**1. Introduction**

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which attacks the motor system. There is a family history in approximately 10% percent of cases and 20% of such families have point mutations in the Cu, Zn superoxide dimutase 1 (SOD1) gene. Pre-symp‐ tomatic loss of motor neurons has been identified prior to the onset of symptoms in SOD1 mice. This loss was biphasic with initial loss in the pre-symptomatic phase followed by a period of stabilisation and then gradual loss at time of weakness to death. (Kong & Xu, 1998).

In order to determine the time course of motor neurone loss prior to symptomatic onset of disease, a longitudinal study of at-risk asymptomatic individuals (i.e. SOD1 mutation carriers with no neurological symptoms or signs as determined by a neurologist) was performed. There was no detectable difference in the number of motor units in SOD1 mutation carriers compared to their SOD1 negative family controls. (Aggarwal & Nicholson, 2001). This may indicate that mutation carriers have undetectable loss of motor neurones until rapid and widespread cell death of motor neurones occurs, coinciding with the onset of symptomatic features. This implies that the disease is not the end result of the slow attrition of motor neurones. (Aggarwal, 2009).

This longitudinal study was extended on 20 asymptomatic carriers of the Cu, Zn superoxide dimutase 1 (SOD1) point mutation. There was a sudden reduction in MUNE, several months prior to the onset of weakness. (Aggarwal & Nicholson 2002) and (Aggarwal, 2009). This suggests that gradual pre-clinical loss of motor neurones does not occur in asymptomatic SOD1

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mutation carriers and supports the observation that sudden, catastrophic loss of motor neurones occurs immediately prior to the onset of symptoms and the development of the disease, rather than a gradual attrition of motor neurones over time. These results suggest that there may be a biological trigger initiating rapid cell loss, just prior to the onset of symptoms.

anterior horn cells of the spinal cord, motor nuclei of the brainstem and the descending pathways within the corticospinal tracts. The term amyotrophic lateral sclerosis (ALS) is used synonymously with motor neurone disease (MND) in the USA, but in the UK and Australia is used only to refer to patients who have a combination of upper and lower motor neurone

The Role of the Statistical Method of Motor Unit Number Estimation (MUNE) to…

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It is primarily a condition of middle to late life, with onset of symptoms between the ages of 50 and 70 and a mean age of onset of 57.4 years. (Ringel et al., 1993). Occasionally, it arises as early as the 2nd decade or as late as the 9th decade. In a natural history study, the overall median survival is 4.0 years from the onset of symptoms, but only 2.1 years from the time of diagnosis. (Ringel et al., 1993). In a study performed at the Mayo clinic, approximately 50% of patients died within 3 years of referral, but 20% were still alive at 5 years and 10% were still alive at 10

Aging, motor neurone diseases and many peripheral neuropathies are all associated with loss of motor neurones or axons. When the disorders are recent or rapidly progressive, the extent of the loss may be indicated by weakness and wasting. In slowly progressive denervating conditions, like MND, loss of more than 50-80% of motor units may occur with little or no

It has been showed that patients with substantial chronic denervation could maintain normal muscle twitch tension until loss of about 70-80% of motor units occurred. (McComas, 1971). The surviving motor neurones enlarge their territories, through collateral sprouting (reinner‐ vation) to keep pace with cell loss, to maintain the muscle maximum compound muscle action potential (CMAP), until late in the disease. At this point, collateral reinnervation is no longer

In MND, needle electromyography often reveals evidence of chronic reinnervation (increased motor unit action potential amplitudes and duration with reduced recruitment), but provides little direct evidence to the extent of motor neurone and axonal loss. The supramaximal CMAP amplitude also provides little direct evidence of the extent of motor neurone loss. Normal CMAP amplitudes might mistakenly suggest that motor neurone loss has not occurred yet.

Motor unit number estimation (MUNE) is a more reliable method for following changes in neurogenic disorders than the CMAP amplitude. It estimates the number of functioning lower motor neurones innervating a muscle or a group of muscles i.e. the number of motor units, which can be excited by electrical stimulation. It is therefore an indirect measure of motor neurone loss, rather than a measure of primary pathology. It can identify that the number of motor units may be well below normal, in the presence of normal CMAP amplitudes. (Brown,

Pre-symptomatic loss of motor neurones has been identified in an animal model of the disease (transgenic mice expressing mutant human SOD1-G93A). The initial loss in the pre-sympto‐ matic phase related to severe motor axonal degeneration due to vacuolar changes in motor neurones and a slow decrease in CMAP amplitudes. After a period of stabilisation, there was a gradual loss of motor neurones and a rapid decrease in CMAP amplitude, at the onset of

able to provide full functional compensation. (Campbell et al., 1973).

dysfunction. (Talbot, 2002).

years. (Mulder & Howard, 1976).

clinically apparent weakness.

(Shefner, 2001).

1972).

Current treatment for sporadic ALS or Cu, Zn superoxide dimutase 1 (SOD 1 mutation) familial ALS, produces only a modest increase in survival. The excitatory amino acid neurotransmitter, glutamate, may be involved in the pathogenesis of ALS. Riluzole, an anti-glutamate agent, remains the only disease modifying therapy available for ALS and has been used since 1995. (Cheah et al, 2010). Treatment of human ALS patients or transgenic Cu, Zn superoxide dimutase 1 (SOD 1) mice, most commonly produce a modest but significant increase in survival. (Bensimon et al, 1994). It has also been shown to have a small beneficial effect on bulbar function, but not muscle strength.

Using the statistical motor unit number estimation (MUNE) technique, (Daube, 1995), a longitudinal study was performed to determine whether early institution of Riluzole can reduce that rate of motor unit loss in familial amyotrophic lateral sclerosis (fALS). Motor unit numbers were estimated from the right abductor pollicis brevis (APB) and right extensor digitorum brevis (EDB) muscles. Our subjects had a presumptive diagnosis of fALS, as electromyography (EMG) was "normal" with an absence of fasciculation and fibrillation potentials, normal motor unit potentials and normal recruitment. MUNE is more sensitive that EMG and once changes occur on conventional EMG studies, the window of opportunity to influence the progression of this condition has been missed. They were all commenced on Riluzole therapy in the pre-symptomatic phase, as soon as loss of motor units was detected using motor unit number estimation (MUNE). After commencing Riluzole, "symptomatic" improvement occurred, especially a decrease in muscle fasciculations and an improvement in MUNE. Riluzole is not a disease altering agent but possibly if given early in the pre-sympto‐ matic phase of the disease, before significant motor neurone loss has occurred, it may have some therapeutic benefit.

This effect may have implications for the management of asymptomatic carriers of the SOD 1 gene, as these subjects are at risk of developing ALS.

Regular follow-up of SOD1 carriers with MUNE may lead to early diagnosis, creating an opportunity for future approaches and therapies aimed at preserving motor neurones rather than replacing lost motor neurones. Detecting the onset of motor neurone loss in asymptomatic individuals will identify those who may benefit from early institution of an active management program to improve their quality of life, until more effective treatment modalities are available for this devastating condition.
