Objective To evaluate the clinical characteristics and outcome of non-invasive ventilation (NIV) in an epidemiological based series of amyotrophic lateral sclerosis (ALS) patients.
Methods The study was performed using data from the Piemonte and Valle d'Aosta Register for ALS, a prospective epidemiological register enrolling all ALS incident cases in two Italian regions.
Results Among the 1260 patients incident in the period 1995–2004, 259 (20.6%) underwent NIV. Young male patients and subjects attending the tertiary ALS centres were more likely to undergo NIV. There was a progressive significant increase in the use of NIV during the study but was limited to patients attending the ALS tertiary centres. Median survival after NIV was 289 days (95% CI 255 to 333).
Conclusions In an epidemiological setting, NIV represents an increasingly utilised option for the treatment of respiratory disturbances in ALS and has favourable effects on survival, in particular among patients followed by tertiary ALS centres. Sociocultural factors, such as age, gender and marital status, strongly influence the probability of undergoing NIV. Efforts should be made to remove these obstacles in order to spread the use of NIV in all ALS patients with respiratory failure.
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Amyotrophic lateral sclerosis (ALS) is a neurological disorder of adult life characterised by progressive impairment of motor functions due to degeneration of upper and lower motor neurons. Its cause is still unknown. Five to 10 per cent of patients have a positive family history of ALS while the remaining are sporadic in nature. Respiratory failure can occur at different clinical stages, and is the most frequent cause of death.1 According to current clinical guidelines2 3 and a recent Cochrane systematic review,4 non-invasive ventilation (NIV) is the treatment of choice in the management of respiratory disturbances in ALS. The only controlled trial on NIV in ALS demonstrated a median survival benefit of 205 days compared with non-treated controls but this advantage was limited to a subgroup of patients without severe bulbar signs.5
The aim of the present study was to evaluate the clinical characteristics and outcome of NIV in ALS using data from a prospective epidemiological register.
The Piemonte and Valle d'Aosta Register for ALS (PARALS) is a prospective epidemiological register, established in 1995, collecting all ALS incident cases in two Italian regions (population 4 332 842). Methods and epidemiological data have been reported in detail previously.8 In brief, the main sources for cases were the neurological departments of the two regions. The main secondary sources for cases were the Piemonte Central Regional Archive and the Valle d'Aosta Central Regional Archive, two computerised archives reporting all discharges from all Italian public and private hospitals of individuals resident in Piemonte or Valle d'Aosta. These archives also include data on clinical complications and interventions.
ALS diagnosis was based on the El Escorial diagnostic criteria (EEC) and the EEC revised criteria.9 10 As patients were prospectively followed-up at regular intervals (2–4 months), their EEC diagnosis was regularly verified and, if necessary, modified. A standard form was used for collecting clinical and therapeutic information at each visit, including data on NIV. No patient was lost to follow-up.
In 1995, criteria for the prescription of NIV were presence of respiratory signs and symptoms (dyspnoea at rest or during exertion, orthopnoea, morning headache, disturbed sleep, daytime hypersomnolence, weak cough) and/or vital capacity <50% or 1 l and/or arterial blood gas analysis showing morning pCO2 ≥45 mm Hg (6 kPa).11 In 1999, after the publication of American Academy of Neurology Practice Parameters,12 we also considered nocturnal oxygen desaturation for more than 5 consecutive minutes. These indications and currently available guidelines were spread to all neurological departments in Piemonte and Valle d'Aosta during periodical meetings of the neurologists involved in the ALS register. It was also suggested that general neurologists perform respiratory investigations in their patients at least every 3 months. At the time of the study, in Piemonte and Valle d'Aosta, there were two interdisciplinary tertiary ALS centres, located in Torino and Veruno. Differences in the clinical organisation of these two centres and the general neurological clinics of the Piemonte and Valle d'Aosta regions have been described elsewhere.13
A patient was considered to be attending a tertiary ALS centre if he/she was followed-up for at least two visits by a neurologist of one of the two ALS centres.13 It should be noted that during the first 5 years of the study, only three hospitals in Piemonte had services for NIV. Each neurologist in the region could refer his/her patients to these services. After 2000, a regional network for NIV was implemented, and more than 10 centres for NIV were established.
A patient with bulbar symptoms at the time of NIV was considered to have a severe impairment if the sum of the two bulbar items (speech and swallowing) of the Amyotrophic Lateral Sclerosis Functional Rating Scale-revised was ≤3 out of a maximum score of 8. This information was available for 139 of the 161 patients with bulbar impairment at the time of NIV.
The study was approved by the ethics committee of the coordinating centre (Comitato Etico Regione Piemonte, 1994/134).
Tracheostomy free survival (last day of follow-up, 30 June 2010) was calculated with the Kaplan–Meier method, and curves were compared with the log rank test. Multivariable analysis was performed using Cox's proportional hazards method (backward stepwise) (see table 3 for details). We have considered as NIV treated each patient who was prescribed the use of NIV and used it for at least one day (intention-to-treat analysis). A p value <0.05 was considered significant. All calculations were performed with the SAS statistical package, V.8.2 (SAS Institute Inc.).
During the period 1995–2004, a total of 1260 cases (687 men and 573 women) were diagnosed with ALS in Piemonte and Valle d'Aosta. Mean age at onset was 64.9 years (SD 11.2; range 20–90); mean age at diagnosis was 65.6 years (SD 11.1). The presentation was spinal (including respiratory onset) in 787 cases (62.5%) and bulbar in 473 (37.5%). The mean annual crude incidence rate was 2.90/100 000 population. The overall median tracheostomy free survival of the population included in the epidemiological register was 2.5 years (95% CI 2.4 to 2.6; IQR 1.6–4.5). Of these cases, 259 (20.6%) underwent NIV.
The clinical and demographic characteristics of the patients who did and did not undergo NIV are reported in table 1. NIV was more frequently performed by patients attending tertiary ALS centres (37.2% vs 8.8%) (p=0.0001). The frequency of use of NIV significantly increased among patients attending tertiary ALS centres comparing the two quinquennia of the study (1995–1999 vs 2000–2004) (62 (25.3%), 135 (47.5%); p=0.0001) while it did not modify among patients followed by general neurological clinics (29 (7.8%), 33 (9.2%); p=0.48). NIV was also more frequently used by men, younger patients, patients with spinal onset and married versus unmarried or widow/widower subjects. Patients who previously underwent NIV had a twofold probability of undergoing invasive ventilation via tracheostomy (OR, 2.2 (95% CI 1.5 to 3.2; p=0.0001)).
The clinical and demographic characteristics of the patients attending and not attending tertiary ALS centres are reported in table 2. Patients attending tertiary ALS centres were significantly younger and less frequently had a bulbar onset.
Median tracheostomy free survival from symptom onset of the patients who did not undergo NIV was 2.4 years (95% CI 2.3 to 2.5, IQR 1.5–4.5), slightly shorter than that of the patients who underwent NIV (2.8 years; 95% CI 2.5 to 3.0; IQR 1.9–4.3) (p=0.74).
The overall median survival time after initiation of NIV was 289 days (95% CI 255 to 333; IQR 130–650). The 3 year survival rate was 13.2% (SE 0.02) and the 5 year survival rate was 5.7% (SE 0.02). Survival was significantly longer in patients followed by tertiary ALS centres (316 days; 95% CI 250 to 364; IQ range 143–680) than in those followed by general neurological clinics (229 days; 95% CI 134 to 308; IQR 79–453) (p=0.02) (figure 1), with a 3 month difference. There was no difference in survival after NIV in patients who had or had not bulbar signs at the time of NIV (245 days (95% CI 174 to 351; IQR 115–608) vs 289 days (95% CI 237 to 345; IQR 134–680)) (p=0.49) (figure 2). However, when assessing separately patients with severe bulbar impairment from those with slight or moderate impairment, the former group had a significantly shorter survival after NIV (145 days (95% CI 93 to 187; IQR 53–240) vs 301 days (95% CI 231 to 364; IQR 187–720)) (p=0.0001).
There was a significant difference in survival according to patient age at the time of NIV (≤49 years, 451 days; 50–69 years, 268 days; ≥70 years, 164 days; p=0.0001). Survival after NIV was slightly but not significantly increased in the 2000–2004 period (308 days, 95% CI 270 to 359; IQR 121–731) compared with the 1995–1999 period (237 days, 95% CI 190 to 282; IQR 132–630) (p=0.26).
Thirty day mortality rate was 5.4% (14 patients, nine from the general neurological clinics (15.6% of cases undergoing NIV) and five from tertiary ALS centres (2% of cases undergoing NIV); p=0.0001). Of these patients, 10 (6.3%) had bulbar signs at the time of NIV and four (4%) had no bulbar signs (p=0.41). These early deaths were related to patients' lack of compliance with NIV (11 patients) or pneumonia (three patients).
In Cox multivariable analysis, survival after NIV was significantly related to age, enteral nutrition, marital status and attending a multidisciplinary ALS centre (table 3).
NIV is increasingly used as the treatment of choice for respiratory disturbances in ALS. In our large population based series of cases, in the period 1995–2004, 21% of patients underwent NIV, with an increasing trend in recent years following the publication of the American Academy of Neurology Practice Parameters in 1999.12 However, this increase was almost exclusively limited to patients followed by tertiary ALS centres where in the last years of the study about 50% of patients underwent NIV. Moreover, early deaths (≤30 days after initiation of NIV), an indirect measure of tolerance and compliance with the procedure, were significantly more frequent in patients attending general neurological clinics.
No difference in survival from symptom onset was found in patients who did or did not undergo NIV. This finding is mainly due to the fact that the group of patients who did not perform NIV included mostly subjects with less severe ALS phenotypes.14 15 Another possible explanation is poor adherence to NIV; nevertheless, we had a low 30 day mortality after NIV initiation, indicating general good adaptation to NIV in our series.
Demographic and personal factors strongly influenced the use of NIV and also its outcome. NIV was more frequently performed by young male patients, similarly to what we found for tracheostomy16 and also in keeping with reports from the USA,7 Canada6 and Norway.17 However, different from the USA, in our setting we found that the patient's social status, as indicated by educational level, was not a factor hampering the acceptance of mechanical ventilation, probably because ventilatory interventions and home support are provided at no cost by the Italian National Health System. We have also found that NIV was more frequently performed by married patients, who also had a longer survival after NIV than non-married patients. This indicates that the absence of a family network hinders the use of complex clinical interventions, with negative consequences on patient care and survival.
In our series, almost all patients who received NIV lived in their home. Some were institutionalised only in the terminal phases when admitted to the hospice or when they were tracheostomised which is different from what we observed for patients who underwent tracheostomy.16
Overall survival after initiation of NIV was similar to that observed in the only controlled trial performed in ALS.5 In keeping with the controlled trial and two non-controlled single centre studies,18 19 we found that ALS patients with bulbar symptoms had a similar survival after NIV compared with those with only spinal symptoms (240 vs 289 days). Bulbar patients often cannot perform reliably volitional tests of respiratory muscle strength and can undergo NIV comparatively earlier than patients with predominant spinal involvement. Therefore, the findings on survival after NIV initiation in the bulbar group should be interpreted with caution and warrant further research. When assessing separately patients with severe bulbar impairment from those with slight or moderate impairment, we found that the former had a significantly shorter survival, confirming the fact that severe bulbar symptoms are associated with worse prognosis and that NIV may be less effective in these patients. Nonetheless, considering that NIV can improve quality of life, we support widespread use of NIV in patients with bulbar symptoms, provided that every effort is made to maximise compliance in this group of patients.
Our data strongly suggest that the implementation of current guidelines for the treatment of ALS is better performed in tertiary ALS multidisciplinary clinics, as demonstrated by the progressive increase in the use of NIV in patients attending these clinics. The general neurologists are likely to have a less ‘aggressive’ attitude than neurologists specialised in the care of ALS, in particular regarding life prolonging therapies. Moreover, survival after NIV was significantly longer in patients attending ALS specialised centres; although patients attending ALS tertiary centres were younger and less frequently bulbar than those not attending these centres, the advantage related to ALS centres was confirmed after adjustment for these variables in Cox's multivariable analysis, supporting the notion that multidisciplinary ALS clinics are better suited for the care of patients with complex disorders.13 20 However, as a number of patients, in particular older ones, are still followed by non-specialised neurological centres, the spreading of ALS treatment guidelines to these centres could be important in order to improve the overall care of ALS patients in the community.
In conclusion, in our population based setting, NIV represents an increasingly utilised option for the treatment of respiratory disturbances in ALS and has favourable effects on patient survival. Data on patients with bulbar symptoms at the time of NIV initiation are still unclear, and therefore no firm conclusion can be given at this time. However, we believe that bulbar patients can have improvements in survival comparable with that observed in spinal patients if adequately trained—for example, with initial acclimatisation, possibly in a hospital multidisciplinary setting with specific competences; careful choice of appropriate interface (usually more than one); aggressive management of secretions and maintenance of effective cough; training and support to the family and caregivers; and long term support.21–23
The major obstacles towards the diffusion of the use of NIV are of a social and organisational nature, in particular the patient's need to be supported by their family caregivers, and the poor skill of general neurologists in diagnosing respiratory problems and sometimes their negative attitude towards life prolonging treatments. Every effort should be made to remove these obstacles in order to spread the use of NIV to all ALS patients who need it.
We thank the patients and their families for having collaborated in this study.
Appendix The Parals group
Project coordinator: A Chiò, MD. Collaborating centres: Department of Neuroscience, University of Torino, and AOU S Giovanni Battista, Torino (S Cammarosano, MD, site investigator; A Canosa, MD, site investigator; S Gallo, MD, site investigator; D Cocito, MD, advisory committee; R. Mutani, MD, advisory committee); Department of Neurology, University of Torino, and AOU S Luigi Gonzaga, Orbassano (L Durelli, MD, advisory committee; B Ferrero, MD, site investigator; A Bertolotto, MD, advisory committee); University of Torino, and Istituto Auxologico Italiano, IRCCS, Piancavallo (A Mauro, MD, advisory committee); Department of Neurology, University of Piemonte Orientale Amedeo Avogadro, and AOU Maggiore, Novara (M Leone, MD, advisory committee; F Monaco, MD, advisory committee; N Nasuelli, MD, site investigator); Department of Neurology, AOU S Giovanni Battista, Torino (D Giobbe, MD, site investigator); Department of Neurology, Ospedale Mauriziano, Torino (L Sosso, MD, site investigator; M Gionco, MD, site investigator); Department of Neurology, Ospedale Martini, Torino (D Leotta, MD, site investigator); Department of Neurology, Ospedale Maria Vittoria, Torino (L Appendino, MD, site investigator; D Imperiale, MD, site investigator); Department of Neurology, Ospedale S Giovanni Bosco, Torino (R Cavallo, MD, site investigator); Department of Neurology, Ospedale Gradenigo, Torino (E Oddenino, MD, site investigator); Department of Neurology, Ospedale di Ivrea (C Geda, MD, advisory committee); Department of Neurology, Ospedale di Chivasso (C Geda, MD, advisory committee); Department of Neurology, Ospedale di Pinerolo (F Poglio, MD, site investigator; C Doriguzzi Bozzo, MD, advisory committee); Department of Neurology, Ospedale di Vercelli (P Santimaria, MD, site investigator); Department of Neurology, Ospedale di Biella (U Massazza, MD, site investigator); Department of Neurology, Ospedale di Domodossola (A Villani, MD, advisory committee; R Conti, MD, site investigator); Fondazione S Maugeri, Clinica del Lavoro e della Riabilitazione, IRCCS, Scientific Institute of Pavia (F Pisano, MD, advisory committee); Department of Neurology, AOU Santi Antonio e Biagio, Alessandria (M Palermo, MD, site investigator; E Ursino, MD, advisory committee); Department of Neurology, Ospedale di Casale Monferrato (F Vergnano, MD, site investigator; O Sassone, MD, advisory committee); Department of Neurology, Ospedale di Novi Ligure (P Provera, MD, site investigator); Department of Neurology, Ospedale di Tortona (M T Penza, MD, site investigator); Department of Neurology, Ospedale di Asti (M Aguggia, MD, advisory committee; N Di Vito, MD, site investigator); Department of Neurology, AOU S Croce e Carle, Cuneo (P Meineri, MD, site investigator; I Pastore, MD, site investigator); Department of Neurology, Ospedale di Savigliano (P.Ghiglione, MD, PhD, site investigator; D Seliak, MD, site investigator); Department of Neurology, Ospedale di Alba (C Cavestro, MD, site investigator; G Astegiano, MD, advisory committee); Department of Neurology, Ospedale Regionale di Aosta (G Corso, MD, site investigator; E Bottacchi, MD, advisory committee).
Funding The study was in part supported by Regione Piemonte (Ricerca Finalizzata 2002, grant 12944; Ricerca Scientifica Applicata 2004, grant A317; Ricerca Finalizzata, 2009, grant 30258) and Ministero della Salute, Centro Nazionale per la Prevenzione e il Controllo delle Malattie (CCM) (grant 31, 2009). The research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement No 259867.
Competing interests AC serves on the editorial advisory board of Amyotrophic Lateral Sclerosis and has received research support from the Italian Ministry of Health (Centro Nazionale per la Prevenzione e il Controllo delle Malattie), Regione Piemonte (ricerca finalizzata) and European Commission (Health Seventh Framework Programme). He serves on the ALS advisory board of Biogen Idec. GM has served on the editorial advisory board of Amyotrophic Lateral Sclerosis and has received research support from the Italian Ministry of Health (Ricerca Finalizzata).
Ethics approval Ethics approval was provided by Comitato Etico Regione Piemonte.
Provenance and peer review Not commissioned; externally peer reviewed.