This is a brief review of autoimmune epilepsies, especially autoimmune encephalitis, SREAT, NORSE, FIRES and Rasmussen's encephalitis. A brief overview of investigations and treatment is included.
3. Autoimmunity Epilepsy was
recognized, coined and discussed
for the first time as an independent
clinical entity, and as a possible
direct cause of epilepsy in 2002, in
Nature Immunology paper entitled
“Autoimmune Epilepsy”
Rasmussen’s encephalitis was the
first epilepsy shown to be of
autoimmune etiology.
Glutamate/ AMPA GluR3 antibody
was the first serum antibody
identified in autoimmune epilepsy.
4. Timeline of neural specific antibody discovery
In the last 20 years there has occurred an explosion of research papers on Autoimmune
epilepsies and identification of numerous implicated antibodies.
However, a lot of questions remain regarding pathogenesis,
diagnosis and management of autoimmune epilepsies.
5. Autoimmune epilepsies: a varied entity
• Autoimmune encephalitis targeting neural surface antigens
• FIRES: febrile infection related epilepsy syndrome
• NORSE: new onset refractory status epilepticus
• SREAT: steroid responsive encephalopathy associated with
autoimmune thyroiditis.
• Rasmussens encephalitis
• Epilepsy in patients with systemic autoimmune disorders with CNS
involvement. Eg SLE
• ?Paraneoplastic encephalitis.
6. Paraneoplastic encephalitis: is it autoimmune?
Autoimmune encephalitis Paraneoplastic encephalitis
May or may not be associated with cancer. Definite association with cancer.
Antibodies to neural surface antigens: anti
LGI 1, anti NMDAR, anti GABAR, Anti
CASPR.
Antibodies to intracellular antigens:
ANNA-1 (Anti- Hu), PCA-1 (Anti-Yo),
Anti-Ma1, and Anti-Ma2 (Ta)
The antibodies are pathogenic. These antibodies are epiphenomenon and
are not pathogenic.
The neural injury is generally reversible. The neural injury is generally irreversible.
Good response to immunotherapy. Poor response to immunotherapy
7. Suspect autoimmune etiology when epilepsy is:
New onset epilepsy with frequent seizures
New onset refractory epilepsy
NORSE or FIRES
Inflammatory changes in CSF or serum
Suggestive patterns on MRI brain/ PET scan
Occurrence of anti neural antibodies
Seizures/ epilepsy with personal or family
history of autoimmune illness
New onset unprovoked seizures
Limbic encephalitis
Associated with:
10. The pathogenesis of autoimmune epilepsy can be categorized into two axes: the targets of autoimmunity and the types of autoimmunity. At one end
AE with the detectable antibody is representative of synaptic, limbic, and neuronal damage. NMO, ADEM, and MS are white-matter diseases at the
other end of the axis. Most of the diseases are caused by a combination of adaptive autoimmunity and innate autoimmunity. However, CAIDs are
mainly caused by an innate autoimmune reaction. ADEM: acute disseminated encephalomyelitis, AE: autoimmune encephalitis, CAIDs: cerebral
autoinflammatory diseases, CLIPPERS: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, LGI1:
leucine-rich glioma-inactivated protein 1, NMDAR: N-methyl-D-aspartate receptor, noDAB: no detectable antibody, PCNSA: primary central nervous
system angiitis, SREAT: steroid-responsive encephalopathy-associated thyroiditis.
11.
12.
13. Synaptic dysfunction and hyperexcitability as a result of seizures, inflammation, and antibody-mediated encephalitis. Diagram showing multiple inflammatory/innate
immunity mechanisms triggered by seizures and epileptogenesis, along with inflammation-related transcriptional and nontranscriptional pathways that lead to synaptic
dysfunction, changes in plasticity, and hyperexcitability (corresponding with blue and red arrows). In contrast to these mechanisms, the antibody-mediated encephalitides
such as those associated with NMDAR, AMPAR, LGI1, or GABAbR autoantibodies represent a direct antibody-mediated alteration of the corresponding targets also leading
to synaptic dysfunction, impairment of synaptic plasticity, and hyperexcitability (purple arrow).
14. (A) Top: Patients’ antibodies (blue) against NMDARs bind to GluN1 subunits,
inducing NMDAR clustering and dissociation from Ephrin-B2 receptor
(EphB2R), followed by NMDAR internalization.
Below: Reduction of synaptic NMDARs affects synaptic plasticity, revealed by
decreased long-term potentiation (LTP).
(B) Top: Antibodies against AMPAR GluA2 subunit induce internalization of GluA2-
containing heterodimers after dissociation from TARPs. AMPAR loss is followed by
compensation with insertion of Ca2+-permeable inward-rectifying AMPARs, which
have higher channel permeability. Below: Increase in AMPAR channel conductance
(steeper hyperbola slope) along with reduced channel number (reduced hyperbola
width) noted. Excitatory postsynaptic currents in neurons preincubated with patients’
GluA2 antibodies reveals incorporation of inward-rectifying AMPARs in the synapse.
15. (C) Top: Anti-LGI1 antibodies react with epitopes in leucine-rich repeat
(LRR) and EPTP domains of LGI1, disrupting LGI1’s interaction with
presynaptic ADAM23 and postsynaptic ADAM22, and reducing presynaptic
voltage-gated Kv1.1 channels and postsynaptic AMPARs.
Below: Downregulation of presynaptic Kv1.1 channels increases presynaptic
release probability and enhances glutamatergic transmission, resulting in
increased evoked EPSCs (eEPSCs) and reduced failure rate of synaptic
transmission after minimal stimulation (msEPSCs).
(D) Top: Anti-GABAbR antibodies bind to the GABAb1 subunit, which
localizes at pre- and postsynaptic membranes and contains the GABA-
binding site. Antibody binding does not cause GABAbR internalization
but interferes with baclofen-induced GABAbR activation.
Below: Baclofen blocks spontaneous network activity of cultured
neurons (gray). Anti-GABAbR antibodies interrupt its inhibitory effect
(blue).
16.
17. Antibodies to GluN1 subunit of the NMDA receptor in a patient with anti-NMDAR encephalitis. Live rat
hippocampal neurons incubated with the patient’s CSF are immunolabeled with antibodies against cell surface
antigens; subsequent characterization demonstrated that the antigen is the GluN1 subunit of the NMDA receptor
19. Autoimmune
encephalitis
Any age
Seizures/
Epilepsy
Psychiatric
illness
Movement
disorder
Acute/ subacute
encephalopathy
Like acute viral
encephalitis
Relapsing
encephalopathy/
encephalitis
Rapidly
progressive
cognitive decline
New onset seizures
NORSE/ FIRES
Refractory epilepsy
Personality changes
Mood disorders
Psychosis
Some patients with autoimmune encephalitis, especially those with NMDAR antibodies, experience a viral-
like prodrome including lethargy, headache, upper respiratory symptoms, nausea, diarrhea, among others.
Memory decline
Confusion
Dysexecutive
features
20. Anti NMDAR
encephalitis
Psychiatric symptoms, seizures, memory
deficits, decreased level of consciousness,
facial dyskinesias, seizures, and autonomic
disturbances
80% of affected are young adults,
teenagers, and children with an age-
related association with ovarian teratoma
(uni or bilateral). HSV encephalitis.
Anti LGI 1
encephalitis
Anti GABA-A R
encephalitis
Autoimmune
encephalitis type Clinical presentation Associations
Limbic encephalitis. 60% have
hyponatremia, and less often RBD. 30%–40%
have facio brachial dystonic (FBD) seizures
before the limbic encephalitis.
Median age 60 years (men > women).
Less than 10% have an underlying tumor
(usually thymoma)
Rapidly progressive, severe encephalopathy
with refractory seizures, frequent status.
Cognitive impairment, altered behaviour.
Extensive MRI FLAIR/T2 cortical-
subcortical abnormalities. One-third have
an associated tumor (mostly thymoma)
Anti GABA-B R
encephalitis
Limbic encephalitis (memory loss,
confusion, prominent temporal lobe
seizures with SGTCS). Median age 62 years.
Equal sex distribution.
About 50% of the patients have an
associated cancer (SCLC or other
neuroendocrine tumor). Frequent
coexisting autoimmunities.
21. Anti DPPX
encephalitis
Anti mGluR5
encephalitis
Anti Neurexin 3α
encephalitis
Autoimmune
encephalitis type
Clinical presentation Associations
Preceding severe diarrhea, weight loss.
Prominent neuropsychiatric symptoms, CNS
hyperexcitability, cerebellar or brainstem
dysfunction
Tumor associations are unusual (mostly
B-cell neoplasms). Some develop a
syndrome like PERM or present with
hyperekplexia.
Anti AMPAR
encephalitis
Subacute limbic encephalitis with prominent
psychiatric symptoms. Seizures occur in
<50% of patients. Mainly affects middle
aged women.
About 70% have associated cancer
(breast, thymus, lung). Frequent
coexisting autoimmunities.
Subacute limbic encephalitis preceded by a
viral like prodrome. Seizures are infrequent.
50% have NHL. MRI FLAIR showed
hyperintensities in limbic and extra-
limbic regions.
Encephalopathy with seizures, with a viral
like prodrome. Facial dyskinesias may occur.
No tumor association. MRI may be
normal or show limbic hyperintensities.
22. Autoimmune encephalitis without prominent seizures
Anti mGluR1
encephalitis
Cerebellar ataxia. Rarely, cognitive changes,
psychiatric symptoms, seizures
No tumor association. Some cases noted
with Hodgkins disease, T cell lymphoma.
Anti Dopamine 2
receptor
encephalitis
Mainly in children. Present with basal
ganglia encephalitis, Sydenhams Chorea or
Tourette syndrome.
No tumor association. May occur in those
who had HSV encephalitis. NMDAR
antibodies may also be seen.
Anti IgLON5
disease
Characteristic sleep disorder (REM and
NREM) before or concurrently with the
onset of bulbar symptoms, gait
abnormalities, chorea, oculomotor problems
and, less commonly, cognitive decline.
No tumor association. Poor response to
therapy. Video PSG is needed to identify
sleep abnormalities. Strong association
with the HLA-DRB1*10.01 allele
24. Investigations
• MRI brain with contrast
• CSF analysis
• Autoimmune encephalitis panel in CSF and serum.
• Paraneoplastic antibody profile in serum
• EEG, Video EEG
• Whole body PET CT to screen for malignancies.
• Systemic inflammatory markers.
• Work up for neuroinfection.
• Work up for systemic autoimmune diseases.
25. Patient with LGI 1 IgG limbic
encephalitis. MRI Brain FLAIR
demonstrating bilateral medial
temporal hyperintensities on
axial (A) and sagittal (B)
sections.
Patient with ANNA-1 IgG
limbic encephalitis. Brain MRI
FLAIR sequenc demonstrating
bilateral medial temporal
hyperintensities on axial (C)
and sagittal (D) sections.
Patient with Ma-2 IgG limbic
encephalitis. Brain MRI FLAIR
demonstrating bilateral medial
temporal (right greater than
left) hyperintensities on axial
(E) and sagittal (F) sections.
26. (A) MRI Brain T2 FLAIR in anti-LGI1 encephalitis: typical hyperintensities involving the medial temporal lobes. Similar findings
occur in greater than 50% of patients with AMPA or GABAB receptor antibodies, and less frequently in patients with CASPR2
antibodies. (B) MRI Brain T2 FLAIR anti GABAA receptor encephalitis: hyperintensities involving multiple cortical and subcortical
regions occur in 80% of patients and are unique to this disorder.; diffusion weighted imaging rarely show restricted diffusion. These
multifocal abnormalities appear and disappear in an asynchronous manner, are highly suggestive of GABAA receptor encephalitis.
27. (A) MRI brain T2 FLAIR sequence in an anti-LGI1 encephalitis patient showing swelling and
hyperintensities of mesial temporal structures bilaterally. (B) MRI done 3 months later showing slightly
reduced FLAIR hyperintensities. (C) Mesial temporal hypermetabolism noted on 18FDG PET,
particularly intense on the right side.
28. Limbic encephalitis. (A) 18-FDG PET shows extensive left mesiotemporal hypermetabolism, less on the right side
(red arrows). Relative hypometabolism is evident in the left posterior parietal cortex and in lateral frontal cortex on
both sides (yellow arrows). (B) MRI T2 FLAIR depicts only mild left mesiotemporal hyperintensity (red arrow).
Both hypo- and hypermetabolism can be observed in patients with autoimmune encephalitis.
29. CSF Analysis
• Lymphocytic pleocytosis.
• Elevated proteins.
• OCBs.
• The diagnosis is confirmed by the presence of specific neuronal cell
surface/synaptic antibodies in CSF and serum.
• Cell based assay (CBA) is the gold standard. Immunofluorescent assay and
ELISA are less reliable.
• CSF should always be included in the initial evaluation. Up to 13% of CSF
positive cases had no antibodies detectable in serum.
Half the patients with autoimmune encephalitis may be negative on standard
autoimmune antibody test panels.
30. EEG
• The EEG is abnormal in 95% of cases.
• Usually shows focal or generalized slow or disorganized activity without
epileptic discharges.
• Focal and multifocal spikes, periodic lateralized discharges may occur.
• Focal ictal patterns, Electrographic seizures may occur.
• In NMDAR encephalitis 10%–30% of patients have a unique EEG pattern
called extreme delta brush. This pattern may be associated with prolonged
illness.
• This finding in a proper clinical setting should raise consideration for anti-
NMDAR encephalitis.
31. Extreme delta brush: fast beta (20-30 Hz) activity superimposed over delta waves, usually symmetric and
synchronous, can be seen in any head regions. Named after the delta brush pattern seen in neonates.
32. REKHA MADHURI(4840651)
PLEDs
Longitudinal bipolar montage showing frequent right anterior temporal periodic lateralising
epileptiform discharges (PLEDs) in a patient with limbic encephalitis (HSV PCR negative).
33. REKHA MADHURI(4840651)
PLEDs
Lack of evolution in frequency or amplitude differentiates this from an ictal pattern. The same
PLEDs pattern continued for several days and gradually subsided.
34. Treatment of autoimmune
encephalitis
Treatment should be initiated at the earliest based on clinical
suspicion aided by MRI, CSF and EEG studies, after reasonable
exclusion of other competing diagnosis.
Do not wait for antibody test results.
35. Score of ≥ 4 is 98% sensitive
and 84 % specific for
predicting neural
autoantibody positivity. So an
epilepsy patient with an
APE2 score of ≥4 warrants
neural autoantibody testing.
And a score of ≥7 has a 100%
sensitivity.
36. A RITE2 score of ≥7 has 88% sensitivity
and 84% specificity of a favorable seizure
outcome, defined as at least a 50%
reduction in seizure frequency, following
initiation of immunotherapy.
37. IVIG
0.4 mg/kg/d for 5 days, then
once a week for 5 weeks, then
once every 2 weeks for 6 weeks.
IVMP
1000 mg IV 3-5 days, then
once a week for 5 weeks, then
once every 2 weeks for 6 weeks,
taper and stop over 4-6 months.
Epilepsy surgery
Cyclophosphamide
Rituximab
Plasma Exchange
Antibody negative
Rule out other
causes
Maintenance therapy for 2 years with Azathioprine,
Methotrexate or Mycophenolate
Strong suspicion of
autoimmune encephalitis,
APE2 ≥ 4
Antibody positive
Screen for tumor and
treat if detected
38. Paraneoplastic limbic encephalitis and epilepsy mediated by cytotoxic T cell mechanisms. MRI brain Coronal FLAIR showing mesial temporal hyperintensities
suggestive of limbic encephalitis, in a patient with a seminoma and Ma2 paraneoplastic antibodies (A), and 1 year later, medial temporal lobe sclerosis (B). Subtraction
ictal SPECT coregistered to MRI (SISCOM) showing increased ictal perfusion over the right hippocampus and parahippocampal gyrus (C). Coronal FLAIR image
showing resection of the temporal pole and right mesial temporal lobe structures (D). Inflammatory infiltrates in the surgical specimen; the section of the tissue was
immunostained with TIA-1 antibody, a marker of cytotoxic T cells (shown as brown granular staining). Some TIA-1–positive cells are close to neurons (arrows) (E).
39. Screening for tumors
• If there is a positive antibody result, do PET CT cancer screening.
• Even if antibody testing is negative, screening for cancers should be done if
clinical suspicion is high.
• Repeat imaging every 6 to 12 months for up to 4 years if an antibody is
present that has a high association with a tumor or if the patient is clinically
considered as being at high risk for malignancy.
41. NORSE
• New onset refractory status epilepticus (NORSE)
• It is a clinical entity and not a specific diagnosis.
• Patient should not have epilepsy or any preexisting neurological disorder.
• No acute or active structural, toxic or metabolic cause identified.
42. FIRES
• Febrile infection related epilepsy syndrome (FIRES)
• It is a subset of NORSE.
• Febrile infection between 24 hours and 2 weeks prior to the onset of refractory
status epilepticus with or without fever at the onset of status epilepticus.
• Mostly occurs in previously healthy children aged 3-15 years.
• Seizures can be simple motor, complex partial or secondary generalized.
43. Etiology of NORSE and FIRES
• Autoimmune: most common cause. anti NMDA receptor, anti-VGKC ,anti-
LG1 and less commonly anti-Caspr2
• Paraneoplastic: (in NORSE) anti-Hu, anti-CRMP5,anti-Ma2,anti-
amphiphysin and anti-VGCC
• Viral: HSV 1 is the most common.
• Cryptogenic.
44. • May be normal.
• Non-specific cortical
hyperintensities.
• Mesial temporal hyperintensities.
• Basal ganglia and peri-insular
hyperintensities.
• Claustrum sign: bilateral claustral
hyperintensities on T2, T2 FLAIR
and diffusion-weighted imaging.
ADC is normal and there is no
contrast enhancement
MRI Brain
45. MRI brain axial T2 (left, centre) and FLAIR sequences (right) in a patient with NORSE showing ill
defined hyperintensities in bilateral basal ganglia, peri-insular region and claustrum along with non-
specific cortical hyperintensities.
46. Electrographic seizures in patients with FIRES have characteristic features of prolonged focal fast activity
and hemispheric shifting ictal activity.
47. Case vignette:
• 36 year old gentleman with new onset generalised convulsive status
epilepticus.
• Clinical seizures stopped after administration of Inj Midazolam and
Levetiracetam.
• Shifted to MICU, sedated and paralysed.
• MRI brain was normal. Metabolic work up normal.
• CSF was normal.
• Autoimmune antibody panel was negative.
• Improved with IVMP + IVIG.
48. CCEEG of the patient, bipolar montage showing seizure onset over the left hemispheric
region (arrow) evolving in frequency and amplitude over the entire left hemispheric
region. Diffuse slowing of the background is seen prior to the seizure onset.
49. EEG shows rhythmic spikes mainly over the left temporal region compared to the left
fronto-centro-parietal region. Patient had eye deviation to the right side along with subtle
jerks of right hand and fluctuations in his BP along with reduced pupillary reactivity.
50. Large amplitude rhythmic spikes are seen over the left temporal and fronto-central
regions. Changes begin to appear on the right hemispheric regions as well (blue arrows).
51. EEG shows generalised ictal pattern comprising fast spikes. The patient is E1M1Vt with
evident stiffening of the whole body with subtle jerks of the right face and right UL.
52. The ictal pattern subsided on the left side, due to neuronal exhaustion, while it continued
over the right hemispheric region. Clinical manifestations subsided at this point.
53. There is further exhaustion of the ictal pattern with slower rhythmic spikes on the right
side. There is no ictal pattern over the left side and it is replaced by diffuse slowness.
54. The right sided ictal pattern further evolves into polymorphic slower waves and the
seizure finally terminates. This is followed by diffuse slowing.
55. LALLU SINGH(2764693)
Bilateral Multifocal spikes.
Subsequent EEG Longitudinal bipolar montage of the same patient with refractory status
epilepticus showing frequent multifocal spikes.
56. IVIG
0.4 mg/kg/d for 5 days. May be
repeated weekly if required.
IVMP
1000 mg IV for 5 days followed
by oral steroids
Cyclophosphamide
Tocilizumab
Rituximab
Plasma Exchange
Extensive work
up for various
etiologies
NORSE/ FIRES
Treat Status
epilepticus
Anti epileptic drugs
IV anesthetic agents
Ketogenic diet
Management algorithm for NORSE
61. MRI brain T2 scans of children with
Rasmussen’s encephalitis.
(A) Progressive right hemisphere
atrophy, high signal and basal ganglia
loss over 1 year (from left to right). The
disease was mostly centered near the
right Sylvian fissure (arrow).
(B) Slowly progressive disease with more
subtle right hemisphere atrophy in a
child on immunosuppressant treatment
at 6 months (left), 18 months (center),
and 30 months (right) of disease course.
62. Natural history of Rasmussen’s encephalitis and response to immunotherapy
63. Rasmussen’s
encephalitis
Risk of major
deficits by surgery
Modern variants of
hemispherectomy
Intractable seizures
Immunotherapy
Antiseizure drugs
Immunotherapy
Antiseizure drugs
No
Treatment algorithm for Rasmussen’s encephalitis
Progressive neurological
deterioration
Yes
Risk of major
deficits by surgery
Intractable seizures
No Yes
Risk of major
deficits by surgery
Intractable seizures
No
65. Positive Criteria
Relapsing acute/ subacute encephalopathy
characterised by:
• Cognitive impairment
• Seizures: generalised, focal, myoclonus
• Psychiatric symptoms
• Focal neurologic deficits may be present
Complete or near complete response to
steroids.
Near normal thyroid function
Manifold elevation in anti-thyroid antibodies.
Non-specific EEG and MRI findings.
Negative Criteria
Poor response to steroids
Presence of specific antibodies to other
encephalitis
Severe thyroid dysfunction sufficient to
explain the encephalopathy
Normal or mildly elevated anti-thyroid
antibodies.
Specific EEG and MRI findings.
Diagnosis of SREAT
66. Case vignette
• 42 year old lady presented with acute onset of recurrent seizures and altered
sensorium. For the past week family had noted irritability, poor sleep,
excessive talking, confusion and forgetfulness.
• She was evaluated for infectious and metabolic etiologies.
• MRI brain and CSF were normal.
• EEG showed diffuse slowing.
• Autoimmune encephalitis and paraneoplastic antibody panels were negative.
• TSH was mildly elevated.
67. Clinical course
• Complete response to steroids.
• 2 relapses with seizures and encephalopathy in last 4 years on attempted
steroid taper.
• Currently asymptomatic on low dose steroids.
• Steroid sparing agents were ineffective.
Aug
2018
Feb
2019
June
2019
Dec
2019
March
2020
Jan
2021
Aug
2021
Feb
2022
June
2022
Jan
2023
Anti TPO 518 408 314 211 179 164 215 130 144 130
Anti TG 317 308 355 363 247 500 347 377 283 452
Steroid taper and relapse
68. Conclusion
• Autoimmune epilepsies are an important subset of epilepsies.
• Autoimmune encephalitis is the most important type.
• They are in general treatable with good outcomes.
• Low threshold for diagnostic testing as epilepsy is often intractable and
causes significant neuro-cognitive and behavioural sequelae.
• There should be increasing awareness of this entity and more familiarity with
imaging features and other testing modalities.
• Treatment motto: ‘Hit early and hit hard’
• Need regular follow up to monitor disease activity and treatment side effects.