Neuromuscular Notes: Autoantibody Evaluations for Peripheral Neuropathies

Over the past few decades, there has been a rapidly expanding list of antibody biomarkers that have facilitated the classification and characterization of autoimmune neuropathies.^1-3 Autoantibody testing should be considered after a detailed history and physical examination. Additionally, nerve conduction study (NCS) and EMG, in most cases, provide additional critical information for characterizing the neuropathy phenotype (ie, axonal/Schwann cell predominant process) which can also help narrow down the autoantibody profile (Tables 1 and 2). In this article, we discuss the usefulness of autoantibody testing for peripheral neuropathies and the effective interpretation of autoantibody test results in clinical practice.

Guillain-Barré Syndrome and Variants

Guillain-Barré syndrome (GBS) encompasses a group of heterogeneous but related disorders of peripheral nerves that have an acute onset and usually a monophasic course. Different ganglioside autoantibodies have been associated with GBS variants. These antibodies, however, have varied clinical specificities and positive predictive values for these presentations.

GD1a IgG has been reported in up to 60% of persons of Asian descent with acute motor axonal neuropathy (AMAN),⁴ who are reported to have a severe form of axonal GBS, often requiring mechanical ventilation.⁵ It is unclear, however, whether there is an outcome difference between GD1a IgG seropositive and seronegative AMAN. GM1 IgG positivity has also been reported in AMAN but seems to have a relative lower clinical specificity, considering it has been reported in association with multiple demyelinating neuropathy presentations.⁶

GQ1b IgG has been reported among a group of disorders at times referred to as “anti-GQ1b antibody syndrome,” including Miller Fisher syndrome (MFS), GBS with ophthalmoplegia, Bickerstaff brainstem encephalitis (BBE), and acute ophthalmoparesis without ataxia.⁷ This terminology was not intended to be used as clinical diagnosis but to recognize the varied presentations associated with GQ1b autoantibodies, which have been found in approximately 80% of those with MFS and 68% with BBE.^8,9

Other autoantibody associations include GT1a IgG in association with the pharyngeal-cervical-brachial variant of GBS and GD1b-IgG in association with a minority of acute sensory ataxic neuropathy (35% GD1b IgG seropositive) or ataxic GBS (14% GD1b-IgG seropositive).^10,11 Rarely, autoantibodies against nodal or paranodal proteins such as contactin-1 and contactin-associated protein 1 (CASPR1) been reported in association with acute inflammatory demyelinating polyneuropathy (AIDP).^12-14 Despite these reported associations none of these antibodies are required for the diagnosis of GBS variants.¹¹

Subacute or Chronic Demyelinating Polyradiculoneuropathy or Polyneuropathy

Chronic Inflammatory Demyelinating Polyradiculoneuropathies

Autoantibodies against nodal and paranodal proteins have been reported in about 10% to 20% of people with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and are directed against neurofascin 155 (NF155), neurofascin 140 (NF140), neurofascin 186 (NF186), contactin-1 and CASPR1.¹⁵ Because the targeted antigens are nodal or paranodal proteins, these neuropathies have been classified as nodo-paranodopathies. The majority of cases have had a relatively poor response to intravenous immunoglobulin (IVIG), compared with “antibody-negative” CIDP, but respond favorably to rituximab.³ Testing for these autoantibodies not only helps with diagnosis but also aids in selection of optimal treatment strategy.

NF155 and contactin-1 autoantibodies have been carefully characterized across multiple laboratories/institutions. IgG4 is the predominant subclass for most cases. Among NF155 neuropathies, cases testing specifically for NF155-IgG4 subtypes provides some additional clinical specificity, because people who are NF155 pan-IgG seropositive but NF155-IgG4 seronegative often do not have clinical or histopathologic features associated with NF155 nodoparanodopathies.^16,17 Individuals presenting with subacute or chronic demyelinating polyradiculoneuropathy with weakness that is greater distally than proximally, positive sensory symptoms, sensory ataxia, tremors, dysarthria, neuropathic pain, autonomic dysfunction, or papilledema should be tested for NF155 IgG4.^17-19 Acute or subacute sensory predominant presentations (especially chronic immune sensory polyradiculopathy [CISP] or CISP+) and associated neuropathic pain should lead to consideration of contactin-1 evaluation.^12,20,21 Moreover, some contactin-1 autoantibody seropositive cases have associated membranous glomerulonephropathy.²² However, a considerable proportion of NF155 and contactin-1 nodo-paranodopathies can be difficult to distinguish during initial evaluation, so testing for both antibodies together may be indicated.

Very few people with NF140/186 autoantibody seropositive CIDPs have been reported to date.^16,23 Some cases have been reported to have subacute onset demyelinating neuropathies, at times with cranial nerve involvement and focal segmental glomerulosclerosis.¹⁵ Recently, a series of 8 cases with IgG1 subclass-specific autoantibodies to NF186, NF140, and NF155 isoforms was described.²⁴ Cranial nerve deficits, autonomic dysfunction, and respiratory involvement were common clinical presentations amongst these cases.

CASPR1 IgG was initially reported in 2 individuals with inflammatory demyelinating neuropathy, one with diagnosis of CIDP and another with GBS.¹⁴ A recent study reported that some patients with antibodies binding to CASPR1/CNTN1 complex demonstrate weaker reactivity specifically to CASPR1 protein.¹³ Common neurologic features among these cases included acute and subacute disease progression, cranial nerve involvement, neuropathic pain, and ataxia.

Distal Acquired Demyelinating Symmetric Neuropathy

Approximately half of people with distal acquired demyelinating symmetric (DADS) neuropathy and IgM monoclonal gammopathy are myelin-associated glycoprotein (MAG) IgM seropositive.³ DADS is usually refractory to immunotherapy (eg, IVIG), and the presence or absence of MAG IgM does not affect the clinical outcome,²⁵ such that MAG IgM seropositivity (especially titers >10,000 Bühlmann Titer Unit [BTU]) mostly provides additional data to support the DADS diagnosis in the setting of distal predominant neuropathy phenotype and demyelinating features on NCS. Low MAG-IgM titers (<10,000 BTU) have been reported in persons with nonDADS presentations as well,²⁶ highlighting that MAG-IgM seropositivity is not synonymous with DADS diagnosis.

Multifocal Motor Neuropathy

GM1 IgM antibodies have been reported in 40% to 50% of multifocal motor neuropathy (MMN).^27-29 Similar to lower motor neuron predominant motor neuron disease, MMN typically presents with progressive, painless weakness. Serum GM1 IgM may at times be useful to distinguish these conditions from each other.³⁰

Subacute or Chronic Axonal Polyradiculoneuropathy and Neuropathy

Several neural specific autoantibodies, including antineuronal nuclear antibody type 1 (ANNA1, anti-Hu),³¹ collapsin response-mediator protein-5 (CRMP5, anti-CV2) IgG,³² amphiphysin IgG,³³ Purkinje cell antibody type 2 (PCA2; also known as microtubule-associated protein 1B [MAP1B] IgG),³⁴ and adaptor protein 3, subunit B2 (AP3B2) IgG³⁵ have been described in association with axonal polyradiculoneuropathy. Most of these autoantibodies (ANNA1, CRMP5, amphiphysin, and PCA2) are considered high-risk cancer autoantibodies (>70% cancer association).³⁶ CRMP5 and amphiphysin are usually associated with asymmetric involvement and severe neuropathic pain.^32,33 Additionally, coexisting myelopathy or myeloneuropathy has been reported in some people with ANNA1, amphiphysin IgG, CRMP5 IgG, and AP3B2 IgG.^35,37

Trisulfated disaccharide IdoA2S-GlcNS6S (TS-HDS) IgM has been reported in association with painful, predominantly sensory, axonal polyneuropathy.³⁸ In our clinical practice, we have come across cases of chronic length-dependent neuro-pathies unresponsive to immunotherapy in association with this antibody. Additional validation studies in independent laboratories may improve our understanding of the clinical specificity of this antibody.

Sensory Neuronopathy

The clinical manifestation of sensory neuronopathy includes burning pain, numbness, sensory ataxia, pseudoathetosis, and areflexia. NCS typically show absent or reduced sensory responses asymmetrically or globally with normal to minimal abnormalities of motor responses.³⁹ Paraneoplastic neurologic syndromes should be in the differential diagnosis when these symptoms are present, especially if associated with inflammatory markers in the cerebrospinal fluid (CSF) or motor involvement.^36,40 Common autoantibodies associated with paraneoplastic sensory ganglionopathy include ANNA1, PCA2, CRMP5, and amphiphysin.

In a recent prospective, multicenter study, approximately two-thirds of participants with sensory neuronopathy were reported to have fibroblast growth factor receptor-3 (FGFR3) IgG.⁴¹ Other studies, however, have demonstrated the neuropathy presentations associated with FGFR3 IgG are not limited to sensory ganglionopathy or even nonlength-dependent small fiber neuropathy and ganglionopathy.⁴² Individuals with sensory ganglionopathy should also be asked about sicca symptoms (dry eyes and dry mouth), because Sjögren syndrome is also an immune-mediated cause of this phenotype.

Motor Neuronopathy

Recently, IgLON5 IgG has been described in association with a bulbar-onset motor neuronopathy in a series of 5 people, 4 of whom had coexisting sleep disorders.⁴³ In our clinical practice we have also come across 3 similar cases with possible or probable amyotrophic lateral sclerosis (ALS) that were IgLON5 IgG positive.⁴⁴ All 3, however, had coexisting central nervous system (CNS) findings supportive of IgLON5 autoimmunity including 1 or more of the following: vocal cord paresis, chorea, and rapid eye movement (REM) behavioral disorder. Paraneoplastic motor neuronopathy with features of rhombencephalitis have also been described in association with Ma2 antibody,⁴⁵ ANNA2,⁴⁶ leucine zipper 4 IgG, and kelch-like protein 11 IgG.⁴⁷ Testing for these autoantibodies should only be considered if persons with motor neuronopathy have additional features (eg, REM sleep behavioral disorder, vocal cord dysfunction, involuntary movements, or brainstem/cerebellar involvement).

Peripheral Nerve Hyperexcitability Syndromes

People with peripheral nerve hyperexcitability present with fasciculation, myokymia, muscle stiffness, or cramps.⁴⁸ Many have coexisting dysautonomia and some can have coexisting CNS involvement (eg, encephalopathy or sleep dysfunction). CASPR2 IgG is commonly associated with this presentation, with or without coexisting leucine-rich glioma-inactivated protein-1 (LGI1) IgG.^49,50 Recent data demonstrates the importance of titration of CASPR2 IgG on cell-based assays (CBA), because low titers (<1:100) of CASPR2 IgG in serum do not have high clinical specificity for neurologic autoimmunity.⁵¹ Although LGI1 IgG is more commonly associated with CNS autoimmunity, some cases of peripheral nerve hyperexcitability with only LGI1 IgG seropositivity have also been reported.^52,53 Netrin-1 receptor autoantibodies have been reported in patients with thymoma-associated neuromyotonia and myasthenia gravis.⁵⁴

Small Fiber Neuropathy or Autonomic Neuropathy

In a large retrospective cohort, autoantibodies against TS-HDS and FGFR3 were reported in 28% and 17% of individuals with small fiber neuropathy, respectively.⁵⁵ Approximately 5% were seropositive for both autoantibodies to TS-HDS and FGFR3. Almost all individuals with TS-HDS and/or FGFR3 autoantibodies had dysautonomia, although additional validation work is needed to understand clinical specificity of these autoantibodies.

Autoimmune autonomic ganglionopathy (AAG) is commonly associated with nicotinic α3 acetylcholine receptor (nAChR) autoantibody.^56,57 Several studies suggest a pathogenic potential of nAChR IgG.^58,59 Common clinical presentations among these cases include anhidrosis and orthostatic hypotension or intolerance.⁵⁶ Malignancy is rarely associated with nAChR IgG seropositive AAG. Titers higher than 0.40 nmol (negative <0.02 nmol/L) usually have high specificity for autoimmune autonomic failure, whereas titer below 0.20 nmol/L can be nonspecific.⁶⁰

Autonomic dysfunction, especially chronic gastrointestinal dysmotility, is commonly associated with classic paraneoplastic autoantibodies such as ANNA1 and CRMP5 IgG^.32

Interpretation of Autoantibody Results

Autoantibody results must be correlated with clinical phenotype. When a person with an atypical phenotype has seropositivity, there are several potential explanations to consider. Assay specificity can result in false positives (eg, use of immundots without tissue indirect immunofluorescence assay [TIFA] for paraneoplastic autoantibodies).^61-63 Low antibody titers of some autoantibodies (eg, nAChR IgG) have low specificity for neurologic autoimmunity.⁶⁰ Use of serum alone vs serum and CSF testing for certain antibodies rarely associated with immune-mediated polyradiculoneuropathies (eg, CSF glial fibrillary acidic protein IgG has much higher clinical specificity for neurologic autoimmunity) may also generate false positives.⁶⁴ Testing for specific immunoglobulin isotypes for some antibodies is important (eg, GM1 IgM has much higher specificity for MMN than GM1 IgG).^27-29 Evaluation of IgG subclass is crucial for some antibodies (eg, NF155 IgG4 has higher specificity for nodo-paranodopathy).¹⁸ Finally, seropositivity of some autoantibodies lacks clinical utility (eg, striational IgG).⁶⁵

When a negative test result is received for someone who has clinical features highly suggestive of an immune mediated neuropathy or neuronopathy, clinicians should consider contacting the testing laboratory to check for detection of any unclassified autoantibody on TIFA.

Conclusion

In appropriate clinical settings, autoantibody testing can help the managing clinician confirm the diagnosis, predict the natural history of disease, estimate neuropathy prognosis, guide underlying malignancy search and surveillance, and select appropriate immunotherapy. However, clinical specificity for many of the autoantibodies associated with peripheral neuropathy is not 100%. Therefore, appropriate ordering of antibody tests based on neuropathy presentation and, sometimes, NCS findings, is crucial for high positive predictive value.