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Amyotrophic lateral sclerosis (ALS), also known as “Lou Gehrig’s disease”, is a rapidly progressive neurodegenerative disease affecting voluntary motor control. ALS classically is characterized by a combination of both upper and lower motor neuron degeneration. ALS exists on a spectrum of motor neuron disease. Presentations with purely upper motor neuron symptoms are classified as primary lateral sclerosis (PLS) while those with purely lower motor neuron symptoms are classified as progressive muscular atrophy (PMA).


Most (90-95%) of ALS cases are classified as “sporadic ALS” (sALS) with no prior family history of disease. Up to 10% of ALS cases are classified as “familial ALS” (fALS) with positive family history in at least one other family member. There are roughly 50 identified genetic mutations associated with ALS, the majority of which are inherited in an autosomal dominant pattern. The most common (30-40%) cause of fALS is a hexanucleotide (GGGGCC) repeat expansion in the non-coding region of chromosome 9 open reading frame 72 (C9ORF72). The second most common (15-20%), but first identified, cause of fALS are mutations in the superoxide dismutase 1 (SOD1) gene. Other less common genetic causes of fALS include mutations in fused in sarcoma (FUS) gene and transactivation response DNA-binding protein (TARDBP) gene.1

Epidemiology including risk factors and primary prevention

  • Global incidence is 1 to 2 per 100 0002
  • Lifetime risk of sALS is 1/600 to 1/20002
  • Peak incidence occurs in ages 65 to 74 years, with average onset of age 65.3
  • The incidence is 20% to 60% higher in men than women
  • Exposure to heavy metals, electromagnetic fields, pesticides, smoking and head injury have all been linked to increased incidence of ALS, however a strong association has only been shown with pesticide exposure4
  • Service in the military has been correlated with increased incidence of ALS however no causal link has been identified3
  • Survival is reported to vary from 20-48 months after symptom onset. However, there is wide variability with up to 10% of patients surviving longer than 10 years. Respiratory and bulbar involvement were previously associated with poorer prognosis, however with adequate ventilatory support and nutrition supplementation these patients have a much wider range of survival.5


The pathophysiology of ALS is still not well understood; there appears to be a complex interaction between both genetic and environmental factors that contribute to the onset of disease6.

Neurotoxicity is thought to occur from both glutamate excitotoxicity from reduced uptake in the synaptic cleft as well as activation of microglia and the release of inflammatory cytokines.

C9ORF72, TDP-43, and FUS mutations cause in abnormal RNA translation leading to formation of intracellular aggregates. SOD-1 mutations cause increased oxidative stress leading to mitochondrial dysfunction

Recently, transcranial magnetic stimulation studies have suggested that cortical hyperexcitability may play a major pathophysiological role

Specific secondary or associated conditions and complications

There are many secondary conditions that result from ALS.

  • Restrictive lung disease (RLD) is arguably the most important condition caused by ALS. Majority of mortality is caused by advanced RLD and subsequent respiratory failure
  • Dysphagia
  • Dysarthria
  • Sialorrhea
  • Muscle weakness
  • Malnutrition
  • Depression/adjustment disorder
  • Cognitive impairment. Frontotemporal dementia is thought to be on the same spectrum of disease as ALS and is most associated with TDP-43 mutations
  • Spasticity
  • Muscle cramping
  • Fatigue
  • Neurogenic bowel and bladder. Previously ALS was thought not to affect the bowel and bladder systems, however more recent studies have shown increased prevalence of constipation and urinary incontinence7

Essentials of Assessment


History is variable and dependent on the site of onset. Most patients present with painless weakness and atrophy, although associated stiffness is common. Some patients present with dysphagic symptoms, and with insidious onset of respiratory dysfunction or inability to wean from a ventilator after an illness or surgery

Physical examination

Physical examination should include thorough assessment of the 4 body regions (cranial, cervical, thoracic, lumbosacral) for the presence of upper and lower motor dysfunction. The following table illustrates exam findings that can be seen in ALS patients

Body regionUpper motor neuron signsLower motor neuron signs
CranialSpastic dysarthria, laryngospasm, palmomental reflex, jaw-jerk reflexSlurring of speech, tongue atrophy, tongue fasciculations, temporal wasting, decreased soft palate elevation
CervicalLimb spasticity, hyperreflexia, Hoffman’s signMuscle weakness/atrophy, muscle fasciculations, hyporeflexia
ThoracicNoneAccessory muscle use with respiration, paradoxical breathing
LumbosacralLimb spasticity, hyperreflexia, cross-adductor reflex, upgoing Babinski signMuscle weakness/atrophy, muscle fasciculations, hyporeflexia

Figure 1. Upper and Lower motor neuron signs by body region

Functional assessment

Functional assessment is variable depending on the location of first involvement and the rate/location of progression, but should be comprehensive to include mobility, activities of daily living, speech and swallowing, respiratory status, cognition and behavior, and affective state.


  • Cervical spine magnetic resonance imaging (MRI) is recommended to rule out myelopathy; however, it is rarely utilized for diagnostic purposes, despite usual anterior horn involvement8
  • Brain MRI is recommended to evaluate for abnormalities in the motor tracts and to rule out multiple sclerosis. ALS-associated findings include atrophy of precentral gyri, temporal cortex, parietal cortex, frontal lobe, with poor survival correlated to volume loss in basal ganglia and limbic structures8

Supplemental assessment tools

In addition to history and physical examination, other assessments aid in the diagnosis of ALS. These include laboratory tests, electrodiagnostic testing, pulmonary function testing, as well as imaging mentioned above.

  • Electrodiagnostic studies are an extension of the history and physical examination and should be performed on all patients suspected to have ALS. As well as assisting in diagnosis, electrodiagnostic studies provide information about chronicity and extent of disease. Nerve conduction studies should be used to evaluate for peripheral neuropathy mimicking ALS and should include both motor and sensory studies of the upper and lower extremities with at least one side to side comparison. F waves minimum latencies can be prolonged in ALS but are nonspecific findings. Similarly, repetitive stimulation studies have been shown to have decrement in ALS with one study reporting CMAP amplitude decrease of at least 10% in the median nerve of 34% of patients examined. Needle electromyography should be performed to evaluate for a combination of acute (fibrillations, positive sharp waves) and chronic (long duration, large amplitude motor unit potentials) neurogenic abnormalities and should include examination of sufficient body regions to meet diagnostic criteria as described below9.  In addition, there must be evidence of progression over time and absence of electromyographic or neuroimaging evidence of another disease process that might explain the observed clinical signs.
Definite ALSUMN and LMN signs in 3 body regions
Probable ALSUMN and LMN signs in >=2 body regions with UMN signs rostral to LMN signs
Probable ALS-laboratory supportedUMN and LMN signs in 1 body region with EMG evidence of LMN involvement in another region
Possible ALSUMN and LMN signs in 1 body region OR only UMN signs in >=2 body regions

Figure 2. Revised El-Escorial Criteria. UMN- upper motor neuron, LMN- lower motor neuron, body regions- cranial, cervical, thoracic, lumbosacral

The Awaji-Shima criteria is similar to the el Escorial criteria except that it assigns equal importance to fasciculation potentials as fibrillations and positive sharp waves9. These criteria have been described as too restrictive for inclusion in clinical trials and recently the Gold Coast criteria was developed to address this issue.

Figure 3. Gold Coast Criteria

The Gold coast criteria has been found to have higher sensitivity for ALS diagnosis than the El Escorial and Awaji-Shima criterion10.

  • Pulmonary function testing (PFT) including measurement of forced vital capacity (FVC), minimum inspiratory pressure (MIP), minimum expiratory pressure (MEP), and peak cough should be performed on initial examination to evaluate for evidence of restrictive lung disease. Nocturnal pulse-oximetry studies can be performed to evaluate for nocturnal hypoventilation if PFT is borderline.
  • Laboratory testing should be performed to evaluate for other diseases mimicking ALS. Anti-GM1 antibodies should be tested to evaluate for multifocal motor neuropathy. Creatinine kinase (CK) levels may indicate the presence of primary muscle disease however these values should be interpreted carefully as mild-moderate elevation can be seen in ALS. Vitamin B12 and copper deficiencies can cause myelopathy. Myasthenia gravis antibodies (acetylcholine receptor, MUSK, LRP4) can be sent to evaluate for neuromuscular junction disorders. Infectious causes of myelopathy and motor neuron disease can be assessed with HTLV-1 and HIV viral load.

Early predictions of outcomes

Probability of death within 12 months is increased with the following characteristics11:

  • Age at diagnosis- Patients above the age of 75 at diagnosis have shown a 6 times higher mortality within 12 months than patients 65 years and younger at diagnosis
  • Body mass index (BMI) decrease– Patients having a BMI decrease of >=2 units within the past 6 months preceding diagnosis have been shown to have increased mortality within 12 months
  • Advanced functional impairment– Patients with an ALS function rating scale (ALS-FRS) <32 at diagnosis have been shown to have increased mortality within 12 months

Respiratory variables such as FVC (<75%) are associated with poor prognosis over the course of disease but have not been shown to be a predictor of one year mortality from time of diagnosis.


Evaluation of patient’s environmental surroundings should be a key component of the initial history. Elements such as availability of caregiver support, household accessibility, job requirements should all be elicited. The role of social workers in a multidisciplinary clinic is invaluable to help find solutions for any of these factors that may lead to increased caregiver burden and applying for disability services. Home evaluation by physical and occupational therapists is useful prior to obtaining durable medical equipment (DME) such as power wheelchairs, Hoyer lift devices, grab bars, shower chairs, bedside commodes.  

Social role and social support system

  • Keeping individuals engaged in their work and filial roles as long as possible is important: balance must be achieved between energy-conserving interventions to maintain these roles in the near future, and planning for inevitable loss of function in the distant future
  • Caregiver support should include assisting informal caregivers to consider and purchase nursing care/home health aides/companions to decompress them from basic personal care so that household management can occur

Professional Issues

  • Disclosing the diagnosis should be done as soon as diagnostic certainty is established
  • Life sustaining interventions such as noninvasive ventilation, enteral feeding, and emergency life support measures should be discussed early in the disease process
  • End of life issues such as tracheostomy, do not resuscitate orders, advanced directives should be discussed in timely manner

Rehabilitation Management and Treatments

Available or current treatment guidelines

Current treatment guidelines are available.12

At different disease stages

There is no known cure for ALS. Patients with ALS have heterogeneous symptoms severity independent of chronicity therefore all secondary conditions should be assessed at each patient appointment. Referral should be made to a multidisciplinary ALS center for treatment as this has shown to prolong mortality and improve patient quality of life with earlier patient use of noninvasive ventilation and enteral feeding13.


Medications are approved by the United States Food and Drug Administration for the treatment of ALS12,13.

  • Riluzole (Rilutek) may slow disease progression and should be offered to all patients with ALS. In patients with an FVC>60% and disease duration <5 years, riluzole has been shown to prolong tracheostomy free survival by an average of 2-3 months however some studies suggest a larger benefit. Fatigue and nausea are common side effects, liver function testing must be performed regularly to monitor for elevations in liver enzymes.
  • Radicava (Edaravone) has been reported to provide functional improvement in a subset of patients with ALS and should be offered to all patients who meet those criteria. A slowing of decline in reported ALS-FRS scores was seen in patients with FVC>80%, disease duration <2 years, and initial ALS-FRS with score >=2 in each category. This medication is administered as an infusion over 14 days a month, patients who elect this treatment should be referred to interventional radiology for port placement.
  • Patients can take both riluzole and radicava simultaneously.

Restrictive Lung Disease

  • Pulmonary function testing should be performed every 3 months. Standard measures to perform are FVC, MIP/MEP, and peak cough as mentioned in above sections
  • Nocturnal pulse-oximetry should be used to assess for nocturnal hypoventilation regardless of the FVC
  • Noninvasive ventilation in the form of BiPAP is the intervention that has been proven to have the largest effect on prolonging survival. Treatment should be initiated if FVC<50%, MIP>-60, or a nocturnal pulse-oximetry study is abnormal. Patients with ALS will benefit from a machine with average volume-assured pressure support (AVAPS) functionality as this allows flexibility for adequate support in the event of further respiratory decline between appointments
  • Mechanical insufflation/exsufflation helps to clear both upper and lower airway secretions as well as prevent atelectasis. Treatment should be initiated for peak cough <270.
  • Invasive respiratory support in the form of tracheostomy may be required in end-stage disease in order to prolong survival if that is the patient’s desire

Dysphagia/Weight Loss14

  • Weight loss in ALS is multifactorial with etiologies including progressive dysphagia, significant respiratory burden, hypermetabolism, depression, functional inability to eat, and gastroparesis causing early satiety
  • Early disease weight loss has recently been linked to increased mortality
  • There is an increasing body of evidence that long-term percutaneous endoscopic gastrotomy (PEG) placement leads to increased survival in ALS patients15
  • Discussion of PEG placement should be held early in disease process and placement should ideally occur when the FVC>50%, placement with FVC between 30-50% carries some increased risk, placement with FVC <30% should be discussed with the interventional radiology and anesthesia professionals


  • Dysarthria in ALS may be spastic, flaccid or a combination of these types
  • Continuing evaluation with the aid of a licensed speech and language pathologist should occur on a regular basis
  • Augmented communication strategies should be discussed early and include partner communication, written/typed communication, picture/word board, eye-gaze communication device


  • Treatment of sialorrhea in ALS should be based on how bothersome the symptom is for the patient
  • Medication treatment commonly includes glycopyrrolate, caution should be used before prescribing tricyclic medications for sialorrhea
  • Symptoms refractory to medication may be treated with botulinum toxin injection into the salivary glands


  • Spasticity can be both painful and functionally limiting for ALS patients
  • Medication treatments for spasticity include baclofen, tizanidine, dantrolene, benzodiazepines, gabapentin18. Careful attention should be given to side effects of these medications.
  • Botulinum toxin injection has been shown to be safe in the treatment of moderate-severe spasticity however this should be decided on a case-by-case basis given the effect of making muscles weaker17
  • Intrathecal baclofen pump placement has been shown beneficial in cases of severe painful spasticity particularly in patients with primary lateral sclerosis (PLS)18

Pseudobulbar Affect19

  • Dextromethorphan-quinidine (Neudexta) has been shown to improve pseudobulbar affect (PBA) symptoms in ALS. This medication also seemed to have subjectively measured beneficial effects on overall bulbar function with improved speech, improved dysphagia, decreased secretions reported on ALS-FRS scale

Impaired Mobility and Activities of Daily Living

  • Patient’s mobility and ability to perform activities of daily living (ADLs) should be continually evaluated at each appointment visit. Physical and occupational therapists in a multidisciplinary clinic can help adjudicate a patient’s needs
  • Fall prevention is crucial in the management of ALS patients. Patients with ankle dorsiflexion weakness should be prescribed appropriate ankle-foot orthoses (AFOs). Ground reaction force AFOs are typically the model of choice to help compensate for eventual quadriceps weakness. Rollator walkers are often beneficial as they provide a seat for rest. Custom power wheelchair seating should be discussed early in the disease process and prescribed in the event of recurrent falls despite proper orthotic use
  • Hand weakness causes patient’s difficulty in performing many ADLs such as dressing, eating, and hygiene. Wrist-hand orthoses, built-up utensils, dressing aids can be trialed to see if patient can maintain independence with these adaptations

Muscle Pain/Cramping

  • Narcotic medication should be used with caution in ALS patients due to respiratory side effects
  • Mexiletine has been shown to be beneficial for cramping pain, EKG should be performed prior to prescribing as this medication can prolong the QT interval
  • Anecdotally, over the counter magnesium supplementation and tonic water have shown to be beneficial
  • Other medications such as muscle relaxers and neuropathic medications can be trialed on individual basis

Neurogenic Bowel/Bladder

  • Urinary incontinence is often functional or related to frontal love dysfunction. Timed voiding and intermittent catheterization interventions can be beneficial to keep the bladder empty, an indwelling urinary catheter may be considered in the event of difficulty with self-catheterization or a burdensome bathroom process. Condom catheters at nighttime help prevent the need to get up in the middle of the night to urinate.
  • Constipation is a common complaint in ALS patients. Increased fiber intake and dietary optimization should be addressed by clinic nutritionist. Stool softeners and suppositories may be necessary as part of a daily bowel regimen.


  • Other causes of cognitive decline should be evaluated such as infection, electrolyte abnormality, stroke, vascular abnormality, Alzheimer’s, medication-induced
  • Cognition should be evaluated using standardized tools such as the Mini Mental Status Exam (MMSE) or Montreal Cognitive Assessment (MoCA)
  • Living environment and caregiver support should be adjusted based on the level of cognitive impairment

Depression/Adjustment Disorder

  • The prevalence of depression in ALS patients is recently estimated around 34% with the majority classified as mild or moderate20
  • Treatment with serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) may be initiated as well as referral to psychiatry specialist


  • Fatigue may be multifactorial in ALS patients. Possible etiologies include hypercarbia from restrictive lung disease, depression, poor caloric intake, muscle weakness, poor sleep hygiene, anemia, hypothyroidism. These etiologies should be adjudicated before any potential treatment
  • Increased pressure support on noninvasive ventilation can help mitigate fatigue in patients with significant restrictive lung disease
  • Modafinil has been shown to have some benefit in treating ALS fatigue21

Cutting Edge/ Emerging and Unique Concepts and Practice

Cutting edge concepts and practice

  • Proper caloric supplementation is a more important part of disease management than has been recognized in the past
  • The advancement of communication devices to include eye-gaze interface has increased the quality of life for ALS patients
  • Increased use of AVAPS noninvasive ventilation has led to longer survival outcomes and decreased hospitalizations

Emerging/unique interventions

  • Tofersen, an antisense oligonucleotide to SOD1, showed decreased concentrations of SOD1 concentration in cerebrospinal fluid in a phase 1-2 trial22. Phase 3 trial failed to meet primary endpoint of 6-month ALS-FRS rate of decline relative to placebo however there were some encouraging data in the open label extension that an earlier initiation of tofersen showed slower decline in faster progressing patients and clinical stabilization in slower progressing patients24.
  • AMX0035, a combination of sodium phenylbutyrate and tauroursodeoxycholic acid (TUDCA) was shown to have a positive effect on disease progression as reported by ALS-FRS scale. A modest survival benefit was also reported23. Further study is being conducted with a much larger cohort of patients.
  • The NEUROWN stem cell therapy trial failed to show any benefit over placebo
  • AMX0035 is not yet FDA approved for treatment in the United States, it is approved in both the European Union and Canada
  • Patients frequently confuse AMX0035 with TUDCA and should be educated that TUDCA alone has not been fully studied in the treatment of ALS

Gaps in the Evidence-Based Knowledge

Lack of clear pathophysiological understanding of the disease process makes finding effective treatment difficult


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  2. Hobson EV, Mcdermott CJ. Supportive and symptomatic management of amyotrophic lateral sclerosis. Nat Rev Neurol. 2016;12(9):526-38. doi:10.1038/nrneurol.2016.111
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  10. Hannaford A, Pavey N, van den Bos M, Geevasinga N, Menon P, Shefner JM, Kiernan MC, Vucic S. Diagnostic Utility of Gold Coast Criteria in Amyotrophic Lateral Sclerosis. Ann Neurol. 2021 May;89(5):979-986. doi: 10.1002/ana.26045. Epub 2021 Feb 24. PMID: 33565111.
  11. Wolf J, Safer A, Wöhrle JC, Palm F, Nix WA, Maschke M, Grau AJ. Factors predicting one-year mortality in amyotrophic lateral sclerosis patients–data from a population-based registry. BMC Neurol. 2014 Oct 4;14:197. doi: 10.1186/s12883-014-0197-9. PMID: 25280575; PMCID: PMC4189670.
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Original Version of the Topic

Anthony Chiodo, MD. Amyotrophic Lateral Sclerosis. 12/27/2012.

Previous Revision(s) of the Topic

Jennifer Yang, MD, Nicholas Georgelos DO. Amyotrophic Lateral Sclerosis. 3/27/2017.

Author Disclosure

Shailesh Reddy, MD
Nothing to Disclose

Hannah Machemehl, MD
Nothing to Disclose

Yessar Hussain, MD
Nothing to Disclose