Autoimmune encephalitis

Patients with AIE may present movement disorders such as ataxia, dystonia, myoclonus, and orofacial dyskinesia. Seizures are the most common symptom and different types of seizures may be seen, including refractory status epilepticus. Autonomic disturbances such as sweating, hypertension, tachycardia and hypoventilation are also frequent. Some patients may develop gastrointestinal manifestations (diarrhea, gastroparesis, and constipation) due to involvement of the myenteric plexus. Sleep disturbances such as insomnia, abnormal sleep movements, sleep apnea, and hypersomnia are also found. Some of these findings are suggestive of certain types of encephalitis and may indicate a specific underlying antibody or tumor. == Mechanism ==

Autoimmune encephalitis commonly presents an immune response against neuronal autoantigens with production of antibodies. Anti-neuronal antibodies are classified into antibodies against cell surface antigens (CSAab), antibodies against synaptic antigens (SyAab) and antibodies against intraneuronal antigens (INAab), also known as onconeural antibodies. == Diagnosis ==

Diagnostic criteria for possible autoimmune encephalitis (all three of the following criteria met): • Subacute onset (rapid progression of less than three months) of working memory deficits (short-term memory loss), altered mental status (decreased level of consciousness, lethargy or personality changes), or psychiatric symptoms • At least one of the following: • New focal central nervous system findings • Seizures not explained by previously-known seizure disorder • Cerebrospinal fluid pleocytosis • Magnetic resonance imaging suggestive of encephalitis • Seizures not explained by a previously known seizure disorder. In such cases, an electroencephalogram (EEG) can be a valuable tool to assess brain electrical activity and identify patterns consistent with seizure disorders or encephalopathy, further supporting the suspicion of autoimmune encephalitis. • Reasonable exclusion of alternative causes Criteria for autoantibody-negative but probable autoimmune encephalitis (all four criteria met): • Subacute onset (rapid progression of less than three months) of working memory deficits (short-term memory loss), altered mental status (decreased level of consciousness, lethargy or personality changes), or psychiatric symptoms • Exclusion of well-defined syndromes of autoimmune encephalitis (typical limbic encephalitis, Bickerstaff brainstem encephalitis, acute disseminated encephalomyelitis) • Absence of well-characterized autoantibodies in blood serum and cerebrospinal fluid, and at least two of the following criteria: • Magnetic resonance imaging suggestive of encephalitis • CSF pleocytosis, oligoclonal bands or elevated cerebrospinal fluid IgG index, or both • Brain biopsy showing inflammatory infiltrates and excluding other disorders • Reasonable exclusion of alternative causes == Classification ==

Anti-NMDAR encephalitis Anti-N-methyl-D-aspartate receptor encephalitis is one of the most common causes of AIE and was originally described in 2007 in a cohort of 12 patients, 11 of them with ovarian teratomas. This condition predominantly affects children and young female patients. Underlying malignancies are found mainly in patients between the age of 12–45 years; most of them are ovarian teratomas (94%), followed by extraovarian teratomas (2%), and other tumors (4%). Herpes simplex virus-1 encephalitis appears to be a trigger for anti-NMDAR encephalitis; most AIE cases after herpes zoster are now believed to be anti-NMDAR encephalitis. In most of these patients, CSF analysis showed lymphocytic pleocytosis. A recent study identified an underlying neoplasia in 27% of these patients, mostly thymomas. Similar to that seen in patients with anti-gamma-aminobutyric acid B receptor (GABA-BR) and anti-AMPAR antibodies, they may also present with coexisting autoimmune disorders such as thyroiditis or myasthenia. Other presentations include ataxia and opsoclonus-myoclonus. In a small series of 20 patients with anti-GABA-BR, about 50% were found to have small-cell lung cancer. Males and females appear to be equally affected. The long-term prognosis in anti-GABA-BR encephalitis is determined by the presence of an underlying malignancy. Other rare phenotypes included epilepsy and painful polyneuropathy. Anti-VGKC antibodies, in fact, later turned out to be directed against proteins that form a complex with VGKC called leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR-2). Each of these antibodies lead to specific clinical symptoms. Recently, anti-GlyR antibodies have also been reported in patients with cerebellar ataxia and anti-GAD antibodies and patients with demyelinating diseases including optic neuritis and multiple sclerosis, but their clinical significance remains unclear. Anti-GlyR antibodies are usually not associated with tumors, although there have been reports of patients with underlying thymoma, small-cell lung cancer, breast cancer and chronic lymphocytic leukemia. The outcome of reported cases is generally good after treatment of the lymphoma and immunotherapy. One therapeutic approach to seronegative autoimmune encephalitis is using as a first-line treatment corticosteroids and intravenous immunoglobulin.Other options include the use of rituximab (second-line) and tocilizumab or cyclophosphamide (next-line). A study in a South Korean hospital with 142 patients identified 5 factors that should be considered when evaluating the disease: • Presence of refractory status epilepticus • Advanced age of onset (over or equal to 60 years) • Having the subtype of probable AE (ANPRA) • Infra-tentorium involvement in brain magnetic resonance imaging • Delay of immunotherapy of more than 1 month The less of those factors are present, the better the chance of good recovery in a 2-year period. == Treatments ==

Lines of treatment Treatments for autoimmune encephalitis are separated into three lines: first, second, and last-line. First-line treatments are intended to reduce inflammation and neutralize autoantibodies, while having mild but manageable side effects. If the first-line treatment are not effective, second-line treatments are used. Second-line treatments are more aggressive and are more focused on suppressing the immune system. Last-line treatments are typically reserved only for refractory cases of autoimmune encephalitis that have not responded to first or second-line therapies and involve higher risk treatments. First-line treatments Immunoglobulin therapy Immunoglobulin therapy is used as a first line immunotherapy to treat autoimmune encephalitis by introducing donor immunoglobulin via intravenous infusion (IVIg). Corticosteroid therapy Corticosteroids are first-line treatments for autoimmune encephalitis. Plasmapheresis Plasmapheresis, also called plasma exchange (PLEX) or therapeutic plasma exchange (TPE) is the use of an apheresis machine which separates the different components of blood, the platelets, plasma, red blood cells, and white blood cells. It works to treat autoimmune encephalitis by filtering pathogenic autoantibodies and removing them from the body, while replacing with donor plasma or albumin. Plasmapheresis is typically used in conjunction with other treatments such as steroids or immunotherapy. PLEX for autoimmune encephalitis is commonly administered inpatient using a central venous catheter over the period of 1-2 weeks. Second-line treatments Immunosuppression Immunosuppressive drugs are used as second line therapies to treat or maintain autoimmune encephalitis when first-line treatments are not effective For autoimmune encephalitis, cyclophosphamide is typically administered intravenously. Last-line treatments Stem cell transplant An autologous hematopoietic stem cell transplant (HSCT) is classified as a last-line treatment for autoimmune encephalitis that does not respond to first- or second-line treatments. This treatment involves the collection of hematopoietic stem cells from the patient prior to high doses of immunoablative chemotherapy, which neutralizes all immune cells. The stem cells removed prior to the chemotherapy are reinfused to regenerate the immune system without autoantibodies. Stem cell transplants are considered to be effective, but have significant risks, including severe opportunistic infections, fertility issues, cancer, and mortality. == See also ==