Autonomic dysfunction is associated with disease progression and survival in amyotrophic lateral sclerosis: a prospective longitudinal cohort study.
ALS
Autonomic dysfunction
Motor neuron disease
Non-motor symptoms
Prognosis
Survival
Journal
Journal of neurology
ISSN: 1432-1459
Titre abrégé: J Neurol
Pays: Germany
ID NLM: 0423161
Informations de publication
Date de publication:
Oct 2023
Oct 2023
Historique:
received:
26
04
2023
accepted:
19
06
2023
revised:
17
06
2023
medline:
21
9
2023
pubmed:
26
6
2023
entrez:
26
6
2023
Statut:
ppublish
Résumé
Among non-motor symptoms, autonomic disturbances have been described in amyotrophic lateral sclerosis (ALS) and reported as mild to moderate in up to 75% of patients. However, no study has systematically investigated autonomic symptoms as prognostic factors. The main aim of this longitudinal study was to examine the association of autonomic dysfunction with disease progression and survival in ALS. We enrolled newly diagnosed ALS patients and a healthy control group (HC). Time from disease onset to disease milestone (King's stage 4) and death were calculated to assess disease progression and survival. Autonomic symptoms were assessed by a dedicated questionnaire. Longitudinal evaluation of parasympathetic cardiovascular activity was performed by the heart rate variability (HRV). Multivariable Cox proportional hazards regression models on the risk of the disease milestone and death were used. A mixed-effect linear regression model was used to compare autonomic dysfunction with a HC group as well as its impairment over time. A total of 102 patients and 41 HC were studied. ALS patients, compared with HC, complained of more autonomic symptoms, especially in bulbar onset patients. Autonomic symptoms occurred in 69 (68%) patients at diagnosis and progressed over time (post-6: p = 0.015 and post-12: p < 0.001). A higher autonomic symptom burden was an independent marker of faster development of King's stage 4 (HR 1.05; 95% CI 1.00-1.11; p = 0.022); whereas, urinary complaints were independent factors of a shorter survival (HR 3.12; 95% CI 1.22-7.97; p = 0.018). Moreover, HRV in ALS patients was lower than in HC (p = 0.018) and further decreased over time (p = 0.003), implying a parasympathetic hypofunction that progressed over time. Autonomic symptoms occur in most of the ALS patients at diagnosis and progress over time, implying that autonomic dysfunction represents an intrinsic non-motor feature of the disease. A higher autonomic burden is a poor prognostic factor, associated with a more rapid development of disease milestones and shorter survival.
Sections du résumé
BACKGROUND
BACKGROUND
Among non-motor symptoms, autonomic disturbances have been described in amyotrophic lateral sclerosis (ALS) and reported as mild to moderate in up to 75% of patients. However, no study has systematically investigated autonomic symptoms as prognostic factors.
OBJECTIVES
OBJECTIVE
The main aim of this longitudinal study was to examine the association of autonomic dysfunction with disease progression and survival in ALS.
METHODS
METHODS
We enrolled newly diagnosed ALS patients and a healthy control group (HC). Time from disease onset to disease milestone (King's stage 4) and death were calculated to assess disease progression and survival. Autonomic symptoms were assessed by a dedicated questionnaire. Longitudinal evaluation of parasympathetic cardiovascular activity was performed by the heart rate variability (HRV). Multivariable Cox proportional hazards regression models on the risk of the disease milestone and death were used. A mixed-effect linear regression model was used to compare autonomic dysfunction with a HC group as well as its impairment over time.
RESULTS
RESULTS
A total of 102 patients and 41 HC were studied. ALS patients, compared with HC, complained of more autonomic symptoms, especially in bulbar onset patients. Autonomic symptoms occurred in 69 (68%) patients at diagnosis and progressed over time (post-6: p = 0.015 and post-12: p < 0.001). A higher autonomic symptom burden was an independent marker of faster development of King's stage 4 (HR 1.05; 95% CI 1.00-1.11; p = 0.022); whereas, urinary complaints were independent factors of a shorter survival (HR 3.12; 95% CI 1.22-7.97; p = 0.018). Moreover, HRV in ALS patients was lower than in HC (p = 0.018) and further decreased over time (p = 0.003), implying a parasympathetic hypofunction that progressed over time.
CONCLUSION
CONCLUSIONS
Autonomic symptoms occur in most of the ALS patients at diagnosis and progress over time, implying that autonomic dysfunction represents an intrinsic non-motor feature of the disease. A higher autonomic burden is a poor prognostic factor, associated with a more rapid development of disease milestones and shorter survival.
Identifiants
pubmed: 37358634
doi: 10.1007/s00415-023-11832-w
pii: 10.1007/s00415-023-11832-w
pmc: PMC10511550
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4968-4977Informations de copyright
© 2023. The Author(s).
Références
Mahoney CJ, Ahmed RM, Huynh W et al (2021) Pathophysiology and treatment of non-motor dysfunction in amyotrophic lateral sclerosis. CNS Drugs 35:483–505. https://doi.org/10.1007/s40263-021-00820-1
doi: 10.1007/s40263-021-00820-1
pubmed: 33993457
Elamin M, Phukan J, Bede P et al (2011) Executive dysfunction is a negative prognostic indicator in patients with ALS without dementia. Neurology 76:1263–1269. https://doi.org/10.1212/WNL.0b013e318214359f
doi: 10.1212/WNL.0b013e318214359f
pubmed: 21464431
Nguyen C, Caga J, Mahoney CJ et al (2021) Behavioural changes predict poorer survival in amyotrophic lateral sclerosis. Brain Cogn 150:105710. https://doi.org/10.1016/j.bandc.2021.105710
doi: 10.1016/j.bandc.2021.105710
pubmed: 33725515
Piccione EA, Sletten DM, Staff NP, Low PA (2015) Autonomic system and amyotrophic lateral sclerosis. Muscle Nerve 51:676–679. https://doi.org/10.1002/mus.24457
doi: 10.1002/mus.24457
pubmed: 25211238
pmcid: 4362936
De Carvalho MLL, Motta R, Battaglia MA, Brichetto G (2011) Urinary disorders in amyotrophic lateral sclerosis subjects. Amyotroph Lateral Scler 12:352–355. https://doi.org/10.3109/17482968.2011.574141
doi: 10.3109/17482968.2011.574141
Arlandis S, Vázquez-Costa JF, Martínez-Cuenca E et al (2017) Urodynamic findings in amyotrophic lateral sclerosis patients with lower urinary tract symptoms: results from a pilot study. Neurourol Urodyn 36:626–631. https://doi.org/10.1002/nau.22976
doi: 10.1002/nau.22976
pubmed: 26895486
Nübling GS, Mie E, Bauer RM et al (2014) Increased prevalence of bladder and intestinal dysfunction in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 15:174–179. https://doi.org/10.3109/21678421.2013.868001
doi: 10.3109/21678421.2013.868001
pubmed: 24479577
Nolano M, Provitera V, Manganelli F et al (2017) Non-motor involvement in amyotrophic lateral sclerosis: new insight from nerve and vessel analysis in skin biopsy. Neuropathol Appl Neurobiol 43:119–132. https://doi.org/10.1111/nan.12332
doi: 10.1111/nan.12332
pubmed: 27288647
Pisano F, Miscio G, Mazzuero G et al (1995) Decreased heart rate variability in amyotrophic lateral sclerosis. Muscle Nerve 18:1225–1231. https://doi.org/10.1002/mus.880181103
doi: 10.1002/mus.880181103
pubmed: 7565918
Baltadzhieva R, Gurevich T, Korczyn AD (2005) Autonomic impairment in amyotrophic lateral sclerosis. Curr Opin Neurol 18:487–493. https://doi.org/10.1097/01.wco.0000183114.76056.0e
doi: 10.1097/01.wco.0000183114.76056.0e
pubmed: 16155429
Low PA, Reich SG, Jankovic J et al (2015) Natural history of multiple system atrophy in the USA: a prospective cohort study. Lancet Neurol 14:710–719. https://doi.org/10.1016/S1474-4422(15)00058-7
doi: 10.1016/S1474-4422(15)00058-7
pubmed: 26025783
pmcid: 4472464
De Pablo-Fernandez E, Tur C, Revesz T et al (2017) Association of autonomic dysfunction with disease progression and survival in Parkinson disease. JAMA Neurol 74:970–976. https://doi.org/10.1001/jamaneurol.2017.1125
doi: 10.1001/jamaneurol.2017.1125
pubmed: 28655059
pmcid: 5710320
Stubendorff K, Aarsland D, Minthon L, Londos E (2012) The impact of autonomic dysfunction on survival in patients with dementia with Lewy bodies and Parkinson’s disease with dementia. PLoS One 7:3–8. https://doi.org/10.1371/journal.pone.0045451
doi: 10.1371/journal.pone.0045451
Oliveira MCB, Ling H, Lees AJ et al (2019) Association of autonomic symptoms with disease progression and survival in progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 90:555–561. https://doi.org/10.1136/jnnp-2018-319374
doi: 10.1136/jnnp-2018-319374
pubmed: 30598430
Shaffer F, Ginsberg JP (2017) An overview of heart rate variability metrics and norms. Front Public Health 5:1–17. https://doi.org/10.3389/fpubh.2017.00258
doi: 10.3389/fpubh.2017.00258
Brooks BR, Miller RG, Swash M, Munsat TL (2000) El Escorial revisited: revised criteria for the diagnosis of ALS. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293–299
doi: 10.1080/146608200300079536
pubmed: 11464847
Czaplinski A, Yen AA, Appel SH (2006) Forced vital capacity (FVC) as an indicator of survival and disease progression in an ALS clinic population. J Neurol Neurosurg Psychiatry 77:390–392. https://doi.org/10.1136/jnnp.2005.072660
doi: 10.1136/jnnp.2005.072660
pubmed: 16484652
pmcid: 2077717
Labra J, Menon P, Byth K et al (2016) Rate of disease progression: a prognostic biomarker in ALS. J Neurol Neurosurg Psychiatry 87:628–632. https://doi.org/10.1136/jnnp-2015-310998
doi: 10.1136/jnnp-2015-310998
pubmed: 26152368
Shibuya K, Park SB, Geevasinga N et al (2016) Motor cortical function determines prognosis in sporadic ALS. Neurology 87:513–520. https://doi.org/10.1212/WNL.0000000000002912
doi: 10.1212/WNL.0000000000002912
pubmed: 27402895
Roche JC, Rojas-Garcia R, Scott KM et al (2012) A proposed staging system for amyotrophic lateral sclerosis. Brain 135:847–852. https://doi.org/10.1093/brain/awr351
doi: 10.1093/brain/awr351
pubmed: 22271664
pmcid: 3286327
Strong MJ, Abrahams S, Goldstein LH et al (2017) Amyotrophic lateral sclerosis—frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener 18:153–174. https://doi.org/10.1080/21678421.2016.1267768
doi: 10.1080/21678421.2016.1267768
pubmed: 28054827
pmcid: 7409990
Manera U, Calvo A, Daviddi M et al (2019) Regional spreading of symptoms at diagnosis as a prognostic marker in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry. https://doi.org/10.1136/jnnp-2019-321153
doi: 10.1136/jnnp-2019-321153
pubmed: 31871138
Dubbioso R, Spisto M, Hausdorff JM, Aceto G, Iuzzolino VV, Senerchia G, De Marco S, Marcuccio L, Femiano C, Iodice R, Salvatore E, Santangelo G, Trojano L, Moretta P. Cognitive impairment is associated with gait variability and fall risk in Amyotrophic Lateral Sclerosis. Eur J Neurol. 2023. https://doi.org/10.1111/ene.15936
doi: 10.1111/ene.15936
pubmed: 37335396
Moretta P, Spisto M, Ausiello FP et al (2022) Alteration of interoceptive sensitivity: expanding the spectrum of behavioural disorders in amyotrophic lateral sclerosis. Neurol Sci 43:5403–5410. https://doi.org/10.1007/s10072-022-06231-4
doi: 10.1007/s10072-022-06231-4
pubmed: 35751711
pmcid: 9385786
De Lucia N, Ausiello FP, Spisto M et al (2020) The emotional impact of COVID-19 outbreak in amyotrophic lateral sclerosis patients: evaluation of depression, anxiety and interoceptive awareness. Neurol Sci 41:2339–2341. https://doi.org/10.1007/s10072-020-04592-2
doi: 10.1007/s10072-020-04592-2
pubmed: 32666406
pmcid: 7359442
Visser M, Marinus J, Stiggelbout AM, van Hilten JJ (2004) Assessment of autonomic dysfunction in Parkinson’s disease: the SCOPA-AUT. Mov Disord 19:306–312. https://doi.org/10.1002/mds.20153
doi: 10.1002/mds.20153
Damon-Perrière N, Foubert-Samier A, De Cock VC et al (2012) Assessment of the Scopa-Aut questionnaire in multiple system atrophy: relation to UMSARS scores and progression over time. Parkinsonism Relat Disord 18:612–615. https://doi.org/10.1016/j.parkreldis.2011.12.009
doi: 10.1016/j.parkreldis.2011.12.009
pubmed: 22236582
Dubbioso R, Provitera V, Vitale F et al (2021) Cutaneous sensory and autonomic denervation in progressive supranuclear palsy. Neuropathol Appl Neurobiol. https://doi.org/10.1111/nan.12692
doi: 10.1111/nan.12692
pubmed: 33421177
Kennedy PGE, Duchen LW (1985) A quantitative study of intermediolateral column cells in motor neuron disease and the Shy–Drager syndrome. J Neurol Neurosurg Psychiatry 48:1103–1106. https://doi.org/10.1136/jnnp.48.11.1103
doi: 10.1136/jnnp.48.11.1103
pubmed: 4078575
pmcid: 1028568
Takahashi H, Oyanagi K, Ikuta F (1993) The intermediolateral nucleus in sporadic amyotrophic lateral sclerosis. Acta Neuropathol 86:190–192. https://doi.org/10.1007/BF00334889
doi: 10.1007/BF00334889
pubmed: 8213074
Konno H, Yamamoto T, Iwasaki Y, Iizuka H (1986) Shy-Drager syndrome and amyotrophic lateral sclerosis. Cytoarchitectonic and morphometric studies of sacral autonomic neurons. J Neurol Sci 73:193–204. https://doi.org/10.1016/0022-510X(86)90130-9
doi: 10.1016/0022-510X(86)90130-9
pubmed: 3701375
Weis J, Katona I, Müller-Newen G et al (2011) Small-fiber neuropathy in patients with ALS. Neurology 76:2024–2029. https://doi.org/10.1212/WNL.0b013e31821e553a
doi: 10.1212/WNL.0b013e31821e553a
pubmed: 21646630
Truini A, Biasiotta A, Onesti E et al (2015) Small-fibre neuropathy related to bulbar and spinal-onset in patients with ALS. J Neurol 262:1014–1018. https://doi.org/10.1007/s00415-015-7672-0
doi: 10.1007/s00415-015-7672-0
pubmed: 25683764
Dalla Bella E, Lombardi R, Porretta-Serapiglia C et al (2016) Amyotrophic lateral sclerosis causes small fiber pathology. Eur J Neurol 23:416–420. https://doi.org/10.1111/ene.12936
doi: 10.1111/ene.12936
pubmed: 26806218
Robertson DW, Biaggioni I, Burnstock G et al (2012) Primer on the autonomic nervous system. Elsevier
Shimizu T, Kawata A, Kato S et al (2000) Autonomic failure in ALS with a novel SOD1 gene mutation. Neurology 54:1534–1537. https://doi.org/10.1212/WNL.54.7.1534
doi: 10.1212/WNL.54.7.1534
pubmed: 10751275
Parra-Cantu C, Zaldivar-Ruenes A, Martinez-Vazquez M, Martinez HR (2021) Prevalence of gastrointestinal symptoms, severity of dysphagia, and their correlation with severity of amyotrophic lateral sclerosis in a Mexican cohort. Neurodegener Dis 21:42–47. https://doi.org/10.1159/000517613
doi: 10.1159/000517613
pubmed: 34139704
Toepfer M, Folwaczny C, Lochmüller H et al (1999) Noninvasive 13C-octanoic acid breath test shows delayed gastric emptying in patients with amyotrophic lateral sclerosis. Digestion 60:567–571. https://doi.org/10.1159/000007708
doi: 10.1159/000007708
pubmed: 10545728
Toepfer M, Schroeder M, Klause R et al (1997) Delayed colonic transit times in amyotrophic lateral sclerosis assessed with radio-opaque markers. Eur J Med Res 2:473–476
pubmed: 9385117
Vázquez-Costa JF, Arlandis S, Hervas D et al (2017) Clinical profile of motor neuron disease patients with lower urinary tract symptoms and neurogenic bladder. J Neurol Sci 378:130–136. https://doi.org/10.1016/j.jns.2017.04.053
doi: 10.1016/j.jns.2017.04.053
pubmed: 28566149
Kiernan HAJ (1993) Changes in shapes of surviving motor neurons in amyotrophic lateral sclerosis. Brain 116:203–215. https://doi.org/10.1093/brain/116.1.203
doi: 10.1093/brain/116.1.203
pubmed: 8453457
Pavlovic S, Stevic Z, Milovanovic B et al (2010) Impairment of cardiac autonomic control in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 11:272–276. https://doi.org/10.3109/17482960903390855
doi: 10.3109/17482960903390855
pubmed: 20001491
Dalla Vecchia L, De Maria B, Marinou K et al (2015) Cardiovascular neural regulation is impaired in amyotrophic lateral sclerosis patients. A study by spectral and complexity analysis of cardiovascular oscillations. Physiol Meas 36:659–670. https://doi.org/10.1088/0967-3334/36/4/659
doi: 10.1088/0967-3334/36/4/659
pubmed: 25798998
De Maria B, Bari V, Marchi A, et al (2015) Cardiovascular control indexes in amyotrophic lateral sclerosis patients and their relation with clinical markers. Proceedings of the annual international conference of the IEEE engineering in medicine and biology society, EMBS 2015-November:2055–2058. https://doi.org/10.1109/EMBC.2015.7318791
Lipp A, Tank J, Stoffels M et al (2003) Riluzole and blood pressure in multiple system atrophy. Clin Auton Res 13:271–274. https://doi.org/10.1007/s10286-003-0100-z
doi: 10.1007/s10286-003-0100-z
pubmed: 12955551