narcoleptic patient case study

A practical guide to the pharmacological and behavioral therapy of Narcolepsy 

• Published: 22 April 2021
• Volume 18 , pages 6–19, ( 2021 )

Cite this article

• Christian Franceschini 1 ,
• Fabio Pizza 2 , 4 ,
• Francesca Cavalli 2 &
• Giuseppe Plazzi   ORCID: orcid.org/0000-0002-1051-0472 3 , 4  

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Narcolepsy is a rare, chronic, and disabling central nervous system hypersomnia; two forms can be recognized: narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). Its etiology is still largely unknown, but studies have reported a strong association between NT1 and HLA, as well as a pathogenic association with the deficiency of cerebrospinal hypocretin-1. Thus, the most reliable pathogenic hypothesis is an autoimmune process destroying hypothalamic hypocretin-producing cells. A definitive cure for narcolepsy is not available to date, and although the research in the field is highly promising, up to now, current treatments have aimed to reduce the symptoms by means of different pharmacological approaches. Moreover, overall narcolepsy symptoms management can also benefit from non-pharmacological approaches such as cognitive behavioral therapies (CBTs) and psychosocial interventions to improve the patients’ quality of life in both adult and pediatric-affected individuals as well as the well-being of their families. In this review, we summarize the available therapeutic options for narcolepsy, including the pharmacological, behavioral, and psychosocial interventions.

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Introduction

Narcolepsy is a severe, chronic, and rare disorder, classified by the International Classification of Sleep Disorders Third Edition (ICSD-III) [ 1 ] within the central disorders of hypersomnolence (CDH). Narcolepsy is categorized in narcolepsy type 1 (NT1) and in narcolepsy type 2 (NT2). NT1 is biologically marked by low cerebrospinal fluid hypocretin-1 levels (CSF hcrt-1), caused by the selective loss of hypothalamic neurons producing hypocretins, while NT2 is associated with normal levels of CSF hcrt-1 [ 1 ]. Narcolepsy core symptoms are excessive daytime sleepiness (EDS), cataplexy, sleep paralyses, hallucinations, and disrupted nocturnal sleep including frequent parasomnias. Cataplexy, defined as brief episodes of muscle atonia evoked by strong, mainly positive, emotions, is the pathognomonic symptom of NT1, while NT2 does not present with strictly defined cataplexy. Hypocretin-1 contributes to several functions, including circadian rhythm regulation, arousal and appetite control, as well as mood and behavior modulation [ 2 – 4 ]. This neurotransmitter also influences serotonin, histamine, dopamine, acetylcholine, GABA, and glutamate release [ 5 , 6 ]. The hypocretin-producing cell destruction contributes to most of the symptoms of narcolepsy, including EDS with sleep onset REM periods (SOREMPs), and other symptoms reflecting exaggerated REM sleep pressure such as cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and REM sleep behavior disorder (RBD), all disclosing an intrinsic overlap between REM sleep and other states.

Narcolepsy onset usually occurs between 10 and 20 years of age, although the diagnosis is mostly established with a substantial delay (mean of 10–15 years). Narcolepsy, as a rare disease, has a prevalence that varies from geographical regions ranging from 0.02 to 0.06% in Europe and the USA [ 8 ], to 0.16–0.18% in Japan [ 7 ]. NT1 is considered more frequent than NT2, both in adults and in children [ 9 ], although real prevalence rates are missing and both disorders may be largely underestimated.

The etiology of narcolepsy is still unknown, but recent studies have suggested an autoimmune hypothesis. Indeed, NT1 is strongly associated with the human leukocyte antigen (HLA) DQB1*0602 allele and other genetic features pointing to a specific configuration of the immune system, and environmental risk factors, such as upper airway infections, may act as triggers leading to the destruction of hypothalamic hypocretin-producing neurons [ 10 ]. On the other hand, the pathophysiology of NT2 is still unclear, and within this diagnosis, some subjects may be in a prodromic phase of NT1 (with subsequent appearance of cataplexy) [ 11 ].

NT1 is also associated with significant medical comorbidities, such as obesity, precocious puberty (in the childhood onset form), and cardiovascular problems [ 12 ], as well as with psychological consequences all to psychiatric diseases [ 13 ]. Narcolepsy has a severe impact on patients’ quality of life, with impairment in performance (e.g., at school, at work, at home) and psychosocial difficulties [ 14 ]. Patients also report additional non-sleep related aspects (i.e., decreased sexual activity or memory complaints) that negatively impact on disease perception and quality of life [ 15 ], and patients’ unmet needs could benefit from new multidisciplinary management strategies [ 16 , 17 ]. Indeed, pharmacological symptom management per se may be insufficient to allow for normal everyday life, so behavioral therapies and interventions remain crucial.

This review seeks to offer clinicians an overview of the available pharmacological treatments for narcolepsy core symptoms (i.e., EDS and cataplexy) in adult and pediatric patients, and to provide a summary of some useful behavioral and psychosocial interventions.

The first author (CF) performed a systematic literature search by using different scientific databases and keywords combinations, and selecting references published or available online in the timespan between 1975 and December 2020. The following scientific databases were used: PubMed, Web of Sciences, and PsycINFO. The following keywords were used alone and in combination to retrieve useful literature on narcolepsy treatment: narcolepsy, narcolepsy type 1, narcolepsy type 2, narcolepsy with cataplaxy, narcolepsy without cataplexy, treatment, pharmacotherapy, cognitive behavioral treatment (CBT), peer support, and counseling. The literature search provided a total amount of 4075 results from PubMed, 1716 from Web of Science, and 2344 from PsycINFO. The results obtained were then merged in order to avoid redundancies, and references were selected by applying the following criteria: (1) publication in English; (2) availability of full text; (3) exclusion of reviews on narcolepsy management, and of single case reports/studies; and (4) author judgement of clinical relevance. The final citation list was then narrowed down to 137 references. We classified drugs as first-line treatments on the basis of the available evidence (i.e. clinical trials) and approval by the authorities.

Pharmacological Treatment

Pharmacological treatment for narcolepsy is necessary to manage symptoms and to improve patients’ quality of life. Available treatments may act on one or multiple symptoms, namely, EDS, cataplexy, and disturbed nocturnal sleep. Given the diverse effect of the different drugs, the choice of a first-line approach should consider the complexity of individual patients, the burden of each symptom, the occurrence of multiple symptoms in combination, and the potential comorbidity/side effects taking into account sleep–wake habits and social patients’ needs. In this review, we will distinguish between first- and second-line approaches on the basis of the available evidence (clinical trials, registration by authorities). Indeed, studies directly comparing the effects of different drugs on EDS and cataplexy are lacking; thus, the choice of the initial treatment should rely on the possibility to access the drug, on clinical judgement (including side effects), and on active discussion with the patients. We suggest starting the treatment with monotherapy, thus preferring the use of drugs acting on multiple symptoms in NT1 (i.e., sodium oxybate or pitolisant), and adding treatment(s) should depend on clinical judgement including careful follow-up with discussions with patients and caregivers. We prefer a patient-centered treatment decision (i.e., the choice to start with night-time versus daytime treatment) that takes into account individual habits and needs, so we do not suggest an a priori pharmacological treatment strategy.

For a number of drugs, and for the treatment of pediatric patients, approval is still pending at the European Medicine Agency (EMA) and/or at the Food and Drug Administration (FDA). Moreover, some treatments (antidepressants), albeit not registered for narcolepsy, have been extensively used for decades and have proven efficacious, so they are still prescribed off-label.

In this review, we will try to summarize the main treatments hitherto available for both adults and children with narcolepsy and the recommendations solely for adult patients with the aim of providing a practical guide for clinicians. We provide, in three tables, an overview of the available pharmacological treatment for EDS in adults (Table 1 ), for cataplexy in adults (Table 2 ), and for EDS and cataplexy in children (Table 3 ).

EDS Pharmacological Treatment in Adults

First-line treatments.

Modafinil is a weak inhibitor of dopamine reuptake that leads to an increase in extracellular dopamine. Although it has found that modafinil selectively stimulates wake-generating sets in the hypothalamus [ 18 ], its mechanism of action is still largely unknown [ 19 ]. At the dosage of 200–400 mg/day, modafinil improves subjective EDS and objective vigilance as measured by sleep latencies on Maintenance of Wakefulness Test (MWT), a finding confirmed by positive changes at the Clinical Global Improvement of Change (CGI-C) [ 20 – 24 ].

Modafinil treatment usually starts with 100 mg (in the morning) and can be titrated gradually to 200 mg in a split dose in the morning (at awakening and at lunch time). After several weeks, the dose can be increased to 200 + 200 mg [ 23 , 24 ].

Approved by the FDA and EMA both for adult narcolepsy patients, modafinil is considered a good therapy because of a low addiction potential and mild side effects—generally headache, nausea, tension/anxiety, and insomnia [ 25 – 29 ]. Modafinil decreases the efficacy of oral contraceptives; thus, higher ethinylestradiol or alternative contraceptive methods are suggested [ 30 ].

Armodafinil

Armodafinil is the active R-enantiomer of modafinil and has a longer half-life. Armodafinil has the effect of reducing EDS in narcolepsy with a significant improvement in both MWT sleep latencies (1.3 to 2.6 min) and in the Epworth Sleepiness Scale (ESS) score (3.8 to 4.1). [ 31 ]. Most common side effects include headache, nausea, dizziness, and decreased appetite. Armodafinil has been approved by the FDA in treating narcolepsy adult patients [ 20 , 21 ]. Its recommended dosage should start with a single dose of 100 mg in the morning up to a maximum of 250 mg/day.

Pitolisant is a selective H3 receptor competitive antagonist/inverse agonist. Pitolisant acts at the presynaptic level by blocking the auto-inhibiting activity of histamine and H3R agonists on endogenous histamine release and leading to increased histamine release. Histaminergic neuron activity in the brain is involved in a large variety of functions, including wakefulness, attention, and memory [ 32 – 35 ]. Pitolisant has proven to have a no lesser efficacy on EDS compared to modafinil [ 32 ] and has also proven efficacious in decreasing cataplexy [ 33 , 34 ]. The efficacy on EDS has been assessed on subjective EDS (ESS improvement of 4–6 points), and on secondary outcomes, namely objective vigilance (MWT) and CGI-C. In adults, pitolisant has been approved by the EMA and FDA for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy [ 36 ].

For pitolisant dosage, the EMA recommends a single-dose intake during breakfast starting from 9 mg and titrating up to 36 mg/day in few weeks. The most effective dosage, prescribed by EMA, is commonly 36 mg/day, and its complete efficacy is reached in a couple of weeks, with little evidence of a clinical long-term efficacy. FDA has approved pitolisant at a lower dosage: starting from 8.9 mg/day reaching 17.8 mg per day after 1 week. The maximum daily dosage for FDA is 35.6 mg, after 2 weeks. Pitolisant was generally well tolerated and showed low abuse potential. Commonly reported side effects were headache, insomnia, abdominal discomfort, nausea, and irritability [ 32 , 33 ].

Sodium Oxybate or Gamma Hydroxybutyrrate

Sodium oxybate is the sodium salt of γ-hydroxybutyrate, an endogenous metabolite of the inhibitory neurotransmitter GABA. Sodium oxybate is a gamma-hydroxybutyric acid B-subtype (GABAb) receptor agonist. GABAb receptors within the central nervous system are diffused in the hypothalamus and basal ganglia. Although the mechanism of action of sodium oxybate is unclear, the drug showed a strong effect in promoting nocturnal slow-wave sleep, suppressing REM sleep and leading to an overall improvement of sleep efficiency [ 37 , 38 ]. Sodium oxybate has shown efficacy in reducing subjective EDS and increasing objective alertness with a median increase of > 10 min at MWT [ 39 , 40 ]. Although the mechanism of action of sodium oxybate on EDS has not been elucidated, it may be related to the effect on nocturnal sleep as well as its biphasic dopaminergic activity with immediate suppression promoting sleep, and subsequent release promoting wakefulness. Sodium oxybate also showed efficacy on cataplexy [ 41 , 42 ] and disturbed nocturnal sleep [ 37 , 38 ]. For the more appropriate dosage and best effect on EDS, it is often necessary to wait several weeks in order to allow an individualized titration.

Sodium oxybate is available only in liquid form. The drug has a short half-life (40–60 min), and therefore should be taken in two doses per night. The dosage usually starts with 4.5 g/night (split into two doses of 2.25 g the first at bedtime, the second 2.5–4 h after the first intake, so the patient must be woken up to take the second dose) for 4 weeks and then progressively increasing 1.5 g/night per week to reach the target dosage of 6–9 g/night. According to this titration scheme, EDS improvements should appear in 4–8 weeks from the treatment start.

Side effects for this drug are nausea, dizziness/confusion, weight loss, enuresis, anxiety, and depressive symptoms. Some concerns are related to the potential interactions with other sedating drugs, to the possible depression of the respiratory drive in patients with sleep-related breathing disturbances or lung comorbidities, to the possible misuse as a “date rape” drug, as well as to the important salt load that may have cardiovascular effects.

The FDA has approved sodium oxybate for adults and children narcolepsy patients over 7 years old in narcolepsy for the treatment of EDS or cataplexy, while the EMA has approved the drug for the treatment narcolepsy with cataplexy in adult patients, adolescents, and children from the age of 7 years [ 43 , 44 ].

Solriamfetol

Solriamfetol (75 up to 150 mg/day) is a selective inhibitor of the reuptake of dopamine and norepinephrine. This new treatment is different from other wake-promoting agents for its dual action. Moreover, it does not promote the release of monoamines as amphetamines, thus leading to lower risk of abuse and withdrawal effects. Solriamfetol efficaciously reduced subjective EDS (ESS), and improved vigilance (MWT) with a dose–response effect [ 45 , 46 ]. The effect was confirmed also in long-term clinical trials [ 47 ].

Solriamfetol has been approved for the adult treatment of EDS by FDA and EMA in adult patients with narcolepsy [ 48 ]. Commonly reported side effects include headache, nausea, diminished appetite, nasopharyngitis, dry mouth, and anxiety.

Second-Line Treatments

Methylphenidate.

When other wake-promoting agents show no effectiveness, methylphenidate represents a second-line option. Methylphenidate increases dopamine and norepinephrine transmission. Although widely used, only a few studies [ 49 , 50 ] have reported significant differences in the methylphenidate effect on the ability to stay awake and active in narcolepsy patients. In clinical practice EDS improved within few days of lowest dose administration (10 mg), while a dose of 60 mg and higher can be used to achieve a clinically meaningful response [ 20 , 21 ].

Methylphenidate has been approved for treatment in adult NT1 and NT2 patients by the EMA (but it is not registered in all EU countries) and the FDA.

Side effects of methylphenidate include tachycardia, hypertension, sweating, palpitations, irritability, hyperactivity, mood swings, weight loss, anorexia, and insomnia. Albeit mild, there are risks of abuse and dependence for methilphenidate.

The dosage starts with a dose of 10–20 mg in the morning at breakfast and additional 10–20 mg at lunch, to reach the maximum dosage of 60 mg, usually taken in 2–4 portions during the daytime [ 50 ].

Amphetamines and Other Therapeutic Options

Amphetamines are another treatment option for EDS [ 20 , 21 ]. They increase the concentration of dopamine and norepinephrine, and are approved in some European countries [ 20 ]. Treatment with dextroamphetamine usually starts with 10 mg, and therapeutic dosages may reach a maximum of 60 mg per day [ 49 ]. Other options include selegeline and reboxetine [ 51 , 52 ]. Amphetamines may induce not only common side effects (irritability, aggressiveness, insomnia, and hypertension) but also severe consequences (abnormal movements, cardiac arrhythmias, and psychotic symptoms) that make their use dangerous especially in patients with cardiovascular comorbidity. Moreover, although rare in narcolepsy, amphetamines suffer from a risk of abuse [ 49 , 51 , 52 ].

FDA recently approved two different combinations: one associates amphetamine and dextroamphetamine (Adderall™), and another has amphetamine sulfate as the main active ingredient (Evekeo™).

Cataplexy Pharmacological Treatment in Adults

Sodium oxybate.

Sodium oxybate is recognized as an efficacious drug against cataplexy [ 41 , 42 ]. Several clinical trials, including data on a prolonged follow-up of 18 months, showed a significant decrease in cataplectic attacks after a few weeks of therapy with a dose-dependent effect [ 53 – 56 ]. Importantly, abrupt sodium oxybate withdrawal does not induce a rebound effect. The FDA has approved sodium oxybate for adults and children narcolepsy patients over 7 years of age for the treatment of EDS or cataplexy, while the EMA approved the drug for the treatment of narcolepsy with cataplexy in adult patients, adolescents and children from the age of 7 years [ 43 , 44 ].

Pitolisant has proven efficacy in reducing daily cataplexy attacks [ 57 ]. A randomized double-blind and placebo-controlled trial conducted on 105 NT1 patients taking pitolisant disclosed an important decrease in cataplectic attacks [ 33 ], an effect confirmed in long-term studies [ 58 ].

In adults, pitolisant has been approved by EMA and FDA for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy [ 36 ].

Venlafaxine

Although it is not approved, venlafaxine is a selective serotonine-norepinephrine reuptake inhibitor widely prescribed in NT1 patients, and only on the basis of clinical recommendations it can be considered a first-line pharmacological approach [ 20 , 21 ]. Venlafaxine has an effect as an anticataplectic that reaches its peak in few days. It is well tolerated and has some typical side effects: increased blood pressure, headache, dry mouth, nausea, and dizziness.

Its dosage starts with 37.5 mg reaching the maximum dose of 225 mg in the morning [ 60 ]. Patients should be advised that abrupt withdrawal can produce a severe rebound effect up to the occurrence of subcontinuous invalidating cataplexy episodes, a condition defined as “cataplectic status” [ 61 ].

Other Antidepressants: Fluoxetine, Citalopram, and Clomipramine

As second-line treatments for cataplexy in NT1, there are selective serotonin reuptake inhibitors (SSRIs), especially fluoxetine (10–20 up to 60 mg/day) and citalopram (10–20 up to 40 mg/day) [ 20 , 21 ]. Common side effects are excitation, gastrointestinal problems, insomnia, and sexual difficulties, and they should not be underestimated, because they can limit applicability in clinical practice [ 49 , 59 , 62 , 63 ]. As for venlafaxine, abrupt withdrawal can lead to a severe rebound effect [ 64 ]. Their use should considered with extreme caution by physicians especially when used with young patients.

Also, clomipramine, a tricyclic antidepressant, is used with a daily dosage that ranges from 10–25 up to 75 mg/day. Since the 1960s, several observations have confirmed clomipramine effect on reducing cataplectic attacks, but the drug has not been officially approved by the EMA and the FDA [ 20 , 21 , 65 – 67 ]. Antidepressants (fluoxetine, citalopram, and clomipramine) have only been approved in Germany.

Clomipramine suffers from common side effects, such as dry mouth, sweating, constipation, diarrhea, tachycardia, weight gain, hypotension, difficulty in urinating, and impotence.

EDS Pharmacological Treatment in Childhood

Nowadays, within all the EDS treatments, only sodium oxybate has been approved by FDA and EMA for treatment in children and adolescents. The other treatments for pediatric patients are considered only at empirical level as off-label [ 68 , 69 ].

Modafinil and Armodafinil

Both the treatments are used off-label by physicians for patients under the age of 16, because they have not yet been approved by the FDA for young people below the age of 16 [ 20 , 21 ]. For children, the daily dosage of modafinil and armodafinil is 50–400 mg/day in two doses at the morning to support children in school performance and after lunch, for after-school activities and homework. In case of sudden withdrawal, modafinil does not cause EDS rebound. Commonly reported side effects in young patients are headache, nausea, and vomiting. Moreover, a single case of Stevens–Johnson syndrome has been reported in a patient taking modafinil [ 70 ]. Steven–Johnson syndrome is a delayed hypersensitivity reaction that develops from a few days to weeks after beginning the therapy, and it appears as red or purple skin rash that gradually spreads. The only piece of evidence is a level 4 study by Ivanenko and colleagues [ 71 ]. Modafinil therapy in children and adolescents contributes to a subjective improvement in EDS. Furthermore, the study showed objective improvement in the average sleep latency on the MSLT from a baseline of 6.6 ± 3.7 to 10.2 ± 4.8 min.

Up to now, a few uncontrolled data have reported the efficacy and safety of pitolisant in reducing EDS in children and adolescents. The dosage for children is 4.5 mg up to 36 mg per day.

Minor side effects have been reported (insomnia, headache, hot flushes, leg pain, and hallucinations), and all but insomnia were transient [ 72 ].

Sodium oxybate is used for NT1 treatment in children, for its effects on reducing EDS and cataplexy. The drug is used in monotherapy or in association with other stimulants [ 73 ]. Its efficacy on EDS and cataplexy has been demonstrated in 88% of NT1 children [ 44 , 74 ], but sodium oxybate side effects maintain a high-risk ratio: sleep walking, sleep enuresis, exacerbation of sleep apnea, tremor, constipation, exacerbation of pre-existing depressive tendencies, weight loss, nausea, irritability, and episodes of sleep drunkenness. Abrupt drug withdrawal does not cause rebound effects [ 73 ]. Recent data have also shown a positive effect on sleep disruption and on REM sleep behavior disorder [ 74 – 76 ].

Administration of this treatment requires particular care. In fact, dispensation is made from central pharmacies, and before making out, the prescription clinicians and physicians have to register and train patients or their caregiver for proper use. This high level of care required for the drug assumption is due to the risk of misuse/abuse reported in several clinical cases. Therefore, the patient and his/her family need proper training before starting the treatment. It is recommended that a family member should be in attendance during the drug administration and should be responsible for storing the medication in proper locked place. Given the liquid form of the drug and its salty taste, it can be administrated with addition of flavor. The right dosage varies from 2 to 8 g per night, and the drug should be given in two administrations: one before falling asleep and the other one 3–4 h after the first dose.

Amphetamines and Methylphenidate

Amphetamine (dextro-amphetamine) and andmethylphenidate enhance dopaminergic and norepinephrinergic activity [ 20 , 21 ]. Both drugs are also used to treat attention-deficit/hyperactivity disorder in children and adults. Recommended dosages are 2.5 to 20 mg twice a day for dextro-amphetamine and 10 to 40 mg for methylphenidate. Their use in adults is supported by three phase 2 and four level 5 studies that support the effectiveness of those stimulants in treating EDS [ 21 ]. Side effects include tics, anorexia, headache, nervousness, insomnia, and weight loss [ 77 ]. Their use in children below the age of six is not approved by FDA and is discouraged in children with a diagnosed heart disease [ 78 , 79 ]. Moreover, while rare in narcolepsy, amphetamines and methylphenidate suffer from a risk of abuse.

Cataplexy Pharmacological Treatment in Childhood

To date, only sodium oxybate has been approved by FDA and EMA as a treatment for cataplexy in children and adolescents. Thus, the selection of medications in the pediatric population is based only on an empirical, off-label, basis [ 69 ].

Sodium Oxybate or Gamma Hydroxybutyrate

The information about sodium oxybate’s effect on cataplexy in childhood is included in the previous paragraph “EDS pharmacological treatment in childhood.”

Ongoing trials are evaluating the efficacy and safety profile of pitolisant in children, and to date, a slight improvement of cataplexy frequency and severity has been reported in children in an uncontrolled case series [ 72 ].

Selective Norepinephrine Reuptake Inhibitors

Venlafaxine is commonly used against cataplexy with a dosage of 37.5–75 mg per day [ 20 , 21 ]. Due to the high risk of suicide reported in adolescents, the administration of venlafaxine for adolescents and children must be strictly controlled [ 80 ]. In addition, side effects due to the interactions with monoamine oxidase inhibitors include dizziness, headache, and insomnia. Further studies are warranted, given that only a few observational data are available with 2-year follow-up [ 81 , 82 ].

Tricyclic Agents

In addition, imprimine, clomipramine, and protryptiline are commonly used for control cataplexy. Their dosages are, respectively, 10–100 mg, 10–150 mg, and 2.5–5 mg per day. The most commonly reported side effects are dry mouth, blurring, drowsiness, orthostatic hypotension, and weight gain [ 20 , 21 ].

Selective Serotonin Reuptake Inhibitors

Within SSRI, the most typically used agent is fluoxetine with a daily administration dosage of 10–30 mg [ 20 , 21 ]. Commonly reported side effects are nervousness, insomnia, and tremor. As for other antidepressants, sudden drug withdrawal or irregular intake may induce a rebound of cataplexy up to “status cataplecticus” [ 83 ].

Immunotherapy

Findings reported associations that support an autoimmune mechanism underlying the onset of NT1 that suggest the use of immunomodulation therapy with intravenous immunoglobulin G (IVIG) close to disease onset. Only a few studies [ 84 – 87 ] have analyzed IVIG therapeutic efficacy in early onset NT1cases. To date, the results have been controversial due to the small sample size, open label design, and self-reported observations. However, an improvement in cataplexy frequency and severity, as well as in EDS, was reported, but further data are required to exclude the possibility of a spontaneous improvement in NT1 symptoms during the disease course [ 88 ]. Overall, despite some promising results, further studies should address the role of immunotherapy in NT1 [ 89 ].

Non-pharmacological Treatment

Psychological difficulties are one of the main issues affecting narcolepsy patients, who often report a significantly lower quality of life [ 14 , 90 – 92 ]. In fact, narcolepsy is associated with some difficulties including work performance, sexual activity [ 93 ], higher risk of car accidents [ 94 ], neuropsychiatric alterations [ 95 – 100 ], and psychological disorders [ 97 – 101 ]

Non-pharmacological treatments are regularly used to manage EDS, either as an adjunct to drug therapy or as an alternative treatment. Several authors have reported that medications alone may not completely resolve EDS, in particular about 15% of patients with narcolepsy depend on medications alone [ 98 ] and up to 54% of these patients require behavioral strategies [ 102 , 103 , 104 ].

Although only a little evidence on the effect of daytime napping on EDS in NT1 is available [ 105 ], the importance of cognitive and behavioral therapies for narcolepsy treatment is fully recognized from a clinical point of view. The American Academy of Sleep Medicine is the only institution presenting treatments other than the pharmacological ones [ 20 ], while scheduled naps, sleep hygiene, balanced diet, and physical activities are within the clinical guidelines of associations of sleep medicine or neurology from several countries. Among these, both the UK and European Association of Neurology for Europe, the American Academy of Sleep Medicine for North America, and the Brazilian Sleep Society [ 20 , 21 , 106 , 107 ] agree on the importance of cognitive and behavioral actions to contain narcolepsy symptoms, reduce the negative effects, and gain a better compliance with drug therapy. In particular, the guidelines proposed by the UK Consensuses [ 106 ] suggest a symptomatologic approach, focused on increasing the patient’s knowledge of his/her disease, integrated with psychological support, in planning scheduled naps, promoting regular nocturnal sleep duration, and helping with the management of work, the home and recreational activities.

Cognitive Behavioral Therapy

Several countries recommend use of cognitive and behavioral strategies as adjunctive treatment to reduce the patient’s dysfunctions, to obtain a better response, to and decrease the amount of drugs that need to be administered. Within behavioral sleep medicine (BSM), cognitive behavioral therapy for insomnia (CBT-I) has gained prominence as an empirically supported treatment for chronic insomnia. Up to now, less attention has been paid to develop and validate methods for disorders related to the hypersomnia family.

The main goals of CBT are to apply strategies focused on the resolution of symptoms, identify, and modify dysfunctional thought patterns with negative influence on behaviors and emotions. In particular, it is possible to help narcoleptic patients to identify and improve dysfunctional cognitions, enhance treatment adherence, take medications at the appropriate times, maintain good sleep hygiene, and take scheduled naps to address the psychosocial needs of such patients. This sort of therapy should be performed only by psychologists, interested in BSM, who graduated from a school with an AASM-accredited sleep program or with a teacher with experience in sleep, and who completed a sleep-related internship at a local sleep clinic.

Currently, there is an insufficient number of clinical studies on patients with narcolepsy that present a standardized and unambiguous protocol on how to manage symptomatology and its psychosocial functioning. Patients under CBT also receive help to manage the impact that narcolepsy has on their quality of life, ranging from emotional to social levels [ 108 ] and health-related stigma [ 109 ].

A randomized study reported that patients undergoing cognitive therapy showed significant improvements in the subjective perception of their quality of life (i.e., physical function, social function, vitality, and emotional role) and EDS, through self-reported measures (i.e., the ESS, Ullanlinna Scale, SF-36) [ 110 , 111 , 112 ]. The aim of this study was to evaluate whether a multicomponent (sleep satiation, nap training, cognitive restructuring, and problem-solving techniques) treatment could provide better results than the standard treatments alone (control group, 6 months, and 1 year on treatment).

Other studies tried to assess how effective the cognitive measures could be in coping with narcolepsy [ 113 ]. To estimate the extent to which CBT—based on cognitive restructuring intervention—was effective, these authors measured quality of life, beliefs, and attitude of narcolepsy patients, finding that patients under CBT had significantly superior ( p  < 0.005) post-treatment assessment scores than the control and drug treatment groups.

Finally, Ong et al. have developed a novel CBT for hypersomnia (CBT-H) in people with CDH and co-occurring depressive symptoms, using an online access model for delivery and assessment [ 114 ]. At baseline and post-treatment, 35 adults with a diagnosis of CDH were evaluated with Patient-Reported Outcomes Measurement Information System measures, ESS, and other patient-reported outcomes. Moreover, they received a six-section CBT-H, delivered individually or in a small group, using a telehealth online platform by an expert psychologist therapist. Cognitive interventions were aimed at processing changes in personal identity or functional limitations that emerged due to symptoms of CDH. Topics included treating the stigma of CDH diagnosis, implications of CDH symptoms on self-perception, professional goals and interpersonal relationships, and specific coping skills to manage mood and anxiety, associated with the unpredictability of CDH symptoms.

Further research and clinical trial are needed to support the sporadic clinical evidence of CBT programs in narcolepsy.

Behavioral Treatment for EDS

Such techniques represent a useful tool for improving or controlling sleep disorder behaviors. Several studies have shown [ 20 , 21 ] that planning two or three short (15–20 min) naps at specific times of the day ( scheduled daytime naps ) is the most common behavioral recommendation [ 102 , 115 – 119 ]. Naps should be short to avoid sleep inertia at reawaking [ 102 , 105 , 106 ,  115 , 119 – 121 ].

Nevertheless, this is just an indication, since not every narcoleptic patient benefits from short naps [ 115 ] Indeed, some patients could benefit from longer naps [ 115 ]. Moreover, other studies have suggested an overall benefit in daytime alertness, when scheduled naps are associated with regular nocturnal bedtime [ 102 ].

Another strategy for improving EDS is reaching sleep satiation through sleep extension . Based on the sleep homeostasis theory, sleep satiation technique requires scheduled extension of nocturnal sleep: for 2 weeks from 10.00 p.m. to 6.00 a.m. [ 122 ]. This technique requires the detection of the behavior frequency: identifying the degree of sleepiness and filling in a sleep diary that determines the number of sessions. After that, continuous 1-day episodes are scheduled without light–dark cues. Improvements that follow naps and scheduled nocturnal sleep extension can be clarified by this behavioral disposition.

Physical activity may also has a positive effect on EDS. Experimental studies (in mice) showed that wheel running increased wakefulness in not only hypocretin knockout, but also cataplexy [ 123 ]. A relationship between physical activity and quality of sleep was recorded in healthy adolescents. This led to the hypothesis that physical activity may stabilize the circadian rhythm, following the improvement in sleep quality, but the mechanism that explain this relationship remains under investigation.

In any case, an actigraphic study with NT1 children and adolescents detected that regular physical activity was associated with significant differences in children’s sleepiness (lower subjective ESS-CHAD scores) and sleep/wake profile (fewer daily naps and less time asleep during daytime), but without triggering cataplexy [ 124 ].

In addition, narcoleptic patients also reported the utility of controlling their environment (e.g., avoiding hot rooms, keeping the room cool, seeking fresh air), engaging themselves in certain activities (e.g., being active in conversations, avoiding boring events, restricting evening events), and different physical activities (e.g., pinching oneself and clenching one’s teeth) on EDS management [ 103 , 111 ].

Broughton and Murray reported the success of these self-behavioral stimulations in six out of 13 patients [ 125 ]. Furthermore, a survey evaluating the most common behavioral strategies found that daytime napping (86%), scheduled nocturnal sleep (i.e., bedtime and wake-up time, 76%), caffeine use (76%), physical exercise (57%), diet (50%), temperature manipulations (42%), chewing gum (30%), nicotine (23%), mindfulness (21%), and yoga (18%) were efficacious in managing EDS [ 99 ].

However, no clinical trials have addressed the efficacy of behavioral approaches on EDS in narcolepsy, and therefore, further research is needed on patients.

Cognitive and Behavioral Treatment for Cataplexy

CBT is also used for cataplexy treatment, particularly through systematic desensitization, that helps patients to find coping strategies to manage their emotions. This symptomatic strategy—an evidence-based therapy approach that combines relaxation techniques with gradual exposure to help overcome a particularly stressful condition—gradually reduces the impact of the emotional triggering stimulus by guiding the patient through situations where the frequency and intensity of this stimulus increase. To arrange the systematic desensitization technique, it is necessary for stressful and hyperactivating stimuli (e.g., like a funny video), to be previously assessed by patients, confirming that they are triggers for cataplexy. Then, clinicians ask the patients, in a state of deeply relaxation, to figure in their mind the hyperactivating stimulus, through the illustration of the situations in all their details [ 126 ].

Within the CBT approach, other procedures for cataplexy reduction are the emotional techniques (e.g., avoiding emotional experience, excitement) for the management of symptoms and the stimulus satiation, in which the clinician maintains what reinforces the cataplectic behavior in the patient until it loses its effect [ 126 ]. In a qualitative study on the cataplexy experience, some patients reported a sort of ability to control the attacks by focusing on the inhibition/avoidance of the emotional triggers (such as laughter), or seeking support or trying to sit down, to avoid falling to the ground [ 127 ].

This approach should be performed only by a psychologist experienced in behavioral sleep medicine.

Psychological counseling offers a space to improve symptom management and treatment for both patients and relatives, through proper education and information about the disease, particularly when the diagnosis has just been made. With psychological counseling patients can better understand how narcolepsy can change their life and accordingly develop strategies to deal with it. Through psychological counseling patients can be informed about all the available pharmacological and behavioral therapies (e.g., good sleep hygiene) and their outcomes, and finally other lifestyle factors that could affect the symptoms (e.g., the influence of alcohol on EDS) [ 128 ].

Furthermore, researchers are becoming increasingly aware of the importance of peer support, as a form of psychosocial support offered by someone with experiential knowledge of the disease [ 128 ]. With peer support, patients can also face the sense of isolation, improve their knowledge and confidence in dealing with the symptoms [ 129 ], and positively influence each other’s hopes about the future, despite the limitations of the disease. Indeed, the support coming from sharing experiences with others has been shown to be constructive also for patient’s family members [ 130 , 131 , 132 ]. However, finding peer support could be complicated when experiencing a rare disease [ 130 , 131 , 132 ], but there still are chances to recover, also thanks to all the associations that operate to bring the patients closer and fill this gap. Furthermore, the development of new technologies may be of help to connect patients and peers.

In Italy, narcoleptic patients are grouped in the Associazione Italiana Narcolettici ed Ipersonni (AIN onlus, http://www.narcolessia.org/ ). The association now gives support to many narcoleptic patients, representing not only the opportunity to be in contact with other people who share the same condition but also a place where sleep experts can cooperate and share information about different and specific case/symptoms, and thus improve their knowledge of the disease. This network was founded by the father of a young patient, after considerable efforts made to find a diagnosis and a cure. Today, the AIN is very active also at international level. Indeed, the AIN is working to spread the connections with other European narcoleptic patient associations, through eNAP, the new European Narcolepsy Alliance for Patient ( https://narcolepsy.eu/ ). Furthermore, we report the website address of other important patient support associations:

Austria: www.narkolepsie.at

Belgium: www.narcolepsie-cataplexie.be

Denmark: www.dansknarkolepsiforening.dk

France: www.anc-narcolepsie.com

Germany: http://www.dng-ev.de/

Ireland: http://soundireland.ie/

Netherlands: www.narcolepsie.nl

Norway: http://www.sovnforeningen.no/

Poland: http://www.narkolepsja.pl/

Spain: http://www.narcolepsia.org/

Sweden: http://www.narkolepsiforeningen.se/

Switzerland: https://www.snane.ch/

UK: www.narcolepsy.org.uk

USA: NORD (National Organization for Rare Disorders): https://rarediseases.org/rare-diseases/narcolepsy/

USA: Wake up Narcolepsy: https://www.wakeupnarcolepsy.org/

USA: Narcolepsy Network: www.narcolepsynetwork.org

USA: Project Sleep: https://project-sleep.com/

In summary, the following intervention is proposed for patients with narcolepsy, to be adopted especially in a multidisciplinary sleep medicine center. The first choice is pharmacological treatment with the integration of behavioral strategies for EDS and night sleep management. For those patients with impaired quality of life, anxiety-depressive comorbidity, and serious consequences on emotional and working life, pharmacological treatment should be integrated with a CBT treatment, focused on the cognitive and psychopathological consequences of narcolepsy. In addition, a counseling service and focus group therapy centered on peer support should be offered to increase the awareness of the disease condition, the patient’s personal esteem, and a proper management of drug therapy, in terms of safety and compliance to the medication therapy.

Child and Relatives

Narcolepsy has a major negative impact on the child’s social realm. Parents and caregivers facing child problems could undergo truly overwhelming stress levels, for the problems expressed that they cannot fully understand or detect.

Moreover, professional figures do not always offer enough support to the child, probably due to the rarity of the disorder and the consequent focus that physicians have to invest in the diagnostic and medical challenges. Encouragements mainly come from close family members who may be unprepared to meet the child’s worries.

Kippola-Pääkkönen and colleagues studied the expectations and perceive support of children with narcolepsy after the pandemic influenza in Finland [ 133 ]. In their research, they proposed educational, psychological, and social interventions: lectures, individual psychosocial counseling, group discussions, and skill training. Also, parents completed a baseline (58) and a final (40) questionnaire. Findings reported that parents’ worries were focused on the impact of narcolepsy on coping skills and the limitation of their time as a couple. In addition, parents received most of the support from their partners (77%), then from sleep physicians (27%) or teachers and school educators (23%). Then, researchers recommended offering psychological support to patients also during the hospitalizations in order to help families obtain informal and professional support.

The 20–40% incidence of depressive symptoms in narcoleptic pediatric patients [ 134 ] should encourage the scientific community to build a task force of experts that tries to understand the most disabling aspects of childhood or adolescent narcolepsy, such as access to drugs, symptom management with peer and family, school management of scheduled naps or management of drug therapy during school trips, psychopathological symptoms and their support, and support for families with access to peer help groups.

Conclusions

NT1 is a rare chronic disorder characterized by EDS, cataplexy, hypnagogic hallucinations, sleep paralysis, and disrupted night-time sleep [ 1 ]. For its diagnosis, multiple sleep latency test (MSLT) and polysomnography (PSG) are used [ 1 , 36 ,  134 ]. The occurrence of hallucinations and sleep paralysis shifts in terms of frequency and impact in narcoleptic patients. In some cases, sodium oxybate turned out to be effective in reducing the number of hallucinations during the day [ 135 ], but other therapies, such as venlafaxine, also have a good therapeutic effect [ 28 ].

A recent review of the literature on disrupted nighttime sleep in patients with narcolepsy has shown that nocturnal sleep is characterized—both in PSG and subjective reports—by frequent brief awakenings, awakenings, and a high level of light sleep, which is also associated with poor quality of sleep at night [ 135 ]. Sodium oxybate seems to be a gold standard treatment in consolidating nocturnal sleep [ 38 , 74 , 75 ].

Today, narcolepsy is still a complex disease, and despite new scientific discoveries about its pathophysiology, currently available treatments remain scarce and only symptomatic. Moreover, many drugs used in the clinical practice to cure children are still prescribed as “off-label” treatments.

Furthermore, new immune-modulating and hypocretin replacement treatments should be verified more systematically [ 89 ], especially in patients and children with recent-onset narcolepsy in order to figure out their potential in treating the disease. Non-pharmacological interventions as well have been shown to contribute in helping patients and family members and to have a role in improving patients’ quality of life, so for the future, it is advisable that outcome measures and multicompetent interventions should be guaranteed to patients and their families [ 17 , 105 ].

Recently, research to find proper treatments for rare disorders has received a new attention from the European Union that has addressed programs and policies also to this area of health programs and policies, in order to balance attention between rare and common disorders (European Commission, 2014) [ 136 ].

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Franceschini, C., Pizza, F., Cavalli, F. et al. A practical guide to the pharmacological and behavioral therapy of Narcolepsy . Neurotherapeutics 18 , 6–19 (2021). https://doi.org/10.1007/s13311-021-01051-4

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Anesthetic management of a patient with narcolepsy by combination of total intravenous and regional anesthesia: a case report

• Daiki Takekawa 1 ,
• Tetsuya Kushikata 1 ,
• Masato Kitayama 2 &
• Kazuyoshi Hirota 1  

JA Clinical Reports volume  3 , Article number:  37 ( 2017 ) Cite this article

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Narcolepsy is a neurological disease characterized by excessive daytime sleepiness, cataplexy, and/or a sudden loss of muscle tone due to malfunction of the orexinergic system, which may cause delayed emergence from general anesthesia. We report a successful anesthetic management of 24-year-old female narcoleptic patient undergoing left anterior cruciate ligament reconstruction. Anesthesia was induced and maintained with total intravenous anesthesia (TIVA) using propofol and remifentanil. Ultrasound-guided left femoral nerve block was also performed with 0.375% ropivacaine 20 ml. Acetaminophen 1000 mg was intravenously administered as part of a multimodal analgesia. After the surgery, the trachea was extubated 9 min after termination of TIVA, and then, the patient correctly responded to verbal commands. The postoperative course was uneventful without any narcoleptic symptoms.

Narcolepsy is a neurological disease characterized by excessive sleep during the day, catalepsy, and sleep paralysis due to malfunction of the orexinergic (oxergic) system such as loss of OXergic neurons and deficiency of orexins (Oxs) [ 1 ]. OXergic neurons widely project throughout the central nervous system (CNS) such as the noradrenergic locus coeruleus, the cholinergic basal forebrain, the dopaminergic ventral tegmental area, the serotonergic raphe nuclei, and the histaminergic tuberomammillary nucleus to regulates various physiological functions including not only sleep wakefulness but also analgesia, sympathetic nervous system, feeding behavior, and emotional behavior [ 1 , 2 ].

The mechanism of loss of consciousness by general anesthesia partially includes the activation and suppression of endogenous sleep- and wakefulness-promoting pathways [ 3 ]. Therefore, it is possible that activation of orexinergic nervous system decrease anesthesia times. In fact, it was reported that intracerebroventricular administration of orexin significantly decreased general anesthesia time in the rat [ 4 , 5 , 6 ]. Thus, prolonged emergence from general anesthesia would be expected in patients with narcolepsy. The desirable anesthetic management of patients with narcolepsy is to decrease the dosage of general anesthetic and analgesic agents and/or use short-acting agents to prevent delayed emergence. Thus, the combination of general and regional anesthesia may be one of the best options.

Here, we report anesthetic management of a narcoleptic patient undergoing left anterior cruciate ligament (ACL) reconstruction under a combination of total intravenous anesthesia (TIVA) with femoral nerve block.

Case presentation

We have obtained a written informed consent from the patient and healthy volunteers for publication of this case report and measurement of plasma OXA concentrations before and 1 h after anesthesia induction and at emergence from anesthesia using a commercial enzyme-linked immunosorbent assay kit (Peninsula Laboratories, San Carlos, CA).

A 24-year-old woman (160 cm, 61 kg) with narcolepsy was scheduled to undergo left ACL reconstruction. The patient took prescribed modafinil 200 mg to treat excessive sleepiness with activation of histaminergic and OXergic neurons in narcoleptic patients [ 7 ]. However, she sometimes claimed intolerable daytime drowsiness. She did not have any other abnormal medical history and abnormal physical examination data.

On the morning of the surgery, she took her daily dose of modafinil and roxatidine 75 mg as anesthetic premedication but other routine premedications such as benzodiazepines were avoided not to be sedated deeply. Indeed, the BIS was over 90 before induction of general anesthesia. Anesthesia was uncomplicatedly induced by propofol 120 mg, remifentanil 0.5 μg/kg/min, and rocuronium bromide 40 mg followed by tracheal intubation. After the induction, ultrasound-guided left femoral nerve block was performed with 0.375% ropivacaine 20 ml. Anesthesia was maintained with propofol 6–8 mg/kg/h and remifentanil 0.1–0.2 μg/kg/min to keep BIS value between 40 and 60. Intravenous acetaminophen 1000 mg was also administered as a part of multimodal analgesia. As hemodynamics were stable during anesthesia, vasoactive agents were not required. The duration of surgery was 50 min. The patient emerged from anesthesia and extubated 9 min after discontinuation of propofol and remifentanil infusion. Her consciousness was clear and the BIS values were above 90. Intravenous fentanyl 100 μg was required for relief of pain of sciatic nerve region.

She moved to the intensive care unit (ICU) for postoperative care. The postoperative course was uneventful without any hemodynamic instability, respiratory depression, and progress of narcoleptic symptoms. Then, she was discharged on the 9th postoperative day.

The measured plasma OXA were always lower than the data of healthy adult volunteers (Table  1 ).

Anesthetic management of patients with narcolepsy has yet to be established, because of the rarity of the disease. It is considered that effects of anesthetics depend on the severity of the disease. Cavalcante and colleagues [ 8 ] recently reported a case-control study for determination of the perioperative risk of narcoleptic patients undergoing general anesthesia compared with matched control patients ( n  = 76 each). They found that narcoleptic patients compared to control patients were more often prescribed CNS stimulants (73.7 vs 4.0%, P  < 0.001) and antidepressants (46.1 vs 27.6%, P  = 0.007) and more often revealed obstructive sleep apnea (40.8 vs 19.1%, P  < 0.001) in the preoperative period. Although intraoperative course was similar because of no differences in the using frequency of vasoactive agents and fluid administration between groups, narcoleptic patients had a higher frequency of emergency response team (ERT) activations (6.6 vs 1.3%, P  = 0.04) in postoperative period. ERT activation was caused by hemodynamic instability such as hypotension, tachycardia, or bradycardia in all patients. One narcoleptic patient showed excessive sedation with respiratory depression. Thus, narcoleptic patients may have higher postoperative risk.

As our patient claimed intolerable daytime drowsiness, the narcoleptic symptoms were not sufficiently controlled by modafinil. Therefore, we gave a daily dose of modafinil that would improve anesthesia recovery [ 9 ], avoided sedative premedication, and chose propofol-remifentanil TIVA with femoral nerve block under BIS monitoring. Propofol and remifentanil are well-known to be short-acting agents to avoid residual effects. BIS monitoring was also useful to titrate anesthetic agents [ 10 ] and detect narcolepsy-catalepsy episode [ 11 ]. In addition, to reduce opioid, which may cause delayed emergence, for analgesia, multimodal analgesia such as femoral nerve block and iv acetaminophen was performed. Indeed, the patient was emerged from general anesthesia within 10 min without narcoleptic symptoms following discontinuing propofol. The dose of propofol and remifentanil in this patient was quite normal compared to non-narcoleptic patients.

Fentanyl was required for postoperative analgesia in this patient. Although in our hospital to avoid the delay of operation schedule for knee surgeries, we do not perform sciatic nerve block, we should have done it in this patient to avoid postoperative narcotic analgesia.

We found that OXA level of this patient is lower compared with control values obtained from some healthy human. Plasma OXA concentrations in this patient were lower than that of awake healthy adult volunteers and patients under general anesthesia [ 12 ]. Although it is clinically difficult to determine whether plasma OXA originates from the central nervous system, Higuchi and colleagues reported that plasma OXA concentration in narcolepsy patients was lower than that in healthy volunteers [ 13 ]. In addition, plasma OXA in this patient increased at emergence from TIVA. This increase was similar to the data of our previous report [ 12 ]. Thus, the degeneration of OXergic neurons might yet to be completed although we did not measure the cerebrospinal fluid concentration of OXA.

Conclusions

In summary, we could successfully manage an anesthetic case of a narcoleptic patient with a combination of TIVA and regional anesthesia.

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Takekawa, D., Kushikata, T., Kitayama, M. et al. Anesthetic management of a patient with narcolepsy by combination of total intravenous and regional anesthesia: a case report. JA Clin Rep 3 , 37 (2017). https://doi.org/10.1186/s40981-017-0107-4

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• General anesthesia

Narcolepsy & Hypersomnia

Narcolepsy Type 1 (NT1) Including Information on Cataplexy, Sleepiness, Sleep Paralysis, and Hypnagogic Hallucinations

The main symptoms of narcolepsy type 1 (NT1) are excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep.  It affects about 0.03% of the population (1 for 3,000 individuals) in most countries in the world.  About half of all patients start narcolepsy before age 18, in rare cases as young as 3 years old, and in general the younger it starts, the more severe and abruptly the disease strikes; in young children one often observed a regression where tantrums and bad behavior restarts because the child is always exhausted. A rapid gain of weight often also occurs.

Since the 1960s it has been known that several of the disabling symptoms of narcolepsy, such as sleep paralysis, cataplexy and hypnagogic hallucinations, are pathological equivalents of REM sleep (a stage of sleep when we dream but are paralyzed to avoid moving in our dreams). Indeed, patients with narcolepsy enter REM sleep abnormally fast, minutes after falling asleep unlike normal people where REM sleep only appear after one hour of sleep (see History of Narcolepsy). 

Cataplexy is unique to NT1. Cataplexies are sudden, brief episodes of muscle weakness triggered by emotions. Typically, the patient's knees buckle and may give way upon laughing, elation, surprise, or anger. In other typical cataplectic attacks, the head may drop or the jaw may become slack. In severe cases, the patient might fall and become completely paralyzed for a few seconds to several minutes. Reflexes are abolished during the attack.  Although cataplexy is most often triggered by emotions such as a good joke or a funny cartoon, in children close to onset, it can be atypical and manifest by mouth opening, jaw dropping with tongue protrusions that are not always obviously triggered by emotions. Children can also feel generally weak, having trouble walking. Only after many months the cataplexy starts then to transform into the “adult” form only triggered by jokes or laughing.

Sleepiness is the most problematic symptom in narcolepsy. In general, patients feel exhausted all the time and would fall asleep as soon as they are not moving or being stimulated (for example as a passenger in a car). On top of this background of constant sleepiness, sudden sleep attacks can appear that are so strong that the patient cannot stay awake and struggles.  If the patient can, he/she would take a nap and very often would feel better even after 15-30 min of sleep. Other times, patients would fight though sleep attacks and this can lead to “automatic behaviors”.   During these events, patients continue the activity they initiated half asleep and have no recollection, for example continuing to write gibberish on a piece of paper. 

In sleep paralysis , a frightening symptom considered to be an abnormal episode of REM sleep atonia, the patient suddenly finds himself unable to move for a few minutes, most often upon falling asleep or waking up. During hypnagogic hallucinations , patients experience dream-like auditory or visual hallucinations, while dozing (during sleep attacks) or falling asleep. These events, together with vivid dreams that often feel so real that it takes minutes after waking up to make sure it did not happen, perturb sleep in patients with narcolepsy. Sleep is often perceived as exhausting and not restful. As the disease progress, patients start to sleep less over the entire day and night, but this improvement during the day becomes associated with dreadful episodes of time when at night the patient is wide awake and unable to sleep. Nocturnal sleep becomes disturbed not only by vivid dreams and sleep paralysis, but by intractable bouts of insomnia inthe middle of the night.

Many patients with NT1 also develop obesity .  The reason for this is partly behavioral, as patients are exhausted and stop moving or exercising, and likely partially metabolic, as the burning of calories becomes slower. Obesity also leads to sleep apnea, and some patients as a result are misdiagnosed. This is particularly problematic in children, when the onset of the disease is abrupt.

Cause of Narcolepsy Type 1 (NT1)

Thanks to research conducted by our lab in the 1990-2000, we now know the cause of NT1. Much of the research that led to these discoveries was made thanks to dogs, as some dogs have a genetic form of narcolepsy, unlike humans were the disease is more often sporadic and rarely familial (see History of Narcolepsy). All the symptoms of type 1 narcolepsy are due to the loss of about 20,000 neurons (brain cells) producing a peptide chemical called hypocretin or orexin . The cause of the loss of hypocretin neurons is autoimmune , which means that the immune system, normally involved in fighting infections, misdirects its efforts and attacks the hypocretin neurons thinking they are infected or foreign. In many ways, narcolepsy is very similar to type 1 diabetes, but instead of the immune system attacking pancreas islet cells secreting insulin (type 1 diabetes patients need insulin treatment all their live to regulate their glucose), in type 1 narcolepsy it is the hypocretin/orexin cells that are attacked.

Another particularity of NT1 is that the abnormal immune response seems to be often triggered by flu infections (sometimes without symptoms) and strep throats. In fact, in narcolepsy, the immune response to some flu strains becomes too strong and abnormally cross react with hypocretin confusing the hypocretin molecule with a piece of the flu. Once it is started, the immune system only stops attacking the hypocretin cells when they are 95% destroyed. At this point the patient has all the symptoms of narcolepsy. This process is however rare, and it is fair to say that developing narcolepsy is the result of a lot of bad luck, having a certain genetic predisposition that many others have, and getting certain types of infections and flu at exactly the wrong time in your life. Because of this, patients with narcolepsy have only a 1-2% chance to have a child with narcolepsy, and even identical twins raised in the same family with similar infections only both have narcolepsy 25% of the time.

Once the cells that secrete hypocretin/orexin are killed, recovery is impossible, and the disease is life-long. Effective treatments are however available and are life changing, so that many patients do well if treated aggressively and early with the right medication and if given the right advice.

Current Diagnosis of Narcolepsy Type 1 (NT1)

Narcolepsy can be diagnosed using specific medical procedures: the diagnosis of narcolepsy is usually easy if all the symptoms of the illness are present. More often, however, the symptoms of dissociated REM sleep such as cataplexy are mild, and a nocturnal polysomnogram (PSG), followed by the multiple sleep latency test (MSLT ) , a test where patients are asked to nap 4-5 times during the day, is suggested. This test, performed at a sleep disorders clinic, will confirm the daytime sleepiness by showing that patients fall asleep quickly, typically in less than 8 minutes as a mean, and go abnormally fast into REM period in multiple naps (“SOREMPs”). Other causes of daytime sleepiness, such as sleep apnea or periodic leg movements, are also excluded by the nocturnal recordings.  The MSLT is good but not perfect, it can be negative in about 8% of true patients and can be positive in about 4% of controls.

In some cases, and more frequently in Europe, to make sure that patients have type 1 narcolepsy, hypocretin is directly measured but this necessitates a lumbar puncture as hypocretin/orexin is primarily produced in the brain.   Showing that hypocretin/orexin is very low or absent in the CSF is the best test and the gold standard to make sure a patient has narcolepsy type 1 .  It is generally done after a genetic test called HLA testing is done and has showed that the patient has a HLA marker called DQB1*06:02 , the reason being that 98% of type 1 narcolepsy versus 25% of controls are positive for this immune gene variant. The HLA testing is only useful to exclude type 1 narcolepsy as about 25% of the general population have the gene.

Narcolepsy Type 2 (NT2) and Idiopathic Hypersomnia (IH) What's the Socioeconomic Impact?

Many patients do not have all the symptoms of narcolepsy, for example, they can be tired and need to take multiple naps without having cataplexy. Some need 12 hours of sleep every day and still feel exhausted. Other are plagued by vivid dreams and sleep paralysis but never experienced cataplexy. Typically, in these cases, an MSLT is done and if the pattern looks like NT1 (mean sleep latency ≤ 8 min; ≥ 2 SOREMPs in 5 naps), the patient is called type 2 narcolepsy (NT2, or narcolepsy without cataplexy). If the MSLT shows sleepiness with a short mean sleep latency (≤ 8 minutes) but does not show REM sleep in more than 1 nap, or reports sleeping every day more than 10 hours while still feeling tired, the patient is diagnosed as Idiopathic Hypersomnia.

For all intent and purposes, narcolepsy type 2 and idiopathic hypersomnia are not really different diseases, and in fact recent data suggest that when MSLTs are repeated, patients often move from one type to the other. The treatment is also similar, but unlike NT1, little is known regarding evolution of the disease, which can sometimes improve with time, so that it is important to consider stopping the treatment if people are doing much better as they get older. For these reasons, we are very careful when using addictive stimulants such as short acting amphetamines in NT2 and IH patients.

Narcolepsy and hypersomnia are disabling and underdiagnosed illnesses. The effect of type 1 narcolepsy on its victims for example is devastating. Studies have shown that even treated narcoleptic patients are often markedly psychosocially impaired in the area of work, leisure, interpersonal relations, and are more prone to accidents. Patients often face stigma and struggle to be as effective as other people. These effects are even more severe than the well-documented deleterious effects of epilepsy when similar criteria are used for comparison.

Treatment of Narcolepsy and Idiopathic Hypersomnia

Treatment is a combination of behavioral changes and medications. Every patient is different, even when they have the same cause, for example a loss of hypocretin/orexin neurons like in NT1. We like to say that narcolepsy does not develop in a “vacuum” but in a real person with a particular personality, particular interests, dislikes and likes, and wanting to live their life in a particular way. The situation is slightly different in children where it is even more important to treat rapidly and aggressively to avoid schooling problems and loss of confidence associated with not being able to do well and suddenly becoming obese. Treatment involves a combination of one or several medications that help stay awake, sleep better and block having cataplexy or abnormal dreams. Tailoring the treatment to each patient, and giving behavioral advice is also essential. 

Narcolepsy and hypersomnia are not hopeless conditions , and even if sometimes a clear cause is not found, there are active therapies. The first difficulty when facing a patient with excessive daytime sleepiness is to assess what is the cause of the problem. Is it a loss of hypocretin/orexin cells? What is the participation of sleep apnea, even if mild, or of poor sleep at night, abnormal circadian rhythms, or other complex neuropsychiatric issues that remain yet to be understood at the neurobiological level? 

To establish that the cause of the problem is hypocretin/orexin deficiency as in NT1 is useful as it allows the patient to stop searching for the cause of the major portions of its symptom. We also have a lot of experience on how NT1 patients react to specific medications and what would help them. For example, we were among the first to realize that sodium oxybate is more active than any other therapies in NT1, notably in children, although use of this drug needs a specialize expertise as it does not come without serious side effect. Finally, it will likely be more and more important to know if patients are hypocretin/orexin deficient or not,  as new drugs that replace orexin/hypocretin are now in clinical trials at Stanford . These are likely to be more effective in people who have this defect, not unlike insulin is uniquely effective in insulin dependent diabetes.

Unfortunately, however, the only way to be sure that a patient has hypocretin/orexin deficiency to date is to measure hypocretin/orexin in the cerebrospinal fluid, a test invented at Stanford. This test is only conducted in complex cases when there is a doubt, after verifying that the patient has the HLA-DQB1*06:02 marker mentioned above. Research we conduct at Stanford aims at finding a more convenient diagnostic blood test (probably immune or proteomics), or at finding ways to record and monitor sleep at home for better diagnostic and monitoring.

For other patients that do not have narcolepsy due to an orexin/hypocretin defect (NT1), whether they have narcolepsy type 2 (NT2) or idiopathic hypersomnia (IH) is largely academic, although sadly, it can make a big difference in the way patients get their medications covered by insurance. We and other have shown that to differentiate NT2 and IH based the MSLT as a diagnostic test results is meaningless. Often one patient who will have multiple SOREMPs on one MSLT test (consistent with NT2) will not have any SOREMP if retested a week later (consistent with IG). In brief, the MSLT only works repetitively to diagnose narcolepsy when there is hypocretin deficiency, as only in these cases it is then repeatable (although of course even in NT1, it is not perfect, and has about 5% false negative). 

In NT2 and IH, what is more important therapeutically is to find the most likely contributing factors to daytime sleepiness for each patient. A better understanding of the cause(s) leads to personalized treatment, although sometimes, a physician comes to the realization there is no clear answer and trial and error with known medications is needed. In this context, treating mild sleep apnea with surgery or CPAP, behavioral therapies, removing existing sedative medications, using various types of stimulants, psychiatric medications such as antidepressants or lithium, or treating with sodium oxybate to ensure deeper nighttime sleep can all have life transforming effects. 

Why Better Diagnostic Tools are Needed And why immunology research in type 1 narcolepsy still important

It is clear the MSLT has outlived its purpose as a diagnostic test . First as mentioned above, the MSLT is only reliable to diagnose NT1, i.e., cases with orexin/hypocretin deficiency and typically cataplexy. Yet these cases are the ones where an MSLT is not useful, as a simple blood test (HLA typing, see above) plus clinical acumen is generally sufficient to get a reliable diagnosis. In doubt, CSF hypocretin/orexin can always be measured, as increasingly done in countries outside of the United States. Second, the MSLT not measuring the true problem of a patient with daytime sleepiness and is outdated technologically. Indeed, the MSLT can be confounded by shiftwork, sleep deprivation, and this creates false positive.  It is also a test that measures the ability to fall asleep during the daytime, not the inability to stay awake which is the true complain of these patients.  It is also an artificial test, not a real-life situation.  

Criticism is easy but art is difficult. What do we do if the MSLT is not adequate anymore? Before the MSLT was invented at Stanford, assessment of narcolepsy or hypersomnia involved 24-48 hours of continuous EEG recordings in a sleep laboratory. The MSLT replaced these older tests because it was faster, cheaper and because the primary goal of diagnosis at the time was to identify NT1 patients. One advantage of the older 24-48 h continuous recording tests was that it was possible to objectively evaluate sleep and wake during the day and the night. It is still used in Europe, with the caveat that an exact protocol is not fully agreed upon, with some laboratories mandating subjects to stay in bed trying to sleep as much as possible, while others are asking patients to walk around and come to bed only when they need it. 

The solution lies in the explosion of new hardware and software technologies. As an example of software development, our team has created a deep learning program which analyzes nocturnal sleep PSG results and diagnoses NT1 patients as well as the 2-day long MSLT procedure. The program works because it can detect atypical half-dreaming half-awake “states” in patients with hypocretin/orexin deficiency, as predicted from the description of their symptoms. We are also starting to develop artificial intelligent programs that can automatically detect a whole host of sleep problems and predict development of various cardiovascular or neurodegenerative diseases (see Mignotlab.com).

More excitingly however, it is now increasingly possible to monitor sleep using various consumer devices , although those that are currently available do not typically include EEG, the signal needed to identify sleep and study brain activity. We believe that the solution, attainable today, is to build a home monitoring device that can monitor wake and sleep EEG during the day, and breathing, EEG and leg movements during the night. This device would be used for 48 hr., for example during a weekend, and the signal sent to us by internet for automatic analysis.  Analysis of sleep and wake at home in real life circumstances would allow sleep doctors to objectively evaluate what is wrong with each patient. Differential patterns of “wakefulness” may also start to be identified, reflecting the fact people cannot concentrate, are sleep deprived, in brain fog, etc. We would also be able to compare daytime alertness to sleep quality the night before, therefore properly classifying patients into subjects who are tired because they don’t have good sleep at night versus patients who seem to need to sleep all the time. This would for the rationale for a truly useful new classification of patients with narcolepsy type 2 or Idiopathic Hypersomnia. The test could also be repeated after treatment, ensuring response to any intervention and better titration of medications. 

In parallel with this, new biological tests in sleep medicine are needed. Indeed, one of the other revolutions in medicine today is large scale analytics of metabolites and proteins. As described in my research lab page, we are now developing new diagnostic tests based on the multivariate integration of multiple analytes, notably proteins. These novel biomarkers will be able to differentiate if a specific patient is tired because she or he doesn’t get enough sleep at night and is somehow sleep deprived, or because their endogenous circadian clock is abnormal and they are in permanent jet lag, or because they are hypoxic at night because of sleep apnea. These tests may also be usable to monitor these variables in response to treatment.

We see a future where a combination of biological and home monitoring tests will, with proper analytics, revolutionize sleep medicine and the therapy of patients. 

Our current results indicate that NT1 is associated with specialized autoreactive CD4+ T cells recognizing fragments of hypocretin presented by DQ0602, the HLA allele strongly associated with the disease.  As the cause of the symptoms is the loss of hypocretin, we believe this population of autoreactive CD4+ T cells is likely within the causal pathway for narcolepsy.  Influenza A, notably 2009 pH1N1 is a likely environmental trigger of the autoreactive CD4 + responses. This would explain why cases of narcolepsy in young children (where onset is abrupt), often start in the spring or summer, a few months after a presumed flu infection (that may sometimes be asymptomatic). It would also explain why cases of narcolepsy have been triggered by a specific swine flu vaccine called Pandemrix in 2009-2010. 

Finding the causative narcolepsy autoimmune cells is high priority research in our laboratory.   Indeed, once identified, we may be able to use their presence in blood as a diagnostic marker for narcolepsy. This would replace measuring CSF hypocretin-1 which requires a lumbar puncture. Second, understanding this process could lead us to modify flu vaccines to prevent not only the flu but the development of narcolepsy. Third, whereas a few years ago researchers believed that the brain and neurons were somewhat protected from autoimmune attacks, this knowledge is now outdated as new immune diseases affecting the brain are now being identified at a rapid pace (see mignotlab.com). Even neurodegenerative diseases like Parkinson’s and Alzheimer’s diseases are also believed to have important immune component.  Understanding narcolepsy may thus serve as a model to understand T cell autoimmunity. 

Finally, suffice to say that neurological complications following Covid -19 are now well recognized, not unlike what happened after the 1918 flu and encephalitis lethargica or after the 2009 H1N1 swine flu and narcolepsy. In this direction, understanding the interplay of normal and pathological immunity is going to be more and more important to understand and treat cancer, neurodegeneration, and a host of new diseases. Further, vaccines like mRNA vaccines, will become more and more potent and important in the fight against diseases, and with these active therapies will come cross-reactivity and side effects.  

Lucid dreaming in narcolepsy

Affiliations.

• 1 Sorbonne Universites, UPMC Univ Paris 06, Paris, France.
• 2 Brain Research Institute (CRICM - UPMC-Paris6; Inserm UMR_S 975; CNRS UMR 7225) Paris, France.
• 3 Sleep Disorders Unit, Pitié-Salpêtrière University Hospital, APHP.
• 4 National Reference Center on Narcolepsy, France.
• 5 Department of Biostatistics, Salpêtrière Hospital, ER4, Sorbonne Universites, UPMC Univ Paris 06, Paris, France.
• PMID: 25348131
• PMCID: PMC4335518
• DOI: 10.5665/sleep.4516

Objective: To evaluate the frequency, determinants and sleep characteristics of lucid dreaming in narcolepsy.

Settings: University hospital sleep disorder unit.

Design: Case-control study.

Participants: Consecutive patients with narcolepsy and healthy controls.

Methods: Participants were interviewed regarding the frequency and determinants of lucid dreaming. Twelve narcolepsy patients and 5 controls who self-identified as frequent lucid dreamers underwent nighttime and daytime sleep monitoring after being given instructions regarding how to give an eye signal when lucid.

Results: Compared to 53 healthy controls, the 53 narcolepsy patients reported more frequent dream recall, nightmares and recurrent dreams. Lucid dreaming was achieved by 77.4% of narcoleptic patients and 49.1% of controls (P < 0.05), with an average of 7.6±11 vs. 0.3±0.8 lucid dreams/ month (P < 0.0001). The frequency of cataplexy, hallucinations, sleep paralysis, dyssomnia, HLA positivity, and the severity of sleepiness were similar in narcolepsy with and without lucid dreaming. Seven of 12 narcoleptic (and 0 non-narcoleptic) lucid dreamers achieved lucid REM sleep across a total of 33 naps, including 14 episodes with eye signal. The delta power in the electrode average, in delta, theta, and alpha powers in C4, and coherences between frontal electrodes were lower in lucid than non-lucid REM sleep in spectral EEG analysis. The duration of REM sleep was longer, the REM sleep onset latency tended to be shorter, and the percentage of atonia tended to be higher in lucid vs. non-lucid REM sleep; the arousal index and REM density and amplitude were unchanged.

Conclusion: Narcolepsy is a novel, easy model for studying lucid dreaming.

Keywords: EEG coherence; REM sleep; dreaming; lucid dreaming; narcolepsy; spectral power.

© 2015 Associated Professional Sleep Societies, LLC.

Publication types

• Research Support, Non-U.S. Gov't
• Arousal / physiology
• Case-Control Studies
• Cataplexy / complications
• Dreams / physiology*
• Dreams / psychology
• Dyssomnias / complications
• Hallucinations / complications
• Interviews as Topic
• Mental Recall
• Narcolepsy / physiopathology*
• Narcolepsy / psychology
• Self Report
• Sleep Paralysis / complications
• Sleep Stages / physiology
• Sleep, REM / physiology
• Young Adult

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Narcolepsy and psychosis: A systematic review

Cyril hanin.

1 Centre de Référence des Maladies Rares à Expression Psychiatrique, Department of Child and Adolescent Psychiatry, Pitié‐Salpêtrière University Hospital, Assistance Publique‐Hôpitaux de Paris, Sorbonne University, Paris France

2 Faculté de Médecine Sorbonne Université, Groupe de Recherche Clinique n°15 ‐ Troubles Psychiatriques et Développement (PSYDEV, Paris France

Isabelle Arnulf

3 National Reference Center for Rare Hypersomnias, Pitié‐Salpêtrière University Hospital, Assistance Publique‐Hôpitaux de Paris, Sorbonne University, Paris France

Jean‐Baptiste Maranci

Michel lecendreux.

4 Pediatric Sleep Center and National Reference Center for Narcolepsy and Hypersomnia, Robert Debré University Hospital, Assistance Publique‐Hôpitaux de Paris, Paris VII University, Paris France

Douglas F. Levinson

5 Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford CA, USA

David Cohen

6 CNRS UMR 7222, Institute for Intelligent Systems and Robotics, Sorbonne University, Paris France

Claudine Laurent‐Levinson

Associated data.

Narcolepsy is a rare sleep disorder in which psychotic‐like symptoms can present diagnostic and therapeutic challenges. We aimed to review the association between, and medical management of, narcolepsy and psychosis in children and adults.

We reviewed the full text of 100 papers from 187 identified by a PubMed search on narcolepsy plus any of these keywords: psychosis , schizophrenia , delusion , side effects , safety , and bipolar disorder .

Three relevant groups are described. (i) In typical narcolepsy, psychotic‐like symptoms include predominantly visual hallucinations at the sleep‐wake transition (experienced as “not real”) and dissociation because of intrusion of rapid eye movement (REM) sleep phenomena into wakefulness. (ii) Atypical patients (“the psychotic form of narcolepsy”) experience more severe and vivid, apparently REM‐related hallucinations or dream/reality confusions, which patients may rationalize in a delusion‐like way. (iii) Some patients have a comorbid schizophrenia spectrum disorder with psychotic symptoms unrelated to sleep. Psychostimulants used to treat narcolepsy may trigger psychotic symptoms in all three groups. We analyzed 58 published cases from groups 2 and 3 ( n  = 17 and 41). Features that were reported significantly more frequently in atypical patients include visual and multimodal hallucinations, sexual and mystical delusions, and false memories. Dual diagnosis patients had more disorganized symptoms and earlier onset of narcolepsy.

Epidemiological studies tentatively suggest a possible association between narcolepsy and schizophrenia only for very early‐onset cases, which could be related to the partially overlapping neurodevelopmental changes observed in these disorders. We propose a clinical algorithm for the management of cases with psychotic‐like or psychotic features.

• Besides substance‐induced psychotic events, there are three main groups of patients with narcolepsy and psychotic‐like symptoms. Despite overlapping symptoms, clinical cues may help differentiate between patients with narcolepsy and atypical‐severe psychotic‐like symptoms and patients with a dual diagnosis of narcolepsy and a psychotic disorder.
• Early‐onset narcolepsy or psychosis could be associated with a higher risk of co‐occurrence of both disorders.
• Modafinil and pitolisant are apparently the wake‐promoting drugs with the least propensity to induce psychotic symptoms in patients with narcolepsy.

Limitations

• The small number of cohort studies and the rarity of narcolepsy comorbid with schizophrenia prevent us from conducting a formal meta‐analysis.
• The systematic review draws primarily on case reports and small cohort studies using diverse research designs to explore the overlap between narcolepsy and psychosis. Larger, well‐designed epidemiological and treatment studies (particularly in children) will be needed to advance our understanding in this domain.

1. INTRODUCTION

Narcolepsy is a chronic central disorder of hypersomnolence, affecting 1:5000 to 1:3300 people. 1 Subtypes include Narcolepsy Type 1 (NT1, with cataplexy and/or hypocretin deficiency), and Narcolepsy Type 2 (NT2, without cataplexy or hypocretin deficiency; 15–25% of cases). Age at onset has two peaks, at ages 15 and 35. The sex ratio is ~1. 2 , 3 Sleep‐related daytime hallucinations are reported in 45–87% of NT1 patients and 28% of NT2 patients. 4 Dissociation or delusions are less common. These symptoms may suggest a comorbid or primary diagnosis of psychotic disorder, 5 , 6 , 7 , 8 generating diagnostic, and therapeutic dilemmas. Here, we review the literature on the association between narcolepsy and psychosis, propose a framework for differential diagnosis, and suggest an approach to pharmacotherapy in patients with psychotic‐like or psychotic symptoms.

By current criteria, 2 the diagnosis of NT1 and NT2 requires excessive daytime sleepiness daily for 3 months. NT1 then requires either :

• low CSF hypocretin‐1 (≤110 pg/mL or 1/3 of mean values by a standard assay), or
• both cataplexy and two sleep study findings: mean sleep latency ≤8 minutes; and ≥2 sleep‐onset rapid eye movement (REM) periods (SOREMPs) (either both on a Mean Sleep Latency Test [MSLT], or one on MSLT and one within 15 minutes of sleep onset on nocturnal polysomnogram).

NT2 requires the above sleep study findings, without cataplexy or low CSF hypocretin‐1 (or untested hypocretin). Other causes of daytime sleepiness should be ruled out (Table  1 ), especially in children. (See Ref. 9 for discussion of diagnostic complexities.)

Evaluation of medical causes of secondary narcolepsy

The table summarizes the known medical causes of secondary narcolepsy and the typical clinical/laboratory evaluations for each type. Consideration should be given on a case‐by‐case basis to the possibility of any of these diagnoses and the need for evaluation, particularly in children presenting with possible narcolepsy.

CSF, cerebrospinal fluid; DAT, dopamine transporter positron emission tomography scan; NMDA, anti‐N‐methyl‐D‐aspartate.

Narcolepsy is typically caused by polygenic risk factors and environmental factors. 10 HLA allele DQB1*06:02 is carried by almost all NT1 patients (except for familial cases), 1 , 11 and 42% of NT2 patients, vs. ~20% in the population. 12 When cataplexy is unclear, genotyping may be used as a screening test before proposing lumbar puncture to assay CSF hypocretin‐1. Substantial evidence suggests that in most NT1 and some NT2 cases, HLA, and other risk loci 13 produce susceptibility to an autoimmune response triggered by environmental factors (eg, streptococcus or H1N1 influenza infection or vaccination), resulting in the destruction of >90% of hypocretin‐1‐expressing neurons in NT1. 14 , 15 Hypocretin‐1 stimulates wake‐inducing monoamines, activating arousal systems which consolidate wakefulness into a single daily episode. NT2 has been considered a prodromal/incomplete form of NT1, 16 , 17 or a syndrome resembling idiopathic hypersomnia. 18

Narcolepsy impacts school and work functioning, driving, interpersonal relationships, and quality of life. 19 Typically, brief sleep attacks are followed by several hours of normal wakefulness. Total daily sleep time is usually normal but may be prolonged in children (rarely in adults) or around disease onset. 20 Cataplexy consists of seconds to minutes of sudden, bilateral loss of muscle tone, with maintained consciousness, usually triggered by positive emotions. 21 Weight gain is frequent at onset. Other symptoms include sleep‐related hallucinations, 1 sleep paralysis, dyssomnia, nightmares, REM sleep behavior disorder, atypical eating disorders, attention problems, and depression. Atypical features in childhood or at onset include general weakness instead of cataplexy, avoidance behavior, 22 hyperactivity, 23 complex movement disorders, and loss of orofacial muscle tone. 24

Psychotic disorders are characterized by delusions and hallucinations. Delusions are firm beliefs that differ from convictions based on false or incomplete information, confabulation, or dogma. True hallucinations are sensory experiences in the absence of an external stimulus, perceived as “real.” They differ from dreaming because they occur during wakefulness, and from illusions (which are misperceptions of real stimuli). Here, we use “psychotic‐like symptoms” to describe experiences of narcolepsy patients which are not classically “psychotic”: (i) “hallucinations” (usually visual) occurring at the sleep/wake boundary (hypnagogic hallucinations at sleep onset or hypnopompic at sleep offset), rapidly recognized by the patient as “not real”; (ii) delusion‐like explanations offered by some patients for their vivid hallucination‐like experiences; (iii) dissociation or derealization. Rarely, narcolepsy patients also have hallucinations when awake, for example, while driving. 4 , 25 Psychotic‐like symptoms are sometimes mistaken for psychotic symptoms of schizophrenia, 26 , 27 , 28 for example, in an adolescent with sleep disturbances and “visions,” thus delaying appropriate narcolepsy therapy. But some narcolepsy patients do experience classical psychotic symptoms, apparently because of a comorbid psychotic disorder or side effects of stimulants.

We report here on a systematic review of the literature on psychotic and psychotic‐like symptoms in adults and children with narcolepsy, a topic last fully reviewed in 2003. 29 Less comprehensive discussions have appeared recently in case reports or cohort studies. 4 , 30 , 31 , 32 We reviewed cohort reports, reports of cases with narcolepsy and psychotic features, and papers relevant to the treatment of cases with these features (including drug‐induced psychosis). We also report a statistical analysis of clinical differences between reported narcolepsy cases with psychosis‐like symptoms vs. those with comorbid psychotic diagnoses.

1.1. Aims of the study

The objectives are to (i) facilitate correct diagnosis by defining subgroups of cases with these features; and (ii) provide guidance for clinical management, including the safety and use of psychostimulants, and the indications and choice of antipsychotic drug treatments.

2. MATERIALS AND METHODS

2.1. medline search.

We searched pubmed.ncbi.nlm.nih.gov/on 27 April 2020 for narcolepsy[MeSH Major Topic] AND (psychosis OR schizophrenia OR delusion OR bipolar disorder OR side effect OR safety) . We omitted “hallucinations” because, as a core narcolepsy symptom, it yielded hundreds of largely non‐relevant results. We examined articles in English or French since 1950, excluding those that were not about narcolepsy in humans, or did not address psychotic‐like or psychotic symptoms. We selected additional relevant papers from the references in papers reviewed in full text.

2.2. Quantitative analysis

The cohort reports were not amenable to meta‐analysis because of their variable study designs and outcome measures. We performed quantitative analyses (using SPSS 23.0) comparing 17 reported cases with psychotic‐like symptoms attributed to narcolepsy, and 41 diagnosed by the authors as narcolepsy plus a psychotic disorder. Each case was reviewed (by C.H.) with a checklist of clinical features (Table  S3 ), rating features “present” (mentioned/strongly suggested) or “absent” (denied/not described). For ages at onset of sleep and psychotic symptoms, normality of the distribution was inspected graphically and confirmed (Kolmogorov–Smirnov test), equality of variance confirmed (Levene's test), and the groups were contrasted with Student's t tests. For dichotomous variables, χ 2 tests were performed.

3.1. Literature search

Systematic PubMed search identified 187 articles. Based on abstracts, we excluded 44 articles that were not about narcolepsy and psychotic symptoms, 4 with inaccessible full text, 12 not in English or French; 9 in a non‐narcolepsy cohort, 15 about non‐relevant outcomes, and 1 letter to the editor without additional data/hypotheses. We reviewed the full text of the remaining 100 articles, including 26 reviews, 27 case reports, 23 cohort studies, 20 clinical trials, and 4 meta‐analyses (of narcolepsy treatment trials) (Figure  1 ; Table  S2 lists citations for each article type).

Flow chart of review process. The systematic literature search was conducted on 27 April 2020, using the following Search Builder: narcolepsy[MeSH Major Topic] AND (psychosis OR schizophrenia OR delusion OR bipolar disorder OR safety OR side effect, yielding 187 records. An additional 48 records were identified via reference lists from the 187 selected records, or from supplementary Medline searches (15 papers on mechanisms or adverse effects of drugs used to treat narcolepsy; 12 with relevance to the discussion of the relationship between narcolepsy and psychosis; and 21 with more relevance to discussion of narcolepsy or to psychosis but not their relationship). None of the additional records were cohort or case reports. We list as excluded records those that were identified by systematic search but not selected as eligible for inclusion in the qualitative or quantitative analyses for the reasons cited

3.2. Systematic review: Qualitative results

Since the first 13 cases published in 1884, 33 case and cohort reports have discussed the relationship between narcolepsy and psychotic symptoms. Authors generally described three groups: 27 (i) hallucinations as part of the narcolepsy process, clearly different from psychosis; (ii) patients with narcolepsy and a comorbid, independent psychotic disorder (schizophrenia, schizoaffective disorder, or more rarely a mood disorder with psychotic features); and (iii) psychotic symptoms provoked by psychostimulants treatment. Based on a larger number of reports, we suggest a modified grouping approach. Group 1 is typical narcolepsy. Group 2 (sometimes called “the psychotic form of narcolepsy”) comprises more severe and atypical psychotic‐like symptoms thought to be driven by the same mechanisms as in Group 1. Group 3 patients probably have two independent diagnoses, although an etiological relationship remains possible, especially in childhood‐onset cases. Psychostimulant‐induced psychosis can occur in each group, particularly at high dosages.

3.3. Psychotic‐like symptoms in typical narcolepsy

Hallucinations are described in 20% 34 to 80% 25 of NT1, and in 28.2% of NT2 patients, when falling asleep (55% of those with hallucinations), waking up (3%), or both (42%), with 18% reporting daytime hallucinations while wide awake. 4 They increase when lying supine, which is not observed in psychotic disorders.

An observational study found that hallucinations (predominantly non‐verbal) were as frequent in 28 NT1 patients without psychotic diagnoses as in 21 schizophrenia patients. 8 All sensorial modalities were observed in both groups. Hallucinations were predominantly sleep‐related in narcolepsy (75% vs. 4.8%, p  < 0.0001) and multimodal (predominantly auditory verbal) in schizophrenia (76% vs. 3.6%, p  < 0.0001). The groups had similar proportions with visual hallucinations (shadows, monsters, demons, or animals [zoopsia]).

Fortuyn et al. interviewed 60 patients with NT1, 102 with schizophrenia, and 120 healthy controls using the Schedules for Clinical Assessment in Neuropsychiatry 2.1. 25 More NT1 patients than controls (83% vs. 2%, p  < 0.001) reported hallucination‐like experiences that are not considered as definitely “psychotic” in psychiatric studies (presence of unseen‐unheard visitors, falling/flying sensations, out‐of‐body experiences, altered perception of time, déjà‐vu, derealization), but this percentage was not different in schizophrenia patients (70%). Compared with schizophrenia, narcolepsy patients more often reported visual hallucinations (15% for simple and 38% for complex images), non‐verbal auditory hallucinations (footsteps, slamming/creaking of doors, animal sounds – 50% vs. 15%), kinesthetic and tactile hallucinations (heat, pain, crawling under the skin or in the genital area, 48%) and less frequently olfactory hallucinations. Verbal hallucinations were less frequent (18 vs. 45%). NT1 and schizophrenia patients equally experienced multimodal hallucinations. NT1 patients had more fantastic delusions and false memories than controls. Rarely, NT1 patients reported grandiose (2%), fantastic (5%), or persecutory delusions (2%).

Leu‐Semenescu et al 4 studied the characteristics of hallucinations in 100 narcolepsy patients (54 NT1, 46 NT2) and 100 Parkinson's disease patients. Among the 45% of narcolepsy patients with hallucinations (59% in NT1, 28% in NT2), 24% had auditory (changing voices, footsteps) or visual illusions (including dyschromatopsia); 15% had unformed hallucinations (presence of a person; a passing animal); 95% had formed, visual hallucinations (human, animal, or fantastic figures such as ghosts, vampires; complete or distorted, with vivid colors) with more than half of these reporting kinetic hallucinations (lateral movement in bed as if on a slippery surface, falling, being sucked into the bed, flying, levitating, out‐of‐body experiences). One‐third of patients reported tactile hallucinations (air blowing on oneself, being touched, burned, bitten, trampled, strangled, or sexually abused). Auditory hallucinations could be non‐verbal (44%, doors opening, alarm ringing, footsteps, plates breaking) or verbal (33%, being called by name, hearing conversation fragments). Hallucinations were usually multimodal (98%, primarily NT1) and sometimes holistic (42%). Hallucinations were associated with sleep paralysis and REM sleep behavior disorder but not with cataplexy, HLA positivity, or sleepiness, consistent with other studies. 35

3.4. Narcolepsy with atypical psychotic‐like symptoms

The term “psychotic form of narcolepsy” has been suggested in patients with psychotic‐like features resembling more severe forms of typical narcolepsy symptoms, sometimes leading to a misdiagnosis of schizophrenia. 27 , 36 They had vividly realistic and emotional dreams (8% of narcolepsy patients in Leu‐Semenescu et al 4 ) and hallucinations (which can be nightly). Episodes of dream‐reality confusion were reported by 83% of 46 NT1 patients vs. 15% of 41 healthy controls ( p  < 0.0001), 37 lasting up to several weeks and associated with severe, frequent cataplexy, and treatment‐resistance. These symptoms may be worsened by antipsychotic drugs 26 , 38 and reduced by psychostimulants. 39

Some patients explain these experiences with what appear to be secondary “delusional” thoughts, 38 with fantastic, persecutory, sexual abuse, mystical, megalomaniacal, referential, or paranormal themes. Several case studies mentioned medico‐legal consequences after sincere but possibly false rape allegations. 40 , 41 Several hypotheses have been proposed. Fortuyn et al 25 noted that some narcolepsy patients (otherwise mentally healthy) had difficulty in differentiating hallucinations from reality. Impaired insight was more common in narcolepsy than in Parkinson's disease. 4 Memory deficits have been reported (false beliefs based on false memories). 37 Narcolepsy patients often complain of memory problems and may have deficits in source memory (monitoring a memory's origin), 42 but show no deficits on formal memory testing. 43 , 44

Children with narcolepsy have hallucinations (39–50%) and may have difficulty in distinguishing dreaming from reality. 7 Clinicians sometimes misinterpret their hallucinations and behavioral changes as psychotic disorganization. 45

3.5. Quantitative comparison of atypical narcolepsy and dual diagnosis cases

Comorbidity of narcolepsy with a psychotic disorder has been documented primarily in case reports or series (Table  S1 ). A separate psychotic disorder diagnosis has usually been assigned when the symptoms met diagnostic criteria and appeared unrelated to REM intrusion. Table  S1 describes 58 cases: 41 with a dual narcolepsy and psychotic disorder diagnosis (Group 3); and 17 described as “psychotic” or “delusional” narcolepsy (Group 2). Table ​ Table2 2 summarizes analyses of group differences (Table  S4 provides details of our ratings). Dual diagnosis patients usually developed narcolepsy first, and then (6.8 years later on average) psychosis, mostly (38/41 cases) in the schizophrenia spectrum. They more often had disorganized symptoms including thought disorder (65.9% vs. 17.6%). Group 2 cases were more likely to have visual (88.2% vs. 19.5%) and multimodal hallucinations, zoopsia, sexual and mystical delusions, and false memories.

Case reports of “psychotic form of narcolepsy” vs. comorbid narcolepsy and psychotic disorder: Differences in clinical features

We classified 58 cases (reported in 27 papers, Table  S2 ) according to the authors’ diagnostic conclusion (psychotic form of narcolepsy vs. comorbid narcolepsy and psychotic disorder). For each case, we recorded age at onset for sleep and psychotic‐like symptoms and presence/absence of the clinical features listed in the table. A feature was considered “present” if it was explicitly mentioned or very clearly suggested by the clinical description, otherwise, it was considered “absent,” that is, we attempted not to infer the presence of symptoms beyond the data in the report. P ‐values less than 0.05 are bolded.

These symptomatic differences are not a validation of these subgroupings. Rather, they quantify the clinical judgments of the various authors (and probably a consensus of the field) that Group 2 patients are experiencing a more severe form of classical narcolepsy symptoms, with the same underlying pathophysiology. No large‐scale or prospective data exist to better describe or validate these subgroups and the gray areas between them, but they have implications for treatment as discussed below.

More rarely, 38 narcolepsy emerges as a possible primary diagnosis in “schizophrenia” patients in whom antipsychotics were poorly tolerated or overly sedating (as discussed further below). This is a challenging clinical situation, 10 because antipsychotic medications interfere with polysomnography and MSLT by reducing REM sleep time and daytime mean sleep onset latency. By contrast, antipsychotic withdrawal can produce REM sleep rebound and a false positive narcolepsy diagnosis. 10 Undertaking prolonged antipsychotic washout is a difficult decision. An alternative is to measure CSF hypocretin‐1 levels, which remain in the normal range during antipsychotic treatment. 113

3.6. Is there an association between narcolepsy and psychotic disorders?

Older studies suggested an increased prevalence of narcolepsy among schizophrenia patients 31 , 36 and (retrospectively) a greater risk of schizophrenia among narcolepsy patients vs. among controls. 46 Narcolepsy was diagnosed in 7% of a schizophrenia cohort, 38 but the study design was flawed (the estimation of 7% was based on 5 misdiagnosed in‐patients plus a small cohort of current out‐patients, rather than collecting an in‐patient cohort during a defined time period). A well‐designed study could not replicate this finding 32 : narcolepsy symptom questionnaires were administered to 366 consecutive hospitalized adults with schizophrenia spectrum disorders. Among 24 with possible narcolepsy (after sleep medicine consultations), 5 carried HLA DQB1*06:02, of whom 3 accepted lumbar puncture, but all had normal hypocretin‐1 levels, thus no NT1 cases were detected. Sleep studies were not performed because antipsychotics could not be discontinued. Further, among 548 adult NT1 patients in two large sleep centers, 1.8% had a history of schizophrenia spectrum psychoses (close to population prevalence), in whom anti‐NMDA antibodies were not detected. 47 However, early‐onset NT1 (<16 years old) was more common in patients with (60%) than without (35%) a comorbid psychotic disorder.

A significant association of schizophrenia was reported in early‐onset NT1 in a prospective study of 151 narcolepsy patients in Taiwan's only child/adolescent sleep clinic. 31 Ten of 102 NT1 patients (9.8%) had comorbid schizophrenia based on clinical and research interviews. Average age at onset was 11.25 for NT1 and 15.8 for schizophrenia. Compared with 37 age‐matched NT1‐only and 13 schizophrenia‐only cases, comorbid cases had poorer antipsychotic response and increased weight. However, in a population‐based study of 38 narcoleptic children in Western Sweden (most with cataplexy, sleep study abnormalities, and exposure to anti‐H1N1 vaccination, but no hypocretin deficiency), 43% had a psychiatric diagnosis, but no psychotic disorder. 48 Thus, the Taiwan finding awaits replication. We note that in the largest recent series of comorbid cases, onset of sleep symptoms occurred before 16 years of age in 10/10 5 and 6/10 cases 47 (Canellas et al 5 provide a useful structured interview to evaluate such cases).

There is an ongoing discussion in the literature about possible common genetic or environmental risk factors or shared hypocretin pathophysiology 49 in producing overlapping symptoms. 5

3.7. Proposed mechanisms of psychotic‐like symptoms in narcolepsy

Typical hallucinations in narcolepsy are attributed to partial REM sleep intrusions while awake. 4 , 38 , 50 Typical sleep‐related hallucinations generally improve with adequate wake‐promoting (and not with antipsychotic) treatment, and in some cases serotonergic antidepressants are added because they suppress REM activity (see discussion below), suggesting that these symptoms are directly related to narcolepsy. 27 , 38

Overlapping autoimmune mechanisms have been hypothesized. There is an extensive literature on infectious and autoimmune factors in schizophrenia. 51 Older studies suggested an association of HLA DQB1*0602 with schizophrenia, 52 but recently Sekar et al 53 reported strong evidence that genetic association near the HLA region on chromosome 6 is largely explained by structural sequence variants in the complement 4 gene which has a role in synaptic pruning. There are conflicting data regarding anti‐NMDA antibodies in dual diagnosis cases. 47 , 54 It has been proposed that loss of hypocretin neurons (which project to the ventral tegmental area, prefrontal cortex, and nucleus accumbens) leads to impaired mesocortical‐pathway signaling and psychosis, 55 possibly interacting with an independent susceptibility to psychosis. 29

3.8. Medication‐induced psychosis in narcolepsy patients

All primary narcolepsy drug treatments enhance dopaminergic neurotransmission, a mechanism associated with a risk of provoking psychosis. Classical psychostimulants ( methylphenidate , amphetamines , and methamphetamine –now considered second‐line narcolepsy treatments) increase synaptic dopamine primarily by noncompetitively blocking the dopamine transporter (reuptake site) without increasing presynaptic release. 56 Methylphenidate 57 and amphetamines are generally considered safe in narcolepsy. 58 A Japanese‐language paper on a study of 329 NT1 patients 59 followed up after a mean of 15.4 years (mentioned in reference 27 but not accessible to us) reported a 3.2% rate of psychostimulant‐induced psychosis. An English‐language chapter by the same author about the same study 60 describes the methodology as retrospective data collection by self‐report questionnaire. Another retrospective study (chart review) reported psychotic events in 5% of 58 patients on “standard” dosages of psychostimulants, primarily methylphenidate, vs. 24% of 58 patients receiving “high” dosages (>120 mg/day; odds ratio = 12.0), with additional adverse psychiatric outcomes. 61

Modafinil , a first‐line treatment, indirectly reduces dopamine and norepinephrine reuptake through serotonin‐mediated inhibition of aminobutyric acid (GABA) release 62 and enhances dopamine‐dependent modulation of adrenergic receptors, 63 with a good safety profile in narcolepsy. 64 , 65 , 66 Psychiatric adverse events have been reported, including rare cases of psychosis, 67 , 68 elated mood, 69 , 70 , 71 , 72 and switch to mania with psychosis. 72 , 73 , 74 In a pharmacovigilance study, 2,416 modafinil prescribers reported one manic and two psychotic episodes. 75 A small study of children with narcolepsy reported one case with exacerbation of a pre‐existing psychotic disorder. 68 A meta‐analysis of adjunctive modafinil and its derivative armodafinil in schizophrenia showed no improvement, and no increase in psychotic symptoms. 76

Sodium oxybate (gamma hydroxybutyrate, GHB) inhibits dopamine release via activation of GABA‐B circuits and the GHB receptor 77 , 78 which could upregulate dopamine receptors. It is generally well‐tolerated in adults and children with narcolepsy. 79 , 80 , 81 , 82 , 83 Psychotic symptoms have been reported (usually shortly after starting or resuming treatment). 73 , 84 , 85 , 86 , 87 Emergence or exacerbation of psychotic symptoms by sodium oxybate was retrospectively reported in 5 of 90 narcoleptic patients with no psychiatric history, 87 and 1 of 63 children in a clinical trial. 88 Mazindol , a sympathomimetic amine, reduces dopamine and norepinephrine reuptake. Psychotic symptoms were not reported in a retrospective study of 94 adult and child patients 89 or a clinical trial ( n  = 37). 90 Pitolisant enhances histaminergic transmission via inhibition of presynaptic uptake (inverse histamine H3 receptor agonist effect). 91 It indirectly increases release of dopamine, norepinephrine, and acetylcholine. 92 Anxiety and depression have been observed but not psychosis, 93 , 94 , 95 in limited data.

3.9. An algorithm for clinical practice

Based on literature review, we suggest an algorithm for evaluating and treating narcolepsy patients with psychotic symptoms (Figure ​ (Figure2 2 ).

Algorithm for evaluating and treating narcolepsy patients with psychotic symptoms

Typical sleep‐related hallucinations of narcolepsy, recognized as such by the patient, and without other psychotic features (Group 1), are treated with drugs for narcolepsy, and not antipsychotics. The most common psychosis‐related complication in all groups is the onset of psychotic or worsening atypical psychotic‐like symptoms after a wake‐promoting drug has been introduced or its dosage increased. The new drug is generally stopped, or the previous dosage restored; if symptoms resolve rapidly, drug‐induced psychosis is the likely diagnosis. Brief treatment with a less sedating antipsychotic (eg, aripiprazole or risperidone) may be helpful, but further optimization of narcolepsy treatment should then be attempted. If the psychosis was provoked by classical stimulants, modafinil or pitolisant might be considered.

Both the typical wake‐state hallucinations of narcolepsy (Group 1) and their atypical variants (Group 2) are presumed to represent REM intrusions into wakefulness, with atypical patients sometimes developing delusion‐like ideas to rationalize the experiences. Antidepressants with serotonergic activity are known to suppress REM sleep, 96 and in clinical practice, they are frequently prescribed for typical narcoleptic patients to control REM intrusion phenomena such as cataplexy and hallucinations. 97 This is based on anecdotal observations 98 and consensus guidelines 99 , 100 rather than controlled studies. The same strategy may be attempted in Group 2 patients, in the hope that additional treatment of REM intrusions will improve both the atypical hallucinations and the delusion‐like rationalizations. Optimizing wake‐promoting medication or adding an SSRI/SNRI is recommended to reduce psychotic‐like symptoms. Psychiatric consultation is advised for patients with dangerous impulses or behaviors.

A comorbid psychotic disorder should be considered if hallucinations and delusional ideas emerge and appear unlikely to be related to REM intrusions. We found no published clinical trials for the treatment of patients with dual diagnoses. Narcolepsy misdiagnosed as schizophrenia is probably rare in adults but might be more common in children with narcoleptic and psychotic‐like symptoms. Treatment of dual diagnosis cases is challenging because stimulants increase dopamine release which can induce psychosis, whereas antipsychotic drugs can worsen sleepiness by blocking dopamine and histamine transmission. Kishi et al 27 recommended maintaining a wake‐promoting drug (despite the small risk of psychotic exacerbation), preferably modafinil because of its predominantly non‐dopaminergic mechanism. 67 Pitolisant may be useful in our experience, although there is limited evidence regarding its potential to provoke psychosis. Less sedating antipsychotics like risperidone or aripiprazole are recommended 4 , 5 , 101 , 102 ; aripiprazole may stabilize rather than simply block dopaminergic neurotransmission. 102 In some case reports, olanzapine, clozapine, haloperidol, or quetiapine was effective. 30 , 47 , 103 , 104 The clinical management of these complex situations requires further study.

4. DISCUSSION

Most narcolepsy patients with psychotic or psychotic‐like symptoms will fit into one of three groups, and patients in any group may experience drug‐induced psychosis (especially those on high doses of psychostimulants and those with previous psychotic symptoms):

• Patients with typical hallucinations of narcolepsy. The intrusion of REM sleep phenomena into wakefulness causes hallucinations (usually visual, at sleep‐wake transitions, recognized by the patient as “not real”), cataplexy, and sleep paralysis. These patients are recognized as “not psychotic” by sleep medicine specialists.
• Atypical narcolepsy with psychotic‐like symptoms (“psychotic form of narcolepsy”). These patients have more severe and vivid hallucinatory, daytime dream‐like experiences and may develop delusion‐like rationalizations (analogous to severe obsessive‐compulsive disorder with delusion‐like ideas about obsessions). They may have deficits in insight and source memory. They may worsen on antipsychotic drugs and improve on psychostimulants. Misdiagnosis is more common, especially in children.
• Narcolepsy with a comorbid psychotic disorder. These patients have psychotic symptoms unrelated to sleep phenomena, often including disorganized behavior and thought disorder starting years after narcolepsy onset (Table ​ (Table2, 2 , Table  S2 ). It is unlikely that narcolepsy is frequently misdiagnosed as schizophrenia in adults, 32 although case reports demonstrate that it can occur. However, children and adolescents with NT1 may be at increased risk of comorbid schizophrenia spectrum disorders. 31 It remains unclear whether there are shared autoimmune mechanisms. 105

The possible association of NT1 with schizophrenia spectrum disorders in childhood deserves further study—a difficult challenge given that both presentations are rare in the population. Studies of children with NT1 have consistently found increases of more common psychiatric disorders, 45 , 106 including attention deficit‐hyperactivity disorder (ADHD), internalizing (depressive and anxiety) disorders, and learning problems. 48 , 107 , 108 , 109 , 110 , 111 This broad vulnerability has been attributed in part to excessive daytime sleepiness 111 and impulsive/hyperactive counterstrategies to fight it, 108 to persistent, frightening sleep‐related hallucinatory experiences 107 and to psychological distress because of the overall disease burden. However, an additional role of organic lesions is suggested by the association of depression with severity of brain white matter structural changes observed in adult NT1 using diffusion tensor imaging. 112

If the association of early‐onset NT1 with schizophrenia is confirmed in future studies, several explanations are possible. A direct effect of central Hcrt‐1 deficiency has been considered, because Hcrt‐1 influences dopaminergic neurotransmission in the midbrain and prefrontal cortex, which are involved in the pathophysiology of schizophrenia. 55 However, schizophrenia is rare in adult‐onset NT1 patients despite the dramatic loss of central Hcrt‐1, and CSF Hcrt‐1 is normal in schizophrenia 113 , 114 (although these small studies do not exclude a low‐Hcrt‐1 subgroup). CSF Hcrt‐1 is also typically normal in adult major depression. 55 It seems unlikely that reduced Hcrt‐1 directly leads to psychosis.

Narcolepsy onset in childhood is typically associated with symptoms never observed in adult‐onset cases, including complex movement disorders (lasting up to two years after onset and then disappearing), massive weight gain, and psychiatric symptoms. This suggests that there is transient inflammation in the hypothalamus that extends beyond hypocretin neurons, 115 or an acute destabilization of dopaminergic‐hypocretinergic interactions. 24 Furthermore, Hcrt‐1 deficiency in childhood could impair normal neurodevelopment in ways that either increase the child's risk of schizophrenia or that lead to an earlier age at onset in predisposed individuals. There is a partial overlap in the structural MRI changes observed in childhood‐onset schizophrenia 116 and in childhood NT1, 117 including reduced gray matter volume in prefrontal cortex and cerebellum. It is possible that these and other changes have a major impact on schizophrenia risk in a minority of children (representing a syndromic type of schizophrenia), or that they constitute an additional risk factor for schizophrenia which has a large number of interacting genetic 118 , 119 and environmental 120 risk factors. Larger‐scale data are needed on prospective follow‐up and on structural brain changes and cognitive functioning in children and adolescents with narcolepsy. Future studies of the association of childhood narcolepsy and schizophrenia could inform our understanding of the etiopathology of both disorders.

5. PERMISSION TO REUSE AND COPYRIGHT

Figures, tables, and images will be published under a Creative Commons CC‐BY license and permission must be obtained for use of copyrighted material from other sources (including re‐published/adapted/modified/partial figures and images from the Internet). It is the responsibility of the authors to acquire the licenses, to follow any citation instructions requested by third‐party rights holders, and cover any supplementary charges.

CONFLICT OF INTEREST

During the last two years, David Cohen reported past consultation for or the receipt of honoraria from Otsuka, Shire, Lundbeck, and IntegraGen. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

AUTHOR CONTRIBUTIONS

CH conducted the literature search, reviewed references, and wrote the first draft of the manuscript. CL and DC reviewed key papers and contributed to revisions. IA, ML, and JBM contributed to the final revision of the manuscript with their expertise in sleep medicine. All authors read and approved the final manuscript and contributed to the drafting and revising of the paper.

PEER REVIEW

The peer review history for this article is available at https://publons.com/publon/10.1111/acps.13300 .

Supporting information

Supplementary Material

ACKNOWLEDGMENTS

CH and CLL would like to express their appreciation for the contributions and expertise of the Sleep Disorder Unit of Pitié‐Salpétrière Hospital and to the Department of Functional Exploration of Robert Debré Hospital. The authors declare that this study was conducted without funding.

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Taxpayers Were Overcharged for Patient Meds. Then Came the Lawyers.

A group of politically connected lawyers teamed up to go after insurers and made millions from one of the largest Medicaid settlements in history.

By Shalina Chatlani

Shalina Chatlani examined the health care system in Mississippi as a part of The Times’s Local Investigations Fellowship .

In 2018, when Mike DeWine was Ohio’s attorney general, he began investigating an obscure corner of the health care industry.

He believed that insurers were inflating prescription drug prices through management companies that operated as middlemen in the drug supply chain. There were concerns that these companies, known as pharmacy benefit managers, or P.B.M.s, were fleecing agencies like Medicaid, the government-run health insurance program for the poor.

Three years later, after Mr. DeWine became governor of Ohio, the state announced an $88 million settlement with one of the nation’s largest insurance companies, Centene.

The case led to a nationwide reckoning for the company, as attorneys general in one state after another followed Ohio’s lead, announcing multimillion-dollar settlements and claiming credit for forcing Centene to reform its billing practices.

On the surface, it appeared that these settlements, which now total nearly $1 billion, were driven by state governments cracking down on a company that had ripped off taxpayers.

But a New York Times investigation, drawing on thousands of pages of court documents, emails and other public records in multiple states, reveals that the case against Centene was conceived and executed by a group of powerful private lawyers who used their political connections to go after millions of dollars in contingency fees.

The lawyers were first hired in Ohio, without competitive bidding. Then, they gathered evidence against Centene of questionable billing practices across the country.

Using information they acquired from Centene and other sources, they negotiated with the company to set the basic framework of an agreement that could be applied in other states. With that in hand, they approached attorneys general in multiple states and made a compelling offer: hire them, at no direct cost to taxpayers, and recoup millions of dollars Centene had already set aside.

So far, the lawyers have been awarded at least $108 million in fees.

The Centene case is just one example in a thriving industry that allows private lawyers to partner with elected attorneys general and temporarily gain powers usually reserved for the government. Under the banner of their state partners, these lawyers sue corporations and help set public policy while collecting millions of dollars in fees, usually based on a percentage of whatever money they recoup. The practice has become standard fare in the oversight of major industries, shifting the work of accountability away from legislators and regulators to the opaque world of private litigation.

Private lawyers do not have to publicly defend the deals they make or prove how aggressively they went after a company accused of wrongdoing. Nearly all their work happens in secret, especially if companies settle before the stage of a lawsuit when evidence is filed with the court.

The lawyers do not even have to disclose who worked on a case or who was paid, so the public may be left unable to monitor potential conflicts of interest even as the lawyers pursue litigation on behalf of the people.

The Centene case was organized by the Mississippi-based law firm Liston & Deas along with at least three other firms, several with close ties to former Gov. Haley Barbour of Mississippi, who was once considered one of the most influential Republican power brokers in the nation.

The lawyers included Paul Hurst, who served as Mr. Barbour’s chief of staff when he was governor and who married into Mr. Barbour’s family, and David H. Nutt, one of the richest men in Mississippi, who amassed a fortune funding state lawsuits against tobacco companies. Cohen Milstein, a huge national law firm with deep experience in contingency work for state attorneys general, was also part of the venture.

Though he is not listed in any government contracts as a lawyer of record, Mr. Barbour himself was a member of the legal team when Liston & Deas vied for the contract in Ohio.

At the time, Mr. Barbour also worked for Centene as a federal lobbyist .

Even now, close to three years after Centene signed its first settlements, no one has fully explained Mr. Barbour’s role in the case for the company. There is no way for the public to know whether he influenced the outcome or to measure whether Centene paid its full share, because the data used to calculate what Centene overcharged remains hidden from the public under provisions designed to protect attorney work product.

Mr. Barbour and other lawyers said that the former governor worked on the case for less than a year when the group was examining several insurance companies, and that he cut ties when Centene emerged as the primary target. Mr. Barbour said he informed Centene and his colleagues about the development and was never involved in negotiations or legal matters. He continued representing Centene as a lobbyist, he said, but his role in the case on behalf of the company was as “more of an observer.”

The lawyers said that Mr. Barbour was never paid for his work and that the settlement was not influenced by Mr. Barbour’s connections to Centene or to the lawyers who remained. They said each state attorney general reviewed Centene’s billing practices when deciding whether to enter a settlement agreement.

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In recent years, P.B.M.s have been widely criticized , including by members of Congress, who have held multiple hearings and proposed legislation. The Centene settlements stand as the most successful attempt to hold a company operating in the industry accountable.

Liston & Deas and its partner law firms uncovered that Centene had arranged discounts with CVS Caremark on certain drugs and then pocketed the savings instead of passing them on to Medicaid. In some states, they revealed that Centene layered on unnecessary management fees that it had not disclosed. Although Centene settled without admitting guilt, the company agreed to be more transparent in how it sets reimbursement rates.

The lawyers noted that they spent several years investigating Centene and negotiating with the company at their own risk, saving states the cost of building a case.

Mr. Nutt, one of the lawyers who pursued the case, said states were happy with the terms of the settlements.

“Almost every one of those states audited to determine if our damage model was fair,” Mr. Nutt said.

“The formula was based on a triple damages model that we developed. And everybody was quite satisfied with it, because it was three times what anybody could have proven in court.”

Hiring Outside Counsel

For most of their history, state attorneys general were largely focused on advising state officials on legal matters and representing local agencies in court.

That changed drastically almost 30 years ago, when states came together to sue tobacco companies and won a $206 billion settlement to cover the cost of medical care related to smoking. The lawsuit helped redefine the role of the attorney general as one of the most powerful positions in state government and a natural place to start a political career.

Through high-profile lawsuits against corporations, an attorney general could directly affect policy and build a reputation as a champion of the people.

But complex litigation against large companies can require years of investigation and legal work, with no guarantee of success. Increasingly, states have turned to private lawyers willing to work on contingency as a way to stretch limited resources.

The rise of contingency fee cases kicked off a new wave of lobbying across the nation. Law firms looking for contracts have poured money into attorney general election campaigns and sponsored conferences at high-priced resorts, where private lawyers mingle with attorneys general and pitch their latest ideas for lawsuits.

Many states have capped how much lawyers can be paid in contingency fees and have increased oversight of private firms working for the government. But there remains concern about undue political influence and potential conflicts of interest.

“In theory, there’s an incentive to have the settlement be as big as possible, and of course that’s great for the state,” said Paul Nolette, a professor at Marquette University who has studied how the role of attorneys general has changed over time.

But in reality, lawyers have an incentive to recover the largest amount of money in the shortest amount of time, which could pressure them to water down settlements and compromise on punitive measures, Dr. Nolette said.

“I think that does raise some questions about how forcefully A.G.s and private attorneys are prosecuting a particular case,” he said.

Several experts said that contingency cases had recouped billions of dollars on behalf of the public and had become a critical way to regulate the behavior of powerful industries and large corporations.

But inviting private lawyers to help set public policy has inherent risks, they said.

Private lawyers may be more likely to have conflicts of interest because they generally represent many businesses and individuals, not just the citizens of a state.

And unlike most attorneys general, private lawyers are not elected officials. They are not generally governed by open records laws or subject to public pressure, as from legislators setting their budgets.

In the Centene case, Mr. Barbour’s associations with both Centene and the private lawyers raise “important questions” about who controlled the case to make sure it was pursued in the best interests of states that settled, said Kathleen Clark, a professor of legal ethics at Washington University in St. Louis.

“Did state A.G.s proactively pursue these cases, or did they passively accept the ‘free money’ or ‘easy money’ of the proposed settlements that the law firms had already negotiated with Centene?” Ms. Clark asked.

Christina Saler, a partner at Cohen Milstein, said Mr. Barbour’s early association with the legal team was not a conflict of interest because Mr. Barbour withdrew from the case before lawyers started investigating Centene.

“After Mr. Barbour’s disassociation, we had no further contact with Mr. Barbour on this matter,” she said.

A Well-Connected Team

Mr. Barbour’s involvement in the Ohio case against P.B.M.s illustrates the potential for favoritism when states hire private lawyers.

Mr. Hurst noted the involvement of Mr. Barbour when seeking the contract in Ohio, according to emails acquired from the Ohio attorney general’s office through a public records request.

In a June 22, 2018, email exchange, just a few days before the state hired Liston & Deas, Mr. Hurst recalled meeting with the attorney general’s staff in Ohio.

Mr. Hurst went on to note that members of his team had worked with Governor Barbour while he was in office and that they all “continue to work together now.”

In an email a week later, an assistant attorney general shared Mr. Barbour’s cell number with Mr. DeWine, saying that Mr. Barbour had shared it so he could “call him about this case anytime.”

Mr. Barbour, who had served two terms as governor of Mississippi, was a former chairman of the Republican Governors Association and a former chairman of the Republican National Committee. Known as a prolific fund-raiser , he was credited with bringing in hundreds of millions of dollars to support Republican candidates across the nation.

In 1991, Mr. Barbour co-founded BGR Group, a lobbying firm that quickly became one of the most influential in Washington.

Mr. Barbour had known Mr. DeWine since he was first elected to the Senate in 1995.

Two decades later, when Mr. DeWine was in the midst of a hard-fought campaign for governor, Mr. Barbour’s close associates solicited him for the legal work on the Centene case. In October 2018, less than three months after Mr. DeWine hired Liston & Deas, he traveled to Washington to visit Mr. Barbour’s lobbying firm for several hours, according to calendar records.

At the time, Mr. Barbour and others at BGR were registered lobbyists for Centene.

Mr. Barbour has never been named in state contracts as one of the private lawyers on the case in Ohio or anywhere else. His involvement has rarely, if ever, been publicly reported.

Ms. Saler, of Cohen Milstein, said there was no need to inform state officials because Mr. Barbour had not been involved in the Centene portion of the case and had exited the venture several years before states hired the lawyers.

At least four law firms were involved in the case in two or more states, according to retainer agreements and financial records showing broadly how settlement funds were disbursed.

According to Max Littman, a former data analyst with HealthPlan Data Solutions, the analytics firm that helped identify Centene’s overcharges in Ohio, one important role for many of the lawyers was to use their connections as they presented the overcharges to various states.

Mr. Littman, who said he worked closely with the legal team, described the dynamic: Liston & Deas, with roots in a deeply red state, would approach Republican attorneys general, and Cohen Milstein, “who were our Democrats,” would focus on Democratic states.

When The Times asked for records showing Liston & Deas’s qualifications to be hired to represent the State of Ohio, the attorney general’s office said no records existed. Cohen Milstein and other law firms had submitted such documentation in the past when seeking contracts in Ohio.

Settling With States

In June 2021, nearly three years after Ohio hired its outside counsel, two states announced the first settlements with Centene on the same day: Ohio would get $88 million, Mississippi $55 million.

After that, Centene settled in one state after another, often with just months between announcements.

In fact, Centene had already set aside $1.1 billion to handle all subsequent cases. The company estimated the amount after early discussions with the private lawyers that did not involve the state attorneys general who would later work with them.

With a settlement in hand and an estimate of how much each state could collect, the private lawyers had a powerful pitch. The team also had the option to file whistle-blower lawsuits, which can advance without a state attorney general’s having to hire outside counsel.

The team pursued whistle-blower lawsuits in Texas, California and Washington.

In Texas, the whistle-blower lawsuit came with a benefit for Attorney General Ken Paxton: Under Texas law , his office is allowed to recoup “reasonable attorney’s fees” for work associated with such cases. It collected nearly $25 million in legal fees on the Centene case while spending just 561 hours on it, financial records show. That comes out to more than $44,000 per hour of work. The Texas attorney general’s office declined to comment.

Ms. Saler said all the state attorneys general decided their own strategies in reaching settlements with Centene based on the best interest of taxpayers in their states.

In states that hired the lawyers on contingency, the attorney general closely reviewed Centene’s billing practices. But no state has revealed whether its own overcharge calculations matched those of the private lawyers.

State officials who hired Liston & Deas and the other firms knew that the lawyers had previously negotiated with Centene. But in a vast majority of states, officials did not explicitly address that fact when talking publicly about the settlements.

In addition, Liston & Deas and most of the states the firm worked for have not revealed exactly how much Centene overcharged for drugs or how settlement amounts were calculated. A few states have offered sparse descriptions, which vary widely.

The New Hampshire attorney general’s office wrote in its settlement announcement that Centene’s activities had a “$2.4 million negative financial impact.” Centene agreed to pay the state nearly 10 times that amount.

The attorney general’s office in Washington, one of the few states where officials agreed to discuss basic details about the settlement with The Times, said the $33 million it recovered amounted to treble damages.

A news release from the California attorney general’s office said the state recovered double its damages, for a total settlement of more than $215 million.

As of last month, Centene had settled in at least 19 states. The Liston & Deas website says Centene will ultimately pay about $1.25 billion to 22 states.

A Sweetheart Deal?

Some observers believe Centene would have faced stricter penalties if the federal government had taken up the case instead of private lawyers hopscotching from one state to the next.

Several experts in health care fraud litigation and whistle-blower cases said the best way to recoup money for taxpayers would have been to file a federal whistle-blower case, similar to what the lawyers did in state court in Texas and California.

A federal case could have triggered the involvement of the Justice Department, which might have investigated Centene more thoroughly. And a federal case probably would have gotten more attention and media coverage, required more transparency and taken longer to complete, the experts said.

Mr. Hurst and other lawyers in the case said they had not filed any type of federal action against Centene.

A spokesperson for the Justice Department confirmed that it had inquired about the P.B.M. and Centene cases in Ohio, but no further federal action was taken. The department declined further comment.

Mary Inman, a lawyer at Whistleblower Partners L.L.P. with decades of experience, said one of the reasons Liston & Deas wound up in state court might have been that its case relied on whistle-blowers the federal government was unlikely to approve.

The whistle-blower in Texas was Mr. Hurst. In California, the whistle-blower was Matthew McDonald, a lawyer at David Nutt & Associates and the son of Bryan McDonald, who worked in Mr. Barbour’s administration when he was governor.

Ms. Inman said whistle-blowers are typically insiders with firsthand knowledge of wrongdoing who share information at some risk to themselves, not lawyers who gain information while on the job.

“It’s very unusual,” Ms. Inman said. “And it’s something that I, as a longtime lawyer in this space, I would not want to do because atmospherically and reputationally it doesn’t look great.”

Mr. Barbour said he believes everyone walked away from the settlements happy — including executives at Centene. As evidence, he cited the company’s stock performance.

“I can’t speak for them, but if I had agreed to pay a big settlement and my stock went up after the first day, I would think it was a pretty good settlement,” Mr. Barbour said.