Summary

  • MND exhibit variable phenotypes
  • ALS is the commonest and most lethal of the phenotypes
  • Cognitive impairment is a feature of MND

Introduction

Motor neuron disease (MND) encompasses a group of rapidly progressive and universally fatal neurodegenerative disorders of the human motor system, first described in the mid-19th century by the French Neurologist Jean Martin Charcot.1 Amyotrophic lateral sclerosis (ALS) is the commonest MND phenotype, clinically characterised by progressive neurological deterioration and co-existence of upper and lower motor neuron signs.2 In addition, the varied clinical presentations of MND also include (i) progressive muscle atrophy (PMA, ~ 10% of MND cases), a clinically pure lower motor neuron (LMN) phenotype, (ii) primary lateral sclerosis (PLS, 1-3% of MND cases), a clinically pure upper motor neuron (UMN) phenotype and (iii) progressive bulbar palsy (PBP, 1-2% of MND cases), an isolated bulbar phenotype with relative preservation of spinal motor neurons. More recently, an association between ALS and frontotemporal degeneration (FTD) has been established, suggesting that ALS forms a continuum with primary neurodegenerative disorders, a notion underscored by the identification of the c9orf72 hexanucleotide expansion.3,4 Despite the clinical heterogeneity, median survival of MND remains three years, although the atypical phenotypes exhibit a longer survival.5

Amyotrophic lateral sclerosis

In European-based population studies the incidence of ALS appears uniform at 2.16 per 100,000 person-years with a prevalence of 4-6 per 100,000,6 with a lifetime risk of developing ALS being 1 in 400, where the incidence is slightly higher in males [1.2-1.5:1].6 Sporadic ALS peaks between the ages of 50 to 75 years and declines after the age of 80,5 with the age-specific incidence remaining stable over the past decade.7 The frequency of ALS is significantly lower in non-Caucasian populations,8 suggesting a role for genetic factors in ALS susceptibility. A genetic aetiology has been identified in up to 20% of apparently “sporadic” and 60% of familial ALS cases, in which two or more family members are clinically affected, with at least 16 genes and genetic loci implicated in ALS pathogenesis.9

Clinically, ALS is characterised by co-existence of upper and lower motor neuron signs encompassing multiple body regions, with evidence of progressive deterioration.2 Lower motor neuron signs are clinically characterised by fasciculations, muscle wasting and weakness, while UMN signs include slowness of movement, increased tone, hyper-reflexia and extensor plantar responses. The majority of ALS patients present with limb-onset disease (65-75%),10 spreading along the neuraxis to affect contiguous motor neurons.11,12 Preferential wasting and weakness of thenar muscles, termed the split-hand phenomenon (Figure 1), is a specific feature of ALS.13,14 While fasciculations are a cardinal feature of ALS, they are infrequently the presenting symptom.15 Patients presenting solely with fasciculations and muscle cramping should be monitored as these may infrequently progress to develop ALS.16 Extra-ocular and sphincter muscles are preserved until advanced stages of the disease,17 and sensory nerves are not typically affected.5

Figure 1: Split hand index refers to preferential wasting of first dorsal interosseous (FDI) and abductor pollicis brevis (APB) with relative preservation of the abductor digit minimi (ADM) muscle.

Bulbar-onset disease may be evident in 20-25% of patients, characterised by progressive dysarthria, dysphagia, hoarseness, tongue wasting, weakness and fasciculations as well as emotional lability.2 Aspiration pneumonia, malnutrition and weight loss are consequent features resulting in an adverse prognosis.18 Respiratory dysfunction is a late feature of ALS, ultimately resulting in terminal respiratory failure,19 although rarely may be the presenting symptom.20,21

The “split hand” sign refers to preferential wasting of the thenar group of muscles, including the abductor pollicis brevis (APB) and first dorsal interosseous (FDI), when compared to the abductor digit minimi (ADM) [Figure 1].14,22 This pattern of muscle atrophy is specific for ALS, and may differentiate ALS from potential mimic disorders.13 The ability to quantify the split hand sign, through the development of a split-hand index (SI), was recently demonstrated to be of diagnostic significance in ALS.23 The mechanisms underlying the split hand in ALS remain elusive, although cortical hyperexcitability seems to be most plausible mechanism.23

In addition to pure motor symptoms, subtle cognitive abnormalities may be evident in up to 50% of ALS patients,24 characterised by executive dysfunction, language and memory impairment along with behavioural abnormalities, which may precede the onset of motor symptoms.24 Recognition of cognitive dysfunction has implication for vital management of ALS, as these symptoms may adversely impact on patient compliance and decision-making abilities. At the extreme end of the spectrum, frontotemporal dementia may develop in up to 15% of ALS patients,6,24 and is clinically characterised by executive and language dysfunction, irrational behavioural, personality changes, apathy, poor insight, loss of empathy, irritability and disinhibition.25

The presence of psychiatric features in the setting of FTD-ALS may be indicative of a recently discovered genetic mutation in the c9orf72 gene on chromosome 9p21.25   Specifically, increased hexanucleotide repeat expansion (GGGGCC) in the intornic segment of the c9orf72 gene, which appears to be dominantly inherited, is causative for both ALS and frontotemporal dementia.3,4 Importantly, the c9orf72 hexanucleotide expansion appeared to underlie over 40% of familial and 20% of sporadic ALS cases in the original studies,3,4 although subsequent studies have established a frequency of 4.1-8.3% in apparently “sporadic” ALS cohorts.26 In addition to predisposition for dementia, the c9orf72 ALS cohorts exhibit an earlier age of onset and shorter survival.27 The c9orf72 discovery has radically altered the understanding of ALS pathogenesis, implying that ALS is a multisystem neurodegenerative disorder, rather than a pure neuromuscular disease.9 Importantly, accumulation of TDP-43 along with p62 positive TDP-43 negative inclusions in hippocampus and cerebellar neurons appears to be neuropathological hallmarks of c9orf72 associated ALS and FTD,28 suggesting the existence of a common pathophysiological pathway, although the precise pathophysiological mechanisms appear to be complex and remain to be fully elucidated.29

The diagnosis of ALS remains clinically based relying on identifying a combination of UMN and LMN signs, with evidence of disease progression.30 Nerve conduction studies (NCS) and electromyography (EMG) are important clinical investigations, excluding potential mimic disorders,2 and identifying widespread LMN dysfunction, a cardinal feature of ALS. Specifically, LMN dysfunction may be heralded by the presence of ongoing activity (fibrillation potentials and positive sharp waves) and chronic neurogenic changes (large-amplitude, long-duration, polyphasic motor unit potentials), and if widespread appear to exhibit a high sensitivity and specificity for ALS.31 Importantly, the EMG changes may be evident sub-clinically, thereby enabling an earlier diagnosis of ALS.32 In addition, widespread fasciculations with a high firing frequency and increased frequency of double fasciculations, may also be a diagnostic feature of ALS,33 especially when combined with clinical features and disease progression.

Atypical MND phenotypes

Atypical MND phenotypes include progressive muscular atrophy, the clinically “pure” lower motor neuron phenotype, encompassing the flail-arm and some of the flail leg variants. The flail-limb variants are characterised by neurogenic weakness confined to the proximal upper limbs (flail-arm, at least for 24 months) or lower limbs (flail-leg, confined to lower limbs for at least 12 months).34,35 Importantly, one-third of PMA cases may develop UMN dysfunction, and while the overall prognosis for the flail-arm and leg variants is favourable,35 a progressive course akin to that evident in ALS may also be evident in PMA,36 underscoring the notion that PMA falls into the spectrum of MND diseases.

Of further relevance, primary lateral sclerosis refers to the pure UMN phenotype, characterised by a slowly progressive UMN syndrome (Table 1) affecting the spinal and bulbar regions with relative preservation of the lower motor neurons for at least four years after symptom onset.37,38 Importantly, lower motor neuron signs may develop within four years of symptom onset, and this group is then classified as upper motor neuron predominant-ALS.38 The PBP phenotype remains localised within the bulbar region for a prolonged period (>6 months) and is characterised by female predominance and UMN bulbar dysfunction, although clinical features of ALS may develop.39 The rates of survival for the UMN phenotypes of MND are typically prolonged, although significant functional impairment occurs.29

In conclusion, MND appears to be a clinically heterogeneous disorder with varied clinical presentation encompassing a range of upper and lower motor neuron dysfunction. The overlap in clinical features, along with evidence of disease progression underscores the notion that common pathophysiological processes underlie varied MND phenotypes. Discovering the processes that regulate the development of the varied clinical phenotypes, may yet result in development of adequate therapeutic strategies.

References

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