Journal of the Neurological Sciences 263 (2007) 49 – 53 www.elsevier.com/locate/jns
Sleep quality in Facioscapulohumeral muscular dystrophy Giacomo Della Marca a,⁎, Roberto Frusciante a , Catello Vollono a,b , Serena Dittoni a , Giuliana Galluzzi c , Cristina Buccarella a , Anna Modoni a , Salvatore Mazza a , Pietro Attilio Tonali a,b , Enzo Ricci a a
c
Department of Neurosciences, Catholic University, Rome, Italy b Fondazione Pro Juventute Don C. Gnocchi, Rome, Italy Centre for Neuromuscular Diseases, UILDM-Rome Section, Rome, Italy
Received 29 March 2007; received in revised form 19 May 2007; accepted 23 May 2007 Available online 26 June 2007
Abstract Objective: To evaluate the subjective sleep quality, the prevalence of daytime sleepiness and the risk of sleep-related upper airways obstruction in patients with genetically proven Facioscapulohumeral muscular dystrophy (FSHD). FSHD is an autosomal dominant myopathy, characterized by an early involvement of facial and scapular muscles with eventual spreading to pelvic and lower limb muscles. Patients and methods: Forty-six patients were enrolled, 27 women and 19 men, mean age 43.6 ± 14.1 years. Study protocol included: a Clinical Severity Scale (CSS) for FSHD, Pittsburgh Sleep Quality Index (PSQI), Italian version of the Epworth Sleepiness Scale (ESS) and the search for clinical predictors of sleep-related airways obstruction. Results: Twenty-seven patients presented snoring, 12 reported respiratory pauses during sleep. One half (23/46) had PSQI scores above the normal threshold (=5). Correlations were found between the CSS and: the total PSQI score, the components C1 sleep quality, C5 sleep disturbances, C7 daytime dysfunction. Conclusion: Our data support the hypothesis that patients with FSHD have an impaired sleep quality, and that this impairment is directly related to the severity of the disease. A systematic polysomnographic evaluation of these patients will be necessary to confirm the presence of sleep disruption and to clarify its pathogenesis. © 2007 Elsevier B.V. All rights reserved. Keywords: Sleep; Facioscapulohumeral muscular dystrophy; Sleepiness; Sleep quality; OSAS; Pittsburgh Sleep Quality Index; Epworth Sleepiness Scale
1. Introduction Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease with an estimated prevalence of 1:20,000, corresponding to the third most frequent form of Muscular Dystrophy, after Duchenne Dystrophy and Myotonic Dystrophy. The gene for the disease has been mapped to the long arm of chromosome 4 (region 4q35) [1,2]. In this ⁎ Corresponding author. Unit of Sleep Medicine, Department of Neurosciences, Catholic University, Policlinico Universitario “A. Gemelli”, L.go A. Gemelli, 8 - 00168 Rome Italy. Tel.: +39 06 30154276; fax: +39 06 35501909. E-mail address:
[email protected] (G. Della Marca). 0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2007.05.028
region, which carries a long stretch of 3.3 kb KpnI repeat units called D4Z4, the 4q35 telomeric probe p13E-11 has been shown to detect EcoRI polymorphic fragments larger than 40 kb in healthy individuals and smaller fragments (10 to 40 kb in size) in both sporadic and familial cases of FSHD. The size variation of the 4q35 fragments in affected individuals is due to a deletion which involves the D4Z4 locus, and the clinical features of FSHD develop when the number of the KpnI repeat units falls below a critical threshold [3]. No transcripts unambiguously derived from this locus have been identified in vivo, either in muscle or in other tissues [4], and an increasing number of observations suggest that epigenetic mechanisms are involved in the pathogenesis of the disease [5]. However, studies on
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genotype–phenotype correlation unequivocally showed that the number of KpnI repeats left on the shortened chromosome 4 inversely correlates with the severity of the disease [6–8]. The phenotypic spectrum is wide and heterogeneous. The most typical clinical presentation is characterized by an early involvement of facial and scapular muscles with eventual spreading to pelvic and lower limb muscles; foot extensors are often affected earlier and more severely than pelvic muscles. The age of onset, the clinical severity and the pattern of muscular involvement show a high degree of variability both between and within families. Disease severity ranges from very mild forms, in which the patient can be unaware of the disease, to severe muscular impairment in wheelchair-bound patients [9]. Extramuscular involvement includes neurosensorial hearing loss and retinal vasculopathy [10], which rarely reach clinical relevance. Mental impairment is rare too, occurring in the most severe form of the disease, with infantile onset. The involvement of respiratory muscles is uncommon. In a large Dutch series [11], only 10 patients (approximately 1%) suffered from respiratory insufficiency which required nocturnal ventilatory support. Sleep abnormalities, i.e. subjectively impaired sleep quality and excessive daytime sleepiness, are common in muscular dystrophies [12–14]. Sleep quality impairment and daytime somnolence in these diseases are often secondary to SDB. In particular, SDB has been described in Duchenne muscular dystrophy [15], in Myotonic dystrophy [16] and in limb girdle muscular dystrophy [17]. Breathing abnormalities in these diseases may consist either in alveolar hypoventilation of central origin, due to impaired ventilatory control [16–18], or in upper airways obstruction, due to pharyngeal muscles weakness and collapse [15,19]. A search of the PubMed Medline, using ‘Facioscapulohumeral’ and ‘sleep’ as key words, did not reveal any paper systematically addressing the issue of sleep disturbances in FSHD. In a report by Bushby et al. [20], concerning 4 patients with FSHD and chronic muscular pain, it is stated that all patients complained of disturbed sleep. The aim of the present study was to evaluate the subjective sleep quality, the prevalence of excessive daytime sleepiness (EDS) and the risk of sleep-related upper airways obstruction in a large sample of patients affected by genetically proven FSHD.
p13E-11 (D4F104S1) were performed as described [22,23]. Pulsed field gel electrophoresis (PFGE) analysis of p13E-11 alleles was performed as described [23]. One patient was excluded because the dimension of the mutated fragment was longer than 50 Kb; another patient was excluded because of genetic mosaicism. Therefore, 46 patients were finally enrolled, 27 women and 19 men, with an average age of 43.6 ± 14.1 years. The study design was approved by the local Ethical committee, and all the patients were fully informed and gave their written consent. All patients underwent a full medical and neurological evaluation. In order to measure the clinical severity of the disease, a Clinical Severity Scale (CSS) was applied, with scores ranging from 0.5 (mild) to 5 (severe). Muscle strength was evaluated by using the Manual Muscle Testing. For a detailed description of the scale, see Ricci et al. [8].
2. Methods
The average size of the p13E-11 EcoRI fragment was 21.6 ± 6.2 kb. Pathological cut-off was considered for size ≤40 kb. The mean Clinical Severity score was 2.8± 1.5. As concerns the PSQI, the average score in the sample, was 5.9± 3.8; since a PSQI N 5 is considered abnormal [24], 23 patients (50%) showed pathological levels. The ESS average score was 4.4 ± 3.3, only two patients presented a ESS scoreN 10. Average BMI was 24.9± 4.6 Kg/m2; average neck circumference was 37.2 ± 4.3 cm. Two patients (#32 and #39) presented both BMI and neck circumference above the levels considered at risk for sleep
2.1. Patients Forty-eight consecutive patients affected by FSHD, followed at the Institute of Neurology of the Catholic University in Rome, were enrolled. Diagnosis was made on a clinical basis [21], and confirmed by means of genetic tests. In particular, restriction of genomic DNA, 32P-labeling, and hybridization with L1LA5 (D4S163), pH30 (D4S139), and
2.2. Sleep quality evaluation Subjective evaluation of sleep quality was performed by the Pittsburgh Sleep Quality Index (PSQI) [24]. The Italian version has been translated from English into Italian and then retranslated for comparison with the original version. A global score N5 was considered as an indicator of relevant sleep disturbances [24,25]. For the evaluation of EDS, the validated Italian version of the Epworth Sleepiness Scale (ESS) [26] was applied. Moreover, in all subjects an evaluation of the symptoms and clinical signs predictors of OSAS were performed, including neck circumference, Body Mass Index (BMI), presence of habitual snoring, nocturia, morning headache, arterial hypertension, and apneas reported by the bed-partner. 2.3. Statistical analysis The correlation between sleep parameters (PSQI, including single sections and total score, and ESS score) and clinical measures (BMI, neck circumference, CSS and fragment size) were evaluated by means of the Pearson correlation index. Due to multiple comparisons, the critical value of the Pearson product–moment correlation coefficient was set to r(44) = 0.34, corresponding to a significance level p b 0.02. 3. Results
G. Della Marca et al. / Journal of the Neurological Sciences 263 (2007) 49–53
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Table 1 Demographic, genetic and clinical data, PSQI and ESS scores in the 46 FSHD patients Pittsburgh Sleep Quality Index (PSQI) No.
Age
Sex
BMI
Neck
4q35
CSS
ESS
C1
C2
C3
C4
C5
C6
C7
Total
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Mean SD
64 44 54 42 57 35 42 27 54 30 48 59 52 29 26 45 61 36 35 31 26 60 40 27 26 33 18 26 68 48 44 50 71 36 38 64 57 26 26 60 45 54 36 64 59 36 43.67 14.07
F M F F M F M F M F M F F F M M M F F M F F F M F F M F M F M F F M F M M M M F F F F F M F
20.6 24.3 20.0 29.3 23.8 21.4 26.3 21.3 23.7 21.3 25.8 29.0 37.3 20.0 21.9 26.9 27.1 18.8 22.0 27.5 18.6 19.1 23.4 19.6 18.8 21.2 23.9 26.2 21.8 33.2 27.8 29.4 21.5 25.7 21.7 24.2 28.0 26.2 35.7 21.3 33.4 33.3 25.4 29.6 26.2 24.6 24.96 4.64
33 38 32 40 42 34 42 32 40 31 41 37 39 31 37 42 39 32 33 41 30 32 34 39 31 31 36 34 39 41 44 42 35 46 32 40 42 41 45 33 37 38 39 40 40 35 37.22 4.35
21 22 21 15 24 17 26 21 21 21 22 28 15 15 15 23 16 17 19 35 16 19 20 20 18 19 15 15 33 16 22 36 27 19 23 18 21 27 26 17 35 29 10 17 32 32 21.65 6.24
3 1.5 3.5 4 3.5 3 3 1 4 0 1 3.5 4.5 4.5 4.5 3 4.5 4 4 1 1 3.5 3.5 4 1.5 1 2.5 1 3.5 4 3.5 4 3.5 2.5 3 3 2.5 1 1.5 4 3 0.5 4 3.5 4 4 3.04 1.25
4 0 4 8 10 4 4 5 3 5 1 7 6 1 3 1 3 5 1 3 9 3 16 5 5 3 0 5 4 9 1 3 1 5 4 2 5 0 1 6 13 10 3 5 2 5 4.41 3.36
1 1 1 2 1 2 1 0 1 0 1 2 2 1 1 1 1 1 0 1 0 2 1 1 1 1 0 0 0 1 0 1 1 0 1 1 1 1 0 1 2 1 1 1 1 2 0.93 0.61
1 0 1 3 0 2 1 0 1 0 1 1 0 2 0 1 0 1 1 0 0 1 1 1 2 1 0 0 0 1 0 2 2 0 1 0 2 1 1 1 0 0 0 1 2 1 0.80 0.78
0 1 0 3 1 2 0 1 0 1 1 1 2 0 1 1 1 1 0 1 0 2 1 0 1 1 0 0 0 2 0 1 0 1 1 1 2 1 0 2 2 2 0 1 2 1 0.91 0.78
0 0 0 3 1 1 0 0 0 0 1 3 1 0 0 0 0 1 0 1 0 3 0 0 1 0 0 0 0 0 0 3 3 0 0 0 0 0 0 3 0 0 1 1 3 2 0.70 1.09
1 0 1 3 2 2 1 1 2 1 1 3 2 1 1 3 3 2 1 1 1 2 1 1 1 2 1 1 1 2 1 2 1 1 1 2 2 1 1 2 2 2 1 2 2 2 1.52 0.69
2 2 0 0 0 0 0 0 0 0 0 3 3 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.35 0.92
1 1 0 2 1 0 2 0 0 0 0 2 1 1 1 1 2 1 1 0 1 2 1 1 0 1 0 0 0 1 0 1 0 0 2 0 1 0 0 1 1 1 0 0 1 1 0.72 0.69
6 5 3 16 6 9 5 2 4 2 5 15 11 5 4 7 7 7 3 4 2 15 5 4 6 6 1 1 1 7 1 13 7 2 6 4 8 4 2 10 7 6 3 6 11 9 5.93 3.77
BMI = Body Mass Index (Kg/m2); Neck = neck circumference (cm); 4q35 = size of the 4q35 deleted fragment (Kb, Kilobases); CSS = Clinical Severity Scale; ESS = Epworth Sleepiness Scale; C1–C7: subcomponents of the PSQI; Total = global PSQI score; SD = standard deviation.
disordered breathing (BMI N29 kg/m2; neck circumference N 41 cm for women, N 43 cm for men). Twenty-seven patients presented snoring (occasional or frequent, referred by the bedpartner), and 12 presented respiratory pauses during sleep (occasional or frequent, referred by the bed-partner). High blood pressure was present in 17 patients, nocturia in 14, morning headache in 9.
Significant correlations were found between the age and the CSS (r(44) = 0.35; p b 0.02), and between the CSS and the components of the PSQI: total PSQI score (r(44) = 0.36; p b 0.02), components C1 sleep quality (r(44) = 0.45; p b 0.02), C5 sleep disturbances, (r(44) = 0.36; p b 0.02), and C7 daytime dysfunction (r(44) = 0.36). No correlation was found between the CSS and the components C2 sleep
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onset latency (r(44) = 0.18), C3 sleep duration (r(44) = 0.09), C4 sleep efficiency (r(44) = 0.30) and C6 use of sleep medications (r(44) = 0.37). No significant correlations were found between the EcoRI fragment size and the subjective sleep parameters evaluated, nor between the ESS scores and other clinical data. Demographic and clinical details and the scale scores in all FSHD patients are listed in Table 1. 4. Discussion Our observation concerns the subjective evaluation of sleep quality and daytime sleepiness in a population of genetically proven FSHD. The main finding of the study is the reduced sleep quality in FSHD patients. One half of the patients (23/46) showed values N5 (which is considered the cut-off for normality), and the average PSQI value in the group was 5.9 ± 3.8. Moreover, the analysis of the correlation between the CSS, which is a validated index of severity of the disease [8], and the PSQI components showed an inverse correlation between subjective sleep quality and the clinical severity of FSHD. In particular, the analysis of the components of the PSQI (Table 1) revealed that the principal determinants of poor sleep quality, and those which were significantly related to severity of clinical involvement, were sleep quality (C1), sleep disturbances (C5) and daytime dysfunction (C7). No abnormal levels of daytime sleepiness were measured by the ESS (only 2 patients showed scores ≥n13). The possible causes for sleep disruption and poor sleep quality in FSHD are numerous, and our study design only allows speculations. One possible cause could be sleep disordered breathing (SDB). Obesity is a risk factor for Obstructive Sleep Apnea Syndrome (OSAS), and our results reveal that 4 out of 5 obese patients (BMI N 30) had PSQI scores over 5; while for the remaining non-obese subjects, only 19 out of 41 (46%) had PSQI scores over 5. SDB and in particular OSAS have been described in several forms of muscular dystrophy, including Duchenne muscular dystrophy [15], Myotonic dystrophy [16] and Limb Girdle muscular dystrophy [17]. With regard to the risk of OSAS, the clinical observation in our sample showed controversial findings: even though the anthropometric measures (BMI and neck circumference) revealed a risk of SDB in only 2 patients, snoring (occasional or habitual) and sleep-related respiratory pauses were reported in many cases (27 and 12 respectively). This is in agreement with the observation that patients with neuromuscular impairment could present SDB even in the absence of obesity or other morphological abnormalities of the upper airways, as revealed by the BMI and neck circumference [27]; in these patients history and physical examination must be considered poor predictors of SDB, since they have high specificity but low sensitivity [28]. SDB is strictly associated with impaired daytime function and increased diurnal sleepiness. In this respect, our data seem discordant, since the items of PSQI related with
diurnal dysfunction showed relatively high scores in our population (mean= 0.72± 0.69) with strong direct relation with the clinical severity index, whereas the Epworth scores were normal in most subjects. This discrepancy probably depends on the differences between the two scales, since the ESS is a ‘pure’ sleepiness scale, whereas the PSQI, in the item #7, includes 2 questions concerning ‘sleepiness’ and ‘enthusiasm’. Another possible cause of sleep disruption in dystrophic patients is nocturnal pain [5,29]. Nocturnal pain, localized in neck, shoulders and low back, has been observed in more than a half of FSHD patients [5,20]. Also reduced spontaneous motility during sleep can be hypothesized as a mechanism of sleep disruption in FSHD. Body movements during sleep are periodically necessary to allow changes of body position and to avoid peripheral nerves compressions, resulting in paresthesias and pain. Reduced motility during sleep is reported by FSHD patients, but has never been addressed by systematic video–polygraphic recordings during sleep. The hypothesis that poor sleep quality is provoked by reduced spontaneous motility during sleep is in agreement with the finding that sleep disruption is closely, directly related to the CSS (which measures, essentially, motility and muscle strength [8]. Finally, a functional involvement of central nervous system in FSHD could be hypothesized. In fact, although a clinically relevant central dysfunction, with mental retardation and epilepsy, has been observed only in extremely severe forms of FSHD [30], demonstrated changes in motor cortex excitability also in subject with relatively mild FSHD. In conclusion, our data support the hypothesis that patients with FSHD have an impaired sleep quality, and that this impairment is directly related to the severity of the disease. Some clinical observation suggests the possibility of SDB, though the normal levels of daytime sleepiness do not support this hypothesis. Other possible causes of sleep disruption which can be simply hypothesized, are nocturnal pain or reduced spontaneous motility in sleep. Though the PSQI [24] and the ESS [26] are widely employed, validated instruments for the subjective measurement of sleep quality and daytime sleepiness, especially in large and homogeneous populations, a more extensive and systematic video– polysomnographic evaluation of these patients is essential to confirm the presence of sleep disruption, to assess or rule out SDB, and to clarify the pathogenesis of sleep disorders. References [1] Sarfarazi M, Wijmenga C, Upadhyaya M, et al. Regional mapping of facioscapulohumeral muscular dystrophy gene on 4q35: combined analysis of an international consortium. Am J Hum Genet 1992;51:396–403. [2] Wijmenga C, Hewitt JE, Sandkuijl LA, et al. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat Genet 1992;2:26–30. [3] Van Deutekom JC, Wijmenga C, van Tienhoven EA, et al. FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum Mol Genet 1993;2:2037–42.
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