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 the second most common type of AE in adults and is associated with the leucine-rich, glioma-inactivated 1 (LGI1) antibody. This affects men above 60 years, who outnumber women by a ratio of 3:1. The most common primary symptoms include short and long term memory impairment, mental and behavioral abnormalities, myoclonus, or tonic seizures, especially faciobrachial dystonic (FBDS) seizures which are unique to LGI1 encephalitis and are a useful clinical differentiator, which denote the onset of encephalitis. Seizures typically precede the onset of cognitive impairment, with a progressive amnesia usually developing at their crescendo. Prominent amnesia is a hallmark of limbic encephalitis associated with LGI1-antibodies; autobiographical memory is particularly impaired, often with significant confusion and disorientation. An isolated amnestic syndrome can occur in up to 10% of cases. Spatial disorientation, hallucinations, are also common and some patients may suffer from sleeping disorders and autonomic dysfunctions, for example, sexual dysfunction, sweating, and sinus bradycardia. A tenth has autonomic symptoms and low sodium levels occur in about 60%. Autonomic and muscle hyperexcitability, pain only. FBDS appear earlier than other symptoms in many patients while tonic-clonic seizures often occur concurrently or immediately after a decline in the patient’s cognitive function.
Looking at longterm outcomes cognitive deficits correlate with antibody titer and are most marked for verbal memory while processing speed and executive function are relatively spared. Most patients have a chronic cognitive impairment, with memory predominantly affected but deficits of attention and executive function also reported. Greater disease severity, delays to immunotherapy, or longer courses of immunotherapy (likely mandated by greater disease severity) are all associated with more profound cognitive dysfunction in LGI1 encephalitis. See fact sheet.
CASPR2 antibodies associate with a wide range of neurological syndromes, which often overlap in the same patient. Similar features of limbic encephalitis are often seen; seizures, cognitive impairment, personality change. Cognitive dysfunction is common with memory impairments but confusion and behavioral disorders are less prominent. Anterograde and episodic memory disorders are typically seen.
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), paroxysmal movement disorders, limbic encephalitis, 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 tumor; 10% mortality rate; up to 30% relapse rate.
Long term cognitive outcomes for CASPR2 encephalitis are not clear. Looking at the long term outcome of CASPR2 patients cognitive deficits correlate with antibody titer and are most marked for verbal memory while processing speed and executive function are relatively spared.
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 is common.
In the acute phase deficits across all domains; memory, information processing, attention, executive function, language, visuospatial processing, and social cognition are all affected. The post-acute phase episodic memory, processing speed, and executive function remain impaired with the greatest deficit in episodic and delayed verbal memory.
Dysautonomia. Outcomes: Overall: mortality up to 15%, relapse rate up to 30%. With immunotherapy, > 75% of patients with mRS < 3. See fact sheet.
AMPA antibody-associated encephalitis
Due to its rarity, the clinical course of AMPAR encephalitis is not yet well characterized. 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. May present with prominent memory impairment, confusion, seizures, or severe and sudden encephalitis onset. May also present with isolated amnesia, or a type of memory loss involving the inability to remember new information (anterograde) amnesia, cognitive impairment, disordered sleep, movement disorders. Immunotherapy brings about remission, relapse is common in 60%.
The common memory loss in patients can complicate treatment, and often becomes irreversible after a few relapses have occurred, being accompanied by cognitive impairment which remains a universally prominent feature and isolated amnesic syndromes have also been observed with a focal impairment to anterograde memory. 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.
There are limited data available on the neuropsychological outcomes of AMPAR encephalitis patients. Case reports have described considerable neurocognitive improvement at follow-up. Although in general outcomes appear favorable, psychiatric symptoms or severe or sudden onset of encephalopathy at onset are associated with a poor prognosis.
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/behavioral symptoms are seen in two-thirds of patients, movement disorders; lower titers associated with stiff person syndrome, opsoclonus-myoclonus. Memory deficits and confusion are less consistently reported in GABAAR encephalitis. 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%. No published neuropsychological long-term outcomes have been reported as of 2020.
Anti-GABA-B (γ-Aminobutyric acid B) receptor encephalitis is also typical limbic encephalitis with seizures, memory loss, as well as cognitive and behavioral symptoms which are almost universally seen. Status epilepticus or seizure activity is predominant due to the involvement of the inhibitory GABA receptors. Cognitive impairment and seizures remain the central symptoms, almost universally affecting patients in the acute phase. Memory deficits and confusion present in 47% of patients. The nature of neuropsychological impairments have not been examined in detail.
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. This recent case series identified a subset of patients with GABABR encephalitis presenting with a “rapidly progressive dementia” with subacute cognitive impairment in the absence of seizures. 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%. Prognosis is often poor, with a median survival of 17 months, and the long term outcomes for GABABR encephalitis have yet to be studied.
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.
(GFAP) autoimmune astrocytopathy with glial fibrillary acidic protein, affected patients present with symptoms of one or more of meningitis (headache and neck ache), encephalitis (delirium, tremor, seizures, or psychiatric symptoms), and myelitis (sensory symptoms and weakness). Optic disc papillitis (blurred vision) is common. CSF is more reliable than serum (blood) for GFAP-immunoglobulin G antibody (IgG) testing. It can co-exist with anti-NMDAr or aquaporin-4 (AQP4). Ovarian teratoma commonly exists within anti-NMDAr cases. Corticosteroid-responsiveness is a hallmark of the disease. Relapses occur in approximately 20% of patients, necessitating the transition to a steroid-sparing drug such as Cellcept (mycophenolate mofetil), or azathioprine (Imuran). Reported outcomes vary, though early and sustained intervention usually portends recovery.
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”
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.