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The diagnosis of amyotrophic lateral sclerosis can be challenging due to its heterogeneity in clinical presentation and overlap with other neurological disorders. Diagnosis early in the disease course can improve outcomes as timely interventions can slow disease progression. An evolving awareness of disease genotypes and phenotypes and new diagnostic criteria, such as the recent Gold Coast criteria, could expedite diagnosis. Improved prognosis, such as that achieved with the survival model from the European Network for the Cure of ALS, could inform the patient and their family about disease course and improve end-of-life planning. Novel staging and scoring systems can help monitor disease progression and might potentially serve as clinical trial outcomes. Lastly, new tools, such as fluid biomarkers, imaging modalities, and neuromuscular electrophysiological measurements, might increase diagnostic and prognostic accuracy.

Amyotrophic lateral sclerosis is a progressive adult-onset neurodegenerative disease that primarily affects upper and lower motor neurons, but also frontotemporal and other regions of the brain. The extent to which each neuronal population is affected varies between individuals. The subsequent patterns of disease progression form the basis of diagnostic criteria and phenotypic classification systems, with considerable overlap in the clinical terms used. This overlap can lead to confusion between diagnosis and phenotype. Formal classification systems such as the El Escorial criteria and the International Classification of Diseases are systematic approaches but they omit features that are important in clinical management, such as rate of progression, genetic basis, or functional effect. Therefore, many neurologists use informal classification approaches that might not be systematic, and could include, for example, anatomical descriptions such as flail-arm syndrome. A new strategy is needed to combine the benefits of a systematic approach to classification with the rich and varied phenotypic descriptions used in clinical practice.

This review considers the origin and significance of fasciculations in neurological practice, with an emphasis on fasciculations in amyotrophic lateral sclerosis (ALS), and in benign fasciculation syndromes. Fasciculation represents a brief spontaneous contraction that affects a small number of muscle fibres, causing a flicker of movement under the skin. While an understanding of the role of fasciculation in ALS remains incomplete, fasciculations derive from ectopic activity generated in the motor system. A proximal origin seems likely to contribute to the generation of fasciculation in the early stages of ALS, while distal sites of origin become more prominent later in the disease, associated with distal motor axonal sprouting as part of the reinnervation response that develops secondary to loss of motor neurons. Fasciculations are distinct from the recurrent trains of axonal firing described in neuromyotonia. Fasciculation without weakness, muscle atrophy or increased tendon reflexes suggests a benign fasciculation syndrome, even when of sudden onset. Regardless of origin, fasciculations often present as the initial abnormality in ALS, an early harbinger of dysfunction and aberrant firing of motor neurons.

The split-hand phenomenon, a specific feature of amyotrophic lateral sclerosis (ALS), refers to preferential wasting of abductor pollicis brevis (APB) and first dorsal interosseous (FDI) with relative preservation of abductor digiti minimi (ADM). The pathophysiological mechanisms underlying the split-hand phenomenon remain elusive and resolution of this issue would provide unique insights into ALS pathophysiology. Consequently, the present study dissected out the relative contribution of cortical and peripheral processes in development of the split-hand phenomenon in ALS. Cortical and axonal excitability studies were undertaken on 26 ALS patients, with motor responses recorded over the APB, FDI and ADM muscles. Results were compared to 21 controls. Short interval intracortical inhibition (SICI), a biomarker of cortical excitability, was significantly reduced across the range of intrinsic hand muscles (APB(SICI ALS) 0.3±2.0%, APB(SICI controls) 16.0±1.9%, P<0.0001; FDI(SICI ALS) 2.7±1.7%, FDI(SICI controls) 14.8±1.9%, P<0.0001; ADM(SICI ALS) 2.6±1.5%, ADM(SICI controls) 9.7±2.2%, P<0.001), although the reduction was most prominent when recorded over APB/FDI. Changes in SICI were accompanied by a significant increase in motor evoked potential amplitude and reduction of cortical silent period duration, all indicative of cortical hyperexcitability, and these were most prominent from the APB/FDI. At a peripheral level, a significant increase in strength-duration time constant and reduction in depolarising threshold electrotonus were evident in ALS, although these changes did not follow a split-hand distribution. Cortical dysfunction contributed to development of the split-hand in ALS, thereby implying an importance of cortical hyperexcitability in ALS pathogenesis.

Diagnosis of amyotrophic lateral sclerosis (ALS) remains problematic, with substantial diagnostic delays. We assessed the sensitivity and specificity of a threshold tracking transcranial magnetic stimulation (TMS) technique, which might allow early detection of upper motor neuron dysfunction, for the diagnosis of the disorder. We did a prospective study of patients referred to three neuromuscular centres in Sydney, Australia, in accordance with the Standards for Reporting of Diagnostic Accuracy. Participants had definite, probable, or possible ALS, as defined by the Awaji criteria; or pure motor disorder with clinical features of upper and lower motor neuron dysfunction in at least one body region, progressing over a 6 month follow-up period; or muscle wasting and weakness for at least 6 months. All patients underwent threshold tracking TMS at recruitment (index test), with application of the reference standard, the Awaji criteria, to differentiate patients with ALS from those with non-ALS disorders. The investigators who did the index test were masked to the results of the reference test and all other investigations. The primary outcome measures were the sensitivity and specificity of TMS in differentiating ALS from non-ALS disorders; these measures were derived from receiver operator curve analysis. Between Jan 1, 2010, and March 1, 2014, we screened 333 patients; 281 met our inclusion criteria. We eventually diagnosed 209 patients with ALS and 68 with non-ALS disorders; the diagnosis of four patients was inconclusive. The threshold tracking TMS technique differentiated ALS from non-ALS disorders with a sensitivity of 73·21% (95% CI 66·66–79·08) and specificity of 80·88% (69·53–89·40) at an early stage in the disease. All patients tolerated the study well, and we did not record any adverse events from performance of the index test. The threshold tracking TMS technique reliably distinguishes ALS from non-ALS disorders and, if these findings are replicated in larger studies, could represent a useful diagnostic investigation when combined with the Awaji criteria to prove upper motor neuron dysfunction at early stages of ALS. Motor Neuron Disease Research Institute of Australia, National Health and Medical Research Council of Australia, and Pfizer.

Hereditary transthyretin amyloidosis (ATTRv) is a severe, adult-onset autosomal dominant inherited systemic disease predominantly affecting the peripheral and autonomic nervous system, heart, kidney and the eyes. ATTRv is caused by mutations of the transthyretin (TTR) gene, leading to extracellular deposition of amyloid fibrils in multiple organs including the peripheral nervous system. Typically, the neuropathy associated with ATTRv is characterised by a rapidly progressive and disabling sensorimotor axonal neuropathy with early small-fibre involvement. Carpal tunnel syndrome and cardiac dysfunction frequently coexist as part of the ATTRv phenotype. Although awareness of ATTRv polyneuropathy among neurologists has increased, the rate of misdiagnosis remains high, resulting in significant diagnostic delays and accrued disability. A timely and definitive diagnosis is important, given the emergence of effective therapies which have revolutionised the management of transthyretin amyloidosis. TTR protein stabilisers diflunisal and tafamidis can delay the progression of the disease, if treated early in the course. Additionally, TTR gene silencing medications, patisiran and inotersen, have resulted in up to 80% reduction in TTR production, leading to stabilisation or slight improvement of peripheral neuropathy and cardiac dysfunction, as well as improvement in quality of life and functional outcomes. The considerable therapeutic advances have raised additional challenges, including optimisation of diagnostic techniques and management approaches in ATTRv neuropathy. This review highlights the key advances in the diagnostic techniques, current and emerging management strategies, and biomarker development for disease progression in ATTRv.

Early reports of cognitive and behavioural deficits in motor neuron disease might have been overlooked initially, but the concept of a frontotemporal dementia-motor neuron disease continuum has emerged during the past decade. Frontotemporal dementia-motor neuron disease is now recognised as an important dementia syndrome, which presents substantial challenges for diagnosis and management. Frontotemporal dementia, motor neuron disease, and frontotemporal dementia-motor neuron disease are characterised by overlapping patterns of TAR DNA binding protein (TDP-43) pathology, while the chromosome 9 open reading frame 72 (C9orf72) repeat expansion is common across the disease spectrum. Indeed, the C9orf72 repeat expansion provides important clues to disease pathogenesis and suggests potential therapeutic targets. Variable diagnostic criteria identify motor, cognitive, and behavioural deficits, but further refinement is needed to define the clinical syndromes encountered in frontotemporal dementia-motor neuron disease.

Spinal muscular atrophies (SMAs) are a group of inherited disorders characterized by motor neuron loss in the spinal cord and lower brainstem, muscle weakness, and atrophy. The clinical and genetic phenotypes incorporate a wide spectrum that is differentiated based on age of onset, pattern of muscle involvement, and inheritance pattern. Over the past several years, rapid advances in genetic technology have accelerated the identification of causative genes and provided important advances in understanding the molecular and biological basis of SMA and insights into the selective vulnerability of the motor neuron. Common pathophysiological themes include defects in RNA metabolism and splicing, axonal transport, and motor neuron development and connectivity. Together these have revealed potential novel treatment strategies, and extensive efforts are being undertaken towards expedited therapeutics. While a number of promising therapies for SMA are emerging, defining therapeutic windows and developing sensitive and relevant biomarkers are critical to facilitate potential success in clinical trials. This review incorporates an overview of the clinical manifestations and genetics of SMA, and describes recent advances in the understanding of mechanisms of disease pathogenesis and development of novel treatment strategies.

Key Points Cortical hyperexcitability is an early pathophysiological feature of amyotrophic lateral sclerosis (ALS) Cortical hyperexcitability potentially mediates motor neuron degeneration in ALS via a dying-forward, trans-synaptic, glutaminergic mechanism The identification of the C9orf72 hexanucleotide repeat expansion as a major cause of familial and apparently sporadic ALS, as well as frontotemporal dementia, underscored the importance of cortical dysfunction Cortical hyperexcitability is an important diagnostic biomarker of ALS, and could enable more-definitive diagnosis at an earlier stage of the disease process Evidence is accumulating that cortical dysfunction — in particular, cortical hyperexcitability — is an early feature of amyotrophic lateral sclerosis (ALS), thereby lending support to the 'dying-forward' hypothesis of ALS pathogenesis. The authors present an overview of recent insights into ALS pathophysiology, focusing on the importance of cortical hyperexcitability as a pathogenic and diagnostic biomarker. Cortical dysfunction — specifically, the development of hyperexcitability — seems to be an early and intrinsic feature of sporadic and familial amyotrophic lateral sclerosis (ALS) phenotypes, preceding the onset of lower motor neuron dysfunction and correlating with ensuing lower motor neuron dysfunction and degeneration. In fact, cortical dysfunction could provide a pathogenic basis for ALS, with corticomotor neuronal hyperexcitability mediating motor neuron degeneration via a trans-synaptic, glutamate-mediated, excitotoxic mechanism. The recent identification of C9orf72 repeat expansion as an important genetic risk factor for both ALS and frontotemporal dementia has underscored the importance of cortical function in ALS pathogenesis, and has helped to confirm that the disease forms part of a spectrum of central neurodegenerative processes. Changes in cortical function that develop in ALS could prove useful as diagnostic biomarkers, potentially enhancing the diagnosis of ALS at an early stage of the disease process. Pathophysiological and diagnostic biomarkers of cortical function might also provide insights to guide the development of future therapeutic approaches, including stem cell and genetic interventions, thereby providing potential for more-effective management of patients with ALS.