The document discusses autoimmune encephalitis (AE), including several case vignettes. It notes that AE can develop after infections like herpes simplex encephalitis (HSE), with symptoms emerging weeks or months later. Childhood AE often presents with movement disorders, while adult AE more commonly involves psychiatric symptoms. Treatment involves immunotherapy like IVIG, plasma exchange, and steroids. Outcomes vary and full recovery is not always achieved.

1. Autoimmune
Encephalitis
Dr.M. I. N. Ikram
Registrar in Psychiatry
PGIM – Colombo
2023

2. Autoimmune Encephalitis

3. ● Age 24yrs
● Female
● Admitted to mental health unit
● p/c- auditory hallucinations (1st onset psychosis)
● After admission- involuntary movements with
catatonic posturing
● Within a week - she became confused
episode of GTC fits
Case Vignette - 1

4. ● Initial Ix
● MRI brain – normal
● EEG- diffuse slowing - diffuse but non-specific encephalopathy
● CSF – 5 WBC/HPF
protein 1.12g/dl
No oligoclonal bands (?)
● RFT - normal
● LFT - normal
● WBC/DC - normal
● NMDAR antibodies - detected

5. ● Tachycardia
● Hypotention
● Later required invasive ventilation
● CT chest, abdomen and pelvis – non diagnostic
● PET – hypermetabolic L/ovary
● Laparoscopic – oophorectomy
○ Histology - ovarian teratoma

6. ● Treatment
● plasma exchange was initiated
● followed by a course of high dose oral steroids
● Removal of teratoma of ovary
● Able to perform ADL after 12 months from initial admission

7. ● 13yr old boy was admitted to medical prof. unit
● P/C – acute onset altered behaviour
confusion
fluctuating levels of consciousness
deterioration of speech
selective mutism
● Brief Hx of fever before onset of behavioural change
● After one day – started to give vague Hx of abuse by grand mother
● SHx – lower socio-economic back ground
punitive father with alcohol misuse behaviour
Case Vignette - 2

8. ● Ix
● CT scan brain - Normal
● EEG - Normal
● CSE - Normal
● WBC/DC - Normal
● Mx – IM haloperidol 5mg stat
developed severe dystonic reactions
● Transferred to Paed. Ward after 4days for accommodation
● Experienced clinician had suspicion and empirically started on IVIg
● Drastically improved in 2 days without any functional impairment

9. ● 16yr old girl
● P/C – depressive symptoms
● Got admitted to a psychiatry ward
● 6 ECT given - no improvement
● gradually developed behavioural changes
● After one month Neurology referral done to exclude organic cause
Case Vignette - 3

10. ● AIE diagnosed at neurology ward
○ IVIg given
○ High dose oral Steroids started
● Deteriorated and had to keep in ICU and assisted ventilation done
for 6 weeks
● Gradually recovered

11. ● An immune-mediated neurological disease
● more often refers to the targeting of neuronal cell surfaces, synapses,
or intracellular antigens by autoantibodies
● may result in developmental delay or regression in children
● pathogenesis of AE is not clear
● immune system disorders after infection likely play an important role
Autoimmune Encephalitis

12. Targets of Antibodies in AE
neuronal surface antigens
influenced by B cell immunity
Ex: Anti-NMDAR antibodies
Anti-D2R antibodies
Anti – VGKC antibodies
1
intracellular antigens
mediated by cytotoxic T cells
Ex: Anti-Hu antibodies
Anti-Ma2 antibodies
Anti-GAD antibodies
2

13. ● Several types of AE, including anti-Hu encephalitis and anti-Ma2
encephalitis are associated with tumours (called neurological PNS)
● Tumours are rare in children
● paediatric AE is different from adult AE in terms of
○ the clinical features
○ autoantibody profiles
○ Treatment response
○ long-term outcomes
Autoimmune Encephalitis

14. ● Seizures (83%) – Most common
● Behavioural disorders (63%)
● Neuropsychiatric disturbances (56%) – includes agitation &
hallucinations
● Altered levels of consciousness
● Confusion (50%)
● Movement disorders (30%-38%) – includes choreoathetosis, ataxia,
dystonia, myoclonus, orofacial dyskinesias or tremor
● Disturbed sleep
● memory impairment
● Autonomic dysfunction
Neurological manifestations of Paediatric AE

15. It is difficult for those
caring for very young
children with AE to fully
assess memory and
language difficulties

16. ● anti-NMDAR encephalitis
● anti-GABAAR encephalitis
● D2R encephalitis
● anti-metabotropic glutamate receptor 5 encephalitis
Associated with
flulike or gastrointestinal symptoms
Ex : headache, fever, irritability, nausea, diarrhoea
Triggers of AE

17. ● Infections with pathogenic microorganisms
○ Mycoplasma
○ Epstein-Barr virus
○ Streptococci
○ Varicella zoster virus
○ Cytomegalovirus
○ Human herpes virus
○ Enterovirus
Triggers of AE

18. ● AE is likely to be associated with infection YET treatments for AE and
infections are different
● AE may be treatable by immunosuppressive treatments
● therapies for AE are associated with infectious complications

19. Post-infection AE
Clinical manifestations Children Adults
latent period before AE Shorter Longer
movement disorders More common Less common
psychiatric symptoms Less common More common

20. ● The incidence of AE is higher during the winter and spring months
and in locations that are far from the equator, coinciding with the
peak timing and location of respiratory tract diseases
● 56% of children with AE commonly present with prodromal
symptoms followed by neuropsychiatric symptoms, which indicates
that the infection was associated with AE
● Approximately 19% of paediatric patients with anti-NMDAR
encephalitis have detectable human herpesvirus in their CSF
● acute mycoplasma infection may affect approximately 50% of people
with anti-NMDAR encephalitis who do not have a neoplasm
Relationship btw AE and infection

21. ● Some patients who were positive for herpesviruses (HSV, VZV, EBV,
CMV, HHV) had detectable neural and/or nonneural antibodies in
their CSF
● 42% of patients with anti-D2R encephalitis had b-haemolytic
streptococcal infections, mycoplasma pneumonia, and enteroviral
infections before they developed AE

22. Anti - NMDAR Encephalitis
• the most common type of encephalitis in children
• Most patients with HSE have biphasic disease
• HSE phase - fever, seizures, and disturbance of consciousness
symptoms improves with acyclovir

23. Anti - NMDAR Encephalitis
• AE phase - develop new symptoms several weeks or months
after the onset of HSE
recurrent seizures (85% to 93%)
psychiatric symptoms (51% to 93%)
movement disorders (80%), and
decreased levels of consciousness
does not respond to antiviral therapy
HSV1/2 PCR in the CSF is negative
compared with HSE, anti-NMDAR encephalitis results in fewer seizures
and a higher frequency of movement disorders

24. Anti - NMDAR Encephalitis
Children < 4y Children < 12y Adults
Common
manifestations
Choreoathetosis Movement
disorders
Memory deficits
Reduced LOC Seizures Hypoventilation
median time from HSE to the onset of AE was 32 days

25. Anti - NMDAR Encephalitis
● 27% of patients with HSE develop AE
● They are all positive for neuronal antigens
○ 64% were positive for NMDAR antibodies
○ 36% were positive for other antibodies (GABAAR ab, GAD65
ab)
● Some studies reported that children with chorea after HSE should be tested for
NMDAR and D2R in serum and/or CSF samples
● In children with AE
○ erythrocyte sedimentation rate
○ C-reactive protein level
○ platelet count
typically normal

26. ● In CSF tests at the onset of AE
○ white blood cell counts
○ protein levels
● nucleic acid tests to detect pathogenic microorganisms (PCR) were
negative
● anti-NMDAR encephalitis and GABAB receptor encephalitis, which
were associated with Epstein-Barr virus and varicella zoster virus
infections, had elevated WBC counts and protein levels in their CSF
(Linnoila et al.)
Slightly elevated

27. ● MRI in paediatric patients with post infection AE typically shows
contrast enhancement, similar to the findings during HSE
● All brain MRI scans of patients who developed anti-NMDAR
encephalitis after HSE showed necrosis with cystic lesions 4 months
after the onset of HSE

28. ● BBB dysfunction occurs before the onset of AE due to encephalitis
● Subsequently,
○ the immune response,
○ genetic factors, and
○ bystander activation or epitope spreading
appear to promote AE development and progression
causal relationship between
autoimmune CNS diseases and infections

29. Pathogens have proteins that are similar to neuronal antigens that
activate B and T cells
the inflammatory response attacks brain tissue
BBB dysfunction
glycans of lipo-oligosaccharides
from Campylobacter can induce
antibodies against glycans on
nerve gangliosides,
Epstein-Barr virus antigens are
structurally similar to myelin basic
protein

30. ● However, there is no evidence that HSV and NMDAR proteins are
similar.
● In addition, in anti-NMDAR encephalitis after HSE, various kinds of
neuronal antigens, such as GAD65 receptors and GABA receptors,
can be detected after HSV infection

31. ● In the CNS, microglia are a type of immune cells responsible for the
immune response to injury and infection
● infection induces proinflammatory cytokine production and the
expression of MHC II
● Neutrophils have been associated with BBB dysfunction in
experimental models of AE, and they are able to produce many
proinflammatory factors
● The depletion of neutrophils delays or even attenuates the
development of AE
The immune response

32. ● Toll-like receptors
○ promote the interaction of microglia with exogenous and
endogenous ligands
○ enable microglia to express antigens and then activate the
adaptive immune response
○ also recognize host-derived agonists
○ promote T cell infiltration

33. ● Cytokines
○ The protein levels of pentraxin 3 and IL-6 are increased in the
CSF of patients with anti-NMDAR encephalitis
○ AE with refractory status epilepticus were treated with
tocilizumab targeting the IL-6 receptor, their seizure activity
improved
● B lymphocytes, T lymphocytes, dendritic cells, and antigen-
presenting cells are essential factors in the adaptive immune system
○ patients with anti-NMDAR encephalitis was found to have
increased number of CD19+ cells in their CSF

34. ● Patients with anti-GABABR encephalitis had increased levels of
CD19+, CD138+, CD4+, and CD8+ lymphocytes
● patients with increased CD8+ T cell counts had relatively worse
neuropsychological outcomes

35. ● LGI1 encephalitis is associated with 7 SNP in the human leukocyte
antigen (HLA) II region
● HLA-DR7 and HLA-DRB4 were strongly related to nonneoplastic anti-
LGI1 encephalitis
● There was no association of HLA genotypes with anti-NMDAR
encephalitis
Genetic susceptibility

36. ● Post infection AE is likely associated with the inflammatory environment
○ infection activates the immune response (B cells)
○ B cells leads to antibody production and tissue damage
○ injured tissue releases antigens that are taken up by antigen-presenting
cells leading to the production of autoantibodies
● HSE shows an anatomic affinity for limbic structures, and this damaged brain
tissue releases neuronal antigens that are unknown to the immune system.
● Therefore, these antigens cause autoimmune activation
● Th17 lymphocytes are thought to be associated with basal ganglia encephalitis
Bystander activation or epitope spreading

37. ● Most patients with AE are responsive to immunotherapy
● first-line - intravenous immunoglobulins, steroids, and plasma exchange
● second-line - rituximab, cyclophosphamide, or others
● patients with post infection AE had a worse prognosis than those with classic AE
● older children appeared to be more responsive to immunotherapy
Treatment of autoimmune encephalitis in
children

38. ● whether immunotherapy during HSE can prevent the development of
AE remains unclear
● there is no evidence that the use of steroids during the course of
infection can inhibit the onset of AE
● there were no significant differences between patients who
developed AE after HSE and those who did not (Armangue et al.)

39. ● indicate screening for AIE in patients with psychotic symptoms
● sudden-onset paranoid psychosis or rapid deterioration
● prodromal headache or raised temperature prior to onset of psychosis
● cognitive impairment (short-term memory, disorientation) including evidence of
delirium
● Catatonia - Orofacial dyskinesia
● Seizures - faciobrachial seizures
● autonomic disturbance (hypo-/hyperthermia, unstable blood pressure, raised
respiratory rate, tachycardia); suspected neuroleptic malignant syndrome
● hyponatraemia (indicator of anti-VGKC-complex LGI1 encephalitis)
Red flag signs

40. Which test to perform?
● anti-NMDA receptor antibodies
● Anti-VGKC-complex ( LGI1 or CASPR2 )
● Other antibodies – rare and not in association with primary
psychiatric presentations
Other Ix
● EEG - epileptiform activity or slow waves
● MRI - Medial temporal hyperintensity
● CSF - for specific antibodies
● raised CSF protein- non specific
● Pleocytosis and oligoclonal bands in CSF
● ESR/CRP – usually normal
screen for an underlying malignancy
● whole-body CT scan and if negative, a PET scan
● MRI scans are useful - teratomas may be missed by CT and PET

41. ● Among patients with AE, children are less likely to have tumours
● prodromal symptoms of AE were associated with infections
● several studies have reported that 14% to 27% of patients with HSE have “relapse” symptoms;
antiviral treatment is ineffective, but immunotherapy is useful
● multiple mechanisms underlying these relationships (including molecular mimicry, bystander
activation, and epitope spreading), and the host innate and adaptive immune systems may be
involved in the onset and progression of AE
Conclusion

42. ● HLA haplotypes, play roles in the mechanisms underlying post infection AE
● treatment of AE consists of immunotherapy
● However, the optimal timing and duration of corticosteroid treatment have not yet been
determined
● Recovery is not always to the premorbid level (Dalmau et al.)
● Clinical symptoms of this disorder correlate with antibody levels (Dalmau et al.)
Conclusion