Abstract
ObjectiveTo investigate the nature of prodromal headache in anti‐NMDA receptor (NMDAR) encephalitis.MethodsRetrospective review of the clinical information of 39 patients with anti‐NMDAR encephalitis admitted between January 1999 and September 2017. Five patients with an atypical presentation were excluded. Thus, in 34 patients (median 27 years [range, 12–47 years]; 28 [82%] female), the clinical features were compared between patients who initially reported headache and those who did not report.ResultsTwenty‐two patients (65%) reported headache either transiently (n = 5) or continuously (n = 17). Encephalitic symptoms (psychobehavioral memory alterations, seizure, dyskinesias, or altered level of consciousness) developed in 20 patients with median 5.5 days (range, 1‐29 days) after headache onset. In one patient, NMDAR antibodies were detected in CSF 3 days after headache onset. Patients with headache had more frequently fever (14/22 [64%] vs. 2/12 [17%] p = 0.013) and higher CSF pleocytosis (median white blood cells 79/μl [range, 6‐311/μl] vs. 30/μl [range, 2‐69/μl], p = 0.035) than those without headache, but there was no difference in gender, age at onset, seizure, migraine, CSF oligoclonal band detection, elevated IgG index, tumor association, or brain MRI abnormalities between them.ConclusionsHeadache often developed with fever and pleocytosis, but it was rapidly replaced by psychiatric symptoms. Based on current knowledge on the antibody‐mediated mechanisms that cause a decrease of synaptic NMDAR through crosslinking and internalization leading to a state mimicking “dissociative anesthesia,” we speculated that prodromal headache is not likely caused by direct effect of the autoantibodies but rather meningeal inflammation (noninfectious aseptic meningitis) that occurs in parallel to intrathecal antibody synthesis as an epiphenomenon of NMDAR autoimmunity. Psychobehavioral alterations following headache is an important clue to the diagnosis.
Highlights
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis caused by autoantibodies against the extracellular conformal epitope on the NR1 subunit of the NMDA receptor (NMDAR) (Dalmau et al, 2007, 2008)
Headache, fever, or other associated symptoms that developed before the onset of encephalitic symptoms were regarded as prodromal symptoms, but headache or fever following the onset of encephalitic symptoms was not included in prodromal symptoms
The interval from headache onset to encephalitic symptoms onset was determined in 20 patients with headache; 2 patients, who complained of headache with fever after the onset of encephalitic symptoms, were not included
Summary
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis caused by autoantibodies against the extracellular conformal epitope on the NR1 subunit of the NMDAR (Dalmau et al, 2007, 2008). Patients typically present with predictable multistage illness beginning with prodromal illness and followed by prominent psychiatric symptoms and seizures (Dalmau et al, 2007, 2008; Iizuka et al, 2008; Titulaer et al, 2013). Afterward, they rapidly fall into an unresponsive state characterized by profoundly decreased level of consciousness, central hypoventilation, intractable orofacial-limb dyskinesias, seizures, and autonomic symptoms (Dalmau et al, 2007, 2008; Iizuka et al, 2008; Titulaer et al, 2013). We reviewed the clinical features of patients with anti-NMDAR encephalitis and report potential mechanisms of prodromal headache in this disorder
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