Multiple co-existing antibodies in Autoimmune Encephalitis

September 3, 2020

Dr. Ryan Kammeyer and Dr. Amanda Piquet (University of Colorado) discuss a patient with autoimmune encephalitis (AE) with multiple auto-antibodies and review the literature to look at how these multiple auto-antibodies might relate to an underlying malignancy, and how unique features of the auto-antibodies may blend together into a new presentation.

AE can occur with or without an underlying malignancy, and certain autoantibodies tend to have a higher association with underlying malignancies then others. Classic onconeural auto-antibodies (like anti-Hu, anti-Ri, or anti-Ma antibodies) target antigens in the cell, and their presence is highly associated with an underlying malignancy, generally > 95%. Antibodies to extracellular antigens target synaptic proteins or ion channels, such as anti-NMDAR, anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (anti-AMPA-R), or anti-γ-aminobutyric acid-A or B receptor (anti-GABAA- R or GABAB-R). These antibodies alter neuronal function by several mechanisms, and are directly pathogenic to cells. When immunotherapy is initiated early, a good recovery may be seen with removing the pathogenic antibody. In contrast, a lower immunotherapy response is seen in encephalitis associated with antibodies to intracellular antigens.

This particular patient had co-existence of multiple auto-antibodies in the CSF (anti-NMDAR, anti-Ma1/Ma2) and serum (anti-GAD65), raising concern for an underlying malignancy, particularly in the setting of antibodies such as anti-Ma1/Ma2.

The presence of multiple anti-neuronal antibodies raises the probability of an underlying malignancy and may be predictive of a specific malignancy. For example, in one study with patients with identified tumors, the frequency of an identified thymoma was 36% when both muscle acetylcholine receptor and striational antibodies were present. This frequency increased to 85% with co-occurrence of the collapsin response-mediator protein-5 (CRMP-5) antibody.

When a patient is diagnosed with an AE, appropriate, and targeted malignancy screening should be undertaken, focusing on the patient’s risk factors. Additional guidance is provided from the specific auto-antibodies discovered, as certain auto-antibodies have high associations with particular tumors. Paraneoplastic antibodies may predate any evidence of a primary malignancy, so continued, regular malignancy screening is necessary, recommended at least every six months for four years, depending on the antibody syndrome.

Co-existing auto-antibody neurologic syndromes have clinical and radiographic features that may be common for each antibody-mediated disorder individually combining in a single, unique presentation that would be atypical for either antibody alone. For example, limbic encephalitis related to anti-GABAB-R antibodies may co-exist with a progressive sensorimotor neuropathy when anti-Hu antibodies are present or demonstrate more prominent psychiatric symptoms in the presence of anti-NMDAR antibodies.

In this patient, the brainstem and limbic encephalitis fit clinically and radiologically with a paraneoplastic neurologic syndrome associated with anti-Ma1/Ma2 antibodies. The NMDA-R antibody was present in the CSF, and although present at low levels, some component of his subacute cognitive and memory decline may be referable to this. His anti-GAD65 antibodies were present at a much lower concentration than seen in neurologic syndromes and were only found in the serum. Therefore, they are unlikely to represent true neurological autoimmunity in this setting, but are instead a marker of increased auto-antibody production in response to tumor cell breakdown and antigen release, or represent a low-titer “false positive” result as seen in 8% of the general population. One disadvantage of this case is that the presence and type of lung neoplasm were not confirmed. However, given the presence of well-characterized onconeural antibodies, this case still meets the criteria for a definite PNS. His pattern of auto-antibodies would suggest a tumor of testicular or lung origin.

The authors conclude that in the setting of multiple auto-antibodies, a careful evaluation for malignancy is warranted, with initial and continued malignancy screening dictated by the antibodies present.