Antibody Tests for Neurologic Diseases
Number: 0340
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses antibody tests for neurologic diseases.
-
Medical Necessity
Aetna considers antibody testing for neurological diseases medically necessary for any of the following when applicable criteria are met (see Appendix for additional information):
- Myasthenia gravis (MG) when selection criteria are met:
- Acetylcholine receptor (AChR) antibody testing (binding, blocking, or modulating antibodies) when all of the following criteria are met:
- Member presents with clinical signs and symptoms consistent with MG, including fluctuating muscle weakness, ptosis, diplopia, bulbar symptoms, or generalized weakness; and
- Testing is performed as part of initial diagnostic evaluation for suspected MG; and
- Testing methodology includes radioimmunoassay (RIA) or cell-based assay (CBA); or
- Muscle-specific kinase (MuSK) antibody testing when all of the following criteria are met:
- Member has clinical presentation consistent with MG; and
- AChR antibody testing is negative; and
- Clinical suspicion for MG remains high based on symptoms, examination findings, or electrophysiological testing; or
- Striated muscle antibodies (titin, ryanodine receptor) when the following criteria are met:
- Member has confirmed AChR antibody-positive MG; and
- Has either of the following:
- Member is less than 50 years of age and computed tomography (CT) or magnetic resonance imaging (MRI) findings are indeterminate for thymoma; or
- Member is 50 to 65 years of age with late-onset MG who has an enlarged thymus by imaging and thymectomy is being considered; or
- LRP4 antibody testing when all of the following criteria are met:
- Member has clinical presentation consistent with MG; and
- Both AChR and MuSK antibody testing are negative (double-seronegative MG); and
- Testing is performed at a specialized laboratory using validated methodology; or
- Acetylcholine receptor (AChR) antibody testing (binding, blocking, or modulating antibodies) when all of the following criteria are met:
- Lambert-Eaton myasthenic syndrome (LEMS) when all the following criteria are met:
- Member presents with clinical signs and symptoms consistent with LEMS, including progressive proximal muscle weakness, hyporeflexia, and autonomic dysfunction; and
- After history, physical examination, and completion of conventional diagnostic studies (e.g., electrophysiology studies), a definitive diagnosis remains uncertain; and
- LEMS antibody test to detect antibodies to the P/Q VGCC will be used to confirm diagnosis and guide management; or
-
Paraneoplastic neurologic disorders (see Appendix for examples) when all of the following are met:
- Member displays clinical features of the paraneoplastic neurologic disease in question, and
- Testing will be phenotype-directed; and
- Test result will alter management or be used to guide therapy; and
- After history, physical examination, and completion of conventional diagnostic studies (e.g., electrophysiology studies), a definitive diagnosis remains uncertain, and one of the following antibodies is suspected:
- Anti-AChR
- Anti-mGluR5
- Anti-AMPAR
- Anti-amphiphysin
- Anti-bipolar cells of the retina
- Anti-CASPR2 (cell-based assay)
- Anti-CV2/CRMP5
- Anti-GABA receptor
- Anti-Hu (ANNA-1)
- Anti-KLHL11
- Anti-LGI1 (cell-based assay)
- Anti-Ma (MA1, MA2) (Anti-Ta)
- Anti-nAChR
- Anti-NMDA receptor
- Anti-recoverin
- Anti-Ri (ANNA-2)
- Anti-SOX1
- Anti-Tr
- Anti-VGCC (P/Q‑type voltage‑gated calcium channel antibody)
- Anti-Yo (APCA-1); or
- Immune checkpoint inhibitor–associated paraneoplastic neurologic syndromes (ICI‑PNS) when all of the following are met:
- Member is currently receiving, or has received within the prior 12 months, an immune checkpoint inhibitor (e.g., PD‑1/PD‑L1, CTLA‑4, or LAG‑3); and
- A high‑risk or intermediate-risk PNS phenotype is present (see Appendix for examples); and
- Test result will alter management or be used to guide therapy; and
- Test includes applicable paraneoplastic antibodies for the primary diagnosis; or
- Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD)
Measurement of CSF and serum MOG-IgG antibody testing for evaluation of members with clinical presentations that should raise suspicion for MOGAD. Clinical presentations that should raise suspicion include the following:
- Either unilateral or bilateral optic neuritis that involves the anterior optic pathway, and is associated with optic disc edema; or
- Acute disseminated encephalomyelitis (ADEM) or ADEM-like presentations accompanied by large, poorly demarcated T2 hyper-intense lesions in the brain and with T2 lesions within the spinal cord; or
- MOG-IgG-associated encephalomyelitis (MOG-EM); or
- Unilateral cortical encephalitis with headache, fever, seizures, encephalopathy, or other focal neurologic findings with cortical T2 hyper-intensity and swelling; or
- A complete (rather than partial) spinal cord syndrome, especially with prominent bowel, bladder, or erectile dysfunction symptoms;
-
Non-paraneoplastic neurologic disorders/diseases (for examples see Appendix) when all of the following are met:
- Member displays clinical features of the neurologic disease in question; and
- Test result will alter management or be used to guide therapy; and
- After history, physical examination, and completion of conventional diagnostic studies, a definitive diagnosis remains uncertain, and one of the following antibodies is suspected:
- Anti-AChR
- Anti-asialo-GM1
- Anti-GAD
- Anti-GD1a
- Anti-GD1b
- Anti-GM1
- Anti-GM2
- Anti-GQ1b
- Anti-GT1a
- Anti-La
- Anti-MAG
- Anti-MUSK
- Anti-Ro
- Anti-SGPG
- Anti-sulfatide
- Anti-VGCC (P/Q‑type voltage‑gated calcium channel antibody); or
-
The following antibody tests when criteria are met:
- Anti-aquaporin-4 (AQPR) antibody test for members suspected of having neuromyelitis optica spectrum disorder (NMOSD);
- Neural antibody testing (serum and cerebrospinal fluid) for autoimmune encephalitis when all of the following criteria are met (see Appendix D: Antibody Testing Panels, Testing Requirements, Frequency Limitations):
- Clinical presentation requirements
The member presents with acute or subacute onset (less than or equal to 3 months) of one or more of the following:
- Altered mental status or decreased level of consciousness; or
- Autonomic dysfunction or central hypoventilation; or
- Movement disorders (dyskinesias, rigidity, abnormal postures, chorea, dystonia, tremor, myoclonus, ataxia); or
- New-onset cognitive dysfunction or memory deficits; or
- Psychiatric symptoms (behavioral changes, psychosis, personality changes); or
- Seizures not explained by previous seizure disorder; or
- Speech dysfunction (pressured speech, verbal reduction, mutism); and
- Supportive diagnostic evidence
At least one of the following supportive findings must be present:
- Clinical syndrome consistent with limbic encephalitis, acute disseminated encephalomyelitis (ADEM), or Bickerstaff brainstem encephalitis; or
- Cerebrospinal fluid (CSF) abnormalities (pleocytosis, elevated protein, or oligoclonal bands); or
- Electroencephalogram (EEG) abnormalities (focal or diffuse slow/disorganized activity, epileptic activity, or extreme delta brush pattern); or
- MRI findings compatible with encephalitis (T2/FLAIR hyperintensities, gadolinium enhancement suggesting inflammation or demyelination); and
- The following alternative diagnoses have been excluded:
- Active infectious encephalitis (particularly herpes simplex virus, Japanese B encephalitis)
- Metabolic encephalopathy
- Toxic encephalopathy
- Hashimoto's encephalopathy
- Primary psychiatric disorder without neurological features
- Structural brain lesions explaining symptoms;
- Clinical presentation requirements
- Measurement of serum folate receptor autoantibodies (e.g., FRAT [Folate Receptor Antibody Test]) for evaluation of members with cerebral folate deficiency syndrome;
- RNA polymerase III antibody testing for diagnosis and prognostication of scleroderma (systemic sclerosis);
-
Testing for LRP4 antibodies for sero-negative individuals with an uncertain diagnosis of myasthenia gravis after electrodiagnostic testing.
- Myasthenia gravis (MG) when selection criteria are met:
-
Not Medically Necessary
The following antibody tests are considered not medically necessary:
- Antibody testing for screening purposes in asymptomatic individuals
- Antibody testing in members without clinical features of encephalitis
- Isolated VGKC (voltage-gated potassium channel) antibody testing without LGI1 and CASPR2 specificity, as VGKC positivity alone is not a clear marker of autoimmune inflammation
- Repeat testing more frequently than specified above without documented clinical justification.
-
Experimental, Investigational, or Unproven
The following tests are considered experimental, investigational, or unproven because the effectiveness of these approaches has not been established:
- Anti-HH3 and Ns6S antibody testing for the diagnosis/evaluation of amyotrophic lateral sclerosis (ALS)-motor neuron disease;
- Antibody tests for screening of neurologic diseases - these tests are only considered medically necessary when ordered selectively for evaluating members with signs and symptoms of specific immune-mediated neuromuscular conditions;
- Measurement of ΒP180 antibody levels for predicting risk for relapse of bullous pemphigoid (BP) or informing changes in therapy for BP;
- Repeat MOG testing for follow-up/monitoring of members with MOG-positive optic neuritis;
- Routine anti-neuronal antibodies testing for early (less than 3 years of age) childhood-onset epilepsy without other features of autoimmune encephalitis
- Voltage-gated potassium channel (VGKC)-complex Abs testing for the diagnosis of childhood-acquired demyelinating syndromes.
-
Related Policies
Background
Antibody testing has become an important adjunct in the evaluation of select neurologic disorders, particularly those with suspected autoimmune or paraneoplastic etiologies. These assays are designed to detect pathogenic or disease-associated antibodies directed against neuronal cell surface, synaptic, or intracellular antigens, which may help support a specific diagnosis, guide further diagnostic evaluation, and inform treatment decisions. Antibody results must be interpreted in the appropriate clinical context, including symptomatology, neuroimaging, electrophysiologic findings, and cerebrospinal fluid analysis, as antibody presence alone does not establish disease causality or severity. Consequently, antibody testing is generally used as a complementary tool rather than a stand‑alone diagnostic modality, and its clinical utility varies by condition, antibody target, and testing methodology.
Autoantibodies to nervous system components have been detected in patients with neurologic symptoms such as paresthesia, weakness, and twitching. Many autoantibodies have been discovered and characterized; however, research is ongoing in the field of neuroimmunology and there remains a paucity of clinical trials in the peer-reviewed medical literature describing their usefulness in clinical practice. In a review on the use of autoantibodies as predictors of disease, Scofield (2004) stated that long-term large studies of outcome are needed to assess the use of assaying autoantibodies for prediction of disease. A review of laboratory testing in peripheral nerve disease indicated that the use of antibody assays should be very selective and should not be used as "screening" studies. Antibody testing often produces results that can be confusing; thus, a stepwise and directed approach to the evaluation of peripheral neuropathy utilizing clinical examination and electrodiagnostic testing can increase the yield of finding a treatable cause (Chang, 2002).
Antibodies Associated with Paraneoplastic Syndromes and Associated Cancers (See Appendix for Examples)
Paraneoplastic neurologic syndromes are a heterogeneous group of neurologic disorders associated with systemic cancer and caused by mechanisms other than metastases, metabolic and nutritional deficits, infections, coagulopathy, or side effects of cancer treatment. These syndromes may affect any part of the nervous system, from the cerebral cortex to the neuromuscular junction and muscle, either damaging one area or multiple areas. Although a pathogenic role of paraneoplastic antibodies has not been proven, their presence indicates the paraneoplastic nature of a neurologic disorder, and in many cases, can narrow the search for an occult tumor to a few organs.
Polyclonal immunoglobulin G (IgG) anti-Hu antibodies (previously called ANNA-1) are found predominantly in patients with paraneoplastic neurologic syndromes associated with small-cell carcinoma of the lung. Anti-Hu antibodies are also expressed in most neuroblastomas and occasional other tumors (including several types of sarcoma and prostate carcinoma). Anti-Hu antibody reacts with 35- to 42-kD proteins present in the nuclei and cytoplasm of virtually all neurons. The role of Hu proteins in small-cell lung cancer and the other cancers in which they are expressed is unclear (Mehdi and Ko, 2002). Some investigators have argued that detection of anti-Hu antibody is important to determine whether a paraneoplastic syndrome is immune-mediated and thus, in theory, amenable to immunosuppressive therapy (Santacroce et al., 2002; Senties-Madrid and Vega-Boada, 2001). However, the value of immunosuppressive therapy in antibody-associated paraneoplastic syndromes has not been proven in clinical studies. Although the titer of anti-Hu antibodies has been suggested as a prognostic indicator of paraneoplastic neurologic syndromes, the clinical course of these syndromes is unpredictable (Liebeskind, 2001).
Paraneoplastic limbic encephalitis (PLE) is a rare disorder characterized by personality changes, irritability, depression, seizures, memory loss, and sometimes dementia. The diagnosis is difficult because clinical markers are often lacking, and symptoms usually precede the diagnosis of cancer or mimic other complications. Limbic encephalitis may be associated with voltage-gated potassium channel antibodies (VGKC) (53%). However, responsiveness to treatment is not limited to patients with VGKC antibodies (Bataller, 2007). Other paraneoplastic encephalomyelitis antibodies include anti-CV2, anti-Ma1, anti-Ma2 (anti-Ta, anti-MaTa), and several other atypical antibodies. The targets of such antibodies may be quite varied, including neuropil and intraneuronal sites. Testicular cancer is associated with anti-Ma2 antibodies. The Ma2 antigen is selectively expressed in neurons and the testicular tumor. Ma2 shares homology with Ma1, a gene that is associated with other paraneoplastic neurologic syndromes, particularly brainstem and cerebellar dysfunction. Treatment of the tumor is reported to have more effect on neurologic outcome than the use of immune modulation (Gultekin, 2000).
The diagnosis of Lambert-Eaton myasthenic syndrome (LEMS) is usually made on clinical grounds and confirmed by electrodiagnostic studies. A serum test for voltage-gated calcium channel antibodies (VGCC) is commercially available. Treatment involves removing the cancer associated with the disease. If cancer is not found, immunosuppressive medications and acetylcholinesterase inhibitors are used with moderate success. Patients with idiopathic LEMS should be screened every six months with chest imaging for cancer (Mareska, 2004).
Anti-Yo antibodies (also called Purkinje cell antibody type 1 or PCA-1) primarily occur in patients with paraneoplastic cerebellar degeneration (PCD) who have breast cancer or tumors of the ovary, endometrium, and fallopian tube. The target antigens of anti-Yo antibodies are the cdr proteins that are expressed by Purkinje cells and ovarian and breast cancers. A cytotoxic T cell response against cdr2 has also been identified in these patients.
Anti-CV2 antibodies, directed against a cytoplasmic antigen in some glial cells and against peripheral nerve antigens, have been associated with several syndromes, including cerebellar degeneration, limbic encephalitis, encephalomyelitis, peripheral neuropathy, and optic neuritis. The most common tumors are SCLC, thymoma, and uterine sarcoma.
Opsoclonus is a disorder of ocular motility characterized by spontaneous, arrhythmic, conjugate saccades occurring in all directions of gaze without a saccadic interval. Although opsoclonus can be paraneoplastic in origin, it can also result from viral infections, post-streptococcal pharyngitis, metabolic disorders, metastases, and intracranial hemorrhage. The most frequent tumor associated with opsoclonus myoclonus in adults is small cell lung cancer. In women, however, the detection of anti-Ri (anti-neuronal nuclear autoantibody type 2, or ANNA-2) usually indicates the presence of breast cancer, although other tumors have been reported (e.g., gynecologic, lung, bladder). The target antigens of anti-Ri antibodies are the Nova proteins.
In a cross-sectional study, Pranzatelli et al. (2002) examined paraneoplastic antibodies in 59 children with opsoclonus-myoclonus-ataxia; 86% of them were moderately or severely symptomatic, and 68% of them had relapsed at the time of testing. This total number of patients includes 18 children with low-stage neuroblastoma (tested after tumor resection); six of them had never been treated with immunosuppressants. All were sero-negative for anti-Hu, anti-Ri (IgG autoantibody ANNA-2), and anti-Yo (antibodies against a Purkinje cell cytoplasmic antigen, called Yo), the three paraneoplastic antibodies most associated with opsoclonus-myoclonus or ataxia in adults. The findings of this study suggested that anti-Hu, anti-Ri, and anti-Yo do not explain relapses in pediatric opsoclonus-myoclonus-ataxia.
Paraneoplastic optic neuritis has been described in a few reports, usually in association with paraneoplastic encephalomyelitis or retinitis and small cell lung cancer. Some of these patients harbor antibodies to the 62 kDa collapsin-responsive mediator protein-5 (CRMP-5, also called anti-CV2). However, the small number of patients, the extensive number of accompanying symptoms, and the frequent co-occurrence of other antibodies suggest low specificity and sensitivity of CRMP-5 antibodies as markers of paraneoplastic optic neuritis or retinitis associated with small cell lung cancer.
Anti-Ro/SSA and anti-La/SSB antibodies, which are directed against two extractable nuclear antigens, have been detected with high frequency in patients with Sjögren's syndrome. They also have diagnostic usefulness in patients with SLE. Indications for ordering an anti-Ro/SSA antibody test include: women with SLE who have become pregnant; women who have a history of giving birth to a child with heart block or myocarditis; patients with a history of unexplained photosensitive skin eruptions; patients suspected of having a systemic connective tissue disease in whom the screening ANA test is negative; patients with symptoms of xerostomia, keratoconjunctivitis sicca, and/or salivary and lacrimal gland enlargement; and patients with unexplained small vessel vasculitis or atypical multiple sclerosis.
Retinal antibodies have been associated with small cell carcinoma of the lung (Tidy, 2007).
In patients with neurologic symptoms of unknown cause, detection of Zic4 antibodies has been associated with cerebellar degeneration and small-cell lung cancer (SCLC) and often associates with anti-Hu or CRMP-5 antibodies (Bataller, 2004). However, there is insufficient evidence on the clinical usefulness of measuring Zic4 antibodies in the peer-reviewed medical literature.
In a retrospective study conducted by Paterson et al. (2014), the clinical significance of positive voltage-gated potassium channel (VGKC)-complex antibodies was evaluated, as these antibodies can be linked to various immunotherapy-responsive conditions such as limbic encephalitis, Morvan's syndrome, and acquired neuromyotonia, though their significance remains uncertain in some patients. Over four years, 1,053 samples were tested, with 55 returning positive results; the clinical presentations, final diagnoses, and responses to any administered immunotherapies were analyzed, categorizing the likelihood of autoimmunity as definite, possible, unlikely, or undetermined (modified from Zuliani et al. 2012). Among the 32 patients with low-positive levels (100-400 pM), only 4 were deemed definitely autoimmune, with 3 exhibiting peripheral nerve hyperexcitability and 1 having a thymoma; 3 received immunotherapies. Of the remaining 28 low-positive patients, 13 were classified as possibly autoimmune (3 with tumors), while 15 were considered unlikely or undetermined, with only 1 receiving unsuccessful immunotherapy. In contrast, of the 23 patients with high-positive levels (>400 pM), 12 were treated with immunotherapies, 11 of whom responded well; 11 were classified as definitely autoimmune (10 with limbic encephalitis and 1 with a tumor), while the remaining 12 were categorized as possibly (n=9) or unlikely (n=3) autoimmune, with many not having received immunotherapies. The findings underscore the importance of assessing the clinical relevance of VGKC-complex antibodies, particularly those in the 100-400 pM range, which were associated with rare conditions and tumors, while high-positive levels were more frequently linked to definite or possible clinical relevance, despite not all patients presenting with classical limbic encephalitis or receiving immunotherapy.
van Sonderen et al. (2016) highlight that a diverse range of clinical syndromes has been linked to antibodies against voltage-gated potassium channels (VGKCs). However, 6 years ago, it was revealed that these patients do not actually possess antibodies to the potassium channels themselves, but rather to associated proteins, leading to the identification of 3 distinct VGKC-positive subgroups — those with anti-leucine-rich glioma-inactivated 1 (LGI1) antibodies, those with anti-contactin-associated protein like-2 (Caspr2) antibodies, and VGKC-positive patients who lack both types of antibodies. Patients with LGI1 antibodies typically present with limbic encephalitis, often accompanied by hyponatremia, and about half experience characteristic faciobrachial dystonic seizures. In contrast, Caspr2 antibodies are associated with a more variable syndrome affecting the peripheral or central nervous system, predominantly in older males. Immunotherapy appears to be beneficial for patients with LGI1 or Caspr2 antibodies, underscoring the importance of early diagnosis. Notably, half of VGKC-positive patients do not have antibodies to either LGI1 or Caspr2, representing a heterogeneous group with various clinical syndromes, which raises questions about the true significance of VGKC positivity in these cases. Data regarding this issue are limited, but a recent study found no clinical relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Given the essential differences among the 3 VGKC-positive subgroups, the term "VGKC-complex antibodies" should be reconsidered and potentially discarded.
Michael et al. (2020) state that autoantibodies to LGI1 and CASPR2 are associated with clinically distinctive syndromes that are highly immunotherapy responsive, such as limbic encephalitis, faciobrachial dystonic seizures, Morvan's syndrome and neuromyotonia. These autoantibodies target surface-exposed domains of LGI1 or CASPR2, and appear to be directly pathogenic. In contrast, VGKC antibodies that lack LGI1 or CASPR2 reactivities (double-negative) are common in healthy controls and have no consistent associations with distinct syndromes. The authors state that these antibodies target intracellular epitopes and lack pathogenic potential. Moreover, the clinically important LGI1 and CASPR2 antibodies comprise only approximately 15% of VGKC-positive results, meaning that most VGKC-antibody positive results mislead rather than help. Further, initial VGKC testing misses some cases that have LGI1 and CASPR2 antibodies. The authors conclude that these collective observations confirm that laboratories should stop testing for VGKC antibodies and instead, test only for LGI1 and CASPR2 antibodies, and that this change in practice will lead to significant patient benefit.
Graus et al. (2021) present updated diagnostic criteria for paraneoplastic neurologic syndromes (PNS), developed by an international panel of 14 neurologists with expertise in PNS from 8 countries. These revised criteria incorporate new phenotypes and immune-mediated pathogenic mechanisms identified since 2004, emphasizing a causal relationship with cancer rather than a mere chronological one, and necessitating the detection of neuronal antibodies using gold standard techniques, excluding VGKC antibodies. The panel notes that cell surface antibodies, such as LGI1 and CASPR2, are linked to nonparaneoplastic forms of limbic encephalitis, yet due to the existence of various LE variants that are frequently associated with cancer, this condition remains classified as a high-risk phenotype. This classification is important because the neurologic presentations of paraneoplastic and nonparaneoplastic cases can be indistinguishable, and certain antibodies can manifest as paraneoplastic LE in over 50% of cases. While onconeural antibodies like anti-Hu and anti-Ma2 are typically found in adults with underlying cancer, Hu antibodies are rarely detected in children with LE and usually do not correlate with cancer. Morvan syndrome is predominantly associated with CASPR2 antibodies, sometimes alongside LGI1 and netrin 1 receptor antibodies. Although PNS can be diagnosed without neuronal antibody testing in certain cases, the identification of neuronal antibodies is invaluable for PNS diagnosis, serving as critical biomarkers. Gold standard detection methods include rodent brain tissue immunohistochemistry/immunofluorescence and confirmatory studies using immunoblotting with recombinant proteins or cell-based assays. However, brain immunohistochemistry is ineffective for two antibodies, and the utility of tissue immunohistochemistry for SOX1 antibodies remains unclear. Sensitivity and specificity for serum or CSF analysis vary among antibodies, so testing both samples is recommended. Laboratory studies using serum-only cell-based assays may yield false-positive and false-negative results, making CSF screening essential for suspected autoimmune or paraneoplastic encephalitis associated with neuronal surface antigens. Patients with neuronal surface antibodies detected only in serum should undergo further examination in research laboratories or confirmatory tissue immunohistochemistry/immunofluorescence before a definitive diagnosis is made. However, some antibodies, like those against LGI1, are more reliably detected in serum than in CSF. Despite the recommended gold standard techniques, few laboratories utilize both methods, and several antibodies related to rapidly progressive cerebellar syndrome remain poorly characterized due to limited studies or isolated case reports. Further research involving larger cohorts is necessary to validate the clinical and oncologic associations of these new antibodies, with input from research laboratories to enhance diagnostic accuracy. The panel acknowledges that the proposed criteria may underestimate PNS cases without neuronal antibodies, but the use of these biomarkers ensures diagnostic certainty and facilitates sample homogenization for research. According to the new criteria, a diagnosis of definite PNS requires the presence of a high- or intermediate-risk phenotype, a corresponding high- or intermediate-risk antibody, and the presence of cancer, which is essential for defining definite PNS. If the cancer is atypical for the antibody type, demonstrating antigen expression by the tumor is necessary for a definite diagnosis.
The PNS-Care score (Graus et al., 2021) is an evidence-based scoring system that may be used by neurologists to diagnose paraneoplastic neurologic syndromes (PNS). It assigns points based on clinical phenotype, antibody type, and cancer presence to classify the likelihood of PNS as "Definite ≥ 8", "Probable 6-7", "Possible 4-5", and "Non-PNS ≤ 3".
"Antibodies against P/Q type voltage-gated calcium channels (VGCCs) are present in nearly 90% of the patients, although their detection is not needed for the diagnosis. These antibodies occur similarly in the paraneoplastic and nonparaneoplastic forms of the disease. Conversely, antiglial nuclear antibodies (or SOX1 antibodies) are strongly associated with SCLC or paraneoplastic syndromes associated with SCLC; therefore, their detection in patients with LEMS strongly suggests the presence of an underlying SCLC" (Graus et al., 2021).
Antibodies to Glycolipid and Glycoprotein-Related Saccharides (See Appendix for Examples)
- G refers to ganglio;
- M, D, T, and Q refer to the number of sialic acid residues (mono, di, tri, and quad); and
- numbers and lower case letters refer to the sequence of migration on thin layer chromatography.
The gangliosides most commonly recognized by neuropathy associated autoantibodies are GM1, asialo-GM1, GD1a, GD1b, and GQ1b.
Chronic immune-mediated polyneuropathies in which the peripheral nerves are selectively affected include chronic inflammatory demyelinating polyneuropathy (CIDP), demyelinating polyneuropathy associated with IgM anti-myelin-associated glycoprotein (anti-MAG) antibodies or anti-sulfoglucuronyl paragloboside (anti-SGPG) antibodies, multifocal motor neuropathy associated with IgM anti-ganglioside M1 (anti-GM1) or anti-GD1a antibodies, and sensory polyneuropathy associated with IgM anti-sulfatide antibodies or anti-GD1b or disialosyl ganglioside antibodies. Some of these autoantibodies also occur as IgM monoclonal gammopathies in patients with non-malignant monoclonal gammopathies.
Detection of ganglioside M1 (GM1) antibody, usually of the IgM isotype, is associated with multifocal motor neuropathy and lower motor neuropathy, characterized by muscle weakness and atrophy. Multifocal motor neuropathy may occur with or without high serum titers of anti-GM1 antibodies. GM1 antibodies are detected in approximately 50% of persons with multifocal motor neuropathy (Tidy, 2007). However, whether the presence of anti-GM1 antibody or its titer has any bearing on the response to therapy is controversial (Sridharan and Lorenzo, 2002).
GM1 antibodies of the IgG and IgA isotypes may be found in association with amyotrophic lateral sclerosis (ALS). European Federation of Neurological Societies (EFNS) guidelines (2006) on amyotrophic lateral sclerosis recommend testing for anti-GM1, as well as anti-MAG and anti-Hu antibodies (see below) in selected cases.
Ganglioside glycolipid antibodies may be associated with different forms or aspects of Guillain-Barré Syndrome (GBS). Increased titers of IgG anti-GM1 or GD1a ganglioside antibodies have been associated with GBS and acute motor axonal neuropathy and may be useful in persons suspected of having these syndromes. Antibodies to GM1 and GD1a are mostly associated with axonal variants of GBS. Antibodies to GT1a are associated with swallowing dysfunction. The GD1b ganglioside is present in peripheral nerves on the surface of sensory neurons in the dorsal root ganglion. Antibodies to GD1b are associated with pure sensory GBS.
Increased IgG anti-GQ1b ganglioside antibodies are closely associated with the Miller-Fisher syndrome and may be useful in the evaluation of patients suspected of having this syndrome. Antibodies against GQ1b are found in 85% to 90% of patients with the Miller-Fisher syndrome, characterized by ataxia, areflexia, and ophthalmoplegia. In clinical practice, commercially available testing for serum IgG antibodies to GQ1b is useful for the diagnosis of Miller-Fisher syndrome, having a sensitivity of 85% to 90%. GQ1b antibodies are also found in GBS patients with ophthalmoplegia, but not in GBS patients without ophthalmoplegia. Antibodies to GQ1b may also be present in Bickerstaff encephalitis and the pharyngo-cervical brachial GBS variant, but not in disorders other than GBS.
Myelin-associated glycoprotein (MAG) is a constituent of peripheral and central nervous system myelin. High titer IgM antibodies to MAG are associated with sensorimotor demyelinating peripheral neuropathy and are associated with multiple sclerosis, myasthenia gravis, and systemic lupus erythematosus (SLE) (Tidy, 2007).
Antibodies recognizing MAG react with a carbohydrate determinant that is also present on SGPG. Initial assays for MAG antibody utilized SGPG as the target antigen. However, some laboratories now perform two separate enzyme-linked immunosorbent assay (ELISA) procedures, one utilizing SGPG as antigen and one utilizing the entire MAG as antigen, to maximize detection of MAG antibodies. Researchers are currently examining the cross-reacted relationship of IgM binding to both SGPG and MAG and their significance in neuropathy (Garces-Sanchez, 2008).
MAG antibodies are usually associated with the presence of an IgM monoclonal protein; approximately 50% of patients with IgM monoclonal gammopathies and associated peripheral neuropathies have detectable MAG antibodies. Detection of MAG antibodies may be useful in paraprotein demyelinating neuropathies. EFNS guidelines (2006) state that a causal relationship between a paraprotein and a demyelinating neuropathy is highly probable if there is an immunoglobulin M (IgM) paraprotein (monoclonal gammopathy of uncertain significance [MGUS] or Waldenström's) and there are high titers of anti-MAG or anti-GQ1b antibodies. A causal relationship is probable in persons with IgM paraprotein (MGUS or Waldenström's) with high titers of IgM antibodies to other neural antigens (GM1, GD1a, GD1b, GM2, sulfatide) and slowly progressive predominantly distal symmetrical sensory neuropathy.
Guidelines from the British Society of Haematology recommend testing for anti-MAG in persons with Waldenström's macroglobulinemia who present with neurological symptoms (Johnson et al., 2005).
High titers of antibodies to the ganglioside asialo GM1 (anti-GA1) have been associated with motor or sensorimotor neuropathies. In most cases, these antibodies cross-react with the structurally related glycolipids GM1 and GD1b, although specific anti-asialo GM1 antibodies have also been reported (Lopez, 2006). Some individuals with proximal lower motor neuron syndromes (P-LMN) (30%) have selective serum antibody binding to asialo-GM1 ganglioside; however, there is no evidence that P-LMN syndromes respond to immunosuppressive treatment.
Antibodies to Myelin Oligodendrocyte Glycoprotein (MOG)
Mariotto and colleagues (2019) determined the diagnostic relevance of myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) in CSF of sero-negative cases by retrospectively analyzing consecutive time-matched CSF of 80 MOG-Ab-seronegative patients with demyelinating disease. The cohort included 44 patients with neuromyelitis optica spectrum disorders (NMOSD) and related disorders and 36 patients with MS. Two independent neurologists blinded to diagnosis analyzed MOG-Abs by live cell-based immunofluorescence assay with goat anti-human immunoglobulin (Ig) G (whole molecule) antibody. Sera were tested at dilutions of 1:20 and 1:40, and a cut-off of 1:160 was considered for serum positivity. CSF specimens were tested undiluted and at 1:2 dilution with further titrations in case of positivity. Anti-IgG-Fc and anti-IgM-µ secondary antibodies were used to confirm the exclusive presence of MOG-IgG in positive cases. CSF of 13 MOG-Abs sero-positive cases and 36 patients with neurodegenerative conditions was analyzed as controls. A total of 3 sero-negative cases had CSF MOG-Abs (4% of the whole cohort or 7% of cases excluding patients with MS, in which MOG-Abs appeared to lack diagnostic relevance). In particular, 2 patients with neuromyelitis optica spectrum disorder (NMOSD) and 1 with acute disseminated encephalomyelitis had MOG-Abs in CSF. Analysis with anti-IgG-Fc and anti-IgM confirmed the exclusive presence of MOG-IgG in the CSF of these patients. Among the control group, MOG-Abs were detectable in the CSF of 8 of 13 MOG-Ab-sero-positive cases and in none of the patients with neurodegenerative disorders. The authors concluded that although serum is the optimal specimen for MOG-Ab testing, analyzing CSF could improve diagnostic sensitivity in sero-negative patients. These researchers stated that this observation has relevant diagnostic impact and might provide novel insight into the biological mechanisms of MOG-Ab synthesis. These findings suggested that CSF testing could be useful in patients with negative serum MOG-Abs if the clinical features are highly suggestive. These researchers stated that larger systematic studies are needed to determine the relevance of restricted CSF MOG-Abs and whether MOG-specific CSF antibodies reflect a distinct phenotype.
In an editorial that accompanied the aforementioned study, Waters and Vincent (2019) noted that “The findings in this report raise questions. Would the results have been the same if patients were tested earlier in the disease course? Could there be a different etiologic basis for CSF-positive/serum-negative patients? Other aspects of MOG-IgG-associated disease require answers, some of which are now priorities. For how long do we treat MOG-IgG-positive patients? Do we treat children in a fashion similar to the way we treat adults? How can we predict relapsing patients? Currently, we capture relapsing patients but cannot predict relapses; perhaps CSF evaluation at first episode will take us a step closer. Further prospective studies in pediatric and adult cohorts are a priority.”
Yazbeck et al. (2021) report that acquired demyelinating syndromes (ADS) are often linked to myelin oligodendrocyte glycoprotein (MOG) antibodies in children, with clinical phenotypes varying widely, which can complicate diagnosis, particularly when relapses are atypical and resemble conditions like multiple sclerosis or neuromyelitis optica spectrum disorders. The authors present two cases — one child who experienced progressive cognitive and behavioral decline with seizures following a single relapse, the other exhibited similar impairments with multiple relapses. Brain magnetic resonance imaging (MRI) in both patients revealed progressive leukodystrophy-like lesions characterized by diffuse bilateral white matter damage. Cerebrospinal fluid (CSF) analysis indicated pleocytosis and elevated protein levels without the presence of oligoclonal bands, and all metabolic and inflammatory blood markers were negative. A brain biopsy in the second child showed nonspecific inflammatory lesions without evidence of histiocytosis or tumors. Both patients achieved clinical and radiological stabilization following active immunotherapy. Retrospective analysis revealed that anti-MOG antibodies were positive in the early stages of the disease but became negative after treatment and during follow-up. The findings suggest that leukodystrophy-like ADS associated with anti-MOG antibodies may present a distinct progressive phenotype and carry a severe neurological prognosis, highlighting the importance of early diagnosis and appropriate treatment to improve outcomes in affected children.
Ambrosius et al. (2020) describe myelin oligodendrocyte glycoprotein (MOG)-associated disease (MOGAD) as a rare, antibody-mediated inflammatory demyelinating disorder of the central nervous system (CNS) that presents in various forms, including optic neuritis, transverse myelitis, acute demyelinating encephalomyelitis (ADEM), and cortical encephalitis. Although its clinical presentation can sometimes resemble that of neuromyelitis optica spectrum disorder (NMOSD), most experts regard MOGAD as a distinct condition with a different underlying immune pathology. MOG is a molecule found on the outer membrane of myelin sheaths, primarily expressed in the brain, spinal cord, and optic nerves. Though its exact function remains unclear, it may serve as a cell surface receptor or adhesion molecule. The unique positioning of myelin makes it susceptible to autoimmune antibodies and cell-mediated responses during demyelination. In adults, optic neuritis is the most common initial phenotype, while ADEM is more prevalent in children. Various research groups have identified serum anti-MOG antibodies using optimized cell-based assays, particularly in patients with phenotypes such as ADEM, brainstem or cortical encephalitis, optic neuritis (unilateral or bilateral), transverse myelitis, and longitudinally extensive transverse myelitis. Accurate diagnosis relies on the detection of pathogenic serum MOG antibodies through specific and sensitive methods, ideally using optimized cell-based assays (CBA). MRI imaging can also aid in distinguishing MOGAD from other neuro-inflammatory disorders. Although reports from randomized controlled trials are limited, observational studies suggest that high-dose steroids and plasma exchange may be effective for treating acute attacks, while immunosuppressive therapies, including steroids, oral immunosuppressants, and rituximab, may be beneficial for maintenance treatment.
Chen and Bhatti (2020) reviewed the clinical characteristics, radiological manifestations, and treatment of myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G (IgG) optic neuritis (ON). These investigators noted that serum antibodies to MOG have recently been found to be a biomarker of MOG-IgG-associated disorder (MOGAD), a demyelinating disease distinct from both MS and aquaporin-4-IgG NMOSD (AQP4-IgG-positive NMOSD). The phenotype of MOGAD is broad and includes ON, TM, and ADEM. Optic neuritis is the most common presentation in adults, whereas ADEM is the most common presentation in children. Clinical characteristics suggestive of MOG-IgG ON include recurrent ON, prominent disc edema, and perineural enhancement of the optic nerve on MRI. Although the nadir of vision loss is severe with MOG-IgG ON, the recovery is typically better than AQP4-IgG ON and thus has a favorable overall prognosis. Patients with relapsing disease will often need chronic immunotherapy. Rituximab, azathioprine, mycophenolate mofetil, and monthly intravenous immune globulin (IVIG) are the most commonly used treatments. The authors concluded that MOGAD is a unique entity that is separate from both MS and AQP4-IgG-positive NMOSD. These investigators stated that recognition of the clinical and radiologic features allowed for the correct diagnosis.
Wendel et al. (2022) stated that the spectrum of MOGAD comprises monophasic diseases such as ADEM, ON, and TM, as well as relapsing courses of these presentations. Persistently high MOG antibodies (MOG immunoglobulin G [IgG]) are found in patients with a relapsing disease course. Prognostic factors to determine the clinical course of children with a 1st MOGAD are still lacking. In a prospective, hospital-based, multi-center study, these researchers examined the clinical and laboratory prognostic parameters for a risk of relapse and the temporal dynamics of MOG-IgG titers in children with MOGAD in correlation with clinical presentation and disease course. This trial included children with a 1st demyelinating attack and a complete data set comprising clinical and radiologic findings, MOG-IgG titer at onset, and clinical and serologic follow-up data. Serum samples were analyzed by live cell-based assay, and a titer level of 1:160 or higher was classified as MOG-IgG-positive. A total of 116 children (female/male = 57/59) with MOGAD were included, and initially diagnosed with ADEM (n = 59), unilateral ON (n = 12), bilateral ON (n = 16), myelitis (n = 6), NMOSD (n = 8), or encephalitis (n = 6). The median follow-up time was 3 years in monophasic, and 5 years in relapsing patients. There was no significant association between disease course and MOG-IgG titers at onset, sex, age at presentation, or clinical phenotype. Sero-conversion to MOG-IgG-negative within 2 years of the initial event showed a significant risk reduction for a relapsing disease course. 42/116 patients (monophasic n = 26, relapsing n = 16) had serial MOG-IgG testing in years 1 and 2 after the initial event. In contrast to relapsing patients, monophasic patients showed a significant decrease of MOG-IgG titers during the 1st and 2nd years, often with sero-conversion to negative titers. During the follow-up, MOG-IgG titers were persistently higher in relapsing than in monophasic patients. Decrease in MOG-IgG of 3 or higher dilution steps after the 1st and 2nd years was shown to be associated with a decreased risk of relapses. In this cohort, no patient experienced a relapse after sero-conversion to MOG-IgG-negative. The authors concluded that in this study, patients with declining MOG-IgG titers, especially those with sero-conversion to MOG-IgG-negative, are shown to have a significantly reduced relapse risk.
Xu et al. (2023) stated that MOGAD has gained recognition in recent years as an immune-mediated inflammatory demyelinating disease of the CNS. The clinical features and prognosis of MOGAD adult cerebral cortical encephalitis (adult CCE) have not been fully elucidated. These investigators characterized the clinical symptoms, MRI findings, and prognosis of CCE with anti-MOG antibody. They presented 2 adult cases of CCE with anti-MOG antibody and summarized the clinical symptoms, MRI findings, and prognosis of this phenotype via a completed systematic review of the literature. These researchers found a total of 39 cases of MOGAD adult CCE (36% women; average age of onset of 29 years). Among them, 85% had seizures, 82% had headaches, 64% had cortical symptoms, 64% had fever, 54% had changes of consciousness, and 38% had ocular symptoms. All cases showed cerebral cortical T2 fluid-attenuated inversion recovery (FLAIR) lesions on MRI. Of the 25 patients (with seizure or not) who had EEG reports, 76% of patients showed abnormal EEG; CSF white blood cell count of 90% of patients and CSF total protein of 67% of patients were elevated. In 16 patients with available CSF cytology data, 11 (69%) had abnormal cytology findings with monocytic predominance. In the 15 cases for which MOG antibody IgG was tested in both serum and CSF, 14 (93%) revealed a higher positive MOG IgG titer in serum than CSF. The majority of patients were treated with immunosuppressive therapy (97% corticosteroids, 15% mycophenolate mofetil, 13% IVIG, 5% azathioprine, and 5% other). The majority of patients had a favorable prognosis following treatment, as indexed by improved clinical symptoms and imaging; 2 patients relapsed. The authors concluded that the clinical presentation and prognosis of adult CCE remain less understood in comparison to more common MOGAD phenotypes. These investigators noted that it is important to consider MOGAD as an underlying etiology for adult CCE, as early detection and immunotherapy may improve outcomes.
Banwell et al. (2023) noted that serum antibodies directed against MOG are found in patients with acquired CNS demyelinating syndromes that are distinct from MS and AQP4-IgG-positive NMOSD. Based on an extensive literature review and a structured consensus process, these investigators proposed diagnostic criteria for MOGAD in which the presence of MOG-IgG is a core criterion. According to the proposed criteria, MOGAD is typically associated with ADEM, ON, or TM, and is less commonly associated with CCE, brainstem presentations, or cerebellar presentations. MOGAD can present as either a monophasic or relapsing disease course, and MOG-IgG cell-based assays are important for diagnostic accuracy. Diagnoses such as MS need to be excluded, but not all patients with MS should undergo screening for MOG-IgG.
In an UpToDate review titled “Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis”, Flanagan and Tillema (2024) highlight several clinical presentations that should raise suspicion for MOGAD. These include bilateral optic neuritis involving the anterior optic pathway, accompanied by optic disc edema; acute disseminated encephalomyelitis (ADEM) or ADEM-like presentations characterized by large, poorly demarcated T2 hyperintense lesions in the brain and T2 lesions in the spinal cord; unilateral cortical encephalitis presenting with headache, fever, seizures, encephalopathy, or other focal neurological signs, along with cortical T2 hyperintensity and swelling; and a complete spinal cord syndrome, particularly when prominent bowel, bladder, or erectile dysfunction symptoms are present. Serum MOG-IgG antibodies are tested using a cell-based assay, which is indicated for patients exhibiting characteristic clinical, MRI, and laboratory features of MOGAD, as well as those with a CNS demyelinating syndrome that is atypical for multiple sclerosis (MS). Clinical judgment is essential when selecting patients for MOG-IgG testing and interpreting positive results, as false positives can occur. It is not recommended to uniformly test for MOG-IgG in patients who present with clinical features and MRI findings typical of MS.
Antibody Tests for Screening of Neurologic Diseases
Tebo and colleagues (2016) noted that significant progress has been made in understanding the role and diversity of autoantibodies in the pathogenesis, diagnosis and management of paraneoplastic syndrome (PNS) and related autoimmune neurologic diseases. These investigators evaluated the positivity rates for diverse autoantibody panels to rationalize testing strategies and utilization. The result patterns for different autoantibody panels for PNS offered at 2 reference laboratories in the U.S. were retrospectively reviewed for the same period. The positivity rates were evaluated and compared for specific autoantibodies within panels offered at both laboratories. For the Hu, Ri, Yo, and amphiphysin antibodies offered by both laboratories, no significant difference in positivity rates was observed. The positivity rates for non-classic PNS markers were 0% [AGNA and PCCA-Tr], and 0.06% [ANNA-3 and PCAC-2] while the prevalence of antibodies associated with neuromuscular autoimmunity varied from 1.40% to 4.44% [Striated muscle, AChR binding, ganglionic AChR, VGCC, P/Q- and N-type VGCC]. The authors concluded that these data suggested that test utilization could be substantially improved based on ordering practice geared towards clinical manifestations and prevalence of autoantibodies. Moreover, they stated that concerted efforts towards streamlining diagnostic algorithms based on risk, clinical manifestations, characterization of autoantibodies and their associations as well as therapeutic strategies are needed.
Anti-HH3 and Ns6S Antibody Testing for Amyotrophic Lateral Sclerosis (ALS)-Motor Neuron Disease
Pestronk et al. (2010) noted that serum IgM binding to GM1 ganglioside (GM1) is often associated with chronic acquired motor neuropathies. These researchers compared the frequency and clinical associations of serum IgM binding to a different antigen, a disulphated heparin disaccharide (NS6S), with the results of IgM binding to GM1. They retrospectively analyzed serums and clinical features from 75 patients with motor neuropathies and 134 controls with amyotrophic lateral sclerosis (ALS), chronic immune demyelinating polyneuropathy (CIDP), and sensory neuropathies. Clinical correlations of positive IgM anti-GM1 testing found in 27 of 2,113 unselected serums were also reviewed. Serum testing for IgM binding to NS6S and GM1 utilized covalent antigen linkage to ELISA plates. High-titer IgM binding to NS6S and GM1 each occurred in 43% of motor neuropathy patients, and binding to one of the two was found in 64% of these patients. Motor neuropathy syndromes were present in 25 of the 27 patients with high-titer serum IgM binding to GM1 in the unselected serums. IgM anti-GM1 or NS6S antibody-related motor neuropathy syndromes typically present with asymmetric, predominantly distal, upper extremity weakness. The authors concluded that IgM binding to the NS6S disaccharide was associated with motor neuropathy syndromes and occurred with a frequency similar to that of IgM binding to GM1. Testing for IgM binding to NS6S, in addition to GM1, increased the frequency of finding IgM autoantibodies in motor neuropathies from 43% to 64%. High titers of serum IgM binding to GM1, tested with covalent ELISA methodology, had 93% specificity for motor neuropathy syndromes. High titers of serum IgM binding to NS6S also demonstrated specificity for immune motor neuropathies compared with ALS and CIDP.
Furthermore, an UpToDate review on “Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease” (Elman and McCluskey, 2021) does not mention anti-HH3 and NS6S antibody testing as a management option.
Anti-KLHL11 Antibody Testing
Song et al. (2023) stated that anti-Kelch-like protein 11 (KLHL11) antibody encephalitis is a rare clinical condition characterized by autoimmune-mediated encephalomyelitis associated with the presence of KLHL11 antibodies. Diagnosis requires the detection of serum and CSF anti-KLHL11 antibodies, while immunotherapy serves as the main therapeutic approach. These investigators discussed a case report highlighting the emergence of anti-KLHL11 antibody encephalitis. This case entailed a 66-year-old man who presented with seizures, impaired cognitive function, disturbance of consciousness, apathy, hypologia, dysphoria, and ataxia. Serum and CSF were identified as positive for anti-KLHL11 antibodies, resulting in a diagnosis of autoimmune encephalitis associated with KLHL11 antibodies. After treatment with glucocorticoid, the patient did not experience further convulsions and recovered consciousness, with improved cognitive function. Tumor screening suggested the presence of an underlying malignancy. The authors concluded that KLHL11 antibody encephalitis lacks typical clinical manifestations; its diagnosis requires a combination of clinical symptoms, signs, and supplementary examinations, and relies mainly on detection of anti-KLHL11 antibodies in serum and/or CSF. These investigators stated that anti-KLHL11 antibody encephalitis should be considered in males with acute or subacute onset, progressive exacerbation, and brainstem or cerebellar damage with or without limbic lobe damage. Early recognition is essential, and immunotherapy and tumor treatment can prevent neurological dysfunction and improve prognosis.
An UpToDate review on “Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis” (Dalmau and Rosenfeld, 2024) states that “Antibodies to Kelch-like protein 11 (KLHL11) have been described in patients with a predominant brainstem/cerebellar encephalitis, often with sensorineural hearing loss, and are often but not invariably associated with tumors, most commonly benign teratoma or a testicular tumor. Other symptoms may include limbic encephalitis, myelitis, hypersomnia, and seizures. Both males and females can be affected, and patients ranging in age from 9 to 76 years have been reported. These antibodies have also been described in patients with other types of autoimmune encephalitis, including anti-N-methyl-D-aspartate (NMDA) receptor and anti-Ma2 encephalitis. In these patients, the presence of KLHL11 antibodies did not confer distinct clinical features.”
Anti-Neuronal Antibodies Testing in Children with Seizures Under 3 Years of Age
In a prospective, national cohort, population-based study, Symonds and colleagues (2020) reported the prevalence of anti-neuronal antibodies in children presenting with seizures before their third birthday. This trial involved all children presenting with new-onset epilepsy or complex febrile seizures before their third birthday over a three-year period. Patients with previously identified structural, metabolic, or infectious causes for seizures were excluded. Serum samples were obtained at first presentation and tested for seven neuronal antibodies using live cell-based assays. Clinical data were collected with structured proformas at recruitment and 24 months after presentation. Additionally, patients with seizures and clinically suspected autoimmune encephalitis were independently identified by reviewing the case records of all children under three years of age in Scotland who had undergone EEG. A total of 298 patients were identified and recruited for autoantibody testing. Antibody positivity was found in 18 of 298 (6.0%). The identified antibodies included GABA receptor B (n = 8, 2.7%), contactin-associated protein 2 (n = 4, 1.3%), glycine receptor (n = 3, 1.0%), leucine-rich glioma inactivated 1 (n = 2, 0.7%), NMDA receptor (n = 1, 0.3%), and GABA receptor A (n = 1, 0.3%). None of these patients exhibited a clinical picture of autoimmune encephalitis. Seizure classification and clinical phenotype did not correlate with antibody positivity. The authors concluded that a small proportion of children presenting with seizures in the first 36 months of life have circulating neuronal antibodies, and in only a very small fraction of cases were these antibodies associated with a clinical picture of autoimmune encephalitis. The significance of antibody positivity in those without encephalitis is unclear, but it is unlikely to provide an etiologic explanation for the epilepsy. Consequently, the investigators did not recommend routine testing for neuronal antibodies in patients presenting with early childhood-onset epilepsy, as antibody positivity is of doubtful clinical significance in the absence of other features of autoimmune encephalitis. They suggested that antibody testing should be reserved for patients with additional features of encephalitis.
The authors acknowledged several drawbacks of this study. First, the prevalence of positive neuronal antibodies in healthy young children without epilepsy is unclear, as they relied on published data from adult healthy controls. Second, in the majority of patients, only serum samples were tested; testing for antibodies in the cerebrospinal fluid (CSF) may be appropriate only if lumbar puncture is clinically indicated. Third, samples were tested only at initial presentation with seizures, and repeat testing over time may provide insights into the natural course of antibody positivity. Fourth, the study included only children under three years of age, an age group not typically considered at high risk for autoimmune encephalitis. Fifth, in young infants, immunoglobulin G antibodies may be trans-placentally transmitted from the mother, and the researchers did not test mothers in this cohort for antibodies. Sixth, the study was limited to common neuronal antibodies and did not test for other rarer encephalitis-associated neuronal antibodies. Finally, future follow-up studies of these patients are needed to establish the natural course and the relationship between antibody positivity and the later development of autoimmune neurologic syndromes.
Anti-Synthetase Syndrome
Kalluri et al (2009) stated that the anti-synthetase syndrome consists of interstitial lung disease (ILD), arthritis, myositis, fever, mechanic's hands, and Raynaud phenomenon in the presence of an anti-synthetase autoantibody, most commonly anti-Jo-1. It is believed that all the anti-synthetases are associated with a similar clinical profile, but definitive data in this diverse group are lacking. These researchers examined the clinical profile of anti-PL-12, an anti-synthetase autoantibody directed against alanyl-transfer RNA synthetase. A total of 31 subjects with anti-PL-12 autoantibody were identified from the databases at the Medical University of South Carolina, the University of Pittsburgh Medical Center, Johns Hopkins Medical Center, and Brigham and Women's Hospital. The medical charts were reviewed and the following data were recorded: demographic information; pulmonary and rheumatological symptoms; connective tissue disease (CTD) diagnoses; serological autoantibody findings; CT scan results; BAL findings; pulmonary function test results; lung histopathology; and treatment interventions. The median age at symptom onset was 51 years; 81% were women and 52% were African American; 90% of anti-PL-12-positive patients had ILD, 65 % of whom presented initially to a pulmonologist; 90 % of anti-PL-12-positive patients had an underlying CTD. Polymyositis and DM were the most common underlying diagnoses. Raynaud phenomenon occurred in 65% of patients, fever in 45% of patients, and mechanic's hands in 16% of patients. Test results for the presence of antinuclear antibody were positive in 48% of cases. The authors concluded that anti-PL-12 is strongly associated with the presence of ILD, but less so with myositis and arthritis.
Aquaporin-4 Autoantibodies (AQP4)
Neuromyelitis optica spectrum disorder (NMOSD) is a severe, immune-mediated inflammatory condition of the central nervous system that primarily affects the optic nerves and spinal cord but can also involve the brain and brainstem. It is pathophysiologically distinct from multiple sclerosis (MS) due to the presence of aquaporin-4 (AQP4) antibodies, which are directly implicated in its mechanism. NMOSD typically presents with acute episodes of bilateral or sequential optic neuritis, transverse myelitis, and area postrema syndrome, and may also include symptoms such as narcolepsy, seizures (especially in children), and neuroendocrine disturbances. The disease follows a relapsing course in over 90% of cases. Diagnosis involves a thorough clinical evaluation, MRI of the brain and spinal cord, serologic testing for AQP4-IgG and MOG-IgG antibodies, and often cerebrospinal fluid analysis. Differentiation from MS and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is critical due to differences in pathogenesis, prognosis, and treatment (Glisson, 2025).
Patients suspected of NMOSD should undergo serum testing for aquaporin-4 immunoglobulin G (AQP4-IgG), ideally during acute attacks and prior to immunotherapy, as treatment may induce seroreversion. One study reported that seroreversion occurred in approximately 11% of initially seropositive patients. Conversion from seronegative to seropositive status is rare, so retesting is recommended only when clinical suspicion remains high. AQP4-IgG, also known as NMO-IgG, is a highly specific biomarker targeting the AQP4 receptor, which plays a direct role in NMOSD pathogenesis. Diagnostic assays have evolved from the original NMO-IgG test, which had moderate sensitivity (73%) and high specificity (91%), to more refined cell-based and ELISA methods demonstrating up to 91% sensitivity and 100% specificity. Despite these improvements, approximately 12% of clinically diagnosed NMOSD patients remain seronegative, and emerging data suggest this subgroup may differ phenotypically, including a balanced sex ratio and a higher likelihood of simultaneous optic neuritis and transverse myelitis at onset (Glisson, 2025).
Waschbisch et al. (2013) stated that recurrent optic neuritis is frequently observed in multiple sclerosis (MS) and is a typical finding in neuromyelitis optica (NMO). Patients who lack further evidence of demyelinating disease are diagnosed with recurrent isolated optic neuritis (RION) or chronic relapsing inflammatory neuropathy (CRION) if they require immunosuppressive therapy to prevent further relapses. The etiology and disease course of this rare condition are not well-defined. These investigators studied a series of 10 patients who presented with recurrent episodes of isolated optic neuritis (ON, n = 57) and were followed over a median of 3.5 years. Visual acuity was severely reduced at the nadir of the disease (20/200 to 20/800). All patients had MRI non-diagnostic for MS/NMO and were aquaporin-4 antibody negative. Six patients fulfilled the CRION criteria. In 2 of these, a single ON followed by a long disease-free interval preceded the development of CRION for years, suggesting the conversion of an initially "benign" isolated ON into a chronic relapsing course. Cerebrospinal fluid (CSF) analysis revealed mild pleocytosis in 5 patients, and identical oligoclonal bands in serum and CSF were observed in 2 patients, while the others remained negative. The authors concluded that recurrent ON is a disease entity that requires aggressive glucocorticoid and eventually long-term immunosuppressive therapy to prevent substantial visual impairment.
Petzold and Plant (2014) noted that CRION is an entity that was described in 2003. Early recognition of patients suffering from CRION is relevant because of the associated risk for blindness if treated inappropriately. These researchers performed a systematic literature review, irrespective of language, on CRION. They retrieved 22 case series and single reports describing 122 patients with CRION between 2003 and 2013. They reviewed the epidemiology, diagnostic work-up, differential diagnosis, and treatment (acute, intermediate, and long-term) in view of the collective data. These data suggested that CRION is a distinct nosological entity, which is seronegative for anti-aquaporin-4 autoantibodies and recognized by and managed through its dependency on immunosuppression.
Sakalauskaite-Juodeikiene et al. (2018) stated that NMO is frequently associated with AQP4 autoantibodies (AQP4-Ab); however, studies of NMO in Lithuania are lacking. These researchers examined positivity for AQP4-Ab in patients presenting with inflammatory demyelinating CNS diseases other than typical MS in Lithuania. Data were collected from the two largest university hospitals in Lithuania. During the study period, there were 121 newly diagnosed typical MS cases, which were included in the MS registry database. After excluding these typical MS cases, these investigators analyzed the remaining 29 cases of other CNS inflammatory demyelinating diseases, including atypical MS (n = 14), acute transverse myelitis (TM; n = 8), acute disseminated encephalomyelitis (ADEM; n = 3), clinically isolated syndrome (CIS; n = 2), atypical optic neuritis (ON; n = 1), and NMO (n = 1). These researchers assessed positivity for AQP4-Ab for the 29 patients and evaluated clinical, laboratory, and instrumental differences between AQP4-Ab seropositive and AQP4-Ab seronegative patient groups. The AQP4-Ab test was positive for 3 (10.3%) patients in this study, with initial diagnoses of atypical MS (n = 2) and ADEM (n = 1); 1 patient was AQP4-Ab negative despite being previously clinically diagnosed with NMO. There were no significant clinical, laboratory, or instrumental differences between the groups of AQP4-Ab positive (3 [10.3%]) and negative (26 [89.7%]) patients. The authors concluded that the AQP4-Ab test was positive for 1 in 10 patients with CNS inflammatory demyelinating diseases other than typical MS in this study. They stated that AQP4-Ab testing is highly recommended for patients presenting with not only TM and ON but also an atypical course of MS and ADEM.
Autoimmune Encephalitis
Autoimmune encephalitis (AE) is a group of immune-mediated inflammatory disorders of the central nervous system characterized by subacute onset of neuropsychiatric symptoms, including altered mental status, cognitive decline, seizures, movement disorders, and autonomic dysfunction. The condition is most commonly associated with antibodies directed against neuronal cell-surface, synaptic, or intracellular antigens, such as NMDA receptor, LGI1, CASPR2, GABA receptors, and paraneoplastic antigens. Antibody testing, performed in serum and/or cerebrospinal fluid, supports diagnosis by identifying a specific immune target and may guide prognosis, tumor evaluation, and treatment decisions. However, antibody results must be interpreted in clinical context, as false positives occur, some patients are seronegative, and diagnosis remains fundamentally clinical, supported by neuroimaging, EEG, and CSF findings rather than antibody testing alone.
Graus et al. (2016) discuss the clinical approach to diagnosis of autoimmune encephalitis, noting that a significant number of patients do not present with a clearly defined syndrome. In some cases, demographic information and certain comorbidities, such as diarrhea, ovarian teratoma, and faciobrachial dystonic seizures, may initially suggest specific underlying disorders like anti-dipeptidyl-peptidase-like protein-6 (DPPX), anti-NMDA receptor, or anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis; however, these features are not pathognomonic and may be absent in some patients. Consequently, the diagnosis of definite autoimmune encephalitis heavily relies on the results of autoantibody tests. In contrast, there are disorders where the clinical syndrome and MRI findings can lead to a classification of probable or definite autoimmune encephalitis even before autoantibody status is determined. These include limbic encephalitis, acute disseminated encephalomyelitis, and other syndromes characterized by MRI features that primarily affect white matter, as well as anti-NMDA receptor encephalitis and Bickerstaff’s brainstem encephalitis.
Hara et al. (2018) evaluated a cohort of 300 patients to determine the frequency and clinical relevance of immunoglobulin (Ig)G, IgA, and IgM N-methyl-d-aspartate receptor (NMDAR) antibodies in several diseases, and whether the IgG antibodies occur in disorders other than anti-NMDAR encephalitis. The patients with anti-NMDAR encephalitis, stroke, dementia, schizophrenia, or seronegative autoimmune encephalitis were evaluated for IgG, IgA, and IgM NMDAR antibodies in serum. Antibodies and their effect on cultured neurons were examined with cell-based assays and brain and live neuronal immunostaining. Retrospective analysis of the clinical diagnoses of a cohort of 1,147 patients with IgG NMDAR antibodies identified since 2005. The authors found that IgG NMDAR antibodies were only identified in those with anti-NMDAR encephalitis and all reacted with brain and live neurons. By cell-based assay, IgA or IgM antibodies were detected in 22 of 300 patients (7%) with different diseases, but only 10 (3%) reacted with brain and 7 (2%) with live neurons. In cultured neurons, IgG but not IgA or IgM antibodies caused a decrease of synaptic and extrasynaptic NMDAR. Among the cohort of 1,147 patients with IgG NMDAR antibodies, 1,015 (88.5%) had anti-NMDAR encephalitis, 45 (3.9%) a limited form of the disease, 41 (3.6%) autoimmune post-herpes simplex encephalitis, 37 (3.2%) overlapping syndromes (anti-NMDAR encephalitis and demyelinating disease), and 9 (0.8%) atypical encephalitic syndromes; none had schizophrenia. The authors concluded that IgG NMDAR antibodies are highly specific for anti-NMDAR encephalitis and cause a decrease of the levels of NMDAR. In contrast, IgA or IgM antibodies occur infrequently and nonspecifically in other diseases and do not alter the receptor levels.
Abboud et al. (2021) describe autoimmune encephalitis (AE) as a heterogeneous group of non‑infectious, immune‑mediated inflammatory disorders of the brain parenchyma that commonly involve cortical or deep grey matter, with possible involvement of white matter, meninges, or spinal cord. AE was initially characterized in the context of paraneoplastic syndromes associated with antibodies against intracellular onconeuronal antigens (e.g., ANNA‑1/anti‑Hu), which are considered non‑pathogenic markers of T‑cell‑mediated anti‑tumor immunity with secondary nervous system involvement. In contrast, more recently identified antibodies targeting neuronal surface or synaptic antigens, such as N‑methyl‑D‑aspartate receptor (NMDAR) and leucine‑rich glioma‑inactivated 1 (LGI1), are thought to be directly pathogenic, are typically more responsive to immunotherapy, and are less frequently associated with malignancy. Additional AE phenotypes are associated with antibodies against oligodendrocytes (e.g., myelin oligodendrocyte glycoprotein [MOG]–associated brainstem encephalitis) and astrocytes (e.g., aquaporin‑4 [AQP4]–associated diencephalic encephalitis and glial fibrillary acidic protein [GFAP] meningoencephalitis), while a substantial proportion of patients remain seronegative, reflecting either yet‑unidentified antibodies or T‑cell–mediated disease. Because commercially available neuronal autoantibody (NAA) panels have limited sensitivity, expanding antigen scope, and turnaround times that often preclude availability during early evaluation, Abboud et al. emphasize that AE must be approached initially as a clinical diagnosis when guiding investigations and initiating treatment, with long‑term management subsequently refined based on antibody status when identified. To confirm an autoimmune inflammatory etiology and exclude alternative diagnoses, the authors highlight cerebrospinal fluid (CSF) analysis as the most critical diagnostic test, generally performed after brain MRI and required in all suspected encephalitis cases absent contraindication. In their expert opinion, “CSF analysis should include cell count and differential, protein, glucose, CSF/serum glucose ratio, albumin quotient, IgG index and synthesis rate, oligoclonal bands, broad viral studies including HSV1/2 PCR and varicella zoster virus (VZV) PCR and IgG/IgM, bacterial/fungal cultures when appropriate, cytology, flow cytometry, NAAs panel (eg, Autoimmune encephalopathy/encephalitis panel, etc), and in some cases, prion disorder panel (preferably RTQuIC when available).” CSF abnormalities such as lymphocytic pleocytosis, elevated protein, and evidence of intrathecal IgG synthesis may be the sole findings supporting empiric immunotherapy once infection is excluded, although normal CSF does not exclude AE. The authors further note that NAA testing in both CSF and serum is often necessary due to variable antibody sensitivity by specimen type and significant syndromic overlap, and that comprehensive antibody panels may be most practical in patients with less defined presentations. Concurrent blood testing is recommended to exclude competing infectious, metabolic, toxic, or systemic autoimmune etiologies, with attention to subtype‑specific features such as hyponatremia in LGI1‑associated AE, and blood samples should be obtained prior to treatment with intravenous immunoglobulin or plasmapheresis to avoid confounding test results.
Nosadini et al. (2021) highlight the importance of immunotherapy in improving outcomes and reducing relapses in individuals with N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis (NMDARE); however, the superiority of specific treatments and combinations remains unclear. The authors conducted a systematic review and meta-analysis to map the use and safety of immunotherapies in NMDARE patients, identify early predictors of poor functional outcomes and relapse, evaluate changes in immunotherapy use and disease outcomes over the 14 years since the first reports of NMDARE, and assess the Anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. PubMed articles were searched from inception to January 1, 2019, selecting those that included patients with NMDARE who had positive NMDAR antibodies and available individual immunotherapy data. Individual patient data on immunotherapies, clinical characteristics at presentation, disease course, and final functional outcomes (modified Rankin Scale [mRS] score) were entered into multivariable logistic regression models. The main outcomes measured were functional outcomes at 12 months from disease onset (good, mRS score of 0 to 2; poor, mRS score greater than 2) and monophasic course (absence of relapse at 24 months or later from onset). The results evaluated data from 1550 patients across 652 articles, revealing that 1105 of 1508 (73.3%) were female and 707 of 1526 (46.3%) were 18 years or younger at disease onset. Factors significantly associated with good functional outcomes included adolescent age and first-line treatment with therapeutic apheresis, corticosteroids plus intravenous immunoglobulin (IVIG), or corticosteroids plus IVIG plus therapeutic apheresis. Conversely, factors linked to poor functional outcomes were age younger than 2 years or 65 years or older at onset, intensive care unit admission, extreme delta brush pattern on electroencephalography, lack of immunotherapy within the first 30 days of onset, and maintenance IVIG use for 6 months or more. Rituximab use or maintenance IVIG for 6 months or more were significantly associated with nonrelapsing disease, while adolescent age at onset was linked to relapsing disease. The use of rituximab increased from 13.5% (52 of 384; 2007 to 2013) to 28.3% (311 of 1100; 2013 to 2019) (P < .001), coinciding with a decrease in relapse rates over the same period (22% [12 of 55] in 2008 and earlier; 10.9% [35 of 322] in 2017 and later; P = .006). The modified NEOS score (including 4 of 5 original NEOS items) was associated with the probability of poor functional status at 1 year (20.1% [40 of 199] for a score of 0 to 1 points; 43.8% [77 of 176] for a score of 3 to 4 points; P = .05). The authors concluded that the factors influencing functional outcomes and relapse are distinct and should be considered independently in developing evidence-based optimal management guidelines for patients with NMDARE.
In a review article about autoimmune encephalitis, Irani (2024) emphasize that “Antibodies against central nervous system proteins characterize various autoimmune encephalitis syndromes. The most common targets include leucine-rich glioma inactivated protein 1 (LGI1), N-methyl-d-aspartate (NMDA) receptors, contactin-associated proteinlike 2 (CASPR2), and glutamic acid decarboxylase 65 (GAD65). Each antibody-associated autoimmune encephalitis typically presents with a recognizable blend of clinical and investigation features, which help differentiate each from alternative diagnoses. The rapid expansion of recognized antibodies and some clinical overlaps support panel-based antibody testing. The clinical-serologic picture guides the immunotherapy regime and offers valuable prognostic information.”
ΒP180 Antibody Levels and Bullous Pemphigoid
Chen et al. (2025) noted that bullous pemphigoid (BP) is an acquired autoimmune bullous disease that often occurs in the elderly. Some BP patients with early onset of the disease were observed to have difficulty in receiving applicable disease control. It remains challenging for clinicians to choose the appropriate treatment for these patients. These researchers examined the differences between patients of different ages at disease onset and explored the possible mechanisms of these differences. A total of 215 BP patients seen at the dermatology department of Peking Union Medical College Hospital between January 2009 and September 2020 were included. Participants were allocated to 5 groups according to the age at disease onset. Clinical data were collected via medical records as well as telephone follow-up interviews. Analyses of anti-BP180 antibody sub-classes, anti-BP230 antibodies, complement fixation, serum cytokine levels, and single nucleotide polymorphisms (SNPs) were carried out. Almost 52% of patients under 60 were misdiagnosed on their first visit, often presenting with oral mucosal involvement. The anti-BP180 immunoglobulin (Ig) E titers and C3 deposition increased in patients under 60 (p = 0.044 and p = 0.014, respectively), while the anti-BP230 IgG titers decreased (p = 0.043). The hospitalization rate of patients under 50 was significantly higher than that of patients aged 80 and older (p < 0.001). Subjects under 60 years of age had a significantly higher serum concentration of interleukin (IL)-13, tumor necrosis factor (TNF)-α, and interferon gamma (IFN-γ) (p < 0.005, respectively). These investigators observed significant differences in the distribution of genotypes or alleles of TNF-α rs1799964, TNF-α rs1800630, and IFN-γ rs2069705. Approximately one-third of the elderly patients suffered from neurological diseases. Elderly patients usually presented with peripheral eosinophilia (p = 0.013). No significant difference was identified in the recurrence rate and complement-activating capacity among the age groups. The authors concluded that the early age of BP onset was associated with a more severe clinical presentation, higher titers of anti-BP180 IgE, lower titers of anti-BP230 IgG, and significantly higher serum concentrations of IL-13, TNF-α, and IFN-γ. It may also be associated with the presence of SNPs of cytokines, including TNF-α rs1799964, TNF-α rs1800630, and IFN-γ rs2069705 variants.
Furthermore, an UpToDate review on “Management and prognosis of bullous pemphigoid” (Murrell and Ramirez-Quizon, 2025) states that “Limited data suggest an association between BP180 antibody levels and risk for relapse. Although data to confirm the best approach to the use of serum antibody levels to guide therapy are lacking, observed correlations among antibody levels, clinical activity, and disease relapse have contributed to the use of periodic measurement of serum BP180 antibody levels as an adjunct to the physical examination in clinical practice. Approaches have included awaiting substantial reductions from pretreatment levels to support reductions in therapy and following trends in an attempt to predict disease exacerbations that may warrant increases in therapy. Additional study is needed to explore the use of BP180 antibody levels for informing changes in therapy.”
Demyelinating Syndromes
Derfuss and Meinl (2012) stated that the identification of autoantigens in demyelinating diseases is essential for understanding the pathogenesis. Immune responses against these antigens could serve as biomarkers for diagnosis, prognosis, and treatment responses. Knowledge of antigen-specific immune responses in individual patients is also a prerequisite for antigen-based therapies. A proportion of patients with demyelinating disease have antibodies to aquaporin 4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG). Patients with anti-AQP4 antibodies present with the distinct clinical picture of neuromyelitis optica (NMO) and often harbor other autoimmune responses. In contrast, anti-MOG antibodies are seen in patients with various disease entities, such as childhood multiple sclerosis (MS), acute demyelinating encephalomyelitis (ADEM), anti-AQP4 negative NMO, and optic neuritis, but are rarely found in adult MS. Several new candidate autoantigens have been identified and await validation. Antigen-based therapies primarily aim to tolerize T-cell responses against myelin basic protein (MBP) and have shown only modest or no clinical benefit so far. The authors concluded that currently, only a few patients with demyelinating diseases can be characterized based on their autoantibody profile, with MOG and AQP4 being the most prominent antigens. They emphasized the need for further research to validate newly discovered antigens as biomarkers.
Reindl et al. (2013) noted that MOG has been identified as a target of demyelinating autoantibodies in animal models of inflammatory demyelinating diseases of the central nervous system (CNS), such as MS. Numerous studies have aimed to establish a role for MOG antibodies in patients with MS, although the results have been controversial. Cell-based immunoassays using MOG expressed in mammalian cells have demonstrated the presence of high-titer MOG antibodies in pediatric patients with ADEM, MS, AQP4-seronegative NMO, or isolated optic neuritis (ON) or transverse myelitis (TM), but only rarely in adults with these disorders. These studies indicated that MOG antibodies could be associated with a broad spectrum of acquired human CNS demyelinating diseases. The authors discussed the current literature on MOG antibodies, their potential clinical relevance, and their role in the pathogenesis of MOG antibody-associated demyelinating disorders.
Hacohen and colleagues (2014) noted that autoantibodies to glial, myelin, and neuronal antigens have been reported in a range of central demyelination syndromes and autoimmune encephalopathies in children, but there has not been a systematic evaluation across the range of CNS autoantibodies in childhood-acquired demyelinating syndromes (ADS). Children under the age of 16 years with first-episode ADS were identified from a national prospective surveillance study; serum from 65 patients had been sent for a variety of diagnostic tests. Antibodies to astrocyte, myelin, and neuronal antigens were tested or re-tested in all samples. A total of 15 patients (23%) were positive for at least one antibody (Ab): AQP4-Ab was detected in 3 (2 presenting with NMO and 1 with isolated ON); MOG-Ab was detected in 7 (2 with ADEM, 2 with ON, 1 with TM, and 2 with clinically isolated syndrome [CIS]). N-Methyl-D-Aspartate receptor (NMDAR)-Ab was found in 2 (1 presenting with ADEM and 1 with ON). Voltage-gated potassium channel (VGKC)-complex antibodies were positive in 3 (1 presenting with ADEM, 1 with ON, and 1 with CIS). Glycine receptor antibody (GlyR-Ab) was detected in 1 patient with TM. All patients were negative for the VGKC-complex-associated proteins LGI1, CASPR2, and contactin-2. The authors concluded that a range of CNS-directed autoantibodies were found in association with childhood ADS. Moreover, they stated that although these antibodies are clinically relevant when associated with the specific neurological syndromes described, further studies are needed to evaluate their roles and clinical relevance in demyelinating diseases.
Fadda et al, (2021) states that "Although much remains unknown about the biological mechanisms behind MOGAD, data from retrospective studies guide considerations on the most appropriate management. Because of improved diagnostic criteria and high-quality assays for antibody detection, diagnosis of pediatric multiple sclerosis, MOGAD, and AQP4-NMOSD is now more accurate."
"Testing serum for the myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) autoantibody and the aquaporin-4 (AQP4) IgG autoantibody is indicated for patients presenting with suspected ADEM" (Lotez, 2025).
Dermatomyositis/Polymyositis
Several serological abnormalities, such as the formation of specific autoantibodies, have been identified in patients with dermatomyositis (DM) and polymyositis (PM); however, their routine use has not yet been established. As a group, these antibodies are termed myositis-specific antibodies (MSAs) and include antibodies to EJ, Jo-1, Ku, Mi-2, OJ, PL-7, PL-12, signal recognition protein (SRP), and U2 small nuclear ribonucleoprotein (snRNP). Pappu and Seetharaman (2009) stated that anti-nuclear antibody assay findings are positive in one-third of patients with PM and in only 15% of patients with inclusion body myositis, with about 4% of patients with PM having antibodies to SRPs. Miller (2009) noted that electromyography (EMG) and tissue biopsies of skin and/or muscle are important facets of the evaluation of patients with possible DM or PM. Abnormalities in EMG may support the diagnosis of DM or PM but are not diagnostic. Moreover, skin biopsy findings, such as Gottron's sign, the shawl sign, and erythroderma, can provide confirmation of the diagnosis of DM. In addition, muscle biopsy is the definitive test for PM, in which skin lesions are not seen.
Although MSAs may offer valuable information regarding prognosis and potential future patterns of organ involvement, there is no reliable evidence that the detection of these antibodies influences clinical management. Furthermore, while there is some limited evidence on the association between the presence of MSAs and cancer-associated myositis (CAM), the available literature on this association is limited. Chinoy et al. (2007) stated that these antibody tests are not foolproof and do not replace the need for intensive surveillance for cancer in persons with new-onset myositis. The authors concluded that before these results can be applied clinically, confirmation in a large independent trial with prospective follow-up is needed.
GALOP Autoantibody
A peripheral neuropathy syndrome described by Pestronk (1994) is the gait disorder, autoantibody, late-age onset, polyneuropathy (GALOP) syndrome, which resembles anti-MAG neuropathies with distal sensory loss, ataxia, and demyelinating features on nerve conduction velocity testing. High titer IgM antibodies bind to a central nervous system myelin antigen preparation that copurifies with myelin-associated glycoprotein (MAG). GALOP syndrome appears to be immune-mediated. However, there is insufficient evidence on the clinical usefulness of measuring the GALOP autoantibody for the diagnosis and treatment of GALOP syndrome in the peer-reviewed medical literature.
Finally, it has been estimated that up to one-third of peripheral neuropathies are idiopathic. These neuropathies are classified by their clinical syndrome, which includes sensory axonal polyneuropathy with large and small fiber involvement, small-fiber sensory neuropathy, large-fiber sensory neuropathy, sensorimotor neuropathy, and autonomic neuropathy (Shy-Drager syndrome). Treatment is usually symptomatic, although some patients may respond to a trial of immunotherapy. More research into their causes, as well as the development of better diagnostic tests and treatments, is needed (Chang, 2002).
Immune Checkpoint Inhibitor–Associated Paraneoplastic Neurologic Syndromes (ICI‑PNS)
Graus et al. (2021) explain that immune checkpoint inhibitors (ICIs) enhance antitumor immunity by blocking immune checkpoint molecules found in T lymphocytes and tumor cells, such as programmed cell death protein 1 and cytotoxic T-lymphocyte–associated antigen 4. The integration of ICI treatment into oncological practice has resulted in improved survival rates and long-term remissions, even among patients with advanced metastatic cancer. However, a significant drawback of ICIs is the risk of immune-related adverse events (irAEs), which can include severe neurologic syndromes occurring in 1% to 3% of cases, manifesting as either the exacerbation of preexisting autoimmune neurologic diseases or the emergence of new ones. The panel advises that the initial step in addressing these disorders is to assess whether the syndrome meets the criteria for paraneoplastic neurological syndromes (PNS) after ruling out other potential causes, such as carcinomatous meningitis. Both peripheral and central nervous system complications have been reported, and there is evidence that certain neurologic syndromes, particularly those associated with Ma2 and Hu antibodies, can be triggered by cancer immunotherapy. Nonetheless, many cases remain seronegative despite thorough screening, and antibody detection is not a prerequisite for diagnosing irAEs. Unlike classical PNS, which can precede cancer diagnosis, neurologic syndromes induced by ICIs typically arise after cancer has been diagnosed, usually shortly after ICI treatment begins. Interestingly, in a few patients who developed antibody-associated irAEs and had samples taken before ICI treatment, retrospective analyses showed the presence of Ma2 or Hu antibodies prior to the onset of PNS in four cases, similar to findings in three cases of ICI-triggered myasthenia gravis. While optimal management strategies for ICI-induced neurologic autoimmunity have yet to be established and fall outside the scope of these diagnostic guidelines, the panel recommends several considerations — routine neuronal antibody testing for all patients experiencing neurologic irAEs resembling high or intermediate-risk PNS; careful evaluation of the risk/benefit ratio of ICIs in patients with current or previous PNS, as recent studies indicate that 50% of such patients experienced worsening symptoms during ICI treatment; further research into the potential benefits of assessing neuronal antibodies before initiating ICIs, particularly in patients with cancers known to be associated with PNS; and close neurologic monitoring for antibody-positive cases.
Wang (2023) highlights that immunotherapeutic strategies, particularly immune checkpoint inhibitors and adoptive T-cell therapy, have transformed cancer treatment, now being approved for various solid and hematologic cancers. The article reviews the unique neurologic side effects associated with these therapies and their management. Although neurologic immune-related adverse events (irAEs) are rare, they can pose serious complications of immune checkpoint inhibitors, affecting both the peripheral and central nervous systems and often necessitating a pause or discontinuation of treatment. Chimeric antigen receptor T-cell therapy can lead to immune effector cell-associated neurotoxicity syndrome, while the side effects from checkpoint inhibitors are thought to be mediated by T-cell activity against antigens expressed in normal tissue, increased levels of preexisting autoimmune antibodies, heightened proinflammatory cytokines, or activation of the complement system. The incidence of neurologic irAEs ranges from 1% to 5% for monotherapy and about 12% for combination therapy, with these events accounting for up to 15% of fatalities related to immune checkpoint inhibitors. Neurologic complications are more commonly reported in patients with melanoma, non-small cell lung cancer, those receiving combination anti-PD1 or PD-L1 and anti-CTLA-4 therapy, and in older individuals. There is also an association between biological females and meningitis, encephalitis, myelitis, and demyelinating disorders among patients on these agents. Symptoms typically manifest within the first 6 months of treatment, and any onset of symptoms beyond 12 months post-infusion warrants investigation for other causes. The peripheral nervous system (PNS) is more frequently affected, with neuromuscular disorders comprising over 50% of cases. Prompt diagnosis and initiation of anti-inflammatory or immunosuppressive treatments are essential for recovery, as symptoms can range from mild to severe, including delirium and seizures. Effective management of these neurologic complications requires early detection and a multidisciplinary approach to ensure both neurologic recovery and effective cancer control.
Farina et al. (2024) highlight that immune checkpoint inhibitors, which are oncological treatments designed to enhance antitumor immunity, can lead to neurological adverse events that closely resemble paraneoplastic neurological syndromes. Unlike other neurological side effects associated with these drugs, paraneoplastic neurological syndromes occurring after immune checkpoint inhibitor treatment primarily affect the central nervous system and are linked to neural antibodies and cancer types that are also commonly seen in spontaneous paraneoplastic neurological syndromes. Additionally, these post-treatment syndromes tend to result in worse neurological outcomes compared to other neurological adverse events related to immune checkpoint inhibitors. Early diagnosis and the prompt initiation of immunosuppressive therapy are likely critical for preventing further neurological disability. Notably, the neural antibodies present in patients with post-immune checkpoint inhibitor paraneoplastic neurological syndromes can sometimes be detected prior to treatment, suggesting that these antibodies may serve as predictors for the onset of neurological adverse events. Both experimental and clinical evidence indicate that these post-treatment syndromes likely share immunological characteristics with spontaneous paraneoplastic syndromes. Therefore, investigating post-immune checkpoint inhibitor paraneoplastic neurological syndromes may provide insights into the immunopathogenesis of paraneoplastic neurological syndromes and help identify new therapeutic targets.
The National Comprehensive Cancer Network clinical practice guideline on management of immune checkpoint inhibitor-related toxicities (NCCN, 2025) recommend paraneoplastic panel testing in patients on an immune checkpoint inhibitor who presents with encephalitis or transverse myelitis. The NCCN does not discuss the autoantibody marker that should be included in the test panel.
Limbic Encephalitis
Limbic encephalitis (LE) typically manifests with rapid progression of short-term memory loss, seizures, and psychiatric symptoms within a span of less than three months. The diagnostic criteria for LE were revised in 2016, and since 2004, significant advancements have been made in antibody discovery related to this condition. Previously, both paraneoplastic and autoimmune forms of LE were often underdiagnosed, with reported cases being considerably fewer than those of rapidly progressive cerebellar syndromes and sensory neuronopathies. Notably, some of the most common cell surface antibodies linked to LE, such as leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies, are typically associated with nonparaneoplastic forms of the disease. Consequently, the traditional view of LE as primarily a cancer-associated phenotype has shifted significantly over the past decade. Nevertheless, due to the existence of various LE variants, including rarer forms that are almost always linked to cancer, the disorder continues to be classified as a high-risk phenotype. This classification is essential for two reasons. First, the neurological presentations of paraneoplastic and nonparaneoplastic cases can be indistinguishable, and second, certain associated antibodies, such as gamma-aminobutyric acid B receptor (GABABR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), can present as paraneoplastic LE in over 50% of cases. While onconeural antibodies like anti-Hu and anti-Ma2 are typically found in adults with underlying cancer, the presence of Hu antibodies in children with LE is exceedingly rare and generally not associated with cancer (Graus et al., 2021).
Measurement of Serum Folate Receptor Autoantibodies (e.g., FRAT (Folate Receptor Antibody Test)) for Evaluation of Patients with Cerebral Folate Deficiency Syndrome
Cerebral folate deficiency (CFD) is a condition in which concentrations of 5-methyltetrahydrofolate (5MTHF) are low in the brain as measured in the CSF despite being normal in the blood. Symptoms typically appear at about 5 to 24 months of age. Without treatment, there may be poor muscle tone, trouble with coordination, trouble talking, and seizures.
Ramaekers et al. (2005) noted that in infantile-onset CFD, 5MTHF levels in the CSF are low; however, folate levels in the serum and erythrocytes are normal. These investigators examined serum specimens from 28 children with CFD, 5 of their mothers, 28 age-matched control subjects, and 41 patients with an unrelated neurologic disorder. Serum from 25 of the 28 patients and 0 of 28 control subjects contained high-affinity blocking autoantibodies against membrane-bound folate receptors that are present on the choroid plexus. Oral folinic acid normalized 5MTHF levels in the CSF and resulted in clinical improvement. The authors concluded that CFD is a disorder in which autoantibodies could prevent the transfer of folate from the plasma to the CSF.
Ramaekers and Quadros (2022) stated that CFD syndrome (CFDS) is defined as any neuropsychiatric or developmental disorder characterized by decreased CSF folate levels in the presence of normal folate status outside the nervous system. The specific clinical profile appeared to be largely determined by the presence or absence of intra-uterine folate deficiency as well as post-natal age at which cerebral folate deficiency occurs. The primary cause of CFDS is identified as the presence of serum folate receptor-alpha (FRα) autoantibodies impairing folate transport across the choroid plexus to the brain, whereas, in a minority of cases, mitochondrial disorders, inborn errors of metabolism, and loss of function mutations of the FRα (FOLR1) gene are identified. Early recognition and diagnosis of CFDS and prompt intervention is important to improve prognosis with successful outcomes.
Multi-Analyte Assays with Algorithmic Analyses (MAAAs)
Multi-analyte assays with algorithmic analyses (MAAAs) are laboratory measurements that use a mathematic formula to analyze multiple markers that may be associated with a particular disease state and are designed to evaluate disease activity or an individual’s risk for disease. The laboratory performs an algorithmic analysis using the results of the assays and sometimes other individual information, such as gender and age and converts the information into a numeric score, which is conveyed on a laboratory report. Generally, MAAAs are exclusive to a single laboratory that owns the algorithm; MAAAs are suggested to assess risk, to diagnose or monitor disease activity of conditions such as epilepsy, as well as autoimmune connective tissue disease (CTD) and hepatitis C.
- contactin-associated protein-like 2 (CASPR2),
- glutamic acid decarboxylase (GAD65),
- leucine-rich, glioma inactivated 1 (LGI1),
- NMDA Receptor (NR1), and
- voltage-gated potassium channel complex (VGKC).
Myasthenia Gravis
Myasthenia gravis (MG), an autoimmune disorder, is caused by the failure of neuromuscular transmission, which results from the binding of autoantibodies to proteins involved in signaling at the neuromuscular junction. These proteins include the nicotinic acetylcholine receptors (AChRs) or, less frequently, a muscle-specific tyrosine kinase (MuSK) involved in AChR clustering. Chan and Liu (2005) noted that the diagnosis of MG relies on clinical as well as investigatory evidence. Among the usual investigatory tools, the Tensilon (edrophonium chloride) test has been credited as a test of high sensitivity (80% to 85%). Antibodies to AChRs are found in about 80% of persons with myasthenia gravis (Tidy, 2007).
Vincent and Leite (2005) noted that some of the 20% of patients with MG who do not have antibodies to AChRs have antibodies to MuSK, but a full understanding of their frequency, the associated clinical phenotype, and the mechanisms of action of the antibodies has not yet been achieved. Moreover, some patients do not respond well to conventional corticosteroid therapy. These researchers reported that MuSK antibodies are found in a variable proportion of AChR antibody-negative MG patients who are often, but not exclusively, young adult females, with bulbar, neck, or respiratory muscle weakness. The thymus histology is normal or only very mildly abnormal. Surprisingly, limb or intercostal muscle biopsies exhibit no reduction in AChR numbers or complement deposition. However, patients without AChR or MuSK antibodies appear to be similar to those with AChR antibodies and may have low-affinity AChR antibodies. A variety of treatments, often intended to enable corticosteroid doses to be reduced, have been used in all types of MG with some success, but they have not been subjected to randomized clinical trials. The authors noted that MuSK antibodies define a form of MG that can be difficult to diagnose, can be life-threatening, and may require additional treatments. An improved AChR antibody assay may be helpful in patients without AChR or MuSK antibodies. Randomized clinical studies of drugs in other neuroimmunological diseases may help to guide the treatment of MG.
Romi et al. (2005) examined MG severity and long-term prognosis in seronegative MG compared with seropositive MG, specifically reviewing anti-AChR antibody-negative and anti-MuSK antibody-negative patients. A total of 17 consecutive seronegative non-thymomatous MG patients and 34 age- and sex-matched contemporary seropositive non-thymomatous MG controls were included in a retrospective follow-up study for a total period of 40 years. Clinical criteria were assessed each year, and muscle antibodies were assayed. There was no difference in MG severity between seronegative and seropositive MG. However, when thymectomized patients were excluded from the study at the year of thymectomy, seropositive MG patients had a more severe course than seronegative (p < 0.001). One seropositive patient died from MG-related respiratory insufficiency. The need for thymectomy in seronegative MG was lower than in seropositive MG. None of the seronegative patients had MuSK antibodies. The findings of this study showed that the presence of AChR antibodies in MG patients correlates with a more severe MG. The authors noted that with proper treatment, especially early thymectomy for seropositive MG, the outcome and long-term prognosis are good in patients with and without AChR antibodies.
Lee et al. (2006) stated that several reports from Western countries suggest differences in the clinical features of patients with MuSK antibody-positive and MuSK antibody-negative seronegative MG. These investigators performed the first survey in Korea of MuSK antibodies, studying 23 patients with AChR-antibody seronegative MG. MuSK antibodies were present in 4 (26.7%) of 15 generalized seronegative MG patients and none of 8 ocular seronegative MG patients. All 4 MuSK-positive patients were females, with pharyngeal and respiratory muscle weakness, and required immunosuppressive treatment. However, overall disease severity and age at onset were similar to that of MuSK-negative MG, and treatment responses were equally good.
In the appropriate clinical setting (lack of AChR antibodies and typical clinical features listed below), MuSK testing can clarify the diagnosis and perhaps direct treatment. However, the initial management of clinically apparent myasthenia should be the same for patients with or without AChR antibodies; this would change only if future studies find additional therapeutic differences related to MuSK status.
Although some differences between MuSK-positive and MuSK-negative MG have been found, the initial management of clinically apparent MG should be the same for patients with or without MuSK antibodies; this would change only if future studies show significant therapeutic differences related to MuSK status.
Graus and colleagues (2016) proposed a practical, syndrome-based approach to the early diagnosis of autoimmune encephalitis that prioritizes clinical assessment and conventional investigations over immediate reliance on antibody testing or treatment response. The authors define autoimmune encephalitis as a subacute, usually less than three months, progressive encephalopathy characterized by new memory deficits, altered mental status, psychiatric symptoms, seizures, or focal neurologic findings, and they introduce tiered diagnostic categories of possible, probable, and definite autoimmune encephalitis. For initial evaluation, the paper emphasizes prompt brain MRI, preferably with T2 FLAIR and diffusion-weighted sequences, to identify inflammatory patterns such as bilateral medial temporal lobe abnormalities suggestive of limbic encephalitis or multifocal gray and white matter lesions, while noting that MRI can be normal early and does not exclude the diagnosis. EEG is recommended as part of routine workup to identify diffuse or focal slowing, epileptiform discharges, nonconvulsive seizures, or characteristic patterns such as extreme delta brush in anti NMDA receptor encephalitis, although EEG findings are generally nonspecific and supportive rather than diagnostic. Cerebrospinal fluid analysis is considered central and should include cell count, protein, IgG index, oligoclonal bands, infectious testing, particularly herpes simplex virus PCR, and neuronal antibody studies; mild lymphocytic pleocytosis, elevated protein, or intrathecal IgG synthesis support an inflammatory process but may be absent in some antibody mediated syndromes such as LGI1 associated encephalitis. The authors strongly recommend that antibody testing be performed in both CSF and serum, as CSF testing is more specific, can be positive when serum is negative, and correlates better with clinical course, particularly in anti NMDA receptor encephalitis. Routine laboratory studies are incorporated into the workup to allow reasonable exclusion of alternative causes, which is a required diagnostic criterion at every level and includes evaluation for infectious, metabolic, toxic, vascular, neoplastic, and degenerative etiologies of rapidly progressive encephalopathy. Within patients who lack well characterized neuronal antibodies or a defined syndrome, the paper discusses Hashimoto’s encephalopathy as a diagnosis of exclusion, recommending measurement of serum thyroid antibodies including thyroid peroxidase and thyroglobulin antibodies, while stressing their poor specificity, frequent presence in the general population, and need for correlation with compatible clinical features, typically nonspecific or normal MRI findings, absence of other neuronal antibodies, and careful exclusion of alternative causes. Overall, the study advocates an early MRI EEG CSF centered diagnostic strategy that enables timely recognition and treatment of autoimmune encephalitis based on clinical and paraclinical evidence, with antibody testing and malignancy screening used to refine diagnosis, prognosis, and management once results become available.
In a retrospective diagnostic study, Mirian et al. (2022) compared the specificity and sensitivity of a commercially available fixed cell-based assay (F-CBA) to radioimmunoprecipitation assay (RIPA) for AChR antibody (anti-AChR) detection in MG. These investigators reviewed the clinical information of suspected MG patients assessed at the London Health Sciences Centre MG clinic who had anti-AChR RIPA and then F-CBA performed, in order to classify them as MG or non-MG. Classification of each patient as anti-AChR F-CBA-negative/positive, RIPA-negative/positive, and MG/non-MG permitted specificity and sensitivity calculations for each assay. A total of 618 patients were included in this trial. The median patient age at the time of sample collection was 45.8 years (range of 7.5 to 87.5), and 312/618 (50.5%) were female. Of 618 patients, 395 (63.9%) were classified as MG. Specificity of both F-CBA and RIPA was excellent (99.6% versus 100%, p > 0.99). One F-CBA-positive patient was classified as non-MG, although in retrospect, ocular MG with functional overlay was challenging to exclude. Sensitivity of F-CBA was significantly higher than RIPA (76.7% versus 72.7%, p = 0.002). Overall, 20/97 (21%) otherwise seronegative MG (SNMG) patients after RIPA evaluation had anti-AChR detected by F-CBA. The authors concluded that anti-AChR F-CBA and RIPA both exhibited excellent specificity, while F-CBA had 4% higher sensitivity for MG and detected anti-AChR in 21% of seronegative MG patients. These investigators stated that these findings showed that F-CBA is a viable alternative to RIPA for anti-AChR detection.
Spagni et al. (2022) stated that live CBA can detect AChRs or MuSK antibodies in a proportion of patients with radioimmunoassay (RIA)-double sero-negative myasthenia gravis (dSN-MG). A commercial fixed CBA for AChR and MuSK antibodies has recently become available; however, comparative studies on fixed and live CBAs are lacking. These researchers compared the performance of fixed and live CBAs in patients with RIA-dSN MG and examined their sensitivity in RIA-positive MG samples and their specificity. AChR and MuSK antibodies were tested in 292 serum samples from two Italian MG referral centers by live and fixed CBAs: 192 from patients with MG and 100 from controls. All samples had been previously evaluated by RIA: 66 were AChR-positive, 40 MuSK-positive, and 86 dSN. All controls were negative. Two independent raters examined the CBA results. Fixed and live CBAs were compared with the McNemar test; inter-rater and inter-laboratory agreement were examined with Cohen's kappa or inter-class correlation coefficient (ICC), as appropriate. In 86 RIA-dSN samples, fixed CBA detected antibodies in 10 cases (11.6%, 95% CI: 5.7% to 20.3%), whereas live CBA detected antibodies in 16 (18.6%, 95% CI: 11.0% to 28.5%) (p = 0.0143). Of these sera, those positive by fixed CBA were also positive by live CBA. Furthermore, live CBA could detect MuSK antibodies in 4 and AChR antibodies in 2 samples that were negative by fixed CBA, providing an 8% (95% CI: 2.9% to 16.6%) further increase in the antibody detection rate. These findings were confirmed by flow cytometry. In the RIA-positive cohort, the sensitivity for AChR antibodies was 98.5% (95% CI: 91.9% to 99.9%) for fixed CBA and 100% (95% CI: 94.6% to 100%) for live CBA (p = 0.1573). For both assays, the sensitivity for MuSK antibodies was 100% (95% CI: 91.2% to 100%), and the specificity was 100% (95% CI: 96.4% to 100%). Inter-rater agreement was almost perfect for live and fixed CBAs (Cohen's kappa 0.972 and 0.978, respectively), similar to inter-laboratory agreement. Inter-rater agreement for the CBA score ranged from good to excellent (ICC: 0.832 to 0.973). The authors concluded that fixed CBA represented a valuable alternative to RIA for AChR and MuSK antibody detection in patients with MG and could be considered as a first-step diagnostic test. Live CBA could be useful in the serologic evaluation of RIA- and fixed CBA-negative samples.
Damato et al. (2022) noted that patients with MG without AChR or MuSK antibodies detected by RIPAs are classified as seronegative myasthenia gravis (SNMG). Live CBA (l-CBAs) could detect additional antibodies to clustered AChR, MuSK, and low-density lipoprotein receptor-related protein 4 (LRP4); however, positivity rates are variable, and both clinical relevance and utility of CBA platforms remain unclear. Sera from 82 patients with SNMG were tested by l-CBAs. Human embryonic kidney cells were transfected to individually express clustered AChR, MuSK, or LRP4; or transfected to jointly express both clustered adult AChR and MuSK. Sera from 30 and 20 patients positive by RIPA for AChR or MuSK antibodies, respectively, were used as comparators. A total of 53 of 82 (72%) patients with SNMG had generalized disease, and 29 (28%) had ocular disease. The clustered AChR CBA detected antibodies in 16 of 82 patients (19.5%; including 4 patients with solely fetal AChR antibodies), while 7 of 82 (8.5%) patients had MuSK antibodies. A novel exploratory combined adult AChR-MuSK l-CBA efficiently detected all these antibodies in a subset of the SNMG cohort. No LRP4 antibodies were identified. Overall, patients with SNMG with clustered AChR antibodies, CBA-positive MuSK-MG, or triple sero-negative were younger and had less severe disease than patients with RIPA-positive MG and had a better clinical outcome when immunotherapy was started soon after disease onset, although the time interval from onset to immunotherapy was not different when compared with patients with RIPA-positive MG. The authors concluded that about one-third of patients with SNMG had AChR or MuSK antibodies by l-CBAs, which were efficiently detected with a combined l-CBA. These investigators stated that the results in this large and unselected cohort of patients with MG showed the diagnostic usefulness of performing CBAs and the importance of making these tests more widely available.
Li et al. (2023) stated that MG is the most common immune-mediated disorder of the neuromuscular junction; anti-AChR, anti-MuSK, and anti-lipoprotein receptor-related protein 4 (anti-LRP4) antibodies are the three well-defined pathogenic antibodies. Patients with MG can also have other antibodies, such as anti-titin, anti-ryanodine receptor (anti-RyR), anti-Agrin, and anti-KV1.4 antibodies. Since MG is heterogeneous in terms of pathophysiology, antibody status, and other factors, serological tests are crucial for clinical diagnosis confirmation and treatment choice. The authors noted that anti-LRP4 antibodies are predominantly of the IgG1 and IgG2 subtypes. In contrast to patients with anti-MuSK antibodies, most of these patients present with isolated ocular or only mild generalized MG and rarely experience a crisis; thus, in most reports, anti-LRP4 antibodies appear to indicate a more favorable prognosis.
Diogenes et al. (2024) stated that MG is an autoimmune disorder characterized by pathogenic autoantibodies (AAbs) targeting nicotinic AChR, disrupting neuromuscular communication. RIPA is recommended to detect AChR antibodies; however, its complexity and radioactive requirements limit widespread use. These researchers compared non-RIPA anti-AChR immunoassays, including CBA and two ELISA kits, against the gold standard RIPA. A total of 145 samples were included with a medical indication for anti-AChR testing. By means of the RIPA method, 63 were negative (RIPA-Neg less than 0.02 nmol/L), 18 were classified as borderline (greater than or equal to 0.02 to 1 nmol/L), and 64 were positive (RIPA-Pos greater than 1 nmol/L). The competitive ELISA showed poor agreement with RIPA (Kappa = 0.216). The indirect ELISA showed substantial agreement with RIPA (Kappa = 0.652), with approximately 76% sensitivity and approximately 94% specificity for MG diagnosis. The CBA, where fixed cells expressing clustered AChR were used as substrate, exhibited almost perfect agreement with RIPA (Kappa = 0.984), yielding approximately 98% sensitivity and 96% specificity for MG. Furthermore, a semi-quantitative analysis revealed a strong correlation between CBA titration, indirect ELISA, and RIPA levels (r = 0.793 and r = 0.789, respectively). The authors concluded that the CBA displayed excellent analytical performance for MG diagnosis when compared to RIPA, making it a potential replacement for RIPA in clinical laboratories. Some solid-phase assays (such as the indirect ELISA applied here), as well as CBA titration, offer reliable options to estimate anti-AChR antibody levels after confirming positivity by the CBA.
Mousavi et al. (2024) noted that acquired MG is an autoimmune disease targeting specific proteins in the post-synaptic muscle membrane. These investigators noted that 50% of ocular and 80% of generalized MG patients have AChR antibodies (AChR Abs); 1% to 10% of MG patients have antibodies against MuSK; and 2% to 50% of seronegative MG cases have antibodies against LRP4 (LRP4 Abs). Serological testing is essential for diagnosing and determining the appropriate therapeutic approach for MG patients. The radioimmunoprecipitation assay (RIPA) method is a historical standard test for detecting AChR Abs and MuSK Abs. While it has nearly 100% specificity in AChR Abs detection, its sensitivity is between 50% to 92%. The sensitivity and specificity of RIPA for detecting MuSK Abs are much lower. The fixed and live cell-based assays (f-CBA and L-CBA) have higher sensitivity than RIPA. With advancements in the serological diagnosis and management of MG, the authors now recommend a complete reflex testing algorithm on the first pre-treatment sample of a suspected MG patient, starting with the binding and blocking assays for AChR Abs by RIPA and/or f-CBA. If AChR Abs are negative, then reflex to MuSK Abs by RIPA and/or CBAs. If AChR and MuSK Abs are negative, then use clustered L-CBA by request.
An UpToDate review on the "Diagnosis of myasthenia gravis" (Bird, 2025) indicates that testing for LRP4 antibodies is reserved for seronegative patients with an uncertain diagnosis following electrodiagnostic testing. Additionally, the review emphasizes that the initial laboratory test to confirm a diagnosis of myasthenia gravis (MG) should be an immunologic assay to detect circulating AChR antibodies, which are present in up to 90% of patients with generalized MG.
Repeat MOG Testing in Follow-Up/Monitoring of patients with MOG-Positive Optic Neuritis
Cleveland Clinic’s webpage on “Approaches to Diagnosis, Treatment and Management of Optic Neuritis” (2025) mentions aquaporin-4 antibody testing can be repeated in 6 months; and brain MRI should be repeated in 6 months. However, it does not mention repeat MOG testing.
Furthermore, UpToDate reviews on “Optic neuritis: Pathophysiology, clinical features, and diagnosis” (Osborne and Balcer, 2025a), “Optic neuritis: Prognosis and treatment” (Osborne and Balcer, 2025b), and “Optic neuropathies” (Osborne and Balcer, 2025c) do not mention repeat MOG testing as a management option.
RNA Polymerase III Antibody Testing for Diagnosis and Prognostication of Scleroderma (Systemic Sclerosis)
Wielosz et al. (2020) stated that anti-RNA polymerase III (a-RNA Pol III) antibodies are marker antibodies in patients with systemic sclerosis (SSc). These investigators examined the prevalence of a-RNA Pol III in patients with SSc and identified the differences in the disease picture in SSc patients with and without a-RNA Pol III antibodies. The study was carried out in 126 SSc patients. The subtype of SSc, incidence of internal organ involvement, malignancy, death, and serological profiles were determined in the entire group. The study groups were studied according to the presence of antibodies by applying the commercial test—EUROLINE SSc Profile. Due to the presence of a-RNA Pol III, patients were divided into 2 groups: the a-RNA Pol III (+) SSc group of 19 patients, and the a-RNA Pol III (–) SSc group of 107 patients. A-RNA Pol III were present in 19/126 patients with SSc (15%), and 13/19 (68.4%) patients had no other SSc marker antibodies. A-RNA Pol III were more common in patients with diffuse cutaneous SSc (p = 0.049). These researchers showed a significant positive association between a-RNA Pol III and the occurrence of malignancy (p = 0.007), scleroderma renal crisis (p = 0.001), and decreased diffusing capacity of the lung for carbon monoxide (DLCO) (p = 0.007). The authors concluded that anti-a-RNA Pol III antibodies were common in patients with SSc, especially with a diffuse subtype. In more than 50% of patients with a-RNA Pol III antibodies, they may be present as the sole marker of antibodies. In SSc, a-RNA Pol III antibodies are often associated with malignancy occurrence, kidney, and lung involvement.
These investigators stated that according to these findings, a-RNA Pol III antibodies are quite common in patients with SSc, particularly with a diffuse subtype. In more than 60% of patients, a-RNA Pol III antibodies may be present as the sole marker of SSc antibodies. In SSc, a-RNA Pol III antibodies are often associated with malignancy occurrence and the development of scleroderma renal crisis. To sum up, measurements of a-RNA Pol III antibodies are useful in routine clinical practice because they are one of the marker antibodies in SSc diagnosis, and in many cases, they identify the subset of the disease with severe skin and renal involvement. In addition, the presence of a-RNA Pol III antibodies should alert physicians to an increased risk of scleroderma renal crisis and monitoring of blood pressure (BP) for early detection of this complication since the prompt introduction of angiotensin-converting enzyme (ACE) inhibitor can be life-saving. Moreover, the presence of a-RNA Pol III antibodies in SSc patients requires screening for associated cancer, even in the absence of clinical signs.
Junior et al. (2022) conducted a systematic review of the clinical manifestations and complementary examinations of patients with myopathies and SSc overlap syndrome (MyoSScOS). Systematic review from January 1976 to November 2021 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement on 3 electronic databases: PubMed, Web of Science, and Scopus. Studies were analyzed based on the following eligibility criteria: at least 1 combination of the terms described in the search strategy appeared in the title; written in English, Portuguese, or Spanish; and addresses MyoSScOS. Brief communications, reviews, studies that addressed myopathies in children, congress proceedings, monographs, and dissertations were excluded. A total of 35 studies were selected. MyoSScOS appeared to be more common in women. It also often affects the esophagus and joints with symmetrical and bilateral muscle involvement, Raynaud's phenomenon, and impairment of forced vital capacity. Concerning SSc, the most common subtype was the diffuse form. Cardiovascular and pulmonary complications are an important cause of death. Anti-centromere, anti-PM/Scl, anti-Scl70, anti-RNA polymerase III, anti-Ku, and anti-RNP were more correlated with this entity; EMG patterns were quite similar to those found in inflammatory myopathies.
Almaabdi et al. (2023) noted that SSc is a systemic autoimmune rheumatic disease characterized by immune abnormalities, leading to vasculopathy and fibrosis. Autoantibody testing has become an increasingly important part of diagnosis and prognostication. These investigators stated that anti-topoisomerase I, anti-centromere, and anti-RNA polymerase III antibodies were deemed vitally important in the concept of SSc due to their ability to distinguish SSc from other systemic autoimmune rheumatic diseases (SARD), such that they were included in the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for SSc.
Furthermore, an UpToDate review on “Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults“ (Varga, 2024) states that “Anti-RNA polymerase III antibody. Antibodies to RNA polymerase III are found in patients with dcSSc and are generally associated with rapidly progressive skin involvement as well as an increased risk for scleroderma renal crisis (SRC). These patients may also be at increased risk for concomitant cancer.”
Stiff-Person Syndrome
Stiff-person syndrome (formerly called stiff-man syndrome) is an uncommon disorder characterized by progressive muscle stiffness, rigidity, and spasm involving the axial muscles. The muscle spasms are triggered by different stimuli and may lead to limb deformities and fractures. Electrophysiological studies show continuous discharges of motor unit potentials, which improve during sleep or general anesthesia. Paraneoplastic stiff-person syndrome usually occurs in patients with breast cancer and small cell lung cancer (SCLC). Paraneoplastic muscle rigidity in association with myoclonus has also been described in patients with SCLC and progressive encephalomyelitis. The serum of patients with paraneoplastic stiff-person syndrome often contains antibodies against a protein called amphiphysin. In contrast, patients with stiff-person syndrome who do not have cancer (but who usually develop diabetes and other symptoms of endocrinopathy) have antibodies against glutamic acid decarboxylase (GAD). Both GAD and amphiphysin are nonintrinsic membrane proteins that are concentrated in nerve terminals, where a pool of both proteins is associated with the cytoplasmic surface of synaptic vesicles.
To better understand GAD antibodies (GADAb) and stiff-person syndrome (SPS), Murinson et al. (2004) studied a population of patients with clinically suspected SPS. A total of 576 patients with suspected SPS underwent immunocytochemistry (ICC). Of these, 286 underwent radioimmunoassay (RIA) for GADAb; 116 were GADAb-positive by one or both tests. Ninety-six percent of those positive by ICC had RIA values several standard deviations above normal. RIA did not correlate with age or illness duration. Marked elevations of RIA for GADAb were characteristic of ICC-confirmed SPS, and modest elevations were not. The findings of this study indicated that patients with clinically suspected SPS almost always have either very high GADAb or undetectable GADAb. An additional important observation was that the specificity of RIA for GAD-positive SPS is sharply dependent on the diagnostic cut-off value. The authors noted that until a universal standard for GAD65 RIA is adopted, interpretation will depend on knowing the particularities of each testing laboratory.
In an editorial, Chang and Lang (2004) stated that "the data from Murinson et al. do not imply a pathogenic role because they found no correlation between age or duration of illness and GADAbs and no change over the course of the disease in individuals. Thus, there is no value in monitoring the antibody titer during the course of the disease.... Although the exact role of GADAbs in the pathogenesis of SPS still remains elusive, Murinson et al. have established the reliability of RIA in measuring these antibodies. Nevertheless, clinical criteria remain the benchmark for the diagnosis of SPS."
Graus et al. (2021) states that stiff-person syndrome (SPS) is characterized by painful muscular spasms that can occur spontaneously or be triggered by activity or external sensory stimuli, accompanied by stiffness resulting from the coactivation of agonist and antagonist muscles. Paraneoplastic SPS is primarily associated with amphiphysin antibodies and breast cancer. In contrast to nonparaneoplastic SPS, which is typically linked to glutamic acid decarboxylase 65 (GAD65) antibodies, patients with amphiphysin-related paraneoplastic SPS tend to be older and often exhibit neck and upper limb involvement. While some patients with anti-GAD65-associated SPS may have cancer, a paraneoplastic cause should only be considered if GAD65 is expressed by the tumor cells. Additionally, there are focal variants of SPS, such as stiff-leg syndrome, that share the same antibody and tumor associations as classic SPS. Another disorder within the SPS spectrum is progressive encephalomyelitis with rigidity and myoclonus, which typically presents with hyperekplexia, brainstem dysfunction, and dysautonomia, and is primarily associated with glycine receptor antibodies in a nonparaneoplastic context.
Appendix
Appendix A: Paraneoplastic Neurologic Syndrome Examples
Paraneoplastic neurologic syndromes (PNS) are rare, immune-mediated disorders triggered by an underlying cancer. Also see Tables 2-4 below:
-
High‑Risk Neurological Phenotypes
(Strong cancer association; classic phenotypes; not an all-inclusive list)- Encephalomyelitis
- Gastrointestinal pseudo-obstruction (enteric neuropathy)
- Lambert-Eaton myasthenic syndrome (LEMS)
- Limbic encephalitis (LE)
- Opsoclonus-myoclonus syndrome
- Rapidly progressive cerebellar syndrome
- Sensory neuronopathy
- Intermediate‑Risk Neurological Phenotypes
(Cancer association possible; antibody‑ and context‑dependent; not an all-inclusive list)
- Anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis
- Brainstem encephalitis
- Encephalitis other than well-defined limbic encephalitis, when criteria for possible autoimmune encephalitis are fulfilled
- Isolated myelopathy
- Morvan syndrome
- Polyradiculoneuropathies, especially axonal pattern and concurrent central nervous system involvement
- Stiff-person syndrome (SPS)
Source: Graus et al., 2021; Dalmau and Rosenfeld, 2024
Appendix B: Non-Paraneoplastic Neurologic Disorders/Diseases Examples
Non-paraneoplastic neurological disorders/diseases arise from causes unrelated to malignancy, such as autoimmunity, infection, or genetic factors. The following examples is not an all-inclusive list; also see Table 1 below:
- Anti‑MAG demyelinating neuropathy
- Autoimmune encephalitis (non‑malignancy‑associated)
- Autoimmune epilepsy (antibody‑associated forms) (anti-GAD)
- Chronic immune‑mediated neuropathies (anti-GD1b)
- Lambert–Eaton myasthenic syndrome (non‑malignancy‑associated) (anti‑VGCC; P/Q‑type voltage‑gated calcium channel antibody)
- Immune‑mediated sensory or sensorimotor neuropathy (anti-sulfatide)
- Miller Fisher syndrome (MFS) (anti-GQ1b)
- MOG antibody disease (MOGAD) (anti-MOG IgG)
- Motor neuron syndromes (anti-asialo-GM1, anti-GD1a, anti-GM1, anti-GM2, )
- Myasthenia gravis (anti-AChR, anti-MuSK)
- Myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD)
- Neuromyelitis optica spectrum disease (NMOSD)
- Pharyngeal–cervical–brachial variant of Guillain-Barré syndrome (anti-GT1a)
- Sensory ataxic neuropathy (anti-GD1b)
- Sjögren's syndrome (anti-La, anti-Ro)
- Stiff-person syndrome (SPS) (non-malignancy-associated) (anti-GAD)
- Systemic lupus erythematosus (anti-La, anti-Ro)
| Neuropathy Syndrome | Antibody Target | Antibody Isotype |
|---|---|---|
| Chronic Sensory-Motor Demyelinating |
Myelin-associated glycoprotein (MAG) Other: SGPG |
IgM (monoclonal) |
| Chronic ataxic neuropathy | GD1b, GQ1b | IgM (monoclonal) |
| Motor neuropathy | GM1 | IgM (polyclonal or monoclonal) |
| Sensory neuropathy | Sulfatide | IgM (monoclonal or polyclonal) |
| Acute motor axonal neuropathy | GM1, GD1a | IgG |
| Miller Fisher syndrome Bickerstaff's brainstem encephalitis Acute ophthalmoparesis Ataxic Guillain-Barré syndrome |
GQ1b, GT1a | IgG |
| Pharyngeal-cervical-brachial weakness | GT1a (GQ1b) | IgG |
Adapted from: Pestronk, 2008.
| Antibody | Typical Neurologic Phenotypes | Cancer Association Estimate (%) | Usual Tumors | Notes |
|---|---|---|---|---|
| Amphiphysin | Polyradiculoneuropathy, SNN, EM, SPS | 80 | Breast cancer, SCLC | Isolated amphiphysin → usually women with breast cancer |
| Anti-Hu (ANNA-1) | SNN, EM, LE, chronic GI pseudo‑obstruction | 85 | SCLC, NSCLC, other neuroendocrine tumors, neuroblastoma | LE is typically non‑paraneoplastic in children |
| Anti-Ri (ANNA-2) | Brainstem/cerebellar syndrome, OMS | Greater than 70 | Breast greater than lung (SCLC and NSCLC) | Breast cancer in women; lung cancer in men |
| CV2/CRMP5 | EM, SNN | 80 | SCLC, thymoma | Thymoma cases often younger; may have MG |
| KLHL11 | Brainstem/cerebellar syndrome | 80 | Testicular cancer | Young men |
| Ma2 and/or Ma | LE, diencephalitis, brainstem encephalitis | Greater than 75 | Testicular cancer and NSCLC | Young men → testicular tumors and isolated Ma2 positivity; older patients → SCLC and both Ma 1/2 positivity |
| PCA‑2 (MAP1B) | Sensorimotor neuropathy, rapidly progressive cerebellar syndrome, EM | 80 | SCLC, NSCLC, breast | Often multisystem involvement |
| SOX1 | LEMS ± cerebellar syndrome | 90 | SCLC | Strong tumor correlation, less phenotype‑specific |
| Tr (DNER) | Rapidly progressive cerebellar syndrome | 90 | Hodgkin lymphoma | None |
| Yo (PCA-1) | Rapidly progressive cerebellar syndrome | Greater than 90 | Ovary and breast cancers | Almost all female; in men, antigen expression by tumor should be proven |
Abbreviations: ANNA = antineuronal nuclear antibody; CRMP5 = collapsin response-mediator protein 5; DNER = delta/notch-like epidermal growth factor–related receptor; EM = encephalomyelitis; KLHL11 = Kelch-like protein 11; LE = limbic encephalitis; LEMS = Lambert-Eaton myasthenic syndrome; MAP1B = microtubule-associated protein 1B; MG = myasthenia gravis; NMDAR = NMDA receptor; NSCLC = non–small-cell lung cancer; OMS = opsoclonus-myoclonus syndrome; PCA = Purkinje cell antibody; SCLC = small-cell lung cancer; SNN = sensory neuronopathy; SPS = stiff-person syndrome.
Source: Adapted from Graus et al., 2021
Antibody Typical Neurologic Phenotypes Cancer Association Estimate (%) Usual Tumors Notes AMPAR LE Greater than 50 SCLC and malignant thymoma Paraneoplastic origin is more likely when other onconeuronal antibodies co-occur CASPR2 Morvan syndrome 50 Malignant thymoma CASPR2 is considered intermediate-risk antibody only in setting of Morvan syndrome. When associated with other neurologic syndromes, the risk of cancer is very low GABABR LE Greater than 50 SCLC Paraneoplastic cases are more commonly observed in elderly men, smokers, with associated anti-KCTD16 antibodies; most of young patients are not paraneoplastic mGluR5 Encephalitis 50 Hodgkin lymphoma None NMDAR Anti-NMDAR encephalitis 38 Ovarian or extraovarian teratomas Tumor (mostly ovarian teratomas) predominates in female aged between 12 an d45 years (50%); elderly have less frequent tumors (less than 25%), but are usually carcinomas; paraneoplastic cases in children are very rare (less than 10%) P/Q VGCC LEMS, rapidly progressive cerebellar syndrome 50 (LEMS; nearly 90 for rapidly progressive cerebellar syndrome) SCLC Co-occurrence with N-type VGCC antibodies might be slightly more common in paraneoplastic LEMS
Abbreviations: AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; GABABR = gamma-aminobutyric acid-b receptor; KCTD16 = potassium channel tetramerization domain containing; LE = Limbic encephalitis; LEMS = Lambert-Eaton myasthenic syndrome; mGluR5 = metabotropic glutamate receptor type 5; NMDAR = NMDA receptor; SCLC = small-cell lung cancer; VGCC = voltage-gated calcium channel.
Source: Adapted from Graus et al., 2021
| Antibody | Typical Neurologic Phenotypes | Cancer Association Estimate (%) | Usual Tumors | Notes |
|---|---|---|---|---|
| AQP4 | NMOSD | Less than 5 | Adenocarcinomas | Older age, male, and severe nausea/vomiting at onset |
| CASPR2 | LE, acquired neuromyotonia (Isaac syndrome), and Morvan syndrome | Less than 30 | Malignant thymoma | Moran syndrome is more associated (approx 50%) with malignant thymoma, whereas LE is almost always nonparaneoplastic |
| DPPX | Encephalitis with central nervous system hyperexcitability and PERM | Less than 10 | B-cell neoplasms | None |
| GABAAR | Encephalitis | Less than 30 | Malignant thymoma | Paraneoplastic origin is less frequent (10%) in children than in adults (60%) |
| GAD65 | LE, SPS, cerebellar ataxia | Less then 15 | SCLC, other neuroendocrine tumors, and malignant thymoma | Paraneoplastic patients are older, more frequently male, with associated neuronal antibodies, and atypical clinical presentations |
| GFAP | Meningoencephalitis | 20 | Ovarian teratomas and adenocarcinomas | May occur as an immunologic accompaniment in anti-NMDAR encephalitis with ovarian teratomas |
| GlyR | LE and PERM | Less than 10 | Malignant thymoma and Hodgkin lymphoma | None |
| LGI1 | LE | Less than 10 | Malignant thymoma and neuroendocrine | Paraneoplastic cases are mainly observed in patients with Morvan syndrome and both serum LGI1 and CASPR2 antibodies |
| mGluR1 | Cerebellar ataxia | 30 | Mostly hematologic | None |
| MOG | MOG antibody-associated disease | 5 cases reported | Mostly ovarian teratomas | None |
Abbreviations: AQP4 = aquaporin 4; CASPR2 = contactin-associated protein-like 2; DPPX = dipeptidyl peptidase-like protein; GABAAR = gamma-aminobutyricacid-A receptor; GAD = glutamic acid decarboxylase; GFAP = glial fibrillary acidic protein; GlyR = glycine receptor; LE = limbic encephalitis; LGI1 = leucine-rich glioma-inactivated protein 1; mGluR1 = metabotropic glutamate receptor type 1; MOG = myelin oligodendrocyte glycoprotein; NMDAR = NMDA receptor; NMOSD = Neuromyelitis optica spectrum disorder; PERM = progressive encephalomyelitis with rigidity and myoclonus; SCLC = small-cell lung cancer; SPS = stiff-person syndrome.
Source: Adapted from Graus et al., 2021
Appendix C: PNS-CARE Score
The PNS-CARE score (Paraneoplastic Neurologic Syndromes Care Score) is a 2021 diagnostic tool that assigns a numerical value to determine the likelihood of paraneoplastic neurological syndromes. It combines clinical phenotype, antibody type (high, intermediate, low risk), and the presence of cancer to classify cases as definite, probable, or possible.
Clinical Level
- High-risk phenotypes: 3 points
- Intermediate-risk phenotypes: 2 points
- Defined phenotype epidemiologically not associated with cancer: 0 points
Laboratory Level
- High-risk antibody (greater than 70% cancer association): 3 points
- Intermediate risk antibody (30-70%): 2 points
- Lower risk antibody (less than 30%) or negative: 0 points
Cancer
- Found, consistent with phenotype and (if present) antibody, or not consistent but antigen expression demonstrated: 4 points
- Not found (or not consistent) but follow-up less than 2 years: 1 point
- Not found and follow-up greater than or equal to 2 years: 0 points
Diagnostic Level
- Definite greater than or equal to 8
- Probable 6 to 7
- Possible 4 to 5
- Non-PNS less than or equal to 3
Source: Graus et al., 2021
Appendix D: Antibody Testing Panels, Testing Requirements, Frequency Limitations
Tier 1: Core Antibody Panel (all members) (testing should include both serum and CSF samples when possible):
Cell-Surface and Synaptic Antibodies:
- Anti-AMPA receptor (GluR1/GluR2)
- Anti-CASPR2 (contactin-associated protein-like 2)
- Anti-DPPX (dipeptidyl-peptidase-like protein-6)
- Anti-GABA-A receptor
- Anti-GABA-B receptor
- Anti-GFAP (glial fibrillary acidic protein)
- Anti-glycine receptor
- Anti-GM1
- Anti-GQ1b
- Anti-IgLON5
- Anti-LGI1 (leucine-rich glioma-inactivated 1)
- Anti-mGluR5 (metabotropic glutamate receptor 5)
- Anti-MOG (myelin oligodendrocyte glycoprotein)
- Anti-NMDA receptor (NR1 subunit)
Intracellular Antibodies:
- Anti-amphiphysin
- Anti-GAD65 (glutamic acid decarboxylase-65)
- Anti-Hu
- Anti-Ma2/Ta
- Anti-Ri
- Anti-Yo
Tier 2: Syndrome-Specific Testing
Additional antibody testing is considered medically necessary when syndrome-specific clinical or radiological features are present:
- Anti-aquaporin-4: For demyelinating disease features
- Anti-dopamine 2 receptor: For basal ganglia encephalitis
- Anti-glutamate kainate 2 receptor: For cerebellar syndrome or cerebellitis
- Anti-Kelch-like protein 11: For brainstem syndrome
- Anti-GQ1b: For Bickerstaff brainstem encephalitis (BBE)
- Anti-ZSCAN: For ROHHAD syndrome (rapid onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation)
Testing Methodology Requirements
Medically necessary testing must utilize appropriate validated methodologies:
- Cell-based assays (CBA) for confirmation and characterization
- Immunoblot when indicated for specific antibodies
- Tissue-based immunofluorescence assay (IFA) for initial screening
Note: Testing of paired serum and CSF samples is strongly recommended, as CSF testing is more sensitive for most neuronal surface antibodies (exceptions: LGI1, CASPR2, MOG, aquaporin-4 may be better detected in serum).
Frequency Limitations
Testing is considered medically necessary at the following frequency:
- Initial diagnostic testing:
One comprehensive antibody panel per episode of suspected autoimmune encephalitis - Follow-up testing / Repeat antibody testing
- Initial testing performed on serum only, with subsequent CSF testing to confirm diagnosis
- New clinical presentation suggesting relapse or different antibody-mediated syndrome
- Monitoring treatment response when initial testing was positive (maximum every 3 months during active treatment)
References
The above policy is based on the following references:
- Abboud H, Probasco JC, Irani S, et al. Autoimmune encephalitis: Proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry. 2021;92(7):757-768.
- Aguirre-Cruz L, Charuel JL, Carpentier AF, Clinical relevance of non-neuronal auto-antibodies in patients with anti-Hu or anti-Yo paraneoplastic diseases. J Neurooncol. 2005;71(1):39-41.
- Almaabdi K, Ahmad Z, Johnson SR. Advanced autoantibody testing in systemic sclerosis. Diagnostics (Basel). 2023;13(5):851.
- Ambrosius W, Michalak S, Kozubski W, Kalinowska A. Myelin oligodendrocyte glycoprotein antibody-associated disease: Current insights into the disease pathophysiology, diagnosis and management. Int J Mol Sci. 2020;22(1):100.
- 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):268-282.
- Bataller L, Dalmau JO. Paraneoplastic disorders of the central nervous system: Update on diagnostic criteria and treatment. Semin Neurol. 2004;24(4):461-471.
- Bataller L, Kleopa KA, Wu GF, et al. Autoimmune limbic encephalitis in 39 patients: Immunophenotypes and outcomes. J Neurol Neurosurg Psychiatry. 2007;78(4):381-385.
- Bataller L, Wade DF, Graus F, et al. Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer. Neurology. 2004;62(5):778-782.
- Baumann N, Harpin ML, Marie Y, et al. Antiglycolipid antibodies in motor neuropathies. Ann N Y Acad Sci. 1998;854:322-329.
- Bird SJ. Diagnosis of myasthenia gravis. UpToDate [online serial], Waltham, MA: UpToDate; reviewed February 2025.
- Cats EA, Jacobs BC, Yuki N, et al. Multifocal motor neuropathy: Association of anti-GM1 IgM antibodies with clinical features. Neurology. 2010;75(22):1961-1967.
- Chan AY, Liu DT. Bread-and-butter in diagnosis of myasthenia gravis. Arch Neurol. 2005;62(6):1002-1003.
- Chang I. Diagnosis of peripheral neuropathies. CNI review library. Colorado Neurological Institue. Englewood, CO:2002;13(2). Available at: http://www.thecni.org/reviews/13-2-p11-chang.htmAccessed May 7, 2008.
- Chang T, Lang B. GAD antibodies in stiff-person syndrome. Neurology. 2004;63(11):1999-2000.
- Chen JJ, Bhatti MT. Clinical phenotype, radiological features, and treatment of myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) optic neuritis. Curr Opin Neurol. 2020;33(1):47-54.
- Chen X, Zhang B, Mao X, et al. Clinical characteristics of bullous pemphigoid patients of different ages and the possible mechanism. J Dermatol. 2025;52(4):672-681.
- Chinoy H, Fertig N, Oddis CV, et al. The diagnostic utility of myositis autoantibody testing for predicting the risk of cancer-associated myositis. Ann Rheum Dis. 2007;66(10):1345-1349.
- Conrad K, Schneider H, Ziemssen T, et al. A new line immunoassay for the multiparametric detection of antiganglioside autoantibodies in patients with autoimmune peripheral neuropathies. Ann N Y Acad Sci. 2007;1109:256-264.
- Dalmau J, Gultekin HS, Posner JB. Paraneoplastic neurologic syndromes: Pathogenesis and physiopathology. Brain Pathol. 1999;9(2):275-284.
- Dalmau J, Rosenfeld M. Paraneoplastic syndromes affecting peripheral nerve and muscle. UpToDate [serial online]. Waltham, MA: UpToDate; reviewed September 2006.
- Dalmau J, Rosenfeld MR. Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2024.
- Dalmau J, Rosenfeld MR. Overview of paraneoplastic syndromes of the nervous system. UpToDate [online serial]. Waltham, MA: UpToDate; updated September 2024.
- Damato V, Spagni G, Monte G, et al. Clinical value of cell-based assays in the characterisation of seronegative myasthenia gravis. J Neurol Neurosurg Psychiatry. 2022;93(9):995-1000.
- Derfuss T, Meinl E. Identifying autoantigens in demyelinating diseases: Valuable clues to diagnosis and treatment? Curr Opin Neurol. 2012;25(3):231-238.
- Diogenes L, Dellavance A, Baldo DC, et al. Detection of autoantibodies against the acetylcholine receptor, evaluation of commercially available methodologies: Fixed cell-based assay, radioimmunoprecipitation assay and enzyme-linked immunosorbent assay. J Neuromuscul Dis. 2024;11(3):613-623.
- Dyck PJ, Low PA, Windebank AJ, et al. Plasma exchange in polyneuropathy associated with monoclonal gammopathy of undetermined significance. N Engl J Med. 1991;325(21):1482-1486.
- Elman LB, McCluskey L. Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2021.
- Eurelings M, Moons KG, Notermans NC, et al. Neuropathy and IgM M-proteins: Prognostic value of antibodies to MAG, SGPG, and sulfatide. Neurology. 2001;56(2):228-233.
- Fadda G, Armangue T, Hacohen Y, et al. Paediatric multiple sclerosis and antibody-associated demyelination: Clinical, imaging, and biological considerations for diagnosis and care. Lancet Neurol. 2021;20(2):136-149.
- Farina A, Villagrán-García M, Vogrig A, et al. Neurological adverse events of immune checkpoint inhibitors and the development of paraneoplastic neurological syndromes. Lancet Neurol. 2024;23(1):81-94.
- Finsterer J, Muellbacher W, Halbmayer WM, et al. Anti-GM1 antibodies in polyneuropathies of unknown origin. J Clin Pathol. 1996;49(5):422-425.
- Flanagan EP, Tillema J-M. oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed February 2024.
- Fluri F, Ferracin F, Erne B, Steck AJ. Microheterogeneity of anti-myelin-associated glycoprotein antibodies. J Neurol Sci. 2003;207(1-2):43-49.
- Garces-Sanchez M, Dyck PJ, Kyle RA, et al. Antibodies to myelin-associated glycoprotein (anti-Mag) in IgM amyloidosis may influence expression of neuropathy in rare patients. Muscle Nerve. 2008;37(4):490-495.
- Glisson CC. Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2025.
- Goroll AH. Primary Care Medicine. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:952.
- Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
- Graus F, Vogrig A, Muñiz-Castrillo S, et al. Updated diagnostic criteria for paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm. 2021;8(4):e1014.
- Griffin JW, Hsieh ST, McArthur JC, et al. Laboratory testing in peripheral nerve disease. Neurol Clin. 1996;14(1):119-133.
- Gronseth GS, Barohn R, Narayanaswami P. Practice advisory: Thymectomy for myasthenia gravis (practice parameter update): Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2020;94(16):705-709.
- Gultekin SH, Rosenfeld MR, Voltz R, et al. Paraneoplastic limbic encephalitis: Neurological symptoms, immunological findings and tumour association in 50 patients. Brain. 2000;123 ( Pt 7):1481-1494.
- Hacohen Y, Absoud M, Woodhall M, et al; On behalf of UK & Ireland Childhood CNS Inflammatory Demyelination Working Group. Autoantibody biomarkers in childhood-acquired demyelinating syndromes: Results from a national surveillance cohort. J Neurol Neurosurg Psychiatry. 2014;85(4):456-461.
- Hara M, Martinez-Hernandez E, Ariño H, et al. Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor. Neurology. 2018;90(16):e1386-e1394.
- Hayes KC, Hull TC, Delaney GA, et al. Elevated serum titers of proinflammatory cytokines and CNS autoantibodies in patients with chronic spinal cord injury. J Neurotrauma. 2002;19(6):753-761.
- Hughes RA. Peripheral neuropathy. BMJ. 2002;324(7335):466-469.
- Irani SR. Autoimmune encephalitis. Continuum (Minneap Minn). 2024;30(4):995-1020.
- Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of paraproteinemic demyelinating neuropathies. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Soc. J Peripher Nerv Syst. 2006;11(1):9-19.
- Junior JG, Mugii N, Inaoka PT, et al. Inflammatory myopathies overlapping with systemic sclerosis: A systematic review. Clin Rheumatol. 2022;41(7):1951-1963.
- Kalluri M, Sahn SA, Oddis CV, et al. Clinical profile of anti-PL-12 autoantibody. Cohort study and review of the literature. Chest. 2009;135(6):1550-1556.
- Klein CJ, Beecher G, Lamb C, et al. LRP4-IgG service line testing in seronegative myasthenia gravis and controls. J Neuroimmunol. 2022;368:577895.
- Lancaster E. Paraneoplastic disorders. Continuum (Minneap Minn). 2017;23(6, Neuro-oncology):1653-1679.
- Latov N, Sferruzza A. Laboratory diagnosis of peripheral neuropathy. Clinical Application Paper. Madison, NJ: Quest Diagnostics; updated November 2007. Available at: http://www.questdiagnostics.com/hcp/intguide/jsp/showintguidepage.jsp?fn=CAP_LabDiagnosis_PeripheralNeurop.htm. Accessed December 3, 2008.
- Lee JY, Sung JJ, Cho JY, et al. MuSK antibody-positive, seronegative myasthenia gravis in Korea. J Clin Neurosci. 2006;13(3):353-355.
- Li Y, Peng Y, Yang H. Serological diagnosis of myasthenia gravis and its clinical significance. Ann Transl Med. 2023;11(7):290.
- Liebeskind DS. Paraneoplastic encephalomyelitis. eMedicine Neurology Topic 300. Omaha, NE: eMedicine.com; updated November 2, 2005. Available at: http://www.emedicine.com/neuro/topic300.htm. Accessed January 31, 2006.
- Lilleker JB, Jones MS, Mohanraj R, et al. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology. 2016;87(17):1848-1849.
- Lopez PH, Comín R, Villa AM, et al. A new type of anti-ganglioside antibodies present in neurological patients. Biochim Biophys Acta. 2006;1762(3):357-361.
- Lotze TE. Differential diagnosis of acute central nervous system demyelination in children. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2014.
- Low PA, Stevens C, Suarez GA, et al. Diseases of peripheral nerves. In: Clinical Neurology. RJ Joynt, RC Griggs, eds, Philadelphia, PA: Lippincott-Raven; 1996;4(51):91-92.
- Lucchinett CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology. 1998;50(3):652-657.
- Maisonobe T, Chassande B, Verin M, et al. Chronic dysimmune demyelinating polyneuropathy: A clinical and electrophysiological study of 93 patients. J Neurol Neurosurg Psychiatry. 1996;61(1):36-42.
- Mareska M, Gutmann L. Lambert-Eaton myasthenic syndrome. Semin Neurol. 2004;24(2):149-53.
- Mariotto S, Gajofatto A, Batzu L, et al. Relevance of antibodies to myelin oligodendrocyte glycoprotein in CSF of seronegative cases. Neurology. 2019;93(20):e1867-e1872.
- Mehdi A, Ko DY. Paraneoplastic cerebellar degeneration. eMedicine Neurology Topic 299. Omaha, NE: eMedicine.com; updated January 30, 2002. Available at: http://www.emedicine.com/neuro/topic299.htm. Accessed October 17, 2002.
- Michael S, Waters P, Irani SR. Stop testing for autoantibodies to the VGKC-complex: Only request LGI1 and CASPR2. Pract Neurol. 2020;20(5):377-384.
- Miller ML. Clinical manifestations and diagnosis of adult dermatomyositis and polymyositis. UpToDate [online serial]. Waltham, MA: UpToDate; September 2009.
- Mirian A, Nicolle MW, Edmond P, Budhram A. Comparison of fixed cell-based assay to radioimmunoprecipitation assay for acetylcholine receptor antibody detection in myasthenia gravis. J Neurol Sci. 2022;432:120084.
- Mousavi A, Kumar P, Frykman H. The changing landscape of autoantibody testing in myasthenia gravis in the setting of novel drug treatments. Clin Biochem. 2024;133-134:110826.
- Murinson BB, Butler M, Marfurt K, et al. Markedly elevated GAD antibodies in SPS: Effects of age and illness duration. Neurology. 2004;63(11):2146-2148.
- Murrell DF, Ramirez-Quizon M. Management and prognosis of bullous pemphigoid. UpToDate [online serial], Waltham, MA: UpToDate; reviewed February 2025.
- National Comprehensive Cancer Network (NCCN). Management of immune checkpoint inhibitor-related toxicities. NCCN Clinical Practice Guidelines in Oncology, Version1.2026. Plymouth Meeting; PA; October 2025.
- Nosadini M, Eyre M, Molteni E, et al. Use and safety of immunotherapeutic management of N-methyl-d-aspartate receptor antibody encephalitis: A meta-analysis. JAMA Neurol. 2021;78(11):1333-1344.
- O'Ferrall EK, White CM, Zochodne DW. Demyelinating symmetric motor polyneuropathy with high titers of anti-GM1 antibodies. Muscle Nerve. 2010;42(4):604-608.
- Osborne B, Balcer LJ. Optic neuritis: Pathophysiology, clinical features, and diagnosis. UpToDate [online serial], Waltham, MA: UpToDate; reviewed February 2025a.
- Osborne B, Balcer LJ. Optic neuritis: Prognosis and treatment. UpToDate [online serial], Waltham, MA: UpToDate; reviewed February 2025b.
- Osborne B, Balcer LJ. Optic neuropathies. UpToDate [online serial], Waltham, MA: UpToDate; reviewed Februuary 2025c.
- Pappu R, Seetharaman M. Polymyositis: Differential diagnoses & workup. Omaha, NE: eMedicine.com; updated November 6, 2009. Available at: http://emedicine.medscape.com/article/335925-diagnosis. Accessed March 15, 2010.
- Paterson RW, Zandi MS, Armstrong R, et al. Clinical relevance of positive voltage-gated potassium channel (VGKC)-complex antibodies: Experience from a tertiary referral centre. J Neurol Neurosurg Psychiatry. 2014;85(6):625-630.
- Pearce DA, Atkinson M, Tagle DA. Glutamic acid decarboxylase autoimmunity in Batten disease and other disorders. Neurology. 2004;63(11):2001-2005.
- Pestronk A. Treatable gait disorder and polyneuropathy associated with high serum IgM binding to antigens that copurify with myelin-associated glycoprotein. Muscle and Nerve. 1994;17:1293-1300.
- Pestronk A. Washington University. Neuromuscular Disease Center [website]. St. Louis, MO; Washington University; 2008. Available at: http://www.neuro.wustl.edu/NEUROMUSCULAR/index.html. Accessed April 24, 2008.
- Pestronk A, Chuquilin M, Choksi R. Motor neuropathies and serum IgM binding to NS6S heparin disaccharide or GM1 ganglioside. J Neurol Neurosurg Psychiatry. 2010;81(7):726-730.
- Petzold A, Plant GT. Chronic relapsing inflammatory optic neuropathy: A systematic review of 122 cases reported. J Neurol. 2014;261(1):17-26.
- Pourmand R. Autoantibody testing. Neurol Clin. 2004;22(3):703-717, vii.
- Pranzatelli MR, Tate ED, Wheeler A, et al. Screening for autoantibodies in children with opsoclonus-myoclonus-ataxia. Pediatr Neurol. 2002;27(5):384-387.
- Ramaekers VT, Quadros EV. Cerebral folate deficiency syndrome: Early diagnosis, intervention and treatment strategies. Nutrients. 2022;14(15):3096.
- Ramaekers VT, Rothenberg SP, Sequeira JM, et al. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med. 2005;352(19):1985-1991.
- Reindl M, Di Pauli F, Rostásy K, Berger T. The spectrum of MOG autoantibody-associated demyelinating diseases. Nat Rev Neurol. 2013;9(8):455-461.
- Romi F, Aarli JA, Gilhus NE. Seronegative myasthenia gravis: Disease severity and prognosis. Eur J Neurol. 2005;12(6):413-418.
- Ropper AH, Gorson KC. Neuropathies associated with paraproteinemia. N Engl J Med. 1998;338(22):1601-1607.
- Sakalauskaite-Juodeikiene E, Armaliene G, Kizlaitiene R, et al. Detection of aquaporin-4 antibodies for patients with CNS inflammatory demyelinating diseases other than typical MS in Lithuania. Brain Behav. 2018;8(11):e01129.
- Santacroce L, Gagliardi S, Latorre V, et al. Paraneoplastic syndromes. eMedicine Neurology. Topic 1747. Omaha, NE: eMedicine.com; July 3, 2002. Available at: http://www.emedicine.com/med/topic1747.htm. Accessed October 17, 2002.
- Scofield RH. Autoantibodies as predictors of disease. Lancet. 2004;363(9420):1544-1546.
- Selcen D, Fukuda T, Shen XM, Engel AG. Are MuSK antibodies the primary cause of myasthenic symptoms? Neurology. 2004;62(11):1945-1950.
- Senties-Madrid H, Vega-Boada F. Paraneoplastic syndromes associated with anti-Hu antibodies. Israel Med Assoc J. 2001;3:94-103.
- Song Y, Hu Q, Zhang Q. Anti-Kelch-like protein 11 antibody encephalitis: A case report and literature review. Front Neurol. 2023:14:1273051.
- Spagni G, Gastaldi M, Businaro P, et al. Comparison of fixed and live cell-based assay for the detection of AChR and MuSK antibodies in myasthenia gravis. Neurol Neuroimmunol Neuroinflamm. 2022;10(1):e200038.
- Spiro SG, Gould MK, Colice GL; American College of Chest Physicians. Initial evaluation of the patient with lung cancer: Symptoms, signs, laboratory tests, and paraneoplastic syndromes: ACCP evidenced-based clinical practice guidelines 2nd edition). Chest. 2007;132(3 Suppl):149S-160S.
- Sridharan R, Lorenzo N. Focal muscular atrophies. eMedicine Neurology Topic 137. Omaha, NE: eMedicine.com; updated July 17, 2001. Available at: http://www.emedicine.com/neuro/topic137.htm. Accessed October 17, 2002.
- Steck AJ, Erne B, Gabriel JM, et al. Paraproteinaemic neuropathies. Brain Pathol. 1999;9(2):361-368.
- Symonds JD, Moloney TC, Lang B, et al. Neuronal antibody prevalence in children with seizures under 3 years: A prospective national cohort. Neurology. 2020;95(11):e1590-e1598.
- Tagawa Y, Yuki N, Ohnishi A, et al. Parameters for monitoring treatment effects in CIDP with anti-MAG/SGPG IgM antibody. Muscle Nerve. 2001;24(5):701-704.
- Taylor BV, Gross L, Windebank AJ. The sensitivity and specificity of anti-GM1 antibody testing. Neurology. 1996;47(4):951-955.
- Tebo AE, Haven TR, Jackson BR. Autoantibody diversity in paraneoplastic syndromes and related disorders: The need for a more guided screening approach. Clin Chim Acta. 2016;459:162-169.
- Tidy C. Plasma autoantibodies disease associations. Patient UK. Leeds, UK: Egton Medical Information Systems (EMIS); updated January 10, 2007. Available at: http://www.patient.co.uk/showdoc/40001200. Accessed November 11, 2008.
- Tobin WO, Pittock SJ. Autoimmune neurology of the central nervous system. Continuum (Minneap Minn). 2017;23(3, Neurology of Systemic Disease):627-653.
- Toro J, Cuellar-Giraldo D, Duque A, et al. Seronegative paraneoplastic limbic encephalitis associated with thymoma. Cogn Behav Neurol. 2017;30(3):125-128.
- van Sonderen A, Schreurs MW, Wirtz PW, et al. From VGKC to LGI1 and Caspr2 encephalitis: The evolution of a disease entity over time. Autoimmun Rev. 2016;15(10):970-974.
- Varga J. Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2024.
- Vedeler CA, Antoine JC, Giometto B, et al.; Paraneoplastic Neurological Syndrome Euronetwork. Management of paraneoplastic neurological syndromes: Report of an EFNS Task Force. Eur J Neurol. 2006;13(7):682-690.
- Vincent A, Leite MI. Neuromuscular junction autoimmune disease: Muscle specific kinase antibodies and treatments for myasthenia gravis. Curr Opin Neurol. 2005;18(5):519-525.
- Wang N. Neurologic complications of cancer immunotherapy. Continuum (Minneap Minn). 2023;29(6):1827-1843.
- Waschbisch A, Atiya M, Schaub C, et al. Aquaporin-4 antibody negative recurrent isolated optic neuritis: Clinical evidence for disease heterogeneity. J Neurol Sci. 2013;331(1-2):72-75.
- Waters P, Vincent A. Myelin oligodendrocyte glycoprotein CSF testing needs testing. Neurology. 2019;93(20):871-872.
- Wendel EM, Thonke HS, Bertolini A, et al; BIOMARKER Study Group. Temporal dynamics of MOG antibodies in children with acquired demyelinating syndrome. Neurol Neuroimmunol Neuroinflamm. 2022;9(6):e200035.
- Wielosz E, Dryglewska M, Majdan M. Clinical consequences of the presence of anti-RNA Pol III antibodies in systemic sclerosis. Postepy Dermatol Alergol. 2020;37(6):909-914.
- Willison HJ, Yuki N. Peripheral neuropathies and anti-glycolipid antibodies. Brain. 2002;125(Pt 12):2591-1625.
- Wills AJ, Turner B, Lock RJ, et al. Dermatitis herpetiformis and neurological dysfunction. J Neurol Neurosurg Psychiatry. 2002;72(2):259-261.
- Wolfe GI, Nations SP. Guide to antibody testing in peripheral neuropathies. Neurologist. 2001;7(4):195-207.
- Xu M, Ma C, Dong M, et al. Two case reports and a systematic review of the literature on adult cerebral cortical encephalitis with anti-myelin oligodendrocyte glycoprotein antibody. Front Immunol. 2023;14:1203615.
- Yazbeck E, Maurey H, Leroy C, et al. Progressive leukodystrophy-like demyelinating syndromes with MOG-antibodies in children: A rare under-recognized phenotype. Neuropediatrics. 2021;52(4):337-340.
- Zvartau-Hind M, Lewis R. Chronic inflammatory demyelinating polyneuropathy. eMedicine Neurology Topic 467. Omaha, NE: eMedicine.com; updated April 22, 2002. Available at: http://www.emedicine.com/neuro/topic467.htm. Accessed October 17, 2002.
