Narcolepsy¶
VERSION: 1.1 CREATED: January 30, 2026 REVISED: January 31, 2026 STATUS: Draft - Pending Review
DIAGNOSIS: Narcolepsy (Type 1 and Type 2)
ICD-10: G47.411 (Narcolepsy with cataplexy), G47.419 (Narcolepsy with cataplexy, unspecified), G47.421 (Narcolepsy without cataplexy), G47.429 (Narcolepsy without cataplexy, unspecified)
SYNONYMS: Narcolepsy, narcolepsy type 1, narcolepsy type 2, narcolepsy with cataplexy, narcolepsy without cataplexy, NT1, NT2, hypocretin deficiency syndrome, orexin deficiency syndrome, Gelineau syndrome, excessive daytime sleepiness with cataplexy, central disorder of hypersomnolence, sleep attack disorder
SCOPE: Diagnosis and management of narcolepsy type 1 (with cataplexy/orexin deficiency) and type 2 (without cataplexy) in adults. Covers diagnostic workup including PSG/MSLT, CSF orexin, pharmacologic treatment of excessive daytime sleepiness and cataplexy, and long-term management. Excludes idiopathic hypersomnia as separate entity, Kleine-Levin syndrome, and secondary narcolepsy due to structural brain lesions.
DEFINITIONS: - Narcolepsy Type 1 (NT1): Central disorder of hypersomnolence with cataplexy and/or CSF hypocretin-1 (orexin-A) ≤110 pg/mL; caused by loss of hypothalamic hypocretin-producing neurons - Narcolepsy Type 2 (NT2): Central disorder of hypersomnolence without cataplexy and with normal or untested CSF hypocretin-1 levels - Cataplexy: Sudden, brief episodes of bilateral skeletal muscle weakness triggered by strong emotions (laughter, surprise, anger) with preserved consciousness - Sleep-Onset REM Period (SOREMP): REM sleep occurring within 15 minutes of sleep onset on PSG or MSLT - Excessive Daytime Sleepiness (EDS): Inability to maintain sustained wakefulness during the day; the hallmark and most disabling symptom of narcolepsy - Hypnagogic/Hypnopompic Hallucinations: Vivid, often frightening, dream-like experiences at sleep onset (hypnagogic) or upon awakening (hypnopompic) - Sleep Paralysis: Inability to move or speak while falling asleep or waking up, lasting seconds to minutes
DIAGNOSTIC CRITERIA (ICSD-3-TR):
Narcolepsy Type 1 — All of the following:
- Daily periods of irrepressible need to sleep or daytime lapses into sleep
- At least one of the following:
- Cataplexy AND either:
- Mean sleep latency ≤8 min with ≥2 SOREMPs on MSLT (a SOREMP within 15 min on preceding nocturnal PSG may replace one SOREMP on MSLT)
- CSF hypocretin-1 concentration ≤110 pg/mL or less than one-third of mean normal values
- Cataplexy AND either:
Narcolepsy Type 2 — All of the following:
- Daily periods of irrepressible need to sleep or daytime lapses into sleep for ≥3 months
- Mean sleep latency ≤8 min with ≥2 SOREMPs on MSLT (a SOREMP within 15 min on preceding nocturnal PSG may replace one SOREMP on MSLT)
- No cataplexy
- CSF hypocretin-1 either not measured or >110 pg/mL
- Not better explained by another sleep, medical, or psychiatric disorder, or medication/substance use
Classic Narcolepsy Tetrad (present in ~10-15% of NT1):
- Excessive daytime sleepiness (100% of patients)
- Cataplexy (~70% of NT1; absent in NT2)
- Sleep paralysis (~25-50%)
- Hypnagogic/hypnopompic hallucinations (~30-60%)
Epworth Sleepiness Scale (ESS) Severity: - Normal: 0-10 - Mild sleepiness: 11-14 - Moderate sleepiness: 15-17 - Severe sleepiness: 18-24
PRIORITY KEY: STAT = Immediate | URGENT = Within hours | ROUTINE = Standard | EXT = Extended/atypical cases | - = Not applicable to this setting
1. LABORATORY WORKUP¶
1A. Essential/Core Labs (All Patients)¶
| Test | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| CBC (CPT 85025) | Exclude anemia contributing to fatigue | Normal | ROUTINE | ROUTINE | ROUTINE | - |
| CMP (CPT 80053) | Renal/hepatic function; electrolytes; pre-treatment baseline | Normal | ROUTINE | ROUTINE | ROUTINE | - |
| TSH (CPT 84443) | Exclude hypothyroidism causing fatigue/hypersomnia | Normal | ROUTINE | ROUTINE | ROUTINE | - |
| Serum ferritin (CPT 82728) | Iron deficiency contributes to EDS and RLS comorbidity | >30 ng/mL | - | ROUTINE | ROUTINE | - |
| Urine drug screen (CPT 80307) | Exclude substance use causing sleepiness; required pre-MSLT | Negative | URGENT | ROUTINE | ROUTINE | - |
1B. Extended Workup (Second-line)¶
| Test | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| CSF hypocretin-1 / orexin-A (sent to Stanford reference lab) | Definitive diagnosis of NT1 if ≤110 pg/mL; useful when MSLT equivocal or impractical | ≤110 pg/mL diagnostic of NT1; >200 pg/mL normal | - | EXT | EXT | - |
| HLA-DQB1*06:02 typing (CPT 81383) | Present in >90% of NT1; supportive but not diagnostic (also in 25% general population) | Positive supports NT1 diagnosis | - | - | EXT | - |
| Vitamin B12 (CPT 82607) | Deficiency can cause fatigue | >400 pg/mL | - | ROUTINE | ROUTINE | - |
| HbA1c (CPT 83036) | Diabetes screening; metabolic contributors to fatigue | <5.7% | - | ROUTINE | ROUTINE | - |
| Hepatic function panel (CPT 80076) | Baseline before medication initiation | Normal | - | ROUTINE | ROUTINE | - |
1C. Rare/Specialized¶
| Test | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| Anti-streptococcal antibodies (ASO, anti-DNase B) | Pediatric/young adult onset following streptococcal infection | Document; may support autoimmune etiology | - | - | EXT | - |
| Anti-tribbles homolog 2 (TRIB2) antibodies | Research biomarker for autoimmune etiology of NT1 | Document | - | - | EXT | - |
| Serum cortisol / ACTH | If adrenal insufficiency suspected | Normal | - | - | EXT | - |
2. DIAGNOSTIC IMAGING & STUDIES¶
2A. Essential/First-line¶
| Study | Timing | Target Finding | Contraindications | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| Polysomnography (PSG) (CPT 95810) | Night before MSLT; required for MSLT interpretation | Exclude OSA, PLMD; document SOREMP within 15 min | None | ROUTINE | ROUTINE | - | |
| Multiple Sleep Latency Test (MSLT) (CPT 95805) | Day following PSG; at least 2 weeks off REM-suppressant medications | Mean sleep latency ≤8 min with ≥2 SOREMPs | Must have preceding PSG; stop REM-suppressants 2 weeks prior | - | ROUTINE | ROUTINE | - |
2B. Extended¶
| Study | Timing | Target Finding | Contraindications | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| MRI brain with and without contrast (CPT 70553) | If secondary narcolepsy suspected (structural hypothalamic lesion) | Rule out hypothalamic mass, demyelination, sarcoidosis | Per MRI contraindications | - | ROUTINE | ROUTINE | - |
| Actigraphy (2 weeks) (CPT 95803) | Pre-MSLT; document adequate sleep schedule | ≥7 hours nightly sleep for 2 weeks before MSLT | None | - | - | ROUTINE | - |
| Sleep diary (2 weeks) | Pre-MSLT; confirm adequate sleep duration | ≥7 hours nightly for 2 weeks | None | - | - | ROUTINE | - |
2C. Rare/Specialized¶
| Study | Timing | Target Finding | Contraindications | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| Maintenance of Wakefulness Test (MWT) (CPT 95805) | Treatment response monitoring; fitness-for-duty evaluation | Mean latency >8 min (normal >40 min) | None | - | - | EXT | - |
| Repeat MSLT | If initial MSLT equivocal or performed while on REM-suppressants | Confirm or refute diagnosis | Same as initial MSLT | - | ROUTINE | EXT | - |
LUMBAR PUNCTURE¶
Indication: CSF hypocretin-1 (orexin-A) measurement for definitive diagnosis of NT1 when MSLT is equivocal, impractical, or when patient cannot discontinue REM-suppressant medications Timing: ROUTINE; elective in outpatient or inpatient setting Volume Required: 1-2 mL (standard diagnostic)
| Study | Rationale | Target Finding | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|
| CSF hypocretin-1 / orexin-A | Definitive biomarker for NT1; ≤110 pg/mL diagnostic | ≤110 pg/mL (NT1); >200 pg/mL normal; 110-200 intermediate | - | ROUTINE | ROUTINE | - |
| Cell count | Rule out inflammatory process | WBC <5, RBC 0 | - | ROUTINE | ROUTINE | - |
| Protein | Rule out CNS inflammation | 15-45 mg/dL | - | ROUTINE | ROUTINE | - |
| Glucose with serum glucose | Baseline; rule out infection | >60% serum glucose | - | ROUTINE | ROUTINE | - |
Special Handling: CSF must be frozen immediately and sent to reference laboratory (Stanford Narcolepsy Center or equivalent); assay not widely available Contraindications: Coagulopathy; increased intracranial pressure; infection at puncture site
3. TREATMENT¶
3A. Non-Pharmacologic Treatment (All Patients)¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Scheduled daytime naps | - | EDS management; adjunct to all pharmacotherapy | 15-20 minute naps 1-2 times daily; schedule at predictable times (mid-morning, early afternoon) | None | Symptom response | - | ROUTINE | ROUTINE | - |
| Sleep hygiene optimization | - | Consolidate nocturnal sleep; reduce daytime sleepiness | Regular sleep-wake schedule; 7-9 hours nightly; cool dark room; limit screen time before bed | None | Adherence | - | ROUTINE | ROUTINE | - |
| Avoid sedating substances | - | Prevent worsening of EDS | Avoid alcohol, sedating antihistamines, benzodiazepines; limit caffeine to morning only | None | Symptom response | ROUTINE | ROUTINE | ROUTINE | - |
| Safety counseling | - | Prevent injury from sleepiness or cataplexy | Driving restrictions until EDS controlled; avoid heights, swimming alone, operating heavy machinery | None | Compliance | ROUTINE | ROUTINE | ROUTINE | - |
3B. First-Line Treatment - Excessive Daytime Sleepiness¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Modafinil (Provigil) | PO | First-line wake-promoting agent for EDS | 100 mg :: PO :: daily :: Start 100 mg each morning; increase to 200 mg daily after 1 week; may split 200 mg AM + 200 mg early afternoon if needed; max 400 mg/day | Hypersensitivity; severe hepatic impairment; may reduce efficacy of hormonal contraceptives | Blood pressure; rash (rare Stevens-Johnson); sleep quality; contraceptive efficacy | - | ROUTINE | ROUTINE | - |
| Armodafinil (Nuvigil) | PO | First-line wake-promoting agent for EDS; longer duration than modafinil | 150 mg :: PO :: daily :: Start 150 mg each morning; may increase to 250 mg daily; longer half-life than modafinil; max 250 mg/day | Hypersensitivity; severe hepatic impairment; may reduce efficacy of hormonal contraceptives | Blood pressure; rash (rare Stevens-Johnson); sleep quality; contraceptive efficacy | - | ROUTINE | ROUTINE | - |
| Solriamfetol (Sunosi) | PO | EDS in narcolepsy; dopamine/norepinephrine reuptake inhibitor | 75 mg :: PO :: daily :: Start 75 mg once daily upon awakening; may increase to 150 mg daily after ≥3 days; max 150 mg/day for narcolepsy | Concurrent MAOIs; uncontrolled hypertension; severe renal impairment (eGFR <15); end-stage renal disease | Blood pressure; heart rate; psychiatric symptoms; weight; renal function | - | ROUTINE | ROUTINE | - |
| Pitolisant (Wakix) | PO | EDS and cataplexy in narcolepsy; histamine-3 receptor antagonist/inverse agonist | 8.9 mg :: PO :: daily :: Start 8.9 mg once daily upon awakening; titrate weekly: 8.9 mg to 17.8 mg to 35.6 mg; max 35.6 mg/day | Severe hepatic impairment; concurrent strong CYP2D6 inhibitors (max 17.8 mg); QT-prolonging drugs | QTc interval if risk factors; hepatic function; insomnia; headache | - | ROUTINE | ROUTINE | - |
3C. Treatment - Cataplexy and REM-Related Symptoms¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Sodium oxybate (Xyrem) | PO | First-line for cataplexy; also improves EDS and disrupted nocturnal sleep; REMS program (Xyrem REMS) | 2.25 g :: PO :: BID nightly :: Start 4.5 g/night divided into 2 equal doses (2.25 g at bedtime + 2.25 g 2.5-4 hours later); titrate by 1.5 g/night every 1-2 weeks; effective range 6-9 g/night; max 9 g/night | Succinic semialdehyde dehydrogenase deficiency; concurrent sedative-hypnotics or alcohol; concurrent opioids; untreated sleep-disordered breathing | Respiratory depression; CNS depression; sleepwalking; depression/suicidality; sodium intake (high sodium content); abuse potential | - | ROUTINE | ROUTINE | - |
| Lower-sodium oxybate (Xywav) | PO | First-line for cataplexy; 92% less sodium than Xyrem; also improves EDS and disrupted nocturnal sleep; REMS program (Xywav REMS) | 2.25 g :: PO :: BID nightly :: Start 4.5 g/night divided into 2 equal doses at bedtime and 2.5-4 hours later; titrate by 1.5 g/night every 1-2 weeks; max 9 g/night | Succinic semialdehyde dehydrogenase deficiency; concurrent sedative-hypnotics or alcohol; concurrent opioids | Respiratory depression; CNS depression; sleepwalking; depression/suicidality; abuse potential | - | ROUTINE | ROUTINE | - |
| Venlafaxine | PO | Anticataplectic agent; also treats comorbid depression and anxiety | 37.5 mg :: PO :: daily :: Start 37.5 mg daily; increase by 37.5-75 mg every 1-2 weeks; target 75-225 mg/day; max 225 mg/day | Concurrent MAOIs; uncontrolled hypertension; abrupt discontinuation risk | Blood pressure; heart rate; serotonin syndrome; discontinuation symptoms if stopped abruptly; suicidality in young adults | - | ROUTINE | ROUTINE | - |
| Fluoxetine | PO | Anticataplectic agent; also treats comorbid depression | 10 mg :: PO :: daily :: Start 10-20 mg daily; increase by 10-20 mg every 2-4 weeks; target 20-60 mg/day; max 80 mg/day | Concurrent MAOIs; concurrent pimozide or thioridazine | Serotonin syndrome; QTc at higher doses; activation/insomnia; suicidality in young adults | - | ROUTINE | ROUTINE | - |
| Clomipramine | PO | Potent anticataplectic agent; tricyclic antidepressant with strong REM-suppressive properties | 10 mg :: PO :: QHS :: Start 10-25 mg at bedtime; titrate by 25 mg every 1-2 weeks; target 25-75 mg/day; max 150 mg/day | Recent MI; concurrent MAOIs; cardiac conduction disease; urinary retention; narrow-angle glaucoma | ECG if dose >75 mg/day or age >40; anticholinergic effects; orthostatic hypotension; weight gain; sexual dysfunction | - | ROUTINE | ROUTINE | - |
3D. Second-Line / Refractory Treatment¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Methylphenidate (Ritalin) | PO | EDS refractory to first-line agents; rapid onset of action | 5 mg :: PO :: BID :: Start 5 mg BID (morning and early afternoon); titrate by 5-10 mg/week; max 60 mg/day; avoid evening dosing | Concurrent MAOIs; severe anxiety or agitation; motor tics/Tourette; glaucoma; structural cardiac abnormalities | Blood pressure; heart rate; weight; appetite; growth (pediatric); psychiatric symptoms; abuse potential | - | ROUTINE | ROUTINE | - |
| Dextroamphetamine (Dexedrine) | PO | EDS refractory to modafinil/solriamfetol; potent wake-promoting agent | 5 mg :: PO :: daily :: Start 5 mg once or twice daily; titrate by 5 mg/week; max 60 mg/day; avoid evening dosing | Concurrent MAOIs; advanced atherosclerosis; symptomatic cardiovascular disease; moderate-severe hypertension; glaucoma; agitated states; history of drug abuse | Blood pressure; heart rate; weight; appetite; psychiatric symptoms; abuse potential (Schedule II) | - | ROUTINE | ROUTINE | - |
| Mixed amphetamine salts (Adderall) | PO | EDS refractory to first-line agents; combined amphetamine formulation | 5 mg :: PO :: daily :: Start 5 mg once or twice daily; titrate by 5-10 mg/week; max 60 mg/day; avoid evening dosing | Concurrent MAOIs; advanced atherosclerosis; symptomatic cardiovascular disease; moderate-severe hypertension; glaucoma; agitated states; history of drug abuse | Blood pressure; heart rate; weight; appetite; psychiatric symptoms; abuse potential (Schedule II) | - | ROUTINE | ROUTINE | - |
| Protriptyline | PO | Anticataplectic agent with stimulant properties; less sedating TCA | 5 mg :: PO :: daily :: Start 5 mg in the morning; titrate by 5-10 mg every 1-2 weeks; max 60 mg/day | Recent MI; concurrent MAOIs; cardiac conduction disease; urinary retention; narrow-angle glaucoma | ECG if dose >20 mg/day or age >40; anticholinergic effects; dry mouth; urinary retention | - | - | EXT | - |
3E. Adjunctive / Symptomatic Treatment¶
| Treatment | Route | Indication | Dosing | Contraindications | Monitoring | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|---|---|
| Melatonin | PO | Disrupted nocturnal sleep; circadian rhythm support | 3 mg :: PO :: QHS :: 3-5 mg 30 minutes before bedtime; may help consolidate nighttime sleep | Autoimmune conditions (theoretical) | Daytime sedation; next-day grogginess | - | ROUTINE | ROUTINE | - |
| Trazodone | PO | Disrupted nocturnal sleep; comorbid insomnia | 25 mg :: PO :: QHS :: Start 25-50 mg at bedtime; max 100 mg; avoid if nocturnal oxybate used | Concurrent MAOIs; may worsen daytime sedation | Priapism (rare); orthostatic hypotension; next-day sedation | - | ROUTINE | ROUTINE | - |
| Atomoxetine | PO | EDS with comorbid ADHD; norepinephrine reuptake inhibitor with mild anticataplectic properties | 40 mg :: PO :: daily :: Start 40 mg daily; increase to 80 mg after ≥3 days; max 100 mg/day | Concurrent MAOIs; narrow-angle glaucoma; pheochromocytoma; severe cardiovascular disease | Blood pressure; heart rate; hepatic function (rare hepatotoxicity); suicidality in children/adolescents | - | - | EXT | - |
4. OTHER RECOMMENDATIONS¶
4A. Referrals & Consults¶
| Recommendation | ED | HOSP | OPD | ICU |
|---|---|---|---|---|
| Sleep medicine specialist for PSG/MSLT scheduling, diagnosis confirmation, and treatment optimization | - | ROUTINE | ROUTINE | - |
| Neurology for evaluation of secondary causes if structural brain lesion suspected or atypical presentation | ROUTINE | ROUTINE | ROUTINE | - |
| Psychiatry for management of comorbid depression, anxiety, or behavioral issues associated with narcolepsy | - | ROUTINE | ROUTINE | - |
| Social work for disability evaluation, vocational counseling, and community resource coordination | - | - | ROUTINE | - |
| Occupational therapy for workplace accommodation strategies and energy conservation techniques | - | - | ROUTINE | - |
| Pulmonology if concurrent obstructive sleep apnea identified on PSG requiring CPAP titration | - | ROUTINE | ROUTINE | - |
4B. Patient/Family Instructions¶
| Recommendation | ED | HOSP | OPD | ICU |
|---|---|---|---|---|
| Narcolepsy is a lifelong neurological condition caused by loss of brain cells that produce hypocretin; it is not laziness or a psychological problem | ROUTINE | ROUTINE | ROUTINE | - |
| Do not drive until excessive daytime sleepiness is adequately controlled with treatment (risk of sleep attacks at the wheel) | ROUTINE | ROUTINE | ROUTINE | - |
| Report to state DMV as required by local law; obtain fitness-to-drive evaluation through MWT when applicable | - | - | ROUTINE | - |
| Take scheduled 15-20 minute naps during the day to improve alertness (naps are therapeutic, not a sign of inadequate treatment) | - | ROUTINE | ROUTINE | - |
| Do not abruptly stop antidepressant medications used for cataplexy as this may cause severe rebound cataplexy (status cataplecticus) | ROUTINE | ROUTINE | ROUTINE | - |
| Notify all providers about narcolepsy diagnosis before any sedation or anesthesia (heightened sensitivity to sedatives) | ROUTINE | ROUTINE | ROUTINE | - |
| Avoid alcohol, which worsens excessive sleepiness and disrupts nocturnal sleep | ROUTINE | ROUTINE | ROUTINE | - |
| Wear medical alert identification stating narcolepsy diagnosis, especially if taking sodium oxybate | - | ROUTINE | ROUTINE | - |
| Narcolepsy Network (narcolepsynetwork.org) and Wake Up Narcolepsy (wakeupnarcolepsy.org) for patient resources and support groups | - | - | ROUTINE | - |
4C. Lifestyle & Prevention¶
| Recommendation | ED | HOSP | OPD | ICU |
|---|---|---|---|---|
| Maintain strict sleep-wake schedule with consistent bedtime and wake time to consolidate nocturnal sleep | - | ROUTINE | ROUTINE | - |
| Regular moderate exercise (30 minutes daily) to improve alertness and overall health; avoid vigorous exercise close to bedtime | - | - | ROUTINE | - |
| Avoid heavy meals during the day as postprandial sleepiness exacerbates EDS | - | ROUTINE | ROUTINE | - |
| Limit caffeine to morning hours only; excessive caffeine may disrupt nighttime sleep without adequately controlling EDS | - | ROUTINE | ROUTINE | - |
| Inform employer about narcolepsy for reasonable workplace accommodations (scheduled nap breaks, flexible schedule) under ADA | - | - | ROUTINE | - |
| Avoid shift work and jobs requiring sustained vigilance (air traffic control, long-haul driving) unless EDS is well-controlled | - | - | ROUTINE | - |
| Emotional management strategies to reduce cataplexy triggers; cognitive behavioral techniques for emotional regulation | - | - | ROUTINE | - |
| Weight management as narcolepsy type 1 is associated with obesity and metabolic syndrome | - | - | ROUTINE | - |
5. DIFFERENTIAL DIAGNOSIS¶
| Alternative Diagnosis | Key Distinguishing Features | Tests to Differentiate |
|---|---|---|
| Obstructive sleep apnea (OSA) | Snoring, witnessed apneas, obesity; EDS improves with CPAP; no cataplexy; MSLT may show shortened latency but typically <2 SOREMPs | PSG with respiratory scoring; AHI >5 events/hour |
| Idiopathic hypersomnia | Prolonged non-refreshing sleep; sleep inertia/drunkenness; no cataplexy; MSLT mean latency ≤8 min but <2 SOREMPs; long total sleep time (>11 hours) | MSLT (<2 SOREMPs); actigraphy showing prolonged sleep; CSF orexin normal |
| Insufficient sleep syndrome | Chronic sleep restriction; resolves with sleep extension; no cataplexy; ESS elevated but normalizes with adequate sleep | Sleep diary/actigraphy showing <7 hours habitual sleep; resolution with sleep extension |
| Depression with hypersomnia | Depressed mood, anhedonia, psychomotor retardation; fatigue more than true sleepiness; no cataplexy; MSLT usually normal | Psychiatric evaluation; PHQ-9; MSLT typically mean latency >8 min |
| Medication-induced somnolence | Temporal relationship to medication initiation; resolves with dose reduction or discontinuation; no cataplexy | Medication review; temporal correlation |
| Hypothyroidism | Fatigue, cold intolerance, weight gain, constipation; no cataplexy; no SOREMPs | TSH elevated; free T4 low |
| Periodic limb movement disorder | Nocturnal limb movements; EDS from sleep disruption; no cataplexy | PSG with PLMS >15/hour without other narcolepsy features |
| Kleine-Levin syndrome | Recurrent episodes of hypersomnia lasting days-weeks with cognitive/behavioral changes; asymptomatic between episodes | Episodic pattern; normal inter-episode PSG/MSLT |
| Epilepsy (atonic seizures) | Sudden falls with loss of consciousness (vs. preserved consciousness in cataplexy); may have postictal confusion | EEG; video-EEG monitoring; no emotional trigger |
| Conversion disorder (functional cataplexy) | Atypical triggers; prolonged episodes; variable pattern; no other narcolepsy symptoms | PSG/MSLT normal; CSF orexin normal; psychiatric evaluation |
6. MONITORING PARAMETERS¶
| Parameter | Frequency | Target/Threshold | Action if Abnormal | ED | HOSP | OPD | ICU |
|---|---|---|---|---|---|---|---|
| Epworth Sleepiness Scale (ESS) | Each visit | ESS ≤10 (normal range) | Adjust wake-promoting agent dose or switch therapy | - | ROUTINE | ROUTINE | - |
| Cataplexy frequency (episodes/week) | Each visit | Reduction ≥50% from baseline | Adjust anticataplectic dose; add or switch therapy | - | ROUTINE | ROUTINE | - |
| Blood pressure | Each visit; more frequently if on stimulants or solriamfetol | <140/90 mmHg | Dose reduction; add antihypertensive; switch medication | ROUTINE | ROUTINE | ROUTINE | - |
| Heart rate | Each visit if on stimulants | <100 bpm resting | Dose reduction; cardiology referral if persistent tachycardia | ROUTINE | ROUTINE | ROUTINE | - |
| Weight/BMI | Every 3-6 months | Stable or improving | Dietary counseling; exercise; evaluate medication effects | - | ROUTINE | ROUTINE | - |
| Mood/depression screening (PHQ-9) | Every 3-6 months | PHQ-9 <5 | Psychiatric referral; adjust medications; monitor suicidality | - | ROUTINE | ROUTINE | - |
| QTc interval (if on pitolisant) | Baseline and with dose changes | QTc <470 ms (women) / <450 ms (men) | Reduce dose or discontinue; correct electrolytes; cardiology referral | - | ROUTINE | ROUTINE | - |
| Hepatic function (if on pitolisant or atomoxetine) | Baseline; 6 months; annually | Normal ALT/AST | Dose reduction or discontinuation | - | ROUTINE | ROUTINE | - |
| Sodium intake assessment (if on Xyrem) | Each visit | Dietary sodium within guidelines | Switch to Xywav (lower-sodium formulation); dietary counseling | - | ROUTINE | ROUTINE | - |
| Sleep quality / nocturnal disruption | Each visit | Consolidated nocturnal sleep | Adjust sodium oxybate dose; evaluate comorbid sleep disorders | - | ROUTINE | ROUTINE | - |
| Driving safety assessment | Every 6-12 months | Able to maintain wakefulness during driving | Reinforce driving restrictions; consider MWT; adjust treatment | - | - | ROUTINE | - |
| Substance use screening (if on stimulants) | Every 6-12 months | No misuse | Consider non-stimulant alternatives; refer to addiction medicine | - | - | ROUTINE | - |
7. DISPOSITION CRITERIA¶
| Disposition | Criteria |
|---|---|
| Outpatient management | Majority of patients; newly suspected or established narcolepsy for diagnostic workup and chronic management |
| Admit for PSG/MSLT | Patients requiring in-lab sleep study; schedule PSG night followed by next-day MSLT; ensure REM-suppressants discontinued ≥2 weeks |
| Admit to floor | Severe rebound cataplexy (status cataplecticus) after abrupt discontinuation of anticataplectics; narcolepsy with concurrent medical condition requiring inpatient management |
| Transfer to higher level | Not typically applicable; consider if respiratory depression from sodium oxybate or overdose |
| Sleep medicine referral | All patients with suspected narcolepsy for diagnostic confirmation and treatment initiation |
| Neurology referral | Atypical presentation; suspected secondary narcolepsy; treatment-refractory cases |
| Follow-up frequency | Every 2-4 weeks during initial titration; every 3-6 months once stable |
8. EVIDENCE & REFERENCES¶
| Recommendation | Evidence Level | Source |
|---|---|---|
| ICSD-3 diagnostic criteria for narcolepsy type 1 and type 2 | Consensus guidelines | Trotti LM. Curr Med Res Opin 2016 |
| CSF hypocretin-1 ≤110 pg/mL diagnostic for narcolepsy type 1 | Class I | Mignot et al. Arch Neurol 2002 |
| CSF hypocretin deficiency in narcolepsy with cataplexy | Class I | Nishino et al. Ann Neurol 2001 |
| Modafinil efficacy for EDS in narcolepsy | Class I, Level A | US Modafinil in Narcolepsy Multicenter Study Group. Neurology 2000 |
| Modafinil systematic review and meta-analysis | Class I, Level A | Golicki et al. Br J Clin Pharmacol 2010 |
| Solriamfetol efficacy for EDS in narcolepsy (TONES 2) | Class I, Level A | Thorpy et al. Ann Neurol 2019 |
| Pitolisant efficacy for EDS in narcolepsy (HARMONY I) | Class I, Level A | Dauvilliers et al. Lancet Neurol 2013 |
| Pitolisant long-term efficacy and safety (HARMONY III) | Class II, Level B | Dauvilliers et al. Sleep 2019 |
| Sodium oxybate efficacy for cataplexy | Class I, Level A | Xyrem International Study Group. Sleep Med 2005 |
| Sodium oxybate systematic review for narcolepsy-cataplexy | Class I, Level A | Alshaikh et al. J Clin Sleep Med 2012 |
| European guideline on narcolepsy management (modafinil, pitolisant, SXB, solriamfetol strong; methylphenidate, amphetamines weak for EDS) | Guideline, GRADE methodology | Bassetti et al. J Sleep Res 2021 |
| Venlafaxine and clomipramine strong recommendation for cataplexy | Guideline | Bassetti et al. J Sleep Res 2021 |
| Scheduled naps improve alertness in narcolepsy | Class II, Level B | Expert consensus; Bassetti et al. J Sleep Res 2021 |
| HLA-DQB1*06:02 associated with narcolepsy type 1 (>90%) | Class I | Mignot et al. Arch Neurol 2002 |
| Rebound cataplexy with abrupt antidepressant discontinuation | Class III, Level C | Expert consensus; case reports |
| Sodium oxybate REMS program required | FDA mandate | FDA labeling / REMS |
NOTES¶
- Narcolepsy type 1 is caused by autoimmune-mediated destruction of hypocretin-producing neurons in the lateral hypothalamus
- EDS is the most disabling and universal symptom; cataplexy is pathognomonic for NT1 but absent in NT2
- MSLT must be performed after adequate nocturnal sleep (≥6 hours on preceding PSG) and after ≥2 weeks off REM-suppressant medications (antidepressants, tramadol)
- A SOREMP within 15 minutes on the preceding nocturnal PSG can replace one SOREMP on MSLT
- CSF hypocretin-1 testing is the most specific test for NT1 but is not widely available (reference lab only)
- HLA-DQB1*06:02 is present in >90% of NT1 patients but also in ~25% of the general population; it is supportive but not diagnostic
- Sodium oxybate (Xyrem/Xywav) is unique in treating EDS, cataplexy, and disrupted nocturnal sleep simultaneously; requires REMS enrollment
- Xywav (lower-sodium oxybate) contains 92% less sodium than Xyrem; preferred in patients with sodium-sensitive conditions
- Abrupt discontinuation of anticataplectic medications (especially SNRIs, TCAs) can cause severe rebound cataplexy (status cataplecticus)
- Weight gain and obesity are common in NT1 due to hypocretin deficiency affecting metabolism; monitor BMI and metabolic parameters
- Comorbid psychiatric conditions (depression, anxiety) are common and require concurrent treatment
- Narcolepsy onset is typically in adolescence/young adulthood (peak ages 10-25); diagnosis is often delayed 8-15 years from symptom onset
- Pregnancy management: discontinue sodium oxybate and stimulants; scheduled naps are primary treatment; low-dose methylphenidate may be considered with informed consent
CHANGE LOG¶
v1.1 (January 31, 2026)
- Standardized structured dosing format to dose :: route :: frequency :: instructions for all 15 medications in sections 3B-3E
- Added ICU column to sections 4B (Patient/Family Instructions) and 4C (Lifestyle & Prevention) for table consistency
- Updated version metadata and revised date
v1.0 (January 30, 2026) - Initial template creation - ICSD-3-TR diagnostic criteria for NT1 and NT2 - Comprehensive pharmacologic treatment: wake-promoting agents (modafinil, armodafinil, solriamfetol, pitolisant) and anticataplectics (sodium oxybate, venlafaxine, fluoxetine, clomipramine) - Second-line stimulants (methylphenidate, amphetamines) - Non-pharmacologic interventions including scheduled naps and safety counseling - PubMed citations for all major evidence sources - Lumbar puncture section for CSF hypocretin-1 testing
APPENDIX A: MSLT Preparation Protocol¶
Prerequisites for Valid MSLT:
- Sleep diary or actigraphy for ≥2 weeks documenting adequate sleep (≥7 hours/night)
- Discontinue REM-suppressant medications ≥2 weeks prior (≥5 weeks for fluoxetine due to long half-life):
- SSRIs (fluoxetine, sertraline, paroxetine, escitalopram, citalopram)
- SNRIs (venlafaxine, duloxetine, desvenlafaxine)
- TCAs (clomipramine, amitriptyline, nortriptyline, protriptyline)
- Tramadol
- MAOIs
- Discontinue stimulants ≥2 weeks prior (modafinil, methylphenidate, amphetamines)
- Urine drug screen on day of study to confirm medication discontinuation and absence of recreational drugs
- Preceding nocturnal PSG must show:
- ≥6 hours total sleep time
- No untreated severe OSA (AHI >30) that could confound results
- MSLT protocol:
- 5 nap opportunities at 2-hour intervals starting 1.5-3 hours after morning awakening
- Each nap opportunity lasts 20 minutes; extended to 35 minutes if sleep onset occurs (to evaluate for SOREMP)
- Record sleep latency and presence of REM sleep for each nap
- Positive result: Mean sleep latency ≤8 minutes with ≥2 SOREMPs
APPENDIX B: Sodium Oxybate (Xyrem/Xywav) Prescribing Guide¶
REMS Program Requirements: - Prescriber, pharmacy, and patient must all be enrolled in the REMS program - Distributed only through central pharmacy (Jazz Pharmaceuticals) - Patient must sign acknowledgment of risks
Dosing Protocol: 1. Starting dose: 4.5 g/night divided into 2 equal doses 2. First dose: 2.25 g at bedtime (in bed, ready for sleep) 3. Second dose: 2.25 g taken 2.5-4 hours later (set alarm) 4. Titrate: Increase by 1.5 g/night (0.75 g per dose) every 1-2 weeks 5. Effective range: 6-9 g/night 6. Maximum dose: 9 g/night
Critical Safety Instructions: - Prepare both doses before bedtime; place second dose at bedside - Do not take within 2 hours of eating (food delays absorption) - Do not take with alcohol or other CNS depressants - Allow ≥6 hours between second dose and any activity requiring alertness - Store in secure location out of reach of others (abuse potential) - Monitor for sleepwalking, confusion, respiratory depression