Sleep disordered breathing in facioscapulohumeral muscular dystrophy

Journal of the Neurological Sciences 285 (2009) 54–58

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Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s

Sleep disordered breathing in facioscapulohumeral muscular dystrophy Giacomo Della Marca a,⁎,1, Roberto Frusciante a,1, Serena Dittoni a, Catello Vollono a,b, Cristina Buccarella a, Elisabetta Iannaccone a, Monica Rossi c, Emanuele Scarano d, Tommaso Pirronti e, Alessandro Cianfoni f, Salvatore Mazza a, Pietro A. Tonali a,c, Enzo Ricci a,c a

Department of Neurosciences, Catholic University, Policlinico Universitario “A. Gemelli” L.go A. Gemelli, 8, 00168 Rome, Italy Ospedale Pediatrico “Bambino Gesù” IRCCS, Rome, Italy Fondazione 'Pro Juventute' Don Carlo Gnocchi, Rome, Italy d Institute of Otorhinolaryngology, Catholic University, Rome, Italy e Department of Bioimaging and Radiological Sciences, Catholic University, Rome, Italy f Neuroradiology Section, Department of Radiology, MUSC – Medical University of South Carolina, Charleston, SC, USA b c

a r t i c l e

i n f o

Article history: Received 20 March 2009 Received in revised form 5 May 2009 Accepted 13 May 2009 Available online 5 June 2009 Keywords: Facioscapulohumeral muscular dystrophy Sleep Sleepiness Body mass index Sleep disordered breathing Polysomnography

a b s t r a c t Facioscapulohumeral muscular dystrophy (FSHD) is one of the most frequent forms of muscular dystrophy. The aims of this study were: 1) to evaluate the prevalence of sleep disordered breathing (SDB) in patients with FSHD; 2) to define the sleep-related respiratory patterns in FSHD patients with SDB; and 3) to find the clinical predictors of SDB. Fifty-one consecutive FSHD patients were enrolled, 23 women, mean age 45.7 ± 12.3 years (range: 26–72). The diagnosis of FSHD was confirmed by genetic tests. All patients underwent medical and neurological evaluations, subjective evaluation of sleep and full-night laboratory-based polysomnography. Twenty patients presented SDB: 13 presented obstructive apneas, four presented REM related oxygen desaturations and three showed a mixed pattern. Three patients needed positive airways pressure. SDB was not related to the severity of the disease. Body mass index, neck circumference and daytime sleepiness did not allow prediction of SDB. In conclusion, the results suggest a high prevalence of SDB in patients with FSHD. The presence of SDB does not depend on the clinical severity of the disease. SDB is often asymptomatic, and no clinical or physical measure can reliably predict its occurrence. A screening of SDB should be included in the clinical assessment of FSHD. © 2009 Elsevier B.V. All rights reserved.

1. Introduction Facioscapulohumeral muscular dystrophy (FSHD) is the third most frequent form of muscular dystrophy, after Duchenne muscular dystrophy and myotonic dystrophy. FSHD is a genetic disease with autosomal dominant transmission; 95% of patients with a confirmed diagnosis carry a chromosomal rearrangement within the subtelomeric region of chromosome 4q (4q35) [1]. This region consists of a polymorphic structure of 3.3 Kb KpnI repeat units called D4Z4. The size of the 4q35 fragment in affected individuals is variable and the clinical features of FSHD develop when the number of the KpnI repeat units falls below a critical threshold [1]. Genotype–phenotype correlation studies show that the number of KpnI repeats left on the 4q35 region inversely correlates with the severity of the disease [2]. FSHD is characterized by a wide and heterogeneous phenotypic spectrum. The severity ranges from mild forms in which the patient can be unaware of the disease, to severe muscular impairment in wheelchair-bound

⁎ Corresponding author. Tel.: +39 06 30154276; fax: +39 06 35501909. E-mail address: [email protected] (G. Della Marca). 1 These authors contributed equally to this work. 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.05.014

patients. Muscle weakness can appear from infancy to adulthood, but typically the onset occurs in the second decade. The disease initially involves facial and scapular muscles, followed by spreading to lower limbs muscles [3]. Extra-muscular involvement includes neuro– sensorial hearing loss and retinal vasculopathy [4], which are commonly of no clinical relevance. The involvement of respiratory muscles is uncommon: Wohlgemuth et al. [5] esteemed that only 1% of Dutch patients with FSHD suffered from respiratory insufficiency which required nocturnal ventilatory support. Sleep disordered breathing (SDB) is common in muscular dystrophies [6–8]; it has been described in Duchenne muscular dystrophy [6,7,9,10], in myotonic dystrophy [6,7,11] and in limb–girdle muscular dystrophy [12]. SDB may consist in central alveolar hypoventilation [6–8,11,13], upper airways obstruction due to pharyngeal muscle weakness [6,11] or thoracic restrictive pathology due to kyphoscoliosis [6,7]. A systematic evaluation of SDB in FSHD has not been performed. In a previous study, we addressed the issue of subjective sleep quality in FSHD patients; the conclusions of that study were that FSHD patients have a poor sleep quality directly related with the severity of the disease [14]. The preliminary study evaluated the relationship between disease severity and subjective sleep complaints, while the present one explores the relation between subjective sleep complaints and disease severity with

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polysomnographic findings, and in particular with SDB. Therefore, the aims of the present study were: 1) to evaluate the prevalence of SDB in a population of patients affected by genetically confirmed FSHD; 2) to define the sleep-related respiratory patterns in FSHD patients affected by SDB; and 3) to evaluate the presence of signs or symptoms which could predict the presence of SDB. 2. Methods and material 2.1. Patients Fifty-one consecutive adult patients affected by FSHD were enrolled, 23 women and 28 men, with mean age of 45.7 ± 13.0 years (range: 26–72). Exclusion criteria were: age below 18 years, genetic mosaicism and size of the deleted fragment N40 Kb. The diagnosis of FSHD was made on clinical basis [15] and confirmed by genetic tests. In particular, restriction of genomic DNA, 32P-labeling, and hybridization with L1LA5 (D4S163), pH30 (D4S139), and p13E-11 (D4F104S1) were performed as described elsewhere [16,17]. Pulsed field gel electrophoresis (PFGE) analysis of p13E-11 alleles was performed as described elsewhere [16]. All patients underwent a full medical and neurological evaluation. Muscle strength was evaluated by using the Manual Muscle Testing (MMT) and a score was assigned according to the Medical Research Council Scale (MRC, 1976) [18]. MMT score ranges from 0 = “no movement, no visible or palpable contraction” to 5 = “segment movement through full range of motion against gravity and ability to hold against resistance”. In order to measure the clinical severity of the disease, a 10 grade clinical severity scale (CSS) [2] was adopted. The CSS score ranges from 0.5 = “facial weakness”, to 5 = “wheelchair bound”. According to this scale, CSS score ≤ 2 was assigned to patients with facial and shoulder muscle weakness, whereas higher scores (N2) were assigned to patients showing also pelvic and lower limb muscle weakness. The study design was approved by the local Ethics Committee, the patients were fully informed and all gave a written consent to participate in the study. 2.2. Sleep questionnaires All patients underwent a detailed sleep anamnesis which included the subjective evaluation of sleep. The protocol for subjective sleep evaluation has been described in detail previously [14]; it included the Pittsburgh Sleep Quality Index (PSQI) [19], the Italian version of Epworth Sleepiness Scale (ESS) [20] and the search for symptoms and clinical signs predictive of SDB: body mass index (BMI) N 29 Kg/m2 and neck circumference N41 cm (for women) or N43 cm (for men) [21]. 2.3. Polysomnography Full-night, laboratory-based polysomnographies were recorded in acclimatized, sound-proof rooms, following adaptation. Recording montage included EEG leads filled with electrolyte applied to the following locations: C3, C4, O1, and O2; reference electrodes applied to the left (A1) and right (A2) mastoids; 2 EOG electrodes applied to the outer ocular cantus and referred to the contra-lateral mastoid, surface EMG of sub-mental and intercostal muscles, airflow measured by nasal–cannula pressure transducers, thoracic and abdominal effort, EKG and peripheral hemoglobin saturation measured by a clip sensor placed on a finger or on the earlobe. Continuous audio and video recording was performed by means of infra-red cameras. Sleep recordings were analyzed on a computer monitor, and sleep stages were visually classified according to the criteria of the American Academy of Sleep Medicine (AASM, 2007) [22]. Fast-frequency EEG arousals were scored according to the rules of the American Sleep Disorders Association (1992) [23]. The arousal indexes (number of

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arousals per hour) were calculated for total sleep, NREM and REM stages. The scoring of sleep-related respiratory events was performed according to the criteria established by the AASM (1999) [24]. The analysis of the SpO2 parameters was made with a dedicated software (Rembrandt SleepView-Medcare®). Oxygen desaturation events were scored when a fall in SpO2 ≥ 4% was observed. The parameters considered were: baseline SpO2, lowest SpO2, and oxygen desaturation indexes (ODI) in total sleep, in NREM and in REM. Hypoventilation was defined by the presence of repeated oxygen desaturation events during sleep (ODI N 10 events/hour of sleep) not explained by apnea or hypopnea events [24]. Snoring was quantified according to a 4 point score: − (no snoring), + (snoring occurring in slow wave sleep or REM and in supine position), ++ (snoring occurring in slow wave sleep or REM, regardless of the position, or in supine position, regardless of the sleep stage), +++ (snoring occurring in all positions and in all sleep stages). Sleep disordered breathing was defined by the presence of at least one of the following findings: 1) apnea–hypopnea index (AHI) N5 events per hour of sleep (including obstructive and mixed events); 2) oxygen desaturation index (ODI) N10 events per hour of sleep, not explained by apnea or hypopnea events. 2.4. Anatomic evaluation of upper airways A detailed evaluation of upper airway anatomy was performed in all patients who presented polysomnographic findings consistent with SDB. These patients underwent an otorhinolaryngologic evaluation and a standard skull Rx for cephalometry. Otorhinolaryngologic evaluation was aimed at measuring the morphology of upper airways and identifying potential sites of collapse. The main parameters considered were Mallampati score [25], Fujita's class (presence of palatal or pharyngeal narrowing) [26] and cephalometry. The cephalometry was performed according to the criteria proposed by Riley et al. [27]. The parameters considered were: mandibular and maxillary discrepancies (angles SNA, SNB and ANB), posterior airways space (PAS), distance between mandibular planus and hyoid bone (MP–H), and length of the soft palate (PNS-P). 2.5. Statistical analysis On the basis of PSG results, patients were divided into 2 groups: patients with sleep disordered breathing (SDB+) and patients without sleep disordered breathing (SDB–). The SDB+ group included all subjects with AHI N 5 events/h, or ODI N 10 events/h. The anthropometric and clinical features (age, sex, BMI, neck circumference, CSS score, PSQI score, ESS score, and predictors of SDB) were compared between the 2 groups SDB+ and SDB–. Continuous variables (age, PSQI score, ESS score, BMI, and neck circumference) were compared by means of one-way analysis of variance (ANOVA), followed by the Games–Howell post hoc test, since the two groups SDB+ and SDB– showed unequal variances. The level of significance was set to p b 0.01. CSS scores in the 2 groups were compared by means of a non-parametric test, Kruskal–Wallis one-way analysis of variance. Categorical variables (sex, reported snoring, reported apneas, nocturia, morning headache and presence of arterial hypertension) were analyzed and compared in the 2 groups SDB+ and SDB– by means of chi-square test, (χ2) with Yates' correction for continuity. Correlations between PSG findings and clinical features were tested by means of the Pearson's correlation index. In particular, the values of the Pearson's index were calculated between PSG findings (AHI, ODI, respiratory disturbance index in NREM and in REM sleep, and arousal index) versus clinical features (clinical severity scale, Epworth sleepiness scale score, BMI, and neck circumference). Due to multiple correlations, the critical value of the Pearson's productmoment correlation coefficient was set to r(51) = 0.30, corresponding

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to a significance level p b 0.02. Statistics were performed by means of the SYSTAT 12 software version 12.02.00 for Windows (copyright SYSTAT® Software Inc. 2007).

Table 2 Demographic, genetic, clinical data and main results of the PSG study in the three subgroups of SDB+ patients (OSAS, REM-related desaturations and mixed pattern).

3. Results The average size of the p13E-11 EcoRI fragment was 23.1 ± 6.1 Kb (range: 10–40 Kb). The mean clinical severity scale score was 3.1 ± 1.1 (range: 1 to 5), one patient (patient #22) was wheelchair bound. The clinical evaluation of the FSHD patients did not include spirometric evaluation of pulmonary function because the facial weakness did not allow, in many patients, a correct execution of this test. Table 1 shows the main demographic, genetic and clinical data of the FSHD patients, as well as the comparison between the SDB+ and the SDB– subgroups. 3.1. Subjective sleep evaluation The results of the subjective sleep evaluation are summarized in Table 1. The average PSQI score in the FSHD sample was 6.2 ± 3.8; since a PSQI N 5 is considered abnormal [19], 25/51 patients (49%) reported a subjective impairment of sleep quality. As concern the clinical signs and symptoms of SDB, 6 patients had BMI N 29 kg/m2 (5 SDB+ and 1 SDB–), 6 had neck circumference above the limits considered as risk for OSAS (5 SDB+ and 1 SDB–), and 3 presented simultaneously both these findings (2 SDB+ and 1 SDB–). Four patients presented an ESS score ≥10, indicative of subjective excessive daytime sleepiness (all SDB–). 3.2. Polysomnographic evaluation Useful PSG recordings were obtained in all patients. A summary of the results of the respiratory parameters analysis is reported as supplementary data (Supplementary Table 1). All patients in the quiet wakefulness prior to sleep onset presented SpO2 N95%. Snoring was present in 14/51 patients, and continuous, loud snoring, independent from the body position, was observed in 2/51. Central apnoeas or hypopnoeas were observed only occasionally, and no patient presented an index of central events N2 per hour. Fourteen patients presented repetitive obstructive or mixed events, with an AHI N 5 events/hour, which is considered the cut-off value for the PSG diagnosis of OSAS [24,28]. Sixteen patients presented an ODI N 10 Table 1 Demographic, genetic, clinical data and results of the comparison between patients with (SDB+) and without (SDB−) sleep disordered breathing.

Age Sex EcoRI (Kb) Clinical severity scale Body mass index (Kg/m2) Neck circumference (cm) Pittsburgh sleep quality index Epworth sleepiness scale Reported snoring Reported apneas Nocturia Morning headache Arterial hypertension

FSHD patients (n = 51)

SDB+ (n = 20)

SDB− (n = 31)

Comparison SDB+/− (p)

45.7 ± 13.0 28 M–23 F 23.1 ± 6.1 3.1 ± 1.1

45.3 ± 12.3 14 M–6 F 23.6 ± 7.1 3.3 ± 1.2

46.0 ± 13.6 15 M–16 F 22.7 ± 5.3 3.0 ± 1.1

24.6 ± 4.2

27.5 ± 4.4

22.8 ± 2.8

ANOVA p = 0.849 χ2 p = 0.218 ANOVA p = 0.639 Kruskal–Wallis p = 0.233 ANOVA p = 0.000⁎

38.3 ± 4.1

40.6 ± 3.3

36.8 ± 4.0

ANOVA p = 0.001⁎

6.2 ± 3.8

6.4 ± 4.1

6.1 ± 3.7

ANOVA p = 0.761

4.4 ± 3.3

4.0 ± 2.8

4.7 ± 3.6

ANOVA p = 0.430

27 11 16 7 14

14 6 5 2 8

13 5 11 5 6

χ2 χ2 χ2 χ2 χ2

p = 0.094 p = 0.408 p = 0.632 p = 0.838 p = 0.197

EcoRI = size of the deleted fragment. Values are expressed as mean ± standard deviation. χ2 = chi-square test with Yates' correction for continuity. Results of one-way ANOVA and χ2 test are expressed as values of p.

Age Sex Apnea/hypopnea index (AHI) Oxygen desaturation index (ODI) ODI in NREM sleep ODI in REM sleep EcoRI (Kb) Clinical severity scale Body mass index (Kg/m2) Neck circumference (cm) Pittsburgh sleep quality index Epworth sleepiness scale Reported snoring Reported apneas Nocturia Morning headache Arterial hypertension

OSAS (n = 13)

REM-related desaturations (n = 4)

Mixed pattern (n = 3)

46.3 ± 13.4 11M–2F 14.3 ± 10.3

47.5 ± 9.6 1M–3F 1.0 ± 0,8

37.7 ± 10.4 2M–1F 4.3 ± 1.9

20.0 ± 15.7

15.7 ± 5.6

15.7 ± 0.6

16.0 ± 14.8 30.5 ± 15.9 24.2 ± 7.6 3.3 ± 1.2 27.1 ± 4.0

12.5 ± 2.3 33.5 ± 29.5 19.3 ± 6.7 3.6 ± 0.8 30.0 ± 6.4

12.6 ± 1.7 25.4 ± 4.0 26.0 ± 1.4 3.0 ± 1.7 25.5 ± 2.6

41.2 ± 3.2

38.8 ± 2.1

40.0 ± 4.6

6.3 ± 4.7

7.8 ± 2.2

5.0 ± 3.6

3.6 ± 2.8

5.5 ± 2.6

3.3 ± 3.5

8/13 5/13 4/13 2/13 5/13

4/4 1/4 1/4 0/4 3/4

2/3 0/3 0/3 0/3 0/3

EcoRI = size of the deleted fragment. Values are expressed as mean ± standard deviation.

events/h, disregard of the presence of apnoeas and hypopnoeas. Desaturation events were particularly associated with REM sleep: in the average, FSHD patients presented an ODI in NREM sleep = 7.8± 9.7 events/hour, which rose up to 17.5 ± 16.3 in REM sleep. In total, 20 patients presented an alteration of at least one of the 2 main respiratory index (AHI or ODI). Nine patients presented abnormal values of both parameters. The desaturation events during sleep occurred with three different patterns: 1) repetitive, phasic, falls of SpO2, followed by immediate return to the baseline (‘saw-tooth’ pattern), which is typical of OSAS; 2) a tonic desaturation pattern, characterized by slow, progressive decrease of SpO2, particularly during REM sleep; this pattern is common in neuromuscular diseases [29]; 3) a mixed pattern, with an overlap of the previous ones. Among the 20 patients with SDB, 13 showed pure OSAS, 4 showed REM sleep-related desaturations, and 3 showed a mixed pattern. Clinical and anthropometric data concerning these three sub-groups are listed in Table 2. Three patients with moderate or severe OSAS needed positive airways pressure (PAP) treatment [30]. The mean arousal index was 11.7 ± 6.5. Three patients presented periodic limb movements during sleep. 3.3. Upper airways evaluation The results of the clinical and radiological examination of upper airways are listed in Table 3. Five out of 20 had a Mallampati score = 3, none had a Mallampati score = 4. Uvular hypertrophy was present in 2/20, hypotonia in 6/20. Cephalometric evidence of pharyngeal narrowing (PAS b 10 mm) was present in 3 patients. The MP–H distance showed the greatest variability among the RDB+ patients: values ranged from 6.5 to 33.1 mm (mean: 15.6 ± 7.0 mm). The length of soft palate (PNS-P), on the contrary, was rather uniform (mean: 32.3 ± 5.2 mm, range 22.2 to 42.6 mm). No patient presented a ANB angle N10°. No significant correlations were found between cephalometric measures and PSG respiratory indexes. 3.4. Analysis of clinical-PSG correlations The results of the comparisons between the SDB+ and the SDB– groups are reported in Table 1. Patients with SDB+ had significantly greater neck circumference and BMI. No significant differences were

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Table 3 Results of othorhynolaryngoiatric and cephalometric evaluations in the 20 patients with abnormal polysomnoghraphic scores. Patient

Age

Sex

Years 3 4 5 8 9 11 12 13 14 16 25 26 28 32 36 38 41 48 49 50 Mean St. Dev.

44 45 62 44 60 34 72 26 47 31 26 60 52 36 33 47 57 41 45 48 45.6 12.8

F M M M M M M M F M M F F M M M F M M F

AHI

ODI

Events/hour

Events/hour

23.8 6.2 6.5 5.6 5.7 0.8 18.4 10.4 3.3 29.7 3.0 5.8 2.1 8.1 11.2 36.4 1.0 6.4 18.6 0.1 9.4 9.8

29.0 7.7 3.4 8.5 9.6 10.1 22.8 16.8 16.4 56.5 15.2 10.1 20.4 6.9 15.3 38.2 11.6 15.6 35.6 20.5 18.0 13.0

Snoring +++ − + ++ − + − + − + + − − − ++ + − ++ +++ −

BMI

Neck

kg/m2

cm

26.7 25.7 25.8 27.8 26.5 25.6 26.5 36.1 22.7 27.5 26.2 21.3 37.3 20.0 31.2 30.0 23.7 27.7 27.7 33.2 27.5 4.5

43 40 39 44 40 39 40 44 35 41 41 33 39 40 46 43 36 44 43 41 40.4 3.3

Mallampati score

Fujita class

SNA°

3 2 1 1 2 2 3 2 1 n.a. 3 1 2 2 3 3 2 1 2 0

3 0 0 2 3 2 2 3 0 n.a. 2 1 0 1 0 2 0 3 2 2

83 79 85 79 84 102 87 91 85 n.a. 88 81 87 88 84 81 83 89 81 86 85.5 5.4

SNB° 86 83 83 85 84 94 93 88 86 n.a. 86 78 85 89 82 77 80 82 78 82 84.1 4.7

ANB° 3 4 2 6 0 8 6 3 1 n.a. 2 3 2 1 2 4 3 7 3 4 3.4 2.2

PAS

MP–H

mm

mm

PNS-P mm

11.6 13.2 16.0 14.5 18.1 13.4 13.5 13.3 8.1 n.a. 9.9 14.4 19.8 7.9 16.8 17.2 16.2 11.3 14.4 12.6 13.9 3.2

6.5 14.7 17.0 33.1 8.9 16.3 17.2 14.4 11.0 n.a. 14.3 8.9 10.6 11.2 12.4 23.6 7.9 30.3 17.7 11.5 15.6 7.0

28.3 32.4 34.9 39.7 34.4 42.6 36.2 30.6 33.1 n.a. 23.7 35.2 31.7 28.0 31.7 31.0 30.6 26.4 22.2 36.6 32.3 5.2

AHI = apnea–hypopnea index; ODI = oxygen desaturation index; BMI = body mass index; Neck = neck circumference; SNA° = angle between sella turcica, nasion and maxilla; SNB° = angle between sella turcica, nasion and mandibula; ANB° = difference between SNA° and SNB°; PAS = posterior airways space; MP–H = distance between mandibular planus and hyoid bone; PNS-P = length of soft palate. Snoring is indicated according to the following scale: − = absent; + = snoring in REM sleep plus supine position; ++ = snoring in REM sleep or supine position; +++ = continuous snoring in all sleep stages and in all body positions; n.a. = data not available.

observed in sex, prevalence of reported snoring, reported apneas, nocturia, morning headache and arterial hypertension. In the SDB+ group, 5 patients presented BMI and 5 presented neck circumference above the limits considered predictive of OSAS [21]. Two patients in the SDB+ group (patients #13 and #36) and one in the SDB– group (patient #24) presented both BMI and neck circumference above the limits considered predictive of OSAS. No significant correlation was found between PSG respiratory findings and clinical features. 4. Discussion The main finding of the present study is that 20/51 subjects (39%), from a series of consecutive patients with genetically confirmed FSHD, presented PSG findings of SDB. Thirteen patients presented obstructive apnoeas during sleep (OSAS); three of them had an AHI N 20 events per hour and needed treatment with positive airways pressure ventilation [24]. In four patients we observed REM-related oxygen desaturations, not associated with apnoic or hypopnoic events: these suggested REM hypoventilation [24], which is a common finding in neuromuscular disorders [13,29]. Three patients presented mixed patterns (obstructive apnoeas plus REM desaturations without obstructive events). SDB in our FSHD patients was scarcely symptomatic. SDB+ patients, when compared with SDB–, did not show differences in age, sex, daytime sleepiness, subjective sleep quality, frequency of reported snoring, reported apnoeas, nocturia, morning headache and arterial hypertension. Conversely, some anthropometric measures significantly differed in the 2 groups: SDB+ patients had higher values of BMI and neck circumference. These data are in agreement with what is known about the epidemiology of OSAS [28]. Nevertheless, the application of the known clinical predictors of SDB (neck circumference and BMI) to our FSHD population could have identified only a minority of the subjects with abnormal PSG indexes (8/20 on the basis of a single predictor, either neck or BMI; 2/20 if the two predictors were considered together). Notably, no subject in the SDB+ group complained of excessive sleepiness (ESS scores always b10). On the other hand, one subject in the SDB– group presented both BMI and neck circumference above the cut-off values, and four SDB– patients had ESS scores ≥ 10. This allows to conclude that SDB in FSHD patients

may occur in a subclinical, asymptomatic, expression. This confirms what is reported in literature, that, in patients with neuromuscular disorders, history and physical examination must be considered poor predictors of SDB, with low sensitivity [7]. In our study we looked for correlations between clinical features and PSG findings. No relation was found between the CSS score and presence of SDB; therefore, the presence of sleep-related respiratory events does not seem to depend on the severity of the disease. Moreover, the clinical and radiological evaluation, performed in SDB+ patients, did not show anatomic conditions which could predispose to upper airways collapse during sleep [26,27]. The higher BMI and neck circumference in the SDB+ group seems to suggest that FSHD patients are susceptible to develop SDB in the presence of weight gain. In a previous report we observed, on the basis of subjective sleep evaluations, that FSHD patients complain of poor sleep quality, and that this complaint is directly related to the severity of the disease, measured by the CSS score [14]. These data were confirmed in the present study. Anyway, poor sleep quality was observed with the same frequency in both SDB+ and SDB– patients, and no correlation between PSG parameters and the PSQI score was found. Our study suggests that the prevalence of SDB in FSHD, and the respiratory patterns observed during sleep, closely resemble those observed in Duchenne's and Becker's muscular dystrophies [6,7,9,10], in myotonic dystrophy [6,11] and in limb–girdle muscular dystrophy [12]. There are no systematic data available in literature concerning SDB in FSHD [31,32]. The lack of data on FSHD probably depends on its clinical course which rarely leads to extra-muscular involvement and to a severe respiratory impairment [5]. It must be considered that evaluation of respiratory function in wake, by means of traditional pulmonary function tests, can be biased by the inability of these patients to undergo spirometry, because of the facial weakness and the consequent difficulty to blow [33,34]. In fact, patients with neuromuscular diseases characterised by facial or bulbar muscle weakness often cannot effectively seal the lips around the mouthpiece, especially during forced manoeuvres such as spirometric and maximal respiratory pressure measurements [33,34]. In conclusion, our PSG data suggest that FSHD patients are at risk for developing SDB. This risk is not dependent on the severity of the

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disease, but is higher in the presence of weight gain and increased neck circumference. Notably, no clinical issue can reliably predict SDB in FSHD. In particular, this population does not seem to complain of excessive daytime sleepiness, snoring, apnoeas, nocturia or morning headache. Consequently, a screening of sleep-related breathing abnormalities, by means of serial nocturnal cardio–respiratory monitoring and, in case, PSG should be included in the clinical assessment of patients with FSHD. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.jns.2009.05.014. References [1] Wijmenga C, Hewitt JE, Sandkuijl LA, Clark LN, Wright TJ, Dauwerse HG, Gruter AM, Hofker MH, Moerer P, Williamson R, et al. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat Genet 1992;2:26–30. [2] Ricci E, Galluzzi G, Deidda G, Cacurri S, Colantoni L, Merico B, et al. Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of kpni repeats at the 4q35 locus and clinical phenotype. Ann Neurol 1999;45:751–7. [3] Tawil R, Van Der Maarel SM. Facioscapulohumeral muscular dystrophy. Muscle Nerve 2006;34:1–15. [4] Padberg GW, Brouwer OF, de Keizer RJ, Dijkman G, Wijmenga C, Grote JJ, et al. On the significance of retinal vascular disease and hearing loss in facioscapulohumeral muscular dystrophy. Muscle Nerve 1995;2:S73–80. [5] Wohlgemuth M, van der Kooi EL, van Kesteren RG, van der Maarel SM, Padberg GW. Ventilatory support in facioscapulohumeral muscular dystrophy. Neurology 2004;63:176–8. [6] Dhand UK, Dhand R. Sleep disorders in neuromuscular diseases. Curr Opin Pulm Med 2006;12:402–8. [7] Gozal D. Pulmonary manifestations of neuromuscular disease with special reference to duchenne muscular dystrophy and spinal muscular atrophy. Pediatr Pulmonol 2000;29:141–50. [8] Guilleminault C, Stoohs R, Quera-Salva MA. Sleep-related obstructive and nonobstructive apneas and neurologic disorders. Neurology 1992;42:53–60. [9] Khan Y, Heckmatt JZ. Obstructive apnoeas in duchenne muscular dystrophy. Thorax 1994;49:157–61. [10] Smith PE, Edwards RH, Calverley PM. Ventilation and breathing pattern during sleep in duchenne muscular dystrophy. Chest 1989;96:1346–51. [11] Coccagna G, Martinelli P, Lugaresi E. Sleep and alveolar hypoventilation in myotonic dystrophy. Acta Neurol Belg 1982;82:185–94. [12] Dohna-Schwake C, Ragette R, Mellies U, Straub V, Teschler H, Voit T. Respiratory function in congenital muscular dystrophy and limb girdle muscular dystrophy 2i. Neurology 2004;62:513–4. [13] Sivak ED, Shefner JM, Sexton J. Neuromuscular disease and hypoventilation. Curr Opin Pulm Med 1999;5:355–62. [14] Della Marca G, Frusciante R, Vollono C, Dittoni S, Galluzzi G, Buccarella C, et al. Sleep quality in facioscapulohumeral muscular dystrophy. J Neurol Sci 2007;263:49–53.

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