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Observational Study
. 2018 Sep;17(9):760-772.
doi: 10.1016/S1474-4422(18)30244-8. Epub 2018 Jul 23.

Frequency, Symptoms, Risk Factors, and Outcomes of Autoimmune Encephalitis After Herpes Simplex Encephalitis: A Prospective Observational Study and Retrospective Analysis

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Free PMC article
Observational Study

Frequency, Symptoms, Risk Factors, and Outcomes of Autoimmune Encephalitis After Herpes Simplex Encephalitis: A Prospective Observational Study and Retrospective Analysis

Thaís Armangue et al. Lancet Neurol. .
Free PMC article

Abstract

Background: Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication.

Methods: We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis.

Findings: Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001).

Interpretation: The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy.

Funding: Mutua Madrileña Foundation, Fondation de l'Université de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX.

Conflict of interest statement

Conflicts of interest:

Dr. Dalmau holds patents for the use of Ma2, NMDAR, GABAbR, GABAaR, DPPX and IgLON5 as autoantibody tests. Dr. Graus holds a patent for the use of IgLON5 as an autoantibody test. Dr. Rosenfeld holds patents for the use of Ma2 and NMDAR as autoantibody tests. Drs. Dalmau, Graus, and Rosenfeld receive royalties related to autoantibody tests from Athena Diagnostics and Euroimmun, Inc. The rest of the authors have no conflicts of interest.

Figures

Figure 1:
Figure 1:
Patients included in Cohorts A and B Algorithm demonstrating the total number of patients studied (107) and those who fulfilled the inclusion criteria (99). Overall, 58 patients had antibody confirmed AE post-HSE.
Figure 2:
Figure 2:. Timing of antibody detection, development of AE, and follow-up of serum testing and neurologic status.
(A) Patients from Cohort-A, who developed neuronal surface antibodies in association with AE. None of the patients had neuronal surface antibodies at the time of HSE onset, but all were antibody positive at onset of symptoms of AE. In all patients the presence (+) or absence (−) of neuronal cell-surface antibodies in serum was followed for 1 year. The neurological status was measured with the modified Rankin Scale (mRS) and is color coded. (B) Patients from Cohort-A, who developed neuronal surface antibodies without AE. These patients became antibody negative sooner than those of patients with AE. *In all patients, the highest serum titers were identified within the first 2 months of follow-up; ** NMDAR antibodies with co-existing GABAAR antibodies; ***NMDAR antibodies with co-existing GAD65 antibodies; at 1 year follow-up only GAD antibodies remained detectable (not shown). AE, autoimmune encephalitis; CSF, cerebrospinal fluid; d, day; F, female; HSE, herpes simplex encephalitis; M, male; mRS, modified Rankin score; na, not available.
Figure 3:
Figure 3:. Antibodies against neuronal surface antigens.
Sagittal sections of rat hippocampus immunostained with CSF from a patient with NMDAR antibodies (A), CSF from a patient with antibodies against unknown neuronal antigens (C), or CSF from a patient without neuronal antibodies (E). The same patients’ samples were used to immunolabel primary cultures of live rat hippocampal neurons (B, D, F) respectively. In B, D and F, the nuclei of the neurons are shown with DAPI. Scale bars in A, C, E = 500 μm; Scale bars in B, D and F = 10 μm.
Figure 4:
Figure 4:. MRI follow-up in patients who developed AE compared with those who did not develop AE.
Each row corresponds to a different patient and includes MRIs obtained at diagnosis of HSE, at 1–3 month follow, and at 6–9 month follow-up. The first three columns of images correspond to FLAIR sequences, and the last 3 columns to T1 sequences, all with contrast (except case 1 last follow-up). Patient 1 (first row): 10 month-old boy (case #4) who developed AE post-HSE with NMDAR antibodies. Patient 2 (second row): 56 year-old woman (case #10) who developed AE post-HSE with antibodies against unknown neuronal surface antigens. Patient 3 (third row): 49 year-old woman who developed HSE without AE or neuronal antibodies (she had history of lung adenocarcinoma, brain metastasis, and cranial radiotherapy). Patient 4 (fourth row): 66 year-old woman (case #24) who developed NMDAR and GAD65 antibodies but without symptoms of AE. In all patients the MRIs obtained at the 1–3 month follow-up show areas of FLAIR hyperintensity (larger or similar to those obtained at diagnosis of HSE); however, the MRIs of patients who developed AE (1st and 2nd patients) show more extensive areas of post-necrotic cystic abnormalities than those who did not develop AE (3rd and 4th). Note that all patients, except patient 4th, have areas of contrast enhancement at 1–3 month follow-up.

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