ALS pathophysiology: Insights from the split-hand phenomenon

Highlights

• Axonal dysfunction, as assessed by the axonal excitability technique, is a ubiquitous feature in amyotrophic lateral sclerosis (ALS) evident across the range of intrinsic hand muscle.

• The split-hand phenomena is a specific clinical feature of ALS.

• Axonal dysfunction may appear as a downstream process that develops secondary to the intrinsic pathophysiological origins of ALS.

Abstract

Objective

The aim of the present study was to assess whether peripheral mechanisms, mediated through axonal dysfunction, may contribute to development of the split-hand in amyotrophic lateral sclerosis (ALS).

Methods

Median and ulnar nerve motor axonal excitability studies were undertaken on 21 ALS patients with motor responses recorded over the abductor pollicis brevis (APB), abductor digit minimi (ADM) and first dorsal interosseous (FDI) muscles, and results compared to 24 controls.

Results

The split-hand index (SI), an objective biomarker of preferential atrophy of APB and FDI muscles, was significantly reduced in ALS (SI_ALS 7.8 ± 1.7, SI_CONTROLS 13.1 ± 1.1, P < 0.0001). Axonal excitability studies identified significant prolongation of strength-duration time constant in ALS patients when recording over the APB (P < 0.05) and ADM axons (P < 0.05) but not FDI axons (P = 0.22). Greater changes in depolarising threshold electrotonus were also evident across the range of intrinsic hand muscles and were accompanied by increases of superexcitability in APB (P < 0.01) and FDI (P < 0.05) axons.

Conclusion

The present study reinforces the significance of the split-hand phenomenon in ALS and argues against a significant peripheral contribution in the underlying development.

Significance

Axonal dysfunction may appear as a downstream process that develops secondary to the intrinsic pathophysiological origins of ALS.

Introduction

Dissociated atrophy of intrinsic hand muscles, termed the split hand phenomenon, refers to preferential wasting of abductor pollicis brevis (APB) and first dorsal interosseous (FDI) muscles with relative preservation of the abductor digit minimi [ADM] (Kuwabara et al., 1999, Wilbourn, 2000). The split-hand sign appears to be an early and specific clinical feature of amyotrophic lateral sclerosis (ALS), not evident in other common clinical mimic neuromuscular disorders (Weber et al., 2000, Wilbourn, 2000, Kuwabara et al., 2008, Menon et al., 2011, Menon et al., 2013), although it has been reported with normal ageing and in some neurodegenerative disorders such as spinocerebellar ataxia type 3, juvenile muscular atrophy and autosomal dominant spinal muscular atrophy (Schelhaas et al., 2003, Voermans et al., 2006).

The mechanisms underlying the development of the split-hand pattern of wasting in ALS remains to be elucidated, with resolution of this issue of potential pathophysiological importance in understanding ALS onset and patterns of disease spread. Given that wasted intrinsic hand muscles are innervated by an overlap of similar myotomes (C8-T1), dysfunction of local spinal segments are unlikely to account for the split-hand phenomena in ALS per se. Rather, three potential mechanisms have been proposed including a cortical-based process related to a larger central representation of the thenar complex group of muscles (APB/FDI), abnormalities at a peripheral level and increased metabolic demands of the motor neurons innervating the thenar and FDI muscles (Weber et al., 2000, Kuwabara et al., 2008, Menon et al., 2011, Menon et al., 2013).

Perhaps of relevance, upregulation of persistent Na⁺ conductances, as reflected by an increase in strength-duration time constant, and reduction in K⁺ currents, have been extensively documented in ALS (Bostock et al., 1995, Mogyoros et al., 1998, Kanai et al., 2006, Kanai et al., 2012, Vucic and Kiernan, 2006a, Vucic and Kiernan, 2007, Vucic et al., 2008). Importantly, changes in axonal excitability, particularly upregulation of persistent Na⁺ conductances, have been linked to the process of neurodegeneration and survival in ALS (Kanai et al., 2006, Kanai et al., 2012). While these studies established that dysfunction of axonal ion channel conductances was part of the pathophysiological process in ALS, only single nerves were assessed, precluding any conclusions as to whether specific or more generalised abnormalities in axonal excitability contributed to the development of the split-hand phenomenon.

A study in healthy controls reported a relative increase in strength-duration time constant and greater abnormalities of threshold electrotonus in motor axons innervating the APB and FDI muscles compared to ADM (Bae et al., 2009). These findings implied that axons innervating the thenar muscles and FDI may seem physiologically prone to develop hyperexcitability and thereby susceptible to degeneration in ALS. Recently, a greater increase in strength-duration time constant and more prominent abnormalities of depolarising threshold electrotonus were reported in axons innervating the APB muscle compared to ADM in sporadic ALS (Shibuya et al., 2013). While these findings suggested that dysfunction at a peripheral axonal level may contribute to the development of the split hand, the excitability properties of FDI axons was not assessed. As a consequence, axonal excitability properties of motor axons innervating the APB, FDI and ADM muscles were assessed “en bloc”, in order to determine whether dysfunction at a peripheral axonal level determined the pathophysiological basis of the split hand in ALS.