Abstract
Objective: To explore the clinical efficacy of high-dose intravenous gammaglobulin (IVIG) in acute Guillain-Barre syndrome (GBS) and its effect on serum concentrations of inflammatory factors. Methods: A total of 111 patients with acute GBS were enrolled in this retrospective study. They were admitted to Ji’nan City People’s Hospital from January 2019 to December 2020. According to the treatment method, the patients were divided into a control group (n=53, received routine treatment) and an observation group (n=58, received high-dose IVIG in addition to routine treatment). The clinical efficacy, Barthel index for activities of daily living (ADL), serum concentrations of inflammatory factors (IL-6, TNF-α, NO) in peripheral blood, potential of electromyography signals, abnormal rates of motor and sensory conduction velocity, and F wave abnormality rate were compared. Also, the risk factors affecting IVIG treatment efficacy were analyzed. Results: The overall response rate, and Barthel index for ADL were higher, while serum concentrations of IL-6, TNF-α, and NO were lower in the observation group than the control group (all P<0.05). There were differences in spontaneous potential and motor potential before and after treatment in both groups (both P<0.05). The observation group showed lower abnormal rates of motor and sensory conduction velocity, F wave abnormality rate, and prolonged latency rate than the control group (all P<0.05). Concomitant lung infection, respiratory muscle involvement, and treatment with high-dose IVIG >2 weeks from onset were independent risk factors for treatment efficacy. Conclusion: High-dose IVIG has good clinical efficacy in treating acute GBS by reducing the serum concentrations of IL-6, TNF-α, and NO, improving patients’ abnormal muscle electrical condition, and promoting recovery. It is recommended for use clinically at an early stage. At the same time, lung infection must be prevented.
Keywords: Acute Guillain-Barre syndrome, intravenous gammaglobulin, clinical response, inflammatory factors, electromyography, risk factors
Introduction
Guillain-Barre syndrome (GBS), also known as acute inflammatory demyelinating polyneuropathy, is a common disease in neurology and a major cause of acute flaccid paralysis [1-3]. GBS is an autoimmune disease with rapid onset, characterized by demyelinating of nerve roots and peripheral nerves, and inflammatory damage to lymphocytes and macrophages around small vessels [4,5]. The clinical symptoms include limb paralysis, radicular pain, weakening or disappearance of tendon reflex, and respiratory dysfunction or even suffocation caused by respiratory muscular paralysis [6]. Thus, it is of great significance to treat GBS early. At present, the cause of GBS is not clear. Infection, hepatitis B surface antigen, vaccination, and organ transplantation can cause cellular and humoral immunity to trigger autoimmune response, leading to the occurrence of GBS [7]. Clinically, electrocardiogram monitoring and mechanical ventilation are used in symptomatic therapy. Due to the unknown cause of the disease, at present, there is no specific drug. A study has confirmed that immunoglobulin therapy is effective based on the changes in clinical muscle strength and electromyography, despite lack of serological indicators [8]. It has been reported that inflammatory factors such as IL-6, TNF-α, and NO are abnormally expressed in the cerebrospinal fluid of neurological diseases [9]. These factors have been less studied in evaluating treatments for GBS. Moreover, due to the high price of gamma globulin, it is particularly important to analyze the risk factors influencing treatment efficacy. Therefore, in this study, we explored the clinical efficacy of high-dose IVIG on treatment for GBS, its effects on serum concentrations of inflammatory factors and electromyography changes, and the risk factors for treatment efficacy, with the aim of providing possible evaluation targets for the therapy of GBS.
Materials and methods
General data
A total of 111 patients with acute GBS were enrolled in this retrospective study. They were admitted to Ji’nan City People’s Hospital from January 2019 to December 2020. According to treatment method, the patients were divided into a control group (n=53, received routine treatment) and an observation group (n=58, received high-dose IVIG in addition to the routine treatment). This study has been approved by the Ethics Committee of Ji’nan City People’s Hospital.
Inclusion criteria: (1) Patients’ clinical manifestations, electrophysiological measurement results and cerebrospinal fluid (CSF) examination results met the criteria for GBS [10]. (2) Patients had a history of the prodromal period of infection. (3) Patients’ condition worsened progressively and peaked within two weeks. (4) Patients had symmetrical muscle weakness with or without respiratory muscle weakness. (5) Patients had paresthesia or autonomic dysfunction. (6) CSF biochemical assays presented signs of protein-cell isolation.
Exclusion criteria: (1) Patients died during the treatment. (2) Patients had other autoimmune diseases. (3) Patients had hepatic and renal insufficiency. (4) Patients had IVIG allergy or contraindications. (5) Patients had malignant tumors or cachexia.
Methods
Treatments
After admission, patients in the control group received conventional nutritional neurotherapy (intramuscular injection of Methylcobalamin, 500 μg/time, 3 times/d; vitamins B1 and B6 oral, both 10 mg/time, 3 times/d). At the same time, assisted mechanical ventilation, and anti-infection treatment were implemented. Patients in the observation group were given IVIG based on conventional nutritional neurotherapy. IVIG was commonly used at a dose of 0.2 g/(kg.d), and the maximum dose was up to 0.4 g/(kg.d). In this study, IVIG at a dose of 0.4 g/(kg.d) was adopted with intravenous infusion, once a day, continuously for 5-7 days. After treatment, the clinical efficacy was recorded.
Determination of clinical efficacy
The clinical response rate was determined based on the patient’s muscle strength recovery. Muscle strength that returned to level IV with the disappearance of muscle paralysis was regarded as full recovery. Muscle strength returning to level IV with a significant improvement in muscle paralysis was considered very effective. Muscle strength returning to level 1 with an improvement in respiratory muscle paralysis was regarded as effective. No improvement, or even worsening in muscle and respiratory paralysis was called ineffective [11]. Overall response rate = (Case of full recovery + very effective + effective)/total number of cases *100%.
Electromyography detection
Electromyography/evoked potential instrument (KEYPOINT, Denmark) was adopted for measuring muscle potential before and after treatment. A surface electrode was used to measure motor and sensory conduction velocity, distal latency, and changes in F wave.
Detection of serum concentrations of IL-6, TNF-α, and NO
Before and after treatment, 3-5 mL of peripheral venous blood was collected from patients. The blood sample was centrifuged (Sigma 3-30K, Germany) and stored. ELISA was used to detect the serum concentrations of IL-6, TNF-α, and NO. The reagents were from Shanghai Ricky Biotechnology Co., Ltd., China.
Evaluation of activities of daily living (ADL) by Barthel index
The Barthel index (maximum score: 100 points) was adopted for ADL evaluation, such as turning over, standing and sitting, using the restroom, walking, and climbing the stairs. Between 26-100 points, higher scores indicate a better athletic ability. Less than 25 points was defined as complete incapacitation [12].
Statistical analysis
SPSS 23.0 software was adopted for statistical analysis. Measured data were expressed as mean ± standard deviation (x̅ ± sd). Independent t-test was carried out for comparison between groups. The counted data were tested by χ2. One-way logistic regression analysis was carried out on each risk factor respectively. Stepwise logistic regression was done for P value, OR value, and 95% CI. P<0.05 was considered a significant difference.
Results
Comparison of general data
No statistical significance in terms of age, sex, disease course, or site of infection were found in the two groups. The baseline data were comparable. See Table 1.
Table 1.
Comparison of general data
| Group | Observation group (n=58) | Control group (n=53) | t/χ2 | P |
|---|---|---|---|---|
| Sex (male/female) | 27/21 | 24/29 | 0.813 | 0.367 |
| Age (years) | 35.8±11.5 | 36.1±9.8 | 0.148 | 0.882 |
| Disease course (days) | 5.06±0.89 | 4.97±0.92 | 0.523 | 0.602 |
| Site of infection | ||||
| Gastrointestinal tract | 29 | 32 | 0.882 | 0.365 |
| Respiratory tract | 29 | 21 |
Comparison of clinical efficacy
The observation group revealed a higher overall response rate than the control group. See Table 2.
Table 2.
Comparison of clinical efficacy
| Group | Case (n) | Very effective (n) | Effective (n) | Ineffective (n) | Overall response rate (%) |
|---|---|---|---|---|---|
| Control group | 53 | 26 | 1 | 26 | 27/53 |
| Observation group | 58 | 35 | 6 | 17 | 41/58 |
| χ2 | 4.550 | ||||
| P | 0.033 | ||||
Comparison of potential of electromyography parameters before and after treatment
There were no differences in spontaneous and motor potentials between the two groups before treatment. After treatment, the score of motor potential in the observation group was higher than that in the control group (P<0.001). See Table 3.
Table 3.
Comparison of potential of electromyography parameters before and after treatment (n, %)
| Potential | Before treatment | After treatment | ||
|---|---|---|---|---|
|
|
|
|||
| Control group | Observation group | Control group | Observation group | |
| Spontaneous potential | 49 | 51 | 24 | 12 |
| Motor potential | 4 | 7 | 29 | 46 |
| χ2 | 0.665 | 0.010 | ||
| P | 0.415 | 6.563 | ||
Note: Comparison of the incidence between groups was detected by χ2 test.
Comparison of motor and sensory conduction velocity before and after treatment
Motor conduction velocity was measured for 111 patients, including a total of 256 nerves, such as median nerve, ulnar nerve, common peroneal nerve, and tibia nerve. Among them, 134 nerves were detected in the control group and 122 in the observation group. 96 sensory nerves were detected, 46 in the control group and 50 in the observation group. Before treatment, no differences in motor or sensory conduction velocity abnormality were found between the two groups. After treatment, the observation group revealed lower abnormality rates than the control group (both P<0.001). See Table 4.
Table 4.
Comparison of motor and sensory conduction velocity before and after treatment (n, %)
| Item | Slow motor conduction velocity | Lost motor conduction velocity | Slow sensory conduction velocity | Lost sensory conduction velocity |
|---|---|---|---|---|
| Before treatment | ||||
| Control group | 110 | 24 | 32 | 14 |
| Observation group | 109 | 13 | 35 | 15 |
| χ2 | 2.163 | 0.031 | ||
| P | 0.141 | 0.860 | ||
| After treatment | ||||
| Control group | 56 | 12 | 20 | 9 |
| Observation group | 39 | 6 | 9 | 4 |
| χ2 | 4.430 | 11.896 | ||
| P | 0.035 | 0.001 | ||
Note: Comparison of the incidence between groups was detected by χ2 test.
Comparison of F wave abnormality rate and prolonged latency rate before and after treatment
F wave were detected from 222 nerves in 111 cases. Among them, 106 nerves in the control group and 116 nerves in the observation group were detected. As a result, 24 were not ejected, 78 had prolonged latency, and 34 had a reduced incidence of F wave. Before treatment, the F wave abnormality and prolonged latency rates showed no significant differences between the two groups. After treatment, the F wave abnormality and prolonged latency rates in the observation group were lower than those of the control group (both P<0.001). See Table 5.
Table 5.
Comparison of the rates of abnormality in F wave and prolonged latency before and after treatment (n, %)
| Abnormal F wave | Before treatment | After treatment | ||
|---|---|---|---|---|
|
|
|
|||
| Control group | Observation group | Control group | Observation group | |
| Not ejected | 13 | 11 | 8 | 3 |
| A reduced incidence | 34 | 44 | 31 | 18 |
| Prolonged latency | 17 | 17 | 11 | 8 |
| In total | 64 | 72a | 50 | 29b |
Note: Compared to before treatment;
P>0.05.
Compared to control group;
P<0.05.
Comparison of serum concentrations of inflammatory factors before and after treatment
Compared to before treatment, serum concentrations of inflammatory factors (IL-6, TNF-α, and NO) were lower after treatment (all P<0.001). See Figures 1, 2 and 3.
Figure 1.
Comparison of serum concentrations of IL-6 before and after treatment. Compared to the observation group after treatment, ***P<0.001.
Figure 2.
Comparison of serum concentrations of NO before and after treatment. Compared to the observation group after treatment, ***P<0.001.
Figure 3.
Comparison of serum concentrations of TNF-a before and after treatment. Compared to the observation group after treatment, ***P<0.001.
Comparison of the Barthel index for ADL before and after treatment
After treatment, the observation group had better the Barthel index for ADL than the control group (P<0.001). See Figure 4.
Figure 4.
Comparison of the Barthel index for activities of daily living before and after treatment. Compared to the control group after treatment, ***P<0.001.
Univariate logistic regression analysis of risk factors for treatment efficacy
The results revealed that concomitant lung infection, respiratory muscle involvement, and IVIG treatment after two weeks from onset were all the risk factors influencing the effect of IVIG treatment. At the same time, the above factors were taken as the independent variable, and the IVIG treatment efficacy was taken as the dependent variable (1= poor treatment efficacy; 0= good treatment efficacy) in the logistic regression model for analysis. As a result, lung infection, respiratory muscle involvement, and IVIG treatment after two weeks from the onset were adverse factors. See Tables 6, 7 and 8.
Table 6.
Univariate logistic regression analysis of risk factors for treatment efficacy (n)
| Group | Case | Age of onset >40 years old | Respiratory muscle involvement | Cranial nerve involvement | Concomitant lung infection | IVIG treatment > two weeks from onset | Isolation pretreatment on cerebrospinal fluid protein |
|---|---|---|---|---|---|---|---|
| Valid | 41 | 23 | 3 | 25 | 4 | 8 | 27 |
| Invalid | 17 | 9 | 6 | 11 | 10 | 10 | 11 |
| χ2 | 0.001 | 5.200 | 0.010 | 12.34 | 10.074 | 0.002 | |
| P | 0.980 | 0.023 | 0.975 | 0.000 | 0.002 | 0.966 |
Note: IVIG, intravenous gammaglobulin.
Table 7.
Assignment for independent variable
| Independent variable | Assignment | |
|---|---|---|
|
| ||
| 1 | 0 | |
| Concomitant lung infection | Yes | No |
| Respiratory muscle involvement | Yes | No |
| IVIG treatment > two weeks from onset | Yes | No |
Note: IVIG, intravenous gammaglobulin.
Table 8.
Logistic regression analysis of IVIG treatment efficacy
| Indicator | Standardized β | SE | Wald χ2 | OR | 95% CI | P |
|---|---|---|---|---|---|---|
| Concomitant lung infection | 2.172 | 1.76 | 6.93 | 8.776 | 3.768-18.776 | 0.001 |
| IVIG treatment > two weeks from onset | 1.844 | 1.53 | 4.71 | 6.321 | 2.338-21.330 | 0.002 |
| Respiratory muscle involvement | 1.268 | 1.44 | 2.35 | 3.553 | 1.12-2.97 | 0.041 |
Note: IVIG, intravenous gammaglobulin.
Discussion
GBS is a peripheral neuropathy caused by autoimmune diseases with a high disability rate. It is mainly manifest as peripheral nerve monocyte and lymphocyte infiltration, phased demyelination and axial mutation pathologically. This may cause nervous system damage, especially for peripheral nerves and nerves connecting respiratory muscle [13]. Effective treatment is the main intervention to save the patient’s life and athletic ability. Based on the pathogenesis of GBS, the current guidelines recommend the use of immunotherapy, including plasma exchange, hormone therapy, and high-dose IVIG therapy [14,15]. IVIG has become a recognized treatment for GBS with good therapeutic effect, due to multiple complications and unsatisfactory clinical treatment outcomes of hormone therapy with a high cost and many contraindications of plasma exchange. Besides, guidelines for GBS treatment suggests that high-dose IVIG showed better clinical efficacy when compared to different doses of IVIG [16]. In this study, the observation group showed better clinical efficacy than the control group, which is similar to the data provided in the previous study [17]. This further consolidated the conclusion of the study on the efficacy of IVIG in the treatment of GBS.
Electrophysiological testing is the main non-invasive means for GBS and the main auxiliary method for assessing the patient’s condition. It has been confirmed that motor and sensory conduction velocity, and changes in electromyography and F waves were the main manifestations in electrophysiologic detection of GBS [18]. In this study, slow and lost motor and sensory conduction velocity, and F wave abnormality were observed in 111 cases. After treatment, the above-mentioned detected nerves were restored to varying degrees in the two groups, and the observation group showed better results than the control group. The possible mechanisms are as follows. IVIG activates complement and effectively removes immune complexes; a large amount of IVIG binds to macrophage-related receptors, blocking their antigen presentation function, thereby blocking the immune response. Besides, IVIG plays a competitive site-binding role to antagonize the binding of autoantibodies, usually inhibiting macrophage function to produce antibodies and directly repairing the myelin function of nerve cells, ultimately improving the clinical symptoms of patients. This is supported by the conclusions from previous research [19,20].
Inflammatory factors, such as IL-6 and TNF-α, have biologic effects in multiple systems of the body, and participate in immune regulation and mediate inflammatory response. IL-6 is a cytokine necessary for B cells to terminally differentiate and produce antibodies. It promotes myelin destruction and loss by boosting B cell differentiation and producing antibodies against peripheral nerve myelin sheaths. TNF-α can not only increase the permeability of the blood nerve barrier, and induce the expression of NO to cause damage to the myelin sheath and axon of the peripheral nerves, but also directly mediate the loss of the myelin sheath. NO, as a non-classical neurotransmitter, a regulator of cell function or a messenger, also participates in the biologic functions of many systems, and directly damage Schwann cells and myelin sheaths [21-23]. The overexpressions of IL-6, TNF-α and NO in patients with GBS have been confirmed in the latest study [24]. In this study, IL-6, TNF-α and NO were decreased to varying degrees after treatment in the two groups, and were lower in the observation group than those of the control group, confirming the anti-inflammatory and NO inhibitory function of IVIG, which is similar to previous reports [24,25].
This study explored whether IVIG improves patients’ athletic ability. Results revealed that the patients’ motor ability improved significantly after treatment in both groups, and the observation group had higher scores than the control group. This was associated with IVIG improving immune status and anti-IL-6/ TNF-α /NO. This suggests that the direct nerve injury effect of TNF-α, the effect of IL-6-related lymphocytes, and the demyelinating injury of NO were reduced, which supports the conclusion of a past study [26].
Finally, the risk factors influencing the IVIG treatment efficacy were further analyzed. This indicated that concomitant lung infection, respiratory muscle involvement, and IVIG treatment after two weeks from onset (P=0.002, OR=6.321, 95% CI: 2.338-21.330) were independent influencing factors. The underlying mechanism is related to the persistence of immune responses mediated by autoantibodies, complement activation, the participation of a variety of immune cells and inflammatory mediators, and heavy damage to the nerve myelin sheath and axon 2 weeks after onset. The poor efficacy of IVIG therapy may be related to its mechanism, which is mainly directed at the body’s immune response and has no effect on lung infections or respiratory muscle involvement [27,28].
However, some limitations still exist in this study. This single-center retrospective study only included a small sample size. A multicenter prospective large-sample study is necessary to further confirm the clinical efficacy of IVIG. The mechanism for anti-inflammatory action of IVIG and NO pathways should be added to the conclusions of this study. In addition, this study adopted dosages of IVIG suggested by guidelines, so as to avoid lungdamage to the patients, so no regular dose groups were established. This reduced the reliability of the results to some extent.
In conclusion, high-dose IVIG has good clinical efficacy in the treatment of acute GBS, improves patients’ abnormal muscle electrical condition, and promotes the life quality and athletic ability, which may be related to anti-autoimmunity and inflammation.
Disclosure of conflict of interest
None.
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