Association analysis of the major histocompatibility complex,class II,DQ β1 gene,HLA-DQB1, with narcolepsy in Han Chinese patients from Taiwan

BackgroundNarcolepsy is a rare, chronic, disabling neuropsychiatric disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis, and abnormal rapid eye movement sleep. It is strongly associated with the HLA-DQB1¹06:02 allele in various ethnic groups. Our study aimed to investigate the allelic spectrum of HLA-DQB1 in a sample of Han Chinese patients with narcolepsy and control subjects from Taiwan.MethodsWe determined the genotype of the major histocompatibility complex, class II, DQ β1 gene, HLA-DQB1, in 72 narcolepsy subjects (44 men, 28 women), including 52 narcolepsy subjects with cataplexy (narcolepsy + cataplexy), 20 narcolepsy subjects without cataplexy (narcolepsy–cataplexy), and 194 control subjects (94 men, 100 women) using a sequence-specific oligonucleotide-probe hybridization technique.ResultsWe found a strong HLA-DQB1¹06:02 association in narcolepsy + cataplexy subjects (odds ratio [OR], 321.4 [95% confidence interval {CI}, 70.7–1461.4]). The association was less prominent in narcolepsy–cataplexy subjects (OR, 6.9 [95% CI, 2.4–20.1]). In addition to the DQB1¹06:02, we found that ¹03:01 also was a predisposing allele (OR, 2.0 [95% CI, 1.1–3.7]) in narcolepsy + cataplexy subjects, though the ¹06:01 was a predisposing allele (OR, 2.8 [95% CI, 1.2–6.7]) in narcolepsy–cataplexy subjects. Furthermore, we found a significant overrepresentation of DQB1¹06:02 homozygotes in narcolepsy + cataplexy subjects.ConclusionsOur data add further support to the strong association of the HLA-DQB1¹06:02 allele with narcolepsy, especially in narcolepsy + cataplexy patients. Our study also indicates additional HLA-DQB1 alleles may modify the presentation of narcolepsy + cataplexy patients, such as DQB1¹03:01 and DQB1¹06:01 in our study. Our results are limited by the small sample size and can only be considered as preliminary findings.     

Narcolepsy in the Pediatric Population

Narcolepsy is characterized by excessive daytime sleepiness, with or without cataplexy. Associated features include sleep paralysis, hypnagogic or hypnopompic hallucinations, and disturbed nocturnal sleep. Narcolepsy is strongly associated with the HLA DQB1*0602 allele, and its symptoms stem from destruction of hypocretin-secreting neurons in the hypothalamus. Recently identified autoantibodies to Tribbles homologue 2 in some patients, as well as cases associated with H1N1 vaccination, support an autoimmune mechanism. There are many challenges in diagnosing and treating pediatric narcolepsy. Caution must also be used in interpreting polysomnography and multiple sleep latency test results in children. HLA testing is nonspecific, and no commercial test exists to measure cerebrospinal fluid hypocretin levels. Neuroimaging has not yet proven useful in primary narcolepsy. Treatment of sleepiness and cataplexy in children requires extrapolating from adult studies. Hopefully, further insights into the pathophysiology of narcolepsy will allow for new therapeutics to manage the symptoms and modify the course of the disease.     

Increased plasma level of tumor necrosis factor α in patients with narcolepsy in Taiwan

BackgroundNarcolepsy is a neuropsychiatric disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and abnormal rapid eye movement (REM) sleep. Tumor necrosis factor α (TNF α) and its cognate receptors have been reported to be involved in the pathophysiology of narcolepsy in addition to the HLA antigen system. Our study aimed to determine if the TNF-α system was associated with narcolepsy in our patients.MethodsWe first measured the plasma level of TNF α in 56 narcoleptic patients and 53 control subjects using a highly sensitive enzyme-linked immunosorbent assay. We next determined the genotype of three single nucleotide polymorphisms (SNPs) (T-1031C, C-863A, and C-857T) at the promoter region of the TNF-α gene and one missense SNP (T587G, M196R) at the exon 6 of the tumor necrosis factor receptor 2 gene, TNFR2, in a sample of 75 narcoleptic patients and 201 control subjects by direct sequencing analysis.ResultsWe found a significant elevation of plasma level of TNF α in patients with narcolepsy compared with the control subjects (4.64 pg/mL vs 1.06 pg/mL; P = .0013). However, we did not find significant differences between these two groups in the allelic and genotypic distributions of the investigated polymorphisms.ConclusionsOur study suggests that an increased TNF-α level was associated with narcolepsy in our patients, and that chronic inflammation due to various factors might have led to the increased TNF-α levels found in our patients.     

Cataplectic Facies: Clinical Marker in the Diagnosis of Childhood Narcolepsy—Report of Two Cases

BackgroundNarcolepsy is a chronic disease and is commonly diagnosed in adulthood. However, more than half of the patients have onset of symptoms in childhood and/or adolescence. The full spectrum of clinical manifestations, namely excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis, is usually not present at disease onset, delaying diagnosis during childhood. Mean delay in diagnosis since symptom onset is known to be several years. Initial manifestations can sometimes be as subtle as only partial drooping of eyelids leading to confusion with a myasthenic condition.PatientsWe present two children who presented with “cataplectic facies,” an unusual facial feature only recently described in children with narcolepsy with cataplexy.ResultThe diagnosis of narcolepsy was confirmed by multiple sleep latency test along with human leukocyte antigen typing and cerebrospinal fluid hypocretin assay.ConclusionThe diagnosis of narcolepsy with cataplexy at onset can be challenging in young children. With more awareness of subtle signs such as cataplectic facies, earlier diagnosis is possible. To date, only 11 children between 6 and 18 years of age presenting with typical cataplectic facies have been reported in the literature. We present two patients, one of whom is the youngest individual (4 years old) yet described with the typical cataplectic facies.     

Degenerative pontine lesions in patients with familial narcolepsy

Background and purposeNarcolepsy is characterized by chronic excessive daytime sleepiness with episodic sleep attacks. There are several associated symptoms of narcolepsy: cataplexy (bilateral muscle weakness without loss of consciousness provoked by an emotional trigger, e.g. laughter), sleep paralysis and hypnagogic-hypnopompic hallucinations. Most cases are sporadic; familial narcolepsy contributes to only 1–5% of all cases. While most cases of narcolepsy are idiopathic and are not associated with clinical or radiographic evidence of brain pathology, symptomatic or secondary narcolepsy may occur occasionally in association with lesions caused by tumours, demyelination or strokes of the diencephalon, midbrain, and pons. There are some examples of non-specific brainstem lesions found in magnetic resonance imaging (MRI) in patients with idiopathic narcolepsy.Material and methodsThe authors present eleven patients from a five-generation family with many members who suffer from episodic excessive daytime sleepiness. Narcolepsy was diagnosed in 9 patients. Sleepiness was frequently associated with cataplexy, hypnagogic-hypnopompic hallucinations and sleep paralysis. Improvement in their clinical state was observed during the treatment with modafinil. All probands had MRI of the brain, routine blood tests, EEG, polysomnography, examination of the level of hypocretin in cerebrospinal fluid and evaluation by means of Epworth and Stanford Sleepiness Scales.ResultsIn 9 patients with narcolepsy, decreased thickness of the substantia nigra was found and in six of them degenerative lesions in the pontine substantia nigra were also noticed.ConclusionsThe significance of these changes remains unclear. No data have been published until now concerning the presence of any brain lesions in patients with familial narcolepsy.     

Validation of the Brazilian Portuguese version of the narcolepsy severity scale

IntroductionNarcolepsy type 1 is a sleep disorder and the most common cause of hypersonia of central origin. It is characterized by sleep attacks, cataplexy, sleep-related hallucinations, sleep paralysis and sleep fragmentation in a pleomorphic presentation. The Narcolepsy Severity Scale (NSS), questionnaire which assesses the frequency and impact of the main symptoms of narcolepsy was developed in order to determine its clinical severity, needing translation, cultural adaptation and validation in many languages. The objective is to validate the Brazilian Portuguese version of the NSS.MethodsThe Brazilian version of the NSS was translated to Brazilian Portuguese and applied to patients with a diagnosis of narcolepsy type 1 at the Daytime Excessive Sleepiness Service, at Psychobiology Department of the Universidade Federal de São Paulo (UNIFESP) between February 2018 and July 2019.ResultsA total of 52 patients completed the questionnaire. Cultural adaptations were made to better comprehension of patients. The Brazilian version of the NSS showed high internal consistency, demonstrated by the Cronbach's alpha coefficient of 0.82. It showed good reproducibility capacity, verified through the test-retest, whose intraclass correlation was 0.98. The average severity of Brazilian patients was 33.94 (±11.24), higher than the values found in other population, which also underwent validation of this scale. There was a correlation between sleep latency in diagnostic polysomnography and the NSS.ConclusionsThe Brazilian Portuguese version of NSS showed to be valid and reproducible tool for assessing the severity of patients with type 1 narcolepsy and have potential impact on clinical practice.     

Clinical and neurobiological aspects of narcolepsy

Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy and/or other dissociated manifestations of rapid eye movement (REM) sleep (hypnagogic hallucinations and sleep paralysis). Narcolepsy is currently treated with amphetamine-like central nervous system (CNS) stimulants (for EDS) and antidepressants (for cataplexy). Some other classes of compounds such as modafinil (a non-amphetamine wake-promoting compound for EDS) and gamma-hydroxybutyrate (GHB, a short-acting sedative for EDS/fragmented nighttime sleep and cataplexy) given at night are also employed. The major pathophysiology of human narcolepsy has been recently elucidated based on the discovery of narcolepsy genes in animals. Using forward (i.e., positional cloning in canine narcolepsy) and reverse (i.e., mouse gene knockout) genetics, the genes involved in the pathogenesis of narcolepsy (hypocretin/orexin ligand and its receptor) in animals have been identified. Hypocretins/orexins are novel hypothalamic neuropeptides also involved in various hypothalamic functions such as energy homeostasis and neuroendocrine functions. Mutations in hypocretin-related genes are rare in humans, but hypocretin-ligand deficiency is found in many narcolepsy-cataplexy cases. In this review, the clinical, pathophysiological and pharmacological aspects of narcolepsy are discussed.     

Two cases of childhood narcolepsy mimicking epileptic seizures in video-EEG/EMG

Narcolepsy is characterized by excessive sleepiness, hypnagogic hallucinations, and sleep paralysis, and can occur with or without cataplexy. Here, we report two children with narcolepsy presenting with cataplexy mimicking epileptic seizures as determined by long-term video-electroencephalography (EEG) and electromyography (EMG) monitoring.Case 1 was a 15-year-old girl presenting with recurrent episodes of “convulsions” and loss of consciousness, who was referred to our hospital with a diagnosis of epilepsy showing “convulsions” and “complex partial seizures”. The long-term video-polygraph showed a clonic attack lasting for 15?s, which corresponded to 1–2?Hz with interruption of mentalis EMG discharges lasting for 70–300?ms without any EEG changes. Narcolepsy was suspected due to the attack induced by hearty laughs and the presence of sleep attacks, and confirmed by low orexin levels in cerebrospinal fluid (CSF). Case 2 was an 11-year-old girl presenting with recurrent episodes of myoclonic attacks simultaneously with dropping objects immediately after hearty laughs, in addition to sleep attacks, hypnagogic hallucinations, and sleep paralysis. The long-term video-polygraph showed a subtle attack, characterized by dropping chopsticks from her hand, which corresponded to an interruption of ongoing deltoid EMG discharges lasting 140?ms without any EEG changes. A diagnosis of narcolepsy was confirmed by the low orexin levels in CSF.These cases demonstrate that children with narcolepsy may have attacks of cataplexy that resemble clonic or myoclonic seizures.     

Hypocretin Ligand Deficiency in Narcolepsy: Recent Basic and Clinical Insights

Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. Both sporadic and familial forms exist in humans. Recently, the major pathophysiology of human narcolepsy was indicated, based on discovery, through animal study, of narcolepsy genes involved in the pathology of hypocretin/orexin ligand and its receptor. Hypocretin ligand deficiency is found in most patients with narcolepsy with cataplexy. This deficiency likely is the result of postnatal cell death of hypocretin neurons, and involvement of autoimmune mechanisms is suggested. Hypocretin deficiency also is found in symptomatic narcolepsy and excessive daytime sleepiness with neurologic conditions, including immune-mediated neurologic disorders. These findings have significant clinical relevance and promote understanding of hypocretin cell death mechanisms. Already, discoveries in humans have led to a new diagnostic test for narcolepsy. Currently, hypocretin replacement therapy has emerged as a promising therapeutic option, and experiments using gene therapy and cell transplantation are in progress.     

The effect of modafinil on cortical excitability in patients with narcolepsy: A randomized,placebo-controlled,crossover study

ObjectiveTo investigate the effect of modafinil on cortical excitability in patients with narcolepsy using transcranial magnetic stimulation (TMS).MethodsNineteen drug-naïve narcolepsy patients with cataplexy (10 males, 9 females, and mean age 28.5 years) and 25 age- and sex-matched healthy controls were recruited. In this double-blind, randomized, crossover study, patients and controls received a single dose of 400 mg modafinil or placebo. Modafinil and placebo administrations were separated by a 2-week washout period. TMS parameters, such as resting motor thresholds (RMT), motor-evoked potential (MEP) amplitudes, cortical silent periods (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF), were measured before and 3 h after administering modafinil or placebo. The differences of TMS parameters were statistically tested between patients and controls and between before and after modafinil or placebo administration.ResultsNarcolepsy patients had significantly increased CSP durations compared to controls (independent t-test, P < 0.05), indicating decreased excitability of cortical networks in human narcolepsy. In patients after modafinil administration, MEP amplitudes, SICI, and ICF increased, and CSP duration shortened significantly, meaning enhanced motor excitability, whereas in controls modafinil did not change TMS parameters significantly. Placebo administration did not affect TMS parameters both in patients or controls.ConclusionsNarcolepsy patients with cataplexy showed decreased cortical excitability than normal healthy controls. Single dose modafinil significantly increased motor excitability in narcolepsy patients but had no effect in healthy controls.     

The influence of narcolepsy on olfactory function: a review

IntroductionNarcolepsy is a sleep disorder associated with loss of hypocretin cells characterized by irrepressible need to sleep, often accompanied by cataplexy, sleep fragmentation, hypnagogical and hypnopompic hallucinations, and sleep paralysis. It is also correlated with alterations in the sleep–wake cycle, dysautonomia, olfactory dysfunction, and eating disorders.MethodsThis is a review about influence of narcolepsy on human olfaction. Pubmed, Embase, Ovid and Cochrane databases were searched for articles on the evaluation of olfactory function in narcoleptic patients including terms as narcolepsy, olfaction disorder, amongst others.ResultsSeven articles met the inclusion criteria. In five of them, the olfaction of narcoleptic patients was diminished in comparison with healthy control groups. The diagnosis of narcolepsy relates to worse performance in olfactory tests.Experimental researches showed that hypocretin and hypocretin receptors are present in the olfactory system, and this neuropeptide may have a role on olfactory sensitivity and on the olfactory modulation. The cause of hyposmia appears to be multifactorial. Among them, it stands out the hypocretin deficiency, therefore, that seems to be involved in the olfactory impairment in narcoleptic patients.     

Pediatric narcolepsy

Narcolepsy is a disabling disease with a prevalence of 0.05%. It is characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnogogic hallucinations, automatic behavior, and disrupted nocturnal sleep. The presentation can be very variable, making diagnosis difficult. Loss of hypocretin containing neurons in the lateral hypothalamus has been noted in autopsy studies, and the cerebrospinal fluid level of hypocretin is reduced in patients with narcolepsy with cataplexy. New treatment options are available for the many symptoms of this disease. Early recognition and treatment can greatly improve the quality of life of patients with narcolepsy. A detail review of the epidemiology, pathophysiology, and management of narcolepsy in children is presented.     

Adherence to wakefulness promoting medication in patients with narcolepsy

ObjectiveNarcolepsy management usually requires lifelong pharmacotherapy. However, we know little about adherence to prescribed treatment in narcolepsy. We assessed adherence to wakefulness-promoting agents in narcolepsy patients.Patients and methodsWe retrospectively assessed adherence to wakefulness promoting medication in patients with narcolepsy using the Medicines Possession Ratio (MPR). Three levels of adherence were defined: poor (≤50%), intermediate (51–79%), and good (≥80%). Refractory daytime sleepiness was defined as an Epworth sleepiness scale (ESS) score >12 despite trialling at least three wakefulness-promoting agents. We compared demographic and clinical factors, and prescribed medications between patients, stratified by levels of adherence, as well as by presence or not of refractory sleepiness.ResultsWe included 116 patients with narcolepsy (54.3% female, mean age 39.4 (±14) years). In sum, 93 (80.2%) patients had a diagnosis of narcolepsy type 1 (NT1), and 23 (19.8%) of type 2 (NT2). Suboptimal symptom control was common: 39.8% had refractory sleepiness, and 47.3% of NT1 patients had persistent cataplexy. Good adherence was seen in only 55.2% of patients, while 12.9% were intermediately and 31.9% poorly adherent. Patients with poor adherence were more likely to have a diagnosis of NT2, but adherence did not vary according to gender, age, the presence of psychiatric co-morbidity, or the presence of apparent intractable symptoms. Levels of good adherence to therapy were no better in patients with refractory sleepiness than in those with satisfactory symptom control (56.5% vs 54.3%; p = 0.81).ConclusionSuboptimal adherence to prescribed therapy is common in narcolepsy patients, including those with apparent intractable symptoms, and particularly in patients with NT2.     

Conventional autoantibodies against brain antigens are not routinely detectable in serum and CSF of narcolepsy type 1 and 2 patients

Narcolepsy with cataplexy (NT1) is a chronic hypothalamic disorder with a presumed immune-mediated etiology leading to a loss of hypocretin neurons. Previous studies reported conflicting results in terms of presence of auto-antibodies involved in narcolepsy pathophysiology. A total of 86 patients with primary/idiopathic narcolepsy (74 NT1, 12 NT2) and 23 control patients with excessive daytime sleepiness due to other causes were tested for the presence of a wide range of anti-neuronal antibodies in both serum and cerebrospinal fluid (CSF). Anti-neuronal antibodies were rarely found in patients with narcolepsy (n = 2) and in controls (n = 1). Our results are in line with previous reports. We can therefore support the current evidence, that conventional anti-neuronal antibodies are not routinely detected during the workup of NT1 and other CDH patients.     

Parkinson's disease and narcolepsy-like symptoms

ObjectiveVarious sleep-related problems, for example, insomnia and symptoms of rapid eye movement behavior disorder (RBD), are common in patients with Parkinson's disease (PD). We studied the prevalence of symptoms of narcolepsy (NARC), hallucinations, and RBD and their association with other symptoms.MethodsAltogether, 1447 randomly selected patients with PD, aged 43–89 years, participated in a questionnaire study. A structured questionnaire with 207 items was based on the Basic Nordic Sleep Questionnaire. Questions on demographics, PD, RBD, and other issues were included.ResultsThe response rate was 59.0%; of these patients, 73% had answered to all questions that were used in the analyses (N = 623). The occurrence of suspected narcolepsy (Ullanlinna Narcolepsy Scale ≥ 14 and Epworth Sleepiness Scale ≥ 11) was observed in 9.3% of the subjects (PD with NARC), RBD (REM Sleep Behavior Disorder Screening Questionnaire ≥ 6) in 39.2% of all patients with PD, and in 62.1% of those with PD and NARC. In patients with PD, hallucinations before going to bed in the evening occurred in 5.8%, hypnagogic hallucinations in 4.0%, hallucinations during night 8.3%, and hypnopompic hallucinations in 3.2%. Cataplexy symptoms occurred in 43.1% of subjects with PD and NARC. In a logistic regression analysis, PD with NARC was associated with RBD, all types of hallucinations, daytime sleepiness, fatigue, insomnia, and intense dreaming also when adjusted for age, sex, disease duration, and levodopa.ConclusionsNarcolepsy-like symptoms may be present in patients with PD. Symptoms of RBD were associated with symptoms of narcolepsy including symptoms of cataplexy.     

Prevalence of narcolepsy-cataplexy in Korean adolescents

Background –  Narcolepsy typically begins between adolescence and early adulthood causing severe neuropsychiatric impairments, but few prevalence studies are available on adolescent narcoleptics. In the present study, we investigated the prevalence of narcolepsy-cataplexy in adolescents.
Methods –  In total 20,407 students, aged 14–19 years, participated in this study. Ullanlinna Narcolepsy Scale (UNS) was applied to all subjects and those with a UNS score of ≥14 were contacted by phone for semi-structured interview. Subjects then suspected of having narcolepsy participated in a laboratory investigation, which included polysomnography and HLA typing, or were interviewed in detail by telephone.
Results –  Three subjects were finally diagnosed as narcolepsy with cataplexy and seven subjects might be diagnosed as narcolepsy without cataplexy. Among three narcoleptics with cataplexy, two subjects were HLA-DQB1*0602 and DRB1*1501 positive, but one subject had no test of HLA typing. The prevalence of narcolepsy with cataplexy in Korean adolescence was thus determined to be 0.015% (95% confidence interval = 0.0–0.0313%).
Conclusion –  This epidemiologic study is the first of its type on adolescent narcolepsy to use the International Classification of Sleep Disorders, 2nd edition (ICSD-2) diagnostic criteria. Considering those cases with an onset after adolescence were not included, the prevalence of narcolepsy with cataplexy determined in the present study is comparable with that of other studies in adults.     

Anti-streptococcal antibodies in Chinese patients with type −1 narcolepsy

BackgroundNarcolepsy type 1 (NT1) is considered to be an autoimmune disease, and streptococcal infection may be an environmental trigger. However, previous studies from Asian narcolepsy patients did not reveal elevated anti-streptolysin O [ASO]. The aim is to investigate whether large sample Chinese patients with NT1 have an increase in antistreptococcal antibody titers.MethodsA total of 214 narcolepsy patients and 360 healthy controls were recruited. All patients were DQB110602 positive with clear-cut cataplexy or had low CSF hypocretin-1. Participants were tested for ASO and anti DNAse B [ADB]. These patients were divided into five groups according to disease duration, including 29 patients less than 3 months; 25 from 3 months to 1 year; 40 from 1 to 3 years; 61 from 3 to 10 years and 59 patients over 10 years. Comparison was also made between children and adults with age matched controls, respectively.ResultsThere were no significant differences between patients and healthy controls in regard to both ASO ≥200 IU (19.2% vs. 16.9%, p = 0.50) and ADB≥480IU (9.8% vs. 10.3%, p = 0.86). For children narcolepsy patients, ASO positive rates (19.8% vs. 18%, p = 0.68) and ADB positive rates (10.4% vs. 12%, p = 0.72) had no differences compared to age matched controls. No difference was observed in adult narcolepsy patients either, with ASO positive rates (18.5% vs. 13.8%, p = 0.39) and ADB positive rates (9.3% vs. 5.3%, p = 0.42) compared to age matched controls, respectively. ASO and ADB positive rates had no significant differences among different disease duration groups (p = 0.55 and 0.9, respectively).ConclusionStreptococcus infection reflected by increase of ASO and ADB levels was not found in Chinese patients with type 1 narcolepsy, additional triggers for narcolepsy need to be addressed in this population.     

Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications

Narcolepsy is a chronic, debilitating neurological disorder of sleep-wake state instability. This instability underlies all narcolepsy symptoms, including excessive daytime sleepiness (EDS), symptoms of rapid eye movement (REM) sleep dysregulation (ie, cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis), and disrupted nighttime sleep. Several neurotransmitter systems promote wakefulness, and various neural pathways are involved in regulating REM sleep-related muscle atonia, providing multiple targets for pharmacologic intervention to reduce EDS and cataplexy. Medications approved by the US Food and Drug Administration (FDA) for the treatment of EDS in narcolepsy include traditional stimulants (eg, amphetamines, methylphenidate), wake-promoting agents (eg, modafinil, armodafinil), and solriamfetol, which mainly act on dopaminergic and noradrenergic pathways. Sodium oxybate (thought to act via GABA_B receptors) is FDA-approved for the treatment of EDS and cataplexy. Pitolisant, a histamine 3 (H₃)-receptor antagonist/inverse agonist, is approved by the European Medicines Agency (EMA) for the treatment of narcolepsy with or without cataplexy in adults and by the FDA for the treatment of EDS in adults with narcolepsy. Pitolisant increases the synthesis and release of histamine in the brain and modulates the release of other neurotransmitters (eg, norepinephrine, dopamine). Antidepressants that inhibit reuptake of serotonin and/or norepinephrine are widely used off label to manage cataplexy. In many patients with narcolepsy, combination treatment with medications that act via different neural pathways is necessary for optimal symptom management. Mechanism of action, pharmacokinetics, and abuse potential are important considerations in treatment selection and subsequent medication adjustments to maximize efficacy and mitigate adverse effects in the treatment of patients with narcolepsy.     

Differences in diffusion tensor imaging changes between narcolepsy with and without cataplexy

ObjectiveThe distinctive clinical finding of Type 1 narcolepsy compared to Type 2 is the presence of cataplexy. Several neuroimaging studies have also reported abnormalities in narcolepsy patients with or without cataplexy. However, there are conflicting results to differentiate them. In this study, we aimed to clarify the white matter changes in narcolepsy patients both with and without cataplexy and compared them with healthy adults to evaluate microstructural differences in the brain.MethodsEleven narcolepsy patients with cataplexy (NC), 12 narcolepsy patients without cataplexy (NOC) and healthy age- and gender-matched controls (N = 16) were studied. Whole-brain diffusion tensor imaging (DTI) was obtained and tract-based spatial statistics were used to localize white matter abnormalities.ResultsCompared with the healthy controls, both NC and NOC patients exhibited significant fractional anisotropy (FA) decreases in the bilateral cerebellar hemispheres, bilateral thalami, the corpus callosum and left anterior-medial temporal white matter. Compared with the controls, the NC patients' FA values were also decreased in the midbrain. No significant correlations were found between FA values and clinical-polysomnographic variables.ConclusionThis DTI study has demonstrated white matter abnormalities in the midbrain–brainstem regions as a distinctive finding of narcolepsy patients with cataplexy. Involvement of bilateral temporal lobes with greater changes on the left lobe is also a supporting finding of patients with cataplexy. DTI changes in the midbrain–brainstem and bilateral temporal lobes can be signs of different pathological mechanisms in these patients.     

Narcolepsy with cataplexy

Narcolepsy is a rare, disabling sleep disorder, with a prevalence of 20 to 30 per 100,000. Its onset, from childhood to the fifties, peaks in the second decade. The main features are excessive daytime sleepiness and cataplexy or sudden loss of muscle tone triggered by emotional situations. Other less consistent symptoms include hypnagogic hallucinations, sleep paralysis, sleep maintenance insomnia, REM sleep behavior disorders, attention deficit and weight gain at disease onset. Narcolepsy with cataplexy remains a clinical diagnosis but nighttime and daytime polysomnography (multiple sleep latency tests) are useful to document a mean sleep latency below 8 min and at least two sleep-onset REM periods. HLA typing shows an association with HLA DQB1*0602 in more than 92% of cases but was not included in the new diagnostic criteria. In contrast, a low hypocretin levels (values below 110 pg/ml) in the cerebrospinal fluid (CSF) was highly specific for narcolepsy with cataplexy. The deficiency of the hypocretin system is well-established in animal models of narcolepsy (murine and canine narcolepsy) but also in human narcoleptics with a 90% reduction of CSF hypocretin levels in relation with an early loss of hypocretin neurons. The cause of human narcolepsy remains unknown, however an autoimmune process is most probable. The treatment of narcolepsy includes stimulants against sleepiness (modafinil, methylphenidate), anticataplectic drugs (antidepressants) and sodium oxybate. The current therapeutic target is oriented towards hypocretine agonists, histamine (an arousal system) H3 antagonists and immunosuppressants.