The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies

We thank Yeo et al. for the comments and agree that clinical context is very important as stated extensively in our article. [1] The risk for autoimmunity is much higher in patients with limbic encephalitis (LE)/encephalomyelitis (EM) than other clinical phenotypes, both in patients with and without positive VGKC-tests (without LGI1/Caspr2-antibodies). Matching for clinical phenotype is essential and we matched based on diagnoses by referring physicians. Autoimmune criteria, similar to those recently proposed, [2] were blindly assessed and patients assigned a definitive diagnosis. Unfortunately, some diagnosed as LE/EM were reassigned, thereby rendering the matching incomplete as mentioned in the discussion. [1] Comparing only patients with LE/EM, no differences were found (p=0.18), although power was limited by sample size. In both VGKC-positive and VGKC-negative patients, additional antibodies were identified (2 and 3, respectively). In both groups, patients fulfilled autoimmune criteria and most benefited from immunotherapy, irrespective of VGKC-result.

The presence of novel antibodies in some patients with LE/EM is likely. Some antibodies might even be linked to the VGKC-complex. However, as the likelihood of autoimmunity is high in VGKC-negative patients with LE/EM as well, all patients currently diagnosed with seronegative autoimmune encephalitis should be searched for novel antibodies. [2]

1. van Sonderen A, Schreurs MW, de Bruijn MA, et al. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology 2016;86:1692-1699.

2. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391-404.

For disclosures, please contact the editorial office at [email protected].

We read with interest the study by van Sonderen et al., [1] and the editorial by Graus et al., [2] on the clinical relevance of voltage-gated potassium channel (VGKC) radioimmunoassay (RIA) positivity without antibodies to LGI1 and Caspr2. VGKC-positive patients without LGI1/Caspr2 antibodies were compared to VGKC-negative patients. No statistical difference was observed in the proportions of patients with evidence of autoimmune inflammation between the two groups.

While 10 of the 25 VGKC-positive patients without LGI1/Caspr2 antibodies had limbic encephalitis (LE)/encephalomyelitis (EM) (syndromes found to be associated with autoimmunity), [1] we noted 11 patients with clinical syndromes that would not satisfy the authors' criteria for autoimmunity. Analyzing the main study group as a whole attenuates the proportion of LE/EM patients with autoimmune inflammation. Perhaps studies investigating only LE patients who are VGKC-positive without LGI1/Caspr2 antibodies, using proposed diagnostic criteria for autoimmune LE compared to appropriately matched controls, could yield meaningful differences. [3]

We agree that positive VGKC RIA is not a standalone marker of autoimmunity. However, it needs to be interpreted in the appropriate clinical context. Immune-mediated encephalitis is an emerging field in neurology. Keeping an unprejudiced approach at this stage would facilitate further research in identifing novel autoantibodies against yet defined VGKC complex or other neuronal antigens.

1. van Sonderen A, Schreurs MW, de Bruijn MA, et al. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology 2016;86:1692-1699.

2. Graus F, Gorman MP. Voltage-gated potassium channel antibodies: Game over. Neurology 2016;86:1657-1658.

3. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391-404.

For disclosures, please contact the editorial office at [email protected].

We thank Lilleker et al. for the comments on our article. [1]

For our article, we blindly assessed autoimmunity using strict criteria. [1] The review referred to by Lilleker et al. [2] has not gained wide acceptance. Guidelines have been published recently, mirroring our used criteria. [3] These criteria, developed after our study, did not incorporate treatment response either. Response due to or after treatment can be difficult to discriminate, as is prediction of natural history. Steroids also have other effects in addition to immunomodulatory mechanisms.

Our study had limited sample size excluding all LGI1/Caspr2 patients to avoid confusion. [1] The patients with LGI1 or Caspr2 antibodies were clearly different from the VGKC+, but LGI1-/Caspr2- patients. Nevertheless, power was easily sufficient to detect the value of clinical evaluation with appropriate ancillary testing. Clinical phenotype was important to fulfill autoimmunity criteria, while a positive VGKC-test was not. Power was also sufficient to detect differences in treatment response as most patients meeting our criteria did improve after immunotherapy (regardless of VGKC). [1] Previous publications, stripped from the LGI1/Caspr2 patients and other biases, seem to confirm our results. [4]

Regardless of VGKC results, thorough testing in serum and CSF for known antibodies is mandatory in all patients with potential autoimmune encephalitis. In addition, we screened for novel antibodies by immunohistochemistry and live hippocampal neurons, as recommended in recent guidelines. [3]

1. van Sonderen A, Schreurs MW, de Bruijn MA, et al. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology 2016;86:1692-1699.

2. Zuliani L, Graus F, Giometto B, Bien C, Vincent A. Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. J Neurol Neurosurg Psychiatry 2012;83:638-645.

3. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391-404.

4. Graus F, Gorman MP. Voltage-gated potassium channel antibodies: Game over. Neurology 2016;86:1657-1658.

For disclosures, please contact the editorial office at [email protected].

The authors described a lack of consensus on diagnostic criteria for autoimmune encephalitis. However, published criteria for recognizing neuronal surface antibody syndromes (NSAS) are available. [2] These include response to immunosuppression as a feature supporting a definite NSAS diagnosis. Additionally, we reported a cohort of patients with focal epilepsy and VGKC antibodies. [3] Of the six patients described, four were negative for LGI1 and Caspr2. [3] Each of the four patients had at least some response to immunosuppression (e.g. reduced seizure frequency). [3]

At odds with what others have suggested, van Sonderen et al. did not include treatment response in the classification system devised to define autoimmune inflammation. Furthermore, the small sample of 25 double-negative patients (which only included one patient with new-onset focal epilepsy) and lack of testing for antibodies directed against other components of the VGKC complex (e.g. contactin-2) represent significant limitations.

It is possible that this study was simply underpowered to detect autoimmune inflammation in the double-negative group. More restricted conclusions should be made from the data available.

1. van Sonderen A, Schreurs MW, de Bruijn MA, et al. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology 2016;86:1692-1699.

2. Zuliani L, Graus F, Giometto B, Bien C, Vincent A. Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. J Neurol Neurosurg Psychiatry 2012;83:638-645.

3. Lilleker JB, Jones MS, Mohanraj R. VGKC complex antibodies in epilepsy: diagnostic yield and therapeutic implications. Seizure 2013;22:776-779.

For disclosures, please contact the editorial office at [email protected].