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Recognizing and Responding to Neurological Emergencies in the Sleep Lab Christopher Morgan, MD Medical Director, Trinity Health Grand Rapids and Muskegon Sleep Center Program Director, Trinity Health Grand Rapids Sleep Fellowship Associate Program Director, Trinity Health Grand Rapids Neurology Residency Clinical Assistant Professor, Michigan State University College of Human Medicine 9/11/25

Conflicts of Interest 1. I do not have any potential conflicts of interest to disclose, OR X

2. I wish to disclose the following potential conflicts of interest: Type of Potential Conflict

Details of Potential Conflict

Grant/Research Support Consultant

Nyxoah

Speakers’ Bureaus Financial support Other X

3. The material presented in this lecture has no relationship with any of these potential conflicts, OR 4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture:

Learning Objectives • Upon completion of this course, attendees should be able to…

• Understand how to identify Neurological emergencies in the sleep lab • Initiate initial response to neurological emergencies • Understand when to refer the patient to the emergency room

Seizures • Sudden, temporary change in brain activity that can cause a variety of symptoms, including changes in movement, sensation, behavior, or awareness. • Seizures have a variety of semiologies (observable features) • Most seizure occur out of Stage 1 and stage 2 (54-68%) sleep • RARE during REM sleep, almost never

• Most common sleep related seizures

• Temporal Lobe – Most common to see in sleep (because most common epilepsy) • 26% out of sleep

• If occur from sleep, more likely to generalize • Often precede an arousal

• Frontal Lobe - about 37% happen out of sleep • Can see hypermotor movements • Always stereotypical behaviors

S.T. Herman, MD, T.S. Walczak, MD, and C.W. Bazil, MD, PhD; Neurology; June 12, 2001 issue; 56 (11) 1453-1459 https://doi.org/10.1212/WNL.56.11.1453

Prior to Sleep Study • If history of Epilepsy, ask about seizures

• What do they typically do during a seizure • Have they had their seizures sleeping before? • How long do they last? • Have then ever been severe enough to go to the hospital?

• Use Temporal lobe leads for EEG montage • Consider parasomnia leads on arms if diagnosis unclear or workup between seizure and parasomnia

Chowdhury FA, et al.Chowdhury Pract Neurol FA,2021;21:481–491. et al. Pract Neurol 2021;21:481–491. doi:10.1136/practneurol-2019-002341 doi:10.1136/practneurol-2019-002341

Chowdhury FA, et al. Pract Neurol 2021;21:481–491. doi:10.1136/practneurol-2019-002341

Primary Motor Cortex • Clonic movements visible in the left face spreading in a Jacksonian fashion over the left arm as the seizure spreads over the right primary motor cortex, followed by left arm extension (fencing posture) indicating involvement of supplementary motor area, before secondary generalisation Chowdhury FA, et al. Pract Neurol 2021;21:481–491. doi:10.1136/practneurol-2019-002341

Chowdhury FA, et al. Pract Neurol 2021;21:481–491. doi:10.1136/practneurol-2019-002341

Right Orbitofrontal • hyperkinetic seizures that progressed to bilateral tonic seizures with loss of awareness. The EEG onset was seen in the right orbitofrontal region

Chowdhury FA, et al. Pract Neurol 2021;21:481–491. doi:10.1136/practneurol-2019-002341

Temporal Lobe • Psychic and abdominal aura, followed by oral and manual automatisms, then loss of awareness. Before the seizure generalised, there was head and eye version to the right along with a ‘figure-of-4’ sign (left arm flexed and right arm extended), which lateralised the onset to the left hemisphere Chowdhury FA, et al. Pract Neurol 2021;21:481–491. doi:10.1136/practneurol-2019-002341

Seizure on EEG – 30 sec epoch

Seizure on EEG – 10 sec

Spike-wave

Differential Diagnosis of Sleep behaviors • REM behavior disorder

• Complex behaviors which are NOT stereotypical • Always out of REM sleep

• NREM Parasomnias

• Sleepwalking • Night Terrors • Often out of N3 sleep (seizures more rare from there)

• Severe Periodic Limb Movements

• Most common in stage 1, 2 • Have periodic, recurrent pattern for long periods of time

REM Sleep behavior disorder hyperkinetic

Sleep Terror

Continuum; February 2013 issue; 19 (1) 104-131 https://doi.org/10.1212/01.CON. 0000427210.98305.8f

Severe PLMS

Interventions during a seizure • ABCs

• Ensure Airway protection

• If generalized seizure, turn on side to avoid aspiration, ensure airway is clear

• Breathing

• Monitor for severe desaturations/apnea during seizure

• Circulation

• Monitor for arrythmias, particularly heart block

• Recurrent uncontrolled generalized seizures may cause apnea and arrythmias leading to Sudden Unexplained Death in Epilepsy (SUDEP)

• If patient carries seizure relief medication, consider administering if able per your lab policy • eg intranasal diazepam or midazolam

Interventions during a seizure • Bring a tech friend if you have one • Move patient away from any hazards (eg, if close to headboard, side table or headbox) • Keep note of semiology of behaviors with detailed documentation in tech note • Make sure camera is adjusted to show all movements • Pull off sheets if able • Time how long the seizure lasts

When to continue study vs send to ED? OK to keep running study if: • Seizure lasts <5 minutes will full recovery • Unsure if seizure vs parasomnia and pts vitals are stable with normal sleep EEG patterns – do not need to wake up Call EMS if: • Seizure lasting longer then 5 minutes without full recovery: Status Epilepticus

• If has 1 seizure for 2 minutes, but then does not respond to you after, then goes into another seizure a couple minutes later

• aspiration occurs and/or difficulty breathing • tongue biting with bleeding • heart block or tachyarrhythmia that is not improving after seizure • If desats, consider placing O2 while waiting for EMS

Stroke • Sudden damage of brain tissue caused by lack of blood flow from a blood vessel blockage (Ischemic), OR bleeding in the brain (Hemorrhagic) • Happens Suddenly • Cannot see when sleeping • May notice with arousals/bathroom • 14-25% of strokes occur during sleep

Stroke; Volume 26, Issue 12, December 1995; Pages 2361-2365 23

BE FAST • Headaches can occur with hemorrhagic strokes • Drowsiness or decrease consciousness can develop quickly in some strokes • Dizziness and vision changes are common with strokes in the back of the brain (occipital lobe/brainstem) Stroke; Volume 48, Issue 2, February 2017; Pages 479481 24

Initial interventions • Call EMS immediately if suspected, EVEN if symptoms resolve! • TIME IS BRIAIN • 1.9 million neurons are lost each minute after a stroke • Strokes are treatable! • Tenecteplase (TNK) is drug that will dissolve clots if given within 4.5 hours of stroke onset, but prognosis improves the sooner it can be administered • Interventional therapies to remove blood clots can also be done • CT scan needs to be completed immediately to rule out hemorrhagic stroke, which is a contraindication for TNK or thrombectomy

Mechanical Thrombectomy

• Catheter to remove blood clot from the brain • Can be done up to 24 hrs in some cases https://theii.org/stroke-thrombectomy

Acute Confusion/Delerium/Sundowning • Frequently seen in sleep lab, esp. with dementia patients • Look for signs of seizure or stroke

• Especially if sudden onset • Screen for aphasia! – inability to speak fluently or understand simple commands • BE FAST signs

• Other potential causes

• R/o parasomnia behavior – especially if out of N3 or REM sleep • Sedating medications • Dehydration • Hypoglycemia (especially in diabetics)

Acute Confusion/Delerium/Sundowning • Delerium precautions

• Review patients nighttime sedating medications and exactly what meds pt took the day and night before for future review • Assess for any pain/discomfort causing more confusion • Remain CALM and reorient the patient frequently • Use caregiver if present to help familiarize patient • Offer water/juice if suspect dehydration or low sugar

• If agitation, protect yourself and staff. Be careful of close contact until patient is calm • Refer to ED if not resolving or any focal neuro signs!

Severe Headaches • Ask pt the quality of the headache

• If history of Migraine, is this their typical headache? • Is it unilateral with sensitivity to light or sound? – often migraine • Is it a pressure sensation around the head – tension/stress • Is it in the forehead with congestion/sinus pressure – possible sinus H/A

• Ask the severity

• If it is the worst headache of their life and started within 1-2 minutes, this is called “Thunderclap Headache” – Immediately call EMS • This can be caused by bleeding aneurysms causing subarachnoid hemorrhage • Can be related to other clots in the brain veins (sinuses) or spasms/tears of the blood vessels

• Take temperature if available – fever & headache can be meningitis

Severe Headaches • Do a brief neurologic assessment, especially if new headache – BE FAST • Any new dizziness, vision changes, weakness in arms/legs, facial weakness, speech trouble

• Use pts home medications if available • Cold, wet towel on forehead • If titration, give break from PAP

• Try mask with looser straps if possible or different strap configuration • Consider lowering pressure or trying BiPAP in case pressure contributing

Without Sleep

The Future of Sleep Medicine Careers Evolving Opportunities for Sleep Professionals Ahmed Ghanim, M.B.B.Ch Championship Updates in Sleep Medicine September 11, 2025

Conflicts of Interest 1. I do not have any potential conflicts of interest to disclose, OR 2. I wish to disclose the following potential conflicts of interest: Type of Potential Conflict

Details of Potential Conflict

Grant/Research Support Consultant Speakers’ Bureaus Financial support Other 3. The material presented in this lecture has no relationship with any of these potential conflicts, OR 4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture:

Where Are We Going? Where do you see yourself in sleep medicine in 5 years?

Let’s explore the evolving landscape and what it means for your career.

Evolution of Sleep Medicine: Threat vs. Invitation ● PSG era: sleep as a test, not a treatment “For decades, sleep medicine revolved around one thing: the overnight polysomnogram. It was our gold standard, our bread and butter. But it also limited us—we became test-centered, not patient-centered. Sleep became something we measured, not something we treated holistically.”

● Rise of HSAT: access expands, margins shrink“Then came the home sleep test revolution. Suddenly, access improved. More people got diagnosed. That’s great. But what came with it? Lower reimbursements. Less control over the process. Less patient engagement. And we started asking: if we’re not offering fullservice care—what are we offering?”

● From labs to laptops: tech is reshaping care “Now tech is eating into every

corner of the field. AI can score a study in seconds. Wearables claim to ‘diagnose’ sleep problems. Patients are tracking their sleep before they see us. Sleep care is moving from labs to laptops—and the question isn’t ‘if’ we evolve—it’s how we stay relevant.”

● Patient expectations are shifting—fast “Today’s patients don’t just want a diagnosis. They want a plan. A fix. A coach. They expect fast answers, app access, and empathy. They expect sleep doctors to understand anxiety, burnout, tech overload—and how that all ties into their sleep. Our training must evolve to meet this.”

● The future? Integrated, tech-enabled, outcome-driven “What does tomorrow look like? Teams—not individuals. Telehealth, AI support, behavior-based treatment. The future of sleep medicine isn’t just high-tech—it’s high-touch. It’s outcome-focused. And it’s waiting for us to claim our role—not as sleep testers, but as sleep healers.””

Challenges in the Field - Staff shortages (RPSGTs, MDs) - Reimbursement pressures - Commoditization of services - Increasing reliance on AI without human oversight

Emerging Trends & Opportunities • Telemedicine & RPM • Behavioral Sleep Medicine

•

Corporate sleep wellness

• •

AI in scoring and triage Pediatric Sleep Care

New Career Opportunities • Sleep Health Coach • QA & Sleep Medicine Leadership

•

Entrepreneurship

• Digital Health Consultant • Research/Industry roles

What Professionals Need Entrepreneurship and innovation mindset – identifying opportunities, driving solutions, and

creating new care models in a shifting healthcare landscape

Adaptability to rapid change – staying agile in response to evolving technologies, reimbursement models, and patient demands

Cross-training in behavioral and digital tools – integrating CBT-I, motivational interviewing,

and tech-based interventions into holistic sleep care

Embracing technology – effectively using AI, wearables, telehealth, and data platforms to enhance diagnosis and treatment

Leadership and advocacy – championing sleep health within institutions, communities, and public health

systems

Building political capacity – understanding and influencing healthcare policy, reimbursement, and regulation to protect and advance the field of sleep medicine

Pursuing specialized certifications – such as CCSH (Certification in Clinical Sleep Health) and

DBSM (Diplomate in Behavioral Sleep Medicine) to deepen expertise and credibility

What Institutions Should Do Invest in workforce development

Train and retain the next generation of sleep professionals—across behavioral, digital, and clinical domains. Support certification, mentorship, and career advancement pathways.

Support hybrid models of care

Integrate telehealth, home testing, and in-person care into cohesive service lines. Embrace flexibility while maintaining quality and continuity.

Promote flexible career paths

Offer multidisciplinary roles and career mobility. Encourage entrepreneurial thinking, dual roles (e.g., clinical + digital), and crossdepartment collaboration.

Foster tech adaptation

Provide training in AI tools, wearables, remote monitoring, and digital interventions. Build a culture that embraces innovation, not resists it.

Serve as incubators for innovation

Create space for new models of care, research, and technology testing. Partner with startups, fund pilot programs, and reward frontline innovation.

Expand beyond traditional clinical services

Develop sleep and wellness programs for corporations, schools, and public agencies. Position your institution as a community resource for sleep health—not just a diagnostic center.

Questions? - Ahmed Ghanim, M.B.B.Ch - Email: ahgh@med.umich.edu - Direct line: (313) 434-7035

Persistent Pediatric Obstructive Sleep Apnea and Hypoglossal Nerve Stimulation Erin Kirkham, MD MPH FACS Pediatric Otolaryngology, University of Michigan Championship Updates in Sleep Medicine September 12th, 2025

Disclosures • None

Objectives • Updates in management of persistent postadenotonsillectomy (AT) OSA –Guidelines –Drug-induced sleep endoscopy (DISE) –Second-stage surgery –Hypoglossal nerve stimulation in pediatric OSA –Post-AT OSA - Can it be prevented?

Sleep Apnea in Children • Obstructive Sleep Apnea (OSA)

• Repetitive breathing pauses during sleep • Affects 1-4% of children

• Negatively impacts

• Quality-of-life • Cognition • Behavior • School performance

• Associated with

• Biomarkers of cardiovascular risk

Definition of Persistent OSA Post-AT PSG: • AHI >1 with symptoms • AHI >5 with or without symptoms

Ishman et al. (2023) OHNS. 168 (2)

How common is post-AT OSA? • Persistence on PSG – 20-40% typically developing children – 60% in children with risk factors

• Persistent Symptoms – 20-30% typically developing children Marcus et al. (2013) N Engl J Med. 368(25) Fehrm, et al. (2020) JAMA Oto. 146(7) Waters, et al. (2020) Pediatrics. 145(2) Friedman et al. Oto-HNS (2009) 140, 800-808.

Children at risk for post-AT OSA • Obesity • Black race • Severe baseline OSA • Down Syndrome • Neurologic disorders (hypotonia) • Craniofacial disorders

Who should have post-operative PSG? • AASM 2011: PSG indicated after AT for children with risk factors – Preoperative mod-severe OSA – Obesity – Down syndrome – Craniofacial anomalies – Neurologic disorders • AAP 2012/AAOHNS 2019 : Clinicians should reassess symptoms patients with OSA for persisting signs and symptoms after therapy

Aurora et al Sleep 2011;34(3):379-388 Marcus et al Pediatrics 2012;130(3):576-84

• Multidisciplinary care is beneficial; • Refer for weight loss intervention; • Trial of CPAP or second stage surgery both reasonable • DISE-directed surgery can improve OSA • intranasal steroids and montelukast beneficial for mild/moderate

• use of CPAP in children with persistent OSA; • orthodontic/dentofacial orthopedic treatment; • weight loss intervention; • lingual tonsillar hypertrophy; • supraglottoplasty; and • intranasal steroids and montelukast Ehsan Z, Am J Respir Crit Care Med. 2024 Feb 1;209(3):248-261.

ENT Hassan

Yatabe

Sleep Medicine Orthodontics

Kirkham

Refractory OSA Clinic

Edwards

Mott Children’s Hospital

Aronovich

Carver

OMFS

Drug-Induced Sleep Endoscopy (DISE)

DISE indications • Limited utility for SDB / OSA with large tonsils • Persistent OSA • Surgically naïve children (before AT) • Small tonsils • Risk factors for AT “failure”

International Pediatric Sleep Endoscopy Scale (IPSES) • Levels (grade 0, 1, 2) • Nasal cavity • Nasopharynx • Velum • Lateral walls • Tongue base

• Lingual tonsil size

• Epiglottis • Arytenoids

• Pattern of obstruction • Movement assessment Lam, D. J., et al. (2023). Int J Pediatr Otorhinolaryngol 174: 111748.

Causes of Obstruction After AT Nasal Passage 70%

Adenoid Regrowth 57% Soft Palate 45%

Tongue Base 66% Larynx 22%

Durr et al. Arch Otolaryngol Head Neck Surg 2012;138:638-643 Coutras et al. IJPORL 2018;107:190-193. Esteller et al. IJPORL 2019;120:118-122.

Post-AT Sleep Surgery in Children (n=1,318)

Procedure

Revision Adenoidectomy Lingual Tonsillectomy Inferior Turbinate Reduction Expansion Pharyngoplasty (palate) Supraglottoplasty Midline Posterior Glossectomy Epiglottopexy Septoplasty Hyoid Suspension

42 42 23 15 9 6 2 2 2

Success Rates • Procedures difficult to study in isolation • Usually done in combination… • Heterogenous population • Most data is on lingual tonsillectomy • AHI < 5: 52%

Tongue base reduction surgery • Meta analysis (2017) mean diff in AHI 6.9 ev/hr

Camacho, M., Noller, M.W., Zaghi, S. et al. Eur Arch Otorhinolaryngol 274, 2981–2990 (2017)

Hypoglossal Nerve Stimulation in Pediatric OSA

OSA in Down Syndrome • AAP recommends PSG by age 4 • Prevalence ~80% • High risk of post AT OSA

11 yo male with Down Syndrome • Severe OSA s/p T&A

– AHI of 13.5 and oxygen nadir of 88% – CPAP intolerant • Non-obese: BMI 15 (3rd percentile for boys with Down Syndrome of his age) • Comorbidities: hypotonia, congenital cardiac anomaly, profound intellectual disability, autism spectrum disorder, and ADHD • Treatment options?

Hypoglossal Nerve Stimulation in Children • In 2023, the Food and Drug Administration (FDA) approved the HGNS implant for treatment of persistent OSA in children with Down Syndrome who meet the following criteria: • Age 13 – 18 years • Prior adenotonsillectomy • CPAP intolerance or refusal • PSG that demonstrates persistent, severe OSA (AHI 10-50 with less than 25% of the total apnea index comprised of central or mixed apnea events ).17 • No concentric collapse at the soft palate on DISE Strollo P et al. NEJM 2014;370(2):139 Diercks et al. Pediatrics 137(5):e20153663

Airway assessment for Inspire: No, partial, complete concentric collapse Stable lateral walls

Partial lateral wall collapse

Complete lateral wall collapse

Drug-induced sleep endoscopy • Appropriate candidate

• Lower likelihood of benefit from HGNS implantation

Evaluation with baseline PSG and DISE

Implantation

Post-implant Protocol

Implant activation in clinic 1 month postop

Acclimation PSG with goal of AHI<5 1-3 months after surgery

Titration PSGs every 6 months until device optimized

Repeat PSG every 1-2 years for 5 years Chieffe D. Pediatric Down Syndrome Upper Airway Stimulation: Patient Selection and Post-Implantation Optimization. Otolaryngol Head Neck Surg. Apr 2024;170(4):1158-1166.

• N = 42 adolescents with Down syndrome • 67% male, mean age 15 years • Mean decrease in AHI: 12.9 • 12-month response rate (>50% decrease in AHI): 66% • Improvement in QOL and sleepiness Yu et al JAMA Oto 2022;148:522-528 • Mean duration nightly use: 9.0 hrs

Outcomes Thus Far…

Yu PK et al. (2022) JAMA OTO. 148(6):522-528.

Outcomes Thus Far…

Yu PK et al. (2022) JAMA OTO. 148(6):522-528.

Stenerson ME, et al. (2021) Int J Pediatr Oto. 149:110868.

Yu PK, et al. (2021) Laryngoscope. 131(7):1663-1669.

Yu PK, et al. Laryngoscope. 2021 Jul;131(7):1663-1669.

• 53 patients aged 10-22 years with Down Syndrome • 30 adverse events • 17 “nonserious” • Tongue discomfort (9.4%) • Rash at the surgical site (7.5%) • 13 “serious” • Reoperation (15%) • Readmission (9.4%) Chieffe D, Int J Pediatr Otorhinolaryngol. Jan 2024;176:111831.

11 yo male with Down Syndrome • Implanted successfully summer 2023 • 2-month post op activation PSG – Device off AHI 11.3  Device on AHI 0.7

• Good nightly use since implant (9+ hours)

HGNS: Special Consideration in Peds Known Complications in all • Pain • Cellulitis • Unfavorable scarring • Marginal mandibular nerve weakness • Tongue weakness • Battery depletion • Extrusion • Pneumothorax

Considerations in Peds • Behavior / wound picking • Do they need to stay overnight? • Post-operative activation and titration • When can you activate them? • Will they tolerate a sleep study?

• Need for reconfiguration / titration • Adults  clinic • Peds  OR for DISE

Chieffe et al. IJPORL 2024;176:111831

Off-Label Use of Hypoglossal Nerve Stimulation • 4-year-old boy with Down Syndrome and severe OSA OAHI 22.9 LSAT 79%

OAHI 12.1 LSAT 81% AT, supraglottoplasty

OAHI 9.2 LSAT 82%

Intolerant of CPAP

Midline posterior glossectomy HGNS

Sleep Eff 87% OAHI 5.5 Wasserman et al. Pediatrics 2024;153:e2023063330

Off-Label Use of Hypoglossal Nerve Stimulation • HGNS implant in adult with cerebral palsy • 28 yo M with h/o CP, developmental delay, hydrocephalus with VP shunt • Severe OSA after previous AT, intolerant to CPAP, family refused tracheostomy

AHI 112 90% obstructive HGNS

AHI 12.8 Ave usage: 20hr/wk

• Challenges: compliance requiring caregiver assistance, inconsistent follow-up Scheffler et al. Laryngoscope 2024;134:2478-2479

Off-Label Use of Hypoglossal Nerve Stimulation • HGNS implant in adult with Treacher Collins • 32 yo M, Severe OSA after previous AT, CPAP ineffective

AHI 35

AHI 81 HGNS

• Challenges: HGNS may not be enough

Wong ACL, J Clin Sleep Med. 2023 Jan 1;19(1):197-199.

AHI 20 (with CPAP)

Post-AT OSA Can it be prevented?

Treatment of Obstructive Sleep Apnea with Personalized Surgery in Children with Down Syndrome • 6-site, randomized, single-blind trial • Adenotonsillectomy vs. personalized (DISE-directed) surgery

Inclusion Criteria: 1. 2 - 17 years 2. Down syndrome 3. OSA (oAHI ≥ 3) on PSG within 12 months Exclusion Criteria: 1. Previous tonsillectomy (previous adenoidectomy is allowed) 2. Significant cardiopulmonary comorbidity, subglottic or tracheal stenosis, or tracheostomy dependence

Study Overview

Outcome Measures • Primary outcomes:

• Obstructive apnea-hypopnea index (oAHI) • OSA18 – sleep related quality of life

• Secondary outcomes:

• AHI, ODI, min SpO2, etc • PSQ – symptom burden • mESS - modified Epworth sleepiness scale • PedsQL – general quality of life • FSIS – dysphagia quality of life

Treatment of Obstructive Sleep Apnea with Personalized Surgery in Children with Small Tonsils • 2-site, randomized, single-blind trial • Adenotonsillectomy vs. personalized (DISE-directed) surgery

TOPS-ST (small tonsils) Inclusion Criteria: 1. 2 - 17 years 2. Brodsky 1+ or 2+ tonsils (< 50% oropharyngeal obstruction) 3. Moderate (or greater) OSA (oAHI ≥ 3) on PSG within 12 months Exclusion Criteria: 1. Previous tonsillectomy (previous adenoidectomy is allowed) 2. Significant cardiopulmonary comorbidity, subglottic or tracheal stenosis, or tracheostomy dependence

Thank you!

ekirkham@med.umich.edu

Thank you!

ekirkham@med.umich.edu

Role of ORTHODONTICS in managing pediatric

Marilia Yatabe, DDS, MS, PhD

OSA

Conflicts of Interest X

1. I do not have any potential conflicts of interest to disclose, OR 2. I wish to disclose the following potential conflicts of interest:

Type of Potential Conflict

Details of Potential Conflict

Outline - Etiology - Dental clinical exam - Orthodontic assessment - Orthodontic treatment - Conclusions

MULTIDISCIPLINARY treatment

ETIOLOGY skeletal

soft tissue

lifestyle

Mohsenin et al., 2003; Pereira, 2007; Suguimoto et al., 2013

lifestyle

ETIOLOGY

alcohol

obesity

smoking

male gender increased age

Finck et al., 2024 ; Mohsenin et al., 2003; Pereira, 2007; Suguimoto et al., 2013

ETIOLOGY

Macroglossia

hypertrophic soft tissues

soft tissue

low muscle tone Finck et al., 2024; Mohsenin et al., 2003; Pereira, 2007; Suguimoto et al., 2013

skeletal

ETIOLOGY

Retrognathic MD

Retrognathic MX

narrow palate Finck et al., 2024; Mohsenin et al., 2003; Pereira, 2007; Suguimoto et al., 2013

DENTAL OFFICE

DENTAL OFFICE Questionnaires: STOP-Bang* Pediatric Sleep Questionnaire (PSQ) Epworth Sleepiness Scale for Children and Adolescents *Snoring, Hyperactivity, Obstructive breathing, blood Pressure BMI, Age, Neck circumference, Gender

Behrents et al., 2019

Clinical examination

DENTAL OFFICE

- Extra-oral assessment - Skeletal position of mx and md - Neck circumference - BMI

Behrents et al., 2019; Maniaci et al., 2024

Clinical examination

DENTAL OFFICE

- Extra-oral assessment - Skeletal position of mx and md - Neck circumference - Oral Hygiene - Change in taste perception - Periodontal Disease

Behrents et al., 2019; Maniaci et al., 2024

Clinical examination

DENTAL OFFICE

- Extra-oral assessment - Skeletal position of mx and md - Neck circumference - Oral Hygiene - Change in taste perception - Periodontal Disease

Xerostomia*

*open mouth / CPAP Bad oral hygiene

Change in taste*

*preference for saltier/sweeter foods Hypertension / cavities Periodontal Disease

Cavities

Behrents et al., 2019; Maniaci et al., 2024

Clinical examination

DENTAL OFFICE

- Extra-oral assessment - Skeletal position of mx and md - Neck circumference - Oral Hygiene - Change in taste perception - Periodontal Disease - Arch-form

narrow palate = narrow nasal cavity narrow arch —> crowding —> alters tongue position Behrents et al., 2019; Maniaci et al., 2024

Clinical examination

DENTAL OFFICE

- Extra-oral assessment - Skeletal position of mx and md - Neck circumference - Oral Hygiene - Change in taste perception - Periodontal Disease - Arch-form - Macroglossia

Behrents et al., 2019; Maniaci et al., 2024

Clinical examination

DENTAL OFFICE

- Extra-oral assessment - Skeletal position of mx and md - Neck circumference - Oral Hygiene - Change in taste perception - Periodontal Disease - Arch-form - Macroglossia - Palatal length - Swollen tonsils, uvula, adenoids

Behrents et al., 2019; Maniaci et al., 2024

Clinical examination

DENTAL OFFICE

Mallampati score Behrents et al., 2019; Maniaci et al., 2024

Clinical examination

DENTAL OFFICE

anxiety muscle contraction + stress

support airway patency

Behrents et al., 2019; Maniaci et al., 2024

Clinical examination

DENTAL OFFICE

muscle exhaustion, spasm Oral appliances may worsen TMD

Behrents et al., 2019; Maniaci et al., 2024

DENTAL OFFICE Down syndrome

Treacher-Collins syndrome

Pierre Robin Sequence

CLP (12% vs 4.5%)

Behrents et al., 2019 ; Gorucu-Coskuner et al., 2020

Why orthodontists?

adapts

grows

Boundaries of the upper airway: soft and hard tissues Cranial Base

Middle cranial fossa

Piriform Rim

Teeth

Width of the palate Width of the palate

Teeth Cervical Vertebrae

Distance between rami Distance between rami

Hyoid bone

Cervical Vertebrae

Behrents et al., 2019

Why orthodontists?

manage grows Boundaries of the upper airway: soft and hard tissues

American Association of Orthodontists

“…expert in diagnosing and treating irregularities of the teeth and jaws.” Behrents et al., 2019

Why orthodontists?

Imaging exam: Lateral cephalogram CBCT

2D image of 3D structure Limited info on ST Static image

Behrents et al., 2019

TREATMENT OPTIONS ortho skeletal ortho-sx

soft tissue referral

change lifestyle lifestyle

change lifestyle

TREATMENT OPTIONS 2019

2023

BMI

65.5 kg/m2

35.7 kg/m2

AHI

12.3

4.9

Obstructive

Central

0.6

0.1

Hypopnea

11.7

4.8

Min %SpO2 75

Average %SpO2 94

Diagnosis Severe OSA Neck 22”

Mild OSA 15”

change lifestyle

TREATMENT OPTIONS

American Academy of Sleep Medicine

TREATMENT OPTIONS ortho ortho-sx

referral

change lifestyle

ortho

TREATMENT OPTIONS

Rapid Palatal Expansion

Villa et al., 2016; Huang et al., 2013; Pirelli et al., 2004; Li et al., 2004; Guilleminaut et al., 2011; Brunetto et al., 2022

TREATMENT OPTIONS

ortho

Skeletal anchored RPE in adults

Before Regular RPE

After Regular RPE

Carlson et al., 2016 Yoon et al., 2022

Brunetto et al., 2022; Carlson et al., 2016; Guilleminaut et al., 2011; Huang et al., 2013; Li et al., 2004; Pirelli et al., 2004; Villa et al., 2016; Yoon et al., 2022

ortho

TREATMENT OPTIONS

Maxillary expansion + Facemask CPAP may add pressure on the mx, resulting in retropositioned mx and anterior teeth. Lowe, 2012; Miranda et al., 2022

ortho

TREATMENT OPTIONS

Caution with over-expansion

ortho

TREATMENT OPTIONS

Mohsenin et al., 2003; Pereira, 2007; Suguimoto et al., 2013; Brunetto et al., 2022; Maniaci et al., 2024

ortho

Mandibular Advancement

TREATMENT OPTIONS

Significant improvement of AHI

Attia et al., 2024; Chen and Lowe, 2013; Hoffstein, 2006; Knappe et al., 2017; Lowe, 2012; Langaliya et al., 2023; Mohsenin et al., 2003; Pereira, 2007; Pereira et al., 2024; Suguimoto et al., 2013; Brunetto et al., 2022; Maniaci et al., 2024; Yamamoto et al., 2021

ortho

Mandibular Advancement

TREATMENT OPTIONS

Fixed vs Adjustable

Significant improvement of AHI

OASIS Oral/Nasal Airway System Attia et al., 2024; Chen and Lowe, 2013; Hoffstein, 2006; Knappe et al., 2017; Lowe, 2012; Langaliya et al., 2023; Mohsenin et al., 2003; Pereira, 2007; Pereira et al., 2024; Suguimoto et al., 2013; Brunetto et al., 2022; Maniaci et al., 2024; Yamamoto et al., 2021

ortho

Mandibular Advancement Significant improvement of AHI

TREATMENT OPTIONS Short to mid-term studies, lack sample details (skeletal proportions, AHI severity)

How much should we advance? Titration PSG

% of total MD protrusion

30% 50% 70% 100%

- to when patient stops snoring / when starts to feel uncomfortable - may take months - best when done during a PSG

TREATMENT OPTIONS

ortho

Neumann, 2015

TREATMENT OPTIONS

ortho Indicator for OA candidates - healthy teeth - Absence of TMD - Adequate range of motion - Manual dexterity and motivation to wear the appliance - Class II malocclusion Better responders: - Younger - Smaller neck circumference - Supine-dependent OSA

Factors that in uence treatment outcomes: - Appliance device - Severity of OSA - Amount of possible advancement - Initial skeletal relationship

TREATMENT OPTIONS

ortho

Side effect starts at 6m, more permanent if prolonged use: - Excessive salivation OR xerostomia - Headaches - Myofunctional pain Dental and Skeletal effects *not stable if decides to treat and use OA again.

- Increase of ANB and mandibular plane angles - Decreased OJ/OB - Lingual tipping upper incisors - Buccal tipping lower incisors reasons to - Increased LAFH STOP - Widening of lower arch treatment - Mesialization of posterior teeth - Condylar changes*

Souki et al., 2017

*Similar to changes in growing patients. May be favorable, may be a side effect.

ortho

TREATMENT OPTIONS

Extraction or headgear can be etiology of OSA?

NO SCIENTIFIC EVIDENCE

Behrents et al., 2019

TREATMENT OPTIONS ortho ortho-sx

referral

change lifestyle

ortho-sx

TREATMENT OPTIONS

Mohsenin et al., 2003; Pereira, 2007; Suguimoto et al., 2013

CONCLUSION skeletal

soft tissue

lifestyle

CONCLUSION Etiology involves multiple factors

Multidisciplinary treatment

ORTHODONTIST is an adjunct

CONCLUSION

ORTHODONTIST Initial screening

Palatal Expander

Questionnaire Imaging Clinical examination

As orthodontically indicated

MD Adv Device As orthodontically indicated Long-term use

“recommended only when there is an appropriate underlying skeletal condition”

Behrents et al., 2019

REFERENCES Alessandri-Bonetti A, Bortolotti F, Moreno-Hay I, Michelotti A, Cordaro M, Alessandri-Bonetti G, Okeson JP. Effects of mandibular advancement device for obstructive sleep apnea on temporomandibular disorder: a systematic review and meta-analysis. Sleep Medicine Reviews. 2019;48:1-10. Alessandri-Bonetti A, Lobbezoo F, Mangino G, Gallenzi P. Obstructive sleep apnea treatment involves temporomandibular disorder pain. Sleep and Breathing. 2024; 28:203-209. Attia AAMM, Awad SS, Mansour M, Baz H, Zahran KM, Saleh AM. Effects of different treatments for obstructive sleep apnea on temporomandibular joint: a randomized clinical trial. BMC Oral Health. 2024; 24:931. Behrents RG, Shelgikar AV, Conley RS, Flores-Mir C, Hans M, Levine M, McNamara JA, Palomo JM, Pliska B, Stockstill JW, Wise J, Murphy S, Nagel NJ, Hittner J. Obstructive sleep apnea and orthodontics: An American Association of Orthodontists White Paper. Am J Orthod Dentofacial Orthop. 2019 Jul;156(1):13-28.e1. doi: 10.1016/j.ajodo.2019.04.009. PMID: 31256826. Brunetto DP, Moschik CE, Dominguez-Mompell R, Jaria E, Sant’Anna EF, Moon W. Mini-implant assisted rapid palatal expansion (MARPE) effects on adult obstructive sleep apnea (OSA) and quality of life: a multi-center prospective controlled trial. Prog Orthod. 2022;23:3. Chen H, Lowe A. Updates in oral appliance therapy for snoring and obstructive sleep apnea. Sleep Breath. 2013;17:473-486. Carlson C, Sung J, McComb RW, Machado AW, Moon W. Microimplant-assisted rapid palatal expansion appliance to orthopedically correct transverse maxillary deficiency in an adult. Am J Orthod Dentofacial Orthop. 2016 May;149(5):716-28. Finck NS, Pacheco MCT, de Araujo MTM. Association of clinical indicators in TMJ, craniofacial , occlusal, and upper airway changes with symptoms of pediatric obstructive sleep apnea and mouth-breathing. J Cranio and sleep practice. 2024. 24;1-7. Galeotti A, Gatto R, Caruso S, Piga S, Maldonato W, Sitzia E, Viarani V, Bompiani G, Aristei F, Marzo G, Festa P. Effects of rapid palatal expansion on the upper airway space in children with obstructive sleep apnea (OSA): a case-control study. Children. 2023;10:244.

REFERENCES Hamada T, Ono T, Otsuka R, Honda E, Harada K, Kurabayashi T, Ohyama K. Mandibular distraction osteogenesis in a skeletal Class II patient with obstructive sleep apnea. Am J Orthod Dentofac Orthop 2007; 131:415-25. Hoffstein V. Review of oral appliances for treatment of sleep-disordered breathing. Sleep Breath 2007;11:1-22. Howard J. Temporomandibular joint disorders in children. Dent clinic N Am. 2013;57:99-127. Knappe SW, Bakke M, Svanholt P, Peterson A, Sonnesen L. Long-term side effects on the temporomandibular joints and pro-facial function in patents with obstructive sleep apnoea treated with a mandibular advancement device. J Oral Rehab. 2017;44:354-362. Langaliya A, Alam MK, Hedge U, Panakaje MS, Cervino G, Minervini G. Occurence of temporomandibular disorders among patients undergoing treatment for obstructive sleep apnea syndrome (OSAS) using mandibular advancement device (MAD): a systematic review conducted according to PRISMA guidelines and the Cochrane handbook for systematic reviews of interventions. Maniaci A, Lavalle S, Anzalone R, Lo Giudive A, Cocuzza S, Parisi FM, Torrise F, Iannella G, Sireci F, Fadda G, Letning M, Masiello E, La Via L. Oral health implications of obstructive sleep apnea: a literature review. Biomedicines. 2024;12:1382. Miranda F, Garib D, Pugliese F, Bastos JCC, Janson G, Palomo JM. Upper airway changes in Class III patients using miniscrew-anchored maxillary protraction with hybrid and hyrax expanders: a randomized controlled trial. Clin Oral Inv (2022) 26:183–195. Mohsenin N, Mostofi MT, Mohsenin V. The role of oral appliances in treating obstructive sleep apnea. JADA 2003;134:442-449. Nikolopoulou M, Aarab G, Ahlberg J, Hamburger HL, de Lange J, Lobbezoo F. Oral appliance therapy versus nasal continuous positive airway pressure in obstructive sleep apnea: a randomized, placebo-controlled trial on temporomandibular side-effects. Clinical Exp Dent Red. 2020;6:400-406/

REFERENCES Pantin CC, Hillman DR, Tennant M. Dental side effects of an oral device to treat snoring and obstructive sleep apnea. SLEEP. 1999;22(2):237-240 Passos, UL. Avaliação da faringe de pacientes portadores de apneia obstrutiva do sono, por meio da tomografia computadorizada multislice obtida em vigília e durante o sono. 2011. Tese (Doutorado em Radiologia) - Faculdade de Medicina, Universidade de São Paulo, São Paulo, 2011. Pereira A, Gurgel M, Pereira R, Dal Fabbro C, Silva, PB, Costa F, Leite L, Mro A, Cevidanes L, Maia Jr C. Evaluation of condylar and mandibular movements on the upper airway during the use of mandibular advancement device for obstructive sleep apnea treatment. Clin Oral Inv. 2024;28:122 Pereira A. Síndrome da Apneia Obstrutiva do Sono. Fisiopatologia, epidemiologia, consequências, diagnóstico e tratamento. Arquimed 2007;21(5/6):159-73. Robertson C, Herbison P, Harkness M. Dental and occlusal changes during mandibular advancement splint therapy in sleep disordered patients. Eur J Orthod. 2003;25(4):371-6. Rose EC, Staats R, Lehner M, Jonas IE. Cephalometric analysis in patients with obstructive sleep apnea. Part I: diagnostic value. J Orofac Orthop. 2002;63(2):143-53. Togeiro SMGP, Martins AB, Tufik S. Síndrome da apnéia obstrutiva do sono: abordagem clínica. Rev Bras Hipertens. 2005;12(3):147-152. Yamamoto S, Harata S, Miyoshi T, Nakamura N, Sakamoto Y, Murata M, Soutome S, Umeda M. Semi-fixed versus fixed oral appliance therapy for obstructive sleep apnea: a randomized crossover pilot study. J Dent Sc. 2021;16:404-409. Yoon A, Abdelwahab M, Bockow R, Vakili A, Lovell K, Chang I, Ganguly R, Liu SYC, Kushida C, Hong C. Impact of rapid palatal expansion on the size of adenoids and tonsils in children.Sleep Med. 2022;92:96-102.

for y

r attention!

msyatabe@umich.edu

ank y

Central disorders of hypersomnolence in children Suresh Kotagal, M.D. Professor Emeritus, Department of Neurology Mayo Clinic, Rochester, Minnesota

Conflicts of Interest 1. I do not have any potential conflicts of interest to disclose, OR x

2. I wish to disclose the following potential conflicts of interest:

Type of Potential Conflict

Details of Potential Conflict

Grant/Research Support Consultant

UpToDate

Speakers’ Bureaus Financial support Other 3. The material presented in this lecture has no relationship with any of these potential conflicts, OR x

4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture: Maski K, Kotagal S. Clinical features and diagnosis of narcolepsy. www.uptodate.com, 2025

Learning objectives • To describe the central disorders of sleepiness in childhood from the standpoint of management strategies, pearls and pitfalls • To discuss where the management might be headed in these entities in the near future

Introduction

Excessive Daytime Sleepiness • Overwhelming sleepiness despite receiving adequate sleep time at night • Sleep attacks are more prone to occur while sedentary • The sleepiness interferes with function of the ventro-lateral prefrontal cortex, with consequent: impaired executive function and mood swings

What are the central sleepiness disorders? • Narcolepsy type 1 (narcolepsy with cataplexy) – sleep onset REM periods • Narcolepsy type 2 (narcolepsy without cataplexy) – sleep onset REM periods • Idiopathic hypersomnia – no sleep onset REM periods • Kleine Levin syndrome – periodic hypersomnia

How prevalent is excessive sleepiness in children? Liu Y et a, Sleep Medicine 2019; 53: 1-8 Based on Pediatric Daytime Sleepiness Scale score of > 18 / 32

MALE

STAGE 1

STAGE 2

STAGE 3

STAGE 4

STAGE 5

N=1971

N=949

N=1388

N=2413

N=652

18.6%

19.9%

25.6%

28.7%

37.9%

21.7%

32.7%

42.6%

51.7%

FEMALE 21%

One third of narcolepsy patients have onset of symptoms before age 15; based on a meta-analysis Challamel M-J, et al. Sleep 1994

The manifestations of sleepiness in children can be subtle • Pre-school age: hyperactive • School age: mistaken as lazy, unmotivated or inattentive • Teens: Feelings of sadness, mood swings, inattention

Lag between symptom onset and clinical diagnosis in narcolepsy Maski K, et al. J Clin Sleep Med, 2017: a survey of 1451 patients

DIAGNOSTIC DELAY OF OVER 10 YEARS 45 40 35 30 25 20 15 10 5 0

< 17 YEARS

18.3 YEARS

> 35 YEARS

Pediatric Daytime Sleepiness Scale

Drake et al. Sleep 2003; 26(4): 455 8 items, maximum score 32; some sample items below How often do you fall asleep or get drowsy during class periods? Always

frequently

sometimes

seldom

never

sometimes

seldom

never

sometimes

seldom

never

seldom

never

sometimes

seldom

never

How often do you get sleepy or drowsy while doing homework? Always

frequently

* Are you usually alert most of the day? Always

frequently

How often are you ever tired and grumpy during the day? Always

frequently

sometimes

How often do you have trouble getting out of the bed in the morning? Always

frequently

Scoring 4

* Reverse score this item 3

Scores in healthy 6-8th graders: 50th percentile = 16, 90th percentile = 23

Epworth Sleepiness Scale – Children and Adolescents (ESS-CHAD; Johns, 2015) Over the last month, how likely have you been to fall asleep while doing the things described below? 0= would never fall asleep; 1= slight chance of falling asleep; 2= moderate chance of falling asleep;3= high chance of falling asleep

Activity Sitting and reading Sitting and watching TV or a video Internal Consistency on Cronbach α > 0.75

Sitting in a classroom during the morning Sitting and riding in a car/ bus for about half an hour Lying down to rest or nap in the afternoon Sitting and talking to someone Sitting quietly by yourself after lunch Sitting and eating a meal

Chance of falling asleep (0-3)

Does Sleepiness Impact Memory ?

encoding

Wakefulness retrieval

consolidation

Sleep

Video clip of cataplexy- age 12

Narcolepsy subtypes:

International Classification of Sleep Disorders III; 2014 Type 1 •

Cataplexy

•

Sleepiness

•

Disturbed night sleep

•

Hypnagogic hallucinations

• •

Sleep paralysis CSF orexin (hypocretin) is low (< 110 pg/ml) Nocturnal

•

Type 2 • No cataplexy • Sleepiness • Disturbed night sleep • Hypnagogic hallucinations • Sleep paralysis • CSF orexin (hypocretin) is low normal (110-400 pg/ml)

Narcolepsy in pre-school age children • Sleepiness could be mistaken for physiological napping • Mood swings and hyperactivity are common • Cataplexy is subtle, may be restricted to facial and neck muscles • NT1 is more prevalent than NT2

Video clip of 3-year old

Secondary narcolepsy

Disorders Norrie disease Niemann Pick Type C Prader Will syndrome Head Trauma Tumor Encephalitis

MRI head scan, T2-weighted coronal image, post-craniopharyngioma resection, showing bilateral hypothalamic lesions, R > L

II. Pathogenesis of narcolepsy

Von Economo and Encephalitis Lethargica “SLEEP AS A PROBLEM OF LOCALIZATION” Baron Constantin von Economo 1876 - 1931 Paper read before the College of Physicians and Surgeons Columbia University New York, Dec. 3, 1929 Anterior hypothalamic lesions: insomnia Dorsolateral hypothalamic and rostral midbrain lesions: hypersomnia

Components of the Hypocretin (Orexin) System Saper CB, et al. Trends in Neuroscience 2001; 24(12): 726

Arousal component Arousal and REM modulating component

CTX, cortex; TMN, tuberomammillary nucleus; LC, locus coeruleus; LDT, laterodorsal tegmentum; PPT, pedunculopontine tegmentum

Nature, September 19, 2018 T-cell library method, suitable for detecting rare antigen specific and autoreactive T-cells 16 NT-1/NT2 and 14 control subjects Autoreactive, hypocretin-specific CD4+ T-cells all narcolepsy patients T-cells were polyclonal, and reactive against multiple epitopes Present in blood of NT1 patients, even years after disease onset Autoreactive CD8+ T cells also present in 8/13, have the potential to directly kill HCRT neurons

Pathogenesis

Narcolepsy Influx of hypocretin reactive CD8+ T-cells, leading to hypocretin cell loss

Genetic susceptibility (HLA DQB1*0602)

Local inflammation: increased TNF α, interferon ɤ, IL2

Challenges to the immune system

Activation of CD4+ reactive Tcells

Gotter AL, et al. Pharmacol Rev, 2012

Wang C, et al. Front Mol Neurosci 2018

III. Diagnostic tests in hypersomnia disorders

Common diagnostic tests. 1 1. Sleep-wake questionnaires: Pediatric Daytime Sleepiness Scale or Epworth Sleepiness Scale – Children and Adolescents (ESS-CHAD) 2. Sleep logs and actigraphy: to ensure that the child is falling asleep at a physiologically appropriate bedtime, awakening at an appropriate hour, and receiving an adequate amount of sleep at night; daytime napping? sleep hygiene issues? 3. Medications: that might impact sleep or alertness

Common diagnostic tests. 2 Nocturnal polysomnogram: a. Sleep onset REM periods b. Disturbed night sleep (DNS) c. Sleep pathology that might explain sleepiness, e.g. OSA Multiple sleep latency test: a. Speed of sleep-onset during 4-5 planned daytime naps b. Presence of sleep-onset REM periods

Patient with narcolepsy: Hypnogram showing some typical features

Sleep onset REM

Sleep to wake transitions increased

SOREMP: defined as REM sleep within 15 min of sleep onset Nocturnal polysomnography – EEG, eye movements, chin EMG, leg EMG, Respiratory effort, ECG, oxygen saturation and EtCO2 are monitored; Meds: none

REM Sleep Without Atonia

60 seconds page view

Less common investigations • Histocompatibility antigen (HLA) typing - over 95% of NT1 patients are positive for HLA DQB1*0602 • Head MRI scan – in secondary narcolepsy • Lumbar puncture under anesthesia – for hypocretin (orexin) testing • Screens for depression / psychological consultation

Audience Response Question 1 CSF orexin level is: A. low in narcolepsy type 2 B. low in narcolepsy type 1 C. a clue to an underlying autoimmune disorder D. impacted by concurrent antidepressant use

Answer to Audience Response Question 1: Correct answer is B: CSF orexin is low in narcolepsy type 1

CSF Hypocretin (Orexin) Levels In Disorders With Hypersomnia Basetti C et al; Sleep Medicine 2003;4:7

500

Idiopathic Hypersomnia

400 300 pg/ml 200

Hypersomnia, psychiatric Narcolepsy type 2

Hypersomnia, other

Narcolepsy type 1

100 0

CSF hypocretin (orexin) analysis is most useful when patient is receiving psychotropic medications that cannot be safely stopped for PSG and MSLT, and when age is < 5 years

Narcolepsy: Comorbidities

• Obesity around onset of sleepiness • Not from meds • Knockout mouse model also obese • Related to hypocretin deficiency? • Also, precocious puberty

Olmsted county cohort, followed between 2000-2014, average of 9.9 years

Disorder

Odds ratio (95% CI)

Obstructive sleep apnea

13.5 (5.08-36.14)

Chronic low back pain

2.58 (95% CI 1.39-4.77)

Depression

3.79 ( 95% CI 2.12-6.79)

Endocrinopathies

2.45 (1.33-4.49)

Obesity

2.07 (1.15-3.7)

Idiopathic hypersomnia (IH) • Long sleep duration, often > 10 hours, or 24-hour total sleep is > 11 hours on PSG or actigraphy

• • • • • •

Debilitating sleepiness, but no sleep – onset REM, and no cataplexy Naps are longer than in narcolepsy, but are unrefreshing CSF orexin may be slightly low, but not to the level of NT1 Sleep inertia is prominent In children, IH may be an early stage in evolution of narcolepsy Key issues are managing sleepiness and sleep inertia: sleep hygiene, low-sodium oxybate

Audience Response Question 2 Similarities between narcolepsy type 2 and idiopathic hypersomnia (IH) include the following, except: A. disabling chronic daytime sleepiness B. mean sleep latencies on the multiple sleep latency test of < 8 minutes C. a modestly favorable response to wakefulnesspromoting medicines D. lack of 2 or more sleep-onset REM periods in IH

Correct Answer ARS 2 D. IH subjects do not display 2 or more sleep-onset REM periods on the MSLT

Management of Hypersomnia disorders

Key Concepts • The diagnosis of narcolepsy has to be unequivocal • The patient and family are informed that it is life-long • Counseling - family • Adaptations at school: late start, planned naps, extra time for major standardized tests

• Sleep hygiene (regular s-w schedules, exercise, hydration, no alcohol) • Avoid driving for more than short distances • Choice of occupation

Gotter AL, et al. Pharmacol Rev, 2012

Enhancing dopamine Amphetamines Methylphenidate Modafinil / armodafinil Solriamfetol

Daytime sleepiness

Enhancing noradrenaline Solriamfetol, clomipramine Enhancing histamine Pitolisant Enhancing orexin receptors Oveporexton; Others in clinical trials

Drugs for Excessive Sleepiness Drug

Mechanism of action

Level of Evidence

Modafinil

Dopamine reuptake inhibitor

I, II

Armodafinil

Dopamine reuptake inhibitor

Methylphenidate

Increased DA transmission presynaptically, inhibitor of DA uptake > NE uptake by DAT

II, IV

Dextroamphetamine

Increased DA transmission presynaptically, inhibitor of DA uptake > NE uptake by DAT

II, IV

Pitolisant*

Histamine H3 inverse agonist

I - adults

Solriamfetol

DA and norepinephrine reuptake inhibitor

Low sodium oxybate – for idiopathic hypersomnia, or when there is hypertension * Targets both sleepiness and cataplexy

Drugs for Cataplexy Drug

Mechanism of action

Level of Evidence

Sodium oxybate / * Low sodium oxybate * Once nightly oxybate *

GABAA or GABAB agonist?

I, IV

Venlafaxine

5HT> NE reuptake inhibitor

Atomoxetine

Selective NE inhibitor

Fluoxetine, sertraline

Serotonin reuptake inhibitor

Protryptiline, clomipramine

Monoamine uptake blocker

Pitolisant *

Histamine H3 inverse agonist

* Targets both sleepiness and cataplexy

Pitolisant

• A selective H3 receptor agonist • Activates H3 receptors at the level of the tubero-mamillary nucleus, anterior cerebral cortex, hippocampus, amygdala • Histamine activates dopamine, norepinephrine and glutamate receptors • Now approved in Europe and US for children > 6 years for treating sleepiness and cataplexy of narcolepsy

What is around the corner…

Oral orexin receptor-2 selective agonists Takeda Pharmaceuticals • OVEPOREXTON ® [TAK-861-2001] • Dauvilliers Y, et al. NEJM 2025; 392: 1905-16 • Phase 2 RCT involving 90 NT1 adults; subjects received study drug (0.5 mg bid/ 2mg bid/ 2 + 5 mg daily / 7 mg once daily / or placebo for 8 weeks

• Mean MWT scores were 12.5, 23.5, 25.4, 15 and – 1.2 minutes respectively • Mean ESS scores were -8.9, - 13.8, -12.8, - 11.3 and -2.5 minutes respectively • Mean weekly cataplexy incidence was 4.24, 3.14, 2.48, 5.89, and 8.76 respectively

• Most common adverse events were insomnia (48%), urinary urgency (33%) and urinary frequency (32%)

Oral orexin receptor-2 selective agonists Alkermes Pharmaceuticals: Vibrance 2 study, ALKS 2680 Recruiting NT1, NT2 and IH Centessa Pharmaceuticals: ORX 750 Recruiting NT1, NT2, and IH subjects

Can AI Accelerate the Diagnosis of Narcolepsy? Present, without AI Sleepiness is recognized by PCP after months to years

Future, with AI Media blitz; Increased awareness of narcolepsy in parents and PCP

Evaluation by sleep specialist takes another several months to years

Based on history, PCP orders overnight ambulatory polysomnogram (EEG, eye movements, EMG, respiration, etc.)

PSG and MSLT score sleep stages sequentially

Sleep is automatically scored for entire night in 3-second bins using machine learning

Takes several weeks to get the results

Diagnosis established by PCP MSLT no longer needed

Dx confirmed after several months to years Valuable time for early intervention is lost

Sleep specialist confirms Dx, and initiates management

Patient with narcolepsy: Hypnogram showing some typical features

Sleep onset REM

Sleep to wake transitions increased

Stephanson JB et al. Probability distribution of sleep stages. Nature Communications, 2018

Black = REM sleep Light blue = N1 sleep Deep blue N2 White = Wakefulness

Early detection of specific hypersomnia disorder will hopefully enable early recognition and management of co-morbidities.. Obesity, anxiety, depression, sleep apnea, etc.

Thank You! Kotagal.suresh@mayo.edu

Recovering from Stroke: Does Healthy Sleep Help? Championship Updates in Sleep Medicine Sept 11, 2025 Devin L. Brown, MD, MS University of Michigan

Conflicts of Interest 1. I do not have any potential conflicts of interest to disclose, OR x

2. I wish to disclose the following potential conflicts of interest: Type of Potential Conflict

Details of Potential Conflict

Grant/Research Support

NIH

Consultant Speakers’ Bureaus Financial support Other x

M-PI of an NIH-funded project that receives materials support from ResMed and Fisher & Paykel, through the University of Washington

Summary of prevalences Acute (%, 95% CI)

Subacute (%, 95% CI)

Chronic (%, 95% CI)

Mild

67 (64, 70)

66 (59, 72)

66 (59, 73)

Mod

50 (42, 59)

44 (36, 53)

33 (25, 43)

Severe

32 (25, 39)

36 (22, 53)

25 (11, 48)

Insomnia Periodic leg movements of sleep (PLMS)

41 (32, 50)

43 (32, 54)

36 (29, 44)

32 (7, 74)

27 (12, 52)

48 (33, 64)

Restless leg syndrome (RLS)

10 (6, 16)

OSA

Hasan et al. Stroke. 2021;52:655–663.

14 (2, 52)

Prevalence after ischemic stroke, TIA, ICH Cutpoint

% (95% CI)

AHI >5

71 (21.7, 31.2)

Primarily Central SA

12 (5.5, 23.4)

Seiler A, et al. Neurology 2019; 92:e648-e654.

OSA risk factor for incident stroke

Li, et al. Int J Cardiol. 2014;172:466-9

Why might sleep apnea be important in brain recovery?

Intermediate consequences • Oxygen levels in blood decrease • Sleep fragmentation – microarousals • Sympathetic nervous system activation • Inflammation • Blood pressure fluctuations

How does sleep apnea relate to stroke outcomes?

Mortality OSA (AHI ≥15) Adjusted HR 1.76 (1.05, 2.95) OSA

Central SA (AHI ≥15) Adjusted HR 1.07 (0.651.76)

Adjusted for: age, sex, BMI, smoking, HTN, diabetes, AF, MMSE, Barthel ADLs. Sahlin et al. Arch Intern Med. 2008;168:297-301

OSA and dependency • Logistic regression for dependency: – RDI OR 1.06 (1.01, 1.11), p=0.009 • Adjusted for stroke subtype, GCS, limb weakness, age, history of stroke, BMI, neck circumference, hypertension, diabetes

Turkington et al. Thorax 2004; 59: 367-371.

Brain Attack Surveillance in Corpus Christi Project (BASIC) • Population-based stroke surveillance in Nueces County, Texas • All cases of stroke, active/passive surveillance, age ≥ 45 • Validated by stroke fellowship-trained study physicians

• Baseline interview; outcome assessments

Methods: BASIC-Sleep apnea projects • Starting in 2010 • Sleep apnea assessments within 30 days • Home sleep apnea test – Validated portable cardiorespiratory monitor – Raw data edited by registered polysomnographic technologist

• Sleep apnea definition: REI ≥ 10

Hispanic vs non-Hispanic white stroke patients, n=549

Lisabeth LD, et al. Sleep Med. 2017;33:97-102

No association between SDB presence (REI>=10) or SDB severity (REI) with stroke subtype

Brown DL, et al. J Stroke Cerebrovas Dis 2015; 24:388-393

Brainstem infarction • 355 ischemic stroke

Brown, et al., Sleep Med 2014, 15: 887-891

Centrals • • • •

1,346 participants Median CAI 0 (IQR: 0,2) CAI≥5/h and CAI ≥ 50%: 1.4% Associated with: male, severe SA, normal/overweigh (rather than obese)

Schütz et al. Sleep Med 2021; 77: 304-306

Associated with functional and cognitive outcomes ADL/IADL Range (1 to 4) Mean Difference (95% CI)

SDB (REI ≥ 10, yes vs no)

0.15 (0.01 ,0.28)

3MS Range 0 to 100

NIHSS Range 1 to 42

SS-QOL Range 1 to 5

Mean Difference (95% CI)

Relative Difference* (95% CI)

Mean Difference (95% CI)

-2.66 (-4.85 ,-0.47)

1.11 (0.94 ,1.31)

-0.09 (-0.23 ,0.06)

*Models adjusted for socio-demographics (age, sex, ethnicity, education, marital status), pre-stroke functional disability (mRS) and cognitive impairment (IQCODE), health-risk behaviors (alcohol intake and smoking), initial NIHSS, treatment with tPA, and vascular risk factors (body mass index, atrial fibrillation, coronary artery disease, diabetes, hypertension, high cholesterol, history of stroke/TIA).

Lisabeth et al. Ann Neurol 2019;86:241–250

Recurrent ischemic stroke Parameter

REI Mexican American Age Female Body mass index Diabetes Hypertension NIHSS

1.02

Brown DL, et al. Stroke. 2019;50:571-576

Lower CI

Upper CI

1.01

1.03

<0.01

1.02 1.31 0.99 1.34 1.00 1.24 0.98 0.96

Lower CI

Upper CI

1.01 0.80 0.97 0.86 0.97 0.78 0.53 0.91

1.03 2.14 1.01 2.11 1.04 1.98 1.84 1.01

P <0.01 0.29 0.50 0.20 0.99 0.36 0.96 0.08

10-yr trends in post-stroke OSA prevalence

Schütz et al. J Am Heart Assoc. 2022;11:e024169.

Adjusted trends

When does size matter?

Infarction size/stroke severity • AHI ≥10 vs AHI <10 not related to infarction volume (p=0.32) • Stroke severity not different between those with and without sleep apnea

Iranzo, et al. Neurology 2002;58:911–916; Bassetti et al. Stroke 2006;37:967-972

Palatal length

Thickness, retropalatal distance

Lat pharyng wall thickness Brown et al. Sleep Med. 2010;11:540-4.

High retropharyngeal

Tongue/retroglo

Nasopharyngeal area

Detection

Questionnaire

Systematic review of clinical prediction models • Epworth, Berlin, STOP-BANG, other clinical models • 2837 participants in 11 studies • area under the curve (AUC) ranging from 0.68 to 0.83 and specificity from 28 to 71.9%

Yang et al. Systematic Reviews (2024) 13:38

What if we throw some machine learning at it?! • n=1,330 • The machine learning algorithm with the highest AUCs (Distributed Random Forest model) for SDB (REI≥10): • 0.75 • Logistic regression • 0.70

Brown et al. Sleep Med 2020; 75:1-6

Why don’t the questionnaires work well?

• Often asymptomatic • Male predominance not as pronounced • BMI not as predictive

Why high prevalence?

Gravity? • Sleep position • Redistribution of fluid

Sleep studies – 30 PSGs Median (IQR) or N (%) AHI

23 (IQR: 6, 47)

Minimal oxygen saturation % OSA

88 (IQR: 82, 91) 22 (73)

Total record time

415 minutes (IQR: 384, 447)

Total sleep time

262 minutes (IQR: 218, 322)

Sleep time supine

209 minutes (IQR: 131, 270)

% time of sleep supine Brown et al. Stroke 2008; 39:2511-2514.

100 (62, 100)

Supine position • N=55, home sleep apnea tests • 60% supine: first 72 hrs of admission (65% positional SA) • 32% supine: in follow-up ~6 months later (33% positional SA)

Dziewas et al., Neurol Res 2008; 30: 645–648.

Nocturnal rostral fluid shifts • Daytime fluid pooling in the legs may be redistributed  pharyngeal narrowing and increased airway collapsibility  worsen OSA • Stroke • Immobility + IVF  more fluid shifts

Nocturnal rostral fluid shifts • Increase neck circ, decrease calf circ, decrease calf volume associated with AHI: • CHF • ESRD • non obese men with sleep apnea • patients with hypertension

Am J Resp Crit Care Med 2009; 179:241-6 Circulation: Heart Failure 2012; 5:467-74 Nephrol Dial Transplant 2012; 27:1569-73 Hypertension 2010; 56:1077-82

Measurements: before and after sleep

• Calf circumference – decrease overnight • Neck circumference – increase overnight • Leg fluid volume – decrease overnight • Bioimpedance spectroscopy

Calf (cm)

Brown, et al. Stroke 2021; 52:3176:3183

Could help explain OSA improvement post-stroke Apnea/hypop Obstructive Central apnea index nea index apnea index Parra 2000 Hui 2002 Martinez-Garcia 2006

Manconi 2014 Huhtakangas 2018 (thrombolysis) Huhtakangas 2018 (no thrombolysis) Harbison 2002 Bassetti 2006 Dziewas 2008

Sample size

Acute

112

3 months

Acute

1 month

2.5

Acute

139

60-90 days

Acute

0.4

3 months

Acute

33.4

5.5

5.2

6 months

31.6

3.6

Acute

25.1

5.8

6 months

25.8

4.1

5.6

Acute

Week 6-9

Acute

152

6 months

Acute

6 months

Country Spain China Spain

Switzerland Finland Finland UK Switzerland Germany

Baseline and follow-up AHI Comparison of acute vs follow-up AHI Acute

Follow-up

Dziewas Bassetti Harbison Huhtakangas (no T) Huhtakangas (T) Manconi M-G Hui Parra 0

AHI

Lisabeth LD, et al. Stroke 2023; 54:2356–2365.

What should we do about it?

Will CPAP help, hurt, or do neither after stroke? • We don’t know • We have no definitive RCT data that any stroke patient outcome will be improved by CPAP. • Randomization to a no CPAP arm has been considered ethical in trials that enroll high risk CVD patients • Examples include the large SAVE, RICCADSA, and CERCAS trials • An NIH-funded trial, APPLES, randomized >1,000 patients with a mean AHI of 40 (severe OSA) to 6 months of no CPAP • Even in the general OSA population, the 2022 US Preventive Task Force reported no established benefit of CPAP for any health outcome aside from excessive daytime sleepiness and a modest improvement in sleep-related and general health-related quality of life. The clinical significance of these changes is uncertain.

Where do things stand in the stroke world?

Kleindorfer DO, et al. Stroke. 2019; 50:e344-e418. Powers WJ, et al. Stroke. 2021; 52:e364–e467.

Where do things stand in the real world? • Corpus Christi, Tx • 2011-2015 • N=981, 89% ischemic • 63% MA • Offered polysomnography by 90d? • 5.6%

• Test completed? • 2.3%

Brown DL, et al. Sleep Med 2019; 59: 90-93

Treatment options

Sleep Apnea Treatment after Stroke (SATS) design • Acute ischemic stroke – within 7 days • Some disability (mRS ≥ 2) • Physiological screening for OSA • Randomize those with OSA (AHI ≥ 5) (n=32) • CPAP vs subtherapeutic (sham) CPAP • 3 months of blinded treatment

Brown et al, J Stroke Cerebrovasc Dis. 2011

Positional therapy

Positional therapy • Proof of concept trial

Night 1

Night 2

• Outcomes:

Positional therapy

Usual care

Positional therapy

• Randomized, controlled, crossover study • Supine time, AHI

• N=18; 14 days of stroke • Portable respiratory monitoring system

Svatikova et al, Sleep Medicine 2011; 12: 262-266.

Raw data Sleep Apnea Study Characteristics

No Positional Therapy

Positional Therapy

Median (IQR)

Supine time, as % of recording

39 (12, 90)

8 (1, 20)

Time supine, minutes

142 (31, 295)

30 (3, 66)

AHI, events/hour

39 (21, 54)

27 (22,47)

Oxygen Desaturation Index

7 (4, 14)

6 (3, 13)

Mean oxygen saturation, %

95 (93, 97)

95 (95, 97)

Svatikova et al, Sleep Medicine 2011; 12: 262-266.

Accounting for repeated measures • Supine sleep %

• Reduced by absolute 36% (95% CI: 18 – 55%, (P<0.001))

• AHI

• Reduced by relative 19.5% (95% CI: 4.9 – 31.9%, (P=0.011))

Svatikova et al, Sleep Medicine 2011; 12: 262-266.

Next in line

EPAP nasal device

EPAP results

Wheeler NC, et al. J Clin Sleep Med 2016; 12: 1233-1238

Why test OSA tx • High prevalence of OSA (not CSA) after stroke • OSA associated with poor outcomes post stroke • OSA tx associated with better outcomes • CPAP safe • CPAP relatively inexpensive

110 sites

Study Overview

• Investigator-initiated, phase 3 multicenter, prospective randomized open-, blindedendpoint (PROBE) controlled trial • 110 sites nationwide – recruitment from acute or rehab hospitalization • ~3,000 subjects randomized; 15,000 subjects screened • Enrollment over 4 years

Prevention (n=3,062)

Sleep SMART is two trials!

• All subjects: ischemic stroke or high-risk TIA within prior 14 days Recovery (n=1,362) • Ischemic stroke within prior 7 days • NIHSS ≥1 at time of enrollment

Flow

Inclusion criteria

• Inpatient at an enrolling site • ≥ 18 years old • Ischemic stroke, or TIA with ABCD²≥4 within the prior 14 days • Prevention analysis: all subjects • Recovery analysis: NIHSS ≥1, consented within 7 days

Exclusion Criteria - general

• Pre-event inability to perform all of own basic ADLs • Unable to obtain informed consent from subject or legally authorized representative • Incarcerated • Known pregnancy

Exclusions – CPAP specific issues

• Current mechanical ventilation (can enroll later if this resolves) or tracheostomy • Current use of PAP, or use within one month prior to stroke

Exclusions – make CPAP riskier • Anatomical or dermatologic anomaly that makes use of CPAP interface unfeasible • Severe bullous lung disease • Prior or current spontaneous pneumothorax • Hypotension requiring current treatment with pressors (can enroll later if this resolves) • Previous or current massive epistaxis • Cranial surgery or head trauma within the past 6 months, with known or possible CSF leak or pneumocephalus • Recent hemicraniectomy or suboccipital craniectomy (i.e. those whose bone has not yet been replaced), or any other recent bone removal procedure for relief of intracranial pressure • Other specific medical circumstances that could, in the opinion of the site PI, render the patient at risk of harm from use of CPAP

Exclusions - unfeasible

• Current receipt of O2 supplementation >4 liters per minute • Current contact, droplet, or respiratory/airborne precautions

Nox T3 • Applied by study coordinator or RT • Scored centrally

Automatically adjusting CPAP

aCPAP arm - adherence • 6 months of aCPAP + guideline concordant care • Assistance with aCPAP by RT during hospitalization • Show subject and caregiver aCPAP training materials • Telemedicine-based care management after discharge • Remote monitoring of use, residual AHI, mask leak • Proactive management and troubleshooting (including send new equipment directly to subject) • technology team • respiratory therapy team • sleep medicine physicians

Study progress • Currently ~100 open sites • Randomized over 1,798 (59%) so far • Prevention aim enrollment paused 6/28/24 • Recovery aim enrollment continues (93%)

Summary • Obstructive sleep apnea is very common after stroke • But central sleep apnea is uncommon!

• If you want to identify sleep apnea, you need to do a physiologic test • Sleep apnea is associated with first and recurrent stroke, post-stroke functional and cognitive outcome, and mortality • We need trials to tell us if treatment helps

Sleep SMART Study Team • Project PIs: Devin Brown, Ronald Chervin • Project managers: Kayla Novitski (UM), Joelle Sickler (UC) • StrokeNet National Data Management Center (NDMC) Project PI: Valerie Durkalski • StrokeNet National Coordinating Center (NCC) PIs: Joseph Broderick, Pooja Khatri • StrokeNet NDMC PIs: Jordan Elm, Catherine Dillon, Wenle Zhao • Event Adjudicators: Darin Zahuranec, Deborah Levine

• Consultants: Craig Anderson, Dawn Bravata, and Klar Yaggi

• Telemedicine partner: Jeff Durmer (formerly of FusionHealth)

• Independent Medical Safety Monitors: Kingman Strohl, Anna May

• Lewis Morgenstern (Co-I)

• NINDS: Scott Janis, Mariam Afzal

• NCC: Iris Davis, Wren Hanson, Jordyn Schultz

• Clinical enrollment sites!

• NDMC: Faria Khattak, Jocelyn Anderson, Emily Philpot Katie Trosclair, Renee Martin, Jessica Griffin, Sherry Livingston, Henry Merryday

• Participants!

BASIC-Sleep apnea study team Devin Brown, PI

Scott Sands, Co-I

Lynda Lisabeth, PI

Azadeh Yadollahi, consultant

Ronald Chervin, Co-I

Virend Somers, consultant

Lewis Morgenstern, Co-I

William Duncker, Andy Gomez, Lauren Potter, Cricel Villanueva, TJ Canto, current sleep study coordinators

Xu Shi, Co-I

Julie Behnke, Garrett Wieland, Janie Murphy, Maria Soto Gamboa, BASIC staff

Garnett Hegeman, RPSGT Erin Case, Mindy Cox, Project Managers

Prior study coordinators:

Emma Sais, Field Office Director

Alexis Enriquez, Andrew Valverde, Pablo Soto

Madeline Kwicklis, Analyst

April Medina, Marty Toscano, Dulce Hernandez, Jose Rojas

Other BASIC stroke case validators: Darin Zahuranec MD, Will Meurer MD, Joe Carrera MD; recent former validators: Lesli Skolarus MD, Jim Burke MD, Eric Adelman MD, Kevin Kerber, MD Special thanks to the patients who participated in this study.

Thank you!

Emerging Non-Medication Treatments for Chronic Insomnia

J. Todd Arnedt, Ph.D. Professor of Psychiatry and Neurology Director, Behavioral Sleep Medicine Program Co-Director, Sleep and Circadian Research Laboratory Michigan Medicine, University of Michigan, Ann Arbor, MI

Conflict of Interest Disclosures for Speakers X

1. I do not have any relationships with any entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients, OR 2. I have the following relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients.

Type of Potential Conflict

Details of Potential Conflict

Grant/Research Support

Oura, Apple, Inc

Consultant

Eisai Inc., Idorsia Pharmaceuticals Ltd, Purdue Pharma L.P.

Speakers’ Bureaus Financial support Other 3. The material presented in this lecture has no relationship with any of these potential conflicts, OR 4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture: 1. 2. 3.

Learning Objectives 1

Describe the need for non-medication approaches for insomnia other than CBT-I

Discuss CBT-I optimization and adjunct/alternative non-medication treatments

Identify clinical considerations and outstanding research questions

Cognitive Behavioral Therapy for Insomnia (CBT-I) is a brief, multicomponent non-medication treatment BEHAVIORAL

Sleep Restriction Stimulus Control Counter-Arousal Strategies

COGNITIVE

Beliefs/Attitudes

TREATMENT TARGETS

Excessive time in bed

Unrealistic sleep expectations

Irregular sleep schedules

Misconceptions about sleep

Sleep incompatible activities

Sleep anticipatory anxiety

Hyperarousal

Poor cognitive coping skills

Adapted from Morin CM.

EDUCATIONAL Sleep Hygiene

TREATMENT TARGETS Inadequate sleep hygiene

CBT-I is beneficial and safe for chronic insomnia with and without comorbid health conditions No other health conditions1

With other health conditions2

Pooled OR = 3.28 (95% CI 2.30 – 4.68, p<.001) 1Trauer JM. Ann Intern Med 2015;163:191-204.

2Wu JQ. JAMA Intern Med 2015; 175(9):1461-72.

Benefits of CBT-I are sustained up to 2 years post-treatment 24 Month Follow-Up

% Change from Pretreatment

30 20 10 0

Wake during the night

-10

Total sleep time

Sleep efficiency

-20 -30

CBT-I

-40

Medication

Morin CM. JAMA 1999;281:991-9.

In head-to head comparisons, CBT-I does better than medication at post-treatment and follow-up. 200

150

Total Wake Time (min)

46 older adults (mean age 60.8 years) with chronic insomnia randomized to 6 weeks of CBT-I, zopiclone, or placebo

Pre-tx Post-tx (6 wks) 6 mos f/u

100 *p<.001

50 0

Placebo Sivertsen B. JAMA 2006;295:2851-8.

CBT-I

Zopiclone 7.5 mg

Only about 50%from of patients treated withinCBT-I meet Remission insomnia occurs fewer criteria post-treatment than 50%for ofremission patients at who receive CBT-I 60

Arnedt 2023 Kalmbach 2022

McCurry 2021

58 54

Drake 2019

Ritterband 2017

Harvey 2014

Blom 2015 Morin 2009

Adherence to CBT-I treatment components is highly variable and relevant to outcomes Definition

Adherence

Participant-reported Sleep Hygiene

76-100%

Relaxation

70%

SR, SCT, CT

30-90%

Diary-measured ±30 mins of prescribed TIB

37.5-100%

% days adherent to prescribed TIB

60-83%

Agnew S. Sleep Med Clin 2021;16:155-202.

Adverse effects from CBT-I are common and contribute to non-adherence and attrition n=11 adults with chronic insomnia disorder

Visual Analogue Scale Score

80 60

Positive mood

Sleepiness/fatigue

Alert cognition

Negative mood

0 Baseline Miller CB. J Sleep Res 2013;22:266-72.

Week 1

Week 2

Week 3

Patient experiences with sleep restriction are frequently negative, especially early in treatment Just my mood and kinda temperament and it affected my every life, I thought, quite badly I feel it’s been really negative so far, and although I can understand it will probably work eventually, at the moment I just feel really bad

Kyle S. Sleep Med 2011;12:735-47.

This regime would be easy to do if you didn’t have a social life, as soon as you’re going out late, it does seem to go to pot a bit

I feel like I am drunk at the moment, my head’s quite swimming, and not thinking very straight at all

I suppose rationally and logically it did seem like a good idea, but then the first week of actually doing it, I felt worse, and so you kinda… think…give up now

Findings from recent network meta-analyses reinforce CBT-I optimization BT and CT increase odds of remission1

1Furukawa Y. JAMA Psychiatry 2024;81(4):357-65. 2Steinmetz L. Clin Psych Rev 2024;114:102507.

SRT and SCT are complementary2

Brief Behavioral Treatment for Insomnia (BBT-I) is less time intensive than CBT-I and can be delivered by non-specialists Session 1 (45-75 minutes, in-person) A.

Healthy sleep practices

Education regarding good sleep hygiene practices

2-process model of sleep regulation

Education regarding the homeostatic and circadian sleep regulatory systems

Four sleep rules

1. 2 3. 4.

Reduce time in bed (TIB) Consistent wake time Go to bed when sleepy Get out of bed after 20 minutes if awake

Session 2 (<20 minutes, via telephone) Check-in

Review self-reported sleep quality, daily sleep-wake diary results, daytime functioning, and recommendation adherence

Session 3 (30 minutes, in-person) A.

Check-in

Review self-reported progress, sleep-wake diary results, and address challenges with treatment implementation

Sleep schedule titration

Adjust sleep schedule based on patient progress: • •

Increase TIB by 15 minutes if sleep onset latency (SOL) and wake after sleep onset (WASO) <30 minutes Decrease TIB by 15 minutes if SOL and WASO <30 minutes

Session 4 (<20 minutes, via telephone) A.

Check-in

Review self-reported progress, sleep-wake diary results, and address challenges with treatment implementation; Titrate TIB further

Relapse Prevention

Anticipate triggers for insomnia recurrence and strategies for managing sleep; Review TIB titration recommendations

Adapted from Gunn HE. Sleep Med Clin 2019;14:235-43.

BBT-I improves remission/response rates among older adults with chronic insomnia

% Participants

70 60

n=79 older adults with chronic insomnia

BBTI

IC X2=16.9, p<.001 X2=16.9, p<.001

50 40 30 20 10 0

Remission

Response

Buysse DJ. Arch Intern Med 2011;171(10):887-895.

Partial Response

No Response

Meta-analyses support the benefits of BBT-I in diverse patient populations In older adults2

At post-treatment and follow-up1

-20.7 min

d=1.1

+7.4% d=1.0

-20.1 min 1Kwon M. Behav Sleep Med 2022;20:674-94. 2Chen Y-C. Age Aging 2023; 52(1).

“Single-Shot” CBT-I improves acute insomnia symptoms more than wait list control 60

n=40 adults with acute insomnia

CBT-I Control

WASO

100 90 80

SOL

0 Baseline

Ellis JG. Sleep 2015;38(6):971-8.

Follow-up

Percentage

Minutes awake

Alternative and/or adjunctive treatments to CBT-I have been developed

Intensive Sleep Retraining (ISR)

Mindfulness

Acceptance and Commitment Therapy (ACT)

Intensive Sleep Retraining (ISR) is a laboratory-based treatment that re-trains patients how to fall asleep

Lack L. Sleep Med Clin 2019;14:245-52.

ISR provides patients with multiple fall asleep opportunities over a night of sleep deprivation Original Procedure

Current Procedure

Pre-treatment Instructions

None

Restrict TIB to 5 h the night prior

Start Time

2 h prior to bedtime

2300 hours

# of Sleep Onset Trials

50 (1 trial every 30 minutes) over ~24 hours

40 (~5 min break in-between each trial) over ≥12 hours

Duration of Sleep

2-3 minutes

Post-treatment Procedures

Stay awake the following day, then Stay awake the following day, then recovery sleep of 8 h maximum ad-libitum recovery sleep

Adapted from Scott H. J Sleep Res 2023;32:e13894.

ISR reduces sleep onset across the night and improves insomnia symptoms at post-treatment and follow-up

PSQI Score

Pre-tx

Post-tx

p<.001

ISR

SCT

Follow-up

Harris J. Sleep 2012;35(1):49-60.

CTRL

THIM: A wearable sleep tracking ring that accurately detects sleep onset to enable clinical implementation

Mean=0.36 mins diff

Mean=0.50 mins diff

n=20 healthy participants, 10 of whom had insomnia symptoms (ISI ≥ 7)

https://wt-obk.wearable-technologies.com. Scott H. J Clin Sleep Med 2021;17(5):973-81.

AWARENESS NON-ATTACHMENT SELF-COMPASSION

Mindfulness approaches are guided by a metacognitive model of insomnia Rigidity

Secondary Arousal

Metacognitions Absorption

Attachment Bias

Hyper-Arousal Cognitions Sleep expectations

Primary Arousal

Consequences of sleep loss Ong JC. Behav Res Ther 2012;50:651-60.

Increased mental activity in bed

Mindfulness-based Therapy for Insomnia (MBTI) follows three primary principles Awareness

Metacognitive Shift

Adopting a Mindful Stance

Of physical and emotional states (are you sleepy?)

Practice nonattachment to the need for sleep

Allow internal cues to regulate sleep behavior

Courtesy of Jason Ong, PhD

Session

Sample 8-session protocol of MBTI Theme

Key Activities

Introduction/program overview

Introduce concepts of mindfulness and model of insomnia; lead participants through first formal mindful practice

Stepping out of automatic pilot

Begin formal meditation and inquiry; discuss relevance of meditation for insomnia; Introduce Sleep Hygiene (SH)

Paying attention to sleepiness and wakefulness

Discuss sleepiness, fatigue, and wakefulness; Introduce Sleep Restriction (SR)

Working with sleeplessness at night

Review/adjust sleep restriction; Introduce Stimulus Control (SCT)

The territory of insomnia

Acceptance and letting go

Sleeping with the enemy: relationship with sleep

Discuss relationship with sleep (reactions to good and bad nights); informal meditations during everyday life

Eating, breathing, and sleeping mindfulness

Set up an action plan for the future; discuss ways to continue mindfulness meditation beyond this program

Ong JC. Mindfulness-Based Therapy for Insomnia 2016. Ong J. J Clin Psychol 2010;66(11):1175-84.

Discuss model for the territory of insomnia (both daytime and nighttime symptoms) Explain the relevance of acceptance and letting go for working with the territory of insomnia

MBTI reduces pre-sleep arousal and improves insomnia symptoms more than MBSR Pre-Sleep Arousal Scale

Ong J. Sleep 2014;37(9):1553-63.

Insomnia Severity Index

Ong J. Current Opinion in Psychology 2020;34:18-22.

Acceptance and Commitment Therapy (ACT) is a third-wave psychotherapy that promotes openness and acceptance to psychological events • Goals are to increase psychological flexibility and promote value-congruent behavior • In contrast to CBT, ACT proposes that attempting to control experiences, not experiences per se, cause symptoms • ACT aims to change relationship with thoughts/emotions and emphasize function • Consists of 6 interconnected domains that are targeted during treatment Saldaña KS. Sleep Med Clin 2023;18:73-83. https://positivepsychology.com/act-model/.

Sample outline of sessions contrasting CBT-I and ACT-I CBT-I

ACT-I

Sleep education; Introduce SH

Introduce SCT and SH; Identify values to foster acceptance of discomfort related to insomnia; Introduce Mindfulness

Introduce SR/SCT

Sleep education; Introduce SR; Mindfulness practice

Continue SR/SCT; Introduce CT

Cognitive defusion and self as context; Mindfulness practice; Continue SR/SCT

Continue SR/SCT/CT; Introduce Relaxation

Review cognitive defusion/self as context; Continue SR/SCT; Mindfulness practice

5-8

Continue SR/SCT/CT/Relax; Relapse prevention

Continue SR/SCT/Mindfulness practice; Relapse prevention

Session

Adapted from Saldaña KS. Sleep Med Clin 2023;18:73-83.

If I don’t fall asleep soon, I won’t be able to function tomorrow!

CBT-I Identify the thought (Check)

What, when, where does thought arise? What are the associated feelings/behavior?

Challenge the thought (Challenge)

Apply cognitive restructuring techniques (e.g., weigh the evidence)

Develop an adaptive thought (Change)

Develop a more helpful thought and identify how it impacts feelings/behavior

Adapted from Saldaña KS. Sleep Med Clin 2023;18:73-83.

ACT-I

Leaves on a stream

Visualize thoughts on leaves in a stream to defuse thought from self

Physicalizing Visualization Exercise

Visualize insomnia symptoms outside body to emphasize the patient is larger than thought

Clean vs. dirty discomfort

Distinguish “clean” (“I am having trouble falling asleep”) from “dirty” (“I won’t be able to do my job tomorrow”) discomfort

Take your mind for a walk

Listen to mind talking to them and notice feelings that follow

ACT-I significantly improves insomnia symptoms and is non-inferior to CBT-I on some sleep parameters 28

ISI Score

24 20

Pre-tx *** ***

Post-tx *** ***

ACT-I (n=76)

CBT-I (n=76)

6-mo F/U ***p<.001

16 12 8 4 0

WLC (n=75)

El Rafihi-Ferreira RJ. J Consult Clin Psychol 2024;92(6):330-43. Martin JL. J Consult Clin Psychol 2023;91(11):626-39.

Edinger JD. J Clin Sleep Med 2021;17(2):255-62.

Could neuromodulation become a viable nonmedication treatment option for insomnia?

n=147 adults with moderate to severe insomnia

Curry G. Brain Stimul 2024;17(4):782-93. Bressler S. Sci Rep 2024;14(1):13039.

n=21 adults with SOL>30 minutes

Clinical Considerations and Future Research Agenda for Emerging Insomnia Treatments

Adjunctive vs. Alternative

Confirmatory efficacy trials

Effectiveness trials with comorbid populations

Who do they work for?

How do they work?

Additional Effective NonMedication Treatments

Take Home Points CBT-I is the first-line non-medication treatment for chronic insomnia but a substantial proportion of patients have a sub-optimal response Treatments leveraging CBT-I strengths are more time effective and demonstrate efficacy (AASM conditional recommendation) Adjunctive/alternative treatments that focus on different psychological models of insomnia show considerable promise Understanding when, how, and to whom to deliver these emerging nonmedication treatments is critical to advance insomnia care

Breaking the Addiction: Moving Beyond Dopamine Agonists for the treatment of Restless Legs Syndrome Andrew Spector, MD, FAASM, FAAN Professor of Neurology Duke University School of Medicine

Conflicts of Interest 1. I do not have any potential conflicts of interest to disclose, OR x

2. I wish to disclose the following potential conflicts of interest:

Type of Potential Conflict

Details of Potential Conflict

Grant/Research Support Consultant

Noctrix Health, Inc

Speakers’ Bureaus Financial support Other

Oxford University Press royalties for Navigating Life with Restless Legs Syndrome

3. The material presented in this lecture has no relationship with any of these potential conflicts, OR x

4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture: Bogan, et al. 2023: https://doi.org/10.1093/sleep/zsad190 Sing, et al. 2024: https://doi.org/10.1016/j.sleep.2024.08.017

Objectives Identify the risks and reasons for avoiding dopamine agonists for RLS Explain the role of iron supplementation in the treatment of RLS Discuss current best practice for RLS

Definition

Restless Legs Syndrome

Uncomfortable sensation and/or urge to move That is worse in the evening/night Worse at rest

And better with movement

What is it NOT? • Unrelenting pain or dysesthesias • Abnormal movements in bed • Periodic limb movements • Bouncing legs when sitting • RLS is a SENSORY > motor problem

If I could get rid of either diabetes or RLS, I’d choose RLS

Doc, this is worse than the chemo for my cancer!

I’m going to cut my legs off if you can’t find something to stop this

I can’t live like this. If there’s nothing you can do, I’m thinking of killing myself.

History of prescription treatments • Opioids have been used for centuries • Levodopa and benzodiazepines have been used for decades • Gabapentin and pregabalin used in 1990s • Ropinirole* approved for RLS in 2005 – Pramipexole* approved in 2006 – Rotigotine* patch approved in 2008

• Gabapentin enacarbil* approved in 2011 *FDA Approved

Dopamine Agonists +

Augmentation • Symptoms start earlier, get more intense, and/or spread to additional limbs • Occurs with all dopamine drugs • Can occur at any time (7-15%/year) Hypodopaminergic State

Exogenous dopamine

Dopamine agonist Clinical deterioration

Clinical improvement

Suppression of endogenous dopamine

Impulse control disorders

Impulse control disorders • 17% of RLS patients on DA therapy • Shopping and eating probably most common • Risk is highest for pramipexole and ropinirole • Dose dependent • Can start years into therapy • MUST WARN AND SCREEN Cornelius, et al. 2010

DA Withdrawal Syndrome (DAWS) Anxiety/panic

Worsening RLS

Depression

Drug Cravings

Agitation

Generalized Pain

Suicidal Ideation

Discontinuing DAs • Must detox patient – Rapid protocol (“Hopkins”) – Compassionate protocol (“Harvard”)

• Find alternative agent and get symptoms under reasonable control • Slowly withdraw dopamine agonist • Warn patients this is short-term pain for long-term gain

Summary • Dopamine agonists are dangerous. • Use cautiously at low doses or not at all • Patients must be warned about augmentation, impulse control disorders, and difficulty stopping meds

Pathophysiology

What causes RLS? Central nervous system – Iron – Dopamine – Adenosine – Glutamate – Opioid receptors

Alternative theories

– Peripheral neuropathy – Peripheral hypoxemia

Brain Iron Deficiency • Iron-RLS link reported in 1950s • CSF ferritin is low in RLS patients

Earley et al. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology. 54(8); 2000.

Brain iron deficiency

Earley et al. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology. 2000; 54: 1698-1700.

Putting it together Brain iron deficiency

• Due to iron deficiency or poor transport across BBB

Downregulation of A1Rs

Role of opiate receptors?

• Also makes it harder to sleep

Increased glutamate

• Hyperarousal

Increased glutamate-induced dopamine release

• Dopamine agonists work here?

Role of histamine? Downregulation of D2Rs

Iron in RLS

Substantia Nigra Ultrasound

Normal echogenicity

Hypoechogenicity of RLS Godau et al 2009

Iron Targets in RLS

Ferritin >100 mcg/L

Transferrin saturation >20%

Hemoglobin

“Normal” ferritin >11

“Normal” TSAT >15%

Iron testing – interpreting results • Ferritin 25, % transferrin saturation 25% Treatment indicated • Ferritin 125, % transferrin saturation 25% Treatment indicated • Ferritin 280, % transferrin saturation 15% Treatment indicated • Ferritin 25, % transferrin saturation 50% Treatment indicated • Ferritin 300, % transferrin 55% – Consider hemochromatosis

Oral iron replacement • 65-85 mg elemental iron (e.g. ferrous sulfate 325mg) • Every day vs. every other day • Take with vitamin C and not with calcium • Recheck levels in 3 months

IV iron replacement • Available products – LMW iron dextran – Iron sucrose* – Iron gluconate* – Ferumoxytol* – Ferric carboxymaltose* – Iron isomaltoside – Common dose = 1000mg * Multiple doses required

IV iron complications • Very small risk of anaphylaxis with LMW iron dextran and ferumoxytol • Iron infusion reactions – Flushing – Headache – Nausea

• Post infusion problems – Myalgias – Headache – Hypophosphatemia – MRI issues

When to choose IV over oral • Intolerant (GI side effects) • Ineffective (oral iron hasn’t increased levels) • Intensity (symptoms are too severe to wait) • Inflammation (ferritin >75) • Incapable (s/p gastric bypass)

Additional Iron Tips • Iron labs should be in the AM • Skip iron pills and high iron food for 24 hours before labs • Recheck labs 8 weeks after infusion • Repeat infusion criteria: – Improvement from first infusion – Drop in iron since 8-week post-infusion labs – Ferritin <300, saturation < 45%

Nonpharmacological options • Trigger avoidance • Stretching • Massage • Hot baths • Soap in bed • Weighted blanket • SCDs • Pressure point stimulators for feet (brand name Restiffic) • TOMAC

Treatment Options Common

Complex

• Gabapentin • Gabapentin enacarbil • Pregabalin

• Methadone • Buprenorphine • Other opioids

Creative

Cutting edge

• Dipyridamole • (Vitamin D)

• TOMAC

( ) = not included in new guidelines

Gabapentin enacarbil vs Gabapentin Gabapentin enacarbil is a prodrug • Both reduce glutamate •

✅Better absorption and bioavailability ✅ More consistent benefits

✅ Extended release to last the whole night ✅ FDA-approved ❌ Cost

Dipyridamole • Adenosine reuptake inhibitor • Dose: 200-300mg qHS • Side effects: HA, GI distress, bleeding • Great as adjunctive therapy

Opiates for RLS are highly effective! • Low doses typically effective – Suboxone ¼-1 film qHS-BID – Methadone 2.5-10mg qHS-BID – Oxycodone 5-15mg qHS (ER preferred) – Tramadol 50-200mg qHS-QID

• If using opiates, try them all until one works.

Opioid safety

Opioid Registry Data • Median change in dose over 2 years was 0 MME – 41% increased dose – 8% increased >25 MME • Most were males <45yo with comorbid pain, depression, or insomnia

– 5mg of methadone = 23.5 MME

TOMAC • Tonic Motor Activation • Brand name: Nidra • Mechanism: peroneal nerve stimulation • Medicare and VA coverage

PRN/Rescue Therapy • Dopamine agonists • Carbidopa/levodopa • Gabapentin • Tramadol • Oxycodone • TOMAC

Future directions • Pitolisant – Increases CNS histamine • Substantia nigra ultrasound • Use of MRI to identify CNS iron • Role of epigenetics

3 Key Take-Home Messages 1. Dopamine agonists are not recommended for chronic management of RLS due to high risk of complications 2. Iron is foundational to successful RLS management 3. There are many options to treat RLS. No one needs to suffer forever.

Contact Me www.AndrewSpectorMD.com

AndrewSpectorMD andrew.spector@duke.edu

Sleep and Autoimmune Diseases of the Central Nervous System Tiffany J. Braley, MD, MS Associate Professor with Tenure University of Michigan, Divisions of MS/Neuroimmunology and Sleep Medicine

Disclosures • Recent/current support • NIH/NCCIH(1R01AT011341-01) • NIH/NIA (1R01AG074342-01) • Patient-Centered Outcomes Research Institute (MS-1610-36980) • International Progressive MS Alliance (through National MS Society, PA-2304-41156) • Intellectual property: patent application for sleep apnea treatment • Material support IST: Jazz Pharma

Outline • Review basic components of the immune system • Demonstrate how disruptions in the sleep-wake cycle can increase overall risk of autoimmune disorders • Show how autoimmune conditions that involve brainstem and diencephalic regions of the brain cause distinct sleep disorders • Multiple sclerosis • Neuromyelitis optica • IgLON5 Antibody-associated encephalitis • CASPR2 Antibody-associated encephalitis • Discuss how treatment of the underlying immune process may variably improve associated sleep disturbances

Relevance

Understand the crucial role that sleep plays in autoimmunity

Recognize autoimmune diseases of the CNS that include sleep pathology as a prominent feature of the diagnosis

Demonstrate how sleep medicine plays a vital role in interdisciplinary care for people with autoimmune disorders of the CNS

Basic Immunology • Protect the host from foreign pathogens • Delicate balance of efficient recognition and elimination of foreign invaders, while minimizing damage to the host • Recognition of self vs. non-self • 2 components: • Innate immune system • Adaptive/acquired immune system

Immune System Components Innate immune system • “First response” – nonspecific, rapid response (hours) • Barriers (mucous membranes, skin) • Chemical influences (complement system, interferons, lysozymes, others) • Cellular components (natural killer cells, phagocytic cells)

Adaptive (Acquired) immune system (present only in vertebrates) • “Immunological memory” • Achieved through direct contact with a pathogen/antigen • Specific, slow response (days) • Leads to a longstanding ability to withstand a subsequent attack by the same pathogen • Cellular and humoral components (T/B lymphocytes, antibodies) • Maintenance of self-tolerance: Autoimmune disorders result from breakdown in the selftolerance system – cells and antibodies become autoreactive and target host’s tissues

Cellular components of the immune system Innate Immune System Neutrophils Eosinophils Basophils

Acquired Immune System

Monocytes

T-cells

Macrophages/microglia

B-cells

differentiation

Antigen-presenting cells Dendritic cells

CD4+ TH

Plasma cells

CD8+ Tc

TH1, Th2, and Th17

CD25+Tregulatory (self-tolerance)

Cytokines Low molecular weight proteins

Signaling molecules that mediate and regulate immunity, inflammation and other cellular processes

Modulate cellular behavior (effector functions)

Produced by nearly all immune cells and other cell types (neurons)

Traditionally considered “proinflammatory” or “anti-inflammatory” in isolation, but may work differently in vivo

Function to maintain homeostasis

Cells of the CNS synthesize cytokines and possess receptors for cytokine signaling, to regulate sleep • Interleukin (IL)-1 • IL-2 • IL-4 • IL-6 • IL-8 • Macrophage inhibitory protein 1β (MIP-1)

• IL-10 • IL-13 • IL-15 • IL-17 • IL-18 • TNF-α • TNF-β • Interferon-α (IFNα), IFN-β, INF-γ

Immune Consequences of Sleep Deprivation and Sleep Disturbances

Chronic sleep deprivation and impaired host defense • Formation of “immunological memory” and self-tolerance is tightly connected to the sleep-wake cycle • Functions enhanced by sleep: • T/B cell migration • T cell differentiation • T cell proliferation • T-reg activity • Antigen presenting cell activity • Melatonin receptors present on leukocytes and hematopoetic stem cells exhibit circadian oscillations in circulation

Chronic sleep deprivation and susceptibility to autoimmunity • Sleep deprivation can lead to a pro-inflammatory state and accelerate autoimmune disease • Chronic elevation of Il-1, IL-6, and TNF-alpha • Abnormal IL-6 production:

• Associated with polyclonal B-cell expansion and activation of cell lineages that contribute to chronic inflammation • Activation of Th17-cell responses that intensify chronic inflammation

• Experimentally sleep-deprived healthy humans showed impaired suppressive activity of CD25+ regulatory T cells (T-reg), which have a diurnal pattern

Exemplar autoimmune diseases of the CNS

Multiple Sclerosis • Chronic inflammatory disorder of the central nervous system • Multifocal, irreversible myelin damage and axonal degeneration • Most common cause of non-traumatic disability among young adults • Affects 700,000-1M people in the US* • F:M = 2.5:1 *Wallin et al

Normal Brain MRI

Brain MRI in MS

Clinical features of MS • Can be relapsing or progressive • Common physical symptoms: • Paraparesis/hemiparesis • Sensory disturbances • Incoordination/ataxia • Visual disturbances/diplopia • Bowel/bladder dysfunction • Widespread damage not seen on conventional MRI associated with disability and “invisible” symptoms (fatigue, cognitive impairment, pain)

Sleep disturbances and multiple sclerosis share a bidirectional relationship Hedstrom el al Ann Neurol 2011 Braley et al Neurology 2012 Boe Lunde et al, PlosOne 2012 Neau et al Eur Neurol 2012 Merlino et al Sleep Med 2009 Tachibana et al, Eur Neurol 1994 Braley et al, SLEEP 2016 Braley et al, JCSM 2014 Brass et al, JCSM 2014 Braley et al Mult Scler J 2023 Whibley et al Sleep Epid 2024

Brainstem lesions Spinal cord lesions Comorbid symptoms Medications

Sleep disorders (OSA, RLS, Insomnia, shift work)

Characteristics of MS that increase the risk of sleep disorders

• Brainstem lesions→ Sleep Apnea, REM Sleep Behavior Disorder • Spinal cord lesions→ Restless Legs Syndrome • Comorbid symptoms (depression, pain, spasticity, urological)→ Insomnia • Medications→ Insomnia, RLS, Sleep Apnea, RBD

Shift work and MS risk 2 population-based, case-control studies from Sweden linking shift work to MS*

Epidemiological Investigation of MS (EIMS): 1,343 cases + 2,900 controls (incident cases) Genes and Environment in Multiple Sclerosis (GEMS): 5,129 cases + 4,509 controls (prevalent cases)

Shift work: “permanent or alternating working hours other than “ordinary day work”, including night work, day work (before 7 AM), and evening work (after 9 PM)” Cases and controls given questionnaires about shift work, demographic and reproductive factors, heredity, previous health, lifestyle factors, exposures, socioeconomic circumstances, BMI, Vit D *Hedstrom et al, Ann Neurol 2011

Hedstron et al (con’t) Shift work variables: - Duration of shift work - Age when shift work began (<20 years; 20–24, 25–29, 30+ years) - Intensity (number of nights/month) of the shift work

• Nurses’ Health Study: Longitudinal survey study of women nurses • Data collected every 2 years for each respondent • Includes data regarding health conditions, sleep habits, subjective physical and cognitive function • Examined the incidence of mobility decline among >70,000 nurses over 8 years, with a focus on those with specific chronic conditions

• Outcome: Transition to assistive devices or non-ambulatory status between 2008-2016, in nurses with MS, diabetes, and OA were compared to general sample • Exposures: Self-reported OSA or elevated STOP-Bang, sleep duration (<6 hours) and poor sleep quality

Results

Examined signs of sleep disorders at baseline

2017 2013 Used four-way decomposition models to evaluate whether sleep disorders in 2013 mediated or moderated effects between MS and subjective cognitive decline in 2017 •Known or suspected OSA •Insomnia (composite score) •Sleepiness

• Prevalence of all sleep disorders in were higher for nurses with MS (NwMS) than controls • NwMS more likely to report cognitive difficulties in 2017 than controls • Insomnia mediated 5.4%–15.1% of the total effect between MS and following instructions, conversations/plots, and memory impairment • Sleepiness mediated 8.6%–12.3% of the total effect for these outcomes • OSA accounted for 34% of the total effect between MS and following instructions (interaction effect)

Autoimmune Encephalitis

Autoimmune Encephalitides • Group of inflammatory disorders of the brain (+/- spinal cord, optic nerve) • Directed toward specific components (proteins) of neurons and glia (surface or intracellular) • May be associated with specific cancers (paraneoplastic) • Sleep disorders common (73%), particularly when there is an involvement of the diencephalic and brainstem structures that regulate sleep/wake • Sleep problems may improve with immunotherapy* • Distinct sleep presentations: • Neuromyelitis Optica • Anti-IgLON5 Disease • CASPR2-antibody associated encephalitis *Blattner et al J Neurol 2019

Neuromyelitis Optica (NMO, “Devic’s Disease”) • Pathologically distinct from MS • Prevalence 0.5-4/100,000, higher in East Asian/Black populations • F:M = 9:1 • Preferentially involves optic nerve and/or spinal cord, but brain involvement can occur (area postrema, hypothalamus) • Serum Aquaporin-4 IgG antibodies (AQP4IgG) positive in about 70% of cases (expressed on foot processes of astrocytes) • Attacks can be devastating and associated with poorer recovery than MS

Brainstem and cervical spine involvement in NMO Tackley et al, Mult Scler J, 2014

Sleep Disorders in NMO *Mult Scler. 2014 Sep;20(10):1407-8 Mult Scler Relat Disord. 2020 Feb:38:101869 Arch Neurol. 2009 Dec;66(12):1563-6. doi: 10.1001

• Numerous cases of secondary (symptomatic) narcolepsy and excessive daytime sleepiness in patients with hypothalamic involvement (2.5%) • Bilateral hypothalamic lesions • May be presenting feature • CSF Hypocretin-1 low in some cases • Not cataplexy • May respond to steroids used for NMO relapse • Recurrence suggests poor disease control (NMO relapse)

Sleep Disorders in NMO (con’t) • Obstructive sleep apnea (brainstem/cervical lesions) • Central sleep apnea • Restless legs syndrome – associated with more disability? • Less evidence for improvement of these disorders with immunotherapy Sleep Med. 2020 Jun:70:97-105 Tackley et al, Mult Scler J, 2014

Sleep Med. 2016 Jan:17:121-3

Anti-IgLON5 Disease • IgLON5 – surface protein on neurons/glia • Strong association with Human leukocyte antigen (HLA) haplotypes DRB1*10:01 and HLADQB1*05:01 • Secondary (?) neurodegeneration and usually tau deposits • Affects specific brain regions • Brainstem tegmental area, parafacial zone • Hypothalamus • Cortex • Heterogeneous neurological symptoms – bulbar dysfunction (dysphagia), gait/movement disorders, cognitive impairment, autonomic dysfunction • Sleep disturbance is a prominent symptom (up to 75-90% patients) • Sleep Disturbances may be a primary reason for seeking medical care Theis et al Neurology 2023 Honorat et al, Neurol, Neuroimmun, Neuroinflamm

Anti-IgLON5-Associated Sleep Pathology • Sleep breathing difficulties • •

Obstructive sleep apnea 55–95% Laryngeal sleep-related stridor 45–55%

• Abnormal sleep behaviors/parasomnias in NREM and REM • •

•

Circadian sleep-wake rhythm is preserved NREM pathology/disorganized sleep architecture (sleep onset) • Undifferentiated NREM sleep with diffuse irregular theta activity (a) • “Poorly-structured” N2 (b) • Vocalizations and non-purposeful movements REM Sleep Behavior Disorder (c) (latter half of night, less violent?)

• Subjective: Excessive daytime sleepiness (59%), insomnia (73%), non-restorative sleep • Immunotherapy variably improves course/symptoms, may not improve sleep symptoms (early tx better?) Iranzo Neuropsychopharmacology 2019; Devine and St. Louis Neurotherapeutics 2021; Gaig et al Sleep 2019, Sabater et al Lancet Neuro 2014

CASPR2Antibody Associated Disease

• CASPR2 (Contactin-associated protein-like 2): cell molecule expressed in both the central and peripheral nervous system, in voltage-gated potassium channels • Spectrum of symptoms is highly diverse • Limbic encephalitis • Seizures • Peripheral excitability (myokymia, fasciculations) • Cerebellar syndrome • 5-20% of cases are associated with Thymoma (tumor removal associated with favorable prognosis) • Immunotherapy also usually associated with favorable prognosis • 70% males, usually older adults • Serum/CSF antibodies diagnostic if positive

Josephs et al, Journal of Clinical Neurophysiology 2004

Morvan syndrome • Most commonly seen in CASPR2-antibody encephalitis, but may be seen in other autoimmune encephalitides (LGI-1) • Lost circadian rhythmicity, mental confusion, visual hallucinations and abnormal motor activation • Severe insomnia with abnormal sleep-related motor activation or a complete absence of sleep (agrypnia) present in 90% of cases (interruption of thalamo-limbic circuitry?) • Characteristic PSG findings: • Absence of all sleep • Severe reduction/disappearance of K complexes, spindles and slow wave activity “leading to a virtual absence of stages N2 and N3” • Absent REM or brief REM intrusions • REM without atonia • Severely reduced total sleep time • Prominent Theta background • Dream enactment activities from any sleep-wake state (“oneric stupor”)

• Syndrome is variably associated with improvement with immunotherapy depending on the associated form of encephalitis

Other autoimmune paraneoplastic encephalitides • Anti-N-methyl-D-aspartate receptor (AntiNMDAR) encephalitis • Children and young women • Commonly associated with ovarian teratomas • Serum and CSF antibodies • Seizures, neuropsychiatric disturbances and movement disorders • Variable sleep disturbances • Severe insomnia (early) • Hypersomnia (late, recovery phase)

• Anti-Ma antibody encephalitis

• Associated with testicular cancer • Antibodies directed at Ma1 and Ma2 proteins • Serum and CSF antibodies • Affects cerebellum and brainstem structures • Sleep disorders • RBD • 32% with EDS • Symptomatic narcolepsy with reported hypnagogic hallucinations and cataplexy with decreased CSF hypocretin levels also reported (CD8+ inflammatory-mediated response against hypocretin neurons in a case report)

Yin and et, Frontiers in Neuroscience 2021

Neuropsychopharmacology (2020) 45:129–140

Conclusions • Sleep disorders and autoimmune diseases of the CNS are inextricably linked • Mechanisms by which sleep deprivation or sleep disorders contribute to CNS autoimmunity specifically require further study • MS and sleep disorders share a bidirectional association • Distinct pathological sleep patterns are a hallmark of NMO, anti-IGLON5 and anti-CASPR2 encephalitis, and may aid in the diagnosis • Early recognition of these disorders by sleep clinicians could aid in diagnosis, leading to better treatment and outcomes, but additional research is needed to determine if early sleep interventions could improve long-term outcomes

Thank you

EVALUATING & TREATING OSA IN HOSPITALIZED PATIENTS WHY, BUT, AND HOW Eric Olson, MD

Professor of Medicine Division of Pulmonary and Critical Care Medicine Center for Sleep Medicine Mayo Clinic-Rochester

Member, Board of Directors, American Academy of Sleep Medicine

• Recognize reasons for inpatient OSA assessment

LEARNING OBJECTIVES

• Review new AASM clinical practice guideline for inpatient OSA assessment and management • Acknowledge barriers to inpatient OSA assessment • Explain approaches to inpatient OSA assessment

INPATIENT ASSESSMENT OF OSA: WHY? • OSA highly prevalent in inpatients • 40% > 50 yrs Shear. J Clin Sleep Med 2001 • OSA common in common inpatient conditions OSA Prevalence

Naranjo Chest 2020

COPD

Tang. JCSM 2020

RRT

46% 50%

Zhang J Sleep Res 2015 DM2 Kauta JCSM 2014

CHF

Johnson JCSM 2010

Stroke

Sharma JCSM 2015

Obesity

OSA undiagnosed in many (most?)

60% 65% 72% 84%

20%

40%

60%

80%

100%

INPATIENT ASSESSMENT OF OSA: WHY? • Untreated OSA increases risk for adverse outcomes RRT Rate

Mean LOS

INPATIENT ASSESSMENT OF OSA: WHY? • OSA associated with increased inpatient costs

Chest 2014; 145:1032

347 hospitals N=250,907 pts OSA → 22% higher costs

Ann Am Thorac Soc 2020; 20:1784

6,000,000 hospitalizations OSA → 67% higher costs

INPATIENT ASSESSMENT OF OSA: WHY? • Untreated OSA associated with increase readmission rates

7x 30-d COPD readmission rate

3.5x

10x

INPATIENT ASSESSMENT OF OSA: WHY? • “Captured” audience • Overcome disparities

INPATIENT ASSESSMENT OF OSA: WHY?

PA systolic

• Initiation of CPAP for newly diagnosed OSA acutely improves pulmonary hemodynamics, EF in exacerbated CHF patients

CPAP

Controls

PA systolic (mmHg)

-15.8 ± 3.2

-5.2 ± 2.6

Ejection fraction (%)

+3.4 ± 1.5

-0.5 ± 0.5

INPATIENT ASSESSMENT OF OSA: WHY? • Unattended sleep studies and initiation of PAP in hospitalized cardiac patients reduces 30-day readmission and ED visits if PAP adherent

INPATIENT ASSESSMENT OF OSA: WHY? • Post-d/c CPAP results in reduced 1-yr care costs

N=185 N=108

1-year cost of care

1-yr readmission, ED visits

INPATIENT ASSESSMENT OF OSA: WHY? • Post-d/c CPAP improves survival CPAP adherent CPAP non-adherent

PICO Questions • Screening, diagnostic, and treatment for medically hospitalized adults at high-risk for OSA • Inpatient treatment of established but untreated moderate-severe OSA • Inpatient sleep consultation for patients with known or highly suspected OSA • Peri-discharge sleep management for patients with known/highly suspected OSA

Outcomes • Critical: prevention of escalation of care; mortality; readmission; incidence of OSA-related comorbidities; stroke recovery; OSA diagnosis • Important: LOS; daytime sleepiness; QoL; PAP adherence; time to diagnosis/treatment; dyspnea; sleep quality J Clin Sleep Med (in press) ©2025 Mayo Foundation for Medical Education and Research | slide-15

AASM CPG: GOOD PRACTICE STATEMENT • For inpatients with OSA on active treatment, existing treatment should be continued unless contraindicated • Rationale: • Continuation of CPAP in inpatients is low (as low as 5.8%)1 • Use of home PAP devices in hospital may lead to cost savings2

1Lindenauer PK. Chest 2014; 145:1032 2Smith. Laryngoscope 2014; 124:2200

AASM CPG: RECOMMENDATION 1 • For medically hospitalized adults at increased risk for sleep-disordered breathing, AASM suggests in-hospital screening for OSA as part of an evaluation and management pathway that incorporates diagnosis and treatment with PAP rather than no in-hospital screening (conditional) Rationale • OSA screening, diagnosis, and treatment program:

• Reduces mortality (2 RCTs): RR 0.83; Absolute risk diff 10 fewer deaths/1000 pts • Reduces CV events (4 RCTs): RR 0.67; absolute risk diff 67 fewer events/1000 pts • Improves daytime sleepiness: mean ESS difference of -2.70 points J Clin Sleep Med (in press) ©2025 Mayo Foundation for Medical Education and Research | slide-17

AASM CPG: RECOMMENDATION 2 • For medically hospitalized adults with an established diagnosis of moderate-to-severe sleep-disordered breathing and not currently on treatment, AASM suggests inpatient treatment with PAP rather than no positive airway pressure (conditional) Rationale • PAP:

• Reduces mortality (4 RCTs): RR 0.78; Absolute risk diff 14 fewer deaths/1000 pts • Reduces CV events (4 RCTs): RR 0.67; Absolute risk diff 67 fewer events/1000 pts

AASM CPG: RECOMMENDATION 3 • For medically hospitalized adults at increased risk for or with an established diagnosis of OSA, AASM suggests that a sleep medicine consultation be available as part of an evaluation and management pathway, rather than no sleep medicine consultation (conditional) Rationale • Sleep consultation (1 observational study):

• Absolute risk diff 233 more PSG diagnoses/1,000 pts • Absolute risk diff 201 more sleep disordered breathing diagnoses/1,000 pts

AASM CPG: RECOMMENDATION 4 • For medically hospitalized adults at increased risk for or with an established diagnosis of OSA, AASM suggests a discharge management plan to ensure timely diagnosis and effective management of OSA, rather than no plan (conditional) Rationale • Discharge management plan: • Reduces mortality (3 observ studies): RR 0.60; Absolute risk diff 68 fewer deaths/1000 pts • Reduces CV events (1 observ study): HR 0.47; Absolute risk diff 203 fewer events/1000 pts • Reduces readmission (1 observ study): RR 0.38; Absolute risk diff 334 fewer readmissions/1000 pts • Increases PAP adherence (1 RCT) Mean diff +76 min/n J Clin Sleep Med (in press) ©2025 Mayo Foundation for Medical Education and Research | slide-20

INTERIM SUMMARY: WHY • Growing value recognition of addressing OSA in inpatients • High OSA prevalence in inpatients • Association of unrecognized OSA and poor health outcomes • Unique opportunity of inpatient setting • Emerging data on positive impacts of initiating OSA therapy shortly after d/c

INTERIM SUMMARY: WHY • AASM new CPG: • Continue established OSA therapy in hospital • Four conditional recommendations: • In-hospital screening for OSA in at-risk patients • Use of inpatient PAP therapy in untreated moderate-to-severe OSA • Sleep medicine consultation availability in those with increased OSA risk or established OSA • Discharge management plan for timely OSA diagnosis and management

QUESTION • RCTs assessing programs of inpatient OSA screening, testing, and treating have demonstrated which of the following? A. Reduced mortality B. Decreased hospital length of stay C. Improved quality of life D. Decreased readmission rates

ANSWER • RCTs assessing programs of inpatient OSA screening, testing, and treating have demonstrated which of the following? A. Reduced mortality B. Decreased hospital length of stay C. Improved quality of life D. Decreased readmission rates

RATIONALE • RCTs assessing programs of inpatient OSA screening, testing, and treating have demonstrated which of the following? A. Reduced mortality RCT data demonstrates reductions in mortality, CV events, and sleepiness B. Decreased hospital length of stay C. Improved quality of life D. Decreased readmission rates

INPATIENT ASSESSMENT OF OSA: BUT… • Sleep of inpatients is restricted, fragmented • Environmental, physiological, psychological factors • May complicate patient acceptance, use of CPAP • Low awareness and/or prioritization of OSA by the admitting team and/or patient • Type, severity of sleep disordered breathing may change with acute illness trajectory • Supplemental oxygen usage may impact screening oximetry

INPATIENT ASSESSMENT OF OSA: BUT… • Short LOS limits opportunity to assess, address OSA • Resource limitations/logistics • Personnel; PSG; PAP interface options • Reimbursement concerns • Administrative resistance to service line • Inpatients will refuse PAP • Controlled trials of clinically relevant outcomes are limited

AASM CPG ACKNOWLEDGEMENTS • Focus on high-risk patients • Strong consideration should be given to local resource needs, logistics, clinical judgement, and patient value/preferences when attempting to implement recommendations • Much work to be done to determine most effective approaches, clinical impacts

INPATIENT ASSESSMENT OF OSA: HOW ESSENTIAL ELEMENTS

• Identification of high-risk OSA • Diagnostic decision support for care teams • Treatment oversight • Discharge care coordination • Contextualization

INPATIENT ASSESSMENT OF OSA: HOW Medical admission with comorbidities commonly associated with OSA

Heart failure, A Fib, ACS, COPD, PH, Stroke, Severe obesity and/or EDS + ≥ 2 of the following: Habitual, loud snoring Witnessed apnea or gasping/choking Hypertension

Increased risk on screening for moderatesevere OSA

+ STOP, STOP-BANG, and/or Oximetry

Inpatient sleep consultation +/diagnostic testing

Inpatient treatment if no contraindications Consider if hypoxia, comorbidities, OSA severity, patient preferences, access to resources

Outpatient management (diagnosis; treatment; follow-up)

INPATIENT ASSESSMENT OF OSA: HOW

HOW: SHARMA MODEL CV, IM, FP admits with BMI ≥ 30 kg/m2 STOP or STOP-BANG questionnaire ≥2 Inpatient Sleep Medicine consult offered OSA suspected

BCSM APP RT

Overnight oximetry or HSAT if no contraindications Abnormal Inpatient treatment, if no contraindications

HOW: SHARMA MODEL • STOP: nonspecific, but “ice-breaker” to engage patient • Overnight oximetry triages OSA severity • Optimal timing depends on patient’s clinical status, absence of contraindications:

• Patient in unstable state

HOW: OUR APPROACH

Outpatient f/u

Primary service places Sleep consult

House staff OSA education

Triage via chart review, call to requesting service

Attending, Sleep fellow, RT

Overnight oximetry +/- blood gas Consult: oxi results; co-morbidities; convenience

*Criteria: 1. Abnormal oxi • 4% ODI ≥ 20/hr • Nadir SpO2 < 75% or • Mean SpO2 < 88% • SpO2 < 90% ≥ 15% of study 2. Severe CAD 3. CHF 4. Serious arrhythmia 5. Reason to delay sleep apnea testing

Contact RT to initiate PAP* If new CPAP start, RT to introduce CPAP, fit with interface, assess patient willingness

CSA, hypoventilation concern

Inpatient sleep apnea testing RCU if BPAP

HOW: OUR APPROACH Patient agrees to try CPAP

Patient refuses PAP

Sleep consult team sets PAP, O2 settings

RT documents why

AM RT assessment, PAP download

Sleep team contacts primary service with non-PAP OSA mitigations

Overnight oximetry on therapy Inpatient sleep apnea testing

Early outpatient f/u

HOSPITAL SLEEP MEDICINE: COMPONENTS NEEDED • Inpatient sleep team champion • Establish collaborations with care teams managing high-risk OSA • Education of house staff, nursing • RT partnership to initiate, support PAP +/- O2 trials • Access to care unit with vent support capabilities • Dedicated time for consult team duties • Reserved outpatient appointment, testing access • Patient acceptance, f/u highly variable

QUESTION • Approximately what percentage of patients who screen positive for OSA per inpatient overnight oximetry complete their recommended outpatient PSG after discharge? A. 10% B. 20% C. 40% D. 60%

ANSWER • Approximately what percentage of patients who screen positive for OSA per inpatient overnight oximetry complete their recommended outpatient PSG after discharge? A. 10% B. 20% C. 40% D. 60%

RATIONALE

38% did not complete post-d/c PSG

TAKE HOME POINTS • High OSA prevalence in inpatients • Association of unrecognized OSA and poor health outcomes

TAKE HOME POINTS • New AASM CPG: diagnosis and treatment of SDB in hospitalized patients with a high pretest probability of having SDB or who are at high risk for SDB-related complications, and that sleep consultative services be available with discharge management planning to facilitate transition to outpatient care • Local resources, logistics, clinical judgment, and patient values must be considered

QUESTIONS & DISCUSSION Please feel free to reach out! olson.eric@mayo.edu

Treatment of Central Apnea The old and the new M. Safwan Badr, MD Wayne State University School of Medicine John D. Dingell VAMC Detroit Medical Center Detroit, Michigan

Lesson Objectives At the end of this presentation, the learner will be able to : 1. Describe the etiology and risk factors of central apnea in different patient populations. 2. Describe the relationship between central and obstructive apnea 3. Outline a mechanistic approach to management 4. Review the AASM Clinical Practice Guidelines.

Effect of NREM sleep on Ventilation The hypocapnic apneic threshold The CO2 reserve

NREM sleep unmasks a reproducible, highly sensitive, hypocapnic apneic threshold Skatrud et al. JAP. 55:813-22, 1983

Central Sleep Apnea Pathophysiologic Classification •Hypoventilation

• Sleep related hypoventilation: CNS, neuromuscular or chest wall disease • Inadequate ventilatory reserve: hypercapnia not required • May not meet the criteria for “central” or apnea”

•Post- hyperventilation

• No daytime alveolar hypoventilation • Hyperventilation • The most common type of central apnea

Classification of Central Apnea • Central sleep apnea with Cheyne-Stokes breathing (CSR) • Central sleep apnea due a medical disorder without CSR • Central sleep apnea due to high-altitude periodic breathing • Central sleep apnea due to a medication or substance • Primary central sleep apnea • Treatment-emergent central sleep apnea

• 86 year old male • Evaluation of snoring, fragmented sleep and dyspnea on exertion. • Previous smoking history • PFTs: Poor effort and mild airflow obstruction • Echocardiography: EF= 40% • AHI=60/hour of sleep • CAI= 20/hour of sleep • ABGs: PaO2= 82 torr, PaCO2= 34 torr

Recurrent Central Apnea: Apnea Begets Apnea

Hyperventilation Hypocapnia Central apnea ΔPaO2, PaCO2 Δ Sleep State

Hyperventilation

Ventilatory Control Loop Medullary hypercapnia

Plant gain Arterial and medullary Hypocapnia

Controller gain

Apnea Begets Apnea

Central Apnea

Hyperventilation

Ventilatory Control Loop Medullary hypercapnia

Plant gain Arterial and medullary Hypocapnia

Controller gain

Apnea Begets Apnea

Central Apnea

Hypoxia - PCR activity

Hyperventilation

Arousal

Plant gain

Medullary hypercapnia

Ventilatory Control Loop

Arterial and medullary Hypocapnia

Controller gain

Upper Airway Occlusion

Central Apnea

The Loop Gain : An engineering Construct • Diffusion, Mixing, • Circulation

△PCO2 Plant Gain △ PCO2/L/min

Central Pattern Generator “Controller”

Airways, Lung, Chest wall “Plant”

△Ventilation Controller gain △Ventilation/mmHg

High Loop Gain = High propensity to central apnea

Effect of Chemoreceptor Sensitivity Isometabolic line

VE, L/min 10

CO2 Reserve

9 8 7 6 5 4 3 2 1 0

5 32

PaCO2 mm Hg

Effect of Prevailing PaCO2 VE, L/min

Isometabolic line

10 9 8

Ventilatory Reserve

7 6 5 4 3 2

1 0

5 32

PaCO2 mm Hg

Effect of PrevailingPaCO2 VE, L/min

Isometabolic line

Low PaCO2

9 8

Eucapnia

7 6 5 4 3 2 1 0

B 0

5 32

PaCO2 mm Hg

Effect of PrevailingPaCO2 Isometabolic line

VE, L/min 10

Low PaCO2

9 8 7

Eucapnia

6 5 4 3 2 1 0

5 32

PaCO2 mm Hg

Effect of PrevailingPaCO2 Isometabolic line

VE, L/min 10

Low PaCO2

9 8 7

Eucapnia

6 5 4 3 2 1 0

5 32

PaCO2 mm Hg

CENTRAL APNEA RISK FACTORS •Age, gender and menopause •Medical Conditions • CHF, CVA, Atrial fibrillation ? • Narcotics • Endocrine: Hypothyroidism, Acromegaly

•Primary central apnea ?

Central Apnea and Associated Conditions

•Congestive Heart Failure •Opiate analgesics •Obstructive sleep apnea • Treatment-Emergent Central Apnea

• A 62-year-old male • Classic SDB presentation • BMI 29. Chronic conditions include • HTN, CAD, CVA, CKD • LVEF =60% • AHI= 88.9/h • CAI = 39.1/h.

Oropharyngeal airway occlusion during spontaneous CSA

Polysomnographic findings in male heart failure patients with either central (CSA) or obstructive (OSA) sleep apnea.

Javaheri S et al. Circulation. 1998;97:2154-2159

• A 64 year old male • Snoring and EDS • BMI=31

Baseline study • AHI=74 • Total hypopneas =300 • Total OA= 14 • Total CA= 6

Walker et al. J Clin Sleep Med. Aug 15, 2007; 3(5): 455–461.

Central Sleep Apnea in Stable Methadone Maintenance Treatment Patients* Chest. 2005;128(3):1348-1356. doi:10.1378/chest.128.3.1348

Figure Legend: Two examples of CSA found in MMT patients. Top, A: Example of non-PB type of CSA. Bottom, B: PB type but without crescendodecrescendo breathing typical of Cheyne-Stokes respiration. The PB cycle time is shorter than seen in Cheyne-Stokes respiration associated with CHF. The time base is 30 s for the upper epoch and 5 min for the lower epoch for each example. NASAL = nasal pressure; THERM = thermister; THOR = thoracic movements; ABDO = abdominal movement; Sao2 = arterial oxygen saturation. Patients were in stage 2 sleep in both examples.

Baseline: Pre-CPAP

On CPAP

Change in CSAI in ith CPAP-related CSA

•CSA •CPAP-Emergent •N=14

Dernaika, T. et al. Chest 2007;132:81-87

Nigam et alAnn Thorac Med. 2018 Apr-Jun;13(2):86-91. PMID: 29675059

Natural history of treatment-emergent central sleep apnea on positive airway pressure

• • • • •

A systematic review of five studies TECSA Persistent TECSA Delayed-TECSA (D-TECSA) Determinants include: • Higher AHI • Higher CAI • Higher residual AHI

Nigam et al. Ann Thorac Med. 2018 Apr-Jun;13(2):86-91. PMID: 29675059

Treatment of Central Apnea • There is no specific treatment for central apnea • Most modalities dampen post apneic overshoot. • Positive Pressure • CPAP, BPAP, ASV • Altering chemical stimuli • Supplemental O2 or CO2 • Sleep State: hypnotics • Ventilatory Drive: Acetzolamide • Phrenic nerve Stimulation

•Association with OSA •Decreasing overshoot: Plant Gain • Opening the upper airway • Increasing O2 stores

•CPAP has been used for CSR in CHF •Improvement in intermediate outcome •

Oropharyngeal airway occlusion during spontaneous CSA (Badr et al. JAP 1995)

Upper airway narrowing during induced hypocapnic CSA

(Badr et al. JAP 1995)

Prevalence of Central Sleep Apnea among Veterans and Response Rate to Continuous Positive Airway Pressure Therapy

N=90

• • • • •

PAP < 50% Initial PAP response = 25% Improvement after 2 months 4/10 continued to experience high residual events The efficacy of PAP is partial.

Ibrahim et al. Sleep Advances (2024)

Treatment of Central Apnea Central Apnea

Central Hypopnea

Upper airway obstruction

Breathing Instability

The Canadian Continuous Positive Airway Pressure trial (Can PAP)

N= 258 NCPAP: 128 NoCPAP: 130 2-year Follow up

Heart-Transplantation-free Survival

Bradley T et al. N Engl J Med 2005;353:2025-2033

The Canadian Continuous Positive Airway Pressure trial (CanPAP) • CPAP vs. placebo at 3 months

 AHI  EF  Mean nocturnal oxyhemoglobin saturation  Plasma nor-epinephrine levels  Six-minute walk,

• N-CPAP had no effect on survival

Effect of Bi-level PAP on central apnea index

Johnson, K. G. et al. Chest 2005;128:2141-2150

Adaptive Pressure Support Servo-Ventilation

• • • • •

Small and variable ventilatory support The hydrostatic benefits of low levels of nasal CPAP ( 5 cm H20) Baseline pressure swing is 4 cm H2O Increases to provide 90% of the long-term average VE. No hyperventilation

Teschler et al. AJRCCM, 164, 4, 614-619,2001

Adaptive Pressure Support Servo-Ventilation

Javaheri et al. 146#2 CHEST AUGUST 2014

Teschler et al. AJRCCM, 164, 4, 614-619,2001

Adaptive Pressure Support Servo-Ventilation •

Prospective, randomized, cross-over design

•

N=16; gender?

•

Desaturation index (3%) > 15/h

•

Five consecutive nights

• CPAP • Supplemental O2 @ 2L/NC • Bi-level –ST mode • ASV

Teschler et al. AJRCCM, 164, 4, 614-619,2001

Adaptive Pressure Support ServoVentilation

2l/NC

ST mode

Teschler et al. AJRCCM, 164, 4, 614-619,2001

Cumulative Incidence Curves for the Primary End Point, Death from Any Cause, and Cardiovascular Death.

• • • •

N=1325 patients HF-rEF AHI≥15/hour of sleep Predominance of central apnea

Cowie MR et al. N Engl J Med 2015;373:1095-1105.

ASV for sleep-disordered breathing in patients with heart failure with reduced ejection fraction (ADVENT-HF) • Multicenter, multinational, parallel-group, open-label, phase 3 randomized controlled trial.

All

• The study did not reach its prespecified sample size. • ASV abolished both OSA and CSA • Follow-up of 3·6+ 1·6 years • Not significant effect on the primary endpoint or mortality • ASV did not increase mortality in those with CSA.

OSA

• Positive findings include: • Improvements in quality of life • HFrEF symptoms • Degree of sleepiness.

CSA

Cumulative probability of event curves all-cause mortality

Improvement of Idiopathic Central Sleep Apnea with Zolpidem • • • • • • •

N=20, 9 weeks AHI 30.0 ± 18.1 to 13.5 ± 13.3 (p =0.001), CAHI 26.0 ± 17.2 to 7.1 ± 11.8 (p <0.001) Arousals 24.0 ± 11.6 to 15.1 ± 7.7 (p <0.001) ESS 13 ± 5 to 8 ± 5 (p < 0.001). OSA increased in 3 patients In the absence of a randomized, controlled trial, zolpidem cannot be recommended for treatment of ICSA at this time.

Quadri et al. J Clin Sleep Med. 2009 April 15; 5(2): 122–129.

Effect of Supplemental Oxygen on AHI in Patients with CHF

Transvenous neurostimulation for central apnea

Costanzo MR et al. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial.2016 Sep 3;388(10048):974-82

AASM Clinical Practice Guidelines 2025 • Updated AASM guidelines on CSA treatment. • Developed using the GRADE process. • Incorporates new evidence on ASV and phrenic nerve stimulation. • Acknowledges that CSA is not a single disorder but a manifestation of breathing instability in various conditions. • Includes update recommendations on ASV and TPNS

CPAP Therapy • Recommendation: Use CPAP over no CPAP. • Applicable to: • Primary CSA • CSA due to heart failure • CSA due to medication/substance use • Treatment-emergent CSA • CSA due to a medical condition/disorder

• Strength: Conditional, Low certainty.

BPAP with Backup Rate • Recommendation: Use BPAP with backup rate over no BPAP. • Applicable to: • Primary CSA • CSA due to medication/substance use • Treatment-emergent CSA • CSA due to a medical condition/disorder

• Strength: Conditional, Very low certainty.

BPAP without Backup Rate • Recommendation: Against BPAP without backup rate. • Applicable to: • Primary CSA • CSA due to heart failure • CSA due to medication/substance use • Treatment-emergent CSA • CSA due to a medical condition/disorder

• Strength: Conditional, Very low certainty.

Adaptive Servo Ventilation • Recommendation: Use ASV over no ASV. • Applicable to: • Primary CSA • CSA due to heart failure • CSA due to medication/substance use • Treatment-emergent CSA • CSA due to a medical condition/disorder

• Strength: Conditional, Low certainty. • Remarks:

• Shared decision-making is essential. • In HFrEF: use only in experienced centers, with close monitoring.

Low-Flow Oxygen • Recommendation: Use low-flow oxygen over no low-flow oxygen. • Applicable to: CSA due to heart failure and High altitude. • Strength • Conditional, Low certainty ( HF) • Conditional, very low certainty –high altitude

• Transient symptoms in high altitude may not require treatment.

Oral Acetazolamide • Recommendation: Use oral acetazolamide over no acetazolamide. • Applicable to: • Primary CSA • CSA due to heart failure • CSA due to medication/substance use • Treatment-emergent CSA • CSA due to a medical condition/disorder • CSA due to high altitude

• Strength: Conditional, Low certainty. • Very low certainty for high altitude

Transvenous Phrenic Nerve Stimulation TPNS • Recommendation: Use TPNS over no TPNS. • Applicable to: • Primary CSA • CSA due to heart failure

• Strength: Conditional, Very low certainty. • Remarks: Invasive, costly, limited access — consider other treatments first.

Summary of Recommendations Intervention

Applicable Etiologies

Certainty

Strength

CPAP

All listed CSA types

Low

Conditional

BPAP + backup rate

Selected CSA types

Very low

Conditional

BPAP - backup rate

All listed CSA types

Very low

Against

ASV

All listed CSA types

Low

Conditional

Low-flow O2 (HF)

HF-related CSA

Low

Conditional

Low-flow O2 (Altitude) Altitude CSA

Very low

Conditional

Acetazolamide

All listed CSA types

Low/Very low Conditional

TPNS

Primary, HF CSA

Very low

Conditional

Our Approach When Data are few; experts are many ! • • • • •

Similar principles in CSA and PAP-emergent CSA Treat the underlying condition Initiating CPAP is the initial treatment Use other PAP modalities next (ASV or BPAP with backup rate). Combination Therapy (PAP plus O2 or acetazolamide).

High Yield Recent Articles for the Busy Sleep Medicine Clinician

Raman Malhotra, MD, FAASM Professor of Neurology Washington University in St. Louis

Conflicts of Interest X

1. I do not have any potential conflicts of interest to disclose, OR 2. I wish to disclose the following potential conflicts of interest: Type of Potential Conflict

Details of Potential Conflict

Where to find articles that are high yield? • Journal of Clinical Sleep Medicine/Sleep • Journals of the primary specialties (Pulm/Neuro/Psych/ENT) in Sleep • Journals read by people outside the sleep field • (NEJM, JAMA, Lancet, etc.)

• Articles called out by “throw away journals” or email blasts • Articles discussed in public media

Medications for OSA

GLP-1’s agonists and OSA

SURMOUNT-OSA in NEJM in 2024

Change in AHI and Body Weight.

Malhotra A et al. N Engl J Med2024;391:1193-1205

Primary and Key Secondary End Points According to Trial Group for the Treatment-Regimen

Malhotra A et al. N Engl J Med2024;391:1193-1205

Conclusions • Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes.

Another Medication for OSA in the pipeline

Schweitzer PK, et al. Am J Respir Crit Care Med, 2024

How will these medicines change workflow for the clinician? • Who will be prescribing these medications (sleep providers or PCP’s)? • How will payers proceed? (Prior authorizations, Step therapy) • We need to learn how to prescribe some/all of these medicines • Where does it fit in the treatment algorithm for OSA? • What about the Inspire patient that loses weight with a GLP1? • Wider Auto-PAP ranges? • When to re-test?

Health Disparities in Sleep

Different Hypopneas = Different Diagnosis

Certain Groups More Vulnerable Women

Young

Nonobese

Other

Some limitations: • Post-menopausal status not known in patients • BMI difference • Retrospective study

Overall Conclusions: • The AASM AHI overall detects sleep apnea in women better (especially those who are symptomatic) • The 4% criteria worsens health disparity • Women present with “atypical symptoms” of OSA

• More appropriate to say “different” as compared to obese males who were originally diagnosed with this condition • Women present with more fatigue, insomnia, anxiety, depression than males

Overall Findings: • 22% conversion rate at 5 years lower than the 33-35% of other reports and cohorts • Less male predominance of RBD in the Korean population • Are there other groups that are different ?

Hypoglossal Nerve Stimulation

“Recent” changes in criteria for Inspire: • AHI from 15-100

• BMI < 40

• Down’s syndrome age 13 years and up

Respiratory Medicine, 2024, Nov/Dec

AHI

ESS

QOL

Chu Z, Zhang C, Kwok E, Ng Y, Tang T, Toh ST, Loh S, Loh J. Hypoglossal nerve stimulation explantation in patients with obstructive sleep apnoea: a systematic review. J Laryngol Otol. 2024 Oct 25:1-8.

JAMA Otolaryngol Head Neck Surg. 2024 May 1;150(5):421-428.

April 2019 to January 2023

Results: • 78% achieved > 50% reduction in AHI and AHI < 15 • 39% had > 50% reduction in supine AHI and supine AHI < 15 • 49% had AHI less than 5

Overall Findings: • Our outcomes consistent with STAR trial • Decreased odds of responding if BMI 32 to 35 • HGNS does decrease supine AHI, but to a lesser degree • No difference in gender response • No difference in baseline severity of OSA

Orexin Agonists

5 New FDA Approved Medicines for Disorders of Hypersomnia in the last 22 years

2000’s

1900’s

2020

1997 2002 modafinil

1955

methylphenidate

2019

1996

Mixed amphetamine salts

2019

2023

Orexin as a target for therapy: • Dual orexin receptor antagonists already FDA approved for use in insomnia • Ideal use would be an agonist for patients with narcolepsy type 1 given underlying pathophysiology of loss of orexin neurons in the lateral hypothalamus • Orexin peptide does not cross blood/brain barrier

Orexin 2 Receptor is the main target • Orexins (orexin A and orexin B) act through orexin receptor 1 (OX1R) and 2 (OX2R) that are widely distributed throughout the brain • OX1R has more affinity to orexin A. OX2R has similar affinity for both orexin A and orexin B • OX1R and OX2R are involved with a variety of functions (some not sleep-related) including sleep-wake regulation • OXR2 involved with maintenance of wakefulness and onset of REM sleep

Orexin (Intravenous) • IV danavorexton (orexin 2 receptor agonist) has been shown in both animal models and humans with narcolepsy type 1 to greatly improve wakefulness and reduce cataplexy. This change was not seen in orexin 2 receptor (OX2R) knockout mice given this same infusion. • It has also shown improvement (less dramatic) in Narcolepsy type 2, idiopathic hypersomnia, and normal subjects. Evans R, et al. J Sleep Res 2023 Evans R, et al. Proc Natl Acad Sci, 2022 Mignot E, et al. Sleep, 2023 Sep

Healthy Adults

Evans R, et al. J Sleep Res 2023

N=14

N=13

N=14 Evans R, et al. Proc Natl Acad Sci, 2022

Subjective Sleepiness (ESS)

Evans R, et al. Proc Natl Acad Sci, 2022

• TAK-994 which is a highly selective oral OX2R agonist that crosses the blood-brain barrier • Phase 2, randomized placebo-controlled trial • Narcolepsy type 1 patients age 18-65 diagnosed using ICSD-3 criteria • Primary endpoint was MWT change in sleep latency in 8 weeks • Secondary endpoints were cataplexy, ESS, and safety measures Dauvilliers Y, et al. NEJM 2023

Dauvilliers Y, et al. NEJM 2023

Original Article

Oveporexton, an Oral Orexin Receptor 2–Selective Agonist, in Narcolepsy Type 1 Yves Dauvilliers, M.D., Giuseppe Plazzi, M.D., Emmanuel Mignot, M.D., Gert Jan Lammers, M.D., Rafael del Río Villegas, M.D., Ph.D., Ramin Khatami, M.D., Mitsutaka Taniguchi, M.D., Anson Abraham, Ph.D., Yaming Hang, Ph.D., Harisha Kadali, M.D., Marta Lamberton, B.S.Engr., Sarah Sheikh, B.M., B.Ch., Ellie Stukalin, Ph.D., Rachel Neuwirth, M.S., Todd J. Swick, M.D., Shinichiro Tanaka, Ph.D., Christian von Hehn, M.D., Ph.D., Philipp von Rosenstiel, M.D., Hao Wang, Ph.D., Alice Cai, M.D., Melissa Naylor, M.D., Ph.D., and Tina Olsson, Ph.D.

N Engl J Med Volume 392(19):1905-1916 May 15, 2025

Study Overview

• In this phase 2 randomized, placebocontrolled trial involving 112 participants with narcolepsy type 1, oveporexton significantly improved measures of wakefulness, sleepiness, and cataplexy over a period of 8 weeks.

Summary of Efficacy End Points from Baseline to Week 8.

Dauvilliers Y et al. N Engl J Med2025;392:1905-1916

Demographic, Clinical, and Biologic Characteristics of the Participants.

Dauvilliers Y et al. N Engl J Med2025;392:1905-1916

Efficacy End Points.

Summary of Safety Evaluations.

Dauvilliers Y et al. N Engl J Med2025;392:19051916

Conclusions • In this phase 2 trial involving participants with narcolepsy type 1, oveporexton significantly improved measures of wakefulness, sleepiness, and cataplexy over a period of 8 weeks.

MSLT Protocol

Conclusions: • Waking patients up at a standard time for the MSLT can lead to changes in findings on the MSLT • Patients who were allowed to sleep later (ad lib) had longer overnight total sleep times and longer mean sleep latencies on MSLT

September 12, 2025

T&A for Childhood SDB: Why, When & for Whom?

Ronald D Chervin, MD, MS Professor of Neurology, Director, Sleep Disorders Center Michael S Aldrich Collegiate Professor of Sleep Medicine Assistant Dean for Clinical Research

Conflicts of Interest 1. I wish to disclose the following potential conflicts of interest: Type of Potential Conflict

Details of Potential Conflict

Grant/Research Support

NIH

Consultant

Eli Lilly & Company, thru contract with Michigan Medicine

Intellectual Property

Named in copyrighted material and patents, owned by MM, designed to facilitate evaluation and treatment of sleep disorders including OSA

Other

President elect, International Pediatric Sleep Association Member, advisory board, non-profit Pajama Program Author and editor, UpToDate

2. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture: Pediatric sleep questionnaire (PSQ): validity and reliability of scales for sleep-disordered breathing, snoring, sleepiness, and behavioral problems. Chervin RD, Hedger K, Dillon JE, Pituch KJ. Sleep Med. 2000 Feb 1;1(1):21-32. Adenotonsillectomy for Snoring and Mild Sleep Apnea in Children: A Randomized Clinical Trial. Redline S, Cook K, Chervin RD, Ishman S, Baldassari CM, Mitchell RB, Tapia IE, Amin R, Hassan F, Ibrahim S, Ross K, Elden LM, Kirkham EM, Zopf D, Shah J, Otteson T, Naqvi K, Owens J, Young L, Furth S, Connolly H, Clark CAC, Bakker JP, Garetz S, Radcliffe J, Taylor HG, Rosen CL, Wang R; Pediatric Adenotonsillectomy Trial for Snoring (PATS) Study Team. JAMA. 2023 Dec 5;330(21):2084-2095.

Sleep Across the Lifecycle: A moving target, all connected

Daytime Behavioral Problems in Children https://www.youtube.com/watch?v=yRYl9Bf0yhs

Scope of the Problem: ADHD http://www.cdc.gov/ncbddd/adhd/data.html

Why Start Here? • Neurobehavioral problems may well be the most frequent adverse consequences of childhood OSA • Can have immense impact, with high costs to medical care, performance, quality of life, and families • Substantial public health burden

Child Psychiatry vs Gen Peds Waiting Room • Frequency of habitual snoring: • ADHD (n = 27) ------------------------------ 33% • Others at psych clinic (n = 43) ------ 11% • Children at general clinic (n = 73) - 9% • OR 5.2 for ADHD vs. general peds patients

• Chervin RD, et al. Sleep 1997; 20: 1185-1192.

Cross-Sectional Study N=866 children 2.0 – 13.9 yo • Conners’ T score > 1 sd above normal found in: • 22% of habitual snorers • 12% of non-snorers • Much of association derived from boys < 8 yo (Figure)

Chervin RD, et al. Pediatrics 2002;109:449-56.

Conduct Problem Index (CPRS-48)

Chervin RD, et al. J Am Acad Child Adolesc Psychiatry 2003;42;201-8.

Bullying N=341 2nd and 5th grade children

O’Brien LM et al. Sleep Med 2011;12:652-658.

Opportunity? What proportion of children with ADHD symptoms could experience resolution after diagnosis and treatment of underlying OSA? • 25% ? • 15% ?

Chervin RD, et al. Sleep 1997;20:1185-1192 Chervin RD, et al. Pediatrics 2002;109:449-56

Prospective Cohort (N=105) N = 78 subjects before and 1 year after AT N = 27 control subjects at baseline and 1 year

Chervin RD, et al. Pediatrics 2006:117;e769-78

Prospective Cohort (N=105) N = 40 subjects with OSA; pre and post AT N = 38 subjects without OSA; pre and post AT N = 27 control subjects Chervin RD, et al. Pediatrics 2006:117;e769-78

Randomized Clinical Trial -- early adenotonsillectomy (eAT) vs. -- watchful waiting and supportive care (WWSC) for 7 mos.

Marcus CL, et al. N Engl J Med. 2013 :20;368:2366-76 Redline et al. Sleep 2011;34:1509

Change in NEPSY – objective attention/executive functioning – in eAT vs WWSC groups 150 ¶ p = 0.16 (NS)

NEPSY A/E

125

100

Marcus CL, et al. NEJM. 2013 :20;368:2366-76

Baseline 7 Mo eAT

Baseline 7 Mo WWSC

¶ p is for difference in change, from baseline to 7 mos, between eAT and WWSC

BRIEF Global Executive Composite: Improved in eAT Subjective Analog of the NEPSY attention/executive functioning Mean Change (SD) -3.33 (8.45)

Q1 50

Median

T SCORE

Mean Change (SD) 0.39 (8.83)

50 40 30

WWSC Base WWSC 7 mo

eAT Base

P<0.0001

eAT 7 mos

Change in Quality of Life, OSA Symptoms, and Sleepiness

But: PSG variables showed limited, if any predictive value Garetz SL, et al. Pediatrics 2015; 135:e477-e486

Randomized Clinical Trial – Pediatric Adenotonsillectomy Trial for Snoring

Redline S, et al. JAMA. 2023;330:2084-2095 Wang R, et al. BMJ Open 2020;10:e033889

Goals • To understand the role of adenotonsillectomy in children with mild sleepdisordered breathing (mSDB = habitual snoring and AHI <3) in improving cognition, behavior, quality of life, blood pressure, and health care utilization • To identify subgroups that may respond better to adenotonsillectomy, and aid in selection of best candidates for surgery

PATS: Study Designs Parallel-arm, randomized, singled-blinded, controlled trial of eAT vs WWSC across 7 sites • Outcomes measured at 6 and 12 months

Eligibility • Ages 3 to 12 years • Habitual snoring + AHI < 3

Interventions Early Adenotonsillectomy (eAT)

•

Standard clinical AT performed by PATS-certified ENT surgeon within 4 weeks of randomization.

•

Healthy sleep habits education

•

Appropriate clinical referrals for management of comorbidities

Watchful Waiting with Supportive Care (WWSC)

•

Healthy sleep habits education

•

Appropriate clinical referrals for management of co-morbidities

Protocol Overview Study Flow Schedule AT within 1-4 weeks of randomization

ENT clinic General pediatrics clinic Sleep clinic Asthma clinic

eAT

Interview Consent

Baseline Assessments Educational Materials

ENT Visit (if not done clinically)

Research PSG (or confirmatory re-scoring of clinical PSG)

Randomize

Preliminary Screen (EMR review)

6M Behavioral Visit

Supportive Care

WWSC

12 mos PSG and Behavioral Visit

12 Month AHI Levels AHI > 3

Proportion of Children with SDB at 12 months, by randomization arm

AHI >5

Risk Difference -11.2% (-17.5 to -4.9) -7.1 (-11.8 to -2.5) p<0.001

Co-Primary Outcomes (Neurobehavioral) Not Significantly Improved with eAT

12-month Post-AT Secondary Outcomes were Improved - differences in 12-mos changes; 95% CI, FDR corrected - all changes were in desirable direction

• Disease-specific QoL • Behavior – OSA-18 – Child Behavior Checklist • 9.75 (-12.50, -7.00) • -3.09 (-4.70, -1.48) • OSA Symptom Burden – Pediatric Sleep Questionnaire - SleepRelated Breathing Disorder SRBD Scale • -0.16 (-0.19, -0.13)

• Generic QoL (PedsQL) – Physical Subscore • 6.53 (1.29,11.78) – Psychosocial • 3.88 (0.89, 6.88)

• Sleepiness – mESS • -1.18 (-2.04, -0.32)

• Systolic BP (%ile) • -9.02 (-14.77, -3.27) • Diastolic BP (%ile) • -6.52 (-11.59,-1.45)

Percent of Subjects with Abnormal Assessment Scores at 12 months: Adenotonsillectomy vs Watchful Waiting 60 50 40

-30.8*

Difference:

-5.9*

-4.0 (NS)

-13.0*

10 0

BRIEF

PSQ-SRBD

ESS

OSA18

-27.3* Hab Snoring

WWSC

The percent of study participants with at least one elevated score declined from 80% to 38% in the eAT group and to 65% in the WWSC

PATS vs CHAT: Snoring / Mild SDB vs OSA N=459 with MSDB in PATS N=453 with OSA in CHAT • Children with MSDB vs OSA had: • higher sleep efficiency, fewer arousals • worse executive functioning (OR 2.0 [1.3,2.9] • worse Conners scores • inattention (OR 3.2 [2.0, 5.0]) • hyperactive behavior (OR 2.8 [1.8, 4.3] Yu PK, et al. Sleep 2022;12;45:zsac035. Giordani B, et al. J Int Neuropsychol Soc 2008;14:571-581.

24%

12%

Lessons from CHAT + PATS • Children with moderate OSA do not have worse behavioral morbidity than children with primary snoring/mild SDB (AHI<3) • Traditional PSG metrics (AHI)

• Do not predict symptoms, quality of life, or behavior • Do not predict surgical response • Symptoms do predict executive function and symptomatic improvement with surgery

• Adenotonsillectomy • Does not improve objective cognitive measures • Does improve behavior, other symptoms, quality of life, sleepiness, & BP • Improvements occur in children with snoring regardless of AHI severity (or BMI)

Are Any Subgroups More Likely to Benefit? Aims of post-hoc PATS Analysis

1 Define clinically meaningful ATresponsive secondary outcomes

Create a single composite positive benefit variable from those outcomes

Select easy access subgroup characteristics

Test which characteristics are associated with the composite positive benefit outcome

Chervin RD & Gueye-Ndiaye S et al. (submitted)

Who is most likely to benefit from AT? • Sample from PATS: 363 children, ages 3.0 to 12.9 years, randomized to eAT (n=178) or WWSC (n=185), with complete secondary outcome data • 55% > 5 years old, 51% male • 28% Black, 14% Latino • 43% with maternal education ≥ 4 years of college • 15% had asthma; 17% ETS exposure; 51% allergic rhinitis; 37% overweight or obesity • 50% had enlarged tonsils (grades III and IV) • 22% had elevated Mallampati scores (III and IV).

• Analytic Approach

• Create a single composite positive benefit outcome variable • Test interaction models (adjusted for age group, overweight status, race, and study site)

4 Domains of “Clinically Meaningful” Improvement after 12 months • Quality of life • OSA-18 ≥ 20-point decrease, or PedsQL ≥ 4.5-point increase

• Sleepiness symptoms • mESS ≥ 2 points

• Behavior • CBCLTot or CBCLInt ≥ 10-point decrease

• Physical health • For SBP or DBP ≥ 10-point decrease and/or ≤ 50th %ile, with baseline > 50th %ile

SDB Symptoms and PSG Data • Among all 363 children: • 278 (77%) had PSQ-SRBD Scale score ≥ 0.33 • median score (IQR) = 0.45 (0.22 – 0.59)

•115 (32%) had an AHI ≥ 1/hr • median (IQR) = 0.5 (0.2 – 1.1)

TRT, median (IQR)

526 (4

Arousal index, median (IQR)

5.5 (

Sleep efficiency, %, median (IQR)

90 (84

% N1, median (IQR)

6.7 (

% N2, median (IQR)

44.2 (3

% N3, median (IQR)

30 (26

% REM sleep, median (IQR)

17.1 (1

AHI (event/hr), median (IQR)

0.5 (

AHI ≥ 1 event/hr, No. (%)

Minimum oxygen saturation, median (IQR)

92 (

% TST with O2 sat <90%, median (IQR)

Oxygen desaturation index (ODI), median (IQR)

1.6 (

% TST with CO2 > 50 mmHg (n=323), median (IQR)

0.1 (

PLMI ≥ 5 (event/hr), No. (%)

Percentage of Group That Improved

Component Improvement, in 4 Domains, by Treatment Group 100

eAT WWSC

90 80 70 60

40 30 20

37 29

CBCL Tot

CBCL Int

OSA 18

34 28

10 0

Domains:

Behavior

PedQL

Quality of Life

mESS

Subjective Sleepiness

SBP

DBP

Physical Health (Blood Pressure)

Composite Positive Outcome Variable from Responsive Domains

Percentage of Group That Improved

Component/Domain vs Composite Improvement by Treatment Group 100

Improvement in at least 2 domains

eAT WWSC

90 80 70

40 30 20

37 29

CBCL Tot

CBCL Int

34 28

10 0

Behavior

OSA 18

PedQL

Quality of Life

mESS

SBP

DBP

Subjective Physical Health Sleepiness (Blood Pressure)

Composite

Looked Back for Potential Effect Modifiers: What predicts more benefit from eAT over WWSC? … Among baseline variables accessible in clinical practice, prior to AT • Demographics (age group, sex, race, ethnicity, maternal education [proxy for SES]) • Health factors (asthma, nasal allergies, environmental tobacco smoke [ETS], overweight [>85th percentile, for age and sex], short sleep, tonsil size, Mallampati) • Symptom burden (PSQ-SRBD scale and subscales) • Polysomnographic measures (sleep, respiratory, O2 and CO2 indices, PLMI)

Results: OR’s of the Interaction Models for Subgroup Predictors and Composite Outcomes • Among all patients, adenotonsillectomy (AT) treatment effect: • OR 2.8 (CI, 1.8, 4.4); p <0.01

• Subgroups with significantly better AT treatment effects:

• Higher vs lower Mallampati -- III & IV (crowded airway) vs I & II: OR 4.2 (CI, 1.2, 15.6); p = 0.027

• In contrast: No “usual suspects” predicted clinically-meaningful benefit from AT: • Higher apnea-hypopnea index (AHI) • More symptoms • Overweight • Exposure to smoking

(p = 0.47) (p = 0.70) (p = 0.89) (p = 0.10)

Chervin RD & Gueye-Ndiaye S et al. (submitted)

Conclusions • Clinically-meaningful responses to AT in children with little to no sleep apnea (MSDB) arise regardless of age, sex, race, symptom burden, overweight or obesity, tonsil size, and apnea-hypopnea index (AHI) • Benefits are not restricted to groups based on demographics, symptoms, exam, or polysomnography • Exception: higher Mallampati scores predict likely benefit from AT • A polysomnogram negative for SDB need not necessarily preclude AT

Implications • Higher Mallampati – crowding between base of tongue and soft palate – but not tonsillar size predicts more clinical improvement after AT as opposed to WWSC • Spontaneous improvement over 12 months of WWSC (with any tonsillar regression?) may be more likely when extratonsillar airway is unobstructed at baseline. • For children who have extratonsillar obstruction, tonsillar regression not as helpful. • Could interventions to address a low palate or large uvula, in addition to AT, have more complete or long-lasting benefit than AT alone for children with SDB?

Questions • MSDB vs OSA (PATS vs CHAT)

• Similar or worse neurobehavioral morbidity, in SDB with or without hypoxic burden • Arousals and sleep fragmentation also did not predict morbidity • Should we study other measures, to improve patient-centered care? • subcortical arousals, work of breathing, or respiratory cycle-related EEG changes (RCREC) • other biomarkers, PSG phenotyping, questionnaires, physical exam findings • AI / machine learning

• If objective cognitive measures do not improve after AT …

• Could it be that SDB leads to irreversible brain injury? • Could injury occur very early, only to become apparent later at “eloquent” ages? • When does MSDB or SDB in children need to be identified, treated, or prevented?

Questions • MSDB vs OSA (PATS vs CHAT)

• If objective cognitive measures do not improve after AT …

OSA Beyond Early Childhood Are there long-term permanent consequences to sleep problems, especially in a developing child?

OSA Beyond Early Childhood

Early childhood snoring scores were higher among low-performing (LP) than high-performing (HP) 13-14 year-old children

Gozal D and Pope DW. Pediatrics 2001;107:1394

OSA beyond Childhood Baseline habitual snoring in 28 children aged 2 – 13 (at right), vs. Absence of habitual snoring in 191 children aged 2 - 13 (at left) … predicted higher Hyperactivity Index T-scores at 4-year followup.

Chervin RD et al. Sleep 2005;28:885

OSA Long-Term Effects? Avon Longitudinal Study of Parents and Children

Early-life, self-limited witnessed apneas (AP), snoring (SN), and mouth breathing (MB): predict 40 to 50% increased odds of behavior problems at age 7 years.

Bonuck K et al. Pediatrics 2012;129:e857

Potential Developmental Trajectories

Beebe DW. Sleep 2006;29:1115

Potential Developmental Trajectories

Modified from Beebe DW. Sleep 2006;29:1115

Impact of OSA Beyond Childhood – Implications •If:

• OSA may have long-term impact on brain function

Impact of OSA Beyond Childhood – Implications •If:

• OSA may have long-term impact on brain function • Brain damage may be irreversible later in life

Impact of OSA Beyond Childhood – Implications •If:

• OSA may have long-term impact on brain function • Brain damage may be irreversible later in life • Phenotypic expression may be delayed for years

Impact of OSA Beyond Childhood – Implications •If:

• OSA may have long-term impact on brain function • Brain damage may be irreversible (CHAT, PATS cognitive outcomes) • Phenotypic expression

•Then:

• How much earlier must OSA be: • Detected and treated? • Prevented?

Newborns: SDB in the NICU • SDB in otherwise healthy neonates – not simple to study • However: Critically-ill newborns often have EEG monitoring and may agree to PSG

Meerkov MS, et al. Pediatr Pulm 2019;54:557

SDB in the NICU • 12-hour PSGs:

• AHI 10 • Min O2 81% • No events > 20 seconds (threshold NICU monitors)

• Impact?

Meerkov MS, et al. Pediatr Pulm 2019;54:557

SDB in the NICU • Contrary to hypotheses: • Found virtually no associations with 18mos Bayley III • Cognitive • Motor • Language

Meerkov MS, et al. Pediatr Pulm 2019;54:557

Could sleep rather than SDB have more influence?

Saletin JM et al, Sleep 2025;48:zsaf097

SDB vs. Sleep in Neonates • Could sleep more generally be a key issue for neonates? • Efficiency of deep NREM sleep may be key

• Shorter time spent in NREM sleep • Increased low-frequency power in NREM sleep • More attenuation of FTOE on NIRS, in NREM vs wake

• Sleep-wake cycling may be one of the most eloquent functions accomplished by the brain of a neonate

Shellhaas, RA et al. Sleep 2017;40:zsx144

Delta EEG Power in NREM Sleep of Neonates Lower delta power in EEG during NREM (quiet) sleep is associated with higher Thompson scores (reflecting worse neurologic function) Shellhaas, RA et al. Neurology 2014;82:390–395

Sleep in Neonates (n=29): Predictive Value

Thompson Score as Neonate

Shellhaas, RA et al. Sleep 2017;40:zsx144

Neonatal EEG delta power and neurodevelopmental outcomes

Shellhaas, RA et al. Sleep 2017;40:zsx144

Neonatal EEG delta power and neurodevelopmental outcomes

But: is sleep in the NICU modifiable? Shellhaas, RA et al. Sleep 2017;40:zsx144

Impact of Hands-On Care in the NICU Among N = 25 term or near-term infants in NICU, median minutes between contacts by staff was 2.3 min. Handling occurred across all sleep/wake states without bias (p=.99) and often preceded apneic events.

Levy J, et al. Pediatr Pulmonol. 2017;52:84–90

Could we be more aware about when a critically-ill infant is asleep? • Many physiological variables are monitored in the NICU • Not sleep • Could existing signals, or limited additional signals, be used to identify sleep/wake states in real time and guide non-time-sensitive care?

• R33HL154095; Drs. Gliske (MPI), Barks (MPI), Shellhaas, Chervin

Sleep in neonates may be modifiable through simple intervention Playback of recorded maternal voice (reading stories, red) diminished probability of awakening to loud noises in NICU (p = .009)

Shellhaas, RA et al. Pediatrics 2019;144(3):e20190288

SDB in MMC

Sleep-Disordered Breathing in Infants with Myelomeningocele R01 HL147261 Shellhaas, Barks, Chervin for the SDB in MMC Investigators at 9 Sites

Hypothesis: Sleep-disordered breathing (SDB) is frequent in newborns with myelomeningocele even after fetal repair.

Multicenter observational study: 1) Examine SDB in infants with fetal versus post-natal MMC repair. 2) Evaluate potential impact of neonatal SDB on 2-year outcomes. 3) Evaluate potential impact of neonatal sleep on 2-yr sleep outcomes.

Sleep at age 2 years Fetal vs. Post-natal Aim 1 MMC Surgery

Neonatal Sleep

Aim 2 Developmental Outcome at 2 years

Sleep-Disordered Breathing diagnoses among n=173 infants after myelomeningocele closure

Shellhaas RA et al. (submitted)

Preliminary Results N=173; 90 fetal & 83 postnatal MMC closure • 92/173 (53%) had SDB on neonatal PSG. • Univariate Analysis: AHI after fetal rather than postnatal surgery • (median 29, IQR 14-49, vs. 19, IQR 10-36, p=0.008). • Propensity-adjusted models: • Gestational age explained the association of fetal repair with AHI. • left surgery timing without significance. • Neither the clinical need for VP shunt, hindbrain herniation, nor MMC level predicted AHI in adjusted models.

SDB in MMC

Preliminary Conclusions

• Sleep-disordered breathing is common in neonates with myelomeningocele. • The higher AHI after fetal surgery could result from higher rates of prematurity. • SDB assessment may be appropriate as early as the first weeks after delivery. • More data on treatment outcomes are still needed. • As SDB is treatable, early diagnosis and intervention could become an integral part of a multidisciplinary treatment strategy to optimize long-term outcomes.

SDB and sleep in Neonates – Take Home Points • SDB is highly common in neonates who are critically ill (at least), possibly in relation to low gestational age at birth • Abnormal sleep and sleep cycling may have impact • Opportunities may exist -- through simple interventions, avoidance of unnecessary interventions, or feasible choices in care -- to improve neonatal sleep

How early does SDB raise concerns? -Pregnancy?

Pregnancy – Impact of OSA on Mother (n=1305) • Snoring, OSA associated with gestational hypertension, preeclampsia, diabetes • Pregnancy-onset snoring associated with higher SBP by 18 weeks; chronic snoring associated by 3rd trimester.

Dunietz GL, et al. JCSM 2022;18(1):31–38.

Pregnancy – Impact of OSA on Fetus and Newborn • Chronic maternal snoring 

• Risk for preterm birth • Birth with small-for-gestational age • Possibly large-for-gestational age in some subsets

• Fetal heart rate decelerations • Possible epigenetic effects

• ↑ weight, adiposity in offspring • Shortened telomeres

Dunietz GL et al. Paediatr Perinat Epidemiol 2018;32:504-511 O’Brien LO et al. Sleep 2013;36:1625 Telerant A et al. Sci Reports 2018;8:10768 Pitts DS et al. Reprod Sci 2021;28:2601 Khalyfa A et al. J Physiol 2017;595:2551

Key Questions Why? • Childhood SDB and sleep disturbance likely promote brain dysfunction, ADHD, related behavior, cardiovascular, and additional morbidity • Treatment has substantial benefit for parent-reported externalizing and internalizing behavior, sleepiness, QoL • Treatment has potential to reduce lifelong morbidity

Key Questions When? • How early is SDB a concern? • Could we prevent development of pediatric OSA before it appears? • How and when do we need to screen for pediatric OSA? • Do we need to focus on sleep in OSA, and if so, at what ages? • Trajectory of OSA vs appearance of its impact • Could treatment of SDB in infancy improve outcomes in later life?

Key Questions – For Whom • Could treatment of OSA during pregnancy improve outcomes for mothers, infants, children, and adults? • What levels of OSA, using what measures, during which phases of pregnancy or childhood, offer best chance to reduce adverse outcomes?

Key Questions – For Whom 1. How do we recognize who will benefit, today or in the future, from treatment now? 2. How do we know that treatment has been adequate, and more is not needed? 3. How do we screen children to identify treatment candidates more effectively?

NIH Support • Chervin: HL105999, HL080941, HD38461, NS02009 • Marcus/Furth, Redline (CHAT): HL083075, HL083129, RR024134, RR024989 • Redline/Wang (PATS): HL125295, HL125307 • Gliske, Barks: HL154095 • O’Brien: HL089918, HL095739 • Shellhass, Barks, Chervin: HL147261, HD068402

Acknowledgements and Many Thanks (very partial list) • Michael Aldrich, MD • Raouf Amin, MD • Kristen Archbold, PhD • John Barks, MD • Karen Bonuck, PhD • Joseph Burns, PhD • James Dillon, MD • Dawn Dore-Stites, PhD • Galit Dunietz, PhD • Barbara Felt, MD • J. Fetterolf, RPSGT, REEGT

• Susan Garetz, MD • Bruno Giordani, PhD • Stephen Gliske, PhD • C. Guilleminault, MD • Ken Guire, MS • Fauziya Hassan, MBBS • Timothy Hoban, MD • Elise Hodges, PhD • Erica Jansen, PhD • Niko Kaciroti, PhD • Erin Kirkham, MD, MPH

• Carole Marcus, MBBCh • Lisa Matlen, MD • Ron Mitchell, MD • Lora Merley, RPSGT • Louise O’Brien, PhD • Stephanie Rau, MA • Susan Redline, MD, MPH • Carol Rosen, MD • Deborah Ruzicka, PhD • Renee Shellhaas, MD, MS • Robert Weatherly, MD • David Zopf, MD, MS

Advancing Sleep Care: Updates from AASM Anita V. Shelgikar, MD, MHPE President

aasm.org

Conflict of Interest Disclosures I have no relevant financial relationships with ineligible companies to disclose.

Disclaimer I serve on the board of directors of the AASM, and I am giving this presentation as a spokesperson for the organization. The information in this presentation reflects the positions and policies of the AASM and may not represent my personal views and opinions.

About AASM

50 Years 1975 - 2025

aasm.org/about/history

AASM Strategic Plan: 2024 - 2027 Vision | Our Impact Sleep and circadian care is fundamental to health care. Mission | What We Do Advancing sleep care and enhancing sleep health to improve lives

Strategic Goals Sleep Medicine Awareness

Practice Success

Technology Integration

Strategic Initiatives

HSAT Code Change Application

• AMA CPT Editorial Panel • Update the CPT codes for HSAT • Capture new FDAauthorized tech • Accurately reflect services provided • AMA RUC survey

Re-Envisioning Adult OSA Characterization

• To create a framework that addresses the limitations of the AHI • Reviewed other classifications, drafted a process, identified stakeholders • New steering committee to focus on research & development, testing & feedback, and dissemination

Obesity Management

• FDA approval of tirzepatide • Priority topic • Panel discussion webinar • Obesity Medicine Association • April webinar • New task force Image copyright: Obesity Action Coalition

Compensation Analysis

• Physicians, APPs, and sleep technologists • Last report was in 2018 • Data collection in August & September 2024 • New report now available

Patient-reported Longitudinal Assessment Tool for OSA

• PLATO • Finalized & validated • Posted under “Accepted Papers” in JCSM • English & Spanish questionnaire • Free license for clinicians & researchers

Women’s Sleep Health Task Force

• Aims to improve care for women across life stages • Focus on education, research, advocacy, and collaboration • Organizing a summit, webinar series, and clinical and scientific meeting presentations

Sleep Physician Pipeline

• Advancing Innovation in Residency Education (AIRE) pilot programs

 Part-time model  Blended model • Medical Specialties Matching Program • Record “Match” of 207 physicians in December 2024

Emerging Technology

• Emerging Technology Committee • #SleepTechnology • An online resource of trending consumer & clinical sleep tech • Objective assessments for sleep clinicians • aasm.org

Journal of Clinical Sleep Medicine

• Premier journal for human sleep and circadian science • Editor-in-Chief transition: Dr. Safwan Badr became the new editor in January • Springer Nature • jcsm.aasm.org

Sleep is Good Medicine • Multi-year, national PR campaign • Sleep is as important as nutrition and exercise • General public and health care professionals • SleepisGoodMedicine.com

Patient Advocacy Roundtable

• Partnering with patient organizations to advance shared goals • Advocating together for patients who have sleep disorders • Collaborating to raise awareness • Increasing the patient voice in AASM initiatives

Sleep & Student Health

• School Lesson Plans oYoung Minds Inspired oGrades 3-5, 6-8 and 9-12 • High School Video Contest • Student Sleep Health Week oResolution in U.S. House oThird week of September oAnnual awareness event

AASM Advocacy

Federal Support of the Sleep Field

• AASM advocates for federal support of sleep and circadian research and clinical sleep medicine • AASM urges federal leaders to prioritize sleep programs by the NIH, VA, and CMS

Make America Healthy Again

• Commission established by executive order • Report and strategy focusing on children’s health • Describes a “nationwide sleep crisis”

Physician Reimbursement

• CMS proposed rule • 2026 Medicare physician fee schedule • Two conversion factors • AASM comment letter • Final rule

Coalition for Permanent Standard Time

• CpST • AASM, NSF, Save Standard Time, SRS, and SRBR • Advocating at state and federal level • ditchDST.com

AASM Foundation • More than $31.7 million awarded • Key programs include: o Career Development Grants o Strategic Research Grants o Community Sleep Health and Public Awareness Grants o Young Investigators Research Forum foundation.aasm.org

Recently Published Papers

Position Statement: Clinical Significance of Sleepiness

• Born out of the limitations of the AHRQ CPAP Technical Report • Endorsed by several societies • Position states that sleepiness is a critical patient-reported outcome associated with increased risk for adverse health effects & diminished quality of life • April 2025 issue of JCSM

Treatment of RLS & PLMD

• Clinical practice guideline & systematic review • Updates the 2012 practice parameters • Adult & pediatric patients • January 2025 issue of JCSM

Treatment of central sleep apnea in adults Evaluation and management of SDB in adult nonsurgical inpatients

Other Papers in Progress

Combination treatment for chronic insomnia Treatments for shift work disorder Use of HSAT in pediatric populations – Update Diagnostic testing for OSA in adults – Focused Update Medications for residual sleepiness in OSA

Professional Education

• Nov. 14 – 15 • In person in Austin, Texas • Livestreamed

Sleep Medicine Disruptors

• Innovations in sleep health, patient care, and health care delivery • aasm.org/event

• Feb. 20 - 22 • In person in Atlanta, Georgia • Latest clinical developments in sleep medicine

Sleep Medicine Trends

• aasm.org/event

SLEEP Annual Meeting of the APSS

• SLEEP 2026 • Baltimore • 40th annual meeting of the Associated Professional Sleep Societies (APSS) • June 14 to 17 • Pre-conference courses June 13 to 14 • AASM, SRS, and AAST • sleepmeeting.org

Talking Sleep Podcast

Sample episode topics: • RBD phenoconversion • Zolpidem and the glymphatic system • Teledentistry • Sleep and ADHD • Central sleep apnea • Clinician burnout • Women’s sleep health

Questions? Anita V. Shelgikar, MD, MHPE ashelgikar@aasm.org contact@aasm.org accreditation@aasm.org coding@aasm.org membership@aasm.org (630) 737-9700

Enhancing CBT-I with Circadian Strategies to Improve Insomnia Leslie Swanson, Ph.D., D. BSM Professor of Psychiatry University of Michigan

Conflicts of Interest X

1. I do not have any potential conflicts of interest to disclose, OR 2. I wish to disclose the following potential conflicts of interest: Type of Potential Conflict

Details of Potential Conflict

Background and rationale

Outline

Recognizing circadian clues in insomnia Adjunctive circadian interventions for insomnia Summary

BACKGROUND AND RATIONALE

Content Based on a Recent Sleep Medicine Clinics Publication

Swanson LM, Raglan GB. Circadian Interventions as Adjunctive Therapies to Cognitive-Behavioral Therapy for Insomnia. Sleep Med Clin. 2023 Mar;18(1):21-30. doi: 10.1016/j.jsmc.2022.09.004. PMID: 36764783; PMCID: PMC10015491. WITH THANKS TO MY CO-AUTHOR, DR. GRETA RAGLAN

The Need for Adjunctive CBT-I Treatment Components CBT-I is effective for many, but not all, individuals with insomnia Current CBT-I protocols pay limited attention to the circadian system Misalignment between the sleep and circadian systems may underlie persistent insomnia symptoms Adjunctive circadian-focused therapies may enhance outcomes when integrated with CBT-I

Two Process Model of Sleep and Wake Regulation Wake

Homeostatic sleep drive

Melatonin

Wake propensity

Circadian alerting signal

Sleep 9am

3pm

Awake

9pm

3am

Asleep

Dijk DJ et al. J Physiol. 1997;505:851-858. Edgar DM et al. J Neurosci. 1993;13:1065-1079. Kilduff TS, Kushida CA. Circadian regulation of sleep. In: Chokroverty S, ed. Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects. 2nd ed. Boston, MA: Butterworth-Heinemann; 1999:135-145.

9am

What is the Circadian Clock? Circa = about Dia = a day

Videnovic, A. et al. (2014) ‘The clocks that time us’—circadian rhythms in neurodegenerative disorders Nat. Rev. Neurol.

Circadian Entrainment Zeitgebers (“Time Givers”) Social interaction

Meals

Exercise

LIGHT Czeisler CA, Allan JS, Strogatz SH, et al. Bright light resets the human circadian pacemaker independent of the timing of the sleep-wake cycle. Science 1986; 233:667–71. Quante M, Mariani S, Weng J, et al. Zeitgebers and their association with rest-activity patterns. Chronobiol 2019;36(2):203–13.

RECOGNIZING CIRCADIAN CUES IN INSOMNIA

Patient: Linda, 65-year-old retired elementary school teacher

Linda: Early Morning Awakening Insomnia

Chief Complaint: “I wake up way too early and can’t fall back asleep.”

Duration: Symptoms began approximately 8 years ago Bedtime: ~10:00 PM (unable to fall asleep if goes to bed earlier)

Sleep Schedule: Sleep Onset Latency: 10–15 minutes Wake After Sleep Onset: 30 minutes Final Wake Time: ~ 4:00 AM

Daytime Functioning: Feels sleepy in the afternoon

Linda: Early Morning Awakening Insomnia

Medical/Psychiatric History: Mild hypertension; no current depression or anxiety

Sleep Habits: Lies awake in bed until 6:30 am alarm, thinking about her to-do list and worrying about family stressors.

Evening Routine:

Dim lighting, minimal screen time, often reads before bed

Circadian Dysregulation and Insomnia Subtypes: Early Morning Awakening Insomnia Awakening too early, difficulty resuming sleep May be associated with advanced circadian rhythms (“morning larks”) More frequent in older adults Significantly earlier circadian timing per body temperature and melatonin rhythms Sleep period timed so considerable portion overlaps with the wake-up zone Lack LC, Mercer JD, Wright H. Circadian rhythms of early morning awakening insomniacs. J Sleep Res 1996;5(4):211–9.

Patient: Jalen, 24 year old graduate student

Jalen: Sleep Onset Insomnia

Chief Complaint: “I can’t turn off my brain and fall asleep.”

Duration: Symptoms began approximately 2 years ago Bedtime: ~11:30 PM Sleep Onset Latency: 120 minutes

Sleep Schedule: Wake After Sleep Onset: 20 minutes Final Wake Time: ~ 7:30 AM on school days, 10:00 AM on weekends

Daytime Functioning: Feels very groggy in the morning, may nap in the afternoon

Jalen: Sleep Onset Insomnia

Medical/Psychiatric History: Current mild anxiety

Sleep Habits: Uses phone in bed when can’t sleep, stays in bed with racing anxious thoughts about school when unable to fall asleep

Works until 1 hour before bed, Evening Routine:

watches TV on phone in bed until lights out

Circadian Dysregulation and Insomnia Subtypes: Sleep Onset Insomnia Difficulty falling asleep, more common in young adults

May be associated with delayed circadian rhythms (“night owls”)

Adults with sleep onset insomnia have a later melatonin onset time vs. those without

Attempting to sleep during forbidden zone

May be exacerbated by sleeping later on weekends Flynn-Evans EE, Shekleton JA, Miller B, et al. Circadian phase and phase angle disorders in primary insomnia. Sleep 2017;40(12). Wright HR, Lack L, Bootzin RR. Relationship between dim light melatonin onset and the timing of sleep in sleep onset insomniacs. Sleep Biol Rhythms 2006;4:78–80.

ADJUNCTIVE CIRCADIAN INTERVENTIONS FOR INSOMNIA

Overview of Most Commonly Used Adjunctive Circadian Interventions

Bright light

Dim light

Melatonin

TIMING IS IMPORTANT: INCORRECT TIMING CAN EXACERBATE SLEEP PROBLEMS

Summary of Adjunctive Circadian Interventions Sleep Period: Early Morning Awakening Insomnia

Sleep Period: Sleep Onset Insomnia

18:00

19:00

20:00

21:00

22:00

23:00

00:00

01:00

02:00

03:00

04:00

05:00

Clock Time (hh:mm)

Figure 1. Summary of timing of circadian interventions relative to the sleep period by insomnia subtype = bright light therapy;

= dim light or blue-blocking glasses;

= melatonin 0.5 mgs

06:00

07:00

08:00

09:00

10:00

Most potent cue (zeitgeber) for the clock

Strategically Timed Bright Light

Adjunctive use supported in a meta-analysis Impact depends on time of administration van Maanen A, Meijer AM, van der Heijden KB, et al. The effects of light therapy on sleep problems: a systematic review and meta-analysis. Sleep Med Rev 2016;29:52–62.

Phase Response Curve to Light

Emens JS, Burgess HJ. Effect of light and melatonin and other melatonin receptor agonists on human circadian physiology. Sleep Med Clin 2015;10(4):435–453

Morning Bright Light Therapy for Sleep Onset Insomnia

Exposure starting 2 h before habitual wake time will advance (move earlier) circadian clock BUT if timed too early (> 2 h before habitual wake time) can cause phase delay and lead to lengthening of sleep onset

Bright Light Therapy

Morning Bright Light Therapy for Sleep Onset Insomnia

Patient should maintain a consistent wake time throughout therapy Wait to start light therapy until after 2nd CBT-I session • Patient has maintained consistent wake time across work days and days off • Sleeping in on days off can contribute to light therapy causing circadian phase delay on work days

Morning Bright Light Therapy for Sleep Onset Insomnia

10,000 lux light box OR light therapy glasses

Patient instructed to use device for 30-60 minutes as close to their scheduled wake time as possible

Ideally start time is no later than 30 minutes after scheduled wake time

If they wake before scheduled therapy time, they should wait to start treatment until their scheduled wake time

Evening Bright Light Therapy for Early Morning Awakening Insomnia

Light therapy in the evening can delay circadian timing Can start in first session of CBT-I May also help patient to stay awake until scheduled bed time

Evening Bright Light Therapy for Early Morning Awakening Insomnia

2,500 lux light– light box or if necessary, can experiment with bright overhead lighting Patients instructed to use light therapy in the evening, ending at their bed time, or ending up to 3 hours before their scheduled bedtime Initially scheduled to end 1 hour before scheduled bedtime and adjust as needed

Evening Bright Light Therapy for Early Morning Awakening Insomnia

If patient develops difficulty falling asleep, treatment should be ended earlier (1.5-3 hours before bedtime) If early morning awakenings persist, can extend treatment later Adjust timing of treatment along with bedtime as treatment progresses

Bright Light Therapy Considerations: Device Selection • Historically, light boxes were used • Broad spectrum or blue-green light • Lux 2,500 – 10,000 • Early morning awakenings = consider lower lux (used in the evening) • Sleep onset insomnia = Higher lux (used in morning) • Placed 2 feet away from patient

Bright Light Therapy Considerations: Device Selection • Newer, wearable devices are available • Ideally projects light upwards from below the eye so skull does not block light • Enables many activities • Some glasses have lower lux setting and can be used for evening bright light therapy

Bright Light Therapy: Side Effects

Most common side effects: • Headache • Eyestrain • Nausea • Agitation

Often spontaneously remit within 1-2 weeks Can adjust dose to 15-30 minutes to address side effects Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS Spectr 2005;10(8): 647–63

Medical conditions

Bright Light Therapy: Contraindications

• Epilepsy/seizures, lupus or other conditions associated with light sensitivity, retinal pathology, retinal surgery)

Use of photosensitizing medications

Use with caution in patients with a history of mania or bipolar disorder

• Close monitoring required to prevent mania/hypomania

Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS Spectr 2005;10(8): 647–63

Dim Light Therapy

Evidence for improvement of insomnia symptoms

Strategically Timed Dim Light Shechter A, Kim EW, St-Onge MP, et al. Blocking nocturnal blue light for insomnia: a randomized controlled trial. J Psychiatr Res 2018;96: 196–202. Hester L, Dang D, Barker CJ, et al. Evening wear of blueblocking glasses for sleep and mood disorders: a systematic review. Chronobiol 2021;38(10): 1375–83.

Can start at first CBT-I session Patient should be instructed to remain in very dim light • Just enough light to see what you are doing • Ideally, light-emitting devices not used during this time (dim device to lowest possible setting, use blue light filter) • Blue-blocking glasses may be used • May require light-blocking curtains, window coverings

BlueBlocking Glasses

Can aid in preventing light from suppressing melatonin production

Can improve insomnia symptoms

Select glasses that block short wavelength light (~100% of blue light), provide as much coverage around the eye area as possible (wrap-around lenses) and are tinted (orange, amber, brown)

Used during dim light periods Shechter A, Quispe KA, Mizhquiri Barbecho JS, et al. Interventions to reduce short-wavelength (“blue”) light exposure at night and their effects on sleep: a systematic review and metaanalysis. Sleep Adv 2020;1(1). 10.1093/sleepadvances/zpaa002.

Blue-Blue Blocking Glasses Uvex Skyper ($12-$15)

Evening Dim Light for Sleep Onset Insomnia Dim light or blue-blocking glasses starting at least 90 minutes before scheduled bedtime

Can extend up to 120 minutes when possible or if shorter duration not effective

Remain in dim light until scheduled wake time

If need to follow stimulus control rules, employ same dim light protocol

Set daily alarm on phone to remind patient of start time

Morning Dim Light for Early Morning Awakening Insomnia

Dim light (or blue-blocking glasses) throughout their scheduled time in bed period Especially important if they wake earlier than their scheduled wake time Remain in dim light until scheduled wake time Ideal to avoid bright light exposure for first hour after scheduled wake time when possible May require use of dark sunglasses if patient must be outdoors

Morning Dim Light for Early Morning Awakening Insomnia

Dim light or blue-blocking glasses throughout time in bed period, limit use of light-emitting devices

Especially when awake earlier than scheduled time

Remain in dim light until scheduled wake time

Ideally extended into first hour after scheduled wake time

Melatonin

For sleep onset insomnia

Melatonin Low TL, Choo FN, Tan SM. The efficacy of melatonin and melatonin agonists in insomnia - an umbrella review. J Psychiatr Res 2020;121:10–23 Paul MA, Gray GW, Lieberman HR, et al. Phase advance with separate and combined melatonin and light treatment. Psychopharmacology 2011; 214(2):515–23.

Not likely to help sleep maintenance or early morning awakenings Can be used in conjunction with bright light therapy

Melatonin Phase Response Curve

Emens JS, Burgess HJ. Effect of light and melatonin and other melatonin receptor agonists on human circadian physiology. Sleep Med Clin 2015;10(4):435–453

Melatonin Small dose of melatonin (0.5 mgs) taken 5 hours before habitual sleep onset time • Usually requires patient to buy 1 mgs tablets and cut them in half • Avoid extended release as they may lead to spillover of melatonin into zone that could delay circadian timing • Move administration time earlier as bed time is adjusted • Have patient set phone alarm for administration time (many forget!) Burgess HJ, Revell VL, Molina TA, et al. Human phase response curves to three days of daily melatonin: 0.5 mg versus 3.0 mg. J Clin Endocrinol Metab 2010;95(7):3325–31

Drowsiness

Melatonin: Side Effects Andersen LP, Gogenur I, Rosenberg J, et al. The safety of melatonin in humans. Clin Drug Investig 2016;36(3):169–75.

Headaches Dizziness Nausea

Diabetes Hypertension

Melatonin: Contraindications

Clotting/bleeding disorders Seizures/epilepsy Pregnancy/attempting conception

Melatonin. Food, herbs & supplements. In: Natural medicines [internet database]. Somerville, MA: Therapeutic Research Center; 2022

Breastfeeding

CONCLUSIONS AND SUMMARY

Take Home Messages

Some of your patients may not respond fully to CBT-I. Adjunctive circadian-focused interventions may aid in their treatment response. Use your assessment and case conceptualization to identify clues that may point towards integration of adjunctive circadian strategies. Employ strategies based on insomnia subtype and patient’s safety profile.

Summary of Adjunctive Interventions Subtype

Morning Bright Light

Sleep Onset Insomnia

10,000 lux at scheduled wake time

Early Morning Awakening

Evening Bright Light

Morning Dim Light

Evening Dim Light 90-120 min before bedtime

2,500 lux in evening

Bedtime through 1 h after scheduled wake time

Melatonin 0.5 mg 5 h before habitual sleep onset

THANK YOU!

Championship Updates in Sleep Medicine 2025