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RESEARCH ARTICLE
Asia Pac J Clin Trials Nerv Syst Dis 2018,  3:68

Neuroelectrophysiological characteristics of peripheral neuropathy in primary Sjögren's syndrome: study protocol for a prospective case series and pre-preliminary results


1 Department of Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
2 Basic Medical College, Kunming Medical University, Kunming, Yunnan Province, China

Date of Web Publication15-May-2018

Correspondence Address:
Hong Xu
Department of Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province
China
Lian-Mei Zhong
Department of Neurology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-3932.232079

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  Abstract 

Background and objectives: Sjögren's syndrome (SS) is a chronic progressive autoimmune disease. The incidence of peripheral nervous system damage in patients with primary SS (pSS) is 10–30%. Previous studies have shown that there are multiple electrophysiological manifestations in pSS patients presenting with peripheral neuropathy. However, there is no consensus on its neuroelectrophysiological manifestations. Peripheral neuropathy associated with pSS is easily confused with peripheral neuropathy of other etiologies. We hope to observe the neuroelectrophysiological manifestations of peripheral neuropathy associated with pSS to assist in the diagnosis of the disease.
Design: A prospective case series.
Methods: A total of 100 pSS patients with peripheral neuropathy receiving treatment in the Department of Neurology, First Affiliated Hospital of Kunming Medical University, China will be included in this study. Fifty-two patients presenting with peripheral neuropathy associated with pSS have been included in a preliminary investigation.
Outcome measures and preliminary results: The primary outcome measure is the incidence of abnormal motor nerve conduction velocity in these patients. The secondary outcome measures are the incidences of abnormalities in terminal motor latencies, compound muscle action potential amplitudes, sensory nerve conduction velocities, sensory nerve action potential amplitudes, F waves, and sympathetic skin responses. The results of 52 patients included in the preliminary study showed that the incidences of each electrophysiological index was similar between the upper and lower extremities. Abnormal motor nerve conduction velocity occurred more frequently than abnormal compound muscle action potential amplitude. Abnormal sensory nerve conduction velocity was observed significantly more often than abnormal sensory nerve action potential amplitude. Abnormal motor nerve conduction velocity had a similar incidence to abnormal sensory nerve conduction velocity. Abnormal compound muscle action potential amplitude had a similar incidence to abnormal sensory nerve action potential amplitude. Abnormal F waves were observed significantly less frequently than abnormal motor nerve conduction study. Abnormal sympathetic skin response was seen with a similar incidence to abnormal motor nerve conduction study.
Discussion: The results of this study, as indicated by the preliminary investigation, will reveal the neuroelectrophysiological abnormalities in peripheral neuropathy associated with pSS, which will aid diagnosis of the disease.
Ethics and dissemination: This study was approved by Medical Ethics Committee of Kunming Medical University of China on October 14th, 2005 (approval No. 20051014). The study protocol was designed in September 2016 and registered in April 2018. The study protocol received ethics approval from Medical Ethics Committee of Kunming Medical University of China on October 14th, 2016 (approval No. 2016101411). Patient recuritment for the preliminary study was performed during January to October 2017. Patient recuritment for this study will begin in June 2018. Data collection will end in December 2020. The current study will be performed from June 2018 to December 2020. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be published at www.figshare.com.
Trial registration: This trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1800015669).

Keywords: primary Sjögren syndrome; peripheral nerve injury; electrophysiological characteristics; motor nerve; sensory nerve; autonomic nerve; prospective case series


How to cite this article:
Wang D, Li ZM, Zhao MJ, Xue RH, Xu H, Zhong LM. Neuroelectrophysiological characteristics of peripheral neuropathy in primary Sjögren's syndrome: study protocol for a prospective case series and pre-preliminary results. Asia Pac J Clin Trials Nerv Syst Dis 2018;3:68-73

How to cite this URL:
Wang D, Li ZM, Zhao MJ, Xue RH, Xu H, Zhong LM. Neuroelectrophysiological characteristics of peripheral neuropathy in primary Sjögren's syndrome: study protocol for a prospective case series and pre-preliminary results. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2018 [cited 2021 May 12];3:68-73. Available from: https://www.actnjournal.com/text.asp?2018/3/2/68/232079


  Introduction Top


Research background

Sjögren's syndrome (SS) is a diffuse connective tissue disease characterized by invasion of exocrine glands, lymphocytic infiltration, and specific autoantibodies. It is a chronic progressive autoimmune disease that can be classified into primary or secondary categories (Brito-Zerón et al., 2016). When there is no other autoimmune disease, SS is referred to as primary SS (pSS). pSS has a prevalence in China of 0.29-0.77% (Chen et al., 2013) and the pathological mechanism of peripheral neuropathy in pSS is currently unclear. Sural nerve biopsy has revealed pathological changes including vasculitis and perivascular nonspecific inflammatory cell infiltration (Mellgren et al., 1989; Grant et al., 1997; Cao et al., 2005). Studies have also shown that pathological changes in pSS include vascular inflammation and non-vascular inflammatory immune-mediated neurodegeneration, and immune-mediated neurodegeneration in pSS itself may be the major pathological mechanism (Grant Et al., 1997; Cao et al., 2005; Goransson et al., 2006). 10–30% of patients with pSS develop peripheral neurological damage (Tobón et al., 2012). If subclinical patients with neuroelectrophysiological abnormalities are included, the incidence is more than 50% (Mellgren et al. 2007). Peripheral neuropathy caused by pSS can occur in various stages of the disease. Peripheral neuropathy occurs as the first symptom in some cases of pSS (Cheng et al., 2013; Meng and He, 2014).

There are various forms of peripheral nerve damage. pSS mainly includes distal symmetric polyneuropathy, mononeuropathy, and sensory neuropathy (Gemignani et al., 1994). Symmetric polyneuropathy is the most common and manifests as sensory, motor, and autonomic dysfunction. Many studies have reported that pSS involves autonomic neuropathy of small nerve fibers (Sandroni and Low, 2001; Goransson et al., 2006; Wakasugi et al., 2009), manifesting as dystrophy, dryness, numbness, burning sensation, and abnormal sweating of the skin at the end of the limb. The electrophysiological manifestations of peripheral neuropathy in pSS are diverse, and there is no universal consensus. It has been reported that peripheral neuropathy of pSS is mostly axonal neuropathy with predominantly distal lesions and rare demyelination (Rodier and Weber, 1996; Gorson and Ropper, 2003).

Features of this study

The electrophysiological characteristics of peripheral neuropathy associated with pSS differ from other types of peripheral neuropathy. Therefore, analyzing the electrophysiological characteristics of the peripheral neuropathy associated with pSS may help to improve clinical diagnoses and the differential diagnosis of the disease.

Main objective

A prospective case series will be performed to analyze the electrophysiological characteristics of peripheral neuropathy associated with pSS, providing clinical evidence for the diagnosis of peripheral neuropathy associated with pSS.


  Methods/Design Top


Study design

The prospective case series will be performed in the Department of Neurology, First Affiliated Hospital of Kunming Medical University of China. Fifty-two eligible pSS patients with peripheral neuropathy have been included in a preliminary study. Electrophysiological findings of the patients’ upper and lower extremities were compared. The primary outcome measure of this study is the incidence of abnormal motor nerve conduction velocity in these patients. The secondary outcome measures are the incidences of abnormalities in terminal motor latencies, compound muscle action potential amplitudes, sensory nerve conduction velocities, sensory nerve action potential amplitudes, F waves, and sympathetic skin responses.

Recruitment

Recruitment will be performed through posters with detailed clinical trial information on a bulletin board that is used to advertise for patient participants at the First Affiliated Hospital of Kunming Medical University, China. After being informed of the trial objective and procedure, patients interested in participation will be subjected to screening. Eligible patients, according to the following inclusion and exclusion criteria, will be included in this study.



Inclusion criteria

Patients meeting all of the following conditions will be considered for inclusion:

  • At least two of the following:
    1. Serum anti-Sjögren syndrome A (anti-SSA)- and/or anti-SSB-positive, or rheumatoid factor positive with serum antinuclear antibody ≥ 1:320
    2. Ocular staining score (OSS) ≥ 3
    3. Biopsy of the labial gland shows lymphocyte lesions ≥ 1/4 mm2 (at least 50 lymphocyte aggregates within 4 mm2 tissue) (Chen et al., 2013)
  • Presence of sensory, motor, autonomic dysfunction
  • Aged 30-70 years, of either sex
  • Provision of written informed consent.


Exclusion criteria

Patients with one or more of the following conditions will be excluded from this study:

  • A history of external neck, head or face radiation therapy
  • Sarcoidosis, amyloidosis, graft-versus-host disease, or IgG4-related diseases
  • Blood-borne diseases
  • Peripheral neuropathy caused by other diseases
  • Endocrine disease or other connective tissue diseases
  • Severe heart, liver, or kidney insufficiency
  • Alcoholism or mental illness
  • Receiving therapy for abnormal clotting factors and/ or anticoagulant therapy
  • Swelling at the end of the limb
  • Dermatitis
  • Poor compliance or refusal to collaborate
  • Recently suffering from myocardial infarction
  • Taking immunosuppressants
  • Wearing pacemakers or other implantable medical device
  • Highly allergic to electrical stimulation
  • Pregnant women


Withdrawal criteria

Patients presenting with one or more of the following criteria will be withdrawn from this study. The cause of patient withdrawal will be recorded in the Case Report Form. The patients withdrawn from this study will not be included in the final analysis.

  • Severe adverse event
  • No medical records


Outcome measures

Primary outcome measure

  • Incidence of abnormal motor nerve conduction velocities


Secondary outcome measures

  • Incidence of abnormal terminal motor latencies
  • Incidence of abnormal compound muscle action potential amplitudes
  • Incidence of abnormal sensory nerve conduction velocities
  • Incidence of abnormal sensory nerve action potential amplitudes
  • Incidence of abnormal F waves
  • Incidence of abnormal sympathetic skin responses


The above indices will be collected using a Keypoint electromyography machine (Dantec Dynamics Inc., Danmark) in a quiet, shielded environment at 24-26 °C. The extremity skin temperature will remain above 32°C. The criteria for abnormal outcomes will include prolonged terminal motor latency, a decrease in conduction velocity, a decrease in amplitude, no induced waveform, or an abnormality of more than 20% of the normal value. The normal values refer to the reference values of Peking Union Medical College Hospital (Cui, 2006) and a study by David and Preston (2013).

Trial procedure

Flow chart of the study protocol is shown in [Figure 1] and [Table 1].
Figure 1: Flow chart of the trial.

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Table 1: Screening and outcome measure assessment

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Sample size

In accordance with our previous experience (Li et al., 2001; Morgen et al., 2004; Qi and Dong, 2012), a total sample size of 108 patients will be included in this prospective case series.

Statistical analysis

Data analysis will be performed using SPSS 21.0 software (IBM, Armork, NY, USA). Categorical variables will be expressed as a percentage. Comparison between groups will be conducted using the chi-square test. As for continuous variables, one-sample Kolmogorov-Smirnov test will be used. Normally distributed data will be expressed as the mean ± SD. A level of P < 0.05 will be considered statistically significant.

Data collection and management

Case Report Forms will be filled by the investigators accurately, completely, and on time for each patient who provides written informed consent. Electronic case report form system will be reviewed by the investigators authorized by a research representative or a person designated by a research representative. All data will be anonymous. After accuracy recheck, the database will be password protected. Automatic real-time backups for database will be designated. The database will be monitored by a complete and accurate audit trail that provides documented history of information alteration.

Audits

During the course of clinical research, the research hospitals will be visited regularly by a project monitor appointed by the sponsor to ensure all case report forms are accurately filled. Laboratory tests will be performed in strict accordance with standard operating procedures. The clinical laboratory of the trial center will carry out indoor quality control according to regulations and a quality evaluation certificate from the Clinical Testing Center of Ministry of Health, China. All participating investigators should have relevant electrophysiological examination experience, and should have conducted at least 50 relevant electrophysiological examinations. The same electrophysiological testing criteria will be followed, that is to say, the same measurement site and measurement method. Electrophysiological tests will be free of charge for patients included in this study.

Ethics and dissemination

This study was approved by Medical Ethics Committee of Kunming Medical University of China on October 14th, 2005 (approval No. 20051014). During the clinical trial, any modification of the study protocol will be approved by the medical ethics committee. Severe adverse events will be reported to the medical ethics committee in time. Patients can withdraw at any time of their choosing.

The investigators or their designated representatives will fully explain the details of the study to the participants. Written informed consent (Additional file 1 [Additional file 1]) will be obtained. Information such as clinical trial observation forms and informed consent forms will be kept confidential. This will not be available or disclosed to unauthorized persons. This manuscript is prepared and modified according to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines (Additional file 2 [Additional file 2]). Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be published at www.figshare.com.


  Preliminary Results Top


Quantitative analysis of patients

A preliminary investigation was performed between January 2006 and January 2017. Fifty-two pSS patients with peripheral neuropathy were included. These patients consisted of four males and 48 females (male to female ratio of 12:1) and were aged 48.88 ± 8.85 (range, 30-70 years) years. The age of onset was 39.65 ± 10.09 (range 30-52 years) years. pSS was diagnosed in these patients after an average of 2.5 years. Of these patients, five presented with clinical manifestations of peripheral neuropathy and were diagnosed with pSS 3-8 months later. Four patients had no clinical manifestations, but their electrophysiological test results were abnormal, and clinical manifestations of peripheral neuropathy were present 3-6 months later.

Electrophysiological test results

In total, 832 motor nerves and sensory nerves were detected. The motor, sensory, and autonomic nerves of the upper and lower extremities were damaged to different degrees. The incidence of abnormal indices in the upper extremities was similar to that in the lower extremities (P > 0.05; [Table 2]). The median, ulnar, radial, and common peroneal/superficial nerves in the bilateral upper and lower extremities of 52 patients were measured. In total, 416 motor nerves and sensory nerves were included, with 208 motor nerves and sensory nerves for the upper or lower extremities. The abnormal F waves of the median nerve and tibial nerve of the bilateral upper and lower extremities in 52 patients (208 nerves) were measured. Two hundred and eight recordings of sympathetic skin responses in the bilateral upper and lower extremities from 52 patients were included.
Table 2: Abnormal neuroelectrophysiological test results in the upper and lower extremities in patients with primary Sjögren's syndrome

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Abnormal nerve conduction velocity and action potential amplitudes

The incidence of abnormal motor nerve conduction velocities of 416 motor nerves was significantly higher than that of compound muscle action potential amplitudes (χ2 =142.50, P = 0.00). The incidence of abnormal sensory nerve conduction velocities in 416 sensory nerves was significantly higher than that of sensory nerve action potential amplitudes (χ2 = 159.38, P = 0.00). The incidence of abnormal motor nerve conduction velocities was similar to that of abnormal sensory nerve conduction velocity (χ2 = 2.33, P = 0.15). The incidence of abnormal compound muscle action potential amplitudes was similar to that of abnormal sensory nerve action potential amplitudes (χ2 = 0.59, P = 0.49; [Table 2]).

Abnormal F waves, sympathetic skin responses, and nerve conduction

The incidence of abnormal F waves was significantly lower than that of abnormal nerve conduction study (χ2 = 264.72, P = 0.00). The incidence of abnormal sympathetic skin responses was similar to that of abnormal nerve conduction study (χ2 = 3.90, P = 0.05; [Table 2]).


  Discussion Top


Past contributions and existing problems of other scholars in this field of research

In recent years, studies have found a variety of neurological impairments in peripheral neuropathy associated with pSS, but there are no uniform standards based on the electrophysiological results from different types of patients.

Novelty of this study

Our preliminary results have shown that in pSS patients with peripheral neuropathy, the incidence of abnormal motor nerve conduction velocities was significantly greater than that of abnormal compound muscle action potential amplitudes, and the incidence of abnormal sensory nerve conduction velocities was significantly greater than that of abnormal sensory action potential amplitudes. These results suggest that both motor and sensory nerves are damaged, and that myelin loss is more severe than axonal injury. The incidence of abnormal motor nerve conduction velocities was similar to that of sensory nerve conduction velocities. This suggests that the degree of demyelination of motor and sensory nerves is similar in these patients. The incidence of abnormal compound muscle action potentials was similar to that of sensory nerve action potentials, suggesting a similar degree of damage to motor and sensory axons. The incidence of abnormal F waves was significantly lower than that of abnormal nerve conduction study. This suggests that peripheral nerve proximal fibers are lightly damaged and distal fibers are more severely damaged. The incidence of abnormal sympathetic skin responses was similar to that of abnormal nerve conduction study. This suggests that the degree of injury to large diameter myelinated Aα and Aβ fibers is similar to that of autonomic nerve fibers.

Previous studies have only reported different electrophysiological findings in pSS patients with peripheral neuropathy (Sandroni and Low, 2001; Goransson et al., 2006; Wakasugi et al., 2009; Cheng et al., 2013; Meng and He, 2014), but there is no consensus on the neurophysiological characteristics. This study found that pSS has its special neurophysiological manifestations, which can provide an objective basis for the clinical diagnosis and differential diagnosis of this disease. Our preliminary results reveal that the neuroelectrophysiological characteristics of the peripheral neuropathy associated with pSS include damage to the motor, sensory and autonomic nerves; injury mostly occurs in peripheral nerve distal fibers, myelin sheath loss is more severe than axonal injury; and there is no obvious difference in the degree of injury between motor, sensory, and autonomic nerves. It is presumed that the underlying pathological mechanism is likely to be an autoimmune-mediated inflammatory response that attacks the myelin sheath of nerve fibers and triggers extensive acquired demyelinating lesion of peripheral nerves. The neuroelectrophysiological characteristics of peripheral neuropathy associated with pSS are different from those of other types of peripheral neuropathy. Therefore, a better understanding of the neuroelectrophysiological characteristics of peripheral neuropathy associated with pSS are beneficial for clinical diagnosis and the differential diagnosis of this disease.

Limitations of this study

In the preliminary study, patients’ electrophysiological manifestations were investigated, but healthy controls were not involved. Additionally, randomization stratified by patients at different disease courses was not performed. These issues should be addressed in future studies.

Significance of this study

This study will reveal the neuroelectrophysiological manifestations of peripheral neuropathy associated with pSS, providing more objective clinical evidence for the diagnosis of this disease.

Additional files

Additional file 1: Informed Consent Form.

Additional file 2: SPIRIT checklist.

Author contributions

DW conceived and designed the study protocol, wrote and authorized the manuscript. ZML, MJZ, RHX and HX assisted in conduction of trial. All authors approved the final version of this manuscript.

Financial support

None.

Conflicts of interest

All authors state that no competing interests exist during study conduction and manuscript writing.

Institutional review board statement

The study protocol will be performed in strict accordance with the Declaration of Helsinki and relevant ethical requirements for human research. This study received ethical approval from Medical Ethics Committee of Kunming Medical University on October 14th, 2005 (approval number: 20051014).

Declaration of patient consent

The authors certify that they will obtain patient consent forms. In the form, patients will give their consent for their images and other clinical information to be reported in the journal. The patients will understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Reporting statement

This study follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician in the First Affiliated Hospital of Kunming Medical University, China.

Copyright transfer agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) will be available. Informed consent and clinical reports will be available in June 2020. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be published at www.figshare.com.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

 
  References Top

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21.
Figure 1: Flow chart of the trial.  Back to cited text no. 21
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]


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