autoimmune encephalitis -DR PALLAV JAIN

1. APPROACH TO AUTOIMMUNE
ENCEPHALITIS
MODERATOR: DR. VIJAY SARDANA
PRESENTER: DR.PALLAV JAIN
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2. INTRODUCTION
Acute encephalitis -rapidly progressive encephalopathy(usually
in<6 weeks) caused by brain inflammation.
Most frequently recognised causes of encephalitis are
infectious
Past 10 years increasing number of non-infectious, mostly
autoimmune encephalitis cases identified
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3. INTRODUCTION
Associated with antibodies against neuronal cell-surface or
synaptic proteins
Can resemble infectious encephalitis
Difficult clinical diagnosis -similarities in clinical,imaging and
laboratory findings of many forms of autoimmune and infectious
encephalitis
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4. INDIAN LITERATURE
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5. CLUES TO AN AUTOIMMUNE ETIOLOGY
• Change in baseline neurologic function
• Subacute onset (days to weeks) & Fluctuating course
• Personal/family h/o organ- or non-organ-specific autoimmune
disorder
• Systemic markers of autoimmunity : eg elevated ANA or TPO
antibodies
• History of or concurrent malignancy
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6. CLUES TO AN AUTOIMMUNE ETIOLOGY
• CSF studies : elevated WBC (<100 cells/µl), protein
(<100mg/dl), Ig G index, oligoclonal bands, synthesis rate
• EEG : Focal abnormalities
• MRI : T2/FLAIR abnormalities
• PET Brain : areas of hypo/hypermetabolism
• Response to immunosuppression
• Identification of a neural autoantibody
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8. EXCLUSION OF OTHER AUTOIMMUNE
DISORDERS
•ADEM- The characteristic brain lesions, involvement of the optic
nerves or spinal cord
•Multiple sclerosis (MS) -more focal symptoms and characteristic
brain imaging findings
•Lupus -causing neuropathy, vasculitis, myelitis, venous sinus
thrombosis,stroke, etc....
•Vasculitis affecting the CNS
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9. EXCLUSION OF INFECTIOUS CAUSES
•Most cases of infectious encephalitis are viral-HSV, VZV,
enterovirus,West Nile virus (WNV),JE
• Bacterial -listeria, atypical presentations of streptococcus,
syphilis,Lyme disease, and TB.
•Fungal -Cryptococcus or aspergillis are particularly likely in
immunocompromised patients
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10. EXCLUSION OF OTHER MEDICAL
CAUSES
•Wernicke encephalitis
•Intoxications such a neuroleptic malignant syndrome and
serotonin syndrome
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11. FUNCTIONS OF CELL SURFACE
ANTIGENS
•Most of the novel cell surface antigens - involved in synaptic
transmission, plasticity, and neuronal excitability.
•Immune-mediated dysfunction of these proteins results in
prominent neuropsychiatric symptoms, such as
•catatonia,
•psychosis,
• Focal deficits-uncommon
•seizures,
•movement disorders,
•rapidly progressive memory loss or dementia
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12. SUBTYPES OF AUTOIMMUNE
ENCEPHALITIS
First group -classic paraneoplastic -antibodies to intracellular
antigens- involve T-cell responses targeting neurons
The prognosis tends to be poor due to irreversible
- neuronal killing
- severity of associated cancers
-difficulty in controlling these sorts of immune response
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13. SUBTYPES OF AUTOIMMUNE
ENCEPHALITIS
•Second group - autoantibodies to extracellular epitopes of ion
channels, receptors and other associated proteins (NMDA
receptor)
•The cancer associations are variable, and the prognosis tends
to be much better.
•Causes reversible effects on synaptic function in neurons with
relatively little neuronal death
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14. SUBTYPES OF AUTOIMMUNE
ENCEPHALITIS
•Occupying an intermediate position -autoantibodies to
intracellular synaptic proteins such as GAD65.
• A final group - other forms of AE -precise antigens are less
clearly established, such as lupus cerebritis or ADEM
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16. Underlying cellular and synaptic effects
of anti-NMDA receptor antibodies

17. ANTI-NMDAR ENCEPHALITIS
• Most frequent antibody-associated encephalitis
• 2nd MC immune-mediated encephalitis after ADEM
MC in young women and children (80% cases)
(F>>M)
• F>>M less evident in children < 12 years and adults > 45 years.
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18. ANTI-NMDAR ENCEPHALITIS
• Highly characteristic , occurs in multiple stages
• Acute psychiatric symptoms, seizures, memory deficits,
decreased level of consciousness, and dyskinesias
(orofacial, limb, and trunk)
• Autonomic instability (50% cases - central hypoventilation often
requiring mechanical ventilation)
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19. • Children – may present with mood and behavioral change at
times with new onset seizures, movement disorders,
insomnia, or reduction of speech.
• Partial syndromes with predominant psychiatric symptoms or
abnormal movements, and less severe phenotypes can occur
• Atypical symptoms such as cerebellar ataxia or
hemiparesis may occur (children > adults)
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20. • Approximately 45% of females > 18 years – U/L or B/L ovarian
teratomas compared to < 9% of girls < 14 years age.
• Younger children and men only rarely have tumors.
• Isolated reported cases - teratoma of the mediastinum, SCLC,
Hodgkin lymphoma, neuroblastoma, Ca breast , and GCT
testis
• 80% patients - CSF -> lymphocytic pleocytosis and less
commonly, increased proteins and/or oligoclonal bands.
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21. • 35% patients -> increased signal on MRI FLAIR or T2
sequences and less often, faint or transient contrast
enhancement of the cerebral cortex, overlaying meninges,
basal ganglia, or brainstem.
• Abnormal EEG (90%) - generalized slow or disorganized
activity without epileptic discharges that may overlap with
electrographic seizures.
• 30% patients - unique EEG pattern called extreme delta brush
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22. • Diagnosis - demonstration of NMDAR antibodies in CSF and
serum
• Antibodies are IgG subtype and target the GluN1 (previously
called NR1) subunit of the NMDAR.
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23. •The sensitivity of NMDA receptor antibody testing is higher in
CSF than in serum.
•The titre change in CSF is more closely related with relapses
than was that in serum.
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24. Anti-NMDAR (NR1) encephalitis
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25. FDG-PET
• Relative frontal and temporal glucose hypermetabolism
associated with occipital hypometabolism.
•This gradient of brain glucose metabolism correlated with
clinical disease severity, and normalized when the patients
recovered.
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27. Associations
•Herpes simplex encephalitis-
•Mycoplasma infection
•Teratoma
•GBS
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29. VGKC complex antibodies mediated
encephalitis
•Disease associated with VGKC complex antibodies include
limbic encephalitis, epilepsy, neuromyotonia/peripheral nerve
hyper excitability and Morvan’s syndrome.
•Limbic encephalitis is the most common syndrome form.
• The antibodies directed against proteins of the VGKCcomplex
•include LGI1, CASPR2,and Contactin-2.13
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31. Anti-LGI1 encephalitis (“anti-VGKC
encephalitis”)
The vgKC-complex: LGI1, CASPR2 and contactin2 are tightly
associated with vgKCs
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32. ANTI LGI1 LIMBIC ENCEPHALITIS
• LGI1 - leucine-rich glioma inactivated 1 (Previously
described as targeting the voltage-gated potassium channel
(VGKC).
• Predominantly Older men (M:F~3:1, median age 60 years)
• Develop memory loss, confusion, and temporal lobe seizures.
• Approx. 60% - hyponatremia(SIADH)and less often REM
sleep behavior disorders - additional clues in formulating the
differential diagnoses
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33. ANTI LGI1 LIMBIC ENCEPHALITIS
• Tonic or myoclonic-like Faciobrachial dystonic
seizures(FBDS) (40%) that precede the memory and
cognitive deficits.
• Autonomic symptoms ~ 10 %
• May develop additional symptoms of peripheral nerve
hyperexcitability(PNH)(Morvan syndrome).
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34. lLai M, Huijbers MG, Lancaster E, et al. Lancet Neurol
2010; 9(8):776-85. 34

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37. ANTI CASPR2 ASSOCIATED
ENCEPHALITIS
• Contactin-associated protein-like 2 (CASPR2) antibodies.
• Usually develop Morvan syndrome.
• Symptoms involving both
– CNS - encephalopathy, hallucinations, seizures,
insomnia, autonomic dysfunction and
– PNS - PNH-cramps,myokymia,fasciculations, neuropathy,
allodynia
> 50 % complain of neuropathic pain while some develop
severe insomnia.
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38. • Rapidly progressive memory disturbance along with
myoclonic-like movements can lead to the suspicion of rapid
onset dementia such as CJD.
• Usually no cancer associated and < 10% have an underlying
neoplasm(Thymoma).
• MRI shows findings typical of limbic encephalitis.
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39. • CSF usually normal, although mild inflammatory changes or
oligoclonal bandsmay be present.
• Antibodies almost always detectable in both serum and CSF.
• 80% patients - substantial responses to immunotherapy.
• Mild deficits common.
• Relapses occur in about 20% of the patients.
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41. Anti-GAD encephalitis
• Anti-GAD is associated with:
•Encephalomyelitis/limbic encephalitis with/without
associated neoplasm
•Paraneoplastic cerebellar ataxia (PCD)
•Refractory seizures
•SPS including variants: Progressive encephalomyelitis with
rigidity and myoclonus (PERM)
•Diabetes mellitus
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42. Anti-GAD encephalitis (n-9)

43. ANTI-GABAB ENCEPHALITIS
• Male = female
• > 50% cases – associated tumor – almost always SCLC
• Presenting features - almost always those of typical limbic
encephalitis -> memory loss, confusion, and prominent seizures
• Rarely - ataxia or opsoclonus-myoclonus as presenting
complaint – gradually evolve to limbic encephalitis.
• MRI brain - abnormal in 2/3 cases – U/L or B/L medial
temporal lobe FLAIR/T2 signal consistent with limbic
encephalitis.
• CSF - lymphocytic pleocytosis.
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44. • Majority of patients receiving immunotherapy have full or
substantial recoveries, including cases where treatment was
delayed by several months.
• For patients with cancer the neurological outcome appears
dependent on successful treatment of the tumor.
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46. ANTI-GABAA ENCEPHALITIS
• Rapidly progressive, severe encephalopathy that result in
refractory seizures
Extensive MRI abnormalities on FLAIR and T2 imaging with
multifocal cortical-subcortical involvement without contrast
enhancement.
High titers -result in refractory seizures and status epilepticus
Low titers -associate with encephalitis and seizures, but also
with opsoclonus and stiff-person syndrome 46

47. •40% of the patients are children
•Patients with GABA A-R antibodies are often misdiagnosed as
having anti-GAD65-associated encephalitis or Hashimoto’s
encephalitis due to the frequent co-occurrence of GAD65 or
thyroid peroxidase (TPO) antibodies
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48. ANTI AMPA RECEPTOR ENCEPHALITIS
• Predominantly affects middle-aged women (median~ 60 yrs).
• Antibodies target the GluR1/2 subunits of the AMPAR
• Subacute (<8 weeks) symptoms of limbic encephalitis
including confusion, disorientation, and memory loss often
associated with prominent psychiatricsymptoms – may be
confused with Acute Psychosis.
• Seizures - < 50 % cases
• Syndrome lacks movement disorders, autonomic dysfunction
•& hypoventilation
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49. • Approx 70% - underlying tumor in the lung, breast, or thymus.
• MRI brain - usually shows abnormal FLAIR signal involving the
medial temporal lobes
• CSF - lymphocytic pleocytosis.
• Majority respond to immunotherapy
• About 50% have relapses.
• Those with relapses usually respond to treatment but these
responses are often partial, resulting in cumulative memory or
behavioral deficits.
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50. BICKERSTAFF BRAINSTEM
ENCEPHALITIS
• Characterised by subacute onset, < 4 weeks, of progressive
impairment of consciousness along with ataxia and bilateral, mostly
symmetrical, ophthalmoparesis.
• Usually preceded by an infectious event, runs a monophasic course,
and has a good outcome.
• Additionally, patients frequently develop pupillary abnormalities,
bilateral facial palsy, Babinski’s sign, and bulbar palsy.
• Generalised limb weakness can occur, which overlaps with
features of GBS.
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51. • CSF pleocytosis occurs in 45% patients.
• Brain MRI usually normal, but brainstem abnormalities on T2w
FLAIR imaging present in 23% of patients.
• IgG anti-GQ1b antibodies are highly specific for this entity and
related Miller-Fisher syndrome (GQ1b antibody syndrome)
• ~ 32% patients - no detectable antibodies.
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53. Disorders associated with GlyR Antibodies:
•progressive encephalomyelitis with rigidity and myoclonus
(PERM).
•muscle stiffness, hyperactive startle responses and limb
spasms.
•These cases are mostly unrelated to cancer
• Good responses to immunotherapy.
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54. Anti-DPPX Encephalitis:
•Antibodies to dipeptidylpeptidase like protein-6 (DPPX)
•Recently described
•Predominantly affects adults (age 45–76 years).
•Prominent neuropsychiatric symptoms usually preceded by
intense diarrhea.
•Characterized by trunk stiffness, hyperekplexia, marked
cerebellar ataxia in few patients.
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55. •Encephalitis with Antibodies to IgLON5:
•Recently described disorder
• Abnormal REM and non REM sleep movements, and behaviours
and obstructive sleep apnea.
• Brain MRI, EEG, and CSF studies and electromyography is
•often normal.
•Patients usually has a rapidly progressive course with
poor response to immunotherapy.
•Death can occur due to autonomic dysfunction.
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56. Anti mGluR5:
•Antibodies to the metabotropic glutamate receptor
• Can present with cerebellar ataxia, limbic encephalitis.
• The co-occurrence of limbic encephalitis and Hodgkin
lymphoma is known as Ophelia syndrome.
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58. ANTIBODIES TARGETING NEURAL ION
CHANNELS AND RECEPTORS
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60. NEURONAL NUCLEAR, CYTOPLASMIC
AND NUCLEOLAR ANTIBODIES
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61. EOM abnormalities – Vertical
Gaze Plasy
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62. • Autoimmune encephalitis should be included in the differential
diagnosis of any patient, especially if young, 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.
DIFFERENTIAL DIAGNOSIS
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63. DIFFERENTIAL DIAGNOSIS
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64. How to approach & treat?

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66. The Diagnosis and Treatment of Autoimmune Encephalitis J Clin Neurol 2016
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70. CONCLUSIONS
• Evaluation should begin with a detailed history and physical
examination
• A diverse range of infections should be considered
•MRI, EEG, and lumbar puncture may further support a diagnosis
•A broad group of autoantibody tests may be used to diagnose.
•The risk of neoplasm should always be considered.
• Patients may relapse and should receive appropriate follow-up.
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72. REFERENCES
• Bradley’s Neurology in clinical practice 7th edition
• Autoimmune Encephalitis: An update :February 2017
• A clinical approach to diagnosis of Autoimmune Encephalitis:
Lancet Neurol 2016;15;391-404
• The Diagnosis and Treatment of Autoimmune Encephalitis
J Clin Neurol 2016;12(1):1-13
• Autoimmune encephalitis - History & current knowledge :june
2013
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