Case 5 - autoimmune encephalitis

Question 1

epidemiology

Answer 1

80% female
mean age of onset 21 years old
40% have underlying neoplasm

Question 2

pathophysiology

Answer 2

Autoimmune encephalitis refers to acute/subacute, progressive inflammation of the brain associated with antibodies against neuronal cell surface and synaptic protein, most commonly being anti - NMDA receptor encephalitis.
* Within the brain, these autoantibodies tend to congregate within the limbic system and produce inflammatory degeneration.

Question 3

paraneoplasmic syndrome

Answer 3

• Associated tumours may include small cell carcinoma of the lung, Hodgkin’s lymphoma, thymoma, germ cell testicular tumours, neuroblastomas, breast cancer and ovarian teratoma.
• The tumour, if present, usually expresses the same antigen that is bound on the neuronal surface, and this is responsible for breaching the immunologic tolerance and raising an immune reaction against the neurons in question

Question 4

non-paraneoplasmic onset

Answer 4

• Cases with AIE often have an infection as a preceding event, causing inflammation leading to neurological symptoms.
• There have been case reports and observational studies to suggest that herpes simplex virus encephalitis (HSVE) triggers immune response causing Anti- NMDAR encephalitis.
• Also, genetic factors like human leukocyte antigen (HLA) were strongly associated with certain antibody production causing autoimmune response

Question 5

antibody cytotoxic mechanism

Answer 5

• Antibodies that are targeted against intracellular proteins normally serve as markers to cytotoxic T cells that attack the marked neurons and they may be destroyed
• Other antibodies (that mark extracellular proteins) can lead to destruction, blocking and internalisation (anti-mGluR1) of target protein and leave the cell functional

Question 6

symptoms

Answer 6

• Depend on the antibody type of which around 16 have been identified

3 stages:
1. Flu like symptoms
2. Psychiatric issues (behavioural changes, etc.)
3. Neurological issues (catatonia, ataxia, etc.)

Question 7

genetics

Answer 7

• It turns out that some types of autoimmune encephalitis, like limbic encephalitis, are more closely tied to genetic risk factors than other AE types like NMDAR-AE.
• The main genetic factor that has been associated with limbic encephalitis is called human leukocyte antigen (HLA).
• The most common form of limbic encephalitis that is not caused by cancer involves anti-LGI1 antibodies
• Anti-LGI1 limbic encephalitis is associated with a mutation in part of the class II HLA gene complex –> IgG4 isotype
• Anti-NMDAR encephalitis has not been found to have a strong relationship to HLA mutations
• Anti-NMDAR encephalitis is caused by antibodies of the IgG1 isotype, which may explain why there is a weaker association with genetic variations in HLA, which are more strongly associated with the IgG4 isotype  mGluR1 is also IgG1 so probably not HLA associated

Question 8

biomarkers

Answer 8

• Traditional methods for AE diagnosis are using CFS to detect relevant positive Igs
• MRI and EEG may be helpful for excluding other causes (differential diagnosis)

Question 9

detecting mGluR1 AIE

Answer 9

• Cell based assay
  1. Lumbar puncture to collect CSF
  2. Produce plasmids that contain the gene for mGluR1 and a strong promotor
  3. Grow Hek2-cells to desired cell density
  4. Transfect Hek2-cells with the plasmid DNA
  5. Wait for the Hek2 cells to highly express mGluR1
  6. Add the CSF to the Hek2 cells
  7. Then wash away the CSF
  8. Add anti-human-antibody with fluorescent marker
  9. Wash
  10. If there is a signal that means that there was indeed anti-mGluR1 in the CSF of this patient