Low Cerebrospinal Fluid Hypocretin-1 Research Articles

Narcolepsy in African Americans.

Although narcolepsy affects 0.02-0.05% of individuals in various ethnic groups, clinical presentation in different ethnicities has never been fully characterized. Our goal was to study phenotypic expression across ethnicities in the United States. Cases of narcolepsy from 1992 to 2013 were identified from searches of the Stanford Center for Narcolepsy Research database. International Classification of Sleep Disorders, Third Edition diagnosis criteria for type 1 and type 2 narcolepsy were used for inclusion, but subjects were separated as with and without cataplexy for the purpose of data presentation. Information extracted included demographics, ethnicity and clinical data, HLA-DQB1*06:02, polysomnography (PSG), multiple sleep latency test (MSLT) data, and cerebrospinal fluid (CSF) hypocretin-1 level. 182 African-Americans, 839 Caucasians, 35 Asians, and 41 Latinos with narcolepsy. Sex ratio, PSG, and MSLT findings did not differ across ethnicities. Epworth Sleepiness Scale (ESS) score was higher and age of onset of sleepiness earlier in African Americans compared with other ethnicities. HLA-DQB1*06:02 positivity was higher in African Americans (91.0%) versus others (76.6% in Caucasians, 80.0% in Asians, and 65.0% in Latinos). CSF hypocretin-1 level, obtained in 222 patients, was more frequently low (≤ 110 pg/ml) in African Americans (93.9%) versus Caucasians (61.5%), Asians (85.7%) and Latinos (75.0%). In subjects with low CSF hypocretin-1, African Americans (28.3%) were 4.5 fold more likely to be without cataplexy when compared with Caucasians (8.1%). Narcolepsy in African Americans is characterized by earlier symptom onset, higher Epworth Sleepiness Scale score, higher HLA-DQB1*06:02 positivity, and low cerebrospinal fluid hypocretin-1 level in the absence of cataplexy. In African Americans, more subjects without cataplexy have type 1 narcolepsy.

A feminist, narrative analysis of drinking stories

The association between narcolepsy with cataplexy and the hypocretinergic system in the central nervous system is strong since up to 75–90% of all patients have cerebrospinal fluid (CSF) hypocretin-1 deficiency. The predominant occurrence of HLADQB1*0602 tissue type in narcolepsy patients and recent results from genome-wide association studies suggest an underlying immunological mechanism. The present study was initiated to clarify whether measurement of nerve cell biomarkers in CSF could give additional knowledge of the pathophysiological mechanisms causing narcolepsy with cataplexy.Two patient groups with narcolepsy, comprising 18 patients with low CSF hypocretin-1 concentrations and typical cataplexy, and 18 patients with normal CSF hypocretin-1 levels and mild cataplexy-like symptoms, were compared to 17 controls. We measured the nerve cell biomarkers beta-amyloid (Aβ42), total tau protein (T-tau), phosphorylated tau (P-tau) and neuron-specific enolase (NSE) in CSF.The concentrations of all biomarkers were significantly elevated in both patient groups compared to the controls. The concentration of beta-amyloid was significantly higher in the patient group with normal CSF hypocretin-1 concentration than in those with low concentrations, whereas the other biomarkers showed no difference between the patient groups.The findings of elevated levels of CSF biomarkers independent of CSF hypocretin-1 reduction may reflect alterations in cell metabolism. The results suggest a more extensive affection of the sleep regulating cellular network, affecting other neuronal sites important in the regulation of sleep, in addition to the hypocretin-producing neurons.

Increased cerebrospinal fluid levels of nerve cell biomarkers in narcolepsy with cataplexy

BackgroundThe association between narcolepsy with cataplexy and the hypocretinergic system in the central nervous system is strong since up to 75–90% of all patients have cerebrospinal fluid (CSF) hypocretin-1 deficiency. The predominant occurrence of HLADQB1*0602 tissue type in narcolepsy patients and recent results from genome-wide association studies suggest an underlying immunological mechanism. The present study was initiated to clarify whether measurement of nerve cell biomarkers in CSF could give additional knowledge of the pathophysiological mechanisms causing narcolepsy with cataplexy. MethodsTwo patient groups with narcolepsy, comprising 18 patients with low CSF hypocretin-1 concentrations and typical cataplexy, and 18 patients with normal CSF hypocretin-1 levels and mild cataplexy-like symptoms, were compared to 17 controls. We measured the nerve cell biomarkers beta-amyloid (Aβ42), total tau protein (T-tau), phosphorylated tau (P-tau) and neuron-specific enolase (NSE) in CSF. ResultsThe concentrations of all biomarkers were significantly elevated in both patient groups compared to the controls. The concentration of beta-amyloid was significantly higher in the patient group with normal CSF hypocretin-1 concentration than in those with low concentrations, whereas the other biomarkers showed no difference between the patient groups. ConclusionThe findings of elevated levels of CSF biomarkers independent of CSF hypocretin-1 reduction may reflect alterations in cell metabolism. The results suggest a more extensive affection of the sleep regulating cellular network, affecting other neuronal sites important in the regulation of sleep, in addition to the hypocretin-producing neurons.

Narcolepsy in Parkinson’s disease

Non-motor symptoms in Parkinson’s disease (PD), such as excessive daytime sleepiness, ‘sleep attacks’, insomnia, restless legs syndrome and rapid eye movement sleep behavior disorder, are common and provide a challenge to treatment. These sleep symptoms are also described in patients suffering from the sleep/wake disorder, narcolepsy. The International Classification of Sleep Disorders (ICSD-2) narcolepsy criteria uses a number of markers for diagnosis, of which lack or deficiency of cerebrospinal fluid (CSF) hypocretin-1 levels is a key marker. Hypocretin neurons prominently located in the lateral hypothalamus and perifornical nucleus have been proposed to interact with mechanisms involving sleep and arousal. Low hypocretin-1 levels in the CSF have been shown to correlate with hypothalamic hypocretin cell loss in narcolepsy and other forms of hypersomnia; therefore, it has been proposed that degenerative damage to hypocretin neurons (such as in PD) may be detected by low CSF hypocretin-1 concentrations, and may also explain the sleep symptoms experienced by some PD patients. To date, there is mixed conflicting data describing hypocretin-1 levels in the CSF of patients with parkinsonism associated with sleep symptoms, with most studies showing no significant decrease when compared with controls. However, hypocretin-1 CSF deficiency has been shown in some studies to be more prominent in PD patients with sleep symptoms versus those without. Notably, the hypocretin system has been shown not to be selectively disrupted, with one study showing melanin concentrating hormone cell loss in the same patients with hypocretin loss. It is likely that hypocretin deficiency in PD patients occurs secondary to collateral damage caused by the neurodegenerative process involving the hypothalamus. Awareness of narcoleptic events in PD is important for driving related advice, in addition to the possible use of dopamine D3 receptor active agonists.

EFNS guidelines on disease‐specific CSF investigations

We reviewed the literature for disease-specific markers in cerebrospinal fluid (CSF) and evaluated their diagnostic and prognostic relevance in neurological diseases. High tau protein in combination with low amyloid beta levels has a high sensitivity (80%) and specificity (90%) for Alzheimer's disease (AD) against normal aging and can predict conversion of mild cognitive impairment to AD. The detection of 14-3-3 has a high sensitivity (80-90%) and specificity (90%) for the diagnosis of CJD. Low or undetectable CSF hypocretin-1 (orexin-1) levels constitute a diagnostic biomarker for narcolepsy with cataplexy. Detection of beta-2-transferrin indicates CSF contamination in oto- and rhinorrhoe with a sensitivity of > 79% at a specificity of 95% similar to the beta-trace protein (sensitivity > 90%, specificity 100%). However, beta-trace protein is faster and cheaper to perform. Possible future biomarkers are: elevated levels of vascular endothelial growth factor are relatively sensitive (51-100%) and specific (73-100%) for leptomeningeal metastases from solid tumors and are associated with a poor prognosis in this condition. Elevated CSF neurofilament (Nf) levels probably reflect acute neuronal degeneration. The prognostic value of CSF Nf levels is highest in acute conditions such as subarachnoid hemorrhage, acute optic neuritis and neuromyelitis optica.

Decreased CSF Histamine in Narcolepsy With and Without Low CSF Hypocretin-1 in Comparison to Healthy Controls

To examine whether cerebrospinal fluid (CSF) histamine contents are altered in human narcolepsy and whether these alterations are specific to hypocretin deficiency, as defined by low CSF hypocretin-1. Patients meeting the ICSD-2 criteria for narcolepsy with and without cataplexy and who had CSF hypocretin-1 results available were selected from the Stanford Narcolepsy Database on the basis of CSF availability and adequate age and sex matching across 3 groups: narcolepsy with low CSF hypocretin-1 (n=34, 100% with cataplexy), narcolepsy without low CSF hypocretin-1 (n=24, 75% with cataplexy), and normal controls (n=23). Low CSF hypocretin-1 was defined as CSF < or =110 pg/mL (1/3 of mean control values). Six of 34 patients with low CSF hypocretin-1, six of 24 subjects with normal CSF hypocretin-1, and all controls were unmedicated at the time of CSF collection. CSF histamine was measured in all samples using a fluorometric HPLC system. Mean CSF histamine levels were: 133.2 +/- 20.1 pg/mL in narcoleptic subjects with low CSF hypocretin-1, 233.3 +/- 46.5 pg/mL in patients with normal CSF hypocretin-1 (204.9 +/- 89.7 pg/mL if only patients without cataplexy are included), and 300.5 +/- 49.7 pg/mL in controls, reaching statistically significant differences between the 3 groups. CSF histamine levels are reduced in human narcolepsy. The reduction of CSF histamine levels was more evident in the cases with low CSF hypocretin-1, and levels were intermediate in other narcolepsy cases. As histamine is a wake-promoting amine known to decrease during sleep, decreased histamine could either passively reflect or partially mediate daytime sleepiness in these pathologies.

Decreased Csf Histamine in Narcolepsy With and Without Low Csf Hypocretin-1 in Comparison to Healthy Controls

To examine whether cerebrospinal fluid (CSF) histamine contents are altered in human narcolepsy and whether these alterations are specific to hypocretin deficiency, as defined by low CSF hypocretin-1. Patients meeting the ICSD-2 criteria for narcolepsy with and without cataplexy and who had CSF hypocretin-1 results available were selected from the Stanford Narcolepsy Database on the basis of CSF availability and adequate age and sex matching across 3 groups: narcolepsy with low CSF hypocretin-1 (n = 34, 100% with cataplexy), narcolepsy without low CSF hypocretin-1 (n = 24, 75% with cataplexy), and normal controls (n = 23). Low CSF hypocretin-1 was defined as CSF ≤ 110 pg/mL (1/3 of mean control values). Six of 34 patients with low CSF hypocretin-1, six of 24 subjects with normal CSF hypocretin-1, and all controls were unmedicated at the time of CSF collection. CSF histamine was measured in all samples using a fluorometric HPLC system. Mean CSF histamine levels were: 133.2 ± 20.1 pg/mL in narcoleptic subjects with low CSF hypocretin-1, 233.3 ± 46.5 pg/mL in patients with normal CSF hypocretin-1 (204.9 ± 89.7 pg/mL if only patients without cataplexy are included), and 300.5 ± 49.7 pg/mL in controls, reaching statistically significant differences between the 3 groups. CSF histamine levels are reduced in human narcolepsy. The reduction of CSF histamine levels was more evident in the cases with low CSF hypocretin-1, and levels were intermediate in other narcolepsy cases. As histamine is a wake-promoting amine known to decrease during sleep, decreased histamine could either passively reflect or partially mediate daytime sleepiness in these pathologies.

A Study of the Diagnostic Utility of HLA Typing, CSF Hypocretin-1 Measurements, and MSLT Testing for the Diagnosis of Narcolepsy in 163 Korean Patients With Unexplained Excessive Daytime Sleepiness

To study DQB1*0602 status and hypocretin-1 levels in the cerebrospinal fluid (CSF) in a cohort of patients with hypersomnolence and to test International Classification of Sleep Disorders-2 (ICSD-2) criteria for hypersomnia of central origin. Retrospective case series. One hundred sixty-three consecutive patients with unexplained sleepiness and 282 controls recruited at St. Vincent's Hospital, Korea. The gold standard for diagnosis was ICSD-2 criteria. Patients and controls completed the Stanford Sleep Inventory, and agreed to HLA typing. Polysomnography (87%), Multiple Sleep Latency Test (MSLT) (96%), and CSF hypocretin-1 measurements (53%) were conducted in patients. Most patients (80%) could be classified using the ICSD-2. The 33 patients who could not be classified were without cataplexy (4 with low CSF hypocretin-1). These could not be included because of sleep apnea (apnea-hypopnea index > or = 5/h, 84%) and/or because sleep prior to MSLT was less than 6 hours (27%). Narcolepsy with cataplexy cases were 92% HLA positive with low hypocretin-1. Cataplexy at interview was predicted by validated Stanford Sleep Inventory questions regarding cataplexy triggers. In contrast, cataplexy-like events were frequently reported in all groups, including controls. Cases with narcolepsy without cataplexy were frequently men (73%) and heterogeneous biologically (36% HLA positive, 40% with low CSF hypocretin-1). None of the controls had low CSF hypocretin-1, whereas 13% were HLA positive. The ICSD-2 was easily applicable in cases with typical cataplexy. In these cases, the MSLT and further evaluations were almost always positive and may thus not always be needed. Many patients without cataplexy were difficult to classify because of difficulties in interpreting the MSLT in the presence of sleep apnea or reduced sleep.

Narcolepsy Without Cataplexy: 2 Subtypes Based on CSF Hypocretin-1/Orexin-A Findings

Cerebrospinal fluid (CSF) hypocretin-1 levels and their relationship with the clinical characteristics of narcolepsy without cataplexy have not been well elucidated. Our aim was to examine whether clinical characteristics vary with CSF hypocretin-1 levels among narcoleptic patients without cataplexy. Clinical features, variables on the multiple sleep latency test, and results of HLA typing were correlated with CSF hypocretin-1 levels. University-based sleep laboratories and a sleep disorders center. Seventeen patients (5 male, 12 female) who fulfilled the diagnostic criteria of narcolepsy without cataplexy according to the International Classification of Sleep Disorders. INERVENTIONS: Patients underwent lumbar puncture for CSF sampling. Five patients showed a markedly decreased CSF hypocretin-1 level, whereas the remaining 12 patients showed almost normal levels. The mean rapid eye movement (REM) latency was significantly shorter and the age at onset was significantly earlier in the low CSF hypocretin-1 group compared with the normal CSF hypocretin-1 group. HLA-DR2 was positive in all of the patients with low CSF hypocretin-1, whereas only 33.3% of patients with normal CSF hypocretin-1 were DR2 positive. Some narcoleptic patients without cataplexy have low CSF hypocretin-1 levels. In patients who have narcolepsy without cataplexy, short mean REM latency, younger age at onset, and HLA-DR2 are associated with CSF hypocretin-1 deficiency. Markedly decreased CSF hypocretin-1 levels could be a significant marker for identifying subgroups of narcolepsy patients without cataplexy.

Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system

Human narcolepsy is a chronic sleep disorder affecting 1:2000 individuals. The disease is characterized by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep, such as sleep paralysis and hypnagogic hallucinations. Recently, it was discovered that the pathophysiology of (idiopathic) narcolepsy-cataplexy is linked to hypocretin ligand deficiency in the brain and cerebrospinal fluid (CSF), as well as the positivity of the human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602). The symptoms of narcolepsy can also occur during the course of other neurological conditions (i.e. symptomatic narcolepsy). We define symptomatic narcolepsy as those cases that meet the International Sleep Disorders Narcolepsy Criteria, and which are also associated with a significant underlying neurological disorder that accounts for excessive daytime sleepiness (EDS) and temporal associations. To date, we have counted 116 symptomatic cases of narcolepsy reported in literature. As, several authors previously reported, inherited disorders (n=38), tumors (n=33), and head trauma (n=19) are the three most frequent causes for symptomatic narcolepsy. Of the 116 cases, 10 are associated with multiple sclerosis, one case of acute disseminated encephalomyelitis, and relatively rare cases were reported with vascular disorders (n=6), encephalitis (n=4) and degeneration (n=1), and hererodegenerative disorder (three cases in a family). EDS without cataplexy or any REM sleep abnormalities is also often associated with these neurological conditions, and defined as symptomatic cases of EDS. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, review of the literature reveals numerous unquestionable cases of symptomatic narcolepsy. These include cases with HLA negative and/or late onset, and cases in which the occurrences of the narcoleptic symptoms are parallel with the rise and fall of the causative disease. A review of these cases (especially those with brain tumors), illustrates a clear picture that the hypothalamus is most often involved. Several cases of symptomatic cataplexy (without EDS) were also reported and in contrast, these cases appear to be often associated with non-hypothalamic structures. CSF hypocretin-1 measurement were also carried out in a limited number of symptomatic cases of narcolepsy/EDS, including narcolepsy/EDS associated with tumors (n=5), head trauma (n=3), vascular disorders (n=5), encephalopathies (n=3), degeneration (n=30), demyelinating disorder (n=7), genetic/congenital disorders (n=11) and others (n=2). Reduced CSF hypocretin-1 levels were seen in most symptomatic narcolepsy cases of EDS with various etiologies and EDS in these cases is sometimes reversible with an improvement of the causative neurological disorder and an improvement of the hypocretin status. It is also noted that some symptomatic EDS cases (with Parkinson diseases and the thalamic infarction) appeared, but they are not linked with hypocretin ligand deficiency. In contrast to idiopathic narcolepsy cases, an occurrence of cataplexy is not tightly associated with hypocretin ligand deficiency in symptomatic cases. Since CSF hypocretin measures are still experimental, cases with sleep abnormalities/cataplexy are habitually selected for CSF hypocretin measures. Therefore, it is still not known whether all or a large majority of cases with low CSF hypocretin-1 levels with CNS interventions, exhibit EDS/cataplexy. It appears that further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiological mechanisms for the occurrence of EDS and cataplexy.

The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias.

Narcolepsy, a neurological disorder affecting 1 in 2000 individuals, is associated with HLA-DQB1*0602 and low cerebrospinal fluid (CSF) hypocretin (orexin) levels. To delineate the spectrum of the hypocretin deficiency syndrome and to establish CSF hypocretin-1 measurements as a diagnostic tool for narcolepsy. Diagnosis, HLA-DQ, clinical data, the multiple sleep latency test (MSLT), and CSF hypocretin-1 were studied in a case series of patients with sleep disorders from 1999 to 2002. Signal detection analysis was used to determine the CSF hypocretin-1 levels best predictive for International Classification of Sleep Disorders (ICSD)-defined narcolepsy (blinded criterion standard). Clinical and demographic features were compared in narcoleptic subjects with and without low CSF hypocretin-1 levels. Sleep disorder and neurology clinics in the United States and Europe, with biological testing performed at Stanford University, Stanford, Calif. There were 274 patients with narcolepsy; hypersomnia; obstructive sleep apnea; restless legs syndrome; insomnia; and atypical hypersomnia cases such as familial cases, narcolepsy without cataplexy or without HLA-DQB1*0602, recurrent hypersomnias, and symptomatic cases (eg, Parkinson disease, depression, Prader-Willi syndrome, Niemann-Pick disease type C). The subject group also included 296 controls (healthy and with neurological disorders). Venopuncture for HLA typing, lumbar puncture for CSF analysis, primary diagnosis using the International Classification of Sleep Disorders, Stanford Sleep Inventory for evaluation of narcolepsy, and sleep recording studies. Diagnostic threshold for CSF hypocretin-1, HLA-DQB1*0602 positivity, and clinical and polysomnographic features. HLA-DQB1*0602 frequency was increased in narcolepsy with typical cataplexy (93% vs 17% in controls), narcolepsy without cataplexy (56%), and in essential hypersomnia (52%). Hypocretin-1 levels below 110 pg/mL were diagnostic for narcolepsy. Values above 200 pg/mL were considered normal. Most subjects with low levels were HLA-DQB1*0602-positive narcolepsy-cataplexy patients. These patients did not always have abnormal MSLT. Rare subjects without cataplexy, DQB1*0602, and/or with secondary narcolepsy had low levels. Ten subjects with hypersomnia had intermediate levels, 7 with narcolepsy (often HLA negative, of secondary nature, and/or with atypical cataplexy or no cataplexy), and 1 with periodic hypersomnia. Healthy controls and subjects with other sleep disorders all had normal levels. Neurological subjects had generally normal levels (n = 194). Intermediate (n = 30) and low (n = 3) levels were observed in various acute neuropathologic conditions. Narcolepsy-cataplexy with hypocretin deficiency is a genuine disease entity. Measuring CSF hypocretin-1 is a definitive diagnostic test, provided that it is interpreted within the clinical context. It may be most useful in cases with cataplexy and when the MSLT is difficult to interpret (ie, in subjects already treated with psychoactive drugs or with other concurrent sleep disorders).