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Case Report/Case Series |

Hypothalamic Immunopathology in Anti-Ma–Associated Diencephalitis With Narcolepsy-Cataplexy

Yves Dauvilliers, MD, PhD1,2,3; Jan Bauer, PhD4; Valérie Rigau, MD, PhD5; Nicole Lalloyer, MD6; Pierre Labauge, MD, PhD3; Bertrand Carlander, MD1,3; Roland Liblau, MD, PhD7; Christelle Peyron, PhD8; Hans Lassmann, MD4
[+] Author Affiliations
1National Reference Network for Orphan Diseases (Narcolepsy, Hypersomnia, Kleine-Levin Syndrome), Sleep Unit, Department of Neurology, Gui de Chauliac Hospital, CHU Montpellier, France
2INSERM U1061, Montpellier, France
3Department of Neurology, Gui de Chauliac Hospital, CHU Montpellier, France
4Center for Brain Research, Medical University of Vienna, Wien, Austria
5Department of Pathology, CHU, Gui de Chauliac Hospital Montpellier, France
6Immunology Department, CHU Nîmes, France
7INSERM U1043, CNRS, UMR 5282, Toulouse, France
8INSERM U1028, CNRS, UMR 5292, Center for Research in Neuroscience of Lyon, Team SLEEP, Lyon, France
JAMA Neurol. 2013;70(10):1305-1310. doi:10.1001/jamaneurol.2013.2831.
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Importance  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.

Observations  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 and Relevance  The encephalitic process, responsible for narcolepsy-cataplexy and hypocretin deficiency, reflects a CD8+ inflammatory-mediated response against hypocretin neurons.

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Figure 1.
Brain Magnetic Resonance Imaging/Fluid-Attenuated Inversion Recovery Sequences

Images revealed bilateral paramedian hyperintensities in the thalamus, hypothalamus, and mammillary bodies, with lesions surrounding the third ventricle without enhancement after contrast administration.

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Figure 2.
Pathological Alterations in the Hypothalamus of the Ma-Positive Patient

A, Image shows the basic pathology in the hypothalamus, consisting of inflammation and loss of neurons in a section stained with hematoxylin and eosin (H&E). Immunocytochemistry was performed on serial sections stained with the markers indicated on the upper right corner. There is a profound inflammation with perivascular inflammatory infiltrates, consisting of T cells (B and C), macrophages (F), and B cells (G). CD8+ T cells are not only present in the perivascular space but also diffusely dispersed in the tissue (C; the inserts show parenchymal T cells at high magnification). Inflammation is associated with the expression of major histocompatibility antigens (MHC) class I (D) and class II (E). Some neurons express MHC class I antigen on their surface (D, insert). Within the lesions, there is profound astrocytic gliosis (H) and increased expression of aquaporin 4 (AQP4) around inflamed vessels (I). No single hypocretin-positive neuron or axon was found in sections from our patient (J, original magnification ×400). K and l, Images show expression of hypocretin in neurons and axons in the hypothalamus of a control patient at different magnifications. GFAP indicates glial fibrillary acidic protein. For panels A-K, original magnification ×50; for panel L, original magnification ×400.

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Figure 3.
Immunoreactivity of the Ma-Positive Patient’s Serum and Cerebrospinal Fluid (CSF) With Neurons in Normal Hypothalamus

Multiple neurons in the normal hypothalamus are labeled with the Ma-positive patient’s serum (A and B) and CSF (C), while the CSF from a patient with idiopathic hypocretin-deficient narcolepsy-cataplexy showed no reactivity (D). No neurons with reactivity for the Ma-positive patient’s serum were detected in the inflamed hypothalamus of the Ma-positive patient (E). F and G, Double immunohistochemical staining with confocal laser microscopy shows that a fraction of the Ma-positive patient’s serum reactive neurons (red) also express hypocretin (green). Absorption of the patient serum with recombinant Ma2 completely abolishes neuronal immunoreactivity in the hypothalamus of the control patient (I) in comparison with nonabsorbed serum (H). For panel A, original magnification ×100; panels B-E, original magnification ×400; F and G, original magnification ×800; and H and I, original magnification ×200.

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