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Utility of Dissociated Intrinsic Hand Muscle Atrophy in the Diagnosis of Amyotrophic Lateral Sclerosis

The split hand phenomenon refers to predominant wasting of thenar muscles and is an early and specific feature of amyotrophic lateral sclerosis (ALS). A ...

Westmead hospital

University of Sydney, Australia

Although length-dependent axonal excitability changes have been reported in the median nerve, the mechanisms underlying these changes remain to be further clarified.

Clarifying distal axonal properties of the median nerve.

The mechanism of motor weakness in patients with Miller-Fisher syndrome (MFS) remains to be fully elucidated. We performed stimulated single fibre electromyography (sSFEMG) in a clinically weak frontalis muscle in a patient with MFS. Stimulate single fiber EMG revealed increased jitter in over 50% of the apparent single fibre action potentials from the frontalis muscle in addition to increased mean jitter. The findings in the present study suggest dysfunction of neuromuscular transmission in patients with MFS.

Abnormalities of neuromuscular transmission in patients with Miller-Fisher syndrome.

Preferential wasting of the thenar group of muscles, the split hand sign, appears to be a specific feature of ALS. The present study developed a novel split-hand index (SI) and assessed its diagnostic utility in ALS.

Split-hand index for the diagnosis of amyotrophic lateral sclerosis.

The flexor pollicis longus (FPL), a key muscle involved in fractionated thumb movements, may be relatively spared in amyotrophic lateral sclerosis (ALS) compared to the thenar group of muscles, termed the split-hand plus sign. Consequently, the diagnostic utility of the split-hand plus sign was prospectively assessed in ALS. In total, 103 patients (37 ALS and 66 non-ALS) with neuromuscular symptoms underwent assessment of FPL and APB strength using the Medical Research Council (MRC) score. A median nerve strength index (MSI) was developed to quantify differential involvement by expressing the APB strength score as a fraction of the FPL strength score. The APB muscle strength was significantly reduced compared to FPL strength in ALS patients (p < 0.0001), but was comparable in the non-ALS disorders (p = 0.91). In addition, there was a significant reduction of MSI scores in ALS patients (MSIALS 0.8; MSInon-ALS 1.0, p < 0.01). Analysis of receiver operating characteristic (ROC) curves disclosed that MSI < 0.9 exhibited an area under the curve of 0.86 (p < 0.001) with a sensitivity of 85% and specificity of 86% for limb-onset ALS. In conclusion, split-hand plus sign distinguished ALS from non-ALS neuromuscular disorders, thereby suggesting a diagnostic utility of this novel clinical sign in ALS.

Split-hand plus sign in ALS: differential involvement of the flexor pollicis longus and intrinsic hand muscles.

Although abductor pollicis brevis (APB) and flexor pollicis longus (FPL) share a common peripheral nerve supply, these muscles subserve different functions and may be differently affected in neurodegenerative disease such as amyotrophic lateral sclerosis (ALS). As a consequence, differences in cortical excitability may potentially develop in relation to these functional differences. Cortical excitability was assessed using the threshold tracking transcranial magnetic stimulation (TMS) technique in 15 healthy controls with motor responses recorded over the APB and FPL using surface electrode recordings. Short-interval intracortical inhibition (SICI) was significantly reduced from the FPL compared to APB (SICIFPL 6.9±1.8%; SICIAPB 10.7±1.4%, P<0.01). In addition, the FPL motor evoked potential amplitude (MEPFPL 14.7±2.3%; MEPAPB 21.7±3.9%; P<0.01) and cortical silent period duration (CSPFPL 174.7±6.7ms; CSPAPB 205.4±3.9ms, P<0.01) were significantly smaller. The findings in the present study indicate that cortical inhibition and corticomotoneuronal output is reduced when recording over the FPL. The differences in cortical excitability may develop as a consequence of varied function and could potentially explain the dissociated muscle atrophy evident in ALS.

Cortical excitability differences between flexor pollicis longus and APB.

Riluzole, a benzothiazole derivative, has been shown to be effective in prolonging survival in amyotrophic lateral sclerosis. The mechanisms by which riluzole exerts neuroprotective effects in amyotrophic lateral sclerosis remains to be fully elucidated, although inhibition of glutamatergic transmission and modulation of Na+ channel function have been proposed. In an attempt to determine the mechanisms by which riluzole exerts neuroprotective effects, in particular to dissect the relative contributions of inhibition of glutamatergic transmission and Na+ channel modulation, the present study utilized a combination of cortical and peripheral axonal excitability approaches to monitor changes in excitability and function in patients with amyotrophic lateral sclerosis. Cortical assessment was undertaken by utilising the threshold tracking transcranial magnetic stimulation (TMS) technique and combined with peripheral axonal excitability studies in 25 patients with amyotrophic lateral sclerosis. Studies were performed at baseline and repeated when patients were receiving riluzole 100 mg/day. At the time of second testing all patients were tolerating the medication well. Motor evoked potential and compound muscle action potential responses were recorded over the abductor pollicis brevis muscle. At baseline, features of cortical hyperexcitability were evident in patients with amyotrophic lateral sclerosis, indicated by marked reduction in short interval intracortical inhibition (P < 0.001) and cortical silent period duration (P < 0.001), as well as an increase in the motor evoked potential amplitude (P < 0.01). Riluzole therapy partially normalized cortical excitability by significantly increasing short interval intracortical inhibition (short interval intracortical inhibitionbaseline 0.5 ± 1.8%; short interval intracortical inhibitionON riluzole 7.9 ± 1.7%, P < 0.01). In contrast, riluzole did not exert any modulating effect on cortical silent period duration (P = 0.45) or motor evoked potential amplitude (P = 0.31). In terms of peripheral nerve function, axonal excitability studies established that, relative to control subjects, patients with amyotrophic lateral sclerosis had significant increases in depolarizing threshold electrotonus [amyotrophic lateral sclerosisbaseline TEd (90-100 ms) 49.1 ± 1.8%; controlsTEd (90-100 ms) 45.2 ± 0.6%, P < 0.01] and superexcitability (amyotrophic lateral sclerosisbaseline 30.1 ± 2.3%; control subjects 23.4 ± 1.0%, P < 0.01) at baseline. Following institution of riluzole therapy there was a significant reduction in superexcitability (amyotrophic lateral sclerosisbaseline 30.1 ± 2.3%; amyotrophic lateral sclerosisON riluzole 27.3 ± 2.3%, P < 0.05) and refractoriness at 2 ms (amyotrophic lateral sclerosisbaseline 98.7 ± 10.7%; amyotrophic lateral sclerosisON riluzole 67.8 ± 9.3%, P < 0.001). In conclusion, the present study has established that riluzole exerts effects on both central and peripheral nerve function, interpreted as partial normalization of cortical hyperexcitability and reduction of transient Na+ conductances. Taken together, these findings suggest that the neuroprotective effects of riluzole in amyotrophic lateral sclerosis are complex, with evidence of independent effects across both compartments of the nervous system.

Riluzole exerts central and peripheral modulating effects in amyotrophic lateral sclerosis.

The development of hyperexcitability in amyotrophic lateral sclerosis (ALS) is a well-known phenomenon. Despite controversy as to the underlying mechanisms, cortical hyperexcitability appears to be closely related to the interplay between excitatory corticomotoneurons and inhibitory interneurons. Hyperexcitability is not a static phenomenon but rather shows a pattern of progression in a spatiotemporal aspect. Cortical hyperexcitability may serve as a trigger to the development of anterior horn cell degeneration through a 'dying forward' process. Hyperexcitability appears to develop during the early disease stages and gradually disappears in the advanced stages of the disease, linked to the destruction of corticomotorneuronal pathways. As such, a more precise interpretation of these unique processes may provide new insight regarding the pathophysiology of ALS and its clinical features. Recently developed technologies such as threshold tracking transcranial magnetic stimulation and automated nerve excitability tests have provided some clues about underlying pathophysiological processes linked to hyperexcitability. Additionally, these novel techniques have enabled clinicians to use the specific finding of hyperexcitability as a useful diagnostic biomarker, enabling clarification of various ALS-mimic syndromes, and the prediction of disease development in pre-symptomatic carriers of familial ALS. In terms of nerve excitability tests for peripheral nerves, an increase in persistent Na(+) conductances has been identified as a major determinant of peripheral hyperexcitability in ALS, inversely correlated with the survival in ALS. As such, the present Review will focus primarily on the puzzling theory of hyperexcitability in ALS and summarize clinical and pathophysiological implications for current and future ALS research.

The puzzling case of hyperexcitability in amyotrophic lateral sclerosis.

Introduction: Differences in cortical and axonal excitability may underlie preferential atrophy of abductor pollicis brevis (APB) and first dorsal interosseous (FDI) in amyotrophic lateral sclerosis, termed split-hand. Consequently, this study aimed to determine whether differences in excitability follow a split-hand pattern across the intrinsic hand muscles. Methods: Excitability studies were undertaken using threshold tracking techniques in 26 healthy controls with responses recorded over APB, FDI and abductor digiti minimi. Results: Short interval intracortical inhibition was significantly greater from the APB and FDI. In addition, motor evoked potential amplitude was greater, while cortical silent period was longer from APB and FDI. At a peripheral level, the strength-duration time constant was greater when recorded over APB. Discussion: This study establishes that differences in cortical excitability follow the split-hand pattern in healthy controls, a finding potentially explained by evolution of specialized activity of APB/FDI in complex hand tasks. © 2013 Wiley Periodicals, Inc.

Cortical excitability differences in hand muscles follow a split-hand pattern in healthy controls.

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).

ALS pathophysiology: insights from the split-hand phenomenon.

The split-hand phenomenon, a specific feature of amyotrophic lateral sclerosis (ALS), refers to preferential wasting of abductor pollicis brevis (APB) and first dorsal interosseous (FDI) with relative preservation of abductor digiti minimi (ADM). The pathophysiological mechanisms underlying the split-hand phenomenon remain elusive and resolution of this issue would provide unique insights into ALS pathophysiology. Consequently, the present study dissected out the relative contribution of cortical and peripheral processes in development of the split-hand phenomenon in ALS. Cortical and axonal excitability studies were undertaken on 26 ALS patients, with motor responses recorded over the APB, FDI and ADM muscles. Results were compared to 21 controls. Short interval intracortical inhibition (SICI), a biomarker of cortical excitability, was significantly reduced across the range of intrinsic hand muscles (APB(SICI ALS) 0.3±2.0%, APB(SICI controls) 16.0±1.9%, P<0.0001; FDI(SICI ALS) 2.7±1.7%, FDI(SICI controls) 14.8±1.9%, P<0.0001; ADM(SICI ALS) 2.6±1.5%, ADM(SICI controls) 9.7±2.2%, P<0.001), although the reduction was most prominent when recorded over APB/FDI. Changes in SICI were accompanied by a significant increase in motor evoked potential amplitude and reduction of cortical silent period duration, all indicative of cortical hyperexcitability, and these were most prominent from the APB/FDI. At a peripheral level, a significant increase in strength-duration time constant and reduction in depolarising threshold electrotonus were evident in ALS, although these changes did not follow a split-hand distribution. Cortical dysfunction contributed to development of the split-hand in ALS, thereby implying an importance of cortical hyperexcitability in ALS pathogenesis.

Cortical dysfunction underlies the development of the split-hand in amyotrophic lateral sclerosis.

Preferential involvement of thenar muscles compared to flexor pollicis longus (FPL), termed 'the split-hand plus sign', appears to be a clinical feature of amyotrophic lateral sclerosis (ALS). In an attempt to understand the pathophysiological mechanisms underlying this clinical phenomenon, threshold tracking transcranial magnetic stimulation techniques were utilized to assess whether cortical mechanisms may be a significant contributing influence. Cortical excitability studies were undertaken on 17 ALS patients, with motor evoked potentials (MEP) recorded from thenar muscles and FPL. Split-hand plus index (SHPI) was derived by dividing motor amplitudes recorded over APB with those recorded over FPL. Results showed the SHPI was significantly reduced in ALS (SHPIALS 0.87 ± 0.12; SHPICONTROLS 1.7 ± 0.2, p < 0.001). Cortical studies disclosed significant increases in MEP amplitudes recorded over thenar muscles (p < 0.05) but not FPL (p = 0.11), and were significantly correlated with the SHPI (R = -0.83, p < 0.01). The cortical silent period duration was reduced from thenar muscles (p < 0.01). Although there was a ubiquitous reduction in short-interval intracortical inhibition (APB, p < 0.01; FPL < 0.05), this reduction was more prominent over the thenar muscles. In conclusion, findings from the present study suggest that cortical dysfunction in the form of hyperexcitability contributes to the pathophysiological basis of the split-hand plus sign in ALS.

Parvathi Menon

Department of Neurology

Westmead hospital

Utility of Dissociated Intrinsic Hand Muscle Atrophy in the Diagnosis of Amyotrophic Lateral Sclerosis

Parvathi Menon

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Neurology

Westmead hospital

Utility of Dissociated Intrinsic Hand Muscle Atrophy in the Diagnosis of Amyotrophic Lateral Sclerosis

Department of Neurology