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GABAbR

Gamma-aminobutyric acid-B receptor

Description

Autoantibody usually of the IgG1 isotype directed against the GABAb1 subunit of the GABAb receptor. The dominant clinical presentation is limbic encephalitis with seizures. More than half of patients either already have detectable SCLC or will develop it following diagnosis. Serum more sensitive than CSF on commercial CBA however CSF is more sensitive on live assays.

Mechanism of action

GABAb receptors are G protein coupled receptors made up of the GABAb1 and GABAb2 subunits. They are most highly expressed in the hippocampus, thalamus, and cerebellum but may be found throughout the CNS. GABAb receptors mediate presynaptic inhibition, attenuate presynaptic firing frequencies, and indue slow inhibitory post synaptic potential.

The anti-GABAb autoantibodies target the GABAb1 subunit which is necessary for GABA binding and receptor function. Thus the presence of these autoantibodies will impair the action of GABA on its receptor and reduction of pre and post synaptic inhibition.

Associated clinical features

  • Limbic encephalitis manifesting as seizures in 96.6% (1)
  • Cognitive impairment in 81%
  • Psychiatric disturbance in 77.6%, and disturbed level of conscoiusness in 55.2%
  • Memory loss, confusion
  • EEG abnormal in 60% (epileptiform changes and general slowing)
  • MRI abnormal in 63% (showing limbic encephalitis)
  • CSF abnormal in >74% (pleocytosis and/or elevated protein)
  • Rapidly progressive dementia
  • Rarely opsoclonus myoclonus syndrome or gait ataxia
  1. Almost all patients will experience generalised seizures but may have other phenotypes: 15% focal to bilateral tonic clonic, 19% focal with impaired awareness, and 12% focal

Associated neoplasia

More than 50% associated with malignancy, most often SCLC which may not be present at time of diagnosis.

Laboratory method

Commercial CBA

Indirect Immunohistochemistry looking for staining in the cortex and subcortical gray matter with strong positivity of hippogampus and molecular layer of the cerebellum. Live rat hippocampal neuronal assay

Notes of performance characteristics

  • Commercial fixed CBA

    • CSF sensitivity 84%
    • Serum sensitivity 96%
    • Serum specificity 99.7%

    Addition of KCTD16 to an in house fixed CBA will improve sensitivity to that of the commercial fixed CBA and can identify higher titres in CSF and serum. Specificity was unaffected in this study.

Grade

Next steps

85% will respond to immunotherapy. Median improvement in mRS to 2 after immunotherapy.

Seizure freedom may be achieved by median of 6 days of immunotherapy and usually occurs earlier than cognitive symptoms which will improve by median of 35 days. Detailed data on relapse is not available. Median survival is 17 months and is not different for those with tumour.

The presence of KCTD16 antibodies increases the probability of a paraneopastic origin.

  1. Lancaster, Eric, Meizan Lai, Xiaoyu Peng, Ethan Hughes, Radu Constantinescu, Jeffrey Raizer, Daniel Friedman, et al. “Antibodies to the GABAB Receptor in Limbic Encephalitis with Seizures: Case Series and Characterisation of the Antigen.” Lancet Neurology 9, no. 1 (January 2010): 67–76. https://doi.org/10.1016/S1474-4422(09)70324-2. ↩

  2. Graus, Francesc, Alberto Vogrig, Sergio Muñiz-Castrillo, Jean-Christophe G. Antoine, Virginie Desestret, Divyanshu Dubey, Bruno Giometto, et al. “Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes.” Neurology - Neuroimmunology Neuroinflammation 8, no. 4 (July 2021): e1014. https://doi.org/10.1212/NXI.0000000000001014. ↩

  3. Höftberger, Romana, Maarten J. Titulaer, Lidia Sabater, Balazs Dome, Anita Rózsás, Balazs Hegedus, Mir Alireza Hoda, et al. “Encephalitis and GABAB Receptor Antibodies.” Neurology 81, no. 17 (October 22, 2013): 1500–1506. https://doi.org/10.1212/WNL.0b013e3182a9585f. ↩

  4. Jiang, Chunguo, Min Zhu, Dan Wei, Hongyan Duan, Yuhui Zhang, and Xiaokai Feng. “SCLC and Anti-GABABR Encephalitis: A Retrospective Analysis of 60 Cases in China.” Thoracic Cancer 13, no. 6 (2022): 804–10. https://doi.org/10.1111/1759-7714.14323. ↩

  5. Coevorden-Hameete, Marleen H van, Marienke A A M de Bruijn, Esther de Graaff, Danielle A E M Bastiaansen, Marco W J Schreurs, Jeroen A A Demmers, Melanie Ramberger, et al. “The Expanded Clinical Spectrum of Anti-GABABR Encephalitis and Added Value of KCTD16 Autoantibodies.” Brain 142, no. 6 (June 2019): 1631–43. https://doi.org/10.1093/brain/awz094. ↩

Last update: 2022-05-05
Created: 2022-03-29