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Research paper
Split hand syndrome in amyotrophic lateral sclerosis: different excitability changes in the thenar and hypothenar motor axons
  1. Kazumoto Shibuya1,
  2. Sonoko Misawa1,
  3. Saiko Nasu1,
  4. Yukari Sekiguchi1,
  5. Satsuki Mitsuma1,
  6. Minako Beppu1,
  7. Shigeki Ohmori1,
  8. Yuta Iwai1,
  9. Shoichi Ito1,
  10. Kazuaki Kanai1,
  11. Yasunori Sato2,
  12. Satoshi Kuwabara1
  1. 1Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
  2. 2Clinical Research Center, Chiba University Hospital, Chiba, Japan
  1. Correspondence to Dr Satoshi Kuwabara, Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; kuwabara-s{at}faculty.chiba-u.jp

Abstract

Background In amyotrophic lateral sclerosis (ALS), muscle wasting preferentially affects the abductor pollicis brevis (APB) and first dorsal interosseous over the abductor digit minimi (ADM), and this is termed ‘split hand’. Previous axonal excitability studies have suggested increased nodal persistent sodium current and reduced potassium current in motor axons in ALS, but the extent of excitability changes in APB and ADM axons in ALS has never been compared.

Objective To elucidate the peripheral axonal pathophysiology of split hand.

Methods In both APB and ADM motor axons of 21 patients with ALS and 17 age-matched normal controls, threshold tracking was used to measure excitability indices such as strength-duration time constant (SDTC; a measure of persistent sodium current) and threshold electrotonus.

Results In normal controls, SDTC was significantly longer for APB than ADM axons, suggesting that axonal excitability is physiologically higher in APB axons. Compared with normal controls, patients with ALS had longer SDTC and greater threshold changes in depolarising threshold electrotonus in both APB and ADM axons. Furthermore, the difference in extent of SDTC prolongation between normal subjects and patients with ALS was greater in APB than ADM axons.

Conclusions APB axons have physiologically higher excitability than ADM axons, and, in ALS, the hyperexcitability is more prominent in APB axons. Although cortical mechanisms would also be involved, more prominent hyperexcitability of APB axons may contribute to development of split hand, and the altered axonal properties are possibly associated with motor neuronal death in ALS.

  • Motor Neuron Disease
  • Neurophysiology
  • Channels
  • Neurophysiology, Motor
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Introduction

In amyotrophic lateral sclerosis (ALS), the thenar muscle, abductor pollicis brevis (APB), and the first dorsal interosseous (FDI) are predominantly affected, with relative preservation of the hypothenar muscle, abductor digit minimi (ADM).1–5 This strange pattern of dissociated atrophy of the intrinsic hand muscles has been termed ‘split hand’.2 ,3 Moreover, split hand appears to be specific to ALS, rarely being seen in other lower motor neuron disorders.3

APB, ADM and FDI are innervated by the same spinal segments (C8 and Th1), and ADM and FDI have the same supply from the ulnar nerve. Therefore the dissociated muscle atrophy cannot be explained by anatomical innervations. Weber et al6 have suggested a cortical basis for split hand in ALS. By using transcranial magnetic stimulation, they demonstrated that corticomotoneuronal input into the thenar complex is more extensive than that of hypothenar muscles in normal subjects, and that, in ALS, motor-evoked potential amplitudes are significantly more decreased in the thenar complex than in the hypothenar muscles in ALS.

On the other hand, previous excitability studies have shown altered peripheral motor axonal excitability properties in ALS. Specifically, an increase in sodium current and decrease in potassium current have been found in motor axons in patients with ALS.7–9 Separately, another study investigating normal subjects revealed that APB/FDI axons have a longer strength-duration time constant (SDTC) and greater changes in threshold electrotonus than ADM axons, suggesting that excitability is physiologically higher in APB than ADM axons.10 ,11 The findings imply that motor axons with higher excitability are more vulnerable in ALS. However, direct comparison of APB and ADM axons has never been performed in patients with ALS.

In this study, we systematically examined differences in patterns and extent of excitability properties in both APB and ADM axons in patients with ALS and normal controls to clarify the peripheral pathophysiology of split hand.

Materials and methods

Subjects

Twenty-one consecutive patients with sporadic ALS (12 men, nine women), seen at Chiba University Hospital in 2010, were studied (table 1). Their age ranged from 44 to 83 years (mean 65 years). The mean duration between disease onset and examination was 14 months. The first symptoms affected the bulbar region in eight patients, and the non-bulbar region in 13. The patients’ condition fulfilled the revised El Escorial criteria for definite or probable ALS at the time of examination.12 Nerve conduction studies and excitability testing were performed before treatment with riluzole.

Table 1

Clinical profiles and CMAP amplitudes of subjects studied

We excluded patients with ALS complicated by other neurological disorders (eg, diabetic neuropathy, carpal tunnel syndrome and cervical spondylosis). Control data for nerve conduction studies and multiple excitability measurements were obtained from 17 age- and gender-matched normal subjects (10 men and seven women; age 38–91 years, mean 66 years). None had clinical or electrophysiological evidence of a peripheral nerve or lower motor neuron disorder. All subjects gave informed consent, and the study was approved by the ethics committee of Chiba University School of Medicine.

Nerve excitability testing

Multiple excitability measurements were obtained using a computerised programme (QTRAC, V.4.3, with multiple excitability protocol TRONDXM2; copyright, Institute of Neurology, London, UK), as described elsewhere.13–15 Excitability was tested in median motor axons at the wrist with recording of compound muscle action potential (CMAP) from APB, and then in ulnar motor axons at the wrist with CMAP recording from ADM. Skin temperature near the stimulus site was maintained at >32°C.

The following excitability indices were included: SDTC (a measure of persistence of sodium current), threshold electrotonus, and refractoriness, supernormality and late subnormality of the recovery cycle of axonal excitability with a single supramaximal conditioning stimulus.14 In SDTC measurements, the mean of target CMAP levels from 10% to 90% were analysed.

Statistical analysis

All statistical analyses were performed by one author (YaS) using SAS V.4.2 software. Mean age, CMAP amplitude and APB/ADM CMAP amplitude ratios were compared between normal controls and patients using the Student t test. Gender was compared using χ2 analysis. Mean excitability indices of each muscle recording were compared by the paired t test, and those of normal subjects and patients with ALS, in the same muscle, using the unpaired t test. Data are presented as mean (SEM). The level of statistical significance was established at p<0.05.

Results

CMAP amplitudes and split hand

Table 1 shows CMAP amplitudes of APB and ADM, and APB/ADM amplitude ratios. In normal controls, the mean CMAP amplitude in APB was greater than in ADM, and the APB/ADM CMAP amplitude ratio was calculated as 1.1. Patients with ALS had significantly smaller CMAP amplitudes in both APB and ADM than normal, and the APB/ADM CMAP amplitude ratio was significantly reduced, consistent with split hand (more prominent reduction of APB than ADM CMAP amplitude). Therefore the ALS group examined in this study had split hand.

Excitability measurements

Results of multiple excitability measurements are shown in table 2. When APB and ADM axons were compared in normal subjects (column A vs C), APB axons showed longer SDTC and greater threshold changes in depolarising threshold electrotonus than ADM axons.

Table 2

Summary of parameters of nerve excitability testing

In the comparison of APB axons between normal controls and patients with ALS (column A vs B), the ALS group showed significantly longer SDTC, greater threshold changes in depolarising threshold electrotonus, and supernormality. In contrast, SDTC and other excitability indices were not significantly different in ADM axons between the normal and ALS groups (column C vs D) except supernormality. Figure 1 shows summarised findings of SDTC and depolarising threshold electrotonus. In both APB and ADM axons, the mean SDTC was longer and threshold changes in depolarising threshold electrotonus were greater for the ALS group than the normal group, but the differences were statistically significant only for APB axons. Current/threshold relationships showed a trend toward accommodation to long polarising currents (200 ms) being smaller for patients with ALS than for normal controls in both APB and ADM axons, but the differences did not reach statistical significance.

Figure 1

Strength-duration time constant (SDTC) and threshold electrotonus in abductor pollicis brevis (APB) and abductor digiti minimi (ADM) axons of patients with amyotrophic lateral sclerosis (ALS) and normal control subjects. Mean SDTC of APB motor axons (A) and ADM motor axons (B). Mean responses of threshold electrotonus in APB axons (C) and ADM axons (D). APB and ADM axons of patients with ALS had longer SDTC and greater changes on depolarisation (ie, less accommodation) in threshold electrotonus than in normal controls. The extent of the differences between control subjects and patients was more prominent for APB axons than for ADM axons.

In summary, even in normal controls, SDTC was significantly longer for APB than ADM axons, suggesting higher excitability in the former. In ALS, SDTC was even longer, and the extent of differences was greater for APB than ADM axons. Excitability was higher for APB than for ADM axons at baseline (normal), and became even higher in APB axons in ALS.

Discussion

Our study confirms previous results showing more severely reduced CMAP amplitudes in APB than ADM of patients with ALS.3 The findings reflect the split hand phenomenon in ALS. Secondly, our results reveal that SDTC is physiologically longer for APB than for ADM in older normal subjects. Finally, patterns of excitability changes were similar in APB and ADM motor axons; patients with ALS showed longer SDTC and greater threshold changes in electrotonus, consistent with previous study results. However, the extent of the changes in ALS was greater in APB axons than in ADM axons (figure 1). These findings suggest that, compared with ADM axons, APB axons have greater persistent sodium current and smaller potassium current, both of which increase axonal excitability. The differences are physiologically present in normal subjects, but are more prominent in ALS.

The mechanisms for development of split hand in ALS must be complex, but both cortical and spinal/peripheral mechanisms have been suggested to be involved.4 Transcranial magnetic stimulation has shown that the primary motor cortex is hyperexcitable in ALS, and motor evoked potentials are significantly smaller when recorded from the thenar muscles than from ADM, suggesting ‘shrinkage’ of cortical representation of the thenar muscles.6 These findings presumably reflect a cortical basis for split hand.

Separately, peripheral axonal excitability studies in young normal subjects have suggested that APB motor axons have more prominently persistent sodium current than ADM axons,10 ,11 leading to higher excitability and, in ALS, possibly to more ready degeneration.16 ,17 Our results confirm that the differences also exist in older healthy people.

This study first compares axonal excitability of APB and ADM motor axons of patients with ALS, and the results are compatible with the peripheral axonal hypothesis. Changes in SDTC and threshold electrotonus were more prominent in APB axons. A comparison of FDI and ADM axons may be more useful, but axonal excitability properties change substantially in distal axons,18 and, in stimulation of axons at the wrist, the distance from the stimulus site to the target muscle is considerably longer for FDI than for ADM axons. Therefore, we chose to compare APB and ADM axons.

We recently reported that prolonged SDTC measured in APB axons is a strong and independent predictor of shorter survival in patients with ALS.19 The median survival of patients with longer SDTC was significantly shorter than of those with shorter SDTC. Although changes in peripheral axonal properties may not be a primary event in ALS, the findings support the possibility that altered axonal excitability may, at least, increase motor neuronal death in ALS. The concept is consistent with split hand in ALS.

Humans use the APB much more frequently than the ADM, and this may lead to greater oxidative stress and metabolic demands for both upper and lower motoneurons innervating APB. Similar hyperexcitability may occur also in axons of cortical motoneurons, and therefore, mechanisms of the split hand may be multifactorial.20–23

We propose that altered ionic currents and the resulting motor axonal hyperexcitability are related to the pathophysiology of split hand and the increase in motor neuron death in ALS. Pharmacological ion channel modulation with a sodium channel blocker and a potassium channel opener may be a future treatment option for ALS.

References

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Footnotes

  • Contributors KS and SK designed the study. KS, KK, SN, YuS, SaM, MB, YI and SO performed examinations. KS, SoM, SI and SK drafted the manuscript. YaS performed statistical analyses. SK supervised the study.

  • Funding This study was supported in part by a research grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to SM and SK) and Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare of Japan (to SK). Grant numbers: Satoshi Kuwabara – 23591267; Sonoko Misawa – 23790975.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics committee of Chiba University School of Medicine.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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