Als Feeding Tube for 10months but Losing Weight Again

• Journal List
• PLoS One
• PMC5441602

PLoS One. 2017; 12(5): e0177555.

Is survival improved by the apply of NIV and PEG in amyotrophic lateral sclerosis (ALS)? A post-mortem study of lxxx ALS patients

Christian Burkhardt

¹ALS Dispensary/Neuromuscular Diseases Unit, Kantonsspital St. Gallen, St. Gallen, Switzerland

Christoph Neuwirth

ⁱALS Clinic/Neuromuscular Diseases Unit, Kantonsspital St. Gallen, St. Gallen, Switzerland

Andreas Sommacal

^twoSection of Pathology, Kantonsspital St. Gallen, St. Gallen, Switzerland

Peter M. Andersen

³Institute of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden

Markus Weber

¹ALS Clinic/Neuromuscular Diseases Unit, Kantonsspital St. Gallen, St. Gallen, Switzerland

Renping Zhou, Editor

Received 2016 Jul 12; Accepted 2017 April 28.

Supplementary Materials

S1 Table: Concomitant disease found during autopsy. Abbreviations: Accented number of cases with concomitant diseases not leading to death in the series of 80 autopsies.

(PDF)

GUID: 3857425C-5B37-425B-86CD-5DA0CEFFCF56

S2 Table: Causes of decease for different ALS phenotypes. Abbreviations: betwixt the brackets are the accented numbers of ALS phenotypes or causes of death displayed.

(PDF)

GUID: A79FC564-F919-40C9-A5D4-4FE60C7BEEBE

S1 Fig: Weight loss during the course of ALS. Abbreviations: Weight loss between symptom onset and death (in % of the initial body weight at symptom onset). Between the brackets are the absolute numbers of patientes in each group listed.

(PDF)

GUID: 242D595A-62F6-45F9-86D4-8F46BF5B02CB

Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

Abstruse

Groundwork

Non-invasive ventilation (NIV) and percutaneous gastrostomy (PEG) are guideline-recommended interventions for symptom direction in amyotrophic lateral sclerosis (ALS). Their effect on survival is controversial and the affect on causes of death is unknown.

Objective

To investigate the effect of NIV and PEG on survival and causes of death in ALS patients.

Methods

Eighty deceased ALS patients underwent a complete post mortem assay for causes of death between 2003 and 2015. 40-two of these patients consented for genetic testing. Effects of NIV and PEG on survival and causes of death were analyzed in a multivariable Cox proportional hazard regression.

Results

Half dozen patients, who requested assisted suicide causing drug-induced hypoxia, were excluded from final analysis. Respiratory failure was the main cause of death in 72 out of 74 patients. Xv out of 74 died of aspiration pneumonia 23/74 of bronchopneumonia and 8/74 of a combination of aspiration pneumonia and bronchopneumonia. Twenty died of hypoxia without concomitant infection, and six patients had pulmonary embolism alone or in combination with pneumonia. NIV (p = 0.01) and PEG (p<0.01) had a meaning impact on survival. In patients using NIV bronchopneumonia was significantly more frequent (p <0.04) compared to non-NIV patients. This effect was even more than pronounced in limb onset patients (p<0.002). Patients with C9orf72 hexanucleotide repeat expansions showed faster disease progression and shorter survival (p = 0.01).

Conclusion

The use of NIV and PEG prolongs survival in ALS. This report supports current AAN and EFNS guidelines which recommend NIV and PEG equally a treatment pick in ALS. The risk of bronchopneumonia every bit cause of death may be increased by NIV.

Introduction

Expiry is all the same the definite hallmark and a major primary endpoint in many treatment studies in amyotrophic lateral sclerosis (ALS), because reliable biomarkers to measure therapeutic effects are lacking.

Several epidemiological, but only few autopsy studies, accept demonstrated that the master cause of death in ALS is respiratory failure. Other causes of death in ALS are pulmonary embolism, asphyxia, cardiac arrest or suicide.[1–three] An earlier study suggested that defining the cause of death based simply on clinical observations is unreliable to determine the actual cause of death in ALS patients.[3] Fifty-fifty if clinical and dissection records are available a relevant proportion of deaths cannot be determined or are classified every bit "sudden decease".[2,3] Moreover with respect to respiratory failure a articulate stardom between bronchopneumonia, aspiration pneumonia and hypoxia becomes, with increasing post-mortem interval more than and more hard, every bit tissue deposition begins immediately after death.

In 1999 the start evidence-based guidelines for the clinical care of ALS patients and their relatives of the American Academy of Neurology (AAN)[4] were published. Their revision[5] and the European Federation of Neurological Societies (EFNS) 2005[half-dozen] and 2012[seven] guidelines recommend multidisciplinary care and symptom direction including the use of NIV and PEG to in a higher place all maintain quality of life for, but besides to extend the life of patients with ALS. A controlled study demonstrated that NIV prolongs survival in patients without severe bulbar dysfunction,[8] only information technology has been hard to show if the utilize of PEG affects survival.[9] Due to the lack of randomized controlled trials, it is notwithstanding controversial if PEG feeding can positively influence survival or prevent weight loss.[9,x] It is also unknown whether NIV or PEG might have an influence on the cause of death in ALS patients. To elucidate if and how these well-established treatments in ALS care affect disease duration and causes of death we here assessed the furnishings of these interventions in the largest ALS autopsy cohorts later on publication of the guidelines to date.

Methods

This retrospective study was approved by the Ethics Commission of the County of St. Gallen in accord with the ethical standards of the Helsinki Announcement.[11] Written informed consent was obtained from all patients and discussed every bit role of accelerate directives. The study adhered to Swiss legislations, regulations and guidelines regarding terminal intendance, terminate-of-life decisions by the patient and human autopsies. Forty-ii of these patients also consented in writing to participate in genetic research and had Deoxyribonucleic acid analysis performed for a panel of ALS genes (details of the genetic information are available upon asking from the corresponding author: ed.xmg@tdrahkrub.sirhc or Markus Weber: hc.gssk@rebew.sukram). C9orf72-mutations screening was performed using RPPCR coupled with amplicon length analysis, and in positive cases confirmed by Sountern blot" equally described. [12] The clinical information was gathered during regular visits every three months in our outpatient clinic at the specialized ALS Clinic at the Kantonsspital St. Gallen from 2003 to 2015 and on reports from 80 sequent nerveless autopsies of ALS patients. Death was confirmed by an independent physician. Autopsies were performed by the Department of Pathology of the Kantonsspital St. Gallen. The diagnosis of ALS was established according to the revised El Escorial criteria[13] and confirmed in all cases by autopsy. Demographic information included gender, time and site of symptom onset (divers as paresis), fourth dimension from onset to diagnosis (diagnostic filibuster), fourth dimension of death, fourth dimension from death to dissection, body mass alphabetize (BMI) before or at fourth dimension of diagnosis and at death. In addition the revised amyotrophic lateral sclerosis functional rating calibration (ALSFRS-R)[14], time of initiation of NIV or insertion of PEG, information on concomitant diseases and intake of Riluzole were recorded. Survival time was defined as time from symptom onset to death. Diagnostic filibuster was defined as time from symptom onset to diagnosis. The indication for initiation of NIV was, as recommended by the guidelines based on clinical signs of respiratory insufficiency in combination with respiratory parameters (forced vital capacity and sniff nasal force per unit area) with subsequent, nocturnal polysomnography [5,vii]. Recommendation for PEG was given, if progressive malnutrition (weight loss >10%) or risk of aspiration was evident despite of a multidisciplinary nutrition management [five,7]. The respiratory status was not taken into account for the conclusion of PEG equally all patients received NIV during PEG insertion to reduce the run a risk of hypoxia [15].

Assisted suicide by a physician is not explicitly regulated by Swiss law. Only assisted suicide in a person that has the decisional capacity and the person profitable–physician or lay person–is not motivated by reasons of cocky-interest is tolerated.

Defining clinical causes of death were based on the patient history, clinical information and on macroscopic and if necessary microscopic assay of the viscera. Dissimilar sections of the encephalon, spinal cord, peripheral nerves and various muscles were neuropathologically examined. Sections from 3 dissimilar spinal cord levels cervical (segment C6/vii), thoracic (Th6) and lumbar (L3) were stained with hematoxylin and eosin (HE) and immune histochemically stained for ubiquitin and glial fibrillary acidic protein (GFAP). Particular attention was paid to ALS-typical, intracytoplasmatic, neuropathological changes including the presence of Bunina bodies, skein-similar inclusions and threads, motor neuron loss, astrocytosis and sclerosis of the pyramidal tracts to confirm the diagnosis of ALS. Tissue specimens of the middle, liver, lung, spleen, kidney, pancreas, adrenal gland and occasionally other organs were fixed in formalin and afterwards mold in alkane blocks. The sections were stained with HE (and if necessary with additional staining's such every bit Periodic acid–Schiff, Rubberband Van Gieseon or iron staining) and histologically examined. Causes of death were categorized as: aspiration pneumonia, bronchopneumonia, hypoxia, pulmonary embolism, assisted suicide, cardiac ischemia, peritonitis or combined respiratory cause of expiry consisting of aspiration pneumonia and/or bronchopneumonia and/or hypoxia. Aspiration pneumonia was assumed if aspiration material was found macroscopically in the lungs. On histological examination aspiration pneumonia was diagnosed in the presence of putrid pneumonia intermixed with aspiration material, squamous epithelium (from the esophagus and oropharynx) and bacteria also as characteristic brownish coagulation necrosis and hemorrhages of lung tissue as a reaction of gastric acrid. A sudden acute fatal aspiration shows no vital reaction to gastric acid and aspiration textile at the histological level. By contrast bronchopneumonia presents only with putrid inflammation. Isolated respiratory insufficiency (hypoxia) as cause of death was diagnosed with proof of lung dystelectasis, increased amount of macrophages in the alveolar spaces and fresh hypoxic necrosis of hippocampal neurons.

Statistical analysis

Demographic and clinical characteristics of the participants are reported as percentages for categorical variables and ways (SD) and medians (IQR) for continuous variables. Statistical analysis was performed using the R programming linguistic communication (version 3.one.0, https://www.r-projection.org). A threshold of p < 0.05 (two-tailed) was considered significant. Almost half of ALS patients were unable to visit our outpatient clinic during the concluding months of their lifes. Every bit applied previously,[sixteen] the ALSFRS-R at the time of decease was estimated using linear regression for each patient separately, based on three or more ALSFRS-R scores obtained at earlier visits. Negative predicted ALSFRS-R estimates (north = four) were rounded upward to 0. Furnishings of NIV and PEG on survival were adapted in a Cox proportional run a risk regression (Cox PH) for various factors (diagnostic delay, region of onset, predicted ALSFRS-R, gender and age at diagnosis, BMI loss). Riluzole was not included as a cofactor considering more than 90% of the patients used information technology on regular basis. Patients, who committed assisted suicide and those with truncal onset, were not taken into account for the survival analysis to minimize the bias. For statistical analyses of causes of deaths the 2 patients, who died from peritonitis or from acute heart failure, patients who committed assisted suicide, as well as three patients with truncal-onset (presenting with respiratory insufficiency as outset symptom) were too excluded. The affect of genetic mutations on survival was also computed with a multivariable Cox PH model adjusting for diagnostic delay, predicted ALSFRS-R, gender, age, NIV and PEG. A multinomial logistic regression was used to examine the issue of NIV and PEG use on cause of death, adjusting over again diagnostic filibuster, onset region, predicted ALSFRS-R, BMI loss, sex activity and historic period at diagnosis.

Results

Basic demographic and dispensary data of the cohort are reported in Table 1.

Table 1

Characteristic of the autopsy cohort.

Characteristics	ALS (northward = 80)
Age of onset (years)
	median	64.0
	mean	62.vi
	SD	13.1
	range	28–84
Gender, n (%)
	male	47 (sixty%)
	female	32 (40%)
Site of onset
	limb	55 (69%)
	truncal	3 (iv%)
	bulbar	22 (27%)
Duration of disease (months)
	median	36.v
	mean	43.2
	SD	27.1
	range	seven–159
Delay of diagnosis (months)
	median	viii.7
	mean	13.7
	SD	13.four
	range	1–77
BMI		at diagnosis	vs	at death
	median	23.7	vs	xx.2
	mean	24.3	vs	20.7
	SD	three.81	vs	3.95
	range	xviii.9–39.5	vs	12.1–32.3
Weight loss in BMI (% of original body weight) during illness
	mean	iii.8 (16.6%)
	range	-8.0–x.9 (-37.6–46.2%)
Time from death to start of dissection (hours)
	median	4.25
	range	i.25–58
Predicted ALSFRS-R score at expiry (north = 62)
	median	16.seven
	hateful	17.5
	SD	10
	range	0–38.9
Riluzole use	73/fourscore (91.25%)

Most common concomitant diseases are listed in S1 Table in the supplement. The predicted mean ALSFRS-R score at decease was 16.seven. The clinical diagnosis of ALS was neuro-pathologically confirmed in all cases. The median time from death to autopsy was 4 hours. In all cases the cause of death could be autoptically antiseptic. Mean diagnostic filibuster in bulbar onset patients was half-dozen months shorter than in spinal onset patients (9.seven months versus 15.7 months, p = 0.05). Shorter diagnostic delay was significantly associated with shorter survival (HR, 0.97; 95% CI, 0.95–0.99; p = 0.01). After adjustment for diverse factors bulbar onset patients had a non-meaning shorter median survival compared to limb onset patients (32.seven months versus 46.3 months, HR, 0.53; 95% CI, 0.27–ane.06; p = 0.07). 3-quarters of the patients died at domicile or in nursing homes. One quarter of the patients had to be hospitalized due to astute respiratory deterioration.

In nine (seven with positive family history) out of 42 cases a pathological echo expansion in C9orf72 were institute. Half dozen of these patients had cognitive and behavioral changes or later developed full-blown frontotemporal dementia (FTD). Patients with C9orf72 echo expansion had a median survival of 28 months (excluding one patient committing assisted suicide) compared to patients without known mutation with a survival of 47 months. Multivariable analysis showed an increased hazard ratio (Hour) of five.73 (95% CI 1.five–21.86; p = 0.01) for patients with C9orf72 repeat expansion compared with patients without expansion.

The hateful loss in BMI in all ALS patients was three.68 during the form of the disease (S1 Fig). The subgroup with astringent weight loss (loss of >20% of the initial BMI) consisted mostly of limb onset patients (19/25 cases). Within this group with severe weight loss were half dozen out of the 9 patients with C9orf72 repeat expansions.

Causes of deaths

Seventy-two out of 74 patients died of respiratory failure. Six patients died as a consequence of assisted suicide using Sodium-Pentobarbital. These Patients with assisted suicide had a longer median disease during (53.1 months) compared to the rest of cohort (36.iii months). NIV was used in only ii of them and PEG in three patients. The reason for assisted suicide was diminished quality of life due to progressing loss of autonomy, diminished ability of communication or lack of will to live. One out of 74 patients died from spleen rupture with bleeding and peritonitis equally a complication later PEG insertion during hospitalisation and i from cardiac ischemia. By far the most common crusade of decease was pneumonia (46/74) either caused by aspiration in xv/74 patients or past bronchopneumonia in 23/74 patients. Twenty out of eighty patients died from hypoxia. Twelve out of these 20 patients received NIV. Eight patients showed a combined respiratory cause of death (Fig one).

Dissection confirmed causes of death in %.

In six patients (seven.5%) acute pulmonary embolism (PE) alone or in combination with pneumonia led to death. Within this grouping of pulmonary embolism in ALS the ratio between spinal and bulbar onset was balanced (3 leg vs. 3 bulbar onset patients). Four patients were notwithstanding able to walk within the concluding weeks before death caused by PE and at that place was no pregnant divergence in the predicted ALSFRS-R scale (p = 0.39) compared to patients with other causes of expiry. None of these patients had a prior history of deep venous thrombosis or any other embolic outcome or any known run a risk gene for deep vein thrombosis. Detailed information near causes of death in the different ALS phenotypes are listed in S2 Table in the supplement.

Effects of NIV

30-eight out of 71 patients received NIV during the course of the disease (Table 2).

Table ii

Impact of NIV and PEG on survival^*.

Characteristics	NIV -	NIV +	PEG -	PEG +
Number of patients	33/71	38/71	25/71	46/71
Age at onset (years)	64.iv	61.3	64.1	61.ix
Region of onset
• limb onset	26/33	25/38	22/25	31/46
• bulbar onset	7/33	xiii/38	three/25	25/46
Median time to initiation (months)
• overall		35.iii		25.9
• limb onset		41.eight		36.half dozen
• bulbar onset		23.two		19.vi
Median survival (months)
• overall	36.5	47.7	29.8	twoscore.1
• limb onset	39.v	54.iii	30.2	52.3
• bulbar onset	24.2	39.7	fourteen.one	32.7
Cox proportional hazard regression model on survival (overall):	for NIV		for PEG
60 minutes (95% CI)	0.nineteen	(0.05–0.67) (p = 0.01)	0.24	(0.09–0.62) (p<0.01)

Median disease duration from symptom onset to death was more than 10 months longer in patients receiving NIV compared to patients without NIV (47.seven months versus 36.5 months). Univariate Cox-regression revealed no meaning survival benefit for the utilize of NIV, just after adjusting for diverse cofactors (run across methods) NIV analysis significantly increased survival across the whole cohort (60 minutes, 0.19; 95% CI, 0.05–0.67; p = 0.01).

Subgroup analysis of limb onset (HR, 0.75; 95% CI, 0.34–1.64; p = 0.47) and bulbar (60 minutes, 0.72 95% CI, 0.xiv–3.72; p = 0.lxx) patients even showed a greater survival benefit of almost xv months in NIV users. This deviation did not reach statistical significance, probably due to the small sample size in each group. When comparing this survival benefit betwixt limb and bulbar onset patients using NIV there was no meaning difference (p = 0.07) (Table two).

Bronchopneumonia occurred, as the only cause of expiry, more oft (OR, 3.657; 95% CI 1.27–xi.78, p = 0.021) in NIV (17/41) compared to non-NIV users (half dozen/33). This divergence was more pronounced in the subgroup of limb onset patients (Fig two).

Take a chance of bronchopneumonia nether NIV.

In this subgroup 13 out of 25 of these cases could be attributed to bronchopneumonia every bit cause of death compared to a small proportion of bronchopneumonia in patients not using NIV (3/26) (OR, 12.sixteen; 95% CI 2.81–74.05; p<0.002).

Furnishings of PEG

PEG was inserted in 46 patients. Comparing groups with and without PEG feeding (29.eight months versus 40.1 months) with univariate Cox regression revealed no significant positive result on survival. After adjustment for various cofactors (see Methods) PEG insertion revealed a significant survival do good (HR, 0.24; 95% CI, 0.09–0.62; p<0.01, Tabular array ii).

BMI at decease and BMI loss during the affliction course did not differ between the group with PEG (BMI 23.8, -16.8%) and without PEG (BMI 23.8, -17.4%). Noticeably, causes of death did not significantly differ between patients with and without PEG. Patient treated with the combination of PEG and NIV showed a non-meaning trend for longer survival compared to NIV-only (HR, 0.34; 95% CI 0.10–i.14; p = 0.08) or to PEG-only treated patients (HR, 0.51; 95% CI 0.21–i.26; p = 0.15).

Discussion and conclusion

This post-mortem study comprises fourscore ALS patients and is unique equally a very curt delay until autopsy (median 4 hours) allowed a clear definition of causes of expiry. It is the only autopsy- supported study later on institution of the AAN[four,5] and EFNS[6,7] guidelines. Handling adhered to these guidelines especially with regard to NIV and PEG implementation. Despite the diagnostic advances over the concluding decades in other neurodegenerative diseases such as dementia and extrapyramidal syndromes, in at least 10 to 25% of cases, the final diagnosis tin merely be clarified past autopsy.[17–nineteen] By contrast diagnostic certainty in ALS is autopsy-proven excellent, if the current used clinical diagnostic criteria are adhered to stringently.[2,3]

In this mail-mortem study we ostend that respiratory failure is the main crusade of decease in almost all ALS patients (72/74).

In epidemiological studies respiratory dysfunction has been accountable for decease in ALS upwards to eighty%.[20,21] The proportion of pneumonia in these studies has been estimated effectually 15%.[22, 23] Past contrast pneumonias stand out as the leading cause of death in 58% in our study, virtually often equally bronchopneumonia (29%), less frequent aspiration pneumonia (19%) or a combination of both with or without hypoxia (10%). Our findings correlate well with the previous dissection studies with an incidence of pneumonia in 55%[ii] and 71%,[3] respectively. The incidence of pneumonia in general, only in particular silent aspiration pneumonia seems to be widely underestimated, if but based on clinical sentence. Until today only few studies dealt with the trouble of aspiration in ALS with a broad range of causeless aspiration from 13% in epidemiology-based studies to 90% in a fiber-optic endoscopy evaluation.[24–26] This study shows that about i/5 patients died of autopsy-verified aspiration pneumonia, which is a higher proportion equally compared to previously published studies (16% and 11% respectively).[2,three]

These studies still did non provide information nigh postal service-mortem interval until autopsy and articulate definitions of bronchopneumonia, aspiration pneumonia and hypoxia. The lower rate of aspiration pneumonia as well as the high proportion of unknown causes of death of up to 8% in these autopsy studies may be attributed to a longer postmortem interval, as progressive tissue deposition complicates the clear allocation of the cause of death.

In NIV patients survival was most ten months longer compared to the group of non-NIV patients. This survival do good was even more pronounced in the subgroups limb and bulbar onset patients, but did not reach statistical significance. The loss of significance despite the larger effect on survival can most likely exist attributed to the too pocket-sized sample size. Even so, this observation is in line with a contempo observational study showing that likewise bulbar onset patients have a significant survival benefit by using NIV.[27]

Our results show that PEG insertion is a safe procedure.[xv] Seventy-five percentage of patients with PEG lived 6 months or more than after insertion and only 1 out of 46 patients had a severe complication. Survival was, afterward adjustment for cofactors, significantly extended past the use of PEG feeding. This survival benefit tin however not be explained by hateful BMI at death or weight loss from symptom onset to death since these parameters were non influenced by PEG insertion. Whether prevention of aspiration pneumonia can account for the survival do good remains unclear as this written report revealed no significant departure. The positive effect of NIV and PEG on survival leads to the hypothesis that their combination might be superior to each treatment alone. An unexplained finding is that patients using NIV died significantly more than often of bronchopneumonia as compared to non-NIV users. This effect was more significant in the subgroup of limb onset patients. Possible explanations are that longer survival exposes patients to a higher chance for pulmonary infection or alternatively NIV itself may be a adventure cistron for bronchopneumonia. While invasive ventilation is an accepted take chances factor for pneumonia, especially for nosocomial infections,[28] NIV has been used to reduce the risk of nosocomial pneumonia on the ICU[29] and to care for patients with acute pneumonia.[30]

However, until now there are no studies addressing, whether chronic NIV utilize could by itself increase the take chances for pneumonia in neuromuscular patients.

The charge per unit of pulmonary embolism (7.5%) in this study was comparable with ascertainment of a previous post-mortem study,[three] reporting pulmonary embolism in vi%. Epidemiological investigations in elderly non-ALS subjects estimate the annual run a risk of PE in the age grouping 65–69 years with 1.3 per k, steadily increasing with age to two.eight in the age group 85–89 years.[31] Our data therefore imply a 2–iii fold increased risk for PE in ALS compared to these groups. Recently a prospective study[32] suggested that patients with leg weakness and reduced mobility carry a loftier adventure of developing thromboembolic events. By dissimilarity in our series 4 out of 6 patients with pulmonary embolism were nevertheless able to walk within the last weeks of their lives and the ALFFRS-R was not significantly different compared to the patients not dying from embolism. All just i patient with embolism were over 74 years suggesting that age may be a relevant risk cistron for PE in ALS patients.

Limitations of this study include a possible selection bias from a tertiary ALS center with a selected patient group and missing data, specially on objective respiratory parameters such every bit blood gas values, FVC and SNIP to assess the respiratory function adequately before death, the adherence to NIV and PEG or near the use of cough assisting devices. These data could possibly give an indication whether NIV is a true risk cistron for bronchopneumonia.

In summary, this study provides mail service mortem-proven evidence that adherence to current guidelines with respect to NIV and PEG significantly prolongs survival. This benign effect of NIV seems also to be nowadays in bulbar onset patients. Patients receiving NIV, especially with limb onset, may exist at higher risk to die from bronchopneumonia. Consequently an optimized safety pneumonia management and early empiric antibody treatment should be considered in ALS patients in patients using NIV.

Supporting information

S1 Tabular array

Concomitant affliction found during dissection.

Abbreviations: Absolute number of cases with concomitant diseases not leading to death in the series of eighty autopsies.

(PDF)

S2 Tabular array

Causes of death for different ALS phenotypes.

Abbreviations: between the brackets are the absolute numbers of ALS phenotypes or causes of decease displayed.

(PDF)

S1 Fig

Weight loss during the course of ALS.

Abbreviations: Weight loss between symptom onset and death (in % of the initial body weight at symptom onset). Between the brackets are the accented numbers of patientes in each group listed.

(PDF)

Acknowledgments

The authors thank indebted our participants who donated their tissue for this autopsy written report and their caregivers. The authors are thankful to Thou. Margelisch, Due north. Gubler (Department of Pathology St. Gallen) for performing the autopsies and R. Sauter (CTU, St. Gallen) for contribution in the statistical assay.

Funding Argument

Christian Burkhardt receives honoraria from Biogen Idec for training courses and receives inquiry back up from the Swiss ALS Foundation and the European union Joint Programme-Neurodegenerative Disease Inquiry (JPND) projects (grant number SNF 31ND30_141622 (SOPHIA) and 31ND30_151115 (STRENGTH)). Christoph Neuwirth receives honoraria from Biogen Idec, Usa, equally informational board member tasks and training courses and support from the Swiss ALS Foundation and the EU Articulation Programme-Neurodegenerative Disease Inquiry (JPND) projects (grant number SNF 31ND30_141622 (SOPHIA) and 31ND30_151115 (Strength)). Andreas Sommacal reports no disclosures. Peter M. Andersen receives honoraria from Biogen Idec and Neuroimmune for advisory board tasks and counselling on clinical trials. He receives numerous research grants from the Swedish Science Quango and private foundations and patient organizations in Sweden and Norway. Markus Weber receives honoraria from Merz Pharma Schweiz AG, Biogen Idec, USA, as advisory lath member and support from the Swiss ALS Foundation and the Eu Joint Programme-Neurodegenerative Disease Research (JPND) projects (grant number SNF 31ND30_141622 (SOPHIA) and 31ND30_151115 (STRENGTH)).

Data Availability

All relevant information are within the paper and its Supporting Information files.

References

ane. Piao YS, Wakabayashi K, Kakita A, Yamada M, Hayashi S, Morita T, et al. Neuropathology with clinical correlations of sporadic amyotrophic lateral sclerosis: 102 autopsy cases examined betwixt 1962 and 2000. Brain Pathol 2003;13:10–22. [PMC free commodity] [PubMed] [Google Scholar]

2. Kurian KM, Forbes RB, Colville S, Swingler RJ. Cause of death and clinical grading criteria in a accomplice of amyotrophic lateral sclerosis cases undergoing dissection from the Scottish Motor Neurone Disease Register. J Neurol Neurosurg Psychiatry 2009;eighty:84–vii. doi: ten.1136/jnnp.2008.149708 [PubMed] [Google Scholar]

3. Corcia P, Pradat PF, Salachas F, Bruneteau G, Forestier N, Seilhean D, et al. Causes of death in a post-mortem serial of ALS patients. Amyotroph Lateral Scler 2008;9:59–62. doi: 10.1080/17482960701656940 [PubMed] [Google Scholar]

4. Miller RG, Rosenberg JA, Gelinas DF, Mitsumoto H, Newman D, Sufit R, et al. Exercise parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Exercise Parameters Task Strength. Neurology 1999;52:1311–23. [PubMed] [Google Scholar]

5. Miller RG, Jackson CE, Kasarskis EJ, England JD, Forshew D, Johnston W, et al. Practise parameter update: the intendance of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an bear witness-based review): written report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2009;73:1218–26. doi: 10.1212/WNL.0b013e3181bc0141 [PMC costless article] [PubMed] [Google Scholar]

6. Andersen PM, Borasio GD, Dengler R, Hardiman O, Kollewe G, Leigh PN, et al. EFNS task forcefulness on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives. Eur J Neurol 2005;12:921–38. doi: ten.1111/j.1468-1331.2005.01351.x [PubMed] [Google Scholar]

7. Andersen PM, Abrahams S, Borasio GD, de CM, Chio A, Van DP, et al. EFNS guidelines on the clinical direction of amyotrophic lateral sclerosis (MALS)—revised study of an EFNS task force. Eur J Neurol 2012;19:360–75. doi: 10.1111/j.1468-1331.2011.03501.10 [PubMed] [Google Scholar]

viii. Bourke SC, Tomlinson Yard, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Furnishings of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol 2006;v:140–seven. doi: 10.1016/S1474-4422(05)70326-4 [PubMed] [Google Scholar]

x. Spataro R, Ficano 50, Piccoli F, La B, V. Percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: upshot on survival. J Neurol Sci 2011;304:44–8. doi: 10.1016/j.jns.2011.02.016 [PubMed] [Google Scholar]

xi. Rickham PP. Human Experimentation. Code of ethics of the World Medcial Clan. Declaration of Helsinki. Br Med J 1964;two:177 [PMC gratuitous article] [PubMed] [Google Scholar]

12. Akimoto C, Volk EA, van Blitterswijk Grand, Van den Boreck M, Leblond CS, Lumbroso S et al. (2014) A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results amidst 14 laboratories. J Med Genet. 2014. 51:419–24. doi: 10.1136/jmedgenet-2014-102360 [PMC gratis article] [PubMed] [Google Scholar]

13. Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:293–9. [PubMed] [Google Scholar]

14. Cedarbaum JM, Stambler Due north, Malta E, Fuller C, Hilt D, Thurmond B, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase Three). J Neurol Sci 1999;169:xiii–21. [PubMed] [Google Scholar]

xv. Kimura F, Fujimura C, Ishida Southward, Nakajima H, Furutama D, Uehara H, et al. Progression charge per unit of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology 2006;66:265–7. doi: 10.1212/01.wnl.0000194316.91908.8a [PubMed] [Google Scholar]

16. Colosimo C, Hughes AJ, Kilford L, Lees AJ. Lewy body cortical interest may non ever predict dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry 2003;74:852–half-dozen. doi: 10.1136/jnnp.74.vii.852 [PMC complimentary article] [PubMed] [Google Scholar]

eighteen. Victoroff J, Mack WJ, Lyness SA, Chui HC. Multicenter clinicopathological correlation in dementia. Am J Psychiatry 1995;152:1476–84. doi: 10.1176/ajp.152.10.1476 [PubMed] [Google Scholar]

19. Lechtzin Northward. Causes of death amongst French patients with amyotrophic lateral sclerosis: is guideline recommended care getting lost in translation? Eur J Neurol 2009;16:5–half-dozen. doi: 10.1111/j.1468-1331.2008.02327.x [PubMed] [Google Scholar]

twenty. Spataro R, Lo RM, Piccoli T, Piccoli F, La Bella V. Causes and identify of death in Italian patients with amyotrophic lateral sclerosis. Acta Neurol Scand 2010;122:217–23. doi: ten.1111/j.1600-0404.2009.01290.10 [PubMed] [Google Scholar]

21. Gil J, Funalot B, Verschueren A, Danel-Brunaud V, Camu Westward, Vandenberghe North, et al. Causes of decease amid French patients with amyotrophic lateral sclerosis: a prospective study. Eur J Neurol 2008;fifteen:1245–51. doi: 10.1111/j.1468-1331.2008.02307.ten [PubMed] [Google Scholar]

22. Mehal JM, Holman RC, Schonberger LB, Sejvar JJ. Amyotrophic lateral sclerosis/motor neuron illness deaths in the The states, 1999–2009. Amyotroph Lateral Scler Frontotemporal Degener 2013;14:346–52. doi: 10.3109/21678421.2013.787629 [PubMed] [Google Scholar]

23. D'Ottaviano FG, Linhares Filho TA, Andrade HM, Alves PC, Rocha MS. Fiberoptic endoscopy evaluation of swallowing in patients with amyotrophic lateral sclerosis. Braz J Otorhinolaryngol 2013;79:349–53. doi: ten.5935/1808-8694.20130061 [PubMed] [Google Scholar]

25. Sorenson EJ, Crum B, Stevens JC. Incidence of aspiration pneumonia in ALS in Olmsted County, MN. Amyotroph Lateral Scler 2007;eight:87–9. doi: x.1080/17482960601147461 [PubMed] [Google Scholar]

26. Berlowitz DJ, Howard ME, Fiore JF Jr., Vander HS, O'Donoghue FJ, Westlake J, et al. Identifying who will benefit from not-invasive ventilation in amyotrophic lateral sclerosis/motor neurone disease in a clinical accomplice. J Neurol Neurosurg Psychiatry. 2016; 87:280–half-dozen. doi: ten.1136/jnnp-2014-310055 [PubMed] [Google Scholar]

27. Czell D, Bauer Thousand, Binek J, Schoch OD, Weber Thou. Outcomes of percutaneous endoscopic gastrostomy tube insertion in respiratory impaired amyotrophic lateral sclerosis patients under noninvasive ventilation. Respir Intendance 2013;58:838–44. doi: 10.4187/respcare.02024 [PubMed] [Google Scholar]

29. Burns KE, Meade MO, Premji A, Adhikari NK. Noninvasive ventilation as a weaning strategy for mechanical ventilation in adults with respiratory failure: a Cochrane systematic review. CMAJ 2014;186:E112–E122. doi: 10.1503/cmaj.130974 [PMC free article] [PubMed] [Google Scholar]

xxx. Nicolini A, Ferraioli G, Ferrari-Bravo M, Barlascini C, Santo M, Ferrera 50. Early non-invasive ventilation treatment for respiratory failure due to astringent customs-acquired pneumonia. Clin Respir J. 2016;10:98–103. doi: x.1111/crj.12184 [PubMed] [Google Scholar]

31. Kniffin WD Jr., Baron JA, Barrett J, Birkmeyer JD, Anderson FA Jr. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994;154:861–half-dozen. [PubMed] [Google Scholar]

---

Manufactures from PLoS ONE are provided here courtesy of Public Library of Science

---

albersdoopeas.blogspot.com

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441602/

Share this post