Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of sleep and neuromuscular and spinal cord disorders, Duchenne muscular dystrophy, glycogenosis type II, myotonic dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, polyneuropathies, neuromuscular junction disorders, and familial dysautonomia. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Patients with neuromuscular disorders or high spinal cord disease are at risk of development of serious sleep breathing disorders. In particular, patients with weakness or paresis of the diaphragm have the highest risk of respiratory compromise during REM sleep, a stage in which the only functional respiratory muscle is the diaphragm. Fortunately, most patients will respond favorably to application of positive airway pressure, but the diagnosis of respiratory compromise during sleep needs to be ascertained. Noninvasive ventilation has improved the quality of life and increased survival in many forms of neuromuscular disorders. Patients with symptomatic neuromuscular disorders or high spinal cord disease should be considered candidates for evaluation with polysomnography.
• Patients who have neuromuscular disorders are at high risk for development of sleep-related respiratory disorders and respiratory failure.
• The single most important laboratory test in patients with hypersomnolence and nocturnal sleep disturbances is polysomnographic recording. Capnography monitoring should be used.
• Patients with chronic neuromuscular disease should be routinely assessed for sleep-disordered breathing and sleep complaints because these are treatable complications in an otherwise progressive disease process.
• Noninvasive ventilation use has been associated with improved quality of life and survival in patients with amyotrophic lateral sclerosis.
• Administration of up to 400 mg of modafinil daily to patients with myotonic dystrophy and hypersomnolence without sleep apnea disorder increases latencies in the Multiple Sleep Latency Test and improves Epworth Sleepiness Scale scores and sleepiness.
Clinicians and investigators began to be aware of sleep disorders and sleep-related respiratory compromise in patients with neuromuscular diseases after Sarnoff and colleagues directed attention to hypoventilation in poliomyelitis patients and after Benaim and Worster-Drought described alveolar hypoventilation in myotonic dystrophy (74; 08). Similarly, since the description of “Ondine's curse” in brainstem and high cervical cord lesions (77), the role of spinal cord dysfunction in the genesis of sleep disturbances secondary to respiratory dysrhythmias has become apparent. Since the advent of clinical polysomnography, sleep-disordered breathing has been quantified, and the beneficial effects of noninvasive positive breathing treatments have been observed in patients with neuromuscular and spinal cord disorders. Other sleep alterations, such as periodic limb movement disorders in patients with spinal cord disease, have also been uncovered with the widespread use of polysomnography. Culebras and colleagues reported abundant inclusion bodies within the cytoplasm of thalamic neurons in 6 patients with myotonic dystrophy, 4 of whom had mental defect (25). The authors hypothesized that cytoplasmic bodies represented a structural alteration of thalamic neurons likely related to progressive dementia, behavioral changes, slow dominant posterior EEG rhythms, and hypersomnia, thus suggesting a central form of hypersomnia.
Sleep-related abnormalities due to neuromuscular and chest wall disorders are now classified in the International Classification of Sleep Disorders under “Sleep-related hypoventilation/hypoxemia due to medical conditions” in the large category of Sleep Related Breathing Disorders (02).
Sleep disturbances in neuromuscular and spinal cord diseases are generally secondary to respiratory dysfunctions associated with these diseases. This section reviews the sleep disturbances found in myopathies (including polymyositis, polyneuropathies, and polyradiculoneuropathies) neuromuscular junction disorders, and those disorders found in spinal cord diseases (including poliomyelitis, amyotrophic lateral sclerosis, spinal cord tumors, spinal cord trauma, and spinal cord surgery).
General sleep complaints in patients with neuromuscular disorders. In neuromuscular disorders, sleep disturbances are secondary to involvement of the respiratory muscles, the phrenic and intercostal nerves, or the neuromuscular junctions of the respiratory and oropharyngeal muscles. The most common complaint is excessive daytime somnolence; this results from repeated arousals and sleep fragmentation caused by sleep-disordered breathing, hypoventilation, and nocturnal hypoxemia. In addition to the sleep-related respiratory compromise, some patients may complain of insomnia, particularly those with painful polyneuropathies, muscle pain, muscle cramps, immobility due to muscle weakness, and neck pain or "central" pain due to spinal cord diseases.
The complaints in patients with hypersomnia generally include excessive daytime sleepiness, falling asleep under inappropriate circumstances, excessive daytime fatigue, absence of relief from symptoms following additional sleep at night, morning headaches, lack of concentration, listlessness, and impaired motor skills and cognition. Patients with obstructive sleep apnea (OSA) may also complain of excessive snoring, cessation of breathing at night, and gasping for breath on awakening. Patients with neuromuscular diseases often complain of breathlessness, particularly in the supine position.
Patients complaining of sleeplessness may have insufficient sleep, difficulty initiating sleep, repeated awakenings (including early morning awakenings), excessive daytime fatigue, tiredness or sleepiness, irritability, anxiety, lack of concentration, or depression related to sleep deprivation.
Specific neuromuscular disorders. Primary muscle disorders or myopathies manifest a symmetric predominantly proximal limb muscle weakness and wasting without sensory impairment or fasciculations; the disorders may result from a primary defect in the muscle membrane or in the contractile elements. Respiratory disturbances are generally noted in the advanced stage of the illness, but sometimes respiratory failure appears early in the disease.
Duchenne muscular dystrophy. Sleep complaints and sleep-related respiratory dysfunctions are common in Duchenne muscular dystrophy, limb-girdle muscular dystrophies, and myopathies associated with acid maltase deficiency; they may also occur in other congenital or acquired myopathies, mitochondrial encephalomyopathy, and polymyositis. Obstructive sleep apnea has been reported in a 75-year-old woman with daytime somnolence and snoring who was diagnosed with adult-onset oculopharyngeal muscular dystrophy after presenting with ptosis and dysphagia (27). The authors recommended a polysomnographic evaluation searching for sleep-disordered breathing in patients with oculopharyngeal muscular dystrophy. Daytime predictor of sleep-disordered breathing in children and adolescents with neuromuscular disorders is an inspiratory vital capacity of less than 60% (54). Sleep-disordered breathing with nocturnal hypercapnic hypoventilation is predicted by an inspiratory vital capacity of less than 40% and PaCO2 of greater than 40 mm Hg (54).
In a retrospective review (84) of 34 patients with Duchenne muscular dystrophy attending a tertiary pediatric sleep disorder clinic over a five-year period, 22 (64%) reported sleep-related symptomatology. Thirty-two progressed to have polysomnography of which 10 (31%) were diagnostic of obstructive sleep apnea (median age: 8 years). A total of 11 patients (32%) showed hypoventilation (median age: 13 years) during the five-year period. There was a significant improvement in the apnea/hypopnea index (mean difference = 11.31, 95% CI = 5.91-16.70, P = 0.001) following the institution of noninvasive ventilation. The authors concluded that the prevalence of sleep related breathing disorders in Duchenne muscular dystrophy is common. There is a bimodal presentation with obstructive sleep apnea found in the first decade and hypoventilation more commonly seen at the beginning of the second decade. Polysomnography is recommended in children with symptoms of OSA, or at the stage of becoming wheelchair-bound. In patients with the early stages of respiratory failure, assessment with polysomnography identified sleep hypoventilation and assisted in initiating noninvasive ventilation. Lung function is useful to predict nocturnal hypercapnia in patients with Duchenne muscular dystrophy. Moreover, vital capacity under 680 mL is sensitive to predict daytime hypercapnia (87). In-center polysomnography with transcutaneous CO2 capnography is important in the clinical care of patients with Duchenne muscular dystrophy. The utility of portable home studies in Duchenne muscular dystrophy is unclear (38).
In a multicenter, cross-sectional study of 71 patients (all males; median age 12 years, age range 5 to 17 years), fatigue was assessed using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale by child self-report and parent proxy-report (31). The authors found that Duchenne muscular dystrophy across ages and disease stages experienced greater fatigue compared to typically developing controls from published data. Sleep disturbance symptoms and depressive symptoms were associated with greater fatigue by child self-report and parent proxy-report. Lower functional ability was associated with greater fatigue by parent proxy-report. Interestingly, physical activity level and musculoskeletal, respiratory, and cardiac function were not associated with fatigue. The authors conclude that fatigue is a major issue in pediatric Duchenne muscular dystrophy and that sleep disturbance symptoms and depressive symptoms are potentially modifiable factors associated with fatigue.
Glycogenosis type II. In glycogenosis type II or acid maltase deficiency, a deficiency of acid alphaglucosidase affects skeletal and cardiac muscles. The clinical spectrum ranges from very severe cases observed soon after birth to increasingly milder cases affecting infants, children, and adults (07). Children and adults exhibit a slowly progressing myopathy with decreased limb strength and respiratory impairment. Patients with glycogenosis type II may suffer sleep-disordered breathing and hypoventilation, particularly in REM sleep (53), as a result of diaphragmatic weakness. Obstructive sleep apnea secondary to oropharyngeal muscle weakness has also been reported in glycogenosis type II.
Inclusion body myositis (IBM). Polysomnography in 15 patients with IBM revealed sleep-disordered breathing (AHI 23.4±12.8 events/h) in all (Rodríguez et al 2014). There was no consistency between occurrence of sleep-disordered breathing and severity of peripheral muscle weakness. Asymptomatic impairment of respiratory function suggests that sleep studies should be performed routinely in IBM, irrespective of peripheral muscle function.
Myotonic dystrophy. Myotonic dystrophy is an autosomal dominant, polysystemic disorder affecting predominantly the musculoskeletal, endocrine, and central nervous systems. There are two major forms: dystrophia myotonica I (DM1), also known as Steinert disease, and dystrophia myotonica II (DM2), recognized in 1994 as a milder version of DM1. Since the early description of alveolar hypoventilation in myotonic dystrophy (08), many patients with myotonic dystrophy have been described with central, mixed, and upper airway obstructive sleep apneas, alveolar hypoventilation, daytime fatigue, and hypersomnolence (34). Nocturnal oxygen desaturation accompanies alveolar hypoventilation and apneas, becoming worse during REM sleep. Excessive daytime sleepiness and dysregulation of REM sleep occur frequently in patients with DM1 (97). In a study of 29 genetically proven DM2 patients, only 6.9% had excessive daytime sleepiness compared with 44.8% of DM1 patients and 6.2% of population controls using the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, and Checklist Individual Strength (86). The results were compared with 29 adult onset DM1 patients and 65 population controls, both matched for age and sex. Patients with DM1 do not have a consistent defect of hypocretin release, suggesting that the pathophysiologic basis is distinct from narcolepsy (23). A study specifically targeting DM2 patients revealed that RLS, excessive daytime sleepiness, and fatigue are frequent sleep disturbances, whereas obstructive sleep apnea and REM sleep behavior disorder are not (45). Excessive daytime sleepiness was independently associated with DM2 diagnosis, suggesting a primary CNS hypersomnia mechanism as noted by studies in DM1. Excessive daytime sleepiness is common in children and adolescents with DM1. It is associated with reduced quality of life and should be routinely assessed (37). In DM1, respiratory muscle weakness relates to clinical disease severity and involves inspiratory and probably expiratory muscle strength (36). Axonal phrenic nerve pathology may contribute to diaphragm dysfunction.
Amyotrophic lateral sclerosis. Patients with amyotrophic lateral sclerosis with minimal weakness and excessive daytime sleepiness may harbor severe sleep-disordered breathing with oxygen desaturation, and should be studied with overnight polysomnography (05). In a study of 59 patients with amyotrophic lateral sclerosis and 36 controls, the authors noted that patients with amyotrophic lateral sclerosis have a significant poor quality of sleep, and this correlated with the severity of amyotrophic lateral sclerosis and daytime somnolence (47). In one study comparing ALS patients with and without nocturnal hypoxia, those with nocturnal hypoxia (n = 10, 40%) had poor memory retention (p = 0.039) and retrieval efficiency (p = 0.045), suggesting that nocturnal hypoxia can be related to cognitive dysfunction in ALS (64). Many patients with ALS may be exposed to repeated episodes of deoxygenation-reoxygenation during sleep, possibly associated with the generation of reactive oxygen species. Effective intervention might modify manifestations of cognitive dysfunction, but further research is needed. Abnormal REM sleep atonia was observed in one study and correlated with the clinical severity of the disease. However, it was unclear whether patients were at risk for development of REM sleep behavior disorder or if the phenomenon represented a form of isolated rapid eye movement (REM) sleep without atonia (RWSA) in ALS. Patients with ALS frequently present abnormalities of sleep that include insomnia, fragmented sleep, increased PLMS, and abnormalities of REM sleep (48).
Spinal muscular atrophy. In children with spinal muscular atrophy, sleep-disordered breathing may cause relevant impairment of sleep and well-being. Both can be highly improved by nocturnal non-invasive ventilation (52). In a cross-sectional cohort study of 31 children (all males) with spinal muscular atrophy in Queensland, Australia, aged 0.25 to 18.8 years, all children had a full diagnostic polysomnography (20). Sleep disordered breathing was seen in each spinal muscular atrophy type and was more pronounced during REM sleep. No child exhibited obstructive sleep apnea alone. Starting noninvasive ventilation significantly reduced mean total polysomnography apnea-hypopnea index (AHI) scores from a mean of 15.4 events per hour (SD ± 14.6; 95% CI 6.1-24.7) to 4.0 events per hour (SD ± 4.2, 95% CI 1.2-6.5, p = 0.01). The authors concluded that sleep disordered breathing is common in children with spinal muscular atrophy and present in all types. Central sleep apnea was the most common disorder with mixed sleep apnea also present in spinal muscular atrophy types 1 and 2.
Polyneuropathies. Polyneuropathies are characterized by bilaterally symmetric distal sensorimotor manifestations that may result from a variety of heredofamilial and acquired lesions. Breathlessness on exertion and other respiratory dysrhythmias may occur or worsen during sleep as a result of involvement of the phrenic nerves innervating the diaphragm and of the nerves supplying intercostal and accessory muscles.
Neuromuscular junction disorders. Neuromuscular junction disorders (eg, myasthenia gravis, myasthenic syndrome, botulism, and tick paralysis) are characterized by easy fatigability of the muscles, including the bulbar and other respiratory muscles, as a result of failure of transmission of the nerve impulses at the neuromuscular junction. Respiratory failure in these conditions, particularly in myasthenia gravis, may be mild during wakefulness but may deteriorate during sleep. Patients with myasthenia gravis may have central, obstructive, mixed apneas, and hypopneas accompanied by oxygen desaturation (71). A sensation of breathlessness on awakening in the middle of the night and early morning hours may indicate respiratory dysfunction. Older myasthenic patients and those with increased body mass index, abnormal pulmonary function results, and abnormal daytime blood gas values are at particular risk for sleep-related respiratory dysrhythmias (71). Sleep-related hypoventilation and sleep apnea in neuromuscular junctional disorders may be severe enough to require assisted ventilation.
In a study of 75 patients with myasthenia gravis and 65 control patients, restless legs syndrome was present in 43.2% of the myasthenia gravis patients and in 20% of the controls (p = 0.0029) (79). The authors were unable to identify a relationship between the prevalence of restless legs syndrome and the duration and type of myasthenia gravis therapy, other comorbidities, age, or sex of the patients. Patients with myasthenia gravis more frequently reported daytime sleepiness. Almost 10% of the restless legs syndrome-positive myasthenia gravis patients reported that restless legs syndrome symptoms represented the most disturbing manifestation.
In a review of 17 observational, cross-sectional, or clinical studies assessing the quality of sleep and prevalence of sleep disorders in patients with myasthenia gravis, the authors concluded that there was variation of results and that further study of sleep disturbances in patients with myasthenia gravis is needed (Fernandes et al 2015). Only some studies showed that patients with myasthenia gravis have poor sleep quality, excessive daytime sleepiness, presence of restless sleep syndrome, and a higher incidence of sleep apnea.
Spinal cord diseases. Sleep disturbances related to respiratory dysfunction can occur in some patients with spinal cord diseases, particularly in those with upper cervical spinal cord lesions affecting the phrenic nerve nuclei. The incidence of sleep-disordered breathing is high in patients with tetraplegia, particularly if the patient is elderly, has a large neck circumference, has a long duration of the disease, and is on cardiac medications (83). Conditions damaging the phrenic and intercostal motor neurons in the spinal cord are poliomyelitis, amyotrophic lateral sclerosis, spinal cord tumors, spinal trauma, spinal surgery (eg, cervical cordotomy or anterior spinal surgery), and nonspecific or demyelinating myelitis. Patients with syringomyelia and syringobulbia with dysphonia and dysphagia are particularly prone to exhibit severe respiratory disturbances during sleep (59). The most common symptom is hypersomnia secondary to sleep-related respiratory arrhythmias. Occasionally, patients with spinal cord diseases complain of insomnia as a result of immobility, neck pain, and central pain syndrome.
Restless legs syndrome and periodic limb movements in sleep may develop in patients after acute transverse myelitis (17). Periodic limb movements in sleep have been reported in patients with syringomyelia (58). Restless legs syndrome has been reported in the post-polio syndrome, along with abnormal movements of sleep including random myoclonus, periodic limb movements in sleep, and ballistic movements of legs (18). Early formal sleep study in patients with acute complete tetraplegia is recommended. In patients with incomplete tetraplegia and with paraplegia, the incidence of sleep-disordered breathing is significantly higher than the general population, and formal studies would be reasonable (22).
Phrenic nerve damage may cause diaphragmatic paralysis. Unilateral paralysis is asymptomatic, but bilateral paralysis is invariably symptomatic and may be life threatening; paresis or weakness with partial diaphragmatic dysfunction may cause sleep-related ventilatory insufficiency. Bilateral paralysis underlies orthopnea with difficulty on inspiration out of proportion to the cardiopulmonary status. In the supine position, patients complain of profound difficulty with breathing that is the result of a reduction in lung volume and increased respiratory effort as the abdominal contents rise into the thorax. In severe or acute cases, patients present with nocturnal orthopnea, cyanosis, and fragmented sleep followed by morning headaches, vomiting, and daytime lethargy.
Inflammatory myopathies. In adult patients with inflammatory myopathies the frequency of obstructive sleep apnea is high (76). These alterations may play a role in persistent fatigue in these patients.
In patients with Duchenne muscular dystrophy, a vital capacity of less than one liter and REM sleep-related oxygen desaturation may be predictors of subsequent survival (66).
The mean survival in ALS patients with an Apnea-Hypopnea Index (AHI) greater than or equal to 5 was significantly shorter than in ALS without obstructive sleep apnea (OSA) (p = 0.0237) (69). Accurately titrated noninvasive ventilation in ALS patients can stabilize sleep quality and quality of life for at least one year, despite significant disease progression (89).
The prognosis of sleep disturbances in neuromuscular and spinal cord diseases is intimately related to the prognosis of the primary neurologic condition. Heredofamilial muscular dystrophies and polyneuropathies generally pursue a relentlessly progressive course. Sleep-related respiratory disturbances, hypoxemia, and hypercapnia may cause such serious complications as congestive cardiac failure, pulmonary hypertension, and cardiac arrhythmias. Sudden respiratory arrest at night due to dangerous nocturnal hypoventilation and hypoxemia is a dreaded complication in many patients with neuromuscular and high cervical spinal cord diseases.
A 50-year-old woman with a 7-year-old history of amyotrophic lateral sclerosis was evaluated for sleepiness and gurgling sounds while asleep. Her relatives described labored and irregular breathing while she was asleep, particularly if she was supine. The patient required frequent suction of pharyngeal secretions, and as a result, her sleep was fragmented. She slept propped up on pillows at a 45-degree angle. An examination showed wasting of limb, truncal musculature, and facial musculature. The patient’s tongue was atrophic. She had severe dysarthria and was unable to swallow. She was fed via a gastric tube. The patient lived at home and refused polysomnography in the hospital. A noninvasive positive-pressure apparatus was recommended with an estimated initial low positive pressure. After several pressure adjustments, the patient was able to sleep better and required less frequent suction at night. Sleepiness during daytime hours diminished, and the quality of her life, though precarious, was significantly improved.
Sleep-related respiratory dysfunction and ventilatory compromise are the etiologies of sleep disturbances in many neuromuscular and spinal cord diseases. Pain, muscle immobility, contractures, joint pain, muscle cramps, and anxiety may all contribute to sleep disruption. Central dysfunction with excessive daytime sleepiness and reduced chemoreceptor sensitivity may be observed in some congenital muscular disorders.
Powerful mechanisms control ventilation during sleep and ultimately awaken the person if a significant impediment occurs. The control of breathing is different in NREM and REM sleep. The major respiratory muscle groups are the diaphragm, intercostal muscles, and pharyngeal dilators; all receive appropriate signals from a medullary respiratory center. Hypoxia and hypercapnia stimulate arousals independently, but when combined, hypoxia increases the sensitivity to arousals caused by an increase in PaCO2. In NREM sleep, electromyographic activity increases in intercostal muscles as the ventilatory rate decreases, suggesting increased upper airway resistance. In REM sleep, the diaphragm is the only functional respiratory muscle. Upper airway resistance is also higher in REM sleep, contributing to decreased ventilatory efficiency. Patients with weak pharyngeal dilator muscles and a weak diaphragm as a result of a diffuse neuromuscular disorder exhibit the most serious compromise in REM sleep.
Risk factors for the development of sleep dysfunction in neuromuscular disorders and spinal cord diseases are dominated by sleep-related respiratory alterations. Hypoventilation in neuromuscular disease is attributed to both respiratory muscle weakness and reduced chemoreceptor sensitivity essential in ventilatory drive (91). In myopathies, multiple factors may play a role in sleep apnea and hypoventilation, causing nocturnal sleep disturbances and daytime hypersomnolence. These factors are listed below:
(1) Impairment of chest bellows caused by weakness of the chest wall and respiratory muscles.
(2) Increased work of breathing.
(3) Functional impairment of medullary respiratory neurons caused by hyporesponsive or unresponsive chemoreceptors secondary to muscle diseases.
(4) Excessive somnolence that is not corrected with ventilatory assistance, or is in excess, or occurs in the absence of a ventilatory impediment, suggests a central form of hypersomnia.
Myotonic dystrophy. In myotonic dystrophy, weakness and myotonia of the upper airway and other respiratory muscles, as well as an inherited membrane abnormality involving the respiratory and hypnogenic neurons in the brainstem, may be responsible for sleep and breathing disorders (34). Nocturnal polysomnography in 11 patients with myotonic dystrophy uncovered alveolar hypoventilation in all of the patients, along with mild sleep-disordered breathing of a central type in stage 1 and REM sleep (49). Patients with myotonic dystrophy may also have intrinsic hypersomnia related to degeneration of nerve cells in dorsomedial nuclei of the thalamus and perhaps hypothalamus manifested by cytoplasmic eosinophilic inclusion bodies (25). Laberge and colleagues found, in their series of patients with DM1, characteristics similar to those encountered in patients with idiopathic hypersomnia (44). Excessive daytime somnolence was present in 33.1% of patients with the intensity of somnolence correlating with the severity of muscular disease. Measurement of hypocretin levels in CSF in patients with myotonic dystrophy has shown a significant lower content (less than 200 pg/mL) in six patients with myotonic dystrophy, suggesting a dysfunction of the hypothalamic hypocretin system (51). In another study, the authors measured the CSF orexin levels in 17 DM1 patients with excessive daytime sleepiness and compared the results with those obtained in other forms of hypersomnia (61). The CSF orexin levels in DM1 patients were significantly lower than idiopathic hypersomnia patients and higher than narcolepsy type 1 patients (p < 0.001, p < 0.001, respectively). However, the authors pointed out that excessive daytime sleepiness of DM1 patients may not be explained by only orexin deficiency.
Compared to matched controls, patients with DM1 had increased EEG theta spectral power. Increased theta/beta and theta/alpha power spectral ratios in nocturnal polysomnography may reflect DM1 pathology in the CNS (21).
Spinal cord diseases. Sleep disturbances in spinal cord diseases may result from sleep-related respiratory alterations that cause sleep apnea-hypopnea or hypoventilation (73). The two respiratory controlling systems (the voluntary or behavioral system and the metabolic or automatic system) are integrated in the cervical spinal cord. The ventrolateral quadrant containing the automatic system and the dorsolateral quadrant containing the behavioral system control the final common respiratory motor neurons passing through the phrenic and intercostal nerves to the respiratory muscles. Direct dysfunction of these respiratory pathways in the spinal cord may result after cervical spinal surgery (42; 43) and spinal trauma (78), or it may be caused by poliomyelitis, amyotrophic lateral sclerosis, syringomyelia, cervical spinal cord tumor, or multiple sclerosis. Craniovertebral junction malformation or Chiari malformation in adults, with or without syringomyelia and basilar invagination, produce neuronal dysfunction of the brainstem, cerebellum, cranial nerves, and upper spinal cord. The incidence of sleep apnea/hypopnea syndrome is significantly higher in patients with craniovertebral junction malformation, especially if basilar invagination is present (15). Hypercapnia in subjects with complete cervical cord injuries can induce arousal from sleep (03).
To investigate periodic limb movements in patients with tetraplegia, 173 participants with acute (< 12 months) and 92 with chronic (> 12 months) tetraplegia underwent full overnight diagnostic sleep studies (65). Forty-one point six percent had a motor and sensory complete lesion. Both obstructive sleep apnea (87.8% with AHI ≥ 5/hr) and periodic limb movements (58.4% with PLMSI > 15/hr) were highly prevalent. Periodic limb movements were evident during REM and NREM sleep in all of the 153 patients with periodic limb movements of more than 15/hr. Obstructive sleep apnea had no influence on the severity of periodic limb movements. The authors conclude that periodic limb movements are very prevalent in tetraplegia even after controlling for obstructive sleep apnea. There was no association between periodic limb movements and patient characteristics or injury specific aspects.
Neuromuscular junction transmission disorders. Neuromuscular junction transmission disorders may give rise to respiratory failure as a result of easy fatigability of the muscles, including the bulbar and other respiratory muscles, due to failure of the nerve impulses at the neuromuscular junctions of these muscles. This respiratory failure becomes worse during sleep and causes central upper airway obstructive apneas, mixed apneas, and hypopneas accompanied by oxygen desaturation, disturbed nocturnal sleep, and a sense of breathlessness (71).
Polyneuropathies and polyradiculoneuropathies. In polyneuropathies and polyradiculoneuropathies, involvement of the phrenic, intercostal, and other nerves supplying the muscles of respiration may cause breathlessness, sleep apnea, hypoventilation, nocturnal oxygen desaturation, and hypercapnia, all of which result in sleep fragmentation and repeated awakenings at night. Patients with Charcot-Marie-Tooth disease have a high prevalence of sleep apnea disorder (14). A study showed that severity of neuropathy and sleep apnea disorder is highly correlated (28). The authors suggest that pharyngeal neuropathy causes sleep apnea syndrome in patients with Charcot-Marie-Tooth disease. Charcot-Marie Tooth disease encompasses several inherited peripheral motor-sensory neuropathies and is one of the most common inherited neuromuscular diseases. The condition can be associated with restrictive pulmonary impairment, sleep apnea, and vocal cord dysfunction. Restrictive pulmonary impairment has been described in association with phrenic nerve dysfunction, diaphragm dysfunction, or thoracic cage abnormalities. Vocal cord dysfunction, possibly due to laryngeal nerve involvement, is found in association with several CMT types and can often mimic asthma. Studies further suggest that laryngeal symptoms are the result of a slowly progressive neuropathy that appears to be nerve-length dependent (12). Bi-level positive airway pressure may be more appropriate than continuous positive airway pressure for the treatment of sleep apnea in the individual with concomitant restrictive pulmonary impairment. The risk of progression to bilateral vocal cord dysfunction in Charcot-Marie-Tooth disease and the risk of aspiration with laryngeal neuropathy may limit the therapeutic options available for vocal cord paralysis (01).
Amyotrophic lateral sclerosis. Measurement of hypocretin-1 levels in cerebrospinal fluid samples from 20 patients with amyotrophic lateral sclerosis showed results well within the normal range (greater than 200 pg/ml), and individual values showed no correlation with age, gender, and disease duration (90). The authors concluded that it is unlikely that the hypocretin system is involved in the degenerative process of amyotrophic lateral sclerosis.
Familial dysautonomia. Familial dysautonomia is an autosomal recessive disease featuring sensory and autonomic dysfunction. Sudden unexpected death during sleep is the most common cause of death in patients with familial dysautonomia. In one study the authors investigated whether sudden unexpected death during sleep in familial dysautonomia is linked to sleep-disordered breathing (63). They retrospectively identified patients with familial dysautonomia who had died suddenly during sleep and had undergone polysomnography within the 18-month period before death and compared the results to age-matched surviving subjects with familial dysautonomia who had also undergone polysomnography within the 18-month period before study. Participants with sudden unexpected death during sleep were more likely to be receiving treatment with fludrocortisone, have untreated obstructive sleep apnea, and have plasma potassium levels of less than 4 mEq/L, but were less likely to use noninvasive ventilation at night. The authors concluded that application of noninvasive ventilation when required and discontinuation of fludrocortisone treatment may reduce sudden unexpected death during sleep in patients with familial dysautonomia.
In another study, 85% of adults and 91% of pediatric patients with familial dysautonomia had some degree of sleep-disordered breathing. Obstructive sleep apneas were more severe in adults (8.5 events/h in adults vs. 3.5 events/h in children, p = 0.04), whereas central apneas were more severe (10.8 vs. 2.8 events/h, p = 0.04) and frequent (61.8% vs. 45%, p = 0.017) in children. The authors concluded that most patients with familial dysautonomia suffer sleep-disordered breathing. Hypoventilation and hypoxia may occur independently of apneas; therefore, the authors recommend including capnography monitoring during polysomnography in all patients with familial dysautonomia to detect sleep-disordered breathing (81).
The prevalence and incidence of the various neuromuscular and spinal cord diseases determine the prevalence and incidence of sleep disturbances and sleep-related respiratory arrhythmias. A systematic epidemiological study of sleep disturbances in these disorders has not been undertaken.
Slowness, fatigue, and learning difficulties are common in young patients with DM1. These features may indicate poor sleep quality. In a study by Quera-Salva and colleagues (70), 21 patients were evaluated. Mean age was 15.0+/-3.0. Age of onset of myotonic disorders was after birth and before 10 years old. Age of diagnosis was 12.0+/-2.9. Fatigue was reported by 76% of patients, whereas somnolence was present in 52%. Sleep was disturbed by numerous microarousals (mean 16.6+/-7.3/h of sleep) caused by abnormal respiratory events (6/21 patients) or periodic limb movements (8/21 patients). The authors concluded that in young patients with DM1, complaints of fatigue or somnolence should lead to polysomnography to investigate for sleep apnea syndrome and periodic limb movement disorder that were present in two thirds of their population.
The prevalence of sleep disorders was investigated (55) with a questionnaire in 883 uremic patients with end stage renal disease undergoing chronic maintenance dialysis therapy recruited from 20 different dialytic centers. Polyneuropathy was a significant risk factor for sleep disorders (P< 0.05). Results showed presence of insomnia in 69.1%, restless legs syndrome in 18.4%, sleep apnea in 23.6%, excessive daytime somnolence in 11.8%, possible narcolepsy in 1.4%, sleepwalking in 2.1%, nightmares in 13.3%, and possible REM sleep behavior disorder in 2.3%.
In a review of 903 children who underwent polysomnography at a children’s hospital, growing pains were recorded in 43 of 230 children, aged 3 to 16 years and free of neuromuscular or neurologic/developmental disorders, who were referred for polysomnography (95). In the group of children with growing pains, 25.6% had a periodic limb movements of sleep (PLMS) index of 5/h or greater, which was significantly higher than that in children without growing pains (10.2%) (odds ratio 3.04, P = 0.014). The authors concluded that children with growing pains were three times more likely to have a high PLMS index on polysomnography compared to children without growing pains, suggesting that growing pains might be associated with PLMS. These findings support the hypothesis that growing pains might be included in the spectrum of restless legs syndrome.
Sleep apnea or hypopnea and alveolar hypoventilation should be diagnosed early in neuromuscular and spinal cord diseases in order to prevent fatal or dangerous hypoventilation during sleep, respiratory infections, administration of drugs, or anesthetic agents. Sleep disturbances and sleep-disordered breathing should be considered in these patients if they complain of excessive daytime somnolence and breathlessness.
Hypersomnolence due to causes other than the various neuromuscular and spinal cord diseases should be considered in the differential diagnosis. Intrinsic sleep disorders, such as narcolepsy and idiopathic central nervous system hypersomnia, should be considered. Central causes of hypersomnolence may include lesions of the brainstem, diencephalon, and cerebral hemispheres.
In patients with neuromuscular and spinal cord diseases who complain of insomnia, insomnia related to medical or psychiatric disorders, restless legs syndrome, and idiopathic or psychophysiological insomnia should be considered.
A careful history is essential, including present and past sleep history as well as family, drug and alcohol, medical, and psychiatric histories.
The single most important laboratory test in patients with hypersomnia and nocturnal sleep disturbances is polysomnographic recording. Polysomnographic tests must be performed in all patients with excessive daytime somnolence, unless the patient is so severely impaired by the neurologic condition that the diagnosis and treatment of sleep problems will not alter the outcome. Overnight polysomnography is important in patients with sleep complaints secondary to neuromuscular and spinal cord diseases in order to prevent a fatal sleep-related respiratory arrest at night, and to treat dangerous nocturnal hypoventilation and hypoxemia.
Polysomnographic findings in myopathies, including Duchenne and other muscular dystrophies, as well as myotonic dystrophy, may include increased number of awakenings, sleep fragmentation, and sleep disorganization as well as reduced total sleep time. Other findings include central, mixed, and upper airway obstructive sleep apneas or hypopneas associated with oxygen desaturation and nonapneic oxygen desaturation that become worse during REM sleep. Polysomnography should be considered in Duchenne muscular dystrophy when the PaCO2 is greater than 45 mm Hg, particularly if the base excess is elevated (39).
Performance of an unsupervised home sleep apnea test combined with transcutaneous partial pressure of carbon dioxide/oxygen saturation by pulse oximetry monitoring was investigated in 81 patients older than 18 years of age with spinal cord injury (06). Obstructive sleep apnea was found in 81.3% of individuals, central sleep apnea was found in 23.8%, and nonspecific hypopnea events were present in 35%. Nocturnal hypercapnia was present in 28%, and oxygen desaturation was found in 18.3%. Awake transcutaneous partial pressure of carbon dioxide and central sleep apnea were only marginally associated with nocturnal hypercapnia. The authors concluded that unsupervised home sleep apnea testing with transcutaneous capnography effectively identifies sleep-disordered breathing and nocturnal hypercapnia in individuals with spinal cord injury. In painful polyneuropathies and in those neuromuscular conditions associated with muscle pain and muscle cramps, polysomnography may show sleep-onset insomnia and reduced sleep efficiency.
To document the presence and severity of daytime sleepiness and to diagnose associated narcolepsy, a multiple sleep latency test may be performed. A mean sleep-onset latency of less than five minutes is consistent with pathological sleepiness, and the presence of sleep-onset REM in at least two out of four or five nap recordings during multiple sleep latency tests suggests a diagnosis of associated narcolepsy.
Pulmonary function tests with assessment of lung volume, gas distribution and transfer, arterial blood gases, and chemical control of breathing are helpful to exclude intrinsic bronchopulmonary disease and to assess the respiratory control system. In one study of 232 patients (mean age 43.1 ± 15.4 years; 50.0% women; vital capacity 59.2% ± 24.2% of predicted), the authors found a hypoventilation prevalence of 10.3% to 61.2%, depending on the used definition (60). This discrepancy has practical consequences because indication for home mechanical ventilation relies on hypoventilation detection. The authors recommended that capno-oximetry be included in the diagnostic tools used to detect hypoventilation. This is a recommendation that is not captured by current guidelines but is repeatedly mentioned in texts because patients with neuromuscular disorders, particularly in the pediatric years, can develop nocturnal hypoventilation in the absence of clinical symptoms or significant nocturnal desaturation (88). Therefore, monitoring of nocturnal hypoventilation should be included among nocturnal respiratory assessments of these patients as an additional tool to determine when to commence noninvasive ventilation. Transcutaneous capnography is also strongly recommended for reliable detection of nocturnal ventilation in patients with amyotrophic lateral sclerosis (13; Spiesshofer et al 2019). This recommendation can be made extensive to patients with Becker muscular dystrophy (56)
EMG and nerve conduction studies may be necessary in patients with respiratory failure due to the diaphragm, intercostal, and other accessory muscles of respiration being affected. In selected patients, EMG of the diaphragm and intercostal muscles may be necessary. Phrenic and intercostal nerve conduction studies may help diagnose phrenic and intercostal neuropathy in some of these patients.
An intriguing, yet hopeful, finding has been the observation of normal proportion of REM sleep in a series of patients with bilateral diaphragmatic paralysis (09). This was attributed to inspiratory recruitment of extradiaphragmatic muscles in tonic and phasic REM sleep, suggesting brainstem reorganization of stimuli.
Patients who have neuromuscular disorders are at high risk for development of sleep-related respiratory disorders and respiratory failure (24).
Treatment should first be directed toward the underlying neuromuscular condition. In many patients, however, there is no specific treatment, and only symptomatic measures are available.
The goal of treatment in sleep disturbances related to sleep-disordered breathing is to improve quality of life and prevent life-threatening cardiac arrhythmias, pulmonary hypertension, and congestive cardiac failure. Weight reduction should be encouraged for obese patients. Alcohol, sedative drugs, and other medications that may contribute to sleep disturbance and cause depression of breathing during sleep should be reduced or eliminated.
Treatment of obstructive sleep apnea with continuous positive airway pressure improves sleep quality and daytime hypersomnolence due to reduction or elimination of sleep-related obstructive apneas, oxygen desaturations, and arousals. In patients with relentlessly progressive disease, however, such treatment has not been useful.
In patients with neuromuscular disorders, including those with poliomyelitis and postpolio syndrome, ventilatory support is often needed with either negative-pressure or positive-pressure ventilators. Intermittent positive-pressure ventilation can be administered through a nasal mask. The negative-pressure ventilation can be delivered either from a tank respirator or from a cuirass. With ventilatory support, patients with neuromuscular disorders often obtain relief of daytime hypersomnolence and show improvement of sleep architecture.
Noninvasive positive pressure ventilation improves symptoms and quality of life indicators for amyotrophic lateral sclerosis patients and should be offered to patients with symptoms of sleep-disordered breathing. It can also prolong tracheostomy-free survival (19). Bi-level positive airway pressure ventilators are usually better tolerated by patients with neuromuscular disorders. There is one case report showing that a combination of mandibular advancement device and noninvasive positive pressure ventilation improved ventilation and adherence to therapy (92). In a prospective observational study, 24 amyotrophic lateral sclerosis patients were admitted to the sleep laboratory during four nights for in-hospital noninvasive ventilation titration performing polysomnography and nocturnal capnography (93). The authors found that slow wave sleep and REM sleep increased and the arousal-awakening index improved, together with an increase in sleep efficiency. Nocturnal oxygen and carbon dioxide levels also improved. No improvement in respiratory function or sleep structure was found in bulbar patients other than increase in oxygen saturation during REM sleep. Patient-reported outcomes showed improvement in sleep quality and quality of life, whereas bulbar patients reported improvement in very few subscores. The authors concluded that their study showed an improvement of sleep architecture, carbon dioxide, and nocturnal oxygen saturation at the end of noninvasive ventilation titration and after one month of noninvasive ventilation in amyotrophic lateral sclerosis patients. Noninvasive ventilation improves hypercapnia-associated symptoms within the first three months after initiation in spinal as well as bulbar amyotrophic lateral sclerosis patients, and beneficial effects are long-lasting (30).
Tracheostomy is the only effective emergency measure for those patients with marked respiratory failure with severe hypoxemia and for those with sudden respiratory arrest after resuscitation by intubation. Such patients may later be weaned from tracheostomy but may require continuous positive air pressure treatment for obstructive or mixed sleep apneas. Tracheostomy does not guarantee that mechanical ventilation is effective during sleep in patients with Duchenne muscular dystrophy, as inspiratory unintentional leaks may occur, but ensures better nocturnal gas exchanges than noninvasive ventilation (57). A decision about tracheostomy should be carefully weighed in neuromuscular disorders with relentless progression and an overall unfavorable prognosis.
Treatment of sleep-related respiratory disturbances in spinal cord diseases should follow the same general principles as those suggested for neuromuscular disorders. A word of caution comes from a study (04) showing that patients with spinal cord injury on antispasticity medications who are obese may have a higher risk of developing snoring and obstructive sleep apnea. The greatest risk appeared in patients taking diazepam or diazepam and baclofen in combination.
Restless legs syndrome and periodic limb movements in sleep in acute transverse myelitis responded to the administration of pergolide but not to infusion of intrathecal baclofen (17).
Patients complaining of sleeplessness should follow general sleep hygiene measures, such as regular sleep schedule and avoidance of alcohol and caffeine in the evening. Analgesics may be prescribed for pain and patients occasionally may need hypnotics, but these should be used judiciously with low doses not more than two nights to three nights per week.
There is suggestive evidence that administration of up to 400 mg of modafinil daily to patients with myotonic dystrophy and hypersomnolence without sleep apnea disorder, increases latencies in the Multiple Sleep Latency Test and improves Epworth Sleepiness Scale scores (26) and sleepiness (50; 85). This favorable effect has been disputed by another small study using modafinil 300 mg/day conducted in an adult population with DM1 (n=28) and a high prevalence of hypersomnia (62). In this study, modafinil had no significant effect on daytime somnolence as measured with objective maintenance of wakefulness tests. In a placebo-controlled trial with a single dose of 20 mg methylphenidate of 24 patients with myotonic dystrophy type 1 (12 men, 12 women), treatment with methylphenidate showed a favorable effect (68). There was significant change in median scores on the Daytime Sleepiness Scale (-3.0 vs. -0.5; P = 0.003) and the Epworth Sleepiness Scale (-3.0 vs. -1.5; P = 0.039). There was no significant change in mean sleep latency test results. Three patients discontinued methylphenidate due to adverse events including diarrhea, nervousness, and irritability. Loss of appetite, nausea, and palpitations were the most common adverse events reported by patients treated with methylphenidate. The authors concluded that a single 20-mg dose of methylphenidate significantly reduced daytime sleepiness in this small selected population of patients with myotonic dystrophy type 1. In a prospective study of 120 patients with DM1, only 29% of the studied cohort benefited from targeted sleep therapies that included noninvasive ventilation and modafinil (94).
Patients with chronic neuromuscular disease should be routinely assessed for sleep-disordered breathing and sleep complaints because these are treatable complications in an otherwise progressive disease process. Further research is needed to establish the indications for polysomnography and to determine the optimal timing for initiating noninvasive ventilation to treat sleep-disordered breathing in patients with neuromuscular diseases (29). Young and colleagues (96) studied the effect of noninvasive ventilation on clinical outcome and quality of life in children with severe neuromuscular disorders. The authors reviewed records and obtained clinical data from the year prior to commencing noninvasive ventilation and annually thereafter. Data obtained included diagnosis, patient symptoms, mortality, adverse effects, pulmonary function tests, polysomnographic data, length of hospitalizations, and health care costs. Patients and parents completed questionnaires assessing quality of life before and after institution of noninvasive ventilation. Fourteen of 17 (82%) suitable patients ranging from 6 to 84 months (median 30) were enrolled and followed. Symptoms of daytime sleepiness and headache improved after initiation of noninvasive ventilation. Sleep quality assessed by polysomnography also improved. Hospitalization rates (p = 0.002) and health care costs (p = 0.003) decreased significantly. Quality of life remained stable after noninvasive ventilation despite disease progression. The authors concluded that treatment of respiratory failure, in children with neuromuscular disease, with noninvasive ventilation results in a reduction in symptoms, hospitalizations, and health care costs without adverse effects on quality of life.
In general, the impact of ventilatory support on the natural history of neuromuscular disease has been positive (32). Noninvasive ventilation allows some patients with nonprogressive pathology to live to nearly normal life expectancy, extends survival by many years in patients with conditions such as Duchenne muscular dystrophy, and increases survival in those patients with rapidly deteriorating disease like amyotrophic lateral sclerosis. A growing number of children with neuromuscular disorders are surviving to adulthood with the aid of ventilatory support. The combination of noninvasive ventilation with cough-assist techniques decreases pulmonary morbidity and hospital admissions. In most patients with neuromuscular conditions the most effective time to introduce noninvasive ventilation is when symptomatic sleep-disordered breathing develops (80).
In one study, most patients with isolated diaphragmatic dysfunction failed continuous positive airway pressure and required bilevel positive airway pressure (BiPAP) (41). Furthermore, patients with bilateral diaphragmatic dysfunction were more likely to require BiPAP than those with unilateral dysfunction. The study suggests that all patients with diaphragmatic dysfunction should be considered for in-lab sleep studies to determine adequacy of titration and therapy. Initiation of PAP therapy using bilevel modality may prevent the need for device switching as the disease progresses (38). In another study of 32 patients with myotonic dystrophy, noninvasive ventilation significantly improved ventilation and oxygenation in the first night of treatment. Follow-up revealed stable normoxemia and normocapnia without deterioration of sleep outcomes for up to 52 months. However, adherence to treatment was low to moderate, with substantial inter-individual variability. Adherence to noninvasive ventilation remains a major issue in myotonic dystrophy type I (82).
In patients with Duchenne muscular dystrophy serial polysomnographic assessments are recommended as the patients' clinical status evolves with disease progression and the emergence of additional comorbidities such as cardiomyopathies, dysphagia, and chronic aspiration (75).
There is a case report of a 53-year-old woman with Charcot-Marie-Tooth disease, obstructive sleep apnea, and a six-year history of numbness in both upper extremities, feet, and in the trunk whose symptoms resolved with CPAP therapy (67).
In a study of 20 patients with severe spasticity (11), the authors prospectively evaluated the effect of pump-infused intrathecal baclofen infusion in therapeutic doses on sleep quality and on daytime and nighttime respiratory function. Polysomnography and respiratory studies were obtained one week before and at least eight days after pump implantation. Most patients had multiple sclerosis (n = 9) or spinal cord injury (n = 8). Intrathecal baclofen improved total sleep time, and sleep efficiency, and reduced periodic leg movements. It did not modify sleep-related respiratory events, lung function tests, CO2 rebreathing response, or resting energy expenditure. The authors concluded that compared with oral baclofen, intrathecal baclofen infusion did not affect respiratory function and improved sleep continuity. Intrathecal baclofen infusion in therapeutic doses may act at the spinal level rather than at the supraspinal level. In a subsequent pilot study by the same authors, of 11 patients with spinal cord disease and severe spasticity, intrathecal baclofen reduced periodic limb movements but increased the respiratory disturbance index and central apneas (10). The authors observed a significant increase of respiratory events with bolus administration of baclofen. Continuous infusion did not induce a significant modification of sleep-disordered breathing. Preexisting sleep apnea syndromes were generally severely worsened by the bolus mode of administration.
Noninvasive ventilation use has been associated with improved quality of life and survival in patients with amyotrophic lateral sclerosis (16); subjects with orthopnea and preserved bulbar function showed the largest benefit.
The use of a continuous positive airway pressure device is often needed in patients with neuromuscular disorders to maintain free breathing sometimes even during the day. There is one case report of a 29-year-old patient with myasthenia gravis who used continuous positive airway pressure continuously since the age of 12 years (35). Tight fitting of a nasal mask applied enough force to cause severe maxillary deformity. The authors recommend the use of masks with additional forehead and chin support or a regular full face mask in order to spread forces more evenly.
No information available on the effects of pregnancy in sleep disorders associated with neuromuscular and spinal cord disease.
There is a danger of administering anesthetic agents to patients with myotonic dystrophy (40). In Kaufman's series, five patients of 25 myotonic patients had marked respiratory depression during operations, and four other patients died in the postoperative period. It is important to diagnose alveolar hypoventilation in these and other patients with neuromuscular and spinal cord diseases.
Special precautions are warranted in patients with post-polio syndrome presenting for surgery because these patients may have respiratory impairment, sleep apnea, and swallowing difficulties (46).
Antonio Culebras MD FAAN FAHA FAASM
Dr. Culebras of SUNY Upstate Medical University at Syracuse received an honorarium from Jazz Pharmaceuticals for a speaking engagement.See Profile
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