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Sleep Disorders

Symptoms, Causes and Treatment

Aarti Desai, Research Fellow of Advanced Heart Failure and Transplant, Mayo Clinic

Rohan Goswami, MD, Director of Heart Transplant Innovation and Research, Mayo Clinic

Shriya Sharma, MBBS, Division of Advanced Heart Failure and Transplant, Mayo Clinic

Sleep disorders, including Insomnia, Narcolepsy, Sleep apnea, Restless legs syndrome, and Parasomnias affect up to a third of the global population. These disorders disrupt sleep quality and structure, leading to cognitive issues and cardiovascular health risks. Early recognition and management are essential for preventing long-term complications and enhancing well-being.

Sleep disorders encompass a spectrum of conditions disrupting typical sleep patterns, the consequences of which extend to one's overall health, safety, productivity and the quality of life in general. Unprecedented rise in the cases of sleep disorders over the last two decades presents a significant challenge to the clinical healthcare domain. In the 2023 revision of International Classification of Sleep Disorders, ISCD-3, sleep disorders are classified into 6 different categories with numerous subtypes but the most prevalent are insomnia, narcolepsy, sleep apneas, restless legs syndrome, and parasomnias such as nightmares, night terrors and sleepwalking. There are two distinct stages of sleep that are identified by typical changes in EEG and eye movements: Non-Rapid Eye Movement (NREM) and Rapid Eye Movement (REM) stage. Each cycle lasts 90-120 minutes and 4-8 cycles are required to ensure adequate rest.

Insomnia

Insomnia, the most common sleep disorder experienced either in short-term episodes or as a chronic condition, is marked by challenges in both initiating and maintaining sleep. Patients suffer a much lower quality of life due to daytime sleepiness, fatigue, and lack of concentration at work resulting in reduced productivity, increased frequency of errors and accidents in day-to-day activities such as driving. The estimated prevalence of insomnia is around 10%. Furthermore, insomnia is identified as a persistent condition, lasting for more than five years, and impacts more than 40% of individuals who initially experience severe symptoms of insomnia.

It is most commonly precipitated by psychosocial factors such as work-related stress, major life changes (menopause, relocation, medical conditions), relationship difficulties, domestic abuse, and can be caused by substance abuse (alcohol, caffeine). The risk increases with age, female sex (17.6% in females versus 10.1% in men) and psychiatric conditions such as depression, mania, anxiety, and PTSD. COVID-19, its comorbidities and long-term implications have also resulted in an increased incidence of Insomnia worldwide. Clinicians use various scales and questionnaires to assess and diagnose insomnia along with an assessment of medical conditions, psychiatric history and substance use.

The treatment of Insomnia is a huge burden for the healthcare system as it accounts for the loss of more quality-adjusted life-years than any other psychiatric condition or chronic medical condition like hypertension and the direct and indirect costs are in the billions. The most commonly used prescription medications are benzodiazepines such as alprazolam (Xanax), diazepam (Valium), Non-benzodiazepines such as zolpidem (Ambien), eszopiclone (Lunesta). Ramelteon, suvorexant, and doxepin are also used. In addition to medications or as monotherapy, Cognitive Behavioural Therapy for Insomnia (CBTI) remains the first line of treatment and the most comprehensive and here lies the burden.

With increasing prevalence of insomnia, cost of mental health services and continuing lack of trained health care personnel, in-person CBT needed to evolve to be more scalable and sustainable. The rise of cell phone apps that offer mindfulness exercises and customer sleep technology such as fitness trackers made this possible and now we have digital CBT for Insomnia (dCBTI) which is fully automated and has the potential to address these issues. dCBTI reduces the frequency of clinic visits and has the potential to reach vulnerable patient groups that may not be able to afford or have access to physicians and psychologists. While in-person CBT outperforms dCBTI, clinical trials have shown significant improvements in sleep, daytime functioning and overall psychological health. While numerous forms are available, Somryst is the only FDA approved prescription dCBTI available for the treatment of chronic insomnia which is a 9-week program administered via a cell phone application.

Narcolepsy

Narcolepsy, a REM-sleep disorder, is a result of the body’s inability to regulate sleep-wake cycles resulting in excessive daytime sleepiness and may be accompanied by cataplexy (sudden muscle weakness), hallucinations, and sleep paralysis (being awake but unable to move). Normally in an awake state, a neurotransmitter called hypocretin leads to the release of wake-state inducing hormones. Hypocretin levels decrease during sleep leading to atonia. Patients with narcolepsy have reduced levels of hypocretin and it leads to irregular changes between sleep and wake states.

Narcolepsy is diagnosed with a detailed history in patients reporting uncontrollable lapses of daytime sleepiness more than 3 times per week for more than 3 months. Short REM latency and hypocretin deficiency are also seen. Children commonly notice poor school performance, falling asleep in class, irritable or antisocial behavior, while adults may experience job impairment, reduced productivity and lower quality of social interactions, which may lead to embarrassment and social isolation.

Close to 50% patients have symptoms in their teenage years but diagnosis is delayed 10-15 years in most cases. The stigma and lack of public awareness of this disorder results in delayed diagnosis and treatment, mainly due to misinterpretation of symptoms as laziness, carelessness or malingering and diagnosis is especially difficult in children and adolescents who may not recognize signs of cataplexy. Early diagnosis and treatment are essential due to an increased risk of aggressive behavior and emotional distress in younger patients, depression, diabetes, headaches, hypertension, obesity, and other sleep and medical disorders in patients with untreated narcolepsy.

Fortunately, patients respond well to medication and numerous other strategies are used to establish a healthy sleep routine including strategically scheduled naps, regular exercise and counseling for psychosocial support. To decrease daytime sleepiness Modafinil and Amphetamines are used. In addition to daytime sleepiness, Sodium Oxybate helps with cataplexy. For decades, these were the only medications available and were used in combination with other antidepressants and hypnosedatives. Recently, the FDA approved the use of Solriamfetol, a phenylalanine derivative, for excessive daytime sleepiness and Pitolisant, H3 receptor antagonist, for narcolepsy with or without cataplexy. Clinical trials have shown promise for a medication that directly modulates hypocretin receptors and Reboxetine, an SNRI for Narcolepsy in adults.

Sleep Apneas: Obstructive and Central

Obstructive sleep apnea (OSA), which is due to recurrent upper airway collapse during sleep and Central sleep apnea, resulting from impaired respiratory drive, both cause awakening in an attempt to restore breathing and lead to a significantly reduced quality of sleep and have a strong association with obesity and cardiac health.

OSA is far more common, affecting over 900 million adults between the ages of 30-69. It is recognized by loud snoring, choking or gasping at night, drooling, daytime fatigue and sleepiness and headaches. Patients with OSA are also more likely to be involved in driving accidents. Polysomnography remains gold standard and is used to measure Apnea-Hypopnea Index (AHI), or apneic episodes per hour, that guides the diagnosis. The risk is significantly greater in men, obese individuals, those over the age of 50 and individuals with acromegaly. Numerous processes such as chronically elevated inflammatory markers, oxidative stress, endothelial dysfunction, atherosclerotic changes, and metabolic derangements have established a multifactorial link between OSA, obesity, diabetes, systemic and pulmonary hypertension, acute coronary events and arrhythmias.

Continuous Positive Airway pressure (CPAP) is the primary and most effective treatment for OSA. It prevents upper airway collapse and hence the number of apneic events thereby restoring sleep. Due to its association with obesity, weight loss, healthy diet, exercise and smoking cessation contribute significantly. Rarely surgery may be required and options include adenotonsillectomy, tongue surgery, uvula and palate surgery and other anatomical corrections. There is increased emphasis on the use of CPAP and non-pharmacological treatment but this often leads to decreased patient compliance mostly due to the discomfort experienced when using CPAP while sleeping. Obesity and therefore OSA continues to remain one of the most prevalent disorders globally and hence, new techniques using AI or machine learning will be required in the near future to reduce costs and burden on the healthcare system.

Restless legs syndrome

RLS is diagnosed when patients describe a creeping, somewhat stretching or itching sensation followed by an irresistible urge to move their legs. It can occur throughout the day but is reported to be worse at night resulting in jerking movements and therefore insomnia. These urges are worsened by rest and improved with exercise such as walking. While the exact mechanism is not known, it is associated with iron deficiency, renal disease, magnesium, vitamin D and folate deficiency, calcium imbalance and certain medications such as antidepressants, diphenhydramine, alcohol, caffeine, and lithium among others. It affects up to 15% of the population and up to a third of all pregnant patients. Though it resolves after delivery, there is a 4 fold risk of developing chronic RLS indicating an association with high estrogen levels. An electromyography or nerve conduction studies help rule out organic causes but history is usually sufficient to make a diagnosis.

Treatment with medications is unnecessary unless there is a significant reduction in the quality of life primarily due to sleep disturbances. Exercise, massage, vitamin supplements and eliminating stimulants such as caffeine and alcohol help alleviate symptoms in most cases. There are two devices currently approved by the FDA, the Restiffic foot wraps and the NTx100 Tonic Motor Activation (TOMAC) System, which stimulates the patient's legs with the help of vibrations has shown significant improvement in symptoms and quality of life.  For severe cases, dopamine agonists such as pramipexole and ropinirole, rotigotine, and cabergoline have reduced symptoms and improved sleep. Gabapentin and pregabalin can be used initially for patients with severe sleep disturbances, anxiety, and pain. It must be noted that all of these pharmacological options have adverse effects with long term use for RLS.

The data is limited but numerous medications have shown improvements in clinical trials including clonidine which causes a reduced adrenergic response, dipyridamole which affects adenosine levels, glutamate receptor modulation with perampanel, amantadine and ketamine, as well as other anticonvulsants, steroids, bupropion, and cannabis. The treatment aspect of RLS has been gaining momentum due to its decades-long duration of symptoms in severe cases even with treatment and a significantly reduced quality of life.

Parasomnias: Sleepwalking, Nightmares, and Night terrors

Sleepwalking, a form of somnambulism or undesirable movements during sleep, is a NREM sleep disorder which occurs in the first third of the night. There is a complete lack of awareness of the event as it occurs and inability to recall the event afterwards. Patients may run into furniture causing bruises, relocate items around the house, and fall off steps. Very rarely they may exhibit violent or sexually inappropriate behavior. The research into sleepwalking is in its early stages but, the current studies have shown multiple etiologies including a genetic component, excessive sleep deprivation, an association with medications such as Zolpidem, antipsychotics, anticonvulsants, and lithium among others, and hyperthyroidism. While a detailed history is sufficient for diagnosis in most cases, video polysomnography is used in complex and medicolegal cases. Current treatment options are limited and immediate focus is the safety of the patient while they sleepwalk. Locking interior and exterior doors and windows, removing sharp objects from sight help prevent injuries. Scheduling awakening before usual sleepwalking time helps in some cases, along with counseling. No medication has been approved but clonazepam or gabapentin may help if taken one hour before sleep. Research is underway to gain a deeper understanding of the pathophysiology of sleepwalking and the use of psychotherapy for treatment. Medications currently under research are clonazepam for adults and tryptophan for children.

Nightmares occur during REM sleep and are strongly associated with psychiatric disorders such as PTSD with a detailed recall of the actual dream. When associated with trauma and PTSD, the nightmare is related to the event causing PTSD which causes further stress and sleep resistance where patients fear going to sleep in attempts to avoid the experience. Once awake, patients become alert quickly. Reduced sleep quality and quantity lead to daytime fatigue, reduced attention and performance and psychosocial impairments. Stigmatized, undiagnosed, and untreated, nightmares can persist for decades. Prazocin shows significant improvement in nightmares associated with PTSD. Therapeutic approaches that aim to understand the nightmare and reform maladaptive beliefs, such as CBT, imagery rehearsal therapy (IRT), lucid dreaming, exposure therapy, and desensitization therapy have been very successful.

Night terrors occur most commonly in children below the age of 12 during NREM sleep and result in inconsolable screaming or crying with autonomic hyperactivity, feeling helplessness, intense fear, and variable recollection of the event. Most cases are benign fortunately and will outgrow these episodes by adolescence. No specific treatment is required other than reassurance and education. Counseling may help in some cases. Parents are educated to provide support, maintain sleep hygiene and prevent predisposing circumstances such as sleep deprivation and stress. There is also emphasis on avoiding any attempts at interrupting an episode which can result in extreme panic for the child. Benzodiazepines like Clonazepam are used on a short-term basis during periods of elevated terror frequency and intensity causing functional impairment.

Conclusion:

Addressing sleep disorders and promoting healthy sleep habits are essential for individual well-being. Educating patients about good sleep hygiene practices is a fundamental step towards improving sleep quality and preventing long-term complications. Sleep hygiene includes consistent sleep schedules, regular exercise, the reduction of caffeine, alcohol and nicotine, reducing screen exposure before bedtime, and embracing healthy bedtime routines contribute to more restful sleep. It is imperative to document relevant medication and substance usage and emphasize a holistic approach to sleep management to ensure the overall health and safety of patients.

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Author Bio

Aarti Desai

Dr. Desai is a Research Fellow in the Advanced Heart Failure and Transplant division at the Mayo Clinic in Jacksonville, Florida. She is from Canada and received her medical degree from Surat Municipal Institute of Medical Education and Research (SMIMER), India. She looks forward to making an impact in the primary health care sector with prevention and management of chronic illnesses such as cardiac health and mental health disorders and anticipates starting residency training in 2024.

Rohan Goswami

Dr. Goswami is a Transplant Cardiologist practicing at Mayo Clinic in Florida. He is a graduate of the American University of the Caribbean School of Medicine and completed his internal medicine residency at Columbia University College of Physicians and Surgeons – Stamford Hospital, a cardiology fellowship at The University of Tennessee Memphis, and a Transplant Fellowship in 2017 at Mayo Clinic in Florida. He has a keen interest in clinically focused artificial intelligence research to improve outcomes in patients with advanced heart failure. He has published articles in the field of both heart transplantation and artificial intelligence, as well as presented at Ai4 in 2020 on the future impact of AI in healthcare and invited lectures at the International Society of Heart and Lung Transplantation from 2021 to 2023. He looks forward to one day utilizing AI integration to prevent organ failure.

Shriya Sharma

Dr. Sharma, originally from Kathmandu, Nepal, is a Nepalese Army Institute of Health Sciences - College of Medicine graduate. She is currently a Research Fellow in the Division of Advanced Heart Failure and Transplant at the Mayo Clinic in Jacksonville, Florida. She is interested in staying current with the latest developments and contributing to the advancement of medicine with her clinical research in heart failure, artificial intelligence, and transplant medicine. Her aspirations are directed toward a future practicing cardiology, and she eagerly anticipates commencing her Residency training in internal medicine in 2024.

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