Chapter 1

Learning objectives
To provide an overview of
• Definition and Epidemiology of autoimmune encephalitis
• Neuronal surface antibody encephalitis
• Antineuronal antibody/Paraneoplastic encephalitis
• Diagnosis-antibody detection methods and pitfalls. when
it is significant?
• Treatment overview
 Epidemiology

• California Encephalitis Project : 63% patients had no proven

etiology after battery of tests for 16 infectious agents
• A multicenter study in U K: 4% encephalitis patients had
NMDA receptor antibodies, making this as 2nd leading cause of
immune-mediated encephalitis, after ADEM
• In California Encephalitis Project, frequency of anti-NMDA
receptor encephalitis surpassed that of any viral encephalitis
• Hence, autoimmune encephalitis is not so uncommon
• Besides infective causes, parainfectious causes should be
considered : treatable
CNS & Autoimmunity: When good turns bad!!!

• CNS: Immunologically privileged site, not exposed to immune

system since the time of its formation
• Blood brain barrier: 28 weeks of gestation
• Immune tolerance develops by --- weeks of gestation
• Release of sequestered antigens: Basis for autoimmunity
Pathophysiology
 Autoimmune encephalitis

• An inflammatory disorder of brain resulting in altered mental

status, seizures, or focal neurologic deficits, due to an immune
mediated process.
• Autoimmunity can be against neuronal surface proteins or
intracellular proteins
 When to suspect

• Acute or subacute (<12 weeks ) onset of symptoms,

• Evidence of inflammation supported by CSF, imaging, or
histopathological investigations
• Exclusion of other infectious, metabolic and toxic aetiologies

Supportive criteria: history of other autoimmune

comorbidities and a preceding infectious prodrome

Using a combination of these criteria as well as response to

therapy, patients are classified definite, probable or possible
autoimmune encephalitis
J Neurol Neurosurg Psychiatry 2012;83:638–45.
 Chapter 1

Learning objectives
To provide an overview of
• Definition and Epidemiology of autoimmune encephalitis
• Neuronal surface antibody encephalitis
• Antineuronal antibody encephalitis
• Diagnosis-antibody detection methods and pitfalls. when
it is significant?
• Treatment overview
 Neuronal surface Ab Vs Antineuronal Ab

Neuronal Surface Ab Antineuronal ab

Antigenic site extraneuronal (surface) intraneuronal
Examples NMDA, VGKC, AMPA,GABA GAD, Hu, Ri, Ma
Clinical phenotype LE Paraneoplastic Cerebellar
Morvan’s syndrome Degeneration
NMDAR-Ab encephalitis Encephalomyelitis
PERM Limbic Encephalitis
Cerebellar ataxia Brainstem encephalitis
o Paraneoplastic Usually not Frequently (except anti GAD)
o Course Relapsing Progressive
o Reversibility Present Absent
o Prognosis Better Poor
o Response to Good Poor
immunotherapy
 Neuronal Surface Ab Syndromes

• Anti VGKC- LGI1 & CASPR2

• Anti NMDA R
• Anti AMPA R
• Anti GABAb R
• Anti Gly R
 Anti NMDA receptor encephalitis

• Leading cause of autoimmune encephalitis in children

• > 90% patients develop at least 3 of following symptoms
within 1 month of onset: psychiatric, memory disturbance,
speech disorder, seizures, dyskinesias, altered sensorium,
autonomic instability, or hypoventilation
• CSF abnormalities in >90% patients
• MRI abnormalities in 30% children
• EEG- extreme delta brush pattern in 30% patients
• In children, presence of an underlying tumor is uncommon

J Child Neurol. 2012 November ; 27(11) 1460–1469

 Limbic Encephalitis

• Inflammatory process of limbic system: medial temporal

lobes, amygdala and cingulate gyrus
• Initially identified as a paraneoplastic syndrome (1968)
• In adults, occurs in association with LGI1 autoimmunity:
hyponatremia, and various types of seizures, including
myoclonic-like movements, described as faciobrachial
dystonic seizures
• In children, can occur with both NSAbs (VGKC, AMPA,
GABA,NMDA)and antineuronal ab (Hu, Ma, GAD )

Arq Neuropsiquiatr 2012;70(10):817-822

9 year old girl presented with subacute
onset behavioral changes, mood
lability and aggressive behavior for 3
weeks. H/o prodromal gfebrile illnesss
2 weeks before the symptom onset.
No history of seizure, focal deficit or
extrapyramidal features. MRI brain
shows signal changes in the limbic
region(given below). EEG and CSF
examination were wiithin normal
limit.
Diagnosis??
Limbic encephalitis
 Basal ganglia encephalitis

• Unlike anti NMDAR encephalitis, no cortical

involvement
• Movement disorders (dystonia, parkinsonism,
chorea, ocular flutter, motor tics), psychiatric
features (agitation, depression, psychosis), and
associated symptoms (encephalopathy) etc
• Variable CSF lymphocytic pleocytosis
• Neuroimaging shows basal ganglia enhancement in
acute phase and gliosis in chronic phase
Journal of Clinical Neuroscience 21 (2014) 722–730
 Chapter 1

Learning objectives
To provide an overview of
• Definition and Epidemiology of autoimmune encephalitis
• Neuronal surface antibody encephalitis
• Antineuronal antibody encephalitis
• Diagnosis-antibody detection methods and pitfalls. when
it is significant?
• Treatment overview
 Anti neuronal ab encephalitis

• Usually associated with brainstem encephalitis

• Poor prognosis except Anti GAD (may respond to
immunotherapy), anti Ma2

Ab Clinical features Tumor

associated
Anti any part of nervous system -including peripheral nerves, Small cell cancer
Hu dorsal root ganglia and spinal cord of lung

Anti Presence of both hypothalamic (narcolepsy, cataplexy, Testicular

Ma2 hyperphagia, hormonal deficits) and brainstem germinomas
dysfunction (supranuclear gazepalsy)

Current Treatment Options in Neurology (2013) 15:201–209

 Anti GAD encephalitis

• GAD is an intracytoplasmic, rate-limiting enzyme that converts

glutamate into GABA
• Two GAD isoforms (65 and 67 kDa) are found in GABAergic
neurons and pancreatic b-cells
• GAD 65 is highly expressed in CA1 & hippocampal dentate
gyrus
• Implicated in limbic encephalitis

Journal of Child Neurology 2014, Vol. 29(5) 677-683

 Infection & Autoimmunity

• Substantial evidence that HSE can trigger anti-NMDAR

encephalitis
• Possibilities of molecular mimicry and release of antigens
after herpes viral infection
• Unmasking of cryptic epitopes (posttranslational modification
by N-linked glycosylation or deamidation of N368 of GluN1)
•  NMDAR antibodies generated following HSE may differ from
antibodies in classic anti-NMDAR encephalitis

Current Neurology and Neuroscience Reports2015; 15:3

 Other Autoimmune encephalitis

Rasmussen encephalitis
 Progressive refractory partial seizures
 Cognitive deterioration and focal deficits
 Gradual atrophy of one cerebral hemisphere
 Presence of antibodies against GluR3 subunit of AMPA R in
few patients/? Damage due to cytotoxic T-cell mechanisms
 Treatment : high-dose methylprednisolone and IVIg
 Rituximab and intraventricular α-interferon have been
effective in a few isolated patients
 The only definitive treatment is functional hemispherectomy

J Child Neurol. 2012 November ; 27(11) 1460–1469

 Hashimoto encephalopathy
• Females are more affected
• Recurrent or progressive subacute encephalopathy
• Neuropsychiatric features
• Seizures or focal deficit may be seen
• MRI brain usually normal
• EEG may show diffuse slowing
• Anti-TPO antibody titer is usually very high
• May be associated with evidence of autoimmune thyroiditis
with hypothyroidism
• Management-Methylprednisolone pulse, IVIg,
Plasmapheresis, Rituximab
 Secondary Autoimmunity due to systemic
disease
• Connective tissue disorder- SLE
• Hashimoto encephalopathy
 Non specific clinical features- stroke-like symptoms,
tremor, myoclonus, transient aphasia, sleep and behavior
abnormalities, hallucinations, seizures etc
 CSFprotein level may be elevated
 EEG studies show generalized slowing
 Brain MRI is usually normal, can show diffuse WM
abnormalities & meningeal enhancement that resolves
with steroids
J Child Neurol. 2012 November ; 27(11) 1460–1469
 Other encephalitis with status epilepticus

Terms used to describe these include

• Acute Encephalitis with Refractory Repetitive Partial Seizures
(AERRPS)
• Fever-Induced Refractory Epileptic Encephalopathy Syndrome (FIRES)
• Devastating Epilepsy of School-aged Children (DESC)

 Biphasic clinical course of these disorders : Possible infection-

triggered autoimmune process
 CSF OCB, Autoantibodies against GAD, m Glu r, VGKC can be found
 Lack of response to immunotherapy- suggests either absence of
autoimmune process or intracellular antigens
J Child Neurol. 2012 November ; 27(11) 1460–1469
10 year old girl presented with right focal seizures,
choreoathetoid movements, neuropsychiatric features and
altered sleep wake cycle for 4 weeks. Hi story of prodromal
febrile illness 3 weeks before symptom onset. MRI brain and
CSF examination were within normal limits. EEG showed
delta brush pattern. Which autoimmune encephalitis should
be suspected clinically in this child
Anti NMDA receptor encephalitis
 Chapter 1

Learning objectives
To provide an overview of
• Definition and Epidemiology of autoimmune encephalitis
• Neuronal surface antibody encephalitis
• Antineuronal antibody/Paraneoplastic encephalitis
• Diagnosis-antibody detection methods and pitfalls. when
it is significant?
• Treatment overview
 Diagnosis

• Suspicion based on clinical phenotype

• Indirect markers
• Autoantibodies and their significance
 Clinical clues: Cognitive impairment
Clinical features Memory as a conspicuously affected
cognitive domain
Seizures including FBDS
and hyponatremia
Underlying cancer may be associated

Onset Rapid
MRI features and CSF T2/FLAIR hyperintensity
findings on brain MRI, particularly
in medial temporal lobes;
normal CSF usually

Suspect VGKC (LGI1, CASPR2),AMPAR, GABABR, GAD

 Clinical clues: Neuropsychiatric
Clinical features First lifetime episode of psychosis
Associated seizure(s) and movement disorder
Neuromyotonia, dysautonomia and insomnia
(Morvan: CASPR2>LGI1)
Onset Rapid prior to social withdrawl
MRI and CSF findings Various subcortical or cortical T2/FLAIR
changes
May suggestive of demyelination;
CSF pleocytosis and oligoclonal bands

Suspect NMDAR; LGI1 and CASPR2; D2R;AMPAR

 Clinical clues : Epilepsy
Clinical features Frequent, localization related seizures;
Associated cognitive/psychiatric features
young patients(often NMDAR/GAD) or
middle-age (VGKCc/ LGI1)
Onset Rapid, Especially When
No Prior Seizure History
MRI and CSF findings T2/FLAIR hyperintensity on brain MRI,
particularly in medial temporal lobes;
normal CSF usually

Suspect VGKC(especially LGI1), GAD, NMDAR

 Clinical clues: Movement disorders

Clinical features •Variable phenomenologies: chorea, dystonia,

and stereotypies
•Associated neuropsychiatric features
Eg. anxiety, OCD, or depression (NMDAR/D2R)
•Ataxia (CASPR2,GAD, mGluR1/5);
•Preceding streptococcal infection
•Hyperekplexia and rigidity (glycine, DPPX)
Onset Rapid
MRI and CSF findings Usually normal, sometimes medial temporal
lobe hyperintensities
Often normal CSF

Suspect NMDAR, glycine, VGKCc, GAD, DPPX, D2R

 Indirect evidence

• CSF analysis:
 CSF pleocytosis
 Elevated CSF protein
 Elevated CSF globulin/ oligoclonal bands

• Neuroimaging
 Limbic encephalitis
 Basal ganglia encephalitis
 Autoantibody testing: Methods

• Indirect Immunohistochemistry and Cell based assays

(live or fixed)
• Preliminary test: IIH/ IIF on fixed/ frozen rat brain tissue-
Recognizable staining pattern (NSAbs/ Intracellular)
• Gold standard for NSAb: Assay based on mammalian
cells transfected with antigen of interest
• Are antibodies must to diagnose autoimmune disorders?
• Prevalence in healthy controls(NMDAR (up to 10% (with
Ig A and IgM) ;CASPR2 and MOG(1% )

ANN NEUROL 2014;76:168–184

 Antibody testing: Sample to be sent

• Ideally, both serum and CSF samples for antibody testing

• Absolute concentrations of antibodies are usually higher in
serum than in CSF
• VGKC antibodies are not always detectable in CSF
• Serum NSAb are not 100% specific.
• Lower serum titres should be interpreted with caution
• Role of evaluating CSF NSAbs rather than serum titres
may increase diagnostic specificity
• Assessment of intrathecal synthesis: Comparison of CSF
specific Ig/ CSF total Ig and serum specific Ig/ Serum total Ig
 Antibodies titers -NMDA

• All 250 patients had NMDA receptor antibodies in CSF but

only 214 had antibodies in serum (sensitivity 100·0%[98·5–
100·0%] vs 85·6% [80·7–89·4%], p<0·0001)
• All 100 paired serum and CSF samples from control patients
were negative
• Antibody titers in CSF and serum were higher in patients with
poor outcome or teratoma
• Change in CSF was more closely related with relapses than
was that in serum

Lancet Neurol 2014; 13: 167–77

 Autoantibody titers

Normal value High titres Relevance of high titres

Serum <100 pmol/L >400 pmol/L 67% had limbic encephalitis

Anti VGKC 11% Neuromyotonia
5% Morvan syndrome
4% epilepsy
Anti GAD >1000U/ml stiff -person syndrome, cerebellar
ataxia, limbic encephalitis, and
epilepsy
 Autoimmune encephalitis: Diagnosis

Zuliani L, Graus F, Giometto B, Bien C, Vincent A. Central nervous system neuronal surface antibody associated syndromes: review and guidelines
for recognition. Journal of Neurology, Neurosurgery, and Psychiatry. 2012;83(6):638-645. doi:10.1136/jnnp-2011-301237.
 Chapter 1

Learning objectives
To provide an overview of
• Definition and Epidemiology of autoimmune encephalitis
• Neuronal surface antibody encephalitis
• Antineuronal antibody/Paraneoplastic encephalitis
• Diagnosis-antibody detection methods and pitfalls. when
it is significant?
• Treatment overview
 Immunotherapy
• 1st line
– Methylprednisolone Pulse followed by oral steroids
AND
– IV IG or Plasmapheresis(3 to 5 cycles)
• Wait for 1 or 2 weeks
• 2nd line
– Rituximab
– Cyclophosphamide
• Long term( steroid sparing agents)
– Azathioprine,Mycophinolate mofetil,Mtx,
Mitoxantrone
• Tumour surveillance
 Anti NMDA R treatment protocol

Lancet Neurol 2011; 10: 63–74

 Rituximab-Evidence (Retrospective data)

• A total of 144 children and adolescents

– (median age 8 years, range 0.7–17; 103 female)
• NMDAr, NMO, OMA and SLE are the most common
• After median duration of disease of 0.5 years (range 0.05–9.5
years)
• 7.6% had severe infections including death and 12.5% infusion
related AE
• Definite, probable, or possible benefit was reported in 125 of
144(87%) patients.
• Earlier initiation better outcome than later use
• Better to restrict use for severe and morbid disease course.
Neurology® 2014;83:142–150
Courtsey: Dr Ming Lim Reader Paediatric Neurology, Consultant Paediatric Neurology Children’s Neurosciences, Evelina
London Children’s Hospital, Kings Health Partners Academic Health Science Centre, Kings College London Honorary
Consultant Paediatric Neurology Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of
Oxford, UK
 Take Home Messages

• In > 60% patients with AES, no proven etiology

• Clinical suspicion for autoimmune encephalitis important
(after ruling out other causes)
• Autoimmune encephalitis is a treatable cause with timely
immunotherapy
 Suggested reading

• Lancaster E. The Diagnosis and Treatment of Autoimmune

Encephalitis. Journal of Clinical Neurology (Seoul, Korea).
2016;12(1):1-13.
• Ramanathan S, Mohammad SS, Brilot F, Dale RC.
Autoimmune encephalitis: recent updates and emerging
challenges. J Clin Neurosci. 2014 May;21(5):722-30
• Pandit AK, Ihtisham K, Garg A, Gulati S, Padma MV, Tripathi
M. Autoimmune encephalitis: A potentially reversible
cause of status epilepticus, epilepsy, and cognitive
decline. Annals of Indian Academy of Neurology.
2013;16(4):577-584