CSF hypocretin-1 assessment in sleep and neurological disorders

Review

CSF hypocretin-1 assessment in sleep and neurological disorders Patrice Bourgin, Jamie M Zeitzer, Emmanuel Mignot

Concentrations of CSF hypocretin-1 (formerly orexin A) have been measured in many patients with sleep or neurological conditions. Low CSF hypocretin-1 is most predictive of narcolepsy in patients positive for HLA allele DQB1*0602, most of whom have cataplexy. By contrast, the diagnostic significance of low CSF hypocretin-1 is unclear in the presence of acute CNS inflammation or trauma. The clinical usefulness of CSF testing in hypersomnia that is symptomatic of a neurological disorder remains to be evaluated. Determination of CSF hypocretin-1 concentration to diagnose narcolepsy might be most useful in ambulatory patients with cataplexy but with a normal multiple sleep latency test (MSLT) result, or if MSLT is not interpretable, conclusive, or feasible. Because 98% of patients with hypocretin-1 deficiency are positive for HLA DQB1*0602, we suggest that HLA typing is a useful screen before lumbar puncture. Although hypocretin-1 deficiency in narcolepsy might have therapeutic relevance, additional research is needed in this area.

Introduction Narcolepsy, a disabling sleep disorder that affects one in 2000 individuals, is characterised by excessive daytime sleepiness and cataplexy. Narcolepsy, which is closely associated with HLA DQ, is caused by a destruction of hypocretin-producing cells, probably due to an autoimmune process. CSF hypocretin-1 measurements are diagnostic for primary narcolepsy. Low hypocretin-1 concentrations are found in other neurological conditions and suggest a potential role in the assessment of secondary hypersomnias. In this Review, we evaluate the available data on CSF hypocretin-1 concentrations in sleep and neurological disorders to provide guidelines for the use of this test in clinical practice.

Hypocretins and the neurobiology of wakefulness Hypocretins are two hypothalamic neuropeptides (hypocretin-1 and hypocretin-2, also known as orexin A and orexin B) that are the product of the same gene (HCRT),1,2 and are expressed by 50 000–80 000 neurons in the human dorsolateral hypothalamus.3 These neuropeptides are important in the regulation of wakepromoting systems, and loss of hypocretin-containing neurons leads to narcolepsy. Hypocretin neurotransmission is mediated through the activation of two excitatory G-protein-coupled receptors that are highly expressed in monoaminergic cell groups.2 The histaminergic tuberomamillary nucleus and noradrenergic locus coeruleus might be particularly important in mediating the wake-promoting effects of hypocretin.4–6 Hypocretin neurons might also play an essential part in integrating hypothalamic signals, such as those related to appetite, energy homoeostasis, stress, reward, and autonomic and endocrine functions.7,8 Hypocretin excitation of wake-promoting systems is thought to consolidate wakefulness into a single daily episode.7 Loss of hypocretin might lead to a destabilisation of wakefulness and consequently result in the inability to remain awake for extended periods (excessive sleepiness, sleep attacks) and the occurrence of sleep-specific http://neurology.thelancet.com Vol 7 July 2008

phenomena during wake (eg, cataplexy, hallucinations). Of note, the distribution but not the amount of sleep is changed in individuals with narcolepsy.

Narcolepsy and cataplexy Narcolepsy with cataplexy is characterised by excessive daytime sleepiness, disrupted nocturnal sleep, and cataplexy.9,10 Onset can be gradual or abrupt. Onset usually occurs in adolescence, almost always starting with sleepiness and irresistible sleep attacks, followed rapidly by cataplexy within 1–4 years (85% of cases). Cataplexy, the sudden occurrence of muscle atonia triggered by emotions such as laughing or anger, is nearly always pathognomonic.11 Excessive daytime sleepiness is characterised by unpredictable and irresistible sleep attacks against a background of constant sleepiness, and by direct transitions from wakefulness into rapid eye movement (REM) sleep. Other symptoms, such as sleep paralysis (inability to move on awakening), hypnagogic and hypnopompic hallucinations (dream-like events occurring at sleep onset and offset), REM behaviour disorder, and periodic limb movements during sleep are more variable, and are found in approximately 50% of cases. Population-based studies have shown that sleep paralysis and hallucinations are common in the general population and have increased familial occurrence. These symptoms do not correlate with sleep-onset REM periods (SOREMPs) in the general population, but are associated with depression, anxiety, and sleep deprivation.12 Narcolepsy is often diagnosed by use of the multiple sleep latency test (MSLT), in which sleep latency and the presence of SOREMPs are measured over four or five daytime nap opportunities. Short mean sleep latency and at least two SOREMPs during the test are diagnostic of narcolepsy (table 1).13 On the basis of MSLT results and the observation that most patients with, but not without, cataplexy have low CSF hypocretin-1 concentrations, the current classification can be used to distinguish between narcolepsy with and without cataplexy (table 1).14 The biological homogeneity

Lancet Neurol 2008; 7: 649–62 Department of Psychiatry and Behavioral Sciences (P Bourgin MD, J M Zeitner PhD, E Mignot MD), and Department of Biological Sciences (P Bourgin), Stanford University, Stanford, CA, USA; Department of Neurology, School of Medicine, and Laboratory of Rhythms, CNRS UMR 7168/LC2, Louis Pasteur University, Strasbourg, France (P Bourgin); Psychiatry Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA (J M Zeitner); and Howard Hughes Medical Institute, Stanford, CA, USA (E Mignot) Correspondence to: Patrice Bourgin, Laboratoire du Sommeil, Département de Neurologie et UMR 7168/LC2 CNRS, Hôpital Civil, 1 Place de l’Hôpital, F-67091 Strasbourg, France patrice.bourgin@neurochem. u-strasbg.fr

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Review

Excessive daytime somnolence

Cataplexy

Medical or mental disorder accounting for symptoms

Polysomnography

Multiple sleep latency test

Narcolepsy with cataplexy

At least 3 months

Definite history

No

..

Mean sleep latency ≤8 min; ≥2 SOREMPs

Narcolepsy without cataplexy

At least 3 months

None or doubtful; atypical cataplexy

No

..

Mean sleep latency ≤8 min; ≥2 SOREMPs

Idiopathic hypersomnia At least with long sleep time 3 months

Unrefreshing nocturnal sleep of at least 10 h; unrefreshing naps

No, in particular, no sleep disorders causing excessive daytime somnolence

Total sleep time ≥10 h

Mean sleep latency ≤8 min; <2 SOREMPs

Idiopathic hypersomnia At least without long sleep 3 months time

Unrefreshing nocturnal sleep of 6–10 h; unrefreshing naps

No, in particular, no sleep disorders causing excessive daytime somnolence

Total sleep time >6 h and <10 h

Mean sleep latency ≤8 min; <2 SOREMPs

Recurrent hypersomnia*

Episodes lasting 2–28 days

Recurrence at least once or No, in particular, no tumours .. twice a year of the CNS or bipolar disorder

Normal alertness, cognitive functioning, and behaviour between episodes

Secondary narcolepsy

At least 3 months

Possible

Yes

..

Mean sleep latency ≤8 min; ≥2 SOREMPs

Secondary hypersomnia

At least 3 months

None

Yes

..

Mean sleep latency ≤8 min; <2 SOREMPs

*Includes Kleine-Levin syndrome and menstrual-related hypersomnia. SOREMP=sleep-onset rapid-eye-movement period.

Table 1: Diagnostic criteria for narcolepsy and hypersomnia, according to the International Classification of Sleep Disorders18

of narcolepsy with cataplexy is also illustrated by its tight association with HLA DQB1*0602, an allele found in 95% of cases versus 25% of controls.15,16 By contrast, only 40% of cases without cataplexy are HLA DQB1*0602 positive.16 Soon after animal studies linked hypocretin dysfunction with narcolepsy,17,18 testing of this system’s involvement in human pathology was undertaken. Initial findings indicated a dramatic decrease in hypocretin-1 concentrations in patients with narcolepsy versus controls.19 Neuroanatomical studies of post-mortem brains further indicated that the loss of CSF hypocretin-1 was correlated with a loss of hypocretin-expressing neurons, but not with the loss of neighbouring neurons containing melanin-concentrating hormone, in the perifornical area of the hypothalamus.3,20 Limited evidence exists for gliosis in the perifornical area of narcoleptic brains.3,21 Gliosis might be expected, because any autoimmune process leading to neuron destruction would have occurred more than 30 years before autopsy in these cases.

Genetics of hypocretin deficiency A genetic basis for hypocretin deficiency has been found, but only in a single case in which a mutation in HCRT has been observed.20 No other mutations in HCRT or in the genes for the hypocretin receptors (HCRTR1 and HCRTR2) have been reported to be associated with narcolepsy, despite the observation that a mutation in Hcrtr2 in dogs causes the familial form of canine narcolepsy.17 Genetic and pathophysiological studies of narcolepsy are compatible with autoimmune mediation of hypocretin cell destruction. Indeed, hypocretin deficiency and narcolepsy are very closely associated with HLA 650

DQB1*0602.22,23 As in other autoimmune conditions, the HLA association is complex and involves multiple predisposing and protective alleles.15 Low concordance of monozygotic twins (only 25–30%) and adolescent onset are also common in these disorders.24 However, over 10 years of studies have failed to confirm an autoimmune hypothesis,25 suggesting either a very selective and transient process, or another mechanism altogether. Narcolepsy most often occurs sporadically, yet multiplex families have been reported. These familial cases are more likely to be DQB1*0602 negative, as are concordant monozygotic twins.22,23,24 In familial cases, low CSF hypocretin-1 concentration is associated with the presence of HLA DQB1*0602 allele.23,26–28 In the so-called DAN family, a large African–American lineage with HLA-positive and HLA-negative cases, and in the EIC pedigree, a family with only HLA-negative cases, all HLA-negative narcoleptic patients had normal CSF hypocretin-1 concentrations.22,23 These findings suggest that the DQB1*0602 allele could have a major role in conferring low or absent hypocretin neurotransmission. In addition, in the DAN pedigree, normal or intermediate CSF hypocretin-1 concentrations 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 is more weakly associated with the familial form of the disease, and that, in the DAN family, complete hypocretin deficiency could occur more slowly than in most sporadic cases. Furthermore, the observation of increased incidence of HLA negativity in some familial cases with normal hypocretin suggests the existence of a distinct pathophysiological subtype of narcolepsy with increased genetic predisposition. http://neurology.thelancet.com Vol 7 July 2008

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A report of CSF hypocretin-1 measurements in two monozygotic twin pairs further illustrates the complexity of the relation between narcolepsy and low hypocretin concentrations.29 One monozygotic twin pair concordant for narcolepsy with cataplexy and HLA DQB1*0602 positive had normal CSF hypocretin-1 concentrations, suggesting the existence of a genetic form of typical narcolepsy without hypocretin neurotransmitter abnormality.29 It is possible that this concordant twin pair is HLA-positive by chance and pathophysiologically related to other HLA-negative cases. However, another monozygotic twin pair was HLA DQB1*0602 positive and discordant for narcolepsy, with undetectable CSF hypocretin-1 concentrations in the affected twin and

normal concentrations in the unaffected twin, suggesting that environmental factors have a key role in the development of hypocretin deficiency and resulting narcolepsy.30

CSF versus plasma hypocretin-1 The dramatic hypocretin cell loss found in narcolepsy can be assessed clinically by measuring hypocretin-1 concentrations in the CSF.31 In CSF, hypocretin-1 is more stable than hypocretin-2 and is thus easier to measure. Clinically significant concentrations of hypocretin peptides can be measured in brain tissue or CSF, but unfortunately not in blood or other biological fluids. More than 50 studies have reported on plasma “orexin A” concentrations in

700 650 600 550

450 400

100% (9)

92% (37)

59% (41)

250

91% (84)

81% (22)

300

6% (13)

350

8% (3)

10% (7)

1% (1)

150

7% (6)

200 11% (3)

Lumbar CSF hypocretin-1 concentration (pg/mL)

500

31% (22)

50

2% (2)

7% (2)

91% (84)

100

0

HLA–

HLA+ Control

HLA–

HLA+

Narcolepsy with cataplexy

HLA–

HLA+

Narcolepsy without cataplexy

HLA–

HLA+

KLS

OSAS

RLS

Insomnia

Idiopathic hyposomnia

Figure 1: Lumbar CSF hypocretin-1 concentrations in controls versus patients with narcolepsy and other sleep disorders, from an update of the Stanford Center for Narcolepsy Research database Each circle represents the hypocretin-1 concentration as measured in unextracted lumbar CSF of a single individual, derived from Lin et al,22 Mignot et al,23 Bassetti et al,35 and Hong et al.36 Patients are differentiated according to HLA DQB1*0602 status and controls are also included (samples taken during both night and day). Patients are classified according to the International Classification of Sleep Disorders;18 patients without cataplexy are subdivided into cases with atypical cataplexy (triangles) and no cataplexy (squares). Clinical subgroups include narcolepsy with and without cataplexy, idiopathic hypersomnia, periodic hypersomnia (Kleine-Levin syndrome [KLS]), obstructive sleep apnoea syndrome (OSAS), restless legs syndrome (RLS), and insomnia. Secondary narcolepsy/hypersomnia cases are not included. Concentrations are described as low (≤110 pg/mL), intermediate (111–200 pg/mL), or normal (>200 pg/mL). Mean CSF hypocretin-1 concentration was not significantly different between HLA DQB1*0602 positive and negative controls. The percentage and number of patients are specified for each group according to the two CSF hypocretin thresholds.

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various disorders.32 These studies have used commercially available kits that use polyclonal antibodies, but basic experiments on signal specificity have not been done. None of these studies has shown increased extracted concentrations if increasing amounts of plasma are added. Furthermore, in only one instance was high performance liquid chromatography purification of the signal attempted, and this suggested that only part of the signal was genuinely hypocretin-1.32 Studies in patients with narcolepsy and cataplexy have shown either decreased or normal plasma hypocretin-1 concentrations.31 Whether hypocretin can genuinely be measured in blood will only be addressed once assays with improved specificity and sensitivity are available. Preliminary studies in rodents suggest that some of the signal is genuine, although concentrations are significantly higher in narcoleptic rodents than in human beings.32 Uncertainty remains as to whether blood hypocretin concentrations will ever be of diagnostic value because non-neuronal sources of hypocretin might exist and could be unaffected in narcolepsy.

CSF hypocretin-1 in sleep disorders Narcolepsy with and without cataplexy Many studies done in Germany, the UK, Japan, Netherlands, Switzerland, Korea, Spain, and the USA have measured CSF hypocretin-1 in narcolepsy.19,22,23,26–28,33–38 Several hundred patients, independent of concomitant treatments or association with other sleep disorders, have been studied. Overall, approximately 90–95% of randomly selected individuals with narcolepsy and typical cataplexy have low CSF hypocretin-1 concentrations (defined as undetectable or <110 pg/mL). In samples tested at Stanford Center for Narcolepsy (Stanford, CA, USA), a non-random sample enriched in HLA-negative cases, 193 (83%) of 233 cases with cataplexy have low hypocretin-1 concentrations (figure 1). Results are more complex in patients without cataplexy. Only 20% of narcolepsy patients with atypical cataplexy (not triggered by laughter or joking) or no cataplexy have low CSF hypocretin-1 concentrations (figure 1).22,23 Other studies have found similarly low concentrations,27,28,35,36,39 which emphasises the importance of defining cataplexy according to specific criteria.13 Consequently, narcolepsy with cataplexy is now classified as a disease entity that is separate from narcolepsy without cataplexy (table 1).13 Furthermore, patients with atypical cataplexy are defined as “without cataplexy”. Low or undetectable CSF hypocretin-1 concentrations have been detected very early in the course of the disease (1–6 months after clear symptom onset) in patients with cataplexy.23,34,39–42 The observation that only a small number of narcolepsy patients without cataplexy have low CSF hypocretin-1 concentrations corroborates neuropathological data that show a 74% decrease in the number of hypocretincontaining neurons of the hypothalamus in the only narcoleptic patient without cataplexy tested in 652

post-mortem studies.3,20 Narcolepsy without cataplexy might represent a milder form of the disease with partial damage of the hypocretin system and normal or low CSF hypocretin-1 concentrations, especially in HLA-positive individuals.23 Indeed, an alteration of the hypocretin system is still possible in these atypical forms that is not associated with a low hypocretin-1 concentration. For example, some of these cases might result from secondary abnormalities downstream of the hypocretin pathway. Partial lesions of hypocretin neurons might also affect specific projections and lead to sleep abnormalities, without noticeably lowering CSF hypocretin-1.23 All reported hypocretin-deficient individuals,37,39–44 apart from six reported cases worldwide, are HLA DQB1*0602 positive (four in our sample; figure 1), independent of familial predisposition and cataplexy status.21,22,44 On the basis of studies that used randomly selected patients, we estimate that fewer than 1 in 500 HLA-negative patients have low CSF hypocretin-1 concentrations. The finding that almost all HLA-positive cases with cataplexy have hypocretin deficiencies has clinical implications for the diagnosis and treatment of narcolepsy. First, most clinical trials to date have included large proportions of cataplexy cases, and therefore with hypocretin deficiency. Hypocretin-deficient patients are thus likely to react to existing therapies, such as modafinil, anticataplectic antidepressants, and sodium oxybate, in a more predictable way. The possibility that immunoglobulin treatment given at disease onset has a limited efficacy on cataplexy, but not on sleepiness symptoms,42 might be an indication of the complex pathogenesis of narcolepsy without cataplexy. In our experience, many patients without cataplexy (or with atypical cataplexy) might not have a simple pathophysiology. For example, some patients might have a combination of poor sleep hygiene, insufficient sleep, delayed sleep phase (in adolescents), upper airway resistance syndrome or mild sleep apnoea, and psychiatric disorders (eg, depression or conversion disorder). Recent studies in the general population have also shown that 4–10% of the general population display multiple SOREMPs if MSLTs are done systematically.45,46 Multiple SOREMPs were found in men, and correlated weakly with HLA DQB1*0602, habitual shift work, low minimum oxygen saturation (a finding that might reflect sleep apnoea, although no relation was found with the apnoea hypopnoea index), and the use of sedative antidepressants.46 A significant proportion of these individuals did not report daytime sleepiness, suggesting that a positive MSLT occurs without clinical significance, although some might have an HLA-related pathology.

Idiopathic hypersomnia Idiopathic hypersomnia is characterised by excessive daytime sleepiness but with no REM sleep abnormalities on MSLT. Cataplexy is absent. The current classification of sleep disorders distinguishes two entities on the basis of http://neurology.thelancet.com Vol 7 July 2008

Review

normal or excessive total nocturnal and diurnal sleep time (table 1). Idiopathic hypersomnia with long sleep time (≥10 h) is a rare disorder, and is occasionally found in families. Patients not only report severe daytime sleepiness and prolonged sleep, but also experience sleep drunkenness (an inability to wake up after sleep has lasted for hours). However, idiopathic hypersomnia without long sleep time is common, and is typically a diagnosis of exclusion (unexplained daytime sleepiness with short sleep latency on MSLT). As clinical presentation is similar, idiopathic hypersomnia without long sleep time and narcolepsy without cataplexy are thought to form a continuum, especially when naps are refreshing.47 Idiopathic hypersomnia can be as difficult to diagnose as narcolepsy without cataplexy. All idiopathic hypersomnia patients have been found to have normal CSF hypocretin-1 concent rations.23,28,34,35,37 However, some, but not all, of these cases, and a subset of narcolepsy without cataplexy patients, have low CSF histamine and normal hypocretin-1 concentrations.48,49 Histamine release increases with sleep deprivation and decreases during sleep. Thus, different disease entities could be distinguishable on the basis of CSF histamine and hypocretin-1 concentrations.

Secondary narcolepsy References or hypersomnia Absent Immune disorders Multiple sclerosis* Normal

73

0

Intermediate

0

1

76

Low/undetectable

0

2†

38,78

Kleine-Levin syndrome is a rare neurological disorder characterised by relapsing-remitting episodes of hypersomnia in association with cognitive impairment and behavioural abnormalities, such as hypersexuality and megaphagia.50 Onset occurs during adolescence, and often follows a febrile illness, typically associated with influenza-like symptoms. A strong male predominance is found, and familial cases have been reported, with increased predisposition in Ashkenazi Jews.51 An HLA DQB1*02 association has been suggested but not confirmed.51,52 As hypocretins have roles in metabolic and sleep-wake regulation and the hypothalamus is needed to regulate innate behaviours, an abnormality of hypocretin neurotransmission has been proposed in patients with Kleine-Levin syndrome. Normal CSF hypocretin-1 concentrations have been measured in five of six cases.23,28,53,54 However, a two-fold decrease in CSF hypocretin-1 concentrations, although within the normal or intermediate range, has been reported in two patients when symptomatic, suggesting a possible intermittent alteration of hypocretin transmission.28,53,54 Whether this decrease is functionally significant is unknown.

Obstructive sleep apnoea, insomnia, and restless legs syndrome Sleep disordered breathing is a common cause of excessive daytime sleepiness. CSF hypocretin-1 concentrations in obstructive sleep apnoea syndrome and in those with more than two SOREMPs on MSLT are normal in all patients tested (figure 1).23,28,55 Restless legs syndrome is characterised by an urge to move one’s legs in the evening, sometimes with painful http://neurology.thelancet.com Vol 7 July 2008

26,28,77

79

Anti-Ma2 paraneoplastic encephalitis‡ Normal

2

0

Intermediate

0

0

..

Low/undetectable

0

6†

80,81

Guillain-Barré syndrome Normal

27

11

Intermediate

13

0

26,82

8

2

26,82

84–86

Low/undetectable

26,28,82,83

Inherited disorders Niemann-Pick disease type C Normal

2

3

Intermediate

1

4

85–87

Low/undetectable

0

0

..

Myotonic dystrophy Normal

Periodic hypersomnia

Present

19

19

Intermediate

2

4

28,88,89 88,89

Low/undetectable

0

1

88

Degenerative disorders Parkinson’s disease§ Normal

72

13

Intermediate

1

0

28,90–92 91

Low/undetectable

1

1

93

Other degenerative disorders (ie, Alzheimer’s disease, Lewy body dementia, Huntington’s disease) were within the normal range. Lumbar CSF data was derived from the Stanford Center for Narcolepsy database and from selected publications that used similar methods. *Reversibility of symptoms, hypothalamic lesions, and CSF hypocretin-1 concentrations were reported in multiple sclerosis; two additional cases affected with a multiple sclerosis variant, Devic’s neuromyelitis optica, had hypothalamic lesions and low hypocretin-1 concentrations. †Cases associated with hypothalamic lesions. ‡Follow-up of peptide concentrations were not available in anti-Ma2 encephalitis. §Values obtained from ventricular CSF are not included.94 Normal=>200 pg/mL; intermediate=110–200 pg/mL; low/undetectable=≤110 pg/mL.

Table 2: CSF hypocretin-1 concentrations in selected neurological disorders, without and with secondary narcolepsy or hypersomnia

sensations. Sleep onset is delayed, and when sleep occurs, it is typically disturbed by stereotyped, periodic limb movements. Secondary cases are observed in individuals with iron deficiency, peripheral neuropathies, uraemia, and in association with various psychotropic drugs. Genetic factors have recently been isolated,56,57 and suggest a link with developmental genes expressed in the spinal cord and brain.58 The efficiency of levodopa and D2/D3 agonists for the treatment of restless legs syndrome and periodic limb movements suggests the involvement of the dopaminergic system in the pathophysiology of the disease.59 Because hypocretin regulates mesolimbic dopaminergic activity,60,61 it could 653

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CSF hypocretin-1 concentration (pg/mL)

600

200

0 0

20

40 60 Days after disease onset

80

100

Figure 2: CSF hypocretin-1 concentrations in Guillain-Barré syndrome82 Follow-up studies of CSF hypocretin-1 concentrations in Guillain-Barré syndrome show a restoration from low to normal concentrations in some cases. Dotted lines indicate hypocretin-1 concentration thresholds.

be involved in the pathophysiology of the disorder. In one study, slightly increased CSF hypocretin-1 concentrations were found in the evening in early-onset cases.62 Other studies have found normal CSF concentrations.23,63 Very few individuals with insomnia have been studied. In one report, 12 patients with severe, untreated insomnia were studied and all were found to have normal hypocretin-1 concentrations.23 Whether slightly increased or decreased concentrations can be found in patients with and without increased daytime arousal remains to be addressed.

Secondary narcolepsy Cases of secondary or symptomatic narcolepsy are usually defined as those that meet the narcolepsy criteria,13 are associated with a significant underlying neurological disorder that accounts for excessive daytime sleepiness, and show narcoleptic and neurological symptoms within the same temporal frame (table 1). Such cases are rare, and can be with or without cataplexy. An abnormal neurological examination is common, and HLA positivity is not higher than in controls.22 CSF hypocretin-1 concentrations might be low, intermediate, or normal. Causes include hypothalamic lesions, but also various traumatic, vascular, inflammatory, and genetic conditions.64–66 Whereas a low CSF hypocretin-1 concentration has a clear predictive value in the diagnosis of primary narcolepsy, its meaning in secondary narcolepsy is questionable, as detailed below. Even before Van Economo’s description of encephalitis lethargica in 1914 and the potential association of sleepiness in these patients with lesions of the posterior hypothalamic and midbrain areas,64 secondary narcolepsy with cataplexy cases had been reported in 654

association with tumours located close to the floor of the third ventricle.23,65 Brainstem lesions have also been reported in patients with cataplexy,65 which accords with the important role of the pons in regulating REM sleep. Sleepiness and SOREMPs have also been reported in cases with paramedian thalamic stroke.66 CSF hypocretin-1 concentrations have only recently been studied in cases of secondary narcolepsy. As expected, CSF hypocretin-1 was in the normal range in patients with brainstem lesions or paramedian thalamic strokes.67,68 However, patients with hypothalamic damage had lower, but never undetectable, CSF hypocretin-1 concentrations. Scammell and colleagues69 reported narcolepsy symptoms with atypical cataplexy and a CSF hypocretin-1 concentration of 167 pg/mL after a massive hypothalamic stroke. Similarly, after removal of tumours affecting the hypothalamus, CSF hypocretin-1 concentrations were 96 pg/mL and 102 pg/ml in two patients.70,71 Marcus and colleagues72 reported similar concentrations in several children with hypothalamic tumours. Possible explanations include damage to projection sites rather than to cell bodies, or damage to other nearby hypothalamic wake centres, such as the contiguous histaminergic tubermamillary neurons. Interestingly, patients with somnolence after irradiation of the pituitary gland, a not infrequent occurrence,73 have normal CSF hypocretin-1 concentrations.23,74

CSF hypocretin-1 in neurological disorders Immune and inflammatory disorders of the CNS Because narcolepsy with cataplexy is thought to be the consequence of an immune process that targets hypocretin-containing neurons, CSF hypocretin-1 concentrations have been assessed in various neuroimmune disorders, such as multiple sclerosis, acute disseminated encephalomyelitis (ADEM), anti-Ma2 paraneoplastic encephalitis, Rasmussen’s encephalitis, and immune polyneuropathies. Multiple sclerosis has the same HLA haplotype DR2, DQB1*0602 association as narcolepsy.75 Many patients with both long-standing narcolepsy with cataplexy and multiple sclerosis have been reported, most without visible hypothalamic plaques on MRI lesions (in one case with hypothalamic lesions, CSF hypocretin-1 was undetectable).76 These cases probably indicate a chance association, because in patients with HLA-positive multiple sclerosis without narcolepsy, CSF hypocretin-1 concentrations are in the normal range (table 2).26,28,95 Similarly, a patient with both Rasmussen’s encephalitis and HLA-positive narcolepsy has been reported.96 Low CSF hypocretin-1 concentrations have been reported in four patients with a demyelinating disorder and severe hypersomnia (with multiple SOREMPs in one case) who had bilateral hypothalamic lesions on MRI; two patients had multiple sclerosis and two had Devic’s neuromyelitis optica, a variant of multiple http://neurology.thelancet.com Vol 7 July 2008

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750 CSF hypocretin-1 concentration (pg/mL)

sclerosis typically with anti-aquaporin-4 antibodies.38,78,97,98 In three patients, hypersomnia, low CSF hypocretin-1 concentrations, and radiological hypothalamic abnormalities improved after therapy, suggesting reversible inhibition of hypocretin activity. These multiple sclerosis cases were unusual because such hypothalamic lesions are rare (table 2). A similar picture of hypothalamic involvement, hypersomnia, and reversible changes in CSF hypocretin-1 was also reported in four cases of ADEM.99–102 In this context, significant overlaps and differences are increasingly being found in related demyelinating disorders, namely ADEM, multiple sclerosis, and neuromyelitis optica, but systematic CSF hypocretin-1 studies have yet to be done. These results suggest two possible mechanisms of hypocretin abnormalities in demyelinating disorders. First, the association with narcolepsy could be due to chance. These cases typically have cataplexy and narcolepsy that is probably irreversible. Second, acute inflammatory change in the hypothalamic region could lead to hypersomnia and low or undetectable hypocretin-1 concentrations. Whether decreased hypocretin activity is causal for hypersomnia is suggested, but not established, because cases with and without hypersomnia have not been systematically studied. These cases do not have cataplexy. Symptomatic narcolepsy has been reported in 32% of patients with anti-Ma2 encephalitis, a rare paraneoplastic autoimmune condition associated with seminomas and more rarely with other cancers.79–81 Patients with this condition can develop widespread limbic and diencephalic inflammation that can affect the hypothalamus. Some of these patients have cataplexy, low CSF hypocretin-1 concentrations, and MRI evidence of hypothalamic involvement (table 2).79–81 These patients also display sleepiness and hypnagogic hallucinations. However, the condition is rare and difficult to treat. Although symptoms including narcolepsy have been shown to improve with therapies in some cases,81 longitudinal CSF hypocretin-1 studies have not been done. These cases are notable for the presence of cataplexy. Hypocretin concentrations have also been determined in the context of acute immune polyneuropathies— Guillain-Barré syndrome (GBS), Miller-Fisher syndrome, and chronic inflammatory demyelinating polyneuropathy. In the latter disease, reported CSF hypocretin-1 concentrations are normal, except in one case.82 By contrast, a subset of Japanese patients with GBS had undetectable or low CSF hypocretin-1 concentrations and almost half of those with Miller-Fisher syndrome had low hypocretin-1 concentrations.26,82,103 However, this finding was not confirmed in two studies of white patients.28,104 In one study, CSF hypocretin-1 concentrations were lower but within the normal range in patients with hypnagogic-like hallucinations and very disturbed sleep.84 Moreover, all

500

250

0 Acute phase

6-month follow-up

Figure 3: CSF hypocretin-1 concentrations in traumatic brain injury108 Follow-up studies of CSF hypocretin-1 concentrations in traumatic brain injury show a restoration from low to normal concentrations. Values in red are intraventricular CSF values, and are of questionable value. Recovery was also observed in successive lumbar CSF samples. Dotted lines indicate hypocretin-1 concentration thresholds.

GBS patients with hypocretin-ligand deficiency were severely affected, although in one case, CSF concentrations were low before complete disability (table 2).82 In some cases, CSF hypocretin-1 concentration improved after cessation of symptoms (figure 2). Whether decreased CSF hypocretin-1 concentrations are related to high CSF protein or genuine transient inhibition of hypocretin activity, with or without physiological consequences, is unknown. In contrast to multiple sclerosis and ADEM, hypothalamic lesions are not usually observed in GBS.

Traumatic brain injury Sleep disturbances and daytime somnolence, and very rarely cataplexy, are common after traumatic brain injury.105 Low to undetectable CSF hypocretin-1 concentrations have been found in many patients with acute brain trauma or post-CNS haemorrhage.26,106,107 Because adding blood to CSF in vitro does not alter CSF hypocretin-1 concentrations, the possibility of a functional connection has been raised. Baumann and colleagues106 reported abnormally low CSF hypocretin-1 concentrations immediately after traumatic brain injury in approximately 95% of patients with severe-to-moderate brain injury. However, hypocretin-1 concentrations improved to normal in most patients 6 months after traumatic brain injury, suggesting a functional alteration rather than neuronal loss (figure 3).108 Further studies are assessing the prevalence of residual hypersomnia and narcolepsy in correlation with CSF hypocretin-1 concentration and areas of focal damage. A temporary decrease in CSF hypocretin-1 could indicate a decrease in hypocretin tone (eg, if CSF flow dynamics or dilution occurs) and/or contribute to changes in consciousness in patients with traumatic brain injury. 655

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A

B 500 CSF hypocretin-1 (pg/mL)

Number of hypocretin cells

80 000 60 000 40 000 20 000

Hoehn and Yahr stage

C

Control

PD -V

PD -IV

PD -II PD -II I

PD -I

Co nt ro l

0

400 300 200 100 0 0

5

10

15

20

25

Duration of PD (years) Parkinson’s disease

Figure 4: Hypocretin cell pathology and CSF concentrations in Parkinson’s disease Normal CSF hypocretin-1 concentrations do not necessarily indicate normal hypocretin function. Two independent teams identified a hypocretin loss in Parkinson’s disease.130,131 (A) Hypocretin cell loss, expressed according to disease severity at death, was seen in Parkinson’s disease. Adapted with permission from Oxford University Press.131 (B) By contrast, CSF hypocretin-1 concentrations remained normal. Adapted with permission from Elsevier.91 Dotted lines indicate hypocretin-1 concentration thresholds. The clinical stages of Parkinson’s disease indicate disease severity and are based on Hoehn and Yahr criteria.132 (C) Hypocretin cell staining in control and Parkinson’s disease post-mortem human hypothalami (kindly provided by Jerry Siegel, University of California, Los Angeles). Note decreased hypocretin-containing neurons in Parkinson’s disease compared with control.

Genetic disorders and secondary narcolepsy Patients with inherited disorders, including Niemann-Pick disease type C (NPC), myotonic dystrophy, Coffin-Lowry syndrome, Norrie’s disease, and Prader-Willi syndrome, have been reported to show narcolepsy or cataplexy-like symptoms, although these are mainly seen in children.109–111 NPC is an inherited cholesterol metabolic disorder associated with seizures, mental retardation, and hepatosplenomegaly. Patients with NPC do show narcolepsy-like symptoms, including cataplexy,84 although their response to anticataplectic antidepressants is often atypical. CSF hypocretin-1 concentrations are moderately decreased in NPC patients, most notably in cases with abnormal MSLTs and cataplexy (table 2), suggesting a functional effect.23,85–87 However, concentrations observed in NPC are within the range of those observed in many neurological disorders, and thus might not be of clear significance. Myotonic dystrophy type 1 is a multisystem disorder with myotonia, muscle weakness, cataracts, endocrine dysfunction, and intellectual impairment caused by a CTG triplet expansion in the 3Ľ-untranslated region of the DMPK gene on 19q13. It is frequently associated 656

with excessive daytime sleepiness, short sleep latency, and SOREMPs during MSLT, characteristics also observed in narcolepsy. CSF hypocretin-1 concentrations were measured in seven patients and found to be lower than in controls (table 2).28,88 However, a larger study failed to confirm these results.89 Hypocretin-1 concentrations did not correlate clinically with disease severity or duration, or with subjective or objective reports of sleepiness. Because CSF concentrations are often only slightly decreased in some patients, a functional abnormality that causes sleepiness and SOREMPs in myotonic dystrophy type 1 is unlikely to be a common occurrence. Prader-Willi syndrome is a complex genetic disorder characterised by hypotonia, short stature, hypogonadism, mental retardation, behavioural disturbances, and hyperphagia that results in excessive obesity. Intermediate CSF hypocretin-1 concentrations have been reported in a few cases.23,28,112 However, no decrease in the number of hypocretin-containing neurons was observed in post-mortem human adult and infant brains,113 which suggests a lack of involvement of hypocretin in the pathogenesis of the disorder. More generally, this latter result underlies the need for larger studies to determine whether decreased CSF hypocretin-1 remains anecdotal in inherited neurological conditions.

Neurodegenerative disorders Sleep-wake disturbances are common and clinically significant in almost all neurodegenerative disorders.114 Patients affected by Parkinson’s disease, in particular, have fragmented sleep, daytime sleepiness, sudden sleep attacks, SOREMPs, REM sleep behaviour disorder, and hallucinations, all of which are symptoms reminiscent of narcolepsy.115 Similarly, patients with Alzheimer’s disease have excessive daytime sleepiness and insomnia,116,117 whereas patients with Huntington’s disease often have disturbed sleep, with decreased slow-wave sleep.118,119 The possible involvement of the hypocretin system in these pathologies has been explored through CSF and neuropathological studies. In contrast to acute pathological conditions, such as trauma, haemorrhage, or inflammatory CNS disorders (in which decreased CSF hypocretin-1 is found, without evidence for long-term neuronal loss), decreased hypocretin neuronal count has often been reported in the context of normal CSF hypocretin-1 concentrations. In Huntington’s disease, disrupted hypocretin transmission was first suggested through the study of R6/2 mice, a murine model of Huntington’s disease with accelerated disease progression, in which low CSF hypocretin-1 concentrations and decreased hypocretin cell counts were reported.120 Huntington’s disease is an autosomal dominant disorder with impaired motor coordination, caused by a CAG triplet repeat extension in the Huntington’s disease gene (HTT). Huntington’s disease http://neurology.thelancet.com Vol 7 July 2008

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is not associated with hypersomnia, cataplexy, or SOREMPs. Widespread cell loss occurs in Huntington’s disease, including in the hypothalamus.121 A slight (27%) loss of hypocretin neurons was also reported in post-mortem human brains.120 More recent studies have shown that the cell loss is not associated with low CSF hypocretin-1 concentrations,122–125 suggesting some compensation. Indeed, studies in rats have shown that decreased CSF hypocretin occurs only when more than 50% of cells are lost or affected.126,127 Surprisingly, for such a common disorder, few studies have explored hypocretin abnormalities in Alzheimer’s disease. Studies in older rats have suggested a very slight hypocretin cell loss and decreased CSF hypocretin-1 concentrations of unknown significance.128 By contrast, CSF hypocretin-1 concentrations have been shown to be normal in all patients with Alzheimer’s disease,26,28,77,129 although wake fragmentation was correlated with lower CSF hypocretin-1 concentrations in one study.129 Neuropathological studies have not been done. Two recent studies reported significant (50%) hypocretin cell loss in post-mortem hypothalami of patients with Parkinson’s disease, and the presence of Lewy bodies in some hypocretin-producing cells.130,131 In Parkinson’s disease, hypocretin cell loss is 23–62% and correlates with disease severity,131 as measured on the Hoehn and Yahr scale (figure 4).132 However, hypocretin cell loss was not specific, and nearby neurons containing melanin-concentrating hormone were similarly lost (12–74%) in proportion to disease severity.131 Furthermore, almost all studies measuring CSF hypocretin-1 have found normal concentrations in Parkinson’s disease,26,28,90,91,93 even if associated with severe sleepiness,90,92 suggestive of compensation (table 2). Finally, the pathophysiological significance of these two retrospective studies is difficult to assess in the absence of information on sleepiness, sleep-wake architecture, and quality. Fronczek and colleagues130 reported a reduction in ventricular hypocretin concentrations by 25% compared with controls, although not substantial enough to be useful in clinical practice. Another study that measured ventricular concentration found decreased hypocretin concentrations in severely affected patients,94 although a standardised assay was not used. The result is nevertheless intriguing given the similarity of symptoms, including the presence of REM behaviour disorder, a common presymptomatic precursor of Parkinson’s disease. CSF hypocretin-1 concentrations have also been assessed in multiple system atrophy, dementia with Lewy bodies, progressive supranuclear palsy, and corticobasal degeneration.26,28,91,129,133–135 In almost all cases, CSF hypocretin-1 concentrations were normal. The observation of rare cases with low concentrations—for example, in one case with progressive supranuclear palsy or one case with corticobasal degeneration91—are difficult to interpret in the absence of larger studies, and might be incidental. http://neurology.thelancet.com Vol 7 July 2008

Narcolepsy with cataplexy

Narcolepsy without cataplexy

Idiopathic hypersomnia

HLA+

HLA+

HLA+

HLA–

HLA–

HLA–

Hypocretin-1 <110 pg/mL Sensitivity

93%

7%

31%

2%

0%

0%

Specificity

100%

100%

100%

100%

100%

100%

Positive predictive value

100%

100%

100%

100%

..

..

Negative predictive value

56%

70%

27%

39%

67%

59%

Hypocretin-1 <200 pg/mL Sensitivity

94%

19%

41%

9%

0%

8%

Specificity

100%

98%

100%

98%

100%

98%

Positive predictive value

100%

83%

100%

89%

..

75%

Negative predictive value

58%

72%

31%

40%

67%

61%

Sensitivity, specificity, and predictive values were calculated from updated data of the Stanford Center for Narcolepsy Research (figure 1). Data derived from Lin et al,22 Mignot et al,23 Bassetti et al,35 and Hong et al.36

Table 3: Diagnostic value of CSF hypocretin-1 measurement in narcolepsy

Guidelines and cautionary notes Cases of idiopathic hypersomnia, irrespective of sleep time, MSLT results, and HLA positivity, have normal or slightly decreased CSF hypocretin-1 concentrations. However, the use of hypocretin assays is only indicated in narcolepsy. Before using CSF hypocretin-1 testing in clinical practice, one must be aware that results should be interpreted cautiously because of interassay variation (with the commercially available kit). A list of expert laboratories and a detailed protocol has been published.136 All expert laboratories have assessed hypocretin-1 in a large number of CSF samples and shared samples to set up common reference values. Receiver operating curve analysis and subsequent studies have shown the 110 pg/mL cut-off (about a third of mean control values) to be extremely robust. By contrast, plasma analysis and studies of hypocretin in ventricular CSF have not been validated. In the latter case, concentrations can be extremely variable depending on CSF source (ie, lateral vs third ventricle). Current priorities are to establish a widely available non-radioactive CSF hypocretin-1 test and to reliably measure plasma hypocretin-1. In cases with typical cataplexy, the test is rarely needed. Although specificity and sensitivity are high (100% and 93%, respectively; table 3), cataplexy is easily recognisable and current guidelines are sufficient to diagnose narcolepsy.13 We recommend use of this test only if there is suspicion that cataplexy is of psychogenic or malingering origin, after HLA positivity is shown, and if the MSLT is negative or difficult to do (eg, in the presence of psychiatric, pharmacological, or sleep/circadian confounds). Indeed, apart from its definitive biological value, a major advantage of CSF hypocretin-1 testing to diagnose narcolepsy is, unlike the MSLT, its relative insensitivity to psychotropic drugs, associated sleep disorders, sleep deprivation, and circadian timing.31 In all cases, HLA typing should be done first, because 657

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hypocretin deficiency in HLA DQB1*0602-negative patients is rare. Cases without cataplexy or with atypical cataplexy should be defined as without cataplexy.13 Indeed, we found that atypical cataplexy did not predict hypocretin deficiency better than the absence of cataplexy (figure 1). When a patient is HLA positive (40%), a low CSF hypocretin-1 concentration is highly specific (100%), but not sensitive (31%); however, it does define a homogenous group of patients (figure 1). Whether this test is useful depends on whether the MSLT was fully conclusive and whether a positive CSF result will have therapeutic implications. Recent results have shown that a significant portion of the normal population might have a positive MSLT without significant complaints of daytime sleepiness.46 We therefore believe that this test should be reserved for cases with a strong diagnostic suspicion, for example a recent-onset, HLA-positive case with severe daytime sleepiness, vivid dreaming, and irresistible sleep attacks. A slightly different hypocretin-1 cut-off for cases without definite cataplexy is suggested by an increased sensitivity to 41% without change of specificity when a 200 pg/mL cut-off is used (table 3). With or without cataplexy, the main factor in the decision to measure CSF hypocretin-1 should be therapeutic relevance. Indeed, hypocretin deficiency is a life-long abnormality, with social and work consequences, and a defined need for therapeutic intervention. By contrast, the evolution of cases without hypocretin deficiency is not established, and therapy might not be needed on a life-long basis. In this context, aggressive or mild treatment could have positive or negative consequences that vary depending on each patient. This latter point is crucial if treatment is to be used for decades with drugs such as sodium oxybate or amphetamine, which have substantial side-effects, versus the use of low doses of a mild stimulant (ie, modafinil). A young child with significant school difficulties and rapid weight gain might, for example, need more aggressive treatment and a more definitive diagnosis than an individual with mild sleepiness and a positive MSLT. A future priority in clinical research should be to assess therapeutic response in patients with and without hypocretin deficiency. This might be important in recent-onset cases in whom some investigators, but not others, have suggested efficacy of intravenous immunoglobulin in reducing progression of symptoms. Identification of patients with low hypocretin-1 concentrations might also have therapeutic implications if alternative therapeutic options such as hypocretin receptor agonists or gene therapy are developed in the future. However, there is suspicion regarding the diagnostic value of measuring CSF hypocretin-1 in acutely ill patients. In various acute inflammatory disorders affecting the CNS or immediately after severe brain injuries, CSF hypocretin-1 might be temporarily decreased, often in the pathological narcolepsy range. 658

Whether decreased hypocretin-1 in these cases is associated with sleepiness and always reflects decreased hypocretin tone (as opposed to CSF dilution) is unclear. Immune or inflammatory substances could be released during these disorders, acting to shut off hypocretin cell activity—a mechanism that could contribute to decreased metabolism, reduced consciousness, sleepiness, and recovery. Potential candidates for such substances abound, and could include cytokines or, more probably, simple changes in external milieu. For example, increased extracellular glucose or acidosis has been shown to inhibit hypocretin activity in vitro.137,138 Thus, we could speculate that any brain barrier lesion might result in increased glucose or other changes that could inhibit hypocretin tone (and the activity of other neurons). In favour of this hypothesis, low ventricular CSF hypocretin-1 concentrations have been found to correlate with increased CSF glucose in a retrospective study of acutely ill patients.139 Such a hypothesis could also explain low concentrations in GBS, in which the blood–brain barrier is highly disrupted, or in selected infectious diseases, as seen in a patient with Whipple’s disease and insomnia.140 This hypothesis could also explain the lack of cataplexy in neurological disorders associated with low hypocretin-1 concentrations. Indeed, contrary to narcoleptic patients with low hypocretin, those affected with neurological disorders and hypocretin deficiency do not often have cataplexy, indicating the need for further research aimed at deciphering this discrepancy. The use of this test for prognosis and follow-up thus remains to be determined. Variations in CSF concentrations in long-standing neurodegenerative disorders or in the presence of an old neurological lesion and an intact blood–brain barrier might be biologically significant, although a positive finding (CSF ≤110 pg/mL) is extremely rare. This is best illustrated in Parkinson’s disease, in which partial cell loss occurs, but lumbar CSF concentrations are in the normal range (figure 4). In these cases, a low CSF hypocretin-1 concentration would probably be meaningful, indicating either exceptional cases with extreme secondary hypocretin cell loss or a coincident HLA-positive primary narcolepsy in association with a common neurodegenerative disorder. Whether functional alterations of hypocretin transmission that lead to symptoms could occur in the context of normal CSF hypocretin-1 concentrations is unknown; this might be possible, for example, in a subpopulation in which selected projection fields to monoaminergic neurons are affected, with sparing of spinal projections. Further neuropathological studies in Parkinson’s disease and narcolepsy without cataplexy will be needed to answer these questions. Alternatively, imaging studies of hypocretin neurons or other biological tests such as plasma measurements will need to be established and shown to have biological and clinical relevance. If effective, these techniques will be more useful than CSF hypocretin-1 assessment. http://neurology.thelancet.com Vol 7 July 2008

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Search strategy and selection criteria References were identified by use of PubMed with the following search terms: [“(hypocretin OR orexin)”] AND [“neurological disorder,” “sleep disorder,” “narcolepsy,” or “cataplexy”]. The date range of the publications searched was 1998 (discovery of the hypocretin/orexin system) to April, 2008. The search was repeated with the names of all specific neurological conditions mentioned herein. Articles were also identified through searches of the authors’ own files and reference books. Only papers published in English were used.

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12

Conclusions The discovery of hypocretin deficiency in narcolepsy is redefining the clinical entity of narcolepsy and offering novel diagnostic procedures. Studies of histaminergic transmission in hypersomnia cases without cataplexy are continuing and might offer additional subtyping. Several other diseases have been found to be associated with decreased CSF hypocretin-1 concentrations, although the importance and interpretation of these findings remains controversial. We have discussed the meaning of hypocretin deficiency in sleep and neurological disorders and have proposed guidelines for the clinical use of CSF hypocretin-1 concentration as a measure of hypocretin dysfunction.

13

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Contributors PB and EM conceptualised and wrote this Review. PB did the literature search and produced the tables. JMZ produced the figures and contributed to the writing and editing of the Review.

19

Conflicts of interest EM is one of seven inventors in a submitted patent on the use of hypocretin-1 measurements for the diagnosis of narcolepsy. JMZ and PB have no conflicts of interest.

21

Acknowledgments We are grateful to Christian Baumann for providing us with his published data on hypocretin measurements in traumatic brain injury, which allowed us to recalculate the values according to the CSF hypocretin 110 pg/mL and 200 pg/mL cut-offs in figure 3. Jerome Siegel kindly provided us with pictures of hypocretin staining in brain sections of Parkinson’s disease and control post-mortem human brains. Research was supported by grants from the American Sleep Medicine Foundation (grant #31-CA-05) to PB, from US National Institutes of Health (grant 23724) to EM, and from US Department of Veterans Affairs Mental Illness Research, Education, and Clinical Centers to JMZ. References 1 de Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 1998; 95: 322–27. 2 Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92: 573–85. 3 Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000; 27: 469–74. 4 Eriksson KS, Sergeeva O, Brown RE, Haas HL. Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. J Neurosci 2001; 21: 9273–79. 5 Korotkova TM, Sergeeva OA, Eriksson KS, Haas HL, Brown RE. Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci 2003; 23: 7–11.

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