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

Summary

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

Abstract

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<0.0001). Limb-onset ALS patients exhibited the greatest reduction in the split hand index, and a value of 5.2 or less reliably differentiated ALS from other neuromuscular disorders. Consequently, the split hand index appears to be a novel diagnostic biomarker for ALS, perhaps facilitating an earlier diagnosis.

Introduction

The split 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 hand sign, through the development of a novel neurophysiological biomarker, may further aid in ALS diagnosis. Specifically, the split hand index (SI), which quantifies the split 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 process^7-10. A recent modification of the diagnostic criteria were developed¹¹, and although these criteria appear to increase the diagnostic sensitivity^12-16, 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 period^9,17. Consequently, the diagnostic utility of the SI was prospectively assessed in sporadic ALS patients.

Protocol

1. Patient Preparation

1. 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.
2. Determine suitability of ALS patients for testing. Exclude patients who are not diagnosed with ALS or a neuromuscular disorder.
3. Exclude patients with a coexistent focal neuropathy, median neuropathy at the wrist or ulnar neuropathy at elbow.
4. Exclude patients with a generalized neuropathy, such as diabetic polyneuropathy.
5. Extensively investigate and clinically follow-up patients to confirm the diagnosis of ALS or neuromuscular mimic disorders.
6. Ensure that informed consent is provided by all patients, including ALS and neuromuscular mimic disorder patients, for all the neurophysiological procedures.

2. Clinical Assessment

1. Determine the clinical staging of all ALS patients by using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score¹⁸.
2. Determine the rate of disease progression in all ALS patients according to the previously reported formula;
   (48-ALSFRS-R)/duration of symptoms)¹⁹.
3. 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.
4. Determine the site of disease onset, defined as bulbar or limb, in all ALS patients.

3. Neurophysiological Assessment

1. 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.
2. 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).
3. Ensure that the selected stimulation site exhibits the lowest threshold for stimulation such that volume conduction is avoided.
4. 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.
5. Record the size of the compound motor action potential (CMAP) from the APB, ADM, and FDI muscles. Responses to be recorded by 10 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).
6. 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.
7. 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.
8. Ensure the filter settings are between 3 Hz (low-frequency filter) and 10 KHz (high-frequency filter).
9. Ensure that the sweep speed is set to 20 msec, or 2 msec/division.
10. Ensure that the sensitivity for recording CMAP responses is set to 5 mV.
11. Monitor temperature at the site of stimulation throughout the study and ensure that the limb temperature is maintained at 32 °C.

4. Analysis and Interpretation

1. Measure baseline-to-peak CMAP amplitudes (mV) over the APB, FDI and ADM muscles in ALS patients and the neuromuscular mimic disease controls.
2. Calculate the split hand index (Figure 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
   _________________________
              ADM _CMAP
3. 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.
4. Determine optimal diagnostic cutoff values for the split 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.

Results

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...

Discussion

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 “possible” category as per the recently developed diagnostic criteria¹¹, exhibited an abnorma...

Materials

List of materials used in this article

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