1. The document discusses several types of synaptic autoimmune disorders including anti-NMDA receptor encephalitis, anti-AMPA receptor encephalitis, anti-GABA B encephalitis, anti-LGI1 limbic encephalitis, and anti-CASPR2 associated encephalitis. 2. These disorders are treated with immunotherapy such as steroids, intravenous immunoglobulin, and plasma exchange. If tumors are present, they are surgically removed. 3. Outcomes vary by type of disorder, but many patients recover fully or have mild deficits with treatment, though some require long-term support and rehabilitation. Relapses can occur and require continued immunotherapy.

1. Anti NMDA receptor Encephalitis and
other synaptic Autoimmune disorder
Myrna R. Rosenfeld, MD, PhD* and Josep Dalmau, MD, PhD
Department of Neurology, University of Pennsylvania, 3 W. Gates 3400
Spruce St., Philadelphia
Current Treat Options Neurol. Author manuscript; available in PMC 2013
July 09
Sarawut Krongsut resident 1
A. Surat Tanpravate
Neurology medicine department CMU
21 st May 2014

2. Content
• Anti–NMDA-Receptor Encephalitis
• Anti–AMPA-Receptor Encephalitis
• Anti GABA B Encephalitis
• Anti – LGI 1 limbic encephalitis
• Anti CASPR2 Associated Encephalitis
• Outcome
• Treatment

3. Excitatory neuronal transmission Inhibitory neuronal transmission
excitatory glutamate N-methyl-D-aspartate
(NMDA) receptor
 alpha-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) receptor;
the inhibitory gamma-aminobutyric acid
(GABAB) receptor
- leucine-rich glioma-inactivated (LGI1)
:protein, a secreted neuronal protein
-contactin-associated protein 2 (CASPR2), a
protein important to the normal function of
voltage-gated potassium channels
Neuronal transmission and
plasticity

4. A Receptor with a Long Memory
• NMDA receptor
• AMPA receptor
Activated by
glutamate

5. NMDA receptor
Glutamate is bound to the receptor
Allow the passage of Ca2+ and Na+ into the cell
and K+ out of the cell
Postsynaptic cell is depolarized (which
removes the Mg2+ blocking the channel)
: excitatory postsynaptic potential (EPSP)
memory formation

7. Anti–NMDA-Receptor Encephalitis
First described as a clinical in 2005.
4 young women developed acute psychiatric symptoms, seizures, memory deficits,
decreased level of consciousness, autonomic instability, and hypoventilation in
association with the presence of an ovarian teratoma
All had antibodies reacting with a neuronal cell surface protein >> NR1 subunit of the
NMDA receptor

8. Symptoms of anti–NMDA-receptor encephalitis
Viral-like prodrome
Alterations of memory, behavior, and cognition
Psychosis
Seizures
 Dyskinesias (orofacial, limb, and trunk)
Autonomic and breathing instability

9. Anti–NMDA-Receptor Encephalitis
• Mostly initially seen by psychiatry services and can be mis-diagnosed with an
acute psychotic or drug abuse .
• Most children are brought to hospital because of changes in mood, behavior,
or personality , seizures , or language disintegration
• Autonomic instability is a common in adults:
Central hypoventilation : requires mechanical support.
Severe cardiac dysrhythmias : requiring a pacemaker.
Children : urinary incontinence and sleep dysfunction.

10. Anti–NMDA-Receptor Encephalitis
 CSF profile
 Mostly CSF studies with a lymphocytic pleocytosis.
 About 1/3 increased proteins, and 60% have oligoclonal bands.
MRI findings :
 ½ have abnormal MRI findings >>> Increased signal on FLAIR or T2 in the cerebral
or cerebellar cortex or medial temporal lobes.
 Other areas : corpus callosum or brainstem.
 Transient contrast enhancement of the cerebral or cerebellar cortex, overlaying
meninges, or basal ganglia.

11. Anti–NMDA-Receptor Encephalitis
 Movement disorders are common and can be misinterpreted as seizure.
 Dyskinesias : typically orofacial dyskinesias, choreoathetoid movements of the
extremities, dystonia, rigidity, opisthotonic postures.
 EEG : generalized slow or disorganized activity without epileptic discharges.
Dx of anti–NMDA-receptor encephalitis
 Confirmed by the detection in serum or CSF of antibodies to the NR1 subunit of the NMDA
receptor.
 In advanced stages of the disease : CSF antibodies usually remain elevated + no clinical
improvement. whereas serum antibodies may be substantially decreased by treatments.
 The titer of CSF antibodies appears to correlate with the clinical outcome.

12. Choreothetoid , oro lingual diskinesia in Anti NMDA
recptor encehalitis

13. Anti–NMDA-Receptor Encephalitis
>1/2 have an associated tumor :most commonly an ovarian teratoma .
 The detection of an ovarian teratoma is age-dependent:
 ½ of female : age >18 years :unilateral or bilateral ovarian teratoma.
 < 9 % of female : age < 14 years : ovarian teratoma
Detection of a tumor is rare in male patients
Other tumor types :
 teratoma of the mediastinum
 small-cell lung cancer (SCLC)
 Hodgkin’s lymphoma
 Neuroblastoma
 germ-cell tumor of the testes.
 Breast cancer

14. Anti–AMPA-Receptor Encephalitis
 Clinical
• Affects middle-aged women
• Limbic dysfunction : subacute onset of confusion, disorientation, and memory
loss
• Seizures
• Prominent psychiatric symptoms
• 70% : underlying tumor in the lung, breast, or thymus

15. CSF findings :predominant lymphocytic pleocytosis.
Brain MRI :abnormal FLAIR signal involving the medial temporal lobes,
rarely with transient signal changes in other areas.
Can associated with systemic autoimmunity
 stiff-person syndrome
 insulin-dependent diabetes
 glutamic acid decarboxylase [GAD]antibodies
 Hypothyroidism
 Raynaud’s syndrome

16. Anti GABA B Encephalitis
Usually presents with limbic encephalitis and seizures
median age was 62 years (range, 24–75) and both sexes were equally affected.
About ½ : associated tumor  SCLC or neuroendocrine tumor of the lung
frequently have additional antibodies to GAD (glutamic acid decarboxylase) and
several non-neuronal proteins of unclear significance
MRI and CSF findings :
• unilateral or bilateral increases in medial temporal lobe FLAIR or T2 signal consistent
with limbic encephalitis
• CSF : lymphocytic pleocytosis.

17. Anti – LGI 1 limbic encephalitis
 LGI1 is a secreted neuronal protein that interacts with presynaptic and postsynaptic
receptors
 20% : associated with a neoplasm : most commonly thymoma or SCLC
 Memory disturbances, confusion, and seizures(tonic seizures that can mimic myoclonic
type movements )
 MRI findings that are usually typical of limbic encephalitis
 CSF studies : often normal or show only oligoclonal bands with normal total protein
 Hyponatremia or rapid eye movement (REM) sleep-behavior disorders.
 Mutation of LGI1 : assoc with the syndrome of autosomal dominant lateral
temporal lobe epilepsy

18. Anti-CASPR2 Associated Encephalitis
Usually develop symptoms of encephalitis, peripheral nerve
hyperexcitability, or both (Morvan’s syndrome).
cognitive impairment, memory loss, hallucinations, and seizures.
Assoc. with immune-mediated disorders such as
• myasthenia gravis with anti-acetylcholine or muscle specific kinase (MuSK)
antibodies.
Responds to immunotherapy, making the distinction is critical.
CASPR2 antibody–associated syndromes may occur with or without an
associated tumor.

19. Relapses
• Anti–NMDA-receptor encephalitis, anti–AMPA-receptor encephalitis, and LGI1
antibody–associated limbic encephalitis can relapse
• occur in 20% to 25% of patients : Risk of relapse associated with
o the presence or absence of a tumor
o the timing of therapy
• Patients with tumors who received tumor treatment within 4 months of the
onset of neurologic symptoms, often in conjunction with immunotherapy
fewer neurologic relapses
 better overall outcomes than patients without tumors or patients with tumors that
were treated later or not at all

20. Outcome
• In a series of 100 patients with anti–NMDA-receptor encephalitis ,follow up of
17 months
 47 : full recovery,
 28 : mild deficits,
 18 : severe deficits
 7 : illness-related death
• Residual symptoms are often behavioral  long-term follow-up  residual
symptoms continue to improve.

21. Treatment

22. • Mostly will respond to treatment
• recovery can be slow and symptoms may relapse.
• Spontaneous recovery : a few patients after several months
• If tumor is found, it should be removed as soon as possible
• Rx : immunomodulatory therapy : methylprednisolone and intravenous
immunoglobulin (IVIg)
o should be initiated as soon as the diagnosis is confirmed.
o start with a 5-day .
o Plasma exchange can substitute for IVIg: not preference for autonomic
instability and uncooperative patients

23.  If no improvement is seen after IVMP and IVIg
initiate a combination of cyclophosphamide (once every month) + rituximab
(once a week for the first 4 weeks only)
If persistent titers in the CSF suggesting continued need for treatment
No tumor is found : yearly surveillance malignancy for 2–3 years should be
considered
start mycophenolate mofetil or azathioprine for 1 year at recovery (because of the
increased risk of relapses )

24. • Supportive care
 May require prolonged stays with mechanical ventilation in intensive care units.
 Recover which improve over months.
 Need a multi-disciplinary team approach : physical rehabilitation and psychiatric
management.

25. Reference
Myrna R. Rosenfeld, MD, PhD* and Josep Dalmau, MD, PhD
Department of Neurology, University of Pennsylvania, 3 W. Gates 3400 Spruce St.,
Philadelphia
Current Treat Options Neurol. Author manuscript; available in PMC 2013 July 09