Elsevier

Clinical Neurophysiology

Volume 132, Issue 4, April 2021, Pages 1000-1007
Clinical Neurophysiology

Early axonal loss predicts long-term disability in chronic inflammatory demyelinating polyneuropathy

https://doi.org/10.1016/j.clinph.2020.12.017Get rights and content

Highlights

  • Early axonal loss can accurately predict the long-term clinical outcome in patients treated for CIDP.

  • Early axonal loss is associated with the long-term axonal loss in patients treated for CIDP.

  • Delay in treatment is associated with worse axonal loss and clinical outcome.

Abstract

Objective

To investigate early pre-treatment nerve fiber loss as a predictor of long-term clinical outcome in chronic inflammatory demyelinating polyneuropathy (CIDP).

Methods

In 14 patients, motor and sensory conduction studies of the median, fibular, and sural nerves were performed at pre-treatment and follow-up 11–28 years later. Z-scores of amplitudes were combined as biomarkers of axonal loss and Z-scores of conduction properties as demyelination scores. The axonal loss was further examined by electromyography (EMG) and motor unit number estimation. Axonal and demyelination scores were compared to clinical outcomes in the Inflammatory Rasch-built Overall Disability Scale, the Neuropathy Impairment Score, and dynamometry.

Results

At follow-up 12 patients walked independently, one needed support and one could not walk. The initial and follow-up axonal and demyelination scores were markedly abnormal. The initial axonal loss but not demyelination was strongly associated with both the follow-up axonal loss and the clinical measures. Moreover, delay of treatment initiation negatively influenced the axonal scores and clinical outcomes.

Conclusion

In this hypothesis generating limited study, we found that axonal loss at early CIDP was highly predictive for long-term nerve fiber loss and disability.

Significance

The study indicates that prompt initiation of treatment to prevent nerve fiber loss is necessary for outcome in CIDP.

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.

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