Acta Neurol Scand DOI: 10.1111/ane.12355
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Sleep and breathing disorders in myotonic dystrophy type 2 Leonardis L, Blagus R, Dolenc Groselj L. Sleep and breathing disorders in myotonic dystrophy type 2. Acta Neurol Scand: DOI: 10.1111/ane.12355. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objectives – In patients who exhibit myotonic dystrophy type 1 (DM1), sleep disorders and breathing impairments are common; however, in those with DM type 2 (DM2), limited studies on polysomnography (PSG) and none on phrenic compound motor action potential (CMAP) have been performed, which is the aim of this study. Materials and methods – Sixteen patients with DM2 were questioned about respiratory symptoms. They underwent PSG with morning arterial gas analyses (AGA). Respiratory functions and phrenic CMAPs were studied. The data were compared to those of 16 healthy controls and 25 patients with DM1. Results – Daytime tiredness is the most common symptom, but orthopnea was reported in 13% of patients with DM2. A detailed sleep architecture analysis revealed a significantly greater proportion of time in stage 3 and REM sleep, and a shorter time in stage 2 in the DM2 than in controls. Lower respiratory volumes and pressures, abnormalities in AGA, night oxygen desaturation and higher EtCO2 are present in DM2, but are less pronounced than in the DM1 population. Small CMAP amplitudes were presented in 12% of patients with DM2, correlating with smaller respiratory functions and poorer sleep quality. AHI was abnormal in 38% of DM2, mainly due to obstructive apneas. PSG did not reveal hypoventilation. Conclusions – Diaphragm weakness and sleep apneas might be present in patients with DM2; therefore, we suggest regular questioning about symptoms of respiratory insufficiency and monitoring of phrenic CMAP. PSG should be recorded, when patients have suggestive symptoms, abnormalities in AGA or higher BMI.
Introduction
Myotonic dystrophies (DMs) are progressive, multisystemic, dominantly-inherited disorders characterized by muscle weakness with myotonia, cataract, diabetes mellitus, cognitive decline, and heart abnormalities. Two forms are identified: DM type 1 (DM1) (OMIM #160900) caused by an unstable CTG repeat expansion on chromosome 19q13.3 (1, 2) and DM type 2 (DM2) (OMIM #602668) caused by heterozygous expansion of a CCTG repeat on chromosome 3q21.3 (2, 3). DM1 and DM2 are genetically different disorders, but with similar physiological mechanisms. In both diseases, the expression of a mutated
L. Leonardis1, R. Blagus2, L. Dolenc Groselj1 1 Institute of Clinical Neurophysiology, University Medical Center Ljubljana, Ljubljana, Slovenia; 2Medical Faculty, Institute for Biostatistics and Medical Informatics, Ljubljana, Slovenia
Key words: arterial gas analyses; myotonic dystrophy type 2; phrenic nerve conduction studies; polysomnography; respiratory functions L. Leonardis, Institute of Clinical Neurophysiology, University Medical Center Ljubljana, Zaloska 7, SI-1525 Ljubljana, Slovenia Tel.: +386 1 522 1500 Fax: +386 1 522 1533 e-mail: [email protected] Accepted for publication October 31, 2014
gene causes an accumulation of aberrant RNA in the nucleus, which affects the splicing of further genes (4, 5). Their phenotypes are similar, although some clinical differences are well known, such as the presence of the congenital form in DM1 vs its absence in DM2, distal vs proximal muscle involvement in DM1 vs DM2 and milder phenotype in DM2 (6). In DM1, sleep and breathing disorders are common (7–10), while in DM2, only a few polysomnography (PSG) studies and no nerve conduction studies in phrenic nerves have been performed. The extension of sleep and breathing disorders in DM2 is not well known, although excessive daytime sleepiness (EDS), poor sleep quality, decreased sleep efficiency, sleep-disordered breathing, 1
Leonardis et al. alpha-delta sleep, paradoxical breathing during REM sleep, REM sleep without atonia, and periodic limb movements in sleep (PLMS) were reported (11–15). The aim of our study was to investigate sleep and breathing disorders in patients with DM2, so we invited all genetically proven Slovene patients with DM2. We performed full PSG recordings with arterial gas analyses (AGA) on the awakening, phrenic motor nerve conduction studies (MNCS), analyzed respiratory functions and symptoms and compared the results with ageand sex-matched healthy controls and unselected adult-onset patients with DM1. Methods Subjects
An invitation letter was sent to all 17 patients with genetically confirmed DM2 and to 30 randomly selected patients with DM1 from a Slovenian register of patients with neuromuscular disorders. Sixteen healthy volunteers, with no history of neurological, respiratory or sleep disorders participated in the study. The study was approved by the National Ethics Committee of Slovenia, and all subjects provided informed consent before participating in the study.
Pulse Oximeter, Oxismart XL, Covidien-Nellcor, Boulder, CO, USA), CO2 monitoring (EtCO2) (Capnogard; Philips Respironics, Herrsching, Germany), and continuous video monitoring. On awakening the next morning, all subjects underwent AGA analysis (Gas Lyte sampler; Vital signs, Totowa, NJ, USA). All recordings were visually analyzed, and the apnea/hypopnea index (AHI) was scored by a sleep expert, following the European Sleep Research Society guidelines (17) and the American Association for Sleep Medicine guidelines (16). Phrenic MNCS
Phrenic MNCS were measured on the left side with a bipolar stimulating electrode (16893; Medelec, Old Woking, UK), placed supraclavicular between the sternal and clavicular heads or behind the sternocleidomastoid muscle. The disposable self-adhesive disk recording electrodes (Viasys Healthcare, Madison, WI, USA) were glued 5 cm above the xiphoid process (active electrode G1) and 16 cm from G1 on the chest margin (the reference electrode G2) (18, 19). We used a standard EMG system (Keypoint; Natus, Alpine Biomed, Skovlunde, Denmark) with standard settings (filters, 2 Hz–10 kHz). Statistical analyses
Respiratory symptoms and functions
All patients were questioned about dyspnea on exertion, orthopnea, morning headaches, daytime sleepiness, night wakefulness, nightmares, and of tiredness during the day. In further analyses, we used these symptoms as either present (1) or not (0). Respiratory muscle function was assessed in all patients and controls by measurement of vital capacity (VC) (Vitalograph ALPHA, Ennis, Ireland) in both the sitting and lying positions, maximal inspiratory pressure (MIP), and sniff nasal pressure (SNP) (MicroRPM, CareFusion, San Diego, CA, USA). PSG and AGA at awakening
All patients and controls underwent a full, overnight, in-laboratory, technician-attended PSG assessment recorded on a commercial PSG system (Nicolet One nEEG; Neurocare, Madison, WI, USA) using standard PSG settings (16). The recording included EEG, EOG, chin surface EMG, ECG, nasal pressure (nasal pressure cannula), respiratory movements (chest and abdominal belts), oxyhemoglobin saturation (Nellcor 2
Data are presented as the median and interquartile range. The intergroup differences were analyzed with a Mann–Whitney or Fisher exact test. For the binary variables, odds ratios (OR) with 95% confidence intervals (CI) were also calculated. Pearson’s correlation coefficients (R) with the corresponding 95% CI were calculated to estimate the correlation between numeric variables. A P-value of
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Sleep and breathing disorders in myotonic dystrophy type 2 Leonardis L, Blagus R, Dolenc Groselj L. Sleep and breathing disorders in myotonic dystrophy type 2. Acta Neurol Scand: DOI: 10.1111/ane.12355. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objectives – In patients who exhibit myotonic dystrophy type 1 (DM1), sleep disorders and breathing impairments are common; however, in those with DM type 2 (DM2), limited studies on polysomnography (PSG) and none on phrenic compound motor action potential (CMAP) have been performed, which is the aim of this study. Materials and methods – Sixteen patients with DM2 were questioned about respiratory symptoms. They underwent PSG with morning arterial gas analyses (AGA). Respiratory functions and phrenic CMAPs were studied. The data were compared to those of 16 healthy controls and 25 patients with DM1. Results – Daytime tiredness is the most common symptom, but orthopnea was reported in 13% of patients with DM2. A detailed sleep architecture analysis revealed a significantly greater proportion of time in stage 3 and REM sleep, and a shorter time in stage 2 in the DM2 than in controls. Lower respiratory volumes and pressures, abnormalities in AGA, night oxygen desaturation and higher EtCO2 are present in DM2, but are less pronounced than in the DM1 population. Small CMAP amplitudes were presented in 12% of patients with DM2, correlating with smaller respiratory functions and poorer sleep quality. AHI was abnormal in 38% of DM2, mainly due to obstructive apneas. PSG did not reveal hypoventilation. Conclusions – Diaphragm weakness and sleep apneas might be present in patients with DM2; therefore, we suggest regular questioning about symptoms of respiratory insufficiency and monitoring of phrenic CMAP. PSG should be recorded, when patients have suggestive symptoms, abnormalities in AGA or higher BMI.
Introduction
Myotonic dystrophies (DMs) are progressive, multisystemic, dominantly-inherited disorders characterized by muscle weakness with myotonia, cataract, diabetes mellitus, cognitive decline, and heart abnormalities. Two forms are identified: DM type 1 (DM1) (OMIM #160900) caused by an unstable CTG repeat expansion on chromosome 19q13.3 (1, 2) and DM type 2 (DM2) (OMIM #602668) caused by heterozygous expansion of a CCTG repeat on chromosome 3q21.3 (2, 3). DM1 and DM2 are genetically different disorders, but with similar physiological mechanisms. In both diseases, the expression of a mutated
L. Leonardis1, R. Blagus2, L. Dolenc Groselj1 1 Institute of Clinical Neurophysiology, University Medical Center Ljubljana, Ljubljana, Slovenia; 2Medical Faculty, Institute for Biostatistics and Medical Informatics, Ljubljana, Slovenia
Key words: arterial gas analyses; myotonic dystrophy type 2; phrenic nerve conduction studies; polysomnography; respiratory functions L. Leonardis, Institute of Clinical Neurophysiology, University Medical Center Ljubljana, Zaloska 7, SI-1525 Ljubljana, Slovenia Tel.: +386 1 522 1500 Fax: +386 1 522 1533 e-mail: [email protected] Accepted for publication October 31, 2014
gene causes an accumulation of aberrant RNA in the nucleus, which affects the splicing of further genes (4, 5). Their phenotypes are similar, although some clinical differences are well known, such as the presence of the congenital form in DM1 vs its absence in DM2, distal vs proximal muscle involvement in DM1 vs DM2 and milder phenotype in DM2 (6). In DM1, sleep and breathing disorders are common (7–10), while in DM2, only a few polysomnography (PSG) studies and no nerve conduction studies in phrenic nerves have been performed. The extension of sleep and breathing disorders in DM2 is not well known, although excessive daytime sleepiness (EDS), poor sleep quality, decreased sleep efficiency, sleep-disordered breathing, 1
Leonardis et al. alpha-delta sleep, paradoxical breathing during REM sleep, REM sleep without atonia, and periodic limb movements in sleep (PLMS) were reported (11–15). The aim of our study was to investigate sleep and breathing disorders in patients with DM2, so we invited all genetically proven Slovene patients with DM2. We performed full PSG recordings with arterial gas analyses (AGA) on the awakening, phrenic motor nerve conduction studies (MNCS), analyzed respiratory functions and symptoms and compared the results with ageand sex-matched healthy controls and unselected adult-onset patients with DM1. Methods Subjects
An invitation letter was sent to all 17 patients with genetically confirmed DM2 and to 30 randomly selected patients with DM1 from a Slovenian register of patients with neuromuscular disorders. Sixteen healthy volunteers, with no history of neurological, respiratory or sleep disorders participated in the study. The study was approved by the National Ethics Committee of Slovenia, and all subjects provided informed consent before participating in the study.
Pulse Oximeter, Oxismart XL, Covidien-Nellcor, Boulder, CO, USA), CO2 monitoring (EtCO2) (Capnogard; Philips Respironics, Herrsching, Germany), and continuous video monitoring. On awakening the next morning, all subjects underwent AGA analysis (Gas Lyte sampler; Vital signs, Totowa, NJ, USA). All recordings were visually analyzed, and the apnea/hypopnea index (AHI) was scored by a sleep expert, following the European Sleep Research Society guidelines (17) and the American Association for Sleep Medicine guidelines (16). Phrenic MNCS
Phrenic MNCS were measured on the left side with a bipolar stimulating electrode (16893; Medelec, Old Woking, UK), placed supraclavicular between the sternal and clavicular heads or behind the sternocleidomastoid muscle. The disposable self-adhesive disk recording electrodes (Viasys Healthcare, Madison, WI, USA) were glued 5 cm above the xiphoid process (active electrode G1) and 16 cm from G1 on the chest margin (the reference electrode G2) (18, 19). We used a standard EMG system (Keypoint; Natus, Alpine Biomed, Skovlunde, Denmark) with standard settings (filters, 2 Hz–10 kHz). Statistical analyses
Respiratory symptoms and functions
All patients were questioned about dyspnea on exertion, orthopnea, morning headaches, daytime sleepiness, night wakefulness, nightmares, and of tiredness during the day. In further analyses, we used these symptoms as either present (1) or not (0). Respiratory muscle function was assessed in all patients and controls by measurement of vital capacity (VC) (Vitalograph ALPHA, Ennis, Ireland) in both the sitting and lying positions, maximal inspiratory pressure (MIP), and sniff nasal pressure (SNP) (MicroRPM, CareFusion, San Diego, CA, USA). PSG and AGA at awakening
All patients and controls underwent a full, overnight, in-laboratory, technician-attended PSG assessment recorded on a commercial PSG system (Nicolet One nEEG; Neurocare, Madison, WI, USA) using standard PSG settings (16). The recording included EEG, EOG, chin surface EMG, ECG, nasal pressure (nasal pressure cannula), respiratory movements (chest and abdominal belts), oxyhemoglobin saturation (Nellcor 2
Data are presented as the median and interquartile range. The intergroup differences were analyzed with a Mann–Whitney or Fisher exact test. For the binary variables, odds ratios (OR) with 95% confidence intervals (CI) were also calculated. Pearson’s correlation coefficients (R) with the corresponding 95% CI were calculated to estimate the correlation between numeric variables. A P-value of
