Introduction

Guillain-Barré syndrome (GBS) is an immune-mediated acute peripheral neuropathy involving mainly spinal nerve roots, peripheral nerves and cerebral nerves, and is currently the most common cause of acute flaccid paralysis worldwide. As an autoimmune disease (AID) with a high rate of mortality and disability, immunotherapy is essential [1, 2].

Glucocorticoids (GCs) is considered as the most commonly used drug for the treatment of AID worldwide because of its cost-effectiveness and strong immunosuppressive effect [3]. Unfortunately, its use in GBS patients is controversial [4, 5]. Clinical trials in Europe and North America did not observe significant efficacy of GCs alone in GBS, however, as it currently stands, the actual efficacy of GCs may be underestimated, because these above-mentioned studies did not discuss the efficacy of GCs in different subtypes in a categorical manner, and the use and dosage of GCs were not uniform [6,7,8]. Scholars such as Hughes have suggested that patients with GBS with conduction block respond well to GCs, while the use of GCs in patients with denervation delays the recovery of GBS, although the specific mechanism needs to be further explored [9].

According to neuroelectrophysiological studies, GBS consists of two major subtypes, acute inflammatory demyelinating polyneuropathy (AIDP), and acute motor axonal neuropathy (AMAN) [10]. AIDP is associated with macrophage and CD4+ T cell-mediated inflammation and peripheral nerve demyelination, whereas AMAN is mainly associated with the involvement of ganglioside autoantibodies and complement [11]. Given that these two major subtypes have different pathological characteristics and pathogenesis, and their epidemiology in Asia differs from foreign studies, it is necessary to explore the mechanism of action and effects of GCs based on different subtypes.

Methods

Patient ascertainment

This is a retrospective multicenter study and the medical records of consecutive hospitalized patients with a diagnosis of GBS in 31 representative tertiary hospitals, located in 14 provinces in southern China, between 1 January 2013 and 30 September 2016, were collected. Patients who fulfilled the established clinical criteria of Asbury and Cornblath (1990) were enrolled [12]. In addition, the patients whose clinical presentation and ancillary data were typical of GBS except for preservation or exaggeration of reflexes were also included. Details regarding clinical data extraction and analysis, including inclusion and exclusion criteria, were described in our previous study [Information Extraction

Information on age, sex, preceding events, initial symptoms, concomitant symptoms, severity at admission, at nadir, at discharge, length of hospitalization, findings of electrodiagnosis (EDX), treatment regime, types and doses of GCs were extracted. The motor function deficits of included patients were assessed by the Hughes Functional Grading Scale, a widely accepted scale of disability for GBS (grade 6, dead; grade 5, requiring assisted respiration; grade 4, bed-bound; grade 3, able to walk with aid; grade 2, able to walk independently; grade 1, minimal signs and symptoms, able to run; grade 0, normal) [14]. Details regarding clinical data extraction were described in our previous study [17].

A study used a rabbit model of the axonal form of GBS initially explored the reasons for the ineffectiveness of GCs in treating AMAN, suggesting that MPS did not reduce complement C3 deposition and sodium (Nav) channel disruption, but significantly reduced macrophage infiltration in the ventral roots and thus delay the axonal regeneration [18]. Studies of pathophysiology about AMAN have shown that the invasion of macrophages was rare at the acute progressive phase but significantly more frequent at the site of inflammation mainly during the recovery phase, which suggested a role for macrophages in the clearance of damaged myelin and axon fragments and promoting nerve repair and regeneration [19]. Whereas, the classical experimental autoimmune neuritis (EAN) model, which highly replicates human AIDP in terms of clinical manifestations, immunology, histopathology, and electrophysiology [20], indicated that “Classically” activated (M1) macrophages mainly accumulated at the acute phase of EAN and promoted the inflammatory response, while during the recovery phase, macrophages could change their expression profile, M2 macrophages attenuated inflammation and promoted tissue repair [21, 22]. Ultrastructural studies showed that macrophage-mediated nerve injury was a pathological hallmark of AIDP/EAN [21,22,23]. Macrophages (M1) were involved in this process by regulating cytokines, chemokines, adhesion molecules, nitric oxide (NO) and matrix metalloproteinases (MMPs), and as major antigen-presenting and effector cells, macrophages played a key role in EAN pathogenesis by expressing antigens and promoting Th1 and Th17 polarization [24].

In summary, we hypothesize that the different mechanisms of macrophages' role in the inflammatory response of AIDP and AMAN may lead to different effects of GCs therapy. We will further test our hypothesis through animal experiments.

As a multicenter study, we derived relatively powerful results, but there exist inevitably some limitations. First, as a retrospective study, the long-term follow-up information was insufficient to further explore the prognosis of patients with different subtypes treated with different doses of GCs, further studies were anticipated; Second, the number of patients with AMAN subtypes in this study was relatively small; Third, because the study was a retrospective review of medical records and database, extracting bias was unavoidable. However, in order to reduce the bias as much as possible, a unified parameter standard in the analysis of NCS was adopted and data were extracted by our team members through strict training.

Conclusion

In conclusion, our data firstly provides information about whether the responses to GCs differ between the principal subtypes of GBS, and prompts recommendations about the design of future GBS trails. GCs induce different effects in specific GBS subtypes, among which high-dose GCs therapy has a better prognosis for patients with AIDP. The effects of GCs on GBS subtypes should be discussed separately in future clinical trials to explore its mechanism of action and provide more timely and effective treatment measures for GBS patients.