Autoimmune Encephalitis (Encephalopathy) is a rare treatable group of CNS disorders that can be progressive or relapse-remitting. It is caused when the immune system makes auto-antibodies that are not supposed to be there. These auto-antibodies (aka antibodies) begin to attack healthy brain cells wrongly identifying them as foreign. An autoimmune response is now occurring as the body’s immune system mistakes its own healthy brain cells for invaders causing inflammation of the brain.
The antibody attacks by targeting special receptors in the brain. The antibodies can target the attack to receptors on the cell surface of healthy nerve cells in the brain or target the attack to synaptic receptors that are exposed to the attacking antibody or ion channels. These antibodies bind to the healthy brain cell on the outside of the cell. These antibodies are called extracellular because they bind or attach themselves to the healthy brain cells outside surface. The healthy brain cells are now destroyed or no longer function properly. Severe brain inflammation occurs. The brain now malfunctions. All brain functions can be compromised: emotions, psychosis, memory, cognition, problem solving, speech, movement, seizures, balance, visual processing planning, sensory, hunger, thirst, behavior and personality traits, often followed by suppressed levels of consciousness and coma may occur.
These diseases are not always cancer-related which makes them different from the classical paraneoplastic neurological diseases that are associated with, but not caused by, the intracellular antibodies. (See: Paraneoplastic Autoimmune Encephalitis)
Most importantly, Autoimmune Encephalitis IS TREATABLE and almost invariably responds to immunotherapies with considerable potential to reverse the impairments caused by these attacking antibodies. Immunotherapies can slow down the progression of the disease, stop the antibodies from attacking and with some treatments kill the attacking antibody which may sometimes leads to complete recovery.
A unique feature of the autoimmune encephalitis is that they can affect patients of all ages including infants and the elderly, some types more often occurring in children and young adults. Autoimmune Encephalitis occurs more frequently in women than in men and they can develop with or without an underlying tumor. The incidence of autoimmune encephalitis has been reported to be higher among African Americans than Caucasians. Recent epidemiological studies suggest that AE is as common as infectious encephalitis with an estimated prevalence (proportion of the population) rate of 13.7/100,000 and incidence (frequency) rate of 1.2/100,000 persons. This study allows us to estimate that approximately 1 million people worldwide had autoimmune encephalitis in their lifetime. It has also been estimated that, currently, about 90,000 people around the world develop autoimmune encephalitis each year.
Most autoimmune encephalitides occur in patients with no apparent immunologic triggers, leading some investigators to postulate a genetic predisposition to these disorders. One study suggested a genetic predisposition to anti-NMDAr encephalitis in Maori and Pacific Island populations. Four studies showed an association of anti-LGI1 encephalitis with HLA class II genes, including HLA-DRB1*07 (DR7) and HLA-DRB4 in a 2017 Dutch population study and DRB1*07:01–DQB1*02:02 in a 2017 Korean population study. A 2018 German study also showed a link with anti-LGI1 and HLA class II genes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 as well as a genetic component in anti-NMDAr encephalitis with HLA-I allele B*07:02. Recently a 2020 study in the Chinese Han population found a HLA subtype had strong susceptibility of LGI1 autoimmune encephalitis and a May 2018 study by the Oxford group showed a non-heritable but consistent genetic predisposition to LGI1 and CASPR2. Research just published out of China shows genetic link to anti-NMDAR encephalitis. This study for the first time, demonstrates an association between specific HLA class II alleles, DRB1*16:02 in anti-NMDAR encephalitis, providing novel insights into the mechanism by which the disease occurs. This adds to LGI1 and CASPR2 HLA-DRB associations. A possible link between inborn errors of immunity, such as with IRAK4 deficiency, and early onset anti-NMDAR encephalitis may also occur.
WHAT CAUSES AUTOIMMUNE ENCEPHALITIS?
Autoimmune Encephalitis is caused by a tumor or viral trigger. Research has proven that patients can experience a virus triggering synaptic autoimmunity in the case of herpes simplex virus and possibly other viral encephalitides. The patient who first has HSV encephalitis may, a few weeks later, come back to the hospital with what used to be called “choreathetosis HSV” and was thought to be a relapse. Now, it has been identified that 30% of these patients have autoimmune encephalitis mediated by the NMDA receptor. When they had herpes encephalitis, they did not have the NMDA antibody, yet a few weeks later when what looks like a relapse is occurring, it is identified that the patient now has NMDA receptor Autoimmune encephalitis. A 2018 double cohort study suggests a meaningful association between HSV-1 infection (without encephalitis) and the development of anti-NMDAR encephalitis in 49% of children in the combined studies. The virus triggered the change and research has hypothesized molecular mimicry in these two situations. Further studies are needed to determine the timing of anti-NMDAREonset along with studies evaluating the mechanism by which such events are involved in disease progression of the disease.
Recent findings suggest that several viral infections can lead to secondary autoimmune encephalitis, including EBV, HHV-6, enterovirus, adenovirus, hepatitis C or HIV infections.
In 2013, a series of 20 pediatric case reports of anti-NMDAr encephalitis showed novel findings in four patients who had specific viral or bacteriological findings including, a throat swab positive for H. influenza; a CSF PCR positive for Human Herpesvirus 6; serum IgM and IgG antibodies to mumps virus, and a nasopharyngeal aspirate positive for Enterovirus. Indicating the suggestion that anti-NMDAR encephalitis may be associated with mycoplasma pneumonia, measles virus, mumps, and group A hemolytic streptococcus.
In late 2014, a novel and important case report was published of VZV encephalitis that triggered the occurrence of NMDAR antibodies leading to anti-NMDAr encephalitis. As of January 2019, VZV has been documented in the setting of anti-NMDAR encephalitis in three cases.
In a single case report in February 2018, a pediatric patient was diagnosed with anti-NMDA encephalitis triggered by acute acquired toxoplasma gondii infection which had not been previously reported. A single case report in November 2018 of EBV in a post solid organ transplant immunocompromised patient, hypothesized that EBV might be an infectious trigger for anti-NMDA receptor encephalitis.
While several infectious agents have been implicated in anti-NMDA encephalitis, with the exception of HSV’s proven link, these cases are novel and suggestive that it is likely science will show other cases in the future where neurotropic viruses can induce similar pathology. Clinicians should assess the possibility of these infections when evaluating a pediatric patient with anti-NMDAr encephalitis.
Presently in 2020, findings suggest that SARS-CoV-2 (COVID-19) has also triggered secondary autoimmune encephalitis. The following months will show whether such autoreactivity can cause persisting neurological morbidity even after clearance of SARS-CoV-2 and remission of COVID-19.
We await new findings in research around this topic.
Dr. Maarten Titulaer Webinar 1 hour
Autoimmune Encephalitis – anti-NMDAr encephalitis and Beyond 2017
Dr. Josep Dalmau
2016 AAN Autoimmune Encephalitis
Gregory Day, MD, MSc, FRCPC
Antibody Mediated Encephalitis in the Modern Era:
From Witchcraft to Neurologic Wizardry
Eric Lancaster, MD, PhD
Autoimmune Synaptic Encephalitis
Dr. Sarosh Irani
What is being done to improve Autoimmune encephalitis for the future?
Andrew McKeon, M.B., B.CH.,M.D
Co-Director of the Neuroimmunology