Antibodies of Autoimmune
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
Specific syndromes due to antibodies to cell surface antigens
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.
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 above.
LGI1 antibody-associated encephalitis
Limbic encephalitis is most commonly associated with these leucine-rich, glioma-inactivated 1 (LGI1) antibodies, and this affects men above 60 years, who outnumber women by a ratio of 3:1. The most common presentation is with myoclonus or tonic seizures, especially faciobrachial dystonic seizures, which denote the onset of encephalitis, a tenth have autonomic symptoms and low sodium levels occur in about 60%. Autonomic and muscle hyperexcitability, pain only.
Anti-Caspr2 (contactin-associated protein-like 2) antibodies usually lead to slow-onset diffuse encephalitis and autonomic imbalance in many cases, as well as hyperexcitability of the peripheral nerves (in which case it is called Morvan’s syndrome) with neuropsychiatric changes, dysautonomia, sleep disturbance (insomnia, agrypnia excitata) and neuromyotonia. Neuropathic pain is seen in about 60% of cases and relapse is common following tapering of immunotherapy. Patients are typically about 60 years old. Relapse rate and outcome: >80% have favorable responses to immunotherapy – especially in absence of a tumour; 10% mortality rate; up to 30% relapse rate
Is seen in ages throughout the life span, but most commonly younger women
Modal onset: 18–23 years; range: infancy–89 years. Well-defined association with ovarian teratoma in young adult patients; overall rate ~ 25%. Other varied tumors are rare. There is a prodromal period of Flu-like (headache, malaise, mild fever, gastrointestinal symptoms). NMDAr usually has an abrupt or subacute onset Progressive: Prodrome → psychiatric → neurological → critical illness.
Psychiatric symptoms occur in almost all adult patients, less dominant in childhood cases. Polymorphic syndrome involving multiple psychopathological domains, e.g. sleep, mood, psychosis, behavioral, and catatonia. Neurological symptoms include: Seizures common (~ 70%) but rarely frequent
Movement disorder in > 90%. Often multiple simultaneous phenomenologies with a dominant triad of dystonia, stereotypies, and chorea. Orofacial dyskinesia are common
Dysautonomia. Outcomes: Overall: mortality up to 15%, relapse rate up to 30%. With immunotherapy, > 75% of patients with mRS < 3
AMPA antibody-associated encephalitis
Anti-AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor encephalitis affects mostly middle aged women (90%), and presents with limbic or psychiatric features, confusion, seizures, cognitive impairment, amnesia, disordered sleep, movement disorders. Immunotherapy brings about remission, relapse is common in 60%.
Memory loss is common and complicates treatment, and often becomes irreversible after a few relapses have occurred, being accompanied by cognitive impairment. Underlying cancers of breast, lung and thymus are common. Relapse rate and recovery: Most patients show a partial response to oncological management and immunotherapy responsiveness; relapses appear common.
Anti-GABA-B (γ-Aminobutyric acid B) receptor encephalitis is also a typical limbic encephalitis with seizures and memory loss, as well as behavioral aberrations, but status epilepticus or seizure activity is predominant due to the involvement of the inhibitory GABA receptors.
Occurring in older men and women, with an average age of 60 years, these patients often have other antibodies such as N-type voltage-gated calcium channels or glutamic acid decarboxylase antibodies. Lung cancer (small cell) is present in 50%, making this the most common immune encephalitis in this class of patients. Relapse and recovery rate: Some patients are immunotherapy responsive, poor outcomes largely attributed to underlying malignancy; up to 10% may relapse, mortality in up to 40%.
Anti-GABA-A (γ-Aminobutyric acid A) receptor encephalitis occurs in younger age groups, and presents as acute encephalitis with status epilepticus or epilepsy partialis continua when high levels of the antibody are present.
Confusion, disorientation, hallucinations and other psychiatric features, cognitive dysfunction, movement disorders; lower titres associated with stiff person syndrome, opsoclonus-myoclonus. Relapse rate and outcomes: Over 80% may respond to immunotherapy ± tumor removal; but full recovery in only 30%; up to 20% mortality rate (especially in the context of status epilepticus); relapses in 10%
Anti-mGluR1 (metabotropic glutamate receptor 1) is rare, associated with paraneoplastic cerebellar involvement, and Hodgkin’s lymphoma is common.
Anti-mGluR5 (metabotropic glutamate receptor 5) have been reported in a few patients with Ophelia syndrome, which refers to mGluR5- antibody-associated limbic encephalitis with Hodgkin’s lymphoma. Cognitive impairment, memory deficits, confusion and disorientation to time is common, psychiatric symptoms but psychosis is rare. Generally responsive to treatment of Hodgkin lymphoma and immunotherapy.
Anti-DNER (delta/notch-like epidermal growth factor-related receptor) is directed against a Purkinje neuron transmembrane protein and presents with cerebellar degeneration, which is often irreversible. Over 90% of these patients have Hodgkin lymphoma.
Anti-GlyR (Glycine receptor) antibodies occur in stiff-person syndrome (SPS), which may occur along a spectrum characterized by progressive encephalomyelitis with rigidity and myoclonus (PERM) at one end, and hyperekplexia at the other (pathologic startle response, or painful spasms brought on by touch, sound or emotional stimuli).
SPS is not specific for glycine-receptor antibodies, as GAD or amphiphysin antibodies are found in other clinical situations. Relapse rate and outcome: Generally, respond well to immunotherapy, with GlyR antibody stiff person syndrome being more immunotherapy responsive than seronegative cases; may relapse in 15%; 10% mortality rate
Anti-DPPX (dipeptidyl-peptidase-like protein-6) antibodies Dipeptidyl-peptidase-like protein-6 antibodies are directed against a part of a type of potassium channel and has a prodrome of severe diarrhea and weight loss as a primary symptom. Subacute onset of cognitive impairment, agitation, confusion, hallucinations, seizures, sleep dysfunction; tremor, hyperekplexia, myoclonus; bulbar dysfunction, and autonomic dysfunction along with limbic encephalitis. Hyperexcitability is also prominent, in addition to memory loss. Relapse rate and outcome: May have multiple relapses in close to 25%; 60% can respond partially or significantly to (often intensive) immunotherapy, mortality 17%
These are associated with basal ganglia inflammation in children and with Sydenham’s chorea. Parkinsonism, dystonia, hypersomnolence, neuropsychiatric features (obsessive-compulsive disorder, psychosis, emotional lability), ‘basal ganglia encephalitis’. Relapse rate and outcome: Immunotherapy responsive, 25% may relapse.
Glutamic acid decarboxylase is a crucial enzyme in the synthesis of the major inhibitory neurotransmitter, GABA. GAD antibodies have been found in SPS (stiff person syndrome), juvenile diabetes, limbic encephalitis, and temporal lobe epilepsy. Young women are most often affected and show high levels of antibodies. It may often co-occur with GABA(b)-receptor antibodies. Dysautonomia with and without pain, myelopathy, and
spasticity (stiff person syndrome), cerebellar disease are pain associations.
The role of GAD antibodies is not yet established, however, as they occur even in the normal population. Older patients with limbic encephalitis associated with GAD antibodies, or who also have GABA(b)-receptor antibodies, are at increased risk for small cell carcinoma of the lung or thymoma. In general, immunotherapy has limited effects on the outcomes of neurological syndromes associated with GAD antibodies.
Progressive dyssomnia, movement disorders and behavior, gait abnormalities, bulbar and respiratory dysfunction, and cognitive impairment; disease onset often more insidious compared to other autoimmune encephalitis syndromes. Relapse rate and outcome: Severe and progressive, with early reports stating > 70% mortality and minimal response to immunotherapy; later series identify broader phenotype and show immunotherapy may result in improvement and stabilization.
Prodromal fever, headache, gastrointestinal symptoms; subsequent encephalopathy with agitation, seizures, orofacial dyskinesias, and central hypoventilation (marked overlap with NDMAR encephalitis); may have a rapid course.
Pediatric onset 12-36 months; M:F 1:1.4 Opsoclonus, myoclonus, ataxia, cognitive and behavioral impairment associated with low-titer antibodies. Neuroblastoma is seen in about half of the children. The relapse rate and the outcome are not yet known.
Dr. Josep Dalmau presents at the AAN conference: “Autoimmune Encephalitis the cell surface and synaptic antibodies”
Viral disorders can trigger synaptic Autoimmunity
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 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-NMDAREonset 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 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.
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.