Transcript No Slide Title

Orexin, Histamine and
Hyperarousal in RLS
Richard P. Allen, PhD
Diplomate, American Board of Sleep Medicine
Fellow American Academy of Sleep Medicine
Johns Hopkins University School of Medicine
One week with severe RLS
Note lack of symptoms in the morning
Patients with Severe RLS
Sleep Only 5 Hours a Night
• Why don’t patients with RLS fall asleep at stop
lights?
• Why don’t they sleep late in the morning?
• What is the neurobiology of this lack of sleepiness
response to sleep loss
Histaminergic system
• Primary arousal/vigilance system
• Orexin alerting affects require intact histamine
system
Mystery of Anti-histamine and RLS
Average PLMW/hr for SITS
225
Error Bars: ± 1 Standard Error(s)
200
Cell Mean
175
150
125
100
75
50
25
0
Diphenhydramine
Lorazepam
Cell
ANOVA: drug F = 17.2, df = 2.36,
Diphenhydramine vs placebo:
Lorazepam vs placebo:
Diphenhydramine vs lorazepam:
Placebo
P <.0001
P <.0001
P <.02
P <.002
Play CD here
vidoe
H3R SN control vs RLS
Control
RLS
Images captured at 20X
Orexin greater for early-onset RLS
not on RLS treatments
Orexin greater for RLS
on DA treatment for RLS
Orexin is greater with earlier onset of
RLS ( more severe pathology?)
Orexin is greater for lower CSF ferritin
(more severe pathology)
CSF orexin is greater for lower CSF ferritin
(more severe pathology)
even for only early-onset RLS
RLS: CSF orexin greater for greater CSF Biopterin
- indicating greater DA production
RLS: CSF orexin greater for greater CSF 3OMDconsistent with greater DA production
CSF Orexin/hypocretin and activity
• No significant relation to any sleep or activity
measure including:
– PSG measures of sleep (sleep latency, TST, REM etc)
– PLMS and PLMW
– Activity meters before and during sleep
– Observation of times in bed
Iron Model of RLS
Iron Insufficiency
Neuropathology
Dopamine
Adenosine
Glutamate
opioid
Histamine/Hypocretin
What neurological
systems are affected by
low brain iron?
In-vivo: Animal studies
In vitro: cell studies
Confirmation:
Autopsy, CSF, PET
Pharmacological
Physiological
RLS
Other cellular systems
• Histamine
• Orexin (Hypocretin)
• Adenosine ??