근육위축 가쪽경화증 수부분할현상의 신경생리분석

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Introduction

Hand weakness is one of presenting symptoms of ALS which is a common motor neuron disease in adults.

However, ALS has no definite diagnostic biological markers so its diagnosis is usually based on clinical presentations including bulbar and motor signs and muscular atrophy. Although most of patients develop muscular atrophy of hand intrinsic muscles throughout the disease progression, an early detection of the

ISSN 1229-6066 https://doi.org/10.18214/jkaem.2017.19.2.61 J Korean Assoc EMG Electrodiagn Med 19(2):61-66, 2017

J Korean Assoc

Electrodiagn MedEMG

This is an Open Ac cess article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

근육위축 가쪽경화증 수부분할현상의 신경생리분석

권수연, 김창환

인하대학교 의과대학 재활의학교실

Electrophysiologic Analysis of the Split Hand Phenomenon in Amyotrophic Lateral Sclerosis

Su-Yeon Kwon, Chang-Hwan Kim

Department of Physical & Rehabilitation Medicine, Inha University School of Medicine, Incheon, Korea

Objective: We investigated the clinical and electrophysiological expressions of the thenar muscular atrophy in patients with amyotrophic lateral sclerosis (ALS) and evaluated whether the selective involvement of thenar muscles was caused by the split hand phenomenon or by overlapping peripheral neuropathies.

Method: We retrospectively compared electrophysiologic data of 35 ALS patients to 50 age-matched healthy control subjects. We further compared electrophysiologic data of the ALS patients with peripheral neuropathies to those who had none, to evaluate the influence of concurrent peripheral neuropathies on the thenar muscular atrophy.

Results: All ALS patients showed prolonged motor latencies and decreased sensory amplitudes in median nerve conduction study, compared to those in ulnar nerve conduction study. Healthy subjects did not show a difference between median and ulnar nerve conduction studies. The patients with ALS showed delayed latencies and amplitudes of median nerve CMAP, regardless of the presence of peripheral neuropathies.

Conclusion: The selective thenar atrophy in ALS is prominently due to the pathophysiological disease progression, regardless of the presence of concomitant peripheral neuropathies.

Key Words: amyotrophic lateral sclerosis, peripheral nerve injuries, hand muscle atrophy, split hand

Received August 29, 2017

Revised (1st) November 7, 2017, (2nd) November 16, 2017, (3rd) November 20, 2017

Accepted November 30, 2017

Corresponding Author: Chang-Hwan Kim

Department of Physical & Rehabilitation Medicine, Inha University Hospital, 27 Inhang-ro, Jung-gu, Incheon 22332, Korea

Tel: 82-32-890-2480 , Fax: 82-32-890-2486, E-mail: [email protected] This study has been supported by InHa University Research Grant.

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muscular atrophy in ALS is actually at a low rate (10%).¹

The split-hand index has previously proved its sensitivity as 74% and specificity as 80% for the diagnosis of limb-onset ALS.² Several western studies have reported cases of thenar atrophy in patients with ALS, and we have also encountered ALS patients with this condition not infrequently.

Therefore, we conducted this study to describe the split hand phenomenon in Korean population.

We further conducted a retrospective evaluation of clinical neurophysiologic results in order to determine the primary cause of the split hand phenomenon.

Suspected causes were ALS per se, coexistent peripheral neuropathies, and senile atrophy.

Materials and Methods

We initially enrolled 266 subjects who had been diagnosed of probable or definite ALS based on el Escorial criteria, at Inha University Hospital from 1996 to 2011. Then we selected 35 definite-ALS patients who had sufficient electrophysiological data. Fifty healthy subjects who volunteered to provide normal NCS results were enrolled.

We excluded patients with an inflammatory or metabolic neuropathies, or motor neuron disease of another origin, such as spinal muscular atrophy, considering their confounding effects on muscular atrophy. Patients with progressed ALS were also excluded because they could not receive nerve conduction studies due to severe muscular atrophy.

We finally gathered electrophysiologic data of 35 subjects with ALS and 50 age-matched healthy control subjects, and compared the nerve conduction findings between the two groups. The nerve conduction studies (NCS) of thenar and hypothenar muscles were compared. For thenar muscles, median nerves recorded at abductor pollicis brevis (APB) were examined. For hypothenar muscles, ulnar nerves recorded at abductor digit minimi (ADM) were examined. Particularly we evaluated compound muscle action potential-

amplitudes (CMAP-As) and latencies (CMAP-Ls) for motor nerves, and sensory nerve action potential - amplitudes (SNAP-As) and velocities (SNAP-Vs) for sensory nerves.

We further divided the 35 subjects with ALS into two subgroups according to the presence of concomitant peripheral neuropathies, particularly median and ulnar nerve entrapments. Subjects with ALS those who had 1) median CMAP-Ls > 4.2 ms or ulnar CMAP-Ls > 3.8 ms, with CMAP-As > 5 mV, 2) median or ulnar CMAP-Ls at least 1.0 ms delayed compared with the normal values, with CMAP-As < 5 mV, and 3) SNAP-Vs of median and/

or ulnar nerve < 42 m/s,³ were categorized as the group of subjects with ALS who had overlapping peripheral neuropathies. The other group consisted of patients without concurrent peripheral neuropathies. Then we compared the nerve conductions studies between these two groups to determine the associations between the presence of coexistent neuropathies and preferential thenar atrophy in ALS.

SPSS version 19 was used for statistical analysis. The T-test was applied to compare CMAP-As, CMAP-Ls, SNAP-As and SNAP-Vs of median with ulnar nerves within and between the patient and control groups.

Statistical significance was accepted for p-values < 0.05.

Results

Mean age of ALS patients was 61.7 ± 11.1 years and that of control subjects was 53.5 ± 13.9 years, which was not a significant difference (p > 0.05).

We gathered 45 NCS cases of 35 subjects with ALS, and 50 NCS cases of 50 healthy subjects. In 50 control subjects, the CMAP-Ls of median nerves were delayed compared with those of ulnar nerves but still within normal ranges and no statistical differences (median 3.1 ± 0.4 ms, ulnar 2.7 ± 0.3 ms, p > 0.05). The CMAP-As of median and ulnar nerves were also normal values and no significant differences nerves (median 7.7 ± 1.8 mV, ulnar 7.7 ± 1.7 mV, p > 0.05) (Table 1). In contrast, in 35 ALS patients, the CMAP-Ls of median nerves were

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delayed compared with those of ulnar nerves (median 4.1 ± 0.9 ms, ulnar 3.1 ± 0.5 ms, p < 0.001), and CMAP-As of median nerves were markedly smaller than those of ulnar nerves (median 3.9 ± 2.7 mV, ulnar 5.5

± 2.4 mV, p < 0.001) (Table 2).

In 50 control subjects, no significant differences were observed in the SNAP-As and SNAP-Vs of median nerves compared with those of ulnar nerves (median 41.5 ± 18.5 μV, ulnar 36.5 ± 17.3 μV; median 45.5

± 4.1 m/s, ulnar 45.6 ± 7.6 m/s, p > 0.05) (Table 1).

Likewise, in 35 ALS patients, no significant difference was observed between SNAP-As and SNAP-Vs of median compared with those of ulnar nerves (median 22.0 ± 11.4 μV, ulnar 19.9 ± 8.8 μV; median 41.5 ± 7.6 m/s, ulnar 42.0 ± 5.9 m/s, p > 0.05) (Table 2).

We further divided the 35 subjects with ALS into two subgroups according to the presence of concomitant peripheral neuropathies, particularly median and ulnar nerve entrapments. As a result, one group included 28 patients without concomitant peripheral neuropathies (25 NCS cases) and the other included 7 patients with concomitant peripheral neuropathies (20 NCS cases).

I n t h e 2 8 A L S p a t i e n t s w i t h o u t p e r i p h e r a l

neuropathies, the CMAP-Ls of median nerves were delayed compared with those of ulnar nerves (median 3.8 ± 0.7 ms, ulnar 3.1 ± 0.6 ms, p < 0.001), and the CMAP-As of median nerves were smaller than those of ulnar nerves (median 3.3 ± 2.2 mV, ulnar 4.8 ± 2.4 mV, p < 0.001) (Table 3). Likely, in the 7 ALS patients with peripheral neuropathies, the CMAP-Ls of median nerves were delayed compared with those of ulnar nerves (median 4.5 ± 1.2 ms, ulnar 3.1 ± 0.5 ms, p <

0.001) and the CMAP-As of median nerves were smaller than those of ulnar nerves (median 4.7 ± 3.3 mV, ulnar 6.0 ± 2.1 mV, p < 0.001) (Table 4).

The 7 subjects with ALS who had concomitant peripheral neuropathies showed smaller SNAP-As and slower SNAP-Vs (median 19.4 ± 9.9 μV, ulnar 17.6 ± 8.9 μV; median 36.4 ± 9.3 m/s, ulnar 38.9 ± 7.0 m/s, p >

0.05) (Table 4) compared with 28 ALS patients without concomitant peripheral neuropathies (median 30.0 ± 2.2 μV, ulnar 25.2 ± 8.7 μV; median 45.5 ± 3.8 m/s, ulnar 44.3 ± 4.4 m/s, p > 0.05) (Table 3). But these were no statistical significance.

Table 1. Motor and Sensory Nerve Conduction Studies of Median and Ulnar Nerves of Healthy Subjects

CMAP SNAP

Latency (ms)

Amplitude (mV)

Amplitude (μV)

Conduction velocity (m/s) Median 3.1 ± 0.4 7.7 ± 1.8 41.5 ± 18.5 45.5 ± 4.1 Ulnar 2.7 ± 0.3 7.7 ± 1.7 36.5 ± 17.3 45.6 ± 7.6 CMAP: compound motor action potentials, SNAP: sensory nerve action potentials

p > 0.05

Table 3. Motor and Sensory Nerve Conduction Studies of Median and Ulnar Nerves of Subjects with ALS Who Had No Concomitant Peripheral Neuropathies

CMAP SNAP

Latency (ms)

Amplitude (mV)

Amplitude (μV)

Conduction velocity (m/s) Median 3.8 ± 0.7

}* 3.3 ± 2.2

}* 30.0 ± 2.2 45.5 ± 3.8 Ulnar 3.1 ± 0.6 4.8 ± 2.4 25.2 ± 8.7 44.3 ± 4.4 CMAP: compound motor action potentials, SNAP: sensory nerve action potentials

*p < 0.001

Table 2. Motor and Sensory Nerve Conduction Studies of Median and Ulnar Nerves of Subjects with ALS

CMAP SNAP

Latency (ms)

Amplitude (mV)

Amplitude (μV)

}*3.9 ± 2.7

*p < 0.001

Table 4. Motor and Sensory Nerve Conduction Studies of Median and Ulnar Nerves of Subjects with ALS Who Had Concomitant Peripheral Neuropathies

CMAP SNAP

Latency (ms)

Amplitude (mV)

Amplitude (μV)

}* 4.7 ± 3.3

*p < 0.001

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To summarize, the patients with ALS showed delayed

CMAP-Ls and decreased CMAP-As of median nerves, regardless of the presence of peripheral neuropathies.

However, the SNAP-As and SNAP-Vs of median and ulnar nerves were without significant changes in ALS patients.

Discussion

The term ‘split hand’, introduced by Willbourn,4 refers to the atrophy of the thenar complex, including abductor pollicis brevis (APB) and first dorsal interossei (FDI) with relative sparing of the hypothenar complex, such as abductor digit minimi (ADM). This preferential lateral muscle wasting occurs despite innervation of FDI and ADM through the same spinal segments (C8 and T1) and commonly through the ulnar nerve.

Split hand syndrome also occurs during normal aging, however, the mechanisms differ. Aging primarily involves peripheral axonal excitability and greater oxidative stress and metabolic demands due to frequent use. A previous study found that the CMAP amplitude ratios of APB or FDI muscles and ADM muscles decreased significantly with age, and thus, concluded that the clinical phenomenon of split hand is a form of physiologic senile atrophy.⁵

On the other hand, although the mechanism of split hand syndrome in ALS is not completely understood, it distinctively involves cortical and spinal mechanisms.⁶ The fractionated hand function is related to increases in the size and complexity of the motor cortex. In a previous study it was noted that during its early stage ALS showed motor cortex hyper-excitability, which induced degeneration via glutamate-induced excitotoxicity.⁷ In addition, it was found that ALS patients had smaller motor evoked potentials (MEP) and CMAP amplitudes than healthy control subjects, and that these differences were particularly prominent in the MEP amplitudes of the thenar complex. Accor- dingly, it was suggested that preferential impairment of cortico-motor-neuronal input to the thenar complex

was probably responsible for split hand phenomenon in ALS.⁷

In this study, ALS patients showed smaller CMAP amplitudes for median nerves than for ulnar nerves, and this was more prominent in older ALS patients.

However, due to a lack of elderly ALS survivors, it was not possible to determine the influence of senility.

We could not determine whether this reduction in median CMAP amplitudes was due to ALS per se or to superimposed senile atrophy.

Peripheral neuropathies and ALS may occur simul- taneously or individually. In fact, coexistent focal or generalized neuropathies in ALS are not uncommon.

Kothari MJ et al.⁸ reported that 45 of 126 (36%) ALS patients had coexistent entrapment neuropathies, ten (8%) has non-localized ulnar neuropathy and nine (7%) had generalized sensory polyneuropathy. The high prevalence of peripheral neuropathies in previous study would be due to the high cut-off values for median neuropathy at the wrist, that is, 1) CMAP-Ls > 4.2 msec, 2) decreased antidromic SNAP-As < 18 μV and/

or decreased SNAP-Vs < 42 m/sec, and 3) when ulnar CMAP-Ls is normal, and high cut-off values for ulnar neuropathy at the elbow, that is, 1) motor velocity < 15 m/sec as compared with the forearm segment and 2) decreased SNAP-As < 15 μV and/or decreased SNAP-Vs

< 42 m/sec. They reported that the 54% of ALS patients were compatible with peripheral neuropathies. But Kollewe K et al.⁹ has reported retrospective review of 554 ALS patients, the nerve compression was mostly carpal tunnel syndrome and its prevalence was 1.8%.

Considering the diagnostic criteria and different cohort, there might be some differences in the prevalence of peripheral neuropathy between studies.

In our study, CTS would be the first differential diagnosis of split hand phenomenon and the motor nerve conduction study could be a part of this. We have used the difference in median to ulnar motor distal latency as a part of differential diagnosis for CTS.¹⁰

It is difficult to determine whether neuropathies in ALS are unrelated to ALS or develop during the course

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of the disease. Accordingly, misdiagnosis and confusion after nerve conduction studies may lead to delayed diagnosis of ALS and inappropriate treatment.

Because ALS is considered to mainly affect motor neuron degeneration, sensory abnormalities should not be observed in ALS. Nonetheless, in the current study, we observed subclinical sensory abnormalities, that is, tendencies toward smaller amplitudes and delayed median nerve latency. It has been suggested that the moderate sensory nerve dysfunction in ALS patients may represent a variant of ALS or peripheral sensory axonal neuropathy and a ganglionopathy.¹¹ And in recent study¹² at early stage of ALS sensory impairment could be shown with evidence of changes in spinal diffusion tensor image and somatosensory evoked potentials. Over sixty percent of early ALS patients showed abnormalities and they insisted underestimation of sensory impairment in subclinical state. But in other study¹³ sensory nerve amplitude and conduction velocities were preserved in ALS patients, so further studies would be needed to determine the neurodegenerative process affecting peripheral sensory nerve. Because the morphometric comparison of spinal neuron showed that both alpha motor and dorsal root sensory neurons were affected in ALS, but motor neurons are more vulnerable than sensory neurons.¹⁴ Accordingly, the sensory symptoms would be underestimated than the motor symptoms in ALS patients.

Some limitations of our study require consideration.

First, electrophysiologic records were gathered from one medical center, thus, it was difficult to recruit a large number of patients. Second, we did not have nerve conduction studies of ulnar nerves recorded at FDI, which could have made a thorough investigation of the electrophysiological expressions of split hand phenomenon. Third, because the study was not longitudinal, we did not include ALS patients at an early or late disease stage. Fourth, in this retrospective study we cannot differentiate possible peripheral nerve involvement with physical symptoms and signs. So the

electrophysiologic evaluation has been used for the differential diagnosis for this split hand phenomenon.

Further studies are required in order to examine the central nervous basis underlying motor and sensory abnormalities in ALS, including MRI and transcranial magnetic stimulation studies.

Conclusion

The selective thenar atrophy in ALS is prominently due to the pathophysiological disease progression, regardless of the presence of concomitant peripheral neuropathies.

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