Bassetti, Claudio L.

Baumann, Christian R.

Scammell, Thomas E.

RERO DOC Digital Library

LETTER TO THE EDITORParkinson’s disease, sleepiness and hypocretin/orexinChristian R. Baumann,1,2 Thomas E. Scammell2 and Claudio L. Bassetti11Department of Neurology, University Hospital Zurich, Switzerland and 2Department of Neurology, Beth Israel DeaconessMedical Center, Harvard Institutes of Medicine, Boston, USACorrespondence to: Christian R. BaumannE-mail: c.r.b@swissonline.ch; christian.baumann@usz.chdoi:10.1093/brain/awm220Advance Access publication September 26, 2007Sir, Sleepiness and disrupted sleep substantially impairquality of life in people with Parkinson’s disease (PD)(Arnulf et al., 2000). The hypocretin/orexin neuropeptidesstabilize wakefulness and sleep, and in two recent studies,Fronczek et al. (2007) and Thannickal et al. (2007) showedthat patients with late-stage PD have a 38–45% loss of thehypothalamic hypocretin-producing neurons. These studiesprovide novel and important insights into the neuropathol-ogy of PD, but several questions remain about whether thispartial loss of hypocretin neurons actually causes the sleep–wake disturbances of PD.First, are the sleep-related symptoms of PD consistentwith a loss of hypocretin neurons? Narcolepsy is caused bya 90–95% loss of the hypocretin neurons and ischaracterized by excessive daytime sleepiness and cataplexy(sudden loss of muscle tone with strong emotions), withfragmented sleep, sleep paralysis (immobility either at sleeponset or upon awakening), hypnagogic hallucinations andsleep-onset REM sleep (SOREM) during daytime naps(Bassetti and Aldrich, 1996; Peyron et al., 2000). Certainly,PD patients often have fragmented sleep, daytime sleepi-ness, SOREM, and hallucinations (Arnulf et al., 2000). Ourown clinical experience, however, is not in agreement withthe statements by Thannickal et al. that the daytime sleepattacks in PD resemble sleep attacks in narcolepsy, nor dowe agree that sleep–wake disturbances are often moredisturbing for PD patients than their motor symptoms.Furthermore, narcoleptics may have hypnagogic hallucina-tions at the transitions between wakefulness and sleep, butPD patients often have delusions and illusions rather thandream-like hallucinations (Aarsland et al., 1999). Last,cataplexy has not been reported to occur in PD. Therefore,while there are some similarities, the sleepiness and othersymptoms of PD differ in many ways from those seen innarcolepsy.Second, do patients with PD have a physiologicallysignificant loss of hypocretin signalling? In narcolepsy withcataplexy, the almost complete loss of hypocretin neurons isaccompanied by severe reductions in lumbar CSF hypocre-tin levels (Peyron et al., 2000; Thannickal et al., 2000;Nishino et al., 2000). However, most studies have foundnormal hypocretin levels in PD (Ripley et al., 2001;Overeem et al., 2002; Yasui et al., 2006). In fact, wefound normal CSF concentrations of hypocretin even inPD patients with objectively confirmed severe excessivedaytime sleepiness, hallucinations and SOREMs (Baumannet al., 2005a).One group reported very low hypocretin levels inventricular CSF of late-stage PD patients (Drouot et al.,2003), raising the question of whether ventricular orlumbar CSF more accurately reflects the integrity of thehypocretin system. Fronczek et al. found that hypocretinlevels in ventricular CSF of PD patients are slightly reducedcompared to controls and correlate with the loss ofhypocretin neurons, but in the absence of normative data,it is unclear whether these levels are physiologically low.In two patients with simultaneous sampling of lumbar andventricular CSF, we found no significant differences inhypocretin levels (Baumann et al., 2005b). Overall, itappears that in patients with PD, hypocretin signalling asmeasured in CSF appears normal.Third, does PD selectively injure the hypocretin neurons?Thannickal et al. found that hypothalami of PD patients alsohave fewer neurons producing melanin concentrating hor-mone. This supports the assumption that PD kills many typesof hypothalamic neurons, and loss of non-hypocretin neuronsmay contribute to the sleep–wake disturbances of PD.Overall, we suspect that the moderate loss of hypocretinneurons in PD is accompanied by compensation in theremaining cells to achieve relatively normal hypocretinsignalling. Furthermore, hypocretin cell loss may be a non-specific finding of late-stage PD, in which injury to manyneuronal systems produces sleep–wake disturbances differ-ent from those seen in narcolepsy.Brain (2008), 131, e91 The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.orgReferencesAarsland D, Larsen JP, Lim NG, et al. Range of neuropsychiatricdisturbances in patients with Parkinson’s disease. J Neurol NeurosurgPsychiatry 1999; 67: 492–6.Arnulf I, Bonnet AM, Damier P, et al. Hallucinations, REM sleep,and Parkinson’s disease: a medical hypothesis. Neurology 2000; 55:281–8.Bassetti C, Aldrich MS. Narcolepsy. Neurol Clin 1996; 14: 545–71.Baumann C, Ferini-Strambi L, Waldvogel D, Werth E, Bassetti CL.Parkinsonism with excessive daytime sleepiness–a narcolepsy-likedisorder? J Neurol 2005a; 252: 139–45.Baumann CR, Stocker R, Imhof HG, et al. Hypocretin-1(orexin A) deficiency in acute traumatic brain injury. Neurology2005b; 65: 147–9.Drouot X, Moutereau S, Nguyen JP, et al. Low levels ofventricular CSF orexin/hypocretin in advanced PD. Neurology 2003;61: 540–3.Fronczek R, Overeem S, Lee SY, et al. Hypocretin (orexin) loss inParkinson’s disease. Brain 2007; 130: 1577–85.Overeem S, van Hilten JJ, Ripley B, Mignot E, Nishino S, Lammers GJ.Normal hypocretin-1 levels in Parkinson’s disease patients with excessivedaytime sleepiness. Neurology 2002; 58: 498–9.Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin(orexin) deficiency in human narcolepsy. Lancet 2000; 355: 39–40.Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onsetnarcolepsy and a generalized absence of hypocretin peptides in humannarcoleptic brains. Nat Med 2000; 6: 991–7.Ripley B, Overeem S, Fujiki N, et al. CSF hypocretin/orexin levels innarcolepsy and other neurological conditions. Neurology 2001; 57: 2253–8.Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S,Aldrich M, et al. Reduced number of hypocretin neurons in humannarcolepsy. Neuron 2000; 27: 469–74.Thannickal TC, Lai YY, Siegel JM. Hypocretin (orexin) cell loss inParkinson’s disease. Brain 2007; 130: 1586–95.Yasui K, Inoue Y, Kanbayashi T, Nomura T, Kusumi M, Nakashima K.CSF orexin levels of Parkinson’s disease, dementia with Lewy bodies,progressive supranuclear palsy and corticobasal degeneration. J NeurolSci 2006; 250: 120–3.e91 Brain (2008), 131 Letter to the Editor

Parkinson's disease, sleepiness and hypocretin/orexin

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library