Hypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy-cataplexy.
OBJECTIVE
Idiopathic narcolepsy with cataplexy is thought to be an autoimmune disorder targeting hypothalamic hypocretin neurons. Symptomatic narcolepsy with low hypocretin level has been described in Ma antibody–associated encephalitis; however, the mechanisms underlying such an association remain unknown.


METHODS
We described a 63-year-old man with clinical criteria for diencephalic encephalitis with sleepiness, cataplexy, hypocretin deficiency, and central hypothyroidism, together with brainstem encephalitis reflected by supranuclear ophtalmoparesis and rapid eye movement sleep behavior disorder with underlying abnormalities on brain magnetic resonance imaging. An autoimmune process was demonstrated by the detection of antibodies against Ma protein. Death occurred 4 months after disease onset without any tumor detected. Neuropathology, immunohistochemistry, and immunoreactivity results were compared with those obtained in idiopathic narcolepsy-cataplexy and with normal control brains. The principal findings revealed almost exclusive inflammation and tissue injury in the hypothalamus. The type of inflammatory reaction suggests cytotoxic CD8+ T lymphocytes being responsible for the induction of tissue injury. Inflammation was associated with complete loss of hypocretinergic neurons. Autoantibodies of the patient predominantly stained neurons in the hypothalamus and could be absorbed with Ma2.


CONCLUSIONS
The encephalitic process, responsible for narcolepsy-cataplexy and hypocretin deficiency, reflects a CD8+ inflammatory-mediated response against hypocretin neurons.
Yves
Y
Dauvilliers
Jan
J
Bauer
Valérie
V
Rigau
Nicole
N
Lalloyer
Pierre
P
Labauge
Bertrand
B
Carlander
Roland
R
Liblau
Christelle
C
Peyron
Hans
H
Lassmann
D015703:Antigens, CD / Q000378:metabolism; D051401:Aquaporin 4 / Q000378:metabolism; D001323:Autoantibodies / Q000097:blood / Q000134:cerebrospinal fluid; D018792:Encephalitis, Viral / Q000150:complications / Q000276:immunology / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D015488:HIV Antigens / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009290:Narcolepsy / Q000150:complications*; D009479:Neuropeptides / Q000378:metabolism; D000068797:Orexins; D020542:Third Ventricle / Q000473:pathology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
C496030:AQP4 protein, human; D015703:Antigens, CD; D051401:Aquaporin 4; D001323:Autoantibodies; D005904:Glial Fibrillary Acidic Protein; D015488:HIV Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1