Demyelinating Neuropathies

Nerve conduction studies (NCSs) can determine whether a neuropathy is due to injury to the nerve axon (axonal neuropathy) or to the myelin sheath (demyelinating neuropathy). As the number of conditions that cause demyelinating neuropathy is quite limited, this distinction is clinically important and helps focus the diagnostic evaluation. While specific electrophysiologic findings vary between hereditary and acquired demyelinating neuropathies, slowed conduction velocities (< 70% normal) and prolonged distal motor latencies (> 150% normal) are characteristic features in both.

A.

Diffusely and uniformly slowed nerve conduction velocities strongly suggest an inherited demyelinating neuropathy. In contrast, variably slowed conduction velocities, conduction block, or abnormal temporal dispersion suggest an acquired process. Acute axonal injury or nerve transection can electrodiagnostically mimic conduction block before Wallerian degeneration of the distal axon occurs. This is known as “pseudoconduction block” and can be clarified by repeating NCS after several days or weeks.
B.

Charcot-Marie-Tooth disease (CMT) refers to a group of hereditary sensory and motor polyneuropathies categorized by electrophysiologic findings (demyelinating or axonal) and clinical and genetic features. Features that raise suspicion for a hereditary neuropathy include foot deformities (i.e., pes cavus, hammertoes) and a family history of similar neuropathies. CMT1A, which is caused by a duplication in the PMP22 gene, accounts for ~ 70% of hereditary demyelinating neuropathies. There is no disease-modifying therapy currently available for any form of CMT, and treatment consists primarily of supportive care such as bracing and physical therapy.
C.

Hereditary neuropathy with liability to pressure palsies (HNPP) causes a polyneuropathy with intermediate conduction velocities, as well as multiple demyelinating mononeuropathies at sites of common nerve entrapment (i.e., median neuropathies at the wrists, ulnar neuropathies at the elbows, and common peroneal neuropathies at the fibular heads). HNPP is caused by PMP22 deletion (allelic with CMT1A). As with CMT, there is no disease-specific treatment.
D.

In patients with demyelinating neuropathies with hereditary features, genetic testing can provide a definitive diagnosis. The exact testing strategy (i.e., testing for a single gene mutation, a panel of genetic tests, whole exome sequencing) depends on local cost and availability of different approaches. Thorough genetic testing will uncover a responsible gene mutation in up to 90% of patients with hereditary demyelinating neuropathies.
E.

In addition to HNPP, multiple demyelinating mononeuropathies at sites of common nerve entrapment should prompt consideration of transthyretin ( TTR ) hereditary amyloidosis. TTR hereditary amyloidosis often causes an axonal polyneuropathy in addition to multiple compression neuropathies, and is also associated with cardiac and renal disorders. Identification of TTR amyloid is essential given effective disease-modifying therapy (patisiran and inotersen).
F.

Guillain-Barré syndrome (GBS) is a clinically heterogeneous group of acute inflammatory neuropathies. The most common subtype is acute inflammatory demyelinating polyneuropathy (AIDP), a rapidly progressive demyelinating polyneuropathy causing ascending weakness and numbness. Axonal GBS variants have similar clinical characteristics but lack demyelinating findings on NCS. Often preceded by a mild viral or diarrheal illness, GBS is thought to be related to antigenic molecular mimicry of proteins found on nerve axons or the myelin sheath. Cytoalbuminologic dissociation (elevated protein with normal white blood cells) in the cerebrospinal fluid (CSF) supports a diagnosis of GBS, but may be absent early in the disease course. While a variety of disorders can mimic GBS clinically, fewer conditions produce both rapidly progressive sensorimotor symptoms and the peripheral demyelination seen on NCS in AIDP. These include human immunodeficiency virus (HIV)-related inflammatory demyelinating polyradiculoneuropathy, diphtheritic neuropathy, polyneuropathy associated with immune checkpoint inhibitors (including nivolumab, pembrolizumab, and nivolumab), hexacarbon or arsenic toxicity, and, rarely, atypical cases of lymphomatous neuropathy. By definition, AIDP is a monophasic illness with slow recovery over weeks to months. Treatment with intravenous immunoglobulin (IVIG) or plasmapheresis improves recovery. Disease relapse or clinical worsening more than 8 weeks after symptom onset should prompt consideration of chronic inflammatory demyelinating polyneuropathy (CIDP).
G.

A number of conditions cause a more chronically progressive demyelinating neuropathy. CIDP typically causes slowly progressive, relatively symmetric, weakness and numbness. Weakness is typically more prominent than sensory loss and involves both proximal and distal muscles. As in AIDP, CSF cytoalbuminologic dissociation helps confirm the diagnosis, though both HIV and immune checkpoint inhibitors can cause CIDP associated with elevated CSF protein and leukocytes. Initial treatment should consist of corticosteroids or IVIG; plasmapheresis may also be used. If refractory, rituximab, cyclophosphamide, and azathioprine may be considered. Consider testing refractory patients for anti-neurofascin antibodies; when present, consider rituximab therapy. Multifocal acquired demyelinating sensory and motor polyneuropathy (MADSAM), a variant of CIDP, presents with asymmetric weakness and numbness, and multifocal motor neuropathy (MMN), which is associated with anti-GM1 antibodies, present with pure motor symptoms, most prominent in the upper extremities. Some chronic demyelinating neuropathies are associated with serum paraproteins, and are often refractory to traditional CIDP treatment (see Chapter 91 ).