Autoimmune encephalitis is a debilitating neurological disorder that usually appears as a rapidly progressive form of brain dysfunction, typically developing in less than six weeks, caused by inflammation in the brain. These conditions show a wide range of clinical and immunological presentations and are generally divided into two main types.

The first type includes what are called paraneoplastic syndromes. In these cases, the immune system produces antibodies in response to a tumor that mistakenly target parts of the nervous system. The antibodies are not directly harmful themselves, but they are a sign that the immune system has launched a T-cell-driven attack on brain tissue because it recognizes a protein that's found both in the tumor and in the nervous system. These forms usually follow a single, non-repeating course and tend to respond poorly to treatment, which mostly focuses on removing or treating the underlying tumor and using immunotherapy to reduce the immune response.

The second type includes what we more properly call autoimmune encephalitis, where the immune system produces antibodies that directly attack proteins on the surface of neurons or on synaptic receptors in the brain. Unlike in paraneoplastic syndromes, these antibodies are directly responsible for the disease, and they don't usually indicate the presence of a tumor. Most people with this type of autoimmune encephalitis-around 70% to 80%-respond well to treatment with immunotherapy and can make a good or even full recovery. However, in about 20% of cases, the disease can come back or lead to long hospital stays, with a slower or only partial recovery.

There is also a third group of autoimmune encephalitides where the antibodies target synaptic proteins. These may or may not be linked to cancer, and the proteins they target are usually found inside the cells rather than on their surface.

A fourth group includes what are called seronegative autoimmune encephalitides. These are cases that meet the clinical criteria for autoimmune encephalitis, but no specific antibodies have been identified so far. Among the autoimmune neurological disorders without known antibodies is Susac syndrome, a rare condition that affects the brain, the retina, and the inner ear. It's especially interesting because its features suggest the involvement of antibodies, even though no disease-causing antibodies have yet been found.

The diagnosis of autoimmune encephalitis is based on clinical signs and symptoms, the detection of specific antibodies in blood or spinal fluid, and, in paraneoplastic cases, identifying the underlying tumor. To detect autoantibodies, doctors use various lab techniques, including immunoblotting and different types of immunofluorescence tests-some based on cultured cells, others on brain tissue from rodents.

Despite important progress in recent years, many cases of autoimmune encephalitis remain undiagnosed. One reason is that the disease can begin with vague or incomplete symptoms, making it difficult to recognize. Another issue is that current testing methods might not be sensitive enough to detect all possible antibodies. This means that the group of patients diagnosed with seronegative autoimmune encephalitis might actually include people who have antibodies we just haven't discovered yet.

In many cases, especially in the seronegative forms, the exact cause of the disease is still not fully understood.

The main goal of this study is to better understand how autoimmune encephalitis develops, especially in cases involving antibodies that target proteins on the surface of brain cells-such as NMDAR, GABABR, AMPAR, LGI1, and DNER-as well as in seronegative autoimmune encephalitis and in Susac syndrome. A second goal is to try to discover new autoantibodies that could explain the disease in patients who currently test negative.

Prospective and retrospective observational study

Inclusion Criteria:

• Patients > 18 years of age
• Patients able to provide informed consent
• For the patient group: patients diagnosed with autoimmune encephalitis associated with anti-NMDAR, GABABR, AMPAR, LGI-1, DNER antibodies, seronegative autoimmune encephalitis, or Susac syndrome, without other concomitant autoimmune diseases
• For the control group: patients without a diagnosis of autoimmune encephalitis associated with anti-NMDAR, GABABR, AMPAR, LGI-1, DNER antibodies, seronegative autoimmune encephalitis, or Susac syndrome
• For the control group: patients with other neurological disorders in whom the presence of antibodies against neuronal antigens has been excluded

Exclusion Criteria:

• Patients ≤ 18 years of age
• Deceased patients

For the autoimmune encephalitis group: Patients diagnosed with encephalitis associated with antibodies against NMDAR, GABABR, AMPAR, LGI-1, DNER, seronegative autoimmune encephalitis, and Susac syndrome belonging to the IRCCS Fondazione Policlinico A. Gemelli on an outpatient basis, who meet the inclusion and exclusion criteria of the study, will be enrolled consecutively.

For the control group: patients with other neurological disorders, in whom the presence of antibodies against neuronal antigens has been excluded, belonging to the IRCCS Fondazione Policlinico A. Gemelli on an outpatient basis, who meet the inclusion and exclusion criteria of the study, will be enrolled consecutively.