. CHANGING MORTALITY FOR MOTOR NEURON DISEASE IN FRANCE (1968-2007): AN AGE-PERIOD-COHORT ANALYSIS

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Clinical features that predict survival

ALS is an incurable disease that is rapidly progressive for most patients. Population-based studies estimate median survival times of 30 months from symptom-onset and 19 months from diagnosis,(140) but the disease can be unpredictable, with some patients surviving months and others decades.(80) No phenotypes have been shown to have uniformly unique survival patterns that might suggest unique causes. Until causes and more robust therapies are discovered, anticipating survival time is important to patients, physicians and researchers.
A variety of clinical factors have been reported to be associated with shorter survival in ALS, including older age, bulbar-onset, and a shorter interval from onset of symptoms to diagnosis.(141-147) Poor strength and motor function (132, 145) or breathing capacity,(145, 148, 149) as well as weight loss (44, 150) and female gender (142, 151, 152) may also predict shorter survival.
Patients with older age and bulbar-onset have been consistently reported to have shorter survival rates, both in clinic-based,(44, 141, 143, 145, 146, 149, 153) and population-based (142, 144, 148, 152, 154) studies. Bulbar-onset occurs with increased frequency in older age groups,(155) but this association is not thought to fully explain the worse prognosis of those with bulbar-onset symptoms.(148) The delay between symptom onset and first visit, a surrogate for the rapidity of disease progression, has also been shown to predict survival, with shorter intervals having worse prognosis.(141-145, 147, 149, 155-159) Motor function, as assessed by strength or functional scale scores (132, 145, 146, 149) also predicts survival. Some studies indicate that breathing capacity is also an important predictor (44, 146, 148, 149, 160) of survival. A cluster analyses of multiple variables indicated that the strongest predictors in one sample were site-of-onset and interval from onset to first evaluation.(159) A calculation of the rate of progression as first visit using the ALSFRS-R score and time from symptom onset has also been shown to predict survival.(161, 162).
Findings are less consistent for gender and psychosocial factors. While most studies have shown no effect of gender on outcome, two population-based and several small retrospective studies found worse outcome in women.(142, 151, 152) Psychosocial stressors including perceived stress, depression, hopelessness and poor mood may portend worse prognosis,(163) and cognitive impairment has been associated with shorter survival.(7) Some research indicates that being underweight could also lead to shorter survival time,(44, 150) and other studies show that multidisciplinary care,(27) early use of non-invasive ventilation (NIV),(50) and nutritional support(164) could contribute to improved prognosis.

IMPROVING SURVIVAL IN A LARGE ALS CENTER COHORT

Research indicates that the median survival time for ALS is 30 months from onset and 19 months from diagnosis(140). Multidisciplinary care,(27) early use of non-invasive ventilation (NIV),(50) and nutritional support(164) may improve outcome. Riluzole use extends survival (36).
Different clinical factors are associated with worse outcome, including older age at onset, bulbar-onset, and a shorter interval from onset of symptoms to diagnosis (141-147). Poor strength and motor function (132, 145), breathing capacity (145, 148, 149), weight loss (44, 150) and female gender (142, 151, 152) may also predict shorter survival rates.
In the 1860s and 70s, Jean-Martin Charcot described different forms of motor neuron disease at the Salpêtrière Hospital, now the largest ALS referral center in France.(175) In 1989, the center developed an electronic database for patients’ clinical information; in 1995, a standardized multidisciplinary approach was developed for patient care; In 2002, multidisciplinary care was standardized at centers across France; and in 2004, the Paris center began a more aggressive approach to respiratory management.
The objective of this second part of the research was to analyze survival during 2002- 2009, the years after multidisciplinary care was standardized, to determine whether rates have changed at the Paris center.

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PREDICTING SURVIVAL IN ALS AT PRESENTATION: A 15-YEAR EXPERIENCE

Amyotrophic lateral sclerosis (ALS) is still an incurable disorder without known cause. No unique phenotypes have been identified that have clearly distinct survival patterns to suggest common etiologies. Survival prediction is important to patients, physicians and researchers.
We analyzed baseline features to report patient and disease prognostic factors at the ALS Center at the Salpêtrière Hospital from 1995, the year multidisciplinary care was developed through 2009. This dataset included 3830 patients. We analyzed a separate dataset starting in 2002 that included 2037 patients.
Patients residing in Paris were older (p<0.0001), more likely to be women (p=0.012) and to have bulbar-onset (p=0.0097), weigh less (p<0.0001), and have better strength (p<0.0001) than those residing in the rest of France.
Similar to the previous project, we found that as time passed, patients became older (p=0.0007), were more likely to reside in Paris (p<0.0001), came to the clinic sooner after symptom-onset (p<0.0001), and were stronger at baseline (p<0.0001).
3211 patients had died by the end of the follow-up. Median survival after disease onset was of 2.80 years overall, and was shorter for patients from the Paris region (2.66 years) than the rest of France (3.00 years) (logrank, p=0.0004). The median survival times from first visit to the center were 1.60 years overall (1.68 years for Paris and 1.52 years for the rest of France; Logrank p=0.0033). The HR of death from a Cox-model was 0.88 (95% CI=0.82-0.95, p<0.0001) for the Paris region versus the rest of France, a difference explained mainly by age at first visit: in a Cox model with age as the time axis, the HR of death for the Paris region was no longer significant (HR=1.01, 95% CI=0.94-1.09, p=0.70).
Age at baseline was a strong predictor of survival (logrank, p<0.0001). The HR of death per an increase of 10 years was 1.36 (95% CI=1.32-1.40, p<0.0001). Age was therefore used as the time axis in subsequent analyses.

Table of contents :

1. INTRODUCTION
1.1. Amyotrophic lateral sclerosis: clinical features, diagnosis and care…
1.1.1. Riluzole
1.1.2. Multidisciplinary care
1.1.3. Nutrition
1.1.4. Respiration
1.1.5. Palliative care
1.1.6. Symptomatic therapy
1.2. Epidemiology……….
1.2.1. Incidence and mortality
1.2.2 Risk factors ……
1.3. Measuring progression
1.4. Clinical features that predict survival
1.5. Clinical trials
1.6. Major questions
2. CHANGING MORTALITY FOR MOTOR NEURON DISEASE IN FRANCE (1968-2007): AN AGE-PERIOD-COHORT ANALYSIS
2.1. Results
3. IMPROVING SURVIVAL IN A LARGE ALS CENTER COHORT…
3.1. Results
4. PREDICTING SURVIVAL IN ALS AT PRESENTATION: A 15-YEAR EXPERIENCE
4.1. Results
5. SUMMARY
6. CONCLUSIONS AND PERSPECTIVE
7. BIBLIOGRAPHY

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