Csf Hypocretin1 Levels From Typical Narcolepsy To The Narcolepsy Borderland

The involvement of the hypocretin system in the pathophysiology of human narcolepsy was first demonstrated though studies of human CSF samples (37). Measuring CSF hypocretin-1 is becoming an established diagnostic procedure (40), and it is possible that, in the future, hypocretin-1 will be measurable in plasma.

6.1. Typical Cases: Narcolepsy with Definite Cataplexy and HLA Positivity

Nishino et al. (37) were the first group to measure hypocretin-1 levels in narcolepsy-cataplexy patients and in control subjects. Hypocretin-2 was found to be undetectable in all samples, an observation likely to be caused by the biological instability of the hypocretin-2 peptide in vivo. Nishino et al. (37) reported undetectable hypocretin-1 levels (<40 pg/mL) in the CSF of seven of the nine narcolepsy cataplexy cases tested. All cases with undetectable levels were HLA DQB 1*0602 positive. This finding has now been replicated by multiple groups. Undetectable CSF hypocretin-1 levels are found in more than 90% of sporadic narcoleptic patients with cataplexy, and such cases are almost always HLA DQB 1*0602 positive (37,41-48). Subjects with low hypocretin-1 levels more frequently display typical cataplexy and abnormal MSLTs and are more often HLA DQB1*0602 positive (42). Other characteristics typical of narcoleptics do not statistically influence the probability of low hypocretin-1 level. Typical cataplexy has a better predictive value for low hypocretin-1 levels than abnormal MSLT results (42). Overall, these results indicate that narcolepsy with typical cataplexy and HLA positivity is strongly associated with a hypocretin deficiency, as reflected by low CSF hypocretin-1.

6.2. Atypical Cases: Narcolepsy with Atypical Cataplexy or Without Cataplexy and Familial and HLA Negative Cases

Results are more difficult to interpret in the atypical forms of the disease. Only 20% of cases with atypical cataplexy (not triggered by laughter or joking) have low CSF hypocre-tin-1, emphasizing the importance of a careful definition of cataplexy (42). Narcolepsy without cataplexy and HLA DQB1*0602-negative cases are also generally associated with normal levels of hypocretin-1 in the CSF. More rarely, low levels of hypocretin-1 can also be observed in narcoleptic patients who do not have cataplexy (approximately 10-30%, especially children) or who are HLA DQB1*0602 negative (only a few cases known in the entire world), but not both. (41-44,47,48). The observation that only a minority of narcoleptic patients without cataplexy have low CSF hypocretin-1 corroborates neuropatho-logical data indicating a 74% decrease in the number of hypocretin-containing neurons of the hypothalamus in the only narcoleptic patient without cataplexy tested in postmortem studies (32,38). It has been speculated that narcolepsy without cataplexy may represent a milder form of the disease, with partial lesion of the hypocretinergic system and normal or low CSF hypocretin-1 (42).

In familial cases, concentrations of CSF hypocretin-1 are also tightly associated with the presence of the HLA DQB1*0602 allele; all DQB1*0602-negative narcoleptic-cataplectic patients in multiplex families tested to date had normal levels of hypocretin-1 in the CSF (41,42,44,48). In the DAN family, a large African American lineage with both HLA-positive and HLA-negative cases, and the EIC pedigree, a family with only HLA-negative cases, all HLA-negative narcoleptic patients had normal CSF hypocretin-1 levels (42). These findings suggest that the DQB1*0602 allele may have a major role in conferring low or absent hypocre-tin neurotransmission. In addition, in the DAN pedigree, normal or intermediate hypocretin levels of CSF hypocretin-1 were reported among younger HLA-positive narcoleptic patients or in relatives affected with isolated daytime naps or lapses into sleep. This suggests that hypocretin deficiency as measured by CSF hypocretin levels is more weakly associated with the familial form of the disease and that, in the DAN family, complete hypocretin deficiency may occur more slowly than in most sporadic cases. This observation does not exclude the involvement of the hypocretin system in the physiopathology of familial forms of the disease, even if a patient is HLA negative, since the function of the hypocretin receptors or the efficacy of the signal transmission might be altered. As mentioned above, however, hypocretin receptor mutations have also been screened in familial cases without success.

The recent report of CSF hypocretin-1 measurements in two monozygotic twin pairs further illustrates the complexity of the relationship between narcolepsy and low hypocretin levels. One monozygotic twin pair concordant for narcolepsy-cataplexy and HLA DQB1*0602 positive had normal CSF hypocretin-1 levels, suggesting the existence of a genetic form of typical narcolepsy without hypocretin neurotransmitter abnormality (49). It is interesting to speculate that perhaps this concordant twin pair is HLA positive by chance and is pathophys-iologically related to other, HLA-negative cases (more often familial in nature and with normal CSF hypocretin-1; see above). On the other hand, another monozygotic twin pair was HLA-DQB1*0602 positive and discordant for narcolepsy, with undetectable CSF hypocretin-1 in the affected twin and normal levels in the unaffected twin, suggesting that environmental factors may play a key role in the development of hypocretin deficiency and resulting narcolepsy (50).

In conclusion, whereas HLA-positive sporadic cases with typical cataplexy are likely to be etiologically homogeneous and typically associated with low CSF hypocretin-1, only a minority of atypical cases have low CSF hypocretin-1 (Fig. 2). A possible explanation may be etiological heterogeneity in these other situations. However, an alteration of the hypocre-tin system is still possible in these atypical forms not associated with a low level of hypocre-tin-1. For example, some of these cases may be secondary to hypocretin receptor-1 or-2 defects, or any abnormality downstream of the hypocretin pathway. It is also possible that partial lesions of hypocretin neurons may affect specific projections and lead to sleep abnormalities, without noticeably low CSF hypocretin-1 (42).

6.3. Idiopathic Hypersomnia and Secondary Cases

Idiopathic hypersomnia is characterized by excessive daytime somnolence and no REM sleep abnormalities. In the classic form, excessive amounts of nocturnal and diurnal sleep are reported. All patients with monosymptomatic or polysymptomatic idiopathic hypersomnia tested to date had normal CSF hypocretin-1 levels (42,43,47,48), demonstrating that hypocretin-1 dysfunction does not appear to be the final, common pathway of the pathophysiology of most hypersomnias.

Secondary narcolepsy and hypersomnia cases are discussed elsewhere in this book. Hypersomnia and narcolepsy-like symptoms have been reported in various disorders. Thus, hypocretin-1 has been measured in such cases after traumatic brain injury (42,48), acute

Hypocretin Narcolepsy Brain

Fig. 2. Lumbar cerebrospinal fluid (CSF) hypocretin-1 concentrations in controls, narcoleptics, and other pathologies. Each point is the concentration of hypocretin-1 in the crude (unfiltered) lumbar CSF of a single individual. Represented are controls (samples taken during night and day) and narcoleptics, including those with typical cataplexy, with atypical cataplexy, with cataplexy but who are HLA negative, and without cataplexy, as well as narcolepsy family probands. Individuals with hypersomnia owing to idiopathic hypersomnia, periodic hypersomnia, or hypersomnia caused by secondary etiology are also shown, as are those with other diagnostically described sleep disorders (obstructive sleep apnea [n = 17], restless legs syndrome [n = 12], insomnia [n = 12]) and those with a variety of neurologic disorders. Specific pathologies are described for individuals with low (<110 pg/mL) or intermediate (110-200 pg/mL) concentrations of hypocretin-1. (Data from ref. 42.)

Fig. 2. Lumbar cerebrospinal fluid (CSF) hypocretin-1 concentrations in controls, narcoleptics, and other pathologies. Each point is the concentration of hypocretin-1 in the crude (unfiltered) lumbar CSF of a single individual. Represented are controls (samples taken during night and day) and narcoleptics, including those with typical cataplexy, with atypical cataplexy, with cataplexy but who are HLA negative, and without cataplexy, as well as narcolepsy family probands. Individuals with hypersomnia owing to idiopathic hypersomnia, periodic hypersomnia, or hypersomnia caused by secondary etiology are also shown, as are those with other diagnostically described sleep disorders (obstructive sleep apnea [n = 17], restless legs syndrome [n = 12], insomnia [n = 12]) and those with a variety of neurologic disorders. Specific pathologies are described for individuals with low (<110 pg/mL) or intermediate (110-200 pg/mL) concentrations of hypocretin-1. (Data from ref. 42.)

disseminated encephalomyelitis (51,52), hypothalamic sarcoidosis (53,54) or histiocytosis X, multiple sclerosis (MS) (44,48,55,56), and Parkinson's disease (42,48,57,58). In some cases, lesions of the hypothalamic hypocretin centers have been clearly identified using magnetic resonance imaging, as in bilateral MS plaques in the hypothalamus and tumors of the third ventricle (59-62). Cataplexy may not be present in these cases, and the CSF hypocretin-1 levels may be either in the narcolepsy range (<100 pg/mL) or in the intermediate range (40). The disorders may cause damage to nearby hypocretin projection sites, with adequate preservation of cell bodies to maintain detectable levels, or may be simply coincidental (40).

Genetic disorders such as Niemann-Pick disease type C, Coffin-Lowry syndrome (63-66), and Norrie's disease (67) have been reported to be associated with daytime sleepiness and/or cataplexy. CSF hypocretin-1 has been measured in cases of Neimann-Pick disease type C, and intermediate levels have been found in some cases with comorbid cataplexy

(42,68,69). Some diseases are associated with the development of both narcolepsy and sleep-related breathing disorder, such as myotonic dystrophy and Prader-Willi syndrome (40); in these patients, some but not all have very low CSF hypocretin-1 levels (<110 pg/mL), suggesting hypocretin deficiency (40,42,48,70). Similarly, in one case of late-onset congenital hypoventilation syndrome (a disorder with reported hypothalamic abnormalities), very low CSF hypocretin-1 levels were found in an individual with otherwise unexplained sleepiness and cataplectic-like episodes (42) and who had an excellent response to anticataplectic therapy. CSF hypocretin-1 levels are thus potentially helpful in complex clinical situations in which the history, polysomnography, and/or MSLT data are difficult to interpret (40).

6.4. Indications and Significance of Hypocretin Measurement in Narcolepsy

Hypocretin measurements have been performed in CSF and blood. Plasma levels of hypocretin-1 are very low in comparison with CSF concentrations and are typically similar between control subjects and narcoleptic subjects, even though these two groups have dramatically different CSF concentrations of hypocretin-1 (71-73). These results may suggest that the hypocretin deficiency in narcolepsy is restricted to the central nervous system (CNS). Alternatively, methodological issues pertaining to measuring hypocretin-1 levels in plasma may be involved. Indeed, plasma hypocretin-1 levels are close to the detection limit of the assay, and the signal may be partially masked by the background noise of the assay. CSF hypocretin-1 is measured by direct radioimmunoassay (RIA) and after peptide extraction. Only hypocretin-1 can be detected. Hypocretin-1 levels do not differ significantly by age or sex (74). Normal levels are higher than 200 pg/mL, and decreased (narcolepsy) levels are less than 110 pg/mL. The significance of intermediate (110-200 pg/mL) and high (>500 pg/mL) hypocretin-1 levels is still unclear and needs further investigation.

As lumbar CSF is typically the measured source of hypocretin-1 concentrations, the question arises as to the functional correlation between lumbar CSF concentrations of hypocretin-1 and hypothalamic hypocretin neuron status. Based on studies in narcolepsy-cataplexy, it is clear that undetectable CSF hypocretin-1 reflects a lack of hypocretin in the brain (32,38). In rats, an average loss of 73% of hypocretin neurons, caused by the injection of hypocre-tin-2-saporin into the hypothalamus, produces a 50% decrease in CSF hypocretin levels (75). This result suggests some degree of compensation in cases with partial lesions. As the spinal cord receives robust innervation by hypocretin neurons (76), it is also possible that lumbar CSF concentrations of hypocretin-1 reflect spinal release, rather than cortical levels, of hypocretin-1.

Cisternal CSF concentrations of hypocretin-1 display a robust daily rhythm in nocturnal rodents and diurnal primates (77,78). Concentrations of lumbar CSF in humans also exhibit a diurnal fluctuation, but the fluctuation amplitude is only 6% (79), indicating that sampling lumbar CSF at any time of day is likely to be an accurate diagnostic measure. Lesions of the suprachiasmatic nucleus (SCN), the locus of the mammalian circadian clock, results in a loss of rhythmic CSF hypocretin-1 in rats (98). Importantly, however, the dynamic range of hypocretin is the same in animals lacking their SCN as in controls. Thus, even in individuals with circadian rhythm disturbance, sampling at any time of day should yield diagnostically relevant results.

Sleep deprivation can also alter CSF hypocretin-1 levels. Sleep deprivation has been shown to increase CSF hypocretin in a variety of species, including canines, rats, and monkeys (78,80,81). The effects of sleep deprivation are, however, typically limited to increasing CSF hypocretin concentrations to a peak that is normally observed during wake time, and not above this normal peak. As chronic sleep deprivation is often observed in disorders in which the measurement of CSF hypocretin-l could be useful, it is important to recognize that CSF concentrations are probably slightly elevated, but as the variation in human lumbar CSF is small, it is unlikely to impact the diagnostic value of a lumbar tap.

The CSF hypocretin-l measurement can provide valuable information to aid in the diagnosis and characterization of narcolepsy, especially when presenting as an atypical pattern or in pediatric and secondary forms. Low hypocretin-l concentrations are highly (99%) specific in cases of narcolepsy with atypical cataplexy, but the sensitivity is low (l6%) (42). This indicates, of course, that measurement of CSF hypocretin cannot preclude the clinical and electrophysiological evaluation of the disease as well as HLA subtyping. Evaluation of hypocretin-l levels may also be of critical importance at the onset of the disease, as a measure to evaluate the retardant effect of immunosuppressive treatment (82).

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  • donald
    How to raise hypocretin level?
    2 years ago

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