FormalPara Key Points

We defined an algorithm for the management of the main symptoms of narcolepsy (excessive daytime sleepiness and cataplexy), depending on the persistence and discomfort-related symptoms and associated comorbid conditions.

We recommend better defining of relevant outcome measures to monitor treatment efficacy and to provide guidance on whether the treatment goals are being met.

The discovery of hypocretin deficiency in narcolepsy opens new therapeutic options oriented towards hypocretin-based and immune-based therapies at disease onset.

1 Introduction

Central disorders of hypersomnolence are rare and under-diagnosed conditions that include at least Narcolepsy Type 1 (NT1) and Narcolepsy Type 2 (NT2), as defined by the International Classification of Sleep Disorders (ICSD-3) [1].

NT1, or hypocretin-deficiency syndrome, affects 0.026–0.05 % of the general population [2]. It may start at any age; however, symptoms usually appear within the first two decades of life (median age at onset: 16 years) [3]. NT1 is caused by the loss of hypocretin/orexin-containing neurons in the lateral hypothalamus [4, 5]. The precise mechanism leading to such loss remains unknown, but an autoimmune process is strongly suspected [6]. Excessive daytime sleepiness (EDS) is usually the presenting and often the most incapacitating symptom, with episodes of irresistible, typically short daily sleep that are associated with dreaming and followed by a feeling of being refreshed. NT1 is also characterized by the occurrence of cataplexy (i.e., the sudden loss of muscle tone triggered by strong emotions) as well as frequent sleep paralysis, hypnagogic/hypnopompic hallucinations, disturbed nighttime sleep [7] with periodic leg movements, restless legs syndrome (RLS) [8, 9], and REM-sleep behavior disorder [10]. About 30 % of patients are obese and weight gain often occurs close to disease onset [11]. The co-occurrence of psychiatric disorders, such as depression and anxiety, is also often reported and they may further worsen the patient’s quality of life [12]. NT1 is a chronic disease with an often stable clinical course. With age, sleepiness and cataplexy severity may improve in some patients, whereas nighttime sleep disturbance may worsen.

NT2 shares many symptoms with NT1, except for the absence of cataplexy [13]. Cerebrospinal fluid (CSF) hypocretin-1 levels were not included in the previous classification of sleep disorders [14], and 10–20 % of patients with narcolepsy without cataplexy were hypocretin deficient. Since 2014 (ICSD-3) [1], all patients with low CSF hypocretin-1 levels are considered as having NT1 (even in the absence of cataplexy), and all patients without cataplexy and normal CSF hypocretin-1 levels are classified as having NT2. The prevalence and the clinical course of NT2 remain unclear. Some patients may later develop cataplexy, while others may have a stable condition. However, in half of them, EDS symptoms improve spontaneously without the persistence of neurophysiological hallmarks of narcolepsy [15].

No cure exists for narcolepsy, and most patients (especially those with NT1) require lifelong treatment. European and US guidelines for the treatment of narcolepsy were developed several years ago [16–19]. Current treatments include stimulant drugs to suppress daytime sleepiness, antidepressants for cataplexy, and sodium oxybate for both symptoms. Some of these drugs have been approved for narcolepsy by the European Medicine Agency (EMA) or the US Food and Drug Administration (FDA), while others are used off-label on the basis of their recognized utility in the management of narcolepsy symptoms. In this review, we discuss the best management strategies for narcolepsy, the treatment of comorbid conditions, and the options for drug-resistant narcolepsy.

2 Treatment Options for Narcolepsy Type 1

2.1 Excessive Daytime Sleepiness

2.1.1 Behavioral Strategies

Behavioral individualized strategies, such as avoiding sedentary activities, maintaining a regular nighttime sleep schedule, planning a single, long nap early in the afternoon or short naps through the day, may reduce excessive daytime sleepiness with some additional benefits compared with medications [20]. Avoiding driving or dangerous work situations should also be considered until the drug treatment starts to have an effect and in the case of resistance to therapy.

Caffeine, an adenosine A1 and A2a receptor antagonist, and energy drinks are often-consumed stimulants to fight EDS, but with limited efficacy and some side effects producing detrimental effects on subsequent sleep [21]. Education is always required to help patients to recognize and act against symptoms, and to define, together with their physician, the treatment goals. For instance, some patients may modify their medication regimen by taking a stimulant agent before driving.

2.1.2 Modafinil/Armodafinil

Modafinil is the first-line treatment to reduce EDS associated with narcolepsy [22, 23] and is approved by the FDA and EMA. Its mechanism of action is still unclear, but it may enhance the activity of wake-promoting neurons by increasing the extracellular concentration of dopamine via blockade of the dopamine transporter [24]. Four major class I evidence-based studies showed the efficacy of modafinil on EDS in narcolepsy at doses ranging between 200 and 400 mg/day [25–28]. It is a long-acting drug, with an elimination half-life of 13.8 h [16, 18]. The maximum concentration is achieved in 2–4 h [16, 18]. The drug is started at 100 mg twice per day (morning and lunch time) and can be increased, if required, to 200 mg twice per day [29]. The maximum approved dose for modafinil is 400 mg per day. Based on our experience, we recommend increasing the dosage up to 600 mg per day in resistant cases, after careful assessment of the benefit–risk ratio. Modafinil is well tolerated, with rare and mild side effects, such as headache, nausea, insomnia, and anxiety, especially in the first few days of treatment [25–29]. Severe cutaneous allergic reactions have been described, but they remain extremely rare [16, 30]. Modafinil can increase the hepatic concentration of cytochrome P450 enzymes and the metabolism of oral contraceptives [16, 18]. Accordingly, we recommend increasing the dose of ethinylestradiol to 50 μg/day, although this recommendation is not based on any published data. A progesterone contraceptive agent or another contraceptive method could also be proposed. Clinical experience suggests that modafinil is also safe and effective for managing EDS in children [31], but no clinical trial on this population has been published. Modafinil can be combined with other medications, such as sodium oxybate, to improve EDS management [32]. Armodafinil, the R-enantiomer of modafinil (not available in Europe), has a more prolonged effect during the day and could better improve sleepiness in the late afternoon in narcolepsy [33]. The maximum dose is 250 mg per day, in a single intake, with similar indications and side effects as modafinil [33]. Objective and subjective tests proved its efficacy compared with placebo [33]. So far, no study has compared modafinil and armodafinil in patients with narcolepsy.

2.1.3 Sodium Oxybate

Sodium oxybate (SXB), the sodium salt of gamma hydroxybutyrate (GHB), is a gamma-aminobutyric acid receptor B agonist. However, the mechanism that explains its efficacy in treating narcolepsy remains unclear. SXB improves sleep quality, increases slow-wave sleep, has major anticataplectic effects and also promotes wakefulness [34]. Several class I evidence-based studies and one meta-analysis support SXB effectiveness in reducing both cataplexy and EDS [32, 35]. SXB is the only medication approved by the FDA and EMA for cataplexy treatment in adult patients with narcolepsy [35, 36]. SXB half-life is short (40–60 min), but the effect persists longer [16, 18, 36]. Patients should start with 4.5 g per day with 2.25 g at bedtime before sleeping, and then 2.25 g after 2.5–4 h following the first intake (i.e., the patient must be woken up to take the second dose) for 4 weeks and then progressively increase to 6 g per day in two doses [16, 18]. The optimal dose is 9 g per day and the maximum efficacy is reached after 4–8 weeks of treatment [16, 18, 34]. Adverse effects include dizziness, headache, nausea, weight loss, RLS, parasomnias (sleepwalking and enuresis), and neuropsychiatric symptoms (confusion, anxiety, or depressive symptoms) [32, 35–37]. Instead of SXB (i.e., the prescribed form), the major problem with GHB is its non-medical use as a ‘date rape’ drug, because of its rapid sedating effect. However, clinical experience indicates a very low risk of abuse and misuse of SXB [37]. A multicenter controlled trial, versus placebo, is currently ongoing to assess its safety and efficacy in children.

2.1.4 Methylphenidate

Methylphenidate is a stimulant that primarily blocks the reuptake of monoamines (mainly dopamine) and, unlike amphetamines, does not inhibit the vesicular monoamine transporter [38]. Despite its wide utilization, only one class II evidence-based study showed significant improvement of EDS in patients with narcolepsy with doses ranging from 10 mg to 60 mg per day [39]. Methylphenidate is a second-line therapy for EDS, when modafinil (or armodafinil, when available) and SXB are not fully effective. Both short-acting and sustained-release formulations exist, with fewer side effects and less abuse risk for the latter. Adverse side effects include tachycardia, hypertension, palpitations, neuropsychiatric symptoms such as anxiety, and weight loss [38].

2.1.5 Pitolisant

Pitolisant is a recent treatment option for EDS management in narcolepsy. This selective histamine H3 receptor inverse agonist acts presynaptically and activates histamine neurons [40]. It has recently been approved by the EMA, and is available in Europe but not in the US. Pitolisant improves wakefulness in healthy animals and decreases EDS in orexin knock-out mice and human patients with narcolepsy [40]. The starting daily dose is 10 mg and it may be increased up to 40 mg, given once per day [41]. According to a class I evidence-based study, pitolisant is an effective treatment for EDS, superior to placebo and equal to modafinil [41]. Pitolisant is generally well tolerated, with only few adverse events that include headache, nausea, and insomnia [40, 41]. Pitolisant is an effective therapeutic alternative for patients with narcolepsy.

2.1.6 Amphetamines

Amphetamines are a third-line therapy for NT1. They increase the concentration of dopamine and norepinephrine. The d-amphetamine isomer targets more specifically dopaminergic transmission with improved stimulant effect. Dextroamphetamine is the only amphetamine approved for EDS treatment in narcolepsy and is only approved for this use in some countries [16, 18]. Three class II studies found a marked improvement in EDS with amphetamines [42–44]. The recommended dose starts at 5 mg per day to a maximum of 60 mg daily [44]. Side effects are quite similar to those of methylphenidate (irritability, aggressiveness, insomnia, and hypertension) [44, 45]. Moreover, at high doses, amphetamines can induce abnormal movements, cardiac arrhythmias, and psychotic symptoms [45]. Amphetamines are not recommended in patients with a past history of cardiovascular disease or drug abuse. Despite the potential for drug abuse or tolerance using psychostimulants, narcoleptic patients rarely exhibit addiction to this medication [46].

2.1.7 Mazindol

Mazindol is a tricyclic imidazolidine derivative that can be obtained only after specific approval by the National Drug Agency, at least in France. Mazindol blocks the reuptake of dopamine and norepinephrine and has a weak releasing effect on dopamine [47, 48]. Its elimination half-life is 10 h [16, 18]. Class II evidence-based studies support the effectiveness of mazindol (1–4 mg/day) for sleepiness in narcolepsy [47, 49]. Adverse effects include dry mouth, nervousness, and constipation, with rare reports of pulmonary hypertension and valvular heart disease [47, 49]. A careful cardiology follow-up is thus recommended.

The guidelines for the best treatment options to manage excessive daytime sleepiness in patients with narcolepsy are as follows: modafinil (100–400 mg/day) is the first-line treatment for EDS in narcolepsy. This medication is well tolerated and doses up to 600 mg/day can be used in the case of insufficient response. Sodium oxybate (4.5–9 g/day) can also be a first-choice treatment, especially in the presence of associated symptoms (i.e., frequent cataplexy, disturbed nighttime sleep, sleep paralysis, hallucinations). In the absence of response to modafinil, methylphenidate (immediate or extended-release forms) is an effective second-line treatment for EDS. Amphetamines and mazindol are third-line therapies. Pitolisant is the first and promising representative of a novel drug class and where available could be included in the guidelines for patients with narcolepsy, as first or second choice.

2.2 Cataplexy

2.2.1 Behavioral Strategies

There is no established behavioral treatment for cataplexy. Patients may try avoiding situations that might trigger cataplexy attacks; however, this approach is rarely effective enough to be recommended.

Cataplexy pharmacological treatment should not be systematic, but based on cataplexy severity (intensity, frequency, and the nature of the triggering factors) and the associated functional impairment. Pharmacological studies have demonstrated that both adrenergic- and serotonergic-uptake inhibitors are particularly efficient in reducing cataplexy, hallucinations, and sleep paralysis [48]. SXB and antidepressants are the most effective drugs to treat cataplexy in humans. However, the effectiveness of drugs used to treat cataplexy is difficult to evaluate and often the used methods (i.e., recall history, scales, diaries to assess the frequency and intensity of attacks, or video recordings) vary from one study to another.

2.2.2 Sodium Oxybate

Four class I evidence-based controlled studies and one meta-analysis support SXB effectiveness in reducing cataplexy frequency and intensity [35, 36]. At doses between 4.5 and 9 g per day, SXB is effective within 4 weeks of treatment, with higher effects after 8 weeks, and benefits are maintained during long-term therapy without any evidence of tolerance [34–36]. Moreover, differently from that observed with antidepressant drugs, SXB interruption does not result in cataplexy rebound [18, 34, 48].

2.2.3 Antidepressant Drugs

Although widely used for cataplexy treatment, the efficacy and safety of tricyclic antidepressants (TCAs), of serotonin and norepinephrine reuptake inhibitors (SNRIs), and of selective serotonin-reuptake inhibitors (SSRIs) have never been assessed for this indication in placebo-controlled clinical trials. Their use is only based on expert opinion and has not been approved by any regulatory agency. By blocking norepinephrine and serotonin reuptake, antidepressants reduce REM sleep and also cataplexy [16, 18, 48]. The dose required to obtain the anticataplectic effect and the rapid response (within a few hours) differs from that observed when they are used as antidepressant agents [16, 18, 48]. The risk of severe cataplexy rebound is frequent when treatment with antidepressants is abruptly stopped [50].

The SNRI, venlafaxine, is one of the most widely used antidepressants for cataplexy. Venlafaxine has a short duration of action and thus the extended-release form is preferable to cover the whole day, with effective doses ranging from 37.5 to 300 mg per day. Good clinical evidence of its efficacy for cataplexy treatment is lacking, and its use is based only on expert opinion [16, 18, 51, 52]. A few minor side effects have been reported, such as headache, dry mouth, hyperhidrosis, constipation, nausea, and dizziness [16, 18, 51]. SSRIs also are effective and well tolerated for cataplexy management (fluoxetine 20–60 mg per day and citalopram 20–40 mg per day) [53, 54]. TCAs were the first drugs used to treat cataplexy in patients with NT1. These are non-specific monoamine reuptake inhibitors that increase the availability of serotonin, norepinephrine, and also dopamine (only some compounds) [48, 52]. Clomipramine (10–25 mg per day and up to 75–100 mg per day in severe cases) remains the most frequently prescribed TCA for cataplexy treatment [16, 18, 55]. However, adverse effects are more frequent than with SNRIs or SSRIs and they include anticholinergic effects such as orthostatic hypotension, anorexia, diarrhea, weight gain, tiredness, sleepiness, and decreased libido [16, 18, 55]. Norepinephrine reuptake inhibitors, such as reboxetine or atomoxetine, are less frequently prescribed, but may also be effective for cataplexy with a few adverse effects [56] such as nausea, dry mouth, decreased appetite, insomnia, and fatigue [16, 18].

Some psychostimulants, such as mazindol and amphetamines, may also have some anticataplectic effects, as also reported for pitolisant [16, 18, 52].

The guidelines for the best treatment options to manage cataplexy are as follows: with the exception of patients with severe cataplexy, the pharmacological treatment of cataplexy should be started after optimal control of sleepiness and clinical evaluation of the residual cataplexy symptoms and burden. The first-line pharmacological treatment for cataplexy should be SXB. Antidepressants, mainly SNRIs (venlafaxine), could also be considered, on the basis of their good benefit–risk ratio; however, clinical evidence of their efficacy is lacking and their use is based on expert consensus only.

2.3 Associated Symptoms

In patients with narcolepsy, nighttime sleep is often fragmented with frequent awakenings and difficulty in falling asleep [7]. A regular sleep–wake schedule is essential, but is rarely enough in severe cases. Class I evidence-based studies have shown that SXB significantly improves sleep quality, decreases nocturnal awakenings, and increases the proportion of slow-wave sleep [32, 34]. The use of benzodiazepines (clonazepam, triazolam) and the related hypnotic Z-drugs (zolpidem and zopiclone) may also improve sleep disturbances; however, the benefit should be balanced with the potential EDS increase [16, 18, 57]. Although not approved by the FDA, we recommend that SXB should be the first-line treatment for disturbed nocturnal sleep in narcolepsy.

Hypnagogic hallucinations and sleep paralysis are considered as phenomena associated with REM sleep dysregulation and drugs used to treat cataplexy are often proposed for their management. SXB and antidepressants are the most effective drugs for these symptoms [16, 18, 52].

Patients with NT1 may have vivid and frightening dreams and REM behavior disorder (RBD). So far, no study has evaluated any drug specific for RBD in narcolepsy. The pharmacological treatment should start with conventional medications, such as clonazepam and melatonin [58, 59]; however, clinical experience suggests that SXB also has some beneficial effects [60].

3 Treatment Options for Narcolepsy Type 2

EDS is the major symptom of NT2, but often it is less severe than in NT1 [13]. By definition, cataplexy is absent in NT2; however, hypnagogic hallucinations and sleep paralysis may occur.

To our knowledge, no pharmacological study has focused exclusively on patients with NT2; however, most studies conducted in narcolepsy included patients with and without cataplexy. Current medications and guidelines to treat EDS and symptoms associated with REM sleep dysregulation or disturbed nocturnal sleep in NT2 should be the same as for NT1.

4 Comorbidity Management in Narcolepsy

4.1 Narcolepsy-Associated Comorbid Disorders

Patients with narcolepsy often present comorbid conditions, such as metabolic and cardiovascular diseases, psychiatry diseases, musculoskeletal chronic pain, and other specific sleep disorders. A recent epidemiological study reported that most patients with narcolepsy had at least one associated medical condition or psychiatric disorder that required treatment [61].

Patients with narcolepsy are frequently overweight or obese [62], a clinical condition that may increase the risk of cardiovascular disease, sleep apnea or diabetes mellitus. The occurrence of diabetes can be mainly explained by obesity-dependent disturbances of the glucose metabolism [62]. On the other hand, cardiovascular vulnerability may also be related to autonomic dysfunctions, especially in patients with hypocretin deficiency [63, 64]. Psychiatric disorders can be observed in patients with NT1, especially mood, anxiety, and eating disorders, and attention deficit hyperactivity disorder (ADHD) [61, 65, 66]; however, the coexistence of NT1 and psychosis remains a particularly rare condition. The co-occurrence of NT1, metabolic, and psychiatric disorders may delay or lead to inappropriate diagnosis and management [22, 23, 65, 67]. Other specific sleep disorders, such as obstructive sleep apnea syndrome (OSAS), RLS, periodic limb movements during sleep, or non REM sleep parasomnias, are highly associated with narcolepsy, especially NT1 [7–10, 22, 23, 65, 67]. Optimal control of these comorbid sleep disorders is required to improve nighttime sleep quality and decrease EDS severity.

4.2 Comorbidity Management

The potential association of narcolepsy with other disorders makes both diagnosis and management more complex because some narcolepsy treatments may improve or aggravate the comorbid condition (Table 1).

Table 1 Interactions between drugs for narcolepsy and comorbidities
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Most patients with narcolepsy, especially NT1, must take psychostimulants for the rest of their lives. These drugs can affect the autonomic nervous and cardiovascular systems. Accordingly, patients with past history of cardiovascular diseases should not be treated with stimulants, except for low doses of modafinil, low doses of long-release methylphenidate in the absence of modafinil efficacy, or pitolisant, when available (Table 1). Careful monitoring of the cardiovascular functions is required in these patients.

Comorbid metabolic conditions, such as diabetes, can be of particular relevance in narcolepsy, especially NT1, because of the associated obesity and weight control issues. Treatment with SXB is often associated with weight loss in patients with narcolepsy [68]; however, it may also exacerbate OSAS. The presence of moderate or severe OSAS should be determined before prescribing SXB, and sleep apnea must be treated prior to initiating therapy [69]. SXB therapy has also been associated with increased frequency of RLS and non REM parasomnias, whereas it may decrease RBD [60, 70].

Antidepressant intake could be associated with increased weight gain. In patients with narcolepsy and obesity without significant OSAS, SXB can be the first-line treatment for cataplexy. Clinicians should be aware of the potential increased risk of RLS, periodic leg movement during sleep, and RBD with antidepressants (Table 1).

Depressive symptoms are frequent in patients with narcolepsy, especially in the presence of hypocretin deficiency; however, major depressive disorders are rarely diagnosed [65]. Dopaminergic stimulants and SXB may worsen psychiatric (particularly anxiety, depression, or psychotic) symptoms. Patients should be screened for mood disorders, especially for suicidality, prior to initiating any therapy with psychostimulants and SXB. The optimal management of depression and psychotic symptoms remains to be defined in patients with narcolepsy. For patients with NT1 and psychosis (a rare, but very serious comorbid association), we recommend, based on our clinical experience, the use of non-dopaminergic stimulants such as pitolisant for EDS, and antipsychotic drugs such as aripiprazole for psychotic symptoms because it does not worsen sleepiness (Table 1). Methylphenidate should be the first-line treatment for EDS in patients with comorbid ADHD or sleepiness-related ADHD symptoms.

Finally, most psychostimulants promote impulsivity and risk-taking behaviors that could result in substance abuse and dependence [71]. However, a recent study revealed similar frequency of drug use, abuse, and dependence in patients with narcolepsy, independently of their hypocretin status and of their treatment (drug-free or not), compared with a control group from the general population [46]. Nevertheless, this study reported an increased regular and frequent alcohol drinking habit in patients with NT1 compared with controls, with some concerns regarding the concomitant use of SXB. SXB is not recommended in situations of alcohol consumption.

5 Evaluation of the Burden of Narcolepsy and Treatment Response

Treatment decisions should take into account the patient’s major complaint. Frequently, this concerns EDS because it is present in all patients and can affect the patient’s daily life due to the risk for driving- or work-related accidents. In addition to the discomfort caused by EDS persistence, clinicians should investigate the presence and severity of the associated symptoms, which patients might not report because they do not realize that they are part of narcolepsy (e.g., cataplexy), or they may be reluctant to raise on their own (e.g., unpleasant and bizarre dreams). Narcolepsy management requires a regular evaluation of symptoms (type and severity) and their effects on daily functions as well as monitoring the treatment goal achievement and drug efficacy and safety [18]. Many clinically relevant subjective and objective measures are available, although systematic and standardized narcolepsy-specific outcome assessment instruments are lacking [18]. Self-report measures, such as the Epworth Sleepiness Scale [72] or the Karolinska Sleepiness Scale, may help clinicians to evaluate EDS severity and its response to medication. Objective measurements of sleepiness and vigilance also exist with good sensitivity, including the Maintenance of Wakefulness Test (MWT), Multiple Sleep Latency Test, Sustained Attention to Response Task, and Psychomotor Vigilance Test. From a forensic perspective, the MWT should be performed to quantify the residual daytime sleepiness in patients employed as drivers. However, this measure might not correlate with the patient’s complaints. Other tools can also be used in this context, such as a specific diary to evaluate the frequency of daytime sleepiness and cataplexy, visual analogic scales to assess the clinical response from the patient’s point of view, the Insomnia Severity Index [73] to measure nocturnal sleep disturbances, and the Beck Depression Inventory and the Columbia Suicide Severity Rating Scale [74] to monitor mood and suicidality before and after drug intake. The treatment effects on general health and well-being can be measured using a quality-of-life self-report scale, such as the European Quality of Life 5-Dimension questionnaire (EQ-5D) [75].

However, to date, no consensus exists on the main objective and subjective outcome measures required to monitor the treatment response or to provide the best recommendations for effective management of patients with narcolepsy. There is a real need for a specific tool to clinically assess the severity of the main narcolepsy symptoms at baseline and during follow-up, to provide guidance on whether the treatment goals are being achieved.

Dose adjustment, switching to another medication, or prescription of multiple medications is often required during the regular follow-up of patients with narcolepsy. Based on our clinical experience, we propose an algorithm for the management of the main symptoms of narcolepsy (EDS and cataplexy), depending on the persistence and discomfort related to these symptoms and the associated comorbid conditions (Fig. 1).

Fig. 1
figure 1

Decision tree for starting and then adapting the therapy for excessive daytime sleepiness (EDS) and cataplexy; and options for drug-resistant narcolepsy. First-line treatment option for EDS should be modafinil 100–400 mg/day. As second-line options, modafinil doses may be increased up to 600 mg/day or methylphenidate can be used. Once adequate improvement of EDS is obtained, treatment options for cataplexy should be considered after evaluation of the cataplexy severity, night-time sleep quality and comorbid conditions. Venlafaxine and sodium oxybate should be first-line treatment options for cataplexy. In case of insufficient therapeutic response, alternative options for drug-resistant EDS and cataplexy are proposed

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6 Future Perspectives in Narcolepsy Management

The discovery of hypocretin deficiency in NT1 opens up new therapeutic options oriented towards hypocretin-based and immune-based therapies at disease onset.

Hypocretin replacement could be the best therapy to treat both sleepiness and cataplexy in patients with NT1 [22]. The proof of principle that hypocretin replacement therapy is effective came from a study in which narcolepsy in orexin/ataxin-3 neuron-ablated mice was suppressed by hypocretin intraventricular administration [76]. However, peripheral administration of hypocretin-based treatments in patients with NT1 has been disappointing because peptides do not easily cross the blood-brain barrier [52, 77]. Intranasal administration is a non-invasive method that targets drugs to the brain along the olfactory and trigeminal neural pathways, bypassing the blood-brain barrier and minimizing systemic exposure and side effects [77, 78]. However, the results of hypocretin nasal administration remain disappointing and controversial to date [77, 78]. A recent study reported the discovery of a potent non-peptide, selective orexin receptor 2 agonist with potential to treat narcolepsy [79]. Hypocretin cell transplantation was successfully tested in animals [80] and the improved pluripotent stem-cell technology offers long-term potential for very severe cases resistant to pharmacological compounds [81]. Finally, hypocretin gene therapy in a mouse model of narcolepsy also seems a promising option [82].

Based on the hypothesis of the immune-mediated destruction of hypocretin neurons, immune-based therapies could modify the natural history and the long-term disease outcomes if administered at disease onset, when the ‘autoimmune’ process targeting hypocretin neurons is not too advanced and might still be reversed. Immune-based therapies such as corticoids, intravenous immunoglobulins (IVIg), plasmapheresis, immunoadsorption, and alemtuzumab have been tested with variable efficacy [83, 84]. In one patient with undetectable CSF hypocretin-1 level, IVIg treatment only 15 days after disease onset completely reversed the clinical symptoms with clear improvement of cataplexy and normalization of CSF hypocretin-1 [85]. Further well designed immune-based drug trials in patients close to disease onset are needed, as is more information on the process that kills the hypocretin neurons.

New psychostimulants for patients with narcolepsy are currently being developed, such as JZP-110, a phenylalanine derivative with dopaminergic and noradrenergic activity [86]. A double-blind, placebo-controlled, randomized, cross-over study on JZP110 showed a major increase in the mean sleep latency on the MWT and a significant reduction in the Epworth Sleepiness Scale score [87]. Slow-wave sleep-enhancing treatments (i.e., longer acting SXB and R-baclofen, an enantiomer-specific form of racemic baclofen), thyrotropin-releasing hormone direct or indirect agonists [88], and the combination of modafinil with connexin inhibitors to potentiate its effect [89, 90] could also emerge as alternative therapeutic options in the next few years.

7 Conclusion

NT1 and NT2 are complex diseases both for diagnosis and treatment. Despite major advances in our understanding of the NT1 neurobiological basis, there is no cure and the current therapy is only symptomatic. Several effective drugs exist to treat narcolepsy symptoms and often behavioral and pharmacological therapies are combined based on the symptom severity and the patient’s goals and lifestyle. Importantly, the symptoms should be regularly monitored using specific measures to determine their presence/absence, severity and impact, the treatment goal achievement, and the drug efficacy and safety, with the ultimate aim of improving the patients’ quality of life. Clinical evidence shows that drugs approved for adult patients with narcolepsy are also effective in children; however, narcolepsy treatment in children crucially needs specific guidelines. Finally, the discovery of hypocretin deficiency might pave the way to new NT1 treatments focused on immune-based therapies administered as early as possible after disease onset and on hypocretin replacement therapy for patients with severe symptoms.