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Table of Contents
Year : 2021  |  Volume : 18  |  Issue : 3  |  Page : 200-204

Major advances in amyotrophic lateral sclerosis in 2020

1 Department of Neurosciences, Neo Hospital, Noida, Uttar Pradesh, India
2 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India

Date of Submission02-Aug-2021
Date of Decision06-Sep-2021
Date of Acceptance20-Aug-2021
Date of Web Publication07-Sep-2021

Correspondence Address:
Achal Kumar Srivastava
Department of Neurology, All India Institute of Medical Sciences, Room 60, Ground Floor, CN Center, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/am.am_91_21

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Research in amyotrophic lateral sclerosis (ALS), a neurodegenerative condition, has seen advancement in several key areas of research in 2020. These include a thrust to move the classification of ALS from a neuromuscular condition to a neurodegenerative condition, due to research suggesting involvement of cortical areas, and early cortical hyperexcitability. A new criterion for ALS, called the Gold Coast criterion, has been described. The Gold Coast criteria have removed the categories of possible, probable, and definite ALS, to make the diagnosis of ALS more inclusive and permit enhanced eligibility of patients in clinical trials for ALS. New biomarkers, both imaging and protein based, have been described. Advances in therapy have also occurred, with a large phase II clinical trial reporting benefits with sodium phenylbutyrate-taurursodiol.

Keywords: Amyotrophic lateral sclerosis, COVID-19, Gold Coast, sodium phenylbutyrate-taurursodiol

How to cite this article:
Garg D, Srivastava AK. Major advances in amyotrophic lateral sclerosis in 2020. Apollo Med 2021;18:200-4

How to cite this URL:
Garg D, Srivastava AK. Major advances in amyotrophic lateral sclerosis in 2020. Apollo Med [serial online] 2021 [cited 2021 Dec 6];18:200-4. Available from: https://www.apollomedicine.org/text.asp?2021/18/3/200/325681

  Introduction Top

Amyotrophic lateral sclerosis (ALS) is a progressive neurological condition characterized by inexorable degeneration of upper and lower motor neurons. The incidence is 2–3 per 100,000 per year. The lifetime risk of developing ALS ranges from 1 in 400 for women and 1 in 350 for men.[1],[2] This male predominance of distribution is more frequently seen in younger age groups. The usual age of onset is in the seventh decade, although onset may range from adolescents to elderly individuals. There is an age-dependent increase in risk up to the eighth decade.

Nearly 10% of ALS may be familial and the remaining 90% is sporadic in origin. The disease course is inexorable although variable between patients, with a usual life expectancy between 2 and 3 years from diagnosis. Respiratory failure is the usual cause of death.[3],[4]

Considering the relentless nature of the disease, ALS is a field of expansive research, focused on risk factors, diagnosis, and treatment modalities. Epidemiological data indicate that high levels of physical fitness or athleticism and slimness increase the risk of ALS.[5] Sports with concussive risks, such as football or soccer, carry increased risk.[6] Certain professions that have been associated with increased risk include athletes, military personnel, hairdressers, veterinarians, and power plant operators.[7] Several environmental risk factors have been explored without definitive evidence of increased risk, such as heavy metals and electric shock.

There have been several important advances in the field of ALS in 2020, which we will recapitulate in this review. In essence, there is thrust to shift the classification of ALS from that of a neuromuscular disorder to a neurodegenerative condition, considering mounting evidence for cortical involvement. There is also increasing evidence of early cortical hyperexcitability in ALS. There have also been several biomarkers and therapy-based advances, which we summarize below.

  Search Methodology Top

We searched PubMed with the following search terms: “Amyotrophic lateral sclerosis” and “motor neuron disease.” We searched all articles published in the English language in 2020. Reviews, original articles, and case series relevant to this review article were identified and included. Cross-references were also searched and relevant ones incorporated.

  Classification of Amyotrophic Lateral Sclerosis: “Neurodegenerative” Rather Than “Neuromuscular” Top

There has been a concerted effort to transition out the classification of ALS from that of a neuromuscular disorder to a broadly neurodegenerative condition.[8] The classification of ALS within neuromuscular disorders is placed on typical features of lower motor neuron involvement, including muscle atrophy, fasciculation, and weakness. This is based on aggregating evidence that ALS involved the central nervous system as well as the peripheral nervous system (PNS), unlike neuromuscular disorders which are confined to the realm of the PNS. Due to generally prominent lower motor neuron features such as atrophy and fasciculation, neuromuscular diseases that form a close differential for ALS include Kennedy's disease, myasthenia gravis, hereditary motor neuropathy, and multifocal motor neuropathy with conduction block, and hence, the traditional bracketing of ALS is with neuromuscular disorders.

However, this classical notion was challenged by the discovery in 2006 that motor neurons in ALS contained TDP-43-positive inclusions, which are also a hallmark feature of frontotemporal dementia, hence creating a definite overlap between these two conditions.[9]

Current evidence garnered from clinical data, neuroimaging, pathology, genetic studies demonstrate that it is more appropriate to classify ALS as a neurodegenerative disease rather than strictly as a neuromuscular disease.

  Diagnosis of Amyotrophic Lateral Sclerosis: The Gold Coast Criteria Top

The El Escorial criteria, which were initially published in 1994 and revised in 2000, provide different levels of diagnostic certainty including definite, probable, possible, and laboratory-supported probable, supported by electromyography findings. The Awaji criteria further modified these criteria in 2008, which permitted the presence of fasciculation to substitute for fibrillation-positive sharp waves as lower motor neuron findings, in muscles that demonstrated neurogenic changes. The Awaji criteria also removed the entity of “laboratory-supported ALS.” These criteria are complex and have low test–retest reliability. In addition, disease progression may not necessarily proceed along possible to probable to definite categories in succession. Newly proposed Gold Coast criteria, defined in 2020, are a simplified set of criteria.[10] These require that for the diagnosis of ALS, there should be progressive motor impairment preceded by normal motor function, the presence of upper and lower motor neuron dysfunction in at least one body region or lower motor neuron dysfunction in at least two body regions, and exclusion of other diseases.

Hence, the Gold Coast criteria have removed the categories of possible, probable, and definite ALS, to make the diagnosis of ALS more inclusive and permit enhanced eligibility of patients in clinical trials for ALS.[11]

  New Pathogenetic Mechanism: Cortical Hyperexcitability Top

ALS is characterized by the abnormal location of the TAR-DNA-binding protein (TDP-43) from the nucleus to the cytoplasm. The contribution of mis-localization of TDP-43 on pathogenesis has been studied in murine models. It is evident that the localization of TDP-43 to the cytoplasm leads to an altered cortical excitability phenotype as well as abnormal synaptic function in motor neurons.[12]

In another study, cortical function was assessed using threshold tracking transcranial magnetic stimulation. Cortical hyperexcitability increased with increased disease duration and was more prominent in the later disease stages of ALS.[13]

  Biomarkers in Amyotrophic Lateral Sclerosis Top

There have been rapid advancements in the field of biomarkers in ALS, providing an opportunity toward an enhanced understanding of disease pathogenesis.[14]

  Neuroimaging Biomarkers Top

Neuroimaging biomarkers are being explored as frontrunner biomarkers in ALS. Brain network analysis may provide insights into disease progression and prognosis. Computer-simulated computational model developed to predict progression in ALS was found to mimic true disease progression.[15] In this study, a random walker model based on magnetic resonance imaging scans could predict neurodegeneration on longitudinal follow-up. This study also supported the progression of disability in ALS beginning from the motor cortex, and subsequently spreading spatiotemporally along white matter tracts.

Another important area of advancement is the recognition of disruption of nonmotor networks in ALS, apart from motor networks. Considering the extensive disturbance of both motor and nonmotor circuitry, quantitative electroencephalography has been proposed as a potential biomarker, as it may detect upper motor system changes in ALS in both motor and nonmotor regions.[16]

Metabolic changes in the brain have also been demonstrated in presymptomatic individuals who carry the hexanucleotide repeat expansion in C9orf72 protein with the use of fluorine 18-labeled fluorodeoxyglucose positron-emission tomographic imaging.[17] This was evaluated in a case–control study involving 46 participants. Glucose metabolic changes in presymptomatic persons preceded clinical onset as well as elevation of neurofilament levels, making this modality a potential tool for detection of ALS even at a presymptomatic stage.

  Neurofilament Proteins Top

Another promising biomarker is serum neurofilament light, which was recently clinically validated in a prospective study as a prognostic marker.[18] Another similar putative biomarker is phosphorylated neurofilament heavy.

  Chitinase Proteins Top

Chitinase proteins, which are markers of glial activation, have also been evaluated in the cerebrospinal fluid (CSF) and plasma as biomarkers. These include chitotriosidase (Chit-1), chitinase-3-like protein 1 (CHI3 L1), and chitinase-3-like protein 2 (CHI3 L2).[19] The Chit-1 response has been seen to be a feature of late presymptomatic and early symptomatic phases of ALS.[20]

  Treatment Research Initiative to Cure Amyotrophic Lateral Sclerosis Top

This initiative was launched in 2020 as an initiative focused on better treatment-based research. One of the foremost aims of this initiative was to identify the barriers to translational research. A recent position paper of the treatment research initiative to cure amyotrophic lateral sclerosis highlighted some of these impediments and also suggested solutions in the form of stringent eligibility criteria in trials, the use of more inclusive severity scales and novel trial designs.[21]

  Advances in Therapy Top

Both riluzole[22],[23] and edaravone[24] have been approved by the United States Food and Drug Administration for ALS due to their effects on disease course. However, effects of both these drugs on disease course in ALS are at best, modest. Riluzole may increase survival by 3–5 months. Edaravone has demonstrated mild effects on functional decline in specific cohorts of ALS.

  AMX0035 Top

Sodium phenylbutyrate-taurursodiol

In a promising phase II multicenter, randomized blinded trial, AMX0035 was assessed among participants with ALS. These patients were randomized in a 2:1 ratio to receive a combination of sodium phenylbutyrate (3 g) and taurursodiol (1 g) (AMX0035) which was given once daily for 3 weeks followed by twice daily compared to placebo for a total of 24 weeks.[25]

The main outcome was a rate of decline in the total score on the ALS functional rating scale-revised (ALSFRS-R). A number of secondary outcomes were also assessed including rates of decline in isometric muscle strength; plasma phosphorylated axonal neurofilament H subunit levels, and slow vital capacity, time to death, tracheostomy or permanent ventilation, or hospitalization.

In this trial, 137 patients were recruited, 89 received sodium phenylbutyrate, and 48 received placebo. The mean change in ALSFRS-R score was −1.24 points per month for the drug compared to −1.66 points for the placebo, the difference being 0.42 points per month (95% confidence interval 0.03–0.81; P = 0.03). There were no significant differences in any of the secondary outcome measures.

In ALS, protein aggregation is linked to endoplasmic reticulum-related stress, and mitochondrial dysfunction is also implicated in pathogenesis.[26],[27] Sodium phenylbutyrate upregulates heat shock proteins, thereby neutralizing this stress.[28] Taurursodiol promotes mitochondrial bioenergetics and elevates cellular apoptotic threshold.[29] A European study is ongoing, evaluating the effect of taurursodiol versus placebo as a phase III study.

Tofersen (BIIB067)

Tofersen is an antisense oligonucleotide that decreases superoxide dismutase 1 (SOD 1) synthesis by degrading SOD1 messenger RNA. It is administered intrathecally. A phase 1–2 ascending dose trial evaluated tofersen in patients with ALS due to SOD1 mutations.[30] For each dose cohort of 20, 40, 60, and 100 mg, patients were randomized in a 3:1 ratio to receive tofersen or placebo. Tofersen was administered in five intrathecal doses for 12 weeks. The primary outcome was safety and pharmacokinetics. The secondary outcome was a change in SOD1 levels in the CSF on day 85, compared to baseline. Fifty patients with ALS with SOD1 mutations were randomized. Most common adverse events were related to lumbar puncture. Decrease in CSF SOD1 levels was seen with the highest dose of tofersen. A phase 3 trial is planned now for tofersen. Other antisense oligonucleotide-based therapies which are in the preclinical phase are those for C9orf72 for ALS in association with frontotemporal dementia, as well as ataxin-2, which influences the expression of TDP-43.

  Active Clinical Trials in Amyotrophic Lateral Sclerosis Top

Antisense oligonucleotide trials

A phase III trial is underway assessing the efficacy of tofersen among ALS patients with SOD1 mutations.[31]

The antisense oligonucleotide BIIB078 is also undergoing a phase I trial, targeting the C9orf72 mutation in patients with familial ALS.[32] Preclinical studies involve murine models of the C9orf72 mutations.[33]

Impact of COVID-19 pandemic

There are specific connotations of the COVID-19 pandemic on patients with ALS. Patients with ALS are vulnerable to contracting and developing severe complications of COVID-19 due to respiratory muscle impairment. In addition, lockdowns and pandemic precautions deter may deter or prevent these patients from obtaining timely health care despite rapid deterioration. Moreover, lockdowns have been associated with increased caregiver burden.[34] One of the solutions to this problem is the use of telemedicine to provide multidisciplinary care to persons with ALS. The role of administering health care with the use of telemedicine has been assessed in small studies and yielded good patient satisfaction.[35] Telemedicine may be considered as a reasonable option of offering follow-up treatment to patients even after the pandemic-related restrictions end.[36]

  Conclusions Top

There have been exciting advances in ALS pertaining to pathogenesis, cellular and molecular biology, neuroimaging, and biomarkers in recent times. There is a move to simplify and broaden the diagnostic criteria of this heterogeneous condition to offer the benefit of enrolment into therapy-related clinical trials for patients with ALS. There has been increased understanding toward both nonmotor phenomena in ALS as well as a general shift toward reclassification of this condition as a neurodegenerative rather than a neuromuscular condition. Finally, the COVID-19 pandemic bears specific implications for patients with ALS as well as their caregivers. This energetic momentum in ALS-related advancements must continue to gain speed in the coming years as well.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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Search Methodology
Classification o...
Diagnosis of Amy...
New Pathogenetic...
Biomarkers in Am...
Neuroimaging Bio...
Neurofilament Pr...
Chitinase Proteins
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