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

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Multi disciplinary Care

ALS care is challenging because the disease is progressive and terminal, and there are, as yet, no treatments that reverse symptoms. Standardized multidisciplinary clinics were instituted in France in 2002, and most large centers in developed countries currently use a multidisciplinary approach to care.(41) At least 17 specialized ALS centers now exist across France. Consensus guidelines have been developed for the diagnosis and care of patients with ALS in France.(42) According to the guidelines, the diagnosis depends on findings of UMN degeneration in areas of amyotrophy with confirmation of LMN degeneration by EMG and exclusion of other conditions. Genetic tests are done in familial cases. Coordinated evaluations are recommended to provide individualized treatments for specific symptoms, including the timing of nutritional and respiratory support. Data suggest that patients who receive multidisciplinary care may survive longer.(27) Patients are evaluated frequently, typically every three months, so that impending problems are detected and treated early. The specialty care can be obtained through normal consultation, but patients and families in multidisciplinary clinics benefit from having questions answered in one sitting by professionals from different disciplines, conserving energy and time. Typically, professionals at multi-disciplinary clinics also see many patients with ALS, still a rare disease, so their level of experience may be higher than in other settings. Care is centered around the patient’s decisions, with a focus on education and support. The neurologist and health team give information to help in treatment decisions, including discussions about advanced directives and treatments for nutritional and respiratory insufficiency.(41) Advanced directives allow patients to make educated decisions in advance about future ventilator support should it become necessary, and help guide the multidisciplinary team in setting goals for care. The neurologist also explains research advances in the field. The neurologist and nurse oversee patient care, physical and occupational therapists evaluate skilled motor function, a dietitian evaluates nutritional status, a speech pathologist assesses bulbar function, a respiratory therapist treats respiratory symptoms, and a social worker assists with health insurance coverage and disability payments. Other professionals affiliated with the clinic usually include a pulmonologist who treats respiratory problems, a gastroenterologist who assists with gastrostomy placement, an orthotist who prescribes braces for those with focal weakness, and a psychiatrist or psychologist who treat symptoms of depression and anxiety. Information is also given to patients regarding services outside the clinic,(41) including home care and hospice. Non-pharmacological therapies include communication devices; gaze -assisted technology; canes, walkers and wheelchairs; home adaptations; and exercise regimens.

Respiration

As respiratory muscle weakness advances, patients develop symptoms of dyspnea, orthopnea, sleep fragmentation, daytime fatigue, and morning headaches. A weakened cough due to diaphragmatic and bulbar muscle weakness can lead to excess secretions, poor airway clearance, aspiration and pneumonia. The history, physical examination, overnight pulse oximetry and VC are standard assessments and are done serially, as part of the multidisciplinary clinic or referral. The maximal inspiratory and expiratory pressures (MIP and MEP) also correlate with respiratory muscle weakness(45) and become reduced in ALS. A MIP of <60 cm H2O is a predictor of reduced survival. Sniff nasal inspiratory pressure (SNIP), a noninvasive measure of inspiratory force, estimates intrathoracic pressure and can give an early indication of respiratory muscle strength. It decreases predictably over time in ALS patients, predicts survival and may better reflect hypercapnea than MIP or VC. A transcutaneous carbon dioxide sensor can also be used to assess rising carbon dioxide levels due to muscle weakness.
Nocturnal noninvasive positive-pressure ventilation (NIPPV), often called simply non-invasive ventilation (NIV) because it is the most common form of NIV used in ALS, has become the standard intervention for patients with respiratory insufficiency.(41) The bi-level intermittent positive-pressure ventilator is triggered by the patient’s inspiratory efforts and so facilitates physiological function. Because the ventilator is intermittent, it does not overwhelm expiratory efforts with continuous pressure. Patients are counseled on the use of NIV when the VC drops to 50% of predicted or when the MIP falls to <60 cm H20,(45) or with the onset of respiratory symptoms. NIV reduces the work of breathing, and improves gas exchange as well as sleep quality,(49) extends survival, particularly in those compliant at least 4 hours per day,(50) enhances quality of life and may improve cognition.(51) Oxygen is usually not prescribed without NIV to prevent inhibiting respiratory drive in the setting of elevated serum carbon dioxide levels. Theoretically, using NIV can reduce energy expenditure from overworked respiratory muscles, and so may not only support respiration but also reduce weight loss.
In 2004, standardized and more aggressive use of NIV was instituted at the ALS Center of the Salpêtrière Hospital.(52) From that time, all patients have received a thorough respiratory examination at each visit. If there are symptoms of respiratory muscle insufficiency (dyspnea, orthopnea) or hypercapnia (morning cephalgia); blood gas measures showing elevated CO2; VC less than 50% predicted; or nocturnal oxymetry with >10% of time spent <90% saturation (this parameter is considered one of the most important in the practice), the patient is referred to a pulmonologist for prescription of NIV.

Palliative Care and Hospice

All of ALS care is palliative because there is no treatment that reverses the progressive course. The care at the end of life is thought to be particularly important to avoid suffering. Approximately 60% of ALS patients die rapidly, often within 24 hours of worsening in their clinical condition and some die suddenly. Advance directives help prevent invasive ventilation being instituted emergently, but the key is ongoing and open communication between the patient and the healthcare team so that a patient understands the disease course and his wishes are known in advance. Anticipating symptoms before they occur is an important part of ALS care. Medications to relieve suffering, including anticholinergic agents, anxiolytics and opioids, can be prescribed in the home under the direction of a hospice team. Narcotic medications are effective for treating pain, nocturnal discomfort and breathlessness long before the terminal phase of the illness.(56) There is no evidence that opioids shorten life, but when relief of distress is the goal, some sedation may be necessary.
Palliation at the end of life is usually done at home, but inpatient palliative care teams can be used for those patients who do not wish to die at home. Hospice teams not only provide symptom management through the use of medications, but also emotional support for patients and families.

Symptomatic treatments

A wide variety of medications are used to treat symptoms due to ALS (Table 3), but most are used off label and have not been tested specifically in ALS. Some treatments have been shown to improve quality of life and a few may extend life.

Clinical features that predict survival

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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.
In clinical trials, Cox proportional hazards models using stepwise entry of clinical variables have examined predictors of survival. The original trials of riluzole showed that age, disease duration, breathing capacity, bulbar dysfunction, and scores on tiredness as well as stiffness scales predicted survival.(33) In a phase III trial of pentoxifylline, age; disease duration; and lower BMI, ALSFRS-R, strength and VC predicted shorter survival.(165).

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

Some (65, 67), but not all (61, 63, 64, 68, 69) studies indicate that the incidence of ALS and MND have increased over time. Mortality has consistently increased in different studies (73-75). Studies of mortality may underestimate incidence, but they have the advantage of large sample sizes studied during long periods, providing good power to examine change. Study of mortality rates can contribute to the descriptive epidemiology of the disease, and examination of reasons for changing rates might lead to new hypotheses for etiologies.
A previous mortality study conducted in France showed that the mortality rate increased from 0.71/100,000 in 1968 to 1.52/100,000 in 1982.(76) A study from the United States showed that mortality rate increased from 1.25/100,000 in 1969 to 1.82/100,000 in 1998.
Our project examined mortality from MND in France during 1968-2007 and used a form of Poisson regression known as Age-Period-Cohort (APC) modeling to determine whether the variables age, period of death, or cohort of birth best explained the changing mortality rates.(173, 174). A period effect influences all individuals during a period of time independently of their age, and can be explained by social, medical, or economic factors, including improved treatment or diagnosis. A cohort effect, seen as a change in the rates for a cohort of individuals born during the same period of time, can be due to changing environmental exposures.
37,624 deaths from MND were recorded in people aged 40 to 89 years during 1968-2007. The crude mortality rate over the whole study period was 1.74 per 100,000 person-years; 1.90/100,000 in men and1.58 in women.
Standardized mortality ratios (SMRs), taken as the ratio of the number of observed deaths to the number of expected deaths each year using the overall population (1968-2007) as the reference (indirect standardization), increased with time, from 54 (95% CI = 49-59) in 1968 to 126 (95% CI = 120-132) in 2007. This trend was similar for each gender, but the sex ratio declined over time from 1.80 in 1968 to 1.45 in 2007. The mortality rates began to increase with time period in subjects aged 60-64, a trend that strengthened with advancing age. The rates also increased according to birth cohorts.
In APC analyses, the model including age only (model 1) showed that mortality increased to a peak between 75 and 79 years (ratio of deviance to degrees of freedom for the model = 34.86). The age-drift model (model 2) estimated that the relative risk (RR) per one year increase in age was 1.018 (95% CI=1.017-1.019) and that mortality increased 19.6% every 10 years (ratio of deviance to degrees of freedom = 13.03). The age-period model (model 3) showed that mortality increased during the study period (ratio of deviance to degrees of freedom = 12.23). The age-cohort model (model 4) showed that the RR of dying from MND increased with time; this model fit the data better than the other models (ratio of deviance to degrees of freedom =1.09), suggesting that a cohort effect best explained the increasing mortality rate in France. In analyses stratified by sex, the cohort effect was more pronounced in women than in men, corresponding to the decrease in male to female gender ratio over time.

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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