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Limbic encephalitis

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  • 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
  • 6. 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
  • 7. 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
  • 8. 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.
  • 9. 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.
  • 10. 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.
  • 11. Choreothetoid , oro lingual diskinesia in Anti NMDA recptor encehalitis
  • 12. 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
  • 13. 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
  • 14. 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
  • 15. 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.
  • 16. 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
  • 17. 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.
  • 18. 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
  • 19. 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.
  • 20. Treatment
  • 21. • 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
  • 22.  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 )
  • 23. • 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.
  • 24. 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