Autoimmune post-herpes simplex encephalitis of adults and teenagers

Abstract

Objective: 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.

Methods: Prospective observational study of patients diagnosed between June 2013 and February 2015. Immunologic techniques have been reported previously.

Results: 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, p < 0.01) and decreased level of consciousness (2/8 vs 6/6, p < 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, p = 0.037).

Conclusion: 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.

Figure 1. Drawings by patient 8 at presentation of relapsing symptoms post–herpes simplex virus encephalitis and after immunotherapy

Drawings by patient 8 at the time of relapsing symptoms (tree, family, and house, A, D, and G), 3 weeks after immunotherapy (B, E, H), and at a 6 months follow-up (C, F, I). At presentation of relapsing symptoms, the patient had severe anterograde amnesia, confusion, disorganized thoughts, and disorientation to place, time, and person. After immunotherapy, her symptoms resolved except for amnesia and temporal orientation.

Figure 2. Demonstration of brain autoantibodies in a patient with autoimmune relapse post–herpes simplex virus encephalitis

Consecutive sections of rat brain immunostained with CSF of a participant without NMDA receptor (NMDAR) antibodies (A, negative control), a patient with classical anti-NMDAR encephalitis (B, positive control), and the CSF of patient 9 by the time of herpes simplex virus encephalitis (C) and on day 19 when relapsing neurologic symptoms due to autoimmune encephalitis occurred (D). The CSF of patient 9 shows a pattern of antibody reactivity typical of NMDAR but superimposed with diffuse background staining (compare B with D), likely representing disruption of the blood–brain barrier or additional antibodies against other autoantigens (targets unknown). A similar background staining was noted in the CSF of the other patients; this dirty background usually clears up during CSF follow-up studies and eventually disappears (e.g., the reactivity becomes clear and indistinguishable from that seen in B; data not shown). In B and D, the presence of NMDAR antibodies was confirmed with cell-based assay (not shown). Bar = 500 μm.

Figure 3. MRI findings in patients with relapsing symptoms post–herpes simplex encephalitis

Axial fluid-attenuated inversion recovery sequences of patients 1 (A, B) and 2 (C, D) during herpes simplex virus encephalitis (HSE) (A, C) and during relapsing symptoms due to autoimmune encephalitis (B, D). In both cases, there is an interval change due to areas of encephalomalacia, brain atrophy, and white matter changes. Panels E–H correspond to T1 sequences with contrast from patient 3 obtained during HSE (E), a few weeks later during relapsing symptoms due to autoimmune encephalitis (F, G), and after symptom improvement (H). Note that the areas of contrast enhancement during autoimmune encephalitis resolved after symptom improvement. Panels I–L correspond to patient 4 during HSE (I, T2; J, T1 with contrast) and 1 year later (K, T2; L, T1 with contrast). In this patient, the relapsing symptoms post-HSE were not recognized as autoimmune encephalitis for 1 year; during this year, he did not receive immunotherapy and had persistent symptoms and contrast enhancement in MRI.