Funding support from the Motor Neuron Disease Research Institute of Australia (MNDRIA), Sylvia and Charles Viertel Charitable Foundation Clinical Investigator grant, Ramaciotti Foundation and National Health and Medical Research Council of Australia (Project grant number APP1024915)&#160;is gratefully acknowledged.&#160;

1. Patient Preparation
<ol>
	<li>Recruit patients prospectively and consecutively. Note: The following protocol is approved by the Sydney West Area Health Service Human Research Ethics Committees. Informed consent was provided by all patients. Patients were recruited prospectively and consecutively from the ALS/neuromuscular clinic at Westmead Hospital.</li>
	<li>Determine suitability of ALS patients for testing. Exclude patients who are not diagnosed with ALS or a neuromuscular disorder.</li>
	<li>Exclude patients with a coexistent focal neuropathy, median neuropathy at the wrist or ulnar neuropathy at elbow.</li>
	<li>Exclude patients with a generalized neuropathy, such as diabetic polyneuropathy.</li>
	<li>Extensively investigate and clinically follow-up patients to confirm the diagnosis of ALS or neuromuscular mimic disorders.</li>
	<li>Ensure that informed consent is provided by all patients, including ALS and neuromuscular mimic disorder patients, for all the neurophysiological procedures.</li>
</ol>
2. Clinical Assessment
<ol>
	<li>Determine the clinical staging of all ALS patients by using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score18.</li>
	<li>Determine the rate of disease progression in all ALS patients according to the previously reported formula; 
	(48-ALSFRS-R)/duration of symptoms)19.</li>
	<li>Determine muscle strength in all patients using the Medical Research Council (MRC) rating scale20. Develop a total MRC score comprising upper limb (shoulder abduction; elbow flexion; elbow extension; wrist dorsiflexion; finger abduction; thumb abduction, total score 60) and lower limb (hip flexion; knee extension; ankle dorsiflexion, total score 30) muscle groups. The total MRC score should be 90 if muscle strength is normal.</li>
	<li>Determine the site of disease onset, defined as bulbar or limb, in all ALS patients.</li>
</ol>
3. Neurophysiological Assessment
<ol>
	<li>Undertake motor nerve conduction studies on the median and ulnar nerves with compound muscle action potential (CMAP) responses recorded from the abductor pollicis brevis (APB), first dorsal interosseous (FDI) and abductor digit minimi (ADM) muscles.</li>
	<li>Prepare the stimulating sites at the wrist, by cleaning the skin surface with an abrasive gel to reduce skin resistance, followed by application of an alcohol wipe. Set the stimulating current to 20% above the intensity required to produce a maximal CMAP response (supramaximal current).</li>
	<li>Ensure that the selected stimulation site exhibits the lowest threshold for stimulation such that volume conduction is avoided.</li>
	<li>Prepare recording site over each muscle by cleaning the skin surface with an abrasive gel to reduce skin resistance, followed by application of an alcohol wipe.</li>
	<li>Record the size of the compound motor action potential (CMAP) from the APB, ADM, and FDI muscles. Responses to be recorded by 10&#160;mm gold disc electrodes positioned in a belly tendon arrangement over each muscle. Specifically, position the active electrode over the midpoint of the respective muscle ensuring a negative take-off of the CMAP response, while reference electrode to be positioned over the base of thumb (APB and FDI CMAP recordings) and base of digit 5 (for ADM CMAP recordings).</li>
	<li>Set the distance between the stimulating cathode and active electrode for APB and ADM compound motor action potential responses to 5 cm and the distance to the FDI at 8 cm.</li>
	<li>Position the electrosurgical neutral earth plate on the dorsal aspect of the hand, between stimulating and G1 electrode, with conductive gel to reduce artifact. Prior to application of the neutral earth prepare the site by cleaning the skin surface with an abrasive gel to reduce skin resistance, followed by application of an alcohol wipe.</li>
	<li>Ensure the filter settings are between 3 Hz (low-frequency filter) and 10 KHz (high-frequency filter).</li>
	<li>Ensure that the sweep speed is set to 20 msec, or 2 msec/division.</li>
	<li>Ensure that the sensitivity for recording CMAP responses is set to 5 mV.</li>
	<li>Monitor temperature at the site of stimulation throughout the study and ensure that the limb temperature is maintained at 32 &#176;C.</li>
</ol>
4. Analysis and Interpretation
<ol>
	<li>Measure baseline-to-peak CMAP amplitudes (mV) over the APB, FDI and ADM muscles in ALS patients and the neuromuscular mimic disease controls.</li>
	<li>Calculate the split&#160;hand index (Figure&#160;1) by multiplying the CMAP amplitude recorded over the APB and FDI muscles, and dividing this product by the CMAP amplitude recorded over the ADM muscle, as follows: 
	SI = APB CMAP * FDI CMAP 
	_________________________ 
	&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;&#160;ADM CMAP</li>
	<li>Determine the diagnostic utility of the split hand index by comparing the SI values between ALS patients and neuromuscular mimic disorder pathological controls according to the standards for reporting of diagnostic accuracy (STARD) criteria.</li>
	<li>Determine optimal diagnostic cutoff values for the split&#160;hand index by using the receiver operating characteristic (ROC) curves. Derive ROC curve by plotting the sensitivity (y-axis) and 1-specificty (x-axis) for SI values derived from ALS and neuromuscular disorder patients.</li>
</ol>

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J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+&#8220;split+hand+syndrome&#8220;.">The &#8220;split hand syndrome&#8220;.</a> Muscle Nerve. 23, 138 (2000).</li><li>Kuwabara, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dissociated+small+hand+muscle+atrophy+in+amyotrophic+lateral+sclerosis:+frequency,+extent,+and+specificity.">Dissociated small hand muscle atrophy in amyotrophic lateral sclerosis: frequency, extent, and specificity.</a> Muscle Nerve. 37, 426-430 (2008).</li><li>Kuwabara, S., Mizobuchi, K., Ogawara, K., Hattori, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dissociated+small+hand+muscle+involvement+in+amyotrophic+lateral+sclerosis+detected+by+motor+unit+number+estimates.">Dissociated small hand muscle involvement in amyotrophic lateral sclerosis detected by motor unit number estimates.</a> Muscle Nerve. 22, 870-873 (1999).</li><li>Menon, P., Kiernan, M. C., Vucic, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Appearance,+phenomenology+and+diagnostic+utility+of+the+split+hand+in+amyotrophic+lateral+sclerosis.">Appearance, phenomenology and diagnostic utility of the split hand in amyotrophic lateral sclerosis.</a> Neurodegener. Dis. Manag. 1, 457-462 (2011).</li><li>Brooks, B. R., Miller, R. G., Swash, M., Munsat, T. 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Psychiatr. 81, 646-649 (2010).</li><li>Noto, Y. I., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Awaji+ALS+criteria+increase+the+diagnostic+sensitivity+in+patients+with+bulbar+onset.">Awaji ALS criteria increase the diagnostic sensitivity in patients with bulbar onset.</a> Clin. Neurophysiol. 123, 382-385 (2012).</li><li>Schrooten, M., Smetcoren, C., Robberecht, W., Van Damme, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Benefit+of+the+Awaji+diagnostic+algorithm+for+amyotrophic+lateral+sclerosis:+A+prospective+study.">Benefit of the Awaji diagnostic algorithm for amyotrophic lateral sclerosis: A prospective study.</a> Ann. 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Sci. 169, 13-21 (1999).</li><li>Kimura, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Progression+rate+of+ALSFRS-R+at+time+of+diagnosis+predicts+survival+time+in+ALS.">Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS.</a> Neurology. 66, 265-267 (2006).</li><li>O'Brien, M. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Aid to the examination of the peripheral nervous system. , (2010).</li><li>Menon, P., Kiernan, M. C., Yiannikas, C., Stroud, J., Vucic, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Split-hand+index+for+the+diagnosis+of+amyotrophic+lateral+sclerosis.">Split-hand index for the diagnosis of amyotrophic lateral sclerosis.</a> Clin. Neurophysiol. 124, 410-416 (2013).</li><li>Kiernan, M. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Amyotrophic+lateral+sclerosis.">Amyotrophic lateral sclerosis.</a> Lancet. 377, 942-955 (2011).</li><li>Vucic, S., Cordato, D. J., Yiannikas, C., Schwartz, R. S., Shnier, R. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Utility+of+magnetic+resonance+imaging+in+diagnosing+ulnar+neuropathy+at+the+elbow.">Utility of magnetic resonance imaging in diagnosing ulnar neuropathy at the elbow.</a> Clin. Neurophysiol. 117, 590-595 (2006).</li><li>Siao, P., Cros, D., Vucic, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Practical approach to electromyography. , (2011).</li></ol>

The authors have nothing to disclose.

The present study reports on the diagnostic utility of the split hand index in ALS, a novel neurophysiological diagnostic biomarker. The SI reliably distinguished ALS from neuromuscular disorders, with an optimal diagnostic cut-off value of 5.2. The reduction in the SI was most prominent in limb-onset ALS patients. Importantly, a substantial proportion of ALS patients that were classified in the diagnostic &#8220;possible&#8221; category as per the recently developed diagnostic criteria11, exhibited an abnormal SI. Taken together, findings from the present study suggest that the split hand index may be a diagnostic biomarker of ALS, potentially aiding in an earlier diagnosis of ALS.
Diagnostic criteria, relying on the presence of upper and lower motor neuron dysfunction in multiple regions, have been developed to aid the diagnosis of ALS6,11,22. These criteria, however, have been shown as insensitive and at times limited by patient tolerability due to the need to perform extensive needle EMG sampling7-10,14-16. Consequently, critical diagnostic delay may ensue, perhaps beyond the therapeutic window period.
The split hand index, a simple neurophysiological biomarker, can be readily performed in a clinical setting. Importantly, the present study underscores the diagnostic utility of the split hand index in ALS, particularly in limb-onset disease. Of relevance, the finding that reduction in the split hand index was an early feature in ALS, further underscores its diagnostic utility. Ultimately, the application of SI may lead to recruitment of ALS patients into clinical trials at an earlier stage in the disease process where effectiveness of future neuroprotective agents may be at their peak.
A potential limitation of the split hand index may occur in the setting of coexistent focal pressure mononeuropathies, particularly carpal tunnel syndrome and ulnar neuropathy at the elbow. Clinical, neurophysiological, and radiological correlation should then be utilized to assess for a specific pattern of pathology and alternative techniques need to be implemented so as to establish a diagnosis of ALS23,24. In addition, the SI may be limited in advanced disease, when there may be global atrophy of intrinsic hand muscles. As with focal mononeuropathies, other diagnostic modalities should be utilized to confirm the diagnosis of ALS. In addition, avoiding a contribution from a volume conducted response to the CMAP amplitude is critical prior to conclude the diagnostic value of the SI. Volume conduction may be reduced by appropriate positioning of recording electrodes so as to ensure a CMAP response with negative take-off and appropriate stimulation intensities should be utilized to prevent cross stimulation. If all such potential limitations are addressed, the SI could be utilized as a potential diagnostic aid in ALS.

The split&#160;hand, refers to preferential atrophy of the thenar complex group of intrinsic hand muscles [abductor pollicis brevis (APB) and first dorsal interosseous (FDI)], with relative preservation of hypothenar muscles, and is a specific and early clinical feature of amyotrophic lateral sclerosis (ALS)1-4. The finding that the split hand sign is specific for ALS, suggests a potential role for the split hand sign as a diagnostic biomarker in ALS3.
Quantification of the split&#160;hand sign, through the development of a novel neurophysiological biomarker, may further aid in ALS diagnosis. Specifically, the split&#160;hand index (SI), which quantifies the split&#160;hand phenomenon, is derived by multiplying the compound muscle action potential (CMAP) amplitude recorded over the thenar complex muscles (APB and FDI), and dividing this product by the CMAP amplitude recorded over the hypothenar muscles (namely the abductor digiti minimi, ADM)5.
The diagnosis of ALS relies largely on clinically based criteria encompassing a combination of upper and lower motor neuron signs6. These criteria, however, were deemed insensitive especially in establishing a diagnosis of ALS in the early stages of the disease process7-10. A recent modification of the diagnostic criteria were developed11, and although these criteria appear to increase the diagnostic sensitivity12-16, the increase sensitivity seems restricted to bulbar-onset ALS patients15.
In the absence of a pathognomonic test, the diagnosis of ALS may be significantly delayed8. Ultimately, the institution of neuroprotective therapies and recruitment into clinical trials may be delayed, perhaps beyond the critical therapeutic window period9,17. Consequently, the diagnostic utility of the SI was prospectively assessed in sporadic ALS patients.

<table><tbody><tr><td>Abrasive gel (Nu Prep)</td><td>Weaver and Company</td><td>N-TA\/P\H-3 ENG</td><td>Skin preperation</td></tr><tr><td>Alcohol wipe</td><td>Triad Disposables</td><td>103101</td><td>Skin preperation</td></tr><tr><td>Recording gel (Ten20 Conductive gel)</td><td>Weaver and Company</td><td>N-TA\/P\H-3 ENG</td><td>Recording motor responses</td></tr><tr><td>Amyotrophic lateral sclerosis rating scale-revised questionnaire</td><td>Publication</td><td>Experimental builder</td><td>Stage disease</td></tr><tr><td>Medical Research Council muscle strength scale</td><td>Medical Research Council-UK</td><td>Experimental builder</td><td>Stage disease</td></tr><tr><td>&lt;strong&gt;Equipment&lt;/strong&gt;</td><td>&lt;strong&gt;Company&lt;/strong&gt;</td><td>&lt;strong&gt;Catalog number&lt;/strong&gt;</td><td>&lt;strong&gt;Comments&lt;/strong&gt;</td></tr><tr><td>Nerve conduction machine (Synergy/Nicolet EDX)</td><td>CareFusion</td><td>SA110106M</td><td>To measure split hand index</td></tr><tr><td>Synergy software</td><td>CareFusion</td><td>765654679</td><td>To measure split hand index</td></tr><tr><td>Tem millimeter gold cup disc electrodes</td><td>Grass Technologies</td><td>F-E5GH-60</td><td>To record motor responses</td></tr><tr><td>Neural earth plate</td><td>Westmead Hospital</td><td>Experimental builder</td><td>To record limb temperature</td></tr><tr><td>Thermometer</td><td>Westmead Hospital</td><td>Experimental builder</td><td>To record limb temperature</td></tr></tbody></table>

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 novel split hand index (SI) was developed to quantify the split hand phenomenon, and its diagnostic utility was assessed in ALS patients. The split hand index was derived by dividing the product of the compound muscle action potential (CMAP) amplitude recorded over the abductor pollicis brevis and first dorsal interosseous muscles by the CMAP amplitude recorded over the abductor digiti minimi muscle. In order to assess the diagnostic utility of the split hand index, ALS patients were prospectively assessed and their results were compared to neuromuscular disorder patients. The split hand index was significantly reduced in ALS when compared to neuromuscular disorder patients (P&#60;0.0001). Limb-onset ALS patients exhibited the greatest reduction in the split&#160;hand index, and a value of 5.2 or less reliably differentiated ALS from other neuromuscular disorders. Consequently, the split&#160;hand index appears to be a novel diagnostic biomarker for ALS, perhaps facilitating an earlier diagnosis.

Clinical Phenotype
In total, 44 ALS patients were studied, of which 76% (N=33) were classified as definite or probable and 24% (N=11) as possible ALS according to the Awaji criteria11. The diagnosis of ALS was confirmed in the “possible” cohort after extensive investigations and clinical follow-up for up to 3 years and 53% died during this period. Bulbar-onset disease was evident in 41%, while limb-onset in 59% of ALS patients. At the time of assessment, mean disease duration was 18.9±3.1 months, with a median ALSFRS-R score being 41(32-45), indicating a moderate degree of disability.
The neuromuscular control group comprised 121 patients (mean age 54 years) and included the following diagnosis: entrapment neuropathies-carpal tunnel syndrome (CTS) and ulnar neuropathy at the elbow (UNE), N=62; demyelinating neuropathy (N=9); axonal sensorimotor polyneuropathy (N=36); cervical radiculopathy (11); spino-bulbar muscular atrophy (N=1); Hirayama’s disease (N=1); spinal muscular atrophy (N=1).
Neurophysiological Studies
In ALS patients, there was a significant reduction of CMAP amplitude recorded over the APB (ALS, 3.9±0.5 mV; neuromuscular disorders 8.1± 0.2 mV, P&lt;0.001), FDI (ALS, 4.8±0.7 mV; neuromuscular disorders 10.7±0.3 mV, P&lt;0.001) and ADM (ALS, 6.1±0.5 mV; neuromuscular disorders 9.7±0.2 mV, P&lt;0.001). Importantly, the reduction in CMAP amplitudes was more prominent when recording over the APB (CMAPAPB 3.9±0.5 mV; CMAPADM 6.1±0.5 mV P&lt;0.001) and FDI (CMAPFDI 4.8±0.7 mV; CMAPADM 6.1±0.5 mV P&lt;0.05) muscles then ADM in the ALS cohort.
Of further relevance, the extent of CMAP reduction was more prominent in limb-onset patients when recording over APB (CMAPLIMB-ONSET 3.8±0.4 mV; CMAPBULBAR-ONSET 5.3±0.6 mV P&lt;0.05), FDI (CMAPLIMB-ONSET 4.4±0.7 mV; CMAPBULBAR-ONSET 7.0±0.9 mV P&lt;0.05) and ADM (CMAPLIMB-ONSET 5.8±0.5 mV; CMAPBULBAR-ONSET 7.6±0.6 mV P&lt;0.01) muscles compared to bulbar onset ALS patients. In contrast, the reduction in CMAP amplitudes was most prominent when recording over the APB (8.1±0.2 mV, P&lt;0.0001) and ADM (9.7±0.2 mV, P&lt;0.01) muscles in the neuromuscular cohort (CMAPFDI 10.7±0.3 mV).
Combining the CMAP amplitudes, it was evident that there was a significant reduction of the split hand index in ALS patients compared to neuromuscular disorder patients (ALS 3.5±0.6; neuromuscular disorders 9.1±0.3, P&lt;0.0001, Figure 2A)21. While this reduction in the split hand index was a ubiquitous finding in ALS, it was most pronounced in ALS patients with limb-onset disease (SILIMB-ONSET2.3±0.5; SIBULBAR-ONSET 5.3±1.2, P&lt;0.0001, Figure 2B)21.
Analysis of receiver operating characteristic curves disclosed a good diagnostic accuracy of the split hand index in differentiating ALS from other neuromuscular disorders, as indicated by the fact that the area under curve (AUC) was 0.83 (P&lt;0.0001, Figure 3A)21. An SI value of 5.2 or less, as indicated by dotted black lines (Figure 3A), differentiated ALS from other neuromuscular disorders21. Importantly, the diagnostic utility of the split hand index was greater in ALS patients with limb-onset disease (Figure 3B)21.
In order to assess the diagnostic utility of the split hand index, SI values were compared between those ALS patients meeting the “definite” versus “possible” diagnostic category on the Awaji-Shima criteria11. Importantly, there was a significant reduction of SI in patients classified as “possible” ALS (ALS POSSIBLE SI 5.1±0.8; neuromuscular disorders 9.1±0.3, P&lt;0.01). In addition, of the 11 patients classified as possible ALS, 64% exhibited a reduction in the split hand index value of less than 5.2. Taken together, these findings suggest that an abnormal split hand index may support a diagnosis of ALS in up to 64% of patients not meeting the “definite/probable” Awaji diagnostic criteria.
Of potential prognostic relevance, the split hand index significantly correlated with the total MRC score (rho = 0.7, P&lt;0.001) and MRC score from the thenar eminence (rho = 0.8, P&lt;0.001). Of further relevance, the SI exhibited a significant correlation with the rate of disease progression (rho = - 0.4, P&lt;0.05). These findings indicate that SI is associated with disease severity and progression, thereby suggesting a potential role for the SI in ALS prognostication.
<img alt="Split hand index formula with hand muscle anatomy; diagram for medical analysis." fo:content-width="5in" fo:src="/files/ftp_upload/51056/51056fig1highres.jpg" src="/files/ftp_upload/51056/51056fig1.jpg" data-altupdatedat="1747911167000" data-alt="Figure 1"> 
Figure 1. Split hand sign refers to preferential wasting of the thenar complex group of muscles [abductor pollicis brevis (APB) and first dorsal interosseous (FDI)] muscles when compared to the hypothenar [abductor digit minimi (ADM)] muscles. The split hand index is calculated by multiplying the compound muscle action potential (CMAP) amplitude recorded over the APB by that recorded over the FDI and dividing the product by the CMAP amplitude recorded over the ADM. (In part reproduced from Menon and colleagues. Split hand index for the diagnosis of amyotrophic lateral sclerosis. From Menon et al.21 
<img alt="Bar chart comparing split-hand index between ALS, NMS, limb, and bulbar groups, showing differences." fo:content-width="5in" fo:src="/files/ftp_upload/51056/51056fig2highres.jpg" src="/files/ftp_upload/51056/51056fig2.jpg" data-altupdatedat="1747911167000" data-alt="Figure 2"> 
Figure 2. (A) The split hand index (SI) was significantly reduced in amyotrophic lateral sclerosis (ALS) when compared to neuromuscular disorder patients (NMS). (B) The reduction in SI was most prominent in ALS in patients with limb-onset disease. ***P&lt;0.001; ****P&lt;0.0001.
<img alt="ROC curve analysis comparing sensitivity and specificity; threshold at SI 5.2, graph A and B results." fo:content-width="5in" fo:src="/files/ftp_upload/51056/51056fig3highres.jpg" src="/files/ftp_upload/51056/51056fig3.jpg" data-altupdatedat="1747911167000" data-alt="Figure 3"> 
Figure 3. (A) The split hand index (SI) robustly differentiated amyotrophic lateral sclerosis (ALS) from neuromuscular disorder patients (NMS), with an optimal diagnostic cut-off value being 5.2. (B) The diagnostic utility of SI was more prominent in limb-onset ALS patients. (In part reproduced from Menon and colleagues. Split hand index for the diagnosis of amyotrophic lateral sclerosis. From Menon et al.21

Watch this Scientific Journal Video about Utility of Dissociated Intrinsic Hand Muscle Atrophy in the Diagnosis of Amyotrophic Lateral Sclerosis at JoVE.com

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

Dissociated atrophy of intrinsic hand muscles, termed the split hand, appears to be a specific feature of amyotrophic lateral sclerosis (ALS).&#160;Consequently, a novel neurodiagnostic test, termed the split hand&#160;index, was developed to quantify the clinical phenomenon of the split hand, which differentiated ALS from mimic disorders.

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

utility-dissociated-intrinsic-hand-muscle-atrophy-diagnosis

Nanyang Technological University

Research

JoVE Journal

Medicine

31.6K Views.  Westmead Hospital.  Gedissocieerde atrofie van intrinsieke handspieren, de zogenoemde split kant, lijkt een specifiek kenmerk van amyotrofische lateraal sclerose (ALS) zijn. Bijgevolg is een nieuwe neurodiagnostische test zogenaamde split kant index werd ontwikkeld om de klinische verschijnsel van de gesplitste hand, die ALS opzichte van aandoeningen nabootsen kwantificeren. 

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

A Protocol for Comprehensive Assessment of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis (ALS)

Improved methods for assessing bulbar impairment are necessary for expediting diagnosis of bulbar dysfunction in ALS, for predicting disease progression across speech subsystems, and for addressing the critical need for sensitive outcome measures for ongoing experimental treatment trials. To address this need, we are obtaining longitudinal profiles of bulbar impairment in 100 individuals based on a comprehensive instrumentation-based assessment that yield objective measures. Using instrumental approaches to quantify speech-related behaviors is very important in a field that has primarily relied on subjective, auditory-perceptual forms of speech assessment1. Our assessment protocol measures performance across all of the speech subsystems, which include respiratory, phonatory (laryngeal), resonatory (velopharyngeal), and articulatory. The articulatory subsystem is divided into the facial components (jaw and lip), and the tongue. Prior research has suggested that each speech subsystem responds differently to neurological diseases such as ALS. The current protocol is designed to test the performance of each speech subsystem as independently from other subsystems as possible. The speech subsystems are evaluated in the context of more global changes to speech performance. These speech system level variables include speaking rate and intelligibility of speech.
The protocol requires specialized instrumentation, and commercial and custom software. The respiratory, phonatory, and resonatory subsystems are evaluated using pressure-flow (aerodynamic) and acoustic methods. The articulatory subsystem is assessed using 3D motion tracking techniques. The objective measures that are used to quantify bulbar impairment have been well established in the speech literature and show sensitivity to changes in bulbar function with disease progression. The result of the assessment is a comprehensive, across-subsystem performance profile for each participant. The profile, when compared to the same measures obtained from healthy controls, is used for diagnostic purposes. Currently, we are testing the sensitivity and specificity of these measures for diagnosis of ALS and for predicting the rate of disease progression. In the long term, the more refined endophenotype of bulbar ALS derived from this work is expected to strengthen future efforts to identify the genetic loci of ALS and improve diagnostic and treatment specificity of the disease as a whole. The objective assessment that is demonstrated in this video may be used to assess a broad range of speech motor impairments, including those related to stroke, traumatic brain injury, multiple sclerosis, and Parkinson disease.

A Protocol for Comprehensive Assessment of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis ALS

Objective assessments of the physiological mechanisms that support speech are needed to monitor disease onset and progression in persons with ALS and to quantify treatment effects in clinical trials. In this video, we present a comprehensive, instrumentation-based protocol for quantifying speech motor performance in clinical populations.

Improved methods for assessing bulbar impairment are necessary for expediting diagnosis of bulbar dysfunction in ALS, for predicting disease progression ...

Manual Muscle Testing:  A Method of Measuring Extremity Muscle Strength Applied to Critically Ill Patients 

Survivors of acute respiratory distress syndrome (ARDS) and other causes of critical illness often have generalized weakness, reduced exercise tolerance, and persistent nerve and muscle impairments after hospital discharge.1-6 Using an explicit protocol with a structured approach to training and quality assurance of research staff, manual muscle testing (MMT) is a highly reliable method for assessing strength, using a standardized clinical examination, for patients following ARDS, and can be completed with mechanically ventilated patients who can tolerate sitting upright in bed and are able to follow two-step commands. 7, 8 
This video demonstrates a protocol for MMT, which has been taught to &ge;43 research staff who have performed &gt;800 assessments on &gt;280 ARDS survivors. Modifications for the bedridden patient are included. Each muscle is tested with specific techniques for positioning, stabilization, resistance, and palpation for each score of the 6-point ordinal Medical Research Council scale.7,9-11 Three upper and three lower extremity muscles are graded in this protocol: shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension, and ankle dorsiflexion. These muscles were chosen based on the standard approach for evaluating patients for ICU-acquired weakness used in prior publications. 1,2.

Manual Muscle Testing:  A Method of Measuring Extremity Muscle Strength Applied to Critically Ill Patients

Survivors of acute respiratory distress syndrome (ARDS) and critical illness frequently develop long-lasting muscle weakness. Manual muscle testing (MMT) is a standardized clinical examination commonly used to measure strength of peripheral skeletal muscle groups. This video demonstrates MMT using the 6-point Medical Research Council scale.

Survivors of acute respiratory distress syndrome (ARDS) and other causes of critical illness often have generalized weakness, reduced exercise tolerance, ...

Electrophysiological Motor Unit Number Estimation (MUNE) Measuring Compound Muscle Action Potential (CMAP) in Mouse Hindlimb Muscles

Compound muscle action potential (CMAP) and motor unit number estimation (MUNE) are electrophysiological techniques that can be used to monitor the functional status of a motor unit pool in vivo. These measures can provide insight into the normal development and degeneration of the neuromuscular system. These measures have clear translational potential because they are routinely applied in diagnostic and clinical human studies. We present electrophysiological techniques similar to those employed in humans to allow recordings of mouse sciatic nerve function. The CMAP response represents the electrophysiological output from a muscle or group of muscles following supramaximal stimulation of a peripheral nerve. MUNE is an electrophysiological technique that is based on modifications of the CMAP response. MUNE is a calculated value that represents the estimated number of motor neurons or axons (motor control input) supplying the muscle or group of muscles being tested. We present methods for recording CMAP responses from the proximal leg muscles using surface recording electrodes following the stimulation of the sciatic nerve in mice. An incremental MUNE technique is described using submaximal stimuli to determine the average single motor unit potential (SMUP) size. MUNE is calculated by dividing the CMAP amplitude (peak-to-peak) by the SMUP amplitude (peak-to-peak). These electrophysiological techniques allow repeated measures in both neonatal and adult mice in such a manner that facilitates rapid analysis and data collection while reducing the number of animals required for experimental testing. Furthermore, these measures are similar to those recorded in human studies allowing more direct comparisons.

Electrophysiological Motor Unit Number Estimation MUNE Measuring Compound Muscle Action Potential CMAP in Mouse Hindlimb Muscles

We present refined protocols that allow in vivo monitoring of motor unit function in the mouse. Techniques to measure compound muscle action potential (CMAP) and motor unit number estimation (MUNE) in the mouse hind limb muscles innervated by the sciatic nerve are described.

Compound muscle action potential (CMAP) and motor unit number estimation (MUNE) are electrophysiological techniques that can be used to monitor the ...

Behavior

Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in progressive degeneration of motoneurons. Peak of onset is around 60 years for the sporadic disease and around 50 years for the familial disease. Due to its progressive course, 50% of the patients die within 30 months of symptom onset. In order to evaluate novel treatment options for this disease, genetic mouse models of ALS have been generated based on human familial mutations in the SOD gene, such as the SOD1 (G93A) mutation. Most important aspects that have to be evaluated in the model are overall survival, clinical course and motor function. Here, we demonstrate the clinical evaluation, show the conduction of two behavioural motor tests and provide quantitative scoring systems for all parameters. Because an in depth analysis of the ALS mouse model usually requires an immunohistochemical examination of the spinal cord, we demonstrate its preparation in detail applying the dorsal laminectomy method. Exemplary histological findings are demonstrated. The comprehensive application of the depicted examination methods in studies on the mouse model of ALS will enable the researcher to reliably test future therapeutic options which can provide a basis for later human clinical trials.

Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis ALS

A mouse model for amyotrophic lateral sclerosis (ALS) is examined clinically and behaviorally. As a prerequisite for an accompanying immunohistological analysis the preparation of the spinal cord is depicted in detail.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in progressive degeneration of motoneurons. Peak of onset is around 60 ...

Measuring Neuromuscular Junction Functionality

Neuromuscular junction (NMJ) functionality plays a pivotal role when studying diseases in which the communication between motor neuron and muscle is impaired, such as aging and amyotrophic lateral sclerosis (ALS). Here we describe an experimental protocol that can be used to measure NMJ functionality by combining two types of electrical stimulation: direct muscle membrane stimulation and the stimulation through the nerve. The comparison of the muscle response to these two different stimulations can help to define, at the functional level, potential alterations in the NMJ that lead to functional decline in muscle.
Ex vivo preparations are suited to well-controlled studies. Here we describe an intensive protocol to measure several parameters of muscle and NMJ functionality for the soleus-sciatic nerve preparation and for the diaphragm-phrenic nerve preparation. The protocol lasts approximately 60 min and is conducted uninterruptedly by means of a custom-made software that measures the twitch kinetics properties, the force-frequency relationship for both muscle and nerve stimulations, and two parameters specific to NMJ functionality, i.e. neurotransmission failure and intratetanic fatigue. This methodology was used to detect damages in soleus and diaphragm muscle-nerve preparations by using SOD1G93A transgenic mouse, an experimental model of ALS that ubiquitously overexpresses the mutant antioxidant enzyme superoxide dismutase 1 (SOD1).

A functional assessment of the neuromuscular junction (NMJ) can provide essential information on the communication between muscle and nerve. Here we describe a protocol to comprehensively evaluate both the NMJ and muscle functionality using two different muscle-nerve preparations, i.e. soleus-sciatic and diaphragm-phrenic.

Neuromuscular junction (NMJ) functionality plays a pivotal role when studying diseases in which the communication between motor neuron and muscle is ...

Neuroscience

Repeated Measurement of Respiratory Muscle Activity and Ventilation in Mouse Models of Neuromuscular Disease

Accessory respiratory muscles help to maintain ventilation when diaphragm function is impaired. The following protocol describes a method for repeated measurements over weeks or months of accessory respiratory muscle activity while simultaneously measuring ventilation in a non-anesthetized, freely behaving mouse. The technique includes the surgical implantation of a radio transmitter and the insertion of electrode leads into the scalene and trapezius muscles to measure the electromyogram activity of these inspiratory muscles. Ventilation is measured by whole-body plethysmography, and animal movement is assessed by video and is synchronized with electromyogram activity. Measurements of muscle activity and ventilation in a mouse model of amyotrophic lateral sclerosis are presented to show how this tool can be used to investigate how respiratory muscle activity changes over time and to assess the impact of muscle activity on ventilation. The described methods can easily be adapted to measure the activity of other muscles or to assess accessory respiratory muscle activity in additional mouse models of disease or injury.

This paper introduces a method for repeated measurements of ventilation and respiratory muscle activity in a freely behaving amyotrophic lateral sclerosis (ALS) mouse model throughout disease progression with whole-body plethysmography and electromyography via an implanted telemetry device.

Accessory respiratory muscles help to maintain ventilation when diaphragm function is impaired. The following protocol describes a method for repeated ...

In Vivo Electrophysiological Measurement of Compound Muscle Action Potential from the Forelimbs in Mouse Models of Motor Neuron Degeneration

Assessing the functionality of the nerve axon provides detailed information on the progression of neuromuscular disorders. Electrophysiological recordings provide a sensitive approach to measure nerve conduction in humans and rodent models. To broaden the technical possibilities for electromyography in mice, the measurement of compound muscle action potentials (CMAPs) from the brachial plexus nerve in the forelimb using needle electrodes is described here. CMAP recordings after stimulating the sciatic nerve in hindlimbs have been previously described. The newly introduced method here allows for the evaluation of the nerve conductivity at an additional site, and thus provides a more profound overview of the neuromuscular functionality. The technique provides information on both the relative number of functional axons and the myelination level. Thereby, this method can be applied to assess both axonal diseases as well as demyelinating conditions. This minimally invasive method does not require extraction of the nerve and therefore it is suitable for repeated measurements for longitudinal follow-up in the same animal. Similar recordings are performed in clinical setups to emphasize the translational relevance of the method.

In Vivo Electrophysiological Measurement of Compound Muscle Action Potential from the Forelimbs in Mouse Models of Motor Neuron Degeneration

The measurement of nerve conduction is a useful tool to assess mouse models of neurodegeneration but it is frequently only applied to stimulate the sciatic nerve in hindlimbs. Here, we describe a technique to measure compound muscle action potential (CMAP) in vivo in the mouse forelimb muscles innervated by the brachial plexus.

Assessing the functionality of the nerve axon provides detailed information on the progression of neuromuscular disorders. Electrophysiological recordings ...

The Muscle Cuff Regenerative Peripheral Nerve Interface for the Amplification of Intact Peripheral Nerve Signals

Robotic exoskeletons have gained recent acclaim within the field of rehabilitative medicine as a promising modality for functional restoration for those individuals with extremity weakness. However, their use remains largely confined to research institutions, frequently operating as a means of static extremity support as motor detection methods remain unreliable. Peripheral nerve interfaces have arisen as a potential solution to this shortcoming; however, due to their inherently small amplitudes, these signals can be difficult to differentiate from background noise, lowering their overall motor detection accuracy. As current interfaces rely on abiotic materials, inherent material breakdown can occur alongside foreign body tissue reaction over time, further impacting their accuracy. The Muscle Cuff Regenerative Peripheral Nerve Interface (MC-RPNI) was designed to overcome these noted complications. Consisting of a segment of free muscle graft secured circumferentially to an intact peripheral nerve, the construct regenerates and becomes reinnervated by the contained nerve over time. In rats, this construct has demonstrated the ability to amplify a peripheral nerve's motor efferent action potentials up to 100 times the normal value through the generation of compound muscle action potentials (CMAPs). This signal amplification facilitates high accuracy detection of motor intent, potentially enabling reliable utilization of exoskeleton devices.

This manuscript provides an innovative method for developing a biologic peripheral nerve interface termed the Muscle Cuff Regenerative Peripheral Nerve Interface (MC-RPNI). This surgical construct can amplify its associated peripheral nerve's motor efferent signals to facilitate accurate detection of motor intent and the potential control of exoskeleton devices.

Robotic exoskeletons have gained recent acclaim within the field of rehabilitative medicine as a promising modality for functional restoration for those ...

Bioengineering

Isometric and Eccentric Force Generation Assessment of Skeletal Muscles Isolated from Murine Models of Muscular Dystrophies

Critical to the evaluation of potential therapeutics for muscular disease are sensitive and reproducible physiological assessments of muscle function. Because many pre-clinical trials rely on mouse models for these diseases, isolated muscle function has become one of the standards for Go/NoGo decisions in moving drug candidates forward into patients. We will demonstrate the preparation of the extensor digitorum longus (EDL) and diaphragm muscles for functional testing, which are the predominant muscles utilized for these studies. The EDL muscle geometry is ideal for isolated muscle preparations, with two easily accessible tendons, and a small size that can be supported by superfusion in a bath. The diaphragm exhibits profound progressive pathology in dystrophic animals, and can serve as a platform for evaluating many potential therapies countering fibrosis, and promoting myofiber stability. Protocols for routine testing, including isometric and eccentric contractions, will be shown. Isometric force provides assessment of strength, and eccentric contractions help to evaluate sarcolemma stability, which is disrupted in many types of muscular dystrophies. Comparisons of the expected results between muscles from wildtype and dystrophic muscles will also be provided. These measures can complement morphological and biochemical measurements of tissue homeostasis, as well as whole animal assessments of muscle function.

Muscle function measurements contribute to the evaluation of potential therapeutics for muscle pathology, as well as to the determination of mechanisms underlying physiology of this tissue. We will demonstrate the preparation of the extensor digitorum longus and diaphragm muscles for functional testing. Protocols for isometric and eccentric contractions will be shown, as well as differences in results between dystrophic muscles, representing a pathological state, and wildtype muscles.

Critical to the evaluation of potential  therapeutics for muscular disease are sensitive and reproducible physiological  assessments of muscle function. ...

Biology

Quantifying Phrenic Motor Unit Function in Rodent Models of Neurodegeneration

Assessing Rat Diaphragm Motor Unit Connectivity Outcome Measures as Quantitative Biomarkers of Phrenic Motor Neuron Degeneration and Compensation

Loss of ventilatory muscle function is a consequence of motor neuron injury and neurodegeneration (e.g., cervical spinal cord injury and amyotrophic lateral sclerosis, respectively). Phrenic motor neurons are the final link between the central nervous system and muscle, and their respective motor units (groups of muscle fibers innervated by a single motor neuron) represent the smallest functional unit of the neuromuscular ventilatory system. Compound muscle action potential (CMAP), single motor unit potential (SMUP), and motor unit number estimation (MUNE) are established electrophysiological approaches that enable the longitudinal assessment of motor unit integrity in animal models over time but have mostly been applied to limb muscles. Therefore, the objectives of this study are to describe an approach in preclinical rodent studies that can be used longitudinally to quantify the phrenic MUNE, motor unit size (represented as SMUP), and CMAP, and then to demonstrate the utility of these approaches in a motor neuron loss model. Sensitive, objective, and translationally relevant biomarkers for neuronal injury, degeneration, and regeneration in motor neuron injury and diseases can significantly aid and accelerate experimental research discoveries to clinical testing.

Author Spotlight: Studying Neuromuscular Responses and Motor Neuron Plasticity in Neurodegenerative Diseases

In this study, we present an in vivo method for estimating motor unit number and size to quantify rat diaphragm motor unit connectivity. A step-by-step approach to these techniques is described.

Loss of ventilatory muscle function is a consequence of motor neuron injury and neurodegeneration (e.g., cervical spinal cord injury and amyotrophic ...

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

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