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Symptomatic Narcolepsy in Patients With Neuromyelitis Optica and Multiple Sclerosis:  New Neurochemical and Immunological Implications FREE

Takashi Kanbayashi, MD, PhD; Takayoshi Shimohata, MD, PhD; Ichiro Nakashima, MD, PhD; Hiroaki Yaguchi, MD; Ichiro Yabe, MD, PhD; Masatoyo Nishizawa, MD, PhD; Tetsuo Shimizu, MD, PhD; Seiji Nishino, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Neuropsychiatry, Akita University School of Medicine, Akita City (Drs Kanbayashi and Shimizu), Department of Neurology, Brain Research Institute, Niigata University, Niigata (Drs Shimohata and Nishizawa), Department of Neurology, Tohoku University School of Medicine, Sendai (Dr Nakashima), and Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo (Drs Yaguchi and Yabe), Japan; and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California (Dr Nishino).


Arch Neurol. 2009;66(12):1563-1566. doi:10.1001/archneurol.2009.264.
Text Size: A A A
Published online

ABSTRACT

Objective  To characterize factors that contribute to symptomatic narcolepsy and excessive daytime sleepiness in neuromyelitis optica and multiple sclerosis.

Setting  Japanese university hospitals.

Design  Case study.

Patients  Seven Japanese patients whose initial diagnoses were multiple sclerosis and who were exhibiting excessive daytime sleepiness.

Main Outcome Measures  Lesions on magnetic resonance imaging, cerebrospinal fluid hypocretin-1 levels, and serum anti–aquaporin 4 (AQP4) antibody titer.

Results  Bilateral and symmetrical hypothalamic lesions associated with marked or moderate hypocretin deficiency were found in all 7 cases. Four of these patients met the International Classification of Sleep Disorders 2 narcolepsy criteria. Three patients, including 2 patients with narcolepsy, were seropositive for anti-AQP4 antibody and diagnosed as having neuromyelitis optica–related disorder.

Conclusion  Since AQP4 is highly expressed in the hypothalamic periventricular regions, an immune attack on AQP4 may be partially responsible for the bilateral and hypothalamic lesions and hypocretin deficiency in narcolepsy/excessive daytime sleepiness associated with autoimmune demyelinating diseases.

Figures in this Article

Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), cataplexy, and other rapid eye movement sleep abnormalities.1 The idiopathic form of narcolepsy with cataplexy is highly associated with a deficiency in a hypothalamic neuropeptide, hypocretin/orexin.1,2 The hypocretin deficiency is possibly due to the postnatal cell death of hypocretin-containing neurons. Since narcolepsy is also tightly associated with HLA antigen positivity (HLA DR2/DQB1*0602), an involvement of autoimmune mechanisms in its etiology is suggested, but this has not been proven yet.1

Narcolepsy also occurs during the course of various neurological conditions (ie, symptomatic narcolepsy or narcolepsy due to medical conditions), and inherited disorders, tumors, and head trauma are the 3 most frequent causes for symptomatic cases.3 Interestingly, however, a recent meta-analysis indicated that 10 of 116 symptomatic cases of narcolepsy are associated with multiple sclerosis (MS),3 a disease of autoimmune demyelination. Symptomatic narcoleptic cases consist of heterogeneous disease conditions, but the hypocretin systems are often impaired.2,3 Gaining the basic knowledge of symptomatic narcolepsy in immune-mediated conditions will be not only useful for selecting the most appropriate treatment and predicting the prognosis of the disease but also for understanding the etiological mechanism of narcolepsy.

REPORT OF CASES

We recently had 7 cases of EDS in Japanese patients occurring in the course of MS or neuromyelitis optica (NMO) with symmetrical hypothalamic inflammatory lesions together with hypocretin ligand deficiency,48 which contrasts with the characteristics of classic MS cases (Table). Cerebrospinal fluid (CSF) hypocretin-1 levels in these patients were markedly (n = 4; ≤110 pg/mL) or moderately (n = 3; 110 to 200 pg/mL) reduced (Table) (Figure). Four patients thus met the International Classification of Sleep Disorders 2 criteria13 for narcolepsy due to medical condition, and 3 patients met the criteria for hypersomnia due to medical condition. Six of these patients were female, and 4 had either or both optic neuritis or spinal cord lesions, sharing the clinical characteristics of NMO. HLA antigen was evaluated in only 2 cases (case 2 and case 4) and was negative for DQB1*0602. Repeated evaluations of the hypocretin status were carried out in 6 patients, and CSF hypocretin-1 levels returned to the normal levels or significantly increased with marked improvements of EDS and hypothalamic lesions in all 6 patients. By immunological evaluations, we found that 3 of 7 patients were anti–aquaporin 4 (AQP4) antibody positive, thus being diagnosed with an NMO-related disorder.

Place holder to copy figure label and caption
Figure.

Magnetic resonance imaging findings (fluid-attenuated inversion recovery [FLAIR] [A-C, F, and G] or T2 weighted [D and E]) of cases 1 through 7. A typical horizontal slice including the hypothalamic periventricular area from each case is presented. AQP4 indicates aquaporin 4; +, positive.

Graphic Jump Location
Table Graphic Jump LocationTable. Demographic and Clinical Characteristics of Patients With MS/NMO With Narcolepsy/EDSa

COMMENT

Narcolepsy associated with patients with MS was reported several decades ago. Since both conditions are associated with HLA-DR2 positivity, an autoimmune target on the same brain structures has been proposed to be a common etiology for both diseases.14 However, the discovery of the selective loss of hypothalamic hypocretin neurons in idiopathic narcolepsy indicates that narcolepsy in patients with MS coincidently occurs when MS plaques appear in the hypothalamic area and there is secondary damage to the hypocretin/orexin neurons.3 Supporting this interpretation, the hypocretin system is not impaired in patients with MS who do not exhibit narcolepsy,15 although patients with MS frequently show other sleep problems, such as insomnia, parasomnia, and sleep-related movement disorders.16 Nevertheless, it is also the case that a subset of patients with MS predominantly shows EDS and rapid eye movement sleep abnormalities, and it is likely that specific immune-mediated mechanisms may be involved in these cases.

Interestingly, 3 of our 7 patients were anti–AQP4 antibody positive, and these patients were diagnosed as having an NMO-related disorder. Carlander et al9 also reported a case of a white female with NMO who was anti–AQP4 antibody positive and had associated EDS and hypocretin deficiency (Table). These results suggest a functional relation between AQP4 and hypothalamic damage.

Aquaporin 4, a member of the aquaporin superfamily, is an integral membrane protein that forms pores in the membrane of biological cells.17 Aquaporins selectively conduct water molecules in and out of the cell while preventing the passage of ions and other solutes and are known as water channels. Aquaporin 4 is expressed throughout the central nervous system, especially in periaqueductal and periventricular regions,17,18 and is found in nonneuronal structures such as astrocytes and ependymocytes but is absent from neurons. Recently, the NMO-IgG autoantibody, which can be detected in the serum of patients with NMO, has been shown to selectively bind to AQP4.19

Since AQP4 is enriched in periventricular regions in the hypothalamus where hypocretin-containing neurons are primarily located, symmetrical hypothalamic lesions associated with reduced CSF hypocretin-1 levels in our 3 NMO cases with anti–AQP4 antibody (together with the Carlander et al case) might be caused by the immune attack on AQP4, and this may secondarily affect the hypocretin neurons. Two additional NMO cases presenting with EDS with symmetrical hypothalamic lesions are also available,20 although neither anti–AQP4 antibody titer nor CSF hypocretin-1 level were measured in these cases.

However, our other 4 patients with MS with EDS and hypocretin deficiency were anti–AQP4 antibody negative at the time of blood testing (Table). Hypothalamic lesions were observed in only 3 patients among 89 who were diagnosed with NMO and 31 patients with high-risk NMO, and existence of sleep symptoms was not specifically described in these cases.18 It is possible that other antibody-mediated mechanisms are additionally responsible for the bilateral symmetric hypothalamic damage causing EDS in the patients with NMO/MS. Possibly, the 4 patients with MS whose anti–AQP4 antibody titers were negative could still have NMO, since anti–AQP4 antibody titer was tested only once for each subject during the course of the disease, and the assay was not standardized among the institutes. It is thus essential to further determine the immunological mechanisms that cause the bilateral hypothalamic lesions with hypocretin deficiency and EDS and their association with NMO and AQP4. This effort may lead to establishment of a new clinical entity, and the knowledge is essential to prevent and treat EDS associated with MS and its related disorders. None of our cases exhibited cataplexy, contrary to the 9 of 10 cases with symptomatic narcolepsy and MS reported in the past.3 Early therapeutic intervention with steroids and other immunosuppressants may thus prevent irreversible damage of hypocretin neurons and prevent chronic sleep-related symptoms.

ARTICLE INFORMATION

Correspondence: Seiji Nishino, MD, PhD, Sleep and Circadian Neurobiology Laboratory, Center of Narcolepsy, Stanford Sleep Research Center, Stanford University, 1201 Welch Rd, MSLS, P213, Palo Alto, CA 94304-5489 (nishino@stanford.edu).

Accepted for Publication: February 13, 2009.

Author Contributions: Dr Kanbayashi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kanbayashi, Shimohata, Nishizawa, Shimizu, and Nishino. Acquisition of data: Nakashima and Nishizawa. Analysis and interpretation of data: Yaguchi, Yabe, and Nishino. Drafting of the manuscript: Kanbayashi, Shimizu, and Nishino. Critical revision of the manuscript for important intellectual content: Shimohata, Nakashima, Yaguchi, Yabe, Nishizawa, and Nishino. Administrative, technical, and material support: Shimohata and Nakashima. Study supervision: Shimohata, Nakashima, and Nishino.

Financial Disclosure: None reported.

Additional Contributions: T. Kato, MD, PhD, Y. Oka, MD, PhD, and M. Nakamura, MD, PhD, provided valuable case reports. K. Tanaka, MD, PhD (Niigata University), and T. Takahashi, MD, PhD (Tohoku University), performed anti–AQP4 antibody assays.

REFERENCES

Nishino  S Clinical and neurobiological aspects of narcolepsy. Sleep Med 2007;8 (4) 373- 399
PubMed Link to Article
Bourgin  PZeitzer  JMMignot  E CSF hypocretin-1 assessment in sleep and neurological disorders. Lancet Neurol 2008;7 (7) 649- 662
PubMed Link to Article
Nishino  SKanbayashi  T Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med Rev 2005;9 (4) 269- 310
PubMed Link to Article
Kato  TKanbayashi  TYamamoto  K  et al.  Hypersomnia and low CSF hypocretin-1 (orexin-A) concentration in a patient with multiple sclerosis showing bilateral hypothalamic lesions. Intern Med 2003;42 (8) 743- 745
PubMed Link to Article
Oka  YKanbayashi  TMezaki  T  et al.  Low CSF hypocretin-1/orexin-A associated with hypersomnia secondary to hypothalamic lesion in a case of multiple sclerosis. J Neurol 2004;251 (7) 885- 886
PubMed Link to Article
Nozaki  HShimohata  TKanbayashi  T  et al.  A patient with anti-aquaporin 4 antibody who presented with recurrent hypersomnia, reduced orexin (hypocretin) level, and symmetrical hypothalamic lesions. Sleep Med 2009;10 (2) 253- 255
PubMed Link to Article
Baba  TNakashima  IKanbayashi  T  et al.  Narcolepsy as an initial manifestation of neuromyelitis optica with anti-aquaporin 4 antibody. J Neurol 2009;256 (2) 287- 288
PubMed Link to Article
Nakamura  MNishii  MMaki  SNakamuara  MSuenaga  TA MS cases with EDS and bilateral hypothalamic lesions [in Japanese]. Clin Neurol 2005;45 (2) 187
Carlander  BVincent  TLe Floch  APageot  NCamu  WDauvilliers  Y Hypocretinergic dysfunction in neuromyelitis optica with coma-like episodes. J Neurol Neurosurg Psychiatry 2008;79 (3) 333- 334
PubMed Link to Article
Kanbayashi  TInoue  YChiba  S  et al.  CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia. J Sleep Res 2002;11 (1) 91- 93
PubMed Link to Article
Tanaka  KTani  TTanaka  M  et al.  Anti-aquaporin 4 antibody in selected Japanese multiple sclerosis patients with long spinal cord lesions. Mult Scler 2007;13 (7) 850- 855
PubMed Link to Article
Takahashi  TFujihara  KNakashima  I  et al.  Establishment of a new sensitive assay for anti-human aquaporin-4 antibody in neuromyelitis optica. Tohoku J Exp Med 2006;210 (4) 307- 313
PubMed Link to Article
 ICSD-2—International Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.  Westchester, IL American Academy of Sleep Medicine2005;
Poirier  GMontplaisir  JDumont  M  et al.  Clinical and sleep laboratory study of narcoleptic symptoms in multiple sclerosis. Neurology 1987;37 (4) 693- 695
PubMed Link to Article
Ripley  BOvereem  SFujiki  N  et al.  CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 2001;57 (12) 2253- 2258
PubMed Link to Article
Tachibana  NHoward  RSHirsch  NPMiller  DHMoseley  IFFish  D Sleep problems in multiple sclerosis. Eur Neurol 1994;34 (6) 320- 323
PubMed Link to Article
Amiry-Moghaddam  MOttersen  OP The molecular basis of water transport in the brain. Nat Rev Neurosci 2003;4 (12) 991- 1001
PubMed Link to Article
Pittock  SJWeinshenker  BGLucchinetti  CFWingerchuk  DMCorboy  JRLennon  VA Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol 2006;63 (7) 964- 968
PubMed Link to Article
Lennon  VAKryzer  TJPittock  SJVerkman  ASHinson  SR IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 2005;202 (4) 473- 477
PubMed Link to Article
Poppe  AYLapierre  YMelancon  D  et al.  Neuromyelitis optica with hypothalamic involvement. Mult Scler 2005;11 (5) 617- 621
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

Magnetic resonance imaging findings (fluid-attenuated inversion recovery [FLAIR] [A-C, F, and G] or T2 weighted [D and E]) of cases 1 through 7. A typical horizontal slice including the hypothalamic periventricular area from each case is presented. AQP4 indicates aquaporin 4; +, positive.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Demographic and Clinical Characteristics of Patients With MS/NMO With Narcolepsy/EDSa

References

Nishino  S Clinical and neurobiological aspects of narcolepsy. Sleep Med 2007;8 (4) 373- 399
PubMed Link to Article
Bourgin  PZeitzer  JMMignot  E CSF hypocretin-1 assessment in sleep and neurological disorders. Lancet Neurol 2008;7 (7) 649- 662
PubMed Link to Article
Nishino  SKanbayashi  T Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med Rev 2005;9 (4) 269- 310
PubMed Link to Article
Kato  TKanbayashi  TYamamoto  K  et al.  Hypersomnia and low CSF hypocretin-1 (orexin-A) concentration in a patient with multiple sclerosis showing bilateral hypothalamic lesions. Intern Med 2003;42 (8) 743- 745
PubMed Link to Article
Oka  YKanbayashi  TMezaki  T  et al.  Low CSF hypocretin-1/orexin-A associated with hypersomnia secondary to hypothalamic lesion in a case of multiple sclerosis. J Neurol 2004;251 (7) 885- 886
PubMed Link to Article
Nozaki  HShimohata  TKanbayashi  T  et al.  A patient with anti-aquaporin 4 antibody who presented with recurrent hypersomnia, reduced orexin (hypocretin) level, and symmetrical hypothalamic lesions. Sleep Med 2009;10 (2) 253- 255
PubMed Link to Article
Baba  TNakashima  IKanbayashi  T  et al.  Narcolepsy as an initial manifestation of neuromyelitis optica with anti-aquaporin 4 antibody. J Neurol 2009;256 (2) 287- 288
PubMed Link to Article
Nakamura  MNishii  MMaki  SNakamuara  MSuenaga  TA MS cases with EDS and bilateral hypothalamic lesions [in Japanese]. Clin Neurol 2005;45 (2) 187
Carlander  BVincent  TLe Floch  APageot  NCamu  WDauvilliers  Y Hypocretinergic dysfunction in neuromyelitis optica with coma-like episodes. J Neurol Neurosurg Psychiatry 2008;79 (3) 333- 334
PubMed Link to Article
Kanbayashi  TInoue  YChiba  S  et al.  CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia. J Sleep Res 2002;11 (1) 91- 93
PubMed Link to Article
Tanaka  KTani  TTanaka  M  et al.  Anti-aquaporin 4 antibody in selected Japanese multiple sclerosis patients with long spinal cord lesions. Mult Scler 2007;13 (7) 850- 855
PubMed Link to Article
Takahashi  TFujihara  KNakashima  I  et al.  Establishment of a new sensitive assay for anti-human aquaporin-4 antibody in neuromyelitis optica. Tohoku J Exp Med 2006;210 (4) 307- 313
PubMed Link to Article
 ICSD-2—International Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.  Westchester, IL American Academy of Sleep Medicine2005;
Poirier  GMontplaisir  JDumont  M  et al.  Clinical and sleep laboratory study of narcoleptic symptoms in multiple sclerosis. Neurology 1987;37 (4) 693- 695
PubMed Link to Article
Ripley  BOvereem  SFujiki  N  et al.  CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology 2001;57 (12) 2253- 2258
PubMed Link to Article
Tachibana  NHoward  RSHirsch  NPMiller  DHMoseley  IFFish  D Sleep problems in multiple sclerosis. Eur Neurol 1994;34 (6) 320- 323
PubMed Link to Article
Amiry-Moghaddam  MOttersen  OP The molecular basis of water transport in the brain. Nat Rev Neurosci 2003;4 (12) 991- 1001
PubMed Link to Article
Pittock  SJWeinshenker  BGLucchinetti  CFWingerchuk  DMCorboy  JRLennon  VA Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol 2006;63 (7) 964- 968
PubMed Link to Article
Lennon  VAKryzer  TJPittock  SJVerkman  ASHinson  SR IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 2005;202 (4) 473- 477
PubMed Link to Article
Poppe  AYLapierre  YMelancon  D  et al.  Neuromyelitis optica with hypothalamic involvement. Mult Scler 2005;11 (5) 617- 621
PubMed Link to Article

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