Autoantibodies: disease markers …

Neuroimmunology

Updated 09.10.2025
Released 12.19.2015
Expires For CME 09.10.2028

Autoantibodies: disease markers

Authors: Monica Budianu MD, Kareena Kumar, Phildrich Teh MD, Erin Tullis MD

See Contributor Disclosures

Editor: Anthony T Reder MD

Cite this article

Autoantibodies: disease markers

In This Article

Quick Link

Introduction

Overview

Advances over the last couple of decades in the field of autoimmune neurology, specifically relating to autoantibody discovery, are tremendous. The number and incidence of known autoreactive antibodies have increased over time due to the ongoing discovery of these biomarkers (197). The discovery of certain antibodies like AQP4 Ab and MOG Ab has led to the recognition of new neurologic disease entities. In the case of paraneoplastic neurologic syndromes, autoreactive antibodies may be directly pathogenic and cause neurologic clinical symptoms; in other cases, they represent an epiphenomenon with no clearly identified role in the pathogenesis or a post-infectious process (as with anti-NMDAR encephalitis after herpes simplex virus encephalitis) (13). Detection of autoreactive antibodies helps to establish a diagnosis and also helps detect occult malignancies. Testing autoreactive antibodies can be quite expensive. Therefore, to avoid futile tests, it is important to know their sensitivity and specificity for the diagnosis or the possibly associated cancer. The reliability of the techniques used for antibody detection is also reviewed in this article.

Key points

	• Autoreactive antibodies against central or peripheral nervous system antigens may be useful for diagnosing several neurologic diseases.
	• In paraneoplastic neurologic disorders, their detection can also help identify an associated cancer at a stage before it is clinically overt, potentially leading to early successful therapy.
	• Testing autoreactive antibodies might often be quite expensive.
	• The sensitivity and specificity and the reliability of the commercially used techniques are important to evaluate to avoid useless tests.

Historical note and terminology

Autoreactive antibodies occur in various neurologic disorders involving the central and peripheral nervous system. These antibodies may be directly responsible for the disease process or represent an epiphenomenon without having a specific pathogenic role. The role of autoreactive autoantibodies is well-established in the pathogenesis of neuromuscular junction disorders such as myasthenia gravis and Lambert-Eaton myasthenic syndrome. Myasthenia gravis was first proposed as an autoimmune disorder by Simpson in 1960 (173). The association of anti-acetylcholine receptor (anti-AChR) antibodies with myasthenia gravis was first reported in the 1970s (06). The presence of antibodies to a defined antigen specific to the disease process, clinical response to immunomodulatory therapy, and transmission of the disease to animals by passive transfer of immunoglobulins provide evidence for antibody-mediated autoimmune mechanisms in this and in other neurologic disorders of the peripheral nervous system.

In the CNS, however, the pathogenic role of autoantibodies is not as well-defined and relies on their temporal relationship with the disease onset and the response to immunological therapies. The CNS disorders associated with autoreactive antibodies can be divided into those with known autoantigens, such as neuromyelitis optica with circulating antibodies to aquaporin-4 (108). Similar to myasthenia gravis, there are some patients in whom the association is tight and others in whom no antibodies are identified despite a typical clinical picture. There are other disorders in which no specific antigen has yet been identified, such as multiple sclerosis (102). Various autoreactive antibodies, including anticardiolipin, antinuclear, and antithyroid antibodies, which are usually associated with specific vasculitic or systemic syndromes, may occur in multiple sclerosis patients. Autoimmune diseases do not seem to occur with higher frequency in patients with multiple sclerosis and their family members (152).

Autoantibodies against central or peripheral nervous system antigens can, eventually, occur in paraneoplastic neurologic disorders. Although a pathogenic role for autoantibodies has been established only for some paraneoplastic neurologic disorders, the presence of autoantibodies can be extremely important in the diagnostic workup. In fact, the clinical symptoms and antibodies associated with paraneoplastic neurologic disorders precede the detection of a tumor by several months in almost 80% of patients, and positron emission tomography might detect a tumor or tumor recurrence in 90% of antibody-positive paraneoplastic neurologic disorder patients (112; 79). These antibodies are sometimes highly specific for a particular cancer and can help identify it at a stage before it is clinically overt, potentially leading to early successful therapy.

This article evaluates the usefulness of autoantibody testing for diagnosing neurologic diseases, reviewing the sensitivity and specificity of autoantibody testing. When sensitivity and specificity are indicated or can be calculated from the data of relevant papers, the number of patients and healthy controls or other neurologic disease patients will also be indicated to show reliability.

Autoantibodies are detected with different immunoassays. Both serum and CSF testing are recommended in the evaluation of patients with autoimmune CNS disorders. Some antibodies detected in the CSF are of greater clinical importance than when they are found in serum only (eg, N-methyl-D-aspartate receptor [NMDA-R] IgG); in contrast, some antibodies, such as aquaporin-4 IgG and LGI1-IgG serum specimens, may be preferred (their sensitivity is higher in the serum than in the CSF). MOG-IgG is more readily detected in the serum than CSF, but recent evidence demonstrated that a subgroup of MOGAD patients may harbor CSF exclusive antibodies (117). The presence of CSF antibodies in MOGAD and LGI1 encephalitis appears to be associated with more severe disease (24; 122).

Screening using two methods is recommended for most antibodies, particularly paraneoplastic antibodies.

Tissue-based assays. Tissue-based immunofluorescence assays are performed using cryosections of adult murine tissue immobilized on glass slides. Patients’ antibodies are identified in the brain tissue of rodents or primates. The antigen-antibody complex is stained with anti-human-IgG chemically linked to a fluorophore (indirect immunofluorescence) or conjugated to an enzyme, such as peroxidase, that can catalyze a color-producing reaction (indirect immunohistochemistry).

Immunoblot. Antibodies are identified as specific bands. Patients’ antibodies are separated through gel electrophoresis by size, charge, or other differences in individual proteins. Separated antibodies are then transferred onto a nitrocellulose membrane and are identified by specific antibodies. The antigen-antibody complex is stained with peroxidase-conjugated anti-human-IgG.

Cell-based assays. These are commercially available fixed cell-based assays, which can be transported and stored easily. Patients’ antibodies are identified on suitable cell lines (eg, HEK293 cells) transfected with an eukaryotic expression vector (plasmid) encoding the antigen.

The patient sample is incubated with cells (either live or fixed) that express the target protein. An anti-human secondary antibody conjugated with a fluorophore is introduced. Seropositivity is determined by visual observation on a fluorescence microscope.

For neural antibodies that target extracellular antigens, cell-based assay provides higher sensitivity with retained specificity when compared to tissue-based immunofluorescence assays or other protein-specific assays.

For some autoantibodies, live cell-based assays (where the patient antibody is incubated with live cells at 4 degrees) appear to be more sensitive than fixed cell-based assays. Live cell-based assays are more labor intensive, have a shorter time window for use, and are usually performed only in specialized research centers.

Live cell-based flow cytometry has proven especially useful for the detection of aquaporin 4 and MOG IgG. HEK-293 cells are transfected with plasmid encoding both GFP and the protein of interest. This method has a greater clinical sensitivity compared to other assays for aquaporin 4 IgG and a specificity of 100%. This technique has greater sensitivity when compared to fixed cell-based assay for the detection of MOG IgG but has comparable sensitivity to live direct-visualization cell-based assay (200).

Enzyme-linked immunosorbent assay (ELISA). A recombinant antigen is immobilized on a solid support, and the detection antibody is added, forming a complex with the antigen. The antigen-antibody complex is then stained with peroxidase-conjugated anti-human-IgG. This technique allows the determination of antibody titer.

When an autoantibody test is useful for a disease diagnosis, the most relevant technique for each test will also be indicated. This will provide clinicians with important information on autoantibodies that are really useful in the correct diagnosis.

Radioimmunoprecipitation assays (RIPA). Radioimmunoprecipitation assays are a sensitive quantitative method for rapidly assessing for the presence and positive values of antigen-specific antibodies, which is particularly useful for detection of antibodies even at low concentrations (eg, detection of GAD-65 IgG in the CSF, where very low concentrations carry clinical significance) (61).

Diseases affecting the CNS

CNS autoimmune disorders without defined antibodies

Multiple sclerosis.

Type of antibodies seen. An increased frequency of non-organ-specific autoreactive antibodies, including antinuclear, antithyroid, and antiphospholipid antibodies, occurs in patients with multiple sclerosis (Table 1) (186; 46; 56; 123). Increased titers of antithyroglobulin and antiperoxidase antibodies are detected in a significant percentage of multiple sclerosis patients, too (46; 123). The presence of these antibodies is probably an epiphenomenon of a disseminated immunological dysfunction without any usefulness for multiple sclerosis diagnosis.

Increased titers of myelin-specific antibodies in serum and spinal fluid are frequently observed in patients with multiple sclerosis (Table 1). Many patients with multiple sclerosis show a persistent autoantibody response to myelin basic protein or myelin oligodendrocyte glycoprotein (35; 206; 169). An antibody response to myelin basic protein or myelin oligodendrocyte glycoprotein also occurs in patients with other neurologic inflammatory or even noninflammatory disorders, and in healthy family members, at a frequency not significantly different than in multiple sclerosis (154). Testing antimyelin basic protein or antimyelin oligodendrocyte glycoprotein is not useful for diagnosing multiple sclerosis, a diagnosis that is still based on clinical and MRI findings (149).

Table 1. Antibodies Associated with Multiple Sclerosis

Antibody	Serum	CSF	Reference
Myelin basic protein	+	+	(35; 169)
Myelin oligodendrocyte glycoprotein	-	+	(206)
Myelin-associated glycoprotein	+/-	+	(14)
Antinuclear antibody	+	+	(186)
Antiphospholipid antibody	+	+	(57)
Antithyroid antibody	+	-	(46; 123; 33)

Pathogenic significance. Multiple sclerosis is an immune-mediated disorder traditionally thought to be caused by T-cell-mediated inflammation, leading to demyelination and damage to oligodendrocytes. A general immune dysregulation seems to exist in multiple sclerosis patients, and, therefore, these patients may have exaggerated responses to different antigens and autoantigens (134). This dysregulation probably accounts for non-organ-specific or organ-specific, but not myelin-specific, antibodies. However, humoral mechanisms and, more specifically, antibody-mediated demyelination may contribute to disease progression in at least a subgroup of patients with multiple sclerosis (47; 58; 08; 32). The widespread success of B-cell depleting therapies in humans has focused attention on the central role of B cells in the etiology and progression of multiple sclerosis.

Antibodies to interferons in interferon beta–treated multiple sclerosis. Interferon-beta treatment can elicit anti–interferon beta antibodies, more so in patients with multiple sclerosis than in other indications (104). Anti-interferon antibodies can be measured by binding assays such as ELISA and, rarely, by radioimmunoprecipitation or column chromatography assays. The antibodies measured by these assays are termed “binding antibodies.” They can also be measured by evaluating how much of the in vitro interferon bioactivity is blocked by the serum to be tested (presumably due to anti-interferon antibodies). These are termed “neutralizing antibodies.” Methods to measure neutralizing antibodies include the virus-induced cytopathic effect assay, which remains the gold standard, and assays of induction of myxovirus A protein or RNA (49; 150; 71). A new assay uses luciferase (48; 98). This assay is faster, simpler, and less expensive than cytopathic effect assay and myxovirus A protein induction test. Unfortunately, different companies and different laboratories provide results that are difficult to compare because of differences in units and in principles used in measurement.

The Neutralizing Antibodies in Multiple Sclerosis (NABIMS) working group is attempting to clarify these issues. Simplification of techniques, agreement on which antigen to use in assays, and unitage should be the basis for agreement in the field. It has now been agreed that results should be reported as "10-fold reduction units" (TRU) as per Kawade and Grossberg (70).

When high levels of neutralizing antibodies are present, bioavailability of the drug is compromised, ie, the drug ceases to act by binding to its receptor. Bioavailability of interferons can be measured directly using the in vivo induction of myxovirus A protein mRNA. In this test, myxovirus A protein mRNA is measured in lymphocytes isolated from peripheral blood before and 12 hours after a test injection of interferon (137). The term “high antibody levels” should be reserved for the levels in which bioavailability is abrogated. As a rule of thumb, this level of inhibition is attained between 100 and 400 TRUs. The loss of clinical effect of the injected interferon due to neutralizing antibodies may vary from product to product; lower neutralizing antibody titers block interferon beta 1a products more easily than interferon beta 1b products (20). Practical application of these tests will be slow to appear and will vary between countries, as different conclusions on their use and indications have been reached by an expert committee of the European Neurological Association and the TTA committee of the American Association of Neurology (63; 75). The NABIMS committee has been attempting to bridge this gap, but with limited success (148).

Neuropsychiatric systemic lupus erythematosus (NPSLE). Neuropsychiatric disturbances occur in more than 50% of patients with systemic lupus erythematosus (189), with a higher incidence in the central nervous system at 90% compared to the peripheral nervous system at 10% (88). Systemic lupus erythematosus is a B-cell mediated disorder accompanied by a reduction of T-cell function. A variety of autoantibodies directed against neural antigens appear in patients with systemic lupus erythematosus, leading to neuroinflammation. These include antineuronal, antineurofilament, antiribosomal P, and antiganglioside antibodies (69; 89). Serum antiribosomal P antibodies and anti-N-methyl-D-aspartate receptor (anti-NMDAR)-NR2 subunit antibodies are more frequently seen in patients with neuropsychiatric systemic lupus erythematosus than in patients with regular systemic lupus erythematosus and increase during the active phase of the disease (203; 89). Antiribosomal P antibodies were detected in 18 out of 20 patients with psychosis secondary to systemic lupus erythematosus. They are not specific for this disease, however, and not useful for its diagnosis.

In a murine model of NPSLE based on antibodies that cross-react with dsDNA and NMDAR, a subset of anti-DNA antibodies binds a pentapeptide consensus sequence present in the NR2A and NR2B subunits of NMDAR. These antibodies cross-react with both murine and human NMDAR, and they mediate neuronal death in vitro when added to cultures of fetal brain cells and in vivo when injected into a mouse brain. NMDAR antagonists protected neurons from antibody-mediated injury. These murine antibodies impair cognition when they access the CNS through a breach in the blood-brain barrier triggered by lipopolysaccharide.

Kowal and colleagues showed that serum with reactivity to DNA and NMDAR extracted from lupus patients elicited cognitive impairment in mice receiving the serum intravenously and given lipopolysaccharide to compromise blood-brain barrier integrity (95). Brain histopathology showed hippocampal neuron damage, and behavioral testing revealed hippocampus-dependent memory impairment. IgG was eluted from a NPSLE lupus patient’s brain; the IgG bound DNA and NMDAR and caused neuronal apoptosis when injected into mouse brains. Four more brains of patients with NPSLE displayed endogenous IgG co-localizing with anti-NMDAR antibodies. Endogenous IgG antibodies were not detected in the brains of two patients with Parkinson disease. Thus, lupus patients have circulating anti-NMDAR antibodies capable of causing neuronal damage and memory deficit if they breach the blood-brain barrier, and the antibodies exist within patients’ brains. Several clinical questions remain, such as which aspects of NPSLE may be mediated by anti-NMDAR antibodies, how often, and in which patients. Importantly, the target epitope on the NMDA receptor in this data is different from the epitope measured with autoimmune encephalitis panels.

In a cohort of 107 patients with systemic lupus erythematosus, Gono and colleagues found that NPSLE was the most significant independent variable associated with anti-NR2A antibody positivity, estimated by multiple linear regression analysis (62).

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an autoantigen associated with neuropsychiatric disorders. Serum anti-GAPDH IgG was detected in 51% of patients with schizophrenia and 50% with major depression. Patients with systemic lupus erythematosus and comorbid psychiatric manifestations had higher serum levels of anti-GAPDH antibodies than patients without psychiatric manifestations (p=0.004). Levels of serum anti-GAPDH antibodies correlate with cognitive disfunction in patients with systemic lupus erythematosus. These antibodies can induce neurite retraction and impair neuronal plasticity by blocking and binding synaptic molecules. In vivo administration of GAPDH autoantibodies in the right cerebral ventricle of C57BL/6J mice resulted in a detrimental cognitive and emotional profile (41).

Anti-triosephosphate isomerase (anti-TPI) antibodies in NPSLE show greater occurrence of aseptic meningitis and higher levels of serum IgG. TPI is a glycolytic enzyme in red blood cells and neuronal cells. The clinical features of anti-TPI-positive and anti-TPI-negative NPSLE were compared, and 10 of 31 NPSLE patients had anti-TPI positivity (32.3%). The clinical features of anti-TPI-positive NPSLE were comparable with those of anti-TPI-negative NPSLE, except for a higher frequency of aseptic meningitis (p = 0.027) and a lower frequency of acute confusional state (P = 0.026) (166).

In a randomized controlled trial, CSF anti-UCH-L1 (anti-ubiquitin carboxyl hydroxylase L1) antibody levels were elevated in patients with NPSLE, with a sensitivity of 53% and specificity of 91% for NPSLE; these autoantibodies were associated with organ involvement (110). Among neurologic disease–related proteins, only UCH-L1 levels were elevated in the CSF samples of severe NPSLE patients compared to those with mild NPSLE (p=0.020) and systemic lupus erythematosus controls (p=0.037). Autoantibodies against amino acids 58 to 69 of UCH-L1 (UCH58-69) had a high degree of specificity and diagnostic relevance in distinguishing patients with NPSLE from those with systemic lupus erythematosus without neuropsychiatric symptoms. Serum anti-UCH58-69 levels are higher in NPSLE compared to systemic lupus erythematosus patients without neuropsychiatric symptoms and correlate with disease severity (73; 113).

Antiendothelial cell antibodies (AECA) are associated with psychosis and mood disturbances (31). AECA are present in 11 of 17 (64.7%) systemic lupus erythematosus patients with psychosis and mood disorders and in 10 of 34 (29.4%) patients without psychiatric manifestations other than anxiety (p=0.03). The high prevalence of serum AECA in systemic lupus erythematosus patients with psychosis and mood disorders suggests a biological origin.

Antiphospholipid antibodies are strongly associated with neuropsychiatric lupus, manifesting as cerebrovascular disease, headache, and seizures. In a retrospective study of 323 patients with systemic lupus erythematosus, 185 had neuropsychiatric manifestations, and the presence of antiphospholipid antibodies was associated (p< 0.001) (165). Multivariate analysis showed that antiphospholipid antibodies were independently associated with cerebrovascular disease (OR: 6.17, 95% CI: 2.94–12.9, p = 0.001), headache (OR: 2.04, 95% CI: 1.17–3.55, p = 0.01), and seizures (OR: 2.89, 95% CI: 1.18–7.10, p = 0.02). Lupus anticoagulant was independently associated with white matter hyperintensity lesions on MRI (OR: 3.0, 95% CI: 1.12–8.05, p = 0.027).

Rasmussen encephalitis. Rasmussen encephalitis is a rare but severe disorder leading to unilateral hemispheric atrophy associated with hemiparesis, cognitive decline, and intractable childhood epilepsy. It is believed to be an autoimmune disease mediated by antibodies and cytotoxic T cells. Antibodies against the subunit 3 of the ionotropic glutamate receptor are found in 6% to 10% of patients. Antibodies against the presynaptic protein Munc18-1, the NMDAR-e2 subunit, and the alpha7 nicotinic AChR, the neuronal AChR alpha-7 subunit, and NMDA receptors 2A to 2D, specifically glutamate receptor epsilon2, have been reported (201; 07). None of the autoantibodies, however, appear in more than a small number of patients with Rasmussen encephalitis, and responses to plasma exchange are unpredictable. Therefore, the role of CNS autoantibodies in the pathogenesis of Rasmussen encephalitis is still unclear. Cytotoxic T lymphocytes may also play a major part in the pathogenesis, and the inflammatory or destructive pathology often coexists with malformative or dysplastic features in cortical architecture, raising questions about the possible relationships between the two pathologies (178; 190).

Antibody-mediated nervous system demyelinating disorders

Neuromyelitis optica spectrum disorders (Devic disease). Neuromyelitis optica, originally described as Devic disease and seen then as an autonomous entity, was initially considered a “form of multiple sclerosis.” The discovery of the presence of a specific antibody against aquaporin-4 in a proportion of patients with optic neuritis and transverse myelitis has permitted refocusing the pathogenesis towards an antibody-mediated process, probably directed against aquaporin-4 on astrocytes. Antibodies to aquaporin-4 can be measured with over 40 different immunoassays, including cell-based assay (cells transfected with the antigen of interest), tissue-based assay (immunohistochemical), and protein-based (ELISA, western blotting) techniques (83). According to a meta-analysis of 30 studies, the approximated sensitivity for cell-based assay was 0.76 (95% CI 0.67-0.82), for tissue-based assay was 0.59 (95% CI 0.50-0.67), and for ELISA was 0.65 (95% CI 0.53-0.75) (160). The mean specificity of cell-based assay was 0.99 (95% CI 0.97-0.99), of tissue-based assay was 0.98 (95% CI 0.97-0.99), and of ELISA was 0.97 (95% CI 0.96-0.99). Aquaporin-4 detection in serum with immunoassays is a great tool for diagnosing patients with neuromyelitis optica due to the high specificity, allowing the clinician to differentiate this disease from other neurologic conditions that resemble neuromyelitis optica. The immunoassay that shows the best diagnostic performance is cell-based assay, but the other immunoassays are specific enough to be clinically useful for a correct diagnosis in patients with neuromyelitis optica, as well as to clarify the cases in which the rest of the clinical, paraclinical, and imaging studies are not enough to diagnose definite neuromyelitis optica. Neuromyelitis optica and CNS Sjogren disease overlap, with a similar clinical and MRI profile (87). CNS Sjogren predominantly affects young, non-white women. Neuromyelitis optica-IgG is less likely to be positive, and salivary gland inflammation is very frequent.

Anti-aquaporin-4 antibodies are involved in neuromyelitis optica pathogenesis because they damage the astrocytes, and the disease can be transferred to animals with anti-aquaporin-4 antibodies (161).

Myelin oligodendrocyte glycoprotein-related disorder (MOGAD). MOGAD, just like NMOSD, was originally described as multiple sclerosis but became antibody-mediated with identification of the specific antibody. MOGAD has different clinical characteristics, treatment response, and prognosis compared to multiple sclerosis and NMOSD. Common presentations of MOGAD include recurrent optic neuritis, transverse myelitis, acute disseminated encephalomyelitis (ADEM), and, less commonly, cerebral cortical encephalitis, brainstem, and cerebellar demyelinating attacks (15). Optic neuritis is the most common onset feature among adults, whereas ADEM with or without concomitant optic nerve involvement is the typical first manifestation in children.

The disease course may be monophasic or relapsing, with relapses leading to cumulative neurologic disability, especially visual and motor deficits. This disorder affects people of all ages, with an incidence of 1.6 to 3.4 per million per year. In the pediatric population, MOG IgG is often associated with acute disseminated encephalomyelitis presentation preceded by infection; this population is also more likely to have a transient titer elevation suggestive of a monophasic process rather than a recurrent one (202). The prognosis of MOGAD is generally more favorable than that of NMOSD and is often steroid-responsive.

In contrast to neuromyelitis optica where antibodies to aquaporin-4 are pathogenic, the extent to which anti-MOG-specific antibodies contribute to CNS damage in MOGAD is unclear.

The diagnosis of MOGAD requires detection of IgG antibodies that bind exposed conformational epitopes of MOG, commonly measured by cell-based assays, in conjunction with a clinical demyelinating event (optic neuritis, transverse myelitis, ADEM, cerebral monofocal or polyfocal deficits, infratentorial deficits, cerebral cortical encephalitis). Live cell-based assays represent the gold standard test; live cell-based assays (ie, Oxford live cell CBA or flow cytometry Mayo live cell fluorescence-activated cell sorting assay) had superior positive predictive values compared to fixed assays (ie, Euroimmun fixed CBA), 100%, 95.5%, and 82.1%, respectively, indicating that positive results in these assays are more reliable indicators of MOGAD (200). Serum is the preferred specimen type for MOG-IgG testing.

Glial fibrillary acidic protein astrocytopathy. Glial fibrillary acidic protein autoimmunity typically presents with acute or subacute meningoencephalomyelitis with prodromal flu-like symptoms, for which tumors and T-cell dysfunction are frequent triggers. Most patients follow a monophasic course with good outcomes and are generally steroid-responsive (68).

Stiff-person syndrome.

Clinical manifestations. Stiff-person syndrome is a rare disease associated with muscle stiffness, rigidity, and painful spasms involving axial and limb muscles (37). Symptoms may be exacerbated by heightened emotion or startle (118). Its “plus” variant is progressive encephalomyelitis with rigidity and myoclonus, where rigidity is associated with severe myoclonus (42). There is a wide range of clinical presentations, from limited form, such as stiff limb syndrome, to additional neurologic features, such as ataxia, epilepsy, and progressive encephalomyelitis with rigidity and myoclonus (PERM), leading to the term “stiff person syndrome disorder” (127). Stiff-person syndrome can occur in association with autoimmune disorders such as insulin-dependent diabetes mellitus (30% of the patients), hyperthyroidism, pernicious anemia, and vitiligo. In some patients, stiff-person syndrome develops as a paraneoplastic neurologic disorder associated with breast or small-cell lung cancer (78).

Type of antibodies. Autoantibodies against glutamic acid decarboxylase (GAD) are detected in up to 85% of stiff-person syndrome patients, and a proportion of such antibodies are synthesized intrathecally; autoantibodies against GABA receptor-associated protein (GABARAP) occur in 65% of patients with stiff-person syndrome and autoantibodies against amphiphysin in 5%. Autoantibodies against glycine receptor (GlyR-IgG) were detected in the serum or CSF fluid of 34% of patients with stiff person spectrum disorder (28). Autoantibodies against gephyrin have been described in a single patient (36). Autoantibodies against amphiphysin or gephyrin occur in association with the paraneoplastic variant and can occasionally also be seen in patients with small cell lung cancer with or without associated different paraneoplastic syndrome (164). GAD, an enzyme involved in the synthesis of the inhibitory neurotransmitter GABA, exists as two isoforms, GAD65 and GAD67, according to their molecular weights. In stiff-person syndrome, levels of anti-GAD in serum are usually highly raised and reactive with GAD65 and almost equally so with GAD67. They can be detected by immunoblotting using purified GAD from rat brain. In type 1 diabetes, on the other hand, anti-GAD are usually at low to moderate levels and mostly specific for GAD65 and react predominantly with highly conformational epitopes; therefore, they are rarely detected by immunoblotting (05). In non-paraneoplastic stiff-person syndrome/progressive encephalomyelitis with rigidity and myoclonus (PERM), the prevalence of anti-GAD65 antibodies is 82%; that of anti-GAD67 antibodies is 55%. The sensitivity for anti-GAD65 in stiff-person syndrome/progressive encephalomyelitis with rigidity and myoclonus diagnosis is 82%; its specificity is 99% (22 stiff-person syndrome/progressive encephalomyelitis with rigidity and myoclonus patients; 100 healthy controls) (119).

Anti-GABARAP antibody titers are significantly elevated in up to 70% of stiff-person syndrome patients, with more than twice the mean band intensity of the controls at immunoblot. The sensitivity is 62%; the specificity is 90% (27 stiff-person syndrome patients; 25 other neurologic disease patients) (151). Anti-GAD65 antibodies have also been reported in some 17 patients with subacute or chronic cerebellar ataxia, in almost all without an associated tumor (162).

Stiff-person syndrome is more seldomly associated with anti-amphiphysin antibodies—about 10% of anti-GAD-associated stiff-person syndrome (124). It almost always occurs in females without type 1 diabetes and with cancer (usually breast cancer, more rarely small cell lung cancer). Anti-amphiphysin antibodies are frequently coexpressed with other paraneoplastic antibodies (or, more rarely, anti-GAD65 antibodies) and have been associated with paraneoplastic neurologic disorders, especially sensory neuronopathy, encephalopathy, and myelopathy. They are, therefore, not useful for stiff-person syndrome diagnosis, but their detection mandates a search for cancer. Their sensitivity for the association with cancer is 80% (63 cancer patients) (144). Their specificity is also extremely high, almost 100%, as their association with a non-paraneoplastic neurologic disease has only been reported in a single paper describing three cases of childhood refractory epilepsy so far (111).

Pathogenic significance. An autoimmune pathogenesis of stiff-person syndrome is supported by the presence of autoantibodies, the association with other autoimmune diseases, and the clinical response to immunotherapy. All autoantigens known to date are synaptic proteins involved in inhibitory synaptic transmission (78). Glutamic acid decarboxylase is the rate-limiting enzyme for vesicular GABA synthesis and is also involved in vesicular GABA transport. GABARAP and gephyrin are postsynaptic proteins involved in assembling GABA A receptors and/or glycine receptors, respectively. Amphiphysin is an important binding partner for dynamin and a key protein for vesicular endocytosis in presynaptic nerve endings. The injection of stiff-person syndrome patients' IgG fraction in rats, including anti-amphiphysin antibodies, resulted in a dose-dependent stiffness, with spasms resembling human stiff-person syndrome (175).

Diseases affecting muscles and the peripheral nervous system

Myasthenia gravis

Clinical manifestations. Myasthenia gravis is characterized by fluctuating muscle weakness and weakness on exercise initially involving ocular musculature and generally followed by limb and respiratory muscle involvement. About 10% of Caucasians with myasthenia gravis (versus 30% of Asians) have a tumor of the thymus gland. The rest have follicular hyperplasia (mostly in young people) or a normal atrophic thymus (elderly).

Type of antibodies. Myasthenia gravis is associated with antibodies that react with the nicotinic muscle AChR. Anti-AChR antibodies are found in 85% of patients with generalized myasthenia gravis and in up to 65% of patients with ocular myasthenia gravis (133). Practically all myasthenia gravis patients with thymoma have anti-AChR antibodies. The sensitivity of the radioimmunoassay test is very high in generalized myasthenia gravis (above 85%), and it is lower in ocular myasthenia gravis (71% in 223 patients) (140). In myasthenia gravis and thymoma, it is practically 100%. Specificity of the test approaches 100% in all types of myasthenia gravis, regardless of the topography of the deficit, so the finding of a positive test will be sufficient to support the diagnosis and will have so many clinical consequences that it is imperative to try and use the best technique available. With the ELISA technique, sensitivity is 73%, and specificity is 95% (90 myasthenia gravis patients; 40 healthy controls) (133). In addition, in ELISA, cut-off levels are more difficult to determine because of the difficulty of washing wells, the smaller volumes involved, and reduced reliability. Radioimmunoassay has become the reference for measuring antibodies to the AChR.

Some patients with myasthenia gravis have antibodies that bind to the skeletal and heart muscle, which are known as striational antibodies (157). These antibodies are directed against the muscle proteins titin and ryanodine receptor. They are found in about 50% of patients with myasthenia gravis and up to 97% of myasthenia gravis patients with thymoma. Anti-striational antibodies and CT scan of the anterior mediastinum show a similar sensitivity for thymoma myasthenia gravis. In 146 consecutive myasthenia gravis patients, chest CT scan had a 73% sensitivity and a 90% specificity, anti-titin antibodies a 95% sensitivity and a 76% specificity, and anti-ryanodine receptor antibodies a 73% sensitivity and a 90% specificity (156). Anti-titin antibodies occur more frequently in patients with late-onset myasthenia gravis, and the frequency of titin autoantibodies in late-onset myasthenia gravis not associated with thymoma is approximately 55% (176). The presence of titin/ryanodine receptor antibodies in a young patient with myasthenia gravis strongly suggests the presence of a thymoma. The absence of these antibodies strongly excludes thymoma. Unfortunately, only testing for titin antibodies, and not anti-ryanodine receptor antibodies, is commercially available.

Between 10% and 20% of patients with acquired myasthenia gravis are seronegative for anti-AChR antibodies but still have an autoimmune disorder. A certain proportion of these patients have antibodies against muscle-specific tyrosine kinase (MuSK). These antibodies are not found in anti-AChR antibody-positive patients (196). The MuSK antibody titer seems to positively correlate with symptom severity on both an individual and population basis (106). A multinational study of 633 patients with seronegative myasthenia gravis found 79 anti-MuSK-positive patients, with 13% sensitivity (188). Specificity tested in 162 healthy controls was 98%; specificity tested in 128 patients with other neurologic disease was 94%. Radioimmunoassay was the gold standard in anti-MuSK antibody detection, but it yields only an approximate 6% positivity. Cell-based assays are increasingly used in routine diagnosis to detect myasthenia gravis autoantibodies as they seem able to detect antibodies in sera found to be seronegative with the conventional radioimmunoassay. The very high specificities indicated above refer to sera tested with cell-based assay (188).

Using this test, a further 15% of patients with seronegative myasthenia gravis tested positive for anti-low-density lipoprotein receptor-related protein 4 (anti-LPR4) antibodies. In addition, some patients were double-positive (12% anti-AChR/anti-MuSK, 20% anti-MuSK/anti-LPR4). Finally, 180 randomly chosen myasthenia gravis samples remaining seronegative after the anti-MuSK cell-based assay screening were also tested by cell-based assay for autoantibodies against clustered AChR (α, β, γ, δ, and ε AChR subunits and rapsyn) (107). Of these, seven (4%) were found to be positive. Data on specificity are not available.

Pathogenic significance. Anti-AChR antibodies are located at the end plate of the muscle postsynaptic membrane. The antibodies bind to the receptor and affect neuromuscular transmission by three main mechanisms. They can activate the complement cascade causing destruction of the postsynaptic membrane (106). Additionally, they can promote endocytosis and accelerated degradation of AChR by cross-linking to the receptor, resulting in a faster turnover and reduced receptor number. They also block ACh binding to AChR sites by steric hindrance, and, if they are IgM or of the 1, 2, or 3 IgG isotype, they can attract complement and macrophages, resulting in the destruction of the postjunctional folds. Excellent response to plasma exchange and IVIg in patients with myasthenia gravis confirms the antibody-mediated pathogenesis of myasthenia gravis. The observation that the disease can be transferred passively in mice by injection of IgG obtained from sera of patients with myasthenia gravis further supports autoimmune pathogenesis (187). MuSK is a receptor tyrosine kinase located on the muscle membrane that, once stimulated by agrin, a protein synthesized by motor neurons, promotes the clustering of postsynaptic proteins, including AChR, at the neuromuscular junction during synapse formation. LRP4 is a transmembrane protein and receptor for agrin and for MuSK. Anti-MuSK or anti-LPR4 antibodies reduce agrin-induced clustering of AChR in vitro, but it is not yet clear how they affect the neuromuscular junction in vivo (76).

Lambert-Eaton myasthenic syndrome

Clinical manifestations. Lambert-Eaton myasthenic syndrome is characterized by proximal muscle weakness, distal paresthesias, areflexia, autonomic dysfunction, constipation, and dry mouth. Lambert-Eaton myasthenic syndrome is paraneoplastic in about 50% of patients, most frequently associated with small cell lung cancer, and non-paraneoplastic in the other 50% (136; 205).

Type of antibodies. Lambert-Eaton myasthenic syndrome is associated with highly specific antibodies against voltage-gated calcium channels (VGCC) located at motor nerve terminals (P/Q-type) that are involved in the release of acetylcholine. These antibodies may be present in up to 90% of patients with Lambert-Eaton myasthenic syndrome (121; 125). Small cell lung cancer may be less common in the 10% of patients with Lambert-Eaton myasthenic syndrome seronegative for anti-VGCC antibodies (125). Sensitivity of anti-VGCC antibodies for Lambert-Eaton myasthenic syndrome diagnosis is 92%; specificity is 98%. Their sensitivity for small cell lung cancer is 21%, with an 83% specificity (6842 neurologic patients tested in Mayo Clinic, 236 with anti-VGCC antibodies, 50 of whom with lung cancer, 173 healthy controls) (212). Their sensitivity for the association with small cell lung cancer in patients with Lambert-Eaton myasthenic syndrome is 70%, with an 88% specificity (110 Lambert-Eaton myasthenic syndrome patients, 93 anti-VGCC positive patients) (125). Anti-VGCC antibodies are also occasionally found in patients with paraneoplastic cerebellar degeneration, usually in association with Lambert-Eaton myasthenic syndrome (116; 198). Anti-VGCC antibodies are detected with radioimmunoassay using 125I-labelled synthetic ω-conotoxin identical to Conus genus snail toxin, which binds to both P- and Q-type VGCC. Diagnostic assays using other toxins or other techniques (ELISA, western blotting) are less sensitive.

Some 10% to 15% of patients with Lambert-Eaton myasthenic syndrome have no detectable anti-P/Q type VGCC antibodies. Passive transfer of seronegative Lambert-Eaton myasthenic syndrome sera to mice seemed to reproduce the typical electrophysiological changes seen in mice passively transferred with seropositive sera. Several studies reported antibodies to synaptotagmin, a synaptic vesicle protein partly exposed at the surface during exocytosis, to muscarinic AChRm1, to ELKS/RAB6-interacting/CAST family member 1 (ERC1) protein, or to SOX proteins (belonging to the Sry-like high mobility group superfamily of developmental transcription factors) (185). There is no satisfactory evidence for pathogenicity of any of these antibodies, although some might be relevant for detecting an underlying tumor. Anti-SOX antibodies have a 67% sensitivity and a 95% specificity to discriminate between Lambert-Eaton myasthenic syndrome with or without small cell lung cancer (43 Lambert-Eaton myasthenic syndrome with small cell lung cancer patients; 43 Lambert-Eaton myasthenic syndrome without small cell lung cancer patients) (184). ELISA and western blotting have the same reliability for anti-SOX protein antibody detection.

Pathogenic significance. The antibody-mediated loss of VGCC leads to a decrease in calcium-mediated quantal release of ACh from motor nerve terminals resulting in abnormal transmission at the neuromuscular junction. Passive transfer of human autoantibodies to mice induces disease (94). The dry mouth and constipation commonly seen in Lambert-Eaton myasthenic syndrome are due to the presence of P/Q channels in some smooth muscles (199).

Acquired neuromyotonia or Isaac disease

Clinical manifestations. Neuromyotonia is characterized by muscle twitching, myokymia, continuous muscle fiber hyperactivity, increased sweating, and other autonomic symptoms (126). Electrophysiologically, there is evidence of spontaneous muscle action potentials that persist after nerve block. These potentials disappear with inhibition of neuromuscular transmission by curare, suggesting their origin in distal nerves.

Type of antibodies. Antibodies in patients with acquired neuromyotonia are directed towards the presynaptic voltage-gated potassium channel (VGKC), especially the dendrotoxin-sensitive fast potassium channels located along the distal motor nerve or at the nerve terminal (12). Radio-iodinated alpha-dendrotoxin, which binds with high affinity to three different VGKC subunits, Kv1.1, 1.2, and 1.6, is used to label VGKC extracted from mammalian brain. Most anti-VGKC antibodies bind to associated VGKC-complex proteins and not directly to Kv subunits (81). Contactin-associated protein 2 (Caspr2) co-localizes with Kv1.1 and 1.2 at juxtaparanodes of the nodes of Ranvier. It is expressed on the surface of hippocampal neurons, and it is essential for VGKC clustering in vivo. Leucine-rich glioma inactivated 1 (LGi1) associates specifically with Kv1.1 subunits in CNS presynaptic terminals, and it is a key hippocampal protein that is secreted in the synaptic space.

Their clinical significance is different: peripheral nerve hyperexcitability and limbic encephalitis without thymoma for LGi1; peripheral nerve hyperexcitability, Morvan syndrome, and frequent thymoma for CASPR2. Most anti-VGKC antibodies of patients with neuromyotonia bind to Caspr2. Anti-Caspr2 antibody–positive patients might, however, have neuromyotonia, Morvan syndrome, or limbic encephalitis. The sensitivity of anti-Caspr2 antibodies for neuromyotonia is 37%, and it is 53% for an associated tumor (mostly thymoma) (81; 82). Anti-VGCK complex antibodies are detected using a cell-based assay radioimmunoassay and anti-Caspr2 and anti-LGi1 antibodies with a tissue-based assay (81; 82).

Pathogenic significance. Neuromyotonia is an antibody-mediated potassium channel disorder (channelopathy). These antibodies decrease the density of voltage-gated potassium channel and suppress the voltage-gated outward potassium current, resulting in hyperexcitability of the peripheral nerve and increased motor action potentials (12; 103). The autoimmune etiology of neuromyotonia is proven by the passive transfer of disease in mice following injection of IgG purified from the plasma of patients with neuromyotonia (171).

Acute inflammatory demyelinating polyradiculoneuropathy or Guillain-Barré syndrome

Clinical manifestations. Acute inflammatory demyelinating polyradiculoneuropathy is a postinfectious autoimmune disease characterized by acute monophasic illness with ascending muscle weakness, paresthesia, areflexia, and oftentimes autonomic dysfunction. Electrophysiological studies show slowing of motor nerve conduction. Its variant, Miller-Fisher syndrome, typically presents with lower extremity areflexia, ataxia, and ophthalmoplegia. Acute motor axonal neuropathy and acute motor sensory axonal neuropathy are acute inflammatory demyelinating polyradiculoneuropathy variants that occur more commonly in China and in Japan and have a high association with preceding diarrheal illness and Campylobacter jejuni infection. Electrophysiological studies show motor or motor-sensory axonal neuropathy. Pure acute sensory ataxic neuropathy is another acute inflammatory demyelinating polyradiculoneuropathy variant defined by the presence of sensory ataxia, absence of ophthalmoplegia, and no or minimal muscle weakness.

Type of antibodies. Anti-GM1, -GD1a, -GM1b, and -GalNAc-GD1a IgG antibodies can be found in acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, and acute motor sensory axonal neuropathy (208; 209; 132; 52; 96; 131). They have a high specificity (97% to 100%) but a very low sensitivity, ranging from 15% to 56% according to the different techniques: ELISA 15% (2/13 patients) to 34% (26/78 patients) and immunoblotting 56% (28/50 patients) (04; 55; 18). Reactivity against gangliosides sharing disialosyl epitopes has been reported in pure acute sensory ataxic neuropathy, but, again, the sensitivity is low (58%, 7/12 patients) (155). Immunoblotting has a higher sensitivity because it simultaneously detects multiple anti-ganglioside antibodies. In addition, acute inflammatory demyelinating polyradiculoneuropathy patient sera often react with ganglioside complexes consisting of two different gangliosides (namely, GM1 and GalNAc-GD1a), but not with each constituent ganglioside. Some antibodies can recognize epitopes comprising more than one molecule, which exist in the complex environment of the cell membrane and is not easily reproduced using traditional antibody detection assays (64). Anti-GM1 antibodies may be useful for prognosis, as high levels of anti-GM1 IgG titers are associated with poor outcomes (139). Screening for one or more heteromeric complexes (of gangliosides GM1, GA1, GD1a, GD1b, GQ1b, LM1, and the glycosphingolipid SPGP) might slightly increase the sensitivity but brings about a high specificity for the clinical variants (up to 98% for acute motor axonal neuropathy tested with GM1 or GD1b complexes) (266 acute inflammatory demyelinating polyradiculoneuropathy patients, 579 controls) (74). Antiganglioside antibody testing is not useful for the diagnosis of acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, acute motor sensory axonal neuropathy, or acute sensory ataxic neuropathy, which is better based on clinical and EMG findings. Nonetheless, testing for antiganglioside antibody complexes might be useful for identifying clinical variants and managing prognosis and treatment.

Antibodies to GQ1b ganglioside are detected with ELISA in up to 90% of patients with Miller-Fisher syndrome, with a 96% sensitivity (24 Miller-Fisher syndrome patients) and a 100% specificity (29). They are a useful biological marker of the disease (204), and a negative test should prompt consideration of an alternate diagnosis.

Pathogenic significance. Lipo-oligosaccharides extracted from Campylobacter jejuni (CF90-26) isolated from an acute motor axonal neuropathy patient with anti-GM1 IgG antibody were identical to those of GM1 ganglioside (210). An acute motor axonal neuropathy model (ﬂaccid limb weakness of acute onset with a monophasic course and with high anti-GM1 IgG antibody titers) was established by sensitization of Japanese white rabbits with a bovine brain ganglioside mixture that included GM1 (211). Pathologic ﬁndings corresponded well with those of human acute motor axonal neuropathy. These observations led to the concept that molecular mimicry could play a role in the pathogenesis of the disease.

The anti-GQ1b antibody in Miller-Fisher syndrome recognizes epitopes expressed in the paranodal region of oculomotor and cerebellar molecular layer neurons and dorsal root ganglion cells. The human oculomotor nerve contains more GQ1b, which may explain the association of ophthalmoplegia and anti-GQ1b antibodies in Miller-Fisher syndrome (29). These antibodies block neuromuscular transmission via pre- and postsynaptic mechanisms and might play an important pathophysiological role in Miller-Fisher syndrome (147; 22).

Chronic inflammatory demyelinating polyradiculoneuropathies

Clinical manifestations. Chronic inflammatory demyelinating polyradiculoneuropathy starts with a slowly progressive progression of symptoms (over 8 weeks or more), symmetric proximal and distal weakness with sensory loss, and hyporeflexia. It is associated with elevated CSF protein and EMG evidence of demyelinating neuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy associated with paraproteinemia may differ from chronic inflammatory demyelinating polyradiculoneuropathy not associated with paraproteinemia. The more frequent neuropathy is that associated with IgM monoclonal gammopathy of unknown significance (MGUS), in which antibodies directed against myelin-associated glycoprotein are found in more than 50% of these patients (139). The prevalence of this neuropathy is around 8% in patients with MGUS, which has, in turn, a high prevalence (1% below 60 years of age; 3% above) (129). It is a demyelinating sensory neuropathy with more pronounced and predominantly distal conduction velocity slowing and lower frequency of conduction block compared with chronic inflammatory demyelinating polyradiculoneuropathy, and it has been categorized as distal acquired demyelinating symmetric neuropathy (91). It usually affects elderly men, presents with ataxia, distal sensorimotor involvement, and tremor, and has a poor response to immunotherapy (114; 30). The neuropathy associated with either IgG or IgA MGUS and no myelin-associated glycoprotein antibody is usually similar to chronic inflammatory demyelinating polyradiculoneuropathy without paraproteinemia.

Multifocal motor neuropathy predominantly affects men and is characterized by asymmetric motor weakness in the upper extremities, fasciculations, and cramps in the absence of significant sensory abnormalities or muscle atrophy (141). EMG studies show the presence of motor conduction block in two or more motor nerves that are not at common sites of entrapment; in contrast, sensory nerve conduction studies are normal (135).

Types of antibodies. Antibodies against peripheral myelin protein 22 (PMP22), myelin protein 0 (P0), or neurofascin155 (NF155) are detected in some patients with chronic inflammatory demyelinating polyradiculoneuropathy. The specificity is good: 90% for anti-PMP22 antibodies (17 chronic inflammatory demyelinating polyradiculoneuropathy patients; 30 other neuropathy patients), 100% for anti-P0 antibodies (21 chronic inflammatory demyelinating polyradiculoneuropathy patients, 15 normal controls), and 100% for anti-NF155 IgG4 antibodies (191 chronic inflammatory demyelinating polyradiculoneuropathy patients; 99 controls with other polyneuropathies or multiple sclerosis or healthy controls) (53; 207; Kadoya et 2016). However, the sensitivity is low: 41% for anti-PMP22 (17 chronic inflammatory demyelinating polyradiculoneuropathy patients), 29% for anti-P0 antibodies (21 chronic inflammatory demyelinating polyradiculoneuropathy patients), and 8% for anti-NF155 IgG4 antibodies (191 chronic inflammatory demyelinating polyradiculoneuropathy patients).

By contrast, most patients with distal acquired demyelinating symmetric neuropathy and IgM MGUS have anti-myelin-associated glycoprotein antibodies (129; 174). In these patients, the M-protein reacts with the epitope sulfate-3-glycuronate of myelin-associated glycoprotein and the two glycosphingolipids, SGPG and SGLPG, of peripheral nerve myelin sheath (129; 204). In MGUS patients with polyneuropathy, the sensitivity of anti-myelin-associated glycoprotein antibodies is 97%, with a specificity of 86% (117 MGUS patients; 102 healthy controls) at a titer of 1000 BTU (26). The specificity is 100% at 10,000 BTU. ELISA is a reliable technique. Using human myelin-associated glycoprotein, its reliability is comparable to that of western blotting (86). IgM anti-sulfatide antibodies are associated with IgM MGUS with anti-myelin-associated glycoprotein (MAG) antibodies. They have been associated with chronic painful axonal sensory polyneuropathy, with higher disability, and with favorable response to immunomodulating treatment (27). Increased titers of IgM anti-sulfatide antibodies have been found in 6.8% of patients with neuropathy or related syndromes, and the vast majority (85%) also had an IgM monoclonal gammopathy and increased titers of IgM antibodies to MAG. In these patients, reactivity to sulfatide was most often restricted to the same light chain of the M-protein and corresponded to that of anti-MAG antibodies, suggesting that this reactivity was related to the same antibodies. The clinical and electrophysiological features of patients with both anti-sulfatide and anti-MAG antibodies did not differ from those of patients with only anti-MAG antibodies. In conclusion, testing for IgM anti-sulfatide only rarely provides information that may have some implications on the diagnostic assessment of patients with neuropathy (570 neuropathy patients) (60).

IgM anti-GM1 ganglioside antibodies are detected in approximately 50% to 85% of patients with multifocal motor neuropathy; GM2 and GD1a antibodies occur less frequently (182; 142; 128). Conventional ELISA is still a reliable technique. With combinatorial glycoarray methods, in which antibodies react to heteromeric complexes of two or more glycolipids, out of the 55 possible single glycolipids and their 1:1 complexes, antibodies to the GM1:galactocerebroside complex were the most significantly associated with multifocal motor neuropathy, with a 100% sensitivity and a 93% specificity (with ELISA, 75% sensitivity and 85% specificity) (33 multifocal motor neuropathy patients; 30 other neurologic disease patients; 27 healthy controls) (54). ELISA testing for IgM reactivity to the gangliosides, either GM1 or GM2 or galactocerebroside, or to a 1:10 mixture of GM1 and galactocerebroside yielded a 48% sensitivity and a 93% specificity for anti-GM1 IgM and a 75% sensitivity and a 85% specificity for anti-GM1/galactocerebroside antibodies (40 multifocal motor neuropathy patients; 142 other neuropathy patients) (130).

Pathogenic significance. The pathogenic role of autoantibodies in chronic inflammatory demyelinating polyradiculoneuropathy is suggested by indirect evidence. Anti-P0 antibodies induce conduction block and demyelination after intraneural injection in animals and have been detected in a subgroup of patients who responded well to plasma exchange (207). Systemic transfusion of chickens with monoclonal human anti-myelin-associated glycoprotein IgM antibody produced peripheral demyelination highly characteristic of the human syndrome (181). The pathogenic role of IgM anti-GM1 antibodies in multifocal motor neuropathy is supported only by indirect evidence, such as the high antibody titer and the correlation between antibody titer and weakness, disability, or axonal loss severity (25). A decrease in anti-MAG antibody levels is associated with treatment response (139).

Myopathies

Clinical manifestations. The inflammatory myopathies are acquired diseases characterized by inflammatory infiltrates in the skeletal muscle. Three major diseases can be identified: polymyositis, dermatomyositis, and inclusion-body myositis. Dermatomyositis is a complement-mediated microangiopathy affecting skin and muscle. Polymyositis and inclusion-body myositis are dominated by muscular manifestations (symmetric proximal muscle weakness associated with muscle cell destruction). In dermatomyositis, cutaneous signs accompany or precede muscular involvement. Together with the muscular manifestations, there may be cutaneous, joint, gastrointestinal, pulmonary, heart, and renal manifestations.

Types of antibodies. Antibodies to nuclear and cytoplasmic antigens are detected in patients with idiopathic inflammatory myopathies. They have been divided into myositis-specific autoantibodies and myositis-associated autoantibodies. The latter also occur in autoimmune diseases without myositis (72). Among myositis-specific autoantibodies, the most common is the anti-Jo-1 (anti-histidyl tRNA synthetase) antibody, found in 30% to 40% of polymyositis patients. Other myositis-specific antibodies are anti-Mi-2, anti-p155/140, anti-small ubiquitin-like modifier activating enzyme, anti-signal recognition particle antibodies, and others (21; 59; 153). They can be found in other connective tissue diseases and, despite the name, they have a low specificity for myositis. The diagnosis of myositis is based on clinical, EMG, and histologic (bioptic) criteria.

Pathogenic significance. The pathogenic significance of myositis-specific autoantibodies is not known.

Diseases affecting the central and peripheral nervous systems

Paraneoplastic neurologic disorders

Paraneoplastic neurologic disorders are rare and associated with cancer but not caused by direct invasion, metastasis, or a direct result of cancer therapy treatment, cerebrovascular disease, coagulopathy, infection, or toxic or metabolic causes (44). Initially thought to affect only 0.01% of patients with cancer, it has subsequently been demonstrated that paraneoplastic disorders occur in one in 300 patients with cancer (197). The clinical diagnosis of a paraneoplastic neurologic disorder or the detection of a paraneoplastic antibody, however, can be extremely important in the diagnostic workup. In fact, the clinical symptoms and the paraneoplastic neurologic disorder–associated antibody finding might precede the detection of a tumor by several months in almost 80% of patients, and positron emission tomography might detect a tumor or tumor recurrence in 90% of patients with antibody-positive paraneoplastic neurologic disorder (112; 79). These antibodies are sometimes highly specific for a particular cancer and can help identify it at a stage before it is clinically overt, potentially leading to early successful therapy. Paraneoplastic neurologic disorders are rapidly progressive in many cases, leaving patients severely debilitated within weeks to months (66). Paraneoplastic neurologic disorders usually do not respond well to immunotherapies. However, treatment of the underlying tumor may lead to improvement of symptoms. Patients with autoantibodies have a relatively favorable prognosis compared to patients with identical tumors that are not associated with paraneoplastic disorders or antibodies.

Clinical manifestations. Several distinct paraneoplastic neurologic disorders have been described depending on the clinical presentation.

Limbic encephalitis. Limbic encephalitis usually presents with cognitive dysfunction, seizures, and psychiatric symptoms (105). The diagnosis is made by brain MRI, showing unilateral or bilateral limbic abnormalities, and by finding paraneoplastic antibodies (Tables 2 and 3).

Anti-NMDAR encephalitis. Anti-NMDAR encephalitis presents with prominent psychiatric symptoms or, less frequently, with short-term memory loss. Seizures, progressive unresponsiveness, central hypoventilation, autonomic instability, and orofacial or limb dyskinesias follow thereafter. Although patients may die of status epilepticus if untreated, most patients recover after immunotherapy and tumor removal (100; 65).

Anti-AMPAR encephalitis. Anti-AMPAR encephalitis presents with prominent psychiatric symptoms, followed by the symptoms of limbic encephalitis (100; 65).

Patients with brainstem encephalitis with antineuronal nuclear antibody type 1 (ANNA-1) antibodies usually present with predominant involvement of the medulla that may result in central hypoventilation (163). In contrast, patients with ANNA-2 antibodies develop opsoclonus and various degrees of extrapyramidal rigidity, ataxia, and postural instability. These patients may also have predominant symptoms of jaw dystonia and laryngospasm, at times associated with severe lethal respiratory distress (146). In patients with antiparaneoplastic neurologic Ma protein type 2 (Ma-2) antibodies, brainstem encephalitis affects the rostral brainstem portion with hypokinetic and oculomotor symptoms.

LGI1 encephalitis. Patients with anti-LGI1 encephalitis can present with encephalopathy and faciobrachial dystonic seizures with sudden, brief, lateralized tonic contractions mainly involving the upper limb and the ipsilateral face (occasionally the leg), and hand dystonia. They can be unilateral, or bilateral asynchronous and can recur several times per day. Anti-LGI1 encephalitis is associated with antibodies that have a low-risk association with thymomas (183).

Opsoclonus-myoclonus-ataxia syndrome. Opsoclonus-myoclonus-ataxia syndrome is one of the most common pediatric paraneoplastic syndromes. These patients usually present with subacute ataxia manifesting as gait imbalance, staggering, falls, or a refusal to walk. Autoantibodies have been implicated (ANNA-1, ANNA-2) and are associated with neuroblastoma in children (09). Meanwhile, breast adenocarcinoma and small cell lung cancer are the more frequently reported oncological accompaniments in adults (92).

Progressive encephalomyelitis with rigidity and myoclonus. Progressive encephalomyelitis with rigidity and myoclonus is a hypokinetic disorder presenting with limb and truncal rigidity, painful spasms, brainstem signs, and hyperreflexia. This syndrome is most commonly associated with antibodies to GAD, glycineR, NMDAR, and dipeptidyl-peptidase-like protein 6 (DPPX) (34). About 20% of progressive encephalomyelitis with rigidity and myoclonus cases are paraneoplastic and associated with small-cell lung cancer, lymphomas, melanomas, breast cancer, or thymomas.

Paraneoplastic narcolepsy and cataplexy. Paraneoplastic narcolepsy and cataplexy are seen in young men with anti-Ma2 antibody encephalitis and testicular germ cell tumors. Immunoglobulin-like cell adhesion molecule 5 (IgLON5) has also been associated with sleep-disordered breathing and parasomnias (50).

Paraneoplastic movement disorders. Paraneoplastic movement disorders occur in two other well-differentiated clinical settings. Orobuccolingual and often trunk, abdomen, and extremity movements occur in 80% of patients with anti-NMDAR encephalitis (138). Paraneoplastic chorea is usually associated with anti-collapsin response–mediator brain protein type 5 (CRMP5) antibodies and small cell lung cancer. Most patients present other neurologic symptoms, and brain MRI usually reveals high T2-signal abnormalities in the caudate and putamen (193).

Myelopathy. Myelopathy is often associated with other neurologic syndromes (paraneoplastic encephalomyelitis). However, a study described 31 patients who developed a subacute, usually severe, isolated myelopathy with cerebrospinal fluid pleocytosis and spinal MRI abnormalities (51). Immunotherapy and cancer treatments were not very effective.

Paraneoplastic cerebellar degeneration. Paraneoplastic cerebellar degeneration presents with severe cerebellar ataxia, but other parts of the nervous system may also be involved (170).

Paraneoplastic subacute sensory neuronopathy. Paraneoplastic subacute sensory neuronopathy presents with subacute, painful, predominantly sensory neuropathy with relative preservation of muscle strength (23). Later, pain is replaced by numbness, limb ataxia, and pseudoathetotic movements of the hands due to proprioceptive deficit.

Autonomic neuropathy. Autonomic neuropathy often presents with acute or chronic gastrointestinal pseudo-obstruction with weight loss, persistent constipation, and abdominal distension. Orthostatic hypotension or sexual disturbance are also symptoms of autonomic neuropathy.

PNS and immune checkpoint inhibitors. With the more widespread use of immune checkpoint inhibitors in cancer therapy, there have been multiple reports of paraneoplastic neurologic syndromes thought to be directly related to the use of these therapies. These therapies target immunosuppressive or immunoregulatory molecules, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed death-1 (PD1) or its ligand (PDL1), which enhance endogenous immune responses and anticancer immunity, leading to unwanted outcomes affecting other organ systems. Neurologic complications of immune checkpoint inhibitor therapies, including either development or worsening of existing neurologic autoimmunity, can be seen in approximately 4.2% of patients receiving monotherapy and 14% of those receiving combination CTLA4 and PD1/PDL1 inhibitors (168; 45). This group reported on the neural autoantibody profiles and outcome predictors of a large cohort of immune checkpoint inhibitor-treated patients who subsequently had autoimmune neurologic complications. Neurologic outcome was poor in one third of the patients and was associated with pre-immune checkpoint inhibitor treatment characteristics (older age, female sex, lung cancer, and presence of systemic immune checkpoint inhibitor-related autoimmunity) and clinical phenotype (CNS involvement and severity of clinical symptoms at onset). After commencing immune checkpoint inhibitors, patients with preexistent paraneoplastic CNS autoimmunity and neural autoantibody seropositivity had particularly severe neurologic deterioration that was poorly responsive to protracted immunotherapy. Therefore, the authors recommended screening for autoantibodies in patients with tumors that are traditionally associated with paraneoplastic syndromes, even if patients are neurologically asymptomatic when immune checkpoint inhibitors are going to be part of their cancer treatment regimen (168).

Types of antibodies. Broadly speaking, autoantibodies that are potentially paraneoplastic can be grouped into two categories: those that bind to the cell surface or synaptic antigens and those that bind to intracellular or cytoplasmic antigens (Tables 2 and 3) (100; 65). Antibodies with intracellular antigens are typically not considered directly pathogenic and could involve cytotoxic CD8 T cells, which recognize intracellular antigens expressed on major histocompatibility complex class 1 cell surface molecules that mark the cell for destruction by these cytotoxic T lymphocytes. Intracellular antibodies have a much higher frequency of cancer (greater than 80%). An exception to this rule is anti-GAD65 antibodies, which are less commonly associated with cancer (50). The frequency of an underlying tumor and response to treatment varies depending on the antibody type. In general, intracellular antibodies have a higher association with cancer and poorer response to immune therapies (115). All these antibodies, however, particularly those associated with small-cell lung cancer (ANNA-1, anti-CRMP5, and anti-amphiphysin), can be found in patients with cancer but without paraneoplastic neurologic disorders (120).

Table 2. Antibodies Associated with Intracellular or Cytoplasmic Antigens (Onconeural Antigens)

Antibody	Predominant tumor	Syndrome
PCA-1 (previously anti-Yo)	Ovary, breast cancer	Paraneoplastic cerebellar degeneration
ANNA-1 (previously anti-Hu)	Small cell lung cancer, breast or ovarian cancer, neuroblastoma, prostate cancer	Paraneoplastic sensory neuronopathy, encephalomyelitis, brainstem encephalitis, paraneoplastic cerebellar degeneration
ANNA-2 (previously anti-Ri)	Small cell lung cancer, breast or gynecological and bladder cancers	Brainstem encephalitis, ataxia with or without opsoclonus-myoclonus sometimes with jaw dystonia and severe laryngospasm
ANNA-3	Lung cancer	Sensory neuronopathy, encephalomyelitis, paraneoplastic cerebellar degeneration
Anti-Ma-1	Lung and other cancers	Brainstem encephalitis, paraneoplastic cerebellar degeneration
Anti-Ma-2	Testicular and lung cancer, or intestinal neuroendocrine tumors without paraneoplastic disorders	Limbic encephalitis, brainstem encephalitis, paraneoplastic cerebellar degeneration, narcolepsy-cataplexy
Anti-recoverin	Small cell lung cancer, melanoma, gynecological cancers	Retinopathy
Anti-CRMP5 (previously anti-CV2)	Small cell lung cancer, thymoma	Encephalomyelitis, paraneoplastic cerebellar degeneration, limbic encephalitis, sensory neuronopathy, chorea, isolated myelopathy, optic neuropathy
Anti-amphiphysin	Breast cancer and small cell lung cancer, thymoma	Stiff-person syndrome, limbic encephalitis, paraneoplastic encephalomyelitis, isolated myelopathy
Anti-GAD	Breast cancer and insulin-dependent diabetes mellitus or other autoimmune diseases	Stiff-person syndrome, limbic encephalitis, cerebellar ataxia
Anti-SOX	Small cell lung cancer	Lambert-Eaton myasthenic syndrome
Anti-ZIC	Small cell lung cancer	Paraneoplastic cerebellar degeneration
Anti-TRIM46	Small cell lung cancer, neuroendocrine carcinoma, pancreatic cancer, GI cancers, adenocarcinoma, sarcoma	Cerebellar syndrome, encephalomyelitis, seizures, parkinsonism
Anti-SKOR	Adenocarcinoma	Encephalitis, seizures, cerebellar syndrome

Table 3. Antibodies Against Cell Surface or Synaptic Antigens

Antibody	Syndrome	Associated cancers
Anti-VGCC	Lambert-Eaton myasthenic syndrome, paraneoplastic cerebellar degeneration	Small cell lung cancer, none
Anti-GABABR	Limbic encephalitis	Small cell lung cancer
Anti-AMPAR	Limbic encephalitis	Breast cancer
Anti-Caspr2	Limbic encephalitis, Morvan syndrome, neuromyotonia, painful neuropathy	Thymoma
Anti-LGi1	Limbic encephalitis with hyponatremia and myoclonic jerks	Thymoma, small cell lung cancer
Anti-NMDAR (NR1/NR2 heteromers)	Encephalitis with central hypoventilation, autonomic instability, and orofacial and/or limb dyskinesias	Ovarian teratoma
Anti-DNER	Hodgkin lymphoma	Paraneoplastic cerebellar degeneration
Anti-mGluR-1	Paraneoplastic cerebellar degeneration	Hodgkin lymphoma
Anti-GluR-5	Limbic encephalitis	Hodgkin lymphoma
Anti-ACHR α3 subunit	Autonomic neuropathy, neuromyotonia	Small cell lung cancer (50%); bladder, rectum, and other cancers

Antibodies targeting intracellular antigens are more likely associated with cancers. Well-characterized neurologic syndromes, cancer-specific and paraneoplastic neurologic disorder-associated intracellular antibodies include the following:

	• PCA-1. PCA-1 is usually associated with ovary, breast, or other gynecological malignancies. Its detection is highly specific for a tumor, particularly for gynecological malignancies (100% specificity and 93% specificity for gynecological malignancies; 100% sensitivity and 91% specificity for ovary/fallopian tube/uterus tumor; 18% sensitivity and 86% specificity for tumor) (101 PCA-1-positive patients, 68 with tumor) (144). It is also 99% specific for a paraneoplastic neurologic disorder in cancer patients (107 PCA-1-positive cancer patients) and 90% specific for a subacute cerebellar degeneration syndrome (55 PCA-1-positive patients) (143; 66).
	• ANNA-1. ANNA-1 is not specific for a paraneoplastic neurologic disorder and can be detected in patients with a wide range of neurologic symptoms, from limbic encephalitis to subacute cerebellar degeneration or to subacute sensory neuronopathy. It is, however, quite specific for a tumor, namely small cell lung cancer (68% specificity for tumor; 72% specificity for small cell lung cancer) (217 ANNA-1-positive patients) (144). It is also 84% specific for a paraneoplastic neurologic disorder in cancer patients (196 small cell lung cancer patients without paraneoplastic neurologic disorder) (66).
	• ANNA-2. The specificity for tumor is high, 98% (breast cancer or small cell lung cancer) (17 ANNA-2-positive patients) (144). The specificity for a paraneoplastic neurologic disorder in cancer patients is 96% (181 ovarian cancer patients without paraneoplastic neurologic disorder), and the sensitivity for brainstem encephalitis with ataxia and opsoclonus/myoclonus is 71% (28 ANNA-2-positive patients) (145; 66).
	• ANNA-3. The specificity for tumors is high, 99% (small cell lung cancer or others, mainly an intrathoracic neoplasm) (10 ANNA-3-positive patients) and for a paraneoplastic neurologic disorder in cancer patients is 100% (58 cancer patients without paraneoplastic neurologic disorder) (66; 144). It is not associated with a specific neurologic syndrome.
	• Anti-Ma-2. The specificity for tumors is 96% (55 anti-Ma-2-positive patients) (66). Among tumors it is 87% sensitive and 67% specific for germinal testis tumor in males; it is associated with various tumors if associated with other reactivities (against Ma-1 or Ma-3 protein) (29 anti-Ma protein–positive patients) (158). It is 100% specific for a paraneoplastic neurologic disorder in cancer patients (350 cancer patients without paraneoplastic neurologic disorder) (66). It is usually associated with limbic or brainstem encephalitis, and patients with anti-Ma-2 alone and testis tumors have a better outcome after surgery and immunosuppressive treatment than patients with reactivities to other Ma proteins.
	• Anti-retinal antibodies. Antibodies against different retinal antigens (enolase, carbonic anhydrase II, recoverin, and transducin) can be found in cancer-related retinopathy patients. Associated cancers are usually breast (31%), lung (16%), melanoma (16%), hematological malignancies (lymphoma, leukemias, myelomas) (15%), gynecological neoplasms (9%), prostate (7%), and colon (6%) (01). Anti-retinal antibodies have a low 63% sensitivity and 58% specificity for cancer compared to patients with no cancer-related retinopathy and a higher 81% specificity compared to healthy controls (52 cancer-related retinopathy patients; 141 patients with no cancer-related retinopathy; 79 healthy controls) (03). Anti-recoverin antibodies can be predictive for cancer because they have a high 99% specificity for lung cancer compared with controls (other lung diseases and healthy controls). The very low sensitivity (17%) does not allow one to consider them as a valuable marker of lung cancer (99 small cell lung cancer patients; 44 other lung disease patients; 50 healthy controls) (17). Anti-recoverin or anti-enolase antibodies in women with retinopathy have a strong association with breast cancer (anti-recoverin antibodies: sensitivity 5%, specificity 100%; anti-enolase antibodies: sensitivity 32%, specificity 82%) (111 women with vision loss; 78 healthy controls) (02).
	• Anti-CRMP5. The specificity for tumors is 60% (65% small cell lung cancer patients; 208 anti-CRMP5-positive patients) and for a paraneoplastic neurologic disorder in cancer patients is 90% (74 small cell lung cancer patients without paraneoplastic neurologic disorder) (66; 144). It is not associated with a specific neurologic syndrome.
	• Anti-amphiphysin. The specificity for tumors is high, 98% (48% small cell lung cancer, 38% breast cancer, 26 anti-amphiphysin-positive patients), and for a paraneoplastic neurologic disorder in cancer patients is 99% (146 small cell lung cancer patients without paraneoplastic neurologic disorder) (66; 144). It is not associated with a specific neurologic syndrome.
	• PCA-2. Nine patients with PCA-2 and neurologic symptoms have been reported (85). The specificity for tumors is high, 90% (53% small cell lung cancer, 43 PCA-2-positive patients) and for a paraneoplastic neurologic disorder in cancer patients is 98% (58 cancer patients without paraneoplastic neurologic disorder) (66; 144). It is not associated with a specific neurologic syndrome (paraneoplastic cerebellar degeneration, limbic encephalitis, Lambert-Eaton myasthenic syndrome, autonomic neuropathy, and others).

• Anti-SOX antibodies. They are detected in 64% of patients with Lambert-Eaton myasthenic syndrome and small-cell lung cancer but very rarely in idiopathic Lambert-Eaton myasthenic syndrome. They have a 95% specificity to discriminate between Lambert-Eaton myasthenic syndrome with or without small cell lung cancer (184).

• Anti-ZIC antibodies (zinc fingers of the cerebellum). They have been found in 15% of patients with paraneoplastic cerebellar degeneration and small cell lung cancer, but also in 16% of patients with small cell lung cancer alone and in 29% of patients with a different paraneoplastic neurologic disorder and small cell lung cancer. Despite the low sensitivity (16%), they are 100% specific for small cell lung cancer (74 small cell lung cancer patients; 34 other cancer patients; 20 healthy controls) and for small cell lung cancer and paraneoplastic neurologic disorder (167 small cell lung cancer with paraneoplastic neurologic disorder patients; 48 other tumors and paraneoplastic neurologic disorder patients) (16).

Antibodies against surface or synaptic antigens.

	• Anti-VGCC antibodies. Anti-VGCC antibodies are occasionally found in patients with paraneoplastic cerebellar degeneration, usually in association with Lambert-Eaton myasthenic syndrome (116; 198). Although their sensitivity for small cell lung cancer in paraneoplastic cerebellar degeneration is low (12% to 41%), they have an 88% to 100% specificity (66 paraneoplastic cerebellar degeneration patients with small cell lung cancer; 27 paraneoplastic cerebellar degeneration patients with other tumors) (198) (39 paraneoplastic cerebellar degeneration patients; 21 small cell lung cancer patients; seven paraneoplastic cerebellar degeneration patients with other tumors) (67).
	• Anti-GABABR antibodies. Anti-GABABR antibodies have been detected in some patients with paraneoplastic encephalitis with the classic limbic encephalitic symptoms and MRI findings (19). Their sensitivity for encephalitis/encephalopathy is low (4% to 8%), and their sensitivity for an associated cancer (usually small cell lung cancer) is also low, ranging from 33% to 41% (126 suspected paraneoplastic neurologic disorder or autoimmune encephalitis/encephalopathy patients, 10 anti-GABABR positive) (43) (410 suspected paraneoplastic neurologic disorder or autoimmune encephalitis/encephalopathy patients, 17 anti-GABABR positive) (99).
	• Anti-AMPAR antibodies. Anti-AMPAR antibodies are associated with limbic encephalitis, which may present with prominent psychiatric symptoms. Their sensitivity for encephalitis/encephalopathy is low (2%), and their sensitivity for an associated cancer (usually ovarian cancer) ranges from 33% to 70% (126 suspected paraneoplastic neurologic disorder or autoimmune encephalitis/encephalopathy patients, three anti-AMPAR positive) (43) (10 anti-AMPAR positive) (97).
	• Anti-Caspr2 antibodies. Anti-Caspr2 antibodies are associated with a broader spectrum of symptoms, including Morvan syndrome, neuromyotonia and painful neuropathy, and, more rarely, limbic encephalitis (81; 82). Tumors, especially thymomas, are mostly associated with anti-Caspr2 antibody-positive neuromyotonia or Morvan syndrome, whereas tumors appear to be uncommon in anti-Caspr2 antibody-positive limbic encephalitis. Among patients with CNS or peripheral nerve involvement, anti-Caspr2 antibodies have an 82% sensitivity and an 83% specificity for an associated thymoma (82 CNS or peripheral nerve patients) (195).
	• Anti-LGi1 antibodies. Anti-LGi1 antibodies are associated with limbic encephalitis, often with hyponatremia. They have an 89% sensitivity for limbic encephalitis (81).
	• Anti-NMDAR antibodies. Anti-NMDAR antibodies are associated with the most frequent and best-characterized autoimmune encephalitis, which is clinically different from limbic encephalitis. The syndrome usually develops with a sequential presentation of symptoms, including a prodrome of headache and fever followed by behavioral changes, psychosis, catatonia, decreased level of consciousness, dyskinesias, and autonomic instability, which may require ventilatory support. Seizures can occur at any stage but most commonly occur early. Thirty percent of patients show a unique electroencephalographic pattern named “extreme delta brush” (167). Anti-NMDAR antibody encephalitis usually affects young women (aged 18 to 40 years) with ovarian teratoma. Within encephalitis patients, anti-NMDAR antibodies have a 59% sensitivity for a tumor and a 93% sensitivity for a teratoma (98 anti-NMDAR antibody encephalitis patients) (38).
	• Anti-DNER (previously anti-Tr) antibodies. Anti-DNER antibodies are associated with paraneoplastic cerebellar degeneration and Hodgkin lymphoma. In patients with subacute and severe cerebellar ataxia, anti-DNER antibodies have a 91% sensitivity and a 100% specificity for Hodgkin lymphoma (11 subacute and severe cerebellar ataxia patients; 215 other neurologic disease patients; 31 healthy controls) (40). Anti-DNER antibodies are also absent in patients with paraneoplastic cerebellar degeneration and non-Hodgkin lymphoma (40).
	• Anti-mGluR-1 antibodies. Anti-mGluR-1 antibodies have been found in five patients with pure cerebellar symptoms. Three of the patients had a tumor, and two had Hodgkin lymphoma (84). It is of interest that the passive transfer of patient anti-mGluR-1 IgG into the CSF of mice induced severe, transient ataxia (172).
	• Anti-mGluR-5 antibodies. Anti-mGluR-5 antibodies are associated with encephalitis in patients with Hodgkin lymphoma (Ophelia syndrome) (101). The syndrome is highly similar to limbic encephalitis, but MRI may show involvement beyond the limbic system. So far, they have been reported in less than 10 patients with neurologic symptoms, all with Hodgkin lymphoma (109).
	• Anti-nicotinic AChR α3 subunit antibodies. Anti-nicotinic AChR alpha3 subunit antibodies are associated with autonomic neuropathy or neuromyotonia, usually with anti-VGKC antibodies in the latter disease (67). Their sensitivity for autonomic neuropathy is 41%, for idiopathic autonomic neuropathy is 50%, and for paraneoplastic autonomic neuropathy is 28%. Their specificity for idiopathic or paraneoplastic autonomic neuropathy compared to other types of dysautonomia is high, 95%, and they are not found in patients with non-diabetic dysautonomia or degenerative dysautonomia (chronic progressive pure autonomic failure or multiple system atrophy). Their specificity for a tumor associated with dysautonomia (67% small cell lung cancer) is low, 20% (28 idiopathic autonomic neuropathy patients; 18 paraneoplastic autonomic neuropathy patients; 111 other types of dysautonomia patients) (192; 191).

Evaluation of paraneoplastic antibody testing. The gold standard of detection is tissue-based assay, immunohistochemical staining pattern on brain tissue sections, combined with confirmation by immunoblotting using recombinant purified proteins or with cell-based assay with suitable cell lines (such as HEK293 cells) that are transfected with a eukaryotic expression vector (plasmid) encoding the antigen. Rat cerebellum sections are used for ANNA-1, PCA-1, ANNA-2, anti-CRMP5, anti-Ma protein, anti-amphiphysin, anti-SOX1, and anti-GAD antibodies, and rat hippocampus sections are used for anti-NMDAR, anti-LGi1, anti-Caspr2, anti-AMPAR, and anti-GABABR antibodies. Different companies provide commercially available immunoblots for the most common onconeuronal antibodies (ANNA-1, PCA-1, ANNA-2, anti-CRMP5, anti-Ma proteins, anti-amphiphysin, anti-SOX1, and anti-GAD) or plasmids or already transfected cells for the most common surface proteins (anti-NMDAR, anti-LGI1, anti-Caspr2, anti-AMPAR, anti-GABABR). Specialized laboratories provide in-house cell-based assays to detect additional antibodies such as anti-glycine receptor or anti-mGluR1/5. Immunoprecipitation is used to detect anti-VGCC antibodies (77). Paraneoplastic neurologic disorders are rare diseases, and diagnosis should be performed in experienced centers to guarantee high diagnostic quality. For the three most common paraneoplastic antibodies (ANNA-1, PCA-1, ANNA-2) the sensitivity in established paraneoplastic neurologic disorders was 28.9% for tissue-based assay, 26.3% for western blot, and 31.5% for line blot with a specificity of 95.2% for tissue-based assay, 97.1% for western blot, and 98.1% for line blot (38 established paraneoplastic neurologic disorder patients; 44 other neurologic disease patients) (179). The combined use of the three methods brought sensitivity to 39.4%. For the diagnosis of suspected paraneoplastic neurologic disorder in cancer patients, simultaneously testing ANNA-1, PCA-1, ANNA-2, anti-amphiphysin, anti-CRMP5, and anti-Ma-2 antibodies reported a sensitivity of 11.9% for immunoprecipitation, 7% for tissue-based assay, and 6.3% for immunoblot with a specificity of 98.3% for immunoprecipitation and 99.8% for both tissue-based assay and immunoblot (555 cancer patients with suspected paraneoplastic neurologic disorder; 300 healthy controls) (177).

Pathogenic significance. Most paraneoplastic neurologic disorders are presumably immune-mediated, although the relative contribution of T and B cells remains unclear. The autoimmune hypothesis in paraneoplastic neurologic disorders is supported by the inflammatory CSF findings and T-cell infiltration in the affected part of the nervous system revealed by pathologic examination (79). Tumor expression of the same onconeuronal antigens normally expressed in the neurons triggers an immune response (44). The tumor antigen, which is identical to the neural antigen, is identified as foreign by the immune system, and an attack is mounted against the tumor. On the other hand, namely in paraneoplastic neurologic disorders involving the CNS, the antineuronal antibodies might be an epiphenomenon marking autoimmunity without a direct pathogenic effect (44). Some autoantibodies from patients with paraneoplastic disorders do not cause injury to the cultured neurons (180).

When the target antigens are cell surface or synaptic antigen receptors, the pathogenic role of the autoantibodies is reflected by the response to immunotherapy and by the correlation between antibody titers and outcome. In some cases, experimental evidence confirmed the autoantibody pathogenicity, such as for Lambert-Eaton myasthenic syndrome patients' anti-VGCC IgG that can reproduce the electrophysiologic disturbance in animals (194). In vivo infusion of anti-NMDAR encephalitis patients' CSF or IgG into rodent hippocampus caused cross-linking and internalization of the target receptors and was accompanied by a decrease in synaptic NMDAR-mediated currents (80). Anti-AMPAR antibodies also cause receptor cross-linking and internalization and result in a reversible decrease in AMPAR clusters at synapses (97). Antibodies to the GABABR inhibit receptor function but do not cause receptor internalization (100). Antibodies to nicotinic AChR α3 subunit induce internalization of these receptors and thereby impair synaptic transmission (93).

The role of antibodies directed against intracellular antigens remains questionable in the pathogenesis of paraneoplastic disorders. It has been argued that intracellular antigens can be expressed on cell surface and also that certain antibodies can get access to cytoplasm. The lack of response to plasma exchange in most cases of paraneoplastic disorders associated with antibodies directed against intracellular antigens can be explained by the slow removal of antibodies from the CNS compared to the rapid removal of circulating antibodies and by permanent damage caused by antibodies.

T cells can recognize intracellular antigens presented to them as MHC-peptide complexes and thereby kill neurons. Antigen-specific cytotoxic T cells in paraneoplastic neurologic disorders were clearly documented in patients with acute paraneoplastic cerebellar degeneration and PCA-1 or ANNA-1. Activated T cells in the blood could lyse target cells presenting PCA-1 antigen in vitro (39). For paraneoplastic neurologic disorders of the CNS in which most of the known target antigens are intracellular proteins, animal models have not provided evidence that antibodies have a role in the pathogenesis.

Morvan syndrome

Clinical manifestations. This is a very rare disease characterized by neuromyotonia associated with sleep disturbances, memory loss, confusion, hallucinations, dysautonomia, and neuropathic pain (82).

Type of antibodies. Almost all patients are men, mostly with antibodies against proteins that are complexed with the VGKC of presynaptic nerve terminals (82). They are directed against Caspr2, LGi1, or, commonly, both. Anti-LGi1 antibodies can be found in limbic encephalitis, too. Comparing patients with anti-VGKC complex antibodies and Morvan syndrome or limbic encephalitis (29 Morvan syndrome patients; 64 limbic encephalitis patients), the positivity for anti-VGKC complex antibodies has a 42% sensitivity and a 100% specificity for the association with a tumor (mostly thymoma). Comparing Morvan syndrome patients positive for anti-Caspr2, anti-LGL1, or both (n=24), the positivity for anti-Caspr2 or for both in a Morvan syndrome patient has a 52% sensitivity and a 100% specificity for the association with a tumor. Anti-VGCK complex antibodies are detected using a cell-based assay radioimmunoprecipitation assay, and anti-Caspr2 and anti-LGi1 antibodies with a tissue-based assay (81; 82).

Pathogenic significance. The pathogenic significance of anti-VGKC complex antibodies in Morvan syndrome is not known.

Clinical applications

Autoantibodies are routinely tested in many neuropathies, neuromuscular junction disorders, and myopathies and can be useful in the diagnosis and management.

In CNS disorders, the pathogenic role of autoantibodies is still emerging. Neuromyelitis optica has emerged as a specific pathophysiological entity due to the specificity of aquaporin-4 antibodies. Autoantibodies to CNS antigens can help detect a specific tumor associated with a paraneoplastic disorder and are routinely tested in suspected cases. ANNA-1, anti-VGCC, and anti-CRMP5 antibodies are often associated with lung cancer, PCA-1 and ANNA-2 with gynecologic cancers, and anti-Ma2 with testicular cancer in men and gynecologic cancer in women. The early detection and treatment of the underlying tumor may lead to clinical improvement in some cases. Antibodies to surface or synaptic CNS antigens may be associated with treatable syndromes, which are, at times, paraneoplastic. Disorders associated with anti-NMDAR, anti-GABABR, anti-AMPAR, anti-mGluR, anti-LGi1, anti-Caspr2, and anti-VGCC antibodies may respond to plasma exchange and intravenous immunoglobulin. Antibodies to cell surface or synaptic proteins are directed against conformational epitopes, and the reactivity is usually lost when the antigen is denatured so that these antibodies cannot be detected by standard immunoblot or ELISA. Rather, the detection of these antibodies requires an immunohistochemistry protocol adapted to cell surface antigens, such as the use of tissue-based assay or cell-based assay (159).

The search for more autoantibodies and the effort to better define their contribution to the disease process are ongoing. In the future, new paradigms for their detection and treatment of antibody-mediated diseases may be established.

References

01: Adamus G. Autoantibody targets and their cancer relationship in the pathogenicity of paraneoplastic retinopathy. Autoimmun Rev 2009;8(5):410-4. PMID 19168157
02: Adamus G. Latest updates on antiretinal autoantibodies associated with vision loss and breast cancer. Invest Ophthalmol Vis Sci 2015;56(3):1680-8. PMID 25754855
03: Adamus G, Ren G, Weleber RG. Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmol 2004;4:5. PMID 15180904
04: Alaedini A, Wirguin I, Latov N. Ganglioside agglutination immunoassay for rapid detection of autoantibodies in immune-mediated neuropathy. J Clin Lab Anal 2001;15(2):96-9. PMID 11291112
05: Ali F, Rowley M, Jayakrishnan B, Teuber S, Gershwin ME, Mackay IR. Stiff-person syndrome (SPS) and anti-GAD-related CNS degenerations: protean additions to the autoimmune central neuropathies. J Autoimmun 2011;37(2):79-87. PMID 21680149
06: Almon RR, Andrew CG, Appel SH. Serum globulin in myasthenia gravis: inhibition of alpha-bungarotoxin binding to acetylcholine receptors. Science 1974;186(4158):55-7. PMID 4421998
07: Andermann F, Cross JH, Wiendl H. Rasmussen syndrome. In: Gilman S, editor. Medlink Neurology. San Diego: MedLink Corporation. Available at www.medlink.com. Accessed 2009.
08: Antel JP, Bar-Or A. Do myelin-directed antibodies predict multiple sclerosis. N Engl J Med 2003;349(2):107-9. PMID 12853581
09: Antunes NL, Khakoo Y, Matthay KK, et al. Antineuronal antibodies in patients with neuroblastoma and paraneoplastic opsoclonus-myoclonus. J Pediatr Hematol Oncol 2000;22(4):315-20. PMID 10959901
10: Antunes NL, Khakoo Y, Matthay KK, et al. Antineuronal antibodies in patients with neuroblastoma and
11: paraneoplastic opsoclonus-myoclonus. J Pediatr Hematol Oncol. 2000; 22(4):315-20. PMID: 10959901
12: Arimura K, Sonoda Y, Watanabe O, et al. Isaacs' syndrome as a potassium channelopathy of the nerve. Muscle Nerve 2002;(Suppl 1)1:S55-8. PMID 12116286
13: Armangue T, Spatola M, Vlagea A, et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol 2018;17(9):760-72. PMID 30049614
14: Baig S, Olsson T, Yu-Ping J, Hojeberg B, Cruz M, Link H. Multiple sclerosis: cells secreting antibodies against myelin-associated glycoprotein are present in cerebrospinal fluid. Scand J Immunol 1991;33(1):73-9. PMID 1705050
15: Banwell B, Bennett JL, Marignier R, et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol 2023;22(3):268-82. PMID 36706773
16: Bataller L, Wade DF, Graus F, Stacey HD, Rosenfeld MR, Dalmau J. Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer. Neurology 2004;62(5):778-82. PMID 15007130
17: Bazhin AV, Savchenko MS, Shifrina ON, et al. Recoverin as a paraneoplastic antigen in lung cancer: the occurrence of anti-recoverin autoantibodies in sera and recoverin in tumors. Lung Cancer 2004;44(2):193-8. PMID 15084384
18: Bonyadi MR, Barzegar M, Badalzadeh R, Hashemilar M. Comparison of immunoblotting and ELISA for detection of anti-ganglioside antibodies in children with Guillain-Barre syndrome. Iran J Immunol 2010;7(2):117-23. PMID 20574125
19: Boronat A, Sabater L, Saiz A, Dalmau J, Graus F. GABA(B) receptor antibodies in limbic encephalitis and anti-GAD associated neurological disorders. Neurology 2011;76:795-800. PMID 21357831
20: Boz C, Oger J, Gibbs E, Grossberg SE; the Neurologists of the UBC MS Clinic. Reduced effectiveness of long-term interferon-beta treatment on relapses in neutralizing antibody-positive multiple sclerosis patients: a Canadian multiple sclerosis clinic-based study. Mult Scler 2007;13(9):1127-37. PMID 17967840
21: Briani C, Doria A, Sarzi-Puttini P, Dalakas MC. Update on idiopathic inflammatory myopathies. Autoimmunity 2006;39(3):161-70. PMID 16769649
22: Buchwald B, Bufler J, Carpo M, et al. Combined pre- and postsynaptic action of IgG antibodies in Miller Fisher syndrome. Neurology 2001;56(1):67-74. PMID 11148238
23: Camdessanché JP, Jousserand G, Ferraud K, et al. The pattern and diagnostic criteria of sensory neuronopathy: a case-control study. Brain 2009;132(Pt 7):1723-33. PMID 19506068
24: Carta S, Cobo Calvo Á, Armangué T, et al. Significance of myelin oligodendrocyte glycoprotein antibodies in CSF: a retrospective multicenter study. Neurology 2023;100(11):e1095-108. PMID 36526426
25: Cats EA, Jacobs BC, Yuki N, et al. Multifocal motor neuropathy: association of anti-GM1 IgM antibodies with clinical features. Neurology 2010;75(22):1961-7. PMID 20962291
26: Caudie C, Kaygisiz F, Jaquet P, et al. Diagnostic value of autoantibodies to MAG by ELISA Bühlmann in 117 immune-mediated peripheral neuropathies associated with monoclonal IgM to SGPG/SGLPG. [Article in French] Ann Biol Clin (Paris). 2006;64(4):353-9. PMID 16829480
27: Chavada G, Willison HJ. Autoantibodies in immune-mediated neuropathies. Curr Opin Neurol 2012;25(5):550-5. PMID 22941260
28: Chia NH, McKeon A, Dalakas MC, et al. Stiff person spectrum disorder diagnosis, misdiagnosis, and suggested diagnostic criteria. Ann Clin Transl Neurol 2023;10(7):1083-94. PMID 37212351
29: Chiba A, Kusunoki S, Obata H, Machinami R, Kanazawa I. Serum anti-GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain-Barre syndrome: clinical and immunohistochemical studies. Neurology 1993;43(10):1911-7. PMID 8413947
30: Cocito D, Durelli L, Isoardo G. Different clinical, electrophysiological and immunological features of CIDP associated with paraproteinaemia. Acta Neurol Scand 2003;108(4):274-80. PMID 12956862
31: Conti F, Alessandri C, Bompane D, et al. Autoantibody profile in systemic lupus erythematosus with psychiatric manifestations: a role for anti-endothelial-cell antibodies. Arthritis Res Ther 2004;6(4):R366-72. PMID 15225372
32: Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A. Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2011;76(3):294-300. PMID 21242498
33: Cossburn M, Pace AA, Jones J, et al. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology 2011;77(6):573-9. PMID 21795656
34: Crisp SJ, Balint B, Vincent A. Redefining progressive encephalomyelitis with rigidity and myoclonus after the discovery of antibodies to glycine receptors. Curr Opin Neurol 2017;30(3):310-6. PMID 28306573
35: Cruz M, Olsson T, Ernerudh J, Hojeberg B, Link H. Immunoblot detection of oligoclonal anti-myelin basic protein IgG antibodies in cerebrospinal fluid in multiple sclerosis. Neurology 1987;37(9):1515-9. PMID 2442667
36: Dalakas MC. Stiff person syndrome: advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol 2009;11(2):102-10. PMID 19210912
37: Dalakas MC, Fujii M, Li M, McElroy B. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology 2000;55(10):1531-5. PMID 11094109
38: Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008;7(12):1091-8. PMID 18851928
39: Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003;349(16):1543-54. PMID 14561798
40: de Graaff E, Maat P, Hulsenboom E, et al. Identification of delta/notch-like epidermal growth factor-related receptor as the Tr antigen in paraneoplastic cerebellar degeneration. Ann Neurol 2012;71(6):815-24. PMID 22447725
41: Delunardo F, Soldati D, Bellisario V, et al. Anti-GAPDH autoantibodies as a pathogenic determinant and potential biomarker of neuropsychiatric diseases. Arthritis Rheumatol 2016;68(11):2708-16. PMID 27213890
42: Dinkel K, Meinck HM, Jury KM, Karges W, Richter W. Inhibition of gamma-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann Neurol 1998;44(2):194-201. PMID 9708541
43: Dogan Onugoren M, Deuretzbacher D, Haensch CA, et al. Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series. J Neurol Neurosurg Psychiatry 2015;86(9):965-72 PMID 25300449
44: Dropcho EJ. Update on paraneoplastic syndromes. Curr Opin Neurol 2005;18(3):331-6. PMID 15891421
45: Duong SL, Pruss H. Paraneoplastic autoimmune neurological syndromes and the role of immune checkpoint inhibitors. Neurotherapeutics 2022;19(3):848-63. PMID 35043373
46: Durelli L, Oggero A, Verdun E, et al. Thyroid function and anti-thyroid antibodies in MS patients screened for interferon treatment. A multicenter study. J Neurol Sci 2001a;193(1):17-22. PMID 11718745
47: Esiri MM. Immunoglobulin-containing cells in multiple-sclerosis plaques. Lancet 1977;2(8036):478. PMID 70689
48: Farrell RA, Giovannoni G. Development and validation of Luciferase reporter gene assay to measure anti-interferon beta neutralizing antibodies. Neurology 2007;68 (suppl 1):P03-30.
49: Files JG, Gray JL, Do LT, et al. A novel sensitive and selective bioassay for human type I interferons. J Interferon Cytokine Res 1998;18(12):1019-24. PMID 9877444
50: Flanagan EP. Paraneoplastic disorders of the nervous system. J Neurol 2021;268(12):4899-907. PMID 33904967
51: Flanagan EP, McKeon A, Lennon VA, et al. Paraneoplastic isolated myelopathy: clinical course and neuroimaging clues. Neurology 2011;76(24):2089–95. PMID 21670438
52: Fujikawa K, Nakashima S, Konishi M, et al. The first total synthesis of ganglioside GalNAc-GD1a, a target molecule for autoantibodies in Guillain-Barré syndrome. Chemistry 2011;17(20):5641-51. PMID 21469228
53: Gabriel CM, Gregson NA, Hughes RA. Anti-PMP22 antibodies in patients with inflammatory neuropathy. J Neuroimmunol 2000;104(2):139-46. PMID 10713353
54: Galban-Horcajo F, Fitzpatrick AM, Hutton AJ, et al. Antibodies to heteromeric glycolipid complexes in multifocal motor neuropathy. Eur J Neurol 2013;20(1):62-70. PMID 22727042
55: Gallardo E, Rojas-García R, Belvís R, et al. Antiganglioside antibodies: when, which and for what. [Article in Spanish] Neurologia 2001;16(7):293-7. PMID 11485721
56: Garg N, Weinstock-Guttman B, Bhasi K, Locke J, Ramanathan M. An association between autoreactive antibodies and anti-interferon-beta antibodies in multiple sclerosis. Mult Scler 2007b;13(7):895-9. PMID 17468449
57: Garg N, Zivadinov R, Ramanathan M, et al. Clinical and MRI correlates of autoreactive antibodies in multiple sclerosis patients. J Neuroimmunol 2007a;187(1-2):159-65. PMID 17512610
58: Genain CP, Cannella B, Hauser SL, Raine CS. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 1999;5(2):170-5. PMID 9930864
59: Ghirardello A, Zampieri S, Tarricone E, et al. Clinical implications of autoantibody screening in patients with autoimmune myositis. Autoimmunity 2006;39(3):217-21. PMID 16769655
60: Giannotta C, Di Pietro D, Gallia F, Nobile-Orazio E. Anti-sulfatide IgM antibodies in peripheral neuropathy: to test or not to test? Eur J Neurol 2015;22(5):879-82. PMID 25597226
61: Gilligan M, McGuigan C, McKeon A. Autoimmune central nervous system disorders: antibody testing and its clinical utility. Clin Biochem 2024;126:110746. PMID 38462203
62: Gono T, Kawaguchi Y, Kaneko H, et al. Anti-NR2A antibody as a predictor for neuropsychiatric systemic lupus erythematosus. Rheumatology (Oxford) 2011;50(9):1578-85. PMID 21208977
63: Goodin DS, Frohman EM, Hurwitz B, et al. Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2007;68(13):977-84. PMID 17389300
64: Goodfellow JA, Willison HJ. Antiganglioside, antiganglioside-complex, and antiglycolipid-complex antibodies in immune-mediated neuropathies. Curr Opin Neurol 2016;29(5):572-80. PMID 27427992
65: Graus F, Dalmau J. Paraneoplastic neurological syndromes. Curr Opin Neurol 2012;25(6):795-801. PMID 23041955
66: Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Pyschiatry 2004;75(8)1135-40. PMID 15258215
67: Graus F, Lang B, Pozo-Rosich P, Saiz A, Casamitjana R, Vincent A. P/Q type calcium-channel antibodies in paraneoplastic cerebellar degeneration with lung cancer. Neurology 2002;59(5):764-6. PMID 12221175
68: Gravier-Dumonceau A, Ameli R, Rogemond V, et al. Glial fibrillary acidic protein autoimmunity: a French cohort study. Neurology 2022;98(6):e653-68. PMID 34799461
69: Greenwood DL, Gitlits VM, Alderuccio F, Sentry JW, Toh BH. Autoantibodies in neuropsychiatric lupus. Autoimmunity 2002;35(2):79-86. PMID 12071439
70: Grossberg SE, Kawade Y, Kohase M, Klein JP. The neutralization of interferons by antibody II. Neutralizing antibodies unitage and its relationship to bioassay sensitivity: the tenfold reduction unit J. Interferon Cytokine Res 2001;21(9):743-55. PMID 11576468
71: Grossberg SE, Oger J, Grossberg LD, Gehchan A, Klein JP. Frequency and magnitude of interferon beta neutralizing antibodies in the evaluation of interferon beta immunogenicity in patients with multiple sclerosis. J Interferon Cytokine Res 2011;31(3):337-44. PMID 21226608
72: Gunawardena H, Betteridge ZE, McHugh NJ. Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression. Rheumatology (Oxford) 2009;48(6):607-12. PMID 19439503
73: Guo Y, Li X, Li R, et al. Utility of autoantibody against an UCH-L1 epitope as a serum diagnostic marker for neuropsychiatric systemic lupus erythematosus. Clin Exp Rheumatol 2022;40(11):2078-87. PMID 35084329
74: Halstead SK, Kalna G, Islam MB, et al. Microarray screening of Guillain-Barré syndrome sera for antibodies to glycolipid complexes. Neurol Neuroimmunol Neuroinflamm 2016;3(6):e284. PMID 27790627
75: Hartung HP, Polman C, Bertolotto A, et al. Neutralising antibodies to interferon beta in multiple sclerosis: expert panel report. J Neurol 2007;254(7):827-37. PMID 17457510
76: Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001;7(3):365-8. PMID 11231638
77: Höftberger R, Dalmau J, Graus F. Clinical neuropathology practice guide 5-2012: updated guideline for the diagnosis of antineuronal antibodies. Clin Neuropathol 2012;31(5):337-41. PMID 22939174
78: Holmøy T, Geis C. The immunological basis for treatment of stiff person syndrome. J Neuroimmunol 2011;231(1-2):55-60. PMID 20943276
79: Honnorat J, Antoine JC. Paraneoplastic neurological syndromes. Orphanet J Rare Dis 2007;2:22. PMID 17480225
80: Hughes EG, Peng X, Gleichman AJ, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 2010;30(17):5866-75. PMID 20427647
81: Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain 2010;133(9):2734-48. PMID 20663977
82: Irani SR, Pettingill P, Kleopa KA, et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 2012;72(2):241-55. PMID 22473710
83: Jarius S, Wildemann B. Aquaporin-4 antibodies (NMO-IgG) as a serological marker of neuromyelitis optica: a critical review of the literature. Brain Pathol 2013;23(6):661-83. PMID 24118483
84: Jarius S, Wildemann B. 'Medusa-head ataxia': the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 1: Anti-mGluR1, anti-Homer-3, anti-Sj/ITPR1 and anti-CARP VIII. J Neuroinflammation 2015a;12:166. PMID 26377085
85: Jarius S, Wildemann B. 'Medusa head ataxia': the expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 3: Anti-Yo/CDR2, anti-Nb/AP3B2, PCA-2, anti-Tr/DNER, other antibodies, diagnostic pitfalls, summary and outlook. J Neuroinflammation 2015b;12:168. PMID 26377319
86: Jaskowski TD, Prince HE, Greer RW, Litwin CM, Hill HR. Further comparisons of assays for detecting MAG IgM autoantibodies. J Neuroimmunol 2007;187(1-2):175-8. PMID 17537521
87: Javed A, Balabanov R, Arnason BG, et al. Minor salivary gland inflammation in Devic’s disease and longitudinally extensive myelitis. Mult Scler 2008;14(6):809-14. PMID 18573828
88: Jayasinghe M, Rashidi F, Gadelmawla AF, et al. Neurological manifestations of systemic lupus erythematosus: a comprehensive review. Cureus 2025;17(2):e79569. PMID 40151747
89: Jennekens FG, Kater L. The central nervous system in systemic lupus erythematosus. Part 2. Pathogenetic mechanisms of clinical syndromes: a literature investigation. Rheumatology (Oxford) 2002;41(6):619-30. PMID 12048287
90: Kadoya M, Kaida K, Koike H, et al. IgG4 anti-neurofascin155 antibodies in chronic inflammatory demyelinating polyradiculoneuropathy: clinical significance and diagnostic utility of a conventional assay. J Neuroimmunol 2016;301:16-22. PMID 27852440
91: Katz JS, Saperstein DS, Gronseth G, Amato AA, Barohn RJ. Distal acquired demyelinating symmetric neuropathy. Neurology 2000;54(3):615-20. PMID 10680792
92: Klaas JP, Ahlskog JE, Pittock SJ, et al. Adult-onset opsoclonus-myoclonus syndrome. Arch Neurol 2012;69(12):1598-607. PMID 22986354
93: Kobayashi S, Yokoyama S, Maruta T, et al. Autoantibody-induced internalization of nicotinic acetylcholine receptor α3 subunit exogenously expressed in human embryonic kidney cells. J Neuroimmunol 2013;257(1-2):102-6. PMID 23313381
94: Komai K, Iwasa K, Takamori M. Calcium channel peptide can cause an autoimmune-mediated model of Lambert-Eaton myasthenic syndrome in rats. J Neurol Sci 1999 1;166(2):126-30. PMID 10475106
95: Kowal C, Degiorgio LA, Lee JY, et al. Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc Natl Acad Sci U S A 2006;103(52):19854-9. PMID 17170137
96: Kusunoki S, Kaida K. Antibodies against ganglioside complexes in Guillain-Barré syndrome and related disorders. J Neurochem 2011;116(5):828-32. PMID 21214559
97: Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009;65(4):424-34. PMID 19338055
98: Lam R, Farrell R, Aziz T, et al. Validating parameters of a luciferase reporter gene assay to measure neutralizing antibodies to IFNbeta in multiple sclerosis patients. J Immunol Methods 2008;336(2):113-8. PMID 18511063
99: Lancaster E, Lai M, Peng X, et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 2010;9(1):67-76. PMID 19962348
100: Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 2011a;77(2):179-89. PMID 21747075
101: Lancaster E, Martinez-Hernandez E, Titulaer MJ, et al. Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology 2011b;77(18):1698-701. PMID 22013185
102: Lang B, Dale RC, Vincent A. New antibody mediated disorders of the central nervous system. Curr Opin Neurol 2003;16(3):351-7. PMID 12858073
103: Lang B, Vincent A. Autoantibodies to ion channels at the neuromuscular junction. Autoimmun Rev 2003;2(2):94-100. PMID 12848965
104: Larocca AP, Leung SC, Marcus SG, Colby CB, Borden EC. Evaluation of neutralizing antibodies in patients treated with recombinant interferon-beta(ser). J Interferon Res 1989;9(Suppl 1):S51-60. PMID 2809278
105: Lawn ND, Westmoreland BF, Kiely MJ, Lennon VA, Vernino S. Clinical, magnetic resonance imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis. Mayo Clin Proc 2003;78(11):1363-8. PMID 14601695
106: Lazaridis K, Tzartos SJ. Myasthenia gravis: autoantibody specificities and their role in MG management. Front Neurol 2020;11:596981. PMID 33329350
107: Leite MI, Jacob S, Viegas S, et al. IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 2008;131(Pt 7):1940-52. PMID 18515870
108: Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 2005;202(4):473-7. PMID 16087714
109: Levite M. Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-myasthenia gravisluR1 antibodies or anti-myasthenia gravisluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/psychiatric/cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy. J Neural Transm (Vienna) 2014;121(8):1029-75. PMID 25081016
110: Li X, Sun J, Mu R, et al. The clinical significance of ubiquitin carboxyl hydrolase L1 and its autoantibody in neuropsychiatric systemic lupus erythematosus. Clin Exp Rheumatol 2019;37(3):474-80. PMID 30418114
111: Lin JJ, Chou IJ, Lin KL, Wang HS. Childhood refractory focal epilepsy following acute febrile encephalopathy with anti-amphiphysin antibody. Eur J Neurol 2011;18(6):e70. PMID 21261793
112: Linke R, Schroeder M, Helmberger T, Voltz R. Antibody-positive paraneoplastic neurologic syndromes: value of CT and PET for tumor diagnosis. Neurology 2004;63(2):282-6. PMID 15277621
113: Liu Y, Tu Z, Zhang X, Du K, Xie Z, Lin Z. Pathogenesis and treatment of neuropsychiatric systemic lupus erythematosus: a review. Front Cell Dev Biol 2022;10:998328. PMID 36133921
114: Maisonobe T, Chassande B, Verin M, Jouni M, Leger JM, Bouche P. Chronic dysimmune demyelinating polyneuropathy: a clinical and electrophysiological study of 93 patients. J Neurol Neurosurg Psychiatry 1996;61(1):36-42. PMID 8676156
115: Marsili L, Marcucci S, LaPorta J, et al. Paraneoplastic neurological syndromes of the central nervous system: pathophysiology, diagnosis, and treatment. Biomedicines 2023;11(5):1406. PMID 37239077
116: Mason WP, Graus F, Lang B, et al. Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome. Brain 1997;120 (Pt 8):1279-300. PMID 9278623
117: Matsumoto Y, Kaneko K, Takahashi T, et al. Diagnostic implications of MOG-IgG detection in sera and cerebrospinal fluids. Brain 2023;146(9):3938-48. PMID 37061817
118: McKeon A, Robinson MT, McEvoy KM, et al. Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol 2012;69(2):230-8. PMID 22332190
119: Meinck HM, Faber L, Morgenthaler M, et al. Antibodies against glutamic acid decarboxylase: prevalence in neurological diseases. J Neurol Neurosurg Psychiatry 2001;71(1):100-3. PMID 11413272
120: Monstad SE, Knudsen A, Salvesen HB, et al. Onconeural antibodies in sera from patients with various types of tumours. Cancer Immunol Immunother 2009; 58:1795–1800. PMID 19294382
121: Motomura M, Lang B, Johnston I, Palace J, Vincent A, Newsom-Davis J. Incidence of serum anti-P/O-type and anti-N-type calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome. J Neurol Sci 1997;147(1):35-42. PMID 9094058
122: Muniz-Castrillo S, Haesebaert J, Thomas L, et al. Clinical and prognostic value of immunogenetic characteristics in anti-LGI1 encephalitis. Neurol Neuroimmunol Neuroinflamm 2021;8(3):e974. PMID 33848259
123: Munteis E, Cano JF, Flores JA, Martinez-Rodriguez JE, Miret M, Roquer J. Prevalence of autoimmune thyroid disorders in a Spanish multiple sclerosis Cohort. Eur J Neurol 2007;14(9):1048-52. PMID 17718699
124: Murinson BB, Guarnaccia JB. Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 2008;71(24):1955-8. PMID 18971449
125: Nakao YK, Motomura M, Fukudome T, et al. Seronegative Lambert-Eaton myasthenic syndrome: study of 110 Japanese patients. Neurology 2002;59(11):1773-5. PMID 12473768
126: Newsom-Davis J, Mills KR. Immunological associations of acquired neuromyotonia (Isaacs' syndrome). Report of five cases and literature review. Brain 1993;116 (Pt 2):453-69. PMID 8461975
127: Newsome SD, Johnson T. Stiff person syndrome spectrum disorders; more than meets the eye. J Neuroimmunol 2022;369:577915. PMID 35717735
128: Nobile-Orazio E. Multifocal motor neuropathy. J Neuroimmunol 2001;115(1-2):4-18. PMID 11282149
129: Nobile-Orazio E, Barbieri S, Baldini L, et al. Peripheral neuropathy in monoclonal gammopathy of undetermined significance: prevalence and immunopathogenetic studies. Acta Neurol Scand 1992;85(6):383-90. PMID 1379409
130: Nobile-Orazio E, Giannotta C, Musset L, Messina P, Léger JM. Sensitivity and predictive value of anti-GM1/galactocerebroside IgM antibodies in multifocal motor neuropathy. J Neurol Neurosurg Psychiatry 2014;85(7):754-8. PMID 23907602
131: Ogawa G, Kaida K, Kuwahara M, Kimura F, Kamakura K, Kusunoki S. An antibody to the GM1/GalNAc-GD1a complex correlates with development of pure motor Guillain-Barré syndrome with reversible conduction failure. J Neuroimmunol 2013;254(1-2):141-5. PMID 23000056
132: Ogawara K, Kuwabara S, Mori M, Hattori T, Koga M, Yuki N. Axonal Guillain-Barre syndrome: relation to anti-ganglioside antibodies and Campylobacter jejuni infection in Japan. Ann Neurol 2000;48(4):624-31. PMID 11026446
133: Oger J, Frykman H. An update on laboratory diagnosis in myasthenia gravis. Clin Chim Acta 2015;449:43-8. PMID 26238187
134: Oger J, Roos R, Antel JP. Immunology of multiple sclerosis. Neurol Clin 1983;1(3):655-79. PMID 6209537
135: Olney RK, Lewis RA, Putnam TD, Campellone JV Jr; American Association of Electrodiagnostic Medicine. Consensus criteria for the diagnosis of multifocal motor neuropathy. Muscle Nerve 2003;27(1):117-21. PMID 12508306
136: O'Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 1988;111 (Pt 3):577-96. PMID 2838124
137: Pachner AR, Bertolotto A, Deisenhammer F. Measurement of MxA mRNA or protein as a biomarker of IFNbeta bioactivity: detection of antibody-mediated decreased bioactivity (ADB). Neurology 2003;61(9 Suppl 5):S24-6. PMID 14610107
138: Panzer J, Dalmau J. Movement disorders in paraneoplastic and autoimmune disease. Curr Opin Neurol 2011;24(4):346-53. PMID 21577108
139: Pascual-Goni E, Caballero-Avila M, Querol L. Antibodies in autoimmune neuropathies: what to test, how to test, why to test. Neurology 2024;103(4):e209725. PMID 39088795
140: Peeler CE, De Lott LB, Nagia L, Lemos J, Eggenberger ER, Cornblath WT. Clinical utility of acetylcholine receptor antibody testing in ocular myasthenia gravis. JAMA Neurol 2015;72(10):1170-4. PMID 26258604
141: Pestronk A. Multifocal motor neuropathy: diagnosis and treatment. Neurology 1998;51(6 Suppl 5):S22-4. PMID 9851726
142: Pestronk A, Choksi R. Multifocal motor neuropathy. Serum IgM anti-GM1 ganglioside antibodies in most patients detected using covalent linkage of GM1 to ELISA plates. Neurology 1997;49(5):1289-92. PMID 9371910
143: Peterson K, Rosenblum MK, Kotanides H, Posner JB. Paraneoplastic cerebellar degeneration: a clinical analysis of 55 anti-Yo antibody-positive patients. Neurology 1992;42(10):1931-7. PMID 1407575
144: Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol 2004;56(5):715-9. PMID 15468074
145: Pittock SJ, Lucchinetti CF, Lennon VA. Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol 2003;53(5):580-7. PMID 12730991
146: Pittock SJ, Parisi JE, McKeon A, et al. Paraneoplastic jaw dystonia and laryngospasm with antineuronal nuclear autoantibody type 2 (anti-Ri). Arch Neurol 2010;67(9):1109-15. PMID 20837856
147: Plomp JJ, Molenaar PC, O'Hanlon GM, et al. Miller Fisher anti-GQ1b antibodies: alpha-latrotoxin-like effects on motor end plates. Ann Neurol 1999;45(2):189-99. PMID 9989621
148: Polman CH, Bertolotto A, Deisenhammer F, et al. Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol 2010;9(7):740-50. PMID 20610349
149: Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69(2):292-302. PMID 21387374
150: Pungor E Jr, Files JG, Gabe JD, et al. A novel bioassay for the determination of neutralizing antibodies to IFN-beta1b. J Interferon Cytokine Res 1998;18(12):1025-30. PMID 9877445
151: Raju R, Rakocevic G, Chen Z, et al. Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain 2006;129(Pt 12):3270-6. PMID 16984900
152: Ramagopalan SV, Dyment DA, Valdar W, et al. Autoimmune disease in families with multiple sclerosis: a population-based study. Lancet Neurol 2007;6(7):604-10. PMID 17560172
153: Rayavarapu S, Coley W, Nagaraju K. An update on pathogenic mechanisms of inflammatory myopathies. Curr Opin Rheumatol 2011;23(6):579-84. PMID 21960036
154: Reindl M, Linington C, Brehm U, et al. Antibodies against the myelin oligodendrocyte glycoprotein and the myelin basic protein in multiple sclerosis and other neurological diseases: a comparative study. Brain 1999;122 (Pt 11):2047-56. PMID 10545390
155: Rojas-García R, Querol L, Gallardo E, et al. Clinical and serological features of acute sensory ataxic neuropathy with antiganglioside antibodies. J Peripher Nerv Syst 2012;17(2):158-68. PMID 22734901
156: Romi F, Skeie GO, Aarli JA, Gilhus NE. Muscle autoantibodies in subgroups of myasthenia gravis patients. J Neurol 2000;247(5):369-75. PMID 10896269
157: Romi F, Skeie GO, Gilhus NE, Aarli JA. Striational antibodies in myasthenia gravis: reactivity and possible clinical significance. Arch Neurol 2005;62(3):442-6. PMID 15767509
158: Rosenfeld MR, Eichen JG, Wade DF, Posner JB, Dalmau J. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol 2001;50(3):339-48. PMID 11558790
159: Rosenfeld MR, Titulaer MJ, Dalmau J. Paraneoplastic syndromes and autoimmune encephalitis: five new things. Neurol Clin Pract 2012;2(3):215-222. PMID 23634368
160: Ruiz-Gaviria R, Baracaldo I, Castañeda C, Ruiz-Patiño A, Acosta-Hernandez A, Rosselli D. Specificity and sensitivity of aquaporin 4 antibody detection tests in patients with neuromyelitis optica: A meta-analysis. Mult Scler Relat Disord 2015;4(4):345-9. PMID 26195055
161: Saini H, Rifkin R, Gorelik M, et al. Passively transferred human NMO-IgG exacerbates demyelination in mouse experimental autoimmune encephalomyelitis. BMC Neurol 2013;13:104. PMID 23927715
162: Saiz A, Blanco Y, Sabater L, et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain 2008;131(Pt 10):2553-63. PMID 18687732
163: Saiz A, Bruna J, Stourac P, et al. Anti-Hu-associated brainstem encephalitis. J Neurol Neurosurg Psychiatry 2009;80(4):404-7. PMID 19015226
164: Saiz A, Dalmau J, Butler MH, et al. Anti-amphiphysin I antibodies in patients with paraneoplastic neurological disorders associated with small cell lung carcinoma. J Neurol Neurosurg Psychiatry 1999;66(2):214-7. PMID 10071102
165: Sanna G, Bertolaccini ML, Cuadrado MJ, et al. Neuropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies. J Rheumatol 2003;30(5):985-92. PMID 12734893
166: Sato S, Yashiro M, Asano T, Kobayashi H, Watanabe H, Migita K. Association of anti-triosephosphate isomerase antibodies with aseptic meningitis in patients with neuropsychiatric systemic lupus erythematosus. Clin Rheumatol 2017;36(7):1655-9. PMID 28451873
167: Schmitt SE, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J, Friedman D. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology 2012;79(11):1094-100. PMID 22933737
168: Sechi E, Markovic SN, McKeon A, et al. Neurologic autoimmunity and immune checkpoint inhibitors: autoantibody profiles and outcomes. Neurology 2020;95(17):e2442-52. PMID 32796130
169: Sellebjerg FT, Frederiksen JL, Olsson T. Anti-myelin basic protein and anti-proteolipid protein antibody-secreting cells in the cerebrospinal fluid of patients with acute optic neuritis. Arch Neurol 1994;51(10):1032-6. PMID 7524468
170: Shams'ili S, Grefkens J, de Leeuw B, et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 2003;126(Pt 6):1409-18. PMID 12764061
171: Shillito P, Molenaar PC, Vincent A, et al. Acquired neuromyotonia: evidence for autoantibodies directed against K+ channels of peripheral nerves. Ann Neurol 1995;38(5):714-22. PMID 7486862
172: Sillevis Smitt P, Kinoshita A, De Leeuw B, et al. Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med 2000;342(1):21-7. PMID 10620645
173: Simpson J. Myasthenia gravis: a new hypothesis. Scot Med J 1960;5:419-36.
174: Smith IS. The natural history of chronic demyelinating neuropathy associated with benign IgM paraproteinaemia. A clinical and neurophysiological study. Brain 1994;117 (Pt 5):949-57. PMID 7953604
175: Sommer C, Weishaupt A, Brinkhoff J, et al Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet 2005;365(9468):1406-11. PMID 15836889
176: Somnier FE, Engel PJ. The occurrence of anti-titin antibodies and thymomas: a population survey of MG 1970-1999. Neurology 2002;59(1):92-8. PMID 12105313
177: Storstein A, Monstad SE, Haugen M, et al. Onconeural antibodies: improved detection and clinical correlations. J Neuroimmunol 2011;232(1-2):166-70. PMID 21093932
178: Takei H, Wilfong A, Malphrus A, et al. Dual pathology in Rasmussen's encephalitis: a study of seven cases and review of the literature. Neuropathology 2010;30(4):381-91. PMID 20051019
179: Tampoia M, Zucano A, Antico A, et al. Diagnostic accuracy of different immunological methods for the detection of antineuronal antibodies in paraneoplastic neurological syndromes. Immunol Invest 2010;39(2):186-95. PMID 20136624
180: Tanaka K, Ding X, Tanaka M. Effects of antineuronal antibodies from patients with paraneoplastic neurological syndrome on primary-cultured neurons. J Neurol Sci 2004;217(1):25-30. PMID 14675605
181: Tatum AH. Experimental paraprotein neuropathy, demyelination by passive transfer of human IgM anti-myelin-associated glycoprotein. Ann Neurol 1993;33(5):502-6. PMID 7684583
182: Taylor BV, Gross L, Windebank AJ. The sensitivity and specificity of anti-GM1 antibody testing. Neurology 1996;47(4):951-5. PMID 8857725
183: Thompson J, Bi M, Murchison AG, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018;141(2):348-56. PMID 29272336
184: Titulaer MJ, Klooster R, Potman M, et al. SOX antibodies in small-cell lung cancer and Lambert-Eaton myasthenic syndrome: frequency and relation with survival. J Clin Oncol 2009;27(26):4260-7. PMID 19667272
185: Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol 2011;10(12):1098-107. PMID 22094130
186: Tourbah A, Clapin A, Gout O, et al. Systemic autoimmune features and multiple sclerosis: a 5-year follow-up study. Arch Neurol 1998;55(4):517-21. PMID 9561980
187: Toyka KV, Drachman DB, Griffin DE, et al. Myasthenia gravis. Study of humoral immune mechanisms by passive transfer to mice. N Engl J Med 1977;296(3):125-31. PMID 831074
188: Tsonis AI, Zisimopoulou P, Lazaridis K, et al. MuSK autoantibodies in myasthenia gravis detected by cell based assay--A multinational study. J Neuroimmunol 2015;284:10-7. PMID 26025053
189: Utset TO, Fink J, Doninger NA. Prevalence of neurocognitive dysfunction and other clinical manifestations in disabled patients with systemic lupus erythematosus. J Rheumatol 2006;33(3):531-8. PMID 16511923
190: Varadkar S, Bien CG, Kruse CA, et al. Rasmussen’s encephalitis: clinical features, pathobiology, and treatment advances. Lancet Neurol 2014;13(2):195–205. PMID 24457189
191: Vernino S, Lindstrom J, Hopkins S, Wang Z, Low PA; Muscle Study Group. Characterization of ganglionic acetylcholine receptor autoantibodies. J Neuroimmunol 2008;197(1):63-9. PMID 18485491
192: Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000;343(12):847-55. PMID 10995864
193: Vernino S, Tuite P, Adler CH, et al. Paraneoplastic chorea associated with CRMP-5 neuronal antibody and lung carcinoma. Ann Neurol 2002;51(5):625-30. PMID 12112110
194: Vincent A. Antibodies associated with paraneoplastic neurological disorders. Neurol Sci 2005;26(Suppl 1):S3-4. PMID 15883688
195: Vincent A, Irani SR. Caspr2 antibodies in patients with thymomas. J Thorac Oncol 2010;5(10 Suppl 4):S277-80. PMID 20859119
196: Vincent A, McConville J, Farrugia ME, et al. Antibodies in myasthenia gravis and related disorders. Ann N Y Acad Sci 2003;998:324-35. PMID 14592891
197: Vogrig A, Gigli GL, Segatti S, et al. Epidemiology of paraneoplastic neurological syndromes: a population-based study. J Neurol 2020;267(1):26-35. PMID 31552550
198: Voltz R, Carpentier AF, Rosenfeld MR, Posner JB, Dalmau J. P/Q-type voltage-gated calcium channel antibodies in paraneoplastic disorders of the central nervous system. Muscle Nerve 1999;22(1):119-22. PMID 9883867
199: Waterman SA, Lang B, Newsom-Davis J. Effect of Lambert-Eaton myasthenic syndrome antibodies on autonomic neurons in the mouse. Ann Neurol 1997;42(2):147-56. PMID 9266723
200: Waters PJ, Komorowski L, Woodhall M, et al. A multicenter comparison of MOG-IgG cell-based assays. Neurology 2019;92(11):e1250-5. PMID 30728305
201: Watson R, Jiang Y, Bermudez I, et al. Absence of antibodies to glutamate receptor type 3 (GluR3) in Rasmussen encephalitis. Neurology 2004;63(1):43-50. PMID 15249609
202: Weber MS, Derfuss T, Metz I, Brück W. Defining distinct features of anti-MOG antibody associated central nervous system demyelination. Ther Adv Neurol Disord 2018;11:1756286418762083. PMID 29623106
203: West SG, Emlen W, Wener MH, Kotzin BL. Neuropsychiatric lupus erythematosus: a 10-year prospective study on the value of diagnostic tests. Am J Med 1995;99(2):153-63. PMID 7625420
204: Willison HJ, Yuki N. Peripheral neuropathies and anti-glycolipid antibodies. Brain 2002;125(Pt 12):2591-625. PMID 12429589
205: Wirtz PW, Nijnuis MG, Sotodeh M, et al. The epidemiology of myasthenia gravis, Lambert-Eaton myasthenic syndrome and their associated tumours in the northern part of the province of South Holland. J Neurol 2003;250(6):698-701. PMID 12796832
206: Xiao BG, Linington C, Link H. Antibodies to myelin-oligodendrocyte glycoprotein in cerebrospinal fluid from patients with multiple sclerosis and controls. J Neuroimmunol 1991;31(2):91-6. PMID 1991822
207: Yan WX, Archelos JJ, Hartung HP, Pollard JD. P0 protein is a target antigen in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 2001;50(3):286-92. PMID 11558784
208: Yuki N, Ho TW, Tagawa Y, et al. Autoantibodies to GM1b and GalNAc-GD1a: relationship to Campylobacter jejuni infection and acute motor axonal neuropathy in China. J Neurol Sci 1999a;164(2):134-8. PMID 10402024
209: Yuki N, Kuwabara S, Koga M, Hirata K. Acute motor axonal neuropathy and acute motor-sensory axonal neuropathy share a common immunological profile. J Neurol Sci 1999b;168(2):121-6. PMID 10526194
210: Yuki N, Taki T, Inagaki F, et al. A bacterium lipopolysaccharide that elicits Guillain-Barre syndrome has a GM1 ganglioside-like structure. J Exp Med 1993;178(5):1771-5. PMID 8228822
211: Yuki N, Yamada M, Koga M, et al. Animal model of axonal Guillain–Barré syndrome induced by sensitization with GM1 ganglioside. Ann Neurol 2001;49(6):712-20. PMID 11409422
212: Zalewski NL, Lennon VA, Lachance DH, Klein CJ, Pittock SJ, Mckeon A. P/Q- and N-type calcium-channel antibodies: oncological, neurological, and serological accompaniments. Muscle Nerve 2016;54(2):220-7. PMID 26789908

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Monica Budianu MD

Dr. Budianu of Scripps Clinic/Scripps Green Hospital has no relevant financial relationships to disclose.
See Profile
Kareena Kumar

Ms. Kumar has no relevant financial relationships to disclose.
See Profile
Phildrich Teh MD

Dr. Teh of Scripps Green Hospital has no relevant financial relationships to disclose.
See Profile
Erin Tullis MD

Dr. Tullis of Scripps Health has no relevant financial relationships to disclose.
See Profile

Editor

Anthony T Reder MD

Dr. Reder of the University of Chicago received honorariums from Genentech, Genzyme, and TG Therapeutics for service on advisory boards and as a consultant and stock options from NKMax America for advisory work and an unrestricted lab research grant from BMS.
See Profile

Former Authors

Luca Durelli MD
Rinu Abraham MD

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Autoantibodies: disease markers

Associated Disorders

Acute inflammatory demyelinating polyradiculoneuropathy
Autoimmune glial fibrillary acidic protein astrocytopathy
Cerebellar ataxia
Chronic inflammatory demyelinating polyradiculoneuropathy
Guillain-Barre syndrome
- Isaac disease
- Lambert-Eaton myasthenic syndrome
- Limbic encephalitis
- Morvan syndrome
- Multiple sclerosis
- Myasthenia gravis
- Myelin oligodendrocyte glycoprotein associated disorders
- Neuromyelitis optica spectrum disorders
- Paraneoplastic neurologic disorders
- Rasmussen encephalitis
- Stiff-person syndrome
- Systemic lupus erythematosus

Also Relevant

Acute inflammatory demyelinating polyradiculoneuropathy
Chronic inflammatory demyelinating polyradiculoneuropathy
Interferon beta 1a
Intravenous immune globulin
Lambert-Eaton myasthenic syndrome
- Motor and multifocal motor neuropathies
- Myasthenia gravis
- Neuromyotonia and myokymia
- Rasmussen syndrome
- Stiff-person syndrome

Clinical Categories

Neuroimmunology

Autoantibodies: disease markers …

Autoantibodies: disease markers

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Diseases affecting the CNS

CNS autoimmune disorders without defined antibodies

Table 1. Antibodies Associated with Multiple Sclerosis

Antibody-mediated nervous system demyelinating disorders

Diseases affecting muscles and the peripheral nervous system

Myasthenia gravis

Lambert-Eaton myasthenic syndrome

Acquired neuromyotonia or Isaac disease

Acute inflammatory demyelinating polyradiculoneuropathy or Guillain-Barré syndrome

Chronic inflammatory demyelinating polyradiculoneuropathies

Myopathies

Diseases affecting the central and peripheral nervous systems

Paraneoplastic neurologic disorders

Table 2. Antibodies Associated with Intracellular or Cytoplasmic Antigens (Onconeural Antigens)

Table 3. Antibodies Against Cell Surface or Synaptic Antigens

Morvan syndrome

Clinical applications

References

Contributors

Authors

Editor

Former Authors

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Viral and retroviral myositis

Upadacitinib

Guillain-Barre syndrome in children

Efgartigimod alfa-fcab

Efgartigimod alfa and hyaluronidase-qvfc

Ofatumumab

Neuropathies associated with cryoglobulinemia

Rheumatoid arthritis: neurologic manifestations

Autoantibodies: disease markers

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Diseases affecting the CNS

CNS autoimmune disorders without defined antibodies

Table 1. Antibodies Associated with Multiple Sclerosis

Antibody-mediated nervous system demyelinating disorders

Diseases affecting muscles and the peripheral nervous system

Myasthenia gravis

Lambert-Eaton myasthenic syndrome

Acquired neuromyotonia or Isaac disease

Acute inflammatory demyelinating polyradiculoneuropathy or Guillain-Barré syndrome

Chronic inflammatory demyelinating polyradiculoneuropathies

Myopathies

Diseases affecting the central and peripheral nervous systems

Paraneoplastic neurologic disorders

Table 2. Antibodies Associated with Intracellular or Cytoplasmic Antigens (Onconeural Antigens)

Table 3. Antibodies Against Cell Surface or Synaptic Antigens

Morvan syndrome

Clinical applications

References

Contributors

Authors

Editor

Former Authors

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Viral and retroviral myositis

Upadacitinib

Guillain-Barre syndrome in children

Efgartigimod alfa-fcab

Efgartigimod alfa and hyaluronidase-qvfc

Ofatumumab

Neuropathies associated with cryoglobulinemia

Rheumatoid arthritis: neurologic manifestations

This is an article preview.
Start a Free Account
to access the full version.