1) Autoimmune encephalitis is a debilitating neurological disorder caused by inflammation of the brain. It develops subacutely over weeks and can affect individuals of all ages. 2) It has diverse clinical manifestations and immunological associations. Identification of neural autoantibodies has led to classification of different subtypes. 3) Prominent among these are anti-NMDAR encephalitis commonly seen in young women and children, autoimmune limbic encephalitis, and other syndromes associated with antibodies targeting neuronal cell-surface and intracellular antigens.

1. AUTOIMMUNE ENCEPHALITIS
: CURRENT CONCEPTS
DR. PIYUSH OJHA
DM RESIDENT
DEPARTMENT OF NEUROLOGY
GOVT MEDICAL COLLEGE, KOTA

2. • Acute encephalitis - debilitating neurological disorder
• Develops as a rapidly progressive encephalopathy (usually in less
than 6 weeks) caused by brain inflammation.
• Disease with diverse immunologic associations, clinical
manifestations, and therapeutic outcomes.
• Estimated incidence of encephalitis ~ 5–10 per 100000 / year
• Affect individuals of all ages
• Some syndromes preferentially affect young adults and children
(Armangue et al., 2012).
• Represents a significant burden to patients, families, and society.

3. HISTORY
• Lymphocytic infiltration of the medial temporal lobe (??Limbic
encephalitis) in patients with a remote malignancy
(Brierley et al., 1960)
• Brain et al first described Hashimoto’s thyroiditis - 1966
• Pathogenic autoantibodies described in diseases of the PNS
since 1970’s (Autoimmune myasthenia ,LEMS)
• Gradual discovery of many antibodies
• Vincent et al. 2004 – VGKC antibody complex

5. INDIAN LITERATURE

7. NEUROLOGY INDIA 2015;63;687-96

9. 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
• 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

13. NEURONAL NUCLEAR, CYTOPLASMIC AND
NUCLEOLAR ANTIBODIES

14. EOM abnormalities – Vertical
Gaze Plasy

15. ANTIBODIES TARGETING NEURAL ION
CHANNELS AND RECEPTORS

18. CLASSIFICATION
• Autoimmune encephalopathies without Malignancy
• Paraneoplastic encephalopathies

19. NON-PARANEOPLASTIC
AUTOIMMUNE ENCEPHALOPATHY
- Females >> Males
- Middle aged (Mean age ~ 59 yrs)
- Onset - Subacute 1-6 weeks
- Majority (91 %) have fluctuations
- Coexisting Systemic autoimmune disorder – 48% cases

20. • Subacute Dementia - Most common presentation
• Memory loss almost always present
• Seizures -33% cases
• Neuropsychiatric symptoms – 50 % patients
• Other features – Frontotemporal dementia like syndrome,
stroke like episdoes
• Tremor and Myoclonus –frequent findings

21. INVESTIGATIONS :
• Infectious, Toxic/ Metabolic , Vascular , Structural causes are
more common - So should be ruled out
• CBC ,ESR, CRP , Thyroid function tests, LFT, RFT, Vit B12
• Screening for Non specific Autoimmunity - ANA , ANCA , TPO
• CSF examination – To rule out infectious causes (HSV PCR) ,
Neoplastic causes, 14-3-3 for CJD
• CSF - Mild lymphocytic pleocytosis ,oligoclonal bands

22. IMAGING :
• To exclude vascular disease , ICSOLs , other structural causes
• In autoimmune encephalopathy – MRI typically normal or
involvement of Mesial temporal lobes
• Subcortical white matter abnormalities or cortical ribbon
sign and basal ganglia similar to CJD
EEG :
• Diffuse slowing or epileptiform abnormalities in the temporal
lobes
• Non convulsive status epilepticus

23. • Antibody testing- NMDA/ VGKC
• Search for underlying Malignancy even without antibodies
• Patients with subacute or rapidly progressing Dementia
should undergo antibody testing and receive a trial of steroids
• Biopsy may be required in some cases

24. IMAGING
MRI :
• Mesial temporal hyperintensities, either unilateral or bilateral
with or without enhancement after gadolinium
administration, are classic autoimmune limbic encephalitis
findings.
• Normal imaging is common, particularly in the early illness
stages
• Extratemporal abnormalities sometimes observed.
• If lesions are not in a typical distribution or have avid
enhancement, other inflammatory (eg. neurosarcoidosis) or
oncologic (eg. lymphoma) diagnoses should be considered.

26. FUNCTIONAL IMAGING :
• Global hypometabolism is the most common feature
encountered in patients with autoimmune encephalopathies.
• However, focal hypometabolism can also be encountered.
• In instances where the patient has seizures, hypermetabolism
can occur.

28. AUTOIMMUNE LIMBIC ENCEPHALITIS
• Characterised by rapid development of confusion, working
memory deficit, mood changes, and often seizures.
• The subacute development of short-term memory loss -
considered the hallmark of the disorder
• But can be overlooked because of the presence of other
symptoms.
• CSF - mild-to-moderate lymphocytic pleocytosis (usually less
than 100 WBCs / mm³) in 60–80% of patients
• CSF – elevated IgG index or oligoclonal bands ( 50% cases)

29. • Among all immunological subtypes of limbic encephalitis,
patients with LGI1 antibodies present with a lower frequency
of CSF pleocytosis (41%) or elevated CSF protein
concentrations (47%) and rarely have intrathecal IgG
synthesis.
• Absence of inflammatory changes in CSF of these patients
might initially suggest a non-inflammatory encephalopathy.
• MRI – often shows increased signal on T2w FLAIR in the
medial aspect of the temporal lobes.

30. • Although limbic encephalitis can occur with MRI evidence of
unilateral involvement (or be normal), AAN doesnot consider
these cases as definite limbic encephalitis unless specific
antibodies are subsequently detected.
• Reason - several non-immune disorders may result in similar
unilateral MRI abnormalities, including among others,
seizures, herpes simplex virus encephalitis, or gliomas.

31. • MRI findings of immune-compromised patients with HHV-6-
associated encephalitis can mimic precisely findings from
patients with autoimmune limbic encephalitis, but the clinical
setting is different and directs the diagnosis.
• By contrast, the findings in HHV encephalitis are less confined
to the limbic system, can occur with haemorrhagic features,
and often show restricted diffusion abnormalities and
contrast uptake.

32. • Immunological subtypes established only by measurement of
autoantibodies.
• Distinction among immunological subtypes important - those
associated with onconeuronal antibodies are much less
responsive to immunotherapy than those associated with cell-
surface antibodies.
• Onconeuronal antibodies frequently occuring with limbic
encephalitis are Hu and Ma2. (seropositive patients almost
always have an underlying cancer)
• By contrast, the neuronal cell-surface antibodies more
frequently associated with limbic encephalitis - LGI1, GABA B
receptor and AMPA receptor antibodies.

33. • Antibodies against the intracellular antigen Glutamic acid
decarboxylase (GAD) occur in a subgroup of patients with
limbic encephalitis.
• Mainly young women (median age 23 years) with
predominant seizures and no evidence of cancer.
• The risk of cancer, usually SCLC or thymoma, is higher,
however, among patients with GAD antibodies and limbic
encephalitis who are older than 50 years or have concomitant
GABA B receptor antibodies.

36. ANTI-NMDAR ENCEPHALITIS
• Most frequent antibody-associated encephalitis
• 2nd MC immune-mediated encephalitis after ADEM
(Granerod et al., 2010)
• MC in young women and children (80% cases) (F>>M)
• F>>M less evident in children < 12 years and adults > 45 years.
• Highly characteristic , occurs in multiple stages
• Acute psychiatric symptoms, seizures, memory deficits,
decreased level of consciousness, and dyskinesias
(orofacial, limb, and trunk) (Dalmau et al., 2008).
• Autonomic instability (50% cases - central hypoventilation
often requiring mechanical ventilation)

37. • Many patients initially evaluated by psychiatric services.
• 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
• Although almost all patients eventually develop several
elements of the syndrome (Kayser et al., 2013)
• Atypical symptoms such as cerebellar ataxia or hemiparesis
may occur (children > adults)

38. • By the end of the first month, 498 (87%) of 571 patients had four
or more of the following categories of symptoms (from highest-
to-lowest frequency) :
– Abnormal behaviour and cognition
– Memory deficit
– Speech disorder
– Seizures
– Abnormal movements (orofacial, limb, or trunk dyskinesias)
– loss of consciousness or autonomic dysfunction
– Central hypoventilation; and
– cerebellar ataxia or hemiparesis.
• Only six patients (1%) had one category of symptoms.
Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-
term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort
study. Lancet Neurol 2013; 12: 157–65.

39. • 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.

40. • 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
due to its similarity to the delta brush pattern seen in
neonatal EEG (Schmitt et al., 2012).

41. • Diagnosis - demonstration of NMDAR antibodies in CSF and
serum
• Antibodies are IgG subtype and target the GluN1 (previously
called NR1) subunit of the NMDAR.

44. 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.

45. • 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.

47. 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 (Lancaster et al., 2011).
• > 50 % complain of neuropathic pain while some develop
severe insomnia

48. • Patients may have other coexisting immune-mediated
disorders such as myasthenia gravis with AChR or
MuSKantibodies (Fleisher et al., 2013).
• MRI – often normal
• Tumor Screening – Thymoma
• Good response to immunotherapies

49. ANTI AMPA RECEPTOR ENCEPHALITIS
• Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid receptor (AMPAR)
• Predominantly affects middle-aged women (median~ 60 yrs)
• Subacute (<8 weeks) symptoms of limbic encephalitis
including confusion, disorientation, and memory loss often
associated with prominent psychiatric symptoms – may be
confused with Acute Psychosis
• Seizures - < 50 % cases
• Syndrome lacks movement disorders, autonomic dysfunction
& hypoventilation

50. • Approx 70% - underlying tumor in the lung, breast, or thymus.
• Antibodies target the GluR1/2 subunits of the AMPAR.
• MRI brain - usually shows abnormal FLAIR signal involving the
medial temporal lobesCSF - 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.
• Role of chronic immunosuppression in preventing or reducing
the risk of relapses – not clear

51. 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 (Lai et al., 2010).
• Some patients develop brief 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).

52. Faciobrachial dystonic seizures in an LGI1 VGKC-
complex antibody-mediated encephalitis

54. • 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.
• CSF usually normal, although mild inflammatory changes or
oligoclonal bands may 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.

55. 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 (Hoftberger et al., 2013)
• 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.

56. • 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.

57. ANTI-GABAA ENCEPHALITIS
• Rapidly progressive, severe encephalopathy that result in
refractory seizures (Petit-Pedrol et al., 2014)
• Extensive MRI abnormalities on FLAIR and T2 imaging with
multifocal cortical-subcortical involvement without contrast
enhancement.

59. • 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

60. DIFFERENTIAL DIAGNOSIS

66. THANK YOU

67. REFERENCES
• Bradley’s Neurology in clinical practice 6th edition
• Continuum Review Article : Autoimmune
Encephalopathies and dementias : April 2016
• Seminars in Neurology : Autoantibody associated
CNS Neurologic Disorders : August 2016
• A clinical approach to diagnosis of Autoimmune
Encephalitis : Lancet Neurol 2016;15;391-404

75. • Susac syndrome - usually have multiple hemispheric white
matter lesions involving the corpus callosum, somewhat
mimicking multiple sclerosis, but with prominent, extensive
leptomeningeal enhancement.
• Rapidly resolving large hemispheric T2 abnormalities - should
raise concern for a mitochondrial disorder, such as MELAS.
• Nonenhancing posterior predominant white matter lesions –
consider progressive multifocal leukoencephalopathy.
• Cortical ribbon hyperintensities can be observed in some
patients (and thus may be misleading for CJD).

76. ACUTE DISSEMINATED ENCEPHALITIS
• A monophasic, inflammatory disease of the CNS
• Mainly occurs in children and adults < 40 years.
• The disorder can be preceded by an acute systemic infection
or vaccination.
• Characterised by a variable extent of encephalopathy , and
other neurological signs, such as cranial nerve palsies, ataxia,
hemiparesis, myelopathy, or optic neuritis.

77. • CSF - typically shows mild pleocytosis (less than 50
lymphocytes per mm³), but CSF oligoclonal bands are
uncommon (less than 7% of all cases).
• Brain - multiple, large (>2 cm) abnormalities on T2w FLAIR
imaging that can be present in the supratentorial white
matter, basal ganglia, brainstem, cerebellum, and spinal cord,
with or without contrast enhancement.
• No specific biomarkers of ADEM.

79. • Evidence exists that Myelin oligodendrocyte glycoprotein
(MOG) antibodies can transiently occur in almost 50% of
children with ADEM.
• At present, the inclusion of MOG antibodies in the diagnostic
criteria for ADEM is not considered for two reasons:
– The antibodies can be present in demyelinating disorders
with encephalopathy, but without MRI features of ADEM,
or in patients with demyelinating disorders without
encephalopathy and
– antibody testing remains unavailable at many centres.

80. SUSAC SYNDROME :-
• A rare, but important, D/D in patients who meet criteria for
possible autoimmune encephalitis and have MRI features of
demyelination.
• Considered an autoimmune vasculopathy resulting in
microvessel thromboses at three levels: the brain, retina, and
inner ear.
• In a review of 304 cases, 230 (76%) patients presented with
encephalopathy, but simultaneous involvement of the three
levels at disease onset occurred in only 31 of 247 (13%)
patients.

81. • Diagnosis based on presence of branch retinal artery
occlusions on fluorescein angiography, and MRI findings
including snowball-like lesions or holes in the central portion
of the corpus callosum and other periventricular white
matter abnormalities on T2w FLAIR.
• MRI findings are different from those seen in ADEM and in the
setting of encephalopathy are highly suggestive of Susac’s
syndrome.