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• First study on effect and impact of mechanical ventilation in myotonic dystrophy type 1
  Ghilas Boussaïd, Hélène Prigent, Pascal Laforet, Annane Djillali, David Orlikowski and Frédéric Lofaso
  Published on: 21 April 2025
• Reply to ‘effect and impact of mechanical ventilation in myotonic dystrophy type 1: a prospective cohort study.’
  Charlotte Seijger, Marieke Duiverman, Jellie Nieuwenhuis, Baziel van Engelen and Peter Wijkstra
  Published on: 21 February 2019

• Published on: 21 April 2025

  First study on effect and impact of mechanical ventilation in myotonic dystrophy type 1

  • Ghilas Boussaïd, PT, PhD CIC 1429, INSERM, AP-HP, Hôpital Raymond Poincaré, 92380 Garches, France
  • Other Contributors:
    • Hélène Prigent, MD, PhD
    • Pascal Laforet, MD, PhD
    • Annane Djillali, MD, PhD
    • David Orlikowski, MD, PhD
    • Frédéric Lofaso, MD, PhD

  We thank Dr. Seijger and colleagues for their analysis. These queries are legitimate and most of the answers are in the online repository. Indeed, in order to comply with the guidelines for letters to Thorax (no more than 1000 words and 2 tables / figures), we could not include all our descriptive and univariate analysis.

  We agree that the analysis of survival of patients with type 1 myotonic dystrophy is complex. Our results in Figure 1 and Table R1 demonstrated that patients who refused to initiate NIV, or who delayed NIV initiation, had both a more severe respiratory function and a higher risk for severe event (invasive ventilation or death). Independently from determining whether these severe complications were due to the severity of the initial respiratory function, the lack of compliance to treatment or both, we believe that it was important to underline the presence of this triptych, which is not observed with other neuromuscular groups, such as Duchenne muscular dystrophy where the acceptance of NIV increases with the respiratory dysfunction severity.

  Our suggestion that failure to adhere to home mechanical ventilation was associated with increased mortality (tracheostomy excluded), was based on a Cox model analysing predictors of 10-year mortality among NIV users (Table 1). The Cox model was used to evaluate death risk ratios associated with NIV adherence category and was adjusted for other risk factors described in the literature. The covariates i...

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  We thank Dr. Seijger and colleagues for their analysis. These queries are legitimate and most of the answers are in the online repository. Indeed, in order to comply with the guidelines for letters to Thorax (no more than 1000 words and 2 tables / figures), we could not include all our descriptive and univariate analysis.

  We agree that the analysis of survival of patients with type 1 myotonic dystrophy is complex. Our results in Figure 1 and Table R1 demonstrated that patients who refused to initiate NIV, or who delayed NIV initiation, had both a more severe respiratory function and a higher risk for severe event (invasive ventilation or death). Independently from determining whether these severe complications were due to the severity of the initial respiratory function, the lack of compliance to treatment or both, we believe that it was important to underline the presence of this triptych, which is not observed with other neuromuscular groups, such as Duchenne muscular dystrophy where the acceptance of NIV increases with the respiratory dysfunction severity.

  Our suggestion that failure to adhere to home mechanical ventilation was associated with increased mortality (tracheostomy excluded), was based on a Cox model analysing predictors of 10-year mortality among NIV users (Table 1). The Cox model was used to evaluate death risk ratios associated with NIV adherence category and was adjusted for other risk factors described in the literature. The covariates included were sex, age at NIV introduction, and variables with a p value <0.15 in the univariate analysis identified by progressive selection (also included in the online repository).

  In univariate analysis, having a pacemaker was not significantly associated with mortality. All our DM1 patients are systematically explored in a specialised cardiologic ward [1] which belongs to the same reference center for neuromuscular patients as our unit [2]; therefore patients with diagnosed heart conduction disturbances underwent pacemaker placement [3], which limited their risk of death from cardiac causes. Regarding functional status, all patients were walking.

  One of the main objectives of ventilatory support is to improve gas exchanges regardless the mechanism (respiratory pump failure or respiratory drive dysfunction), which means the normalization of PaCO₂, and to improve the signs and symptoms, which has already been demonstrated by Nugent and al [4]. However, the aim of our study was to identify the long term impact of mechanical ventilation, and not its short-term effectiveness.  Our usual follow-up aims to ensure that patients are well ventilated within the first 3 months of treatment initiation. During nighttime, and daytime when required, both ventilator settings and interfaces are adjusted using repeated polygraphies (with transcutaneous PCO₂), or polysomnographies [5, 6] when necessary, until patients-ventilator interaction is correct and nocturnal transcutaneous PCO₂ improves. Moreover, we also use pharmacological treatments when residual daytime hypersomnolence is due solely to central neurological dysfunction [7, 8], as our specialised sleep laboratory is also certified as a reference centre for daytime sleepiness, where we can objectively evaluate daytime sleepiness and efficiency of different treatments by Multiple Sleep Latency Tests and/or the Maintenance of Wakefulness Tests [9]. NIV and sleep were usually efficient within the first months and were controlled every year [6] when patients accepted to continue mechanical ventilation and to come back. Therefore, it was not our objective to prove the effectiveness of mechanical ventilation in this manuscript, considering that at this stage the most important factor, in our opinion, is the adherence to treatment.

  In conclusion, the main limit of this study is that it involved a single-center which limits the generalization of the findings. However, because there is no data in the literature regarding the long term impact of mechanical ventilation on DM1 patients survival, this study could be considered as the first report on which to base larger, multicenter studies as suggested by Dr. Seijger and colleagues.

   

  Reference

  [1] Wahbi K, Babuty D, Probst V, Wissocque L, Labombarda F, Porcher R, Bécane HM, Lazarus A, Béhin A, Laforêt P, Stojkovic T, Clementy N, Dussauge AP, Gourraud JB, Pereon Y, Lacour A, Chapon F, Milliez P, Klug D, Eymard B, Duboc D. Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1. Eur Heart J. 2017 Mar 7;38(10):751-758.

  [2] Boussaïd G, Wahbi K, Laforet P, Eymard B, Stojkovic T, Behin A, Djillali A,

  Orlikowski D, Prigent H, Lofaso F. Genotype and other determinants of respiratory function in myotonic dystrophy type 1. Neuromuscul Disord. 2018 Mar;28(3):222-228.

  [3] Wahbi K, Meune C, Porcher R, Bécane HM, Lazarus A, Laforêt P, Stojkovic T, Béhin A, Radvanyi-Hoffmann H, Eymard B, Duboc D. Electrophysiological study with prophylactic pacing and survival in adults with myotonic dystrophy and conduction system disease. JAMA. 2012 Mar 28;307(12):1292-301.

  [4] Nugent AM, Smith IE, Shneerson JM. Domiciliary-assisted ventilation in patients with myotonic dystrophy. Chest. 2002 Feb;121(2):459-64.

  [5] Nardi J, Prigent H, Garnier B, Lebargy F, Quera-Salva MA, Orlikowski D, Lofaso F. Efficiency of invasive mechanical ventilation during sleep in Duchenne muscular dystrophy. Sleep Med. 2012 Sep;13(8):1056-65.

  [6] Annane D, Quera-Salva MA, Lofaso F, Vercken JB, Lesieur O, Fromageot C, Clair B, Gajdos P, Raphael JC. Mechanisms underlying effects of nocturnal ventilation on daytime blood gases in neuromuscular diseases. Eur Respir J. 1999 Jan;13(1):157-62.
  [7] Orlikowski D, Chevret S, Quera-Salva MA, Laforêt P, Lofaso F, Verschueren A, Pouget J, Eymard B, Annane D. Modafinil for the treatment of hypersomnia associated with myotonic muscular dystrophy in adults: a multicenter, prospective, randomized, double-blind, placebo-controlled, 4-week trial. Clin Ther. 2009 Aug;31(8):1765-73.

  [8] Hilton-Jones D, Bowler M, Lochmueller H, Longman C, Petty R, Roberts M, Rogers M, Turner C, Wilcox D. Modafinil for excessive daytime sleepiness in myotonic dystrophy type 1--the patients' perspective. Neuromuscul Disord. 2012 Jul;22(7):597-603.

  [9] Orlikowski D, Chevret S, Quera-Salva MA, Laforêt P, Lofaso F, Verschueren A, Pouget J, Eymard B, Annane D. Modafinil for the treatment of hypersomnia associated with myotonic muscular dystrophy in adults: a multicenter, prospective, randomized, double-blind, placebo-controlled, 4-week trial. Clin Ther. 2009 Aug;31(8):1765-73.

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  Conflict of Interest:
  None declared.

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• Published on: 21 February 2019

  Reply to ‘effect and impact of mechanical ventilation in myotonic dystrophy type 1: a prospective cohort study.’

  • Charlotte Seijger, Pulmonologist in training University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Home mechanical ventilation,
  • Other Contributors:
    • Marieke Duiverman, Pulmonologist
    • Jellie Nieuwenhuis, pulmonologist
    • Baziel van Engelen, neurologist
    • Peter Wijkstra, pulmonologist

  To the editor,

  We read with great interest the paper of Boussaïd et al.1. They showed that Myotonic Dystrophy type 1 (DM1) patients who refused or delayed non-invasive ventilation were at higher risk for severe events, the latter defined as invasive ventilation or death. In the NIV users, risk of death was associated with orthopnoea and adherence to therapy. The investigators concluded that non-use or poor adherence of home mechanical ventilation (HMV) may be associated with increased mortality. Despite the importance of these findings several comments can be made.

  First, survival analyses in DM1 patients are complex due to heterogeneity and several other factors which have to be taken into account if the effects of HMV are assessed. For example not only the variance of reduced pulmonary function but also neuromuscular deficits, apathy, cardiac conduction disturbances, presence of obstructive or central sleep apnea do all influence the clinical condition and prognosis of these patients2. In addition, there remains the possibility that hypercapnia might not always be a result of ventilatory pump failure and that HMV might not be effective3. Correction for these confounders is needed to investigate the real effect of HMV. Moreover, both groups differ in vital capacity and presence of hypercapnia at baseline. So, we are not sure whether the risk of a severe event is really higher in the l/noNIV group than in the other groups. Therefore the presented difference...

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  To the editor,

  We read with great interest the paper of Boussaïd et al.1. They showed that Myotonic Dystrophy type 1 (DM1) patients who refused or delayed non-invasive ventilation were at higher risk for severe events, the latter defined as invasive ventilation or death. In the NIV users, risk of death was associated with orthopnoea and adherence to therapy. The investigators concluded that non-use or poor adherence of home mechanical ventilation (HMV) may be associated with increased mortality. Despite the importance of these findings several comments can be made.

  First, survival analyses in DM1 patients are complex due to heterogeneity and several other factors which have to be taken into account if the effects of HMV are assessed. For example not only the variance of reduced pulmonary function but also neuromuscular deficits, apathy, cardiac conduction disturbances, presence of obstructive or central sleep apnea do all influence the clinical condition and prognosis of these patients2. In addition, there remains the possibility that hypercapnia might not always be a result of ventilatory pump failure and that HMV might not be effective3. Correction for these confounders is needed to investigate the real effect of HMV. Moreover, both groups differ in vital capacity and presence of hypercapnia at baseline. So, we are not sure whether the risk of a severe event is really higher in the l/noNIV group than in the other groups. Therefore the presented difference might be due to differences in baseline covariates such as age at first visit, pulmonary function or other factors.

  Second, one of the main goals of ventilatory support is to improve gas-exchange, which means normalisation of the CO2, and to improve signs and symptoms. However, we do not know whether HMV was effective in this study, as information about CO2 reduction during HMV is not presented. Therefore, we have to be careful with strong conclusions.

  Finally, as patients who accepted NIV late or not at all are combined in one group in figure 1, it is not possible to distinguish differences in prognosis between these subgroups. In addition, figure 1 is confusing as the title suggests a mortality curve, but an event is defined as invasive ventilation or death. Also it is unclear which line belongs to which subgroup as the legend of the figure is missing.

  In conclusion, the heterogeneity of DM1 requests for correction of several covariates in statistical analyses. Without these considerations, we must be careful in interpreting the results of this study and we recommend that new studies about the effects of HMV in DM1 must take these heterogeneity aspects into account.
   
  References
  1. Boussaid G, Prigent H, Laforet P, et al. Effect and impact of mechanical ventilation in myotonic dystrophy type 1: A prospective cohort study. Thorax. 2018;73(11):1075-1078.
  2. Turner C, Hilton-Jones D. The myotonic dystrophies: Diagnosis and management. J Neurol Neurosurg Psychiatry. 2010;81(4):358-367.
  3. West SD, Lochmuller H, Hughes J, et al. Sleepiness and sleep-related breathing disorders in myotonic dystrophy and responses to treatment: A prospective cohort study. J Neuromuscul Dis. 2016;3(4):529-537.

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  Conflict of Interest:
  None declared.

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