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The Role of Cerebrospinal Fluid Hypocretin Measurement in the Diagnosis of Narcolepsy and Other Hypersomnias
Emmanuel Mignot, MD, PhD;
Gert Jan Lammers, MD, PhD;
Beth Ripley, MS;
Michele Okun, MA;
Sonia Nevsimalova, MD, PhD;
Sebastiaan Overeem, MS;
Jitka Vankova, MD;
Jed Black, MD;
John Harsh, PhD;
Claudio Bassetti, MD;
Harald Schrader, MD;
Seiji Nishino, MD, PhD
Arch Neurol. 2002;59:1553-1562.
ABSTRACT
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Context Narcolepsy, a neurological disorder affecting 1 in 2000 individuals,
is associated with HLA-DQB1*0602 and low cerebrospinal fluid (CSF) hypocretin
(orexin) levels.
Objectives To delineate the spectrum of the hypocretin deficiency syndrome and
to establish CSF hypocretin-1 measurements as a diagnostic tool for narcolepsy.
Design 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.
Setting Sleep disorder and neurology clinics in the United States and Europe,
with biological testing performed at Stanford University, Stanford, Calif.
Participants 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).
Intervention 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.
Main Outcome Measures Diagnostic threshold for CSF hypocretin-1, HLA-DQB1*0602 positivity,
and clinical and polysomnographic features.
Results 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.
Conclusions 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).
INTRODUCTION
NARCOLEPSY IS characterized by sleepiness and abnormal rapid eye movement
(REM) sleep events such as cataplexy, hypnagogic hallucinations, and sleep
paralysis.1-3 Prevalence
is in 0.02% to 0.05% of the population,4-5
with onset generally occuring in adolescence.1-3
Quality of life is as impaired as in epilepsy or depression.6
Most cases are sporadic, but twin and family studies demonstrate the existence
of genetic factors.1, 5 Current
treatment involves psychostimulants for sleepiness and antidepressants for
cataplexy.2, 7  -Hydroxybutyrate
is used to consolidate nocturnal sleep and reduce cataplexy.2, 7-8
In the International Classification of Sleep Disorders (ICSD),9 narcolepsy is defined by sleepiness plus cataplexy,
or bythe polysomnographic documentation of REM sleep abnormalities. The most
commonly accepted diagnostic test is the multiple sleep latency test (MSLT),10 in which nocturnal polysomnography is performed,
followed by 4 to 5 daytime naps during which sleep latency is measured.9-12 Untreated
patients display short mean sleep latency (MSL) ( 5 or 8 minutes) and
2 or more sleep onset REM periods (SOREMPs).9-12
Using the polysomnographic definition, narcolepsy contrasts with idiopathic
hypersomnia, which is a condition characterized by extended sleep time, no
REM-related symptoms, and a short MSL without SOREMPs.9, 13
The nosology of narcolepsy is controversial. First, narcolepsy can be
diagnosed by patient history alone.9 This may
not always be accurate, as cataplexy overlaps with experiences reported by
healthy subjects.4, 14 Second,
up to 15% of typical narcoleptic patients test negative on the MSLT.11-12 Third, controls and patients with
other sleep disorders may have short MSL and multiple SOREMPs.11
Finally, sleep paralysis and hypnagogic hallucinations are common in the general
population.15-16 The greatest
difficulty is distinguishing narcolepsy without cataplexy from idiopathic
hypersomnia. A definition based on the presence (narcolepsy without cataplexy)
or absence (idiopathic hypersomnia) of 2 SOREMPs on the MSLT is usually adopted,9-11 but some investigators
suggest a continuum between these entities.17-18
The observation that narcolepsy was associated with HLA-DR2 was the
first suggestion of etiological homogeneity in narcolepsy.19
Recent studies have shown that HLA-DQB1*0602 is the main susceptibility allele.20-22 However, 12% to 38%
of controls are DQB1*0602 positive.22 Clinical
and HLA typing studies have identified cataplexy as the most specific symptom,
with probable disease heterogeneity in patients without cataplexy.17, 21 HLA-DQB1*0602 positivity is 90% to
100% in patients with definite cataplexy, but it decreases with atypical cataplexy
or no cataplexy (40%).3, 21 Even
in cataplectic patients, substantial differences in HLA association exist
(70%-100%), suggesting that cataplexy may be overdiagnosed.3, 21
The pathophysiology of narcolepsy involves abnormal hypocretin (orexin)
neurotransmission. In a canine model, the disorder is caused by hypocretin
receptor-2 mutations.23 Preprohypocretin (the
precursor to 2 peptides: hypocretin-1 and hypocretin-2) knockout mice have
narcolepsy.24 Human narcolepsy is generally
not due to gene mutations, but hypocretin neurotransmission is impaired. The
condition is associated with undetectable and, more rarely, elevated hypocretin-1
levels in the cerebrospinal fluid (CSF).25-28
A selective loss of hypocretin messenger RNA (mRNA) and immunoreactivity has
also been reported in the hypothalamus of 6 patients.29-30
Together with the HLA association, these results suggest that most human cases
are caused by an autoimmune-mediated destruction of hypocretin neurons.
The hypocretins were originally believed to be regulators of appetite.31-32 Despite their discrete location in
the lateral and perifornical hypothalamus, hypocretin neurons project widely
throughout the brain, including dense excitatory projections to monoaminergic
cell groups.33 Hypocretin neurons are therefore
uniquely positioned to drive monoaminergic activity across the sleep cycle.34-37 Loss
of this excitatory input may explain the abnormalities seen in narcolepsy.35-36 The hypocretins may also link energy
metabolism and sleep.36-39
In this study, we describe the spectrum of the hypocretin deficiency
syndrome by analysis of CSF hypocretin-1 levels, and clinical, polysomnographic,
and HLA data in more than 250 patients with various sleep disorders. This
is the first study to offer definitive information on the use of CSF hypocretin-1
measurement for the diagnosis of narcolepsy.
SUBJECTS AND METHODS
SUBJECTS
This was a prospective study. Table
1 presents categories and inclusion criteria. Patients and controls
gave informed consent for the study, and lumbar puncture and venopuncture
(for HLA typing) were performed. Patients with a sleep disorder (and their
relatives, when applicable) were identified at Stanford University (Stanford,
Calif; n = 148), Leiden University Medical Center (Leiden, the Netherlands;
n = 66), Charles University (Prague, Czech Republic; n = 23), Zürich
University Hospital (Zürich, Switzerland; n = 21), University of Southern
Mississippi (Hattiesburg; n = 13), and Trondheim University Hospital (Trondheim,
Norway; n = 2). Five patients were contributed by Dr Rye (Emory University
School of Medicine, Atlanta, Ga). One case with central hypoventilation syndrome
and possible narcolepsy was referred by Dr Halbower (John Hopkins University,
Baltimore, Md).
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Table 1. Definition of Diagnostic Categories and Demographic Data of
the Sample Under Study*
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Unrelated controls were healthy subjects without a known sleep disorder
(n = 64) recruited at Stanford University (n = 43), Charles University (n
= 13), and Leiden University Medical Center (n = 8). Patients with various
neurological disorders undergoing a lumbar puncture (n = 228) were also included.
These included 16 new patients recruited at St Charles (n = 12) and Emory
(n = 4), plus 212 previously described patients.27
Sleep disorders were diagnosed clinically and using sleep studies. Patients
were classified based on their primary ICSD diagnosis, blind of HLA and hypocretin-1
results. Seventeen controls had their lumbar puncture during nighttime. All
others were studied during daytime (Table
1). This study includes 212 controls with various neurological disorders,
15 healthy controls, 22 hypersomnia patients, and 43 narcolepsy-cataplexy
patients previously reported.25-27,40-41
Patient ethnicity was 88% white (Europeans and North Americans), 7% Asian
(Chinese, Japanese, and Korean Americans), 2% Black (African Americans), and
3% Latino and mixed.
In narcolepsy, the existence of "definite" cataplexy vs "atypical or
doubtful" cataplexy was confirmed using interviews and a validated inventory.14 Most subjects were treated with amphetaminelike stimulants,
modafinil, antidepressants, and -hydroxybutyrate (Table 1). An effort was made to include patients with unusual forms
of narcolepsy, 27 subjects from 9 multiplex families (4 with HLA-negative
cases), and 7 HLA-DQB1*0602–negative patients with cataplexy.
Idiopathic hypersomnia was diagnosed by ICSD citeria.9
Most patients (83%) had typical (MSL <10 minutes, 0-1 SOREMP) MSLT (MSL
± SE = 7.1 ± 0.7 minutes; mean ± SE SOREMPs = 0.07 ±
0.05). Patients with periodic hypersomnia (n = 3) all had more than 6 previous
episodes (by ICSD criteria9; 2 untreated, 1
treated with modafinil). Those with obstructive sleep apnea (OSA) had a respiratory
disturbance index of 10 episodes per hour (73% treated with continuous pressure
airway pressure therapy). Subjects with severe restless legs syndrome met
international criteria9, 42; all
but 4 were taking dopaminergic medications. Twelve untreated patients with
psychophysiological insomnia9 were studied.
Eighteen patients had secondary hypersomnia or cataplexy. All but 3 had short
MSL on the MSLT (MSL ± SE = 6.4 ± 0.8 minutes; mean ±
SE SOREMPs, 0.38 ± 0.36; n = 18). We also included 7 subjects with
reports of hypersomnia but without confirmatory sleep testing.
HLA TYPING AND CSF EVALUATION
HLA-DQB1*0602 was identified as previously described.22
Cerebrospinal fluid was frozen immediately and stored until radioimmunoassays
(Phoenix Pharmaceuticals, Mountain View, Calif) were conducted. We measured
hypocretin-1 both in reconstituted aliquots from 1 mL of extracted CSF25-26 and directly using 100 µL of
nonextracted CSF.27 The detection limits of
the extracted and direct assay were 40 pg/mL and 100 pg/mL, respectively.
A standard CSF sample was used to correct for interassay variation.
STATISTICAL ANALYSIS
Analyses were performed using SYSTAT 10.0 (SPSS Inc, Chicago, Ill).
Linear or logistic regression modeling was used to assess significance (P .05), controlling for confounding factors such as
sex, age, and ethnicity. Bonferroni corrections were used where applicable.
Ranked data were used for hypocretin-1 analysis. Simple correlations were
computed using Pearson correlations. Finally, for signal detection analysis,
we used quality receiver operating characteristic curves (QROC) to determine
hypocretin-1 values giving the best diagnostic sensitivity/specificity ratios
(patients with ICSD-defined narcolepsy vs all other subject samples, and healthy
controls vs all other subject samples).43
RESULTS
CLINICAL SAMPLE AND HLA TYPING
Age, sex, and ethnicity did not differ across groups (Table 1). Higher body mass index (BMI; calculated as weight in kilograms
divided by the square of height in meters) was observed in patients with OSA,
narcolepsy-cataplexy, atypical or doubtful cataplexy, and idiopathic hypersomnia
(Table 2). When compared with
controls (18% of 64 subjects), the highest DQB1*0602 values were observed
in patients with narcolepsy-cataplexy (93%; odds ratio [OR] = 80; P<.001), followed by those with narcolepsy without cataplexy (56%;
OR = 7.0; P<.01), patients with idiopathic hypersomnia
(52%; OR = 6.0; P<.01), narcolepsy family members
(P<.01), and patients with atypical cataplexy
(35%; OR = 3.3; P = .05).
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Table 2. Biological Data of the Sample Under Study*
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CSF HYPOCRETIN-1 IN CONTROL SUBJECTS AT VARIOUS CIRCADIAN TIMES
Age, sex, ethnicity, HLA-DQB1*0602, BMI, and time of day did not affect
hypocretin-1 levels in healthy controls (Table 2). This confirms data from healthy volunteers using intrathecal
catheters in whom lumbar CSF levels were only slightly (15%) higher at night
(E.M. and Ron Salomon, MD, unpublished data, 2002).
DEFINING HYPOCRETIN DEFICIENCY
Directly measured and extracted hypocretin-1 levels were highly correlated
throughout the entire sample (r = 0.86, P<.001). Levels were lower in patients with narcolepsy with typical
cataplexy, in subjects with atypical cataplexy, and in subjects with neurological
disorders (Table 2). A QROC analysis43 was used to determine hypocretin-1 values "diagnostic"
for ICSD-defined narcolepsy. An identical hypocretin-1 threshold of 110 pg/mL
was obtained for the direct (sensitivity = 60%, specificity = 98%, predictive
value for a positive test [PVP] = 94%, predictive value for a negative test
[PVN] = 84%; n = 570) and extracted (sensitivity = 60%, specificity = 98%,
PVP = 98%, PVN = 83%; n = 379) assays. The QROC analysis indicated a threshold
of 200 pg/mL and 150 pg/mL for the direct and extracted assays, respectively,
of healthy subjects.
The simplicity and accuracy of the direct assay makes it more attractive
for future use; we therefore used direct CSF results in all further analyses.
Subjects were classified as having low (110 pg/mL; n = 113), intermediate
(>110 pg/mL, 200 pg/mL; n = 40), and normal hypocretin-1 levels (>200
pg/mL; n = 417). Of note, we did not confirm our finding of high hypocretin-1
(extracted >500 pg/mL) values in narcolepsy.25-26
In this extended series, high values were also observed in nonnarcoleptic
subjects.
GROUPS WITH LOW HYPOCRETIN-1 LEVELS
Using the 110-pg/mL threshold, 106 of 113 patients with low levels were
patients with ICSD-defined narcolepsy (Figure
1). Three subjects had "secondary hypersomnia/narcolepsy" (Table 3). Four subjects had a neurological
disorder (Figure 1); 3 had acute
Guillain-Barré syndrome, and their cases have been reported27; one was a 38-year-old man with a subacute history
of change in behavior who became comatose. He was later diagnosed with Hashimoto
thyroiditis.
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Figure 1. Cerebrospinal fluid hypocretin-1
levels (direct assay) across various disease categories. Each dot represents
a single patient. Diagnostic categories are as detailed in Table 1. Hypocretin-1 values of 110 pg/mL or less were determined
as the best cutoff point to diagnose International Classification of Sleep
Disorders–defined narcolepsy. A second cutoff point of 200 pg/mL best
determines healthy control values. The number of subjects with hypocretin
values below or equal to 110 pg/mL, above 200 pg/mL, and between these 2 values
is indicated for each category.
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Table 3. CSF Hypocretin-1 Levels in 18 Secondary Narcolepsy or Hypersomnia
Cases*
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GROUPS WITH NORMAL HYPOCRETIN-1 LEVELS
Several groups had mostly normal levels (Figure 1). These included patients with idiopathic hypersomnia (all
but one with intermediate levels), OSA, restless leg syndrome, and insomnia.
Interestingly, 2 patients with OSA and normal levels had residual sleepiness
despite successful continuous pressure airway pressure therapy therapy (1
HLA-negative patient, MSLT SL = 3.9, 1 SOREMP; 1 HLA-positive patient, MSLT
SL = 8.0, no SOREMP).
GROUPS WITH INTERMEDIATE HYPOCRETIN-1 LEVELS
Only 10 subjects in our sleep disorder series had intermediate levels
(Figure 1 and Figure 2). Three also had intermediate levels using the extracted
assay (150 pg/mL) and are most likely to have partial hypocretin deficiency.
The first patient was HLA positive with periodic hypersomnia in the midst
of an episode. The second had idiopathic hypersomnia and was the son of a
patient with narcolepsy-cataplexy (Figure
2, "VER" family); this subject had sleepiness, hypnagogic hallucinations,
and sleep paralysis, but a negative MSLT (MSL = 9 minutes, 0 SOREMP). The
third is HLA positive with a 9-year history of narcolepsy-cataplexy, sleep
paralysis, and hypnagogic hallucinations (MSLT was atypical, with an MSL of
5.4 minutes, but no SOREMP). The other 7 subjects included 5 subjects with
narcolepsy-cataplexy (3 HLA negative, 2 with atypical cataplexy), 1 with idiopathic
hypersomnia, and 1 with hypersomnia undocumented by polysomnography.
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Figure 2. Cerebrospinal fluid hypocretin-1
levels in familial cases of narcolepsy. Black circles indicate narcolepsy
(International Classsification of Sleep Disorders defined); gray circles,
idiopathic hypersomnia; others are healthy relatives. Asterisks indicate a
proband. Note that all HLA-negative narcolepsy cases in these families have
normal hypocretin-1 levels (>200 pg/mL). The "DAN" lineage is African American,
while all others are white. Interestingly, we also found that in multiplex
families with several HLA-positive cases, probands may have low hypocretin-1
levels, while other, younger HLA-positive patients, have normal or decreased
levels ("DAN" and "VER" families). CP+ indicates typical cataplexy; CP±,
doubtful/possible cataplexy; CP-,no cataplexy; HLA+, presence or HLA-,
absence of the DQB1*0602 allele; MSLT+, MSL 8 minutes or  2 SOREMPs;
and MSLT-, inconclusive. Age in years (age of onset of narcolepsy) is
also listed for each patient.
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Thirty of 228 subjects in our neurological disorder survey had intermediate
levels. These previoulsy described patients27
included subjects with head trauma, encephalitis, and Guillain-Barré
syndrome. None of the 74 healthy controls had intermediate levels.
LOW HYPOCRETIN-1 LEVELS IN NARCOLEPSY
Table 4 compares clinical
data in narcoleptic patients with (n = 106) and without (n = 65) low CSF hypocretin-1
levels. Note that these subjects do not represent a random sample of narcoleptic
patients, and include a higher number of subjects without cataplexy and/or
HLA-DQB1*0602. We found that subjects with low hypocretin-1 levels had more
typical cataplexy, more abnormal MSLTs, and were more frequently HLA positive.
Other characteristics were generally similar. Typical cataplexy was a better
predictor of a low hypocretin-1 level than abnormal MSLT. Of the 90 subjects
with low hypocretin-1 levels and available MSLT, 77 (86%) had abnormal MSLT,
but 11 (12%) had borderline MSLT (SL<8 minutes, 0-1 SOREMPs vs SL>8 minutes,
1 SOREMP), and 2 (2%) had normal MSLT (SL>10 minutes, no SOREMPs). This contrasts
with the highly predictive value of cataplexy. Of the 106 narcoleptic subjects
with low levels, 97 (92%) had typical cataplexy, 6 (6%) had atypical/doubtful
cataplexy, and only 3 (3%) had no cataplexy. We explored the value of low
hypocretin levels in narcoleptic patents solely selected on the basis of typical
cataplexy (Table 1). The sensitivity
and specificity of low hypocretin-1 levels in 101 randomly selected patients
with typical cataplexy vs 292 controls was extremely high (87% and 99%, respectively
[PVP = 96%, PVN = 96%]). Of note, in 3 subjects with cataplexy and low CSF
levels, disease duration was 6 months, 8 months, and 9 months, respectively,
but levels were below the detection limit in both assays.
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Table 4. Demographic and Clinical Data of ICSD Narcoleptic Subjects
With Low and Normal Hypocretin-1 Levels*
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NARCOLEPSY WITHOUT CATAPLEXY AND LOW HYPOCRETIN-1 LEVELS
All 3 subjects without cataplexy who had low hypocretin-1 levels were
HLA positive. Two patients with low but detectable hypocretin-1 levels (eg,
>40 pg/mL and 110 pg/mL in the extracted assay) were young narcoleptic
subjects (16 and 25 years old, respectively). One case, that of a 16-year-old
girl (direct assay = 63 pg/mL; extracted assay = 98 pg/mL), was somewhat atypical;
she had narcolepsy without cataplexy following an undetermined viral illness
and generalized lymphadenopathy. Remarkably, in the case of a 58-year-old
patient with a 45-year history of narcolepsy, there were mild hypnagogic hallucinations
and no sleep paralysis. This thoroughly interviewed patient had undetectable
levels using both assays in samples from 2 lumbar punctures.
HLA-NEGATIVE NARCOLEPSY WITH LOW HYPOCRETIN-1 LEVELS
Only 3 narcolepsy subjects with low levels were HLA-DQB1*0602 negative.
One subject had a previously reported preprohypocretin gene mutation (included
because of HLA negativity and unusually early onset at 6 months).29 The second subject had mild cataplexy, no ancillary
symptoms, and a positive MSLT (undetectable levels using both assays in 2
independent lumbar punctures). Onset was unremarkable at 11 years of age,
but hypocretin mutation screening was negative (data not shown). The third
had mild/atypical cataplexy, no ancillary symptoms, and MSLT indicating borderline
sleepiness (MSL = 10.6 minutes, 1 SOREMP).
FAMILIAL CASES
Nine multiplex families were studied (Figure 2). The results correlated with HLA typing. In 2 families
with cataplexy and abnormal MSLT cases (the "EIC" and "RIC" families, respectively),
hypocretin-1 levels were normal. One family ("TER") included an HLA-negative
subject with normal levels, typical cataplexy, multiple SOREMPs, but no subjective
sleepiness. Of special interest was the study of the "DAN" family, a large
African American lineage with 7 affected subjects, 6 of whom reported typical
cataplexy. The 3 eldest subjects with narcolepsy-cataplexy were hypocretin-deficient,
while the other 4, generally younger, had normal CSF hypocretin-1 levels (Figure 2).
NORMAL HYPOCRETIN-1 LEVELS IN NARCOLEPSY
Data from these subjects (n = 65) are reported in Table 4. These subjects were younger and without (26%) or with (35%)
atypical or doubtful cataplexy. Most were HLA negative (66%), and many had
a family history of illness (26%). Importantly, these patients did not have
recent disease onset, making it unlikely that they will develop cataplexy.
Delays between onset and hypocretin-1 measurements were similar in subjects
with low and normal levels.
HYPOCRETIN-1 IN SECONDARY HYPERSOMNIA/CATAPLEXY
Eighteen subjects were studied (Table
3, Figure 1). Three had
low hypocretin-1 levels — a child with central hypoventilation syndrome
and narcolepsylike symptoms, a patient with a probable hypothalamic pathological
illness, and a patient with Prader-Willi syndrome. Notably, a subject with
Niemann-Pick disease type C and severe cataplexy had normal levels.
COMMENT
In this large study, low CSF hypocretin-1 levels were consistently observed
in those with narcolepsy-cataplexy. Two approaches were used — a direct
radioimmunoassay and measurements after extraction. Both techniques were reliable
and highly correlated. A cut-off of 110 pg/mL (representing 30% of the normal
mean value in the direct assay) was determined to have the best sensitivity/specificity
ratio. Since the direct assay is more cost effective and less labor intensive,
we propose using this test for diagnostic purposes. All subjects with a sleep
disorder who tested positive by this criteria had narcolepsy (Figure 1). Importantly, a subset of patients without positive MSLT,
without the classic HLA marker, and/or without cataplexy also tested positive.
We found that 3 subjects with secondary hypersomnia (Table 3) had levels below 110 pg/mL, indicating the existence of
genuine cases of secondary hypocretin deficiency. This extends on 3 previously
reported cases with secondary narcolepsy-cataplexy—one with autosomal
dominant cerebellar ataxia, deafness, and the other 2 with large vascular
and tumoral hypothalamic lesions.44-46
Of note, the new cases reported in this study may also have included impaired
hypothalamic function. Prader-Willi syndrome, a syndrome characterized by
obesity, hypotonia, and daytime sleepiness (not always explained by OSA),
has long been suspected to involve hypothalamic abnormalities.47-49
Similarly, late-onset central hypoventilation syndrome is often associated
with hypothalamic dysfunction.50 These cases
illustrate the value of the CSF test in patients otherwise difficult to diagnose.
This series was also used to describe the clinical spectrum of the narcolepsy
with hypocretin deficiency syndrome (Table
4). Almost all subjects with low levels were HLA-DQB1*0602 positive
with typical cataplexy. Eighty-five percent had positive MSLT, while 63% reported
sleep paralysis, and 86% reported hypnagogic hallucinations. These subjects
also had moderately increased BMI (Table
2), as previously reported in humans2-3,38-39
and mice with hypocretin cell loss.51 Some
patients had recent onset of narcolepsy (eg, 6 months), indicating that hypocretin
deficiency is already established at presentation.
As a diagnostic test, CSF hypocretin-1 measurements could complement
and even replace the MSLT in some instances. In cases of definite cataplexy,
specificity (99%), and sensitivity (87%) for the CSF test are extremely high.
Multiple sleep latency test data in large control samples are unavailable,
and the MSLT is influenced by drugs and other sleep disorders. Moreover, 16%
of hypocretin-deficient narcoleptic patients did not test positive on the
MSLT (Table 4). In contrast, we
found that only 4 of 292 controls (all with neurological disorders) had low
hypocretin-1 levels. Three had quadriplegic Guillain-Barré syndrome.27 In 1 case, levels increased after recovery, suggesting
transitory changes. The fourth subject had myxedema coma secondary to Hashimoto
thyroiditis. These severe neurological problems are unlikely to be confused
for narcolepsy. Interestingly, both Guillain-Barré syndrome and Hashimoto's
thyroiditis occur secondary to autoimmune attacks, which is the proposed cause
of narcolepsy. Hypocretin-1 levels were not significantly influenced by the
use of psychotropic medications (antidepressants, dopamine agonists, hypnotics,
stimulant compounds) or by the presence of other sleep disorders. Hypocretin-1
testing may therefore be most useful in cataplectic patients in whom treatment
has been initiated, and/or when other sleep disorders may confound the MSLT
(eg, insufficient sleep, OSA).
The MSLT remains the test of choice in patients without cataplexy since
very few subjects (n = 3) in this category had low CSF hypocretin-1 levels.
A similar result was recently reported in another study.28
Another limitation of the CSF test is the occurrence of post–lumbar
puncture headaches in 5% to 10% of the cases. Lumbar punctures are, however,
more generally available and may be cheaper than the 2-day MSLT. The MSLT
and CSF tests are also difficult to compare, as the MSLT measures a physiological
process (daytime sleepiness), while the CSF test measures a neurochemical
abnormality. These 2 tests should, therefore, be considered complementary
in most cases.
The finding that cases with secondary hypersomnia, periodic hypersomnia
and/or atypical narcolepsy have intermediate or low levels is noteworthy.
Periodic hypersomnia, often associated with increased appetite and hypersexuality,
has been suspected to involve hypothalamic abnormalities,52-53
and our finding supports this hypothesis. In our survey, 30 of 228 patients
with various neurological conditions had intermediate levels. These subjects
include patients with head trauma, encephalitis, and Guillain-Barré
syndrome, which may alter hypothalamic function,27, 54
result in sleepiness,55-56 and
more rarely, narcolepsy-cataplexy (eg, in the context of the encephalitis
lethargica epidemic).56-60
Intermediate levels may thus point toward a secondary hypothalamic dysfunction.
Alternatively, these levels may reflect changes in CSF flow or blood-brain
barrier permeability and should be interpreted in the clinical context.
The majority of patients with idiopathic hypersomnia and narcolepsy
without cataplexy had normal hypocretin-1 levels. A parsimonious explanation
may be that the etiology of these cases does not involve hypocretins, and
that narcolepsy with typical cataplexy is a distinct entity. It also indicates
that differentiating narcolepsy without cataplexy and idiopathic hypersomnia
may not be justified etiologically, as others have suggested.17-18
Surprisingly, however, HLA-DQB1*0602 frequency was increased in noncataplexy
cases (Table 2), paralleling previous
reports.17, 21 A small number of
patients with typical cataplexy also had normal levels, especially multiplex
and HLA-negative subjects (Figure 1 and
Figure 2). Hypersomnia and
narcolepsy-cataplexy may thus be part of the same disease continuum. In this model, some narcolepsy patients have hypocretin
deficiency in projection areas important for sleep regulation, but they still
have normal CSF levels, especially younger subjects without HLA-DQB1*0602.
Partial hypocretin deficiency would be associated with less severe symptomatology
and less frequent cataplexy.
AUTHOR INFORMATION
Accepted for publication April 29, 2002.
Author contributions: Study concept
and design (Drs Mignot, Lammers, Nevsimalova, Bassetti,
and Schrader); acquisition of data (Drs Mignot, Lammers,
Nevsimalova, Vancova, Black, Harsh, Bassetti, and Nishino, Mss Ripley and
Okun, and Mr Overeem); analysis and interpretation of data (Drs Mignot and Lammers, and Mr Overeem); drafting of the manuscript (Drs Mignot, Lammers, and Harsh and Ms Ripley); critical
revision of the manuscript for important intellectual content (Drs Mignot, Lammers, Nevsimalova, Vancova, Black, Bassetti, Schrader, and
Nishino and Mr Overeem); statistical expertise (Dr
Mignot); obtained funding (Drs Mignot, Nevsimalova,
Black, and Bassetti); administrative, technical, and material support (Drs Mignot, Lammers, Nevsimalova, Vancova, Harsh, Bassetti, Schrader,
and Nishino, Ms Okun, and Mr Overeem); study supervision (Dr Mignot).
This study was supported by grants NS 23724, NS 33797, and MH40041 from
the National Institutes of Health (Bethesda, Md); and grants GA UK 56/99 and
MSM 1111 000 1 from the Czech Republic. Mr Overeem was supported
by the foundation De Drie Lichten (Rotterdam, the Netherlands) and Hersenstichting
Nederland (Den Haag, the Netherlands).
We thank David Rye, MD, for providing cerebrospinal fluid samples; Paul
Stowers, MS, and David Brooks for assistance in organizing and performing
lumbar punctures; Ling Lin, MD, PhD, for HLA typing; Anna Voros for technical
assistance; Goeffrey Harwig for collection of the clinical data in a large
African American lineage; Shahrad Taheri, MD, PhD, and Andrew Ray, PhD, for
editing the manuscript; Jamie Zeitzer, PhD, for editing and preparation of
the figures; and Helena Kraemer, PhD, for statistical assistance with the
quality receiver operating characteristic analysis.
Corresponding author and reprints: Emmanuel Mignot, MD, Center for
Narcolepsy, Stanford University, 701B Lower Welch Rd, Palo Alto, CA 94304-5742
(e-mail: mignot{at}leland.stanford.edu).
From the Center for Narcolepsy, Stanford University, Stanford, Calif
(Drs Mignot, Black, Nishino, and Mss Ripley and Okun); the Department of Neurology
and Clinical Neurophysiology, Leiden University Medical Center, Leiden, the
Netherlands (Dr Lammers and Mr Overeem); the Department of Neurology, Charles
University, Prague, Czech Republic (Drs Nevsimalova and Vankova); University
of Southern Mississippi, Hattiesburg (Dr Harsh); the Department of Neurology,
Zürich University Hospital, Zürich, Switzerland (Dr Bassetti); and
the Department of Neurology, Trondheim University Hospital, Trondheim, Norway
(Dr Schrader).
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