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Autoimmune Encephalitis Antibodies

Autoantibody-mediated encephalitis is a group of inflammatory brain disorders characterized by neuropsychiatric symptoms and the presence of autoantibodies against neuronal antigens. Common clinical features include a change in behavior, psychosis, seizures, cognitive deficits, abnormal movements, dysautonomia and decreased level of consciousness. Autoimmune encephalitis is also known as autoimmune-mediated encephalitis, autoimmune-mediated limbic encephalitis, and autoimmune synaptic encephalitis. Autoimmune encephalitis is the third most common cause of encephalitis after viral infections and acute disseminated encephalomyelitis. These disorders can be categorized by the area of the brain affected, the antibody involved, or the name of the discoverer (eg, Morvan syndrome).

Two potential triggers of autoimmune encephalitis are cancer and viral encephalitis. Some tumor cells express neuronal proteins targeted by autoantibodies. Herpes simplex encephalitis, and possibly other viruses, can incite antibodies against the NMDAR and other neuronal cell surface proteins.

Autoantibodies identified in autoimmune encephalitis fall under two broad categories:

  • Those targeting intracellular (nuclear or cytoplasmic) antigens. Autoantibodies directed to intracellular antigens are believed to arise after cytotoxic T lymphocyte mediated cell injury and exposure of antigens. These syndromes are more likely to be paraneoplastic, cause extensive neuron loss and be less responsive to immunotherapy
  • Those targeting antigens on the neuronal surface such as membrane receptors and ion channels. They alter the structure and function of membrane receptors or ion channels, causing neurologic dysfunction. These syndromes are less likely to be paraneoplastic and more likely to respond to immunotherapy.

Limbic Encephalitis

Patients with limbic encephalitis present with symptoms attributed to dysfunction of mesial temporal lobe regions of the brain such as the hippocampus. Prominent symptoms include short-term memory loss, behavioral disturbances such as agitation and confusion, and psychiatric problems such as depression and psychosis. Recurrent seizures are a salient feature and often progress to status epilepticus. Limbic encephalitis may occur in the absence of malignancy.

Cerebrospinal fluid analysis may be normal or show mild pleocytosis, elevated protein, increased immunoglobulin G synthesis, and oligoclonal banding. In about 60% of patients, MRI shows hyperintense fluid-attenuated inversion recovery (FLAIR) or T2 signal changes in the mesial temporal lobes, reflecting inflammatory changes.

Autoantibodies associated with limbic encephalitis are summarized in the following table.

Antigen Location Antibody Cancer Frequency Cancer Association Neurologic Syndrome
Intracellular ANNA1 (anti-Hu) >75% Small Cell Lung Multiple types
  Anti-CRMP >75% Small cell lung & thymoma Uveitis, optic neuritis, cerebellar
  Anti-Ma2 ~90% Testicular germ cell Limbic or brainstem
  Anti-GAD65 <33% None Stiff person syndrome
Cell surface Anti-NMDA receptor 38% Ovarian teratoma limbic to brainstem
  Anti-LGI1 0 None limbic with faciobrachial dystonic seizures
  Anti-AMPA receptor 70% Thymoma & Breast limbic
  Anti-GABA B receptor 47% Small cell lung limbic

 

LGI1 autoantibodies are the most common causes of limbic encephalitis followed by autoantibodies against gamma aminobutyric acid (GABA) type B receptor and autoantibodies against alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Limbic encephalitis can also be associated with paraneoplastic syndromes associated with autoantibodies against intracellular antigens Hu, Ma2, and GAD65.

Other Causes of Limbic Encephalitis

Other causes of limbic encephalitis need to be ruled out. These include infectious meningoencephalitis, especially due to herpes simplex virus. Thiamine deficiency (Wernicke encephalopathy), drug intoxication, prion disease, Hashimoto encephalopathy, tumor, and subclinical status epilepticus should also be considered. Some of these conditions are associated with the same neuronal autoantibodies detected in limbic encephalitis. For example, autoantibodies against the VGKC complex and NMDA-receptor autoantibodies may be detected in prion disease. Treated herpes simplex viral encephalitis can stimulate the production of NMDA-receptor autoantibodies.

Brainstem encephalitis

The brainstem consists of the midbrain, pons, and medulla. Signs and symptoms of autoimmune encephalitis involving the brainstem include eye movement abnormalities, ptosis, dysphagia, dysarthria, ataxia, facial palsy, vertigo, hearing impairment, reduced consciousness, and hypoventilation.

Anti-Hu, anti-Ri, and anti-Ma2 antibodies are most commonly associated with brainstem encephalitis. Other autoantibodies are listed in the following table.

Antigen Location Antibody Cancer Association
Intracellular Anti-Hu (ANNA1) Small cell lung
  Anti-Ri (ANNA2) Breast, lung
  Anti-Ma2 Testicular germ cell
Cell surface Anti-NMDA receptor Ovarian teratoma
  Anti-GQ1b None
  Anti-NMO (anti-aquaporin 4) None

 

Neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorders (NMO), also known as Devic's disease or opticospinal multiple sclerosis, is a severe autoimmune inflammatory demyelinating disease that selectively involves demyelination of the optic nerves and spinal cord, leading to unilateral or bilateral optic neuritis and transverse myelitis spanning three or more vertebral segments. Brain lesions occur in less than 60% of cases. The initial clinical manifestation may be an encephalitic pattern, affecting predominantly the brainstem, or a more diffuse central nervous system pattern, mimicking acute disseminated encephalomyelitis. Within 5 years, approximately 30% of patients lose vision in at least 1 eye and 10% are unable to walk independently. In North America, the proportion of nonwhite individuals is higher among patients with NMO than among those with classic multiple sclerosis.

Many patients with NMO are misdiagnosed as having multiple sclerosis. Accurate diagnosis is important because prognosis and treatment for the two diseases differ. NMO attacks are often severe resulting in early onset of blindness and paraplegia. NMO is treated with immunosuppression while multiple sclerosis is treated with immuno-modulation. Plasmapheresis is more beneficial for patients with acute attacks of NMO than for those with multiple sclerosis.

Patients with NMO produce an antibody to aquaporin-4 (AQP4), a water channel protein located in astrocytes. NMO is now classified as an autoimmune AQP4 channelopathy. Seropositivity for aquaporin4 IgG allows early diagnosis of NMO. Sensitivity is 80% and specificity is 99%. Aquaporin4 IgG is uniformly negative in patients with classical multiple sclerosis. A positive value is consistent with an NMO spectrum disorder and justifies initiation of early immunosuppressive therapy to prevent severe disability.

Seropositive patients are much more likely to relapse or progress within 2 years than seronegative patients. Seronegativity does not exclude the diagnosis of NMO. Patients already treated with immunosuppressive therapy may not have detectable antibody.

Aquaporin4 IgG autoantibody is synthesized by peripheral lymphoid tissues and is not synthesized intrathecally. Serum autoantibody must reach a significant concentration before autoantibody is detected in cerebrospinal fluid. The optimal specimen for detection of aquaporin4 IgG is serum and not cerebrospinal fluid. Followup testing is recommended within 3 to 6 months after initiation of therapy.

Bickerstaff brainstem encephalitis

Bickerstaff brainstem encephalitis is a rare disease that presents as postinfectious ataxia, ophthalmoparesis, and altered consciousness. It is associated with anti-ganglioside GQ1b autoantibody. MRI is normal in about 90% of cases, so recognizing the clinical presentation and testing for anti-GQ1b autoantibody are critical to diagnosis. Recovery is usually spontaneous and complete and can be hastened by immunotherapy, especially intravenous immunoglobulin.

Other causes of brainstem encephalitis

The differential diagnosis of a presentation of brainstem encephalitis includes:

  • Infectious causes, the most common being Listeria species followed by enterovirus 71 and herpes simplex virus. Tuberculosis, brucellosis, and Whipple disease should also be considered.
  • Primary central nervous system inflammatory and demyelinating conditions, eg, multiple sclerosis and acute disseminated encephalomyelitis.
  • Systemic inflammatory conditions, eg, Beh­çet disease, systemic lupus erythematosus, and sarcoidosis.
  • Direct brainstem neoplastic involvement, as might occur in primary central nervous system lymphoma or leptomeningeal carcinomatosis.

Cerebellar Syndrome

Patients with autoantibody-mediated encephalitis localized predominantly to the cerebellum typically present with dizziness, vertigo, and unsteady gait, progressing eventually to limb and gait ataxia. Symptoms are often subacute, progressing over weeks.

Multiple neuronal autoantibodies have been found to occur with cerebellar encephalitis. In most cases, they are paraneo­plastic, directed against intracellular antigens and not considered to be pathogenic. In such cases, the syndrome is more accurately described as autoantibody-associated rather than autoantibody-mediated.

Antigen Location Antibody Cancer Association
Intracellular Anti-Yo (Purkinje cell) Ovarian & Breast
  Anti-Ri Breast & Lung
  Anti-Tr Hodgkin Lymphoma
  Anti-GAD None
Cell Surface Anti-VGCC Small cell lung
  Anti-mGluR1 Hodgkin lymphoma in remission

 

Only a minority of cases have detectable autoantibodies to cell surface antigens. Examples include autoantibodies to anti-metabotropic glutamate receptor type 1 (anti-mGluR1) and anti-glutamic acid decarboxylase (anti-GAD).

Differential diagnosis of cerebellar syndromes

The differential diagnosis of autoantibody-associated cerebellar syndromes is broad and includes:

  • Alcohol-induced atrophy
  • Drug-induced cerebellar atrophy (eg, from lithium, phenytoin, gabapentin, metronidazole, amiodarone, carbamazepine)
  • Vitamin B1 and E deficiency
  • Hypothyroidism, hypoparathyroidism
  • Neurodegenerative disease (eg, prion disease, multiple system atrophy)
  • Parainfectious causes (eg, after infection with Epstein-Barr virus)
  • Immune-mediated diseases (Miller-Fisher syndrome, associated with anti-GQ1b antibodies, and antigliadin-associated ataxia, which can occur in isolation or as part of celiac disease)

Specific Autoantibodies

AMPA receptor Antibody

Alpha-Amino-3-Hydroxyl-5-Methyl-4-Isoxazolepropionic acid (AMPA) receptors are glutamate receptors that mediate fast excitatory neurotransmission in the brain. Autoantibodies targeting the extracellular domains of either or both GluR1 or GluR2 subunits have been associated with limbic encephalitis. Patients usually present with seizures, memory loss, mood changes, personality changes, psychosis, delirium or sleep disorders. A history of autoimmune disorders, cancer, or cancer risk factors increases the likelihood of autoimmune etiology.

Antibody can be detected in both serum and CSF. If antibody is detected in serum, subsequent testing of CSF adds little value. However, patients with negative serum results sometimes have positive CSF results. High titer antibodies are more specific for limbic encephalitis.

AMPA receptor antibody is detected using immunofluorescence to detect IgG binding to human cells transfected with GluR1 and GluR2 receptor subunits. Transfected cells over-express the cognate protein, increasing the sensitivity of the test. Specimen requirements are a red top tube of blood for serum antibody and 1 mL of CSF in a sterile vial for CSF antibody..

Patients with limbic encephalitis due to AMPA receptor antibody may also have other coexisting autoantibodies such as anti-CRMP5, anti-GAD65 and anti-AGNA/SOX1.

Antineuronal Nuclear Antibody, Type 1 (ANNA1 or Anti-Hu)

Paraneoplastic encephalomyelitis 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), and recognizes a 35-40 kD component found in neuronal cell nuclei.

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.

Antineuronal Nuclear Antibody Type 2 (ANNA2 or Anti-Ri)

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), and recognizes protein antigens of 55 and 80 kD located within neuronal cell nuclei.This autoantibody has also been detected in patients with bladder and cervical cancer.

Antineuronal Nuclear Antibody Type 3 (ANNA3)

This autoantibody causes paraneoplastic syndromes associated with SCLC. Fifteen percent of patients with SCLC will have a second malignancy.

AGNA

Anti-glial/neuronal antibody, also known as Sox-1 antibody is associated with small cell lung carcinoma.

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.

CASPR2

Voltage Gated Potassium Channels (VGKC) are present on the membrane of neurons in both the central and peripheral nervous system. They play a crucial role in returning the cell to the resting state after an action potential. Antibody-mediated disturbance of this process was initially suspected in patients with neuromyotonia, Morvan's syndrome and limbic encephalitis. VGKC complex autoantibody does not bind to the potassium channel itself, but to other subunits of the channel such asleucine-rich glioma-inactivated 1 protein (LGI1) and contactin-associated protein 2 (CASPR2). CASPR2 autoantibody usually correlates with peripheral nerve manifestations and Morvan syndrome. Hyponatremia is often seen in patients with these antibodies. VGKC antibodies can be distinguished from antibodies to (LgI1 and Caspr2 by Western blot.

CRMP-5 IgG

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. Clinical manifestations include: chorea; loss of vision, taste or smell; dementia; myelopathy; and peripheral neuropathy, which is usually sensorimotor.

Autoantibody can be detected in serum and cerebrospinal fluid. Antibody titer usually decreases after treatment of the neoplasm. A rising titer is indicative of tumor persistence or recurrence.

GABA B receptor

Autoantibody targeting the B1 subunit of the gamma-aminobutyric acid-type B (GABA-B) receptor has been reported in patients with limbic encephalitis characterized by psychiatric symptoms and prominent seizures. Approximately 50% of antibody positive patients have small cell lung carcinoma (SLCL). Men and women are affected equally. The mean age of onset is 60 years.

Patients usually present with seizures, memory loss, mood changes, personality changes, psychosis, delirium or sleep disorders. The likelihood of an autoimmune etiology is increased if a patient has a history of autoimmune disorders, cancer, or cancer risk factors such as smoking.

Patients with GABA-B receptor autoantibodies may have other coexisting antibodies such as N type calcium channel antibody, GAD65 antibody, thyroid antibodies, and GNA/SOX 1 antibody.

Antibody can be detected in both serum and CSF. If antibody is detected in serum, subsequent testing of CSF adds little value. However, patients with negative serum results sometimes have positive CSF results. High titer antibodies are more specific for limbic encephalitis.

GABA-B receptor antibody is detected using immunofluorescence to detect IgG binding to human cells transfected with B1 subunit of the GABA type B receptor. Transfected cells over-express the cognate protein, increasing sensitivity of the test.

GAD65

Glutamic acid decarboxylase (GAD) is an enzyme involved in the synthesis of the neurotransmitter, gamma-aminobutyric acid (GABA). GAD65 antibody is the most frequently detected pancreatic islet antibody occurring in 70 to 80% of new onset type 1 diabetes cases. Detection of GAD65 antibody in nondiabetic individuals predicts later development of type 1 diabetes. The presence of this autoantibody is also helpful in distinguishing between type 1 and type 2 diabetes. GAD65 autoantibody also serves as a marker of predisposition to other autoimmune disease that occur with type 1 diabetes such as Graves' disease, Hashimoto's thyroiditis, hypothyroidism, pernicious anemia, premature ovarian failure, Addison's disease and vitiligo.

GAD65 antibodies are not specific for type 1 diabetes and may be present in patients with a variety of autoimmune neurologic disorders including stiff-man syndrome, neuromyelitis optica, myasthenia gravis, limbic encephalitis, cerebellar encephalitis, and Lambert-Eaton syndrome. Tumors associated with GAD65 antibodies include thymoma, renal cell carcinoma, breast cancer and colon adenocarcinoma. Approximately 3% of the general population has detectable GAD65 antibodies.

LGI1

Autoantibodies to leucine-rich glioma inactivated 1 protein (LGI1) account for the majority of cases of limbic encephalitis. LGI1 binds together two epilepsy-related proteins called ADAM22 and ADAM23. Seizures are common and frequently precede other symptoms. About half of people with this diagnosis exhibit a specific type of seizure called faciobrachial dystonic seizures, which resemble brief jerks of the face arm.Approximately 65% of cases exhibit hyponatremia. About 10% of patients with limbic encephalitis and anti-LGI1 autoantibodies also have a thymoma or lung cancer.

NMO IgG

Neuromyelitis optica (NMO), also known as Devic's disease and optic-spinal multiple sclerosis, is a severe idiopathic inflammatory demyelinating disease that selectively affects optic nerves and the spinal cord. It typically spares the brain, and generally follows a relapsing course. Within 5 years, 50% of patients lose functional vision in at least 1 eye or are unable to walk independently. In North America, the proportion of nonwhite individuals is higher among patients with NMO than among those with classic multiple sclerosis.

Many patients with NMO are misdiagnosed as having multiple sclerosis. Accurate diagnosis is important because prognosis and treatment for the two diseases differ. NMO typically has a worse outcome than multiple sclerosis due to early and frequent relapses. NMO is treated with immunosuppression while multiple sclerosis is treated with immunomodulation. Plasmapheresis is more beneficial for patients with NMO than for those with multiple sclerosis.

Early diagnosis and treatment are important to reduce the morbidity of NMO. Patients with NMO produce an antibody to aquaporin-4, a water channel protein located in astrocytes. Seropositivity for NMO autoantibody IgG (NMO-IgG) allows early diagnosis of NMO (73% positive; 91% specific). NMO-IgG is uniformly negative inpatients with classical multiple sclerosis. A positive value is consistent with NMO or a related disorder and justifies initiation of early immunosuppressive therapy.

 Approximately 40% of adult patients with longitudinally-extensive transverse myelitis are seropositive for NMO-IgG, while approximately 15-20% of patients with multiple episodes of optic neuritis test positive. Seropositive patients are much more likely to relapse or progress within 2 years than seronegative patients. Seronegativity does not exclude the diagnosis of NMO. Patients already treated with immunosuppressive therapy may not have detectable antibody.

NMDA receptor

Anti-NMDA receptor encephalitis typically affects women in their 20s and 30s, and about half of patients have an ovarian teratoma. Only 2% of women have a neoplasm other than ovarian teratoma. These other neoplasms include breast adenocarcinoma, ovarian neuroendocrine tumors, sex cord stromal tumor, pseudopapillary neoplasm of pancreas, neuroblastoma, and Hodgkin lymphoma. a. It can also occur in younger patients and in men, in whom it is less likely to be associated with a neoplasm.Neoplasia has been documented in 5% of men with NMDA receptor antibody; either testicular germ cell tumors or small-cell lung carcinoma.The female to male ratio of patients is about 4:1.

Patients with NMDA-receptor antibody often present with headache, fever, nausea, vomiting, diarrhea, or upper respiratory tract symptoms. Shortly afterwards, they develop psychiatric symptoms including anxiety, insomnia, fear, delusions, mania, and paranoia. Movement disorders include oro-lingual-facial dyskinesias, generalized chorea, oculogyric crisis, dystonia, and rigidity. Autonomic manifestations include hyperthermia, tachycardia, hypersalivation, hypertension, bradycardia, hypotension, urinary incontinence, and erectile dysfunction.

Outcome is usually favorable, but recovery may take a year or longer. Approximately one fourth of patients relapse if they do not receive immunotherapy. Removal of a teratoma may be curative.

This antibody is more commonly detected in CSF than in serum. Serum testing yields false negative results in about 14% of cases.

Purkinje Cell Cytoplasmic Antibody Type 1 (anti-PCA1 or anti-Yo)

Anti-Yo autoantibodies interact with cytoplasmic rather than cell surface membrane proteins of Purkinje cells. Autoantibodies directed against intracellular Purkinje cell proteins are endocytosed, leading 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. Reference range is negative.

Purkinje Cell Cytoplasmic Antibody Type 2 (PCA2)

This autoantibody is usually associated with lung cancer, especially SCLC. If lung cancer is not detected, an extrapulmonary primary SCLC should be considered. The antibody is seldom detected in patients with uncomplicated SCLC. Reference range is negative.

Purkinje Cell Cytoplasmic Antibody Tr (PCA-Tr)

This autoantibody has only been detected in 80% of patients with Hodgkin lymphoma and causes subacute cerebellar ataxia. Anti-Tr antibody titer tends to drop after treatment of Hodgkin's disease.

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. Thus, 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 measured quantitatively by immunoprecipitation assays. Serum is the preferred specimen. However, antibody may be detected in cerebrospinal fluid when serum 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.

VGKC complex IgG

Antibodies to voltage-gated potassium channel (VGKC) were originally associated with autoimmune limbic encephalitis. More recently, they have been found to cause rapid cognitive decline resembling frontotemporal dementia and Creutzfeldt-Jakob disease. These antibodies also associated with paraneoplastic neurological syndromes associated with small cell lung carcinoma, thymoma, breast adenocarcinoma and prostate cancer.

Limbic encephalitis associated with VGKC complex antibody usually lacks cerebellar and brainstem dysfunction, which may help distinguish it from other types of autoantibody-mediated limbic encephalitis. VGKC complex antibodies are associated with a wide variety of neurologic conditions, including chronic idiopathic pain, epilepsy, movement disorders, cranial nerve abnormalities, autonomic dysfunction, and gut dysmotility. These antibodies are rare in healthy people and are not associated with cancer. About half of patients with VGKC complex antibody-mediated limbic encephalitis have normal findings on brain MRI.

VGKC complex autoantibody does not bind to the potassium channel itself, but to other subunits of the channel such asleucine-rich glioma-inactivated 1 protein (LGI1) and contactin-associated protein 2 (CASPR2). LGI1 autoantibody is more commonly associated with limbic encephalitis in addition to a distinctive type of seizure affecting the arm and face (faciobrachial dystonic seizure). CASPR2 autoantibody usually correlates with peripheral nerve manifestations and Morvan syndrome. Hyponatremia is often seen in patients with these antibodies. VGKC antibodies can be distinguished from antibodies to (Lgi1) and contactin-associated protein-2 (Caspr-2) by Western blot.

VGKC IgG is more commonly detected in serum than in CSF.

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