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Home , Cataplexy, Narcolepsy, Sleep inertia, Sleep paralysis

Central Disorders of and

Lynn Liu, MD, FAASM, FACNS, FAAN February 10, 2021 Objectives

• Describe the prototypical clinical features of Narcolepsy 1 • Differentiate between NT1 and NT2 • Compare and contrast different hypersomnia CHEST 2014; 146 ( 5 ): 1387 - 1394 Narcolepsy

• Chronic – Inability to control -wake cycles – Excessive daytime sleepiness – Refreshing

• Consequences of untreated, narcolepsy – Psychological, social, and cognitive function and development – Inhibit academic, work, and social activities. Prevalence

• Symptoms start at any age often in childhood (ages 7 to 25)

• Affects males and females equally

• ~135,000 to 200,000 people in the US

• Often goes undiagnosed or misdiagnosed Symptoms

Pelayo R, Lopes MC. Narcolepsy. In: Lee-Chiong TL, ed. Sleep: A Comprehensive Handbook. Hoboken, NJ: Wiley and Sons, Inc.; 2006:145-149. Symptoms

• Most specific symptom of narcolepsy type 1 • Sudden, brief (<2 min) loss of muscle tone with retained consciousness • Triggered by strong , such as laughter, surprise, or anger

N Engl J Med 2015; 373:2654-2662 DOI: 10.1056/NEJMra1500587

Pelayo R, Lopes MC. Narcolepsy. In: Lee-Chiong TL, ed. Sleep: A Comprehensive Handbook. Hoboken, NJ: Wiley and Sons, Inc.; 2006:145-149. Symptoms

• Vivid dreamlike experiences that occur while asleep or waking

Leschziner G Narcolepsy: a clinical review Practical 2014;14:323-331

Pelayo R, Lopes MC. Narcolepsy. In: Lee-Chiong TL, ed. Sleep: A Comprehensive Handbook. Hoboken, NJ: Wiley and Sons, Inc.; 2006:145-149. Symptoms • Hallmark symptom, 100% of patients with narcolepsy • Inability to stay awake and alert during the day

Leschziner G Narcolepsy: a clinical review Practical Neurology 2014;14:323-331

Pelayo R, Lopes MC. Narcolepsy. In: Lee-Chiong TL, ed. Sleep: A Comprehensive Handbook. Hoboken, NJ: Wiley and Sons, Inc.; 2006:145-149. Symptoms • Disturbing, temporary inability to move voluntary muscles or speak during sleep-wake transitions

Leschziner G Narcolepsy: a clinical review Practical Neurology 2014;14:323-331

Pelayo R, Lopes MC. Narcolepsy. In: Lee-Chiong TL, ed. Sleep: A Comprehensive Handbook. Hoboken, NJ: Wiley and Sons, Inc.; 2006:145-149. Symptoms • Most specific symptom of narcolepsy type 1 • Sudden, brief loss of muscle tone with retained consciousness • Triggered by strong emotions, such as laughter, surprise, or anger

• Vivid dreamlike experiences that occur while falling asleep or waking

• 100% of patients with narcolepsy • Inability to stay awake and alert during the day

• Disturbing, temporary inability to move voluntary muscles

• Frequent awakenings due to sleep-wake state instability

Pelayo R, Lopes MC. Narcolepsy. In: Lee-Chiong TL, ed. Sleep: A Comprehensive Handbook. Hoboken, NJ: Wiley and Sons, Inc.; 2006:145-149. Types of Narcolepsy

• Narcolepsy Type 1 – Excessive daytime sleepiness daily for ≥3 months – One or both of the following: • and mean sleep latency ≤8 minutes and ≥2 SOREMPs on MSLT; – SOREMP (≤15 min after ) on preceding nocturnal PSG may replace one of the SOREMPs on MSLT • Low or absent CSF hypocretin-1 levels • Narcolepsy Type 2 – Excessive daytime sleepiness and MSLT findings as above, but without cataplexy – CSF hypocretin-1 levels are unknown or are above the threshold for narcolepsy type 1 – The hypersomnolence and/or MSLT findings are not better explained by other causes • Insufficient sleep, OSA, delayed sleep phase disorder, or the effect of /substances or withdrawal. • Secondary narcolepsy – Injury to the hypothalamus – Typical symptoms of narcolepsy – Severe neurological problems and sleep for long periods (more than 10 hours) each night.

American Academy of . International Classification of Sleep Disorders. 3rd ed. Darien, IL : American Academy of Sleep Medicine; 2014. Etiology

• Autoimmune disorders – Loss of brain cells that produce hypocretin/ due to a combination of genetic and environmental factors

Thannickal, T, Moore, R, Nienhuis, R, et al. Reduced Number of Hypocretin in Human Narcolepsy, , Vol 27, Issue 3, 2000, Pages 469-474. Etiology

• Autoimmune disorders • Family history – Most cases of narcolepsy are sporadic – There are clusters in families • Up to 10 percent of individuals diagnosed with narcolepsy with cataplexy have a close relative with similar symptoms. C. Capittini et al. / Sleep Medicine 52 (2018) 150e157 Etiology

• Autoimmune disorders – Loss of brain cells that produce hypocretin due to a combination of genetic and environmental factors. • Family history – Most cases of narcolepsy are sporadic – There are clusters in families • Up to 10 percent of individuals diagnosed with narcolepsy with cataplexy have a close relative with similar symptoms. • Brain injuries – Rarely, traumatic brain injury to areas that regulate and REM sleep – Tumors – Pediatric Neurology 2018 8427-31DOI: (10.1016/j.pediatrneurol.2017.12.016) Diagnosis

• Clinical evaluation – Detailed medical history – Major symptoms specific to narcolepsy • Cataplexy is the most specific symptom – Physical exam • Identify other neurological conditions – Sleep journal • Sleep habits for 1-2 weeks Diagnosis

• Polysomnogram (PSG) • Overnight recording • Identify early REM sleep • Exclude other conditions – Obstructive – Periodic Limb Movements – Adequate sleep

Leschziner G. Pract Neurol 2014;14:323–331. doi:10.1136/practneurol-2014-000837 Diagnosis

• Multiple sleep latency test (MSLT): • Assesses daytime sleepiness • Sleep Onset REM Periods (SOREMP) • Five short naps separated by two hours

Richardson GS, Carskadon MA, Flagg W: Excessive daytime sleepiness in man: multiple sleep latency measurements in narcoleptic and control subjects. Electroencephalogr Clin Neurophysiol 1978;45:621–627. Diagnosis

• CSF hypocretin/orexin level • – Measure CSF levels of hypocretin-1

The Lancet Neurology 2008 7649-662DOI: (10.1016/S1474-4422(08)70140-6) Treatment

• Medications • Lifestyle Changes • Safety Precautions N Engl J Med 2015; 373:2654-2662 DOI: 10.1056/NEJMra1500587 Treatments

• Lifestyle changes – Take short naps. Regularly scheduled naps at times when they tend to feel sleepiest. – Maintain a regular sleep schedule. Going to and waking up at the same time every day, even on the weekends, can help people sleep better. – Avoid or before bed. Individuals should avoid alcohol and caffeine for several hours before . – Avoid smoking, especially at night. – Exercise daily. Exercising for at least 20 minutes per day at least 4 or 5 hours before bedtime also improves sleep quality and can help people with narcolepsy avoid gaining excess weight. – Avoid large, heavy meals right before bedtime. Eating very close to bedtime can make it harder to sleep. – Relax before bed. Relaxing activities such as a warm bath before bedtime can help promote sleepiness. Also make sure the sleep space is cool and comfortable. Safety precautions

• Safety – Sleep attacks or cataplexy can result in injuries such as stairs, cooking or swimming • Driving – Untreated symptoms can result in automobile accidents • Americans with Disabilities Act – Employers must provide reasonable accommodations – Negotiate with employers to modify their work schedules so they can take naps – Children and adolescents with narcolepsy should work with school administrators • Support groups – Develop better coping strategies – Reduce social isolation and embarrassment about their symptoms – Promote a network of social contacts who can help and provide emotional support Covid-19 and Narcolepsy

• Brazilian study – On-line survey of 78 people with narcolepsy • 25% fewer still going to work, 43% more working from home, 60% lost jobs • Irregular sleep wake schedules • Increased use of • Italian study – Telephone interviews with 50 consecutive NT1 patients • 3 Groups: 40% no changes in schedule, 44% work/study at home, 8% lost job • Increased nocturnal awakenings – Group 1 and 3 • Increased naps and nocturnal sleep and BMI – Group 2

Rodrigues Aguilar AC, et al The effects of the COVID-19 pandemic on patients with narcolepsy. J Clin Sleep Med. 2020 Oct 30. doi: 10.5664/jcsm.8952. PMID: 33124977. Postiglione E, et al. Impact of COVID-19 pandemic lockdown on narcolepsy type 1 management. Brain Behav. 2020 Nov 28:e01955. doi: 10.1002/brb3.1955. PMID: 33247632

• Hypersomnia for at least 3 months • No cataplexy • Sleep and Hypnagogic uncommon • Sleep Drunkenness/Inertia • Longer and unrefreshing naps

CHEST 2015; 148 ( 1 ): 262 - 273 Idiopathic Hypersomnia

• Prevalence unclear • Etiology unknown – Genetic – Low histamine levels – Altered cytokines – Altered GABAA receptors

CHEST 2015; 148 ( 1 ): 262 - 273 PSG and MSLT

• TST of 12-14 hours by PSG or actigraphy • High sleep efficiency of >90% • MSL < 8 minutes • Fewer than 2 SOREMP

CHEST 2015; 148 ( 1 ): 262 - 273 Central Disorders of Hypersomnia NT1 NT2 IH

Clinical Symptoms Hypersomnia >3 months Yes Yes Yes Cataplexy Yes No No Naps Refreshing Refreshing Long and not refreshing Labs Hypocretin levels Very low Low to normal Normal PSG TST >11 hours per 24 hours Sleep Efficiency Poor >90% MSLT MSL < 8 minutes < 8 minutes < 8 minutes SOREMP > 2 > 2 < 2

Modified from SleepJ, 2020,Vol.43, No.8 Kleine-Levin

• Rare disorder of relapsing and remitting symptoms at least once a year – Hypersomnia - up to 20 hours per day lasting a few days to a few weeks – Hyperphagia – Hypersexuality – Cognitive impairment – Mental health changes • Apathy • Derealization • Hallucinations – Interictally typically normal • Prevalence estimated at 1.5 per million – Adolescent with approximately 70 percent are male • Malfunction of the hypothalamus and • Autoimmune?

Lancet Neurol 2012; 11: 918–28

• Intoxication • Structural lesions – typically normal CT or MRI • Non-convulsive status epilepticus • Metabolic or nutritional abnormalities • Endocrinopathies Figure 3

The Lancet Neurology 2012 11918-928DOI: (10.1016/S1474-4422(12)70187-4)

Copyright © 2012 Elsevier Ltd Terms and Conditions Management and Treatment

The Lancet Neurology 2012 11918-928DOI: (10.1016/S1474-4422(12)70187-4) Conclusions • Narcolepsy Type 1 – Cataplexy, Hallucinations, EDS, , and Sleep Disruptions – Loss of hypothalamic hypocretin neurons resulting in low levels – Autoimmune mechanism • Narcolepsy Type 2 – Similar clinical features but without the cataplexy or low hypocretin levels • Idiopathic Hypersomnia – Long sleep times and /drunkenness • Kleine-Levin Syndrome – Relapsing and Remitting hypersomnia Thoughts Comments