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1. AUTOIMMUNE
ENCEPHALITIS
DR SUNEEL KUMAR

2. AUTOIMMUNE ENCEPHALITIS
Autoimmune encephalitis with antibodies, to neuronal cell
surface/synaptic antigens, is a recently described group of
neuropsychiatric disorders, in which the antibodies, react with
extracellular epitopes, of the corresponding target antigen .
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.
These disorders can occur, with and without a cancer
association. BR-1196

3. Neuronal cell surface/Synaptic
Antigens

4. CLINICAL FEATURES
Patients with autoimmune encephalitis, develop complex
neuropsychiatric symptoms, including memory loss, changes
in behavior or cognition, psychosis, seizures and movement
disorders. MCPS
At presentation, one or a few of these symptoms may
predominate, and can mislead the diagnosis ,until additional
symptoms, develop over days or weeks.
Patients may initially, be diagnosed with idiopathic
encephalitis, likely viral, but with negative viral studies.
Autoimmune encephalitis, should be included in the
differential diagnosis of any patient, especially if young, with a
rapidly progressive encephalopathy of unclear origin. BRAD

6. Immunological trigger
The immunological trigger of autoimmune encephalitis,
is varied and in many cases, yet to be established .
The viral-like prodrome, reported by many patients may
play a role and this premise, is supported by recent
studies, showing the development of autoimmune
encephalitis, after herpes simplex encephalitis.
(Mohammad et al., 2014 ).
In all types of AE, MRI brain show abnormal signals in
Medial Temporal lobes.

7. Other Forms of Subacute Encephalitis
A number of uncommon conditions, not covered above are
characterized by regional inflammation in the cerebrum.
Similarly, the restricted inflammatory conditions called
limbic encephalitis and "brainstem encephalitis"-most
often a distant effect of lung cancer-have some
characteristics of a subacute viral encephalitis . ADAM-769

8. DIFFERENCE
Autoimmune encephalitis
Young age
Ab against cell surface
antigens or Synaptic
antigens
Reversible
Paraneoplastic encephalitis
OLD AGE
Ab target
intracellular
proteins,such as Hu
or CRMP5
Irreversible

9. Diagnostic criteria of Limbic Encephalitis
Limbic encephalitis is an increasingly recognized
cause of epilepsy.
Suggested diagnostic criteria include one of
disturbance of episodic memory, temporal lobe
seizures, or affective disturbance plus the presence
of either well-characterized antibodies or
unexplained increased signal in the mesial temporal
structures, or histopathology of mesial temporal
encephalitis. BRAD-1583

11. LIMBIC ENCEPHALITIS
Patients with limbic encephalitis have memory deficits with
relative preservation of other cognitive functions. The memory
deficits may be masked by concurrent confusion, depression,
agitation, and anxiety. Complex partial seizures are also common.
Typical MRI findings,include unilateral or bilateral mesial temporal
lobe abnormalities, best seen on T2-weighted and (FLAIR) images.
The temporal-limbic regions may be hypointense on T1-weighted
sequences and rarely enhance with contrast.
Brainstem encephalitis is characterized by oscillopsia, diplopia,
dysarthria, dysphagia, gaze abnormalities, and subacute hearing
loss. Symptoms may overlap, with patients having involvement of
both limbic and brainstem structures.
Limbic and brainstem encephalitis occur in both paraneoplastic
and nonparaneoplastic settings .

12. Limbic encephalitis
Limbic encephalitis also occurs in autoimmune
encephalitis syndromes ,associated with antibodies to
neuronal cell surface or synaptic receptors ,and is most
prominent in those disorders ,with antibodies to AMPA
receptor, GABA(B) receptor, LGI1 or mGluR5.
In general, limbic encephalitis associated with
antibodies targeting intracellular antigens, is poorly
responsive to treatment
(tumor directed and/or immunotherapy).

13. DTI- TRACTOGRAPHY

14. Detailed Receptor Names
• NMDA, N-methyl-D-aspartate receptor;
• GABAB, gamma-aminobutyric acid-B receptor;
• AMPA, alpha-amino-3-hydroxy-5-methyl-4-
propionic acid receptor;
• LGI1, leucine-rich glioma inactivated protein-1;
• CASPR2, contactin-associated protein-like 2;

15. Autoimmune Encephalitis with Antibodies to Cell Surface
Antigens
Antigen target Syndrome Other associations Responses to
ImmunotherapiesNMDA receptor
GABA-B
receptor
AMPA receptor
CASPR2
LGI1
affects young adults, teens and
kids with an age-related associat:
with ovarian teratoma.
Median age 62 yrs ,About 50%
of the pts,have an assoc:cancer
(SCLC or other neuroendocrine
tumor). Frequent coexisting
autoimmunities.
affects middleaged women; about
70% with an associated cancer
(breast, thymus, lung).
Frequent coexisting
autoimmunities.
Older men, median age 60
years. Less than 10% have
an underlying tumor
(usually thymoma).
Almost 80% of cases have full
or substantial recoveries.
Improvement occurs slowly and
can continue for over 18 mon:
Almost 75% have full or partial
recovery.
70% improve with therapy,but
neurologic relapses without
tumor recurrence are frequent
and lead to disability
About 70% have full or
substantial recovery
Almost 80% have
recovery ,but are often
left with mild residual
deficits.
Psychiatric sx, seizures,
memory defcits,
ALOC,dyskinesias, and
autonomic disturbances
Limbic encephalitis with
prominent seizures
Limbic encephalitis with
prominent psychiatric
sx. Seizures in <50%.
Morvan syndrome.
Neuropathic pain is
frequent
Limbic encephalitis.
60% develop low Na and
less often REM behavior
disorder. Some pts
develop, brief tonic
oromyoclonic-like (called
faciobrachial dystonic)
seizures.

17. Anti-NMDAR Encephalitis
It is the most frequent antibody associated encephalitis, and the
second most common cause of immune-mediated encephalitis,
after acute disseminated encephalomyelitis (ADEM) .
It is most common in young women and children, who represent
about 80% of patients, but can also affect men and older
individuals.
Patients develop acute psychiatric symptoms, seizures, memory
deficits, decreased level of consciousness, and dyskinesias
(orofacial, limb, and trunk).
Autonomic instability is common, and in about half of the patients,
results in central hypoventilation, often requiring weeks of
mechanical ventilation .

18. Anti-NMDAR Encephalitis
Atypical symptoms such as cerebellar ataxia or hemiparesis
can occur and are more common in children than in adults.
Approximately 45% of female patients, over 18 years have
unilateral or bilateral ovarian teratomas, compared to less
than 9% of girls, under 14 years of age.
Isolated cases with other tumor types, including teratoma of
the mediastinum, small-cell lung cancer (SCLC), Hodgkin
lymphoma, neuroblastoma, breast cancer, and germ-cell
tumor of the testis have been reported .
Younger children and men only rarely have tumors.
A special form of paraneoplastic encephalitis presents
itself ,as a acute or subacute psychiatric syndrome .AD-686

19. INVESTIGATIONS
In almost 80% of patients ,the CSF shows lymphocytic pleocytosis and less
commonly, increased proteins and/or oligoclonal bands.
About 35% of the patients ,have 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.
The EEG is abnormal in 90% of cases, and usually shows generalized slow
or disorganized activity without epileptic discharges, that may overlap
with electrographic seizures.
About 30% of patients have a unique EEG pattern called extreme delta
brush due to its similarity to the delta brush pattern seen in neonatal EEG.
This pattern may associate with prolonged illness, and the finding of
extreme delta brush, in a patient with an undiagnosed encephalopathy,
should raise consideration for anti-NMDAR encephalitis .

21. ????????????
HOW WILL YOU CONFIRM NMDAR ENCEPHALITIS?

22. INVESTIGATIONS
Diagnosis of the disorder is confirmed by, demonstration of
NMDAR antibodies in CSF and serum .
As noted earlier, testing of CSF should be done, for all initial
evaluations.
The antibodies are IgG subtype and target the GluN1
subunit of the NMDAR.
These antibodies are highly specific for anti-NMDAR
encephalitis.

23. Anti-NMDA Encephalitis -ADAM
Vaginal ultrasound may be necessary for the
demonstration of the ovarian lesion, but a more
extensive examination, such as CT or PET is needed for
the detection of other tumors.
Improvement after tumor removal, is associated with
subsidence of the antibody titer, over many weeks and a
good outcome occurs in a majority of cases.
It is reasonable to start these same immune treatments,
IVIG while awaiting surgery, in cases that are highly
symptomatic . ADAM-686

24. Anti-GABA-B Receptor Encephalitis
Anti-gamma-aminobutyric acid B receptor (GABA-BR)
encephalitis, affects men and women similarly, and
more than half ,have an associated tumor, almost
always a SCLC.
When the disorder is cancer-related ,the onset of the
encephalitis usually precedes the cancer diagnosis.
The median age of patients, in one study was 62 years,
with older patients ,more likely to have cancer ,than
those that were younger. The presenting features are
almost always those of typical limbic encephalitis with
memory loss, confusion, and prominent seizures.

25. Anti-GABA-B Receptor Encephalitis
Most seizures appear to have a temporal-lobe onset with
secondary generalization, while some patients have status
epilepticus or subclinical seizures demonstrated on EEG.
The brain MRI is abnormal in almost two-thirds of the
patients, showing unilateral or bilateral medial temporal lobe
FLAIR/T2 signal consistent with limbic encephalitis.
As in other autoimmune encephalitis, the CSF can show
lymphocytic pleocytosis .
In addition to the presence of GABAB receptor antibodies,
these patients often have other autoantibodies (e.g., TPO,
ANA, GAD65), reflecting a tendency to autoimmunity or the
presence of an underlying cancer .

26. Anti-AMPA Receptor Encephalitis
Anti-alpha-amino-3-hydroxy-5-methyl-4-propionic acid
receptor (AMPAR) encephalitis ,predominantly affects
middle-aged women (median age 60 years), who usually
present with subacute (<8 weeks) ,symptoms of limbic
encephalitis including confusion, disorientation, and memory
loss often associated with prominent psychiatric symptoms.
Seizures have been reported, in just under half of cases, and
about 70% have, an underlying tumor in the lung, breast, or
thymus.
The antibodies target the GluR1/2 subunits of the AMPAR.
The brain MRI usually shows abnormal FLAIR signal, involving
the medial temporal lobes, rarely with transient signal
changes in other areas.

27. Anti-AMPA Receptor Encephalitis
The CSF often reveals lymphocytic pleocytosis. In the series
reported, half of the patients had a hx of, or concurrent findings of
systemic autoimmunity, such as insulin-dependent diabetes with
glutamic acid decarboxylase (GAD) antibodies, hypothyroidism,
Raynaud syndrome, or stiff-person syndrome.
The majority of patients respond to immunotherapy;
however, about half have relapses. Those with relapses usually
respond to treatment, but these responses are often partial,
resulting in cumulative memory or behavioral deficits.
It is unclear, whether chronic immunosuppression ,has a role in
preventing or reducing the risk of the relapses.

28. Anti-CASPR2 Associated Encephalitis
Patients with contactin-associated protein-like 2 (CASPR2) antibodies
usually develop Morvan syndrome, with symptoms involving, both
the central nervous system (encephalopathy, hallucinations, seizures,
insomnia, autonomic dysfunction) and peripheral nervous system
(PNH, neuropathy, allodynia) .
More than half of the patients complain of neuropathic pain, while
some develop, severe insomnia with abnormal motor activation .
Patients may have other coexisting immunemediated disorders ,such
as myasthenia gravis with antiacetylcholine (AChR) or muscle-specifc
kinase (MuSK) antibodies.
The combination of symptoms related to neuromyotonia and
myasthenia gravis, has led to the suspicion of atypical motor neuron
syndrome in some cases.

29. IAES

30. Anti-CASPR2 Associated Encephalitis
Since patients with CASPR2 antibodies, often have good
responses to immunotherapies. it is important to distinguish
between these diagnoses.
Anti-CASPR2 associated encephalitis, is usually not cancer
related, and those with a tumor (most commonly thymoma)
are more likely to have, Morvan syndrome as opposed, to
isolated central or peripheral nervous system symptoms.
Antibodies to CASPR2, like those to LGI1, were initially
described as targeting the VGKC. The distinction is important
as the specificity and clinical relevance of “antibodies against
VGKC-complex” different from LGI1 and CASPR2 are unclear .

32. MORVAN SYNDROME
Morvan's syndrome:
peripheral and central nervous system and
cardiac involvement with antibodies to voltage-
gated potassium channels.
Morvan's syndrome is characterized by involuntary
and spontaneous muscle activity, muscle cramping,
excessive perspiration and other neurological
symptoms i.e. personality changes, insomnia, and
hallucinations.

33. DIAGNOSIS
The diagnosis of autoimmune encephalitides is confirmed
by the presence of specific neuronal cell surface/synaptic
antibodies in serum and CSF.
While some laboratories, state that evaluation of serum is
sufficient, this is incorrect and CSF should always be included
in the initial evaluation.
A recent study of patients with antiNMDAR encephalitis
demonstrated that, depending on how the testing was
performed, up to 13% of CSF positive cases ,had no antibodies
detectable in serum, and thus the diagnosis would have been
missed .

35. TREATMENT
Despite the severity of many patients’ symptoms, the
majority of patients respond to treatment. Recovery can be
slow and some disorders have a tendency to relapse.
Steroids and/or (IVIg) or PLEX are considered frst-line
therapies and should be considered in all patients.
There are no data, to support the use of IVIg, over PLEX,
although the poor medical condition and autonomic
instability ,of some patients may favor the use of IVIg.
For anti-NMDAR encephalitis, just over half of patients, who
receive first-line immunotherapy and tumor treatment, when
appropriate, have improvement within the first 4 weeks of
treatment . BR-1200

36. TREATMENT
Almost all of these patients had good outcomes at 24
months of follow-up.
Patients who did not respond, to the first-line therapies
and then received, second-line immunotherapy with
rituximab and/or cyclophosphamide had better
outcomes, than those, who continued with first-line
immunotherapy or who received no further
immunotherapy. BRAD-1200
This suggests that prompt initiation of second-line
immunosuppression, when there is no clear response
to first-line treatment should be strongly Considered.

37. THANK YOU
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