Upper motor neuron burden measurement in motor neuron diseases: Does one scale fit all?

Clinical upper motor neuron (UMN) dysfunction arises from biological changes occurring in the cortical motor neurons and their axonal connections. There are a few and well-defined clinical manifestations of UMN dysfunction, including hyperreflexia, spasticity of limbs and tongue, pseudobulbar affect, slowness of movement, and excessive yawning. However, there are many clinical scales that have been used to measure these in trials and observational studies. These scales serve various objectives such as tracking disease progression, cohort enrichment in trials, and/or early diagnosis for various central nervous system (CNS) disorders. There is lack of consensus regarding which scales of clinical UMN dysfunction or what combination of the UMN manifestations are most appropriate for achieving various clinical research and care objectives. Some clinical UMN burden scales used in amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), multiple sclerosis, and other CNS disorders research include (1) timed tests of fine and gross motor movement such as timed peg (eg, Nine-Hole Peg Test), time and distance-based walk tests, finger/foot tapping speed tests; (2) tests for measuring spastic dysarthria such as the automated speech pause analysis, auditory-perceptual dysarthria assessment, and Frenchay dysarthria test; (3) limb spasticity assessments, including various modifications of the Ashworth scale, 0 to 10 numeric rating scale, Multiple Sclerosis Spasticity Scale-8, Rekand spasticity score, adductor tone rating scale, and pendulum test, among others; and (4) assessments of stretch reflexes including Ellis and Massachusetts General Hospital Upper Motor Neuron Burden (MGH-UMNB) scales. The Penn UMN (PUMN) scale is a comprehensive clinical rating scale that summates three separate subscales (CNS-Lability Scale [CNS-LS], modified Ashworth, and reflexes) to measure the UMN dysfunction manifestations of spasticity, hyperreflexia, and pseudobulbar affect in ALS. Quinn et al completed a study to understand the test–retest reliability of the reflexes and spasticity subdomains of the PUMN scale in 15 participants with ALS. This builds on prior knowledge that the CNS-LS subscale has good reliability by itself. The study provided evidence that the summated score of the reflexes and spasticity subdomains of PUMN had good interrater reliability between two blinded raters. The interitem reliability for cervical segment was higher than lumbosacral and bulbar segments. The total PUMN score correlated significantly with the ALS Functional Rating Scale-Revised, providing evidence of its clinical relevance in assessing ALS in patients. The authors' efforts in this article are commendable as the first of many important steps to validate the PUMN scale for its intended purpose as an early diagnostic and trial stratification tool in ALS and PLS. Validation of the PUMN scale in a larger multisite study to assess standardization and consistency of rating across providers involved in ALS care and research would be the logical next step. The CNS-LS has previously been validated and adds to the clinical relevance of the PUMN scale in ALS. The reliability and validity of the modified Ashworth scale has been debated in the past. The authors have elegantly replicated the findings of several prior studies, which indicate that the modified Ashworth scale-upper limb subdomain has better interrater and intrarater reliability compared to lower limb subdomain. The inclusion of the modified Ashworth scale in the PUMN scale may require further validation studies, with patients both receiving and not receiving concomitant antispasticity medications, to better understand how its inclusion affects the sensitivity of the entire PUMN scale for the primary objective of early diagnosis and cohort enrichment in ALS and PLS. Another aspect of the PUMN scale that may benefit from additional validation studies would be the scoring rules regarding carrying forward and adjusting the highest reflex and spasticity score for an item at subsequent follow-up time points. This scoring rule of PUMN is to correct for contamination that may arise due to interval lower motor neuron (LMN) burden progression. Some may view this as a limitation of the scale's sensitivity as a clinical trial outcome because of its tendency to reduce the dynamic range and responsiveness to change over time. The authors also state that another potential application of the PUMN scale would be as an early diagnostic tool in ALS. In this context, this scoring rule may not be applicable either because one may not have a prior baseline UMNB score to serve as reference or the clinical LMN burden may not be high enough at the time of early diagnosis to mask the underlying UMN burden. Quantitative measurement of molecular targets and disease mechanisms at the UMN level is important but challenging in individuals living with ALS. Recent literature suggests that brain positron emission tomography (with radioligands such as [11C]PBR-28, [18F] DPA 714, [18F]FDG), magnetic resonance spectroscopy, magnetic transfer imaging, and transcranial magnetic stimulation are emerging as potentially reliable molecular markers of UMN disease mechanisms and neurodegeneration in ALS. Developing quantitative or semiquantitative clinical markers of pure UMN dysfunction is required to complement the neuroimaging and UMN electrophysiological biomarkers in clinical trials and observational studies. A reliable and valid clinical UMN burden scale may time and cost effectively enrich patient cohorts who have optimal probability of Received: 27 January 2020 Revised: 8 February 2020 Accepted: 15 February 2020