In the past 4 years, we prospectively identified 17 patients with limbic encephalitis in a single institution. A remarkable finding is that 9 (53%) of these patients had antibodies to previously known antigens and 5 (29%) to nCMAg. Considering these patients and those whose serum or CSF samples were sent to us for analysis, 19 of 39 (49%) patients had antibodies known to be associated with limbic encephalitis (paraneoplastic or VGKC). However, 17 of 39 (44%) patients had antibodies to diverse nCMAg that are not measured by currently available commercial tests and were not included in the recently reported diagnostic criteria of paraneoplastic syndromes.17
This finding is important because the disorders associated with cell‐membrane antigens in general (either VGKC or nCMAg) are usually responsive to treatment and have a definitely better prognosis than those associated with intracellular antigens. Correlation between antibody titres and improvement was not determined in this study,4,7,8
partly because the nCMAg antibodies are predominantly found in the CSF and repeat spinal taps were not obtained after improvement in these patients.
A review of a previous series of patients with autoimmune limbic encephalitis shows that most did not adequately reflect the clinical–immunological spectrum of the disorder because of the following:
- Cases were identified from retrospective review of patients known to have cancer11
- Laboratories tested sera or CSF samples selected at multiple institutions1
- The inclusion criteria were restricted to patients with a specific type of cancer or antibody.4,9,18
None of these biases pertains to the 15 patients in our study who were identified on clinical grounds at the HUP and who provide a relative distribution of immunophenotypes in limbic encephalitis.
However, a referral bias was noted in the 22 patients whose sera or CSF samples were sent to us for analysis. The referral pattern seemed to be driven by our recent reports on subtypes of limbic encephalitis.7,8,10
Of the 22 patients, 17 (77%) had anti‐Ma2 (23%) or antibodies to nCMAg (54%). By contrast, the frequency of anti‐Ma2 encephalitis in patients in HUP was markedly lower (6%), while the occurrence of limbic encephalitis with antibodies to nCMAg remained relatively high (29%). Antibodies to nCMAg were found more frequently than anti‐VGKC (18%), suggesting that many patients who are considered to have idiopathic or “non‐herpetic limbic encephalitis without VGKC antibodies”6,19
may indeed have antibodies to nCMAg.
In light of the increasing number of reports on patients with limbic encephalitis and anti‐VGKC, it can be argued that these patients are under‐represented or were missed in our study. This is unlikely for two reasons: (1) the clinical and MRI picture of these patients with either predominant limbic encephalitis or Morvan's syndrome is no more difficult to recognise than the immunophenotypes reported here; and (2) all samples from patients without antibodies to intracellular antigens were examined for anti‐VGKC using at least two and in some cases three different methods (radioimmunoassay, immunohistochemistry with brain tissue, and immunocytochemistry with cells expressing Kv subunits). Although the five patients with anti‐VGKC were positive by all methods used (three patients examined with all three methods), the 17 patients with antibodies to nCMAg were negative by all methods, except for two patients who showed faint reactivity with cells expressing Kv1.4 in one case and Kv1.6 in the other. In both instances, the reactivity with brain was clearly different from polyclonal Kv1.4 and Kv1.6 antibodies (data not shown), indicating that the presence of antibodies to other antigens was more restricted to the hippocampus. In previously reported patients with limbic encephalitis with anti‐VGKC, the prominent antigen was Kv1.1,16
and this was also found in our three patients with anti‐VGKC in whom the subunit specificity was determined.
These findings have important clinical implications:
- Besides the known antibodies associated with limbic encephalitis (paraneoplastic or VGKC), there is an emerging group of patients with treatment‐responsive limbic encephalitis.
- These disorders are associated with antibodies that predominantly react with the neuropil of the hippocampus and may occur without or with a tumour association.
- Among all subphenotypes, there is a group of young women who have apparently benign ovarian cysts, but pathological studies show mature or immature teratoma.8 The importance of recognising these patients is that they may transiently improve with immunotherapy, but preliminary experience suggests that recovery depends on both tumour removal and immunotherapy20,21 (manuscript in preparation).
- At presentation, there are no neurological, MRI or CSF features specific of any immunophenotype, except for the predominant type of tumour in some paraneoplastic disorders (ie, Ma2 and testicular cancer; Hu and small‐cell lung cancer), or the low likelihood of cancer in patients with anti‐VGKC.4,10
The generally favourable outcome in most patients with antibodies to cell‐membrane antigens (either VGKC or nCMAg) validates a previously suggested approach for the management of patients with limbic encephalitis.22
After reasonable exclusion of other disorders (ie, herpes simplex virus encephalitis was diagnosed in 26 patients during the same 4‐year period at the HUP), patients suspected of having autoimmune limbic encephalitis should be considered for immunotherapy (corticosteroids, intravenous immunoglobulin or plasma exchange). Treatment should start even in the absence of antibody testing because patients with limbic encephalitis‐VGKC or ovarian teratoma can deteriorate rapidly, with status epilepticus, hyponatraemia or hypoventilation that may result in death. Also, some patients with limbic encephalitis of unclear aetiology or without antibodies may show dramatic response to corticosteroids, as found in three of our patients.