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Anti NMDA receptor Encephalitis and other synaptic Autoimmune disorder

Myrna R. Rosenfeld, MD, PhD* and Josep Dalmau, MD, PhDDepartment 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 1A. Surat TanpravateNeurology medicine department CMU

21 st May 2014

Content • Anti–NMDA-Receptor Encephalitis

• Anti–AMPA-Receptor Encephalitis

• Anti GABA B Encephalitis

• Anti – LGI 1 limbic encephalitis

• Anti CASPR2 Associated Encephalitis

• Outcome

• Treatment

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

A Receptor with a Long Memory

• NMDA receptor

• AMPA receptor

Activated by glutamate

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

Anti–NMDA-Receptor EncephalitisFirst 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

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

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.

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.

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.

Choreothetoid , oro lingual diskinesia in Anti NMDA recptor encehalitis

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

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

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

Anti GABA B EncephalitisUsually 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.

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

Anti-CASPR2 Associated EncephalitisUsually 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.

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 immunotherapyfewer neurologic relapses

better overall outcomes than patients without tumors or patients with tumors that were treated later or not at all

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.

Treatment

• 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

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 )

• 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.

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