The MITOS System Predicts Long-Term Survival in Amyotrophic Lateral Sclerosis (ALS)

The ALS Milano-Torino Staging (ALS-MITOS) system can reliably foresee the progress of ALS up to 18 months. The result was published in an issue of Journal of Neurology, Neurosurgery and Psychiatry.

Amyotrophic lateral sclerosis (ALS), an idiopathic neurodegenerative disease affects motor neurons and typically leads to death within 3 years from the onset of symptoms. ALS is distinguished by a progressive loss of functions such as speech, swallowing, mobility and respiration. Stage of the disease severity helps in prognosis, decision making and resource planning. However, no commonly used validated staging system is present for ALS that captures the progressive loss of independence and function.

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Functional rating scales like ALS Functional Rating Scale (ALSFRS) and ALSFRS–Revised (ALSFRS-R) measures decline in function and have been used widely for evaluating treatment effects in clinical trials. However, they do not completely capture functional characteristics of late stage ALS progression. In addition, no agreed-upon threshold is available so that a change in ALSFRS/ALSFRS-R score can be considered as an important transition point in functional status. Furthermore, ALSFRS-R scale has limitations in terms of non-linearity, multidimensionality and floor-effects and its usefulness in late stages is being argued. The ALS Milano-Torino staging (ALS-MITOS) system was hence proposed as a unique tool for measuring the progress of ALS and overcoming its limitations.

A study was conducted on 200 patients to validate the use of ALS-MITOS system as a 6-month proxy of survival and was followed up to 18 months. Data from recombinant human erythropoietin Randomized Clinical Trials were used for analysis. Clinical milestones in ALS progression were identified by the loss of independence in four key areas on ALS Functional Rating Scale (ALSFRS): walking/self-care, swallowing, communicating and breathing. The ALS-MITOS system was therefore composed of these four key domains that were included in the ALSFRS-R scale, each areas showing loss of function in the specific ALSFRS-R sub scores. Sensitivity, specificity and area under the curve (AUC) of the ALS-MITOS system stages and ALSFRS-R decline at 6 months was computed and compared with primary outcome measures (survival, tracheotomy or >23-hour non-invasive ventilation) at 12 and 18 months. Logistic regression model was used to assess the predicted possibilities of the ALS-MITOS system at 6 months for any event at 12 and 18 months.

The results obtained showed that the ALS-MITOS system detected 82% sensitivity (n=37/45) and 63% specificity (n=92/146) in terms of disease progression from baseline to 6 months when compared with primary outcome measures (death, tracheotomy or >23-hour non-invasive ventilation at 12 months). Further, the ALS-MITOS system detected 71% sensitivity (n=50/70) and 68% specificity (n=76/111) at 18 months. On further analysis of ALS-MITOS and ALSFRS-R progression at 6-month follow-up showed that predicting a survival rate at 12 and 18 months was 1 for the ALS-MITOS (loss of at least one function), whereas there was a decline of 6 to 9 points in case of ALSFRS-R.

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The study, therefore, concluded that the ALS-MITOS system can dependably predict the course of ALS up to 18 months and may be considered as a unique and valid outcome measure in randomized clinical trials.

In another clinical study published in the journal, Neurology developed ALS-MITOS system and applied it to evaluate patients' clinical, quality of life, and cost outcomes.

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Critical milestones in ALS progression were used by ALSFRS in four key areas swallowing, walking/self-care, communicating, and breathing. Stages 0-5 were defined, with 0 as functional involvement but no loss of independence in any areas; 1-4 was areas in which independence was lost and 5 being death. The patients enrolled were in the age group ≥18 to ≤80 yrs and were used to validate above defined stages. Patients who had definite, probable or probable laboratory supported ALS with no serious comorbidities were included. The study was analyzed at 4, 8, and 12 months, patient's function (10 item ALSFRS), quality of life (QoL; Short Form-36[SF-36]) and direct costs were evaluated.

Among 130 patients included in the study, at baseline, stage 0 had 48.7% patients, 27.7% (stage 1), 11.8% (stage 2), 3.4% (stage 3) and 8.4% at stage 4. At 12 months, Stage 0 had 15.7% patients, Stage 1 (21.7%), Stage 2 (15.7%), Stage 3 (10.4%), Stage 4 (13.9%), and Stage 5 (22.6%). Stages 0-4 had mean (±SE) overall ALSFRS score as 31.0 (±0.4), 22.7 (±0.4), 15.8 (±0.5), 9.5 (±0.7), 3.2 (±0.5) respectively. SF-36 physical and mental health composite scores reduced continuously with each stage. Direct costs however increased with increase in stages.

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The study thus concluded that proposed staging system ALS-MITOS was well linked with functional, QoL and direct cost assessments.

About ALS

The incidence of ALS is 2/100,000 people and it is not a contagious disease. The life expectancy of individual with ALS is about 2 to 5 years from the time of diagnosis; the disease is variable and many people can live with it for 5 years and more. More than half of people with ALS live more than 3 years after diagnosis. The onset of ALS is progressive, eventually taking away ability to walk, dress, write, speak, and swallow and breathe, thereby leading to shortening of life span. The average survival time is 3 years, about 20% people with ALS live for 5 years, 10% of people survive for 10 years and 5% live for more than 20 years. Early symptoms of ALS involve muscle weakness or stiffness. Progression of weakness, wasting and paralysis of muscles of the limbs and trunk and also those that control important functions like speech, swallowing and breathing then generally follows. Significant cost of medical care, equipment and home health caregiving would be incurred later in the disease.

Future Directions

The ALS-MITOS system is based on well-validated and widely used rating scale, having potential to provide meaningful information to clinicians and patients. In addition, it can readily be applied to available datasets for further establishing its validity and facilitate direct comparison with future studies. Further investigations of moving through stages and related changes in costs and quality of life would add to the understanding of the utility of this proposed system. The results of studies are compelling enough and further evaluations of ALS-MITOS system of staging would be needed.

References:

1. Tramacere I, Bella ED, Chiò A, Mora G, Filippini G, Lauria G. The MITOS system predicts long-term survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry, 2014.

2. Chio A, Hammond E, Mora G, Bonito V, Filippini G. Development of a Clinical Staging System for Amyotrophic Lateral Sclerosis. Neurology February 12, 2013; 80

3. Facts You Should Know. ALS Association. Accessed Aug 17 2015. Available from: http://www.alsa.org/about-als/facts-you-should-know.html

Source-Medindia