ORIGINAL ARTICLE
Restless legs syndrome and post polio syndrome: a case control study
a
Neurophysiopathology Unit, Sleep Medicine Centre, Department of Systems Medicine, University of Rome Tor Vergata, Rome; bIRCCS Neuromed, Via Atinense 18, Pozzilli (IS); cDepartment of Neuroscience, University of Rome Tor Vergata; dUOC Governo Clinico in Riabilitazione Azienda Ospedaliera S. Camillo Forlanini, Rome; eNeuropsichiatra Infantile – Centro di Riabilitazione Vaclav Vojta, Rome; fUOC Neurologia Ospedale Monaldi – Napoli, Napoli; gIRCCS Santa Lucia Foundation, Rome; and hDivision of Neurophysiopathology, Sant’Eugenio Hospital, Rome, Italy
Keywords:
fatigue, post polio syndrome, quality of life, restless legs syndrome, SF-36, sleepiness Received 5 April 2014 Accepted 1 September 2014 European Journal of Neurology 2014, 0: 1–7 doi:10.1111/ene.12593
Background and purpose: The aim was to investigate the prevalence of restless legs syndrome (RLS), fatigue and daytime sleepiness in a large cohort of patients affected by post polio syndrome (PPS) and their impact on patient health-related quality of life (HRQoL) compared with healthy subjects. Methods: PPS patients were evaluated by means of the Stanford Sleepiness Scale and the Fatigue Severity Scale (FSS). The Short Form Health Survey (SF-36) questionnaire was utilized to assess HRQoL in PPS. RLS was diagnosed when standard criteria were met. Age and sex matched healthy controls were recruited amongst spouses or friends of PPS subjects. Results: A total of 66 PPS patients and 80 healthy controls were enrolled in the study. A significantly higher prevalence of RLS (P < 0.0005; odds ratio 21.5; 95% confidence interval 8.17–57) was found in PPS patients (PPS/RLS+ 63.6%) than in healthy controls (7.5%). The FSS score was higher in PPS/ RLS+ than in PPS/RLS patients (P = 0.03). A significant decrease of SF-36 scores, including the physical function (P = 0.001), physical role (P = 0.0001) and bodily pain (P = 0.03) domains, was found in PPS/RLS+ versus PPS/ RLS patients. Finally, it was found that PPS/RLS+ showed a significant correlation between International Restless Legs Scale score and FSS (P < 0.0001), as well as between International Restless Legs Scale score and most of the SF36 items (physical role P = 0.0018, general health P = 0.0009, vitality P = 0.0022, social functioning P = 0.002, role emotional P = 0.0019, and mental health P = 0.0003). Conclusion: Our findings demonstrate a high prevalence of RLS in PPS, and that RLS occurrence may significantly influence the HRQoL and fatigue of PPS patients. A hypothetical link between neuroanatomical and inflammatory mechanisms in RLS and PPS is suggested.
Introduction Restless legs syndrome (RLS) is a sleep related movement disorder characterized by uncomfortable and Correspondence: Andrea Romigi, Department of Neurophysiopathology, Sleep and Epilepsy Centre, University of Rome ‘Tor Vergata’, Viale Oxford 81, Zip code 00133 Rome, Italy (tel.: +39 062 0902107; fax: +39 069 7655221; e-mail: [email protected]).
© 2014 EAN
unpleasant sensations localized in the legs, or in the arms in a minority of cases. The sensations begin or worsen during rest, improve or disappear during movement, and occur or exacerbate in the evening or night [1]. Although underdiagnosed, RLS prevalence in the general population is estimated at approximately 5%–10% [2]. RLS may be idiopathic or due to physiological or pathological conditions, such as pregnancy, iron deficiency, end-stage renal
1
EUROPEAN JOURNAL OF NEUROLOGY
A. Romigia,b, M. Pierantozzic, F. Placidia, E. Evangelistaa, M. Albanesea, C. Liguoria, M. Nazzarod, B. U. Risinae, V. Simonellif, F. Izzia, N. B. Mercuria,g and M. T. Desiatoh
2
A. ROMIGI ET AL.
disease, diabetes mellitus, rheumatoid arthritis [1,2]. Moreover, different neurological disorders, including multiple sclerosis [3], peripheral neuropathy [4], spinocerebellar ataxia [5], extrapyramidal syndromes [6] and myelopathies [7], are frequently associated with RLS. Pathogenesis of RLS is still debated, but a sharing of iron metabolism and dopaminergic dysfunction associated with the hyperexcitability of the spinal locomotor generator, caused by the impairment of inhibitory supraspinal descending neurons projecting to the dorsal spinal gray matter, has been hypothesized [8–10]. Post polio syndrome (PPS) is a neurological disorder affecting patients with a history of acute poliomyelitis occurring a long time before and followed by a prolonged period of neurological and functional stability. PPS is characterized by the onset or worsening of muscle weakness and atrophy, joint and muscle pain and swallowing problems, but also by the appearance of new and progressive general fatigue, the latter strongly affecting the quality of life of patients [11]. Therefore recent studies have been conducted in order to investigate the effect of different factors other than neurological disability on the health-related quality of life (HRQoL) of PPS patients. However, few studies have investigated the possible contribution of sleep disorders in PPS patients complaining of general weakness and compromised HRQoL [12,13]. In this study the prevalence of RLS in a large cohort of PPS patients compared with healthy controls was evaluated in order to find a possible correlation between RLS and the severity of sleepiness and fatigue reported by PSS patients and to assess whether RLS can affect their HRQoL.
evaluated by use of the Medical Research Council (MRC) rating in which strength was scored on a six-point ordinal scale (from 0, no palpable or visible contraction in the muscle, to 5, holding against resistance with normal strength). Three muscles of the upper limbs (deltoid, extensor carpi radialis longus, first dorsal interosseous) and three muscles of the lower limbs (iliopsoas, quadriceps, tibialis anterior) were bilaterally evaluated to obtain a global MRC score and two subscores from upper limbs and lower limbs. Ninety age and sex matched control subjects were selected amongst spouses or friends of the probands. Exclusion criteria for both groups were the occurrence of neurological disorders, other than PPS for the patient group, specific conditions known to be induced by or related to secondary forms of RLS, including pregnancy, anemia, renal failure, diabetes mellitus, radiculopathy and peripheral neuropathy; previous or current treatment with clonazepam, dopamine agonists, antidepressant agents or neuroleptic drugs; history of alcohol or other substance abuse; body mass index >30. In addition, evaluation for polyneuropathy was performed by medical chart review for the presence of any sensory or motor symptoms suggestive of distal symmetric polyneuropathy, which was confirmed by standard nerve conduction study. A flow chart of recruitment is included as supplemental data (Fig. S1). All PPS patients and controls provided a written informed consent to participate in the study. The protocol was approved by the local ethics committee (Approval S6-12). The study protocol consisted of the collection of clinical and demographic data. Subjective scales for RLS
Methods Populations
This case control study was carried out in a cohort of patients with PPS and in age-matched healthy controls. Seventy-eight consecutive outpatients affected by PPS were enrolled from the Center for Neuromuscular Disorders of S. Eugenio Hospital of Rome between January 2007 and December 2010. An experienced neurologist (M.T.D.) diagnosed PPS according to PPS International Conference diagnostic criteria [14]. Briefly the diagnostic criteria for PPS were an onset of progressive and persistent new weakness and/or abnormal muscle fatigability in polio survivors after a period of stable neurological functioning and the absence of other medical conditions that could explain the symptoms [14]. The severity of muscle weakness was
A standardized face-to-face interview on RLS and other sleep disorders was performed by a single experienced neurologist expert in sleep medicine board certified by the Italian Association of Sleep Medicine (A.R.) in order to avoid inter-rater variability. Patients and subjects were considered to be affected by RLS if they met four standard criteria: (i) the urge to move the legs, (ii) unpleasant sensations in the legs, (iii) symptoms worsening during rest and relief by movement, and (iv) symptoms worsening in the evening or at night [1] and if the occurrence of RLS symptoms was at least twice per week during the 6 months preceding the interview. Patients and controls that fulfilled RLS criteria underwent the validated international RLS rating scale (10 items, score range between 0 and 40) [15,16] in order to measure the severity of RLS symptoms and were defined as ‘RLS sufferers’.
© 2014 EAN
PPS AND RLS
3
asked to indicate the scale value that best described their level of sleepiness–alertness. Steps vary between ‘feeling active and vital; wide awake’ (score 1) and ‘almost in reverie; lost struggle to remain awake’ (score 7). All subjects underwent SSS at a standard time (between 9 and 11 am).
Subjective scales (fatigue, quality of life, diurnal sleepiness)
The existence and the severity of fatigue were assessed using the Italian version of the Fatigue Severity Scale (FSS), obtained by means of the standard forwardbackward procedure; the FSS is a self-administered questionnaire developed to measure fatigue in medical and neurological diseases, which is generally used to measure general fatigue also in PPS [17–22]. The FSS consists of nine statements for evaluating the impact of fatigue. The subject was asked to rate the severity of the fatigue symptoms experienced in the last week using a numerical scale ranging from 1 (strong disagreement with the statement) to 7 (strong agreement with the statement). The total score was calculated by averaging the scores of each item [17,18]. Health-related quality of life was evaluated by means of the Italian version of the Short Form Health Survey (SF-36) questionnaire (4-week version) [23,24]. The SF-36 is grouped in eight multi-item scales: physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems and mental health. It is scored from 0 to 100, 0 indicating extreme problems and 100 indicating no problems. To standardize the scores, the difference between the individual’s raw score and the mean score of the corresponding Italian normative group was calculated. This difference was then divided by the standard deviation of the normative group. These standard scores (z-scores) express individuals’ distance from their normative group mean in terms of the standard deviation of the distribution. Any score equal to the normative mean will be equivalent to a z-score of zero. Negative or positive z-scores are produced for persons falling below or above the mean respectively. The Italian version of the Stanford Sleepiness Scale (SSS), a Likert-type seven-point scale, was used to investigate daytime sleepiness [25]. Subjects were
Subgroup classification and statistical analysis
According to the mentioned criteria, patients and controls were classified into four subgroups: (1) patients affected by PPS without RLS (PPS/RLS ); (2) patients affected by PPS and RLS (PPS/RLS+); (3) controls without RLS (C/RLS ); (4) controls with RLS (C/RLS+). Statistical analysis included the v2 test and independent t test performed by means of Statistica 10.0 (Statsoft Inc., Tulsa, OK, USA). All statistical analyses were two-tailed, and the level of statistical significance was set at P < 0.05. The Pearson correlation test was utilized when appropriate.
Results A total of 66 PPS outpatients (24 men, 42 women; mean age 57.4 8.55 years, range 31–83; median of PPS duration 8.5 years, SD 6.03) were enrolled. Eighty age and sex matched healthy subjects (35 men, 45 women; age 55.8 8.6 years, range 29–76) were recruited as a control group (Table 1). Demographic features and mean score of FSS and SSS of both PPS patients and controls are summarized in Table 1. The main comorbidities of PPS patients are reported in Table S1. Restless legs syndrome prevalence between groups
Of the 66 PPS patients, 42 patients (63.6%) reported experiencing RLS symptoms at least twice per week during the 6 months preceding the interview, with a
Table 1 Demographic parameters and subjective scale scores of subjects included in this study Post polio patients
Men Women Total Subjective scales FSS SSS
Control subjects
n
Age (years)
BMI (Kg/m )
n
Age (years)
BMI (Kg/m2)
P
24 42 66
60.5 (11.8) 56.1 (5.62) 57.7 (8.6) Score 50.2 (14.23) 3.06 (1.64)
25.75 (3.5) 25.86 (4.28) 25.8 (3.97) Range 14–63 1–7
35 45 80
56.8 (10.5) 55.6 (7.5) 55.8 (8.9) Score 23.2 (11.6) 1.91 (0.77)
26.3 (3.48) 24.4 (3.92) 25.22 (3.8) Range 9–46 1–3
NS NS NS
66 66
2
80 80
BMI, body mass index; FSS, Fatigue Severity Scale; SSS, Stanford Sleepiness Scale. Values are expressed as mean (SD). *Level of significance
Restless legs syndrome and post polio syndrome: a case control study
a
Neurophysiopathology Unit, Sleep Medicine Centre, Department of Systems Medicine, University of Rome Tor Vergata, Rome; bIRCCS Neuromed, Via Atinense 18, Pozzilli (IS); cDepartment of Neuroscience, University of Rome Tor Vergata; dUOC Governo Clinico in Riabilitazione Azienda Ospedaliera S. Camillo Forlanini, Rome; eNeuropsichiatra Infantile – Centro di Riabilitazione Vaclav Vojta, Rome; fUOC Neurologia Ospedale Monaldi – Napoli, Napoli; gIRCCS Santa Lucia Foundation, Rome; and hDivision of Neurophysiopathology, Sant’Eugenio Hospital, Rome, Italy
Keywords:
fatigue, post polio syndrome, quality of life, restless legs syndrome, SF-36, sleepiness Received 5 April 2014 Accepted 1 September 2014 European Journal of Neurology 2014, 0: 1–7 doi:10.1111/ene.12593
Background and purpose: The aim was to investigate the prevalence of restless legs syndrome (RLS), fatigue and daytime sleepiness in a large cohort of patients affected by post polio syndrome (PPS) and their impact on patient health-related quality of life (HRQoL) compared with healthy subjects. Methods: PPS patients were evaluated by means of the Stanford Sleepiness Scale and the Fatigue Severity Scale (FSS). The Short Form Health Survey (SF-36) questionnaire was utilized to assess HRQoL in PPS. RLS was diagnosed when standard criteria were met. Age and sex matched healthy controls were recruited amongst spouses or friends of PPS subjects. Results: A total of 66 PPS patients and 80 healthy controls were enrolled in the study. A significantly higher prevalence of RLS (P < 0.0005; odds ratio 21.5; 95% confidence interval 8.17–57) was found in PPS patients (PPS/RLS+ 63.6%) than in healthy controls (7.5%). The FSS score was higher in PPS/ RLS+ than in PPS/RLS patients (P = 0.03). A significant decrease of SF-36 scores, including the physical function (P = 0.001), physical role (P = 0.0001) and bodily pain (P = 0.03) domains, was found in PPS/RLS+ versus PPS/ RLS patients. Finally, it was found that PPS/RLS+ showed a significant correlation between International Restless Legs Scale score and FSS (P < 0.0001), as well as between International Restless Legs Scale score and most of the SF36 items (physical role P = 0.0018, general health P = 0.0009, vitality P = 0.0022, social functioning P = 0.002, role emotional P = 0.0019, and mental health P = 0.0003). Conclusion: Our findings demonstrate a high prevalence of RLS in PPS, and that RLS occurrence may significantly influence the HRQoL and fatigue of PPS patients. A hypothetical link between neuroanatomical and inflammatory mechanisms in RLS and PPS is suggested.
Introduction Restless legs syndrome (RLS) is a sleep related movement disorder characterized by uncomfortable and Correspondence: Andrea Romigi, Department of Neurophysiopathology, Sleep and Epilepsy Centre, University of Rome ‘Tor Vergata’, Viale Oxford 81, Zip code 00133 Rome, Italy (tel.: +39 062 0902107; fax: +39 069 7655221; e-mail: [email protected]).
© 2014 EAN
unpleasant sensations localized in the legs, or in the arms in a minority of cases. The sensations begin or worsen during rest, improve or disappear during movement, and occur or exacerbate in the evening or night [1]. Although underdiagnosed, RLS prevalence in the general population is estimated at approximately 5%–10% [2]. RLS may be idiopathic or due to physiological or pathological conditions, such as pregnancy, iron deficiency, end-stage renal
1
EUROPEAN JOURNAL OF NEUROLOGY
A. Romigia,b, M. Pierantozzic, F. Placidia, E. Evangelistaa, M. Albanesea, C. Liguoria, M. Nazzarod, B. U. Risinae, V. Simonellif, F. Izzia, N. B. Mercuria,g and M. T. Desiatoh
2
A. ROMIGI ET AL.
disease, diabetes mellitus, rheumatoid arthritis [1,2]. Moreover, different neurological disorders, including multiple sclerosis [3], peripheral neuropathy [4], spinocerebellar ataxia [5], extrapyramidal syndromes [6] and myelopathies [7], are frequently associated with RLS. Pathogenesis of RLS is still debated, but a sharing of iron metabolism and dopaminergic dysfunction associated with the hyperexcitability of the spinal locomotor generator, caused by the impairment of inhibitory supraspinal descending neurons projecting to the dorsal spinal gray matter, has been hypothesized [8–10]. Post polio syndrome (PPS) is a neurological disorder affecting patients with a history of acute poliomyelitis occurring a long time before and followed by a prolonged period of neurological and functional stability. PPS is characterized by the onset or worsening of muscle weakness and atrophy, joint and muscle pain and swallowing problems, but also by the appearance of new and progressive general fatigue, the latter strongly affecting the quality of life of patients [11]. Therefore recent studies have been conducted in order to investigate the effect of different factors other than neurological disability on the health-related quality of life (HRQoL) of PPS patients. However, few studies have investigated the possible contribution of sleep disorders in PPS patients complaining of general weakness and compromised HRQoL [12,13]. In this study the prevalence of RLS in a large cohort of PPS patients compared with healthy controls was evaluated in order to find a possible correlation between RLS and the severity of sleepiness and fatigue reported by PSS patients and to assess whether RLS can affect their HRQoL.
evaluated by use of the Medical Research Council (MRC) rating in which strength was scored on a six-point ordinal scale (from 0, no palpable or visible contraction in the muscle, to 5, holding against resistance with normal strength). Three muscles of the upper limbs (deltoid, extensor carpi radialis longus, first dorsal interosseous) and three muscles of the lower limbs (iliopsoas, quadriceps, tibialis anterior) were bilaterally evaluated to obtain a global MRC score and two subscores from upper limbs and lower limbs. Ninety age and sex matched control subjects were selected amongst spouses or friends of the probands. Exclusion criteria for both groups were the occurrence of neurological disorders, other than PPS for the patient group, specific conditions known to be induced by or related to secondary forms of RLS, including pregnancy, anemia, renal failure, diabetes mellitus, radiculopathy and peripheral neuropathy; previous or current treatment with clonazepam, dopamine agonists, antidepressant agents or neuroleptic drugs; history of alcohol or other substance abuse; body mass index >30. In addition, evaluation for polyneuropathy was performed by medical chart review for the presence of any sensory or motor symptoms suggestive of distal symmetric polyneuropathy, which was confirmed by standard nerve conduction study. A flow chart of recruitment is included as supplemental data (Fig. S1). All PPS patients and controls provided a written informed consent to participate in the study. The protocol was approved by the local ethics committee (Approval S6-12). The study protocol consisted of the collection of clinical and demographic data. Subjective scales for RLS
Methods Populations
This case control study was carried out in a cohort of patients with PPS and in age-matched healthy controls. Seventy-eight consecutive outpatients affected by PPS were enrolled from the Center for Neuromuscular Disorders of S. Eugenio Hospital of Rome between January 2007 and December 2010. An experienced neurologist (M.T.D.) diagnosed PPS according to PPS International Conference diagnostic criteria [14]. Briefly the diagnostic criteria for PPS were an onset of progressive and persistent new weakness and/or abnormal muscle fatigability in polio survivors after a period of stable neurological functioning and the absence of other medical conditions that could explain the symptoms [14]. The severity of muscle weakness was
A standardized face-to-face interview on RLS and other sleep disorders was performed by a single experienced neurologist expert in sleep medicine board certified by the Italian Association of Sleep Medicine (A.R.) in order to avoid inter-rater variability. Patients and subjects were considered to be affected by RLS if they met four standard criteria: (i) the urge to move the legs, (ii) unpleasant sensations in the legs, (iii) symptoms worsening during rest and relief by movement, and (iv) symptoms worsening in the evening or at night [1] and if the occurrence of RLS symptoms was at least twice per week during the 6 months preceding the interview. Patients and controls that fulfilled RLS criteria underwent the validated international RLS rating scale (10 items, score range between 0 and 40) [15,16] in order to measure the severity of RLS symptoms and were defined as ‘RLS sufferers’.
© 2014 EAN
PPS AND RLS
3
asked to indicate the scale value that best described their level of sleepiness–alertness. Steps vary between ‘feeling active and vital; wide awake’ (score 1) and ‘almost in reverie; lost struggle to remain awake’ (score 7). All subjects underwent SSS at a standard time (between 9 and 11 am).
Subjective scales (fatigue, quality of life, diurnal sleepiness)
The existence and the severity of fatigue were assessed using the Italian version of the Fatigue Severity Scale (FSS), obtained by means of the standard forwardbackward procedure; the FSS is a self-administered questionnaire developed to measure fatigue in medical and neurological diseases, which is generally used to measure general fatigue also in PPS [17–22]. The FSS consists of nine statements for evaluating the impact of fatigue. The subject was asked to rate the severity of the fatigue symptoms experienced in the last week using a numerical scale ranging from 1 (strong disagreement with the statement) to 7 (strong agreement with the statement). The total score was calculated by averaging the scores of each item [17,18]. Health-related quality of life was evaluated by means of the Italian version of the Short Form Health Survey (SF-36) questionnaire (4-week version) [23,24]. The SF-36 is grouped in eight multi-item scales: physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems and mental health. It is scored from 0 to 100, 0 indicating extreme problems and 100 indicating no problems. To standardize the scores, the difference between the individual’s raw score and the mean score of the corresponding Italian normative group was calculated. This difference was then divided by the standard deviation of the normative group. These standard scores (z-scores) express individuals’ distance from their normative group mean in terms of the standard deviation of the distribution. Any score equal to the normative mean will be equivalent to a z-score of zero. Negative or positive z-scores are produced for persons falling below or above the mean respectively. The Italian version of the Stanford Sleepiness Scale (SSS), a Likert-type seven-point scale, was used to investigate daytime sleepiness [25]. Subjects were
Subgroup classification and statistical analysis
According to the mentioned criteria, patients and controls were classified into four subgroups: (1) patients affected by PPS without RLS (PPS/RLS ); (2) patients affected by PPS and RLS (PPS/RLS+); (3) controls without RLS (C/RLS ); (4) controls with RLS (C/RLS+). Statistical analysis included the v2 test and independent t test performed by means of Statistica 10.0 (Statsoft Inc., Tulsa, OK, USA). All statistical analyses were two-tailed, and the level of statistical significance was set at P < 0.05. The Pearson correlation test was utilized when appropriate.
Results A total of 66 PPS outpatients (24 men, 42 women; mean age 57.4 8.55 years, range 31–83; median of PPS duration 8.5 years, SD 6.03) were enrolled. Eighty age and sex matched healthy subjects (35 men, 45 women; age 55.8 8.6 years, range 29–76) were recruited as a control group (Table 1). Demographic features and mean score of FSS and SSS of both PPS patients and controls are summarized in Table 1. The main comorbidities of PPS patients are reported in Table S1. Restless legs syndrome prevalence between groups
Of the 66 PPS patients, 42 patients (63.6%) reported experiencing RLS symptoms at least twice per week during the 6 months preceding the interview, with a
Table 1 Demographic parameters and subjective scale scores of subjects included in this study Post polio patients
Men Women Total Subjective scales FSS SSS
Control subjects
n
Age (years)
BMI (Kg/m )
n
Age (years)
BMI (Kg/m2)
P
24 42 66
60.5 (11.8) 56.1 (5.62) 57.7 (8.6) Score 50.2 (14.23) 3.06 (1.64)
25.75 (3.5) 25.86 (4.28) 25.8 (3.97) Range 14–63 1–7
35 45 80
56.8 (10.5) 55.6 (7.5) 55.8 (8.9) Score 23.2 (11.6) 1.91 (0.77)
26.3 (3.48) 24.4 (3.92) 25.22 (3.8) Range 9–46 1–3
NS NS NS
66 66
2
80 80
BMI, body mass index; FSS, Fatigue Severity Scale; SSS, Stanford Sleepiness Scale. Values are expressed as mean (SD). *Level of significance
