Antibodies
There are multiple types of antibodies in Autoimmune Encephalitis. They have different clinical presentations and syndromes and have different responses to treatment. We know from the immunology world that antibodies come in many shapes and forms. There is a growing list of antibodies in each category. Autoimmune encephalitis may be divided into several groups of diseases: Those antibodies that can access the cell surface of an antibody or the synaptic receptor of an antibody that is accessible to the targeting antibody because it is exposed on the outside. Cytoxic T-cell diseases associated with antibodies to intracellular antigens, and those associated with other autoimmune disorders.
Extracellular antibodies target the receptor on the outside surface of the cell. There, it binds to the receptor on the outside surface of the healthy neuronal cell.
As more cases appeared, and neuronal targets could not be identified, that lead researchers to discover that the unknown cell surface antigens were not cell surface antigens at all, but in fact were found to be synaptic receptors, including the N-methyl-D-aspartate receptor (NMDAR). This discovery led investigators to distinguish a new category of autoimmune encephalitis those where the offending antibody is actually targeting the synaptic receptors in the brain.
In the disorders investigated so far that occur with autoimmune encephalitis, researchers who have studied their underlying mechanisms have seen that the antibodies alter the structure or function of the antigen they have targeted and bonded too. This attacking antibody that the immune system has created, now causes the antibody it has attached itself to, to malfunction or die.
These attacks can occur throughout the brain. Symptoms wax and wane (come and go in severity) as the attacks occur. At times, some symptoms may be more dominate and not so severe at other times. This is due to the fact that different areas of the brain may be under attack at different times. It is the fluctuation of symptoms and the vast array of symptoms the patient is experiencing that causes the neurologist unfamiliar with these disorders to fail in arriving at an accurate and timely diagnosis. This is a key reason we advocate that those suffering from Autoimmune Encephalitis hire a top expert in the field who has published on the disease as experience bares out that this leads to an accurate and expedited diagnosis and aggressive treatment plan that leads to best outcomes.
The first antibody was identified in 2005 and published about in 2007. Since that time, many antibodies have been identified and still some are yet to be discovered.
Overlapping Immune Responses~
Although it is not common, sometimes more than one antibody may be occurring. NMDAr may occur with AQP4 or MOG antibodies. These patients have NMDAr autoimmune encephalitis and Neuromyelitis Optica spectrum disorder (NMO/NMOSD). NMDAr may occur with demyelinating disorders seen clinically and/or MRI demyelination
Caspr2 and LGI1 each associate with VGKCs
Before 2007, the only cell-surface antibodies associated with autoimmune encephalitis (limbic encephalitis and Morvan’s syndrome) were attributed to antibodies specific for the Kv1.1 and Kv1.2 subunits of the Shaker family of voltage-gated potassium channels (VGKCs). This was later shown to be wrong.
The VGKC antibody test is based on immunoprecipitation of a complex of protein containing VGKCs, LGI1, Caspr2 and other proteins. For 15 years, before the LGI1 and Casper2 antibodies were recognized, patients with VGKC antibodies were thought, incorrectly, to have antibodies to potassium channel subunits themselves. The VGKC test may still detect patients with LGI1 or Caspr2 immunity, but low titer serum positive results have uncertain clinical significance. For instance, Paterson et al. reported that only 4 of 32 patients with low titer VGKC results (100-400 pM) actually had an autoimmune disorder. Therefore, a low titer serum VGKC result without corresponding evidence of LGI1 or Caspr2 antibodies, ideally in the CSF, should not be taken as definitive evidence of autoimmune encephalitis.
In his September 2016 presentation on autoimmune encephalitis, Dr. Josep Dalmaua talked about the importance of specifying the type of molecular target as either LGI1 or CASPR2. If these impressions are negative for these 2 antibodies, and the VGKC are positive, you really don’t know what you are dealing with, he explained. When they get some of these cases to qualify, it has been found that they do not react at all with the cell surface. They are not against the potassium channels and researchers really don’t know what it is. Presently, there has been increasing interest in the VGKC patients without LGI1/Caspr2 antibodies questioning its relevance in clinical practice. These cases can be associated with many foreign disorders. Although the percentage is much lower proportionally, positive VGKC levels can be seen in normal individuals.
To summarize: Anti-LGI1 encephalitis and anti-Caspr2 encephalitis are separate clinical entities. A retrospective Dutch study showed that (LGI1) was the second most frequent autoimmune encephalitis, with an incidence of 0.83 cases per 1 million persons. Early recognition and treatment is necessary and rewarding. The term VGKC-complex antibodies, lumping patients with anti-LGI1, anti-Caspr2 antibodies or lacking both, should be considered obsolete. Clinicians are told to be careful that they specify either LGI1 or CASPR2 and these are associated with specific types of syndromes as seen in the chart below.
Dr. Josep Dalmau presents at the AAN conference: "Autoimmune Encephalitis the cell surface and synaptic antibodies"
Dr. Dalmau on Herpes Simplex Virus >NMDAr AE
Viral disorders can trigger synaptic Autoimmunity
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 20% of these
patients have an 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-NMDARE
onset along with studies evaluating the mechanism by which such events are involved
in disease progression of the disease.
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 pneumoniae, 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 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.
We await new findings in research around this topic.
Paraneoplastic disorders are, in general, autoimmune disorders that are triggered by tumors. These disorders are strongly cancer associated, meaning that each of these conveys a distinct risk profile for various tumors. They involve T cell responses targeting the brain neuron. These are called intracellular antigens (antibodies). Intracellular antibodies in Autoimmune Encephalitis attack the brain cell by seeping inside the cell. These disorders tend to have a more malignant, severe clinical course. Patients will show early atrophy on their MRI and tend to be in the ICU. They may go into status epilepticus. Their EEG is typical of multi focal interictal epileptiform discharges (IEDs). So it is a wider spread disease.
Since patients tend to have an underlying malignancy at the time of diagnosis, the physician will search intently for an underlying occult malignancy. This is a cancer that is determined to be at the metastatic stage at the time of diagnosis but a primary tumor cannot be identified. The malignancy may not be found because it is microscopic so the physician will continue to screen the patient every 3 to 6 months. Tumor screening and treatment is essential to the proper management of these disorders for several reasons. 1) Treating the relevant tumor is thought to be helpful for treating the autoimmune disorder. 2) Tumor therapy and immune therapy may need to be given simultaneously and in a coordinated fashion. 3) Treatment with steroids, Rituximab, or Cyclophosphamide could complicate tumor diagnosis in the case of tumors like Lymphoma.
Paraneoplastic disorders are associated with, but not caused by, the intracellular antibodies. The antibodies in these disorders are useful tumor markers, and aid the clinician as to where they need to search for an associated tumor. For example, paraneoplastic syndromes such as cerebellar degeneration or Limbic Encephalitis are associated with highly specific antibodies against intracellular neuronal proteins and aggressive cytotoxic T cell responses that usually lead to irreversible functional and structural neuronal damage.
The prognosis tends to be poor because of the irreversible progressive neuronal cell death and neurological decline caused by these antibodies; the severity of associated cancers, and the difficulty in controlling these sorts of T-cell immune responses targeting the brain cells because they tend to not respond to immunotherapy.
Anti-NMDAr
The anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score
The anti-NMDAr antibody (ab), was first identified in 2007 by Dr. Josep Dalmau. It is now believed to be the most common type of autoimmune encephalitis. Some patients experience a prodromal phase when the disease is developing with symptoms of viral-like or flu-like illness that usually presents 1-2 weeks before the development of psychiatric symptoms. It is not known whether the symptoms are due to NMDAR dysfunction, the systemic immune response to autoimmune disease or secondary responses to a viral infection which later precipitate autoimmune disease as seen in herpes simplex virus (HSV). The diagnosis of anti-NMDAR encephalitis is confirmed by the detection of CSF antibodies against the GluN1 subunit of the NMDAR; serum testing is less reliable, with false negative results in up to 14% of cases. Therefore, it is important that both serum (blood) and CSF (spinal fluid) are tested as spinal fluid is 100% accurate to confirm the diagnosis.
Anti-NMDAR encephalitis affects predominantly children and young adults (median age, 21 years), with a predominance of cases in females (4:1) that becomes less evident after the age of 45 years. Up to 58% of affected young female patients have an ovarian teratoma. in men and children, the association with tumors is less frequent. In patients older than 45 years, the clinical picture is similar to that of younger patients, but the outcome is less favorable. In this age group, 23% of patients had an underlying tumor (carcinomas instead of teratomas), and delays in diagnosis and treatment were more frequent than in younger patients.
NMDA receptors are proteins that control electrical impulses in the brain. Their functions are critical for judgement, perception of reality, human interaction, the NMDA receptor is essential for the development of new memory and retrieval of memory so patients later have no memory of certain times in their life while the disease was occurring. Speech production is affected; it is described like aphasia but it does not fit with any type of aphasia. Children may become almost mute. The control of unconscious activities such as breathing and swallowing, also known as autonomic functions, is impaired.
The presentation of NMDAR encephalitis in children with behavioral abnormalities may initially suggest autistic regression, early onset schizophrenia, or childhood disintegrative disorder. Presentations with adults may initially suggest undiagnosed Bipolar disorder, or recreational drug or alcohol abuse. Compared with adults, children more often present initially with insomnia, abnormal movements or seizures, or a change in behavior such as irritability, temper tantrums, agitation, and reduction of verbal output. Then in the ensuing days or weeks progress to develop a syndrome similar to that of the adults. Teenagers and adults more often present with psychiatric symptoms, including agitation, hallucinations, delusions, and catatonia, which may lead to hospital admission for psychosis. The disease progresses in a period of days or weeks to include reduction of speech, memory deficit, orofacial and limb dyskinesias, seizures, decreased level of consciousness, and autonomic instability manifested as excess salivation, hyperthermia, fluctuations of blood pressure, tachycardia, or central hypoventilation.
Most patients with autoimmune encephalitis respond within weeks to first-line treatments, but anti-NMDAR encephalitis patients are the slowest among autoimmune encephalitis to respond. For the 47% of patients who do not respond to first-line treatments, a second-line immunotherapy is started with rituximab or cyclophosphamide or both. The outcome of the second-line immunotherapy in patients is improved in 65% of cases. Generally, the frequency of improvement is better for patients with tumor (80%) when compared to patients without tumor (48%). Patients without tumors consequently require more often a second-line immunotherapy. Despite this second-line treatment, relapse can occur in 20%–25% of the case. To prevent relapses, immunosuppressive treatment can be continued with mycophenolate mofetil or azathioprine during 1 year.
There is an association of higher CSF titers for teratoma and higher CSF tiiters and worse outcomes. High CSF titers can also be associated with relapses. Usually when the patients start to recover from the autonomic dysfunction, they start getting better. Recovery is slow, greater than two years, and occurs in inverse order of symptom development. Patients are then left with several executive dysfunctions that can last for a long time; some of which they may not recover.
 NMDAr due to binding |  Clinical spectrum |
|---|---|
 NMDA development |  NMDAr |
 anti-NMDA |  Anti-NMDA emerging differential diagnosis |