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Brain. 2019 Jun 1;142(6):1631-1643. doi: 10.1093/brain/awz094.

The expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies.

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Department of Neurology, Erasmus Medical Center, Dr. Molewaterplein 40, GD, Rotterdam, The Netherlands.
Department of Biology, Division of Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, CH, Utrecht, The Netherlands.
Department of Immunology, Erasmus Medical Center, Dr. Molewaterplein 40, GD, Rotterdam, The Netherlands.
Department of Biochemistry, Erasmus Medical Center, Dr. Molewaterplein 40, GD, Rotterdam, The Netherlands.
Department of Neurology, University Medical Center Utrecht, Heidelberglaan 100, CX, Utrecht, The Netherlands.
Department of Neurology, Leiden University Medical Center, Albinusdreef 2, ZA, Leiden, The Netherlands.


In this study we report the clinical features of 32 patients with gamma aminobutyric acid B receptor (GABABR) antibodies, identify additional autoantibodies in patients with anti-GABABR encephalitis that mark the presence of an underlying small cell lung carcinoma and optimize laboratory methods for the detection of GABABR antibodies. Patients (n = 3225) were tested for the presence of GABABR antibodies using cell-based assay, immunohistochemistry and live hippocampal neurons. Clinical data were obtained retrospectively. Potassium channel tetramerization domain-containing (KCTD)16 antibodies were identified by immunoprecipitation, mass spectrometry analysis and cell-based assays. KCTD16 antibodies were identified in 23/32 patients with anti-GABABR encephalitis, and in 1/26 patients with small cell lung carcinoma and Hu antibodies, but not in 329 healthy subjects and disease controls. Of the anti-GABABR encephalitis patients that were screened sufficiently, 18/19 (95%) patients with KCTD16 antibodies had a tumour versus 3/9 (33%) anti-GABABR encephalitis patients without KCTD16 antibodies (P = 0.001). In most cases this was a small cell lung carcinoma. Patients had cognitive or behavioural changes (97%) and prominent seizures (90%). Thirteen patients developed a refractory status epilepticus with intensive care unit admittance (42%). Strikingly, 4/32 patients had a rapidly progressive dementia. The addition of KCTD16 to the GABABR cell-based assay improved sensitivity of the in-house fixed cell-based assay, without loss of specificity. Twenty-two of 26 patients improved (partially) to immunotherapy or chemotherapy. Anti-GABABR encephalitis is a limbic encephalitis with prominent, severe seizures, but patients can also present with rapidly progressive dementia. The co-occurrence of KCTD16 antibodies points towards a paraneoplastic origin. The addition of KCTD16 improves the sensitivity of the cell-based assay.


antineuronal autoantibodies; autoimmune encephalitis; neuronal surface antigens; paraneoplastic neurological disorders

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