Neuropathy in sporadic inclusion body myositis: A multi-modality neurophysiological study

Highlights

• A majority of sIBM patients have conventional nerve conduction or thermal threshold abnormalities.

• Markers of neuropathy in sIBM do not correlate with clinical markers of sIBM severity.

• sIBM axons have altered excitability - depolarization or adaptation to myopathy are possible causes.

Abstract

Objective

Sporadic inclusion body myositis (sIBM) has been associated with neuropathy. This study employs nerve excitability studies to re-examine this association and attempt to understand underlying pathophysiological mechanisms.

Methods

Twenty patients with sIBM underwent median nerve motor and sensory excitability studies, clinical assessments, conventional nerve conduction testing (NCS) and quantitative thermal threshold studies. These results were compared to established normal controls, or results from a normal cohort of older control individuals.

Results

Seven sIBM patients (35%) demonstrated abnormalities in conventional NCS, with ten patients (50%) demonstrating abnormalities in thermal thresholds. Median nerve motor and sensory excitability differed significantly in sIBM patients when compared to normal controls. None of these neurophysiological markers correlated significantly with clinical markers of sIBM severity.

Conclusion

A concurrent neuropathy exists in a significant proportion of sIBM patients, with nerve excitability studies revealing changes possibly consistent with axolemmal depolarization or concurrent neuronal adaptation to myopathy. Neuropathy in sIBM does not correlate with muscle disease severity and may reflect a differing tissue response to a common pathogenic factor.

Significance

This study affirms the presence of a concurrent neuropathy in a large proportion of sIBM patients that appears independent of the severity of myopathy.

Introduction

Sporadic inclusion body myositis (sIBM) is the most common primary myopathy in the >50 years population of the developed world (Dimachkie and Barohn, 2014, Callan et al., 2017) and is an insidiously progressive myopathy of unclear pathophysiology. The 2011 European Neuromuscular Centre (ENMC) criteria defines sIBM by a mix of clinical and histopathological features reflecting its predilection for clinical involvement of the quadriceps complex and the forearm flexors alongside mixed inflammatory and degenerative features seen on muscle biopsy (Rose and Group, 2013). sIBM progresses very slowly, causing significant disability with a median progression to wheelchair use of approximately 14 years, but is not the cause of death in the majority of individuals affected, with most sufferers dying with rather than from the disease (Benveniste et al., 2011). As yet, no disease modifying therapy has robustly demonstrated efficacy to date (Rose et al., 2015).

sIBM diagnosis is complicated by the variable appearance of patients on electrophysiological investigations, with mixed myopathic and “pseudo-neurogenic” features described on conventional electromyography (EMG) analysis (Eisen et al., 1983, Joy et al., 1990, Needham and Mastaglia, 2016). This contributes to the high rate of initial misdiagnosis, with an average delay to diagnosis of more than half a decade from symptom onset (Needham et al., 2008, Benveniste et al., 2011).

Contention has previously existed as to the possibility of concurrent nerve involvement in sIBM patients. Epidemiologically there is no doubt that peripheral neuropathy has been seen in a variable but large proportion of confirmed sIBM cases (Lotz et al., 1989, Schroder and Molnar, 1997).

Histopathological studies provide evidence of a concurrent neuropathy in a proportion of sIBM patients. Both intramuscular and sural nerve studies have demonstrated myelinated fibre axonal loss and Wallerian degeneration in sIBM patients on both conventional and electron microscopy (Lindberg et al., 1990, Hermanns et al., 2000). The interpretation of these findings is unclear, given the non-specific nature of the nerve histopathology alongside the older age of many of these patients and the possible presence of confounding co-morbidities.

Neurophysiology in sIBM yields a similarly mixed picture. A significant proportion of biopsy-proven sIBM patients have conventional nerve conduction study (NCS) abnormalities including mild slowing or evidence of a sensory axonal neuropathy alongside apparently neurogenic EMG recruitment patterns (Joy et al., 1990, Lindberg et al., 1990, Needham and Mastaglia, 2016), and other authors have also demonstrated quantitative abnormalities in sensory function (Arnardottir et al., 2003). These apparently neurogenic features on conventional studies however, are discounted by other authors employing more detailed quantitative EMG (Brannagan et al., 1997, Barkhaus et al., 1999) and single-fibre EMG analyses in studies of small numbers of sIBM patients demonstrating classically myopathic patterns (Hatanaka and Oh, 2007). The older age of sIBM patients again confounds NCS interpretation, with most prior studies not comparing results against age-matched controls.

In the current cross-sectional study, we have used threshold tracking techniques to examine the excitability of motor and sensory axons in sIBM. Alongside conventional NCS, we aim to confirm dysfunction of axons in sIBM and understand the basis of nerve involvement in this disease.