Frequency, symptoms, risk factors, and outcomes of

autoimmune encephalitis after herpes simplex

encephalitis: a prospective observational study and

retrospective analysis

Thaís Armangue, Marianna Spatola, Alexandru Vlagea, Simone Mattozzi, Marc Cárceles-Cordon, Eloy

Martinez-Heras, Sara Llufriu, Jordi Muchart,

María Elena Erro, Laura Abraira, German Moris, Luis Monros-Giménez, Íñigo Corral-Corral, Carmen

Montejo, Manuel Toledo, Luis Bataller,

Gabriela Secondi, Helena Ariño, Eugenia Martínez-Hernández, Manel Juan, Maria Angeles Marcos, Laia

Alsina, Albert Saiz, Myrna R Rosenfeld,

Francesc Graus, Josep Dalmau, on behalf of the Spanish Herpes Simplex Encephalitis Study Group* Lancet Neurol 2018; 17: 760–72

Hintergrund

Herpes simplex virus encephalitis

• Worldwide incidience of 2-4 cases / million per year (1)

• Peak age children/elderly

• Mortality 10-25%; 40-55% of surving patients resume act. daily

living (2)

• Relapses 5-26% (3-6), some cases with persistance HSV-PCR in

CSF, some cases negative HSV-PCR autoimmun encephalitis

• Symptoms in previous studies: children – Choreoathetosis (15),

adults – psychiatric and behavioral symptoms (8, 16)

Aim of study:

• Frequency? Clinical symptoms? Frequency of neuronal

antibodies? Neurological long-term outcome?

Study design / Methods

Prospective observational study and retrospective

analysis

• 19 secondary + tertiary centers in Spain

• Follow up 1a

• Prospective: Cohorte A (01/14 – 10/17)

• Retrospective: Cohorte B (10/11 – 10/17)

Study design – Inclusion / Exclusion

Inclusion:

• Diagnosis of HSV-encephalitis + Pos. PCR of CSF (HSV 1/2)

• Aciclovir i.v. 1500mg/m2 if <13a, 30mg/kg KG für >12a divided every 8h for

14-21 days. Steroids, i.v.-immunglobulins at physicians discretion

Exclusion Cohort A:

• Death <3 weeks of recruitment

• Interval >10d between symptom onset and recruitment

Exclusion Cohort B:

• Interval > 4 mo between symptom onset of autoimmune encephalitis and

determination of serum/CSF antibodies

Consideration of probable autoimmune encephalitis if:

• Development of new-onset CNS-symptoms or worsening of deficits > 24h,

negative PCR of CSF for HSV and exclusion of other complications

Procedures

Cohort A:

• Clinical informations with standardised questionnaires at: Diagnosis

HSV-encephalitis, stop aciclovir and at 2-/6-/12-month follow up

• Assesment of neurogical function (modified Ranking Scale) at: 2-/6-

/12 months follow up

• Anti-IgG vs. NMDAR + other neuronal surface proteins in serum and

CSF at diagnosis HSV-encephalitis + Stop aciclovir and in serum at

2-/6-/12-month follow up (+ new-onset symptoms)

• Brain MRI at discretion of treating clinician (centrally viewed)

Procedures – Cohort B

Cohort B:

• Questionnaires on all patients suspected of having autoimmune

encephalitis

• Serum + CSF: autoantibodies

• Study of symptoms while autoimmune encephalitis (not

retrospective)

Results N=50 HSV1

N=1 HSV2

Results Cohort A – baseline characteristics (1/2)

Baseline char. (2/2)

2/21/2019

Präsentationstitel in der Fusszeile des Folienmasters definieren

Results -

Overview

Results – closer look

Results Cohort A – Brain MRI

No development

of AE (n = 37)

Development

of AE (n = 14)

p-value

Lesion volume in Brain MRI at

onset HSV-enzephalitis

No significant difference

Contrast enhancementat

comparable during viral

encephalitis

6/10 patients

(60%)

9/11 patients

(82%)

Progression of local white-

matter or grey-matter

abnomalities or local atrophy

No significant difference

Necrosis with cystic lesions >

4 mo after HSV-encephalitis

n = 7/14 (50%) n = 9/9

(100%)

p = 0.019

2/21/2019 Präsentationstitel in der Fusszeile des Folienmasters definieren 13

Results Cohort A - Antibodies

No development of AE (n = 37) Development of AE (n = 14) P-value

IgG-Ab

in CSF

Overall

time

3-week

follow

up

30% (n=11/30) pos.

• 27% (3/11) NMDAR-Ab, 73%

Ab against unknown antigen

14% (5/37) Ab-pos.

100% (n=14) pos.

• 64% (9/14) NMDAR-Ab, 1/14

GABA-receptor-AB, 36% (5/14)

Ab against unkown antigens

64% (9/14) pos.

p<0.001

p=0.001

IgG-Ab

in

serum

4% (1/26) 50% (7/14) Ab-pos. p=0.001

CSF at

onset

AE

HSV1/HSV-PCR neg., pleocytosis

(median 17/mm3), Protein ↑

(median 61mg/dl)

Results Cohort B - Antibodies

Cohort B (median age 8.8 years, IQR 1.1-44.2) n=48

• 92% (n = 44/48) Ab-pos. (77% (n = 34/44) NMDAR-Ab,

23% (n = 10/44) Ab vs. unknown antigens

• 100% (n = 44/44) in CSF vs. 76% (n = 25/33) in serum

Präsentationstitel in der Fusszeile des Folienmasters definieren

* 58% (18/31)

presented with

psychosis

*

*** No

difference in

outcome

between

patients with

NMDAR-Ab

and those with

other neuronal

surface Ab ***

Results Cohort A + B - AE

**

** median age

NMDAR-Ab

2.2 years

Other-Ab 56

years

Sensitivity, specificity, positive predictive

value, and negative predictive value of neuronal

surface antibodies for the risk of

developing of AE post-HSE*

?

Summary

• Cohort A: 27% of patients with HSV-encephalitis

symptoms of autoimmune encephalitis within 3 months

post treatment aciclovir

• Symptoms Cohort A + B (> 4 years): predominantly

behavioral change and psychiatric symptoms (58%

psychosis)

• Risk factors Cohort A: the detection of neuronal

antibodies at 3-week follow-up

• Any neuronal Ab: p = 0.001, OR 11.52 (2.72-28.79)

• NMDAR-Ab: p = 0.001, OR 14.40 (1.45-143.7)

Discussion – Limitations and take home

Limitations:

• No. of individuals in Cohort A relatively small

• Only serum testing for Ab in later follow-ups (development

of CSF-Ab of non-AE patients at a later time possible)

• Retrospective information of HSV-enzephalitis in Cohort B

• Cohort B: 4 adult patients developed late symptoms of AE

(306 days) or relapses at 60, 699, 723 days after HSV-

encephalitis ( of HSV oder autoimmun?)

Take home message: Awareness. Clinical follow ups?

Vielen Dank für die Aufmerksamkeit!

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