T cells in patients with narcolepsy target self-antigens of hypocretin neurons.

Narcolepsy is a chronic sleep disorder caused by the loss of neurons that produce hypocretin. The close association with HLA-DQB1*06:02, evidence for immune dysregulation and increased incidence upon influenza vaccination together suggest that this disorder has an autoimmune origin. However, there is little evidence of autoreactive lymphocytes in patients with narcolepsy. Here we used sensitive cellular screens and detected hypocretin-specific CD4+ T cells in all 19 patients that we tested; T cells specific for tribbles homologue 2-another self-antigen of hypocretin neurons-were found in 8 out of 13 patients. Autoreactive CD4+ T cells were polyclonal, targeted multiple epitopes, were restricted primarily by HLA-DR and did not cross-react with influenza antigens. Hypocretin-specific CD8+ T cells were also detected in the blood and cerebrospinal fluid of several patients with narcolepsy. Autoreactive clonotypes were serially detected in the blood of the same-and even of different-patients, but not in healthy control individuals. These findings solidify the autoimmune aetiology of narcolepsy and provide a basis for rapid diagnosis and treatment of this disease.

Hypothalamic involvement assessed by T1 relaxation time in patients with relapsing-remitting multiple sclerosis.

Recent work in multiple sclerosis, focusing on neuropathological abnormalities, found a frequent and severe hypothalamic involvement. The possible clinical implications are disturbances in sleep and sexual activity, depression, memory impairment and fatigue. Despite this there are no magnetic resonance imaging studies focusing on in vivo hypothalamic pathology in multiple sclerosis. Our objective was to investigate magnetic resonance imaging-detectable abnormalities related to pathological changes in the hypothalamus of patients with multiple sclerosis, and to subsequently explore the relationship with fatigue. We used T1 relaxation time as a sensitive measure of pathology. Using region of interest analysis, median T1 values in the hypothalamus were measured in 44 relapsing-remitting multiple sclerosis patients and in 13 healthy controls. Fatigue was assessed using the Fatigue Severity Scale, and patients were divided in two subgroups, fatigued and non-fatigued, according to Fatigue Severity Scale scores. We found a significantly higher T1 relaxation time in the hypothalamus of multiple sclerosis patients compared with controls (p = 0.027). There was a significant correlation between T1 values and fatigue severity (rho 0.437, p = 0.008), and median T1 values were different among the study groups. Our results show that pathological involvement of the hypothalamus in relapsing-remitting multiple sclerosis is detectable using magnetic resonance imaging, and that the pathology measured by quantitative T1 might reflect fatigue.

The syndrome of polymicrogyria, thalamic hypoplasia, and epilepsy with CSWS.

OBJECTIVE: We explored the long-term follow-up of continuous spike-and-wave complexes during sleep (CSWS) in polymicrogyria and the anatomic volumetric variables that influence the risk of developing this age-related epileptic encephalopathy. METHODS: We performed prospective follow-up of 27 patients with polymicrogyria/CSWS (mean follow-up 14.3 years; range 2-31 years) and comparative volumetric analysis of the polymicrogyric hemispheres and ipsilateral thalami vs 3 subgroups featuring polymicrogyria without CSWS, benign rolandic epilepsy (BRE), and headache. Receiver operator characteristic analysis of the power of volumetric values was determined to predict CSWS. RESULTS: CSWS peaked between 5 and 7 years (mean age at onset 4.7 years). Remission occurred within 2 years from onset in 21%, within 4 years in 50%, and by age 13 years in 100%. We found smaller thalamic and hemispheric volumes in polymicrogyria/CSWS with respect to polymicrogyria without CSWS (p = 0.0021 for hemispheres; p = 0.0003 for thalami), BRE, and controls with headache (p < 0.0001). Volumes of the malformed hemispheres and ipsilateral thalami reliably identified the risk of incurring CSWS, with a 68-fold increased risk for values lower than optimal diagnostic cutoffs (436,150 mm(3) for malformed hemispheres or 4,616 mm(3) for ipsilateral thalami; sensitivity 92.54%; specificity 84.62%). The risk increased by 2% for every 1,000 mm(3) reduction of the polymicrogyric hemispheres and by 15% for every 100 mm(3) reduction of ipsilateral thalami. CONCLUSIONS: The polymicrogyria/CSWS syndrome is likely caused by a cortico-thalamic malformation complex and is characterized by remission of epilepsy within early adolescence. Early assessment of hemispheric and thalamic volumes in children with polymicrogyria and epilepsy can reliably predict CSWS.