Disease-Modifying Therapies & Symptom Management
Written by Margaret Anne Rockwood | Last updated April 29th, 2026
Medically reviewed by Jennifer Morganroth, MD, MBA and Doreen Ho, MD
Disease progression in ALS varies based on the site of onset (bulbar vs. limb), the presence of genetic mutations (e.g., C9orf72, SOD1), and the rate of functional decline, as measured by the ALS Functional Rating Scale–Revised (ALSFRS-R).
Progression is characterized as the spread of weakness from one body region to others, leading to eventual respiratory failure, and is highly heterogeneous. While median survival is historically 3 to 5 years from symptom onset, recent data suggest this is improving. Currently, about 10% of patients survive more than 10 years.
Distinct clinical phenotypes describe these slower-progressing variants from classic ALS:
- Flail Arm/Leg Syndromes: Typically associated with slower progression and longer survival
- Primary Lateral Sclerosis (PLS) variant: Involves predominantly upper motor neurons and progresses much more slowly than classic ALS. Often, several years of observation are needed to confirm transition from PLS to ALS.
Standard of Care in Disease-Modifying Therapies
Tofersen is a gene-targeted antisense oligonucleotide (ASO) therapy that has a notable impact on biomarkers and functional decline. Tofersen is administered to those with confirmed pathogenic or likely pathogenic SOD1 mutation, which is present in approximately 2% of patients with ALS.
- The VALOR trial for tofersen did not reach its 6-month primary endpoint, but at 52 weeks, early starters had a 3.5-point ALSSFRS-R advantage over those who began after 6 months of placebo (late start), losing 9.5 points versus 13.5. Both groups performed better than separately sourced data on untreated ALS patients, who typically lose 22–34 points in the same period. Notably, around 25% of early starters saw strength and function improvements at 148 weeks, which is uncommon in ALS.
- Asymptomatic Carriers: The ATLAS study is investigating whether starting tofersen before ALS symptoms appear can delay or prevent onset in people with the fast-progressing SOD1 (A4V) mutation. Tofersen is currently only approved for symptomatic individuals. Researchers use neurofilament light chain (NfL) blood tests as early markers, since data has shown that NfL often rises 6–12 months before symptoms.In ATLAS, carriers are regularly tested and, if NfL levels increase, are randomized to treatment vs. placebo, aiming to find the optimal time to start therapy before disease progression.
Guidelines also recommend riluzole for nearly all eligible patients, as it shows modest impact on progression.
Adding edaravone in patients may be considered for patients with:
- Symptom history of ≤ 2 years
- Relatively preserved physical function ≥ 2 points on every item of the ALSFRS-R)
- Forced Vital Capacity (FVC) ≥ 80%,
- Able to perform most activities of daily living (ADLs)
- Toleration of treatment burden.
Note: Oral edaravone is now the preferred formulation over IV to reduce treatment burden
Other FDA-approved medications for specific ALS complications:
- Dextromethorphan/quinidine (Nuedexta): Specifically for pseudobulbar affect, reducing CNS-Lability Scale (CNS-LS) scores and frequency of inappropriate laughing/crying episodes.
- Tiglutik/Exservan: These are oral suspensions and oral film formulations of riluzole, which facilitate administration in bulbar-predominant ALS, helping with dysphagia.
FDA-approved agents that are standard of care in slowing ALS progression across familial and sporadic ALS
| Medication | Features |
| Tofersen (Qalsody) | Mechanism: ASO targeting SOD1; reduces SOD1 protein synthesis. Intrathecal administration. Impact: Targeted Therapy. SOD1-ALS only; 3.5-point functional advantage vs delayed start; ~27% show strength gains at 3 years. Adverse Effects: Myelitis, ↑ intracranial pressure, aseptic meningitis, back pain |
| Riluzole (Rilutek, Tiglutik, Exservan) | Mechanism: Glutamate modulation (Na⁺ channel inhibition). Oral. Impact: Standard of Care. Extends median survival by ~2–3 months (up to 6–19 months in real-world data). Adverse Effects: ↑ Alanine AminoTransferase/Aspartate AminoTransferase (ALT/AST), nausea, asthenia, dizziness |
| Edaravone (Radicava IV/ORS) | Mechanism: Free radical scavenger (antioxidant). IV or oral. Impact: Broadly Applied. Slows functional decline (ALSFRS-R) by ~33% over 24 weeks in selected patients. Adverse Effects: Bruising, gait disturbance, headache, hypersensitivity reactions |
| Relyvrio (AMX0035)(withdrawn) | Mechanism: Sodium phenylbutyrate + taurursodiol. Impact: Removed from Market. Withdrawn in 2024 after negative PHOENIX trial. Adverse Effects: N/A |
Note: Diaphragmatic pacing is generally not recommended as a standard of care and may actually be harmful; the DiPALS study showed decreased survival in patients receiving pacing compared to standard care.
Clinical Summary
- Riluzole at 50 mg twice daily is standard of care and prolongs median survival by several months, with real-world data suggesting 6–19 months in some cohorts.
- Indicated for SOD1-ALS, intrathecal tofersen is given at 100 mg per dose. Beginning with three loading doses at 14-day intervals. It is shown to reduce neurofilament biomarkers by ~60% and provide a 3.5-point functional advantage over three years in early-start versus delayed-start patients.
Benefits of each therapy appear enhanced by earlier gastrostomy, timely non-invasive ventilation, and structured symptom control, particularly in spinal-onset disease.
ALS within the ALS–FTD spectrum
Up to 30–50% of individuals with ALS develop cognitive or behavioral changes, most commonly within the frontotemporal dementia (FTD) spectrum, and a smaller subset meets criteria for overt ALS-FTD. C9orf72 mutations are the most common genetic link between ALS and FTD. Manifestations may include executive dysfunction, apathy, disinhibition, loss of empathy, language impairment, and impaired insight.
The presence of FTD is often correlated with faster physical decline and shorter survival.
Routine, brief cognitive/behavioral screening and early involvement of neuropsychology and social work are recommended, especially when planning complex interventions such as non-invasive ventilation (NIV) or Percutaneous Endoscopic Gastrostomy (PEG) placement.
ALS without associated FTD
These patients retain full executive and cognitive function despite progressive physical paralysis. In advanced stages, they are at higher risk for “locked-in” syndrome, in which eye movements (and sometimes minimal facial movement) become the primary means of communication. For these patients, providing early access to eye-gaze devices and other augmentative and alternative communication (AAC) technologies is critical for maintaining autonomy and participation in care decisions.
Symptom Management
Care in a specialized multidisciplinary ALS clinic (neurology, respiratory medicine, rehabilitation, nursing, dietetics, speech-language pathology, psychology, palliative care, social work) is consistently associated with improved survival, reduced hospitalizations, and an optimized quality of life.
Front-line physicians begin and can offer ongoing support as part of the multidisciplinary care team through:
- Early recognition and referral: Diagnosis and multidisciplinary management should begin once suspected, rather than waiting for advanced disability.
- Regular monitoring of respiratory function, nutrition, communication needs, mood and cognition, even between specialist visits.
- Coordination with community services (home ventilation programs, home health, hospice) to avoid crisis-driven decisions late in the disease course.
- Using screening tools and capacity assessments to track physical and cognitive functionECAS (Edinburgh Cognitive and Behavioral ALS Screen): A leading instrument for ALS-specific cognitive/behavioral screening.CNS-LS: Used to screen for pseudobulbar affect.ALSFRS-R: To track functional decline.
The literature demonstrates that patients commonly derive benefit from timely:
- Non-invasive ventilation (NIV): BiPAP use >4 hours/day extends survival and improves sleep quality/cognition by clearing CO2. NIV is now increasingly recommended at the earliest signs of respiratory muscle weakness (e.g., SNIP <40 cm, SVC <50%), even in asymptomatic patients, to improve long-term tolerance. Nighttime use reduces morning headaches and daytime somnolence by correcting nocturnal hypoventilation and hypercapnia.
- Gastrostomy: Percutaneous Endoscopic Gastrostomy (PEG) or radiologically inserted gastronomy (RIG) helps assure adequate hydration, prevents malnutrition-induced muscle wasting and reduces aspiration pneumonia risk. Insertion is ideally performed before Forced Vital Capacity (FVC) falls below 50% to reduce procedural risk.
- Proactive symptom management: Treatment of cramps and spasticity, pain and sialorrhea prevents “crisis” ER visits.
- Psychosocial support: Besides the ethical responsibilities of expressing concern for the patient, support counseling for caregivers and respite services reduce caregiver burnout, which is a major contributor to patient hospitalization.
Specific symptom management and palliative care treatments
Motor symptoms
- Cramps and spasticity
- Oral baclofen and tizanidine are mainstays and have similar antispastic efficacy, with more weakness and hypotonia associated with baclofen and more somnolence/xerostomia with tizanidine.
- Mexiletine: A sodium-channel blocker, now a first-line treatment to significantly reduce the frequency and severity of ALS-related muscle cramps.
- Gabapentin: An anti-convulsant that can reduce spasticity scores and is useful when neuropathic pain coexists, though it is not considered first-line monotherapy for spasticity.
- Pain
- Pain from immobility, spasticity, contractures is common and often undertreated. Baclofen and other GABA-modulating agents help earlier in disease, while opioids (e.g., morphine, fentanyl) are effective in advanced stages for refractory pain or dyspnea, with careful titration.
- NSAIDs and tramadol are reasonable for mild-to-moderate nociceptive pain. Physical positioning, stretching, splinting, and pressure-relieving mattresses are essential non-pharmacologic adjuncts.
- Fatigue and stiffness
- Fatigue is among the most prevalent and bothersome ALS symptoms yet is infrequently treated. Management includes optimizing sleep and ventilation, treating mood disorders, energy conservation strategies, and cautious trials of stimulants (e.g., modafinil) in selected patients.
- Regular, low-intensity, non-fatiguing (submaximal) aerobic and resistance exercise helps reduce stiffness, prevent contractures, and maintain function without accelerating weakness.
Bulbar symptoms: sialorrhea, dysphagia, PBA
- Sialorrhea (drooling)
- First-line pharmacotherapy: low-dose anticholinergics such as sublingual atropine drops and oral glycopyrrolate. Amitriptyline, transdermal scopolamine, oral or transdermal hyoscine could also be considered in certain cases.
- Refractory cases:
- Botulinum toxin A or B injections into parotid and/or submandibular glands, significantly and persistently reduce saliva for up to ~4 months.
- Salivary gland irradiation is a viable alternative for patients who cannot tolerate or access injections.
- Dysphagia and nutrition
- Early referral to speech-language pathology for texture modification, postural techniques (chin tuck, head turn), and swallow safety training.
- PEG or RIG is recommended when there is weight loss (>5-10% of baseline), aspiration risk, or prolonged, effortful mealtimes, ideally while FVC remains above 50%.
- Pseudobulbar affect (PBA)
- Dextromethorphan/quinidine (Nuedexta) is the only FDA-approved therapy for PBA in ALS and demonstrates reduced Center for Neurologic Study-Lability Scale (CNS-LS) scores and PBA episode frequency in phase 3 trials.
- SSRIs or tricyclic antidepressants can provide off-label benefit, particularly when Nuedexta is not tolerated or available.
Respiratory function and ventilation
Assessment and noninvasive ventilation (NIV)
- Monitor MIP (Maximal Inspiratory Pressure) and SNIP (Sniff Nasal Inspiratory Pressure), which is more sensitive than FVC alone in early detection of diaphragm weakness.
- Monitor for orthopnea, morning headaches, daytime somnolence, weak cough, and declining FVC/MIP. Early NIV (BiPAP) is recommended once nocturnal hypoventilation or symptomatic hypercapnia or a SNIP score <40 cm H₂O is evident. Randomized and observational data show NIV improves survival by several months and enhances quality of life, especially in limb-onset ALS and with ≥4 hours/day usage.
Airway clearance and advanced support
- Mechanical insufflation–exsufflation, manual assisted cough, and mucolytics —help manage secretions and reduce infection risk.
- Tracheostomy ventilation is reserved for patients who explicitly choose long-term invasive support when NIV is insufficient or poorly tolerated.
Psychological symptoms and patient–caregiver support
- Depression and anxietySSRIs are first-line for depression and generalized anxiety in ALS and may also alleviate associated Pseudobulbar Affect (PBA) in some patients with low respiratory reserve.Short-term benzodiazepines (e.g., lorazepam) may be added for acute anxiety or dyspnea-related panic, with caution regarding respiratory depression and dependence, particularly when combined with NIV.
- Multidisciplinary and palliative supportRegular multidisciplinary clinic visits are linked to longer survival and better psychosocial outcomes through coordinated decision-making, caregiver training, and earlier palliative care integration.Early advance care planning— including discussions about NIV, tracheostomy, feeding tubes, and place of care— should be revisited regularly as disease progresses.
Comfort through connection
Front-line physicians and specialists play a complex role in symptom management for patients with ALS. This role often goes beyond minimizing dysfunction and discomfort, to include helping the patient and family optimize quality of life, in many cases gaining a sense of connectedness with the care team and, as desired, others with ALS, or rare diseases more broadly. Some early reading has proven helpful for many patients with a new diagnosis:
- Living with ALS” series(ALS Association).
- “Every Note Played” by Lisa Genova (fiction, but clinically accurate regarding progression).
- I AM ALS(Advocacy and clinical trial matching).
References
- Amyotrophic lateral sclerosis. Brown, R. H., & Al-Chalabi, A. (2017). New England Journal of Medicine, 377(2), 162–172.
- Trial of tofersen in SOD1 amyotrophic lateral sclerosis. Miller, T. M., et al. (2022). NEJM, 387(12), 1099–1110.
- Tofersen offers lasting benefit for SOD1 ALS: Three-year update. Miller, T. M., et al. (2026). JAMA Neurology.
- Tofersen treatment leads to sustained stabilization of disease progression in SOD1 ALS: Clinical experience from a single center. Meyer, T., et al. (2025). Annals of Clinical and Translational Neurology.
- Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to ALS (DiPALS): multicentre, open-label, randomized controlled trial. McDermott, C. J., et al. (2015). The Lancet Neurology, 14(12), 1183–92.
- Effects of non-invasive ventilation on survival and quality of life in ALS: A randomized controlled trial. Bourke, J. P., et al. (2006). The Lancet Neurology, 5(2), 140–147.
- Digital alternative communication for individuals with amyotrophic lateral sclerosis: What we have. Fernandes da Silva Felipe R., et al. (2023). Journal of Clinical Medicine, 12(16), 5235.
- Mexiletine for muscle cramps in amyotrophic lateral sclerosis: A randomized double-blind crossover trial. Oskarsson, B., et al. (2018). Muscle & Nerve, 58(1), 42–48.
- Effects of non-invasive ventilation on survival and quality of life in ALS: A randomized controlled trial. Bourke, J. P., et al. (2006). The Lancet Neurology, 5(2), 140–147.
- Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to ALS (DiPALS). McDermott, C. J., et al. (2015). Lancet Neurol, 14(12), 1183–1192.
- Amyotrophic lateral sclerosis (ALS). National Institute of Neurological Disorders and Stroke. (2025).
- Practice parameter update: The care of the patient with amyotrophic lateral sclerosis. Miller R.G., et al. (2009; reaffirmed 2023).
- Amyotrophic lateral sclerosis–frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria. Strong M.J., et al. (2017). Amyotroph Lateral Scler Frontotemporal Degene.
- Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease. Radunovic A., et al. (2017). Cochrane Database Syst Rev.
- Screening for cognition and behaviour changes in ALS. Abrahams S., et al. (2014). Amyotroph Lateral Scler Frontotemporal Degener.
- Pseudobulbar affect: An under-recognized and under-treated neurological disorder. Work S.S., et al. (2019). Adv Ther.
- The ALSFRS-R: A revised ALS functional rating scale. Cedarbaum J.M., et al. (1999). J Neurol Sci.
- Recent advances in the diagnosis and management of amyotrophic lateral sclerosis. Goutman S.A., et al. (2022). Lancet Neurol.
- Multidisciplinary care for adults with ALS. Ng L., Khan F., Mathers S. (2017). Cochrane Database Syst Rev.
- Enhanced characterization of pseudobulbar affect in ALS. Smith RA, et al. (2018). Amyotroph Lateral Scler Frontotemporal Degener.
- Caregiver burden and patient support in ALS. Chio, A., et al. (2020). J Neurol Neurosurg Psychiatry.