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