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Abnormalities in cortical and peripheral excitability in flail arm variant amyotrophic lateral sclerosis
  1. Steve Vucic1,
  2. Matthew C Kiernan2
  1. 1Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University of New South Wales, Australia
  2. 2Institute of Neurological Sciences, Prince of Wales Hospital, Randwick, Sydney, Australia
  1. Correspondence to:
 Professor Matthew C Kiernan
 Prince of Wales Medical Research Institute, Barker Street, Randwick, Sydney, NSW 2031, Australia; M.kiernan{at}unsw.edu.au

Abstract

Background: While some regard the flail arm syndrome as a variant of amyotrophic lateral sclerosis (ALS), others have argued that it is a distinct clinical entity. Consequently, the present study applied novel central and peripheral nerve excitability techniques to further explore disease pathophysiology in flail arm syndrome.

Methods: Cortical and peripheral nerve excitability studies were undertaken in 11 flail arm patients, defined by muscle weakness limited to the proximal aspects of the upper limbs for at least 24 months.

Results: Mean age at disease onset (60.3 years) was similar to other ALS phenotypes (58.3 years), with strong male predominance (male:female distribution: flail arm 10:1; ALS 1.5:1; p<0.05) and prolonged disease duration (flail arm 62.5 months; ALS 15.8 months; p<0.05). There was evidence of cortical hyperexcitability in flail arm patients, similar to findings in ALS, with reduction in short interval intracortical inhibition (flail arm 0.8 (0.6)%; ALS 4.1 (1.1)%; controls 8.5 (1.0)%; p<0.0001) and resting motor threshold (flail arm 53.4 (2.8)%; ALS 56.6 (1.8)%; controls 60.7 (1.5)%; p<0.05), along with an increase in motor evoked potential amplitude (flail arm 49.5 (9.0)%; ALS 44.4 (4.9)%; controls 25.8 (2.8)%; p<0.05). Peripheral nerve excitability studies demonstrated changes consistent with upregulation in persistent Na+ currents and reduction of slow K+ conductances, similar to findings in ALS.

Conclusion: This study has demonstrated the presence of cortical hyperexcitability in flail arm syndrome, along with abnormalities in peripheral nerve excitability, findings consistent with previous studies in other ALS phenotypes. By demonstrating the presence of upper motor neuron dysfunction, the present study suggests that the flail arm syndrome is an unusual variant of ALS.

  • ALS, amyotrophic lateral sclerosis
  • ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised
  • CMAP, compound muscle action potential
  • MEP, motor evoked potential
  • SICI, short interval intracortical inhibition
  • UMN, upper motor neuron

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The “man-in-the barrel” syndrome is clinically characterised by severe bilateral weakness of the shoulder girdle musculature, originally reported in the setting of cerebral infarction.1 A neurogenic variant of “man-in-the barrel” syndrome resulting from cervical anterior horn cell loss has been reported.2,3 While the “man-in-the barrel” syndrome was first described by Vulpian,4 and elegantly illustrated by Gowers,5 later studies by Hu and colleagues2 reaffirmed the original observations that this phenotype was a variant of amyotrophic lateral sclerosis (ALS).

Others have argued that the neurogenic “man-in-the-barrel” syndrome represents a entity distinct from ALS (brachial amyotrophic diplegia3). Indeed, the flail arm syndrome or “brachial amyotrophic diplegia” may be clinically differentiated from classic ALS by the unique pattern of muscle weakness, absence of upper motor neuron signs in the affected upper limbs and prolonged survival.2,3

The diagnosis of ALS relies on the presence of a combination of upper and lower motor neuron features with evidence of disease progression over time.6 Clinical evidence of upper motor neuron (UMN) dysfunction may be elusive,7 particularly in the early stages of ALS, or when UMN dysfunction becomes obscured by severe motor neuron loss. Given the uncertainties of the neurogenic “man-in-the-barrel” syndrome, the aim of the present study was to implement novel cortical threshold tracking transcranial magnetic stimulation techniques to further explore disease pathophysiology compared with more typical ALS phenotypes.

PATIENTS AND METHODS

Patients

Eleven patients were studied with the flail arm syndrome, defined as the presence of progressive weakness limited to the proximal aspects of the upper limbs for a period of 24 months, with neurophysiological evidence of lower motor neuron dysfunction. All patients were staged using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R),8 Medical Research Council rating scale9 and an UMN score10 after informed consent was obtained.

Cortical excitability

Cortical excitability was measured by applying transcranial magnetic stimulation to the motor cortex by means of a 90 mm circular coil. A threshold tracking paradigm was applied to record the stimulus response curves, short interval intracortical inhibition (SICI) and central motor conduction time, as previously described.11 Peripheral nerve excitability studies were also undertaken in the same sitting,12 with the median nerve stimulated at the wrist using 5 mm Ag-AgCl electrodes. The resultant compound muscle action potential (CMAP) was recorded using surface electrodes positioned over the abductor pollicis brevis and measured from baseline to negative peak. The Neurophysiological Index was also derived.13

Cortical and peripheral nerve excitability in flail arm patients was compared with other ALS phenotypes (n = 26)14 and previously published normative data.11 The Student’s t test was used to compare differences between groups with analysis of variance for multiple comparisons. Results are expressed as mean (SEM).

RESULTS

Two typical patients with the flail arm syndrome are illustrated in fig 1A and 1B and the clinical features of all 11 flail arm patients are summarised in table 1. Mean age at disease onset was similar for flail arm patients and other ALS phenotypes (flail arm 60.3 (3.0) years; other ALS phenotypes 58.3 (1.8) years). There was a significant male predominance in the flail arm patients compared with the other ALS phenotypes (flail arm 10:1; other ALS phenotypes 1.5:1; p<0.05), and the mean duration of illness was significantly longer (flail arm 62.5 (15.6) months; other ALS phenotypes 15.8 (2.3) months; p<0.05).

Table 1

 Clinical details for the 11 patients with flail arm syndrome

Figure 1

 (A) Anterior view (patient No 5) and (B) lateral view (patient No 4) of two patients from the present series with flail arm syndrome attempting shoulder abduction. There is marked wasting of the anterior and posterior shoulder girdle muscles, with an inability to abduct the shoulders, with a resultant “man-in-the-barrel” syndrome. (C) Stimulus–response curves obtained following transcranial magnetic stimulation stimulation in 8 flail arm patients, 26 patients with other amyotrophic lateral sclerosis (ALS) phenotypes and 39 normal controls. The motor evoked potential (MEP) is expressed as a percentage of the compound muscle action potential (CMAP) amplitude, recorded following electrical stimulation. The MEP amplitude was significantly increased in flail arm and other ALS patients compared with controls over stimulus intensities from 110 to 150% (p<0.05) of resting motor threshold (RMT). (D) Short interval intracortical inhibition, defined as the stimulus intensity required to maintain a target output of 0.2 mV, was reduced in both flail arm (n = 8, p<0.0001) and other ALS patients (n = 26, p<0.001) compared with controls. Informed consent was obtained for publication of this figure.

Although muscle weakness was initially confined to the proximal upper limbs, lower limb symptoms, including fasciculations, muscle wasting and bilateral foot drop, developed in 18% of patients, on average 58.8 months after symptom onset. Bulbar symptoms, including dysarthria, tongue weakness and dysphagia, developed in 27% of patients, and respiratory symptoms occurred in 18% of patients, with these patients subsequently requiring ongoing non-invasive ventilatory support.

Cortical excitability was assessed in eight flail arm patients, on average 47 months after symptom onset (range 31–96 months), and the mean ALSFRS-R score at the time of testing was 38 (range 15–46). Central motor conduction time was not significantly different compared with ALS patients or normal controls (flail arm 5.9 (0.4) ms; ALS 5.1 (0.5) ms; controls 5.1 (0.3) ms).

Resting motor threshold in flail arm patients was similar to other ALS phenotypes but was significantly reduced compared with controls (flail arm 53.4 (2.8)%; ALS 56.6 (1.8)%; controls 60.7 (1.5)%; p<0.05). MEP amplitude, expressed as a percentage of CMAP amplitude, was increased in flail arm patients compared with normal controls (p<0.05) (fig 1C), but was similar to ALS patients (p = 0.3) (fig 1C).

SICI was significantly reduced in both flail arm (averaged SICI from 1 to 7 ms, −0.8 (0.6)%; p<0.0001) and other ALS phenotypes (4.1 (1.1)%; p<0.01) compared with normal controls (8.5 (1.1)%; p<0.0001) (fig 1D). After SICI, a period of intracortical facilitation followed, and was significantly increased in flail arm patients compared with controls (p<0.05) (fig 1D).

Peripheral nerve excitability studies were undertaken in nine flail arm patients. Stimulus–response curves were shifted to the right in the flail arm patients and other ALS phenotypes for stimuli of both 0.2 and 1 ms duration, indicating that axons were of higher threshold relative to controls. CMAP amplitude (flail arm 2.0 (1.6) mV; ALS 2.6 (1.2) mV; controls 9.8 (0.5) mV; p<0.001) and Neurophysiological Index (flail arm 0.5 (0.1); ALS 0.8 (0.1); controls 2.5 (0.1); p<0.0001) were significantly reduced in flail arm and other ALS phenotypes compared with controls.

Strength–duration time constant reflects nodal persistent Na+ conductance, while rheobase is defined as the threshold current for a stimulus of infinitely long duration.15 As previously established in ALS,16 the mean τSD was longer in flail arm patients compared with controls (flail arm 0.45 (0.05) ms; ALS 0.49 (0.03) ms; controls 0.41 (0.02) ms) and rheobase was increased (flail arm 3.5 (1.2) mA; ALS 3.3 (1.1) mA; controls 3.1 (1.1) mA; p = 0.5).

The type I abnormality of threshold electrotonus, which reflects a greater change in response to a sub-threshold depolarising pulse, has been reported previously in ALS.17 Mean data in flail arm patients revealed the presence of this type I abnormality (flail arm 49.6 (2.2); ALS 49.8 (1.4); controls 45.6 (0.7); p<0.05). There was no significant change in any of the parameters of the recovery cycle or current–threshold relationship in flail arm patients.

DISCUSSION

The present study has further defined the flail arm phenotype, which is clinically characterised by proximal upper limb weakness, male predominance and prolonged survival. Despite the absence of upper motor neuron features (increased tone, hyperreflexia and extensor plantar responses), the present study has established the presence of cortical hyperexcitability, as indicated by reduction in resting motor threshold and short interval intracortical inhibition, together with increases in MEP amplitude and cortical stimulus–response curve gradient in flail arm patients. Changes in cortical excitability were accompanied by abnormalities of peripheral axonal excitability, including an increase in persistent Na+ conductances and reduction in slow K+ conductances. Taken together, these changes in cortical and peripheral excitability are in keeping with findings in ALS, and provide supportive evidence that the flail arm syndrome is indeed a variant of ALS.

Prior to considering the diagnosis of flail arm variant of ALS, a number of secondary disorders that can result in the same clinical phenotype need to be excluded. Cortical,1 pontine18 and spinal cord lesions,19 along with demyelinating neuropathies, are important differential diagnoses that may mimic the flail arm syndrome.20 All of these conditions were excluded in the present study on the basis of clinical investigations, including imaging of the brain and cervical spine, neurophysiological studies and laboratory testing.

The present study has provided evidence for UMN dysfunction in flail arm patients by establishing a significant reduction in SICI. SICI is believed to be cortical in origin, mediated by GABA secreting inhibitory cortical interneurons via GABAA receptors.21 Loss of these inhibitory cortical interneurons partly accounts for the reduction in SICI in flail arm syndrome, as previously established in ALS.22 By demonstrating the presence of UMN dysfunction in the setting of clinical disease progression, the present study suggests that the flail arm syndrome is an unusual variant of ALS.

Given that neurophysiological studies have revealed similar abnormalities of cortical and axonal excitability between flail arm and ALS patients, it remains unclear what underlies the differences between the clinical phenotype. The greater male predominance in flail arm patients may suggest an influence of hormonal factors. In the central nervous system, expression of the androgen receptor is relatively high in spinal motor neurons.23 Studies investigating the function of the androgen receptor and its agonists, such as testosterone, may yet prove useful in unlocking this clinical mystery.

Acknowledgments

SV was awarded the Clinical Fellowship of the Motor Neurone Disease Research Institute of Australia (MNDRIA), with funding provided by the Motor Neuron Disease Association of NSW. Grant support was also received from the NSW Ministry for Science and Medical Research Spinal Cord Injury and Related Neurological Conditions Research Grant Program. The authors would like to acknowledge Dr Con Yiannikas for helpful discussion.

REFERENCES

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Footnotes

  • Published Online First 10 January 2007

  • Competing interests: None.

  • This study was presented in part at the 18th World Congress of Neurology, Australia and the 16th International Symposium on ALS/MND, Republic of Ireland.

    Informed consent was obtained for publication of fig 1.

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