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 healthy neuronal cell and then bind to the receptor on the outside surface of the cell.
As more cases appeared, and neuronal targets could not be identified, 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 to. This attacking antibody that the immune system has created, now causes the neuron 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 of autoimmune neurology 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. Along with the rapidly expanding spectrum of autoimmune encephalitis (AE), probable AE with no detected autoantibody (AE-NoDab) has become a major category of AE. Approximately 25-30% of patients do not have an identified antibody. (antibody negative/seronegative/possible, probable AE).
This easy-read handout explains What are intracellular and extracellular antibodies and what do the differences mean for patients with autoimmune encephalitis?
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
Is seen in ages throughout the life span, but most commonly in 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, behavior, 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. In 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.
Prognosis: A 2021 study presents comprehensive longitudinal data for the cognitive outcome. All patients had cognitive deficits about 2 years after disease onset, mainly affecting memory and executive function. After 4 years, moderate or severe cognitive deficits persisted in 2/3 of patients despite the good functional neurological outcome. Impaired cognitive outcome was predicted by delayed treatment and higher disease severity. However, continued improvement of cognitive function was observed for several years after disease onset in some patients.
Cognitive deficits are frequent and severe long-term sequelae following NMDAR encephalitis. These deficits show a slow and incomplete recovery and persist beyond recovery of other neuropsychiatric symptoms of the disease. Rapid diagnosis and treatment at disease onset as well as for continued and customized cognitive rehabilitation to improve the long-term outcome is of vital importance.
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 subacute progressive short and long-term memory impairment, mental, behavioral, and space orientation abnormalities, neuropathic pain, myoclonus, or tonic seizures, especially faciobrachial dystonic (FBDS) seizures which are unique to LGI1 encephalitis and are a useful clinical differentiator, which denotes 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 appears 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 long-term 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 are 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. A 2021 study on relapse and outcome reports that LGI1 has a relapse rate of 15%. Most patients achieve functional improvement after a year of treatment. The most common residual symptoms are cognitive impairment, followed by epileptic seizures and personality changes (particularly irritability). Approximately 5%–11% of cases are associated with cancer; the most common associated tumor is thymoma. See fact sheet.
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 were present in 47% of patients. The nature of neuropsychological impairments has 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, with poor outcomes largely attributed to underlying malignancy; up to 10% may relapse, and mortality is 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.
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, and 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, cognitive decline, seizures, sleep disturbance (insomnia, agrypnia excitata), weight loss, 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 although rare pediatric cases have been described. The disorder is usually not associated with cancer. A tumor, usually thymoma, may be revealed in up to 32% of cases. Patients with tumors are more likely to develop Morvan syndrome. 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.
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.
MOG (Myelin oligodendrocyte glycoprotein)
Mog antibodies are associated with relapsing syndromes involving brainstem or cortical encephalitis, sometimes with optic neuritis and transverse myelitis, which particularly involve children and young adults. Seizures may present as the index event and the syndrome can evolve to a more diffuse encephalitis, including one which radiologically mimics classical acute disseminated encephalomyelitis. Patients typically respond well to corticosteroid therapies, although the duration of their administration remains controversial as relapses are common.
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
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, and 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-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 have a prodrome of severe diarrhea and weight loss and other gastrointestinal symptoms which occur in ~75% of patients with anti-DPPX encephalitis; these symptoms almost always precede (median ~4 months) the symptoms of encephalitis. Subacute onset of cognitive impairment, agitation, confusion, hallucinations, seizures, sleep dysfunction; tremor, hyperekplexia (exaggerated startle response), myoclonus; bulbar dysfunction, and autonomic dysfunction along with limbic encephalitis. Hyperexcitability is also prominent, in addition to cognitive dysfunction or memory loss. Occasionally, patients with DPPX antibodies can have neuro-ophthalmic manifestations. Some patients harbor an underlying malignancy, frequently B-cell lymphoma. Relapse rate and outcome: May have multiple relapses in close to 25%; 60% can respond partially or significantly to (often intensive) immunotherapy, mortality 17%
Progressive dyssomnia (a collection of sleep disorders that negatively impact the quantity and quality of sleep, struggling to fall asleep at night or feeling the need to sleep excessively), and predominant discrete figural memory impairment are seen at the onset. Movement disorders and behavior, gait abnormalities, bulbar, respiratory dysfunction, cognitive deterioration, and dysregulation of autonomic central nervous system (CNS) activity; disease onset is often more insidious compared to other autoimmune encephalitis syndromes.
The prevalence of anti-IgLON5 antibodies is estimated at 12 out of 150 000 patients per year, although it is believed to be higher due to numerous cases being incorrectly diagnosed and reported. Most commonly, diagnosis is made among elderly patients, with no sex predominance, although the disease onset is designing and may occur between the ages of 45 and 70. The literature points out that anti-IgLON5 antibodies found in serum or CSF are the necessary element of a definite diagnosis. A strong association between this disease and the presence of HLA-DRB1*10:01 and HLA-DQB1*05:01 alleles (Human Leukocyte Antigens) may be evidence for the theory of genetic predisposition to autoimmune disease development, but infections are also considered as a potential disease trigger. IgLON5-antibodies can co-exist with anti-γ-aminobutyric acid B (GABA-B)-receptor molecules, associated with small-cell lung tumor development and seizures.
Relapse rate and outcome: Severe and progressive, with early reports stating > 70% mortality due to respiratory failure and minimal response to immunotherapy; later series identify broader phenotype and show immunotherapy may result in improvement and stabilization. Reported neuropathologic findings of “tauopathy,” which unifies a number of disorders, such as progressive supranuclear palsy (PSP), and corticobasal degeneration, have also reinforced the concept of IgLON5 autoimmunity having a poor prognosis.
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.
(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), cerebellar ataxia, and myelitis (sensory symptoms and weakness). Optic disc papillitis (blurred vision) in patients is common (approximately 25%–50% of patients). 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. Underlying malignancies are found in 14%–38% of patients. 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.
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.
Glutamate kainate receptor subunit 2 is associated with an encephalitis with prominent cerebellar involvement as seen clinically and on MRI. Cerebellar symptoms, cerebellitis, May Co-exists with anti-AMPAR and anti-NMDAR encephalitis. The antibody effects are predominantly mediated by internalization of GluK2.
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.
This new antibody was identified in January 2021. Two patients were identified. The patients were associated with preceding meningitis or neuroendocrine carcinoma and responded to 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-mGluR1 (metabotropic glutamate receptor 1) is rare, associated with paraneoplastic cerebellar involvement, and Hodgkin’s lymphoma is common. Isolated or combined with dysgeusia, memory or attention deficits, psychiatric problems.
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.
Septin-5 is a biomarker of a rapidly progressive, but treatable, form of autoimmune cerebellar ataxia. It is a severe neurologic disorder, treatable in some patients but potentially fatal. Septin-5 antibodies are detectable in both serum (blood) and CSF. Cerebellar degeneration leads to disability from loss of balance, incoordination, and speech impairment and can also affect cognitive function. Testing for an autoimmune cause is an important diagnostic endeavor in affected patients, particularly those with a subacute onset and rapidly progressive course. Affected patients may have an immunotherapy-responsive disease, occult cancer, or both.
SEZ6L2 (seizure-related 6 homology 2) antibody syndrome
Autoantibodies to the brain membrane protein SEZ6L2 have been recently reported in a small number of patients with a cerebellar syndrome (ataxia, dysarthria) with extrapyramidal symptoms (bradykinesia, hypomimia, postural instability). SEZ6L2 antibodies are predominantly IgG4 and do not cause internalization of their target antigen on cultured neurons.
An autoimmune limbic encephalitis syndrome usually presents with isolated, severe short-term memory loss. Other symptoms reported are delusional thoughts, confusion, agitation, and aggressive behavior. There is no association with cancer but the response to immunotherapy is poor.
Antibodies against Zic4 may occur with paraneoplastic neurological disease associated to small cell lung cancer with or without neurological symptoms. Most Zic4 positive patients also produce antibodies against Hu and CV2. Patients who have only Zic4 antibodies usually display symptoms of cerebellar degeneration. Cerebellar degeneration leads to disability from loss of balance, incoordination, and speech impairment and can also affect cognitive function. Patients with a combination of Zic4 and other autoantibodies suffers from a broader spectrum of symptoms.
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.
- Paraneoplastic encephalitis: clinically based approach on diagnosis and management
- Paraneoplastic Syndrome and Mimics: What radiology and clinicians need to know
- Paraneoplastic Neurologic Disorders: A brief overview
- Which antibody and which cancer in paraneoplastic syndromes
- Paraneoplastic and Other Autoimmune Disorders of the Central Nervous System
Specific Syndromes with antibodies against intracellular antigens
ANNA1 or Anti-Hu
Antineuronal Nuclear Antibody, Type 1 is a Paraneoplastic encephalomyelitis and is almost always associated with small cell lung carcinoma (SCLC). The relevant antibody (previously called anti- Hu) is termed anti-neuronal nuclear antibody type 1 (ANNA1).
ANNA1 antibody is found almost exclusively in patients with a history of tobacco use or passive exposure. Women are affected twice as often as men. Cancer has been found in >90% of seropositive patients. Small cell lung carcinoma (SCLC) has been found in 83% of patients. A second malignant neoplasm is found in 13% of patients positive for ANNA1 who have SCLC.
The most common clinical presentation of patients positive for ANNA1 is peripheral neuropathy (sensory >sensorimotor>autonomic>>motor), but they can exhibit any element of encephalomyeloradiculopathy. Approximately 10% of patients present with gastroparesis or intestinal obstruction. ANNA1 has also been detected in children with intestinal dysmotility, cerebellar ataxia, and brainstem encephalitis with and without neuroblastoma.
ANNA1 antibody is detected in 5 to 10% of patients with small cell lung carcinoma who do not have a paraneoplastic syndrome. ANNA1 is not recommended as a screening test for lung cancer.
CSF results are sometimes positive when serum results are negative. If a lumbar puncture is going to be performed as part of the diagnostic workup, CSF testing is recommended to improve the detection rate.
ANNA2 or Anti-Ri
Antineuronal Nuclear Antibody Type 2. Patients usually present with signs of midbrain, brain stem, cerebellar and/or spinal cord dysfunction. Ocular opsoclonus-myoclonus may be a prominent symptom. Paraneoplastic opsoclonus, characterized by involuntary rapid movement of the eyes in both vertical and horizontal planes, is most often associated with breast cancer and SCLC. The relevant antibody is termed anti-neuronal nuclear antibody type 2(ANNA-2)This autoantibody has also been detected in patients with bladder and cervical cancer.
Antineuronal Nuclear Antibody Type 3 . This autoantibody causes paraneoplastic syndromes associated with SCLC. Fifteen percent of patients with SCLC will have a second malignancy.
Anti-glial/neuronal antibody, also known as Sox-1 antibody is associated with small cell lung carcinoma, paraneoplastic cerebellar degeneration, isolated or combined with brainstem encephalitis neuropathy, Lambert-Eaton syndrome.
CRMP-5 IgG (anti-CV2)
Symptoms include: chorea, loss of vision, taste or smell, cognitive dysfunction, memory loss (dementia), asymmetric and painful sensorimotor axonal neuropathy, and cerebellar symptoms, myelopathy, and peripheral neuropathy, which is usually sensorimotor. Collapsin response-mediator protein-5 (CRMP) is a cytoplasmic antigen that is highly expressed in neurons throughout the central and peripheral nervous system and in a subset of glial cells. IgG autoantibody to this antigen is associated with a paraneoplastic syndrome in patients with small cell lung cancer, thymoma or renal cell carcinoma. This autoantibody is more commonly present in patients with small cell lung cancer than ANNA1 autoantibody.
Autoantibody can be detected in serum (blood) and cerebrospinal fluid. The antibody titer (volumn) usually decreases after treatment of the neoplasm. A rising titer is indicative of tumor persistence or recurrence.
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. A variety of efferent neuro-ophthalmic manifestations has been reported in association with GAD65 antibodies. Nystagmus is a common finding.
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. The frequency of cancer detection is approximately 15%, which is roughly the same percentage found among samples sent to the Mayo Clinic neuroimmunology laboratory for paraneoplastic antibody testing that test seronegative for all known antibodies. In addition, low titers of GAD65 may be seen in healthy individuals or those with Type 1 diabetes mellitus. In general, immunotherapy has limited effects on the outcomes of neurological syndromes associated with GAD antibodies.
KLHL11 also called Kelch-11
Called “testicular cancer-associated paraneoplastic encephalitis,“ the disease causes severe neurological symptoms in men. They progressively lose control of their limbs, eye movements, and, in some cases, speech. Rhomboencephalitis (symptoms referable to inflammation of the brainstem and cerebellum), most commonly with ataxia, vertigo, diplopia, auditory symptoms (hearing loss and tinnitus), with tinnitus often presenting early. Other manifestations include dysarthria and seizures. Neuropsychiatric dysfunction can manifest in these patients too, causing anxiety and panic attacks or cognitive decline. Additionally, KLHL11 has been linked to reported cases of limbic encephalitis, either with or without concurrent rhombencephalitis. The disease begins with a testicular tumor, which appears to cause the immune system to attack the brain. Affected men often find themselves misdiagnosed or undiagnosed and appropriate treatment is delayed.
Anti-mGluR1 (metabotropic glutamate receptor 1) is rare, associated with paraneoplastic cerebellar involvement, and Hodgkin’s lymphoma is common. Approximately 50% of reported cases are associated with an underlying tumor. Isolated or combined with dysgeusia (distorts sense of taste), memory or attention deficits, psychiatric problems (auditory hallucinations, paranoia). Ocular involvement, including oscillopsia, vertical nystagmus, gaze-evoked nystagmus, diplopia, and saccadic pursuits have been commonly reported.
anti-PCA1 or anti-Yo
Purkinje Cell Cytoplasmic Antibody Type 1.
Anti-Yo autoantibodies interact with cytoplasmic rather than cell surface membrane proteins of Purkinje cells. Autoantibodies directed against intracellular Purkinje cell proteins lead to cell death and paraneoplastic cerebellar degeneration. Paraneoplastic cerebellar degeneration is associated with breast or gynecological (ovarian, fallopian, endometrial) tumors. Less commonly it is associated with lung (SCLC) cancer or Hodgkin lymphoma. More than 90% of seropositive patients present with subacute cerebellar ataxia and approximately 5% present with sensorimotor or motor neuropathy.
PCA1 autoantibody is rarely found in patients with neurologic diseases without breast or gynecologic cancer. Conversely it is rarely found in patients with breast or gynecologic cancer without neurologic dysfunction.
Purkinje Cell Cytoplasmic Antibody Type 2.
This autoantibody is usually associated with lung cancer, especially SCLC. The antibody is seldom detected in patients with uncomplicated SCLC.
PCA-Tr (also known as amphiphysin, Ma2)
Purkinje Cell Cytoplasmic Antibody Tr
This autoantibody has only been detected in 80% of patients with Hodgkin lymphoma and causes subacute cerebellar ataxia. Anti-Tr antibody titer (volumn) tends to drop after treatment of Hodgkin’s disease.
Subacute parkinsonism / PSP phenotype with supranuclear gaze palsy (vertical > horizontal) and constant eye closure resembling apraxia of lid opening, combined with additional signs of limbic, diencephalic or brainstem encephalitis, myelopathy or radiculoplexopathy; red flags: hypothalamic-pituitary endocrine dysfunction, weight gain, prominent sleep disorders; MRI: T2 hyperintensities of pons, midbrain, thalamus, basal ganglia, cerebellar peduncles, hypothalamus, amygdala, or temporal lobe; sometimes only atrophy or no abnormalities.
Zinc finger proteins, encoded by Zic genes and expressed in both the mature and developing CNS, contribute significantly to cerebellar development. The association of Zic proteins with cerebellar development implies that autoantibodies targeting these proteins can lead to significant cerebellar effects. Autoantibodies targeting these proteins, particularly Zic4, are associated with significant cerebellar effects.
SCLC is the predominant tumor type associated with Zic4 antibodies, found in about 90% of cases. PCD is the most common syndrome in both isolated Zic4 cases and those with additional onconeural antibodies.
In cases of rapidly progressive dementia, a diagnosis of autoimmune encephalitis should be considered, presenting with cognitive decline, seizure-like activity, and newly emerging movement disorders. Although Zic4 antibodies are mainly linked to SCLC, there are reports of associations with other malignancies like B-cell lymphoma and neuroblastoma.
Amphiphysin antibody IgG
Amphiphysin antibody is present in about 5 percent of patients with stiff person syndrome and may be associated with a paraneoplastic neurological syndrome associated with small cell lung cancer and breast tumors.
P/Q Voltage-Gated Calcium Channel
Voltage-gated calcium channel (VGCC) is a large transmembrane protein with multiple subunits that are named P, Q, N, L, T and R. P/Q channels play a role in release of acetylcholine from nerve endings, while N type channels are key components of the autonomic conduction system. P/Q-type VGCCs make up greater than 95 percent of the functioning receptors at the neuromuscular junction.
Lambert-Eaton myasthenic syndrome (LEMS) is an uncommon disorder of neuromuscular junction transmission that causes slowly progressive symmetrical proximal muscle weakness. Autonomic dysfunction such as dry eyes, dry mouth, impaired sweating and erectile dysfunction may also be present. Early recognition is particularly important because approximately 50% of cases are associated with a malignancy, mainly small cell lung cancer (SCLC).
Diagnosis of LEMS is confirmed by electrophysiology studies and testing for the presence of antibodies to voltage-gated calcium channel (VGCC). Antibodies against P/Q-type VGCC are present in approximately 85 to 95 percent of patients and antibodies against N-type VGCC are found in about 30 to 40 percent of patients with LEMS. Antibodies directed against VGCC interfere with the normal calcium flux required for the release of acetylcholine. Synaptic transmission fails when antibodies cause a critical loss of calcium channels.
A high titer P/Q-type VGCC antibody is strongly suggestive of LEMS in patients with a high pretest probability of LEMS. It is important to realize that P/Q-type VGCC antibodies are present in a variety of other diseases. Low tittered antibodies are present in some patients with myasthenia gravis, amyotrophic lateral sclerosis and other autoimmune diseases. They also may be detected in paraneoplastic disorders associated with lung, ovarian, or breast carcinoma. So while the VGCC antibody test is confirmatory in patients with clinical and electrophysiologic features of LEMS, the antibody test alone is not diagnostic, especially in the presence of malignancy or amyotrophic lateral sclerosis.
Antibodies may not be present at onset of LEMS. Testing should be repeated later if clinical suspicion remains high. Titers are generally higher in patients with severe weakness, but severity cannot be predicted by antibody titer.
Calcium channel binding antibodies (IgG and IgM) are identified in blood tests. However, antibody may be detected in cerebrospinal fluid when blood results are negative. If a spinal tap has been already been performed, it is recommended that CSF be submitted with serum and tested if serum is negative.