Background:  This Fast Fact reviews available published evidence and expert opinion regarding prognostication for amyotrophic lateral sclerosis (ALS), an incurable, progressive neurodegenerative disease. See Fast Facts #73, 299, 300, 301, and 411 for further information regarding ALS.

Description of Advanced or End-Stage ALS:  Most patients with ALS have a linear pattern of decline, however, the speed of that decline is quite variable between individuals. Median survival from time of onset has been shown to be three to five years (1). Most patients experience progressive limb and/or bulbar weakness that progresses over months to years and eventually manifests as a bedbound individual who may also experience dysarthria and/or dysphagia. End-stage ALS generally refers to the presence of dysphagia and/or respiratory failure from neuromuscular weakness. Interventions such as gastrostomy tube to ensure adequate nutrition and mechanical ventilation via tracheostomy can prolong life in ALS (2).  While many fear they will suffer a distressing death (many fear choking to death), a retrospective analysis suggest that nearly 90 percent of patients who are not mechanically ventilated experience a peaceful death in which they progressively slip into a deeper coma from hypercapnia (1). 

Disease-specific prognostication in ALS:  The European Network for the Cure of ALS (ENCALS) model is the most recognized evidence-based, disease-specific model to predict prognosis in ALS (3).  It was developed to predict survival for patients with ALS who were not treated with a tracheostomy nor continuous non-invasive ventilation. Survival outcomes are reported three ways: as an individualized prognostic estimate (specific patient compared to average patient), prognostic groups (very long, long, intermediate, short, or very short), or as a point estimate within a survival curve. ENCALS uses clinical, cognitive, and genetic variables to predict survival based on data from over 11,000 European patients with ALS from 1992-2016. The most relevant prognostic factors from ENCALS include:  

• Site of onset (spinal vs bulbar) 
• Age of onset of muscle weakness or bulbar symptoms
• Time from onset of weakness or bulbar symptoms to diagnosis
• Whether the diagnosis of ALS was definite, probable, or possible 
• Forced vital capacity (FVC)
• The revised ALS Functional Rating Scale (ALSFRS-R)
• The presence of frontotemporal dementia (cognitive factor)
• Presence of the C9orf72 mutation (Genetic factor)

ALS hospice guidelines:  Patients are considered eligible if they meet one of three criteria (4,5):

1. Critically impaired breathing capacity: meaning dyspnea at rest; vital capacity less than 30% of normal (if results are available); and patient declines mechanical ventilation (though external ventilation via bilevel support can be used for symptom control).
2. Significant functional decline: e.g., going from ambulation to bed bound status; losing the ability to swallow/speak; going from a normal to a pureed diet within 12 months. 
3. Life threatening complications: e.g., aspiration pneumonia, sepsis, or a stage 3 sacral wound.

Prognostic evidence for ENCALS and ALS hospice eligibility guidelines:  

• ENCALS has been critiqued since it does not include relevant treatment factors such as riluzole, enteral nutrition, or ventilation as prognostic variables. Yet, the authors note that the median survival benefit of riluzole in a Cochrane meta-analysis was three months.  This is substantially smaller than the combined effect of the predictors in ENCAL (HR 0.84 vs 15.29) (5).
• A systematic review compared nineteen predictor models for survival in ALS. Only ENCALS was shown to have good discrimination and calibration and a low risk of bias (6). 
• The ENCALS model can predict survival time in months and can thus be used to determine survival likelihood less than six months, indicating hospice eligibility. 
• The validity of hospice eligibility criteria in predicting prognosis in ALS is less known. A 2004 study of 97 consecutive ALS patients admitted into hospice from a tertiary ALS center found that although only five met Medicare criteria at the time of enrollment (7). While the mean number of days on hospice was 85, there was wide range: 1-534 days (7). The Medicare criteria have subsequently been revised; however, the sensitivity and specificity of the revised Medicare criteria remain unknown. 

Online resources:  See references #3-4 for determining ENCALS, ALSFRS-R, and ALS hospice criteria.

Limitations: Some patients with ALS experience plateau periods, others experience rapid progression. Therefore, the clinical application of ENCAL’s population-based prognostic data for individualized care requires thoughtfulness and complex communication skills. Clinician gestalt by an ALS specialist that is aware of the patient’s clinical scenario is crucial for accurate prognostication. See references 8-10 for tips on communicating prognosis based on population data.

Bottom Line:  In conjunction with a careful assessment of functional status, the ENCALS model can be a helpful tool to predict prognosis in ALS.  Further research is needed to determine if ENCALS offers prognostic benefit over clinician gestalt from an ALS specialist. 

References

1. Neudert C, Oliver D, et al. The course of the terminal phase in patients with amyotrophic lateral sclerosis. Journal of Neurology 2001; 248:612-616.
2. Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology [published correction appears in Neurology. 2009 Dec 15;73(24):2134] [published correction appears in Neurology. 2010 Mar 2;74(9):781]. Neurology. 2009;73(15):1218-1226. 
3. Henk-Jan Westeneng T et al. Prognosis for patients with amyotrophic lateral sclerosis:  development and validation of a personalised prediction model. Lancet Neurol. 2018; 17: 423–33
4. Local Coverage Determination for Hospice – Determining Terminal Status (L33393) (cms.gov)
5. Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 2012; 3: CD001447.
6. Xu L, He B et al. Prognostic models for amyotrophic lateral sclerosis: a systematic review. J Neurology. Published online Mar 2021. https://doi.org/10.1007/s00415-021-10508-7
7. McCluskey L and Houseman G. Medicare Hospice Referral Criteria for Patients with Amyotrophic Lateral Sclerosis: A Need for Improvement. J Pall Med. 2004. 7(1): 47-53
8. Back AL, Arnold RM. Discussing Prognosis: How Much Do You Want to Know? Talking to Patients Who Are Prepared for Explicit Information. Journal of Clinical Oncology, 2006. 24(25): 4209-4213 
9. Back AL, Arnold RM. Discussing Prognosis: How Much Do You Want to Know? Talking to Patients Who Do Not Want Information or Who Are Ambivalent. Journal of Clinical Oncology, 2006. 24(25): 4214-4217 
10. Van Eenennaam RM et al. Discussing Personalized Prognosis in Amyotrophic Lateral Sclerosis: Development of a Communication Guide. BMC Neurology. 2020; 20: 446.

Author Affiliation: University of Pittsburgh Medical Center, Pittsburgh, PA

Version History: First electronically published in January 2022, originally edited by Sean Marks MD

Conflicts of Interest: None to report