Keywords
Narcolepsy - Diagnosis - Comorbidity - Therapeutics
Palavras-chave
Narcolepsia - Diagnóstico - Comorbidade - Terapêutica
INTRODUCTION
Narcolepsy manifests with symptoms such as excessive daytime sleepiness (EDS), cataplexy,
hypnagogic hallucinations, sleep paralysis, and sleep fragmentation.[1] The occurrences of cataplexy, hypnagogic hallucinations, and sleep paralysis are
associated with REM sleep.[2] This condition is a primary central nervous system (CNS) disorder resulting from
a complex interplay of genetic, environmental, and immunological factors. The prevalence
is ∼0.02% in the general population.[3] Global investigations into narcolepsy prevalence have yielded similar results in
regions such as Hong Kong, the United States, and Europe.[4]
[5] It does not display a gender predominance, with the highest incidence during adolescence
and a secondary peak after the age of 40 in women, particularly around menopause.[6]
Efforts have been invested in studies to elucidate the intricate pathophysiology of
narcolepsy. A new finding is the reduction in hypocretin-1 levels observed in patients
with narcolepsy and cataplexy, attributed to the disappearance of producer cells in
the hypothalamus. Postmortem studies on narcoleptic patients affirm the loss of cells
producing this neuropeptide in the lateral hypothalamus (∼50,000 to 100,000 cells).[7]
[8] A higher prevalence of the HLA-DQB1*0602 allele and a low hypocretin concentration
in the central nervous system characterize individuals with narcolepsy and cataplexy.
Although cataplexy is highly specific to narcolepsy, it can manifest in other clinical
scenarios, including medication use and certain genetic diseases.[9]
The diagnostic process can be challenging due to the influence of psychiatric disorders,
clinical illnesses, shift work, sleep deprivation, and medication use, particularly
in patients with type II narcolepsy.[10] This ambiguity in diagnosis may have adverse implications for individuals with narcolepsy
in various aspects of their lives, including personal, professional, and legal domains.[11] This narrative review aims to comprehensively examine and discuss the current understanding
of narcolepsy, specifically focusing on its clinical implications.
HISTORICAL ASPECTS
Narcolepsy was initially recognized in 14 cases with uncontrollable sleep attacks
by Gelineau[12] in 1889. Subsequent years saw the delineation of additional symptoms, with Lowenfield,
Kinner, and Lhernitte describing cataplexy, hypnagogic hallucinations, and sleep paralysis
in these patients, respectively.[13] In the second decade of the last century, while residing in Vienna amidst the Spanish
flu outbreak, von Economo reported on EDS in patients with hypothalamus damage during
infection with H1N1.[14]
In 1930, Daniels coined the term “Gelineau tetrad” to describe the association of
EDS, cataplexy, hypnagogic hallucinations, and sleep paralysis.[13] The understanding of narcolepsy's pathophysiology significantly advanced with Rechschaffen's
electroencephalographic studies in 1967, which revealed sleep phases and exceptionally
rapid eye movements (REM).[13]
In 1973, narcolepsy was also described in Doberman dogs with an autosomal recessive
or dominant Mendelian transmission pattern, depending on the canine species.[15] In the 1980s, a Japanese study demonstrated a higher prevalence of the HLA-DR2 allele
in patients with narcolepsy.[16] In 1995, the association of Caucasian patients with narcolepsy and cataplexy with
the presence of the HLA-DQB1*0602 allele in 95% of cases was described.[17]
In 1998, the neuropeptide hypocretin or orexin, produced in the lateral hypothalamus
with a regulatory function of sleep and appetite, was characterized. A few years later,
a reduction in hypocretin-1 levels was evidenced in patients with narcolepsy. In 2005,
the II International Classification of Sleep Disorders recognized sleep fragmentation
as an element related to narcolepsy.[18] In 2010, an increase in cases of narcolepsy with cataplexy was linked to H1N1 vaccination
in Asia and Europe. Studies have confirmed the association of narcolepsy with GSK
vaccination with the adjuvant AS03.[19]
[20] The immunological theory was strengthened by identifying differences in patterns
at the T lymphocyte receptor (TCR) locus and with specific tribbles homolog two antibodies
described in patients diagnosed with narcolepsy in the first decade of this century.[21]
EDS has been treated with typical stimulants such as methylphenidate since the 1960s.
The evolution of treatment for narcolepsy will be discussed in a separate topic.
GENETICS
The presence of the HLA-DQB1*0602 allele, a variant of the HLA-DQB1 gene, in the North
American Caucasian population with narcolepsy and cataplexy is as high as 95%. However,
the HLA-DQB1*0602 allele is not greater than 40% in patients without cataplexy. Due
to this discrepancy, the HLA-DQB1*0602 allele is no longer used in clinical practice.[22] Nevertheless, the HLA-DQB1*0602 allele holds predictive value for individual variations
in average sleep conditions, especially in sleep deprivation situations.[17] Fernandes et al.[17] demonstrated that the association between the HLA-DQB1*0602 allele and cataplexy
could predict hypocretin-1 deficiency, offering potential utility in diagnosing diagnosis
and treatment of narcolepsy.
In canine populations (Doberman and Labrador), autosomal recessive or dominant Mendelian
transmission patterns have been confirmed depending on the breed. In 1999, the absence
of hypocretin-2 receptors was confirmed as a crucial element in the pathophysiology
of narcolepsy in these animals. Human narcolepsy does not have a Mendelian genetic
transmission pattern.[15]
HYPOCRETIN (OREXIN)
Hypocretin, or orexin, is a neuropeptide produced in the lateral hypothalamus with
two recognized receptors called 1 and 2 (using cyclic GMP with action on calcium and
NMDA as a second messenger, respectively). Hypocretin affects sleep-wake modulation,
pain, appetite control, and energy homeostasis. Hypocretin interfaces with the central
nervous system (CNS) and the peripheral nervous system (dorsal root ganglion).[23] Human narcolepsy type I is characterized by low levels of hypocretin-1 following
loss of hypocretinergic cells in the lateral hypothalamus.[24]
Authors demonstrate that hypocretin exhibits seasonal and circadian variations, with
increased levels of CSF during periods of attention or physical activity. Reduced
or absence of hypocretin-1 levels drives volatility of the sleep-wake cycle with episodes
of sleep attacks, hallucinations, sleep paralysis, cataplexy, and sleep fragmentation.[8]
PATHOPHYSIOLOGICAL HYPOTHESES OF NARCOLEPSY
PATHOPHYSIOLOGICAL HYPOTHESES OF NARCOLEPSY
The pathophysiological mechanism of narcolepsy remains incompletely understood, with
various theories proposed. The degenerative theory advocates premature cell death
of hypocretin-producing cells. Genetic theory associates narcolepsy with an increased
familial predisposition of narcoleptic patients, as well as an earlier onset of signs
and symptoms of narcolepsy in subsequent generations. It is worth noting that the
prevalence of narcolepsy in children of a narcoleptic father or mother is less than
1%.[25] The environmental theory observes the interaction of the environment as physical,
chemical, or biological agents with the loss of the affected cell population. The
association between narcolepsy and infection by the H1N1 virus and after patients
with rheumatic fever have been described.[19]
However, the HLA-DQB1*0602 allele is more present in patients with narcolepsy and
cataplexy, with a decrease in the population of hypocretinergic cells directly to
an immunological mechanism.[17]
[26] Clinical improvement after using immunoglobulin and prednisone strengthens this
hypothesis.[27]
[28] The association between narcolepsy and the TCR α locus, as well as the decrease
in the concentration of soluble CD40 ligand (CD40L) in patients with narcolepsy, are
strong indications of an autoimmune mechanism.[21]
[29]
A recent publication reported the loss of specific immunological protection in the
affected twin in a genome study of discordant twins.[30] The immunological theory would explain cell loss in the lateral hypothalamus in
patients with narcolepsy due to self-harm due to an imbalance in the immune complex
formed by TCR, HLA, and CD40L.[17]
[21]
[29] Furthermore, patients with narcolepsy with cataplexy have more specific tribbles
homolog two antibodies, which, although present in all patients with narcolepsy, would
be more prevalent in the initial phase of the disease.[31]
The production of anti-hypocretin-2 receptor antibodies has also been described in
patients who developed post-vaccination narcolepsy.
Diagnosis and classification
The diagnosis of narcolepsy is established by clinical and electrophysiological criteria
and the level of hypocretin-1 in the CSF. Clinical criteria depend on the characterization
of EDS associated with cataplexy, sleep paralysis, hypnagogic or hypnopompic hallucinations,
and sleep fragmentation.[1] We used the Epworth Sleepiness Scale (ESS) to quantify EDS.[32] Scores above ten in [Table 1] already characterize EDS. The electrophysiological diagnosis of the multiple sleep
latency test (MSLT) is the study of five daytime naps for 15 minutes with intervals
of 2 hours between each one. [Figure 1] Typically, MSLT is preceded by all-night polysomnography (PSG), and the patient
must be free from the use of stimulants or centrally-acting drugs such as antidepressants
for at least four weeks or depending on the half-life of the medication being used.
Prior PSG should ensure a minimum of 6 hours of sleep and the exclusion (alternatively
ruling out) of other sleep disorders that trigger EDS.[1]
Table 1
Epworth sleepiness scale
|
0
|
1
|
2
|
3
|
|
1. Chance of dozing off while sitting and reading?
|
Never
|
Slight
|
Moderate
|
High
|
|
2. Chance of dozing off while watching TV?
|
Never
|
Slight
|
Moderate
|
High
|
|
3. Chance of dozing off while Sitting, inactive in a public place?
|
Never
|
Slight
|
Moderate
|
High
|
|
4. Chance of dozing off as a passenger in a car for an hour without a break?
|
Never
|
Slight
|
Moderate
|
High
|
|
5. Chance of dozing off while lying down to rest in the afternoon when circumstances
permit?
|
Never
|
Slight
|
Moderate
|
High
|
|
6. Chance of dozing off while sitting and talking to someone?
|
Never
|
Slight
|
Moderate
|
High
|
|
7. Chance of dozing off while sitting quietly after lunch without alcohol?
|
Never
|
Slight
|
Moderate
|
High
|
|
8. Chance of dozing off while in a car, while stopped for a few minutes in traffic?
|
Never
|
Slight
|
Moderate
|
High
|
|
Scores can be interpreted as follows:
0–5 lower normal daytime sleepiness.
• 6–10 normal daytime sleepiness.
• 11–12 mild excessive daytime symptoms.
• 13–15 moderate excessive daytime symptoms.
• 16–24 severe excessive daytime symptoms.
|
Source: Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness
scale. Sleep. 1991;14:540–5. PubMed ID: 179888.
Figure 1 Multiple sleep latency test. Notes: 3 SOREMPS; Mean sleep latency – two minutes.
The International Classification of Sleep Disorders (ICSD-3) classifies Narcolepsy
into two types, I and II.[1]
[18]
The ICSD-3 defines the criteria for narcolepsy as MSLT with a mean latency of less
than or equal to 8 minutes, in addition to two or more episodes of REM sleep during
naps, possibly adding an early REM on the polysomnography that precedes the MSLT (less
than 15 minutes). Recent revision of ICSD-3 recognizes the diagnosis of narcolepsy
with characteristic clinical signs and symptoms of the disease with the presence of
early REM in PSG. In cases of diagnostic uncertainty, repeating the MSLT may be a
good option, just as another study demonstrates an exciting relationship between NREM
and REM sleep, which characterizes an episode of REM sleep preceded and followed by
NREM during naps in TMLS in patients with narcolepsy.[1]
[33]
[34]
The presence of the HLA-DQB1*0602 allele is not part of the diagnostic criteria for
narcolepsy and is performed for research purposes. Hypocretin-1 in the CSF should
be measured whenever there is a clinical or electrophysiological doubt. Hypocretin-1
below 110 pg/mL or with a drop of ⅓ of the value of a previous dosage (children and
adolescents starting the disease) is characteristic of type I narcolepsy. Patients
with type II narcolepsy usually have levels of hypocretin-1, one greater than 200
pg/mL.[1]
[35]
The literature should provide a more comprehensive discussion of the gray zone between
110 pg/mL and 200 pg/mL. Studies have reported cases of patients with hypocretin-1
levels within this range. Some exhibit the HLA-DQB1*0602 allele, along with cataplexy,
sleep hallucinations, and sleep paralysis. Others, however, do not meet all the criteria
for narcolepsy type I. While biomarkers are beneficial for identifying type I narcolepsy,
identifying patients with narcolepsy type II remains challenging in many cases.[35]
Unfortunately, in real life, there is a delay of over ten years for the diagnosis
of narcolepsy around the world.[36] Many causes can explain this reality, such as the lack of knowledge on the disorder,
incorrect diagnosis of depression, prejudice of familiar members and society about
EDS, and few tools for clinicians. Recently, the Stanford Cataplexy Questionnaire
and Narcolepsy Severity Scale were translated and validated for Portuguese in Brazil.[37]
[38]
COMORBIDITIES
Patients with narcolepsy often present with various comorbidities. Notable among these
are obesity, a higher prevalence of psychiatric disorders, pain, olfactory impairment,
fatigue, immunological diseases, and numerous side effects associated with medications,
including an elevated risk of cardiovascular events.[39]
[40]
[41]
[42]
The relationship between narcolepsy and psychiatric conditions has been a subject
of extensive discussion. A recent study investigated the association of narcolepsy
with schizophrenia (SCZ), major depressive disorder (MDD), and attention-deficit hyperactivity
disorder (ADHD) using three distinct genome-wide approaches. The findings indicated
a higher risk of SCZ associated with narcolepsy, a potential causal relationship between
narcolepsy and MDD, while no significant relationship with ADHD was observed.[43]
Despite daytime sleepiness being a critical criterion for diagnosing narcolepsy, individuals
with this condition also exhibit a higher prevalence of fatigue. Patient-reported
outcome measures have underscored a more frequent experience of fatigue in both types
of narcolepsy, independent of sleepiness, depression, and obesity.[44]
Researchers have reported a higher prevalence of endocrinological changes in teenagers
with narcolepsy experiencing precocious puberty.[45] Managing these comorbidities is crucial to enhancing the well-being of these patients,
directly impacting their overall quality of life.[11]
Metabolic syndrome is particularly prevalent in children with narcolepsy. A retrospective
study conducted in a French pediatric population revealed that 79.3% of narcolepsy
patients exhibited high homeostasis model assessment for insulin resistance, 25.9%
had an increased body mass index, 24.1% had low high-density lipoprotein cholesterol
(HDL-C), and 12.1% had elevated triglyceride levels. Insulin resistance emerged as
the central metabolic disturbance in both obese and nonobese children. Those with
narcolepsy and metabolic syndrome also demonstrated more severe daytime sleepiness
and a higher prevalence of night eating.[46]
Patients with narcolepsy may encounter increased weight gain, olfactory changes, and
a diminished quality of life. Studies have shown a more significant weight gain and
abdominal obesity in patients with narcolepsy type 1, influenced by factors such as
education level and olfactory function test scores. Data indicate that aging and hypocretin
deficiency correlate with abdominal obesity, while years of study are primarily influenced
by olfactory function.[40]
Narcolepsy symptoms, coupled with concurrent medical conditions, adversely affect
the daily activities of patients. Lower scores across all domains of quality-of-life
questionnaires have been observed, particularly in narcolepsy patients type 1 and
obese narcolepsy type II. Poor health status has been noted in Brazilians with narcolepsy
type 2, suggesting that obesity negatively impacts physical domains.[47]
Hypocretin-1 regulates nociception and pain in the central and peripheral nervous
systems. Patients with narcolepsy exhibit a higher frequency of chronic pain. Depression
is known to influence pain perception, and obesity may contribute to increased pain
intensity in narcolepsy.[48]
[49]
Recent evidence suggests a higher risk of bone fractures in patients with narcolepsy.[50] These individuals also show decreased cerebrospinal fluid (CSF) concentration of
klotho and increased CSF levels of FGF-23, potentially predisposing them to a higher
risk of osteoporosis and subsequent fractures.[51]
[52]
TREATMENT
The treatment of narcolepsy must be chosen individually and guided by standards recommended
in modern guidelines in sleep medicine.[53]
[54] The regular follow-up of these patients in specialized centers guarantees the best
result with the interaction of the multidisciplinary team.[53]
[54]
[55] A greater risk of accidents should always be highlighted, and potential risk situations
should be avoided, even when using medication. Early identification and diagnosis
provide better social and intellectual performance for these patients. The social
and family integration of patients with narcolepsy must be guaranteed, with particular
attention to depression and anxiety. Support and continuing education with information
targeted at patients and their families are essential.[53]
[54]
Patients should have good sleep hygiene with regular bedtimes and avoid the consumption
of alcoholic beverages or other stimulating substances. In addition, scheduled naps
of around 20 minutes and regular exercise improve complaints of daytime sleepiness.[53]
[54]
Treatment aims to control EDS and cataplexy attacks.[55]
[56]
[Table 2] summarizes the main drugs available for these symptoms. Methylphenidate has been
a therapeutic option for decades and is prescribed in the morning and after lunch
in a daily dose ranging from 10 to 60 mg.[54] Lisdexamfetamine, available in the Brazilian market for treating ADHD like methylphenidate,
has shown efficacy in treating narcolepsy in one study. However, further research
is needed to establish the efficacy and safety of this drug.[57]
Table 2
Pharmacological options to treat narcolepsy patients
|
Drug
|
Recommendation
|
Strengths of recommendation
|
Quality of evidence
|
Dosage
|
Side effects/notes
|
|
Modafinil
|
Excessive daytime sleepiness
|
Strong
|
Moderate
|
100–400mg
|
Headache, nausea, dry mouth, nervousness, dyspepsia, pain, vomiting, increased blood
pressure, psychosis, and mania. # Risk of cardiovascular disorders.[56]
|
|
Armodafinil
|
Excessive daytime sleepiness
|
Strong
|
Moderate
|
150–250mg
|
Headache, nausea, dry mouth, nervousness, dyspepsia, pain, vomiting, increased blood
pressure, psychosis, and mania. # Risk of cardiovascular disorders.[56]
[57]
[58]
|
|
Methylphenidate
|
Excessive daytime sleepiness
|
Weak
|
Low
|
5–60mg
|
Headache, nausea, dry mouth, nervousness, dyspepsia, pain, vomiting, increased blood
pressure, psychosis, and mania. # Risk of cardiovascular disorders.[56]
|
|
Amphetamines
|
Excessive daytime sleepiness
|
Weak
|
Low
|
Lisdexanfetamina
10–70mg
|
Headache, nausea, dry mouth, nervousness, dyspepsia, pain, vomiting, increased blood
pressure, psychosis, and mania. # Risk of cardiovascular disorders.[56]
[62]
|
|
Solriamfetol
|
Excessive daytime sleepiness
|
Strong
|
Moderate
|
37.5mg-150mg
|
Insomnia, headache, nausea, decreased appetite, anxiety.[56]
Solriamfetol is not available in Brazil.
|
|
L-Carnitine
|
Excessive daytime sleepiness
|
Weak
|
Low
|
510mg
|
It is safe during pregnancy.[65]
[66]
[69]
|
|
Selegiline
|
Excessive daytime sleepiness
|
Strong
|
Low
|
5–10mg
|
Dry mouth, headache, insomnia, sweating.[56]
|
|
Caffeine
|
Excessive daytime sleepiness
|
Weak
|
Low
|
200mg
|
Complementary therapy.[70]
|
|
Hypocretin receptor agonists
|
Excessive daytime sleepiness and cataplexy
|
No evidence
|
No evidence
|
–
|
A recent study was published with promissory results and liver toxicity.[61]
|
|
Pitolisant
|
Excessive daytime sleepiness and cataplexy
|
Strong
|
Moderate
|
8.9–35.6mg
|
Headache, insomnia, and abdominal discomfort.[56]
Pitolisant is not available in Brazil.
|
|
Sodium Oxybate
|
Excessive daytime sleepiness and Cataplexy
|
Strong
|
Moderate
|
1.5–9 g
|
Nocturnal confusion, enuresis, dizziness, nausea, weight loss, psychosis, depression,
and worsening of OSA.[56]
Oxybate is not available in Brazil.
|
|
Tricyclic antidepressants
|
Cataplexy
|
Strong
|
Low
|
Clomipramine
10–150mg
|
Weight gain, sexual dysfunction, constipation, and dry mouth.[56]
|
|
Other antidepressants
|
Cataplexy
|
Strong
|
Low
|
Venlafaxine
37.5–225mg
|
Nausea, dizziness, decreased appetite, irritability, insomnia, weight gain, sexual
dysfunction, hyperhidrosis, diarrhea, constipation.[56]
|
|
Baclofen
|
Cataplexy
|
Weak
|
Low
|
10–40mg
|
Sleepiness, nausea, vomiting, diarrhea, headaches, dry mouth, blurred vision or difficulty
focusing, excessive sweating, and rash.[64]
|
We highlight the use of atypical stimulants known as modafinil and armodafinil, which
are included in many guidelines around the world for narcolepsy treatment.[54] Modafinil improves wakefulness at 100 to 400 mg doses in adults but does not affect
controlling cataplexy. Usually, we divide the total dosage by two times per day, in
the morning and the last taken before 3 pm, to avoid insomnia. Recently, armodafinil has been available in Brazil. Armodafinil
is prescribed once daily, in the morning, at 150 or 250mg. Armodafinil and modafinil
both had a mean single-dose terminal elimination half-life (12 hours) and similar
mean maximum plasma drug concentration (C(max)). However, after C(max), plasma concentrations
decline in a monophasic manner with armodafinil and in a biphasic manner with modafinil
due to the initial rapid elimination of its S-isomer. As a result, plasma drug concentrations
are 33% and 40% higher, respectively, with armodafinil compared with modafinil on
a milligram-to-milligram basis.[58]
[59]
New therapeutic possibilities such as pitolisant (acting on histamine receptors) and
solriamfetol (dual action - norepinephrine and dopamine) have been used to treat drowsiness
complaints but are unavailable in Brazil.[60]
[61] A new class of drugs for narcolepsy is in an advanced testing phase, which is orexin
two receptor agonists. Recent work demonstrates the benefit of this new class of medications
in controlled studies, mainly in patients with narcolepsy type I but with liver toxicity.[54]
[62]
Cataplexy can be treated with tricyclic and other classes of antidepressants such
as citalopram, fluoxetine, and venlafaxine. The drug that has also been successfully
used to control cataplexy is sodium oxybate or hydroxybutyric acid, which is not available
in Brazil.[54] Recently, new presentations of sodium oxybate with a lower amount of sodium and
a single nocturnal intake have been marketed in the United States of America.[63] Authors demonstrate the benefit of using baclofen in preventing cataplexy attacks.[64]
An important point to be considered is related to the fact that the drugs used in
the treatment of narcolepsy are Class C in pregnancy.[65] L-carnitine is an option to treat pregnancy patients. Authors have recently demonstrated
partial improvement of symptoms after treatment with L-carnitine at the onset of symptoms,
including pregnancy, in a systematic review.[66]
[67] Authors observed that the therapeutic efficacy of L-carnitine as a treatment for
patients with narcolepsy in a population of 31 patients showed improvement in EDS.[68] Other authors have shown symptomatic improvement after using prednisone and immunoglobulin.[27]
[69] However, these treatments are experimental. They are under investigation, including
a recent study that showed that caffeine, 200mg, can be a successful adjuvant treatment
for treating EDS in narcolepsy patients.[70]
Narcolepsy is a disease whose investigation integrates several areas of knowledge,
such as neurology, immunology, sleep medicine, psychiatry, and genetics.[6] Patients with narcolepsy have personal, professional, and family impairments.[11] Many advances have been made in this exciting disease, an essential tool in disseminating
information about the condition to medical colleagues and the general population.[11] New medications such as orexin agonists are promising to improve the quality of
life of these patients.[62]
Bibliographical Record
Fernando Morgadinho Santos Coelho. Narcolepsy: an interface among neurology, immunology,
sleep, and genetics. Arq Neuropsiquiatr 2024; 82: s00441779299.
DOI: 10.1055/s-0044-1779299
