Emerging role of prodromal headache in patients with anti-N-methyl-D-aspartate receptor encephalitis

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis patients often present with psychiatric symptoms, cognitive dysfunction, epilepsy and memory deficits. A previous study has suggested that headache can occurr during the early stages of anti-NMDAR encephalitis. However, the exact association between headache and anti-NMDAR encephalitis has hardly been investigated, apart from a few case studies. This is probably due to the severity of encephalitis symptoms, and the mechanism underlying headache-associated anti-NMDAR encephalitis remains largely unclear.This study aimed to investigate the role of prodromal headache in 28 patients diagnosed with anti-NMDAR encephalitis.Clinical data related to the prodromal headache characteristics of anti-NMDAR encephalitis patients were prospectively collected from January first 2017 to June first 2018. Autoimmune antibodies in the cerebrospinal fluid (CSF) of anti-NMDAR encephalitis patients were detected by an indirect immunofluorescence staining kit. The differences between age, sex, clinical symptoms (fever, epilepsy, psychiatric symptoms, cognitive impairment, disturbance of consciousness), CSF, brain MRI abnormalities, and modified Rankin Scale (mRS) score were compared between patients with and without headache. In addition, the association of headache severity with brain MRI abnormalities, antibody titers, and mRS score was examined.Twenty-eight patients with anti-NMDAR encephalitis (median, 29 years; range, 15-62 years) reported headache. Among them, 18 (64%) were female, 24 (86%) had fever, 21 (75%) were positive for serum virus antibody, 19 (68%) had severe pain intensity (scored 4-7 out of 10 on the visual analog scale), 18 (64%) presented with pulsating character, and 5 (18%) patients accompanied by vomiting. Moreover, headache was detected in the frontal lobe of 14 (50%) patients and temporal lobe of 12 (43%) patients. Encephalitic symptoms (psychiatric symptoms, cognitive dysfunction, epilepsy, and memory deficits) appeared in 23 patients at average 5.5 days (range, 1-21 days) followed by headache attack. In five patients, the headache was lasted for 21 days.Prodromal headache is commonly found in the temporal lobe and frontal lobe of young patients, and hardly accompanied by vomiting. Headache is rapidly substituted by encephalitis symptoms in the majority of patients, while gradually relieved in a few patients after the recovering from encephalitis symptoms. The results strongly suggest that the NR1 subunit of NMDAR is involved in prodromal headache. In sum, the symptom of prodromal headache is crucial for the diagnosis of anti-NMDAR encephalitis.