Curr Neurol Neurosci Rep (2015) 15:21 DOI 10.1007/s11910-015-0546-0
SLEEP (M THORPY, M BILLIARD, SECTION EDITORS)
Sleep Disorders in Multiple Sclerosis. Review Christian Veauthier
# Springer Science+Business Media New York 2015
Abstract Sleep disorders are common in patients with multiple sclerosis (MS) and play a crucial role in health and quality of life; however, they are often overlooked. The most important sleep disorders in this context are as follows: insomnia, restless legs syndrome, periodic limb movement disorders, and sleep-related breathing disorders (SRBD). It is unclear if MS-related processes (lesions, brain atrophy) can cause symptomatic forms of sleep apnea. MS-related narcolepsy-like symptoms are described in the literature and, in some cases, have resolved with methylprednisolone pulse therapy. Similarly, REM sleep behavior disorder (RBD) is very rare in MS, but it can be an initial sign of MS where cortisone therapy may be helpful and can be taken into account in this specific context. Independent diagnosis and treatment is required for all of the abovementioned conditions. Treating physicians and neurologists should be aware of these comorbidities and initiate specific therapy. Highly fatigued or sleepy MS patients should have polysomnography in order not to overlook these diagnoses. Keywords Restless legs syndrome . Periodic limb movement disorder . Nocturia . Insomnia . Sleep apnea . Polysomnography
Introduction Multiple sclerosis (MS) is an inflammatory disorder of the brain, spinal cord, and optic nerves with unknown etiology This article is part of the Topical Collection on Sleep C. Veauthier (*) Interdisciplinary Center of Sleep Medicine, Charité University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany e-mail: [email protected]
arising as a result of complex interactions between genetic and environmental factors [1–3]. It affects twice as many women as men and typically develops between the ages of 20 and 40 years (the average age of MS onset is 30 years) [4]. According to the World Health Organization (WHO), MS affects more than two million people worldwide with the highest prevalence rate in North America and Europe, and the disease is one of the most common disabling nontraumatic neurological conditions in young adults [5, 6]. Sleep disorders are very common in the general population: 4 % of middle-aged men and 2 % of women in the workforce are likely to meet minimal diagnostic criteria for sleep apnea syndrome [7]. The prevalence of restless legs syndrome (RLS) is up to 10.6 % affecting women more often than men [8]. Insomnia affects 6 to18 % of the general population, depending on which criteria are used [9]. These are only examples of the most common sleep disorders, and their high prevalence rate suggests that MS patients will certainly be suffering from comorbid sleep disorders as does a large part of the general population. It can be sometimes difficult to distinguish if fatigue is related to sleep disorders or to MS. There is a link between some sleep disorders and MS; for example, the prevalence rate of RLS is four times higher in MS than in the general population [10], and some MS patients present narcolepsy-like symptoms. It is sometimes impossible to elucidate if these symptoms are related to MS or whether they are independent of it (e.g., idiopathic narcolepsy) [11]). A recent cross-sectional polysomnographic trial found sleep disorders in 74 % of consecutive MS patients (49 out of 66 patients) [12]. The objective of this review is to describe sleep disorders in MS and to highlight the complex relationship and interaction between them. This review is written not only for clinicians, sleep specialists, and neurologists treating MS patients in order to improve understanding of the subject matter but also for researchers indicating future research directions.
21
Page 2 of 10
Methods A PubMed database search last accessed on October 15, 2014, was conducted with the terms sleep disorders AND multiple sclerosis (n=342), restless legs syndrome AND multiple sclerosis (n=46), insomnia AND multiple sclerosis (n=94), narcolepsy AND multiple sclerosis (n=96), hypersomnia AND multiple sclerosis (n=89), REM Sleep Behavior disorder AND multiple sclerosis (n=16). After having read the abstracts of the articles, only relevant articles were included. Moreover, the references of these articles were read and hand-searched for potentially relevant studies or articles as well. Additionally, a PubMed database with the terms human leukocyte antigen (HLA) DRB1 AND multiple sclerosis was performed (n=561), and only relevant articles were used.
Sleep-Related Breathing Disorders Obstructive sleep apnea (OSA) [13•], also known as obstructive sleep apnea hypopnea (OSAH) syndrome, is the most common sleep-related breathing disorder (SRBD). Other less frequent SRBDs are central sleep apnea syndrome (CSA) [13•], central alveolar hypoventilation [13•], obesity hypoventilation syndrome (OHS) [13•, 14] (defined as a combination of obesity and daytime hypercapnia), and complex sleep apnea with persisting central apneas after starting continuous positive airway pressure (CPAP) therapy [15]. Moreover, in the last few years, a possible new entity, the so called upper airway resistance syndrome (UARS), has been described as a new SRBD requiring eosophageal manometry to detect an increase of inspiratory esophageal pressure [16, 17]. To date, we do not have exact data about the prevalence of OSA or other SRBDs in MS patients [18•]. Kaminska et al. [19] found OSA in 58 % of MS patients and 49 % of healthy controls using the American Academy of Sleep Medicine (AASM) research criteria [20] (apnea or hypopnea for 10 s associated with arousal or desaturation ≥4 %) and an apnea/hypopnea index (AHI) cutoff of ≥15/h. When using only desaturation-associated hypopnea/apnea (without arousal-associated hypopnea/apnea), 11 % were suffering from OSA. Veauthier et al. [12] found SRBD in 12 % of consecutive MS patients using the older AASM Task force criteria from 1999 [21] and an AHI cutoff of ≥10/h. In both studies, the follow-up studies showed that sleep medical treatment started subsequently improved fatigue [22, 23]. Kallweit et al. [24] investigated 69 fatigued MS patients with overnight respirography, and they found SRBD in 41 %; subsequently started CPAP therapy improved fatigue as well.
Curr Neurol Neurosci Rep (2015) 15:21
Braley et al. [25] investigated 30 MS patients and 30 healthy controls (HC) by polysomnography using a lower AHI-cut-off of 5/h and they found OSA in 80 % of MS patients and 63 % of controls. Chen et al. [26] investigated 21 MS patients and 10 HC using the same low AHI cutoff of ≥5/ h, and none of the patients or controls had an AHI ≥5/h. The main problem of the variability of these results is the use of different scoring instruments, classification systems, and cutoff values, especially different AHI cutoffs. The International Classification of Sleep Disorders third edition (ICSD3) [13•] defines OSA as having an AHI ≥15/h or as having an AHI ≥5/h and daytime symptoms. As many MS patients are suffering from fatigue and depression, as well as cognitive dysfunction, it is difficult to conclude if these symptoms are related to OSA or to the MS. In fatigued MS patients, an AHI of almost 5/h is required for OSA diagnosis if the fatigue is related to OSA, which normally is not known. In absence of daytime dysfunction, an AHI of almost 15/h is requested for the diagnosis of OSA. As many MS patients are suffering from fatigue which can be the consequence of a misdiagnosed OSA, a large number of f a t i g u e d MS p a t i e n t s sh o u l d b e in v e s t i g a t e d b y polysomnography (PSG). In order to find a screening instrument in this particular issue, Veauthier and Paul [27•] performed a retrospective ROC analysis of their original cohort [12] and recommended the combination of the Modified Fatigue Impact Scale (MFIS) [28, 29] and the Pittsburgh Sleep Quality Index (PSQI) [30]. By jointly applying the MFIS cutoff of 34 and the PSQI cutoff of 5 (either MFIS >34 or PSQI >5 or both), a sensitivity of 89.8 % was achieved for detecting sleep disorders with a specificity of 58.8 % (positive predictive value 86.3 %, negative predictive value 66.7 %). Fatigued MS patients with MFIS values >34 or PSQI values >5 should undergo polysomnographic investigations in order not to misdiagnose treatable sleep disorders. Braley et al. [31•] retrospectively analyzed the polysomnographic data of 48 MS patients compared with 48 controls matched for age, gender, and body mass index (BMI), and they found more severe OSA, as well as more severe CSA, in MS patients than in controls. Furthermore, MS patients with clinical or radiographic evidence of brainstem involvement showed a higher AHI than MS patients without brainstem lesions. Even if this study has some methodical limitations (retrospective design, different classification system used: Rechtschaffen and Kales [32] at the beginning and later the new AASM criteria [20]), it is the first study investigating the possible pathophysiological mechanism of unexplored and presumed Bsymptomatic^ SRBD in MS and further prospective trials using standardized magnetic resonance imaging of the brain and the spinal cord are needed in order to elucidate the impact of specific brain lesions and neuroinflammation/ neurodegeneration on the etiology of this suspected symptomatic SRBD. By theoretical consideration (breath regulation in
Curr Neurol Neurosci Rep (2015) 15:21
the brainstem), the region of interest in this study has been the brainstem. In further prospective studies, it would be desirable to investigate the whole central nervous system (CNS) without a predetermined conclusion, because we cannot exclude that other brain regions are involved in the pathophysiology of symptomatic SRBD as well. Moreover, in order to avoid inaccurate conclusions, it is important for a careful interpretation of these findings to point out at this stage, that previous studies investigating normal OSA patients (without MS) did not show an association between the severity of OSA (AHI and saturation) and daytime fatigue [33, 34].
Insomnia To date, there is no study investigating insomnia in MS using the criteria described by the ICSD-3 [13•], the Diagnostic Statistical Manual (DSM) [35] or the criteria of insomnia as defined by the tenth edition of the International Classification of Diseases (ICD-10) [36]. There is only one study investigating insomnia according to ICSD-2 criteria reporting insomnia in 25 % of MS patients [12]. Moreover, to our knowledge, there is no study investigating insomnia in MS patients compared with the general population. Even if the prevalence of insomnia seems to be higher in MS than in the general population, we do not have robust data confirming this hypothesis. The ICD-10 (1992) [36] of the World Health Organization (WHO ICD-10) defines insomnia as nonorganic insomnia (incapability to initiate sleep, or as disrupted sleep or early morning awakenings). The ICSD-3 defines insomnia as a Bpersistent difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep, and results in some form of daytime impairment^— including nonorganic and organic insomnia as well. Brass et al. [37] found moderate to severe insomnia in 31.6 % in a written survey of 2375 patients using validated questionnaires. Leonavicius et al. [38] found sleep disturbances in 45.3 % of MS patients using the Medical Outcomes Study Sleep (MOSS) measure [39], and Tachibana et al. [40] reported sleep problems in 53.6 % of MS patients— including discomfort in the legs, snoring, nocturia, and sleep apnea. For a detailed review about studies investigating insomnia in multiple sclerosis patients, please see the review by Veauthier and Paul [18•]. In sum, approximately one fourth to one half of MS patients are suffering from insomnia and the prevalence of insomnia in MS seems to be higher than in the general population, but studies comparing the prevalence of insomnia in MS with the general population in a systematic manner are lacking today. The therapy of insomnia includes the treatment of the
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primary condition and the therapy of nonorganic insomnia consists of medication and psychological or behavioral therapies [41].
Restless Legs Syndrome and Periodic Limb Movement Disorder The ICSD-3 [13•] defines RLS as Ban urge to move the legs, usually accompanied by or thought to be caused by uncomfortable and unpleasant sensations in the legs^ which (i) begin or worsen during periods of rest or inactivity, (ii) are relieved by movement, and (iii) occur (exclusively or predominantly) in the evening or night. Moreover, the ICSD-3 requires that these features are not accounted for as symptoms of another medical or behavioral condition and cause distress, sleep disturbances, or daytime impairment. Polysomnography (PSG) is not routinely indicated in RLS even if PSG may be helpful in some cases in order to rule out comorbid disorders as sleep apnea. RLS may be idiopathic or symptomatic of an underlying condition (i.e., chronic renal failure, anemia, and iron deficiency). The prevalence of RLS is four times higher in MS than in the general population [10]. Iron deficiency and subsequent dopaminergic dysfunction play a major role in the etiology of RLS [42]. Low iron stores and decreased ferritin serum levels were found in periodic limb movement disorder (PLMD) [13•] as well [43], and PLMD is considered to be an endophenotype of RLS [44]. Drug treatment for RLS consists of dopaminergic therapy [45•, 46], but iron substitution [47•], opioids [45•, 46], and pregabaline [48] are effective as well. To date, there is no evidence of any pharmacological treatment for PLMD alone [45•]. RLS can be misdiagnosed in MS, and RLS symptoms may be attributed to comorbid spasticity. In case of doubt, a dopaminergic therapy may be helpful to distinguish spasticity from RLS.
Narolepsy, HLA DRB1*1501-DQB1*0602 and the Autoimmune Hypothesis Narcolepsy type 1 (hypocretin deficiency syndrome) is mainly characterized by excessive daytime sleepiness (EDS) and signs of REM sleep dissociation, the most specific of which is cataplexy, and it is caused by a deficiency of hypothalamic neuropeptide hypocretin (orexin) signaling [13•]. Apart from EDS for at least 3 months, the diagnosis of narcolepsy type 1 requires either the presence of cataplexies, reduced sleep latencies in the multiple sleep latency test (MSLT) of ≤8 min in combination with two or more sleep-onset REM periods (SOREMP) or reduced hypocretin-1 (HCRT-1) levels in the cerebrospinal fluid (CSF) (either ≤110 pg/mL or 110 pg/mL or >1/3 of mean valuesa or not measured and no cataplexy and on a MSLT: mean sleep latency ≤8 min ≥2 SOREMPs and not better explained by other causes such as insufficient sleep, obstructive sleep apnea, delayed sleep phase disorder, or the effect of medication or substances or their withdrawal
Narcolepsy type 2
Idiopathic hypersomnia
Hypersomnia due to a medical disorder
On 24-h PSG or by wrist actigraphy in association with a sleep log
Obtained in normal subjects with the same standardized assay
In disorders associated with both sleep apnea and narcolepsy type 2, such as myotonic dystrophy or Prader-Willi syndrome, a diagnosis of narcolepsy type 2 should only be made if abnormal MSLT findings persist after the sleep apnea is adequately treated
c
b
a
OSA obstructive sleep apnea, PSG polysomnogram
Please note: A repeat MSLT at a later date is advisable if the clinical suspicion for narcolepsy or idiopathic hypersomnia remains high
Diagnostic criteria
EDS for ≥3 months EDS for ≥3 months either CSF-HCRT1: ≤110 pg/mL or
SLEEP (M THORPY, M BILLIARD, SECTION EDITORS)
Sleep Disorders in Multiple Sclerosis. Review Christian Veauthier
# Springer Science+Business Media New York 2015
Abstract Sleep disorders are common in patients with multiple sclerosis (MS) and play a crucial role in health and quality of life; however, they are often overlooked. The most important sleep disorders in this context are as follows: insomnia, restless legs syndrome, periodic limb movement disorders, and sleep-related breathing disorders (SRBD). It is unclear if MS-related processes (lesions, brain atrophy) can cause symptomatic forms of sleep apnea. MS-related narcolepsy-like symptoms are described in the literature and, in some cases, have resolved with methylprednisolone pulse therapy. Similarly, REM sleep behavior disorder (RBD) is very rare in MS, but it can be an initial sign of MS where cortisone therapy may be helpful and can be taken into account in this specific context. Independent diagnosis and treatment is required for all of the abovementioned conditions. Treating physicians and neurologists should be aware of these comorbidities and initiate specific therapy. Highly fatigued or sleepy MS patients should have polysomnography in order not to overlook these diagnoses. Keywords Restless legs syndrome . Periodic limb movement disorder . Nocturia . Insomnia . Sleep apnea . Polysomnography
Introduction Multiple sclerosis (MS) is an inflammatory disorder of the brain, spinal cord, and optic nerves with unknown etiology This article is part of the Topical Collection on Sleep C. Veauthier (*) Interdisciplinary Center of Sleep Medicine, Charité University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany e-mail: [email protected]
arising as a result of complex interactions between genetic and environmental factors [1–3]. It affects twice as many women as men and typically develops between the ages of 20 and 40 years (the average age of MS onset is 30 years) [4]. According to the World Health Organization (WHO), MS affects more than two million people worldwide with the highest prevalence rate in North America and Europe, and the disease is one of the most common disabling nontraumatic neurological conditions in young adults [5, 6]. Sleep disorders are very common in the general population: 4 % of middle-aged men and 2 % of women in the workforce are likely to meet minimal diagnostic criteria for sleep apnea syndrome [7]. The prevalence of restless legs syndrome (RLS) is up to 10.6 % affecting women more often than men [8]. Insomnia affects 6 to18 % of the general population, depending on which criteria are used [9]. These are only examples of the most common sleep disorders, and their high prevalence rate suggests that MS patients will certainly be suffering from comorbid sleep disorders as does a large part of the general population. It can be sometimes difficult to distinguish if fatigue is related to sleep disorders or to MS. There is a link between some sleep disorders and MS; for example, the prevalence rate of RLS is four times higher in MS than in the general population [10], and some MS patients present narcolepsy-like symptoms. It is sometimes impossible to elucidate if these symptoms are related to MS or whether they are independent of it (e.g., idiopathic narcolepsy) [11]). A recent cross-sectional polysomnographic trial found sleep disorders in 74 % of consecutive MS patients (49 out of 66 patients) [12]. The objective of this review is to describe sleep disorders in MS and to highlight the complex relationship and interaction between them. This review is written not only for clinicians, sleep specialists, and neurologists treating MS patients in order to improve understanding of the subject matter but also for researchers indicating future research directions.
21
Page 2 of 10
Methods A PubMed database search last accessed on October 15, 2014, was conducted with the terms sleep disorders AND multiple sclerosis (n=342), restless legs syndrome AND multiple sclerosis (n=46), insomnia AND multiple sclerosis (n=94), narcolepsy AND multiple sclerosis (n=96), hypersomnia AND multiple sclerosis (n=89), REM Sleep Behavior disorder AND multiple sclerosis (n=16). After having read the abstracts of the articles, only relevant articles were included. Moreover, the references of these articles were read and hand-searched for potentially relevant studies or articles as well. Additionally, a PubMed database with the terms human leukocyte antigen (HLA) DRB1 AND multiple sclerosis was performed (n=561), and only relevant articles were used.
Sleep-Related Breathing Disorders Obstructive sleep apnea (OSA) [13•], also known as obstructive sleep apnea hypopnea (OSAH) syndrome, is the most common sleep-related breathing disorder (SRBD). Other less frequent SRBDs are central sleep apnea syndrome (CSA) [13•], central alveolar hypoventilation [13•], obesity hypoventilation syndrome (OHS) [13•, 14] (defined as a combination of obesity and daytime hypercapnia), and complex sleep apnea with persisting central apneas after starting continuous positive airway pressure (CPAP) therapy [15]. Moreover, in the last few years, a possible new entity, the so called upper airway resistance syndrome (UARS), has been described as a new SRBD requiring eosophageal manometry to detect an increase of inspiratory esophageal pressure [16, 17]. To date, we do not have exact data about the prevalence of OSA or other SRBDs in MS patients [18•]. Kaminska et al. [19] found OSA in 58 % of MS patients and 49 % of healthy controls using the American Academy of Sleep Medicine (AASM) research criteria [20] (apnea or hypopnea for 10 s associated with arousal or desaturation ≥4 %) and an apnea/hypopnea index (AHI) cutoff of ≥15/h. When using only desaturation-associated hypopnea/apnea (without arousal-associated hypopnea/apnea), 11 % were suffering from OSA. Veauthier et al. [12] found SRBD in 12 % of consecutive MS patients using the older AASM Task force criteria from 1999 [21] and an AHI cutoff of ≥10/h. In both studies, the follow-up studies showed that sleep medical treatment started subsequently improved fatigue [22, 23]. Kallweit et al. [24] investigated 69 fatigued MS patients with overnight respirography, and they found SRBD in 41 %; subsequently started CPAP therapy improved fatigue as well.
Curr Neurol Neurosci Rep (2015) 15:21
Braley et al. [25] investigated 30 MS patients and 30 healthy controls (HC) by polysomnography using a lower AHI-cut-off of 5/h and they found OSA in 80 % of MS patients and 63 % of controls. Chen et al. [26] investigated 21 MS patients and 10 HC using the same low AHI cutoff of ≥5/ h, and none of the patients or controls had an AHI ≥5/h. The main problem of the variability of these results is the use of different scoring instruments, classification systems, and cutoff values, especially different AHI cutoffs. The International Classification of Sleep Disorders third edition (ICSD3) [13•] defines OSA as having an AHI ≥15/h or as having an AHI ≥5/h and daytime symptoms. As many MS patients are suffering from fatigue and depression, as well as cognitive dysfunction, it is difficult to conclude if these symptoms are related to OSA or to the MS. In fatigued MS patients, an AHI of almost 5/h is required for OSA diagnosis if the fatigue is related to OSA, which normally is not known. In absence of daytime dysfunction, an AHI of almost 15/h is requested for the diagnosis of OSA. As many MS patients are suffering from fatigue which can be the consequence of a misdiagnosed OSA, a large number of f a t i g u e d MS p a t i e n t s sh o u l d b e in v e s t i g a t e d b y polysomnography (PSG). In order to find a screening instrument in this particular issue, Veauthier and Paul [27•] performed a retrospective ROC analysis of their original cohort [12] and recommended the combination of the Modified Fatigue Impact Scale (MFIS) [28, 29] and the Pittsburgh Sleep Quality Index (PSQI) [30]. By jointly applying the MFIS cutoff of 34 and the PSQI cutoff of 5 (either MFIS >34 or PSQI >5 or both), a sensitivity of 89.8 % was achieved for detecting sleep disorders with a specificity of 58.8 % (positive predictive value 86.3 %, negative predictive value 66.7 %). Fatigued MS patients with MFIS values >34 or PSQI values >5 should undergo polysomnographic investigations in order not to misdiagnose treatable sleep disorders. Braley et al. [31•] retrospectively analyzed the polysomnographic data of 48 MS patients compared with 48 controls matched for age, gender, and body mass index (BMI), and they found more severe OSA, as well as more severe CSA, in MS patients than in controls. Furthermore, MS patients with clinical or radiographic evidence of brainstem involvement showed a higher AHI than MS patients without brainstem lesions. Even if this study has some methodical limitations (retrospective design, different classification system used: Rechtschaffen and Kales [32] at the beginning and later the new AASM criteria [20]), it is the first study investigating the possible pathophysiological mechanism of unexplored and presumed Bsymptomatic^ SRBD in MS and further prospective trials using standardized magnetic resonance imaging of the brain and the spinal cord are needed in order to elucidate the impact of specific brain lesions and neuroinflammation/ neurodegeneration on the etiology of this suspected symptomatic SRBD. By theoretical consideration (breath regulation in
Curr Neurol Neurosci Rep (2015) 15:21
the brainstem), the region of interest in this study has been the brainstem. In further prospective studies, it would be desirable to investigate the whole central nervous system (CNS) without a predetermined conclusion, because we cannot exclude that other brain regions are involved in the pathophysiology of symptomatic SRBD as well. Moreover, in order to avoid inaccurate conclusions, it is important for a careful interpretation of these findings to point out at this stage, that previous studies investigating normal OSA patients (without MS) did not show an association between the severity of OSA (AHI and saturation) and daytime fatigue [33, 34].
Insomnia To date, there is no study investigating insomnia in MS using the criteria described by the ICSD-3 [13•], the Diagnostic Statistical Manual (DSM) [35] or the criteria of insomnia as defined by the tenth edition of the International Classification of Diseases (ICD-10) [36]. There is only one study investigating insomnia according to ICSD-2 criteria reporting insomnia in 25 % of MS patients [12]. Moreover, to our knowledge, there is no study investigating insomnia in MS patients compared with the general population. Even if the prevalence of insomnia seems to be higher in MS than in the general population, we do not have robust data confirming this hypothesis. The ICD-10 (1992) [36] of the World Health Organization (WHO ICD-10) defines insomnia as nonorganic insomnia (incapability to initiate sleep, or as disrupted sleep or early morning awakenings). The ICSD-3 defines insomnia as a Bpersistent difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep, and results in some form of daytime impairment^— including nonorganic and organic insomnia as well. Brass et al. [37] found moderate to severe insomnia in 31.6 % in a written survey of 2375 patients using validated questionnaires. Leonavicius et al. [38] found sleep disturbances in 45.3 % of MS patients using the Medical Outcomes Study Sleep (MOSS) measure [39], and Tachibana et al. [40] reported sleep problems in 53.6 % of MS patients— including discomfort in the legs, snoring, nocturia, and sleep apnea. For a detailed review about studies investigating insomnia in multiple sclerosis patients, please see the review by Veauthier and Paul [18•]. In sum, approximately one fourth to one half of MS patients are suffering from insomnia and the prevalence of insomnia in MS seems to be higher than in the general population, but studies comparing the prevalence of insomnia in MS with the general population in a systematic manner are lacking today. The therapy of insomnia includes the treatment of the
Page 3 of 10 21
primary condition and the therapy of nonorganic insomnia consists of medication and psychological or behavioral therapies [41].
Restless Legs Syndrome and Periodic Limb Movement Disorder The ICSD-3 [13•] defines RLS as Ban urge to move the legs, usually accompanied by or thought to be caused by uncomfortable and unpleasant sensations in the legs^ which (i) begin or worsen during periods of rest or inactivity, (ii) are relieved by movement, and (iii) occur (exclusively or predominantly) in the evening or night. Moreover, the ICSD-3 requires that these features are not accounted for as symptoms of another medical or behavioral condition and cause distress, sleep disturbances, or daytime impairment. Polysomnography (PSG) is not routinely indicated in RLS even if PSG may be helpful in some cases in order to rule out comorbid disorders as sleep apnea. RLS may be idiopathic or symptomatic of an underlying condition (i.e., chronic renal failure, anemia, and iron deficiency). The prevalence of RLS is four times higher in MS than in the general population [10]. Iron deficiency and subsequent dopaminergic dysfunction play a major role in the etiology of RLS [42]. Low iron stores and decreased ferritin serum levels were found in periodic limb movement disorder (PLMD) [13•] as well [43], and PLMD is considered to be an endophenotype of RLS [44]. Drug treatment for RLS consists of dopaminergic therapy [45•, 46], but iron substitution [47•], opioids [45•, 46], and pregabaline [48] are effective as well. To date, there is no evidence of any pharmacological treatment for PLMD alone [45•]. RLS can be misdiagnosed in MS, and RLS symptoms may be attributed to comorbid spasticity. In case of doubt, a dopaminergic therapy may be helpful to distinguish spasticity from RLS.
Narolepsy, HLA DRB1*1501-DQB1*0602 and the Autoimmune Hypothesis Narcolepsy type 1 (hypocretin deficiency syndrome) is mainly characterized by excessive daytime sleepiness (EDS) and signs of REM sleep dissociation, the most specific of which is cataplexy, and it is caused by a deficiency of hypothalamic neuropeptide hypocretin (orexin) signaling [13•]. Apart from EDS for at least 3 months, the diagnosis of narcolepsy type 1 requires either the presence of cataplexies, reduced sleep latencies in the multiple sleep latency test (MSLT) of ≤8 min in combination with two or more sleep-onset REM periods (SOREMP) or reduced hypocretin-1 (HCRT-1) levels in the cerebrospinal fluid (CSF) (either ≤110 pg/mL or 110 pg/mL or >1/3 of mean valuesa or not measured and no cataplexy and on a MSLT: mean sleep latency ≤8 min ≥2 SOREMPs and not better explained by other causes such as insufficient sleep, obstructive sleep apnea, delayed sleep phase disorder, or the effect of medication or substances or their withdrawal
Narcolepsy type 2
Idiopathic hypersomnia
Hypersomnia due to a medical disorder
On 24-h PSG or by wrist actigraphy in association with a sleep log
Obtained in normal subjects with the same standardized assay
In disorders associated with both sleep apnea and narcolepsy type 2, such as myotonic dystrophy or Prader-Willi syndrome, a diagnosis of narcolepsy type 2 should only be made if abnormal MSLT findings persist after the sleep apnea is adequately treated
c
b
a
OSA obstructive sleep apnea, PSG polysomnogram
Please note: A repeat MSLT at a later date is advisable if the clinical suspicion for narcolepsy or idiopathic hypersomnia remains high
Diagnostic criteria
EDS for ≥3 months EDS for ≥3 months either CSF-HCRT1: ≤110 pg/mL or
