Sleep Disturbances in Fibromyalgia Patients

1. Sleep Disturbances in Fibromyalgia Patients Robert Bennett MD, FRCP, MACR

2. Disclosure Research support : Forest, Jazz, Pfizer Advisory Boards: Lilly, Jazz Speaker Bureaus: None

3. 3 Key References Rosenthal MS, Physiology and neurochemistry of sleep. Am. J. Pharm. Educ., 62, 204-208, 1998 Passarella Set al. Diagnosis and treatment of insomnia. Am J Health-Syst Pharm. 2008; 65:927-34 Moldofsky H. Rheumatic manifestations of sleep disorders. CurrOpinRheumatol 2010;22(1):59-63

4. Objectives Historical aspects of sleep in FM Physiology of sleep Insomnia Disturbed sleep in FM patients Evaluation of disturbed sleep in FM Disturbed sleep and pain Management

5. Objectives Historical aspects of sleep in FM Physiology of sleep Insomnia Disturbed sleep in FM patients Evaluation of disturbed sleep in FM Disturbed sleep and pain Management

6. THE PRINCIPLES AND PRACTICE OF MEDICINE DESIGNED FOR THE USE OF PRACTITIONERS AND STUDENTS OF MEDICINE BY WILLIAM OSLER, M. D. FELLOW OF THE ROYAL COLLAGE OF PHYSICIANS, LONDON PROFESSOR OF MEDICINE IN THE JOHNS HOPKINS UNIVERSITY AND PHYSICIAN-IN-CHIEF TO THE JOHNS HOPKINS HOSPITAL, BALTIMORE FORMERLY PROFESSOR OF THE INSTITUTES OF MEDICINE MOOILL UNIVERSITY, MONTREAL AND PROFESSOR OF OLINIOAL MEDICINE 1H THE UNIVERSITY CF PENNSYLVANIA PHILADELPHIA NEW YORK D. APPLETON AND COMPANY 1892 William Osler 1849 - 1919

7. The Principles and Practice of MedicineWilliam Osler MD, 1892 “Neurasthenia”:a condition of weakness or exhaustion of the nervous system 1. Sleeplessness is a frequent concomitant2. The majority are moody or depressed3. They have weariness on the least exertion4. The aching pain in the back of the neck is the most constant complaint5. There are spots of local tenderness in the spine

8. Alpha-deltasleep

9. First “Scientific” Study in FM Delta (≈1cps) Alpha + delta Auditory stimulation in a healthy control Moldofsky et al. Psychosomatic Med. 37:341-351, 1975

10. Objectives Historical aspects of sleep in FM Physiology of sleep Insomnia Disturbed sleep in FM patients Evaluation of disturbed sleep in FM Disturbed sleep and pain Management

11. Sleep stages REM sleep Non-REM sleep Stage 1 - Transition from wake to sleep Stage 2 – Largest percentage of sleep Stages 3 and 4 – Restorative sleep There are 4 to 5 cycles of REM and non-REM sleep each night Each cycle lasts 1.5 to 2 hours

12. Sleep stages REM Stage 1 Stage 2 Stage 3 Stage 4

13. Polysomnography

14. Polysomnography • Polysomnographic data is reviewed in 30 second "epochs" • Sleep latency • Sleep efficiency • Percent time in REM and non-REM sleep • Percent time in each of the 4 sleep stages • Electro-oculogram (EOG) • EMG chin • EMG tibialis anterior • Nasal air flow • Chest and abdominal movements • Oxygen saturation • ECG The number of minutes of sleep divided by the number of minutes in bed. Normal is approximately 85 to 90% or higher. Iber, C et al. The AASM Manual for the Scoring of Sleep: American Academy of Sleep Medicine, Westchester, IL 2007

15. Sleep architecture Decreasing frequency Increasing amplitude

16. Drowsy EEG EOG Eyes open Chin EMG EEG leads Beta waves (12-30 HZ) Alpha waves (8 – 12 HZ) Eyes closed During the earliest phases of sleep, when people are drowsy the brain produces beta waves (13–35 Hz). As the brain begins to relax slower alpha waves(8–12 Hz)are produced. During this time when you are not quite asleep, people may experience vivid sensations known as hypnagogic hallucinations. Another very common event is myoclonic jerks.

17. Stage 1 sleep Slow rolling eye movements EOG Chin EMG EEG leads Theta waves (4–7.5 Hz) with some alpha Stage 1 is a transition period between wakefulness and sleep. In Stage 1, the brain produces high amplitude theta waves (4–7 Hz), which are very slow brain waves. This period of sleep lasts only 5-10 minutes. If you awaken someone during this stage, they might report that they weren't really asleep.

18. Stage 2 sleep Minimal eye movement Minimal chin EMG Theta waves (4–7 Hz) Stage 2 lasts for approximately 20 minutes, mainly theta waves (4–7 Hz). Then the brain begins to produce bursts of rapid, rhythmic brain wave activity known as sleep spindles and K-complexes. Body temperature starts to decrease and heart rate begins to slow.

19. Stages 3 and 4 of non-REM sleep Some eye movement Predominant delta waves (0.5–3.5 Hz) Stages 3 and4 are often referred to as delta sleep because slow brain waves known as delta waves (0.1 – 4 Hz) occur during this time. Stages 3/4 are a deep sleep that lasts for approximately 30 minutes. Bed-wetting, night terrors and sleepwalking are most likely to occur at the end ofstage 4 sleep. It is followed by REM sleep.

20. REM sleep Starts after loss of chin EMG Rapid eye movements • Rapid eye movement (REM) sleep is characterized by eye movement, increased respiration rate and increased brain activity. . Vivid dreams often occur in this sleep stage. Dreaming occurs is due to increased brain activity, but voluntary muscles become paralyzed. Bursts of alpha activity

21. Sleep control mechanisms Encephalitis lethargica

22. Sleep control mechanisms Encephalitis lethargica An epidemic that spread throughout the world from 1977 to 1928. A somnolent-opthalmoplegicform withprofoundsleepiness often leading to coma and death, paralysis of cranial nerves and expressionless faces. A hyperkinetic form with restlessness, twitching of muscles, anxiety andsevere insomnia. An akineticform with muscle weakness, rigidity, and severe insomnia (postencephaliticparkinsonism). • Postulated cause is a mutation of the H1N1 influenza virus • ? N-methyl-D-aspartate (NMDA) receptor antibody mediated

23. Sleep control mechanisms Von Economo, reported that encephalitis lethargica was due to injury to the posterior hypothalamus and rostral midbrain. He recognized that one group of individuals infected during the same epidemic instead had the opposite problem: a prolonged state of insomnia that occurred with lesions of the pre-optic area and basal forebrain. He hypothesized that lesions of the posterior hypothalamus could cause the disease we now call narcolepsy. Based on his observations, von Economo predicted that the region of the hypothalamus near the optic chiasma would contain sleep-promoting neurons, whereas the posterior hypothalamus would contain neurons that promote wakefulness. Constantin von Economo 1876 - 1931

24. Sleep control mechanisms Orexin neuronal projectins Orexinneurons originating in the posterior hypothalamus regulate sleep and wakefulness by sending excitatory projections to the entire CNS, with particularly dense projections to monoaminergic and cholinergic nuclei in the brain stem.

25. Sleep control mechanisms Sleep Awake VLPO = ventrolateral pre-optic nucleus (GABA & galanin) ORX = orexin nucleus (orexins) LC = locus ceruleus(nor-adrenaline) Raphe = raphe magnus(serotonin) TMN = tubermammilary nucleus (histamine)

26. Objectives Historical aspects of sleep in FM Physiology of sleep Insomnia Disturbed sleep in FM patients Evaluation of disturbed sleep in FM Disturbed sleep and pain Management

27. Insomnia – definition DSM-IV criteria for primary insomnia: 1) A complaint of difficulty falling asleep, staying asleep or non-restorative sleep 2) Duration of ≥1 month 3) Causes clinically significant distress or impairment 4) Does not occur exclusively during the course of a mental disorder 5) Is not due to another medical or sleep disorder or effects of medications/substance abuse

28. Insomnia - consequences Fatigue / malaise Impaired attention, concentration, memory Vocational dysfunction Daytime sleepiness Motivation / energy / initiative reduction Proneness for errors / accidents at work or while driving Tension headache Obesity / diabetes Hypertension Depression / anxiety Coronary heart disease Increased mortality Sleep loss may transiently improve depression Riemann et al. Pharmacopsychiatry. 2011 Jan;44(1):1-14.

29. Insomnia – mechanisms Stressors Hyperarousal Sleep disturbance Dysfunctional behavior Neurobiological alterations Long-term consequences

30. Insomnia – mechanisms Am J Psychiatry 2004; 161:2126–2129

31. Insomnia – mechanisms Interacting neural networks are involved in the neurobiology of insomnia: 1. General arousal system (ascending reticular formation and hypothalamus), 2. Emotion-regulating system (hippocampus, amygdala, and anterior cingulate cortex), 3. Cognitive system (prefrontal cortex) Patients with insomnia: brain areas where metabolism was not decreased in waking and sleep states Healthy subjects: brain areas where metabolism, while awake, was higher than in patients with insomnia

32. Objectives Historical aspects of sleep in FM Physiology of sleep Insomnia Disturbed sleep in FM patients Evaluation of disturbed sleep in FM Disturbed sleep and pain Management

33. Sleep disturbances in FM • Insomnia • α intrusion rhythm • cyclic alternating rhythm (CAP) • Periodic limb movements (PLM/RLS) • Snoring and arousals • Apnea and hypopnea • Periodic breathing • Bruxism

34. First “Scientific” Study in FM (1975) Delta (≈1cps) Alpha + delta Auditory stimulation in healthy controls Moldofsky et al. Psychosomatic Med. 37:341-351, 1975

35. Alpha – delta sleep Normal sleep EEG leads Chin EMG ECG R. leg L. leg α-EEG sleep

36. Cyclic alternating pattern (CAP) in FM J Rheumatol2004; 31:1193–9 Cyclic Alternating Pattern: A New Marker of Sleep Alteration in Patients with Fibromyalgia? Maurizio Rizzi, Piercarlo Sarzi-puttini, Fabiola Atzeni, Franco Capsoni, Arnaldo Andreoli, Marica Pecis, Stefano Colombo, Mario Carrabba, Margherita Sergi Found CAP pattern in 68% FM patients vs 45% controls.Hypothesized that CAP in FM maybe a result of chronic pain reducing sleep efficiency, causing more CAP and more arousals and increasing the occurrence of periodic breathing.

37. Cyclic alterating pattern in FM R. EOG L. EOG EEG EEG EMG Air flux Thorax Abdomen %O2 sat. Sergi et al. Eur Resp J 1999; 14:203-208

38. Upper airway resistance syndrome Sleep 2004 May 1;27(3):459-66 The upper airway resistance syndrome (UARS) is a form of sleep-disordered breathing in which repetitive increases in resistance to airflow within the upper airway lead to brief arousals and daytime somnolence. Patients do not meet criteria for obstructive sleep apnea. Manometryand pneumotachographicare the "gold standard" for diagnosis. Now considered to be same as “cyclic alterating rhythm”

39. Periodic leg movements (PML) • PLM is a repetitive cramping or jerking of the legs during  sleep; it can range from a small movements in the ankles and toes, to wild flailing of all 4 limbs • PLM is the 4th leading cause of insomnia • PLM affects about 5% of total population • More common in women (~20% of females age ≥ 50) • PLM affects about 60% of all FM patients Natarajan R. Review of periodic limb movement and restless leg syndrome. J Postgrad Med 2010;56:157-6

40. Restless legs syndrome J Clin Sleep Med 2010;6(5):423-427 Conclusions: There is a high prevalence and odds of having RLS in FM patients. Clinicians should routinely query FM patients regarding RLS symptoms because treatment of RLS can potentially improve sleep and quality of life in these patients. RLS symptoms FM patients = 33% Healthy controls = 3.1%

41. RLS associations Hereditary (~50%) Uremia (~50%) Narcolepsy (~50%) Pregnancy (~20%) Diabetes REM sleep behavioral disorder Parkinson’s disease Hypothyroidism Iron deficiency (ferritin ≤ 50 ng/ml) Some drugs (TCAs, SSRIs, DA, L-thyroxine, tramadol, benadryl) Opioid / benzodiazapine withdrawal

42. Sleep apnea

43. Sleep apnea • Excessive daytime sleepiness *Epworth score usually ≥ 15 • Loud snoring - more prominent in obstructive sleep apnea • Abrupt awakenings with shortness of breath – more prominent in central sleep apnea • Observed episodes of apnea during sleep • Awakening with a dry mouth or sore throat • Morning headache • Difficulty losing weight • Hypertension, gastric reflux, arrythmias

44. Obstructive sleep apnea

45. Central sleep apnea Central

46. Objectives Historical aspects of sleep in FM Physiology of sleep Insomnia Disturbed sleep in FM patients Evaluation of disturbed sleep in FM Disturbed sleep and pain Management

47. Epworth sleepiness scale(http://epworthsleepinessscale.com) How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just tired? 0 = no chance, 1= slight chance 2 = moderate chance 3 = high chance ANALYSISScore of 1-6 getting enough sleep Score of 4-8 the average score Score of 9-15 very sleepy and need further evaluation Score of ≥16 dangerously sleepy and urgently need specialist evaluation/polysomnogram

48. Restless legs questionnaire • Do you have uncomfortable feelings or sensations in the legs (or urge to move the legs) while sittingor lying down? • (2) Is the discomfort was worse when resting? • (3) Is the discomfort improved or resolved with • walking? • (4) Isthe discomfort worse in the evening or nighttime? Crawling Tingling Cramping Creeping Pulling Painful Electric Itchy Gnawing Aching Score of 4 provides 90% diagnostic sensitivity HeningWA et al. The Johns Hopkins diagnostic interview for the restless legs syndrome. Sleep Med 2003;4:137-41

49. Periodic limb movement disorder (PLMD) (nocturnal myoclonus) Diagnostic considerations: • 80% of RLS patients have periodic limb movement disorder (PLMD) • Paradoxically only 30% PLMD patients have RLS Patient has RLS Report from sleep partner Polysomnogram Response to dopamine agonist * * A diagnosis of PLMS requires 3 periods of ≥30 movements followed by partial arousal or awakening

50. Polysomnography