This file is a presentation on basics of Autoimmune Encephalitis

1. AUTOIMMUNE ENCEPHALITIS

2. WHAT IS AUTOIMMUNE
ENCEPHALITIS

3. • The immune reactions in brain depends on
the interaction between the immune system,
innate (glial cells) or adaptive (lymphocytes),
and nervous tissue and is modified by blood
brain barrier.
• This interaction is seen in many diseases of
the nervous system like the multiple sclerosis
or neurodegenerative diseases

4. • A more specific form of autoimmunity in CNS is
now recognized in the form of antibodies that
bind to neuronal cell surface/synaptic receptors
or ion channel related proteins.
• These antibodies are detected in adults as well
as the children.
• The antigens, essential for cellular function and
neurotransmission, are expressed to different
extent in the CNS.
• The clinical signs may depend on the extent of
brain regions targeted by the antibodies.
• The effects may be reversible and the patient may
frequently recover.

5. • Some of these disorders may be paraneoplastic.
These disorders are often known to be associated
with cancer.
• They however differ from paraneoplastic
encephalitis because in the latter, the antibodies
affect the intracellular proteins such as Hu or
CRMP5, and the T cell mechanisms lead to
irreversible neuronal dysfunction.
• In contrast to classical paraneoplastic syndromes,
these conditions respond to immunotherapy.

6. WHY IS IT IMPORTANT TO KNOW
ABOUT AUTOIMMUNE ENCEPHALITIS

7. • Large multicentre trials e.g. UK encephalitis
study and California Encephalitis project, have
demonstrated that almost one fifths of the
acute or subacute encephalitis patients who
are not detected to have an infection may be
autoimmune encephalitis.
• This and the response to immunotherapy has
led to a paradigm shift in approach to
autoimmune encephalitis

8. DETECTION OF AUTOIMMUNE
ENCEPHALITIS

9. • The key clinical features of the autoimmune
encephalopathy are
– seizures,
– altered mental state- confusion, disorientation,
– behavioral changes,
– cognitive impairment,
– movement disorders,
– autonomic dysfunctions and
– sleep disorders.
• There may be a preceding prodrome of headache
and fever suggesting a viral illness.
• The symptoms overlap and the cause may not be
apparent from history and examination.

10. • Seizures suggests a encephalitic process but
the inflammation may not be evident in the
radiological scans or cerebrospinal fluid.
Hence encephalopathy is a more apt term, but
may be used interchangeably with
autoimmune encephalitis.

11. • The most specific and appropriate tests are cell based
assays. These allow detection of antibodies binding
epitopes of neuronal surface antigens in a manner
similar to when the antigens are exposed in a
circulating fluids.
• The antigen is transfected to a suitable human cell line
and the mosaic of such fixed cells expressing different
antigens may be used commercially.
• Alternatively, live cell assays can be developed but are
much more time consuming.
• Both serum and csf may be used, however csf may
yield much more positive results (given the normal
ratio of serum to CSF immunoglobulin G levels of
around 400). Besides serum is more sticky.

12. • Other methods such as IHC, immunoblotting
and radioimmunoprecipitation assays can be
used but have individual limitations.

13. WHEN TO SUSPECT AUTOIMMUNE
ENCEPHALITIS

14. • Most clinicians rely on algorithm based parameters to
support autoimmune or immune causes.
• This is more so since the threshold for considering
immunotherapy becomes important.
• Autoimmune encephalitis should be considered in any
patient with a rapidly progressive encephalopathy of
unclear origin.
• Any immunological type of autoimmune encephalitis can
have a relapsing course and therefore the diagnosis of
these disorders should be considered in patients with a
past history of encephalitis or relapsing encephalopathy.
• The final diagnosis relies upon identification of neuronal
antibodies and/or positive response to immunotherapy.
• Attempts have been made to categorize the likelihood of
autoimmune cause to definite, probable, or possible.

15. LIMITATIONS OF THE TESTS

16. • While the diagnosis is based on
demonstration of antibodies, the tests may be
negative frequently. One should consider the
follows in the situation-

17. 1. The samples are best taken when the patient is
symptomatic and maximally affected. Outside the
clinical event, the test may be negative. The tests may
be repeated on samples previously collected.
2. The immunotherapy, once initiated may influence the
results. Where plasmapheresis may result in false
tests, use of immunoglobulins may actually yield false
positive tests.
3. CSF samples yield a better report than the serum.
4. It is possible that the test is negative because the
precise antigenic target has yet to be identified. Thus
the absence on identification of a known antibody
should not exclude the diagnosis of autoimmune
encephalopathy or preclude initiation of treatment

18. CASE 1
• The patient a 26 year old female presented to
the hospital with a history of
– Altered speech and behavior,
– Gradually increasing drowsiness,
– Brief episode of mild fever,
– Gradually progressive deterioration of sensorium.

19. • On examination,
– Drowsy
– Arousable with difficulty
– Moving all 4 limb
– Sensory system and cerebellar system could’nt be
examined
– Reflexes were brisk.

20. • MRI Brain showed symmetrical T2/FLAIR
hyperintense signal involving bilateral medial
thalamus, caudate, putamen, external and
internal capsule, periaqueductal grey white
matter, dorsal midbrain, left frontal white matter
with patch DWI restriction with swelling of basa
ganglia and patchy minimalenhancement
suggestive of encephalitis.
• CSf was normal. An autoimmune panel was sent
that later came out negative.

21. • The patient was considered to have possible
autoimmune encephalitis.
• A course of steroids was initiated and her
sensorium showed improvement.

22. TREATMENT OPTIONS

23. The treatment options include
1. Removal or suppression of circulating
antibodies via plasma exchange or IvIg.
2. Attenuate production of production of
autoimmune antibodies via steroids and
other immunosuppressive therapy.

24. • Concomitant and early use of intravenous
steroids and IVIGs and/or plasmapheresis are
often effective in achieving control of
symptoms and remission.
• There is no data supporting the use of IvIg
over plasma exchange.

25. • Second line therapy with immunosuppresants
may yield additional benefits when first line
therapy fails e.g. rituximab and/or
cyclophosphamide. Prompt initiation of
second line drugs is recommended if the first
line therapy fails.
• If the patient remains symptomatic despite
first- and second-line treatment, repeated and
combination therapeutics may help.

26. • Treatment of tumours, if associated, helps
recovery and reduces the risk of relapses

27. CASE2
• A previously healthy four year old girl presented with
– progressive gait instability of two weeks.
• She was clinically diagnosed as viral encephalitis and
empirically treated with acyclovir at a centre.
• MRI brain and cerebrospinal fluid (CSF) cell count,
biochemical analysis and bacterial culture were
normal.
• There was progression of her disease activity.
– developed generalized tonic clonic seizures,
– choreoathetoid movements, and
– aphasia over the next 2 weeks.

28. • On admission she was
– disoriented,
– Aphasic
– Glasgow coma scale was 8/15
– had choreoathtoid movements involving all the
limbs,
– hypotonia,
– quadriparesis
– brisk deep tendon reflexes and extensor plantar
response.
– had multiple episodes of generalized tonic clonic
seizures.

29. • Investigations showed
– liver and renal function test, serum electrolytes
were normal.
– Repeat MRI brain was normal
– CSF analysis showed normal protein, lymphocytic
pleocytosis, negative virology and bacterial
culture.
– CSF NMDAR antibody was positive confirming the
diagnosis of NMDAR encephalitis.

30. • She was treated with
– IV Immunoglobulin (2gm/kg),
– IV methyl prednisolone,
– anticonvulsants and
– supportive measures.
• Her involuntary movements decreased, though
she continued to be unresponsive to
surroundings with intermittent visual fixation and
following. She also started having stereotypic
movements.
– Given 8 doses of rituximab (375mg/m2) at weekly
intervals.

31. • Gradually,
– her sensorium improved,
– involuntary movements decreased in intensity and
– seizures were under control.
– Child was discharged after 2 months of hospital
stay.
• She was on immunosuppression with oral
prednisolone and at one month follow up,
child was seizure free with persisting
quadriparesis.

32. BRIEF REVIEW OF THE COMMONEST
AUTOIMMUNE ENCEPHALITIS

33. NMDA receptor encephalitis
• The patient presents
with
– psychiatric symptoms,
– seizures,
– memory deficits,
– altered sensorium,
– dyskinesias, and
– autonomic disturbances.
• It affects predominantly
the young adults and
teenagers with age
related association to
ovarian teratoma.
• The patients usually
recover well with
immunotherapy.

34. LIMBIC encephalitis
The syndrome shows antibodies to different targets
and the symptoms vary according to the site.
1.GABA B receptor.
• Patients have limbic encephalitis with
predominant seizures.
• The patients are usually of advanced age
(approximately 62 years)
• Associated SCLC or neuroendocrine tumors.
• As many as 75% patients show partial to full
recovery with immunotherapy.

35. 2.AMPA receptor.
• The patients show limbic encephalitis with
predominant psychiatric symptoms.
• They may have associated breast, lung or
thymus cancer.
• Almost 70% patients show recovery with
immunotherapy but relapses are frequent.

36. 3. LG1 receptor.
• These patients present with hyponatremia,
REM behavior disorders and seizures- tonic or
myoclonic.
• They are infrequently associated with
thymoma
• 80% patients recover with immunotherapy
but mild residual deficit may persist.

37. 4. mGluR5 and mGluR1 receptor.
• The patients are commonly found to have
association with Hodgkin's lymphoma
• Recover well with immunotherapy.

38. GABA A receptor encephalitis
• Rapidly progressive severe encephalopathy
with refractory seizures is a common
presentation of these patients
• Commonly associated with other autoimmune
conditions e.g. TPO and GAD antibodies.
• Patients have good response to treatment.
• Medical complications of the status
epilepticus is common and can be fatal.

39. CASPAR2 receptor encephalitis.
• The patients present with Morvan syndrome
and frequently have associated neuropathic
pain.
• 70% of the patients show a full or substantial
improvement.

40. TO RECAP, A FLOWCHART TO
APPROACH