Conduction block in immune‐mediated neuropathy: paranodopathy versus axonopathy

Abstract

Background and purpose Conduction block is a pathognomonic feature of immune‐mediated neuropathies. The aim of this study was to advance understanding of pathophysiology and conduction block in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). Methods A multimodal approach was used, incorporating clinical phenotyping, neurophysiology, immunohistochemistry and structural assessments. Results Of 49 CIDP and 14 MMN patients, 25% and 79% had median nerve forearm block, respectively. Clinical scores were similar in CIDP patients with and without block. CIDP patients with median nerve block demonstrated markedly elevated thresholds and greater threshold changes in threshold electrotonus, whilst those without did not differ from healthy controls in electrotonus parameters. In contrast, MMN patients exhibited marked increases in superexcitability. Nerve size was similar in both CIDP groups at the site of axonal excitability. However, CIDP patients with block demonstrated more frequent paranodal serum binding to teased rat nerve fibres. In keeping with these findings, mathematical modelling of nerve excitability recordings in CIDP patients with block support the role of paranodal dysfunction and enhanced leakage of current between the node and internode. In contrast, changes in MMN probably resulted from a reduction in ion channel density along axons. Conclusions The underlying pathologies in CIDP and MMN are distinct. Conduction block in CIDP is associated with paranodal dysfunction which may be antibody‐mediated in a subset of patients. In contrast, MMN is characterized by channel dysfunction downstream from the site of block.

Quantitative magnetic resonance imaging of the brachial plexus shows specific changes in nerve architecture in chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and motor neuron disease

“…This can be the result of various cellular mechanisms, such as demyelination or a disturbance of the cytoskeleton caused by a loss of neurofilaments and microtubules. We think that our findings may reflect demyelination rather than a disturbance of the cytoskeleton as histological studies reported myelin detachment The mechanism of paranodal myelin detachment is present in some patients with CIDP, as described in earlier electrophysiological studies [42][43][44]. Taken together, the changes in FA, MD and RD in our CIDP group most likely reflect the loss of myelin.…”

“…We think that our findings may reflect demyelination rather than a disturbance of the cytoskeleton as histological studies reported myelin detachment and myelin loss without damage to axons induced by macrophages around the (inter)nodal regions in patients with CIDP [ 3 , 4 , 5 , 38 , 39 , 40 , 41 ]. The mechanism of paranodal myelin detachment is present in some patients with CIDP, as described in earlier electrophysiological studies [ 42 , 43 , 44 ]. Taken together, the changes in FA, MD and RD in our CIDP group most likely reflect the loss of myelin.…”

Motor unit number index (MUNIX) in chronic inflammatory demyelinating polyneuropathy: A potential role in monitoring response to intravenous immunoglobulins

“…Nerve excitability studies in CIDP suggest disruption of nodal sodium-channel function and resulting hyperpolarisation may interfere with nerve conduction and cause block (Cappelen-Smith et al 2000, 2001Boerio et al 2010;Lin et al 2011). Elevated thresholds on nerve excitability studies have also been demonstrated in CIDP patients with and without conduction block compared to healthy controls, possibly related to changes in the paranodal region (Garg et al 2019). Although autoantibodies are only identified in a minority of patients (Devaux et al 2016), it is hypothesized that IVIg competes with functionally important autoantibodies, producing rapid although reversible improvement in nodal function (Boerio et al 2010;Berger et al 2013).…”

Multifocal motor neuropathy: controversies and priorities

“…Depolarisation at the site of CB may result in this observation via intracellular sodium (Na + ) accumulation possibly due to sodium channel or Na + /potassium (K + )-pump dysfunction. Recent mathematical modelling by Garg and colleagues suggested reductions of Na + and K + ion channel function along the axon distal to CB 24. These functional disturbances of the axonal membrane have been hypothesised to lead to increased ectopic generation manifesting as positive symptomatology such as fasciculations and cramps 23.…”

“…Using indirect immunofluorescence on rat teased nerve fibres incubated with sera of 11 MMN patients, Garg et al identified only one patient with a paranodal staining pattern despite 55% of patients being anti-GM1 IgM positive 24. In contrast, 9 of 11 CIDP patients with CB showed staining at the node, paranode and/or myelin.…”