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Lancet. Author manuscript; available in PMC 2023 October 15.
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Published in final edited form as:

Lancet. 2022 October 15; 400(10360): 1363–1380. doi:10.1016/S0140-6736(22)01272-7.
Amyotrophic lateral sclerosis

Eva L Feldman, MD, PhD1 [Professor], Stephen A Goutman, MD1 [Associate Professor],
Susanne Petri, MD2 [Professor], Letizia Mazzini, MD3 [Professor], Masha G Savelieff, PhD1,
Pamela J Shaw, MD4 [Professor], Gen Sobue, MD5 [Professor]
1Department of Neurology, University of Michigan, Ann Arbor, MI, United States
2Department of Neurology, Hannover Medical School, Hannover, Germany
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3ALS Center Department of Neurology, Maggiore Della Carità Hospital and University of
Piemonte Orientale, Novara, Italy
4SheffieldInstitute for Translational Neuroscience (SITraN), the University of Sheffield, Sheffield,
United Kingdom
5Aichi Medical University, Nagakute, Aichi, Japan
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal central nervous system neurodegenerative
disease. Despite intense research, current ALS management remains suboptimal, from diagnosis
to prognosis. Recognition of ALS phenotypic heterogeneity, global central nervous system
dysfunction, genetic architecture, and development of novel diagnostic criteria are clarifying the
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spectrum of clinical presentation and facilitating diagnosis. Insights into ALS pathophysiology,
identification of disease biomarkers and modifiable risks, along with new predictive models,
scales, and scoring systems, and a clinical trial pipeline of mechanism-based therapies are
changing the prognostic landscape. Although most recent advances have yet to translate to patient
benefit, the view of ALS as a complex syndrome is already having tangible effects in the clinic.
This review will outline these recent insights and discuss the status of ALS management for the
general neurologist, along with future prospects, which may improve care and outcomes for ALS
patients.
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Correspondence to: Eva L Feldman MD, PhD, [email protected], Department of Neurology, Michigan Medicine, University of
Michigan, Ann Arbor, MI 48109, United States.
Contributors
All authors contributed to conceptualization, writing - original draft, and writing - review & editing.
Declaration of interests
ELF has a patent US20200253977A1 issued. SAG reports personal fees from Biogen, ITF Pharma, and Watermark, outside the
submitted work; in addition, SAG has a patent US20200253977A1 issued. SP reports grants from the German Neuromuscular Society,
the German-Israeli Foundation for Scientific Research and Development (GIF), and personal fees from Cytokinetics, Desitin Pharma,
Italfarmaco, Biogen, Roche, and Zambon outside the submitted work. LM declared no conflicts of interest. MGS declared no conflicts
of interest. PJS reports consultancy and advisory board membership with Biogen, Benevolent AI, QurALIS, Quell, and Aclipse
Therapeutics, outside the submitted work. GS reports personal fees from Mitsubishi Tanabe Pharma Corporation, Cyberdyne, Biogen
Japan, Takeda Pharmaceutical, Nihon Pharmaceutical, and Teijin Pharma, outside the submitted work.
Feldman et al. Page 2
Keywords
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Amyotrophic lateral sclerosis; biomarker; clinical overlap; diagnosis; epidemiology; exposome;

genetic architecture; motor neuron disease; pathophysiology; phenotype; prognosis; scoring;
staging
Introduction
Amyotrophic lateral sclerosis (ALS), a fatal central nervous system neurodegenerative
disease, can be difficult to recognize, especially in the early stages. The disease is rare and
more common illnesses are considered before ALS, frequently delaying diagnosis. However,
the lifetime risk of ALS is approximately 1 in 350, though limited life expectancy reduces
the prevalence.(1) Recent recognition of phenotypic heterogeneity and ALS as a complex
syndrome that frequently includes behavioral deficits, may help physicians better recognize
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ALS earlier in the disease course. Development of new diagnostic criteria and identification
of genetic risk factors could also expedite the diagnostic process.(2) Regarding prognosis,
our clearer understanding of the multisystem nature of ALS including cognitive dysfunction
and behavioral changes, has important ramifications for caregiving support and end of life
decision making. Moreover, newly developed predictive models, scales, and scoring systems
can give ALS patients and their physicians a clearer idea of their disease course.(2) Finally,
advances in our understanding of disease pathophysiology are leading to mechanism-based
and potentially disease-modifying therapies, currently in clinical trials. This review will
outline these topics and current clinical practice for ALS, along with research advances,
which may facilitate future improvements in diagnosis and prognosis for ALS patients.
ALS epidemiology
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ALS incidence rises with age and is highest around 60 to 79 years,(3, 4) although variation
can occur by ancestral background.(5) Some studies show stable incidence over the past two
or three decades,(1) whereas others report a possible increase.(6, 7) Changes in perceived
incidence may arise from improved diagnosis or changes in reporting standards over time,
advocating the construction of well-curated population registries. It is unclear whether ALS
incidence has changed in the past couple of decades, although it is anticipated to grow
with an aging population.(8) ALS prevalence is also expected to increase due to an aging
population in addition to improved management, which supports increased life expectancy.
(8, 9) Still, ALS remains a relatively rare disease. Standardized global ALS incidence by
meta-analysis is only 1·68 per 100,000 person-years of follow-up but varies by region.(10)
In populations of predominantly European descent, such as Europe and North America,
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incidence is slightly higher than the global average and ranges from 1·71 to 1·89 per
100,000 and may even be higher within population-based studies.(11) Asian populations
have lower incidences, varying from 0·73 per 100,000 in South Asia to 0·94 per 100,000
in West Asia, whereas Oceania universally has among the highest incidence rates.(7, 10)
ALS incidence also varies by sex with an overall standardized male-to-female ratio of 1·35,
which is affected by age of onset.(12) Genetics also plays a role; heritability is higher in
mother-daughter pairs(1) whereas the most common known ALS risk gene, C9orf72, lowers

onset age in males versus females.(13) Thus, ALS arises from complex interrelationships
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between age, sex, and genetics,(14) which has implications for preclinical and clinical
research and clinical trials.
ALS clinical presentation

ALS phenotypic heterogeneity
ALS presents as a combination of upper (UMN) and lower motor neuron (LMN)
dysfunction affecting the bulbar, cervical, thoracic, and/or lumbar segments.(2) This
leads to progressive weakness of voluntary skeletal muscles involved in limb movement,
swallowing (dysphagia), speaking (dysarthria), and respiratory function, with different
clinical presentations (Panel 1). Sphincter and extraocular muscles are classically spared,
although autonomic dysfunction in ALS is increasingly recognized, e.g., urinary urgency
and incontinence.(15) Clinical weakness spreads contralaterally and rostrally and caudally,
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most often in an anatomically contiguous manner. A recent survey of ALS patients found
that 85% had focal onset in one body segment, which progressed to the contralateral side
and then to adjacent anatomical segments.(16) Disease spread to non-contiguous segments
was less common.
ALS presents as multiple phenotypes (Figure 1A–B; Appendix Table 1). Bulbar onset and
spinal (cervical, lumbar) onset ALS are the most common presentations, each constituting
about a quarter to a third of cases, with less frequent manifestations of flail arm and leg,
primary lateral sclerosis, progressive muscular atrophy, respiratory onset, and hemiplegic
presentations.12,13 This review considers primary lateral sclerosis and progressive muscular
atrophy are on the spectra of ALS phenotypes, although they may also be considered as
separate clinical entities. Age, sex, and genetics contribute to ALS phenotypes. Older female
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patients may more commonly develop bulbar onset ALS, younger males classical ALS,
younger males and females pure UMN diseases, males flail arm variant, older males flail
leg variant and respiratory onset.(14) Specific genetic mutations favor certain phenotypes
(see “ALS genetic architecture” section). One recent study of German and Chinese registries
suggest that phenotypes may vary globally.(18) German ALS patients have an older onset
age (66.6 years), larger proportion of bulbar onset (35.9%), and smaller male-to-female ratio
(1.33) versus Chinese patients (53.2 years onset age, 22.8% bulbar, 1.51 male-to-female
ratio).(18) Consensus phenotyping between registries would advance our knowledge of age,
sex, genetics, and racial/ethnic contributions to phenotypes.
ALS cognitive and behavioral changes

Classically, ALS was predominantly considered a disease of motor dysfunction, e.g.,
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dysarthria, dysphagia, weakness of upper and/or lower limb muscles. However, cognitive
and behavioral changes, which can occur early in the disease course,(19, 20) are now
recognized to occur in 35 to 50% of ALS patients.(21, 22) Individuals with ALS experience
loss of normal language and executive function, i.e., poor working memory, inhibition,
and fluency. Typically, more long-term memory and spatial domains remain intact.(21)
Other behavioral changes include apathy, irritability, disregard for hygiene, and eating habit
changes. Approximately 15% of ALS cases meet the diagnostic criteria for frontotemporal

dementia (FTD).(20, 23) Furthermore, depression, anxiety, and sleep disruptions occur in
ALS(24) along with pseudobulbar affect, which causes emotional lability.16
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These cognitive and behavioral changes support the concept that ALS is a global
neurodegenerative disease along the same continuum as FTD (Figure 1C). Transactive
response DNA binding protein (TDP)-43 proteinopathy, an almost universal pathological
hallmark of ALS, is present in ~97% of cases and ~50% of FTD cases. Mild deficits in
executive function, language, and fluency have 100% specificity for TDP-43 pathology in
non-motor brain regions corresponding to these domains.(25) Certain patient characteristics,
such as C9orf72 status(26, 27) and bulbar onset,(27) are strong determinants of cognitive
impairment and may help the physician and patient to anticipate this complication.
Furthermore, cognitive dysfunction and behavioral abnormalities may be prognostic of
disease stage.(21) In a report of 146 ALS patients, cognition worsened in 30% of cases after
6-months, even among patients that were initially normal.(22) Those patients with cognitive
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decline had a more rapid clinical progression and shorter survival. Network analyses of
brain MRIs demonstrate widespread disruption of motor and extra-motor networks that
correspond with ALS phenotypes. Specifically, abnormal structural connectivity correlates
with motor impairment, whereas disrupted functional connectivity aligns with changes in
cognition and behavior.(28)
Collectively, this new understanding of ALS as a multi-system disorder underscores

the importance of managing cognitive decline and neuropsychological problems, e.g.,
depression, dysfunctional sleep, apathy and irritability.(24) Importantly, when cognitive
symptoms emerge, care teams should engage early with patients and their families to
inquire about end-of-life care preferences to ensure the patient plays an active role in these
important conversations.
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ALS diagnosis
ALS criteria
ALS patients are unlikely to encounter a neurologist early in the diagnostic journey;(29, 30)
therefore, there should be a low threshold for neurological referral when patients present
with progressive dysarthria, dysphagia, limb weakness, or neuromuscular respiratory failure.
The ALS Association “thinkALS” tool encourages early neurological referral to avoid
unnecessary procedures, begin patients on disease-modifying treatments, and fast-track
patient enrollment into clinical trials.(31) Additional clues indicating a diagnosis of ALS
include unexplained weight loss, pseudobulbar affect, changes in cognition or executive
functioning, and a family history of ALS or other neurodegenerative diseases. Clinical
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features that do not support ALS include sensory, sphincter, and autonomic nervous system
dysfunction and anterior visual pathway abnormalities. A detailed neurological examination
should identify signs of UMN and LMN dysfunction in bulbar, cervical, thoracic, and/or
lumbosacral segments (Panel 2).
Clinical history and neurological examination are accompanied by serological and

electrodiagnostic testing. ALS patients have normal serology, except for elevated creatine
phosphokinase levels in some cases. Other abnormal serologies call into question an

ALS diagnosis (see “Differential diagnosis and ALS overlap syndromes” section). Nerve
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conduction studies exclude sensory nerve involvement and motor nerve conduction block
and needle electromyography confirm LMN involvement, with the provision that testing of
distal muscles and muscles in the involved clinical segment have the highest sensitivity.(33,
34) Most neurologists still use the revised El Escorial criteria to subclassify ALS, which
categorizes patients as possible, probable, probable laboratory supported, and definite ALS,
depending on clinical presentation and electromyography findings. The revised El Escorial
criteria are outlined in Panel 2, since they are most widely used.(32)
Regarding advances in diagnostic criteria for ALS, the Gold Coast Criteria were recently
proposed to simplify and potentially replace the revised El Escorial and improve inter-rater
reliability (Appendix Table 2).(35) The Gold Coast criteria are primarily based on clinical
presentation, although they do not consider cognitive changes, which the authors noted were
covered by the 2017 Strong criteria.(36) Gold Coast classifies patients as having or not
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having ALS, streamlining diagnostic certainty and eliminating confusion to patients and
their relatives from El Escorial terminology. A comparison of the sensitivity and specificity
of the various criteria reveal that Gold Coast criteria are the most sensitive while El Escorial
are the most specific (Appendix Table 2). Additionally, the revised El Escorial Criteria
provide information that the Gold Coast criteria do not, such as the distribution of clinical
segmental involvement, which is important for stratifying disease severity in ALS patients.
Although the revised El Escorial presently remain the mainstay of ALS diagnosis, the field
may be slowly moving towards simpler criteria, such as the Gold Coast.
Overall, early diagnosis of ALS is important. Educational efforts for physicians most likely
to encounter ALS patients during initial symptom onset are essential to support prompt
recognition of the disease with timely initiation of treatment. As simplified diagnostic
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criteria become more universally accepted, we anticipate that more practitioners will
recognize and treat ALS early in the disease course.
ALS cognitive assessment

While not part of formal ALS diagnostic criteria, it is essential to evaluate cognition
and behavior in ALS patients, despite potentially further fatiguing individuals undergoing
long and complex clinical visits. Assessments of cognitive and behavioral impairment
are essential as they relate to prognosis and progression rate, and, thus, inform clinical
management.(21, 22) Assessment of cognitive impairment in ALS patients should include
multiple cognitive domains (e.g., executive and language dysfunction, social cognition).(37)
Behavioral impairment (e.g., apathy, disinhibition, loss of empathy, compulsive behavior,
etc) also affects the well-being of patients and family-members and requires evaluation.
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Some ALS patients are diagnosed with FTD (ALS-FTD), as defined by the Neary(38) or
Rascovsky(39) criteria. For patients not meeting formal FTD criteria, the revised Strong
criteria define ALS patients with cognitive dysfunction as “ALS cognitive impairment”
(ALSci), with behavioral problems as “ALS behavioral impairment” (ALSbi) or with both,
as “ALS combined cognitive behavioral deficits” (ALScbi) (Appendix Table 3).(36) Several
assessment batteries can classify these changes. The Edinburgh Cognitive and Behavioral
ALS Screen (ECAS) is a validated, multidomain assessment tool developed for ALS

patients, which can be administered by neuropsychological and non-neuropsychological

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professionals.(37) ECAS, available in 23 languages, covers the largest number of

ALS-specific cognitive or behavioral assessment scales. Incorporating ECAS into ALS
management has a positive impact on the quality of care, by stimulating end-of-life care
discussions, referrals to other services, and identifying caregiver support needs.(40)
The ALS Cognitive Behavioral Screen, available in three languages, can also identify
cognitive and behavioral impairment and FTD, in ALS patients.(37) The ALS-FTD
Questionnaire (ALS-FTD-Q) is completed by healthcare professionals or caregivers to
assess behavioral changes in ALS patients.(37) ALS-FTD-Q, translated into nine languages,
identifies patients with behavioral variant FTD. The Beaumont Behavioral Inventory is a
new screening tool for evaluating behavioral impairment in ALS patients and may be more
sensitive than ALS-FTD-Q.(37)
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Overall, it is important to recognize that cognitive symptoms are a manifestation of

ALS, and properly identifying these symptoms improves disease management, counseling,
and prognostication. Since cognitive symptoms may change with disease progression,
it is critical to regularly assess them to best care for the patient. Future directions
include standardizing cognitive assessments for in-clinic screening, determining whether
neuropsychologists should become part of the regular multidisciplinary team, and
developing evidence-based treatments for cognitive impairment in ALS.
ALS genetic architecture

ALS is presently classified as either familial or sporadic. Familial ALS, which constitutes
10 to 15% of cases, is defined as inheritance among family members of ALS and associated
syndromes, e.g., FTD.(41) About 70% of familial cases have mutations within known
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ALS genes. Sporadic ALS, which constitutes the remaining approximately 85% of cases,
is defined as disease arising in patients lacking a family history of ALS. About 15% of
sporadic ALS patients harbor “private” pathogenic mutations to known ALS genes, i.e.,
mutations limited to a single individual, hence lacking a family history of ALS.(41) There
is no known cause in the remaining 85% of sporadic ALS cases. Apparently sporadic cases
harboring low penetrant mutations and belonging to small families or having incomplete
or poor knowledge of family history may in fact be familial ALS. Thus, familial ALS
may be underreported and represent closer to 20% of cases.(42),(43) As genetic testing
becomes more widely implemented and potential candidate therapies more targeted, it may
become useful to drop the familial versus sporadic dichotomy of ALS in favor of genetically
confirmed versus non-genetically confirmed ALS, i.e., presence versus lack of an ALS
mutation underpinning molecular subclassification of disease.
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ALS genetic architecture is highly complex and largely based on monogenic inheritance
of rare variants, i.e., single disease-causing genes (Figure 2A).(44) To date, over 40
ALS-associated genes have been identified,(45, 46) which vary in frequency, mode of
inheritance (mostly dominant, rarely recessive), and penetrance (Figure 2B; Appendix Table
4). The most common and penetrant mutations are C9orf72, TARDBP, SOD1, and FUS,(45)
although the frequency of genetic subtypes does vary by population ancestry.(47) Some ALS

genes are not necessarily disease-inducing, but rather confer an increased risk of developing
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ALS, e.g., ANG, ATXN2, DCTN1.(45) Importantly, uncertainty remains on the relevance
of some identified genes to ALS, which require further confirmation and replication efforts.
(48) Consortia of ALS genetics experts can curate and maintain an up-to-date list of ALS
genes as evidence emerges,(49) facilitating clinical translation for genetic testing. Since ALS
genetic architecture is complex, it is advisable that specialist ALS centers perform genetic
testing to avoid over diagnosing or missing genetic ALS. It is also important to recognize
that genetic testing in ALS might not identify rare pathogenic variants, i.e., allele frequency
less than 1%.
In addition to primary monogenic inheritance in ALS, interest in the impact on oligogenic

and polygenic inheritance on disease risk has also gained traction. Several studies highlight
that oligogenic inheritance, meaning a trait or disease controlled by inheritance of several
genes, may have a role in ALS risk and/or disease progression (Figure 2C).(50, 51) Genetic
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screening identified a subset of sporadic ALS patients harboring two or more variants in
ALS genes; these patients were more likely to have earlier onset disease versus patients
harboring one or no variants.(50, 51) Polygenic inheritance, arising from inheritance of
multiple genetic variants, is also a component of ALS genetic architecture (Figure 2D).(52,
53) Analysis of ALS genetic profiles identified shared polygenic risk of ALS with traits
and single nucleotide polymorphisms correlated with smoking status, physical activity,
cognitive performance, and educational attainment,(52) as well as obesity-related traits,
(52, 53) particularly hyperlipidemia. Our growing knowledge of ALS genetic architecture
is due in great part to large collaborative projects, which are driving discovery in this
relatively rare disease, such as the ALS Sequencing Consortium,(54) International ALS
Genomics Consortium,(55) Genomic Translation for ALS Care Consortium,(54) Answer
ALS Foundation,(54) and Project MinE.(54) We anticipate that these consortia will continue
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to bear fruit and foster further investigation.
Importantly, ALS is also characterized by incomplete heritability, meaning genetics does

not fully account for all disease burden. Estimates vary but most studies report heritability
of 45 to 50% in ALS dyads, driven in large part by rare genetic variants.(1) However,
heritability estimates can be as high as 66% in some dyad comparisons and as low as 37% in
patients lacking a known genetic risk.(1) In addition to rare variants,(56) several additional
factors can account for “missing heritability” in ALS, such as alterations in the non-coding
genome, structural variants,(57) epigenetic changes,(58) and environmental factors.(59) The
contribution of the environment has led to the “gene-time-environment” hypothesis of
ALS,(60) which proposes that an interaction of genes and environment over time causes
ALS through a multistep process.(61) An evolving body of evidence demonstrates that
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the environment does impact ALS risk and progression in a gene-dependent manner (see
“Environmental exposure in ALS” section).
As therapeutics that target certain genetic forms of ALS become a possibility, genetic testing
for all patients with ALS will likely become standard practice. Genetic treatment paradigms
will increase the need for classifying and assessing genetic variants in ALS. Additionally,
partnership with genetic counselors will expand to facilitate discussions of these complex
results with patients and their families.(62)

Differential diagnosis and overlap syndromes

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General physicians and even specialist neurologists, may not initially recognize an ALS
diagnosis in a patient with ALS symptoms due to overlap of disease presentation with
other conditions. Thus, classical differential diagnosis based on clinical presentation is an
important element of the diagnostic process in ALS (Figure 3; Appendix Table 5).
Diseases more common than ALS are often considered and thoroughly evaluated first,
which ultimately delays an ALS diagnosis. Conditions that most commonly mimic ALS
include multifocal motor neuropathy with conduction block, axonal motor predominant
chronic inflammatory demyelinating polyneuropathy, spinobulbar muscular atrophy, and
inclusion body myositis.(63) Simultaneous cervical nerve root and spinal cord compression
by disc herniations, tumors or malformations may cause combined LMN signs in the
arms and UMN in the legs, and be misdiagnosed as classical ALS.(63) UMN dominant
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ALS or primary lateral sclerosis may be confused with hereditary spastic paraplegias
or primary progressive multiple sclerosis. Additional, but rare, differential diagnoses
include hyperparathyroidism and hexosaminidase A-/B-deficiency.(63) Since some of these
conditions are treatable, it is important to rule out these possibilities.
In conjunction with clinical presentation, genetic testing is increasingly utilized to explain

disease cause and predict family risk. Risk ALS genes can cause other syndromes or
phenocopy alternative neurodegenerative diseases (Appendix Table 4). C9orf72 expansions,
the most common ALS gene, are linked to movement disorders(64, 65) and phenocopy
Huntington’s disease in patients lacking huntingtin (HTT) expansions.(66) Conversely,
ALS patients may harbor HTT repeat expansions simultaneously with TDP-43 inclusions.
(67) Thus, patients may present with atypical ALS delaying diagnosis. Additional ALS
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genes overlap with other syndromes and an improved understanding of the complexity of
genotype-phenotype relationships will expedite ALS diagnosis. Finally, ALS is associated
with neuropsychiatric illnesses, such as psychosis and suicidal ideation;(68, 69) thus,
clinicians should obtain comprehensive detailed family history, not just of ALS, but of
neurodegenerative and neuropsychiatric illnesses.
ALS risk, progression, and pathophysiology

Identifying factors that increase ALS risk and progression is central to patient diagnosis
and care. Genetics are a major ALS risk factor (see “ALS Genetic Architecture”; Appendix
Table 4). For instance, C9orf72 expansions are penetrant and confer high ALS risk, and
are also associated with bulbar onset(14) and a decreased survival (70) in some studies.
However, there are genetic mutations that confer risk but do not impact progression;
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therefore, risk and progression can be independent processes and factors influencing either
or both are an active area of research.(71) It is increasingly recognized that a patient’s
cumulative environmental lifetime exposures, known as the exposome, can also confer ALS
risk and may accelerate disease progression.(72) Independent of whether risk is secondary
to genetics and/or the exposome, a knowledge of ALS pathophysiology will promote the
development of novel treatment and prevention strategies, such as genetic therapies for
asymptomatic carriers of highly penetrant pathogenic mutations.(73)

Molecular pathomechanisms in ALS

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In ALS, pathological processes arise from toxic gain-of-function or loss-of-function

mutations to the approximately 40 ALS genes known to date. Toxicity also occurs from
aggregates of both wild-type and mutant proteins, which is a universal pathological feature
in sporadic and familial ALS.(74) Pathophysiological processes broadly fall into four
major categories, impaired RNA metabolism, altered proteostasis/ autophagy, cytoskeletal/
trafficking defects, and mitochondrial dysfunction.(75) Several ALS genes, including
C9orf72, TARDBP, and FUS, impair RNA metabolism. Aggregation of the DNA/RNA
binding proteins, TDP-43 and FUS, into inclusions impairs their normal function, causing
broad changes to transcription and RNA processing. TDP-43, among several other ALS
genes, also dysregulates proteostasis and autophagy by preventing the clearance of
damaged proteins. Multiple mutant ALS genes, such as tubulin alpha 4a (TUBA4A) and
profilin 1 (PFN1), induce cytoskeletal and/or tubulin defects, blocking axonal trafficking.
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Mitochondrial dysfunction, as triggered by SOD1, is a central ALS characteristic, which

also increases oxidative stress.
Although much progress has been made, the full molecular underpinnings of ALS
pathophysiology are incompletely understood. In addition to the major abovementioned
processes, TDP-43 and SOD1 aggregates also transfer from cell-to-cell in prion-like
transmission,(76, 77) which would propagate ALS pathology. TARDBP, FUS, and a handful
of other genes, are linked to dysfunctional DNA repair in ALS; for instance, loss of
nuclear TDP-43 induces accumulation of double-stranded DNA breaks,(78) which would
compromise genome stability. TDP-43 aggregates,(79) mutant FUS,(80) and C9orf72 repeat
expansions(81) also impair nucleocytoplasmic transport, the shuttling of cargo between the
nucleus and cytoplasm.(79) Dipeptide repeat proteins derived from mis-translated C9orf72
expansion transcripts are neurotoxic and may promote heterochromatin anomalies(82) and
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TDP-43 aggregation.(83)
Central and peripheral inflammatory mechanisms are important contributors to ALS,(84)

both in the context of specific genetic mutations(85–87) and likely as a consequence
of the general disease process in sporadic disease.(88, 89) In ALS, changes occur in
specific immune cell levels,(88, 89) their activation state,(88) and cytokine production.
(86, 87) Importantly, immune system involvement in ALS is double-edged; a protective
initial response is overcome by a destructive cytotoxic phase.(84) Hypermetabolism is
also a broad ALS characteristic,(90) both dependent and independent of ALS mutations,
and metabolomics investigations(91) could shed light on the specific molecular changes
that underscore disease progression. Pathways related to ALS genes, inflammation,
hypermetabolism and other continued insights into the pathological mechanisms underlying
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ALS provide an essential knowledge base for ALS therapeutic development (see “Novel
ALS treatment approaches” section) and ALS prevention strategies.
Environmental exposure in ALS

The gene-time-environment hypothesis of ALS suggests that genetic susceptibility, age-
related cellular damage, and a burden of environmental exposures combine to trigger ALS.
(60) Several lines of evidence support this model. First, genetic variants do not fully account

for ALS.(92) Second, population-based modeling of ALS indicates that disease occurs
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in a multi-step process,(61) even in patients with highly penetrant monogenic mutations,

e.g., mutant SOD1.(93) Third, a growing body of research supports the association of
environmental exposures with disease risk, with a new focus on the ALS exposome.(59)
The ALS exposome is defined as the cumulative lifetime impact of environmental

exposures, including lifestyle factors. Since the exposome involves exposures throughout
a patient’s lifespan, multiple study designs are needed to interrogate its role in ALS. Many
case-control studies have explored the relationship between occupational, residential, and
avocational environmental risk factors on ALS risk. While studies leveraging population-
based registries would provide a higher level of evidence, studies based on retrospective
cohorts show reassuringly consistent results (Appendix Table 6).
Of exposures with documented relevance to ALS, plasma persistent organic pollutants(94)

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and blood metals(95),(96) correlate with disease risk and shortened survival.(72) Lifestyle
factors associate with ALS risk, including higher cigarette pack-years, a lower current body
mass index and lifetime alcohol consumption.(97) Some relationships are dependent on
C9orf72 status,(97) demonstrating an interaction between genes and environment. Physical
activity as an ALS risk is supported by several studies,(97, 98) including analysis of the
National Football League players.(99) Military service is also a recurring theme in ALS risk
assessments.(100)
There are important unanswered questions relating to the ALS exposome. Are there periods
of greater susceptibility to exposure throughout life, which increase ALS risk? Will it
be possible to adopt a preventative approach to ALS if modifiable risks are identified?
Prospective studies using well curated population registries and biorepositories can help
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answer these questions and are a future goal of the field.(59)
ALS prognosis
ALS prognosis is dependent on disease progression. Currently, clinicians monitor ALS
progression using the ALS functional rating score-revised (ALSFRS-R), a multidomain
assessment, which also serves as the gold standard for primary efficacy outcomes in clinical
trials.(101) Respiratory function, which is a domain of the ALSFRS-R, provides prognostic
information.(102) One shortcoming of the ALSFRS-R is that certain subscores increase with
symptom improvement despite continued underlying disease progression.(101, 103) The
Rasch-Built Overall ALS Disability Scale (ROADS) was designed to specifically capture
functional decline arising from the underlying disease course,(103) thereby overcoming the
limitations of the ALSFRS-R. The ROADS currently awaits clinical validation prior to
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widespread adoption.
New staging paradigms have also been developed to inform prognosis. Patients assessed
with these tools, the King’s(104) and ALS Milano-Torino Staging (ALS-MiToS),(105)
consistently progress along stages, which are associated with decreasing median survival
(Figure 4A–B). The King’s is more sensitive early in the disease course, the ALS-MiToS

later in the disease course.(106, 107) Neither staging system is yet in widespread clinical
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use.
Although median survival in ALS is only 2 to 4 years, there is a broad distribution of

individual patient survival, affecting both the clinician’s ability to discuss and the patient’s
ability to understand, disease prognosis. This is attributable to various factors that influence
ALS survival (Figure 4C), such as clinical and demographic features (e.g., age at onset, site
of onset, presence of FTD), genetic architecture (e.g., rapidly progressive SOD1A5V, slowly
progressive DCTN1 mutations; Appendix Table 5), and the exposome (e.g., environmental
exposures). The European Network for the Cure of ALS (ENCALS) model was created
to predict personalized survival (defined as survival without tracheostomy or non-invasive
ventilation >23 hours/day) based on eight parameters: onset age, time to diagnosis,
ALSFRS-R progression rate, forced vital capacity, bulbar onset, definite ALS by revised
El Escorial criteria, FTD, and C9orf72 repeat expansion (Figure 4D).(70) Although not in
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routine clinical use, the ENCALS prediction tool can potentially benefit patients by giving
them a more accurate perspective of life expectancy.
Overall, accurate prognostication of the clinical course of ALS remains in its infancy since
even predictions by the best models retain uncertainty. Thus, clinical care teams should
advise patients and their families on the anticipated disease course and range of expected
symptoms, with the caveat that these predictions can vary with each patient. Variation of
disease phenotypes even within the same family attests to this unpredictability. Finally,
although clinical staging methods provide useful metrics for comparing participant stages in
clinical research populations, their use in the clinic remains to be determined.
ALS treatment
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As ALS remains incurable, treatment is focused on using disease modifying therapies and
maximizing quality of life. The American Academy of Neurology, the European Federation
of Neurological Societies, the United Kingdom National Institute for Health and Care
Excellence (NICE)(108) and ALS Canada(109) have published evidence-based and expert
consensus guidelines for managing ALS, and supportive multidisciplinary care improves
survival and quality-of-life for ALS patients (Table 1).(110) The two medications with
approval in some countries for slowing ALS are riluzole and edaravone. Riluzole, an
anti-glutamate agent, improves ALS patient survival in clinical trials and post-marketing
analyses, but whether this prolongation occurs at all stages of ALS or just at advanced
disease stages remains a topic of debate.(116, 117) The antioxidant edaravone for 6 months
showed some efficacy in post hoc analysis of the first phase 3 trial for participants meeting
the criteria of definite or probable ALS (El Escorial and revised Airlie House diagnostic
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criteria), disease duration less than 24 months, FVC >80%, and ALSFRS-R subscale scores
all >2.(121) The trial was repeated prospectively using this defined patient population,
(118, 122) and again reported edaravone slowed disease progression. However, this trial
design may lack generalizability to the broader ALS patient population and post-marketing
analyses raise questions about edaravone’s safety and benefits.(119, 120) Thus, edaravone
use remains controversial and has not obtained worldwide approval. A combination of
dextromethorphan and quinidine is approved in the United States for managing symptoms

of pseudobulbar affect.(123) This drug is not marketed in all countries and alternative and
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more cost-effective treatments are available. Non-invasive ventilation also improves ALS
survival and quality of life.(124) For this reason, patients with ALS should be regularly
monitored for respiratory symptoms and undergo the appropriate respiratory assessments
such as overnight oximetry or measures for blood gas partial pressure of CO2, blood
bicarbonate levels, vital capacity, or maximum inspiratory pressure to confirm if they qualify
for non-invasive ventilation.(125)
Gastrostomy is also an effective therapy for supporting nutrition and is likely of

greater benefit when established earlier in the disease course. Gastrostomy tubes can be
inserted using percutaneous endoscopic gastrostomy, radiologically inserted gastrostomy,
and per-oral image-guided gastrostomy placement with similar mortality.(126) Factors
that associated with a poor outcome following gastrostomy include use of non-invasive
ventilation > 16 hours per day, older age, body mass index <20 kg/m2 and recurrent
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accumulation of airway secretions.(127) High calorie nutrition has also been investigated
for treating ALS(90) and post-hoc analysis of a phase 3 trial suggests that it might be helpful
for rapidly progressing patients,(128) though confirmatory trials are needed.
Additional treatments are outlined in Table 1. ALS patients may also contemplate
alternative and off label treatments, often found on the internet. ALS Untangled (https://
www.alsuntangled.com/), was conceived to provide a systematic review of unproven
treatments. ALS care guidelines encourage providers to have an open dialogue about the
use and risks of these treatments, especially as some can carry medical or financial risk.
Emerging directions in ALS

Novel ALS treatment approaches
Author Manuscript
Recognition of ALS heterogeneity, genetics, and a deeper understanding of pathophysiology

bring new treatment approaches to the ALS community. These span new trial designs to
address heterogeneity, genetic therapies, immune-targeting agents against inflammation, and
stem cells to enrich the CNS environment.
New trial designs: New ALS clinical trials can leverage a basket design of targeted
agents against phenotypically- or genetically-defined participant populations (see Genetic
therapies section).(129, 130) Novel platform trial paradigms simultaneously evaluate
multiple therapies in distinct arms against a single placebo group, lowering the number of
required participants and shortening trial duration.(129) Adaptive designs can further shorten
trial duration by response-adaptive randomization, which increases participant allocation
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to more promising arms.(129) Several major trials with novel compounds and treatment
approaches are currently underway (Appendix Table 7).
Genetic therapies: There is growing consensus that gene therapy is a promising avenue
in ALS. One strategy is silencing toxic gain-of-function genes by targeting mRNA and
pre-mRNA using antisense oligonucleotides (ASOs). The first clinical trial of the SOD1
ASO, BIIB067, demonstrated safety, evidence of target engagement, and promising trends
in exploratory secondary outcome measures.(131) However, the phase 3 clinical trial did

not meet its primary efficacy outcome of slowing disease progression as measured by the
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ALSFRS-R, though cerebrospinal fluid (CSF) SOD1 protein levels and neurofilament levels
were significantly decreased.(132) A new approach is earlier intervention with BIIB067
during the pre-symptomatic phase of disease in mutant SOD1 carriers (NCT04856982;
Appendix Table 7). Clinical trials are also underway of ASOs targeting other autosomal
dominant gain-of-function mutations, including C9orf72, FUS, and ATAXN2.(133)
Antibodies: Monoclonal antibodies against mutant C9orf72 and TDP-43 are in preclinical
development.(134) Several clinical trials have also been launched, but besides demonstrating
safety, none were effective, e.g., tocilizumab, ozanezumab.(134) A few antibody candidates
are still in the clinical trial pipeline, including AP-101 against SOD1 aggregates
(NCT05039099), ANX005 against C1q protein (NCT04569435), and AT-1501 against
CD40L protein (NCT04322149; Appendix Table 7).
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Immune-targeting: New anti‐inflammatory therapies targeting the immune system are

also in the clinical pipeline (Appendix Table 7). Phase 1/2 clinical trial results report that
low-dose IL-2 is well tolerated and immunologically effective in increasing regulatory T cell
numbers, although its effect on ALS progression is still being evaluated in a phase 2b/3 trial
(MIROCALS).(135) Autologous infusion of expanded Treg cells in a small patient cohort
slowed disease progression.(136) Masitinib, a tyrosine kinase inhibitor, reduces microglial
activation and showed promise in a phase 2/3 trial.(137) These reports underscore the
feasibility of immune-targeting drugs as ALS candidate therapies.
Stem cells: Stem cells offer the unique opportunity to simultaneously target multiple
dysregulated pathways while providing CNS neurotrophic support.(138) They can derive
from diverse sources, e.g., mesenchymal stem cells, neural progenitor cells (Appendix
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Table 7), each offering distinct advantages and disadvantages.(138) A recent meta-analysis
concluded that adult stem cells are safe and well tolerated;(139) however, apart from a
possible transient positive effect, trials have failed to demonstrate long-lasting efficacy from
stem cells.
Novel diagnostic ALS biomarkers

There is an urgent need for ALS biomarkers to expedite diagnosis, particularly in atypical
phenotypes, and enable improved prognosis of disease course. Biomarkers can also refine
clinical trial participant stratification, facilitate the estimation of progression rates, monitor
target engagement, and detect early potential treatment effects.
Neurofilaments: CSF and plasma neurofilaments are well-characterized and promising

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fluid biomarkers. Elevated CSF and plasma neurofilament light chain levels correlate with
shorter survival, more aggressive disease phenotypes, and presence of C9orf72 expansion.
(140–142) Plasma neurofilaments are also elevated up to five years prior to disease onset
in sporadic and familial ALS cases,(143, 144) and indicate phenoconversion in clinically
asymptomatic mutant SOD1 carriers.(143) Recent clinical trials support their use as
pharmacodynamic markers of ALS progression.(131, 145)

Brain imaging: While routine magnetic resonance tomography (MRI) cannot diagnose
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ALS, MRI with quantitative analysis of fluid-attenuated inversion recovery (FLAIR) can
identify increased corticospinal tract and corpus callosum intensities in ALS patients.(146)
More advanced structural and functional MRI techniques are not yet in routine clinical
practice but may provide new diagnostic biomarkers. Examples include diffusion tensor
imaging (DTI)(147, 148) and multimodal(147, 149) approaches, such as quantitative
susceptibility mapping to detect iron-related motor cortex changes and connectome analyses
of motor- and non-motor networks. T1-weighted imaging and DTI detects abnormalities
(cortical and subcortical atrophy, white matter changes), already present in presymptomatic
C9orf72 repeat expansion carriers.(150) While not a disease-specific biomarker, positron
emission tomography using tracers to quantify brain metabolism ([18F]-fluorodeoxyglucose)
or glial activation ([11C]-PBR28) provides new insights into disease mechanisms and may
prove useful as pharmacodynamic indices in future clinical trials.(151, 152)
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Neurophysiological: Neurophysiological markers of disease-associated changes are

currently available. Spectral electroencephalogram mapping reveals brain connectivity
changes in ALS, which correlate with MRI findings and could become useful, cost-effective
markers of cortical network disruption.(153, 154) Magnetoencephalography shows enhanced
connectivity during ALS progression.(155)
Cortical motor neuronal hyperexcitability can sometimes be detected by routine transcranial

magnetic stimulation (TMS); however, more often, refined techniques such as threshold-
tracking TMS measuring short-interval intracortical inhibition and intracortical facilitation
are necessary to detect subclinical UMN involvement.(156) Cortical hyperexcitability across
ALS phenotypes distinguishes ALS from non-ALS disorders, correlates with clinically
affected body regions,(157) disease spread,(157) and cognitive dysfunction.(158) TMS may
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also have a role in prognosis, with increased cortical hyperexcitability associated with longer
disease duration(159) and cortical inexcitability with poorer clinical trajectory.(160) Change
in short-interval intracortical inhibition was the primary endpoint in a phase 2 ALS trial of
retigabine, a potassium channel activator, demonstrating the potential of neurophysiological
outcome measures as pharmacodynamic disease markers.(161)
LMN degeneration can be quantified by the non-invasive motor unit index (MUNIX), which
correlates with the number of functioning motor units.(156) MUNIX detects motor unit
decline already in clinically unaffected muscle groups and can monitor motor unit loss over
time. When used as an outcome measure in clinical trials, MUNIX requires thorough rater
qualification to ensure reliability.(162)
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Conclusions
ALS remains difficult to diagnose and manage. This is due to heterogenous ALS
presentation and phenotype, and symptom and sign overlap with other illnesses. Earlier
on in the diagnostic process, physicians should refer patients presenting with progressive
dysarthria, dysphagia, limb weakness, or respiratory failure to a neurologist. This aligns
with suggestions by advocate groups, as they lobby to help patients seek early treatment
and enroll in clinical trials. Unfortunately, effective disease-modifying drugs are lacking, and

treatment revolves around multidisciplinary care to manage symptoms and aid end-of-life
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planning.
Research into improved diagnostic and prognostic tools could expedite diagnosis and
give patients a better understanding of their disease course. Thus, we anticipate future
directions in clinical ALS management will move towards simpler diagnostic criteria, such
as the Gold Coast, and widespread genetic testing. Research will evaluate whether newly
developed scoring, staging, and predictive tools will give patients meaningful and accurate
insight into their anticipated clinical trajectory. Pathophysiology research and novel trial
designs are developing rational, targeted candidates, which are passing through the clinical
testing pipeline more efficiently. We anticipate that these research efforts will translate into
improved outcomes for current and future patients with ALS.
Search strategy and selection criteria

Author Manuscript
We searched PubMed for English language articles from September 15th, 2021, to
October 5th, 2021, and then again January 2022, with the terms, in addition to
“amyotrophic lateral sclerosis”: Epidemiology section: “epidemiology”. ALS clinical
presentation section: “phenotype”. ALS diagnosis section: “diagnostic”, “diagnosis”,
“cognition”, and “cognitive”. ALS genetic architecture section: “GWAS,” “genetic”,
“risk”, “oligogenic”, “polygenic”, “heritability”. Differential diagnosis section: “mimic”,
“GWAS” combined with every ALS gene in turn. ALS risk, progression, and
pathophysiology section: “pathophysiology”, “mechanism”, “nucleocytoplasmic transport”,
“cell-to-cell transmission”, “immune system”, “exposure”, “environment”, “pollutant”,
“toxin”, “metals”, “traffic”. ALS prognosis: “prognosis”, “scoring”, “scaling”, “staging”.
ALS treatment: “multidisciplinary care”, “riluzole”, “edaravone”, “non-invasive ventilation”,
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“gastrostomy”. Emerging directions in ALS: “gene therapy”, “antisense oligonucleotide,

“antibody,” “immune,” “clinical trial”, “neurofilaments”, “imaging”, “PET”, “connectome”,
“EEG”, “hyperexcitability”. The search focused on articles published from Jan 1st, 2017, to
Jan 31st, 2022, though seminal older articles were also considered. We also included articles
from the authors’ personal reference lists. Selected articles were based on relevance to this
review. Additionally, we searched clinicaltrials.gov for “amyotrophic lateral sclerosis”.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Author Manuscript
SAG and ELF receive funding from the National ALS Registry/CDC/ATSDR (1R01TS000289; R01TS000327);
National ALS Registry/CDC/ATSDR CDCP-DHHS-US (CDC/ATSDR 200-2013-56856); NIEHS K23ES027221;
NIEHS R01ES030049; NINDS R01NS127188; NINDS R01NS120926; ALS Association 20-IIA-532;
NeuroNetwork for Emerging Therapies, the NeuroNetwork Therapeutic Discovery Fund, the Peter R. Clark Fund
for ALS Research, the Sinai Medical Staff Foundation, Scott L. Pranger, University of Michigan. LM research is
partly funded by the AGING Project for Department of Excellence at the Department of Translational Medicine
(DIMET), Università del Piemonte Orientale, Novara, Italy. PJS receives funding from the National Institute for
Health Research (NIHR), including for the NIHR Sheffield Biomedical Research Centre, UK Medical Research
Council, LifeArc, Motor Neurone Disease Association, MyName’5 Doddie Foundation, the Darby Rimmer
Foundation, the Nick Smith Foundation, Fight MND, EU Innovative Medicines Initiative, EU Innovative Training

Network, and EU Horizon 2020. SG is supported by Japan Agency for Medical Research and Development, AMED
under Grant Number JP21wn0425009h0001, JP21ak0101111h0003, JP21ak0101124h0002, JP21ek0109492h0002.
Author Manuscript
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Panel 1.
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Definitions of ALS motor signs and phenotypes

Lower motor neurons (LMN): Brainstem cranial motor nerve nuclei or anterior horn
cells; LMN dysfunction is characterized by muscle weakness, atrophy, and fasciculations.
Upper motor neurons (UMN): Betz cells in layer 5 of the primary motor cortex; UMN
dysfunction is characterized by increase and pathologic reflexes (including Hoffmann,
Babinski, snout), pathologic spread of reflexes, preserved reflexes in a weak limb, and/or
spasticity.
Bulbar ALS: Phenotype presents with weakness starting in the muscles controlling
speaking and swallowing. Both LMN and UMN signs are present.
Pseudobulbar palsy: A nonclassical subset of bulbar onset, characterized by prominent

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bulbar features, predominantly from UMN signs, which slowly spread to limbs.
Pseudobulbar affect (PBA): Uncontrollable emotional outbursts, including laughing,

crying, and excessive yawning.
Classical ALS: Phenotype presents with muscle weakness starting in the limbs. Both
LMN and UMN signs are present.
Cervical onset ALS: A subset of classical ALS with weakness commencing in the upper
limbs, especially hand weakness.
Lumbar onset ALS: A subset of classical ALS with weakness commencing in the lower
limbs, especially foot drop.
Flail arm: Prominent LMN dysfunction initially causing proximal > distal muscle
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weakness in the arms. Unlike progressive muscular atrophy, patients with flail arm do
manifest progressive UMN dysfunction. This entity may also be referred to as brachial
amyotrophic diplegia.
Flail leg: LMN dysfunction causing muscle weakness in the legs. Unlikely progressive
muscular atrophy, this phenotype does not generalize or generalizes very slowly.
Primary lateral sclerosis*: UMN dysfunction causing weakness in muscles controlling

limbs, swallowing, and speaking. Less commonly causes respiratory dysfunction.
Pyramidal: Like PLS but additionally eventually exhibiting LMN signs.

Progressive muscular atrophy*: LMN dysfunction causing weakness in muscles
controlling limbs, swallowing, speaking, and respiratory function.
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Respiratory onset: LMN and UMN dysfunction causing weakness commencing in the
respiratory muscles.
Hemiplegic: Predominantly UMN dysfunction causing muscle weakness in one side of

the body.
Cachexia: Unexplained weight and muscle loss.

*This review considers primary lateral sclerosis and progressive muscular atrophy are on
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the spectra of ALS phenotypes, although they may also be considered as separate clinical
entities.
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Panel 2.
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ALS diagnosis
Clinical history: Symptoms (e.g., weakness, time course) and family history of ALS or
other neurodegenerative diseases.
Neurological examination: Signs of UMN and LMN dysfunction in bulbar, cervical,

thoracic, and/or lumbosacral segments, e.g., hand weakness (split hand), foot
drop. Unexplained weight loss, cognition or executive functioning dysfunction, and
pseudobulbar affect are additional signs.
Electrodiagnostic testing: Nerve conduction studies and needle electromyography to

confirm LMN signs.
Laboratory testing: Serology should be normal except for elevated creatine

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phosphokinase levels, which can also lead to abnormal liver function tests.
Magnetic resonance imaging (MRI): Imaging the spinal cord by MRI is essential to rule
out more common differential diagnoses, e.g., disc herniation, cord compression.
Criteria: Most neurologists employ the revised El Escorial criteria.(32)

Classifies ALS patients as possible, probable, probable laboratory supported, and
definite, based on clinical presentation and electrodiagnostic findings.
The revised El Escorial criteria are:
(A) Presence of:
(A:1) LMN signs by clinical, electrodiagnostic testing, or neuropathologic exam,

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(A:2) UMN signs by clinical examination, and
(A:3) progressive symptom or sign spread within a region or to other regions, as

determined by history or exam,
With:
(B) Absence of:
(B:1) electrodiagnostic or pathological evidence of other diseases explaining LMN and/or

UMN signs, and
(B:2) neuroimaging evidence of other diseases explaining the observed clinical and
electrodiagnostic signs.
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The diagnostic categories are:
Clinically definite: Clinical evidence of (1) UMN + LMN signs in the bulbar and two
spinal regions OR (2) UMN + LMN signs in three spinal regions.
Clinically probable: Clinical evidence of UMN + LMN signs in at least two regions with
UMN signs rostral to LMN signs.

Clinically probable – laboratory supported: Clinical evidence of (1) UMN + LMN signs
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in one region or UMN signs alone in one region AND (2) LMN by electrodiagnostic
criteria in at least two regions.
Clinically possible: Clinical evidence of (1) UMN + LMN in one region OR (2) UMN
signs in two or more regions OR (3) LMN signs are rostral to UMN signs.
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Figure 1. ALS phenotypic variation and spectrum with FTD.

(A) Schematic showing upper motor neurons (UMN; blue), which relay signals from
the motor cortex to the lower motor neurons (LMN; yellow, i.e., cranial motor nerve
nuclei in the brainstem and anterior horn cells in the spinal cord), which relay signals
to the muscles. Motor neurons connecting within the brain stem innervate, among other
muscles, cranial muscles. Initial UMN and LMN degeneration in the brain stem are linked
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to bulbar onset ALS. Motor neurons connecting within the cervical region of the spinal
cord innervate, among other muscles, upper limb and respiratory muscles. Motor neurons
connecting within the thoracic and lumbar regions of the spinal cord innervate, among
other muscles, accessory respiratory, abdominal, and lower limb muscles. Initial UMN and
LMN degeneration in the cervical and lumbar regions are linked to spinal onset ALS. (B)
ALS patients can present with signs of UMN (blue), LMN (yellow), and combined UMN
+ LMN (green) dysfunction. Most common ALS phenotypic presentations are bulbar and
classical spinal limb onset (cervical, lumbar). Less common ALS phenotypic presentations

are flail leg, pyramidal, flail arm, primary lateral sclerosis (PLS), progressive muscular
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atrophy (PMA), respiratory onset, and hemiplegic. Proportion of various ALS phenotypes
shown in the figure as the percentage (%) of a total representative ALS population.(14, 17)
Pyramidal is predominantly UMN, as shown in the figure, but still exhibits some LMN
signs, differentiating it from PLS. See Appendix Table 1 for more information. (C) ALS
occurs on a continuum with FTD. ALS is on one end of the spectrum and presents with
pure motor signs from UMN + LMN neurodegeneration (green, spinal cord and motor
cortex degeneration). FTD is on the other end of the spectrum and presents with behavioral
and/or cognitive deficits from frontotemporal neurodegeneration (purple frontotemporal lobe
degeneration). After pure ALS are ALS patients not meeting FTD criteria, defined as ALS
cognitive impairment (ALSci), ALS behavioral impairment (ALSbi), and ALS cognitive and
behavioral impairment (ALScbi) (green, spinal cord and motor cortex degeneration; small
purple sphere of frontotemporal lobe degeneration). Next are ALS patients meeting FTD
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criteria, defined as ALS-FTD (green, spinal cord and motor cortex degeneration; purple
frontotemporal lobe degeneration). Patients on the remainder of the continuum have FTD
but do not meet the criteria for ALS. Patients still exhibiting evidence of motor neuron
disease (MND) with FTD are defined as MND-FTD (dark grey, spinal cord and motor cortex
degeneration; purple frontotemporal lobe degeneration) and patients with no MND signs
have FTD (purple, frontotemporal lobe degeneration).
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Figure 2. ALS genetic architecture.

ALS genetics is characterized by monogenic, oligogenic, and polygenic risk; image
featuring only three representative chromosomes (within each panel, chromosomes on the
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left for healthy person, on the right for person with ALS). (A) Monogenic inheritance in
ALS, characterized by inheritance of a single gene. (B) ALS genes are not fully penetrant
and pathogenicity of certain variants is uncertain. Left: In a population of gene carriers,
low penetrance variants lead to a low frequency of ALS onset (red figures). Right: In
a population of gene carriers, high penetrance variants lead to a high frequency of ALS
onset (red figures). (C) Oligogenic inheritance in ALS, characterized by inheritance of
several genes (four shown in the figure). (D) Polygenic inheritance in ALS, characterized

by inheritance of many genes (nine shown in the figure). Created with BioRender.com.
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Adapted, with permission, from Goutman et al. The Lancet Neurology, 2022.
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Figure 3. ALS differential diagnosis.

Differential diagnosis, represented here by a flowchart for the classical process using
symptoms and signs, is central to the diagnostic process in ALS. At minimum, individuals
suspected of ALS will undergo physical and neurological exams, electrodiagnostic
assessment, MRI of involved regions, and relevant serological testing. This figure is
based on a summary of potential differential diagnoses for diseases more common or as
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common as ALS is outlined in Appendix Table 3. Overlap of known ALS genes with
other diseases and syndromes also occurs and is outlined in Appendix Table 4. CFS, cramp-
fasciculation syndrome; CIDP, chronic inflammatory demyelinating polyneuropathy; HSP,
hereditary spastic paraparesis; IBM, inclusion body myositis; LMN, lower motor neuron;
MMN, multifocal motor neuropathy; MG, myasthenia gravis; PPMS primary progressive
multiple sclerosis; rEEC, revise El Escorial criteria; SBMA, spinobulbar muscular atrophy;
UMN, upper motor neuron. *Several potential differential diagnoses present with proximal

weakness and should be considered along with flail arm ALS, which also presents with
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proximal greater than distal upper extremity weakness. Thus, check for increased proximal
reflexes on exam and neurogenic motor unit action potentials on electromyography.
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Figure 4. ALS risk and prognosis.

(A) King’s staging with four stages indicated (1, 2A/B, 3, 4A/B; blue); time to progress to
stages and median survival at each stage (in months) are also annotated. (B) ALS-MiToS
staging with six stages indicated (0, 1, 2, 3, 4, 5; orange); staging based on four functional
domains from the ALSFRS-R: (i) movement (walking/self-care; ALSFRS-R question 6 or
8); (ii) swallowing (ALSFRS-R question 3); (iii) communicating (ALSFRS-R questions
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1 and 4), and (iv) breathing (ALSFRS-R question 10 or 12). Intensifying color indicates
progression along stages for both King’s and ALS-MiToS. (C) Schematic overview of
factors that affect ALS risk (onset) and prognosis, which include clinical and demographic
features (e.g., age at onset, segment onset, ALSFRS-R progression rate, forced vital
capacity, FTD), genetic architecture (e.g., rapidly progressive SOD1A5V, slowly progressive
DCTN1 mutations), and exposome (e.g., environmental exposures). (D) ENCALS prediction
model of ALS prognosis, represented, with permission, from Westeneng, The Lancet

Neurology, 2018.(70) The model leverages 8 clinical predictors to the composite endpoint
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(survival without tracheostomy or non-invasive ventilation >23 hours per day): age at onset,
time to diagnosis, ALSFRS-R progression rate, forced vital capacity, bulbar onset, definite
ALS by revised El Escorial criteria, FTD, and C9orf72 repeat expansion. Top: The model
defines five survival groups: very short (red; predicted median survival [MS] 17·7 months),
short (orange; predicted MS 25·3 months), intermediate (light orange; predicted MS 32·2
months), long (light green; predicted MS 43·7 months), and very long (predicted MS
green; 91·0 months). The dashed black line represents MS without employing the ENCALS
prediction model, which is overly optimistic for ALS patients classified to the very short
and short survival groups, i.e., they end up with less time, and overly pessimistic for
patients classified to long and very long groups, i.e., they end up with more time. Bottom:
Horizontal bars have dots to represent median times to composite outcome, thick lines
to represent probability interquartile range, thin lines to represent 10 to 90% probability
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intervals to composite outcome. Created, in part, with BioRender.com.

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Table 1.
ALS management
Indication Treatments and interventions*
Disease-modifying treatments
Feldman et al.
Only two drugs with regulatory approval are available, riluzole and edaravone. They are of marginal efficacy and only in select populations and merely lengthen survival
Disease progression
by a few months;(116–118) however, even within select populations, the efficacy of edaravone is contested.(119, 120)
Symptomatic management
A multidisciplinary clinic plans the comprehensive, multidisciplinary care needed to manage symptoms in ALS patients. Care spans managing respiration and oral
Comprehensive care
symptoms (speech, swallowing) nutrition and gastrointestinal symptoms, pain and symptoms secondary to muscle loss, and cognition, mood and behavioral changes.
Respiratory and oral symptoms

Cease provoking medications. Administer mucolytics if the patient exhibits sufficient cough flow, which includes N-acetylcysteine, anticholinergic bronchodilator,
β-receptor antagonist and nebulized saline, furosemide, and guaifenesin. Mechanical or non-pharmacological approaches are also available, which include manual
Bronchial secretions
assisted cough, mechanical insufflator-exsufflator, portable home suction device, and room humidifier. Additionally, patients are encouraged to remain hydrated or drink
pineapple or papaya juice to break up secretions.
Evaluate speech-language regularly and identify language impairments. Provide assistive communication tools, such as electronic writing, voice banking, and voice
Dysarthria
amplification devices.
Dyspnea Options include elevating the head of the bed, use of a hospital bed for elevation, noninvasive ventilation, and invasive tracheostomy ventilation.
Administer anticholinergics, such as amitriptyline, atropine ophthalmic drops, glycopyrrolate, scopolamine patch. If sialorrhea is refractory to anticholinergics,
Sialorrhea botulinum toxin injections, external beam radiation therapy, and surgery may be considered. A portable suction device is a less aggressive approach. Dark grape juice
and ginger tea are reported to decrease saliva production.
Nutrition and gastrointestinal symptoms

Constipation Increase fluid and fiber intake or adjust enteral nutrition. Administer an osmotic or stimulant laxative. Increase physical activity.
Evaluate speech-language pathology regularly and provide swallowing technique education. Gastrostomy feeding tube placement by percutaneous endoscopic
Dysphagia gastrostomy, radiologically inserted gastrostomy, or per-oral image-guided gastrostomy. Ideally, gastrostomy placement should occur early in the disease course
prior to significant weight loss.

Nutrition Dietary evaluation by a nutritionist and modify food and fluid consistency accordingly. Administer appetite stimulants and/or high-protein/high-caloric supplements.
Pain and symptoms secondary to muscle loss

Administer magnesium, levetiracetam, mexiletine, or quinidine (controversial). Non-pharmacological approaches span physiotherapy, exercise, massage, and
Cramps
hydrotherapy. Hydration with tonic water.
Administer analgesics, including acetaminophen and nonsteroidal anti-inflammatory drugs. Non-pharmacological approaches span physical therapy, especially to limit
Joint pain
joint contractures, and repositioning, pressure relief, mechanical support for weak limbs.
Administer spasmolytic drugs (tizanidine, baclofen, intrathecal baclofen pump), benzodiazepines, dantrolene, or botulinum toxin injections. Tetrahydrocannabinol is a
Spasticity
novel direction. Non-pharmacological approaches include stretching and range of motion physical therapy.
Venous thromboembolism Administer anticoagulants. Non-pharmacological preventive approaches span physiotherapy, limb elevation, and compression stockings.
To address upper limb weakness, occupational therapy for adaptive equipment and hand splints. To address lower limb weakness, physical therapy, which includes
Weakness transfer and gait assessments.
Fall prevention. Various aids, such as ankle-foot orthoses, Hoyer lift, walker, transport wheelchair, and powered wheelchair.
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Indication Treatments and interventions*
Disease-modifying treatments
Mood
Depression and anxiety Administer antidepressants or anxiolytics. Non-pharmacological approaches span psychotherapy and counseling.
Feldman et al.
Fatigue Address related symptoms (e.g., sleep disturbances, depression, cramps, pain, respiratory distress). Encourage patients to conserve energy.
Insomnia Address related symptoms (e.g., depression, cramps, pain, respiratory distress). Monitor sleep hygiene and address the role of noninvasive ventilation.
Administer tricyclic antidepressants, selective serotonin reuptake inhibitors (fluvoxamine, citalopram), or dextromethorphan-quinidine. Educate patients that these are
Pseudobulbar affect
ALS symptoms.
Care planning
Cognitive dysfunction Encourage early discussions regarding treatment goals while the patient still retains decision-making capacity. Educate family and caregivers. Respite care.
Administer benzodiazepine and/or opioids for symptomatic dyspnea or intractable pain. Encourage early conversations with patients, family members, and caregivers
Palliative and end-of-life care
regarding treatment choices. Palliative care referral can occur early in the disease course with hospice care at end of life.
Sources: EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis,(62) The American Academy of Neurology,(111–113) the United Kingdom National Institute for Health and
Care Excellence (NICE),(108) ALS Canada(109) and other Canadian guidelines,(114) and Bradley and Daroff’s Neurology in Clinical Practice.(115) These therapies, in most cases, represent good clinical
practice as few clinical trials involving patients with ALS exist to provide a robust evidence base for these interventions.

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Published in final edited form as:

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis; biomarker; clinical overlap; diagnosis; epidemiology; exposome;

Lancet. Author manuscript; available in PMC 2023 October 15.

ALS clinical presentation

ALS cognitive and behavioral changes

Lancet. Author manuscript; available in PMC 2023 October 15.

Collectively, this new understanding of ALS as a multi-system disorder underscores

Clinical history and neurological examination are accompanied by serological and

Lancet. Author manuscript; available in PMC 2023 October 15.

ALS cognitive assessment

Lancet. Author manuscript; available in PMC 2023 October 15.

patients, which can be administered by neuropsychological and non-neuropsychological

professionals.(37) ECAS, available in 23 languages, covers the largest number of

Overall, it is important to recognize that cognitive symptoms are a manifestation of

ALS genetic architecture

Lancet. Author manuscript; available in PMC 2023 October 15.

In addition to primary monogenic inheritance in ALS, interest in the impact on oligogenic

to bear fruit and foster further investigation.

Importantly, ALS is also characterized by incomplete heritability, meaning genetics does

Lancet. Author manuscript; available in PMC 2023 October 15.

Differential diagnosis and overlap syndromes

In conjunction with clinical presentation, genetic testing is increasingly utilized to explain

ALS risk, progression, and pathophysiology

Lancet. Author manuscript; available in PMC 2023 October 15.

Molecular pathomechanisms in ALS

In ALS, pathological processes arise from toxic gain-of-function or loss-of-function

Mitochondrial dysfunction, as triggered by SOD1, is a central ALS characteristic, which

Central and peripheral inflammatory mechanisms are important contributors to ALS,(84)

Environmental exposure in ALS

Lancet. Author manuscript; available in PMC 2023 October 15.

in a multi-step process,(61) even in patients with highly penetrant monogenic mutations,

The ALS exposome is defined as the cumulative lifetime impact of environmental

Of exposures with documented relevance to ALS, plasma persistent organic pollutants(94)

answer these questions and are a future goal of the field.(59)

Lancet. Author manuscript; available in PMC 2023 October 15.

Although median survival in ALS is only 2 to 4 years, there is a broad distribution of

Lancet. Author manuscript; available in PMC 2023 October 15.

Gastrostomy is also an effective therapy for supporting nutrition and is likely of

Emerging directions in ALS

Recognition of ALS heterogeneity, genetics, and a deeper understanding of pathophysiology

Lancet. Author manuscript; available in PMC 2023 October 15.

Immune-targeting: New anti‐inflammatory therapies targeting the immune system are

Novel diagnostic ALS biomarkers

Neurofilaments: CSF and plasma neurofilaments are well-characterized and promising

Lancet. Author manuscript; available in PMC 2023 October 15.

Neurophysiological: Neurophysiological markers of disease-associated changes are

Cortical motor neuronal hyperexcitability can sometimes be detected by routine transcranial

Lancet. Author manuscript; available in PMC 2023 October 15.

Search strategy and selection criteria

“gastrostomy”. Emerging directions in ALS: “gene therapy”, “antisense oligonucleotide,

Lancet. Author manuscript; available in PMC 2023 October 15.

in worldwide incidence of amyotrophic lateral sclerosis: a meta-analysis. Int J Epidemiol.

Lancet. Author manuscript; available in PMC 2023 October 15.

Neurol Neurosurg Psychiatry. 91 2020. p. 779–80. [PubMed: 32404381]

database. BMC Neurol. 2013;13:160. [PubMed: 24499173]

Lancet. Author manuscript; available in PMC 2023 October 15.

2018;4(3):e239. [PubMed: 29845113]

Lancet. Author manuscript; available in PMC 2023 October 15.