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Table 84-4 CSF Hypocretin-1 and HLA Results: Selected Examples in Secondary Narcolepsy and Hypersomnias
8-year-old white boy without
cataplexy (onset within 6
88 pg/mL
Diagnostic for narcolepsy,
treatment with modafinil, later
in association with venlafaxine
17-year-old boy with rape
hallucinations; suspicious and
difficult to interview; possible
Undetectable ( < 40 pg/mL)
Narcolepsy associated with
16-year-old girl with a 5-year
history of depression and
drug-resistant insomnia;
cataplexy on interview
Undetectable ( < 40 pg/mL)
Impossible to stop
not done
Diagnostic for narcolepsy, now
successfully treated with
sodium oxybate, modafinil,
and atomoxetine
32-year-old man, after resection
of hypothalamic pharyngioma;
very impaired, possible
152 pg/mL
Impossible to
conduct, too
Questionable narcolepsy;
possibly lesions of other areas;
partial effect of stimulants
33-year-old woman successfully
treated with d -amphetamine
and fluoxetine; recently moved
to the area; no cataplexy
( < 40 pg/mL)
Not interpretable,
was taking
Diagnostic for narcolepsy
No change in treatment, but
considering modafinil
15-year-old girl with sleepiness,
no cataplexy
310 pg/mL
Narcolepsy without cataplexy
Treatment with modafinil
67-year-old man, narcolepsy
without cataplexy, diagnosed
at age 50, AHI = 25 events/hr,
noncompliant with CPAP,
currently with falls not
triggered by laughing
( < 40 pg/mL)
First tried venlafaxine without
effect, then sodium oxybate
with very positive response
Positive test result criteria: HLA, HLA-DQB1*0602-positive; MSLT, sleep latency < 8 min, 2 SOREMPs
AHI, apnea-hypopnea index; CPAP, continuous positive airway pressure ventilation; CSF, cerebrospinal fluid; HLA, human leukocyte
antigen; MSLT, multiple sleep latency test; Neg, negative; Pos, positive; SOREMP, sleep-onset REM period.
Experiments aimed at studying the effects of hypocretin
on sleep after nasal, systemic, and central administration
(e.g., intracerebroventricular injection or local perfusion in
selected brain areas) have been conducted. 171-173 Central
administration of hypocretin-1, for example in the ven-
tricle of wild-type rodents or normal canines, is strongly
wake-promoting 172 and reverses cataplexy and sleep abnor-
malities in narcoleptic rodents. 174 The effect is likely to be
at least in part mediated by the HCRTR2 because intra-
crebroventricular hypocretin-1 at the same dose (10 to
30 nmol) has no effect in HCRTR2-mutated narcoleptic
canines. 175 Interestingly, hypocretin-2 administration has
few if any central effects even in normal animals, most
probably not because it is inactive but because it is biologi-
cally unstable and rapidly degraded. The instability might
also explain why hypocretin-1 but not hypocretin-2 is
detectable in native CSF. 175
Experiments conducted after intravenous administra-
tion of hypocretin-1 have been performed in HCRTR2-
mutated canines and in two hypocretin-deficient narcoleptic
dogs. In spite of a previous report, 171 we were unable to
detect any significant effect even at extremely high doses
in hypocretin receptor-2 mutated animals. 172 This result
was not surprising considering the lack of effects after
central administration of the same dose in these animals
lacking HCRTR2 (see earlier). More interestingly, a pos-
sible very slight and short-lasting suppression of cataplexy
was observed in a single hypocretin-deficient narcoleptic
animal at extremely high doses. 160
The effect of intranasal hypocretin-1 in rodents and
humans has been studied 173 with the hope that hypocretin-1
would penetrate into the brain via the olfactory nerve
endings. Although we found central uptake of radiolabeled
hypocretin counts in rodents, in vivo experiments did not
reveal any behavioral effects. In contrast, another study
found a significant reversal of MRI abnormalities induced
by sleep deprivation after intranasal administration, 173 a
finding that suggests the need to conduct similar studies in
narcoleptic patients. We also examined the possibility of
intrathecal administration by implanting a Medtronic
pump with catheterization of the cisterna magna in a single
hypocretin-deficient narcoleptic canine. 176 Our hope was
that at a high dose, some reverse low would occur back
into deeper brain structure, providing therapeutic relief. A
positive result would have had therapeutic application,
because these pumps are often used in humans to treat pain
or spasticity using intrathecal administration. Disappoint-
ingly, however, we did not observe any significant effect
on cataplexy, 176 probably because the hypocretin did not
diffuse in upper ventricular compartments. Additional
studies using intraventricular rather than intracisternal
injections will be needed to verify that hypocretin-deficient
narcoleptic canines are responsive to supplementation.
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