Pattern of paresis in ALS is consistent with the physiology of the corticomotoneuronal projections to different muscle groups

Abstract

ObjectiveA recent neuroanatomical staging scheme of amyotrophic lateral sclerosis (ALS) indicates that a cortical lesion may spread, as a network disorder, both at the cortical level and via corticofugal tracts, including corticospinal projections providing direct monosynaptic input to α-motoneurons. These projections are involved preferentially and early in ALS. If these findings are clinically relevant, the pattern of paresis in ALS should primarily involve those muscle groups that receive the strongest direct corticomotoneuronal (CM) innervation.MethodsIn a large cohort (N=436), we analysed retrospectively the pattern of muscle paresis in patients with ALS using the UK Medical Research Council (MRC) scoring system; we subsequently carried out two independent prospective studies in two smaller groups (N=92 and N=54).ResultsThe results indicated that a characteristic pattern of paresis exists. When pairs of muscle groups were compared within patients, the group known to receive the more pronounced CM connections was significantly weaker. Within patients, there was greater relative weakness (lower MRC score) in thumb abductors versus elbow extensors, for hand extensors versus hand flexors and for elbow flexors versus elbow extensors. In the lower limb, knee flexors were relatively weaker than extensors, and plantar extensors were weaker than plantar flexors.ConclusionsThese findings were mostly significant (p<0.01) for all six pairs of muscles tested and provide indirect support for the concept that ALS may specifically affect muscle groups with strong CM connections. This specific pattern could help to refine clinical and electrophysiological ALS diagnostic criteria and complement prospective clinicopathological correlation studies.

The Cortical “Upper Motoneuron” in Health and Disease

“…Other recent studies have highlighted significant differences in the pattern of weakness in ALS patients which are consistent with the known connectivity of the CSP in humans and non-human primates [ 68 , 69 ]. An example is shown in Figure 1 from a recent study by Ludolph et al [ 68 ], which included both retrospective and prospective studies of a large cohort of ALS patients whose muscle strength was assessed in different pairs of both upper and lower limb muscles, using the MRC scale. The study looked for any statistical sign of asymmetry, in each patient, between pairs of muscle groups, with one group known to receive strong CM connections and the other known to receive weaker connections.…”

“…Blue bars indicate a difference in the opposite direction. The p -value derived from the sign test of these differences is given at the top of each panel (from Ludolph et al 2020 [ 68 ] Permission obtained).…”

Corticospinal vs Rubrospinal Revisited: An Evolutionary Perspective for Sensorimotor Integration

“…These studies support the idea that after CS tract damage, the muscles with the greatest CM influence show greater weakness, and there may be RM involvement in compensatory (rebalancing) mechanisms for motor alterations (Palmer and Ashby, 1992;Belhaj-Saïf and Cheney, 2000;Zaaimi et al, 2012;Ludolph et al, 2020;Sangari and Perez, 2020). In this way, more recently it has been described in Celsr3| Emx1 mutant mice model, where CST is specifically and fully absent, that axonal projections from RN to the spinal cord are increased and lesions of the RS tract lead to defective forelimb use, with almost no recovery.…”

“…For example, in patients with amyotrophic lateral sclerosis, a condition that affects the cortex and corticofugal fibers, muscles controlled by α-motoneurons and CM cells are differentially affected. Ludolph et al (2020) compared strength between elbow extensors (triceps) and flexors (biceps), reporting greater relative weakness in flexors relative to elbow extensors; in addition, they also reported greater relative weakness of extensors vs hand flexors. Similarly, in participants with cervical spinal cord damage (tetraplegia) who received transcranial magnetic stimulation, motor-evoked potentials were smaller in triceps relative to controls, suggesting that there is less CS input to the elbow extensors (Sangari and Perez, 2020).…”

Split-hand and split-limb phenomena in amyotrophic lateral sclerosis: pathophysiology, electrophysiology and clinical manifestations

“…Although the literature appraising this particular phenomenon is scarce, recent studies emphasised that in upper limbs, the biceps brachii is invariably weaker than of the triceps, irrespective of handedness. [21][22][23] More recently, the presence of the split elbow phenomenon was confirmed in a larger study, although contradictory findings have been reported. 23 24…”