encef tratam

• Antineural antibodies


  • Antibodies to intracellular neuronal antigens
  • Antibodies to neuronal surface antigens

  
• Anti-NMDAR antibodies


  Identified in 2007, most frequent syndromes are anti-NMDAR encephalitis and limbic encephalitis
• Antineural antibodies


  • Variable presence of tumour, sometimes rare/absent
  • Disease onset can be at any age, also in children
  • Disease onset more acute/subacute
• Antineural antibodies


  • Can influence the antigen function or cause antigen internalization: pathogenetic role
  • Good response to immunotherapy
• Onconeuronal antibodies


  • Cannot access the antigen under physiological circumstances
  • Antibodies are not pathogenic
  • Neuronal tissues show prevalent infiltration by T lymphocytes
  • Poor response to immunotherapy
  • Very rare in children
• NMDAR antibodies


  • Directly cause reduction of surface NMDA receptor clusters and protein
  • Titer-dependent
  • Selective
  • Reversible
  • NMDARs cross-linking and internalisation
• NMDAR antibodies bind to GluN1 subunits, inducing NMDAR clustering and dissociation from Ephrin-B2 receptor, leading to NMDAR internalisation
• The loss of synaptic NMDAR is functionally reflected by decreased synaptic NMDAR currents in dissociated neuronal cell cultures
• NMDAR-ab are epileptogenic (passive transfer mouse model)
• NMDAR-ab alter memory and behavior (cerebroventricular transfer of patients' antibodies to mice)
• NMDARE


  • Beneficial effect of immunotherapy (IT) versus no IT on outcome and relapses
  • Beneficial effect of early versus late IT on outcome
• International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis

  1. 2-step Delphi method

  2. Practical approach
• First-line immunotherapy


  • Corticosteroids
  • Intravenous immunoglobulin
  • Therapeutic plasma exchange
• Corticosteroids


  • IV methylprednisolone (IVMP) should be the first immunotherapy used
  • Oral prednisone, oral dexamethasone pulses, or IVMP pulses can be given as an extended taper following an initial course of IVMP
• Corticosteroids treatment regimen


  1. IVMP 30 mg/kg/day (max 1 g/day) for 3-5 days

  2. Oral prednisone taper
• Corticosteroids safety


  • Short-term use: increased appetite, weight gain, fluid retention, gastritis, irritability, increase in blood sugar, hypertension
  • Long-term use: gastritis/gastric ulcers, osteoporosis, growth suppression, fluid and electrolyte balance, increase in blood sugar, myopathy, hypothalamic-pituitary-adrenal axis suppression
• Intravenous immunoglobulin (IVIG)


  • Used for > 40 years as replacement therapy in immune deficiencies and immunomodulatory agent in autoimmune disorders
  • Mechanism of action: anti-inflammatory, immunomodulatory, neutralizing antibodies
• IVIG treatment regimen


  IVIG 2 g/kg in 2-5 days, repeated every 3-4 weeks
• IVIG safety


  • Higher risk of adverse reactions with higher doses, higher rate of infusion, and first infusion
  • 20-50% of patients experience immediate or delayed, mostly mild, transient, reversible events
  • Potentially serious reactions in 2-6% (anaphylaxis, thromboembolic events, renal impairment)
• Therapeutic plasma exchange (TPE)


  • Blood of the patient is passed through a medical device which separates out plasma from other components of blood, either by membrane filtration or centrifugation
  • The plasma is removed with subsequent substitution of a replacement solution (e.g., human albumin and/or plasma) or a combination of crystalloid/colloid solution
• Therapeutic plasma exchange treatment regimen

  1. In each exchange 1 to 2 total plasma volume equivalents are replaced over several hours

  2. 3-7 separate exchange procedures undertaken at 24- to 48-hourly intervals
• Therapeutic plasma exchange in children

  • May be difficult to carry out in small, dysautonomic, uncooperative patients
  • Difficulty in obtaining and maintaining large-bore peripheral access in smaller children
  • Feasibility in small children often depends on the expertise of the apheresis team
• Therapeutic plasma exchange preparation and administration

  1. ICU

  2. Bloods

  3. Central venous catheter

  4. Premedication

  5. Monitoring of blood pressure and other vital signs

  6. Avoid invasive procedures for 4-6 hours after exchange
• In a child who has only received one first-line immunotherapy and who has severe disease or is failing to improve after 1 wk post initiation of corticosteroids, another first-line immunotherapy (i.e., corticosteroids + TPE or corticosteroids + IVIg) should be considered
• Therapeutic apheresis


  Procedure where blood is removed from the body, a specific component is separated, and the remainder is returned
• Therapeutic apheresis in children

  • May be difficult to carry out in small, dysautonomic, uncooperative patients (i.e. anti-NMDAR encephalitis)
  • Difficulty in obtaining and maintaining large-bore peripheral access in smaller children
  • Feasibility in small children often depends on the expertise of the apheresis team
• Treatment preparation


  1. ICU

  2. Bloods

  3. Central venous catheter

  4. Premedication

  5. Monitoring of blood pressure and other vital signs

  6. Avoid invasive procedures for 4-6 hours after exchange
• First-line immunotherapies


  • Corticosteroids
  • Intravenous immunoglobulin
  • Therapeutic plasma exchange
• Prolonged first-line immunotherapy can be offered for up to 3–12 mo, depending on severity and improvement (i.e., especially in countries without access to second-line therapies)
• Prolonged first-line immunotherapy


  • Corticosteroids (OP, monthly IVMP, and oral DEX pulses)
  • 3–4 weekly IVIg (regardless of initiation of second line)
• Second-line immunotherapies


  • Rituximab
  • Cyclophosphamide
  • Tocilizumab
• In patients who are failing to improve approximately 2 weeks after initiation of 2 or more first-line therapies, second-line therapy is favored over further first-line therapies
• Second-line immunotherapy should be offered to patients with severe disease
• Rituximab (RTX)


  Anti-CD20 chimeric monoclonal antibody that binds to cell surface CD20 located on B lymphocytes, resulting in destruction of the lymphocyte by different potential mechanisms
• Rituximab


  • B cell depletion
  • T cell depletion (beside B-cell depletion, RTX may also induce depletion of a subset of CD20+ T cells)
• RTX depletes autoantibody-producing cells indirectly as a result of depletion of the pool of pre-B cells and mature B cells
• Rituximab treatment regimen


  1. RTX 375 mg/m2 weekly for 4 weeks

  2. RTX 1000 mg x 2, 2 weeks apart
• Rituximab safety


  • Infusion reactions (headache, fever, chills, sweats, dyspnea, rash, chest pain, mild hypotension, nausea, lightheadedness, anaphylaxis, allergic reactions)
  • Risk of infection (pneumocystis carinii infection, cryptococcal meningitis, CMV colitis)
  • Hypogammaglobulinaemia
  • Progressive multifocal leukoencephalopathy
  • Human antichimeric antibodies to RTX
  • Late-onset neutropaenia
• Cyclophosphamide (CPA)


  Prodrug that is converted to its active form (phoshoramide mustard) in the liver, which alkylates DNA bases and impairs essential DNA processes, leading to cell apoptosis
• Cyclophosphamide treatment regimen


  CYC 600-750 mg/m2 monthly for 6 months