Early axonal loss predicts long-term disability in chronic inflammatory demyelinating polyneuropathy
Introduction
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated polyneuropathy (McCombe et al., 1987, Prineas and McLeod, 1976) associated with a variable degree of axonal loss (Nagamatsu et al., 1999). Nerve conduction studies consistent with demyelination are mandatory for the diagnosis (Cornblath et al., 1991, Van den Bergh et al., 2010, Van den Bergh and Piéret, 2004), whereas the occurrence and the role of the axonal loss are less well-defined. Previously axonal loss was considered a secondary event in demyelinating disorders (Bouchard et al., 1999, Said, 2006, Said et al., 1981), whereas recent studies indicate that axonal damage occurs early in the disease (Barnett et al., 2016). Several electrophysiological studies have shown axonal loss with denervation of muscle fibers at electromyography (EMG), reduced amplitude of the compound muscle action potential (CMAP), and a reduced number of motor units at motor unit number estimation (MUNE) (Kuwabara et al., 2006, Paramanathan et al., 2016, Sghirlanzoni et al., 2000).
Long-term CIDP is associated with a variable degree of disability, motor weakness with impaired walking performance being a frequent disturbance (Al-Zuhairy et al., 2020, Dyck et al., 1975, McCombe et al., 1987). As for the Guillain-Barré Syndrome (Willison et al., 2016), it is a general assumption that axonal loss in CIDP is the pathophysiological mechanism that underlies permanent disability (Bouchard et al., 1999, Mathey et al., 2015, Said et al., 1981). In a long-term CIDP study, disability was associated with the axonal loss but not with demyelination (Harbo et al., 2008a) whereas other studies were unable to establish such a connection (Kerasnoudis et al., 2015).
Due to its heterogeneous phenotype, it has been difficult to define biomarkers that may predict the course of CIDP and the degree of permanent disability. Early axonal loss in chronic CIDP could represent a long-term deficit, and we hypothesize that early axonal loss is a predictor of long-term axonal loss and long-term clinical disability. If the axonal loss is decisive for long-term disability the therapeutic strategy at the time of diagnosis might need a more comprehensive consideration in the future. To test this hypothesis, a study of the long-term disability and the electrophysiological changes was carried out in a group of patients 10–30 years after diagnosis. We examined whether the degree of axonal loss and not demyelination at the time of treatment initiation was predictive for, 1) the severity of axonal loss at follow-up, and 2) the long-term disability. As a biomarker of axonal loss, we calculated an axonal score from the deviations of the amplitudes of the compound muscle (CMAP) and sensory nerve (SNAP) action potentials from controls, and as a biomarker of demyelination, a demyelination score from the deviations of the motor and sensory conduction velocities and the decay of the CMAP between distal and proximal stimulation sites. As biomarkers of the clinical status, we used the Rasch-built Overall Disability Scale for immune-mediated peripheral neuropathies (I-RODS), the Neuropathy Impairment Score (NIS), and measurement of isokinetic strength (IKS).
Section snippets
Study population
The study population consisted of a subgroup of the 51 patients with probable or definite CIDP (Van den Bergh et al., 2010) treated with immunotherapy (i.e. immunoglobulins, plasma exchange, corticosteroids, azathioprine, or cyclophosphamide) during the period between Jan 1st, 1985 and Dec 31st, 2006 previously described (Al-Zuhairy et al., 2020). Exclusion criteria were other neuropathies, other neurological disorders, and disabling musculoskeletal disorders. A total of 16 eligible CIDP
Characteristics of the CIDP patients
The clinical data of the patients are presented in Table 1, Table 2. At the initial visit, four patients had no ambulation. In the follow-up study, 12 patients walked independently while one had lost ambulation and five of the patients were in remission.
Axonal loss as indicated by NCS, EMG, and MUNE
The amplitudes of the CMAPs and the SNAPs deviated strongly from normal controls and there was no difference between the combined axonal Z-scores at the initial and at the follow-up study (Table 1, Fig. 2A). At univariate regression analysis,
Discussion
The main and novel finding of this study was a strong association between the early axonal loss at the time of treatment initiation of CIDP and the degree of disability and impairment 11–28 years later. The ages of the patients varied greatly between 44 and 75 years, but the association between axonal loss and clinical disability was only slightly affected by age in a multivariate analysis. In contrast, the degree of demyelination was not predictive of clinical disability. Recognizing that
Author contributions
AA: Contributed to the design of the study, writing the protocol, coordination, clinical assessments, statistical analyses, and writing and revising the manuscript.
JJ: Contributed to the design of the study and writing and revising the manuscript.
CK: Contributed to the design of the study, electrophysiological examination, statistical analyses, and writing and revising the manuscript.
Acknowledgements
This study was partially funded with a grant from Takeda Pharmaceutical Company without any involvement in the work performed.
Declaration of interest
AA: Declarations of interest: None.
JJ: Received a research grant from Takeda Pharmaceutical Company to partially cover the expenses for a post-doc study including the present study without providing any personal benefits for JJ.
CK: Declarations of interest: None.
References (48)
- et al.
Serum cytokine and chemokine profiles in patients with chronic inflammatory demyelinating polyneuropathy
J Neuroimmunol
(2015) - et al.
Reproducibility, and sensitivity to motor unit loss in amyotrophic lateral sclerosis, of a novel MUNE method: MScanFit MUNE
Clin Neurophysiol
(2017) - et al.
The utility of motor unit number estimation methods versus quantitative motor unit potential analysis in diagnosis of ALS
Clin Neurophysiol
(2018) - et al.
Detection of early motor involvement in diabetic polyneuropathy using a novel MUNE method - MScanFit MUNE
Clin Neurophysiol
(2019) - et al.
Axonal loss in patients with inflammatory demyelinating polyneuropathy as determined by motor unit number estimation and MUNIX
Clin Neurophysiol
(2016) - et al.
Chronic relapsing polyneuritis
J Neurol Sci
(1976) Chronic inflammatory demyelinating polyneuropathy
Neuromuscul Disord
(2006)- et al.
Guillain-Barré syndrome
Lancet
(2016) - et al.
A population-based study of long-term outcome in treated chronic inflammatory demyelinating polyneuropathy
Muscle Nerve
(2020) - et al.
Axonal damage in central and peripheral nervous system inflammatory demyelinating diseases: common and divergent pathways of tissue damage
Curr Opin Neurol
(2016)
Sensory action potentials and biopsy of the sural nerve in neuropathy
Brain
Estimating motor unit numbers from a CMAP scan
Muscle Nerve
Clinicopathologic findings and prognosis of chronic inflammatory demyelinating polyneuropathy
Neurology
Electrophysiologic correlations with clinical outcomes in CIDP
Muscle Nerve
Peroneal muscular atrophy (PMA) and related disorders. I. Clinical manifestations as related to biopsy findings, nerve conduction and electromyography
Brain
Evoked action potentials and conduction velocity in human sensory nerves
Brain Res
Follow-up nerve conduction studies in CIDP after treatment with IGIV-C: Comparison of patients with and without subsequent relapse
Muscle Nerve
Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force
Neurology
Advances in chronic inflammatory demyelinating polyneuropathy: disease variants and inflammatory response mediators and modifiers
Curr Opin Neurol
Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort
Neurology
Chronic inflammatory polyradiculoneuropathy
Mayo Clin Proc
A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy
Ann Neurol
Clinical, Sonographic, and Electrophysiologic Longitudinal Features of Chronic Inflammatory Demyelinating Polyneuropathy
J Neuroimaging
The N-Pact Factor: Evaluating the Quality of Empirical Journals with Respect to Sample Size and Statistical Power
PLoS One
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