<h3>Objective:</h3> To report 14 patients with immune-mediated relapsing symptoms post–herpes simplex encephalitis (HSE) and to compare the clinical and immunologic features of the teenage and adult group with those of young children. <h3>Methods:</h3> Prospective observational study of patients diagnosed between June 2013 and February 2015. Immunologic techniques have been reported previously. <h3>Results:</h3> Among the teenage and adult group (8 patients, median age 40 years, range 13–69; 5 male), 3 had an acute symptom presentation suggesting a viral relapse, and 5 a presentation contiguous with HSE suggesting a recrudescence of previous deficits. Seven patients developed severe psychiatric/behavioral symptoms disrupting all social interactions, and one refractory status epilepticus. Blepharospasm occurred in one patient. Five patients had CSF antibodies against NMDA receptor (NMDAR) and 3 against unknown neuronal cell surface proteins. In 5/6 patients, the brain MRI showed new areas of contrast enhancement that decreased after immunotherapy and clinical improvement. Immunotherapy was useful in 7/7 patients, sometimes with impressive recoveries, returning to their baseline HSE residual deficits. Compared with the 6 younger children (median age 13 months, range 6–20, all with NMDAR antibodies), the teenagers and adults were less likely to develop choreoathetosis (0/8 vs 6/6, <i>p</i> < 0.01) and decreased level of consciousness (2/8 vs 6/6, <i>p</i> < 0.01) and had longer delays in diagnosis and treatment (interval relapse/antibody testing 85 days, range 17–296, vs 4 days, range 0–33, <i>p</i> = 0.037). <h3>Conclusion:</h3> In teenagers and adults, the immune-mediated relapsing syndrome post-HSE is different from that known in young children as choreoathetosis post-HSE and is underrecognized. Prompt diagnosis is important because immunotherapy can be highly effective.
