Steve Vucic

SeminarAmyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease of the human motor system. In this Seminar, we summarise current concepts about the origin of the disease, what predisposes patients to develop the disorder, and discuss why all cases of ALS are not the same. In the 150 years since Charcot originally described ALS, painfully slow progress has been made towards answering these questions. We focus on what is known about ALS and where research is heading-from the small steps of extending longevity, improving therapies, undertaking clinical trials, and compiling population registries to the overarching goals of establishing the measures that guard against onset and finding the triggers for this neurodegenerative disorder.

Controversies and priorities in amyotrophic lateral sclerosis.

Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events.

Guillain-Barré syndrome : An update

Guillain-Barré syndrome (GBS) is an acute polyneuropathy consisting of different subtypes. Acute inflammatory demyelinating polyradiculoneuropathy, the classic demyelinating form of GBS, accounts for 90% of all GBS cases in the Western world. Acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN) are axonal forms of GBS that are more prevalent in Asia, South and Central America, often preceded by infection by Campylobacter jejuni. AMAN and AMSAN may be mediated by specific anti-ganglioside antibodies that inhibit transient sodium ion (Na+) channels. The efficacy of plasmapheresis and intravenous immunoglobulin has been established in large international randomised trials, with corticosteroids proven ineffective. Although axonal demyelination is an established pathophysiological process in GBS, the rapid improvement of clinical deficits with treatment is consistent with Na+ channel blockade by antibodies or other circulating factors, such as cytokines. This review provides an update on the epidemiology, clinical features, diagnosis, pathogenesis and treatment of GBS.

FUS mutations in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and genetic analysis

Objective FUS gene mutations were recently identified in familial amyotrophic lateral sclerosis (ALS). The present studies sought to define the clinical, post-mortem and neurophysiological phenotypes in ALS families with FUS mutations and to determine the frequency of FUS mutations in familial and sporadic ALS. Methods FUS was screened for mutations in familial and sporadic ALS cases. Clinical, post-mortem and neurophysiological features of large families with FUS mutations are described. Results and conclusions FUS mutations were evident in 3.2% (4/124) of familial ALS, representing the second most common gene abnormality to be described in familial ALS after SOD1. No mutations were present in 247 sporadic ALS cases. The clinical presentation in 49 affected patients was consistent with a predominantly lower motor neuron disorder, supported by post-mortem findings. Upper motor neuron involvement varied, with Wallerian degeneration of corticospinal tracts present in one post-mortem case but absent in a second case from the same family. Features of cortical hyperexcitability demonstrated upper motor neuron involvement consistent with other forms of familial and sporadic ALS. One case presented with frontotemporal dementia (FTD) indicating that this may be a rare presenting feature in families with FUS mutation. Ubiquitin-positive cytoplasmic skein-like inclusions were present in lower motor neurons, but in contrast to sporadic ALS, no TDP-43 pathology was evident. Mutation-specific clinical features were identified. Patients with a R521C mutation were significantly more likely to develop disease at a younger age, and dropped-head syndrome was a frequent feature. Reduced disease penetrance was evident among most affected families.

Motor Neuron dysfunction in frontotemporal dementia

Frontotemporal dementia and motor neuron disease share clinical, genetic and pathological characteristics. Motor neuron disease develops in a proportion of patients with frontotemporal dementia, but the incidence, severity and functional significance of motor system dysfunction in patients with frontotemporal dementia has not been determined. Neurophysiological biomarkers have been developed to document motor system dysfunction including: short-interval intracortical inhibition, a marker of corticospinal motor neuron dysfunction and the neurophysiological index, a marker of lower motor neuron dysfunction. The present study performed detailed clinical and neurophysiological assessments on 108 participants including 40 consecutive patients with frontotemporal dementia, 42 age- and gender-matched patients with motor neuron disease and 26 control subjects. Of the 40 patients with frontotemporal dementia, 12.5% had concomitant motor neuron disease. A further 27.3% of the patients with frontotemporal dementia had clinical evidence of minor motor system dysfunction such as occasional fasciculations, mild wasting or weakness. Biomarkers of motor system function were abnormal in frontotemporal dementia. Average short-interval intracortical inhibition was reduced in frontotemporal dementia (4.3 ± 1.7%) compared with controls (9.1 ± 1.1%, P < 0.05). Short-interval intracortical inhibition was particularly reduced in the progressive non-fluent aphasia subgroup, but was normal in patients with behavioural variant frontotemporal dementia and semantic dementia. The neurophysiological index was reduced in frontotemporal dementia (1.1) compared with controls (1.9, P < 0.001), indicating a degree of lower motor neuron dysfunction, although remained relatively preserved when compared with motor neuron disease (0.7, P < 0.05). Motor system dysfunction in frontotemporal dementia may result from pathological involvement of the primary motor cortex, with secondary degeneration of lower motor neurons in the brainstem and anterior horn of the spinal cord.

Advances in treating amyotrophic lateral sclerosis: insights from pathophysiological studies

Amyotrophic lateral sclerosis (ALS) is the most frequently occurring of the neuromuscular degenerative disorders, with a median survival time of 3-5 years. The pathophysiological mechanisms underlying ALS are multifactorial, with a complex interaction between genetic factors and molecular pathways. To date 16 genes and loci have been associated with ALS, with mutations in DNA/RNA-regulating genes including the recently described c9orf72 (chromosome 9 open reading frame 72) gene, suggesting an important role for dysregulation of RNA metabolism in ALS pathogenesis. Further, dysfunction of molecular pathways, including glutamate-mediated excitotoxicity, has been identified in sporadic and familial ALS, indicating the existence of a common pathogenic pathway. These pathophysiological insights have suggested novel therapeutic approaches, including stem cell and genetics-based strategies, providing hope for feasible treatment of ALS.

Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons in the motor cortex, brainstem and spinal cord. A combination of upper and lower motor neuron dysfunction comprises the clinical ALS phenotype. Although the ALS phenotype was first observed by Charcot over 100 years ago, the site of ALS onset and the pathophysiological mechanisms underlying the development of motor neuron degeneration remain to be elucidated. Transcranial magnetic stimulation (TMS) enables non-invasive assessment of the functional integrity of the motor cortex and its corticomotoneuronal projections. To date, TMS studies have established motor cortical and corticospinal dysfunction in ALS, with cortical hyperexcitability being an early feature in sporadic forms of ALS and preceding the clinical onset of familial ALS. Taken together, a central origin of ALS is supported by TMS studies, with an anterograde transsynaptic mechanism implicated in ALS pathogenesis. Of further relevance, TMS techniques reliably distinguish ALS from mimic disorders, despite a compatible peripheral disease burden, thereby suggesting a potential diagnostic utility of TMS in ALS. This review will focus on the mechanisms underlying the generation of TMS measures used in assessment of cortical excitability, the contribution of TMS in enhancing the understanding of ALS pathophysiology and the potential diagnostic utility of TMS techniques in ALS.

Assessment of cortical excitability using threshold tracking techniques.

Conventional paired‐pulse transcranial magnetic stimulation (TMS) techniques of assessing cortical excitability are limited by fluctuations in the motor evoked potential (MEP) amplitude. The aim of the present study was to determine the feasibility of threshold tracking TMS for assessing cortical excitability in a clinical setting and to establish normative data. Studies were undertaken in 26 healthy controls, tracking the MEP response from abductor pollicis brevis. Short‐interval intracortical inhibition (SICI) occurred up to an interstimulus interval (ISI) of 7–10 ms, with two distinct peaks evident, at ISIs of ≤1 and 3 ms, followed by intracortical facilitation to an ISI of 30 ms. Long‐interval intracortical inhibition (LICI) occurred at ISIs of 50–300 ms, peaking at 150 ms. The present study has confirmed the effectiveness of the threshold tracking TMS technique in reliably and reproducibly measuring cortical excitability. Simultaneous assessment of upper and lower motor neuronal function with threshold tracking techniques may help to determine the site of disease onset and patterns of progression in neurodegenerative diseases. Muscle Nerve, 2005

Persistence on therapy and propensity matched outcome comparison of two subcutaneous interferon beta 1a dosages for multiple sclerosis

Objectives To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics. Methods Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded. Results Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as “lack of efficacy” (3.3% vs. 1.7%), “scheduled stop” (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages. Conclusions Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from “real-world” database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry.

Multifocal motor neuropathy Decrease in conduction blocks and reinnervation with long-term IVIg

Background: Multifocal motor neuropathy with conduction blocks (MMNCB) is an immune-mediated motor neuropathy. Previous long-term IV immunoglobulin (IVIg) treatment studies have documented improvement in muscle strength and functional disability but revealed a concomitant increase in acute axonal degeneration (AD) and conduction block (CB). Objective: To determine the long-term effects of IVIg therapy on clinical and neurophysiologic outcome measures in MMNCB patients responsive to IVIg. Methods: The authors reviewed medical records of 10 patients with MMNCB for outcomes in muscle strength (Medical Research Council score), functional disability (Modified Rankin Disability score), CB, and AD. All patients had received IVIg (2g/kg in 5 days for 3 consecutive months), followed by monthly maintenance therapy. Results: Patients were followed for an average of 7.25 years (range, 3.5 to 12 years). There was significant and sustained improvement in muscle strength and functional disability while on IVIg therapy. Furthermore, the authors found significant improvement in CB, decrease in AD, and evidence of reinnervation by the end of the follow-up period. Conclusion: Long-term IV immunoglobulin therapy improves muscle strength and functional disability, decreases the number of conduction blocks and the extent of axonal degeneration, and promotes reinnervation. These findings differ from previous reports of deterioration in neurophysiologic outcome measures. Comparison of the IV immunoglobulin regimen in those reports and this study shows that the authors’ patients were treated with significantly higher IV immunoglobulin maintenance doses. These findings have implications for the long-term treatment of patients with multifocal motor neuropathy with conduction blocks.