Clinical Information

Immune-mediated neuropathies refer to a group of disorders that share overlapping sensory, motor, and autonomic clinical, laboratory, and electrodiagnostic features. Testing for autoantibodies associated with immune-mediated neuropathies should be considered after a detailed history and physical examination is completed. In most situations, nerve conduction studies and electromyography are crucial in distinguishing between primary axonal, primary demyelinating, or mixed axonal and demyelinating neuropathies. This enables a more focused testing approach for disease-relevant autoantibodies. This evaluation focuses on persons with immune-mediated demyelinating neuropathies.

The antibody tests included in this evaluation aim to support the diagnosis of an immune-mediated demyelinating neuropathy as well aid in distinguishing between the more common forms of immune-mediated demyelinating neuropathies that are associated with sensitive and specific antibody biomarkers.

Autoantibodies directed against myelin-associated glycoprotein are associated with sensory motor demyelinating peripheral neuropathy. A distal acquired demyelinating symmetric (DADS) neuropathy phenotype is the most commonly-associated presentation. This may mimic distal forms of chronic inflammatory demyelinating polyneuropathy (CIDP). Patients typically have a slowly progressive symmetric sensory ataxia with or without distal weakness and an IgM monoclonal gammopathy of undetermined significance. Nerve conduction studies typically demonstrate a characteristic progressive sensory-predominant mixed axonal and demyelinating neuropathy with reduced distal conduction velocities that are greater distally. In general, patients with a DADS neuropathy show limited treatment responses to intravenous immunoglobulin (IVIG), and more aggressive immunotherapy may be needed.

A subset of patients with suspected CIDP have been identified with autoantibodies targeting nodal-paranodal proteins. These patients share common immunopathological mechanisms of disease, clinical features, and treatment responses that are distinct from classic CIDP. A common target of these autoantibodies is the neurofascin-155 (NF155)-contactin-1 (CNTN1) adhesion complex, which is critical in maintaining the paranodal myelin-axon junction. NF155 is expressed at the paranodal loops of Schwann cells where it interacts with CNTN1 expressed on adjacent axons. This interaction stabilizes and allows the proper organization of the paranodal axoglial junction. Antibody-mediated disruption of this interaction in animal models recapitulates the pathophysiology observed in humans.

NF155 IgG antibodies are present in approximately 5% to 10% of patients with CIDP-like presentations and, more rarely, in those with more acute forms of demyelinating polyradiculoneuropathy. NF155 IgG positive cases are more likely to present with distal weakness, gait disturbance, tremor, and dysarthria as compared to classic CIDP. Most patients who are seropositive for NF155 IgG have been reported to be refractory to IVIG therapy and often require second-line treatment that includes B-cell depleting therapies, such as rituximab. The detection of NF155 IgG4 is a highly-specific finding and has not been reported in other disease mimics, such as hereditary neuropathies, distal acquired demyelinating symmetric neuropathy, and motor neuron disease.

CNTN1 IgG antibodies are present in approximately 2% of patients with CIDP-like presentations. CNTN1 IgG-positive cases are more likely to present with neuropathic pain, sensory ataxia, and subacute progressive demyelinating polyradiculoneuropathy or polyradiculopathy. The majority of seropositive patients have been reported to be refractory to treatment with IVIG. However, some of these patients respond well to B-cell depleting therapies, such as rituximab. Up to half of CNTN1 IgG-positive patients with CIDP or CIDP-like presentations have been reported to develop membranous nephropathy, and thus, screening for proteinuria may be warranted.

Autoantibodies targeting ganglioside GQ1b are associated with a group of disorders that includes Miller Fisher syndrome (MFS), Bickerstaff brainstem encephalitis (BBE), and classic Guillain-Barre syndrome (GBS) with ophthalmoplegia. Collectively these are referred to as GQ1b IgG-related syndromes, which reflects the diverse clinical presentations associated with these autoantibodies. The prevalence of GQ1b IgG in MFS and BBE is high and has been reported to be greater than 80% in well-defined clinical cohorts. GQ1b IgG may occur in patients with GBS but generally with a lower prevalence.

Autoantibodies targeting ganglioside GD1b antibodies frequently occur in sensory ataxic conditions such as chronic, ataxic, neuropathy, ophthalmoplegia, IgM gammopathy, cold agglutinins, and disialosyl antibodies (CANOMAD), acute sensory ataxic neuropathy (ASAN), and chronic ataxic neuropathy with disialosyl antibodies (CANDA).

Autoantibodies targeting ganglioside GM1 more commonly occur in patients with multifocal motor neuropathy (MMN), multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy, and motor-predominant Guillain-Barre syndrome.