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Movement Disorders in Sleep
Introduction
Sleep is a universal experience; infants spend more than half of their time sleeping and adults about one-third of the day asleep. Sleep is an active process, often accompanied by various movements, some of which are normal, whereas others might have a more pathologic basis. Pediatric neurologists are frequently confronted with interpreting descriptions of movements that occur during sleep. Is the described movement abnormal, a component of a sleep-related disorder, an extension of a preexisting movement disorder, or a seizure? Physicians have long known that sleep disturbances could represent a sign of disease, but the recognition of the existence of primary sleep disorders first occurred in the 1950s. The discovery of rapid eye movement (REM) sleep and subsequently the nightly repetitive cycles of non-rapid eye movement (NREM) and REM sleep led to the recognition that sleep is an active process with distinct neurophysiological abnormalities. In this chapter, movements in sleep are divided into four areas ( Table 19.1 ), with the emphasis on involuntary movements that occur around the time of sleep. A brief review of sleep physiology is provided before the discussion of sleep abnormalities, recognizing that sleep–wake cycles are often used to categorize these anomalies.
Table 19.1
Classification of Movement Disorders in Sleep.
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Overview of Sleep Physiology
The sleep–wake cycle is subdivided into three states: wake, NREM, and REM sleep. NREM sleep typically initiates sleep, that is, drowsiness merges with sleep and its three stages (N1–N3) cyclically alternates with REM sleep throughout the sleep cycle ( Fig. 19.1 ). This normal transition from wake to sleep is defined by electroencephalogram (EEG) scalp recordings that show a typical progression, that is, shift from alpha (8–12 Hz) to an increase in theta (4–7 Hz) activity. NREM stage N1 (drowsy and physically relaxed) has the loss of the posterior dominant rhythm, mild slowing of the background activity, and the appearance of vertex sharp waves; stage N2 (true sleep) has distinctive features of sleep spindles (7–14 Hz) or K complexes; and stage 3 (slow-wave sleep) has the presence of large amplitude slow (0.5–4 Hz) delta frequency waves. REM sleep is characterized by distinct intermittent REMs, a low-amplitude mixed-frequency pattern on EEG, the absence of muscle tone in voluntary muscles, and behavioral quiescence.
Normal sleep architecture in older children and adults consists of progressive cycles throughout the night. At the onset of sleep, the individual moves from drowsiness into the NREM phase stage N1, then progresses to stage N2, and subsequently into delta or slow-wave sleep (stage N3). After about 80–90 min, the first period of REM sleep occurs, lasting about 5–10 min. The individual then typically returns to stage N1 or N2 sleep before again entering delta sleep. The next episode of REM sleep occurs in about 60–90 min. As the night progresses, NREM–REM cycles continue with fewer stages of N3 sleep. In the early-morning hours, cycles alternate between stages N1–N2 and REM. Most delta sleep occurs during the first third of the night and most REM sleep occurs in the last third. Developmentally, sleep systems in children mature rapidly: Prior to 32 weeks of gestation, sleep is not differentiable into stages. REM and non-REM sleep are distinguishable by the second postgestational month and by age 6 months sleep can be classified into N1-3 stages. In the first year of life, REM sleep predominates, but in the preschool and school-age years NREM stage 3 predominates, with longer periods of deeper stages of sleep. Normal sleep movements, such as position shifts, are common in infants and decrease with age. Infants also lack the typical REM motor inhibition seen in older children and adults. In adults, about one-half of the sleep period is spent in stage N2 sleep, 20% in N3, and 25% in REM sleep ( Fig. 19.1 ).
The mechanisms for the induction and maintenance of normal sleep and the control of both circadian (24-h) and ultradian (90–120 min cycles of NREM/REM) rhythm generation are complex; involve coordination of neuronal activity among the hypothalamus, brainstem, thalamus, and cortex. Simplistically, “wake regions” consist of the brainstem reticular activating system that includes the pedunculopontine nucleus (acetylcholine), lateral dorsal tegmentum (acetylcholine), locus coeruleus (norepinephrine), dorsal and median raphe nuclei (serotonin), subcoeruleus complex (glutamate), and ventral periaqueductal gray (dopamine) (see Fig. 19.2 ).
The hypothalamus is widely recognized to have primary regulation over the sleep–wake cycle systems. Several areas in the hypothalamus, including orexin-containing cells in the lateral hypothalamus and histaminergic neurons in the tuberomammillary nucleus, have a major role in the induction and maintenance of the waking state. In contrast, outputs from the ventrolateral preoptic area using GABA and galanin, and cells in the median preoptic area, possessing melanin concentrating hormone and GABA, have inhibitory influences on these “wake regions.” Hence, the preoptic area of the hypothalamus appears to be a major sleep-promoting area with neurons in this region inhibiting neurons in the brainstem that are involved with arousal, that is, neurons in the pedunculopontine, lateral dorsal tegmental nuclei, locus coeruleus, and dorsal raphe.
Other regions playing a role in sleep induction include the basal forebrain, via its acetylcholine and adenosine secreting neurons, and melatonin released from the pineal gland. Regulation of sleep–wake cycles by the circadian system is related to, but separate from, the promotion of sleep. The suprachiasmatic nucleus (SCN), located in the anterior hypothalamus is the recipient of information on light via the retino-hypothalamic tract, is believed to be the major circadian pacemaker (oscillator) for motor activity. Other factors mediating the SCN include humoral factors, mTOR signaling, pathway mediators located in the subparaventricular zone of the hypothalamus, and “clock genes” such as the period gene rPer2.7. Body temperature regulation, controlled by the hypothalamus, can also influence sleep; increases in body temperature generally lead to postponement of sleep. It is also recognized that thalamo-cortical interactions are important in generating the sleep rhythms recorded on scalp electrodes.
Sleep-Related Movement Disorders
Myoclonic Disorders
Hypnic Jerks (aka, Sleep starts, Hypnagogic jerks)
The transition between periods of wakefulness and NREM sleep may feature sleep starts or hypnic jerks. These movements, often accompanied by an illusion of falling, a vivid dream, or some other sensation, are a sudden, abrupt myoclonic jerk of all or parts of the body. They occur in approximately 70% of people, are considered a physiological condition, however, on occasions may occur in clusters and cause insomnia (labeled “intensified hypnic jerks”). Excessive sleep starts in children have been reported in association with migraine as well as in neurologically impaired individuals. Lifestyle activities (caffeine, smoking), anxiety and hereditary factors may influence hypnic jerks. In patients with parkinsonism, hypnic jerks are a frequent, underestimated, sleep-related motor phenomenon causing sleep disruption and insomnia. Hypnic jerks are believed to represent a release phenomenon generated at the level of the brainstem or spinal cord secondary to a brief loss of suprasegmental descending inhibitory inputs. Electromyography shows brief (burst duration less than 250 ms) complexes that may be simultaneous or sequential. No treatment is necessary, and most cases are benign.
Benign Neonatal Sleep Myoclonus
In benign neonatal sleep myoclonus, movements may be focal or generalized, rhythmic or nonrhythmic, and typically occurs more in distal rather than proximal limbs. They appear during all stages of sleep, most commonly in NREM. Onset is usually in the first month of life and myoclonus persists for several months, but rarely into early childhood. Jerks may be triggered by noise and usually occur in brief clusters for several minutes before stopping spontaneously. The frequency of movement is about one per second with burst duration of 40–300 ms in clusters of four to five. Clusters typically do not arouse or wake the infant and cease with awakening. , Neurologic examination is normal, and there is no association with developmental delay or seizures. Benign neonatal myoclonus is not linked to KCNQ2 or KCNQ3 genetic mutations; genes associated with benign neonatal seizures. EEG and neuroimaging studies are normal, and there is no subsequent association with developmental delay or seizures. EEGs, however, may be deceptive, since myoclonus can evoke visually identifiable EEG potentials on vertex electrodes corresponding to somatosensory responses. Treatment, other than education, is not necessary and the use of anticonvulsants may exacerbate the myoclonus.
Propriospinal Myoclonus
Propriospinal myoclonus (PSM) is characterized by muscle jerks that usually start in the midthoracic region and spread up and down into the spinal cord, causing irregular jerky flexions, or extension of the trunk, neck, and hips. The disorder is uncommon, primarily occurs in adults, and has several phenotypes—one that worsens at sleep onset. , The disorder can be symptomatic, but up to 80% appear idiopathic or functional (psychogenic). Movements can cause difficulty with sleep induction but are abolished by light sleep. The mechanism appears to involve excitatory impulses that travel through relatively slowly conducting intersegmental propriospinal pathways. PSM at sleep-onset should be distinguished from intensified hypnic jerks (longer, slower velocity, more patterned, usually start in the midthoracic segment) and periodic limb movements (involve primarily the distal limbs, have a periodic or pseudo-periodic pattern, and lack a propriospinal pattern). Diagnostically a polysomnogram with multichannel surface EMG recordings is required for diagnosis. A spinal MRI is also recommended, even in the presence of a normal examination and electrophysiological studies. Functional PSM has been identified by the disappearance of movements in sleep and the presence of a Bereitschaftspotential preceding the jerk. Clonazepam has been beneficial in case series, and several anticonvulsants have been tried in single cases.
Excessive Fragmentary Myoclonus
Fragmentary myoclonus (FM) consists of brief, sudden, usually minor (may not even be visible), asymmetric, arrhythmic focal jerks/twitches of muscles or muscle fibers in the face and limbs, during sleep. These movements are detectable during either, or both, NREM and REM sleep by surface EMG, are found in 100% of healthy subjects. In contrast, the prevalence of abnormal amounts of FM, labeled as excessive FM (EFM), occurs in about 10% of healthy individuals. EFM is also associated with a variety of sleep (sleep apnea, hypoventilation syndromes, periodic limb movements disorder, narcolepsy, insomnia) and neurodegenerative disorders (Niemann–Pick disease type C, mitochondrial encephalopathy, spinocerebellar ataxia type 3, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis). The precise etiology and site of origin for FM is unknown with possibilities including the spinal cord, peripheral nerves, and supraspinal structures. It has been recommended that an EMG/NCV be obtained in patients with EFM to investigate the presence of peripheral nerve pathology. Since EFM typically represents an incidental finding, no treatment is recommended.
Sleep-Related Facio-Mandibular Myoclonus
Sleep-related facio-mandibular myoclonus (SRFMM) is an uncommon disorder that is often misdiagnosed as sleep bruxism or epilepsy. It consists of isolated or short runs of shock-like jaw movements predominantly in stages 1 and 2 NREM sleep. The disorder primarily occurs in adults, is more prevalent in males, and most are initially misdiagnosed. A mother and son with tongue biting and bleeding during sleep attributed to SRFMM has been reported. The pathophysiology of this disorder is unknown but believed to be related to activation of trigeminal and hypoglossal nerves. The simultaneous acquisition of a video EEG and surface EMG has been beneficial in clarifying this diagnosis. Most patients improved with clonazepam but not with other antiepileptics.
Neck Myoclonus/Head Jerks
The presence of neck myoclonus during REM sleep can be associated with other REM sleep disorders such as REM behavioral disorder (typically involves the limbs, but occasionally the head). Periodic neck myoclonus, however, has also been reported in a small number of individuals during NREM sleep. Suggestions that periodic neck movements may be linked to periodic limb movements of sleep (PLMS) require further investigation. Treatment is generally not required.
Dyssomnia-Associated Disorders
Dyssomnias are disorders characterized by excessive daytime sleepiness (EDS) or complaints of difficulty initiating or maintaining sleep. Three movement disorders in this category include: (1) cataplexsy (discussed under narcolepsy); (2) restless legs syndrome (RLS); and (3) periodic limb movements of sleep (PLMS). Since cataplexy is typically integrated within narcolepsy (type 1), the various components of this disorder are reviewed.
Narcolepsy
Narcolepsy is characterized by its core components of hypersomnia (EDS), sleep hallucinations, sleep paralysis, and disturbed sleep. Its diagnosis in children is often delayed, since hypersomnia is often less pronounced or presents as irritability or hyperactivity. Narcolepsy is formally divided into two distinct disorders: Type 1, narcolepsy with cataplexy (aka, narcolepsy/hypocretin deficiency disorder) and Type 2, narcolepsy without cataplexy. Narcolepsy is quite rare, with a prevalence of 20–50 per 100,000 persons. About 34% of narcoleptic subjects have onset of symptoms before the age of 15 years and about 16% before age 10 years.
In children, narcolepsy is commonly a primary disorder, although symptomatic cases have been reported in association with Niemann–Pick disease type C, Norrie's disease, Prader–Willi syndrome, tumors, trauma, and brainstem lesions. Children with narcolepsy also have difficulties with concentration, attention, educational difficulties, conduct, and emotional problems.
Clinical Features
- (i)
Excessive daytime sleepiness : EDS , usually the main and most disabling symptom, is required for the diagnosis of narcolepsy. It consists of a continuous, irresistible sleepiness that fluctuates and often includes involuntary naps or “sleep attacks” while driving, walking, talking, and eating. Sleep attacks and episodes of decreased vigilance may be mistaken for syncope or seizures.
- (ii)
Cataplexy : The term cataplexy is derived from the Greek “kata” (down) and “plak” (strike) It indicates brief intrusions of voluntary muscle paralysis that are typically associated with REM sleep. In children, cataplexy is present in 15%–80% of cases with narcolepsy and may be the first symptom in 3%–9%. , Episodes are typically provoked by sudden emotional stimuli (laughter, pleasant surprise) and less commonly by negative emotions (anger, fear, embarrassment), all in the presence of a normal state of consciousness. In children, typical triggers may be absent and cataplectic attacks may occur spontaneously. Movements often involve antigravity muscles and occur in various forms, including face drooping, eyelid closure, sagging jaw, atonia of facial movements, simple buckling of the knees, weakness in the arms, or collapsing to the floor. In children, atonia of the facial muscles (mouth opening with tongue protrusion, and stuttering speech), knees, and head, are the most compromised body regions. The presence of positive motor phenomena (facial muscle twitches, grimacing, head nodding, prolonged tongue protrusion, neck extensions) in some cases has led to concerns regarding diagnoses of epilepsy or another movement disorder. Events can occur daily with durations lasting seconds to a minute. The cataplectic muscle weakness is associated with muscle hypotonia, absence of muscle stretch reflexes, and preservation of consciousness. Rarely, cataplexy has been the initial symptom in narcolepsy type 1, occurring in the absence of excessive sleepiness. Cataplexy has also been reported in Niemann-Pick type C, Coffin-Lowry syndrome, and Norrie disease. A functional magnetic resonance imaging (fMRI) study in children with cataplexy showed increased signal in the amygdala, nucleus accumbens, and ventromedial prefrontal cortex. Pathophysiologically, although cataplexy is linked to reduced orexin signaling, the specific mechanism remains undetermined. Therapeutically, sodium oxybate is a first-line treatment for cataplexy with low dose clomipramine and venlafaxine having been shown to be beneficial.
- (iii)
Sleep hallucinations , or dream-like experiences, may occur while the individual is falling asleep (hypnagogic hallucinations) or while awakening (hypnopompic hallucinations). Hallucinations can be simple or complex and tend to be visual, but can include auditory, olfactory, gustatory, or somatosensory sensations. They are reported in 15%–66% of patients with narcolepsy.
- (iv)
Sleep paralysis is the inability to move during REM sleep, sleep onset (hypnagogic sleep paralysis), or awakening (hypnopompic sleep paralysis). Muscle atonia and paralysis last for less than 10 min. Sleep paralysis is reported by 17%–80% of narcoleptic patients, but it also occurs in normal individuals.
- (v)
Sleep disturbances: Other motor sleep disturbances (RLS, periodic limb movements), sleep disordered breathing, nightmares, and vivid dreams with bizarre content are also common in patients with narcolepsy.
Diagnosis
Diagnosing narcolepsy in children may be challenging and confounded by test limitations. The diagnosis is based on the presence of the previously described clinical features and several laboratory tests. In the sleep laboratory, testing should include an overnight polysomnogram followed by a multiple sleep latency test (MSLT). Narcolepsy in the former is defined by a short sleep latency, that is, REM sleep occurring within 15 min of sleep onset. The MSLT, which requires adequate sleep prior to the study, measures sleep-onset time and presence of REM sleep on five 20-min nap opportunities spaced 2 h apart. In this test, a mean sleep latency of 8 min or less and at least two naps containing REM periods is required for narcolepsy confirmation. Other diagnostic approaches include the presence of the HLA markers DQB1∗06:02 found in over 90% of cases, and the specific and sensitive measure of a low level of cerebrospinal fluid (CSF) hypocretin-1 (orexin) (e.g., less than 100 pg/mL). ,
Pathophysiology
The etiology of narcolepsy is unclear. An autoimmune-induced loss of hypocretin (orexin)-producing neurons is believed to be the primary cause of narcolepsy type 1. , , Hypocretins are excitatory neuropeptides synthesized in a few thousand cell bodies within the dorsolateral region of the hypothalamus. These neurons project widely in the central nervous system (CNS), including to regions involved in the sleep and wake system such as the limbic system, intrahypothalamic nuclei, periventricular areas, and monoaminergic cell groups (locus ceruleus, raphe nuclei, ventral tegmental area, substantia nigra, and tuberomammillary nuclei). The precise role of hypocretin in the regulation of normal sleep continues to be defined. In studies of patients with narcolepsy-cataplexy, reduced levels of CSF hypocretin-1, less than 110 pg/mL, have been diagnostic. , , Cataplexy, which is accompanied by reduced EMG tone and areflexia, is proposed to be the result of disinhibition of a ponto-medullary-spinal pathway. Supporting evidence for the autoimmune-induced etiology includes the presence of cytotoxic CD8+ T cells specific for hypocretin neurons in CSF and serum of some patients, HLA-DQB1∗06:02 positivity in patients with classic cataplexy, and the association of narcolepsy with both the influenza A (H1N1) virus and a monovalent adjuvanted vaccine for the H1N1 virus.
Treatment
The treatment of narcolepsy includes education, good sleep habits, daytime naps, counseling, and pharmacotherapy. The child should observe regular sleep onset and morning arising times, avoid alcohol, and exercise regularly. Although not FDA approved, modafinil, armodafinil, and stimulant medications (methylphenidate, amphetamines) are effective for EDS. Frequent or severe cataplexy is treated with tricyclic antidepressants (imipramine, clomipramine) or serotonin-specific reuptake inhibitors (fluoxetine, paroxetine), venlafaxine, or sodium oxybate. , Sodium oxybate, FDA approved for patients 7 years and older, is a formulation of gamma hydroxybutyrate shown to be highly effective in reducing cataplexy and at higher doses to reduce daytime sleepiness. , Mechanistically, it activates GABA-B receptors and is believed to induce slow-wave sleep and REM sleep, reducing sleep fragmentation. Results of studies with immunotherapy are variable and trials with pitolisant, an inverse agonist of the histamine H3 receptor, are underway in children.
Restless Legs Syndrome
RLS, also known as Willis–Ekbom disease (WED) is a neurological, sensorimotor disorder that affects both adults and children. , , The disorder was first described by Thomas Willis in 1685 and formal criteria were established by Karl-Axel Ekbom in 1945. Criteria for this disorder have been recently revised and include a fifth essential criterion, the addition of specifiers to delineate clinical significance of a classification as either chronic-persistent or intermittent, and a merging of pediatric with adult criteria. , RLS is now characterized by the following:
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