Seronegative AE means AE without any identifiable pathogenic antibody. Because it is a subgroup defined after the exclusion of seropositive AE in which any pathogenic antibody is detected in serum or CSF, the etiologies of seronegative AE are heterogeneous. For example, some might have a hidden autoantibody that cannot be detected in current laboratory methods, or some might have non-antibody mechanisms such as by activated T cells, microglia, macrophages, or cytokines. When physicians say the patient has seronegative AE, it means that the doctors excluded other etiologies as much as they can, and their reasoning based on the clinical presentation, MRI, CSF analysis, and other autoimmune biomarkers lead the conclusion that the patient can be diagnosed as AE even though a pathogenic antibody has not been detected.
Because the diagnosis of AE is made after exclusion of other etiologies, such as infectious, tumor, vascular, degenerative, metabolic, and congenital causes, the diagnosis of seronegative AE always remains uncertain, while autoantibody can be the diagnostic hallmark of seropositive AE. Graus criteria 2016 is helpful when we design clinical trials or analyses of patients’ data set. However, the real-world diagnosis of seronegative AE largely depends on the individual patient data and the experience of the physician. For the reasoning, the clinical presentation, disease course, laboratory data from huge amount of blood labs, CSF analysis and MRI, and the response to empirical immunotherapy are all considered.
The symptoms and signs of seronegative AE can have all kinds of neurologic deficits, also including the typical symptoms of AE such as memory loss, altered mentality, psychiatric symptoms, and seizure. When seronegative AE involves brain cortical area, focal neurologic deficits such as language dysfunction, motor deficits, and focal seizures are possible. When it presents as brainstem encephalitis or cerebellitis, motor and coordination deficits such as gaits instability, slurred speech, dizziness, and bulbar palsy are predominant. Compared to the seropositive AE, seronegative AE patients are often more male, have severe initial mRS score, more impaired consciousness, more weakness, higher prevalence of abnormal CSF profiles and brain MRI, and poorer response to immunotherapy.
Systemic screening of a tumor is important in seronegative AE because it can be a clue of autoimmune or paraneoplastic encephalitis. Some tumors such as small cell lung cancer, thymoma, teratoma, Hodgkins’ lymphoma, plasma cell disorders, and neuroendocrine tumor are more frequently associated with autoimmune paraneoplastic encephalitis. Sometimes, other cancers such as non-small cell lung cancer, breast cancer, renal cell carcinoma, lymphoma, can be associated with paraneoplastic syndrome. Immune-checkpoint inhibitors used to treat cancer can induce autoimmune encephalitis although it’s not common.
Currently, the regimen of immunotherapy is similar between seronegative and seropositive AE. However, because there exists uncertainty in the diagnosis of seronegative AE during the whole treatment course, the immunotherapy is largely empirical and conducted in a very careful way. The physicians check the response after every treatment, and decide whether to move forward with a more intensive immunotherapeutic agent. Accordingly, they usually choose an initial regimen with less side effects and least term-term consequences, such as steroid, immunoglobulin, and plasma exchange. If the physicians find more evidence for the diagnosis of seronegative AE, such as partial response to initial empirical immunotherapy, more exclusion of other etiologies, and clues of autoimmunity other than antibody, then they can try advanced immunotherapeutic agents using rituximab, cyclophosphamide, tocilizumab, anakinra, bortezomib, in cases with remaining neurological deficits. If the regimen for the induction of disease remission is completed, they decide whether to use maintenance immunosuppression, in which oral immunosuppressants or intermittent infusion of biologics can be used. Recently, clinical trials are initiating to expand the repertoire of immunotherapeutic agents in AE.
The outcome of seronegative AE is poorer than that of seropositive AE. This is because seropositive AE has many synaptic antibody diseases, in which there exist less neuronal damage and better recovery after immunotherapy, and not because seronegative AE is intractable to immunotherapy. More than half of the seronegative AE patients are improved by immunotherapy, and become able to look after their own affairs without assistance. Factors associated with good outcomes include younger age, milder baseline neurologic deficits, and early initiation of immunotherapy.
Because the pathogenesis and treatment of seropositive AE has been largely improved, more researchers are focusing on the seronegative AE to find out hidden antibodies, pathogenesis, and definite diagnostic markers, and more effective treatments. Nevertheless, seronegative AE is still unrecognized. Upcoming studies in years should significantly improve the diagnosis, treatment and prognosis for the many patients and families suffering from the disease.
Soon-Tae Lee, MD, PhD, Associate Professor, Department of Neurology at the Seoul National University Hospital. Dr. Lee is focused on novel treatments of autoimmune encephalitis and neurologic complications of cancer. Although treatments of autoimmune encephalitis are improving rapidly, many patients still have poor responses to the current immunotherapies, resulting in long-standing disease burdens. To develop better therapeutic protocols, Dr. Lee researches the mechanism of refractoriness and conducts clinical trials using novel immunotherapeutic agents in the disease.