients did not. Subjects in the ‘strength improved’ cohort demonstrated median survival = 21.0 months [ 95% CI =17.0 to 23.0 months ] that was significantly prolonged [ P=0.001 Kaplan-Meier Logrank test ] compared with the subjects in the ‘strength not improved’ cohort median survival = 12.0 months [ 95% CI = 5.0 to 18.0 months ].
Discussion and conclusions
A proportion of ALS patients receiving riluzole, vitamin E, vitamin B12, folic acid, vitamin D show improvement in isometric muscle strength in sentinel muscles observed within 4 weeks of treatment initiation that is associated with slower disease progression as measured by increased survival. Assessing early response to riluzole treatment may be an independent milestone that might be employed in prognostic models as well as prediction model based clinical trial analysis. Replication of this observation as well as further investigation of early non-responders with respect to riluzole pharmacokinetics may provide insights as to whether patients are treatment resistant or may need riluzole dose adjustment.
References
Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Miller RG, et al. Cochrane Database Syst Rev. 2012; (3):CD001447.
A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. Bensimon G, Lacomblez L, Meininger V. N Engl J Med. 1994 Mar 3;330(9):585-91.
Neck weakness is a potent prognostic factor in sporadic amyotrophic lateral sclerosis patients. Nakamura R, et al J Neurol Neurosurg Psychiatry. 2013; 84(12):1365-71.
Relative preservation of triceps over biceps strength in upper limb-onset ALS: the 'split elbow'.
Khalaf R, et al J Neurol Neurosurg Psychiatry. 2019 Jul;90(7):730-733. doi: 10.1136/jnnp-2018-319894. Epub 2019 Mar 7.
Active Hip Flexion is a predictor of mobility in Amyotrophic Lateral Sclerosis. Santos CL, et al NeuroRehabilitation. 2016;38(4):395-400.
Lower extremity muscle force measures and functional ambulation in patients with amyotrophic lateral sclerosis. Slavin MD,et al Arch Phys Med Rehabil. 1998 Aug;79(8):950-4.
Acknowledgements
Supported by Muscular Dystrophy Association Care Center Grant, Atrium Health Foundation Carolinas ALS Funds as well as Pinstripes Foundation and ALS Charlotte Clinical Crew Funds.