Immunotherapy for GRIN2A and GRIN2D-related epileptic encephalopathy

Epilepsy Res. 2020 Jul:163:106325. doi: 10.1016/j.eplepsyres.2020.106325. Epub 2020 Apr 2.


Background: GRIN-related developmental-epileptic encephalopathies are associated with a spectrum of neurodevelopmental disorders, including intellectual disability, epilepsy including continuous spike-and-wave during sleep syndrome (CSWS), or epilepsy-aphasia spectrum phenotypes such as in Landau-Kleffner syndrome. Efficacy of IVIG treatment was recently reported in a patient with LKS related to GRIN2A mutation.

Aim and methods: We describe the efficacy of Immunotherapy in 5 consecutive patients (4 males, age range 6 months-13 years) with molecularly confirmed GRIN-related epileptic encephalopathy (4 with GRIN2A- related epilepsy-aphasia spectrum/epileptic encephalopathy with CSWS, accompanied by verbal, communicative and behavioural regression, and one patient with GRIN2D - related infantile developmental-epileptic encephalopathy). All patients had global developmental delay/ intellectual disability in various degrees, and were resistant to anticonvulsants, but none of the patients had frequent clinical seizures. All patients received monthly infusion of IVIG 2 g/ kg for 6 months; 2 patients were also treated with high-dose corticosteroids.

Results: Normalization or near normalization of the EEG was noted in 3 patients, from whom 2 had mild improvement in verbal abilities and communication skills. Perceptual/spatial abilities, as well as executive functions and attention span, remained significantly impaired.

Conclusion: according to this preliminary, open-label study, Immunotherapy may lead to a clinical and electrographic improvement in patients with GRIN-related developmental-epileptic encephalopathies. Further studies to validate the efficacy of immunotherapy and the potential role of autoimmunity in GRIN-related disorders are needed.

Keywords: Developmental epileptic encephalopathy; Epilepsy-Aphasia spectrum; Epileptic encephalopathy; Epileptic encephalopathy with continuous spike-and-wave during sleep syndrome; GRIN2A; GRIN2D; IVIG; Landau-Kleffner.

MeSH terms

  • Anticonvulsants / therapeutic use*
  • Brain / drug effects
  • Brain / physiopathology
  • Brain Diseases / drug therapy*
  • Brain Diseases / immunology
  • Child
  • Electroencephalography / drug effects
  • Electroencephalography / methods
  • Epilepsy / drug therapy
  • Epilepsy / immunology
  • Epilepsy, Generalized / drug therapy
  • Epilepsy, Generalized / genetics
  • Female
  • Humans
  • Infant
  • Male
  • Mutation / genetics
  • Receptors, N-Methyl-D-Aspartate / drug effects*
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Seizures / drug therapy
  • Seizures / immunology


  • Anticonvulsants
  • GRIN2D protein, human
  • Receptors, N-Methyl-D-Aspartate
  • N-methyl D-aspartate receptor subtype 2A