encefalitis

• Encephalitis


  Inflammation of the brain parenchyma with associated neurologic dysfunction
• Main aetiologies of encephalitis

  • Infectious (40%)
  • Autoimmune/Immune-mediated (20-30%)
  • Unknown (30-40%)
• Autoimmune/Immune-mediated encephalitis


  Caused by antineural antibodies
• Types of antineural antibodies

  • Antibodies to neuronal surface antigens
  • Antibodies to intracellular neuronal antigens
• Types of autoimmune/immune-mediated encephalitis

  • Antibody-mediated encephalitis
  • Demyelinating diseases
  • Hashimoto's encephalopathy
  • Rasmussen encephalitis
  • Systemic autoimmune conditions
  • Iatrogenic
• Antibody-mediated encephalitis


  Caused by antibodies to neuronal surface antigens or intracellular neuronal antigens
• Paraneoplastic neurological syndromes


  Caused by antibodies that are not pathogenic and cannot access the antigen under physiological circumstances
• Paraneoplastic neurological syndromes


  • Encephalomyelitis
  • Limbic encephalitis
  • Rapidly progressive cerebellar syndrome
  • Opsoclonus-myoclonus
  • Sensory neuronopathy
  • Gastrointestinal pseudo-obstruction (enteric neuropathy)
  • Lambert-Eaton myasthenic syndrome
• Antibody-mediated encephalitis


  Antibodies have access to the epitopes and can potentially alter the structure and function of the cognate antigen
• Paraneoplastic neurological syndromes


  Antibodies cannot reach the intracellular epitopes, and cytotoxic T-cell mechanisms are predominantly involved
• Antibodies in autoimmune encephalitis

  • Anti-NMDAR (2007)
  • Anti-LGI1 (2010)
  • Anti-CASPR2 (2010)
  • Anti-GABAAR (2014)
  • Anti-D2R (2012)
  • Anti-AMPAR (2009)
  • Anti-GABABR (2010)
  • Anti-GlyR (2008)
  • Anti-DPPX (2013)
  • Anti-IgLON5 (2014)
  • Anti-mGluR5 (2011)
  • Anti-mGluR1
  • Neurexin-3α (2016)
• Anti-NMDAR encephalitis


  Most frequent syndrome of antibody-mediated encephalitis
• Anti-NMDAR encephalitis


  • Recent identification: anti-NMDAR antibodies in 2007
  • Variable presence of tumour, sometimes rare/absent
  • Disease onset can be at any age, also in children
  • Disease onset more acute/subacute
  • Antibodies can influence the antigen function or cause antigen internalization: pathogenetic role
  • Good response to immunotherapy
• NMDAR-antibody encephalitis was first described in 2007 in women with ovarian teratoma
• NMDAR


  Ion channels gated by the excitatory neurotransmitter glutamate, widespread in the CNS and essential mediators of synaptic transmission and plasticity, play a key role in brain development and function
• Triggers of NMDAR-antibody encephalitis

  • Ovarian teratoma or other tumour
  • Preceding HSV encephalitis
  • Unknown trigger
• Pathogenesis of NMDAR-antibody encephalitis

  1. NMDAR expressed in nervous tissue contained in the tumor, or released by viral-induced neuronal destruction, is either in soluble form or loaded in antigen-presenting cells transported to the regional lymph nodes where it is presented to the immune system

  2. Naive B cells exposed to NMDAR by antigen-presenting cells, and with cooperation of CD4+ T cells, become antigen-experienced memory B cells, differentiating into antibody-producing plasma cells

  3. Memory B cells reach the brain crossing the BBB or the choroidal plexus, undergo restimulation, antigen-driven affinity maturation, clonal expansion, and differentiation into antibody-producing plasma cells
• Pathogenesis of NMDAR-antibody encephalitis

  Patients' antibodies bind to NMDAR, inducing NMDAR clustering and dissociation from Ephrin-B2 receptor, leading to NMDAR internalization and reduction of synaptic NMDARs, affecting synaptic plasticity
• Clinical features of NMDAR-antibody encephalitis

  • Prodromal symptoms (headache, fever, or a viral-like process)
  • Psychiatric symptoms (anxiety, agitation, bizarre behavior, hallucinations, delusions, disorganized thinking, psychosis)
  • Sleep disorder (sleep reduction at disease onset, hypersomnia during recovery)
  • Memory deficits (working, verbal, visuospatial memory and attention)
  • Seizures (70% acute phase, <5% risk of post-encephalitis epilepsy)
  • Language dysfunction (diminished language output, mutism, echolalia)
  • Decreased consciousness (stupor with catatonic features)
  • Movement disorder
  • Autonomic instability (hyperthermia, fluctuations of blood pressure, tachycardia, bradycardia)
• NMDAR-antibody encephalitis has an age at onset median of 20 years, range <1–85 years, with 46% onset in paediatric age
• NMDAR-antibody encephalitis occurs in 70-80% of females overall, and ~60% in children
• Diagnostic criteria for autoimmune encephalitis

  • 2013 Venkatesan criteria
  • 2016 Graus criteria
  • 2020 Cellucci criteria
• The 2013, 2016, and 2020 diagnostic criteria do not differentiate autoimmune from infectious encephalitis
• Specific autoimmune encephalitides in children

  • NMDAR
  • LGI1 and CASPR2
  • GABAAR
  • D2R
• PRODROMAL SYMPTOMS


  • Headache, fever, or a viral-like process
• PSYCHIATRIC SYMPTOMS


  • Anxiety, agitation, bizarre behavior, hallucinations, delusions, disorganized thinking, psychosis
• SLEEP DISORDER


  • Sleep reduction at disease onset, hypersomnia during recovery
• MEMORY DEFICITS


  • Working, verbal, visuospatial memory and attention
• SEIZURES


  • Seizures 70% acute phase, <5% risk of post-encephalitis epilepsy
• LANGUAGE DYSFUNCTION


  • Diminished language output, mutism, echolalia
• DECREASED CONSCIOUSNESS


  • Stupor with catatonic features
• MOVEMENT DISORDER


  • Orofacial, choreoathetoid movem, dystonia, rigidity, opisthotonus
• AUTONOMIC INSTABILITY


  • Hyperthermia, fluctuations of blood pressure, tachycardia, bradycardia, cardiac pauses, and sometimes hypoventilation requiring MV
• NMDAR-antibody encephalitis
• Cumulative symptoms during the first month of the disease
• Titulaer 2013
• MRI


  • Normal in about 60-70%
  • In the remaining patients, it may show nonspecific T2/FLAIR hyperintensities
• EEG


  • Focal/diffuse slowing: 72%
  • Extreme delta brush: 11-30% adults, 6% children
• RECOVERY


  • Good outcome (mRS 0-2): 70-80%
  • Death (mRS 6): 6%
  • Relapses: 12-13%
• Specific AEs in children

  • NMDAR
  • LGI1 and CASPR2
  • GABAAR
  • D2R